General and Synthetic Methods Vol.6

General and Synthetic Methods

Volume 6

A Specialist Periodical Report

General and Synthetic Methods Volume 6

A Review of the Literature Published during 1981

Senior Reporter G. Pattenden, Department of Chemistry, University of Nottingham Reporters R. C. Brown, Fisons p.l.c., Loughborough, Leicestershire J. M. Clough, I.C.I. Plant Protection Division, Bracknell S. C. Eyley, Fisons p.l.c., Loughborough, Leicestershire P. F. Gordon, I.C.1, Organics Division, Manchester P. R. Jenkins, University of Leicester A. P. Johnson, University ofleeds R. C. F. Jones, University of Nottingham G. Kneen, Wellcome Research Laboratories, Beckenhem, Kent D. W. Knight, University of Nottingham

S. V. Ley, Imperial College, London A. J. Nelson, I.C.I. Organics Division, Manchester R. A. Porter, Imperial College, London G. M. Robertson, University of Nottingham

The Royal Society of Chemistry Burlington House, London, W I V OBN

ISBN 0-85 186-874-6 ISSN 0141-2140

Copyright @ 1983 The Royal Society of Chemistry AN Rights Reserved No part of this book may be reproduced or transmitted in any form or by means-graphic, electronic, including photocopying, recording, taping or information storage and retrieval systems-without written permission from the Royal Society of Chemistry

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

Introduction This sixth Report on General and Synthetic Methods covers the literature from January to December 1981. The presentation of most data is similar in scope and format to the previous volumes in the series, with the exception that a new chapter ‘Highlights in Total Synthesis of Natural Products’ replaces the earlier title ‘Strategy and Design in Synthesis’. Dr. Knight, one of only two remaining members of the original team of contributors to the Reports, provides his last contribution in Volume 6, and I thank him for his enthusiastic collaboration over the past six years. G. PATTENDEN

December 1982

V

Contents Chapter 1 Saturated and Unsaturated Hydrocarbons By J. M. Clough

1

1 Saturated Hydrocarbons

1

2 Olefinic Hydrocarbons

5

3 Conjugated 1,3-Dienes

38

4 Non-conjugated Dienes

44

5 Allenic Hydrocarbons

11

6 Acetylenic Hydrocarbons

47

7 Enynes and Diynes

50

8 Polyenes

52

Chapter 2 Aldehydes and Ketones By S. C. Eyley

56

1 Synthesis of Aldehydes and Ketones Oxidative Methods Reductive Methods Methods Involving Umpolung Other Methods Cyclic Ketones

58 61 63 67

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

72 72 80 85

3 Protection and Deprotection of Aldehydes and Ketones

88

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

89 89 92

Chapter 3 Carboxylic Acids and Derivatives By P. R. Jenkins

56

56

95

98 98

1 Carboxylic Acids General Synthesis

101 vii

...

Conten ts

Vlll

Diacids Hydroxy -acids Keto-acids Unsaturated Acids Decarboxylation Protection and Deprotection

102 103 104 104 107 108

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

109 109 109 111 114 116 118 123 123

3 Lactones General Synthesis @Lactones Butyrolactones Butenolides Phthalides Tetronic Acids a-Methylenebutyrolactones Valerolactones

124 124 125 126 133 136 137 137 139

4 Macrolides

140

5 Carboxylic Acid Amines Synthesis Macrocyclic Lactams Reactions

142 143 143 143

6 Amino-acids Synthesis Unsaturated a-Amino-acids Asymmetric Hydrogenation Protection and Deprotection Peptide Synthesis

144

Chapter 4 Alcohols, Halogeno-compounds, and Ethers By R. C. F. Jones 1 Alcohols Preparation Carbonyl Group Reduction

144 147 147 150 151 154

154 154 157

ix

Contents Asymmetric Reductions Allylic and a-Allenic Alcohols Other Unsaturated Alcohols Diols Protection Reactions

160 153 166 169 173 178

2 Halogeno-compounds Preparation Vinyl halides Reactions Halogen Displacement by Nucleophiles-Phase-transfer Methods

180 180 182 183

3 Ethers Preparation Reactions

185 185 186

4 Thiols and Thioethers

187

5 Macrocylic ‘Crown’ Polyethers and Related Compounds Synthesis Applications

189 189 191

Chapter 5 Amines, Nitriles, and Other Nitrogen-containing Functional Groups By G.Kneen

193

184

1 Amines Primary Amines Secondary Amines Tertiary Amines

193 193 197 200

2 Nitriles and Isocyanides

202

3 Nitro- and Nitroso-compounds

207

4 Hydroxylamines

210

5 Hydrazines

210

6 Azo-compounds

210

7 Imines

211

8 Carbodi-imides

213

9 Enamines

213

Contents

X

10 Azides and Diazonium Compounds

214

11 Isocyanates, Thiocyanates, Isothiocyanates, Selenocyanates, 215 and Isoselenocyanates 12 Nitrones

217

13 Nitrates

217

Chapter 6 Organometallics in Synthesis Part I The Transition Elements By S. V. Leyand R, A. Porter

218

1 Introduction

218

2 Reduction

219

3 Oxidation

220

4 Isomerization and Rearrangement

223

5 Carbon-Carbon Bond-forming Reactions

224

6 Synthesis of Heterocycles

233

7 Miscellaneous Reactions

235

Part II Main Group Elements By P. F. Gordon and A. J. Nelson

236

1 Group I Selective Lithiation Alkenyl Anions and Synthetic Equivalents Miscellaneous

236 236 242 244

2 Group XI Magnesium Zinc and Mercury

246 246 249

3 Group XI1 Boron Aluminium and Thallium

249 249 254

4 GroupIV Silicon C-C Bond Formation Silicon-based Reagents Tin and Lead

255 255 255 262 264

xi

Contents

5 Group V Phosphorus Arsenic and Bismuth

265 265 268

6 GroupVI Sulphur Selenium Tellurium

269 269 272 276

Chapter 7 Saturated Carbocyclic Ring Synthesis By D. W. Knight

277

1 Three-membered Rings General Methods Natural Cyclopropanes

277 277 279

2 Four-membered Rings

280

3 Five-membered Rings Fused Five-membered Rings Naturally Occurring Fused Cyclopentanoids

283 285 289

4 Six-membered Rings Diels-Alder Reactions Other Six-membered Ring Synthesis Steroids An thracyclines

293 293 298 301 3 02

5 Polyene Cyclizations

304

6 Seven-membered Rings

306

7 Ring Expansion Methods

307

8 Medium and Large Rings

309

9 Spiro-ring Compounds

310

Chapter 8 Saturated Heterocyclic Ring Synthesis By R. C.Brown 1 Oxygen-Containing Heterocycles Oxirans Oxetans Five-membered Rings Six-membered Rings

312

3 12 312 3 14 3 14 318

xii

Contents

2 Nitrogen-containing Heterocycles Three-membered Rings Four-membered Rings Five-membered Rings Five-membered Rings with two or more Nitrogen Atoms Six-membered Rings

321 321 322 327 33 1 336

3 Sulphur-containing Heterocycles Thiirans, Thietans, and Thiophen Derivatives Thiapyran Derivatives

346 346 348

4 Ring Systems of more than Six Members Containing Heteroatoms of One Type Benzoxepins Rings Containing Nitrogen Rings Containing Sulphur

349

5 Heterocycles Containing Both Oxygen and Nitrogen Three-membered Rings Five-membered Rings Six-membered Rings

355 355 356 359

6 Heterocycles Containing Both Oxygen and Sulphur Four-membered Rings Six-membered Rings

362 362 363

7 Heterocycles Containing Both Nitrogen and Sulphur Three- and Four-membered Rings Five-membered Rings Six-membered Rings Seven-membered Rings

363 363 364 365 369

8 Heterocycles Containing Nitrogen, Oxygen, and Sulphur

370

349 349 354

Chapter 9 Highlights in Total Synthesis of Natural Products 371 B y A . P. Johnson 1 Introduction

37 1

2 Terpene and Other Carbocyclic Systems

371

3 Steroids

379

4 Anthracyclinones

380

5 Alkaloids

382

6 Stereochemically-complex Oxygen Heterocycles

387

...

xi11

Contents

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

390

1 Olefins

390

2 Aldehydes and Ketones

390

3 Nitrogen-containing Functional Groups

390

4 Organometallics Boron Silicon Tin Transition Elements

390 390 390 390 391

5 Ring Synthesis

391

6 Heterocycles

391

7 Photochemical Methods

392

8 Oxidation

392

9 Asymmetric Synthesis

392

10 Polymer Supports in Synthesis

392

11 Protecting Groups

392

12 Natural Product Synthesis

393

13 General

393

14 Miscellaneous

394

Author Index

395

1 Saturated and Unsaturated Hydrocarbons BY J. M. CLOUGH

1 Saturated Hydrocarbons Several new and improved methods for the reductive removal of functional groups have been presented during the year. Extending a process developed for the reduction of secondary alcohols, Barton and his co-workers have shown that primary alcohols, derivatized as xanthate or thiobenzoate esters, or as thiocarbony1 imidazolides, are deoxygenated without competing Chugaev elimination on treatment with tri-n-butyltin hydride at 130-150 O C . l Selective derivatization of primary hydroxyl groups is straightforward, enabling them to be removed without affecting secondary hydroxyl or other functional groups. Primary and secondary alcohols, or their methyl or trimethylsilyl ethers, are conveniently deoxygenated via the corresponding iodides generated in situ by successive treatment with sodium iodide, chlorotrimethylsilane, and zincm2 Diaryl- or triarylmethanols are reduced to the corresponding arylmethanes on refluxing with iron pentacarbonyl and benzoyl chloride in me~itylene.~ A mixture of sodium borohydride and palladium chloride reduces aryl ketones and benzyl alcohols to the corresponding hydrocarbons. Carboxylic acid esters and non-activated hydroxyl groups are not affected by this new reducing system, but ketones are reduced to alcohols, and aromatic chlorine atoms are r e m ~ v e d . ~ Bis(benzoyloxy)borane, prepared in situ from BH,*THF and benzoic acid, is a convenient alternative to catecholborane for the reduction of the tosylhydrazone derivatives of aldehydes and ketones to hydrocarbons under mild condition^.^ Ketones that are relatively unhindered can be deoxygenated in the gas phase at 190 "Cin the presence of hydrogen over a nickel-alumina catalyst.6 The main drawback of the method is the lack of selectivity: other functional groups are also lost under the reaction conditions. A mixture of sodium borohydride and cerium trichloride in methanol at room temperature fully reduces the carbonyl group of thiochromones to give the corresponding thiochromenes (Scheme l).' Chromones or their thiones remain unchanged under these reaction conditions. D. H. R. Barton, W. B. Motherwell, and A. Stange, Synthesis, 1981, 743. T. Morita, Y. Okamoto, and H. Sakurai, Synthesis, 1981, 32. Tien-Yau Luh, Synth. Comrnun., 1981,11,829. T. Satoh, N. Mitsuo, M. Nishiki, K. Nanba, and S. Suzuki, Chem. Lett., 1981, 1029. G . W. Kabalka and S. T. Summers, J. Org. Chem., 1981,46, 1217. W . F. Maier, K. Bergmann, W. Bleicher, and P. von R. Schleyer, Tetrahedron Lett., 1981,22,4227. ' H. Yamaoka, T. Hakucho, and K. Akiba, Heterocycles, 1981, 15, 1159.

1

General and Synthetic Methods

2 0

R',R2=H or Me Scheme 1

Non-activated primary, secondary, or tertiary alkyl fluorides (as well as chlorides) are reduced in high yield to hydrocarbons by a solution of potassium and dicyclohexyl-18-crown-6 in diglyme or toluene at ambient temperature.8 Organotin hydrides can be supported on inorganic carriers like alumina or silica, enabling alkyl halides to be reduced under heterogeneous condition^.^ As an alternative to its use in dipolar aprotic solvents, sodium borohydride can be used to reduce alkyl chlorides, bromides, and iodides as well as sulphonate esters to alkanes under phase-transfer conditions." Dichloromethane solutions of the readily-available reagents P214and PI3 reductively remove the halogen from a-iodo- and a-bromo-ketones, usually at room temperature and in high yield." The research groups of Tanner12 and Ono" have independently reported that tertiary and some secondary nitro groups are removed by reduction with tri-nbutyltin hydride in the presence of a radical initiator. Keto, ester, cyano, phenylthio, and primary nitro groups remain unchanged under the reaction conditions. The sulphonyl group of a-nitrosulphones is replaced by hydrogen on treatment with N- benzyl-l,4-dihydronicotinamide (BNAH) in deoxygenated DMF (Scheme2).14 Keto and cyano groups are not affected. In the presence of a catalytic amount of azobis(isobutyronitrile), or under irradiation, BNAH also reduces alkylmercury(I1)acetates to alkane^.'^ 0,N SO,Ph BNAH+

0

& 0

Scheme 2

Olah and his co-workers have discovered that the reducing ability of magnesium in methanol is dramatically enhanced by the addition of a catalytic amount of palladium metal on carbon; even non-activated multiple carboncarbon bonds are rapidly and completely reduced under these reaction conditions.16 Following their recent disclosure of a three-step process for the replacement of oxygen in ketones by two methyl groups, Reetz and his co-workers have now

* T. Ohsawa, T. Takagaki, A. Haneda, and T. Oishi, Tetrahedron Lett., 1981,22,2583. H. Schumann and B. Pachaly, Angew. Chem., Int. Ed. Engl., 1981,20,1043. F.Rolla, J. Org. Chem., 1981,46,3909. J. N. Denis and A. Krief, Terrahedron Lett., 1981,22, 1431. l2 D.D.Tanner, E. V. Blackburn, and G. E. Diaz, J. A m . Chem. SOC.,1981,103,1557. l 3 N. Ono, H. Miyake, R. Tamura, and A. Kaji, Tetrahedron Lett., 1981,22, 1705. 14 N. Ono,R. Tamura, R. Tanikaga, and A. Kaji, J. Chem. Soc.,-Chem. Commun., 1981,71. l S H.Kurosawa, H. Okada, and T. Hattori, Tetrahedron Lett., 1981,22,4495. G . A. Olah, G. K. S. Prakash, M. Arvanaghi, and M. R. Bruce, Angew. Chem., Int. Ed. Engl., 1981,20, 92. lo

3

Saturated and Unsaturated Hydrocarbons

shown that the transformation can be accomplished directly by treatment of the ketone with dimethyltitanium dich10ride.l~Smooth geminal methylation occurs even when the product has two neighbouring quaternary carbon atoms, e.g. the terpene 'cuparene' (1). Methyltitanium chlorides (prepared from dimethylzinc 0 2MezT'C'2

and titanium tetrachloride in suitable proportions), or dimethylzinc and catalytic quantities of titanium tetrachloride, also methylate t - a l c o h o l ~ ,t-ethers, ~~ t(reported in 1980) and s- (but not primary-) alkyl chlorides, and gem-dihalides (e.g. Scheme 3).18

OC' -0 Me,Zn-TiCI.,

Scheme 3

Metzger et al. have examined the addition of alkanes to a representative selection of activated, non-activated, and de-activated olefins at high temperature (650-723 K) and under high pressure (ca. 200 bar)." Yields are strongly dependent on the reaction conditions and the olefin: alkane ratio, but regioselectivity, which seems to be controlled mainly by steric rather than electronic factors, is remarkably high in some cases, e.g. Scheme 4.

+O

miY23

r+ 30%

1.5%

Scheme 4

l9

M. T. Reetz, J. Westermann, and R. Steinbach, J. Chem. SOC.,Chem. Commun., 1981, 237. M. T. Reetz, R. Steinbach, and B. Wenderoth, Synth. Commun., 1981, 11, 261. J. Metzger, J. Hartmanns, and P. KOII, Tetrahedron Lett., 1981, 22, 1891.

4

General and Synthetic Methods

The free radicals generated by treating t-butyl, allyl, or benzyl halides with three equivalents of chromous chloride couple to form symmetrical dimers. Alternatively, a careful choice of reaction conditions enables good yields of cross-coupled products to be prepared, e.g. (2) + (3).20

Reagents: i, 3CrCl3-3LiEt,BH; ii, Bu'Br

Benzyl chlorides and bromides undergo reductive coupling at room temperature and under neutral conditions on treatment with a small excess of chlorotris(triphenylphosphine)cobalt(I), e.g. (4) -B (5).*l Benzal bromide gives E-stilbene under the same conditions. Alternatively, benzyl, alkyl, and aryl chlorides, bromides, and iodides can be reductively coupled by using lithium in tetrahydrofuran under the influence of ultrasound.22 Little or no reaction occurs in the absence of sonic waves. Long straight-chain iodoalkanes (e.g. 1iodotetradecane) undergo reductive coupling to give n-alkanes on treatment with hydrazine and a catalytic amount of palladium, but yields fall dramatically with shorter

CoCI(PPh,),

, /

Larock and Leach have described the first general method for the alkylation of a wide variety of organomercurials. For example, primary alkylmercurials cross-couple with alkylcuprates to give moderate yields of alkanes, e.g. (6) -+ (7);

Reagents: i, Li,CuMe,; ii, MeI-0,

reactions involving secondary alkylmercurials are less efficient.24 [ 1.,3Bis(diphenylphosphin0) propane] nickel(I1) chloride catalyses the cross-coupling of alkylmagnesium halides or alkylalanes with arylphosphates to furnish arylalkanes in high yields (e.g. Scheme 5).25 Lipschutz and his co-workers have reported that the mixed cuprates prepared from cuprous cyanide and two 2o

22

23 24 25

R. Sustmann and R. Altevogt, Tetrahedron Lett., 1981,22, 5167. Y. Yamada and D. Momose, Chem. Left.,1981,1277. Byung Hee Han and P. Boudjouk, Tetrahedron Lett., 1981, 22, 2757. R. Nakajima, K. Morita, and T. Hara, Bull. Chem. SOC.Jpn., 1981,54, 3599. R. C. Larock and D. R. Leach, Tetrahedron Lett., 1981,22, 3435. T. Hayashi, Y. Katsuro, Y. Okamoto, and M. Kumada, Tetrahedron Letr., 1981, 22,4449.

Saturated and Unsaturated Hydrocarbons

5

Bun I

Scheme 5

equivalents of an alkyl- (or vinyl-) lithium are highly reactive species; they smoothly couple at low temperatures even with unactivated secondary alkyl bromides and iodides to give hydrocarbons (Scheme 6).26Though less reactive, secondary alkyl tosylates are also suitable substrates, but secondary alkyl chlorides and mesylates are almost inert. -

i

A-

1

i

i

-

\

h

Reagents: i, Et,CuCNLi,; ii, (CH,=CH)2CuCNLi,

Scheme 6

2 Olefinic Hydrocarbons

Several research groups are exploring synthetic routes to tetra-t-butylethylene, regarded as the ultimate sterically-hindered olefin, and a number of new 'tied back' relatives have been described. Warner and Jacobson and their c o - w o r k e r ~ ~ ~ have shown that the gem- dibromocyclopropane (8) undergoes carbene dimerization on treatment with methyl-lithium to give, albeit in low yield, the olefin (9).

Spectroscopic data indicate that there are no severe non-bonded repulsions in (9),and that the double bond is planar. The groups of Guziec28 and Krebs2' have described syntheses of the hindered olefins (lo), (ll),and (12). Conversion of (10) into tetra-t-butylethylene itself failed when functionalization of the aromatic rings could not be achieved without cleavage of the double bond2* 26 27

*'

29

B. H. Lipshutz, R. S. Wilhelm, and D. M. Floyd, J. A m . Chem. SOC.,1981,103,7672. P. Warner, S.-C. Chang, D. R. Powell, and R. A. Jacobson, Tetrahedron Lett., 1981, 22, 533. E. R. Cullen, F. S. Guziec, jun., M. I. Hollander, and C. J. Murphy, Tetrahedron Lett., 1981, 22, 4563. A. Krebs, W. Ruger, and W.-U. Nickel, Tetrahedron Lett.. 1981, 22, 4937.

General and Synthetic Methods

6

Convincing evidence for the existence of methylenecyclopropene has been provided by trapping it in the form of a [4 + 21 cycloadduct for the first time; treatment of the sulphonium salt (13) with sodium cyclopentadienide furnished the hydrocarbon (14)in 13% yield.30

Adam and his co-workers have shown that sterically congested E-olefins are conveniently prepared by the p-lactone route shown in Scheme 7.31Stereocontrol is achieved because a-lithiocarboxylates condense with aldehydes and ketones to give p- hydroxy acids of predominantly threo- configuration; once formed, dehydrative cyclization is straightforward because the bulky substituents force the carboxy and hydroxy groups into juxtaposition.

R..H..H - ul&R-R HO C 0 2 H

’” R-’ H R H R (R= But or 1-adamantyl) Reagents: i, 2Pr’,NLi; ii, RCHO; iii, H’; iv, PhS0,CI-py; v, 180 “C RCH,C02H

Scheme 7

Bicyclic bridgehead olefins with a carbonyl group in the largest bridge can be constructed by oxy-Cope rearrangement of 3-hydroxy-1,s-dienes of types (15)32 and (16).33Considerable interest has been shown in the strained bicyclic enone (17) and several independent syntheses have been

+ KH

30 31

32 33 34

A. Weber and M. Neuenschwander, Angew. Chem., Int. Ed. Engl., 1981,20,774. W. Adam, G . Martinez, J. Thompson, and F. Yany, J. Org. Chem., 1981,46, 3359. S. G. Levine and R. L. McDaniei, jun., J. Org. Chem., 1981,46, 2199. S. L. Schreiber and C. Santini, Tetrahedron Lett., 1981, 22, 4651. A. B. Smith, 111, B. H. Toder, S. J. Branca, and R. K. Dieter, J. Am. Chem. Soc.. 1981, 103, 1996; M. J. Begley, K. Cooper, and G . Pattenden, Tetrahedron Lett., 1981, 22, 257; Tetrahedron, 1981, 37, 4503; D. K. Klipa and H. Hart, J. Org. Chem., 1981, 46, 2815; N. E. Schore and M. C. Croudace, J. Org. Chem., 1981,46,5436.

7

Saturated and Unsaturated Hydrocarbons

Umani-Ronchi and his co-workers have prepared various new active metals that consist of highly dispersed palladium or nickel on graphite and which selectively catalyse the semi-hydrogenation of acetylenes to 2-ole fin^.^' A different catalyst for the same process can be prepared by successive treatment of chloromethylated polystyrene beads with anthranilic acid and palladium chloride.36 Alternatively, acetylenes can be reduced to 2-olefins by a catalytic transfer process using sodium phosphinate as the hydrogen donor and an easily prepared lead- or mercury-modified palladium cataly~t.~’ Demerseman and Dixneuf have reported that acetylenes react with Cp2Ti(CO)2 in wet hexane to give vinyltitanium complexes (18), the vinylic hydrogen atoms originating from water (Scheme 8). Cleavage of the carbontitanium bonds by aqueous acid is stereospecific, releasing 2-olefins ( 19).38 R

FR

CPzTi,

2R-G-R -4CO

O,

ii

2

R T R

dTiCPZ R

(19) R = C02Me,C02Et,or Ph

R

(18) Reagents: i, 2Cp2Ti(CO),-H,0; ii, aq.HC1

Scheme 8

Vinyl sulphides are cleanly reduced to the corresponding olefins without stereomutation or over-reduction by 2-propylmagnesium bromide and a catalytic amount of bis(triphenylphosphino)nickel(II) chloride. Acetals, ethers, aromatic systems, and isolated olefins are compatible with these reaction In a mild alternative to the Hofmann elimination, acrydinium salts (20), prepared from the corresponding pentacyclic pyrilium salt and primary amines, are converted into terminal olefins (21) on heating with the non-nucleophilic base triphen~lpyridine.~’Small quantities of 2-alkenes are formed as by-products.

’’ D. Savoia, C. Trombini, A. Umani-Ronchi, and G. Verardo, J. Chem. SOC.,Chem. Commun.,

1981, 540; D. Savoia, E. Tagliavini, C. Trombini, and A. Umani-Ronchi, J. Org. Chem., 1981, 46, 5340; ibid., p. 5344. 36 N. L. Holy and S. R. Shelton, Tetrahedron, 1981,37, 25. ” R. A. W. Johnstone and A. H. Wilby, Tetrahedron, 1981, 37, 3667. B. Demerseman and P. H. Dixneuf, J. Chem. SOC.,Chem. Commun., 1981,665. B. M. Trost and P. L. Ornstein, Tetrahedron Lett., 1981, 3463. 40 A. R. Katritzky and A. M. El-Mowafy, J. Chem. SOC.,Chem. Commun., 1981,96.

’’ ’’

General and Synthetic Methods

8

Ph

Acid-sensitive t-alcohols can be dehydrated by a process that is related to the Chugaev reaction but which takes place at much lower temperatures (refluxing THF) (Scheme 9).41 uic-Diols react with iodoform, triphenylphosphine, and imidazole to give the corresponding olefin, probably via reductive elimination from a di-iodo intermediate;42 this method is particularly useful for preparing unsaturated sugars.

[w] S

i.ii

/

\

,

3CO

Me

/

/

\

\

Reagents: i, 2NaH; ii, CS2

Scheme 9

uic -Dibromides and dichlorides are dehalogenated to give olefins in almost quantitative yields on treatment with sodium sulphide in DMF at room temperat~re.~~ Clive and KTilk have shown that p- oxygenated selenides, sulphides, and iodides are smoothly and stereospecifically converted into olefins on treatment with chlorotrimethylsilane and sodium iodide in acetonitrile, e.g. (22) -+ (23).44 A specific use for this transformation is the reversal of various cyclofunctionalization processes, allowing them to be used to protect at the same time a double bond and an attached nucleophile, e.g. (24) + ( 2 5 ) . A related use for

Me,SiCI-NaI

'

P2" (25)

(24) X = PhSe,PhS, or I 41

S. J. Bailin, K. D. Grande, A. Kunin, S. Thanabalasundrum, and S. M. Rosenfeld, Synth. Commun.. 1981, 11, 141.

42

43 44

M. Bessodes, E. Abushanab, and R. P. Panzica, J. Chem. SOC.,Chem. Commun., 1981.26. K. Fukunaga and H. Yamaguchi, Synthesis, 1981,879. D. L. J. Clive and V. N. K X , J. Org. Chem., 1981,46,231.

Saturated and Unsaturated Hydrocarbons

9

chlorotrimethylsilane and sodium iodide in acetonitrile is the stereospecific deoxygenation of oxirans to give olefins, e.g. Scheme

-

Me,SiO

0

Et

Et

Scheme 10

Primary alkyl phenyl tellurides undergo elimination to form terminal olefins in high yields on treatment with an excess of N-chloro-N-sodio-4-methylbenzenesulphonamide (chloramine-T) in refluxing THF.46 uic -Dinitro compounds and p -nitrosulphones are converted into olefins via free-radical elimination processes on treatment with tributyltin hydride in the presence of catalytic quantities of azobis(isobutyronitri1e) (AIBN).47Elimination from the dinitro compounds shows no stereocontrol; by contrast, elimination from p- nitrosulphones is highly stereoselective, e.g. (26) + (27), presumably because elimination from the intermediate radical is faster than rotation about the central carbon-carbon bond. 02NgT:N MeEt

Bu3SnH

~

AIBN

CN 2:E = 9 7 : 3

(26)

(27)

y-Trimethylsilyl t-alcohols (28) undergo a carbonium ion rearrangement under acidic conditions with a phenyl or hydride shift and loss of the silyl group.48 Competing hydride and alkyl shifts are observed with alcohols (28) in which R’ is an alkyl group.

GR2 BF3.2AcOH

Me$

OH

R’

(28) R’= H or aryl; R2# H

The Horner modification of the Wittig reaction, in which a diphenylphosphinoyl group is the anion-stabilizing function, can be used to prepare olefins of either E- or Z-geometry. Reaction of a lithiated alkyldiphenylphosphine oxide with an aldehyde gives predominantly the erythro- alcohol (29) (precursor of the Z- olefin), whereas successive acylation and reduction gives predominantly the threo- alcohol (30) (Scheme 1lh4’ 45

R. Caputo, L. Mangoni, 0. Neri, and G. Palumbo, Tetrahedron Lett., 1981,22, 3551.

T.Otsubo, F. Ogura, H. Yamaguchi, H. Higuchi, Y. Sakata, and S. Misumi, Chem. Lett., 1981,447. *’ N. Ono,H. Miyake, R. Tamura, I. Hamamoto, and A. Kaji, Chem. Lett., 1981,1139. 48 I. Fleming and S. K. Patel, Tetrahedron Lett., 1981, 22, 2321. 49 A. D.Buss and S. Warren, J. Chem. SOC.,Chem. Commun., 1981,100.

46

General and Synthetic Methods

10

i,iii

1

Reagents: i, Bu"Li; ii, R'CHO; iii, R*CO,Et; iv, NaH; v, NaBH,

Scheme 11

Baker and Sims have shown that addition of a catalytic quantity of 15-crown-5 to a Wadsworth-Emmons reaction greatly facilitates olefin f ~ r m a t i o n . ~For ' example, reaction between the aldehyde (3l ) , phosphonate (32), and sodium hydride in the presence of 15-crown-5 gave the heterocyclic stilbene analogue (33) (45% : the key step in a synthesis of the furanosesquiterpene pallescensinE).'l

9 '

+

( E t 0 ) 2 0 p yC00 , M e

~

%ozMe

15-crown-5

\

CHO

NaH

I

02)

1

(3 1)

(33)

[(Phenylthio)methyl]carbinyl benzoate esters, e.g. (34), easily prepared from ketones, undergo reductive elimination to give high yields of olefins, e.g. (35) on treatment with titanium metal in refluxing T H F (Scheme 12).52 SPh

(34)

(35)

Reagents: i, PhSCH,Li; ii, Bu"Li; iii, (PhCO),O; iv, TiC1,-K; v, MeOH

Scheme 12

Kauffmann and his co-workers have developed a series of titanium or chromium reagents (Me3SiCH2TiC1,, Me3SiCH2CrC12,Me,GeCH2TiC13) which 50 51

R. Baker and R. J. Sirns, Synthesis, 1981, 117. R. Baker and R. J. Sirns, Tetrahedran Lett., 1981, 22, 161; J. Chem. Soc., Perkin Trans. I , 1981,

52

S.C. Welch and J.-P. Loh, J. Org. Chem., 1981, 46, 4072.

3087.

Saturated and Unsaturated Hydrocarbons

11

selectively methylenate aldehydes in moderate to high yields e.g. Scheme 13; ketones react to only a very small extent or not at all.53The reagents are easily generated in siru by treatment of the corresponding magnesium compounds with TiC14 or CrC13.

Scheme 13

The first method for preparing alkylidene-bridged bimetallic complexes with bridging groups other than methylene e.g. (36) has been discovered, and preliminary experiments have shown that these too are capable of converting ketones into olefins, e.g. cyclohexanone + (37), and esters into vinyl Bu'

Aromatic aldehydes or ketones can be coupled to give stilbenes by the low-valent titanium method without affecting carboxylate, tosylate, or haloaromatic substituents in the A synthetic sequence has been discovered in which aldehydes which are not branched at the a-position undergo formal reductive dimerization to give symmetrical olefins (e.g. Scheme 14).56At the key step, a-stannylalkyl halides, which are stable and easily handled, smoothly couple on treatment with n-butyl-lithium under very mild conditions (-78 to 0 "C).Furthermore, the difference in reactivity between a -stannylalkyl iodides and chlorides enabled a moderate yield of a cross-coupled olefin from two different aldehydes to be obtained. aBranched aldehydes exhibit a different pattern of reactivity, furnishing terminal olefins instead of coupled products (Scheme 15), probably for steric reasons. Ph

Ph eCHO -* . ... P h q S n B u n 3 CI

Reagents: i, Bu",SnLi; ii, aq. NH,CI; iii, TsCI-py; iv, Bu"Li

Ph

Scheme 14

Reagents: i, Bu",SnI.i; ii. aq. NH,CI; iii, PPhl-CBr,; iv, Bu"Li

Scheme 15

'' T. Kauffrnann,R. Konig, C. Pahde, and A. Tannert, Tetrahedron Left., 1981, 22, 5031. 54 55

F. W. Hartner, jun., and J. Schwartz, J. A m . Chem. SOC.,1981, 103,4979. L. Castedo, J. M. Saa, R. Suau, and G. Tojo, J. Org. Chem., 1981, 46, 4292; W. H. Richardson, Synth. Commun.,1981, 11, 895. Y.Torisawa, M. Shibasaki, and S. Ikegami, Tetrahedron Lett., 1981, 22, 2397.

12

General and Synthetic Methods

Mol and his co-workers have reported that self-metathesis of w- olefinic nitriles (to give unsaturated dinitriles) and co-metathesis between w- unsaturated nitriles and olefins (to give new unsaturated nitriles) can be achieved with the catalytic system WCl,-Me4Sn. Cross-coupling reactions between alkenylmercurials and alkylcuprates, or arylmercurials and alkenylcuprates, furnish moderate yields of olefins, e.g. (38) -+ (39); alkenylcuprate-alkenylmercurial combinations give 1 , 3 - d i e n e ~ . ~ ~ Alternatively, alkenyl- or alkynyl-mercurials can be methylated in high yield by a stoicheiometric quantity of the readily-available bis(tripheny1phosphine)methyldi-iodorhodium(rII), e . g (40) -+ (41). Attempts to perform the methylation with methyl iodide and catalytic amounts of the rhodium complex were less successful because of competing dimerization proce~ses.’~

’’

-

i,ii

W

H

g (38)

C

1

(39)

Reagents: i, LiCu(Me),; ii, MeI-0,

2-Dialkenylcuprates couple smoothly with iodoarenes in the presence of zinc bromide and a catalytic amount of Pd(PPh3)4to give vinylarenes of greater than 99% 2-configuration (Scheme 16). Importantly, a variety of functional groups are tolerated.” Alternatively, vinylarenes can be prepared by nickel-catalysed cross-coupling of aryl phosphates with alkenylalanes (readily prepared from the corresponding phenols and acetylenes, respectively) (Scheme 17).251-Alkenyl1,3,2-benzodioxaboroles and phenyl iodides selectively cross-couple in a ‘headto-tail’ manner when the reaction is catalysed by palladium black in triethylamine

Y

Y = H , B r , 0 M e , N 0 2 , or C 0 2 M e

Reagents: i, R,CuLi; ii, ZnBr,; iii, Pd(PPh,),; iv,I

I5

Scheme 16

Scheme 17

’’ R. H. A. Bosma,, A. P. Kouwenhoven, and J. C. Mol, J. Chem. SOC.,Chem. Commun., 1981,1081. ’’ R. C.Larock and S . S . Hershberger, Tetrahedron Lett., 1981,22,2443. s9

N. Jabri, A. Alexakis, and J. F. Normant, Tetrahedron Lett., 1981, 22, 3851.

13

Saturated and Unsaturated Hydrocarbons

(Scheme 18),60 sharply contrasting the 'head-to-head' selectivity previously observed under strongly basic conditions.

6- Bub

PhI-Pdo-Et3N,

+

Bun

\ /

\ /

96

4

Scheme 18

Negishi and his co-workers have developed several approaches to allylated arenes involving cross-coupling reactions. Preliminary studies established that aryl-aluminium, zirconium, or zinc compounds readily undergo palladium-catalysed cross-coupling with allylic halides or acetates (Scheme 19).6'Later in the year it was shown that allylic alcohol derivatives containing -0AIR2,

,&,

Pd(PPh3)4, 91%

Scheme 19

-OPO(OR)2, or -OSiR3 groups also participate in the coupling reaction.62 However, this more thorough investigation also revealed that attack at either end of the allylic moiety can occur (Scheme 20), the product ratio depending mainly on the phenylmetal and solvent chosen, and not on the regiochemistry or leaving group of the allylic substrate. Alternatively, allylated arenes can be

+ 62

:

R 38

Scheme 20

constructed highly regio- and stereo-selectively (298% pure single isomers) by cross-coupling between benzylzincs and alkenyl halides, or alkenylalanes and benzyl halides, each in the presence of catalytic amounts of palladium complexes (Scheme 21).63Pure geometric isomers of the olefinic intermediates are readily available, making this a highly convenient approach. 6o

62 63

N. Miyaura and A. Suzuki, J. Organomet. Chem., 1981,213, (253. H. Matsushita and E. Negishi, J. A m . Chem. SOC.,1981, 103, 2882. E. Negishi, S. Chatterjee, and H. Matsushita, Tetrahedron Lett., 1981, 22, 3737. E. Negishi, H. Matsushita, and N. Okukado, Tetrahedron Lett., 1981, 22, 2715.

General and Synthetic Methods

14

VZnBr +

Scheme 21

Kumada and his co-workers have reported an interesting series of crosscoupling reactions between phenylmagnesium bromide and allylic ethers where the regiochemistry of the product is dependent entirely on the catalyst. For example, reaction with either of the isomeric allylic ethers (42) or (43) under the influence of catalytic quantities of [1,l‘-bis(dipheny1phosphino)ferrocene]palladium(~~) chloride gives predominantly the internal olefin (44). By contrast, use of the corresponding nickel catalyst furnishes the terminal olefin preferentially (>81%) in each case.64

PhMgBr

9 0 S i E t 3 PdClz(dppf)

96 91

:

4

:

9

(43)

Potassium phenolates react with allylic halides in the presence of catalytic amounts of zinc chloride to afford ortho- allylated phen01s.~’The less hindered allylic phenol is always formed, via allylic rearrangement where necessary (Scheme 22), and the reaction fails only with highly electron-deficient phenolates or hindered allylic halides.

-

PhOK-ZnC1,

a -

ZhOK-ZnCl2

dc,

/

Scheme 22

It has now been shown that the photoinitiated reaction between olefins and cyanoheteroaromatic bases, which leads to allylated heterocycles, is a general process.66 Cyclic olefins are the most useful reactants since they give single products (Scheme 23); acyclic olefins usually lead to mixtures of isomeric species. 64 65

66

T. Hayashi, M. Konishi, K. Yokota, and M. Kumada, J. Chem. Soc., Chem. Cornmun., 1981,313. F. Bigi, G. Casiraghi, G. Casnati, and G. Sartori, Synthesis, 1981, 310. R. Bernardi, T. Caronna, S. Morrocchi, P. Traldi, and B. M. Vittimberga, J. Chem. Soc., Perkin Trans. I, 1981, 1607.

Saturated and Unsaturated Hydrocarbons

15

Scheme 23

Nakamura and his co-workers have reported that isoprene, in the form of the zirconium complex (45), couples with simple olefins with a remarkably high regioselectivity (>98%) with respect to both olefin and diene. For example, pent-2-ene furnishes a high yield of 2,5-dimethyloct-2-ene (Scheme 24), contaminated only with 1%of the isomeric 2-methy1-5-ethylhe~t-2-ene."~

CpJr

(A) 2 2

2 Q2Zr >%+

(45)

Scheme 24

a-t-Butyldimethylsilyl aldehydes, which have been isolated for the first time

by careful hydrolysis of the corresponding imines, serve as vinyl cation equivalents for the synthesis of disubstituted olefins (Scheme 25). Stereocontrol is possible because addition of organomagnesium or lithium reagents to the silyl aldehydes gives p- hydroxysilanes of almost pure erythro- stereochemistry.68

A" R'

j-jii

H-x-H

Bu'SiMe2 OH

-%

Rz+o

R2

ButSiMe,

Et

R' = cyclohexyl R2 = n-hexyl

RzReagents: i, LDA-Bu'Me,SiCI; BF,.OEt,; vi, KH

ii, LDA-R'Br; iii, AcOH-H,O-CH,CI,;

iv, EtMgBr or EtLi; v,

Scheme 25

Z-Dialkenylcuprates undergo Michael addition to a$- unsaturated sulphones to give, following desulphonylation, high yields of olefins; the 2-geometry of the cuprate is preserved throughout the sequence (Scheme 26).69 Bu" Bu" Bun HCECH

A b c U L i 12

-

b

S

Reagents: i, Bu",CuLi; ii, Me,C=CHSO,Ph; iii, 6% Na-Hg

0

2

P

h Z :E > 9 9 : 1

Scheme 26 67 68 69

H. Yasuda, Y. Kajihara, K.Nagasuna, K. Mashima, and A. Nakamura, Chem. Lett., 1981, 719. P. F. Hudrlik and A. K. Kulkarni, J. A m . Chem. SOC., 1981, 103,6251. G. De Chirico, V. Fiandanese, G. Marchese, F. Naso, and 0. Sciacovelli, J. Chem. SOC., Chem. Commun., 1981,523.

General and Synthetic Methods

16

Cuprate species of the type R3Cu2MgX(X = C1or Br) add regio- (and stereo-) specifically to terminal acetylenes to give 1,l-disubstituted olefins e.g. (46) + (47).70 The choice of starting materials from which the cuprates are generated, as well as the incorporation of an excess of lithium bromide, is important if dimerization of the intermediate vinylcuprates is to be avoided. n-C,H,,C=CH

i,Me3Cu2MgCI(LiB& ii,H+

(46)

+

n-C,H13

A

(47)

Ally1 cations generated from 2-alkyl allylic chlorides, e.g. (48), and zinc chloride react with substituted olefins to give good yields of highly substituted Where unsymmetrical substrates lead to more than cyclopentenes, e.g. (49).71 one cyclopentene the thermodynamically most stable isomer predominates.

A combination of recently-reported transformations provides a sequence for the conversion of cycloalkenes into exo -methylenecycloalkanes of the same ring size (Scheme 27).72

Reagents: i, 9-BBN; ii, CO-Li(MeO),AIH; iii, LiAIH,; iv, MeS0,H; v, PhCHO

Scheme 27

Under the catalytic influence of Ni(PPh3)4, both E- and Z-1,2dichloroethylene react with Grignard reagents without stereomutation to give vinyl chlorides of defined geometry (Scheme 28); vinyl Grignard reagents give l-chlor0-1,3-dienes,~~On treatment with the copper(1) chloride complex of triphenylphosphine or triphenylphosphite at 150-180 “C, vinyl bromides are converted into the corresponding vinyl chlorides in high yields and without stere~mutation.~~

Scheme 28 70

” ” ” 74

H. Westmijze, H. Kleijn, J. Meijer, and P. Vermeer, Red. Trau. Chim. Pays-Bas, 1981, 100, 98. H. Klein and H. Mayr, Angew. Chem., Int. Ed. Engf., 1981, 20, 1027. H. C. Brown and T. M. Ford, J. Org. Chem., 1981,46,647. V. Ratovelomanana and G. Linstrumelle, Tetrahedron Lett., 1981, 22, 315. G. Axelrad, S. Laosooksathit, and R. Engel, Synth. Commun.. 1981, 11, 405; J. Org. Chem., 1981,46,5200.

Saturated and Unsaturated Hydrocarbons

17

In the presence of catalytic quantities of zinc halides, propargyl halides are converted into allenyl cations; these undergo stepwise [2 + 21 or [3 + 21 cycloaddition to olefins to furnish moderate yields of a-halobenzylidenecyclobutanes or 1-halocyclopentenes depending on the substitution pattern of the propargyl halide (Scheme 29).75

Scheme 29

p,p- Dibromoalcohols, which are readily prepared by addition of dibromomethyl-lithium to aldehydes or ketones, undergo reductive elimination on treatment with zinc and acetic acid in refluxing methylene chloride to give vinyl bromides as mixtures of E- and 2-isomers (Scheme 30).76 Conjugated 1-bromo-dienes or -trienes can be prepared from the appropriate unsaturated carbonyl compounds.

rB

-& Reagents: i, CHzBrz-(C6H, ,)JW; ii, Zn-CH,CO,H

E :Z= 55:45

Scheme 30

Vinylboronic acids, easily prepared by hydroboration of acetylenes, react with iodine monochloride at low temperatures to give good yields of E-vinyl iodides (Scheme 31). This mild alternative to an earlier approach is compatible with hydroxy, alkoxy, and carbomethoxy groups.77Following monocarbozirconation, treatment of 1-pentynyldimethylalane (50) with iodine gives 1,l-di-iodo-2methylpent-1-ene (51) in 92% yield.78

c1*Reagents: i,

i, ii

-a

; ii,

/

B(OH)2 A 3 (-

/ I

H,O;iii, ICl-NaOAc

Scheme 31 " 76

" 'I8

H. Mayr, B. Seitz, and I. K.Halberstadt-Kausch, J. Org. Chem., 1981,46,1041. D.R. Williams, K.Nishitani, W. Bennett, and S. Y . Sit, Tetrahedron Lett., 1981,22, 3745. G. W.Kabalka, E. E. Gooch, and H. C. Hsu, Synrh. Commun., 1981,ll.247. T.Yoshida and E. Negishi, J. Am. Chem. SOC.,1981,103,1276.

18

General and Synthetic Methods

Reagents: i, C1(Me)ZrCp2;ii, I,

Wittig reactions between allyl formates and stabilized or semi-stabilized phosphonium ylides give allyl vinyl ethers in moderate to good yields, e.g. ( 5 2 ) --+ ( 5 3 ) ;by contrast, non-stabilized ylides give none of the expected ether^.'^ In a related olefination, carboxylic esters and 6- or 7-membered lactones react with an excess of the triphenylphosphine-carbon tetrachloride reagent to give variable yields of 2,2-dichlorovinyl ethers, e.g. (54) + (5 5 ).8 0

(54)

(55)

c1

Silver salts catalyse the addition of carboxylic acids to acetylenes to give enol esters, often in good yields, e.g. (56) -+ (57)." Symmetrical acetylenes are the most satisfactory substrates because regioselectivity is not high.

OCOR (57) R = Me,Et, or Ph

Stang and Anderson have reported that isopropylidenecarbene, generated from the silylvinyltriflate ( 5 8 ) , is trapped by alkyl or aryl isocyanates to give, following quenching with water, moderate yields of vinyl carbamates.82

(58)

R = But,C6H11, or Ph

Reagents: i, Bun4hF;ii, RNCO; iii, H,O

N-Acyl amino acids or peptides (59) can be converted in three steps into the corresponding enamides (60) via Scheme 32.83 79

M. Suda, Chem. Lett., 1981,967;C. J. Burrows and B. K. Carpenter, J. A m . Chem. Soc., 1981,

103,6983.

83

M.Suda and A. Fukushima, Tetrahedron Lett., 1981,22, 759. Y.Ishino, I. Nishiguchi, S. Nakao, and T. Hirashima, Chem. Lett., 1981,641. P.J. Stang and G . H. Anderson, J. Org. Chem., 1981,46,4585. U.Redeker, N.Engel, and W. Steglich, Tetrahedron Letr., 1981,22, 4263.

Saturated and Unsaturated Hydrocarbons

19

Reagents: i, Ac20-4-Me2N-CsH4N-Et3N; ii, NH,OH-NaOAc; iii, TosCI-Et,N

Scheme 32

Seebach and Knochel have shown that 2-nitro-3-pivaloyloxyprop-1-ene(61) smoothly transfers a 2-nitroallyl group to both stabilizeds4 and non-stabilizeds5 nucleophiles (e.g. ketone or ester enolates; alkyl, vinyl, or acetylenic lithium or magnesium derivatives). Importantly, the pivaloyloxy group, itself sterically protected from nucleophilic attack, is not eliminated at the temperatures at which Michael addition takes place (-70 to -110 "C),excluding the possibility of a second addition. Nitroalkanes can be converted into the corresponding 1-nitroalkenes by a-phenylselenenylation followed by the usual oxidative elimination.86 Although the intermediate selenides can be isolated, a one-pot procedure gives higher overall yields. NO,

(61) Reagents: i, Bu'LLi; ii, 2% aq.AcOH

Vinyl carbanions, generated from ketones by treatment of trisylhydrazone derivatives with butyl-lithium, react cleanly with chlorodiphenylphosphine to give vinyldiphenylphosphines or, following oxidation, the corresponding phosphine oxides. Unsymmetrical ketones are converted regiospecifically into the less-substituted vinyl phosphine oxide (Scheme 33).x7 OPPh2

I

--*

ii,iii

d

Reagents: i, 2Bu'Li; ii, Ph2PCI; iii, H,O, or CH,CO,H-Na2C0,

Scheme 33

Optimum conditions for the direct conversion of simple terminal olefins into vinylsilanes using triethylsilane and rhodium catalysts have been established. Ally1 and saturated silanes are by-products.88 Hexamethyl-, chloromethyl-, and methoxymethyldisilanes add regiospecifically to allene or buta- 1,2-diene at 84

85 86

P. Knochel and D. Seebach, Nouu. J. Chim., 1981,5,75. P.Knochel and D. Seebach, Tetrahedron Lett., 1981, 22, 3223. T. Sakakibara, I. Takai, E. Ohara, and R. Sudoh, J. Chern. SOC., Chem. Cornmun., 1981,261. D. G. Mislankar, B. Mugrage, and S. D. Darling, Tetrahedron Lett., 1981, 22, 4619. A. Millan, E. Towns, and P. M. Maitlis, J. Chem. Soc., Chem. Commun., 1981, 673.

20

General and Synthetic Methods

100-120 "C in the presence of a catalytic amount of Pd(PPh3)4 to give 1: 1 adducts containing both vinylsilane and allylsilane units, e.g. (62).89

//c'

fi

Si2Me6-Pd(PPh3),

I

R=HorMe

SiMe, (62)

Treatment of either 1- (63) or 3-trimethylsilylally1 acetate (64) with nucleophiles (enamines or sodium derivatives of active methylene compounds) in the presence of a catalytic mixture of Pd(PPh3)4and triphenylphosphine gives . ~ ~ E :2-ratio of the products is vinylsilane derivatives, e.g. (65),e x c l ~ s i v e l yThe almost the same whichever ally1 acetate is used, suggesting that the same intermediate T-allylpalladium complex is involved in each case. C0,Et M e 3 s i y

-!.+ M e 3 S i ~ C 0 , E 1 & P O A C SiMe,

OAc (63)

(65)

(64)

Reagent: i, NaCH(CO,Et),-Pd(PPh,),-PPh,

Catalytic amounts of either t-butyl-lithium or lithium aluminium hydride induce smooth isomerization of E- (1-iodo-1-alkenyl)trimethylsilanes,uia (l-lithio-lalkeny1)silane intermediates, into the corresponding 2 -isomers which show >97'/0 isomeric purity.g1 Straight-chain terminal olefins can be directly and selectively lithiated to form E- 1-lithio-1-olefins using lithium in the presence of catalytic amounts of 1,6,6aA 4- trithiapentalene derivatives and metal salts (Scheme 34).92 (n = 0, 1 , 3 , or 5)

s. ,s Reagent: i, 2Li- P

h

u

P

h -ZnC1,

Scheme 34

p -Hydroxyorthothioesters, e.g. (66), which can be prepared from orthothioesters and aldehydes or ketones, are transformed into keten thioacetals, e.g. (67), on treatment with P214 and triethylamine. pHydroxythioacetals furnish vinyl sulphides under the same conditions, and the method works equally well with the selenium analogue^.'^ The ylide generated from the stable phosphonium salt (68) is a convenient reagent for the transformation of aliphatic or aromatic aldehydes (but not ketones) into keten dithioacet als.94 89 90

91

92

93 94

H. Watanabe, M. Saito, N. Sutou, and Y. Nagai, J. Chem. SOC.,Chem. Commun., 1981,617. T. Hirao, J. Enda, Y. Ohshiro, and T. Agawa, TetrahedronLett., 1981,22,3079. G.Zweifel, R. E. Murray, and H. P. On, J. Org. Chem., 1981,46,1292. B. BogdanoviC and B. Wermeckes, Angew. Chem., Int. Ed. Engl., 1981,20,684. J. N. Denis, S. Desauvage, L. Hevesi, and A. Krief, Tetruhedron Lett., 1981,22,4009. S.Tanimoto, S. Jo, and T. Sugimoto, Synrhesis, 1981,53.

Saturated and Unsaturated Hydrocarbons

HC(SMe),

Ph

I

OH SMe SMe

-

21 SMe

Ph+

/ SMe

Me SMe (66) Reagents: i, Bu"Li; ii, PhCOMe: iii, P,I,-Et,N

I. Bu"Li

The cyclic oxime ether (69) can be selectively lithiated at either the 3-methyl or the 4-methylene position by choosing an appropriate lithium dialkylamide. Scheme 35 illustrates how this provides the basis for a new synthesis of amethylene ketone^.^'

Reagents: i, LiNMe,; ii, PhCH,Br; iii, LiNBu'Pr'; iv, MeI; v, Et,O+BF;; vi, Me,N; vii, Si02-H20

Scheme 35

A useful sequence has been described for the conversion of aldehydes and ketones, via their silyl enol ethers, into a-methyl-a,P- unsaturated aldehydes or ketones (Scheme 36).96 When applied to cyclic ketones, the products are a-methylcycloalkenones with one extra carbon atom in the ring." Je3

i ,M ?e

CI

ii or iii,

Reagents: i, Cl,CHCH3-Bu"Li; ii, refluxing PhMe; iii, Et,N-refluxing MeOH

Scheme 36

The readily-available vinamidinium salt (70) reacts with aliphatic, aromatic, or benzylic organolithium or Grignard reagents to produce, following acidic work-up, 3-substituted-2-phenylacroleins (71).98

Reagents: i, RMgX or RLi; ii, H' 95 96

9' 98

R Lidor and S.Shatzmiller, J. A m . Chem. Soc., 1981, 103, 5916. L. Blanco, P. Amice, and J.-M. Conia, Synthesis, 1981, 291; L. Blanco, N. Slougui, G. Rousseau, and J.-M. Conia, Tetrahedron Leu., 1981, 22, 645. L. Blanco, P.Amice, and J.-M. Conia, Synthesis, 1981, 289. J. T. Gupton and C. M. Polaski, Synth. Commun., 1981, 11, 561.

22

--

General a n d Synthetic Methods

Lithium trialkylalkynylborates react stereoselectively with benzo- 1,3dithiolium fluoroborate to give functionalized vinylboranes (72) of mainly E- configuration (Scheme 37). Hydrolysis furnishes stereochemically pure E-a,P-unsaturated aldehydes because the small proportion of 2-vinylborane is relatively

Q

/\/\/+

/

BR,&

~

A R

Reagents: i,

as>

E:Z35:1 (72)

CHO

ii,iii

BR2

R

BF,; ii, Pr'C0,H; iii, HgO-BF,

' s

Scheme 37

Allyltrimethylsilyl ethers, e.g. (73), react with aryl iodides in the presence of stoicheiometric amounts of palladium acetate and lithium chloride to afford moderate yields of E-6- aryl-a,& unsaturated carbonyl compounds, e.g. (74).'"" When the products are ketones they are contaminated with the corresponding saturated species.

AOSiMe, ' PhI-Pd(OAc)z-LiCI

p h A C H O (74)

(73)

Irradiation of oxygenated acetonitrile solutions of q3-allylpalladium complexes leads to a,@-unsaturated aldehydes or ketones (Scheme 38).'01

I

PdCl/2

39%

0 3 2o/'

Scheme 38

Fleming and Perry have shown that the p-silylenone (75) is an a3d2-synthon (76) (Scheme 39); furthermore, the corresponding 0-silylynone is an analogous 2a3d2-~ynthon.102 The importance of the silyl group is that it can be relied on to remain in place during the d2-reaction, and then it can be removed, unmasking the conjugated carbon-carbon double bond. 99

loo

lo'

A. Pelter, P. Rupani, and P. Stewart, J. Chem. SOC.,Chem. Commun., 1981, 164. T. Hirao, J. Enda, Y.Ohshiro, andT. Agawa, Chem. Lert., 1981,403. J. Muzart, P. Pale, and J.-P. Pete, J. Chem. SOC.,Chem. Commun., 1981, 668. I. Fleming and D. A. Perry, Tetrahedron, 1981, 37,4027.

Saturated and Unsaturated Hydrocarbons

23

(76) Reagents: i, Me,CuLi; ii, Me,SiCI; iii, PhSCH(CI1Pr"; iv, Raney Ni; v, PTAB; vi, HBr; vii, DBU

Scheme 39

On heating, the p- silylsulphoxide (77) undergoes rapid syn- elimination to give the enone (78). Hpwever, when substrates with a hydrogen-atom alpha to the silyl group are heated, the hydrogen atom is selectively lost and the products are p-silylenones e.g. (79) + (8O).lo3

Me,Si

fi

C C I , , ~ ~ T +MejSi

(79)

(80)

3-Trimethylsilylallylc alcohols of the type (81) react with phenylsulphenyl chloride to give unstable allylic sulphoxides which rearrange spontaneously at room temperature; hydrolysis then furnishes a,@-unsaturated aldehydes (Scheme 40).Io4

R2

Reagents: i, PhSCl-Et,N; ii, aq.AgN0,

Scheme 40 '03

I. Fleming and D. A. Perry, Tetrahedron Lett., 1981, 22, 5095. I. Cutting and P. J. Parsons, Tetrahedron Len.. 1981, 22, 2021.

24

General and Synthetic Methods

a-Phenylselenoaldehydes, which are readily converted into a,@-unsaturated aldehydes, can be formed directly under mild conditions from unactivated aldehydes using N,N- diethylbenzeneselenamide. Ketones and carboxylic esters are inert.lo5 Anodic oxidation of solutions of the potassium salts of a,a-disubstituted-pketo acids in aqueous potassium hydroxide gives moderate to high yields of a,P -unsaturated ketones, e.g. (82) -+ (83).'06 p -Keto acids with an a -hydrogen atom give only saturated ketones.

Pyridinium chlorochromate in dichloromethane and pyridine has been used to oxidize an a-cyanoketone to the corresponding a-cyano-a,& unsaturated ketone,lo7 and a-acetylenic ketones are reduced stereospecifically to the corresponding E- enones by chromous sulphate.lo8 Cyclopentenones are formed when P,y- olefinic ketones are treated successively with bromine and sodium hydroxide, as illustrated by a straightforward synthesis of dihydrojasmone (Scheme 41).'09 y- Ketoaldehyde acetals can be

Scheme 4 1

converted in one operation into 2-alkylcyclopentenones using an ion-exchange resin which is a mixture of sulphonic acid beads and quaternary ammonium hydroxide beads (Scheme 42).'lo Other convenient syntheses of 2-alkylcyclopentenones (from cyclopentanone) have been described.' l1

Reagent: i, R-276 Rexyn 300 (H-OH)ion-exchange resin

Scheme 42 lo' '06

lo'

'09 ''O

M. Jefson and J. Meinwald, Tetrahedron Left., 1981,22,3561. M. Chkir, D. Lelandais, and C. Bacquet, Can. J. Chem., 1981,59,945. Y . Mori, M. Tsuboi, and M. Suzuki, Chem. Pharm. Bull., 1981,29,2478. A. B. Smith, 111, M. A. Guaciaro, S. R. Schow, P. M. Wovkulich, B. H. Toder, and T. W. Hall, J. A m . Chem. Soc., 1981,103,219. T. Fujisawa and K. Sakai, Chem. Left., 1981, 5 5 . J. C. Stowell and H.F. Hauck, jun., J. Org. Chem., 1981,46,2428. A. Barco, S. Benetti, P. G. Baraldi, and D. Simoni, Synthesis, 1981, 199; N. Ono, H. Miyake, and A. Kaji, Synthesis, 1981, 1003.

25

Saturated and Unsaturated Hydrocarbons

The a-(carboethoxy)vinylcuprate (84), generated by conjugate addition of lithium cyanomethylcuprate to ethyl propiolate, reacts with a,@-unsaturated acid chlorides to form divinyl ketones. Subsequent Nazarov-type cyclization, now shown to be promoted by trimethylsilyl iodide, yields highly substituted cyclopentenones (Scheme 43)."*

1

(84)

2Me3SiI

Scheme 43

The enone mesylate (85), prepared in almost quantitative yield from cyclohexane-l,3-dione, reacts at room temperature with various nucleophiles (e.g. NaOEt, Me2NH, PhCH,SNa) to give p -functionalized cyclohexenones, e.g. (86).l13Dimedone is also a suitable precursor, but the sequence fails with acyclic 1,3-diones. By contrast, the dilithio species (87), functioning as an equivalent of the p- vinyl carbanion of cyclohexenone, reacts with electrophiles (e.g. alkyl iodides, aldehydes, ketones) to give P -substituted cyclohexenones, e.g. (88).'l4

(85)

(86) X = C1, Br, or I

Reagents: i, MeS02CI-K2C0,; ii, PhCH2NEt3X-BF,

n

? J d,.ldLi

0

O-OLi

ii,iii

(87) Reagents: i, 2Bu"Li;ii, MeI; iii, H30'

2-Chloro-2-nitropropane, behaving as an acetone equivalent, reacts by a radical chain process with P-diketones and P-ketoesters to give their isopropylidene derivatives, as keto-enol tautomeric mixtures in some cases, e.g. 'I2

'I3

'I4

J. P. Marino and R. J. Linderman, J. Org. Chem., 1981,46, 3696. C. J. Kowalski and K. W. Fields, J. Org. Chem., 1981,46, 197. C. Shih and J. S. Swenton, Tetrahedron Lett., 1981, 22,4217.

26

General and Synthetic Methods

(89) + (90).'15 Liotta and his co-workers have described modifications of Reich's a-selenation method that allow P-diketones, p- ketoesters, and pketoaldehydes to be oxidized to the corresponding unsaturated p- dicarbonyl species."6

Reagents: i, NaH; ii, Me,C(NO,)CI, hv

a -1odo-a$-unsaturated aldehydes, e.g. (91), have been prepared for the first time."'

I

(91)

Brittelli has described a cheap and general one-pot synthesis of a,& unsaturated acids based on the Wadsworth-Emmons reaction (Scheme 44).'" A straightforward and high yielding synthesis of p- unsubstituted-a,& unsaturated acids which is suitable for large-scale preparations has been developed (Scheme 43."' a,P-Unsaturated acids can be prepared in high yield by cobalt carbonyl-catalysed carbonylation of vinyl bromides under phase-transfer conditions.12'

Reagents: i, 3NaH or 3NaOEt; ii, R'CHBrC0,H; iii, R2CHO; iv, H 2 0

Scheme 44

HO. RCH,CO,H

R&=T .A x o

%

R

CO,H

(X= H or CH20H) Reagents: i, H2NCMe2CH20H;ii, HCHO-KOH; iii, H'

Scheme 45

'16

'I7

120

G. A. Russell, B. Mudryk, and M. Jawdosiuk, Synthesis, 1981,62. D. Liotta, C. Barnum, R. Puleo, G. Zima, C. Bayer, and H. S. Kezar, 111, J. Org. Chem., 1981, 46, 2920;D. Liotta, M.Saindane, C. Barnurn, H. Ensley, and P. Balakrishnan, Tetrahedron Lett., 1981,22,3043. R. Antonioletti, M. D'Auria, G. Piancatelli, and A. Scettri, Tetrahedron Lett., 1981,22, 1041. D.R. Brittelli, J. Org. Chem., 1981,46,2514. S.Serota, J. R. Simon, E. B. Murray, and W. M. Linfield, I.Org. Chem., 1981,46,4147. J.-J. Brunet, C. Sidot, and P. Caubere, Tetrahedron Lett., 1981,22,1013.

27

Saturated and Unsaturated Hydrocarbons

(Trimethylsilyl)acetyltrimethylsilane (92) can be elaborated in a highly stereoselective, stepwise manner into disubstituted E-a,P-unsaturated acylsilanes (93), precursors of E-a,@-unsaturated acids or aldehydes.'"

R'= Me,Et,allyl, or benzyl

E :Z ~ - 9 8 : 2 (93)

Reagents: i, LDA; ii, R'X; iii, R'CHO

Suzuki and Miyaura have shown that 1-alkenylboranes react rapidly with carbon monoxide in the presence of palladium chloride and sodium acetate in methanol to give methyl a,@-unsaturated carboxylates.122Importantly, carbon replaces boron with retention of configuration, so the complete sequence constitutes a stereo- and regio-specific anti-Markownikoff hydrocarboxylation of acetylenes (Scheme 46). Thermolytic elimination of sulphur and hydrogen

R2 Reagents: i, a

E

J

H ; ii, CO-MeOH-NaOAc-PdC1,-LiC1-p-benzoquinone

Scheme 46

halides from a-halosulphides of the type (94) furnishes a,@-unsaturated esters. The method can also be used to prepare a#-unsaturated nitriles and ketones, and a,a-dihalosulphides give a-halo-a$- unsaturated products.'23 Following

R2

R2

,l, R'

Br

2 l . A SH

R'

S

C0,Me 'R'

Reagents: i, BrCH,CO,Me; ii, Br,, h v ; iii, 420-550

"C-low pressure

aldol-type condensation between the 2-keten acetal (95) and aldehydes, elimination in the same pot furnishes a,@-unsaturated esters.124The geometry of the product is strongly dependent on the Lewis acid used: aluminium chloride furnishes products of almost exclusive E- configuration, whereas the opposite is observed when titanium tetrachloride is used (as shown in Scheme 47). lZ1 lZ2 lZ3 lZ4

J. A. Miller and G. Zweifel, J. A m . Chem. Soc., 1981,103,6217. N.Miyaura and A. Suzuki, Chem. Lett., 1981,879. J.-C. Pommelet, C. Nyns, F. Lahousse, R. MerCnyi, and H. G. Viehe, Angew. Chem., Int. Ed. Engl., 1981,20, 585. I. Matsuda and Y. Izumi, Tetrahedron Lett., 1981,22, 1805.

