General and synthetic methods

General and Synthetic Methods Volume 8 A Specialist Periodical Report General and Synthetic Methods Volume 8 A Revi...

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General and Synthetic Methods Volume 8

A Specialist Periodical Report

General and Synthetic Methods Volume 8

A Review of the Literature Published during 1983

Senior Reporter

G. Pattenden, Deparfment of Chemistry, University of Nottingharn Reporters J. M. Clough, ICI Plant Protection Division, Jealott3 MIA Berkshire K. Cooper, Hizer Central Research, Sandwich, Kent S. G. Davies, University of Oxford S. C. Eyley, Fisons p.l.c., Loughborough, Leicestershire C. R. A. Godfrey, lCl Plant Protection, Jealott's Hi14 Berksbire P. F. Gordon, lCl Organics Division, Mancbester L. M. Harwood, University of Oxford D. W. Knight, University of Nottingham T. W. Lee, University of Bristol S. G. Lister, Wellcome Research Laboratories, Beckenham, Kent K. E. B. Parkes, University of Nottingham G. M. Robertson, University of Nottingham S. E. Thomas, University of Oxford P. Whittle, Pfizer Central Research, Sandwich, Kent

The Royal Society of Chemistry Burlington House, London WIV OBN

ISBN 0-85186-894-0 ISSN 0141-2140 Copyright 01986 The Royal Society of Chemistry 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 Royal Society of Chemistry

Printed in Great Britain by Adlard & Son Ltd, Dorking

Introduction

This report on General and Synthetic Methods covers the literature published between January and December 1983. The aim of the Reports has been to provide a summary and assessment of reactions and methods in organic chemistry which are new (or useful variants of existing ones) and appear sufficiently general to be useful in synthesis. Interconversions between all the major functional groups are covered in five chapters (Chapters 1-5), and the applications of organometallic compounds in synthesis are treated in Chapter 6, Two further chapters deal with developments in the synthesis of saturated carbocycles (Chapter 7) and saturated heterocycles (Chapter 8) and the final chapter provides a summary of ‘Highlights in Total Synthesis of Natural Products’. A list of reviews on General and Synthetic Methods is collected at the end of the Report. Future volumes in this series will be produced from camera-ready copy of manuscripts. July 1985

G. PATTENDEN

Contents Chapter 1 Saturated and Unsaturated Hydrocarbons By J. M. Clough and C. R. A. Godfrey 1 2 3 4 5 6 7 8

Saturated Hydrocarbons Olefinic Hydrocarbons Conjugated 1,3-Dienes Non-conjugated Dienes Allenic Hydrocarbons Acetylenic Hydrocarbons Enynes and Diynes Polyenes

Chapter 2 Aldehydes and Ketones By S. C. Eyley 1 Synthesis of Aldehydes and Ketones Oxidative Methods Reductive Methods Methods Involving Umpolung Other Methods Cyclic Ketones

1 1

6 57 65 69 72 75 79 84 84 84 87 89 93 98

2 Synthesis of Functionalized Aldehydes and Ketones Unsaturated Aldehydes and Ketones a-Substituted Aldehydes and Ketones Dicarbonyl Compounds

02 102 109 117

3 Protection and Deprotection of Aldehydes and Ketones

120

4 Reactions of Aldehydes and Ketones Reactions of Enolates Aldol Reactions Conjugate Addition Reactions

123 123 126 128

Chapter 3 Carboxylic Acids and Derivatives By D. W. Knight 1 Carboxylic Acids General Synthesis Acid Chlorides and Anhydrides

131 131 131 134

...

Contents

Vlll

Diacids Hy droxy-acids Keto-acids Unsaturated Acids Protection and Deprotection Decarboxylation

134 136 138 139 142 142

2 Esters Esterification General Synthesis Diesters Hydroxy-esters Keto-esters Unsaturated Esters Thioesters

144 144 145 148 151 155 160 167

3 Lactones P-Lactones Butyrolactones a-Methylenebutyrolactones Butenolides and Phthalides Tetronic acids Valerolactones Macrolides

168 168 168 175 177 181 181

4 Carboxylic Acid Amides Synthesis Reactions Thioamides Peptide Bond Formation

185 185 187 189 190

5 Amino-acids Synthesis Dehydroamino-acids AsymmetricHydrogenation Protection and Deprotection

192 192 194 196 196

Chapter 4 Alcohols, Halogeno-compounds, and Ethers By L. M. ffarwood 1 Alcohols Preparation by Addition to Alkenes Preparation by Reduction of Carbonyl Compounds ChemoselectiveCarbonyl Reductions Stereoselective Carbonyl Reductions Asymmetric Carbonyl Reductions Enzymic Asymmetric Carbonyl Reductions

183

200 200 200 204 204 206 207 210

Contents

ix Preparation by Nucleophilic Addition Allylic Alchols Homoallylic Alcohols Other Unsaturated Alcohols Diols General Methods of Preparation Allylic Alcohols Homoallylic and Other Unsaturated Alcohols Diols Protection and Deprotection Reactions of Alcohols Oxidation Hydrogenolysis and Deoxygenation Halogenation Chiral Auxilliaries Other Reactions

211 213 215 218 219 219 221 221 223 224 226 226 227 228 229 229

2 HalogenoCompounds Preparation Reactions

230 230 232

3 Ethers 4 Thiols and Thioethers 5 Macrocyclic Polyethers

234 237 239

Chapter 5 Amines, Nitriles, and Other Nitrogenconta ining FunctionaI G roups By S. G. Lister 1 Amines Primary Amines Secondary Amines Tertiary Amines

2 3 4 5 6 7 8 9 10 11 12 13 14 15

Enamines Allylamines, Homoallylamines, and Alkynylamines Amino-alcohols Amino-aldehydesand Amino-ketones Amides and Thioamides Nitriles and Isocyanides Nitro- and Nitroso-compounds Hydrazines Hydroxylaminesand Hydroxamic Acids Imines, Iminium Salts, and Related Compounds Oximes Carbodi-imides Azides and Diazo-compounds Azo- and Azoxy-compounds

245 245 245 254 262 264 268 270 279 280 283 294 300 300 301 304 305 306 308

Contents

X

16 Isocyanates, Thiocyanates, Isothiocyanates, and Selenocy anates 17 Nitrones 18 Nitrates and Nitrites

Chapter 6 Organometallics in Synthesis Part I The Transition Elements By S. G.Davies and S. E. Jhomas 1 2 3 4 5

Introduction Reduction Oxidation Isomerizations and Rearrangements Carbon-CarbonBond Formation via Organometallic Electrophiles via Organometallic Nucleophiles via Coupling Reactions via Carbonylation and Related Reactions 6 Synthesis of Heterocycles 7 Miscellaneous Reactions

Part II Main Group Elements By/? E Gordon 1 Group1

Selective Lithiation Synthetic Equivalents Sulphur-stabilized Anions and Dianions Miscellaneous Reactions

309 309 311 312 312 312 312 314 317 318 318 323 328 333 335 337 338 338

338 342 344 346

2 Group11 Magnesium Zinc and Mercury

348 348 351

3 Group111 Boron Aluminium

353 353 358

4 GroupIV Silicon Tin

360 360 367

5 GroupV Phosphorus

369 369

6 GroupVI Sulphur Selenium Tellurium

373 373 378 380

Contents

xi

Chapter 7 Saturated Carbocyclic Ring Synthesis By 7: V: Lee

381

1 Three-memberedRings 2 Four-membered Rings 3 Five-memberedRings Fused Five-membered Rings Naturally Occurring Fused Cyclopentanoids

381 382 384 387 390

4 Six-memberedRings Diels-Alder Reactions Intramolecular Diels-Alder Reactions Other Six-membered Ring Syntheses Steroids

391 391 394 395 399

5 Seven-membered,Medium, and Large Rings 6 Ring Expansion Methods 7 Spiro-ringCompounds

400 402 404

Chapter 8 Saturated Heterocyclic Ring Synthesis By K Cooper and P. J. Whiftle 1 Oxygen-containingHeterocycles

Oxiranes Four-membered Rings Five-membered Rings Tetrahydrofur ans Dihy drofurans Five-membered Rings with More than One Oxygen Atom Six-membered Rings Tetrahydropyrans Dihy dropyrans [5 .n]-Spiroacetals Six-membered Rings with More than One Oxygen Atom Seven- and Eight-membered Rings 2 Sulphur-containingHeterocycles 3 Heterocycles ContainingMore than One Heteroatom Nitrogen- and Oxygen-containing Rings Three-membered Rings Five-membered Rings Six- and Eight-membered Rings Oxygen and Sulphur-, and Nitrogen and Sulphur-containing Rings

407

407 407 410 412 412 418 424 425 425 426 434 439 441 443 448 448 448 448 450 453

xii

Contents 4 Nitrogen-containingHeterocycles Three-memberedRings Four-memberedRings Five-memberedRings Containing One Nitrogen Atom Five-membered Rings Containing More than One Nitrogen Atom Six-membered Rings Containing More than One Nitrogen Atom Medium Ring Nitrogen Heterocycles Rings Containing One Nitrogen Atom Rings Containing More than One Nitrogen Atom

454 454 456 457 472 480 483 483 487

5 19-Lactams,Penicillins, Cephalosporinsand Related Compounds 488

Chapter9 Highlights in Total Synthesis of Natural Products By K E 6.Parkes and G.Pattenden

497

Introduction Terpenes Steroids Anthracyclinones 5 Alkaloids 6 Prostaglandins and Leukotrienes 7 Spiroacetals 8 Pseudomonic Acids 9 Sugars 10 Macrolides and Ionophores 11 Other Natural Products

497 497 507 508

Reviews on General and Synthetic Methods By G. Pattenden and G.M. Robertson

541

1 2 3 4

1 2 3 4

Olefins Aldehydes and Ketones Carboxylic Acids Alcohols, Halogeno-compounds, and Ethers 5 Nitrogen-containingFunctional Groups 6 Organometallics General Transition Elements Boron and Thallium 7 Ring Synthesis 8 Heterocycles 9 Electrochemical Methods 10 Photochemical Methods

511

522 524 527 529 532 537

541 541 542 542 542 542 542 542 543 543 543 544 544

...

Contents

Xlll

11 12 13 14

Peptide Synthesis Asymmetric Synthesis General Miscellaneous

Author Index

545 545 546 547 548

1 Saturated and Unsaturated Hydrocarbons BY J. M. CLOUGH AND C. R. A. GODFREY

1 Saturated Hydrocarbons

Many new methods for the preparation of alkanes via reductive removal of functional groups have been reported during the year. A preparatively useful method for the conversion of carboxylic acids into alkanes has been developed by Barton and his co-workers. Primary, secondary, and tertiary carboxylic esters (1) RC02H

i .ii

R

Ao,Q S

iii or

IV

RH

(1) Reagents: i, (COCI),; ii,

@ ; iii, Bun,SnH; iv, Bu'SH HO

S

derived from thiohydroxamic acids such as N-hydroxypyridine-2-thione undergo efficient radical chain decarboxylation to the corresponding nor-alkanes on treatment with either tri-n-butyltin hydride or t-butylmercaptan. Under these mild reaction conditions, ketones, olefins, and normal carboxylic esters remain unchanged. Decarboxylation of carboxylic acids can also be effected using sodium persulphate and a catalytic amount of silver nitrate. Unstabilized alkyl radicals from aliphatic acids afford alkanes or, in the presence of copper(I1) salts, alkenes.2 By contrast, arylacetic acids give benzylic radicals, and these dimerize to give 1,2-diarylethanes in moderate yield^.^ Williams and Moore have reported that the reduction of a variety of heterocyclic thiones to the corresponding methylene compounds occurs readily on heating with an excess of tri-n-butyltin hydride and a radical initiator (e.g. Scheme l).4Conversion of the cyclic thiocarbonate (2) into the 1,3-dioxolane ( 3 ) is noteworthy in that the Corey-Winter reaction does not take place under the reaction conditions. The desulphurization of thiols and thioketones to alkanes D. H. R. Barton, D. Crich, and W. B. Motherwell, J . Chem. Soc., Chem. Commun., 1983,939;D. H. R. Barton and G . Kretzschmar, Terruhedron Lett., 1983, 24, 5889. W. E. Fristad, M. A. Fry, and J. A. Klang, J . Org. Chem., 1983,48, 3575. W. E. Fristad and J. A. Klang, Tetrahedron Lett., 1983, 24,2219. D. K.Williams and J. L. Moore, Tetrahedron Lett., 1983, 24, 339.

1

General and Synthetic Methods

2

0 6un3Sn H , A 1 BN

0-

Bun3SnH, A1 BN

*

do (3)

Scheme 1

and alkenes using sodium triethylborohydride and iron(I1) chloride is improved by adsorption of the borohydride onto a l ~ r n i n aMoreover, .~ this heterogeneous reaction occurs at room temperature and products are easily isolated by simple filtration. A variety of benzylic di- and tri-arylmethyl mercaptans react with stoicheiometric amounts of [Fe3(C0)12]or [co2(CO),] under phase-transfer conditions to give the corresponding hydrocarbons in good yields.6 Monosubstituted thiiranes are reduced to alkanes on treatment with Raney nickel in ethanol at -4O"C, conditions under which olefinic bonds are ~naffected.~ On irradiation, solutions of diselena[3.3]cyclophanes in HMPA are transformed cleanly into the corresponding cyclophanes (e.g. Scheme 2) .,

h v , HMPA

Scheme 2

Treatment of (hydroxymethy1)diphenylphosphine oxides (4) with P214in carbon disulphide at room temperature affords excellent yields of the alkyldiphenylphosphineoxides (5) with no trace of the corresponding iodide^.^

it* ( 4 )R', R2 = a l k y l

'

(5)

H. Alper, S. Ripley, and T. L. Prince, J. Org. Chem., 1983,48,250. H. Alper, F. Sibtain, and J. Heveling, Tetrahedron Lett., 1983, 24,5329. J. R. Schauder, J. N. Denis, and A. Krief, Tetrahedron Lett., 1983,24,1657. H. Higuchi, M. Kugimiya, T. Otsubo, Y. Sakata, and S. Misumi, Tetrahedron Lett., 1983,24, 2593. M. Yamashita, K. Tsunekawa, M. Sugiura, T. Oshikawa, and S. Inokawa, Chem. Lett., 1983, 1673.

Saturated and Unsaturated Hydrocarbons

3

Suzuki and his co-workers have shown that benzyl alcohols are smoothly deoxygenated on treatment with P214in boiling benzene. The reaction works well even with sterically hindered secondary benzyl alcohols, as illustrated in

Scheme 3

Scheme 3.1° Extending this work, the same group has reported that a mixture of LiA1H4 and P214offers a mild alternative to conventional methods for the deoxygenation of aromatic ketones (e.g. Scheme 4). l1 Halogens , esters, and olefinic bonds are not affected by these reaction conditions.

Q

Q Scheme 4

Ueno and his co-workers have described conditions under which tosylates, including those derived from primary alcohols, undergo efficient radical deoxygenation to give hydrocarbons.12 A noteworthy example is the selective removal of the tosyl group from the diol derivative (6) which takes place without the need to protect the free hydroxy-group. OH Bun3SnH, N a I

OTs

+ HO@ 56 "lo

20 ' l o

Several reports describing the use of lithium triethylborohydride for the reduction of alkyl halides, especially alkyl fluorides, have been published during the year. l 3 Catalytic amounts of silver perchlorate markedly accelerate the reduction H. Suzuki, H. Tani, H. Kubota, N. Sato, J. Tsuji, and A. Osuka, Chem. Lett., 1983,247. H. Suzuki, R. Masuda, H. Kubota, and A. Osuka, Chem. Lett., 1983, 909. l2 Y. Ueno, C . Tanaka, and M. Okawara, Chem. Lett., 1983, 795. l3 S. Krishnamurthy and H. C. Brown,J. Org. Chem., 1983,48,3085;S. Brandange, 0.Dahlman, and J. Olund, Acta Chem. Scand., Ser. B, 1983,37, 141. lo

l1

4

General and Synthetic Methods

of 1,l-dibromocyclopropanes to the corresponding monobromides by LiAlH4.l4 This catalyst also facilitates the reduction of tertiary or sterically hindered alkyl bromides which are normally resistant to LiA1H4. gem-Bromochlorocyclopropanes react with a mixture of diethyl phosphonate and triethylamine to give the corresponding chlorocyclopropanes exclusively, and (trichloromethy1)benzene is reduced to (dichloromethy1)benzene in a yield of 86% under the same ~0nditions.l~ Photostimulated reduction of either cyclohexyl chloride or bromide with LiA1H4 in the presence of di-t-butyl peroxide gives cyclohexane in good yield. Vinyl bromides are converted into olefins under these conditions, but yields are only moderate.16 a-Halogenocarbonyl compounds are smoothly dehalogenated on treatment with sodium hydrogen telluride, generated in situ from tellurium and NaBH4 in ethan01.l~ a-Nitrohydrazones (7),readily prepared from the corresponding nitroalcohois (8), are cleanly reduced to the hydrazones (9) on treatment with LiAlH4. However, the reaction fails for nitrohydrazones (7) in which R2 and R3 are both hydrogen atoms.18

. . R2 R3

(8)

(7)

(9)

Reagents: i, Na,Cr,O,; ii, NH,NHTs; iii: LiA1H4

Dimeric products often encountered during the reduction of nitroalkenes to the corresponding nitroalkanes with NaBH4 can be avoided by carrying out the reaction at 25°C in the presence of silica gel, in a mixture of chloroform and propan-2-01.l~ Reasonable yields of alkanes can be obtained by electrohydrogenation of both alkenes and alkynes using a nickel-plated cathode coated with Raney nickel powder.20However, many other functional groups are also reduced under these conditions. Alper and Heveling have reported the first examples of organometallic phasetransfer catalysis under acidic conditions.*l For example, hydrogenation of 9,9'bifluorenylidene (10) or diarylethylenes occurs on treatment with [Co,(CO),] or [CO~(CO)~(PBU and ~ ) ~tetrafluoroboric ] acid under phase-transfer conditions. Anthracene, however, is not reduced. The solvated ion pair [(CSH17)3NMe][RhCI4]- catalyses the hydrogenation of a variety of unsaturated compour,ds under phase-transfer conditions.22Even aromatic substrates may be +

N. Shimizu, K. Watanabe, and Y . Tsuno, Chem. Lett., 1983, 1877. T. Hirao, S. Kohno. Y. Ohshiro, and T. Agawa, Bull. Chem. Soc. Jpn., 1983, 56, 1881. l6 A. L. J. Beckwith and Swee Hock Goh, J . Chern. SOC.,Chem. Cornmun., 1983, 907. A. Osuka and H. Suzuki, Chem. Lett., 1983, 119. l8 G. Rosini, R. Ballini, and V. Zanotti, Synthesis, 1983, 137. l5 A . K. Sinhababu and R. T. Borchardt, Tetruhedron Lett., 1983,24,227. 20T.Chiba, M. Okimoto, H . Nagai, andY. Takata, Bull. Chem. SOC.Jpn., 1983, 56, 719. H . Alper and J. Heveling, J. Chem. SOC., Chem. Commun., 1983, 365. 22 J. Hum, I. Amer, A. Zoran, and Y. Sasson, Tetrahedron Lett., 1983, 24,4139. l4 l5

Saturated and Unsaturated Hydrocarbons

5

(10) Reagents: i , C12H25C6H4S03Na+, C,H6, 50% HBF,, [Co2(CO),]

reduced to the corresponding alkanes at room temperature and under a pressure of 2 atm of hydrogen, but reaction rates are sensitive to steric effects. Reactive halides such as benzyl bromide undergo homo-coupling on treatment with titanocene methylene-zinc halide complexes of the type [Cp,TiCH,.ZnX,] (X=Cl or I).23 Reetz and Westermann have reported that treatment of lithium alkoxides of the type (11) with a 1:l mixture of MeTiC1, and Me,TiCl, at -40°C affords the methylated products (12), which are potentially useful as synthetic tetra-

/

OMe

OMe (11)

Me

OMe (12) R’, R 2 = alkyl Reagents: i, R2Li; ii, MeTiC1, : Me2TiC1, (1: 1)

hydrocannabinoid interrnediate~.~~ Undesirable Wagner-Meerwein rearrangements or retro-Friedel-Crafts reactions are not observed under these reaction conditions. By contrast, gem-dimethylation of the optically active disubstituted cyclopentanone (13) using Me2TiC12affords a mixture of racemic cuparene (14) n

23 24

J. J. Eisch and A. Piotrowski, Tetrahedron Lett., 1983,24,2043. M. T. Reetz and J. Westermann, J . Org. Chem., 1983, 48, 254.

6

General and Synthetic Methods

and the olefin (15), products which can be accounted for in terms of intermediate carbonium ions.25 2 Olefinic Hydrocarbons

Although the extremely hindered olefin tetra-t-butylethylene has still not been synthesized, the closely related compounds ( 16),26(17), (18), and (19)27have been prepared and characterized, and some of these are potential precursors of tetrat-butylethylene itself.

House and his co-workers have synthesized further examples of strained enones, either by elimination or by intramolecular Wadsworth-Emmons reactions. 2-Phenylbicyclo[3.3.l]non-l-en-3-one (20) is stable when protected from oxygen, or nucleophiles such as water.28By contrast, the bicyclo[3.2.l]octane species (21) and (22) could only be generated as transient intermediates which

l>o

( Me0I2P

T NaOHor

ob cEt3N --

NaOMe I

0

(22)

I

OS02Me

were trapped with nucleophiles or, in the case of (22), as a cycloadduct with f~ranA . ~ simple ~ two-step preparation of bicyclo[3.3.0]oct-l-en-3-onealso makes use of an intramolecular Wadsworth-Emmons reaction (potassium carbonate and 18-crown-6 in benzene at 60°C) to close the second ring.30 G. H. Posner and T. P. Kogan, J . Chem. SOC., Chem. Commun., 1983, 1481. T. Loerzer, R. Gerke, and W . Luttke, Tetrahedron Lett., 1983,24, 5861. 27 A. Krebs, W. Born, B. Kaletta, W.-U. Nickel, and W. Riiger, Tetrahedron Lett., 1983,24,4821. 28 H. 0. House, R. J . Outcalt. J. L. Haack. and D. VanDerveer, 1. Org. Chem., 1983,48,1654. 29 M.0. House, J. L. Haack, W. C . McDaniel, and D. VanDerveer, J . Org. Chem., 1983, 48, 1643. 30 P. A. Aristoff, Synth. Commun., 1983,13,145. 25

26

Saturated and Unsaturated Hydrocarbons

7

Bicyclo[5.1.l]non-l(8)-ene (23) has been synthesized by Ramberg-Backlund reactions using each of the stereoisomericbromosulphones (24) and (25) (Scheme 5 ) . No competing 1,2-dehydrobromination is observed.31Although isolable, the

(24)

(23) Scheme 5

olefin (23) shows the usual high reactivity towards oxygen, acids, and dienes. Another way of constructing bridgehead olefinsis via intramolecular Diels-Alder reactions, but high temperatures are usually required. Shea and Gilman have now shown that, in the presence of stoicheiometric amounts of diethylaluminium chloride, these reactions take place smoothly at room temperature. A particularly impressive example is the reaction shown in Scheme 6 which gives a 70% yield of the bridgehead olefin within 5 minutes.32

0 Scheme 6

Marshall and Flynn have reported that trans-hydroxymethylcycloalkenes [e.g. (26)] of known absolute configuration and high optical purity can be prepared by the Sharpless kinetic resolution procedure. The (+)-(R)-trans-cycloalkene (26) was converted in six steps into (+)-(R)-[lo. 101-betweenanene (27) with better than 90% optical purity (Scheme 7).33 f+

steps

(27) Reagents: i, TiCl,, Li; ii, H2,Pt-C

Scheme 7 K. B. Becker and M. P. Labhart, Hefv.Chim. Acta, 1983,66, 1090. K. J. Shea and J. W. Gilman, Tetrahedron Lett., 1983,24,657. 33 J. A. Marshall and K. E. Flynn, J . Am. Chem. SOC., 1983, 105,3360. 32

General and Synthetic Methods

8

The low-valent titanocene species generated by reducing [Cp,TiCl2] with sodium naphthalenide is a highly efficient and almost stereospecific catalyst for the isomerization of simple non-functionalized terminal alkenes to (15)2 - a l k e n e ~The . ~ ~transformation is complete within minutes at room temperature and internal olefinic bonds of either configuration are inert under the reaction conditions. Hex-1-ene is rapidly converted into a stereoisomeric mixture of hex2-enes on treatment with a catalytic amount of the stable and commercially available complex [OsHBr(CO)(PPh,),] in toluene at 150°C.35 Partial hydrogenation of acetylenes to olefins is often accomplished using the Lindlar catalyst. A systematic study with nine metal ions has now shown that the chemoselectivity for semihydrogenation, especially for monosubstituted acetylenes, is significantly and reproducibly improved when the catalyst is modified with manganese(I1) Suzuki and his co-workers have described two new systems for the partial reduction of acetylenes to (2)-olefins at room temperature. The first, a catalytic amount of palladium chloride in polyethylene glycol and dichloromethane, allows diphenylacetylene to be hydrogenated to (2)-stilbene at atmospheric pressure , but over-reduction appears to be a problem.37Much better selectivity is achieved with the second system in which NaBH, replaces hydrogen.3sSimple 1,3-dienes can be hydrogenated specifically to olefins at -78 "C using allyl(hydrido)platinum(II) complexes as catalysts.39 Oxiranes are conveniently deoxygenated to give olefins using hydrogen iodide generated in situ from toluene-4-sulphonic acid and sodium iodide in acetonitrile. The transformation is complete within minutes at room t e m p e r a t ~ r e . ~ ~ Vinyl sulphones are reduced to the corresponding olefins in high yield and with retention of configuration on treatment with alkyl Grignard reagents and nickel or palladium catalysts in THF at room temperature (e.g. Scheme 8).41Coupling

99.5'10 (21-isomer Reagents: i, Bu"MgC1, [Pd(acac),], DABCO

Scheme 8

products between the sulphone and Grignard reagent are only formed to a small extent (generally <6%) under these conditions. Another new method for the M. Akita, H. Yasuda, K. Nagasuna, and A. Nakamura, Bull. Chem. SOC. Jpn., 1983, 56, 554. R. A. Sanchez-Delgado, A. Andriollo, and N. Valencia, J . Chem. SOC.,Chem. Commun., 1983,444. 36 J. Rajaram, A. P. S. Narula, H. P. S. Chawla, and S. Dev, Tetrahedron, 1983,39, 2315. 37 N. Suzuki, Y . Ayaguchi, and Y. Izawa, Chem. Ind. (London), 1983,166; N. Suzuki, Y. Ayaguchi, T. Tsukanaka, and Y . Izawa, Bull. Chem. SOC. Jpn., 1983, 56, 353. 38 N. Suzuki, T. Tsukanaka, T. Nomoto, Y. Ayaguchi, andY. Izawa, J . Chem. SOC., Chem. Commun., 1983, 515. 39 R. Bertani, G. Carturan, and A . Scrivanti, Angew. Chem., Int. Ed. Engl., 1983, 22,246. 4o R. N. Baruah, R. P. Sharma, and J. N. Baruah, Chem. Ind. (London), 1983,524. 41 J.-L. Fabre and M. Julia, Tetrahedron Lett., 1983, 24, 4311. 34

35

9

Saturated and Unsaturated Hydrocarbons

reduction of vinyl sulphones to olefins is illustrated by the examples shown in Scheme 9.42Its success stems from the regiospecific 1,4-addition of tributylstan-

'

Ph

Ph

Ph

"'

Ph/\\l

Ph

(€I:(

(

f I : ( Z 1 = 1.6: 1

z 1 = 1 : 2.2

( € ) : ( I =1:1.1 )

Reagents: i, Bun,SnLi; ii, MeI; iii, silica gel

Scheme 9

nyl-lithium to vinyl sulphones in THF at -78"C, and the instability of the resulting P-tributylstannylsulphones,which collapse to form olefins on treatment with silica gel. A drawback of the method is its lack of stereochemical control, but it does provide a chance to modify the product by treating the intermediate sulphonyl-stabilized anion with electrophiles such as methyl iodide (Scheme 9) or aldehydes (which give allylic alcohols). Vinylsilanes with a hydroxy-group in the @-positionare rapidly desilylated via a homo-Brook rearrangement on treatment with potassium hydride (e.g. Scheme 10).43 Si Me3 KH

+

0 - SiMe3

\Y+

-

Scheme 10

-aOSiMe3

A sequence for the reduction of a cyclopentenone to the corresponding cyclopentene without scrambling of the position of the olefinic bond has been devised as part of a synthesis of a prostaglandin analogue (Scheme 11).44

-

i , ii

iii, i v

R = (CH~),I+CO~E~ Reagents: i , (Me,Si),, Bu,N+ F-; ii, L-Selectride; iii, (CF,SO,),O, py, DMAP; iv, HI

Scheme 11 42 43

M. Ochiai, T. Ukita, and E. Fujita, J. Chem. SOC., Chem. Commun., 1983, 619. S. R. Wilson and G. M. Georgiadis, J. Org. Chem., 1983,48, 4143. M. Shibasaki, H. Fukasawa, and S. Ikegami, Tetrahedron Lett., 1983, 24,3497.

10

General and Synthetic Methods

Tritylpotassium rapidly dehydrohalogenates secondary alkyl bromides and iodides at 0°C to give high yields of 01efins.~~ The reagent is less satisfactory with secondary alkyl chlorides and it fails altogether with primary alkyl halides. When solutions of phenethyl or secondary alkyl bromides are treated with 2.5 equivalents of alumina-supported potassium fluoride, smooth dehydrobromination takes place, but without regio- or stereo-~ontrol.~~ Under the same conditions, 1,2-dibromides and vinyl bromides are converted into acetylenes, and 2-phenoxyethyl bromide gives phenyl vinyl ether. In contrast to the well-known selenoxide elimination, little has been reported concerning olefin formation by elimination of telluroxides. Uemura and Fukuzawa have now shown that although primary alkyl phenyl telluroxides undergo elimination only at high temperatures, secondary alkyl phenyl telluroxides readily decompose at room temperature to give isomeric mixtures of olefins (e.g. Scheme The use of appropriate precursors allows the reaction to be

Br

PhTeBr2

-

1

iii

+

5:2

L

PhTe= 0.H20

J

( € ) : ( I )=19:4

Reagents: i, (PhTe),, NaBH,; ii, Br,; iii, aq. NaOH

Scheme 12

applied to syntheses of allylic alcohols and allylic and vinyl ethers, and this is of more preparative value since elimination is both regio- and stereo-specific in these cases (e.g. Scheme 13). On heating in DMSO, 2-cycloalkoxytropones7 prepared from cycloalkanols, tropolone , and DCC, undergo stereospecific trans-elimination to give high yields of cycloalkenes. Experiments with deuterium-labelled precursors support the concerted intramolecular mechanism shown in Scheme 14.48The analogous tropone derivatives of acyclic alcohols give acyclic olefins under the same conditions, but these are contaminated with ketones derived from the original alcohols. Reductive debromination of vic-dibromides to give olefins is conveniently conducted using sodium sulphide or sodium hydrogen sulphide under aqueous D. R. Anton and R. H. Crabtree, Tetrahedron Lett., 1983,24,2449. J. Yamawaki, T. Kawate, T. Ando, and T. Hanafusa, Bull. Chem. SOC. Jpn., 1983,56,1885. 47 S , Uemiira and S. Fukuzawa, J . Am. Chem. SOC., 1983,105,2748. 48 H. Takeshita and H. Mametsuka, J . Chem. SOC., Chem. Commun., 1983,483.

45

Saturated and Unsaturated Hydrocarbons A,-

0

11

HO

i.ii

.

iii

HO /

#

-

P hTeBr2

iv. iii

Rv, R = Me(CH2I7

R y y 4 0 . H 2 0 Me0

Ph

v_ OMe

v PhTeBr2 Reagents: i, (PhTe),, NaBH,; ii, Br,; iii, aq. NaOH; iv, (PhTe),, Br,, MeOH; v, 2OCk-24OoC

Scheme 13

n =1--4, or 0

Scheme 14

phase-transfer condition^.^^ Elimination takes place with at least 85% antistereoselectivity. A variety of functional groups (hydroxyl, ketone, lactone) tolerate the reaction conditions, but olefinic bonds can migrate into conjugation with carbonyl groups. The same transformation takes place when benzene solutions of vic-dibromides are irradiated with U.V.light in the presence of three equivalents of triethylamine, but generally without s t e r e o c ~ n t r o l .a#~~ Dihalogeno-ketones and -esters are converted into a,P-unsaturated ketones or esters under the same conditions. Sodium hydrogen telluride reduces l-nitro1-(l-nitrocyclohexyl)cyclohexane, a vic-dinitro-compound, to cyclohexylidenecyclohexane in a yield of 86%.51 Hindered methyl esters which possess a suitably placed benzylic or allylic bromine atom undergo fragmentation on heating in HMP-A to give high yields of olefins (e.g. Scheme 15).52 New experimental conditions for the Wittig reaction involve passing an aldehyde in a gaseous state through a heated bed of a phosphonium salt and potassium ~ a r b o n a t eThe . ~ ~olefinic product, also a gas under the reaction conditions, is collected, leaving the triphenylphosphine oxide adsorbed on the solid bed. A wide range of aldehydes are suitable, provided they have sufficient J. Nakayama, H. Machida, and M. Hoshino, Tetrahedron Lett., 1983,24, 3001. Y. Izawa, M. Takeuchi, and H. Tomioka, Chem. Lett., 1983,1297. 51 A. Osuka. H. Shimizu, and H. Suzuki, Chem. Lett., 1983, 1373. 52 J. L. Belletire and D. R . Walley, Tetrahedron Lett., 1983, 24, 1475. 53 E. Angeletti, P. Tundo, and P. Venturello, J . Chem. SOC., Chem. Commun., 1983, 269. 49

5u

General and Synthetic Methods

12

MeO2C Br

140-145'C

Scheme 15

volatility, but ketones do not react. Wittig reactions performed with reactive ylides under solid-liquid phase-transfer conditions (potassium carbonate in wet 1,6dioxane or methanol) allow selective mono-olefination of terephthalic aldehyde54or olefination of phenolic benzaldehydes without protection of the phenolic group.55Furthermore, Wittig reactions between aldehydes and resonance-stabilized phosphoranes are strongly accelerated if performed under high pressure (10 kbar) and there is also an improvement in the (E)-stereo~electivity.~~ Warren and his co-workers have described optimum conditions for the stereoselective synthesis of e r ~ t h r o -or~ ~t h r e ~ /3-hydroxyphosphine -~~ oxides which, on purification and treatment with sodium hydride, collapse to form disubstituted (2)-or (E)-olefins specifically. Stereochemicallypure trisubstituted olefins can also be prepared using the same adaptation of the Horner-Wittig reaction.59Belletire and Namie have described related work with phosphonium salts,60and a variation on this theme gives trisubstituted olefins with complete deuteriation at the vinyl position (e.g. Scheme 16).61

3

Fh 'g

/

Scheme 16

Almost 20 years ago it was observed that exchange takes place between DMSO and the a-hydrogen atom of phosphorus ylides. Use of an excess of deuteriated DMSO for this exchange, followed by a Wittig reaction, enables regiospecifically Y. Le Bigot, M. Delmas, and A. Gaset, Synth. Commun., 1983, 13, 177. Y. Le Bigot, M. Delmas, and A. Gaset, Tetrahedron Lett., 1983, 24, 193. 56 A. Nonnenmacher, R. Mayer, and H. Plieninger, Liebigs Ann. Chem., 1983,2135. 57 A . D. Buss and S. Warren, Tetrahedron Lett., 1983,24,3931. 58 A . D. Buss, R. Mason, and S. Warren, Tetrahedron Lett., 1983, 24, 5293. 59 A. D. Buss and S. Warren, Tetrahedron Lett., 1983,24,111. J. L. Belletire and M. W. Namie, Synth. Commun., 1983, 13, 87. J. L. Belletire, Synth. Commun., 1983,13, 589. 54

55

Saturated and Unsaturated Hydrocarbons

13

deuteriated olefins with better than 95% deuterium incorporation to be prepared directly from non-deuteriated fragments (e.g. Scheme 17).62 Under suitable con-

-

D

i or ii

BrPh36-

-

\

\

( Z ) : ( E ) = 7:3 Reagents: i, MeLi, then [D,]DMSO; ii, NaCD,SOCD3 in [D,]DMSO; iii, PhCHO

Scheme 17

ditions, enolizable carbonyl compounds undergo olefination without scrambling of the deuterium atom. Another method for preparing deuteriated olefins, also via Wittig reactions between non-deuteriated precursors, uses labelled water or alcohols as the source of deuterium (e.g. Scheme 18).63Deuteriation is again highly regioselective (at least 95%) but reaction yields are not high.

m.

,O

( Z ) : ( f ) =3:1 Scheme 18

Simple alkylphosphonates without additional anion-stabilizing a-substituents have found little use in Wadsworth-Emmons olefinations: although their lithioderivatives add smoothly to aldehydes and ketones, the resulting intermediates are reluctant to undergo cyclo-elimination to give olefins. As a solution to this problem it has now been shown that simple p-hydroxyphosphonates such as (28) are transformed cleanly into olefins when heated with an excess of caesium fluoride in DMF (e.g. Scheme 19).@The same research group has reported that a

(28) Reagents: i, (MeO),POCH,Li; ii, CsF

Scheme 19 A. B. Reitz and B. E. Maryanoff, Synth. Commun ., 1983,13, 845. D. Beeman, C . Wenger, and H. D. Perlmutter, Synth. Commun., 1983, 13. 853. 64 T. Kawashima, T. Ishii, and N. Inamoto, Chem. Lett., 1983,1375. 6,

63

14

General and Synthetic Methods

silicon-carbon bond of the a-silylated phosphonate (29) is cleaved by fluoride ion in refluxing THF to generate a carbanion which reacts with aldehydes and ketones in Wadsworth-Emmons fashion.65Certain olefinations, like the one shown in Scheme 20, give much higher yields under these conditions than with the conventional a-lithiophosphonate.

( I ) : ( € )= 3 : l Scheme 20

Zwanenburg and his co-workers have shown that certain a-silylcarbanions react with sulphines to give olefins.@It is suggested that the reaction occurs via a modified Peterson olefination followed by extrusion of sulphur, as shown by the example in Scheme21. Unfortunately, this new olefin synthesis is of limited scope since most types of a-silylcarbanions give only traces of olefinic products.

->S

-??

Scheme 21

When alkyldimesitylboranes [e.g. (30)] are treated with sterically hindered bases, boron-stabilized a-carbanions are formed instead of the usual ‘ate’ complexes encountered with less hindered substrates. These anions react smoothly with aldehydes and ketones in a boron analogue of the Wittig reaction to give 65

T. Kawashima, T. Ishii, and N. Inamoto, Tetrahedron Lett., 1983,24,739. P. A. T. W. Porskamp, M. van der Leij, B. H. M. Lammerink, and B. Zwanenburg, Reel.:J . R. Neth. Chem. SOC., 1983, 102,400.

Saturated and Unsaturated Hydrocarbons

15

olefins (e.g. Scheme 22).67In the single example reported where (E/Z)-isomeric olefins could result , the product had 299.9% (E)-geometry.

(30)

Reagents: i,

Bi

; ii, PhzCO

/

Scheme 22

Eisch and Piotrowski have reported that the titanocene methylene-zinc halide complex (31) methylenates ketones in essentially quantitative yield at - 10°C (e.g. Scheme 23).23Although the complex is easily prepared from readily avail-

i ,ii

CH92

111

[Cp2TiCH2.ZnXz]

( 3 1 ) X=CL or1

Ph

Reagents: i, Zn; ii, [Cp,TiCl,]; iii, Ph

Scheme 23

able starting materials, its use is limited by its high reactivity towards other functional groups such as carboxylic acid chlorides, nitriles, benzyl halides, and even acetylenic bonds. Kauffmann and his co-workers have described four new molybdenum species which methylenate aldehydes and , less satisfactorily, ketones.68The most accessible of these, which probably exists as the equilibrium mixture (32), is formed by treating molybdenum pentachloride with two equivalents of methyl-lithium.

(32) Reagent: i, 4-MeOC6H,CH0 67

A. Pelter, B. Singaram, and J . W. Wilson, Tetrahedron Lett., 1983, 24, 635. T. Kauffmann, B. Ennen, J. Sander, and R. Wieschollek, Angew. Chem., Int. Ed. Engl., 1983,22, 244.

16

General and Synthetic Methods

Vinyl iodides with remote hydroxy-groups protected as tetrahydropyranyl ethers are suitable substrates for palladium-catalysed cross-coupling reactions with Grignard reagents. Their geometry, as usual, is preserved during the process (e.g. Scheme 24).69Reduction of the vinyl iodide to the corresponding olefin is a

10- 30°/0 Reagents: i, [Pd(PPh,),]; ii, BunMgBr

Scheme 24

minor side reaction when alkyl Grignard reagents are used. Molander and his co-workers have shown that tris(dibenzoylmethido)iron(m) is an effective catalyst for the cross-coupling of vinyl halides with aryl Grignard reagents (e.g. Scheme 25).70 The formation of up to 25% of homo-coupled products, and

90 O/O Reagents: i, PhMgBr, [Fe(dbm),]

Scheme 25

frequent stereomutation of (2)-vinyl halides during coupling, generally makes the catalyst less favourable than palladium or nickel complexes. However, iron complexes are cheap and they are easy to handle because of their stability to air and moisture. Aryl mercurials cross-couple with vinyl bromides and iodides on heating in HMPA with lithium chloride and Wilkinson's catalyst, but vinyl halides of (2)configuration undergo stereomutation (e.g. Scheme 26) .71 a#-Unsaturated I

A.4

PhHgCl , LiC1 M

[ClRh( PPh313I

-Ph

( E ) : ( Z ) = 3:l

Scheme 26

ketones, nitriles, and esters can also be prepared by this method using vinyl iodides bearing the appropriate functional groups on the olefinic bond. Both (E)- and (&)-isomers of P-trimethylsilylstyrene react within 30 minutes at room temperature with aryldiazonium tetrafluoroborates in the presence of D. Michelot, Synthesis, 1983, 130. G. A. Molander, B. J. Rahn, D. C . Shubert, and S . E. Bonde, Tetrahedron Lett., 1983,24, 5449. 71 R. C . Larock, K. Narayanan, and S. S . Hershberger, J . Org. Chem., 1983,48,4377. 69

70

Saturated and Unsaturated Hydrocarbons

17

bis(dibenzy1ideneacetone)palladium to give mixtures of (Qstilbenes (33) and 1-phenyl-1-arylethylenes(34).72 X

50 - 86% I

14 -42%

X = H,Me, Br, or NO2

SiMe3 Reagents: i, 4-XC6H4N2+BF,-,(Pd(dba),]

(331

(34)

Allylic chlorides and bromides cross-couple with phenyl- or vinyl-tin reagents in the presence of palladium catalysts to give allylbenzenes or 1,4-dienes respectively (e.g. Scheme 27).73Vinyl-tin reagents react without stereomutation, but, in

Reagents: i, * Bu",SnPh, cl [Pd(dba),], PPh3

-

Scheme 27

% \

/

the allylic partner, coupling shows selectivity for a primary rather than a secondary allylic carbon centre. Importantly, the reaction tolerates a variety of functionality including ester, nitrile, hydroxy , and formyl groups. Primary and secondary allylic pivalates couple efficiently with both lithium diorganocuprates' and alkylmagnesium halide :copper(1) iodide (2 : 1) complexes.74A useful reversal in regioselectivity is generally observed between the two types of organometallic reagents, the lithium species giving mainly the product of direct displacement (with retention of configuration of the allylic double bond) and the magnesium species leading mainly to the product of allylic rearrangement (e.g. Scheme 28).

R Reagent: 2 MeLi ,CuI 7 : 1 2 MeMg1,CuI 1 : 6

Scheme 28 K. Kikukawa, K. Ikenaga, F. Wada, and T. Matsuda, Chem. Lett., 1983, 1337. 73 F. K. Sheffy and J. K. Stille, J . Am. Chem. Soc., 1983, 105, 7173. 74 H.-J. Liu and L.-K. Ho, Can. J . Chem., 1983,61,632. 72

18

General and Synthetic Methods

Grignard reagents couple with racemic ally1 phenyl ethers in the presence of catalytic amounts of [(-)-(2s ,3s)-2,3-bis(dipheny lphosphino)bu tane]nickel(11) chloride to give high yields of optically active 01efins.~~ Scheme 29 shows a

\P).Ph2

97.7‘10 optical yield

Scheme 29

particularly favourable example where asymmetric induction is very high. Secondary organozinc halides give higher asymmetric induction (up to 86% enantiomeric excess) than the corresponding Grignard reagents during cross-coupling with vinyl bromides in the presence of catalytic dichloro{(R)-N,N-dimethyl1-[(S)-2-(diphenylphosphino)ferrocenyl]ethylamine}palladium(11) .76 A catalytic mixture of isopropylmagnesium bromide and [Cp2TiC1] or [Cp2TiC12]converts simple 175-dienes into isomeric cyclic olefins or acyclic dienes. The isomerization takes place within an hour at room t e m p e r a t ~ r e . ~ ~ Although some 175-dienes give mixtures of severai isomeric species, 3,4disubstituted hexa-175-dienesisomerize with synthetically useful selectivity (e.g. Scheme 30).

a-&+& i

H

H

96:4 Catalyst: i, [Cp,TiClJ, Pr’MgBr

Scheme 30

Barluenga and his co-workers have previously reported that a-chloroketones are converted regiospecifically into olefins on successive treatment with either a Grignard reagent or a reducing agent, then lithium. They have now broadened the scope of this approach by showing that the appropriate a-chloroketones can be generated in situ from carboxylic acid chlorides78 or their a-chloro-derivat i ~ e sEach . ~ ~ of the examples shown in Schemes 3178and 3279is carried out as a ‘one-pot’ process. Simple P-keto-sulphones are easily elaborated by selective alkylation at the aand a’-positions, and the carbonyl group can be replaced with a bromine atom 75

76

G. Consiglio, F. Morandini, and 0. Piccolo, J . Chern. SOC., Chern. Comrnun., 1983, 112. T. Hayashi, T. Hagihara, Y. Katsuro, and M. Kumada, Bull. Chem. SOC.Jpn., 1983,56,363. H. Lehmkuhl and Y.-L. Tsien, Chem. Ber., 1983, 116,2437. J. Barluenga, M. Yus, J. M. Concellh, and P. Bernad, 1. Org. Chern., 1983,48,3116. J. Barluenga, M. Yus, J. M. ConcellBn, and P. Bernad, J. Org. Chem., 1983,48,609.

’*

19

Saturated and Unsaturated Hydrocarbons OMgBr I

Reagents: i, CH,N,; ii, HC1; iii, PrnMgBr,MgBr,; iv, LiAlH,, AlCl,; v, Li

Scheme 31

Scheme 32

using sodium hypobromite. These transformations are the basis of a versatile approach to a-bromosulphones, which are converted into olefins using the Ramberg-Backlund reaction.** Scheme 33 exemplifies the sequence with a highyielding synthesis of non-6-en-1-01, the sex attractant of the Mediterranean fruit fly * S02Me

- OH

i - iii

-

Jso2

vi.vii

\

w

HO2C

Reagents: i, NaH; ii, BunLi; iii, EtBr; iv, NaOH, Br,; v, H30+;vi, EtONa; vii, LiAIHl

Scheme 33 8o

D. Scholz, Liebigs Ann. Chem., 1983,98.

2

General and Synthetic Methods

20

Burton and Cox have reported a novel one-pot synthesis of polyfluorinated olefins of the type (35) which involves Wittig olefination of acyl fluorides.s1 The phosphoranium salt (36), prepared in situ from tri-n-butylphosphine and trichlorofluoromethane, reacts readily with fully fluorinated acyl fluorides (but not chlorides) at room temperature. Hydrolysis of the resulting phosphonium salt (37) then leads stereospecifically to the chain-extended fluorinated olefin (35).

Reagents: i , R,COF; ii, NaOH

(Z)-1,2-Difluorovinylsilanessuch as (38), readily available from chlorotrifluoroethylene, undergo protodesilylation on treatment with potassium fluoride in aqueous DMSO. Alternatively, silicon can be replaced by a t-butyl group using t-butyl chloride in the presence of aluminium chloride.82 Both transformations are stereospecific (e.g. Scheme 34). The direct difluorovinylation of tertiary enolates has been achieved using difluoroacetylene generated in situ from trifluoroethylene and t-butyl-lithium at -78°C.83

Reagents: i, KF, DMSO, H,O; ii, Bu'C1, AlCl,

Scheme 34

2,2-Difluoro-l-arylethenyldiphenyl phosphate (39) reacts successively with lithium dibutylcuprate and allylic halides in THF containing TMEDA to give, instead of coupling products, allylic gem-difluoro-alkenes (40). By contrast, the corresponding diethyl phosphate (41) gives the enol phosphate (42) ChloroD. J. Burton and D. G. Cox, J . Am. Chem. SOC., 1983,105,650. S . Martin, R. Sauvetre, and J.-F. Normant, Tetrahedron Lett., 1983,24, 5615. 83 A. S. Kende and P. Fludzinski, J. Org. Chem., 1983,48, 1384. & T. Ishihara, M. Yamana, and T. Ando, Tetrahedron Lett., 1983,24, 5657.

21

Saturated and Unsaturated Hydrocarbons

/ ..I1.I11...

0 It CF2ClCPh

L FJ+,/op(oR)2

II

R=Ph

Ph

(40)

0

Ph

(39)R =Ph ( 4 1 ) R =Et

Ph (42) Reagents: i, HP(Q)(QR),, Et,N; ii, Bun,CuLi, TMEDA; iii, CH,=CHCH,Br

difluoromethyl ketones (43) can be converted into the corresponding 2,2difluoro-enol silyl ethers (44) by treatment with zinc and trimethylsilyl chloride in acetonitrile at 60°C. Reaction in situ with acetyl chloride affords the enol acetate derivatives (45)directly.85

F

(43)

(44)

F (45)

Reagents: i, Zn, Me,SiCl; ii, AcCl

a,a-Dichlorosulphoxides (46), prepared by alkylation of the organolithium compound (47), afford terminal vinyl dichlorides on pyrolysis.86 Analogous a-fluorosulphoxides behave similarly, giving high yields of vinyl fluorides.87

(Trimethylsily1)dichloromethyl-lithium (48) reacts smoothly with aldehydes at temperatures below - 100°C to afford, following careful acidic work-up, the corresponding P-hydroxysilanes. On subsequent treatment with boron M. Yamana, T. Ishihara, and T. Ando, Tetrahedron Lett., 1983,24, 507 V. Reutrakul and K. Herunsalee, Tetrahedron Lett., 1983, 24, 527. 87 V. Reutrakul and V. Rukachaisirikul, Tetrahedron Lett., 1983,24, 725. 86

22

General and Synthetic Methods

trifluoride etherate or sulphuric acid in methanol, elimination of trimethylsilanol takes place to give 1,l-dichloroalkenes (e.g. Scheme 35).88

CL Reagents: i , Me3SiCC1,Li (48); ii, BF,.OEt,; iii, H,SO,

Scheme 35

Silyl ethers bearing a-di- or tri-halogenomethyl substituents, such as (49), react with two equivalents of n-butyl-lithium at low temperatures to afford exclusively

CC 13

0siMe2Buf Me

k

OSiMe2Bu'

*-,

2BunLi

Me

(491

(Z)-hal~genoalkenes.~~ Under these conditions, the trihalogenomethyl derivatives are thought to decompose to halogenocarbenes, which rearrange via a stereospecific hydrogen migration. Eliminative deoxygenation of a-halogenosulphoxides has been used to prepare phenyl vinyl and phenyl chlorovinyl sulphides (e.g. Scheme 36).90

Scheme 36

Suzuki and his co-workers have developed a simple stereo-, regio-, and chemoselective synthesis of 2-bromo- and 2-iodo-l-alkenes via halogenoboration of terminal acetylene^.^^ B-Bromo- and B-iodo-9-borabicyclo[3.3. llnonane undergo cis-addition to terminal acetylenes to give Markovnikov adducts. Internal acetylenes do not react under these conditions. Protonolysis then gives A . Hosomi, M. Inaba, and H. Sakurai, Tetrahedron Lett., 1983,24,4727. M. C . Pirrung and Jih Ru Hwu, Tetrahedron Lett., 1983,24,565. V. Reutrakul and P. Poochaivatananon, Tetrahedron Lett., 1983,24, 531. 91 S. Hara, H. Dojo, S. Takinami, and A . Suzuki, Tetrahedron Lett., 1983, 24,731. 89

Saturated and Unsaturated Hydrocarbons

23

2-halogeno-1-alkenes in excellent yields, or, alternatively, successive treatment with lithium acetylides and iodine affords halogenated enynes of the type (50).% 1-Halogeno-1-alkynes can be converted into isomeric mixtures of 1,2dihalogenoalkenes using related m e t h ~ d o l o g y . ~ ~

X

I

\ "'r" iii.iv

X = Br or I

X (50) Reagents: i, B-Br-9-BBN or B-I-9-BBN; ii, AcOH; iii, R2C=CLi; iv, 1,

Barton's group has published improved conditions for the conversion of hydrazones into vinyl iodides. Yields are considerably improved by the use of strong hindered guanidine bases under anhydrous conditions (e.g. Scheme 37) .94

i

Me0

Me0 Reagents: i, 12,ButN= C(NMe,),

Scheme 37

Alkylation of lithiated allyldimesitylborane occurs specifically at the y-position to give (E)-vinylboranes such as (51) in excellent yield. Since these may be converted into the corresponding aldehydes, this represents a useful three-carbon homologation p r ~ c e d u r e . ~ ~

Reagents:

; ii, EtI

S. Hara, Y. Satoh, H. Ishiguro, and A. Suzuki, Tetrahedron Lett., 1983,24,735. S. Hara, T. Kato, and A . Suzuki, Synthesis, 1983, 1005. 94 D. H. R . Barton, G. Bashiardes, and J.-L. Fourrey, Tetrahedron Lett., 1983,24, 1605. 95 A. Pelter, B . Singaram, and J. W. Wilson, Tetrahedron Lett., 1983, 24, 631.

92

93

General and Synthetic Methods

24

Aromatic and aliphatic N-acyldehydroamino acids such as (52) and peptides undergo stereoselective decarboxylation at 145 “C in the presence of bases and copper powder to afford enamides (50-75% yields).96

-“‘“-4,

OMe

OMe

PY.cu.145°c

NHCOMe

NHCOMe

Highly regioselective syntheses of both kinetic and thermodynamic potassium enoxyborates of unsymmetrical ketones have been described (e.g. Scheme 38).97 OKBEt 3

OKBEt 3

Reagents: i, KN(SiMe,),, BEt3; ii, KH, BEt,

Scheme 38

In contrast to the corresponding potassium enolates, these derivatives react regiospecifically with electrophiles and are readily soluble in organic solvents such as THF. Substituted methoxy(pheny1thio)methanes (53) and the corresponding sulphones (54) can be converted into methyl enol ethers under the mild conditions shown in Scheme 39.98

Reagents: i , PhSCHLiOMe; ii, m-C1C6H,C03H; iii, PhS0,CHLiOMe; iv, KOBut

Scheme 39 96 U.

Schmidt and A. Lieberknecht, Angew. Chem., Int. Ed. Engl., 1983,22,550. E. Negishi and S. Chatterjee, Tetrahedron Lett., 1983, 24, 1341. 98 T. Mandai, K. Hara, T. Nakaiima, M. Kawada. and J. Otera, Tetrahedron Lett.. 1983.24. 4993. 97

Saturated and Unsaturated Hydrocarbons

25

On lithiation, phosphine oxides such as (55),readily accessible via treatment of chlorodiphenylphosphine with orthoformates, react with a wide range of aldehydes and ketones at - l 0 O T to afford hydroxyphosphine oxides. Subsequent treatment with potassium t-butoxide effects elimination to give ketene acetals in high overall yields (Scheme 40).99

Reagents: i, LDA; ii, R1R2CO;iii, KOBu'

Scheme 40

Krafft and Holton have shown that high yields of the thermodynamic silyl enol ether derivatives can be generated almost regiospecifically from cyclic ketones by treatment with bromomagnesium di-isopropylamide and trimethylsilyl chloride in diethyl ether at 25°C (e.g. Scheme 41).looEnol boranes, readily prepared in

97:3 Reagents: i, Pri,NMgBr, Me,SiCl, Et,O

Scheme 41

isomerically pure form by reaction of a-diazoketones with boranes, undergo smooth exchange with N-trimethylsilylimidazole to afford the corresponding trimethylsilyl enol ethers (e.g. Scheme 42).lo1Furthermore, (E)-trimethylsilyl

Reagents: i , Bu",B; ii, QN-SiMe,

Scheme 42 A. M. van Schaik, A. V. Henzen, and A. van der Gen, Tetrahedron Lett., 1983,24, 1303. M. E. Krafft and R. A. Holton, Tetrahedron Lett., 1983,24,1345. J. Hooz and J . Oudenes, Tetrahedron Lett., 1983,24,5695.

99 T. loo lo'

26

General and Synthetic Methods

enol ether derivatives of unsymmetrical ketones can be synthesized stereo- and regio-specificallyvia rhodium-catalysedisomerization of the correspondingp-trimethylsilylallyl alcohols (e.g. Scheme 43).lo2Interestingly, the reaction requires

+-+ OH

Reagents: i, [HRh(CO)(PPh,),],

OSiMej

Hr

Me3Si

Scheme 43

the presence of catalytic amounts of both [HRh(CO)(PPh,),] and l-phenyl2-trimethylsilylprop-2-en-1-one. Intermediate a-trimethylsilyl ketones can be isolated in high yield when the reaction is carried out in the presence of [HRh(PPh,),].lo3 a-Halogenoketones react with (trimethylsily1)tributyltin in the presence of two equivalents of trimethyl phosphite and catalytic amounts of palladium chloride to furnish the corresponding enol silyl ethers in high yield (e.g. Scheme 44).lo4

Reagents: i, Me,SiSnBun3,2P(OMe),, PdCl,

Scheme 44

a-Halogenoesters give alkyl silyl ketene acetals under the same conditions. Alternatively, esters bearing electron-withdrawing0-substituents are converted into alkyl silyl ketene acetal derivatives simply on treatment with silyl triflates in the presence of triethylamine.lo5 Alkyl acetates are efficiently converted into the corresponding (trialkylsi1oxy)methylene derivatives on reaction at 200 "C with trialkylsilanes and carbon monoxide at a pressure of 50 atm; the presence of catalytic amounts of [Co2(CO),] is essential.lo6Under these conditions, siloxymethylenation of p- and y-lactones also takes place (e.g. Scheme 45).

(yo"i_ (y Qo

.--!-*

4;'

OSiEtZMe

02SiEt2Me

Si Et 2Me Reagents: i, HSiEt,Me,CO, [Co,(CO),)

Scheme 45 I. Matsuda. S. Sato, and Y. Izumi, Tetrahedron Lett., 1983, 24,2787. S. Sato, I. Matsuda, and Y. Izumi, Tetrahedron Lett., 1983, 24, 3855. 104 M. Kosugi, T. Ohya, and T. Migita, Bull. Chem. SOC.Jpn., 1983, 56, 3539. m 5 H. Emde and G. Simchen, Liebigs Ann. Chem., 1983, 816. N. Chatani, S. Murai, and N. Sonoda, J . Am. Chem. SOC., 1983,105,1370. '02

1O3

27

Saturated and Unsaturated Hydrocarbons

1,2-Diaryl-l,2-bis(trimethylsilyl)alkenes(56) are readily prepared as mixtures of (E/Z)-stereoisomers by the reductive silylation of a-diketones.lo7

0

OSiMe3

(56)

Enol triflates, which are useful intermediates in the regiospecific synthesis of alkenes from ketones, may be prepared by treatment of enolate anions with N-phenyltrifluoromethanesulphonimidein either THF or DME at room temperature.los A noteworthy example is the formation of the enol triflate (57), a compound which has previously defied synthesis, in a yield of 72% from camphor.

K Treatment of sulphoxides with trimethylsilyl iodide in the presence of sterically hindered tertiary amines leads to (E/Z)-isomeric mixtures of vinyl sulphides via eliminative deoxygenation. lo9 Under these conditions, the unsymmetrical sulphoxide (58) gives the less substituted regioisomer (59) in 81% yield, and the allylic sulphoxide (60) affords the functionalized diene (61). Flynn has prepared

0 P

II h

-

0

II

I

S

(60)

w

P

h

S

w

(61 1

Reagents: i, Me,SiI, Pri,NEt

the steroidal vinyl sulphide (62) via the unusual intramolecular Wittig reaction shown."O K. Rasmussen, L. R . Krepski, S. M. Heilmann, H . K. Smith, jun., and M. L. Tumey, Synthesis, 1983, 457. Io8 J. E. McMurry and W. J. Scott, Tetrahedron Lett., 1983, 24, 979. IO9 R. D. Miller and D. R. McKean, Tetrahedron Lett., 1983, 24,2619. llu G. A . Flynn, J . Org. Chem., 1983,48, 4125.

lo7 J.

General and Synthetic Methods

28

OH

i

L

-iii

O

(62)

Reagents: i, Ph,P= CH,; ii, H30+;iii, KOBu'

Ley and Simpkins have reported an approach to synthetically important vinyl sulphones using Peterson olefination. ll1 Following lithiation, phenylsulphonyl(trimethylsily1)methane reacts smoothly with aldehydes and ketones at -78°C to afford (E/Z)-isomeric mixtures of vinyl sulphones such as (63) directly. Other functional groups such as esters, acetals, epoxides, and silyl ethers are inert under the reaction conditions. PhS02 Me3Si CHLiS02Ph

*

%@

OSi Me2But

ASiMeZBd

(63)

A new stereoselective synthesis of vinylsilanes has been developed by Fujita and his co-workers.'12 Sequential treatment of vinyl sulphones (64) with tributylstannyl-lithium and trimethylsilyl chloride affords the a-silyl-p-stannyl sulphones (65). These can be transformed selectively into either ( E ) - or (2)vinylsilanes (Scheme 46).

SiMe3 SnBun3 i .ii

I

296

R*so2ph\ SiMe3

(65)

R

( Z 1 - isomer

SiMe3

W

)88% ( E 1- isomer Reagents: i, Bun3SnLi;ii, Me3SiC1;iii, silica gel (70-230 mesh), CHC13, reflux

mesh), CHCl,, r.t.; iv, silica gel (23-00

Scheme 46 ll1

112

S. V. Ley and N. S. Simpkins, J . Chem. SOC., Chem. Commun., 1983, 1281. M. Ochiai, T. Ukita, and E. Fujita, Chem. Lett., 1983, 1457.

Saturated and Unsaturated Hydrocarbons

29

Oshima and his co-workers have shown that silyl-alumination , -magnesiation, or -zincation of terminal acetylenes in the presence of transition-metal catalysts provides a useful route to substituted ~inylsi1anes.l~~ The regio- and stereochemical outcome of the reaction is strongly dependent on the nature of both the metal and the catalyst. For example , palladium-catalysed silylalumination of propyne followed by treatment with iodine provides an 88 : 12 mixture of just two of the four possible vinylsilanes (Scheme 47). The same research group has shown //

i , ii

//-

T

I

-t

F S i M e l P h

i

SiMeZPh

88:12 Reagents: i, PhMe,SiAlEt,, [PdC12{P(2-MeC,H,),},1; ii, I,

Scheme 47

that vinyl phosphates can be transformed into the corresponding vinylsilanes with complete retention of configuration by treatment with silylmagnesium or silylaluminium reagents in the presence of palladium catalysts (e.g. Scheme 48).l14 0

II

Reagents: i , PhMe,SiMgMe, [PdC12(PPh&]

Scheme 48

Hydromagnesiation of 1-trimethylsilyl-1-alkynes (66) with isobutylmagnesium bromide in the presence of a catalytic amount of [Cp,TiC12] is highly regio- and stereo-selective. Reaction of the resulting vinylmagnesium species (67)’with alkyl iodides and copper(1) iodide, or with reactive halides, leads to (2)-1,2disubstituted vinylsilanes (68) in high yield. 115 SiMe3 R’-e-SiMe:,

(66)

.

SiMe3

R ’ d M g B r

(67)

( 6 8 ) R’, R2 = alkyl or ally1

Reagents: i, Bu’MgBr, [Cp,TiCl,]; ii, R21, CuI

Although a-silyl-sulphoxides and -selenoxides undergo a sila-analogue of the Pummerer rearrangement on heating, the corresponding N-4-tolyl113

114

lL5

H. Hayami, M. Sato, S. Kanemoto, Y. Morizawa, K. Oshima, and H. Nozaki, 1.A m . Chem. Soc., 1983, 105, 4491. Y. Okuda, M. Sato, K. Oshima, and H. Nozaki, Tetruhedron Lett., 1983, 24, 2015. F. Sato, H. Watanabe, Y. Tanaka. T. Yamaji, and M. Sato, Tetrahedron Lett., 1983,24,1041.

General and Synthetic Methods

30

sulphonylchalcogenimidesof the type (69) give vinylsilanes (70) via syn-elimination under these conditions.116

X = S, Se, or Te

(69)

Reagents: i, BunLi,TMEDA; ii, R1R2CH(Hal);iii, chloramine-T; iv, A

Halogenated vinylsilanes (71), which are available from the corresponding terminal silyl acetylenes via alanes (72) , undergo smooth reaction with t-butyllithium in diethyl ether to afford four-, five-, or six-membered cyclic vinylsilanes in high yield. In non-donor solvents such as pentane or benzene, however, the alane (72; n= 1) cyclizes spontaneously to 1-(trimethylsilyl)cyclobutene . l 1 7

- @c

n = 1,2,

(71)

(72)

SiMeg

Or 3

Reagents: i , I,; ii, BdLi

Alkenyl-zinc species (73) bearing a-alkoxy , a-alkylthio, or a-trialkylsilyl substituents undergo highly stereoselective cross-coupling with aryl and alkenyl

X =OR1, SR', or S i R i

(73)

Reagents: i, Bu'Li; ii, ZnC1,; iii, PhI, [Pd(PPh,),]; iv, R2-I,

[Pd(PPh,),]

halides in the presence of a palladium catalyst to afford functionalized alkenes or 1,3-dienes respectively.118 The corresponding alkenyl-lithium species are essentially unreactive under comparable conditions. 116 11' 11*

F. Ogura, T. Otsubo, N. Ohira, and H. Yamaguchi, Synthesis, 1983,1006. E. Negishi, L. D. Boardman, J. M. Tour, H. Sawada, and C. L. Rand, J . Am. Chem. Soc., 1983,105, 6344. E. Negishi and F.-T. Luo, J . Org. Chem., 1983,48, 1560.

Saturated and Unsaturated Hydrocarbons

31

a,@-Unsaturated aldehydes and ketones can be prepared by direct dehydrogenation of the corresponding saturated carbonyl compounds using silver or tin(I1) triflates, amines, and stoicheiometric amounts of palladium(I1) complexes. 119 Ketones, carboxylic esters, and aliphatic chlorine atoms are inert under the conditions used for the dehydrogenation of aldehydes. A stoicheiometric mixture of 2-(phenacylthio)benzothiazole (74) and trin-butylphosphine reacts with aldehydes and ketones to give a,@-unsaturated

Bu”~P

-CHO

Ph

(74)

phenyl ketones with mainly (E)-geometry (63-94% yields).12* 2-Mercaptobenzothiazole is a by-product of the reaction and can be re-cycled. The adducts of bis(pheny1thio)acetals and aldehydes rearrange under acidic conditions to give a-phenylthioketones; thermolysis of the corresponding sulphoxides leads stereospecifically to (E)-enones (e.g. Scheme 49)

Reagents: i, BuLi; ii, Me,CHCH,CHO; iii, TsOH; iv, NaIO,; v, PhMe, reflux

Scheme 49

On lithiation, the a-silyl-ketimine (75) reacts with aldehydes and ketones as a regiospecific ethyl methyl ketone aldol equivalent. 122 The reagent is especially useful for preparing a,@-unsaturated methyl ketones with highly substituted olefinic bonds of (2)-configuration (e.g. Scheme 50).

83:17

(75) Reagents: i, LDA; ii, w

o

; iii, H30+,silica gel

Scheme 50 119 T.

Mukaiyama, M. Ohshima, and T. Nakatsuka, Chem. Lett., 1983,1207. Y. Ueno, L. D. S. Yadav, and M. Okawara, Chem. Lett., 1983, 831. 121 J. Durman, J. Elliott, A. B. McElroy, and S. Warren, Tetrahedron Lett., 1983,24,3927 lzz A. A. Croteau and J. Termini, Tetrahedron Lett., 1983,24,2481.

lZo

32

General and Synthetic Methods

Mixtures of tetramethoxy- or tetraethoxy-silane and caesium or potassium fluoride promote a variety of aldol-type condensations leading to a,@-unsaturated aldehydes, ketones, or esters. 123 Wittig-Horner reactions with ethyl diethylphosphonoacetate or diethyl 2-oxoalkanephosphonates, which lead to a,@-unsaturated esters or ketones respectively, are conveniently performed under heterogeneous liquid-liquid conditions using concentrated aqueous solutions of potassium carbonate with no organic solvent or phase-transfer catalyst. 124 Alexakis and his co-workers have reported that carboxylic acid chlorides cleanly acylate alkenyl-copper reagents in the presence of catalytic [Pd(PPh,),] to give a,@-unsaturated ketones; similarly , ethyl chloroformate gives a,@unsaturated esters. 125 Importantly, the alkenyl-copper reagents are easily prepared in stereodefined forms and their configuration is conserved during acylation (e.g. Scheme 51).

X = Br or C I Reagents: i, EtCu.MgX,; ii, PhCOC1, [Pd(PPh,),]

Scheme 51

(a-Methoxyviny1)trimethyltin (76) efficiently cross-couples with acid chlorides in the presence of 1 mol% of [PhCH2Pd(PPh3)2C1]to give a-methoxyenones (77). These can be elaborated to give methoxydienes or rearranged enones (Scheme 52).126In related work, Hegedus and Russell have shown that zinc salts of enol

(76)

(77)

Reagents: i, RCOC1, [PhCH,Pd(PPh,),Cl]; ii, Ph,P=

CH,; iii, H,O+

Scheme 52

ether anions such as (78) couple with vinyl bromides or iodides under palladium(0) catalysis to give , after hydrolysis, a,/?-unsaturated ketones (e.g. Scheme 53).127The geometry of the vinyl halide is retained, but a five-fold excess

- 1‘ i.ii

A O E t

iii.iv

/

OEt

(78)

Reagents: i, Bu‘Li; ii, ZnC1,; iii, [Pd(dba),], 2Ph3P; iv, Ph/-?Br;

v, MgSO,

Scheme 53 C. Chuit, R. J. P. Corriu, and C. ReyC, Synthesis, 1983,294. J. Villieras and M. Rambaud, Synthesis, 1983,300. 125 N. Jabri, A. Alexakis, and J. F. Normant, Tetrahedron Lett., 1983,24,5081. lZ6J. A. Soderquist and W. Wei-Hwa Leong, Tetrahedron Lett., 1983, 24, 2361. 12’ C. E. Russell and L. S. Hegedus, J . Am. Chem. SOC., 1983, 105,943. 123

33

Saturated and Unsaturated Hydrocarbons

of the zinc salt is required for acceptable yields. Zinc salts of allenic ethers [e.g. (79)] couple with aryl and vinyl halides in the same way to furnish a,P-unsaturated aromatic ketones or penta-174-dien-3-ones respectively. The steps shown in Scheme 54, all performed in one pot and giving an overall yield of 60%, illustrate

Reagents: i, BunLi; ii, MeI; iii, ZnC1,; iv, [PdCl,(PPh,),], DIBAL; v, 2-MeC6H,I; vi, H 3 0 i

Scheme 54

how salts of allenic ethers are conveniently constructed from readily available acetylenic precursors. Deprotonation of 1-t-butylthio-3-methoxy-1-alkenes such as (80) occurs selectively at the 1-,2-, or 3-position depending on the choice of base, the geometry of the olefinic bond, and whether there is a substituent at the 3-po~ition.l~~ For example ,use of s-butyl-lithium allows 3-substituted (2)-isomers to be alkylated at the 2-position in almost quantitative yield (Scheme 55). Since alkenes like (80) are Me0

SBut

A

-+/-y Me0

. ..

,..

SBu'

I .II

(80) Reagents: i, BuSLi; ii, MeLi; iii, MeI, MeCN, H,O

Scheme 55

easily prepared and hydrolysed, elaboration of the type described above provides access to a wide variety of a$-unsaturated aldehydes. 2-Substituted allylsilanes are oxidized to a$-unsaturated aldehydes (6372%) on treatment with iodosobenzene and boron trifluoride etherate in d i 0 ~ a n e . IIsolated ~~ olefinic bonds, as well as acetoxy-groups (Scheme 56), remain intact during the transformation. SiMe3

Ph-I=O

AcO

AcO

BF3.0Et2

Scheme 56

lZ9

C. Bibang Bi Ekogha, 0. Ruel, and S . A. Julia, Tetrahedron Lett., 1983,24,4825,4829. M. Ochiai, E. Fujita, M. Arimoto, and H. Yamaguchi, Tetrahedron Lett., 1983, 24, 777.

34

General and Synthetic Methods

Trialkyl(1-alkyny1)borates react readily with triethyl orthoformate and TIC4to give, following an oxidative work-up, highly substituted a,P-unsaturated aldehydes (e.g. Scheme 57).130The appropriate borates are prepared in situ from

ti Bun$ - E -Ph

ri BunKo

( N u = nucleophile 1

EtO

Bun

Ph

L

Reagents: i , (EtO),CH, TiC1,; ii, aq. NaOH, H,O,

Scheme 57

lithiated acetylenes and trialkylboranes. If trialkyl orthoacetates or orthopropionates are used in place of triethyl orthoformate, a$-unsaturated methyl or ethyl ketones are formed, but yields are lower (40-65%). Related reactions described later in the year by the same research group provide new approaches to P,Pdialkyl-a,P-unsaturated esters and P-ethoxy-a$-unsaturated ketones. 131 On treatment with boron trifluoride, P'-hydroxy-a$-epoxysilanes such as (81) are transformed into a$-unsaturated aldehydes or ketones via a skeletal rearrangement and elimination of trimethylsilanol. 132 Although some substitution patterns lead to a single product, others, such as that of the example shown in Scheme 58, give regioisomeric mixtures via competing rearrangements. Both cyclic and acyclic P-pyrrolidino-a,P-unsaturated ketones are converted (65-68% yields) into the corresponding P-alkyl compounds on treatment with alkyl-lithium species in hydrocarbon solvents (e.g. Scheme 59).133The choice of a non-polar solvent is important, since it increases the nucleophilicity and decreases the basicity of the alkyl-lithium species, thereby minimizing simple deprotonation of the substrate. Alkenyl- or alkynyl-lithium species give dienones or enynones respectively under the same conditions and tend to give higher yields. When the olefinic bond of methyl vinyl ketone is protected as its DielsAlder adduct with cyclopentadiene, normal a-alkylations and Grignard additions can be carried out at the carbonyl group. Subsequent deprotection by passing the substrate in the vapour phase through a hot tube gives almost quantitative yields of a,#?-unsaturated ketones or allylic alcohols (Scheme 60). 134 S. Hara, H. Dojo, and A. Suzuki, Chem. Lett., 1983,285. S. Hara, H. Dojo, T. Kato, and A. Suzuki, Chem. Left., 1983,1125. 13* F . Sato, Y . Tanaka, and H. Kanbara, J. Chem. SOC., Chem. Commun., 1983,1024. 133 T . Mukaiyama and T. Ohsumi, Chem. Lett., 1983,875. 134 R. Bloch, Tetrahedron, 1983, 39, 639. 131

Saturated and Unsaturated Hydrocarbons

35

-

- Me3Si 0H

+ 1:l Reagents: i, Bu'MgBr, [Cp,TiCl,]; ii, MeCHO; 111, m-ClC,H,CO,H; iv, BF,.OEt,

Scheme 58

Petroleum e t h e r

Scheme 59

+R

A

0 *i,ii.iv

0 i-iv

Reagents: i, LDA; ii, RX; iii, MeMgI; iv, 450 "C, 50 ms

Scheme 60

Active zinc species of uncertain structure prepared by treatment of alkyl iodides with a zinc-copper couple efficiently promote the acylation of aliphatic olefins with acid chlorides. The usual products, following treatment with a base, are a,P-unsaturated ketones, though l-methylcyclohexene gives mainly deconjugated compounds (Scheme 61).135The reagent of the Simmons-Smith type derived from methylene iodide usually leads to highest yields and gives no products of cyclopropanation. The key step in a new approach to a-phenylthioenones, which are not easily prepared by direct condensation of ketones with a-phenylthioketones, is the 135

T. Shono, I. Nishiguchi, M. Sasaki, H. Ikeda, and M. Kurita, J . Org. Chem., 1983,48,2.503.

36

e0 0-

General and Synthetic Methods

i

- iii

0 - J+

+

i-iii

po 4 - 6 '10

63 - 70 ' l o Reagents: i, Zn/Cu, CH,12; ii, RCOC1; iii, KOH

Scheme 61

thermal rearrangement of trifluoroacetyl derivatives of allenic alcohols such as (82) to give dienol trifluoroacetates (83). Methanolysis then furnishes the a-phenylthioenones, as (E/Z)-stereoisomeric mixtures where p0ssib1e.l~~ Aromatic ketones are not suitable precursors. OH SPh

---

-

SPh

% @cN

+

t82) iii , iv

I

4:l

5%

SPh

SPh

v_

&°C0cF3 (83)

Reagents: i, Bu"Li, TMEDA, HMPA; ii,

\SPh

@

; iii, (CF,CO>,O, Et,N; iv, 65 "C; v, K,CO,, MeOH

Scheme 62 shows an example of a new method for the 1,4-transposition of the carbonyl group of a$-unsaturated aldehydes or ketones.13' The key transforma-

L-

li

Reagents: i , Anode, MeOH, AcOH, Et,N+ TsO-: ii. NaBH,; iii, TsCl, Et,N; iv, Me,CO, H,O, reflux

Scheme 62 136 137

A. J. Bridges and R. D. Thomas, J . Chem. SOC., Chem. Commun., 1983,485 T. Shono and S. Kashimura, J . Org. Chem., 1983,48,1939.

Saturated and Unsaturated Hydrocarbons

37

tion is the regiospecific y-methoxylation of the starting material, accomplished by anodic oxidation of the corresponding dienol acetate. Simple cycloalkenes are efficiently converted into the corresponding 2-cycloalkenones (71-88% yields) using the simple photo-oxygenation procedure exemplified by Scheme 63. The process works well even on a mole scale.138

Q

'02

-, DMAP

Scheme 63

Acyclic olefins are also suitable substrates, but regioisomeric mixtures of enones may be formed. 2-Substituted cyclopentanones are oxidized to the corresponding 2-cyclopentenones by anhydrous copper(I1) bromide in a refluxing mixture of chloroform and ethyl acetate.139 Scheme 64 shows a new high-yielding route to a-vinyl- or a-aryl-P-methylcyclopentenones via an acid-catalysed ring expansion of cyclobutane derivatives

. .. I , II

OSi Me3

OSi Me3

MeGiO

OMe

dfR

R = a r y l or vinyl Reagents: i, RCH(OMe),, BF,.OEt,; ii, Ph,P=

CH,; iii, CF3CO2H

Scheme 64

(84)." Although P-unsubstituted enones can be made by a modified procedure, ring expansion fails for derivatives (84) of aliphatic acetals. Two research groups have shown that intramolecular acylation of vinylsilanes occurs smoothly under Lewis acid cata1y~is.l~~ However, stabilization by silicon of E. D. Mihelich and D. J. Eickhoff, J . Org. Chern., 1983,48, 4135. D. D. Miller, K. B. Moorthy, and A . Hamada, Tetrahedron Lett., 1983,24,555. I4O E. Nakamura, J. Shimada, and I. Kuwajima, J. Chern. SOC., Chern. Cornrnun., 1983,498. 141 K. Mikami, N. Kishi, andT. Nakai, TetrahedronLett., 1983,24,795; E. Nakamura, K. Fukuzaki, and I. Kuwajima, J . Chern. SOC., Chern. Cornrnun., 1983,499. 138

13y

38

General and Synthetic Methods

positive charge at the /3-position is not always strong enough to direct the cyclization exclusively to the expected product (e.g. Scheme 65).

) 95% ( € 1 Scheme 65

(E):(Z)=52:48

- isomer

Taost and Adams have reported an unusual Lewis acid-catalysed rearrangement which leads to spirocyclic cyclopentenones (85). 14*

SOzPh

n = 3,4,or 8

(CH&

Tsuji and his co-workers have reported methods which enable certain enol ethers to be converted selectively into a,P-unsaturated or a-allylated aldehydes and ketones. For example, ally1 enol carbonates such as (86) are converted cleanly into y, &unsaturated ketones such as (87)143or a,P-unsaturated ketones

0

Reagents: i, Pd(OAc),, dppe, 80 "C; ii, Pd,(dba),.CHCI,, PPh,, 0 "C 142

143

B. M. Trost and B. K.Adams, J . Am. Chem. SOC., 1983, 105,4849. J. Tsuji, I. Minami, and I. Shimizu, Tetrahedron Lett., 1983, 24, 1793.

Saturated and Unsaturated Hydrocarbons

39

such as (88),144depending on the palladium catalyst and precise reaction conditions used. Importantly, regioisomeric allyl enol carbonates, prepared by quenching enolates generated under kinetic or thermodynamic conditions with allyl chloroformate, each lead to specific products. Silyl enol ethers145and enol acetates146are also transformed into a$- or y,&unsaturated ketones on treatment with diallyl or allyl methyl carbonate and palladium catalysts under suitable conditions. Scheme 66 shows an example of a new sequence which is analogous to the Robinson annulation but which yields the transposed enones. The annulation

SPh Reagents: i, &$Ph,

C1- (89), K,CO,; ii, TiCl,, AcOH; iii, DBU

Scheme 66

reagent (89) is generated in situ from a readily prepared bis-phosphonium salt and potassium carbonate. Hydrolysis of the intermediate vinyl sulphides yields the required enones together with thiophenol; since these have a tendency to react with each other, elimination of thiophenolate has to be performed as an extra step.

The stable phosphorane (90) reacts with sodium hydride and a,@-unsaturated aldehydes to give variable yields (21-83 %) of 6-alkoxycarbonylcyclohex-2-en1-ones, sometimes with a high degree of stereoselectivity (e.g. Scheme 67).148

NaH +

0

Scheme 67 I. Shimizu, I. Minami, and J. Tsuji, Tetrahedron Lett., 1983,24, 1797. J. Tsuji, I. Minami, and I. Shimizu, Tetrahedron Lett., 1983, 24,5635; Chem. Lett., 1983,1325. 146 J. Tsuji, I. Minami, and I. Shimizu, Tetrahedron Lett., 1983, 24, 5639. 14’ R. J. Pariza and P. L. Fuchs, J. Org. Chem., 1983,48,2304. iJ8 K. M. Pietrusiewicz, J. Monkiewicz, and R. Bodalski, I . Org. Chem., 1983, 48, 788.

144 145

General and Synthetic Methods

40

In sharp contrast to the stereoselectivity observed with normal HornerEmmons reagents, the bis(trifluoroethy1)phosphono-esters (91) and (92) react 0

ii

'I

( F3CH20 12p

C02Me

(92)

( Z ) : ( E ) =46:1

C02Me

Reagents: i, Me(CH,),CHO, KN(SiMeJ2, 18-crown-6

with aldehydes to give mainly (2)-@unsaturated esters, especially when used in conjunction with highly dissociated bases.*49Both aliphatic and aromatic aldehydes are suitable substrates, and (E)-enals or (E,E)-dienals give ( E ,2)dienes or ( E ,E, 2)-trienes respectively under the same conditions. The stabilized telluronium ylide derived from the salt (93) reacts with aldehydes and ketones to give a,@-unsaturated esters (e.g. Scheme 68) instead of Bun2;evCOZEt

Br

-

(93) ( E ) : ( Z = 11:l Reagents: i, KOBu'; ii, PhCOMe

Scheme 68

the a,@-epoxyesters expected by analogy with the reactions of the corresponding sulphonium or selenonium ylides. lj0 cw,D-Unsaturated esters can also be prepared (68-90% yields) from dilithiated ethyl mercaptoacetate (94) and aldehydes via the pathway shown in Scheme 69, triethyl phosphite assisting desulphurization. l j l 1

Reagents: i , 2 LDA; ii, RCHO; iii, CIC0,Et; iv, (EtO),P

Scheme 69 W. C. Still and C. Gennari, Tetrahedron Lett., 1983, 24, 4405. Osuka, Y . Mori, H. Shimizu, and H. Suzuki, Tetrahedron Lett., 1983, 24,2599. 151 S. Matui, K. Tanaka, and A . Kaji, Synthesis, 1983, 127.

149

150 A.

Saturated and Unsaturated Hydrocarbons

41

The 2-methylenebicyclo[3.1 .O]hexane (95) undergoes smooth ring opening in the presence of electrophilic or free-radical reagents to form highly substituted cyclopentenes of the types (96) and (97).152In addition, the diastereomeric

(96)

x-Y

Reagent C13 C-

(97)

Cl (+A1 BN 1

PhS-H But OCI

I-menthyl ester analogues of (95) are easily prepared and can be separated by chromatography, allowing cyclopentenes (96) and (97) to be prepared with high optical purity and known absolute configuration. Di-t-butyl methylenemalonate can be prepared in multigram quantities by a straightforward Knoevenagel-type condensation of di-t-butyl malonate with formaldehyde.lS3It promises to be a useful synthetic intermediate since, in contrast to other methylenemalonates, it does not polymerize on standing, yet it is still a powerful Michael acceptor. (E)-Cinnamic acids are conveniently transformed into the corresponding (2)isomers via regiospecific palladium-catalysed carboxylation of (Z)-styryl bromides under phase-transfer conditions (Scheme 70). 154 X

X

+

Reagents: i, Br,; ii, NaHCO,; iii, CO, NaOH, PhCH,NEt, C1-, t-amyl alcohol, H 20, [Pd(PPh,),] or [Pd(diphos),]

Scheme 70

Ley, Simpkins, and Whittle have described a new synthesis of 4-substituted butenolides developed during the first total synthesis of the insect antifeedant ajugarin I.1ssThe steps shown in Scheme 71 are performed successively in the same flask and give an overall yield of 45%. The butenolide synthon is easily prepared from propargyl alcohol. Scheme 72 shows another new pathway to 4-substituted butenolides. 156 The key step is the regiospecific intramolecular addition to an acetylenic bond of the radical derived from the a-bromoacetal(98). R. A. Roberts, V . Schull, and L. A . Paquette, J . Org. Chem., 1983,48, 2076. P. Ballesteros, B. W. Roberts, and J. Wong, J . Org. Chem., 1983, 48, 3603. lS4 V. Galamb and H. Alper, Tetrahedron Lett., 1983, 24, 2965. ls5 S. V. Ley, N. S. Simpkins, and A . J. Whittle, J . Chem. SOC., Chem. Commun., 1983, 503. 156 G . Stork and R. Mook, Jr., J . A m . Chem. SOC., 1983, 105, 3720.

15*

153

42

General and Synthetic Methods

Reagents: i, Bu"Li; ii, ButMe,SiOCH2C=CC02Et; iii, Bun,NF

Scheme 71

I

I

R

R

lii

R

Reagents: i, BrCH,CH(Br)OCH,CH,Cl, PhNMe,; ii, Bun,SnH, AIBN; iii, Na, THF, NH,; iv, PDC; v, DBU

Scheme 72

P-Hydroxysulphones (99), prepared from methyl phenyl sulphone and aldehydes, react smoothly with butyl-lithium to form dianions which can be elaborated by the steps shown in Scheme 73 to form 5-substituted buten01ides.l~~

koH .

PhS02

i ii

R

~

PhSO2 x H C 0 2 H

R

iii.iv,

R

(99) Reagents: i, 2Bu"Li; ii, ICH,CO,Na; iii, TsOH; iv, Et,N

Scheme 73

Butenolides substituted at the 4-position can be prepared from the appropriate P-hydroxysulphones in the same way. In another approach, dimethoxydihydrofurans (100) , prepared from the corresponding 2-substituted furans (using, for example, bromine and a weak base in methanol), are converted into 157

K. Tanaka, K. Ootake, K. lmai, N.Tanaka, and A . Kaji, Chem.Left., 1983, 633.

Saturated and Unsaturated Hydrocarbons

43

5-substituted butenolides on treatment with an excess of trimethylsilyl iodide (Scheme 74). Yields, however, are variable.158

Me0 (100)

Scheme 74

Maleic anhydride, protected as its endo-Diels-Alder adduct (101) with cyclopentadiene, can be elabortated with Grignard reagents and by alkylation to give, after deprotection, high yields of 3,5,5-trisubstituted butenolides (lO2).lS9 i - iii ___)

(1011

R*

(102) R1, R2 = a l k y l , a r y l or benzyl Reagents: i, 3R'MgX; ii, LDA; iii, R2X; iv, 280 "C

Kozikowski and Ghosh have developed a new route to a-methylene-y-lactones using dipolar cycloadditions of the nitrile oxide (103) derived from 2-nitroethanol (e.g. Scheme 75). Alternatively, a-methylene-y-lactones can

6 - L C

-

JoTHP

(103)

r=

Y O Ph

I

Ph

Ph

T

H

i,ii

Ph

Reagents: i, HZ,Raney Ni; ii, Ph,P=CH2; iii, TsOH; iv, MnO,

Scheme 75 ls8 159

160

B. L. Feringa and W. Dannenberg, Synth. Commun., 1983,13,509. P. Canonne, M. Akssira, and G. Lemay, Tetrahedron Lett., 1983,24,1929. A. P. Kozikowski and A. K. Ghosh, Tetrahedron Lett., 1983,24, 2623.

P

44

General and Synthetic Methods

be prepared by intramolecular palladium-catalysed reaction between the olefinic and chloroformate groups of homoallylic alcohol derivatives such as (104). 161 It is

Reagents: i , NaHCO,, [Pd(PPh3).,],PPh,

important to add triphenylphosphine to the reaction mixture to suppress migration of the exo-methylene group of the product. Unfortunately, intermolecular reactions between olefins and chloroformates under the same conditions give only traces of a$-unsaturated esters. The dianion from methallyl alcohol reacts with epoxides to form 1,5-diols such as (105), which may be oxidized to a-methylene-&lactones (106). The success

of the sequence stems from the nature of the dianion: the alkoxide function directs subsequent carbanion formation to the remote allylic position. A novel approach to a variety of synthetically versatile enaminones has been described, which involves reaction of enol silyl ethers with oxime sulphonates in the presence of diethylaluminium chloride.163 As illustrated by Scheme 76, the ,OMS

,OMS

+kOSiMe3

i

j

+&

i*%o

Reagent: i , Et2AlCl (2-3

equiv.)

Scheme 76 F. Henin and J.-P. Pete, Tetrahedron Left., 1983, 24, 4687. M. Carlson and L. L. White, Synth. Commun., 1983, 13,237. Matsumura, J. Fujiwara, K. Maruoka, and H. Yamamoto, J . Am. Chem. Soc., 1983,105,6312.

16* R. 163 Y.

Saturated and Unsaturated Hydrocarbons

45

reaction proceeds regiospecificallywith respect to both substrates, Oxime sulphonates derived from aromatic ketones or from cyclopentanones, however, fail to react cleanly. McNab and his co-workers have shown that flash vacuum pyrolysis of tertiary aminomethylene Meldrum’s acid derivatives such as (107) leads to 1,2dihydropyrrol-3-ones (108).164

10-2r,6OO0C

% 0

An efficient new procedure for the synthesis of cyclic p-enamino-esters from lactams has been reported (e.g. Scheme 77).165

&f N ‘Me Reagents: i, COC1,; ii,

iii

.

w C o z

O

‘Me

‘Me

; iii, EtOH

Scheme 77

a-Lithioalkanenitriles react with protected cyanohydrins at -78 “C to afford 4-alkoxy-3-amino-2-alkenenitriles (109) in good yields (e.g. Scheme 78) The

success of this highly selective cross-Thorpe reaction is attributed to activation of the carbanion via complexation to the alkoxy-substituent. H. J. Gordon, J. C. Martin, and H. McNab, J . Chem. SOC., Chem. Commun., 1983,957. P. CClCrier, M. G. Richaud, and G. Lhommet, Synthesis, 1983, 195. 166 K. Kobayashi and T. Hiyama, Tetrahedron Lett., 1983,24,3509.

lM

165 J.

46

General and Synthetic Methods

A high-yielding synthesis of (E)-3-~ilylacrylates(110) involves reaction of silanes with an excess of methyl acrylate in the presence of [ C O ~ ( C O ) ~ ] . ~ ~ Although general with respect to the silane, the reaction fails with methyl methacrylate and methyl crotonate.

It has been reported that addition of propiolic acid to a solution of methylmagnesium iodide in THF leads, after work-up with acetic acid, to an 80% yield of (2)-3-iodoacrylic acid. The mechanism for the formation of this unexpected product is not clear. Other acetylenic acids, with substituents at the 3-position, do not undergo an analogous reaction. A convenient one-pot synthesis of enol acetates of a-keto-esters has been developed by Mukaiyama and his co-workers.169 Lithiation of the trimethylsilyl cyanohydrin (111) with LDA in THF-HMPA followedby treatment with ally1 or NCyC02Me

i.ii

~

[..xC02M;1

OSiMe3

Me350

CN

iii

P

h

y C02Me OAc

(1111 Reagents: i, LDA, Pri,NH; ii, PhCH,Br; iii, A%O

benzyl bromides and then acetic anhydride gives the corresponding enol acetates in good yields. It has been shown that in the presence of [VO(acac),] and (Me3Si0)*both primary and secondary allylic alcohols rearrange to give tertiary isomers in good yields (e.g. Scheme 79). 170 Isomerization of primary to secondary allylic alcohols, however, is less effective.

Reagents: i, (Me3SiO),, [VO(acac),]

Scheme 79

Primary allylic iodoso-compounds, generated in situ from the corresponding iodides, undergo spontaneous [2,3]-sigmatropic rearrangement to give allylic K. Takeshita, Y . Seki, K. Kawamoto, S. Murai, and N. Sonoda, J . Chem. SOC.,Chem. Commun., 1983, 1193. M. E. Jung, J. A . Hagenah, and Z . Long-Mei, Tetrahedron Lett., 1983,24,3973. 169 T. Mukaiyama, T. Oriyama, and M . Murakami, Chem. Lett., 1983,985. 170 S . Matsubara, K. Takai, and H. Nozaki, Tetrahedron Lett., 1983,24, 3741. 16'

Saturated and Unsaturated Hydrocarbons

47

alcohols (e.g. Scheme 8O).l7lThe reaction is best carried out in a two-phase system using an excess of peroxy-acid and an inorganic base.

-I

rn-cIC6H~C03H

, ’ C02Me

n-Allylpalladium complexes are oxidized by t-butyl hydroperoxide in the presence of catalytic amounts of [ M ~ O ~ ( a c a cto) ~the ] corresponding allylic alcohols (e.g. Scheme S1).172Oxidation occurs preferentially at the palladium side of the

Reagents: i, Bu‘OOH, py, [M~O,(acac)~]

Scheme 81

complex, and the regiospecificity is opposite to that observed for carbon-carbon bond formation at n-allylpalladium complexes. Stereospecific alkylation of the vinylsilane (112) can be achieved either by metallation or by coupling with cuprate reagents. 173 Deprotection of the hydroxygroup and desilylation with anhydrous potassium fluoride in DMSO at 150°C then leads to the corresponding (E)-allylic alcohols (113). SiMe3

THPO d

B

r

THPO

(112)

HO(113 1 ) 99

(

’ R E 1 - isomer

Reagents: i, BusLi, R1; ii, R(PhS)CuLi; iii, HCl; iv, KF

Kumada and his co-workers have shown that the Grignard reagent (1 14) , which is readily available and reasonably stable at room temperature, can be used The reagent cross-couples regio- and stereoas a synthon for ‘HOCH2-7.174 171

s. Yamamoto, H. Itani, T. Tsuji, and W. Nagata, J . Am. Chem. Soc., 1983, 105,2908.

K. Jitsukawa, K. Kaneda, and S. Teranishi, J . Org. Chem., 1983,48,389. R. B. Miller and M. I. Al-Hassan, Tetrahedron Lett., 1983,24.2055. 174 K. Tamao, N. Ishida, and M. Kumada, J . Org. Chem., 1983,48, 2120. 173

48

General and Synthetic Methods

specifically with vinyl and allylic halides in the presence of copper, nickel, or palladium catalysts to give silanes which can be transformed into allylic or homoallylic alcohols by oxidation (e.g. Scheme 82).

-

SiMe( PriO)2

i

w13Jr

+cl

iii

II

C6H13

CgH1

. )

Reagents: i, (PriO),MeSiCH,MgC1 (114), [NiCl,(dppp)]; ii, H202;iii, (114) CuI

Scheme 82

4-Chloro-2-lithiobut-1-ene (115) is generated by treatment of the corresponding 2-trimethylstannyl compound with methyl-lithum at -78 0C.175 Addition to aldehydes and ketones takes place smoothly to give either allylic alcohols (116) or the products of cyclization (117). Vinyl and aryl bromides and iodides undergo

dC',/"

(116)

yI

i

I

Li

MegSn

(115)

R'% R2

(117)

Reagents: i, MeLi; ii, RlR*CO; iii, R1R2C0,HMPA; iv, KH

addition to aldehydes to furnish allylic or benzylic alcohols on treatment with chromium(I1) ch10ride.l~~ Ketones and nitriles are inert under these conditions (e.g. Scheme 83).

A

C

H I

O

=

L

O

H

Scheme 83 175

E. Piers and V. Karunaratne, J . Org. Chem., 1983,48, 1774. Takai, K. Kimura, T. Kuroda, T. Hiyama, and H. Nozaki, Tetrahedron Lett., 1983, 24, 5281.

176 K.

Saturated and Unsaturated Hydrocarbons

49

Pattenden and Robertson have reported that , on electrochemical reduction, the terminal allenic ketones (118) and (119) cyclize via the exo-mode to give the tertiary allylic or homoallylic alcohols (120) or (121) respectively. 177

4

H (120)

n =2

n =1

(118) n =1 (119) n = 2

H (121)

A novel olefin cyclization, promoted by a Beckmann rearrangement of oxime sulphonates, leads to a,@-unsaturated imines. An example is shown in Scheme 84.178In principle, cyclization can result in the formation of four isomeric pro-

ducts. However, molecular constraints, including those arising from the usual stereospecificity of the Beckmann rearrangement, lead to single products in the examples reported. Importantly, the oxime sulphonates, prepared by direct mesylation of the corresponding oximes, do not undergo stereomutation under the mild reaction conditions. Overman and his co-workers have reported that ( E ) - or (2)-vinylsilanes of the type (122) cyclize cleanly and with complete regiochemical control on heating with aldehydes under acidic conditions to afford 172,5,6-tetrahydropyridines (123). The method is particularly useful for the synthesis of N-aryl-tetra-

Me3si7 HY R ~ C H O t. i +

R2

(122)

I

(123)

hydropyridines (123; R1 = aryl), which are generally not available from pyridine precursors. 179 17*

G. Pattenden and G. M. Robertson, Tetrahedron Lett., 1983,24,4617. S. Sakane, Y. Matsumura, Y. Yamamura, Y. Ishida, K. Maruoka, and H. Yamamoto,J. Am. Chem. SOC., 1983, 105, 672. L. E. Overman, T. C. Malone, and G . P. Meier, J . Am. Chem. SOC., 1983,105,6993.

50

General and Synthetic Methods

y-Allenic amines cyclize to (E)-2-alkenyl-pyrrolidines on treatment with either silver nitrate, or mercury(I1) chloride followed by NaBH,. 6-Allenic amines give the corresponding piperidines under the same conditions (Scheme 85).lS0

I

n = l or2

R’

Reagents: i, AgNO,; ii, HgCl,; iii, NaBH,

Scheme 85

The first intramolecular ene reactions of unsaturated imines have been described by Fowler and his co-workers.lS1For example, the alkenyl-pyrrolidine (124) was obtained in quantitative yield by flash pyrolysis of the hydroxamic acid derivative (125). Cavalla and Warren have shown that substituted allylic amides

0OC02Me

-

Lo,,, (125)

- &,

0QH-

0

Lo,,,

L 0 2 E t (124)

can be prepared with full regio- and stereo-chemical control from the dianions of 3-(acy1amino)alkylphosphine oxides via the Horner-Wittig reaction. lg2 Allylic acetates are converted into the corresponding allylsilanes on treatment with tris(trimethylsily1)aluminium in the presence of transition-metal catalysts.183 Nakamura and his co-workers have shown that highly regioselective acylation of isoprene can be effected via the zirconium complex (126).lg4 Reaction with both saturated and unsaturated esters occurs selectively at the more hindered C-1 position to give intermediate complexes (127) which decompose on treatment with acid to give P,y-unsaturated ketones of the type (128).

Reagents: i, RICO,RZ;ii, AcOH 180 S.

Arseniyadis and J. Gore, Tetrahedron Lett., 1983,24, 3997. K. Koch, J.-M. Lin, and F. W. Fowler, Tetrahedron Lett., 1983,24, 1581. D. Cavalla and S. Warren, Tetrahedron Lett., 1983, 24,295. la3 B. M. Trost, J. Yoshida, and M. Lautens, J . Am. Chem. Soc., 1983,105, 4494. lMM. Akita, H. Yasuda, and A . Nakamura, Chem. Lett., 1983,217.

181

Saturated and Unsaturated Hydrocarbons

51

Treatment of 3-phenylsulphonylcyclobutanolsof the type (129) with n-butyllithium, sodium hydride, or potassium t-butoxide leads exclusively to the /3,yunsaturated ketones (130). By contrast, significant amounts of the /3-methylene ketones (131) are obtained when an excess of potassium hydride is used.185

Tin enolates, generated in situ by treatment of enol acetates with tri-n-butyltin methoxide, react regio- and stereo-specifically with vinyl bromides in the presence of catalytic amounts of [PdCI2(PAr&] (Ar = 2-tolyl) to form @,y-unsaturated ketones (e.g. Scheme 86).186The reaction is sensitive to steric hindrance and works well only for enol acetates derived from methyl ketones.

Reagents: i, Bun,SnOMe; ii,

Scheme 86

2-Bromo-2-enones are converted into p7y-unsaturated ketones on treatment with diethyl phosphite and triethylamine, but the products are contaminated with small amounts of the corresponding conjugated species (e.g. Scheme 87).187

96:4 Scheme 87

Acyclic substrates selectively afford p, y-unsaturated ketones with the ( E ) configuration. 0-Silyl ester enolates react with P-chlorosulphides in the presence of catalytic amounts of zinc bromide to give, after oxidative elimination, /3, y-unsaturated T. Takeda, K. Ando, and T. Fujiwara, Chem. Lett., 1983,1285. M. Kosugi, I. Hagiwara, and T. Migita, Chem. Lett., 1983, 839. lB7 T. Hirao, T. Masunaga, K. Hayashi, Y. Ohshiro, and T. Agawa, Tetrahedron Lett., 1983,24,399. lS6

3

52

General and Synthetic Methods

esters.lS8Some examples, such as that shown in Scheme 88, proceed with impressive selectivity.

Reagents: i, PhSCl; ii,

-

C02Me

C02Me

-0Me

, ZnBr,; iii, NaIO,; iv. A

OSiMe;

Scheme 88

The difluoroallylsilane (132) , readily prepared from 3,3,3-trifluoropropene7 undergoes base-induced addition to carbonyl compounds exclusively from the y-position (Scheme 89).lS9

cF31 ' \\ F y

S i M e 2 P h

~

ii

___)

.'& F

F

F

(132) Reagents: i, Me3SiSiMe,Ph, BunsN+F-; ii, R1R2C0,KOBut

Scheme 89

High enantioselectivity (>95%) is observed in the reaction between (R)3-phenyl-3-(trimethylsilyl)propene (133) and hindered aldehydes (ButCHO,

H

(133)

Pr'CHO , but not MeCHO) at low temperatures in the presence of TiC14.As well as having high optical purity, the resulting homoallylic alcohols have exclusively the (E)-configuration.lW Lewis acid-catalysed allylation of the chiral acetals (134) takes place with high (>96 :4) diastereoselectivity . Successive oxidation and base-catalysed p-elimination then furnishes homoallylic alcohols with greater than 90% enantiomeric S. K. Pate1 and I. Paterson, Tetrahedron Lett., 1983,24, 1315. Hiyama, M. Obayashi, and M. Sawahata, Tetrahedron Lett., 1983, 24,4113. 190 T. Hayashi, M. Konishi, and M. Kumada, J. Org. Chem., 1983,48,281. 188

189 T.

Saturated and Unsaturated Hydrocarbons

53

excess (Scheme 9O).l9l The synthesis of both (R)- and (S)-alcohols is possible using this procedure, since (R,R)-and (S,S)-forms of the acetals are both readily available. Allylic chromium species, complexed with chiral bidentate auxiliaries R

R

H

ii , iii

(134) Reagents: i, CH,=CHCH,SiMe,,

TiCl,, Ti(PrlO),; ii, PCC; iii, KOH

Scheme 90

such as lithium ephedrinate, react with aldehydes to give optically active homoallylic alcohols with modest enantiomeric excesses. 19* The borane (135), which is easily prepared in an optically pure form from (+)-a-pinene, readily condenses with aldehydes at -78°C to provide, after oxidative work-up, optically active secondary homoallylic alcohols with excellent enantiomeric purities (Scheme 91)

I

(135 1

R

Reagents: i, RCHO; ii, NaOH, H,02

Scheme 91

Bulky allylboronates of the type (136) bearing polar heteroatomic substituents at the a-position react with aldehydes to give substituted allylic alcohols with predominantly the (Z)-configuration.194

Y

pii<

B

-

0

X

(136) X = CL , Br, SEt, SBu', or OMe

X )/80°/0(2)-isomer

Yamamoto and his co-workers have shown that aldehydes and ketones react with crotylmagnesium chloride in the presence of A1C13 to afford mainly P. A . Bartlett, W. S. Johnson, and J. D. Elliott, J . Am. Chem. Soc., 1983,105,2088. B. Cazes, C. Verniihe, and J. Gort, Synth. Commun., 1983, 13,73. 193 H. C. Brown and P. K. Jadhav, J . Am. Chem. SOC., 1983, 105,2092. 194 R. W. Hoffmann and B. Landmann, Tetrahedron Lett., 1983,24,3209.

191 192

General and Synthetic Methods

54

a-adducts (e.g. Scheme 92), whereas the use of other Lewis acids such as TiC14, SnC14,or SnClzleadsto the y-adducts exclusively.195The same research group has

\

+ wMgCl

+

&

87 : 13

(€):(Z)=7 8 1 2 2

erythro : t h m = 1:l

Scheme 92

published related work with but-2-eny1tributyl~tannane.l~~ Furthermore, allylstannanes, when subjected to high pressures, react at room temperature with aldehydes to give homoallylic alcohols (Scheme 93). 197 Allylsilanes are inert under these neutral conditions.

+

R

ArCHO Scheme 93

A reductive rearrangement which transforms alkynyl halohydrins such as (137) into (E)-homoallylic alcohols (138) takes place at ambient temperature on treatment with LiAlH4 or DIBAL.198

(yl

I_ CI (137)

Reagents: i, MeC=CLi;

-0 (138)

ii, LiA1H4,NaOMe

Itoh and his co-workers have described the allylation of a variety of cyclic P-bromo-ethers with allylsilanes and AgBF4.199Under the reaction conditions, a carbonium ion is produced which can either react directly or, following an intramolecular hydride shift, indirectly with the allylsilane to give a mixture of allylated products. In the case of tetrahydropyranyl derivatives such as (139), however, products (140) , resulting from rearrangement, are formed exclusively.

Yamamoto and K. Maruyama, J. Org. Chem., 1983,48, 1564. Yamamoto, N. Maeda, and K. Maruyama, J . Chem. SOC.,Chem. Commun., 1983,742. lW Y. Yamamoto, K. Maruyama, and K. Matsumoto, J. Chem. SOC.,Chem. Commun., 1983,489. 19* P. A. Wender, D. A. Holt, and S. M. Sieburth, J. Am. Chem. SOC., 1983,105, 3348. 1wH. Nishiyama, T. Naritomi, K. Sakuta, and K. Itoh, J . Org. Chem., 1983,48, 1557. 195 Y.

196 Y.

Saturated and Unsaturated Hydrocarbons

55

Allylsilanes also react with both cyclic and acyclic a-chloro-ethers in the presence of catalytic amounts of either trimethylsilyl iodide or triflate to give good yields of homoallylic ethers (e.g. Scheme 94).200

Scheme 94

Stereospecific routes to homoallylic amine derivatives201and unsaturated vicamino-alcohols202have been developed by Weinreb and his co-workers. The new methodology allows complete control of both relative configuration and doublebond geometry, as illustrated by the synthesis of threo-sphingosine (141) in Scheme 95.

ii -iv

I

Reagents: i, SOCl,, py; ii, PhMgBr; iii, P(OMe),; iv, Ba(OH),

Scheme 95

On treatment with LDA, acyclic allylic glycolates such as (142) undergo enolate Claisen rearrangement to give functionalized homoallylic ethers (143) Substrates with (E)- or (2)-geometry give high syn- or anti-stereoselectivity respectively.203The homoallylic ether (143) was converted in four steps into (f)-thre0-4-methylheptan-3-01 (144) , an aggregation pheromone of the European elm bark beetle.

A

-

Reagents: i, LDA; ii, Me,SiCl; iii, MeOH; iv, CH2N, *O0 H.

Sakurai, Y. Sakata, and A. Hosomi, Chem. Lett., 1983,409. R. S. Garigipati, J. A. Morton, and S. M. Weinreb, Tetrahedron Lett., 1983,24, 987. 202 R. S. Garigipati and S. M. Weinreb, J . Am. Chem. Soc., 1983, 105, 4499. 203 J. Kallmerten and T. J. Gould, Tetrahedron Lett., 1983, 24, 5177. 201

General and Synthetic Methods

56

3-(Allyloxy)acrylic acids such as (145) undergo Claisen rearrangement to give y, &unsaturated aldehydes directly, since thz a-formyl acids which are formed

initially decarboxylate under the pyrolysis conditions. The importance of this new modification is that the precursors are easily prepared by addition of a wide variety of primary or secondary (though not tertiary) allylic alkoxides to the betaine (146).,04

roN (145)

Hexa-l,5-dien-3-ols undergo smooth oxy-Cope rearrangement at room temperature in the presence of [PdCl,(PhCN),] provided they are substituted at the 3and 5 - p o ~ i t i o n sThe . ~ ~ example ~ shown in Scheme 96 gives a quantitative yield of the unsaturated ketone.

HO

Scheme 96

The allylic carbanionic species generated from allyltrimethylsilane and fluoride ion undergoes exclusive 1,4-addition to a$-unsaturated esters, nitriles and tertiary carboxamides (e.g. Scheme 97); unsaturated aldehydes, however, give

only products of 1,2-addition, and unsaturated ketones give regioisomeric mixtures.,06 Best results are achieved for non-enolizable substrates using Bun4NFin a 204 205

206

G. Biichi and D. E. Vogel, J . Org. Chem., 1983,48,5406. N. Bluthe, M. Malacria, and J. GorC, Tetrahedron Left., 1983, 24, 1157. G. Majetich, A. M. Casares, D. Chapman, and M. Behnke, Tetrahedron Lett., 1983, 24, 1909.

Saturated and Unsaturated Hydrocarbons

57

mixture of DMF and HMPA. The reaction also works well in an intramolecular sense, in which case it leads to five-membered rings (e.g. Scheme 98).207 H

H

H Scheme 98

Simple cyclic a-silyloxyhydroperoxides such as (147) ring-open on treatment with iron(I1) sulphate and copper(I1) acetate to give o-olefinic carboxylic acids (44-77% yields) .208 HOO OSi But Me2

OSiBut Me2

I

0 -0 (147)

Reagents: i, H202,TFA; ii, FeSO,. Cu(OAc),

--

II

C02H

Olefinic nitriles of the formula CH2=CH2(CH2),CN (n=2, 3, 4, or 5 ) undergo self-metathesis with high conversions in the presence of the catalyst Re207-A1203activated with a small amount of tetramethyl- or tetraethyl-tin. Efficient co-metathesis between these nitriles and symmetrical olefins can also be performed under the same conditions.209 3 Conjugated 1,3-Dienes

( E ,E)-2-Phenylsulphonyl-1,3-dienes such as (14q2loare reduced to ( E ,Z)-1,3dienes (149) on treatment with n-butylmagnesium chloride in the presence of palladium or nickel catalysts, but yields are only moderate (35-51%).’11

P d -SOzPh

(148) Reagents: i, Bu”MgC1, [Ni(acac),], Bun,P

(149) 97 ‘/o ( E , Z

)

- isomer

Lithium chloride-copper(I1) chloride ( 2 : 1)is the catalyst of choice for preparing 2-substituted buta-1 ,3-dienes by cross-coupling buta-l,3-dien-2-ylmagnesium G. Majetich, R. Desmond, and A. M. Casares, Tetrahedron Lett., 1983,24, 1913. I. Saito. R. Nagata, K. Yuba, and T. Matsuura, Tetrahedron Lett., 1983, 24,4439. 209 G. C. N. van den Aardweg, K. H. A, Bosma, and J. C. Mol, J. Chem. SOC., Chem. Commun., 1983, 262. T. Cuvigny, C. HervC du Penhoat, and M. Julia, Tetrahedron Letr., 1983, 24, 4315. 211 T. Cuvigny, J.-L. Fabre, C. HervC du Penhoat, and M. Julia, Tetrahedron Left., 1983,24,4319. Also see reference 41.

zu7

208

58

General and Synthetic Methods

chloride with alkyl bromides or iodides.212Aryl iodides also react under these conditions but they do so more slowly, and substrates containing both alkyl and aryl iodine atoms couple specifically at the alkyl centre (e.g. Scheme 99). A useful

CLMg

Scheme 99

complementary catalyst which directs coupling towards the aromatic centre is [Pd(PPh,),]. Grignard reagents derived from phenyl, benzyl, or primary alkyl halides cross-couple with alka-l,3-dien-2-y1 phosphates in the presence of nickel(11) catalysts to give 1,3-dienes (e.g. Scheme 0

0““II

OP(0Et 12

MeMgCl

[ NiCI2(dppe)l

Scheme 100

Jabri, Alexakis, and Normant have published a detailed account of their stereospecific synthesis of 1,3-dienes by cross-coupling (2)-alkenyl-zinc bromides with alkenyl iodides in the presence of palladium catalysts.’14 The zinc species are prepared in situ from (2)-dialkenyl-cuprates , though unfortunately this procedure allows only one of the two alkenyl groups of the cuprate to be utilized. Scheme 101 shows a striking example of the complementary discriminating

Reagents: i, ZnBr2, [Pd(PPh,),]; ii, HMPA

Scheme 101

abilities of the zinc and cuprate species towards different types of iodide. The same research group has shown that alkenyl-copper reagents associated with S. Nunomoto, Y. Kawakami, and Y. Yamashita, J . Org. Chem., 1983,48, 1912. C. Sahlberg, A. Quader, and A . Claesson, Tetrahedron Lett., 1983, 24, 5137. 214 N. Jabri, A. Alexakis, and J. F. Normant, Bull. SOC. Chim. Fr., 1983, 11-321. 212

213

59

Saturated and Unsaturated Hydrocarbons

magnesium salts also couple with alkenyl iodides to give conjugated dienes of extremely high stereochemical purity (e.g. Scheme 102).*15 This coupling is par-

EtMgBr

-+

111

Cu .Mg Brz

i*ii

-3...

9 9 . 8 % ( I , Z 1 - isomer Reagents: i, CuBr; ii, MeC=CH;

iii,

[Pd(PPh3)4l

Scheme 102

ticularly suited to 1,3-dienes which are heavily substituted at the 1- and 4-positions. Furthermore, both alkenyl groups of a (2)-dialkenyl-cuprate may be utilized for coupling by transmetallation to mixtures of zinc and magnesium species. (E)-Alk-1-enyl-boronic acids cross-couple with ( E ) - or (2)-alkenyl iodides in the presence of catalytic amounts of [Pd(PPh&] in aqueous sodium hydroxide, the resulting (E,E)- or (E,2)-1,3-dienes retaining the geometry of both reactants (e.g. Scheme 103).*16Aryl, benzyl, and ally1 halides are also suitable substrates.

-

I

Me(CH217

99Ol0(Z,€ )-isomer

Reagents: i, [Pd(PPhJ4], NaOH

Scheme 103

The required boronic acids, which are often stable crystalline solids, are readily prepared by hydroboration of 1-alkynes. The dispersed metallic nickel formed by reduction of nickel(I1) chloride with zinc powder in the presence of potassium iodide and/or thiourea catalyses the homocoupling of vinyl bromides and iodides to give 173-dienes. However, stereomutation of at least one fragment occurs (e.g. Scheme 104).217

Reagents: i, NiCl,, Zn, KI

Scheme 104 N. Jabri, A. Alexakis, and J. F. Normant, Bull. SOC. Chim. Fr., 1983, 11-332. i16 G . Cassani, P. Massardo, and P . Piccardi, Tetrahedron Lett., 1983,24, 2513. *I7 K. Takagi and N. Hayama, Chem. Lett., 1983,637. *I5

60

General and Synthetic Methods

The titanium reagent generated by treatment of lithiated allyldiphenylphosphine with Ti(Pri0)4reacts with aldehydes to give a-erythro-adducts (150) almost exclusively; these collapse to (2)-1,3-dienes (151) on treatment in

S (151) &93"lo(Z)-isomer Reagents: i, Bu'Li; ii, Ti(OPri),; iii, RCHO; iv, Me1

situ with methyl iodide.218The corresponding (@-isomers [(E) : (Z)>9 : 11 are easily prepared by conventional Horner reactions with aldehydes and lithiated allyldipheny lphosphine oxide. Block and his co-workers have reported that under basic conditions the products of the free-radical addition of bromomethanesulphonyl bromide to olefins undergo both elimination of hydrogen bromide and Ramberg-Backlund reaction to give 1,3-dienes (e.g. Scheme 105).*19A variety of dienes, including types which Br

(R

= n - C 5H11)

I

Br

99

(€

- isomer

Reagents: i, BrCH,SO,Br, hv; ii, Et,N; iii, KOBu'

Scheme 105

are not readily accessible by other routes, may be prepared from appropriate olefins, often with a high degree of stereocontrol. Scheme 106 illustrates some of the transformations that can be performed. trans-2,5-Disubstituted-3-sulpholenes such as (152) can be prepared by regiospecific and stereoselective dialkylation of 3-sulpholene provided the labile anionic species are generated in the presence of an alkyl iodide so that they are trapped before undergoing ring-opening. The products can be converted either *18

219

J. Ukai, Y. Ikeda, N . Ikeda, and H. Yamamoto, Tetrahedron Lett., 1983,24,4029. E. Block and M. Aslam, J. Am. Chem. Soc., 1983, 105, 6164; E. Block, M. Aslam. V. Eswarakrishnan, and A. Wall, ibid., p. 6165.

Saturated and Unsaturated Hydrocarbons

61

56%

(3-

Scheme 106

G

into ( E ,E)-dienes by heating with a base in a protic solvent, or into mixtures of the two possible (E,2)-dienes by reductive desulphonylation (e.g. Scheme 107).220 -(CH2)6Me

0

--( CH2)6Me

i,ii,i,L

502

502 (152) (+11'/0

T ( C H 2 ) g M e

\

+

cis-isomer)

r /

(CH2I6Me

Reagents: i, LiN(SiMe,),; ii, Me(CH&I; iii, MeI; iv, K,CO,, EtOH; v, LiAlH,

Scheme 107

Derivatives of vitamin D3 have been prepared using methodology of this kind.221 Scheme 108 illustrates a related synthesis of (E,E)-1,3-dienes in which a high degree of stereocontrol originates from selective alkylation at the less hindered

(153)

(CH2)70H

96 - 3'10 ( Z, E - i so mer

r

liv

1

f--

- so2

Reagents: i, BunLi; ii, I(CH2),0THP; iii, TsOH; iv, 600 "C,

CCI.

50 ms

Scheme 108 220 221

S. Yamada, H. Ohsawa, T. Suzuki, and H. Takayama, Chem. Left., 1983, 1003. S. Yamada, T. Suzuki, H. Takayama, K. Miyamoto, I. Matsunaga. and Y. Nawata, J. Org. Chem., 1983, 48, 3483.

62

General and Synthetic Methods

face of the Diels-Alder adduct (153).222The product in the example shown, (E,E)-dodeca-8,10-dieno17is a pheromone from the codling moth. If trimethylsilyl chloride 222 or ketones or aldehydes 223 are used as electrophiles in place of alkyl iodides, thermolysis gives l-trimethylsilyl-173-dienes or 2,4-dien1-01s respectively. Scheme 109 shows an example of a novel regiospecific pentannulation sequence .224 In an intermolecular variant of this process, cyclododecanone SOZPh

rn

KOH,

KOH,

a

Scheme 109

reacts with methyl phenyl sulphone and potassium t-butoxide to give (E)3-methylenecyclododecene . Reaction between a$-unsaturated aldehydes or ketones and an organocopper reagent derived from buta-173-dien-2-ylmagnesium chloride is regiospecific with respect to both reactants: only 173-dienes derived from 174-addition are formed.225Both examples shown in Scheme 110 gave isolated yields of greater

Reagents: i

,

y , CuBr.Me,S MgCl

Scheme 110

than 80%. p-Quinones and a,/?-unsaturated aldehydes and ketones undergo pentadienylation without competing Diels-Alder reaction on treatment with penta-2,4-dienyltrimethylstannaneand a Lewis acid (e.g. Scheme 111).226

Reagents: i. , ,

SnMe,, Lewis acid

Scheme 111 222 223 224 22s

226

R. Bloch and J. Abecassis, Tetrahedron Lett., 1983, 24, 1247. R. Bloch, D. Hassan, and X. Mandard, Tetrahedron Lett., 1983,24,4691. C. Fehr, Helv. Chim. Acia, 1983, 66,2519. K. J. Shea and P. Q. Pham, Tetrahedron Lett., 1983,24,1003. Y. Naruta, N. Nagai, Y. Arita, and K. Maruyama, Chem. Lett., 1983, 1683.

Saturated and Unsaturated Hydrocarbons

63

Corey and Albright have described a new procedure for the homologation of sensitive aldehydes to ( E ,E)-2,4-dienals containing four extra carbon atoms.*17 On treatment with [Mo(CO),] and bis(trimethylsilyl)acetamide, allylic acetates smoothly eliminate the elements of acetic acid to give 1,3-dienes, generally as regio- and stereo-isomeric mixtures where possible. The transformation is most useful where elimination can take place in only one direction (e.g. Scheme 112).228

iii

A

C

0

2

M

e

w

C (

0

2

M

e

f , € ):(f,Z1 = 5: 1

Reagents: i, 4-C1C,H,S(0)CH,COzMe, piperidine; ii, Ac,O, DMAP; iii, [Mo(CO),], BSA

Scheme 112

The reagent (154), prepared by addition of diethyl trimethylsilyl phosphite to acrylonitrile undergoes successive Peterson and Wittig reactions with aidehydes or ketones in one pot to give 2-cyanobuta-1,3-dienes (e.g. Scheme 113).l19

2 isomers, 94:6

(154) Reagents: i, 2LDA; ii, 2Me,CHCHO

Scheme 113

Substituted methoxyallenes (155), which are easily prepared from methoxyallene itself isomerize to the corresponding methoxy-l,3-dienes (156) on treatment with pyridinium tol~ene-4-sulphonate.~~~ OMe

+ 111 R

&-, R

(155)

(156) > 8 3 % ( €)-isomer

Reagents: i, Bu"Li; ii, RCH,X (X=Br or I); iii, TsOH.py

E. J. Corey and J. 0. Albright, J . Org. Chem., 1983,48,2114. B. M. Trost, M. Lautens, and B. Peterson, Tetrahedron Lett., 1983,24,4525. 229 M. Nakano and Y . Okamoto, Synthesis, 1983,917. 230 A. Kucerovy, K. Neuenschwander, and S. M. Weinreb, Synth. Commun., 1983,13, 875.

227

228

64

General and Synthetic Methods

A variety of 1,3-dienes which are substituted with halogens and sulphur or selenium can be prepared regiospecifically from 1,4-dichlorobut-2-yne by addition-elimination sequences such as those shown in Scheme 114.231 SPh

1

I

cL

\

SPh

Cl Reagents: i, PhSC1; ii, Al/Hg; iii, DBU

Scheme 114

Buta-l,3-diene-l,4-bis-sulphonium 232 and -phosphonium 233 salts, as well as the stable and crystalline 1,3-dienes (157),234have been prepared for the first time.

(157) n = O , l , o r 2 ; R = C H z P h or But

Convenient syntheses of the alkylidenebutenolides (158) and (159) ,235 and new ~ ~ a,P-unsaturated ~ ketene approaches to a variety of 1,3-dienyl ~ u l p h i d e sand diphenylthioacetals 237 have been reported. A (Z,Z)-1,3-diene has been purified for the first time by urea inclusion.238 R

Do

(158) R = M e or Ph

(159) n = 3,4,5,or9

A. J. Bridges and J. W. Fischer, Tetrahedron Lett., 1983, 24, 445. P. J. Duggan. J. L. Leng, D. R. Marshall, and C. J. M. Stirling,J. Chem. Sac., Perkin Trans.1,1983, 933. 233 H.-J. Cristau, G. Duc, and H. Christol, Synthesis, 1983, 374. 234 L. E. Overman, C. B. Petty, T. Ban, and G. T. Huang, J . Am. Chem. SOC., 1983,105,6335. 235 R. W. Saalfrank, P. Schierling, and P. Schatzlein, Chem. Ber., 1983,116, 1463; R. W. Saalfrank, P. Schierling, and W. Hafner, ibid., p. 3482. 236 K. S. Kyler and D. S. Watt, J . Am. Chem. Soc., 1983, 105, 619; T. Nishio, T. Tokunaga, and Y. Omote, Chem. Ind. (London), 1983, 243; R. H. Everhardus, R. Grafing, and L. Brandsma, Synthesis, 1983, 623; M. Reglier, 0. Ruel, R. Lome, and S. A. Julia, ibid., p. 624. 237 0. G . Kulinkovich, I. G. Tishchenko, N. A . Roslik, and I. V. Reznikov, Synthesis, 1983, 383. 238 C. E. Bishop and G. W. Morrow, J . Org. Chem., 1983,48, 657.

231 232

Saturated and Unsaturated Hydrocarbons

65

4 Non-conjugated Dienes

Shea and his co-workers have reported that bridgehead divinylbicycloalkanes undergo spontaneous [3,3]-sigmatropic rearrangement at or below room temperature to give bridgehead dienes such as (160) with (E,E)-geometry with respect to the larger ring.239Another research team has independently prepared the diene (160) via a closely related pathway.240

L

(160) Reagent: i, 2Ph3P= CH,

Negishi and Miller have shown that 1-trimethylsilyloct-1-yne undergoes ;egiospecific allylzincation on treatment with allylzinc bromide. The products, after iodinolysis, are two stereoisomeric 1,4-dienes which can be converted into substituted cyclopentenones (Scheme 115).241 Allylzincation of internal SiMe3 1

Reagents: i, CH,=CHCH2ZnBr; ii, I,; iii, disiamylborane; iv, NaOH, H,Oz; v, CrO,; vi, MeLi; vii, 2Bu'Li; viii, CO, Et,N, 1 equiv. [Pd(PPh,),]

Scheme 115

acetylenes is more difficult, but takes place on treatment with diallylzinc in the presence of a zirconium catalyst. When allylic alkoxides are heated with the reagent (161)) successive displacement of fluoride ion, sigmatropic rearrangement, and dehydrosulphenylation take place to give good yields of 2-methoxycarbonyl-l,6dienes contaminated K. J. Shea, A. C. Greeley, S. Nguyen, P. D. Beauchamp, and S. Wise, Tetrahedron Lett., 1983,24, 4173. 240 P. Warner, I-Shan Chu, and W. Boulanger, Tetrahedron Lett., 1983, 24, 4165. 241 E. Negishi and J. A . Miller, J . Am. Chem. SOC., 1983, 105, 6761.

239

66

General and Synthetic Methods

with less than 12% of the isomeric conjugated dienes (e.g. Scheme 116).242 The reagent (161) is prepared in five steps from 1,l,l-trifluoroacetone.

d-"" '6 KH

Me0

9: 1

SOPh

(1611

Scheme 116

Despite earlier suggestions to the contrary, neat mixtures of alk-2-ynol chlorides and cyclopentadiene undergo clean Diels-Alder cycloaddition at 0 "Cto give, after methanolysis, methyl norbornadiene-2-carboxylates (78434%) (Scheme 117).243

C02Me

R = M e , Ph, or But Reagents: i, Cyclopentadiene; ii, MeOH, NaHCO,

Scheme 117

Pentadienylboranes, generated in situ from pentadienyl anions, react at the 3-position with aldehydes and ketones to give non-conjugated products exclusively (Scheme 118).244

OH

Reagents: i, BunLi; ii, BunLi, KOBu'; iii, Ph,BBr; iv, R'R2CO; v, NaOH

Scheme 118 J.-M. Vatele, Tetrahedron Lett., 1983, 24, 1239. E. Bauml and H. Mayr, J. Org. Chem., 1983,48,2600. 244 M. G . Hutchings, W. E. Paget, and K. Smith, J. Chem. Res. (S), 1983, 31. 242 243

67

Saturated and Unsaturated Hydrocarbons

Cutting and Parsons have reported five examples of a new silicon-mediated rearrangement of epoxides (Scheme 119).245Catalysis by Lewis acids other than tin(I1) chloride fails. R' SnClb

R2 *OH

R2

26

-L 5 %

R1,R2 = H or alkyl

Scheme 119

Allylic chlorides and bromides undergo reductive coupling at room temperature on treatment with stoicheiometric amounts of [CoCl(PPh,),] .246 Although mixtures of regioisomeric 1,5-dienes are formed, the geometry of the allylic double bond is preserved during coupling (e.g. Scheme 120).

R

R

R

63 '10

R=

L

.

16 '10

+

0

9O I O Reagent: i, [CoCl(PPh,),]

Scheme 120

On treatment with TiC14, vinylketene methyl silyl acetals undergo homocoupling to give high yields of 1,5-dienes, probably via bis-allylic dititanium complexes.247With favourable substitution patterns, the product of y, y-coupling, which always predominates, is formed almost exclusively (e.g. Scheme 121). OSiMe3

I

+

M e 0 2 C A 7 p C02Me

96:4 Scheme 121 I. Cutting and P. J. Parsons, J . Chem. Soc., Chem. Commun., 1983, 1435. D. Momose, K. Iguchi. T. Sugiyama, and Y. Yamada, Tetrahedron Lett., 1983, 24, 921. 247 K. Hirai and 1. Ojima, Tetrahedron Lett., 1983, 24, 785. 24s

246

68

General and Synthetic Methods

Overman and Renaldo have shown that 2-alkyl-1,S-dienes with an electronwithdrawing group at the 3-position (162) reliably undergo Cope rearrangement (64-94% yields) at only 40°C under the influence of palladium(iI) catalysts.248By contrast, under similar reaction conditions, 5-alkyl-l,5-dienes with an electronwithdrawing group at the 3-position (163) undergo a novel rearrangement to give moderate yields (21-53%) of cyclohexenes ( 164).249

Ee R

c a t . [ Pd CI 2( MeCN 12 1

(162)

R

R (163) R = a l k y L ; E = C 0 2 R , C O R , o r CN

(164)

The functionalized dienes (165) dimerize regio- and stereo-specifically to give cyclo-octadienes (166) in the presence of nickel(0) catalysts.*jO [ N i ( a c a c 1 2 1 . EtZAIOEt,PPh3

-

-X X = C02Me or OSiMe3

1

mx I

or “i(cod121

(165)

(166)

[2,3 :5,6]Dicyclobuta-p-benzoquinone(167), a crystalline solid, is the most strained annelated p-benzoquinone to have been made so far.251(E,E)-Cycloundeca-l,5-diene (168), a distillable liquid, has been prepared for the first time,252

(167)

(168)

and evidence for the transient existence of ( E ,E)-cyclonona-l,5-diene has been presented. 2s3 L. E. Overman and A. F. Renaldo, Tetrahedron Lett., 1983,24,3757. L. E. Overman and A. F. Renaldo, Tetrahedron Lett., 1983, 24,2235. 250 P. Brun, A. Tenaglia, and B. Waegell, Tetrahedron Lett., 1983,24, 385. 251 Y . Kanao, M. Iyoda, and M. Oda, Tetrahedron Lett., 1983, 24, 1727. 252 G. Haufe, Synthesis, 1983, 235. 253 A. C . Connell and G. H. Whitham, J . Chem. SOC., Perkin Trans. I, 1983, 995.

248

249

Saturated and Unsaturated Hydrocarbons

69

5 Allenic Hydrocarbons Buchwald and Grubbs have described an experimentally simple approach to di-, tri-, and tetra-substituted allenes.254In the example shown in Scheme 122, treatment of the titanacyclobutane (169) with 1,l-diphenylallene (170) leads to the metallacycle (17 1) in quantitative yield; subsequent reaction with cyclopentanone affords the allene (172).

3
C p2Ti

(169 1 R = M e or Pr'

a

CpZTi

II

A

Ph

0

Ph

Ph

Ph

II

Q A

Ph

Ph

(170)

Scheme 122

1,3-Dien-2-01 phosphates such as (173) react with Grignard reagents in the presence of catalytic amounts of copper(1) salts to give allenes (174) contaminated with only small quantities of the dienes (175).2ss

(173)

major

minor

R=alkyl or benzyl (174) (175)

Prop-2-ynyl-lithiums of the type (176), which are readily prepared by metallation of the corresponding alk-2-ynes (177) with s-butyl-lithium, react regioselectively with epoxides in the presence of 0.5-1 equivalent of HMPA to give the 1,ldisubstituted allenic alcohols (178). However , on stirring at -75 "C for 2 h with 5 equivalents of HMPA, the prop-2-ynyl-lithiums (176) isomerize to the propadienyl-lithiums (179), which give 1,3-disubstituted allenes such as (180) on treatment with epoxides or alkyl halides.256 On complexation with dimethyl sulphide, dialkylcuprates react with the chiral alkynyl epoxy-alcohol (181) to afford dihydroxyallenes of high optical purity 254

2s5

256

S. L. Buchwald and R. H. Grubbs, 1.Am. Chem. SOC., 1983, 105, 5490. A. Claesson, A . Quader, and C. Sahlberg, Tetrahedron Lett., 1983, 24, 1297. C. Huynh and G. Linstrumelle, J. Chem. SOC., Chem. Commun., 1983, 1133.

70

General and Synthetic Methods Li

RL=-

- - +

R 1 - ~ J

HO

(178)

(176)

(177)

R1

liii iv

L - C 7

LdR

___)

Li (179)

(180)

0

Reagents: i, BusLi; ii,

R2&

.,HMPA (0.5-1

4 '

equiv.); iii, HMPA ( 5 equiv.); iv,

R2

(Scheme 123).257 The sulphide appears to inhibit the previously observed stereomutation of allenes in the presence of organocuprates. R

\C

-

/ /

H

II

H an ti

H (181)

anti : syn = 98: 2 Reagents: i, (-)-DET, Ti(OPri),, Bu'OOH; ii, R,CuLi, Me,S

Scheme 123

Dimethylvinylidenecarbene, generated under phase-transfer conditions, reacts with primary and secondary alcohols to afford mixtures of the propargyl and allenyl derivatives (182) and (183) respectively. However, the carbene reacts with the corresponding lithium alkoxides to give allenylcarbinols (183)

R', R2 = alkyl or aryl

(182)

Reagents: i, HC=CCMe2C1, KOH, BzEt,N+ C1257

A. C. Oehlschlager and E. Czyzewska, Tetrahedron Lett., 1983,24, 5587.

(183)

Saturated and Unsaturated Hydrocarbons

71

exclusively.258With lithium allyloxide, competing addition of the carbene to the allylic bond is observed (Scheme 124).

Reagents: i, Me$=

C= CHBr, LiOBu'

Scheme 124

Although metallated 2-alkynyl ethers normally react with carbonyl compounds to give a-adducts, the lithiated 2-butynyl carbamate (184) reacts predominantly at the y-position to afford the allene (185) as a mixture of diastereomers. Furthermore, the corresponding titanium reagent (186) produces the y-adducts

0 ( 1 8 4 ) M = Li (186) M = T i ( 0 P r ' 13

(185)

exclusively, and as single d i a s t e r e o m e r ~Wang . ~ ~ ~ and his co-workers have shown that the propargylic borane (187) also reacts at the y-position with aldehydes and ketones to give only allenic products (e.g. Scheme 125).260Reactions of the

-

R

. I

Me3Si-=J

-111...

Me3Si-=

<9

Y Pa

(187) R = H (188) R = P r n

SiMe3 ph+cwR OH Reagents: i, Bu'Li: ii, B-MeO-9-BBN; iii, BF,.0Et2; iv, PhCIIO; v, NaOH, H,O,

Scheme 125 T. Harada, Y. Nozaki, and A: Oku, Tetrahedron Lett., 1983, 24, 5665. D. Hoppe and C. Riemenschneider, Angew. Chem., Int. Ed. Engl., 1983, 22, 54. 260 K. K. Wang, S. S. Nikam, and C. D. Ho, J. Org. Chem., 1983,48,5376. 258

259

General and Synthetic Methods

72

substituted derivative (188), however, are much less selective, gwing mixtures of

a- and y-adducts. HO

R2

R'

SPh ( 1 89)

Reagents: i, 2Bu"Li; ii, PhSCl; iii, PhSC1, Et,N; iv, 2PhSC1; v, MeLi

Scheme 126

Cutting and Parsons have described two new approaches to the versatile allenyl sulphoxides (189) (Scheme 126).261 The related allenes (190) can be prepared from propargylic alcohols such as (191) via a [2,3]-sigmatropic rearrangement .262 0

II

SPh

?H

PhSCL, Et3N

SiMe3

(191)

(190)

6 Acetylenic Hydrocarbons

On the basis of labelling and trapping experiments, Gilbert and Baze have postulated that cyclopentyne (192) is formed as a transient intermediate during the base-promoted reaction of cyclobutanone with diethyl (diazomethy1)phosphonate (Scheme 127).263 Bestmann and his co-workers have reported details of a general method for the synthesis of acetylenes via acyl ylides of the type (193) (Scheme 128).264This method is particularly attractive since the ylides (193) are easily constructed from readily available phosphonium salts and carboxylic acid derivatives, and the position of the triple bond in the final product is unambiguous. *6l 262 263

264

I. Cutting and P. J. Parsons, 1. Chem. SOC., Chem. Commun., 1983, 1209. I. Cutting and P. J. Parsons, Tetrahedron Lett., 1983, 24, 4463. J. C. Gilbert and M. E. Baze, J. Am. Chem. SOC., 1983, 105,664. €I.-J. Bestmann, K. Kumar. and W. Schaper, Angew. Chem., Znt. Ed. Engl., 1983, 22, 167.

Saturated and Unsaturated Hydrocarbons

73

Reagents: i, (EtO),POCHN,, base; ii, BunOH; iii,

Scheme 127

Reagents: i, (CF,SO,),O; ii, Na/Hg

Scheme 128

In the presence of TiC14, alkynylsilanes react with a$-unsaturated acyl yields) even when this is unfavourable for steric reasons (e.g. Scheme 129).265 cyanides to give products of 1,4-addition (55--80%

Scheme 129

Lewis acid-catalysed addition of alkynylsilanes to chiral acetals such as (194) proceeds with high diastereoselectivity . Chromatographic separation of the diastereomeric products is straightforward, and these can be converted via oxidation and elimination into optically pure propargylic alcohols (e.g. Scheme 130).266 n-C8H17

. I

Me

-

..

, II

(194) Reagents: i, Me,SiC=CH,

TiCl,; ii, separation; iii, PCC; iv, KOH

Scheme 130 265

A. Jellal, J.-P. Zahra, and M. Santelli, Tetrahedron Lett., 1983, 24, 1395. W. S. Johnson, R. Elliott, and J. D. Elliott, J . Am. Chem. Soc., 1983, 105, 2904.