General and SyntheticMethods

28 OSiMe, HO ~ e 3 ~ i d o Mn-C,H;;t ~

C0,Me SiMe,

(95)

-

n - C c ~ ~ 2 ~ e

Z :E = 95:5

Z :E = 95:5 Reagent: i, n-C8H,,CHO-'I'iCI,

Scheme 47

Barrett and Adlington have shown that allenic dianions (96), prepared from a-keto-amides uia the Shapiro reaction, react at C-2 with aldehydes, acetone,

and deuterium oxide to form a variety of substituted acrylamide derivative^.'^^

Reagents: i, R2CH,COCl; ii, H,O; iii, ArSO,NH.NH,; iv, 3-5 Bu"Li; v, D,O

A new procedure for the conversion of a y-lactone into the corresponding a-methylene-y- lactone has been developed during a total synthesis of the pseudoguaianolide (*)-aromatin (Scheme 48). 126 The readily-prepared complex cation (97) functions as an a- acrylic ester cation equivalent, converting cyclo-

i+{qoL{

hexanone lithium enolate into the cis- and trans-a- methylene-y- lactones (98).lZ7

@0 HO

Me,N

Reagents: i, (Me,N),CHOMe; ii, DIBAL

Scheme 48

0 0 4 -

LiO

[Fp = CsHiFe(C0)2]

(98)

Reagents: i, NaBH, or L-Selectride; ii, HPF,.Et,O; iii, Et,NBr

Semmelhack and Brickner have shown that suitable hydroxy vinyl bromides undergo intramolecular alkoxycarbonylation on treatment with an excess of Ni(C0)4or Ni(C0)2(PPh3)2to give a-methylene lactones, e.g. (99)+

12'

R. M. Adlington and A. G . M. Barrett, J. Chem. SOC.,Chem. Commun., 1981,65;Tetrahedron, 1981,37,3935. F. E. Ziegler and J.-M. Fang, J. Org. Chem., 1981,46,825. T. C. T. Chang and M. Rosenblum, J. Org. Chem., 1981,46,4626. M. F. Semmelhack and S. J. Brickner, J. Org. Chem., 1981.46,1723.

Saturated and Unsaturated Hydrocarbons

29

The reaction was used as a step in a synthesis of the sesquiterpene a-methyleney- lactone ( ~ ) - f r ~ l l a n o l i d e . ' ~ ~

I

OH (99)

E-a- Phenylsulphinyl-a#-unsaturated esters (lol), which are useful synthetic intermediates, can be prepared in moderate yields directly from the zinc enolate (102) and aldehydes.'j'

(102) Reagents: ' i, NaH; ii, ZnCI,; iii, RCHO

The anion of the ylide (103),functioning as a vinyl anion equivalent, undergoes alkylation then elimination of triphenylphosphine to give substituted diethyl fumarates (104).13' Organocopper species derived from Grignard reagents and the cuprous bromide-dimethyl sulphide complex add stereospecifically to dimethyl acetylenedicarboxylateto give 2-substituted r n a l e a t e ~ . ' ~ ~

Reagents: i, LDA; ii, RX (X= Br or I); iii, PhCO,H, A

On treatment with cyanide ion, vinyl sulphones are converted into a,& unsaturated nitriles in which the direction of olefin polarization has been reversed, e.g. (105) + (106).'33 Allylic sulphones are also suitable starting materials since they can be equilibrated with vinyl sulphones by adding potassium t-butoxide to the reaction mixture. With magnesium as counter-ion, the triphenylsilylacetonitrile anion undergoes stereoselective Peterson olefination

Reagent: i. KCN-dicyclohexyl-18-crown-6-methyleneblue

13'

M.F.Semmelhack and S. J. Brickner, J. Am. Chem. Soc., 1981,103,3945. Q. B. Cass, A. A. Jaxa-Chamiec, and P. G. Sammes, J. Chem. SOC.,Chem. Commun., 1981,1248. M.P. Cooke, jun., Tetrahedron Lett., 1981,22,381. H.Nishiyama, M.Sasaki, and K. Itoh, Chem. Lerr., 1981,905.

133

D. F. Taber and S. A. Saleh, J. Org. Chem., 1981, 46,4817.

lZ9 13'

General and Synthetic Methods

30

reactions with aldehydes to give a,p- unsaturated nitriles of mainly Z configuration (Scheme 49).134 Ph,SinCN

% Ph,Si-C,, NMgI Z:E=9:1

Reagents: i, LDA; ii, MgI,; iii,

Scheme 49

The research groups of T r o ~ t ' ~and ' T ~ u j ihave l ~ ~shown that in the presence of a palladium(0) catalyst vinyl epoxides can be regio- and stereo-selectively alkylated with various carbon acids under neutral conditions; the main products are E-allylic alcohols resulting from 1,4-addition, e.g. (107) -P (108). The reaction tolerates ester and ether groups. In the presence of a base, alkyl-lithiums

(108)

undergo regiospecific 1,4-addition to vinyl epoxides to give allylic alcohols of ~ ~ same selectivity operates when almost exclusively 2-c ~ n f i g u r a t i o n ; ' the diethylaluminium benzenethiolate reacts with vinyl epoxides in benzene at room temperature giving mainly 2-4-phenylthiobut-2-en- 1-01 derivatives (Scheme 50).13'Selenoboranes react regioselectively with trisubstituted epoxides to form allylic alcohols in which the hydroxy group is linked to the less-substituted carbon atom, e.g. (109) + (l10).'39

Reagents: i, Bu"Li-Bu"0Li; ii, H,O+; iii, Et,AISPh

Scheme 50

OH

(109)

(1 10) 7 6'/o

OH

8O/o

Reagents: i, B(SeMe),; ii, aq.NaHC0, 134

13' 136 13'

139

Y. Yamakado, M. Ishiguro, N. Ikeda, and H. Yamamoto, J. Am. Chem. Soc., 1981,103,5568. B. M. Trost and G. A. Molander, J. Am. Chem. Soc., 1981,103,5969. J. Tsuji, H. Kataoka, and Y. Kobayashi, Tetrahedron Lett., 1981,22,2575. M.Tamura and G. Suzukamo, Tetrahedron Left., 1981,22,577. A. Yasuda, M. Takahashi, and H. Takaya, Tetrahedron Lett., 1981,22,2413. A. Cravador and A. Krief, Tetrahedron Lett., 1981,22,2491.

Saturated and Unsaturated Hydrocarbons

31

Allyltrimethylsilanes are converted into allylphenylselenides on successive treatment with phenylselenenyl chloride and tin(I1) chloride or florisil; where possible, primary selenides are formed regiospecifically, via allylic rearrangement if necessary. The usual oxidative rearrangement then provides allylic alcohols (Scheme 51),140

2

V

OAc SiMe,

S

e

P

h

OAc

iii

-P OAc OH

Reagents: i, PhSeCl; ii, SnCI, or Florisil; iii, H20,-py

Scheme 51

Internal acetylenes react with isobutylmagnesium halides in ether in the presence of a catalytic amount of Cp,TiC12 to affordE- alkenyl Grignard reagents in almost quantitative yields. The regioselectivity of this hydromagnesiation is high for alkylarylacetylenes (Scheme 52) and silylacetylenes, but is less satisfactory for unsymmetrical dialkylacetylenes. 14' Under the same reaction conditions, propargylic alcohols undergo hydromagnesiation regio- and stereo-specifically ; alkylation then affords high yields of allylic alcohols free from isomeric species (Scheme 53).142

o*' Bu'MgBr,

/

MgBr

@

Cp,TiCI,

+

pMg

/ ca. 9 : 1

Scheme 52

Reagents: i, 2BuiMgCI-Cp2TiC12;ii, Me1

Scheme 53

Zirconium-catalysed methylalumination of the propargylic and homopropargylic species (111) is uniformly highly regio- and stereo-selective; the resulting alanes (112) are versatile olefin s y n t h o n ~ . ' ~ ~

(111)

(112)

n = 1 or 2; Z = OH, OSiMe2Bu', SPh, or I 140 141

143

H. Nishiyama, K. Itagaki, K. Sakuta, and K. Itoh, Tetrahedron Lett., 1981,22,5285;H.Nishiyama, S. Narimatsu, and K. Itoh, Tetrahedron Lett., 1981,22,5289. F. Sato, H.Ishikawa, and M. Sato, Tetrahedron Lett., 1981,22,85. F. Sato, H.Ishikawa, H. Watanabe. T. Miyake, and M. Sato, J. Chem. SOC., Chem. Commun., 1981,718. C. L. Rand, D. E. Van Horn, M. W. Moore, and E. Negishi, J. Org Chem., 1981,46,4093.

32

General and Synthetic Methods

Electrolysis of isoprenoids in an aqueous sodium chloride-dichloromethane system results in a regioselective ene-type chlorination of the terminal isopropylidene group to give allylic chlorides, e.g. (113) + (114).144Acetylenic, sulphonyl, and carboxylic ester groups are not affected by the reaction conditions, but isoprenoids containing hydroxyl groups give lower yields.

The Schweizer synthesis of allylic aniines is highly E- stereoselective when vinyltri-n-butylphosphonium bromide is used instead of the usual vinyltriphen ylphosphonium salt. 145 p- Acetamido selenides, easily prepared from olefins, undergo regioselective oxidative elimination to give high yields of allylic amides (e.g. Scheme 54).146 PhSe H Me Reagents: i, PhSeCI-CF,SO,H;

Me

NHCOMe

y N H C O M e

ii, H,O,

Scheme 54

Allylsilanes can be prepared by reductive silylation of allyltrimethylsilyl ethers using lithium and ,chlorotrimethylsilane, in the presence of a nickel catalyst if necessary. The thermodynamically more stable regioisomer (as a mixture of geometric isomers where possible) is the only product (Scheme 55).14' Tertiaryallylic acetates (115) are converted with allylic rearrangement into allylsilanes (116) on treatment with Fleming's silylcuprate reagent (117).1481-(Trimethylsily1)alkylmagnesium halides undergo palladium- or nickel-catalysed crosscoupling with enol phosphates without stereomutation of the carbon-carbon

Reagent: i, Li-Me,SiCI

Scheme 55

"* S. Torii, K.Uneyama, T. Nakai, and T. Yasuda, Tetrahedron Lett., 1981,22,2291. 145

'41 '41

A. I. Meyers, J. P. Lawson, and D. R. Carver, J. Org. Chem., 1981,46, 31 19. A. Toshimitsu, H. Owada, T. Aoai, S. Uemura, and M. Okano, J. Chem. SOC.,Chern. Commun., 1981,546; J. Org. Chem., 1981,46,4727. C. Biran, J. Dunogubs, R. Calas, J. Gerval, and T. Tskhovrebachvili, Synthesis, 1981, 220. I. Fleming and D. Marchi, jun., Synthesis, 1981, 560.

Saturated and Unsaturated Hydrocarbons

33

double bond to give allylsilanes (Scheme 56).1492-Alkyl-3-trimethylsilylmethyl3-butenoic acids (118), easily prepared by regioselective alkylation of the parent compound, undergo intramolecular decarboxylation on heating to furnish 2methylallylsilanes of mainly 2-configuration (119).lSo 0

& % Ph Reagents: i, LDA; ii, CIPO(OEt),; iii, Me3SiCH2MgCI-Pd(PPhB),

Scheme 56 130-150 : '

Me,Si +C02H (118)

-co,

Me,Si

R

R Z:Eca.4:1 (119)

Treatment of olefins with toluenesulphinyl chloride and ethylaluminium dichloride in ether at room temperature gives allylic sulphoxides uia a formal ene reaction (Scheme 57).lS1The Lewis acid acts both as a catalyst for the rearrangement and as a proton scavenger, reacting with the hydrogen chloride produced to give ethane and aluminium chloride. 0

(To1 = CH&H4) Reagent: i, TolSOCI-EtAICI,

Scheme 57

Treatment of allylic diphenylphosphates with various soft bases (sodium iodide, cyanide, sulphide, or benzenethiolate) in DMF at room temperature results in smooth displacement of the diphenoxyphosphinyloxy group to yield the corresponding allylated species.lS2 The reactions are regiospecific, giving only a-substitution products, and the geometry of the double bond is preserved, e.g. (120) + (121).

NaX

X (120)

149

(121) X = CN or SPh

T. Hayashi, T. Fujiwa, Y.Okamoto, Y. Katsuro, and M. Kumada, Synthesis, 1981,1001. H. Nishiyama, K. Itagaki, K. Takahashi, and K. Itoh, Tetrahedron Lett., 1981,22, 1691. B. B. Snider,J. Ore. Chem., 1981,46,3155. S . Araki, K. Minami, and Y. Butsugan, Bull. Chem. Soc. Jpn., 1981,54,629.

General and Synthetic Methods

34

Novel syntheses of P,y- unsaturated ketones, free from the conjugated isomers, by acylation of (cyclopropylmethyl) trimethylsilane ( 122)ls3or l-trimethylsilyl2-methylcyclopropane (123)ls4 have been described. Acylations of the latter type are stereospecific, the trans- cyclopropane (123), for example, producing exclusively the Z-p,y- unsaturated ketone (124). 0

n

I

CI

R = alkyl

Ru'COCI-AICI,

(124)

Me (123)

Hudrlik and Kulkarni have shown that a-t-butyldimethylsilyl aldehydes serve as vinyl cation equivalents for the synthesis of P,y- unsaturated ketones (and esters).68 Addition of lithium enolates to the a-silyl aldehydes is highly erythroselective, enabling products of either E- or 2-geometry to be obtained (Scheme 58). In a related process, phenylselenoacetaldehyde has been used to transform ketones into the corresponding a-vinylketones (Scheme 59); phenylselenoacetone enables a-isopropenylation of ketones in an analogous fashion. lS5 OLi

ii-iv

n-C6H1

1

3

Reagents: i, BF,.OEt,; ii, LiAlH,; iii, KH; iv, CrO,-H,SO,

Scheme 58

Reagents: i, LDA; ii, ZnCI,; iii, PhSeCH,CHO; iv, MeS0,CI-Et,N

Scheme 59

I"'

M. Grignon-Dubois, J. Dunogues, and R. Calas, Can.J. Chem., 1981, 59, 802. M. Grignon-Dubois, J. Dunogues, and R. Calas, Tetrahedron Leu., 1981, 22, 2883. D. L.. J. Clive and C. G. Russell, J. Cliem. Soc., Chem. Commun., 1981, 434.

Saturated and Unsaturated Hydrocarbons

35

Ketones can also be converted into their a-isopropenyl derivatives using the hyl isopropen yl ether)]'[BFJ. 56 complex [C5H5Fe(CO)2(et Dianions of 2-alkenyloxyacetic acids (125) undergo smooth Wittig rearrangement at -78°C to give, following oxidative decarboxylation, good yields of P,y- unsaturated aldehydes. lS7

HO

co;

1

iii

t iv

R-CHO

Rq

>95% E-isomer Reagents: i, NaH-BrCH2C0,H; ii, LDA; iii, H'; iv, NaIO,

Rousseau and Conia have discovered an improved and convenient modification of the Barbier reaction: allyl bromides react smoothly, with exclusive allylic inversion, with nitriles in the presence of zinc-silver couple to give high yields of P,y-unsaturated ketone^.'^' 8- Vinyl-& propiolactone reacts regio- and stereo-selectively with Grignard reagents in the presence of catalytic amounts of copper(1) iodide, or with unsaturated carboxylic acids diorganocuprates, to give mainly E-P,y(Scheme 60).'59Vinyl or allyl reagents give 3,6- or 3,7-dienoic acids, respectively. New and versatile syntheses of P,y- unsaturated-a- amino-acids have been reported.68v160

C02H

MeMgBr

+A C O 2 H

E :Z= 92:8 97

3

Scheme 60

Cohen and Matz have shown that 2-vinylcyclobutanones rearrange by acyl migration under acidic conditions to give either 2-cyclopentenones (126) or 2-cyclohexenones (127) depending on whether or not there is a 2-alkyl substifuent.l6l By contrast, the alkoxides resulting from hydride or alkyl-lithium addition to 2-vinylcyclobutanones undergo rearrangement at 25-70 "C to give 156

15' 31'' 159

T. C. T. Chang and M. Rosenblum, J. Org. Chern., 1981,46,4103. T.Nakai, K. Mikami, S. Taya, Y. Kimura, and T. Mimura, Tetrahedron Lett., 1981,22,69. G.Rousseau and J.-M. Conia, Tetrahedron Lett., 1981,22,649. T.Sato, M. Takeuchi, T. Itoh, M. Kawashima, and T. Fujisawa, Tetrahedron Lett., 1981,22,1817: I. Hoppe and U. Schollkopf, Synthesis, 1981,646;F. Heinzer and D. BelluS, Helu. Chim. Acta,

1981,64,2279. 16'

J. R. Matz and T. Cohen, Tetrahedron Lett., 1981,22,2459.

General and Synthetic Methods

36

a 0

0

MeS03H-P205

0

0 (127)

cyclohexen-3-01 derivatives (128) + (129).'62The stereochemical features of the related alkoxy-accelerated vinylcyclopropane rearrangement, where the products are cyclopenten-3-ols, have been established. 163 OH

(128)

(129)

Readily prepared T-allyltitanium complexes of the type (130) react regiospecifically at the more substituted y-carbon atom of the allyl group with aldehydes and ketones; hydrolysis and aerial oxidation then give high yields of homoallylic alcohols (Scheme 61).164(q5 - C5H5)*TiC12is recovered almost quantitatively and can be recycled. Chlorine, ester, and olefinic substituents on the aldehyde or ketone remain unchanged. Homoallylic alcohols can also be prepared by addition of allyl cerium iodide, generated in situ from allyl iodide and cerium amalgam, to ketones.165

Reagents: i,

-Pr"MgBr; ii, Me,CO; iii, HC1-air Scheme 61

The reaction of allylsilanes with acetals to give homoallylic ethers is usually conducted with stoicheiometric amounts of Lewis acids; it has now been shown that a catalytic quantity of iodotrimethylsilane is equally eff ective.'66 Michael addition of allyltrimethylsilane to a-nitro-olefins in the presence of aluminium chloride gives, following a Nef-type reaction, y,S- unsaturated

163

164

16' 166

R. L. Danheiser, C. Martinez-Davila, and H. Sard, Tetrahedron, 1981,37,3943. R. L. Danheiser, C. Martinez-Davila, R. J. Auchus, and J. T. Kadonaga, J. Am. Chem. Soc., 1981,

103,2443. F. Sato, S. Iijima, and M. Sato, Tetrahedron Lett., 1981,22,243. T. Imamoto, Y. Hatanaka, Y. Tawarayama, and M. Yokoyama, Tetrahedron Lett., 1981,22,4987. H. Sakurai, K. Sasaki, and A. Hosomi, Tetrahedron Lett., 1981,22,745.

Saturated and Unsaturated Hydrocarbons

37

ketones (Scheme 62).167y,&Unsaturated ketones can also be prepared by palladium-catalysed reaction of ketone enolates with allylic acetates, e.g. Scheme 63,16' or by hydrolysis of the imines formed by successive additions of vinylmagnesium bromide to imidoyl chlorides (131) or secondary amides (132).169

Reagents: i, CH,=CHCH2SiMe,-AIC13; ii, H,O; iii, TiCI,-NaOMe-NH,OAc

Scheme 62

-

?Ac

Pd(dba), :dppe 1:l

Scheme 63 N R ~

Rlw N R ~

NHR~

9$

4=

1

(131)

iii

R'

(132)

L

Reagents: i, CH,=CHMgBr; ii, H,O; iii, SiO, or acidic AI,O,

Ally1 vinyl ether derivatives undergo smooth Claisen rearrangement at room temperature on treatment with an excess of EtzAISPh or Et,AlCl-PPh, to give high yields of y,6- unsaturated aldehydes. Alternative organoaluminium reagents enable simultaneous rearrangement and reduction to the corresponding olefinic alcohols (Scheme 64).17'

Scheme 64

1,S-Dienes can be converted selectively into 2-y,S- unsaturated sulphones via complexes as illustrated by Scheme 65. Unsymmetrical dienes give regioisomeric mixtures of T-allylpalladium

168 169

' 7 1 171

M. Ochiai, M. Arimoto, and E. Fujita, Tetrahedron Lett., 1981, 22, 1115. J.-C. Fiaud and J.-L. Malleron, J. Chem. Soc.. Chem. Comrnun., 1981, 1159. K. S. Ng and H. Alper, J. Org. Chem., 1981,46, 1039. K. Takai, I. Mori, K. Oshima. and H. Nozaki, Tetrahedron Lett., 1981, 22,3985. Y. Tamaru, M. Kagotani, R. Suzuki. and Z. Yoshida, J. Org. Chem., 1981,46,3374.

38

General and Synthetic Methods

p-Lactams”* and t - a m i d e ~ havebeen ’~~ used for the first time as the carbonyl components in Wittig reactions. In addition, intramolecular Wittig reactions between phosphorane and carbonate functionalities have been used for the first time; the products are 2-phenoxychromones, for example (133), whose derivatives have recently emerged as a new class of natural p r o d u ~ t . ”Bestmann ~ and Bansal have prepared the first cumulated ylide of arsenic, triphenylarsoranylideneketen; it undergoes sequential addition and Wittig-type reactions in the same way as its phosphorus ana10gue.‘~’ S02CH2CMe2Ph

----* ii

eS0,CH,CMe2Ph

PdC1/2 Reagents: i, PdC1,-AcOH-NaSO,CH,CMezPh; ii, dimethylglyoxime-MeOH

Scheme 65

On treatment with n-butyl-lithium in THF at -78 “C, five-membered cyclic trithiocarbonates (134) are converted stereospecifically into olefins via a synelimination process. 176 Since the trithiocarbonates can be prepared by antiaddition to olefins, the sequence constitutes a method for the interconversion of geometric olefins that is especially useful for the preparation of sensitive 2-isomers.

PhO

A0 S

r

SBU-

3 Conjugated 1,3-Dienes The very high stereochemical purity of 2-1-dialkenylcuprates can be incorporated into conjugated dienes via equilibration with the corresponding zinc species (Scheme 66).177 17’

173 174

17’ 176

177

M. L. Gilpin, J. B. Harbridge, T. T. Howarth, and T. J. King, J. Chem. SOC.,Chem. Commun., 1981,929. J. V. Cooney and W. E. McEwen, J. Org. Chem., 1981,46,2570. H. Takeno and M. Hashimoto, J. Chem. SOC., Chem. Commun., 1981, 282; H. Takeno, M. Hashimoto, Y. Koma, H. Horiai, and H. Kikuchi, J. Chem. SOC.,Chem. Commun., 1981,474. H.J. Bestmann and R. K. Bansal, Tetrahedron Lett., 1981,22, 3839. K. Hatanaka, S. Tanimoto, T. Oida, and M. Okano, Tetrahedron Lett., 1981,22, 5195. N.Jabri, A. Alexakis, and J. F. Normant. Tetrahedron Lett., 1981,22, 959.

Saturated and Unsaturated Hydrocarbons

39

99.5% 2,Zisomer

Scheme 66

The geometry of both reactants is preserved during the palladium-catalysed cross-coupling of 1-alkenylboranes with 1-alkenyl bromides under strongly basic conditions even when each of the substrates .has a 2-configuration (Scheme 67)."8 Under more weakly basic conditions, reactions of this type give mainly head-to-tail coupled products (Scheme 68).60

98% 2,Z-isomer

Scheme 67

Ph 94

: 6

Scheme 68

In an interesting synthetic parallel of the Wittig reaction, allylic alcohols and acetates react with aldehydes in the presence of triphenylphosphine and a catalytic amount of Pd(acac)2 to give moderate yields of 1,3-dienes (Scheme 69).17'

Scheme 69

The readily-prepared silylboronate (135) reacts diastereoselectively with aldehydes to form, following removal of the borate group, /3- hydroxysilanes (136).The usual deoxysilylation gives 1,3-dienes of high stereochemical purity.'" The (hydroxymethy1)allyl sulphones (137) react stereoselectively with tri-nbutyltin hydride in the presence of a radical initiator to give allyltin derivatives 178

179

N. Miyaura, H. Suginome, and A. Suzuki, Tetrahedron Lett., 1981, 22, 127. M. Moreno-Mafias and A. Trius, Tetrahedron Lett., 1981, 22,3109. D. Jieh Shyh Tsai and D. S. Matteson, Tetrahedron Lett., 1981,22, 2751.

General and Synthetic Methods

40

(138) of mainly 2-configuration. On distillation, the allyltin compounds undergo fragmentation to furnish 2-alkylbuta-1,3-dienes ( 139).18'

Reagents: i, RCHO; ii, (HOCH,CH,),N; iii, H,SO,; iv, KH

R R H

O

A

+ ii

S02Tol . Ho* , A

(137)

(138)

5 R

SnBu"3

(139)

Reagents: i, Bu",SnH-AIBN; ii, distillation

A particularly successful general approach to 2,4-dienoic acids and their derivatives is to construct an intermediate which, following sigmatropic rearrangement, can undergo elimination to form a diene. The examples shown in Scheme 70 are representative of several new variations on this theme. 157*182-184

NPr',

>95

Oo /

E,E- isomer

Reagents: i, CF3CH,SOPh-2KH; ii, OH-; iii, H'; iv, CaCO,, A; v, 4-MeC6H,S-~-NPri,; NaIO,; vii, A

vi,

Scheme 70

Y.Ueno, H. Sano, S. Aoki, and M. Okawara, Tetrahedron Lett., 1981, 22,2675. Y.Tamura, H.-D. Choi, H. Maeda, and H. Ishibashi, Tetrahedron Lett., 1981,22, 1343; K. Tanaka, M. Terauchi. and A. Kaji, Chem. Lett., 1981,315. T. Nakai, K. Tanaka, K. Ogasawara, and N. Ishikawa, Chem. Lett., 1981. 1289. T. Nakai, H. Setoi, and Y . Kageyama. Tetrahedron Lett., 1981, 22,4097.

Saturated and Unsaturated Hydrocarbons

41

In an alternative method, cyclopropanecarboxylates of the type (140), prepared from benzyl sulphones and ethyl 4-bromocrotonate, are converted into EYE-5 aryl-2,4-dienoates (141) on treatment with potassium t - b ~ t o x i d e . ' ~ ~ S0,Ph

I

Heck and his co-workers have shown that 2,4-dienals can be prepared by coupling a,@ unsaturated aldehydes, protected as acetals, with vinyl bromides in the presence of palladium catalysts, followed by hydrolysis (Scheme 71).'"

Reagents: i, piperidine-Pd(OAc),-P(o-Tol),;

ii, H+

Scheme 71

However, high temperatures (100 "C)and long reaction times (24 hours) are required, With an alternative palladium catalyst, vinyl iodides couple directly with a,P-unsaturated ketones at room temperature.'" A model system (142) for the aglycone of carbomycin B was synthesized using this method to effect the cyclization step. 0

0

I

55 %

0 (142) Reagent: i, PdCI,(MeCN),-high dilution

3-Acetoxy- 1,4-dienes rearrange regio- and stereo-selectively to 1-acetoxy2,4-dienes under the influence of palladium(11) catalysts. Rearrangement, which is complete within a few minutes at room temperature, occurs preferentially at E-disubstituted double bonds, e.g. (143) + (144).'88 PdCI,(McCN),

AcO

(143)

OAc

E,Z:E,E-4:1 (144)

A. TomaiiC and E. Ghera, Tetrahedron Lett., 1981, 22, 4349.

'" B. A. Patel, J.-I. I. Kim, D. D. Bender, L.-C. Kao, and R. F. Heck, J. Org. Chem., 1981,46, 1061. la'

F. E. Ziegler, U. R. Chakraborty, and R. B. Weisenfeld, Tetrahedron,1981, 37,4035. B. T. Golding, C. Pierpoint, and R. Aneja, J. Chem. SOC.,Chem. Commun., 1981, 1030.

General and Synthetic Methods

42

Propargyltrimethylsilane (145) reacts with aldehydes and ketones in the presence of titanium tetrachloride to give 2-chloro- 1,3-dienes (146) instead of the expected a- allenic alcohols.'89 l-Trimethylsilylbut-2-ynereacts in the same way if the reaction mixture is allowed to warm to room temperature.'"

Cyclic a,& unsaturated ketones can be converted into their a-isopropenyl derivatives by the two-stage sequence illustrated by Scheme 72.I9l Open-chain 2-acylbutadienes, less stable than their cyclic relatives, can be prepared by Friedel-Crafts acylation of butadiene complexes of the type (147).19*

Reagents: i, CH2=C=CH2, hv; ii, BF,.OEt,

Scheme 72

Reagents: i, Fe,(CO),; ii, MeCOCI-AICl,; iii, H'

p- Alkoxy- or p- amino-a,& unsaturated ketones, esters, or nitriles undergo electrochemical reductive coupling to give moderate yields of symmetrical 1,4diketo-, dicarboxy-, or dicyanobuta- 1,3-dienes. 193 Norcaradiene has been directly observed for the first time.194 4 Non-conjugated Dienes

l-Alkenyl-aluminium or -zinc species cross-couple with allylic halides or derivatives of allylic alcohols (e.g. acetates or phosphates) under the influence of Pd(PPh3)4 to give 1,4-dienes. In favourable examples coupling occurs with complete retention of stereo- and regio-chemistry of both alkenyl and ally1 substrates, and it is free from formation of homocoupled products (Scheme 73).61 However, partial allylic inversion was observed in reactions involving E- crotyl 190

'91 193

194

J . Pornet, Tetrahedron Lett., 1981, 22,453. J. Pornet and B. Randrianoelina, Tetrahedron Lett., 1981, 22, 1327. Do Khac Manh Duc, M. Fetizon, I. Hanna, and S. Lazare, Synthesis, 1981, 139. M. Franck-Neumann, D . Martha, and F. Brion, Angew. Chem., Int. Ed. Engl., 1981,20,864. L. Mandell, F. J. Heldrich, and R. A. Day, jun., Synth. Commun., 1981, 11, 5 5 ; G. Mabon, C. Moinet, and J. Simonet, J. Chem. SOC., Chem. Commun., 1981, 1040. M. B. Rubin, J. A m . Chem. SOC.,1981. 103, 7791.

Saturated and Unsaturated Hydrocarbons

,*

BunL A I M e , -

Bun

43

B

u

/

n

/ n

298% E,E- isomer

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

ii,

bcl -Pd(PPh,),

Scheme 73

acetate or the corresponding chloride.62 In the presence of Li2PdCl,, vinylmercurials react with monocyclic olefins to give T - allylpalladium species; if triethylamine is added, 1,4-dienes, e.g. (148), are the major products.'Y5

]

[ ~ , j But 4

Bu~*HgC1

Reagent: i,

PdC132'

0

(148)

-Li,PdC14-Et3N

Isoprene, in the form of the zirconium complex (149), adds to acetylenes almost regiospecifically with respect to isoprene to give 1,4-dienes ( 150).67

E- 1-Benzenesulphonyl-2-(trimethylsilyl)ethylene(15 1)is a useful equivalent of acetylene for Diels-Alder reactions (Scheme 74).'96It can also function as an equivalent of monosubstituted acetylenes because it is possible to alkylate the Diels-Alder adduct via an a-sulphonyl carbanion before elimination.

A&

PhS02'+SiMe,

S0,Ph

ii

,h 1

(151) + -

1

SiMe,

Reagents: i, cyclopentadiene; ii, Bu4NF

Scheme 74

The thioaldehydes formed during thio-Claisen rearrangement of ally1 2,2dichlorovinyl sulphides (152) undergo chlorine migration and desulphurization under the reaction conditions to give 1,2-dichloropent-1,4-dienes(153).197

(152) 19' 197

(153)

R. C. Laruck, K. Takagi, S . S . Hcrshbcrger, and M. A. Mitchell, Tetrahedron Lett., 1981,22,5231. L. A. Paquette and R. V. Williams, Tetrahedron Lett., 1981,22,4643. E. Nagashima, K.Suzuki. and M. Sekiya, Tetrahedron Lett., 1981,22,2587.

General and Synthetic Methods

44

Oppolzer and his co-workers have reported that sulphenylation of 3-triethylsilyloxypenta-l,3-diene (154) occurs specifically at the y- position. Successive alkylation, cleavage of the silyl ether, and oxidative elimination then furnishes dienones (155).19*

Reagents: i, Bu"Li; ii, MeSSMe; iii, LDA; iv, RX (X = Br or I); v, KF; vi, m-CPBA

1,5-Dienes are conveniently constructed by successive Wittig and Horner reactions using 1,l-diphenylphospholanium bromide (Scheme 75). lg9 0

(CH,),OTHP bii-v

(CH,),OTHP Reagents: i, Bu'OK; ii, THPO(CH,),CHO; iii, Bu"Li; iv, Me(CH,),CHO; v, NaH

Scheme 75

A thorough investigation of the Wittig rearrangement of unsymmetrical bisallylic ethers, e.g. (156), has been made.20oImportantly, lithiation occurs almost exclusively on the ally1 moiety that is less-substituted at the a- and y-positions, resulting in the formation of only one 1,5-dien-3-01, e.g. (157). A degree of stereocontrol can also be achieved.

5 Allenic Hydrocarbons

Vermeer and his co-workers have shown that organozinc chlorides cross-couple with both allenic and propargylic halides in the presence of palladium catalysts to give allenes (Scheme 76).201Regioselectivity, which favours allenes to an extent of at least 99%, is higher than that observed previously with the corresponding Grignard reagents. Aryl-, 1-alkenyl-, and l-alkynyl-zinc chlorides are

'" 199

W. Oppolzer, R. L. Snowden, and P. H. Briner, Helo. Chirn. A m , 1981, 64, 2022. J. M. Muchowski and M. C. Venuti, J. Org. Chem., 1981,46,459. T. Nakai, K. Mikami, S. Taya, and Y. Fujita, J. A m . Chem. SOC.,1981,103,6492. K . Ruitenberg, H. Kleijn, C. J. Elsevier, J. Meijer, and P. Vermeer, Tetrahedron Lett., 1981, 22. 1451.

Saturated and Unsaturated Hydrocarbons

45

Scheme 76

suitable reactants. Cyclohexanone and benzaldehyde undergo a novel alkenylidenation reaction when treated with the 1,l-dimetalloalkene (158) to give good yields of allenes (159).'*

I

(159) R2 Reagents: i, Me,Al-CI,TiCp,; ii, CI(Me)TiCp,; iii, R'R'CO

Allenyl-lithium reagents, generated by metallation of allenic hydrocarbons or from haloallenes by halogen-metal exchange, react with various electrophiles with retention of the allenic structure to give functionalized allenes.202High yields of allenylsilanes and sulphides, allenic acids and dialkylamides, and pallenic alcohols are available by this method. However, additions to ketones are less satisfactory since propargylic alcohols are formed in some cases. Propargyl iodides, formed in situ from the corresponding bromides, react successively with stannous chloride and aldehydes to give high yields of mixtures of a-hydroxyallenes and p- hydroxyacetylenes. Importantly, y- substituted propargyl iodides usually give a-hydroxyallenes almost exclusively (Scheme 77).203

Reagents: i, SnC1,-NaI; ii, PhCHO

Ph 97

:

3

Scheme 77

The organometallic species formed by treatment of trimethylsilylpropargyl bromide (160) with aluminium amalgam condenses regioselectively with aldehydes and ketones to give a-hydroxymethyl(trimethylsilyl)allenes (161).'04 SiMe,

'02 '03

J.-C. Clinet and G. Linstrumelle, Synthesis, 1981,875. T.Mukaiyama and T. Harada, Chern. L e a , 1981,621. R. G. Daniels and L. A. Paquette, Tetrahedron Lerr., 1981,22,1579.

General and Synthetic Methods

46

Propargyltrimethylsilane (162) reacts with saturated aldehydes and ketones in the presence of a catalytic quantity of tetra-n-butylammonium fluoride to produce a-hydroxyallenes ( 163).'05 a,@-Unsaturated or aromatic aldehydes give products contaminated with j3- hydroxyacetylenes. Analogous reactions with 1-trimethylsilylbut-2-yne are preferably performed at low temperatures (-60 "C) with titanium tetrachloride as catalyst. 190 Propargyltrimethylsilane also reacts with acid chlorides at low temperatures and in the presence of aluminium chloride to give moderate yields of a- allenic ketones ( 164).'06

R

R=MeorBu'

(164)

Treatment of 6-ethynyl-j3-propiolactone (165) with alkyl, aryl, or vinyl Grignard reagents in the presence of a catalytic amount of copper(1) iodide affords high yields of alka-3,4-dienoic acids ( 166).207

Organolithium and magnesium reagents react regiospecifically with bifunctionalized enynes of the type (167) to give moderate yields of bifunctionalized allenes (168).208

X = NMe2 or OMe Y = N M e 2 , 0 M e , o r OH

1,4-Dialkoxy-2-alkynes (169) isomerize smoothly to the corresponding 1,2dienes (170) when treated with a catalytic quantity of potassium t - b u t o ~ i d e . ~ ' ~ The solvent of choice depends on whether or not the starting material has alkyl substituents. (Dialky1amino)allenes (172), which are thermally unstable and 'OS

206 *07

20*

'09

J. Pornet, TetrahedronLett., 1981,22, 455. J.-P. Pillot, B. Bennetau, J. Dunogues, and R. Calas, TetrahedronLett., 1981,22, 3401. T.Sato, M. Kawashima, and T. Fujisawa, Tetrahedron Lett., 1981,22, 2375. D. Mesnard, J.-P. Charpentier, and L. Miginiac, J. Organornet. Chem., 1981,214,15; ibid., 23. P. E. van Rijn, R. H. Everhardus, J. van der Ven, and L. Brandsma, Red. Trav. Chirn. Pays-Bas, 1981,100,372.

Saturated and Unsaturated Hydrocarbons

47

moisture- and oxygen-sensitive, can be prepared in a reasonable state of purity and in high yield by isomerization of dialkyl-2-propynylamines(17 1).210

Reagents: i, 2R'NH; ii, Bu'OK-THF; iii. Bu'OK.Bu'OH-HMPT

The doubly-bridged allene [8][ 1O]screw[2]ene (173) has been synthesized in an optically active form.*"

6 Acetylenic Hydrocarbons Schrock and his co-workers have prepared several tungsten(v1) neopen'tylidyne complexes, e.g. (174), which react with diphenylacetylene to give the product of acetylene metathesis (175). More importantly, the complexes catalytically metathesize many acetylenes with remarkable ease.212 Ph-G-Ph

+ W(CBU')(OBU')~

Y74) + Ph-E-Bu'

W(CPh)(OBu')3

(175)

Olefins of the type (177), which are readily prepared from the ketenanthracene adduct (176), undergo retro-Diels-Alder reactions to give high yields of mono- or di-substituted acetylenes.213 R2

several steps

'lo

500-550 "C

0.05 Torr

H. D. Verkruijsse, H. J. T. Bos, L. J. de Noten, and L. Brandsma, Red. Trau. Chim. Pays-Bas,

1981,100,244. 'I1

'I2 213

M. Nakazaki, K. Yamamoto, and M. Maeda, Chem. Lett., 1981,1035. J. H.Wengrovius, J. Sancho, and R. R. Schrock, J. Am. Chem. SOC.,1981,103,3932. B. Tarnchompoo, Y. Thebtaranonth, S. Utamapanya, and P. Kasemsri, Chem. Letr., 1981, 1241.

General and Synthetic Methods

48

Symmetrical or unsymmetrical diarylcyclopropenones (178) undergo smooth decarbonylation on treatment with alumina pellets in refluxing o- dichlorobenzene, providing a versatile route to diarylacetylenes (179).2'4 Symmetrical diarylacetylenes (181) can be prepared in moderate yields by treating substituted p- nitrostyrenes (180) with hydrogen peroxide and triethylamine. Nitroepoxides are probably the initial products of these reactions.215

i-iii

c1

c1

iv p

~

Ar

Ar1-E-

Ar2

Ar2

(179)

Reagents: i. AlC1,-Ar'H; ii, Ar'H; iii, H20; iv, A120,

R'

(181) R' = H or OMe, R2 = OMe;

R', R2= OCH2O Successive treatment of phenylacetylene with butyl-lithium and potassium t-butoxide leads to the ortho- metallated phenylacetylide (182). Subsequent addition of methyl iodide or dimethyl disulphide gives the corresponding orthosubstituted phenylacetylenes,2'6 or, following appropriate potassiummagnesium or potassium-lithium exchanges, halogens can be introduced (Scheme 78).217

Reagents: i, 2BuLi-Bu'OK; ii, MeI; iii, H 2 0 ; iv, 2MgBr2.Et20;v, I,

Scheme 78

a,P-Acetylenic ketones can be prepared in high yields by carbonylation or aromatic or vinylic bromides and iodides in the presence of terminal acetylenes, triethylamine, and a catalytic amount of a suitable palladium(I1) complex, e.g. 21s 216

,''

D. H. Wadsworth and B. A . Donatelli, Synthesis, 1981, 285. P. G. Karmarker, A. A. Thakar, and M. S. Wadia, Tetrahedron Lett., 1981, 22, 2301. H. Hommes, H. D. Verkruijsse, and L. Brandsma, J. Chem. SOC.,Chem. Commun., 1981,366. H. Hommes, H. D. Verkruijsse, and L. Brandsma, Tetrahedron Lett., 1981, 22,2495.

Saturated and UnsaturatedHydrocarbons

49

(183) + (184).’18 Trimethylsilylallenes (185) undergo autoxidation to give propargylic hydroperoxides under an atmosphere of oxygen at room termperature. Of more use from a synthetic point of view is the observation that a,P-acetylenic ketones (186) are the main products if Collins reagent is added to the reaction mi~ture.~” 0

(185)

(186)

< 10%

>go%

Reagents: i, 02-py; ii, CrO,(py),; iii, aq. HCI

The 2-8silylvinyl sulphoxide (187) undergoes rapid syn- elimination on heating with the formation of an acetylenic bond. By contrast, the geometry of the corresponding E- isomer (188)does not allow elimination to take place.”’

.187),

JI

ivi e3

(188)

Staqnylethynyl ethers (189), which are readily prepared from the corresponding ethynyl ethers, are converted into acylethynyl ethers (190) on treatment with acyl halides.220 0

Reagents: i, BuLi; ii, Me,SnCI; iii, PhCH,COX (X = halogen)

Locher and Seebach have shown that lithium acetylides undergo 1,4-addition to l,l,l-triphenyl-3-penten-2-one(191), and the resulting acetylenic trityl ketones (192) are smoothly cleaved to acetylenic alcohols (193) by lithium triethylborohydride .221

Reagents: i, Me(CH,),C=CLi; ii, LiBHEt,

”* ’19 220

”’

T. Kobayashi and M. Tanaka, J. Chem. SOC.,Chem. Commun., 1981,333. T. Yogo, J. Koshino, and A. Suzuki, Synrh. Commun., 1981,11,769. G.Himbert and L. Henn, Tetrahedron Len.,1981,22,2637. R. Locher and D. Seebach, Angew. Chem., Int. Ed. Engl., 1981,20,569.

General and Synthetic Methods

50

Several new highly strained acetylenes have been prepared. For example, bicyclo[6.1 .O]non-2-yne (194) is moderately stable at room temperature,"' and acenaphthyne (195) has been prepared by irradiation of the appropriate matrixisolated cyclopropenone in argon at 15 KeZz3

7 Enynes and Diynes Brown and Molander have shown that alkenylcopper reagents, generated stereospecifically from alkynes via alkenylboranes, undergo cross-coupling with 1-bromo- (or 1-iodo-) 1-alkynes with retention of configuration to give conjugated enynes (Scheme 79).''4 i, ii

>98% E-isomer Reagents: i, NaOMe; ii, CuBr.SMe,; iii, P r T r C B r ; iv, H'

Scheme 79

The first examples of linear co-dimerization of acetylenes with buta- 1,3-diene have been reported. Aliphatic terminal acetylenes (196) react with buta-l,3diene in the presence of a catalytic amount of an appropriate ruthenium complex at 60-80 "Cto give almost quantitative yields of E-conjugated enynes (197).225

With magnesium as counterion, the carbanion derived from the bissilylpropyne (198) reacts regio- and stereo-selectively with saturated aldehydes (Peterson olefination) to give 1,3-enynes of almost exclusive 2 -configuration (Scheme 80).134Although still highly regioselective, reactions with aromatic or a,P -unsaturated aldehydes are less stereoselective. Organocuprates add to 1,3-diynes to give regioisomeric mixtures of adducts; by contrast, organoargentates, which are less reactive, add regiospecifically to 222 223

224 225

H. Meier, C. Schulz-Popitz, and H. Petersen, Angew. Chem., Int. Ed. Engl., 1981,20,270. 0. L. Chapman, J . Gano, P. R. West, M. Regitz, and G . Maas, J. A m . Chem. Soc., 1981,103,7033. H. C. Brown and G . A. Molander, J. Org. Chem., 1981,46,645. T . Mitsudo, Y. Nakagawa, H. Watanabe, K. Watanabe, H. Misawa, and Y. Watanabe, J. Chem. SOC.,Chem. Commun., 1981,496.

Saturated and Unsaturated Hydrocarbons

51

\iii

L SiMe,

I

d' 2 : E > 50: 1

Reagents: i, Bu'Li; ii, MgBr,; iii, CH,(CH&CHO

Scheme 80

Reagents: i, [R'AgBr]MgCI(LiBr), ; ii, C02,12, or NBS

give adducts (199),and subsequent addition of electrophiles allows a variety of functionalized 1,3-enynes (200) to be prepared.226 Zweifel and Pearson have developed a new high-yielding synthesis of 1,3enynols (203) from acetylenes via borane intermediates (Scheme 8 1).227The key feature of this transformation is the selective migration, with retention of configuration, of an alkenyl group from boron to carbon, (201) + (202). The sequence can be modified to furnish 1,2,4-trienols.

Reagents: i, 2CICH,CzCLi; ii, R3CHO; iii, H20,-NaOH

Scheme 81 226 227

H. Kleijn, M. Tigchelaar, J. Meijer, and P. Vermeer, Red. Trau. Chirn. Pays-Bas, 1981, 100, 337. G . Zweifel and N. R . Pearson, J. Org Chem., 1981, 46. 829.

52

General and Synthetic Methods

1,3-Dilithiopropargyl phenyl sulphide (204) reacts cleanly with allylic bromides to give high yields of phenylthio-substituted 1,5-enynes (205). Following re-metallation at the terminal position to prevent reduction of the triple bond, the phenylthio group is easily removed by treatment with lithium in liquid ammonia. The overall procedure is at least 99% stereoselective.228

Reagents: i, 2Bu"Li; ii,

RLer


Corey and Kang have shown that, under suitable conditions, metal acetylides couple regioselectively with allenic bromides to give high yields of 1,4-diynes. This new procedure was used as a step in the first synthesis of 11(R)-HETE, a natural product related to arachidonic acid (Scheme 82).229 z-4 i-iii

/

, (CH

2) 3

co,Me

B " l M e 2 s i o H~ c 5 H l

Reagents: i, Bu"Li; ii, CuCN; iii, CH,=C=CBr[(CH,),CO,Me].

Scheme 82

8 Polyenes Trost and Fortunak have shown that palladium(0)-catalysed decarboxylative elimination of P- acetoxycarboxylic acids, previously used to prepare 1,3-dienes, also provides a convenient entry to sensitive conjugated polyenes (Scheme 83).230 Importantly, the newly-formed double bond is mainly of E-geometry irrespective of the configuration of the P-acetoxy acid. The Michael-induced Ramberg-Backlund reaction has been used as the key step in a sequence for the homologation of head-to-tail linked conjugated isoprenoids (Scheme 84).231Alternatively, homologation can be performed using the C5-synthon (206) (Scheme 85), but yields are only Irradiation of benzocyclopropene (207) in the presence of thiocyanogen or iodine furnishes 1,6-dithiocyanato- or 1,6-di-iodo-cycloheptatriene (208) respectively.233Various other 1,6-disubstituted cycloheptatrienes, e.g. (209),can be prepared from these intermediates.

*" 229

230

232

233

E. Negishi, C. L. Rand, and K. P. Jadhav, J. Org. Chem., 1981, 46, 5041. E. J. Corey and J. Kang, J. A m . Chem. SOC.,1981,103,4618. B. M. Trost and J. M. D. Fortunak, Tetrahedron Lett., 1981.22, 3459. J. J. Burger, T. B. R. A. Chen, E. R. de Waard, and H. 0. Huisman, Tetrahedron, 1981, 37, 417. J. Camps, J. Font, and P. de March, Tetrahedron, 1981.37, 2493. R. Okazaki, M. 0-oka, N. Tokitoh, Y. Shishido, and N. Inamoto, Angew. Chem., Int. Ed. Engl., 1981, 20,799.

Saturated and UnsaturatedHydrocarbons

53

CO2Et

C0,Et

Reagents: i,

co; ; ii, H 2 0 ; iii, MeCOCI-C,H,N; Scheme 83

; ii, LDA; iii, (CI3C),; iv, PhS0,Na

Scheme 84

(206) Reagents: i, NaH; ii, H,O-(CO,H),

Scheme 85

Reagents: i, I,, h v ; ii, Bu"MgBr-Ni(dppp)CI,

iv, (Ph,P),Pd-Et,N

General and Synthetic Methods

54

Following an isolated report in 1980, it has now been shown that the rearrangement of diacetylenic diamines (210), uia their lithio-derivatives, into conjugated triene-diamines (21l), is a general process. However, some examples rearrange only very slowly.234

Ladika and Stang have demonstrated that bis(trimethylsily1)butadiyne (212) can be converted, via 1- (butadiyny1)vinyl trifluoromethanesulphonates, e.g. (213), into unsymmetrical conjugated triynes, e.g. (214).235

Reagents: i, Bu'CH,COCl-AICI,; ii, 2,6-But,-4-Me-py; iii, (F,CSO,),O; iv, 2,6-But,-C6H,OK

Unhindered vinyl cuprates, prepared from the corresponding vinyl-lithiums by treatment with pentynyl copper, react regioselectively with primary or secondary propargylic tosylates to give vinylallenes (Scheme 86); hindered cuprates give only 1,4-enynes resulting from direct displacement of the tosyloxy group.236 The first general synthetic approach to vinyl trimethylsilylallenes has been reported (Scheme 87).237

A ' Scheme 86

R'

CI

R1

Reagents: i, Li-Me,SiCI; ii, Mg-Me,SiCI-HMPA

Scheme 87 234

R. Epsztein and N. Le Goff, Terrahedron Lett., 1981, 22, 1965.

"' M. Ladika and P. J. Stang, J. Chem. SOC.,Chem. Commun., 1981,459; Synthesis, 1981, 29. 236

R. Baudouy and J. God, J. Chem. Res. (S),1981,278. J.-P. Dulcere, J. Grimaldi, and M. Santelli, Tetrahedron Left., 1981, 22, 3179.

Saturated and Unsaturated Hydrocarbons

55

Allenylcopper(1) compounds (2 15) react with l-iodo-l-alkynes to give allenynes (216) exclusively.238

(215) Reagents: i, Bu"Li; ii, CuBr; iii, R'C-CI

A series of novel silicon-, germanium-, or tin-functionalized cumulenes (218) has been prepared by insertion of alkadienylidenecarbenes (2 17) into the appropriate metal h y d r i d e ~ The . ~ ~cumulenes ~ are isolable but moderately oxygen-sensitive compounds that rearrange or polymerize on standing at room temperature. An improved synthesis of 1,2,3-butatrienyl ethers has been developed. 240

(218) M=Si, Ge, or Sn

Isobenzofulvene (220), a highly unstable blue compound, has been directly observed and characterized for the first time following flash vacuum pyrolysis of the diacetate (219).241 OAc

''' K. Ruitenberg, J. Meijer, R. J. Bullee, and P. Vermeer, J. Organomet. Chem., 1981,217,267. 240

P. J. Stang and M. R. White, J. A m . Chem. SOC.,1981,103,5429. R. G.Visser, H. J. T. Bos, and L. Brandsma, R e d . Trao. Chim. Pays-Bas, 1981,100,34.

241

G . Gross, R. Schulz, A. Schweig, and C. Wentrup, Angew. Chem., Int. Ed. Engl., 1981,20,1021.

239

2 Aldehydes and Ketones ~~

~

_

_

_

BY S.C.EYLEY

1 Synthesis of Aldehydes and Ketones Oxidative Methods.-The oxidation of alcohols to carbonyl compounds using DMSO activated by electrophiles, e.g. oxalyl chloride or trifluoroacetic anhydride, has been reviewed.’ DMSO-Metal oxide oxidations of alcohols have been described using molar, or catalytic, amounts of a new oxide of molybdenum.2 This yellow oxide, ‘Mo-y’, is prepared by hydrogen peroxide oxidation of molybdenum or its t r i ~ x i d e .N~ Iodosuccinimide in combination with tetrabutylammonium iodide oxidizes primary and secondary alcohols to aldehydes and ketones in dichloromethane ~ o l u t i o nThe . ~ corresponding bromo-combination gave inferior yields, and the chloro-combination resulted in polychlorination of the carbonyl product. The porosity of the poly(viny1pyridine) resin used is an important factor in determining the efficiency of oxidation of alcohols by poly(viny1pyridinium) chlorochromate and poly(viny1pyridinium) d i ~ h r o m a t eIncreased .~ porosity also aids in recycling of the polymer-based reagents, which are easily handled in molar amounts. Solid sodium permanganate monohydrate oxidizes secondary alcohols to ketones in hexane, primary alcohols giving carboxylic acids.6 Allylic alcohols are oxidized more slowly than saturated alcohols. Solid potassium permanganate, adsorbed on bentonite or copper sulphate pentahydrate, oxidizes allylic alcohols in dichloromethane solution to give enones with minimal degradation of the double bond.’ Secondary alcohols furnish ketones in high yield with benzyltriethylammonium permanganate.’ Some CY -cleavage is observed, but primary alcohols give only carboxylic acid derivatives. The reaction of alcohols with ethyl nitroacetate, diethyl azodicarboxylate, and triphenylphosphine gives aldehydes or ketones via their aci-nitroesters.’

‘ A. J. Mancuso and D. Swern, Synthesis, 1981,165. Y. Masuyama, A. Tsuhako, and Y. Kurusu, Tetrahedron Lett., 1981,22,3973.

’ Y.Kurusu, Bull. Chem. SOC.Jpn., 1981,54,293.

‘ S.Hanessian, D. H. Wong, and M. Therien, Synthesis, 1981,394. ’

J. M. J. FrBchet, P. Darling, and M. J. Farrall, J. Org. Chem., 1981,46,1728. F. M. Menger and C. Lee, Tetrahedron Lett., 1981,22,1655. N. A. Noureldin and D. G. Lee, Tetrahedron Lett., 1981,22,4889. H.-J. Schmidt and H. J. Schafer, Angew. Chem., Int. Ed. Engl., 1981,20,104. 0.Mitsunobu and N. Yoshida, Tetrahedron Lett., 1981. 22,2295.

56

Aldehydes and Ketones

57

The selective oxidation of alcohols in the presence of phenylthio- or phenylseleno-groups may be carried out using dimesityl diselenide and t-butyl hydroper0xide.l' In benzene, R u C ~ ~ ( P Pis~ effective ,)~ for the oxidation of a primary alcohol in the presence of a secondary alcohol, as evidenced by the oxidation of 1,lO-undecanediol. ' ' The same ruthenium complex catalyses the oxidation of secondary alcohols by iodosylbenzene and primary alcohols by phenyl iodosodiacetate to the corresponding carbonyl compounds.12 Ruthenium(I1) catalyses the homogeneous oxidation of allylic alcohols to carbonyl compounds by molecular oxygen,13 whereas palladium [as Pd(OAc),/PPh, or Pd(PPh,),] oxidizes unsaturated alcohols to the corresponding ketones using aryl bromides as 0 ~ i d a n t . l ~ Alkyl halides are converted into carbonyl compounds by oxidation with 4-dimethylaminopyridine N- oxide in the presence of diazabicycl~undecane.'~ This reagent is more reactive than pyridine N-oxide, and requires lower temperatures than the similar reaction using DMSO as oxidant. Dehydrogenation of amines may be achieved by thermolysis of sulphinamides, although benzylic or allylic activation is required to control the regioselectivity of elimination (Scheme 1).l 6 A biomimetic oxidative deamination of primary

0 I

H

ivl

Y

ArS-N

RCHO

Reagents: i, ArS(0)Cl; ii, RCH,Br; iii, A; iv, H30+

Scheme 1

amines is accomplished by prototropic rearrangement of the imine from pyridine2-carboxyaldehyde [equation (l)]."

lo l1

l2 l3

l4 1s

l6

M. Shimizu, H. Urabe, and 1. Kuwajima, Tetrahedron Lett., 1981, 22, 2183. H. Tomioka, K. Takai, K. Oshima, and H. Nozaki, Tetrahedron Lett., 1981,22, 1605. P. Miiller and J. Godoy, Tetrahedron Lett., 1981, 22, 2361. M. Matsumoto and S. Ito, J. Chem. SOC.,Chem. Cornmun., 1981, 907. Y. Tamaru, K. Inoue, Y. Yamada, and Z. Yoshida, Tetrahedron Lett., 1981,22, 1801. S. Mukaiyama, J. Inanaga, and M. Yamaguchi, Bull. Chem. SOC.Jpn., 1981, 54, 2221. B. M. Trost and G. Liu, J. Org. Chem., 1981,46,4617. J. H. Babler and B.J. Invergo, J. Org Chem., 1981, 46, 1937.

58

General and Synthetic Methods

Aliphatic nitro-compounds, as their nitronate anions, react with molybdenum peroxide, MoO,.py.HMPA, to give carbonyl compounds.18Primary nitroalkanes give the carboxylic acid. A re-appraisal of potassium permanganate as oxidant for primary nitroalkane salts indicates this can be an excellent reagent for the preparation of aldehydes, particularly quaternary aldehydes. l 9 Supporting sodium periodate on silica gel produces a superior reagent to sodium periodate alone for, amongst other oxidations, the cleavage of carbocyclic uic-diols to the dialdehyde.20 N-Iodosuccinimide has been found to be an efficient reagent for 1,2-diol cleavage, with release of iodine.21 Diols may also be cleaved by catalytic, rather than molar, amounts of triphenylbismuth carbonate, using N- bromosuccinimide as oxidant for triphenylbismuth.22The presence of potassium carbonate and water is essential. Carbon-carbon bond cleavage of the covalent dibutyl stannylene derivatives of 1,2-diols has been observed with various Oxidation is possible under strictly aprotic conditions. Reductive Methods.-Carboxylic acids, unlike esters, on treatment with isobutylmagnesium bromide and catalytic amounts of dichlorobis[r- cyclopentadienylltitanium afford aldehydes after hydrolytic w o r k - ~ p However, .~~ cinnamic acid failed to give the aldehyde. Palladium complexes, e.g. tetrakis(triphenylphosphine)palladium(O), catalyse the reaction of acyl chlorides with tributyltin hydride to give aldehydes ~pecifically.~’ The reaction appears to be general, and a,@-unsaturatedacid chlorides may be reduced to the unsaturated aldehyde. The reduction of acid chlorides using sodium borohydride usually gives only the alcohol. Aldehydes may be isolated in high yield from reduction in DMF-THF mixtures as solvent provided care is given to the conditions for work-up.26 The use of propionic acid-dilute hydrochloric acid-ethyl vinyl ether is recommended. Further studies on the selectivity of reductions of acid chlorides with complex copper(1) borohydrides have Benzimidazolium salts are rapidly reduced to 2,3-dihydrobenzimidazoleswith sodium borohydride, offering a route from acids to aldehydes suitable for the introduction of deuterium at C-1 (Scheme 2).29 2-Deuterio-1,3-benzodithioliumperchlorate (1,X = C104)has been described as a useful synthon for the preparation of deuterioaldehydes from organometallic regent^.^' However, the extreme sensitivity of 1,3-benzodithiolium perchlorate, and perchlorates in general, towards detonation is highlighted in a communication by Pelter, who indicates that the corresponding tetrafluoroborate (1,X = BF,) is easily handled, and behaves chemically in a similar fashion to the M. R. Galobardes and H. W. Pinnick, Tetrahedron Lett., 1981, 22, 5235. N. Kornblum and A. S. Erickson, J. Org. Chem., 1981,46, 1037. 2o D . N. Gupta, P. Hodge, and J. E. Davies, J. Chem. Soc., Perkin Trans. 1 , 1981, 2970. ’’ T. R. Beebe, P. Hii, and P. Reinking, J. Org. Chem., 1981, 46, 1927. 22 D. H. R. Barton, W. B. Motherwell, and A. Stobie, J. Chem. Soc., Chem. Commun., 1981, 1232. 23 S. David and A. Thitffry, Tetrahedron Lett., 1981, 22, 2885. 24 F. Sato, T. Jinbo, and M. Sato, Synthesis, 1981, 871. 25 P. Four and F. Guibe, J. Org. Chem., 1981,46,4439. 26 J. H. Babler and B. J. Invergo, Tetrahedron Lett., 1981, 22, 11. ” G . W. J. Fleet and P. J. C. Harding, Tetrahedron Lett., 1981, 22, 675. ” P. N. Davey, G. W. J. Fleet, and P. J. C. Harding, J. Chem. Res. ( S ) , 1981, 336. 29 J. C. Craig, N. N. Ekwuribe, C. C. Fu, and A. M. Walker, Synthesis, 1981,303. 3” I. Degani, R. Fochi, and V. Regondi, Tetrahedron Lett., 1981,22, 1821. l9

Aldehydes and Ketones

59

Reagents: i, PPA; ii, NaOEt; iii, MeI; iv, NaBH,; v, HCI-H,O

Scheme 2

O : ) H ( D )

\

X-

s (1)

per~hlorate.~' Organometallic reagents may also be formylated very efficiently by N- f~rmylpiperidine,~~ and aldehyde acetals may be obtained from the reaction of phenyldialkylorthoformates and various organometallic reagents.33The mixed orthoformate proved particularly reactive towards allylic and vinylic magnesium, zinc, and aluminium reagents. In the preparation of ketones from carboxylic acids and aryl-lithium reagents, aniline or dry gaseous formaldehyde have been recommended for the destruction of excess aryl-lithium in order to minimize carbinol formation.34The advantages of organomanganous iodides are exemplified by their use in the preparation of keto~teroids.~' The reagents react with acid chlorides to form ketones, but are very slow to react with esters, even forrnates. Dichloromethane may be used as a co-solvent, which may be particularly advantageous for substrates with low solubility in the ether solvents conventionally used for organometallic reactions. Ketones may also be prepared from acid chlorides or thioesters and alanes complexed to copper(I1) bis(acety1acetonate) and triphenylph~sphine.~~ Unlike simple trialkyl alanes, the complexed alane does not react with the ketone product. Acyl cobalt(II1) complexes are central to a methyl ketone synthesis r e p ~ r t e d . ~The ' complex (2) reacts with methylmagnesium iodide to give the ketone in good yield, no tertiary alcohol formation being observed even with vast excesses of the Grignard reagent [equation (2)]. 31

32 33 34

" 36

''

A. Pelter, Tetrahedron Lett., 1981, 22, i. G. A. Olah and M. Arvanaghi, Angew. Chem., Int. Ed. Engl., 1981, 20,878. F. Barbot, L. Poncini, B. Randrianoelina, and P. Miginiac, J. Chem. Res. ( S ) , 1981, 343. D. E. Nicodem and M. L. P. F. C. Marchiori, J. Org. Chem., 1981,46,3928. G . Cahiez, Tetrahedron Lett., 1981, 22, 1239. K. Takai, K. Oshima, and H. Nozaki, Bull. Chem. SOC.Jpn., 1981, 54, 1281. I. Tabushi, K. Seto, and Y. Kobuke, Tetrahedron, 1981, 37, 863.