H

General and Synthetic Methods

74

Yamaguchi and his co-workers have shown that alkynyldifluoroboranes such as (195) ,generated in situ from lithium acetylides and boron trifluoride, react under mild conditions with a variety of electrophiles to give acetylenic products. For example, reactions with e p o x i d e ~or~tertiary ~~ amides2@jgive alcohols (196) or ketones (197) respectively, and lactams react to give adducts which can be reduced to five-, six-,or seven-membered cyclic amines such as (198).269 The same

(196)

Y

i ii

iv

(198)

Po

Reagents: i, Bu"Li; ii, BF,.OEtZ;iii,

; vi, LiAlH,

Me

research group has reported that lithium acetylides react cleanly with oxetanes in the presence of boron trifluoride to give ring-opened acetylenic alcohols (e.g. Scheme 131).270

Reagents: i, BunLi; ii,

0

, BF3

Scheme 131

Trimethylsilylacetylene cross-couples with halogenated nitrogen heterocycles in the presence of catalytic amounts of both copper(1) iodide and [Pd(PPh&C12] (e.g. Scheme 132).271 M. Yamaguchi and I. Hirao, Tetrahedron Lett., 1983, 24, 391. M. Yarnaguchi, T. Waseda, and I. Hirao, Chern. Lett., 1983,35. 269 M. Yamaguchi and I. Hirao, Tetrahedron Lett., 1983,24, 1719. 270 M. Yarnaguchi, Y. Nobayashi, and I. Hirao, Tetrahedron Lett., 1983,24, 5121. 271 T. Sakamoto, M. Shiraiwa, Y. Kondo, and H. Yarnanaka, Synthesis, 1983, 312. 267

Saturated and Unsaturated Hydrocarbons

Reagents: Me,SiC=CH,

75

[Pd(PPh,),Cl,], CuI, Et,N; ii, KOH

Scheme 132

1-Alkynyltrimethylsilanesare efficiently converted into acetylenic ketones on brief treatment with thiol esters; the presence of a catalyst is essential, AgBF4 being the most effective (e.g. Scheme 133).272Brown and his co-workers have

Scheme 133

described a one-pot synthesis of acetylenic ketones from 1-bromo-1-alkynes via boron-containing intermediate^.^^^ Tertiary 1-alkynylamines such as (199) can be prepared by direct electrophilic amination of 1-alkynyl-cuprates (200) .274 A slight drawback with this method is that only two of the three alkynyl ligands of the cuprate can be utilized, even when an excess of aminating agent is employed.

(200)

(199)

Reagents: i, MeS03NMe2;ii, Ph2P(0)ONMe2

7 Enynes and Diynes Miller and Zweifel have shown that the reactivity of the 3-alkynyl bond of terminal 1,3-diynes is significantly increased by the presence of a 1-trimethylsilyl (201) is substituent. Thus selective reduction to (E)-l-trimethylsilyl-l-yn-3-enes Y. Kawanami, T. Katsuki, and M. Yamaguchi, Tetrahedron Lett., 1983,24,5131. H. C. Brown, N. G. Bhat, and D. Basavaiah, Synthesis, 1983, 885. 274 G. Boche, M. Bernheim, and M. Niessner, Angew. Chern., Int. Ed. Engl., 1983, 22, 53. 272

273

General and Synthetic Methods

76

possible, and desilylation or further reduction then furnishes enynes (202) or (2,E)-dienes (203) respectively (Scheme 134).275

Reagents: i, LiAIHBul,Bun; ii, H 3 0 + ;iii, KF; iv, Bul,AIH

Scheme 134

In the presence of catalytic amounts of [Cu(acac)*], alkenyldicyclohexylboranes such as (204) undergo cross-coupling with 1-bromo-1-alkynes to afford

Cu (acacl21,NaOH

(204)

good yields of 1,3-enynes with almost exclusively the (E)-c~nfiguration.~~~ This represents an inexpensive alternative to earlier procedures using palladium catalysts. The lithium acetylide (205) can be prepared by treating the methyl allenyl ether (206) with LDA; n-butyl-lithium is not effective. It adds cleanly to aldehydes to give adducts which, on standing in DMSO at room temperature, decompose to give high yields of l-methoxy-l,3-enynes (207) as (E/Z)-stereoisomeric mixtures.277 Corey and his co-workers have transformed the terminal diyne (208) into the corresponding (2)-enyne during syntheses of two isomeric metabolites of arachidonic acid which occur in mammalian blood platelets.27s J. A. Miller and G. Zweifel, J . A m . Chem. SOC., 1983, 105, 1383. Also see reference 281. M. Hoshi, Y. Masuda, and A. Arase, Bull Chem. SOC. Jpn., 1983, 56, 2855. 277 1. Kuwajima, S. Sugahara, and J . Enda, Tetrahedron Lett., 1983,24,1061. 278 E. J. Corey, J. Kang, B. C. Laguzza, and R. L. Jones, Tetrahedron Lett., 1983, 24, 4913. 275 276

77

Saturated and Unsaturated Hydrocarbons OMe Li-E< SiMe3

-

OMe

L DA

(205)

=c< Si Me3

(206)

lRCHO T

O

M

e

(207)

(208) Reagents: i, 2EtMgBr; ii, I,; iii, disiamylborane; iv, AcOH; v, LDA

A l Bui31i n-C6H13

JLi rc - i*

n'C6H13

/==C" (209)

(210) Reagents: i, Bui,Al; ii, Me,C=

CHCH,Br

In contrast to their organolithium precursors, allenic alanates such as (209) react almost exclusively at the y-position with electrophiles .279 For example, treatment with prenyl bromide at -78°C leads to the 1,Senyne (210) contaminated with only 1% of the allenic product formed via reaction at the a-position. Keinan and Peretz have described a novel approach to 1,5-enynes (211) via palladium-catalysed reaction of allenyl(tributy1)stannane with a variety of allylic acetates.280The regioselectivity is sensitive to substituent effects, with reaction on 279

G. Hahn and G. Zweifel, Synthesis, 1983, 883. E. Keinan and M. Peretz, J . Org. Chern., 1983,48,5302.

General and Synthetic Methods

78

= A r ~"-Ph,H,or Reagents: i, Bu,SnCH=

C-

CN

(211)

CH,, [Pd(PPh3),]

the allylic acetate taking place predominantly at the carbon atom bearing the more electronegative group. An efficient synthesis of l-trimethylsilyl-l,3-diynes (212) has been developed which involves the coupling of (bromoethyny1)trimethylsilane (2-13) with copper(1) acetylides (e.g. Scheme 135). On subsequent treatment with an excess of

(212) R =SiMe3 (214) R = H Reagents: i, BunLi;ii, CuBr; iii, Me,SiC=CBr

(213)

Scheme 135

potassium fluoride in DMF, desilylation takes place to give the corresponding terminal 1,3-diynes (214) in high yields.2s1 Treatment of cobalt complexes of 3-substituted propargyl acetates with trialkynyl-alanes at low temperatures leads smoothly to the corresponding 1,4diyne complexes. The free 1,4-diynes are efficiently liberated under mild oxidative conditions (e.g. Scheme 136).282

Reagents: i, (Bu"C=C)~A~;ii, (NH,),Ce(N02)6

Scheme 136

Unsymmetrically substituted 1,4-diamino-1,3-diynes (215)283and 'push-pull' 1,3-diynes of the type (216)284can both be prepared from the corresponding 4-amino-l,l,2-trichloro-1,3-enynes (217) (Scheme 137). J. A. Miller and G. Zweifel, Synthesis, 1983, 128. Also see reference 275. S. Padmanabhan and K. M. Nicholas, Tetrahedron Lett., 1983,24, 2239. 283 M. Feustel and G. Himbert, Tetrahedron Lett., 1983, 24,2165. 284 U. Stampfli, R. Galli, and M. Neuenschwander, Helv. Chim. Acta, 1983,66, 1631.

281

79

Saturated and Unsaturated Hydrocarbons

CI

RlRZN-=-=--

(217)

li R

N-

-

NR3RL

(215) .. ...

=-

E-L i]

RIR2N-

=-_ - C O R ~ (21 6)

Reagents: i, 2Bu"Li; ii, BrCN; iii, R3RJNH; iv, R5COCl

Scheme 137

8 Polyenes

(E)-Pentadienyldithiocarbamates (218) undergo stereospecific double [3,3]sigmatropic rearrangement on heating to give quantitative yields of (E, E)1,3-dienes (219). The dienes (219) can be elaborated to give a variety of other 1,3-dienes or (E, E)-conjugated trienes (220); alternatively, they can be converted into all-(E)-conjugated tetraenes via a-allylation and oxidative de~ulphurization.~~~

i , ii

LCdJ

II

S

S

(218) ( + y - a n d E-alkylated products)

liii

R i.iv

? C N 3

II

S

Rw/ (220) Reagents: i, LDA; ii, RI; iii, PhMe, reflux; iv, Me,SiCH,I; v, MeI, LiF, Li,CO, 285

T. Hayashi, M. Yanagida, Y. Matsuda, andT. Oishi, TetrahedronLetr., 1983,24,2665;T. Hayashi, I . Hori, and T. Oishi, 1.Am. Chem. SOC., 1983,105,2909.

80

General and Synthetic Metho&

The readily available a-silylsulphone (221) can be elaborated by Peterson olefination and, if required, regio- and stereo-specific alkylation. The products extrude sulphur dioxide on thermolysis to give (E)-vinylallenes (e.g. Scheme 138).223

/ -

-c

Reagents: i, Bu"Li; ii, EtCHO; iii, MeI; iv, 650 "C, ca. 50 ms

Scheme 138

Terminal acetylenes cross-couple with allenic bromides in the presence of catalytic amounts of [Pd(PPh3),] and copper(1) iodide to give good yields of allenynes (e.g. Scheme 139).286A variety of functionality is tolerated in the acetylenic partner, including hydroxy , tertiary amino, silyl, or acetoxy groups.

Scheme 139

A variety of methoxy-substituted polyenes can be prepared by treatment of methoxyallenes such as (222) with 1-alkenyl-, 1,2-alkadienyI-, 1-alkynyl, or aryl(but not simple alkyl-) zinc chlorides in the presence of [Pd(PPh,),]. In each case, only the product of allylic displacement is observed (e.g. Scheme 140).287

287

T. Jeffery-Luong and G. Linstrumelle, Synthesis, 1983, 32. H. Kleijn, H. Westmijze, J. Meijer, and P. Vermeer, R e d : J . R. Neth. Chem. SOC.,1983,102,378.

81

Saturated and Unsaturated Hydrocarbons

Extending their earlier work, Heck and his co-workers have shown that vinyl bromides react with conjugated dienes in the presence of palladium(I1) catalysts and an excess of triethylamine to give moderate yields of conjugated trienes.288 The reaction, which works best when one reactant contains a conjugated carboxylic acid or ester group (e.g. Scheme 141), can be extended to syntheses of

41 O10

+

+ / -

d

C

0

2

M

e

13 OI* Reagents: i, Pd(OAc),, (2-MeC6H,),P, Et,N

Scheme 141

tetra- and penta-enes. However, significant stereomutation occurs under the harsh reaction conditions, making the process most useful for the preparation of crystalline (all-E)-polyenoates. Alkenyl and alkynyl Grignard reagents add regiospecifically to N-methoxycarbonylpyridinium chloride to give good yields of 2-substituted N-methoxycarbony1-l72-dihydropyridines(Scheme 142).289 Reactions using alkyl Grig-

nard reagents are less useful since they give mixtures of products arising from both 1,2- and 174-addition. The first synthesis of cumulenes via Peterson olefination has been reported (Scheme 143).290 Only non-enolizable aldehydes and ketones are suitable substrates owing to the high basicity of the a-silyl anion. On treatment with a stoicheiometric amount of [Ni(PPh,),] , the di-iododiene (223) (or its dibromo-analogue) is converted into the radialenes (224) and (225), 288

W. Fischetti, K. T. Mak, F. G. Stakem, J.-I. f i m , A. L. Rheingold, and R. F. Heck,J. Org. Chern.,

289

1983, 48, 948. R. Yamaguchi, Y. Nakazono, and M. Kawanisi, Tetrahedron Lett., 1983, 24, 1801. J. J. Doney and C. H. Chen, Synthesis, 1983,491.

290

General and Synthetic Methods

82

Reagents: i, LiC=CSiMe,;

ii, Bu"Li; iii, R1R2C0

Scheme 143

probably through the intermediacy of 2,5-dimethylhexa-2,3,4-triene. The reaction may be directed towards the product of choice by use of an appropriate solvent .291

I (223)

Solvent : Benzene DMF

48% 1. 3 % (224)

0 OIo 50

(225)

Biitikofer and Eugster have synthesized hydroxymethyl-carotenoids via 1,2addition of polyenic vinyl anions to polyenals, followed by an acid-catalysed rearrangement .292 Scheme 144 shows a model reaction. The (2,Z)-diene (226) is a useful building block for the preparation of (all-2)polyisoprenoids, such as (2,Z)-farnesol (227).293 The synthesis of all of the sixteen possible geometric isomers of vitamin A has now been completed with the first preparation and characterization of the highly M. Iyoda, S. Tanaka, M. Nose, and M. Oda, J . Chem. SOC., Chem. Commun., 1983, 1058. P.-A. Butikofer and C. H. Eugster, Helv. Chim. Acta, 1983,66, 1148. 293 K. Sato, 0. Miyamoto, S. Inoue, F. Furusawa, and Y. Matsuhashi, Chem. Lett., 1983, 725.

291

Saturated and Unsaturated Hydrocarbons Shopire

qo 83

Ph (all - E 1 : (f,Z,f 1 = 4 :1

Scheme 144

OH

OH

(227)

(226) Reagents: i, Bu"Li; ii, Li, EtNH,

( 2 2 8)

(229)

hindered (7-2,9-2,11-2)- and (all-2)- (228) isomers.294The first member of the pericyclyne family to have been prepared is decamethyl[5]pericyclyne (229), a colourless, air-stable solid.295 294 295

A. E. Asato, A. Kini, M. Denny, and R. S. H. Liu, 1.Am. Chem. SOC., 1983,105,2923. L. T. Scott, G. J. DeCicco, J. L. Hyun, and G. Reinhardt, J . Am. Chem. SOC., 1983,105,7760.

4

2 Aldehydes and Ketones BY S. C. EYLEY

1 Synthesis of Aldehydes and Ketones

Oxidative Methods.-The scope of the palladium-catalysed oxidation of primary and secondary alcohols to aldehydes and ketones under basic conditions by aryl bromides has been assessed. The optimal conditions described generally employed 1-3 mole% of the palladium(0) or palladium(I1) catalyst, and bromobenzene as the oxidant. The heterogeneous oxidation of secondary alcohols to ketones using solid potassium permanganate gives much improved yields under the influence of ultrasonic irradiation.* The heterogeneous oxidation by hydrated copper permanganate is inhibited in the presence of alkenes, except for allylic alcohol^.^ The observation is of significance when considering reagents for the oxidation of complex alcohols. Magnesium and zinc permanganates have been prepared as their hexahydrates, and react very vigorously with common organic solvent^.^ The reagents can however be handled conveniently when supported on silica gel, oxidizing a variety of organic substrates. Of particular interest are the oxidations of a cyclic olefin to a ketol, and the cleavage of ethylene acetaI'6 of aromatic ketones to the parent carbonyl compounds. Ease of preparation, increased rate of reaction, and long storage times have been discussed as advantages of barium manganate over manganese dioxide as an oxidant for organic compound^.^ Neutral phase-transfer oxidations using potassium dichromate as oxidant have shown benefit in the preparation of isoxazole aldehydes6 In the steroid field, the selectivity for the oxidation of allylic alcohols over saturated alcohols using pyridinium chlorochromate is enhanced in the presence of 3,5dimethylpyrazole, as for other chromium oxidant^.^ Trimethylsilyl chlorochromate, prepared in situ from the silyl chloride and chromium trioxide, offers an alternative reagent for the oxidation of alcohols under non-aqueous conditions.8Saturated alcohols, in contrast to allylic and benzylic alcohols, are not oxidized by the newly described tetrabutylammonium chlorochrornate with moderate reagent ratios. Oxidation Y. Tamaru, Y. Yamada, K. Inoue, Y. Yamamoto, and Z.-I. Yoshida, J . Org. Chem., 1983,48,1286. J. Yamawaki, S. Sumi, T. Ando, and T. Hanafusa, Chem., Left., 1983,379. D. G. Lee and N. A. Noureldin, J . Am. Chem. SOC., 1983, 105,3188. S. Wolfe and C . F. Ingold, J . Am. Chem. SOC., 1983,105,7755. H. Firouzabadi and Z. Mostafavipoor, Bull. Chem. SOC.Jpn., 1983, 56,914. N. R. Natale and D. A. Quincy, Synth. Commun., 1983, 13, 817. E. J. Parish and A. D. Scott, J . Org. Chem., 1983,48,4766. J. M. Aizpurua and C . Palomo, Tetrahedron Lett., 1983,24,4367.

84

85

Aldehydes and Ketones

does however proceed with high ratios (6: 1) of ~ x i d a n tJones' .~ reagent can be used for the efficient oxidation of trimethylsilyl ethers directly to ketones.l0The reaction was only reported for ethers of secondary alcohols. The cobalt(1) complex chlorotris(triphenylphosphine)cobalt(I) converts bromohydrins into carbonyl compounds, possibly via P-hydroxyalkylcobalt intermediates. l1 Air-oxidation of benzylic alcohols has been shown to be catalysed by cerium(1v) ammonium nitrate adsorbed on charcoal.l2 Benzylic alcohols, and a-hydroxyketones, may also be oxidized to the corresponding carbonyl compounds by cerium(1v) triethylammonium nitrate. l3 Catalysis of t-butyl hydroperoxide oxidations by vanadyl species provides a high degree of selectivity for secondary alcohols over primary.14 Primary and secondary alcohols are oxidized to the carbonyl compound by trimethylsilyl peroxide when catalysed by tris(triphenylphosphine)ruthenium(II) ch10ride.l~ Selective oxidations may be performed, since primary alcohols are oxidized preferentially. The peroxide may be used in non-selective oxidations in conjunction with chromium oxidants, preferably pyridinium chlorochromate. Secondary alcohols are oxidized in good yield to ketones by sodium bromite in aqueous acetic acid.16As is often observed, primary alcohols give rise to oxidative esterification products. The periodinane (1), generated by bromate oxidation of 2-iodobenzoic acid, has been developed as a mild reagent for the oxidation of both primary and secondary alcohols to the corresponding carbonyl compound.17 rn-Iodosylbenzoic acid effects smooth ruthenium-catalysedoxidations of primary alcohols to aldehydes.l8 AcO OAc

N-Hydroxyphthalimide has emerged from studies of anodic oxidations of hydroxamic acids as an efficient electron carrier in the electrochemicaloxidation of alcohols.19With the exception of ethanol, yields of aldehydes from primary alcohols were far inferior to those from secondary alcohols. The opposite selectivity has been noted when electro-oxidation is nitroxyl-mediated,20conditions which can also promote the oxidation of primary amines to carbonyl E. Santaniello, F. Milani, and R. Casati, Synthesis, 1983, 749. R. Baker, V. B. Rao, P. D. Ravenscroft, and C. J. Swain, Synthesis, 1983, 572. l1 D.-I. Momose and Y. Yamada, Tetrahedron Lett., 1983, 24,2669. l2 Y. Hatanaka, T. Irnarnoto, and M. Yokoyama, Tetrahedron Lett., 1983,24,2399. l3 H. Firouzabadi and N. Iranpoor, Synth. Commun., 1983, 13, 1143. l4 K. Kaneda, Y. Kawanishi, K. Jitsukawa, and S. Teranishi, Tetrahedron Lett., 1983, 24, 5009. l5 S. Kanemoto, K. Oshima, S. Matsubara, K. Takai, and H. Nozaki, TetrahedronLett., 1983,24,2185. l6 T. Kageyama, Y. Ueno, and M. Okawara, Synthesis, 1983, 815. l7 D. B. Dess and J. C . Martin, J . Org. Chem., 1983,48,4155. P. Muller and J. Godoy, Helv. Chim. Acta, 1983, 66, 1790. l9 M. Masui, T. Ueshima, and S. Ozaki, J . Chem. SOC., Chem. Commun., 1983,479. 2o M. F. Semmelhack, C. S. Chou, and D. A. Cortes, J . Am. Chem. SOC., 1983,105,4492. lo

86

General and Synthetic Methods

compounds.21Anodic methoxylation of carbamates forms the key step in a simple transformation of primary amines to dimethyl acetals or the corresponding carbonyl compounds.22 Bis-(p-methoxypheny1)selenoxidepromotes the catalytic oxidation of benzylic alcohols to aldehydes by selenium dioxide.23This oxidizing system, which may be generated from either the dioxide or the metal, gave superior yields when compared with oxidations using stoicheiometric amounts of purified selenium dioxide. The complex formed between dimethyl selenide and N-chlorosuccinimide oxidizes alcohols to carbonyl corn pound^.^^ In contrast to the well-established sulphur-based reaction, allylic alcohols are satisfactory substrates, not giving the allylic chlorides. The selenium may be used as part of the substrate, giving rise to a-seleno-substituted ketones. Benzylic alcohols are oxidized to aldehydes in good yield by N-iodosuccinimide when the reaction mixture is irradiated with a tungsten lamp.25The formation of tetrahydrofurans in very high yield from reaction of primary aliphatic alcohols suggeststhat hypoiodites are intermediates. Phase-transfer catalysed oxidations of terminal alkenes to methyl ketones have been described. With cupric chloride as co-catalyst in a Wacker-type process, palladium(rr) chloride 26 or rhodium or ruthenium complexes27are effective. Cleavage of alkenes to carbonyl compounds occurs with oxygen in the presence of rhodium catalysts.28 Anions of sulphones are oxidized to carbonyl compounds by bis(trimethylsilyl)peroxide, a reaction useful for the preparation of l*O-labelled ketones.29Sulphoxidesare oxidized at the a-carbon atom by trimethylsilyl iodide and a hindered amine base to afford vinyl s ~ l p h i d e sThe . ~ ~reaction may be used for the \preparation of phenylthiobutadienes. Precise reaction conditions are important for the outcome of the oxidation of alkyl phenyl sulphides with sulphuryl chloride and moist silica gel.31Aldehydes have been found to be the major products when silica gel is added after the oxidation, whereas it is known that oxidation in the presence of the support gives the sulphoxide. A detailed account of oxidative decyanation of secondary nitriles to ketones has been published.32A simple procedure for benzylic nitriles uses aerial oxidation in basic dimethyl s ~ l p h o x i d e . ~ ~ Electrolysis of nitro-compounds over platinum electrodes affords ketones M. F. Semmelhack and C. R. Schmid, J. Am. Chem. SOC., 1983, 105,6732. T. Shono, Y. Matsumura, and S. Kashimura, J. Org. Chem., 1983,48, 3338. 23 F. Ogura, T. Otsubo, K. Ariyoshi, and H. Yamaguchi, Chem. Lett., 1983,1833. 24 K. Takaki, M. Yasumura, and K. Negoro, J. Org. Chem., 1983,48,54. 25 T. R. Beebe, R. L. Adkins, C. C. Bogardus, B. Champney, P. S. Hii, P. Reinking, J. Shadday, W. D. Weatherford, M. W. Webb, and S. W. Yates, J. Org. Chem., 1983,48,3126. 26 K. Januszkiewicz and H. Alper, Tetrahedron Lett., 1983,24, 5159. 27 K. Januszkiewicz and H. Alper, Tetrahedron Lett., 1983, 24, 5163. 28 H. Bonnemann, W. Nunez, and D. M. M. Rohe, Helv. Chim. Actu, 1983,66, 177. 29 J. R. Hwu, J. Org. Chem., 1983, 48,4432. 30 R. D. Miller and D. R. McKean, Tetrahedron Lett., 1983,24,2619. 31 D. T. W. Chu, J. Org. Chem., 1983, 48, 3571. 32 R. W. Freerksen, S. J. Seliksoc, R. R. Wroble, K. S. Kyler, and D. S. Watt, J. Org. Chem., 1983,48, 4087. 33 S. S. Kulp and M. J. McGee, J . Org. Chem., 1983,48,4097.

21

22

87

Aldehydes and Ketones

under neutral condition^.^^ A related method utilizes electrogenerated superoxide ion for this c o n v e r ~ i o n The . ~ ~ N,N,N’,N’-tetramethyl-W-t-butylguanidine salt of rn-iodoxybenzoic acid, in the presence of excess of the base, is a mild reagent for the oxidative Nef reaction.36 Reductive Methods.-N,N-Dimethylchloromethyleniminium chloride activates carboxylic acids towards reduction by lithium tri-t-butoxyaluminiumhydride at low temperature, providing good yields of the aldehyde.37Other reducing agents resulted in formation of the alcohol. Reductive cleavage of aryl oxazolines to aromatic aldehydes via the oxazolinium salt is well established. An alternative route is through the N-chlorosuccinimideoxidation of the benzylamine formed on reduction of the heterocycle by di-isobutylaluminium hydride (Scheme 1).38 The

H

i

ii

Cl

___)

ArkN*OH

A r - N x O H

- I

iii

iv

ArCHO

ArvNxOH

Reagents: i, DIBAL; ii, NCS; iii, A1203;iv, S O 2

Scheme 1

ready cleavage of ,B-hydroxy-a-(methy1thio)sulphones to aldehydes enables the conversion of esters into aldehydes by the three-step sequence outlined (Scheme 2).39

A

R

A

R

OR’

S02Ar

0

R+sMe S02Ar

-

H

OH

hfSMe

R

S02Ar

Ar = p - t o l y l Reagents: i, NaH; ii, NaBH,; iii, base, e.g. K2C03

Scheme 2 J. Nokami, T. Sonoda, and S. Wakabayashi, Synthesis, 1983, 763. W. T. Monte, M. M. Baizer, and R . D. Little, J . Org. Chem., 1983,48, 803. 36 D. H. R. Barton, W. B. Motherwell, and S. Z . Zard, Tetrahedron Lett., 1983,24,5227. 37 T. Fujisawa, T. Mori, S. Tsuge, and T. Sato, Tetrahedron Lett., 1983,24,1543. 38 A. I. Meyers, R. J. Himmelsbach, and M. Reuman, J . Org. Chem., 1983,48,4053. 39 K. Ogura, N. Yahata, K. Takahashi, and H. Iida, Tetrahedron Lett., 1983, 24, 5761.

34

35

88

General and Synthetic Methods

Investigations of a series of N-formyl amines, including established reagents, as formylating agents for Grignard reagents have indicated the benefits of additional chelating groups in the e l e ~ t r o p h i l e Such . ~ ~ groups reduce the quantities of secondary alcohols formed, N-(N-formyl-N-methy1)aminopiperidine being recommended for the preparation of aldehydes. Carboxylic acids may be activated towards attack by Grignard reagents to form ketones using either a-chloroenamine~~~ or dichlor~triphenylphosphorane~~ as a condensing agent. Quenching reaction mixtures from carboxylic acids and methyl-lithium with trimethylsilyl chloride traps excesses of the alkyl-lithium, significantly reducing tertiary alcohol formation, leading to high yields of the methyl ketone.43Alcohol formation is also greatly suppressed when the reaction of acids with Grignard reagents is catalysed by nickel(I1) chloride complexed with 1,2-bi~(diphenylphosphino)ethane.~ The reaction of organocuprates with 2-pyridyl esters forms ketones in excellent yield.45 With simple lithium dialkylcuprates, both alkyl groups were transferred, contrasting the reaction with that of acid chlorides. Selenoesters also react with organocuprates to form ketones.46Alkenyl copper(1) reagents give a$-unsaturated ketones.47 The titanium-based reagent (2), which acts as a methylenating agent for ketone and ester carbonyl groups in a Wittig-type reaction, has been found to react in a different fashion with acyl chlorides, giving methyl ketones (Scheme 3).48 0

A

R

X

+ R

C p = C5H5-

(2) Reagents: i , MeI; ii, H 2 0

Scheme 3

Titanium enolates are implied as intermediates, and can be trapped by the addition of methyl iodide to give ethyl ketones. Metallic nickel has been reported to be an effective reagent for the preparation of benzyl ketones by the reductive W. Amaratunga and J. M. J. Frkchet, Tetrahedron Lett., 1983, 24, 1143. T. Fujisawa, T. Mori, K. Higuchi, and T. Sato, Chem. Lett., 1983, 1791. 42 T. Fujisawa, S. Iida, H . Uehara, and T. Sato, Chem. Lett., 1983, 1267. 43 G. M. Rubottom and C.-W. Kim, J . Org. Chem., 1983,48, 1550. 44 V. Fiandanese, G. Marchese, and L. Ronzini, Tetrahedron Lett., 1983, 24, 3677. 45 S. Kim and J. I. Lee, J. Org. Chem., 1983,48,2608. 46 A . F. Sviridov, M. S . Ermolenko, D. V. Yashunsky, and N. K. Kochetkov, Tetrahedron Lett., 1983, 24, 4355. 47 A . F. Sviridov, M. S. Ermolenko, D. V. Yashunsky, and N. K. Kochetkov, Tetrahedron Lett., 1983, 24, 4359. 48 T.-S. Chou and S.-B. Huang, Tetrahedron Lett., 1983, 24, 2169.

4o 41

Aldehydes and Ketones

89

coupling of benzylic halides with acid chlorides.49 Palladium-phosphine complexes catalyse the reaction of organozinc compounds 50 and unsymmetrical organotin reagents5I with acyl chlorides. Methyl and butyl groups are not transferred from tin, enabling selective transfer to be achieved. N,N-Dimethylchloromethyleniminium chloride activates. aci-nitroalkanes towards attack by Grignard reagents in a new synthesis of ketoximes (Scheme 4) .52

I

OLi

IL

f

/

+

Reagents: i, BunLi; ii, ClCH=NMe,

+;Me,- - L

-.-

J

C1-; iii, R3MgX, Cul (cat.); iv, hydrolysis; v, R2Li

Scheme 4

Methods Involving Umpolung.-(2-Trimethylsilylethoxy)methyl chloride, a reagent for the protection of alcohols, has been used to advantage for the homologation of aldehydes and ketones to aldehydes via the phosphoranederived enol ether (Scheme 5).53Hydrolysis was effected by hydrogen fluoride in acetonitrile. Further details of the generation of a variety of aldehydic enol ethers SiMe3

C l e o -

i ,ii

Ph3P

'

pv S i M e 3 0

I

iii

ci v-

R'-,p-SiMep

"'YCHO R2

R2

Reagents: i, PPh,, C,H,; ii, DMSO, NaH, 20°C; iii, R'R T O; iv, 5% HF, MeCN

Scheme 5

49

S.-I. Inaba and R. D. Rieke, Tetrahedron Lett., 1983, 24, 2451.

so E.-I. Negishi, V. Bagheri, S. Chatterjee, F.-T. Luo, J. A. Miller, and A. T. Stoll, Tetrahedron Lett.,

1983, 24,5181. J. W. Labadie, D. Tueting, and J. K. Stille, 1. Org. Chern., 1983,48, 4634. 52 T. Fujisawa, Y. Kurita. and T. Sato, Chem. Lett., 1983,1537. 53 K. Schonauer and E. Zbiral, Tetrahedron Lett., 1983, 24, 573. 51

90

General and Synthetic Methods

and enamines from dimethyl diazomethylphosphonate have appeared [equation (111.54 qp-unsaturated ketones were reported not to give the diene derivatives.

Y = OR or NR2

A new route to the related alkylthio- and arylthio-methylphosphonates via sulphenylation of the a-lithio-methylphosphonate has been p ~ b l i s h e d . ~ ~ Homologation of carbonyl compounds to the versatile vinyl sulphones via Peterson reaction with phenylsulphonyltrimethylsilylmethane depends crucially on the choice of 1,2-dimethoxyethane as solvent [equation (2)].56

Addition of alkyl-lithium reagents to 1-phenylthio-1-trimethylsilylethene proves to be a successful strategy for the development of acyl anion equivalents for the preparation of ketones.57The anions may not be formed by simple deprotonation. Alkylation with (preferably primary) alkyl halides followed by the established oxidative conversion into the carbonyl compound completes the sequence.58The use of 1-bromo-1-trimethylsilyl-1-alkenes as both carbonyl anion and cation equivalents has been described (Scheme 6).59The halogen allows either metallation with organolithium or coupling with organocopper reagents to occur.

V

RJ

R’

Reagents: i, BuSLi;ii, R’I; iii, (PhS)RICuLi; iv, m-C1C6H,CO3H, CH2C12;v, 30%H2So4,MeOH

Scheme 6 J . C . Gilbert and U. Weerasooriya, J . Org. Chem., 1983,48, 448. J. C. Smith, M. S. Finck, B. D. Kontoleon, M. A . Trecoske, L. A . Giordano, and L. A. Renzulli, J . Org. Chem., 1983, 48, 1110. 56 S. V. Ley and N. S. Simpkins, J . Chem. SOC.,Chem. Commun., 1983, 1281. 57 D. J. Ager, Tetrahedron Lett., 1983, 24, 95. 58 D. J. Ager, J . Chem. Soc., Perkin Trans. 1, 1983, 1131. 59 R. B. Miller, M. I. Al-Hassan, and G. McGarvey, Synth. Commun., 1983, 13, 969.

54

55

91

Aldehydes and Ketones

a-Branched sulphones may be converted into dithioacetal S,S-dioxides, providing a convenient route to acyclic ketones, exemplified by a synthesis of the sex pheromone of the Douglas Fir Tussock Moth (Scheme 7).60

-

'i

SMe

i, ii,i ,iii

S02Ar

Ar = p-tolyl R1 = n-CloH21 R 2 = n-CgHv

R2

S02Ar

liv

(3) Reagents: i, BunLi;ii, R*C=C(CH,),I;

iii, (MeS),; iv, CuCl,, SiO,; v, H2, Pd/BaSO,

Scheme 7

Reactions of acyl anion equivalents derived from protected cyanohydrins and a-dialkylaminonitriles have been reviewed.61 Stereochemical studies of the alkylation of such anions suggest that the reactions do not involve radical intermediates. 62 Aldehydes have been prepared from methoxy(pheny1thio)methyl-lithium and alkylboronic esters, a sequence encompassing a mercury(I1)-induced alkyl migration in the intermediate, and an oxidative work-up (Scheme 8).63Of particular

&n- + i , ii

' 0

I

iii-v

Me

I

iv

'n

1

oB ,o'

Reagents: i, BHBr,.SMe,, CH,Cl,; ii, Me3SiO(CH2),0SiMe3;iii, PhSCHLiOMe; iv, HgCl,; v, H,O,, PH 8

Scheme 8 Y. Murata, K. Inomata, H. Kinoshita, and H. Kotake, Bull. Chem. SOC. Jpn., 1983,56,2539. 61 J. D. Albright, Tetrahedron, 1983, 39, 3207. 62 E. Hebert, N. Maigrot, and Z . Welvart, Tetrahedron Lett., 1983,24,4683. 63 H. C. Brown and T. Imai, J. Am. Chem. SOC., 1983, 105,6285.

General and Synthetic Methods

92

interest are the stereochemical control available as a result of the stereospecificity of the initial hydroboration to form the boronic ester and the retention of configuration during the migration from boron to carbon. For example, both threo- and erythro-2,3-dirnethylpentanal were obtained with high diastereomeric purity, starting from (E)- and (2)-3-methylpent-2-ene respectively. Boron is central to another route to aldehydes where the anion of allyldimesitylborane acts as a homoenolate equivalent of propanal (Scheme 9) .@

-

-

i.ii

Ar2B

R

liv -0

i ,iii

ArgB-

A r 2 B T o L i

R

iiv

Ar = mesityl

BR

R

HO Reagents: i, ArLi; ii, RI; iii, RCHO; iv, NaOH, H20,

Scheme 9

The anion may also be converted into a y-lactol following reaction with an aldehyde. The Grignard reagent from 2-(2-bromoethyl)-l,3-dioxolaneis also equivalent to this h ~ m o e n o l a t e .The ~ ~ reagent couples with a variety of alkyl halides in the presence of dilithium tetrachlorocuprate to form the aldehyde acetal. The method allows the preparation of functionalized aldehydes containing, inter alia, nitrile or ester groups. Hornoenolate anions and their equivalents have been the subject of review.66 Radicals generated by borohydride reduction of the products of mercuryinduced ring opening of cyclopropanyl trimethylsilyl ethers are trapped by electron-poor olefins to yield aldehydic products (Scheme 10).67 H OSiMe3

OSiMe3

wy I

t2 R’ F

\

R2

X

+ 0s i Me3

X , Y electron - withdrawing, @.g.CN , C 0 2 R AcO

y+

X Reagents: i, Me,SiCl; ii, CHJ,, Cu/Zn; iii, Hg(OAc),, AcOH; iv, NaBH,

Scheme 10 Pelter, B. Singaram, and J. W. Wilson, Tetrahedron Lett., 1983, 24, 631. R. A. Volkmann, J. T. Davis, and C. N. Meltz, J . Org. Chem., 1983,48, 1767. 66 N. H. Werstiuk, Tetrahedron, 1983, 39, 205. 67 B. Giese and H. Horler, Tetrahedron Lett., 1983,24, 3221.

61 A. 65

93

Aldehydes and Ketones

Other Methods.-Allylic, benzylic, and vinylic halides undergo a palladiumcatalysed direct formylation by carbon monoxide and tri-n-butyltin(1v) hydride ,a reaction which tolerates ketones, esters, alcohols, and aromatic nitro-groups.68 Formylation with a trialkylsilane, this time catalysed by octacarbonyldicobalt , converts alkyl acetates into the homologated silyl enol ether.69The transformation has been applied to other esters, including an interesting carbonylating opening of lactones [equation (3)]. Further details of the photochemically

Re -t CO

4-

EtzMeSiH

I

COz[CO)()

0si MeEt2 R

(3)

C02S iMe Et 2

induced hydroformylation of alkenes by cobalt carbonyl reagents have been published, discussing mechanisms and regioselectivity using octenes as models.70 Palladium-catalysed reactions of aryl iodides , alkyl halides, and carbon monoxide, with a zinc-copper couple as reductant, form a method for the synthesis of unsymmetrical ketones.71In some examples quoted, formation of biphenyls was noted as a side-reaction, and with benzylic halides as the alkyl component diarylmethanes and 1,2-diarylethanes were observed. Carbonylations of diaryliodonium salts in the presence of zinc and a catalytic quantity of palladium acetate give diaryl ketones, together with substantial amounts of diaryl diketones [equation (4)].72The formation of the latter is preferred at higher pressures of carbon monoxide. Ar2I

+

X

-

+

CO

+

Zn

I

Pd ( O A C ) ~

ArCOAr

+

ArCOCOAr

+

ArI

(4)

Boron chemistry continues to be exploited for the development of new ways to prepare carbonyl compounds. Ate-complexes from the reaction of boranes with the lithium salt of 4,4-dimethyl-2-oxazoline afford symmetrical ketones on methylation followed by a basic peroxide work-up (Scheme ll).73 The alkyl migrations were shown to be intramolecular, but unfortunately unsymmetrically V. P. Baillargeon and J. K. Stille, J. Am. Chem. Soc., 1983, 105,7175. N. Chatani, S. Murai, and N. Sonoda, J . Am. Chem. Sac., 1983,105,1370. 70 M. J. Mirbach, N. Topalsavoglou, T. N. Phu, M. F. Mirbach, and A. Saus, Chem. Ber., 1983,116, 1422. 71 Y . Tamaru, H. Ochiai, Y. Yamada, and Z.-I. Yoshida, Tetrahedron Lett., 1983, 24,3869. 72 M. Uchiyama, T. Suzuki, and Y. Yamazaki, Chem. Lett., 1983, 1201. 73 T. Baba and A. Suzuki, Synth. Commun., 1983, 13,367.

68

69

I,x:.]

94

General and Synthetic Methods

J;>2 . ..

-L

[&m3 N

Li

Me

+

1'. Reagents: i, BunLi; ii, BR3; iii, MeI; iv, NaOH, H202

Scheme 11

substituted boranes were not investigated as an extension of the method to nonsymmetrical ketones. Another approach utilizing ate-complexes, this time derived from 172-dimethoxyethenyl-lithium , generates aldehydes after a Lewis acid-induced rearrangement (Scheme 12).74 Investigations of the conveniently hOyOMe

iii

R ' $ M e

Br

R 3-8

iv

R L

H

O

R2B Li

+

Reagents: i, BunLi; ii, BR,; iii, BF3.Et20;iv, H30+

Scheme 12

stored and handled dimesitylborane have shown this to be a highly regioselective reagent for the hydroboration of alkynes, apparently responding to steric effects.75Alkenes react very slowly with this borane, again offering increased chemoselectivity . Phosphorus ylides have been used for the preparation of selected phosphine-stabilized mono-organoboranes, useful reagents in the synthesis of aldehydes and ketones (Scheme 13).76 The aryl borinate derivative employed offers a reasonable compromise between high reactivity and low tendency for disproportionation. Migration of the less highly substituted alkyl group in a-diazo-/3-hydroxy-esters has been reported with a variety of metal catalysts, including Wilkinson's catalyst, and palladium and cobalt chlorides , giving a regioselective homologation of ketones under neutral conditions [equation (5)].77 The reaction was developed for application to a regioselective ring expansion. An asymmetric, stereospecific pinacol rearrangement promoted at low temperatures by triethylaluminium offers a route to a-vinyl or a-aryl ketones with high optical purity.78The starting J. Koshino, T. Sugawara, T. Yogo, and A. Suzuki, Synth. Commun., 1983,13,1149. A . Pelter, S. Singaram, and H. Brown, Tetrahedron Lett., 1983,24, 1433. 76 H. J. Bestmann and T. Roder, Angew. Chem., Int. Ed. Engl., 1983,22,782. 77 K. Nagao, M. Chiba, and S.-W. Kim, Synthesis, 1983,197. 78 K. Suzuki, E. Katayama, and G.-I. Tsuchihashi, Tetrahedron Lett., 1983, 24,4997. 74

75

Aldehydes and Ketones

-

95

i.ii

R’APPh3

RlnBH2.PPh3

liv R2

R2

+

+

MePPhg

I

-

Reagents: i, BH,.THF; ii, A; iii, 2,4,6-Me3C&OH; iv, R2CH=CR3R4, MeI; v, C1,CHOMe; vi, LiOCEt,; vii, NaOH, H 2 0 2

Scheme 13

diol derivative is however required to be chiral, the optical -activitybeing maintained in the transformation [equation (6)]. The conversion of epoxides into ketones has been achieved under electrolytic conditions for the generation of the acid catalyst req~ired.’~ Lithium, sodium, and magnesium perchlorates were the most efficient electrolytes found.

~e

3Et3Al

- CH2Cl2

OH

MeOzSO 79

H

-78

O C

(6)

H

k2

K. Uneyama, A. Isimura, K. Fujii, and S. Torii, Tetrahedron Lett., 1983, 24,2857.

96

General and Synthetic Methods

Further developments in the regioselectivity of dipolar additions of nitrile oxides to olefins have mapped out the preparative applications of isoxazolines for the diastereospecific synthesis of 2-substituted aldols.80,81 Raney-nickel and boric acid are recommended components in the reduction of the heterocycle to the aldol.*l Photolysis of the heterocycle and pentacarbonyliron in methanol fragments the ring to give two carbonyl products, as if from a retro-aldol reaction (Scheme 14).82 A substituent is necessary at the 5-position. The reaction

Reagents: i, hv, MeOH, [Fe(CO),]

Scheme 14

highlights an interesting synthetic relationship between the products and likely starting materials for the formation of the heterocycle, and extends the utility of C-alkylations of isoxazolidines. Aldehydic morpholino-enamines have been prepared by a nett formylation of substituted acetic acids by 4-(methoxymethylene)morpholinium methyl sulphate [equation (7)] .83 The reaction was also used to prepare l-dimethylamino2 LiNPr'Z

+ OMe R2N4 (7)

NR2

= NMe2,

n

1-alkenes. Trimethylsilyl trifluoromethylsulphonate is a convenient reagent for the preparation of N-silylated enamines from a aminonitrile derivatives [equation (8)i -84 S. F. Martin and B. Dupre, Tetrahedron Lett., 1983,24, 1337. D. P. Curran, J . Am. Chem. SOC., 1983,105,5826. s2 M. Nitta and T. Kobayashi, Chem. Lett., 1983, 51. 83 R. Knorr, P. Low, and P. Hassel, Synthesis, 1983,785. g4 H. Ahlbrecht and E.-0. Duber, Synthesis, 1983,56.

97

Aldehydes and Ketones R’HN

-

CN

R’ NSiMe3

Me+ i 0 SO2 C F3

R

2

3

+

R2’$

Et3N

R3

Me3SiCN

(81

R3

Improved conditions for the reductive conversion of nitro-alkenes into ketones have been disclosed (Scheme 15), using electrochemical reduction at a lead cathode in solutions containing perchloric Work-up with either aqueous

0 Reagents: i, R2CH2N02;ii, CH2Cl,, dioxan, HC104, (Pb) 4e; iii, NH,OH.HCl, AcONa; iv, H,O, HCHO; v, MeOH, H,SO,, (Pt) 4e; vi, Raney Ni, EtOH, H,O, NaH,PO,; vii, hydrolysis

Scheme 15

formaldehyde or hydroxylamine gives the ketone or oxime, respectively. Reduction has also been reported on electrolysis over a platinum cathode in methanolic sulphuric acid, giving the oxime,86 and on treatment with Raney-nickel and sodium hypophosphite at pH 5 , giving the ketone.*’

R’

R3

-

OMe iii ,i\

AcO

R2

R1

OMe R2

0 Reagents: i, Anode, MeOH, AcOH, Et,N+ p-MeC,H,SO,-; ii, NaBH,, MeOH; iii,p-MeOC,H,SO,Cl; iv, Me,CO, H 2 0

Scheme 16 S. Torii, H. Tanaka, and T. Katoh, Chem. Lett., 1983,607. T. Shono, H. Hamaguchi, H. Mikami, H. Nogusa, and S. Kashimura, 1. Org. Chern., 1983,48,2103. 87 D. Monti, P. Gramatica, G. Speranza, and P. Manitto, Tetrahedron Lett., 1983,24, 417.

86

98

General and Synthetic Methods

Methods for 1,Ztranspositions of the carbonyl group have been reviewed in an article covering early terpenoid and steroid work, but mainly more recent methods based on sulphur, on boron, and on silicon.88A method for 1,4-carbonyl transposition has been reported using anodic y-methoxylation of dienol acetates as the key step (Scheme 16).89 Cyclic Ketones.-The Nazarov cyclization of divinyl ketones and their precursors to give cyclopentenones has been reviewed.90Iron(m) chloride has been found to induce this cyclization for /3-silyl-substituteddivinyl ketones with control over the regiochemistry of the double bond in the product.91Steric factors associated with remote substituents can control the stereochemical sense of cyclization, and the necessity for stoicheiometric amounts of water to be present in the reaction medium was d e m ~ n s t r a t e dLewis . ~ ~ acids mediate the intramolecular acylation of vinylsilanes to form cycloalkanones, an approach in which the precise product obtained depends markedly on the substitution pattern on the double bond.93,94 The synthesis of ketones via intramolecular cyclization of a sulphur-stabilized carbanion into an amide on an o-aminothiophenol template has been extended to prepare medium (8-12 membered) ring ketones (Scheme 17).95Esters may be

1

ii.iii

iv

0-

\

Reagents: i , Br(CH,),+,COCI; ii, ButOK, high dilution; iii, NaIO,; iv, LiNPr',; v, Al/Hg

Scheme 17 V. V. Kane, V. Singh, A. Martin, and D . L. Doyle, Tetrahedron, 1983, 39, 345. T. Shono and S. Kashimura, J . Org. Chem., 1983,48,1939. C. Santelli-Rouvier and M. Santelli, Synthesis, 1983, 429. 91 T. K. Jones and S. E . Denmark, Helv. Chim. Acta, 1983,66,2377. 92 T . K. Jones and S. E . Denmark, Helv. Chim. Acta, 1983,66,2397. 93 K. Mikami, N . Kishi, and T. Nakai, Tetrahedron Lett., 1983,24,795. 94 E . Nakamura, K. Fukuzaki, and I. Kuwajima, J . Chem. SOC.,Chem. Commun., 1983,499. 95 Y . Ohtsuka and T. Oishi, Chem. Pharm. Bull., 1983,31, 454. 88

89

Aldehydes and Ketones

99

substrates for acyclic ketone synthesis by this method if sulphones or sulphoxides stabilize the anion.96 Reduction of titanium(Ir1) chloride by lithium aluminium hydride forms a reagent which reductively couples keto-esters to form cycl~alkanones.~~ Small, medium, and large rings can be formed, and the method has been utilized to close the nine-membered ring in a synthesis of isocaryophyllene [equation (9)].98 The

cyclization substrate was that designed for a synthesis of caryophyllene, but during the course of the ring formation double-bond inversion occurred. [3 4Phenylt hio) buta- 1,3-dienyl]triphenylphosphonium chloride has been developed as a reagent for the annulation of P-keto-esters to cyclohexenones (Scheme 18).99The method complements the Robinson annulation in that the sequences give relatively transposed products.

2c1-

Reagents: i, K,CO,; ii, base, DMF; iii, TiCl,, AcOH; iv, base

Scheme 18

Hindered enones take part in classical Robinson annulation sequences with difficulty. However, the reaction may be induced at very high pressure.lm Reaction of @unsaturated aldehydes, including cycloalkene carboxaldehydes, with (3-ethoxycarbonyl-2-oxopropylidene)triphenylphosphorane affords cyclohexenones in moderate yield.lo1 The highly regioselective rhodium-catalysed insertion of diazo-P-keto-esters to form 3-alkylcyclopentanones has been extended to provide an enantioselective Y. Ohtsuka and T. Oishi, Chem. Pharm. Bull., 1983,31,443. J. E. McMurry and D. D. Miller, J . Am. Chem. Soc., 1983, 105, 1660. 98 J. E. McMurry and D . D . Miller, Tetrahedron Lett., 1983, 24, 1885. 99 R. J. Pariza and P. L. Fuchs, J . Org. Chem., 1983,48, 2304. loo W. G . Dauben and R. A. Bunce, J . Org. Chem., 1983,48, 4642. lol K. M. Pietrusiewicz, J . Monkiewicz, and R. Bodalski, J . Org. Chem., 1983,48,788. 97

100

General and Synthetic Methods

cyclization by the expedient of using esters of chiral alcohols derived from camphor [equation (lo)]. lo2 Optical resolution of 3-methylcycloalkanones has

R

been reported using chiral 176-bis-(o-halogenylphenyl)-1 ,6-diphenylhexa-2,4diyne-l,6-diols (4) as complexing agents. lo3

Synthetic methods for the construction of cyclopentanone derivatives continue to benefit from improved carbonylation procedures. Stereoselectivity studies of intramolecular alkyne-alkene-octacarbonyldicobalt cyclizations have appeared , the results aiding the preparation of intermediates for the synthesis of dl-coriolin [equation (ll)].Io4 Alkyne hexacarbonyldicobalt complexes interact with 2,5-

dihydrofurans to give functionalized cyclopentenone derivatives directly, although the range of substituents allowable remains to be determined [equation (12)1.105

lo*

lo3 lo4 Io5

D. F. Taber and K. Raman, J . Am. Chem. SOC., 1983,-105,5935, F. Toda, K. Tanaka, T. Omata, K. Nakamura, and T. Oshima, J . Am. Chem. SOC., 1983,105,5151. C. Exon and P. Magnus, J . Am. Chem. SOC., 1983,105,2477. D. C. Biilington, Tetrahedron Lett., 1983, 24, 2905.

Aldehydes and Ketones

101

Allylzinc reagents have been found to be among the few species known so far to be capable of carbometallation of terminal alkynes and, with greater regiochemical control, silylacetylenes. The vinyl iodides formed on work-up with iodine can undergo either a stoicheiometric palladium-mediated cyclization with carbon monoxide or base-induced cyclization of a derived terminal carboxylic acid to give cyclopentanoid products (Scheme 19). Investigations of nucleophilic additions of

-

R

SiMe3

SiMe3

i,ii

R-E-

SiMe3

iv - v i

qH-

R

SiMe3

R

SiMe,

vii ,viii

8

0

Reagents: i, H,C=CHCH,ZnBr; ii, I,; iii, CO, Et,N, [Pd(PPh,),]; iv, Sia,BH; v, H,O,, NaOH; vi, Cr0,; vii, MeLi; viii, Bu'Li

Scheme 19

carbanions to 1,3-diene tricarbonyliron complexes indicate the possibility of a general synthesis of 3-substituted cyclopentanones via cyclization of the acyliron intermediates (Scheme 20) .lo7

$

CHO

-

i . i i ( $

CN

\ Fe(CO13

F -

0

i,ii

Fe(C013

CN

Reagents: i, Me,C(CN)Li; ii, H+

Scheme 20

Solvolysis of homoallylic brosylates with hydrogen peroxide offers a new route to medium-ring ketones via a two-carbon ring expansion [equation (13)].'08

OH E.-I. Negishi and J. A. Miller, J . Am. Chem. SOC., 1983, 105, 6761. M. F. Semmelhack, J. W. Herndon, and J. P. Springer, 1.Am. Chem. SOC., 1983, 105,2497 lO8 R. C. Ronald and T. S. Lillie, J . Am. Chem. Soc., 1983,105, 5709. Io7

General and Synthetic Methods

102

Macrocyclic ketones have been obtained from a three-carbon ring expansion of bromo-lactones of form ( 5 ) or the derived sulphones (Scheme 21).lo9The reaction

0 I

C

a R

\

OH

iv , ii

/i

Reagents: i, HBr, hv, petrol; ii, MeCO,H, BF,.Et,O; iii, Li, BrCH,CH,Br; iv, PhSH, AIBN; v, LiNPr',; vi, Al/Hg

Scheme 21

of related sulphonyl ketones affords penta-annulated products, which are also intermediates to large-ring ketones, e.g. muscone.l10 2 Synthesis of Functionalized Aldehydes and Ketones

Unsaturated Aldehydes and Ketones.-Dehydrogenation of aldehydes to the a$unsaturated derivative may be carried out using silver trifluoromethanesulphonate and a tertiary amine base, preferably N-methylmorpholine, catalysed by [PdCl,(PhCN),] .ll1 The method is applicable to ketones if stannous trifluoromethanesulphonate and N-ethylpiperidine are used. Direct dehydrogenation of 2-alkylcyclopentanones with cupric bromide is of interest in the preparation of prostanoid intermediates.ll* Rhodium trichloride catalyses the rearrangement of 2-methylenecyclopentanone to the endocyclic isomer.113 Oxidation of aldehyde trimethylsilyl enol ethers with lead(1v) acetate gives the enal when the starting material bears two /?-carbon sub~tituents.~'~ With other substitution patterns, or in the presence of potassium acetate and acetic acid, the product is the a-acetoxy-derivative. Ketone enolates 115 and their silyl enol C. Fehr, Helv. Chim. Acta, 1983,66, 2512. C. Fehr, Helv. Chim.Acta, 1983, 66,2519. l l 1 T. Mukaiyama, M. Ohshima, and T. Nakatsuka, Chem. Lett., 1983,1207. 112 D. D. Miller, K. B. Moorthy, and A. Hamada, Tetrahedron Lett., 1983,24,555. 113 B. W. Disanayaka and A. C . Weedon, Synthesis, 1983,952. 114 G. M. Rubottom, R. Marrero, and J. M. Gruber, Tetrahedron, 1983,39,861. I. Shimizu, I. Minami, and J. Tsuji, Tefrahedron Lett., 1983,24, 1797.

103

Aldehydes and Ketones

ethers 116 are dehydrogenated to enones via palladium-catalysed decomposition of their allyl enol carbonates. In the presence of tributyltin methoxide, the reaction may be extended to enol acetates [equation (14)].117 OAc

0

+

MeOSnBu3

4-

c02

+

(14)

AcOMe

Photolytically generated singlet oxygen has been reported as a reagent for the oxidation of a variety of simple cyclic olefins to the corresponding enones.l18The method was also shown to be applicable to acyclic olefins, and could be carried out on the mole scale. The activation of iodosobenzene with boron trifluoride etherate provides a reagent combination useful for the oxidation of 2-substituted allyl silanes to 2-(methy1ene)aldehydes [equation (191.119 PhI-0

R

BF3.Et20 -dioxan

(151

R H

The addition of alkenyl copper reagents and organocuprates to acyl halides to form enones is catalysed by palladium(0) complexes.120The catalyst appears to ,C02C

4 i ,ii ,i ,iii

0

H 2 Ph

ivl

1'

0

Reagents: i, KOH; ii, ButPh,SiC1, imidazole; iii, (COCI),; iv, Bu,SnH, AIBN; v, CO, cat. [BzClPdIIP W 2 1

Scheme 22 J. Tsuji, I. Minami, and I. Shimizu, Tetrahedron Left., 1983, 24, 5635. '1 J. Tsuji, I. Minami, and I. Shimizu, Tetruhedron Lett., 1983, 24, 5639. 11* E. D. Mihelich and D. J. Eickhoff, J . Org. Chem., 1983,48,4135. M. Ochiai, E. Fujita, M. Arimoto, and H. Yamaguchi, Tetrahedron Left., 1983, 24, 777. 120 N. Jabri, A. Alexakis, and J. F. Normant, Tetrahedron Lett.. 1983, 24, 5081. lI6

104

General and Synthetic Methods

reduce significantly further reactions of the product enones. Stereo-definition in the copper reagent is retained. A similar coupling occurs between an acyl halide and a tin derivative of benzyl acrylate and has been used to prepare precursors to the macrolide antibiotic pyrenophorin (Scheme 22).I2l Dithioacetals have been used as the equivalent of an alkenyl anion in a connective approach to the synthesis of enones (Scheme 23).12*In conjunction with alkyl iodides, a zinccopper couple promotes the acylation of alkenes by acid chlorides, in an aliphatic Friedel-Crafts-type reaction. 123

- '1 i.ii

PhS-SPh

PhS

SPh

OH

.

i iii

PhS

SPh

liv SPh Reagents: i, BunLi; ii, RICH,Br; iii, R2CHO; iv, p-MeC,H,SO,H; v, NaIO,

Scheme 23

Conditions for the use of 3-(dimethy1amino)acrolein derivatives for vinylogous Vilsmeier formylations of aromatic substrates have been determined. 124 Michael addition of organolithium reagents to enamino-ketones results in the formation of enones in improved yield when the reaction is carried out in hydrocarbon solvents.125Reduced basicity of the lithium reagent is a major factor controlling the success of this route to enones. Factors influencing stereoselectivity in the conjugate addition-elimination reaction of cuprates withp-alkylthioenones include the reaction temperature and choice of ethereal solvent.126Reaction of (E)-substrates occurs with predominant retention of configuration in tetrahydrofuran solvent systems, whereas under diethyl ethereal conditions the stereochemistry is reversed. The nitro-group controls regiochemistry in a sequence for the preparation of a-methylene-ketones via a hydroxymethylation under weakly basic conditions (Scheme 24). 127 In condensations of a-silylketimines with carbonyl compounds to form enones, silicon controls both the site of deprotonation of the imine and the stereochemisJ. W. Labadie and J. K. Stille, Tetrahedron Lett., 1983, 24,4283. J. Durman, J. Elliott, A . B. McElroy, and S . Warren, Tetrahedron Lett., 1983, 24, 3927. Iz3 T. Shono, I. Nishiguchi, M. Sasaki, H. Ikeda, and M. Kurita, J . Org. Chem., 1983,48,2503. F.-W. Ullrich and E . Breitmaier, Synthesis, 1983, 641. 12s T. Mukaiyama and T. Ohsumi, Chem. Lett., 1983,875. 126 R. K. Dieter and L. A . Silks, J. Org. Chem., 1983, 48,2786. lZ7 N. Ono, H. Miyake, M. Fujii, and A, Kaji, Tetrahedron Lett., 1983, 24, 3477.

12*

105

Aldehydes and Ketones

0

0

liii

Reagents: i, HCHO, cat. PPh,, PriOH; ii, Ac,O, py; iii, Bu,SnH, AIBN; iv, DBU

Scheme 24

try of the elimination step [equation (16)]. 128 The reaction gives substantial amounts of the less readily available (2)-isomer of the enone, and has been applied in the synthesis of retinal analogues. Improved conditions for the pre-

R2 Me35

0 (16)

I?'*

R

R

paration of unsaturated ketones by Horner-Wittig reactions of diethyl 2-0x0alkanephosphonates with aldehydes have been developed, using highly concentrated aqueous solutions of potassium carbonate in the absence of an organic solvent. 129 In contrast to esters, orthoesters react with alkynylborates in the presence of titanium(1v) chloride, giving, after the usual alkaline peroxide oxidation, a,/?unsaturated ketones [equation (17)].130 The result of nucleophilic addition to the

allenyl thioacetal S-oxides (6) depends on the reagent employed (Scheme 25) .131 The control offered allows considerable scope for the preparation of a wide range of enone derivatives. A. A. Croteau and J. Termini, Tetrahedron Lett., 1983, 24,2481. J. Villieras and M. Rambaud, Synthesis, 1983, 300. 130 S. Hara, H. Dojo, and A. Suzuki, Chem. Lett., 1983, 285. 131 I. Cutting and P. J. Parsons, J . Chem. SOC., Chem. Commun., 1983, 1209. 12*

129

General and Synthetic Methods

106

i.ii

H

O

R2

A

\\\

0

II kc=(,,

R'

R2

... 111

~

R'

SPh

H

(6)

R'

vi X = OEt or SPh

R2

CHO

SPh

SPh

OH

SPh Reagents: i, 2Bu"Li; ii, 2PhSCl; iii, MeLi; iv, Me,CuLi; v, NaX; vi, HgCl,, H,O, MeCN

Scheme 25

A new unsaturated lithium reagent , prepared from (a-ethoxybutenyl)tributyltin, shows promise for the preparation of propenyl ketones (Scheme 26).132Zinc salts of enol ether anions couple with alkenyl (and aryl) halides when

iii

OH Reagents: i, BunLi; ii, R1K2CO;iii, H,O+

Scheme 26

catalysed by a palladium(0) species, forming enol ether derivatives of enones (Scheme 27).133Allenyl ethers react under similar conditions, to achieve an acryloylation of an alkenyl halide. Polyenic enol ethers of enals have been formed iv. ii, iii

1

Reagents: i, Bu'Li; ii, ZnC1,; iii, PdO, PPh3, R1R2C= CHI; iv, BunLi; v, H 3 0 +

Scheme 27 132 133

J.-P. Quintard, B. Elissondo, and M. Pereyre, J. Org. Chem., 1983,48, 1559. C. E. Russell and L. S. Hegedus, J . Am. Chem. Soc., 1983,105, 943.

Aldehydes and Ketones

107

by homologation of enals with (alkoxymethy1)phosphonate reagents.134Predominant (E)-stereoselectivity in the newly formed double bond was noted. l-tButylthio-3-methoxy-1-alkenes show intriguing potential as reagents for the preparation of unsaturated carbonyl compounds. The site of deprotonation of the (2)-isomer is highly base-dependent. n-Butyl-lithium in conjunction with potassium t-butoxide metallates at the 1-position, whereas the 2-lithio-derivative is the product of deprotonation by s-b~tyl-lithium.'~~ In contrast, the (E)-isomer forms the allylic anion.136All these anions have complementary properties in strategies for the design of syntheses of enones (Scheme 28). 0 R1+H

R' MQsBu' Me0 R'

R2

SBu'

AJ R'

Me0

.

iii iv

Me0

I

SBu'

I

Reagents: i, KOBut, Bu"Li; ii, BusLi; ii, LiNPr',; iv, RI; v, hydrolysis

Scheme 28

A deconjugated enone is the product from acylation of the zirconacene complex of isoprene with The reaction is highly regioselective for the 1-position of the diene, and works for a,@-unsaturated esters, giving the a,@,@', y' -unsaturated ketone [equation (18)]. Deconjugation occurs on debromination of a-bromo-a,@-unsaturated cyclic ketones with diethyl phosphte. 138

Tributyltin enolates are alkylated by 1-bromo-1-alkenes with retention of configuration in the presence of palladium chloride complexes [equation (19)].139 Y . Vo-Quang, D. Carniato, L. Vo-Quang, and F . Le Goffic,J. Chem. SOC., Chem. Commun., 1983, 1505. 13s C. Bibang Bi Ekogha, 0. Ruel, and S . A. Julia, Tetrahedron Lett., 1983,24,4825. 136 0 .Ruel, C. Bibang Bi Ekogha, and S . A. Julia, Tetrahedron Lett., 1983,24,4829. 137 M. Akita, H. Yasuda, and A. Nakamura, Chem. Lett., 1983, 217. 138 T. Hirao, T. Masunaga, K.-I. Hayashi, Y. Ohshiro, and T. Agawa, TetrahedronLett., 1983,24,399. 139 M. Kosugi, I. Hagiwara, and T. Migita, Chem. Lett., 1983, 839.

lM

General and Synthetic Methods

108

The same metals appear in a method for the coupling of allylic halides, stannanes, and carbon monoxide [equation (20)] a-Alkenylated ketones also result from a reductive rearrangement of alkynyl hal0h~drins.I~~ Unfortunately, under the

reaction conditions further reduction occurs, necessitating reoxidation to obtain the ketone (Scheme 29). The stereochemistry required by the rearrangement process is that observed in the major product from addition of alkynyl carbanions

L

iii

0li1 R

Reagents: i, LiAlH, or DIBAL; ii, H+; iii, CrO,, py

Scheme 29

to a-halogeno-ketones. Base-induced fragmentation of 3-sulphonylcyclobutanols can be induced to afford p-methylene-ketones if potassium hydride is employed as base [equation (21)].142

OH

141

14*

F. K. Sheffy and J. K . Stille, J . Am. Chem. Soc., 1983, 105, 7173. P. A. Wender, D. A. Holt, and S. M. Sieburth, J. Am. Chem. SOC.,1983, 105, 3348. T. Takeda, K. Ando, and T. Fujiwara, Chem. Left., 1983, 1285.

Aldehydes and Ketones

109

Alkynyl boranes, prepared from alkynyl carbanions and boron trifluoride etherate, react with tertiary amides at low temperatures in THF to give acetylenic ketones. 143 Boron tribromide catalysis makes the hydroboration of 1-bromoalkynes by thexylchloroborane proceed at a synthetically useful rate (Scheme 30).14 The product is the equivalent of an acylating agent for alkynyl anions. CL

l+,B(

+

-

ii

i

.SMe2

H

Br-e-R’

Br

R’

OPri

hR’

Br

I

iii

OPr’

Reagents: i, cat. BBr,; ii, NaOPr’; iii, LiC=CR2; iv, NaOH, H202

Scheme 30

Thiolesters acylate trimethylsilylacetylenes rapidly in the presence of silver tetrafluoroborate to give the corresponding acetylenic ketone. 145 Stereospecificitesin the synthesis of chiral ynones from optically active terminal alkynes and acid chlorides via Lewis acid- and palladium-catalysed acylations have been assessed.146 a-Substituted Aldehydes and Ketones.-The acylation-rearrangement of nitrones offers a new method for the a-oxygenation of aldehydes and ketones (Scheme 31).147The m-chloroperbenzoic acid oxidation of silyl enol ethers is the key to recent syntheses of the terpene lactones actinidiolide and aeginetolide (7) [equation (22)].148 Boron trifluoride etherate-catalysed rearrangement of ate complexes formed from 1,2-dimethoxyethenyl-lithium and trialkylboranes leads to borane intermediates which may be oxidized to methoxymethyl ketones (Scheme 32; cf. Scheme 12).149 M. Yamaguchi, T. Waseda, and I. Hirao, Chem. Lett., 1983,35. H. C. Brown, N. G . Bhat, and D. Basavaiah, Synthesis, 1983,885. 145 Y. Kawanami, T. Katsuki, and M. Yamaguchi, Tetrahedron Lett., 1983,24,5131. 146 G. Giacomelli, C. Rosini, A. M. Caporusso, and F. Palla, J . Org. Chem., 1983,48,4887. 14’ C. H. Cummins and R. M. Coates, J . Org. Chem., 1983,48, 2070. 14* G . M. Rubottom and H. D. Juve, J . Org. Chem., 1983,48, 422. 149 J. Koshino, T. Sugawara, T. Yogo, and A. Suzuki, Chem. Lett., 1983, 933.

143 144

110

General and Synthetic Methods

0-

no H

I H

111

H

0

li \o

hNx H

Reagents: i, Bu'NHOH, TsOH, Na,SO,, CH,Cl,; ii, RCOCl; iii, H,O, AcOH, AcONa

Scheme 31

OSiMe3

ArC03H

(7)

iiv OMe

Na+

Reagents: i, Bu"Li; ii, BR,; iii, BF3.Et20;iv, NaOMe, MeOH; v , H,02

Scheme 32

The trapping of acyl anions with carbonyl compounds continues to be a general method explored for the synthesis of a-hydroxy-ketones. The uses of the anions derived from N-t-butylhydrazones of aldehydes 150and from the addition of alkylR. M. Adlington, J. E. Baldwin, J. C. Bottaro, and M. W. D. Perry,J. Chem. SOC., Chem. Commun., 1983, 1040.

Aldehydes and Ketones

111

lithium reagents to carbon monoxide 151-153 have been described. Trimethylsilyl ethers of cyanohydrins react with Grignard reagents to form acy10ins.l~~ The reaction requires only small excesses of the Grignard reagent, but is unsatisfactory with alkyl-lithium reagents. Regioselective Lewis acid-mediated a-t-alkylation of acyloins represents a further method for the preparation of highly substituted a-hydroxy-ketones [equation (23)].155

High enantioselectivity has been observed in the protonation of the enediolate derived from benzoin by (2R,3R) 0,O-dipivaloyltartaric acid at low temperatures. 156 An efficient 1,3-asymrnetric induction in the reduction of P-keto-sulphoxides using either sodium borohydride 157 or lithium aluminium hydride 158 leads to carbonyl-protected a-hydroxy-aldehydes(Scheme 33). The two diastereoisomers 0-

0: \

1

og-Ar A r = p -c&i~Me

R2

SR’

R1 = Me or Ar

lii !*

SR

R2

SR

Reagents: i, NaH, R2C02Et;ii, NaBH, or LiAIH4; iii, A q O , py; iv, Cu2CI2,AcOH

Scheme 33

formed have been separated by chromatography or by crystallization158or the substrates may be prepared in optically active form at sulphur by starting the sequence with the resolved formaldehyde dithioacetal S-oxide.15’ The enantioselective preparation of a-hydroxy-aldehydes having a tertiary chiral centre D. Seyferth, R. M. Weinstein, and W.-L. Wang, J. Org. Chem., 1983, 48, 1144. D. Seyferth, R. M. Weinstein, W.-L. Wang, and R. Hui, Tetrahedron Lett., 1983,24, 4907. 153 R. M. Weinstein, W.-L. Wang, and D. Seyferth, J. Org. Chem., 1983, 48, 3367. ls4 L. R . Krepski, S . M. Heilrnann, and J. K. Rasmussen, Tetrahedron Lett., 1983,24,4075. 155 M. T. Reetz and H . Heimbach, Chem. Ber., 1983,116,3702. lS6 L. Duharnel and J.-C. Launay, Tetrahedron Lett., 1983,24,4209. 157 K. Ogura, M. Fujita, T. Inaba, K. Takahashi, and H. Jida, Tetrahedron Lett., 1983,24,503.

15* Is*

General and Synthetic Methods

112

starting from aminals derived from (S)-2-(anilinomethyl)pyrrolidine has been extended to the synthesis of chiral a-benzyloxy-aldehydes (Scheme 34) .159 The reaction was applied in a synthesis of exo-( +)-brevicomin.

- (h i -iv

o p P h

vi

V

Ph

Ph

i

HO

.OxCH0 R H Reagents: i, DIBAL; ii, MeOH; iii, RMgBr; iv, NH,Cl; v, NaH, PhCH,Br; vi, 2% HCl, H 2 0 OMe

R

R

Scheme 34

In a sequence which is equivalent to the epoxidation of an enone, the adduct between the platinum complex (8) and (E)-but-Zenal reacts with trifluoroacetic acid to form the oxirane (9) with high stereoselectivity, a result of significance if the reaction can be made catalytic [equation (24)].la Modest asymmetric induc-

’

+

P ‘lt’ Ph3P

-

0

Ph3P

OHC-

0‘

OHC,

H

(24)

OH?\+ 0

tion occurs in the cyclodextrin-catalysed epoxidation of trans-chalcones.161 2,3Epoxycyclohexanonesof very high optical purity result from resolution via complexation with the optically active diyne (4; X=C1).162 Addition reactions of trimethylsilyl enol ethers and ethoxycarbonylnitrene, formed in situ by thermolysis of ethyl azidoformate, have been found to be selective, giving N-ethoxycarbonyl-a-amino-ketones [equation (25)].163 Optically Me3SiO

+

R l h , R2

-% A

N3C02Et

NHCOzEt

R1

(25)

R2

G . Guanti, E. Narisano, L. Banfi, and C. Scolastico, Tetrahedron Lett., 1983,24,817. M. Asami and T. Mukaiyama, Chem. Lett., 1983, 93. M. J. Broadhurst, J. M. Brown, and R. A. John, Angew. Chem., Znt. Ed. Engl., 1983,22,47. 161 S. Banfi, S. Colonna, and S. Julia, Synth. Commun., 1983,13, 1049. K. Tanaka and F. Toda, J . Chem. SOC., Chem. Commun., 1983,1513. la S. Lociuro, L. Pellacani, and P. A. Tardella, Tetrahedron Lett., 1983,24,593.

lS8

159

Aldehydes and Ketones

113

active N-(t-butoxycarbony1)-a-amino-aldehydeshave been prepared in the past by reduction of amino-acid derivatives. Reduction of the (N-methoxy-Nmethy1)amides using lithium aluminium hydride is reported to give the aldehyde with high optical activity. The lithium salts of N-protected (acyl, alkoxycarbonyl, or arylsulphonyl)chiral a-amino-acids serve as precursors for the synthesis of a-amino-ketones. The carboxylates react with alkyl-lithium and Grignard reagents with very little ra~emizati0n.l~~ Trifluoroacetyl nitrate, prepared in situ from ammonium nitrate and trifluoroacetic anhydride, is an excellent nitrating agent , capable of converting enol acetates regiospecifically into a-nitro-ketones.166The reagent is powerful enough to nitrate tetrasubstituted enol derivatives, providing a method for the preparation of 2-alkyl-2-nitro-alkanones. Replacement of the nitro-group of a-nitro-ketones by hydrogen may be accomplished by treatment of their tosylhydrazoneswith lithium aluminium hydride The use of the corresponding deuteride affords the regiospecifically a-deuteriated product. 168 N-Bromosuccinimide was a suitable reagent for the cleavage of the tosylhydrazone without loss of the isotopic label. P-Phosphono-enamines are intermediates in a convenient route to formyl alkanephosphonates (Scheme 35).169 The method relies on the acidity of alkane

R2

1

iii R *

+H

liv

Reagents: i , BunLi;ii, DMF; iii, H,O; iv, H 3 0 +

Scheme 35

phosphonates and the reaction of the conjugate base with dimethylformamide. a-Phosphono-vinyl sulphides may be converted into (alky1thio)methylketones by reaction with aldehydes in the presence of a thiolate (Scheme 36).170 The reaction was only exemplified using benzaldehydes. J.-A. Fehrentz and B. Castro, Synthesis, 1983,676. C. G . Knudsen and H. Rapoport, J . Org. Chem., 1983,48,2260. 166 P. Dampawan and W. W. Zajac, Synthesis, 1983,545. 167 G . Rosini, R. Ballini, and V. Zanotti, Synthesis, 1983, 137. la G . Rosini and R. Ballini, Synthesis, 1983,228. 169 E. E. Aboujaoude, N. Collignon, and P. Savignac, Synthesis, 1983,634. 170 M. Mikoiajczyk, P. Kielbasinski, and S. Grzejszczak, Synthesis, 1983,332.

165

114 0

II

(EtO)2PW

-

General and Synthetic Methodr 0

0

II

I

( Et

o)2pY-cI SMe

Ar

k\5R

II

(Eto)2pY / liii I1

SMe

At-

-

v ii

0

II

iv. v

$SR SMe

0

(Et0)2PFSR

SMe

Reagents: i , MeSC1; ii, Et,N; iii, RSH, NaOEt, EtOH; iv, NaH; v, ArCHO; vi, RSNa, ArCHO; vii, TiCl,, H 2 0 , MeCN

Scheme 36

Methyl methylthiosulphonate has been shown to be a superior reagent for the a-methylthiolation of enolates of cyclic ketones. 171 Comparison was made with literature methods using either dimethyl disulphide or methyl sulphenyl chloride. A convenient method for the preparation of the thiosulphonate was also described. Cyclic a-diazo-ketones react with phenylsulphenyl chloride to afford a-chloro-a-(pheny1thio)-cycloalkanones7 which are dehydrochlorinated to the enone under basic conditions.17* The reaction also proceeds with terminal diazoketones the products undergoing ready Friedel-Crafts alkylation of benzene to afford a-phenyl-a-(pheny1thio)-ketones [equation (26)]. Conditions have been

L,N -~

R

PhSCl

R%Cl

SnClL PhHb

R%Ph

SPh

(26) SPh

defined for the efficient conversion of a-chloroaldimines into a-sulphenylated aldimines.173 Oxalic acid in a two-phase (water-dichloromethane) system was recommended for hydrolysis to the sulphenylated aldehyde. Carbanion-accelerated Claisen rearrangements of ally1 enol ethers of a-sulphonyl-ketones have been shown to be highly stereoselective as observed in the thermal reaction [equation (27)] The products are in accord with a chairArS02

NaH

__t

yo),

ArS02

\ -K H

(27) I

I

D. Scholz, Synthesis, 1983, 944. M. A. McKervey and P. Ratananukul, Tetrahedron Lett., 1983, 24,117. 173 N. De Kimpe, R. VerhC, L. De Buyck, and N. Schamp, Synthesis, 1983,632. 174 S . E. Denmark and M. A. Harmata, J . Org. Chem., 1983,48,3369.

172

Aldehydes and Ketones

115

like transition state. Rearrangement of a$-epoxy-sulphones in the presence of boron trifluoride etherate gives rise to (presumed) a-sulphonyl-aldehydes (Scheme 37). 175 The corresponding enamines were isolated after treatment of the reaction mixture with a secondary amine.

I

jl

TO1 0 2 s

H

.

A Ar

H

T0102S

lii Ar

NR1R2

> H- ( -

T0102S

+

Reagents: i, PhCH,NEt,, C1-, NaOH, H,O, MeCN, ArCHO; ii, BF3.Et,0, CH,Cl,; iii, R1R2NH

Scheme 37

Addition of a selenosulphonate to an acetylene forms synthetically versatile sulphones which may be converted to, inter aha, a-sulphonyl-ketones. 176 The a-(phenylse1eno)vinyl-sulphones may be converted either into the unprotected P-keto-sulphone by aqueous perchloric acid, or into the acetal under basic conditions (Scheme 38). R1-E-R2

Rj_(024r

,A_ PhSe

R2

- Rgo

/ 0

PhSe

R2

lo iii ,

R2

Reagents: i, PhSeS0,Ar; ii, m-ClC6H,CO3H; iii. (CH,OH),, KOH; iv, HClO,, H,O

Scheme 38

Addition of bromine to a-ethoxyvinyl ketones followed by acidic hydrolysis constitutes a simple route to brornomethyl-l,2-diketone~.'~~ An investigation of the properties of the lithium salt of dichloromethyl phenyl sulphoxide has A. A. M. Houwen-Claassen, J. W. McFarland, B. H. M. Lammerink, L. Thijs, and B, Zwanenburg, Synthesis, 1983, 628. 176 T. G. Back, S. Collins, and R. G. Kerr, J. Org. Chem., 1983,48, 3077. N. K. Hamer, J . Chem. SOC.,Perkin Trans. 1, 1983, 61. 175

5

116

General and Synthetic Methods

revealed its use in the preparation of dichloroketones from aldehydes [equation (28)].178 The addition of chlorine to a,p-unsaturated ketones in tetrahydrofuran -0 RCHO

+

CL

zvk, j, OH

Li --+

Phi-+ CL

-L R

(28)

CHCl2

,SPh

-0

+

at low temperatures has been found to involve incorporation of the solvent [equation (29)].179The reaction is regiospecific, and leads to the a-chloro-/3alkoxy-ketone.

A convenient preparation of bromoacetaldehyde has been published, giving the conditions necessary for the successful ozonolysis of 1,4-dibromobut-2-ene.180 The ozonide was reduced by triphenylphosphine. Uses of the aldehyde as an electrophile in a variety of reactions were also described. In a complementary paper, 1-bromo-2-methoxyvinyl-lithium has been used as a bromoacetaldehyde

[ A] AR' - - -

anion equivalent (Scheme 39). 18* d6r

Me0

HO

ii

-

-

Br

Me0

Br

Me0

iii

& ' R2

R'

R2

8r

0

Br

Reagents: i, BunLi, -8o"C, Et,O; ii, R1R2CO;iii, HCl, H,O

Scheme 39

Examples of the use of sodium hydrogen telluride for the dehalogenation of a-halogeno-ketones have appeared. 182 The method described is mild and high yielding. a-Bromo-ketones act as precursors to silyl enol ethers via debromination using either trimethylsilyltributyltin in the presence of a palladium(0) catalyst [equation (30)] 183 or lithium di-isopropylamide followed by trimethylsilyl

V. Reutrakul and K. Herunsalee, Tetrahedron Letr., 1983, 24,527. M. Bertrand, J.-P. Dulcere, J. Rodriguez, and J.-P. Zahra, Tetrahedron Lett., 1983, 24, 1967. G. A. Kraus and P. Gottschalk, J. Org. Chern.,.1983,48,2111. 181 R. H. Smithers, J . Org. Chern., 1983, 48, 2095. 182 A. Osuka and H. Suzuki, Chern. Lett., 1983,119. M. Kosugi, T. Ohya, and T. Migita, Bull. Chern. SOC.Jpn., 1983, 56, 3539.

178

179

Aldehydes and Ketones

117

ch10ride.l~~ In the latter case, hydrolysis in place of silylation leads to the expected ketone in good yield. The use of zinc in combination with trimethylsilyl chloride for the reduction of a-chloro-ketones to silyl enol ethers has been extended to the preparation of difluoro-enol ethers from chlorodifluoromethyl ketones. lXsThe introduction of fluorine a- to a carbonyl group has been achieved by anodic oxidation of enol acetates in the presence of an acid fluoride salt of triethylamine ls6 and by the use of acetyl hypofluorite as a fluorinating agent for 1,3-dicarbonyl compounds. Ig7 Thermolysis of the adducts formed between aldehydes and the lithium salt of fluoromethyl phenyl sulphoxide leads to fluoromethyl ketones [cf. equation (28)].ls8 Dicarbonyl Compounds.-Coupling of acyl chlorides with vinylstannanes to give enones is catalysed by palladium(I1) salts. The use of vinyl substrates bearing a-methoxy substituents leads to monoprotected a-diketones from which the diketone may be released by acid.lX9Nafion-H has been recommended as a catalyst for the cleavage of a-keto-acetals to the dicarbonyl compound. 190 Nitroaldol reactions with a-keto-aldehydes or their hemiacetals lead to 1,Zdiketones after elimination of the nitrite group [equation (31)]. 191 a-Amino-acids are the

The starting point for a route to 1,2-diketones via isoxazolinones (Scheme 40).192 method is applicable to the synthesis of a - k e t o - a ~ i d s . ' ~ ~ ~ ' ~ ~ Synthetic applications of 3-alkoxyacroleins as equivalents of malondialdehyde have been described. 19s Magnesium salts of cyclic thioureas act as efficient carriers of carbon dioxide for the a-carboxylation of ketones. 196 Acylation of the lithium enolate of trimethylsilyl acetate affords excellent yields of p-keto-acids after the very mild hydrolysis necessary for silyl Methyl ketones were isolated in very good J.-E. Dubois, C. Lion, and J.-Y. Dugast, Tetrahedron Lett., 1983, 24, 4207. M. Yamana, T. Ishihara, and T . Ando, Tetrahedron Lett., 1983, 24,507. lX6 E. Laurent, R. Tardivel, and H. Thiebault, Tetrahedron Lett., 1983,24, 903. 0. Lerman and S. Rozen, J . Org. Chem., 1983,48,724. lax V. Reutrakul and V. Rukachaisirikul, Tetrahedron Lett., 1983, 24, 725. J. A. Soderquist and W. W.-H. Leong, Tetrahedron Lett., 1983, 24, 2361. K. S. Petrakis and J. Fried, Synthesis, 1983, 891. 191 K. S. Petrakis, G. Batu, and J. Fried, Tetrahedron Lett., 1983, 24, 3063. 192 J. Leyendecker, U. Niewohner, and W. Steglich, Tetrahedron Lett., 1983,24,2375. 193 C. Klein, G. Schulz, and W. Steglich, Leibigs Ann. Chem., 1983, 1623. 194 C. Klein, G. Schulz, and W. Steglich, Leibigs Ann. Chem., 1983, 1638. 195 J. Maddaluno and J . d'Angelo, Tetrahedron Lett., 1983, 24, 895. 196 N. Matsumura, N. Asai, and S. Yoneda, J . Chem. SOC., Chem. Commun., 1983, 1487. 197 P. J. Cowan and M. W. Rathke, Synth. Commun., 1983,13,183.

184

118

General and Synthetic Methods

Nxo

H

CF3

Reagents: i, (CF,CO),O; ii, NEt,, CH=CHCO,Bu';

iii, R'MgX or R'Li; iv, HC0,H; v, H,Oi

Scheme 40

yield on slightly more vigorous hydrolysis. 13-Keto-estersare formed in high yield when methyl cyanoformate reacts with regioselectively preformed lithium ketone en01ates.l~~ This electrophile may be used for the direct preparation of nonenolizable keto-esters. A variety of carboxylate derivatives, including dialkylformamides, acyl chlorides, and alkyl carbonates react with P-lithioenamines to form P-ketoaldehydes, -ketones, and -esters , respectively, in excellent yield, after hydrolysis of the enaminone intermediates.199 A range of enaminone derivatives has also been prepared through condensation of enol silyl ethers with oxime mesylates in the presence of organoaluminium reagents (Scheme 41) .200 Ethylaluminium chlorides were the preferred Lewis acids for the induction of the Beckmann rearrangement. ,OS02Me

+

m-

YR OS i Me3

Reagent: i, Et2A1Cl

Scheme 41 L. N. Mander and S. P. Sethi, Tetrahedron Lett., 1983, 24, 5425. L. Duhamel, J.-M. Poirier, and N. Tedga, J . Chem. Res. (S), 1983, 222. *O0 Y. Matsumura, J. Fujiwara, K. Maruoka, and H. Yamamoto, 1. Am. Chem. SOC., 1983,105,6312. lg8

Iw

Aldehydes and Ketones

119

The alkylation of silyl enolates by phenylthioalkyl chlorides has been extended to a-phenylthio-a-chloro-esters 201 and -ketones,2o2leading to synthetic routes to 1,6dicarbonyl derivatives (Scheme 42). y-Keto-aldehydes,-ketones, -esters, and OSiMe3

R

1

4

/

-k

0 R = OMe, a l k y l , or a r y l

R2

R

R1

R2

0

liii

Reagents: i , ZnBr, or TiCI,; ii, NaIO,, MeOH; iii, Raney Ni

Scheme 42

-nitriles result from the reductive coupling of acid anhydrides with activated alkenes [equation (32)].203 The procedure uses chemical or electrochemical

(R’C0120

4-

R2Jz

.

e‘. v i t . hv 812

R

1

q

Z

(32)

R2

z = CHO, CORG,

C O ~ ,Ror~ CN

reduction whilst irradiating in the presence of vitamin BIZ.Other cobalt complexes may be used, serving to modify the reduction potential required for reaction to be observed. Combination of two known reactions, the ready palladium-catalysed allylation of potassium enoxyborates and the mercury(I1)formic acid-mediated hydrolysis of vinyl chlorides to ketones, offers another approach to the synthesis of 1,4- and 1,5-diketones (Scheme 43).204 The ozonolytic cleavage of cyclic enones may be convenient on the very small scale, but with larger amounts care has to be taken with regard to build-up of ozonide intermediates. An ozonide decomposition which may be carried out concomitantly with the ozonolysis has been developed, using basic hydrogen peroxide in the presence of a phase-transfer catalyst [equation (33)].2u5 An added 201

2M ,03 204 ,05

I. Fleming and J. Iqbal, Tetrahedron Lett.. 1983. 24, 327, L. Duhamel, J. Chauvin, and C. Goument, Tetrahedron Lett., 1983, 24.2095. R. Scheffold and R. Orlinski, J. Am. Chem. Soc., 1983,105,7200. E.-I. Negishi, F.-T. Luo, A. J. Pecora, and A. Silveira, J. Org. Chem., 1983,48,2427. J. A. Cella, Synth. Commun., 1983, 13,93.

General and Synthetic Methods

120

I

I

R2

R2

liv

ti,ii

0

R* Reagents: i, KH or KN(SiMe,),; ii, BEt,; iii, ClCH,CH= HCOzH

C(Cl)Me, [Pd(PPh,),]; iv, Hg(OAc),,

Scheme 43

0

benefit is the extraction of the product acid from the dichloromethane phase throughout the oxidation. Investigations of metal-assisted cleavage of silyloxycyclopropanes indicate that silver(1) and copper(I1) tetrafluoroborates lead to symmetrical 1,6-diketones, with deposition of the metal [equation (34)].206

3 Protection and Deprotection of Aldehydes and Ketones Aldehydes and ketones are readily converted into their 1,3-dioxolanes by reaction with a slight excess of ethylene glycol in the presence of trimethylsilyl chloride ,*07 or by bis(trimethylsily1oxy)ethane in the presence of electrochemically generated acid.208Mixed acetals may be prepared without the formation of mixtures by acetoxymercuration of a vinyl ether in the presence of a slight excess of an alcohol.20YDemercuration was effected in basic solution by either sodium borohydride or sodium trithiocarbonate. Copper salts may also be used to I. Ryu, M. Ando, A. Ogawa, S. Murai, and N. Sonoda, J . A m . Chem. SOC.,1983, 105,7192 *a7 T. H. Chan, M. A. Brook, and T. Chaly, Synthesis, 1983, 203. 208 S . Torri and T. Inokuchi, Chem. Lett., 1983, 1349. 2y R. K. Boeckman and C. J . Flann, Tetrahedron Lett., 1983,24,4923. 2rm

Aldehydes and Ketones

121

catalyse the addition of an alcohol or a carboxylic acid to a vinyl ether.210 By maintaining reaction temperatures at ca. 20"C, unsymmetrical acetal derivatives may be prepared. A polystyrene resin-bound diol has been described for the isolation of aldehydes and ketones from mixtures, and as a protecting group for carbonyl compounds during other transformations whilst attached to the resin.211Loadings were of the order of 1 mmole of the carbonyl compound per gram of resin. An interesting observation indicates that cyclohexa-l,6dione forms the monoacetal in ca. 80% yield on acetalization with butane-174-diol, a higher yield of a monoprotected derivative than with many diols.212 Titanium(r1) chloride shows excellent activity in the conversion of aldehydes and ketones into thioacetals with alkyl thiols and d i t h i ~ l s and , ~ ~ ring-opens ~ y-lactols to hydroxy-aldehydes protected as the ethylene d i t h i ~ a c e t a lBis(di.~~~ isobutylaluminium)ethane-1,2-dithiolate converts acetals into ethylenedithioacetals whereas ketones do not react, offering a useful selectivity.215 Cyanohydrin anions are produced from cyanide ion and carbonyl compounds under phase-transfer catalysis by 18-cr0wn-6.~~~ The anions may be trapped in situ by acid chlorides, anhydrides, or alkylating agents. Cyanohydrin ethers may also be formed by treatment of acetals with trimethylsilyl cyanide.217Following the conversions of acetals into cyanohydrin ethers by trimethylsilyl cyanide, the (potentially explosive!) azido-ethers may be prepared in similar fashion from the silyl azide when catalysed by tin(1v) chloride.218 Iron(m) chloride is an effective catalyst for the conversion of a variety of aldehydes into geminal d i a c e t a t e ~ . ~ ~ ~ Trimethylsilyl chloride in combination with acetic anhydride furnishes enol acetates from saturated and conjugated ketones.220Regio- and stereo-selective syntheses of enol boranes enable the selective preparation of enol silyl ethers, as N-trimethylsilylimidazole is an efficient reagent for the exchange of silicon for boron [equation (35)].221 Rhodium-catalysed isomerization of /?-trimethylsilyl

M. Tordeux, R. Dorme, and C. Wakselman, Synth. Commun., 1983, 13,629. P. Hodge and J. Waterhouse, J . Chem. SOC., Perkin Trans. 1, 1983, 2319. 212 J. A . Hyatt, J . Org. Chem., 1983, 48, 129. 213 V. Kumar and S. Dev, Tetrahedron Lett., 1983, 24, 1289. 214 P. C. Bulman-Page, R. A. Roberts, and L. A. Paquette, Tetrahedron Lett., 1983,24,3555. 215 T. Satoh, S. Uwaya, and K. Yamakawa, Chem. Lett., 1983, 667. 216 R. Chhevert, R. Plante, and N. Voyer, Synth. Commun., 1983, 13, 403. 217 S. Kirchmeyer, A. Mertens, M. Arvanaghi, and G. A. Olah, Synthesis, 1983, 498. 218 S. IGrchmeyer, A. Mertens, and G. A . Olah, Synthesis, 1983. 500. 219 K. S. Kochhar, B. S. Bal, R. P. Deshpande, S . N. Rajadhyaksha, and H. W. Pinnick, J . Org. Chem., 1983,48,1765. 220 P. K. Chowdhury, R. P. Sharma, and J . N. Barua, Tetrahedron Lett., 1983,24, 3383. 221 J. Hooz and J. Oudenes, Tetrahedron Lett., 1983, 24, 5695. 210

211

122

General and Synthetic Methods

alcohols offers an additional regioselective route to silyl enol ethers.222

N-Phenyltrifluoromethanesulphonimideis an efficient reagent for the conversion of regiospecifically generated enolates into enol t r i f l a t e ~ . ~ ~ ~ Further examples of the in situ protection of aldehydes as aldimines have been described, allowing for example the selective methylenation of a ketone in the presence of an aldehyde.224 The N-t-butylaldiminewas cleaved during chromatographic isolation of the products. Girard reagents have been used in conjunction with silica gel for the selective in situ protection of carbonyl groups.225More reactive or less hindered carbonyl groups were selectively protected in competitive reduction studies. Titanium tetrakis(dialky1amides)show discrimination in chemoselective blocking of carbonyl groups, enabling Grignard and aldol reactions to be induced at ketonic centres in the presence of aldehydes.226 Shortest possible reaction times, using tetrahydrofuran as solvent and diethyl ether as the recrystallization solvent, have been recommended for the preparation of the sensitive-tosylhydrazones of aldehydes.227 Titanium(1v) chloride, particularly in combination with lithium iodide,228and dimethylboron and diphenylboron bromides 229 have been recommended for the cleavage of acetals and ketals to the parent carbonyl compounds. The two-phase system formic acid-pentane hydrolyses 3-alkenylacetals at room temperature with minimal isomerization to the conjugated enal.230The isomerism may be effected at elevated temperatures. The method has been applied to the formation of 3-alkynylaldehydes. The electrochemical deprotection of thioacetals has been extended to substrates bearing a /3-phosphonium Such thioacetals have considerable potential as d3 reagents for the preparation of enones. Tributyltin fluoride may be used as a selective reagent for the cleavage of silyl enol ethers.232The rate of cleavage is reduced with increasing steric congestion around the double bond. The reaction was catalysed by palladium salts, which however did not appear to contribute significantly to the observed chemospecificity. Triethylammonium c h l o r o ~ h r o m a t eand ~ ~ ~bispyridinesilver ~ e r m a n g a n a t e ~ ~ ~ are further reagents for the oxidative regeneration of carbonyl compounds from oximes. Copper(r1) chloride in aqueous methanolic tetrahydrofuran at room temperature hydrolyses tosylhydrazones to ketones, conditions which esters survive.235 222 I.

Matsuda, S. Sato, and Y. Izumi, Tetrahedron Lett., 1983,24,2787. J. E. McMurry and W. J. Scott, Tetrahedron Lett., 1983,24, 979. 224 G. P. Zecchini, M. P. Paradisi, and I. Torrini, Tetrahedron, 1983,39,270!9. 22s T. Chihara, E. Waniguchi, T. Wakabayashi, and K. Taya, Chem. Lett., 1983, 1647. 226 M. T. Reetz, B. Wenderoth, and R. Peter, J . Chem. SOC., Chem. Commun., 1983,406. 227 S . H. Bertz and G. Dabbagh, J . Org. Chem., 1983,48,116. u8 G. Balme and J. Gort, J . Org. Chem., 1983,48, 3336. 229 Y. Quindon, H. E. Morton, and C. Yoakim, Tetrahedron Lett., 1983,24,3969. w, F. Barbot and P. Miginiac, Synthesis, 1983, 651. Dl H. J. Cristau, B. Chabaud, and C. Niangoran, J . Org. Chem., 1983,48,1527. 23* H. Urabe, Y. Takano, and I. Kuwajima, J . Am. Chem. SOC., 1983,105,5703. 233 C. Gundo Rao, A. S. Radhakrishna,€3. Bali Singh, and S. P. Bhatnagar, Synthesis, 1983, 808. 234 H. Firouzabadi and A. Sardarian, Synth. Commun., 1983, 13, 863. 235 0. Attanasi, M. Grossi, and F. Serra-Zanetti,J . Chem. Res. (S), 1983, 322.

123

Aldehydes and Ketones

4 Reactions of Aldehydes and Ketones Reactions of Eno1ates.-A two-part review of the syntheticuses of silyl enol ethers has appeared, covering their preparation and reactions,236and the chemistry of silyloxybutadienes,including their [4 21 cycloaddition reactions.237 In the alkylation of silyl enol ethers with a-heteroatom-substituted alkyl chlorides the electrophile has been activated by trimethylsilyl iodide or trifluoromethanesulphonate, improving the specificity of halide displacement [equation (36)].238The related alkylations with adducts from vinyl ethers and

+

I R2

Y=ORorSR

phenylsulphenylchloride or phenylselenenyl chloride proceed when catalysed by zinc chloride.239The reaction has been extended to the adducts of simple alkenes, but only in the case of the sulphur adducts, attempted carboselenenylation leading to a-selenenyl-ketones by attack at selenium (Scheme 44). $ R‘ \ y

SePh

y

‘CI

ii

Y = O orCH2

Y

I

I

iii

R2YS R1o R A ‘’O

Reagents: i, PhSC1; ii, PhSeC1; iii, R3C(=CH2)OSiMe3;ZnBr,

Scheme 44

Palladium(I1)-phosphine catalysed allylations of ketone derivativescontinue to be explored, including the rearrangement of allyl carbonates, prepared by trapping enolates with allyl chloroformates (Scheme 45) .240 Extending this to enolates of allyl P-keto-carboxylates as substrates forms a simple method for the regioselective synthesis of a,a-diallyl-ket~nes.~~~ Silyl enol ethers 242 and enol Brownbridge, Synthesis, 1983, 1. P. Brownbridge, Synthesis, 1983, 85. 238 A. Hosomi, Y. Sakata, and H. Sakurai, Chem. Lett., 1983, 405. 239 R. P. Alexander and I. Paterson, Tetrahedron Lett., 1983, 24, 5911. 240 J. Tsuji, I. Minami, and I. Shimizu, Tetrahedron Lett., 1983, 24, 1793. 241 I. Shimizu, Y. Ohashi, and J. Tsuji, Tetrahedron Lett., 1983, 24,3865. 242 J. Tsuji, I. Minami, and I. Shimizu, Chem. Len., 1983, 1325.

u6 P. 237

124

General and Synthetic Methods

Reagents: i, CICO,CH,CH= CH,; ii, Pd,(dba),.CHC13, PPh3;iii, PdO, PPh,, ROCOCH,CH= iv, PdO, dppe, ROCOCH,CH=CH,, Bu,SnOMe

CH,;

Scheme 45

acetates,243the latter in the presence of tributyltin methoxide as base, are also substrates for the reaction. The combination of the tin alkoxide and a palladium(I1)-phosphine catalyst is also capable of coupling enol acetates and aryl bromides to form a-aryl-ketones [equation (37)].244 Counter-cation effects have OAc

(37)

4- PhBr

R1%

cat. BugSnOMe [PdCl2( Ar3P121

R I h P h

R2

R2

been noted to be important for the effective palladium-catalysed allylation of enolates by allylic carboxylates. In particular , zinc enolates and lithium enolates in the presence of triethylborane show high regioselectivity and high product yields.245 Ketone enol ethers undergo an ene reaction with formaldehyde and trimethylaluminium, offering a possible method for sequential reactions at the aand a'-positions of a ketone (Scheme 46) .246 Silver(1)-promoted decomposition of RO

i

ii

Rl+R2

OH

R l f i R 2

OH

Reagents: i, Me,Al, HCHO, CHCl,; ii, e.g. R=SiMe,: F-, E+

Scheme 46 J. Tsuji, I. Minami, and I. Shimizu, Tetrahedron Lett., 1983, 24, 4713. M. Kosugi, I. Hagiwara, T. Sumiya, and T. Migita, J. Chem. SOC., Chem. Commun., 1983, 344. 245 E.-I. Negishi and R. A. John, J . Org. Chem., 1983, 48, 4098. 246 B. B. Snider and G. B. Phillips, J. Org. Chem., 1983, 48, 2789.

243

244

125

Aldehydes and Ketones

peroxydisulphate is a convenient initiator for the alkylation of water-soluble ketones with lipophilic alkenes [equation (38)].247

Using 2-methylcyclohexanone as a substrate, kinetic enolate formation is preferred on treatment with potassium hydride followed by triethylborane, whereas the thermodynarnicall-y more stable enolate is the product using potassium hexamethyldisilazide in place of the h ~ d r i d e Bromomagnesium .~~~ di-isopropylamide and trimethylsilyl chloride form an excellent reagent cornbination for the conversion of cyclic ketones into their thermodynamically more stable silyl enol ethers.249 The sodium salt of the monoanion from t-butyl acetothioacetate may be alkylated as anticipated, but more importantly the dianion derived from the anion and butyl-lithium shows good regioselectivity in its reactions with electrophiles provided that 1,2-dimethoxyethane is used as the solvent for the reaction (Scheme 47) .250 The use of sulphonium salts as electrophiles for the C-alkylation of p-dicar-

Reagents: i, BuSNa; ii, NaH, MeOCH,CH,OMe; iii, RlX; iv, BunLi; v, R2X; vi, R1R2C0

Scheme 47

bony1 compounds may prove to have advantages for the introduction of primary alkyl groups into compounds prone to O - a l k y l a t i ~ n . ~ ~ ~ Methods for the alkylation of aldehydes and ketones via nitrogen derivatives have been reviewed.252Reactions of enarnines are described, and reactions of metallated imine, oxime, and hydrazone derivatives are compared with equivalent enolate cases. A. Citterio, F. Ferrario, and S. De Bernardinis, J. Chern. Res. (S), 1983. 310. E.-I. Negishi and S. Chatterjee, Tetrahedron Lett., 1983, 24, 1341. 249 M. E. Krafft and R. A. Holton, Tetrahedron Lett., 1983. 24, 1345. 250 P. M. Booth, C. M. J. Fox, and S. V. Ley, Tetrahedron Lett., 1983, 24, 5143. 251 M. E. Garst and B. J . McBride, J. Org. Chern., 1983,48, 1362. 252 J. K. Whitesell and M. A . Whitesell, Synthesis, 1983, 517.

247

248

126

General and Synthetic Methods

Aldol Reactions.-An

example of a cross-aldol reaction between aldehydes has been demonstrated using tin(I1) e n o l a t e ~2-Bromo-2-methylpropanal .~~ was used as the precursor to the enolate, the a-branched structure precluding elimination of water from the aldol product to give the enal. Rapid generation of the enolate by metallic tin reduction lessens the self-condensation of the nucleophilic aldehyde component. This reductive method has been used for the generation of the tin(I1) enolate from m e t h y l g l y ~ x a l which , ~ ~ ~ takes part in reactions with aldehydes to give predominantly the syn-isomers of the aldol products [equation (39)].The tin(I1) enolate of 1,3-dibenzyloxypropanone,generated by the tin(I1) RCHO,

R

(39)

OH

H

trifluoromethanesulphonate-N-ethylpiperidine method, undergoes aldol reactions with ketones to provide anti-isomers of aldols, a reaction of significance in syntheses of carbohydrate-related compounds [equation (40)] .255 0

ii0

Sn (OSO2Me12

RO

OR

Et

K ~ o ~ M ~ w

C02Me RO

OR

(40)

R = CH2Ph

Silyl enol ethers react with tributyltin(1v)fluoride and a palladium(I1)catalyst to give the stannyl enolates which readily take part in aldol reactions with aldehydes.z6 The fluoride reacts selectively with less hindered silyl enol ethers, enabling a chemoselective aldol reaction to be carried out on protected diketones [equation (41)]. Tin(1v) chloride converts silyl enol ethers into a-trichlorostannyl-

J.-I. Kato and T. Mukaiyama, Chem. Lett., 1983, 1727. T. Mukaiyama, R. Tsuzuki, and J.-I. Kato, Chem. Lett., 1983, 1825. 255 R. W. Stevens and T. Mukaiyama, Chem. Lett., 1983, 595. 256 H. Urabe and I. Kuwajima, Tetrahedron Lett., 1983,24,5001.

253

254

Aldehydes and Ketones

127

ketones,257which participate in highly erythro-selective aldol reactions with aldehydes at low temperature.258Equivalent reactions have been reported for titanium(1v) chloride .259,260 Titanocene enolates of methyl ketones may be formed by the specific methylenation of acyl chlorides, under conditions where isomerization of the enolate is not observed (Scheme 48; cf. Scheme 3).261Standard aldol reactions could be employed with this enol derivative. 9 T i Cl C p2

/

Cp= C5H5-

R

A

Reagents: i, 0°C; ii, RCOCl; iii, RlCHO; iv, H30t

Scheme 48

Aldol reactions of lithium enolates show increased yields in the presence of cerium(m) chloride, the stereochemistry of the product reflecting the geometry of the enolate generated initially.262 Chiral aldehydes show high diastereofacial preferences in their Lewis acidmediated reactions with silyl enol ethers.263 Further details have appeared on the fluoride-catalysed aldol reactions between silyl enol ethers and carbonyl compounds, generating either tetra-alkylamm ~ n i u m *or ~ ~ tris(dialky1amino)sulphonium e n o l a t e ~ as ~ ~ intermediates. ~ Condensations promoted by tetra-alkoxysilanes in the presence of fluoride ions lead to the unsaturated carbonyl compounds through elimination from the aldol product .266 Silyl enol ethers may be induced to participate in erythro-selective aldol-type reactions with acetals, a method suitable for effective cross-condensations [equation (42)].267 OSi Me3

h

w

+

R

Me+i OSO2CF3

(42)

(Me012CHR

w

E. Nakamura and I. Kuwajima, Chem. Lett., 1983, 59. E. Nakamura and 1. Kuwajima, Tetrahedron Lett., 1983,24, 3347. 259 E. Nakamura, J.-I. Shimida, Y. Horiguchi, and I. Kuwajima, Tetrahedron Lett., 1983, 24, 3341. 2M) E. Nakamura and I. Kuwajima, Tetrahedron Lett., 1983,24,3343. 261 J. R. Stille and R. H. Grubbs, J . Am. Chem. SOC., 1983, 105, 1664. 262 T. Imamoto, T. Kusumoto, and M. Yokoyama, Tetrahedron Lett., 1983,24, 5233. 263 C. H. Heathcock and L. A. Flippin, J . Am. Chem. SOC., 1983,105,1667. 2M E. Nakamura, M. Shimizu, I. Kuwajima, J. Sakata, K. Yokoyama, and R. Noyori, J. Org. Chem., 1983, 48, 932. 265 R. Noyori, I. Nishida, and J. Sakata, J . Am. Chem. SOC., 1983, 105,1598. 266 C. Chuit, R. J. P. Corriu, and C. Reye, Synthesis, 1983, 294. 267 H. Sakurai, K. Sasaki, and A. Hosomi, Bull. Chem. SOC.Jpn., 1983,56,3195. 257 258

General and Synthetic Methods

128

Condensations between aldehydes and silyl enol ethers have been carried out under neutral conditions by dint of using pressures approaching 10 kbar.26sA preference is observed for the oppposite stereoselectivity compared with the titanium(1v) chloride-catalysed reaction. Enaminosilanes have been subjected to aldol reaction conditions using boron trifluoride catalysts , and shown to give products of erythro-selective kinetic reaction [equation (43)].269 Me@ NR'

TiClL

+

RCHO

(43)

CH2Cl2, -78O C

Moderate enantioselectivity has been observed in the aldol-type condensations of chiral a-sulphinyl-hydraz~nes.~~~ Induced chirality at the P-position was retained through the reductive desulphurization (Scheme 49). Me2NN

01

Me2"

0i.ii

R'

A

Ar = p -C6HLMe

,l%st~r

R2

4

OH

i

iii

OH

OH

Reagents: i , BunLi; ii, R2CHO; iii, Na/Hg, NaH2P04,MeOH; iv, CuC1, Scheme 49

Conjugate Addition Reactions.-p-Dicarbonyl and 0-silylated ketene a ~ e t a l sundergo ~ ~ * conjugate addition to enones under neutral conditions at 15 kbar pressure. At such pressures steric factors are reduced, enabling reaction to proceed with higher degrees of substitution on the reactants than is possible with the thermal or Lewis acid-catalysed reactions [equation (44)].

0

2a Y. Yamamoto, K. Maruyama, and K. Matsumoto, J . 269 W. Ando and H. Tsumaki, Chem. Lett., 1983, 1409.

Am. Chem. SOC., 1983, 105, 6963.

L. Colombo, C. Gennari, G. Poli, C. Scolastico, R. Annunziata, M. Cinquini, andF. Cozzi,J. Chem. SOC., Chem. Commun., 1983,403. 271 W. G. Dauben and J. M. Gerdes, Tetrahedron Lett., 1983,24,3841. 272 R. A. Bunce, M. F. Schlecht, W. G. Dauben, and C. H. Heathcock, Tetrahedron Lett., 1983, 24, 4943.

270

129

Aldehydes and Ketones

The efficiency of ligand transfer from cuprates is dependent on the choice of copper(1) salt employed to prepare the reagent. Comparisons of the iodide and the isocyanate provide some evidence for the latter giving rise to ‘higher order’ cuprates, with altered r e a ~ t i v i t i e s .Additions ~~~ of the higher-order cuprate R2Cu(CN)Li2to a$- and P,P-disubstituted unsaturated esters can lead to saturated ketones by 1,2- followed by 1,4-additions [equation (45)].274Such cuprates,

nor +

- nR

R2Cu(CN)Li2

(45)

0

R

O

when complexed to boron trifluoride, add in conjugate fashion to alkyl cyclopropyl ketones to form the y-alkylated product [equation (46)] .275

Enantioselective conjugate additions of mixed cuprates incorporating a chiral ligand derived from L-prolinol have been observed to be improved when the reaction is carried out at higher Enantioselectivity is also highly dependent on small structural changes in the ligand (Scheme 50). The N-methyl

fi - pF% - MeoR i , iii

ii , iii

Ph

HO

*

Me

O

Y

s But

0

Reagents: i, Me,CuMgBr; ii, Me,CuLi; iii, PhhKPh

Scheme 50

derivative gave high chemical and optical yields in the conjugate addition of a methyl group from magnesium cuprates. 4-t-Butylthio-derivatives induced greatest asymmetry in methylation by copper-lithium reagents.277 Chiral oxazolidines derived from a,P-unsaturated aldehydes and ephedrine react with methylcopper 278 and with lithium dialkylcuprates 279 to provide optically active /3-substituted aldehydes [equation (47)]. H Me

+lq$ R:CuLi+ * or

R’

R ~ C U

.‘JJ R’

(47)

0

B. H. Lipshutz, J. A. Kozlowski, and R. S . Wilhelm, J . Org. Chem., 1983, 48, 546. B. H. Lipshutz, Tetrahedron Lett., 1983, 24, 127. 275 C . Moiskowski, S. Manna, and J. R . Falck, Tetrahedron Lett., 1983, 24, 5521. 276 F. Leyendecker, F. Jesser, and D. Laucher, Tetrahedron Lett., 1983,24,3513. 277 F. Leyendecker and D. Laucher, Tetrahedron Lett., 1983, 24, 3517. 278 M. Huche, J. Aubouet, G. Pourcelot, and J. Berlan, Tetrahedron Lett., 1983, 24, 585. 279 P. Mangeney, A. Alexakis, and J. F. Normant, Tetrahedron Lett., 1983,24,373. 273

274

130

General and Synthetic Methods

Diarylzinc compounds will participate in conjugate addition reactions with enones in the presence of nickel acetylacetonate, and may be prepared conveniently by sonication of the aryl bromide, lithium wire, and zinc bromide in an ethereal solvent.280The same transformation may be achieved, this time using aryl iodides, when catalysed by palladium(I1) salts in formic acid containing triethylamine [equation (48)] .281

Mercuration of ketone hydrazones forms precursors for acetoxy-radicals which will add in conjugate fashion to activated olefins (Scheme 51).282The intermedi-

ti

liv

0 R’

0

II,,

Reagents: i, H,NNH,; ii, HgO, Hg(OAc),; iii, KC1; iv, NaBH,, CH,=CHCOMe

Scheme 51

ate organometallic reagent need not be isolated, enabling this coupling reaction to be carried out in one reaction vessel.

J.-L. Luche, C. Petrier, J.-P. Lansard, and A. E. Greene, J. Org. Chem., 1983,48, 3837. Cacchi and A. Arcadi, J. Org. Chem., 1983,48,4236. B2 B. Giese and U. Erfort, Chem. Ber., 1983, 116,1240. B 1 S.

3 Carboxylic Acids and Derivatives BY D.W. KNIGHT

1 Carboxylic Acids

General Synthesis.-One-carbon homologations of alkyl halides to carboxylic acids can be readily achieved using the phenylthio methyl ether (1) (Scheme 1).l Among many other uses, reagent (1) and its phenylsulphonyl analogue can also be employed in one-carbon extensions of ketones to a-acetoxy-acids (2). Onecarbon homologations of non-enolizable aldehydes have also been carried out using the amino-nitrile (3) (Scheme 2).2The a-silyl derivative (4) must be used when the aldehyde contains an a-proton and, although the yields for both methods are variable, the sequence could find use in suitable cases. Similar reactions between (3) and benzoic acid esters ( 5 ) lead to a-keto-amides (6). SPh

.1

I,

Jones

A!l)/,i i , Jones

R'y:bo:"

R-qH

R

(2)

Scheme 1

CN

CN (31

Scheme 2

Me3SiYNMePh---ArC02R

CN

(4)

(5)

NMePh

(6I

T. Mandai, K. Hara, T. Nakajima, M. Kawada, and J. Otera, Tetrahedron Lett., 1983, 24, 4993. K. Takahashi, K. Shibasaki, K. Ogura, and H. Iida, J . Org. Chem., 1983,48,3566; Chem. Lett., 1983, 859; K. Takahashi, T. Masuda, K. Ogura, and H. Iida, Synthesis, 1983, 1043.

131

General and Synthetic Methods

132

Reductive alkylations of Meldrum’s acid by carbonyl compounds in the presence of a borane-amine complex results in an overall two-carbon homologation to carboxylic acids, after acid hydrolysis (Scheme 3) . 3 This simple-looking method gives yields in the range 52-94%. R1>o

{:x 0

0

R2 0

0 Scheme 3

Alper’s group4has developed a much milder set of conditions for the hydrocarboxylation of olefins, [(7)+(8)], consisting of a catalyst system of PdC12-CuC12HC1-H20 under one atmosphere of CO and O2at room temperature. Yields are excellent, and high regioselectivities can be obtained in reactions with unsymmetrical olefins. In related work, it has been briefly demonstrated that strained olefins can undergo simultaneous Pdo-catalysed addition of vinyl, aryl, or benzyl bromides and carbon monoxide [e.g. (9)+( lo)] .5 Octacarbonyldicobalt is used as the catalyst in carboxylations of ammonium salts (11) which yield acids (12) in 7 0 4 5 % yields in a process which can be regarded as a reverse of the Curtius degradation.6 Stability to aqueous base (5M NaOH) and light are substrate requirements for this reaction.

(10)

C02 H (14 1

Although alkyl-mercury species , RHgX, add efficiently to many electrondeficient olefins, such reactions with crotonic esters are not satisfactory. A solution to this limitation is to use the Knoevenagel adducts (13) and to complete the sequence by acid hydr~lysis.~ Overall conversions of RCHO into the twocarbon homologues (14) are in the range 20-50%, although rather brutal conditions (80% H2S04,A) are used in the final step. A systematic study of conjugate additions by the alkyl-copper species RCu.BF3.Bu3Pto unsaturated esters (15) D. M. Hrubowchak and F. X. Smith, Tetrahedron Lett., 1983,24,4951. H. Alper, J . B. Woell, B. Despeyroux, and D. J. H. Smith, J . Chem. SOC., Chem. Commun., 1983, 1270. M. Catellani, G. P. Chiusoli, and C. Peloso, Tetrahedron Lett., 1983, 24, 813. J.-J. Brunet, C. Sidot, and P . Caubere, J . Org. Chem., 1983,48, 1919. B. Giese, H. Harnisch, and S. Lechhein, Synthesis, 1983, 733.

Carboxylic Acids and Derivatives

133

containing a chiral alcohol residue (R*) has resulted in syntheses of P,Pdisubstituted acids (16) with 292% enantiomeric excesses.*Crucially, the chiral alcohol R*must contain a large neo-pentyl ether substituent if high optical yields are to be realized and, although only a few examples have been studied, the method appears to have considerable potential. Full details have been presented for the synthesis of (Z?)-(17), or (S)-sodium [2-2H,2-3H]acetate.9

An unusual and simple oxidation method for converting aryl alcohols or aryl aldehydes into aryl acids, ArC02H, consists of treating the former with sodium hydride and pyrazole in THF under oxygen or air at room temperature.1° Yields are good ( 6 6 9 9 % ) but the method is clearly limited to non-enolizable substrates. The original Ogata method for the a-chlorination of aliphatic acids (Clz02-C1S03H cat.) is not particularly effective when applied to long-chain fatty acids but by substituting TCNQ for oxygen yields are much improved.ll a-Chloroand a-bromo-acids can be obtained in ca. 80% yields from the corresponding a-amino-acids by diazotization in the presence of 48 : 52 (w/w) HF :pyridine and KC1 or KBr.120The sequence is not effective for the preparation of a-iodo-acids, although a related procedure can be used for the synthesis of a- or p-fluoroesters. 12b a-Trifluoromethyl-carboxylic acids are obtainable from simple orthoesters by reaction with trifluoromethanesulphenyl chloride, CF3SC1.l3 Ester and lactone cleavage with Me3SiI is not always successful when the reagent is generated in situ from Me3SiC1 and NaI; in such cases, a mixture of C13SiMeand NaI in acetonitrile may prove effe~t1ve.l~ A triphasic system consisting of poly(ethy1ene glycol) grafted onto polystyrene copolymers-C6H660% aq. KOH has been found to be almost as effective as the usual KOH in aqueous alcohol method for ester saponification. l5 a-N, N-Dialkylamino-ketones can be cleaved by hydrogen peroxide (Scheme 4).16Yields of carboxylic acids are a W. Oppolzer, R. Moretti, T. Godel, A. Meunier, and H. Loher, TetrahedronLett., 1983,24,4971; W. Oppolzer, R. Pitteloud, G. Bernardinelli, and K. Boettig, ibid., P. 4975. See alsoK. Soai, A. Ookawa, and Y. Nohara, Synth. Commun., 1983, 13,27. K. Kobayashi, P. K. Jodhav, T. M. Zydowsky, and H. G. Floss, J . Org. Chem., 1983,48,3510. See also J. D. Rozzell Jr., and S . A. Benner, ibid., p. 1190. lo S. Ohta, T. Tachi, and M. Okamoto, Synthesis, 1983, 291. l 1 R. J. Crawford, J . Org. Chem., 1983, 48, 1364. l2 (a) G. A. Olah, J. Shih, and G. K. S . Prakash, Helv. Chim. Acm, 1983,66,1028; ( b ) S. Hamman and C. G. Beguin, Tetrahedron Lett., 1983, 24, 57. l3 W. L. Mendelson, J.-H. Liu, L. B. Killmer, Jr., and S. H. Levinson, J . Org. Chem., 1983,48,298. l4 G. A. Olah, A. Husain, B. P. Singh, and A. K. Mehrotra, J . Org. Chem., 1983,48, 3667. l5 Y. Kimura and S . L. Regen, Synth. Commun., 1983, 13, 443. l6 D. Wenkert, K. M. Eliasson, and D. Rudisill, J . Chem. SOC.,Chem. Commun., 1983, 392.

134

General and Synthetic Methods

high given that the substrate is otherwise stable to prolonged exposure to 30% H202.

Scheme 4

Acid Chlorides and Anhydrides.-Details of the preparation of polymer-bound PC15have been given.*’The reagent offers the advantage of a very simple work-up procedure, i.e. filtration and evaporation of the reaction solvent (1’2dichloroethane) , in the conversion RCO,H-RCOCl. The same transformation can also be carried out effectively using polymer-supported phosphines and cc14. l8 Symmetrical acid anhydrides can be easily obtained from the parent acids in ca. 80% yield using the formamidium chloride (18).l9 Alternatively, acid chlorides can be converted into symmetrical anhydrides under phase-transfer conditions (toluene-20% aq. NaOH-Bun4NC1) in 6 6 9 0 % yields.20 Diacids.-Fujisawa’s group has further extended its studies on the reactions between Grignard reagents and p-lactones to include condensations between bisGrignard reagents (19) and P-propiolactone. Yields of diacids (20) in this sixcarbon homologation procedure are in the range 60-68% .21 Hydroperoxides (21), derived from cyclic silyl e n d ethers, undergo cleavage and dimerization on MgBr

+ Me2NC=NMe2

(CHZ),

CI

MgBr

I

CI-

CO 2H

I

I

I

(CH2)n+ 4 Li 2CuC14

I

COZH

treatment with FeS04 resulting in a straightforward synthesis of long-chain a,odiacids (22) (53-72%).22 The reactions presumably proceed via the radical (23); when CU(OAC)~ is used in conjunction with FeS04, the dimerization step is suppressed and, instead, o-unsaturated acids (24) are isolated in 4 6 7 7 % yield. Both procedures appear to be milder than many existing methods for achieving such conversions, and should be applicable to more complex substrates.

G. Cainelli, M. Contento, F. Manescalchi, L. Plessi, and M . Panunzio, Synthesis, 1983, 306. C. R. Harrison, P. Hodge, B. J. Hunt, E. Khoshdel, and G. Richardson, J . Org. Chem., 1983,48, 3721. l9 T. Fujisawa, K. Tajima, and T. Sato, Bull. Chem. SOC. Jpn., 1983, 56,3529. 2o F. Roulleau, D. Plusquellec, and E . Brown, Tetrahedron Lett., 1983,24,4195. 21 T . Fujisawa, T. Sato, T. Kawara, and H. Tago, Bull. Chem. SOC.Jpn., 1983, 56,345. I. Saito, R. Nagata, K. Yuba, and T. Matsuura, Tetrahedron Left., 1983,24, 4439. l7

l8

Carboxylic Acids and Derivatives

135

(21)

(22)

(23)

(24)

The preparation of chiral compounds continues to be an area of great activity and examples will be found throughout this and other chapters in this Report. Of relevance to this section is a definition of the structural requirements for efficient asymmetric hydrolyses of dimethyl glutarates, when catalysed by pig liver e s t e r a ~ eThis . ~ ~ method can produce excellent results, such as the conversion of the hydroxyglutarate (25) into the half-ester (26) in virtually 100% optical yield. Copper-catalysed Michael additions by Grignard reagents (RMgX) to the sugar derivative (27) show a notable diversity of stereoselection.24When R is aryl or t-butyl, degradation of the initial adducts leads to diacids (28), whereas when R is ethyl or isopropyl addition occurs from the opposite face of (27) leading, after degradation, to the diacids (29). Optical yields throughout are excellent, and the method can also be used to obtain chiral butyrolactones [e.g. (30)]. Two research

K - Hh

MeOzC

COzMe

MeOzC

(coZEt

COzH

(26 1

(25)

/ /

\

=

R ,'

Et or Pr'

\

I.' C02 H

0< T H

H

COzH (31 1

dH

0

\y1

H

p:o*H

HOz C

H70:& HO2C

(28)

(29)

(30)

P. Mohr, N. Waespe-SarEevit, C. Tamm, K. Gawronska, and J. K. Gawronski, Helv. Chim. Actu, 1983, 66, 2501; W. K. Wilson, S. B . Baca, Y. J. Barber, T. J. Scallen, and C. J. Morrow, J. Org. Chem., 1983,48, 3960. 24 I. W. Lawston and T. D. Inch, J . Chem. Soc., Perkin Trans. 1, 1983, 2629.

23

136

General and Synthetic Methods

groups have reported preparations of some potentially useful additions to the ‘chiral pool’, [e.g. (31)], starting from L-malic acid.25 Hydroxy-acids.-Almost all of the notable work reported in this area during 1983 has been directed towards enantioselective syntheses. Under appropriate conditions, the organometallic species R2Zn or RTi(OPr’)3 add to the (R)glyceraldehyde derivative (32) with stereoselectivities of S90% .26 Subsequent benzylation and degradation of the initial adducts (33) affords largely the (S)-abenzyloxy-acids (34) Three separate syntheses of (2S, 3R)-verrucarinic acid (35) have been developed; 27 chirality was introduced either by enantioselective ester hydrolysi~.~~ Sharpless epoxidation, or asymmetric hydroboration using dilongifolylborane.

--+

An’”

HOzC

R

H O Z C A O H II

Asymmetric condensations between enolates and aldehydes feature in three different approaches to chiral P-hydroxy-acids. The trianion (36) derived from (R)-N-acetyl-a-phenylglycinol reacts with aldehydes to give, after hydrolysis, the acids (39) of 297% enantiomeric purity after one recrystallization.28 Similar

(361

(391

(371

J. S. Bajwa and M. J. Miller,J. Org. Chem., 1983,48, 1114;J. D. Aebi, M. A. Sutter, D. Wasmuth, and D. Seebach, Liebigs Ann. Chem., 1983, 2114. 26 J . Mulzer and A . Angermann, Tetrahedron Lett., 1983, 24, 2843. 27 P. Herold, P. Mohr, and C. Tamm, Helv. Chim. Acta, 1983,66,744. 28 M. Braun and R. Devant, Angew. Chem., Int. Ed. Engl., 1983, 22, 788.

25

Carboxylic Acids and Derivatives

Me0

137

+ isomer

(40)

Scheme 5

condensations using the chiral sulphoxide (37) lead to acids (39) with 24-48% enantiomeric excesses.29In a somewhat different approach, reactions between bivalent tin enolates derived from the thiazolidine-2-thione (38) and aldehydes in the presence of a diamine ligand derived from (S)-proline result in products having optical purities of ca. 90% .30 An approach to chiral p-hydroxy-acids which does not involve carbanions is by [1,3]-dipolar additions between olefins and the nitrile oxide (40), derived from the glyceraldehyde (32) (Scheme 5 ) .31 Although the diastereoselectivities in this step are poor or non-existent, the resulting isomeric isoxazolines are readily separable by chromatography, and so the overall method could be worthwhile in appropriate cases. Closely related [1,3]dipolar additions using the nitrile oxide (41) (Scheme 6) lead to cis-hydroxy-acids . ~ ~ yields are good but after degradation of the initially formed h e t e r ~ c y c l eOverall the conditions used in the degradation steps (H,Raney nickel followed by H5106)clearly impose some constraints on the method.

Scheme 6

A further example of the subtle effects which can be encountered in enzymemediated reactions has been found during an asymmetric synthesis of L-carnitine (44) (Scheme 7),33an amino-acid involved in the metabolism and transport of long-chain fatty acids. Reduction of the ethyl ester of acetoacetate (42) by yeast gives the (S)-isomer of (43) in 55% enantiomeric excess, whereas reduction of the n-octyl ester of (42) occurs at the same rate but gives (R)-(43) with 90% e.e.! R. Annunziatia, M. Cinquini, A. Gilardi, and F. Cozzi, Synthesis, 1983, 1016. N. Iwasawa and T. Mukaiyama, Chem. Lett., 1983,297. 31 A. P. Kozikowski, Y . Kitagawa, and J. P. Springer, J. Chem. SOC., Chem. Commun., 1983, 1460. 32 A. P. Kozikowski and M. Adamczyk, J. Org. Chem., 1983,48,366. 33 B. Zhou, A . S. Gopalan, F. VanMiddlesworth, W. Shieh, andC. J. Sih, J. Am. Chem. SOC.,1983,105, 5925.

29 30

General and Synthetic Methods

138

(42)

(43) Scheme 7

(44)

Large-scale Baeyer-Villiger oxidations are often difficult and potentially dangerous to carry out; thus a recently developed procedure using 30% H202, together with acetic and maleic anhydrides, should find wide application in the preparation of w-hydroxy-acids from cyclic ketones.34 Keto-acids.-A one-pot procedure for the conversion of a-amino-acids (45) into a-keto-acids (46) proceeds via the derived 2-trifluoromethyl-3-oxazolin-5ones.35fl-Keto-acids can be efficiently prepared by acylation of the enolate of trimethylsilyl acetate with acid chlorides: the lability of the silyl ester group is crucial allowing isolation of the keto-acids before decarb~xylation.~~ An alterna-

tive approach to aroylacetic acids is to carboxylate acetophenones using the reagent (47), which can be obtained from DBU.37 Copper-catalysed additions of ethyl diazoacetate to enol ethers (48), followed by saponification, provides the cyclopropane acids (49) which are convertible into y-keto-acids (50) simply by brief treatment with hot, aqueous methanol.38 Yields throughout are excellent and the only significant drawback would seem to be the regioselectivity of attack by the carbenoid species in the first step, in cases involving complex substrates. y-Keto-acids (52) can also be obtained readily by treatment of terminal acetylenes (51) with Me1 and CO in the presence of cobalt and ruthenium ~ a r b o n y l sPreviously .~~ reported work showed that such reactions when catalysed only by [co,(co)8] lead instead to butenolides. An alternative set of conditions for the oxidative cleavage of enones [e.g. (53)454)] has been developed which consists of ozonolysis at -78°C in CHzClz,

I. Bidd, D. J. Kelly, P. M. Ottley, 0. I. Paynter, D. J. Simmonds, and M. C . Whiting,]. Chem. SOC., Perkin Trans. 1, 1983, 1369. 35 C. Klein, G. Schulz, and W. Steglich, Liebigs Ann. Chem., 1983, 1623, 1638. 36 P. J. Cowan and M. W. Rathke, Synth. Commun., 1983,13, 183. 37 N. Matsumura, T. Ohba, and S. Yoneda, Chem. Lett., 1983, 317. 38 H. Kunz and M. Lindig, Chem. Ber., 1983, 116,220. 39 11. Alper and J.-F. Petrignani, J . Chem. SOC., Chem. Commun., 1983, 1154. 3,4

139

Carboxylic A c i h and Derivatives MeOy,

+

M e o RF C 0 2 H

6

R\lfVco2H 0

R (481

(491

(50)

followed by oxidation with 30% H202and aq. NaOH under phase-transfer conditions.40 Unsaturated Acids.-A few preliminary results suggest that aza-Claisen rearrangements involving (L)-valinol derivatives [e.g. (%)] could provide a useful entry into optically active acids [e.g. (56)] (Scheme 8).41The enantiomer of (56) is formed to an extent of 13% and, although the method has only been tested on very simple substrates, it may turn out that even higher optical yields will be realized in rearrangements of more complex substrates.

155 “c ___j

(561

(55)

Scheme 8

y-Brominations of a,/?-unsaturated acids using N-bromosuccinimide are often unsatisfactory, in contrast to similar brominations of the corresponding esters. If the y-bromo-acid is required, then the final ester hydrolysis step can be problematical in this approach. A solution to this is to employ water sensitive trimethylsilyl esters, allowing the conversion [(57)+(58)] to be effected, generally in good overall yields.42 Metallation of terminal allenes (59) by t-butyl-lithium followed by conversion into the tri-isobutylaluminate derivatives, and finally carboxylation affords the acetylenic acids (60) in ca. 70% yields, virtually uncontaminated by the corresponding allenic acids, which are formed as major products when the Zithiurn allenes are directly ~arboxylated.~~ These two methods are thus complementary J. A. Cella, Synth. Commun., 1983, 13, 93. M. J. Kurth and 0. H. W. Decker, Tetrahedron Lett., 1983,24, 4535. 42 M. Bellassould, F. Habbachi, and M. Gaudemar, Synthesis, 1983,745. 43 G. Hahn and G. Zweifel, Synthesis, 1983, 883. 41

140

General and Synthetic Methods

(57)

(59)

(58)

(60)

\

and provide one solution to the perennial problem of acetylene-allene equilibration. y, 6-Acetylenic acids (63) can be prepared by TiC1,-catalysed additions of alkynyl-silanes (61) to unsaturated acyl cyanides (62) followed by aqueous hydrolysis (Scheme 9); overall yields are reasonable .44

(61 1

(62)

(63) Scheme 9

Cobalt-catalysed carbonylations of aryl bromides [(64)+(65)] using one atmosphere of carbon monoxide can be carried out under phase-transfer conditions provided that the mixture is irradiated with a sunlamp.45Yields of the aryl carboxylates (65) are usually in excess of 90%; the method is also effective for the carboxylation of cycloalkenyl bromides and bromostyrene and for the preparation of lactones and lactams in examples where an appropriate nucleophile (OH or NH2)is present as an ortho substituent of the aryl bromide. Benzylic halides (66) can also be carbonylated under phase-transfer conditions, but using [Fe(CO)5]as catalyst; returns of the arylacetic acids (67) in this apparently simple method are in the range 31-75% .46 Alternative approaches to arylacetic acids ArBr

(64)

__f

ArCOzNa

(65)

Ar-X

(66)

ArnCO,H

(67)

involve rearrangements of acetals of a-halogenoalkyl aryl ketones cataiysed by Lewis or of the unprotected ketones, in the presence of HC(OEt), and l'l(N03)3.47b Phase-transfer catalysed carbonylations are also featured in a method for the overall isomerization of trans- to cis-cinnamic acids, involving bromination of the former followed by decarboxylative debromination, to give the cis-bromo-styrene (68), and finally PTC-carbonylation (Scheme lo) .48 Overall yields are in the range 28--47% (cf. ref. 45).

(68 1 Scheme 10 A. Jellar, J.-P. Zahra, and M. Santelli, Tetrahedron Lett,, 1983,24, 1395. .I.-J. Brunet, C. Sidot, and P. Caubere, J . Org. Chem., 1983, 48, 1166. 46 G. Tanguy, B. Weinberger, and H. des Abbayes, Tetrahedron Lett., 1983,24,4005. 47 ( a ) G. Castaldi, A. Belli, F. Uggeri, and C. Giordano, J. Org. Chem., 1983,48,4658; ( b )K. Fujii, K. Nakao, and T. Yamauchi, Synthesis, 1983, 444. 48 V. Galamb and H. Alper, Tetrahedron Lett., 1983, 24,2965.

44 45

Carboxylic Acids and Derivatives

141

A Japanese group has given full details of its studies on the metallation reactions of the benzene-tricarbonylchromium complexes (69); treatment of the intermediate lithiated complexes with COz provides a useful entry to various substituted benzoic acids and quenching with methyl chloroformate yields the corresponding methyl Significantly, the regioselectivity of metallation can be controlled by adjusting the size of the oxygen substitutent ‘R’; when this is small [e.g. (69; R=Me)], metallation at position 2 is favoured by chelation control, but when R is large steric shielding results in attack at position 4. 1-Substituted-2-naphthoic acids (71) can be prepared in 32-84% yields by displacement of the 1-methoxy-group in the oxazoline derivative (70) using organometallic species, followed by hydrolysis of the heterocycle .50 The methoxygroup is sufficiently labile that it is even displaced by the di-isopropylamide group of LDA, a reagent not usually noted for its nucleophilicity. Starting materials for the possible extension of this work, i.e. 1-hydroxy-2-naphthoic acids (73), are , ’ . \

I

I

\ I

OMe ( 69)

(70)

(71)

(73)

( 74 1

R

(72)

usually prepared by Kolbe-Schmitt carboxylation of the corresponding 1-naphthoxides. However, the method is not without its practical difficulties, which has led to the development of an alternative approach involving treatment of 1-hydroxynaphthalenes (72) with Stiles reagent, magnesium methyl carbonate, in DMF at 180°C under ca. 34 atm of n i t r ~ g e n .Yields ~’ of acids (73) are virtually quantitative in the examples quoted. In a tenacious piece of work, a Japanese group has prepared all nineteen possible deuteriated benzoic acids (74) .52 The compounds, which will doubtless be of use in various mechanistic and biosynthetic studies, were mainly prepared by Br/D exchange using Raney Cu-A1 alloy in 10% NaOD-D20.

M. Vemura, N. Nishikawa, K. Take, M. Ohnishi, K. Hirotsu, T. Higuchi, and Y. Hayashi, J . Org. Chem., 1983,48,2349. 50 A . I. Meyers and K. A. Lutomski, Synthesis, 1983, 105. 51 L. A. Cate, Synthesis, 1983, 385. s2 M. Tashiro, K. Nakayama, and G. Fukata, J . Chem. SOC.,Perkin Trans. 1, 1983, 2315.

49

General and Synthetic Methods

142

Protection and Deprotection.-A total synthesis of a major metabolite of PGDz features the use of the Wittig reagent (75) in which a carboxylic acid function is masked using methodology recently brought to prominence by C ~ r e y The .~~ closely related 2,4,10-trioxa-3-adamantyl group can similarly be used, as shown by the successful preparation of Grignard reagents (76; This latter moiety is obtained by treatment of the corresponding nitrile with cyclohexane1,3,5-triol and hydrogen chloride, a standard method for the preparation of such heterocycles. A drawback with both protecting groups is the requirement of sequential acid hydrolysis and base saponification for their removal, which may

na

Ph3P

11

(75)

(76)

rather limit their utility in multi-functional syntheses. Diacids and hydroxy-acids, as well as a number of other bifunctional compounds, can be temporarily protected as the silylene derivatives, prepared using divinylo~ysilanes.~~ This serves to emphasize that one of the easiest ways briefly to protect the acidic proton in carboxylic acids is by conversion into the water-labile trimethylsilyl ester 2"5 .36742,

Decarboxy1ation.-Simple alkanoic acids can be decarboxylated to give the corresponding alkanes by treatment with silver nitrate (catalytic amount) and sodium persulphate in hot, aqueous a c e t ~ n i t r i l eThe . ~ ~ method, which probably proceeds via radical intermediates and involves AgI1species, appears to be quick and straightforward although yields are only moderate; when applied to arylacetic acids, 1,Zdiarylethanes are produced (ca. 50%). In an extension of previous work, it has been found that aliphatic esters derived from N-hydroxypyridine-Zthione can be efficiently decarboxylated via a radical chain reaction in the presence of either Bun3SnHor B u ~ S HWhen , ~ ~ such esters are heated with carbon tetrachloride , the corresponding alkyl chlorides are produced, again probably via a radical chain mechanism, in 70-95% yield, implying that this method is a viable alternative to the classical Hunsdiecker reaction.58The latter reaction is not usually applicable to the synthesis of alkyl fluorides; however, such transformations can be effected by treatment of a carboxylic acid with xenon difluoride-hydrogen fluoride in methylene chloride at room t e m p e r a t ~ r eThe .~~ method works well in many cases (54-84% yields) but is limited (e.g. it fails in the cases of hydroxy- and benzoic acids) not the least because of the need for a tame inorganic chemist to supply the XeF2.The Cristol-Firth modification of the E. J. Corey and K. Shimoji, J . Am. Chem. SOC., 1983,105, 1662. G . Voss and H. Gerlach, Helv. Chim. Acta, 1983, 66,2294. 55 Y. Kita, H. Yasuda, Y. Sigiyama, F. Fukata, J. Haruta, and Y. Tamura, Tetrahedron Lett., 1983,24, 1273. s6 W. E. Fristad, M. A. Fry, and J. A. Klang, J . Org. Chem., 1983,48, 3575; W. E. Fristad and J. A. Klang, Tetrahedron Lett., 1983,24,2219. s7 D. H. R. Barton, D. Crich, and W. B. Motherwell, J . Chem. SOC., Chem. Commun., 1983,939. s8 D. H. R. Barton, D. Crich, and W. B. Motherwell, Tetrahedron Lett.,1983,24,4979. 59 T. B. Patrick, K. K. Johri, and D. H. White, J . Org. Chem., 1983, 48, 4158. 53 54

Carboxylic Acids and Derivatives

143

Hunsdiecker reaction has been successfully applied to the mercury(I1) salts of nicotinic acid, to give 3-halogenopyridines via ipso-halogenation A detailed study of the steric course in dehydrative decarboxylations of P-hydroxy-acids has revealed that whereas the erythro-isomers generally give only (E)-olefins, the threo-isomers lead to either ( E ) -or (Z)-olefins, depending on the substituents present (Scheme 11). Furthermore, when R1=alkyl and R2=Ph, mixtures of the two isomers are produced; a reasonable rationale of these observations is presented.

> 98"Ia

> 98 ' l a

A1

thre o

R' = A r or OR R2 = AIkyl

R' = Ar

R2=

e - r i c h Ar

Scheme -11

A popular method for the direct decarboxylation of P-keto-esters [(77)- (78)] is to heat the latter in wet DMSO (Krapcho's method). A procedure that may well supersede this involves treatment of the keto-ester with the sodium or potassium salt of propane-l,2-diol in propane-1,2-diol at 6&85 "C for 15-30 rnin6*Yields are often, but not always, in excess of 95%. Ethylene glycol or glycerol can be used in place of propanediol; significantly, the method requires both shorter reaction times and lower temperatures than those used in the DMSO procedure. The synthetic utility of the initial adducts formed from p-keto-ester enolates and similar species and cationic cycloalkadienyl-iron complexes can be diminished owing to difficulties in decarboxylation. One solution to this problem is to use

C02Me

(80)

(81)

(82)

(83)

2-(trimethylsily1)ethyl esters, which lead to adducts such as (79), decarboxylation of which is achieved simply by treatment with fluoride.63 S. Vemura, S. Tanaka, M. Okano, and M. Hamana, J . Org. Chem., 1983,48, 3297. J. Mulzer and 0. Lammer, Angew. Chem., Int. Ed. Engl., 1983,22, 628. 62 R . Aneja, W. M. Hollis, A. P. Davies, and G. Eaton, Tetrahedron Lett., 1983, 24, 4641. 63 M. Chandler, P. J. Parsons, and E. Mincione, Tetrahedron Lett., 1983, 24, 5781.

General and Synthetic Methods

144

The classical copper-quinoline method has been successfully applied to the decarboxylation of (2)-a-acetylamino-unsaturatedacids (80), leading to primary (E)-enamides (81) in 50-77% yields.64When pyridine is used as solvent, the lower temperature allows the isolation of significant amounts of the corresponding (2)-isomers. Hindered halogeno-esters [e.g. (82)] can be efficiently degraded to styrenes (83) by thermolysis in HMPA at 140°Cor, more slowly, by refluxing in pyrrolidine .6s 2 Esters Esterificati0n.-A review of methods for esterification and thioester formation has been published.66Further additions to the already extensive list of coupling reagents suitable for ester formation include the oxalic acid-derived homologue of 1,l’-carbonyldi-imidazole ,67 2-chlor0-3,5-dinitropyridine,~~ and 1,l’dimethyl~tannocene.~~ Each reagent could be advantageous in appropriate circumstances. A very simple method for esterfication is to treat a mixture of an acid and an alcohol (excess) with chlorotrimethylsilane.70This mild procedure affords esters in 73-98% yield and can also be used to prepare ketals from ketones. Carboxylic acids react with alkyl chloroformates in the presence of triethylamine and 4-dimethylaminopyridine (DMAP; catalyst) to give alkyl carboxylates rapidly and cleanly (>90% yield usually), in yet another mild esterification p r ~ c e d u r e However, .~~ during a total synthesis of Trichoverrol B, the (2,E)dienoic acid fragment was coupled to a central alcohol unit without isomerization by using the mixed anhydride formed with pivaloyl chloride and the sodium salt of the as the usual ‘mild’procedures involving catalytic amounts of DMAP resulted in extensive isomerization of the dienoic acid, possibly because of reversible Michael additions by this base catalyst. A new route to t-butyl esters involves brief treatment of a carboxylic acid with DMF di-t-butyl acetal at 80°C in benzene or toluene.73Although a number of DMF acetals have been used in esterifications in the past, the method has apparently not been previously applied to t-butyl esters. A full recipe has been given for the preparation of polystyrene-bound diphenylphosphine which, in conjunction with diethyl azodicarboxylate, can be used to form esters from one equivalent each of an acid and an alcohol at ambient temperature in THF with yields of 64-99%.74 Esters can also be formed by the alkylation of acids with one equivalent of an alkyl bromide in the presence of mercuric oxide and H F or HBF,; yields vary between 34 and 79%.7s Schmidt and A. Lieberknecht, Angew. Chem., Int. Ed. Engl., 1983,22, 550. J. L. Belletire and D. R. Walley, Tetrahedron Lett., 1983, 24, 1475. 66 A. Arrieta, T. Garcia, J. M. Lago, and C. Palomo, Synth. Commun., 1983,13, 471. b7 S. Murata, Chem. Lett., 1983, 1819. S. Takimoto, N. Abe, Y. Kodera, and H. Ohto, Bull. Chem. SOC. Jpn., 1983,56,639. 69 T. Mukaiyama, J. Ichikawa, and M. Asami, Chem. Lett., 1983, 683. 70 M. A. Brook and T. H. Chan, Synthesis, 1983, 201. 71 S. Kim, Y. C. Kim, and J. I. Lee, Tetrahedron Lett., 1983,24,3365. 72 W. R. Roush and A. P. Spada, Tetrahedron Lett., 1983, 24,3693. 73 U. Widmer, Synthesis, 1983, 135. 74 R. A. Amos, K.W. Emblidge, and N. Havens, J . Org. Chem., 1983,48,3598. 75 J. Barluenga, L. Alonso-Cires, P. J. Campos, and G. Asensio, Synthesis, 1983,649.

61 U . 65

145

Carboxylic Acids and Derivatives

General Synthesis.-The p-tolylsulphone (85) has been found to be superior to the corresponding methylsulphone for the one-carbon homologation of alkyl halides (84) into esters (86).76Phase-transfer conditions are used in the alkylation step and the resulting intermediates are converted into the esters (86) by sequential oxidation, using hydrogen peroxide, and acidic methanolysis. Furthermore, condensations of (85) with aromatic aldehydes can be used to prepare a-methoxyarylacetates. RX

-csMe

+

so;! p-tol (85)

( 84)

-COtEt

Bu"MeCu(CN)LiZ

\

(88)

(87)

I I

'y

RC02Me

a@-Unsaturatedesters, in contrast to similar ketones, are usually ineffective as Michael acceptors in reactions with the common cuprate reagents, R2CuLi. It has now been found that such additions can be achieved by using higher-order, mixed cuprates having a stoicheiometry of R2C~(CN)Li2.77 The method works well with P-substituted esters [e.g. (87)] and also in the cases of a$-disubstituted substrates (e.g. tiglates), provided that these are esterified with a very bulky t-butyldiphenylsilyl group. In order to avoid wastage of a potentially valuable ligand, R, mixed cuprates [e.g. (SS)] can be used; thus, ethyl crotonate (87) is converted into ester (89) in 86% yield with only 4.5% of the alternative product arising from transfer of the methyl ligand being produced. An alternative strategy for effecting the same overall transformation is to use the known conjugate addition-trapping sequence of unsaturated keto-phosphoranes (90), followed by oxidative degradation (NaOC1) and esterification (CH2N2) (Scheme 12).78 Overall yields are very good, and the method can be applied to relatively sensitive substrates such as terpenoids. Potassium enolates of simple esters and amides

0

RixcO*M

R'

R2

( 90)

Scheme 12 76 l7

K. Ogura, N. Yahata, K. Hashizume, K. Tsuyama, K. Takahashi, and H. Iida, Chem. Lett., 1983,767. B. H. Lipshutz, Tetrahedron Lett., 1983,24, 127. M. P. Cooke, Jr., J . Org. Chem., 1983,48, 744.

146

General and Synthetic Methods

undergo efficient Michael additions to vinyl sulphones, providing yet another method for ester h o m ~ l o g a t i o n . ~ ~ One or two tertiary alkyl groups can be incorporated into the a-position of esters by treatment of trimethylsilyl ketene acetals with tertiary halides in the presence of zinc chloride (Scheme 13).*OUnderstandably, yields are variable but probably compare well with alternative routes to such highly substituted compounds.

Scheme 13

Generally, the method of choice for the production of reactive carbenoid intermediates from diazoacetates is to use a rhodium(I1) carbonyl catalyst. However, when generated in this way, these species are not effective in cyclopropanation reactions of electron-deficient olefins, such as a,P-unsaturated esters. This limitation can be overcome by the use of various nickel catalysts or by using Pd(OAc)2.81Thus, treatment of ethyl diazoacetate and methyl acrylate in hot benzene with this catalyst affords cyclopropane (91) in 85% yield; returns are poorer when the olefin is more highly substituted. Variations in the regioselectivity of cyclopropanation reactions between ethyl diazoacetate and various dienes and trienes as a function of the nature of the catalyst have also been investigated.s2 Carbonylation of 1,l-dibromocyclopropanes (92) with tetracarbonylnickel in hot DMF in the presence of an alcohol (R30H) leads to cyclopropane carboxylates (93) in 4 6 7 8 % yields.83If an appropriately positioned alcohol group is present, lactones [e.g. (94)] can be prepared by this method. As cyclopropanes (92) are usually formed from an olefin and

0

P. R. Hamann and P. L. Fuchs, J . Org. Chem., 1983,48,914. M. T. Reetz, K. Schwellnus, F. Hubner, W. Massa, and R. E. Schmidt, Chem. Ber., 1983,116,3708. M. W. Majchrzak, A . Kotelko, and J . B. Lambert, Synthesis, 1983,469. A . J. Anciaux, A . Demonceau, A . F. Noels, R. Warin, A . J. Hubert, and P. TeyssiC, Tetrahedron, 1983, 39,2169. 83 T. Hirao, Y. Harano, Y . Yamana, Y. Ohshiro, and T. Agawa, Tetrahedron Lett., 1983,24,1255.

79

8o

147

Carboxylic Acids and Derivatives

dibromocarbene, this method represents an alternative to one-step cyclopropanation reactions involving diazoacetate. Enolates of cyclopropane carboxylates (95) can be successfully generated using LDA, although good yields of the dqlkylated products (96) are only realized with reactive electrophiles such as methyl iodide or allylic halides.84 Previous work by Sharpless et al. has been developed into a general method for . ~ ~ the ether cannot the oxidation of benzyl ethers into benzoates by R u O ~Clearly, contain other functions, such as isolated phenyl groups,86which are also oxidized by this reagent. A method for the synthesis of a-bromo-esters, outlined in Scheme 14, looks to be especially suitable for large-scale preparation^.^^ The final decarboxylation step is considerably facilitated by the addition of catalytic amounts of lithium carbonate. @-Iodo-esters[e.g. (97)] are formed on brief treatment of the corresponding a,@-unsaturated acids with Me3SiI;88 this reaction thus could represent a

i, ii

R~ : : 2 "

TCO'" C02Et

COZEt

iii

, R/ycoz Br

Reagents: i, 1 equiv. KOH, EtOH; ii, Br,, AcOH; iii, A, THF, Li2C03

Scheme 14

limitation in the ester dealkylation method using the latter reagent, although reversal of the addition should not be difficult. Isolable titanium homoenolates (98) can be obtained from cyclopropanone acetals and condense with aldehydes to give y-chloro-esters (99).89 The intermediate hydroxy-esters can only be isolated in low yields. Recipes have been provided for the preparation of a variety of substituted aryloxy-acetic acid esters (100; X=SCN, NCS, N3, OR).90 CI

R'

RZ

OSiMe3 (101)

I

NR2 (102)

I. Reichelt and H.-U. Reissig, Chem. Ber., 1983, 116, 3895. P. F. Schuda, M. B . Cichowicz, and M. R. Heimann, Tetrahedron Lett., 1983,24,3829. 86 A. K. Chakraborti and U. R. Ghatak, Synthesis, 1983,746. 87 0. P. Goel and U . Krolls, Tetrahedron Lett., 1983,24, 163. T. Azuhata and Y. Okamoto, Synthesis, 1983,461. E. Nakamura and I. Kuwajima, J . Am. Chem. Soc., 1983, 105,651. 9o J. L. Colin and B . Loubinoux, Synthesis, 1983, 568.

84 85

6

148

General and Synthetic Methods

Ester (and lactone) silyl enolates (101) undergo zinc chloride--catalysedalkylations with dialkylaminomethylethers leading to the Mannich-type adducts (102) in 59-90% yields.91Dienolates can be used, reaction occurring at the y-position. These adducts are useful as precursors to a-methylene-esters and lactones; indeed, when applied to 6-valerolactone, the scheme leads directly to the a-methylene derivative. Silyl enolates (101) can also be alkylated by a-chloroethers (104) obtained from vinyl ethers (103) by the addition of phenylsulphenyl chloride; again dienolates react at the y-positions.92 Carbocyclic analogues of (105) can also be prepared from cycloalkenes by this route. Good to excellent asymmetric inductions have been achieved in alkylations of enolates obtained from esters of (+)-camphor derivatives; these results can be explained in terms of steric shielding and cation c~mplexation.~~ Diestem.-In extensions of previous studies, Trost and Hung have found that reactions between aryl-substituted allylic carbonates (106) or (107) and dimethyl sodiomalonate are completely regioselective when a tungsten carbonyl catalyst is used, and lead exclusively to the more hindered isomer (108) (Scheme 15).94The use of carbonate as leaving group rather than the more usual acetate was necessary because of the former’s greater reactivity in this respect. Malonate enolates also show a marked preference for attack at the more hindered site in molybdenum-catalysed reactions with tertiary allylic acetates [e.g. (109)+ (l10)];95 however, other related nucleophiles tend to add predominantly at the primary centre. A further example of regioselective attack by malonate is in alkylations of enol thi0ethe1-s.~~ Such SN2displacements [(ill)+(112)] seem to be general for other soft nucleophiles related to malonate, resulting in a method of considerable potential. A similar propensity for SN2attack by soft nucleophiles has been observed in reactions between a-bromomethyl-esters (113) and keto-ester enolates (114) which lead largely or exclusively to the Necic acid synthons (115).97 Malonates and related keto-esters and 1’3-diones can be forced to undergo

T. Oida, S . Tanimoto, H. Ikehira, and M. Okano, Bull. Chem. SOC.Jpn., 1983,56,645. R. P. Alexander and I. Paterson, Tetrahedron Lett., 1983,24,5911; S . K. Pate1 and I. Paterson, ibid., p. 1315. 93 G. Helmchen, A . Selim, D. Dorsch, and I. Taufer, Tetrahedron Lett., 1983, 24, 3213. 94 B . M. Trost and M.-H. Hung, J . Am. Chem. Soc., 1983,105,7757. See also T. Hayashi, T. Hagihara, M. Konishi, and M. Kumada, ibid., p. 7767. 95 B. M. Trost and M. Lautens, J . Am. Chem. SOC., 1982,105,3343. % B. M. Trost and A. C. Lavoie, J . Am. Chem. SOC., 1983, 105,5075. 97 F. Ameer, S . E. Drewes, N. D. Emslie, P. T. Kaye, and R. L. Mann, J. Chem. SOC., Perkin Trans. 1, 1983, 2293. For other examples of Neck acid syntheses, see R. S . Glass and M. Shanklin, Synth. Commun., 1983, 13, 545.

91

92

149

Carboxylic Acids and Derivatives Ar

wOC02 Me (106)

1

or

OC02Me (107)

I

(108)

Scheme 15

(11 3)

Michael additions to P,P-disubstituted enones and other sterically hindered substrates by the application of high pressure (ca. 15 kbar).98Such conditions can also be used to effect Michael additions of 0-silyl enolates to enones without the need to add a Lewis acid. Clearly, such a procedure has considerable potential for the synthesis of very acid- or base-sensitive compounds but does have the drawbacks of small reaction scale and/or the availability of suitable apparatus. Simple ester enolates add to 4-bromocrotonate, presumably via a conjugate addition-intramolecular cyclization sequence, to give substituted cyclopropanes in 3 7 4 2 % yield (Scheme 16).99A somewhat similar method for the preparation of cyclopropane-1,1-dicarboxylates from vinyl selenones and malonate enolates has also been devised. loo

W. G . Dauben and J. M. Gerdes, Tetrahedron Len., 1983,24,3841; R. A . Bunce, M. F. Schlecht, W. G . Dauben, and C. H. Heathcock, ibid., p. 4943. 99 P. Prempree, S. Radviroongit, and Y . Thebtaranonth, J. Org. Chem., 1983,48, 3553. loo I. Kuwajima, R. Ando, and T. Sugaware, Tetrahedron Lett., 1983,24,4429. 98

150

General and Synthetic Methods

Scheme 16

A further application of chiral pyrrolidines derived from proline in asymmetric synthesis is in condensations of the enamine (116) with arylidene malonates (117) which give the expected products (118) with >90% diastereoselectivity and >SO% enantiomeric enrichment. lol

The propensity of cyclopropane-1,l-dicarboxylates to act as Michael acceptors has been exploited in a synthesis of the substituted phenols (119) (Scheme 17).lo2 Although yields of (119) are high, the overall conversions are low and the reaction conditions appear to be in need of optimization. An unusual 1,2-ester transposition has been observed when succinates (120) are treated with potassium hydride in glyme.'03 Although the products (121) are formed in high yield presumably via a cyclopropane alkoxide, the method is probably limited to examples where R2is an electron-withdrawing group such as C02Me or CN.

Scheme 17

Ph

%

C02Me

R2

(120)

&

Ph

VMe C02Me

R2

( 121 1

A double hydroesterification of terminal acetylenes leading to maleates (122) has been described (Scheme 18).lO4Yields are generally 70-89% for simple S. J. Blarer and D. Seebach, Chem. Ber., 1983, 116,2250, 3086. G. Sartori, F. Bigi, G. Casiraghi, and G. Casnati, Tetrahedron, 1983,39, 1761. lo3 J. S. Tou and A. A. Schleppnik, J. Org. Chem., 1983,48, 753. lo4 H. Alper, B. Despeyroux, and J. B. Woell, Tetrahedron Left., 1983,24,5691.

lo*

151

Carboxylic Acids and Derivatives

acetylenes; when carried out with methyl alkynes, (E)-monoesters (123) are obtained [cf. (7)- (8); ref. 41. Succinates can be prepared by alkylations of the

(122 1 Reagents: i, PdCl,, CuCI,, HCl, O,, CO (1 atm), MeOH, 20°C

Scheme 18

Reformatsky reagent derived from t-butyl bromoacetate with a-bromoacetates in DMSO. lo5 Similar reactions involving y-bromo-crotonates proceed in an SN2 manner leading to hexenedioates (124). Dianions derived from alkanedioates can be oxidatively coupled intramolecularly , using CuX2, but only when the resulting carbocycles are three- or six-membered [(125) and (126) respectively]. lo6 Acetoxymercurations of cyclopropanes in the presence of fumarates can be used to prepare variously substituted succinates (Scheme 19).lo7 Olefins other than fumarates can also be used successfully; overall yields for these manipulatively simple reactions are between 41 and 75%.

a

CO2 Me C02Me

(I26)

Reagents: i, Hg(OAc),, AcOH; ii, NaBH,

Scheme 19

Hydroxy-esters.-As in previous years, the main developments in this area have been in diastereoselective and asymmetric synthesis. a-Keto-esters derived from (-)-8-phenylmenthol are reduced by K(OBU')~BHin THF to give hydroxy-esters (128) with enantiomeric enrichments of up to 9O%.losPresumably, the phenyl substituent acts as a steric s ~ r e e nlargely ~ , ~ ~preventing attack from one side of the keto-ester group [cf. (127)]. This type of ester seems to have considerable synthetic potential as it has been demonstrated that other nucleophiles such as Grignard reagentslog and alkyl stannaneslo9can also react with (127) to give substituted F. Orsini and F. Pelizzoni, Synth. Commun., 1983, 13, 523. S. K. Chung and L. B. Dunn, Jr., J . Org. Chem., 1983,48, 1125. B. Giese and W. Zwick, Chem. Ber., 1983, 116,1264. lo* J. K. Whitesell, D. Deyo, and A. Bhattacharya, J . Chem. Soc., Chem. Commun., 1983,802. lO9 Y. Yamamoto, N. Maeda, and K. Maruyama, J . Chem. Soc., Chem. Commun., 1983,774.

lO5

152

General and Synthetic Methods

cr-hydroxy-esters with 85-90% enantiomeric enrichments. Tri-n-butylallylstannanes react with isopropyl glyoxylate to give largely (90%) the erythro-isomer [e.g. (129)] in contrast to the corresponding 9-BBN derivative which gives a 3:l mixture in which the threo-isomer predominates. When the same allyl stannane is reacted with the menthyl glyoxalate (127; R=H), the resulting hydroxy-ester can be converted into verrucarinolactone (130), a fragment of verrucarin A, with 91% enantiomeric enrichment, after recrystallization. The erythro-hydroxy-ester (129) can also be obtained with 98% selectivity by a [2,3]-Wittig-type rearrangement of aza-enolates derived from the dihydro-oxazine (131), followed by alcoholysis of the resulting isomeric oxazine (132).'1° As mentioned above, condensations between allyl boranes and glyoxalates give predominantly threo-crhydroxy-esters. Similar reactions with pyruvate derivatives of very bulky phenols

(127)

(128 1

(1 29)

4 I 1

n

A

OH (132)

(e.g. 2,6-di-t-butyl-4-methylphenol) lead exclusively to the threo-isomers [e.g.

(133)]."' Methyl benzoylformate (134) condenses with the chiral allyl silane (135) under standard conditions to give the expected product (136) with 91% enantiomeric enrichment.''* The generality of this approach has not been defined and it may perhaps be limited to examples in which both reactants carry bulky subst ituen ts . 0 P hA C O * M e

(134) 4

+ SiMe,

(133)

@YPh H

Ph

(136)

(135 1 110 K.

Mikami, K. Fujimoto, and T. Nakai, Tetrahedron Lett., 1983, 24,513. 111 Y. Yamamoto, T. Komatsu, and K. Maruyama, J . Chem. SOC.,Chem. Commun., 1983, 191. T. Hayashi, M. Konishi, and M. Kumada, J . Org. Chem., 1983,48,281.

Carboxylic Acids and Derivatives

153

A full report has been given describing optimum conditions for lead tetraacetate oxidations of ester trimethylsilyl enolates to a-acetoxy-esters.ll3 The method is also suitable for oxidations of lactone enolates; yields are often very good. The classical Reformatsky route to P-hydroxy-esters can sometimes be improved by the use of highly reactive zinc-graphite in place of the more conventional metals. 114 An alternative preparation of P-hydroxy-esters involves Lewis acid-promoted condensations between ketones and silyl ketene acetals (ester silyl enolates). The steric limitations of this reaction have now been defined; for example, the approach fails when the ketone is doubly a-branched, as in the case of di-isopropyl ketone.’15 Enolates derived from the heterocyclic amides (137) condense with aldehydes, R2CH0, to give only the erythro-p-hydroxy-esters (138) after oxidation at sulphur and cleavage by methoxide. 116 Yields of the initial condensation products are 45435% but returns from the last two steps are not detailed. In an extension of work previously discussed,30 condensations between the tin(I1) enolate of 3-acetylthiazolidine-2-thione (38) and a-keto-esters in the presence of a diamine ligand derived from (S)-proline produce derivatives (139) with >95% enantiomeric enrichrnent.ll7 A number of additions to the ever increasing list of enantioselective reductions which can be carried out using Baker’s yeast have been reported this year. The potassium salts of /!I-keto-acidsare reduced by the yeast to give hydroxy-esters (140) in chemical yields of 38-59% after esterification and chromatography. 11* Optical yields are essentially quantitative and the method looks to be a distinct improvement of the established approach to esters (140) which involves similar reductions of P-keto-esters. However, reductions of P-keto-esters containing perfluoroalkyl groups have been carried out using Baker’s yeast to give the corresponding P-hydroxy-esters in >90% optical ~ i e 1 d s . Two l ~ ~ isolated examples of yeast reductions worthy of note are those of ethyl a-formylpropionate, leading to hydroxy-propionate (141) with 6 0 - 6 5 %

G. M. Rubottom, J. M. Gruber, R. Marrero, H. D. Juve, Jr., and C. W. Kim, J . Org. Chem., 1983, 48, 4940. 114 G . P. Boldrini, D. Savoia, E. Tagliavini, C. Trombini, and A. Umani-Ronchi, J . Org. Chem., 1983, 48, 4108. 115 G. Wenke, E. N. Jacobsen, G. E. Totten, A. C. Karydas, andY. E. Rhodes, Synth. Commun., 1983; 13, 449. 116 F. Babudri, L. DiNunno, and S. Florio, Tetrahedron Lett., 1983,24,3883. See also C. H . Heathcock and J. Lampe, J . Org. Chem., 1983, 48, 4330. R. W. Stevens and T. Mukaiyama, Chem. Lett., 1983,1799. 11* M. Hirama, M. Shimizu, and M. Iwashita, J . Chem. SOC., Chem. Commun., 1983, 599. T. Kitazume and N. Ishikawa, Chem. Lett., 1983, 237.

113

154

General and Synthetic Methods

enantiomeric enrichment,I2Oand of 3-ketotetrahydrothiophene carboxylate to give, after Raney nickel desulphurization, methyl (S)-3-hydroxy-pentanoate (142).

+ OH

H

C02Me

R &C02Me

H

0

a

HCO;, Et

Alkylations of enolates derived from acetonides (143) by methyl iodide give the a$-dihydroxy-ester derivatives (144) largely or exclusively with the stereochemistry indicated, but, by contrast, condensation of (143; R=Me) and acetone leads to the opposite arrangement (145).122Further work is needed to define fully the possibly considerable potential of this method. An alternative approach to chiral a#-dihydroxy-esters has been briefly examined and is exemplified by the condensation between the benzyloxy-ester (146) and acetaldehyde which leads, after hydrogenolysis, to the (R,R)-erythro-isomer (147) containing 4 0 % of the corresponding threo-isomer.123 Alkoxymercurations of certain S-hydroxy-y-alkyl-a$-unsaturated esters proceed with high diastereoselectivitiesto give the aldol-typeproduct (148).124 Good diastereoselectivities have also been observed in condensations between p-alanine derivatives

H LOB"

(147)

(146)

(148)

OR2

_-_

+ R' CH'O (14 9

C O ~ R ~ (150)

*R

I

Y

co2R~

OH (151

M. F. Ziiger, F. Giorannini, and D. Seebach, Angew. Chem., Int. Ed. Engl., 1983,22, 1012. R. W. Hoffmann and W. Ladner, Chem. Ber., 1983,116,1631. ( a ) W. Ladner, Chem. Ber., 1983, 116, 3413; ( b ) T. Schubert, F. Kunisch, and P. Welzel, Tetrahedron, 1983, 39, 221 1. 123 J. d'Angelo, 0. Pagks, J. Maddaluno, F. Dumas, and G . Revial, Tetrahedron Letr., 1983,24,5869. lZ4 S . Thaisrivongs and D. Seebach. J . A m . Chem. SOC.. 1983,105,7407.

120 121

Carboxylic Acids and Derivatives

155

(150) and alkoxy-aldehydes (149). After quaternization of the amino-group and base-induced elimination, the unsaturated dihydroxy-esters (151) are obtained, largely as the isomers shown.125 Keto-esters.-A number of routes to keto-esters have been developed which may be superior to established methods in certain circumstances. The enolate of the a-aminocrotonate derivative (152), obtained using LDA or KDA, undergoes alkylationslargely or exclusively at the y-position to give a-keto-esters (153) after acid hydrolysis.126Alternatively, a-keto-esters (154) can be simply prepared by condensations between alkyl-cadmiums, R2Cd, and ethyl cyanoformate, NCC02Et,in the presence of zinc chloride; yields, however, are not particularly good (2&-66%). 127 Anions (155) derived from the O-trimethylsilyl cyanohydrin of methyl glyoxalate, on alkylation with allylic or benzylic halides (only!) followed by treatment with acetic anhydride, afford enol acetates (156) of a-ketoesters in ca. 70% yield.128Diketo-esters (157), useful as precursors to pyrroles etc., can be readily derived from conjugate additions of methyl a-nitroacetate to NMe Ph

n

0 RK C 0 2 E 1 (154)

OTMS

(155)

OAc (156 1

0 (157)

vinyl ketones in the presence of triethylamine followed by treatment with methoxide and ozonolysis.129 A popular method for the preparation of P-keto-esters is by condensations of ketone enolates with dialkyl carbonates [i.e. (158)+ (159)]. However, the procedure is not without its limitations and hence an alternative has been developed in which methyl cyanoformate is used as the electrophile.130The key features of this method, which is only successful when lithium enolates of ketones are used, are that the condensations can be performed at -78°C and that there is no need for acidification during work-up. Yields are comparable with the dialkyl carbonate procedure (65-96%) and the method can also be employed to prepare nonenolizable B-keto-esters by direct C-acylation [e.g. (160)- (161)l. A less direct

L. Banfi, L. Colombo, C. Gennari, and C. Scolastico,J. Chem. Soc., Chem. Commun., 1983, 1112. H. Ahlbrecht and H. Simon, Synthesis, 1983,58. lZ7 Y. Akiyama, T. Kawasaki, and M. Sakamoto, Chem. Lett., 1983,1231. 128 T. Mukaiyama, T. Oriyama, and M. Murakami, Chem. Lett., 1983,985. 129 W. J . Thompson and C. A. Buhr, J . Org. Chem., 1983, 48, 2769. L. N. Mander and S. P. Sethi, Tetrahedron Lett., 1983,24,5425.

125

126

156

General and Synthetic Methods OTMS

but nevertheless efficient approach to P-keto-esters (163) involves acylation by diethyl carbonate of the vinyl-lithium species (162), obtained from the corresponding bromide using n-butyl-1ithi~m.l~~ The known adducts (165) formed from diazoacetate enolates (164) and ketones can be rearranged by treatment with catalytic amounts of rhodium(I1) acetate in pentane to provide yet another route top-keto-esters ( 163).132 Clearly, this approach is only useful when there is a large difference in the migratory aptitudes of the substituents R1 and R2;in such cases, yields are often excellent. The Blaise reaction, a relative of the Reformatsky

OH

4

reaction in which /3-keto-esters are obtained by condensations of zinc enolates of esters with nitriles, is little used, mainly because yields are generally poor. Improved conditions have now been developed which could make this a viable method in some cases.133 In an extension of Weiler's method for P-keto-ester homologation, a Dutch group has found that dianions derived from the unsaturated keto-esters (166) react regioselectivity with electrophiles such as alkyl halides, aldehydes, and ketones, to give the deconjugated homologues (167) in excellent ~ i e 1 d s .Vinylic l~~ and allylic halides can be efficiently formylated by treatment with carbon monoxide in the presence of tri-n-butyltin hydride and a palladium(0) catalyst;135for example, the methyl enol ether of y-chloroacetoacetate is converted into the useful aldehydo-ester (168) in 86% yield. L. Duhamel, J.-M. Poirier, and N. Tedga, J . Chem Res. ( S ) , 1983, 222. K. Nagao, M. Chiba, and S.-W. Kim, Synthesis, 1983, 197. 133 S. M. Hannick and Y. Kishi, J . Org. Chem., 1983,48,3833. 134 J. A. M. van den Goorbergh and A . van der Gen, R e d : J . R. Neth. Chem. SOC., 1983,102,393. 135 V. P. Baillargeon and J . K. Stille, J. Am. Chem. SOC., 1983, 105, 7175.

131

13*

157

Carboxylic Acids and Derivatives

E (166)

(168)

(167)

Sodium enolates of B-keto-esters can be C-alkylated using sulphonium salts [e.g. Me3S+BF4-]136 and fluorinated by methyl hypofluorite, AcOF, obtained

from CFC13,fluorine, and sodium acetate.137 a-Amidoethylations of P-keto-esters can be effected by condensations of the latter with aziridines, in the presence of triethylamine. 138 The a-phenylthio-acetate (170) reacts cleanly with 0-silyl enolates of ketones (169) in the presence of zinc bromide to provide a general and efficient route to y-keto-esters (171; R3=SPh) .139 Subsequent desulphurization using nickel affords keto-esters (171; R3=H) while oxidative elimination of the phenylthio-group leads to the unsaturated esters (172). Simple y-keto-esters (174) can also be

0

R’+COz

Me R2 (172 1

obtained from 2,5-dimethoxydihydrofurans(173), readily prepared from the corresponding 2-substituted furans, following dealkylation of the acetal function with one equivalent of iodotrimethylsilane. 140 When three equivalents of the silane are used, dealkylation of the ester function also occurs, resulting in the formation of 4-substituted but-2-enolides. Dichloro-bicyclo[4.1 .O]heptanes (175) are cleaved on treatment with methanolic methoxide to give the cyclohexane carboxylates (176). 141 0

M. E. Garst and B. J . McBride, J. Org. Chem., 1983,48, 1362. 0. Lerman and S. Rozen, J . Org. Chem., 1983,48,724. See also S. T. Purrington and W. A . Jones, ibid., p. 761. 13* H. Stamm and J. Budny, J. Chem. Res. ( S ) , 1983, 54. 13y T. V. Lee and J. 0. Okonkwo, Tetrahedron Lett., 1983,24,323; I. Fleming and J . Iqbal, ibid., p. 327. lJn B. L. Feringa and W. Dannenberg, Synth. Commun., 1983,13,509. 141 M. G. Banwell, J. Chem. SOC., Chem. Commun., 1983.1453.

136 13’

General and Synthetic Methods

158

(175)

(176)

A useful route to vinyl ketones, developed by Stille’s group, is by palladiumcatalysed couplings of acid chlorides and vinyl stannanes. This method has been applied to a synthesis of the pyrenophorin precursor (179) using the pentanoyl chloride (177) and P-stannyl acrylate (178); 142 the stereochemistry of the acrylate is retained. An alternative pyrenophorin precursor (181) has been obtained from diketo-ester (180) in a sequence which features protection of the dione function as an isoxazole during manipulation of the distal double bond (Scheme 20).143

(180)

(181)

Scheme 20

In a continuation of studies on the applications in asymmetric synthesis of chiral hydrazone enolates derived from the N-amino-pyrrolidines ‘SAMP’ and ‘RAMP’, Ender’s group has found that such enolates undergo Michael additions to unsaturated esters leading to 8-keto-esters with 296% enantiomeric enrichment and in 4 5 4 2 % overall yield (Scheme 21).’# It is not difficult to foresee many applications of this method in the future, particularly in view of the relative simplicity and probable generality of the approach, the availability of both enantiomers of the final product in a predictable way [e.g. ‘SAMP’ hydrazones lead to the (R)-isomers as shown, and vice versa], and the fact that the chiral ligand can be recovered and recycled. Many standard Michael reactions can be

Scheme 21 J. W. Labadie and J. K. Stille, Tetrahedron Lett., 1983,24,4283. See also S. Yokota, M. Nishida, and 0. Mitsunobu, Bull. Chem. SOC.Jpn., 1983,56,. 1803. 143 P. G. Baraldi, A. Bareo, S. Benetti, F. Moroder, G. P. Pollini, and D. Simoni, J . Org. Chem., 1983, 48, 1297. D. Enders and K. Papadopoulos, Tetrahedron Lett., 1983,24,4967. 142

159

Carboxylic Acids and Derivatives

carried out by heating the reactants together with caesium fluoride and a tetraalkoxysilane;145this method could be useful in certain cases. Enolates of a-trimethylsilyl acetates generally react with enones in a [1,2] fashion to give dieno ates following a Peterson reaction. However, the bulkier diphenylmethyl derivative (182) adds to enones in a Michael sense when HMPA is a co-solvent to provide, for example, yet another synthesis of methyl jasmonate (Scheme 22).146 i,ii,iii

CO2Et

0 (182 1 Reagents: i, HMPA, THF; ii, B r

m ; iii, KF, MeOH

Scheme 22

The useful homo-Michael acceptor (183) undergoes nucleophilic ring opening by the iron complex Na2Fe(C0)4.qdioxan in the presence of carbon monoxide to give a complex, which can be converted into a number of useful derivatives (Scheme 23) ;147 all overall yields are in the order of 65% . Carbonylation of simple butyrolactones (184) at 50 atm and 140°C using [Co,(CO),] as catalyst and HSiEt2Me as trapping agent provides the masked formyl-esters (185) in high yield.

h

C

02 Et

o

R02c-fco2Et

~

c

oEt z

C02Et

CO2Et

CO,Et

Scheme 23

(186 1

(187 1

J. Boyer, R. J. P. Corriu, R. Perz, andC. Reye, Tetrahedron, 1983,39,117; R. J. P. Corriu, R. Perz, and C. Reye, ibid., p. 999. 146 W. Oppolzer, M. Guo, and K. Baettig, Helv. Chim. Acra, 1983, 66,2140. 14' W. H. Tamblyn and R. E. Waltermire, Tetrahedron Lett., 1983, 24, 2803. N. Chatani, S . Murai, and N. Sonoda, J . Am. Chem. Soc., 1983,105,1370.

145

160

General and Synthetic Methods

+

L i2CuC Ic,

Br(CH*),,C02Et

O@(CH2),+zC02Et H30

+

Scheme 24

The adducts (186), formed from a-nitro-cycloalkanones and methyl vinyl ketone are cleaved by treatment with methanolic sodium methoxide at 0°C to give the keto-esters (287) in 53-93% yield. 149 Simple a-alkyl-cycloalkanones can also be ring-opened to give keto-esters by reactions with oxygen and iron(rI1) chloride in C6HG-MeOHat 60°C; yields, however, are ~ a r i a b 1 e . The l ~ ~ useful Grignard reagent derived from the ethylene acetal of 3-bromopropanal can be coupled efficiently to primary o-bromo-esters on addition of Li2CuC14to provide o-formyl-esters in ca. 80% yield after acid hydrolysis (Scheme 24).151 Unsaturated Esters.-Standard Wadsworth-Emmons reactions between a-phosphonoacetates and aldehydes leading to (E)-@unsaturated esters can be simply and efficiently performed using aqueous potassium carbonate or bicarbonate as base.152Similar transformations can also be effected by utilizing the tellurium ylides (188; R=Me or Bun).153Although these reagents are unlikely to SLi

+ -

R 2Te CHCOzEt

replace the much better known phosphorus analogues in such olefinations, they could find use in the corresponding reactions with ketones as, in these cases, yields of a$-unsaturated esters are quite respectable. The known route to largely (E)-unsaturated esters (190) involving condensations between aldehydes and dianion (189) has been improved by using either triethyl phosphite or hexamethylphosphorus triamide as desulphurizing agents in the final step; 154 overall yields are in the range 68-90%. Exclusively (2)-2-t-butyl-cinnamates can be obtained in 11-62% yields by the sequence outlined in Scheme 25.155It is a very well established principle quoted in all text-books that such Wadsworth-Emmons reactions always lead to the more thermodynamically stable olefin. In a notable piece of perception, Still and Gennari have deduced that the less stable isomer should be obtained if (a) elimination in the initial adduct is faster than adduct equilibration and (b) the counter-cation has a minimal complexational ability. 156 To satisfy these criteria, electron-withdrawing trifluoroethyl groups are incorporated into the phosphonate group and the condensations are carried out using W. Huggenberg and M. Hesse, Helv. Chim. Acta; 1983,66,1519. Ito and M. Matsumoto, J . Org. Chern., 1983,48, 1133. 151 R. A. Volkmann, J. T. Davis, and C. N. Meltz, J . Org. Chern., 1983,48, 1767. 152 J. Villieras and M. Rambaud, Synthesis, 1983, 300. lS3 A. Osuka, Y. Mori, H. Shimizu, and H. Suzuki, Tetrahedron Lett., 1983,24,2599. ls4 S . Matui, K. Tanaka, and A. Kaji, Synthesis, 1983, 127. 155 E. Schaumann and S.' Fittkau, Synthesis, 1983, 449. 156 W. C . Still and C. Gennari, Tetrahedron Len., 1983,24,4405. 149

150 S.

161

Carboxylic Acids and Derivatives

potassium enolates in the presence of 18-crown-6. In this way, a,P-unsaturated esters are obtained with stereoselectivities of between 4: 1 and 50:1 in favour of the (2)-isomers (Scheme 26). The method is also very effective for the homologation of aldehydes into the (2)-a-methyl derivatives (191), by using the corresponding a-methyl-phosphonoacetate. M e s ~ c oEt2 MeS

t
i i , iii

P(OEt12

II

0

0

Reagents: i, 3 equiv, Me,CuLi; ii, NaH; iii, ArCHO

Scheme 25

Reagents: i, KN(SiMe&, 18-crown-6

Scheme 26

Dimerizations of vinyl ketene silyl acetals (192) induced by titanium tetrachloride lead to the octadiene dioates (193).157 Mixtures containing a, y-coupled products are usually obtained with more highly substituted substrates although cross-coupling reactions between (192) and simple ketene silyl acetals can give respectable yields of cross-coupled products contaminated with relatively small amounts of homo-coupled products. Some simple examples of Darzens-type condensations between acetate enolates and a-chloro-ketones have been reported which give rise to y-hydroxy-unsaturated esters (194) in 49-55% yields. 158 Various routes to y-phenylthio-crotonates (195) have been developed 2.

R2 ~

Me3SiO

e

o

2

c

~

0

2

M R+COzEt e

Me0

R2

R’

R’

R2

OH

R1+rc02R --+ R3

--

SPh

157

ls8

R’

K. Hirai and I. Ojima, Tetrahedron Lett., 1983, 24, 785. M. Larcheveque, P. Perriot, and Y. Petit, Synthesis, 1983,297.

General and Synthetic Methods

162

I

PhS

SPh

R

involving [1,2]- or [1,3]-thio shifts.159Enolates derived from these crotonates are alkylated exclusively a - to the ester group to give the deconjugated esters (196). Similarly, enolates formed from the a-phenylthio-crotonate (197) also undergo reactions with electrophiles only at the a-position leading to esters (198).160The normal mode of reaction of an allyl-silane with electrophiles has been used for the elaboration of exclusively y-substituted crotonates [e.g. (200)l. Thus, silyl esters [e.g. (199)], prepared by coupling the lithium enolate of a-trimethylsilylacetate with a vinyl bromide, in the presence of nickel bromide, react with a broad spectrum of electrophiles (RCHO, R1R2C0,acetals, and RCOC1) to give crotonates (200) in moderate to good yields.161 An overall a-substitution of or,@unsaturated esters can be achieved by fluoride-induced condensations of the a-silyl-ester (201) with aldehydes. 162 The substituted products (202) are obtained in 48-90% yields as mixtures of isomers in which the (2)-form predominates. It has been found, unexpectedly, that (a-ethoxycarbonylviny1)cuprates (203), formed by addition of (RICuY)Li to ethyl propynoate, react with monosubstituted epoxides to give exclusively the (2)-crotonates (204), useful as precursors to (Z)-a-alkylidene-butyrola~tones.~~~ Similarly, the cuprate (203) reacts with ketones to give only (2)-a-substituted esters (205) ; condensations with aldehydes produce isomeric mixtures [cf. (202)l. 'OZEt

TiCb,

E+

(203)

C02Et

*

C02 Et

C02Et

(204)

(205)

15y-P.Brownbridge, P. G . Hunt, and S. Warren, Tetrahedron Lett., 1983,24,3391. J. Durman, P. G. Hunt, and S. Warren, Tetrahedron Lett., 1983,24,2113. P. Albaugh-Robertsonand J . A. Katzenellenbogen,J . Org. Chem., 1983,48,5288. 16* Y . Sat0 and S. Takeuchi, Synthesis, 1983,734. 163 J. P. Marino and R . J. Linderman, J . Org. Chem., 1983,48,4621.

163

Carboxylic Acids and Derivatives

A further example of the utility of palladium-catalysed reactions of vinyl~ t a n n a n e sis l ~in~ the conversion of the bromo-acetoacetate derivative (206) into the dienoate (207), without the need to protect the enoate function, following l ~~ method treatment with a tri-n-butylvinylstannane and a palladium ~at a1yst .The can also be used to prepare a-methylene arylpropionates (208) by coupling ethyl bromomethacrylate with a tri-n-butylaryl-stannane. OMe

OMe

During a natural product synthesis, a novel method for the P-methoxycarbonylation of enol ethers has been developed (Scheme 27) .165 A comprehensive study of the generality of the scheme has yet to be carried out. Ketones can be

YOzMe

/!O Reagents: i, Cl,CCOCl, 2,6-di-t-butylpyridine; ii, Mg(OMe),

Scheme 27

converted by a one-carbon homologation via a-oxoketene dithioacetals into a$unsaturated esters (Scheme 28);166yields are generally good to excellent. In a somewhat related two-carbon homologation, imidium salts obtained from lactams condense with Meldrum’s acid in the presence of triethylamine to provide a-alkoxycarbonylmethylidene derivatives in 43-95% yields following alcoholysis (Scheme 29) .16’

Scheme 29

F. K. Sheffy and J. K. Stille, J. Am. Chem. Soc., 1983,105,7173. B. M. Trost, J. M. Balkovec, and M. K.-T. Mao, J . Am. Chem. SOC., 1983,105,6755. 166 B. Byrboh, H. Ila, and H. Junjappa, J. Org. Chem., 1983,48,5327. 167 J. P. Ctltrier, M. G. Richaud, and G. Lhommet, Synthesis, 1983,195.

164

165

General and Synthetic Methods

164

In view of the sometimes lengthy and sophisticated routes which have been devised for the preparation of a-methylene-esters, it is amusing to read168that examples (209) of such compounds can be simply obtained by treating neat mixtures of methyl acrylate and an aldehyde with a trace of DABCO. The method is tolerant of much sensitive functionality and proceeds in 39-95% yields during 4 h to 7 days. A general method for converting a-nitro-esters (210) into a-methylene-esters (212) is by way of routine hydroxymethylation and acetylation to give derivatives (211) followed by denitration (Bun3SnH)and elimination (DBU) ; reasonable overall yields are 0btainab1e.l~~ A previously reported route to 2,4-dienoic acids has been adapted to provide a new approach to y,B-unsaturated-a-methylene-esters (213). 170

R/ 'CO2Et

R'

The efficiency of photochemical deconjugations of a,P-unsaturated esters [e.g. (214)+ (215)] is considerably increased by the addition of a weak organic base such as 1,2-dimethylimidazole. 171 P, y-Unsaturated esters can be constructed starting from y-phosphonatoacetoacetate, as outlined in Scheme 30.17*The key to the success of this approach is the rapid hydration and decarboxylation of the intermediate ketene formed in the Wolff rearrangement step; unfortunately this present version is limited to non-enolizable aromatic aldehydes. Diazo-ester chemistry is also featured in an alternative route to P,y-unsaturated esters which involves treatment of acetals of a$-unsaturated aldehydes with ethyl diazoacetate and BF3.Et20.173 The overall sequence [(216)+ (217)] is formally an insertion of :CHCO,Et into a carbon-carbon bond and could prove to be a very useful procedure in appropriate cases. Doubly fluorinated unsaturated esters (218) are produced in 4 0 4 0 % yield by condensations between simple ester enolates and difluoroacetylene, generated in situ from lf1,2-trifluoroethyleneand Bu'Li. 174

H. M. R. Hoffmann and J. Rabe, Angew. Chem., Int. Ed. Engl., 1983,22,795,796. N. Ono, H. Miyake, M. Fujii, and A . Kaji, Tetrahedron Lett., 1983, 24, 3477. 170 J.-M. Vatele, Tetrahedron Lett., 1983, 24, 1239. 171 I. A . Skinner and A. C . Weedon, Tetrahedron Lett., 1983,24,4299. 172 E. C . Taylor and H. M. L. Davies, Tetrahedron Lett., 1983,24,5453. 173 M. P. Doyle, M. L. Trudell, and J. W. Terpstra, 1.Org. Chem., 1983,48, 5146. A. S. Kende and P. Fludzinski, J . Org. Chem., 1983, 48, 1384.

169

165

Carboxylic Acids and Derivatives

Reagents: i, RCHO; ii, n-CI,H,,C,H,SO,N,;

iii, Rh(OAc),, PhF, A; iv, H,O, A

Scheme 30 F

Ry0Me

~

OMe

(216)

COZEt

RXCOZEt

(217 1

OMe

&R2 F (218)

The Reformatsky reagent derived from ethyl bromoacetate couples largely or exclusively in an SN2 fashion to allylic halides in the presence of Cu(acac)2, providing a simple entry to y, S-unsaturated esters 175 [cf. ref. 971. Some examples of vinylcuprate additions to y, S-unsaturated esters derived from carbohydrates have been found to proceed with excellent diastereoselectivities [>lo:11.176 For example, treatment of ester (219)with (2)-lithium dipropenylcuprate leads very largely to the adduct (220) via a Felkin-type addition anti- to the polar allylic methoxy-group in (219) rather than by co-ordination-directed attack involving the latter substituent .

Reactions between cyclohexadienyl-iron complexes [e.g. (221)] and simple ester enolates, as well as other relatively reactive nucleophiles, in the presence of carbon monoxide lead to substituted cyclohexenes after trapping of the intermediate acyl-iron complex with an electrophile (Scheme 31).177Although as yet few examples of the procedure have been reported, it would appear to have considerable synthetic potential. Three groups 178 have independently investigated the substantial influence of a-alkoxy-groups on the stereochemical outcome of simple Ireland-Claisen ester enolate rearrangements. For example, a 10.2:1 selectivity was observed in favour of isomer (223)when the a-methoxy-ester (222; M. Gaudemar, Tetrahedron Lett., 1983,24,2749. W. R. Roush and B. M. Lesur, Tetrahedron Lett., 1983,24, 2231. 177 M. F. Semmelhack, J. W. Herndon, and J. P. Springer, J . Am. Chem. Soc., 1983, 105,2497. 17s S. D. Burke, W. F. Fobare, and G. J. Pacofsky, J. Org. Chem., 1983,48,5221; J. Kallmerten and T. J. Gould, Tetrahedron Lett., 1983, 24, 5177; T. Sato, E. Tajima, and T. Fujisawa, ibid., p. 729. 175

176

General and Synthetic Methodr

166

R=Me) was subjected to the rearrangement; benzyloxy and MEMO groups were found to be less effective in terms of stereochemical control. In contrast to esters and ketones, but in common with amides and thioamides, dithiopropionates give rise to a preponderence of (2)-lithio-enolates on treatment with lithium di-isopropylamide; subsequent S-allylation and thio-Claisen rearrangement can be used to prepare erythro-esters [e.g. (224)], with diastereoselectivitiesof up to 87: 13

Fe (CO), (221 1 Reagents: i, CO, -78 "C; ii, Me1

Scheme 31

Full details for the preparation of the isolable 5-phosphoranylidene levulinate (225) have been published; the compound reacts cleanly with aldehydes to provide unsaturated keto-esters (226) in 70-90% yields.180 Useful WadsworthEmmons substrates [e.g. (227)] may be obtained by EtAlC1,-catalysed ene reactions between 2-phosphonoacrylates and olefins. 2,4-Dienoates (229), largely as the (E,E)-isomers, have been obtained from aldehydes (228) by a two-carbon homologation involving sequential condensation with methyl a-arylsulphinyl acetate, acetylation, and finally treatment with the 0-silyl enolate of N-trimethylsilylacetamide and [Mo(CO)~];the full potential of the method has not been fully defined.lS2Trienoates [e.g. (230)] and tetraenoates [e.g. (231)] have been obtained by palladium-catalysed couplings of buta-l,3-dienes with one or two equivalents respectively of a fl-bromopropenoate. 183 The brevity and simplicity of the method compensate for the usually lowish yields. Allenic esters (232) can be prepared by chromium(n)-induced debrominations of the corresponding 6-bromo-2-en-4-ynoates.184

P. Beslin, P. Metzner, Y. VallCe, and J. Vialle, Tetrahedron Lett., 1983,24,3617. R . C. Ronald and C. J. Wheeler, J. Org. Chem., 1983,48, 138. lB1B. B. Snider and G . B. Phillips, J . Org. Chem., 1983,48,3685. lB2B. M. Trost, M. Lautens, and B. Peterson, Tetrahedron Lett., 1983,24, 4525. IB3W. Fischetti, K. T. Mak, F. G. Stakem, J.-I. Kim, A. L. Rheingold, and R. F. Heck, J. Org. Chem., 1983,48,948. B. LeDoussal, A. Le Coq, A. Gorgues, and A. Meyer, Tetrahedron, 1983,39,2185. 179

180

167

Carboxylic Acids and Derivatives

Thioesters.-A useful review, containing some 200 references, has been published on the synthesis of dithiocarboxylic acids and estersls5(see also ref. 66). Thioesters can be readily obtained by reactions between 3-acylthiazolidine2-thiones [cf. (38)] and thiols in the presence of triethylamine.ls6 Generally, yields are very good but the by-product, thiazolidine-2-thione, has to be removed by chromatography. The sodium salt of thiosaccharin has been employed in an ‘odourless’ route to thioesters in which the alkylthiol is generated in situ; subsequent coupling with an acid chloride gives the thioester in ca. 90% yield.ls7 Perchloric acid has been found to be superior to hydrogen chloride for the hydrolysis of a-chlorovinyl sulphides to thioesters in the presence of thiophenol.188S-Aryl thiobenzoates can be obtained in 80-94% yields by Ullman-type couplings of aryl iodides with copper salts of thiobenzoates in hot HMPA .lS9 Acetylenic alcohols (233) undergo [2,3]-sigmatropic rearrangements on treatment with phenylsulphenyl chloride to give allenes (234) which, when simply warmed in ether, rearrange to the unsaturated thioesters (235; R’, R2#H), presumably via a sila-Pummerer mechanism.’” During a synthesis of bufadienolides, a new route to y-hydroxy-a,P-unsaturatedthioesters has been used, an outline of which is given in Scheme 32.1g1Presumably, the last step involves a process reminiscent of a Pummerer rearrangement.

(233 1

( 234 1

(235)

S. R. Ramadas, P. S. Srinivasan, J. Ramachandran, and V. V. S . K. Sastry, Synthesis, 1983,605. K. Soai, H. Hayashi, and A. Ookawa, J . Chem. Res. ( S ) , 1983, 20. 187 H. Yamada, H. Kinoshita, K. Inomata, and H. Kotake, Buff. Chem. SOC.Jpn., 1983, 56,949. V. Reutrakul and P. Pooehaivatananon, Tetrahedron Lett., 1983,24,535. 189 A. Osuka, N. Ohmasa, Y. Uno, and H. Suzuki, Synthesis, 1983, 68. lW I. Cutting and P. J. Parsons, Tetrahedron Lett., 1983,24, 4463. 191 P. E. Bauer, K. S. Kyler, and D. S. Watt, J . Org. Chem., 1983,48,34, lX3

General and Synthetic Methods

168

Reagents: i. BuSLi;ii, R1R2CO;iii, O2

Scheme 32

Enolates derived from dithioesters are soft nucleophiles judging from the observations that such species add in a Michael fashion to enones 192 andP-vinyl$lactones ly3 (Scheme 33). Yields from such additions are variable, partly because of the tendency for reaction at sulphur as well as at carbon, which results in the formation of dithioketene acetals as by-products. The synthetic utility of these reactions may be enhanced by new procedures for the conversion of a variety of thiocarbonyls into carbonyls by reaction with either N-nitrosopiperidine or N-nitroso-N-methylaniline in 4M-HC1-CH2C12.194

0

A

R'

s

SMe

S

Scheme 33

3 Lactones

P-Lactones.-Enolates (236) derived from p-lactones add in a largely or completely stereoselective manner to dimethyl maleate to give the a-substituted lactones (237).ly5 Butyro1actones.-Considerable degrees of regioselectivity have been achieved in oxidations of simple 2,2-disubstituted butane-l,4-diols to butyrolactones [e.g. P. Metzner and R. Rakotonirina, Tetrahedron Lett., 1983, 24, 4203. Fujisawa, T. Itoh, and T. Sato, Chem. Lett., 1983, 1901. Iy4 K. A . Jmgensen, M. T. M. El-Wassimy, and S.-0. Lawesson, Tetrahedron. 1983, 39, 469. 195 J . Mulzer, A. Chucholowski, 0.Lammer, I. Jibril, and G. Huttner,J. Chem. SOC.,Chem. Commun., 1983, 869.

192

193 T.

Carboxylic Acids and Derivatives R'

169

G' -.

nu

K

.

NPr',

Reagents: i, MeSO,H, MeOH, Hg(OAc),; ii, h-ClC6H,CO3H, BF,

Scheme 34

(238)- (239)] using mixtures of bromine and nickel(I1) alkanoates. lY6 An efficient and highly diastereoselective approach to 3-methyl-4-alkylbutyrolactones is via a three-carbon extension of aldehydes using titanium enolates of O-allylic carbamates (Scheme 34).197 An interesting and seemingly facile preparation of 4-substituted and 3,4-disubstituted butyrolactones is by Hg'I-mediated cyclopropane cleavages in the presence of an internal nucleophile (Scheme 35).198 The method can be highly stereoselective and is applicable to the synthesis of other ring systems. Similarly substituted butyrolactones have also been obtained, but with a high degree of cis stereoselectivity, by radical-mediated cyclizations of ally1 trichloracetates [(240)+ (241)] triggered by CuCl in acetonitrile at 140°C.199 The initial products (241) are completely dechlorinated in a separate step using

"0

W

C

O

Z

N

a

-

Scheme 35

M. P. Doyle, R. L. Dow, V. Baheri, and W. J. Patrie, J. Org. Chem., 1983,48,476. See also T . Kageyama, S. Kawahara, K. Kitamura, Y. Ueno, and M . Okawara, Chem. Lett., 1983, 1097; Y. Tamaru, Y. Yamada, K. Inoue, Y. Yamamoto, and Z. Yoshida, 1.Org. Chem., 1983, 48,1286; Y. Ishii, K. Osakada, T . Ikariya, M . Saburi, and S. Yoshikawa, Tetrahedron Lett., 1983, 24, 2677. 197 D . Hoppe and A. Bronneke, Tetrahedron Lett., 1983,24, 1687. 198 D. B. Collum, F. Mohamadi, and J. S. Hallock, J . A m . Chem. SOC., 1983, 105, 6882. See also Y. Yokoyama and M. Yunokihara, Chem. Lett., 1983, 1245. 199 H. Nagashima, H. Wakamatsu, K. Itoh, Y. Tomo, and J. Tsuji, Tetrahedron Lett., 1983.24, 2395.

General and Synthetic Methods

170

R’

(2421

(2431

tri-n-butyltin hydride. Only the threo-adduct (242) is obtained when the corresponding butyrolactone 0-silyl enolate is condensed with acetaldehyde using TIC4 as catalyst; similar reactions with other aldehydes have yet to be reported.2004,4Disubstituted lactones (243) can be prepared in 50-70% yield using SnC14catalysed additions of ethyl a-chloro-cr-arylthioacetate to olefins.201 During an approach to naturally occurring lignans, a new dianion (244) derived from mercaptosuccinic acid has been used to obtain butyrolactones (245) by condensation with aryl aldehydes; yields are in excess of 50% .202 An apparently better route to the related 4-arylparaconic acids (246) is by condensations between aromatic aldehydes and succinic anhydride using a ZnCl2.Et3Ncomplex as catalyst .*03 C02 Me

-

C02Me

ArCHO

M e 5 4

0

A simple route to a-hydroxy-butyrolactones (248) involves condensations between metallated cyanohydrin derivatives (247) and monosubstituted epoxides.2a Yields are high throughout, and the intermediate (1-ethoxy)ethoxylactones can also be isolated. Related P-hydroxy-butyrolactones (249) are obtainable in 61-99% yields by condensations between trimethylsilyl ester enolates and b r o m~a ceta ld ehyde.Crucial ~ ~ ~ to the success of this method is the use of readily hydrolysable silyl esters (other esters fail or give low yields) and the K. Yamamoto and Y. Tomo, Chem. Lett., 1983,531. M. Wada, T. Shigehisa, H. Kitani, and K. Akiba, Tetrahedron Lett., 1983, 24, 1715. 202 A. Pelter, R, S. Ward, P. Collins, R., Venkateswarlu, and I. T. Kay, TetrahedronLett., 1983,24,523. 203 J. M. Lawlor and M. B. McNamee, Tetrahedron Lett., 1983, 24,2211. *04 G. A. Garcia, H. Munoz, and J. Tamariz, Synth. Commun., 1983, 13, 569. 205 G. A . Kraus and P. Gottschalk, J. Org. Chem., 1983,48,5356.

M’

201

171

Carboxylic Acids and Derivatives

development of a convenient preparation of anhydrous bromoacetaldehyde. Excellent diastereoselectivities have been observed in iodolactonizations of the 3-hydroxy-4-enoic acids (250; R', R2=H or Me), leading to the P-hydroxy-

OH R2

(250)

(251) R

R

I

(252)

YH 1

(253)

+co2Me OH (254)

butyrolactones (251) .206 Perhaps not surprisingly, cis-dihydroxylations of butenolides (252) by KMn0,-dicyclohexano-18-crown-6also proceed with very high diastereoselectivitieswhen the y-substituent is very large (e.g. R=Ph3C0 or Ph2MeSiO), to give the dihydroxy-butyrolactones (253) in 50-60% yields.207 When the substituent is much smaller (e.g. R=Bu"), the selectivity is only ca. 3:l in favour of (253). More remarkable is the finding that similar hydroxylations of (E)-y-hydroxy-a$-unsaturated esters [e.g. (254)], using OsO, and N-methylmorpholine N-oxide, give only trans-dihydroxy-butyrolactones[e.g. (255)] whereas the corresponding (2)-esters give rise exclusively to cis-dihydroxy-lactones [e.g. (256)].208 A reasonable rationale of these results is given which may well be of predictive value.

2M

A. R. Chamberlin, M. Dezube, P. Dussault, andM. C . McMills,]. Am. Chem. SOC., 1983,205,581Y. T. Mukaiyama, F. Tabuse, and K. Suzuki, Chem. Lett., 1983, 173. G . Stork and M. Khan, Tetrahedron Lett., 1983,24,3951.

172

General and Synthetic Methods

i*

0Me

L

H

HP - H6?o ii, iii

OMe

Reagents: i , p-MeC,H,S03H; ii, H,O+; iii, PCC

Scheme 36

A neat application of an acid-catalysed intramolecular Michael addition forms the basis of a new method for the annelation of butyrolactones (Scheme 36).209 This single example suggests that this type of cyclization could well be exploited in other syntheses. Another, currently fashionable, cyclization procedure employs free radicals as key intermediates. An illustration of this is a new procedure for the construction of annelated butyrolactones from crotonyl esters of /3-hydroxyselenides (Scheme 37) .210 Unfortunately, the method is not effective when applied to the corresponding acrylate esters. More established methods have been used to exploit the availability of dienylacetic acids [e.g. (257)]63 in stereoselective syntheses of fused [e.g. (258)] and 3,4-disubstituted [e.g. (259)] butyrolactones .211

as> ac, SePh

ii)

0

j

&o I

H

Reagents: i, MeCH=CHCO,Ag; ii, Ph,SnH

Scheme 37 CHO

CHO ( 257 1

(258)

(259)

G. Stork and K. S. Atwal, Tetrahedron Lett., 1983, 24, 3819. D. L. J. Clive and P. L. Beaulieu, J . Chem. Soc., Chem. Commun., 1983,307. 211 A. J. Pearson, T. Ray, I. C. Richards, J. CIardy, and L. Silveira, Tetrahedron Lett., 1983,24,5827. 209

*lo

Carboxylic Acids and Derivatives

173

trans-Hydroxy-lactones [e.g. (261)] can easily be obtained from bicyclic diacids [e.g. (260)] by treatment with commercial bleach.*l2 This procedure, which is

reminiscent of halogenolactonization, does not afford lactones directly from similar monocyclic or acyclic olefinic acids, but rather the corresponding transdihydroxy-derivatives. Total syntheses of Aeginetolide (262) and the related butenolides Dihydroactinidiolide and Actinidiolide have been reported.213The key steps consist of oxidation of an appropriate cyclohexanone silyl enol ether to give an a-hydroxycyclohexanone followed by acetylation and closure of the lactone ring by an intramolecular condensation.

4co*H C02H

H*co*H

- -0

'0

(2601

(261 1

(262)

The glyoxylic acid derivative (263) reacts with 1,3-dienes in the presence of an acid catalyst (MeS03H) to give cx-acylamino-y-alkenyl-butyrolactones (264) as major products while the expected Diels-Alder adducts arising from the intermediate acyliminium species are produced in much lower yields Simple alkylations of (S)-P-amino-butyrolactone derivatives, readily available from (L)-aspartic acid, give largely the trans-homologues (265) .*I5 Chiral annelated butyrolactones (267) have been obtained with enantiomeric enrichments of 58-88% by reduction of imides (266) derived from (R)-2-amino2-phenylethanol; *16 the carbocyclic ring size is between three and six carbons in the examples examined. One of Mukaiyama's lactonization reagents, 2-chlorol-methylpyridinium iodide, has been found to be very effective in the preparation of strained trans-fused butyrolactones [e.g. (268)] from the corresponding trans-yhydroxy-acids.217

J. B. Hendrickson and V. Singh, Tetrahedron Lett., 1983,24,431. G. M. Rubottom and H. D. Juve, Jr., 1. Urg. Chem., 1983,48,422. 214 D. Ben-Ishai and S. Hirsch, Tetrahedron Lett., 1983, 24, 955. 215 G. J. McGarvey, R. N. Hiner, Y. Matsubara, and T. Oh, Tetrahedron Lett., 1983, 24,2733. 216 T. Mukaiyama, H. Yamashita, and M. Asami, Chem. Lett., 1983,385. 217 L. Strekowski, M. Visnick, and M. A . Battiste, Synthesis, 1983, 493.

212

*13

General and Synthetic Methods

174

Details of the preparation of bis-lactones [e.g. (269)] from glyoxal and dimethylketene acetals have been given.218New procedures for the construction of spiro-butyrolactones [e.g. (270) and (271)] have been developed using the well established cyclopropanol+ cyclobutanone ring expansion method originally reported by Trost, and have been applied to a total synthesis of Plumericin (272).219

Qo (270)

A promising new route to (E)-alkylidene-butyrolactones(Scheme 38) has in the key step an intramolecular trapping of an epoxy-silane by a carboxylic acid group.220Oddly, the intermediate hydroxy-silane does not undergo direct basecatalysed syn-elimination to give the corresponding (2)-isomers. The method is also effective in the preparation of alkylidene-tetrahydrofurans. OH

R

Reagents: I, m-ClC,H,CO,H; ii, Ac@; iii, F-

Scheme 38

Tetraethoxyallene acts as the synthetic equivalent of a malonate ester dianion in condensations with a,o-diacid chlorides which lead to the ylidene-lactones C. G. Bakker, J. W. Scheeren, and R. J. F. Nivard, R e d : J . R . Neth. Chem. SOC., 1983,102,96. B. M. Trost and M. K.-T. Mao, J . Am. Chem. SOC.,1983,105,6753; B. M. Trost, J. M. Balkovec, and' M. K.-T. Mao, ibid., p. 6755. 220 F.-T. Luo and E. Negishi, J . Org. Chem., 1983,48, 5144.

*19

Carboxylic Acids and Derivatives

175

[(273) ; n =2 4 1 .221 The known a-amino-acid derivatives (274) can be simply converted into the potential protease suicide substrates (275) by treatment with an N-halogenosuccinimide .222

a-Methylenebutyro1actones.-Ban's group has summarized its work on the preparation of lactones and lactams by Pd"-catalysed carbonylation of vinyl halides containing a hydroxy or secondary amine group respectively.223Among other uses,45,48 such transformations [(276)-+(277)] provide a useful entry into four-, five, and six-membered a-methylene-lactones. Oxidations of ally1 silanes [e.g. (278)] using iodosobenzene and BF,.Et,O provides a new entry into enals (279), further oxidation of which by sodium chlorite leads to a-methylenebutyrolactones (280) in reasonable overall yields.224Simply by positioning the acetoxygroup 6- to the silyl group, the method can also be used to prepare a-methylenevalerolactones (281). y-Substituted lactones (280) are also available by Pdo-catalysed cyclizations of chloroformates (282), derived from homoallylic alcohols and phosgene.225

173-Dipolaradditions between the nitrile oxide (283) and cis-olefins followed by hydrogenolysis lead to the butane-174-diols(284) which can be converted into lactones (285) following methenyl,ation, deprotection, and oxidation.z26

222 223

R. W. Saalfrank and W. Rost, Angew. Chem., Int. Ed. Engl., 1983,22, 321. M. J. Sofia, P. K. Chakravarty, and J. A . Katzenellenbogen, J. Org. Chem., 1983,48,3318. M. Mori, Y. Washioka, T. Urayama, K. Yoshiura, K. Chiba, and Y. Ban, J . Org. Chem., 1983,48, 4058.

M. Ochiai, E., Fujita, M. Arimoto, and H. Yamaguchi, Tetrahedron Len., 1983, 24, 777. 225 F. Henin and J.-P. Pete, Tetrahedron Lett., 1983, 24,4687. 226 A. P. Kozikowski and A . K. Ghosh, Tetrahedron Lett., 1983,24,2623.

224

176

General and Synthetic Methods

Although reasonably efficient, the method is limited to olefinic substituents (R) that are not affected by the Raney nickel hydrogenolysis conditions required; problems of regioselectivity may also arise in reactions beginning wtih an unsymmetrical olefin. A full report has been published on an alternative but nonstereoselective route to p, y-disubstituted-a-methylenebutyrolactones [cf. (285)] by distillation of mixtures of cyclopropanecarboxylates (286) and Me3SiI.227 The cyclopropanes (286) are constructed using carbene additions to olefins, so again there are considerable restrictions on the types of substituent (R1, R2)that can be used. In another full report is detailed the preparation of butyrolactones (287) by condensations between a-acetoxy-aldehydes and the enolate of ethyl a-phenylthiopropanoate .228 Oxidation at sulphur followed by thermolysis of cis(287) leads to the a-methylene derivatives (288) whereas similar treatment of the trans-isomers gives largely lactones (288) along with some of the corresponding butenolides. Hydrolysis of the acetoxy-group prior to oxidation gives rise to the cc-rresponding /3-hydroxy-a-methylene-butyrolactones.The stable iron salts (289) act as vinyl cation equivalents in condensations with /3-keto-ester enolates, leading largely to the trans-disubstituted lactones (290) following reduction, acidcatalysed elimination of ethanol, and d e m e t a l l a t i ~ nUnder . ~ ~ ~ the present conditions, the method is only really efficient when R=Me.

In an extension of previous work, it has been shown that condensations between anions derived from phenylthiomethacrylates and aldehydes or ketones represent an efficient and general approach to a-phenylthiomethylene-butyrolactones (291).230Another total synthesis of (+)-Avenaciolide (292) has been achieved starting from a-phenylthi0-,8-vinylbutenolide.~~~ a-Methylenebutyrolactones (293) can be efficiently deconjugated to give (E)/(Z)-mixtures of butyrolactones (294) by irradiation at 254 nm in 227 H.

Saimoto, K. Nishio, H. Yamamoto, M. Shinoda, T. Hiyama, and H. Nozaki, Bull. Chem. SOC., Jpn., 1983, 56, 3093. 228 P. Barbier and C . Benezra, 1. Org. Chem., 1983,48,2705. 229 T. C. T. Chang and M. Rosenblum, Tetrahedron Lett., 1983,24,695. 2x1M. Kitaoka, Y. Takahashi, H. Kosugi, and H. Uda, Chem. Left., 1983,1065. D l F. %do, Y. Tooyama, Y . Noda, and A. Yoshikoshi, Chem. Lett., 1983,881. zz F. HCnin, R. Mortezaei, and J.-P. Pete, Synthesis, 1983, 1019.

Carboxylic Acids and Derivatives

177

SPh

(291

(292 1

(294)

(293)

Butenolides and Phthalides.-Radical-mediated cyclizations210are featured in a new method for the preparation of a wide variety of /?-substituted butenolides (Scheme 39).233'Double' cyclization is also possible [e.g. (295)+ (296)], and when applied to allylic ethers [e.g. (297)], trans-substituted butyrolactones [e.g. (298)] are obtained stereoselectively and in good overall yield. Another new route to /?-substituted butenolides, developed during a total synthesis of the clerodane diterpene insect antifeedant Ajugarin 1,involves conjugate addition of metallated sulphones to an appropriate acetylenic acid ester followed by deprotection and desulphurization (Scheme 40).234Overall yields are ca. 45% but distinct advantages are the availability of the starting materials and the relative simplicity of the procedure. Metallated sulphones have also been used to prepare butenolides by sequential alkylations with an alkyl halide and sodium iodoacetate; in this case elimination of the sulphone group provides the olefinic bond (Scheme 41).235y-Substituted derivatives can also be obtained from aryl methyl sulphones by a similar sequence involving sequential condensations with an aldehyde and ICH2C02Na. Bc3SnH

R\

-*b0/VCI I

Scheme 39

G. Stork and R. Mook, Jr., J. Am. Chem. SOC., 1983,105,3720; G. Stork, R. Mook, Jr., S. A. Biller, and S. D. Rychnovsky, ibid., p. 3741. 234 S. V. Ley, N. S . Simpkins, and A. J. Whittle, J. Chem. SOC., Chem. Commun., 1983,503. 235 K. Tanaka, K. Ootake, K. Imai, N. Tanaka, and A, Kaji, Chem. Lett., 1983,633. 233

178

General and Synthetic Methods

A novel and reasonably efficient route to a,y-disubstituted butenolides (301) consists of conversion of the unsaturated sulphones (299) into vinyl stannanes (300) by sequential treatment with Bun3SnLiand an aldehyde, R2CHO; the sequence is then completed by tin-lithium exchange, carboxylation, and acidcatalysed ring closure.236The related butenolides (303) can be obtained from (302), formed from the cyclopentadiene-maleic anhydride Diels-Alder adduct and RlMgX, following alkylation [LDA; R2X]and retro-Diels-Alder reaction.237 Dealkylation of 2-methoxyfuran by Me,SiI in the presence of the enone (304) leads to the butenolide (305).238This single example suggests that such an approach could have a wider application. a-Silylfurans can also serve as butenolide precursors following oxidation with AcOOH as outlined in Scheme

Scheme 40

M. Ochiai, T. Ukita, and E. Fujita, Tetrahedron Lett 1983,24, 4025. P. Canonne, M. Akssira, and G. Lemay, Tetrahedron Lett., 1983,24,1929. z3a G. A. Kraus and P. Gottschalk, Tetrahedron Lett., 1983,24,2727.

236

237

179

Carboxylic Acids and Derivatives

42.239It seems likely that more complex butenolides could be prepared by this met hod.

n=lor 2 I I

Scheme 42

P-Lithio-acrylates have been used as key intermediates in rather inefficient but very brief syntheses of the natural butenolides Lepichlorin (306) 240 and Umbelactone (307) .241 Metallation of the N, N-diethylamide of 2-furylacrylic acid by LTMP takes place at the P-acrylate position rather than at the more usual 5-position of the furan to give anion (308), condensation of which with ketones leads directly ,to butenolides (309).242A related species can be generated from pyrrolidine (310) using LDA as base; again condensation with aldehydes or ketones gives butenolides of general formula (311) .243P-Amino-as well asp-thioderivatives of butenolides [(312); X=NR or S] can be easily obtained from the corresponding P-halogenobutenolides by an addition-elimination sequence with secondary amines or sodium thiolates as nucleophiles respectively.244

D. Goldsmith, D. Liotta, M. Saindane, L. Waykole, and P. Bowen, Tetrahedron Lett., 1983, 24, 5835. **D. Caine and V. C. Ukachukwa, Tetrahedron Lett., 1983, 24, 3959. 241 D. Caine, A. S. Frobese, and V. C. Ukachukwa, J . Org. Chem., 1983,48,740. 242 R . R. Schmidt and R. Hirsenkorn, Tetrahedron, 1983,39, 2043. 243 R. R. Schmidt, J. Kast, and H. Speer, Synthesis, 1983, 725. 244 F. Farina, M. V. Martin, F. Sanchez, M. C. Maestro, and M. R. Martin, Synthesis, 1983, 397.

239

7

180

General and Synthetic Methods

A promising route to chiral butenolides and tetronic acids (Scheme 43) relies on asymmetric Sharpless epoxidations to provide optically active intermediates and has been applied to a total synthesis of ( - ) - V e r t i n ~ l i d e . ~ ~ ~ OH OH OH R

0

Symmetrical acetylenes can be carbonylated at relatively high temperatures and pressures in the presence of a rhodium carbonyl catalyst and an alcohol (R20H)to give good to excellent yields of the alkoxy-butenolides (313).*%Not surprisingly, unsymmetrical acetylenes lead to mixtures of both possible products. A new route to ylidenebutenolides (316) is by condensation between enolizable 1,2-diones (314) and the vinylidenephosphorane (315) .247 The approach seems to be widely applicable and yields are usually good to excellent.

(313 1

(314)

(315)

(316)

A full report has been published on an efficient and general route to 3-hydroxyphthalides and hence phthalides themselves, in which a key step is the temporary protection of the aldehyde group of an o-bromobenzaldehyde by hemiaminal formation (Scheme 44) A related procedure involving chiral oxazolines formally derived from o-bromobenzoic acids has been used to prepare OR

OR

OR

Br

OLi Reagents: i, N-Lithiomorpholine; ii, BunLi, -78 "C, CO,, H 3 0 + ;iii, NaBH,

Scheme 44 J. E. Wrobel and B. Ganem, J . Org. Chem., 1983,48,3761. 246 T. Mise, P. Hong, and H. Yamazaki, J . Org. Chem., 1983,48, 238. 247 R. W. Saalfrank, P. Schierling, and P. Schatzlein, Chem. Ber., 1983,116, 1463; R. W. Saalfrank, P. Schierling, and W. Hafner, ibid., p. 3482. 248 A. K. Sinhababu and R. T. Borchardt, J . Org. Chem., 1983,48,2356.

245

Carboxylic Acids and Derivatives

181

3,3-disubstituted phthalides with enantiomeric enrichments of 20-25% .249 Much higher enrichments (40-80%) can, however, be obtained by reactions between the corresponding o-keto-oxazolines and Grignard reagents. Further examples have been given of the preparation of 3-arylphthalides by Diels-Alder reactions between cyclohexa-l,3-dienes and 4-aryl-4-hydroxybut-2-ynoates.2so Tetronic Acids.-The Dieckmann route to 3-acyltetronic acids has been significantly improved (Scheme 45).2s1 The key features are the use of dianions derived fromp-keto-thioesters, Masamune's transesterification procedure, and the use of fluoride as base in the ring-closure step. The approach has been successfully applied to a synthesis of (S)-carlosic acid by using (S)-dimethyl malate in the transesterification step. 0-Alkyl-tetronic acids can be obtained from 4-hydroxybut-2-ynoates or the corresponding orthoesters using Hg-Nafion-H.2s2

'0--0

Reagents: i, NaH, Bu"Li, DME, RlX; ii, R*CH(OH)CO,Me, Ag02CCF3;iii, Bun,NF

Scheme 45

Valero1actones.-Dye-sensitized photo-oxygenation of cyclohexane-l,2-diones (317; R=alkenyl or alkynyl) gives the 8-keto-acids (318) in very high yields; conversion into the &substituted valerolactones (319) is then straightforward (NaBH,; H,O+).253 Examples of the synthesis of chiral valerolactones reported this year include those of (I?)-( +)-5hexadecanolide (320), a pheromone isolated from the oriental hornet ,254 and the potential erythronolide A precursors (321) and (322).255A stereoselective synthesis of the (4RS,6SR)-mevalonolactone derivative (323) has also been developed .256 A. 1. Meyers, M. A. Hanagan, L. M. Trefonas, and R. J. Baker, Tetrahedron, 1983, 39,1991. P. A . Harland and P. Hodge, Synthesis, 1983,419. 251 P. M. Booth, C. M. J. Fox, and S. V. Ley, Tetrahedron Lett., 1983, 24, 5143. 252 H . Saimoto, M. Shinoda, S. Matsubara, K. Oshima, T. Hiyama, and H. Nozaki, Bull. Chem. SOC. Jpn., 1983,56, 3088. 253 M. Utaka, H. Kuriki, T. Sakai, and A. Takeda, Chem. Lett., 1983,911. 254 S. Servi, Tetrahedron Lett., 1983, 24, 2023. 255 I. Paterson, S. K. Patel, and J. R. Porter, Tetrahedron Lett., 1983, 24, 3395. 256 H. Ferres, I. K. Hatton, L. J. A . Jennings, A . W. R. Tyrrell, and D. J. Williams, Tetrahedron Lett., 1983,24,3769.

249

2so

General and Synthetic Methods

182

During efforts towards the total synthesis of Quassinoids, the intramolecular Michael addition [(324)+ (325)] has been found effective for the formation of a valerolactone unit. 257 The cyclization was performed using Me3SiI and may proceed via the corresponding ,&iodo-silyl enol ether: other, more conventional Reformatsky-type conditions failed to produce the required lactone. Readily available 2-bromoallyl boronates react with aldehydes to give excellent yields of the (2)-homoallylic alcohols (326). One synthetic utility of these compounds is in the formation of unsaturated valerolactones (327) by carbonylation using [Ni(CO),] .258 Pummerer rearrangement of readily available a-phenylsulphinyl-valerolactone leads to the good Michael acceptor (328). Subsequent reaction with a range of appropriate nucleophiles followed by oxidative elimination of the phenylsulphenyl group gives the ,&substituted unsaturated lactones (329); yields are good throughout .259 A straightforward synthesis of a-methylenevalerolactones (331) is by condensation between the methallyl alcohol dianion (330) and mono-substituted epoxides followed by oxidation of the allylic alcohol function.260 Overall yields are in the range 13-61%. S-Alkoxycarbonylmethylene-valerolactones can be obtained by Wittig reactions between certain phosphoranes derived from a-halogenoesters and glutaric anhydride.261 r

0 Me3SiI %

M. Voyle, N. K. Dunlap, D. S . Watt, and 0. P. Anderson, J . Org. Chem., 1983,48, 3242. R. W. Hoffrnann and B. Landmann, Tetrahedron Lett., 1983,24,3209. 259 M. Kato, A. Ouchi, and A. Yoshikoshi, Chem. Lett., 1983, 1511. 260 R. M. Carlson and L. L. White, Synth. Commun., 1983, 13, 237. 261 S. Tsuboi, H. Fukurnoto, and A, Takeda, Chem. Lett., 1983, 1219. 257

258

Carboxylic Acids and Derivatives

183

Macro1ides.-A new and potentially very valuable technique for macrolide formation consists of heating a suspension of a potassium salt of an w-bromo-acid in toluene with a small amount of the phase-transfer catalyst Bun4NBr.262 Yields of macrolides are >90% in the simple examples examined at apparent concentrations of up to 0.1M. A full account has been given of the ‘template’ approach to

RNH

(332)

NHR

0 ( 333 1

macrolides from w-hydroxy-acids and Bun2Sn0.263 Overall, the method is essentially one of double-activation, and has been used in a very brief synthesis of the naturally occurring ion carrier Enterobactin (333), in 23% isolated yield, by ‘trimerization’ of the /3-lactone (332).264 A feature of work in this area during the past year, however, has been the emphasis placed on macrolide formation by C 4 rather than C 4 bond formation. Polymer-bound palladium has been used to effect ring closures of vinyl epoxides (334) to give macrolides (335) in yields of 70437% at concentrations of 0.1--0.5M.265 The method is limited to bis-sulphones but is applicable to very large rings (e.g. 27-membered). More conventional palladium(0) catalysts have been used in a synthesis of antibiotic A26771B (337), which involves cyclization of the allylic acetate (336).266This key step could well find use elsewhere as a y-keto-a,P-unsaturated lactone unit is commonly found in such compounds. A number of classical C 4 bond-forming reactions have also been employed in Y. Kimura and S. L. Regen, J. Org. Chem., 1983,48,1533. K . Steliou and M.-A. Poupart, J. Am. Chem. SOC., 1983,105, 7130. 264 A. Shanzer and J. Libman, J. Chem. SOC., Chem. Commun., 1983,846. 265 B. M. Trost and R. W. Warner, J . Am. Chem. SOC., 1983, 105,5940. 266 B. M. Trost and S. J. Brickner, J. Am. Chem. SOC., 1983, 105,568.

262 263

General and Synthetic Methods

184

0

0

(334)

(335) 0

(336)

( 337 1

macrolide formation. Synthesis of (S,S)-( +)-Grahamimycin A (338) has been achieved by an intramolecular pinacol-type coupling of an a,o-dialdehyde using Zn/Cu-TiCl,, followed by oxidation.267A Lewis acid-catalysed intramolecular Diels-Alder reaction has been used to prepare the sensitive bridgehead olefin (340) from the acrylate (339) in 85% yield,268and recently described ketenylidene phosphoranes are key intermediates in another version of the intramolecular Wittig-type approach to macrolides (Scheme 46) .269 Although yields are usually good, in this latter method, high dilution conditions are required. Reasonable yields ofp-keto-macrolides (342) can be realized by cyclization of thep-keto-ester dianions (341).”O The method has been used to prepare 14-16-membered lactones as well as a 26-membered example containing one ck-double bond. 9-27Membered lactones have been prepared by photolysis of w-methylsulphenyl Yields are in the range 36--80% at fairly esters of N-hydr~xyalkylphthalides.~~~ high dilutions (2.9-7.0 mM in acetone).

267

268

269

*’O

D. Ghiringhelli, Tetrahedron Lett., 1983, 24, 287. K. J. Shea and J. W. Gilman, Tetrahedron Lett., 1983,24,657. H. J. Bestmann and R. Schobert, Angew. Chem., Int. Ed. Engl., 1983, 22, 780. R. J. Sims, S. A . Tischler, and L. Weiler, Tetrahedron Lett., 1983, 24,253. M. Wada, H . Nakai, K. Aoe, K. Kotera, Y. Sato, Y. Hatanaka, andY. Kanaoka, Tetrahedron,1983, 39, 1273.

Carboxylic Acids and Derivatives

185

Scheme 46

( 342 1

(343)

I No2

0 ( 346 1

(347)

(348 1

Two examples of a four-atom ring expansion method for converting a-nitrocycloalkanones into macrolides [(343)+ (344)] have been described.272The mildness of the conditions used suggests that this method may have further potential. a-Methoxy-hydroperoxides formed by olefin ozonolysis in methanol undergo a Criegee rearrangement, complementary to the Baeyer-Villiger rearrangement, on treatment with trifluoroacetic anhydride to give esters or lac tone^.^^^ Using this method, the enol ether (345) can be converted into caprolactone (346), and the bicyclodecene (347) affords the macrolide (348).

4 Carboxylic Acid Amides Synthesis.-Some new methods for amide bond formation from acids and amines have been added to the already vast number. The use of P214as coupling agent is very efficient and may offer advantages in cases involving unreactive acids or a m i n e ~An . ~ alternative, ~~ very mild procedure consists of reactions between acid chlorides and N-silylamines .275 An alternative method for the oxidation of a-amino-nitriles to amides is by passage of oxygen through a solution of the former in 50% aqueous NaOH and DMSO containing B z E ~ ~ N CClearly ~ . * ~ the ~ method is limited to non-enolizable K. Kostova and M. Hesse, Helv. Chim. Acta, 1983, 66, 741. S. L. Schreiber and W.-F. Liew, Tetrahedron Lett., 1983, 24, 2363. 274 H. Suzuki, J. Tsuji, Y. Hiroi, N. Sato, and A. Osuka, Chem. Lett., 1983, 449. 275 J. R. Bowser, P. J. Williams, and K. Kurz, J . Org. Chem., 1983, 48, 4111. 276 F. Yuste, A. E. Origel, and L. J. Brefia, Synthesis, 1983, 109.

272

273

186

General and Synthetic Methods

products such as benzamides. Such Strecker intermediates can also be hydrolysed to a-amino-amides using solid-state catalysis; some refinements of this method have been reported.277Hemiaminals derived from an aldehyde and morpholine can be oxidized to the corresponding amides by reaction with bromobenzene and a palladium(I1) catalyst; yields are in the range 50-90%.278 a-Hydroxy-amides can be obtained in >80% yields, except in cases of severe steric hindrance, by a modification of the Passerini reaction involving condensations between aldehydes or ketones and the titanium imine (349), derived from methyl isocyanide and TiC14 (Scheme 47).279 Chiral P-hydroxy-amides (351) of unknown absolute configuration, have been obtained in 6 6 9 9 % e.e. by condensations between the magnesium enolate of amide (350) and aldehydes, followed by desulphurization (Na-Hg) .280 The corresponding lithium enolates give much lower optical yields of the opposite configuration. o-Stannoxy-amides (352; n =&3) can be obtained from the corresponding lactones and Me3SnNEt, and, on acidification, provide excellent overall yields of the w-hydroxy-amides (353).281Coupling of the salt (352;n=3) with ally1 bromide or benzoyl chloride leads to the ether (354) or the benzoate (355) respectively.

OH

OTiCIj

( 3 4 91

Scheme 47 0 H+

4

Me3 Sn0-CONEt2

(350)

(352)

H 0 -CONEtZ

(353)

I

1

RCHO

\)I HO -0-CONEt2 /

R

(351)

Ph CO 2-CONEt

(354)

( 3 5 51

The dianion (357) derived from 3-hydroxy-5-methylisoxazole(356) represents a protected form of the hypothetical acetoacetamide dianion related to Weiler’s acetoacetate d i a n i ~ n and , ~ ~as~ such reacts with electrophiles at the 5-methyl group to provide homologues (358) in variable yields, hydrogenolysis of which leads to P-keto-amides (359) (Scheme 48).282Related keto-amides (361) can also R. Sola, J. Brugidou, J. Taillades, and A. Commeyras, Tetrahedron Lett., 1983, 24, 1501. Y. Tamaru, Y. Yamada, and Z. Yoshida, Synthesis, 1983, 474. 279 M. Schiess and D. Seebach, Helv. Chim. Acta, 1983,66, 1618. 280 R. Annunziata, M. Cinquini, F. Cozzi, F. Montanari, and A. Restelli, J. Chem. SOC., Chem. Commun., 1983, 1139. 281 A. Ricci, M. N. Romanelli, M. Taddei, G. Seconi, and A. Shanzer, Synthesis, 1983, 319. 282 T. A. Oster and T. M. Harris, J. Org. Chem., 1983,48, 4307. 277

278

Carboxylic Acids and Derivatives

187

be assembled by treatment of phosphoranes (360), readily obtained from phosphorylides and an acid chloride, with phenyl isocyanate, followed by hydrolysis.283Various methods for the oxidation of N,N-disubstituted P-ketoamides to the corresponding or$-diketo-derivatives (362) have been developed.284

(356)

(357)

(358)

(3591

Scheme 48

Further examples of the excellent stereoselectivities which are often observed in Eschenmoser amide-acetal Claisen rearrangements have been reported.2g5 Reactions.-Primary amides can be activated by conversion into N-acylpyrroles using readily available dichlorodimethoxybutane.286Subsequent displacement of the pyrrole by primary or secondary amines proceeds smoothly to give secondary or tertiary amides respectively (Scheme 49). This method will be particularly useful with base-sensitive substrates and can also be used to prepare methyl esters from the initial amides by reaction of the intermediate pyrroles with NaOMe. Mono-N-alkylation of primary amides [(363)+ (364)] can also be achieved using monosubstituted olefins and Hg(N03)2.287 Yields are variable (17-99%), but when it works well the method looks to be very attractive and simple to perform. Secondary amides are efficiently O-alkylated to give imides (365) by alkyldiphenylsulphonium salts, RPh2S+BF4-,which, although less reactive than the more commonly encountered oxonium salts, have the advantage that ‘R’ groups other than methyl or ethyl can be used.288Similar treatment of tertiary amides leads to the imidate salts corresponding to (365). Me0

OMe

Scheme 49 283 H. J. Bestmann and K. Kumar, Chem. Ber., 1983, 116,2708. 2&1 W.-D. Malmberg, J. Voss, and S. Weinschneider, Liebigs Ann.

Chem., 1983, 1694. C. H. Heathcock and B. L. Finkelstein, J . Chem. SOC.,Chem. Commun., 1983,919; E. H. Smith and N. D. Tyrrell, ibid., p. 285. 286 S. D. Lee, M. A. Brook, and T. M. Chan, Tetrahedron Lett., 1983,24, 1569. 287 J. Barluenga, C. Jimknez, C. Najera, and M. Yus, J . Chem. SOC., Perkin Trans. 1, 1983, 591. 2R8 M. Julia and H. Mestdagh, Tetrahedron, 1983, 39, 433.

285

General and Synthetic Methods

188

OR

A further example of very high stereoselectivity in hydride reductions is that of P-keto-amides [e.g. (366)] which, on treatment with zinc borohydride in ether at -78 "C,give virtually pure erythro-P-hydroxy-amides [e.g. (367)] in very high yields.289Some useful regioselectivities of attack by nucleophiles onto N , N diethylsorbamide (368) have been reported .290 Thus, simple Grignard reagents effect mainly [1,4]-additions whereas lithium dialkylcuprates add in a [1,6] manner. The subtle effects that counter-cations can have on the course of anionmediated reactions is further demonstrated in the case of dianions obtained from the cyclohexene carboxamide (369) .291 Whereas the dilithium derivative gives mixtures of isomers, addition of MgBr2 prior to the electrophile gives largely or exclusively the traris-l,4-disubstituted cyclohexenes (370). N- Allyl-amides (372) can be obtained by Wittig-Horner reactions of dianions derived from phosphine oxides (371).292Addition of a symmetrical ketone gives only one diastereoisomer of the intermediate P-hydroxy-phosphine oxide and only two diastereomers are obtained after reaction with acetaldehyde: stereochemical control over the methyl group a- to nitrogen is thus complete.

(366 1

(368 1

(367)

L

(369)

(370)

(371)

(372)

A useful overview of the salient features of directed metallations in secondary and tertiary benzamides has been given.293o-Lithiated benzamides (373) can be converted into anthranilamides (374) in 31-71 % yields by sequential reactions with tosyl azide and sodium borohydride .294 This procedure, which overall provides a source of NH2+,can also be used to aminate other lithiated species. When Y. Jto and M. Yamaguchi, Tetrahedron Lett., 1983, 24, 5385. F. Barbot, A. Kadib-Elban, and Ph. Miginiac, Tetrahedron Lett., 1983,24, 5089. 291 P. Beak, J . E. Hunter, and Y. M. Jun, J. Am. Chem. SOC., 1983,105,6350. 292 D. Cavalla and S. Warren, Tetrahedron Lett., 1983, 24,295. 2y3 P. Beak, A . Tse, J. Hawkins, C.-W. Chen, and S. Mills, Tetrahedron, 1983, 39, 1983. See also M. Iwao, K. K. Mahalanabis, M. Watanabe, S. 0. DeSilva, and V. Snieckus, ibid., p. 1955. 294 J . N. Reed and V. Snieckus, Tetrahedron Lett., 1983, 24,3795. 28y

290

Carboxylic Acids and Derivatives

189

two ortho-positions in a benzamide are open to metallation, the more reactive site can be blocked by silylation allowing metallation and electrophilic substitution to be carried out at the less reactive position; subsequent desilylation can be effected by C S F . Thus, ~ ~ ~ the 3-methoxybenzamide (375) can be converted into the homologues (376) in a five-step sequence. However, silyl groups are not always suitable for the protection of phenol functions during such metallations, as 0-C migration can occur. For example, treatment of O-trimethylsilylbenzamide (377) with BusLi at -78 "C followed by warming to room temperature gives the C-silyl derivative (378) .296

OMe ( 373 1

(377)

OMe

(374)

( 37 5 )

( 376 1

(378)

( 3 7 91

(380)

An S-+C shift of a dialkylamino-group has been observed when o-carboxysulphonamides (379) are reacted with thionyl chloride leading to the benzamides (380) in virtually quantitative yields.297A simple method for the conversion of amides into their a-nitro-derivatives has been reported.298Subsequent treatment with a potassium hypohalite leads to the corresponding a-halogeno-a-nitroamides. Thioamides.-Aldonitrones (381) are converted into thioamides (382) in 67-75% yields on heating in benzene with 1,l'-thiocarbonyl-di-imidazole or t r i a ~ o l e The . ~ ~ Willgerodt-Kindler ~ procedure for the conversion of aromatic

ArCHO ( 3 8 31

+ ArCNMqZ (384)

aldehydes (383) into thioamides (384) or of acetophenones into phenylthioacetamides can be problematical when volatile amines are used, R. J. Mills and V. Snieckus, J . Org. Chem., 1983,48, 1565. R. J. Billedeau, M. P. Sibi, and V. Snieckus, Tetrahedron Lett., 1983, 24, 4515. 297 K . Hovius, A. Wagenaar, and J. B. F. N. Engberts, Tetrahedron Left., 1983,24,3137 298 H. Feuer, C . S. Panda, L. Hou, and H. S. Bevinakatti, Synthesis, 1983, 187. 299 D. N. Harpp and J. G. MacDonald, Tetrahedron Lett., 1983,24, 4927.

295

2q6

190

General and Synthetic Methods

because of the relatively high temperatures required (ca. 200 "C). Such drawbacks can be simply overcome by using the corresponding amine hydrochloride^.^^ Procedures for carrying out thio-Claisen rearrangements (Scheme 50) have been described in detail.301Diastereoselectivities, although variable, are often excellent especially when secondary thioamides are used, although in these examples yields are lower (40-50%). Ketene S, N-acetals (385), derived from the corresponding thioamide under standard conditions (LDA, TMSCl), condense with benzaldehyde in the presence of Bun4NFor TiC14 to give largely the ery thro-P-hydroxy-t hioamides (386).302 Most types of thioamides (387) are converted into amides (388) in 72-98% yield simply by treatment with rn-chloroperbenzoic acid in methylene chloride at room temperature.303

i

R2

R Reagents: i, BunLi, R*CH=CHCH,X

(X=Cl, Br, or OTs); ii, A , THF

Scheme 50

SSiMe,

S

0

ll

II

R1CNR2R3 ---f R'CNR2R3

NMe2

Peptide Bond Formation.-Mostly analogues and homologues of established coupling reagents have been reported this year, some of which have particular features which may make their use advantageous in certain circumstances. Dibenzotriazole carbonate offers the advantage that the by-product, 1-hydroxybenzotriazole can be removed by washing with 1% aqueous sodium bicarbonate.304Bis-succinimides derived from oxalic acid can be used to activate carboxylic acid groups prior to coupling with unprotected a-amino-acids in aqueous a c e t ~ n i t r i l e Other . ~ ~ ~ related coupling agents which can also be used in ester and thioester synthesis are oxazolinyl phosphates306 and N, N'carbonyldibenzoisoxazolinone.307 Carboxylic acid groups can also be activated by esterification with o-hydroxybenzaldehyde oxime; couplings are then carried out under neutral conditions.308All the foregoing methods are virtually or comp300 301

J. 0. Amupitan, Synthesis, 1983, 730.

Y. Tamaru, Y. Furukawa, M. Mizutani, D. Kitao, and Z. Yoshida, J . Org. Chem., 1983,48, 3631. C. Goasdoue, N. Goasdoue, and M. Gaudemar, Tetrahedron Lett., 1983,24,4001. 303 K. S. Kochhar, P. A. Cottrell, and H. W. Pinnick, Tetrahedron Lett., 1983, 24, 1323. 304 M. Veda, H. Oikawa, and T. Teshirogi, Synthesis, 1983,908. See also M. Furukawa, N. Hokama, and T. Okawara, ibid., p. 42. 305 K. Takeda, I. Sawada, A. Suzuki, and H. Ogura, Tetrahedron Lett., 1983,24,4451. 306 T. Kunieda, T. Higuchi, Y. Abe, and M. Hirobe, Tetrahedron, 1983,39,3253. 307 M. Ueda, H. Oikawa, N. Kawaharasaki, and Y. Imai, Bull. Chem. SOC.Jpn., 1983,56,2485. 30*

191

Carboxylic Acids and Derivatives

letely free of racemization. Racemization and urethane formation are sometimes serious drawbacks when mixed anhydrides are used as activated intermediates in peptide coupling. These can often be minimized if N-methylpiperidine is used as base during anhydride formation from chloroformates.3090- or p-Aminobenzoic acids can be efficiently incorporatedinto peptides without protection of the less nucleophilic aromatic aminogroup.310 Na-Fmoc protecting groups are particularly useful because of their extreme ease of removal by secondary amines; unfortunately deprotection can occur prematurely by reaction with the incoming amino-group during peptide bond formation. This can be avoided by using very reactive perfluorophenyl esters of W-Fmoc a-amino-acids; couplings with a-amino-esters are then very clean and rapid. 311 Solid-state peptide synthesis can be performed using polystyrene-bound p-nitrobenzophenone oxime groups to form an ester linkage to the first Na-protected - cr - amin ~- a cid This . ~ ~ ~method may offer some advantages in the final removal step of the completed peptide. Alternatively, such solid-state syntheses can be carried out using a 4-(2-chloropropionyl)phenylacetamidomethyl resin which is photolabile at A=350 nm.313 A new concept for the elaboration of peptides, which could potentially be used for automated synthesis, is outlined in Scheme 51.314 Photolysis of 5-azido-3,4oxadiazoles (389), derived in six steps from Na-protected cr-amino-acids,gives the acyl cyanides (390) which are trapped in situ by an unprotected amino-derivative of another 1,3,4-oxadiazole. The process can then be continued by addition of an azido-group to the 5-position of the heterocyle followed by photolysis and trapping, and so on.

(3891

(390)

R’

R*

Scheme 51 1. Hayachi and K. Shimizu, Bull. Chem. SOC.,Jpn., 1983, 56, 3197. F. M. F. Chen, R. Steinauer, and N. L. Benoiton, J . Org. Chem., 1983,48,2939. 310 F. H. C . Stewart, A w t . J . Chem., 1983,36,1629,2511. 311 L. Kisfaludy and I. Schon, Synthesis, 1983, 325. 312 S. H. Nakagawa and E. T. Kaiser, J . Org. Chem., 1983,48,678. 313 F.-S. Tjoeng and G. A. Heavner, J . Org. Chem., 1983,48,355. 314 P. N. Confalone and R. B. Woodward, J . Am. Chem. SOC., 1983,105,902.

3w

192

General and Synthetic Methods

5 Amino-acids Synthesis.-A broad review of new naturally occurring amino-acids has been published which contains a discussion of some synthetic approaches to these compounds.315Schollkopf has summarized his group's work on the synthesis of chiral amino-acids by reactions between various electrophiles and metallated bislactim ethers,316and has further demonstrated the utility of this approach in syntheses of (R)-a-methyl-S-alkylcysteine methyl esters, (R)-isovaline, ( R ) serine analogues, and chiral ,8-fl~oro-a-amino-acids.~~~ A full report has been published concerning the preparation of chiral a-amino-acid analogues (392) by alkylations of enolates derived from Schiff's bases (391) .318 Chemical yields are good but optical yields are variable. Analogues (392) have also been prepared in 4 6 8 5 % e.e. by closely related procedures starting with the a-D-galactose-(L)alanine adduct (393) ,319 or with Schiff's bases derived from hydroxypinanone~.~'" In the latter case, enantiomeric enrichments are between 15 and 90%.

TheP- and y-iodo-a-amino-esters (394; n = l or 2) can be coupled to lithium dialkylcuprates to provide derivatives (395) in 42-89% yields without r a c e m i z a t i ~ nThese . ~ ~ ~ reactions are especially notable in the case of (394; n = l ) , which usually undergoes only E2 elimination of hydrogen iodide when treated with nucleophiles. Complete Walden inversion occurs when trifluoromethanesulphonates (396) of chiral a-hydroxy-esters are treated with primary or secondary amines to give a-amino-esters (397).322This procedure will be of value as the direct alkylation or arylation of a-amino-esters has many limitations and similar displacements involving poorer leaving groups are usually accompanied by extensive racemization. I. Wagner and H. Musso, Angew. Chem., Int. Ed. Engl., 1983, 22, 816. U. Schollkopf, Tetrahedron, 1983, 39,2085; Pure Appl. Chem., 1983,55,1799. 317 U. Groth and U. Schollkopf, Synthesis, 1983,37,673; U. Schollkopf and R. Lonsky, ibid., p. 675; U. Schollkopf, U. Groth, M.-R. Gull, and J. Nozulak, Liebigs Ann. Chem., 1983, 1133. 315

316

M. Kolb and J. Barth, Liebigs Ann. Chem., 1983, 1668. I. Hoppe, U. Schollkopf, and R. Tolle, Synthesis, 1983, 789. 320 J. A. Bajgrowicz, B. Cossec, Ch. Pigikre, R. Jaquier, and Ph. Viallefort, Tetrahedron Lett., 1983,24, 3721. 321 A. Bernardini, A. El Hallaoui, K. Jacquier, Ch. Pigiere, Ph. Viallefont, and J. Bajgrowicz, Tetrahedron Lett., 1983, 24, 3717. See also R. M. Adlington, J. E. Baldwin, A. Basak, and R. P. Kozyrod, J . Chem. Soc., Chem. Commun., 1983,944. 322 F. Effenberger, U. Burkard, and J. Willfahrt, Angew. Chem., Znt. Ed. Engl., 1983, 22, 65. 318 319

193

Carboxylic Acids and Derivatives

C02Me

(394)

(396)

@t2H

-

(397)

t Scheme 52

The principle of 'self-reproduction of chirality' is illustrated in Scheme 52 in a synthesis of (S)-proline analogues.323The stereochemistry of the original optical centre in (S)-proline completely controls the orientation of a second chiral centre formed by condensation with pivalaldehyde. Enolization then destroys optical activity at the original site but electrophilic attack is directed to the re-face by the newly created second site. High diastereoselectivity is also observed at the third potentially chiral carbon formed when the enolate is condensed with unsymmetrical ketones. The (2S,3S,4R)-aminopentanoicacid (399), the central connecting unit in Bleomycin A2, has been obtained in extremely high optical yield by acylation of the enolate of oxazolidinone (398) with Na-Boc-(D)-alanine anhydride followed by zinc borohydride reduction289and hydrolysis (Scheme 53) .324 OH

BocNH

+ ( 398 1

Scheme 53

Essentially complete enzymic resolution of N-acetylphenylalanine methyl esters has been achieved on a preparative scale using a commercially available serine protease; the enzyme catalyses hydrolysis of the (Qmethyl ester only.325 D. Seebach, M. Boes, R. Naef, and W. B. Schweizer, J. Am. Chem. SOC., 1983, 105,5390. R. M. DiPardo and M. G. Bock, Tetrahedron Lett., 1983, 24, 4805. 325 J. M. Roper and D . P. Bauer, Synthesis, 1983,1041, See also K. Bernauer, R. Deschenaux, and T . Taura, Helv. Chim. Acta, 1983,66,2049; Y . Tachibana, M. Ando, and H. Kuzuhara, Bull. Chem. SOC.Jpn., 1983, 56, 3652.

323 324

194

General and Synthetic Methods

Further work on the uses of aziridine-2-carboxylic acid derivatives in the synthesis of a-amino-acids has resulted in new routes to threo-3-methyl-(~)-cysteine,3,3dimethylcystine, and cystine itself .326 cis-2-Amino- and cis-2-cyano-aziridines can be converted into P-fl~oro-a-amino-acids~~~ using Olah’s reagent [pyridiniumpoly(hydrogen fluoride)] ,327 the former leading selectively to the threo-isomers. An efficient new route to racemic N-Boc-Coronamic acids (400; R=H, alkyl, or Ph), which are related to a structural feature of the bacterial toxin Coronatine, is by addition of a diazoalkane to dehydroalanine followed by thermolysis (90°C in toluene) and base hydrolysis.328a-Methoxylation of protected a-amino-acids can be achieved electrochemically in methanol containing sodium chloride .329 P-Amino-acid derivatives (403)91are obtained in 42-95% yield by condensations between ketene silyl acetals (402) and either O-benzyloximes (401; R1=H orMe)330or N,N,N-trialkyl-hexahydrotria~ines;~~~ yields are between 20 and 95%.

C02H

R ( 40 0)

+

R’]

4NHBo~

NOB~ (4011

-

.j=(oTMs

R3

OR^ (4021

R2 R3

R$”(

CO, R 4 NHOBz

(403)

The more soluble p,p’-diphenyl analogue of Lawesson’s reagent has been found to be very effective for the conversion of protected a-amino-amides into the corresponding t h i ~ a r n i d e sDuring . ~ ~ ~ a preparation of the dipeptide sweetening agent aspartame and of thioaspartame, Lawesson’s reagent itself was used first as a coupling reagent and subsequently in its more usual role as a thiation reagent .333 Aspartic acid is the starting material for syntheses of L-serine stereospecifically labelled at C-3 with deuterium, the key step being a Baeyer-Villiger oxidation,334 and of L-glutamic acid also specifically labelled at C-3 with deuterium and nonstereospecifically with tritium at C-4; a Wolff rearrangement with retention of stereochemistry forms the key step in the latter

Dehydroamino-acids.-Phosphonates (404) can be obtained from glycine using conventional methods and undergo typical Wadsworth-Emmons reactions with aldehydes to give dehydroamino-acid derivatives (405) .336Alcoholysisof azlactones (406) derived from an aldehyde and hippuric acid also leads to unsaturated amino-esters (405) .337 The reactions are stereoselective; thus the (E)-isomer of K. Nakajima, H. Oda, and K. Okawa, Bull. Chem. SOC. Jpn., 1983,56,520; K . Nakajima and K. Okawa, ibid., p. 1565; T. Wakamiya, K . Fukase, K. Shimbo, and T. Shiba, ibid., p. 1559. 327 A. I. Ayi and R. Guedj, J . Chem. SOC., Perkin Trans. 1, 1983,2045. 328 M. Suzuki, E. E. Gooch, and C. H. Stammer, Tetrahedron Lett., 1983,24, 3839. 329 T. Shono, Y. Matsumura, and K. Inoue, J . Org. Chem., 1983,48, 1388. 330 K. Ikeda, K. Achiwa, and M. Sekiya, Tetrahedron Lett., 1983,24, 4707. 331 K. Ikeda, K. Achiwa, and M. Sekiya, Tetrahedron Lett., 1983,24, 913. 332 G. Lajoie, F. Lepine, L. Maziak, and B. Belleau, Tetrahedron Lett., 1983,24, 3815. 333 B. Yde, I. Thomsen, M. Thorsen, K. Clauson, and S . - 0 . Lawesson, Tetrahedron, 1983,39, 4121. 334 D. Gani and D. W. Young, J . Chem. SOC.,Perkin Trans. 1, 1983,2393. 335 S. J. Field and D. W. Young, J. Chem. SOC., Perkin Trans. I , 1983, 2387. 336 R. Kober and W. Steglich, Leibigs Ann. Chem., 1983, 599. 337 C . Cativiela, M. D. Diaz dc Villegas, J. A. Mayoral, and E. Melendez, Synthesis, 1983, 899.

326

195

Carboxylic Acids and Derivatives

azlactones (406) can be converted into esters (407), and, although this work has only dealt with azlactones derived from thiophenecarboxaldehydes, the route should be more generally applicable. 0

I

(404)

(405)

Ph (406)

R4

(407)

Aryl bromides can be coupled with N-acetyldehydroalanine in the presence of Pd(OAc), and a tertiary amine to give a-acetamidocinnamic acids in 25-75% yields.338P-Hydroxy-a-acylamino-esters are smoothly and stereospecifically dehydrated by (diethy1amino)sulphur trifluoride (DAST) , the threo-isomers leading to (2)-unsaturated a-amino-esters whereas the erythro-isomers afford only the corresponding (E)-isomers .339 Dehydration of N-hydroxy-N-acetyl-aamino-esters can be quickly and easily achieved using tosyl chloride and triethylamine to give largely (E)-a-acetamido-unsaturated esters.340 Peptides containing a central dehydroamino-acid residue can be obtained by simultaneous coupling of two a-amino-acids with N-carboxy-a-dehydroaminoacid anhydrides (Scheme 54).341This attractive looking method can clearly also be used to incorporate terminal unsaturated amino-acid residues.

TFAA,

R*

0

R4

Scheme 54 M. Cutolo, V. Frandanese, F. Naso, and 0. Sciacovelli, Tetrahedron Lett., 1983, 24, 4603. 339 L. Somekh and A . Shanzer, J. Org. Chem., 1983,48, 907. 340 T. Kolasa, Synthesis, 1983, 539. 341 C. Shin, T. Yamada, and Y. Yonezawa, Tetrahedron Lett., 1983, 24,2175. 338

196

General and Synthetic Methods

Asymmetric Hydrogenation.-A brief but useful review of this topic has been published.342A chiral ligand derived from an (S)-2,2’-diaminobiphenyl has been found which, in conjunction with rhodium(I), catalyses the hydrogenation of a-acetamidoacrylic acid to give N-acetyl-(R)-alanine in up to 81% optical yield.343 Further, but not always impressive, examples of asymmetric hydrogenations of dehydro-dipeptides by chiral Rhl-diphosphine complexes have been reported .344 In general, rhodium(1)-based catalysts are not capable of effecting the hydrogenation of tetrasubstituted a-acylamino-a$-unsaturated esters. Such reductions can however be effected very easily by using iridium-derived catalysts although optical yields are as yet rather Protection and Deprotection.-Ally1 esters can be effective in carboxylic acid protection during peptide synthesis as they are .stable to hydrolysis under conditions acidic enough to remove Boc and Z groups and are themselves cleaved under essentially neutral conditions by [ (Ph3P)3RhCl].346 2-Bromoethyl ester blocking groups have been successfully employed in glycopeptide synthesis.”’ The usual method of removal (conversion into the iodoethyl derivative and zinc reduction) does not affect Z protecting groups or sensitive O-glycoside bonds. Dithiane-based Dim esters (4O8), prepared by Al( OPr’)3-catalysed transesterification of the corresponding methyl esters, are relatively acid stable but can be readily removed by oxidation to the sulphoxide/sulphone derivatives, using hydrogen peroxide and ammonium molybdate, followed by exposure to mildly basic conditions of pH Related methodology has previously been used in amino-group protection; one significant drawback associated with Dim derivatives in general is the group’s incompatibility with cysteine residues. Another amino-protecting group which can be used in the masking of carboxylic acids is the 9-fluorenylmethyl (Fm) function.349Again, removal is under very mild basic conditions by treatment with a secondary amine .311 A preliminary report concerning CAM esters [(409); carboxyamido methyl] suggests that these groups could provide yet another general method of acid protection. Prepared by reaction

(4081

(4091

W. S. Knowles,Acc. Chem. Res., 1983,16,106. See also P. Pine and G. Consiglio, PureAppl. Chem., 1983,559, 1781. 343 A. Vehara, T. Kubota, and R. Tsuchiya, Chem. Lett., 1983, 441. 344 M. Yatagai, M. Zama, T. Yamagishi, and M. Hida, Chem. Left., 1983, 1203. 345 L. A. Oro, J. A . Cabeza, C. Catwiela, M. D. Diaz de Villegas, and E. Melendez, J . Chem. Soc., Chem. Commun.. 1983, 1383. 346 H. Waldmann and H. Kunz, Liebigs Ann. Chem., 1983, 1712. 347 M. Buchholz and H. Kunz, Liebigs Ann. Chem., 1983, 1859. 348 H . Kunz and H. Waldmann, Angew. Chem., Znt. Ed. Engl., 1983. 22, 62. 349 H. Kessler and R. Siegmeier, Tetrahedron Lett., 1983, 24, 281.

342

Carboxylic Acids and Derivatives

197

between the caesium salts of Na-protected-amino-acids and a-chloroacetamide, the function remains intact while Boc, Z, and Fmoc groups are removed under the usual conditions and is itself cleaved by mild aqueous base, without affecting the foregoing groups.”O Anhydrous toluene-p-sulphonic acid and toluene-psulphonyl chloride in ethanol is reported to be a useful mixture for the esterification of a-amino-acids such as tryptophan which are rather resistant to such derivatization under other more usual condition^.^^' Yet another reagent for the preparation of Na-Boc derivatives of a-amino-acids is t-butyl benzotriazol-l-yl carbonate.3552 (For a complete list, consult the current Fluka catalogue.) An easily handled, stable crystalline solid, the compound is especially suited to those in a hurry as reaction times are less than thirty minutes. The benzotriazolylcarbonyl (Btc) group itself can be used to block amino-functions during peptide coupling and is easily removed by acid hydrolysis.353An exceptionally acid-labile amino-protecting group is the t-Bumeoc moiety (410); kinetic studies have shown that it is removed 4000X faster than Na-Boc functions in 80% aqueous acetic acid.354Procedures for the preparation of Na-2,2,2trichloroethoxycarbonyl (Na-Troc) and Na-Fmoc derivatives of amino-acids using activated carbonates derived from N-hydroxysuccinimide look to be useful additions to existing methodology.3ssN-Alkylation of Na-Fmoc-a-amino-acids can be achieved by formation of oxazolidinone derivatives (411) using an aldehyde,

R2CH0, and tosic acid followed by reduction with t r i et hyl ~i l ane.The ~~~products (412) are obtained with <0.1% racemization. Full accounts have been given of the preparation and use of polystyrene- and silica-bound piperazine for the deblocking and scavenging of W-Fmoc groups; the silica-based reagent seems to be the one of A drawback of using piperidine to remove Na-Fmoc groups is that the reagent also partly cleaves benzyl ester groups in aspartyl residues, although this undesirable side reaction occurs more slowly under solidstate conditions .3s8Perhaps the silica-bound piperazine reagent mentioned above could be used to advantage in such cases. J. Martinez, J. Laur, and B. Castro, Tetruhedron Lett., 1983, 24, 5219. I. Arai and I. Murarnatsu, J . Org. Chem., 1983, 48, 121. 352 S. Kim and H. Chang. J . Chem. Soc., Chem. Commun., 1983,1357. See also R. B. Harris and I. B. Wilson, Tetrahedron Lett., 1983, 24, 231. 353 I. Butula, B. Zore, and M. LjubiC. Synthesis, 1983, 327. 354 W. Voelter and J. Miiller, Liebigs Ann. Chem., 1983, 248. 355 L. Lapatsanis, G. Milias, K. Froussios, and M. Kolovos, Synthesis, 1983, 671. See also J. F. Carson, ibid., p. 669. 356 R. M. Freidinger, J. S. Hinkle, P. S . Perlow, and B. H. Arison, J. Org. Chem., 1983,48, 77. 357 L. A. Carpino, E. M. E. Mansour. C. H. Cheng, J . R. Williams, R. MacDonald, J. Knapczyk, M. Carman, and A . Lopusinski, J . Org. Chem., 1983,48,661; L. A. Carpino, E. M. E. Mansour, and J . Knapczak, ibid., p. 666. 358 I. Schon, R . Colombo, and A . Csehi, J. Chem. Soc., Chem. Commun., 1983. 505. 350

351

198

General and Synthetic Methods

A new method for protecting amino-groups is by formation of 2-(2pyridy1)ethoxycarbonyl (Pyoc) derivatives (413) .359 Such compounds can be readily and efficiently prepared and are stable to both acidic and basic conditions; a notable feature is that they are also water soluble. They are unaffected by conditions acidic enough to cleave t-butyl-based protecting groups and can be removed by quaternization using methyl iodide followed by treatment with a base such as dimethylamine. A disadvantage with this method of cleavage is that any sulphur-containing residues will also be alkylated. Improvements have been described in the Na-phthaloylation of a-amino-acids and alcohols by N-(etho~ycarbonyl)phthalimide.~~ The established method for the removal of N%-nitrophenylsulphenyl (Nps) groups using ammonium thiocyanate has also been significantly improved.361The key is to add (2-methyl1-indoly1)acetic acid as scavenger; the unwanted by-products can then be removed by an aqueous base wash. Optimum conditions have been formulated for the widely applicable HF-Me2S-p-cresol deprotection method, which can be used to remove Boc and Z groups as well as 0-benzyl groups and for the deformylation of M-f~rmyltryptophan.~~~ The acid-resistant Troc can also be used to protect the indolic nitrogen in tryptophan; removal is by treatment with either a cadmium salt in acetic acid or hydrazine in aqueous sodium Problems with arginine protection during solid-state peptide synthesis have been group to overcome by using the 4-methoxy-2,3,6-trimethylbenzenesulphonyl protect the NG-function in place of the previously reported 4-methoxybenzenesulphonyl group.364 The known 2-(trimethylsilyl)ethoxycarbonyl (Teoc) group can also be used to protect Nw-amino groups in a,@-diaminoThe derivatives are prepared by treating copper complexes of the latter

with 2-(trimethylsily1)ethyl 4-nitrophenyl carbonate and remain intact while Na-Boc groups are removed by tosic acid in ethanol. The Teoc group is also stable to hydrogenolysis, so it should also be possible specifically to remove Z groups in its presence. Hydroxy-groups in a-amino-acids can be specifically methylated [e.g. (414) + (415)] by using a bulky trityl group to protect the amino-function and sodium hydride as base.366Similarly, Na-protected tyrosines can be 0-alkylated using an alkyl halide and sodium hydride in DMF.367N-Acetyl-(L)-tyrosine H. Kunz and R., Barthels, Angew. Chem., Int. Ed. Engl., 1983,22,783. C. R. McArthur, P. M. Worster, and A. V. Okon, Synth. Commun., 1983, 13,311,393. 361 I. F. Luscher and C. H. Schneider, Helv. Chim. Acta, 1983, 66, 602. 362 J. P. Tam, W. F. Heath, and R. B. Merrifield, J . Am. Chem. SOC., 1983,105,6442. 363 Y. Kiso, M. Inai, K. Kitagawa, and T. Akita, Chem. Lett., 1983, 739. 364 E. Atherton, R. C. Sheppard, and J. D. Wade, J . Chem. SOC., Chem. Commun., 1983,1060. 36s A. Rosowsky and J. E. Wright, J . Org. Chem., 1983,48,1539. 366 K. Barlos, D. Papaioannou, P. Cordopatis, and D. Theodoropoulos, Tetrahedron, 1983,39,475. 367 W. L. Mendelson , A . M. Tickner, and I. Lantos, J . Org. Chem., 1983,48, 4127.

359

360

Carboxylic Acids and Derivatives

199

has been efficiently esterified by ethanol using immobilized chymotripsin as catalyst at pH 4.2 in a biphasic mixture of water and chloroform.368The thiol group in cysteine can be protected as the dimethylphosphinothioyl(Mpt) function, which is fairly acid stable and can be removed by silver or mercury salts.369 Suitably protected (DL)-P-carboxyasparticacids have been prepared in readiness for the synthesis of Asa-containing pep tide^.^^^

J. L. Vidaluc, M. Baboulene, V. Ypeziale, A. Lattes, and P. Monsan, Tetrahedron, 1983, 39,269. M. Veki and K. Shinozaki, Bull. Chem. SOC.Jpn., 1983,56, 1187. 37c D. H. Rich and M. K. Dhaon, Tetrahedron Lett., 1983,24, 1671. 368 369

4 Alcohols, Halogeno-cornpou nds, a nd Ethers BY L. M. HARWOOD

The pattern of this Report is similar to that used previously. Miscellaneous reactions of a particular class of compound are considered at the end of each section; cross-referencing to earlier Reports follows the established style.

1 Alcohols

Preparation by Addition to A1kenes.-The relative reactivities of various alkenes towards hydroboration with catecholborane have been investigated. * The reagent appears to be generally less selective than other borane reagents. The preparation of dimesitylborane (l),an air-stable solid, has been described.2Used as a suspension in ethereal solvents it is the most selective reagent so far reported for the hydroboration of unsymmetrical olefins, homogeneity of the mixture indicating complete reaction.

The reaction of various organoboranes with several allylic alcohols possessing a 2-methyl group has been studied3with the finding that the threo-configuration is favoured in the resultant diols. This has allowed the strategy of double allylic hydroboration to be developed in which the stereochemistry at one carbon dictates the stereochemistry of four new centres (Scheme 1). Two-step hydroxytelluration of olefins followed by conversion of the adducts into the telluroxides results in ready elimination to form allylic alcohols in good overall yield (Scheme 2).4 H. C. Brown and J. Chandrasekharan, J. Org. Chem., 1983, 25, 5080. A. Pelter, S. Singaram, and H. C. Brown, Tetrahedron Lett.. 1983, 24, 1433 W. C. Still and J. C. Barrish, J. A m. Chem. SOC., 1983, 105,2487. S. Uemura and S. Fukuzawa, J . Am. Chem. SOC., 1983, 105, 2748.

200

Alcohols, Halogeno-compounds, and Ethers

OCPh3

ph3co+

i ,ii

Ph3CO

201

OCPh3

OH

OH

I

OH

I I

P

~

~

C

OH

O OH

~

O

C

OH

Reagents: i, R,BH; ii, H,O, OH-

Scheme 1

i , ii

Ph T e Br

liii

AReagents: i, RC0,H; ii, PhTeBr,, MeOH; iii, 0.5 N aq. NaOH

Scheme 2

Kishi and co-workers have published two papers5 presenting an empirical rule to predict the stereochemistry of the major products from allylic alcohol or allylic ether osmylation, in which they propose that the relative stereochemistry between the existing hydroxy- or alkoxy-group and the adjacent newly produced hydroxy-group in the major product will be erythro (Scheme 3). They suggest that the stereochemistry results from preferential approach of osmium tetroxide to the face of the olefin opposite to that of the pre-existing oxygen function in the most favoured eclipsed rotamer (Figure 1). Stork et al. have presented a similar study on the osmylation of the y-hydroxy-cqp-unsaturated esters (2) and (3) (Scheme 4).6 For the ester (2) an eclipsed transition state is envisaged with the carbon-oxygen bond in the plane of J . K. Cha, W. J. Christ, and Y. Kishi, Tetrahedron Lett., 1983, 24, 3943, 3947. G. Stork and M. Kahn, Tetrahedron Lett., 1983,24, 3951.

P

~

General and Synthetic Methods

202

OBz OH

IosoL +

BZO&

OBz

dyOH

I

OH

1 .o threo

8.9 erythro

OBz O H

Bzo+-

OH

?H

OBz OH

+

7 ery t hro

Bzo+

OH 1 threo

Scheme 3

the double bond and approach of the osmium tetroxide between the allylic hydrogen and the hydroxy-group (Figure 2a). For the corresponding 2-ester (3) it is suggested that the favoured eclipsed conformer has the allylic hydrogen in the plane of the double bond (Figure 2b). In the case of the 2-ester (3) the rationale of Kishi would not predict the observed product, and it is in the hydroxylation of conjugated double bonds that Kishi notes a discrepancy in the cited example^.^

Figure 1

Alcohols, Halogeno-compounds, and Ethers HO

203 OH

__j

OH

H

(2)

i.ii

H

OH CO2Me

Xo

I

A

(31 Reagents: i, N-Methylmorpholine oxide, OsO, cat., aq. Me,CO, r.t.; ii, aq. NaHSO,

Scheme 4

(b)

Figure 2

Potassium permanganate in the presence of crown ethers has been used to hydroxylate y-butenolides, stereoselectively producing cis-diols in which the hydroxy-groups are anti to the 4-s~bstituent.~ The yields are usually good and, depending on the 4-substituents, syn :anti ratios of 1 :50 have been obtained (Scheme 5).

‘b‘k i,ii

+

__j

OH OH Reagents: i , KMnO,, 18-crown-6, CH,Cl,, -42”C, 12 h; ii, aq. Na,SO,

Scheme 5 T. Mukaiyama, F. Tabusa, and K. Suzuki, Chem. Lett., 1983, 173.

‘

k

OH HO

H

H

o

General and Synthetic Methods

204

Preparation by Reduction of Carbonyl Compounds.-A review has been published in which the use of complex reducing agents (general formula NaH.RONa.MX,) for reduction of ketones is detailed.8 Reduction of esters with lithium borotritide ('Super-tritide') enables a-tritiated alcohols to be obtained in good chemical and radiochemical yield..9 Amides have been shown to be efficiently reduced to alcohols by reduction with sodium in liquid ammonia followed by quenching and recycling of unconverted starting material (Scheme 6). lo

RCH2CONH2

r

0 RCHzCHzOH

+

R

d

NH2 (major product)

I

ii

Reagents: i, Na, liq. NH3; ii, NH,Cl quench; 11 cycles for complete reduction!

Scheme 6

An interesting example of a vacillating reaction has been reported, whereby use of lithium borodeuteride-chromium trioxide as a reducing oxidizing couple permits a-deuterated alcohols to be obtained (Scheme 7).11 RCH20H RCDO RCDzOH Reagents: i, NaBd,, H2Cr04on silica, Et,O, 24 h (20% RCD,OH, 43% RCDHOH, 38% RCH,OH)

Scheme 7

Polynuclear borane anions act as mild reducing agents, and in particular the octahydroborate monoanion [as Bun4N+(B3H8)-], in the presence of various salts which act as promoters, reduces ketones in excellent yields12 (Vol. 6, p. 159). Reductive cyclization of various 4,5-unsaturated ketones with an excess of zinc in the presence of chlorotrimethylsilane has been shown to give rise to cyclopentanols.13Olefins, acetylenes, aldehydes, and cyanides are all able to participate as the unsaturated moiety, and the yields of cyclopentanols are good (Scheme 8).

ChemoseZective Carbonyl Reductions. Carboxylic acids may be reduced under mild, selective conditions in a two-step procedure by reducing the acid chloride with sodium borohydride in dimethylformamide at -78"C.I4 Silica gel has been shown to catalyse lithium aluminium hydride reduction in non-polar solvents. l5 In P. Caubikre, Angew. Chem., Int. Ed. Engl., 1983, 599. S. Hegde, P. M. Coates, and C. J. Pearce, J . Chem. SOC., Chem. Commun., 1983, 1484. lo I. Schon, T. Szirtes, T. Uberhardt, and A. Csehi, J . Org. Chem.,1983,48, 1916. l1 B. Kim and S . L. Regen, Tetrahedron Lett.,1983, 24, 689. l2 W. H. J. Tamblyn, R. E. Aquadro, 0. D. DeLuca, D. H. Weingold, and T. V. Dao, Tetrahedron Lett., 1983, 24, 4955. l3 E. J. Corey and S . G. Pyne, Tetrahedron Lett., 1983, 24, 2821. l4 T. Fuiisawa, T. Mori, and T. Sato, Chem. Lett., 1983, 835. l5 Y. Kamitori, M. Hojo, R. Masuda, T. Izumi, and T. Inoue, Synthesis, 1983, 387. 8

205

Alcohols, Halogeno-compounds, and Ethers

r

OTMS

OTMS

BR

L

1

-

s -fiRH OTMS

OH

RH

R = --CH2,-CH,=O,=CHCO2Me,

ii

or E N

Reagents: i, Zn (20 equiv.), Me,SiCl (6 equiv.), 2,6-lutidine, THF, reflw, 12-18

h; ii, H 2 0

Scheme 8

hexane aldehydes, ketones, and esters are all reduced to their corresponding alcohols in good to excellent yields with this reagent. However, under these conditions, esters are markedly less reactive, requiring refluxing in hexane, and thus this system permits reduction of ketones in the presence of esters in good yields. It has also been shown that aryl ketones and aryl carboxyesters can be selectively reduced in the presence of nitro- and cyano-groups using the same system. l6 Aromatic aldehydes are reduced selectively with borohydride exchange In addiresin in alcoholic solvents in the presence of ketones or nitro-gro~ps.'~ tion, aldehydes attached to electron-deficient aromatic rings are more easily reduced than those attached to electron-rich rings providing a further degree of chemoselectivity (Scheme 9).

Reagents: i, Borohydride exchange resin, MeOH, -1O"C, 1 h

Scheme 9

Tetra-n-butylammonium triacetoxyborohydride shows excellent selectivity for aldehyde reduction in the presence of ketones.18 Even with an excess of the reagent ketone reduction does not occur. Aromatic aldehydes have been shown l6 l7

Y. Kamitori, M. Hojo, R . Masuda, T. Inoue, and T. Izumi, Tetrahedron Lett., 1983,24,2515. N. M. Yoon, K. B. Park, and Y . S . Gyoung, Tetrahedron Lett., 1983,24, 5367. C. F. Nutaitis and G. W. Gribble, Tetrahedron Lett., 1983,24, 4287.

206

General and Synthetic Methods

to be selectively reduced in the presence of aromatic ketones using a complex of pyridine and diborane adsorbed on alumina (Scheme 10).I9 Pyridine-diborane in the absence of alumina reduces carbonyl compounds only very sluggishly.

9 6 '10

I

woH <2

OIO

Reagents: i, BH3 (0.33 equiv.), py, A1,03, r.t., 2 h

Scheme 10

Stereoselective Carbonyl Reductions. Optically active epoxides (4) obtained by asymmetric epoxidation of chalcones are reduced by zinc borohydride in quantitative chemical and optical yield giving the erythro-products (5) .*O

Reagents: i, Zn(BH,),, Et,O, 0°C; ii, H,O

Japanese workers have shown that zinc borohydride can be used to reduce 0-hydroxy-ketones giving the erythro-diols as the favoured products21 (erythro :threo usually better than 85 : 15). Sodium bis(methoxyeth0xy)aluminium hydride was shown to provide complementary reduction of the silylated derivatives giving threo-diols as the major products after deprotection (Scheme 11) although the selectivity was usually lower than with zinc borohydride. The authors suggest a chelated transition state (Figure 3) to explain the erythro selectivity observed with zinc borohydride. In two following reports these workers applied the reductions to the synthesis of blastmycinone** and to production of building blocks with three consecutive chiral centres useful for polyoxy-antibiotic synthesis .23 Zinc borohydride has also been used successfully to reduce 2-substituted 3-keto-amides, when the syn-alcohols are obtained with very high stereoselectivity (Scheme 12).24 l9

2o 22 23 24

J. H. Babler and S. J. Sarussi, J . Org. Chem., 1983, 48, 4416. S. Banfi, S. Colonna, H. Molinari, and S. Julia, Synth. Commun., 1983, 901. T. Nakata, T. Tanaka. and T. Oishi, Tetrahedron Lett., 1983, 24,2653. T. Nakata. M. Fukui, and T. Oishi, Tetrahedron Lett., 1983,24,2657. T. Nakata, M. Fukui, H. Ohtsuka, and T.Oishi, Tetrahedron Left., 1983,24,2661. Y. Ito and M. Yamaguchi, Tetrahedron Lett., 1983,24,5385.

Alcohols, Halogeno-compounds, and Ethers

R2

RIJ

i , ii

R

q

R2

207

preferred product e r y t h r o

OH

0

OSiPhZBut iii,iv+

OH H

R%

R2

" - Y R 2

0

preferred product threo

OH

Reagents: i , Zn(BH,),, Et,O, 0°C; ii, H,O; iii, NaAlH,(OCH,CH,OMe),, NF.3H20, THF

toluene, -78°C; iv, Bun4-

Scheme 11

OH

OH

R l h C O N R 3 R L

Rl+

CONR3RL

R2

+

Rl%CONR3RL

R* SY"

always

> 97

R2 anti

3

Reagents: i, Zn(BH,),, Et,O, -78°C; ii, H,O+

Scheme 12

Asymmetric Carbonyl Reductions. A review of asymmetric reduction using chiral complex aluminium h y d r i d e ~has ~ ~appeared. Borane complexed with (S)-(-)2-amin0-3-methyl-1,l-diphenylbutan-l-ol (6) [obtained in two steps from (S)valine] reduces ketones in quantitative chemical yield with optical yields higher than 94% for the examples cited.26In a study using a similar chirally modified borohydride derived from (S)-valinol the same group obtained optical yields of up 25 26

H. Haubenstock, Top. Stereochem., 1983,14, 231. S. Itsuno, K. Ito, A. Hirao, and S. Nakahama, J . Chem. SOC., Chem. Commun., 1983, 469.

208

General and Synthetic Methods

0 0

\/

j-&

H --

NH2

OH

NO2

to 70% in the asymmetric reduction of n-propyl.pheny1ketone.27Another report describes the use of a borane reagent (7) derived from (R)or (S)-2,2’-dihydroxy6,6’-dimethylbiphenyl and an aromatic amine .28 Reduction of ketones with this reagent in the presence of boron trifluoride etherate proceeded with optical yields of up to 84%. Chiral silanes derived from (-)-P-pinene have been used to reduce ketones in the presence of the Wilkinson catalyst, leading to alcohols with modest enantiomeric excess (Scheme 13).29

/si

MeCL

/SiMeH2

iii,i;

(96O/o) ( 1 7 ) : e.e. 22.5% Reagents: i, Me,SiCl,, H,PtC16; ii, LiAlH,; iii, R*SiMeH,, [Rh(PPh,), Cl]; iv, MeOK, MeOH

Scheme 13

Lithium aluminium hydride complexed with either (S)-4-anilino3-methylaminobutanol(8a) or (S)-4-(2‘,6’-xylidino)-3-methylaminobutanol(8b) provides a means of complementary reduction of a$-unsaturated ketones,30the former reagent (9a) favouring the (S)-alcohol and the latter (9b) the (R)-product (Scheme 14). The chemical yields are usually good with moderate optical yields. Z7 28

29

30

S. Itsuno, A. Hirao, S. Nakahama, and N. Yamazaki, J . Chem. SOC., Perkin Trans. I, 1983, 1673. H. Suda, S . Kanol, N. Umeda, T. Nakajo, and M. Motoi, Tetrahedron Lett., 1983,24, 1513. D. Wang and T. H. Chan, Tetrahedron Lett., 1983,24, 1573. T. Sato, Y. Gotoh, Y. Wakabayashi, and T. Fujisawa, Tetrahedron Lett., 1983, 24,4123.

209

Alcohols, Halogeno-compounds, and Ethers

I

2 1 H b l e

___)

NHR ( 8 ) a ; R =Ph Me

(9)

b ; R+ Me

major product

R2

0 major

product

Reagents: i , LiAlH,, RNH,; ii, (9a); iii, (9b)

Scheme 14

A good optical yield was obtained using lithium aluminium hydride (‘Chirald’) in the reduction of a propargylic ketone to the (R)-alcohol (Scheme 15).31A procedure for overall asymmetric reduction of ketones has been described3*in which the key step involves reductive cleavage of a chiral acetal derived from (2R,4R)pentanediol. Various aluminium hydrides were investigated, but di-isobutylaluminium hydride gave generally good enantiomeric excess in the product alcohols (Scheme 16). 0

li

H

OH

97% 78.6Y0 optical purity Reagents: i, LiA1H4, ‘Chirald’, Et,O, -100 to -65°C

Scheme 15 31 32

S. Senda and K. Mori, Agric. Biol. Chem., 1983,47,280. A . hiori, J. Fujiwara, K. Maruoka, and H. Yamamoto, Tetrahedron Lett., 1983,24,4581.

210

General and Synthetic Methods H

H

H

H

iii, i v

H

OH

R1 l a r g e r than R2

R1 Reagents: i, Pentane-2(R),4(R)-diol, H+; ii, R,AlH; iii, [O]; iv, base

Scheme 16

Enzymic Asymmetric Carbonyl Reductions. The ability of actively metabolizing Baker's Yeast (Saccharomyces cerevisiae) to reduce ketones with good enantioselectivity, coupled with the experimental ease of such procedures, has led to a number of applications of this system (Figure 4). By this means several workers

9 5 "10 e.e.

(10)

OHC

70 - 80°/o yield

(11 1

60

- 65.1. HO

0 R&C02K

(13)

iv

RA

e.e.

H

HO

H

C

0

> 99

Ol0

2 e . e.