General and Synthetic Methods

60

A base-induced rearrangement of alkyl(N- alky1amido)methyl sulphides may find use in the preparation of aryl benzyl ketones [equation (3)].38 Reductive

coupling of benzylic bromides and acyl chlorides by zinc in the presence of a palladium catalyst furnishes benzylic ketones in good yield,39 and a catalytic amount of nickel(I1) chloride activates zinc in amide solvents in the preparation of unsymmetrical ketones from alkyl iodides and 2-[6-(2-methoxyethyl)pyridylI carboxylates [equation (4)].40Thiopyridyl esters and cuprates give ketones when

Me0

the reaction is carried out under an inert a t m o ~ p h e r e .The ~ ~ atmosphere is important, as in the presence of oxygen esters are the major products (Scheme 3).

Reagents: i, LiCuR2,-0,; ii, LiCuR2,-N,

Scheme 3

Readily prepared N- methoxy-N- methylamides couple in excellent yield with organolithium and Grignard reagents to form ketones, and are reduced by hydrides to aldehydes.42 A two-step procedure for the reduction of nitriles to aldehydes has been Nitrilium salts are readily reduced by triethylsilane to the aldimine without the over-reduction to secondary amines observed with sodium borohydride. Hydrolytic work-up liberates the aldehyde in good overall yield [equation ( 5 ) ] . Nitriles are reduced to disilylated enamines by the iron carbonyl complex 38

39 40

41 42

43

Y. Kurebayashi, Y. Ishikawa, Y. Terao, and M. Sekiya, Tetrahedron Lett., 1981, 22, 123. T. Sato, K. Naruse, M. Enokiya, and T. Fujisawa, Chem. Lett., 1981, 1135. M. Onaka, Y. Matsuoka, and T. Mukaiyama, Chem. Lett., 1981, 531. S. Kim, J. I. Lee, and B. Y. Chung, J. Chem. SOC.,Chem. Commun., 1981,1231. S . Nahm and S. M. Weinreb, Tetrahedron Lett., 1981, 22, 3815. J. L. Fry and R. A. Ott, J. Org. Chem., 1981, 46, 602.

Aldehydes and Ketones RCN

61

- Et36

+

RCENEt

Et3SiH

RCH=NEt

H 6 3 RCHO

(3) (Scheme 4).44 These interesting enamines are stable to Grignard reagents and lithium tetrahydroaluminate, and are not hydrolysed under neutral conditions; they yield the aldehyde in aqueous acid, thus allowing the generation of an aldehyde in a protected form.

R' >CHO

R2 Scheme 4

Silyl nitronates derived from primary and secondary nitroalkanes form oximes on reaction with organolithium reagent^.^' Yields are modest, and the concentration of the reaction is important, as above ca. 0.2 M, the major product becomes the silyl ester of a hydroxamic acid (Scheme 5 ) .

> ,

OH

NHOSiR'3

0

Scheme 5

Methods Involving Umpolung.-Simple a1kyl ethers of 2,6-disubsti tu ted benoic acids may be deprotonated with s-b~tyl-lithium,~~ Because of the stability of these esters towards acid, suitable tertiary alcoholic adducts afford ketones with sulphuric acid (Scheme 6). 2-Methoxyethyl esters of these hindered acids may also be considered as nucleophilic acetyl units since they undergo deprotonationelimination-metalation to afford vinyl ester anions [equation (6)]. Effects of vinyl ester structure on rates of metalation and applications of this strategy to the construction of carbonyl compounds have been described.47 In 44 45

46 47

R. J. P. Corriu, J. J. E. Moreau, and M. Pataud-Sat, J. O r g . Chem., 1981,46,3372. E. W.Colvin, A. D. Robertson, D. Seebach, and A. K. Beck, J. Chem. Soc., Chem. Commun., 1981,952. P. Beak and L. G. Carter, J. O r g . Chem., 1981,46,2363. R.K.Boeckman and K.J. Bruza, Tetrahedron, 1981,37,3997.

General and Synthetic Methods

62

Li

ArCO,CH,R

ArCOOCHR

1

iii

Reagents: i, Bu”Li-TMEDA; ii, cyclohexanone; iii, H,SO,

Scheme 6

comparing the rates of deprotonation of phenyl vinyl selenides and sulphides, Reich and his co-workers observed that the rate of deprotonation by lithium di-isopropylamide is strongly depressed by the presence of excess amine, and

x

’ ArCOO

ArCOO+oMe

Bu’Li TMEDA

\

7 ArCOO

k

(6)

\

postulate that a complex of LDA and di-isopropylamine is a considerably weaker base than LDA itself.48These observations have synthetic use since deprotonation is rapid and complete when the sulphide is treated with one equivalent of n-butyl-lithium and a catalytic amount of di-isopropylamine. The method is not advantageous for the selenide since Michael addition and attack at selenium by the alkyl-lithium compete with deprotonation. In diethyl ether-TMEDA, alkyllithium reagents add to phenyl vinyl sulphide or vinyl silanes to give, after silylation or sulphenylation, a new synthesis of 1-phenylthio- 1-trimethylsilylalkanes, which are readily converted into aldehydes uia a sila-Pummerer rearrangement (Scheme 7).49

SPh

4

7

SiMe,

Reagents: i, RLi-TMEDA; ii, Me,SiCl; iii, PhSCl or (PhS),; iv, m-ClC,H,CO,H;

Scheme 7

H. J. Reich, W. W. Willis, and P. D. Clark, J. Org. Chem., 1981,46,2775. D. J. Ager, Tetrahedron Lett., 1981, 22, 587.

v, A; vi,

H,O

Aldehydes and Ketones

63

Amidrazones are new precursors of a-lithioenamines, which act as nucleophilic acyl equivalents (Scheme 8)." The method appears to be limited to precursors derived from acids bearing an a-methylene group. R

NHNHS0,Ar

/-fN-NHSo2Ar R

,NT

Reagents: i, PCI,; ii, morpholine; iii, Bu'Li; iv, E '

Scheme 8

The Wittig-Horner reaction offers a versatile route to enol derivatives of ketones, and hence ketones themselves, but its applicability depends on the availability of a range of a-functionalized phosphine oxides. It has been shown that chlorodiphenylphosphine and acetals form a-alkoxy-phosphine oxides directly in good yield [equation (7)].51Acetals of unsaturated aldehydes react well, but unfortunately dimethoxymethane gives a poor yield of the parent compound. 0 II \ R' Ph,PCI

+ R'CH(OMe),

+ Ph,PCH(OMe)R' +

R'prz\(

(7)

OMe

With n-butyl-lithium-TMEDA, the carbamates (4) yield solutions of the dilithiated esters which are stable at -70 "C,unlike the corresponding deprotonated N,N- dialkyl car barn ate^.^^ These dianions react with electrophiles to give predominantly the enol esters, precursors of carbonyl compounds or specific enolates (Scheme 9). Seebach has published further demonstrations that dienone dianion derivatives are accessible by double deprotonation of y,S- unsaturated ketoness3 These interesting dianions provide not only an umpolung of reactivity, but also a 'remote' activity, as electrophiles react at the &position ( d 5 reactivity) (Scheme 10). Other Methods.-Semicarbazide on silica gel and Girard-T on silica gel have been recommended as reagents for the isolation of aldehydes and ketones.54 50 51 52

53 54

J. E. Baldwin and J. C. Bottaro, J. Chem. Soc., Chem. Commun., 1981, 1121. M. Maleki, A. Miller, and 0.W. Lever, Tetrahedron Lett., 1981, 22, 365. R. Hanko and D . Hoppe, Angew. Chem., Inr. Ed. Engl., 1981,20, 127. D . Seebach and M. Pohmakotr, Tetrahedron, 1981,37,4047. R. P. Singh, H. N. Subbarao, and S. Dev, Tetrahedron, 1981, 37, 843.

General and Synthetic Methods

64

1

(4)

iii

E?o

R2

Reagents: i, Bu"Li-TMEDA; ii, E'; iii, hydrolysis

Scheme 9 0

0

OK

Li' K+

R R = But, Ph, OR'or NRZ

1

iii

0

Reagents: i, KH; ii. Bu'Li-2TMEDA; iii, Ph,CO

Scheme 10

Although this may find its major application in the separation of carbonyl compounds from natural mixtures, occasional use may be found with synthetic mixtures. Regeneration of the aldehyde or ketone was highly effective using aqueous oxalic acid and toluene-heptane mixtures. Aryl- and alkyl-carboxylic dihalophosphoric anhydrides acylate activated arenes without the need for a conventional Friedel-Crafts ~atalyst.'~ The anhydrides are prepared in situ, and the low temperatures required (20°C) allow reasonable yields of ketones to be obtained from mixed anhydrides of low stability, for example those derived from acetic and pivalic acids [equation (S)].

Aromatic palladocycles react regiospecifically with acyl halides to give aryl ketones in good yield [equation (9)].56Unfortunately, at present the method requires the preparation of the palladocycle prior to acylation, and so is not catalytic in palladium. Potassium peroxydisulphate in the presence of cupric ions has been shown to be a convenient reagent for the conversion of electron-rich benzylic hydrocarbons into carbonyl compound^.^'

'' F. Effenberger, G . Konig, and H. Klenk, Chern. Ber., 1981,114, 926. " "

R. A. Holton and K. J. Natalie, Tetrahedron Lett., 1981, 22, 267. M. V. Bhatt and P. T. Perumal, Tetrahedron Lett., 1981, 22, 2605.

Aldehydes and Ketones

65

(9) C1

A new synthesis of unsymmetrical ketones centres on the reactivity of 1,2dimethoxyethenyl trialkyl b o r a t e ~ . ~Treatment ' with methyl or ethyl fluorosulphonate brings about alkyl migration to afford the enol ether (Scheme 11).Two

Reagents: i, BuLi; ii, BR',; iii, RZOSO,F; iv, H,O'

Scheme 11

migrations from boron to carbon occur spontaneously on reaction of boranes with the anion from tris(phenylthio)methane, oxidative work-up yielding the ketone [equation (lo)]." Dl

BR3 + LiC(SPh)3 + RB(SPh)CR2SPh I_) R2C0

(10)

Boron also features in a convenient route to acyl silanes via hydroboration of silyl acetylenes [equation (I1)].60 Anhydrous trimethylamine N- oxide was

found to be the most efficient oxidant for the intermediate vinyl borane. Attempts to prepare acyl silanes from the silyl phosphonate (5) failed.61 Treatment with tributyltin methoxide afforded the stannane (6),whereas the hydroxyphosphonate (7) afforded the ketone under these conditions (Scheme 12). The synthetic uses of acyl silanes continue to be improved. Benzoyl silanes yield aldehydes or ketones on treatment with fluoride ion in DMSO in the presence of water or alkyl iodides.62 A recently-observed nitrogen to carbon acyl migration offers an intriguing opportunity to rearrange cyclic ketones (Scheme 13).63 The highly important hydroformyIation of olefins to aldehydes is a fruitful area for the development and application of new techniques. Photochemically initiated high-pressure f ~ r m y l a t i o nand ~ ~ the use of polymer-bound ruthenium catalysts65are but two examples. The complex role of HCo(CO), in hydroformylation has been reviewed.66 Nickel(0) complexes catalyse an acetylation of aryl T. Yogo, J. Koshino, and A. Suzuki, Chem. Lett., 1981, 1059. A. Pelter and J. M. Rao, J. Chem. SOC.,Chem. Commun., 1981, 1149. 6o J. A. Miller and G. Zweifel, Synthesis, 1981, 288. 61 M. Sekine, A. Kume, andT. Hata, J. Chem. SOC.,Chem. Commun., 1981,969. D. Schinzer and C. H. Heathcock, Tetrahedron Lett., 1981, 22, 1881. 63 G. Liso, G . Trapani, A. Reho, and A. Latrofa, Tetrahedron Lett., 1981, 22, 1641. 64 M. J. Mirbach, N. Topalsavoglu, T. N. Phu, M. F. Mirbach, and A. Saus, Angew. Chem., Int. Ed. EngI., 1981.20, 381. " C . U. Pittman and G . M. Wilemon, J. Org. Chem., 1981,46, 1901. 66 M. Orchin. Acc. Chem. Res., 1981,14, 259. 58 59

General and Synthetic Methods

66

0

II

Me,SiOCH,P(OEt),

0

-

II

p (0Et)2

. ..

I, 11

Me,SiO--( SiMe,

7

Ph HO-/--P(OEt)2

0

Ph< Et

Et

(7) Reagents: i, LDA; ii, Me,SiCl; iii, RX;iv, Bu,SnOMe

Scheme 12

OAR Reagents: i, H’; ii, (RCO),O; iii, A, DMSO

Scheme 13

iodides with carbon monoxide and tetramethyl tin in HMPA [equation (12)].67 The lack of reaction with tetraphenyl tin would appear to point to limitations to the scope of the reaction. Although monoalkyl nickel complexes NiR(Y)L2 react with carbon monoxide to yield acyl complexes with potential for the synthesis of carboxylic acid derivatives, simple dialkyl nickel complexes NiR2L2 give the ketones or aldehydes by insertion of carbon monoxide.68 ArI + CO + SnMe4

67

‘*

HMPA Ni(COMPPh31z

ArCOMe + Me3SnI

M. Tanaka, Synthesis, 1981, 47. T. Yamamoto, T. Kohara, and A. Yamamoto, Bull. Chem. SOC.Jpn., 1981, 54,2161.

(12)

Aldehydes and Ketones

67

Cyclic Ketones.-Many examples exist of reversible reactions that are not preparatively useful because of unfavourable equilibrium constants, and numerous other reactions are preparatively poor through self-condensation of the substrate. Both of these problems occur in the cyclopentenone preparation shown [equation (13)J. However, a cunning solution has been found whereby both the acid- and base-catalysed steps may be carried out concurrently using a mixed-ion-exchange resin consisting of sulphonic acid beads and quaternary ammonium hydroxide beads, giving the cyclopentenone in 87% (crude) yield.69

The oxidative cyclization of vinylallenes to cyclopentenones has been extended, indicating the feasibility of the preparation of 4-vinylcyclopentanones from 1,2,4,6-tetraenes [equation (14) The results of detailed investigations of the OH

L,-

M&(OPh),l

DBU

h-

4’

ArC0,H

&R

(14)

/*

palladium-cataIysed 0-to C-rearrangement of alkylidene vinyltetrahydrofurans (8) into cyclopentanones have appeared [equation (15)].” This constitutes a [1,3] rearrangement of the ally1 vinyl ether, complementing the normal [3,3] thermal rearrangement to cycloheptenones. 0

(8)

I

Cyclizations initiated by thionium ions have been shown to have synthetic potential. Trost and Murayama have shown that dimethyl(methy1thio)sulphonium fluoroborate exhibits a high thiophilicity for initiation of cyclization

reactions of thioketals [equation ( 16)],72whereas Mander and Mundill generate the thionium salt via a Pummerer rearrangement [equation (1 7)].73 69

’O

’‘ ’’

72

J. C. Stowell and H..F. Hauck, J. Org. Chem., 1981, 46, 2428. G. Balme, M. Malacria, and J. Gori, J. Chem. Res., (S),1981, 244. B. M. Trost and T. A. Runge, J. A m . Chem. SOC.,1981,103,2485,7550,7559. B. M. Trost and E. Murayama, J. Am. Chem. SOC.,1981,103,6529. L. N. Mander and P. H. C. Mundill, Synthesis, 1981, 620.

General and Synthetic Methods

68 0

SMe The dithiol ester version of the Dieckmann cyclization takes place under milder conditions than the classical reaction,74which suggested that the half -thiol diesters should show regioselectivity in their condensation. This has indeed been found to be the case [equation (18)].75Regioselectivity of ring closure of certain

1,5-diketones by aldol condensation is achieved by correct choice of reaction conditions (Scheme 14).76*77

Reagents: i, Me,SiCl-HCl; ii, piperidine-HOAc Scheme 14

Lithiated nitriles react with 1,3-dienes to give selectively alkylated cyclohexenones [equation (19)].'* Choice of a lithium base is necessary for the cyclization to occur.

R 1 CN

Medium- and large-ring ketones are conveniently prepared via intramolecular alkylation of protected c y a n o h y d r i n ~ .Both ~ ~ saturated and a,& unsaturated cyclic ketones can be prepared by this reaction, which tolerates the presence of an ester group. Trimethylsilyl iodide has been shown to be another efficient reagent for the preparation of cyclopentenones via Nazarov-type cyclizations." 74

" 76 77

78 79

*'

H.-J. Liu and H. K. Lai, Synth. Commun., 1981,11, 65. Y. Yamada, T. Ishii, M. Kimura, and K. Hosaka, Tetrahedron Lett., 1981, 22, 1353. W. Kreiser and P. Below, Tetrahedron Lett., 1981, 22,429. G. Frher, Tetrahedron Lett., 1981, 22,425. K. Takabe, S. Ohkawa, and T. Katagiri, Chem. Lett., 1981,489. T. Takahashi, T. Nagashima, and J. Tsuji, Tetrahedron Lett., 1981, 22, 1359. J. P. Marino and R. J. Linderman, J. Org. Chem., 198€,46, 3696.

Aldehydes and Ketones

69

The preparation and Diels-Alder reactions of heterosubstituted dienes have been reviewed.81These compounds continue to attract synthetic effort. A convenient synthesis of 1,3-bis(trimethylsilyloxy)buta-l,3-dienehas appeared,82as has a flexible route to substituted 2-ethoxybutadienes (Scheme 15).83 R+R~

-

OEt

0

R+R~- .

~ i-

'PPh,

+PPh,

OEt R3+~2

R'

liv Reagents: i, EtBr; ii, NaNH,; iii, R3CHO; iv, R4COCI

Scheme 15

2-Alkyl-2-vinylcyclobutanones84 undergo acid-catalysed ring expansion via a 1,2-acyl shift to form cyclopentanone~.~~ In the absence of the 2-alkyl group, the predominant reaction is a 1,3-acyl shift giving rise to the cyclohexenone (Scheme 16).

V

'R'=H

p R2

.3

R

&R3

Reagents: i, lithium dimethylaminonaphthalene; ii, R'CH=CR2COR'; THF-H,O; v, MeS0,H-P,O,; vi, MeS0,H

R' iii, H,O; iv, 10% HBF,-

Scheme 16

Cycloaddition of methyl chloromethylene carbene to silyl enol ethers is the first step in a short sequence to ring-expand cyclic ketones to a-methylcycloalkenones [equation (20)].86Thermal elimination of chlorotrirnethylsilanecoma' M. Petrzilka and J. I. Grayson, Synthesis, 83 84

86

1981,753. K. Krageloh and G. Simchen, Synthesis, 1981,30. H.-J. Bestmann and K. Roth, Angew. Chem., Int. Ed. Engl., 1981,20,575. T.Cohen and J. R. Matz, Tetrahedron Lett., 1981,22,2455. J. R. Matz and T. Cohen, Tetrahedron Lett., 1981,22,2459. L.Blanco, P. Amice, and J.-M. Conia, Synthesis, 1981,289.

0

General and Synthetic Methods

70 Me3Si0

6

~ MeCHCI, Bu"Li

e

3

e

~

e

0

(20)

'

pletes the transformation. A carbon version of the 'Zip' reaction has appeared, enabling the four-carbon expansion of a-nitrocycloalkanones [equation (21)].87

'3.

0

/ " 0 2

0

Bu NF

4

0

I

Me0

C02Me

The reaction has also been demonstrated in open-chain systems.88The efficient eight-carbon expansion of cycloalkanones is discussed in detail in a paper by Wender and his co-workers (Scheme 17).89 SMe SMe __*

/

Reagents: i, MeS-SMe; Li

ii, Ac,O; iii, HgCl,; iv, Ph,P=CH,;

v, LiAlH,; vi. CrO,.py; vii,

KH-THF, 25 "C

Scheme 17

Enol phosphates derived from thiol esters couple with organoaluminium reagents, catalysed by tetrakis(tripheny1phosphine) palladium, to form enol thioethers, and hence ketones by hydrolysis [equation (22)Is9"This alkylative 0

II

R lw0P(OPh', SPh 147

89 90

Pd(PPh3)4 R*,AI

w

R'

R2

SPh

-

0 R

I

A

p

(22)

Y. Nakashita and M. Hesse, Angew. Chem., I n r . Ed. Engl., 1981, 20, 1021. A. Lorenzi-Riatsch, Y. Nakashita, and M. Hesse, Helo. Chirn. Acra, 1981, 64, 1854. P. A. Wender, S. McN. Sieburth, J. J. Petraitis, and S. K. Singh, Tetrahedron, 1981,37, 3967. M. Sato, K. Takai, K. Oshima, and H. Nozaki, Tetrahedron Lerr., 1981,22, 1609.

Aldehydes and Ketones

Q

(jSPh psph*p 71

0

i-iv

OP(0Ph)z

"

--*

___)

Reagents: i, LDA;ii. PhSSPh; iii, NaH; iv, CIP(O)(OPh),; v, Me,Al-Pd(PPh3)*; vi, TiCI,-CH3C12H20

Scheme 18

displacement has been extended to afford alkylative 1,2-(Scheme 18) and 1,3(Scheme 19) carbonyl transpositions. 0

Ph

Ph

-Ph k-vii

Ph Reagents: i, PhSLi; ii, CIP(O)(OPh),; iii, Me,Al-Pd(PPh,),; iv, [O];v, 2LDA; vi, PhSSPh; vii, HgC1,-

HzO Scheme 19

A method for the conversion of tosylhydrazones of a,p-enones to transposed allylic sulphides has been described." Combining this with the known methods for regiospecific conversion of allylic thioethers to enones produces a controlled enone transposition with a 1,2-carbonyl shift (Scheme 20). 0NNHTs NNHTs

\

Reagents: i, Bu"Li; ii, PhSSPh; iii, H,O'; iv, NaBH4-HOAc; v, m-CIC,H,CO,H; vii, HgC1,-H,O-CH,CN; viii, PhSH-Bu'OK; ix, [O]

Scheme 20 9'

T. Mimura and T. Nakai, Chem. Lett., 1981, 1579.

vi, LDA;

General and Synthetic Methods

72

2 Synthesis of Functionalized Aldehydes and Ketones

Unsaturated Aldehydes and Ketones.-Irradiation of oxygenated solutions of q 3- allylpalladium complexes leads to unsaturated carbonyl compounds in modest yield.92Oxidation of (steroidal) v-allylpalladium complexes can also be carried out using chromium trioxide .in dimethylformamide containing a trace of sulphuric acid.93 3-Ketosteroids are smoothly oxidized to the 1,4-dien-3-ones by benzene seleninic anhydride. Barton and his group have now made this reaction catalytic in selenium by developing the use of iodylarenes for the in situ oxidation of diphenyldiselenide to the anhydride.94rn- Iodylbenzoic acid was chosen to aid the isolation of the product and the recovery of the aryl iodide. Z- 2- (Trimethylsily1oxy)vinyl-lithium shows promise as a nucleophilic acetaldehyde equivalent in condensation with aldehydes and ketones, since the adducts hydrolyse very readily to unsaturated aldehydes [equation (23)].95 In another

form of a crossed aldol condensation, the acidic clay Montmorillonite K-10 has been shown to have advantages over boron trifluoride etherate or iron(II1) chloride in catalysingthe condensation of acetals with ethyl vinyl ether [equation (24)].96Bis(p-methoxypheny1)telluroxide can ,also function as a catalyst for aldol condensation of ketones with aryl aldehydesg7

R

K-10

-R h

(24)

CHO

R 'OEt

In designing routes to enones, the principle of isomerization of intermediates to the thermodynamically more stable isomer should not be ignored. Applying this principle, synthesis of 2-alkylcyclopentenones can become much more straightforward. Either an enamine-controlled aldol condensation [equation (25)],98 or a modified aldol using the readily prepared a -

92 93 94

95

96 97

98

J. Muzart, P. Pale, and J.-P. Pete, J. Chem. SOC.,Chem. Commun.. 1981,668. J. Y.Satoh and C. A. Horiuchi, Bull. Chem. SOC.Jpn., 1981,54,625. D . H. R. Barton, J. W. Morzycki, W. B. Motherwell, and S. V. Ley, J. Chem. SOC.,Chem. Commun.,

1981,1044. L. Duharnel and F. Tombret, J. Org. Chem., 1981,46,3741. D. Fishrnan, J. T. Klug, and A. Shani, Synthesis, 1981,137. L. Engman and M. P. Cava, Tetrahedron Left., 1981,22,5251. A. Barco, S. Benetti, P. G. Baraldi, and D. Simoni, Synthesis, 1981,199.

Aldehydes and Ketones

73

chlorothioethers [equation (26)]99may be used. Alkylation of enones may be carried -out regioselectively by reaction of enol derivatives of the epoxyketone with organometallic reagents (Scheme 21).100Either a- or a‘-substitution may be selected by use of organolithium or organocopper reagents, respectively.

-oo bo PX

i (X= Li)

Reagents: i, LDA; ii, Me,SiCl; iii, RLi; iv, R,CuLi

Scheme 21 a-Substitution of a,@-unsaturated ketones can be carried out via congugate addition and subsequent aldol condensation (Scheme 22). Of interest here is

CO2Et

X = SPh or SeMe Reagents: i, Et,AIX; ii, RCHO; iii, MeC(OEt),

Scheme 22

the potential for elaboration via an orthoester Claisen rearrangement to afford p- substituted enones. A selenium version of this addition-aldol sequence has also appeared which is applicable to the preparation of ether derivatives [equation (27)].’02

8

iiiMe,SiSePh HC(OMe),

99 ‘00

&cH(oMe’. SePh

bCH(OMe’.

N. Ono, H. Miyake, and A. Kaji, Synthesis, 1981, 1003. P. A. Wender, J. M. Erhardt, and L. J. Letendre, J. Am. Chem. Soc., 1981, 103,2114. A. Itoh, S. Ozawa, K. Oshima, and H. Nozaki, Bull. Chem. SOC.Jpn., 1981, 54, 274. M. Suzuki, T. Kawagishi, and R. Noyori, Tetrahedron Letr., 1981, 22, 1809.

(27)

General and Synthetic Methods

I4

The ease with which the site of deprotonation of the oxime ether (9) may be controlled widens the scope of this reagent for synthesis of CY -methylene ketones (Scheme 23).lo3 Two further vinyl ketone building blocks have been

1

ii, iii

v, vi

Reagents: i, LDA,-95 "C; ii, LiNBu'Pr'; iii, RI; iv, Et,O'BF;;

1

v, Et,N; vi, Si0,-H,O

Scheme 23

des~ribed.'~~ Both * ' ~ ~rely on reactivity at the terminus of 3-triethylsilyloxypentadienyl anions [equation (28)].

X = H or SMe The 'super-acidic' resin Nafion-H is recommended over other resins as catalyst for the Ruppe rearrangement of a-acetylenic alcohols to enones.lo6 A new synthesis of unsaturated aldehydes centres on the [2,3]rearrangement which occurs on sulphenylation of 3-trimethylsilylallyl alcohols (Scheme 24). lo'

0 Reagents: i, LiAIH,; ii, PhSCI-Et,N, -30 "C; iii, 20 "C; iv, AgN03-H20-CH,CN

Scheme 24

The intermediate sulphoxides may be isolated with care, but this purification is not necessary. Full details on the use of propargyl selenides in the synthesis of a,P- unsaturated ketones have appeared. lo3

'06 I"' Io8

R. Lidor and S . Shatzmiller, 3. Am. Chem. SOC.,1981,103, 5916. W. Oppolzer, R. L. Snowdon, and D. P. Simmons, Helu. Chirn. Acta, 1981, 64, 2002. W. Oppolzer, R. L. Snowdon, and P. H. Briner, Helu. Chirn.Acta, 1981, 64, 2022. G. A. Olah and A. P. Fung, Synthesis, 1981, 473. I. Cutting and P. J. Parsons, Tetrahedron Lett., 1981,22, 2021. H. J. Reich, S. K. Shah, P. M. Gold, and R. E. Olson, J. Am. Chem. SOC.,1981,103,3112.

75

Aldehydes and Ketones

Lithium trialkylalkynyl borates react in a stereoselective manner with benzodithiolithium tetrafluoroborate to give vinyl boranes."' Hydrolysis of the vinyl boranes, the rate of which differs significantly for the E- and 2-isomers, gives protected unsaturated aldehydes (Scheme 25).

R'

R2

H

R2

ii

Rl2B

B F4-

R2

H

R'

- H R'

R'

slow

R2 CHO

Reagents: i, R',BCGCR2; ii, Pr'C0,H; iii, HgO-BF,

Scheme 25

a-Methyl-a,P- unsaturated carbonyl compounds are conveniently prepared by chloromethylenation of trimethylsilyl enol ethers [equation (29)]. 11" The

r22 Me3sT2 0

R'

CCIMe,

---*

R'

R

i

v

R

z

(29)

Cl

method has been exemplified by synthesis of the natural products eucarvone (lo), nuciferal (ll),and manicone (12).ll1

0

Butadienyl sulphoxides act as excellent Michael acceptors for nucleophilic acylating agents, particularly lithiated cyanohydrin ethers."' The resulting allylic anions may be alkylated, and simple hydrolyses complete an efficient synthesis of dienones [equation (30)]. lo9

'12

A. Pelter, P. Rupani, and P. Stewart, I. Chem. SOC.,Chem. Commun., 1981, 164. L. Blanco, P. Amice, and J.-M. Conia, Synthesis, 1981, 291. L. Blanco, N. Slougui, G. Rousseau, and J.-M. Conia, Tetrahedron Lett., 1981,22, 645. E. Guittet and S. Julia, Synth. Commun., 1981. 11. 709, 723.

General and Synthetic Methods

76

Following the use of p-silyl carbonyl compounds as masked en one^,"^ an These interesting observation has been made regarding p- silyl-a -sulph~xides."~ undergo a rapid syn-elimination of the silicon and sulphur substituents to give alkenes and alkynes. However, in the olefin-forming reaction, when there is a hydrogen a to the silicon this is lost in preference to silicon (Scheme 26).

-o\+ SPh

Scheme 26

In a paper discussing strategies for the synthesis of the macrocyclic diterpene jatrophone, brief comment is made disclosingthat chromous sulphate can cleanly effect the stereospecific reduction of a- oxoacetylenes to the corresponding E- enone, analogous to the reduction of acetylenic alcohols.' l S Various acid chlorides react with (stannylethyny1)aminesto give aminoethynyl ketones and chlorostannanes.' l 6 Trimethylsilylallenes are readily oxidized by atmospheric oxygen to acetylenic hydroperoxides."' The preparative reaction was carried out in the presence of pyridine, presumably to reduce the hydroperoxide to the alcohol, oxidative work-up (Collins reagent) affording acetylenic ketones (Scheme 27). Acetylenic ketones may also be prepared by the carbonylaOPh Me3Si-

G

i, ii

BR,

,Me,Si-E--(

Me3Si

A+

OPh

L=/

R

1

iv

R

R

Me3Si-

3, 6 0

Me3Si-

-(

OH

Reagents: i, Bu"Li; ii, R,B; iii, NaOMe; iv, 0,-pyridine; v, Collins reagent

Scheme 27

'I7

I. Fleming and D. A. Perry, Tetrahedron, 1981,37,4027. I. Fleming and D. A. Perry, Tetrahedron Lett., 1981,22,5095. A. B. Smith, M. A. Guaciaro, S. R. Schow, B. M. Wovkulich, B. H. Toder, and T. W. Hall, J. A m . Chem. SOC.,1981,103,219. G. Himbert, M.Feustel, and M. Jung, Leibigs Ann. Chem., 1981,1907. T. Yogo, J. Koshino, and A. Suzuki, Synrh. Commun., 1981,11,769.

Aldehydes and Ketones R'X+ co + H C = C R ~

77

NR3,

R'COC=CR~

PdCIzLz

tion of organic halides in the presence of terminal acetylenes [equation (3l)].ll8 Although most examples cited were carried out under 20 atmospheres of carbon monoxide, there was no significant loss of selectivity at atmospheric pressure. Hydrolysis of cumulenic alkyl ethers does not produce allenic aldehydes, since 1,4-addition of water occurs to give the acetylenic derivative. However, the hydrolysis of the trimethylsilyl ethers proceeds with Si-0 bond cleavage to give mainly the allenic aldehyde together with the silyl ketone, formed by Brook rearrangement (Scheme 28).'19 The ratio of these may be controlled by suitable choice of solvent. Alternatively, the silyl ketone may be made the exclusive product. A straightforward synthesis of the simplest a-allenic ketone has appeared, starting from acetylacetone [equation (32)].120a-Allenic ketones can also be prepared by the reaction between propaxgylsilanes and acyl chlorides.'21

R'

R'

ii, iii

R2+7

Me0

OSiMe,

OSiMe,

1

iv. v

R'

SiMe,

)-.=.=(

R2

OSiMe,

vi

R'

R2

t-'>o Me3Si

Reagents: i, Bu'Li; ii, Bu'Li-THF-pentane; iii, H,O;iv, Bu'Li-Et,O-pentane; v, Me,SiCI; vi, HOAc or Et,NF-H,O-THF

Scheme 28

E : Z 93:7

Whereas unsaturated p- dicarbonyl compounds are prepared easily and efficiently via a-selenenylation, particularly by the pyridine complex of phenylselenenyl chloride, followed by oxidative elimination of the seleno-group,'22the use of the less expensive selenium metal as electrophile offers obvious advantages for reactions on a larger scale [equation (33)].123

NaH-THF-HMPA, Se-Me1

@ @ SeMe

(33)

T. Kobayashi and M. Tanaka, J. Chem. Soc., Chem. Commun.,1981, 333. R. G . Visser, L. Brandsma, and H. J. T. Bos, Tetrahedron Lett., 1981, 22, 2827. G . Buono, Synthesis, 1981, 872. ''' J.-P. Pillot, B. Bennetau, J. Dunogues, and R. Calas, Tetrahedron Lett., 1981, 22, 3401. "' D . Liotta, C. Barnum, R. Puleo, G . Zima, C. Bayer, and H. S. Kezar, J. Org. Chem., 1981,46,2920. lZ3 D. Liotta, M. Saindane, C. Barnum, H. Ensley, and P. Balakrishnan, Tetrahedron Lett., 1981, 22, 3043. I"

'I9

General and Synthetic Methods

78

The palladium-catalysed reaction of vinylic halides with alkenes to form carbonyl compounds can be useful synthetically. Acrolein acetals can act as substrates in the presence of amines to form dienals in protected form [equation (34)].'24Addition of terminal vinylic iodides to enones is also possible,

H yielding dienones. This method is applicable to macrocyclization, the macrocyclic lactone (13) being formed in 5 5 % yield [equation (35)].'*' p-Aryl enones can be prepared by the palladium-catalysed arylation of allyltrimethylsilyl ethers, a reaction significantly improved by the presence of lithium chloride.'26

yao 3' 0

PdCI,(CH,CN), CH,CN

,

(35)

(13)

Cyclic 3-hydroxyvinylselenones undergo fragmentation under basic conditions to give unsaturated ketones (Scheme 29)."' When the double bond is tetrasubstituted, acetylenic products are formed, but trisubstituted olefins give, with

1

iv R ' = H

Reagents: i, PhSeSiMe,-ZnI,; ii, R'Li; iii, m- ClC,H,CO,H; iv, R30H-R30Na; v, NaH-THF

Scheme 29

alkoxides as base, mono-en01 ethers of 1,6-dicarbonyl compounds. Selenium may also be used to prepare P,y-unsaturated ketones, as zinc enolates have been shown to condense efficiently with phenylselenoacetaldehyde to yield lZ5

B. A . Patel, J.-I. I. Kim, D. D. Bender, L.-C. Kao, and R. F. Heck, J. Org. Chem., 1981,46, 1061. F. E. Ziegler, U. R. Chakraborty, and R. B. Weinsenfeld, Tetrahedron, 1981, 37, 4035. T . Hirao, J. Enda, Y. Ohshiro, and T. Agawa, Chem. Left., 1981, 403. M. Shimizu, R. Ando, and I. Kuwajima, J. Org. Chern., 1981,46, 5246.

Aldehydes and Ketones

79

products readily converted [equation (36)].'28 OZnX &R2

specifically to the non-conjugated

R1;)VI

enone

OH

PhSeCH,CHO+

R'

MeS0,CI-Et3N

R2

'

R

1 R2

SePh

b

(36)

A zinc-silver couple has been reported to be an improved reagent for the reductive addition of allylic bromides to n i f ~ i 1 e s . l1~-Trimethylsilyl-2-methyl~ cyclopropane is a convenient regio- and stereospecific precursor of P,y- unsaturated ketones [equation (37)].13"The reaction of allylsilanes with a-nitro-olefins has been found to proceed smoothly in the presence of aluminium trichloride [equation (38)].13*The unstable nitronic acid product may be converted readily into the unsaturated ketone by the Nef reaction. RCOCI-AICI,,

-0,+ ,OH N

NO2

M e , S i y R'

+

(37)

TiCI,

8 R 3

R2

R'

R2

wR 0

,

R1

R2

(38)

The [2,3]Wittig rearrangement of bisallyl ethers and ally1 ethers of glycollic acid offers a versatile method of preparing non-conjugated unsaturated aldehydes in a highly stereospecific fashion (Scheme 30).'32*'33 R2 R1+R3

O'1 C02H

R2

R2 R ' A R ' i i + CHO

+ R*R' HO

COzH

Reagents: i, LDA, -78+0 OC;ii, NaI0,-MeOH; iii, Bu"Li;iv, A

Scheme 30 12'

13'

13' 13' 133

D. L. J. Clive and C. G. Russell, J. Chem. SOC., Chem. Commun., 1981,434. G. Rousseau and J. M. Conia, Tetrahedron Lett., 1981, 22, 649. M. Grignon-Dubois, J. Dunogues, and R. Calas, Tetrahedron Lett., 1981, 22, 2883. M. Ochiai, M. Arimoto, and E. Fujita, Tetrahedron Lett., 1981, 22, 1115. T. Nakai, K. Mikami, S. Taya, Y. Kimura, and T. Mimura, Tetrahedron Lett., 1981, 22, 69. K. Mikami, N. Kishi, and T. Nakai, Chem. Lett., 1981, 1721.

General and Synthetic Methods

80

a-Substituted Aldehydes and Ketones.-The use of sulphuryl chloride in the chlorination and sulphinylation of active methylene compounds has been reviewed.'34 a-Iodination of ketones may be performed in acetic acid solution using iodine and cupric iodide.'35 Highly-substituted conjugated enones react with hypochlorous acid in a two-phase system to yield a-chloro-P,y- unsaturated ketones.'36 The reaction appears to be limited to enones which can exist in an s-cis conformation. Chlorinated ketones may be prepared directly from disubstituted olefins by photo-oxidation in pyridine solution containing ferric chloride.'37 Epoxides are converted into a -bromo- and a-iodo-ketones by reaction with the trimethylsilyl halide followed by Jones oxidation.13* aChloroepoxides yield a -fluoroketones with silver tetraflu~roborate.'~~ A useful study points to the susceptibility of the a-chloroepoxide to a-chloroketone transformation towards nucle~philes.'~~ Further details on the use of Qhaloalkyl-lithium reagents for the regiospecific synthesis of a-haloketones have appeared.'41 The anions react with esters at very low temperature to give the a-haloketone after hydrolysis of the hemiacetal [equation (39)].

L

X=C1 or Br

K'

Enones can be converted into their 2-halo derivatives by reaction of their a-seleno derivatives (generated in situ ) with further selenating agent [equation (40)]. 14* Complexes of a-acetylenic alcohols and iodine are oxidized by pyridinium dichromate to a-iodo-enones [equation (41)].'43

R' OH

X

R2

R'

CHO

HI

R2

Phosphorus tri-iodide and diphosphorus tetraiodide cleanly reduce a -bromoand a -iodo-ketones to a -1odo-ketones are deiodinated by thiols and K. Oka, Synthesis, 1981,661. C.A. Horiuchi and J. Y. Satoh, Synthesis, 1981,312. S. G. Hegde and J. Wolinsky, Tetrahedron Lett., 1981,22,5019. 13' A. Kohda, K. Ueda, and T. Sato, J. Org. Chem., 1981,46,509. 138 J. N.Denis and A. Krief, Tetrahedron Lett., 1981,22, 1429. K. Griesbaum, H. Keul, R. Kibar, B. Pfeffer, and M. Spraul, Chem. Ber., 1981,114,1858. 140 J. Gasteiger and C . Herzig, Angew. Chem., Int. Ed. Engl., 1981,20,868. 141 J. Villieras, M. Rambaud, R. Tarhouni, and B. Kirschleger, Synthesis, 1981,68. 142 S.V. Ley and A. J. Whittle, Tetrahedron Lett., 1981,22,3301. 143 R. Antonioletti, M. D'Auria, G. Piancatelli, and A. Scettri, Tetrahedron Lett., 1981,22, 1041. J. N. Denis and A. Krief, Tetrahedron Lett., 1981,22,1431. 134

135

Aldehydes and Ketones

81

selenols under very mild conditions, but a-bromo-ketones react by substitution rather than r e d ~ c t i o n . ' ~ ~ Various methods for the a-hydroxylation of carbonyl compounds have appeared. Iodosobenzene shows a high degree of selectivity in the preparation of a ~ y l o i n s , ' ~ ~and " ~ ' benzeneseleninic anhydride appears to be an excellent reagent for the hydroxylation at the tertiary centre in a-alkylcycloalkanones. 14' Enol silyl ethers give acyloins with osmium tetroxide and N- methylmorpholine Nand a-acyloxycarbonyl compounds with silver acetate and iodine. 15" a-Acyloxyketones may also be prepared conveniently by treatment of oximes with acid chlorides [equation (42)]."l

n

R

0 i, AcCI-Ac20-Et,N

(42)

ii, H,O,A

R

R

R

a,a'-Dibromo-ketones are reduced by finely dispersed mercury in alcoholic solution to give a - a l k o x y k e t o n e ~ The . ~ ~ ~reaction is easy to carry out, using a laboratory ultrasonic cleaning bath to disperse the mercury. Methods for asymmetric synthesis continue to attract attention, and ahydroxyketones offer suitable targets. Recent strategies include asymmetric nucleophilic carbamoylation (Scheme 3 1),lS3the use of sulphoxide-derived chiral

liii

liii HO

R

R'

2

HO

-

k

0

R R2

1

-

k

0

Reagents: i, Li-TMP, -100 "C; ii, R'COR'; iii, MeLi

Scheme 31

14' 146

'41

14R

149

Is* Is3

S. Seshadri, W. J. P e g , and M. Israel, J. O r g . Chem., 1981, 46,2596. R. M. Moriarty, H. Hu, and S. C. Gupta, Tetrahedron Lett., 1981, 22, 1283. R. M. Moriarty, S. C. Gupta, H. Hu, D. R. Berenschot, and K. B. White, J. A m . Chem. SOC., 1981,103,686. K. Yamakawa, T. Satoh, N. Ohba, R. Sakaguchi, S. Takita, and N. Tamura, Tetrahedron, 1981, 37,473. J. P. McCormick, W. Tomasik, and M. W. Johnson, Tetrahedron Lett., 1981,22,607. G. M. Rubottom, R. C. Mott, and H. D. Juve, J. Org. Chem., 1981, 46,2717. G. S. Reddy and M. V. Bhatt, Synthesis, 1981, 223. A. J. Fry and S.-S. S. Hong, J. Org. Chem., 1981, 46, 1962. D. Enders and H. Lotter, Angew Chem., Int. Ed. Engl.. 1981, 20, 795.

General and Synthetic Methods

82

0-

1

Ar = p-CH3C6H4-

Reagents: i, RCHO; ii, Bu,N+OH--Me,SO,;

iii

iii, NaI-I,-PR',;

iv, I,-NaHCO,

Scheme 32

acyl anion equivalents (Scheme 32),lS4and control of stereochemistry via the elaboration of aldehydes protected as chiral hemithioacetals (Scheme 33).l S 5

1

iv-vi

29% from pulegone

I

Reagents: i, Bu"Li; ii, EtCHO; iii, NH4CI; iv, DMSO-(CF,CO),O; v, Et,N; vi, PrMgBr; vii, NCSAgNO,

Scheme 33

Further details on the highly efficient asymmetric synthesis of epoxyaldehydes via bromolactonization of unsaturated N- acylprolines have appeared [equation (43)3. 156 trans-a,p- Epoxyphenylketones are stereoselectively synthe-

154

Is'

'"

L. Colombo, C. Gennari, C. Scolastico, G. Guanti, and E. Narisano, J. Chem. Soc., Perkin Trans. 1, 1981, 1278. E. L. Eliel and J. E. Lynch, Tetrahedron Leu., 1981, 22, 2855. M. Hayashi, S. Terashima, and K. Koga, Tetrahedron, 1981, 37,2797.

83

Aldehydes and Ketones SnF,Br

SnF,

R'CHO

Ph

0

phv O'.'

"

Et,N or

~2

Br

Br

p h T R 2

(44)

R'

Br R'

sized via aldol-type intermediates under mild conditions starting from a,adibromoketones and aldehydes [equation (44)].157 The base-induced cyclization of the bis-dithioacetal (14) provides a practical a -Sulphenylated synthesis of 2-phenylthiocyclobutanone [equation (45)].Is8 aldehydes are obtained from the anodic oxidation of vinyl sulphides [equation (46)],lS9 or by rearrangement of adducts of ketones and methoxy(pheny1thio)methyl-lithium [equation (47)].160 Esters react with phenylthiotrimethylsilylmethyl-lithium to give a-phenylthiomethyl ketones [equation (48)].16' The reaction of a-lithio-aryl methyl sulphoxides with esters of chiral alcohols, e.g. menthol, has been found to be enantiomer-diff erentiating, enabling modest optical, and high chemical yields of optically active p- ketosulphoxides to be isolated [equation (49)].162 Bis-aryl a-thio-oxoketones, which exist as stabIe blue monomers, may be prepared from a-chloroketones and tetraethylammonium thiosulphate [equation (50)].'63

n

CuCI,-TiCI,

phS),CH HC(SPh),

HOAC-H.20

SPh

PhS

(14)

-

PhS

0

CHO

-2e-

RS*Ar

R 'F 0 + L i < R2

OMe SPh

RSAAr

--*

R'

SiMe,

R20

SPh 0

II

"'c

R2

SPh

0

SiMe,

R'

SPh

0

0

II

2R'SCH2Li + R 2 C 0 0 * R 3 + R':CH2COR2 R 3 0 H = menthol 157

158

159 160

161

162 163

(47)

OMe

SPh

0

II + R'SCH3 +R 3 0 H

(49)

optical purity 3-70%

S.-I. Shoda and T. Mukaiyama, Chem. Lett., 1Y81, 723. T. Cohen, D. Ouellette, K. Pushpananda, A . Senaratne, and L.-C. Yu, Tetrahedron Lett., 1981, 22, 3377. A. Matsumoto, K. Suda, and C. Yijima, J. Chem. SOC.,Chem. Commun., 1981, 263. Ae. de Groot and B. J. M. Jansen, Tetrahedron Lett., 1981, 22, 887. D. J. Ager, Tetrahedron Lett., 1981,22, 2803. N. Kunieda, A . Suzuki, and M. Kinoshita, Bull. Chem. SOC. Jpn., 1981, 54, 1143. B. Hahn, B. Kopke, and J. Voss, Liehigs Ann. Chern., 1981, 10.

General and Synthetic Methods

84

X=ClorBr

NN- Diethylbenzeneselenamide has been developed as a useful mild reagent for the direct selenenylation of aldehydes. 164Diphenyl diselenide, in conjunction with an oxidizing agent (t-butylhydroperoxide, bromine and hexabutyldistannoxane, or benzeneseleninic anhydride) converts alkenes to a-phenylseleneno carbonyl c o r n p ~ u n d s . ' ~The ~ * different ~~~ oxidants confer differing regioselectivity on the transformation of terminal olefins. The synthetic uses of the acid-promoted decomposition of a-diazoketones have been reviewed.'67 A comparative study of methods for the synthesis of optically pure N- protected a-aminoaldehydes concludes that borane-THF is the reagent of choice for the reduction of N-protected amino-acids to the amino-alcohol without racemization, and that pyridinium dichromate is satisfactory for the subsequent oxidation to the aldehyde.'68 Since the reaction between amines and a-haloketones is sometimes a poor method for the preparation of a-alkylaminoketones, the far less basic irnidates have been developed as effective nucleophilic components in this reaction [equation (5 1 ) p 9 a-Aminoketones can also be prepared via Wittig rearrangement of iminoethers [equation (52)],'70 or by a-aminomethylation of aldehydes [equation (53)].171

Simple a-trimethylsilyl aldehydes are elusive compounds because of their ready protodesilylation, or rearrangement to silyl enol ethers. Hudrlik and 164

165 166

167 16' 169

17'

M. Jefson and J. Meinwald, Tetrahedron Lett., 1981, 22, 3561. M. Shimizu and I. Kuwajima, Bull. Chem. SOC.Jpn., 1981, 54, 3100. M. Shimizu, R. Takeda, and I. Kuwajima, Bull. Chem. SOC. Jpn., 1981, 54, 3510. A. B. Smith and R. K. Dieter, Tetrahedron. 1981,37,2407. C . F. Stanfield, J. E. Parker, and P. Kanellis, J. Org. Chem., 1981,46,4797. A. Guzmin, J. M. Muchowski, and N. Tun Naal, J. Org. Chem., 1981,46,1224. A. R. Katritzky and N. K. Ponkshe, Tetrahedron Leu., 1981,22, 1215. N. L. J. M. Broekhof and A. van der Gen, Tetrahedron Letf., 1981, 22, 2799.

Aldehydes and Ketones

85

Kulkarni have now reported a potentially general method for the preparation of a-t-butyldimethylsilyl aldehydes by hydrolysis of the a-silyl imines (Scheme 34).172These silyl aldehydes serve as stereoselective vinyl cation NR'

//

ButMe2Si

R' = cyclohexyl

iii

Reagents: i, LDA; ii, ButMe2SiC1; iii, AcOH-H,O-CH,Cl,; vi, BF,Et20

iv, R2Br; v, R3C(OLi)=CH,;

Scheme 34

equivalents in their reactions with organometallicreagents. The transmetallation of tributyl(trimethylsilylmethy1)tin with butyl-lithium has been utilized to synthesize a-trimethylsilylmethyl ketones from carboxylic acids, esters, or acid chlorides [equation (54)].'73 a-Trialkylsilyl ketones can be prepared via the treatment of the silyl enol ethers of a-phenylselenoketones with lithium and dimethylaminonaphthalene [equation ( 5 5 ) ] .174

Me,Si-SnBu3

-Bu"Li

RCOX

R

0 L S i M e ,

(54)

NMe,

Dicarbonyl Compounds.-Samarium di-iodide, which is readily prepared from samarium metal and 1,2-di-iodoethane, rapidly couples acid chlorides to form a - d i k e t o n e ~ . Yields ' ~ ~ are generally good, a-ketols being the main by-products. In another experimentallysimple procedure, disubstituted acetylenes are rapidly oxidized to a-diketones by iodosylbenzene in the presence of ruthenium cata1y~ts.l~~ Yields are relatively insensitive to the ligands on the metal, but only ruthenium complexes were effective. a-Ketoesters and acids can be prepared by the reaction of Grignard reagents with imidazolides derived from oxalic acid.17' Unfortunately, yields were low with alkyl Grignard reagents. P. F. Hudrlik and A. K. Kulkarni, I. Am. Chem. Soc., 1981, 103, 6251. D. E. Seitz and A. Zapata, Synthesis, 1981, 557. 174 I. Kuwajima and R. Takeda, Tetrahedron Lett., 1981, 22, 2381. P. Girard, R. Couffignal, and H. B. Kagan, Tetrahedron Lert., 1981, 22, 3959. "16 P. Muller and J. Godoy, Helu. Chim. Acta, 1981,64, 2531. "' J. S. Nimitz and H. S. Mosher, I. Org. Chem., 1981, 46, 211. 172

173

86

General and Synthetic Methods

Organolithium reagents react with triethoxyacetonitrile to give, after acid work~ * using " ~ a basic work-up, the intermediate up, a-ketoesters in good ~ i e l d . l ~ By imino orthoester can be isolated. Grignard reagents gave orthoesters by substitution of the cyano function. Dithian-protected a-ketoesters are synthesized under phase transfer conditiOns (Scheme 35).lgoThe use of anhydrous base is highly advantageous since with aqueous base only ester hydrolysis occurs.

Reagents: i, HS(CH,),SH-Aliquot 336-K2C0,-toluene, 20 "C; ii, Aliquot 336-K,C03-RX-toluene, 6 0 "C

Scheme 35

In conventional C-acylation of enolates, ideally quantitative enolate formation should be attained prior to the addition of the acylating agent, to prevent acylation of the base employed. Unfortunately, during the enolate preparation side reactions such as self -condensation often occur. Multipolymer systems, employing polymer-bound bases (e.g. trityl-1ithium)and polymer-bound acylating agents in the same reaction mixture have made spectacular improvements over solution reactions in both yield and lack of side reactions.'8' Such 'wolf and lamb' acylations prove superior since the two polymeric reagents cannot react with each other, and the concentration of enolate generated by one polymer remains low through rapid acylation by the second. The scope and limitations of a more common method, the acylation of pre-formed enolates at low temperatures, have been discussed.'82 Acyl phosphonates have been found to be further C-acylating agents for ester and ketone en01ates.l~~Acetylium tetrafluoroborate acylates various silyl enol ethers to give 1 , 3 - d i k e t o n e ~ . ' ~ ~ Highest yields are attained with t-butyldimethylsilyl derivatives, and the reaction is regiospecific, the site of acylation being defined by the enol ether geometry. Silyl enol ethers also react with acyl cyanides when catalysed by titanium t e t r a ~ h l o r i d e , ' and ~ ~ with 2-ethoxy-1,3-dithiolane in the presence of zinc chloride,lg6 giving mono-protected 1,3-dicarbonyl compounds (Scheme 36). Diethoxy~arbenium'~~ and 1 , 3 - d i t h i e n ~ mtetrafluoroborates '~~ are also suitable electrophiles for the introduction of a protected formyl group a to a carbonyl group. 178

179

lS4

IH7

G. P. Axiotis, Tetrahedron Lett., 1981, 22, 1509. W. Kantlehner and J. J. Kapassakalidis, Synthesis, 1981, 480. M. Lissel, Synth. Commun., 1981, 11, 343. B. J. Cohen, M. A . Kraus, and A . Patchornik, J. A m . Chem. SOC.,1981,103, 7620. D. Seebach, T. Weller, G. Protschuk, A . K. Beck, and M. S. Hoekstra, Helu. Chirn. Acta, 1981, 64,716. M. Sekine, A . Kume, M. Nakajima, and T. Hata, Chem. Lett., 1981, 1087. I. Kopka and M. W. Rathke, I . Org. Chem., 1981.46, 3771. G. A. Kraus and M. Shimagaki, Tetrahedron Lett., 1981, 22, 1171. K. Hatanaka, S. Tanimoto, T. Sugimoto, and M. Okano, Tetrahedron Lett., 1981, 22, 3243. W. L. Mock and H.-R. Tsou, J. Org. Chem., 1981, 46, 2557. I. Paterson and L. G. Price Tetrahedron Lett., 1981,22, 2829.

Aldehydes and Ketones

87

'CR3 R'

R2 S

R2

R'

R3

R2

U Reagents: i,

[:>

OEt-ZnCI,; ii, R*COCN-TiC14, -78 "C

Scheme 36

Meldrum's acid condenses readily with imidates to form, after alcoholysis, @- ketoesters. la' No reaction occurred between other active methylene com-

pounds and imidates. A study of the oxidation of p- hydroxyketones has shown that Collins reagent and dimethylsulphoxide-oxalyl chloride are suitable oxidants for the preparation of 1,3-diketone~.''~Using these reagents, neither @- elimination nor retro-aldol fragmentation were observed. a-Diazo-@-hydroxyketones are transformed into P-diketones on treatment with acid, but the need for an acidic medium can limit the generality of the method. However, it has been reported that this transformation occurs rapidly under neutral conditions in the presence of a catalytic amount of rhodium(I1) acetate."' The regiospecificity of metallation of 3,5-dimethylisoxazole permits a specific synthesis of disubstituted isoxazoles, and hence of p- diketones and enones (Scheme 37).lg2 Metallation and alkylation occurs first at the 5-methyl group, subsequent metallation taking place on the 3-methyl substituent. 0

0

. 1 ,

0-N

ii. iii

0-N

1

iv, v

Reagents: i, H,NOH; ii, Bu"Li-THF-78 "C; iii, &; iv, Bu'Li-Et,O, -78 "C;v, * vii, H'-EtOH

6,; vi, H,;

Scheme 37

1,3-Cycloalkadiones have been prepared by ring expansion of 2-hydroxy-2methoxymethyl cycloalkanones [equation (56)].193 The acid-catalysed acylation of a-trimethylsilylallyl sulphides is highly regioselective, and provides a simple method for the preparation of intermediates I89

190 19'

19* '91

J.-P.CBlQier, E. Deloisy, P. Kapron, G. Lhommet, and P. Maitte, Synthesis, 1981, 130. A. B. Smith and P. A. Levenberg, Synthesis, 1981, 567. R. Pellicciari, R. Fringuelli, E. Sisani, and M. Curini, J. Chem. Soc., Perkin Trans. 1, 1981, 2566. D . J. Brunelle, Tetrahedron Lett., 1981, 22, 3699. I. Nishiguchi, T. Hirashima, T. Shono, and M. Sasaki, Chem. Lett., 1981, 551.

General and Synthetic Methods

88

.o HO

'0

for 1,4-diketone synthesis [equation (57)].'94 Direct acylation of the non-silylated ally1 sulphide was not successful. 3-Chloro-2-trimethylsilyloxypropene serves as an efficient electrophile towards a wide range of a-metalated imine derivativesin a convenient synthesis of 1,4-diketones [equation 58].'95 By changing the substituent on the imine nitrogen, regioselectivity of metallation and hence acetonylation can be achieved. R2

PhS+R Me,Si

R3COCI-AIC13

(57)

R'

The alkylation of 0silylated dienolates with 1,3-dithieniumtetrafluoroborate shows useful y-selectivity [equation (59)]."6 The y-alkylated products are selectively protected 1,5-dicarbonylcompounds. Unsaturated 1,5-diketones, precursors of various heterocycles, can be prepared by the reaction of the potassium enolates of methyl ketones with acyl keten dithioacetals [equation (60)].197

BF4SMe

SMe

R l p S M e 0

3 Protection and Deprotection of Aldehydes and Ketones

The methods available for the preparation of acetals from carbonyl compounds have been reviewed.'98Nafion-H is a convenient acid catalyst for the preparation of acetals and thioacetals, and for the hydrolysis of dimethyl a c e t a l ~ . Yields '~~ 19*

K. Hiroi and L.-M. Chen, J. Chem. SOC.,Chem. Commun., 1981,377. A. Hosomi,A. Shirathata, Y. Araki, and H. Sakurai, J. Org. Chem., 1981,46,4631. I. Paterson and L. G. Price, Tetrahedron Lett., 1981,22,2833. K. T. Potts, M. J. Cipullo, P. Ralli, and G. Theodoridis, J. A m . Chem. Soc., 1981, 103, 3584. F. A. J. Meskens, Synthesis, 1981, 501. G. A. Olah, S. C. Narang, D. Meidar, and G. F. Salem, Synthesis, 1981, 282.

Ips

196

'91

'91

Aldehydes and Ketones

89

are high, and isolation of the product is simple as a result of the use of the resin acid. Cross-linked poly(4-vinylpyridine) hydrochloride is also an effective catalyst for acetalization.200This non-hygroscopic polymeric acid may offer advantages over the sulphonic acid resins when other acid-sensitive functional groups are present in polyfunctional substrates requiring carbonyl protection. Transacetalization using 2-ethoxy-1,3,dithiolane and mercuric chloride offers a non-acidic procedure for the conversion of aldehydes and ketones to 1,3dithiolanes.201Phosphorus trichloride is a further catalyst which can be used to convert aldehydes to 1,l-diacetates.202 Cyanohydrin esters are prepared by the reduction of acyl cyanides with sodium borohydide in the presence of an acylating agent.203If no acylating agent is present, unreacted acyl cyanide serves this purpose. Unsymmetrical ketones form the silyl ether of the thermodynamically more stable enol on treatment with trialkylsilyl triflates and trieth~larnine."~The same transformation may be carried out when the triflate is prepared in situ by the reaction of allyltrimethylsilane with a catalytic amount of trifluoromethylsulphonic Further details on the use of /3-silyl substituents as protection for a,@unsaturated ketones have appeared.206 Methods for the regeneration of ketones from dithioacetals continue to be developed, including the use of ceric ammonium nitrate (four equivalents are neces~ary),~~' sulphuryl chloride fluoride,208trimethyloxonium tetrafluoroborate,209mercuric oxide and tetrafluoroboric acid,*l0and pyridinium hydrobromide perbromide under phase-transfer conditions.211 4 Reactions of Aldehydes and Ketones

Reactions of Enolates and Enolate Equivalents.-Highly crowded ketones are prepared by the Lewis acid-catalysed t-alkylation of trimethylsilyl enol ethers.212 Stereoselection is observed in alkylations with tertiary halides which are known to solvolyse stereoselectively owing to anchimeric assistance or other factors.213 The alkylation can be carried out in an intramolecular fashion, but compounds having silyl enol ether and tertiary halide functions are difficult to prepare. However, Lewis acid-mediated cyclization of trisubstituted olefinic active methylene compounds provides an alternative method for the intramolecular 'O0 '01

'02

203 *04 '05

J. Yoshida, J. Hashimoto, and N. Kawabata, Bull. Chern. Soc. Jpn., 1981,54,309. S.Jo,S. Tanimoto, T. Oida, and M. Okano, Bull. Chern. SOC.Jpn., 1981,54,1434. J. K.Michie and J. A . Miller, Synthesis, 1981,824. J. M.Photis, J. Org. Chern., 1981,46,182. H. Emde, A. Gotz, K. Hofmann, and G . Simchen, Liebigs Ann. Chern., 1981,1643. G.A, Olah, A. Husain, B. G . B. Gupta, G. F. Salem, and S. C. Narang, J. Ori Chern., 1981,

46,5212. 206 '07 '08

' 0 9 'lo 211

'12 '13

D. J. Ager, I. Fleming, and S. K. Patel, J. Chern. SOC.,Perkin Trans. 1, 1981,2520. H.-J. Cristau, B. Chabaud, R. Labaudinikre, and H. Christol, Synth. Commun., 1981,11,423. G.A. Olah, S. C. Narang, A. Garcia-Luna, and G. F. Salem, Synthesis, 1981,146. I. Stahl, Synthesis, 1981,135. I. Degani, R. Fochi, and V. Regondi, Synthesis. 1981,51. G.S. Bates and J. O'Doherty, J. Org. Chern., 1981,46,1745. C.Lion and J.-E. Dubois, Tetrahedron, 1981,37, 319. M. T.Reek, M. Sauerwald, and P. Walz, Tetrahedron Lett., 1981,22, 1101.

General and Synthetic Methods

90

a- alkylation [equation (61)].214Carbon-carbon bond formation may be per-

formed with other SN1-reactivesystems, for example allylic a c e t a t e ~ , ~and ” with thioacetals [equation (62)].*16The reaction between aryl- and alkyl-thiomethylamines and enamines offers another approach to a- thiomethyl ketones.217

Amidomethylation can be carried out by the reaction of silyl enol ethers with trialkylhexahydrotriazinesand acetyl chloride [equation (63)].218 OSiMe,

R AcCI-TiCI,

RN-NR

xp”.