Reagents: i, Baker's yeast, aq. sucrose, MeOH, 30°C, 48-72 Baker's yeast, aq. glucose, pH 7,25"C, 48 h

Figure 4

R = CH,=CH CHl-CMe K Me2 C =CH BzOCHZ

(38'10) ( 55°/0) ( 59°/0) (

51 %)

h; ii, Raney Ni; iii, Baker's yeast; iv,

Alcohols, Halogeno-compounds, and Ethers

211

have reported reductions ofa-keto-esters such as and (ll).34 In the case of the y-chloro-P-keto-ester series (12) the product stereochemistry was shown to depend upon the nature of the ester the (R)-alcohol predominating with long-chain alkyl groups and the (S)-alcohol with the ethyl ester. Reductions with extremely high (>99%) enantiomeric excess are possible if the potassium salts (13) are used in place of the esters.36 An improved experimental procedure for asymmetric reduction of trifluoromethyl and methyl ketones uses a large excess of yeast in a small volume of water in the absence of added sugar.37The simpler work-up necessary results in a reduction of manipulative losses. Baker's Yeast has been used in a simple synthesis of (2S,SS)-hexanediol from 2,Shexanedione in 57% yield.38Fungal reduction with Curvularia lunata or Mortierella rammanniana of racemic bicyclo[3.2.0]hept-2-en-6-one(14) results in reduction of only one enantiomer to give 6-endo-( 1S,5R ,6S)-bicyclo[3.2 .O] hept-2-en-6-01 (15) and optically active starting material. 39

(14)

(recovered 1

(15)

Preparation by Nlrcleophilic Addition.-(Di-isopropoxymethylsily1)-methylmagnesium chloride (16) has been developed40 as a synthetic equivalent to the hydroxymethyl anion via transition-metal catalysed coupling with halides followed by deprotection with hydrogen peroxide-fluoride. A second hydroxymethyl anion equivalent, t-butoxymethyl-lithium (17) , has been reported by C ~ r e y .The ~ l reagent is prepared in a two-stage procedure by generation of the anion with s-butyl-lithium-potassium t-butoxide followed by metal exchange with

( Pri 0 12MeSiCH2MgCL

(16)

'HOCH;

=>

But OCHzLi (17)

R. W. Hoffmann and W. Ladner, Chem. Ber., 1983,116,1631. M. F. Zuger, F. Giovannini, and D . Seebach, Angew. Chem., lnt. Ed. Engl., 1483, ICJL?. 35 B. Zhou, A. S . Gopalan, F. Van Middlesworth, W.-R. Shieh, and C . J. Sih, J . Am. Chem. Soc., 1983, 105, 5925. 36 M. Hirama, M. Shimizu, and M. Iwashita, J . Chem. Soc., Chem. Commun., 1983, 599. 37 M. Bucciarelli, A. Forni, I. Moretti, and G. Torre, Synthesis, 1983,897. 38 J. K . Lieser, Synth. Commun., 1983,765. 39 M. J. Dawson, G. C. Lawrence, G. Lilley, M. Todd, D. Noble, S . M. Green, S. M. Roberts, T. W. Wallace, R. F. Newton, M. C. Carter, P.Hallett, J. Paton, D. P. Reynolds, and S . Young, J . Chem. SOC., Perkin Trans. 1, 1983, 2119. K. Tamao, N. Ishida, and M. Kumada, J . Org. Chem., 1983,48,2120. 41 E. J. Corey and T . M. Eckrich, Tetrahedron Lett., 1983,24,3165. 33

3

8

General and Synthetic Methods

212

lithium bromide. The bis-anion (18) generated from 2-methylbenzyl alcohol reacts in the expected manner with aldehyde^.^^

u-Hydroxy-ketones have been prepared by the addition of Grignard reagents to 0-trimethylsilylated cyanohydrins (Scheme 17).43 Less Grignard reagent is OSiMe3 R1-+CN

i,ii

OH R1+=

R2

R2

0 R3

Reagents: i, R3MgX, Et,O, r.t., 2 h; ii, H,O+

Scheme 17

necessary and the yields of adducts are higher than in the usual procedure with cyanohydrins themselves. Terminal epoxides are converted regiospecifically into primary alcohols via reaction with organotin compounds (Scheme 18).44 This reaction has been applied particularly to the preparation of a-amino-alcohols.

R / O O

Reagents: i, Me,SnX, CH,C12;ii, CH2(C02H)2,Et,O

Scheme 18

The addition of cuprates to sterically unbiased /?,y-epoxy-alcohols [e.g. (19)] has been shown to favour C-2 attack (Scheme 19).4s OH

RZCuLi ___)

- 25 OC (19)

Bzow OH R major product

Scheme 19 M. Braun and E . Ringer, Tetrahedron Lett., 1983,24,1233. 43 L. R. Kepsi, S. M. Heilmann, and J. K. Rasmussen, Tetrahedron Lett., 1983, 24,4075. 44 M. Fiorenza, A. Ricci, M. Taddei, and D. T a w , Synthesis, 1983, 64U. 45 M. A. Tius and A. H. Fauq, J . Org. Chem., 1983,48,4131.

42

Alcohols, Halogeno-compounds, and Ethers

213

2,2,2-Trichloro-alcoholsare formed by the addition of electrolytically generated trichloromethyl anion to aldehydes.M An improvement upon the Henry nitroaldol reaction (which suffers from the tendency of nitro-compounds to alkylate on oxygen instead of carbon) has been r ep~ r t ed.~’ The reaction is carried out with the materials adsorbed on to activity I alumina in the absence of solvent. Using this technique high yields of 2-nitro-alkanols have been achieved. Samarium di-iodide has been shown to promote the addition of aryl and alkenyl bromides to aldehydes,48and aryl and alkenyl chromium compounds add selectively to aldehydes in the presence of ketones and cyanides (Scheme 20).49

OH

OH Reagents: i , RX (R=aryl or alkenyl, X=Br or I), CrCl,, DMF, 25°C

Scheme 20

Reetz and co-workers have published procedures whereby 1,2-, 1,3-, and 1,4asymmetric induction can be maximized in the nucleophilic addition to chiral benzyloxy-aldehydes, via chelation control (Scheme 21).50951In the case of 2-benzyloxypropanal (20) use of methyltitanium(w) chloride favours the erythro-product , but use of methyltitanium(rv) isopropoxide reverses the stereochemical outcome. Two procedures are described for 3-benzyloxyaldehydes (21). The first uses methyltitanium(1v) chloride, and the second involves precomplexation with titanium(1v) chloride followed by addition of allysilanes or di-n-butylzinc. In all cases the stereoselectivities are >90%. The prechelation technique when applied to 4-benzyloxypentanal (22) gives a diastereoisomer ratio of 85 : 15. Diethylzinc in the presence of bis- [(-)-camphorquinone-a-dioximato]palladiurn(~~) yields (-)-benzyl alcohols with moderate enantiomeric excess on reaction with aromatic aldehyde^.^^ Allylic Alcohols. The (2)-1-cyanoalkenyl anion (23) adds to ketones and aldehydes to give /3-cyano-allylic alcohols in good yield (Scheme 22).53 Aryl ytterbium halides have been shown to yield allylic alcohols with a&unsaturated 46 47

49

51 52

53

T. Shono, S. Kashimura, K. Ishikazi, and 0. Ishige, Chem. Lett., 1983, 1311. G. Rosini, R. Ballini, and P. Sorrenti, Synthesis, 1983, 1014. J. Souppe, L. Danon, J. L. Nancy, and H. B. Kagan, J . Organomet. Chem., 1983,250,227. K. Takai, K. Kimura, and T. Kuroda, Tetrahedron Lett., 1983,24, 5281. M. T. Reetz, K. Kesseleler, S. Schmidtberger, B. Wendroth, and R . Steinbach, Angew. Chem., Znr. Ed. Engl., 1983, 989. M. T. Reetz and A. Jung, J . Am. Chem. SOC., 1983,105,4833. N. Ogumi, T. Omi, Y. Yamamoto, and A . Nakamura, Chem. Lett., 1983,841. Y. Sat0 and K. Hitomi, J . Chem. SOC.,Chem. Commun., 1983, 170.

214

-

BrO

i

, b C H O

H (

General and Synthetic Methods

s 1-(20)

I

BzO

OH

BzO

OBz OH

OBz H minor

H

OH

major

OBz

iv

CHO

+

(22)

+ H

OBz

H

OH

+

H

OBz

HO

H

85

15

Reagents: i, MeTiCl,, CH2C12,-78°C; ii, MeTi(OPri),, CHC12, -78°C; iii, either MeTiC1, or Tic&, followed by CH,=CHCH,SnMe3 or Bun,Zn; iv, TiCl,; v, Me,Zn, -95°C

Scheme 21

215

Alcohols, Halogeno-compounds, and Ethers

(23) Reagents: i, Bun4N+F-,THF, -15°C; ii, R2R3CO;iii, H30+

Scheme 22

iii

OH

Br

R Reagents: i, LiSnBu,, THF, -78°C; ii, Ph,P, CBr4, Na2S03,CH,Cl,; iii, m-ClC,H,CO,H

Scheme 23

aldehydes,54and y-bromo-allylic alcohols have been prepared from a,p-unsaturated aldehydes via halogenostannanes (Scheme 23) .s5 Allylic alcohols have been produced by the Reformatsky reaction of p-dimethylaminopropionates with a-alkoxy-aldehydes followed by elimination (Scheme 24).s6

R3*CH0

anti (major p r o d u c t )

SY n

Reagents: i, THF, -78°C; ii, MeI, MeOH, 0°C; iii, DBU, Me,CO, r.t.

Scheme 24

Homoallylic Alcohols. The addition of ethoxymethyl-substituted alkyl stannanes to carbonyl compounds has been demonstrated to yield homoallylic alcohols possessing a cis-double bond regardless of the stereo- or regio-chemistry of the initial stannane (Scheme 25) .57 Selective synthesis of branched or linear homo54

55

56 ST

K. Yokoo, Y. Yamanaka, T. Fugawa, H. Tuniguchi, and Y. Fujiwara, Chem. Lett., 1983, 1301. M. Shibasaki, H. Suzuki, Y . Torisawa, and S . Ikegami, Chem. Lett., 1983, 1303. L. Banfi, L. Colombo, C. Gennari, and C. Scholastico,J. Chem. SOC.,Chem. Commun., 1983,1112. Y. Naruta and K. Maruyama, J . Chem. SOC., Chern. Commun., 1983, 1264.

216

General and Synthetic Methods Et O ' y " SnMq

OH PhCHO

Ph A

______)

O

E

t

SnC14 , -78'C

J

Scheme 25 RZBSePh I

II

+

PhSe-

-

R

1

iii, iv

R iii,iv

R +

f--

PhSe/J-4

OH

R'y-R OH

Reagents: i, LDA, THF, -78°C; ii, R,B, -78--0"C, 1h; iii, RICHO, -78°C; iv, H,O; v, R3B, -78°Cr.t., 24 h

Scheme 26

allylic alcohols is possible via the reaction of aldehydes with an allylic boraneselenium system.58Choice of reaction conditions determines the nature of product obtained (Scheme 26). The pentadienylborane system (24) reacts with ketones at the central carbon giving the thermodynamically less stable alcohols (25).59 Zinc-graphite and potassium-graphite lamellar inclusion complexes have been combined with allylic halides resulting in homoallylic alcohols after reaction with carbonyl compounds.60Japanese workers have found that simultaneous addition

58 59

Y. Yamamoto, Y. Saito, and K . Maruyama, J . Org. Chem., 1983,48, 5408. M. G . Hutchings, W. E. Paget, and K. Smith, J . Chem. Res. (S), 1983, 31. G . P. Boldrini, D. Savoia, E. Tagliavini, C. Trombini, and A. Umani-Ronchi, J . Org. Chem., 1983, 48, 4108.

Alcohols, Halogeno-compounds, and Ethers

217

of aromatic aldehydes and ally1 halides to a suspension of manganese in refluxing THF containing iodine can give good yields of alcohols.61By similar simultaneous addition of cinnamyl chloride and benzaldehyde to magnesium, 1,2-diphenyl-but3-en-1-01 has been prepared.62 This is the first description of the successful generation and use of a cinnamyl Grignard reagent. Ally1 boronates (26) are reported to add to aldehydes to give the y-adducts (27) with a high preference for

X

X

(26)

(27)

X = Br, C I , SEt , or OMe

Z-configuration of the double bond.63The reaction of (a-ethoxycarbonyl vinyl)d e m o n ~ t r a t e dhigh ~ ~ diastereofacial selectivity in the tin(1v) chlride-mediated 27) .@The reactions are high yielding, and stereoisomerically pure allylic alcohols

R’

OEt

111

tE, , ,R

A-

R2

c--

OH R3

Reagents: i , R’CuYLi, Et,O, -78°C; ii, R2R3CO;iii, aq. NH,Cl

Scheme 27

are obtained with ketones and epoxides. An allenoate intermediate has been proposed to explain the stereochemical outcome with ketones. Heathcock has d e r n ~ n s t r a t e dhigh ~ ~ diastereofacial selectivity in the tin(1v) chloride-mediated reaction of allysilanes with chiral a- and P-alkoxy-aldehydes (Scheme 28), thus 62

6; 65

T. Hiyama, M. Sawahata, and M. Obayashi, Chem. Lett., 1983,1237. J. M. Coxon, G. W . Simpson, P. J. Steel, and V . C . Trenerry, Tetrahedron Lett., 1983, 24. 1427. R. W. Hoffmann and B. Landmann, Tetrahedron Lett., 1983,24, 3209. J. P. Marino and R. J. Linderman, J . Org. Chem., 1983, 48, 4621. S. Kigooka and C. H. Heathcock, Tetrahedron Lett., 1983, 24, 4765.

218

General and Synthetic Methods OBz

OBz

CH 'O R=H R = Me

B

z

O

35 45

1 1

A CHO

10 Reagents: i, SnC14,Me$

1

Y R Scheme 28

complementing the work of Reet~.~O> 51 Other Lewis acids result in loss of stereoselectivity in this case. In an attempted enantioselective synthesis of homoallylic alcohols, allylic halides and aldehydes were combined in the presence of chromium(I1) chloride and a chiral auxiliary.&However, only low enantiomeric excesses were observed. Some measure of success has been achieved in the Lewis acid-catalysed reaction of optically active diallylbis-(2-phenylbutyl)tin with aldehydes67when enantiomeric excesses of up to 82% were recorded.

Other Unsaturated Alcohols. Lithiated derivatives of butynyl carbonates, on sequential addition of titanium isopropoxide and a ketone, provide diastereomerically pure a-allenyl alcohols (Scheme 29) .68 a-Allenyl alcohols are Me

Me

Reagents: i, BunLi, Et,O, -78°C; ii, Ti(OPrl),, -78°C; iii, R1R2C0

Scheme 29

the major products from the reaction of 1-lithio-1-phenylthioallene(28) with ketones.69Propargyl alcohols are also formed as minor products. High yields of propargyl alcohols are obtained from the reaction of 3-lithio-1-methoxy1-trimethylsilylpropyne(29) with ketones70(Vol. 6, p. 165). 6 67

69 'O

B. Cazes, C . Vernikre, and J. Gore, Synth. Commun., 1983, 73. J. Otera, Y . Kawasaki, H. Mizuno, and Y. Shimizu, Chem. Lett., 1983, 1529. D. Hoppe and C . Riemenschneider, Angew. Chem., Znt. Ed. Engl., 1983, 54. A. J . Bridges and R. D. Thomas, J . Chem. SOC.,Chem. Commun., 1983,485. I. Kuwajima, S. Sugahara, and J. Enda, Tetrahedron Lett., 1983, 24, 1061.

A Ecoh oIs, Halogen o-compounds, and Ethers

219

PhS

OMe

);.=

Li

TMS

(28)

(291

Diols. Sequential treatment of chlorohydrins with n-butyl-lithium and lithium naphthalenide gives an organolithium species which reacts with carbonyl comA diastereoselective synthesis of 1,2-diols has been pounds to produce 1,2-di0ls.~l reported72using the chiral alkoxy-acetate (30). With acetaldehyde as the electrophile the major product has the erythro-configuration (Scheme 30).

erythro

(30)

10 : 1

threo

Reagents: i, Pr,NLi; ii, MeCHO, -120°C; iii, H,, Pd(OH),

Scheme 30

General Methods of Preparation. *-A2-Isoxazolines, prepared by 1,3-dipolar addition of nitriles to olefins, can be hydrogenolysed by Raney-nickel, and the resultant product hydrolysed to give P-hydro~y-ketones.~~ This strategy provides an alternative route to the aldol condensation for obtaining /3-hydroxy-ketones, and has been used in the synthesis of furanone precursor^.^^ In the field of sugar chemistry, a deoxygenative [ 1,2]-hydride shift has been utilized to convert cis-diol monotosylates into inverted secondary alcohols (Scheme 31) .75 Snider has used

DMSO-THF

HO OTs Scheme 31

two sequential ene reactions in an annelation procedure which produces hydroxydecalins from methylenecyclohexane and a$-unsaturated ketones (Scheme 32a) (see Vol. 6, p. 166).76More work by Snider and c o - ~ o r k e r shas ~ ~ demonstrated the utility of reacting enol ethers with formaldehyde in the presence of *Any alcohol preparation which is in fact removal of a protecting group will be listed under Protection and Deprotection. 71 J. Barluenga, J . Flbrez, and M. Yus, J . Chem. SOC. Perkin Trans. 1, 1983, 3019. 72 J. d'Angelo, 0. Pagks, J. Maddaluno, F. Dumas, and C . Revial, Tetrahedron Lett., 1983, 24,5869. 73 D. P. Curran, J . A m . Chem. SOC., 1983,105,5826. 74 S. H. Anderson, K. K. Sharma, and K. G. Torssell, Tetrahedron, 1983,39,2241. 75 F. Hansske and M. J . Robins, J . A m . Chem. SOC., 1983, 105,6736. 76 B. B. Snider and E. A. Deutsch, J. Org. Chem., 1983,48, 1822. 77 B. B. Snider and G. B. Phillips, J. Org. Chem.,1983,48, 2789.

General and Synthetic Methods

220

a

li

J @OH

Hoho R

b

Me

Reagents: i , HCHO, Me,Al, CH,CIZ,0°C; ii, H,O

Scheme 32

organoaluminium compounds (Scheme 32b). An improved procedure for hydrolysing alkyl bromides to alcohols has been reported;78use of mercury(I1) oxide and fluoroboric acid reduces the amount of elimination which may occur giving alcohols in 67-95% yield. Studies using endo-tricyclo.[5.2.1.02,6]decanehave enabled bridgehead hydroxylation to be carried out using rn-chloroperbenzoic acid to give the alcohol (31) in 77% yield79(Vol. 1, p. 156). Zinc-trimethylsilyl

chloride has been shown to act as a mild reducing system for converting epoxides to alcohols; with an unsymmetrical epoxide the alcohol with less a-substitution is the major product. Carboxylate salts have been shown to undergo copper(1)mediated addition to cyclic allylic epoxides giving monoesters of syn-diols.81This 78

79

*O *l

J. Barluenga, L. Alonso-Cires, P. J. Campos, and G. Asensio, Synthesis, 1983, 53 N. Takaishi, Y . Fujikura, and Y . Inamoto, Synthesis, 1983, 293. Y . D. Vankar, P. S. Arya, and C . T. Rao, Synthesis, 1983,869. J. P. Marino and J. C. J a h , Tetrahedron Lett., 1983, 24, 441.

Alcohols, Halogeno-compounds, and Ethers

221

reaction is limited to cyclic compounds where the double bond is constrained in a cisoid relationship to the epoxide. Work by Pelter and co-workers with methyldimesitylboranes2 has demonstrated its use for preparing homologous alcohols from halides. Alcohols labelled with 1 7 0 have been prepared by the action of 1 7 0 gas on trialkylboranes followed by decomposition with acid.83 Organosilicon fluorides can be cleaved oxidatively to alcohols with a combination of peracid, dimethylformamide, and potassium

Allylic Alcohols. Cyclopentadiene has been used to protect the double bond of a$-unsaturated ketones prior to reaction with Grignard reagents;85 reverse Diels-Alder reaction then liberates the double bond providing efficient access to isopropenyl alcohols (Scheme 33). Tertiary allylic alcohols may be prepared by

lii Reagents: i , Cyclopentadiene, heat; ii, MeMgI; iii, 550°C

Scheme 33

isomerization of primary 3,3-disubstituted alcohols with bis(trimethylsily1) peroxide in the presence of [VO(acac),] catalystVs6 This complements the ready, acidcatalysed tertiary to primary alcohol isomerization. A novel oxidatively assisted hydrolysis of allylic iodides to rearranged allylic alcohols has been reported (Scheme 34);s7the key feature of the process is the [2,3]-sigmatropic rearrangement of an allylic iodoso-compound to an allylic hypoiodite. Tin(1v) chloride. mediated rearrangement of the epoxide (32) occurs in moderate yields to give allylic alcohols (33);88a four-membered 0x0-tin intermediate has been implicated.

Homoally lic and Other Unsaturated Alcohols. Cyclopentenols have been prepared via intramolecular photo-oxetane formation from unsaturated P-ketoA. Pelter, B. Singaram, L. Williams, and J. W. Wilson, Tetrahedron Lett., 1983,623; A . P. Pelter, L. Williams, and J. W. Wilson, ibid., p. 627. 83 G . W. Kabalka, T. J. Reed, and S. A . Kunda, Synthesis, 1983,737. K. Tamao, T. Kakui, M. Akita, T. Iwahara, R. Kanatani, J. Yoshida, and M. Kumada, Tetrahedron, 1983, 39, 983. 85 R. Bloch, Tetrahedron, 1983, 39, 639. 86 S. Matsubara, K. Takai, and H. Nozaki, Tetrahedron Lett., 1983, 24, 3741. 87 S. Yamamoto, H. Itani, T . Tsuji, and W . Nagata, J . A m . Chem. SOC., 1983,105,2908. 88 I. Cutting and P. J. Parsons, J . Chem. SOC., Chem. Commun., 1983, 1435.

82

222

General and Synthetic Methods R’

r

R1

R

3

0 x

I

L

I

+

R’

R2

R3+OH

.

R1

R3+(

R2

*Ao

Reagents: i, m-ClC6H,C03H, EtOAc or CH,Cl,, aq. Na2C03

Scheme 34

R’

R1

Si Me3 R2+OH

esters (Scheme 35).89The erythrolthreo selectivity of the [2,3]-Wittig rearrangement of crotyl propargyl ethers (Figure 5 ) has been shown to be dependent upon the terminal substituent of the acetylene.w W. S. Johnson has described the use of acetal templates derived from chiral diols for the asymmetric synthesis of homoallylic91and propargylic alcohols.92The strategy (Scheme 36) permits the preparation of these alcohols in good overall yield with enantiomeric excesses of up to 92%.

HO Reagents: i, hv; ii, NaH ( 3 equiv.), benzene, reflux

Scheme 35 89 91

92

T. H. Kim, Y. Hayase, and S. Isoe, Chem. Lett., 1983, 1421. K. Mikami, K. Azuma, and T. Nakai, Chem. Lett., 1983, 1379. W. S. Johnson and J. D. Elliott, J. Am. Chem. SOC., 1983, 105,2088. W. S. Johnson and J. D. Elliott, J . Am. Chem. Soc., 1983, 105,2904.

Alcohols, Halogeno-compounds, and Ethers

223

N , X erythro

X

TMS

threo

-

100 100 90

Me H

10

F 0 7

N , X

X

TMS Me H

R

73

27

1

99 99

1 Figure 5

R

R1

H H H Reagents: i, R'TMS, TiCl,, CH2Cl,, -78°C; ii, MeOH; iii, PCC; iv, KOH, MeOH

Scheme 36

Diols. A sequence has been described93which converts allylic alcohols into 3-amino-1,2-diols. A polymer-supported diol (34) has been prepared,94finding use in the isolation of carbonyl compounds and as a protecting group. Samarium di-iodide has been shown to mediate the reductive dimerization of aldehydes and ketones to form p i n a c o l ~Similarly, .~~ pyridyl glycols (35) have been prepared in a OH

93 94 95

G . Cardillo, M. Orena, and S. Sandri, J . Chem. SOC., Chem. Commun., 1983,1489. P. Hodge and J. Waterhouse, J . Chem. SOC.,Perkin Trans. 1, 1983, 2319. J. L. Namy, J. Souppe, and H. B. Kagan, Tetrahedron Lett., 1983,765.

General and Synthetic Methods

224

'one-pot' process which is promoted by aqueous titanium(II1) chloride.96(R)-Butl-ene-3,4-diol (36), a valuable intermediate for the synthesis of optically active compounds, has been prepared97in 20% overall yield with 92% enantiomeric excess from (2K,3R)-tartaric acid.

OH OH

(35)

(36)

Protection and Deprotection.-Primary and secondary alcohols may be converted into their methoxymethyl (MOM) ethers using trimethylsilyl iodide and dimeth~xymethane.~~ Tertiary alcohols are converted into the iodides. The methoxymethyl group has proven useful in the protection of uracil residues in oligoribonucleotide synthesis.w Primary alcohols have been protected as their t-butyldiphenylsilyl (TBDPS) ethers in the presence of polyvinylpyridine.looThe advantage of this technique is the non-aqueous work-up procedure which simply requires removal of reagents by filtration and evaporation of the filtrate. Primary hydroxy-groups may be preferentially protected in the presence of secondary hydroxyls by sequential alternative addition of t-butyldimethylsilyl chloride (TBDMS chloride) and silver nitrate in THF.lolTBDMS ethers of tertiary and sensitive alcohols can be prepared by the use of 15 kbar pressure at room temperature. lo2 0-Benzoylation of carbohydrate derivatives is sometimes complicated by migration of the benzoyl group, but phase-transfer catalysis in the presence of additional sodium salts has been shown to minimize such side reactions.lo3 Benzoyl trifluoromethanesulphonate has proven to be an efficient benzoylating agent for hindered alcohols'@' although acetals and epoxides are decomposed. Benzylation of alcohols has been carried out in neutral, non-polar media using potassium exchanged Y-type zeolite resin in refluxing hexane.lo5 Olah has describedlo6the use of a polymeric perfluorinated sulphonic acid resin for the preparation of tetrahydropyranyl (THP) ethers (cf. Vol. 6, p. 175). It was found necessary to add the dihydropyran slowly to the alcohol and resin to avoid decomposition, but following this procedure yields were nearly quantitative with A. Clerici and 0. Porta, Tetrahedron, 1983,39, 1239. D. A. Howes, M. H. Brookes, D. Coates, B. T. Golding, and A. T. Hudson, J . Chem. Res. (S), 1983, 9. 98 G. A. Olah, A. Hussain, and S. C. Narang, Synthesis, 1983, 896. 99 H. Takaku, S. Ueda, and T. Ito, Tetrahedron Lett., 1983, 24, 5363. lMG. Cardillo, M. Orena, S. Sandri, and C. Tomasini, Chem. Ind. (London), 1983, 643. lol K. K. Ogilvie and G. H. Hakimelahi, Carbohydr. Res., 1983, 115, 240. lo2 W. G. Dauben, R. A. Bunce, J. M. Gerdes, K. E. Henegar, A. F. Cunningham, andT. B. Ottoboni, Tetrahedron Lett., 1983, 24, 5709. lo3 W. Szeza, Carbohydr. Res., 1983, 115, 240. lO4 M. Koreeda and L. Brown, J . Chem. SOC., Chem. Commun., 1983,1113. lo5 M. Onaka, M. Kawai, and Y . Kumi, Chem. Lett., 1983,1101. lo6 G. A. Olah, A. Husain, and B. P. Singh, Synthesis, 1983, 897. 96

97

Alcohols, Halogeno-compounds, and Ethers

225

most alcohols except for tertiary alcohols, which eliminated. The THP ethers were obtained by filtration of the reaction mixture. Phenyl ethers have been prepared using 2-0~0-1,3-propanedisulphonates (37) which have the advantage of non-acidity and lack of toxicity. lo7 Kinetic acetalization with p-methoxy-

phenylmethyl ethers and DDQ has been used to protect 1,2- and 1,3-diols.lo8This neutral procedure has the additional advantage of giving largely one epimer of the newly formed acetal (Scheme 37). OH

OH

11

--Me

OC Ph

39

1 V

71 '10 Reagents: i, MeO(C6H,)CH20Me, DDQ, CH2C12

Scheme 37

Ether cleavage reactions which have appeared in the literature up to 1981have been reviewed. lo9 Selective demethylation of rnethoxyanthraquinones using boron trifluoride is possible due to the formation of internally chelated boron enolates. llo Modified boron halides have received much attention as selective deprotecting agents. Dimethylboron bromide deprotects acetals MEM, MOM, and methylthiomethyl (MTM) ethers.lll 2-Chloro-l,3,2-dithioboralancleaves MOM ethers, acetonides, and benzylidene acetals but does not affect benzyl, IM lO8

lo9 110

F. Ogura, H. Yamaguchi, T. Otsubo, T. Nakano, andT. Saito, Bull. Chem. SOC.Jpn., 1983,56,1257. Y. Oikawa, T. Nish, and 0. Yonemitsu, Tetrahedron Lett., 1983,24, 4037. M. V. Bhatt and S . U. Kulkarni, Synthesis, 1983,249. P. N. Preston, T. Winwick, and J. 0. Morley, J . Chem. SOC., Perkin Trans. 1, 1983, 1439. Y. Guindon, C, Yoakim, and H. E. Morton, Tetrahedron Lett., 1983,24, 2969, 3969.

226

General and Synthetic Methods

THP, TBDMS, or TBDPS ethers or methylene acetals.l12Aliphatic MTM ethers are cleaved by trityl fluoroborate 113 and also by trimethylsilyl chloride-acetic anhydride,l14the latter system also cleaving methyl ethers. Pyridinium toluene-psulphonate in butan-2-one or t-butyl alcohol efficiently deprotects allylic MEM and MOM ethers. 115 A solution of titanium(1v) chloride in methylene chloride buffered with solid sodium bicarbonate has been shown to cleave MOM ethers.l16 Trimethylsilyl bromide, although usually too unreactive to cleave ethers, will do so on catalysis with iodine monobromide. 117 Trimethylsilyl chloride-iodine monochloride cleaves only benzyl and tertiary alkyl ethers. Trichloromethylsilane with sodium iodide has been used to cleave ethers, being more reactive than a combination of trimethylsilyl chloride and sodium iodide. 11* Ionexchange resins suspended in methanol efficiently cleave THP ethers lO6, 119 and are particularly useful for acid-sensitive alcohols119(Vol. 4, p. 154). Another mild means of cleaving THP ethers uses sodium periodate-sodium iodide in acetic acid.12*Benzyl ethers have been shown to be oxidized to benzoates by ozone121or ruthenium tetroxide122and thence to alcohols, although the degree of additional functionality which may be present is limited. Reactions of Alcohols.-Oxidation. Work has continued at an undiminished rate to produce mild and selective oxidants. Pyridinium chlorochromate has been used to oxidize 2-nitro-alcohols without promoting reverse aldol cleavage. 123 N-Chlorosuccinimide complexed with dimethyl selenide (38)124and periodinane (39)125have both proven useful in the oxidation of primary alcohols to aldehydes. Me

I I

Se-Me

CI

Sodium bromite oxidizes secondary alcohols , but primary alcohols give esters. 126 The oxidation of secondary alcohols with potassium permanganate is more efficient if ultrasound is applied to the reaction mixture,127but primary alcohols give R. Williams and S. Sakdarat, Tetrahedron Lett., 1983, 24, 3965. P. K. Chowdhury, R. P. Sharma, and J. N. Baruah, Tetrahedron Lett., 1983,4485. N. C. Baruah, R. P. Sharma, and J. N. Baruah, Tetrahedron Left., 1983,24,1189. 115 H. Monti, G. LCandri, M. Klos-Ringuet, and C. Corriol, Synth. Commun., 1983, 1021. 116 N. Morishima, S. Kato, S. Kanemitsu, and S. Zen, Chem. Lett., 1983, 1189. 117 E. C. Friedrich and G. De Lucca, J . Org. Chem., 1983,48, 1678. G. A. Olah, A. Hasain, B. P. Singh, and A. K. Mehrotra, J . Org. Chem., 1983, 48,3667. 119 B. TanBcs, F. Kling, I. Mucha and J. MBrton, Acta Chim. Acad. Sci. Hung., 1983, 112, 233. 120 S. Das, R. N. Baruah, R. P. Sharma, and J. N. Baruah, Chem. Znd. (London), 1983,80. M. Hirama and M. Shimizu, Synth. Commun., 1983,781. lZ2P. F. Schuda, M. B. Cichowicz, and M. R. Heimann, Tetrahedron Lett., 1983,3829. lZ3G. Rosini and R. Ballini, Synthesis, 1983, 543. lZ4K. Takaki, M. Yasumura, and K. Negoro, J . Org. Chem., 1983,48, 54. lzs D. B. Dess and J. C . Martin, J . Org. Chem., 1983,48,4155. lZ6T. Kageyama, Synthesis, 1983, 815. lZ7J. Yamawaki, S. Sumi, T. Ando, and T., Hanafusa, Chem. Lett., 1983, 379.

112 D. 113

Alcohols, Halogeno-compounds, and Ethers

227

limited success. A combination of chromium trioxide and trimethylsilyl chloride is a versatile oxidizing system for secondary alcohols,12*as is pyridinium dichromate and bis(trimethylsily1)peroxide. 129 Potassium dichromate in the presence of Adogen-464 provides a neutral system for acid-sensitive substrates. 130 Polystyrene-bound phenylseleninic acid has been found to oxidize secondary alcohols. 131 Selenium dioxide in catalytic quantities selectively oxidizes benzylic alcohols in the presence of bis-(p-methoxypheny1)selenoxide as a co-oxidant .132 Other reagent systems which selectively oxidize benzylic or allylic alcohols are cerium(1v) ammonium n i t r a t e - c h a r ~ o a l ,cerium(Iv) ~~~ triethylammonium nitrate ,134 ruthenium(n) chloride-bis(trimethylsily1) peroxide ,129 barium manganate,135 and tetra-n-butylammonium c h l o r o c h r ~ m a t e ,although ~~~ the latter reagent when used in a 6 :1ratio with the substrate can be used to oxidize primary alcohols as well. Selective oxidation of primary alcohols to aldehydes in the presence of secondary alcohols is possible using the electrochemically generated nitroxyl species (40) ,13' whereas selective oxidation of secondary alcohols in the

42 I

0 '

presence of primary alcohols may be carried out using a vanadium(1v) catalyst with t-butyl hydroperoxide as the regenerating agent .13* Diols have been oxidized to lactones using palladium(I1)-catalysed aryl bromide oxidation,139sodium bromite ,140 pyridinium chlorochromate on celite ,141 ruthenium complexes with benzylidene acetone as a hydrogen acceptor ,142 and bromine-nickel(I1) carboxylate^.'^^ In the latter two cases the oxidation is regioselective, the least sterically hindered hydroxyl being oxidized (Scheme 38).

Hy drogenolysis and Deoxygenation. A review of deoxygenation techniques has appeared in the literature. 144 A general method for deoxygenation of secondary J. M. Aizpurua and C. Palomo, Tetrahedron Lett., 1983,24,4367. S. Kanemoto, K. Oshima, S. Matsubara, K. Takai, andH. Nozaki, TetrahedronLett., 1983,24,2185. N. R. Natale and D. A. Quincy, Synth. Commun., 1983, 817. R. T. Taylor and L. A. Flood, J . Org. Chem., 1983,48, 5160, 13* F. Ogura, T. Otsuko, K. Ariyoshi, and H. Yamaguchi, Chem. Lett., 1983,1833. 133 Y. Hatanaka, T. Imamoto, and M. Yokoyama, Tetrahedron Lett., 1983, 24, 2399. 134 H. Firouzabadi and N. Iranpoor, Synth. Commun., 1983, 1143. 135 H. Firouzabadi and Z. Mostavivipoor, Bull. Chem. SOC. Jpn., 1983, 56, 914. 136 E. Santianello, F. Milani, and R. Casati, Synthesis, 1983, 749. 13' M. F. Semmelhack, C. S. Chou, and D. A. Cortes, J . Am. Chem. SOC., 1983,105,4492. 138 K. Kaneda, Y. Kawanishi, K. Jitsukawa, and S . Teranishi, Tetrahedron Lett., 1983,24, 5009. 139 Y. Tamaru, Y. Yamada, K. Inoue, Y. Yamamoto, and Z . Yoshida, J . Org. Chem., 1983,48,1286. T. Kageyama, S. Kawahara, K. Kitamura, Y. Ueno, and M. Okawara, Chem. Lett., 1983,1097. 141 T. K. Chakraborty, V. Bushan, and S . Chandrasekaran, Indian J . Chem., Sect. A , 1983, 22, 9. 142 Y. Ishii, K. Osakada, T. Ikariya, M. Saburi, and S. Yoshikawa, Tetrahedron Lett., 1983,24,2677. 143 M. P. Doyle, R. L. Dow, V. Bagheri, and W. J. Patrie, J . Org. Chem., 1983,48,476. lUW. Hartwig, Tetrahedron, 1983, 39, 2609.

1B

129

General and Synthetic Methods

228

R

R

R

major

minor

Reagents: i, (Ref. 142) Ru cat., benzyiideneacetone (2 equiv.), Et,N, toluene, reflux; ii, (ref. 143) Br,, (RC02)*Ni,MeCN

Scheme 38

alcohols via their phenylthiocarbonate esters has been reported14j and a similar technique has been applied in a synthesis of isoclovene. 146 Tri-n-butyltin hydride reduction of tosylates has also been used to accomplish this transformation. 147 Alkylbenzenes have been obtained from benzyl alcohols in one step by refluxing in benzene with diphosphorus t e t r a i ~ d i d e and ' ~ ~ 1,2-diols are deoxygenated to olefins using trimethylsilyl chloride-sodium iodide in acetonitrile. 149

Halogenation. A review covering the nucleophilic replacement of the hydroxygroups with halogens via oxyphosphonium intermediates has been published. 150 Alkyl iodides have been obtained from alcohols in good yields using a combination of sodium hydride, sodium iodide, and trimethylsilyl phosphate in the absence of solvent. lS1 Polymer-bonded phosphorus reagents of structure (41)

/R

Resin-CHZ-N

R

=PBr,

( PCI,)

'

(411

have found use in the preparation of alkyl bromides and ch10rides.l~~ The phosphorus by-products remain bonded to the resin and may be regenerated. Simple 1,2-diols are converted into chlorohydrins using triphenylphosphine-t-butyl h y p ~ c h l o r i t e 'and ~ ~ qu-diols are converted into iodohydrins with diphosphorus tetraiodide in carbon dis~1phide.l~~ In the latter case a primary hydroxy-group is selectively replaced if possible. A continuous extraction process has been described 15j for more efficient preparation of halogenohydrins from a,u-diols. 145 146

14* 149

I5O I5l 152 153

ls4 155

M. J. Robins, J. S. Wilson, and F. Hansske, J . Am. Chem. Soc., 1983,105, 4059. D. Kellner and H. J. E. Loewenthal, Tetrahedron Lett., 1983,24,3397. Y. Ueno, C . Tanaka, and M. Okawara, Chem. Lett., 1983, 795. H. Suzuki, H. Tani, H. Kubota, N. Sato, J. Tsuji, and A . Osuka, Chem. Lett., 1983, 247. J. C. Sarma, N. C. Barua, R. P. Shanna, and J. N. Barua, Tetrahedron, 1983,39,2843. B. R. Castro, Org. Renct., 1983, 29, 1. T. Imamoto, T. Matsumoto, T. Kusumoto, and M. Yokoyama, Synthesis, 1983, 460. G. Cainelli, M. Contento, F. Manescalchi, L. Pessi, and M. Panunzio, Synthesis, 1983, 306. C. N. Barry and S. A . Evans, J . Org. Chem., 1983, 48,2825. W. Buijs, P. Van Elburg, and A. Van der Gen, Synth. Commun., 1983, 387. F. Camps, J. M. Casamor, J. Coll, A. Guerrero, and M. Riba, Org. Prep. Proced. Znt., 1983,15,63.

Alcohols, Halogeno-compounds, and Ethers

229

Chiral Auxilliaries. The asymmetric reduction of carbonyl compounds via chiral boranes26and chiral acetates32and the asymmetric alkylation of carbonyl compounds via their chiral a c e t a l ~ ~ have l > ~ *already been discussed in this chapter. Optically active 1,6-bis-(o-chlorophenyl)-l,6-diphenylhexa-2,4-diyne-l,6-diol (42) may be used to resolve 3-methylcyclohexanones, 5-methyl-y-butyrolacand 2,3-epoxycyclohexanones 157 by complexation and recrystallization.

P

h

w

OH

P

h

OH

(42)

The neryl ether (43) derived from (R)-binaphthol has been cyclized in the presence of various aluminium compounds with good enantioface differentiation to yield (R)-limonene with enantiomeric excesses of up to 77% (Scheme 39).158

(43) Scheme 39

Other Reactions. A review of alcohol dehydration reactions has been published. 159 An improvement on the Mitsonubo reaction for alcohol inversion has been reported which uses in situ generated caesium acetate to displace the mesylate group, permitting easier n.m.r. analysis of the product (Vol. 6 , p. 178). Primary amides can be N-alkylated by alcohols in moderate yield using a ruthenium(rr) catalyst. 161 3-Stannyl alcohols, on treatment with boron trifluorideacetic acid complex, cyclize to cyclopropanes, in marked contrast to the silyl derivatives, which p-eliminate. 162 Allylic alcohols may be coupled with Grignard reagents via the iminium species (44) (Scheme 40).163Such reaction is possible F. Toda, K. Tanaka, T. Omata, K. Namura, and T. Oshima, J . Am. Chem. Sac., 1983,105,5151. K. Tanaka and F. Toda, J . Chem. SOC., Chem. Commun., 1983, 1513. 158 S. Sakane, T. Fujiwara, K. Maruoka, and H. Yamamoto, J . Am. Chem. Soc., 1983, 105,6154. 159 G. H. Foxley, Educ. Chem., 1983, 20, 185. J . W . Huffman and R. C. Desai, Synrh. Commun., 1983, 553. 161 Y. Watanabe, T. Ohta, and Y . Tsuji, Bull. Chem. Soc. Jpn., 1983, 56, 2647. 162 I. Fleming and C . J. Urch, Tetrahedron Lett., 1983,24,4591. 163 T. Fujisawa, S. Iida, H. Yukizaki, and T. Sato, Tetrahedron Lett., 1983,24, 5745.

lS6 Is’

General and Synthetic Methods

230

iii R’

R’

R3

(minor product)

(major product)

Reagents: i, l-Chloro-2-methyl-N,N-tetramethylenepropenylamine; ii, R4MgX, CuI, THF, HMPA

Scheme 40

even in the presence of cyanide, carboxylic ester, ketones, or halide functionalities. Allylic alcohols have also been coupled with aldehydes in the presence of triphenylphosphine and a palladium(I1) catalyst in a Wittig-type olefination. The 2-methylene-4-phenylthio-alcohol (45) is a useful precursor to various ter-

OH

(45)

penes.165Triphenylbismuth acetate has been shown to react with 1,n-diols (n=2S), converting one of the hydroxy-groups into a phenoxy-group.160 Tertiary alcohols react very slowly if at all, and in cyclic systems axial hydroxy-groups are converted preferentially. 1,6Diols are conveniently cyclodehydrated to tetrahydrofurans by the action of trimethylsilyl chloride in DMSO. 167 2 Halogeno Compounds

Preparation.-Reviews of the preparation of alkyl halides from alcohols150and the synthesis of dihalides from unsaturated compounds using purified enzymes168 have been published. A novel, one-step method for conversion of alcohols into 164 165

166

167

M. Moreno-Manas and A. Trius, Bull. Chem. SOC. Jpn., 1983,56,2154. T. Mandai, M. Kawada, and J. Otera, J . Org. Chem., 1983,48,5183. S . David and A. Thieffy, J . Org. Chem.. 1983.48, 441. D. F. Wad and N. D. Ungur, Synthesis, 1983,217. S. L. Neidleman and J. Geigert, Trends Biotechnol., 1983,1,21.

23 1

Alcohols, Halogeno-compounds, and Ethers

bromides or iodides has used a reactive halide, such as ally1 bromide or methyl iodide, with 1,l-carbonyldi-imidazolein a~etonitri1e.l~~ A general method of synthesis of primary alkyl chlorides has been reported involving the DMFcatalysed decarboxylation of alkyl chloroformates (Scheme 41). 170 Primary alkyl

-

0 RO

RCI

+ MezNCHO -k

C02

Scheme 41

iodides have been prepared from terminal olefins by bis(cyclopentadieny1)zinc chloride-catalysed addition of dialkylmagnesium halides followed by displacement of the metal with iodine.1712-Vinyl iodides and bromides may be obtained from terminal acetylenes via halogenoboration with 9-BBN bromide followed by acid treatment of the a d d u ~ tReaction . ~ ~ ~ of the initial adduct with an equivalent of the lithium acetylide yields 2-1-alkynyl-2-halogenoalkenes (Scheme 42)

R'C-CH

-

;f 11

Br

H

Br

\vI \

- iv

R2

Reagents: i, 9-BBN bromide, CHCl,, 0°C; ii, LiC=CR2, pentane, -78°C; iii, I,, -78°C-r.t.; H 2 0 7 ,aq. NaOH; v, AcOH

iv, 30%

Scheme 42

The same research group has reported a similar sequence of reactions using 1-chloroacetylenes. 174 Work with E-vinyl boronic acids has that reaction with sodium bromide and N-chlorosuccinimide yields 2-vinyl bromides by means T. Kamijo, H. Harada, and K. Iizuka, Chem. Pharm. Bull., 1983,31,4189. R. Richter and B. Tucker, J . Org. Chem.,1983,48,2625. 171 U. M. Dzhemilev, 0. S. Vostrikova, and R. M. Sultanov, Izv. Akad. Nauk S.S.S.R. Ser. Khim., 1983,2625 (Chem. Abstr., 1983,98,160304d). 172 S. Hara, H. Dojo, S. Takinami, and A. Suzuki, Tetrahedron Lett., 1983,24, 731. 173 S. Hara, Y . Satoh, H. Ishiguro, and A. Suzuki, Tetrahedron Lett., 1983, 24, 735. 174 S. Hara, T. Kato, and A. Suzuki, Synthesis, 1983, 1005. 175 G. W. Kabalba, K. A. R. Sastry, F. F. Knapp, and P. C. Srivastava, Synth. Commun., 1983, i027. 170

General and Synthetic Methods

232

of an addition-elimination sequence. The preparation of vinyl iodides from

hydrazones has been improved by using a guanidine base, anhydrous conditions, and an inverse addition procedure. 176 Cylopropyl ketones are cleaved in good yield by diphosphorus tetraiodide in acetone to produce 3-iodo-ketones. 177 Epoxides may be converted into 1,2-chlorides using triphenylphosphine in refluxing carbon tetrachloride for extended periods,l’* and to 1,Zdibromides under mild conditions using a dioxodibromomolybdenum(vI)-acetonitrile complex. 179 A convenient synthesis of 1,l-dichloroalkenes has been reported which utilizes the addition of the anion derived from cr-dichloromethyltrimethylsilane to aldehydes (Scheme 43).180 In the first stage low-temperature quenching is crucial for success.

Me3S

OH Reagents:

, Bu*Li or LDA, THF, <-100°C; ii, RCHO; iii, H,O, MeOH (1:9), -80°C; iv, BF,.E%,O, CHZCI, Scheme 43

Asymmetric halogenation of olefins in crystalline cyclodextrin complexes has been shown to be possible.181 Exposure of the P-cyclodextrin complex of methacrylic acid to chlorine gave (+)-2,3-dichloro-2-methylpropanoic acid (53% yield, 88% optical yield). The a-cyclodextrin complex similarly gave the (-)antipode. Reactions.-Complex reducing agents,8 prepared from a combination of an alcohol, an excess of sodium hydroxide, and a transition metal salt in dimethoxyethane can be used, by choice of the constituents, to give a wide range of reducing abilities and selectivity. For example l-bromo-2-chlorobenzene can be hydrogenolysed to chlorobenzene in 96% yield. Zinc borohydride lS2 and zinc-modified sodium cyanoborohydride lg3 are both selective reagents which reduce benzyl halides. Lithium triethylborohydride has been found to hydrogenolyse alkyl halides under milder conditions than lithium aluminium hydride. lS4 Alkyl and aryl halides may be dehalogenated homolytically by treatment with a solution of LiA1H4and potassium t-butoxide in THF and irradiating with U.V.light.lS5 D. H. R. Barton, G. Bashiardes, and J.-L. Fourrey, Tetrahedron Lett., 1983, 24, 1605, J. N. Denis and A. Krief, J . Chem. Soc., Chem. Commun., 1983, 229. 178 A. P. Croft and R. A. Bartsch, J . Org. Chem., 1983,48, 3353. 179 H. Arzoumanian, H. Krentzien, R. Lai, J . Metzger, and J. F. PCtrignani, J . Organomet. Chem., 1983, 242, 175. 180 A. Hosomi, M. Inaba, and H. Sakurai, Tetrahedron Lett., 1983, 24, 4727. ‘ g l Y. Tanaka, H. Sakuraba, and H. Nakanishi, J . Chem. SOC., Chem. Commun., 1983, 947. S . Kim, C. Y . Hong, and S. Yang, Angew. Chem., lnt. Ed. Engl., 1983, 562. 183 S. Kim, Y. J. Kim, and K. H. Ahn, Tetrahedron Lett., 1983, 24, 3369. lR4 S. Krishnamurthy and H. C. Brown, J . Org. Chem., 1983,48, 3085. A. L. J. Beckwith and S. H. Goh, J . Chem. SOC., Chem. Commun., 1983,229. 177

Alcohols, Halogeno-compounds, and Ethers

233

Tritylpotassium has been used to dehydrohalogenate secondary bromides and iodides rapidly under mild conditions. 186 Reductive debromination of 1,2dibromides to alkenes has been carried out using sodium hydrosulphide lX7 or sodium dithionitelSS under phase-transfer conditions and with poly(styrylmethylthio1) in methanol. 189 Palladium catalysis has been used to promote coupling of anions of enol ethers with aryl and vinyl halides.190Hydrolysis of the initial adducts results in an overall acylation process (Scheme 44). 1,3-Dienes may be similarly prepared from palladium-catalysed coupling of E-1-alkenylboronic acids and vinyl iodides. 191

R

ZnCl

H

R = a r y l or v i n y l Reagents: i, Bu'Li, -70-4"C; ii, ZnCl,, THF; iii, RX, 5% PdO; iv. H,O'

Scheme 44

Metallic nickel, prepared by reduction of nickel iodide with lithium-naphthalene, mediates the cross coupling of benzyl halides and acyl halides to form benzyl ketones. 19* A combination of nickel chloride, zinc, and potassium iodide has been used to couple vinylic halides to afford symmetrical 1 , 3 - d i e n e ~ .Buta-1,3-dien'~~ 2-ylmagnesium (46), in the presence of lithium chloride-copper(I1) chloride, undergoes cross coupling with alkyl bromides and iodides.194The copper(1) bromide-dimethyl sulphide complex has been used to catalyse similar conversions. 195 Higher-order cuprates (47) have been found to couple more efficiently with alkyl

(46)

(471

bromides than do dialkyl-lithiocuprates. 196 1,l-Dibromocyclopropaneshave been utilized in a two-step spiroannelation sequence with cyclic cuprates (Scheme 45).'97Ally1 halides can be efficiently cross coupled to vinyl tin compounds with D. R. Anton and R. H. Crabtree, Tetrahedron Lett., 1983, 24, 2449. J. Nakayama, H. Machida, and M. Hoshino, Tetrahedron Lett., 1983,24, 3001. 18K Z . Goren and I. Willner, J . Am. Chem. Soc., 1983,105,7764. la9 V. Janout and P. Cefelin, Tetrahedron Lett., 1983. 24, 3913. 190 C. E. Russell and L. S. Hegedus, J . A m. Chern. SOC., 1983, 105,943. 191 G. Cassani, P. Massardo, and P. Piccardi, Tetrahedron Lett., 1983, 24, 2513. 19? S. Inaba and R . B. Rieke, Tetrahedron Lett,, 1983 24, 2451. 193 K. Tagaki and N. Hayama, Chem. Lett., 1983, 637. 194 S. Nunomoto, Y. Kawakani, and Y. Yamashita, J . Org. Chem., 1983,48, 1912. 195 K. J . Shea and P. Q. Pham, Tetrahedron Lett., 1983,24, 1003. 196 B. H. Lipshutz, D. Parker, J. A. Kozlowski. and R . D. Miller, 1. Org. Chem., 1983, 48, 3334 197 F. Scott, B. G. Mafunda, J. F. Normant, and A. Alexakis, Tetrahedron Lett., 1983.24, 5767.

lK6

J87

234

General and Synthetic Methods

liii Reagents: i, CuBr, THF, -40°C; ii,

{.pi:

; iii, Me(CH2),C=CLi,

THF, -90°C; iv, r.t.

Scheme 45

palladium catalysis under mild conditions which permit a wide range of functionalities including ester, nitro-, nitrile, aldehyde, and hydroxy-groups. 19* The same group has reported 199 the palladium-catalysed converion of allyl, vinyl, and aryl halides into homologated aldehydes using tri-n-butyltin hydride and carbon monoxide. A regioselective conversion of primary allylic halides into allyltrimethylsilanes, the position of the trimethylsilyl substituent depending upon the reaction conditions, has been reported (Scheme 46).*O0

-R

1/1

TMS

TMS

98

2

(80O l e )

100

( 7 6 %I

X R-

0

Reagents: i, CuI, Me,SiLi, HMPA, ether, -60°C; ii, Me,SiLi, HMPA, ether, -60°C

Scheme 46

3 Ethers* Further examples of ether formation by Raney-nickel reductive desulphurization of thionesters (prepared from esters using Lawesson's reagent) have been reported201 (Vol. 6, p. 185). Ready access to 1,l-disubstituted ethyl ethers is * For additional specific ether preparations and reactions see Alcohols: Protection and Deprotection, and references 4 and 78. 198 F. K. Sheffy and J. K . Stille, J. Am. Chem. Soc., 1983, 105, 7173. V. P. Baillergeon and J. K. Stille, J. Am. Chem. Soc., 1983, 105, 7175. *O0 J. G. Smith, N. R. Quinn, and M. Viswanathan, Synth. Commun., 1983, 773. ?O1 J. S. Bradshaw, B. A. Jones, and J. S . Gebhard, J . Org. Chem., 1983,&, 1127.

Alcohols, Halogeno-compounds, and Ethers

235

provided by the reaction of ethyl diphenyl orthoformate with Grignard reagents.2o2Alkenes react with sodium iodide-alcohols in the presence of lead tetra-acetate to produce i o d ~ e t h e r sAn . ~ ~improved ~ synthesis of glycidyl ethers204 from the 2,3-epoxy-halides makes use of phase-transfer catalysis. Methyl ethers have been obtained from C-3 steroidal hydrazones using hydrated copper(I1) chloride in methanol.205(Ch1oroethoxy)methyltributylstannane has been used to synthesize ethyl benzyl ethers from aromatic aldehydes.206Chloromethyl benzyl ethers may be prepared in a general two-step process from benzyl alcohols via their MTM ethers (Scheme 47).2MAn improvement of the Ullmann bisaryl ether

R

d

R

Reagents: i, ClCH,SMe, NaH, NaI, DME; ii, SO,Cl2, CH,Cl2

Scheme 47

synthesis carries out the coupling with copper(1) phenyl acetylide in pyridine giving 41-77% yields of products.208In a new synthesis of t-butyl aryl ethers the A new t-butyl acetal of dimethylformamideis heated with the requisite means of access to ally1 vinyl ethers210involves the cohalogenation of olefins in ethylene oxide followed by reaction of the initial dibromo-adduct with potassium t-butoxide (Scheme 48). Alkyl phenyl selenides may be simply converted into

Y Reagents: i, Br,, ethylene oxide, -80°C; ii, KOBu', 18-crown-6, benzene, reflux

Scheme 48

alkyl methyl ethers by reaction with excess MCPBA in methanol.211The reaction is considered to involve decomposition of the selenoxide formed in situ by methanol (Scheme 49). 2M ,03 ,04 205

*06 ,07

*11

L. Poncini, Bull. SOC.Chim. Belg., 1983,92,215; New Zealand J. Sci., 1983,26, 31. S. Motohashi, M. Satomi, Y. Fujimoto, and T. Tatsumo, Chem. Pharm. Bull., 1983,31, 1788. G. Mouzin, H. Cousse, J.-P. Rieu, and A. Duflos, Synthesis, 1983,117. R. Ballini, Chem. Ind. (London), 1983, 317. J.-P. Quintard, B. Elissondo, and D. Mouko-Mpegna, J . Organomet. Chem., 1983, 251, 175. T. Benneche, P. Strande, and K. Undheim, Synthesis, 1983,762. A. Afzali, H. Firouzabadi, and A. Khalafi-nejad, Synrh. Commun., 1983, 335. E. Mohacsi, Synth. Commun., 1983, 827. J. Rodriguez, J. P. Dulcerre, and M. Bertrand, Tetrahedron Lett., 1983, 4423. S. Uemura, S.4. Fukuzawa, and A. Toshimitsu, J. Chem. SOC., Chem. Commun., 1983,1501.

236

General and Synthetic Methods MCPBA

*

RSePh

ROMe

I 0 Scheme 49

The use of acetylene diethers as a means of entry to oxocarbons has been reviewed.212Allyl phenyl ethers have been coupled with Grignard reagents in the presence of the chiral nickel(I1) complex (48) with high enantio~electivity.~~~

Generation and elaboration of the a-anions of benzyl ethers is possible without interference from Wittig rearrangement of the anion by carrying out the procedure on the chromium tricarbonyl-arene complex.214The aromatic ligand is obtained free of the metal by an oxidative procedure (Scheme 50). Allyl ethers

- VOMe . ..

OH

mR V

e--

OMe

Reagents: i, [Cr(CO),], thermolysis; ii, MeOH, H,SO,; iii, Bu"Li, -40°C; iv, RX; v, 02, sunlight, Et,O

Scheme 50

have been shown to react with dichlorocarbene to form a zwitterionic intermediate which undergoes a novel Claisen rearrangement to produce 2,2-dichloropent-4-enyl 212

*15

F. Serratosa, Acc. Chem. Res., 1983, 16,170. G. Consiglio, F. Morandini, and 0. Piccolo, J . Chem. SOC., Chem. Commun., 1983, 112, S . G . Davies, N. J. Holman, C. A . Laughton, and B. E. Mobbs, J. Chem. SOC.,Chem. Commun., 1983, 1316. R. Malherbe, G. Rist, and D. BelluS, J. Org. Chem., 1983, 48, 860.

Alcohols, Halogeno-compounds, and Ethers

237

4 Thiols and Thioethers

Selective demethylation of methyl aryl thioethers to aryl thiols has been carried out using sodium methanethiolate in refluxing DMF.216Other thioether groups on the same molecule are not cleaved. Reaction of 3-acylthiazolidine-2-thiones(49) with thiols permits the synthesis of thiol Thiols have been coupled to form symmetrical disulphides R

S

using catalytic quantities of 8-aza-3,10-dimethylisoalloazine,218 bis-(2,2’bipyridyl)copper(II) permanganate 219 or iron(u) nitrate supported on bentonite.220Desulphurization of thiols to the corresponding hydrocarbons has been carried out using an iron carbonyl under phase-transfer conditions; 221 no desulphurization occurs in the absence of catalyst. Dithiocarbonates have been used as a source of thiolate anions for reaction with halides under phase-transfer catalysis,222often giving improved yields of product compared with the usual method. Symmetrical thioethers may be obtained from halides via the formation of 3-alkylthio-l,2-benzisothiazole1,ldioxides (Scheme 51).223Phenyl aryl thioethers are produced by the &action of SR

[RSH] 0

-

RSR

0

Scheme 51

ethyl phenyl sulphide with b e n ~ y n eThe . ~ ~unstable ~ allyl sulphide (50) has been prepared in a three-step sequence225and has been shown to undergo ready rearrangement to the more stable rearranged allyl sulphide (51). Trichloromethylsilane-sodium iodide, a reagent system already described for cleaving ethers,l18 also deoxygenates sulphoxides instantaneously. Vinyl thioethers have been prepared by reaction of acetylenes with thiolate anions, L. Testaferri, M. Tiecco, M. Tingoli, D. Chianelli, and M. Montanucci, Synthesis, 1983, 751. K. Soai, H. Hayashi, and A. Ookawa, J . Chem. Res. (S),1983, 20. 218 Y. Yano, I. Yatsu, E. Oya, andM. Oshima, Chem. Lett., 1983,775. 219 H. Firouzabadi, M. Naderi, A. Sardarian, and B. Vessal, Synfh. Commun., 1983,611. 220 A. Cornelius, N. Depaye, A . Gerstmans, and P. Laszlo, Tetrahedron Lett., 1983, 24, 3103. 221 H. Alper, F. Sibtain, and J. Heveling, Tetrahedron Lett., 1983, 24, 5329. u2 I. Degani, R. Fochi, and V. Regondi, Synthesis, 1983, 630. 223 H. Yamada, H. Kinoshita, K. Inomata, and H. Kotake, Bull. Chem. SOC. Jpn., 1983, 56, 949. 224 J. Nakayama, T. Fujita, and M. Hoshino, Chem. Lett., 1983, 249. 225 R. J. Storr and S. Warren, J . Chem. SOC., Perkin Trans. 1, 1983, 1169.

216

217

238

General and Synthetic Methods

SPh

SPh (51)

(50)

either preformed226or generated in situ using liquid ammonia,227potassium hydroxide,228or n - b ~ t y l - l i t h i u m A .~~ ~ notable feature of all of these additions is the predominant formation of the 2-vinyl sulphides. Propargyl alcohols react similarly to furnish regioselectively the 3-alkylthio-(22)-unsaturated alcohols.230 Propargyl alcohols have been used in the synthesis of allenyl thioethers (Scheme 52).231Vinyl sulphides can be obtained from sulphoxides by addition of trimethylsilyl iodide followed by double elimination from the adduct with di-iso-

R'

-

...

.I , l l . I

111

___)

R'

Fc7

R*

SPh

Reagents: i, Bu"Li (2 equiv.); ii, PhSCl (2 equiv.); iii, MeLi, EtzO, -70°C

Scheme 52

propylethylamine.*'* Elimination of thiophenol from phenylthioacetals with copper(I1) chloride-di-isopropylethylaminein refluxing benzene has also been Systems which have been used to oxidize thioethers to sulphoxides include sodium bromite,126pero~yacylnitrates,~~~ nitric acid with gold(II1) under phasetransfer catalysis,235and electrolysis in the presence of poly-(4-vinylpyridine) .236 Sulphoxides labelled with l80 are efficiently prepared 237 by oxidation of thioethers with bromine in a two-phase solvent system of dichloromethane and 180-enriched water. Thiiranes are regioselectively opened by trimethylsilyl cyanide and trimethylsilyldialkylamines to give, after hydrolysis, 2-cyano- and 2-dialkylaminothiols in which the sulphur remains attached to the most substituted 226

227 229

230 231 232 233

u4

235 236 237

238

R. H. Everhardus, R. Grafing, and L. Brandsma, Synthesis, 1983, 623. Y. Takikawa, K. Shimada, H. Matsumoto, H. Tanabe, and S . Takizawa, Chem. Left., 1983, 1351. M. Reglier, 0. Ruel, R. Lorne, and S . Julia, Synthesis, 1983,624. M. Reglier and S . Julia, Tetrahedron Lett., 1983, 24, 2387. 0 . Ruel, E. Guittet, and S . Julia, Tetrahedron Lett., 1983, 24, 61. I. Cutting and P. J. Parsons, J . Chem. SOC., Chem. Commun., 1983, 1209. R. D. Miller and D. R. McKean, Tetrahedron Lett., 1983, 24, 2619. T. Oida, S. Tanimoto, H. Ikehira, and M. Okano, Bull. Chem. SOC. Jpn., 1983, 56,959. P. C. M. van Noort, H . P. W. Vermeeren, and R. Louw, Reel.: J.R. Neth. Chem. SOC., 1983, 102, 312. F. Gasparrini, M. Giovannoli, D. Misiti, G. Natile, and G. Palmieri, Tetrahedron, 1983, 39, 3181. J. Yoshida, H. Sofuku, and N. Kawabata, Bull. Chem. SOC.Jpn., 1983, 56, 1243. A. Okruszek, J . Labelled Compd. Radiopharm., 1983, 20, 741. M. Taddei, A. Papini, M. Fiorenza, and A. Ricci, Tetrahedron Lett., 1983, 24, 2311

Alcohols, Halogeno-compounds, and Ethers

239

5 Macrocyclic Polyethers

A new synthetic approach reported239involves the synthesis of cyclobutanocrown ethers in good yield by intramolecular photocycloaddition of the terminal vinyl ether groups of a long-chain acyclic polyether. Dithiatetra- and penta-oxocrown ethers have been prepared by oxidation of the acyclic terminal dithiols with iron(m) chloride at high dilution.240The cyclic 'switched on', ionophoric material is converted into the non-ionophoric, acyclic precursor in reducing media. Macrocyclic polyethers incorporating a pyridine moiety have been prepared by reduction of macrocyclic thionodiesters, which are themselves conveniently prepared from the pyridine 2,6-dithionoesters by metal template transesterification with diol polyethers (Scheme 53).241

Reagents: i, HO+--"o+?OH,

MeOM, azeotropic removal of MeOH; ii, W2 Raney Ni

Scheme 53

Novel crown ether structures which have been synthesized by established procedures include spiro-compounds (52) ,242 crown ether acetals (53),243 ferrocene-containing macrocycles (54), (55),244 and (56) ,245 crown ethers containing ['breathing' crown piperazine subunits (57) ,246 and bullvaleno-crown ethers - which were found not to fulfil their potential of adopting cavity sizes to match various cations (Scheme 54)]. Structures (58) and (59) show high selectivity for clathrate formation with unbranched alcohols, especially ethanol and propan2-01.~ Crown ~ ~ ethers containing one or two anthraquinone nuclei [e.g. (60)] have been reported.249 239 240

241 242 243 245

246 247

249

K. Mizuno, T. Hashizume, and Y. Otsuji, J. Chem. SOC.,Chem. Commun., 1983,977. M. Raban, J. Greenblatt, and F. Kandil, J . Chem. SOC., Chem. Commun., 1983, 1409. B. A. Jones, J. S. Bradshaw, P. R. Brown, J. J. Christensen, and R. M. Izatt, 1.Org. Chem., 1983, 48, 2635. M. Ouchi, Y. Inoue, H. Sakamoto, A. Yamahira, M. Yoshinaga, and T. Hakushi, J . Org. Chem., 1983,48, 3168. V. Gold and M. Sghibartz, J . Chem. SOC., Perkin Trans. I , 1983,453. P. J. Hammond, A. P. Bell, and C. D. Hall, J. Chem. SOC., Perkin Trans. I , 1983,707. S. Alabori, Y. Habata, M. Sato, and S . Ebine, Bull. Chem. SOC. Jpn., 1983,56, 1459. P. Chcnevert and R. Plante, Synthesis, 1983, 847. K. Sarma, W. Witt, and G. Schroder, Chem. Ber., 1983,116,3800. E. Weber, F. Vogtle, H.-P. Josel, G. R. Newkome, and W. E. Puckett, Chem. Ber., 1983,116,1906. S . Nakatsuji, Y. Ohmori, M. Iyoda, K. Nakashima, and S. Akiyama, Bull. Chem. SOC.Jpn., 1983, 56, 3185.

General and Synthetic Methods

240

R

(54)

(55)

(56)

. o l

Scheme 54

Alcohols, Halogeno-compounds, and Ethers

x

241

x

X = H or (58)

0

Examples of lipophilic crown ethers include simple structures to which a long or via a phenolic linkage.251By such aliphatic chain is appended, either structural modification highly lipophilic crown ether acids have been prepared.252 Photoresponsive crown ethers containing azobenzenophane subunits exhibit alternating ion binding ability by virtue of configurational change about the azalinkage (Scheme 55).253The research group concerned with this work has also 250 251

252 253

J. Skarzewski and J . Miochowski, Tetrahedron, 1983,39, 309. B. Czech, B. Son, and R. A. Bartsch, Tetrahedron Lett., 1983,24, 2923. R. A. Bartsch, Y , Liu, S. I. Kang, B. Son, G. S. Heo, P. G . Hipes, and L. J. Bills, J . Org. Chem., 1983,48,4864. S. Shinkai, T. Minami, Y . Kusano, and 0. Manabe, J . Am. Chem. SOC., 1983,105,1851.

General and Synthetic Methods

242

Scheme 55

synthesized cylindrical crown ethers (61) containing this 'light switch' funct i ~ n a l i t ySugars . ~ ~ ~have been utilized in the construction of chiral crown ethers255 and crypt and^^^^ and one report 257 describes the synthesis and chiral recognition

properties of macrocycles (62) which incorporate helicene chiral centres. Crown ethers containing natural product related subunits have been synthesized in the hope of combining the two sets of chemical features. Examples which have

S. Shinkai, Y. Honda, T. Minami, K. Ueda, 0. Manabe, and M. Tashiro, Bull. Chem. SOC.Jpn., 1983, 56,1700. 255 A. H. Haines, I. Hodgkisson, and C. Smith, J . Chem. SOC., Perkin Trans. 1, 1983, 311. 256 M. Pietraskiewicz, P. Salanslu, and J. Jurczak, J . Chem. SOC., Chem. Commun., 1983,1184. zn M. Nakazaki, K . Yamamoto, T. Ikeda, T. Kitsuki, and Y. Okamoto, J . Chem. SOC., Chem. Commun., 1983, 787. 2.54

243

Alcohols, Halogeno-compounds, and Ethers

appeared include crowned DOPA derivatives,258nicotinic acid crown ethers,2s9 (cf. Vol. 2, p. 140) and the crown ether flavin mimic (63).260

(64)n = 2 , Na+

(63)

=5,K+

Several syntheses of the so-called 'lariat ethers' have been reported. Potential precursors possessing a hydroxymethyl substituent for further functionalization,261,262 an alkoxymethyl substituent ,263,264 or an aryloxymethyl s ~ b s t i t u e n t ~ ~ ~ have been reported. Similar bis( aminomethyl) crown ether derivatives have been prepared 266 and the amino-alkyl lariat ether (64) shows excellent selectivity for potassium or sodium ions depending upon the length of the pendant chain.267 Other novel macrocylic polyethers include the cavitands (65) ,268 which have Et

Et

Et

Et

Et

Et

Et

Et

M. Berthet and E. Sonveaux, J . Chem. Soc., Chem. Commun., 1983,lO. G . R. Newkome and C. R. Marston, Tetrahedron, 1983, 39, 2001. 260 S. Shinkai, Y. Ishikawa, H. Shinkai, T. Tsumo, and 0. Manabe, Tetruhedron Lett., 1983,24,1539. B. Czech, A . Czech, and R. A. Bartsch, Tetrahedron Lett., 1983, 1327. 262 I. Ikeda, T. Katayama, K. Tsuchiya, and M. Okahara, Bull. Chem. SOC.Jpn., 1983, 56, 2473. 263 S. J. Jungk, J. A . Moore, and R. D. Gandour, J . Org. Chem., 1983, 48, 1116. 2M Y . Nakatsuji, T. Nakamura, M. Okahara, and G. W. Gokel, J . Org. Chem., 1983,48, 1237. 265 A. Kaifer, L. Echegoyen, D. A . Gutowski, D. M. Goh, and G. W. Gokel, J. A m . Chem. Soc., 1983, 105, 7168. 26h H. Macda. T. Kikui, Y . Nakatsuji, and M. Okahara, Synthesis, 1983, 185. 267 Y . Nakatsuji, H. Kobayashi, and M. Okahara, J. Chem. Soc., Chem. Commun., 1983, 800. 2M( R. C. Helgeson, M. Lauer, and D. J. Cram, J . Chem. S O C . , Chem. Commun., 1983,101. 258

25y

9

General and Synthetic Methods

244

R2

2 \ /

R2

k2

(67)

(661

enforced concave inner faces large enough to embrace a variety of organic (Vol. 4, p. 170), compounds, calixarenes (66)269(also termed ~pherands”~) hemispherands (67),271 and c h o r a n d ~in , ~which ~ ~ a paracyclophane moiety has been incorporated into the macrocyclic framework (Scheme 56).

/i

Reagents: i, HSArSH, KOH, EtOH, benzene; ii, m-ClC,H,CO,H, 0°C; iii, hv

Scheme 56 269 270

271 272

C. D. Gutsche, B. Dhawan, J. A . Levine, K . H. No, and L. J. Bauer, Tetrahedron, 1980,39, 409. D. J. Cram, J. R. Moran, E. F. Maverick, and K. N. Trueblood, J. Chem. Soc., Chem. Commun., 1983, 645. D. J. Cram, J. R. Moran, E. F. Maverick, and K. N. Trueblood, J. Chem. Soc., Chem. Commun., 1983, 647. T. W . Bell, G. M. Lein, H . Nakamura, and D. J. Cram, J. Org. Chem., 1983,48,4728.

5 Amines, Nitri les, and Other Nitrogen-containing Functional Groups BY S. G. LISTER

1 Amines Nucleophilic amination of activated double bonds and radical amination of olefins have been comprehensively reviewed. Primary Amines.-Preparation of anilines via reduction of the corresponding nitro-compounds is a well established procedure. Hydrazine hydrate in the presence of Raney nickel has recently been used to effect partial reduction of rn-dinitrobenzenes to 3-nitr0anilines.~Providing substituents can participate in hydrogen bonding, high-yielding selective reductions of nitro-groups ortho to electron-donating substituents are possible; otherwise in the absence of hydrogen-bonding effects the selectivity is decreased and/or reversed (Scheme 1).Also noteworthy was that N-isopropyl-2,4-dinitroaniline(1) gave the corresponding hydroxylamine in quantitative yield, and that 1$dinitronaphthalene (2) afforded a mixture of mono- and di-amino-derivatives in addition to recovered starting material. rn-Nitroanilines have also been prepared from dinitrobenzenes using Raney nickel in glacial acetic acid-propan-2-01 mixtures. The use of hydrazine hydrate and Raney nickel in ethanol also enabled the preparation of 3,4-diaminoquinoline (5) (a versatile synthon for the preparation of various fused heterocycles) from 3-nitro-4-aminoquinoline (4) (Scheme 2).4 Although (4) was obtained in good yield from (3) the value of this synthesis will probably be limited by the low yield of (3) (4%) in the nitration of quinoline. Reduction of aromatic nitro-compounds has also been achieved using dichlorobis(triphenylphosphine)platinum(II) in conjunction with stannic chloride and triethylamine ,5 mercuric chloride-magnesium and titanium tetrachloride in t-butyl alcohol-THF,6 sodium tetrahydridoborate in the presence of ferrous chloride ,7 and Amberlyst A26 anion-exchange resin-supported tetracarbonylhydridoferrate.8

3

6

*

M. B. Gasc, A. Lattes, and J. J. Perie, Tetrahedron, 1983, 39,703. N. R. Ayyangar, U. R. Kalkote, A. G. Lugade, P. V. Nikrad, andV. K. Sharma, Bull. Chem. Soc. Jpn., 1983, 56, 3159. A. Ono, S . Terasaki, and Y. Tsuruoka, Chem. Ind. (London), 1983,477. K. S. Sharma, R. P. Singh, and K. S. Kumari, Synthesis, 1983, 581. Y. Watanabe, Y. Tsuji, T. Oshurnj, and R. Takeuchi, Tetrahedron Lett., 1983,24, 4121. J. George and S. Chandrasekaran, Synth. Cornmun., 1983, 13, 495. A. Ono, H. Sasaki, and F. Yaginuma, Chem. Ind. (London), 1983,480. G. P. Boldrini, G. Cainelli, and A. Umani-Ronchi, J. Organomet. Chem., 1983, 243, 195.

245

246

General and Synthetic Methods

X = H, OH, NEt2, NHEt, or NHPh

02N+qNo2 X

X

u , HzN*Noz\

v

Y X = OH, Y = Me; 98 Yo

X = H, Y = C 0 2 H ; 8 5 ' / 0

Reagents: i, H,NNH,.H,O (3 equiv.), Raney Ni, EtOH

Scheme 1

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

247

Reagents: i, NH,OH.HCl, EtOH, KOH, MeOH; ii, N2H,.H20, Raney Ni, EtOH

Scheme 2

Arylamine synthesis via electrophilic C-amination of aryl-lithiums is an attractive synthetic proposition and use of tosyl azide as the +NH2synthon appears to have widened the applicability of the method.9,lo Formation of lithiotriazenes proceeds smoothly and subsequent reduction to the desired amines can be effected in good to moderate yield by either sodium borohydride under phasetransfer conditions9or by using a nickel-aluminium alloy in an alkaline medium. lo In particular the reaction has been applied to the synthesis of substituted anthranilamides (Scheme 3). Transmetallation with magnesium bromide-diethyl etherate conferred little advantage in terms of overall yield,' and, in cases where competitive benzyne formation was likely, lower reaction temperatures improved yields only marginally. Phenylthiomethyl azide had previously been reported as a useful +NH2synthon, and has been used in the synthesis of a streptovaricin D synthon (6) (Scheme 4)." In this case transmetallation with magnesium bromide was employed. Trimethylsilyl azide has also been used as an amination reagent for organometallic reagents. l2 An alternative method for the electrophilic C-amination of aromatics has been disclosed in which the reactive species was an aminodiazonium ion formed in situ from sodium (or trimethylsilyl) azide, aluminium chloride, and anhydrous hydrogen chloride (Scheme 5).13 Yields were generally good except when a heteroatom electron-withdrawing substituent was present (for example nitrobenzene). Arene amination has also been achieved by direct substitution of phenolic groups using ammonium chloride and aqueous ammonia under forcing conditions (Scheme 6);14the simple and inexpensive nature of the method compensated for the moderate yields. A modification of the Curtius reaction has recently provided a milder and safer preparation of both primary arylamines and alkylamines from the corresponding acid chlorides (Scheme 7) ,15 hydrolyses of which were prevented by azide formation under phase-transfer conditions. Substituted aminonaphthalenes have been

lo l1

l2 l3

l4

J. N. Reed and V. Snieckus, Tetrahedron Lett., 1983,24, 3795. N. S. Narasimhan and R. Ammanamanchi, Tetrahedron Left., 1983, 24, 4733. B. M. Trost and W. H. Pearson, Tetrahedron Lett., 1983, 24, 269. K. Nishiyama and N. Tanaka, J . Chem. SOC., Chem. Comrnun., 1983, 1322. A. Mertens, K. Lammertsma, M. Arvanaghi, and Ci. A. Olah, J . Am. Chem. SOC., 1983,105,5657. A. M. Becker, R. W. Rickards, and R. F. C. Brown, Tetrahedron, 1983, 39,4189. J. R. Pfister and W. E. Wymann, Synthesis, 1983, 38.

General and Synthetic Methods

248 1-111

method ( a ) or

i v - v i method (b)

x

= CONEt2 ( a ) , OCH20Me ( a ) , OCONEt2 (a)

( a ) , H(a),'CONHMe ( b ) , CHNMe,(b)

0

Y

Y

(a) X = CONEt2; Y = 3-OMe, 4-OMe, 6-OMe, 4-Me, 4*CI (b) X = C O N H M e ; Y = 3 - O M e

@ - CONEt2

X

CONEt2 (a)

X

Y

Y

X = 5 - OMe; Y = 6 - S i M e 3 , 6-CH(SiMe3), , 4 - M e Reagents: i, BusLLi, TMEDA, THF, -78"C, 1 h; ii, TsN, (1 equiv.); iii, NaBH,, Bun,NF, p.t.c.; iv, Bu"Li, Et,O, r.t., 24 h; v , TsN, (20 equiv.). 0°C; vi, aq. KOH, Ni/Al Ailoy

Scheme 3

Mewr OMe OMe

MeOCbO

Me*

i71 - i*I. ii

Me

MeOCH20

H2

Me

OMe (6)

OMe

Reagents: i, BunLi,THF, MgBr,; ii, PhSCH,N,; iii, KOH, THF, MeOH, H,O

Scheme 4 NaN3

Q

+ AIC13 +

[HzN-NEN]

+

HCI

[AIC14-1

>

DNHI X

X

Scheme 5

249

Amines, Nitriles, and Other Nitrogen-containing Functional Groups C02 H

CO2H

I

I

I

'

R@OH

R@NH2

Reagents: i, NH,, NH4C1, H20, 180°C (bomb)

Scheme 6

-.>

R Y o Cl

&

R<'

RNHCOCF3

-%

RNHZ

N3

Reagents: i, NaN,, Bu",N+Br-, CH2C1,, H20;ii, F3CC0,H, CH,Cl,; iii, k2C03,H,O/MeOH (4:l)

Scheme 7

prepared by acid-mediated cyclization of 3-phenylprop-2-ylidene malonodinitriles.16>l7 Azide hydrogenolysis is another well established procedure for the preparation of primary amines, and the transformation has been accomplished by catalytic transfer hydrogenation using an excess of ammonium formate with 5% Pd-C in methanol.l* Functionalization of a specific amino-group in a polyamine would represent an important synthetic advance, and recently an azide reduction employing Lindlar's catalyst in ethanol has been applied to circumvent this problem in an efficient synthesis of biologically important monoacylated diamines exemplified by ferulyl- (7) and coumaryl- putrescine (8) (Scheme 8).l9 A fundamentally different H

H

I

COCl i -iv

4

R OM s

&

I

-N3

-L

Q

R

R

OH

OH

(7) R = H ( 8 ) R = OMe Reagents: i, Br(CH,),NH,+Br-, NEt,; ii, NaN,; iii, KOH, MeOH, r.t., 8 h; iv, HCl; v, HI, Lindlar, EtOH, r.t., 2 h

Scheme 8 l6 1:

l9

J. Sepiol, Synthesis,' 1983,504. J. Sepiol. Synrhesiv 1983,559. T. Gartiser, C. Selve, and J. J. Delpuech, Tetrahedron Lett., 1983,24, 1609. G.Kunesch, Tetrahedron Lett., 1983,24,5211.

250

General and Synthetic Methods H w

N

A

A

r

HNyo Ar

(10)

+

+

+ H I

AS

(12 1

BzNT H

rP

H2N

OH

/

0

\

OH

\

Ar

OH

(15)

(16)

Reagents: i, p-NO,C,H,CHO, KOH; ii, BnOCOC1, py (2 equiv.); iii, 0.2M HC1, THF; iv, column chromatography; v, p-coumaric acid, DCCI; vi, BBr, ( 2 equiv.)

Scheme 9

approach culminated in the enantiospecific synthesis of the hydroxylated metabolite (16) via deprotection of the N-benzyloxycarbonyl-1,3-oxazolidine (15) prepared from (S)-( +)-hydroxyputrescine dihydrochloride (9) derived from (R)-malic acid.*OThe success of the synthesis (Scheme 9) relied on the fact that derivatization of the equilibrium mixture (lo)+( 1l)+(12) in dichloromethane favoured the six-membered hetrocycle (13), and that its separation from (14) by column chromatography was relatively straightforward. Reduction of ketoximes, too, promises to become an increasingly useful preparation of primary amines. Lithium aluminium hydride reduction of ketoximes 2o

C . M. Tice and B. Ganem, J . O r g . Chem., 1983,48,5043.

-

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

BnBnO O+

i

BB n 0 n

O

q

-

BB nO*nO R,

Brio OMe

Brio OMe B n = PhCH2

25 1

BnO R2 (17) R’ =H, R 2 = O H (18) R’ =OH, R 2 = H (17): (18) = 3 : l

R’ \

(17)

(18)

(19) R’ = H, R 2 = NH;!

iii, iv

---+

iii. I V

( 2 O ) R ’ = NH2,R2 = H (19) : (20) = 2 : 1

( 2 1 ) R’ = H, R ~ = N H , BnO* Bn0

OH

( 2 2 ) R’ = NH2,R2 = H

BnO

(21): (22) = 3 : 2

Reagents: i, AgF, py; ii, MgCl,, H,O, Me,CO; iii, NH,OII.HCI, MeOH, py; iv, LiAIH,, THF

Scheme 10

has played a part in the synthesis of the epimeric inosamines (19)-(22) from 6-deo~y-6-iodo-sugars.~~ Reduction favours amines arising from hydride transfer to the ,&face, with the selectivity being greater for the S(S)-oxime derived from (17) (Scheme 10). A related, novel method allows reduction to imines, using diphenyl disulphide and tri-n-butylphosphine in THF, which can be allowed to react in situ with either sodium borohydride to yield amines or sodium cyanide to give maminonitriles (Scheme 11).22The former reaction represents an overall reductive ketone aminaPhSSPh

+

Bu~P

BU3P(SPh)Z

-dyNH2 R2

Reagents: i, Bu,P(SPh),, THF; ii, NaCNBH,, AcOH; iii, NaCN, AcOH

Scheme 11 22

D. Semeria, M. Philippe, J. M. Delaumeny, A.-M. Sepulchre, and S. D. Gero, Synthesis, 1983, 710. D. H. R. Barton, W. B. Motherwell, E. S. Simon, and S. 2. Zard, J . Chem. SOC., Chem. Commun., 1984, 337.

252

General and Synthetic Methods

tion and is applicable even to substrates that are sterically hindered. Use of other disulphides , e.g. 2,2'-dipyridyl disulphide , in chlorinated solvents promoted Beckmann rearrangements-a reactivity that might also be utilized further. Although aldoximes were dehydrated under the above conditions, Devarda's (Cu-Zn-Al) alloy has been successfully used to effect a quantitative reduction of an aldoxime to a primary amine in a synthesis of [2-14C]-3-aminomethylindole.23 The method was further exemplified to include ketoxime substrates, and thus seems generally applicable to primary arnine synthesis. Imine reduction should also provide a general route to primary amines. Such a transformation has been reported, arising from an initial Peterson-like reaction between lithium bis(trimethylsily1)amide and aldehydes. The resultant, isolable, N-trimethylsilylimines undergo addition with organometallic nucleophiles to afford substituted primary amines (Scheme 12).24

Reagents: i, LiHMDS, THF; ii, R*MgBr or R*Li; iii, H,O

Scheme 12

Nitriles may also be reduced to primary amines, and reduction of vicinal dinitriles, obtained by addition of potassium cyanide to &unsaturated cyanoacetates, with lithium aluminium hydride has led to the synthesis of substituted propylamines .25 Since the reaction involves hydride-initiated retroMichael elimination prior to 1,4-hydride donation to the resultant acrylonitrile , product mixtures arise when elimination can occur in more than one direction (Scheme13). Alane has also been used to effect the nitrile to primary amine

Rlj"Hz

II

R1 +H* I

CN

R2 Rz

R2 # H

R*

=H

ArL

+

NHZ Reagents: i, KCN, EtOH; ii, LiA1H4

Scheme 13 23 24 25

J. Schallenberg and E. Meyer, Z . Naturforsch., B: Anorg. Chem., Org. Chem., 1983, 38, 108. D. J. Hart, K.-i.Kanai, D. G . Thomas, and T.-K. Yang, J . Org. Chem., 1983,48,289. J. S. New and Y. P. Yevich, Synthesis, 1983, 388.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

253

conversion in a synthesis of l-(aminornethyl)-2-benzyl-l72,3,4-tetrahydroisoquinoline.26A further potentially useful method involves synthesis of primary amines from corresponding amides with iodosobenzene and formic acid in aqueous acetonitrile .27 N-Demethylation using palladium black in the presence of a borate buffer and air in aqueous dioxane has been demonstrated to be a viable preparation of primary amines in the carbohydrate area.28Best results were obtained when the primary hydroxy-group of the sugar was protected. 2-Aminopyridines have been prepared inter alia by reaction of activated acetonitriles with 5-nitrop~rimidines,*~ and in a three-component condensation of methyl ketones with aldehydes and mal~nonitrile.~~ Vicinal primary diamines can be prepared by treatment of olefins with cynamide and N-bromosuccinimide .31 The resultant bromoalkyl cyanamides furnish ethoxyimidazolines, after sequential treatment with ehanolic hydrogen chloride and a mild base, which after more vigorous basic hydrolysis yield the desired diamines (Scheme 14). H

Br

OEt Jiii

R' \

R2

,

t

H2N

NH2

HN

YN OEt

Reagents: i , H2NCN, NBS; ii, HCl, EtOH; iii, NEt3;iv, Ba(OH)2

Scheme 14

4- and/or 5-aryl-substituted oxazolidones have been proposed as chiral derivatizing agents for the resolution of chiral primary amines via formation of diastereomeric a l l ~ p h a n a t e sThese . ~ ~ compounds which could be prepared from either racemic amines and cis-4,5-diphenyl-2-oxazolidone-3-carbamyl chloride or were found to be chroracemic isocyanates and cis-4,5-diphenyl-2-oxazolidone, matographically separable and easily hydrolysed to the resolved amines. N-Acylated 1-aryl-1-aminoalkanes may also be resolved chromatographi2h

27

29

30 31

32

D. Beaumont, R. D. Waigh, M. Sunbhanich, and M. W. Nott, J. Med. Chem., 1983,26, 507. A. S. Radhakrishna, C. G. Rao, R. K. Varma, B. B. Singh, and S . P. Bhatnagar, Synthesis, 1983, 538. T. Tsuchiya, S. Nishimura, and S. Umezawa, Carbohydr. Res., 1983,112, C9. V. N. Charusin and H. C. Van der Plas, Recl.: J. R. Neth. Chem. SOC., 1983, 102,373. S. M. A. D. Zayed and A. Attia, J. Heterocycl. Chem., 1983,20, 129. H. Kohn and S.-H. Jung, J. A m . Chem. Soc., 1983, 105,4106. W. H. Pirkle and K. A. Simmons, J. Org. Chem., 1983, 48,2520.

254

General and Synthetic Methods

cally when a silica-bonded chiral stationary phase derived from N-(3,5dinitrobenzoy1)phenylglycine is used.33 Secondary Amines.-Optically

pure (lS, 1’s)and (lR, 1’R)-1-aryl-N-(1-alkyl-

2’-hydroxyethyl)-2-phenylethylamineshave been prepared by the addition of benzylmagnesium chloride to (E)-(S)- and (E)-(R)-N-( 1-alkyl-2-hydroxyethy1)arylmethylideneamines r e ~ p e c t i v e l yThe . ~ ~ intermediates were made by reaction of aromatic aldehydes with S-amino-alcohols derived from L-alanine, L-leucine, and L-isoleucine or R-alaninol and R-leucinol (Scheme 15). Very good 1,3-asymmetric induction was observed except for those additions to the alaninebased azornethines. Since (E)-(S)-azomethines gave (lS, 1’s)-amines and (E)-(R)-azornethines gave ( l R , 1’R)-amines, addition of the benzyl anion must have occurred from the si-si face of the carbon-nitrogen double bond. Since complexation to the nitrogen and oxygen atoms was probably involved the orientation of the hydroxy-group must have been restricted to a conformation such as (A) [illustrated below for the (E)-(S)-azornethine] rather than one such as (B). However, this was not the case for the alanine-derived substrates (R=Me) where lower diastereoselectivity of addition was explained in terms of less restriction of the hydroxy-group to conformation (A) giving rise to addition of the nucleophile from both the si-si and re-re faces. A second report extended the use and ( l R , 1’R)-1-furyl-N-(1’of the method to include the preparation of (lS, 1’s)alkyl-2‘-hydroxyethyl)-2-phenylethylarnines .35 To date use of the reductive rearrangement of oximes to secondary amines has been severely restricted owing to lack of reagent selectivity (as exemplified by use of lithium aluminium hydride which affords aziridines plus isomeric mixtures of primary and secondary amines). A very important development in secondary amine synthesis has been the perfection of simple methodology to achieve this transformation. It has been shown that ketoxime mesylates afford secondary amines in good to excellent yields upon reaction with an excess of di-isobutylaluminium hydride in d i c h l ~ r o m e t h a n eThe . ~ ~selectivity of the reagent was aptly demonstrated by the fact that a 71% yield of N-benzyl-2-phenylethylamine could be obtained from 1,3-diphenylacetoxime, whereas lithium aluminium hydride reduction gave predominantly 2-benzyl-3-phenylaziridine. The method is also versatile in that it can be extended to the synthesis of both ~ z - a l k y l a t e dand ~~,~~ a,@-dialkylated secondary a m i n e ~In. ~the ~ former case reaction of oxime sulphonates (or alternatively acetates, benzoates, or carbonates) with diethylaluminium iodide (and in some cases iodotrimethylsilane) affords imidoyl iodides which can be transformed into the branched amines by successive reactions with a Grignard reagent and di-isobutylaluminium h ~ d r i d e Alternatively, .~~ organoaluminium reagents capable of an alkyl transfer can be used and the resultant imine reduced with di-isobutylaluminium hydride or further alkylated with a Grignard reagent 33 34

35 36 37

W. H. Pirkle, C. J. Welch, and M. H., Hyun, J. Org. Chem., 1983,48, 5022. Y. Suzuki and H. Takahashi, Chem. Pharm. Bull., 1983.31, 31. H. Takahashi, Y. Chida, T . Suzuki, S. Yanaura, Y. Suzuki, a n d M . Chiharu, Chem. Pharm. Bull., 1983, 31, 1659. S. Sasatani, T. Miyazaki, K. Maruoka, and H. Yamamoto, Tetrahedron Lett., 1983,24, 4711. Y. Ishida, S. Sasatani, K. Maruoka, and H. Yamamoto, Tetrahedron Lett., 1983, 24, 3255.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

R = Me, Bu’, Bus Ar = Ph, 4-MeOC6H4, 2-thieny1, or 2-puryl

R = Me or Bu’ Ar = Ph, 4-MeOC6H4, 2-thienyl,or

re-re

Ph

vW!*

Reagents: i, ArCKO, C6H6; ii, PhCH,MgCl, THF

Scheme 15

2-puryI

255

General and Synthetic Methods

256

\

ox X

=

Ac, COPh\ C02Et,or M s

lii I

Reagents: i, Et,AlI (if X=Ms) or TMSI (if X=CO,Et); ii, R3MgBr; iii, Dibal; iv, R3,Al; v, R*,AlR4 (R4=alkynyl)

Scheme 16

(Scheme 16).38Themethodology has been applied to the synthesis of the alkaloids pumiltoxin C (23), solenopsin A (24), and solenopsin B (25).38Direct regioselective alkynylation is also possible if dialkylalkynylalanes are employed, and thus synthesis of naturally occurring y-keto-amines should be possible .38

(23)

( 2 4 ) n = 10 ( 2 5 ) n = 12

The Beckmann rearrangement of oxime sulphonates has also been used to initiate olefinic cyclizations, and in conjunction with the imine reductions described above these have been employed in the synthesis of various cyclic amines according to one of four possible cyclization modes (Scheme 17)39,40 The terms e n d o ( B ) and e x o ( B ) apply to the origin of the migrating group with respect to the incipient ring. endo(B)-endo cyclizations have facilitated syntheses of solenopsin B (25) , following hydrogenation of the unsaturated rearrangement product (27), and muscopyridine (29) after oxidation of the intermediate product (28) (Scheme 18).39 As well as suffering deprotonation intermediate cations may be intercepted by carbon nucleophiles to afford y-alkylated cyclic amines (Scheme 19).39 dZ-Muscone (30) has also been synthesized using this r n e t h o d ~ l o g y . ~ ~ K. Maruoka, T. Miyazaki, M. Ando, Y. Matsumura, S. Sakane, K . Hattori, and H. Yamamoto, J . Am. Chem. Soc., 1983, 105,2831. 39 S. Sakane, Y. Matsumura, Y . Yamamura,Y. Ishida, K. Maruoka, and H. Yamamoto,J. Am. Chem, SOC., 1983, 105, 672. 4o S. Sakane, K. Maruoka, and H. Yanlamoto,Tetrahedron Lett., 1983,24, 943.

38

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

-

257

Lewis acid

endo (€I)endo

T

R

N ‘OMS

Lewis acid

endo (€?I -ex0

GR -

G

Lewis acid

endo ( B )- e Z o

N

MsO

/

H

H

(2

NR RHN

Lewis acid exo (8) -ex0

Scheme 17

Stereoselective a-alkylations of secondary amines have been achieved in the tetrahydroisoquinoline series.41 Chiral formamidines were prepared by N-formylation followed by condensation with an appropriate amine. These were metallated and alkylated to give after deprotection (S)-l-alkyl-172,3,4-tetrahydroisoquinolines (35) (Scheme 20). Although only moderate diastereoselection was observed in alkylations of (31), very good results were obtained using (32) with two adjacent chiral centres in the auxilary , especially when reaction temperatures were lowered prior to the addition of the alkylating agent. Polyhy droxylated- 1-alkyl-1,2,3,4-tetrahydroisoquino1inesand other novel C-nucleosides have been prepared by the Pictet-Spengler reaction of biogenic amines with carbohydrate^.^^ 41

42

A. I. Meyers and L. M. Fuentes, J . A m. Chem. Soc., 1983, 105, 117. I. M. Piper, D. B. MacLean, I. Kvarnstrom, and W. A . Szarek, Can. J. Chem., 1983,61,2721.

General and Synthetic Methods

258 G

M

e

.

...

..

2

R

(25)

R f i MHe

@ UMe

OH N'

vi

d

Me

Reagents: i, Et,AlCl; ii, Dibal (i, ii: 53%): iii, H,, Pd/C, 96%; iv. MsCl, NEt3;v. Me,SiOTf (iv, v: 80%); vi, MnO,, NEt,

Scheme 18

Another potentially versatile synthesis involves nucleophilic alkylation of N-benzyl-N-aryl-0-(trimethylsily1)hydroxylamines using organoaluminium reagents.43 Mixtures of ortho- and para-substituted N-benzylanilines were obtained unless either position was blocked. This method will facilitate the

. ..

1,Il

63 ' l o

MsO

H NPh

/N

6 Me

,OMS V

N

,Me

Reagents: i, Me,Al; ii, Dibal

Scheme 19 43

J. Fujiwira, Y . Fukutani, H. Sano, K. Maruoka, and H. Yamamot0.J. Am. Chem. Soc., 1983,105, 7177.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

259

H

1.11

CH 0

(31) ’ - ( -)

(35)

- PEA ]

(33) R* = R-(-)-PEA

(34)R* = S,S-(+)-BISPAD

[ S,S -(+)-BlSPADl

Reagents: i, Et30+BF,-; K*NH,; iii, LDA; iv, KX; v, H,NNH,, AcOH

Scheme 20

synthesis of substituted indoles since alkynylation followed by treatment with cuprous iodide in DMF afforded N-benzylindoles (Scheme 21). Successful syntheses of unsymmetrical diarylamines have been achieved by two research groups, In the first of these syntheses coupling of arenes with nitrenium salts derived from aryl azides occurred in the presence of trifluoromethanesulphonic acid.44Unsymmetrical diamines were also prepared, salts by a in ca. 30% overall yield, from 2-ethoxycarbonyl-4,6-diphenylpyrylium multistep procedure involving formation of l-aryl-2-ethoxycarbonyl-4,6diphenylpyridinium salts (Scheme 22) .45 0-Aminophenols too have been made in a multistep procedure. Phenols were converted into N-alkyl-N’-phenoxyureas, which subsequently produced N-(2hydroxypheny1)-N-alkylureas on treatment with trifluoroacetic acid in dichloromethane, the secondary amines being obtained after h y d r o l y ~ i s . ~ ~ 54 45

46

H. Takeuchi and K . Takano. J. Chem. Soc.. Chem. Commun., 1983,447. A . R. Katritzky and A . J. Cozens, J. Chem. Soc., Perkin Trans. 1, 1983, 2611 Y . Endo, K. Shudo, and T. Okamoto, Synthesis, 1983,471.

260

General and Synthetic Methods

aR

X 'Ph

'

+

NH

NH

'Ph

Ph

R =Me, Bu"CZC, /R*

TMS-C=C

or P h C r C

R II

W r?R *

___3

NH P 'h

P 'h

Reagents: i, K,Al (4 equiv.); ii, CuI, CaCO,. DMF

Scheme 21

Some N-(2-hydroxyethyl)anilineswere obtained in reasonable yield by treatment of N(2-hydroxyethyl) (ary1oxy)acetamides with potassium hydride in either DMF or THF-18-crown-6.47 This was the first report of an alkoxide-accelerated Smiles rearrangemeqt. Ph

Ph

Ph

& -A

Ph

I

Ph

COZ Et

Ar

Ph

I

Ar

iii - v

Ph

coz-

1

.1

Ph

viii

Ph

Reagents: i, ArNH,; ii, NaOH, H,O; iii, SOCl,; iv, Ar*NH,; v. HBF,; vi, NaH, PhMe; vii, A; viii, H,O

Scheme 22 47

W. R. Baker, J . Org. Chem., 1983,48, 5140.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

261

Kokko and Beak have extended a previously reported synthesis of primary amines from organolithiums and methoxylamine to include a synthetic route to secondary amines derived from reaction with alkyl-lithiums with three electrophilic N-alkylmeth~xylamines.~~ Selective N-monomethylation of primary amines has been accomplished using both N-trialkysilyl-lit hi oar nine^^^ and N-(alkoxymethy1)arylamines In the latter case evidence for the existence of stable monomeric methyleneamines was presented. Problematical dialkylation of primary amines with epoxides has been overcome, since it has been found that steric factors influencing the extent of alkylation can be controlled by utilizing either benzylamine or dibenzylamine as a synthon for the desired secondary amir~e.~l Thus, a general route to secondary aliphatic amines was developed. In a synthesis of chanoclavine (40) and four related ergoline alkaloids from indole-4-carboxaldehyde (36) the N-methylamino functionality was introduced via the formation, cleavage, and subsequent elaboration of a common isoxazolidine intermediate (39).52The key step of the syntheses involved formation of (39) by a kinetically controlled regio- and stereo-selective intramolecular cyclization of the transient nitrone (38) (Scheme 23).

r

,C07Me

(40)

(39)

Reagents: i, Ph,P=CHCO,Me; ii, Me,NH, H,CO; iii, MeI, KCN; iv, Ni, NaH,PO,; v, MeNHOH; vi, NEt,; x. NaIO,; xi, Pr'NEt,; xii, CH,Cl,, reflux; vii, LiAIH,; viii, H,, Ni; ix, (BU~OCO)~O, Ph,P=CMeCO,Me; xiii, CF,CO,H; xiv, Dibal

Scheme 23 B. J. Kokko and P.Beak, Tetrahedron Lett., 1983, 24, 561. M. J. Calverley, Synth. Commun., 1983, 13, 601. 50 J. Barluenga, A . M. Bayon, and G. Asensio, J . Chem. SOC., Chem. Commun., 1983,1109. 51 P. W. Erhardt, Synth. Commun., 1983, 13, 103. 52 W. Oppolzer, J. I. Grayson, H. Wegmann, and M. Urrea, Tetrahedron, 1983,39, 3695. 48

49

General and Synthetic Methods

262

Secondary amines have also been prepared by treatment of azomethines with

2,6-dimethyl-3,5-bis(ethoxycarbony1)-1,4-dihydropyridine and magnesium perchlorate in refluxing THF7s3in transaminations of n i t r o e n a m i n e ~and , ~ ~by selective deacylation of N,N-disubstituted alkyl carbamates over N-monosubstituted alkyl carbamates with an excess of methyl-lithium bromide in THF.551-Alkoxy1-alkylaminocyclopropanes have also been prepared from a-halogenoazomethines upon treatment with a strong base in alcoholic solution.56 Prolonged reduction of Nj-substituted hydantoins with lithium aluminium hydride in refluxing THF gave N-methylethylenediaminesin moderate to good yields.s7 Unsymmetrical N-substituted y-diamines were prepared in very high yields by sodium-propan-2-01 reduction of 1,3-di-imine~.~~ Tertiary Amines.-Several novel methods for the synthesis of tertiary amines have been published. Among the most interesting of these is the N-alkylation of a secondary amine with two equivalents each of a carboxylic acid and trimethylamine-borane complex in refluxing xylene (Scheme 24) .59 Modification of the reagent stoicheiometries allowed isolation of dialkylamides.

1

1

2

1

I

2

3

I

R’ N ‘

J3

I

R* R3

RkNAO I

R2 Reagents: i, Xylene, reflux, then 10% aq. NaHCO,

Scheme 24

Various tertiary amines have been made available by reaction of Grignard reagents with 13,3-perhydrodioxazepines7although reported yields were variable (Scheme 25).60A third method recently described involves reductive rearrangement of 2-chloroalkanamides with lithium aluminium hydride (Scheme 26) .61 The latter compounds were readily synthesized from the corresponding a-chloroacyl chlorides and secondary amines. 53

J. B. Stevens and U . K. Pandit, Tetrahedron, 1983, 39, 1395.

55

J . S. Sawyer and B. A. Narayanan. Synth. Cornmun., 1983, 13, 135. De Kimpe, R. Verhe, L. De Buyck, P. Sulman, and N. Schamp, Tetrahedron L e tt, 1983, 24, 2885. S. Cortes and H. Kohn, J . Org. Chem., 1983,48, 2246. J . Barluenga, B. Olano, and S. Fustero, 1. Org. Chem., 1983, 48, 2255. G. Trapani, A. Reho, and A. Latrofa, Synthesis, 1983, 1013. H. Kapnang and G. Charles, Tetrahedron Lett., 1983, 24, 1597. K. Suzuki, K. Okano, K. Nakai, Y. Terao, and M. Sekiya, Synthesis, 1983, 723.

’‘ A. Krowczynski and L. Kozerski, Synthesis, 1983, 489. ’f, N.

ST

59

6o 61

Amines, Nitriles, and Other Nitrogen-containing Functional Groups RNH;!

&

,"*)

ii

R-N

'1

263

rR"

-7

L*

R*

Reagents: i, (CH,O),, HOCH,CH,OH, C6Hh,reflux; ii, 2 R*MgX

Scheme 25

Reagents: i , R3R4NH,NEt,, C,H,, 69-93%; ii, LiAlH,, Et,O, 15-76%

Scheme 26

It has been found that direct nucleophilic amination of aryl halides is possible by treatment with N , N-diethylaminotributyltin used in conjunction with palladium-phosphine catalysts.62Dichlorobis(tri-o-tolylphosphine)palladium(II) was found to be the best catalyst and observed variations in yield indicated that typical aryne or S,,l-type mechanisms were not involved. Transalkylation methods have been applied to the synthesis of tertiary amines and it has been shown that primary and secondary amines undergo alkyl exchange in the presence of a palladium catalyst (Scheme 27).63 Although simple, the R' CH 2 C H2NR2

'

H

[

R1CH2CH=NR2

!dH;!]

[

]

R'CH ~ C H N H R ~

$d<

H R2NH2

+

R'CH,CH2NR3R4

Scheme 27

method is highly efficient and applicable to the preparation of both heterocyles and polyamines as well as to the synthesis of unsymmetrical amines. The reaction was assumed to proceed via insertion of palladium into the nitrogen-hydrogen single bond followed by /?-elimination to a hydridoimine complex, which can equilibrate with an enamine complex. The products arise by interception of the imine complex with a second amine. 6* 63

M. Kosugi, M. Kameyama, andT. Migita, Chem. Lett., 1983,927. S.-I. Murahashi, N. Yoshimura, T. Tsumiyama, andT. Kojima, J . Am. Chem. SOC.,1983,105,5002.

General and Synthetic Methods

264

An approach to the synthesis of modified morphine analogues also involved a transalkylation procedure, which was achieved by quaternization of the dialkylmethylamine moiety followed by demethylation using sodium benzenethiolate in butanone-a~etonitrile.~~ Model studies were carried out on N-methylpiperidine. Nucleophilic additions to olefins have featured in the chemistry of tertiary amines. Aminopalladation of allylic amines with secondary amines gave, after reduction, vicinal tertiary diamines in reasonable yields.65The methodology was further extended to include additions of potassiumn phthalimide and N-methyltoluenesulphonamideas equivalents of ammonia and methylamine (primary amines) respectively. Oxidation of o-dialkylaminobenzyl alcohols has allowed preparation of a number of 1,4-dihydro-l-alkyl-2H-3,1-benzoxazines.66 A reactive intermediate, formed in a metallation-formylation-diazotization sequence starting from N, N-di-isopropylbenzamide, was trapped with various dienophiles in the presence of [Cu(acac),] and the resultant cycloadducts were fragmented to give N , N-di-isopropylamino-2-carboxy-4-hydroxy-3,4-dihydronaphthalene^.^^ Although the intermediate species could not be isolated or characterized a novel 2-aza-isobenzofuran was proposed. 3,3-Bis(dialkylaminomethyl)-6,8-dihalogeno-4-chromanonesand 3-substituted 3-dialkylaminornethyl-6,8-dichloro-4-chromanones have been prepared by treatment of the appropriate 2-hydroxy-acetophenones or -propiophenones with dialkylamines and aqueous formaldehyde.68 Simple formaminals and bis(dialky1amino)- and bis(arylalky1amino)-methanes have been prepared by reactions of the appropriate sodium amide bases with either 1,3-benzodioxole or 1,3-ben~oxathiazole.~~ The mixed formaminal N-(6aminohexy1)-N-benzyl-N'-methylmethylenediamine was synthesized as a potential a-adrenoreceptor b10cker.~" 2 Enamines

Owing to the difficulties involved in some syntheses of cr-substituted aldehydes the corresponding enamines have been infrequently used. Two methods in the recent literature appear to have overcome this problem. In the first, dianions of carboxylic acids were added conjugatively to methoxymethaniminium methyl sulphates (derived from either DMF or N-formylmorpholine and dimethyl sulphate), the adducts then collapsing to the enamine with concomitant loss of carbon dioxide (Scheme 28).'l The second method involved homologation of the corresponding lower ketones with dimethyl(diazomethyl)phosphonate, to give, presumably, dialkylidene-carbenes via loss of nitrogen, and their subsequent 64 65 66 b7

6x 69

'O

T. S . Manoharan and K. M. Madyastha, Synthesis, 1983, 809. K . A. Parker and R. P. O'Fee, J . Org. Chern., 1983.48, 1547. F. Kienzle, Tetrahedron Lett., 1983, 24, 2213. P. Beak and C.-W. Chen, Tetrahedron Lett., 1983, 24, 2945. A. Cascaval, Synthesis, 1983, 579. S. Melis, F. Monni, P. P. Piras, and F. Sotigu, J . Heterocycl. Chem., 1983, 20, 463. R. Granados, M. Alvarez, F. LopeL-Calahorra, and M. Salas, Synthesis, 1983, 329. R. Knorr, P. Low, and P. Hasscl, Synthesis, 1983, 785.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

265

R 3 = R 4 = Me, R3, R 4 = + Reagents: i, LDA; ii, MeOCH =NR3R4MeOS0,-

Scheme 28

insertion into the nitrogen-hydrogen bonds. 72 In the latter method, however, a limitation was observed in that a$-unsaturated ketones did not yield the desired enamines, although /!I, y-unsaturated ketones reacted well and without conjugation of the double bond. Under carefully controlled conditions enamines may be prepared by mercury(1r)-mediated addition of secondary amines to terminal alkynes .73 However, yields are moderate and saturated tertiary amines result from over-reduction of the enamines in the borohydride-mediated carbon-mercury bond-cleaving reaction. The conversion of cumulenic amines into enynamines by methanol or water under neutral conditions at ambient temperatures has also been reported. 74 3-Amino-2-alkenenitriles have been obtained in good yields via a multistep procedure equivalent to a highly selective cross-Thorpe reaction75since 4-alkoxy3-amino-2-alkenenitriles7 obtained by addition of a-lithioalkanenitriles to protected cyanohydrins, can be easily deprotected, acylated, and hydrogenolysed to the cyanoenamines. Although this involved a lengthy procedure yields were superior to those observed in reactions of nitriles lacking an a-alkoxy-substituent . The preparation of oxygenated enamines has received considerable attention. For example , ,8-lithioenamines, derived from enamines by bromination, elimnination, and metallation, have been shown to give enamino-aldehydes after reaction with DMF, enamino-ketones on reaction with pivaloyl chloride, and enamino-esters with alkyl carbonates .76 An improved enaminone synthesis from /!I-diketones has been reported,77the method, using ammonium acetate itself or a primary ammonium acetate under azeotropic conditions in refluxing benzene, giving excellent yields of the desired enaminones. N-Acyl-,8-enamino-ketones, which are useful synthons for heterocyclic synthesis, were made by reaction of diethyl N-substituted dithiocarbonimidates and the potassium enolates of methyl ketones in synthetically useful yields at room temperature in THF.78 72

73

14 75

76 7 78

J..C. Gilbert and U. Weerasooriya, J . Org. Chem., 1983,48, 448. J. Barluenga, F. Aznar, R. Liz. and R. Rodes, J . Chem. Soc., Perkin Trans. 1, 1983, 1087. P. E. van Rijn, W. Klop, H. D. Verkruijsse, P. von R. Schleyer. and L. Brandsma, J. Chem. Soc., Chem. Commun., 1983,79. K. Kobayashi and T. Hivama, Tetrahedron Lett., 1983,24,3509. L. Duhamel, J.-M. Poirier, and N. Tedga, J. Chem. Res. (S), 1983, 222; J . Chem. Res. (M), 1983, 2101. P. G. Baraldi, D. Simoni, and S. Manfredini, Synthesis, 1983, 902. K. T. Potts, A. J. Ruffini, and G. R. Titus, J. Org. Chem., 1983,48, 625.

266

General and Synthetic Methods

An attempt to prepare enaminones by reaction of secondary amines and steroidal P-bromoenones met with mixed success since high yields of mixtures ~ displacecontaining both a- and y-substituted products were ~ b t a i n e d . ’Similar however, were more ment reactions of 4-halogeno-5-methoxyfuran-2(5H)-ones, successful, the 4-dialkylamino-derivatives being isolated in over 80% yield.80 3-Amino-2-alkenoic esters in which the enoate moiety was exocyclic with respect to a cyclic amine were synthesized by treatment of isopropylidene (1-methylazacycloalkan-2-y1idene)malonateswith alcohols.81 The acylated Meldrum’s acid derivatives were in turn prepared by reaction of Meldrum’s acid with cyclic 1-chloro-N-methylalkaniminium chlorides in the presence of triethylamine (Scheme 29). The iminium chlorides were isolated after treatment of N-methyl-lactams with phosgene. CI

1

Me

I

Me

5 ( : J%y(zH

CL-

x Me

I

0

Me 0

1

Me Reagents: i, SOCI,; ii, Meldrum’s acid, NEt,; iii, XH

Scheme 29

Cyclic ,8-enamino-esters have also been formed in an improved Blaise synthesis. By using activated zinc in refluxing THF and a slow addition of an excess of a-bromoester to the nitrile high yields of the desired enamino-esters were obtained.82An intermediate (41) previously used for the synthesis of saxitoxin (42) was made in this way (Scheme 30). Dehydrophenylalanine derivatives have been synthesized by arylations of 2-acetamidoacrylic acid using a slight excess of the acid and aryl halides under catalysis either by Pd(OA~)~-triphenylphosphineor dichlorobis(tripheny1phosphine)palladium.83Related a,P-dehydro-a-amino-acid derivatives were prepared from N-acyl-N-hydroxy-a-amino-acidesters, tosyl chloride, and triethylamine. 84 A previosuly described synthesis of 2-nitroenamines from primary nitroalkanes, triethyl orthoformate, and secondary amines catalysed by toluene-psulphonic acid has been studied in detail.54It was found that the best yields were obtained with nitroethane and nitropropane (nitromethane condensing only in poor yield), and that primary heteroaromatic amines reacted better than secondary heteroaromatic amines and anilines. Primary aliphatic amines too gave only negligible yields of the desired products. However, transamination of 79

8o *l 82 R3

x4

T. Koga, Y . Nogami, N . Toh, and K. Nishimura, Synth. Commun., 1983, 13, 1013. F. Farina, M. V. Martin, and F. Sanchez, Synthesis, 1983, 397. J. P. Celerier, M. G. Richand, and G. Lhommet, Synthesis, 1983, 195. S . M. Hannick and Y . Kishi, J . Org, Chem., 1983, 48, 3833. M. Cutolo. V. Fiandanese, F. Naso, and 0. Sciacovelli, Tetrahedron Lett., 1983, 24, 4603. T. Kolasa, Synthesis, 1983, 539.

x

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

R’02C

267

R’0$ J y 3

Br

NH2

OMe

’OM e

.1

Known chemistry

O

w NH

HN

NH

OMe

(42)

(41)

Reagents: i, Zn, THF, R3CN, reflux; ii, BrCH,CO,Me, Zn, THF, reflux; iii, K,CO,

Scheme 30

2-nitroenamines obtained from primary amines with ammonia occurred quantitatively (Scheme 31). 2-Nitro-1-phenyleneamines were prepared regioselectively by reaction of phenylacetylene with mercuric chloride and anhydrous sodium nitrite followed by addition of an a ~ n i n e . ~ ~

Reagents: i , HC(OEt),? A; ii, RNH, (excess)

Scheme 31 85

J. Barluenga, F. Aznar, R. Liz, and M. Bayod, Synthesis, 1983, 159.

268

General and Synthetic Methods

Secondary and primary amines have been found to add to tetraethylethynyldiphosphate to yield doubly phosphorylated enamines, one of which was evaluated as an imine anion precursor in alkylation and Wittig-HornerEmmons reactions. 86 P-Sulphonylenamines have been prepared by the Lewis acid-mediated rearrangement of a$-epoxysulphones followed by in situ reaction of the resultant cr-sulphonylacetaldehydes with an a m i ~ ~The e . ~epoxysulphones ~ were prepared from chloromethyl-4-tolysulphone by a Darzens reaction carried out under phase-transfer conditions. 3 Allylamines, Homoallylamines, and Alkynylamines The synthesis of primary allylic amines from a variety of precursors including allylic halides, azides, and alcohols plus olefins, a$-unsaturated oximes, and aziridines has been reviewed.88 An improved procedure for the preparation of N-alkyl-fi-aminoethyl-phosphonium salts has appeared.89The dianions of these salts, obtained by conjugate addition of primary amines to vinyltriphenylphosphonium bromide in acetonitrile, undergo Wittig-type condensations with aldehydes to yield secondary allylic amines (Scheme 32). A moderate selectivity favouring trans-( E)-olefins was observed with aromatic or a$-unsaturated aldehydes, this selectivity being reversed for reactions of aliphatic aldehydes. Li

Li

I

iii

k* Reagents: i, MeCN; ii, BunLi (2 equiv.); iii, R*CHO

Scheme 32

Both secondary and tertiary (E)-4-amino-alk-2-en-l-ols can be obtained from 4-acetoxy-alk-2-en-1-01splus the corresponding diacetates and chlorides using palladium-phosphine complexes as catalysts.w Under the reaction conditions only monoaminated products were observed. Indeed, in the reaction of 1,4diacetoxybut-2-ene with one equivalent of diethylamine in the presence of 86 *7

88 89

M. A. Whitesell and E. P. Kyba, Tetrahedron Lett., 1983, 24, 1679. A. A. M. Houwen-Claassen, J. W. McFarland, B. H. M. Lamrnerink, L. Thijs, and B. Zwanenburg, Synthesis, 1983, 628. A. Laurent, P. Mison, and A, Nafti, Synthesis, 1983, 685. R. J. Lindermann and A. I. Meyers, Tetrahedron Lett., 1983, 24, 3043. J.-P. Genet, M. Balabane, J. E. Backvall, and J. E. Nystrorn, Tetrahedron Lett., 1983,24,2745.

269

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

Reagents: i, R7RsNH,NEt,, THF, DME, catalyst: [Pd(PPh&], [Pd(diphos),], [Pd(acac),], +4 PPh,

Scheme 33

triethylamine only E-l-acetoxy-N, N-diethylaminobutene was isolated (Scheme 33). Heterogeneous palladium catalysis has also been employed in the preparation of tertiary allylic a m i n e ~ ,which ~l have in addition been produced by hydroboraHowever , in the latter reaction rearrangement protion of propargylamine~.~~ ducts were observed, the tendency to rearrange being largely dependent on the basicity of the starting propargylamine. Wittig reactions between 3-N,Ndimethylaminopropyl- and 4-N, N-dimethylaminobutyl-phosphoniumsalts and various aldehydes have also been reported.93 It is now possible to synthesize homoallylic amines with predictable stereochemistry and olefin geometry, using an elegant hetero-Diels-Alder cycloaddition of dienes with N-sulphinyltoluenesulphonamide.94Hydrolysis of the adducts occurs stereospecifically via a concerted retro-ene mechanism to give substituted 5-N-tosylaminohex-2(E)-enes.In general, E, E-dienes give rise to products with threo-like sterochemistry whereas eryfhhro-like products arise from E, Z-dienes (Scheme 34).

Me

NHTs

Me#Me 1 ' H 6 Me threo

Me

TS

J

- like

erythro -like

85 YO

83%

Reagents: i, TsN= S =0, PhMe, 0°C; ii, 5% NaOH, r.t.; iii, 5% HCl, 0°C

Scheme 34 91

92 93 94

D. E. Bergbreiter and B. Chen, J . Chem. SOC.,Chem. Commun., 1983, 1238. J. L. Torregrosa, M. Baboulene, V. Speziale, and A. Lattes, Tetrahedron, 1983,39, 3101. T . N. de Castro Dantas, J. P. Laval, and A. Lattes, Tetrahedron, 1983, 39, 3337. R. S. Garigipati, J. A. Morton, and S. M. Weinreb, Tetrahedron Lett., 1983,24, 987.

270

General and Synthetic Methods

Efforts to synthesize homoallylic amines via substitution of l-bromol-cyclopropylalkanes were not totally successful. Reactions with piperidine occurred in high yield but product ratios favoured homoallylic substitutions only when direct substitution of the bromine atom was prevented by steric hindrancey5 as illustrated by the two examples (43)-+(44)and (45)-(46) below.

R (43) R = M e

( 4 5 ) R = Bu'

(44a)

( 4 4 b ) 8:92

(46a)

( 4 6 b ) 92:8

l-Alkynylamines have been prepared by electrophilic amination of l-alkynylcuprates which were prepared from the corresponding organolithiums by various routesy6 4 Amino-alcohols

Functionalization of double bonds in either the allylic or homoallylic position in relation to an alcohol has become a well established method for the preparation of amino-alcohols. In addition to the previously reported iodocyclization of allylic trichloroacetamidates (48) to 4-(l-iodoalkyl)-5-alkyl-4,5-dihydro-oxazoles (47) (Scheme 35, path a) it has been shown that [3,3]-sigmatropic rearrangement of (48) prior to iodocyclization leads to the exclusive formation of the regiomeric 4,5-dihydro-oxazole (50) as a cis-trans mixture via the trichloroacetamide (49) (Scheme 35, path b).y7A multistep sequence to 3-amino-1,2-diols was also disclosed and involved separation of the czs- and trans-heterocycles (50) plus sequential formation of the iodohydrin (51), the epoxide (52), and the dihydro-oxazole (53). Cyclization of an allylic trichloroacetamidate initiated by bis(co11idine)iodonium perchlorate formed part of the synthesis of a protected daunosamine derivative from L-rhamnose.98 A related strategy, cyclization of an allylic thiocarbamidate to a cyclic bromocarbamate under the influence of bis(col1idine)bromonium perchlorate, has also been reported.99 After standard debromination the amino-alcohol could be liberated by basic hydrolysis, either before or after N-dealkylation with trifluoroacetic acid (Scheme 36). (&)Sporamine (55) was synthesized via intermediate (54) using this strategy. 95

96 97

98

R. T. Hrubiec and M. B. Smith, Tetrahedron Lett., 1983, 24, 5031. G. Boche, M. Bernheim, and M. Niessner, Angew. Chem., Znt. Ed. Engl., 1983, 22, 53. G. Cardillo, M. Orena, and S. Sandri, J. Chem. SOC., Chem. Commun., 1983, 1489. H. W. Pads and B. Fraser-Reid, J. Chem. SOC., Chem. Commun., 1983, 1031. S. Knapp and D. V . Patel, J. A m . Chem. SOC., 1983,105, 6985.

271

Ainines, Nitriles, and Other Nitrogen-containing Functional Groups CCL 3

CCL3

I

I

R2

(491

(47 1

(b)

i iii

CCL3

A

0 " OH J.v, v i

OH I

x

= CI 1 c13cco2 1:l

r

&p I

I

NHCOCC13

(51) H

Jvii

H viii

"Y

pyr

CC1,

NHCOCC I 3

(53)

(52)

Reagents: i, I,, py, THF, ii, PhMe; iii, NIS; iv: 6M HCl; v, R2=Pr, R1=H, separate isomers; vi, trunsisomer, H,O, MeOH (1:l); vii, Amberlyst A 2 6 (C03- form), MeOH; viii, Amberlyst A26 (C0,2- form), MeOH, A

Scheme 35

cis-Oxyamination of 1,2,3,6-tetrahydropyridineshas been achieved using N-chloro-N-sodio-t-butylcarbamatewith either silver or mercuric nitrate and tetraethylammonium acetate in conjunction with catalytic amounts of osmium tetroxide. loo Better yields of the regiomeric cis-t-butoxycarbonylamino-alcohols were obtained with the silver salt. Deprotection was accomplished with acid. Two independent approaches leading to syntheses of both threo- and erythro-sphingosines (57) and (59) have been published. The first method was related to methodology discussed above (see Section 3, ref. 94) and was based on hetero-Diels-Alder cyclizations of the E, E- and E, Z-sulphinylcarbamates (56) and (58) respectively (Scheme 37).lo1The second approach utilized modified Sharpless epoxidations of octa-2,4-dienol followed by intramolecular cyclization loo lol

S. K. Dubey and E. E. Knaus. Can. J. Chem., 1983,61, 565. R. S. Garigipati and S. M. Weinreb, 1.A m . Chem. Soc., 1983, 105, 4499.

272

General and Synthetic Methods SMe

OH

OM e

OMe

Reagents: i, NaH; ii, Bu'NCS; iii, MeI; iv, Br(collidine),ClO,; v, aq. Na,CO,; vi, TFA; vii, Bun,SnH; viii, aq. NaOH

Scheme 36

of the benzyl-urethanes derived from the epoxy-alcohols thus obtained. The resultant oxazolidinones were then simply deprotected.lo2 Oxyamination of an olefin was also achieved in an approach to the synthesis of lincosamine (64). The vicinal amino-alcohol moiety was established via a regiochemically controlled acetolysis of the N-(dimethylphosphory1)aziridine (63), obtained from the epoxide (62) formed from the corresponding olefin (60) via bromohydrin (61) (Scheme 38).Io3It was found necessary to change protecting groups on the sugar in order to achieve regioselectivity in the acetolysis. Reduction of amino-ketones is an obvious route to amino-alcohols, and reductions of a-dialkylaminoacetophenones and a-dialkylaminopropiophenoneshave LII dichloride to been successfully achieved with (-)-bornan-2-exo-yloxyalumini~ give good yields of the corresponding (§)- and (R)-alcohols respectively. Enantiomeric excesses of between 58% and 92% were observed, arising from a cyclic transition state. Acetylpyridines were also reduced but with much lower (1237%) enantiosele~tivity.~~~ Ring opening of epoxides by nucleophilic amines is another obvious entry into amino-alcohols. In this area, a synthesis of 2-amino-alcohols by treatment of terminal epoxides with dialkylaminotrimethylstannanes105complemented the normal formation of secondary alcohols as exemplified by the preparation of 102 103

104 105

B. Bernet and A. Vasdella, Tetrahedron Lett., 1983, 24, 5491. E. R, Larson and S. Danishefsky, J . Am. Chem. SOC., 1983, 105,6715. A. K. Samaddar, S. K. Konar, and D. Nasipuri, J. Chem. SOC.,Perkin Trans. 1, 1983, 1449. M. Fiorenza, A , Ricci, M. Taddci, and D. Tassi, Synthesis, 1983, 640.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups HOH2C-=-CHzOTB

n - C13H27CHO .

...

1-111

I

ix- xii

273 DMS

, iii

H

n-c13H27

iv

1

H

'0n-C13H27 vi, v i i

1

(59)

(57)

Reagents: i, (MeO),P(O)CH,CH =CHC02Me, LDA; ii, LiAlH,; iii, NaOCN, TFA; iv, SOCl,, py; v, r.t., 14 h; vi, PhMgBr; vii, (MeO),P, MeOH; viii, Ba(OH),, dioxane, H,O; ix, BaMnO,; x, n-C,,H2$H2PPh3+Br-, BunLi;xi, 3.5 N HCl; xii, H,, Lindlarcat.; xiii, Ba(OH),, glyme, H,O

Scheme 37

General and Synthetic Methods

274

I

B z0

OMe H

(60) BZ = PhCO

??

Br

H

B

BM."H z

O

,,

W o BzO

M

e

(61)

iii - - i x

OMe

o
(62)

Me

kHtFj&c H

Reagents: i, NBS, H,O, AcOH; ii, DBN; iii, Bu,N+N,-, TMSN,; iv, TFA; v, MsC1; vi, (MeO),P; vii, NaH; viii, K,CO,, MeOH; ix, (imid),CO, then MeOH; x, AcOH; xi, Ac,O, py

Scheme 38

I-N,N-dimethylaminobutan-2-01 from

1,2-epoxybutane and lithium dimethylamide. lo6 Reduction of cyanohydrins is also a well estalished route to amino-alcohols. A novel variant permitted an overall reductive aminomethylation of aldehydes and ketones by lithium aluminium hydride reduction of methylsilyltricyanohydrins formed from the carbonyl compound and in situ prepared methyltricyanosilane. lo7 106

107

H. Sard, R . P. Duffley, andR. K. Razdan, Synth. Commun., 1983. 13, 813. F. Dubodin, P. Cazeau, 0. Badot, and F. Moulines, Tetrahedron Lett., 1983, 24,4335.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

275

The addition of a-amino carbanions to carbonyl compounds has recently been reported as a potentially versatile method for the preparation of erythro-like amino-alcohols. Protected secondary amines with a phosphorus substituent capable of stabilizing an a-anion have been shown to add to aldehydes, forming 2-oxazolidinones . Elimination of the phosphorus moiety and hydrogenation of the resultant 2-oxazolones afforded erythro-like amino-alcohols after hydrolysis of the resultant cis-oxazolidinone (Scheme 39).loS(+)-Conhydrine (67), (+)ephedrine (65), and (+)-N-methylephedrine (66) were synthesized in this manner.

COzMe

C02Me

J.

vi

Me Ph

~

IX

Ph

A S

Ph

OH

(66)

( 2) -# - methylephedrine

viii

OH

(65) ( 2 )- ephedrine

OH (67) (2 ) -conhydrine

Reagents: i, NaH; ii, MeI, iii, ClPPh?, AcOH; iv, LDA; v, PhCHO; vi, A; vii, 1atm H2,PtO,, AcOH; viii, KOH; ix, LiAlH4

Scheme 39

y-Amino-alcohols have been prepared in high yields by reasonably stereoselective hydrogenations of enaminones obtained by coupling of enol silyl ethers with oxime mesylates promoted by alkylaluminium chlorides (Scheme 40). lo9 The reduction of nitrogen-xygen bonds of various heterocycles has served to provide amino-alcohols. For instance stereoselective reduction of the isoxazoline lO8 lO9

T. Shono, Y. Matsumura, and T. Kanazawa, Tetrahedron Lett., 1983,24,4577. Y.Matsumura, J. Fujiwara, K. Maruoka, and H. Yamamoto, J . Am. Chem. Soc., 1983,105,6312.

10

276

General and Synthetic Methods

ME*te EtNH iii

1

EtNH

0

iii

H

H

EtNH

OH

M

+

EtNH

e

U v

EtNH"

M

e

OH

+

1.5

i

EtNH

OH

OH

+

64 29

Me

Reagents: i, H2C=C(OTMS)C6HI3,Et,AlCl; ii, MeHC =C(OTMS)Et, Et,AlCl; iii, HZ, Pd/C, EtOH, CHC1,

Scheme 40

(68) with Red-A1 gave a hydroxyamino-acid which was demethylated to provide a synthon (69) of nikkomycin B (70) (Scheme 41).llo Hydrogenolysis of the spiro-P-lactam (74) facilitated synthesis of tabtoxin (75) (Scheme 42). 111 The key heterocyclic intermediate (73) was established by DielsAlder reaction of in situ-generated benzyl nitrosoformate (72) with ethyl cyclohexa-l,3-dienecarboxylate(71). 110 111

B. J. Banks, A. G. M. Barrett, M. A. Russell, and D. J. Williams, J . Chem. Soc., Chem. Commun., 1983, 873. J. E. Baldwin, P. D. Bailey, G. Gallacher, K. A. Singleton, and P. M. Wallace, J. Chem. SOC., Chem. Commun., 1983, 1049.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

277

Reagents: i, BunLi (3.1 equiv.), THF, TMEDA; ii, 4-MeOC6H,CH0, THF, TMEDA, AcOH; iii, CF,C02H, CH2C1,; iv, Red-a1 (10 equiv.), THF; v, HBr, AcOH. A

Scheme 41

il

Me NH

CQ.

(75) 0.5% overall

Me

BnO H

(74) Reagents: i, [(2-py)SI2, Ph,P, MeCN; ii, H,, Pd/C, MeOH

Scheme 42

278

General and Synthetic Methods

I

Ar{

+

':a Ar

Ar

Jii

-y(77)

CL

Ar_

(781

(77)

1

iv

H

H

C l g H

t

?OR

(78) R=H

OMe

OMe OMe

OMe

( 79)

Reagents: i, Ph,P =CHCH =CH,, E:Z=9:5; ii, ,'N'

I

PhMe, reflux, column chromatography:

0E-(76)=49%, a:p=10:3; Z-(76)=22%, a:p=5:1;iii, HCl(g), CHCl,; iv, HZ,10% Pd/C: (83) 44%, (84) 14%, iii*, iv* as iii, iv, 35%; v, BunLi. THF, -78°C [3,4-(MeO),C,H,CH=CHC0I20

Scheme 43

Cycloaddition of 2,3,4,5-tetrahydropyridineN-oxide to the terminal double bond of a 1-arylbutadiene produced (76), which after chlorination and hydrolysis of (77) led to the synthesis of (&)-lasubheI (78), (&)-2-epi-lasubineI (79), and (&)-subcosine (80) (Scheme 43).11* H. Iida, M. Tanaka, and C. Kibayashi, J. Chem. SOC., Chem. Cornmun., 1983,1143.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

279

(2S,3S,4R)-4-Amino-3-hydroxy-2-methylpentanoic acid, which is a fragment of the antitumour antibiotic bleomycin A2,has been synthesized using a chiral enolate strategy similar to that developed by Evans.'l3 Kinetic resolution of racemic P-hydroxyamines through enantioselective N-oxide formation with t-butyl hydroperoxide and Sharpless' asymmetric 1 :2 tetraisopropyl orthotitanate-( +)-diethy1 tartrate complex was reported. 114 5 Amino-aldehydes and Amino-ketones Optically active a-(t-butoxycarboxy1amino)-aldehydes have been synthesized efficiently from a - a m i n o - a ~ i d s .The ~ ~ ~method involved the reduction of Nmethoxy-N-methylcarboxamides of the amino-acids with lithium aluminium hydride. Thermolyses of ethyl azidoformate in the presence of enol silyl ethers and subsequent treatment with silica gel has enabled preparation of N-substituted cr-amino-ketones (Scheme 44) ,116 which were also prepared by aminoacyclation of metallo-alkyls and -alkenyls using cr-amino-acids as chiral educts (Scheme 44).117

+M

L

J

J

Y = C02Et (Ref.116);

Y = COMe, COPh, COZEt, or S02Ph (Ref. 117)

Reagents: i, EtOCON,, A; ii, SiO,, H,O; iii, R*Li; iv, RIM; v, H + , H20

Scheme 44 113 114 115

117

R. M. Dipardo and M. G. Bock, Tetrahedron Lett., 1983,24,4805. S . Miyano, L. D.-L. Lu, S. M. Viti, and K. B. Sharpless, J. Org. Chem., 1983,48,3611. J.-A. Fehrentz and B. Castro, Synthesis, 1983, 676. S. Lociuro, L. Pellacani, and P. A. Tardella, Tetrahedron Lett., 1983,24, 593. C . G. Knudsen and H. Rapoport, J. Org. Chem., 1983,48, 2260.