,

(63)

Bis(dibenzy1ideneacetonato)palladium in conjunction with 1,2-bis(diphenylphosphino)ethane is a superior catalyst for the alkylation of lithium enolates with allylic acetates.219Bis(pentan-2,4-dionato)palladium will catalyse the alkylation of pentan-2,4-dione by allylic alcohols, but the reaction is of limited value in its present form since the catalyst has been shown to cause rearrangements and disproportionation of allylic alcohols.220 The a-vinylation of ketones by the use of organo-iron complexes has been extended to allow the introduction of an isopropenyl group (Scheme 38).221The ethyl vinyl ether derivative has advantages over the methyl compound since the latter functions competitively as a methylating agent. Syntheses of p-vetivone and P-vetispirene have been used to demonstrate an intramolecular decarboxylative alkylation route to spirocyclic ketones which does not involve the use of strong base [equation (64)].222 Primary and secondary nitriles have been converted into a-alkylated aldehydes by alkylation of the rnetalloenamine generated in situ

214 215 216

218 219

220 221 222

M. T. Reetz, I. Chatziiosifidis, and K. Schwellnus, Angew. Chem., Znt. Ed. Engf., 1981, 20, 687. M. T. Reetz, S. Huttenhain, and F. Hubner, Synth. Commun., 1981, 11, 217. M. T. Reetz and A. Giannis, Synrh. Commun., 1981, 11, 315. K. Suzuki and M. Sekiya, Synthesis, 1981, 297. K. Ikeda, Y. Terao, and M. Sekiya, Chem. Pharm. Bull., 1981, 29,1156. J. C. Fiaud and J.-L. Malleron, J. Chem. SOC.,Chem. Commun., 1981, 1159. M. Moreno-Mafias and A. Trius, Tetrahedron, 1981,37,3009. T. C. T. Chang and M. Rosenblum, J. Org. Chem., 1981, 46,4103. R. G. Eilerman and B. J. Willis, J. Chem. SOC., Chem. Commun., 1981, 30.

Aldehydes and Ketones

&dJt 91

fJ-.JJ

OSiMe,

+

FP+ F, = C5HSFe(C0)2

iii

Reagents: i, Me,SiH-Rh(PPh,),Cl;

1

ii, Bu"Li, 25 OC; iii, -78 "C; iv, HBF,, -78 'C: v, NaI

Scheme 38

[equation (65)].223 The reaction sequence is carried out in one vessel, and yields are high.

R'

R' i DiBAL

F C N

R2

ii. LDA-HMPA iii, R'X

R'jCHO R3

(65)

Metallation and alkylation of chiral enamines (15 ) lead to 2-alkylcycloalkanones with high enantiomeric purity (Scheme 39).224The basis for the efficient enantioselective alkylation rests with the rigidity of the lithioenamine induced

Reagents: i, LDA; ii, RX; iii, H30'

Scheme 39

223 224

H. L. Goering and C. C. Tseng, J. Org. Chem., 1981,46,5250. A. I. Meyers, D. R. Williams, G. W. Erickson, S. White, and M. Druelinger, J. Am. Chem. SOC., 1981,103.3081.

General and Synthetic Methods

92

by the internal methoxyl ligand. The method is also applicable to acyclic and macrocyclic (C,,, CI2,and CIS)ketones.225

Aldol Reactions.-It is well established that enolate geometry can be of paramount importance in determining the precise outcome of aldol and related reactions. Two particularly thought-provoking papers have appeared concerning enolate chemistry. Narula has presented a frontier-orbital approach to determining which geometry should predominate in enolates prepared by deprotonation of carbonyl compounds by lithium di-isopropylamide.226Consideration is given to which carbonyl HOMO may interact with the lithium ion in a compact transition state leading to the enolate. In what they admit is a speculative discussion, Seebach, Amstutz, and Dunitz discuss lithium enolate chemistry from the standpoint of aggregates of enolates in particularly a tetramer based on a Li,O cubic arrangement, the form lithium enolates take in the solid state.228This change in perspective from monomer to well defined aggregate has many mechanistic implications, for example in 0- versus C- alkylation and acylation, and may prove a powerful position from which to re-evaluate details of lithium enolate chemistry. Heathcock has reviewed recent contributions to the stereochemical control now possible using aldol condensations in acylic systems, particularly his group’s work based on a-dialkyl-a-silyloxyketones.229 Such ketones, on deprotonation, yield lithium 2-enolates, which give high erythro-selectivity in condensations with aldehydes under kinetic conditions. The products are useful as precursors of a wide variety of ketones, making the starting silyloxyketones effective reagents for regio- and stereo-controlled aldol condensations (Scheme 40).230 0 3 k o S i M e 3

OLi +OSiMe3

Reagents: i, LDA; ii, R’CHO; iii, dihydropyran; iv, R’Li; v, H510,-MeOH

Scheme 40

Heathcock’s group has also developed chiral reagents that show not only high erythro-selectivity but also selectivity for one face of a chiral aldehyde.231Such ‘double stereodiff erentiation’ can show very high selectivity when both reactants promote the same sense of chirality at the new centres (Scheme 41).With some 225 226 227

’”

229

230 231

A. I. Meyers, D. R. Williams, S. White, and G. W. Erickson, J. Am. Chem. Soc., 1981, 103, 3088. A. S. Narula, Tetrahedron Lett., 1981, 22, 4119. D . Seebach, R. Amstutz, and J. D. Dunitz, Hefv. Chim. Acru, 1981, 64, 2622. R. Amstutz, W. B. Schweizer, D. Seebach, and J. D . Dunitz, Helv. Claim. A m , 1981, 64. 2617. C. H. Heathcock, Science, 1981, 214, 395. C. T. White and C. H. Heathcock, J. Org. Chem., 1981.46, 191. C. H. Heathcock, C. T. White, J. J. Morrison, and D . VanDerveer, J. Org. Chem., 1981.46,1296.

Aldehydes and Ketones

93

Scheme 4 1

reagents, the benefits of double stereodifferentiation may be obtained even with racemic reagents, as, for example, the R-enolate may react with the R-aldehyde at a significantly greater rate than with the S-aldehyde. Such 'mutual kinetic resolution' has been observed, and used in a short stereoselective synthesis of ( f )-blastmycin~ne.*~~ Under kinetic conditions, E- enolates produce predominantly threo- products in aldol condensations, making erythro- aldols difficult to prepare from cyclic ketones. However, readily isolable titanium enolates show pronounced erythroselectivity in their reactions with aldehydes, irrespective of enolate geometry, the diastereoselection being high for reactions of cyclic ketones Triphenyltin enolates react in an analogous manner.234 [equation (66)].233

(-q -

CITi(OPr'), or

,

BrTi(NR12)3

-

Stereoselective aldol condensation is observed using tris(diethy1amino)sulphonium enolates, and shows a high erythro- selectivity independent of the geometry of the starting silyl enol ether.235The stereoselectivity is suggested to be the result of minimal interaction with the cation, reaction proceding via an extended transition state (Scheme 42). Further studies on the use of boron enolates in stereoselective aldol reactions have appeared. Evans and his group have shown that the anticipated correlation between enolate geometry and the aldol stereochemistry in acyclic systems is not dependent on the boron ligand (Scheme43).236This independence is not 232

C. H. Heathcock, M. C. Pirrung, J. Lampe, C. T. Buse, and S. D. Young, J. Org. Chem., 1981. 46, 2290.

233 234

235

236

M. T. Reetz and R. Peter, Tetrahedron Lett., 1981, 22,4691. Y. Yamamoto, H. Yatagai, and K. Maruyama, J. Chem. SOC.,Chem. Commun., 1981, 162. R. Noyori, I. Nishida, and J. Sakata, J. A m . Chem. SOC.,1981, 103,2106. D. A. Evans, J. V. Nelson, E. Vogel, and T. R. Taber, J. A m . Chem. SOC.,1981, 103, 3099.

General and Synthetic Methods

94

ii

1 -R ‘ H

9$] R2

-

Reagents: i, (Et,N),S+ Me,SiF;; ii, R 3 C H 0

Scheme 42

R’

L1

Ti L

1

+ -iii

111

Reagents: i, R3N-L2BOS02CF,; ii, R’CHO; iii, [O]

R’-G

--

R2’BH

MeLi

Scheme 43

R 1 T B R 2 2

0BRZ2 (67)

Li

noticed with cyclic ketones, but control is possible by choice of appropriate ligands for boron. The preparation of boron enolates by reaction of the ketone with a dialkylboryl triflate and a tertiary amine is recommended. Whereas the enolate is.formed rapidly by reaction of the boryl triflate with a silyl enol ether, the subsequent aldol reaction in the presence of trimethylsilyl triflate shows lower diastereo~electivity.~~~~~~’ Boron enolates of phenyl ketones may also be prepared by acylation of boron-stabilized carbanions [equation (67)].238 237

M. Wada, Chem. Lett., 1981, 153.

238

T.Mukaiyama, M. Murakami, T. Oriyama, and M. Yamaguchi, Chem. Lett., 1981,1193.

Aldehydes and Ketones

95

Boron enolates of chiral ketones (16) have been developed for asymmetric induction in the aldol condensation [equation (68)],239and as a result of their additional high diastereoselectivity,have proved valuable in the stereocontrolled synthesis of 6-deoxyerythronolide

rn OSiMe,Bu'

R',BOTf

OSiMeBu' R2CH0

Conjugate Addition Reactions.-The organocopper species Me5Cu3Li2offers advantages in conjugate addition reactions with a,@-unsaturated aldehydes in that less 1,2-addition is observed than with the more common Me,CuLi, even when quaternary centres are being formed.241Several mixed lithium cuprate reagents having a non-transferable ligand exist for the efficient conjugate addition of 'valuable' alkyl groups. Mesitylcopper(1) may be added to the list of reagents, such as copper acetylides, from which such mixed cuprates may be prepared.242Copper acetylides do not add to enones, but Seebach has reported that lithium acetylides may be added to trityl enones, 1,4-regiospecificity being controlled purely by steric factors [equation (69)].243The method is limited by the few methods available for further elaboration of trityl ketones.

Enolate anions formed by Michael addition may be trapped by methanesulphinyl The resulting sulphoxide undergoes ready elimination to form a new unsaturated ketone, capable of further substitution by conjugate addition [equation (70)].

8

L RMgBr MeSOCl

CUCl2

&Fe 6 A.CaCO,,

(70)

R

Chiral s u l p h o ~ i d efeature s ~ ~ ~ in various methods for enantioselective functionalization of unsaturated aldehydes and ketones, either by imparting chirality to nucleophiles which then add with moderate enantioselectivity to enones (Scheme 44),246 or by confering chirality on the enone itself (Scheme 45).247 239 240

241

242 243

244 245

246 247

S. Masamune, W. Choy, F. A. J. Kerdesky, and B. Imperiali, J. Am. Chem. SOC.,1981,103, 1566. S. Masamune, M. Hirama, S. Mori, Sk. A. Ali, and D. S. Garvey, J. Am. Chem. SOC.,1981, 103, 1568. D. L. J. Clive, V. Farina, and P. Beaulieu, J. Chem. Soc., Chem. Commun., 1981, 643. T. Tsuda, T. Yazawa, K. Watanabe, T. Fujii, and T. Saegusa, J. Org. Chem., 1981,46, 192. R. Locher and D. Seebach, Angew. Chem., Int. Ed. Engl., 1981, 20, 569. T. Fujisawa, A. Noda, T. Kawara, andT. Sato, Chem. Lett., 1981, 1159. G. SolladiC, Synthesis, 1981, 185. L. Colombo, C. Gennari, G. Resnati, and C. Scolastico, Synthesis, 1981,74. G. H. Posner, J. P. Mallamo, and K . Miura, J. A m . Chem. SOC.,1981, 103, 2886.

General and Synthetic Methods

96

Reagents: i, Bu"Li-HMPA; ii, cyclopentenone; iii, P(NMe2),-12; iv, KI; v, I,-NaHC0,-H20

Scheme 44

Reagents: i, MeMgI, -78 "C; ii, H,O+;iii, AI/Hg-H,O-THF

Scheme 45

x"

But

("

Co2Bu'

Reagents: i. L-BU'CHNH~CO~BU'; ii, R'MgBr; iii, R2X-HMPA; iv, H,O+

Scheme 46

BuHBU P

Aldehydes and Ketones

97

Using the latter approach Posner et uLZ4'have developed routes to enantiomerically pure cyclopentanone intermediates for chiral steroid syntheses. L-Leucine t-butyl ester is a highly effective chiral auxiliary for the diastereoselective and enantioselective additions of Grignard reagents to cycloalkene carboxaldehydes as their imines (Scheme 46).249Of particular interest are the stereoselectivitiesobserved on alkylation of the resulting chiral enolates.

248 249

G. H. Posner, M. Hulce, J. P. Mallamo. S. A. Drexler, and J. Clardy, J. Org. Chem., 1981,46,5244. H. Kogen, K. Tomioka, S. Hashimota, and K. Koga, Tetrahedron, 1981,37, 3951.

3 Carboxylic Acids and Derivatives BY

P. R. JENKINS

1 Carboxylic Acids General Synthesis.-A greatly improved procedure for the ruthenium tetroxidecatalysed oxidation of olefins, alcohols, and aromatic rings to carboxylic acids has been reported.' Acetonitrile is added to the traditional CC14-water solvent system; yields are good over a wide range of examples, and the method has already been independently applied in a synthesis of verrucarin A (Scheme 1).2

C02H

Aco=yo-+i

--+.

Reagents: i, D-diethyltartrate-Bu'OOH-Ti(OPr'),; ii, 2% RuC1,-NaIO,; iii, 3 eq. Me,AI; iv, Ac,Opyridine

Scheme 1

Simple alcohols and aldehydes are efficiently oxidized to carboxylic acids using solid NaMnO,.H,O; yields around 70% are ~ b t a i n e dRearrangement .~ products are sometimes observed in the conversion of a-amino acids to a-fluoroacids using NaN02 in polyhydrogen fluoride-pyridinea4However, this problem is effectively suppressed by the use of 48 :52 (w/w) hydrogen fluoride :pyridine (Scheme 2).5 R' R'

I

R2-C-CHC02H I I R NH2

NaNO,

R2--A-CH-C02H

HF: pyridine 48 : 52

I

1

R F

Scheme 2

*

P. H. J. Carlsen. T. Katsuki, V. S. Martin, and K. B. Sharpless, J. Org. Chem., 1981,46,3936.

* W.C. Still and H. Ohmizu, J. Org. Chem., 1981,46,5242.

F. M. Menger and C. Lee, Tetrahedron Lett., 1981,22,1655. F. Faustini, S. De Munari, A. Panzeri, V. Villa, and C. A. Gandolfi, Tetrahedron Lett., 1981,22, 4533. ' G. A. Olah. G. K. S. Prakash, and Y. L. Chao, Helu. Chim. Acta, 1981,64,2528.

98

Carboxylic Acids and Derivatives

99

The SN2 cleavage of esters and lactones is achieved with sodium phenyl selenide generated by the reaction between sodium hydride and benzene selenol, instead of the more usual sodium borohydride reduction of diphenyldiselenide. When generated under the former conditions the phenyl selenide anion is a potent nucleophile and good yields of seleno-acids are obtained from a wide range of esters and lactones (Scheme 3).6

Scheme 3

The analogous conversion of lactones to o-alkylthio or o-arylthio carboxylic acids is brought about in good yield by the thiol in the presence of aluminium tribromide (Scheme 4).' R'

Scheme 4

The spirocyclic-P-lactam (l), which is readily prepared by the reaction of ketens with iminolactones, reacts readily with an alkoxide to provide esters (2) in good yield (Scheme 5).8

Scheme 5

(2)

Several reports have appeared on the use of conjugate addition reactions in the preparation of optically active carboxylic acids. 1,4-Additions to the optically active enoate (3) proceed with high chiral induction. Saponification of the resulting esters (4) furnishes the &substituted alkanoic acids ( 5 ) and the recoverable (-)-&phenylmenthol in good yield. In the case of R2= Ph, the acid ( 5 ) is claimed to be enantiomerically pure (Scheme 6).' Mukaiyama has reported'" that the Michael addition of Grignard reagents to chiral a#-unsaturated carboxylic acid amides derived from 1-ephedrine (6) affords optically active &substituted alkanoic acids (7)after acid hydrolysis. Yields of 48-999'0 for the addition, and 73-979'0 for the hydrolysis were D. Liotta, U. Sunay, H. Santiesteban, and W. Markiewicz, I. Org. Chem., 1981, 46,2605.

' M. Node, K. Nishida, M. Ochiai, K. Fuji, and E. Fujita, J. Org. Chem., 1981,46, 5163. lo

M. Roth, Helv. Chim. Acra, 1981,64, 1930. W. Oppolzer and H. J. Loher, Helv. Chim. Acru, 1981,64, 2808. T. Mukaiyama and N. Iwasawa. Chem. Lett., 1981,913.

General and Synthetic Methods

100

Scheme 6

Me

0

4~ Mk H Me

R \

i-iii

R HO

111

Ph

H

(4)

o

(7)

Reagents: i, R'MgBr; ii, H'-H,O; iii, H,SO,-CH,CO,H,

A

Scheme 7

obtained with enantiomeric excesses of 79-99% (Scheme 7). The method appears to have considerable potential for the synthesis of @-substitutedalkanoic acids. Conjugate addition of lithium dimethylcuprate to the optically pure a(methoxycarbony1)alkenyl sulphoxide @), followed by reduction and saponification, gives (R)-(+)-3-methylnonanoicacid (9) (Scheme 8).11The utility of this scheme clearly depends on the accessibility of the required optically active sulphoxides. .

JSO

Me

PhSO

H-wcO,Me n-C6H,3 C 0 , M e A n-C,H13 (8) (S)-(+)

ii, iii

Me

n-CJ-4 H - h3 o 2 H

(9)

Reagents: i, LiCuMe,; ii, Al-Hg; iii, NaOH-H,O

Scheme 8

The use of an optically active nucleophile in conjugate additions has also been explored; the base-induced reaction of (10) with 1-nitrocyclohexene gives optically active (2-nitrocyc1ohexyl)acetic acid in good yield and reasonable enantiomeric excess (Scheme ,).I2 Modest enantiomeric excesses are obtained in the addition of thioglycolic acid to nitro-olefins catalysed by quinine.l 3 A method of obtaining hydratropic acid in high enantiomeric purity involves the base-catalysed reaction of methyl phenyl

l3

G. H.Posner, J. P. Mallamo, and K. Miura, J. Am. Chem. Soc., 1981,103,2886. T. Takeda, T. Hashiko, and T. Mukaiyama, Chem. Lett., 1981,797. N. Kobayashi and K. Iwai, J. Org. Chem., 1981,46, 1823.

Carboxylic Acids and Derivatives

101

keten with optically active l-phenylethan01.l~ The optical purity of 2,3dideuteriopropionic acid has been determined from the deuterium n.m.r. of the diastereoisomeric methyl mandelate esters." In the natural product area, the synthesis of biotin16and of pyrethroid acids1' have been reported. Diacids.-Dicarboxylic acids are obtained by the reaction of y-butyrolactones with carbon monoxide at atmospheric pressure and room temperature in HFSbF, super acid media." A double-bond cleavage reaction of silyl enol ether using MoOz(acac)2-Bu'00H as oxidizing agent leads to a diacid in the case of (11)and to a ketoacid with (12); yields are high for the nine examples studied." OSiMe,

OSiMe,

I

I

An effective preparation of polyether dicarboxylic acids containing quaternary carbon atoms in the backbone has been achieved (Scheme

-

ClCH2(0CH2CH2),0CH2C1

H02CCMe2CH2(0CH2CH2)nOCH2CMe~C02H (n = 1,2,or 3)

Reagents: i, Me,C=CHOMe-HgCII; ii, NaHCO,; iii, Se0,-H,O, Scheme 10

The absolute stereochemistry of the cyclopropane dicarboxylic acid (13), a degradation product of the orally active antifungal agent ambruticin, has been determined by an efficient chiral synthesis (Scheme 11).21 The synthesis and conformational analysis of cis,cis-l,3,5-trimethylcyclohexane-l,3,5-tricarboxylicacid has been reported.22 l4 l6

J. Jahme and C. Ruchardt, Angew. Chem., Inr. Ed. Engl., 1981,20,885. J. M. Brown and D. Parker, Tetrahedron Lert., 1981, 22,2815. P. ROSSY,F. G. M. Vogel, W. Hoffmann. J. Paust. and A. Nurrenbach, Tetrahedron Lett., 1981, 22, 3493.

D. Arlt, M. Jautelat, and R. Lantzsch, Angew. Chem., Int. Ed. Engl. 1981,20,703. N. Yoneda and A. Suzuki, Chem. Lett., 1981,767. l9 K. Kaneda, N. Kii, K. Jitsukawa, and S. Teranishi, Tetrahedron Lett., 1981, 22, 2595. " R. McCrindle and A. J. McAlees, J. Chem. SOC.,Perkin Trans. 1. 1981, 741. N. J. Barnes, A. H. Davidson, L. R. Hughes, G. Proctor, and V. Rajcoomar, Tetrahedron Lett., 1981,22,1751. 22

D. S. Kemp and K. S. Petrakis, J. Org. Chem., 1981,46, 5140.

General and Synthetic Methods

102

Reagents: i, I,-CH,CN; ii, LiOBu'; iii, LDA; iv, Jones oxidation; v, CF,C02H

Scheme 11

Hydroxy-acids.-Optically active a-hydroxy-acids are obtained from a-ketoaldehydes by the combined effect of glutathione and the immobilized enzymes glyoxalase I and II.23 The reaction appears to provide a practical method for preparing 1-10 g quantities, with enantiomeric excesses in the range 75-99%. The S-absolute configuration of (+)-2-hydroxy-2,3-dimethylbutanoicacid has been established by chemical correlation with the silyl ketone (14).24Work HOZC. OH

HO

continues on the synthesis of chiral prostanoid intermediates from phenol in which the resolved hydroxy-acid (15) is the readily available optically active starting Reactions of chiral enolates derived from lactic and mandelic acids and pivaldehyde with alkyl halides, aldehydes, and ketones are highly diastereoselective (Scheme 12).26

$H LO o x

i,LDA

TEi-

9.A'

1

H O

Et

H (R = MeorPh) Scheme 12

The S-ketone (16), which is readily obtainable from S-mandelic acid, is converted into the P-hydroxy-a-methylcarboxylic acid (17)in high enantiomeric and diastereoisomeric excess by the aldol condensation of the corresponding dicyclopentylborinylenolate (Scheme 13).*' This simple yet highly effective idea, and its extensions, provides the cornerstone of one of the major achievements reported this year, the total synthesis of 6-deoxyerythronolide B (see Section 4). M. A. K. Patterson, R. P. Szajewski, and G. M. Whitesides, J. Org. Chem., 1981,46,4682. H. Wetter, Helv. Chim. Acta, 1981, 64, 761. M. Gill and R. W. Rickards, Aust. J. Chem., 1981,34, 1063. 26 D. Seebach and R. Naef, Helv. Chim. Acta, 1981,64,2704. " S. Masamune, W. Choy, F. A. J. Kerdesky, and B. Imperiali, J. Am. Chem. SOC.,1981,103,1566; W. Choy, P. Ma, and S. Masamune, Tetrahedron Lett., 1981, 22, 3555. 23

24

''

CarboxylicAcids and Derivatives

103

i-iv ___,

*OHHO

Reagents: i,

(

w B O S 0 2 C F 3, PriNEt; ii, CH,O; iii, HF; iv, NaIO,

Scheme 13

High erythro-selectivity has been obtained using optically active zirconium enolates (18) derived from prolinol in an enantioselective aldol condensation (Scheme 14).28 Much lower selectivity was obtained using the corresponding lithium enolate.

(M = CpzCIZr or Li, MEM = MeOCH2CHZOCH2-) Reagents: i, RCHO; ii, H30+ Scheme 14

In their continuing studies Heathcock and his co-workers have reported that preformed lithium enolates of hindered aryl esters condense with aldehydes to give predominantly threo-/3-hydroxy-acids after hydroly~is.~~ Optically active hydroxy-acids have been prepared from optically active propargyl alcohols, which are readily available in high optical purity by reduction of propargyl A 1,6-eliminative ketones with ~-3-pinanyl-9-borabicyclo[3.3.1]n0nane.~~ epoxide cleavage provides an effective synthesis of a naturally occurring aromatic hydroxy-acid, which is a metabolite of ibuprofen.31

Keto-acids.-Cook and his co-workers have continued their interesting work on the synthesis of polyquinanes using the intramolecular acid-catalysed condensation reaction of the keto-acid (19).32An improved preparation of the keto-acid (20),an important intermediate in a synthesis (A) strigol has been published .33 The Diels-Alder reactions of some benzoyl acrylic acids lead to aromatic k e t o - a ~ i d s ;however, ~~ the low yields observed detract from this potentially useful idea. ” 29

30 31 32

33 34

D. A. Evans and L. R. McGee, 1. Am. Chem. SOC.,1981,103,2876, C. H. Heathcock, M. C. Pirrung, S.H. Montgomery, and J. Lampe, Tetrahedron, 1981, 37, 4087. M. M. Midland and P. E. Lee, J. Org. Chem., 1981,46, 3933. R. R. Kurtz and D. J. Houser, J. Org. Chem., 1981,46,202. A. Gawish, R. Mitschka, J. M. Cook, and U. Weiss, Tetrahedron Lett., 1981, 22, 21 1; K. Avasthi, M. N. Deshpande, W. Han, J. M. Cook, and U. Weiss, ibid.. p. 3475. A. B. Pepperman, J. Org. Chem., 1981,46,5039. R. C. Bugle, D. M. S.Wheeler, M. M. Wheeler, and J. R. Hohrnan, J. Org. Chem., 1981, 46,3915.

General and Synthetic Methods

104

CO,H (19)

Unsaturated Acids.-The Claisen rearrangement and related reactions continue to provide useful new methods for synthesizing unsaturated acids and their derivatives. Bartlett and Pizzo have observed modest specificity for the boat transition state in various Claisen rearrangements of cyclohexen-2-ols.35This type of reaction has been used as a key step in the synthesis of (-)- and (+)-nonactic acids from D - m a n n a ~ e . Allylic ~~ alcohols react with 2,2,2trifluoroethyl phenyl sulphoxide and potassium hydride to give a Claisen rearrangement. Subsequent sulphoxide elimination gives alka-2,4-dienoic acids in reasonable yields and sele~tivities.~' Dianions generated from 2-alkenyl oxyacetic acids readily undergo the [2,3]-Wittig rearrangement; posterior elimination leads to conjugated dienoic acids in high yield and excellent E-stereoselectivity (Scheme 15).38 The method appears to be general but in cases where diastereoisomeric products are formed the selectivity is less impressive.

,Me W

C

O

,

H

\

CO, H

Reagents: i, 2LDA; ii, TsCI; iii. Bu'OK

Scheme 15

Sequential [2,3]-Wittig and Claisen rearrangements provide an effective synthesis of E,E-alka-4,7-dienoic acids, esters, or aldehydes depending on the type of Claisen rearrangement employed (Scheme 16).39

R3

Reagents: i, BuLi; ii, (CH,CO),O; iii, LDA; iv, Me3SiC1; v, 70 "C;vi, HCI-H20

Scheme 16

Predominantly 2-or E-y, &unsaturated carboxylic acids are readily prepared by the Ramberg-Backlund rearrangement of the a-halosulphone intermediate " " 37

38 39

P. A. Bartlett and C. F. Pizzo, J. Org. Chem., 1981,46, 3896. R. E. Ireland and J. P. Vevert, Can.J. Chem., 1981,59, 572. T. Nakai, K. Tanaka, K. Ogasawara, and N. Ishikawa, Chem. Lett., 1981, 1289. T. Nakai, K. Makami, S. Taya, Y. Kimura, and T. Mimura, TetrahedronLett., 1981, 22,69. K. Mikami, N. Kishi, and T. Nakai, Chem. Lett., 1981, 1721.

Carboxylic Acids and Derivatives

105

Reagents: i, LiH-DMF; ii, RI; iii, Br,-NaOH; iv, KOH-H20, A; v, Bu'OK

Scheme 17

(21) (Scheme 17).40The stereoselectivity is about 4 : 1, which may be in favour of E or 2,depending on the type of base used in the rearrangement. The Fujisawa group have continued their study of the Cu'-catalysed coupling of Grignard reagents with /3-propiolactones. Studies this year have centered upon @-propiolactoneswith a p-olefinic or acetylenic substituent, and their reaction through an SN2'pathway to give 3,7-dienoic acids,413-alenyl and 3,7,1 l-trienoic acids (Scheme 18).43The stereochemistry of the newly

Reagent: i,

Scheme 18

formed double bond is predominantly E,with selectivities in the range 4 :1 to 9 : 1. An effective short procedure for the synthesis of a-substituted acrylic acids from the oxazoline (22) has been reported (Scheme 19).44Twelve examples are given with overall yields between 65 and 85%.

Reagents: i, 180 "C; ii, HCHO; iii, 180 "C;iv, H+-H,O

Scheme 19

A variation on a literature procedure4*draws attention to a useful method Copper dienolates derived from a,&unsaturfor the synthesis of tetrolic ated acids undergo y-alkylation with a regioselectivity of 9 1 ? / 0 .A ~ ~full paper has appeared from Mulzer and his co-workers on the control of 1,2-/1,4regkselectivity in the additions of carboxylic acid dianions to a,p-unsaturated carbonyl The addition of phenyl acetate dianion (23) (Scheme 20) to a,&unsaturated aldehydes leads to the fhreo-unsaturated p-hydroxycarboxylic acid (24); the threo and eryfhra ratio of 5 examples was >9 : 1. D. Scholz, Chem. Ber., 1981,114,909. T. Sato, M. Takeuchi, T. Stoh, M. Kawashima, and T. Fujisawa, Tetrahedron Lett., 1981,22, 1817. 42 T. Sato, M. Kawashima, and T. Fujisawa, Tetrahedron Lett., 1981,22, 2375. 43 T. Fujisawa, T. Sato, M. Kawashima, and M. Nakagawa, Chem. tetr., 1981, 1307. 44 L. A. Carpino, J. Am. Chem. Soc., 1958,80, 599. '' F. M. Simmross and P. Weyerstahl, Synthesis, 1981, 72. 46 P. M. Savu and J. A. Katzenellenbogen, J. Org. Chem., 1981,46,239. '' J. Mulzer, G. Briintrup. G. Hartz, U. Kuhl, U. Blaschek, and G. Bohrer, Chern. Ber., 1981,114, 40

"

3701.

General and Synthetic Methods

106

2Li+ (23)

H Reagents: i,

(24)

2 ii,0 H,Of Scheme 20 RZ R3

P,y-Unsaturated carboxylic acids are obtained in low enantiomeric excess, but good yield, by the insertion of carbon dioxide into an asymmetric T aliyItitanium(III) complex.48 An effective reversal of the selenolactonization has been achieved in good yield for a range of examples (Scheme 21).49 H Me,SiCI-NaI

Y

PhSe

Scheme 21

cis-Bicyclo[3.3.0]octa-2,6-and -2,7-diene-2-carboxylic acids have been prepared using a selective Woodward oxidation of the 6-membered-ring double bond of (25). The process involves the use of silver acetate, therefore, owing to activity on the United States metal exchange a second independent route, A full paper has appeared on the generation of dianions was also worked derived from furan carboxylic acids and their reaction with various elecInterA synthesis of 5-ethynylorotic acid (26) has been tr~philes.~’ 0

est in unsaturated cyclopropane carboxylic acids has continued. The Favorskii rearrangement of the optically active cyclobutanone (27) to the cyclopropane carboxylic acid (28) in high yield and with a cis- to trans-ratio of 83 : 17 provides a useful entry into this type of compound (Scheme 22).53 The palladium(I1)catalysed isomerization of cis- to trans-chrysanthemic acid and its ethyl ester may also be useful in this ~ o n t e x t . ’ ~ F. Sato, S. Iijima, and M. Sato, J. Chem. SOC.,Chem. Commun., 1981, 180. D. L. 3. Clive and V. N. KHle, J. Org. Chem., 1981, 46, 231. ’O J. K. Whitesell, M. A. Minton, and W. G. Flanagan, Tetrahedron, 1981, 37,4451. ” D. W. Knight and A. P. Nott, J. Chem. SOC.,Perkin Trans. 1 , 1981, 1125. ” R. S. Bhatt, N. G. Kundu, T. L. Chwang, and C. Heidelberger, J. Heterocycf. Chem., 1981,18,771. ” H. Greuter, J. Dingwall, P. Martin, and D. Bellus, Hefu. Chim. Acra., 1981, 64, 2812. ” J. L. Williams and M. F. Rettig, Tetrahedron Lett., 1981, 22, 385.

48

49

Carboxylic Acids and Derivatives

107

(27) Reagents: i, NaOH-H,O, 25 "C; ii, NaOH-H,O, 100 "C

Scheme 22

Synthesis of the naturally occurring unsaturated acids ~ a r k o m y c i n ,(*) ~~ methylenomycin A,56and (*) coronafacic acid5' have appeared. The metabolites of arachidonic acid provide an area of natural products chemistry in which total synthesis is playing a vital role. Corey and his co-workers report impressive advances involving synthesis as a means of structural proof,58and of stereospecific synthesis to provide large quantities of natural products only available in trace amounts.59 The synthesis of some oxidation products of arachidonic acid has also appeared.60 Decarboxy1ation.-During a study of the alkylation of 3-trimethylsilylmethyldienolates it is reported that the 3-trimethylsilylbutenoic acid (29) undergoes a facile decarboxylation to give an 8 : 2 mixture of 2- and E-ally1 silanes in a yield of 92% (Scheme 23).61

Scheme 23

Iodosobenzene has been used to decarboxylate a-keto-acids to afford the lower homologous acid generally in high yield.62 However, the yield is lower for o-nitrophenylpyruvic acid. This method provides a milder alternative to basic hydrogen peroxide to achieve oxidative decarboxylation. A specific two-step decarboxylation mechanism for copper P-keto-carboxylates has been observed which may provide a means of controlling this An intramolecular decarboxylative alkylation reaction to give spirocyclic ketones has appeared illustrated by its application to the synthesis of (*)-0-vetivone (30)and (*)-epi-pvetivone (31) (72% yield ratio 9 : 1); yields are good in most cases and the method appears to have some potential (Scheme 24).64 " 56

Y. Kobayashi and J. Tsuji, Tetrahedron Lett., 1981,22,4295. Y. Takahashi, K. Isobe, H. Hagiwara, H. Kosugi, and H. Uda, J. Chem. Soc., Chem. Commun.,

1981.714. M. Nakayama, S. Ohira, Y. Okamura, and S. Soga, Chem. Lett., 1981,731. 58 E.J. Corey, A. Marfat, and B. C. Laguzza, Tetrahedron Lett., 1981,22, 3339. 59 E. J. Corey, A. Marfat, J. Munroe, K. S. Kim, P. B. Hopkins, and F. Brion, Tetrahedron Lett., 1981,22,1077;E. J. Corey and J. Kang, J. Am. Chem. SOC.,1981,103,4618. 6o G . Just and H. Oh, Can. J. Chem., 1981,59,2729. 61 H. Nishiyama, K. Itagaki, K. Takahashi, and K. Itoh, Tetrahedron Lett., 1981,22, 1691. 62 R. M. Moriarty, S. C. Gupta, H. Hu, D. R. Berenschot, and K. B. White, J. A m . Chem. SOC., 1981,103,686. " T. Tsuda, Y. Chujo, S. Takahashi, and T. Saegusa, J. Org. Chem., 1981,46,4980. 64 R.G.Eilerman and B. J. Willis, J. Chem. SOC., Chem. Commun., 1981.30. 57

General and Synthetic Methods

108

iii, iv

(30) R' = Me,R2 = H (31) R' = H , R 2 = Me Reagents: i, NaH-DMF; ii, LiCI-HMPA, 140 OC; iii, MeLi; iv, pyridinium chlorochrornate

Scheme 24

The conversion of azetidine-2-carboxylicacids into p-lactones is achieved by an oxidative decarboxylation sequence (Scheme 25).65Yields of between 45 and 65% over eight examples are obtained. i-iii

H02C

R

R

Reagents: i, LDA, 0 "C;ii, 02,-78 "C; iii, HCI-H,O

Scheme 25

The decarboxylation of clavulanic acid and its methyl ether has been accomplished using mercury(I1) acetate, albeit in low yield.65The anodic oxidation of P-oxocarboxylate cyclic acetals (32) in anhydrous methanol gives 2-methoxy1,4-dioxacycloalkanes (33) in 40-60% yield. A systematic study of the anodic oxidation of P-keto carboxylate anions has also appeared.66

Protection and Deprotection,-The trimethylsilyl group is a useful protecting group for carboxylic acids. Two new procedures for the preparation of trimethylsilyl esters from acids have appeared using N-trimethylsilyl-2-oxazolidinone67 and N,N'-bis(trimethylsilyl)urea.68Yields are good for a range of examples for both reagents. An illustration of the use of trimethylsilyl protection of a carboxylic acid during hydroboration has been p ~ b l i s h e d . ~ ~ " 66

67

'*

69

D. Lelandais, C. Bacqukt, and J. Einhorn, Tetrahedron, 1981,37,3131. M. Chkir, D. Lelandais, and C. BacquCt, Can. J. Chem., 1981,59, 945. C. Palomo, Synthesis, 1981,809. W. Verboom, G. W. Visser, and D . N. Reinhoudt, Synthesis, 1981,807. G . L. Larson, M. Ortiz, andM. R. Roca, Synth. Commun., 1981,11,583.

Carboxylic Acids and Derivatives

109

2 Esters

Esterification.-Primary alcohols are converted into the corresponding acetate by simply stirring with neutral alumina using ethyl acetate as solvent.'" Yields are between 64 and 99% and this simple neutral procedure may have considerable potential for the acetylation of acid- or base-sensitive primary alcohols, Effective esterification of carboxylic acids with alcohols is brought about using 2-chloro-1,3,5-trinitrobenzenewith ~ y r i d i n e and , ~ ~ 2-fluoro-1,3,5-trinitrobenzene with 4-dimethylamin0pyridine.~~ A wide range of examples are covered in both cases, and the yields are good. Sulphuryl chloride fluoride mediates the esterification of carboxylic acids with alcohol^.'^ In the presence of triethylamine, carboxylic acids react with sulphuryl chloride fluoride to give acyl fluorosulphonates which then react with alcohols to yield the corresponding ester in good yield. A simple method for the esterification of carboxylic acids using chlorosilanes has been described.74A review on the use of diethyl azodicarboxylate and triphenylphosphine for inter- or intra-molecular dehydration reactions has appeared, which contains a section on esterification with other related proces~es.~~ A range of carboxylic esters undergo mild and neutral transesterification when treated with iodotrimethylsilanefollowed by an The reaction is limited to primary and secondary aliphatic alcohols, and yields between 40 and 98% are obtained. Another non protic trans-esterification method involves treatment of the methyl esters of various carboxylic acids with tetra-n-alkylammonium halide at 140 "C, leading to the production of the corresponding n-alkyl The generality of this method clearly depends on the availability of the required tetra-n-alkylammonium halide. Lactones react with iodotrimethylsilane in the presence of an alcohol to provide a convenient route to iodoalkyl esters in good yield.78 General Synthesis and Reactions.-Linear primary alcohols with at least seven carbon atoms are transformed into esters in high yield using copper oxide at temperatures above 170 "C in the liquid phase.79R U , ( C O )catalyses ~~ the conversion of an aldehyde, or an alcohol with the same number of carbon atoms, into an ester in the presence of diphenylacetylene.'' The carbonylation of organic halides in the presence of cyclic ethers is catalysed by PhPdI(PPh,),; it provides a synthesis of halohydrin esters in reasonable yield.'* Cyanohydrin esters have been synthesized by the sodium borohydride reduction of acyl cyanides in the presence of tetra-n-butylammonium bromide.82 G. H. Posner, S. S. Okada, K. A. Babiak, K. Miura. and R. K. Rose, Synthesis, 1981, 789. S. Takimoto, J. Inanaga, T. Katsuki, and M. Yamaguchi, Bull. Chem. SOC.Jpn., 1981, 54, 1470. " S. Kim and S. Yang, Synth. Commun., 1981, 11, 121. 73 G. A. Olah, S. C. Narang, and A. Garcia-Luna, Synthesis, 1981,790. " R. Nakao, K. Oka, and T. Fukumoto, Bull. Chem. SOC.Jpn., 1981,54, 1267. 'IJ 0. Mitsunobu, Synthesis, 1981, 1. 'I6 G. A. Olah, S. C. Narang, G. F. Salem, and B. G . B. Gupta, Synthesis, 1981, 142. " D. Bencivengo and J. S. Fillippo, J. Org. Chem., 1981,46,5222. '* M. Kolb and J. Barth, Synfh. Commun., 1981, 11,763. '' B. Berthon, A. Forestiere, G. Leleu, and B. Sillion. Tetrahedron Lett., 1981, 22,4073. Y. Blum, D. Reshef, and Y. Shuo, Tetrahedron Lett., 1981, 22, 1541. M. Tanaka,,M. Koyanagi, and T. Kobayashi, Tetrahedron Lett., 1981,22,3875. 82 J. M. Photis, J. Org. Chem., 1981, 46, 182. 'O

"

General and Synthetic Methods

110

A solid-phase method for the synthesis of optically active esters has been developed, which involves the alkylation of the polymer-bound oxazoline (34) (Scheme 26).83An optical yield of 56% with chemical yields between 43 and 48% are obtained; the polymer-bound amino-alcohols may be reisolated and used again.

Reagents: i, BuLi; ii, PhCH,CI; iii, H,SO,

Scheme 26

The readily available p-lactam amides (36)have not been used very often because of the difficulty of converting the amide into an acid or ester in the presence of the p-lactam ring. This conversion has now been achieved in moderate yield, in a wide range of examples, by the formation of the corresponding N-nitrosoamides followed by thermal decomposition into esters (Scheme

27).84

(36)

Scheme 27

Rh6(C0)16is a highly active catalyst in the reaction of ethyl diazoacetate with alkenes to give cyclopropyl Yields obtained are better than those obtained using palladium and copper catalysts. Methyl ester derivatives of tricyclo[4.2.0.01~4]octanehave been prepared by a photochemical Wolff rearrangement of a related diazoketone in The alkylation of the chiral ester (37)has been achieved via the 2-ester enolate using THF as solvent to give the product (38)with the S-configuration at the new chiral centre. When a mixture of THF and HMPA is used as solvent the E-ester enolate is produced, which leads to the R-ester (39) (Scheme 28)." Yields between 75 and 84%, with enantiomeric excesses greater than 94%, are achieved using this potentially useful procedure.

85 86

A. R. Clowell, L. R. Duckwall, R. Brooks, and S. P. McManus, J. Org. Chem., 1981,46,3097. H. P. Isenring and W. Hofheinz, Synthesis, 1981,385. M. P. Doyle, W. H. Tamblyn, W. E. Buhro, and R. L. Dorow, Tetrahedron Let?., 1981,22,1783. S.Wolff and W. C. Agosta, J. Chem. Soc., Chem. Commun., 1981, 118. R. Schmierer, G. Grotemeier, G. Helmchen, and A. Selim, Angew. Chew., In?.Ed. Engl., 1981,

20,207.

Carboxylic Acids and Derivatives

111

,iJ

Reagents: i, LiN

r

; ii, C1.&9I

Scheme 28

Full papers on the uses of dissolving metal reduction of esters and thiocarbonyl compounds, which provides an effective method for the deoxygenation of alcohols, have appeared.88 The cathodic reduction of oxalates is another less well developed method for deoxygenation; in this case olefin products are Esters and lactones react with Ph3P-CC14 to give initially dichloroenol ethers, which are subsequently hydrolysed to a-dichloroket~nes.~~ 2(Trimethylsily1)ethyI chloroformate reacts with alcohols to yield carbonates in high yield. The alcohol may be regenerated by the action of fluoride ion on the carbonate, thereby providing a method for the protection of the OH group.”

Diestem.-A novel cycloaromatization reaction is used for the preparation of an aromatic diester, which is subsequently converted into the natural product sclerin (Scheme 29).92Yields are reasonable and the method has been applied to orthoesters, anhydrides, and lactones. ?H Me3Si0 i-iii

a

O

M

e

___*

@OiiMe3 Me Me

Reagents: i, Et3N-ZnC12-Me,SiC1; ii, LDA; iii, Me,SiCl; iv, MeC(OMe),-TiC1,

Scheme 29

High-dilution conditions for the intramolecular application of the malonic ester synthesis to the preparation of macrocyclic diesters have been yields between 9 and 50% are obtained. Dialklacyl phosphonates provide a new method for the acetylation of enolates including the sodium enolate of diethyl mal~nate.’~ An alternative method for the generation of diester enolates involves the reductive a-deacetoxylation of an a-acetoxy diester (Scheme 30).95The

89

91 92 93

94 95

A. G. M. Barrett, C. R. A. Godfrey, D. M. Hollinshead, P. A. Prokopiou, D. H. R. Barton, R. B. Boar, L. Joukhadar, J. F. McGhie, and S. C. Misra, J. Chem. Soc., Perkin Trans. 1, 1981,1501; A. G. M.Barrett, P. A. Prokopiou. and D. H. R. Barton, ibid., p. 1510 D. W. Sopher and J. H. P. Utley, J. Chem. Soc., Chem. Commun., 1981,134. M. Suda and A. Fukushima, Tetrahedron Lett., 1981,22,759. C. Gioeli, N. Balgobin, S. Josephson, and J. B. Chattopadhyaya, Tetrahedron Lett., 1981,22, 969. T.-H. Chan and P. Brownbridge, J. Chem. SOC.,Chem. Commun., 1981,20. M. Casadei, C. Galli, and L. Mandolini, J. Org. Chem., 1981,46,3127. M. Sekine, A. Kume, M. Nakajima, and T.Hata, Chem. Lett., 1981,1087. S . N.Pardo, S. Ghosh, and R. G. Salomon, Tetrahedron Lett., 1981,22,1885.

aH F~(CO 112

General and Synthetic Methods

+

TO2EO2

ii, iii

-----) i

,

OAc Reagents: i, Ac,O-Et,N-DMAP;

ii, Na'[a-(Me,N)-naphthalenidel-;

iii, RX

Scheme 30

enolate is generated under aprotic conditions and may be alkylated in good yield by a range of alkyl halides. Tertiary alkyl malonic ester derivatives are prepared by the 1,4-addition of Grignard reagents under copper(1) catalysis to alkylidene malonic esters.96 Work on the alkenylation of malonate anions with 7r-ally1palladium complexes has continued. A stoichiometric 7r-4-chlorobutenylpalladium complex reacts with two equivalents of malonate anion, whereas the corresponding 7r-4methoxybutenylpalladium complex reacts with one eq~ivalent.~' The catalytic generation of 7r-ally1 palladium complexes from a-acetoxy-P,y-unsaturated nitriles and esters9*and 1,3-diene m o n o e p ~ x i d e susing ~ ~ Pd(PPh&, and their regioselective reaction with a range of carbon nucleophiles including malonate, has been reported by Tsuji and his co-workers. This group of workers has also reported a palladium(r1)-catalysed regioselective acetoxylation of P,y unsaturated esters in yields of around 50% (Scheme 31).'0°

OAc Reagent: i, PdCI,-C,H, ,NO,-KOAc-HOAc

Scheme 31

Chirality transfer via 7r-ally1 palladium complexes is observed during a synthesis of an optically active vitamin E side chain (Scheme 32).'" The optically active lactone (40) is prepared from D-glucose; stereospecific alkylation of the corresponding n-ally1 palladium complex occurs when the nucleophile attacks Me0,C

C0,Me

NaCH(C0 Me)

4 Pd(PPh&

Me (40)

H

0

Scheme 32

from the opposite side to the palladium. A palladium-catalysed decarboxylative elimination of a readily prepared P-acetoxy acid is reported during a synthetic approach to vitamin A ester (Scheme 33).'02 96

97

99

loo

C. Holmberg, Liebigs Ann. Chem., 1981,748. B. Akermark, A. Ljungqvist, and M. Panunzio, Tetrahedron Lett., 1981, 22, 1055. J. Tsuji, H. Ueno, Y.Kobayashi, and H. Okumoto, Tetrahedron Lett., 1981, 22,2573. J. Tsuji, H. Kataoka, and Y. Kobayashi, Tetrahedron Lett., 1981, 22,2575. J. Tsuji, K. Sakai, H. Nagashima, and 1. Shimizu, Tetrahedron Lett., 1981, 22, 131. B. M. Trost and T. P. Klun, J. A m . Chem. Soc., 1981,103,1864. B. M. Trost and J. M. D. Fortunak, Tetrahedron Lett., 1981, 22, 3459.

Carboxylic Acids and Derivatives

113

C0,Et

Ho2c* OAc

C0,Et Scheme 33

Studies of the palladium(I1)-catalysed coupling of vinylic halides with acrylic esters and related compounds, to give 2,4-dienoic ester derivatives in reasonable yield have been p~blished."~ Treatment of diethyl succinate with two equivalents of LDA followed by two equivalents of one alkylating agent or with two different alkylating agents leads to good yields of 2,3-dialkylated diethyl succinate derivative^."^ Generation of the lithium enolate of R,R-dimethyl tartrate acetonide, followed by alkylation, Yields provides a 4 : 1 mixture of truns- and cis-pentasubstituted dioxolan~.~~)' in the range 40-80% are obtained; and hydrolysis of the dioxolan products into the corresponding diacids is achieved with dilute acid. The anion derived from the phosphorane (41) acts as a vinyl anion equivalent when it undergoes alkylation followed by elimination of the triphenylphosphine group (Scheme 34).'06 Yields are good, and the major isomer is usually the fumarate (42). Ph 3 PyI;;

1;

i, ii

,

C0,Et

-

Et0,C

C0,Et

iii

ph3px R C0,Et (41) Reagents: i, LDA; ii, RX; iii, PhC02H, A

R'C02Et

+RiCozEt

(42)

Scheme 34

The idea of generating an o-quinodimethane intermediate from a benzyl silane was first published by Saegusa."' The method was first applied to steroid synthesis by others,1o6but Saegusa and his co-workers have now published their studies in this area.'09 They include the treatment of the benzyl silane (43) with fluoride ion in the presence of dimethyl fumarate to give the diester (44) as a single stereoisomer (Scheme 35).

e + i M e 3 --+ NMe3

\

Me

--*

\

@ \

\

Me

1-

"C0,Me Me (44)

(43) Reagent: i, Bu4NF4imethyl fumarate, 50 "C

Scheme 35 '04

lo'

lo' lo' '09

J. I. Kim, B. A. Patel, and R. F. Heck, J. Org. Chem., 1981,46,1067. N. R.Long and M. W. Rathke, Synth. Commun., 1981,11,687. R. Naef and D. Seebach, Angew. Chem., Int. Ed. Engf., 1981,20,1030. M. P. Cooke, TetrahedronLett., 1981,22,381. Y. Sto, M. Nakatsuka, and T. Saegusa, J. A m . Chem. Soc., 1980,102,863. S. Djuric, T. Sarkar, and P. Magnus, J. A m . Chem. Soc., 1980,102,6885. Y.Sto, M. Nakatsuka, and T. Saegusa, J. Am. Chem. SOC.,1981,103,476.

114

General and Synthetic Methods

The synthesis and Diels-Alder reactions of 1-acylated cyclopenta- 1,3-dienes with dimethyl acetylenedicarboxylate have been reported; moderate overall yields of diesters were The Lewis acid-catalysed Diels-Alder reaction of the chiral diester (45) with anthracene occurs in high yield and excellent enantiomeric excess (Scheme 36).ll1

OH

,CO,Me

OH (45) Reagents: i, anthracene-AICl,-CH,CI,; ii, LiAlH,

Scheme 36

Hydroxy-esters.-Ethyl S-3-hydroxybutanoate is obtained in 87% optical purity by the reduction of ethyl acetoacetate with Bakers yeast."* Two independent chiral synthesis of the leukotriene intermediates (46), R = CHO and R = CH20H, have a ~ p e a r e d . " An ~ effective large-scale conversion of arachidonic acid into 5-hydroxy-6-trans -8,11,14-cis-eicosatetraenoic acid (5)HETE, including its resolution, is also reported by Corey and Hashimoto.'14

0-Alkyl lactic acid esters are useful reagents for the stereoselective construction of erythro- and threo-a-methyl-a,P-dihydroxy-esters (Scheme In the case of (47), R' = R2 = Me, the major product is erythro- (48), but when in (47), R' = CHzPh and RZ = 2,6-t-butyl-4-methyl, the main product is threo(49). Yields are excellent, and the stereoselectivity is greater than 97%. Reasonable enantiomeric excesses have been achieved during a study of the Reformatsky and amide base-mediated condensations of chiral acetates with ketones. * l 6 OH

(47)

OH

(48)

Reagents: i, LDA; ii, Me,CHCHO

Scheme 37

'I2

'I4 'I5

G . Grundke and H. M. R. Hofmann, J. Org. Chem.. 1981,46,5428. G . Helmchen and R. Schmierer, Angew. Chem., Znt. Ed. Engl., 1981,20,205. K. Mori, Tetrahedron, 1981,37, 1341. E.J. Corey, S. Hashimoto, and A . E. Barton, J. A m . Chem. SOC., 1981,103,721;D . P.Marriott and J. R. Bantick, Tetrahedron Lett., 1981,22,3657. E. J. Corey and S. Hashimoto, Tetrahedron Lett., 1981,22,299. C. H. Heathcock, J. P. Hagen, E. T. Jarvi, M. C. Pirrung, and S. D. Young, J. A m . Chem. SOC.,

1981,103,4972. S . Brandange, S. Josephson, L. Morch, and S. Vallen, Acta Chem. Scand., Ser. B, 1981,35,273.

CarboxylicAcids and Derivatives

115

Enantioselective aldol reactions with high threo- or erythro-selectivity are obtained with boron azaenolates derived from chiral and achiral oxazolines, respectively."' Moving the chirality from the boron in (SO), to the heterocyclic in (51), causes the reaction to switch from threo- to erythro-products with high

( 5 1)

(50)

enantioselectivity. A mixture of (2R, 3S)- and (2S, 3S)-ethyl 3-hydroxy-2methylbutyrate (52) (Scheme 38) can be alkylated to give the hydroxy-ester (53), in high enantiomeric excess, as shown by its conversion into the optically active cyclohexenone (54) with 86% e.e.ll*

Reagents: i, 2 eq. LDA; ii, ICH,CH=CCIMe

Scheme 38

A novel method for the generation of an ester enolate from ethoxyacetylene has been developed, and its reaction with aldehydes studied (Scheme 39)."9a The diastereoisomeric a-chloro-P-hydroxy-esters( 5 5 ) and (56) are formed in a ratio of about 2 : 1 in very good yield.

JOZnCl H-C-C-OEt

.l.[l::C=CkoEt

]

iii, iv ___*

Rqo c1

(55)

+

Reagents: i, pyridine N-oxide-MgCI,; ii, Zn; iii, RCHO; iv, H,O

Scheme 39

A. 1. Meyers and Y. Yam'amoto, J. A m . Chem. SOC.,1981,103,4278. G.FrBter, Tetrahedron Len., 1981,22,425, ( a ) T.Mukaiyama and M. Murakami, Chem. Left., 1981, 1129; ( b ) K. Fuji, M. Ueda, K. Sumi, and E. Fujita. Synth. Commun., 1981,11,209.

116

General and Synthetic Methods

2-Lithio-2-ethylthio-1,3-benzodithiole (57) is a methoxycarbonyl anion equivalent, which reacts with various aromatic ketones to give a-hydroxy-esters in yields between 74 and 95% after desulphurization (Scheme 40).l1''

msxsEtI i,ii

s

,Ar

Li

OH

C0,Me

(57) Reagents: i, ArCOR; ii, Mg(CIO,),-MeOH-H,O

Scheme 40

The lithium enolate derived from ethyl dithiane carboxylate reacts with aldehydes to furnish P-hydroxy-ester derivatives in good yield.120 The Lewis acid-promoted additions of carbonyl compounds to donor-acceptor-substituted cyclopropanes, leads initially to P-hydroxy-esters, which undergo subsequent conversion to chlorides or dihydrofurans (Scheme 41).l2lU

Reagents: i, TiCI,-CH,CI,,

-78 "C; ii, i at 25 "C

Scheme 41

Keto-esters.-Acylimidazolides react readily with Grignard reagents to provide a general method for the synthesis of a-keto-esters; yields are variable over a series of 11 examples.121bP-hydroxy-esters and ketones, obtained by the aldol condensation, have been oxidized to P-keto-esters and ketones most efficiently by the Swern procedure using dimethyl sulphoxide and oxalyl chloride.12' Sulphide contraction of thiopyrrolidines has been shown to be an effective synthesis of P -keto-esters and nitriles (Scheme 42).123 S

-RY02R3 NG R1

Y

0

0

R -O ' R'

R' Reagents: i, BrCHR2C02R3;ii,bis(3-morpholinylpropyl)phenylphosphine;iii, HCl-H,O

Scheme 42 '20

12'

123

M. Braun and M. Esdar, Chem. Ber., 1981,114,2924. 1981,22, 2981;( b ) J. S. Nimitz and H. S . Mosher, J. Org. Chem., 1981,46,211. A. B.Smith and P.A. Levenberg, Synthesis, 1981,567. K. Shiosaki, G. Fels, and H.Rapoport, J. Org. Chem., 1981,46,3230. ( a ) H.-U. Reissig, Tetrahedron Lett.,

Carboxylic Acids and Derivatives

117

Dieckmann-type cyclization of the dithiolester (58) proceeds regiospecifically to the P-keto-thiolester (59).124Similarly, the half thiolester (60) is converted exclusively into the p-keto-ester (61), rather than the corresponding thiolester;'*' yields for both these cyclization reactions are good although only a small number of examples are reported.

Etshs .& NaH

R

0

,

COSEt

EtSH

(59)

(58)

c C o s E t NaH , SvCO,Me (60)

C0,Me

(61)

a-Acyloxyketones have been prepared by the sequential treatment of enolsilyl ethers with silver acetate-iodine and then fluoride ion (Scheme 43);126yields are good over a range of examples. However, with larger ring sizes, the formation of a-iodo-ketones occurs as a side reaction. The divinylcyclopropane rearrangement provides an effective regiospecific preparation of 2-(carbomethoxy)-4methylcyclohept-4-enone. * 27

Reagents: i, AgOCOMe-I,; ii, Et,NHF

Scheme 43

2,4,6-Trianions derived from the methyl ester and dimethylamide of 3 3 diketo-hexanoic acid are well known to react with activated halides and carbonyl compounds at the 6-position, and several examples have been reported this year (Scheme 44).12*

Li'

Na' Li'

Scheme 44

Lithium trialkylalkynyl borates react with alkylidene malonates and acetoacetates by an uncatalysed Michael reaction with concomitant migration of an alkyl group from boron to carbon. Oxidation of the resulting borane leads to a 124 125

12'

"*

H.-J. Liu and H. K. Lai. Synth. Commun., 1981, 11, 65. Y. Yamada, T. Ishii, M. Kimura, and K. Hosaka. Tetrahedron Lett., 1981, 22, 1353. G. M. Rubottom, R. C. Mott, and H. D. Juve, J. Org. Chem., 1981,46,2717. J. P. Marino and M. P. Ferro, J. Org. Chem., 1981,46, 1912. J. S. Hubbard and T. M. Harris, J. Org. Chem., 1981 46, 2566.

118

General and Synthetic Methods

keto-ester.129 Michael addition of a substituted 0-keto-ester to methyl vinyl ketone leads to a normal 1,5-dicarbonyl compound, which can be cyclized to two different unsaturated keto-esters, depending on the type of acidic conditions Cook and his co-workers have continued their studies on the cyclization reactions of p-keto-esters to include the influence of steric factors on the A novel cyclization of dicarbonyl compounds with dimethyl 3-ketog1~tarate.l~~ cyclization reaction of alkenyl-p-keto-esters, in which a phenyl seleno group When p-toluenesulphonic acid is migrates, has been reported (Scheme 45).132 used, cyclization at oxygen occurs to give a tetrahydrofuran as a kinetic product. 0 0

II

Scheme 45

SePh

An effective method for the 'de-ethoxycarbonylation' of a P-keto-ester is simply to heat the substrate with magnesium or calcium chloride in dimethyl sulphoxide; yields between 50 and 60% are The preparation of an activated cyclopropane, and its application to the synthesis of iridoid natural products has been d e ~ c r i b e d . ' ~ ~ Unsaturated Esters.-Magnesium enolates derived from a-silylated esters react with aldehydes to afford almost exclusively one tliastereoisomer of the two possible p-hydroxy-silanes, Subsequent acidic work up leads to E-unsaturated esters in good yield and excellent selectivity (98%) for the three examples r e ~ 0 r t e d . l ~Similar ' results were obtained under Lewis acidic conditions with the keten acetal (62) and an aldehyde. Here the intermediate p-hydroxy-silane undergoes anti-elimination in situ to lead to the unsaturated ester (63) in high yield and stereoselectivity (93%) (Scheme 46).136

+C8H17CH0 OSiMe,

*""

SiMe, p 8 y C O 2 M ]

(62) - HOSMe,

Scheme 46 129

C02Me (63)

A. Pelter and J. M. Rao, Tetrahedron Lett., 1981,22,797. W. Kreiser and P. Below, Tetrahedron Lett., 1981,22,429. K. Avasthi, M. N. Deshpande, W. C. Han, J. M. Cook, and U. Weiss, Tetrahedron Lett., 1981,

lJo 13'

22,3475. 133 134

lJ5

W. P. Jackson, S.V. Ley, and J. A. Morton, Tetrahedron Lett., 1981,22, 2601. Y.Tsuda and Y. Sakai, Synthesis, 1981, 119. P.Gallant, H. De Wilde, and M. Vandewalle, Tetrahedron, 1981,37, 2079 and 2085. M. Larchevtque and A. Debal, J. Chem. SOC.,Chem. Commun., 1981,877. I. Matsuda and Y. Izumi, Tetrahedron Lett., 1981,22,1805.

Carboxylic Acids and Derivatives

119

A synthesis of unsaturated o-acetylenic vinyl esters has been reported that uses the elimination of trimethylsilyl acetate as a key step.13' Yields are good for a range of examples, but vinyl-3-butynoate was not accessible by this route. 2-Isocyanoacrylic acid esters are useful as precursors of heterocyclic and unsaturated amino-acids. These compounds are prepared in a stereoselective manner and in good yield using the Wittig-Horner reaction of tbutyl(diphenylphosphiny1)isocyanoacetatewith a 1 d e h ~ d e s . cis-Enoates l~~ have been prepared by the reaction of a-diazoesters with R ~ ( O A C ) ~An . ~interesting ~' one-pot synthesis of a-fluoro-a$-unsaturated esters from ethyl chloromalonate and carbonyl compounds works well using 'spray dried' potassium fluoride but not with other forms of this salt (Scheme 47); the E-ester was the major product with a stereoselectivity of 86--96%. 140 CICH(CO,Et),

i, ii

R-CH-CF(CO2Et),

OH

1

+ RCH=CF-CO,Et

Reagents: i, spray dried KF-sulpholane; ii, RCHO

Scheme 47

The synthesis of ene-sulphides derived from 2-methoxycarbonylcyclopentanone has been described along with their interconversion to other ~ ~convenient route to the enesulphides via the corresponding S - o x i d e ~ . ' A prostaglandin intermediates butyl-5-oxocyclopentene-l-acetateand heptanoate involves the condensation between 1-morpholinocyclopentene and an appropriate aldehydo ester.142 The process whereby a P-keto-ester is converted into an a,&unsaturated ester via an enolphosphate has been applied to the synthesis of isoprenoid natural products (Scheme 48),143and in a regiospecific synthesis of 6-deoxyanthracycline intermediates. 144 C02Me

R'

i,ii

R'

R'

Reagents: i, NaH; ii, ClPO(OEt),; iii, RZzCuLi

Scheme 48

The first total synthesis of the epoxyisonitrile natural product (64) involves a base-induced fragmentation reaction to provide the unsaturated ester fragment (Scheme 49).145 The stereospecific rearrangement of 2,2-dimethylcyclobutanol into optically active 1,2-cis -disubstituted cyclopropanes has been reported (Scheme 50).146 M. C. Croudace and N. E. Schore, J. Org. Chem., 1981,46,5357. J. Rach6n and U. Scholkopf, Liebigs Ann. Chem., 1981,99. N.Ikota, N.Takamura, S. D. Young, and B. Ganem, TetrahedronLetr., 1981,22,4163. 140 T. Kitazume and N. Ishikawa, Chem. Lett., 1981,1259. 141 Y. Yamada, K.Ohnishi, K. Ohata, and K. Hosaka, Synthesis, 1981,64. 142 A.Barco, S. Benetti, P. G. Baraldi, and D. Simoni, Synthesis, 1981,199. 143 F. W.Sum and L. Weiler, Tetrahedron, 1981,37 (Suppl. No. 9),303. 144 J.-P. Gesson, J.-C. Jacquesy, and M. Mondon, TetrahedronLett., 1981,22, 1337. T. Fukuyama and Y. M. Yung, Tetrahedron Lett., 1981,22,3759. M.Karpf and C. Djerassi, J. Am. Chem. Soc., 1981,103,302.