General and Synthetic Methods

280

P-Amino-ketones have been made available by oxidative cleavage of the erythro-like and threo-like homoallylic amines (81) and (82) described above (see Section 3, ref. 94). 6 Amides and Thioamides Amide formation by reaction of weak carboxylic acids with amines has often been an unsatisfactory procedure. Thus several methods for carboxyl activation have been invented to overcome the problem. However, some problems-unstable or unselective reagents, over-reaction giving rise to side products, etc.-still remain. Efficient condensation of weak acids with amines using diphosphorus tetraiodide and 2,6-lutidine in refluxing dichloromethane has been reported,'18 with simple work-up affording high yields of extremely pure amides. The reagents combine the advantages of commercial availability, ease of manipulation, and compatability with many functional groups. Arylcarboxylic acid N-arylamides have also been difficult to prepare, but use of 2-chloro-l,3,2-dioxaphospholane permits their preparation from the corresponding acids and amines in excellent yield.'19 Amides can also be formed from acidamine mixtures on reaction with carbon tetrachloride (either neat or as a 10% solution in 172-dichloroethane) in the presence of a 1% crosslinked phosphinecontaining polystyrene resin. 120 Reactions of acid chlorides with silylamines can be controlled to give a variety of products. Slow additions of acyl halides to hexamethyldisilazane in a 1:l ratio in hexane allow isolation of N-trimethylsilylamides whereas addition of hexamethydisilazane to an excess of an acid chloride in refluxing ether or THF favours imide formation.121 N-Trimethylsilylalkyl- and N-trimethylsilyldialkyl-amides react in hexane to give the expected amides, and by replacing the acyl halide with a diacid chloride imidoyl chlorides may be obtained, albeit in moderate yield, from reactions with 1:1 stoicheiometry. Amides may also be obtained from imines by treatment with phosphorus pentachloride followed by water in a one-pot procedure ,122 from cr-quaternary nit rile^,'^^ and also by electrophilic amination of organomagnesium reagents with azidomethyl phenyl sulphide as a +NH2 ~ y n t h 0 n . lIn~ ~the latter procedure triazenes are formed at -78'C, then acylated at O'C, and finally treated with H. Suzuki, J. Tsuji, Y. Hiroi, N. Sato, and A. Osuka, Chem. Lett., 1983,449. C. I. Chiriac, Rev. Roum. Chem., 1983,28, 863. lZo C. R. Harrison, P. Hodge, B. J. Hunt, E. Khoshdel, and G . Richardson, J . Org. Chem., 1983, 48, 3721. lZ1 J. R. Bowser, P. J. Williams, and K. Kurz, J . Org. Chem., 1983, 48, 4111. lz2 H. Singh, S. K. Aggarwal, and N. Malhotra, Synthesis, 1983, 791. lz3 A. N. Mandal, S. R. Raychaudhuri, and A. Chatterjee, Synthesis, 1983, 727. lZ4 B. M. Trost and W. M. Pearson, J . Am. Chem. SOC., 1983,105,1054. 11*

119

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

R = PhCH2CH2, cyclo-CsH,,,

(Om

R * = Me, Ph, or

6

,

281

or Me0

0 Reagents: i, Mg; ii, PhSCH,N,; iii, R*COX; iv, Bun4N+HCO,-, or KOH, Me2S0, or KOH, H,O, MeOH, THF

Scheme 45

either potassium hydroxide in DMSO or tetra-n-butylammonium formate in DMF to effect fragmentation to the corresponding acetamide (Scheme 45). Both E- and 2-allylamides can be made with full regio- and stereo-control from aldehydes and ketones by Horner-Wittig reactions with P-(acy1amino)alkylphosphine oxide dianions (Scheme 46)

I

iv- vi. iii

"

ph2

Me Me OLi

1$.A. Li

lviii

Me

vi i

0 Me y e 0

0

R H

ix

/,

Me ,p 0 i

l

L

P

h

p

N

A HP

h

R' R Reagents: i, BunLi, Me,CO; ii, PhCN, H2S04,TFA; iii, Bu*Li (2 equiv.); iv, BunLi, MeC0,Et; v, NH,OAc, NaB(CN)H3, MeOH; vi, PhCOCl, Et3N; vii, RCHO, NH,Cl; viii, RIRZCO, NH,Cl; ix, NaH, DMSO

Scheme 46 125

D. Cavalla and S. Warren, Tetrahedron Lett., 1983, 24, 295.

282

General and Synthetic Methods

a-Keto-amides were obtained through hydrolysis of P-hydroxy-a-cyanoenamines produced by condensation of a-(N-methylani1ino)acetonitrile with esters,lz6 and ,!?-keto-amides were prepared by hydrogenation of 5-alkyl-3hydroxyisoxazoles formed by C-alkylations of the dianion obtained on deprotonation of 5-methyl-3-hydroxyisoxazole.127 The selective monoalkylation of amides has been studied by several research groups and various monoalkylamides have been prepared by Markovnikov amidation of olefins. 128 This was achieved using an amidomercurationborohydride demercuration procedure. Monoalkylated amides have been prepared in lower but still reasonable, yields by dichlorotris(tripheny1ph0sphine)ruthenium-catalysed reactions of amides and alcohols at high temperatures. 129 Photolytic dehydrochlorination of N-chloro-N-alkylamides with formation of N-(a-methoxyalky1)amides (with the parent amides as minor products) has been investigated7130as has the conversion of primary amides into acylpyrroles with 1,4-dichloro-174-dimethoxybutane and Amberlyst A21 resin . l 3 I Amides are now also available from the corresponding thioamides by using a slight excess of rn-chloroperbenzoic acid under nitrogen in dichloromethane at 0°C.132 No epoxidation of olefinic bonds was observed under these conditions. Thioamides in turn have been synthesized in an extension of the WillgerodtKindler reaction. Modification of the reaction conditions allows easier preparation of N,N-dimethylthiocarboxamides from aldehydes and ketones using elemental sulphur dimethylamine hydrochloride, and sodium acetate in either pyridine, DMSO, or DMF.133 The latter solvent was preferred since it allowed the use of lower reaction temperatures and easy isolation of the thioamides as all other reaction products were water soluble (Scheme 47). X

X

NMe2

H X

X

Me Reagents: i, S,, Me,NH.HCl, DMF (or DMSO or py), NaOAc

Scheme 47 K. Takahashi, K. Shibasaki, K. Ogura, and H. Iida, Chem. Lett., 1983, 859. T. A . Oster and T. M. Harris, J . Org. Chem., 1983,48, 4307. 128 J. Barluenga, C. Jimenez, C. Najera, and M. Yus, J . Chem. SOC., Perkin Trans. I , 1983, 591. Iz9 Y. Watanabe, T. Ohta, and Y . Tsuji, Bull. Chem. SOC. Jpn., 1983,56,2647. 1M X. T. Phan and P. J. Shannon, J . Org. Chem., 1983,48,5164. 131 S . D. Lee, M. A. Brook, andT. H. Chan, Tetrahedron Len., 1983,24, 1569. 132 K. S. Kochhar, D. A. Cottrell, and H. W. Pinnick, Tetrahedron Lett., 1983,24, 1323. 133 J. 0. Amupitan, Synthesis, 1983, 730. lZ6

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

283

7 Nitriles and Isocyanides The dehydration of carboxylic acid amides is prominent among well known procedures for nitrile preparation. Owing to the normally vigorous conditions required for the Von Braun reaction, this method has rarely been used in nitrile synthesis. Use of phosphorus oxychloride in refluxing benzene, however, allows use of this method, enabling a milder synthesis of nitriles from the corresponding t-butylamides. 134 Unsubstituted amides can be similarly dehydrated using phenyl phosphorodichloridite ,135 1,l-dibromotetrachloroethane-triphenylphosphineat - 10°C,136and also oxalyl chloride-DMF-pyridine;137the latter reagent system has been used in the synthesis of glycosyl cyanides, which have also been prepared by Lewis acid-catalysed addition of cyanotrimethylsilane to glucals.138 N-Tosyl-isobutyramide has been converted into the corresponding nitrile in the presence of phosphorus pentachloride at elevated temperatures via elimination of toluene-p-sulphonyl chloride from the intermediate N-sulphonylimino-chloride formed.135)Reaction of this intermediate with lithium azide also resulted in nitrile formation. A high-yield ( S O % ) conversion of carboxylic acids into nitriles is also possible using ammonia and ethyl polyphosphate, which effects both amide formation and dehydration. 14* Aromatic aldehydes may be converted into nitriles via reaction with hydroxylamine hydrochloride, magnesium sulphate , and toluene-p-sulphonic acid in refluxing toluene or xylene141or by using hydroxylamine hydrochloride in conjunction with polyphosphoric acid in acetic acid. 142 Since hydroxylamine results from treatment of nitromethane with polyphosphoric acid, nitromethane may be used instead of hydroxylamine hydrochloride in the latter method. 142 Obviously aldoximes should provide a useful source of nitriles via dehydration. Such transformations have been achieved with trichloroacetyl chloride and triethylamine ,143 1-chlorosulphinyl-4-dimethylaminopyridiniumchloride [thionyl chloride-4-(dimethylamino)pyridine] ,144 cupric acetate monohydrate in refluxing acetonitrile ,145 trimethylsilyl iodide-hexamethyldisilazane ,l4 1,2-dibromotetrachloroethane or hexabromoethane and triphenylphosphine at low temperature, 136 and carbon disulphide-aqueous sodium hydroxide-benzene under phasetransfer conditions with tetra-n-butylammonium bisulphate. 147 Chromone-2carbonitriles too have been synthesized by a method involving aldoxime dehydration. 148 134

135 136 137 13*

139 141

142

145

147

la

R. B. Perri and G. W. Gribble, Org. Prep. Proced. Znt., 1983, 15, 297. C. Chiriac, Rev. Roum. Chem., 1983, 28, 33. G. Bringmann and S . Schneider, Synthesis, 1983, 139. G. Grynkiewicz and J. N. BeMiller, Carbohydr. Res., 1983, 112, 324. F. G . De las Heras, A. S. Felix, and P. Fernandez-Resa, Tetrahedron, 1983,39, 1617. G. L'Abbe, A. Van Asch, and F. Godts, Bull. SOC. Chim. Belg., 1983, 92, 79. T. Imamoto, T. Takaoka, and M. Yokoyama, Synthesis, 1983, 142. I. Ganboa and C. Palomo, Synth. Commun., 1983, 13,219. I. Ganboa and C. Palomo, Synth. Commun., 1983, 13,999. A. Saednya, Synthesis, 1983, 748. A. Arrieta and C. Palomo, Synthesis, 1983,472. 0. Attanasi, P. Palma, and S. Serra-Zanetti, Synthesis, 1983, 741. M. E. Jung and Z . Long-Mei, Tetrahedron Lett., 1983, 24,4533. H. Shinokazi, M. Imaizumi, and M. Tajima, Chem. Lett., 1983,929. P. G. Giattini, E. Morera, and G. Orta, Synthesis, 1983, 311.

General and Synthetic Methods

284

0-Alkyl-4-nitrobenzaldoximeswere found to yield 4-alkoxybenzonitriles on reaction with an excess of sodium hydride in DMF at room temperature.149 Dehydration was followed by substitution of the nitro-group by the alkoxide formed in the dehydration (Scheme 48).

n

R = Me, C H 2 d , C H z P h , CH(Me)CH,Me,

or Et

Reagents: i, NaH, DMF, r.t.

Scheme 48

Unsaturated nitriles have been isolated by trimethylsilyl triflate-catalysed Beckmann rearrangement-fragmentations of cyclic (E)-P (or ,@)-trimethylsilylketoxime acetates. 150 The variation in the position of the trimethylsilyl group allowed direction of the fragmentation in one of two possible modes (Scheme 49). A Beckmann-like fragmentation has also allowed preparation of dinitriles from steroidal a-azidoketoximes (Scheme 50).l5I

R3= H W A C Reagents: i, Me,SiOTf (0.1 equiv.), CH,Cl,, NEt, (0.1 equiv.), aq. NaHCO,

Scheme 49

Ketones may be indirectly converted into nitriles via conversion into the corresponding tertiary chlorides and subsequent treatment with ~yanotrimethylsilane.~~~ The path of the reaction is thought to involve initial isocyanide formation followed by rearrangement. Other S,l-active compounds, e.g. a-chloroethers and anomeric acetates, were also found to react well. Primary nitroalkanes and arylnitromethanes were deoxygenated to give nitriles using i~dotrimethylsilane.~~~ D. Mauleon, R. Granados, and C. Minguillon, J. Org. Chern., 1983,48, 3105. H. Nishiyama, K. Sakuta, N. Osaka, and K. Itoh, Tetrahedron Lett., 1983, 24, 4021. 151 T. T. Takahashi, K. Nomura, and J. Y. Satoh, J. Chern. SOC., Chern. Cornrnun., 1,983, 1441. lJ2 M. T. Reetz, I. Chatzhosifidis, H. Kunzer, and H. Muller-Starke, Tetrahedron, 1983, 39,961. 153 G. A. Olah, S . C. Narang, L. D. Field, and A. P . Fung, J. Org. Chern., 1983,48,2766.

149

150

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

I N2

.

-

4

285

*1

N2NC

H

L IY

OH Reagents: i, POCl,, py or TsCl, py or SOCI,, py

Scheme 50

Amine oxidation has also featured in classical nitrile syntheses and this transformation was recently achieved electrolytically using 2,2,6,6-tetramethylpiperidine N-oxyl, 2,6-lutidine, and a primary amine in a 0.5M solution of lithium perchlorate in acetonitrile. 154 Cyanation of terminal olefins under catalysis by a nickel(0) complex and a Lewis acid (usually aluminium chloride) has been r e ~ 0 r t e d . The l ~ ~ reaction was catalysed by several complexes, and preparation of primary cyanoalkanes from internal olefins was also described. Malononitriles have been prepared by reduction of the corresponding a$unsaturated dinitriles using 2-phenylbenzimidazoline as a source of hydrogen. 156 Arylmalononitriles were prepared from a-lithiated arylacetonitriles by reaction with 2-chlorobenzyl thiocyanate. 157 This particular reagent had the advantage that formation of aryltricyanomethanes was never observed , thus making the reagent far more selective than, for example, cyanogen chloride. Arylmalononitriles may also be prepared in moderate yield directly from aryl iodides and malononitrile anion in the presence of cuprous iodide and hexamethylphosphoric triamide at elevated temperatures (Scheme 51) .I5* Similar conditions permitted reaction of aryl iodides or bromides with cyanoacetate ion to give, after hydrolysis and decarboxylation, arylacetonitriles (Scheme 51) .159, 160 154

l55 I56 lS7 158

Is9

M. F. Semmelhack and C. R. Schmid, J . Am. Chem. SOC., 1983,105,6732. W. Keim, A. Behr, J. P. Bioul, and J. Weisser, Erdol, Kohle, Erdgas, Petrochem., 1982, 35, 436; Chem. Abstr. 1983, 98, 71466. H. Chikashita, S. Nishida, M. Miyazaki, and K. Itoh, Synth. Commun., 1983, 13, 1033. W. A . Davis and M. P. Cava, J . Org. Chem., 1983,48, 2774. H. Suzuki, T. Kobayashi, and A. Osuka, Chem. Lett., 1983, 589. H. Suzuki, T. Kobayashi, Y . Yoshida, and A. Osuka, Chem. Lett., 1983, 193. A. Osuka, T. Kobayashi, and H. Suzuki, Synthesis, 1983,67.

286

General and Synthetic Methods

Reagents: i, NaH (2.2 equiv.), HMPA, H,C(CN), (2 equiv.), CuI (2 equiv.); ii, NaH (2.0 equiv.), HMPA, H,C(CN)CO,Et (2.0 equiv.), CuI (2.0 equiv.); iii, 1.2 M NaOH (aq.)

Scheme 51

Monoalkylations of phenylacetonitrile have been achieved in very high yield with either sodium or potassium hydroxide impregnated alumina161and in lower yield using 60% aqueous potassium hydroxide and poly( ethylene glycol monomethyl ether).162The latter solid support system was also used for allylations of 1-phenyl-1-alkylacetonitriles. Potential antispasmodic and/or anaesthetic N-substituted-4-cyano-4-phenylpiperidines have been synthesized utilizing phase-transfer-catalysed double alkylations of phenylacetonitrile with N-substituted bis-(2-~hloroethyl)amines. 163 Modification of the Sommelet-Hauser rearrangement has enbabled synthesis of

/OMe

p;l&y SMe

C02 Me

Reagents: i , MeONa (excess), MeOH; ii, NaH, NaCN, HMPA; iii, NaH, NaCH(CO,Me),, HMPA; iv, NaH, NaCH(SPh)CO,Et, HMPA

Scheme 52 161 16*

K. Sukata, Bull. Chem. SOC.Jpn., 1983, 56, 3306. Y. Kimura, P. Kirszensztein, and S. L. Regen, J. OrR. Chem., 1983,48,385. D. Thompson and P. C. Reeves, J. Heterocycl. Chem., 1983,20, 771.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

287

an arylacetonitrile with an o-methylthiomethyl substituent (Scheme 52). 164 Although only one example of the reaction leading to arylacetonitrile formation was presented it may find more general applicability. Phase-transfer oxidative coupling of 4-halogenonitriles using sodium hydroxide and benzyltriethylammonium chloride has led to the synthesis of trans-l,2dicyanoethenes and 1,2-di~yanoethanes.~~j Aryl-substituted 1,2-dicyanoethanes have been isolated after conjugate additions of cyanide anion to 3-aryl2-cyanoacrylates. 25 1,n-Dicyano-1,n-diamino-1,n-diarylalkanes, used as precursors in the synthesis of symmetrical diketones, have been prepared by condensation of a-amino-a-arylacetonitrile anions with 1,(n- 2)-dibromoalkanes. The synthesis of a$-unsaturated nitriles has been studied and a stereocontrolled synthesis of 2-methylalk-2-enenitriles accomplished by reaction of C-methyl-C, N-bis(trimethylsily1)ketenimine with aldehydes in the presence of mixtures of titanium tetrachloride and tetraisopropyl orthotitanate. 167 Good Z/E-selectivity was observed when the titanium species were mixed in a 1:3 ratio, with this selectivity completely reversed in some cases when a 1:l ratio of these reagents was employed. The reaction could be effected both by magnesium bromide and by boron trifluoride-diethyl ether but in each case control of stereochemistry was not possible. with carbonyl Reaction of diethyl2-cyano-2-trimethylsilylethanephosphonate has been exploited compounds to give a variety of 2-cyanoalk-2-enephosphonates to give a preparation of 2-cyanobuta-l,3-dienes by further deprotonation and olefination with a second carbonyl component.168The reagent was made by conjugate addition of diethyl trimethylsilyl phosphate to acrylonitrile. Unsaturated nitriles of the general formula H2C= CH(CH,),CN where n>l were found to undergo metathesis under heterogeneous catalysis by Re207-A1203in the presence of either tetramethyl- or tetraethyl-tin as co-catalyst to give chainextended unsaturated dinitriles. 169 Cyanation of heterocycles represents an important area within organic synthesis. Recently modified Reissert-Henze reactions have led to regioselective a-cyanations of pyridine and quinoline N-oxides. Two groups utilized cyanotrimethylsilane in conjunction with either dimethylcarbamyl chloride170or triethylamine in acetonitrile (Scheme 53).171 The affinities of the hard trimethylsilyl group for the N-oxide and the soft cyanide anion for the a-position were used to rationalize the observed regio~electivity.'~~ In the Reissert synthesis of cyanoisoquinolines, the use of 18-crown-6 as a solid-liquid phase-transfer catalyst was shown to minimize formation of pseudobase side products. 172 T.-J. Lee and W. J. Holtz, Tetrahedron Lett., 1983, 24, 2071. V. N. Gogte, A . A . Natu, and V. S. Pandit, Tetrahedron Lett., 1983, 24, 4131. 166 K. Takahashi, M. Matsuzaki, K. Ogura, and H. Iida, J . Org. Chem., 1983,48,1909. 16' H. Okada, I. Matsuda, and Y. Izumi, Chem. Lett., 1983, 97. M. Nakano and Y . Okamoto, Synthesis, 1983,917. 169 G. C . N. van den Aardweg, R. H. A . Bosma, and J. C. Mol., J . Chem. SOC., Chem. Commun., 1983, 262. 170 W. K. Fifwe, J . Org. Chem., 1983,48, 1375. 171 H. Vorbruggen and K. Krolikiewicz, Synthesis, 1983, 316. R. Chenevert, E. Lemieux, and N. Voyer, Synth. Commun., 1983,13,1095.

Iti5

288

General and Synthetic Methods I

R

J$JI 6-

R = H, 2 - M e l 3-Me, 4-Me; 4 examples, 94 -100'1.

R*= H, 2-Me, 3-Me, 4-Me, 3-CNl 3 - W I 3-COzH, 3-CONH2,

11 examples, 66- 90'1.

a-m .. .

I

CN

0-

iv

0CN Reagents: i, Me3SiCN,Me,NCOCl; ii, Me,SiCN, MeCN or Me,SiCl, NaCN, DMF, or Me,SiCN, THF, Bun,N+F-; iii, Me3SiC1 (5 equiv.), NaCN (2 equiv.), DMF; iv, Me3SiCN (3 equiv.), N-methylpyrrolidone

Scheme 53

Cyanosubstitution in the a-position of piperidines has been shown to facilitate both electrophilic and nucleophilic reactions at this centre. 173 Such functionalization was employed in a biomimetic approach towards synthesis of the decahydroquiniline ring system of pumilotoxin (Scheme 54) ,174 in which chromatography of crude (83) afforded (84) via dehydrocyanation, cyclization, dehydration, and 1,4reintroduction of cyanide anion. Five-membered heteroaromatic systems too may be cyanated in the a-position as exemplified by preparation of 2-cyanoergolines by anodic ~ y a n a t i o n 'and ~~ synthesis of 2-cyanofuran by treatment of furan with chlorosulphonyl isocyanate. 176 A. Koskinen and M. Lounasmaa, Tetrahedron, 1983, 39, 1627. M. Bonin, R. Besselievre, D. S. Grierson, and H.-P. I-Iusson, Tetrahedron Lett., 1983, 24, 1493. 175 K. Siefert, S. Hartling, and S . Johne, Tetrahedron Lett., 1983, 24, 2841. 176 A. J. Floyd, R. G. Kinsman, Y . Roshan-Ah, and D. W. Brown, Tetrahedron, 1983, 39, 3881.

173

174

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

Me

289

i, ii

J

Reagents: i, H,, 10% Pd/C; ii, LDA, THF, -3O"C, Cl(CH,),C(Me)

iii

'1 ,

r.t,, 1.5 h , 55%; iii, 1 N 0 ' HCl, MeOH, 1:l; iv, Al,03 (act. 11-111); v, NH,, Na, THF; vi, H'; vii, NaBH,, MeOH or NaBH3CN, THF, pH 4

Scheme 54

A limited number of 2-cyano-3,4-dihydro-2H-l,4-benzoxazines were prepared on treatment of o-aminophenols and 2-chloroacrylonitrile with potassium carbonate in acetone. 17' Some 2-cyanotetrahydrothiophenesres-ulted from addition of 2-t-butylthioacrylonitrile to dienophiles. 178 The use of cyanohydrins and protected cyanohydrins (in addition to a-dialkylaminonitriles) as acyl anion equivalents has become increasingly more important in recent years, and accordingly reactions of these compounds have been reviewed. 179 0-Trimethylsilylcyanohydrins have recently served as a source of acyloins by reaction with Grignard reagents followed by acidic hydrolysis. 180 The versatility of silylated cyanohydrins as synthetic intermediates has been further demonstrated by conversion of (85) into 6-methoxy-1-naphthalenecarbonitrile (87) and its 3,4-dihydro-derivative (86),both of which are potentially useful intermediates for steroid syntheses. lS1 H. Bartsch and 0. Schwarz, J . Heterocycl. Chem., 1983, 20, 45. D. Dopp and H. Libera, Tetrahedron Lett., 1983, 24, 885. 179 J. D. Albright, Tetrahedron, 1983, 39, 3207. 180 L. R. Krepski, S. M. Heilmann, and J. K. Rasmussen, Tetrahedron Lett., 1983, 24, 4075 l 8 I S. A. Jacobs and R. G. Harvey, J . Org. Chem., 1983,48,5134. 17*

General and Synthetic Methods

290

The advent of cyanotrimethylsilane has thus prompted the use of silylated cyanohydrins in synthesis. Furthermore, it has been shown that choice of the correct Lewis acid to catalyse their formation is very important. Zinc iodide often accelerates the reaction and is commonly used although the use of potassium cyanide with 18-crown-6 has recently proved more reliablels2 and applicable to the synthesis of substituted cyanohydrins in general.ls3 The demonstration that acetals react with cyanotrimethylsilane (Scheme 55)lW obviously widens the applicability of the reagent. Furthermore, pentane2(R),4(R)-diol-derived acetals reacted with cyanotrimethylsilane in the presence of titanium tetrachloride to give cyanohydrin ethers in a highly diastereoselective fashion (Scheme 55). Thus syntheses of cyanohydrins, a-amino-alcohols, and fl-hydroxy-esters in greater than 90% optical purity were facilitated.

R I

Me HO

;I

Me

Reagents: i, Me,SiCN, TiC14

Scheme 55

Orthoesters and cyanotrimethylsilane plus catalytic quantities of stannous chloride or boron trifluoride etherate afforded 2,2-dialkoxyalkanenitriles. ls6 Some racemic cyanohydrins were (partially) resolved in the presence of brucine,ls7 although addition of brucine and HCN to the corresponding carbonyl compounds failed to produce optically active cyanohydrins. (E)-2-(l-Hydroxyalkyl)alk-2-enenitrileshave been prepared from the corresponding vinyl anions, produced by fluoride ion-induced desilyation of (E)2-trimethylsilylalk-2-enenitriles, in the presence of carbonyl compounds. ls8 The silyl compounds were in turn synthesized from aldehydes and N,C,Ctris(trimethylsily1)ketenimine (Scheme 56). W. J. Greenlee and D. G. Hangauer, Tetrahedron Lett., 1983, 24,4559. R. Chenevert, R. Plante, and N. Voyer, Synth. Commun., 1983, 13, 403. S. Kirchenmeyer, A. Mertens, M. Arvanaghi, and G. A. Olah, Synthesiss,1983, 498. J. D. Elliot, V. M. F. Choi, and W . S . Johnson, J . Org. Chem., 1983,48,2294. K. Utimoto, Y. Wakabayashi, T. Horiie, M. Inoue, Y . Shishiyama, M. Obayashi, and H. Nozaki, Tetrahedron, 1983, 39,961. ls7 F. Toda and K. Tanaka, Chem. Lett., 1983,661. lSa Y. Sat0 and K. Hitomi, J . Chem. SOC., Chem. Commun., 1983,170.

la

la3

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

29 1

OH R' = n-C7H15, EtBu"CH, cyclo- C6Hll or Ph R 2 = M e or Ph R3= H or M e Reagents: i, (Me,Si),C =C =NSiMe,, BF,,OEt,, C,H,; ii, Bun,N+F-; iii, R2R3C0

Scheme 56

Alkyloxy- and aryloxy-2-phenylpropenonitrileshave been prepared and their electrochemisty has been studied. lg9 These compounds underwent carbonoxygen bond cleavage rather than cathodic coupling. Derivatives of 2-hydroxyacrylonitrile have been used to prepare cyclopropyl cyanohydrins on reaction with diazo-compounds or carbenes (Scheme 57) .190 Both acetyl- and trimethylsilyl-cyclopropyl cyanohydrins could be hydrolysed to the parent compounds. CN

Reagents: i, Photolysis; ii, CuS04, Et,O (dark)

Scheme 57

A method for the stereoselective cis-cyanohydroxylation of olefins has been reported. 191 The method involves dipolar [3+2] cycloadditions of ethoxycarbonylformonitrile oxide to olefins followed by decarboxylative ring fragmentation of the resultant 3-carboxyisoxazolines (Scheme 58). The reagent was prepared by base treatment of ethyl chloro-oximidoacetate, in turn prepared by nitrosation of glycine ethyl ester hydrochloride. A related fragmentation of isoxazoles is discussed below. Reaction of thiiranes with cyanotrimethylsilane in the presence of aluminium chloride has been shown to give regioselective ring opening to 2-thioalkylnitriles. 192 However , reaction of 2-methylthiirane was complicated by the formation of trimethylsilyl isothiocyanate and 4-methylthietanone (Scheme 59). 3-Oxoalkanenitriles have been prepared in good yield in a single-step synthesis involving metallation of cyanoacetic acid with excess butyl-lithium and reaction with acid chlorides.193 18y

191

ly2

lY3

M. Cariou, G. Mabon, G. le Guillanton, and J. Simonet, Tetrahedron, 1983,39, 1551. A. Okum T.-a. Yokoyama, and T. Harada, J . Org. Chem., 1983,48,5333. A. P. Kozikowski and M. Adamczyk, J . Org. Chem., 1983,48, 366. M. Taddei, A. Papioni, M. Fiorenza, and A . Ricci, Tetrahedron Lett., 1983, 24, 2311. J. C. Krauss, T. L. Cupps, D. S . Wise, and L. B. Townsend, Synthesis, 1983,308.

General and Synthetic Methods

292

CL

I

Et 02C-C=NOH

+

- Rfo

-

. .. I II

R2*’

CN

Reagents: i, Na2C03(as.), Et,O; ii, Et,N, EtO,; iii, 10% NaOH (aq.)

Scheme 58

+

+

Me3SiNCS

4

li M e T C N SH Reagents: i, Me,SiCN (1 equiv.), A1Cl3 (0.1 equiv.); ii, MeOH, CC1,

Scheme 59

The formation of isoxazoles by reaction of hydroxylamine hydrochloride with p-amino-a,p-unsaturated ketones and diketones followed by reduction with sodium in methanol has afforded good yields of 2-cyanoketones and 2-cyano-l,3diketones respectively (Scheme 60) .194

R * = acyl Reagents: i, H2NOH-HC1,MeOH; ii, Na, MeOH, Et,O

Scheme 60 ‘9,

G. Menozzi, P. Schenone, and L. Mosti, J . Heterocycl. Chem., 1983,20,645.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

293

Conjugate addition of lithiophenylsulphonylacetonitrileto cycloalkenones was successfully achieved and this provided, after reductive desulphurization, cyanomethylcycloalkanes. 195 y-0x0-a,P-unsaturated nitriles have been prepared via the corresponding y-hydroxy-compounds. lg6 Alkyl cyanides were metallated with lithium di-isopropylamide and treated with a-chloroketones and hexamethylphosphoric triamide. Hydrolysis of the resultant epoxides to rearranged allylic alcohols and oxidation gave the desired enones. Acyl cyanides have also featured as important intermediates in a number of synthetic procedures. a#-Unsaturated acyl cyanides, prepared via reaction of acyl halides with cuprous cyanide in acetonitrile, have been used as substrates for the preparation of 3-alkynylacyl cyanides by conjugate addition of 1-trimethylsilylalkynes in the presence of titanium tetrachloride. 197 In some cases 2-cyano-4H-pyrans, resulting from subsequent cyclization, were observed. 3-Vinyl-6-cyan0-3~4-dihydr0-2H-pyran-2-oneswere observed after trialkylamine-mediated self-condensation of ethylenic acyl cyanides.198The corresponding 2-pyranones were isolated when the self-condensation was effected with catalytic amounts of potassium fluoride. Aroyl cyanides have been prepared from the corresponding halides by reaction with either cyanotrimethylsilane and tin tetrachloride in dichl~romethane'~~ or potassium cyanide in acetonitrile under ultrasonification conditions.200 An interesting report of a photochemically induced radical cyclization of cr-bromoacetals derived from cycloalk-3-en-1-01shas appeared.2o1The cyclized radical species was trapped with t-butyl isocyanide with ejection of the stable t-butyl radical (Scheme 61). OEt

I

H Reagents: i, Ph,SnSnPh,, :C =NBu', degassed C6H,. hv

Scheme 61

Hexabromoethane and 1,2-dibromotetrachloroethane with triphenylphosphine in the presence of base have both been employed in the preparation of isocyanides from N-formyl- and N-thioformyl-protected primary a m i n e ~ . ' ~ ~ E. Hatzigrigoriu and L. Wartski, Synth. Contmun., 1983, 13, 319. M. Larcheveque, P. Perriot, and Y. Petit, Synthesis, 1983, 297. Ig7 A. Jellal, J.-P. Zahra, and M. Santelli, Tetrahedron Lett., 1983, 24, 1395. 19R A. Jellal and M. Santelli, Tetrahedron Lett., 1983, 24, 2847. 199 G. A. Olah, M. Arvanaghi, and G. K. Surya Prakash, Synthesis, 1983, 636. T. Ando, T. Kawate, J. Yamawaki, and T. Hanafusa, Synthesis, 1983, 637. w1 G. Stork and M. P. Sher, J . Am. Chem. Soc., 1983,105,6765.

195

294

General and Synthetic Methods

2-Hydroxycyclohexyl isocyanide has also been isolated in the reaction of cyclohexene epoxide with cyanotrimethylsilane and trace amounts of zinc chloride in chloroform.202This observation is contrary to results obtained when the reagent was used in the presence of an aluminium catalyst, again demonstrating that variation of the catalyst can greatly modify the reactivity of cyanotrimethylsilane. 13CN.m.r. spectroscopy has been used to study the deoxygenation of isocyanates to isocyanides using t-butyldimethylsilyl-lithium.203With cyclohexyl isocyanate the reaction was shown to proceed via the intermediates (88) and (89). It was

found also that the anion formed in situ from trichlorosilane and triethylamine in dichloromethane also effected the deoxygenation, as well as the preparation of isocyanides from both carbamates and phenyl isothiocyanate. 8 Nitro- and Nitroso-compounds Although methods for the reduction of aromatic nitro-compounds are numerous, few reagents capable of effecting the reverse transformation have been documented. Of these peracids or hydrogen peroxide in the presence of a strong acid are the most commonly used. However, a recent study has indicated that sodium perborate in acetic acid can be an equally effective reagent for the oxidation of anilines to the corresponding nitro compounds.204Electron-deficient anilines were oxidized very smoothly, although side products arising from over-oxidation were observed in oxidations of anilines with an electron-donating substituent. The reagent also effected oxidation of sulphides to either sulphoxides or sulphones. Oxidation of both amino- and sulphide groups can thus be carried out simultaneously, e.g. (90)+ (91).

SMe

The nitric acid-tin tetrachloride complex has been added to the list of reagents effecting nitration of aromatic nuclei.205High yields of nitration products were obtained in dichloromethane, although in the case of anisole 2,6-bis202 203 205

G. 0. Spessard, A. R. Ritter, D. M. Johnson, and A. M. Montgomery, Tetrahedron Lett., 1983,24, 655. J. E. Baldwin, A. E. Derome, and P. D. Riordan, Tetrahedron, 1983,39,2989. A. McKillop and J. A. Tarbin, Tetrahedron Lett., 1983, 24, 1505. J. Einhorn, S. 'H. Desportes, P. Demerseman, and R. Royer, J . Chem. Res. (S), 1983,98.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

295

(4-methoxyphenyl)-l,4-benzoquinonewas produced in an unprecedented reaction. Selective mononitration of polycyclic aromatic hydrocarbons with dinitrogen tetroxide in dichloromethane has also been reported.206In some cases this reaction was subject to catalysis with methanesulphonic acid. The possibility of nitrophenol synthesis by treatment of halogenonitrobenzenes or nitroanilines with aqueous base has been studied and accomplished although the reported yields varied considerably.207 The preparation of 4-nitro3-oxobutyrate has been described2OSand also its use in cyclo-condensations to form highly substituted s a l i c y l a t e ~ . ~ ~ ~ ~ ~ ~ ~ Substituted 2-hydroxybenzaldehydes have been used in the synthesis of a number of nitro-substituted heterocyclic systems. Reactions with nitrostyrenes in the presence of base afforded 2-ary1-3-nitr0-2H-chromenes;~~~ condensations, in refluxing toluene, with methyl nitroacetate in the presence of either n-propylammonium chloride or diethylammonium chloride gave rise to 3-nitrocoumarins (Scheme 62).211 H

Reagents: i, ArCH =CHNO,, NEt,; ii, O,NCH,CO,Me, PrnNH3+C1- or Et,NH,+ C1-

Scheme 62

Nitrations of the aromatic heterocycles 1,3-dimethyluracil, l-methyl2-pyridone, and thiophene with sodium nitrite and palladium(I1) acetate were achieved in moderate yield212and 2-arylindoles were nitrated using 2-cyano2-propyl nitrate, potassium hydroxide, and 18-crown-6 in a ~ e t o n i t r i l e .The ~~~ latter reaction carried out at higher temperatures afforded hydroxyimino-compounds via nitrosation. The intermediacy of nitrated products in the latter reactions was discounted since 3-nitro-2-phenylindole afforded N-nitroso-3-nitro2-phenylindole under the high-temperature conditions. A novel nitroethylation of indole using in situ generated nitroethylene has been reported.214The nitro-olefin was produced by heating a benzene solution of 2-nitroethyl phenyl sulphoxide, which underwent a concerted intramolecular fragmentation. The reagent was simply prepared by treatment of 2-nitroethyl phenyl sulphide with PhIO,! in benzene-trifluoroacetic acid. The nitro-olefin was 206 207 208 ,09

210 211

212 213

*I4

F. Radner, Acta Chem. Scand., Ser. B., 1983, 37, 65. J. S. Anderson and K. C. Brown, Synth. Commun., 1983, 13, 233. R. 0. Duthaler, Helv. Chim. Acta, 1983, 66, 1475. R. 0. Duthaler, Helv. Chim. Acra, 1983,66,2543. S . R. Deshpande, H. H. Mathur, and G . K. Trivedi, Zndian J. Chem., Sect. B, 1983,22,166. D. Dauzonne and R. Royer, Synthesis, 1983, 836. T. Itahara, R. Ebihara, and K. Kawasaki, Bull. Chem. SOC.Jpn., 1983, 56,2171. A. Gonzales and C. Galvez, Synthesis, 1983, 212. D. Ranganathan, S. Ranganathan, S. Bamezai, S. Mehrotra, and P. V. Ramachandran, J. Chem. Res. ( S ) , 1983, 78.

General and Synthetic Methods

296

used as a Diels-Alder dienophile as well as for nitroethylation of other heterocycles. The spectrum of potential biological activities of A-ring modified oestrone derivatives has prompted studies concerning the nitration of this steroid. Classical procedures exhibited little or no regioselectivity in nitration, but recently claysupported ferric nitrate2I5and the use of boron trifluoride-diethyl ether-mediated formation of nitronium ion from N-nitropyrazole216have both allowed isolation of 2-nitro-oesterone, in 55 % and 40-45 % yields respectively, as the exclusive nitration product of oestrone. In a related report, nitration of N-(6-methoxy-1,2,3,4tetrahydronaphthalen-1-yl)methylpropanamide,prepared from the cyanohydrin (85),yielded not only the expected 5- and 7-nitro-substituted compounds but also the novel tricyclic compound (92) resulting from ‘ipso’ nitration.217 0

The anodic nitration of olefins to give conjugated nitroalkenes has been described218 and the preparation of 3,6-dinitrocholesta-3,5-dienefrom 3,8-acetoxy-6-nitrocholest-5-ene by more conventional techniques reported.219

2’-Nitroprop-2’-en-l’-yl 2,2-dimethylpropanoate (93) has been prepared and used as a nitroallylating reagent.220The reagent reacted with a variety of heteroatomic nucleophiles (e.g. amines and thiols) as well as carbanions (enolates, 2-lithio-l,3-dithianes, and aryl-lithiums). (93) also reacted with heterocycles, e.g. thiophene (3-position), indole (3-position), N-methylindole (3-position), and N-t-butoxycarbonylindole (2-position). The resultant nitroallylated products were themselves versatile synthetic intermediates capable of reaction as DielsAlder dienophiles and as substrates for further nucleophilic additions (Scheme 63). Low-yield radical nitromethylations of alkenes via the generation of nitromethyl radicals by oxidative deprotonation of nitromethane using manganese(m) acetate either with or without cupric acetate have been described.”l Reactions were complicated by formation of side products. The power of 1-nitroalkenes as Michael acceptors has been aptly demonstrated with the preparation of trimethyl( 1-nitromethylalky1)silanes by addition- of i. e. introduction of a nitroorganometallics to trimethy1(2-nitrovinyl)~ilane,~~~ 215 216 217

218

219 220 221

222

A . Cornelis, P. Laszlo, and P. Pennetreau, J . Org. Chem., 1983, 48, 4771. E. Santaniello, M. Ravasi, and P. Ferraboschi, J . Org. Chem., 1983,48,739. N. R. A. Beeley, G. Cremner, A . Dorlhene, B. Mompon, C. Pascard, and E. Tran Huu Dau, J . Chem. Soc., Chern. Commun., 1983,1046. A. Kunai, Y. Yanagi, and K. Sasaki, Tetrahedron Lett., 1983, 24, 4443. S. Ullah and S. Husain, J . Chem. Res. ( S ) , 1983, 255. D . Seebach and P. Knochel, Helv. Chim. Acta, 1983,66,261. M. E. Kurz, L. Reif, and T. Tantratrat, J . Org. Chem., 1983, 48, 1373. T. Hayama, S. Tomoda, Y . Takeuchi, and Y. Nomura, Tetrahedron Lett., 1983,24,2795.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

297

/ kene

(931

Scheme 63

group reversed the polarity of the normal vinylsilane reactivity. The nitrovinylsilane was prepared by a nitroselenenylation-oxidation sequence carried out on trimethylvinylsilane. The nitroethene Michael acceptor (94) was used in a short synthesis of (-)-PGE1 from the chiral cyclopenanoid (95) and the organocuprate derived from the iodide (96), the enolate anion resulting from the conjugate addition in turn adding to (94) to give the prostaglandin after trin-butyltin hydride denitration of the adduct (97) followed by standard deprotecti on^.^^^ 0

v NO2 C

O

z

M

Q

e

TBDMSO’ ( 94)

(95)

IUUM3U

(96)

H

H

OTBDMS

(97)

1,4-Hydride transfer by sodium borohydride to nitroalkenes has been an important method for the synthesis of nitroalkanes, although the reduction, especially of 2-aryl-l-nitroalkenes, has always been complicated by the formation of dimers. However, performance of the reaction in the presence of silica gel has led to the rapid high-yield isolation of nitroalkanes without the formation of dimeric products. 224 223 224

T. Tanaka, T . Toru, N. Okamura, A . Hazato, S . Sugiura, K . Manabe, S . Kurozumi, M. Suzuki, T. Kawagishi, and R. Noyori, Tetrahedron Lett., 1983,24, 4103. A . K. Sinhababu and R. T. Borchardt, Tetrahedron Lett., 1983,24, 227.

298

General and Synthetic Methods

C-Alkylation of nitroalkanes has been achieved with potassium fluoride and tetra-n-butylammonium chloride under reflux conditions,225and C-hydroxyalkylations in nitroaldol (Henry) reactions have been accomplished on alumina in the absence of solvent.226 Oxidations of nitroaldols with chromium reagents in strongly acid media have previously suffered in as much as yields were often poor (owing to possible retroaldol and/or elimination reactions). Use of pyridinium chlorochromate with 3 8, molecular sieves, however, significantly improved this situation since the desired oxidations could be carried out efficiently under mild conditions.227 Although at least three methods for the synthesis of cyclic a-nitroketones exist, no really satisfactory method for the synthesis of 2-alkyl-2-nitrocyclohexanes had been established until the recent report of nitration of 2-alkylcycloalkane enol acetates using trifluoroacetyl nitrate.22RThe reagent, a much more powerful nitrating agent than acetyl nitrate, was prepared in situ by addition of ammonium nitrate to trifluoroacetic anhydride. Nitrations of N , N-dialkylcarboxylic acid amides at the active methylene group have been achieved in high yield via enolate formation and subsequent reaction with n-propyl nitrate.22y Anions of a-nitrocycloalkanones were shown to be capable of 1,4-addition to Michael acceptors, and the resultant 2-alkyl-2-nitrocycloalkanes could be fragmented to yield open-chain derivatives upon reaction with a n u ~ l e o p h i l eUse .~~~ of non-nucleophilic bases led to ring expansion (carbon-zip reaction) to provide an entry into medium-sized cyclic nitrodiketones, although mixtures of products were observed in 2-[1-(3-oxobutyl)]-2-nitrocycloalkanone fragmentations. However, Michael adducts from 2-nitrocycloalkanones and 3-oxopent-4-enoates gave good yields of ring-expanded (by four carbon atoms) nitrodiketone-esters (Scheme 64).231Bicyclic products and nitroalcohols were observed when the latter reactions were carried out in the presence of triphenylphosphine. It was also demonstrated that deprotonation of nitroalkanes facilitated preparation of a, adinitro-compounds, a-nitrosulphones, and a-nitronitriles by reactions with nitrite, benzenesulphinate, and cyanide ions respectively, in the presence of potassium ferricyanide, which acts as an oxidant (cf. Agl) (Scheme 65).232 The synthesis of 1-deoxy-1-nitroaldoses by ozonolysis of N-glycosylnitrones has been achieved233and the anomeric effect of the nitro-group studied.234Nitroenamine synthesis has been discussed a b o ~ e . ~The ~ , * synthesis ~ of furazan N-oxides via addition of dinitrogen trioxide to olefins followed by dehydration of the nitronitroso-adducts so formed has been Retro-Diels-Alder reac225 z26

2i7 22R

22y

230 231 232 233 234

B. Renger, Arch. Pharm. (Weinheim, Ger.), 1983, 316, 193. G. Rosini, R. Ballini, and P. Sorrenti, Synthesis, 1983, 1014. G. Rosini and R. Ballini, Synthesis, 1983, 543. P. Dampawan and W. W. Zajac, Jr., Synthesis, 1983, 545. H. Feuer, C. S. Panda. L. Hou, and H. S. Bevinakatti, Synthesis, 1983, 187. W. Huggenberg and M. Hesse, Helv. Chim. Acta, 1983,66, 1519. Y . Nakashita and M. Hesse, Helv. Chim. Acta, 1983, 66, 845. N. Kornblum, H. K. Singh, and W. J. Kelly, J . Org. Chem., 1983, 48, 332. B. Aebischer and A . Vasclla, Helv. Chim. Acta, 1983, 66, 789. B. Aebischer, R. Hollenstein, and A. Vasella, Helv. Chim. Acta, 1983, 66, 1748. J. F. Barnes, M. J. Barrow, M. M. Harding, R . M. Paton, A. Sillitoe, P. L. Ashcroft, R. Bradbury, J. Crosby, C. J. Joyce, D. R . Holmes, and J. Milner, J . Chem. SOC., Perkin Trans. 1 , 1983, 293.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

299

0

n

= 4,5,6

or10

No2

n = 5,6 or 10

Reagents: i, MeCOCH =CH,, THF; ii, NaOMe, MeOH; iii, Bu,NF (cat.); iv, Bu,NF (2.1 equiv.); v, H,C =CHCOCH,Me, Ph,P

Scheme 64

tions of fused oxazines have proved useful for the generation of nitroso-olefins, which can be trapped in situ by, inter alia, indoles.236 N-Nitroso-compounds have been the subject of many chemical studies owing to their significance as chemical pollutants. It has been shown that tertiary and secondary amines can be nitrosated in moderate yield by Fremy's salt in basic R' R2

C-

NO;!

I

> R'

R?A)C-

A =NO;!,CN

NO* or PhSO;!

Reagents: 1, A - , K,Fe(CN),

Scheme 65 236

D. E. Davies and T. L. Gilchrist, J . Chem. SOC., Perkin Trans. I , 1983, 1479.

300

General and Synthetic Methods

media.237These conditions are milder than the previously reported nitrosations in acidic media. Formation of nitrosamines by alkylation of d i a z o t a t e ~and ~~~ steroelectronic effects in tertiary amine n i t r o ~ a t i o nhave ~ ~ ~been studied. and the mechanisms Syntheses of novel N-nitrosoureas have been carried of their formation240plus their conformations in non-polar studied by 15Nand 13Cn.m.r. spectroscopic examination of specifically labelled compounds. 2-Cyanothionitrosobenzenes have been observed as transient species in thermolyses and pyrolyses of 3-azido-2, l-benzis~thiazoles.~~~ Their existence was demonstrated by trapping them as Diels-Alder adducts. 9 Hydrazines

1,l-Disubstituted ureas, which are available from secondary amines by a variety of methods, have proven to be convenient precursors for 1,l-disubstituted h y d r a z i n e ~ .Providing ~~~ the ureas do not contain functionality sensitive to the oxidative reaction conditions good yields of hydrazines can be obtained by Hofmann rearrangement on treatment with sodium hydroxide. can be conveniently prepared by reaction of Pure 1-alkyl-1-phenylhydrazines 1-phenylhydrazine with a slight excess of sodamide in THF and allowing the resdtant anion to react in situ with an alkyl halide.244 The reactivity of N , N-dimethylaminomethylene derivatives (98) of P-ketoesters containing an alkenyl substituent with phenylhydrazine can be controlled (99).245 to provide either alkenylpyrazoles or 4-0~0-1,4,5,6-tetrahydropyridines

10 Hydroxylamines and Hydroxamic Acids Improved oxidations of secondary amines to the corresponding N-substituted hydroxylamines using either disodium hydrogen phosphate or a cross-linked 4-vinylpyridine copolymer as an auxiliary base have been reported.26 Yields of the hydroxylamine products were further improved by hydrolysis of the inter237

L.Castedo, R . Riguera, and M. Pilar Vazquez, J . Chem. SOC., Chem. Commun., 1983,301.

238

C. S. Cooper, A. L. Peyton, and R. J. Weinkam, J. Org. Chem., 1983,48, 4116. R. N. Loeppky and W. Tomasik, J . Org. Chem., 1983,38, 1751. J. W. Lown and S. M. S. Chauhan, J. Org. Chem., 1983,48, 507. J. W. Lown and S. M. S. Chauhan, J. Org. Chem., 1983,48,513. M. F. Joucla and C. W. Rees, J. Chem. SOC., Chem. Commun., 1983,374. Y. Murakami, Y. Yokoyama, C. Sasakura, and M. Tamagawa, Chem. Pharm,. Bull., 1983,31,423. U. Lerch and J. Konig, Synthesis, 1983, 157. S. Gelin and C. Deshayes, Synthesis, 1983, 566. A. J. Bilsski and B. Ganem, Synthesis, 1983, 537.

239

240 241

242 243 244 245 246

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

301

mediate 0-benzoylhydroxylamines with anhydrous potassium methoxide in methanol (Scheme 66).

R = CH2Ph

or Bun

A

i or ii

+

XAN-0

1

Ph

iii

X = CH2 or 0

A

xuN-oH Reagents: i, Poly-(4-~inylpyridine),THF, (PhCO,),; ii, Na2HP04,THF, (PhC02)*,Et,O; iii, KOMe, MeOH, Et,O

Scheme 66

0-Alkyl-N, N-dialkylhydroxylamines have been obtained in a novel bimolecular reduction of isoxazolidinium salts with lithium aluminium hydride .247 Oxime dianions are versatile synthetic intermediates, and a recent investigation of their reaction with imines has increased this versatility since a number of 2-hydroxylaminoazetidines were prepared in good yield.248 N, N-Diarylhydroxylamines are known to be readily oxidized to diarylnitroxyls , and these radicals have recently been synthesized by formation of the hydroxylamines by reaction of pentyl nitrite with an excess of an aryl Grignard reagent.249 N, N-Dialkylpropane- (and benzene-) sulphenamides have been prepared by treatment of the corresponding symmetrical disulphides with dialkylamide anions in THF.250 High yields of hydroxamic acids may be obtained by desilylation of adducts formed after additions of N, N, 0-tris(trimethylsily1)hydroxylamine to acid chlorides. 251

11 Imines, Iminium Salts, and Related Compounds Much of recent imine chemistry has resulted from their importance as synthetic intermediates. The Schmidt reaction has been applied to tertiary alcohols from A. Liquori, G. Sindona, and N. Uccella, Tetrahedron, 1983, 39, 683. M. Bellassoued, R. Chtara, F. Darzoide, and M. Gaudemar, Synthesis, 1983, 951 249 C . Berti, Synthesis, 1983, 793. 2M H. Ikehira and S. Tanimoto, Synthesis, 1983,716. 251 W. Ando and H. Tsumaki, Synth. Commun., 1983, 13,1053. 247

248

302

General and Synthetic Methoh

the indane series and 2-substituted dihydroquinolines have been prepared.252It has also been demonstrated that primary aminoalkenes of the type H2C=CH(CH2),NH2(n=3 or 4) can be cyclized to pyrrolines and piperidines under the conditions of the Wacker oxidation.253Aminoalkenes with secondary or tertiary amino-groups yield cyclic enamines and aminoketones respectively under the same conditions. 4-Azahomoadamant-4-ene was prepared by acid treatment of 3-endoazidomethylbicyclo[3.3.l]non-6-eneand by treatment of 3-endo-hydroxymethylbicyclo[3.3.l]non-6-ene with sodium azide and methanesulphonic 4-Azahomo-adamant-3-ene and 4-aza-4-homo-brend-3-enes have been synthesized via use of intramolecular aza-Wittig reactions, and the reactive bridgehead imines trapped as alcohol a d d u ~ t sSimilarly . ~ ~ ~ bicyclic a-amino-ethers have been prepared by trapping the bridgehead imine 2-azabicyclo[3.2.l]oct-l-ene,prepared by photochemical ring expansion of l-azidobicyclo[2.2.1]heptane,in Azadienes have been used extensively in Diels-Alder syntheses, and this topic has been reviewed.257More recently 2-azabuta-l,3-dienes have been made and used in a new three-step N-heterocyclic a n n ~ l a t i o nleading , ~ ~ ~ ultimately to the preparation of 3,4-dihydro-2-quinolines. l-Aryl-Zaza-1,3-dienes were prepared by rhodium(1)-catalysed isomerization of N-allylimines,259 and l-amino2-azabutadienes were formed in a novel acid decomposition of 5-amino-1-vinyl4,Sdihydro- 1H-1,2,3-triazoles .260 Dimethyl 5-(3-N-phenyliminoprop- 1-enyl)furan-2,3-dicarboxylate was isolated after cycloaddition of N-phenylbetaine to dimethyl acetylenedicarboxylate.261 a-Di-imines (plus a-iminoketones and a-aminopropionamidines) have been prepared by oxidative alkyl and arylaminomercurations of prop-2-ynyl alcohols. 262 Imines may also serve as dienophiles in hetero-Diels-Alder cycloadditions, and the acylated imine (101) was postulated to be the reactive intermediate in the thermolysis of (100) to the bicycliclactam (102). This reaction formed the key step in a synthesis of epi-lupinine (103) (Scheme 67).263 The demonstration that non-enolizable aldehydes reacted with lithium hexamethyldisilazide to give N-trimethylsilylaldimines at ambient temperatures has been discussed above in connection with a reductive alkylation-amination-type synthesis of a-substituted benzylamines from the corresponding aldehydes (see Section 1, ref. 24). G . Adam, J. Andrieux, and M. M. Plat, Tetrahedron Lett., 1983, 24, 3609. B. Pugin and L. M. Venanzi, J. Org. Chem., 1983,48,6877. 254 T. Sasaki, S. Eguchi, N. Toi, T. Okano, and Y. Furukawa, J. Chem. SOC., Perkin Trans. 1, 1983, 2529. 255 T. Sasaki, S. Eguchi, andT. Okano, J. Am. Chem. SOC., 1983, 105,5912. 2% R. S. Sheridan and G. A. Ganzer, J. Am. Chem. SOC., 1983, 105, 6158. 257 D. L. Boger, Tetrahedron, 1983, 39,2869. 258 C. K. Govindan and G. Taylor, J. Org. Chem., 1983, 48, 5348. 259 R. Grigg and P. J. Stevenson, Synthesis, 1983,1009. Z60 M. M. Ito, Y. Nomura, Y. Takeuchi, and S. Tomoda, Bull. Chem. Sac. Jpn., 1983,56,641. 261 G. Ferguson, K. J. Fisher, B. E. Ibrahim, C. Y. Ishag, G. M. Iksander, A. R. Katritzky, and M. Parvez, J. Chem. SOC., Chem. Commun., 1983,1216. 262 J. Barluenga, F. Aznar, and R. Liz, J. Chem. SOC., Perkin Trans. 1, 1983, 1093. 263 M. L. Bremmer, N. A. Khatri, and S. M. Weinreb, J. Org. Chem., 1983,48,3661.

252

253

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

f0B" (100)

,"""1 (101)

303

,Oh

H.

f

(102)

(10 3)

Reagents: i, 1,2-C1,C6H,; ii, H,, Pd/C, MeOH; iii, BH3,THF, A Scheme 67

Synthesis of imines of a,P-acetylenic ketones has also been studied.264 Phosphine imines have been prepared from amines by sequential additions of triphenylphosphine, triethylamine, and hexachloroethane; vinyl-substituted phosphine imines prepared in this way have been used to synthesize 2-iminotetrahydrof~rans.~~~ The isolation of P-phosphoranylideneamino-a#ethylene ketones following treatment of isoxazoles with triphenylphosphine has been reported.266 Oxime sulphonates have proved to be extremely useful precursors to a number of classes of compound, and it has been shown that they may be reacted with dialkylaluminium thiolates or selenolates to give iminothioethers and iminoselenoethers r e s p e ~ t i v e l y .A ~ ~similar reaction with cyanotrimethylsilane and diethylaluminium chloride afforded iminonitriles .38 Reports of O-alkylcaprolactim preparation from cyclic amides via imidoyl chlorides267and iminothioether synthesis from thioamides using trialkyloxonium fluoroborates268,269 have also appeared. a-Sulphenylated aldimines have been prepared from the corresponding a-halogenoaldimines and t h i o l ~ . ~ ~ ~ The preparation of tritylsulphenimines from carbonyl compounds and triphenylmethanesulphenamide, pyridinium toluene-p-sulphonate, and magnesium sulphate in dichloromethane was studied and their lithiated derivatives were found to undergo temperature-dependent alkylations, C-alkylation occurring at -78°C and N-alkylation being observed at -20"C.271Reactions with carbony1 compounds followed by facile hydrolytic cleavage of the resulting hydroxyalkyltritylsulphenimines afforded products equivalent to those that would be obtained from 'directed-aldol' reactions (Scheme 68). Highly regioselective deprotonations of acyclic ketimines, which allowed electrophilic substitution at either structurally or stereochemically isomeric positions, were also described.272

264

265

266 267

268 269

270 271

27z

P. Margaretha, C. Schroder, S. Wolff, and W. C. Agosta. J . Org. Chem., 1983,48, 1925. €I. Wamhoff, G . Haffmanns, and H. Schmidt, Chem. Ber., 1983, 116, 1691. T. L. Lemke and K. N. Selway, J . Heterocycl. Chem., 1983,20,899. J. Jurczak, T . Kozluk, W. Kulicki, M. Pietraszkiewcz, and J. Szymanski, Synthesis, 1983, 382. T. Kaneko, H. Wong, andT. W. Doyle, Tetrahedron Lett., 1983,24, 5165. M. A. Casadei, B. Di Rienzo, and F. M. Moracci, Synth. Commun., 1983,13,753. N. De Kimpe, R. Verhe, L. De Buyck, and N. Schamp, Synthesis, 1983,632. B. P. Branchaud, J . Org. Chem., 1983,48,3531. J. K. Smith, M. Newcomb, D. E. Bergbreiter, D. R. Williams, and A. I. Meyers, Tetrahedron Lett., 1983, 24, 3559.

General and Synthetic Methods

304

NSTr Tr+,

R

*'+R Me

R*

NSTr

NSTr

0

OH

R'+

R5

R+ 5 exampies, 72-89'1.

Reagents: i, BusLi, THF, then MeI, -78°C; ii, Bu*Li,THF, then MeI, -20°C; iii, LDA, THF, NH,Cl, H,O; iv, BuSLior LDA, THF; v, R4R5CO;vi, AgN03

Scheme 68

Alkyldiphenylsulphonium salts have been used to achieve O-alkylation of amides and ureas with high yields of iminium salts produced from dimethylformamide and dimethylacetamide in particular.273 The photochemistry of iminium salts and related hereroaromatic systems has been reviewed,274and the possibility of forming C-vinylazomethine ylides via a sequential electron-transfer-desilylation pathway examined.275 Caesium fluoride-induced desilylations of iminium salts derived from amides, thioamides, and vinylogous amides have led to the formation of reactive azomethine y l i d e ~A. ~range ~ ~ of substituents that allow thermal 1,3-dipole formation from imines has also been identified.277 Use of a cationic aza-Cope (2-azonia-[3,3]-sigmatropic) rearrangement of iminium salts was reported in a ring-expansion-pyrrolidine annulation reaction of cyclopentane-derived a m i n o - a l c ~ h o l s . ~ ~ ~

12 Oximes Oximes can be obtained in good yields from nitro-compounds after activation with N,N-dimethylchloromethyleniminium chloride and then treatment with a Grignard reagent (Scheme 69)279or from nitroalkenes by electrochemical reducM. Julia and H. Mestdagh, Tetrahedron, 1983, 39,433. P. S . Mariano, Tetrahedron, 1983,39,3845. 275 S.-f. Chen, J. W. Ullrich, and P. S. Mariano, J . Am. Chem. SOC., 1983, 105, 6160. 276 A. Padwa, G. Haffrnans, and M. Tornas, Tetrahedron Lett., 1983,24,4303. 2n R. Grigg, H. Q. N. Gunarantne, V. Sridharan, and S. Thianpatanagui, Tetrahedron Lett., 1983,24, 4363. 278 L. E. Overman, E. J. Jacobsen, and R. J. Doedens, J . Org. Chem., 1983,48, 3393. 279 T. Fujisawa, Y . Kurita, and T. Sato, Chem. Lett., 1983, 1537.

273 274

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

305

lii R = E t , Pr", n-C6l-43 , or l+C--LHCH;! Reagents: i , BunLi, THF; ii, DMF, (COCl),, CH,Cl,; iii, CuI (2 equiv.), RMgX (2.2 equiv.), THF

Scheme 69

tion in an aqueous perchloric acid-dichloromethane-dioxane-lead electrode system utilizing a hydroxylamine hydrochloride-sodium acetate work-up.280 Treatment of secondary nitroalkanes with iodotrimethylsilane and hexamethyldisilazane has also been shown to afford k e t 0 ~ i m e s . Brief l ~ ~ treatment of active methylene compounds with freshly distilled nitrosyl chloride in chloroform provided a further source of oximes.281 3~-Acetoxy-6-nitrocholest-5-ene gave 3cr, 5cr-cyclocholestan-6-one-(E)-oxime upon treatment with an excess of lithium dimethylcuprate.282 13 Carbodi-imides

A modified Tiemann rearrangement of cyclic amidoxime 0-methanesulphonates has facilitated syntheses of cyclic c a r b ~ d i - i m i d e s The . ~ ~ ~starting cycloalkylene amidoximes were prepared from lactam ethers (Scheme 70). 1,3-Diazacycloocta-l,2-diene was also formed by dehydrosulphuration of pentamethylenethiourea.

n = 5 , 6 , 7 , 1 0 or 1 1 Reagents: i, MeSO,Cl, py; ii, KOBu' or NaOH or KOH

Scheme 70 2m 281

283

S. Torii, H. Tanaka, and T. Katoh, Chem. Lett., 1983,607. J. L. Soto, C. Seoane, J . A . Valdes, andF. J. Fernandez, Org. Prep. Proced. Int., 1983, 15, 41. S. Stiver and P. Yates, J . Chem. SOC.,Chem. Commun., 1983,50. R. Richter, B. Tucker, and H. Ulrich, J . Org. Chem., 1983,48,1694.

306

General and Synthetic Methods

14 Azides and Diazo-compounds Use of the Schmidt reaction to transform tertiary alcohols into the corresponding azides has been discussed above (see Section 11, ref. 252). Preparation of azidotrimethylsilane by reaction of chlorotrimethylsilane and sodium azide in anhydrous DMF has been reported, and the use of the reagent as an electrophilic NH2+synthon for amination of aryl organometallic compounds investigated. l2 The reagent has found several other synthetic applications including preparation of silylated azidohydrins from epoxides in conjunction with titanium and vanadium Regioselectivities ranging between 77 and 100% favouring formation of the primary azide from propylene oxide were observed. Azidotrimethylsilane in addition has been employed in conversions of acetals into the corresponding a-azidoethers, plus transformations of acetals containing phenyl substituents into geminal diazides .285 Syntheses of steroidal azides have been studied. Steroidal 4,6-dien-3-ones appear to react with chromium trioxide and sodium azide in acetone to give

0

(104) X = O H

(105)

4 , -

Me+ i

N3

N=N-N-Pb(OAc

t

d

X = N3

bl

H20

OH

13

N 3 + Pb(OAc)4 4 N=N=N-Pb(OAcI3

0 Scheme 71 285

C. Blandy, R. Choukroun, and D. Gervais, Tetrahedron Lett., 1983,24,4189. S. Kirchenmeyer, A. Mertens, and G. A. Olah, Synthesis, 1983,500.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

307

6~-hydroxy-7a-azido-derivatives plus small amounts of 6p,7a-diazido-compounds (Scheme 71).286A reaction pathway involving (104) and (105) was used to interpret these results. Reactions of azidotrimethylsilane and lead tetra-acetate with the same enones afforded the diazido-compounds along with small amounts of 7a-azido-3-en-3-ones (Scheme 71) .287 When bromo- and azido-trimethylsilanes were used in admixture 6~-bromo-7a-azido-derivatives were formed exclusively. Several methods for preparing aroyl azides have appeared. They can be isolated from reactions of u,w-dibromoacetophenones with sodium azide (Scheme 72) ,288 after treatment of aroyl chlorides with azidotrimethylsilane ,289 and from

+

HCN

+ N2 +2NaBr

via

II N+ NII

+ Reagents: i, NaN, (2.3 equiv.), Me,CO, H 2 0

Scheme 72

reactions of metal salts of carboxylic acids with sodium azide plus phenyl phosphorochloridate and tetra-n-butylammonium bromide in dichloromethane.2" Synthesis of acyl azides from acid chlorides under phase-transfer conditions has already been discussed in connection with the synthesis of primary amines (see Section 1, ref. 15). Azidoindoles and azidotryptophans can now be synthesized efficiently by diazotization of the corresponding primary amino-derivatives, since use of 80% aqueous acetic acid in the diazotizations circumvents the sensitivity of the products to the mineral acid solutions that were previously employed.291 Trapping experiments have indicated that the hitherto unknown phenylethynylazide is formed during reaction of 1-chloro-2-phenylethyne with sodium azide .292 286 288 289 290

*91 292

R. W. Draper, J . Chem. SOC., Perkin Trans. 1, 1983, 2781. R. W. Draper, J . Chem. SOC., Perkin Trans. 1, 1983, 2787. G . Weber, S. Hauptmann, H. Wilde, and G. Mann, Synthesis, 1983, 191. G . K. S. Prakash, P. S. Iyer, M. Arvanaghi, and G. A. Olah, J . Org. Chem., 1983,48, 3358. J. M. Lago, A. Arrieta, and C. Palomo, Synrh. Commun., 1983, 13,289. L. L. Melhado and N. J. Leonard, J . Org. Chem., 1983, 48, 5130. R. Tanaka and K. Yarnabe, J . Chem. SOC., Chem. Commun., 1983,329.

11

308

General und Synthetic Methods

Trimethylsilyldiazomethane has been made by addition of trimethylsilyl trifluoromethanesulphonate to a solution of alcohol-free diazomethane in the presence of Hunig's base as a proton scavenger.293 Hydroxylamine-O-sulphonic acid in the presence of aqueous sodium hydroxide can be used in the preparation of a-diazo-(1,3,3-thiadiazol-5-yl)-a-carboxylic acid from the corresponding ~ x i m e . ~ ~ ~ 15 Azo- and Azoxy-compounds

Azoarenes have been prepared both by barium manganate oxidation of aromatic a m i n e ~and ~ ~ by ~ treatment of nitrosoarenes with arylimino-dimagnesium reagents.296 2'-Hydroxyazobenzenes together with 4'-substituted 4-hydroxyazobenzenes were isolated following Wallach rearrangement of 4,4'disubstituted a z o ~ y b e n z e n e s . Preliminary ~~~ investigations suggested that o-cyano-l-arylazonaphthalenes could be formed by reaction of cyclo-palladated l-arylazonaphthalenes with tetrabutylammonium cyanide in the presence of triphenylph~sphine.~~~ Some evidence for the intermediacy of a Pd"-isocyano complex was presented. C-Alkylation of alkylhydrazone anions was facilitated by utilizing the sterically hindered t-butylhydrazones. C-Hydroxyalkyl-t-butylazo-compoundswhich were unstable towards reversion to the parent hydrazone and carbonyl compound-were formed on addition of the anion to carbonyl compounds (Scheme 73).299

i, ii

B'',N/N\yR' H H

Bu% t' 3

HO

N/

R2

Reagents: i, BunLi (1.1 equiv.); ii, R2R3C0(1.1 equiv.); iii, BunLi (1.4 equiv.); iv, H,O

Scheme 73 293

294 295

296 297

298 2w

M. Martin, Synth. Commun., 1983, 13, 809. G. L'abbe, J. P. Dekerk, and M. Deketele, J. Chem. SOC., Chem. Commun., 1983,588. H . Firouzabadi and Z. Mostafavipoor, Bull. Chem. SOC.Jpn., 1983,56,914. M. Okubo, T. Takahashi, and K. Koga, Bull. Chem. SOC.Jpn., 1983,56,302. I. Shimao and S . Oae, Bull. Chem. SOC.Jpn., 1983,56,643. K. Gehrig, A. J. Klaus, and P. Rys, Helv. Chim. Acta, 1983, 66,2603. R. M. Adlington, J. E. Baldwin, J. C . Bottaro, and M. W. D. Perry, J . Chem. SOC., Chem. Commun., 1983, 1040.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

309

Azoxyarenes have also been prepared from nitroarenes using arylimino-dimagnesium reagents (in some cases being reduced to the azo-compounds when an excess of the reagent was employed,296by reduction of unhindered nitro-compounds with sodium hydrogen telluride300(sterically hindered nitrobenzenes yield anilines) , and from nitrosobenzenes after treatment with carbonylbis(tripheny1phosphine)ruthenium under carbon dioxide301 (this reagent system also effecting reduction of azoxy-compounds to azo-compounds in lower yield). The synthesis of specifically and selectively deuteriated a,d-bisalkoxyazoxybenzene derivatives has been reported302with azoxy-compounds also observed in reactions of monosubstituted hydroxylamines with palladium black at elevated temperatures .303 16 Isocyanates, Thiocyanates, Isothiocyanates, and Selenocyanates

Isothiocyanates have been converted into isocyanates by heating with palladium chloride in the presence of oxygen.304Thiocyanates of high purity can be prepared from alkyl halides in the absence of solvent using silica gel-supported potassium thiocyanate .305 Oxidative elimination of P-(phenylse1eno)alkyl isothiocyanates yielded vinylic isothiocyanates contaminated with small amounts of the isomeric allylic derivat i v e ~The . ~ ~selenated ~ compounds were produced by kinetically controlled reactions of olefins with phenylselenenyl chloride and mercuric thiocyanate in benzene. Use of the mercury salt served to maximize N-selectivity and accelerate isomerization of the P-(phenylse1eno)alkyl thiocyanates to the corresponding isothiocyanates (Scheme 74). It has been demonstrated that in the absence of light iodine-thiocyanogen addition to olefins proceeds by a regioselective ionic mechanism to give, predominantly, vicinal iodoisothiocyanates, whereas a radical addition producing vicinal iodothiocyanates was promoted by ultraviolet irradiation307 Even under such irradiation, however, ionic addition to l-methylene-4-t-butylcyclohexane occurred with almost total exclusion of the radical pathway. 17 Nitrones

As part of a mild, multistep procedure for the oxidative deamination of benzylamines 4,6-diphenylpyridinium-2-carboxylateshave been converted into nitrones by reaction with p-nitroso-N, N-dimethylaniline in refluxing dichloromethane (Scheme 75).308 300

303 304 305

3a7

M8

A. Osuka, H. Shimuzu, and H. Suzuki, Chem. Lett., 1983, 1373. F. Porta, M. Pizzotti, and S. Cenini, J . Organomet. Chem., 1983, 222, 279. N. Boden, R. J. Bushby, and L. D. Clark, J . Chem. Soc., Perkin Trans. 1, 1983,543. S.4. Murahashi, H. Mitsui, T. Watanabe, and S.4. Zenki, Tetrahedron Lett., 1983, 24, 1049. S. M. Paraskewas and A . A. Danopoulos, Synthesis, 1983, 638. M. Kodomari, T. Kuzuoaka, and S. Yoshitomi, Synthesis, 1983, 141. A. Toshimitsu. S. Uemura. M. Okano, and N. Watanabe, J . Org. Chem., 1983,48,5246. R. C. Cambie, P. S. Rutledge, G. A . Strange, and P. D. Woodgate, J . Chem. SOC., Perkin Trans. 1, 1983. 553. A. R. Katritzky, N. Dabbas, R. C. Patel, and A . J. Cozens, Red.: J . R . Neth. Chem. Soc., 1983,102, c1

310

General and Synthetic Methods 2PhSeCI

+

Hg(SCN12

2PhSeSCN

C6H6

2

+

HgCl2

''3 R2

[

H

R'

,SCN

HgCI2

- SCN2

:):;SePh]+

R* 'SePh ;I

(NCSHgCi2)SCN(NCSHgC12)-

14 examples,

70 - 99'10 2 H i 11:h

f

"y"

+

R2 it

Reagents: i, 03,CH,Cl,, -78°C; ii, CC14

Scheme 74 Ph

aNM

co2 Ar

Ar

Reagents: i , p-Me2NC6H,N0

Scheme 75

'i Ho/N,

z

R2

R'NHOH

II

-

plyH L OHNLR2

R'\ /

II N

R3

yY;2

X = COZEt, Ph , OBU', or OTHP

'R' Reagents: i, Pd black, 80-110°C; ii, truns-R3CH=CHX added to reaction mixture (X=CO,Et, Ph, OBu", or OTHP)

Scheme 76

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

311

Treatment of N, N-disubstituted hydroxylamines with palladium black has resulted in formation of nitrones plus regio- and stereo-selective formation of heterocyclic adducts if the reaction is carried out in the presence of an olefin (Scheme 76).303 Treatment of methyl 3,s-dimethoxybenzoate with thallium(m) nitrate in trifluoroacetic acid at low temperature has been shown to lead to the formation of

4-(2-methoxycarbonyl-4,6-dimethoxyphenyl)imino-3-methoxycarbonyl-5-methoxycyclohexa-2,5-dien-l-one N-oxide (106).309

(106) E = C02Me

18 Nitrates and Nitrites Facile transnitrosylation between alcohols and t-butyl nitrite has been accomplished310and applied to the synthesis of two steroidal nitrites. Three thionitrites were prepared in a similar manner.

B. S. Bajwa, S. V. Bhat, J. Reden, N. J. de Souza, and H. W. Fehlhaber, Synth. Commun., 1983,13, 649. 310 M. P. Doyle, J . W. Terpstra, R. A. Pickering, and D. M. LePoire, J . Om. Chem., 1983,48,3379. 309

Organometa IIics in Synthesis BY S. G.DAVIES, S. E. THOMAS, AND P. F. GORDON

PART I: The Transition Elements by S . G. Davies and S . E. Thomas 1 Introduction

The expansion in the number of examples of organotransition metal reactions being exploited for synthesis has continued again this year, and owing to the limitations of space this survey is therefore selective. For newcomers to this area the book by Davies provides an introduction to the literature up to the middle of 1980. The format of this Report is similar to that of previous years except that the section covering carbon-carbon bond-forming reactions has been subdivided to reflect the increasing interest in this area. The use of homogeneous metal catalysts in organic photochemistry has been reviewed.* 2 Reduction

Many examples of the use of homogeneous catalysts for the reduction of carboncarbon double bonds have again been reported. An innovation to note is the stereoselective reduction of allylic and homoallylic alcohols with the iridium The alcohol catalyst [Ir(cod)pyr(PCy3)]PF6in dichloromethane (Scheme group acts as an efficient ligand for iridium and directs the hydrogenation syn to itself. Thus for example, the cyclohexenols (1) and (2) are reduced stereoselectively syn (>100:1) and the alcohol (3) gives mainly the trans-indanone product (trans:cis= 96:4) by this method. The latter observation is in contrast to heterogeneous catalytic hydrogenations (e.g. 5 % Pd/C) where the corresponding cisindanone is obtained almost exclusively. A review of the asymmetric hydrogenation of enamides and enol ethers has a ~ p e a r e dThe . ~ use of iridium rather than rhodium catalysts in such reactions allows the reduction of tetrasubstituted alkenes to be achieved.6 l ) . 3 9 4

1

S. G. Davies, ‘Organotransition Metal Chemistry: Applications to Organic Synthesis’, Pergamon Press, Oxford, 1982. R. G. Salomon, Tetrahedron, 1983,39, 485. G . Stork and D. E. Kahne, J. Am. Chem. SOC., 1983,105,1072. R. H. Crabtree and M. W. Davis, Organometullics, 1983, 2, 681. W. S. Knowles, Acc. Chem. Res., 1983, 16, 106. L. A. Oro, J. A. Cabeza, C. Cativiela, M. D. Diaz de Villegas, and E. Melendez, J . Chem. SOC.,Chem. Commun., 1983. 1383.

312

Organometallics in Synthesis

313

( 2 ) R=Meor Pri OH

Scheme 1

Selective monohydrogenation of cross-conjugated cyclohexadienones, e.g. santonin (4),can be achieved using [Fe2(C0)9]-H20 (Scheme 2) .' Only partial reduction occurs because of formation of an intermediate dienol iron tricarboayl complex from which the enone product is released on ceric oxidation.

Santonin ( 4 )

Reagents: i, [Fe,(CO),], H,O; ii, Cew

Scheme 2

The stereospecific reduction of 2-phenylsulphonyl-l,3-dienesto conjugated E, 2-dienes using BunMgBrin the presence of Pd", or preferably Ni", catalysts has been employed in the synthesis of, for example, the pheromone 92,llE-tetradecadienyl acetate ( 5 ) with a stereochemical purity of 93% (Scheme 3).8 P. Eilbracht and R. Jelitte, Chem., Ber., 1983, 116,243.

* T. Cuvigny, J. L. Fabre, C. Heme du Penhoat, and M. Julia,Tetrahedron Lett., 1983,24,4319.

314

General and Synthetic Methods S0,Ph I

Scheme 3

The reduction of vicinal oxygen functions, one of which is allylic, to dienes can be achieved using [Pd(PPh,),] .9 The first step is formation of an-ally1 complex by loss of the allylic oxygen function followed by loss of the second oxygen group to generate the diene. This method has been applied to steroids to convert, for example, 4-acetoxy-withanolide E into withaperuvin C (Scheme 4).

J 9 5 @I@ Scheme 4

The method for the reductive coupling of aldehydes and ketones to olefins using low-valent titanium reagents has been reviewed (Scheme 5). lo R,C=O

[Ti1

R,C=CR,

Scheme 5

3 Oxidation

The Wacker oxidation of olefins to ketones has now been applied to w-unsaturated amines to yield cyclic imines (Scheme 6).11Whereas the Wacker oxidation of terminal olefins normally leads to ketones, electron-withdrawing substituents in the 2-position direct oxidation to the terminal carbon. l2 E. Keinan, M. Sahai and I. Kirson, J. Org. Chem., 1983, 48,2550. J. E. McMurry, Acc. Chem. Res., 1983,16,405. B . Pugin and L. M. Venanzi, J. A m. Chem. SOC., 1983,105,6877. l2 T . Hosokawa, T. Ohta and S.-I. Murahashi, J . Chem. Soc., Chem. Commun., 1983, 848.

lo

315

Organometallics in Synthesis

A(cH,),,-cH,NH, culf, o *,

n = 2 or3

70-75 '1.

Scheme 6

A review of the use of palladium complexes to achieve some stereoselective 1,2- and 1,4-additions to olefins and 1,3-dienes respectively has appeared. l 3 The first example of a homogeneous metal-catalysed oxidation of acetals has been achieved with ButOOH in the presence of the palladium catalyst Pd(OCOCF3)(00But) (Scheme 7). l4

.- 70 ' I r Scheme 7

The use of palladium salts to effect the direct dehydrogenation of aldehydes and ketones to their @unsaturated derivativeP7 l6 has been used in preference to dehydrotrimethylsilylation. The recommended procedure employs palladium chloride-palladium acetate in aqueous dioxane (Scheme 8).l5 Improved procedures for the dehydrotrimethylsilylation reaction have also been described. l7 The same transformation may also be executed via treatment of ally1 enol carbonates with palladium acetate in the presence of phosphines (Scheme 9).lS

H

H

Scheme 8

J . E. Backvall, Acc. Chem. Res., 1983, 16, 335. T. Hosokawa, Y . Imada, and S.-I. Murahashi, J . Chem. SOC., Chem. Commun., 1983,1245. l5 A. E. Greene, M.-J. Luche and J.-P. Depres, J . Am. Chem. Soc., 1983,105,2435. l6 T. Mukaiyama, M. Ohshima, and T. Nakatsuka, Chem. Lett., 1983, 1207. l7 J. Tsuji, I. Minami, and I. Shimizu, Tetrahedron Lett., 1983,24, 5635. l8 I . Shimizu, I. Minami, and J. Tsuji, Tetrahedron Lett., 1983, 24,1797, 5639.

l3

l4

316

General and Synthetic Methods

oco/-,

b \

Pd-phosphine

98 ' l o

oc0, I -

0-

Pd -phosphine

8 1 'lo

Scheme 9

The stereospecific cis-l,2-diamination of alkenes can be achieved with cyclopentadienylnitrosylcobalt dimer under an atmosphere of nitrous oxide followed by LiA1H4reduction (Scheme 10).l9

-

2 i

JEt

2

ii

Et

Et

80 '1. Reagents: i, [CpCo(NO)],, 2 NO; ii, LiAlH,

Scheme 10

Readily available cyclohex-2-enols yield the corresponding cycloheyadienetricarbonyliron complexes with pentacarbonyliron. These complexes can be dehydrogenated to give specifically substituted arenes (Scheme 11).20

d

OH

R2

- 70

'1.

Reagents: i, [Fe(CO),]; ii, Ph,C+; iii, CeiV

Scheme 11 l9 *O

P. N. Becker and R. G. Bergman, Organometallics, 1983,2,787. D. Farcasiu and G. Marino, J. Organomet. Chem., 1983,253, 243.

35-50

"lo

317

Organornetallies in Synthesis 4 Isomerizations and Rearrangements

Monosubstituted l-alkenes can be isomerized in a highly stereoselective manner (>99: 1) to yield E-2-alkenes using [(Me5C5)2TiC12]-NaCloH8(Scheme 12).21 2-Alkyl substituents prevent this isomerization and therefore, for example, (7). 2-methylhexa-l,5-diene (6) is isomerized to E-2-methylhexa-l,4-diene

-

98 100 * l o E : Z > 99:l

(6)

(7) Scheme 12

Hexa-l$dienes with an electron-withdrawing substituent in the 3-position rearrange under the influence of palladium chloride at 25°C to give cyclohexenes.22If a 2-alkyl substituent is also present then palladium chloride catalyses the competing Cope rearrangement (Scheme 13). Clean y-alkylation of vinyl esters and acids can be achieved by this route [e.g. (8)+(9)].23 R’

I

(77- 94 %)

(53 %) R

R

(9) (83%)

(8)

Reagents: i, PdCl,, 40°C (R1=Me, R2=H, Z=CO,Et, COR, or CN); ii, PdCl,, 25°C (R1=H, Rz=Me, Z=Me, Z=C02Et or CN); iii, LDA, HMPA; iv, CH,=CHCH,Br; v, PdCl,

Scheme 13

Secondary allylic alcohols are efficiently isomerized to ketones with the catalyst .24 This catalyst also works well for primary ally1 tran~-[Mo(N~)~(dppe)~] dialkylamine~~~ but not for primary allylic alcohols or ether^.^^,^^ M. Akita, H. Yasuda, K. Nagasuna, and A. Nakamura, Bull. Chem. SOC.Jpn., 1983,56, 554. L. E. Overman and A. F. Renaldo, Tetrahedron Lett., 1983,24,2235. 23 L. E. Overman and A. F. Renaldo, Tetrahedron Lett., 1983,24,3751. 24 Y. Lin and X. Lu, J . Organomet. Chem., 1983,251, 321. 25 T. Tatsumi, K. Hashimoto, H. Tominaga, Y. Mizuta, K . Hata, M. Hidai, and Y . Uchida, J . Organomet. Chem., 1983,252, 105. 21

22

318

General and Synthetic Methods

P-Trimethylsilylallyl alcohols (10) are isomerized catalytically to the corresponding a-trimethylsilyl ketones (11)with [HRh(PPh,),l. These a-trimethylsilyl ketones may in turn be isomerized regiospecifically to the trimethylsilylenol ethers (12) using [HRh(CO)(PPh,),] as catalyst.26 [HRh(CO)(PPh,),] also catalyses the direct isomerization of the ally1 alcohols (10) to the enol ethers (12) (Scheme 14).27

I

ii

I

78 - 96 '1.

I

Reagents: i, [HRh(PPh,),]; ii, [HRh(CO)(PPh,),]

Scheme 14

The rearrangement of a-cyanoallyl acetates to y-cyanoallyl acetates by [Pd(PPh,),] has been used in the total synthesis of d,l-sirenin (13) (Scheme 15).28

d l - Sirenin (13)

Scheme 15

5 Carbon-Carbon Bond Formation via Organometallic Electrophi1es.-The conversion of alkenes into methylcyclopropanes can be accomplished via ethylidene transfer from the iron complex [(CSH5)Fe(CO),(=CHMe)]. This complex must be generated in situ by 26 27

S. Sato, I. Matsuda, and Y. Izumi, Tetrahedron Lett., 1983, 24, 3855. I. Matsuda, S . Sato, and Y. Izumi, Tetrahedron Lett., 1983, 24, 2787. T. Mandai, K. Hara, M. Kawada, and J. Nokami, Tetrahedron Lett., 1983, 24, 1517.

Organometallics in Synthesis

319

protonation of the corresponding methyl ether complex (15), which is obtained from the readily available acetyl complex (14) (Scheme 16).29 Good syn stereoselectivity is observed and best results are obtained with di- and tri-substituted olefins. H i , ii

-

RP-

.. .

i l l

I

R

oc

oc

(14)

Me

I

H

(15) 91 '10

Reagents: i, MeOS02CF3;ii, BH4-; iii, cis-RCH=CHR, Hi

Scheme 16

The resolved complex (16) allows the asymmetric methylcyclopropanation of styrene to be carried out with an enantiomeric excess of 85-90% and chemical yield of 75% (Scheme 17).30

I

oc

/i''F<

OMe H

ph/\\

Ht

HMHHxp +

Me

Me

1

(16) L = Ph2PCH,CHMeEt

Me

Ph

:

H

3.5

Scheme 17

The use of the cationic iron vinyl ether complexes (17) as vinyl carbonium ion equivalents has been developed into a method of generating 3,4-disubstituted 0-methylene-y-lactones such as protolichesterinic acid (18) (Scheme 18).31 Allylic substitution catalysed by palladium complexes continues to be developed. The stereo- and regio-selective isomerization-alkylation of 1,3-diene monoepoxides has been used for the synthesis of m a c r ~ l i d e s ,prostaglandin^,^^ ~~ and digitoxigenin (Scheme 19).34 Molybdenum [Mo(CO),] and tungsten [W(CO)3(MeCN)3] catalysts can replace palladium compounds in the reactions of allylic acetates with stabilized carbanions (Scheme 20). 35 M. Brookhart, J. R. Tucker, and G. R. Husk, J . Am. Chem. SOC., 1983,105,258. M. Brookhart, D. Timmers, J. R. Tucker, G. D. Williams, G. R. Husk, H. Brunner, andB. Hammer, J. Am. Chem. SOC., 1983,105, 6721. 31 T. C. T. Chang and M. Rosenblum, Tetrahedron Lett., 1983,24,695. 32 B. M. Trost and R. W. Warner, J . Am. Chem. Soc., 1983, 105,5940. 33 T. Takahashi, H. Kataoka, and J. Tsuji, J. Am. Chem. SOC., 1983, 105, 147. 34 J. Wicha and M. M. Kabat, J . Chem. SOC., Chem. Commun., 1983,985. 35 B. M. Trost and M. Lautens, J. Am. Chem. SOC., 1983, 105, 3343; B. M. Trost and M. Lautens, Organometallics, 1983,2, 1687; B. M. Trost and M.-H. Hung, J . Am. Chem. SOC., 1983,105,7757. 29

General and Synthetic Methods

320

C0,Et FG-AOEt

/ iii - v

0

R (18) (95'1.1

ow

C02Me

Reagents: i,

; ii,

H-; iii, H+; iv, Me,CO; v , H,O

C~~HY

Scheme 18

(74'/el

-

0 [Pdl phosphite

-

11 deoxy- PGE,

(60-70'Ie) 0

Digitoxigenh

(60'/el Scheme 19

Organometallics in Synthesis

7

321

R

i

d

w

I M+

OAc

R

z' ,z2=C02Me,W2Ph Reagents: i, [Mo(CO),] or [W(CO)3(MeCN),]; ii, Z1Z2CH-

Scheme 20

Palladium complexes have been shown to catalyse decarboxylation reactions, again resulting in overall allylic substitution (Scheme 21). The stereochemistry of this reaction has been i n ~ e s t i g a t e d . ~ ~

x = CHR'COR~,OR, or NR'R'

0

+

Me0

QoMe Me0

cis trans

91

9

64

36

Reagents: i, [Pd(PR,),]; ii, Pd(OAc),, PPh,

Scheme 21

The use of the chiral diphosphine ligand [( -)-(2S,3S)-bisdiphenylphosphinobutane] in the Felkin reaction has resulted, in one case, in a very high asymmetric induction (Scheme 22). In general, however, optical yields are only fair .37

6

t EtMgBr

t

L2 NiC$

97.7'10 optical yield 85 O/.

chemical yield

Scheme 22

Diene tricarbonyliron complexes such as (19) are susceptible to nucleophilic attack in the presence of carbon monoxide to give metallalactones. Decomplexation of these metallalactones with electrophiles then yields a variety of 3-substituted y, &unsaturated carbonyl compounds (Scheme 23) .38 The process is J. E. Backvall, R. E. Nordberg, and J. Vagberg, Tetrahedron Lert., 1983,24,411. G. Consiglio, F. Morandini, and 0. Piccolo, J . Chem. Soc., Chem. Commun., 1983, 112. 38 M. F. Semmelhack, J. W. Herndon, and J. P. Springer, J . Am. Chem. SOC., 1983, 105,2497; M. F. Semmelhack and J. W. Herndon, Organometallics, 1983, 2, 363.

36

37

322

General and Synthetic Methods R

81 01. (R=%H,cN, E+= H+)

(19)

R = stabilized carbanian, E+=H+or Me1

Scheme 23

stereoselective with trans-formation of the two new carbon-carbon bonds being observed. Co-ordination of arenes to tricarbonylchromium makes the arenes susceptible to nucleophilic attack , generating cyclohexadienyltricarbonylchromium anions, which may be methylated on chromium with methyl iodide. Subsequent decomplexation with triphenylphosphine or iodine occurs with acetyl migration from chromium to carbon to generate trans-5,6-disubstituted cyclohexadienes stereoselectively (Scheme 24).39

n f Cr(CO),

Reagents: i,

c:h,

'f e

i

0

; ii, MeI, CO; iii, I, or PPh,

Scheme 24

1,4-Dimethoxynaphthalene selectively co-ordinates tricarbonylchromium to the unsubstituted ring. The resulting complex undergoes regio- and stereo-selective nucleophilic addition at C-6 to give (20), as above, or (21) after protonation and decomplexation. Sequential hydrolysis and hydrogenation then leads to (22) (Scheme 25).40 Secondary benzyl acetates complexed to tricarbonylchromium react with trimethylsilyl enol ethers in the presence of zinc chloride to give a-benzylated 39

E. P. Kundig and D. P. Simmons, J . Chem. SOC.,Chem. Commun., 1983,1320. E. P. Kundig, V. Desobry, and D. P. Simmons, J. Am. Chem. Soc., 1983, 105, 6962.

Organometallics in Synthesis

323

n ____)

OMe

OMe

OMe

(211

ii,v, iv

Reagents: i , [Cr(CO)J; ii,

c b: 5

S

(-J+ I.!,

I

OAc

I

iii, H + ;iv, I, or PPh3; v, Me1

Scheme 25

+

6e & I ' l l )

\ /

68 ' l o

C r (CO),

82 '1. Reagents: i, ZnC1,; ii, I2

Scheme 26

ketones (Scheme 26). These carbon-carbon bond-forming reactions can be completely stereo~elective.~~ via Organometallic Nucleophiles.--cr,fl-Unsaturated esters, which often do not undergo Michael additions with R2CuLireagents, are smoothly fl-alkylated by the mixed cuprates R2Cu(CN)Li2(Scheme 27) .42 41

42

M. T. Reetz and M. Sauerwald, Tetrahedron Lett., 1983,24,2837. B . H . Lipshutz, Tetrahedron Lett., 1983,24, 127.

324

General and Synthetic Methods -CO,

Me

t

R2Cu(CN)Li2-+

7 CO,

Me

R (65-94’1.)

R = Bu, Ph, vinyl, or Pr

Scheme 27

The use of chiral cuprates results in stereoselective P-methylation of chalcone , with enantiomeric excesses of up to 88% being observed.43 Butenylmagnesium chloride reacts with [ (C5H5)2ZrC12]to generate the bismethallylzirconium reagent (23) , which adds stereoselectively to aldehydes (RCHO) with high threo-selectivity (e.g. R=Me, 91%; R=Et, 92%; R=Prl, 86%) at -110°C (Scheme 28).“

Cp =C,H,

(23)

Reagents: i, MeCH= CHCH,MgBr; ii, RCHO; iii, H+

Scheme 28

Similarly, the titanium reagent (24) adds regio- and stereo-selectively to aldehydes to give the threo-compounds (25) as essentially the only products in up to 88% yield (Scheme 29).45

-hMe H

Cp,Ti

l

?*

H

OPh

OPh H

J

Scheme 29

The selectivity observed for the reactions of titanium allyls with aldehydes has been developed into a new stereoselective method for the one-pot preparation of Z-1.3-dienes (Scheme 30).46 Enolates derived from the readily available iron acyl complexes (26) undergo highly stereoselective C-alkylations with alkyl halides.47Oxidative decomplexaF. Leyendecker, F. Jesser, and D. Laucher, Tetrahedron Lett., 1983,24,3513,3517. K. Mashima, H. Yasuda, K. Asami, and A. Nakamura, Chem. Lett., 1983, 219. 45 F. Sato, H. Uchiyama, K. Iida, Y. Kobayashi, and M. Sato, J. Chem. SOC., Chem. Commun., 1983, 921. 46 J. Ukai, Y. Ikeda, N. Ikeda, and H. Yamamoto, Tetrahedron Lett., 1983, 24, 4029. 47 G. J. Baird and S. G. Davies, J. Organomet. Chem., 1983, 248, C1. 43

325

Organometallics in Synthesis

0Reagents: i, BuLi; ii, (Pr’O),Ti; iii, RCHO; iv, Me1

Scheme 30

tion then generates a variety of carbonyl functionalities (Scheme 31). The high stereoselectivities observed in these alkylations arise because the preferred anticonformation of the E-enolate can only be alkylated from one

6uLi

.F=

oc”

__t

1

y ‘H

Ph,P

Ph3P

R

(95

(26)

V O )

Scheme 31 I

The biscyclopentadienyl methylene reagent [Cp,Ti= CH,], which can be generated in a variety of ways, reacts with acid chlorides to generate titanium enolates which are regiostable. These enolates undergo normal enolate reactions; for example, protonation generates methyl ketones, and aldol products are formed with aldehydes (Scheme 32).49

Cp =C,H,

Scheme 32

49

G. J. Baird, J. A. Bandy, S. G. Davies, and K. Prout, J . Chem. Soc., Chem. Commun., 1983,1202. J . R. Stille and R. H. Grubbs, J . Am. Chem. Soc., 1983,105, 1664.

326

General and Synthetic Methods

A convenient method for generating a titanium methylene reagent involves the reaction of [(CsHs)2TiC12]with CH2(ZnI),. The product [(CsHs)2TiCH2ZnX2] reacts with a variety of functional groups (Scheme 33).50

R2C = C H ,R CO L

Cp,Ti =CH2*ZnXz

> 80 '10

-

,p~~oc, R A

Cp = C,H,

M e

RCN, 70 "10

RCOCI, 20 '1.

Scheme 33

Regioselective C-1 acylation of isoprene can be achieved via its complex with

[(C5H5)2Zr](Scheme 34). si

50

OC

>90 ' l o

OEt

Scheme 34

The regioselectjve ortho-metallation of methoxyarene tricarbonylchromium complexes has been employed in a synthesis of the antibiotic frenolicin (28) (Scheme 35). Alkylation of the copper derivative (27) proceeded in 96% yield and a second alkylation was achieved by nucleophilic addition to the resulting tricarbonylchromium complex.52

M e3Si

I

1

I

Cr (COl3

C r (co),

Cr(CO),

(27)

I

1'

61 "1.

OMe

Pr

'1COZH (28 1 [Overall yield 4 'lo (15 steps)] Reagents: i , BuLi; ii, CuI: iii, Br

w

Pr; iv, CH,=CHCH,CH,CHCN;

Scheme 35 J. J. Eisch and A. Piotrowski, Tetrahedron Lett., 1983, 24, 2043. M. Akita, H. Yasuda, and A. Nakamura, Chem. Lett., 1983,217. s2 M. F. Semmelhack and A . Zask, J . Am. Chem. SOC., 1983, 105,2034. 50 51

v. H+

327

Organornetallies in Synthesis

The regioselective metallation of 7-methoxytetralols complexed to tricarbonylchromium has been used to introduce a formyl group at C-6 for the synthesis of anthraquinoness3 and calamenenes (Scheme 36) .54 R'

R'

0

R1

Reagents: i, 2 BuLi, TMEDA; ii, DMF

Scheme 36

Lithiation of tricarbonyl(tri-isopropylsily1oxybenzene)chromium occurs preferentially in the meta-position. Trapping this anion with electrophiles results in overall meta-substitution of phenol (Scheme 37) .s5

Co-ordination of benzyl alkyl ethers and thia-ethers to tricarbonylchromium allows a-substitution via the a-carbanions to be achieved by suppression of the Wittig and related rearrangements (Scheme 38) .56

Cr (CO),

XR = OMe or SEt

E = Me, Et, Pr i, PhCH,

(65

, or PhCO

- 88'/0)

Scheme 38 M. Uemura, K. Take, and Y. Hayashi, J. Chem. SOC., Chem. Commun., 1983,858. M. Uemura, K. Isobe, K. Take, and Y. Hayashi, J. Org. Chem., 1983,48, 3855. 55 N. F. Masters and D. A. Widdowson, J. Chem. SOC., Chem. Commun., 1983, 955. 56 S . G . Davies, N. J. Holrnan, C. A. Laughton, and B. E. Mobbs, J. Chem. SOC., Chem. Commun., 1983, 1316. 53 54

328

General and Synthetic Methods

via Coupling Reactions.-l,5-Dienes may be synthesized by coupling of allylic bromides with [(Ph3P)3CoC1].The coupling is stereospecific, the geometry of the starting ally1 bromide being retained in the product. This method has been applied to the stereospecific synthesis the analogue of squalene (Scheme 39).57

2 F

*@

B

r [(Ph3P)~COCII

Scheme 39

The coupling of propargyl derivatives and PhZnCl with [Pd(PPh,),] as catalyst proceeds with anti-stereoselectivity (anti:syn >82: <18). In this way optically active allenes can be prepared (Scheme 40). In steroids much higher stereoselectivity is observed.s8 ~~

Ph /

Hc E c

4AH \X

(R) X = MeCO, , CF, C%, or MeS02 0

98

2

Reagents: i, PhZnC1, [PdfPPh,),]

Scheme 40

The formation of allene products from the reactions of propargyl derivatives with carbon nucleophiles can be completely suppressed by prior co-ordination of the propargyl derivative to [Co,(CO),]. In this way 1,4-diynes may be prepared, and even 3-substituents are tolerated to give 3-substituted 1,4-diynes (Scheme 41).59 Arylacetic acid esters have been prepared from the nickel-catalysed reaction of ethyl bromoacetate and arylzinc chlorides (Scheme 42). The arylzinc chlorides can be prepared from aryl halides by halogen-metal exchange reactions.@' 57 58 59

D.-I. Momose, K. Iguchi, T. Sugiyama, and Y. Yamada, Tetrahedron Lett., 1983,24,921. C . J. Elsevier, P. M. Stehouwer, H. Westmijze, and P. Vermeer, J . Org. Chem., 1983,48, 1103. S. Padmanabhan and K. M. Nicholas, Tetrahedron Lett., 1983,24,2239. T. Klingstedt and T. Frejd, Organometallics, 1983, 2, 598.

329

Organometallics in Synthesis /

@

OAc (BuC=Cl3AI HCEC---(R

M

HCEC----<

1CO,(CO), R

I Co,(CO),

Bu CeIY

-HCEC-CCHR-CeCBu R = Ph, 83 ' l o

(60- 90 'lo)

R = H , M e or Ph

Scheme 41 /C02Et

Br

Reagents: i, BuLi; ii, ZnC1,; iii, [Ni(acac),], PPh,Cy; iv, BrCH,CO,Et

Scheme 42

The nickel-catalysed allylation of aromatic Grignard reagents can be readily achieved with a variety of ally1 derivatives (Scheme 43). This method has been applied to the synthesis of many mono- and bis-aryl natural products.61 R

w

+

ArMgBr [(PPh3)gNiCIz1/

wAr

R

X = OH,OMe, OEt, SH, or SMe R = H or Ph

Scheme 43

The cross-coupling of Grignard reagents with primary alkyl bromides in the presence of Li2CuC14 has been applied to the synthesis of a variety of functionalized aliphatic aldehydes (Scheme 44) .62 Y(CH2)n+2-X

0 [:yMgsr + Li2CuCt4

Br(CH,),X

H

X = OMe, Cl, CN, or C0,Et

(>80 ' l o )

Scheme 44

A considerable amount of effort continues to be devoted to the coupling of carbanions with vinyl and aryl derivatives. In particular the range of leaving groups has been extended. Aryl triflates give substituted arenes with Wenkert, J. B. Fernandes, E. L. Michelotti, and C. S. Swindell, Synthesis, 1983, 701. R. A. Volkmann, J. T. Davis, and C. N. Meltz, J . Org. Chem., 1983,48,1767.

61 E. 62

330

General and Synthetic Methods

R2Cu(CN)Li2(Scheme 45). The yields are generally 70-95% and acyl, alkyl, and methoxy substituents can be tolerated; the organocuprate may be primary, secondary, or tertiary.63 OSO, CF3

@

R2Cu(CN)Li2

~

8

X

X

X = R'CO, R' ,or OMe

R = Bun, Bus, or But

Scheme 45

Enol thiaethers give alkenes with Grignard reagents in the presence of [L2NiCI2](L= tertiary phosphine) .Non-reducing Grignard reagents give substitution products whereas others, e.g. Pr'MgBr, give reduction products (Scheme 46) .61,64 The ready availability of enol thiaethers makes this carbon-carbon bondforming reaction particularly attractive.

Isosafrole

Bisa bolene Reagents: i, Pr'MgBr, [(PPh,)2NiC1,]; ii, MeMgBr, [(PPh3),NiCl,]

Scheme 46

Aryl alkyl thiaethers also undergo this type of coupling reaction. Aryl bis(alky1 thiaethers) undergo selective replacement of the less hindered sulphur, allowing the introduction of two different alkyl or aryl groups (Scheme 47).65 cr-Phenyl ketones can be prepared from enol acetates via the [(o-t0l~P)~PdC12] catalysed coupling of the corresponding tributyltin-enolates, derived in situ, with J. E. McMurry and S. Mohanraj, Tetrahedron Lett., 1983,24,2723. B. M. Trost and A . C. Lavoie, J . A m . Chem. SOC., 1983, 105,5075. 65 M. Tiecco, L. Testaferri, and M. Tingoli, Tetrahedron, 1983, 39, 2289. @

331

Organometallics in Synthesis R

SMe

R

R'

6 SMe

I

iii

~

.

SPr'

Reagents: i, RMgX, [(PPh3),NiC1,]; ii, R'MgBr, [(PPh3),NiC1,]; iii, [(PPh,),NiCl,]; iv, CH, =CHCH,MgBr, [(PPh3),NiC12]

CH,=CMeMgBr,

Scheme 47

bromobenzene (Scheme 48).% The regiochemistry of the enol acetate is maintained.

&

Ph (67 'lo)

0 i

,

Ph

( 6 0 '/o) Reagents: i, Bu3SnOMe, PhBr, [L,PdCl,]

Scheme 48

a-Carbanions derived from enol ethers and enol thiaethers couple with vinyl halides in the presence of palladium catalysts, e.g. [Pd(PPh3),], to provide a stereoselective (>98%) route to heterosubstituted 1,3-dienes (Scheme 49) .67,68 Allenic ether anions may also be used (Scheme 50).68 The asymmetric cross-coupling of chiral Grignard reagents with vinyl bromide, catalysed by NiC12 in the presence of chiral aminophosphine ligands, has led to enantiomeric excesses of up to 86% (Scheme 51).69 M. Kosugi, I. Hagiwara, T. Sumiya, and T. Migita, J . Chem. SOC., Chern. Cornrnun.,1983, 344. E. Negishi and F.-T. Luo, J. Org. Chern., 1983,48, 1560. 68 C. E. Russell and L. S. Hegedus, J. Am. Chern. SOC., 1983,105,943. 6y T. Hayashi, T. Hagihara, Y . Katsuro, and M. Kumada, Bull. Chem. SOC. Jpn., 1983, 56, 363; T. Hayashi, M. Konishi, M. Fukushima, K. Kanehira, T. Hioki, and M. Kumada, J. Org. Chern., 1983, 48,2195. 66 67

332

General and Synthetic M e t h o h

*Iznc, OEt

i, i i

-2 ii i

( 74 %)

5"ll

SEt SEt

I

SEt

"SH1l

( 81 ' l o ) Reagents: i, Bu'Li, TMEDA; ii, ZnC1,; iii, trans-ICH-

CHC,H,,, [(PPh,),Pd]; iv, BuSLi,HMPA

Scheme 49

RCZZCCH20Me

iiii

*

R)=C
i,iii

d

+'*OM'

~

Fi

H

0

ZnCl /

R Ar Reagents: i, BuLi; ii, RlX; iii, ZnC1,; iv, ArI, [Pd(PPh,),]; v, H 3 0 + FIG 50

*

L

(82

- 95 '/a)

chiral aminophosphines Scheme 51

Pyrimidinyl mercuric salts can be coupled with furanoid glycals in the presence of stoicheiometricPd(OAc)2to provide a regio- and stereo-specificsynthesis of aor ,@C-nucleosides (Scheme 52).'O 70

U. Hacksell and G. D. Daves, J. Org. Chem., 1983, 48,2870; Organometallics, 1983,2,772.

333

Organometallics in Synthesis

HgOAc

OH

Scheme 52

The palladium-catalysed cross-coupling of vinyl tin ,71 copper ,72 and derivativeswith acid chlorides to produce a,P-unsaturated ketones has received a considerable amount of attention. via Carbonylation and Related Reactions.-Aryl and vinyl iodides and benzyl and ally1 halides can be converted into the corresponding aldehydes on treatment with Bu",SnH in the presence of Pdo catalysts, e.g. [Pd(PPh3),], under 1-3 atm of carbon monoxide (Scheme 53).74 The reaction conditions do not affect nitro, ketone, ester, or alcohol groups elsewhere in the molecule.

RX

+

Bu,SnH

(95 ' l o )

Reagents: i, [Pd(PPh,),], CO

Scheme 53

The synthesis of cyclopentenones from an acetylene plus olefin and carbon monoxide mediated by [Co2(C0),] has been extended to the direct formation of bicyclo[3.3.0]enones from enynes, and has been employed in a total synthesis of the sesquiterpene coriolin (Scheme 54) .75 The carbonylativecyclizationproved to be very stereoselective in this case. J. A. Soderquist and W. W.-H. Leong, Tetrahedron Lett., 1983,24,2361; J. W. Labadie, D. Tueting, and J. K. Stille, J. Org. Chem., 1983,48,4634; J. W. Labadie and J. K. Stille, J. Am. Chem. SOC., 1983, 105, 6129. 72 N. Jabri, A. Alexakis, and J. F. Normant, Tetrahedron Lett., 1983,24, 5081. 73 E. Negishi, V. Bagheri, S. Chatterjee, F.-T. Luo, J. A. Miller, and A. T. Stoll, Tetrahedron Lett., 1983, 24, 5181. 74 V. P. Baillargeon and J. K. Stille, J. Am. Chem. SOC., 1983,105, 7175. 75 C. Exon and P. Magnus, J . Am. Chem. SOC., 1983,105,2477.

71

General and Synthetic Methods

334

SiMe, w

But Me,S i O

0

A ( 3 %)

Reagents: i, LiC=CSiMe,;

ii, ButMe,SiC1; iii, [Co,(CO),]

Scheme 54

Further examples of the use of transition metals for /?-lactam synthesis have been reported. Iron olefin complexes have been employed in the synthesis of 3-methoxycarbonylcarbapenam ,76 and 3-substituted~-lactamsare produced from ally1tricarbonyliron lactone complexes derived from vinyl epoxides and pentacarbonyliron (Scheme 55).77 H FP +

c-o '2Me

0 C02Me

Fp = (C5H5)Fe(C0)2

C5H5

C0,Me

liv

Y

q

0

1

C0,Me

Reagents: i, NH,; ii, NaBH,; iii, A ; iv, 0,; v, [Fe(CO),], hv; vi, PhCH,NH,, ZnCI,; vii, Ce"

Scheme 55 76

S. R. Berryhill, T. Price, and M. Rosenblum, J . Org. Chem., 1983, 48, 158. G. D. Annis, E. M. Hebblethwaite, S. T. Hodgson, D. M. Hollinshead, and S. V. Ley, J . Chem. SOC., Perkin Trans. I , 1983, 2851.

Organornetallies in Synthesis

335

R

R = But or Me3Si

Scheme 56

The most interesting development in this area has been the regiospecific rhodium-catalysed ring expansion of aziridines to /?-lactams (Scheme 56). The reported examples are limited to 2-arylaziridines, and for these the reaction was completely regiospecific, producing 3-aryl-P-lactams q~antitatively.~~

6 Synthesis of Heterocycles Palladium-catalysed cyclizations of 3-acetoxy-l-(4-aminoalkyl)cyclohexenes provides a convenient route to the spirocyclic 1-azaspiro[S,5]undecane systems found in the histrionicotoxin alkaloids (Scheme 57).79, This novel spirocyclization methodology can also be applied to 1-oxaspirocycles (Scheme 58).81

[ P d (PPh3)4 1

phcH

Scheme 57

/1=3 (3O"le)

n =4

Reagents: i, BuLi; ii, [Pd(dppe),]

Scheme 58

Optically active ally1 carboxylates can be cyclized with palladium catalysts to give 2-substituted tetrahydrofurans of known absolute stereochemistry . For the H. Alper. F. Urso, and D. J. H. Smith, J . Am. Chem. Soc., 1983,105,6737. S. A. Godleski, D. J. Heacock, J. D. Meinhart, and S. V. Wallendael, J. Org. Chem., 1983,48,2101. 8o W. Carruthers and S. A. Cumming, J. Chem. SOC., Chem. Commun., 1983,360. 81 S. A. Stanton, S. W. Felman, C. S . Parkhurst, and S. A. Godleski, J . Am. Chem. Soc., 1983, 105, 1964.

78

79

336

General and Synthetic Methods

(95 % )

A r = 2,6 -dichlorophenyl

Scheme 59

E-alcohol (Scheme 59) complete transfer of chirality is observed with a chemical yield for the cyclization of 95 % .82 Amine-directed ortho-palladation of benzylamines has been developed into a new tetrahydroisoquinoline synthesis. The intermediate aryl palladium complex is trapped with methyl vinyl ketone and the product subsequently cyclized to the heterocycle (Scheme 60).83

I

i i 73 ' I .

0

0

Reagents: i, Li,PdCl,; ii, CH,='CHCOMe

Scheme 60

The trimerization of triple bonds to aromatic molecules mediated by [(C5H5)Co(C0),]has been adapted to make intermediates for the synthesis of protoberberine@and camptothecin (Scheme 61).85 82 83 85

G. Stork and J. M. Pokier, J. Am. Chem. SOC., 1983,105,1073. N. Barr, S. F. Dyke, and S. N. Quessy, J. Organometal. Chem., 1983, 253, 391. R. L. Hillard, C. A. Parnell, and K. P. C. Vollhardt, Tetrahedron, 1983, 39,905. R. A. Earl and K. P. C . Vollhardt, J. Am. Chem. SOC., 1983, 105,6991.

337

Organornetallics in Synthesis Me0 Me0

F

OMe

Si Me3

c w (58 "la)

(81 " l o )

4.

i

il

It1

+

SiMe,

I

N=C=O

Camptothecin

Si Me3

0

Reagents: i, [CpCo(CO)J, PhCN; ii, [CPCO(CO)~];iii, Me$iC=COMe

Scheme 61

7 Miscellaneous Reactions

Titanium amides Ti(NR2)4(R=Me or Et) selectively protect aldehydes in the presence of ketones so that Grignard and aldol reactions occur only at the latter (Scheme 62).86 0 Ph A

C

H

HO

O

CH CO Et

Ph =CHo

+

99: 1

P

hCO, Et

h

6H

Reagents: i , Ti(NR,),; ii, LiCH,CO,Et

Scheme 62 86

M. T. Reetz, B. Wenderoth, and R . Peter, .IChem. . SOC.,Chem. Commun., 1983,406.

338

General and Synthetic Methods OSiMe,

OSiMe,

OSiMe,

OSiMe

R

( 9 1 .I.)

JyJ-

0

A

OSiMe,

OSiMe,

,,

OSiMej

x;lgyJ 0

H

Scheme 63

The differentiation between two ketone groups has been achieved by the selective desilylation of trimethylsilyl enol ethers with Bun3SnFin the presence of [{(~-tol),P}~PdCl~] as catalyst. The relative rates of reaction of various trimethylsilyl enol ethers are shown in Scheme 63.87A distinct advantage of this method is that it allows purification of thermodynamically favoured silyl enol ethers by removal of isomeric impurities (Scheme 63).

Part 11: Main Group Elements by P. F. Gordon 1 Group I

Selective Lithiations.-Specific ortho-lithiation of aromatics is now a well precedented reaction with several functional groups capable of exerting the desired regiocontrol. Nevertheless, the addition of new groups able to promote this useful reaction is always to be welcomed, and this is the case for the carbamate and tetramethylphosphonic diamide groups published this year. The carbamate (1; X=H) can be lithiated at -78°C to yield the derivative (1; X=Li) which then 87

H. Urabe, Y. Takano, and I. Kuwajima, J. Am. Chem. Soc., 1983, 105,5703.

Organometallics in Synthesis

339

reacts with electrophiles (E+) giving phenols (2; X=E) after hydrolysis, or alternatively rearranges to the salicylamide (2; X=CONEt2) if allowed to warm to room temperature. The phosphonic diamide (3) also lithiates specifically at the ortho-position, and then reacts with various electrophiles as shown in Scheme 1.2

+

II

I

I I C

p/h 'Ph

OH

UH

0 II

0

0 Reagents: i , BuLi; ii, Ph,CO; iii, PhCHO; iv, R1R2CO;v, Ph,PCl; vi, H,O,;-vii, Me,SiCl; viii, CO,; ix, PhCOPO(OEt),

Scheme 1

A syntheticallyuseful and general route to o-amino aromatics (4) also goes by way of the corresponding ortho-lithiated derivative, and is effected by treating the lithiated aromatic with tosyl azide followed by reduction with either sodium borohydride3" or Ni-A1 alloy.3bThe reaction works well with aromatic compounds containing conventional ortho-directing groups as well as for the carbamate group just described. Apart from the studies on the carbamate group described above, Snieckus and his co-workers have used the ortho-lithiation reaction in the construction of 1,3,5-trisubstituted benzenes (5) utilizing the silyl M. P. Sibi and V. Snieckus, J . Org. Chem., 1983,48, 1935. L. Dashan and S. Trippett, Tetrahedron Lett., 1983,24,2039. (a) J. N. Reed and V. Snieckus, Tetrahedron Len., 1983, 24, 3795; ( b ) N. S. Narasimhan and R. Ammanamanchi, Tetrahedron Lett., 1983,24,4733.

12

340

General and Synthetic Methods

group as a temporary protecting group.4For example, the silylated benzene (6), which is readily prepared by lithiation and silylation, can be re-lithiated, then reacted with an electrophile (E+),and finally deprotected with caesium fluoride to give (5). E

OMe

(5) CONEt,

OMe

(6)

I

,

OCONEt , or OCH,OMe

( 41

Asymmetric induction using lithium reagents has developed into an area of considerable importance over recent years, and this year has seen further useful advances. For example, the proline derivative (7; X=H), obtained from proline and pivaldehyde, can be lithiated and then reacted with electropliles (E+)to give, after deprotection, a-substituted proline derivatives (7; X=E) with retention of configuration, representing a case of self-reproduction of ~hirality.~" In separate studies threonine and a cysteine derivative were similarly alkylated at the a-position with equally high s e l e c t i ~ i t yIn . ~the ~ ~ same ~ vein, several papers have been published describing asymmetric conjugate additions. For example, almost complete 1,6-asymrnetricinduction is observed in the synthesis of 5-keto-esters (8) and is effected by the addition of lithiated ( S or R ) hydrazones (9) to a$unsaturated esters6 Similarly, high stereocontrol is also found in the Michael addition of p-lactone enolates (10) to dimethyl maleate to give predominantly (11) with control of both newly formed chiral centre^,^ and the key step in an elegant triply convergent total synthesis of L-( -)-prostaglandin E2is the conjugate addition-alkylation involving the chiral lithium reagent (12) and the vinyl sulphone (13) .8 Enantioselective control in aldol-type reactions deserves and receives much attention because of the central role this reaction plays in synthetic chemistry. This aspect is demonstrated in the synthesis of mallein methyl ether (14), 53% e.e., from the ortho-toluate carbanion (15) generated using the chiral lithium amide bases (16) .g Presumably these bases will find further useful applications. R. J. Mills and V. Snieckus, J . Org. Chem., 1983,48, 1565. (a) D. Seebach, M. Boes, R. Naef, and W. B. Schweizer,J . Am. Chem. SOC.,1983,105,5390; ( b ) D. Seebach and J. D. Aebi, TetrahedronLett., 1983,24,3311;( c )D . Seebach andT. Weber, ibid., p. 3315. D. Enders and K. Papadopoulos, Tetrahedron Lett., 1983,24,4967. J. Mulzer, A. Chucholowski,0. Lammer, I. Jibril, and G. Huttner,J . Chem. Soc., Chem. Commun., 1983, 869.

R. E. Donaldson, J. G. Saddler, S. Byrn, A. T. McKenzie, and P. L. Fuchs, J . Org. Chem., 1983,48, 2167. A. C. Regan and J. Staunton, J . Chem. SOC., Chem. Commun., 1983,764.

341

Organometallics in Synthesis

0

4

O

SO, Ph

H-C5"

CO,Me

R2

R'

0

RO

/ ButMe2Si 0

'C0,Me

(11 1

(12)

(13)

The chiral sulphoxide (17) also undergoes enantioselective aldol-type condensations with aldehydes to yield p-hydroxy-hydrazones and -ketones of good enantiorneric purity.'O

4

qcH2Li \

W \

M

e

Ph

CO, Et

H

"Me,

*

LI NR

T"'lJI,

OH

Obie 0 (14 1

(15 1

(16 1

(17)

The strategy of using chiral auxiliaries to induce further chirality into a molecule has already been demonstrated above; however, the effect is apparent in many different systems, as shown in the enantioselective alkylation of the heterocycles (18) and (19). 1-(S)-Alkyltetrahydroquinolines (20) are prepared in

W N H'

R' = Pr, R * = H

(+I

R' = Pr, R2 = Me

( - 1 R' = H , R~ = ~r

(-1

R ' = Me,R2= Pr (22)

(+I

(21)

lo

R

L. Colombo, C. Gennari, G . Poli, C. Scolastico, R. Annunziata,M. Cinquini, andF. Cozzi, J . Chem. SOC.,Chem. Commun., 1983,403.

342

General and Synthetic Methods

good chemical and enantiomeric yield from (18) by lithiation and alkylation," and chiral tetrahydropyridines (19) provide a new approach to both optical isomers of the alkaloids coniine (21) and dihydropinidine (22).12 In all cases the chiral auxiliaries are removed at the final stage. Synthetic Equivalents.-The ability of organolithium reagents to act as synthetic equivalents of species too reactive to be isolated or even generated in situ has proven to be useful methodology for the synthetic chemist. This year has seen several papers devoted to this field of lithium chemistry. Thus, cheap and commercially available t-butyl methyl ether can be metallated directly to afford a reactive and synthetically useful hydroxymethyl anion equivalent ;13a the same resesrchers have extended this reaction to other alkoxy- and aryloxy-methyllithium reagents, although with these species the lithiation is carried out via Li-Sn exchange.13bThree papers have also been published concerned with the in situ trapping of organolithium-carbon monoxide mixtures by lactones, aldehydes , and ketones, to give c r - h y d r o ~ y - k e t o n e sA. ~point ~ ~ ~ worthy of note here is that the lactone ring usually remains intact during the trapping reaction. Two papers published by Julia and his c o - ~ o r k e r s ~highlight ~ ~ , ~ the versatility of butylthiomethoxyalkenes as anion equivalents. Thus, the t-butylthioalkenes (23) can be deprotonated either at H, or Hbdepending upon the reaction conditions. If potassium t-butoxide-n-butyl-lithium is used, then H, is lithiated to provide an anion equivalent to (24) whereas if s-butyl-lithium is the base then Fib undergoes Li-H exchange to yield an anion equivalent to (25). Furthermore, if the E-isomer of (23), or of (23; R=H), is generated and lithiated then allylic deprotonation takes place, yielding yet another anion equivalent, i.e. (26). It thus seems that the E- and 2-isomers of these t-butylthioalkenes are extremely useful reagents for the preparation of various @unsaturated ketones with the bonus that the yields tend to vary between good and excellent.

New acyl anion equivalents have been popular targets for research over recent years. Apart from the two above-mentioned examples, further examples are provided by the acetylene (27) and the oxathiane (28). Lithiation of (27; X=H) provides the acyl anion equivalent (27; X=Li), which can be reacted with silyl, germyl, or stannyl chlorides to yield the corresponding alk-1-ynyl ketones after A . I. Meyers and L. M. Fuentes, J . Am. Chem. SOC., 1983, 105, 117. L. Guerrier, J . Royer, D. S. Grierson, and H.-P. Husson, J . Am. Chem. SOC., 1983,105,7754. l3 (a) E. J. Corey and T. M. Eckrich, Tetrahedron Lett., 1983, 24, 3165; (b) ibid., p. 3163. l4 (a) D. Seyferth, R. M. Weinstein, W.-L. Wang, and R . C. Hui, TetrahedronLett., 1983,24,4907; ( b ) R. M. Weinstein, W.-L. Wang, and D. Seyferth, J . Org. Chem., 1983,48,3367; (c) ibid., p. 1144. (a) C. B. Bi Ekogha, 0.Ruel, and S. A . Julia, Tetrahedron Lett., 1983,24,4825; ( b ) ibid., p. 4829. l1

l2

Organometallics in Synthesis

343

removal of the protecting group.16 Similarly, if the oxathiane (28; X=OH) is lithiated then (28; X=Li) is formed, which reacts with two electrophiles successively, e.g. PhCN, MeI, to give 2-benzoyl-2-methyl-l,3-oxathiane in a one-pot p r ~ c e d u r e . ~More ' precisely then, (28) can be considered to be an acyl dianion 0 -\ Me$;-

n

/

k0

C s C- C-X

Me3Si

X

equivalent. Another example of a dianion equivalent is pentadienylcarbamate, which acts as a 1,5-dianion equivalent, as shown in Scheme 2; its success relies upon the ease with which the thiocarbamate group undergoes the necessary thermal [3,3]-sigmatropic shifts.l*

S

S

Iii L

S

Reagents: i, LDA, RX; ii, A; iii, LDA, E+

Scheme 2

1,l-Dibromo-2-methoxyethenealso functions as an anion equivalent since it undergoes ready Li-Br exchange, and then reacts with ketones (R1R2CO)to give the corresponding bromo-a#-unsaturated aldehydes (29). l9 Finally, in this section, a simple sequence of reactions converts the lithiated sulphoxide (30) into trans-3-trimethylsilylallyl alcohols (from ketones and aldehydes) and trans-4trimethylsilyl-3-alken-1-01s (from epoxides); (30) therefore acts as a 2-trimethylsilylvinyl anion equivalent. 2o

, Li

M t,Si CH CH

'SPh

II

0 (29) l6 K.

(301

J. H. Kruithof, R. F. Schmitz, and G. W. Klumpp, J . Chem. SOC., Chem. Commun., 1983, 239. l7 K. Fuji, M. Ueda, and E. Fujita, J . Chem. SOC., Chem. Commun., 1983, 49. l8 (a) T. Hayashi, I. Hori, and T. Oishi, J . Am. Chem. SOC., 1983, 105, 2909; (6) T. Hayashi, M. Yanagida, Y. Matsuda, and T. Oishi, Tetrahedron Lett., 1983,24,2665. l9 R. H. Smithers, J . Org. Chem., 1983,48, 2095. C.-N. Hsiao and H. Shechter, Tetrahedron Left., 1983, 24,2371.

General and Synthetic Methods

344

Sulphur-stabilized Anions and Dianions.-Thio-stabilized anions are exceedingly useful synthetic intermediates because of their ready generation, reactivity, and the scope for further functionalization provided by the introduction of the sulphur group into a molecule. Several examples above have already testified to this fact: however, more examples are listed below. Lithiated phenylthiosilylmethanes (31), formed by direct lithiation or alternatively by addition of RLi to the alkene (32), provide convenient access to the corresponding carbonyl compounds by the sequence: alkylation, oxidation, and In similar fashion, lithiated phenylthiopropene (33) adds to ketones to yield cr#-unsaturated thioesters (34) after oxidation, and also undergoes conjugate addition to unsaturated ketones in good yield.22”,bA notable feature of reactions involving (33) is the very high regioselectivity of attack at the y-position which contrasts with the 0-selectivity observed with simple thioallyl-lithium reagents. SiMe,

OH

R’

I

CHZ= C P M e 3 ‘SPh

R-CLi

I

SPh

R2h ! - S P h SPh

The phenylthioallene (35), generated from 1-phenylthioprop-1-yne, adds to ketones (R*R2CO)and after rearrangement and methanolysis of the intermediates leads to C-3-homologated 0-phenylthioenones (36), which are useful intermediates in their own right.23uIn a related paper the same researchers report on the lithiation of the allene (37); with methyl-lithium the C-Si bond is cleaved whereas preferential cleavage of the C- S bond results when butyl-lithium is Interestingly, neither Michael addition nor metallation is observed. PhS

Li

phscMe ’ 0

Me,Si

SPh

\ A /

‘C’

L

II II

c

CH2

II II

C

R’

C

Me

‘Me

The sulphoxide and sulphone groups are usually the preferred sulphur groups for activating protons on a-carbons, and such carbanions have been used for the synthesis of terminal vinyl halides, dichloroketones, vinyl fluorides, fluoromethyl 21

( a ) D. J. Ager, J. Chem. Soc., Perkin Tram. 1,1983,1131; ( b )D. J. Ager, TetrahedronLett., 1983,24, 95.

(a) P. E. Bauer, K. S. Kyler, and D. S. Watt, J . Org. Chem., 1983, 48, 34; ( 6 ) K. S. Kyler, M. A. Netzel, S. Arseniyadis, and D. S. Watt, J. Org. Chem., 1983, 48, 383. 23 (a) A. J. Bridges and R. D. Thomas, J. Chem. Soc., Chem. Commun., 1983,485; ( 6 )A. J. Bridges, V. Fedij, and E. C. Turowski, ibid., p. 1F3.

345

Organometallics in Synthesis

ketones, and vinyl sulphones, with generally good yields in all cases. Specifically, vinyl dichlorides and dichloroketones are prepared by addition of the sulphoxide (38) to alkyl halides and aldehydes, respectively; the double bond in both cases is obtained by pyrolysis concomitant with loss of PhSOH.24"A very similar approach results in the formation of vinyl fluorides and fluoromethyl ketones using the sulphoxide (39).246On the other hand, a new route to synthetically useful vinyl sulphones (40) proceeds via the lithiated sulphone (41), and the reaction conditions are such that a wide range of other functional groups is tolerated in the co-reacting ketones, e.g. e p o x i d e ~ . ~ ~ 0

0

II

II

PhS-CC1,

PhS-CHF Li

I

Li

Me, S ixHS02

R1

Ph

LI

The generation of multiple ions is often required so that a position of lower basicity within a molecule can be activated, an example being the terminal methyl group in polyketones. Harris has now reported that N-methoxy-Nmethylacetamide efficiently acetylates such ions, e.g. (42)+(43) .26 Multiple ions (44) generated from tosylhydrazones of a-keto-amides react with aldehydes R2CH0 (after a Shapiro reaction) to give azetidin-2-ones (45),27and a simple solution to the oxazole problem in virginiamycin is provided by the dianion (46), which reacts specifically at the metallated ring methyl.28In this case the C-5 position must be blocked by a silyl group.

n = 1-3

(a) V. Reutrakul and K. Herunsalee, Tetrahedron Len., 1983, 24, 527; (b) V. Reutrakul and V. Rukachaisirikul, ibid., p. 725. 2s S. V. Ley and N. S. Simpkins, J . Chem. SOC., Chem. Comrnun., 1983, 1281. 26 T. A. Oster and T. M. Harris, Tetrahedron Lett., 1983,24,1851. 27 R. M. Adlington, A. G. M. Barett, P. Quayle, A . Walker, and M. J. Betts, J . Chem. SOC., Perkin Trans. 1, 1983, 605. 28 R. D. Wood and B. Ganem, Tetrahedron Lett., 1983,24,4391. 24

346

General and Synthetic Methods

Another dianion (47) reacts with a variety of aldehydes giving E-2-alkenoic esters in high yield with a stereoselectivity greater than 85%.29In this case trivalent phosphorus reagents, in hexamethylphosphorous triamide, are used as the desulphurization agents. Miscellaneous Reactions.-Within this category falls a number of synthetically useful transformations. The preparation of vinyl dichlorides has been exemplified earlier; an alternative procedure starts from the lithium compound (48) and aldehydes3* trans-Difluoro-olefins (49) are also available from lithiated compounds: however, the starting material here is already an olefin (chlorotrifluoroethene), and the lithium compound (50) is therefore obtained by Li-C1 exchange. Once generated (50) is silylated and then reacted with an organolithium compound (RLi) resulting in the formation of (49).31Extensions of this reaction have been reported, to give fluoro-olefins with the silyl group replaced by various functional groups.

(481

(501

(491

The versatility of lithium reagents as sources of unsaturated systems is further illustrated in a new and general method for the synthesis of y-hydroxy- and y-0x0-a$-unsaturated esters and nitriles as described in Scheme 3 .32 Similarly, a-lithio-alkenenitriles react with protected cyanohydrins to give the 'crossed' Thorpe-products (51) .33

X = CN or CO,R

1 2

x

R3

R'

0 Reagents: i , R3CHXLi;ii, B-, MnO,

Scheme 3 S. Matui, K. Tanaka, and A. Kaji, Synthesis, 1983, 127. A. Hosomi, M. Inaba, and H . Sakurai, Tetrahedron Lett., 1983, 24,4727. 31 S. Martin, R. Sauvetre, and J.-F. Normant, Tetrahedron Lett., 1983,24, 5615. 32 M. Larcheveque, P. Perriot, and Y. Petit, Synthesis, 1983,297. 33 K. Kobayashi and T. Hiyama, Tetrahedron Lett.,1983,24, 3509.

29

347

Organornetallies in Synthesis

Metallation of methylacetylenes provides an easy regiocontrolled route to both unsaturated allenic compounds and condensed bicyclic thiophenes, as illustrated in Scheme 4.34",b.

i, i i

K

A

R

L

R'

R-C=,C-CH3 1

= R'CEC

-

.-*iii

R = akyl

R' 'C=C=C H'

/"

E'

2

R =H, alkyl, NR2 or SR Reagents: i, BuLi; ii, CS,; iii, E+

Scheme 4

One of the major problems associated with the transformation of carboxylic acids into the corresponding methyl ketones using methyl-lithium has been the co-production of tertiary alcohols; this problem has now been largely overcome by using chlorotrimethylsilane as the quenching agent immediately following the On the other hand, cyclic ketones, e.g. cyclopenaddition of methyl-lithi~m.~~ tanones, are formed by conjugate addition of organolithium (RLi) to the diester (52) followed by cyclization to give the substituted cyclopentanone (53) .36 0

(53)

( 5 4 ) X, Y = CN, CO,R, COIW,

As might be expected the preponderance of references to Group I organometallics is to lithium reagents. However, as the two references below demonstrate, other elements in Group I, in this case potassium, must not be overlooked. In the first, potassium anions of (54) prove to be substantially more reactive than the corresponding lithium anion and in several instances yield products where the lithium compound fails totally.37 Secondly, in the preparation of 2-hydroxymethylcyclopentanone, an important and useful building block, potassium 41

( a ) C . Huynh and G. Linstrumelle, J . Chem. SOC., Chem. Commun., 1983,1133; (6) R . L. P. de Jong

and L. Brandsma, ibid., p. 1056. G. M. Rubottom and C.-W. Kim, J. Org. Chem., 1983,48, 1550. 36 W. A. Nugent and F. W. Hobbs, jun., J. Org. Chem., 1983,48,5364. 37 P . R. Hamann and P. L. Fuchs, J . Org. Chem., 1983,48,914. 35

348

General and Synthetic Methods

hydride proves to be the best base in a classical formulation of cy~lopentanone.~~ Previously reported syntheses are generally low yielding. 2 Group11

Magnesium.-The reactivity and synthetic utility of magnesium-based reagents has long been recognized, and despite their basic similarity to organolithium reagents it is sometimes possible to find a magnesium reagent whose reactivity is radically different and sometimes complementary to that of a structurally similar organolithium. Just such an example is illustrated this year in a paper concerned with the regiospecific preparation of thermodynamically favoured silyl enols. Bromomagnesium di-isopropylamide generates the thermodynamically favoured enolate (>20:1 over kinetic product), which can be readily silylated to give the silyl enol ether, a reaction which contrasts sharply with that of lithium di-isopropylamide .39 Not surprisingly the majority of papers that deal with organomagnesium compounds relate to their use as conventional Grignard reagents. In recent years the trend in this area has been towards reagents capable of reacting in a specific sense and 1983 proved to be no exception. In the total synthesis of (+)methylpseudomonate from carbohydrates, a Grignard reagent from (55) has been used to open the epoxide (56).40 The reaction is characterized by the regiospecificity of the nucleophilic ring-opening of the epoxide to (57), the specific formation of the E-double bond, and the formation of the normal, unrearranged Grignard reagent. High stereocontrol is also seen in the addition of methylmagnesium iodide to propiolic acid to give 2-3-iodoacrylic acid in conditions only slightly different to those used to prepare butenolides from propiolic acid .41 In common with lithium reagents, magnesium reagents can promote asymmetric inductions via the agency of a chiral auxiliary or chiral solvent. For

0

s-

OH

II

S-CONMe 1

2

&CON R *

Me2

I

To I

(581

(59)

P. E. Eaton and P. G. Jobe, Synthesis, 1983, 796. M. E. Krafft and R. A . Holton, Tetrahedron Lett.,1983,24,1345. J. Beau, S. Aburaki, J . Pougny, and P. Sinay, J . A m . Chem. SOC.,1983,105,621. 41 M. E. Jung, J. A. Hagenah, and Z. Long-Mei, Tetrahedron Idett.,1983,24, 3973. 38

39

Organometallics in Synthesis

349

example, very high levels of asymmetric induction are possible during the condensation of the chiral sulphoxides (58) with aldehydes (RCHO) using t-butylmagnesium bromide as base.42After reductive cleavage of the sulphoxide group the P-hydroxy-amides (59) are obtained in good yield. A similar highly enantioselective synthesis is observed during the addition of Grignard reagents to keto-esters of 8-phenylmenthol, resulting in good yields, both chemical and optical, of tertiary alcohols.43A slightly different approach has been used in Grignard crosscoupling reactions leading to optically active alkenes where the chiral auxiliary is in the ~ a t a l y s t .In~ both > ~ ~cases the chiral catalyst is a nickel salt containing chiral phosphorus ligands. Continuing in the same vein, transition-metal catalysts have been used in the synthesis of the alkenes and butadienes shown in Scheme 5. In two cases nickel

R

R

R2 iii R z A r

(Ref. 48)

d

RMg X

Ar Ar

Reagents: i ,

7

; iii.

OP(OEt)?

Ar

RlxB; R

; ii, ArI-X

-

R’

Scheme 5

catalysts with phosphorus ligands are ~ ~ e dand, in~ the ~ third , ~ an ~ iron catalyst (FeDBM), is found to be an excellent promoter of the cross-coupling reaction.48 This year several syntheses of alkenes from Grignard reagents have been reported, a further example here being the preparation of terminal alkenes from acyl chlorides as shown in Scheme 6.49Best results are obtained when ether is used R’

RCOC~ i.ii

\C/OMgBr

~

R2’

.. .

R’

Ill

‘CH2Li

Reagents: i, CH2N,; ii, R2MgBr, MgBr,; iii, Li

Scheme 6 45R. Annunziata, M. Cinquini, F. Cozzi, F. Montanari, and A . Restelli, J . Chem. SOC., Chem. Commun., 1983, 1138. 43 J. K. Whitesell, D . Deyo, and A. Bhattacharya, J . Chem. SOC., Chem. Commun., 1983, 802. 44 G. Consiglio, F. Morandini, and 0. Piccolo, J . Chem. SOC., Chem. Commun., 1983, 112. 45 T. Hayashi, M. Konishi, M. Fukushima, K. Kanehira, T. Hioki, and M. Kumada, J . Org. Chem., 1983,48,2195. C. Sahlberg, A . Quader, and A . Claesson, Tetrahedron Lett., 1983,24,5137. 47 E. Wenkert, J. B. Fernandes, E. L. Michelotti, and C. S. Swindell, Synthesis, 1983,701. G. A . Molander, B . J. Rahn, D. C . Shubert, and S. E. Bonde, Tetrahedron Lett., 1983,24,5449. 49 J . Barluenga, M. Yus, J. M. Concellon, and P. Bernad, J . Org. Chem., 1984, 48, 3116.

350

General and Synthetic Methods

as solvent for the addition of the Grignard reagent, and then THF is added as co-solvent for the final lithiation reaction. In the preparation of the pentacycloundecane (60) two sequential Grignard additions to the corresponding diketone (61) provide access to the desired product in good yield.50The silylated compound (Me,SiCH,HgCl) is the preferred reagent, and the method is found to be far superior to the classical Wittig reaction.

Grignard reagents are very effective in the synthesis of a-hydroxy-ketones (62) from readily available silylated cyanohydrins (63) ,sl whereas ketones have been prepared from carboxylic acids and Grignard reagents using the chloroenamine (64) as a condensation agent.52The Grignard reagent actually attacks the intermediate (65), formed in situ from the carboxylic acid and the chloroenamine. The same reagent (64) and ally1 alcohols give an intermediate which provides excellent yields of cross-coupled aikenes upon treatment with Grignard reagents.53 A notable feature in this reaction is the high level of regiocontrol during the attack of the Grignard reagent at the a-position for PhCH2CH2MgBrand at the y-position for aryl Grignard reagents. 0

d

CI

OTMS

In the preparation of Grignard reagents from 3-halogenoethers it is imperative that highly reactive magnesium metal is used in the formation of the Grignard reagent to prevent competing cyclopropane formation.s4New Grignard reagents are fairly rare; however, the Grignard reagent (66) is an example of a new versatile nucleophilic hydroxymethylating agent for organic halides (RX) .55 Alkylation of (66) with an alkyl, aryl, or heteroaryl halide in the presence of a metal catalyst (Pd, Ni, Cu) gives compound (67), which readily oxidizes to alcohols (68). Finally, the magnesium complex (69; X=MgBr) is an efficient fixation agent for carbon dioxide, and the carboxylate complex (69; A. P. Marchand and R . Kaya, J . Org. Chem., 1983,48,5392. L. R. Krepski, S. M. Heilmann, and J . K. Rasmussen, Tetrahedron Lee., 1983,24,4075. 52 T. Fujisawa, T. Mori, K. Higuchi, and T. Sato, Chem. Lett., 1983, 1791. 53 T. Fujisawa, S. Iida, H. Yukizaki, and T. Sato, Tetrahedron Lett., 1983, 24, 5745. 54 T. P. Burns and R. D . Rieke, J . Org. Chem., 1983,48,4141. 55 K. Tamao, N. Ishida, and M. Kumada, J . Org. Chem., 1983,48,2120. 51

351

Organornetallies in Synthesis

X = C02MgBr) so formed transfers the carboxy-group to ketones (R1COCH2R2) to give the corresponding a-carboxy-ketone~.~~

(Pri0)2MeSiCHtMgCI

(Pri0I2McSiCHZR

RCH20H

X-N

N-X \ I (CHZ),

Zinc and Mercury.-Once again activity in the zinc area has been of a low order; however, two papers have appeared providing details of some useful synthetic transformations involving organozinc compounds. In the first , a novel synthesis of a,,&unsaturated cyclopentenones via allylzincation of silylalkynes (Scheme 7)

n- C6H,

n - C 6 H 13 e S i M e 3

n- C6H,3-CEC-SiMe3

&

P

OH l ii

CO,H Reagents: i , CH2=CHCH2ZnBr, I*; ii, [O]; iii, MeLi; iv, BuLi

Scheme 7

is reported.57 Interestingly, the presence of the silicon group in the alkyne is essential since no carbometallation is found to occur in its absence. In the second paper organozinc compounds (RlZnX) were found to react with acyl chlorides (PdPR3, cat.), providing a very general and convenient route to ketones.58 Danishefsky and his co-workers have been active in the field of mercury-based reagents and have developed a synthesis of S-coniceine (70) from the alkene (71) via intramolecular ureidomercuration. Reductive coupling to give (72) followed by two simple steps results in the formation of d - ~ o n i c e i n eThe . ~ ~ same authors ha:e also used a mercury-catalysed cyclization and reductive coupling reaction of the acrylanilide (73) to generate the tricycle (74).60 Similarly, mercuric acetate N. Matsumura, N. As&, and S. Yoneda, J . Chem. SOC., Chem. Commun., 1983,1487. E.-i. Negishi and J. A. Miller, J . Am. Chem. SOC., 1983, 105, 6761. 58 E.4. Negishi, V. Bagheri, S. Chatterjee,F. Luo, J. A. Miller, and A . T. Stoll, TetrahedronLen., 1983, 24, 5181. 59 S. Danishefsky, E. Taniyama, and R. R. Webb, jun., Tetrahedron Lett., 1983, 24, 11. S. Danishefsky and E. Taniyama, Tetrahedron Lett., 1983,24,15. s6 57

352

General and Synthetic Methods

facilitates ring closure of p-lactams (75),yielding the lactam (76) after bromination. The preceding cyclizations all rely upon conventional mercury cyclizing reagents; however, mercury(n) trifluoromethanesulphonate-amine complex is a new cyclization reagent promoting the cyclization of various farnesol derivatives in good yield and with high selectivity.62

Cbz (71 1

(70)

(72)

R (73) H

0

H

”

Two papers concerned with the coupling ofp-acetamido-radicals, generated by reduction of the corresponding organomercurials, both involve their addition to electron-deficient alkenes. Kozikowski sees the products (77; R=H) as useful building blocks for alkaloid constr~ction,~~ and Henning converts (77; R=C1) into proline derivatives as described below .@

Two useful-looking general syntheses also rely upon the intermediacy of meradd the elements of mercuric chloride across curials. 4-Hydroxyalk-2-yn-1-ones the triple bond to give vinylmercurials (78; R=Me) in a reaction which is claimed to represent the first example of syn-addition of mercuric chloride.65Vinyl mercurials (78) can then be dehydrated to 3-mercurialfurans, which carbonylate to give 3-furylcarbonyl compounds. One drawback of this mercuration reaction appears to be its sensitivity to substituent effects, since anti- as well as synaddition occurs in some cases, e.g. when R1=R2=Me, or R=OMe. A M. L. Phillips, R. BonjoukSan, N. D. Jones, A. H. Hunt, and T. K. Elzey, Tetrahedron Len., 1983, 24,335. 62 M. Nishizawa, H. Takenaka, H. Nishide, and Y. Hayashi, Tetrahedron Lett., 1983, 24, 2581. 63 A. P. Kozikowski and J. Scripko, Tetrahedron Lett., 1983,24,2051. R. Henning and H. Urbach, Tetrahedron Lett., 1983,24,5343. 65 R. C. Larock and C. Liu, J . Org. Chem., 1983,48,2151. 61

Organometallics in Synthesis

353

benzoyloxy-mercuration-demercuration reaction has been used to good effect in a new strategy for the synthesis of aldol-type products, since the diastereoselective construction of certain carbon skeletons bearing alternate OR and alkyl substituents, e.g. (79), by classical aldol reaction can still be problematical.66 Thus, the alternative reaction sequence is by the a-alkylation of/3-hydroxy-esters, followed by a two-carbon chain extension (via Wittig olefination) and culminating in the benzoyloxymercuration, e.g. (79)-+(80). Me

(781

(791

Me

(801

3 Group I11

Boron.-Several papers have appeared relating to asymmetric hydroborations and therefore further extending the scope of this useful reaction. For example, the boron reagents prepared from borane and the chiral amino-alcohols (S)valin01~~" and (81)67breduce ketones in high chemical and optical yields, and particularly the amino-alcohol (81), which is claimed to give enantiomeric excesses (e.e.'s) of 94-100% accompanied by chemical yields of -100%. The chiral borane-amine complexes (82) also reduce ketones to the corresponding chiral both enantiomers of the alcohol can be formed separately depending upon the enantiomer of 2,2'-dihydroxy-6,6'-dimethylbiphenyl( R or S ) used. In a similar fashion the borane (83) reduces aryl-a-halogenoalkyl ketones to the corresponding halohydrins in very high optical and chemical yields, although the aliphatic analogues give a somewhat lower yield.69Likewise hydroboration of certain a-chiral olefins and ketones with highly hindered boranes also shows high s e l e ~ t i v i t yIn . ~this ~ case disiamyl- and dicyclohexyl-borane both show selectivity exceeding that of 9-BBN in the reduction of a-chiral olefins such as (84; X=CH2) and attaining greater than 98% epimeric purity for the very sterically hindered bis-trans-2-methylcyclohexylboranereagent. Interestingly, the reduction of the related ketones (84; X=O) proceeds with high selectivity but in an opposite sense to 9-BBN and, perhaps surprisingly, to trialkylborohydrides; the latter have previously been reported to reduce cyclohexanones in the same sense as dialkylborohydrides. 9-BBN and thexylborane have also been used with good results in the diastereoselective synthesis of threo-diols (85) from secondary allylic alcohols (86).'l Diastereoselectivities vary between 8:1and 15:1,and furthermore S. Thaisrivongs and D. Seebach, J . Am. Chem. SOC., 1983,105,7407. (a)S . Itsuno, A. Hirao, S. Nakahama, and N. Yamazaki, J . Chem. SOC., Perkin Trans. 1, 1983,1673; ( b ) S. Itsuno, K. Ito, A. Hirao, and S. Nakahama, J. Chem. SOC.,Chem. Commun., 1983,469. H. Suda, S. Kanoh, N. Umeda, T. Nakajo, and M. Motoi, Tetrahedron Left., 1983, 24, 1513. H. C. Brown and G. G. Pai, J . Org. Chem., 1983,48, 1784. 70 M. M. Midland and Y. C. Kwon, J . Am. Chem. SOC., 1983, 105,3725. 71 W. C. S till and J. C. Barrish, J . Am. Chem. SOC.,1983,105,2487.

67

@

@

354

General and Synthetic Methods

9-BBN is found to be most suitable when the alkene is at the terminal position, whereas thexylborane works better for trisubstituted olefins.

0 0 \ /

H/B‘NR’ (81 1

R2R3

(83 1

(82)

Me

OH

( 8 41

Me

OMc

OH (87 1

(85)

Boronates have featured in a number of useful transformations this year. For instance, the boronic esters (87) react with the lithium reagent [LiCH(OMe)SPh] to give, after treatment with mercuric chloride, the boronate ester (88), which may then be oxidized to the corresponding aldehyde (RCH0).72Since (87) can be readily obtained by selective hydroboration of an alkene, the overall sequence provides a convenient new method for introducing a formyl group into alkenes in a regio- and stereo-controlled manner. Another boronic ester homologation occurs with 99% enantioselectivity, and is demonstrated in the synthesis of the pheromone (3S,4S)-4-methylheptan-3-01(Scheme 8) .73 The addition of zinc chloride is critical for both high selectivity and high chemical yield. Similar methodology has been applied to the synthesis of em-Brevicomin. Allylboronates are present as intermediates in three useful syntheses all involving the production of stereo-defined homoallylic alcohols. The allylboronate (89), formed by reaction between (90) and an alkenyl-lithium followed by rearrangement, reacts at the y-position with aldehydes (RCHO) to give the homoiii,iv

‘0

R‘

;I

Reagents: i, LiCHCl,; ii, ZnC1,; iii, R’MgBr; iv, H,O,

Scheme 8 7* H. 73 D.

C. Brown and T. Imai, J . Am. Chem. Soc., 1983,105,6285. S. Matteson and K. M. Sadhu, J . Am. Chem. SOC.,1983, 105, 2077.

~

v\fc OH

OH

Organometallics in Synthesis

355

allylic alcohols (91).74Similarly, the allylboronate (92) gives high yields of the 2-alkene (93) ,75 and the allylboronate (94) reacts in a highly diastereoselective fashion with the chiral aldehyde (95) to give (96), which can then be converted in two steps into a D-fucose d e r i ~ a t i v eIn . ~ an ~ analogous reaction the allylborane (97) reacts at the y-position with pyruvates to yield the threo-alcohol (98).77

(90

(92 1

(91

w8 B N bH (96)

(97)

(98)

Branched- and straight-chain homoallylic alcohols are obtained from the same allylborane system simply by altering the reaction conditions; the key to the method is the use of the selenylallylborane (99)) which readily rearranges to the borane Once formed the borane (100) can be trapped with aldehydes to give linear homoallylic alcohols or alternatively isomerized to the borane (101)) which can then be trapped by aldehydes to yield branched-chain homoallylic alcohols. The whole reaction sequence depends on the relatively slow (compared with conventional allylboranes) iosomerization (loo)-+( 101). An unusually slow thermal isomerization of alkyldihalogenoboranes also allows for a highly regiospecific and stereospecific synthesis, in this case) of alkyldihalogenoborane~.'~ It has been found that 3-hexylboranes, e.g. (102)) isomerize 22 R kePh Pr- CH- Et PhSc

R

(99)

R

(100)

m6RzSePh

(101 1

I

BCL,SMe (102

P. G. M. Wuts, P. A. Thompson, and G. R. Callan, J . Org. Chem., 1983,48,5398. R. W. Hoffmann and B. Landmann, Tetrahedron Lett., 1983,24,3209. 76 W. R. Roush, D. J. Harris, and B. M. Lesur, Tetrahedron Lett., 1983,24,2227. TI Y. Yamamoto, T. Komatsu, and K. Marayama, J . Chem. SOC., Chem. Commun., 1983,191. 78 Y. Yamamoto, Y. Saito, and K. Maruyama, J . Org. Chem., 1983,48,5408. 79 H. C. Brown and U . S. Racherla, J . Org. Chem., 1983,48,1389. 74

75

356

General and Synthetic Methods

times slower than the corresponding 9-BBN derivative, which was previously the only 3-hexylborane to be resistant to thermal isomerization. Thus hydroboration of labile olefins where isomerism is undesirable now seems feasible using, HBC12.SMeas hydroborating reagent. Several papers have been published pertaining to the boronation of alkynes and the various useful synthetic reactions arising from the organoboron intermediates so obtained. Some of these papers are highlighted in Scheme 9.

X = Br

(Ref.83) -x=~iorar xi i

R-c-c-x iv, v

But

Br

R

I R’

X X

= I or

Br

Reagents: I , Catecholborane; ii, cis-ICH= CHR’; iii, trans-ICH= CHR1; iv, BuLi; v, BF3.0Et2; 0 vi, ; vii, N-0; viii, LiAIH,; I X , X B Q ; x, AcOH; xi, LiC-CR1; xii, R? RI R’

A

Pelter and his group have released a number of interesting papers concerning the use of the bulky dimesitylboron group in organic synthesis. Dimesitylborane (103), a readily available, solid, stable borane, is reported to be an extremely selective reagent for regioselective hydroboration of unsymmetrical alkenes and alkynes; being sensitive to steric factors, it tends to attack at the least hindered so G. Cassani, P. Massardo, and P. Piccardi, Tetrahedron Lett., 1983,24,2513.

( a ) M. Yamaguchi and I. Hirao, Tetrahedron Lett., 1983, 24, 391; ( b ) ibid., p. 1719. (a) S. Hara, H. Dojo, S. Takinami, and A. Suzuki, Tetrahedron Lett., 1983,24,731; ( 6 ) S. Hara, Y. Satoh, H . Ishiguro, and A. Suzuki, ibid., p. 735. 83 S. Hara, T. Kao, and A. Suzuki, Synthesis, 1983, 1005. 84 H. C. Brown, N. G. Bhat, and D. Basavaiah, Synthesis, 1983,885. 81

82

Organometallics in Synthesis

357

part of the molecule.8saFurthermore, the bulky dimesitylboron group favours the formation of a-carbanions, by deprotonation. These anions can then be alkylated and oxidized to give alcohols [equation (l)]and condensed with ketones and aldehydes to give alkenes in a boron equivalent of the Wittig reaction [equation (2)] .8sLd Heteroatom-substituted derivatives (104) are also prepared easily and some deprotonate readily to give synthetically useful anions,8se as does the alkylborane (105) to give the anion (106), which then reacts regio- and stereospecifically at the y-position to give trans-vinylboranes .8sf The latter can be oxidized to give aldehydes. Mes 28H2MR

Mcs 2BH

(104)M = Si, Sn,Pb, S, or Hg

(103)

M~S,BCH,-

M e s 2 8 e

Mes2-6 (105 1

(106)

-

M ~ ~ ~ B C H ~ % M ~ S R~ B C RCHOH H~

- R2

3

R'

Li

+

Me2BCR' R2

+

R3R4C0

(11

Simple boron reagents are capable of promoting a number of useful functional group interchanges as evidenced by their further use this year. Trimethylamineborane is a useful reagent for the N-acylation or N-alkylation of amines by carboxylic acids,86whereas the borolane (107) cleaves the carbon-oxygen bond in methoxyethoxymethyl ethers (MEM)in high yield even at -78 "C.% Similarly dimethylboron and diphenylboron cleave MEM,MOM,and MTM ethers as well

(109)

(108

(107)

OH I *SOPh

C02Me I

But Mc2Si0

(a) A. Pelter, S . Singaram, and H. Brown, Tetrahedron Left., 1983, 24, 1433; ( b ) A. Pelter, L. Williams, and J. W. Wilson, ibid., p. 627; (c) A. Pelter, B. Singaram, and J. W. Wilson, ibid., p. 635; A. Pelter, B . Singaram, L. Williams, and J. W. Wilson, ibid., p. 623; ( e )M. V. Garad, A. Pelter, B . Singaram, and J. W. Wilson, ibid., p. 637; (f) A. Pelter, B . Singaram, and J. W. Wilson, ibid., p. 631. 86 G . Trapani, A. Reho, and A. Latrofa, Synthesis, 1983, 1013.

85

(cf)

358

General and Synthetic Methods

as a c e t a l ~and , ~ ~diphenylboron ~ bromide cleaves aliphatic, aromatic, and cyclic ethers efficiently.876 The elegant work carried out on boron enolates in the past few years has been continued this year and is exemplified by the directed aldol condensations of the boron enolates (108) and (109) to give the racemic ester (110) and the chiral ester (ill), respectively, in high yield.88The ester (110) is used in the synthesis of (4RS, 6S,7S)-serricormine. Aluminium.-Not surprisingly, fewer references have been found for aluminium reagents than for the corresponding boron reagents. Nevertheless, several very useful transformations may be accomplished using organoaluminium compounds as the following demonstrates. Ethylaluminium dichloride (EtAlCl,) in toluene causes the ‘cyclic ketone (112) to undergo a cyclocontraction-spiroannulation reaction to give the bicycle (113), thus representing a stereoselective approach to s p i ro ~ y cle s The .~~ choice of solvent is important in giving a clean reaction and’ thereby avoiding formation of (114). In a related reaction dimethylaluminium chloride (Me2A1C1) initiates cyclization of the dienone (115) to provide the trans-fused hydrindenone (116) in 50% yield, a reaction with obvious implications.% The same reagent also catalyses two sequential ene reactions between aJ-unsaturated carbonyl compounds and alkylidenecycloalkenes (117) to yield bicyclic alcohols (118), albeit in rather variable yieldsg1 OH

0

H (116)

B s’

(117)

(I181

Lithium aluminium hydride promotes a facile reductive rearrangement of the alkynylhalohydrins (119) to give a-alkenylhydroxy-compounds (120), via a cyclic aluminium intermediate, and thence the corresponding keto-compounds after ~xidation.~, Reductive cleavage of the chiral acetals (121), also using an aluminium hydride (R,AlH), results in the formation of chiral alcohols (122).93 Since acetals (121) can be obtained readily from ketones (R1R2CO)and the chiral (a) D . R . Williams and S. Sakdarat, Tetrahedron Lett., 1983,24,3965; ( b ) Y. Qindon, H. E. Morton, and C. Yoakim, Tetrahedron Lett., 1983, 24, 3969; (c) ibid., p. 2969. R. Barker and J. A . Devlin, J . Chem. SOC., Chem. Commun., 1983,147. 89 B. M. Trost and B. R. Adams, J . Am. Chem. Soc., 1983, 105,4849. B. B . Snider and T. C. Kirk, J. Am. Chem. SOC., 1983,105,2364. 91 B. B . Snider and E. A . Deutsch, J . Org. Chem., 1983,48,1822. 92 P. A. Wender, D. A . Holt, and S. M.Sieburth, J . Am. Chem. SOC., 1983,105,3348. 93 A . Mori, J . Fujiwara, K. Maruoka, and H. Yamamoto, Tetrahedron Lett., 1983,24, 4581. 87

Organornetallies in Synthesis

359

auxiliary (121a) this reaction represents a convenient method for the asymmetric reduction of ketones. Similarly, achiral trialkylaluminium reagents (R3A1) attack 2,3-epoxy-alcohols (123) to provide a-chiral aldehydes (124) after a periodate OH

_-C=CR

I,,

R2

OH

RZTC=C, (1201

OH

R

(121a)

(1 19)

H

OH

(121)

OH

(123 1

(122)

I1 2 4 )

treatment.94 In contrast, in the enantioselective ortho-hydroxyalkylation of phenols, the aluminium reagent is the source of the chirality as depicted in Scheme

x

X

x

Scheme 10

Trialkylaluminium, formaldehyde, and the enol ether (125) react to form the adduct (126) .% Interestingly, the reaction shows high threo-selectivity (9&95%) regardless of the isomer of the enol ether (125) used. Finally, in this section, tristrimethylsilylaluminium effects the chemoselective and stereocontrolled umpolung of aryl and vinyl halides (Ni or Pd catalyst) yielding the corresponding silyl derivatives, e.g. (127)-+( 128) and (129)-+( 130).97

(125)

(126)

(127)

SiMe, I

W. R.Roush, M. A . Adam, and S. M. Peseckis, Tetrahedron Lett., 1983,24,1377. F. Biga, G. Casiraghi, G. Casnati, G. Sartori, and L. Zetta, J . Chem. SOC., Chem. Commun., 1983, 1210. % B. B. Snider and G. B. Phillips, J . Org. Chem., 1983,48,2789. 97 B. M. Trost and J . 4 . Yoshida, Tetrahedron Lett., 1983,24,4895.

9.1

95

General and Synthetic Methods

360 4 GroupIV

Silicon.-Allylsilanes are versatile intermediates as evidenced by the large volume of literature published in recent years concerned with their use in synthetic chemistry. Consequently new syntheses of allylsilanes are useful additions in this area, and this is so for the two papers detailed below. In the first, various allylsilanes have been synthesized in high yield from the corresponding allylic phosphonates and the reagent combination PhMe2Si-A1Et2.98The method is flexible so that the same reagent can be used to prepare vinylsilanes from enolphosphonates. Tertiary allylic acetates also give allylsilanes; however, unlike the previous method the silyl groups are introduced y- to the leaving acetate group. In this way, stereo-defined cyclohexanes (131a) and (131b) have been prepared in high yield, thus extending the scope of this general reaction.99

mx

9

H SiMe3

Ph

(131 1 a; X = SiMe2Ph,Y = Me

(132 1

b; X = Me, Y = SiMe,Ph

Once again a number of useful enantioselective syntheses involving allylsilanes have been reported. For example, with Lewis acid catalysis the optically active cyclic allylsilanes shown in Scheme 11react with ethylene oxide and aldehydes to

Reagents: i , HSiMeCl,, [PdCl,{(R)-(S)-PPFA}]; ii, EtOH, NEt,; iii, MeLi; it, TiCl,, RCHO

0

v , TiCI4,

Scheme 11

give the corresponding hydroxyalkyl-cyclopentenes and -cyclohexenes in good yields.100In an analogous fashion the allylsilane (132) reacts with aldehydes to yield homoallylic alcohols with high enantioselectivity.lOOIn contrast, the achiral 98

99 loo

Y . Okudo, M. Sato, K. Oshima, and H. Nozaki, Tetrahedron Lett., 1983, 24,2015. I. Fleming and N. K. Terrett, Tetrahedron Left., 1983, 24, 4151. ( a )T. Hayashi, K . Kabeta, T. Yamamoto, K. Tamao, and M. Kumada, Tetrahedron Lett., 1983,24, 5661; ( b ) T. Hayashi, M. Konishi, and M. Kumada, J . Org. Chem., 1983, 48, 281.

Organometallics in Synthesis

361

silanes allyl- and methallyl-trimethylsilane attack the chiral alkoxy-aldehydes (133) and (134) to give chiral homoallylic alcohols (135) and (136), respectively. lol For a-alkoxy-aldehydes, e.g. (133), diastereofacial preference is excellent with isomer ratios of >35 :1attainable, althoughp-alkoxy-aldehydes show a somewhat inferior selectivity (7-12: 1).A more remote asymmetric induction than that just described is seen in the protodesilylation of the allylsilanes (137) resulting in the formation of alcohols (138).lo2 Interestingly, when the acetates corresponding to (137) are used the opposite stereochemistry is produced at the new chiral centre.

x:::

PhCH20&

CHO OH

(133)

(134)

R

(135)

Mt,

OH (136)

(137)

R (138)

The synthesis of several homoallylic alcohols has already been described above; however, further evidence for the utility of allylsilanes in the preparation of homoallylic alcohols is apparent in the highly erythro-selective reaction between E-crotyl- and E-cinnamyl-trimethylsilanesand various aldehydes. lo3 Unfortunately the selectivity is relatively poor for the 2-isomers. In a new siliconmediated rearrangement of epoxides, allyl alcohols (140) are formed from allylsilanes (139).'04 Surprisingly, none of the isomer (141) is formed in this reaction.

(139)

(140 1

(141 1

In a quite different reaction of allylsilanes, the silyl enamine (142) condenses with various enamines to give m-aminophenols; the presence of the silyl group in (142) ensures a selective cross-condensation reaction and avoids self-condensations. l o 5 ~ The , structure of the m-aminophenol that is formed depends upon the S.-i. Kiyooka and C. H. Heathcock, Tetrahedron Lett., 1983,24,4765. S. R. Wilson and M. F. Price, Tetrahedron Lett., 1983, 24,569. lo3 T. Hayashi, K. Kabeta, I. Hamachi, and M. Kumada, Tetrahedron Lett., 1983, 24, 2865. I. Cutting and P. J. Parsons, J . Chem. SOC., Chem. Commun., 1983,1435. 1°5 (a) T. H. Chan and G . J. Kang, Tetrahedron Left., 1983,24, 3187; ( b ) ibid., p. 3051. lol

lM

General and Synthetic Methods

362

nature of the enamine used to react with (142); if acyclic enamines (143) are used then rn-aminophenols (144) are formed, whereas if cyclic enamines [143; R1R2=(CH2)"; n=2 or 31 are co-reactants then m-aminophenols (145) are formed in preference. However, for cyclic enamines derived from medium-ring cyclic ketones [143; R1R2=(CH2)9]the balance is tipped back in favour of rn-aminophenols [144; R1R2=(CH,),]. The latter compounds have also been resolved into optical isomers.

Me,Si

(142)

&OH

Me

C0,Mc (143 1

OH

(144)

(145 1

Vinylsilanes are yet another class of valuable synthetic intermediates and examples of their use abound in the literature. This year, for example, a novel, general synthesis of four- to six-membered carbocyclic rings has been achieved via intramolecular acylation of n-trimethylsilyl-n-alkenoyl chlorides, where n=4 or 5 .Io6 Another intramolecular acylation of vinylsilanes provides a new synthesis of various cyclopentenones. lo7 The route is versatile, allowing the preparation of cyclopentenones (146) from vinylsilanes (147), and can also be used for the construction of spirocyclopentenones. In this context, the spiro-compound (148) is prepared readily from the vinylsilane (149), thus providing a rapid construction of a trichothecane-type carbon framework.

The cleavage of carbon-silicon bonds by fluoride ion is a well recognized reaction though not always a clean procedure, especially for the cleavage of the C-Si bond in vinylsilanes. It now seems that the presence of one or two phenyl rings on the silicon atom, i.e. PhMe2Sior Ph,MeSi, greatly facilitates the cleavage lo6

lCn

K. Mikami, N. Kishi, and T. Nakai, Tetrahedron Lett., 1983,24,795. E . Nakamura, K. Fukuzaki, and I. Kuwajima, J. Chem. SOC., Chem. Commun., 1983, 499.

363

Organometallics in Synthesis

reaction (with Bu,NF) and a clean reaction and good yields of desilylated alkenes are obtained.los In the same vein, the C-Si bond in the 2-unsaturated nitrile (150) is cleaved readily and the anion so generated can be trapped with carbonyl compounds to give hydroxynitriles (151) with complete retention of configuration.lo9 CN

CN

OH

(150)

(151)

Trimethyl-(2-nitroviny1)silane reacts with organometallic compounds regioselectively to yield useful looking trimethyl-(1-nitromethylalky1)silanes in excellent yields.l'* This is therefore claimed to be the first example of reactivity umpolung of 1-alkenylsilanes. The vinylsilane (152) is yet another useful intermediate since it acts as a single synthon for both the (E)-P-formylvinyl cation and anion depending on how the bromine atom is replaced in the alkylation reaction.lll Such alkylation results in the vinylsilane (153), which can then be converted into the a,P-unsaturated aldehyde (154) by standard synthetic manipulation. a$-Unsaturated compounds (155) are also formed after a BF3,0Et2-induced Pearrangement of epoxysilanes (156), which are in turn obtained from the vinylsilanes (157).'lk a different type of rearrangement occurs when the vinylsilanes (157) are treated with catalytic amounts of NaH in HMPA.112bIn this case a 1,3 silyl group shift occurs from carbon to oxygen, representing the first case of a rearrangement of silicon from an sp2 carbon to oxygen. THPOCRiMe,

H

Br

THPOCH,

R

\=\

(153)

R2

0

CHO

X

H

(152 1

R'

SiMe,

R'

HO

R

(154)

SiR,

HO

H. Oda, M. Sato, Y. Morizawa, K. Oshima, and H. Nozaki, Tetrahedron Lett., 1983, 24, 2877. Y. Sat0 and K. Hitomi, J . Chem. SOC., Chem. Commun., 1983,170. I l 0 T. Hayama, S. Tomoda, Y. Takeuchi, and Y . Nomura, Tetrahedron Lett., 1983, 24,2795. l l 1 R. B. Miller and M. I. Al-Hassan, Tetrahedron Lett., 1983, 24,2055. 11* (a)F. Sato, Y. Tanaka, and H. Kanbara,J . Chem. SOC.,Chem. Commun., 1983,1024; (b) F. Sato, Y. Tanaka, and M. Sato, ibid., p. 165. lo8

364

General and Synthetic Methods

New or improved routes to vinylsilanes are always welcome. Thus, direct ) ~catalyst, ] results in the hydrosilylation of methyl acrylate, using [ C O ~ ( C Oas formation of methyl (E)-3-silylacrylates in high yield and is a far superior method to the low-yielding route from prop-2-yn-1-01.113 Hydromagnesiation of l-alkynylsilanes by isobutylmagnesium bromide (cat. [Cp2TiC12])followed by treatment of the Grignard compound with alkyl iodide-copper provides excellent yields of 2-1,2-dialkylvinylsilanes. 114The sequence has been used in a very simple two-step construction of dihydrojasmone. Alternatively, the alkynylsilane Me3SiC=CBr reacts with copper acetylides to furnish the l-trimethylsilyl-l,3diynes (158), which can then be desilylated (F-) to yield terminal a 1 k ~ n e s . lIf~ ~ (158) is reduced with lithium di-isobutyl-n-butylaluminium hydride, then stereodefined 2-enynes (159) are obtained, and a further reduction with di-isobutylaluminium hydride yields the dienes (160).1156 The silyl group therefore allows appreciable discrimination between the adjacent carbon-carbon triple bonds.

R R

H

i“

HO”

(161 1

1

Me

(162 1

The formation of chiral propargylic alcohols, as described below, further demonstrates the varied chemistry possible with l-silylalkynes. 1-Trimethylsilylalkynes(R1C=CSiMe3, R1=Me or SiMe3)react with chiral acetals (161), giving chiral propargylic ethers (162) from which the alcohol can be liberated simply by treatment with alcoholic KOH. 116 Chemical yields are excellent and enantiomeric excesses of the propargyl alcohols are generally very high. In contrast, the chiral synthesis of the propargyl silane shown in Scheme 12 requires a chiral catalyst for asymmetric induction.117 Once formed the propargyl silane can be converted into chiral allenes and chiral silanes. Organosilicon reagents of the type R3SiXare capable of a wide variety of useful functional group interchanges such as dealkylation, cyanidation, azidation, etc. K. Takeshita, Y . Seki, K. Kawamoto, S. Murai, and N. Sonoda, J . Chem. SOC., Chem. Commun., 1983, 1193. 114 F. Sato, H. Watanabe, Y. Tanaka, T. Yamaji, and M. Sato, Tetrahedron Lett., 1983, 1041. 115 (a)J. A. Miller and G. Zweifel, Synthesis, 1983, 128; ( b ) J. A. Miller and G. Zweifel, J . Am. Chem. Soc., 1983, 105, 1383. 116 W. S . Johnson, E. Elliott, and J. D. Elliott, J . Am. Chem. SOC., 1983, 105, 2904. 117 T. Hayashi, Y . Okamoto, and M. Kumada, Tetrahedron Lett., 1983,24, 807. 113

Organometallics in Synthesis

365 ,SiMt3

PhCEC-Br

+

i P m h-CEC-C,&Ph

Mc3siybBr

Ph

H‘

Ph

But

1

/

Fc
ii i

PhCH2CH2-C-Ph

Ph

.SiMc3

H ‘

Reagents: i, [PdCl,{(R)-(S)-PPFA}]; ii, BuC1; iii, H2, Pd/C

Scheme 12

Scheme 13 describes a further crop of uses for the versatile reagents Me3SiI and Me3SiC1and Scheme 14 summarizes further uses of trimethylsilyl cyanide and azide. In some cases new ‘in situ’ preparations of the above reagents are also described. R ~ O

OR^

R ’ X R 2

R’CO~R’

--

\ ix

CI x i l x = c , Q 4X ’= 3I

R 1

Six

..-*,. .

“3

x = CL

T

R’CN

iv

- R’OH .. ~

x =I

+ R20H

R’OCH20Mc

Z= OH, M t , = O , NHAc, or =CH,

I

Reagents: i, R’CHNOH, (Me,Si),NH, Ref. 118; ii, RICH,NO,, Ref. 119; iii, R13CN02, Ref. 119; iv, R10R2,Ref. 120; v, R1R2CNOX,Ref. 121; vi, RlOH, MeOCH,OMe, Ref. 122;vii, R1SOR2, Ref. 123; viii, R1COC(Y)(R2)CH2CH2C=Z, Zn, Ref. 124;ix, R1C02H,R*OH, Ref. 125;x, AcO, ,O R1R2C0, R 3 0 H , Ref. 126; xi, R,&R~,

Ref. 127

Scheme 13 M. E. Jung and Z. Long-Mei, Tetrahedron Lett., 1983,24,4533. G. A. Olah, S. C. Narang, L. D. Field, and A. P. Fung, J . Org. Chem., 1983,48,2766. lU) G. A. Olah, A. Husain, B. P. Singh, and A. K. Mehrotra, J . Org. Chem., 1983,48,3667. Y. Ishida, S. Sasatani, K. Maruoka, and H. Yamamoto, Tetrahedron Lett., 1983, 24,3255. lZ2 G. A. Olah, A. Husain, and S. C. Narang, Synthesis, 1983, 896. lZ3R. D. Miller and D. R. McKean, Tetrahedron Lett., 1983,24,2619. lz4 E. J. Corey and S. G. Pyne, Tetrahedron Lett., 1983,24,2821. M. A. Brook and T. H . Chan, Synthesis, 1983,201. 126 T. H. Chan, M. A. Brook, and T. Chaly, Synthesis, 1983, 203. lz7 H. Nishiyama, K. Sakuta, N. Osaka, and K. Itoh, Tetrahedron Lett., 1983,24,4021. 119

366

General and Synthetic Methods

R ' = CO,H, H, Mc,or CN

OH R'-c

=cN

1 1

-CH,R 2 R3

CN R'

R Reagents: i , R I G . Ref. 128a, b; ii, R1COCH,R2R3,KCN, 18-crown-6, Ref. 129; iii, N+ I 0-

H

oxo

,u.. ,

TiCI,, Ref. 130; iv, R1R2C(OR3)2,Ref. 131; v, ZnI,, ArCOCl, Ref. 132

Scheme 14

Apart from the silicon reagents just mentioned several less conventional reagents have been reported. For example, disilanes are cleaved by Bn4N+F(TBAF) in HMPA, giving metal-free silyl anions which further react with aldehydes and 1,3-dienes to yield a-silyl-alcohols and 1,4-disilyl-alkenes respect i ~ e 1 y . Particularly l~~ noteworthy is that the fluoride ion attacks at the less hindered silicon in unsymmetrical disilanes so that the disilane Ph3SiSiMe3reacts with aldehydes RCHO to give the a-silyl-alcohol RCH(OH)SiPh3 exclusively. Similarly, TBAF catalyses the addition of benzyltrimethylsilane to aldehydes and ketones (R1R2CO)forming the corresponding alcohols R1R2CH(OH)CH2Ph,in the first reported use of benzyltrimethylsilanes as a benzylating reagent. 134 The wide Me3SiCH2N3is an efficient aminating reagent for Grignards and aryllithium salts,135and in the asymmetric reduction of ketones the silane (163), prepared from (-)-P-pinene, also exhibits reasonable selectivity.136 Phenols or phenol ethers containing silicon groups are usually brominated (BrTHOAc), where possible, ortho- orpara- to the oxygen group, and retain the silicon group. However, by using NCS-Br- or -I-, acetylated phenols containing a silicon group are brominated or iodinated with replacement of the silyl (a) H . Vorbruggen and K. Krolikiewicz, Synthesis, 1983,316;(b) W. K. Fife, J . Org. Chem., 1983,48, 1375. W. J. Greenlee and D. G . Hangauer, Tetrahedron Lett., 1983,24,4559. J. D. Elliott, V . M. F. Choi, and W. S. Johnson, J . Org. Chem., 1983,48,2294. 131 S. Kirchmeyer, A . Mertens, M. Arvanaghi, and G. A . Olah, Synthesis, 1983,498. 13* G . K . Surya Prakash, P. S. Iyerm M. Arvanaghi, and G. A . Olah, J . Org. Chem., 1983,48,3358. 133 T. Hiyama, M. Obayashi, I. Mori, and H . Nozaki, J . Org. Chem., 1983,48,912. 134 B. Bennetau and J. Dunogues, Tetrahedron Lett., 1983, 24, 4217. 135 K. Nishiyama and N. Tanaka, J . Chem. SOC., Chem. Commun., 1983, 1322. lM D . Wang and T. H . Chan, Tetrahedron Lett., 1983,24,1573. 128

lZ9

367

Organometallics in Synthesis

d’

R’

fSiMeH2

8 (163)

NCCH,NCH, SiMe,

1

I

CH2Ph

CH,Ph

(164)

(165)

(166) X = SEt or NR’R2

(167)

moiety. 13’ The method is therefore a regiospecific synthesis of ortho-metapara-brominated or iodinated phenols. More conventionally, the silyl group in the a-cyanosilane (164) is cleaved on treatment with fluoride ion to yield a species which reacts (in situ) with electron-deficient alkenes, giving pyrrolidines (165).138 The silane (164) is therefore acting as an azomethine ylide equivalent. Similarly, silylformamidines and silylthioformimidatesreact with acyl fluorides (ArCOF) to give azomethines (166), which are then trapped to provide another synthesis of pyrrolidines (167).139 Tin.-In common with their silyl analogues allylstannanesare exceedinglyuseful intermediates. But-2-enyltributylstannane reacts with aldehydes in the presence of A1C13-PriOH to provide products derived predominantly from a-addition. Interestingly, in the presence of other Lewis acid catalysts, e.g. TiC14, SnC14, BF3,0Et2,the y-adduct is obtained exclusively, therefore providing a simple route to both types of product. The same stannane reacts with glyoxylate esters, at the y-position,to yield erythro-propionates (168), a reaction that has been applied to the enantioselective synthesis of verrucarinolactone.141 If pressure is used in the reaction of simple allystannes (RICH= CHCH2SnR13)with aldehydes no catalyst is needed at all.142Pressures are high (10 kbar) and yields are generally good though it appears that steric hindrance seriously inhibits the reaction. Alkoxymethyl-substituted allylstannanes, ROCH2CH(SnMe3)CH= CH, and ROCH2CH= CHCH2SnMe3,have been prepared by displacement of the ally1 bromide atom with SnMe3 and will allylate carbonyl compounds, e.g. regardbenzaldehyde, to give the corresponding cis-4-alkoxymethylbut-3-en-l-ol On the less of the regio- and stereo-chemistry of the starting a1lyl~tannane.l~~ D. S. Wilbur, W. E. Stone, and K. W. Anderson, J . Org. Chem., 1983,48, 1542. Padwa and Y.-Y. Chen, Tetrahedron Lett., 1983,24,3441. 139 T. Livinghouse and R. Smith, J . Chem. SOC., Chem. Commun., 1983,210. Y. Yamamoto, N. Maeda, and K. Maruyama, J . Chem. SOC., Chem. Commun., 1983,142. 141 Y. Yamamoto, N. Maeda, and K. Maruyama,J . Chem. SOC., Chem. Commun., 1983,774. 142 Y. Yamamoto, K. Maruyama, and K. Matsumoto, J . Chem. SOC.,Chem. Commun., 1983,489. 143 Y. Naruta and K. Maruyama, J . Chem. SOC., Chem. Commun., 1983,1264. 137

138 A.

368

General and Synthetic Methods

other hand a-ethoxyallylstannane has been used in the synthesis of carbonyl compounds via enol ethers or monoprotected 1,2-diols as shown in Scheme 15.14 Ph

I

~

c

o

z

R’

RBu3Sn OH

Reagents: i , PhCHO; ii, p-MeC,H4S03H;iii, C,H,,CHO; iv, H,S04; v, Me2C=CHCOMe; vi, P20,

Scheme 15

y-Stannyl alcohols, e.g. (169), cyclize upon treatment with a Lewis acid (BF,,Et,O) to yield cyclopropenes, e.g. (170), stereospecifically and with inversion of configuration at both carbon atoms.145In this case the starting materials are obtained easily by 1,4-addition of Bu3SnLi to a#-unsaturated ketones followed by addition of an alkyl-lithium or Grignard reagent to the ketone. The aldol reaction of a-stannyl ketones is also highly stereoselective and results in the formation of the erythro-isomer in up to 20:l ratio (vs. threo).14&Jb The stannyl ketones are formed easily from a silyl enol ether and a tin halide. A new synthesis of vinylstannanes relies upon the regioselective attack of trimethylstannylcopper-DMS on w-substituted alkynes to furnish a series of useful looking w-substituted 2-trimethylstannyl-1-alkenes. 147 In a similar vein, the vinylstannane (171) undergoes clean cross-coupling (Pd cat .) with acid chlorides

eM{

R&

n Me,

OMt

+C02CH2Ph

R 3 Sn

*OCH

OSiButPhZ

Ph

0

J.-P. Quintard, B. Elissondo, and M. Pereyre, J . Org. Chem., 1983,48, 1559. I. Fleming and C. J. Urch, Tetrahedron Lett., 1983,24,4591. 146 (a)E. Nakamura and I. Kuwajima, Tetrahedron Leff.,1983,24,3347; (b)H. Urabe and I. Kuwajima, ibid., p. 5001. 147 E. Piers and J. M. Chong, J . Chem. SOC., Chem. Commun., 1983, 934.

144

145

369

Organornetallies in Synthesis

to give a,P-unsaturated ketones (172) which have then been converted into unsymmetrical a-diketones, butadienyl ethers, and methyl vinyl ketones. 148 Stille and his co-workers have published a number of papers concerned with palladium-catalysed organotin reactions; for instance two papers describe Pd-catalysed coupling reactions of organotin compounds with acid chlorides. In the first, acid chlorides (RCOC1) are coupled with unsymmetrical organotin A noteworthy aspect of this reagents R13SnR2to give ketones RCOR1.149a~b reaction is that only one of the groups attached to the tin is transferred, whereas the other three remain anchored. Groups that transfer easily are: acetylenic, aryl, vinyl, methoxymethylene, allyl, and benzyl groups; as might be expected, alkyl groups remain attached to tin. In this way the vinyl-tin (173) has been coupled with 4-t-butyldiphenylsiloxypentanoylchloride to give the keto-ester (174), a precursor to the macrocyclic antibiotic pyrenophorin. Cyclic ethers have also been made in good yield by a Pd-catalysed cross-coupling reaction, in this case between a-halogeno-ketones or -aldehydes and acetonyl- or allyl-stannanes. Thus, oxiranes, oxetanes, and tetrahydrofurans have all been obtained under mild reaction conditions. Similarly, allyl- and aryl-tin compounds readily crosscouple with allyl bromides to give a variety of alkenes containing various other functional groups, e.g. ester, ether, alkenyl, or aryl.151 5 Group V Phosphorus.-As might be expected a significant proportion of the publications in this area have been concerned with some aspect of the Wittig reaction or one of its modifications. Warren and his co-workers have published a number of papers dealing with the Horner-Wittig reaction and its application to the preparation of stereo-defined alkenes. For example, if the phosphine oxides (175) are lithiated and reacted with esters then a-phosphonato-ketones (176) are formed in good

H 0 4 - d

H

0

II

(176)

R, R' = H, alkyl, aryl

Ph,PCH,R

"04, ti (177) J. A. Sonderquist and W. Wei-Hwa Leong, Tetrahedron Lett., 1983,24,2361. 149 (a)J. W. Labadie, D. Tueting, and J. K. Stille, J . Org. Chem., 1983,48,4634; (b)J. W. Labadie and J. K. Stille, Tetrahedron Lett., 1983,24,4283. lM I. Pri-Bar, P. S. Pearlman, and J. K. Stille, J . Org. Chem., 1983,48,4629. 151 F. K. Sheffy and J. K. Stille, J . Am. Chem. SOC., 1983,105,7173.

General and Synthetic Methods

370

yield.lS2”Reduction of these ketones with sodium borohydride occurs stereoselectively (ca. 9: 1) in favour of the threo-isomer (177), which then undergoes elimination to give the E-alkene. In this way E-isosaffrole, E-anethole, and E-feniculin have been synthesized. In contrast the 2-alkene is prepared by reacting lithiated (175) with aldehydes to yield erythro-(177), which then gives the 2-alkene by elimination.152b This last reaction shows strong solvent and temperature dependence, with best results coming from the use of donating solvents (DME, THF, TMEDA, DMI) and low temperatures (-78 to -lOO°C). This general strategy has also been used in the preparation of E- and 2-isomers of y,S-unsaturated acetals and E- and 2-trisubstituted alkenes, thus providing a route to 2-abisabolene. l S 2 ~ , Previously it has not been possible to prepare allylamines of the type (178) using the Horner-Wittig reaction. However, the same authors have shown that the corresponding allylamides are formed with full regio- and stereo-chemical control from dianions of p-(acy1amino)alkylphosphine oxides (179) , thereby providing a convenient access to the corresponding ally la mine^.^^^' R’ R 2

gNRz

R3

(178) R’

Li

alkyl

(179)

R Z = alkyl or H

(180)

In the preparation of 2-unsaturated esters extremely high specificity (>50:1) in favour of the 2-isomer is possible when the phosphono-ester (TFE0)2POCHMeC02Me is reacted with aliphatic and aromatic aldehydes.153 The choice of reaction conditions is again important in maintaining the high specificity, and it appears that the reagent combination KN(TMS)T18-crown-6-THF is far superior to others. Aldehydes and ketones can also be converted into their homologous ketone-0, 0-acetals using dialkoxymethyldiphenylphosphine oxides [Ph2POCH(OR)2].1s4 In all the previous reactions, deprotonation of the alkylphosphine oxide is carried out by strong base. An alternative procedure reported this year is to start 152

lS3 ls4

(a) A. D. Buss, R. Mason, and S. Warren, Tetrahedron Lett., 1983,24,5293; ( b ) A. D. Buss and S. Warren, ibid., p. 3931; (c)C. A. Cornish and S. Warren, ibid., p. 2603; (d)A. D. Buss and S. Warren, ibid., p. 111; (e) D. Cavalla and S. Warren, ibid., p. 295. W. C. Still and C. Gennari, Tetrahedron Lett., 1983,24,4405. T. A. M. van Schaik, A. V. Henzen, and A. van der Gen, Tetrahedron Lett., 1983,24,1303.

371

Organometallics in Synthesis

from the silylalkylphosphonate and generate the anion using fluoride ion.155Of course if there are activating groups attached to the alkylphosphonate then only weaker bases are required to abstract the a-proton, as can be seen in the synthesis of butadienylphosphonates (180) .15& The latter have been further reacted with oxosulphonium and phosphonium ylides, leading to functionalized cyclopentenylphosphonates (181). The Wittig reaction still provides a source of new and useful synthetic transformations. A new approach to fluoro-olefin synthesis involves the reaction of fluorine-containing phosphonium salts (R3PCF-R3P.X),prepared from tertiary phosphines and fluorotrihalogenomethanes, with perfluoroaryl f l ~ 0 r i d e s . l ~ ~ ~ Hydrolysis then gives chain-extended olefins (182). Another homologation of aldehydes and ketones is achieved by means of the phosphorus ylide (Ph3P= CHOCH2CH2SiMe3) which reacts to give enol ethers (R1R2C= COCH2CH2SiMe3).lS7 The enol ethers are then simply unmasked to give the homologated aldehydes (R1R2CHCHO).In turn aldehydes may be transposed to allylamines via their (Wittig) reaction with N-alkyl-aminoethylphosphonium salts, prepared by an improved procedure from primary amines and commercially available vinyltriphenylphosphonium bromide. 158 Similarly, (3-pheny1thio)buta1,3-dienyltriphenylphosphonium chloride undergoes a conjugate addition/ intramolecular Wittig reaction with enolates (183) to yield a$-unsaturated ketones (184), after hydrolysis, in a reaction quite analogous to the Robinson annulation yet differing in that it yields the transposed e n ~ n e . ' ~ ~

(182)

(183 1

(184

A new method for carrying out the Wittig reaction circumvents the phosphine oxide problem. Under gas-liquid phase-transfer conditions an aldehyde is passed through a solid bed of potassium carbonate and a phosphonium salt, resulting in the formation of an alkene which is removed as gas, conveniently leaving the phosphine oxide adsorbed on the solid bed. The use of phosphonium salts is not just restricted to the Wittig reaction as illustrated by several papers. P-Branched a$-unsaturated ketones are produced in good yields from a,p-unsaturated ketones by the sequence described in Scheme 16.161 A notable feature of this sequence is the highly efficient electrochemical T. Kawashima, T. Ishii, and N. Inamoto, Tetrahedron Lett., 1983, 24, 739. (a)T. Minami, T. Yamanouchi,S. Takenaka, and I. Hirao, TetrahedronLeft.,1983,24,767; (b)D. J. Burton and D. G . Cox, J . Am. Chem. SOC., 1983,105,650. ls7 K. Schonauer and E. Zbiral, Tetrahedron Lett., 1983,24,573. R . J. Lindemann and A . I. Meyers, Tetrahedron Lett., 1983,24,3043. 159 R. J. Pariza and P. L. Fuchs, J . Org. Chem., 1983,48,2304. E. Angeletti, P. Tundo, and P. Venturello, J . Chem. SOC.,Chem. Commun., 1983,269. H. J. Cristeau, B. Chabaud, and C. Niangoran, J . Org. Chem., 1983,48,1527. 155

156

13

372

General and Synthetic Methods

deprotection of the dithioacetal. The less esoteric phosphorus ylide (pH$-CMe,) has been used in a stereoselective synthesis of (1R)-transchrysanthemic acid (185) and its dibromo-analogue. 162 The critical step in the synthesis of these important pyrethroid intermediates is the stereocontrolled

R

Reagents: i , BuOK; ii, RX

Scheme 16

addition of the ylide to chiral dimenthyl fumarate. Phosphonium ylides also react with chlorodifluoromethane in a synthesis of 1,l-difluro-1-alkenes by a procedure that is an alternative to the standard Wittig r e a ~ t i 0 n . Both l ~ ~ primary and secondary ylides give the corresponding difluoromethylene olefins in yields that are significantly better than those from the Wittig reaction, provided that no strongly electron-withdrawing groups are present in the alkylidenephosphorane. Other advantages lie in the avoidance of the formation of phosphine oxide, which means that the phosphorus-containing moieties may be recycled. A further synthesis of fluorine-containing molecules is evident in the preparation of fluoro-@unsaturated ketones, which relies upon a number of phosphorus intermediates as depicted in Scheme 17, and interestingly involves a 1,2transposition of the carbonyl group from the acyl chloride. 164 Finally in view of the ever increasing use of chiral auxiliaries in asymmetric syntheses it is worthwhile noting the preparation of simple chiral M. J. De Vos and A. Krief, Tetrahedron Lett., 1983,24, 103. G. A. Wheaton and D. J. Burton, J . Org. Chem., 1984,48,918. 164 T. Ishihara, T. Maekawa, and T. Ando, Tetrahedron Lett., 1983, 24, 4229. 162

163

373

Organometallics in Synthesis

/R , RF+

0 Reagents: i, P(OEt)3; ii, BuLi, CuI; iii, MeNH,; iv, base, RCHO

Scheme 17

organophosphorus reagents should they prove useful in this, if not in other, respects. For example optically active 2-aminoalkyl-phosphonic and -phosphoric acids (186) are prepared by the reaction of sodium alkylphosphinates or dialkylphosphonates, respectively, with tosylaminotosylates of aminoalcohols,165and chiral a-hydroxyphosphonate esters (187) are obtained by reaction of o-nitrobenzaldehyde with dialkylphosphonates in the presence of catalytic quantities of quinine.'& OH

6 GroupVI

Sulphur.-The utility of sulphur in organic synthesis has long been recognized and this year has seen a continuing high level of activity in this general area. Scheme 18, for example, illustrates several uses for substituted chloromethylsulphides, and in doing so demonstrates the diverse chemistry possible once a sulphur group has been introduced into a molecule, providing access to aldehydes, unsaturated systems, ring systems, etc. 167-171 In an analogous fashion phenylthiomethyl ether (PhSCH,OMe) provides a new route to various functional groups. Thus, deprotonation of the methylene group followed by alkylation, or alternatively addition of aldehydes, yields an intermediate M. E. Duggan and D. S . Karanewsky, Tetrahedron Lett., 1983,24,2935. H. Wynberg and A . A. Smaardijk, Tetrahedron Lett., 1983, 24, 5899. 16' I. Fleming and J. Iqbal, Tetrahedron Lett., 1983, 24, 327. la T. V. Lee and J. 0. Okonkwo, Tetrahedron Lett., 1983, 24, 323. 169 M. A . McKervey and P. Ratananukul, Tetrahedron Lett., 1983,24, 117. 170 D. T. W. Chu, J . Org. Chem., 1983,48, 3571. 171 M. Wada, T. Shigehisa, H. Kitani, and K.-y. Akiba, Tetrahedron Lett., 1983,24, 1715.

166

General and Synthetic Methods

374

iv

liii

R’ CHO CO, Me

V SPh

OTMS Reagents: i, R3,/j? R4

TiCl,, Ref. 167, 168; ii, Raney-Ni; iii, NaIO,, A; iv, PhH, SnCl,, Ref. 169; v , Me

Zn, AcOH; vi, S O , , H 2 0 , Ref. 170; vii, SnCl,,

R2AR4 , Ref. 171

Scheme 18

[R1R2CHXCH(SPh)OMe] from which aldehydes, methylals, carboxylic acids, and enol or dienol ethers can readily be obtained.172 Addition of phenylsulphinyl chloride (PhSC1) across the triple bond of 1,4dichlorobutyne and 1,4-elimination yields the dienes (lSS), which are interesting intermediates in their own right.173aIn fact the latter have been used to prepare the para-substituted benzene (189) via their Diels-Alder reaction with methyl vinyl ketone and subsequent dehydrohalogenation of the adduct. 173b The regiochemistry of addition is controlled mainly by the sulphur group and very similar results are obtained with the selenium analogues. Sulphoxide reagents have been noted already in Groups I and I1 in relation to their lithium and magnesium carbanions. However, sulphoxides have wider application, as shown for example by their use in the synthesis of cyclopentenones. Thus, the cyclopentenones (190) and (191) are obtained by conjugate addition of enolate anions to alkenylsulphoxides and then ring closure of the acyclic intermediate (192).174The nature of the cyclopentenone obtained is determined by the R group in (192), i.e. methyl vs. ester. In the same paper a similar approach allows 2-phenylsulphinyloct-1-en-3-oneto be used as a convenient electrophilic prostanoid 16-side-chainprecursor. The ease with which sulphur-oxygen groups migrate through a n-system has been used to good effect in several syntheses, and forms the basis for a prepara172

173

T. Mandai, K. Hara, T. Nakajima, M. Kawada, and J. Otera, Tetrahedron Lett., 1983, 24,4993. (a) A. J. Bridges and J. W. Fischer, Tetrahedron Lett., 1983, 24, 445; (b) ibid., p. 447. P. J. Brown, D. N. Jones, M. A . Khan, and N. A . Meanwell, Tetrahedron Lett., 1983,24, 405.

Organometallics in Synthesis

375

Y

x , Y = CI, Br

SPh

(191 1

(192 1

tion of allenic sulphoxides (193) from acetylenic alcohols [R1R2CH(OH)C= By suitable manipulation of the sulphoxides (193) a new route to allenyl sulphides (using MeLi) and a,P-unsaturated aldehydes (194) can also be achieved. In previous years interest in sulphone chemistry has been at a high level, and this interest continues, as illustrated by the thermal rearrangement of chiral sulphinates (195) to chiral sulphones (196).176The solvent has a quite dramatic effect upon the course of the reaction, with best yields ( 8 6 1 0 0 % ) and highest stereospecificity (>80%) attainable in DMF, whereas in several other common solvents yields are very poor. In their turn, chiral allenic sulphones cyclize to chiral y-sultines (197) in good to excellent yield.177 0

I1

R2

R2

bCs,,

d

? ’

R’

SPh

O

R

O

H

II I TolS-C-CCH=CH, II I (196)

c=c I

/

R’

‘R2

OCH,

I

(194) R3=OEt or SPh

(193)

s-

H:Ho.. TO[--

H\

X

(195)

Q

(197) X = Br or SMe

One of the attractions of using sulphone groups is their ability to activate the a-position to deprotonation, and this has been used to convert alkyl, allyl, benzyl, and cycloalkyl sulphones (R1R2CHS02Ph)into aldehydes and ketones (R1R2CO) 175 176

In

I. Cutting and P. J. Parsons, J. Chem. SOC., Chem. Commun., 1983, 1209. K. Hiroi, R. Kitayama, and S. Sato, J. Chem. SOC., Chem. Commun., 1983,1470. S . Braverman and T. Duar, J. Am. Chem. SOC., 1983, 105, 1061.

376

General and Synthetic Methods

in good yield using BuLi followed by Me3SiOOSiMe3.178 Significantly, if oxygenlabelled peroxysilane is used then 180-labelled carbonyl compounds are obtained. In a quite different application of organosulphone chemistry, Trost and his co-workers have used the bisulphone (198) as a synthon for a propylene 1,3dipole.179The cyclopropane is cleaved readily by carbon nucleophiles to yield an intermediate which is readily alkylated (RX) to species such as (199), of obvious synthetic utility.

Paquette and his- co-workers have continued their work with simple vinyl sulphones. In a full paper phenyl vinyl sulphone and the vinyl sulphone (200) have been used as synthons for ethylene, 1-alkenes, acetylene, and monosubstituted alkynes in the Diels-Alder reaction.ls0 One of the attractions of using the sulphone (200) is that it reacts to form adducts which readily undergo a mild fluoride-induced elimination to form the double bond. Advantage has been taken of this mild elimination in the synthesis of several functionalized dibenzobarralenes. Similarly, vinyl sulphones can also be desulphonylated to provide the corresponding alkene upon treatment with tributylstannyl-lithium followed by silica gel.lsl As might be guessed the stannyl-lithium adds to the vinyl sulphone and the silica gel treatment results in the elimination of the elements Bu3SnS02Ph.This therefore constitutes a new desulphonylation reaction. Vinyl sulphones also eliminate the sulphone group to furnish the corresponding alkene if treated with n-butylmagnesium chloride in the presence of Ni or Pd catalysts. 182a Retention of configuration is observed and yields can be excellent. Similar high stereoselectivity is observed in the related desulphonylation of benzenesulphonyl-l,3-dienes,using the same reagents to give conjugated 2,Edienes1826Jc and in the elimination of SO2from cyclic sulphones (201) to form E, Edienes (202). lS3

J. R. Hwu, J . Org. Chem., 1983,48, 4432. B. M. Trost, J. Cossy, and J . Burks, J . Am. Chem. Soc., 1983, 105, 1052. R. V. C. Carr, R. V. Williams, and L. A. Paquette, J . Org. Chem., 1983,48, 4976. M. Ochiai, T. Ukita, and E. Fujita, J . Chem. Soc., Chem. Commun., 1983,619. (a)J. L. Fabre and M. Julia, Tetrahedron Lett., 1983,24,4311; ( b )T. Cuvigny, J. L. Fabre, C. H. du Penhoat, and M. Julia, ibid., p. 4319; (c)T. Cuvigny, C. H. du Penhoat, and M. Julia, ibid., p. 4315. 183 R. Bloch, D. Hassen, and X. Mandard, Tetrahedron Lett., 1983,24,4691.

Organornetallies in Synthesis

377

Dithioacetals have proved to be valuable synthetic building blocks and are especially useful in view of their ready availability. Two new metal-catalysed preparations published this year further add to the list of useful preparative methods. In the first titanium tetrachloride was found to be a highly efficient catalyst for their preparation from aldehydes and ketones and alkyl thiols or dithiols,lsk whereas in the second magnesium or zinc triflates were found to be very effective.lMbAn example of their use is found in the synthesis of a#unsaturated ketones not available by the aldol reaction where dithioacetals are used in both steps as shown in Scheme 19.185 Using this sequence AR-turmerone has been prepared. OH

R2 ”fi.3

PhS

i,ii

~

RZ

R’+R~

SPh

iii, iv

PhS

~

0

SPh

Reagents: i, BuLi; ii, RICH,CHO; iii, p-C6H4S0,H;iv, NaIO,, A

Scheme 19

A new highly stereoselective and regiospecific method for the homologation of ketones to a$-unsaturated esters once again relies upon the intermediacy of ketene dithioacetals.ls6Thus, the ketones (203) are converted into the esters (204) in very acceptable yields via the dithioacetals (205) using only sodium borohydride and then boron trifluoride etherate in methanol. Ketene dithioacetals, e.g. (206), also play an important part in the synthesis of the furan sesquiterpene (+)-myodesmone (207) in just three steps, and allow for the easy incorporation of the furan ring and side-chain.187

0

SMt

%?

Me

(206)

(207)

(a)V. Kumar and S. Dev, Tetrahedron Left.,1983,24,1289; ( b )E. J. Corey and K. Shimoji, ibid., p. 169. lss J. Durman, J. Elliott, A. B. McElroy, and S. Warren, Tetrahedron Left., 1983,24,3927. B. Myrboh, H. Ila, and H. Junjappa, J . Org. Chem., 1983,48,5327. lS7 R. K. Dieter and J. W. Dieter, J . Chem. Soc., Chem. Commun., 1983, 1378.

lw

378

General and Synthetic Methods

Finally, the N-sulphinylcarbamate (208) provides a new stereoselective approach to threo- and erythro-amino-alcohols (209) via its Diels-Alder reaction with E, E- or E, 2-1,4-disubstituted butadienes, respectively. 188 The Diels-Alder adduct (210) is converted into the corresponding amino-alcohol following treatment with phenylmagnesium bromide and trimethyl phosphite. R

S

II

NCO CH, Ph

(208)

CO;, yMe

.. Me ‘

V

X

Y

X

C H2

CH2 P h

Y

X =NHCO,CH2Ph,Y = H

X = H, Y = R‘

X = H, Y = NHC02CH2Ph

X =R’, Y = H

(209)

(210 1

Selenium.-Activity in the organoselenium field seems to have slowed this year; nevertheless, there have still been a number of useful contributions. A major area of interest for organoselenium reagents has been in their propensity to initiate ring closures, a reaction which has been exploited this year in a synthesis of y-lactones from alkenes.lSyThus, successive treatment of alkenes (RICH= CHR2) with phenylselenyl chloride and silver crotonate affords the selenolesters (211) which then yield y-lactones (212) upon reaction with triphenyltin hydride in the presence of AIBN. Similarly, N-phenylselenophthalimideinitiates the ring closure of the aminoalkenes (213) giving a selenium intermediate which reacts with the allyltin reagent (Bu3SnCH2CH= CH2)in the presence of AIBN to give cyclized product (214). The overall process amounts to an intramolecular ureidoallylation, and is akin to the ureidomercuration work described in Group 11.

. - I

‘NHCbz

Reports of useful new selenium reagents are fairly uncommon; however, the vinylselenium (215) is such a reagent and is a new synthetic equivalent of methacrolein.lY1Its preparation and use in model studies of the lycopodium alkaloid selagine have been reported. Particularly.interesting is the novel cyclization of the vinyl selenide (216), formed from (215) and the corresponding R. S. Garigipati and S. M. Weinreb, J . Am. Chem. SOC., 1983, 105,4499. D. L. J. Clive and P. L. Beaulieu, J . Chem. SOC.,Chem. Commun., 1983,307. R. R. Webb, jun. and S. Danishefsky, Tetrahedron Lett., 1983,24,1357. 191 D . Gravel, R. Deziel, and L. Bordeleau, Tetrahedron Lett., 1983,24, 699.

IE9

Organometallics in Synthesis

379

cyclohexanone, to give the bicycle (217). Similarly, the vinyl selenides (218), prepared from alkenes and phenylselenyl bromide, act as electrophiles upon treatment with silver perchlorate in nitromethane solvent (- 15"C), reacting with electron-rich aromatic molecules, such as furan, thiophene, pyroles, and 1,3,5trialkoxybenzenes, to give, for example, (219) from f ~ r a n .In ' ~the ~ formation of another vinyl selenide (220), nitromethane is the co-reactant in the formation of nitroselenide (O,NCH,SePh), which can then be converted into (220) using an aldehyde (RCHO) , acetic anhydride, and base. 193 I

!Ph

d

ScPh

The first regioselective synthesis of allyl selenides, e.g. (221), starts from selenoacetals [R1CH(SeR2)2]and uses the sequence butyl-lithium, DMF, CH2=PPh3.194The reactions of (221) have been investigated, and it was found that allyl methyl selenides (221; R2=Me) rearrange in the presence of even a trace of acid whereas their phenyl analogues, contrary to previous reports, were found to be thermally stable but highly light sensitive. Organoselenium compounds in higher oxidation states are also useful reagents as illustrated in the synthesis of diacylcyclopropanes (222), where good yields are achieved by the reaction between 1,3-dicarbonyl compounds (R1COCR2=COK) and the vinyl selenone (CH2=CHSe02Ph).195A novel route to ketones and Q-unsaturated ketones involves the addition of alkyl and alkenyl copper(1) reagents, respectively, to selenoesters with yields varying between 80

S. Halazy and L. Hevesi, J . Org. Chem., 1983,48, 5242. T. Sakakibara, M. devi Manandhar, and Y. Ishido, Synthesis, 1983, 920. 194 T. Di Giamberardino, S. Halazy, W. Dumont, and A . Krief, TefruhedronLett., 1983,24, 3413. 195 R. Ando, T. Sugawara, and I. Kuwajima, J . Chem. SOC., Chem. Commun., 1983,1514.

193

380

General and Synthetic Methods

and 98% ,19&7 and selenoesters themselves are prepared by treatment of the dimagnesium salt of hydrazones with Se2C12 in the presence of trin-butylamine. 197 Tellurium.-Activity in the tellurium area has, as usual, been at a low level this year. However, two papers worthy of note are concerned with the use of dialkyltelluronium ylides. In the first , dialkyltelluronium ethoxycarbonylmethylides (R2TeCHC02Et)react with aldehydes and ketones to give a,punsaturated carboxylic esters with a predominantly E - c o n f i g ~ r a t i o n . In ' ~ ~all cases none of the a,p-epoxy-esters, which might be expected by analogy with sulphonium and selenonium ylides, was obtained. In the second paper, dialkyltelluronium allyiides (R,TeCHCH= CH2) are shown to react with aldehydes giving rise to @unsaturated epoxides with moderate Z-selectivity and in good yields.'98b

(a) A. F. Sviridov, M. S. Emolenko, D. V. Yashunsky, and N. K. Kochetkov, Tetrahedron Lett., 1983, 24, 4355; ( b ) ibid., p. 4359. 197 R. Okazaki, A. Ishii, and N. Inamoto, . I . Chem. Soc., Chem. Commun., 1983, 1429. 198 (a) A. Osuka, Y . Mori, H. Shimizu, and H. Suzuki, Tetrahedron Lett., 1983,24,2599; (b) A. Osuka and H. Suzuki, ibid., p. 5109.

*%

7 Saturated Carbocyclic Ring Synthesis BY T. V. LEE

1 Three-membered Rings

The oxidati.vecyclization of the bis-anion (l),in the presence of copper(r1) salts, provides ready access to cyclopropanes, and an excellent alternative to the acyloin and Dieckmann cyclizations of diesters. An improved synthesis of cyclopropane acetals involves the addition of diethylzinc-methylene iodide to ketene alkyl silyl acetals.2 Phenyl (tribromomethy1)mercury has been used as a source of singlet dibromomethylene for use in cyclopropane ~ynthesis,~ and a study of optical induction in cyclopropanation using chiral carbene complexes should be of interest to many chemist^.^ Electron-deficient olefins react with dichloromethane in the presence of copper(1) chloride to form adducts, e.g. ( 2 ) , CH , (CHZIIl,

C02Me

CUI'

C HC02Me

,CH-C02Me (CH2In 'CHCO2 Me

I

(11

(n=3-6)

CH2=CHCN

CI

+

> - CL?

CI hu

I CI(CH2)zCHCN

&CN

(2)

CHzCl2

which upon electrochemical reduction provide cyclopropanes in high yield.5 Three-membered rings can also be obtained by reaction of the vinylselenone (3) with the anion of an active methylene compound. It is proposed that conjugate addition to the vinylselenone is followed by cyclobutane formation and ring opening to the enolate anion (4), which then cyclizes to form the final product S. K. Chung and L. B. Dunn, jun., J . Org. Chem., 1983,48,1125. G . Rousseau and N. Slougui, Tetrahedron Lett., 1983, 24, 1251. J. B. Lambert, E. G. Larson, and R. J. Bosch, Tetrahedron Lett., 1983,24,3799. M. Brookhart, D. Timmers, J. R.Tucker, G. D. Williams, G. R. Husk, H. Brunner, and B. Hammer, J . Am. Chem. SOC., 1983, 105, 6721. M. Mitani, Y. Yamamota, and K. Koyama, J . Chem. SOC., Chem. Commun., 1983,1446.

381

General and Synthetic Methods

382

II,

Me

Me

CHO

(41 Scheme 1

(Scheme 1) . 6 , 7 Full details of the use of 1,5-bis(trimethylsiloxy)-l,5-dimethoxypenta-l,6dienes in preparing cyclopropanes have appeared,8 as have two new chiral syntheses of chrysanthemic acid derivative^.^^'^

2 Four-membered Rings A conceptually simple and attractive approach to cyclobutanone is the reaction of 1,3-bis(bromomagnesio)propane ( 5 ) with carbon dioxide, although the yield is poor. l 1 Previously difficult to obtain dichlorocyclobutenes (6) have now been

('1 MgBr

BrMg

ii, yo

II 0

(5)

prepared by reaction between dichloroketene and acetylene in the presence of phosphorus oxychloride (Scheme 2). l2 Alkynylsilanes react in the normal fashion with dichloroketene to form cyclobutanones.13

Reagents: i, R1 --C=C-R*.

, ii, Zn(Cu), POCl, Scheme 2

R. Ando, T. Sugawara, and I. Kuwajima, J. Chem. SOC.,Chem. Commun., 1983, 1514. R. Ando, T. Sugawara, and I. Kuwajima, Tetrahedron Lett., 1983,24,4429. I. H. M. Wallace and T. H. Chan, Tetrahedron, 1983,39,847. S. Toni, T. Inokuchi, and R. Oi, J. Org. Chem., 1983,48,1944. lo T. Mukaiyama, H. Yamashita, and M. Asami, Chem. Len., 1983,385. l1 J. W. F. L. Seetz, R. Tol, S. Akkemann, and F. Bickelhaupt, Synthesis, 1983,721. l2 A. Massner and J. L. Dillon, J. Org. Chem., 1983,48, 3382. l3 R. L. Danheiser and H. Sard, Tetrahedron Lett., 1983,24,23.

Saturated Carbocyclic Ring Synthesis

383

An interesting thermal intramolecular ene-allene cyclization reaction of (7) is the key step in a new synthesis of (+)-lineatin,14 and a detailed study of the

=c=Y A

(7)

intramolecular [2+2]photocycloaddition of 2-(alkenyloxy)cyclohexa-2-enones (8) has led to a new preparation of cyclobutanes (Scheme 3). The products

H

Iiii Mso@

.1

HO Me02C

L

Ad

O

HO

H

I

r

o

H

Me02Cd

vi

H O

Reagents: i, hv; ii, rn-C1C6H4CO3H,Et3N;iii, rn-C6H4C03H,MeONa; iv, NaBH,; v, MeS0,Cl; vi, Si02

Scheme 3

obtained by the latter route are easily convertible into cyclobutanones and cyclopentanones as shown. l5 Silicon-substituted alkynyl-metal derivatives (Scheme 4) have been shown to undergo an unprecedented cyclization to the

1

61(C H 2),2

Br(CHz)2 C E C - S i M e 3

-&

Me

/JSiMe3

,c=c,

A lMe2

J

SiMe3

i i ,

Me

(9)

Reagents: i, Me,AI, [Cp,ZrCl], BrCH2CH,Br; ii, H30+

Scheme 4 l4 L.

l5

Skattebol and Y. Stenstrom, Tetrahedron Lett., 1983, 24, 3021. M. Ikeda, M. Takahashi, T. Uchino, K. Ohno, Y. Tamura, and M. Kido, J. Org. Chem., 1983,48, 4241.

384

General and Synthetic Methods

useful cyclobutenylsilane (9) in high yield.16 Finally, ally1 cations have now been utilized in a [2+2] cycloaddition with alkenes to form cyc10butanes.l~ 3 Five-membered Rings Utilizing the cyclic metal chelate of P-keto-ester anions, such as (lo), gives an intramolecular conjugate addition five-membered ring product (11), with no trace of the cis-fused product. It is probable that this arises via the transition state (12) in which the acceptor chain is orientated away from the chelate ring.18 This

-Ma .N a* -

NaH

15 min r.t.

0

I

H

(11)

(10)

procedure is obviously applicable to the synthesis of trans-indanones. Various enantiomerically pure cyclopentanones have been prepared by aldol cyclization of the bis-aldehyde (14) derived from (-)-quinic acid (13) (Scheme 5)19 in a

'6 H2Ph

0

HO'

,

OCHZPh

*

CH0 OHC

OCH2Ph

t

OH (13)

'

I H
I

O/CH,Ph

(14)

Reagents: i, Pb(OAc),; ii, LiI, Et,O; iii, HO(CH,),OH

Scheme 5

sequence which may prove to be highly useful in the synthesis of five-membered cyclic ketones, as illustrated by a synthesis of 13-0xa-prostaglandins.~~ Another application to prostaglandin synthesis is the preparation of (16), which is readily formed by the regiospecific cyclization of the thioenol (15) in a process which greatly improves one of the earliest approaches to prostaglandins, viz.cyclization of a 1,4-diketone derivative (Scheme 6).21 l6 E.

Negishi, L. D. Boardman, J. M. Tour, H. Sawada, and C. L. Rand, J . Am. Chem. SOC., 1983,105, 6344. l7 H. Klein, G. Freyberger, and H. Mayr, Angew. Chem., Int. Ed., Engl., 1983, 22,49. l8 G. Stork, J. D. Winkler, and N. A, Saccomano, Tetrahedron Lett., 1983, 24,465. l9 J. C. Barriere, J. Cleophax, S. D. Gero, and M. Vuilhorgne, Helv. Chim. Acta, 1983,66,296. 2o J. C. Barriere, J. Cleophax, S. D. Gero, and M. Vuilhorgne, Helv. Chim. Acra, 1983,66, 1392. 21 R . Danelli, G. Martelli, G. Spunta, S. Rossini, G . Cainelli, and M. Panunzio,J. Org. Chem., 1983,48, 123.

385

Saturated Carbocyclic Ring Synthesis

Reagents: i, LiNPr',; ii, EtOzCCHBr(CH2)&O2Et;iii, NaH

Scheme 6

Butadienyl phosphonates bearing electron-withdrawing groups react with both sulphur and phosphorus ylides to form cyclopentenes. Thus, the phosphonate ester (17) undergoes nucleophilic attack at the terminus of the dienyl chain to form the zwitterion (18), which cyclizes to a five-membered ring.**

A new approach to cyclopentenones is to treat the 2,3,5-trien-l-o1 (19) with t-butyl hydroperoxide in the presence of [VO(acac),] as catalyst. This procedure Me I

(19)

( 50 '10)

has led to a simple synthesis of methylenomycin B.23As shown in Scheme 7 a-substituted p,yenones (20) can be used in a further novel synthesis of cyclopentenones .24 Me

Ph CH2

pcH2&Me@ oa:H

0

PhCHz

Me

Me

PhCH,

&MMeO e

PhCH2

g o M ?

(20)

Reagents: i, m-ClC,H,CO,H; ii, HC1; iii, electrolysis, MeOH; iv, H,O+; v, Na,CO,, A

Scheme 7 T. Minami, T. Yamanouchi, S. Takenaka, and I . Mirao, Tetrahedron Lett., 1983, 24,767. A. Doutheau, J. Sartoretti, and J. Gore, Tetrahedron, 1983, 39,3059. 24 Y . Fujita and T. Nakai, Synthesis, 1983, 997.

22

23

386

General and Synthetic Methods

The iodo-vinylsilane (21) is available from the addition of allylzinc bromide to 1-trimethylsilyloct-1-yne followed by treatment with iodine. Carbonylation of (21) in the presence of a palladium(0) complex gives the interesting and highly functionalized dienone (22) .25 Iron-activated olefins such as (23) have been shown to give moderate yields of cyclopentanes upon base treatment,26 and l-bromo1,5-dienes cyclize to cyclopentenes in a palladium-catalysed process.27

The Nio-catalysed [3 +2] cycloaddition of methylenecyclopropane and acrylic esters has been shown to proceed with a good degree of asymmetric induction when a chiral 8-phenylmenthyl acrylic ester is used.28Furthermore, the use of a chiral ester in the cyclization of the a-diazo-P-keto-ester (24) allows the formation of a chiral cyclopentane with up to 90% enantiomeric excess.29By contrast a chiral rhodium catalyst has been used to prepare a cyclopentanone from the aldehyde (25) in 50% enantiomeric excess.3o

Me Ph A

H

0

E. Negishi and J. A. Miller, J . Am. Chem. SOC., 1983,105,6761. P. Lennon and M. Rosenblum, J . Am. Chem. SOC., 1983,105,1233. 27 C . K. Narula, K. T. Mack, and R. F. Heck, J . Org. Chem., 1983,48,2792. 28 P. Binger, A. Brinkman, and W . J. Richter, Tetrahedron Lett., 1983,24, 3599. 29 D. F. Taber and K. Raman, J. Am. Chem. SOC., 1983,105,5935. B. R. James and C . G . Young, J . Chem. SOC., Chem. Commun., 1983,1215.

25

26

Saturated Carbocyclic Ring Synthesis

387

Full details of the thermolysis of (1-trimethylsilylcyclopropy1)ethylene to form cyclopentenes have been published,31as have details on earlier work on the [3+2] addition of (trimethylsily1)allenes and electron-deficient alkenes to give cyclopentenes .32 The useful conversion of dienoic a-diazo-compounds into cyclopentenes has been extended to the preparation of bicyclic cyclopentene lactones, e.g. (26),33and Lewis acid treatment of thefi-keto-ester (27) provides a good yield of the substituted cyclopentane (28) in an example of an ‘endo-mode’ ring c1osu1-e.~~ Cyclopentenes are also readily derived by fragmentation of the homoallylic alkoxides (29) derived from n o r b ~ r n a n o l s . ~ ~

H

Fused Five-membered Rings.-A very useful review on the Nazarov cyclization has appeared,36 as have full details on the silicon-assisted Nazarov cyclization Iodine has been used to achieve the cyclization of cyclo-octareported in 1982.37338 and a full discussion of Trost’s use of the 1,5-diene to bicycl0[3.3.0]octanes,~~ palladium-mediated cycloaddition approach to fused cyclopentanoids should L. A. Paquette, G . J. Wells, K. A . Horn, and T. H. Yan, Tetrahedron, 1983,39,913. R. L. Danheiser, D. J. Carini, D. M. Fink, and A. Basak, Tetrahedron, 1983, 39, 935. 33 T. Hudlicky, D. B. Reddy, S. V. Govindan, T. Kulp, B. Still, and J. P. Sheth, J. Urg. Chem., 1983,48, 3422. 34 E. E. van Tamelen, J. R. Hwu, and T. M. Leiden, J . Chem. Soc., Chem. Commun., 1983,62. 35 R. L. Snowden, Helv. Chim. Acta, 1983,66,1031. 36 C. Santelli Rouvier and M. Santelli, Synthesis, 1983, 429. 37 T. K. Jones and S. E. Denmark, Helv. Chim. Acta, 1983,66,2377. 38 T. K. Jones and S . E. Denmark, Helv. Chim. Acta, 1983,66,2397. 39 S. Vemera, S. Fukuzawa, A. Toshimitsu, M. Okana, H. Tezuka, andS. Sawada, 1. Org. Chem., 1983, 48,270.

31

32

General and Synthetic Methods

388

prove of use.4oMore details on the cyclization of the dienone (30) to a trans-fused hydrindenone have appeared.41The dianion (31) allows a rapid synthesis of fused five-membered rings via its alkylation with the iodide (32), as This strategy should be applicable to the synthesis of many cyclopentanoid natural products.

H

(30)

Indanediones (33) are produced by Wittig reaction with phthalic anhydride derivative^,^^ and the highly useful enone (34) is readily prepared by an intramolecular Wadsworth-Emmons reaction using a crown ether-base mixture to achieve cyclization.44The bicyclic nitronic ester (35), derived as shown has been utilized in a preparation of the bicyclo[3.3.0]octane system via a ring contracti~n.~~

n

0

(331 Ph

+

Ph

,IPh

02N

Me

(a) B. M. Trost and D. M. T. Chan,J. A m . Chem. Soc., 1983,105,2315; (b) B. M. Trost and D. M. T. Chan, ibid., p. 2326. 41 B. B. Snider and T . C. Kirk, J. A m . Chem. SOC., 1983,105,2364. 42 M. Koreeda and S. G. Mislanker, J . A m . Chem. SOC., 1983, 105, 7203. 43 P. Babin and J. Dunogues, Tetrahedron Lett., 1983, 24, 3071. P. A. Aristoff, Synth. Commun., 1983, 13, 145. 45 G. Barbarella, G . Pitacco, C. Russo, and E. Valentin, Tetrahedron Lett., 1983, 24, 1621. 40

Saturated Carbocyclic Ring Synthesis

389

Radical cyclizations continue to inspire new chemistry and are becoming of great use in synthesis. A recent report involves the treatment of olefinic ketones such as (36) with zinc-chlorotrimethylsilane. This route, like virtually all the radical cyclizations yet studied, appears to have great potential in synthesis.46Tin hydride reduction is the most common method used to initiate cyclization as shown by the formation of a tetrahydroindane from the bromide (37).47A second OH M e

'w

Zn Me3SiCI

C02 Me

C02Me

wBr

H

BunpH AIBN

C 0 2M e

C02 Me

137)

(88' l o )

example is the reaction of the iodolactone (38), prepared as shown in Scheme 8, although in this case substantial quantitites of the decalin (39) were produced.48 A very clean method of achieving radical cyclization is by electrolysis, as exemplified by reaction of the allenic ketone (40) to form the alcohol (41).49

(40) Reagents: i , Na, NH, (liq.); ii, Br-

(41)

(39) ; iii, KI, NaHCO,; iv, Bun3SnH

Scheme 8 E. J. Corey and S. G. Pyne, Tetrahedron Lett., 1983,24,2821. A. L. J. Beckwith, D. M. O'Shea, and D. H . Roberts, J . Chem. Soc., Chem. Commun., 1983, 14-45. 48 C. P. Chuang and D. J. Hart, 1. Org. Chem., 1983,48, 1782. 49 G. Pattenden and G. M. Robertson, Tetrahedron Lett., 1983,24,4617. 46 47

General and Synthetic Methods

390

Naturally Occurring Fused Cyc1opentanoids.-Although less effort has been expended in this area than in previous years nevertheless some new and interesting chemistry has appeared. For instance, a simple route to hirsutene has been described which involves, as the key step, the skeletal rearrangement, via homoenolization, of the ketone (42), which is itself readily derived from dicyclopentadiene.50 A full account of Greene’s iterative three-carbon annulation, demonstrated by a synthesis of hirsutic acid, should be of great use to anyone wishing to use this versatile ring forming sequence.51 In a characteristically elegant synthesis of coriolin, Magnus has used the intramolecular octacarbonyldicobalt alkene-alkyne cyclization of (43) to form the fused cyclopentenone A new synthesis of highly substituted bicyclo[3.3.0] (44) stereo~pecifically.~~

OSi Me *But k

l

M

e

-

(43)

0 (44)

octanes involves the addition of the anion (45) to the phosphonium salt (46) (Scheme 9) to form the ylide intermediate (47) which then cyclizes spontaneously to the keto-ester (48), an intermediate of potential in the synthesis of c ~ r i o l i n . ~ ~ The arene-olefin cycloadditions described last year have now been applied to the synthesis of ( + ) - ~ o r i o l i n . ~ ~

Scheme 9 B. A. Dawson, A. K. Ghosh, J. L. Jurlina, and J. B. Stothers, J . Chem. SOC., Chem. Commun., 1983, 204. 51 A. E. Greene, M. J. Luche, and J. P. Depres, J . Am. Chem. Soc., 1983,105,2435. 52 C. Exon and P. Magnus, J . Am. Chem. SOC., 1983,105,2477. 53 A. T. Hewson and D. T. MacPherson, Tetrahedron Lett., 1983,24,5807. 54 P. A. Wender and J. J. Howbert, Tetrahedron Lett., 1983,24,5325. 50

391

Saturated Carbocyclic Ring Synthesis

The internal cyclopropanation of the exocyclic acrylate (49) (Scheme 10) leads to the vinylcyclopropane (50), which undergoes rearrangement to the fused tricyclic system (51). This facile sequence is of use in the preparation of cyclopentanoid terpenic acids such as isocomenic Cyclization of the aldehyde (52) is a key step in a new synthesis of (k)-pentallene.s6

TMe 9; Me

L

C02Et

EtO,

CO, Et

H

H

(52) Reagents: i, CuSO,, [Cu(acac),], A , reflux in benzene; ii, PbCO,, 580°C

Scheme 10

4 Six-membered Rings

Diels-Alder Reactions.-Comprehensive studies of the Diels-Alder reaction of cyclohexadienones have appeared, as have studies of the effects of specific reaction parameters in this r e a c t i ~ nThe . ~ ~full ~ ~potential ~ of isobenzofurans in synthesis has still to be realized. However, one interesting extension has been reported this year whereby the 2-azaisobenzofuran (53) has been generated and its cycloaddition reactions studied.59Interestingly the aqueous-medium DielsAlder reaction of the dienoate (54) is highly facile, in contrast to the corresponding ester reaction in hydrocarbon solvents.60More use of high pressure for [4+2] cycloadditions has been described with the reactions of the Salkoxypentadienoates (55) being studied.61 Activation of terminal and cyclic olefins by formation of a vinylsulphone enables them to be used in [4+2] cycloadditions. Thus, conversion of cyclopentene into the vinylsulphone (56) and reaction with the diene (57) gave a 69% yield of the adduct (58) as the only product, from which the sulphonyl group can be R. P. Short, J. M. Revol, B. C. Ranu, and T. Hudlicky, J . Org. Chem., 1983,48,4453. L. A . Paquette and G. D . Annis, J . Am. Chem. SOC., 1983, 105,7358. 57 F. Fringuella, L. Minuti, F. Pizzo, A. Taticchi, T. D. J . Halls, and E. Wenkert, J . Org. Chem., 1983, 48, 1810. 58 F. Fringuella, F. Pizzo, A. Taticchi, and E. Wenkert, J . Org. Chem., 1983,48,2802. 59 P. Beak and C. W. Chen, Tetrahedron Lett., 1983,24,2945. P. A . Grieco, K. Yoshida, and P. Garner, J. Org. Chem., 1983, 48, 3137. 61 G. Revial, M. Blanchard, and J. D’Angelo, Tetrahedron Lett., 1983,24,899. 55

s6

General and Synthetic Methods

392

YPri 2

OH C02Me

C02Na

4

2

OR (55)

reductively removed.62Fully detailed accounts of this great benefit.

0

PhSe SO2 Ph hL)

'

Me

Me

SO, Ph (56)

will be of

Me

S02Ph

(58)

(57)

Diethyl acetylenedicarboxylate has been used as an equivalent of butatriene (Scheme 11) for the synthesis of polycyclic compounds by a repetitive series of [4+2] cycloadditions. The sequence used in this concept involved conversion of the initially formed adduct (59) into the di-iodide (60) and reaction with a zinc-

<

'

II

'

-a -rJJ

+ i C

II

i, L i A I H 4 ii, Me3SiCI, N a l

I

Scheme 11 L. A. Paquette and G. D. Crouse, J . Org. Chem., 1983,48,141. 63 R . V. C. Carr, R. V. Williams, and L. A. Paquette, J . Org. Chem., 1983,48, 4976. W. A. Kinney, G. D. Crouse, and L. A . Paquette, J. Org. Chem., 1983,48,4986. @

393

Saturated Carbocyclic Ring Synthesis

copper couple.65Many new 1,3-dienes have been reported this year; they include 1,4-di-t-butoxybuta-1,3-diene (61),66the diene (62), in which the acylamine group displays total regiochemical control,67 plus the dienes (63)-(65) .68-70 Additionally, allylidenecyclopropane (66) has been studied71 and the diene (67) has

tut <

OMe

Q

SPh

NHC02CH2 Ph

OBut

'"-5

PPh3

OMe

AcO

(66)

been utilized in a reaction with methyl propiolate to assess the effect of ring strain on the regiochemistry of Diels-Alder reactions .72 Cross-conjugated trienes have also been studied for their Diels-Alder r e a ~ t i v i t y . ~ ~ Br

Me3Si

Me3Si

'

Br

(68)

( 69) M = Sn or Si

Reagents: i, Br,, CCl,, -100°C; ii, (PhSO,),CHNa

Scheme 12 R. 0. Angus and R. P. Johnson, J . Org. Chem., 1983,48,273. H. Hiranuma and S. I. Miller, J . Org. Chem., 1983, 48, 3096. 67 L. E. Overman, C . B. Petty, T . Ban, and G. T. Huang, J . A m. Chem. Soc., 1983,105,6335. H. J. Cristau, G. Duc, and H. Christol, Synthesis, 1983, 374. 69 T. Mandai, K. Osaka, T. Wada, M. Kawada, and J. Otera, Tetrahedron Lett., 1983, 24, 1171. 70 B. M. Trost, C. G. Caldwell, E. Murayama, and D. Heissler, J . Org. Chem., 1983,48,3252. 71 F. Zutterman and A. Krief, J . Org. Chem., 1983,48, 1135. 72 J. Hodge Markgraf, E. W. Greene, M. D. Miller, and W. J. Zaks, Tetrahedron Lett., 1983, 24,241. 73 0. Tsuge, E. Wada, and S. Kanemasa, Chem. Lett., 1983, 239. 65

394

General and Synthetic Methods

One of the most interesting new dienes recently introduced must be the bissilane (68) ,whose cycloadducts allow a tandem 6,5 annulation (Scheme 12).74The related diene (69) has also been studied in depth.75 An interesting new dienophile of utility in Diels-Alder reactions is the nitrovinylsilane (70) , which forms cycloadducts possessing a range of useful funct i o n ~ Carbene .~~ complexes, such as (71), have been used as highly reactive dienophiles in the Diels-Alder reaction,77and the chiral enones (72) 78 and (73) 79 herald an advancement in the development of chiral dienophiles for asymmetric Diels-Alder reactions. 0

( 7 2 ) R = But

(73) R = cyclohexyl

Intramolecular Diels-Alder Reactions.-This area has continued to provide some major developments and is now established as a powerful method for the synthesis of polycyclic compounds in a stereospecific manner. Amongst the natural products whose synthesis or partial synthesis has been approached by the intramolecular Diels-Alder reaction are the cytochalasins,80the taxane skeleton,81the fungal metabolite mevinolin ,82 and i k a r ~ g a m y c i n Silyl-terminated .~~ butadienes (74) have been shown to be of use in these reactions in some elegant model studies on nagilactone ~ y n t h e s i sand , ~ ~the related diene (75) has also been studied.85 The intramolecular Diels-Alder reaction of the furan diene (76) afforded the tricyclic compound (77), which is a useful precursor for the synthesis of ll-ketosteroids,% and that of the diene (78) has led to the synthesis of non-aromatic steroids.87Furthermore, it has now been shown that the reaction can be used to give trans-fused, angularly methylated decalins.88Finally, alkenylallenes, such as (79), are also useful substrates, with the product (80) being used as a model study for the synthesis of chlor~thricolide,~~ and the cyclization of (81) to (82) is a key step in a new synthesis of quadrone.gO B. M. Trost and M. Shimazu, J . A m. Chem. SOC., 1983, 105,6757. H. Sakurai, A. Hosomi, M. Saito, K. Sasaki, H. Iguchi, J, Sasaki, and Y . Araki, Tetrahedron, 1983, 39, 883. 76 A. Padwa and J. G. MacDonald, J . Org. Chem., 1983,48,3189. W. D. Wulff and D. C. Yang, J . Am. Chem. SOC., 1983, 105,6726. 78 S. Masamune, L. A. Reed 111, J. T. Davis, and E. Choy, J . Org. Chem., 1983,48,4441. 79 W. Choy, L. A. Reed 111, and S. Masumune, J . Org. Chem., 1983,48, 1137. 8o G. Stork and E. Nakamura, J . A m. Chem. SOC., 1983,105, 5510. 81 K. Sakan and B. M. Craven, J . A m. Chem. SOC., 1983,105, 3732. E. A. Deitsch and B. B. Snider, Tetrahedron Lett., 1983, 24, 3701. 83 R. K. Boeckman, jun., J. J. Napier, E. W. Thomas, and R. I. Sato, J . Org. Chem., 1983, 48, 4152. 84 S. D. Burke, S. M. Strickland, and T. H. Powner, J . Org. Chem., 1983,48, 454. 85 S. R. Wilson, A. Shedrinsky, and M. Serajul Hague, Tetrahedron, 1983,39, 895. 86 L. A. Van Royen, R. Mijngheer, and P. J. De Clerq, Tetrahedron Lett., 1983, 24, 3145. 87 T. Kametani, Y. Suzuki, H. Furuyama, and T. Honda, J . Org. Chem., 1983,48, 31. ** S. D. Burke, T. H. Powner, and M. Kageyama, Tetrahedron Lett., 1983,24,4529. 89 B. B. Snider and B. W. Burbaum, J . Org. Chem., 1983,48,4370. 9o R. H. Schlessinger, J. L. Wood, A. J. Poss, R. A. Nugent, and W. H. Parsons, J . Org. Chem., 1983, 48, 1146. 74

75

395

Saturated Carbocyclic Ring Synthesis

(74)

Si Me 3 ( 75)

Other Six-membered Ring Syntheses.-Reactions at high pressure continue to provide new opportunities in synthesis, and have now been applied to a Robinson annulation sequence in a reaction with hindered enones (Scheme 13). The initially formed bridged product (83) readily rearrangesto the fused system upon

396

General and Synthetic Methods

(83) Me3Si

x

0

(84) Reagents: i, 15 kbar, 30°C, 3:l MeCN:Et,N; ii, H 3 0 +

Scheme 13

acid treatment.91The enolate anions generated by cuprate addition to enones have been reacted with the silylenone (84) to furnish the Robinson annulation product .% An exciting new methodology for constructing polycyclic carbon frameworks is shown in Scheme 14. This involves two Michael additions and an aldol condensation in what is formally a [2+2+2] annulation by addition of the enolate anion (85) to the enone (86). The 40% mixture of products obtained was converted into the one product (87), a key intermediate in the synthesis of

( 2 5 '10)

-

t

(86)

+

Me0 2C

-oy/

A

( 16 ' l o )

(85)

Scheme 14 91

92

W. G. Dauben and R. A. Bunce, J. Org. Chem., 1983,48, 4642. R. K. Boeckmann, jun., Tetrahedron, 1983, 39,925.

397

Saturated Carbocyclic Ring Synthesis

a f l a ~ i n i n eA . ~useful ~ alternative to the normal Robinson annulation is to use the phosphonium salt (88) , which allows the preparation of the regiotransposed enone (89).94 This has been used in the synthetic approach to the quassinoid b r ~ c e a n t i nChiral . ~ ~ syntheses continue to be developed and carbohydrates continue to be highly useful precursors to chiral products. A recent example is the preparation of (-)-shikimic acid from D-mannose, in which the key step is the cyclization of the lactol (90) by base.96

CI -

c1(88)

1

TIC^^) H ~ O +

The ylide (91) reacts in the presence of base with a,,!?-unsaturated aldehydes to form, presumably in the manner shown, a substituted cyclohexanone, in what is

(921 Reagents: i, NaH; ii, H30+;iii, Et30+BF,-; iv, Bu'O- K+ S. Danishefsky, S. Chackalamannil, M. S. Silvestri, and J. Springer, J. Org. Chem., 1983,48,3615. R . J. Pariza and P. L. Fuchs, J . Org. Chem., 1983,48,2304. 95 R. J . Pariza and P. L. Fuchs, J . Org. Chem., 1983, 48,2306. % G . W. J. Fleet and T. K. Shing, J . Chem. SOC., Chem. Commun., 1983,849.

93 9 . 1

398

General and Synthetic Methods

formally a [3+3] cycloaddition reaction.97 Full details of the reaction of oxosulphonium salts98 and of 1-butadienylsulphonium salts99in epoxyannulations, to give (92) for example, have appeared. The Tio-induced cyclization of carbonyl compounds has now been extended to keto-esters, providing a general synthesis of cycloalkanones. loo Hexa-l95-dienescontaining electron-withdrawing groups. e.g. (93), are converted into cyclohexenes by treatment with paIladium(rr) chloride,lol and the reaction of the alkene (94) with methyl vinyl ketone in the presence of dimethylaluminium chloride causes two sequential ene reactions to give the alcohol (95).lo2 In a biogenetic-type approach to limonene and bisabolene, use has been made of the chiral bis-naphthol mononeryl ether (96). Thus, as shown, treatment of (96) with the organoaluminium reagent (97) gave a 58% yield of D-limonene in an enantiomeric excess of 77% .lo? This type of biomimetic cyclization promises to be of use in the future.

Me

(93)

(94)

(95)

K. M. Pietrusiewicz, J. Monkiewicz, and R. Bodalski, J. Org. Chem., 1983, 48, 788. E. Garst, B. J . McBride, and A . T. Johnson, J. Org. Chem., 1983,48,8. E. Garst and P. Arrhenius, J. Org. Chem., 1983,48, 16. loo J. E. McMurry and D. D. Miller, J . Am. Chem. SOC., 1983,105,1660. lol L. E. Overman and A. D . Renaldo, Tetrahedron Lett., 1983,24,2235. B. B. Snider and E. A. Deutsch, J . Org. Chem., 1983,48, 1822. lo3 S. Sakane, J. Fujiwara, K. Maruoka, and H. Yamamoto, J . Am. Chem. SOC., 1983,105,6154. 97

98 M. 99 M.

Saturated Carbocyclic Ring Synthesis

399

Steroids.-Once again, biomimetic cyclizations dominate this area. A significant achievement is the synthesis of the first genuine non-aromatic sterol prepared by a non-enzymic polycyclization route; thus, tin(Iv) chloride treatment of the epoxide (98) gave (99) in 44% yield.'@' Me

I

Me

c

I

c=o

L

(98)

O

(99,

Silicon has been used by three independent groups of workers to control biomimetic cyclizations. The allylsilane function in the acetal(lO0) terminates the tin(rv) chloride-mediated cyclization very clearly,lo5and an analogous cyclization has been reported by a Canadian group. lo6 The silicon group in (101) controls the

lo4 Io5 lo6

E. E. van Tamelen and J. R. Hwu, J . Am. Chem. SOC., 1983, 105,2490. W. S. Johnson, Y.-Q. Chen, and M. S. Kellogg, J. Am. Chem. SOC., 1983,105,6653 R. J. Armstrong and L. Weiler, Can. J . Chem., 1983,61,215.

400

General and Synthetic Methods

regiochemistry of the reaction by directing cyclization to the methylated terminus of an intermediate ally1 cation. lo7 Mercury(I1) trifluoromethanesulphonate-N,N-dimethylanilinecomplex has been recommended for initiating polyene cyclizations,losand iron(m) chloride treatment of the epoxide (102) gave (103), a key intermediate in a synthesis of ( +)-aphidicolin.lo9

OMe

OMe

Me OH (103)

(102)

5 Seven-membered, Medium, and Large Rings The hydroazulene ring system has been prepared in an interesting application of the intramolecular nitrile oxide cycloaddition reaction. Thus, treatment of the nitro-ester (104) with phenyl isocyanate, while heating in benzene in the presence of triethylamine, gave an 83% yield of the hydroazulene (105) possessing the stereochemistry shown.ll0 The titanium(1v) chloride-catalysed intramolecular directed aldol reaction of acetals and 0-silylated enolates, e.g. (106), gives a low yield of the eight-membered ring (107), the reaction presumably going via an intermediate in which both the enol and acetal are co-ordinated to titanium."l )Me

PhNCO _____5

H (104)

@ 0-N

(105)

Tic14

M

1

OSi Meg

(106)

( 107)

P. M. Bishop, J. R. Pearson, and J. K. Sutherland, J . Chem. SOC., Chem. Commun., 1983, 123. M. Nishizawa, H. Takenaka, H. Nishide, and Y . Hayashi, Tetrahedron Lett., 1983, 24, 2581. lo9 E. E. van Tamelen, S. R. Zawacky, R. K. Russell, and J. G. Carlson, J . Am. Chem. SOC., 1983,105, 142. 110 A. Kuzikowski, B. B. Mugrage, B. C. Wang, and Z. Xo, Tetrahedron Lett., 1983,24,3705. 111 G . S. Cockerill and P. Kocienski, J . Chem. SOC., Chem. Commun., 1983, 705.

lo'

lo*

401

Saturated Curbocy cl ic Ring Synthesis

In an elegant and simple approach to sesterterpene synthesis, Paquette has applied the oxy-Cope rearrangement to the synthesis of the ophiobolin carbon skeleton. This involves the addition of cyclopentenyl-lithium to the vinyl ketone (108),the product of which undergoes a spontaneous oxy-Cope rearrangement to the enolate anion (109), which can be alkylated to give (l1O).ll2 The intramolecular alkylation of protected cyanohydrins is well known as a useful cyclization reaction which has now been applied to the preparation of the cyclodeca-2,6dienone (111).113 This strategy has been applied to the synthesis of germacrone .l14

ae

I

0-

f 109)

(108)

iMe* H

&OTs

(111) (78%)

A diastereoselective cyclization of the bromoaldehyde (112) allows a simple synthesis of asperdiol (113).115 /OCH20CH

I

Me

(112) lI2 113 115

ZPh

/OH

Me (113)

L. A. Paquette, D. R . Andrews, and J. P. Springer, J . Org. Chem., 1983,48, 1147. T. Takahashi, €1. Nemoto, and J. Tsui, Tetrahedron Len., 1983, 24,2005. T. Takahashi, K, Kitamura, H. Nemoto, and J. Tsui, Tetrahedron Lett., 1983, 24, 3489. W. C. Still and D. Mobilio, J . Org. Chem., 1983,48,4785.

General and Synthetic Methods

402 6 Ring Expansion Methods

The unusual migration of a less substituted carbon in the cyclopropyl-carbinylcyclobutyl rearrangements provides ready access to 2,4-disubstituted cyclobutanones. Thus, treating the alcohol (114) with triethyloxonium tetrafluoroborate gave the cyclobutanone (115).1*6It is thought that the migratory aptitude is influenced by the inductive effect of the remote (acyloxy) methyl group.

V

t02Bu'

0'

Further work on the cycloaddition of vinylketenes and the ring expansion of the derived vinylcyclobutanones to cyclopentenones should be useful. 117 The well known cyclopentanone synthesis from the action of diazomethane on cyclobutanones has now been applied to the synthesis of (-t )+cuparenone. 118 Cyclopentanones are produced by the Lewis acid-catalysed ring expansion of 1-acyl-1-methylthiocyclobutanes(Scheme 15), which are in turn derived from methylthioacetonitrile (116) via the nitrile (117).l19 a-Lithioselenoxides add to

cyclobutanones to form anions which rearrange at 65°C to form cyclopentanones via exclusive migration of the more highly substituted carbon atom (Scheme 16).120

65 C ' ___)

Scheme 16 B. M. Trost and P. L. Ornstein. J . Org. Chem., 1983,48, 1131. A. Jackson, M. Rey, and A. S . Dreiding, Tetrahedron Lett., 1983,24,4817. 11* A. E. Greene, J. P. Lansard, J. L. Luche, and C. Petrier, J . Org. Chem., 1983,48,4163. 119 M. Yamashita, J. Onozuka, G . Tsuchihashi, and K. Ogura, Tetrahedron Lett., 1983,24,79. lzn R. C. Gadwood, J . Org. Chern., 1983,48,2098.

116

117 D.

403

Saturated Carbocyclic Ring Synthesis

a-Vinyl- and a-aryl-cyclopentenones are readily produced by acid-catalysed ring enlargement of cyclobutane derivatives (118) (Scheme 17).121A novel four-

( 118 )

Reagents: i, LiAlH,; ii, Me,SiCl; iii, SnCl,

Scheme 17

carbon interpolation procedure has been developed in which the ring expansion step is dependent upon the stabilization of an anion by a nitro-group (Scheme 18). Thus, reaction of 2-nitrocycloheptanone with methyl-3-oxopent-4-enoate (1 19) in the presence of tetra-n-butylammonium fluoride gave the Michael adduct (120). Further reaction formed the anion (122) which ring-opened to give the 0

w

+---

Scheme 18

-73 TMSOTf

(123)

(124)

0

OH (126) 12*

E. Nakamura, J. Shimada, and I. Kuwajima, J. Chem. SOC., Chem. Commun., 1983,498.

14

General and Synthetic Methods

404

cycloundecane derivative (121) in 90% overall yield.122(*)-Muscone has been prepared by mild Lewis acid-catalysed Beckmann rearrangement of the olefinic oxime sulphonate (123) to give the enimine (124), which was convereted into muscone. 123, 124 The intramolecular Grignard reaction of the bromide (125) has been shown to afford the ring-expanded product (126).12s 7 Spiro-ring Compounds

The concept of intramolecular photoaddition-cyclobutane fragmentation to give spiro-compounds has now been applied to the synthesis of (+)-acoradiene.lZ6The ‘cyclocuprate’ species (127) facilitates the preparation of spirocyclic compounds, albeit in low yield,127and a useful route to spiro[3.4]octa-5,7-diene(128) has been described, involving the sequence shown in Scheme 19.128

0

0

.1

iii, iv

8

v, vi

8.8

Reagents: i , CH,N,; ii, Zn, AcOH; iii, TsNHNH,; iv, McLi; v, NBS, vi, ButOK

Scheme 19

In an inspired approach to the synthesis of plumericin Trost has demonstrated that the readily prepared vinylcyclopropanol derivative (129) spontaneously and stereoselectively ring-expands upon epoxidation to the cyclobutanone (130). Y. Nakashita and M. Hesse, Helv. Chim. Acta, 1983, 66, 845. S. Sakane, K. Maruoka, and H. Yamamoto, Tetrahedron Lett., 1983,24,943. lZ4 S . Sakane, Y. Matsumura, Y. Yamamura, Y. Ishida, K. Maruoka, andH. Yamamoto,J. Am. Chem. Soc., 1983, 105, 672. lZ5 C. Fehr, Helv. Chim. Acta, 1983, 66, 2512. lZ6 W. Oppolzer, F. Zutterman, and K. Battig, Helv. Chim. Acta, 1983,66,522. lz7 F. Scott, B. G. Mafunda, J. F. Normant, and A. Alexakis, Tetrahedron Lett., 1983,24, 5767. I. Erden and E. M. Sorenson, Tetrahedron Lett., 1983,24,2731.

lZ2

123

Saturated Carbocyclic Ring Synthesis

405

This sequence constitutes an 0-substitution-spiroannulation of a saturated ketone. 129,130Additionally, spiroannulation can be achieved by the reaction of the allylsilane (131) with ethylaluminium dichloride in toluene to give the enone (132) Presumably the spirocycle arises owing to a pinacol-type rearrangement of the expected product (133), giving the p, y-unsaturated ketone( 134), which

0"

-

SiMe, tVO(acad21

(130)

( 129 1

EtAIC12

'(-&

SiMe,

(132)

S02Ph

c

/

L

isomerizes to the observed product. An intramolecular version of the well known reaction of vinylsilanes and acyl chlorides has been developed for the preparation of spirocyclopentenones. The silyl group in (135) controls the cyclization to form just one product, in contrast to the corresponding olefin acylation of (136).132

TiClL

(135) R = SiMe,

1;" ( 6 5 "/o)

(136) R = H M. Trost and M. Mao, J . Am. Chem. SOC., 1983, 105,6753. B. M. Trost, M. Mao, and J. K. Balkovec, J . Am. Chem. SOC., 1983,105,6755. 131 B. M. Trost and B. R. Adams, J . Am. Chem. SOC., 1983,105,4849. 132 E. Nakamura, K. Fukuzaki, and I. Kuwajima, J . Chem. SOC., Chem. Commun., 1983,499. 129 B.

406

General and Synthetic Methods

Marked improvements in the yield of the intramolecular ene reaction of acetylenic carbonyl compounds to form spiroketones are possible by using a catalytic amount of a mercury(I1) salt.133 An interesting version of the vinylidene-cyclopropane rearrangement has led to a new synthesis of spirovetivanes. Thus, thermolysis of the enolsilane (137) (Scheme 20), prepared as shown, gave the spiro-ketone (138) in good ~ i e l d . l ~ ~ T h e

(137)

n=lor2

(138)

Reagents: i , [ P C u S P h I L i ; ii, LiNPrI,; iii, Me,SiCl; iv, 425°C

Scheme 20

process has been used in preparing the spiro[5.7]-ring system,135and in a new route to (k)-/%hima~halene.~~~ A new, but poor yielding route, to spiro[4S]decanol derivatives involves irradiation of the keto-ester (139) to form an oxetane, which upon base treatment leads to the spirodecalin (140). 137

M. Boaventura, J . Drovin, and J . M. Conia, Synthesis, 1983, 801. E. Piers, C . K. Lau, and I. Nagakura, Can. J . Chem., 1983,61,288. 135 E. Piers, H. E. Morton, I. Nagakura, and R. W. Thies, Can. J . Chem., 1983,61, 1226. 136 E. Piers and E H. Ruediger, Can. J . Chem., 1983, 61,1239. 137 T. H. Kim, 1.. ,ayase, and S. Isoe, Chem. Lett., 1983, 1421.

133

134

Saturated Heterocyclic Ring Synthesis BY K. COOPER AND P. J. WHITTLE

1 Oxygen-containing Heterocycles

0xiranes.-The preparation and wide synthetic applications of oxiranes have been reviewed,l with a fairly large section having been devoted to asymmetric synthesis, which continues to receive much attention. Details of the use of natural polypeptides to achieve high enantioselectivity in the epoxidation of olefins have now appeared,2and the optically active oxidizing agents (1) and (2), which were previously used for the asymmetric synthesis of sulphoxides, have been used in unfunctionalized olefin epoxidation giving much higher e .e .s than previously possible (typically 2 U O % ) . 3

Several new reagents for the epoxidation of alkenes have appeared in 1983;for example both dinitratodioxochromium(v1) in DMF4and dilute hydrogen peroxide in the presence of tungstate-phosphate under phase-transfer conditions are effective epoxidation reagents. Peroxy-acids have long been used for epoxidation, and recently alkoxycarbonylimidazoles have been used as a convenient source of peroxycarbonic acids. The same research group has now developed the use of alkoxycarbonyltriazoles as intermediates for peroxycarbonic acids, with 1

A . S. Rao, S . K. Paknikar, and J. G. Kirtane, Tetrahedron, 1983, 39,2323. S. Colonna, H. Molinari, S. Banfi, S. Julia, J. Masana, and A . Alvarez, Tetrahedron, 1983,39, 1635. F. A . Davis, M. E. Harakal, and S. B. Awad, J . Am. Chem. Soc.,1983,105,3123. N. Miyaura and J. K. Kochi, J . Am. Chem. SOC.,1983,105,2368. C. Venturello, E. Alneri, and M. Ricci, J . Org. Chem., 1983,48, 3831.

407

General and Synthetic Methods

408

the advantage that only 1.2 equivalents are needed for high-yielding epoxidations .

0

II

ROCOOH

One of the most commonly used peroxy-acids, m-chloroperbenzoic acid, has been used for the high-yielding (80-96%) epoxidation of the acid-labile a$unsaturated acetals (4),where the use of KF-NaF is crucial to the success of the rea~tion.~

Ally1 and homoallyl trimethylsilyl ethers can be successfully epoxidized if the system comprising t-butyldioxytrimethylsilane-vanadyl acetoacetate-tris(trimethylsilyl) phosphate is used, but the stereoselectivityis not as good as that achieved for the Sharpless system.8 The opposite stereoselectivity to the Sharpless vanadyl acetoacetate system can be achieved (i.e. threo rather than erythro) by epoxidation of allylic alcohols with t-butyl hydroperoxide-tris-t-butyloxyaluminium in benzene at 0°C. The yields are usually good (>70%).' Corey et al. have shown that P-peroxy-mercurials, generated by peroxy-mercuration of olefins, afford epoxides ( 5 ) on reduction with sodium borohydride. The reaction is thought to go via P-peroxy-radicals.lOTrisubstituted olefins react with iodine-pyridinium dichromate under anhydrous conditions at room temperature to give epoxides via the corresponding iodohydrins, which can be isolated with shorter reaction times (see Scheme 1).l1 Y. Tsunokawa, S. Iwasaki, and S. Okuda, Chem. Pharm. Bull., 1983,31,4578.

' F. Camps, J. Coll, A . Messeguer, and F. Pujol, Chem. Lett., 1983, 971.

T. Hiyama and M. Obayashi, Tetrahedron Lett., 1983,24,395. K. Takai, K. Oshima, and H. Nozaki, Bull. Chem. SOC.Jpn., 1983,56, 3791. E. J. Corey, G. Schmidt, and K. Shimoji, Tetrahedron Lett., 1983,24, 3169. R. Antonioletti, M. D'Auria, A . De Mico, G. Piancatelli,and A. Scettri, Tetrahedron, 1983,39,1765.

409

Saturated Heterocyclic Ring Synthesis

" R2

R3

d [

OH H

B

R

A

-

R'

0

R f i R 3

Reagents: i, Bu'Me,SiOOH, Hg(02CCF3)2,-90°C; ii, NaBH,, H,O, O'C, iii, I,, PDC

Scheme 1

1,2-Diols can be converted directly into epoxides with carbon tetrachloridetriphenylphosphine-potassium carbonate, probably via l,Zchlorohydrins, in variable yield depending on the substitution pattern. l2 a-Halogeno-ketones react with acetonyl- and allyl-tin in the presence of a palladium(I1) catalyst to give epoxides (6) generally in good yield (65%). The reaction is also applicable to the synthesis of oxetanes and tetrahydrofurans. l3

Sulphur ylides are commonly used to epoxidize ketones, and more recently non-stabilized arsonium ylides have been used in a similar manner. This method has now been extended to the synthesis of the vinyl epoxides (8) from the stabilized allylic arsonium ylides (7) in high yield.14 The vinyl epoxides (10) can also be synthesized from aldehydes by the addition of the organotin reagent from 1-chloro-3-iodopropene and tin(11) chloride, followed by treatment of the intermediates (9) with methoxide. The yields are moderate (50%) and the reaction shows cis-stereoselectivity .l5 Finally, full details on the useful conversion of ketones or aldehydes into a&epoxytrimethylsilanes using chloromethyl(trimethylsilyl)lithium have now appeared.l6 C. N. Barry and S. A. Evans, jun., Tetrahedron Lett., 1983,24, 661, I. Pri-Barr, P. S. Pearlman, and J. K. Stille, J . Org. Chem., 1983: 48, 4629. l4 J. B. Ousset, C. Mioskowski, and G . Solladie, Tetrahedron Lett., 1983, 24, 4419. J. Auge and S . David, Tetrahedron Lett., 1983, 24, 4009. l6 C. Burford, F. Cooke, G . Roy, and P. Magnus, Tetrahedron, 1983,39, 867.

12

l3

410

General and Synthetic Methods

..

R2

.----.. (7)

I R'

+

CICH-CHCHZI

SnC12

- wMeO-

+ DMF OSnCL2I

R

(9)

(10)

Four-membered Rings.-Variations on cycloadditions continue to be popular for the formation of the oxetane ring system. Thus, the deactivated ketene acetals (11) add to carbonyl compounds under high pressure (12 kbar) at much greater

R"'FR3

OMe

+

R2

(11 1

OMe

Rd

R2 OMe

rates than at atmospheric presssure.17 When the reaction is carried out with benzaldehyde, trans-oxetanes predominate , again in contrast to atmosphericpressure conditions where the cis-form predominates. Photochemical cycloaddition of aryl carbonyl compounds with vinyloxy compounds has been investigated by two groups of workers this year. Ruotsalainen and Karki have shown that aryl aldehydes (12) add to vinyl acetate giving mixtures of oxetanols where the 3-isomer predominates,ls whereas Shimizu and co-workers have demonstrated that benzophenone adds to trimethylsilylenol ethers, giving the oxetanes (13) in generally high yield (>80%). l9 R. W. M. Aben and H. W. Scheeren, Tetrahedron Lett., 1983,24,4613. H. Ruotsalainen and T. Karki, Acta Chem. Scand., Ser. B, 1983,37, 151. 19 N. Shimizu, S. Yamaoka, and Y. Tsuno, Bull. Chem. SOC.Jpn., 1983, 56, 3853.

17

18

Saturated Heterocyclic Ring Synthesis 0

+

Ar A H (12)

-

411

hV

(OAC

P

Ar

O

A

C

2

7

,R~

R* 0 PhA

CHR~ P

h

+

R1AOSiMe3

R1

i, h v

P

ii a MeOH, K2CO3

Ph

OH Ph (13)

or p-TsOH, MeOH

3-Hydroxyoxetane itself can be readily prepared from epichlorohydrin as outlined in Scheme 2.20The method is particularly suitable for large-scale synthesis.

-

OH

lii A

c

O

T

C

L

f-111

OH

OEt Reagents: i , AcOH; ii, CH,=CMe(OEt),

H + ; iii, NaOH

Scheme 2

The benzyl ethers (14) are deprotonated using the hindered base lithio-2,4dimethylpiperate, and undergo intramolecular attack at the epoxide leading to oxetanes, tetrahydrofurans, and tetrahydropyrans in high yield; the formation of oxetanes is particularly favoured.21 Full details on the direct conversion of ketones into oxetanes using S-methyl-S(sodiomethyl)-N-(4-tolylsulphonyl)sulphoxime,developed by Welch et al., have now appeared,22and a similar reaction using trimethylsulphoxonium methylide (15) as the methylene transfer agent has been reported.23Thus treatment of epoxides with one equivalent of (15) leads to the oxetanes (16), and treatment of ketones with two equivalents of (15) also leads to (16). K. Baum, P.T. Berkowitz, V. Grakauskas, and T. G . Archibald, J . Org. Chem., 1983, 48, 2953. D . R. Williams and J . Grote, J . Org. Chem., 1983, 48, 134. 22 S. C. Welch, A . S. C . Prakasa Rao, J. T. Lyon, and J.-M. Assercq, J . Am. Chem. SOC., 1983,105,252. 23 K. Okuma, Y. Tanaka, S. Kaji, and H. Ohta, J . Urg. Chem., 1983,48, 5133.

2o

General and Synthetic Methods

412

(14) n =0- 2

A review of the synthesis and properties of 1,2-dioxetanes has been published during 1983.24 Five-membered Rings.-Tetrahydrofurans. Although a well used method for tetrahydrofuran ring formation, new variations on the intramolecular ether formation still appear. For example, the acyl-lithium reagents (17), generated in situ by the addition of alkyl-lithiums to carbon monoxide, add to 5-chloropentan2-one to afford the acyl tetrahydrofurans (18) in high yield.25In a similar type of reaction the addition of 4-chloro-2-lithiobut-1-ene to aldehydes or ketones leads

RLi

+

+

lLi Rh ii,iii)

I

CO

R

(17)

(18) 80 -95’/0

Reagents: i, THF, E t 2 0 , pentane (4:4:1); ii, MeCOCH,CH,Cl; iii, -110 to 47°C

(19) Reagents: i, MeLi,THF, -78°C; ii, RIRZCO;iii, NH,Cl, -78°C; iv, HMPA, -78°C to r.t.; v, KH, THF 24 25

W. Adam and G . Cilento, Angew. Chem., Int. Ed. Engl., 1983, 22, 529. R. M. Weinstein, W.-L. Wang, and D. Seyferth, J . Org. Chem., 1983,48,3367

413

Saturated Heterocyclic Ring Synthesis

to 3-methylenetetrahydrofurans (19) in moderate yields (51--63%) .26 The mixture triphenylphosphine-t-butyl hypochlorite-potassium carbonate is a useful complement to the triphenylphosphine-carbon tetrachloride method for the preparation of tetrahydrofurans from 1,4-diols.” The tribromides (21), which were reported previously to cyclize to tetrahydrofurans, are prepared much more readily by the bromination of the cyclopropyl ketones (20). The tribromides (21) were then cyclized to give methoxy- or cyano-tetrahydrofurans, again by intramolecular ether formation.28 Br I

Ar

dBr Ar%

Ar

Me0

Reagents: i, Br,, CC1,; ii, NaOH, MeOH, H 2 0 ; iii, NaCN, MeOH

The allylic alcohols (22) when treated with a PdO catalyst in carbon tetrachloride are converted into oxaphosphonium compounds which then give the (x-al1yl)palladium complexes (23). The chloride anion, formed in situ, cleaves the triethylsilyloxy-group, generating an alkoxide anion which then undergoes intramolecular displacement to afford tetrahydrofurans (see Scheme 3) .29 A further use of alkoxide opening of (n-ally1)palladium complexes has been described by Stork and P ~ i r i e rwhere , ~ ~ the optically pure allylic benzoates (24) and (26) afford the tetrahydrofurans (25) and (27) respectively, with high chirality transfer, in the presence of PdO catalyst. The primary tosylates (28) are reduced using a tri-n-butyltin hydride-sodium hydride mixture, generating a radical which is captured by the double bond to give tetrahydrofurans or tetrahydropyrroles in high yield.31 Similarly the a-halogenosulphones (29) reductively cyclize under the same conditions to give tetra hydro fur an^,^^ and the ease with which the latter reaction proceeds is in E. Piers and V. Karunaratne, J . Org. Chem., 1983,48, 1774. C. N. Barry and S. A. Evans, jun., J . Org. Chern., 1983,48,2825. 28 M. Takahashi, N. Takeshi, K. Myojoh, H. Sano, and T. Morisawa, J . Heterocycl. Chern., 1983, 20, 209. 29 S. A. Stanton, S. W. Felman, C . S. Parkhurst, and S. A . Godleski, J . Am. Chem. SOC., 1983, 105, 1964. 30 G. Stork and J. M. Pokier, J . Am. Chem. Soc., 1983,105, 1073. 31 Y. Ueno, C. Tanaka, and M. Okawara, Chem. Lett., 1983,795. 32 Y. Ueno, R. K. Khare, and M. Okawara, J . Chem. SOC., Perkin Trans. 1, 1983, 2637.

26

27

414

General and Synthetic Methods

m

OSiEt3 OH

H

Scheme 3

HO [ Pd ( PP h3),.]

0 (241

Et3N. MeCN

(26)

(25)

(27)

Bu3SnH,

NaH

*d

azobisisobutyron i t r i Le

DME

(28)

R = H or Ph

X = O or NTs

y,f R

p -To ISO2

R’ (29)

Saturated Heterocyclic Ring Synthesis

415

direct contrast with the ease of nucleophilic substitution of halogen in a-halogenosulphones . Intramolecular opening of epoxides features in two approaches to tetrahydrofurans reported this year. In the first the trimethylsilyl olefinic alcohols (30) are epoxidized with rn-chloroperbenzoic acid and the resulting epoxides treated with potassium hydride to give a-alkylidenetetrahydrofurans(31) via sequential epoxide opening and ~yn-elimination.~~ In the second method the epoxides (34), which are generated by addition of the stabilized carbanions (33) to the iodolactone (32), cyclize in situ to give mixtures of 2- and E-a-alkylidenetetrahydr~furans.~~ The 2-compounds predominate when X is an oxygenbased stabilizing group. The known cycloaddition of 3-oxidopyrilium ylides to olefins to give tetrahydrofurans has been extended by Sammes and his group. They have found that

iKH

(30) I

I (31)

(32)

x (34) R

2

+

X

YLi + ( 3 3 ) R = H or Me

R ' S ' . / O H

X = PhSO2 ,PhzPO, COZR1, or CN 33

F.-T. Luo and E. Negishi, J . Org. Chem., 1983,48,5144. Batmangherlich,A. H. Davidson, and G . Procter, Tetrahedron Left., 1983,24,2889.

41 S .

f

416

General and Synthetic Methods

the ylides add to electron-rich and strained olefins, not only under thermal conditions but also at room temperature in the presence of base. For example the 3-oxidopyrilium ylide (35) adds to ethyl vinyl ether to give the tetrahydrofuran (36).35 The method has also been applied to a series of potential herbicides demonstrating the feasibility of the intramolecular variant (Scheme 4).36In a OEt

b or tertiary base

AcO

R

+ /

OEt (36)

(35)

AcO

qo Scheme 4

+

(38) R3

35 36

J

P. G. Sammes and L. J. Street, J . Chem. SOC.,Perkin Trans. 1 , 1983,1261. P. G. Sammes, L. J. Street, and P. Kirby, J . Chem. Soc., Perkin Trans. 1, 1983,2729.

Saturated Heterocyclic Ring Synthesis

417

similar type of reaction, originally investigated by Biichi, the cycloaddition of the pyrones (37) giving tricycles containing a tetrahydrofuran ring has been reported. 37 The intramolecular Diels-Alder reaction of the alkenyl oxazole-Scarbarnates (38) proceeds cleanly to give tetrahydrofuropyrrolidines (39), in contrast to the intermolecular reaction which affords p y r i d i n e ~ . ~ ~ The treatment of dibromocyclopropane ethers with methyl-lithium is known to give tetrahydrofurans via intramolecular carbene insertion: this reaction has now been extended to the conversion of cyclopropyl acetals (40) into tetrah y drofurans. 39

R1

-

R2

MeLi

-78

OC

Br Br

(40)

A new method for the synthesis of tetrahydrofurans and tetrahydropyrans involving the oxidative cyclization of olefinic alcohols has been reported this year. Thus, treatment of the olefins (41) with DDQ in methylene chloride affords tetrahydrofurans or tetrahydropyrans depending on the substitution pattern, the reaction only working for E-olefins.40

R'O

/

R2= H

DDQ.CHzCI2

/

R' 0

x = -+OM 6R2 (41)

M. E. Garst, B. J . McBride, and J. G. Douglass 111, Tetrahedron Left., 1983, 24, 1675. S. Shimada and T. Tojo, Chem. Pharm. Bull., 1983, 31,4247. 39 J. Arct, L. Skattebol, and Y. Stenstrom, Acta Chem. Scand., Ser. B, 1983, 37, 681. 4o Y. Oikawa, K. Horita, and 0. Yonemitsu, Heterocycles, 1983, 20, 135.

37

38

418

General and Synthetic Methods

1,6-Dioxaspir0[4,4]nonanesoccur in many natural products and a delightfully efficient method for their synthesis has been published. It entails the deprotonation of acetone N , N-dimethylhydrazone and treatment with an epoxide followed by a second treatment with base and epoxide to give the diols (42) which then cyclize to give the spirotetrahydrofurans (43) in excellent overall yield (5082%) .41 The availability of chiral epoxides allows optically active compounds to be synthesized. Furofurans are also featured in several natural products and a synthesis of perhydrofurofurans (44) via the well used iodolactonization sequence has been reported.42

OLi

OH

OH (42)

H

(44) Reagents: i, Bu"Li; ii, -15°C

0

; iii, RZ,i/o;

(43)

iv, Amberlite 1R 120A, THF, A; v , I,, NaHCO,, MeCN,

Dihydrofurans.The Lewis acid-catalysed reaction of a-(t-buty1thio)-a-chloroacetone with the olefins (45) affords 2,3-dihydrofurans in moderate yield (45%) accompanied by varying amounts of the ene products (46).43The reaction has also been applied to the synthesis of y-butyrolactones as shown in Scheme 5. a-Hydroxy-l,3-diketones are known to undergo acid-catalysed cyclodehydration to give furanones, and Curran and Singleton have now published a new entry into a'-hydroxydiketone equivalents via nitrile oxide cycloaddition to enol ethers.44The adducts (47) are reduced with Raney nickel and cyclized in the presence of acid to afford the dihydrofurans (48). The method has been applied to the synthesis of bullatenone (49). Bullatenone and geiparvarin have been synthesized by another general procedure for the synthesis of dihydrofurans reported by Raphael and Jackson.45The procedure involves the hydration of the acetylenic ketones (51) which are conveniently prepared by palladium-assisted coupling of acetylenes with the acid bromide (50). The resulting enamines (52) cyclize on treatment with acid to give dihydrofurans, where (53) was converted in a few steps into geiparvarin (54). D. Enders, W. Dahmen, E. Dederichs, and P. Weuster, Synth. Commun., 1983, 13, 1235. M. Jalali, G . Boussac, and J.-Y. Lallemand, Tetrahedron Lett., 1983,24, 4307. 43 M. Wada, T. Shigehisa, H. Kitani, and K. Akiba, Tetrahedron Lett., 1983,24,1715. 44 D. P. Curran and D. H. Singleton, Tetrahedron Lett., 1983,24,2079. 45 R. F. W. Jackson and R. A. Raphael, Tetrahedron Lett., 1983,24,2117.

41

42

419

Saturated Heterocyclic Ring Synthesis

+

(45)

R’$TR2

Buts

0

ArS

CL

+

-

R1

SnC14

R1 Scheme 5

+

HO

(471 70 - 98 ‘lo

(48) 50- 71 ‘10

OEt +(OH

R2 R3

Ph

Me

The 3-metalloenaminegenerated by deprotonation of the enamine (55) adds to ketones or aldehydes to give adducts in moderate to good yield (40-78%), which can then be transformed into either dihydrofurans (56) by thermolysis or tetrahydrofurans (57) by solvolytic cyclization.46 Enamines also feature in an unusual photocoupling reaction: the irradiation of enamines of amines in the presence of cobalt trisacetoacetate affords the aminodihydrofurans (58) in variable yield (42-75%) depending on the structure of the amine or enamine.47Di-iminodihydrofurans (61), a class of compounds 46 47

H. Ahlbrecht and H. Simon, Synthesis, 1983, 61. T. Sato and K. Watanabe, Chem. Lett., 1983, 1499.

General and Synthetic Methods

420

Reagents: i, [Pd(PPh,),Cl,], Et,N, CuI; ii, Et,NH; iii, AcOH, H20

.I -... 111

R' OH

- qph

'NPh

R2

C02Me

(55)

R2

Me02C

Me02C Me0%2: (57)

(56)

Reagents: i, LDA, -78°C; ii, K1R2CO;iii, CF,CO,H, -+O"C;iv, A; v, H2S04,MeOH

R3

/I/RL '

R' N' R2

\

hv

or

[Co(acac131, M e C ND3 : &

R3

R'

N '

R2

/

O N/R

/I/RL

1

R2

(58)

1

421

Saturated Heterocyclic Ring Synthesis

R1

(60)

(59)

R’ 0

A

N2J-Lo*E1

+

(62)

R3

which were previously unknown, can be prepared by the addition of isocyanides to the acylketeneimines (60), which are prepared by thermolysis of the diazoketones (59) in the presence of triphenylphosphane imides.@The thermolysis of ethyl diazopyruvate in the presence of enol ethers affords 2,3dihydrourans (62) in variable yield ( 3 6 7 9 % ) depending on the structure of the enol ether, but complete regio- and stereo-specificity is observed and the reaction also succeeds with ketene a c e t a l ~ . ~ ~ It is known that o-allyl-substituted phenols (63) can be converted into 2,3dihydrobenzofurans by reaction with thallium(m) acetate and subsequent reaction of the organothalium intermediate. It has now been reported that simply by using thallium(m) nitrate the reaction proceeds in one step, giving the benzofurans (64) as mixtures of isomers.50The yields of 2,3-dihydrobenzofurans (65) from the Nick1 reaction have been substantially improved by using the lithiophenolate in toluene rather than the sodio-derivative in mefhan01,~land the L. Capuano, P. Morsdorf, and H. Scheidt, Chem. Ber., 1983,116,741. M. E. Alonso, P. Jano, M. I. Hernandez, R. S. Greenberg, and E. Wenkert, J . Org. Chem., 1983,48, 3047. M. L. Forcellese, C. Alfonsi, S. Calvitti, and E. Mincione, Heterocycles, 1983, 20, 1559. 51 F. Bigi, G. Casiraghi, G. Casnati, and G. Sartori, Tetrahedron, 1983,39,169. 49

General and Synthetic Methods

422 R

(64)R' =Me or NO2

(63)

R (65)

synthesis of benzofurans by the six-electron cyclization of phenyl vinyl ethers has been reviewed.52 The acetylene compounds (67) cyclize in the presence of a catalytic amount of potassium hydride in DMSO to afford 2-metho~y-2,5-dihydrofurans.~~ The

LO A

=c
(66)

i

R' R 2 C 0

m;

Me0

Rl K H , DMSO

pH= R2

("' Si Me3

molecules (67) are conveniently prepared by the addition of the lithium acetylide (66), the product from the base-promoted rearrangement of methyl 1-trimethylsilylalkenyl ether to ketones or aldehydes. Hiyama and his group have also studied the synthesis of dihydrofurans from derivatives of acetylene-1,4diols. Thus the acetylenic diols (68) can be converted either to the 2,5dihydrofurans (69) by silver-mediated cyclization of the monoacetate, or to the furanones (70) directly, using the polymer reagent Hg/Nafion H.54Similarly, a A. G. Schultz, Ace. Chem. Res., 1983, 16, 210. I. Kuwajima, S. Sugahara, and J. Enda, Tetrahedron Lett., 1983,24,1061. 54 H. Saimoto, T. Hiyama, and H. Nozaki, Bull. Chem. SOC., Jpn., 1983,56,3078.

52

53

Saturated Heterocyclic Ring Synthesis

423

R1

R’

R2

R2

.A

Ac2Y

( 69)

range of 2,5-dihydro- and 4,5-dihydro-furanonescan be prepared from acetylenic diol derivatives in generally good yield and in one step (see Scheme 6).55

R’ .+R2

EtO

OH

iii > 5 0 %

EtO

R’ R30>=

0

- .+R2

ii 3 0 - 8 5 %

- 0

OH

Reagents: i, H,SO,, MeOH; ii, Hg, Nafion H; iii, CF,CO,H, Hg(OAc),

Scheme 6 55

H. Saimoto, M. Shinoda, S. Matsubara, K. Oshima, T. Hiyama, and H. Nozaki, Bull. Chem. SOC., Jpn., 1983, 56, 3088.

General and Synthetic Methods

424

Five-memberedRings with More than One OxygenAtom. The photo-oxygenation of diarylcyclopropanes (71) in the presence of 9,lO-dicyanoanthracene leads to 3,5-diaryl-l,2-dioxolanes as mixtures of isomers but in generally excellent yields (>85%). Yields only fall when the oxidation potentials of the cyclopropanes are high (typically >0.9 V).s61,2-Dioxolanes are also readily prepared in good yield by the silver ion-assisted cyclization of the peroxybromides (73), which are generated by intermolecular alkylation of t-butyl hydroperoxide by the dibromide (72).57The procedure offers a much safer alternative to the use of hydrogen peroxide on the dibromides (72), and can be extended to the synthesis

A

Ar’

A‘fiAr2

0-0

\Ar2

(71) DCA = d icyan oant hracene

‘CH2Br

R

Br

4

( C H 2In

-C H

Br

0 0

(72)

of 1,2-dioxanes. Full details on the preparation of 1,2-dioxolanes by the Lewis acid-catalysed reaction of ozonides with olefins have appeared.s8

COzH

I

(74)

Q

I

*-Me “O H

i

(75) .. ...

1

11, 111

iv, v

(76) Reagents: i, Bu‘CHO, H+; ii, LDA; iii, I(CH,),CMe,

/o-

; iv, LiAlH,; v, H+

0-

Scheme 7 56

57 5*

K. Mizuno, N. Kamiyama, and Y. Otsuji, Chern. Lett., 1983, 477. N. A. Porter and J. C. Mitchell, Tetrahedron Lett., 1983, 24, 543. M. Yoshida, M. Miura, M. Nojima, and S . Kusabayashi, J . Am. Chern. SOC., 1983,105,6279.

Saturated Heterocyclic Ring Synthesis

425

An increasing number of total syntheses of natural products containing 1,3dioxolanes have appeared, usually relying on intramolecular acetal formation as the ring-forming step. One example has been selected to illustrate these reactions, where the principle of ‘self-reproduction of chirality’ is beautifully demonstrated by the total synthesis of R-( +)-frontalin (76) from S-( +)-lactic acid. Initially the chirality of the acid (74) is transferred to the t-butyl-bearing carbon of the 173-dioxolane(75),and then transferred back in the alkylation step (Scheme 7).59 Six-membered Rings.-Tetrahydropyrans. The intramolecular cyclization of the chloroformate (78), generated by reaction of the y,S-unsaturated alcohol (77) with phosgene, gives the tetrahydropyran (79) in 57% yield under Lewis acid catalysis.‘j0

CH2CL2 ,O°C

SiMe3

SiMe3

(77)

( 7 8)

(79)

The 6,8-dioxabicyclo[3.2. lloctane (81) is readily prepared by intramolecular alkylation of the acetal (80). Two selective reductions of the bicycle (81) then afford the tetrahydropyran (S2).61A more general but rather unusual synthesis of SOZPh

I

H

H

(80)

1

Bu”Li

+OH H

i , N a ,Et OH,TH F

H

,I

702Ph

Q--H ,/OMS

ii, AIC13, LiALH4

OMS

(81)

(82) 59

R. Naef and D. Seebach, Liebigs Ann. Chem., 1983, 1930. K. Isaac, P. Kocienski, and S. Campbell, J . Chem. SOC., Chem. Commun., 1983,249. Y . Masaki, Y. Serizawa, K . Nagata, and S. Kaji, Chem. Lett., 1983. 1601.

426

General and Synthetic Methods

tetrahydrofurans, contained in the 6,8-dioxabicyclo[3.2. lloctane ring system, has been published during this reporting period. Thus, base-catalysed oxygenation of the dibromides of 2,6-disubstituted cyclohexanones (83) affords the tetrahydropyranyl carbolactones (84) in generally good yield;62the regiochemistry of the reaction in the case of non-symmetrical ketones is said to be under investigation.

I

MeOH, NaOH, 02

The intramolecular Diels-Alder reaction in molecules which contain an ester linkage are beset with difficulties, but Boeckman and Flan have shown that the mixed acetal equivalent (85) behaves well in thermal reactions so that cyclohexane-fused tetrahydropyrans are readily prepared by thermolysis of (85) in yields of 70% or more with no accompanying elimination of methanol.63

Dihydropyrans. In an extension to the previously reported synthesis of dihydr opyrone spiroacetals, Crimmins and Bankaitis have developed a synthesis of 2,3-dihydropyrones from 1-methoxy-but-1-en-3-yne (86).@Thus, deprotonation of (86) and addition to aldehydes followed by acid-catalysed ring closure of the adducts gives the dihydropyrones (87) in 40-80% yields. A preliminary communication on the general preparation of dihydropyrans annelated to cyclopentadienes has appeared. The method was primarily aimed at a short synthesis of virbutinal(88) as shown in Scheme 8, but can be applied to a range of dihydropyrans (89). 65 M. TJtaka, H. Makino, Y . Oota, S. Tsuboi, and A . Takeda, Tetrahedron Lett., 1983,24, 2567. R. K. Boeckman, jun. and C . J. Flann, Tetrahedron Lett., 1983,24,5035. 64 M. T. Crimmins and D. M. Bankaitis, Tetrahedron Lett., 1983, 24, 5303. h5 J.-L. Brayer, J.-P. Alazard, and C. Thal, J . Chem. SOC., Chem. Commun., 1983,257. 62 63

427

Saturated Heterocyclic Ring Synthesis

b

R R

(86)

(87)

ivl /*

R

FCHO

Reagents: i, BunLi; ii, RCHO; iii, p-TsOH, THF, H20,30% HClO,; iv, 30% HClO,, O'C, 20 min; v, 30% HClO,

The use of the hetero-Diels-Alder reaction to construct the dihydropyran ring system has again featured heavily in this year's literature. a,P-Unsaturated carbonyl compounds are known to undergo the hetero-Diels-Alder reaction as the 4n component but often require extreme conditions. Yamauchi and his group have discovered that the introduction of an electron-withdrawing group at the a-position allows the reaction with vinyl ethers to proceed at room temperature in .

I

- ... 111

HO

OH

f!, '0 H

(88) Reagents: i , Na; ii, MeCH(Br)CO,Et; iii, LiAlH,; iv, Me,NCH(OMe),; v, NaOH, (CO,H),, pH 4; vi, benzene, (CO,H),, A; vii, DDQ

Scheme 8

428

General and Synthetic Methods

excellent yield (>96%) .66 Where the cr,,&nsaturated carbonyl compound (90) is non-symmetrical the reaction is selective for the dihydropyran (91) where R3=Me over R3=OEt or Ph, and selective for (91) where R3=Ph over R3=OEt. The triacyl compounds (92; R=H) also react only very slowly with enol ethers (reaction times of typically 200 h). It has been found that the acylated compound (92;

R’0

+

eR4 - $PR4 R2

0

0R’

(91)

(90)

R=Ac) reacts much faster (ca. 8 h) quantitatively to give dihydropyrans, and a chiral acyl group such as camphanoyl leads to asymmetric induction of around 50% e.e.67 Danishefsky and his group have continued their studies on the hetero-DielsAlder reaction and have reported on several important developments. The first was the discovery that [Eu(fod),] functions well as the Lewis acid catalyst for the reaction and that for the first time the dihydropyran intermediates (93) could be isolated, and then stereoselectively converted into the dihydropyrans (94) or tetrahydropyrans (95).68From this observation they showed that using a catalyst

A

OMe

66 67

M. Yamauchi, S. Katayama, 0. Baba, and T . Watanabe, J . Chem. SOC. Chem. Commun., 1983,281. L.-F. Tietze and K.-H. Glusenkamp, Angew. Chem., Int. Ed. Engl., 1983, 22,887. M. Bednarski and S . Danishefsky, J . Am. Chem. SOC.,1983,105, 3716.

Saturated Heterocyclic Ring Synthesis

429

which bears a chiral ligand, e.g. Eu[3-(heptafluoropropylhydroxymethylene)-dcamphor at^]^, [Eu(hfc),], some chiral induction is observed in the reaction. Higher inductions are seen with more bulky groups on the diene component and when the reaction is carried out at lower temperatures (Scheme 9).69By including an 1-menthyl group as R1 there is a significant interaction between the menthyl group and the [Eu(hfc),] catalyst (i. e. better than additive) giving enantioselectivities of up to 13:1 in the tetrahydropyrans (96) .70 MQSio$

R3

Y3

M e $ : D 0 ~ P h

+

R2

ii

O p ,R3. P h

I_)

R2 I

OR’

bR1

(96)

liii R3

on=ph

R2

&?I

Reagents: i, PhCHO, [Eu(hfc),], CDCl,, r.t.; ii, TFA; iii, Et,N, MeOH

Scheme 9

The hetero-Diels-Alder reaction of 1-hydroxy-4-aminobutadienes with carbonyl compounds usually gives a-aminodihydropyrans. However ,by increasing the electron-donating ability of the hydroxy-group, for example by conversion into the t-butyldimethylsilyl ether, the reaction shows the opposite regiochemistry , as shown in Scheme 172,3-Tricarbonyl compounds (97) are efficient dienophiles in the hetero-Diels-Alder reaction, giving a variety of spirodihydropyrans (98) in variable yield (32-87%), when the diene is electron

Scheme 10 69

M. Bednarski, C. Maring, and S. Danishefsky, Tetrahedron Lett., 1983,24,3451.

70 M. Bednarski and S. Danishefsky, J. Am. Chem. SOC., 1983,105, 6968. 71 R. R. Schmidt and A. Wagner, J. Am. Chem. SOC., 1983,24,4661. 7i

R. R. Schmidt and K. Vogt, Synthesis, 1983,799.

430

General and Synthetic Methods

x={D,

{-“o, -NH

{ - -0 Ox

The viability of a quasi intramolecular Diels-Alder reaction has been addressed by Snider and his co-workers. Reaction of the alcohols with Lewis acid forms the aluminate (99) which directs the dienophile and increases the stereoand regio-selectivity of the reaction depending on the substitution pattern to give the dihydropyrans (100).73

R ’ y o H

9 R2

(1001

As an extension to the synthesis of cycloalkenes from bromodienes, Heck et al. have studied the palladium-catalysed cyclization of bromodialkenyl ethers (101).74The cyclization occurs at the least substituted end of the double bond, preferentially giving five-membered rings if possible; however, five-, six-, and seven-membered oxygen heterocycles are available by this method. 73 74

B. B . Snider, G . B. Philips, and R. Cordova, J . Org. Chem., 1983, 48, 3003. L. Shi, C. K. Narula, K. T. Mak, L. Kao, Y. Xu, and R. F. Heck, J . Org. Chem., 1983,48,3894.