General and Synthetic Methods

120

0 , C H H O CH,CO,Me

(64)

Reagents: i, Bu‘OK; ii, MCPBA; iii, MsCI-Et,N; iv, COCI,

Scheme 49 POCI, pyridine

HOh C 0 2 M e

’

C0,Me

Scheme 50

The conversion of acetylenes into olefinic esters by use of addition reactions has been illustrated by the following two examples. (i) l-Alkenyl boranes, which are readily prepared by the hydroboration of alkynes, are converted into a,punsaturated carboxylic esters in good yield by reaction with carbon monoxide in the presence of palladium chloride and sodium acetate in methanol; the process is carried out at atmospheric pressure and occurs with retention of configuration with respect to the alkenyl b 0 ~ a n e . (ii) l ~ ~Carboxylic acids add to acetylenes in the presence of silver carbonate to provide a novel synthesis of enol esters, which are formed in an 8 :2 mixture of isomers.148 A1kylation of dimethyldithioacet al-5,s -dioxide under phase-transf er conditions leads to an intermediate which is converted into an unsaturated ester in the appropriate case after oxidation and hydrolysis (Scheme 5 l).14’ Saturated esters are also prepared using this method. ,SMe R

A

B

r

+ CH\,

SMe R b S O , M e

+ -.

R-CO,Me

S0,Me

Reagents: i, trioctylmethylammonium chloride-NaOH-H20-toluene; ii, H202-CH,C02H; iii, HCI-MeOH Scheme 51

The syntheses of p-enamino esters and related compounds from cyclic149and acyclic’sop-enamino Meldrums acid derivativeshave been described; good yields in a range of cases are obtained. In the natural product area, unsaturated esters that are biologically active analogous of leukotriene &,lS1 and a pheromone of the ‘ComstockMealybug”’* have been synthesized using conventional methods. 14’ 14’ 149

N. Miyaura and A. Suzuki, Chem. Lett., 1981,879. Y.Ishino, I. Nishiguchi, S. Nakao, and T. Hirashima, Chem. Lett., 1981,641. J. P. Cilirier, G. Lhommet, and P. Maitte, Tetrahedron Leu., 1981,22,963. J. P. CClerier, E. Deloisy, P. Kapron, G. Lhommet, and P. Maitte, Synthesis, 1981,130. K.C.Nicolaou, N. A. Petasis, and S. P. Seitz, J. Chem. SOC.,Chem. Commun. 1981,1195. K. Mori and H. Ueda, Tetrahedron, 1981,37, 2581.

Carboxylic Acids and Derivatives

121

Vinyl carbanions derived from acrylic esters and their P-phenyl derivatives react with several carbon electrophiles to give a-substituted and a,P-disubstituted derivative^.'^^ While P-alkyl substituted acrylates have been shown to dimerize in the presence of potassium catalyst at 110 0C.154 Three simple unsaturated esters undergo palladium(0)-catalysed codimerization with methylenecyclopropane to furnish methylenecyclopentanecarboxylic esters in reasonable yield.”’ An efficient procedure for the oxidation of isatins to anthranilic acid esters has appeared. 15‘ Methyl 2,4,6-tri-isopropylbenzoate forms a dipole-stabilized carbanion on reaction with Bu’Li, which then reacts with carbon electrophiles [e.g. E = BuI, (CH&CO, or CH3CHO] to give a range of ester derivatives in good yield (Scheme 52).15’

Reagents: i, BuLi; ii, CO,; iii, SOCI,; iv, MeOH; v, Bu”Li-TMEDA; vi, E’

Scheme 52

The ortho-ester Claisen rearrangement continues to provide a versatile method for the preparation of unsaturated esters. Reaction of trimethylmethoxyorthoacetate with an ally1 alcohol furnishes a-methoxy-y,G-unsaturated esters in 22-55% yields.”* A stereospecific synthesis of both enantiomers of the insect pheromone methyl E-2,4,5-tetradecatrienoateinvolves the conversion of the R-acetylenic alcohol (65) (Scheme 53) into the R-allenic ester (66) as its key step. This process was repeated with the S-alcohol to provide the enantiomer of (66).lS9The optically active erythro-alcohol(67), readily available

B. A. Feit, U. Melamed, R. R. Schmidt, and H. Speer, J. Chem. Soc., Perkin Trans. 1, 1981, 1329. J. Shabtai, E. Ney-Igner, and H. Pines, J. Org. Chem., 1981,46,3795. P. Binger and U. Schuchardt, Chem. Ber., 1981,114,3313. 156 G. Reissenweber and D. Mangold, Angew. Chem., Int. Ed. Engl., 1981, 20, 882. ”’ P. Beak and L. G. Carter, J. Org. Chem., 1981,46, 2363. G. W. Daub, D . H. Teramura, K. E. Bryant, and M. T. Burch, J. Org. Chem., 1981,46, 1485. l S 9 K. Mori, T. Nukada, and T. Ebata, Tetrahedron, 1981, 37, 1343.

lS3

lS4

”’

122

General and Synthetic Methods

from R-glyceraldehyde acetonide, was rearranged into a 4 : 1 mixture of 2-(68) and E-(69) y,&unsaturated esters (Scheme 53).160The Z-isomer (68) was converted into a substituted furan on heating with dilute acid. An enantioselective allylic acetate rearrangement, catalysed by PdC12(CH3CN)2, has been reported. The Diels-Alder reaction is the most popular method for the synthesis of unsaturated esters this year. In a thorough study by Oppolzer and his co-workers, it has been demonstrated that a series of chiral acrylate esters prepared from enantiomerically pure monoterpenes, undergo TiC1,-promoted Diels-Alder addition to cyclopentadiene giving either ( 2 R ) -or (2S)-adducts with 63-88% asymmetric induction (Scheme 54).162The most interesting facet of the work is the degree to which the stereochemical outcome of the reaction may be controlled. The acrylate (70a) leads to the R-adduct (71a) with 89% enantiomeric excess, whereas the acrylate (70b) gives the S-adduct (72b) in 88% enantiomeric excess.

0 /iCo2R*

___* TiCI,

+

\

a; R* = j &

Me Scheme 54

Allenic esters also react with cyclopentadiene in a Diels-Alder reaction; endoselectivity up to 86% was observed in most cases.'63 The unsaturated esters (73) and (74) have been prepared, and their reactions with acyclic dienes studied. The ester (73) undergoes concomitant eliminations of benzenesulphinic acid to give a cyclohexadiene in modest yield,164whereas (74) requires a separate treatment with base to bring about its conversion into an aromatic COzEt PhS

C02Me

'c'

II

I

' 1I1 S02Ph

CHR

I6O

163

165

J.-C. Depezay and Y. Le Merrer, Bull. SOC.Chim. Fr., 1981,11,435. P. A. Grieco, P. A. Tuthill, and H. L. Sham, J. Urg. Chem., 1981,46,5005. W. Oppolzer, M. Kurth, D. Reichlin, C. Chapius, M. Mohnhaupt, and F. Moffat, Helu. Chim. Acta, 1981,64, 2802;W.Oppolzer, M. Kurth, D. Reichlin, and F. Moffat, Tetrahedron Lett., 1981,22,2545. Z. M. Ismail and H. M. R. Hoffmann, J. Org. Chem., 1981,46,3549. Q. B. Cass, A. A. Jaxa-Chamiec, and P. G. Samfnes, J. Chem. SOC.,Chem. Commun., 1981,1248. M. Shen and A. G. Schultz, TetrahedronLett., 1981,22,3347.

Carboxylic Acids and Derivatives

123

Two different groups of workers have reported the stereocontrolled synthesis of unsaturated ester steroid side chains using a Lewis acid-catalysed ene reaction (Scheme 55).'66 Et AlCl 2

C0,Me H

COzMe Scheme 55

Thioesters.-Mixed anhydrides prepared from 2,4,6-trichlorobenzyl chloride and a carboxylic acid react with various thiols in the presence of 4-dimethylaminopyridine to give thioesters in 78--86% isolated yield. 167 Somewhat less impressive yields were obtained in a few of the cases studied when l-fluor0-2,4,6trinitrobenzene was used to couple the acid and the thio1.'68 Treatment of 1-acylimidazoles with thiols in the presence of a catalytic amount of Mg(OEt)* furnishes thioesters in good yields. 169 Diphenyl-2-oxo-3-oxazolinylphosphonate brings about effective reaction between acids and thi01s.l~' Thiolacetates are efficiently prepared using the reaction of an alcohol with triphenylphosphine and di-isopropyl azodicarboxylate in the presence of thiolacetic acid, 17* A synthesis of some amino-acid derivatives containing the thioester functional group is achieved by the reaction of a vinyloxyborane with a Schiffs base (Scheme 56).'72 R'CH=NR2

+ H2C=C

NHR* 1 /OBBu2 R'-CHCH2COSBuf

'SBU Scheme 56

The synthesis of a series of thioesters of thiocarbamic acid for use in a study l~~ have been on the acylation of proteins has been r e p 0 ~ t e d . @-Keto-thioesters employed in the construction of fused and bridged ring systems with a functionalized substituent in the angular p0siti0n.l~~ Vinylogous Esters.-The extensive studies on the preparation and synthetic utility of vinylogous esters has been impressive this year. Smith and his coworkers have applied their new route to 3(2H)-furanones (Scheme 57)17' to 166

167

168 169

170 171 172

173 174 175

W. G. Dauben and T. Brookhart, J. A m . Chem. SOC.,1981,103,237; A . D . Batcho, D . E. Berger, M. R. Uskokovit, and B. B. Snider, ibid., p. 1293. Y . Kawanami, Y. Dainobu, J. Inanaga, T. Katsuki, and M. Yamaguchi, Bull. Chem. SOC.Jpn., 1981, 54, 943. S. Kim and S. Yang, Chem. Lett., 1981, 133. S . Ohta and M. Okamoto, Tetrahedron Lett., 1981, 22, 3245. T. Kunieda, Y. Abe, and M. Hirobe, Chem. Lett., 1981, 1427. R. P. Volante, Tetrahedron Lett., 1981, 22, 3119. M.Otsuka, M. Yoshida, S. Kobayashi, Y. Umezawa, M. Ohno, and H. Morishima, Tetrahedron Lett., 1981, 22, 2109. J. R. Dalton, A . Kirkpatrick, and J. A . Maclaren, Aust. J, Chem., 1981, 34, 759. H.-J. Liu, L.-K. Ho, and H. K. Lai, Can. J. Chem., 1981, 59, 1685. A. B. Smith, P. A . Levenberg, P. J. Jerris, R. M. Scarborough, and P. M. Wovkulich, J. A m . Chem. Soc., 1981,103, 1501.

General and Synthetic Methods

124

Reagents: i, LDA; ii, RCHO; iii, Cr0,-pyridine; iv, HCI-H20

Scheme 57

the synthesis of n~rmethyljatrophone'~~ and g e i ~ a r v a r i n 'as ~ ~well as carrying out an asymmetric total synthesis of (+)-kjellmarianone from methoxycyclopenten~ne."~ Another independent route to 3(2H)-furanones from acetylenic precursors has also appeared.'79 Koreeda and Chen have reported an elegant route to (*)-desepoxy-4,5-didehydromethylenomycin A (75)in which a 3-alkoxycyclopentenone is first y-alkylated then a-alkylated (Scheme 58).lg0

-y$

0

iii, iv

SPh

0

0

-OH

Reagents: i, LDA; ii, ICH,SPh; iii, LDA; iv, C H 2 0

Scheme 58

Efficient synthesis of (k)sativenelS1and (*) solavetivone'82have appeared. Both routes involve the alkylation of a vinylogous ester, methoxycyclopentenone in the former case and 5-methyl-3-methoxycyclohexenonein the latter case, the follow this with an intramolecular Diels-Alder reaction.

3 Lactones General Synthesis.-The catalyst R U H , ( P P ~brings )~ about the oxidative condensation of diols to lactones, in addition to the conversion of alcohols to w-Benzyloxymethyl esters are converted into lactones in 7 1-9 1% yield when+treated with the hydride abstractor Ph,C'BF; or the radical cation (p-BrPh),NSbCl, (Scheme 59).lE4 Asymmetric bromolactonization of the acylproline (76) gives the lactone (77) in good yield and high stereoselectivity (99°/~).185 A review article on A. B. Smith, M. A. Guaciaro, S. R. Schow, P. M. Wovkulich, B. H. Toder, and T. W. Hall, 1. A m . Chem. SOC.,1981,103,219. P. J. Jerris and A. B. Smith, J. Org. Chem., 1981,46, 577. "la D. Boschelli, A. B. Smith, D. D. Stringer, R. H. Jenkins, and F.A. Davis, Tetrahedron Lett., 1981, 22,4385. D. R. Williams, A. Abbaspour, and R. M. Jacobson, Tetrahedron Lett., 1981, 22, 3565. M. Koreeda and Y.P. L. Chen, Tetrahedron Lett., 1981,22, 15. R. L. Snowden, Tetrahedron Lett., 1981, 22,97 and 101. A. Murai, S. Sato, and T. Masamune, J. Chem. SOC.,Chem. Commun., 1981,904. S. Murahashi, K. Ito, T. Naota, and Y.Maeda, Tetrahedron Lett., 1981,22,5327. T. R. Hoye, M. J. Kurth, and V. Lo, Tetrahedron Lett., 1981, 22, 815. M. Hayashi, S. Terashima, and K. Koga, Tetrahedron, 1981,37,2797.

176

Carboxylic Acids and Derivatives

125

(n = 1or2) Reagents: i, Ph,?BF,; ii, (p-BrPh),N"SbCI,

Scheme 59

organoselenium-induced cyclizations covers various aspects of selenolactonization.lS6 The conversion of lactones to thionolactones using trimethyloxonium tetrafluoroborate followed by sodium hydrosulphide has been described by Kaloustian and Khouri. 18' Five-, six-, and seven-membered thionolactones are formed in 44-90% yield, but thioester by-products were also formed in some cases. Ethers are formed from lactones by reaction with di-isobutylaluminium hydride followed by triethylsilane and BF,-OEt,; yields in the range 50-88% are achieved.18' P-Lactones.-Studies continue on the synthesis and reactions of p-lactones derived from acid dianions and carbonyl compounds. The decarboxylation of these compounds to sterically hindered olefin~,"~ and the steric control of the process by acid catalysis has been described (Scheme 6O).l9O In the latter case, increasing the acidity of the reaction medium changes the stereochemistry from retention (>98%) to inversion (>98%) of configuration.

C0,Ar But

H-H-H % C0,Ar H C02Ar But

=

%

/

H

I

\

Bu'

Reagents: i, dichlorobenzene, 100 "C; ii, CF,CO,H-dichlorobenzene, 25 "C

Scheme 60 la'

190

K. C. Nicolaou, Tetrahedron, 1981,37,4097. M. K. Kaloustian and F.Khouri, Tetrahedron Left., 1981,22,413. G. A. Kraus, K. A. Frazier, B. D. Roth, M. J. Taschner, and K. Neuenschwander, J. Org. Chem., 1981,46,2417. W.Adam, G.Martinez, J. Thompson, and F. Yang, J. Org. Chem., 1981,46,3359. J. Mulzer and M. Zippel, J. Chem. Soc., Chem. Commun., 1981,891.

126

General and Synthetic Methods

a-Chloro-P-lactones are produced in modest yield when certain a,p-unsaturated acids are treated with hypochlorous acid.lg' Butyro1actones.-y Epoxyesters have been used as effective precursors of butyrolactones; in one case sodium benzenethiolate brings about epoxide opening and lactonization occurs in a separate Similarly, attack of a vinyl cuprate on the epoxyester (78) leads directly to a mixture of lactones from which the trans-lactone (79) is isolated; the latter compound is the wing gland pheromone of the male african sugar-cane borer (Scheme 61).lg3 i, ii

0 (79)

(78) Reagents: i,

CuLi; ii, h.p.1.c. separation

Scheme 61

During a recent study of acylic stereoselection, the ketone (80) was converted into a 1 O : l mixture of isomers (81) and (82). This selectivity was sufficiently high to enable the natural lactone (*)-blastmycinone (83) to be isolated as a pure substance in 20% overall yield after crystallization (Scheme 62). lg4

I Reagents: i, LDA; ii, ?'MEDA-PhAOACHO

iv, H,-HCI-Pd-C;

v,

; iii, H,IO,-H,O;

iv, v

'Bu

z O -pyridine

Scheme 62

(83)

Substituted butyrolactones are formed in moderate yields by the photoalkylation of alcohols to 5,6-dihydr0-2-pyrone.l~~ 191

192 193

D. Solas and J. Wolinsky, Synth. Commun., 1981,11,609.

L.Strekowski and M.A. Battiste, Tetrahedron Lett., 1981,22, 279. G. Kunesch, P. Zagatti, J. Y.Lallemand, A. Debal, and J. P. Vigneron, Tetrahedron Lett., 1981, 22. 5271.

194

19'

C.'H. Heathcock, M. C. Pirrung, J. Lapme, C. T. Buse, and S. D. Young, J. Org. Chem., 1981, 46,2290. A.Guzman, S. Mendoza, and E. Diaz, Synthesis, 1981,989.

Carboxylic Acids and Derivatives

127

Iodolactonization and related reactions continue to provide one of the most effective means of preparing butyrolactones. 3-Hydroxyd-alkenoic acids produce the thermodynamically less stable cis-lactones in good yield and with high stereoselectivity under the usual iodolactonization conditions. 19' Iodolactones are formed from bicyclo[2,2,2]oct-5-ene-2-carboxylic acids using this pro~ e d u r e , ' ~or' chloro- y-lactones are obtained using chloroamine T.19' An exclusive anti-S,2' reaction of the cyclopentenyl allylic lactone (84) has been proved by the conversion of the resulting unsaturated acid (85) to the iodolactone (86) by iodolactonization. 199 PhCHlO ' * * y 0 C H 2 P h

b0q

OCH,Ph

Me2CuLi

--+

CO,H

0

0

(84)

0

(85)

(86)

The unsaturated acid (87) undergoes selenolactonization to provide the butyrolactone (88) which cyclizes further to (89) with rearrangement of the phenylseleno-group when treated with acid (Scheme 63).'0° C02H /

-J i

* * : D o+ ii

/' H' (87)

Se Ph

(88)

@o PhSe (89)

Reagents: i, PhSeC1-AcONHEt,; ii, CH,SO3H-CH2CI2

Scheme 63

y-Acetylenic acids react with N-chloro-, N-bromo-, and N-iodo-succinimides in the presence of base to form butyrolactones in good yield.201A hydride-shift mechanism has been invoked to explain the tendency of the alkylidene malonate (90) to undergo lactonization to give (91) when treated with acid.202

Activated zinc has been found to promote the reaction of dimethyl maleate with carbonyl compounds to give y-butyrolactone derivatives in yields between '91

19' '91

199

' 0 1

202

A. R. Chamberlin, M. Dezube, and P. Dussault, Tetrahedron Lett., 1981,22,4611. V. Alberts, D. J. Brecknell, R. M. Carman, and S. S. Smith, Aust. J. Chem., 1981,34,1719. B. Damin, A . Forestiere, J. Garapon, and B. Sillion, J. Org. Chem., 1981,46,3552. P. A.Grieco and C. V. Srinivasan, J. Org. Chem., 1981,46,2591. A . Rouessac, F. Rouessac, and H. Zamarlik, Tetrahedron Lett., 1981,22,2641;F.Rouessac and H. Zamarlik, ibid., p. 2643. G. A. Krafft and J. A. Katzenellenbogen, J. Am. Chem. SOC.,1981,103,5459. R.Verht, N. DeKimpe, L. DeBuyck, and N. Schamp, Synth. Commun., 1981,11,35.

128

General and Synthetic Methods

23 and 86% .*03Benzoyl peroxide-catalysed addition of bromo-acids to ~ l e f i n s , ~ ' ~ and the peroxydisulphate oxidation of aliphatic carboxylic acids in the presence of ole fin^,^'^ provide new electron-transfer methods for the synthesis of ybutyrolactones. (92) and The sequential dialkylation of S-y-trityloxymethyl-y-butyrolactone subsequent lactone carbonyl transposition provides a highly stereoselective synthesis of P,P-disubstituted-y-butyrolactones (93) (Scheme 64).206This process is complimented by the report that the lactone (92) may be converted into its R-enantiomer using the Mitsunobu inversion pr~cedure."~

-

HO i-iii

iv-vi

R' Reagents: i, LDA-HMPA-R'X; vi, Jones oxidation

ii, LDA-HMPA-R2X; iii, HCI-MeOH; iv, LAH; v, Na10,-H,O;

Scheme 64

The stereoselective alkylation and aldol reactions of S-P-hydroxybutyrolactone dianion have been described; the highest selectivity was obtained with pivaldehyde and yields are between 40 and 50% .208 2,3-0-Isopropylidene-Rglyceraldehyde (94)is converted into a 3 : 1mixture of tribromoacetates (95)/(96) by reaction with carbon tetrabromide and acetylation; this mixture is then easily converted into a mixture of diacetyl lactones (Scheme 65),209 S

O

oJcHo

.

..

%O

#O

O A C B r , +O+Br3

(94)

OAc (95)

(96) OAc

\ii

Reagents: i, CBr,-SnF,; ii, Ac20-pyridine; iii, AgN0,-H20

Scheme 65

Midland and his co-workers have continued their work on the reduction of acetylenic keto-esters, e.g. (97), with chiral boranes to include a highly efficient synthesis of the insect pheromone (98).210Catalytic hydrogenation of the lactone tetra-acetate (99) in the presence of triethylamine gives the triacetate (100) by 203

'04 205

'06 *07 '08

209

2'o

T. Shono, H. Hammaguchi, I. Nishiguchi, M. Sasaki, T. Miyarnoto, M. Miyamoto, and S. Fujita, Chem. Lett., 1981, 1217. T. Nakano, M. Kayama, H. Maysumoto, and Y. Nagai, Ckem. Lett., 1981,415. C. Giordano, A. Belli, F. Gasagrande, G. Guglielmetti, and A. Citterio, J. Org. Chem., 1981, 46, 3 149. K.Tomioka, Y.4. Cho, F. Sato, and K.Koga, Chem. Lett., 1981, 1621. S. Takano, M. Yonaga, and K.Ogasawara, Synthesis, 1981,265. H.-M. Shieh and G. D. Prestwich, J. Org. Chem., 1981,46,4319. T. Mukaiyama, M. Yamaguchi, and J. Kato, Chem. Lett., 1981, 1505. M. M. Midland and N. H. Nguyen, J. Org. Chem., 1981,46,4107.

129

CarboxylicAcids and Derivatives

H

roH

Fy OH HO

OAc

LOAc

( 100)

(99)

(101)

elimination followed by reduction.211Similarly, L-ascorbic acid is readily hydrogenated to ~-gulono-1,4-lactone( 101).212 In contrast to the predictions of Meyers, it has been reported that the a,P-unsaturated oxazoline (102) reacts with an allylic lithium reagent to give the trans-lactone (103) with 95% selectivity (Scheme 66).213Saturated lithium reagents produce mainly the corresponding cis-lactone. 0 ,N

J

Reagents: i, &Li

; ii, H2S0,-MeOH-H,O

Scheme 66

(3S,4S)-3,4-Dimethyl-y-butyrolactoneis readily prepared from R-(+)tartaric acid; it has been used in a chiral synthesis of potential insect pheromones. 21 Regioselective oxidation of primary, secondary 1,4-diols with bromine and a nickel(I1) salt provides y-substituted butyrolactones in good yields.21s The tetrahydrofuran (104, R = Me) is also oxidized regioselectively with chromic anhydride to the lactone (105) in low yield, but the reaction has been used in the synthesis of compounds related to methylenomycin.216 However, the *I1 212

213

215

216

G. C. Andrews, T. C. Crawford, and B. E. Bacon, J. Org. Chem., 1981,46,2976. K.Bock, I. Lundt, and C. Pedersen, Acru Chem. Scand., Ser. B, 1981,35,155. F. E.Ziegler and P. J. Gilligan, J. Org. Chem., 1981,46,3874. S. Bystrom, H.-E. Hogberg, and T. Norin, Tetrahedron,1981,37,2249. M. P. Doyle and V. Bagheri, J. Org. Chem., 1981,46,4806. D.Boschelli, R. M. Scarborough, and A. B. Smith, Tetrahedron Lett., 1981.22. 19.

General and Synthetic Methods

130

oxidation of (104, R = CHMe2) using the same reagent leads to an equal mixture of lactones (105) and (106) in modest yield which are intermediates in cyclopentenoid antibiotic ~ynthesis.~” Iodotrimethylsilane brings about the ring opening of cyclopropyl esters, and subsequent treatment with a base produces y-butyrolactones in 72-89% (Scheme 67).218The cyclopropyl ester (107) is converted into lactone (108) by this method, and by contrast into lactone (109) on heating with acid. In a related transformation the vinyl cyclopropane (110) produces the butyrolactone (111) in good yield when treated with bis(trimethylsilyl)sulphate, a mild Lewis acid catalyst (Scheme 68).219

mo 0 GCO2,, 7

(los)

-;ao

(107)

Reagents: i, N,CCO,Et; ii, Me,SiI; iii, K,CO,-AgNO,; iv, HCl, A

(109)

Scheme 67 (Me,SiO),SO,

%co2Et

C02Et (111)

Scheme 68

y-Methylene-y-butyrolactone is formed from ally1 4-pentenoate in a process mediated by Pd(PPh,),; the reaction is thought to occur by oxidative addition of the allylic ester to the Pdo to give a palladium carboxylate complex.22o Carbocyclic anhydrides have been converted into spirocyclic butyrolactones by reaction with a di-Grignard reagent.221This reaction has also been applied to the synthesis of 6-lactones; yields are good for ten examples. The Diels-Alder reaction has been used extensively for the construction of various butyrolactones. The simplest example of this is the attachment of diene and dienophile via an ester linkage (112); intramolecular cyclization then leads

220

D. Boschelli and A. B. Smith, TetrahedronLett., 1981,22,3733. S . P.Brown, B. S.Bal, and H. W. Pinnick, TetrahedronLett., 1981.22.4891. Y.Morizawa, T.Hiyama, and H. Nozaki, TetrahedronLett., 1981,22,2297. T. Tsuda, Y.Chujo, and T. Saegusa, Synth. Comrnun., 1981,11,775. P. Canonne, D. BClanger, G. Lemay, and G. B. Foscolos, J. Org. Chem., 1981.46.3091.

Carboxylic Acids and Derivatives

131

to a bicyclic butyrolactone (113).222In similar vein Kametani and his co-workers report in full the pyrolysis of unsaturated benzocyclobutene esters, e.g. (114), which leads to the butyrolactone (115) presumably via a quinodimethane intermediate.223 Using this method a series of compounds are prepared which resemble the basic skeletons of some naturlly occurring lactonic terpenes. Vinylfuran derivatives also undergo intramolecular Diels-Alder reactions to give tricyclic furan lactones in good yield.224

(114)

(115)

U

A bridged tricyclic lactone is formed by the reaction of furfuryl alcohols with maleic anhydride which is thought to occur via initial esterification followed by intramolecular Diels-Alder ~ y c l i z a t i o n 3-Methoxyfuran .~~~ undergoes a similar intermolecular cycloaddition with octylvinylketone to give the endo-bicyclic alcohol (116) after stereoselective reduction. Further transformations lead to the butyrolactone (117) and the bislactone (118) (Scheme 69); the latter compound is used as an intermediate in the synthesis of (k)avenacolide.226

(117) Reagents: i, 0,-MeOH; ii, Jones oxidation; iii, K2C0,-H20-MeOH; iv, Pb(OAc),

Scheme 69

A synthesis of the first lignan to be found in humans and animals has been reported by Kirk and his c o - ~ o r k e r s . ~The ~ ’ final stages of the route involve 222

223

224

22s 226 227

J. D. White and B. G . Sheldon, J. Org. Chem., 1981, 46, 2273. T. Karnetani, T. Honda, H . Matsurnoto, and K . Fukurnoto, J. Churn. Soc., Perkin Trans. 1. lY81, 1383. H. Kotsuki, A. Kawamura, M. Ochi, and T. Tokoroyama, Chem. Lett., 1981,917. T. Imagawa, T. Nakagawa, K. Matsuura, T. Akiyama, and M. Kawanisis, Chem. Lett., 1981,903. A. Murai, K. Takahashi, H. Taketsuru, and T.Masarnune, J. Chem. Soc., Chem. Commun., 1981, 221. G . Cooley, R. D. Farrant, D. N. Kirk, and S. Wynn, Tetrahedron Lett., 1981, 22, 349.

132

General and Synthetic Methods

reduction of the anhydride (119), followed by removal of the acetate groups to give the racemic lactone (120) (Scheme 70).

Reagents: i, NaBH,-DMF; ii, NaHC03-MeOH-H20 Scheme 70

The reaction of enolates derived from lactones (121) with aromatic aldehydes has been used effectively in the synthesis of lignan lactones, e.g. (122)228and related compounds.229 U

An alternative approach to structures similar to (122) involves initial construction of the saturated ring followed by a lactonization sequence.23oMeyers and Avila have described the conversion of naphthyloxazolines into lignan lactone derivatives with the same basic structure as (122).231Bislactone lignans are obtained by the instantaneous oxidative dimerlzation of p-alkoxycinnamic acids with thallium(II1)trifluoroacetate or cobalt(iI1) trifl~oride.'~'Although the yields are only between 12 and 54%, the method provides a convenient entry into these complicated The synthesis of several terpenoid natural lactones has been described. Butyrolactones are formed efficiently by the cyclization of hydro~y-acids,'~~ and acid olefin c y ~ l i z a t i o n The . ~ ~ ~diester (123) has been converted independently into the isomeric lactones cinnamolide ( 124),235and drimenin (125) (Scheme 71).236Selective reduction of the a$-unsaturated ester was used in the latter case, whereas selective oxidation of the corresponding allylic alcohol with manganese dioxide was used in the former. Manganese dioxide has also been 228 229 230 231 232

233

P. A . Ganeshpure and R. Stevenson, J. Chem. SOC., Perkin Trans. 1, 1981,1681. P.A . Ganeshpure, G. E. Schneiders, and R. Stevenson, Tetrahedron Lett., 1981,22,393. A. S. Kende, M. L. King, and D. P. Curran, J. Org. Chem., 1981,46,2826. A. I. Meyers and W. B. Avila, J. Org. Chem., 1981,46,3881. E.C. Taylor, J. G. Andrade, G. J. H. Rail, K. Steliou, G. E. Jagdmann, and A . McKillop, J. Org. Chem., 1981,46,3078. T. Tokoroyama, Y. Fukuyama, T. Kubota, and K. Yokatani, J. Chem. SOC.,Perkin Trans. 1, 1981?

1557. 234 235

A . Saito, H. Matsushita, Y. Tsujino, and H. Kaneko, Chem. Lett., 1981,757. S. C. Howell, S. V. Ley, M. Mahon, and P. A . Worthington, J. Chem. SOC.,Chem. Commun.,

1981,507. 236

M. Jallali-Naini, G . Boussac, P. Lemaitre, M. Larcheveque, D . Guillern, and J.-Y. Lallemand, Tetrahedron Lett., 1981,22, 2995.

Carboxylic Acids and Derivatives

133

@C02MeC 0 2 M e

T (123)

(125) Reagents: i, LiAlH,; ii, Ag,CO, celite or BaMnO,; iii, (i-C4H,),A1H, -78 'C; iv, p-TSA.

Scheme 71

used to bring about the cyclization of an allylic alkyl diol to a butyrolactone in the synthesis of the marine diterpene isogathola~tone.~~~ Buteno1ides.-Interest continues in the carbonylation reaction catalysed by transition metals as a route to butenolides. The catalyst Rhs(CO)12 is used in the carbonylation of acetylenes in the presence of olefins; yields of 5 alkyl-2(5H)-furanones are good, but mixtures of products are obtained in unsymmetrical cases.238The reaction between trichloroacetic acid and olefins is mediated by R u C ~ ~ ( P Pand ~ ~gives ) ~ ,initially 2,2-dichloro-4-alkylbutanolides which undergo dehydrochlorination to 4-alkylideneb~t-2-enolides.~~~ These compounds are also obtained by the cyclization of acetylenic acids (126) + (127).240A general synthesis of disubstituted butenolides (128) has been published, which is simple and effective (Scheme 72).241 R R

PhS

xz

i,ii

R2

phsc R'

,

CO,H

iii,iv

R'

,P

R2

R2

-.,ao R'

~

v.vi

s

~

(128) Reagents: i. LDA; ii, ICH,CO,-Li+; iii, NaBH,; iv, HCl-H,O; v, NaIO,; vi, A

Scheme 72

,'' P. M. Imamura, M. G. Sierra, and E. A. Ruveda, J. Chem. SOC.,Chem. Commun., 1981,734. 238, 239 240

241

P. Hong, T. Mise, and H. Yamazaki, Chem. Lett., 1981,989. T. Nakano and Y. Nagai, J. Chem. SOC.,Chem. Commun., 1981,815. M. Yamamoto, J. Chem. SOC.,Perkin Trans. 1, 1981, 582. P. Brownbridge, E. Egert, P. G. Hunt, 0. Kennard, and S. Warren, J. Chem. SOC.,Perkin Trans. 1, 1981,2751.

134

General and Synthetic Methods

Stereoselective condensation of an a-silyl ester anion with an a-keto- acetal leads to a mixture of E and 2-olefins, which is converted into a A’-butenolide on hydrolysis and reduction (Scheme 73).’” Clearly only the 2-olefin will cyclize to the butenolide, and the high yields obtained reflect the high selectivity of the addition-elimination sequence. R ’ A O M e

__* i,ii

R 1 q z OMe R z

OMe Reagents: i, Me3%

iii, iv

,

OMe

C02R2;ii, -Me,SiO-; iii, H,SO,-H,O-SiO,;

v+

iv, NaBH,

Scheme 73

Li

Several aspects of furan chemistry are useful for the preparation of butenolides. Furfural is readily converted to the hydroxy butenolide (129), which reacts with two equivalents of an alkyl-lithium reagent to give the 4-substituted butenolide (130) (Scheme 74).243 iii, ii

HO (129) Reagents: i, O,, hv; ii, HCI-H,O; iii, RLi

Scheme 74

Butenolides of general structure (130) are also obtained by the reaction of 2-aceto~yfuran’~~ and 2-trimethylsilyloxyf~ran~~~ with carbon electrophiles. Yields are good for a range of examples, and in the latter case reaction with an aldehyde leads to an alkylidene butenolide after dehydration. Kuwajima and Urabe report the reaction of a series of 2-trimethylsilyl furans (131) with peracetic acid to give A3-butenolides (132) in yields between 30 and 84°/0.246

OR CH3C03H,

Me,Si

(131)

flR

0

0

(132)

The Diels-Alder adduct of furan and maleic anhydride reacts with Grignard reagents to form lactones, which are converted to butenolides in a thermal cycloreversion rea~tion.’~’ Work continues on the synthesis of 4ylidenebutenolides using the Wittig reaction on substituted maleic anhydrides; the products have been converted into ~yclopentene-l,3-diones.~~~ 242 243

244 24s 246 247 248

M. Larcheveque, C. Legueut, A. Debal, and J. Y. Lallemand, Tetrahedron Lett., 1981, 22, 1595. F. W. Machado-Araujo and J. Gore, Tetrahedron Lett., 1981, 22, 1969. T. Shono, Y. Matsumura, and S . Yamane, Tetrahedron Lett., 1981, 22, 3269. M. Asaoka, N. Yanagida, K. Ishibashi, and H. Takei, Tetrahedron Lett., 1981, 22, 4269. I. Kuwajima and H. Urabe, Tetrahedron Lett., 1981, 22, 5191. P. Canonne, M. Akssira, and G. Lemay, Tetrahedron Lett., 1981, 22, 2611. N. G. Clemo, D. R. Gedge, and G. Pattenden, J. Chem. SOC.,Perkin Trans. 1, 1981, 1448; P. J. Babidge and R. A. Massey-Westropp, Aust. J. Chem., 1981, 34, 1745; R. A. Massey-Westropp and M. F. Price, ibid., p. 2369.

135

Carboxylic Acids and Derivatives

Several butenolide natural products of terpenoid origin have been synthesized from furan precursors.249On the other hand furan natural products are synthesized from butenolide precursors, e.g. ancistrofuran (133) (Scheme 75).250The synthesis of two members of the drimane class of sesquiterpenes containing a butenolide ring have been reported. The first synthesis provides a route to racemic c i n n a m ~ d i a land , ~ ~the ~ second describes the synthesis of optically active confertifolin (134) from the natural product manool. A rather doubtful mechanism is proposed’for the most important reaction in this sequence (Scheme 76).”*

(133)

Reagents: i, DIBAL; ii, H2S04

Scheme 75

Scheme 76

(134)

Pennanen has disclosed a further use of the a-epoxyketone-ynamine route to 2-furanones, this time in the synthesis of (+)-erem~philenolide.~~~ Other reports in the natural product area have included the photochemical synthesis ~ ~ ~the of an optically active isomer of the germacranolide i s o a r i t o l a ~ t o n e ,and ~ ~ ’ readily available D -ribonolacconstruction of the cardenolide ~ i d e - c h a i n . The tone derivatives (135) have been converted into cyclic orthoformates, which on heating for several hours lead to the optically active butenolides (136) (Scheme 77).256Yields are good for three examples; other methods for the conversion

HC(OEt),

H’

,

OH

H’

. ‘OH

(135)

H’ O Y O OEt Scheme 77

S. V. Ley and M. Mahon, Tetrahedron Lett., 1981,22,4747. T. R. Hoye and A. J. Caruso, J. Org. Chem., 1981, 46, 1198; F. Kido, Y. Noda, T. Maruyarna, C. Kabuto, and A. Yoshikoshi, ibid., p. 4264. *’’ L. P. J. Burton and J. D. White, J. Am. Chem. SOC.,1981, 103, 3226. T. Nakano and M. A. Maillo, Synth. Commun., 1981, 11,463. S. I. Pennanen, Acta Chem. Scand., Ser. B, 1981,35,555. 254 G. L. Lange, S. So, M. Lautens, and K. Lohr, Tetrahedron Lett., 1981, 22, 311. A. Kurek, M. Gumulka, and J. Wicha, J. Chem. SOC.,Chem. Commun., 1981, 25. 256 P. Camps, J. Font, and 0. Ponsati, Tetrahedron Lett., 1981, 22, 1471. 249

”’

’” ’”

136

General and Synthetic Methods

of 1,2-diols into olefins give unsatisfactory results. An effective trans-addition of a dithiane carbanion followed by trapping with benzyl bromide on butenolide itself demonstrates the synthetic utility of these compounds in the preparation of substituted butyrola~tones.~’~

Phtha1ides.-Anthracyclinone natural products continue to provide a stimulating arena for the application of phthalide chemistry in synthesis. Earlier model studies2’* on the reaction of the dilithiated species (137) with aldehydes to give phthalides have been applied to the total synthesis of two anthracyclinone natural products (Scheme 78).’j9

@

) \

ph+oHc-$y+

OCH,

OCH,

(137)

/

OCH, H Scheme 78

Preformed phthalides provide anions such as (138), which undergo a Michael addition with quinonemonoacetals to give eventually a 1,4-dioxygenated anthraquinone (139) after acid treatment (Scheme 79).260Phthalides without the benzenesulphonyl group react in a similar fashion with conjugated olefins to give hydroxytetralones and naphthols.261 By contrast the bromophthalide (140) acts as an electrophile in another anthracyclinone synthesis.262Finally, the intriguing photochemical conversion of the aldehyde (141) into the methoxyphthalide (142) during further synthetic studies in the anthracyclinone area has been

0

+Q*

Me0 Me

ii, HCI

Me Me0

OMe

0

oC0” (139)

Scheme 79

0

OMe

hu

\

Me6

Br

(140)

OH

bMe (141)

CHO

,@ \

OMe (142)

‘”A. Pelter, P. Satyanarayana, and R. S. Ward, Tetrahedron Lett., 1981, 22, 1549. 259

260

261 262

J. E. Baldwin and K. W. Bair, Tetrahedron Lett., 1978, 2559. A. S. Kende and J. P. Rizzi, Tetrahedron Lett., 1981, 22, 1779; A. S. Kende and S. D. Boettger, J. Org. Chem., 1981,46,2799. R. A. Russell and R. N. Warrener, J. Chem. SOC.,Chem. Commun., 1981, 108. N. J. P. Broom and P. G. Sammes, I. Chem.SOC.,Perkin Trans. 1, 1981,465. S. D. Kimball, D. R. Walt, and F. Johnson, J. A m . Chem. SOC.,1981,103, 1561. M. E. Jung and R. B. Blum. J. Chem. SOC.,Chem. Commun., 1981,962.

137

Carboxylic Acids and Derivatives

Tetronic Acids.-The removal of the bromine atom from (143) by catalytic hydrogenation provides a convenient synthesis of tetronic acid (144).264Gelin and Chantegrel have reported the first synthesis of 3-formyltetronic acid (145) from (144) and its conversion into several These studies are motivated by the potent anti-inflammatory activity of 3-dimethylaminomethylenetetronic acid.

a-Methylenebutyro1actones.-A full paper describing the thorough studies of Adlington and Barrett on the use of the Shapiro reaction in the synthesis of a-methylenelactones has appeared.266The strategy used involves the synthesis of an appropriately substituted a-acrylic acid derivative, which is cyclized to give the lactone. Several other methods are based on this approach, e.g. the generation of a y-acetoxy-ester by a sulphoxide rearrangement of (146) followed by treatment with acid leads to substituted lactones (147) in good yield (Scheme 80).267The acid (148) is readily prepared from tartaric acid and cyclizes to the lactone (149) under acidic conditions.26s An effective route to a-methylenebutyrolactones has been developed using the iron complex (150) as an a-acrylic ester cation

(146)

(147)

Reagents: i, PhSNa; ii, R2R3C(OAc)CHO;iii, MCPBA; iv, A; v, P(OMe),; vi, CH,C6H4S0,H

Scheme 80

R', ,R2

R' 40Et

(148)

(149)

(150

The p-amino-ester (151) has been used as an acrylate anion equivalent which is alkylated and after elimination gives an unsaturated ester (152); subsequent D. G. Schmidt and H. Zimmer, Synrh. Commun., 1981, 11,385. S. Gelin and B. Chantegrel, J. Heterocycl. Chern., 1981, 18, 663; S. Gelin, ibid., p. 535; S . Gelin and P. Pollet, ibid., p. 719. 266 R. M. Adlington and A. G. M. Barrett, J. Chern. Sac., Perkin Trans. 1 , 1981,2848. "'J.-P. Corbet and C. Benezra, J. Org. Chem., 1981,46, 1141. "* A, Tanaka and K. Yamashia, Chem. Lert., 1981, 319. 269 T. C. T. Chang and M. Rosenblum, J. Org Chern., 1981,46,4626. 264 265

138

General and Synthetic Methods

iodolactonization leads to a-methylenelactones (Scheme 8 1).270The lactone (153) is prepared from an allenic dianion obtained by application of the Shapiro cyclization is used in the reaction to m e t h y l i ~ o n i t r i l eA. ~mercury(r1)-mediated ~~ synthesis of naturally occurring Lauraceae lactones (154).272The diester (155) is prepared by the ene reaction of dimethyl acetylenedicarboxylate and the appropriate olefin; it readily forms a butyrolactone on treatment with

Hvo.i\r R

; iii, MeI; iv, DBN

Scheme 81

MeO, d 0

B

u

C02Me C0,Me

I

Transition-metal-promoted carbonylation reactions continue to provide interesting new routes to a-methylene lactones. The ‘trans’-vinyl bromide (156) reacts with Ni(C0)4 to give the cis-fused lactone (157)274in 95% yield. By contrast, the reaction of the ‘trans’-acetylenic alcohol (158) with carbon monoxide and PdC1, leads to the trans-fused lactone corresponding to ( 157).275 The ether (159) has been oxidized with Cr03-pyridine to the corresponding lactone, which was obtained as a mixture of isomers in modest yield.276

(159)

A total synthesis of racemic eriolanin is reported in which a-methylenation of a butyrolactone is carried out in the final The use of the ubiquitous Brederick’s reagent [Bu‘OCH(NMe,),] for this same purpose appears in a synthesis of racemic a r ~ m a t i n . ~Another ’~ interesting point about the route is 270

271 272

273 274

’”

’” 277 278

L.-C.Yu and P. Helquist, J. Org. Chem., 1981, 46, 4536; Synrh. Commun., 1981, 11, 591. R. M. Adlington and A. G. M. Barrett, J. Chem. SOC.,Chem. Commun., 1981,65. S. W. Rollinson, R. A. Amos, and J. A. Katzenellenbogen, J. Am. Chem. SOC.,1981, 103, 4114. A. W. Hanson, A. W. McCulloch, and A. G. McInnes, Can. J. Chem., 1981, 59, 288. M. F. Semmelhack and S. J. Brickner, J. Org. Chem., 1981, 46, 1723; J. Am. Chem. SOC.,1981, 103,3945. T. F. Murray, E. G. Samsel, V. Varma, and J. R. Norton, J. Am. Chem. Sor., 1981, 103,7520. T. J. Brocksom and J. T. B. Ferreira, Synrh. Commun., 1981, 11, 105. M. R. Roberts and R. H. Schlessinger, J. A m . Chem. SOC.,1981,103,724. F. E. Ziegler and J.-M. Fang, J. Org. Chem., 1981, 46, 825.

139

Carboxylic Acids and Derivatives

its use of the amide-acetal Claisen rearrangement to prepare a y,&unsaturated amide, which readily undergoes iodolactonization.

Valero1actones.-D-Mevalonolactone has been prepared in high enantiomeric excess using a rather long sequence starting from (+)-~ulegone.~’~ Catalyic asymmetric hydrogenation of cyclic anhydrides using a ruthenium(I1) chiral phosphine complex leads to 3-substituted hexanoic acid S-lactones directly; however the highest enantiomeric excess obtained is 20% .’” High optical yields are obtained in the microbiological hydrolysis of dimethyl 2,4-dimethylglutarate acid (160), which leads to the 2R,4S-lactone (161) on reduction; the enantiomer of (161) is also obtained using a different micro-organism.28’The 2R,SR-lactone (162) has been prepared from a sugar precursor.282 H

H

The use of iodolactonization in the synthesis of 6-lactones is demonstrated in routes to a prostaglandin endoperoxide analogue,2s3 and to the antibiotic m a l y n g ~ l i d e The . ~ ~ ~latter compound (164) has also been prepared as a mixture of C-2 epimers by lactonization of the epoxide (163).”’ Stereoselective sulphenyl-lactonization plays an important role in a synthesis of octahydroleukotrienes,284and cyclization of the cyclopropyl acid (165) leads to the lactone (166).287A spirocyclic dilactone has been prepared and undergoes

(165) 279 ”O

”’ 282

283

284

286

287

(166)

E. L. Eliel and K. Soai, Tetrahedron Lett., 1981, 22, 2859. K. Osakada, M. Obana, T. Ikariya, M. Saburi, and S. Yoshikawa, Tetrahedron Lett., 1981,22,4297. C.-S.Chen, Y. Fujimoto, and C. J, Sih, J. Am. Chem. SOC.,1981, 103, 3580. S. Hanessian, G. Demailly, Y. Chapleur, and S. Leger, J. Chem. SOC., Chem. Commun., 1981, 1125. S. P. Briggs, D. I. Davies, R. F. Newton, and D. P. Reynolds, J. Chem. SOC., Perkin Trans. I , 1981,146 and 150. G. Cardillo, M. Orena, G . Porzi, and S. Sandri, J. Org. Chem., 1981,46, 2439. S. Torii, T. Inokuchi, and K. Yoritaka, J. Org. Chern., 1981,46,5030. R. N. Young, W. Coombs, Y. Guindon, J. Rokach, D. Ethier, and R. Hall, Tetrahedron Lett., 1981,22,4933. R. L. Danheiser, J. M. Morin, M. Yu, and A. Basak, Tetrahedron Lett., 1981, 22,4205.

140

General and Synthetic Methods

stereoselective a-methylation to give an effective route to a macrolide fragment.288 Several synthesis of the Prelog-D jerassi l a ~ t o n eelevate ~ ~ ~ the compound almost to the position of cis-jasmone in terms of its popularity as a synthetic target. Full details of the Danishefsky route to (&)-quadrone have appearedz9' as well as a report of a concurrent A new method for the preparation of &lactones involving the reaction of a y,&unsaturated aldehyde with NaOH followed by oxidationzg2has been applied to the synthesis of (&)-pentalenol a ~ t o n eThe . ~ ~first ~ total synthesis of (+)-compactin has been 4 Macrolides w -Bromo-acids are converted into macrolides under basic conditions by heatingz95or by the use of microemulsions,z96and o-hydroxy-acids can be cyclized in good yield using l-phenyl-2-tetrazoline-5-thione.z97 Oxazoles may be used as masked activated carboxylic acids owing to their formation of triamides by reaction with singlet oxygen. Subsequent cyclization of the triamide, by heating under mild acidic conditions, leads to macrolides in good yield by a type of double activation reaction (Scheme 82).298Yields are good for simple lactones and the method has been applied to several natural products.

Ph

P h x R p h

+ Ph c s ( C H 2 ) 1 2 0 H

O2

1

0'

(CH2),,0H

Scheme 82

An SN2displacement of a caesium carboxylate on a remote mesylate group is used in an effective synthesis of R - ~ e a r a l e n o n eThis . ~ ~ ~compound has also been prepared by carbon-carbon bond formation using the displacement of a tosylate group by a protected cyanohydrin ~arbanion.~"The intramolecular coupling of a terminal vinyl iodide with an enone catalysed by PdC12(CH3CN)z has been used as a route to an unsaturated 16-membered m a c r ~ l i d e . ~ ~ ' 288 289

290 291

292

293 294 295

'% 297

298

299

300

301

T. R. Hoye, D. R. Peck, and P. K. Trumper, J. Am. Chem. SOC.,1981,103,5618. R. E. Ireland and J. P. Daub, J. Org. Chem., 1981,46, 479;M.Isobe, Y.Ichikawa, and T. Goto, Tetrahedron Lett., 1981,22,4287; D. J. Morgans, ibid., p. 3721;W. C. Still and K. R. Shaw, ibid., p. 3725. S. Danishefsky, K. Vaughan, R. Gadwood, and K. Tsuzuki, J. A m . Chem. SOC.,1981,103,4136. W. K. Bornack, S. S. Bhagwat, J. Ponton, and P. Helquist, J. A m . Chem. SOC., 1981, 103,4647. L. A. Paquette, G. D. Annis, H. Schostarez, and J. F. Blount, J. Org. Chem., 1981,46,3768. L.A. Paquette, H. Schostarez, and G. D. Annis, J. A m . Chem. SOC.,1981,103,6526. N.Y.Wang, C. T. Hsu, and C. J. Sih, J. Am. Chem. SOC.,1981,103,6538. T. Sato, T. Kawara, Y. Kokuba, andT. Fujisawa, Bull. Chem. SOC.Jpn., 1981,54,945. A. Gonzalez and S. L. Holt, J. Org. Chem., 1981,46,2594. U.Schmidt and M. Dietsche, Angew. Chem., In?. Ed. Engl., 1981,20,771. H. H.Wasserman, R. J. Gambale, and M. J. Pulwer, Tetrahedron Lett., 1981, 22, 1737;H. H. Wasserman and R.J. Gambale, ibid., p. 4849;H. H. Wasserman, R. J. Gambale, and M. J. Pulwer, Tetrahedron, 1981,37,4059. W. H. Kruizinga and R. M. Kellogg, J. Am. Chem. SOC.,1981,103,5183. T. Takahashi, H. Ikeda, and J. Tsuji, Tetrahedron Letr., 1981,22,1363;T. Takahashi, I. Minami, and J. Tsuji, ibid., 22,p. 2651. F. E. Ziegler, U. R. Chakraborty, and R. B. Weisenfeld, Tetrahedron, 1981,37,4035.

Carboxylic Acids and Derivatives

141

Ring cleavage of the enol ether (167) has been achieved by hydrolytic nitrosation to give the oxime (168),which is easily converted into the corresponding ketone."* Another rearrangement route to macrolides occurs in the reaction of the hydroxyketone (169) with base (Scheme 83);303the macrolides (170) are obtained after removal of the benzenesulphonyl group. A related fragmentation of disubstituted cyclohexane- 1,3-diones leads to macrolides but mixtures of products are sometimes

Scheme 83

The cyclization of pyridine thioesters is used in the final stages of the Woodward synthesis of erythr~mycin,~"and in a partial synthesis of a compound related to ~ e r r u c a r i n . ~Tertiary '~ butylthioester intermediates are cyclized using copper(1) trifluoromethanesulphonate in the total synthesis of 6-deoxyerythronolide B,307and also in a route to a macrocyclic pyrrolizidine alkaloid.308The Mitsunobu procedure for the cyclization of hydroxytrimethylsilyl ethyl esters using diethyl azodicarboxylate and triphenylphosphine provides the final stage of an impressive total synthesis of verrucarin A.309Neomethyolide and (k) brefeldin A have been synthesized by the mixed-anhydride method using trinitrobenzoyl chloride3" and trichlorobenzoyl ~ h l o r i d e , ~respectively. " 302

303 '04 30J

'06 307

310 311

J. R. Hahajan and H. C. de Araujo, Synthesis, 1981,49. V. Bhat and R.C. Cookson, J. Chem. SOC.,Chem. Commun., 1981, 1123. P. W. Scott, I. T. Harrison, and S. Bittner, J. Org. Chem., 1981,46, 1914. R.B. Woodward, E. Logusch, K. P. Nambiar, K. Sakan, D. E. Ward, B. W. Au-Yeung, P. Balaram, L. J. Browne. P. J. Card, C. H. Chen, R. B. Chenevert, A. Fliri, K. Frobel, H.-J. Gais, D. G. Garratt, K. Hayakawa, W. Heggie, D. P. Hesson, D. Hoppe, J. A. Hyatt, D. Ikeda, P. A. Jacobi, K. S. Kim, Y. Yobuke, K. Kojima, K. Krowicki, V. J. Lee, T. Leutert, S. Malchenko, J. Martens, R. S. Matthews, B. S. Ong, J. B. Press, T. V. R. Babu, G. Roseau, H. M. Sauter, M. Suzuki, K. Tatsuta, L. M. Tolbert, E. A. Truesdale, I. Uchida, Y. Ueda, T. Uyehara, A. T. Vasella, W. C. Vladuchick, P. A. Wade, R. M. Williams, and H, N.-C. Wong, J. Am, Chem. Soc., 1981. 103, 3210,3213, and 3215. E. Notegen, M. Tori, and C. Tamm, Hefu. Chim. Acra, 1981,64,316. S. Masamune, M. Hirama, S. Mori, S. A. Ali, and D. S. Garvey, J. A m . Chem. SOC.,1981, 103, 1568. J. Huang and J. Meinwald, J. Am. Chem. Soc., 1981,103,861. W. C. Still and H. Ohmizu, J. Org. Chem., 1981,46, 5242. J. Inanaga, Y. Kawanami, and M.Yamaguchi, Chem. Lett., 1981,1415. M. Honda, K. Hirata, H. Sueoka, T. Katsuki, and M. Yamaguchi, Tetrahedron Lett., 1981,22,2679.

142

General and Synthetic Methods

The intramolecular cyclization of a stabilized phosphonate carbanion onto an aldehyde has proved to be an effective method for the synthesis of brefeldin A,312 polyene m a c r o l i d e ~ ,and ~ ~ ~in a formal synthesis of carbomycin B.314 R,R- Pyrenophorin has been synthesized using a pent-3-enoic acid d5 reagent;31’ two other routes to the racemic compound have also appeared.316 Macrocyclic polyether macrolides have been prepared by cy~lization,~~’ and by ozonolysis of a furan crown-ether 5 Carboxylic Acid Amides

Synthesis.-Carboxylic acids are converted into amides by reaction with an amine in the presence of 2,2’-dibenzothiazolyl disulphide and triphenylphos~ h i n e . ~S’ ~and N-Acyl derivatives of 2-mercaptobenzoxazole are highly effective acylating agents for amines; amides are obtained in high yield, and the method is also applied to the synthesis of Benzyl(triethy1)ammonium permanganate reacts with tertiary amines in a homogeneous oxidation, to give NJV-dialkylarnides in high yield.321Less satisfactory results are obtained with primary and secondary amines. Trichloroacetonitrile, and other activated cyanides, react with triphenylarsine oxide to give iminotriphenylarsoranes which are readily hydrolysed to the corresponding amide.322Conjugated dienamides are smoothly prepared using the ynamine-Claisen rearrangement with an arylthioynamine (17l ) , followed by oxidation and elimination (Scheme 84).’” Yields are good and the selectivity for the formation of the E,E-isomer of (172) is greater than 95% in some cases. Another use of ynamines in this area involves the reaction of 1-(diethylamino)propyne with aromatic dithioesters to give a,P-unsaturated thioamides by analogy with the corresponding reaction of ketones and t h i o k e t o n e ~ . ~ ~ ~ ArS- f-NR2

Reagents: i, BF,OEt, or A; ii, NaI0,-MeOH; iii, A, toluene

Scheme 84 312

313 314

315

316 317

319

320

321 322 323 324

P. Raddatz and E. Winterfeldt, Angew. Chem., Int. Ed. Engl., 1981,20,286. D.M. Floyd and A. W. Fritz, Tetrahedron Lett., 1981,22,2847. K. C.Nicolaou, M. R. Pavia, and S. P. Seitz, J. A m . Chem. SOC.,1981,103,1224. R. S.Mali, M. Pohmakotr, B. Weidmann, and D. Seebach, Liebigs. Ann. Chem., 1981,2272. M. Asaoka, T. Mukuta, and H. Takei, Tetrahedron Lett., 1981,22, 735;T.A. Hase, A. Ourila, and C. Holmberg, J. Org. Chem., 1981,46,3137. B. Thulin and F. Vogtle, J. Chem. Res., (S),1981,256. B. L. Feringa, Tetrahedron Lett., 1981,22,1443. K. Ito, T. Ida, T. Fujita, and S. Tsuji, Synthesis, 1981,287. M. Ueda, K. Seki, and Y. Imai, Synthesis, 1981,991. H.-J. Schmidt and H. J. Schafer, Angew. Chem., Inr. Ed. Engl., 1981,20, 109. C.Gadreau, A. Foucaud, and P. MCrot, Synthesis, 1981,73. T. Nakai, H. Setoi, and Y. Kageyama, Tetrahedron Lett., 1981,22,4097. V. H.M. Elferink, R. G. Visser, and H. J. T. Bos, R e d . Trau. Chim. Pays-Bas, 1981,100,414.

143

Carboxylic Acids and Derivatives

Macrocyclic Lactams.-Two spermidine alkaloids have been prepared by the reaction of spermidine itself with a thiazolidine 2-thione diamide derivative under high-dilution conditions; the two regioisomers produced were separated by chr~matography.~’~ An interesting boron-template cyclization of the aminoester (173) to the lactam (174) has been used to prepare several members of the celacinnine group of natural products (Scheme 85).326

H

H

Ring-expansion reactions are also important in this area as demonstrated by the reaction of the barbiturate derivative (175)with KF to give the lactam ( 176),327 and by the synthesis of (*)-dihydroperiphylline by successive ring

(175)

(176)

expansions of smaller heterocyclic units (Scheme 86).”’ Studies directed towards the synthesis of m a y t a n s i n o i d ~and ~~~ r i f a m y ~ i n s ~have ~ ’ continued.

Reagents: i, Me,bBF,; ii,

Ph

Scheme 86

Reactions.-Allylic amides have been prepared in good yield by the selenoxide fragmentation of P-amid~alkylphenylselenides~~~ and phase-transfer conditions for the N-alkylation of carboxamides and sulphonamides have been r e p ~ r t e d . ~ ~ ’

331

Y. Nago, S. Takao, T. Miyasaka, and E. Fujita, J. Chem. SOC.,Chem. Commun., 1981, 286. H. Yamamoto and K. Maruoka, J. A m . Chem. Soc., 1981,103,6133. C. Jenny and M. Hesse, Helu. Chim. Actu, 1981,64, 1807. H. H. Wasserman and H. Matsuyama, J. A m . Chem. SOC.,1981,103,461. A. I. Meyers and J. P. Hudspeth, Tetrahedron Lett., 1981, 22, 3925; M. Isobe, Y. Ichikawa, M. Kitamura, and M. Goto, Chem. Lett., 1981,457. H . Nagaoka, G . Schmid, H. Iio, and Y. Kishi, Tetrahedron Lett. 1981, 22, 899; H. Nagaoka and Y. Kishi, Tetrahedron, 1981, 37, 3873. A. Toshimitsu, H. Owada, T. Aoai, S. Vemura, and M. Okano, J. Chem. SOC.,Chem. Commun.,

332

T. Gajda and A. Zwierzak, Synthesis, 1981, 1005.

325

326 327

328 329

330

1981,546.

144

General and Synthetic Methods

A re-investigation of the reaction between diketen and amides has shown that N-acetoacetylcarboxamides are formed most efficiently in the presence of trimethylsilyli~dide.~~~ Olefins react with primary amides in the presence of mercury(I1) nitrate to give N-substituted amides after NaBH4 reduction.334The method provides a convenient procedure for the Markovnikov amidation of double bonds; yields vary from 17 to 99% over 11examples. Direct C-alkylation of secondary thioamides is achleved by the reaction of the dianion (177) with an activated halide to give (178).335Esters of malonic, cyanoacetic, and P-keto acids are readily C-amidoethylated by N-acylaziridines in the presence of trieth~lamine.~~~[

y

p

h

(177)

S (178)

Amino-alkyl amides form amidines reversibly on heating337and under acidic In the latter case amidines are proposed as intermediates in transamidation reactions. A full paper on a modified Shapiro reaction of hydrazones derived from secondary a-keto-amides has appeared.339Ultra sound is reported to produce improvements in the heterogeneous reaction between amides and P4s10.340

6 Amino-acids

Synthesis.+- and o-Amino-acids, as well as a,@-diamino-acids, are readily prepared from the corresponding bromo-esters by reaction with potassium cyanate followed by acid hydrolysi~.~"~ Phenyl isocyanide reacts with amethoxyurethanes in the presence of TiC14 to give a-amino-acids after acid hydrolysis; yields are good in general for ten examples.342A synthesis of the four stereoisomers of y-hydroxyarginine (179) uiu the corresponding isomers of y-hydroxyornithine has been Readily available 5 -chlorohydantoin (180) condenses with malonic ester to give (k)-P-carboxyaspartic acid (lSl).'"" 3-Amino-5-hydroxybenzoic acid plays a key role in the biosynthesis of maytansinoid and ansamycin antibiotics and a synthesis of the unlabelled and carboxyl-labelled amino-acid has appea~ed.~"' Slopianka and Gossauer have reported a synthesis of P-amino-acids, which involves regioselective olefination 333

334 335

336 337 338

339 340

341

342

343 344

345

Y. Yamamoto, S.Ohnishi, and Y. Azurna, Synthesis, 1981, 122. J. Barluenga, C. JirnCnez, C. Niijera, and M. Yus,J. Chem. Sac., Chem. Commun., 1981,670. Y.Tamura, M. Kagotani, Y. Furukawa, Y. Amino, and Z. Yoshida, Tetrahedron Lett., 1981, 22, 3413. H. Stamm and V. Gailius, Chem. Ber., 1981,114, 3599. R. N. Butler, J. D. Thornton, and P. Moynihan, J. Chem. Res. ( S ) , 1981,84. C. Heidelberger, A. Guggisberg, E. Stephanou, and M. Hesse, Helu. Chim. Actu, 1981, 64, 399. R. M. Adlington and A. G. M. Barrett, Tetrahedron, 1981, 37, 3935. S. Raucher and P. Klein, J. Org. Chem., 1981,46, 3558. F. Effenberger, K. Drauz, S.Forster, and W. Muller, Chem. Ber., 1981, 114, 173. T. Shono, Y. Matsumura, and K. Tsubata, Tetrahedron Lett., 1981, 22, 2411. K. Mizusaki and S. Makisurni, Bull. Chem. SOC.Jpn., 1981,54,470. E. B. Henson, P. M. Gallop, and P. V. Hauschka, Tetrahedron, 1981, 37, 2561. A. J. Herlt, J. J. Kibby, and R. W. Rickards, Ausr. J. Chem.. 1981, 34, 1319.