Saturated Heterocyclic Ring Synthesis

431

The epoxidation of the 2-furancarbinols (102) under Sharpless conditions affords the 3,4-dihydropyrans (103) in moderate yield (45-70%), and is reported to be more convenient than previously reported oxidations since a neutral sideproduct is given.75

A reinvestigation of the synthesis of the benzoxepines (105) by reaction of the ketones (104) with methoxymethylsulphonium ylide, originally published some time ago ,76a has shown that the side-product chromans, occasionally encountered during the original reaction, can be made the main Thus, treatment of the benzoxepines (105) with TFA gives the corresponding chromans in excellent yield.

(104)

As part of a programme directed towards the total synthesis of the antibiotic frenolicin, Semmelhack and Zask have developed a general synthesis of b e n ~ o p y r a n s .The ~ ~ method entails the palladium-catalysed intramolecular alkoxycarbonylation of the olefinic alcohols (106), giving selectively the pyrans T.-L. Ho and S. G. Sapp, Synth. Commun., 1983,13,207. (a) P. Bravo, C. Ticozzi, C. Fronza, R . Bernadi, and D. Maggi, Gazz. Chim. Itul., 1979,109,137; ( b ) F. M. Dean and M. A. Jones, Tetrahedron Lett., 1983,24,2495. 77 M. F. Semmelhack and A. Zask, J . Am. Chem. SOC., 1983,105,2034.

75

76

432

General and Synthetic Methods

(107) with a cis-arrangement of substituents. The olefinic alcohols (108) oxidatively cyclize in the presence of four equivalents of ceric ammonium nitrate to give the naphthoquinones (109) as a mixture of hydroxyl isomers.78

OMe R1

OMe (108)

0

R'

0

OH

(109)

Ketenes are well known to undergo [2+2] cycloaddition reactions but they are also capable of undergoing [4+2] cycloadditions as the dienophile either at the carbon-carbon double bond or at the carbonyl group. Both of these additions have been put to use as methods for the synthesis of 2-pyranones via dihydropyrans. Thus, the cycloaddition of ketenes with @-unsaturated ketones (110) affords 2-pyranones after reduction of the intermediate dihydropyrans where R1= halogen,79and the reaction of ketenes with the dienes (111) affords R3 R~

R*

1

i , (111)

(110). 8OoC

I

1t3n

Zn, A c O H

R' = halogen

: &R

R3

: : YR

R3 R R4

h

o

R4 (110)

( 1111

T. A . Chorn, R. G. F. Giles, I. R. Green, and P. R. K. Mitchell,J . Chem. SOC., Perkin Trans. I, 1983, 1249. l9 W. T. Brady and M. 0. Agho, J. Org. Chem., 1983,48,5337.

Saturated Heterocyclic Ring Synthesis

433

2-pyranones after double-bond rearrangement of the intermediate dihydropyrans.8*Dichloroketenes also add to enaminones to afford 2-pyranones in variable yield and the method has been applied to the synthesis of a range of benzoxepine analogues (see Scheme 11).*l

Ct

+o

NR2

CI

'

0

Scheme 11

2-Pyrones can also be prepared by the enol-lactonization of the /3, y-unsaturated-S-keto-esters (113) in the presence of TFA/TFAA.82The keto-esters (113) can be readily prepared by the conjugated addition of ester anions to P-methylthio-a,/3-enmes (112) followed by acidic hydrolysis, and thus the method allows the systematic variation of the substitution pattern of the final product.

T FA

+

R2&

TFAA

W. T. Brady and M. 0. Agho, J . Heterocycl. Chem., 1983,20,501. G . Menozzi, L. Mosti, and P. Schenone, J. Heterocycl. Chem., 1983, 20,539. ** R. K. Dieter and J. R. Fishpaugh, J . Org. Chem., 1983,48,4439. 8o R1

R'

434

General and Synthetic Methods

Methylthio-, ethylthio-, and benzylthio-diphenylcyclopropeniumsalts (114) react with five- and six-membered cyclic 1,3-diketones in the presence of triethylamine at room temperature to give annelated 2-alkylthio-2H-pyrans (1 15) in good to excellent yields (60-90%).83

[S.n]Spiroacetals. A large number of natural products with a wide variety of biological actions, such as the insecticidal avermectins and milbemycins, and the avian toxins talaromycin A and B, incorporate a spiroacetal ring system and this has stimulated great interest amongst organic chemists. The majority of methods have had as the key spiroacetal-forming step either a keto-diol cyclization or a related reaction. A few examples from this year's literature have been selected highlighting the ingenuity used in the construction of the precursors to the cyclization step. In the first example the precursor is prepared by bis-alkylation of 1,3-dithian giving the protected keto-alcohol(ll6) in four steps. Deprotection and cyclization occur in one step to give exclusively the required spiroacetal(117), which was then transformed into talaromycin B.84

1

i,HgCIz,H20, MeCN ii, MezC(OMe12

OH

Talaromycin B 83

- HoT(117)

H. Yoshida, M. Nakajima, T. Ogata, and K. Matsumoto, Hererocycles, 1983, 20, 1013. S. L. Schreiber and T. J. Sommer, Tetrahedron Lea., 1983,24,4781.

Saturated Heterocyclic Ring Synthesis

435

The P-diketone (119), prepared by acylation of the ketone (118), cyclizes in a cascading fashion to form the spiroacetal (120) as a mixture of epimers at C-L8’

Ph

(118)

(119) /HBFL

aq., E t 2 0

0

Two groups have independently approached the spiroacetal portion of the avermectins by broadly similar approaches, which involve the addition of an acetylide to a lactone followed by internal acetalization. In both cases the starting materials were optically pure and cyclization gave one isomer only. Thus, Hannessian et al. have synthesized the spiroacetal unit of avermectin Bl a aglycon by addition of the acetylene (122) to the lactone (121) followed by partial reduction and cyclization,86whereas Baker and his group added the acetylene (124) to the lactone (123) and, after complete reduction of the acetylene, cyclized the product to the spiroacetal (125).*’ In a more general synthesis of spiroacetals the enyne (126) has been developed as a synthon for the formylacetone dianion (128). The lithio-derivative of (126) adds to lactones to give adducts which can be converted into the spiroacetals (127) as outlined in Scheme 12, where the two-step procedure usually gives better yields.88 Danishefsky has applied the Lewis acid-catalysed hetero-Diels-Alder reaction to a synthesis of w-hydroxyalkyl dihydropyrans which then cyclize to give spiroacetals in the presence of alumina or by intramolecular oxymercuration 85

86 8’

D. R. Williams and B. A. Barner, Tetrahedron Lett., 1983,24, 427. S. Hannessian, A . Ugolini, and M. Therien, J . Org. Chem., 1983, 48, 4427. R. Baker, R. H. 0. Boyes, D . M. P. Broom, J. A. Devlin, an&C. J. Swain, J . Chem. SOC., Chem. Commun., 1983,829. M. T. Crimmins and D. M. Bankaitis, Tetrahedron Lett., 1983,24, 4551.

15

General and Synthetic Methods

436

sioT +

Ph 2But

OCH2Ph

(121)

(124)

(123)

HO

$7

I

vii

- ix

v,vi

f p h f i o T > y H

OSiBu' Ph2

I

OSi But Ph2

(125) Reagents: i, BunLi, -78°C; ii, H,, Pd/BaSO,; iii, BF3-Et20;iv, Bu,NF, THF; v, BunLi;vi, MeOH, H+; vii, H,, Pd/C, 1 h; viii, H+; ix, HS, Pd/C, 18 h

followed by reduction as shown in Scheme 13.89In the final example which involves a keto-diol or related ring closure Kocienski and Yeates have reported on a short entry to spiroacetals using the addition of the organocuprate (129) to epoxides and subsequent cyclization.90 89

S. J. Danishefsky and W. H. Pearson, J. Org. Chem., 1983,48,3865.

* P. Kocienski and C. Yeates, Tetrahedron Lett., 1983, 24, 3905.

Saturated Heterocyclic Ring Synthesis

437

xr i ,ii

R’

0

M 0 )”yOH (/+e (CH’

R2

R’

liv

n

OMe

+d

0-

0-

(128)

(126)

Reagents: i, (126); ii, Bu”Li; iii, K2C03, MeOH; iv, 30% HClO,, CH2Cl,

Scheme 12

The formation of cyclic ethers by intramolecular hydrogen abstraction of oxyradicals is well precedented and two reports have appeared this year applying this method to the spiroacetal ring system. Thus, irradiation of the hypoiodites (130) gives the spirostan sapogenins (131) in 80% yield, where the reaction is

(CH2),,0Si But Me2

+

. .. RCHO

‘J“

+

-/ iiii 0

Et3SiO iv

Reagents: i, (Yb(fod),]; ii, Pd(OAc),; iii, A1,03; iv, DIBAL; v , Hg(OAc),; vi, NaBH,

Scheme 13

R

-

General and Synthetic Methods

438 . ..

iii , iv

I , II

4

(129)

% OH

Reagents: i, Bu'Li; ii, CuI; iii, L O T H P ; iv, H+

thought to proceed via a seven-membered cyclic transition The second method involves the unusual acid-catalysed rearrangement of the tetrahydropyranyl ether (132) to the ether (133), which is then oxidatively cyclized via its hypoiodite to give the spiroacetal (134) after acid treatment.92

lhv

(132)

R' I

(133)

1

i, 12, HgO ii,TFA

OCH2CCI3 (134) C. G. Francisco, R. Freire, R. Hernandez, M. C. Medina, and E. Suhrez, Tetrahedron Lett., 1983,24, 4621. 92 I. T. Kay and E. G. Williams, Tetrahedron Lett., 1983,24,5915.

91

Saturated Heterocyclic Ring Synthesis

439

Finally in this section, Ireland's group, in a synthesis of the antibiotic methymycin, have synthesized spiroacetals via hetero-Diels-Alder reactions as shown in Scheme 14.93

(major isomer) Scheme 14

Six-membered Rings with More than One Oxygen Atom. The addition of singlet oxygen to the functionalized dienes (135) proceeds smoothly at -78°C to give endoperoxides which can be further manipulated under mild conditions to give keto- or hydroxy-endoperoxides.94

1 R2

R' = OSiMe3,R2=OMe

'02,-782

0

R' (135)

OMe

R2

THF. 0 . 0 0 5 M HCI

I

R1= H R2 = OSiMe3 THF, 0.005M HCI

OH

I

Two groups have published procedures for the synthesis of zoapatenol analogues containing the 1,6dioxolane ring system. The first procedure used a transacetalization followed by an intramolecular 0-alkylation to form the dioxolane ring (see Scheme 15),95and the second constructed the dioxolane ring by R. E. Ireland, J. P. Daub, G . S . Mandel, and N. S . Mandel, J . Org. Chem., 1983,48,1303, 1312. E. L. Clennan and R. P. L'Esperance, Tetrahedron Left., 1983,24,4291. 95 J. B. Jiang, M. J. Urbanski, and Z . G. Hajos, J . Org. Chem., 1983,48,2001.

93

94

General and Synthetic Methods

440

1

i , KOH, M e O H

ii, HCI, Me2CO

Zoapatanol

analogues

f--

Ph -0

Scheme 15

intramolecular acid-catalysed ring closure of the epoxy-alcohol (136), itself prepared by an epoxide opening.96

Z o a p a t a n o l analogues

-

c02me QoI0\OH

0

The research group of Jefford has developed a synthesis of 1,3,4-trioxanes by the reaction of 1,Zdioxetanes with ketones or aldehydes. The method involves the acid-catalysed reaction of the dioxetanes (137) with aldehydes, giving variable yields of the trioxanes (138);97the reaction also works for 1,4-endopero~ides.’~ Further work has shown that the intermediate zwitterions from the photooxygenation of enol ethers can be captured in situ by aldehydes giving the 1,2,4trioxanes (139).99 Jefford et al. have also published a method for the synthesis of the previously unknown 1,2,4-trioxan-5-ones (140) in good yields by the reaction of peroxyesters with ketones or aldehydes in the presence of trimethylsilyl triflate at -78 “C.loo M. C. Wani, B. R. Vishmuvajjala, W. E. Swain, jun., D. H. Rector, C. E. Cook, V. Petrow, J. R. Reel, K. M. Allen, and S. G. Levine, J . Med. Chem., 1983, 26, 426. 97 C. W. Jefford, J . Boukouvalas, and S. Kohmoto, Helv. Chim. Acta, 1983, 66, 2615. 98 C. W. Jefford, D. Jaggi, J. Boukouvalas, and S. Kohmoto, J. Am. Chem. SOC., 1983,105, 6497. 99 C. W. Jefford, S. Kohmoto, J. Boukouvalas, and U. Burger, J . Am. Chem. Soc., 1983, 105,6498. loo C. W. Jefford, J.-C. Rossier, and G . D. Richardson, J . Chem. SOC., Chem. Commun., 1983, 1064. 96

Saturated Heterocyclic Ring Synthesis

441 R3

p-?, ArO

Rl

+?

Am berli te

+

R3CH0

&:

0

resin

ArO

R2

(137)

R'

R2

R1 MeCHO

'0 2

_I_)

~

R

R (138)

R3

R3

OMe (139)

Quite independently Schmid and Hofheinz have completed a total synthesis of the naturally occurring antimalarial qinghaousu (143), in which the key 1,2,4trioxane-forming step was the cyclization of the presumed hydroperoxide ketone (142) formed by the singlet oxygenation of the olefin (141) in the presence of methanol. lol 0-OSiMe3

0

OSiMe3

0

0

Me0

/

HO2C

lo2 +

-H -H

MeOH

HCO2H

HOO, Me0

___I)

-H

Me0 HO2C

0 (141 1

(142)

(143)

Seven- and Eight-membered Rings.-The intramolecular TiC1,-catalysed aldol condensation of silyl enol ethers with acetals has been applied to the synthesis of six-, seven-, and even eight-membered rings without the need for high-dilution techniques. The reaction only works with TiC14and is thought to proceed via a titanium template effect giving moderate to good yields of the heterocycles as outlined in Scheme 16.1°2 lol lCn

G. Schrnid and W. Hofheinz, J . Am. Chem. SOC., 1983,105,624. G. S. Cockerill and P. Kocienski, J . Chem. SOC., Chem. Commun., 1983,705.

General and Synthetic Methods

442

OSi PhMe2

iL

O v 0

3

1

OSi PhMe2

Reagents: i , TiCl,, CH,CI,, -78°C

Scheme 16

The [2+2] cycloaddition of alkenes to the benzofuran (144) affords adducts which undergo retro-aldol reactions giving benzoxepinones (145) in moderate overall yield (typically 50%).lo3

‘Ac (145) lo3

J. H. M. Hill and S. T. Reid, J . Chem. SOC., Chem. Commun., 1983,501.

443

Saturated Heterocyclic Ring Synthesis

. ..

LL

Q-x x (146) X = Br or CL

liii (148)

(147)

Reagents: i, CHX,, NaOH; ii, A ; iii, LIAlH,, Et,O, 25°C; iv, LiAlH,, THF, 40°C

The ring expansion of 1,4-benzodioxine by carbene insertion and rearrangement affords the dihalogenoalkenes (146) which are immediately reduced either partially, to the previously unknown halogenobenzodioxepines (147) or fully to the again previously unknown benzodioxepine (148) .lo4 Finally in this section, a range of the extremely unusual pentaoxacyclo-octanes (150) have been prepared in a general method whereby the ozonides (149) are treated with ketones in the presence of chlorosulphonic acid and acidic hydrogen peroxide. lo5

20

OC

(149)

(150)

2 Sulphur-containing Heterocycles In a series of papers on thromboxane A2analogues, the total syntheses of (&)- and (+)-thiathromboxane (151) and (&)-dithiathromboxane (152) have been reported, using the known intramolecular displacement reaction to form the thietane ring.lo6 Further studies on the cycloaddition of thiocarbonyl ylides to dipolarophiles by Huisgen’s group have revealed that the yields in this series of reactions can be considerably improved by generating the ylide in situ. lCnThus 2,2-diphenyl-l,3,4lo4

G. Guillaumet, G. Coudert, and B. Loubinoux, Angew. Chem., Int. Ed. Engl., 1983,22,64. Miura, A. Ikegami, M. Nojima, S. Kusabayashi, K. J. McCullough, and M. D. Walkinshaw, J . Chem. Soc., Perkin Trans. 1, 1983,1657. S. Ohuchida, N. Hamanaka, and M. Hayashi, Tetrahedron, 1983,39,4263,4269,4273. L. Xingya and R. Huisgen, Tetrahedron Lett., 1983, 24,4181; R. Huisgen and L. Xingya, Heterocycles, 1983, 20, 2363.

lo5 M.

lW

444

General and Synthetic Methods

-

SAC I

01=/\/\C02Me MsO

NaoMe

I

I

OAc (151)

MeOzC

S’ I

OBz i , NaOMe ii,NaOH,THF

thiadiazolide extrudes nitrogen at -45 “C, giving the thiocarbonyl ylihz (153), which adds to a range of dipolarophiles in situ, e.g. with substitutedalkenes giving tetrahydrothiophenes (Scheme 17). The scope of the synthesis of tetra-

- xsl Ph

PhxC=S

CH2N2

-78OC

Ph N=N

Scheme 17

Saturated Heterocyclic Ring Synthesis

445

hydrothiophenes (154) by the reaction of a$-unsaturated carbonyl compounds with sodium polysulphide has been studied and the authors have concluded that only 1,3-diaryl-a,,t?--unsaturatedketones (chalcones) give the reaction, although when the reaction is successful yields are good (>63%).Io8

The t-butylthioacrylonitrile (155) undergoes cycloaddition reactions with electron-deficient dienophiles as a 4n-component to give either tetrahydrothiophenes (156) or 2,3-dihydrothiophene (157).lo9The reaction is accompanied by the loss of the t-butyl group as isobutylene, and the yields are variable.

/

(156) X = 0 or NPh C02Me

NC

I

C02Me C02Me

(157)

a-Thiol-aldehydes (159) are known to react with vinylphosphonium salts or vinylphosphonates to give 2,5-dihydrothiophenes, but the thiol-aldehydes have not been readily available. However, a-thiol-carboxylic acids are known, and a convenient synthesis of thiol-aldehydes has now been developed from the acids (158), involving the DIBAL reduction of oxathiolanes, which are readily prepared from (158)."O In a broadly similar approach to ring construction, the 3-thiatestosterone analogue (162) was prepared by intramolecular Wittig reaction of the intermediate (161) generated by addition of triphenylphosphonium methylide to the disulphide (160). ll1

lo9

M. G . Reinecke, D . W. Morton, and D. Delmazza, Synthesis, 1983, 160. D. Dopp and H. Libera, Tetrahedron Lett., 1983, 24,885. J. M. McIntosh and M. A. Siddiqui, Can. J . Chem., 1983, 61, 1872. G. A. Flynn, .I. Org. Chem., 1983,48, 4125.

-

General and Synthetic Methods R2

DlBAL

R~+CHO

Toluene -78OC

SH (159)

Ph3P-CH=CH2

1

i, Ph3P=CH2 ii,HCt

OSi But Me.

(161)

K+ But d.DMSO OSiBu‘ Me2

The regiochemistry of thiocarbonyl Diels-Alder reactions with dienes to give dihydrothiapyranshas been studied by Vedejs and his group with reference to the substituent R (see Scheme 18).”*They have found that path ‘a’is preferred when R is an electron-donating group, whereas path ‘b’ is the preferred pathway when 112

E. Vedejs, D. A. Perry, K. N. Houk, and N. G. Rondan, J. Am. Chem. SOC., 1983,105,6999.

447

Saturated Heterocyclic Ring Synthesis R’

-A ‘a‘

+

R

R

/ i R

2

R

R2

qR2 R’ = OMe or H

R2 = OSiBufMe2

Scheme 18

R is electron withdrawing. These results agree with a similar study carried out by Baldwin and Lopez who generated the required thioaldehydes by thermolysis of thiosulphinates, and interestingly they found that the Diels-Alder reaction can be carried out intramolecularly to give the dihydrothiopyran (163).113

(163)

The known synthesis of dihydropyran S-oxides by the cycloaddition of dienes with sulphines can be carried out with complete asymmetric induction when using a chiral ~u1phine.l~~ Thus the camphor or sulphoximino sulphines react with 2,3dimethylbutadiene to give exclusively the adducts (164).

113

‘14

J. E. Baldwin and R . C. G. Lopez, Tetrahedron, 1983,39,1487. P. A. T. W. Porskamp, R. C. Haltiwanger, and B. Zwanenburg, Tetrahedron Lett., 1983,24,2035.

General and Synthetic Methods

448

3 Heterocycles Containing More than One Heteroatom

Nitrogen- and Oxygen-containingRings.-Three-membered Rings. The synthesis of N-sulphonyloxaziridines by peracid epoxidation of sulphonimines has been modified to give, after fractional crystallization, optically pure oxaziridines The method entails treating the sulphonimines (165) with (+)-peroxycamphoric acid at low temperature under basic conditions.

(165)

-6O0C,CHZCI2,M e O H , p H S - I 0 , 3 h

I+)- p e r o x y c a m p h o r i c acid

Five-memberedRings. A new synthesis of nitrones, the well known isoxazolidine intermediates, has been reported whereby hydroxylamines are oxidized and a,,P-unsaturated catalytically in the presence of palladium metal at 100°C,116 sulphones have been shown to be suitable olefin partners in the cycloaddition reaction with nitrones, giving 4-sulphonylisoxazolidines.117 Allylic thiocarbamidates, which are easily prepared from the corresponding alcohols by treatment with isothiocyanate, undergo bromocyclization to give, exclusively, 2-0x0-oxazolines (166) in high overall yield. 118 N-Sulphonyl-2-0~0SMe

R’

(166) Reagents: i, NaH; ii, MeNCS; iii, MeI; iv, Br(collidine),ClO,; v, aq. Na2CO3

oxazolines (168) can be prepared by the base-mediated cyclization of the sulphamides prepared from the chlorosulphonyl isocyanate adducts (167) Two new cycloaddition reactions to form oxazolidin-6ones have been reported this year. Thus, a-bromoisobutyramides on treatment with sodium hydride give the dipoles (169), which add to dimethylformamide giving the oxazolidones (170) M. Bucciarelli, A . Forni, S. Marcaccioli, I. Moretti, and G . Torre, Tetrahedron, 1983, 39, 187. S.-I. Murahashi, H. Mitsui, T. Watanabe, and S . Zenki, Tetrahedron Lett., 1983,24, 1049. 11’ P. D . Croce, C. L. Rosa, R. Stradi, and M. Ballabio, J. Heterocycl. Chem., 1983,20, 519. 118 S. Knapp and D . V. Patel, J. Am. Chem. Soc., 1983, 105, 6985. J.-L. Montero, G . Dewynter, B. Agoh, B. Delaunay, and J.-L. Imbach, Tetrahedron Lett., 1983,24, 3091. 115 116

-

Saturated Heterocyclic Ring Synthesis

RNH2

X- 0 y N ~ s o 2 c 1

0 (167)

x

-

449

O)fNH\50*NHR 0

A t 3 N

n O KNso2NHR 0 (168)

in good yield, and the authors have shown that azetidinones or 1,2,3-triazolones also provide a source of the dipoles (169). 120 In the other method diphenylketenes were added to S, S-dimethyl-N-acylsulphiliminesto give adducts which were then reduced directly to give the oxazolidinones (171).

N=N

(171) 120 I2l

P. Scrimin, F. D’Angeli, A. C. Veronese, and V. Baioni, Tetrahedron Lett., 1983,24, 4473. D. M. Ketcha, M. Abou-Gharbia, F. X. Smith, and D. Swern, Tetrahedron Lett., 1983,24,2811.

450

General and Synthetic Methods

The 1,2,5-oxadiazole 2-oxide (172) undergoes two sequential nitrone-olefin cycloadditions to give the azadioxabicyclo[3.3.O]octanes (174) ,where the initially formed adduct (173) eliminates ethyl cyanoformate to form the second nitrone.122

Six- and Eight-membered Rings. Gilchrist and his co-workers have published further details on the synthesis of 5,6-dihydro-4H-l,2-oxazines from a-nitrostyrenes, and have extended the scope of this hetero-Diels-Alder reaction by Thus, treatment of the using more electrophilic vinyl nitroso-c~mpounds.~~~,~~~ halogeno-oximes (175) with base in the presence of olefins affords the dihydrooxazines (176), presumably by capture of the vinyl nitroso intermediates.

"'x:

+ NOH

NO

-

RL

(175) R1 = H, Me or OEt

0 R3

(176)

Benzylic alcohols and dialkylanilines each undergo oxidation with Mn02, but when these functional groups are present in the same molecule in an ortho-relationship, MnO, oxidation gives the benzoxazines (177) in generally T. Schimizu, Y . Hayashi, and K. Teramura, J . Org. Chem., 1983,48, 3053. E. Davies, T. L. Gilchrist, and T. G. Roberts, J . Chem. Soc., Perkin Trans. I , 1983, 1275. 124 T. L. Gilchrist and T. G . Roberts, J . Chem. Soc., Perkin Trans. 1 , 1983,1283. lzz

123 D .

Saturated Heterocyclic Ring Synthesis

45 1

high yield Reinhoudt et al. have also published a synthesis of benzoxazines (178), by adapting a method they had published previously.126

I

I

I

R"YO

Rl")

Two methods for the annelation of a 1,4-0xazinones have been compared using the amino-alcohols (179) as starting materials (Scheme 19).lZ7 The classical approach, i.e. acylation of the amine followed by 0-alkylation, gave poor yields

I

a

OH

83,

" R

iv, v

7

0 Reagents: i, CICH,COCI, base; ii, NaH, DMSO; iii, -0; v, NaOH, MeCN; vi, BF,.OEt,, CH,Cl,

iv,p-HO,CC,H,SO,N,,

DBU, MeCN;

Scheme 19 lz5 F.

lZ7

Kienzle, Tetrahedron Lett., 1983, 24, 2213. W. Verboom, B. G. van Dijk, and D. N. Reinhoudt, Tetrahedron Lett., 1983, 24, 3923. D. E. McClure, P. K. Lumma, B. H. Arison, J. H. Jones, and J. J. Baldwin,J. Org. Chem., 1983,48, 2675.

General and Synthetic Methods

452

(route ‘a’)whereas the ketocarbene addition (route ‘b’) gave overall yields of 50% or better. The 5-aza-2-oxabicyclo[2.2.llheptanes (180) have been prepared in good to excellent yield (56-93%) by the intramolecular Mitsunobu reaction of 4-hydroxyproline analogues,128 and the 2,4-diaza-9-oxabicyclo[3.3. llnonanes (181) were prepared by treatment of glutaraldehyde with ureas under aqueous conditions, a reaction which had previously only given polymers. 129

”, DEAD, PPh3

f

0’

P

6’

J2”

Several examples of the rare 1,4,5-benzodioxazocine ring system have been synthesized by modification of methodology developed for the analogous 1,5,6benzodioxazocines as outlined in Scheme 20. 130 0

Ph

Ph

1

iv,v

% ’ ’R R2

-N

/O

Ph Reagents: i, BrCH,CH,OH; ii, PBr,; iii, a c o \ N O - K + ;

co’

iv, NH2NH2.H20,EtOH; v, HCl

Scheme 20 M. M. Bowers-Nemia and M. M. Joullie, Heterocycles, 1983,20, 817. H. Matsuda, A. Ninagawa, A. Baba, and K. Sato, Tetrahedron Lett., 1983,24,789. I3O E. J. Browne, L. M. Engelhardt, and A. H. White, Aust. J . Chem. 1983,36,2555.

lz8 lz9

Saturated Heterocyclic Ring Synthesis

453

Oxygen and Sulphur-, and Nitrogen and Sulphur-containing Rings.-The synthesis of a series of dihydrobenzoxathiines (182), potential antihypertensive agents, has been described by Tegeler et al. and is based on the intramolecular displacement of halide by a1k0xide.I~~ The reaction was found to give the best yields when carried out in diglyme with the sodioalkoxide.

,+

Me0

diglyme

CI

,

Me0

HO

Cl (182)

The dihydropyrimidine thione derivatives (184) have in the past proved to be useful intermediates for the synthesis of various 1,3-thiazines.13*They have now been shown to give dioxothiazolidines (183) or oxothiazolines (185) depending on the substrate used, so that reaction of (184) with a-halogenocarboxylic acids gives (183), whereas reaction with a-halogenoketones gives (185). Thiazolines (n= 1)

(183)

(1 84 )

(185)

can also be prepared by acid-catalysed cyclization of the thioureas (186), which are prepared by addition of amines to i ~ ot hi ocyana t es.The ~~~reaction also Me0 Me0W

N

H (CH2)n

I

OH

i

Me0

Me0T N Y W

J/

(CH2)n

I

(116) OH iv

Me0

Me0

Me0 M e

o

T

'f

N /NHR

Reagents: i, RNCS, benzene, A; ii, MeI; iii, MeOH, KOH; iv, EtOH, HC1 Scheme 21 J. J. Tegeler, H. H. Ong, and J. A. Profitt, 1. Heterocycl. Chem., 1983, 20, 867. H. Singh, P. Singh, and K. Deep, Tetrahedron, 1983, 39, 1655. 133 F. Fiilop, M. S. El-Gharib, A. Sohajda, G . Bernath, J. Kobar, and G. Dombi, Heterocycles, 1983,20, 1325. 131

132

General and Synthetic Methods

454

succeeds for 1,3-thiazinesand the thiocarbamides can also be converted into 1,3oxazo-compounds (187) as outlined in Scheme 21. A convenient synthesis of the previously unknown dihydro-173-thiazin-4-ones (188) has been described where isothiazolonesare ring-expandedby reaction with rarbenes generated from diazo-compounds and a rhodium catalyst.134

(188)

Dihydro-1,4-thiazines (190) on the other hand can be prepared by the isomer,~~~ ization of N-vinylaziridines (189) in the presence of potassium t h i ~ c y a n a t eand benzo-174-thiazines(191) are available from the reaction of N-allylanilines with sulphur dichloride.136

___)

DME,

A (190)

R' SCL 2 ___.)

-HCI

4 Nitrogen-containingHeterocycles Three-membered Rings.-172,3-Trisubstituted aziridines (195) have been prepared by the reaction of phenyldiazomethane with imines (192) in the presence of zinc iodide. 137 cis-Aziridines are formed exclusively, probably via the intermediacy of (193) and (194). Attempts to obtain other aziridine derivatives using aliphatic diazo-compounds were unsuccesstul. Aza-1-bicyclobutanes (197) were D. Crow, I. Gosney, and R. A. Ormiston, J . Chem. SOC., Chem. Commun.,1983,643. Y. Gelas-Mialhe, E. Touraud, and R. Vessiere, Heterocycles, 1983, 20, 2391. 136 M. Muhlstadt, K. Hollman, and R. Widera, Tetrahedron Lett., 1983,24,3203. 137 R. Bartnik and G. Mloston, Synthesis, 1983, 924.

134 W.

135

Saturated Heterocyclic Ring Synthesis

Ar

R'

455

i,Znl2

---+

>N--RZ

ii, PhCH=N2

(192) (193 1

Ph

A\'

I

N

I

R2

readily obtained by photolysis of carbamates (196),138and a one-step synthesis of an aziridino-mitosene analogue (199), involving an intramolecular Darzens-type

Ph

RIR K hv

0

(196)

phJ$ N (197) R = Ph , 77 'lo R = E t , 40°/o

reaction, has been reported starting from 2-(N-phenylformimidoyl)indole (198)

% 0 2 , . Br

L

Br

-

I

075

NPh

'C02Me

(198) 13*

139

(199) 60 '10

R. Bartnik, Z. Cebulska, and A. Laurent, Tetrahedron Lett., 1983,24, 4197. R. M. Cory and B. M. Ritchie, J . Chem. SOC., Chem. Commun., 1983, 1244.

456

General and Synthetic Methods

Full details have appeared of the formation of a-cyanoaziridines by cyanation of a-halogenoketimines,14 and further studies of the reaction of 2-azido-alcohols with trialkyl phosphites to produce aziridines have been reported.141 Four-membered Rings.-A one-pot synthesis of 2-aryl-N-arenesulphonylazetidines (202) has been described starting from N-arenesulphonylimines (200) and dimethylsulphoxonium methylide (201). 142 Reaction of (201) with benzylideneaniline, however, failed to give any azetidine product. 0 Ar1-CH=N-S-Ar2

-

Me

II II 0

+

2

DMSO

\! /+\

N2,r.t.

Me CH2 (201)

(200)

A ! p 2 A r 2

(202)21-47 '10

Dilithio-derivatives of oximes (203) have been shown to react with aldimines (204) to produce 2-hydroxyaminoazetidines (205) as a mixture of isomers in generally good yields,143and the 1-hydroxyazetidines (208) have been prepared i , 2 BunLi ,THF, O°C

R3-CH2

ii, ArCH=NR1(20LI

)cN-OH

R2

~

iii, NHbCI , H20

p;:

H

R2

( 2 0 5 ) 55-

(203)

81 '10

by reductive cyclization of the 0-protected oxime tosylates (206).14 In the absence of 0-protection, facile cyclization to produce the isoxazolidine (207) occurs. NHOR

NaCNBH3

H R=H,R1=Me

CH20Ts

(206)

(207)

1

R = CHZPh

Pd/C.H:

'YH (208)

N. De Kimpe, P. Sulman, R. VerhC, L. De Buyck, and N. Schamp, J . Org. Chem., 1983,48,4320. A. Willeit, E. P. Muller, and P. Peringer, Helv. Chim. Actu, 1983, 66,2467. 142 U. K. Nadir and V. K. Koul, Synthesis, 1983,554. 143 M. Bellassoued, R. Chtara, F. Dandoize, and M. Gaudemar, Synthesis, 1983,951. M. L. M. Penning, D . Kuiper, and D. N. Reinhoudt, Tetrahedron Lett., 1983, 24,825. 141

Saturated Heterocyclic Ring Synthesis

457

Five-membered Rings Containing One Nitrogen Atom.-Two reviews relevant to the synthesis of five- and six-membered nitrogen heterocycles have appeared this year. Stella has described the synthetic potential of homolytic heterocyclizations of N-chloroalkenylamines145 and Mariano in a review of electron-transfer mechanisms in photochemical transformations of iminium salts, also describes synthetic applications of such processes. 146 A major interest this year has been the generation and trapping of nonstabilized azomethine ylides and related 1,3-dipolar nitrogen ylides to produce pyrrolidines. Roussi and co-workers have generated the ylide (210) by base treatment of trimethylamine N-oxide (209)7147 and Padwa et al. have prepared the related species (211) by treatment of a-cyanoaminosilane (212) with silver flu01ide.l~~Cycloadditions with substituted alkenes to form pyrrolidines (213) Me

I

N -Me

Me-

J-

0 (2091 i, L D A , -78

OC

1

i i , unactivated alkene

AgF, MeCN

aelectron - deficient

[CH2=!-CH]

alkene

1

(210) R = M e

NCCHzNCH2SiMe3

I

CH2Ph

(212)

(211 I R = CH2Ph

"H"' N

I

R (213)

proceed in moderate to good yields and are stereospecific, but surprisingly the two ylides (210) and (211) differ markedly in their reactivity: (210) is trapped by unactivated alkenes such as hex-1-ene or cyclohexene, whereas 211) only reacts with electron-deficient alkenes. L. Stella, Angew. Chem., Int. Ed. Engl., 1983, 22,337. S . Mariano, Acc. Chem. Res., 1983, 16, 130. 14' R. Beugelmans, G. Negron, and G. Roussi, J . Chem. SOC., Chem. Commun. 1983, 31. 148 A. Padwa and Y.-Y. Chen, Tetrahedron Lett., 1983, 24, 3447. 145

146 P.

458

General and Synthetic Methods

The fluoride ion-induced desilylation reaction of immonium salts has been extended in several novel ways as a route to substituted pyrrolidines. Padwa et al. have shown that the reaction can be applied to immonium salts derived from amides, thioamides, and vinylogous amides to provide access to reactive azomethine ylides in generally good ~ i e 1 d s .The l ~ ~ lactam (216), for example, was produced in 75% overall yield from the enamide (214) via the cycloadduct (215). 0

- b+ OMe

i, Me1

NHCH2ph

ii. MejSiCH2OTf

y C H 2 S i Me3

I CHzPh

(214)

1

CH2=CHC02Me

CsF

0

OMe

COzMe

\

CH2Ph

(215)

0

% I

CHZPh

(216) 75'10 overall

Two other research groups have also reported on the generation of thioimidate methylides and related species. Vedejs and West, in an extension of their earlier work, have shown that pyrrolines (218) are produced in higher yields from the thioimidate precursors (217) than from the analogous imidates,150 and Living-

(217 1 149

(218)

-1, 6 6 % n = 2,61

A. Padwa, G. Haffmanns, and M. Tomas, Tetrahedron Lett., 1983,24,4303. Vedejs and F. G. West, J . Org. Chem., 1983,48,4773.

150 E.

Saturated Heterocyclic Ring Synthesis

459

house and Smith have reported an efficient synthesis of pyrrolidine derivatives (220) and (222) by the acyl fluoride-mediated generation and trapping of N-acylimidate methylides (219) and (221) (Scheme 22).1517152 Although inter-

Me+iCH2NC

Me3SiANA

!-.

SEt

1. (221)

'"I

iii

I

76 Yo

(222)

Reagents: i, C,H,,,NH, CuCl; ii, PhCOF; iii, dimethyl fumarate; iv, EtSH, [Cu(acac),]; v, p-02NCbHdCOF

Scheme 22

molecular trapping of these ylides with unactivated dipolarophileswas unsuccessful, the tricyclic aminal(223) could be prepared by intramolecular cycloaddition with an unactivated alkene.151 Further details have appeared of the formation and trapping of azomethine ylides derived from N-(benzylidene)trimethylsilylmethylamine and acyl 15*

152

T. Livinghouse and R . Smith, J . Chem. Soc., Chem. Commun., 1983,210. R. Smith and T. Livinghouse, J . Org. Chem., 1983,48, 1554.

460

General and Synthetic Methods

Q& .*

PhCOF __+

N-

N

I Me

Si Me3

Me

(223) 90°/o

chlorides,153and a route to N-unsubstituted pyrrolidines (224) has also been re~0rted.l~~ Me3S i 0 S 02CF3 (cat.I

X

CsF (cat .I

Me3SiCH2-

N=CHPh

$Ph

XCH=CHY

I

H

(224)

Azomethine ylides have also been generated by photochemically induced desilylation: irradiation of the iminium perchlorates (225) and (227) in the presence of dimethyl acetylenedicarboxylateled to smooth formation ( 7 6 7 5 % ) of the spirocyclic amines (226) and (228).155A brief review of new applications of dipolar cycloaddition chemistry in heterocyclic synthesis has appeared.156

(&;> Clod

Me

OZCBU' _______) hDMAD, v ( h>280nm) MeCN

SiEtg

(225) n = 1 (227) n = 2

(cH+ MeO2C CO2Me (226) n = 1 (228) n = 2

K. Achiwa, T. Motoyama, and M. Sekiya, Chem. Pharm. Bull., 1983,31,3939. K. Achiwa and M. Sekiya, Heterocycles, 1983,20,167. lS5 S . F. Chen, J. W. Ullrich, and P. S. Mariano, J . Am. Chem. SOC.,1983,105,6160. 156 A. Padwa, Y.-Y. Chen, K. F. Koehler, and M. Tomas, Bull. SOC. Chim. Belg., 1983,92,811.

ls3

154

461

Saturated Heterocyclic Ring Synthesis

Pyrroline (230) has been produced stereospecifically from the imine (229) by 1,5-electrocyclization,157and the synthetic equivalent of an intramolecular

Ar-

Q

AT

,N,CHC02Me

,OMe

(229) AT = 2 - naphthyl

HR

HI.

Ar

H

C02Me

cycloaddition between a diene and a nitrene has been accomplished in the twostep synthesis of azatricyclodecenones(232) from azidopropylcyclohexadienones (231).158

R (231)

&Me

Me 0 (232)R = Me 79% R = But 97%

The pyrrolidone (234) has been prepared in quantitative yield from the acylated hydroxylamine derivative (233) in what is claimed to be the first example of an intramolecular ene reaction of an i ~ i n e . ~ ~ ~

0G

M

I

CH2C02Et

(233)

e

0&--o&

II

CHCO2Et

I

CH2C02Et

(234)lOO%

R. Grigg and H. Q. N. Gunaratne, Tetrahedron Lett., 1983,24,1201. lsa A. G. Schultz, J. P. Dittami, S. 0. Myong, and C.-K. Sha, J . Am. Chem. Soc., 1983,105,3273. 159 K. Koch, J.-M. Lin, and F. Fowler, Tetrahedron Lett., 1983, 24, 1581. 15'

462

General and Synthetic Methods

Overman and his co-workers have published further details of their investigations of the synthetic applications of cationic aza-Cope rearrangements. These include a general synthesis of polysubstituted 3-acylpyrrolidines via a tandem cationic aza-Cope rearrangement-Mannich cyclizationlWand the use of the ringenlarging pyrrolidine annelation reaction in the synthesis of the pentacyclic and trans-3a-aryl-4Aspidosperma alkaloids,161 ~is-3a-aryloctahydroindoles~~~ oxodecahydrocyclohepta[b]pyrroles. 163 Further studies of acyliminium ion cyclizations have been reported by Speckamp and co-workers. Formation of the isomeric pyrrolizidines (236) from the hydroxy-lactam (235) has been shown to

Ar

Ar

(235)

It

-aWAr 0

II

OCHO AT

H

( 2 3 6 1 1:l mixture

proceed stereoselectively via a 2-aza-Cope N-acyliminium ring closure1@and acid-catalysed intramolecular reactions of a-acyliminium ions with ally1 and propargyl silanes have been shown to give bridgehead nitrogen bicyclic compounds regioselectively and in high yields ( 7 6 9 0 % ) (Scheme 23) .165

II n=l

0

n =3

0 Scheme 23 L. E. Overman, M.-a. Kakimoto, M. E. Okazaki, and G. P. Meier, J . Am. Chem. Soc., 1983,105, 6622. 161 L. E. Overman, M. Sworin, and R. M. Burk, J . Org. Chem., 1983,48,2685. 162 L. E. Overman, L. T. Mendelson, and E. J. Jacobsen, J. Am. Chem. SOC., 1983,105,6629. L. E. Overman, E. J. Jacobsen, and R. J. Doedens, J . Org. Chem., 1983,48,3393. lW H. Ent, H. de Koning, and W. N. Speckamp, Tetrahedron Lett., 1983,24,2109. lU H. Hiemstra and W. N . Speckamp, Tetrahedron Len., 1983,24, 1407.

Saturated Heterocyclic Ring Synthesis

463

The pyrrolizidine alkaloids (-)-hastanecine (238)166and (+)-heliotridine (240)167have been synthesized by routes involving stereoselective acyliminium ion cyclizations of hydroxy-lactams (237) and (239) respectively. PhCH-,0

HCO;

O ' -

'

HO

MeS02CI NEt3

0' (239)

An efficient preparation of the tricyclic system (243) has been reported, starting from the N-chlorocyclobutylamine (241), by silver ion-inducedring expansion and Pictet-Spengler cyclization of the intermediate iminium salt (242). 168 Several procedures for the formation of five-membered nitrogen heterocycles by intramolecular addition of a nitrogen nucleophile to an unactivated double bond have been reported. Kametani and co-workers have published further details of their sulphenocycloaminationroute to the pyrrolizidine skeleton 169 and in addition, Danishefsky and co-workers have reported the synthesis of the D. J. Hart and T.-K. Yang, J . Chem. SOC.,Chem. Commun., 1983,135. A. R. Chamberlin and J. Y. L. Chung, J . Am. Chem. SOC., 1983, 105,3653. la F. M. Schell and A. N. Smith, Tetrahedron Lett., 1983,24,1883. 169 T. Ohsawa, M. Ihara, K. Fukumoto, and T. Kametani, J . Org. Chem., 1983,48,3644

16'

General and Synthetic Methods

464

___)

Benzene

Me0

(241 1

( 2 4 3 ) 67%

A1 BN

'Cbr ( 2 4 5 ) 7 0 % overall

NHCbz ( 244 1

yc*HgOAc

NaBH(0Me 13 Me02CCH=CH2

\

~

C02Me

\

Cbz

Cbz

(246) 64

HMe

0

R

( 2 4 9 ) R = a - H , 34OlO

( 2 5 0 ) R = P - H , 11%

overall

Saturated Heterocyclic Ring Synthesis

465

substituted pyrrolidines (245) and (246) from the carbamate (244) by ureidoallylation and ureidomercuration procedures respe~tively;'~~, 171 synthesis of benzoindolizidinone (248) from the acrylanilide (247) was unsuccessful. Closure to give the five-membered products (249) and (250) was the preferred reaction pathway, as was the case with the analogous palladium-mediated cyclizations.17* A regiospecific (5- or 6-exo-trig) cyclization of alkenic amines (251) to produce alkenyl-pyrrolidinesor -piperidines (252) has been reported,173and disubstituted R'

-(CH2)nNHR3

AgN03 Or

i, HgCl2 ii.NaBH4

R2

I

R3

(251) n = l o r 2

(252) 35-95 *lo

proline derivatives (253) have been prepared in moderate overall yields by a stereoselective route involving reductive coupling of acetamidomercurials with (Scheme 24). The proline derivative (253; n=2) electron-deficient a l k e n e ~ l175~ ~ .

(CHzD

n = 1 or2

H ( C H q F C O 2 H

-

/

NHCOMe

( C H i 'HgCl

I COMe (CH21n T > C N

iii

+

NHCOMe

COMe

I

(CHT>--CN

(253) Reagents: i, Hg(NO,),, MeCN; ii, NaCl; iii, CH,=C(CI)CN, NaBH,; iv, NaH; v, 5N-HCl

Scheme 24

has also been prepared by a ring contraction of the appropriate a-chloro1a~tam.l~~ A general route to five- and six-membered nitrogen heterocycles involving olefinic cyclizations promoted by Beckmann rearrangement of oxime sulphoR. R. Webb and S. Danishefsky, Tetrahedron Lett., 1983,24, 1357. S. Danishefsky, E. Taniyama, and R. R. Webb, Tetrahedron Lett., 1983,24,11. S . Danishefsky and E. Taniyama, Tetrahedron Lett., 1983,24, 15. 173 S. Arseniyadis and J. Gore, Tetrahedron Lett., 1983, 24, 3997. 174 R. Henning and H. Urbach, Tetrahedron Lett., 1983, 24,5343. 175 R. Henning, H. Urbach, and E. F. Paulus, Tetrahedron Lett., 1983,24,5347. 176 R. Henning and H. Urbach, Tetrahedron Lett., 1983,24,5339. 170 171

General and Synthetic Methods

466

nates has been described, as exemplified by the formation of the pyrroline (255) and the tetrahydropyridine (257) from precursors (254) and (256) re~pective1y.l~~ R‘

P

SnCIL

R2 “OMS

( 2 5 5 ) 80 - 8 8 %

(7

Et2AICI

OlBAH

The reaction proceeds at low temperature in aprotic solvents with only one equivalent of Lewis acid. Aliphatic and aromatic ketones, either cyclic or acyclic, can be used as starting materials and the products are easily predictable since synlanti equilibration of the oximes does not occur under the mild reaction conditions. 5-Aryl-2-pyrrolidones (259) have been prepared by Beckmann fragmentation in the Wolff-Kishner reduction of the piperidones (258),17*and several base-

CN

R = H o r OH

Me

I

Ar

Me

R

R

t

HzNNH2,KOH 190°C

Me

Ar

I

*‘Pl

Me

Me

Me

OH (258) In

(259)

S. Sakane, Y. Matsumura, Y. Yamamura, Y. Ishida, K. Maruoka, and H. Yamamoto,J. Am. Chem.

SOC.,1983,105, 672. 178 J. Bosch, M. Moral, and M. Rubralta, Heterocycles, 1983, 509.

467

Saturated Heterocyclic Ring Synthesis

catalysed procedures for the synthesis of five-membered nitrogen heterocycles, based upon C-N bond formation by intramolecular reaction of a nitrogen nucleophile have been reported. The pyrrolizidine (261) and the indolizidines (262) and (263) have been prepared by a one-pot 'crisscross annelation' pro-

(260)

NHC0CF3

(262)

+ (263)

a q . HCI

MeOH

0

66 '10

1

NaCNBH3

H

(26314-(262) 9 : 1

cedure from the amido-diketones (260) ,179 and the cyclic unsaturated amino-acid derivatives (265) and (266) have been produced by a route involving anodic oxidation of ornithine and lysine derivatives (264).I8O The cis-octahydroindolone (268) has been prepared from the lactone (267) as part of a reaction sequence which may be useful as a general route to the cis179 T. 180 T.

16

Ohnuma, M. Tabe, K. Shiiya, and Y. Ban, -TetrahedronLett., 1983, 24,4249. Shono, Y . Matsumura, and K. Inoue, J . Chem. SOC., Chem. Commun., 1983,1169,

468

General and Synthetic Metho&

r

1

-2e

I

HNJ ( c H ~ I~ ~ C 0 2 M e C02Me

-2e

MeDH.EtiNOTs

[I! C02Me

CO2Me

C02Me

1

1

i ,MeOH,H+ ii,NHbCI,A

MeOH,NaCI

,'"H:;k::;Me I I

HN

C02Me

COzMe

\

MeOH, H+

C02Me ( 2 6 5 ) n = 0,36 ' / o overall n = 1 , 4 9 % overall

I

C02Me ( 2 6 6 ) n = O a 5 2 '/a overall n = 1 ' 4 3 Ol0 overall

3-aryloctahydroindole nucleus,181and the synthesis of mesembrine (269) from enone (270) has also been reported.182 Base-catalysed cyclization of stilbene carboxamides (271) has led to benzylphthalimidines (272) in high yieldP3 and an improved procedure for the Blaise reaction, followed by in situ intramolecular alkylation of the initial adduct, provides a useful route to pyrrolidine derivatives, as illustrated by the preparation of the saxitoxin intermediate (274) from the cyano-mesylate (273).ls4 The N-acetylindoline (276) has been synthesized in moderate yield by intramolecular electrophilic amination of the carbanion derived from the 0-methylhydroxylamine (275).18s The synthesis of steroidal pyrrolidine derivatives by remote functionalization initiated by phosphoramidate radicals has been described.186 Pyrrolidones (278), P. W. Jeffs, R. Redfearn, and J . Wolfram, J . Org. Chem., 1983,48,3861. I. H. Sanchez, J. de J. Soria, M. I. Larraza, and H. J. Flores, Tetrahedron Lett., 1983,24, 551. E. Napolitano, R. Fiaschi, and A. Marsili, Tetrahedron Lett., 1983,24,1319. lM S. M. Hannick and Y. Kishi, J . Org. Chem., 1983,48,3833. la5B. J. Kokko and P. Beak, Tetrahedron Lett., 1983,24,561. C. Betancor, J . I. Concepcion, R. Hernandez, J . A. Salazar, and E. Suarez, J . Org. Chem., 1983,48, 4430. la*

lE2

Saturated Heterocyclic Ring Synthesis

469

MeNH2

R,R = 0

0

0

N

I H Me (268) R,R=O

H

(267 1

(269) R = H

0

NMe

Me0 OMe

I

0 (271 1

OMe

i,Zn, BrCH2C02Me ii, K 2 C O 3 , DMF

(274) 69%

(273) i , MeLi ii, BunLi

iv. p y , MeCOCl

(275)

QQ I

W N H O M e

COMe (276) 42%

General and Synthetic Methods

470

for example were produced in quantitative yield from the phosphoramidates (277), and the phosphoryl moiety could be easily removed to give the N-unsubstituted compound (279).

Further details have appeared of the regiospecific formation of iminium salts of bicyclic nitrogen heterocycles by distillation of the appropriate carboxyalkyl lactams from soda lime,Ig7and Shono et al. have described a novel zinc-promoted alkylation of iminium salts, the intramolecular version of which provides a useful synthesis of five- and six-membered nitrogen heterocycles, (Scheme 25). lS8

MeomN+ Zn

Me0

('

CH I -2 In1

Me0 Me0

MeCN

n =3,45% n =4,4201~

0 - 3 ~ ~ 4 Scheme 25

Several saturated nitrogen heterocycles, e.g. (281), have been produced in varying yields by photocatalytic cyclization of diamines (280) ,lg9 and a procedure

J. M. McIntosh, L. Z. Pillon, S. 0. Acquaah, J . R. Green, andG. S. White, Can.J . Chem., 1983,61, 2016. T. Shono, H. Hamaguchi, M. Sasaki, S. Fujita, and K. Nagami, J . Org. Chem., 1983,48,1621. 189 S.4. Nishimoto, B. Ohtani, T. Yoshikawa, and T. Kagiya, J . Am. Chem. Soc., 1983,105,7180.

lg]

Saturated Heterocyclic Ring Synthesis

471

for the cyclization of aminoalkenes (282) to pyrrolines (283) or piperidines (284) under catalytic 'Wacker process' conditions has also been reported.lgO

66 (284)

:

34

7 5 % combined yield

Pyrolysis of the Meldrum's acid derivative (285) gives rise to the dihydropyrrol3-one (286) in good yield,19*and further details have appeared of the acidcatalysed thermolytic rearrangement of dicyclopropyl ketimines to give cyclopropyl pyrrolines. 192 0

II

C

0 x 0 600 O C ___)

Torr

(285)

-

1

(286) 6Ooh 1x1B. Pugin and L. M. Venanzi, J . A m . Chem. Soc., 1983,105,6877. 191 H. J. Gordon, J. C. Martin, and H. McNab, J . Chem. SOC., Chem. Commun., 1983,957. 192 H . H. Wasserman and R. P. Dion, Tetrahedron Lett., 1983,24,3409.

472

General and Synthetic Methods

Five-memberedRings Containing More than One Nitrogen Atom.-Activation of the thiazoline (287) by addition of boron trifluoride greatly enhances the reactivity of the imine moiety towards nucleophilic attack and enables a useful yield of (288), an intermediate in the synthesis of biotin, to be achieved.193(+)- and (-)-

Tryptoquivaline G have been prepared by a route which involves as a key step the biomimetic double cyclization of the intermediate (289) to the imidazoindole spirolactone ring systems (290) and (291).lW

Six-membered Rings Containing One Nitrogen Atom.-The synthesis of 2,6disubstituted piperidines, oxanes, and thianes has been reviewed.195Several reports of the synthesis of six-membered nitrogen heterocycles by utilizing the lg3

194

R. A. Volkmann, J. T. Davis, and C. N. Meltz, J. Am. Chem. SOC., 1983,105,5946. M. Nakagawa, M. Taniguchi, M. Sodeoka, M. Ito, K. Yamaguchi, and T. Hino,J. Am. Chem. SOC., 1983, 105, 3709. V. Baliah, R. Jeyaraman, and L. Chandrasekaran, Chem. Rev., 1983,83,379.

473

Saturated Heterocyclic Ring Synthesis

Diels-Alder reaction have appeared but most of these have been extensions or applications of known methodology. A review of Diels-Alder reactions of azadienes has appeared,196and Cheng et al. have published further details of the preparation and intramolecular Diels-Alder reaction of N-acyl-1-azadienes to produce piperidine derivatives.197 Intramolecular cyclization .of an o-quinone methide N-alkylamine has been used as the key step in a formal total synthesis of g e p h y r o t o ~ i n and , ~ ~ ~Weinreb and co-workers, as an extension of their earlier work on the intramolecular imino Diels-Alder reaction, have synthesized the 2oo and cryptopleurine.200 quinolizidine alkaloids epil~pininel~~> The preparation of the hydroisoquinolines(293) and (294) from the azatrienes (292) has been investigated.201 With one exception, combined yields of (293) and (294) were good (7&80%) but although cyclization to give the cis-product (293)

was preferred, the degree of stereoselectivitywas generally low. In an alternative procedure, a potentially general route to cis-hydroisoquinolines (296) has been reported, based upon amino-Claisen rearrangement of the zwitterionic N-vinylisoquinuclidenes (295).202

& +i

1

C02R

I

C

___)

I

'Rl

H

R2

I

H (296) D. L. Boger, Tetrahedron, 1983,39,2869. Y.-S. Cheng, A. T. Lupo, jun., and F. W. Fowler, J. Am. Chem. SOC.,1983,105,7696. lg8 Y. Ito, E. Nakajo, M. Nakatsuka, and T. Saegusa, Tetrahedron Lett., 1983,24,2881. 199 M. L. Bremmer and S. M. Weinreb, Tetrahedron Lett., 1983,24,261. M. L. Bremmer, N. A. Khatri, and S. M. Weinreb, J. Org. Chem., 1983,48,3661. 201 S . F. Martin, S. A. Williamson, R. P. Gist, and K. M. Smith, J. Org. Chem., 1983, 48,5170. 2m F.-A. Kunng, J.-M. Gu, S. Chao, Y . Chen, and P. S. Mariano, J. Org. Chem., 1983,48,4262. 197

General and Synthetic Methods

474

Further studies on the regioselectivity of the photochemical cycloaddition of enamine-carbaldehydes and alkenes to produce 174-dihydropyridineshave also been reported.2o3 The intramolecular Mannich reaction has been utilized in two biomimetic syntheses: quinolizidinesand indolizidines (298) have been prepared from amine acetals (297)7204and acid treatment of amino-nitrile (299) gave the

-

R2

R 2R1 C=CH C0 Me

H N(CH 2)" C H (OE t 1

(297) n = 3 o r 4

I I R'

MeCO C H 2 C N H( C H 2 ) n C H ( OE t l2

I2M

- HCL

H

(

C

T

R2 R1 ( 2 9 8 ) 15-60°/o

azabicyclononanes (300), intermediates in the formation of ladybug alkaloids (301).205

CPh A ___)

10% HCI, MeOH

(299)

L

1

0 0

-

R

(301)

R

(300) R = H , 90°/o R = CcjH11,9O0/o R = Me,

m3 L. F. Tietze, A. Bergmann, and K. Bruggemann, Tetrahedron Lett., 1983,24, 3579. miF. D . King, Tetrahedron Lett., 1983,24,3281. 205

D. H. G. Medina, D . S. Grierson, and H.-P. Husson, Tetrahedron Lett., 1983,24,2099.

Saturated Heterocyclic Ring Synthesis

475

Formation of six-membered nitrogen heterocycles by acyliminium ion-initiated cyclizations continues to be a major interest. Overman et al. have reported the formation of tetrahydropyridines by intramolecular reaction of vinylsilanes with iminium ions in an endocyclic sense [(302)+(303)] .206 Thus, products (305) were produced from the amines (304) via cationic aza-Cope rearrangement and cyclization with complete regiocontrol of the double bond position.

I

R1

( 3 0 4 ) R’ = a l k y l or aryl R2 = H or h e x y l

1

R~CHO, MeCN C S A

R2

0I

R’

-I

L

Kano et al. have described the synthesis of the phenyldecahydroisoquinoline (307) from the carbamate (306) via an N-acyliminium ion-induced polyolefinic heterocycli~ation.~~~ As an extension of known methodology this same research

H

(306)

(307)

group has also reported the synthesis of oxazolo[4,3-a]tetrahydroisoquinolinesby intramolecular cyclization of a-oxa-acyliminium ions ,208, *09 and Hadley et al. have prepared the cyclized products (310) by a route involving a high-yielding, singlestep conversion of the dicarboxylic acid precursors (308) into the imides (309).210 L. E. Overman, T. C. Malone, and G. P. Meier, J. Am. Chem. Soc., 1983,105,6993. S . Kano, T. Yokomatsu, Y . Yuasa, and S. Shibuya, Tetrahedron Lett., 1983,24,1813. S . Kano, Y. Yuasa, T. Yokomatsu, and S. Shibuya, J . Org. Chem., 1983,48, 3835. 209 S. Kano, Y. Yuasa, T. Yokomatsu, and S. Shibuya, Chem. Lett., 1983, 1475. 210 M . S. Hadley, F. D . King, and R. T. Martin, Tetrahedron Lett., 1983,24,91.

476

General and Synthetic Methods

+

H02C-X-Y-CH2C02H

(308) X - Y

HzNCH2CH=CH2

=-CH2-O-,-CHz-S180-230°C

i A

i,NaBHL, H

I

(310) 50 -

OCHO 6 2 '/* overall

(309 1

Okita et al. have described a synthesis of (+)-lupinine and (+)-epilupinine which is based upon the formation of cyclized products (312) by intramolecular C-alkylation, possibly via the intermediacy of the acyliminium ion (311).211

(CH2)n

0

i , anodic oxidation, MeOH

*
ii.TiCI4

x2

~ C 0 2 M e

0

(CH21,

C02Me

(31 2 ) 5 5 -76'10 o v e r a l l

Further details have appeared of the total synthesis of (dl)-gephyrotoxin212and the synthesis of polycyclic isoquinoline derivatives ,213 both involving production of six-membered nitrogen heterocycles by N-acyliminium ion-induced cyclizations. Di- and tetra-hydroquinolines (315) and (316) have been synthesized in generally high yields by palladium-catalysed addition of the protected 2-aminoarylmercurials (313) to enones (314), and subsequent reductive cyclization of the H. Okita, T. Wakamatsu, and Y . Ban, Heterocycles, 1983,20,129,401. J. Hart and K.-i. Kanai, J . Am. Chem. SOC., 1983,105,1255. 213 B . E. Maryanoff, D. F. McComsey, and B. A. Duhl-Emswiler, J . Org. Chem., 1983,48,5062. 214 S. Cacchi and G . Palmieri, Tetrahedron, 1983, 39, 3373. 2l1

212 D.

477

Saturated Heterocyclic Ring Synthesis R'

H

Br(315) 55 - 92 o/o overall

t

HBr A c O H

Zn,HBr

(313) Y = C l or OCOCF3 Z = C 0 2 C H 2 P h , C 0 2 E t or COCF3

1

AcOH

xd H

R2

Details have appeared from two research groups of the synthesis of (k)depentylperhydrohistrionicotoxin by a route involving palladium-catalysed spirocyclization of an aminoalkyl allylic acetate.215* 216 Maruoka et al. have described further studies of the organoaluminium-promoted Beckmann rearrangement of oxime sulphonates and applications of the procedure to the synthesis of a range of nitrogen heterocyclic systems by ring expansion and simultaneous nucleophilic trapping of the intermediate iminocarbocation by the organoaluminium reagent .217 The rearrangement-alkylation sequence, illustrated by the synthesis of pumiliotoxin C, (318), has been described previously but the reaction has now been extended to include the preparation of cyclic thioethers such as (317). The same research group has also

bsMe & f Bui2AlSMe ---

H (3171 70'10 215

i,Pr3Al

___)

"

ii,DI BAH

H

N,

H

\

OTs

( 3 1 8 ) 60%

S. A. Godleski, D. J. Heacock, J. D. Meinhart, and S. Van Wallendael, J . Org. Chem., 1983, 48, 2101. W. Carruthers and S. A. Cumming, J . Chem. SOC.,Chem. Commun., 1983, 360; J . Chem. SOC., Perkin Trans. 1, 1983, 2383. K. Maruoka, T. Miyazaki, M. Ando, Y. Matsumura, S. Sakane, K. Hattori, and H. Yamamoto, J . Am. Chem. SOC., 1983, 105,2831.

General and Synthetic Methods

478

reported a related procedure for the synthesis of six-membered nitrogen heterocycles by olefinic cyclizations promoted by Beckmann rearrangement of oxime ~u1phonates.l~~ This has been described in the previous section and is illustrated by the synthesis of tetrahydropyridine (257). In another ring-expansion sequence the Schmidt reaction has been applied to the synthesis of 2-substituted dihydroquinolines from 1-hydroxy-indanes or -indenes218 The azabicyclo-system (320) has been prepared by reduction of the hydroxypyridinium salt (319) (Scheme 26).219

i,ii

~

w r 2 ) iii ___)

Me 0

I

I C02Me

OMe

I

C02Me

C02Me

n = 3 , 4 or 5

f--

Me0

(320) (319) Reagents: i, -2e, MeOH, Et.,NOTs; ii, furan,p-TsOH; iii, -2e, MeOH, NH,Br; iv, OH-; v, HC1; vi, PtO,, H, or NaBH,, NaOH

Scheme 26

In an extension of their earlier studies of ortho-metallation of tertiary aromatic amides Snieckus and his co-workers have now described a synthesis of phenanthro-quinolizidine and -indolizidine alkaloids which utilizes a new N-hetero ring annelation procedure (Scheme 27).220Full details hdtve appeared of the synthesis of dihydroisoquinolones by the reaction of lithium salts of phthalides with imines221and Marsden and MacLean have used an analogous reaction in a synthesis of the protoberberine system (322) from dihydroquinolines (321) .222 Several research groups have reported chiral syntheses of six-membered nitrogen heterocyclic systems. The Pictet-Spengler reaction of Nb-benzyltryptamine with the sugar derivative (323) obtained from methyl a-D-mannopyranoside for example, gave the two epimeric P-carbolines (324) which were then converted G. Adam, J. Andrieux, and M. M. Plat, Tetrahedron Lett., 1983, 24, 3609. T. Shono, Y . Matsumura, K. Tsubata, K. Inoue, and R. Nishida, Chem. Lett., 1983,21. 220 M. Iwao, K. K. Mahalanabis, M. Watanabe, S. 0.De Silva, and V. Snieckus, Tetrahedron, 1983,39, 1955. 221 D . J. Dodsworth, M. Pia-Calcagno, E. U . Ehrmann, A. M. Quesada, 0.Nunez, andP. G. Sammes, J . Chem. Soc., Perkin Trans. 1, 1983, 1453. 222 R. Marsden and D. B. MacLean, Tetrahedron Lett., 1983,24,2063.

479

Saturated Heterocyclic Ring Synthesis

' . . , I

-111

OH

1

v.vi

OMe

\

,viii

iv, ix d

Reagents: i, BusLi, TMEDA, Et20,THF, -78°C; ii, pyridine-2-CHO;iii, TsOH, PhMe, A; iv, Zn(Cu), 10% KOH, py; v, H,, Pt,AcOH, HC1; vi, xylene, A; vii, N-PhCH2-pyrrole-2-CHO;viii, silica gel, CHCl,, A; ix, CH,N,

Scheme 27

into the indoloquinolizidines (325) .223 Syntheses of optically active tetrahydrobenzisoquinolines (326) *% and phenanthroquinolizidines (327) 22s have been accomplished by mild intramolecular Friedel-Crafts acylation, and further J. Kervagoret, J. Nemlin, Q. Khuong-Huu, and A. Pancrazi, J . Chem. SOC., Chem. Commun., 1983, 1120* 224 E. Gellert, N. Kumar, and D. Tober, Aurt. J . Chem., 1983,36, 157. 225 T. F. Buckley I11 and H. Rapoport, J . Org. Chem., 1983,48,4222.

223

General and Synthetic Methods

480

(321)

‘

R3

0

/

i , LDA,THF.-&O~C ii ,LiAIHL

0 (3241

0 (325)

details have appeared of the use of the 2-cyano-6-oxazolopiperidines(328) as chiral 1,4-dihydropyridineequivalents in the enantiospecific synthesis of (+)- and (-)-conhe and -dihydropinidine.226 Six-membered Rings Containing More than One Nitrogen Atom.-The dihydropyrazinone (330) has been prepared by addition of glycine ethyl ester to the azirine (329), followed by ring expansion.227Two procedures for the synthesis 226

w7

L. Guerrier, J. Royer, D. S. Grierson, and H.-P. Husson, J . Am. Chem. Soc., 1983,105,7754. G . Alvernhe, A. Laurent, and A . Masroua, Tetrahedron Lett., 1983,24, 1153.

481

Saturated Heterocyclic Ring Synthesis i , PC15

ii, SnCLL, benzene

< looc

( 3 2 6 ) 32'1e OMe

R (327) ~ 1 0 0 %

R2

-

F'

R2

pH 3.0

ii,

KCN

H 2N

(328 )

R' = M e , R 2 = P h R' = P h , R 2 = H

'Ue

C L - H ~ ~ C H ~ C Ot Z E Et3N.MeCN

Me

80°C,L8h

c=o (329)

(330) 5 3 %

of six-membered rings containing the guanidine moiety which are improvements over existing methods have been reported. 2-Amino-5,6-dihydropyrimidinones (333) have been synthesized in high yields and under mild conditions by cycliza-

482

General and Synthetic Methods 0

It

(3311

0

(333) 70

(332)

- 100%

tion of guanidines (332) with a$-unsaturated esters (331),228 and the substituted anilines (334) have been cyclized to the tetrahydroquinazolines (335) by a mild R - N D N H

I

NH;!

cy

N H X

II

N/x M"

+

5OoC

( 3 3 5 ) 74 - 83 Yo overall X = CN,C02Me, or COMe

M"+ = CF3C02Ag, H g ( 0 A c I 2 , for

example

two-step process utilizing soft metal cations.229The total synthesis of ptilocaulin (337) via the addition of guanidine to the enone (336) has also been described.230

ns Y. H. Kim and N. J. Lee, Heterocycles, 1983, 20, 1769. H. Obase, N. Nakamizo, H. Takai, and M. Teranishi, Bull. Chern. SOC.Jpn., 1983, 56, 3189. 230 B. B. Snider and W. C. Faith, Tetrahedron Lett., ,1983,24,861. 229

Saturated Heterocyclic Ring Synthesis 483 The first examples of the 2,5-diazabicyclo[4.l.O]heptanesystem (339) have been prepared by double alkylation of the cis-sulphonylamidocyclopropanes (338).231

n

- tJ ArS02-N

A r S 0 2 N w H S O 2 A r

N-SO2Ar

i, OR-

ii. BrCH2CH2Br

( 3 3 8 ) Ar = t o l y l or Ph

(339) Ar = t o l y l , 7l0lO Ar = P h , 73%

Medium Ring Nitrogen Heterocycles.-Rings Containing One Nitrogen Atom. A review of the structure and chemistry of medium ring bicyclic compounds has appeared which describes synthetic routes to bridgehead mono- and d i - a r n i n e ~ . ~ ~ ~ The dioxohexahydroazepines (341)and (342)have been prepared in low overall yields from the dioxopyrrolidine carboxylate (340) by photochemical cycloaddi-

'

\

-

EtOH

\

I Et

Et

(3411

I

R (340)

*=

Et or CH2Ph

HO

0

CO2Et

I

R

tion followed by base-catalysed ring expansion.233A modified two-step Tschernix-Einhorn amidoalkylation reaction has been used to prepare the tetrahydrobenzazepine (344), an intermediate in the total synthesis of (+)-elwesine, (2)231

M. W. Majchrzak, A . Kotelko, and J. B. Lambert, J . Heterocycl. Chem., 1983,20, 815.

w 2 R . W. Alder, Acc. Chem. Res., 1983,16,321. 233 S . T. Reid and D. De Silva, Tetrahedron Lett.,

1983,24, 1949.

General and Synthetic Methods

484

epielwesine, and (+)-oxocrinine, from the carbamate (343),234and a similar procedure has provided an efficient synthesis of the thienoazepines (345) .235

n

n

H

<&N,C02Cti2Ph

0

ii,p-TsOH i'aq*HCHo

_____)

PhH,

<"

& N

0

A

\

CO2C HzPh

(343)

( 3 4 4 ) 9so/o R

R

1

( 3 4 5 ) R = Me, 45% R = PhCH2,47%

Sasaki et al. have reported a novel synthesis of 4-azahomoadamant-3-ene (347) and two other strained bridgehead imines by utilizing the Staudinger reaction followed by an intramolecular aza-Wittig cyclization. The ethanol adduct (348) was isolated from the azide (346) in 92% yield.236The same research group has

(346)

I

-Ph3PO

EtOH

@CEt (348)

(347)

I. H. Sanchez, F. J. Lopez, J. J . Soria, M. I. Larraza, and H. J. Flores, J. Am. Chem. SOC., 1983,105, 7640. 235 S. Kano, Y. Yuasa, T. Yokomatsu, and S. Shibuya, Synthesis, 1983, 585. w6 T. Sasaki, S. Eguchi, and T. Okano, J. Am. Chem. SOC., 1983, 105,5912. 234

Saturated Heterocyclic Ring Synthesis

485

also reported the synthesis of 4-azahomoadamant-4-ene (352) from the azide (349) or alcohol (350) by a n-route cyclization followed by acidolytic ring expansion of the intermediate azide (351).237

poH NY

(351 1

(352)

MeS03H

Two alkaloid syntheses have been reported which involve formation of sevenor eight-membered nitrogen heterocycles. The seven-membered ring system (354) has been prepared from the indole (353) as part of the total synthesis of (k)-

i , POCL3, DMF

ii,DBU

H

(353)

H ( 3 5 4 ) 56'10

clavicipitic acids I and 117238and the seven- and eight-membered rings (356) and (357) have been prepared by irradiation of (355) as part of a synthesis of vinca alkaloids and related corn pound^.^^ A new route to the benzazocine (359), via Beckmann cleavage of the tetralone oxime (358) has been reported,240and the 'crisscross annelation' procedure described earlier in connection with the synthesis of pyrrolizidines (261) and indolizidines (262) and (263), has also been applied to the synthesis of the eightand nine-membered keto-lactams (361) from the diketones (360).a1 T. Sasaki, S. Eguchi, N. Toi, T. Okano, andY. Furukawa,J . Chem. SOC.,Perkin Trans. 1,1983,2529. H. Muratake, T. Takahashi, and M. Natsume, Heterocycles, 1983,20, 1963. 239 C. Szantay, T. Keve, H. Bolcskei, and T. Acs, Tetrahedron Len., 1983,24,5539. B. Iddon, D. Price, and H. Suschitzky, Tetrahedron Lett., 1983,24,413. 241 T. Ohnuma, M. Nagasaki, M. Tabe, and Y. Ban, Tetrahedron Lett., 1983,24,4253. 237

u8

General and Synthetic Methods

486

a$-& H CI

5 o$-& "20

C02Me

C02Me

(355)

(356) 16%

+

H (357)16 '10 Me

Me

I

Me

H

H

- flfl

aq. K2CO3 or LiOH MeOH 50 65OC

-

COCF3

(360) R = Me or CH2Ph n=2or3

Saturated Heterocyclic Ring Synthesis

487

Rings Containing More than One Nitrogen Atom. Two groups have reported further studies of the synthesis of medium ring nitrogen heterocycles by transamidation reactions. Crombie et al. have prepared seven-, eight-, and ninemembered azalactams (363) from azetidin-Zones (362) by a milder variant of 0 liq. NH3

-

sealed tube 20- d5OC 2-Id days

(362)

( 3 6 3 ) 70-90

=2-4 X = C I or Br /t

'lo

Wasserman's published procedure242and used the reaction to synthesize the biseight-membered lactam h ~ m a l i n eFurther . ~ ~ ~ details of a similar route to the same alkaloid have appeared from Wassermann et aZ.,244who have also reported the synthesis of the seventeen-membered ring lactams ( - t ) - ~erbasceni ne~~~ and (+)~ h a e n o r h i n by e ~ means ~~ of the same methodology. Two reports of the preparation of seven-membered nitrogen heterocycles by ring opening of substituted cyclobutanes have appeared. The diazatropones (365) have been prepared by ring opening of the pyrazolines (364),247and the mono-

Rq22 - fi, - 'CNH R3

r.t.

R'kHN2

d

R2 R1

R'

H

(364)

RL

R2

-

Rd

(3651

cyclic seven-membered ring compounds (367) have been synthesized by ring opening of the corresponding 3-azatricycloheptanes (366) .248 The synthesis of the benzodiazepines (370) has been accomplished in high yields by reaction of two equivalents of the corresponding anilines (368) with one equivalent of the bromo-lactam (369),249and a new synthesis of the 3,4,5trihydro-173-diazepin-5-ol ring system (372) has been reported based upon reductive cyclization of the protected cyanohydrin (371) using cobalt b ~ r i d e . ~ ~ O L. Crombie, R. C. F. Jones, S. Osborne, and A. R. Mat-Zin, J . Chem. SOC., Chem. Commun., 1983, 959. 243 L. Crombie, R. C . F. Jones, A. R. Mat-Zin, and S . Osborne, J . Chem. SOC.,Chem. Commun., 1983, 960. 244 H . H. Wasserman and G. D. Berger, Tetrahedron, 1983,39, 2459. 245 H. H. Wasserman and R. P. Robinson, Tetrahedron Lett., 1983,24, 3669. 246 H. H. Wasserman, R. P. Robinson, and C. G. Carter, J . Am. Chem. SOC., 1983,105, 1697. 247 H.-D. Martin, R. Iden, F.-J. Mais, G. Kleefeld, A. Steigel, B. Fuhr, 0. Riimmele, A. Oftring, and E. Schwichtenberg, Tetrahedron Lett., 1983,24,5469. 248 J. Kurita, K. Iwata, M. Hasebe, and T. Tsuchiya, J . Chem. SOC., Chem. Commun., 1983, 941. 249 G. A. Kraus and S . Yue, J . Org. Chem., 1983,48,2936. 250 0 . L. Acevedo, S. H. Krawczyk, and L. B. Townsend, Tetrahedron Lett., 1983,24, 4789. 242

a - xmN

General and Synthetic Methods

488

I

\

C02Me

C02Me

(366) xylene

I

C02Me

(367) X = 0,NC02Et, S,

6

MeNH

-9 0

+

Br

EtO

X

(368) X =H,CL, or OMe

(369)

OHC

hN+TMSCN

ZnCl2

Me2N

Me

80 - 90°/o

or CH,

H

F

(370) 65-76’10

“5 H2

N

N

I Me

Me2N

(3711

”

z

H

OH

HN*JV &IV

I Me

(372) 65%

5 /?-Lactams, Penicillins, Cephalosporins, and Related Compounds

A novel regiospecific synthesis of P-lactams by metal-catalysed ring expansion of aziridineshas been Treatment of aziridines (373) with carbon monoxide in benzene, using chlorodicarbonylrhodium(1) dimer as catalyst, gave the azetidinones (374) in quantitative yield with no detectable formation of the isomeric 1,4-substituted products. The proposed mechanism, involving oxidative addition of rhodium(1) to the more substituted carbon-nitrogen bond, followed by ligand migration and subsequent carbonylation, is shown in Scheme 28. Full details have appeared of the synthesis of P-lactams from n-allyltricarbonyliron (lactone) complexes by reaction with amines in the presence of Lewis 251

252

H. Alper, F. Urso, and D. J. H. Smith, J. Am. Chem. Suc., 1983,105,6737. G. D. Annis, E. M. Hebblethwaite, S. T. Hodgson, D. M. Hollinshead,and S.V. Ley, J. Chem. Suc., Perkin Trans. 1, 1983.2851.

489

Saturated Heterocyclic Ring Synthesis R2

bI + N

R1

(373)

(374) looo/o

1

T

co

oc

I

A'

cL.ihy /

oc

I

R1 =Bu',l-adamantyl,or SiMe3, R2 = Ph,p-BrC6HL, or p - P h c 6 H ~

Scheme 28

P-Lactams (377) have been synthesized in moderate yields by a one-pot reaction of the substituted acetic acids (375) with imines (376) in the presence of toluene-p-sulphonyl chloride and triethylamine ,2s3 and Barrett et al. have

T o s C l , NEt3

R1CH2C02H

(375)

[R1CH2CO~Tos] 3 C H = N R 3 1

3761

R '3

(3771 39 - 64%

investigated the use of isocyanates in p-lactam synthesis as alternatives to the widely used chlorosulphonyl isocyanate.254/3-Lactams (379) were produced in moderate overall yields after reductive deprotection, and addition of trifluoroacetyl isocyanate (378a) to the dihydropyrans (380) provided a convenient entry into the N-unsubstituted 8-aza-2-oxabicyclo[4.2.01 octan-7-one system (381). A range of fused p-lactams of novel structural type, e.g. (384), have been prepared by non-concerted [2+2] cycloaddition reactions of lH-l,2-diazepines (383) with ketenes (382),2ssand Beckwith has described the direct conversion of 253

254

255

M. Miyake, N. Tokutake, and M. Kirisawa, Synthesis, 1983, 833. A. G. M. Barrett, A. Fenwick, and M. J. Betts, J . Chem. SOC.,Chem. Commun., 1983, 299. R. Allmann, T. Debaerdemaeker, G. Kiehl, J.-P. Luttringer, T. Tschamber, A. Wolff, and J. Streith, Liebigs Ann. Chem., 1983,1361; J . Streith, T. Tschamber, and G. Wolff, Liebigs. Ann. Chem., 1983, 1374.

490

General and Synthetic Methods R' X-N=C=O

(378) a ; X = C F $ O b; X =CCL,CH2502 c ; X = CC L 3C H2OS02

v

on Florisil

mo H

R'

R2fio

R

(382)

lzn

H

C02Et (383)

C02Et

(384)

the 3-phenylthiopropionamide (385) into thep-lactam (387) via oxidative cyclization of the a-thioalkyl radical (386), albeit in poor yield.256

starting ma ter ia L

+

M

(385) 62'10

0

'Me

(387)l8"/0 256

A. L. J. Beckwith and C. J. Easton, Tetrahedron, 1983,39,3995.

Saturated Heterocyclic Ring Synthesis

491

Two reports of the synthesis of 3-methyleneazetidinones have appeared. Barrett and his co-workers have published full details of the conversion of a-ketoamides into 3-methyleneazetidinones by utilizing the Shapiro reaction ,257 and Commerson et aE. have described two modifications of an existing procedure which enable moderate to good yields of 1-aryl- and l-alkyl3-methyleneazetidinones (388) to be obtained (Scheme 29).258

Br>coNHR Br Br

I

li

i + RNH2

( 3 8 8 ) 23 - 84 "ie Reagents: i, KOH pulv., CH2C12,Bun4N+Br-

Scheme 29

Kametani and his co-workers have published details of their synthesis of /?-lactams by the sulpheno-cycloamination procedure ,259 and further studies of the diethyl azodicarboxylate-triphenylphosphine-mediatedcyclization of /3-hydroxyamide derivatives to produce P-lactams have been described. Miller et aE. have developed an efficient route to N-hydroxy-2-azetidinonesby cyclization of the appropriate 0-acylated amino-acid hydroxamate and subsequent deprotection,260and the same group has also investigated analogous cyclizations of serylaminomalonates (390) and related compounds.261In this case treatment of the hydroxyamide (390) with DEAD-triphenylphosphine or formation of the dianion of /3-chloroamide (391) resulted in cyclization to the p-lactam (392), but cyclization of the monoanion of (391) gave the pyrrolidinone (389). Townsend et al. have reported full details of similar cyclization studies in connection with the synthesis of (-)-3-aminonocardicinic acid.262 R. M. Adlington, A . G. M. Barrett, P. Quayle, A . Walker, and M. J. Betts, J . Chem. SOC., Perkin Trans. I , 1983, 605. 258 A . Commerson and G. Ponsinet, Tetrahedron Lett., 1983,24, 3725. 259 M. Ihara, Y. Haga, M. Yonekura, T. Ohsawa, K. Fukumoto and T. Kametani, J . Am. Chem. SOC., 1983, 105, 7345. 2@ M. J . Miller, A, Biswas, and M. A . Krook, Tetrahedron, 1983,39,2571. 261 M. J. Miller and P. G. Mattingly, Tetrahedron, 1983,39, 2563. 262 C. A. Townsend, A . M. Brown, and L. T. Nguyen, J . Am. Chem. SOC., 1983,105,919. 257

General and Synthetic Methods

492 Me

Me& 0

CO2Et CO2Et

H

X=OH

DEAD, PPh3

C H ( C 0 2 E t 12

C H ( C 0 2 E t 12

(390);X = OH (391);X = C L

(392) X=Cl 2 LDA

The cephem (394) has been prepared from the diacid (393) by a double cyclization using benzotriazol-l-yloxytris(dimethy1amino)phosphonium hexafluorophosphate (BOP) as the condensing agent .263 The use of dicyclohexylcarbodi-imide gave only a 20% yield of (394). Several reports have appeared this year from different research groups of the synthesis of 2-0x0- or 2-thioxo-penams and their conversion into 2-hetero-substituted penems. Ghosez and co-workers have reported a general route to 2-0x0, Me

H

(393) 0

lSOp

(394) 80°/0 263

J.-C. RozC, J.-P. Pradere, G. Duguay, A. Guevel, H. Quiniou, and S. Poignant, Can. J. Chem., 1983, 61, 1169.

493

Saturated Heterocyclic Ring Synthesis

2-thioxo-, and 2-imino-penams (396) from a single precursor (399, which is readily prepared from penicillin G (Scheme 30) .264 Hydrogenolysis and methyla-

i

C02R2 (395) R' = CH2Ph or But R2 = CH2Ph or p - N O ~ C G H ~ C H ~

( 3 9 6 ) X = O,S,or NMe 2O-59%

Reagents: i, COCi,, NEt,; CSCl,, NEt,; or MeN =CBr,, NEt,

Scheme 30

tion then gave the corresponding 2-hetero-substituted penems. Girijavallabhan et al. have synthesized the optically active 6 4 l-hydroxyethyl) analogue of (396; X=S) by an essentially identical but have also described a more convenient stereospecific synthesis of thioxopenam (398) by base-catalysed cyclization of the dithiocarbamate (397).266Leanza et al. have achieved the same ring closure by starting with the phenoxythiocarbonyl analogue of (397).267

PH

S

II

I 7 Li N(TMS12

JH

J3s-c-N+N ____)

-76

0

C02R

OC

J

0

Q

S

CO2R

(3971 R = a l l y [

(398) 76.10

In an extension of their earlier work, Cooke et al. have now reported a one-pot conversion of the 4-allysulphinylazetidinones (399) into the corresponding penems (401), presumably via the intermediacy of 2-thiacephems (400).268A 0

$

0 C02PNB

C02PNB ( 399 1

(400)

( 4 0 1 ) R = M e ,4 8 % R = Ph , I 8 '/o

M. Cossement, J. Marchand-Brynaert, S. Bogdan, and L. Ghosez, TetrahedronLett., 1983,24,2563. V. M. Girijavallabhan, A. K. Ganguly, P. Pinto, and R. Versace, TetrahedronLett., 1983,24,3179. V. M. Girijavallabhan, A. K. Ganguly, P. Pinto, and R. Versace, J. Chem. SOC., Chem. Commun., 1983, 908. W. J. Leanza, F. DiNinno, D. A. Muthard, R. R. Wilkening, K. J. Wildonger, R. W. Ratcliffe, and B. G. Christensen, Tetrahedron, 1983,39,2505. 268 M. D. Cooke, K. W. Moore, B. C. Ross, and S . E. Turner, Tetrahedron Lett., 1983,24,3373.

264 265

General and Synthetic Methods

494

report from Perrone et al. describing their studies of the synthesis of penems by desulphurization of 2-thiacephems has also appeared.269 The carbene insertion reaction has been utilized in the synthesis of several novel penicillin and cephalosporin analogues. A new route to the isopenam sulphone (403) has been described, via rhodium-catalysed decomposition of the a-sulphonyl diazoester (402) ,270 and Kametani and co-workers have

PhH,8O0C

k02 C H2Ph

(402)

(403)9 5 %

prepared 2-carboxylated penicillin and cephalosporin derivatives by utilizing an initial S-1-C-2 bond cleavage step brought about by reaction of penicillin derivatives with a - d i a z o m a l ~ n a t e s . ~The ~ ~ ’ ~same ~ ~ research group has also prepared the eight-membered cis-oxa-p-lactams (406) by addition of the carbene derived from p-nitrobenzyl a-diazozacetate (405) to the ,!?-face of penicillin derivatives (404) followed by ring expansion.273

(406)2 2 - 27 */o E. Perrone, M. Alpegiani, A . Bedeschi, M. Foglio, and G . Franceschi, Tetrahedron Lett., 1983, 24, 1631. 270 J . Brennan, and I. L. Pinto, Tetrahedron Lett., 1983, 24, 4731. 271 T. Kametani, N. Kanaya, T. Mochizuki, and T. Honda, Heterocycles, 1983,20,455. 272 T. Kametani, N. Kanaya, T. Mochizuki, and T. Honda, Heterocycles, 1983, 20, 435. 273 T. Kametani, N. Kanaya, T. Mochizuki, and T. Honda, Tetrahedron Lett., 1983,24, 221. 269

Saturated Heterocyclic Ring Synthesis

495

Two other routes to related ring-expanded oxa-/3-lactams have also been reported. The seven-membered systems (410) and (411) have been synthesized from the monocyclic azetidinones (408) and (409) by routes which utilize the total carbon-oxygen skeleton of benzyl clavulanate (407),274 and full details have

C(OMe) CH2CHO

(408)

OMe C 0 2 C H2Ph

(410)46%

appeared of the synthesis of l-oxacepham and l-oxahomocepham systems by free-radical cyclization of alkenyl- and alkynyl-substituted a~etidinones.”~ Stoodley and co-workers have reported full details of the synthesis of an iso-

(412) 274 275

( 4 1 3 ) 20%

G. Brooks and E. Hunt, J . Chem. SOC.,Perkin Trans. 1, 1983, 115. M. D. Bachi, F. Frolow, and C. Hoornaert, J . Org. Chem., 1983,48,1841.

General and Synthetic Methodr

496

clavam-3-carboxylate,276 and Philips et al. have prepared some 3-oxa5-carbacephamanaloguesby mercuric acetate-assistedintramolecularcyclization of 4-allylazetidinone-l-alcohols.2n Cyclization of the phosphoramidate (412) has given the novel bicyclic/3-lactam (413) in modest yield,278and Baldwin et al. have prepared the y-lactam analogues (414) and (415) of carbapenicillanic acid and penicillanic acid respectively (Scheme 31).279

i,CH2=CHC02Me

C02Me

.c

ii.Hz.Ra-Ni

iii, MeOH,

0

A

COZMe

1

1

-m

PhOCH2CONH

0 O

E

3

COzK

i02CH2Ph

(414)

- p3 i , CH2N2 ii,NaOH

COZH

Scheme 31

J. Brennan, G. Richardson, and R. Stoodley, J . Chem. SOC., Perkin Trans. 1, 1983,649. M. L. Philips, R. Bonjouklian, N. D. Jones, A. H. Hunt, and T. K. Elzey, Tetrahedron Len., 1983, 24, 335. 27* G. Just, D . Dugat, and W.-Y. Liu, Can. J . Chem., 1983, 61, 1730. 279 J. E. Baldwin, M. F. Chan, G. Gallacher, P. Monk, and K. Prout, J . Chem. SOC., Chem. Commun., 1983, 250.

276

9 Highlights in Total Synthesis of Natural Products BY K. E. B. PARKES AND G. PATTENDEN

1 Introduction This Report is similar in style, format, selectivity, and subjectivity to the previous chapter in the series.

2 Terpenes

Cobalt-mediated carbon-to-carbon bond-formingreactions have featured prominently in a number of elegant natural product syntheses in the past decade. Now Exon and Magnusl have shown that the well known formation of cyclopentenones by reaction between a strained alkene and an alkyne-octacarbonyldicobalt complex can be effected in an intramolecular sense [viz. (1)+(2)], to provide the key bicyclic interdediate (2) in an efficient formal synthesis of coriolin (3). In two alternative new approaches to coriolin, published during 1983, Wender et al. have used their now well documented arene-lefin photocyclization approach, i. e. (4)-+(5), and Koreeda et al. have employed the interesting dianion (6) from 3-isobutoxycyclopent-2-enonein a reaction with 3-iodo-2,2-dimethylpropanal, followed by addition of MOM chloride, to set up the central intermediate (7). A particularly fascinatingroute to the triquinane ring system found in hirsutene (9) is that based on rearrangement by homoenolization of the intermediate (8) (Scheme 1) in the presence of potassium t-b~toxide.~ Little et aL5 have also described a neat approach to hirsutene which uses intramolecular diyl trapping by an unactivated diylophile, viz. (lo), to set up the tricycle. Greene et aL6 have published full details of their total synthesis of hirsutic acid (11) , which fully demonstrates the effectiveness of chloroketene-diazoalkane annelation in the construction of five-membered rings (Scheme 2). This useful annelation procedure has also been used by Paquette and Annis7 to produce the diquinane segment (12) in their synthesis of pentalenene (15), a metabolite of Streptomyces griseochromogenes. The third ring in these authors’ synthesis of C. Exon and P. Magnus, J . Am. Chem. SOC., 1983,105,2477. P. A . Wender and J. J. Howbert, Tetrahedron Len., 1983,24,5325. M. Koreeda and S. G. Mislankar, J . Am. Chem. SOC., 1983,105,7203. B. A. Dawson, A. K. Ghosh, J. L. Jurlina, and J. B. Stothers,J . Chem. Soc., Chem. Commun., 1983, 204. R. D. Little, R. G. Higby, and K. D. Moeller, J . Org. Chem., 1983,48,3139. A. E. Greene, M. Luche, and J. Deprts, J . Am. Chem. SOC., 1983,105,2435. L. A. Paquette and G. D. Annis, J . Am. Chem. SOC., 1983,105,7358.

497

498

General and Synthetic Methods

O

t

0

t

'H OH

I

0Bui (6)

*-%O

OH

OBu'

(7)

OTMS

Reagents: i, LDA, Me,SiCl; ii, CH212,Zn, Ag; iii, NaOH, MeOH; iv, NaNH,, MeI; v, Bu'O-, Bu'OH

Scheme 1

Highlights in Total Synthesis of Natural Products

499

Cl

"""&

IV,

.1

I,III,VI

Meozc\&&-o H

Cl

M eOzC v

a3 .,

-- e* HOzC,,

H

H

O (11)

Reagents: i, Cl,C=C=O;

ii, Me,CuLi, iii, CH,N,; iv, NaBH,; v, Cr(ClO,),; vi, Zn, AcOH

Scheme 2

H

(13)

(15) Reagents: i, Cl,C=C=O;

ii, CH,N,

Scheme 3

17

General and Synthetic Methods

500

0

0

A

(16)

pentalenene was added by SnC1,-catalysed cyclization of the enal(13), leading to (14), which was then converted into pentalenene (15) and its methyl epimer (Scheme 3). The capnellane family of sesquiterpenes found in the soft coral Capnella imbricata continues to attract attention from the synthetic chemist. Thus, Mehta et a1.* have shown that thermolysis, under flash vacuum pyrolysis conditions, of the adduct (17) obtained via the Diels-Alder adduct (16) of methylcyclopentadiene isomers andp-benzoquinone, leads to the tricyclic dione (18) in 60% yield. Several steps then gave A9912-capnellene(19). In the same year, Birch and Pattenden9 have provided full details of the first synthesis of the novel 5,8-fused ring system found in precapnelladiene (22) ,which co-occurswith A9>12-capnellene

in C. irnbricata. The authors’ synthesis uses a highly stereoselective intramolecular photocycloaddition reaction from the enol benzoate (20), followed by retroaldolization to (21), to set up the unusual biocyclic carbon framework found in precapnelladiene. Two groups of researchers have described a new approach to the synthesis of the tetracyclic lactone quadrone (27), based on an intramolecular Diels-Alder

* G . Mehta, D. S. Reddy, and A. N. Murty, J . Chem. SOC., Chem. Commun., 1983, 824; for another synthesis of capnellene see: R. D. Little, G. L. Carroll, and J. L. Petersen, J . Am. Chem. SOC.,1983, 105, 928. A. M. Birch and G. Pattenden, J. Chem. SOC.,Perkin Trans. 1, 1983, 1913.

501

Highlights in Total Synthesis of Natural Products

(24)

(27)

reaction, viz. (23)+(24).l0>l1The two syntheses differ only in the manner in which the adduct (24) was next converted into (25),and then into the tricyclic acid (26), an intermediate used by Danishefsky et al. in their first synthesis of quadrone. In an entirely different approach to quadrone (27), Takeda et a l l 2 have applied solvolytic rearrangement of the substituted bicyclo[4.2.0]octano1(28) followed by cyclopentenone annelation to set up the tricyclic acid intermediate (26),

I II

(28)

J

The useful, but comparatively little exploited, intramolecular Michael reaction has featured in new approaches to the novel ring systems found in clovene (29) l3 and in cedrene (30) l4 published this year, and an interesting approach to a-acoraR . H. Schlessinger,J. L. Wood, A. J. Poss, R. A. Nugent, and W. H. Parsons, J. Org. Chem., 1983, 48, 1146. l1 J. W. Dewanckele, F. Zutterman, and M. Vandewalle, Tetrahedron, 1983,39,3235. l2 K. Takeda, Y. Shimono, and E. Yoshii, J. Am. Chem. SOC., 1983,105,563; see also: S. Burke, C . W. Murtiashaw, and J . A. Oplinger, Tetrahedron Lett., 1983,24, 2949. l3 P. G. Baraldi, A. Barco, S. Benetti, G. P. Pollani, and D. Simoni, Tetrahedron Lett., 1983,24,5669. l4 M. Horton and G. Pattenden, Tetrahedron Lett., 1983, 24,2125.

lo

General and Synthetic Methods

502

=a O

H

0

(30)

diene (33) has as its basis the intramolecular photocycloaddition of the chlorodienone (31), leading to largely (32), followed by reductive cleavage using Li-NH3.

The synthesis of complex polycyclic molecules using intramolecular photocycloaddition followed by fragmentation is also well illustrated in a new synthesis of zizaene (35) starting from the enol acetate (34).16 0

0

(34)

ls,W. Oppolzer, F. Zutterman, and K. Battig, Helv. Chim. Actu, 1983, 66, 522. l6 A. J. Barker and G. Pattenden, J. Chem. Soc., Perkin Trans. 1, 1983, 1901.

.1

Highlights in Total Synthesis of Natural Products

503

An interesting synthesis of bulnesene (38), which features intramolecular cycloaddition involving the 3-oxidopyrylium species (37) generated from the corresponding pyranulose acetate (36), has been published by Sammes et al. l7 The

A

150 *C*

Ac 0

(37)

(36)

J.

0

same general strategy was also employed to develop new syntheses of the terpenes cryptofauronol (39) and valeranone (40).

a 0

I

I

The Diels-Alder reaction remains one of the most useful and subtle methods for elaborating all types of terpene ring systems. This feature is illustrated this year with approaches to the drimane sesquiterpenes, e.g. warburganal (41) ,I8 and

17

l8

P. G. Sammes and L. J. Street, J . Chem. SOC., Chem. Commun., 1983, 666. D. M. Hollinshead, S. C . Howell, S. V. Ley, M. Mahon, N. M. Ratcliffe, and P. A. Worthington, J . Chem. SOC., Perkin Tram. 1, 1983, 1579.

General and Synthetic Methods

504

in an enantioselective synthesis of (-)-P-salltalene dienophile (42).19

(43) using the chiral

Intramolecular reductive coupling of the wester carbonyl compound (44)using Tiois accompanied by E-2-isomerization about the double bond, to produce the ketone precursor (45) of the medium-ring sesquiterpene isocaryophyllene (46) .*O

(44)

1

C02Et

Germacrone (48),a constituent of Geranium macrorhizum, although possessing a labile E,E-1,5-diene system, has been synthesized by a route based on intramolecular alkylation of the carbanion generated from the protected cyanohydrin (47).21 The more elaborately substituted germacrane eucan-

(47)

i, p - T S A ii, NaOH

W. Oppolzer and C. Chapuis, Tetrahedron Lett., 1983, 24, 4665. J E. McMurry and D. D. Miller, Tetrahedron Lett.. 1983. 24, 1885. 21 T. Takahashi, K. Kitamura, H. Nemoto, J. Tsuji, and 1. Miura, Tetrahedron Lett., 1983,24,3489.

l9

Highlights in Total Synthesis of Natural Products

505

nabinolide (51) has been synthesized by a beautifully neat sequence involving oxy-Cope ring expansion of (49) to (50) in the presence of KN(TMS):! at 85 "C as a

OH

OMe (49)

OMe

(50)

key step.22 Still and his c o - w o r k e r ~have ~ ~ also outlined a synthesis of the cembranoid anti-tumour agent asperidiol (54)which uses the diastereoselective macrocyclization of the aldehydo-allylic bromide (52) in the presence of Cr" to produce the diastereoisomer (53) of the macrocycle. Kato et al.24 have also

/br

0-

(52)

(541 W. C. Still, S. Murata, G. Revial, and K. Yoshihara, J . Am. Chem. SOC., 1983, 105, 625. W. C. Still and D. Mobilio, J . Org. Chem., 1983,48,4785. 24 M. Akoi, Y. Tooyama, T. Uyehara, and T. Kato, Tetrahedron Lett., 1983,24,2267.

22

506

General and Synthetic Methods

described a synthesis of asperdiol starting from the ally1 alcohol (56) prepared via intramolecular cyclization of the acid chloride. (55).

i , SnCL4

E 51

TI,

L l C l , LlZCO3

111,

LIALHI,

>

+(54)

(56)

Me02 C

(59)

?\

H

Highlights in Total Synthesis of Natural Products

507

Lombardo and ManderZ5have now extended their elegant synthetic investigations amongst the gibberellin plant hormones, and have outlined a neat synthesis of gibberellin A38methyl ester (63). Their synthesis is based on elaboration of the previously described intermediate (57) to the aldehyde (58),followed by a novel intramolecular Michael reaction, viz. (59)+(60) and intramolecular aldol cyclization, viz. (61)+(62). Other notable achievements amongst the total synthesis of terpenes published in 1983 are the synthesis of the insect anti-feedant ajugarin I (64) ,26 a biogenetictype synthesis of aphidicolin (65) ,27 and synthesis of the biogenetically interesting sesquiterpenes eremolactone (66) and isoeremolactone (67).28+29 0

0

0

3 Steroids The possibilities for the intramolecular variant of the Diels-Alder reaction in the regio- and stereo-controlled synthesis of complex polycycles seem endless. Thus, this year Kametani and his c o - w ~ r k e rhave s ~ ~ demonstrated how the reaction can L. Lombardo and L. N. Mander, J. Org. Chem., 1983,48,2298. S. V. Ley, N . S. Simpkins, and A. J. Whittle, J. Chem. SOC.,Chem. Commun., 1983, 503. 27 E. E. van Tamelen, S. R. Zawacky, R. K. Russell, and J. G . Carlson, J. A m . Chem. SOC., 1983,105, 142. 28 R. Ramage, 0. J. R. Owen, and I. A. Southwell, Tetrahedron Lett., 1983,24, 4487. M. Asaoka, K. Ishibashi, N. Yanagida, and H . Takei, Tetrahedron Lett., 1983,24,5127. 30 T. Kametani, Y. Suzuki, H. Furuyama, and T . Honda, J. Org. Chem., 1983,48, 31. 25

26

18

General and Synthetic Methods

508

be employed to set up the tricycle (68) for elaboration to androstane-2,17-dione (69). Johnson et aL31have described further details of their novel biomimetic polyene cyclization approach to steroids using the allylsilane residue as an appropriate terminator. Thus, treatment of (70) with SnC14in pentane at 0°C (15 min) then at 15°C for 5 min afforded a mixture of (71) and (72) in a useful combined yield of 45%.

R’

RZ

(71) R1 = OCH2CH20H, R 2 = H (72) R 1 = H, R 2 = OCHzCHzOH

4 Anthracyclinones Stoodley and his c o - ~ o r k e r shave ~ ~ outlined a new strategy for elaborating anthracyclines in which the 6a,7- and 10,lOa-bondsare constructed via a DielsAlder reaction. Thus, Diels-Alder reaction between the diene (74) and the oxirane (73) was found to give the adduct (75) with high diastereocontrol. In a sixstep sequence the adduct (75) was then converted into (+)-demethoxy31

32

W. S. Johnson, Y.-Q. Chen, and M. S . Kellogg, J . Am. Chem. SOC.,1983,105, 6653. R. C. Gupta, P. A. Harland, and R. J. Stoodley, J . Chem. SOC., Chem. Commun., 1983, 754.

Highlights in Total Synthesis of Natural Products

509

a+ A;;; OSi Me3

0

0

0 (73)

0

AcOCH,

, I

OAc

(74)

Qy-$J-y 0

OH

0

OH

0

\

6

\

1

O+

(76)

Sugar

(75)

OH

daunomycinone, the aglycone of 4-demethoxydaunomycin (76). The diastereoselection observed in the Diels-Alder reaction between (73) and (74) is particularly interesting and important, since chiral dienes have not previously enjoyed a good reputation of diastereodifferentiation in [4+2] cycloaddition reactions. Sequential intramolecular Michael reaction followed by aldolization from the dione-ester (77) in the presence of [2.2.2]-KH cryptate, leading to (78), provides

Me0

(77)

OH

0 (78)

General and Synthetic Methods

510

the basis of a new biomimetic route to aklavinone (79), the aglycone of aclacinomycin A .33 A synthesis of a-citromycinone (82), one of the rarest anthracyclinones produced in fermentation broth of Streptomyces purpurescens, has been accomplished by Swenton et al.34The author’s synthesis uses the addition of the vinyl-lithium reagent, produced from (80), to (81), followed by hydrolysis and deprotection to elaborate the tetracycle.

1

I

Bu‘MeZSiO

OMe

OR

(81)

(80) OMe OH

F\

OH

A/

H

BCL3)

OH

H>

I

OMe 0

OH

OH

OH

0 (82)

Boeckmann and his co-workers 35 have provided further illustrations of the use of the Diels-Alder strategy between naphthoquinones (83) and the bicycle (84) for elaborating anthracyclinones, by achieving a new total synthesis of daunomycinone (86) and of adriamycinone (87). An approach to

mco~ GR isomers

I

Me0

0

0

(85) 33 34

35

Me0

0

OH

OH

(86) R = H (87) R = OH

K. Maruyama, H. Uno, and Y . Naruta, Chem. Lett., 1983, 1767. D. K. Anderson, C. E. Coburn, A. P. Haag, and J. S . Swenton, Tetrahedron Lett., 1983,24, 1329. R. K. Boeckmann and S. H . Cheon, J . Am. Chem. SOC., 1983, 105,4112.

Highlights in Total Synthesis of Natural Products

511

11-deoxydaunomycinoneand daunomycinone (86) described by Rao et al.36 starts from the ketone (88) and involves sequential Friedel-Crafts alkylation, i. e. (88)+(89), and acylation, i.e. (90)+(91) and (92)-+(93), reactions.

Br

(89)Br

(88)

JI 4

4- \ \

/

OMe

\

OMe

OM e

(91)

OMe

(90)

(89)++ OMe

OH

OMe

OH

5 Alkaloids

The Diels-Alder reaction continues to feature prominently in alkaloid synthesis. Thus, Magnus et al.37 have published the full details of their indole 2,3quinodimethane strategy for the synthesis of (f)-aspidospermidine (lOl), and have also applied the methodology to the synthesis of (+)-kopsanone In the latter synthesis, the Diels-Alder reaction is applied to the imine (94), leading to the tetracyclic intermediate (95). Removal of the carbonate protecting group and re-acylation then gave the sulphoxide (96), which could be cyclized to (97) in a Pummerer-type reaction in the presence of trifluroacetic acid anhydride. Allylation of (97) [to (98)] then set-up the molecule for a second intramolecular DielsAlder reaction producing (99), which was converted into (+)-kopsanone (100) in six further steps. Another Diels-Alder reaction, this time between the 1,4-diarylbutadiene(102) and maleimide, provided the cornerstone of a synthesis of the slime mould 36 3’ 38

A. V. R. Rao, K. B. Reddy, and A. R. Mehendale, J . Chem. SOC., Chem. Commun., 1983,564. T. Gallagher and P. Magnus, J . Am. Chem. SOC., 1983,105,2086. T. Gallagher, P. Magnus, and J. C. Huffman, J . Am. Chem. SOC., 1983,105,4750.

512

General and Synthetic Methods

Ts

TS

(94)

(95)

0

6-jp N

I TS

N J:

&-dH ‘-a

N

I

Ts

(97)

(96)

0

0

Q-Q PhS-

PhS--

QT! I

TS

(98)

-

I

Ts

(99)

Highlights in Total Synthesis of Natural Products

513

metabolite arcyriaflavin B (104) .39 Aromatization of the newly formed cyclohexene ring of (103) using dichlorodicyano-p-benzoquinonefollowed by elaboration of the carbazole residues by nitrene insertion reactions and deprotection, then

I-/

/ H

\ /

\ /

H

OH

H

gave the natural product. A nitrene insertion reaction, viz. (105)+( 106), has also provided a key step in a synthesis of methoxatin (107), a co-enzyme present in methylotropic bacteria.40

39

I. Hughes and R. A. Raphael, Tetrahedron Lett., 1983,24,1441. A. R. MacKenzie, C. J. Moody, and C. W. Rees, J . Chem. SOC., Chem. Commun., 1983, 1372.

General and Synthetic Methods

514

Japanese workers have used the o-iminoquinonemethine (109) as a central intermediate in a synthesis of the tricycle ( l l l ) , a known precursor of the frog neuropoison gephyrotoxin (112) .41 Thus, treatment of the ammonium bromide (108) with caesium fluoride led to the transient intermediate (109), which gave (110) by an intramolecular Diels-Alder reaction. The synthesis of (111) from (110) was then completed by way of a two-step catalytic hydrogenation sequence.

HO

Me@ 0

$?

N-SiMe3

Br -

OMe ( 108 1

H HO

OMe

(109)

Ho41 OMe

(111)

( 1 10)

4 J(

H

Weinreb and his c o - ~ o r k e r have s ~ ~ published full details of their use of acylimine dienophiles in Diels-Alder cycloadditions, with a synthesis of (+)-epilupinine (113). They have also provided a new application of this methodology in a synthesis of (+)-cryptopleunne (114). 41 42

Y . Ito, E. Nakajo, M. Nakatsuka, and T. Saegusa, Tetrahedron Lett., 1983,24,2881. M. L. Bremmer, N. A. Khatri, and S. M. Weinreb, J . Org. Chem., 1983, 48, 3661.

Highlights in Total Synthesis of Natural Products

515

OMe Me0

0 (11 3)

0

Me0 (114)

The intramolecular cyclization (116)+( 117) of a formamide ylide prepared by sequential methylation and fluoride ion-induced desilylation of (115), formed the final step of a new short route to the physostigmine alkaloid (k)-eserethole (117).43The high yield (70%) of this step is particularly impressive. Me

Me (116)

1

1,3-Dipolar cycloaddition was also used in a synthesis of a-isosparteine (121), whereby the tetracycle (120) was elaborated by treatment of 4H-pyran with the nitrone (118) leading to (119), which was then hydrogenated catalytically.MIn addition, Oppolzer et aZ.45have now published full details of their nitrone-based strategy to the clavine alkaloids, e.g. (122). Overman and his co-workersM have applied their ‘ring enlarging pyrrolidine annelation’ sequence to a synthesis of the aspidosperma alkaloid (+)16-methoxytabersonine (129). The key intermediate (126) was prepared by R. Smith and T. Livingstone, J . Org. Chem., 1983,48,1554. H. Oinuma, S. Dan, and H. Kakisawa, J . Chem. SOC., Chem. Commun., 1983,654. 45 W. Opyolzer, J. I . Grayson, H. Wegmann, and M. Urrea, Tetrahedron, 1983,39,3695. 46 L. E. Overman, M. Sworin, and R. M. Burk, J. Org. Chem., 1983,48,2685. 43

44

516

General and Synthetic Methods

methylenation and deprotection of the tricyclic amide (125) which itself was derived from the reaction between (124) and the acyl anion equivalent (123). Treatment of (126) with paraformaldehyde under mildly dehydrating conditions resulted in rearrangement, via (127) and (128), to give the complete aspidosperma ring system (128), which required only methoxycarbonylation to complete the synthesis of methoxytabersonine (129). A full paper on Overman’s synthesis of the related (+)-crimine (130) was also published during 1983.47 The synthesis of the pyrrolizidine family of alkaloids has been a particularly active area during the period of this Report. Noteworthy have been enantiospecific syntheses of (+)-heliotridine (131) from S-malic and of (132), an ant venom, whereby the chirality was introduced by the ubiquitous Sharpless epoxidation procedure.49 In a synthesis of (+)-supinidine (135), the lithiodihydropyrrolidine (133) was used as the pivotal intermediate, allowing the introduction of a four-carbon chain to give (134) .50 The pyrrolidine (134) was then deprotected and cyclized to (?)-supinidine (135), in one-pot by treatment with L. E. Overman, L. T. Mendelson, and E. J. Jacobsen, J. Am. Chem. SOC., 1983, 105, 6629. A. R . Chamberlin and J. Y . L. Chung, J. Am. Chem. SOC., 1983,105, 3653. 49 S. Takano, S. Otaki, and K. Ogasawara, J. Chem. SOC., Chem. Commun., 1983, 1172. T. L. Macdonald and B. A . Narayanan, J . Org. Chem., 1983,48, 1129.

47

48

Highlights in Total Synthesis of Natural Products

/d""

OSiMe3

MeO

\

NH

I

+ .,

co28u'

(123 1

8

517

COzMe

+

/

+

i

(124)

9""'"'"" OMe

(125 1

r

OMe

J

0 Me (126)

(128)

(129)

C02Me

methyl-lithium. Novel lithiation methodology has also been used in a recent synthesis of the potent anti-leukaemic alkaloid (k)-sesbanine (139) .51 Treatment of nicotinamide (136) with lithium tetramethylpiperidide was found to give the 4-lithio-derivative (137), which was successfully trapped with cyclopent-3-enone. 51

M. Iwao and T. Kuraishi, Tetrahedron Lett., 1984, 24, 2649.

518

General and Synthetic Methods

Lactonization and reduction then gave (138), the substrate for a further lithiation to introduce the last required carbon atom. Sesbanine (139) was then prepared from (138) in a further four steps.

I

I

COzMe

COzMe

(132)

@0

NPrI2

(133)

/OH

b

f--

C

I

C

I

COz Me (134)

0, 1

(137)

QCO2H f-

The mercury(I1)-catalysed Ritter reaction has provided the basis of a most impressive one-pot synthesis of some Aristotelia alkaloids.52Thus, (+)-makomakine (142) was obtained in 17% yield from the reaction of indol-3-yl-acetonitrile (141) with (-)-P-pinene (140) in the presence of mercury(I1) nitrate, followed by reductive work-up. Similarly, (+)-a-pinene led to (+)-hobartine (143) in 11%yield, the lack of enantiospecificityin this case being due to the fact that the cyclization can occur at both ends of the allylic mercurial intermediate (144). Stevens et al. have prepared karachine (146) in 66% yield, by a one-pot double annelation of berberine (145).53 52

53

R. V. Stevens and P. M. Kenney, J . Chem. SOC.,Chem. Commun., 1983,384. R . V. Stevens and J . R. Pruitt, J . Chem. SOC., Chem. Commun., 1983,1425.

Highlights in Total Synthesis of Natural Products

519

H

H

'H (143)

(144)

Biomimicry has provided the inspiration for an enantiospecific synthesis of the fungal metabolite (+)-tryptoquivaline G (150). Thus, treatment of the indole (147) , prepared from L-tryptophan methyl ester, with N-bromosuccinimide gave the bromide (148), which was then cyclized without isolation to (149). The synthesis was then completed by deprotection and oxidation.54 ~ published the results of their extensive studies on the Kuehne et u E . ~ have synthesis of minovincine (152) via a presumed biosynthetic precursor , 19-oxosecodine (151). 54

M. Nakagawa, M. Taniguchi, M. Sodeoka, M. Ito, K. Yamaguchi, and T. Hino,]. Am. Chem. SOC.,

55

1983, 105, 3709. M. E. Kuehne and W. G . Early, Tetrahedron, 1983,39,3707, 3715.

General and Synthetic Methods

520

. . O w 0

OvO

Finally in this section, a short synthesis of a known precursor (155) of 7-methoxymitose (156) has been published.56 Thus, photolysis of the aminoquinone (153), and the retention of the irradiated solution on silica for a few days before chromatography, produced (154) as a 5:4 mixture of diastereomers in a combined yield of 72%. Both isomers then formally lose t-butyl formate on treatment with trifluoroacetic acid, giving (155). 56

M. Akiba, S. Ikuta, and T. Takada, J . Chem. SOC., Chem. Commun., 1983,817.

Highlights in Total Synthesis of Natural Products

ov

H CO ;!CH 2 CC I 3

NHCOzCHzCCI3 (147)

0 t--

0 ( 1 50)

521

522

General and Synthetic Methods

6 Prostaglandins and Leukotrienes Noyori and his co-workers have outlined a modification to their route to PGEl, published last year, which uses as a key operation the tandem organocopper conjugate addition/nitro-olefin Michael trapping of the resulting enolate intermediate, identified in Scheme 4.57A synthesis of PGE2described by Fuchs et u E . ~ ~

I

OSiMe2But

Scheme 4

is 'enantioconvergent' in that it uses both enantiomers of the alcohol (157) to make the single enantiomer (158) needed to construct the prostanoid intermediate (159) by reaction with (160) and (161). OH I

N M q >02Ph

y e 2

(ySPh(y *. i i

i, (160)

+

5 11

' , 6SiMe2But

I I

( 1 57)

c ; ; 2 ) 3 c 0 2 M e

I

OSiMe2But

(158) L-if

C5H11

0si Me

Bu'

(159)

I -C02Me

I

(161)

0s i Me 2B ut (160)

The Glaxo group has summarized its work on new total synthesis of PGA2, PGI,,and PGD2.5M1 Leukotriene B5(165), which originates from eicosapentaenoic acid rather than arachidonic acid, is of interest in connection with understanding the basis of the

*coma

i - V )

o

T

o

AcO' (162)

(163)

T. Tanaka, T. Toru, N. Okamura, A. Hazato, S. Sugiura, K. Manabe, S. Kurozumi, M. Suzuki, T. Kawagishi, and R. Noyori, Tetrahedron Lett., 1983,24,4103. 58 R. E. Donaldson, J. C . Saddler, S. Bym, A. T.McKenzie, and P. L. Fuchs, J. Org. Chem., 1983,48, 2167. 59 R. F. Newton, D. P. Reynolds, J. Davies, P. B. Kay, S . M. Roberts, and T. W. Wallace, J . Chem. SOC.,Perkin Trans. 1, 1983, 683. 6o A . D. Baxter, S. M. Roberts, F. Scheinmann, B. J. Wakefield, and R. F. Newton, J . Chern. SOC., Chem. Commun., 1983, 932. 61 E. W. Collington, C. J. Wallis, and I. Waterhouse, Tetrahedron Lett., 1983,24, 3125. 5'

Highlights in Total Synthesis of Natural Products

523 H

PPh3 I-

vii

OH

- xii

Illv=v

(165) Reagents: i, Zn/Hg, HC1; ii, DBU; iii, LiOH; iv, H,, Pd/C; v, PDC; vi, Sharpless epoxidation; vii, Lindlar hydrogenation; viii, Collins reagent; ix, MeOCMe2(CH,),CH= PPh,; x, AcOH, H 2 0 , THF; xi, PPh,, I,, DIPA, imidazole; xii, PPh,; xiii, (163); iv, KOPr'; xv, OH-

Scheme 5

cardiovascular protective effect of dietary fish lipids. Previously LTB5 has only been obtained in minute amount (a few micrograms). Now Corey et a1.62have developed a synthesis of the leukotriene, which starts from the known lactone (162) and proceeds via the phosphonium salt intermediate (164) (Scheme 5). A new synthesis of LTB4 (168) using the chiral intermediates (166) and (167) employed in earlier synthesis emphasizes that the intermediates can be made very effectively from non-carbohydrate precursors!63

HO C02H

62 63

E. J. Corey, S. G . Pyne, and W. Su, Tetrahedron Lett., 1983,24,4883. C. Fuganti, S. Servi, and C. Zirotti, Tetrahedron Lett., 1983, 24, 5285.

524

General and Synthetic Methods 7 Spiroacetals

Interest in the synthesis of spiroacetals has intensified greatly in recent years with the recognition that this structural unit is found in a number of important antibiotics, as well as in insect pheromones. In what looks to be the most economic synthesis of (k)-endo-brevicomin (170), a sex attractant of the female Western pine beetle, Cohen et al.(j4have simply treated the acrolein dimer (169) with three equivalents of ethyl-lithium in the presence of TMEDA, and worked-up with methyl iodide followed by aqueous acid, to secure (170) in 69% yield.65

Y

-0,

OLi

An interesting synthesis of lineatin (172), a pheromone of the ambrosia beetle Trypodendrom lineatum, has, as its key feature an intramolecular [2+2] cycloaddition of the ene-allene (171).66Synthetic work by Mori and his has firmly established the stereochemistry of (+)-lineatin as (lR,4S,5R,7R).

=? A

490

OC

Q

5

O

--w 0

(171)

T. Cohen and M. Bhupathy, Tetrahedron Lett., 1983,24,4163. For other syntheses of brevicomin see: R. J. Ferrier and P. Prasit, J . Chem. SOC., Perkin Trans. 1, 1983, 1645; N. N. Joshi, V. R. Mamdapur, and M. S. Chadha, ibid., p. 2963. 66 L. Skattebol and Y . Stenstrom, Tetrahedron Lett., 1983, 24, 3021. 67 K. Mori, T. Uematsu, M. Minobe, and K. Yanagi, Tetrahedron, 1983, 39, 1735.

65

525

Highlights in Total Synthesis of Natural Products

The acid-catalysed rearrangement of the tetrahydropyranyl ether (173) in the presence of boron trifluoride, leading to (174), constitutes the basis of a new and attractive approach to the pheromone component (175) of the female olive fly

(173)

1

b

H OCH2CC13

woH

OH

(175)

Dacus oleae.@ The talaromycins A and B are toxins isolated from the fungus Talaromyces stipitatus. In a synthesis of talaromycin B (178) the anomeric effect was used to control all four chiral centres of (177) in the cyclization of (1715).~~

OH HgC12 MeCN

OH (177) (178)

R = OH R = Me

The conversion of the furano-carbinol (179) to the pyranone (180)-in the presence of rn-chloroperbenzoic acid constitutes the basis of a short synthesis of the spiroacetal carbinol (181) used by Ireland in his synthesis of the antibiotic In yet another spiroacetal synthesis, the anion (182) was tirandarny~in.~~

69

'O

I. T. Kay and E. G . Williams, Tetrahedron Lett., 1983,24, 5915. S. L. Schreiber and T. J. Sommer, Tetrahedron Lett., 1983,24,4781. P. DeShong, S. Ramesh, and J. J. Perez, J . Org. Chem., 1983,48, 2117.

526

General and Synthetic Methods

OBZ

(180)

527

Highlights in Total Synthesis of Natural Products

employed in a Wittig-Horner reaction to form a mixture of enol ethers, which were then cyclized with acid to give (183), a pheromone from Paravespula vulgaris.71 The spiroacetal segment of avermectin B1, has been synthesized from the two fragments (184) and (185) derived from D-glucose and S-malic acid. Reduction of the intermediate (186) then gave an olefin which could be cyclized to give the optically pure spiroacetal (187).72

8 Pseudomonic Acids French workers have described a neat total synthesis of methyl pseudomonate C (193) using carbohydrate precursors .73 Their synthesis was based on regiospecific ring opening of the epoxide (188) derived from D-xylose using the allylic anion of (189), which itself was produced from D-glucose. The copper-catalysed ring opening of (188) first afforded (190), which was then converted into the acetonide. Selective tosylation of (191a) then afforded (191b), which with Ph I

+

o&

OSiMe, But

(188)

(189 1

OH

(191) a; R = O H b; R =OTS C;

R =CN

potassium cyanide gave (191c), the precursor of the ketone (192). This ketone was finally converted into methyl pseudomonate C (193), as shown in Scheme 6. have also described a synthesis of methyl pseudomonate C Fleet and his from carbohydrates. Thus, L-arabinose served as a precursor to the side chain (194), and D-arabinose was used to prepare the chiral allylic alcohol (195). Two S. V. Ley and B. Lygo, Tetrahedron Lett., 1984, 25, 113. S. Hanessian, A. Ugolini, and M. Thesien, J. Org. Chem., 1983,48,4427. 73 J.-M. Beau, S. Aburaki, J.-R. Pougny, and P. Sinay, J. Am. Chem. SOC., 1983,105, 621. 74 G. W. J. Fleet andT. K. M. Shing, TetrahedronLett., 1983,24,3657; G .W. J. Fleet, M. J. Gough, and T. K. M. Shing, ibid., p. 3661. 71

72

General and Synthetic Methods

528

-Y 0

I

OH

(192)

I

i-v

OH

OH

(193)

Reagents: i, MeC( =NSiMe3)0SiMe3; I(CH,),CO,Me

ii, EtO,CFHPO(OEt),;

iii, H 30+; iv, NaOH; v,

Scheme 6

e'~CoNMe t

Claisen

I'

Qo

I'

CONH?

0s i P h *But

J

i .(196)

'CO,Et

ii, H+

OH

+I J (193)

Scheme 7

529

Highlights in Total Synthesis of Natural Products

Claisen amide acetal rearrangements served to transfer chirality twice from oxygen to the ring in the steps ultimately used to synthesize the pseudomonate (Scheme 7). 9 Sugars The period under review has witnessed a significant interest in the synthesis of less common sugars. this perhaps reflecting a realization of the importance of the sugar moiety to the activity of anthracyclinones as anti-tumour agents. Grethe’s group has published syntheses of the epoxide (196) a known precursor of L-daunosamine (197), by one-carbon extension of ~ - a r a b i n o s eand , ~ ~also by a non-carbohydrate-based route in which chirality is introduced by asymmetric hydroboration with (-)-di-3-pinanylborane (198) .76

(196)

OH

(198)

(197)

A particularly short and high-yielding route to a protected (+ )-daunosamine involved the addition of the nitrone (200), derived from the ester (199), to ethyl vinyl ether which was found to give (201) diastereospecifically . Catalytic hydrogenation of the adduct in acidic methanol, using Pearlman’s catalyst, and acetylation then gave the protected (2)-daunosamine (202) in 58% overall yield.77

(200)

(201)

J

OMe

G. Grethe, T. Mitt, T. H. Williams, and M. R. UskokoviC, J . Org. Chem., 1983,48, 5309. G. Grethe, J. Sereno, T. H. Williams, and M. R. UskokoviC. J . Org. Chem., 1983, 48, 5315. 77 P. DeShong and J. M. Leginus, J . Am. Chem. SOC., 1983, 105, 1686. 75

76

530

General and Synthetic Methoak

Iodo-cyclization of the trichloromethyl imidate ester of allylic alcohols has provided a convenient way of introducing the vicinal cis-amino-alcohol functionality common to many anthracyclinone sugars. Thus, reaction of the sodium salt of the allylic alcohol (204), which is readily available by known chemistry from L-rhamnose (203), with trichloroacetonitrile gave the imidate ester (205), which cyclized to the oxazoline (206) when treated with the iodonium salt (207). Dehalogenation and hydrolysis then produced N-acetylristosamine (208) .78 The daunosamine derivative (210) was prepared similarly from the epimeric alcohol (209) made by Mitsunobu inversion of (204).79

(205)

(204)

cc 13 I

+ c10I;-

O w e I ( 206 1 OMe

OMe

OH

(209)

Danishefsky et al. have now applied their pyrone-forming Diels-Alder reaction of aldehydes to the synthesis of the amino-octose lincosamine (215), which as its methylthioglycoside forms the saccharide portion of the antibiotic lincomycin. Boron trifluoride-catalysed Diels-Alder reaction between the diene (211) and crotonaldehyde gave the expected endo-product (212), which was converted into the pyranose (213) by reduction and treatment with rn-chloroperbenzoic acid in methanol. Functionalization of the 1-propenyl side chain to lincosamine (215) H. W. Pauls and B. Fraser-Reid, J. Org. Chem., 1983,48, 1392. H. W. Pauls and B. Fraser-Reid, J. Chem. SOC., Chem. Commun., 1983, 1031. 8o E. R. Larson and S . Danishefsky, J . Am. Chem. SOC., 1983,105, 6715. 78

79

531

Highlights in Total Synthesis of Natural Products

I

,o

(212 1

was achieved via the bromohydrin (214), which was obtained diastereospecifically on treatment with N-bromosuccinimide in aqueous acetic acid. Also of note in the area of sugar synthesis is the elaboration of the potent aminoglycoside antibiotic apramycin (216) from the previously synthesized neamine (217).81

OH

HO+NH~ ( 217 1 81

OH

K. Tatsuta, K. Akimoto, H. Takahashi, and T. Hamatsu, Tetrahedron Lett., 1983,24,4868.

General and Synthetic Methods

532 10 Macrolides and Ionophores

A major synthetic achievement published during 1983 was the synthesis by Meyers and his thirteen co-workers of 3 mg of the anti-tumour macrocycle (-)maysine (226), which used a convergent approach from the three fragments (218), (219), and (222).82Thus, the cuprate derived from (218) was coupled to the allylic bromide (219), to give the achiral portion of the molecule (220). The epoxide portion (222), which contains all but one of the chiral centres, was prepared from Cl

Me

C\

Me

COz H

H

S-(+)-3-hydroxy-2-methylpropionic acid (221), and coupled to the vinyl-lithium reagent from (220) to give a 1:l mixture of epimers at the C-10 hydroxyl-group, which was separated after methylation and desilyation to (223). Oxidation and acylation of the nitrogen centre in (223) then gave the aldehydo-phosphonate (224), which underwent cyclization to give (225) in the presence of potassium t-butoxide. Deprotection and formation of the cyclic urethane by treatment with phosgene and ammonia at -78°C completed the synthesis. 82

A . I. Meyers, K. A. Babiak, A. L. Campbell, D. L. Comins, M. P. Fleming, R. Henning, M. Heuschmann, J . P. Hudspeth, J . M. Kane, P. J. Reider, D. M. Roland, K. Shimizu, K. Tomioka, and R. D. Walkup, J. Am. Chem. SOC., 1983, 105, 5015.

Highlights in Total Synthesis of Natural Products

533

II

P(OEt 12

M

/

e

0

\

4 Me

/

/

e

OEE SE t SEt

M

\ eo

'%

/

,,Me D

O

OEE SE t SE t

I I

OMe

(225)

OMe

(224)

OMe (226)

An interesting synthesis of the antibiotic S, S-( +)-grahamimycin (229) used the titanium-induced pinacol cyclization of the dialdehyde (227). Oxidation of (228) then gave material identical to the natural product except in the sense of optical rotation; this permitted the assignment of the R, R-configuration to natural grahamirny~in.~~ A tin template effect has been used to prepare the iron carrier enterobactin (233). Thus, refluxing the protected anhydro-serine (230) in chloroform in the presence of the cyclic tin compound (231) led to the trimer (232), which only required deprotection and acylation to complete the synthesis. It is believed that the cyclization proceeds by multiple insertion of the p-lactone into the cyclic tin 83

D. Ghiringhelli, Tetrahedron Lett., 1983, 24, 287.

General and Synthetic Methods

534

0 0

0 W 0

Highlights in Total Synthesis of Natural Products

535

compound followed by expulsion of the trimer and regeneration of the template.84 Stork’s group has published a simplification of their original synthesis of cytochalasin B (236), in which the key Diels-Alder step is performed as an intramolecular reaction, viz. (234)+(235), and the synthesis is completed by elaboration of the allylic alcohol moiety in the cyclohexane ring.85

@

A. Shanzer and J. Libman, J . Chem. SOC., Chem. Commun., 1983,846. G. Stork and E. Nakamura, J . Am. Chem. SOC., 1983,105, 5510.

536

General and Synthetic Methods

Considerable interest has been shown in the synthesis of boromycin (237), routes to the C-3-C-17, and the C-1-C-17 segments being published by Hanessian et al.86 and by White et al.87 respectively. The ionophore antibiotic X-14547A (243), which is of particular interest because of its ability to transport both univalent and bivalent cations, has been synthesized by a convergent approach in which the fragments (239) and (242) are

HO .

H

coupled together using a Julia reaction. The pyran-aldehyde (239) was prepared in sixteen steps from 1,6-anhydro-P-~-glucose(238), and the sulphone (242) was derived from the addition of the lithio-pyrrole (241) to the lactone (240).88 Me

Me

Ft

Me

Me

86

S. Hanessian, D . Delorme, P. C. Tyler, G . Demailly, and Y . Chapleur, Can. J . Chem., 1983,61,634. J. D . White, M. A. Avery, S. C . Choudhry, 0. P. Dhingra, M-c. Kang, and A . J. Whittle, J . Am. Chem. SOC., 1983,105,6517. M. P. Edwards, S. V. Ley, S. G . Lister, and B. D . Palmer,J. Chem. SOC., Chem. Commun., 1983,630.

537

Highlights in Total Synthesis of Natural Products

Ireland et aLS9have published the full details of their synthesis of the nonselective ion carrier and antibiotic lasalocid A (244), and have also used a closely related approach to prepare its enantiomer.90 11 Other Natural Products Tabtoxin (247) ,produced by the infecting agent Pseudomonas tabaci, is the toxin . described ~ ~ responsible for wildfire disease in tobacco plants. Baldwin et ~ 1 have the first synthesis of the toxin, which uses the Diels-Alder reaction between benzyl nitrosoformate and the cyclohexadiene (245) to produce the adduct (246) whose C -N and C -0 bonds define the relative stereochemistryat C-2 and C-5 in (247). The sensitive p-lactam ring in the toxin, which undergoes a facile intramolecular transacylation to the stable, inactive isotabtoxin (248) (tl,*pH 7, 24 h at 25"C), was closed in the final stages of the synthesis. CO;! Et

b +

C02Et

0

II

___)

N 'COzCH2Ph

P&

N

'C02

CH2Ph

(245)

I

0

C02H

4

'$---COzCH, Ph

R. E. Ireland, R. C. Anderson, R. Badoud, B. J. Fitzsimmons, G. J. McGarvey, S. Thaisrivongs, and C. S. Wilcox, J. Am. Chem. SOC., 1983,105,1988. 9o R. E. Ireland, L. Courtney, and B. J. Fitzsimmons, J. Org. Chem., 1983, 48, 5186. 91 J. E. Baldwin, P. D. Bailey, G. Gallacher, K. A. Singleton, andP. M. Wallace,J. Chem. SOC., Chem. Commun., 1983, 1049. 89

General and Synthetic Methods

538

COz C H2 CC I 3

Me0

I

I

Boc iv - v i

(250) Reagents: i, Cl3CCHZO,CC1,NEt,, CHzC1,; ii, Me,O+BF,-; iii, PhC1, A; iv, BF,.OEt,; v, AcC1, DMAP, CH,Cl,; vi, NaBH3CN, AcOH, 50°C; vii, NaOH, THF; viii, C$,OH, DCC; ix, Zn, AcOH; x, DMAP, py

Scheme 8

Highlights in Total Synthesis of Natural Products

539

Wassermann and his c o - w o r k e r ~have ~ ? ~now ~ completed total syntheses of two members, i.e. (+)-verbaxenine (249) and (2)-chaenorhine (250), of the polyamine family of alkaloids. Their strategy is based on successive ring expansions of smaller lactam systems, and is illustrated in Scheme 8 for (&)-chaenorphine. Since the publication that compactin (251), a fungal metabolite of Penicillium brevicompactum, is a potent inhibitor of rat liver microsomal 3-hydroxy3-methylglutaryl CoA reductase, the rate-controlling enzyme in cholesterol biosynthesis, the molecule and its close relative mevinolin (252) have been the subjects of intense synthetic activity. During 1983 no less than three total syntheses of compactin and one of mevinolin were and several research groups have outlined approaches to the salient structural features found in these important molecules.98 There have been many outstanding examples of the chiral syntheses of natural products from carbohydrates published in the past few years. One particularly outstanding example however, is the short and efficient synthesis of (-)-shikimic acid (257) described by Fleet and his co-workers,w which uses the readily available mesylate (253) from D-mannose as starting material. Displacement of the mesylate with the phosphonate anion (254) first leads to the protected alcohol

(253)

(251) R = H

(252) R = Me 0 OH

OH

II

H. H. Wassermann and R. P. Robinson, Tetrahedron Lett., 1983,24,3669. H . H. Wassermann, R. P. Robinson, and C. G. Carter, J . Am. Chem. SOC., 1983, 105, 1697. 94 P. A. Grieco, R. E. Zelle, R. Lis, and J. Finn, J . Am. Chem. SOC., 1983, 105, 1403. 95 C. Hsu, N. Wang, L. H. Latimer, and C. J. Sih, J. Am. Chem. Soc.,1983,105,593. % N. N. Girotra and N. L. Wendler, Tetrahedron Lett., 1983, 24,3687. (n M. Hirama and M. Iwashita, Tetrahedron Lett., 1983, 24, 1811. 98 E.g. E. A . Deutsch and B. B. Snider, Tetrahedron Lett., 1983, 24, 3701. G. W. J. Fleet and T. K. M. Shing, J . Chem. SOC., Chem. Commun., 1983,849.

93

19

540

General and Synthetic Methoak

(255), which is then deprotected and deprotonated to produce the ring-opened intermediate (256). Intramolecular olefination, followed by deprotection, then completes this neat synthesis of shikimic acid. Other interesting natural products whose syntheses have been achieved during the period of the Report include the Laurencia-derived cyclic ethers (258) and (259),'O0 the fungal metabolite cryptosporiopsin (260) ,lol and the intriguing 1,6methano[ 101annulene (261) from the sponge Pleraplysilla spinifera. Io2

Br

(259)

HO

CI (260)

A. B. Holmes, C. L. D. Jennings-White, andD. A. Kendrick, J . Chem. SOC.,Chem. Commun., 1983, 415. Io1 G. B. Henderson and R. A. Hill, J . Chem. SOC.,Perkin Trans. 1, 1983,2595. I M J . A. Marshall and R . E. Conrow, J . Am. Chem. SOC., 1983,105, 5679. loo

Reviews on General Synthetic Methods COMPILED BY G. PATTENDEN AND G. M. ROBERTSON

1 Olefins

E. Block, ‘Olefin Synthesis by Deoxygenation of Vicinal Diols’, Org. React., 1984, 30, 457. W. J. Stec, ‘Wadsworth-Emmons Reaction Revisited’, Acc. Chem. Res., 1983, 16, 411. J. E. McMurry, ‘Titanium-Induced Dicarbonyl-Coupling Reactions’, Acc. Chem. Res., 1983, 16, 405. K. J. Ivin, ‘Olefin Metathesis’ Academic Press, New York, 1983. B. Giese, ‘Formation of CC Bonds by Addition of Free Radicals to Alkenes’, Angew. Chem., Int. Ed. Engl., 1983, 22, 753. W. Smadja, ‘ElectrophilicAddition to Allenic Derivatives: Chemo-, Regio-, and Stereochemistry and Mechanisms’, Chem. Rev., 1983, 83, 263.

2 Aldehydes and Ketones P. Brownbridge, ‘Silyl Enol Ethers in Synthesis-Part 1’,Synthesis, 1983,l; Part 11, ibid., p. 85. D. G. Morris, ‘Carbonyl Group Transpositions’, Chem. SOC.Rev., 1982,11,397. V. V. Kane, V. Singh, A. Martin, and D. L. Doyle, ‘The Chemistry of 1,2Carbonyl Transpositions’, Tetrahedron, 1983, 39, 345. J. K. Whitesell and M. A. Whitesell, ‘Alkylation of Ketones and Aldehydes via their Nitrogen Derivatives’, Synthesis, 1983, 517. D. J. Ager, ‘Silicon-containing Carbonyl Equivalents’, Chem. SOC.Rev., 1982, 11, 493. J. D. Albright, ‘Reactions of Acyl Anion Equivalents Derived from Cyanohydrins, Protected Cyanohydrins, and a-Dialkylaminonitriles’, Tetrahedron, 1983, 39, 3207. N. H. Werstiuk, ‘Homoenolate Anions and Homoenolate Anion Equivalents. Mechanistic Aspects and Synthetic Applications’, Tetrahedron, 1983, 39, 205. G. Consiglio and P. Pino, ‘Asymmetric Hydroformylation’, Top. Curr. Chem., 1982, 105, 77.

3 Carboxylic Acids A. J. L. Cooper, J. Z . Ginos, and A. Meister, ‘Synthesis and Properties of the a-Keto Acids’, Chem. Rev., 1983, 83, 321. S. R. Ramadas, P. S. Srinivasan, J. Ramachandran and V. V. S. K. Sastry, ‘Methods of Synthesis of Dithiocarboxylic Acids and Esters’, Synthesis, 1983, 605.

541

542

General and Synthetic Methods 4 Alcohols, Halogeno-compounds,and Ethers

W. Hartwig, ‘Modern Methods for the Radical Deoxygenation of Alcohols’, Tetrahedron, 1983, 39, 2609. B. R. Castro, ‘Replacement of Alcoholic Hydroxyl Groups by Halogens and Other Nucleophiles via Oxyphosphonium Intermediates’ , Org. React. , 1983, 29, 1. M. V. Mavrov, ‘Advances in the Chemistry of a-Haloallenes’,Russ. Chem. Rev., 1982, 51, 887. R. E. Bands, ‘Preparation, Properties and Industrial Applications of Organofluorine Compounds’, Wiley , New Jersey, 1982. M. V. Bhatt and S. U. Kulkarni, ‘Cleavage of Ethers’, Synthesis, 1983, 249.