CarboxylicAcids and Derivatives NH

145

“Mo

OH

A N Y N ” H,N N Y N \ ~

H02C

NH (179)

i, CH,(CO,Et),

,

NH2 H 0 2 C ~ c 0 2 H

ii, KOH

CO, H

0 (180)

(181)

of N-acetylthioamides (182) (Scheme 87);346 the process has also been applied to N-thioacylurethanes.347 R

Reagents: i, Ph,P=CHCO,Me,;

ii, H2-Pt; iii, HCl-AcOH; iv, EtOH-S0,CI Scheme 87

Several synthetic methods have appeared in which derivatives of amino-acids have been reacted with strong base and then with carbon electrophiles. This process has been used in the a-hydroxymethylation of Schiff bases derived from a-amino-acid esters and good yields of P-hydroxy-a-amino-acids are This type of compound is also prepared using the optically active imine (183); the threo-product was obtained with selectivity ranging from 58 to 92% and optical purity between 43 and 71% (Scheme 88).349The P-hydroxy-aamino-acid (185) is a constituent of the antibiotic bleomycin and its preparation from L-rhamnose has been described.350Studies on the asymmetric synthesis of amino-acids by alkylation of various lactim ethers (186) have continued. LAlanine,35’~ - v a l i n e , ~and ” (S)-O,O-dimethyl-cr-rnethyld~pa~~~ have been used to prepare the heterocyclic intermediates (186), which give a range of aminoacids in high yield and enantiomeric excess. Earlier work has also been extended to the alkylation of the imidazolone anion (187).354 H

Reagents: i, MeMgI; ii, KDA; iii, RCHO; iv, CISiMe,; v, MeC0,H-H,O;

vi, BOC-s-reagent

Scheme 88 346 347

348 34q

350

352

353 354

M. Slopianka and A, Gossauer, Liebigs Ann. Chem., 1981, 2258. M. Slopianka and A. Gossauer, Synth. Commun., 1981, 11, 95. A. Calcagni, D. Rossi, and G. Lucente, Synthesis, 1981, 445. T. Nakatsuka, T. Miwa, and T. Mukaiyama, Chem. Lett., 1981,279. T. Ohgi, and S. M. Hecht, J. Org. Chem., 1981,46, 1232. U. Schollkopf, W. Hartwig, U. Groth, and K. Westphalen, Liebigs Ann. Chem., 1981, 696; U. Schollkopf, U. Groth, and W. Hartwig, ibid., p. 2407. U. Schollkopf, U. Groth, K. Westphalen, and C. Deng, Synthesis, 1981, 969; U. Schollkopf, U. Groth, and C. Deng, Angew. Chern., Inr. Ed. Engl., 1981,20,798. U. Schollkopf, W. Hartwig, K. Pospischil, and H. Kehne, Synthesis, 1981, 966. U . Schollkopf, H. Hausberg, M. Segal, U. Reiter, 1. Hoppe, W. Saenger, and K. Lindner, Liebigs Ann. Chem., 1981,439.

146

General and Synthetic Methods

Danishefsky has extended his work on the synthesis of aromatic amino-acids and their biogenetic precursors, to pretyrosine (189) (Scheme 89).355The dienophile (188) is prepared from L-glutamic acid 2nd pretyrosine (189) is shown to be essentially optically pure by degradation to L-phenylalanine. This strategy has also been applied to the conversion of L-glutamate to dopa.^'^ PhCH,O 0 PhCH

yN/ --f-CO,CH,Ph

Reagents: i, DIBAL; ii, separation; iii, NaOH-H,O-MeOH

/‘\

HO H Scheme 89

(189)

The 1,3-dipolar cycloaddition reaction of nitrones has been used in a short synthesis of 4-hydro~yproline,~” and in an asymmetric synthesis of the proline analogue (190) from a protected mannose ~ x i m e . Baldwin ~’~ and his co-workers have reported a total synthesis of another heterocyclic amino-acid, the antitumour agent AT-125 (191).359Syntheses of pipecolic acid and its analogues (192),360aminopiperidinecarboxylic acids related to nipecotic acid (193),361and cis-3-aminocyclohexane carboxylic acid ( 194)362have also been published.

c1

355 356

”’ ”13

359

360

’‘’

(190) (191) S. Danishefsky, J. Morris, and L. A. Clizbe, J. Am. Chem. SOC.,1981, 103, 1602. S. Danishefsky and T. A. Craig, Tetrahedron, 1981, 37,4081. J. Hara, Y. Inouye, and H. Kakisawa, Bull. Chem. SOC.Jpn., 1981, 54, 3871. A . Vasella and R. Voeffray, J. Chem. SOC.,Chem. Commun., 1Q81, 97. J. E. Baldwin, L. I. Kruse, and J. K. Cha, J. A m . Chem. SOC.,1981,103, 942. V. Asher, C. Becu, M. J. 0. Anteunis, and R. Callens, Tetrahedron Lett., 1981, 22, 141. P. Jacobsen, K. Schaumburg, J. J. Larsen, and P. Krogsgaard-Larsen, Actu Chem. Scund., Ser. B, 1981,35,389. R. D. Allan, G. A. R. Johnston, and B. Twitchin, Aust. J. Chem.,‘1981,34, 2231.

Carboxylic Acids and Derivatives

(192)

147

(194)

(193)

The unusual amino-acid avenic acid (195)’ which possesses iron chelating activity has been synthesized from L-a-hydroxy-y-butyrolactone by two independent groups.363Stimulated by its value in biosynthetic studies a route to chiral methylvaline has been developed based on an unusual specificity in the hydrogenation of an isopropenyl function using Wilkinson’s [3-3HJValine has also been prepared for the same purpose.365

HO

N

I

I

Unsaturated a-Amino-acids.-Protection of the primary amino-group of ethyl glycinate as a ‘stabase adduct,’ renders it stable to organolithium reagents; hence the lithiated species (196) is readily prepared.366Subsequent conversion into racemic 2-aminopent-4-ynoic acid (197) and vinyl glycine (198) is easily achieved (Scheme 90).367 -

=7

NH2 Reagents: i,

Br-e,

I

SiMe, ; ii, KOH-H,O; iii, +Si-CH,CHO; I

(198) iv, BF,.OEt,; v, 6 M-HCl. reflux

Scheme 90

The ene reaction of the activated imino-group in (199) with olefins provides an effective synthesis of the adducts (200)’ which are converted into y,Sunsaturated-a-amino-acids (Scheme 9 1).368 It has also been reported that the ene reaction between a-bromoacrylate and E-2-butene, catalysed by EtA1Cl2, 363

365

366 367

368

Y. Ohfune and K. Nomoto, Chem. Lett., 1981, 827; S . Fushiya, Y. Sato, S. Nakatsuyama, N. Kanurna, and S . Nozoe, ibid., p. 909. D. H. G. Crout, M. Lutstorf, P. J. Morgan, R. M. Adlington, J. E. Baldwin, and M. J. Crimmin, J. Chem. Soc., Chem. Commun., 1981,1175. J. E. Baldwin and T. S . Wan, Tetrahedron, 1981,37, 1589. S. Djuric, J. Venit and P. Magnus, Tetrahedron Lett., 1981, 22, 1787. P. F. Hudrlik and A. K. Kulkami, J. A m . Chem. Soc., 1981,103, 6251. 0. Achmatowicz and M. Pietraszkiewicz, J. Chem. Soc., Perkin Trans. 1, 1981, 2680.

General and Synthetic Methods

148

R3f;1

R2

f02Bu

+ S02C,H4Me /N -p

A, or

R2 R3h::lH4Me-p (200)

Scheme 91

("')

may be used to prepare both diastereoisomers of (*)-2-amino-4-methyl-5hexenoic the amino-group being introduced at a later stage. The bis-lactim-ether method described by Schollkopf and his co-workers has also been applied to the preparation of the R-a-vinylamino-acid (203) (Scheme 92).370A mixture of olefins (201) and (202) (80 :20) is produced that leads to (203) in 64% yield. The lithiation of a-isocyanoacrylicesters provides carbanions

Me02C

Me (203)

Reagents: i, BuLi; ii, PhCOMe; iii, HCI-H,O; iv, SOCI2-2,6-lutidine; v, 0.25 M-HCl

Scheme 92

Li

NC

H2C

\\c-c'

R 2/

\ C02Et

(204)

K+

+

kGCH0

R2

C02Me

(205)

of general structure (204) which react with alkyl halides at the a-position to give a-vinylamino-a~ids.~~~ N-Acyl dehydro-a-amino-acids are prepared from the anion (205) by acylation followed by d e f ~ r m y l a t i o nIn . ~ a~ ~ related scheme, the oxazoline (206) is fragmented to give P,y-unsaturated amino-acids (207) by reaction with zinc (Scheme 93),373 369

370 371 372

373

B. B. Snider and J. V. Duncia, J. Org. Chem., 1981,46, 3223. U. Schollkopf and U. Groth, Angew. Chem., Int. Ed. Engl., 1981,20,977. I. Hoppe and U. Schollkopf, Synthesis, 1981,646. U. Schollkopf and R. Meyer, Liebigs Ann. Chem., 1981, 1469. F. Heinzer and D. BelluS, Helu. Chim. Am, 1981,64,2279.

Carboxylic Acids and Derivatives

149

i-iii

R1&N€-12

R2

C02H

Reagents: i, Zn-DMF, 100 "C;ii, 6 M-HCI,100 "C;iii, propene oxide-MeOH

Scheme 93

(208)

(209)

The dipeptide azlactone (208)has been converted to the protected unsaturated dipeptide (209)by oxidation with DDQ followed by r n e t h a n ~ l y s i sTwo . ~ ~ reports ~ have appeared on the conversion of a-keto-acids and esters into a,P-unsaturated amino-acid derivatives. In the first the anhydride (210) is prepared from an a-keto-acid, then converted into (211) with The second example

0 (210)

involves the reduction, acylation, and elimination of the oxime (212) (Scheme 94);376 five examples are reported and the yields are good. ,CO,Et

RCy2

C

II

i-iii

-R

"OR'

H I /C+

/CO2Et C I HNCOMe

(212) Reagents: i, BH,-pyridine; ii, AcCl-Et3N; iii, DBU

Scheme 94

Asymmetric Hydrogenation.-This important subject has been reviewed.377 Studies on the introduction of new chiral phosphine ligands for the reaction 374

375 376

377

S.W. King and C. H. Stammer, J. Org. Chem., 1981, 46,4780. C. Shin, Y.Yonezawa, and J. Yoshimura, Chem. Leu., 1981, 1635. J. D. M. Hencheid, H.P. H. Scholten, M, W. Tijhuis, and H.C. J. Ottenheijm, Red. Truu. Chim. Pays-Bas, 1981, 100,73. V. taplar, G. Comisso, and V. Sunjik, Synthesis, 1981, 85.

150

General a n d Synthetic Methods

have continued and a full paper on the bicyclic ligand 'norphos' has appeared, including a description of its resolution, X-ray structure, and r e a c t i o n ~ . ~Two '~ optically active bis-phosphine ligands derived from S-phenylalanine and S-valine produce optical yields between 84 and 99% in the reduction of a-acetylaminoacrylic acids to a m i n o - a ~ i d sMore . ~ ~ ~ modest optical yields are obtained in the asymmetric hydrogenation of various dehydrodipeptides (213) using complexes of rhodium(1) modified by known chiral phosphine l i g a n d ~ . ~Polymer ~' attached optically active phosphine ligands have been described which produce high optical yields in the rhodium(1)-catalysed hydrogenation of a c r y l a t e ~ . A ~ ~chiral ' cobalt(I1) complex has been used to reduce methyl N-(acety1amino)acrylate and 34.5o/' enantiomeric excess was the highest achieved.382 In a different approach to the problem an asymmetric hydrogenation of the pyruvamides (214) was achieved using Pd-C as catalyst; the best diastereoisomer ratio was 98 :2.383Asymmetric hydrosilylation and asymmetric hydrogenation have been applied to the N-(a-ketoacy1)-a-amino-esters(215); the former produced good to high diastereoselectivity whereas the latter method was less selective. 384 0

0 0 R' II II CH3-C-C-NH-&H-R2

II

NH-C-CH2-NHAc

R-CH=C

(214)

/

'C02H (213)

0 0

II II

R2

I

R'-C-C-NH-CH-C02Me (215)

Protection and Deprotection.-A -study of the application of N-2,2,2trichloroethoxycarbonylurethane(troc-urethane) as an NH-protecting group for amino-acids has appeared.385 Several N-troc-amino-acids were prepared, and some were converted to protected dipeptides by the DCCI procedure. Deprotection was achieved mainly by known methods of zinc dust reduction. An acidand base-stable, nucleophile-resistant protecting group for amino-acids is produced when the amino-group is converted to the corresponding diallylamine with ally1 bromide and Hunig base. The idea is illustrated by the conversion of L-tyrosine methyl ester into the natural product anticapsin (216) (Scheme 95).386 Another new urethane-type protecting group for amines is provided by the chromone derivative (217). It is known by the initials (T croc) in this case, but it may also be used as a protecting group for acids by the formation of esters, when it is called (T crom). In both cases the group is removed by brief exposure 378 379 380

383 384

38s 386

H. Brunner, W. Pieronzyk, B. Schonhammer, K. Streng, I. Bernal, and J. Korp, Chem. Ber, 1981, 114,1137. W. Bergstein, A. Kleemann, and J. Martens, Synthesis, 1981,76. A. Kleemann, J. Martens, M. Samson, and W. Bergstein, Synthesis, 1981,740. G. L. Baker, S. J. Fritschel, J. R. Stille, and J. K. Stille J. Org. Chem., 1981, 2954; G. L. Baker, S. J. Fritschel, and J. K. Stille, ibid.,p. 2960. S. Takeuchi and Y. Ohgo, Bull. Chem. SOC.Jpn., 1981,54,2136. K. Harada, T. Munegumi, and S . Nomoto, Tetrahedron Lett., 1981, 22, 111. I. Ohima, T. Tanaka, andT. Kogure, Chem. Lett., 1981,823. J. F. Carson, Synthesis, 1981,268. B. C. Laguva and B. Ganem, Tetrahedron Lett., 1981,22,1483.

Carbaxylic Acids and Derivatives

15 1 0

c

C0,Me

H NH,

9 0 , M e

H N(CH,CH=CH,), Scheme 95

R

O

0

to ethanolic hydrazine or other unhindered primary a m i n e ~ (T . ~croc) ~ ~ is used as a protecting group in the synthesis of the peptide bis-s-acetamidomethyl-

dihydros~rnatostatin.~~~ The tertiary butyl group has been shown to be an effective thiol-protecting group in the synthesis of several peptides containing ~ y s t e i n e It. ~is~removed ~ by treatment with (2-nitropheny1)sulphenyl chloride (Nps Cl). The 3-nitro-2pyridinesulphenyl (NPYS) group also acts as an SH protecting group for cysteine; it is resistant to acids and can be removed using tri-n-butylphosphine in the presence of water.390 In contrast to the corresponding S-trityl compound, S(diphenyl-4-pyridylmethyl)-~-cysteine and its derivatives are stable to acid. The latter compounds have been used in peptide synthesis and the products were deprotected using one of four methods: zinc and acetic acid, mercury(I1) acetate, iodine, or by electrolytic This group has also been used for the protection of the imidazole NH in histidine. Brown and Jones have reported the protection of histidine side-chains with benzyloxymethyl and bromobenzyloxymethyl groups.392No side reactions were observed, and the derivatives may be used in both classical and solid-phase peptide synthesis without racemization. Cleavage is achieved using saturated hydrogen bromide-trifluoroacetic acid or catalytic hydrogenation. Peptide Synthesis.-A useful review on side reactions encountered during peptide synthesis has been published.393The degree of epimerization in tripeptide model reactions has been correlated with primary structure to produce a simple predictive equation.394 Peptide synthesis using 3’-iodo-~-tyrosine without ’13’ 388 389 390

391 392

383 394

D. S.Kemp and G. Hanson, J. Org. Chem., 1981, 46,4971. D. S. Kemp, D. R. Bolin, and M. E. Parham, Tetrahedron Lett., 1981, 22, 4575. J. J. Pastuszak and A. Chimiak, J. Org. Chem., 1981, 46, 1868. R. Matsueda, T. Kimura, E. T. Kaiser, and G. R. Matsueda, Chem. Lett., 1981,737. S. Coyle, A. Hallett, M. S. Munns, and G. T. Young, J. Chem. SOC.,Perkin Trans. 1 , 1981, 522. T. Brown and J. H. Jones, J. Chem. Soc.. Chem. Commun., 1981,648. M. Bodansky and J. Martinez, Synthesis, 1981, 333. D. L. Nguyen, J.-R. Dormoy, B. Castro, and D. Prevot, Tetrahedron, 1981,37,4229.

152

General and Synthetic Methods

protection of the phenol group has been achieved.395Models for the extension of the amine-capture strategy to peptide synthesis provide a new approach to the subject. Intramolecular 0,N-acyl transfer via cyclic intermediates of nine and twelve members is now possible.396Intermolecular acyl transfer occurs in the reaction between 3-acyl-l,3-thiazolidine-2-thione (218) and amino-acids to give the corresponding N-acyl derivatives.397

Tetrabutylammoniurnamino-acid salts have been coupled to amino-acid esters and (5-nitropyridy1)diphenyl using bis(o-nitropheny1)phenyl ph~sphonate~~’ p h ~ s p h i n a t eThe . ~ ~heterocyclic ~ phosphonate (219j is also an effective reagent for the activation of carboxylic acids which react with amino-acid esters in its presence to form peptides in good yield.400 Studies on the use of the 4-picolyl esters as soluble compounds,4°1and the applications of 1-aminocyclopropane-1-carboxylic acid in peptide have appeared. During studies on the synthesis of an analogue of lysozyme, carried out by the Kenner gr0up,4~~ various established methods and two new ones have been used to construct large peptide fragments. Clearly the work has tested these methods to their limit. A novel method for the preparation of ansapeptides has been used in a synthesis of dihydrozizyphim G.4Q4 Catalytic hydrogenation at 95 “C of the pentafluorophenyl ester (220) under high-dilution conditions is used to give the intermediate (221) in 67% yield (Scheme 96). In the area of solid-phase peptide synthesis an improved synthesis of 4-(Bocaminoacyloxymethy1)phenylacetic acids, using the photolabile 4methoxyphenacyl group has a ~ p e a r e d . ~Fluorenylmethyloxycarbonyl ” (Fmoc) amino-acid trichlorophenyl esters have been used in solid-phase peptide synthesis in a manner similar to Boc-amino-acid active esters.406 a(Pheny1acetamido)benzylpolystyrene(PAB-resin) is reported to be a useful new polymeric support for peptide synthesis which has improved acid stability.407 395 396

397

398 399 ‘00

‘02 ‘03

404

40s

*O’

B.Rzeszotarska, B.Nadolska, and J. Tarnawski, Liebigs Ann. Chem., 1981,1294. D. S. Kemp, D. J. Kerkman, S.-L. Leung, and G. Hanson, J. Org. Chem., 1981,46,490. Y. Nagao, T.Miyasaka, K. Seno, M. Yagi, and E. Fujita, Chem. Lett., 1981,463. Y.Watanabe, N. Morito, K. Kamekawa, and T.Mukaiyama, Chem. Letr., 1981,65;Y.Watanabe and T. Mukaiyama, ibid., p. 285. T. Mukaiyama, K. Kamekawa, and Y. Watanabe, Chem. Lett., 1981,1367. T.Kunieda, Y. Abe, T. Higuchi, and M. Hirobe, Tetrahedron Lett., 1981,22, 1257. F. H. C. Stewart, Aust. J. Chem., 1981,34,2013. F. H.C. Stewart, Aust. J. Chem., 1981,34,2431. I. J. Galpin, A. Hallett, F. E. Hancock, B. K. Handa, D. Hudson, A. G. Jackson, G. W. Kenner, P. McDowell, B. A. Morgan, P. Noble, R. Ramage, J. H. Seely, and W. D. Thorpe, Tetrahedron, 1981,37,3017,2055,3031,3037, and 3043. U. Schmidt, H. Griesser, A. Lieberknecht, and J. Talbiersky, Angew. Chem., Inr. Ed. Engl., 1981, 20,280and 281. F. S.TjoengandG. A. Heavner, Synthesis, 1981,897. K. M. Sivanandaiah and S. Gurusiddappa, Synthesis, 1981,565. E.Giralt, D. Andreu, M. Pons, and E.Pedroso, Tetrahedron, 1981.37.2007.

Carboxylic Acids and Derivatives

153

i, ii ____*

(220) Reagents: i, Pd-C-dioxan-ethanol-H,;

ii, h.p.1.c. separation

Scheme 96

Finally an interesting report on catalysis of peptide-bond formation using CYchymotrypsin covalently bound to silica has ap~eared;~''results are similar to those obtained with the free enzyme.

'08

A. Konnecke, R. Bullerjahn, and H.-D. Jakubke, Monatsh. Chem., 1981,112,469.

4 Alcohols, Halogeno-compounds, and Ethers BY

R. C. F. JONES

The previously established pattern is maintained in this Report; likewise crossreferencing to earlier Reports follows the style of Vols. 4 and 5, i.e. a citation (2, 113)in the text refers to Vol. 2, page 113 in this series of Specialist Periodical Reports.

1 Alcohols Preparation.-A quaternary ammonium anion-exchange resin, in its carbonate form, is the ‘reagent’ in a new and convenient procedure for the hydrolysis of primary, allyl, and benzyl halides to the corresponding alcohols.’ A shortened (two-stage) sequence for the conversion of primary alkylamines to alcohols mediated by pyrilium salts (cf.2, 113; 4,138) is outlined in Scheme 1;’ treatment of the intermediate pyridinium salt (1)with sodium 2-hydroxymethylbenzoate (or thiobenzoate) leads directly to isolation of the alcohol, rather than the esters obtained when sodium acetate or sodium trifluoroacetate are employed.

- BU4NBFd

Reagents: i, RCH2NH2-Et,N, 20 OC; ii, Scheme 1

Two new methods for the ‘anti-Markovnikov’ hydration of alkenes have appeared this year. One method involves hydrosilylation (Scheme 2) followed by oxidative C-Si bond cleavage either of the organotrialkoxysilate adduct G. Cardillo, M. Orena, G. Porzi, and S. Sandri, Synthesis, 1981,793.

’ A. R. Katritzky, A. Saba, and R. C. Patel, J. Chem. SOC.,Perkin Trans. 1, 1981,1492. 154

Alcohols, Halogeno-compounds, and Ethers

155

(2; X = OEt) or the derived organosilatrane (3).3 The other route requires a nickel-catalysed displacement reaction between a 1-alkene and an optically active organoaluminium reagent (Scheme 3) to give, after oxidation, /3 -chiral primary alcohols with up to 27% enantiomeric excess (e.e.);' of the chiral ligands (L") tried, N,N- dimethylmenthylamine and 2,3-di-O-methy1-1,4-bis(N,Ndimethy1amino)butane gave the best results. ii. iii (X=CI, OEt), O I 7 RCH=CH,

A

RCH,CH,SiX,

-

RCH,CH2Si+N

RCH,CH,OH v (X=OEt)

Reagents: i, HSiX,-H,PtCI,; ii, LiAIH,; iii, N(CH2CH,0H)3-C~(CO),; iv, N(CH&H,OH),-KOH; v, ??t-CIC6H4CO,H

Scheme 2

R'R2C=CH2

A L*(R'R2tHCH2)3AI

R'R2tHCH20H

Reagents: i, L*AIBu',-Ni(N-methylsalicylideneamine),;ii, 0,; iii, H,O'

Scheme 3

Regioselective ring opening of epoxides to the less-substituted alcohol, by hydride capture at the better potential carbenium ion centre, is achieved with a sodium cyanoborohydride-boron trifluoride combination;' anti ring opening is favoured. Unsymmetrical secondary alcohols can be prepared in high yield in 'one-pot' from the formamido-pyridine (4) by two successive Grignard additions (Scheme4) (cf. 3, 132). The first Grignard addition is carried out at O'C, ii, iii

(4)

J

Reagents: i, R'MgX, 0 "C; ii, R'MgX, 65 "C; iii, H 3 0 +

Scheme 4

whereas the second occurs only in refluxing tetrahydrofuran (THF);6 bulky Grignard reagents with P-hydrogens are better added first in this sequence. Another new method that constructs carbinols around a one-carbon unit involves the interaction of lithium tris(pheny1thio)methanide with trialkylboranes "

A. Hosomi, S. Iijima, and H. Sakurai, Chem. Lett., 1981, 243. G. Giacomelli, L. Bertero, and L. Lardicci, Tetrahedron Left., 1981, 22,883. R. 0. Hutchins, I. M. Taffer, and W. Burgoyne, J. Org. Chem., 1981,46, 5214. D. L. Comins and W. Dernell, TetrahedronLett.. 1981, 22, 1085.

General and Synthetic Methods

156

(Scheme 5);7 in contrast to earlier work with bis(pheny1thio)alkyl-lithiums (2,112)and 2-lithio-1,3-benzodithioles (4,139),two of the boron-to-carbon alkyl migrations occur spontaneously and only the third needs to be induced by Hg". A related approach to secondary alcohols from sulphone carbanions and trialkylboranes is illustrated in Scheme 6.' R3B + (PhS)3CLi -+ Li+[R3BC(SPh),]-

h RB(SPh)CR2SPh J. ii

R3COH

t PhSB(X)CR3

Reagents: i, -2LiSPh; ii, HgCl,; iii, H,O,-OH-

Scheme 5 PhS02CH2R'

a Mf[R23BCHR'S02Ph]-

% R'R2CHOH

(M = Li, MgBr) Reagents: i, PhLi or Bu"MgBr, -78 "C; ii, RZ3B;iii, -78 OC + 20 OC, -PhSO,M; iv, H,O,-OH-

Scheme 6

A new route to monoalkylboranes from borane and alkylidene triphenylphosphoranes, when used in combination with hydroboration, forms the basis for a synthesis of tertiary carbinols (Scheme 7 ) ; 9 the free monoalkylboranes are obtained in solution from their triphenylphosphine complexes by quaternization (and hence removal) of the phosphine. R'R2C=PPh3

.

[R1R2CHBH2 PPh3]

R'R2CHB(CHR4CHRSR6)2

& v-vii R'R2CHC(OH)(CHR4CHRSR6)2 Reagents: i, BH,.THF; ii, AH;iii, R31; ivyR4CH = CRSR6;v, C1,CHOMe; vi, LiOCEt,; vii, H202OH-

Scheme 7

The alkylation of ester enolates derived from acyloxy bornanes such as ( 5 ) has been shown to occur with excellent diastereoselectivity; chromatographic purificationof the major diastereomer, followed by reduction, gives enantiomerically pure p -chiral primary alcohols (Scheme 8)." Interestingly a marked solvent

-Q/

&MOZPh

'

h p 2i*ii 0 : &- -

\o- iii, iv

OCOCH ZR I HH

R~RGHCH~OH

OCOCHR'R' HH

(5) Reagents: i, LiNPr'(cyclohexyl), -78 "C; ii, R'X, -40 "C; iii, diastereomer purification; iv, Ca(BH,), or LiAlH,

Scheme 8

' A. Pelter and J. M. Rao, J. Chem. SOC.,Chem. Commun., 1981,1149. lo

D. Uguen, Bull. SOC.Chim. Ft., 1981,II,99. H.J. Bestmann, K.Siihs, and T. Rader, Angew. Chem., Znt.Ed. Engl., 1981,20,1038. R. Schmierer, G. Grotemeir, G. Helmchen, and A. Selim, Angew. C h e m YZnt. Ed. Engl., 1981, 20,207.

Alcohols, Halogeno-compounds, and Ethers

157

effect on the alkylation has been observed that can be rationalized in terms of preferred enolate geometry; for example with ( 5 ; R' = Me) and R'X = n -CI4H2J the new chiral centre is established with configurational selectivity 98.5(S): 1.5(R) in THF, but 94(R):6(S)in THF: HMPT(4 : 1). Full details have appeared of the cr -oxo-lithiation of 2,6-disubstituted benzoate esters (6) having sterically protected carbonyl groups (cf. 3, 133)." Reaction of the lithio derivatives, formed from (6) by reaction with excess base or regenerated from the stannane (7) by treatment with stoicheiometric methyllithium, with alkyl halides or carbonyl compounds followed by ester cleavage leads to alcohols and diols, respectively (Scheme 9). ArC02CH2R' (6)

5 ArCO'CHLiR' -%R'R'CHOH ii

iii

\

ArC02CH(SnBu3)R'

R'CH(OH)C(OH)R3R4

Reagents: i, Bu'Li-TMEDA; ii, Bu,SnCl; iii, MeLi; iv, R2Hal; v, LiAlH,(Ar = a) or H,O+(Ar vi, R3COR4

=

b);

Scheme 9

Carbonyl Group Reduction. As in previous years there has been a large number of publications in this area, with emphasis moving towards methods that display chemo- and/or stereo-selectivity, Thiol esters are reduced to primary alcohols by sodium borohydride in ethanol without significant transesterification.l2 These conditions do not affect oxygen esters whereas sodium borohydride used either in polyethylene glycols such as PEG-400 at 65 'C,13 or in DMSO containing methanesulphonic acid,14has been shown to reduce esters to primary alcohols; the borohydride-acidic DMSO system also reduces carboxylic acids, other than conjugated aromatic acids, to alcohols. An improved procedure for rapid reduction of esters to alcohols with borane-dimethylsulphide involves using THF as solvent at reflux, with an aqueous alkaline work-up." A new method in this area involves hydrosilylation with the cheap and readily available ethoxyhydrogenosilanes (EtO),SiH and Me(EtO),SiH activated by alkali-metal fluorides in the absence of solvents (cf. 4, 142).'6*" These salts are presumed to increase the hydride character of the Si-H bonds such that esters

'' P. Beak and L. G. Carter, J. Org. Chem., 1981,46,2363. l2 l3

l4 Is l6 17

H.-J. Liu, R. R. Bukownik, and P. R. Pednekar, Synrh. Comrnun., 1981,11, 599. E. Santaniello, P. Ferraboschi, and P. Sozzani, J. Org. Chem., 1981,46,4584. S. R. Wann, P. T. Thonen, and M.M. Kreevoy, J. Org. Chem., 1981,46,2579. H. C. Brown and Y. M. Choi, Synthesis, 1981,439. J. Boyer, R. J. P. Corriu, R. Pen, M. Poirier, and C. Reye, Synthesis, 1981,558. J. Boyer, R. 3. P. Corriu, R. Pen, and C. Reye, J. Chem. SOL, Chem. Commun., 1981, 121; Tetrahedron, 1981. 37,2165.

General and Synthetic Methods

158

are reduced to alcohols by the silanes and CsF.16 Selectivity is possible with these systems; (EtO),SiH or Me(EtO),SiH with CsF will reduce ketones in the presence of esters, and (EtO),SiH-KF will reduce aldehydes in the presence of ketone^.'^ The reagents have been suggested as competitors for borohydrides. Triethoxysilane (or the trimethoxy derivative) has also been reported as useful for the reduction of aldehydes and ketones in catalytic hydrosilylations with Rh' or Ru" catalysts;I8the alcohol silyl ethers produced are best converted to the corresponding alcohols by ethanolysis (or methanolysis). The reduction of nickel salts in solution with sodium borohydride yields a finely divided black precipitate of nickel boride ('Ni2B') that has been shown to have properties similar to Raney nickel as a catalyst for hydrogenation of various functional groups, including aldehydes." Recent reports on homogeneous catalytic hydrogenation of aldehydes and ketones include studies with cationic rhodium complexes,2o such as [Rh(n~rbornadiene)(Et~P)~ 3]+C104-, and anionic hydridoruthenate catalysts,21 such as K+[(Ph3)P2Ph2-RuH21-s C10&* Et2O. Reductions of carbonyl compounds catalysed by alcohol dehydrogenase enzymes consume the expensive coenzyme NADH [equation (l)], and several new procedures have appeared from Whitesides and his co-workers for the recycling of oxidized coenzyme NAD' (cf. 5,153; 3,136). Glucose 6-phosphate dehydrogenase has been employed in a coupled enzyme reaction with either glucose 6 - p h o ~ p h a t eor~ ~the easier to prepare glucose 6-sulphate2, as substrate; these methods, although good for lab-scale preparations, have the disadvantage on a large scale of producing gluconic acid derivatives as by-product. In contrast, the use of a hydrogenase with various cofactors or redox dyes, and molecular hydrogen as the ultimate reducing agent, is reported to be too complex for small-scale work but of potential interest on a larger scale.24 R'R~CO+ NADH

+ H+ --+R'R~CHOH+ NADH

(1)

A recently reported reducing system for aldehydes and ketones is sodium formate in refluxing N-methylpyrrolidone, an inexpensive combination but requiring rather harsh condition^.^' Formic acid also features in another new reducing agent (Scheme 10); an adduct formed from it by addition of two equivalents of a Grignard reagent, and which possibly has a structure of type

A

[R'CH(OMgX)2] ii'iii B R'C02H (8) Reagents: i, 2R'MgX; ii, R'CHO; iii, H,O+ Scheme 10 HCO2H

l8 l9 2o

21 22

23 24

25

+ R2CH20H

H. Matsumoto, Y. Hoshino, and Y. Nagai, Bull. Chem. SOC.Jpn., 1981,54, 1279. J. A. Schreifels, P. C. Maybury, and W. E. Swartz, J. Org. Chem., 1981,46,1263. H. Fujitsu, E. Matsumura, K. Takeshita, and I. Mochida, J. Org. Chem., 1981,46,5353; J. Chem. SOC.,Perkin Trans. 1, 1981,2650. R. A. Grey, G. P. Pez, and A. Wallo, J. Am. Chem. SOC.,1981,103,7536. C.-H. Wong and G. M. Whitesides, J. Am. Chem. SOC.,1981,103,4890. C.-H. Wong, J. Gordon, C. L. Cooney, and G. M. Whitesides, J. Org. Chem., 1981,46,4676. C.-H. Wong, L. Daniels, W. H. Orme-Johnson, and G. M. Whitesides, J. Am. Chem. SOC.,1981, 103,6227. J. H. Babler and S. J. Sarussi, J. Org. Chem., 1981,46,3367.

Alcohols, Halogeno-compounds, and Ethers

159

(8), converts aldehydes to alcohols.z6Both of these methods are slower with ketones, suggesting possible selectivity. ‘Fontainebleau sand’ (a slightly hydrolysed microcrystalline silica) has been shown to be an efficient support for sodium borohydride in the reduction of aldehydes and ketones in the absence of organic ketones with insufficient vapour pressure (such as steroidal examples) are not reduced, in agreement with the proposed ‘evaporating-hopping’rationale for these reactions. A further publication (cf.1,158)on the properties of tetraethyl- and tetrabutylammonium borohydrides has concluded that they are not generally useful for selective reduction of aldehydes in the presence of ketones,28and has counselled caution in making claims of such general chemoselectivity as reactivity depends greatly on the steric and electronic situation of a carbonyl group. Continued studies of the reduction of carbonyl compounds by sodium borohydride in the presence of lanthanide cations (cf.3, 141) have shown that NaBH4-ErC13 in aqueous ethanol is an effective system for reduction of conjugated aldehydes in the presence of non-conjugated ones (probably because of formation from the latter of hydrates stabilized by lanthanide cation ~ h e l a t i o n )and , ~ ~ that NaBH4CeC13 6 H z 0in methanol are optimal conditions for regioselective 1,2-reduction of a,@-enones to allylic alcohols.30

Modification of sodium borohydride with hindered phenols has afforded the triaryloxyborohydrides (9), as THF-soluble reagents able to reduce aldehydes in the presence of ketones, including the demanding case of aliphatic aldehyde us. unhindered cyclohe~anones.~’ A useful and new borohydride reagent to be introduced this year is the bis(triphenylphosphine)copper(I) borohydride, (Ph,P)2CuBH4; amongst its properties are the reduction, in the presence of strong acids such as HCl or AlC13, of aldehydes and ketones to alcohols, of aldehydes in the presence of ketones, and of a,@-unsaturated aldehydes to allylic The closely related reagent (10) has been shown to have potential for chemoselective aldehyde reduction in neutral or mild acid condition^.^^ Two new boranes that will reduce aldehydes and ketones are bis(trifluoroacetoxy)borane . THF34 and l-pyrrolylborane THF;35 the latter reagent also reduces a,& unsaturated aldehydes and ketones to allylic alcohols. J. H. Babler and B. J. Invergo, Tetrahedron Len., 1981, 22,621. G. Bram, E. d’Incan, and A. Loupy, J. Chem. SOC.,Chem. Commun., 1981,1066. 28 D. J. Raber, W. C. Guida, and D. C. Shoenberger, Tetrahedron Lett., 1981,22, 5107. 29 A. L. Gemal and J.-L. Luche, Tetrahedron Lett., 1981, 22, 4077. 30 A. L. Gemal and J.-L. Luche, J. Am. Chem. Soc., 1981,103, 5454. 31 S. Yamaguchi, K. Kabuto, and F. Yasuhara, Chem. Lett., 1981,461. ” G. W. J. Fleet and P. J. C. Harding, Tetrahedron Lett., 1981, 22, 675. 33 P. N. Davey, G. W. J. Fleet, and P. J. C. Harding, J. Chem. Res. ( S ) , 1981, 336. 34 B. E. Maryanoff, D. F. McComsey, and S. 0. Nortey, J. Org. Chem., 1981, 46, 355. ” M. Anez, G . Uribe, L. Mendoza, and R. Contreras, Synthesis, 1981,214. 26 27

General and Synthetic Methods

160

Among aluminium-based reducing agents, a report on the highly hindered hydride reagent lithium tris[(3-ethyl-3-pentyl)oxy]aluminium hydride, LiAl(OCEt,)H, has illustrated its excellent chemoselectivity (98-100%) for aldehyde reduction even in the presence of unhindered reactive ketones such as cycl~hexanone,~~ and has claimed superiority over other systems available. The aryloxydialkylaluminiumreagent (11)has been developed as a stereoselective reducing agent in the prostaglandin area,37 and p -branched trialkylaluminium reagents, such as tri-isobutylaluminium, have been shown to give selective 1,2-reduction of a,@-enones to allylic alcohols especially when used in ether as In further studies on nucleophilic alkylation of aldehydes and ketones (to give secondary and tertiary alcohols, respectively) using alkyltitanium(1v) compounds, the earlier work on methyl tri-isopropoxytitanium (5,155) has been extended to other alkyl tri(a1koxy)titanium The observed chemoselective addition to the aldehyde in benzaldehyde-acetophenone mixtures [equation (2)] illustrates that these systems are less reactive but more selective PhCHO

+ PhCOCH,

RTi(0Pr’)3

PhCH(0H)R + PhCOCH3

(2)

than alkyl-lithiums. The corresponding zirconium reagents RZr(OBu), have been prepared for comparison to the Ti’” species and shown to be selective nucleophiles towards aldehydes and ketones, but with low basi~ity.~’ A combination of titanium tetrachloride and a dialkylzinc has been found to give nucleophilic alkylation of aldehydes, although the reaction with ketones is less the reactive species here may well be R2TiC12.Reaction of TiC14-Et2Zn with 2-phenylpropanal shows diastereoselectivity (77 :23) for the ‘Cram’-type product only slightly improved over that shown by EtMgBr (75 :25),41whereas some octahedral complexes of MeTiCl, show rather better ‘Cram’s rule’ diastereoselectivity (78-85 :22-15) with 2-phenylpropanal than that produced by MeMgBr (67: 33);42the best selectivity reported ( 8 5 :15) is with the THF complex MeTiC13(THF)2which is superior to MeTiCl, itself (81: 19). Asymmetric Reductions. In a review of asymmetric syntheses via chiral organoborane intermediates, Brown has surveyed ketone-to-alcohol reductions with chiral trialkylboranes, chiral borohydrides, and mono- or di-isopinocampheylb~rane.~, Full details have appeared on the reduction of aryl alkyl ketones with reagents prepared from sodium borohydride, a carboxylic acid, and 1,2 :5,6-di-0isopropylidene-ar-D-glucofuranose (DIPGF; 12) (cf.5 , l 57);44 best results are S. Krishnamurthy, J. Org. Chem., 1981,46,4628. S. Iguchi, H. Nakai, M. Hayashi, H. Yamamoto, and K. Maruoka, Bull. Chem. SOC.Jpn., 1981, 54,3033. ’* G. Giacomelli, A. M. Caporusso, and L. Lardicci, Tetrahedron Lert., 1981,22,3663. 39 B. Weidmann, L. Widler, A. G. Olivero, C. D. Maycock, and D. Seebach, Helv. Chim. Acra, 1981, 64,357. 40 B. Weidmann, C. D. Maycock, and D. Seebach, Helv. Chim. Acta, 1981,64,1552. 41 M. T.Reetz, R. Steinbach, and B. Wenderoth, Synrh. Commun., 1981,11,261. 42 M. T.Reek and J. Westermann, Synth. Commun., 1981,11,647. ” H.C. Brown, P. K. Jadhav, and A. K. Mandal, Tetrahedron, 1981,37,3547. 44 A. Hirao, S. Itsuno, M. Owa, S. Nagami, H. Mochizuki, H. H. A. Zoorov, S. Niakahama, and N. Yamazaki, J. Chem. SOC.,Perkin Trans. 1, 1981,900. 36 37

Alcohols, Halogeno-compounds, and Ethers

161

obtained at 0 "C with isobutyric acid and ratios NaBH, :Me2CHC02H:DIPGF of 1: 1.2 :2, when (R)-carbinols having enantiomeric excess (e.e.) up to 83% are isolated. Full details are also now available of the related system NaBH,: ZnC12:DIPGF (cf. 4, 143).,' Using a ratio 1 : 0.33 :2 at 0-50 "C in THF, freshly prepared complex has been shown to give (S)-alcohols in up to 68% optical yield from aryl alkyl ketones. OH

OH

O.\

R' = Bun,R2 = Me b; R' = (R)-PhCHMe, R2 = H c; R' = (R)-PhCHMe, R2 = Me d; R' = (S)-PhCHMe, R2 = Me

(14) a;

The complexes of chiral amino-alcohols of type (13)with borane are reported to reduce aryl alkyl ketones to alcohols in optical yields up to 60% [for propiophenone reduction with (13; R = CHMe2)],46whereas the asymmetric reduction of phenyl alkyl ketones with amine-boranes formed from chiral amines (such as l-phenylethylamine or various ~ - aamino-esters) has been found to give low optical yields of alcohols, i.e. up to 23%.47 Chiral trialkylalanes such as tri[(S)-2-methylbutyl]aluminium have been shown to give only low asymmetric induction (up to 14.5% e.e.) in the reduction of a,P -enones to allylic Lithium aluminium hydride modified with chiral ligands is a well recognized approach to asymmetric reduction, and among recent developments in this area is modification with the chiral 1,2-amino-diols ( 1 4 a - ~ i )available ,~~ from reaction of amines with the appropriate epoxide. The best asymmetric inductions in reduction of aceto- and propio-phenone (82 and 77% e.e., respectively) were obtained when the directing effects of carbinol chirality and chirality a- to N in (14) are in unison, i.e. in (14d). A reagent formulated as (15) and prepared from LiAIH,, optically pure 2,2'-dihydroxy1,l'-binaphthyl, and either ethanol or methanol (ratio 1: 1: 1) has been found to reduce a number of a,P-alkynyl ketones at -100 "C to -78 "C to afford propargylic alcohols having (with one exception) 84-96% e.e.;,' (S)-binaphthol as modifier leads to (S)-alkynols and vice versa. A publication detailing asymmetric syntheses based on chiral diamines having a pyrrolidine ring includes the modification of lithium aluminium hydride with the diamine (16) to produce a reagent that reduces ketones to secondary alcohols A. Hirao, M. Ohwa, S. Itsuno, H. Mochizuki, S. Nakahama, and N. Yamazaki, Bull. Chem. Soc. Jpn., 1981, 54, 1424. 46 A. Hirao, S. Itsuno, S. Nakahama, and N. Yamazaki, J. Chem. Soc., Chem. Commun., 1981, 315. '' M. F. Grundon, D. G. McCleery, and J. W. Wilson, J. Chem. SOC.,Perkin Trans. 1, 1981, 231. '' J. D. Morrison, E. R. Grandbois, S. I. Howard, and G. R. Weisman, Tetrahedron Lett., 1981, 22, 2619. 49 M. Nishizawa, M. Yamada, and R. Noyori, Tetrahedron Lett., 1981, 22, 247. "

General and Synthetic Methods

162

Li

+

with 26-96% e.e. (cf. 2, 116; 3, 137);” also discussed is the use of the diaminoalcohol (17) as a ligand in the enantioselective addition of organolithiums to aldehydes to produce chiral secondary alcohols having 40-80% e.e. (cf. 3,137; 4, 144).50Closely related to this latter method is a report of the chiral catalysis of addition of alkyl-lithiums to aldehydes using binaphthyl diamines such as (18);” optical yields of up to 92% e.e. were recorded in ether at -120°C for additions to benzaldehyde.

8

Wd

\

/

g

\ \

/

Asymmetric reductive alkylation has also been reported in reactions between benzaldehyde and chiral alkyl(tria1koxy)titanium aryl carbinols are obtained with up to 88% e.e., best results coming from the menthol or binaphthol derivatives, (19) and (20), respectively. Enantioselective transfer hydrogenation (from propan-2-01) of some ketones catalysed by iridium(1)complexes with chiral Schiff -base ligands has been reported, giving product alcohol of up to 33% e.e. with propiophenone as Other new reductive routes to chiral secondary.alcohols involve the asymmetric hydrogenation of enol phosphinates (21)catalysed by chiral ferrocenyl-rhodium 50

T. Mukaiyama, Tetrahedron, 1981,37,4111.

’’ J.-P. Mazaleyrat and D. J. Cram, J. Am. Chern. Soc., 1981,103,4585. 52 ”

A. G. Olivero, B. Weidmann, and D. Seebach, Helo. Chim. Acta, 1981.64.2485. G. Zassinovich, C. Del Bianco, and G. Mestroni, J. Organomet. Chem., 1981, 222, 323.

Alcohols, Halogeno-compounds, and Ethers

163

complexes (Scheme 1l),giving up to 78% e.e. in the product^,'^ and the borohydride reduction of fi -oxosulphoximides (22) chiral at sulphur (Scheme 12) (cf. 4,144 for related work with fi-oxos~lphoxides).~~ R‘

H

,&( --% R1cHCH2R2 I

Z

R~COCH~R~

Ph2PO

It

R2

iv’v

R1?H(OH)CH2R2

OPPh,

It

0

0

(21) Reagents: i, LiNPr’,, -78 “C; ii, Ph,P(O)CI; iii, H,-[Rhl-

iv, MeLi; v, H,O+

Fe PPhz

Scheme 11

0

I1

PhS*-Me II NMe

0 It

0

A

It

PhS*-CH2COR II NMe

A PhS*-CH2&OH)R I1 NMe

5 CH,;H(OH)R

(22) Reagents: i. LiNPr’,-RC0,Et; ii, NaBH,, -78 “C; iii, AI-Hg

Scheme 12

Allylic and a-Allenic Alcohols. The electrochemical generation of a selenenylating reagent, presumably PhSeOR, from a catalytic amount of diphenyl diselenide in the presence of water or an alcohol (ROH) is the basis of a new method for direct conversion of alkenes to allylic alcohols or ethers (Scheme 13).s6 Regiospecific ‘Markovnikov’ oxyselenenylation followed by electrochemical oxidation and selenoxide elimination, regenerating a selenenylating species, accounts for a sequence that is obviously closely related to the bromide-mediated method reported last year (5, 158). (PhSe), + R’OH

[GR] -:,bR, 0R2

0R2 [PhSeOH]

Scheme 13

A publication surveying uses of trimethylsilyl trifluoromethanesulphonate in synthesis includes the isomerization of epoxides to give allylic alcohols (cf. 4, 145);” in unsymmetrical cases ring opening occurs at the more substituted epoxide carbon atom (Scheme 14), and the same regiochemistry is observed in

’‘ T. Hayashi, K. Kanehira, and M. Kumada. Tetrahedron Left., 1981, 22, 4417. ’’ R. Annunziata, M. Cinquini, and F. Cozzi. J. Chem. SOC.,Perkin Trans. 1, 1981, 1109. S. Torii, K. Uneyama, M. Ono, and T. Bannou, J. A m . Chem. SOC.,1981,103,4606. ’’ R. Noyori, S. Murata, and M. Suzuki, Tetrahedron, 1981, 37, 3899. s6

General and Synthetic Methods

164

the recently reported reaction of trisubstituted epoxides with selenoboranes to give allylic alcohols (also Scheme 14).58

Reagents: i, Me,SiOSO,CF,-DBU; ii, KF-MeOH; iii, B(SeR),; iv, NaHC0,aq. Scheme 14

The radical-induced epoxide ring-opening of a,P -epoxy-0-thiocarbonylimidazolides (23) [equation (3)] has been reported to be a convenient alternative to the Wharton rearrangement (action of hydrazine on epoxides of a,@unsaturated ketones) for production of allylic P,y-Disubstituted allylic alcohols with 2-configuration are the major products formed on addition of alkyl-lithiums to the vinyl epoxide (24) [equation (4)].60

R'

R' 0/R2

3 Bu SnH

(3)

>OH R2

major

minor

Ally1 silanes have been found to undergo a phenylselenodesilylation sequence that places the phenylselenyl group at the least substituted terminus of the allylic system (Scheme 15), whereas phenylthiodesilylation usually occurs regiospecifically at the y-position;6' oxidation of the allyl selenide and [2,3]sigmatropic rearrangement of the selenoxide to a selenenate, that is trapped in situ, completes a sequence that provides allylic alcohols at the more substituted allyl terminus. 58 59

6o

A. Cravador and A. Krief, TetrahedronLett., 1981,22, 2491. D. H. R. Barton, R. S. H. Motherwell, and W. B. Motherwell, J. Chem. SOC.,Perkin Trans. I , 1981,2363. M. Tamura and G. Suzukamo, TetrahedronLett., 1981, 22, 577. H. Nishiyama, K. Itagaki, K. Sakuta, and K. Itoh, TetrahedronLett., 1981, 22, 5285.

Alcohols, Halogeno-compounds, and Ethers h4e3Si&R3

R'

i,ii

165 R3

~

R4

R'

iii

R3

R4

R4

Reagents: i. PhSeC1, -78 "C, ii, SnCl,, 0 "C, or Florid; iii, H,O,-py

Scheme 15

In a study of the reactivity of organocopper compounds with a,p -unsaturated aldehydes, allylic and acetylenic cuprates have been found to give selective 1,2-addition to afford allylic alcohols, in contrast to the predominant 1,4-addition observed with homoallylic, phenyl, and vinyl cuprates;62secondary alkyl cuprates give both types of addition product. Normant has reviewed the carbometallation of alkynes to give stereospecific syntheses of alkenyl-metal derivatives, and their addition to aldehydes and ketones to afford allylic Specific titanium-catalysed syn- hydromagnesiation of 2-propynylic alcohols (Scheme 16),64 and the related zirconiumcatalysed syn- carboalumination of propargylic alcohol itself (also Scheme 16) or its t-butyldimethylsilyl ether (cf. 3, 139; 4, 160)65can both lead to allylic alcohols. R2R2R30MgCi R1CGCCR2R30H ClMg

I

R=<"""

Me

H

H

iii,iv

"(R' = R2 =

\

R3 = H)

CH20H iv

+ H,C<

HHcH20H

Me,Al

-

ii(R2 = R3 = H)

Me

R'

,CR2R30H

b=(

2H

H

Me

Reagents: i, Bu'MgC1-Cp2TiC12; ii, MeI; iii, 'H,O; iv, H,O'; v, Me3Al-C~,ZrCI2

Scheme 16

Four reports have appeared recently on the synthesis of a -allenic alcohols as the major products from addition of propargyl derivatives to carbonyl compounds; p -acetylenic alcohols are co-products. Propargyl trimethylsilane (25 ; R' = H) adds successfully to most aldehydes and ketones in the presence of tetrabutylammonium fluoride,66 whereas 1-trimethylsilyl-2-butyne (25; R' = Me) reacts efficiently to give a-allenic alcohols as major products only with aldehydes and in the presence of titanium tetrachloride at low temperatures (Scheme 17).67In the other reports propargyl organochromium reagents (pre" 64

C. Chuit, J. P. Foulon, and J. F. Normant, Tetrahedron, 1981,37, 1385. J. F. Normant and A. Alexakis. Synthesis, 1981, 841. F. Sato, H. Ishikawa, H. Watmabe, T. Miyake, and M. Sato, J. Chem. Soc., Chem. Commun., 1981,718.

C. L. Rand, D. E. Van Horn, M. W. Moore, and E. Negishi, J. Org. Chem., 1981,46,4093. 66 J. Pornet, Tetrahedron Len., 1981,22,455. " J. Pornet and B. Randrianoelina, Tetrahedron Lett., 1981.22, 1327.

65

General and Synthetic Methods

166

pared in situ from the bromides and CrC1,-LiAlH4) are treated with aldehydes and ketones,68 and propargyl iodides are shown to add to aldehydes in the presence of a stannous halide (Scheme 18).69

4

H2C=C=CHCR2R30H

R’C

f CCH2SiMe3

(25)

(R

=

H2C= C=C(Me)CHR40H

Me)

Reagents: i, R2COR3-Bu,NF; ii, R4CHO-TiCI,, -60 “C

Scheme 17

R’CH=C=CR2CR3R40H

(X = Br)

R’CH(X)C r C R 2

1 H2C=C=CR2CHR50H Reagents: i, LiAIH4-CrC1,-R3COR4; ii, SnHal,-RSCHO

Scheme 18

Other Unsaturated Alcohols. The review mentioned above of carbometallation of alkynes, includes a survey of additions of alkenyl-metal derivatives to epoxides to give homoallylic The zirconium-catalysed carboalumination of propargylic systems (Scheme 16) is also applicable to the homopropargylic to homoallylic alcohol transf~rmation.~’ In a publication on the applications of alkylaluminium halides, Snider has revealed further details (cf.5, 161) of the ‘ene’ addition of aldehydes to alkenes, in particular 1,l-disubstituted examples, in the presence of stoicheiometric Me2AlC1 to give homoallylic alcohols (Scheme 19);” it is likely that these reactions are mechanistically of the ‘Prins’ type, passing through carbenium ion intermediates. R3

Reagents: i, R3CHO-Me2AlCl; ii, H 3 0 +

Scheme 19

For the reasons outlined last year (5,162), explorations of the reaction of various 2-alkenyl organometallic species with aldehydes and ketones to produce homoallylic alcohols, and its stereochemical outcome, have continued unabated. Two new approaches, shown in Scheme20, are both analogous to Grignard reactions; in one, ally1 iodide is treated with cerium amalgam in the presence of a ketone,’* and in the other allylic bromides or iodides in the presence of metallic tin react with allylic inversion with a wide range of aldehydes and 69 ’O

P. Place, C. VerniBre, and J. Gort, Tetrahedron, 1981,37,1359. T. Mukaiyama and T. Harada, Chem. Lett., 1981,621. B. B. Snider, D. J. Rodini, M. Karras, T. C. Kirk, E. A. Deutsch, R. Cordova, and R. T. Price, Tetrahedron, 1981,37,3927. T. Imamoto, Y. Hatanaka, Y. Tawarayama, and M. Yokoyama, Tetrahedron Lett., 1981,22,4987.

Alcohols, Halogeno-compounds, and Ethers

167

ketones.72 .rr-Allyl-dicyclopentadienyltitanium(II1)complexes prepared in situ have been found to react rapidly with aldehydes or ketones at the more substituted ally1 terminus, as exemplified in Scheme21, to lead to homoallylic alcohol^;'^ the 1-methylally1 complex is reported to give predominantly the threo-diastereomer from additions to aldehydes. OH

OH

Reagents: i, R2COR3-Ce-Hg; ii, R2COR3-Sn

Scheme 20

R’

\\

OH

Reagents: i, R’COR’; ii, 4N-HC1

Scheme 21

In related work, the but-2-enyltitanium(1~)dicyclopentadienyl halides(26), obtained as illustrated in Scheme 22 from .rr-allyltitanium(III) complexes and but-2-enyl halides or from dicyclopentadienyltitanium dihalide and but-2-enylmagnesium bromide, have been shown to add to aldehydes with high threoselectivity to afford the a l ~ o h o l s ( 2 7 )the ; ~ ~best selectivities (threo :erythro 90100: 10-0) were found with (26; X = I or Br) and were independent of the original configuration of the but-2-enyl unit. The addition of either cis- or trans-but-2-enyl bromide to aldehydes in THF mediated by the CrC13-LiAlH4 reagent (cf. 2, 120), or by commercial CrC12, has also been reported to give good threo-selectivity (threo :erythro 90-100 : 1 0 4 ) in the products (27) (also Scheme 22),7s and a publication on but-2-enylzirconium derivatives (28) formed in situ from but-2-enylmagnesium chloride or 1-methylallyl-lithium (also Scheme 22) has shown that they too add to aldehydes to give predominantly threo-products (threo :erythro 73-94 :27-6).76 In this latter method best results were achieved with the reagent formed from but-2-enylmagnesium chloride and when the stoicheiometry was such as to produce bis(but-2-enyldicyclopentadienylzirconium(28b). Addition of the chromium-based reagent to 2-methylbutanal,” and of the zirconium reagent (28b) to 2-phenylpr0panal~~ gave a marked predominance of the threo- ‘Cram’ diastereomer in the product mixtures [64% of (29a) and 75% of (29b), respectively]. Full details have appeared this year of yet another method selective for the threo -homoallylic alcohol diastereomer (27), namely the addition of 1-methylallyl-lithium to aldehydes in T. Mukaiyama and T. Harada, Chem. Lett., 1981, 1527. F. Sato, S. Iijima, and M. Sato, Tetrahedron Lett., 1981, 22, 243. 74 F. Sato, K. Iida, S. Iijima, H. Moriya, and M. Sato, J. Chem. SOC.,Chem. Commun., 1981, 1140. ” T. Hiyarna, K. Kirnura, and H. Nozaki, Tetrahedron Lett., 1981,22, 1037. 76 Y. Yamamoto and K. Maruyama, Tetrahedron Lett., 1981, 22,2895. 72 73

168

General and Synthetic Methods iv (X = Br)

MeCH=CHCH2X

v

MeCH=CHCH2MgX

\ ii b (X = Br)

(X = a)

Cp2TiX(CH2CH=CHMe) (26)

OH

'\ ~~~

Cp2ZrC1, (CH&H=CHMe),

/

[MeCH CH-CHz]-Li+

(28) a; rn = n = 1 b ; m = O,n = 2

\ [MeCH= CHCH2BR$]-Li+

Me

/

(27)

(30) Reagents: i, Cp2Ti[MeCH-CR'-CHR21; ii, Cp,TiX,; iii, R'CHO; iv, R3CH0 and LiAlH,-CrCl, or CrCl,; v, Cp,ZrCl,; vi, R43B

Scheme 22

the presence of certain trialkylboranes (also Scheme 22);77presumably the allylic 'ate' complex (30) is involved here in producing 60-85O/0 threo- selectivity. All of these methods can be rationalized if it is assumed that E-but-2-enyl organometallic derivatives are involved, and the reactions proceed via chair transition states (31) with a preference for equatorial substituents (cf. 5, 163).

Me

Me

(29)a; R = Pr b; R = Ph As expected from the above rationale, a -silyl- or a -stannyl-E-but-2-enyl-9BBN derivatives in the presence of pyridine (or an alkyl-lithium; presumably to form an 'ate' complex) add to aldehydes to-give the threo-adducts (32) available for further conversions (Scheme 23);78the new carbon-carbon double bond has the Z-configuration, reflecting an axial disposition for the silyl or stannyl group in the transition state, cf. (31), to minimize non-bonded interactions with the hydrogens of 9-BBN.

y BQ -

2R-M

M (M = SiMe3 or SnMe3)

(M = SnMe,)

Me

OH(32)

(M =

s n x

Me W

R

R'(\=/

OH Me

OH Reagents: i, RCHO-py; ii, Bu"Li; iii, (CH,O),; iv, Me1

Scheme 23 ??

Y. Yamamoto, H. Yatagai, and K. Maruyama, J. Am. Chem. Soc., 1981,103,1969. Y. Yamamoto, H. Yatagai, and K. Maruyama, J. Am. Chem. Soc., 1981,103, 3229.

"

"

Alcohols, Halogeno-compounds, and Ethers

169

Hoff mann has published full details of his diastereoselective synthesis of homoallylic alcohols from crotyl boronates (cf. 4, 149) and aldehydes (Scheme 24)." In results consistent with the rationalization presented above, E-boronates gave threo -alcohols and 2-boronates gave the erythrodiastereomer with virtually complete diastereoselectivity,i.e. threo :erythro ratios in the products mirroring the E :2 ratio in the starting boronates. A full account has also appeared of work by the same group on addition of chiral allylboronates such as (33) to aldehydes to produce optically active homoallylic alcohols (Scheme 25) (cf. 3, 143), with approx. 70% e.e. in the case of saturated aldehydes and having the configuhtion as illustrated." v, vi

-R Me v. vi

vii, ii, iv

L/

OH

L

Me Reagents: i, Mg; ii, CIB(NMe2)2; iii, ZnBr, and distillation; iv, Me,C(OH)C(OH)Me,; v, RCHO, -78 "C;vi, N(CH$H,OH),; vii, K0Bu'-Bu"Li

Scheme 24

Ph (33) Reagents: i, RCHO, -40 "C; ii, N(CH2CH,0H)3

Scheme 25

The Claisen rearrangement of aliphatic ally1 vinyl ethers, when promoted by trialkylaluminium compounds, provides a route to S,E -alkenyl alcohols (Scheme 26) by uptake of a nucleophile on the aldehydic carbon produced." S,E- Alkynyl alcohols are available from sterically guided 1,4-addition of lithium acetylides to propenyl trityl ketone followed by reductive cleavage of the trityl group.'* Dio1s.-An n.m.r. spectroscopic method has been reported for determination of the stereochemistry of 1,2-diols by examination of the trans -N,N,N',N'tetramethylcyclohexane-1,2-diamine complexes of their cyclic osmate(v~)esters.*~ Organic selenoxides such as Ph2Se0 have been introduced as new 79

R. W. Hoffmann and H.-J. ZeiJ3, J. Org. Chem., 1981,46,1309. T. Herold, U. Schrott, and R. W. Hoffmann, Chem. Ber., 1981,114,359;R. W.Hoffman and T. Herold, ibid., p. 375. K.Takai, I. Mori, K. Oshima, and H. Nozaki, Tetrahedron Lett., 1981,22,3985. R.Locher and D. Seebach, Angew. Chem., Int. Ed. Engl., 1981,20,569. J. F. Resch and J. Meinwald. Tetrahedron Lett., 1982.22, 3159.

General and Synthetic Methods

170

(7R1[qR R3,A1

,

\

R2

(R’

=

Bu’)

HovR

R’

Scheme 26 0

0

,

I

Reagents: i, LiCGCR; ii, LiBHEt,

Scheme 27

oxidative recycling reagents for the hydroxylation of alkenes using osmium tetroxide in catalytic q~antities;’~ the diphenyl selenide PhzSe by-product can itself be re-oxidized by singlet oxygen. One recently reported synthesis of diols has been discussed earlier (Scheme 9).11 In a publication already mentioned in this Report on asymmetric syntheses based on chiral diamines containing a pyrrolidine ring, a synthesis of optically active diols (Scheme 28) from two consecutive Grignard additions to

q N ), Ph

MeO,C (34)

ii-iv

--* i

___)

CHO ‘&-R2 OH

V +

CH,OH +R2 R’ O H

R’

Reagents: i, R’MgBr-MgCl,; ii, R’MgBr; iii, NH,Cl aq.; iv, 2% HCl aq.; v, NaBH,

Scheme 28

the aminal (34) is discussed.50In a somewhat related method, enantiomerically pure diols are available from nucleophilic carbamoylation of ketones (Scheme 29), followed by separation of the diastereomeric products (35) and (36), and reductive cleavage with excess methyl-lithi~m.~’

84

85

A. G. Abatjoglou and D. R. Bryant, Tetrahedron Lett., 1981,22,2051. D.Enders and H. Lotter, Angew. Chem., Int. Ed. Engl., 1981,20,795.

Alcohols, Halogeno-compounds, and Ethers

171

LNqoMe .KMe OH

2 R'-

R1**

P CHO O M

e

L< R 2-

(35)

OH

OkNQ R10 (36)

Reagents: i, R'CORZ- LiN

R 2 OH

R2 0

R 2- +&Me R ' OH

OMe

; ii, MeLi

Scheme 29

Regio- and stereo-selective functionalization of allylic and homoallylic alcohols (37; n = 1or 2) to give 1,2- or 1,3-diols,respectively, has been reported via the carboxylation-halogenation sequence shown in Scheme 3OvS6 R2 R ! - - . , , ( C H ~ ) ~ ~I_ Ri, ii~) R ~ c H ~ + i - iii, - iv~ ~ R y C H 2 ) n + . / - R 3

,

OH

OH

R2

OH

O Y O 0

(37) n = 1or 2

Reagents: i, Bu"Li-CO,; ii, I,; iii, Bu,SnH; iv, base

Scheme 30

Both E- and 2-7methoxyallylboronateshave been found to undergo addition to aldehydes to produce /3 -methoxyhomoallylic alcohols (Scheme 3 1) in good yields with good to excellent diastereo~electivity.~'Another asymmetric synthesis MeOCH=C=CH, OMe

-.Ap OH

MeOCH,CH= CH,

vii. iii, iv

M e& =0B :n

OMe Reagents: i, PhSH-HBF,; ii, potassium naphthalenide; iii, ClB(NMeJ2; iv, Me,C(OH)C(OH)Me,; v, RCHO; vi, N(CH,CH,OH),; vii, Bu"Li-TMEDA

Scheme 31 86

G. Cardillo, M.Orena, G. Porzi, and S. Sandri, J. Chem. SOC.,Chem. Commun., 1981,465. R. W. Hoffrnann and B. Kemper, Tetrahedron Lett., 1981,22,5263.

General and Synthetic Methods

172

of @ -methoxy-alcohols reported this year starts with carbanion formation from the optically active sulphoxide (38) and is shown in Scheme 32;" in the examples reported the a -methoxy-aldehyde precursors to the methoxy-alcohols had 46 and 70% e.e. A new potential route to 1,4-diols is also based on a-lithiation of optically active sulphoxides (Scheme 33) but, as shown, it was observed that the relative stereochemistry of the backbone was independent of the configuration of the s~lphoxide.'~ 0

.S-STol II Tol.'

i-iii

?.

~

.RTO~ iv,v

MeoO+S---Tol

Me0

?*

(38)

\vi

L

H

Me0 Reagents: i, Bu" Li, -78 "C; ii, RCHO; iii, Me,S04-Bu4NOH-CH,CI,-H,O; 1,-NaHCO, aq.; vi, NaBH,

iv, NaI-1,-R',P;

v,

Scheme 32

..

Me

1

OH

Me

nil

rn

-

Reagents: i, LiNPr',, -78 "C; ii, PhCHO; iii, Ra-Ni

Scheme 33

3-Bromoallylsilane has been prepared and exploited as an a- or y hydroxypropenyl synthon in reaction of its Grignard derivative with epoxides followed by phenylselenodesilylation or phenylsulphenyldesilylation, respectively (Scheme 34)90(cf. ref. 61). I

i-iii

MeCH=CHBr

SPh

OAc

OAc

I

I

xi, viii

ix. x

OAc O H

OAc /O\

Reagents: i, NBS; ii, HSiC1,-Et,N-CuCI; iii, 3MeMgBr; iv, Mg; v, RCH-CH,-CuI; vi, Ac,O-py; vii, PhSCI, -78 "C;viii, SnCI,, 0 OC, or silica gel; ix, NaIO,; x, (MeO),P-MeOH; xi, PhSeC1, -78 "C

Scheme 34 88

89

90

L. Colombo, C. Gennari, C. Scolastico, G. Guanti, and E. Narisano, J. Chem. Soc., Perkin Trans. I , 1981, 1278. D.R. Williams, J. G. Phillips, and J. C. Huffman, J. Org. Chem., 1981,46,4101. H. Nishiyama, S. Narimatsu, and K. Itoh, Tetrahedron Lett., 1981.22, 5289.

Alcohols, Halogeno-compounds, and Ethers

173

The selective formation of phenyl ethers from one hydroxy-group of a diol has been achieved with triphenylbismuth diacetate, Ph3Bi(OAc),." Two new protecting groups suitable for 1,2- and 1,3-diols are shown in the ketal (39)92 and the t-butylsilylene derivative (40).93 To,

(CH,), SiBu'2 L O ' VMe

(40)

(39) n = 2 o r 3

Protection.-There have been three reports this year on the selective acetylation of primary alcohols in the presence of secondary alcohols or phenols by transesterification with ethyl acetate (used as solvent) promoted by neutral alumina.94Other acetates can be used, and substitution of the ethyl acetate with ethyl propionate or methyl benzoate leads to primary alkyl propionate and benzoate esters, respe~tively.~~' The removal of acetate groups by transesterification in methanol has been shown to be catalysed by bis(trimethy1silyl)sulphate,(Me3Si0)2S02.95 Aromatic acetates can be deacylated by activated zinc metal in methanol, conditions which do not affect acetates of aliphatic hydroxy-gr~ups.~~ Facile nucleophilic cleavage of the phosphorus-arbonyl carbon bond is the key to the action of a new group of acylating agents for alcohols, the dialkyl acylphosphonates (41).97Benzoylation with (41; R = Ph) has been shown to be much faster for primary than secondary alcohols, allowing selective benzoylation of primary centres. The 'masked' levulinoyl esters (42) have been used to protect hydroxy-groups in oligosaccharide They are stable to the hydrazinolysis conditions used to cleave the levulinoyl (4-oxopentanoyl) group, but are themselves readily converted (using aqueous Hg")to levulinoyl esters for removal. R

A

n P(OEt), II

0 (41)

X&+.(oR 0

s+OR

0 (42)

(43) a; X = SiMe3 b; X = S02Ph

Among newly reported alcohol protecting groups of the alkoxycarbonyl type are the 2-trimethylsilylethoxycarbonyl (TMSEC)99 and 2-phenylsulphonylethoxycarbonyl (PSEC)"' groups; the TMSEC derivatives (43a) are cleaved by 91 92

93

cN

95

96 97 98

S. David and A. Thieffry, Tetrahedron Lett., 1981, 22, 5063. B. H. Lipshutz and M. C. Morey, J. Org. Chem., 1981.46,2419. B. M. Trost and C. G. Caldwell, Tetrahedron Left., 1981, 22, 4999. ( a ) G. H. Posner, S. S. Okada, K. A. Babiak, K. Muira, and R. K. Rose, Synthesis, 1981, 789; ( 6 ) S. S. Rana, J. J. Barlow, and K. L. Matta, Tetrahedron Left., 1981, 22, 5007; (c) G. H. Posner and M. Oda, ibid., p. 5003. Y. Morizawa, I. Mori, T. Hiyama, and H. Nozaki, Synthesis, 1981,899. A. G. Gonzalez, Z. D. Jorge, H. L. Dorta, and F. R. Luis, Tetrahedron Lett., 1981, 22, 335. M. Sekine, A. Kume, and T. Hata. Tetrahedron Left., 1981, 22, 3617. H. J. Koeners, C. H. M. Verdegaal, and J. H. van Boom, R e d . Trau. Chim. Pays-Bas, 1981,100, 118.

C. Gioeli, N. Balgobin, S. Josephson, and J. B. Chattopadhyaya, Tetrahedron Lett., 1981, 22, 969. '* N. Balgobin, S. Josephson, and J. B. Chattopadhyaya, Tetrahedron Lett., 1981,22,3667. 99

General and Synthetic Methods

174

fluoride ion (Bu4NF)or Lewis acid (ZnBr2,ZnC12) whereas the PSEC group is removed from protected alcohols (43b) by weak base (Et3N,NH3 in aqueous dioxan, or K2C03 in aqueous dioxan). The 2-(methy1thiomethoxy)ethoxycarbony1 (MTMEC) protecting group is another newly reported development in this area."' The MTMEC-alcohols (44) can be deprotected by first removing the 'methylthiomethyl' portion (Scheme 3 3 , exposing a hydroxy function that presumably accelerates the ammonia-mediatedremoval of the rest of the protecting group. It has been found that allyloxycarbonyl derivatives (45) of alcohols can be converted in the presence of a Pdo complex to either the corresponding ally1 ethers, or by hydrogenolysis to the alcohols (Scheme 36), via 7-ally1 palladium complexes.'o2An interesting new method for carbonate-type protection of alcohols is to use the hydroquinoxy-derivatives (46),which can be cleaved by a simple electrochemicaloxidation [equation (5)].Io3 All of the alkoxycarbonyl protecting groups mentioned above are readily introduced by the corresponding chloroformates.

(44) Reagents: i, Hg(CI04),-2,4,6-collidine; ii, NH,-dioxan aq.

Scheme 35 ROH

-OKoR 0 ROCH,CH=CHz

(45) Reagents: i, Pd(PPh,),; ii, Bu,SnH-p-nitrophenol; iii, Bu,SnH; iv, H,O+

Scheme 36 OCO, R

@ OEt

H#-e

_ I

@ I 1 +ROH

(5)

0

(46)

The formation of 2-tetrahydropyranyl (THP) ethers from dihydropyran and primary, secondary, or tertiary alcohols has been found to be catalysed by polymers of 4-vinylpyridinium p-toluenesulphonate (or of the 2-vinyl compound).lo4Bis(trimethylsily1)sulphate (see above) has also been reported as a catalyst both for the formation of THP ethers from alcohols and dihydropyran, lo'

lo2 lo3

S. S.Jones, C. B. Reese, and S. Sibanda, Tetrahedron Lett., 1981, 22, 1933. F. Guibe and Y.Saint M'Leux, Tetrahedron Lett., 1981, 22, 3591. R. W. Johnson, E. R. Grover, and L. J. MacPherson, Tetrahedron Lett., 1981,22,3719. F. M. Menger and C. H. Chu,J. Org. Chem., 1981,46,5044.

Alcohols, Halogeno-compounds, and Ethers

175

and for their cleavage by transacetalization in methan01.'~ A new preparation of methoxymethyl ethers from primary or secondary alcohols and dimethoxymethane employs 'Nafion-H', a perfluorinated solid superacid resin, as catalyst, thereby reducing the work-up to a filtration rather than aqueous base treatment. lo5 A recently introduced alternative to the methoxymethyl group for hydroxy-group protection is the use of ethoxymethyl ethers;lo6 they are made by treatment of the alcohol or phenol with diethoxyethane (as solvent) and various acid catalysts, distilling out the ethanol formed as an azeotrope with diethoxyethane. Another acetal-type protecting group reported this year is guiacylmethyl (GUM),'" introduced by reaction of guiacylmethyl chloride (47) with metal alkoxides or phenoxides, or more selectively by treating alcohols with (47) and aqueous base under phase-transfer conditions (Scheme 37). The GUM ethers are stable to some acidic conditions that cleave THP, 2-tetrahydrofurfuryl (THF), and t-butyldimethylsilyl (TBDMS) ethers, whereas they are less stable towards acid than 2-methoxyethoxymethyl (MEM) or 2-trimethylsilylethoxymethyl (SEM) ethers, and are removed instantaneously by ZnBr2.

OMe

00"': OCH,CI

OCH,OR

--%

ROH

(47) Reagents: i, PC1,-CCl,; ii, RO-M', or ROH-Bu,NHSO,-NaOH aq.-PhH; iii, ZnBr,

Scheme 37

Benzyl trichloracetimidate (48) is a new reagent for acid-catalysed benzylation of alcohols in the presence of trifluoromethanesulphonic acid, lo' and benzyl p-toluenesulphonate-potassium carbonate has been recommended as a benzylating system for phenols, especially in cases where benzyl chloride-potassium carbonate gives C-alkylated imp~rities.'~'Facile removal of benzyl ether protecting groups has been achieved by catalytic transfer hydrogenation with Pd(OH), on carbon and cyclohexene as hydrogen-donor."' A new procedure for 0-tritylation by treatment of an alcohol trimethylsilyl ether with trityl trimethylsilyl ether is shown in equation (6).11' The synthesis and characterization has been completed of 4-dimethylamino-N-triphenylmethylpyridiniumchloride (49),"' a postulated intermediate in the formation of trityl ethers from alcohols NMe, I

CPh, (49) lo' '06

lo' lo* '09

'lo

'I2

G. A. Olah, A. Husain, B. G. B. Gupta, and S. C. Narang, Synthesis, 1981,471. U.-A. Schaper, Synthesis, 1981,794. B. Loubinoux, G. Coudert, and G. Guillaumet, Tetrahedron Lett., 1981,22,1973. T.Iversen and D. R. Bundle, J. Chem. Soc., Chem. Commun., 1981,1240. P. M.Dewick, Synth. Commun., 1981,11,853. S. Hanessian, T. J. Liak, and B. Vanasse, Synrhesis, 1981,396. S . Murata and R. Noyori, Tetrahedron Lett., 1981,22,2107. 0.Hernandez, S. K. Chaudhary, R. H. Cox, and J. Porter, Tetrahedron Lett., 1981,22, 1491.

General and Synthetic Methods

176 ROSiMe3

+ Ph3COSiMe3 Me3SiOSO2CF,b

(Me3Si)*0 + ROCPh:,

(6)

and triphenylmethyl chloride catalysed by 4-dimethylaminopyridine (4,155); salt (49) is itself effective in selective conversion of primary alcohols to trityl ethers. The selective blocking of primary or secondary hydroxy-groups with electroactive protecting groups reduced at different potentials is illustrated in Scheme 38 with tritylone (cf. 4,155) and 4-cyanobenzyl ethers, removed at -1.4 and -2.2 volts, respectively (relative to an Ag/AgCl electr~de)."~

U

H

HO

Reagents: i,

@

-H+; ii, NaH-

Ph OH

0 CH,Br

; iii, -1.4 volts, LiBr-MeOH; iv, -2.2 volts,

CN

Bu,NF-MeOH

Scheme 38

The hydrogen-activated complex [Ir(cycl~-octadiene)(PMePh~)~PF~] has been utilized in carbohydrate chemistry for the isomerization of allyl ether protecting groups to the corresponding enol ethers that can then be removed hydrolytically (cf. 5 , 168).l14 The potential of allyl as a protecting group for phenols has been increased by the report of direct cleavage of allyl phenyl ethers to release the phenols on treatment with bis(benzonitrile)palladium(II) chloride, [(PhCN)2PdC12].'l5 A new method for the preparation of trimethylsilyl (TMS) and TBDMS ethers under mild phase-transfer conditions"6 involves treatment of an alcohol with the appropriate silyl chloride and solid K2C03(or Na2C03)in the presence of

''' C. van der Stouwe and H. J. Schafer, Chem. Ber., 1981,114,946. 'I5

J. J. Oltvoort, C. A. A. van Boeckel, J. H. de Koning, and J. H. van Boom,Synthesis, 1981, 305. J. M. Bruce and Y. Roshan-Ali, J. Chem. Res. (M), 1981,2564; (S),193.

'I6

M. Lissel and J. Weiffen, Synrh. Commun., 1981.11. 545.

'I4

177

Alcohols, Halogeno-compounds, and Ethers

the quaternary ammonium salt 'Aliquat 336'. N,N'-Bis(trimethylsily1)urea has been found to be a useful silylating reagent for alcohols in dichloromethane solution without acid or base catalyst^;^" precipitation of urea is observed. Three publications have appeared extending the use of allylsilanes as silylating agents for alcohols (cf. 5 , 167) [equation (7)]. In one report the reaction is R'3SiCH2CR2=CH2 + R 3 0 H+ R',SiOR3

+MeCR2=CH2

(7)

catalysed by trimethylsilyl iodide or by iodine;"' it is possible I2 catalysis operates by in situ generation of Me3SiI from the allysilane. The other reports both use allyltrimethylsilane with trifluoromethanesulphonic acid catalysis to form TMS ethers,' 19~120 presumably via generation in situ of trimethylsilyl trifluoromethanesulphonate (TMS triflate) [equation (S)]as the actual silylating species; other silanes, such as phenyltrimethysilane, may be substituted for the allyltrimethylsilane although the corresponding silylations may be slower.'20 CH2=CHCH2SiMe3

+ CF3S03H -P

CH2=CHMe

+ CF3S03SiMe3

(8)

Two other trialkylsilyl trifluoromethanesulphonates, the TBDMS and triisopropylsilyl (TIPS) compounds, have been prepared and used in silylation reactions catalysed by 2,6-lutidine;12' TBDMS triflate allows formation of TBDMS ethers from tertiary and unreactive secondary alcohols, and TIPS triflate reacts effectively with primary and secondary alcohols. Use of the perfluorinated resin sulphonic acid trimethylsilyl ester 'Nafion-TMS', an immobilized TMS triflate, as a silylating agent for alcohols (cf. 5 , 167) is discussed in a publication on applications of TMS triflate in ~ynthesis.~' Full details have appeared of application of the C-silylated ester Me3SiCH2C02Et to silylations of alcohols mediated by fluoride ion (cf. 1,170).'22In an extension of earlier work with the TMS enol ethers of esters (4,154), ketene methyl TBDMS acetal (50) has been advocated as a stable readily available reagent for conversion of alcohols to TBDMS ethers under mild condition~.'~~ In a related approach the O-silylated derivatives (51) and (52), readily formed from acetylacetone (R = Me) or methyl acetoacetate (R = OMe), have been found to be effective reagents for the transformation of alcohols to their TBDMS'24" and TMS ethers,1246respectively; reagents (5 1)require acid catalysis whereas (52) react without catalyst. Some further details have appeared

xz

Me0

OSiMezBu'

(50)

'I7

lZo

122 123 124

OSiMe,

(5 1) R = Me or OMe

A-COR (52) R = Me or OMe

W. Verboom, G. W. Visser, and D. N. Reinhoudt, Synthesis, 1981,807. A. Hosomi and H. Sakurai, Chem. Lett., 1981, 85. T. Morita, Y. Okamoto, and H. Sakurai, Synthesis, 1981, 745. G. A. Olah, A. Husain, B. G. B. Gupta, G. F. Salem, and S. C. Narang, J. Org. Chem., 1981, 46,5212. E . J. Corey, H. Cho, C. Rucker, and D. H. Hua, Tetrahedron Lei., 1981,22,3455. E. Nakamura, K. Hashimoto, and I. Kuwajima, Bull. Chem. SOC.Jpn., 1981, 54, 805. Y. Kita, J. Haruta, T. Fujii, J. Segawa, and Y. Tamura, Synthesis, 1981,451. ( a )T. Veysoglu and L. A. Mitscher, Terruhedron Left., 1981,22, 1299; ( b ) ibid., p. 1303.

General and Synthetic Methods

178

of the cleavage of TBDMS ethers with aqueous HF in acetonitrile (4,154), a method developed during prostaglandin synthesi~.~''

Reactions.-A new chiroptical method has been developed for determining the absolute configuration of allylic alcohols from CD measurements on their benzoate esters.126Enantiomeric composition, and in some cases absolute configurations, of alcohols (and thiols) can be derived from n.m.r. spectroscopic measurements on the ester derivatives formed with optically active a -[1-(9anthryl)-2,2,2-trifluoroethoxy]acetic acid (53).127 Two publications have appeared on the preparation of a chiral stationary phase (54)for h.p.1.c. that consists of optically active N-(3,5-dinitrobenzoyl)phenylglycineionically bonded to a y -aminopropyl silanized silica;'*' enantiomers of various classes of solute, including aryl alkyl carbinols, can be separated on columns containing (54)and their orders of elution related to absolute configurations by a chiral-recognition model. The enantioselective hydrolysis of racemic acetate esters by Rhizopus nigricans has been shown to produce optically active alcohols of absolute configuration (55), where R' is 'effectively larger' than R2,having 28-83'/0 e.e.12' This is a kinetic resolution method, and another example of this approach to appear recently is the resolution of racemic allylic alcohols by enantioselective ep~xidation.'~'Using t-butyl hydroperoxide-titanium(1v)isopropoxide with excess (+)-di-isopropyl tartrate as the reagent combination, the enantiomer (56) is the slower reacting and if the reaction is allowed to proceed to at least 50-60% conversion then allylic alcohols (56)may often be isolated with good e.e.

(54)

(53) HO H

/4R2 R' (55)

S

R'

3 \OH

ROK

X

(57) a; x = N R ' ~ b; X = SMe

R2 H c;

x=

NAN

u

d; X = OPh

The mesylate esters of secondary alcohols undergo clean inversion upon nucleophilic substitution with caesium carboxylates, especially the propionate

12'

'21 1 2 '

'" lZ9 130

R. F Newton, D. P. Reynolds, C. F. Webb, and S. M. Roberts, J. Chem. SOC., Perkin Trans. 1, 1981,2055. N. Harada, J. Iwabuchi, Y. Yokota, H. Uda, and K. Nakanishi, J. Am. Chem. SOC.,1981,103,5590. W. H. Pirkle and K. A. Simmons, J. Org. Chem., 1981,46,3239. W. H. Pirkle and J. M. Finn, I. Org. Chem., 1981,46, 2935;W.H. Pirkle, J. M. Finn, J. L. Schreiner, and B. C. Hamper, J. Am. Chem. Soc., 1981,103,3964. K.Kawai, M. Imuta, and H. Ziffer, Tetrahedron Lett., 1981,22,2527. V. S. Martin, S. S. Woodard, T. Katsuki, Y. Yamada, M. Ikeda, and K. B. Sharpless, J. Am. Chem. Soc.. 1981,103,6237.

Alcohols, Halogeno-compounds, and Ethers

179

in DMF, to afford esters from which the 'inverted' alcohols are readily obtained by hydr01ysis.l~' Reports this year on the deoxygenation of alcohols to alkanes include full details of the dissolving metal reduction of esters with either lithium-ethylamine (for hindered cases) (cf.3, 146) or the sodium-potassium eutectic and t-butylamine containing 18-cr0wn-6,'~~ and a full account of the reduction of the thiocarbamates (57a)with potassium-t-butylamine in the presence of 18-crown-6 (4, 15l).133 The radical-induced trialkyltin hydride reduction of dithiocarbonate esters has been extended to primary alcohol derivatives ( S 7 b , ~ ) ,and ' ~ ~secondary alcohols have been smoothly deoxygenated by tributyltin hydride reduction of the phenoxythiocarbonyl derivatives (57d).I3' Primary and secondary alcohols or methyl ethers are reported to be deoxygenated to alkanes by a trimethylsilyl chloride-sodium iodide-zinc reagent in good yields. 136 Two related recent variants of the Claisen rearrangement based on allylic alcohols are shown in Scheme 39 and lead to a,P,y,S-dienoic acids or deriva-

I

0

II

kSPh

O

y

R

'

R2

\

J

O=SPh

NR:

Reagents: i, CF,CH,S(O)Ph-KH; ii, H,O-OH ; iii, CCI, reflux-CaCO,; iv, PhSCsCNR3,-toluene reflux (Rz# H), or BF,, 20 'C (R2 = H); v, NaIO,; vi, toluene reflux Scheme 39

tives.13' The dianions formed from 2-alkenyloxyacetic acids (58) give exclusively [2,3]Wittig rearrangement at low temperature (Scheme 40),as part of a synthesis of P,y-unsaturated aldehydes or conjugated dienoic 13'

133 134

13'

'37

13'

W. H. Kruizinga, B. Strijtveen, and R. M. Kellogg, J. Org. Chem., 1981, 46, 4321. A. G. M. Barrett, C. R. A. Godfrey, D. M. Hollinshead, P. A. Prokopiou, D. H. R. Barton, R. B. Roar, L. Joukhadar, J. F. McGhie, and S. C. Misra, J. Chem. SOC.,Perkin Trans. 1, 1981, 1501. A. G. M. Barrett, P. A. Prokopiou, and D. H. R. Barton, J. Chem. SOC.,Perkin Trans. 1,1981, 1510. D. H. R. Barton, W. B. Motherwell, and A. Stange, Synthesis, 1981, 743. M. J. Robins and J. S. Wilson, J. A m . Chem. Soc., 1981, 103, 932. T. Morita, Y. Okamoto, and H. Sakurai, Synthesis, 1981, 32. T. Nakai, K. Tanaka, K. Ogasawara, and N. Ishikawa, Chem. Lett., 1981, 1289; T. Nakai, H. Setoi, and Y. Kageyama, Tetrahedron Lett., 1981.22, 4097. T. Nakai, K. Mikami, S. Taya, Y. Kimura, and T. Mimura, Tetrahedron Letr., 1981, 22, 69.

General and Synthetic Methods

180

R

1

A

R

3

*R'3

CHO

CO,H

Reagents: i, BrCH,CO,H-NaH; ii, LiNPr',, -78 "C; iii, TsCI-H,O';

iv, KOBu'; v, H,O'; vi, NaIO,

Scheme 40

2 Halogeno-compounds Preparation.-A recent extensive review of fluorination methods in organic chemistry includes discussion of methods involving CF30F (1,173, fluorine A reported diluted with nitrogen (5, 172), and fluoride ion as a nu~leophi1e.l~~ improvement to the hexachloroacetone-triphenylphosphine procedure for conversion of allylic alcohols to the chlorides (2, 148; 4, 158) is to use sulpholane as solvent rather than the hexachloroacetone, and to thus reduce the proportion of the latter reagent to 1 molar equivalent or less.14o Imidazolylsulphonate has been developed as an efficient and versatile leaving group, illustrated by the conversion of primary and secondary alcohols via the imidazolylsulphonate esters (59) to alkyl fluorides, chlorides, and iodides (Scheme 41).141 Spray-dried KF has been shown to be less hygroscopic and to ROSiMe, , / u

ROS02N4N

u\

RX

(59)

ROH

-

[ ~ o s O ~ N ~ h l e I R~I

i&

u

ROS0,CI Reagents: i, Bu,NF; ii,

zSO, ; iii, NaH; iv, SO,CI,; v, imidazole; vi, X--;vii, Me1

Scheme 41

be more effective as a fluorinating agent than the usual calcine-dried KF, for example in preparation of alkyl fluorides from Tertiary and secondary alkyl fluorides have been converted to iodides by means of trimethylsilyl iodide, or reagent combinations thought to produce Me3SiI in situ (Me3SiC1-NaI 13'

14' 14'

M. R. C. Gerstenberger and A. Haas, Angew. Chem., Int. Ed. Engl., 1981, 20, 647. R. M. Magid, B. G. Talley, and S. K. Souther, J. Org. Chem., 1981, 46, 824. S. Hanessian and J.-M. Vatkle, Tetrahedron Lett., 1981, 22, 3579. N. Ishikawa, T. Kitazume, T. Yamazaki, Y. Mochida, and T. Tatsuno, Chem. Lett., 1981, 761.

Alcohols, Halogeno-compounds, and Ethers

181

or Me3SiSiMe3-12);143 the by-product here is Me3SiF and formation of the strong Si-F bond is thought to contribute to the driving force of the process. Tertiary chlorides are also converted to iodides by these reagents. A variety of aliphatic sulphur-containing compounds, such as sulphonic and sulphinic acids, sulphonates, thiolsulphonates, thiols, and disulphides, are all transformed efficiently to alkyl iodides by triphenylphosphine-iodine.144 A simple 'one-pot' modification of the Hunsdiecker reaction for conversion of carboxylic acids to alkyl bromides with decarboxylation has appeared recently which involves conversion to the T1' carboxylate followed by addition of 1.5 molar equivalents of bromine (Scheme RC02H

A

H2C03 + RCO2TI' !+ RBr

Reagents: i, TI,CO,; ii, 1.5Br,-CC14 reflux

Scheme 42

An electrochemical chlorination of isoprenoid-type alkenes in a methylene chloride-water-sodium chloride system to produce allylic chlorides has been reported [equation (9)];146presumably Cl' is generated by anodic oxidation as the reactive species. The selectivity of chlorination is affected markedly by the conditions, but trisubstituted 'terminal' double bonds of the type shown in equation (9) are the most reactive.

Anode

Organotriethoxysilanes (2; X = OEt) or organosilatranes (3), available by hydrosilylation of alkenes (Scheme 2) can be converted to primary bromides using NBS to give overall 'anti-Markovnikov' hydrohal~genation.~ Various procedures have been published this year for the transformation of trialkylboranes to alkyl halides. Alkyl chlorides are prepared by treatment with C1,NTs (dichloramine-T) or C12NC02Et,14' bromides by treatment in the absence of light with bromine or BrC1,I4*the latter either freshly prepared or made in situ from NaBr and TsNClNa (chloramine-T), and iodides by treatment Combined with a hydroborwith IC1 prepared in situ (NaI-~hloramine-T).~~~ ation, these methods lead to 'anti-Markovnikov' hydrohalogenation of alkenes, but not all of the three alkyl groups on the organoborane are halogenated. This drawback is alleviated by the use of unsymmetrical trialkylboranes (60) such as B-alkyl-9-BBN derivatives147 or dicyclohexylalkylboranes'48.'49 (Scheme 43) '43 144

'" 14'

147 148 149

G. A. Olah, S. C. Narang, and L. D. Field, J. OrK. Chem., 1981, 46, 3727. S. Oae and H. Togo, Synthesis, 1981, 371. R. C. Carnbie, R. C. Hayward, J. L. Jurlina, P. S. Rutledge, and P. D. Woodgate, J. Chem. Soc., Perkin Trans. 1, 1981, 2608. S. Torii, K. Uneyarna, T. Nakai, and T. Yasuda, Tetrahedron Lett., 1981, 22, 2291. V. B. Jigajinni, W. E. Paget, and K. Smith, J. Chem. Res. ( S ) , 1981, 376. G. W. Kabalka, K. A. R. Sastry, H. C. Hsu, and M. D. Hylarides, J. Org. Chem., 1981, 46, 3113. G. W. Kabalka and E. E. Gooch, J. Org. Chem., 1981,46,2582.

182

General and Synthetic Methods

and this approach has also been applied to the conversion to iodides using ICl-NaOAc reported last year (5, 172).l5O R1CH=CH2

R'CH2CH2BR22

RCH2CH2X

(60) Reagents: i, RZzBH;ii, 'X"

Scheme 43

Vinyl Halides. E- or 2-Vinyl fluorides can be prepared stereospecifically by trans-addition of 'BrF' (prepared in situ from NBS and HF- pyridine complex) to alkenes followed by trans-coplanar elimination of HBr (Scheme 44)15' in a sequence very similar to one featured in an earlier Report (3,153). Both isomers R'

IF-

R 2 i B r R' I H

w

H

..

R2

R' H

R2

Reagents: i, NBS-HF-py; ii, KOH

Scheme 44

of 1-chloroalkenes are available by Nio-catalysed Grignard addition to trans or cis - 1,2-dichloroethylene (Scheme 45).15' The addition of a reliable desilylation method to the known conversion of 1-alkynylsilanes to E- or Z-l-halo-lalkenylsilanes (via hydroalumination-halogenation) has generated a new route

Reagents: i,

CI

rnCl-Ni(PPh,),;

ii,

CI

'@Cl-Ni(PPh,),

Scheme 45

(Scheme 46) to both isomers of vinyl halides (X = Cl,Br, or I) from a 1 k ~ n e s . l ~ ~ Vinyl bromides can also be obtained from alkynes via hydroboration to vinyl boronic acids followed by treatment with IC1 (Scheme47),'54 and a recent alternative approach to vinyl bromides by condensation of carbonyl compounds with dibromomethane is outlined in Scheme 48.155 lS0

"' lS2 lS3

lS4 lS5

E. E. Gooch and G. W. Kabalka, Synth. Commun., 1981,11, 521. G. Boche and U. Fahrmann, Chem. Ber., 1981,114,4005. V. Ratovelomanana and G. Linstrurnelle, Tetrahedron Letr., 1981, 22, 315. H. P. On, W. Lewis, and G. Zweifel, Synthesis, 1981, 999. G. W. Kabalka, E. E. Gooch, and H. C. Hsu, Synth. Commun., 1981,11,247. D. R. Williams, K.Nishitani, W. Bennett, and S. Y. Sit, Tetrahedron Lett., 1981, 22, 3745.

Alcohols, Halogeno-compounds, and Ethers RCECSiMe,

RHSiMc,

H

X

-

183 RHX

H

R

R

SiMe,

X

LJ

-X

Reagents: i, Bu',AIH; ii, NCS(X = CI), or Ar, ( X = Rr), or I, (X = I); iii, hltBr, (X = C1 or Br), or Bu'Li (X = I); iv, NaOMe-MeOH

Scheme 46

RC_CH

2 [RCH=CHB(OH),?] 3 RCH=CHI

Reagents: i, o o > ;R ii, H,O; l l iii, ICI-NaOAc

/ o

Scheme 47

R'COR'

J R'R2C(OH)CHBr2 % R'R*C=CHBr

Reagents: i, LiN(cyclohexyl),-CH,Br,; ii, Zn-HOAc

Scheme 48

Reactions.-If allylic chlorides are treated with strong base in the presence of a primary bromide then a -haloallyl-lithiurns are both generated and alkylated in situ [equation (lo)], thus avoiding 'self-consumption' of the allyl ha1ide;ls6 exclusive a! -alkylation is observed.

Methods reported this year for the reduction of alkyl halides to alkanes include the potassium-dicyclohexyl- 18-crown-6 reduction of alkyl sodium borohydride reduction of alkyl chlorides, bromides, and iodides (or sulphonate esters) under liquid-liquid phase-transfer ~ o n d i t i o n s , and ' ~ ~ the selective reduction of tertiary alkyl, benzyl, and allyl halides with the borate (61).ls9Continuing Li +Bu,-,Bu B

15'

159

T. L. Macdonald, B. A. Narayanan, and D. E. O'Dell. J. Org. Chem., 1981,46, 1504. T. Ohsawa, T. Takagaki, A. Haneda, and T. Oishi, Tetrahedron Lett., 1981, 22, 2583. F. Rolla, J. Org. Chem., 1981, 46, 3909. H. Toi, Y. Yamamoto, A. Sonoda, and S. Murahashi, Tetrahedron 1981, 37, 2261.

General and Synthetic Methods

184

studies on the complex reducing agents formed from sodium hydride, sodium t-amylate, and metal halides MX, (known as MCRA) have revealed their ability to reduce organic halides;16’ NiCRA and ZnCRA are selective reducing systems, for example for alkyl bromides in the presence of chlorides.

Halogen Displacement by Nucleophiles-Phase-transfer Methods. Publications this year on catalysis by phase-transfer (PT) of the SNreactions of alkyl halides [equation (1l)] have concentrated on heterogeneous polymer-bound catalysts RX

+ M+Y-

-P

RY

+ M’X-

(11)

(triphase catalysis, TC) and some newly developed systems. Conditions for the reaction of l-bromo-octane or benzyl bromide in organic solution with aqueous sodium cyanide and catalysed by the polystyrene-based benzyltributylphosphonium salt (62) have been studied in detail;16’ for example, reaction rates increase with mechanical stirring rate up to an optimum of 600 r.p.m., with decrease in catalyst particle size, and with increased swelling power of the organic solvent! Full details are now available of the properties as PT catalysts of crown ethers and cryptands, such as (63) and (64) respectively, bonded to polystyrene

by long spacer chains (cf. 2, 137);16’ reactions catalysed include various nucleophilic substitutions on l-bromo-octane, and the catalytic activity was found to be better for the cryptands than for the crowns or corresponding ‘onium’ salts. Studies on a similar set of test reactions with the polymeric crown (65) have shown that a ‘pendant’ crown, i.e. with long spacer chain, is not necessary for catalytic activity (cf. 4,162 for a similar conclusion with ‘onium’ salt polymer^).'^^ Some immobilized benzo-18-crown-6 derivatives, such as (66), have been studied as catalysts for the l-bromo-octane-KCN reaction in both 160

16’ 16*

163

R. Vanderesse, J.-J. Brunet, and P. Caubere, J. Org. Chem., 1981,46, 1270. M. Tomoi and W. T. Ford, J. Am. Chem. SOC.,1981, 103, 3821, 3828. F. Montanari and P. Tundo, J. Org. Chem., 1981,46,2125. K. Fukunishi, B. Czech, and S. L. Regen, J. Org. Chem., 1981,46, 1218.

185

Alcohols, Halogeno-compounds, and Ethers

solid-liquid-liquid and solid-solid-liquid modes; 164 rates increase with increased functionalization of the polymer backbone. P

O

T

e C H 2 O C H z (65)

The tetrakis-sulphoxides (67) have been reported as a new type of PT catalyst in a solid-liquid mode, for example in S, reactions of l-bromo-octane.'h' Nucleophilic substitutions of 1-bromo-octane and benzyl bromide are again the test reactions in a report on the use of the sucrose-ethylene oxide adducts (68a) as PT catalysts in both solid-liquid and liquid-liquid modes.'"" The methacrylate ester derivative (68b) has been polymerized to a cross-linked gel that acts in a TC capacity for the same reactions. In a related approach some modified dextran anion exchangers carrying lipophilic substituents, such as the modified hydroxypropylated dextran gel shown in (69), have been synthesized and shown to catalyse displacement reactions including the alkyl bromide to iodide transformation under TC condition^.^"' CH20R

CH,OR

(68) a; R = + C H 2 C H 2 0 j , H b; R = +CH2CH20j,COCMe=CH2

3 Ethers Preparation.-A new procedure for the conversion of esters to ethers via desulphurization of the corresponding thionoesters is shown in Scheme 49. I"' lh5

'"

167

A. van Zon, F. de Jong, and Y. Onwezen, Reel. Trav. Chim. Pays-Bas, 1981,100,429. H. Fujihara, K. Imaoka, N. Furukawa, and S. Oae, Chem. Lett., 1981,1293. H. Gruber and G. Greber, Monatsh. Chem., 1981,112,1063. H.Kise, K.Araki, and M. Seno, Tetrahedron Lett., 1981,22, 1017. S. L. Baxter and J. S. Bradshaw, J. Org. Chem., 1981,46, 831.

General and Synthetic Methods

186 R'C02R2

0 ,,

Reagents: i, MeO,

p,

,p O

S II

R1COR2 % R'CH20R2 O

M

e ; ii, Ra-Ni

S

Scheme 49

A recently described variant of the Williamson synthesis is the reaction of primary alkyl bromides or iodides with T1' alkoxides of hydroxy-compounds containing an additional oxygen atom suitably placed to form a 5-,6-, or 7membered complex of type (70).169

The synthesis of allylic ethers from alkenes via electrochemical oxyselenenylation has been mentioned earlier in this Report (Scheme 13).'" Details have appeared of the reaction of acetals of a,p -unsaturated aliphatic aldehydes with Grignard reagents in the presence of Tic& to give allylic ethers in high yields [equation (l2)];l7' it was also found that the 2,4-dichlorophenoxy-groupcould R'CH=CHCH(OR2)2 + R3MgBr

-78 "b

R'CH=CHCH(OR2)R3

(12)

be displaced by Grignard reagents from the mixed acetals (71) formed from aromatic aldehydes or alkyl vinyl ethers. The reaction of allylsilanes with acetals to give homoallylic ethers [equation (13)], previously known to be mediated by R3SiCR1R2CR3=CR4R5+ R6R7C(OR8)2+ R'R2C=CR3CR4R5C(OR8)R6R7 (13)

TiC14 (1,179) and by TMS triflate (5, 175),has now been reported using catalytic quantities of trimethylsilyl iodide, or with catalytic I2 and a slight excess of the allylsilane (i.e. in situ generation of Me3SiI).17' Reactions.-New methods for the synthesis and cleavage of benzyl and trityl ethers, and for the cleavage of ally1 ethers have been discussed in an earlier section (Protection of Alcohols). Primary and secondary alkyl methyl ethers have been demethylated by the combination boron tribromide-sodium iodide15-crown-5,172 The reagent methyltrichlorosilane-sodium iodide is a new combination for regioselective ether cleavage;'73 for example aliphatic methyl ethers undergo predominant demethylation to alcohols (for primary or secondary alkyl groups) or iodides (in tertiary cases).

'" 170 17' 17'

173

H.-0. Kalinowski, G. Crass, and D. Seebach, Chem. Ber., 1981, 114,477. H. Ishikawa, T. Mukaiyama, and S. Ikeda, Bull. Chem. SOC.Jpn., 1981,54,776. H. Sakurai, K. Sasaki, and A. Hosomi. Tetrahedron Lett., 1981, 22, 745. H. Niwa, T. Hida, and K. Yamada, Tetrahedron Lett., 1981,22, 4239. G. A. Olah, A. Husain, B. G. B. Gupta, and S. C. Narang, Angew. Chem., Int. Ed. Engl., 1981, 20, 690.

187

Alcohols, Halogeno-compounds, and Ethers

Three reports have appeared on the regio- and stereo-selective [2,3]Wittig (cf.also this Report, rearrangements of unsymmetrical bis(ally1ic) Scheme 40); using butyl-lithium at low temperatures exclusive 2,3-migration is observed, controlled by predominant lithiation of the ally1 moiety carrying the smaller total of a- and y-alkyl substituents, as shown in equation (14).174The R3

Bu“Li, 85 ‘C

-’R

~

O RZ T

R

3

R’+R2

(14) OH

product 1,5-dien-3-ols can be used in subsequent reactions and those investiand the sequences gated include several variants of the Claisen rearrange~nent,’~’ outlined in Scheme 50 for regiocontrolled joining of two or three allylic moieties. 176

oxy-Cope/Claisen

[2,3] Wittig /

Scheme 50

4 Thiols and Thioethers

The S-alkylation of the sodium salt (72) of thiosaccharin is the basis of a new route to thiols from alkyl halides (Scheme 51),177The conversion of alkyl halides (RX) to thiolacetates (RSCOMe), and hence to thiols by saponification, has been shown to be effected by a quaternary ammonium resin with thiolacetate as c o ~ n t e r i o n . ”Thiolacetates ~ are also available in one step from alcohols in 17‘

’” 176

177

17’

T. Nakai, K. Mikami, S. Taya, and Y. Fujita, J. Am. Chem. Soc., 1981,103, 6492. K. Mikami, N. Kishi, and T. Nakai, Chem. Lett., 1981, 1721. K. Mikami, S. Taya, T. Nakai, and Y. Fujita, J. Org. Chem., 1981,46, 5447. K. Inomata, H. Yamada, and H. Kotake, Chern. Lett., 1981, 1457. G. Cainelli. M. Contento, F. Manescalchi, and M. C. Mussatto, Synthesis, 1981, 302.

188

General and Synthetic Methods

high yield using thiolacetic acid-triphenylphosphine-di-isopropylazodicarboxylate.'71 The acid catalysed rearrangement of dialkyl xanthates to S,S'-dialkyl dithiocarbonates is the key step in another new sequence for transformation of alcohols to thiols (Scheme 52);l8' a new procedure for the crown ether-catalysed synthesis of xanthates from alcohols is also relevant here.181 N R;

SR'

(72) Reagents: i, R'X; ii, R2,NH

Scheme 51 0

ROH -!=% ROCS2Me

II RSCSMe A RSH

Reagents: i, NaH; ii, CS,; iii, MeI; iv, CF3C0,H; v, H2N(CH2)2NH2 or HS(CH2),0H

Scheme 52

Benzylic alcohols have been converted directly to benzyl alkyl sulphides by treatment with an organic disulphide and P214.182Primary amines can be transformed to alkyl phenylthioethers by treatment of the pyridinium salts (l), obtained from the amines (Scheme l),with sodium thiophenoxide.2 Symmetrical and unsymmetrical thioethers can be prepared from an aldehyde or ketone and a thiol in the presence of pyridine-borane [equation (15)].'83 Full details have

now appeared for the synthesis of ally1 sulphides by phenylthio migration in

p -phenylthio-alcohols, controlled by a trimethylsilyl group (cf.1,18O);lg4this encourages, for example, the thermodynamically unfavourable migration of phenylthio from secondary to secondary or tertiary centres (73) + (74).

$

,

' z x H TsOH s i M e 3

R2 (73)

PhS

R2

R'

(74)

New reagents for the sulphoxide to sulphide reduction are trimethylsilyl chloride-sodium bromide (Me3SiBr in situ),'85 trimethylsilyl chloride-zinc,lg6 and t-butyl b ~ 0 m i d e . l ~ ~ 179

R. P. Volante, Tetrahedron Lett., 1981,22,3119.

la'

M.W.Fichtner and N. F. Haley, J. Org. Chem., 1981,46,3141.

la'

R. Chenevert, R. Paquin, and A. Rodrique, Synth. Commun., 1981,11,817. H. Suzuki and N. Sato, Chem. Lett., 1981,267. Y . Kikugawa, Chem. Lett., 1981,1157. I. Fleming, I. Paterson, and A. Pearce, J. Chem. SOC.,Perkin Trans. I , 1981,256. A. H. Schmidt and M. Russ, Chem. Ber., 1981,114,1099. A. H.Schmidt and M. Russ, Chem. Ber., 1981,114,822. C. Tenca, A. Dossena, R. Marchelli, and G. Casnati, Synthesis, 1981,141.

la3 la4

la6

'13'

Alcohols, Halogeno-compounds, and Ethers

189

5 Macrocyclic ‘Crown’ Polyethers and Related Compounds Synthesis.-A safe and efficient procedure for the isolation and purification of crown ethers (avoiding vacuum distillations that have been reported to give explosions in some circumstances) involves complex formation with alkalineearth metal alkanedisulphonates, for example BaCH2(SO3)?for 1 8 - c r o ~ n - 6 ; ’ ~ ~ selective complexation with non-ionic compounds such as nitromethane and dimethyl oxalate or carbonate is an alternative technique. 189 Silica gel-bound sulphonate cation-exchange resins can be used as the stationary phase in iondipole association chromatographic separation and purification of crown ethers;”’ the crowns are retained according to the metal cation on the ion exchanger. The intramolecular bromo-alkoxylation shown in Scheme 53 is a new variant in crown synthesis and produces a bromomethyl crown ether.’” HOCH2fCH20CH2j,CH20H A CH2=CMeCH20CH2+CH20CH2jnCH20H

-+, Me

B r CH ( n = 3 or 4)

Reagents: i, Na-CH,=CMeCH2Cl; ii, NBS-MBF,

Scheme 53

Transesterification in the presence of a ternplating metal cation has been used to prepare some tetra-ester polyether macrocycles from dimethyl malonate [equation ( 16)],19’ and intramolecular transesterification of (75) is one of the

c H ~ ( C 0 2 M e+) ~HOtCH2CH20jnH MCI TsOH 150°C: ( n = l or 2)

5”;lf 0

O y 0

(16)

0 n

methods reported for the synthesis of the mono-ester crown ethers (76);193 the alternatives are direct cyclodehydration, or treatment with a sulphonyl chloride and base (cf.4,167), of the hydroxy-acid corresponding to (75).

190 19’ 19’

193

F. de Jong, D. N. Reinhoudt, A. van Zon, G . J. Torny, and E. M. van der Vondervoort, R e d . Trao. Chim. Pays-Bas, 1981, 100,449. A. van Zon, F. de Jong, D. N. Reinhoudt, G. J. Torny, and Y. Onwezen, R e d . Trav. Chim. Pays-Bas, 1981, 100,453. S. Aoki, M. Shiga, M. Tazaki, H. Nakamura, M. Takagi, and K. Ueno, Chem. Lett., 1981, 1583. T. Nakamura, Y.Nakatsuji, and M. Okahara, J. Chem. SOC.,Chem. Commun., 1981,219. B. Thulin and F. Vogtle, J. Chem. Res. ( S ) , 1981, 256. Y. Nakatsuji, N. Kawarnura, M. Okahara, and K.Matsushima, Synthesis, 1981,42.

General and Synthetic Methods

190

HOCH2fCH20CH2j,CH20CH2CH20CH2C02Me NazC033 (75) n = 1 or 2

150"C,

e

13l"

O

V

(76)

Some thia-crown ethers have been prepared from the reaction between caesium thiolates of appropriate 1,o-dithiols and polyethylene glycol dibromides. 194 The synthesis of mono-aza-crown ethers from dialkanolamines [equation (17)] can be performed without the need for a protecting group on

nitrogen under strongly basic conditions where alkoxide formation is expected to favour 0-alkylation over the undesired N-alky1ati0n.l~~Another recent approach to mono-aza-crown ethers is based on cyanamide (Scheme 54).196 Over-alkylation of nitrogen in the construction of aza-crown ethers can be avoided by a quaternization-demethylationsequence, illustrated by the conversion (77) + (78).19'

nhhn o o o x

x

( n = 2,3)

Reagents: i, NaH-H,NCN; ii, MeOH-KCN; iii, AcOH aq.

Scheme 54

(78) Reagents: i, I(CH2)20(CHz)zO(CH2)21; ii, L-Selectride L94 19' 196

19'

J. Buter and R. M. Kellogg, J. Org. Chem., 1981, 46,4481. H. Maeda, Y. Nakatsuji, and M. Okahara, J. Chem. Soc., Chem. Commun., 1981,471. H. Maeda, Y. Nakatsuji, and M. Okahara, Tetrahedron Lett., 1981, 22, 4105. G . R. Newkome, V. K. Majestic, and F. R. Fronczek, TetrahedronLett., 1981, 22, 3039.

Alcohols, Halogeno-compounds, and Ethers

191

Applications.-Amino-acid anions have been shown to be transported across organic solvent membranes against their concentration gradient as counterions to metal-cation transport by macrocylic crown-type carriers. lug Optically active chiral crown ionophores have been used in liquid membrane electrodes for direct potentiometric determination of the enantiomeric excess in chiral ammonium ions. 199 Among chiral crown systems the optically active ligand (79) has been reported to have a selectivity of 2.6 for (R) over (S)-a-phenylethylammonium ions, the highest selectivity observed potentiometrically for such ions.2oo Details have been given of the mutual chiral recognition of hosts (80), containing one binaphthy1 unit, for amino-acid and -ester salts (cf.5, 180),20'and preliminary investigations of enantiomer recognition with chiral ammonium salts have been reported for the new chiral diaza-18-crown-6 derivatives (81),202prepared from optically active a -amino-acids or the derived p -amino-alcohols.

The aldol-type condensation of aromatic aldehydes with arylacetonitriles is catalysed in a two-phase system by polyethylene glycol dimethyl ethers,203and the Wadsworth-Emmons olefination of an aromatic aldehyde or ketone with an arylmethanephosphonate and sodium hydride to produce stilbene derivatives has been found to be accelerated in the presence of 1 5 - c r o ~ n - 5 . ~ ~ ) ~ Optically active binaphthyl crown catalysts of type (82) are reported to catalyse Michael additions to give adducts in high optical yield;205for example the conversion (83) + (84) with potassium t-butoxide and methyl vinyl ketone is H. Tsukube, TefruhedronLett., 1981, 22, 3981. W. Bussmann and W. Simon, Helv. Chim. A m , 1981, 64, 2101. 200 W. Bussmann, J.-M. Lehn, U. Oesch, P. PlumerC, and W. Simon, Helo. Chim. Acia., 1981,64,657. 2"1 D. S. Lingenfelter, R. C. Helgeson, and D. J. Cram, J. Org Chem., 1981, 46, 393. ' 0 2 D. J. Chadwick, I. A. Cliffe, I. 0. Sutherland, and R. F. Newton, J. Chem. Soc., Chem. Commun., 1981,992. '03 B. ZupanEiE and M. Kokalj, Synthesis, 1981, 913. R. Baker and R. J. Sims, Synthesis, 1981, 117. '"'D. J. Cram and G. D. Y. Sogah, J. Chem. Soc., Chem. Commun., 1981,625. 19' 199

General and Synthetic Methods

192

C02Me + CH,=CHCOMe

-

KOBU'-(S, s)-(82)

0 (83)

0 (84)

catalysed by (S,S)-(82) to give adduct ( R ) -(84) in 99% e.e. Further publications on the template-driven lactonization of o -hydroxy-crown thioesters reported in previous years (4,171; 5, 182) have detailed synthesis of the thiol-crown substrates206and some experiments designed to investigate the mechanism of macrolide closure.2o7

2u6 '07

W. H. Rastetter and D. P. Phillion, J. Org. Chem., 1981,46, 3204. W. H. Rastetter and D. P. Phillion, J. Org. Chem., 1981, 46, 3209.

5 Amines, Nitriles, and Other Nitrogen-containing Functional Groups BY G. KNEEN

1 Amines

Primary Amines.-The aromatic nitro-to-amine conversion has figured prominently in the current literature,'-6 with the emphasis once again on ~ e l e c t i v i t y . ' ~ Thus, sodium borohydride-stannous chloride,' lithium cobalt(x) phthalocyanine,' and conc. hydrochloric acid-iron powder3 have been utilized for selective conversions. Also, (Ph3P)2CuBH4has been used for a selective azide-to-amine conver~ion.~ A new approach to the amination of organometallics offers several advantages.' Azidomethyl phenyl sulphide (l),a synthon for NH;, reacts with organometallic reagents to give triazenes (2), which can be isolated or hydrolysed directly to the corresponding primary aromatic amines (Scheme 1). Steric factors are minimal and selectivity is consistent with the products of directed metallation. Efforts to extend this procedure to aliphatic and heteroaromatic systems have been unfruitful. ArH

ArBr

L ArM f

i-iii

~

ArNHN=NCH2SPh

--+

ArNH2

(2) (M = metal)

Reagents: i, MgBr,; ii, PhSCH,N,(l); iii, NH,CI

Scheme 1 T. Satoh, N. Mitsuo, M. Nishiki, Y. Inoue, and Y. Ooi, Chem. Pharm. Bull., 1981,29,1443.

H.Eckert, Angew. Chem., f n f .Ed. Engl., 1981,20,208. D.H. Klaubert, J. H. Selltedt, C. J. Guinosso, R. J. Capetola, and S. C. Bell, J. Med. Chem., 1981,24,742.

S.J. Clarke, G. W. J. Fleet, and E. M. Irving, J. Chem. Res. ( S ) , 1981, 17. A. Nose and T. Kudo, Chem. Pharm. Bull., 1981,29,1159. D. Savoia, C. Trombini, A. Umani-Ronchi, and G. Verardo, J. Chem. Sac., Chem. Commun.,

1981,540.

B.M. Trost and W. H. Pearson, J. A m . Chem. SOC., 1981,103,2483.

193

General and Synthetic Methods

194

A homogeneous metal-catalysed synthesis of anilines by amination of benzoic acids,8 and the oxidative amination of 1,2,4,5-tetrazines' have been described. Anthranilic acids are useful reagents in synthetic chemistry, and two new and convenient syntheses have appeared. 'O,' In one,l0 carbonylation of bromoacetanilides utilizes palladium catalysis, and in the other," oxidation of isatins with hydrogen peroxide in the presence of sodium methoxide provides a ready source of anthranilic esters. Improved procedures for the reduction of amides,l2-I4 and nit rile^'^ to the corresponding amines have been reported. The requirement of 'no more borane reagent than the calculated quantity' for the borane-dimethyl sulphide reduction of primary amides is a consequence of distilling dimethyl sulphide out of the reaction mixture (Scheme 2), and represents a significant improvement in RCONH2

-% RCH2NH2.HCI

Reagents: i, BH,.Me,S; ii, Et,O-HCl

Scheme 2

methodology.'* The limitations associated with the use of borane-dimethyl sulphide, however, still apply. For secondary and tertiary amides, reduction does require excess reagent; this problem has been circumvented by carrying out the reduction in the presence of a molar equivalent of boron trifluoride etherate (Scheme 3).l 3 Under these conditions, the boron trifluoride combines preferentially with the amine, eliminating the need for excess borane reagent. Similarly, R2

R2

Reagents: i, BH,.Me,S-BF,.Et,O;

ii, HCl-H,O; iii, NaOH; iv, TMEDA-Et,O

Scheme 3

the borane-dimethyl sulphide reduction of nitriles to the corresponding primary amines has been improved to give a simple procedure which is both rapid and quantitative (Scheme 4).15 RCN

. ...

'-I1'

b

RCHzNHz

Reagents: i, BH,.Me,S, 0.25 .h; ii, HCl, H,O, or MeOH; iii, NaOH

Scheme 4

In a similar vein, it has been found that sodium borohydride in dimethyl sulphoxide is an effective reagent for the reduction of amides to the corresponding a m i n e ~ . 'Although ~ yields of products are no better than for lithium

l3

I4 Is

G. G. Arzoumanidis and F. C. Rauch, J. Org. Chem., 1981, 46, 3930. A. Counotte-Potman and H. C. van der Plas, J. Heterocycl. Chem., 1981,18, 123. D. Valentine, jun., J. W. Tilley, and R. A. Le Mahieu, J. Org. Chem., 1981,46, 4614. G . Reissenweber and D. Mangold, Angew. Chem., Int. Ed. Engl., 1981 20, 882. H. C. Brown, S. Narasimhan, and Y. M. Choi, Synthesis, 1981,441. H. C. Brown, S. Narasimhan, and Y. M. Choi, Synthesis, 1981,996. H. C. Brown, Y.M. Choi, and S . Narasimhan, Synthesis, 1981,605. S . R. Wann, P. T. Thorsen, and M. Kreevoy, J. Org. Chem., 1981, 46, 2579.

195

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

aluminium hydride reduction, this method has the advantages that anhydrous solvent is not required, sodium borohydride is easier to handle, and offers selectivity. A little used synthesis of primary alkylamines is the amination of organoboranes. Organoboranes have now been shown16 to react with chloramine-T prepared in situ from ammonium hydroxide and sodium hypochlorite to give the corresponding amines (Scheme 5 ) . This procedure then represents a mild, one-pot synthesis of various primary alkylamines from alkenes.

R3B+ NH40H

N:z

RNH2

Reagents: i, BH,THF; ii, NH,OH; iii, NaOCl

Scheme 5

Diphenyl sulphimine (3) can be alkylated with benzyl bromide to give N-benzyl S,S-diphenylsulphimine (4). Using new procedures,” (4) can be reduced to diphenyl sulphide and benzylamine, which is extracted in quantitative yield from the reaction mixture. This reaction may then provide another useful method for the conversion of alkyl halides to the corresponding primary arnines. PhCH2Br

PhzS=NCH2Ph (4)

% PhCH2NH2

Reagents: i, Ph2S=NH(3)-NaOMe-MeOH; ii, TiC1,-Zn

Scheme 6

1H-Pyrrole-1-ethylamine ( 5 ) is a potentially useful intermediate in synthetic heterocyclic chemistry, and is now available in large quantities via the amide (6), which can be readily hydrolysed under alkaline conditions (Scheme 7).’*

I

CH,CH,NHCOMe

CH,CH,NH, (5)

(6)

1

iii

I CH,CH,NHEt Reagents: i, NH,CH,CH,NH,-MeCO,H-dioxan;

ii, KOH-H,O; iii, LAH

Scheme 7 l6

la

G. W. Kabalka, K. A. R. Sastry, G. W. McCollum, and H. Yoshioka, J. Org. Chem., 1981,46,4296. J. Drabowicz, P. Lyzwa, and M. Mikolajczyk, Synthesis, 1981, 890. I. Jirkovsky and R. Baudy, Synthesis, 1981,481.

General and Synthetic Methods

196

The synthesis of substituted cyclohexylamines from the corresponding cyclohexanones can now be achieved in good chemical yield with high stereoselectivity. l9 The key step is the hydrogenation of imines derived from 1-phenylethylamine (Scheme 8) yielding secondary amines, which are then hydrogenolysed to the thermodynamically less-stable isomers of the primary amines (7). By utilizing optically active 1-phenylethylamine, products of high optical purity result.20 It is remarkable that, in this case, the key hydrogenation step runs under both high diastereoselective and enantioselective control. A similar approach21 to the synthesis of chiral cyclohexylamines also utilizes imines derived from optically active 1-phenylethylamine to initiate acid-catalysed cyclizations of polyenes. Me I NHCHPh.HC1

Me I NCHPh

+ i R

Q

___* ii,iii

R

Q

NH, .HCI i

V

.

0

R

R

(R= 2,3, or 4-Me)

(7)

Me

I

Reagents: i, H,NCHPh; ii, H,-Ni; iii, HCl; iv, H,-Pd/C

Scheme 8

A new procedure2' for the preparation of 2-aminotetralins exploits the use of diphenylphosphorazidate in a modified Curtius reaction from the corresponding carboxylic acid (Scheme 9).

a -a i-iii

CO, H Reagents: i, (PhO),P(O)N,-NEt,-OH;

NH*

ii, PhCH,OH; iii, H,-Pd/C

Scheme 9

An investigation of the synthesis of allylamines via vinylphosphonium salts (Schweizer reaction), has displayed its generality for their preparation in high stereochemical Thus, the reaction between phthalimide, vinyltri-nbutylphosphonium bromide, and an aldehyde in the presence of sodium hydride gives the E-imide (8),from which the free E-allylamines can be liberated (Scheme 10). Ketones do not react. RCHO +PhthH

& Phth-

(Phth = phthalimido) Reagents: i, CH,=CH+Bu,Br--NaH;

,

iioriii,iv

,H,N

(8) ii, H,NNH,; iii, Na,S; iv, (CO,H),

Scheme 10 l9 2o

22

23

G. Knupp and A. W. Frahm, J. Chem. Res.(S), 1981,164. A. W. Frahm and G. Knupp, Tetrahedron Lett., 1981,2633. G. Demailly and G. Solladie, J. Org. Chem., 1981, 46, 3102. A. P. S. Narula and D. I. Schuster, Tetrahedron Lett., 1981, 3707. A. I. Meyers, J. P. Lawson, and D. R. Carver, J. Org. Chem., 1981,46, 31 19.

/

R

Amines, Nitriles, and Other Nitrogen-containingFunctional Groups

197

a,@-Fluoroaminesare the products of the ring opening of a ~ i r i d i n e s It . ~ is ~ possible to synthesize selectively each diastereoisomeric fluoroamine by proper choice of the fluorinating reagents. New syntheses of 1,2-alkanediamines from imidazolin-2-ones via photochemical c y ~ l o a d d i t i o nfrom , ~ ~ 2-ethyl-4,5-dihydro-1,3-oxazole, a new aziridine equivalent,26 and from allylamines via aminomercuration4emercuration2' have been reported. A novel approach to the synthesis of chiral vicinal amino-ketones and -alcohols depends on high enantiomeric retention in the Friedel-Crafts reaction of Nprotected amino-acids (Scheme 11).**

y'

2

98% chiral purity

OH

Reagents: i, PCI,-Et,O, 0 "C;ii, AlCI,-CH2C12, RT; iii, HSiMe,-NEt,; iv, THF; v, HCI, A; vi, LAH Scheme 11

Other new syntheses of primary P-amino-alcohols via 0-silylated cyanoh y d r i n ~and , ~ ~via a diastereoselective silyl nitro-aldol reaction3' have also been reported. Thiocarbonyl olefination provides a new synthesis of p-amino-acids from N-thioa~ylurethanes.~'

Secondary Amines.-The reduction of imines to the corresponding secondary amines can be effected by various methodologies. New additions are the sodium triacyloxyborohydrides (easily obtainable from sodium borohydride and N-acyl derivatives of optically active amino-acids), which are used for the asymmetric reduction of cyclic i m i n e ~ Also . ~ ~ now available33 is a highly stereoselective reduction of N-benzylimines derived from substituted cyclohexanones, with alkali-metal borohydrides, in particular L-selectride. A further addition is the first report of the reduction of aldimines by hydrogen transfer from propan-2-01, 24

25 26 27

29 30

31

32

33

G. M. Alvernhe, C. M. Ennakoua, S. M. Lacombe, and A. J. Laurent.J. Org. Chem., 1981,46,4938. K.-H. Scholz, J. Hinz, H.-G. Heine, and W. Hartmann, Liebigs Ann. Chem., 1981, 248. G. S. Poindexter, Synthesis, 1981, 541. J. Barluenga, C. Jimenez, C. Najera, and M. Yus, Synthesis, 1981, 201. D. E. McClure, B. H. Arison, J. H. Jones, and J. J. Baldwin, J. Org. Chem., 1981,46, 2431. R. Amouroux and G. P. Axiotis, Synthesis, 1981, 270. D. Seebach, A. K. Beck, F. Lehr, T. Weller, and E. Colvin, Angew. Chem., Int. Ed. Engl., 1981, 20,397. M. Slopianka and A. Gossauer, Synth. Commun., 1981, 11, 95. K. Yamada, M. Takeda, and T. Iwakuma, Tetrahedron Lett., 1981, 3869. J. E. Wrobel and B. Ganem, Tetrahedron Letr., 1981, 3447.