5 Nitrogen-containingFunctional Groups R. B. Cheikh, R. Chaabouni, A. Laurent, P. Mison, and A. Nafti, ‘Synthesis of Primary Allylic Amines’, Synthesis, 1983, 685. M. B. Gasc, A. Lattes, and J. J. Perie, ‘Amination of Alkenes’, Tetrahedron, 1983, 39, 703. P. W. Hickmott , ‘Enamines: Recent Advances in Synthetic Spectroscopic, Mechanistic, and Stereochemical Aspects-11’ , Tetrahedron, 1982, 38, 3363. T. L. Gilchrist, ‘Nitroso-alkenes and Nitroso-alkynes’, Chem. SOC. Rev., 1983, 12, 53. J. 2. Witczak, ‘Synthesis and Preparative Applications of Monosaccharide Thiocyanates’ , Heterocycles, 1983, 20, 1435. V. G. Granik, ‘Advances in the Chemistry of Amidines’, Russ. Chem. Rev., 1983, 52, 377.

6 Organometallics General ‘Organometallic Chemistry Directed Toward Organic Synthesis’, ed. J. Tirouflet and M. Schlosser , Pure Appl. Chem., 1983,55, (11). D. W. Macomber, W. P. Hart, and M. D. Rausch, ‘Functionally Substituted Cyclopentadienyl Metal Compounds’, Adv. Organomet. Chem., 1983, 21, 1.

Transition Elements ‘Transition Metals in Organic Synthesis’, ed. R. Scheffold, Wiley-Interscience, New York, 1984. J.-E. Backvall, ‘Palladium in Some Selective Oxidation Reactions’, Acc. Chem. Res., 1983, 16, 335. B. Weidmann and D. Seebach, ‘Organometallic Compounds of Titanium and Zirconium as Selective Nucleophilic Reagents in Organic Synthesis’, Angew. Chem., Int. Ed. Engl., 1983,22, 31.

Reviews on General Synthetic Methods

543

M. T. Reetz, ‘Organotitanium Reagents in Organic Synthesis. A Simple Means to Adjust Reactivity and Selectivity of Carbanions’, Top. Curr. Chem., 1982,106, 3. R. S. Dickson, ‘Organometallic Chemistry of Rhodium and Iridium’, Academic Press, New York, 1983. D. Astruc, ‘Organo-Iron Complexes of Aromatic Compounds. Applications in Synthesis’, Tetrahedron, 1983,39,4027.

Boron and Thallium A. Suzuki, ‘Some Aspects of Organic Synthesis Using Organoborates’, Top. Curr. Chem., 1983, 112, 67. ‘Synthetic Reagents, Volume 5, Thallium(m) Acetate and Trifluoroacetate; Ammonia; Iodine Monochloride’, ed. J. S. Pizey , Wiley-Interscience, New York, 1983. 7 Ring Synthesis C. Santelli-Rouvier and M. Santelli, ‘The Nazarov Cyclization’, Synthesis, 1983, 429. R. J. Ferrier and P. Prasit, ‘Routes to Prostaglandins from Sugars’, Pure Appl. Chem., 1983, 55, 565. V. A. Mironov, A. D. Federovich, and A. A. Akhrem, ‘Synthetic Methods for Cyclohexa-1,3-dienes’, Russ. Chem. Rev., 1983, 51, 43. R. W. Alder, ‘Medium-Ring Bicyclic Compounds and Intrabridgehead Chemistry’, Acc. Chem. Res., 1983, 16, 321. L. N. Mander, ‘New Strategies for the Construction of Highly Functionalised Organic Molecules: Applications to CI9 Gibberellin Synthesis’, Acc. Chem. Res., 1983, 16, 48. J. Redpath and F. J. Zeelen, ‘Stereoselective Synthesis of Steroid Side-chains’, Chem. SOC.Rev., 1983,12,75. 8 Heterocycles A. S. Rao, S. K. Paknikar, and J. G. Kirtane, ‘Recent Advances in the Preparation and Synthetic Applications of Oxiranes’, Tetrahedron, 1983, 39, 2323. J. K. Crandall, and M. Apparu, ‘Base-Promoted Isomerizations of Epoxides’, Org. React., 1983, 29, 345. E. G. Lewars, ‘Oxirenes’, Chem. Rev., 1983, 83, 519. G. A. Iacobucci and J. G. Sweeney, ‘The Chemistry of Anthocyanins, Anthocyanidins and Related Flavylium Salts’, Tetrahedron, 1983, 39, 3005. G. L’abbe, ‘Some Ring Transformation Reactions of Sulphur-Containing Heterocycles’, Tetrahedron, 1982, 38, 3537. B. Iddon, ‘Cycloaddition, Ring-Opening and Other Novel Reactions of Thiophenes’, Heterocycles, 1983, 20, 1127. L. H. Klemm, ‘Synthesis of Tetracyclic and Pentacyclic Condensed Thiophene Systems’, Adv. Heterocycl. Chem., 1982, 32, 127.

General and Synthetic Methods

544

M. P. Sammes and A. R. Katritzky, ‘The 2H- and 3H- Pyrroles’, Adv. Heterocycl. Chem., 1982, 32, 234. S. M. Weinreb and R. R. Staib, ‘Synthetic Aspects of Diels-Alder Cycloadditions with Heterodienophiles’, Tetrahedron, 1982, 38, 3087. D. L. Boger, ‘Diels-Alder Reactions of Azadienes’, Tetrahedron, 1983,39,2869. I. Hermecz and Z. Meszaros, ‘Chemistry of Pyrido[ 1,2-a]pyrimidines’, Adv. Heterocycl. Chem., 1983, 33,242. A. Albert, ‘Annelation of a Pyrimidine Ring to an Existing Ring’, Adv. Heterocycl. Chem., 1982, 32, 3. V. K. Majectic and G. R. Newkome, ‘Pyridinophanes, Pyridinocrowns, and Pyridocryptands’, Top. Curr. Chem., 1982, 106, 79. V. Ballah, R. Jeyaraman, and L. Chandrasekaran, ‘Synthesis of 2,6-Disubstituted Piperidines, Oxanes and Thianes’, Chem. Rev., 1983, 83,379. R. Rastogi and S. Sharma, ‘2-Aminobenzimidazoles in Organic Synthesis’, Synthesis, 1983, 861. S.-J. Lee and J. M. Cook, ‘Synthesis of Azaphenalenes’, Heterocycles, 1983,20, 87. B. Robinson, ‘The Fischer Indole Synthesis’, Wiley-Interscience, New York, 1982. W. W. Paudler and R. M. Sheets, ‘Recent Developments in Naphthyridine Chemistry’, Adv. Heterocycl. Chem., 1983, 33, 147. J. P. Freeman, ‘A4-Isoxazolines(2,3-Dihydroisoxazoles)’,Chem. Rev., 1983,83, 241. F. Kurzer, ‘1,2,4-Thiadiazoles’, Adv. Heterocycl. Chem., 1982, 32, 286. M. H. Elnagdi, H. A. Elfahham, and G. E. H. Elgemeie, ‘Utility of a$Unsaturated Nitriles in Heterocyclic Synthesis’, Heterocycles, 1983, 20, 519. 9 Electrochemical Methods M. M. Baizer and H. Lund, ‘Organic Electrochemistry’, 2nd Ed., Marcel Dekker, New York, 1983. J. S. Swenton, ‘Quinone Bis- and Monoketals via Electrochemical Oxidation. Versatile Intermediates for Organic Synthesis’, Acc. Chem. Res., 1983,16,74. 10 Photochemical Methods

G. G. Wubbels, ‘Catalysis of Photochemical Reactions’, Acc. Chem. Res., 1983, 16, 285. W. H. Laarhoven, ‘Photochemical Cyclizations and Intramolecular Cycloadditions of Conjugated Arylolefins’, Recl.: J. R . Neth. Chem. SOC.,1983,102,185. P. S. Marian, ‘The Photochemistry of Iminium Salts and Related Heteroaromatic Systems’, Tetrahedron, 1983,39.3845. F. B. Mallory and C. W. Mallory, ‘Photocyclization of Stilbenes and Related Molecules’, Org. React., 1983, 30, 1. H. Rau, ‘Asymmetric Photochemistry in Solutions’, Chem. Rev., 1983, 83, 535. M. A. Fox, ‘Organic Heterogeneous Photocatalysis: Chemical Conversions Sensitized by Irradiated Semiconductors’, Acc. Chem. Res., 1983, 16, 314.

Reviews on General Synthetic Methods

545

R. G. Salomon, ‘Homogeneous Metal-Catalysis in Organic Photochemistry’ , Tetrahedron, 1983, 39,485. W. H. Laarhoven, ‘Photochemical Cyclizations and Intramolecular Cycloadditions of Conjugated Arylolefins. Part 2: Photocyclizations without Dehydrogenation and Photocycloadditions’, Rec. : J . R. Neth. Chem. SOC., 1983,102,241. A. G. Schultz, ‘Photochemical Six-Electron Heterocyclization Reactions’, Acc. Chem. Res., 1983, 16,210. S. T. Reid, ‘The Photochemistry of Oxygen- and Sulphur-Containing Heterocycles’, Adv. Heterocycl. Chem., 1983, 33, 1.

11 Peptide Synthesis V. N. R. Pillai, ‘New Perspectives in Polymer-Supported Peptide Synthesis’, Top. Curr. Chem., 1982, 106,119. S. V. Vurov and M. P. Smirnova, ‘Protection of the Amino Group in Peptide Synthesis’, Russ. Chem. Rev., 1982, 51, 902.

12 Asymmetric Synthesis K. B. Sharpless, C. H. Behrens, T. Katsuki, A. W. M. Lee, V. S. Martin, M. Takatani, S. M. Viti, F. J. Walker, and S. S. Woodward, ‘Stereo- and Regioselective Openings of Chiral 2,3-Epoxy Alcohols. Versatile Routes to Optically Pure Natural Products and Drugs. Unusual Kinetic Resolutions’, Pure Appl. Chem., 1983,55, 589. H. Haubenstock, ‘Asymmetric Reductions with Chiral Complex Aluminium Hydrides and Tricoordinate Aluminium Reagents’, Top. Stereochem., 1983, 14,213. M. Nakazaki , ‘The Synthesis and Stereochemistry of Chiral Organic Molecules with High Symmetry’, Top Stereochem., 1984, 15, 199. S. Hanessian, ‘Synthetic Design with Chiral Templates’, Pergamon Press, Elmsford, N.Y. , 1983. E. I. Klabunovskii, ‘Advances in Enantioselective Hydrogenation in the Presence of Chiral Complexes of Rhodium, Palladium, and Cobalt’, Russ. Chem. Rev., 1982, 51,630. S. W. Knowles, ‘Asymmetric Hydrogenation’, Acc. Chem. Res., 1983, 16, 106. H. G. Floss and M.-D. Tsai, ‘Stereochemistry of Biological Reactions at Proprochiral Centres’, Top. Stereochem., 1984, 15, 253. T. Hayashi and M. Kumada, ‘Asymmetric Synthesis Catalysed by TransitionMetal Complexes with Functionalised Chiral Ferrocenylphosphine Ligands’, Acc. Chem. Res., 1982, 15,395. S. Masamune and W. Choy, ‘Advances in Stereochemical Control: The 1,2- and 1,3-Diol Systems’, Aldrichimica Acta, 1982, 15, 47. G. Quinkert and H. Stark, ‘Stereoselective Synthesis of Enantiomerically Pure Natural Products’, Angew. Chem., Int. Ed. Engl., 1983, 22, 637.

546

General and Synthetic Methods

C. H. Behrens, ‘New Transformations of 2,3-Epoxy Alcohols and Related Derivatives. Easy Routes to Homochiral Substances’,Aldrichimica Acta, 1983, 16, 67. 13 General ‘The Total Synthesis of Natural Products, Volume 5, Sesquiterpenes’, ed. J. ApSimon, Wiley-Interscience, New York, 1983. R. B. Bates and C. A. Ogle, ‘Carbanion Chemistry’, Springer-Verlag,New York, 1983. L. Rossa and F. Vogtle, ‘Synthesis of Medio- and Macrocyclic Compounds by HiLh Dilution Principle Techniques’, Top. Curr. Chem., 1983, 113, 1. P. Caubkre, ‘Complex Reducing Agents (CRA’s) - Versatile, Novel Ways of Using Sodium Hydride in Organic Synthesis. [New Synthetic Methods (39)], Angew. Chem., Int. Ed. Engl., 1983, 22, 599. D. Ginsburg, ‘The Role of Secondary Orbital Interactions in Control of Organic Reactions’, Tetrahedron, 1983, 39, 2095. S. Warren, ‘Organic Synthesis: The Disconnection Approach’, Wiley , New Jersey, 1982. E. Stahl, ‘A Quarter Century of Thin-Layer Chromatography - An Interim Report’, Angew. Chem., Int. Ed. Engl., 1983, 22, 507. P. J. Strong and M. R. White, ‘Triflic Acid and its Derivatives’, Aldrichimica Acta, 1983, 16, 15. J. Ackroyd and F. Scheinmann, ‘The Synthesis of Leukotrienes: A New Class of Biologically Active Compounds Including SRS-A’, Chem. SOC. Rev., 1982,11, 321. R. H. Green and P. F. Lambeth, ‘Leukotrienes’, Tetrahedron, 1983, 39, 1687. P. Cmagne, J. Elguero, and R. Gallo, ‘The Present Use and the Possibilities of Phase Transfer Catalysis in Drug Synthesis’, Heterocycles, 1983, 20, 1379. U. E. Wiersum, ‘Flash Vacuum Thermolysis, A Versatile Method in Organic Chemistry. Part 11, Fragmentation Patterns in Specific Classes’, Recl.: J . R. Neth. Chem. SOC., 1982, 101, 365. F. Minisci, A. Citterio, and C. Giordano, ‘Electron-Transfer Processes: Peroxydisulphate, a Useful and Versatile Reagent in Organic Chemistry’,Acc. Chem. Res., 1983, 16,27. R. M. Adlington and A. G. M. Barrett, ‘Recent Applications of the Shapiro Reaction’, Acc. Chem. Res., 1983, 16, 55. T. H. Black, ‘The Preparation and Reactions of Diazomethane’, Aldrichimica Acta, 1983, 16, 3. L. Stella, ‘Homolytic Cyclization of N-Chloroalkenylamines [New Synthetic Methods (38)]’, Angew. Chem., Int. Ed. Engl., 1983, 22, 337. A. Zamoiski, A. Banaszek, and G. Grynkiewicz, ‘The Synthesis of Sugars from Non-Carbohydrate Substrates’, Adv. Carbohydr. Chem. Biochem., 1982, 40, 1. G . M. Whitesides and C.-H. Wong, ‘Enzymes as Catalysts in Organic Synthesis’, Aldrichimica Acta, 1983, 16, 27. J. Retey and J. A. Robinson, ‘Stereospecificity in Organic Chemistry and Enzymology’, Volume 13, Verlag Chemie, Deerfield Beach, FL. , 1982.

Reviews on General Synthetic Methods

547

14 Miscellaneous

S. A. Narang, ‘DNA Synthesis’, Tetrahedron, 1983,39,3. H. J. Sigel, ‘Lithium Halocarbenoids. Carbanions of High Synthetic Versatility’, Top. Curr. Chem., 1982, 106,55. A. P. Croft and R. A. Bartsch, ‘Synthesis of Chemically Modified Cyclodextrins’,

Tetrahedron, 1983, 39, 1417. G. (3. Yakobson and N. E . Akhmetora, ‘Alkali Metal Fluorides in Organic Synthesis’, Synthesis, 1983, 169. K. B. Beckers, ‘Synthesis of Stilbenes’, Synthesis, 1983, 341. W. H. Okamura, ‘Pericyclic Reactions of Vinylallenes: From Calciferols to Retinoids and Drimanes’, Acc. Chem. Res., 1983, 16, 81. B. B. Jarvis and E. P. Mazzola, ‘Macrocyclic and Other Novel Trichothecenes: Their Structure, Synthesis and Biological Significance’, Acc. Chem. Res., 1982, 15, 388. H.-J. Timpe and A. V. El’tsov, ‘Pseudoazulenes’, Adv. Heterocycl. Chem., 1983, 33, 185. E . F. V. Scriven, ‘4-Dialkylminopyridines: Super Acylation and Alkylation Catalysts’, Chem. Soc. Rev., 1983, 12, 129.

Author Index

Abe, N., 144 Abe, Y., 190 Abecassis, J . , 62 Aben, R. W. M., 410 Abou-Gharbia, M., 449 Aboujaoude, E. E., 113 Aburaki, S., 348, 527 Acevedo, 0. L., 487 Achiwa, K., 194,460 Acquaah, S. 0 ., 470 Acs, T., 485 Adam, G., 302,478 Adam, M. A. 359 Adam, W., 412 Adamczyk, M., 137,291 Adams, B. R., 38,358,405 Adkins, R. L., 86 Adlington, R. M., 110, 192, 308,345,491 Aebi, J. D., 136, 340 Aebischer, B., 298 Afzali, A , , 235 Agawa, T., 4, 51, 107, 146 Ager, D. J., 90,344 Aggarwal, S. K . , 280 Agho, M. O., 432,433 Agoh, B., 448 Agosta, W. C., 303 Ahlbrecht, H., 96,155,419 Ahn, K. H., 232 Aizpurua, J. M., 84,227 Akiba, K., 170,373, 418 Akiba, M., 520 Akimoto, K., 531 Akita, M., 8,50, 107,221, 317,326 Akita, T., 198 Akiyama, S., 239 Akiyama, Y., 155 Akkemann, S., 382 Akoi, M . , 505 Akssira, M., 43, 178 Alabori, S., 239 Alazard, J.-P., 426 Albaugh-Robertson, P., 162 Albright, J. D., 91, 289 Albright, J. O., 63 Alder, R. W., 483 Alexakis, A., 32, 58, 59,103, 129,233,333,404 Alexander, R. P., 123, 148 Alfonsi, C., 421 Al-Hassan, M. I., 47, 90,363 Allen, K. M., 440

Allmann, R., 489 Alneri, E., 407 Alonso, M. E., 421 Alonso-Cires, L., 144,220 Alpegiani, M., 494 Alper, H., 2 , 4 , 41, 86, 132, 138, 140,150,237, 335,488 Alvarez, A., 407 Alverez, M.. 264 Alvernhe, G., 480 Amaratunga, W . , 88 Ameer, F., 148 Amer, I., 4 Ammanamanchi, K., 247,339 Amos, R. A., 144 Amupitan, J . O., 190, 282 Anciaux, A. J., 146 Anderson, D. K., 510 Anderson, J. S .,295 Anderson, K. W. 367 Anderson, 0. P., 182 Anderson, R. C., 537 Anderson, S. H., 219 Ando, K., 51, 108 Ando, M., 120,193, 256,477 Ando, R., 149,379,382 Ando, T., 10,20, 21,84, 117, 226,293,372 Ando, W., 128,301 Andrews, D. R., 401 Andrieux, J . , 302,478 Andriollo, A , , 8 Aneja, R., 143 Angeletti, E., 11, 371 Angermann, A , , 136 Angus, R. O., 393 Annis, G. D., 334, 391, 488, 497 Annunziata, R., 128,137, 186, 341,349 Anton, D. R., 10, 233 Antonioletti, R., 408 Aoe, K., 184 Aquadro, R. E., 204 Arai, I., 197 Araki, Y., 394 Arase, A., 76 Arcadi, A . , 130 Archibald, T. G . , 411 Arct, J . , 417 Arimoto, M., 33,103, 175 Arison, B. H., 197,451 Aristoff, P. A., 6, 388 Arita, Y . , 62

548

Ariyoshi, K., 86,227 Armstrong, R. J . , 399 Arrhenius, P., 398 Arrieta, A., 144, 283, 307 Arseniyadis, S., 50, 344, 465 Arvanaghi, M., 121,247,290, 293,307, 366 Arya, P. S . , 220 Arzoumanian, H., 232 Asai, N., 117, 351 Asami, K., 324 Asami, M., 112, 144, 173, 382 Asaoka, M., 507 Asato, A. E., 83 Asensio, G., 144,220, 261 Ashcroft, P. L., 298 Aslam, M., 60 Assercq, J.-M., 411 Atherton, E., 198 Attanasi, O., 122, 283 Attia, A., 253 Atwal, K. S., 172 Aubouet, J . , 129 Auge, J . , 409 Avery, M. A., 536 Awad, S. B., 407 Ayaguchi, Y., 8 Ayi, A. I., 194 Ayyangar, N. R., 245 Aznar, F., 265, 267, 302 Azuhata, T., 147 Azuma, K., 222 Baba, A., 452 Baba, O., 428 Baba, T., 93 Babiak, K. A., 532 Babin, P., 388 Babler, J. H., 206 Baboulene, M., 199, 269 Babudri, F., 153 Baca, S. B., 135 Bachi, M. D., 495 Back, T. G., 115 Backvall, J. E., 268, 315,321 Badot, O., 274 Badoud, R., 537 Baettig, K., 159 Bauml, E., 66 Bagheri, V., 89,169,227, 333, 351 Bailey, P. D., 276, 537 Baillargeon, V. P., 93, 156, 234,333

Author Index Baioni, V., 449 Baird, G . J., 324, 325 Baizer, M. M., 87 Bajgrowicz, J. A., 192 Bajwa, B. S . , 311 Bajwa, J. S . , 136 Baker, R., 85, 435 Baker, R. J . , 181 Baker, W. R., 260 Bakker, C. G., 174 Bal, B. S . , 121 Balabane, M., 268 Baldwin, J. E., 110, 192, 276, 294,308,447, 496, 537 Baldwin, J. J . , 451 Baliah, V., 472 Bali Singh, B., 122 Balkovec, J . M., 163, 174,405 Ballabio, M., 448 Ballesteros, P., 41 Ballini, R., 4, 113, 213,226, 235,298 Balme, G., 122 Bamezai, S., 295 Ban, T., 64, 393 Ban, Y . , 175,467,476,485 Bandy, J . A . , 325 Banfi, L., 112,155,215 Banfi, S . , 112,206,407 Bankaitis, D. M., 426, 435 Banks, B. J., 276 Banwell, M. G., 157 Baraldi, P. G., 158, 265, 501 Barbarella, G., 388 Barber, Y. J . , 135 Barbier, P., 176 Barbot, F., 122, 188 Barco, A., 158, 501 Barker, A. J . , 502 Barker, R.,358 Barlos, K . , 198 Barluenga, J., 18, 144, 187, 219,220,261,262,265,267, 282, 302,549 Barner, B. A,, 435 Barnes, J. F., 298 Barr, N., 336 Barrett, A. G. M . , 276, 345, 489,491 Barriere, J. C., 384 Barrish, J . C., 200, 353 Barrow, M. J., 298 Barry, C. N., 228, 409,413 Barth, J . , 192 Barthels, R., 198 Bartlett, P. A . , 53 Bartnik, R., 454, 455 Barton, D. H. R., 1,23, 87, 142,232,251 Bartsch, H. 289 Bartsch, R . A . , 232,241,243 Baruah, J. N., 8, 121,226, 228 Baruah, N. C., 226,228 Baruah, R. N., 8,226

549 Basak, A., 192,387 Basavaiah, D., 75, 109,356 Bashiardes, G., 23,232 Batmangherlich, S., 415 Battig, K., 404, 502 Battiste, M. A . , 173 Batu, G., 117 Bauer, D. P., 193 Bauer, L. J . , 244 Bauer, P. E., 167, 344 Baum, K., 411 Baxter, A. D., 522 Bayod, M., 267 Bayon, A. M., 261 Baze, M. E., 72 Beak, P., 188,261,264, 391, 468 Beau, J.-M., 348, 527 Beauchamp, P. D., 65 Beaulieu, P. L., 172, 378 Beaumont, D., 253 Becker, A. M., 247 Becker, K. B., 7 Becker, P. N., 316 Beckwith, A. L. J., 4,232, 389,490 Bedeschi, A., 494 Bednarski, M., 428,429 Beebe, T. R., 86 Beeley, N. R. A., 296 Beeman, D., 13 Beguin, C. G., 133 Behnke, M., 56 Behr, A , , 285 Bell, A. P., 239 Bell, T. W., 244 Bellassoued, M., 139, 301,456 Belleau, B., 194 Belletire, J. L., 11, 12, 144 Belli, A., 140 BelluS, D., 236 BeMiller, J. N., 283 Benetti, S., 158, 501 Benezra, C., 176 Ben-Ishai, D., 173 Benneche, T., 235 Benner, S. A., 133 Bennetau, B., 366 Benoiton, N. L., 191 Bergbreiter, D. E . , 269, 303 Berger, G. D., 487 Bergman, R. G., 316 Bergmann, A , , 474 Berkowitz, P. T., 411 Berlan, J., 129 Bernad, P., 18,349 Bernadi, R., 431 Bernardinelli, G., 133 Bernardini, A . , 192 Bernath, G., 453 Bernauer, K., 193 Bernet, B., 272 Bernheim, M., 75,270 Berryhill, S. R., 334

Bertani, R., 8 Berthet, M., 243 Berti, C., 301 Bertrand, M . , 116, 235 Bertz, S. H., 122 Beslin, P., 166 Besselievre , R . , 288 Bestmann, H. J., 72,94,184 187 Betancor, C., 468 Betts, M. J., 345,489,491 Beugelmans, R., 457 Bevinakatti, H. S . , 189, 298 Bhat, N. G., 75, 109,356 Bhat, S. V., 311 Bhatnagar, S. P., 122, 253 Bhatt, M. V . , 225 Bhattacharya, A., 151,349 Bhupathy, M., 524 Bibang Bi Ekogha, C., 33, 107, 342 Bickelhaupt, F., 382 Bidd, I . , 138 Bigi, F., 150,359,421 Billedeau, R. J., 189 Biller, S. A., 177 Billington, D. C., 100 Bills, L. J . , 241 Biloski, A. J., 300 Binger, P., 386 Bioul, J. P., 285 Birch, A. M., 500 Bishop, C . E., 64 Bishop, P. M . , 400 Biswas, A., 491 Blanchard, M., 391 Blandy, C., 306 Blarer, S. J., 150 Bloch, R., 34,62, 221,376 Block, E., 60 Blum, J . , 4 Bluthe, N., 56 Boardman, L. D., 30, 384 Boaventura, M., 406 Boche, G., 75,270 Bock, M. G., 193,279 Bodarski, R., 39,99, 398 309 Boden, N., Boeckmann, R. K., jun., 120, 394,396,426,510 Bolcskei, H., 485 Bonnemann, H., 86 Boes, M . , 193,340 Boettig, K., 133 Bogardus, C. C., 86 Bogdan, S . , 493 Boger, D. L., 302,473 Boldrini, G. P., 153,216,245 Bonde, S. E., 16,349 Bonin, M . , 288 Bonjouklian, R., 352,496 Booth, P. M., 125,181 Borchardt, R. T., 4, 180,297 Bordeleau, L., 378

550 Born, W., 6 Bosch, J., 466 Bosch, R. J. 381 Bosma, R. H. A., 57,287 Bottaro, J . C., 110,308 Boukouvalas, J., 440 Boulanger , W., 65 Boussac, G. 418 Bowen, P., 179 Bowers-Nemia, M . M . , 452 Bowser, J. R., 185,280 Boyer, J., 159 Boyes, R. H. O., 435 Bradbury, R . , 298 Bradshaw, J . S., 234,239 Brady, W . T . , 432,433 Branchaud, B. P., 303 Brandange, S., 3 Brandsma, L., 64,238,265, 347 Braun, M., 136,212 Braverman, S . , 375 Bravo, P., 431 Brayer, J . - L . , 426 Breitmaier, E., 104 Bremmer, M. L., 302,473,514 Breiia, L. J . , 185 Brennan, J., 494,496 Brickner, S. J . , 183 Bridges, A . J., 36, 64,218, 344,374 Bringmann, G., 283 Brinkman, A . , 386 Broadhurst, M. J . , 112 Bronneke, A . , 169 Brook, M. A . , 120,144,187, 282,365 Brookes, M. H., 224 Brookhart, M., 319,381 Brooks, G., 495 Broom, D. M. P., 435 Brown, A. M., 491 Brown, D. W., 288 Brown, E., 134 Brown, H . , 94, 357 Brown, H. C., 3,53,75,91, 109,200,232,353,354,355 356 Brown, J . M., 112 Brown, K. C., 295 Brown, L., 224 Brown, P. J . , 374 Brown, P. R., 239 Brown, R. F. C., 247 Brownbridge, P., 123,162 Browne, E. J., 452 Bruggemann, K., 474 Brugidou, J . , 186 Brun, P . , 68 Brunet, J.-J., 132, 140 Brunner, H . , 319,381 Bucciarelli, M., 211, 448 Buchholz, M . , 196 Buchwald, S. L., 69

General and Synthetic Methods Buckley, T.F.,111, 479 Budny, J., 157 Buchi, G., 56 Butikofer, P.-A., 82 Buhr, C. A . , 155 Buijs, W., 228 Bulman-Page, P. C., 121 Bunce, R. A . , 99, 128,149, 224,396 Burbaum, B. W., 394 Burford, C., 409 Burger, U., 440 Burk, R. M., 462, 515 Burkard, U., 192 Burke, S., 501 Burke, S . D., 165,394 Burks J . , 376 Burns, T. P., 350 Burton, D. J., 20,371,372 Bushan, V . , 227 Bushby, R. J., 309 Buss, A. D., 12,370 Butula, I., 197 Byrboth, B., 163 Byrn, S., 340,522 Cabeza, J . A . , 196,312 Cacchi, S., 130,476 Caine, D., 179 Cainelli, G., 134, 228, 245, 384 Caldwell, C. G., 393 Callan, G. R., 355 Calverley, M . J . , 261 Calvitti, S., 421 Cambie, R. C., 309 Campbell, A. L., 532 Campbell, S., 425 Campos, P. J . , 144, 220 Camps, F., 228, 408 Canonne, P., 43, 178 Caporusso, A. M . , 109 Capuano, L., 421 Cardillo, G., 223,224,270 Carini, D. J., 387 Cariou, M . , 291 Carlson, J. G., 400, 507 Carlson, R. M . , 44, 182 Carman, M . , 197 Carniato, D., 107 Carpino, L. A., 197 Carr, R. V. C., 376, 392 Carroll, G. L., 500 Carruthers, W., 335,477 Carson, J . F., 197 Carter, C. G., 487,539 Carter, M. C., 211 Carturan, G., 8 Casadei , M. A. , 303 Casamor, J. M . , 228 Casares, A . M., 56, 57 Casati, R . , 85, 227 Cascaval, A . , 264 Casiraghi, G., 150, 359, 421 Casnati, G., 150, 359, 421

Cassani, G., 59,233,356 Castaldi, G., 140 Castedo, L., 300 Castro, B., 113,197,279 Castro, B. R., 228 Cate, L. A. 141 Catellani, M . , 132 Cativiela, C., 194, 196, 312 Caubere, P., 132, 140 Caubi&re,P., 204 Cava, M. P., 285 Cavalla, D., 50,188,281,370 Cazeau, P., 274 Cazes, B., 53,218 Cebulska, Z . , 455 e ef elin, P., 233 CBlkrier, J. P . , 45, 163, 266 Cella, J. A . , 119, 139 Cenini, S., 309 Cha, J. K . , 201 Chabaud, B . , 122,371 Chackalamannil, S., 397 Chadha, M. S., 524 Chakraborti, A. K., 147 Chakraborty, T. K., 227 Chakravarty, P. K., 175 Chaly, T., 120, 365 Chamberlin, A. R., 171,463, 516 Champney , B ., 8 6 Chan, D. M. T., 388 Chan, M. F., 496 Chan, T. H., 120, 144, 187, 208,282,361,365,366,382 Chandler, M . , 143 Chandrasekaran, L., 472 Chandrasekaran, S., 227,245 Chandrasekharan, J., 200 Chang, H., 197 Chang, T. C. T., 176,319 Chao, S . , 473 Chapleur, Y . , 536 Chapman, D .,56 Chapuis, C . , 504 Charles, G., 262 Charusin, V. N., 253 Chatani, N., 26,93, 159 Chatterjee, A . , 280 Chatterjee, S., 24,89,125, 333,351 Chatzhosifidis, I., 284 Chauhan, S.M. S . , 300 Chauvin, J . , 199 Chawla, H. P. S . , 8 Chen, B., 269 Chen, C. H., 81 Chen, C.-W., 188,264,391 Chen, F. M. F., 191 Chen, S. F., 304, 460 Chen, Y . , 473 Chen, Y.-Q., 399,508 Chen, Y.-Y., 367,457,460 Chhevert, R . , 121,239,287, 290

Author Index Cheng, C. H., 197 Cheng, Y.-S., 473 Cheon, S. H., 510 Chianelli, D., 237 Chiba, K., 175 Chiba, M., 94, 156 Chiba, T., 4 Chida, Y., 254 Chihara, T., 122 Chiharu, M . , 254 Chikashita, H., 285 Chiriac, C. I., 280, 283 Chiusoli, G . P., 132 Choi, V. M. F., 290,366 Chong, J. M., 368 Chorn, T. A., 432 Chou, C. S . , 85,227 Chou, T.-S. 88 Choudhry, S. C., 536 Choukroun, R., 306 Chowdhury, P. K., 121,226 Choy, E., 394 Choy, W., 394 Christ, W. J., 201 Christensen, B. G., 493 Christensen, J. J . , 239 Christol, H., 64, 393 Chtara, R., 301,456 Chu, D. T. W., 86,373 Chuang, C. P. 389 Chucholowski, A,, 168,340 Chuit, C., 32, 127 Chung, J. Y. L., 463,516 Chung, S. K., 151,381 Cichowicz, M. B., 147,226 Cilento, G., 412 Cinquini, M., 128, 137, 186, 341,349 Citterio, A . , 125 Claesson, A , , 58,69, 349 Clardy, J., 172 Clark, L. D., 309 Clauson, K . , 194 Clennan, E. L., 439 Cleophax, J., 384 Clerici, A., 224 Clive, D. L. J., 172,378 Coates, D., 224 Coates, P. M . , 204 Coates, R. M . , 109 Coburn, C. E . , 510 Cockerill, G. S., 400,441 Cohen, T., 524 Colin, J. L., 147 Coll, J., 228, 408 Collignon, N., 113 Collington, E. W., 522 Collins, P., 170 Collins, S., 115 Collum, D. B., 169 Colombo, L., 128,155,215, 341 Colombo, R., 197 Colonna, S., 112,206, 407

55 1 Comins, D. L., 532 CommerGon, A., 491 Commeyras, A., 186 ConceUbn, J. M . , 18,349 Concepcion, J . I. , 468 Confalone, P. N., 191 Conia, J. M . , 406 Connell, A. C., 68 Conrow, R. E . , 540 Consiglio, G . , 18, 196, 236, 321,349 Contento, M . , 134,228 Cook, C. E., 440 Cooke, F., 409 Cooke, M. D., 493 Cooke, M. P., jun., 145 Cooper, C. S . , 300 Cordopatis, P., 198 Cordova, R., 430 Corey, E. J., 63,76, 142,204, 211, 342,365, 377, 389,408, 523 CornClis, A., 237, 296 Cornish, C. A., 370 Corriol, C., 226 Corriu, R. J. P., 32,127, 159 Cortes, D. A., 85,227 Cortes, S . , 262 Cory, R. M., 455 Cossec, B., 192 Cossement, M . , 493 Cossy, J., 376 Cottrell, D. A., 190, 282 Coudert, G., 443 Courtney, L., 537 Cousse, H., 235 Cowan, P. J., 117,138 Cox, D. G., 20, 371 Coxon, J. M . , 217 Cozens, A. J . , 259,309 Cozzi, F., 128,137,186,341, 349 Crabtree R. H,, 10,233, 312 Cram, D. J . , 243,244 Craven, B. M., 394 Crawford, R. J . , 133 Cremner , G., 296 Crich, D., 1, 142 Crimmins, M. T., 426,435 Cristan, H.-J., 64,122, 371, 393 Croce, P. D., 448 Croft, A. P . , 232 Crombie, L., 487 Crosby , J . ,298 Croteau, A. A., 31, 105 Crouse, G . D., 392 Crow, W. D., 454 Csehi, A., 197,204 Cumming, S. A., 335,477 Cummins, C. H., 109 Cunningham, A. F., 224 Cupps, T. L., 291 Curran, D. P., 96, 219,418

Cutolo, M . , 195,266 Cutting, I., 67,72, 105, 167, 221,238,361,375 Cuvigny, T., 57,313, 376 Czech, A., 243 Czech, B., 241,243 Czyzewska, E., 70 Dabbagh, G., 122 Dabbas, N., 309 Dahlman, O., 3 Dahmen, W., 418 Dampawan, P., 113, 298 Dan, S., 515 Dandoize, F., 456 Danelli, R., 384 D’Angeli, F., 449 d’Angelo, J., 117, 219, 391 Danheiser, R. L., 382, 387 Danishefsky, S., 272, 351, 378, 397,428,429,465, 530 Danishefsky, S. J., 436 Dannenberg, W., 43,157 Danon, L., 213 Danopoulos, A. A., 309 Dao, T. V., 204 Darzoide, F., 301 Das, S . , 226 Dashan, L., 339 Daub, J. P . , 439 Dauben, W. G., 99, 128, 149, 224, 356 D’Auria, M . , 408 Dauzonne, D., 295 Daves, G. D., 332 David, S., 230, 409 Davidson, A. H., 415 Davies, A. P., 143 Davies, D. E., 299, 450 Davies, H. M. L., 164 Davies, J., 522 Davies, S. G., 236,312,324, 325,327 Davies, F. A., 407 Davis, J. T., 92, 160,329, 394, 472 Davis, M. W., 312 Davis, W. A., 285 Dawson, B. A., 390,497 Dawson, M. J., 211 Dean, F. M., 431 Debaerdemaeker, T., 489 De Bernardinis, S . , 125 De Buyck, L., 114, 262,303, 456 de Castro Dantas, T. N., 269 De Cicco, G. J., 83 Decker, 0. H. W., 139 De Clerq, P. J . , 394 Dederichs, E., 418 Deep, K . , 453 Degani, I . , 237 Deitsch, E. A., 394 dc Jong, R. L. P., 347

General and Synthetic Methods

552 Dekerk, J. P., 308 Deketele, M . , 308 De Kimpe, N., 114,262,303, 456 de Koning, H., 462 De las Heras, F. G., 283 Delaumeny, J. M., 251 Delaunay , B .,448 Delmas, M . , 12 Delmazza, D., 445 Delorme, D., 536 Delpuech, J. J., 249 De Luca, 0 . D., 204 De Lucca, G., 226 Dedmailly, G., 536 Demerseman, P., 294 De Mico, A . , 408 Demonceau, A., 146 Denis, J. N., 2, 232 Denmark, S. E., 98,114,387 Denny, M., 83 Depaye, N., 237 Deprks, J.-P., 315, 390,497 Derome, A. E., 294 des Abbayes, H., 140 Desai, R. C., 229 Deschenaux, R . , 193 Deshayes, C., 300 DeShong, P., 525,529 Deshpande, R. P . , 121 Deshpande, S. R., 295 De Silva, D., 483 De Silva, S. O., 188,478 Desmond, R., 57 Desobry, V., 322 de Souza, N. J., 311 Despeyroux, B., 132, 150 Desportes, S. H., 294 Dess, D. B., 85,226 Deutsch, E. A . , 219, 358,398, 539 Dev, S . , 8, 121, 377 Devant, R., 136 devi Manandhar, M., 379 Devlin, J. A,, 358, 435 De Vos, M. J., 372 Dewanckele, J. W., 501 Dewynter, G., 448 Deyo, D., 151,349 Deziel, R ., 378 Dezube, M . , 171 Dhaon, M. K., 199 Dhawan, B ., 244 Dhingra, 0. P., 536 Diaz de Villegas, M. D., 194, 196,312 Dieter, J. W . , 377 Dieter, R. K., 104, 377,433 Di Giamberardino, T., 379 Dillon, J. L., 382 Di Ninno, F., 493 Di Nunno, L., 153 Dion, R. P . , 471 Di Pardo, R. M., 193,279

Di Rienzo, B .,303 Disanayaka, B. W., 102 Dittami, 3. P . , 461 Dodsworth, D. J., 478 Doedens, R. J., 304,462 Dopp, D., 289,445 Dojo, H., 22,34,105,231, 356 Dombi, G., 453 Donaldson, R. E ., 340,522 Doney, J. J., 81 Dorlhene, A . , 296 Dorme, R., 121 Dorsch, D., 148 Douglass, J. G., 111, 417 Doutheau, A., 385 Dow, R. L., 169,227 Doyle, D. L., 98 Doyle, M. P., 164, 169,227, 311 Doyle, T. W . , 303 Draper, R . W., 307 Dreiding, A. S . , 402 Drewes, S. E . , 148 Drovin, J., 406 Duar, T., 375 Dubey, S. K . , 271 Dubodin, F., 274 Dubois, J.-E., 117 Duc, G., 64,393 Diiber, E.-O., 96 Duffley, R. P., 274 Duflos, A., 235 Dugast, J.-Y., 117 Dugat, D., 496 Duggan, M. E., 373 Duggan, P . J., 64 Duguay, G . , 492 Duhamel, L . , 111, 118, 119, 156,265 Duhl-Emswiler, B. A., 476 Dulcere, J.-P., 116, 235 Dumas, F., 154, 219 Dumont, W . , 379 Dunlap, N. K., 182 Dunn, L. B., jun., 151,381 Dunogues, J . , 366, 388 du Penhoat, C. H . , 376 Dupre, B., 96 Durman, J., 31, 104, 162,377 Dussault, P., 171 Duthaler, R. O., 295 Dyke, S. F., 336 Dzhemilev, U. M., 231 Earl, R. A., 336 Early, W. G., 519 Easton, C. J . , 490 Eaton, G., 143 Eaton, P. E., 348 Ebihara, R., 295 Ebine, S., 239 Echegoyen, L., 243 Eckrich, T. M., 211,342 Edwards, M. P., 536

Effenberger, F., 192 Eguchi, S . , 302,484, 485 Ehrmann, E. U . , 478 Eickhoff, D. J., 37, 103 Eilbracht, P., 313 Einhorn, J., 294 Eisch, J. J . , 5 , 326 El-Gharib, M . S., 453 El Hallaoui, A . , 192 Eliasson, K. M., 133 Elissondo, B ., 106,235,368 Elliott, E., 364 Elliott, J., 31, 104, 377 Elliott, J. D., 53, 73, 222, 290, 364,366 Elliott, R., 73 Elsevier, C. J., 328 El-Wassimy, M. T. M . , 168 Elzey, T. K., 352,496 Emblidge, R. W., 144 Emde, H., 26 Emslie, N. D., 148 Enda, J., 76,218, 422 Enders, D., 158,340,418 Endo, Y.,259 Engberts, J. B. F. N., 189 Engelhardt, L. M., 452 Ennen, B., 15 Ent, H., 462 Erden, I . , 404 Erfort, U . , 130 Erhardt, P. W., 261 Ermolenko, M. S . , 88, 380 Eswarakrishnan, V., 60 Eugster, C. H., 82 Evans, S. A . , jun., 228,409, 413 Everhardus, R. H., 64,238 Exon, C., 100,333,390, 497 Fabre, J.-L., 8,57, 313, 376 Faith, W. C., 482 Falck, J. R., 129 Farcasin, D., 316 Farina, F., 179,266 Fauq, A . H., 212 Fedij, V., 344 Fehlhaber, H. W., 311 Fehr, C., 62, 102, 404 Fehrentz, J.-A., 113,279 Felix, A. S , ,283 Felman, S. W., 335,413 Fenwick, A . , 489 Ferguson, G., 302 Fernandes, J. B., 329, 349 Fernandez, F. J., 305 Fernandez-Resa, P . , 283 Feringa, B. L., 43,157 Ferraboschi, P., 296 Ferrario, F., 125 Ferres, H., 181 Ferrier, R. J., 524 Feuer, H., 189,298 Feustel, M . , 78

553

Author Index Fiandanese, V., 88, 266 Fiaschi, R., 468 Field, L. D., 284, 365 Field, S. J., 194 Fife, W. K . , 287, 366 Finck, M. S . , 90 Fink, D. M., 387 Finkelstein, B. L., 187 Finn, J . , 539 Fiorenza, M., 212,238,272, 291 Firouzabadi, H . , 84,85, 122, 227,235,237,308 Fischer, J. W., 64, 374 Fischetti, W., 81, 166 Fisher, K. J., 302 Fishpaugh, J. R., 433 Fittkau, S., 160 Fitzsimmons, B. J . , 537 Flann, C. J., 120,426 Fleet, G. W. J . , 397,527, 539 Fleming, I . , 119,157,229,360, 368,373 Fleming, M. P., 532 Flippin, L. A . , 127 Flood, L. A , , 227 Flores, H. J., 468, 484 Flbrez, J., 219 Florio, S., 153 Floss, H. G ., 133 Floyd, A. J . , 288 Fludzinski, P., 20, 164 Flynn, G. A . , 27,445 Flynn, K . E . , 7 Fobare, W. F., 165 Fochi, R., 237 Foglio, M . , 494 Forcellese, M. L., 421 Forni, A . , 211, 448 Fourrey, J.-L., 23, 232 Fowler, F. W., 50, 461,473 Fox, C. M. J., 125,181 Foxley, G. H., 229 Franceschi, G., 494 Francisco, C. G., 438 Frandanese, V., 195 Fraser-Reid, B., 270,530 Frkhet, J. M. J., 88 Freerksen, R. W., 86 Freidinger, R. M., 197 Freire, R., 438 Frejd, T., 328 Freyberger, G., 384 Fried, J., 117 Friedrich, E. C . , 226 Fringuella, F., 391 Fristad, W. E., 1, 142 Frobese, A. S., 179 Frolow, F., 495 Fronza, C., 431 Froussios, K., 197 Fry, M. A . , 1,142 Fuchs, P. L., 39, 99, 146, 340, 347,371,397,522

Fulop, F., 453 Fuentes, L. M., 257, 342 Fuganti, C., 523 Fugawa, T., 215 Fuhr, B., 487 Fuji, K., 343 Fujii, K., 95, 140 Fujii, M., 104, 164 Fujikura, Y . , 220 Fujimoto, K., 152 Fujimoto, Y . , 235 Fujisawa, T., 87,88,89, 134, 165,168,204,208, 229, 304, 350 Fujita, E., 9,28, 33, 103, 175, 178,343, 376 Fujita, M., 111 Fujita, S., 470 Fujita, T., 237 Fujita, Y . , 385 Fujiwara, J . , 44, 118, 209,258, 275,358,398 Fujiwara, T., 51,108,229 Fujiwara, Y . , 215 Fukasawa, H., 9 Fukase, K., 194 Fukata, F., 142 Fukata, G., 141 Fukui, M., 206 Fukumoto, H . , 182 Fukumoto, K . , 463,491 Fukushma, M . , 331,349 Fukutani, Y . ,258 Fukuzaki, K., 37,98,362,405 Fukuzawa, S . , 10,200, 235, 387 Fung, A . P . , 284,365 Furukawa, M . , 190 Furukawa, Y . , 190,302, 485 Furusawa, F., 82 Furuyama, H., 394, 507 Fustero, S . , 262 Gadwood, R. C., 402 Galamb, V., 41, 140 Gallacher, G., 276, 496, 537 Gallagher, T., 511 Galli, R., 78 Galvez, C., 295 Ganboa, I., 283 Gandour, R. D., 243 Ganem, B., 180,250,300,345 Ganguly, A. K., 493 Gani, D., 194 Gamer, G. A . , 302 Garad, M. V., 357 Garcia, G. A . , 170 Garcia, T . , 144 Garigipati, R. S . , 55, 269, 271, 378 Garner, P., 391 Garst, M. E., 125, 157, 398, 417 Gartiser, T., 249

Gasc, M. B. , 245 Gaset, A . , 12 Gasparrini, F., 238 Gaudemar, M . , 139,165, 190, 301,456 Gawronska, K., 135 Gawronski, J . K., 135 Gebhard, J. S., 234 Gehrig, K . , 308 Geigert, J., 230 Gelas-Mialhe, Y . , 454 Gelin, S., 300 Gellert , E., 479 Genet, J.-P., 268 Gennari, C., 40,128, 155,160, 215,341, 370 George, J .,245 Georgiadis, G. M., 9 Gerdes, J. M., 128, 149,224 Gerke, R., 6 Gerlach, H., 142 Gero, S. D., 251,384 Gerstmans, A , , 237 Gervais, D., 306 Ghatak, U. R., 147 Ghiringhelli, D., 184, 533 Ghosez, L., 493 Ghosh, A . K., 43,175,390, 497 Giacomelli, G., 109 Giattini, P. G., 283 Giese, B., 92,130, 132,151 Gilard, A . , 137

Gilbert, J. C., 72,90,265 Gilchrist, T. L., 299, 450 Giles, R. G . F., 432 Gilman, J. W., 7, 184 Giordano, C., 140 Giordano, L. A . , 90 Giovannini, F., 154, 211 Giovannoli, M., 238 Girijavallabhan, V. M., 493 Girotra, N. N., 539 Gist, R. P . , 473 Glass, R. S., 148 Glusenkamp, K.-H., 428 Goasdoue, C., 190 Goasdoue, N., 190 Godel, T., 133 Godleski, S. A , , 335, 413,477 Godoy , J., 85 Godts, F., 283 Goel, 0. P., 147 Gogte, V. N., 287 Goh, S. H., 232 Gokel, G. W., 243 Gold, V., 239 Golding , B . T., 224 Goldsmith, D., 179 Goli, D. M., 243 Gonzales, A . , 295 Gooch, E. E., 194 Gopalan, A. A . , 137,211 Gordon, H. J., 45,471

554 Gor6, J., 50,53,56,122,218, 385, 465 Goren, Z., 233 Gorgues, A , , 166 Gosney, I . , 454 Gotoh, Y . , 208 Gottschalk, P., 116, 170, 178 Gough, M. J . , 527 Gould, T. J., 55, 165 Goument, C., 119 Govindan, C. K., 302 Govindan, S. V., 387 Grafing, R ., 64 Grafing, R . , 238 Grakauskas, V., 411 Gramatica, P., 97 Granados, R . , 264,284 Gravel, D . , 378 Grayson, J. I . , 261, 515 Greeley, A. C., 65 Green, I. R . , 432 Green, J. R . , 470 Green, S. M . , 211 Greenberg, R. S . , 421 Greenblatt, J., 239 Greene, A. E., 130, 315, 390, 402,497 Greene, E. W., 393 Greenlee, W. J . , 290, 366 Grethe, G., 529 Gribble, G. W . , 205, 283 Grieco, P. A . , 391, 539 Grierson, D. S . , 288, 342,474, 480 Grigg, R . , 302,304,461 Grossi, M., 122 Grote, J . , 411 Groth, U., 192 Grubbs, R. H., 69, 127, 325 Gruber, J. M., 102,153 Grynkiewicz, G., 283 Grzejszczak, S . , 113 Gu, J.-M., 473 Guanti, G., 112 Guedj, R . , 194 Guerrero, A., 228 Guerrier, L., 342, 480 Guevel, A., 492 Guillaumet, G.,443 Guindon, Y . ,225 Guittet, E., 238 Gull, M.-R., 192 Gunaratne, H. Q. N., 304,461 Gundo Rao, C., 122 Guo, M . , 159 Gupta, R. C., 508 Gutowski, D. A . , 243 Gutsche, C. D., 244 Gyoung, Y. S . , 205 Haack, J. L . , 6 Haag, A. P., 510 Habata, Y . ,239 Habbachi, F., 139

General and Synthetic Methods Hacksell, U., 332 Hadley, M. S . , 475 Haffmanns, G., 303,304,458 Hafner, W., 64, 180 Haga, Y , ,491 Hagenah, J. A . , 46,348 Hagihara, T., 18, 148, 331 Hagiwara, I . , 51,107,124,331 Hahn, G., 77,139 Haines, A. H . , 242 Hajos, Z . G., 439 Hakimelahi, G. H., 224 Hakushi, T., 239 Halazy, S., 379 Hall, C . D., 239 Hallett, P . , 211 Hallock, J . S., 169 Halls, T. D. J., 391 Haltiwanger, R. C., 447 Hamachi, I., 361 Hamada, A., 37,102 Hamaguchi, H . , 97,470 Hamana, M., 143 Hamanaka, N . , 443 Hamann, P. R., 146,347 Hamatsu, T., 531 Hamer, N. K . , 115 Hamman, S., 133 Hammer, B., 319, 381 Hammond, P. J . , 239 Hanafusa, T., 10, 84, 226,293 Hanagan, M. A., 181 Hanessian, S . , 435, 527,536 Hangauer, D. G., 290,366 Hannick, S. M., 156,266,468 Hansske, F., 219, 228 Hara, K . , 24,131, 318,374 Hara, S . , 22,23, 34,105, 231, 356 Harada, H.; 231 Harada, T., 71, 291 Harakal, M. E., 407 Harano, Y., 146 Harding, M. M., 298 Harland, P. A . , 181, 508 Harmata, M. A., 114 Harnisch, H., 132 Harpp, D. N., 189 Harris, D. J . , 355 Harris, R. B., 197 Harris, T. M., 186, 282, 345 Harrison, C. R . , 134,280 Hart, D. J., 252,389,463,476 Hartling, S., 288 Hartwig, W., 227 Haruta, J . , 142 Harvey, R . G., 289 Hasain, A . , 226 Hasebe, M., 487 Hashimoto, K . , 317 Hashizume, K . , 145 Hashizume, T., 239 Hassan, D . , 62, 376 Hassel, P., 96, 264

Hata, K . , 317 Hatanaka, Y . , 85,184,227 Hatton, I. K., 181 Hattori, K . , 256, 477 Hatzigrigoriu, E., 293 Haubenstock, H., 207 Haufe, G., 68 Hauptmann, S . , 307 Havama, N., 59 Havashi, T., 52 Havens, N . , 144 Hawkins, J., 188 Hayachi, I., 191 Hayama, N., 233 Hayama, T., 296,363 Hayami, H., 29 Hayase, Y ., 222, 406 Hayashi, H., 167,237 Hayashi, K . , 51, 107 Hayashi, M., 443 Hayashi, T., 18,79,148,152, 331,343,349,360,361,364 Hayashi, Y . , 141, 327, 352, 400,450 Hazato, A., 297,522 Heacock, D. J., 335,477 Heath, W. F., 198 Heathcock, C. H., 127, 128, 149,153,187,217, 361 Heavner, G. A . , 191 Hebblethwaite, E. M., 334, 488 Hebert, E . , 91 Heck, R. F., 81,166, 386,430 Hedge, S., 204 Hegedus, L. S . , 32,106,233, 331 Heilmann, S. M., 27, 111,212, 289,350 Heimann, M. R., 147,226 Heimbach, H., 111 Heissler , D . , 393 Helgeson, R. C., 243 Helmchen, G., 148 Henderson, G. B., 540 Hendrickson, J. B., 173 Henegar, K. E., 224 Henin, F . , 44, 175,176 Henning, R., 352,465,532 Henzen, A. V., 25,370 Heo, G. S . , 241 Hernandez, M. I., 421 Hernandez, R.,438,468 Herndon, J. W., 101, 165, 321 Herold, P., 136 Hershberger, S. S., 16 Herunsalee, K., 21. 116, 345 HervC du Penhoat, C., 57,313 Hesse, M., 160, 185,298,404 Heuschmann, M., 532 Heveling, J., 2, 4, 237 Hevesi, L., 379 Iiewson, A. T., 390 Hida, M., 196

Author Index Hidai, M . , 317 Hiemstra, H., 462 Higby, R. G., 497 Higuchi, H., 2 Higuchi, K., 88, 350 Higuchi, T., 141, 190 Hii, P. S., 86 Hill, J. H. M., 442 Hill, R. A . , 540 Hillard, R. L., 336 Himbert, G., 78 Himmelsbach, R. J., 87 Hiner, R. N., 173 Hinkle, J. S., 197 Hino, T., 472,519 Hioki, T., 331, 349 Hipes, P. G., 241 Hirai, K., 67, 161 Hirama, M., 153,211,226,539 Hiranuma, H., 393 Hirao, A . , 207, 208, 353 Hirao, I., 74,109, 356, 371 Hirao, T., 4,51, 107,146 Hirobe, M . , 190 Hiroi, K., 375 Hiroi, Y . , 185,280 Hirotsu, K., 141 Hirsch, S., 173 Hirsenkorn, R., 179 Hitomi, K., 213,290, 363 Hiyama, T., 45,48,52,176, 181,217,265,346, 366,408, 422,423 Ho, C . D., 71 Ho, L.-K., 17 Ho, T.-L., 431 Hobbs, F. W., jun., 347 Hodge, P.,121,134, 181,223, 280 Hodge Markgraf, J., 393 Hodgkisson, I., 242 Hodgson, S. T., 334, 488 Hoffmann, H. M. R., 164 Hoffmann, R. W., 53, 154, 182,211,217,355 Hofheinz, W., 441 Hojo, M., 204,205 Hokama, N., 190 Hollenstein, R., 298 Hollinshead, D. M., 334, 488, 503 Hollis, W. M., 143 Hollman, K . , 454 Holman, N. J., 236,327 Holmes, A . B., 540 Holmes, D. R . , 298 Holt, D. A . , 54, 108,358 Holton, R. A., 25,125,348 Holtz, W. J., 287 Honda, T . , 394, 494,507 Honda, Y . , 242 Hong, C. Y., 232 Hong, P., 180 Hoornaert, C., 495

555 Hooz, J., 25, 121 Hoppe, D., 71,169,218 Hoppe, I., 192 Hori, I . , 79, 343 Horiguchi, Y . , 127 Horiie, T., 290 Horita, K., 417 Horler, H., 92 Horn, K. A., 387 Horton, M., 501 Hoshi, M . , 76 Hoshino, M., 11,233, 237 Hosokawa, T., 314,315 Hosomi, A . , 22, 55, 123, 127, 232, 346, 394 Hou, L., 189,298 Houk, K. N., 446 House, H. O., 6 Houwen-Claassen, A. A. M., 115,268 Hovius, K., 189 Howbert, J. J. , 390, 497 Howell, S. C., 503 Howes, D. A., 224 Hrubiec, R. T., 270 Hrubowchak, D. M., 132 Hsiao, C.-N., 343 Hsu, C., 539 Huang, G. T., 64,393 Huang, S.-B., 88 Hubert, A. J., 146 Huche, M., 129 Hudlicky, T., 387, 391 Hudson, A. T., 224 Hudspeth, J. P . , 532 Hiibner, F . , 146 Huffman, J. C., 511 Huffman, J. W., 229 Huggenberg, W., 160,298 Hughes, I . , 513 Hui, R., 111,342 Huisgen, R.,443 Hung, M.-H., 148, 319 Hunt, A . H., 352, 496 Hunt, B. J., 134,280 Hunt, E., 495 Hunt, P. G., 162 Hunter, J. E., 188 Husain, A . , 133,224, 365 Husain, S., 296 Husk, G. R., 319,381 Husson, H.-P., 288,342, 474, 480 Hutchings, M. G., 66, 216 Huttner, G., 168, 340 Huynh, C., 69,347 Hwu, J. R., 86, 376, 387, 399 Hyatt, J . A . , 121 Hyun, J. L., 83 Hyun, M. H., 254 Ibrahim, B. E . , 302 Ichikawa, J., 144 Iddon, B., 485

Tden, R . , 487 Iguchi, H., 394 Iguchi, K., 67, 328 Ihara, M., 463 491 Iida, H., 87, 111, 131, 145, 278,282,287 Iida, K., 324 Iida, S., 88,229, 350 Iizuka, K., 231 Ikariya, T., 169, 227 Ikeda, H.. 35,104 Ikeda, I., 243 Ikeda, K., 194 Ikeda, M., 383 Ikeda, N., 60, 324 Ikeda, T., 242 Ikeda, Y . , 60,324 Ikegami, A., 443 Ikegami, S., 9,215 Jkehira, H., 148,238, 301 Ikenaga, K., 17 Jksander, G. M., 302 Ikuta, S., 520 Ila, H . , 163, 377 Jmada, Y . , 315 Imai, K., 42,177 lmai, T., 91, 354 Imai, Y . , 190 Imaizumi, M., 283 Imamoto, T., 85,127,227, 228,283 Imbach, J.-L., 448 Inaba, M., 22,232, 346 Inaba, S . , 89,233 Inaba, T., 111 Inai, M., 198 Inamoto, N., 13,14,371,380 Inamoto, Y . , 220 Inch, T. D., 135 Ingold, C. F., 84 Inokawa, S., 2 Inokuchi, T., 120, 382 Inomata, K., 91, 167,237 Inoue, K., 84,169,194,227, 467,478 Inoue, M., 290 Inoue, S . , 82 Inoue, T., 204, 205 Inoue, Y . , 239 Iqbal, J., 119, 157, 373 Iranpoor, N., 85,227 Ireland, R. E., 439, 537 Isaac, K., 425 Ishag, C. Y . , 302 I-Shan Chu, 65 Ishibashi, K., 507 Ishida, N . , 47, 211, 350 Ishida, Y . , 49,254,256. 365, 404,466 Ishido, Y , , 379 Ishiguro, H., 23,231,356 Ishihara, T., 20,21,117, 372 Ishii, A . , 380 Ishii, T., 13,14, 371

556 Ishii, Y., 169, 227 Ishikawa, N., 153 Ishikawa, Y., 243 Ishikazi, K., 213 Isimura, A . , 95 Isobe, K., 327 Isoe , S., 222,406 Itahara, T., 295 Itani, H., 47, 221 Ito, K., 207, 353 Ito, M., 472,519 Ito, M. M., 302 Ito, S., 160 Ito, T., 224 Ito, Y . , 188,206,473,514 Itoh, K., 54, 169, 170,284, 285, 365 Itoh, T., 168 Itsuno, S . , 207, 208, 353 Iwahara, T., 221 Iwao, M., 188,478,517 Iwasaki, S . , 408 Iwasawa, N., 137 Iwashita, M., 153,211, 539 Iwata, K., 487 Iyer, P. S., 307, 366 Iyoda, M., 68, 82,239 Izatt. R. M . , 239 Izawa, Y., 8, 11 Izumi, T., 204, 205 Izumi, Y., 26, 122,287, 318 Jabri, N . , 32, 58, 59, 103, 333 Jackson, D. A . , 402 Jackson, R. F. W., 418 Jacobs, S. A . , 289 Jacobsen, E. J., 304, 462, 516 Jacobsen, E. N . , 153 Jacquier, R . , 192 Jadhav, P. K., 53 JaCn, J. C., 220 Jalali, M., 418 James, B. R., 386 Jano, P., 421 Janout, V., 233 Januszkiewicz, K., 86 Jeffery-Luong, T., 80 Jefford, C. W., 440 Jeffs, F. W . , 468 Jelittc, R . , 313 Jellal, A . , 73, 140, 293 Jennings, L. J. A . , 181 Jennings-White, C. L. D., 540 Jesser, F . , 129, 324 Jeyaraman, R., 472 Jiang, J. B . , 439 Jibril, I., 168. 340 Jih Ru Hwu, 22 Jimknez, C., 187,282 Jitsukawa, K., 47, 85, 227 Jobe, P. G., 348 Jodhav, P. K., 133 J~rgensen,K. A , , 168 John, R. A . , 112, 124

General and Synthetic Methods Johne, S . , 288 Johnson, A . T., 398 Johnson, D. M., 294 Johnson, R. P., 393 Johnson, W. S . , 53, 73, 222, 290,364, 366,399, 508 John, K. K., 142 Jones, B. A , , 234, 239 Jones, D. N., 374 Jones, J. H . , 451 Jones. M. A . . 431 Jones, N. D., 352,496 Jones, R. C. F., 487 Jones, R. L., 76 Jones, T. K., 98,387 Jones, W. A . , 157 Josel, H.-F., 239 Joshi, N. N . , 524 Joucla, M. F . , 300 Joullie, M. M., 452 Joyce, C. J., 298 Julia, M., 8, 57, 187,304, 313, 376 Julia, S . , 112, 206, 238, 407 Julia, S. A . , 33, 64,107, 342 Jun, Y. M., 188 Jung, A . , 213 Jung, M. E., 46, 283, 348, 365 Jung. S.-H., 253 Jungk, S. J., 243 Junjappa, H., 163, 377 Jurczak, J., 242, 303 Jurlina, J . L., 390, 497 Just, G., 496 Juve, H. D., jun., 109, 153, 173 Kabalka, G. W., 221, 231 Kabat, M. M., 319 Kabeta, K., 360,361 Kadib-Elban, A , , 188 Karki, T., 410 Kagan, H. B., 213,223 Kageyama, M., 394 Kageyama, T., 85,169,226, 227 Kagiya, T., 470 Kahn, M . , 201 Kahne, D. E., 312 Kaifer, A , , 243 Kaiser, E. T., 191 Kaji, A . , 40,42. 104, 160,164 177,346 Kaji, S., 411, 425 Kakimoto, M.-a., 462 Kakisawa, H., 515 Kakui, T., 221 Kaletta, B., 6 Kalkote, U. R., 245 Kallmerten, J., 55, 165 Kametani, T., 394, 463, 491, 494,507 Kameyama. M., 263

Kamijo, T., 231 Kamitori, Y . , 204, 205 Kamiyama, N., 424 Kanai, K.-i., 252, 476 Kanao, Y, , 68 Kanaoka, Y . , 184 Kanatani, R., 221 Kanaya, N., 494 Kanazawa, T., 275 Kanbara, H., 34, 363 Kandil, F . , 239 Kane, J. M., 532 Kane, V. V., 98 Kaneda, K., 47, 85,227 Kanehira, K., 331, 349 Kaneko, T., 303 Kanemasa, S . , 393 Kanemitsu, S., 226 Kanemoto, S . , 29,85,227 Kang, G. J., 361 Kang, J., 76 Kang, M.-c., 536 Kang, S. I . , 241 Kano, S., 475,484 Kanoh, S., 208,353 Kao, L., 430 Kao, T., 356 Kapnang, H . , 262 Karanewsky, D. S., 373 Karunaratne, V., 48, 413 Karydas, A. C., 153 Kashimura, S., 36, 86,97, 98, 213 Kast, J., 179 Kataoka, H., 319 Katayama, E., 94 Katayama, S . , 428 Katayama, T., 243 Kato, J.-I., 126 Kato, M., 182 Kato, S., 226 Kato, T., 23, 34, 231,505 Katoh, T., 97, 305 Katritzky, A . R., 259, 302, 309 Katsuki, T., 75, 109 Katsuro, Y., 18, 331 Katzenellenbogen, J. A . , 162, 175 Kauffmann, T., 15 Kawabata, N., 238 Kawada, M., 24, 131, 230, 318, 374,393 Kawagishi, T., 297, 522 Kawahara, S . , 169, 227 Kawaharasaki, N., 190 Kawai, M., 224 Kawakami, Y . , 58,233 Kawamoto, K., 46, 364 Kawanami, Y., 75,109 Kawanishi, Y . , 85, 227 Kawanisi, M., 81 Kawara, T., 134 Kawasaki, K., 295 Kawasaki, T., 155

Author Index Kawasaki, Y., 218 Kawashima, T., 13, 14, 371 Kawate, T., 10, 293 Kay, I. T., 170, 438,525 Kay, P. B., 522 Kaya, R., 350 Kaye, P. T., 148 Keim, W., 285 Keinan, E., 77,314 Kellner, D., 228 Kellogg, M. S . , 399, 508 Kelly, D. J., 138 Kelly, W. J., 298 Kende, A. S., 20, 164 Kendrick, D. A , , 540 Kenney, P. M., 518 Kepsi, L. R., 212 Kerr, R. G., 115 Kervagoret, J., 479 Kesseler, K., 213 Kessler, H., 196 Ketcha, D. M., 449 Keve, T., 485 Khalafi-nejad, A . , 235 Khan, M., 171,374 Khare, R. K., 413 Khatri, N. A . , 302, 473, 514 Khoshdel, E., 134,280 Khuong-Huu, Q., 479 Kibayashi, C., 278 Kido, F., 176 Kido, M., 383 Kiehl, G., 489 Kielbasinski, P . , 113 Kienzle, F . , 264, 451 Kikui, T., 243 Kikukawa, K., 17 Killmer, L. B., jun., 133 Kim, B., 204 Kim, C.-W., 88,153, 347 Kim, J.-I., 81, 166 Kim, S., 88, 144, 197, 232 Kim, S.-W., 94,156 Kim, T. H., 222,406 Kim, Y. C., 144 Kim, Y. J., 232 Kim, Y . H., 482 Kimura, K., 48,213 Kimura, Y . , 133,183,286 King, F. D., 474, 475 Kini, A . , 83 Kinney, W. A., 392 Kinoshita, H., 91,167, 237 Kinsman, R. G., 288 Kirby, P., 416 Kirchmeyer, S . , 121,290, 306, 366 Kirisawa, M., 489 Kirk, T. C., 358,388 Kirson, I., 314 Kirszensztejn, P., 286 Kirtane, J. G . , 407 Kisfaludy, L., 191 Kishi, N., 37, 98, 362

557 Kishi, Y., 156, 201,266,468 Kiso, Y., 198 Kita, Y., 142 Kitagawa, K., 198 Kitagawa, Y . , 137 Kitamura, K., 169,227,401, 504 Kitani, H., 170,373,418 Kitao, D., 190 Kitaoka, M., 176 Kitayama, R., 375 Kitazume, T., 153 Kitsuki, T., 242 Kiyooka, S.-i., 217, 361 Klang, J. A . , 1, 142 Klaus, A . J., 308 Kleefeld, G., 487 Kleijn, H., 80 Klein, C., 117,138 Klein, H., 384 Kling, F., 226 Klingstedt, T., 328 Klop, W., 265 Klos-Ringuet , M ., 226 Klumpp, G. W . , 343 Knapczyk, J., 197 Knapp, F. F., 231 Knapp, S . , 270,448 Knaus, E. E., 271 Knochel, P., 296 Knor, R.,96,264 Knowles, W. S., 196, 312 Knudsen, C. G., 113, 279 Kobar, J., 453 Kobayashi, H., 243 Kobayashi, K., 45, 133, 265, 346 Kobayashi, T., 96, 285 Kobayashi, Y., 324 Kober, R., 194 Koch, K., 50,461 Kochetkov, N. K., 88,380 Kochhar, K. S . , 121,190,282 Kochi, J. K., 407 Kocienski, P., 400, 425, 436, 441 Kodera, Y.,144 Kodomari, M . , 309 Koehler, K. F., 460 Koga, K., 308 Koga, T., 266 Kogan, T. P., 6 Kohmoto, S . , 440 Kohn, H., 253, 262 Kohno, S., 4 Kojima, T., 263 Kokko, B. J., 261,468 Kolasa, T., 195, 266 Kolb, M., 192 Kolovos, M., 197 Komatsu, T., 152, 355 Konar, S. K., 272 Kondo, Y . ,74 Konig, J., 300

Konishi, M., 52, 148, 152,331, 349,360 Kontoleon, B. D., 90 Koreeda, M., 224, 388, 497 Kornblum, N., 298 Koshino, J., 94, 109 Koskinen, A . , 288 Kostova, K., 185 Kosugi, H., 176 Kosugi, M . , 26. 51, 107, 116, 124,263,331 Kotake, H., 91,167,237 Kotelko, A . , 146, 483 Kotera, K., 184 Koul, V. K., 456 Koyama, K., 381 Kozerski, L., 262 Kozikowski, A . P., 43, 137, 175,291,352 Kozlowski, J. A . , 129, 233 Kozluk, T., 303 Kozyrod, R. P., 192 Krafft, M. E., 25, 125,348 Kraus, G. A., 116,170,178, 487 Krauss, J. C . , 291 Krawczyk, S. H., 487 Krebs, A . , 6 Krentzien, H., 232 Krepski, L. R., 27, 111,289, 350 Kretzschmar, G., 1 Krief, A., 2 , 232, 372,379, 393 Krishnamurthy, S . , 3, 232 Krolikiewicz, K., 287, 366 Krolls, U., 147 Krook, M. A . , 491 Krowczynski, A . , 262 Kruithof, K. J. H., 343 Kubota, H., 3,228 Kubota, T., 196 Kucerovy, A . , 63 Kuehne, M. E., 519 Kugimiya, M., 2 Kuiper , D ., 456 Kulicki, W . , 303 Kulinkovich, 0. G., 64 Kulkami, S. U., 225 Kulp, S. S . , 86 Kulp, T., 387 Kumada, M., 18,47, 52,148, 152, 211,221,331, 349,350, 360,361,364 Kumar, K., 72, 187 Kumar, N., 479 Kumar, V., 121, 377 Kumari, K. S . , 245 Kumi, Y . ,224 Kunai, A . , 296 Kunda, S. A . , 221 Kundig, E. P., 322 Kunesch, G., 249 Kunieda, T., 190 Kunisch, F., 154

558 Kunng, F.-A.,473 Kunz, H., 138, 196,198 Kunzer, H., 284 Kuraishi, T., 517 Kuriki, H., 181 Kurita, J., 487 Kurita, M., 35, 104 Kurita, Y., 89, 304 Kuroda, T . , 48,213 Kurozumi, S . , 297, 522 Kurth, M. J., 139 Kurz, K., 185,280 Kurz, M. E., 296 Kusabayashi, S . , 424, 443 Kusano, Y., 241 Kusumoto, T . , 127, 228 Kuwajima, I., 37,76,98,122, 126,127,147,149, 218,338, 362,368,379,382,493,405, 422 Kuzikowski, A , , 400 Kuzuhara, H., 193 Kuzuoaka, T., 309 Kvarnstrom, I . , 257 Kwon, Y . C., 353 Kyba, E. P., 268 Kyler, K. S., 64, 86,167, 344 Labadie, J . W., 89, 104, 158, 333,369 L’Abbe, G., 283,308 Labhart, M. P., 7 Ladner, W . , 154,211 Lago, J . M., 144,307 Laguzza, B. C., 76 Lai, R., 232 Lajoie, G., 194 Lallemand, J.-Y., 418 Lambert, J. B., 146,381,483 Lammer, O., 143,168, 340 Lammerink, B. H. M., 14, 115,268 Lammertsma, K., 247 Lampe, J . , 153 Landmann, B., 53, 182, 217, 355 Lansard, J.-P., 130,402 Lantos, I . , 198 Lapatsanis, L., 197 Larcheveque, M., 161,293, 346 Larock, R. C., 16, 352 Larraza, M. I . , 468, 484 Larson, E. G., 381 Larson, E. R., 272,530 Laszol, P., 237,296 Latimer, L. H., 539 Latrofa, A , , 262, 357 Lattes, A . , 199,245, 269 Lau, C. K. 406 Laucher, D., 129,324 Lauer, M., 243 Laughton, C. A . , 236, 327 Launay, J.-C., 111

General and Synthetic Methods Laur, J., 197 Laurent, A . , 268,455,480 Laurent, E., 117 Lautens, M., 50, 63, 148,166, 319 Laval, J. P., 269 Lavoie, A . C., 148,330 Lawesson, S.-O., 168,194 Lawlor, J. M., 170 Lawrence, G. C., 211 Lawston, I . W., 135 LCandri, G., 226 Leanza, W. J., 493 Le Bigot, Y., 12 Lechhein, S . , 132 Le Coq, A . , 166 LeDoussal, B., 166 Lee, D. G., 84 Lee, J. I . , 88, 144 Lee, N. J., 482 Lee, S. D., 187,282 Lee, T.-J., 287 Lee, T. V., 157,373 Leginus, J. M., 529 Le Goffic, F., 107 le Guillanton, G., 291 Lehmkuhl, H., 18 Leiden, T. M., 387 Lein, G. M., 244 Lemay, G., 43,178 Lemieux, E., 287 Lemke, T. L., 303 Leng, J . L., 64 Lennon, P . , 386 Leonard, N. J., 307 Leong, W. W.-H., 117,333 Lepine, F., 194 LePoire, D. M., 311 Lerch, U., 300 Lerman, O., 117, 157 L’Esperance, R. P., 439 Lesur, B. M., 165, 355 Levine, J. A , , 244 Levine, S. G., 440 Levinson, S. H., 133 Ley, S. V., 28,41,90,125, 177,181,334,345, 488,503, 507,527,536 Leyendecker, F., 129,324 Leyendecker, J., 117 Lhommet, G . , 45,163,266 Libera, H., 289,445 Libman, J., 183,535 Lieberknecht, A . , 24, 144 Lieser, J. K., 211 Liew, W.-F., 185 Lillie, T. S., 101 Lin, J.-M., 50, 461 Lin, Y., 317 Linderman, R. J., 162, 217, 268, 371 Lindig, M., 138 Linstrumelle, G., 69,80, 347 Lion, C . , 117

Liotta, D., 179 Lipshutz, B. H., 129,145,233, 323 Liquori, A , , 301 Lis, R., 539 Lister, S. G., 536 Little, R. D., 87, 497,500 Liu, C., 352 Liu, H.-J., 17 Liu, J.-H., 133 Liu, R. S. H., 83 Liu, W.-Y., 496 Liu, Y., 241 Livinghouse, T., 367,459, 515 Liz, R., 265,267, 302 Ljubit, M., 197 Lociuro, S., 112, 279 Loher, H., 133 Loeppky, R. N., 300 Loerzer, T., 6 Low, P., 96 Loewenthal, H. J. E., 228 Lombardo, L., 507 Long-Mei, Z., 46,283, 348, 365 Lonsky, R., 192 Lopez, F. J . , 484 Lopez, R. C. G., 447 Lopez-Calahorra, F., 264 Lopusinski, A . , 197 Lorne, R., 64,238 Loubinoux, B., 147,443 Lounasmaa, M., 288 Louw, R., 238 Low, P., 264 Lown, J. W., 300 Lu, L. D.-L., 279 Lu, X . , 317 Luche, J.-L., 130,402 Luche, M.-J., 315,390,497 Luscher, I . F., 198 Liittke, W., 6 Lugade, A. G., 245 Lumma, P. K., 451 LUO,F.-T., 30, 89, 119,174, 331,333,351,415 Lupo, A. T., jun., 473 Lutomski, K. A., 141 Luttringer, J.-P., 489 Lygo, B., 527 Lyon, J. T., 411 Mabon, G., 291 McArthur, C. R., 198 McBride, B. J., 125, 157, 398, 417 McClure, D. E., 451 McComsey, D. F . , 476 McCullough, K . J .,443 McDaniel, W. C., 6 MacDonald, J. G., 189, 394 MacDonald, R., 197 Macdonald, T. L., 516 McElroy, A . B. , 31,104,377

Author Index McFarland, J. W., 115,268 McGarvey, G., 90 McGarvey, G. J., 173,537 McGee, M. J., 86 Machida, H., 11,233 McIntosh, J. M., 445, 470 Mack, K. T., 386 McKean, D. R., 27, 86,238, 365 MacKenzie, A. R., 513 McKenzie, A. T., 340,522 McKervey, M. A . , 114,373 McKillop, A , , 294 MacLean, D. B . , 257,478 McMills, M. C., 171 McMurry, J. E., 27,99, 122, 314, 330,398, 504 McNab, H., 45, 471 McNamee, M. B., 170 MacPherson, D. T., 390 Maddaluno, J . , 117, 154, 219 Madyastha, K. M., 264 Maeda, H., 243 Maeda, N., 54,151,367 Maekawa, T., 372 Maestro, M. C . , 179 Mafunda, B. G., 233,404 Maggi, D., 431 Magnus, P., 100,333, 390, 409,497,511 Mahalanabis, K. K., 188, 478 Mahon, M., 503 Maigrot, N., 91 Mais, F.-J., 487 Majchrzak, M. W., 146, 483 Majetich, G., 56, 57 Mak, K. T., 81, 166,430 Makino, H., 426 Malacria, M., 56 Malherbe, R.,236 Malhotra, N., 280 Malmberg, W.-D., 187 Malone, T. C., 49,475 Mamdapur, V. R.,524 Mametsuka, H., 10 Manabe, K., 297,522 Manabe, O., 241,242,243 Mandai, T . , 24,131,230, 318, 374,393 Mandal, A. N., 280 Mandard, X., 62, 376 Mandel, G. S., 439 Mandel, N. S . , 439 Mander, L. N., 118, 115,507 Manescalchi, F., 134, 228 Manfredini, S., 265 Mangeney, P., 129 Manitto, P., 97 Mann, G., 307 Mann, R. L., 148 Manna, S., 129 Manoharan, T. S., 264 Mansour, E. M. E., 197 Mao, M. K.-T., 163, 174,405

559 Marcaccioli, S., 448 Marchand, A . P., 350 Marchand-Brynaert, J . , 493 Marchese, G., 88 Margarethd, P., 303 Mariano, P. S., 304,457, 460, 473 Maring, C., 429 Marino, G., 316 Marino, J. P., 162,217,220 Marrero, R., 102, 153 Marsden, R., 478 Marshall, D. R., 64 Marshall, J. A . , 7, 540 Marsili, A., 468 Marston, C. R., 243 Martelli, G., 384 Martin, A . , 98 Martin, H.-D., 487 Martin, J. C., 45,85,226, 471 Martin, M., 308 Martin, M. R., 179 Martin, M. V., 179,266 Martin, R. T., 475 Martin, S., 20, 346 Martin, S. F., 96,473 Martinez, J., 197 Miirton, J . , 226 Maruoka, K., 44,49, 118,209, 229,254,256,258,275, 358, 365, 398,404,466, 477 Maruyama, K., 54, 62, 128, 151,152,215,216, 355,367, 510 Maryanoff, B. E., 13, 476 Masaki, Y . , 425 Masamune, S . , 394 Masana, J., 407 Mashima, K . , 324 Mason, R., 12, 370 Masroua, A . , 480 Massa, W., 146 Massardo, P., 59,233, 356 Massner, A . , 382 Masters, N. F., 327 Masida, R., 3,204, 205 Masuda, T., 131 Masuda, Y., 76 Masui, M., 85 Masunaga, T., 51,107 Mathur, H. H., 295 Matsubara, S., 46, 85, 181, 221,227,423 Matsubara, Y . , 173 Matsuda, H., 452 Matsuda, I., 26, 122,287,318 Matsuda, T., 17 Matsuda, Y., 79, 343 Matsuhashi, Y . , 82 Matsumoto, H., 238 Matsumoto, K . , 54, 128, 367, 434 Matsumoto, M., 160 Matsumoto, T., 228

Matsumura, N., 117, 138, 351 Matsumura, Y., 44,49,86, 118,194,256,275, 404,466, 467,477,478 Matsunaga, I., 61 Matsuura, T., 57, 134 Matsuzaki, M., 287 Matteson, D. S . , 354 Mattingly, P. G., 491 Matui, S., 40, 160,346 Mat-Zin, A. R., 487 Mauleon, D., 284 Maverick, E. F., 244 Mayer, R., 12 Mayoral, J. A . , 194 Mayr, H., 66,384 Maziak, L., 194 Meanwell, N. A . , 374 Medina, D. H. G., 474 Medina, M. C., 438 Mehendale, A. R.,511 Mehrotra, A. K., 133,226,365 Mehrotra, S . , 295 Mehta, G., 500 Meier, G. P., 49, 462, 475 Meijer, J . , 80 Meinhart, J. D., 335, 477 Melendez, E., 194,196,312 Melhado, L. L., 307 Melis, S . , 264 Meltz, C. N., 92, 160, 329, 472 Mendelson, L. T. , 462, 516 Mendelson, W . L., 133, 198 Menozzi, G., 292, 433 Merrifield, R. B., 198 Mertens, A . , 121,247,290, 306,366 Messeguer, A . , 408 Mestdagh, H., 187,304 Metzger, J . , 232 Metzner, P., 166, 168 Meunier, A., 133 Meyer, A . , 166 Meyer, E., 252 Meyers, A . I., 87, 141, 181, 257,268,303,342,371,532 Michelot, D., 16 Michelotti, E. L., 329, 349 Midland, M. M., 353 Miginiac, P., 122,188 Migita, T., 26, 51, 107, 116, 124,263, 331 Mihelich, E. D., 37, 103 Mijngheer, R.,394 Mikami, H., 97 Mikami, K., 37,98, 152,222, 362 Mikolajczyk, M., 113 Milani, F., 85, 227 Milias, G., 197 Miller, D. D., 37, 99,102,398, 504 Miller, J . A . , 65, 76,78, 89, 101, 333,351,364, 386

560 Miller, M. D., 393 Miller, M. J., 136. 491 Miller, R. B., 47,90,363 Miller, R. D., 27, 86,233,238, 365 Miller, S. I . , 393 Mills, R. J., 189, 340 Mills, S . , 188 Milner, J . , 298 Minami, I . , 38,39,102,103, 123,124,315 Minami, T., 241,242, 371, 385 Mincione, E., 143,421 Minguillon, C., 284 Minobe, M., 524 Minuti, L., 391 Mioskowski, C . , 409 Mirao, I . , 385 Mirbach, M. F . , 93 Mirbach, M. J . , 93 Mise, T., 180 Misiti, D., 238 Mislankar, S. G., 388, 497 Mison, P . , 268 Misumi, S . , 2 Mitani, M., 381 Mitchell, J. C . , 424 Mitchell, P. R. K., 432 Mitsui, H., 309, 448 Mitsunobu, O., 158 Mitt, T., 529 Miura, I,, 504 Miura, M., 424, 443 Miyake, H., 104, 164 Miyake, M., 489 Miyamoto, K . , 61 Miyamoto, O., 82 Miyano, S . , 279 Miyaura, N., 407 Miyazaki, M., 285 Miyazaki, T., 254,256, 477 Mizuno, H., 218 Mizuno, K., 239,424 Mizuta, Y . ,317 Mizutani, M., 190 Mlochowski, J., 241 Mloston, G., 454 Mobbs, B. E., 236,327 Mobilio, D., 401, 505 Mochizuki, T., 494 Moeller, K. D., 497 Morsdorf, P., 421 Mohacsi, E., 235 Mohamadi, F., 169 Mohanraj, S . , 330 Mohr, P., 135, 136 Moiskowski, C., 129 Mol, J. C., 57, 287 Molander, G. A., 16, 349 Molinari, H., 206, 407 Momose, D., 67,85, 328 Mompon, B., 296 Monk, P., 496 Monkiewicz, J., 39, 99, 398

General and Synthetic Methods Monni, F., 264 Monsan, P . , 199 Montanari, F., 186, 349 Montanucci, M., 237 Monte, W. T., 87 Montero, J.-L., 448 Montgomery, A. M., 294 Monti, D., 97 Monti, H., 226 Moody, C. J., 513 Mook, R., jun., 41,177 Moore, J. A , , 243 Moore, J. L., 1 Moore, K. W., 493 Moorthy, K. B., 37, 102 Moracci, F. M., 303 Moral, M., 466 Moran, J. R . , 244 Morandini, F., 18,236, 321, 349 Moreno-Mafias, M., 230 Morera, E., 283 Moretti, I., 211, 448 Moretti, R., 133 Mori, A . , 209,358 Mori, I., 366 Mori, K., 209, 524 Mori, M., 175 Mori, T., 87, 88,204,350 Mori, Y . , 40, 160, 380 Morisawa, T., 413 Morishima. N., 226 Morizawa, Y . , 29, 363 Morley, J. O . , 225 Moroder, F . , 158 Morrow, C. J . , 135 Morrow, G. W., 64 Mortezaei, R., 176 Morton, D. W., 445 Morton, H. E., 122, 225,358, 406 Morton, J. A . , 55,269 Mostafavipoor, Z . , 84, 227, 308 Mosti, L., 292, 433 Motherwell, W. B., 1, 87,142, 25 1 Motohashi, S . , 235 Motoi, M., 208, 353 Motoyama, T., 460 Mouko-Mpegna, D., 235 Moulines, F., 274 Mouzin, G . ,235 Mucha, I., 226 Muhlstadt, M., 454 Muller, E. P . , 456 Muller, J . , 197 Muller, P., 85 Mugrage, B. B., 400 Mukaiyama, T., 31, 34, 46, 102,104,112,126, 137,144, 153,155,171,173, 203, 315, 382 Muller-Starke, H., 284

Mulzer, J., 136,143, 168, 340 Munoz, H., 170 Murahashi, S.-I., 263,309, 314, 315, 448 Murai, S . , 26,46, 93,120, 159, 364 Murakami, M., 46, 155 Murakami, Y . , 300 Muramatsu, T., 197 Murata, S . , 144,505 Murata, Y . ,91 Muratake, H., 485 Murayama, E., 393 Murtiashaw, C. W., 501 Murty, A. N., 500 Musso, H., 192 Muthard, D. A , , 493 Myojoh, K . , 413 Myong, S. O., 461 Myrboh, B., 377 '

Naderi, M., 237 Nadir, U. K., 456 Naef, R., 193,340,425 Nafti, A., 268 Nagai, H., 4 Nagai, N., 62 Nagakura, I . , 406 Nagami, K., 470 Nagao, K., 94, 156 Nagasaki, M., 485 Nagashima, H., 169 Nagasuna, K . , 8,317 Nagata, K., 425 Nagata, R., 57, 134 Nagata, W . , 47,221 Ngjera, C., 187,282 Nakagawa, M., 472,519 Nakagawa, S. H., 191 Nakahama, S . , 207,208,353 Nakai, H., 184 Nakai, K . , 262 Nakai, T., 37,98, 152,222, 362,385 Nakajima, K., 194 Nakajima, M., 434 Nakajima, T., 24, 131, 374 Nakajo, E., 473, 514 Nakajo, T., 208, 353 Nakamizo, N., 482 Nakamura, A . , 8, 50, 107,213, 317,324,326 Nakamura, E., 37,98, 127, 147, 362,368,394, 403,405, 535 Nakamura, H., 244 Nakamura, K., 100 Nakamura, T., 243 Nakanishi, H., 232 Nakano, M., 63,287 Nakano, T., 225 Nakao, K . , 140 Nakashima, K., 239 Nakashita, Y., 298,404

Author Index Nakata, T., 206 Nakatsuji, S., 239 Nakatsuji, Y., 243 Nakatsuka, M., 473, 514 Nakatsuka, T., 31, 102, 315 Nakayama, J., 11,233,237 Nakayama, K., 141 Nakazaki, M., 242 Nakazono, Y . , 81 Namie, M. W., 12 Namuta, K., 229 Namy, J . L., 213,223 Napier, J. J., 394 Napolitano, E., 468 Narang, S. C., 224,284,365 Narasimhan, N. S., 247, 339 Narayanan, B. A , , 262,516 Narayanan, K., 16 Narisano, E., 112 Naritomi, T., 54 Narula, A. P. S . , 8 Narula, C . K., 386, 430 Naruta, Y . , 62,215, 367, 510 Nasipuri, D., 272 Naso, F., 195,266 Natale, N. R., 84, 227 Natile, G., 238 Natsume, M . , 485 Natu, A. A., 287 Nawata, Y., 61 Negishi, E.-i., 24, 30, 65, 89, 101, 119, 124, 125, 174, 331, 333,351, 384,386,415 Negoro, K., 86,226 Negron, G . , 457 Neidleman, S. l., 230 Nemlin, J., 479 Nemoto, H., 401,504 Netzel, M. A . , 344 Neuenschwander, K . , 63 Neuenschwander, M., 78 New, J . S., 252 Newcomb, M., 303 Newkome, G. R., 239, 243 Newton, R. F., 211,522 Nguyen, L. T., 491 Nguyen, S . , 65 Niangoran, C., 122,371 Nicholas, K. M . , 78, 328 Nickel, W.-U., 6 Niessner, M . , 75, 270 Niewohner, U., 117 Nikam, S. S., 71 Nikrad, P. V., 245 Ninagawa, A . , 452 Nish, T., 225 Nishida, I . , 127 Nishida, M . , 158 Nishida, R., 478 Nishida, S., 285 Nishide, H., 352,400 Nishiguchi, I . , 35, 104 Nishikawa, N., 141 Nishimoto, S . 4 , 470

561 Nishimura, K . , 266 Nishimura, S., 253 Nishio, K., 176 Nishio, T., 64 Nishiyama, H., 54. 284, 365 Nishiyama, K., 247, 366 Nishizawa, M . , 352, 400 Nitta, M., 96 Nivard, R. J. F., 174 No, K. H., 244 Nobayashi, Y., 74 Noble, D., 211 Noda, Y . , 176 Noels, A . F., 146 Nogami, Y., 266 Nogusa, € I . , 97 Nohara, Y., 133 Nojima, M . , 424, 443 Nokami, J . , 87, 318 Nomoto, T., 8 Nomura, K., 284 Nomura, Y., 296,302,363 Nonnenmacher, A . , 12 Nordberg, R. E., 321 Normant, J. F., 20, 32,58, 59, 103, 129,233, 333, 346, 404 Nose, M., 82 Nott, M. W . , 253 Noureldin, N. A , , 84 Noyori, R., 127, 297, 522 Nozaki, H., 29, 46, 48, 85, 176, 181. 221.227, 290, 360, 363, 366,408,422, 423 Nozaki, Y . , 71 Nozulak, J., 192 Nugent, R. A., 394, 501 Nugent, W. A . , 347 Nunez, O., 478 Nunez, W., 86 Nunomoto, S., 58, 233 Nutaitis, C. F . , 205 Nystrom, J. E., 268 Oae, S . , 308 Obase, H., 482 Obayashi, M., 52, 217, 290, 366,408 Ochiai, H., 93 Ochiai, M., 9,28, 33, 103, 175, 178, 376 Oda, H., 194,363 Oda, M., 68, 82 Oehlschlager, A. C., 70 Olund, J., 3 O’Fee, R. P . , 264 Oftring, A . , 487 Ogasawara, K., 516 Ogata, T., 434 Ogawa, A., 120 Ogilvie, K. K., 224 Ogumi, N., 213 Ogura, F., 30, 86, 225,227 Ogura, H., 190

Ogura, K., 87, 111, 131, 145, 282,287,402 Oh, T., 173 Ohashi, Y., 123 Ohba, T., 138 Ohira, N., 30 Ohmasa, N ., 167 Ohmori, Y., 239 Ohnishi, M., 141 Ohno, K., 383 Ohnuma, T., 467, 485 Ohsawa, H., 61 Ohsawa, T., 463,491 Ohshima, M., 31,102, 315 Ohshiro, Y., 4, 51, 107, 146 Ohsumi, T., 34, 104 Ohta, H., 411 Ohta, S . , 133 Ohta, T., 229, 282, 314 Ohtani, B., 470 Ohto, H., 144 Ohtsuka, H., 206 Ohtsuka, Y . , 98, 99 Ohuchida, S., 443 Ohya, T., 26, 116 Oi, R., 382 Oida, T., 148, 238 Oikawa, H., 190 Oikawa, Y . , 225, 417 Oinuma, H., 515 Oishi, T., 79,98, 99,206, 343 Ojima, I . , 67, 161 Okada, H., 287 Okahara, M . , 243 Okamoto, M . , 133 Okamoto, T., 259 Okamoto, Y., 63, 147, 242, 287,364 Okamura, N., 297, 522 Okano, K., 262 Okano, M., 143,148,238,309, 387 Okano, T., 302, 484, 485 Okawa, K., 194 Okawara, M., 3,31, 85, 169, 227,228, 413 Okawara, T., 190 Okazaki, M. E., 462 Okazaki, R., 380 Okimoto, M., 4 Okita, H., 476 Okon, A . V., 198 Okonkwo, J. O., 157,373 Okruszek, A . , 238 Oku, A., 71 Okubo, M., 308 Okuda, S., 408 Okuda, Y., 29,360 Okum, A . , 291 Okuma, K., 411 Olah, G. A., 121, 133,224, 226, 247,284,290, 293, 306, 307,365,366 Olano, B . , 262

General and Synthetic Methods Omata, T., 100, 229 Omi, T., 213 Omote, Y . , 64 Onaka, M., 224 Ong, H. H., 453 Ono, A . , 245 Ono, N . , 104, 164 Onozuka, J., 402 Ookawa, A . , 133, 167, 237 Oota, Y . , 426 Ootake, K., 42, 177 Oplinger, J. A . , 501 Oppolzer, W., 133, 159, 261, 404, 502,504, 515 Orena, M., 223,224, 270 Origel, A. E., 185 Oriyama, T., 46, 155 Orlinski, R., 119 Ormiston, R. A . , 454 Ornstein, P. L., 402 Oro, L. A . , 196, 312 Orsini, F., 151 Orta, G., 283 Osaka, K., 393 Osaka, N., 284, 365 Osakada, K . , 169,227 Osborne, S . , 487 O’Shea, D. M., 389 Oshikawa, T., 2 Oshima, K . , 29, 85, 181,227, 360, 363,408, 423 Oshima, M., 237 Oshima, T . , 100, 229 Oshumi, T., 245 Oster, T. A., 186,282,345 Osuka, A . , 3 , 4 , 11,40, 116, 160,167,185,228, 280,285, 309, 380 Otaki, S., 516 Otera, J., 24, 131, 218,230, 374,393 Otsubo, T., 2,30, 86,225 Otsuji, Y . , 239, 424 Otsuka, T., 227 Ottley, P. M., 138 Ottoboni, T. B., 224 Ouchi, A . , 182 Ouchi, M., 239 Oudenes, J., 25, 121 Ousset , J . B ., 409 Outcalt, R. J., 6 Overman, L. E., 49,64,68, 304, 317,393, 398, 462,475, 515,516 Owen, 0. J. R., 507 Oya, E., 237 Ozaki, S . , 85 Pacofsky, G. J., 165 Padmanabhan, S., 78,328 Padwa, A . , 304,367,394,457, 458,460 Pagb, O., 154,219 Paget, W. E., 66,216

Pai, G. G., 353 Paknikar, S. K . , 407 Palla, F., 109 Palma, P., 283 Palmer, B. D., 536 Palmieri, G., 238, 476 Palomo, C., 84,144, 227,283, 307 Pancrazi, A . , 479 Panda, C. S . , 189,298 Pandit, U . K . , 262 Pandit, V. S., 287 Panunzio, M., 134,228,384 Papadopoulos, K., 158,340 Papaioannou, D., 198 Papini, A . , 238, 291 Paquette, L. A . , 41, 121,376, 387, 391,392,401,497 Paradisi, M. P., 122 Paraskewas, S. M., 309 Parish, E. J., 84 Pariza, R. J., 39,99,371, 397 Park, K. B., 205 Parker, D . , 233 Parker, K. A . , 264 Parkhurst, C. S., 335, 413 Parnell, C. A . , 336 Parson, P. J., 67, 72, 105, 143, 167,221,238,361, 375 Parsons, W. H., 394,501 Parvez, M., 302 Pascard, C., 296 Patel, D. V . , 270, 448 Patel, R. C., 309 Patel, S . K., 52, 148, 181 Paterson, I . , 52, 123, 148, 181 Paton, J., 211 Paton, R. M., 298 Patrick, T. B., 142 Patrie, W. J., 169, 227 Pattenden, G., 49, 389,500, 501,502 Pauls, H. W., 270, 530 Paulus, E. F., 465 Paynter, 0. I., 138 Pearce, C. J . , 204 Pearlman, P. S., 369, 409 Pearson, A. J., 172 Pearson, J. R., 400 Pearson, W. H., 247, 280,436 Pecora, A. J., 119 Pelizzoni, F., 151 Pellacani, L., 112, 279 Peloso, C., 132 Pelter, A . , 15, 23, 92, 94, 170, 200,221, 357 Pennetreau, P., 296 Pennings, M. L. M., 456 Peretz, M., 77 Pereyre, M., 106,368 Perez, J. J., 525 Perie, J. J., 245 Peringer, P. , 456 Perlmutter, H. D., 13

Perlow, P. S . , 197 Perri, R. B., 283 Perriot, P., 161,293,346 Perrone, E., 494 Perry, D . A . , 446 Perry, M. W. D., 110, 308 Perz, R., 159 Peseckis, S. M., 359 Pessi, L., 228 Pete, J.-P., 44, 175, 176 Peter, R., 122, 337 Petersen, J. L., 500 Peterson, B., 63, 166 Petit, Y . , 161,293,346 Petrakis, K. S . , 117 Petrier, C., 130, 402 PCtrignani, J.-F., 138,232 Petrow, V . , 440 Petty, C. B., 64,393 Peyton, A. L., 300 Pfister, J. R., 247 Pham, P. Q., 62,233 Phan, X . T., 282 Phillippe, M., 251 Phillips, G. B., 124, 166,219, 359,430 Phillips, M. L., 352, 496 Phu, T. N., 93 Pia-Calcagno, M., 478 Piancatelli, G., 408 Piccardi, P., 59, 233,356 Piccolo, O., 18,236,321, 349 Pickering, R. A . , 311 Piers, E., 48,368, 406,413 Pietraszkiewicz, M., 242, 303 Pietrusiewicz, K. M., 39, 99, 398 Pigikre, Ch., 192 Pilar Vazquez, M., 300 Pillon, L. Z., 470 Pine, P., 196 Pinnick, H. W., 121, 190,282 Pinto, I. L., 494 Pinto, P., 493 Piotrowski, A . , 5, 326 Piper, I. M., 257 Piras, P. P., 264 Pirkle, W. H., 253, 254 Pirrung, M. C., 22 Pitacco, G., 388 Pitteloud, R., 133 Pizzo, F., 391 Pizzotti, M., 309 Plante, R., 121,239,290 Plat, M. M., 302,478 Plessi, L., 134 Plieninger, H., 12 Plusquellec, D., 134 Poignant, S . , 492 Pokier, J.-M., 118, 156, 265, 336,413 Poli, G., 128, 341 Pollini, G. P., 158, 501 Poncini, L., 235

Author Index Ponsinet, G., 491 Poochaivatananon, P., 22,167 Porskamp, P. A. T. W., 14, 447 Porta, F., 309 Porta, O., 224 Porter, J. R., 181 Porter, N. A., 424 Posner, G. H., 6 Poss, A. J., 394, 501 Potts, K. T., 265 Pougny, J.-R., 348, 527 Poupart, M.-A., 183 Pourcelot, G., 129 Powner, T. H., 394 Pradere, J.-P., 492 Prakasa Rao, A. S. C., 411 Prakash, G. K. S., 133,307 Prasit, P., 524 Prempree, P., 149 Preston, P. N., 225 Pri-Bar, I., 369, 409 Price, D ., 485 Price, M. F., 361 Price, T., 334 Prince, T. L., 2 Procter, G., 415 Proffitt, J. A., 453 Prout, K., 325,496 Pruitt, J. R., 518 Puckett, W. E., 239 Pugin, B., 302,314, 471 Pujol, F . , 408 Purrington, S. T., 157 Pyne, S. G., 204, 365,389,523 Quader, A., 58, 69, 349 Quayle, P., 345,491 Quesada, A. M., 478 Quessy, S. N., 336 Quincy, D. A., 84,227 Quindon, Y., 122, 358 Quiniou, H., 492 Quinn, N. R., 234 Quintard, J.-P., 106,235,368 Raban, M., 239 Rabe, J., 164 Racherla, U. S., 355 Radhakrishna, A. S., 122,253 Radner, F., 295 Radviroongit, S., 149 Rahn, B. J., 16, 349 Rajadhyaksha, S. N., 121 Rajaram, J., 8 Rakotonirina, R., 168 Ramadas, S. R., 167 Ramachandran, J., 167 Ramachandran, P. V., 295 Ramage, R., 507 Raman, K., 100,386 Rambaud, M., 32,105, 160 Ramesh, S., 525 Rand, C. L., 30,384

563 Ranganathan , D . ,295 Ranganathan, S., 295 Ranu, B. C., 391 Rao, A. S., 407 Rao, A. V. R., 511 Rao, C. G., 253 Rao, C. T., 220 Rao, V. B., 85 Raphael, R. A., 418,513 Rapoport, H., 113,279,479 Rasmussen, J. K., 27, 111, 212,289,350 Ratananukul., P., 114,373 Ratcliffe, N. M., 503 Ratcliffe, R. W.,493 Rathke, M. W., 117, 138 \ Ravasi, M., 296 Ravenscroft, P. D ., 85 Ray, T., 172 Raychaudhuri, S. R., 280 Razdan, R. K., 274 Rector, D. H., 440 Reddy, D. B., 387 Reddy, D. S., 500 Reddy, K. B., 511 Reden, J., 311 Redfearn, R., 468 Reed, J. N., 188,247,339 Reed, L. A., 111,394 Reed, T. J., 221 Reel, J. R., 440 Rees, C. W., 300,513 Reetz, M. T., 5, 111, 122, 146, 213,284,323,337 Reeves, P. C., 286 Regan, A. C., 340 Regen, S. L., 133,183,204, 286 Reglier, M., 64,238 Regondi, V., 237 Reho, A., 262,357 Reichelt, I., 147 Reid, S. T., 442, 483 Reider, P. J., 532 Reif, L., 296 Reinecke, M. G., 445 Reinhardt, G., 83 Reinhoudt, D. N., 451,456 Reinking, P., 86 Reissig, H.-U., 147 Reitz, A. B., 13 Renaldo, A. F., 68, 317,398 Renger, B., 298 Renzulli, L. A., 90 Restelli, A., 186,349 Reuman, M., 87 Reutrakul, V., 21,22, 116, 117,167,345 Revial, G., 154,219,391,505 Revol, J. M., 391 Rey , M., 402 ReyC, C., 32,127, 159 Reynolds, D. P., 211,522 Reznikov, I. V., 64

Rheingold, A. L., 81, 166 Rhodes, Y. E., 153 Riba, M., 228 Riccim A., 186,212,238,272, 291 Ricci , M. , 407 Rich, D. H., 199 Richards, I. C., 172 Richardson, G., 134,280,496 Richardson, G. D., 440 Richaud, M. G., 45,163,266 Richter, R., 231, 305 Richter, W. J., 386 Rickards, R. W., 247 Rieke, R. D., 89,233,350 Riemenschneider, C., 71,218 Rieu, J.-P., 235 Riguera, R., 300 Ringer, E . , 212 Riordan', P. D., 294 Ripley, S., 2 Rist, G., 236 Ritchie, B, M., 455 Ritter, A. R., 294 Roberts, B. W., 41 Roberts, D. H., 389 Roberts, R. A., 41, 121 Roberts, S. M., 211,522 Roberts, T. G., 450 Robertson, G. M., 49,389 Robins, M. J., 219,228 Robinson, R. P., 487, 539 Rodes, R., 265 Rodriguez, J., 116,235 Roder, T., 94 Rohe, D. M. M., 86 Roland, D. M., 532 Romanelli, M. N., 186 Ronald, R. C., 101,166 Rondan, N. G., 446 Ronzini, L., 88 Roper, J. M., 193 Rosa, C. L., 448 Rosenblum, 176,319,334,386 Roshan-Ali, Y . , 288 Rosini, C., 109 Rosini, G., 4,113,213,226, 298 Roslik, N. A., 64 Rosowsky, A., 198 Ross, B. C., 493 Rosier, J.-C., 440 Rossini, S., 384 Rost, W., 175 Roulleau, F . , 134 Roush, W. R., 144,165,355, 359 Rousseau, G., 381 Roussi, G., 457 Roy, G., 409 Royer ,J., 342,480 Royer, R., 294,295 Roie, J.-C., 492 Rozen, S., 117,157

General and Synthetic Methods Rozzell, J. D., jun., 133 Rubottom, G. M., 88, 102, 109,153,173,347 Rubralta, M . , 466 Rudisill, D., 133 Ruediger, E. H., 406 Ruger, W., 6 Ruel, O., 33,64, 107,238, 342 Riimmele, O . , 487 Ruffini, A. J., 265 Rukachaisirikul, V., 21, 117, 345 Ruotsalainen, H., 410 Russell, C. E., 32, 106, 233, 331 Russell, M. A., 276 Russell, R. K., 400, 507 Russo,C., 388 Rutledge, P. S . , 309 Rychnovsky, S. D., 177 Rys, P., 308 Ryu, I . , 120 Saalfrank, R. W., 64,175,180 Saburi, M., 169,227 Saccomano, N. A . , 384 Saddler, J. C., 340, 522 Sadhu, K. M., 354 Saednya, A . , 283 Saegusa, T., 473, 514 Sahai, M., 314 Sahlherg, C., 58, 69, 349 Saimoto, H., 176, 181,422, 423 Saindane, M., 179 Saito, I., 57, 134 Saito, M., 394 Saito, T., 225 Saito, Y., 216, 355 Sakai, T., 181 Sakakibara, T., 379 Sakamoto, H . , 239 Sakamoto, M., 155 Sakamoto, T., 74 Sakan, K., 394 Sakane, S . , 49,229,256,398, 404,466,477 Sakata, J . , 127 Sakata, Y., 2,55, 123 Sakdarat, S . , 226, 358 Sakuraba, H., 232 Sakurai, H., 22, 55, 123,127, 232,346,394 Sakuta, K., 54,284, 365 Salanski, P., 242 Salas, M., 264 Salazar, J. A., 468 Salomon, R . G., 312 Samaddar, A. K., 272 Sammes, P. G., 416, 478,503 Sanchez, F., 179,266 Sanchez, I. H . , 468, 484 Shnchez-Delgado, R. A . , 8 Sander, J . , 15

Sandri, S . , 223,224,270 Sano, H., 258, 413 Santaniello, E., 85,227,296 Santelli, M . , 73,98, 140,293, 387 Santelli-Rouvier, C., 98, 387 Sapp, S. G., 431 Sard, H., 274,382 Sardarian, A , , 122, 237 Sarma, J. C., 228 Sarma, K., 239 Sartoretti, J., 385 Sartori, G., 150,359,421 Sarussi, S. J . , 206 Sasaki, H., 245 Sa ki, J., 394 Sazki, K . , 127,296,394 Sasaki, M., 35, 104,470 Sasaki, T., 302, 484,485 Sasakura, C., 300 Sasatani, S., 254, 365 Sasson, Y . , 4 Sastry, K. A. R., 231 Sastry, V. V. S. K., 167 Sato, F., 29, 34,324, 363,364 Sato, K., 82,452 Sato, M., 29,239, 324,360, 363,364 Sato, N., 3,185,228, 280 Sato, R. I . , 394 Sato, S . , 26, 122,318, 375 Sato, T., 87,88, 89, 134, 165, 168,204,208,229, 304,350, 419 Sato, Y . , 162, 184, 213,290, 363 Satoh, J. Y . , 284 Satoh, T., 121 Satoh, Y . , 23,231, 356 Satomi, M., 235 Sauerwald, M., 323 Saus, A , , 93 Sauvetre, R., 20, 346 Savignac, P., 113 Savoia, D., 153,216 Sawada, H., 30,384 Sawada, I., 190 Sawada, S . , 387 Sawahata, M . , 52,217 Sawyer, J. S., 262 Scallen, T. J., 135 Scettri, A . , 408 Schatzlein, P., 64, 180 Schallenberg, J . , 252 Schamp, N., 114,262, 303, 456 Schaper, W., 72 Schauder, J. R., 2 Schaumann, E., 160 Scheeren, H. W., 410 Scheeren, J. W., 174 Scheffold, R., 119 Scheidt, H . , 421 Scheinmann, F., 522 Schell, F. M., 463

Schenone, P., 292,433 Schierling, P . , 64, 180 Schiess, M., 186 Schlecht, M. F., 128,149 Schleppnik, A . A . , 150 Schlessinger, R. H., 394, 501 Schleyer, P. von R., 265 Schmid, C. R. , 86,285 Schmid, G., 441 Schmidt, G., 408 Schmidt, H., 303 Schmidt, R. E., 146 Schmidt, R. R., 179,429 Schmidt, U., 24, 144 Schmidtberger, S . , 213 Schmitz, R. F., 343 Schneider, C. H., 198 Schneider, S., 283 Schobert, R., 184 Schollkopf, U., 192 Schon, I., 191,197, 204 Schonauer, K., 89,371 Scholz, D., 19, 114 Schreiber, S. L., 185, 434,525 Schroder, C., 303 Schroder, G., 239 Schubert, T., 154 Schuda, P. F., 147,226 Schull, V . , 41 Schultz, A. G., 422, 461 Schulz, G., 117, 138 Schwarz, O., 289 Schweizer, W. B., 193, 340 Schwellnus, K . , 146 Schwichtenberg, E., 487 Sciacovelli, O., 195, 266 Scolastico, C., 112, 128, 155, 215,341 Scott, A . D., 84 Scott, F., 233,404 Scott, L. T., 83 Scott, W. J., 27, 122 Scrimin, P., 449 Scripko, J . , 352 Scrivanti, A . , 8 Seconi, G., 186 Seebach, D., 136,150, 154, 186,193,211,296, 340, 353, 425 Seetz, J. W. F. L., 382 Seki, Y . , 46,364 Sekiya, M., 194,262,460 Selikson, S. J . , 86 Selim, A . , 148 Selve, C., 249 Selway, K. N., 303 Semeria, D., 251 Semmelhack, M. F., 85, 86, 101,165,227,285, 321, 326, 431 Senda, S . , 209 Seoane, C., 305 Sepiol, J . , 249 Sepulchre, A.-M., 251

565

Author Index Serajul Hague, M., 394 Sereno, J., 529 Serizawa, Y . , 425 Serratosa, F., 236 Serra-Zanetti, F., 122, 283 Servi, S., 181, 523 Sethi, S. P., 118, 155 Seyferth, D., 111, 342,412 Sghibartz, M., 239 Sha, C.-K., 461 Shadday, J., 86 Shanklin, M . , 148 Shannon, P. J., 282 Shanzer, A , , 183,186, 195,535 Sharma, K. K., 219 Sharma, K. S., 245 Sharma, R. P., 8, 121,226, 228 Sharma, V. K., 245 Sharpless, K. B., 279 Shea, K. J., 7, 62, 65, 184,233 Shechter, H., 343 Shedrinsky, A . , 394 Sheffy, F. K., 17, 108, 163, 234,369 Sheppard, R . C., 198 Sher, M. P., 293 Sheridan, R. S., 302 Sheth, J. P., 387 Shi, L., 430 Shiba, T., 194 Shibasaki, K . , 131, 282 Shibasaki, M., 9. 215 Shibuya, S . , 475, 484 Shieh, W.-R., 137,211 Shigehisa, T., 170,373, 418 Shih, J . , 133 Shiiya, K., 467 Shimada, J., 37,403 Shimada, K., 238 Shimada, S . , 417 Shimao, I . , 308 Shimazu, M., 394 Shimbo, K., 194 . Shimida, J.-I., 127 Shimizu, H., 11, 40, 160, 380 Shimizu, I., 38,39, 102,103, 123, 124, 315 Shimizu, K., 191, 532 Shimizu, M., 127,153, 211, 226 Shimizu, N., 4, 410 Shimizu, T., 450 Shimizu, Y . , 218 Shimoji, K., 142,377,408 Shimono, Y , ,501 Shimuzu, H., 309 Shin, C., 195 Shing, T. K. M . , 397,527, 539 Shinkai, H., 243 Shinkai, S., 241,242, 243 Shinoda, M . , 176,181,423 Shinokazi, H., 283 Shinozaki, K., 199

Shiraiwa, M., 74 Shishiyama, Y . , 290 Shono, T., 35,36, 86,97, 98, 104, 194,213,275,467,470, 478 Short, R. P., 391 Shubert, D. C., 16, 349 Shudo, K., 259 Sibi, M. P., 189, 339 Sibtain, F., 2, 237 Siddiqui, M. A . , 445 Sidot, C., 132, 140 Sieburth, S. M., 54, 108, 358 Siefert, K., 288 Siegmeier, R., 196 Sigiyama, Y . , 142 Shi, C . J., 137,211, 539 Silks, L. A., 104 Sillitoe, A., 298 Silveira, A , , 119 Silveira, L., 172 Silvestri, M. S . , 397 Simchen, G., 26 Simmonds, D. J . , 138 Simmons, D. P., 322 Simmons, K. A . , 253 Simon, E. S., 251 Simon, H., 155, 419 Simonet, J . , 291 Simoni, D., 158,265, 501 Simpkins, N. S . , 28, 41, 90, 177,345,507 Simpson, G. W., 217 Sims, R. J., 184 Sinay , P . , 348, 527 Sindona, G., 301 Singaram, B., 15, 23, 92,221, 357 Singaram, S . , 94, 200 Singh, B. B., 253 Singh, B. P . , 133, 224,226, 365 Singh, H., 280,453 Singh, H. K . , 298 Singh, P., 453 Singh, R. P . , 245 Singh, V . , 98, 173 Singleton, D. H., 418 Singleton, K. A . , 276, 537 Sinhababu, A. K., 4, 180,297 Skarzewski, J., 241 Skattebol, L., 383, 417, 524 Skinner, I. A . , 164 Slougui, N., 381 Smaardijk, A. A., 373 Smith, A. N., 463 Smith, C . , 242 Smith, D. J. H., 132,335,488 Smith, E. H., 187 Smith, F. X., 132, 449 Smith, H. K., iun., 27 Smith, J. C., 90 Smith, J . G., 234 Smith, J. K., 303

Smith, K . , 66,216 Smith, K. M., 473 Smith, M. B., 270 Smith, R., 367,459,515 Smithers, R. H., 116, 343 Snider, B. B . , 124, 166,219, 358,359,388,394, 398, 430, 482, 539 Snieckus, V., 188,189,247, 339,340,478 Snowden, R. L., 387 Soai, K., 133,167, 237 Sodeoka, M . , 472,519 Soderquist, J. A . , 32, 117,333, 369 Sofia, M. J., 175 Sofuku, H., 238 Sohajda, A., 453 Sola, R., 186 Solladie, G., 409 Somekh, L., 195 Sommer, T. J., 434,525 Son, B . , 241 Sonoda, N., 26, 46,93, 120, 159,364 Sonoda, T., 87 Sonveaux, E., 243 Sorenson, E. M., 404 Soria, J. de J . , 468, 484 Sorrenti, P . , 213, 298 Sotigu, F., 264 Soto, J. L., 305 Souppe, J . , 213,223 Southwell, I. A . , 507 Spada, A. P., 144 Speckamp, W. N., 462 Speer, H., 179 Speranza, G., 97 Spessard, G. O., 294 Speziale, V . , 199,269 Springer, J. P . , 101, 137, 165, 321,397,401 Spunta, G., 384 Sridharan, V., 304 Srinivasan, P. S . , 167 Srivastava, P. C., 231 Stampfli, U.. 78 Stakem, F. G., 81, 166 Stamm, H., 157 Stammer, C. H., 194 Stanton, S. A , , 335,413 Staunton, J., 340 Steel, P. J . , 217 Steglich, W., 117,138,194 Stehouwer, P. M., 328 Steigel, A . , 487 Steinauer, R.,191 Steinbach, R., 213 Steliou, K., 183 Stella, L., 457 Stenstrom, Y., 383,417, 524 Stevens, J . B., 262 Stevens, R. V . , 518 Stevens, R. W., 126, 153

566 Stevenson, P. J., 302 Stewart, F. H. C., 191 Still, B . , 387 Still, W. C., 40, 160,200,353, 370,401,505 Stille, J. K., 17, 89,93, 104, 108, 156,158,163, 234,333, 369,409 Stille, J. R., 127, 325 Stirling, C. J. M., 64 Stiver, S., 305 Stoll, A. T., 89,333,351 Stone, W. E., 367 Stoodley, R. J., 496, 508 Stork, G., 41, 171, 172,177, 201,293,312,336,384,394, 413,535 Storr, R. J., 237 Stothers, J. B., 390, 497 Stradi, R., 448 Strande, P., 235 Strange, G. A., 309 Street, L. J., 416, 503 Streith, J., 489 Strekowski, L., 173 Strickland, S. M., 394 Su, W., 523 SuBrez, E., 438,468 Suda, H., 208,353 Sugahara, S., 76,218,422 Sugawara, T., 94,109,149, 379,382 Sugiura, M., 2 Sugiura, S., 297, 522 Sugiyama, T., 67, 328 Sukata, K., 286 Sulman, P., 262,456 Sultanov, R. M., 231 Sumi, S., 84,226 Sumiya, T . , 124, 331 Sunbhanich, M., 253 Surya Prakash, G. K . , 293,366 Suschitzky, H., 485 Sutherland, J. K., 400 Sutter, M. A., 136 Suzuki, A., 22,23,34,93,94, 105, 109,190,231, 356 Suzuki, H., 3,4,11,40,116, 160,167,185,215,228,280, 285,309,380 Suzuki, K., 94,171,203,262 Suzuki, M., 194,297, 522 Suzuki, N., 8 Suzuki, T . , 61,93, 254 Suzuki, Y., 254,394, 507 Sviridov, A. F . , 88, 380 Swain, C. J., 85, 435 Swain, W. E., jun., 440 Swee Hok Goh, 4 Swenton, J. S., 510 Swern, D . , 449 Swindell, C. S., 329,349 Swonn, M . , 462,515 Szantay, C . , 485

General and Synthetic Methods Szarek, W. A., 257 Szeza, W., 224 Szirtes, T., 204 Szymanski, J., 303 Tabe, M., 467,485 Taber, D. F., 100,386 Tabusa, F., 171,203 Tachi, 133, Tachibana, Y., 193 Taddei, M., 186,212,238,272, 291 Tagaki, K., 233 Tagliavini, E., 153, 216 Tago, H., 134 Taillades, J., 186 Tajima, E., 165 Tajima, K., 134 Yajima, M . , 283 Takada, T., 520 Takagi, K., 59 Takahashi, H., 254,531 Takahashi, K., 87,111,131, 145,282,287 Takahashi, M., 383, 413 Takahashi, T . , 308,319,401, 485,504 Takahashi, T. T., 284 Takahashi, Y., 176 Takai, H., 482 Takai, K., 46,48, 85,213,221, 227, 408 Takainami, S., 356 Takaishi, N., 220 Takaki, K., 86,226 Takaku, H., 224 Takano, K., 259 'Takano, S., 516 Takano, Y., 112,338 Takaoka, T., 283 Takata, Y., 4 Takayama, H., 61 Take, K., 141,327 Takeda, A., 181,182,426 Takeda, K . , 190,501 Takeda, T., 51,108 Takei, H., 507 Takenaka, H., 352,400 Takenaka, S., 371,385 Takeshi, N., 413 Takeshita, H., 10 Takeshita, K., 46,364 Takeuchi, H., 259 Takeuchi, M., 11 Takeuchi, R., 245 Takeuchi, S . , 162 Takeuchi, Y . , 296,302,363 Takikawa, Y., 238 Takimoto, S., 144 Takinami, S., 22,231 Takizawa, S., 238 Tam, J. P., 198 Tamagawa, M., 300

Tamao, K., 47,211,221,350, 360 Tamariz, J., 170 Tamaru, Y., 84,93, 169, 186, 190,227 Tamblyn, W. H., 159, 204 Tamm, C., 135,136 Tamura, Y . , 142, 383 Tanabe, H., 238 Tanacs, B . , 226 Tanaka, C., 3,228,413 Tanaka, H., 97,305 Tanaka, K., 40,42,100,112, 160, 177,229,290, 346 Tanaka, M., 278 Tanaka, N., 42,177,247,366 Tanaka, R., 307 Tanaka, S., 82,143 Tanaka, T., 206,297,522 Tanaka, Y., 29,34,232, 363, 364, 411 Tanguy, G., 140 Tani, H., 3, 228 Taniguchi, M., 472, 519 Tanimoto, S., 148,238,301 Taniyma, E., 351,465 Tantratrat, T., 296 Tarbin, J. A., 294 Tardella, P. A., 112, 279 Tardivel, R., 117 Tashiro, M., 141,242 Tassi, D., 212, 272 Taticchi, A., 391 Tatsumi, T., 317 Tatsumo, T., 235 Tatsuta, K., 531 Taufer, I., 148 Taura, T., 193 Taya, K., 122 Taylor, E. C., 164 Taylor, G., 302 Taylor, R. T., 227 Tedga, N., 118,156,265 Tegeler, J. J., 453 Tenaglia, A , , 68 Teramura, K . , 450 Teranishi, S., 47, 85,227,482 Terao, Y., 262 Terasaki, S., 245 Termini, J., 31, 105 Terpstra, J. W., 164, 311 Terrett, N. K., 360 Teshirogi, T., 190 Testaferri, L . , 237, 330 TeyssiC, P., 146 Tezuka, H., 387 Thaisrivongs, S., 154,353,537 Thal, C . , 426 Thebtaranonth, Y . , 149 Theodoropoulos, D., 198 Therien, M., 435, 527 Thianpatanagui, S., 304 Thiebault, H., 117 Thieffy, A , , 230

Author Index Thies, R. W. 406 Thijs, L., 115,268 Thomas, D. G., 252 Thomas, E. E., 394 Thomas, R. D., 36,218, 344 Thompson, D .,286 Thompson, P. A., 355 Thompson, W. J., 155 Thomsen, I . , 194 Thorsen, M., 194 Tice, C. M . , 250 Tickner, A. M., 198 Ticozzi, C., 431 Tiecco, M., 237, 330 Tietze, L.-F., 428,474 Timmers, D., 319, 381 Tingoli, M., 237, 330 Tischler, S. A . , 184 Tishchenko, I. G., 64 Titus, G. R., 265 Tius, M. A , , 212 Tjoeng, F.-S., 191 Tober, D., 479 Toda, F., 100,112,229,290 Todd, M., 211 Tolle, R., 192 Toh, N., 266 Toi, N., 302, 485 Tojo, T., 417 Tokunaga, T., 64 Tokutake, N., 489 Tol, R., 382 Tomas, M., 304,458,460 Tomasik, W., 300 Tomasini, C., 224 Tominaga, H., 317 Tomioka, H., 11 Tomioka, K., 532 Tomo, Y., 169 Tomoda, S . , 296,302, 363 Tooyama, Y., 176,505 Topalsavoglou, N., 93 Tordeux, M., 121 Torii, S., 95, 97, 120,305, 382 Torisawa, Y., 215 Torre, G., 211,448 Torregrosa, J. L., 269 Torrini, I., 122 Torssell, K. G., 219 Toru, T., 297, 522 Toshimitsu, A., 235,309, 387 Totten, G. E., 153 Tou, J. S., 150 Tour, J. M., 30, 384 Touraud, E., 454 Townsend, C. A . , 491 Townsend, L. B., 291,487 Tran Huu Dau, E., 296 Trapani, G . , 262, 357 Trecoske, M. A . , 90 Trefonas, L. M., 181 Trenerry, V. C., 217 Trippett, S., 339 Trius, A ., 230

567 Trivedi, G. K., 295 Trombini, C . , 153,216 Trost, B. M., 38, 50,63, 148, 163,166,174,183,247,280, 319,330,358,359, 376, 388, 393,394,402, 405 Trudell, M. L., 164 Trueblood, K. N., 244 Tschamber, T., 489 Tse, A . , 188 Tsien, Y.-L., 18 Tsubata, K . , 478 Tsuboi, S., 182,426 Tsuchihashi, G., 94,402 Tsuchiya, K., 243 Tsuchiya, R., 196 Tsuchiya, T . , 253, 487 Tsuge, O., 393 Tsuge, S., 87 Tsui, J., 401 Tsuji, J., 3,38, 39,102, 103, 123,124,169,185, 228,280, 315,319, 504 Tsuji, T., 47,221 Tsuji, Y., 229,245,282 Tsukanaka, T., 8 Tsumaki, H., 128, 301 Tsumiyama, T., 263 Tsumo, T., 243 Tsunekawa, K., 2 Tsuno, Y., 4,410 Tsunokawa, Y . ,408 Tsuruoka, Y., 245 Tsuyama, K., 145 Tsuzuki, R., 126 Tucker, B., 231, 305 Tucker, J. R., 319,381 Tueting, D., 89, 333, 369 Tumey, M. L., 27 Tundo, P., 11,371 Tuniguchi, H., 215 Turner, S. E., 493 Turowski, E. C., 344 Tyler, P. C., 536 Tyrrell, A. W. R., 181 Tyrrell, N. D., 187 Uccella, N., 301 Uchida, Y., 317 Uchino, T., 383 Uchiyama, H., 324 Uchiyama, M., 93 Uda, H., 176 Uberhardt, T., 204 Ueda, K., 242 Ueda, M., 190,343 Ueda, S . , 224 Uehara, H., 88 Uematsu, T., 524 Uemura, M., 327 Uemura, S . , 10,200, 235,309 Ueno, Y., 3,31, 85,169, 227, 228,413 Ueshima, T., 85

Uggeri, F., 140 Ugolini, A., 435, 527 Ukachukwa, V. C., 179 Ukai, J., 60, 324 Ukita, T., 9,28, 178,376 Ullah, S., 296 Ullrich, F.-W., 104 Ullrich, J. W., 304, 460 Ulrich, H., 305 Umani-Ronchi, A . , 153,216, 245 Umeda, N., 208,353 Umezawa, S . , 253 Undheim, K., 235 Uneyama, K., 95 Ungur, N. D., 230 Uno, H . , 510 Uno, Y., 167 Urabe, H., 122, 126, 338,368 Urayama, T., 175 Urbach, H., 352,465 Urbanski, M. J . , 439 Urch, C. J., 229,368 Urrea, M., 261, 515 Urso, F., 335, 488 UskokoviC, M. R., 529 Utaka, M., 181,426 Utimoto, K., 290 Uwaya, S., 121 Uyehara, T., 505 Vagberg, J . , 321 Valeds, J. A . , 305 Valencia, N., 8 Valentin, E., 388 VallCe, Y., 166 Van Asch, A., 283 van den Aardweg, G. C. N., 57, 287 van den Goorbergh, J. A. M., 156 van der Gen, A., 25,156,228, 370 van der Leij, M., 14 Van der Plas, H. C., 253 Van Derveer, D., 6 Vandewalle, M., 501 van Dijk, B. G., 451 Van Elburg, P., 228 Vankar, Y. D., 220 Van Middlesworth, F., 137, 211 van Noort, P. C. M., 238 van Rijn, P. E., 265 Van Royen, L. A., 394 van Schaik, T. A. M., 25,370 van Tamelen, E. E., 387,399, 400,507 Van Wallendael, S . , 477 Varma, R. K., 253 Vasdella, A., 272 Vasella, A., 298 Vatele, J.-M., 66, 164 Veda, M., 190

568 Vedejs, E., 446, 458 Vehara, A . , 196 Veki, M . , 199 Vemura, M . , 141 Vemura, S., 143, 387 Venanzi, L. M., 302,314,471 Venkateswarlu, R., 170 Venturello, C., 407 Venturello, P., 11, 371 Verboom, W., 451 VerhC, R., 114,262,303,456 Verkruijsse, H. D., 265 Vermeer, P . , 80,328 Vermeeren, H. P. W., 238 Vernikre, C., 53,218 Veronese, A . C., 449 Versace, R., 493 Vessal, B., 237 Vessiere, R., 454 Vialle, J., 166 Viallefont, Ph., 192 Vidaluc, J. L., 199 Villieras, J., 32, 105, 160 Vishmuvajjala, B. R., 440 Visnick, M., 173 Viswanathan, M . , 234 Viti, S. M . , 279 Vlad, D. F., 230 Voelter, W., 197 Vogel, D. E . , 56 Vogt, K., 429 Vogtle, F . , 239 Volkmann, R. A . , 92, 160, 329,472 Vollhardt, K. P. C., 336 Vo-Quang, L., 107 Vo-Quang, Y . , 107 Vorbruggen, H., 287, 366 Voss, G., 142 Voss, J., 187 Vostrikova, 0. S., 231 Voyer, N., 121,287, 290 Voyle, M., 182 Vuilhorgne, M., 384 Wada, F . , 17, 393 Wada, M., 170,184,373,418 Wada, T., 393 Wade, J. D., 198 Waegell;B., 68 Waespe-SarEeviL, N., 135 Wagenaar, A . , 189 Wagner, A . , 429 Wagner, I., 192 Waigh, R . D . , 253 Wakabayashi, S . , 87 Wakabayashi, T., 122 Wakabayashi, Y . , 208, 290 Wakamatsu, H., 169 Wakamatsu, T., 476 Wakamiya, T., 194 Wakefield, B. J., 522 Wakselman, C., 121 Waldmann, H., 196

General and Synthetic Methods Walker, A . , 345,491 Walkinshaw, M. D., 443 Walkup, R. D., 532 Wall, A . , 60 Wallace, I. H. M . , 382 Wallace, P. M . , 276, 537 Wallace, T. W., 211, 522 Wallendael, S. V., 335 Walley, D. R., 11, 144 Wallis, C. J . , 522 Waltermire, R. E., 159 Wamhoff, H., 303 Wang, B. C., 400 Wang, D., 208,366 Wang, K. K., 71 Wang, N., 539 Wang, W.-L., 111,342,412 Wani, M . C., 440 Waniguchi, E., 122 Ward, R. S . , 170 Warin, R., 146 Warner, P., 65 Warner, R. W., 183, 319 Warren, S., 12, 31, 50, 104, 162,188,237,281, 370, 377 Wartski, L., 293 Waseda, T., 74, 109 Washioka, Y . , 175 Wasmuth, D., 136 Wassermann, H. H., 471, 487, 539 Watanabe, H., 29, 364 Watanabe, K., 4,419 Watanabe, M., 188, 478 Watanabe, N., 309 Watanabe, T., 309,428, 448 Watanabe, Y . , 229,245,282 Waterhouse, I., 522 Waterhouse, J., 121,223 Watt, D. S . , 64, 86, 167, 182, 344 Waykole, L., 179 Weatherford, W. D., 86 Webb, M. W., 86 Webb, R. R., jun., 351, 378, 465 Weber. E., 239 Weber, G . , 307 Weber, T., 340 Weedon, A. C., 102,164 Weerasooriya, U., 90,265 Wegmann, H., 261,515 Wei-Hwa Leong, W., 32,369 Weiler, L . , 184, 399 Weinberger, B., 140 Weingold, D. H., 204 Weinkam, R. J., 300 Weinreb, S . M., 55,63,269, 271,302,378,473, 514 Weinschneider, S . , 187 Weinstein, R. M . , 111, 342, 412 Weisser, J., 285 Welch, C. J., 254

Welch, S. C., 411 Wells, G. J., 387 Welvart, Z . , 91 Welzel, P., 154 Wender, P. A . , 54, 108,358, 390, 497 Wenderoth, B., 122,213, 337 Wendler, N. L., 539 Wenger, C., 13 Wenke, G., 153 Wenkert, D., 133 Wenkert, E., 329, 349, 391, 421 Werstiuk, N. H., 92 West, F. G., 458 Westermann, J., 5 Westmijze, H., 80, 328 Weuster, P . , 418 Wheaton, G. A . , 372 Wheeler, C. J., 166 White, A. H., 452 White, D. H., 142 White, G. S., 470 White, J. D., 536 White, L. L., 44, 182 Whitesell, J. K., 125, 151, 349 Whitesell, M. A . , 125, 268 Whitham, G. H., 68 Whiting, M. C., 138 Whittle, A . J., 41, 177, 507, 536 Wicha, J . , 319 Widdowson, D. A . , 327 Widera, R., 454 Widmer, U . , 144 Wieschollek, R., 15 Wilbur, D. S . , 367 Wilcox, C. S . , 537 Wilde, H., 307 Wildonger, K. J., 493 Wilhelm, R. S., 129 Wilkening, R. R., 493 Willeit, A . , 456 Willfahrt, J., 192 Williams, D. J., 181, 276 Williams, D. R., 1, 226, 303, 358,411,435 Williams, E. G . , 438, 525 Williams, G. D., 319, 381 Williams, J. R., 197 Williams, L., 221, 357 Williams, P. J., 185, 280 Williams, R. V., 376, 392 Williams, T. H., 529 Williamson, S. A . , 473 Willner, I., 233 Wilson, I. B . , 197 Wilson, J. S., 228 Wilson, J. W., 15,23,92,221, 357 Wilson, S. R., 9, 361,394 Wilson, W. K., 135 Winkler, J. D., 384 Winwick, T., 225

569

Author Index Wise, D. S . , 291 Wise, S . , 65 Witt, W., 239 Woell, J. B., 132, 150 Wolfe, S., 84 Wolff, A., 489 Wolff, G . , 489 Wolff, S., 303 Wolfram, J., 468 Wong, H., 303 Wong, J . , 41 Wood, J. L., 394,501 Wood, R. D., 345 Woodgate, P . D., 309 Woodward, R. B., 191 Worster, P. M., 198 Worthington, P. A . , 503 Wright, J. E., 198 Wrobel, J. E., 180 Wroble, R. R., 86 Wulff, W. D., 394 Wuts, P. G. M . , 355 Wymann, W. E., 247 Wynberg, H., 373 Xingya, L., 443 xo, z . , 400 Xu, Y., 430 Yadav, L. D. S., 31 Yaginuma, F., 245 Yahata, N., 87, 145 Yamabe, K., 307 Yamada, H . , 167,237 Yamada, S., 61 Yamada, T., 195 Yamada, Y., 67,84,85,93, 169, 186,227, 328 Yamagishi, T., 196 Yamaguchi, H., 30,33, 86, 103,175,225,227 Yamaguchi, K., 472,519 Yamaguchi, M., 74, 75, 109, 188,206,356 Yamaguchi, R., 81 Yamahira, A . , 239 Yamaji, T., 29, 364 Yamakawa, K . , 121 Yamamoto, H . , 44, 49, 60, 118,176,209,229,254,256, 258,275, 324,358, 365, 398, 404,466,477 Yamamoto, K . , 170, 242 Yamamoto, S . , 47, 221 Yamamoto, T., 360

Yamamoto, Y., 54, 84,128, 151,152,169,213,216,227, 355,367,381 Yamamura, Y., 49,256, 404, 466 Yamana, M., 20, 21,117 Yamana, Y., 146 Yamanaka, H., 74 Yamanaka, Y., 215 Yamanouchi, T., 371,385 Yamaoka, S., 410 Yamashita, H., 173, 382 Yamashita, M., 2,402 Yamashita, Y., 58, 233 Yamauchi, M . , 428 Yamauchi, T., 140 Yamawaki, J . , 10,84,226,293 Yamazaki, H . , 180 Yamazaki, N., 208, 353 Yamazaki, Y., 93 Yan, T. H., 387 Yanagi, K., 524 Yanagi, Y., 296 Yanagida, M., 79, 343 Yanagida, N., 507 Yanaura, S., 254 Yang, D. C., 394 Yang, S., 232 Yang, T.-K.,252,463 Yano, Y., 237 Yashunsky, D. V., 88,380 Yasuda, H., 8, 50, 107, 142, 317, 324, 326 Yasumura, M., 86, 226 Yatagai, M., 196 Yates, P., 305 Yates, S . W., 86 Yatsu, I., 237 Yde, B., 194 Yeates, C., 436 Yevich, Y. P., 252 Yoakim, C., 122,225,358 Yogo, T., 94,109 Yokomatsu, T., 475,484 Yokoo, K., 215 Yokota, S . , 158 Yokoyama, K., 127 Yokoyama, M., 85,127,227, 228,283 Yokoyama, T.-a., 291 Yokoyama, Y., 169,300 Yoneda, S . , 117,138,351 Yonekura, M., 491 Yonemitsu, O., 225, 417 Yonezawa, Y., 195 Yoon, N. M., 205

Yoshida, H . , 434 Yoshida, J., 50,221,238,359 Yoshida, K., 391 Yoshida, M., 424 Yoshida, Y . , 285 Yoshida, Z., 84,93,169,186, 190,227 Yoshihara, K., 505 Yoshii, E., 501 Yoshikawa, S., 169,227 Yoshikawa, T., 470 Yoshikoshi, A . , 176, 182 Yoshimura, N., 263 Yoshinaga, M., 239 Yoshitomi, S . , 309 Yoshiura, K., 175 Young, C . G., 386 Young, D. W., 194 Young, S . , 211 Yuasa, Y., 475,484 Yuba, K., 57,134 Yue, S., 487 Yukizaki, H., 229, 350 Yunokihara, M., 169 Yus, M., 18,187,219,282, 349 Yuste, F., 185 Zahra, J.-P., 73,116,140,293 Zajac, W. W., jun., 113, 298 Zaks, W. J., 393 Zama, M., 196 Zanotti, V . , 4, 113 Zard, S. Z., 87, 251 Zask, A . , 326, 431 Zawacky, S. R., 400,507 Zayed, S . M. A . D., 253 Zbiral, E, 89, 371 Zecchini, G. P., 122 Zelle, R. E., 539 Zen, S . , 226 Zeng, L.-M., 46, 283,348,365 Zenki, S.-i., 309, 448 Zetta, L., 359 Zhou, B., 137,211 Zirotti, C., 523 Zoran, A., 4 Zore, B., 197 Zuger, M. F., 154,211 Zutterman, F., 393,404, 501, 502 Zwanenburg, B., 14, 115,268, 447 Zweifel, G., 76, 77, 78, 139, 364 Zwick, W., 151 Zydowsky, T. M., 133