198

General and Synthetic Methods

catalysed by rhodium complexes.34The latter method is particularly useful since the use of water or air-sensitive materials is avoided. An attractive route to secondary amines has always been the monoalkylation of primary amines. However, over-alkylation has been an inevitable problem with this approach, and new methodologies that avoid this complication are always welcome. One such method3' is the transition-metal catalysed N-alkylation of amines by alcohols (Scheme 12). An alternative procedure utilizes aminosilanes (Scheme 13),36which react readily with primary halides in the presence of sodium methoxide to afford, selectively, the corresponding secondary amines.

R2

R2

(R2= Bun o r PhCH2) Scheme 12 RNH2 + RNHSiMe3

2

RNHR'

Scheme 13

A further new selective approach to the N-alkylation of polyamines involves the novel reductive cleavage of the C-N bond in cyclic amidines by di-isobutyl aluminium h ~ d r i d e . ~ ~ The lability to nucleophilic displacement of a methoxyl group in the orthoposition of aryloxazolines is well known, and this reaction has now been developed to provide new syntheses of indolines, tetrahydroquinolines, and tetrahydro-1-benzazepinsby cyclization (Scheme 14).38

(n = 2-4) Reagents: i, LDA; ii, hydrolysis

Scheme 14

The formamidine derivatives of secondary amines stabilize carbanions a to the nitrogen, and are readily alkylated to the homologous amine (cf. Vol. 5 , p. 34 35

36 37

R. Grigg, T . R. B. Mitchell, and N. Tongpenyai, Synthesis, 1981, 442. R. Grigg, T. R. B. Mitchell, S. Sutthivaiyakit, and N. Tongpenyai, J. Chem. SOC.Chem. Commun., 1981,611. W. Ando and H. Tsumaki, Chem. Lett., 1981,693. H. Yamamoto and K. Muruoka, J. A m . Chem. Soc., 1981,103,4186. A. I. Meyers, M. Reuman, and R. A. Gabel, J. Org. Chem., 1981,46,783.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

199

188). N-Methylanilines, indolines, tetrahydroq~inolines,~~ and tetrahydroi s o q u i n ~ l i n e shave ~ ~ all now been shown to be capable of elaboration in this fashion (Scheme 15).

+ E Reagents: i, HC0,Et; ii, Et,O+BF,-; iii. Bu‘NH,; iv, Ru‘Li; v, E’; vi, hydrolysis

Scheme 15

Cyclic secondary amines are also produced by the ring expansion of 0sulphonyloximes via a Beckmann rearrangement,4’ the cyclization of a,waliphatic diamines by a ruthenium catalyst,42 the palladium-promoted ring ~ ~ the sulphonamidomercuration of 1,4- and closure of a m i n o - a l k e n e ~ ,and 1 , 5 - d i e n e ~The . ~ ~latter two reactions form part of a wealth of new literature434* on the amination of 0 1 e f i n s ~ ~and ~’ via a m i n ~ m e r c u r a t i o n ~ ~ ~ ~ * and via palladium Secondary amines are also the products of the deamination of 1,l-disubstituted aromatic h y d r a ~ i n e s ,and ~ ~ the ring-opening and recyclization of N-alkyl-2benzylpyridinium salts to form 2-alkylaminobiphenyls.”O a-Alkylaminoketones are useful intermediates for the synthesis of biologically important molecules. Three new ~ y n t h e s e s ~now ~ - ~add ~ considerably to the available methodology for the preparation of these compounds. In one (Scheme 16),51iminoethers (9) are converted by LDA into a-aminoketones (lo), the first report of the imino-Wittig rearrangement. In another (Scheme 17),‘* formimidates (11) are alkylated by a-bromoketones to give the intermediate aformamido-ketones (12) which yield a-amino-ketones (13) upon hydrolysis. 39 40 41

42

A. I. Meyers and S. Hellring, Tetrahedron Lett., 1981,5119. A. I. Meyers, S. Hellring, and W. Ten Hoeve, Tetrahedron Lett., 1981,5115. B.-T. Khai, C. Concilio, and G. Porzi, J. Org. Chem., 1981,46,1759. K. Hattori, Y. Matsumura, T. Miyazaki, K. Maruoka, and H. Yamarnoto, J. A m . Chem. SOC.,

1981,103,7368. 43

44 45 46

47 48 49

’’ 52

B. Pugin and L. M. Venanzi, J. Organomet. Chem., 1981,214. 125. J. Barluenga, C. Jirnenez, C. Najera, and M. Yus, J. Chem. SOC., Chem. Commun., 1981. 1178. J. Barluenga, L. Alonso-Cires, and G . Asensio, Synthesis, 1981, 376. J. Barluenga, J. Villamana, and M. Yus, Synthesis, 1981,375. J. J. Bozell and L. S. Hegedus, J. Org. Chem., 1981,46,2561. J. Barluenga, F. Aznar, and R . Liz, J. Chem. SOC., Chem. Commun., 1981, 1181. M. D e Rosa and P. Haberfield, J. Org. Chem., 1981.46, 2639. A.N. Kost, R . S. Sagitullin, and A. A. Fadda, Org. Prep. Proc. Int., 1981,13,203. A. R. Katritzky and N. K. Ponkshe, Tetrahedron Letr., 1981, 1215. A. Guzman, J . M. Muchowski, and N. T. Ndal, J. Org. Chem., 1981.46,1224.

General and Synthetic Methods

200 NAr

NAr

II

II

”1

RCHOCPh + RCH-CPh

RCH20CPh % L

I

OH

(9)

Scheme 16

-B

Ph

I

RCOCHNHAr

(10)

0

R,,?$NHR3-

HBr

t

RltC&:HO

R2

R2

Scheme 17

Finally,53 aziridinones (14) react with 2-lithio-1,3-dithian to give (15), masked 6-amino-a-ketoaldehydes (Scheme 18). R R 0

I

I

H

Scheme 18

New syntheses of secondary 2-amino-alcohols,54 3-amino-alcohols,55 and P-amino-thiolic have also been reported.

Tertiary Amines.-The co-ordinating properties of tertiary aliphatic nitrogen atoms have once again been made use of for the directed metallation of aromati?’ and allylicSBsystems. Although several examples of ortho-palladated E. R. Talaty, A. R. Clague, J. M. Behrens, M. 0. Agho, D. H. Burger, T. L. Hendrixson, K. M. Korst, T. T. Khanh, R. A. Kell, and N. Dibaji, Synth. Commun., 1981,11,455. 54 L. E. Overman and L. A. Flippin, Tetrahedron Lett., 1981, 195. 55 F. Fulop and G. Bernath, Synthesis, 1981, 628. s6 M. Otsuka, M. Yoshida, S. Kobayashi, and M. Ohno, Tetrahedron Lett., 1981, 2109. ” R. A. Holton and K. J. Natalie, jun., Tetrahedron Lett., 1981, 267. 5 8 J. J. Fitt and H. W. Gshwend, J. Org. Chem., 1981,46, 3349.

s3

Arnines, Nitriles, and Other Nitrogen-containing Functional Groups

201

benzylarnines are known, the first example of an apparently nucleophilic reagent has now been described," giving rise to ortho-acylated products (16). With the allylic when N,N-dimethylmethallylamine is treated with n-butyllithium at 0°C and lithiated species (17) is formed, which reacts with various electrophiles (Scheme 20).

Scheme 19

Scheme 20

Tertiary amino-alcohols are also the products of an improved, one-step procedure for the Grignard reaction of dimethylaminopropyl chloride with various carbonyl Two new syntheses of tertiary amino-ketones have been published.60*61In one,6" the reaction between aldehydes and a-amino-phosphine oxides (cf. Vol. 5, p. 201) has been extended to provide a-amino-ketones (18) by thermolysis of the intermediate phosphine oxides (19). The overall sequence thus involves an aminomethylation of the parent aldehyde (Scheme 21). In the second synthesis a new carbon-carbon bond-forming reaction at the a-position of secondary amines has been exploited to provide p-amino-ketones (20).61

Another convenient method for the transformation of tertiary amides to the corresponding amines, via the reduction of the thioimidates (21) with sodium borohydride or cyanoborohydride, has appeared62 (cf. Vol. 5, p. 190). This method avoids the use of triethyloxonium tetrafluoroborate (Scheme 23).

59

6o 61

A. Miodownik, J. Kriesberger, M. Nussim, and D. Avnir. Synth. Commun., 1981, 11,241. N. L. J. M. Broekhof and A. van der Gen, Tetrahedron Lett., 1981, 2799. T. Shono, Y. Matsumura, and K. Tsubata, I.A m . Chem. SOC.,1981,103, 1172. R. J. Sundberg, C. P. Walters, and J. D. Bloom, I. Org. Chem., 1981, 46, 3730.

General and Synthetic Methods

202

C0,Me

C0,Me

1

ii

I

I Me

CO,Me

(20)

OSiMe,

Reagents: i, anodic oxidation; ii,

'

AR Scheme 22 S

RCONR';?

I1

RCNR';?

SMe

I + -% RC=NR121- --% RCHZNR'2 (21)

Reagents: i, P,S,; ii, MeI; iii, H-

Scheme 23

New syntheses of cyclic tertiary amines from N - c h l ~ r a m i n e s allylic , ~ ~ tertiary amines from Pd(0) c o m p l e x e ~2,6-disubstituted ,~~ anilines from e n a m i n e ~and ,~~ 2-arylaminoalcohols via a photo-Smiles rearrangement66 have been published. The palladium-catalysed telomerization of 1,3-dienes with 2-ethyleneamines6' and with secondary amines68has been reported.

2 Nitriles and Isocyanides Many methods are available for the dehydration of aldoximes to nitriles; new and chloromethylenedimethylalternatives include N-trifluor~acetylimidazole,~~ ammonium ~ h l o r i d e 'as ~ reagents to effect this transformation under mild conditions. A new method7' for the direct conversion of aromatic aldehydes to the corresponding nitriles in high yields involves the use of pyridine hydrochloride in the presence of nitroethane. The method is, however, less convenient for the preparation of aliphatic nitriles because of partial hydrolysis of the product, or incomplete reaction. L. Stella, B. Raynier, and J. M. Surzur, Tetrahedron,1981,37, 2843. T. Yamamoto, 0. Saito, and A. Yamamoto, J. Am. Chem. SOC.,1981,103, 5600. " P. Camps, C. Iaime, and J. Molas, Tetrahedron Lett., 1981, 2487. 66 K. Mutai and K. Kobayashi, Bull. Chem. SOC.Jpn., 1981, 54,462. 67 C. Moberg, Tetrahedron Lett., 1981, 4827. 68 K. Kaneda, H. Kurosaki, M. Terasawa, T. Imanaka, and S. Teranishi, J. Org. Chem., 1981,46,2356. 69 T. Keumi, T. Yamamoto, H. Saga, and H. Kitajima, Bull. Chem. SOC. Jpn., 1981, 54, 1579. 70 J.-P. Dulcere, Tetrahedron Lett., 1981, 1599. 71 D. Dauzonne, P. Demerseman, and R. Royer, Synthesis, 1981, 739. 63 6*

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

203

Cyanohydrins are commonly obtained from the reaction of aldehydes or ketones with hydrogen cyanide, This methodology has now been extended72to the asymmetric addition of hydrogen cyanide to benzaldehyde catalysed by cyclo-(L-phenylalanyl-L-histidine)to give the (R)-antipode in extremely high optical yield. Although the reaction of enol silyl ethers with acid chlorides and anhydrides provides P-diketones in good yields, the reaction with acyl cyanides has now to give P-ketocyanohydrins (22),which can be further elaborated been to P-diketones or unsaturated ketonitriles (Scheme 24). TiCI,

MeCOCN + R 3

(-78~)

R2

Scheme 24

Acyl cyanides are the starting materials for a new synthesis74of cyanohydrin esters via a two-phase reduction with sodium borohydride in the presence of tetra-n-butylammonium bromide. The replacement of an alkoxy-group in acetals or orthoesters with a cyanogroup via the use of trimethylsilyl cyanide, provides 2-alkoxy- or 2,2-dialkoxyalkane nitriles, r e ~ p e c t i v e l y lithio-derivatives ;~~ of the latter are useful as synthetic equivalents of methyl lithioformate (Scheme 25).

‘koR2 RkcN ~

R

OR2

R

OR2

Rii,=iii, H,

R’=OR*

ORZ I n-C,H,, -C-CN I OR2

1 n-C,H

C0,Me

Reagents: i, Me,SiCN, BF,.Et,O, or SnCI,; ii, LDA; iii, n-C,H,7J3r

Scheme 25

a,p-Oxidonitriles are the products of the reaction of a-halogenoketones with potassium cyanide under phase-transfer condition~.’~ Functional group replacement by cyano is an important synthetic transformation since it frequently allows homologation by hydrolysis to the carboxylic acid, or by reduction to an amine. The replacement of sulphinyl by cyano via trimethylsilylcyanide thus provides a preparation of aliphatic cyanomethyl and this useful reagent has been further employed to provide cyclic a-acylaminonitriles by the replacement of m e t h o x y - g r ~ u p sThe . ~ ~ replacement of a primary amino-group by cyano is an often sought after transformation, and 72 73

74

76 77 78

J. Oku and S . Inoue, J. Chem. SOC.,Chem. Commun., 1981,229. G. A. Kraus and M. Shirnagaki, Tetrahedron Lett., 1981, 1171. J. M. Photis, J. Org. Chem., 1981, 46, 182. K. Utimoto, Y. Wakabayashi, and Y. Shishiyama, Tetrahedron Lett., 1981,4279. K. Takahashi, T. Nischizuka, and H. Iida, Synth. Commun., 1981, 11, 757. J. A. Schwindeman and P. D. Magnus, Tetrahedron Lett., 1981,4925. V. Asher, C. Becu, M. J. 0. Anteunis, and R. Callens, Tetrahedron Lett., 1981, 141.

General and Synthetic Methods

204

is well documented in the aromatic series. An efficient method for the conversion Hof benzylamines into the corresponding arylacetonitriles has now been reported,79 and utilizes the readily prepared 1-substituted 4,6-dipheny1-2-methylthiopyridinium salts (23) to achieve nucleophilic diplacement of the primary amino-group (Scheme 26). SMe ArCH,NH,

&

ArCH,N' 9 P h

a ArCH,N'

Ph

Reagents: i,

I-

9 P h

5 ArCH,CN

Ph (23)

'Oph

; ii, MeI; iii, NaCN-DME

Ph

Scheme 26

Similarly, the transformation of alcohols to nitriles is a much sought after transformation, and a new procedure" now allows the direct one-step conversion by the use of sodium cyanide-trimethylsilyl chloride and a catalytic amount of sodium iodide in dimethylformamide-acetonitrile. The chlorine in 2-chloropyrimidines and 2-chloroquinazolines is also replaced by cyano, following conversion to the trimethylammonio-derivatives and subsequent reaction with tetraethylammonium cyanide.81 Acylcyanides are useful synthetic intermediates and are sometimes not easily prepared, often involving the use of heavy-metal cyanides. A new procedure82 efficiently converts aroyl chlorides to aroyl cyanides with potassium cyanide in acetonitrile or aqueous acetonitrile. Palladium-catalysed carbonylation of aromatic iodides in the presence of potassium cyanide also gives aroyl cyanides via cyanocarb~nylation.~~ The efficient trapping of kinetic ketone-enolates with cyanation reagents has previously eluded the synthetic organic chemist. A new procedure has now been developed84 and utilizes p-toluenesulphonyl cyanide as the cyanation reagent for the preparation of P-ketonitriles from cyclic ketones (Scheme 27).

Reagents: i, LDA-THF, -78

"c;ii,

Me

Scheme 27 79

8o

'* 83 84

P. M. Fresneda, M. J. Lidon, P. Molina, and M. J. Vilaplana, Synthesis, 1981, 711. R. Davis and K. G. Untch, J. Org. Chem., 1981,46, 2985. K. Herrnann and G. Sirnchen, Liebigs Ann. Chem., 1981,333. M. Tanaka and M. Koyangi, Synthesis, 1981,973. M. Tanaka, Bull. Chem. SOC.Jpn., 1981, 54,637. D. Kahne and D. B. Collurn, Tetrahedron Lett., 1981, 5011.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

205

The alkylation of arylacetonitriles is effected by various procedures, and purification methods have been developed to allow the isolation of pure monoalkylated products (cf. Vol. 4, p. 180). A new selective catalytic monoalkylation of arylacetonitriles by primary alcohols can be achieved at a100 "C using a catalyst prepared in situ from rhodium trichloride, triphenylphosphine, and sodium carbonate, or more effectively, RuH2 (PPh& (Scheme 28).85

R' R+"zcN ( R = H or C1)

l + R

e (!HCN

(R'= M e , Et, or PhCHJ

Reagents: i, R'OH-RhC13~3H,0-PPh3-Na2C0, or RuH,(PPh,),

Scheme 28

a-Lithioarylacetonitriles react with sulphinic acid esters to give a-cyanosulphoxides with S + C chirality transfer,86and with a,@-ethylenesulphones to give cyanocyclopropanes,R7 Vinyl sulphones are smoothly converted to a,@-unsaturated nitriles on exposure to potassium cyanide-dicyclohexyl- 18-crown-6 in refluxing t-butyl The reaction proceeds with the reversal of olefin polarization and concomitant carbon-carbon bond formation (Scheme 29). The method appears to be general and allows the preparation of a wide variety of unsaturated nitriles, including a-methylene nitriles, and is compatible with base-labile functionality.

Me

Me

ACH,CH;

Reagent: i, KCN-Bu'OH-I 8-crown-6

Scheme 29

a,@-Unsaturatednitriles are also prepared by the following methods: (a) from vicinal dinitro-compounds or 0-nitrosulphones by free-radical chain elimination with tri-n-butyltin hydride,*' (b) palladium-catalysed regioselective reactions of a-acetoxy-P,y-unsaturated nitriles with nu~leophiles,~~) (c) from a-cyanoketones

R. Grigg, T. R. B. Mitchell, and S. Sutthivaiyakit, Tetrahedron Lett., 1981,4107. R.Annunziata, M. Cinquini, S. Colonna, and F. Cozzi, J. Chem. SOC., Perkin Trans. I , 1981,614. '' T. Agawa, Y. Yoshida, M. Komatsu, and Y. Ohshiro, J. Chem. SOC.,Perkin Trans. 1, 1981,751. D. F. Taber and S. A . Saleh, J. Org. Chem., 1981,46,4817. 89 N. Ono, H. Mikaye, R. Tarnura, I. Hamamoto, and A. Kaji, Chem. Left., 1981,1139. 90 J. Tsuji, H. Ueno, Y. Kobayashi, and H. Okumoto, Tetrahedron Lett., 1981,2573. A5

86

General and Synthetic Methods

206

via p-hydroxynitriles," (d) from arylacetonitriles via a polyethyleneglycol-catalysed two-phase aldol-type condensation with ben~aldehydes,~~ (e) the reaction of a-lithio-a-silyated acetonitrile with aldehydes,93 and (f) from the reaction of phenylsulphinylacetonitrile with aldehydes or ketones.94 The latter reaction produces 4-hydroxy-2-alkenenitriles which are suitable substrates for elaboration to furans (Scheme 30). /OH

+ PhS(O)CH,CN

RCH,COCH,

-----*

OH

R=C-jHll R = geranyl

.

b

R=C5H11

H

1 : 0

l : o

R = geranyl

1 : 1 1 : 6

R=C5H11

'% 1 : 7

-MeOH, RT; ii,

Reagents: i,

\,A,

0

-PhH, reflux; iii,

H

0

-MeCO,H-PhH, reflux

H

Scheme 30

Hydroboration of ethylidene steroids proceeds in a highly selective manner from the a-face of the steroid, and the resulting 9-BBN derivative reacts with chloroacetonitrile in the presence of base to produce a 21-cyano steroid possessing the correct natural configuration at C-17 and C-20.95 New syntheses of cu-nitronitrile~,~~ 4-ar~lbutanenitriles,~' mercaptoa ~ e t o n i t r i l e a-irninonitrile~,~~ ,~~ 2-~yanopyrroles,'~~ and 3-cyano-4-azahomoadamantanes"' have also been reported. The reactions of carbon nucleophiles (e.g. lithio-acetonitriles) with arenechromium complexes (cf. Vol. 5, p. 193) have been further developed,"* and A. Chaterjee, D. Roy,and S. K. Chatterjee, Synthesis, 1981, 449. B. Zupancic and M. Kokalj, Synthesis, 1981, 913. 93 Y. Yarnakado, M. Ishiguro, N. Ikeda, and H. Yamamoto, J. A m . Chem. Soc., 1981,103, 5568. 94 J. Nokami, T. Mandai, Y. Imakura, K. Nishiuchi, M. Kawada, and S. Wakabayashi, Tetrahedron Lett., 1981, 4489. 95 M. M. Midland and Y. C. Kwan, J. Org. Chem., 1981,46, 229. 96 R. Ketari and A. Foucaud, J. Org. Chem., 1981,46,4498. " I. H. Sanchez and M. A. Aguilar, Synthesis, 1981, 55. 9a E. Mathias, and M. Shimanski, J. Chem. SOC.,Chem. Commun., 1981, 569. 99 F. Pochat, Tetrahedron Lett., 1981, 955. loo C. E. Loader and H. J. Anderson, Can. J. Chem., 1981,59,2673. lo' T. Sasaki, S. Eguchi, and T. Okano, J. Org. Chem., 1981, 46,4474. lo' M. F. Sernrnelhack, G. R. Clark, J. L. Garcia, J. J. Harrison, Y. Thebtaranonth, W. Wulff, and A. Yamashita, Tetrahedron, 1981, 37, 3957. 91

92

Amines, Nitriles, and Other Nitrogen-containing Functional Groups i,ii

,

207

ArqNc

(EtO)zP (0)

C0,Et

OEt (24) Reagents: i, NaH-CH2CI,; ii, ArCHO Scheme 31

metallation of (24)leads to a Wittig-Horner reagent, which reacts with aromatic, or heteroaromatic aldehydes to yield a$-unsaturated isocyanides.103 The synthesis of NeSMIC [(+)-(neomenthylsulphony1)methyl isocyanide], the first chiral sulphonylmethyl isocyanide, and its application to the synthesis of chiral cyclobutanones has been published.lo4

3 Nitro- and Nitroso-compounds The nitration of aromatics is an important chemical reaction, and new reagents include N-nitropyrazole in the presence of a Lewis acid,lo5 metal nitrates in trifluoroacetic anhydride,In6and silver nitrate-boron trifluoride in a~etonitrile."~ Metal salts, especially cerium(1v) acetate, also promote aromatic nitromethylation. ' 0 8 (Phenylsulphony1)nitromethane is C-alkylated preferentially by benzyl halides, primary alkyl iodides, and allylic acetates, the latter in the presence of catalytic tetrakis( triphenylphosphine)palladium,providing secondary a-nitrosulphones (cf. Vol. 5, p. 197).109 The synthetic utility of this process, other than for the preparation of a-nitrosulphones themselves, has been enhanced by the l o thus providing an overdevelopment of efficient desulphonation all synthesis of nitroalkanes. Nitroalkanes are also the products of the replacement of tertiary nitro groups by nitromethyl via sodio nitromethane."' Although procedures for the C-acylation of nitromethane have been reported, they generally require prior preparation of activated derivatives of carboxylic acids. In a new procedure,'12 nitromethane is directly C-acylated by aromatic carboxylic acids using a combination of diethyl phosphorocyanidate and triethylamine in DMF (Scheme 32), to provide a-nitroketones (25). CH3N02+ ArC02H -+- ArCOCH2N02 (25) Scheme 32 lo4

lo6

109

'lo

I"

'I2

J. Rachon and U. Schollkopf, Liebigs Ann. Chem., 1981,1693. D. van Leusen, P. H. F. M. Rouwette, and A. M. van Leusen, J. Org. Chem., 1981,46,5159. G . A. Olah, S. C. Narang, and A. P. Fung, J. Org. Chem., 1981,46,2706. J. V.Crivello, J. Org. Chem., 1981,46,3056. G.A. Olah, A. P. Fung, S. C. Narang, and J. A. Olah, J. Org. Chem., 1981,46,3533. M. E. Kurz and P. Ngoviwatchai, J. Org. Chem., 1981,46,4672. P. A. Wade, H. R. Hinney, N. V. Amin, P. D. Vail, S. D. Morrow, S. A. Hardinger, and M. S. Saft, J. Org. Chem., 1981,46,765. N. Ono, R. Tamura, R. Tanikaga, and A. Kaji, J. Chem. Soc., Chem. Commun., 1981,71. N.Kornblum and A. S. Erickson, J. Org. Chem., 1981,46,1037. Y.Hamada, K. Ando, and T. Shioiri, Chem. Pharm. Bull., 1981,29,259.

208

General and Synthetic Methods

2-Nitrocyclohexanones'13 and 2-nitrocyclopentanones"4 are the products of the nitration of the corresponding cycloalkanone enol acetates. The synthesis of nitroacetaldehyde dialkylacetals has previously been technically too difficult to allow large-scale preparation of these potentially useful ~ allows the preparation of a compounds. A convenient new p r o c e d ~ r e " now number of dialkyl acetals (26) by reaction between an alkyl orthoformate and an excess of a nitroalkane. R'O R'O

R'O

,R2

'CHOR' /

+ CH

-$

%NO2

R'O

R2 'CHkHNOz / (26)

Reagent: i, ZnCI, or zinc dust

Scheme 33

a-Nitro-olefins are important synthetic intermediates, and various new methods are now available for their synthesis.116-118The nitro-olefin (27) efficiently transfers a 2-nitroallyl group to a variety of orgonolithium and organomagnesium derivatives, independent of their reactivity (Scheme 34).1'6*117 Since the acceptor property of the nitrogroup can be further exploited, (27) constitutes a reagent corresponding to the synthon (28). Phenylselenyl bromide reacts with nitroalkanes to give nitro(phenylse1eno)alkanes from which a-nitroalkenes can be obtained by oxidative elimination.'"

0

(27)

Scheme 34

a-Nitro-olefins are well known as Michael acceptors. The importance of this synthetic reaction is reflected in a number of recent publications.' '9-'23 The Michael additions of aliphatic, acyclic, and arylsubstituted nitro-olefins and enamines lead to y-nitroketones in good chemical and excellent (>90%) diastereomeric yields (Scheme 35); a topological rule has been formulated, also

Scheme 35 'I1

'''

H. Ozbal and W. W. Zajac, Jun., J. Org. Chem., 1981, 46, 3082. F. E. Elfehail and W. W. Zajac, Jun., J. Org. Chern., 1981, 46, 5151. L. Rene and R. Royer, Synthesis, 1981, 878. P. Knochel and D. Seebach, Tetrahedron Lett., 1981, 3223. P. Knochel and D. Seebach, Nouv. J. Chim., 1981,575. T. Sakakibara, I. Takai, E. Ohara, and R. Sudah, J. Chem. SOC.,Chem. Commun., 1981,261.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

209

applicable to various other C-C bond-forming processes between prochiral centres. l 9 Asymmetric Michael addition of optically active perhydro- 1,4-oxazepin-5,7diones,12*and of thioglycollic acid in the presence of a cinchona alkaloid as catalyst,121 to a-nitro-olefins yields y-nitrocarboxylic acids and 2-nitrothio ethers, respectively, with reasonable enantiomeric excess. Allylsilanes add to a-nitro-olefins in the presence of aluminium chloride to give unsaturated njtronic acids, which are further transformed in a Nef-type reaction to give y,S-enones (Scheme 36).12* Nitro-compounds are also converted into the corresponding carbonyl compounds upon treatment with base and MoO,.py.HMPA, a new modified Nef reaction.123

Reagents: i, AIC1,-CH,CI,;

ii, TiCI,, pH 1 or 5

Scheme 36

Disproportionation in a Michael reaction has been o b s e r ~ e d , " ~ and the fluoride ion-catalysed addition of nitroalkanes to activated double bonds has also been r e p ~ r t e d . ' ~ ~ The usefulness and uniqueness of 3-nitro-2-cycloalkenones (29) as cycloalkynone equivalents has been demonstrated.126Thus, (29) behaves as a dienophile providing adducts (30) in good yield and at much lower temperatures than are

Reagents: i, 110 "C,32 h; ii, DBN-THF

Scheme 37 'I9

D. Seebach and J. Golinski, Helu. Chim. Acta, 1981,64, 1413.

12'

N. Kobayashi and K. Iawai, J. Org. Chem., 1981,46, 1823.

'*" T. Takeda, T. Hoshiko, and T. Mukaiyama, Chem. Lett., 1981, 797. M. Ochiai, M. Arimoto, and E. Fujita, Tetrahedron Lett., 1981, 1115. M. R. Galobardes and H. W. Pinnick, Tetrahedron Lett., 1981, 5235. 124 S. Hoz and D. Speizman, J . Org. Chem., 1981, 46, 450. '*' K. Matsumoto, Angew Chem., Int. Ed. Engl., 1981, 20, 770. 126 E. J. Corey and H. Estreicher, Tetrahedron Left., 1981, 603.

General and Synthetic Methods

210

required for the reaction of simple cyclic enones. Further, the adducts obtained with unsymmetrical dienes possess a substitution pattern opposite to that available from reaction with a,@-enones(Scheme 37). The nitro-group in tertiary or secondary aliphatic nitro-compounds is directly replaced by hydrogen (or deuterium) upon treatment with tri-n-butyltin hydride."' Some a- and P-halonitrosoalkenes have bepn synthesized and characterized.128

4 Hydroxylamines Sodium cyanoborohydride-acetic acid and triethylsilane-trifluoroacetic acid have been found to be excellent reducing systems for oxime benzoates, providing a new general synthesis of 0-acylhydroxylamines (Scheme 38).l Z 9

RxH

R' >NOCOPh R2 Reagents: i, NaCNBH,-MeCO'H;

R2

NHOCOPh

ii, Et,SiH-CF,CO,H

Scheme 38

5 Hydrazines

A new synthesis of monoalkyl hydrazines has been reported which overcomes many problems associated with previous methodology.130 In a modified procedure analytically pure monoalkylhydrazine hydrochlorides are available from aldehydes or ketohes by reaction with t-butyl carbazate. The use of the t-butyl group greatly facilitates hydrolysis of the intermediate carbazate, giving direct in situ formation of the hydrazine hydrochloride salts (Scheme 39).

'>NHNH2 R'

.HCI

Reagents: i, BH,.THF; ii, 6 N-HCl

Scheme 39

6 Azo-compounds Azo-compounds are conveniently prepared by oxidation of hydrazo-compounds, and 1-chloroisatin is a new oxidant to effect this tran~formation.'~'Seven-

''' 128

N. Ono, H. Miyake, R. Tamura, and A. Kaji, Tetrahedron Lett., 1981,1705. E.Francotte,, R. Merenyi, B. Vandenbulcke-Coyette, and H.-G. Viehe, Helv. Chim. Actu, 1981,

64,1208.

D.D.Sternbach and W. C. L. Jamison, Tetrahedron Lett., 1981,3331. N. I. Ghali, D. L. Venton, S. C. Hung, and G. C. le Breton, J. Org. Chem., 1981,46,5413. C. Berti and L. Greci, Synth. Cornrnun., 1981,11,681.

21 1

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

membered cyclic azo-compounds are the products of the aerial oxidation of the corresponding hydrazo-c~mpounds,'~~ and aerial oxidation of hydrazocarboxylic acid esters in the presence of 10% palladium on charcoal provides the corresponding azo~arboxylates.'~~ The use of phase-transfer techniques for azo-coupling reactions (cf. Vol. 5, p. 198) has been greatly improved by the choice of a cationic catalyst in both liquid-liquid and liquid-solid two-phase systems (Scheme 40). 134

BF4Reagent: i, Na+[3,5-(CF,),C6HJ4B--PhH

Scheme 40

Strained polycyclic azo-compounds offer a variety of uses to the organic chemist, and several attractive syntheses have been described (cf.Vol. 3, p. 177; Vol. 4, p. 186; Vol. 5 , p. 199). One such method is the oxidative hydrolysis of urazoles for which a new convenient and mild method has now been de~cribed.'~' In all cases the new hydrazinolysis method (Scheme 41) gave yields at least as good as or better than previous methods. Addition of triazolinedione to bicylobutane, followed by oxidative hydrolysis gives the previously unprepared azo-compound (3l),which decomposes to give bicyclobutane. 13'

&Yq0 I

&&J.

N2H4. 22 "C

NKN-Me

N=N

0

(31)

Scheme 41

The first preparation of both the cis- and trans-isomers of azocyclopropane have been de~cribed.'~' A preparation of azo-compounds by the N-deoxygenation of azoxycompounds utilizes Fe,(CO),, or Mo(CO)~on alumina.138 7 Imines

Sulphenylation-dehydrosulphenylation has previously proved useful for the formation of carbon-carbon double bonds, and this methodology has now been applied to the introduction of unsaturation to a nitrogen atom.'39 Imines (32) are thus the products of thermolysis of sulphinamides (33), the synthesis of C. G. Overberger and T. F. Merkel. J. Org. Chem., 1981,46,442. G. Gaviraghi, M. Pinza, and G. Pifferi, Synthesis, 1981, 608. 134 H. Kobayashi, T. Sonoda, H. Iwamoto, and M. Yoshimura, Chem. Lett., 1981, 579. 13' W. Adam, L. A. Arias, and 0. D e Lucchi, Synthesis, 1981, 543. 13' M. H. Chang and D. A. Dougherty, J. Org. Chem., 1981,46,4092. 137 P. S. Engel and D. B. Gerth, J. Am. Chem. Soc., 1981, 103, 7689. H. Alper and M. Gopal, J. Org. Chem., 1981,46, 2593. 139 B. M. Trost and G.-J. Liu, J. Org. Chem., 1981, 46, 4617. 13'

133

General and Synthetic Methods

212

/

RCH,Br

i or ii

Ar S(O)NH

0

Reagents: i, Bu,N'Cl--PhH-NaOH;

(33)

ii, NaH-DMF; iii, xylene, reflux

Scheme 42

which can be approached by two different routes (Scheme 42), thereby providing a synthesis of imines (and the corresponding aldehydes) from amines, or benzylic or allylic halides. An alternative pr~cedure'~'for the preparation of aldehydes via N-alkyl aldimines involves N-alkylation of nitriles with triethyloxonium tetrafluoroborate or, preferably, isopropyl chloride-iron(II1) chloride, and subsequent reductive capture of the resulting nitrilium ions with an organosilicon hydride, a very mild reducing agent. Without isolation of the aldimines hydrolysis gives the corresponding aldehydes in generally good yields (Scheme 43). RC=NEtBF;

Reagents: i, EtO'BF;;

-% RCH=NEt

ii, Pr'CI-FeCI,; iii, Et,SiH; iv, H,O

Scheme 43

A full paper describing the asymmetric 1,4-addition of Grignard reagents to chiral a,p-unsaturated aldimines (cf. Vol. 4, p. 188; Vol. 5 , p. 200) has appeared.14' Trimethoxyacetonitrile reacts with alkyl- and heteroaryl-lithiums at low temperature to give, after the addition of methanol, a-imino-orthocarboxylic acid esters (Scheme 44).142With pyridylmethyl-lithium, the tautomeric enamine form (34) results. New bridgehead imines are generated by the photolysis of 3-azidoh o m ~ a d a m a n t a n eand , ~ ~the ~ synthesis and reactions of C-sulphenylketenimines has been r e p ~ r t e d . ' ~ ~ 14' 142

144

J. L. Fry and R. A. Ott, J. Org. Chem., 1981,46, 602. H. Kogen, K.Tomioka, S.-I. Hashimoto, and K. Koga. Tetrahedron, 1981, 37, 3951. W. Kantlehner and J. J. Kapaesakalidis, Synthesis, 1981, 480. T. Sasaki, S. Eguchi, S. Hattori, and T. Okano, J. Chem. Soc., Chem. Commun., 1981, 1193. J. Motoyoshiya, I. Yamamoto, and H. Gotoh, J. Chem. SOC.,Perkin Trans. 1, 1981, 2127.

Amines, Nitriles, and Other Nitrogen-containingFunctional Groups NH II (Me0)3CC-R

(Me0)3CCN

213

THZ (Me0)3CC=CHR (34)

(R = 2-py, 3-py, or 2-oxazolinyl) Reagents: i, RU, -68 "C;ii, MeOH

Scheme 44

8 Carbodi-imides Carbodi-imides are useful reagents in synthetic organic chemistry, and new methods for their preparation are constantly being sought. An extremely useful new method145 is a modification of known methodology, and now allows the preparation and isolation of various carbodi-imides, even unstable ones (Scheme 45). R'NHCONHR~

Ph3PBr2

R'N=C=NR*

Scheme 45

The synthesis of N- (tosylmethy1)carbodi-imides,and their application to the synthesis of 2-amino- 1,3-0xazoles, has been reported. 146

9 Enamines Cyclic p-enaminoketones are useful intermediates in synthetic chemistry. A new from P-diketones and amines (low-boiling amines can be employed with no disadvantage) utilizes boron trifluoride etherate as complexing agent with advantageous results over previous methodology (Scheme 46). Further

Scheme 46

regioselective elaboration of cyclic P-enaminoketones is now possible via deprotonation to give kinetic enolate anions, which can be alkylated in synthetically useful yields (Scheme 47).148

(R = Me or PhCH2) Scheme 47 14'

'41 '41

C. Palomo and R. Mestres, Synthesis, 1981, 373. A. M. van Leusen, H. J. Jeuring, J. Wildeman, and S. P. J. M. van Nipsen, J. Org. Chem., 1981, 46,2069. M. Azzaro. S. Geribaldi, and B. Videau, Synthesis, 1981, 880. Y.L. Chen, P. S. Mariano, G. M. Little, D. O'Brien, and P. L. Huesmann, J. Org. Chem., 1981, 46,4643.

General and Synthetic Methods

214

A new and versatile route to p-enaminoesters is based on the reactivity of Meldrum’s acid (35) towards imidates derived from the corresponding nitriles (Scheme 48).149 RCN

R>fiH2CIM eO

4

A

R ~ I X

ii, iii

H2N

,

R>cHC02Et H2N

0 0

Reagents: i,

c:x

(39, NEt,, CHCl,, or PhM; ii, NaOEt-EtOH; iii, H,O

0

Scheme 48

The synthesis of aminomethylene derivatives of open-chain active methylene

corn pound^,^^^ and a synthesis of d i e n a m i n ~ n e s ’have ~ ~ also been described. Phosphoenamines are the products of Horner-olefination of N-substituted

aminomethane-bis-phosphonicacid esters. 15* The synthesis of /3-halogenated enamines has been reviewed,ls3 and the role of E- and 2-lithioenamines in the asymmetric synthesis of acyclic and macrocyclic a-alkyl ketones has been

10 Azides and Diazonium Compounds A reinvestigation of the reaction of hydrazoic acid with dimethyl acetylenedicarboxylate has revealed that the enazide product is a mixture of E- and Z stereoisomers. 155 The attempted diazotization of (36) leads unexpectedly to a 65% yield of the diazodiketone (37),lS6and other 3-substituted 2-amino-1H-phenalen-1-ones have also been found to undergo anomalous diazotization to diazodiketones in good yield.

In a similar vein, 3-amino-2-nitrobenzofuranundergoes an anomalous reaction with ethylene oxide, in 90% acetic acid, to give the diazolactone (38).”’ 149

”’ lS5

lS6

”’

J.-P. Celerier, E. Deloisy, P. Kapron, G. Lhommet, and P. Maitte, Synthesis, 1981, 130. 0. S. Wolfbeis, Chem. Ber., 1981,114, 3471. V. Nair and C. S. Cooper, J. Org. Chem., 1981, 46, 4759. B. Costisella, I. Keitel, and H. Gross, Tetrahedron, 1981, 37, 1227. N. De Kimpe and N. Schamp, Org. Prep. Proc. Int., 1981, 245. A. I. Meyers, D. R. Williams, S. White, and G. W. Erickson, J. Am. Chem. SOC.,1981,103,3088. G. L‘abbe, J.-P. Dekerk, and P. Van Stappen, Bull. SOC.Chim. Belges., 1981,90, 1073. M. Kuroki and Y. Tsunashima, Bull. Chem. SOC.Jpn., 1981,54939. P. Dernerseman, S. Risse, and R. Royer, J. Heterocycl. Chem., 1981, 18, 695.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

215

Scheme 50

Polymer-anchored sulphonylazide has been compared with its efficiency in the diazo-group transfer reaction of to~ylazide.'~'Although yields with the polymeric reaction are slightly lower than with tosylazide, the greater thermostability of the polymeric reagent and ease of work-up make this an attractive synthetic alternative. The geminal fluorination of diazo-compounds has been reported.

11 Isocyanates, Thiocyanates, Isothiocyanates, Selenocyanates, and Isoselenocyanates Isocyanates are not easily prepared from the corresponding azides; usually drastic conditions are required. A new method'60 now allows the transformation of phenyl azide to the corresponding isocyanate to be performed under mild conditions utilizing a transition-metal catalyst (Scheme 5 1). PhNHCONHPh PhN3

Reagents: i, CO -

&

PhNCO

u::

...

PhNHC0,Et

-RhCI(CO)(PPh,),, 80 "C; ii, PhNH,; iii, EtOH

Scheme 51

Syntheses of isocyanates from carboxylic acids,161and by the thermolysis of N-substituted 4-hydroxy-2-oxazolidones162 have recently appeared. In the latter method, the oxazolidones are prepared from amines and the overall reaction thus represents a conversion of amines to isocyanates without the use of phosgene. The photochemical rearrangement of 2-aminopyrrolin-5-ones to aminocyclopropyl isocyanates, and of bis(aminopyrro1inones) to bis-isocyanates has been p u b 1 i ~ h e d . l ~ ~ 1-Haloethylcarbamoyl chlorides react with a-pinene to give a mixture of vinyl isocyanate and the hitherto unknown 1-haloethyl isocyanates (39), probably via mono- and bis-dehydrohalogenation, respectively. 16* ''13 159 ''O

'* 163

H. Durr, G. Hauck, W. Bruck, and H. Kober, 2. Nuturforsch., Ted B,1981,36, 1149. T. B. Patrick, J. J. Scheibel, and G. L. Cantrell, J. Org. Chem., 1981,46, 3917. G. La Monica and S. Cenimi, J. Orgunomet. Chem., 1981,216, C35. P. L. Gendler and H. Rapoport, J. Med. Chem., 1981, 24, 33. N. Saito, K. Hatakeda, S.Ito, T. Asano, and T. Toda, Heterocycles, 1981,15, 905. B. J. Swanson, G. C. Crockett, and T. H. Koch, J. 'Org. Chem., 1981,46, 1082. K.-H. Konig, K.-H. Feuerherd, V. M. Schwendemann, and H.-G. Oeser, Angew Chem., In?. Ed. Engl., 1981, 20, 883.

General and Synthetic Methods

216

x

x

X

(X = C1 or Br)

(39) Scheme 52

The synthesis and reactions of carbonyl isocyanate, i s o t h i o ~ y a n a t e 'and ~~ di-isothiocyanate have been reported. A series of papers detailing a continuation of the study of the synthesis and reactions of vic-iodothiocyanates and -iodoisothiocyanates has been publ i ~ h e d . ' ~ ~ Similarly, -'~~ the treatment of alkenes with 'thiocyanogen bromide' [from equimolar quantitites of bromine and thallium(1) thiocyanate] gives moderate-to-high yields of uic-bromothiocyanates. 170 Unlike the analogous uiciodothiocyanates, the bromo-compounds are not readily isomerized to the corresponding isothiocyanates. Various epoxides react smoothly with the triphenylphosphine-thiocyanogen reagent to give a-thiocyanatovinyl ketones, uic-dithiocyanates, or uicthiocyanatohydrins, depending on the structures of the epoxides used. 17' In accord with the view that thiocyanogen may be regarded as a pseudohalogen, it has recently been that a wide range of aliphatic and steroidal ketones undergo a-thiocyanation when their solutions in methanol are stirred at room temperature with a suspension of copper(I1) thiocyanate (Scheme 53). Cyclic ketones, as well as undergoing thiocyanation, may also be converted into their dimethyl acetals, from which the free a-thiocyanato ketones are readily obtained by hydrolysis. RCOCH3

Cu(SCN),

RCOCH2SCN

Scheme 53

Phenyl selenocyanate is an important reagent for organic synthesis, capable of a wide variety of selenylation reactions. Until now the method of preparation has employed a diazo reaction; however, in a new synthesis benzeneselenyl chloride reacts with trimethylsilyl cyanide to give phenyl selenocyanate in quantitative yield (Scheme 54). 173 Since isolation simply involves evaporation of the solvent, this reaction represents a very simple synthesis of the useful reagent. PhSeCN + Me3SiC1

PhSeCl + Me3SiCN 5-10 mins.

Scheme 54 166 16' 16'

169

170

17'

'71

173

R. Bunnenberg and J. C. Jochirns, Chem. Ber., 1981,114,2064. R.Bunnenberg and J. C. Jochims, Chem. Ber., 1981,114,2075. R. C. Carnbie, D. Chambers, P. S. Rutledge, P. D. Woodgate, and S. D. Woodgate, J. Chem. SOC.,Perkin Trans. 1, 1981,33. R. C. Cambie, D. Chambers, P. S. Rutledge, and P. D. Woodgate, J. Chem. Soc., Perkin Trans. 1, 1981,40. R. C. Cambie, G. D. Mayer, P. S. Rutlege, and P. D. Woodgate, J. Chem. Soc., Perkin Trans. I, 1981,52. R. C. Carnbie, D. S. Larsen, P. S. Rutledge, and P. D. Woodgate, J. Chem. SOC.,Perkin Trans. 1, 1981,58. Y . Tarnura, T. Kawasaki, H. Yasuda, N. Gohda, and Y. Kita, J. Chem. Soc., Perkin Trans. 1, 1981,1577. S . M. Ali, D. Clarke, G. R. Cliff, and G. A. Morrison, J. Chem. Res.(S), 1981,234. S. Tomoda, Y. Takeuchi, and Y. Nomura, Chem. Lett., 1981,1069.

Amines, Nitriles, and Other Nitrogen-containingFunctional Groups

217

2-(2-Pyridyl)phenyl selenocyanates are the products of the thermal or photochemical rearrangement of 2,1,3-benzoselenadiazoles. 174 A simplified procedure for the preparation of phenyl isoselenocyanate involves the reaction of phenyl isocyanide dichloride with sodium selenide, generated in situ from elemental selenium and sodium borohydride, followed by the addition of one equivalent of sodium hydroxide (Scheme 55).175 Cl PhN=C

/

[NaHSe]

--+ PhN=C=Se

‘C1

Scheme 55

12 Nitrones The oxidation of E-benzaldehyde oxime (cf.Vol. 5, p. 206 for a similar reaction with benzil E-mono-oxime) using N-chlorosuccinimide-dimethylsulphide leads to N-methylthiomethylnitroneas the major product, together with the nitrone (40).17‘ The Z-oxime affords only benzonitrile and dimethyl sulphoxide. 0,

(40)

Scheme 56

13 Nitrates The conversion of primary amines into nitrate esters via 2,4,6-triphenylpyridinium salts is well known (cf. Vol. 5 , p. 206). A new variation on this methodology has appeared,” and involves the use of 1-substituted 4,6-diphenyl2-methylthiopyridinium salts (41) for the preparation of benzyl nitrates (Scheme 57). Benzyl nitrates are also the products of the cleavage of polymethylated dibenzyl selenides and selenoxides with nitric

9

A r C H , N H 2 - - - - + ArCH,N+’

‘Ph

SMe

ArCH,ONO,

+

DPh

N

SMe

(41)

Scheme 57 174

175

176

177

M. R. Bryce, C. D. Reynolds, P. Hanson, and J. M. Vernon, J. Chem. SOC.,Perkin Trans. 1, 1981, 607. D. L. Klayman, J. P. Scovill, J. F. Bartosevich, and C. J. Mason, Eu’r. J. Med. Chem.-Chim. Ther., 1981,16,317. N. S . Ooi and D. A. Wilson, J. Chem. Res.(S),1981,18. H. Suzuki and K. Ohnishi, Chem. Left., 1981,1 1 1.

Organometal Iics in Synthesis BY S. V. LEY, R. A. PORTER, P. F. GORDON, AND A. J. NELSON

Part I: The Transition Elements by S. V.Ley and R. A. Porter

1 Introduction This Report follows the format established in previous years. We are conscious of the enormous increase in literature in transition-metal chemistry, and owing to limitations of space, the Report is more selective. This is especially true in the development of organopalladium chemistry in synthesis, where both new reactions and significant modifications to existing chemistry are being discovered at what seems to be an exponential rate.

2 Reduction A timely review on the use of homogeneous asymmetric catalysts in the synthesis of chiral organic molecules has appeared.' The review provides an excellent starting point for anyone considering adopting these methods in their synthetic strategy. One of the problems of asymmetric hydrogenation in synthesis is the apparent lack of predictability of the reactions. In an effort to develop a rational approach, Bosnich and his co-workers have investigated the effects of several chiral ligands for Rh' catalysts during the asymmetric reduction of amino-acid precursors. This work provides some general conclusions that may prove useful in predicting optical yields from an asymmetric synthesis.* Methods for achieving enantioselective reduction of prochiral ketones are always of interest. This can be achieved by asymmetric hydrogenation of corresponding enol diphenylphosphinates using a cationic rhodium complex of ( R ) -1[(S)- 1',2-bis(diphenylphosphino)-ferrocenyl]ethan01.~Although optical yields of up to 78% are reported, only simple ketonic substrates were used; further developments, therefore, would be welcome. Although aldimines can be reduced to amines by various reagents, the use of the Wilkinson catalyst in the presence of propan-2-01 as a hydrogen donor is an especially clean, mild, and easily operated m e t h ~ d which ,~ could well be translated into an asymmetric procedure.

*

V. taplar, G. Comisso, and V. SunjiC, Synthesis, 1981,85. P. A. MacNeil, N. K. Roberts, and B. Bosnich, J. A m . Chem. Soc., 1981,103,2273. T.Hayashi, K. Kanehira. and M. Kumada, Tetrahedron Lett., 1981,22,4417. R. Grigg, T.R. B. Mitchell, and N. Tongpenyai, Synthesis, 1981,442.

218

Organometallics in Synthesis

219

To date, the direct reduction of carboxylic acids to aldehydes can only be achieved by a limited number of reagents. However, the use of catalytic quantities of dichlorobis(w -cyclopentadienyl)titaniurn and 2 molar equivalents of isobutylmagnesium bromide smoothly effects this conversion (Scheme l).'

H

Scheme 1

A new method for the regeneration of carbonyl compounds from 2,4-dinitrophenylhydrazones has been reported.6 The reaction involves a reductive hydrolysis using VC12-H20. The yields are generally very good, although functional group compatibility was not fully explored. Hydrozirconation of thioketones affords a versatile intermediate, which can be converted into a range of organosulphur compounds depending upon the work-up conditions.' Of particular interest is the reaction of these intermediates with CO-Br2 in the presence of alcohols to provide a new synthesis of ethers (Scheme 2). The reduction of the C-X bond continues to be extensively studied. For example, it is well recognized that vinyl sulphides are important in organic synthesis. However, their desulphurization to afford olefins especially using Raney nickel can be accompanied by problems, such as over-reduction. A neat way of overcoming these difficulties, in a stereospecific fashion, involves the use of 2-propylmagnesium bromide in the presence of 3-8 mol.% (Ph3P)2NiC12.8

' *

F. Sato, T. Jinbo, and M. Sato, Synthesis, 1981, 871. G . A. Olah, Y. L. Chao, M. Arvanaghi, and G. K. S. Prakash, Synthesis, 1981,476. D. E. Laycock and H. Alper, J. Org. Chem., 1981,46,289. B. M. Trost and P. L. Ornstein, Tetrahedron Lett., 1981, 22, 3463.

General and Synthetic Methods

220 R,C=S

+ CpZr

/

1

C 'I

R7C-S -ZrCp2 I

H

CO-Br,

R'OH

RICHOR'

R2CHSBr

J t l

R2CHSCOCOOMe

R2CHSCH2CH2COMe R2CHSCOMe Scheme 2

This procedure was used as a key step in the preparation of the sex pheromone from the Douglas fir tussock moth. A full paper on the use of the palladium-catalysed tributyltin hydride reduction of acyl chlorides to aldehydes has appeared.' The importance of the palladium species in these reactions is clearly seen during the reduction of the acid chloride (l),which gives citronella1 in the presence of catalyst, but yields menthone in its absence (Scheme 3).

(1) Scheme 3

Further use has been made of the chloroform-soluble borohydride complex (Ph3P)2C~BH4.9 In this paper, it is shown that aromatic azides can be reduced selectively in the presence of nitro- or aliphatic azido-groups."

3 Oxidation As we predicted in last year's Report, the Sharpless chiral epoxidation procedure for allylic alcohols is beginning to make its impact with the synthesis of several important synthetic intermediates and natural products. l1 We highlight here just one application"" to the synthesis of a key building block (2) for methymycin synthesis. This epoxide was produced in 79% yield and in >95% e.e. (Scheme 4). Owing to the water solubility of (2) modified work-up conditions were also developed and discussed. This enantioselective epoxidation method has been applied to produce a remarkably high kinetic resolution procedure for lo If

P.Four and F. Guibe, J. Org. Chem., 1981,46,4439. S.J. Clarke, G. W. J. Fleet, and E. M. Irving, J. Chem. Res., 1981,17. e.g. ( a ) B. E. Rossiter, T. Kabuki, and K. B. Sharpless, J. Am. Chem. SOC.,1981,103,464; (b)

E. J. Corey, S.-i. Hashimoto, and A. E. Barton, J. Am. Chem. Soc., 1981,103,721;(c) K.Mori and T. Ebata. Tetrahedron Lett., 1981 22, 4281.

Organometallics in Synthesis

221

(2) Reagent: i, Ti(OPr'),-Bu'OOH-(+)-diethyltartrate-CH2C12, 20 "C

Scheme 4

racemic allylic alcohols.'2 It is noteworthy that the titanium alkoxide-tartrate system is substantially more erythro -selective than the previously developed V O ( a ~ a croute. )~ It has also been pointed out that increased tartrate to titanium ratios are important, contrary to earlier recommendations. Using the VO(acac)2-Bu'OOH method, highly stereoselective epoxidations of acyclic homoallylic alcohols are possible. Stereoselectivity in a predictable manner has been demonstrated using a detailed transition-state model in which a chair-like conformation is adopted wherein the steric interactions of the various substituents are minimized according to accepted principles of conformational ana1y~is.l~ For example, the homoallylic alcohol (3) affords the epoxide (4) in greater than 400: 1 selectivity via the transition-state model shown in Scheme 5 .

(4)

Scheme S

A greatly improved and reliable procedure for ruthenium tetroxide-catalysed oxidation of organic substrates has been reported.14This process simply involves the addition of acetonitrile to the traditional CC14-H20 solvent system. Several examples of oxidation of alcohols, olefins, aromatic rings, and ethers are given. Of special note are the very low levels of epimerization at a -centres upon glycol oxidation, and the facile oxidation of aromatic rings to carboxylic acids, which were not observed by the older methodology (Scheme 6). Another development in ruthenium-catalysed processes involves the use of 1% R U C ~ ~ ( Pand P~~)~ OH

H M e

H Me

96% e.e.

94% e.e.

Scheme 6

l4

V. S. Martin, S. S. Woodard, T. Katsuki, Y. Yamada, M. Ikeda, and K.B. Sharpless, J. A m . Chem. SOC.,1981,103,6237. E.D.Mihelich, K.Daniels, and D. J. Eickhoff, J. Am. Chem. Soc., 1981,103,7690. P. H. J. Carlsen, T. Katsuki, V.S. Martin, and K. B. Sharpless, J. Org. Chem., 1981,46,3936.

222

General and Synthetic Methods

a 1.3-2 fold excess of iodosylbenzene to oxidize alcohols. Alternatively, the use of phenyliodosodiacetate as co-oxidant allows the isolation of an aldehyde from a primary As selectivity during oxidation reactions is of prime importance in organic synthesis, the use of R u C ~ ~ ( PinP benzene ~ ~ ) ~ to effect the oxidation of a primary hydroxyl group in the presence of a secondary hydroxyl group is a useful contribution. The oxidation of 1,lO-undecanediol to 10-hydroxy-undecanal in 89% yield typifies the selectivity.16Other procedures have also been studied." Further oxidation reactions of trimethylsilyl enol ethers have been reported. For example, Mo02(acac)2and Bu'OOH can be used very effectively to cleave these systems to carbonyl compounds. This procedure is quoted as being more convenient and certainly more selective than the alternative ozonolysis method (Scheme Trimethylsilyl enol ethers also react with silver carboxylate-iodine

Scheme7

followed by a fluoride work-up to afford a-acyloxy-carbonyl derivatives. The reaction conditions can also be varied to produce a-iodo-compounds.l S b Oxidation of a -nitrocarbanions with MoO,-py-HMPA produces the corresponding carbonyl systems in excellent yield. This process is much milder than the classical Nef reaction. As the use of nitro-compounds in synthesis is steadily growing, this modification should prove useful. l 9 The formation of lactones from anomeric methoxy-derivatives can be achieved using MoO,-H2O2 as an oxidant, and the method has been used in a short synthesis of (*)-massoialactone (Scheme 8).20

92

H11Cs-0

OMe

QOMe

15'

0

0

Reagents: i, 15-20 Kbar, 50-60 "C; ii, Mo0,-30% H,O,

Scheme 8

Finally in this Section, benzyl(triethy1)ammonium permanganate, which is soluble in dichloromethane, has proved to be an efficient oxidant for various amines.21Tertiary amines, for example, afford amides in yields of between 75% and 98%.

''

l6 18

l9

2o 21

P. Muller and J. Godoy, Tetrahedron Lett., 1981, 22, 2361. H. Tomioka, K. Takai, K. Oshima, and H. Nozaki, Tetrahedron Lert., 1981, 22, 1605. M. P. Doyle and V. Bagheri, J. Org. Chem., 1981, 46, 4806. ( a ) K. Kaneda, N. Kii, K. Jitsukawa, and S. Teranishi, Tetrahedron Lett., 1981, 22, 2595; (6) G . M. Rubottom, R. C. Mott, and H. D. Juve, jun., J. Org. Chem., 1981,46, 2717. M. R. Galobardes and H. W. Pinnick, Tetrahedron Lett., 1981,22, 5235. M. Chmielewski and J. Jurczak, J. Org. Chem., 1981, 46, 2230. H. J. Schmidt and H. J. Schafer, Angew. Chem., Int. Ed. Engl., 1981, 109.

223

Organometallics in Synthesis

4 Isomerization and Rearrangement Although Lewis acid-promoted rearrangements of epoxides are well known, it seems that the presence of an CY -hydroxyl substituent can substantially alter the standard behaviour. Rearrangements of 2,3-epoxynerol and 2,3-epoxygeraniol for example with very weak Lewis acids, such as Ti(OPr’)4, afford allylic diols with high selectivity (Scheme 9).22It is hoped that this selectivity can be exploited in more complex examples. OH

Reagent: i, Ti(OPri),-CH2CI,, RT

Scheme 9

In view of the importance of the pyrethrin insecticides, new methods for the efficient isomerization of the cyclopropanyl moiety from the unnatural cis -series to the natural trans-compounds are important. It has now been shown that cis-chrysanthemic acid (5) can be transformed quantitatively to the trans-acid using 0.06 M-(PhCN),PdCl, as the catalyst in 5.5 h (Scheme 10). The reaction was shown to be very sensitive to the quantity of catalyst used, and obviously proceeded more rapidly at higher concentration^.^^ Nevertheless, this mild method compares very favourably with alternative isomerization procedures.

(5)

- 2--co2 Scheme 10

A new protecting group for amines has been studied and used in the first chiral synthesis of a n t i c a p ~ i nThe . ~ ~ route involves initial bis-allylation to give a base-stable group resistant to nucleophiles, but which can be easily deprotected using the known allyl-to-propenyl isomerization reaction promoted by transition-metal complexes (Scheme 11). Further examples of the palladium-catalysed 1,3-(oxygen-to-carbon) rearrangement in allyl vinyl ethers have been noted.” Detailed mechanistic and stereochemical considerations have lead to a clear picture of how these reactions can be used in cyclopentanone synthesis. The reaction nicely complements the normal thermal [3.3]rearrangement of allyl vinyl ethers.

’*

D. J. Morgans, jun., K. B. Sharpless, and S.G . Traynor, J. A m . Chem. SOC., 1981,103,462. J. L.Williams and M. F. Rettig, Tetrahedron Lert., 1981,22, 385. 24 B. C. Laguzza and B. Ganem, Tetrahedron Lett., 1981,22, 1483. ’’ ( a ) B. M . Trost and T. A. Runge, J. A m . Chem. SOC.,1981,103,2485;( 6 ) ibid., 1981,103,7550 and 7559. 23

General and Synthetic Methods

224 0

- 6:. .

...

1-111

H* Q0zH NH, Reagents: i, 30% H,O,-NaOMe; ii, (Ph,P),RhCI; iii, 1 equiv. NaOH, 0 "C

Scheme 11

5 Carbon-Carbon Bond-forming Reactions

The role of sterically demanding metal centres in the stereocontrol of the aldol condensation is now well recognized. For example, zirconium enolates derived from chiral amides exhibit high levels of stereoregulation.26 Also, titanium enolates (which are reported to be easily accessible using cheap reagents, distillable and miscible in THF, ether, methylene chloride, or pentane) display pronounced erythro -selectivity in reaction with aldehydes.27 The diastereoselectivity of the addition of but-2-enyltitanium compounds, (q5C5H5)2Ti(CH2CH=CHMe)X, to aldehydes is highly dependent on the halide ligand This reaction is stated X and shows high threo-selectivity when X is Br or to be a convenient general method for the preparation of threo -p -methyl homoallyl alcohols irrespective of the bulk of the aldehyde. This contrasts with the results obtained from the chromium(I1)-mediated reaction of but-2-enyl halides with aldehyde^.^' Similar crotylzirconium derivatives have also been shown to undergo a rapid reaction with aldehydes to afford predominantly the threo The use of titanium species in organic synthesis is increasing notably. Ketones react with dimethyltitanium dichloride under mild conditions leading directly to the corresponding geminal dimethyl-substituted compounds (Scheme 12).31 As the geminal dimethyl substituent occurs in many natural products, this procedure could find many applications.

%

%

Me _____* Me2TiC12

Me

Me

Me Scheme 12

26

" 29 'O

D. A. Evans and L. R. McGee, J. Am. Chem. SOC.,1981,103,2876. M. T.Reetz and R. Peter, Tetrahedron Lett., 1981,22,4691. F. Sato, K. Iida, S. Iijima, H.Moriya, and M. Sato, J. Chem. SOC.,Chem. Commun.. 1981,1140. T . Hiyama, K.Kimura, and H. Nozaki, Tetrahedron Lett., 1981,22,1037. Y. Yamamoto and K. Maruyama, Tetrahedron Lett., 1981,22,2895. M. T. Reetz, J. Westermann, and R. Steinbach, J. Chem. SOC.,Chem. Commun., 1981,237;see also references therein.

225

Organometallics in Synthesis

Other interesting organotitanium derivatives have been prepared and some of their chemistry i n ~ e s t i g a t e d Trialkoxy-titanium .~~ alkyls, (R'O),TiR, which are thermally more stable than their lithium counterparts, can have their reactivity modified by a change in the R'O group. Promising but rather low levels of enantioselectivity during the addition of related chiral species to an aldehyde have also been The high basicity associated with many of these titanium reagents can restrict their usage. However, the corresponding zirconium analogues, which have greatly reduced basicities, still react readily with carbon compounds, especially highly enolizable Several examples of the titanium- or zirconium-catalysed stereospecific addition of various reagents to acetylenic compounds have appeared.34 These methods are being increasingly used in natural product synthesis, notably in the terpenoid area,34a as illustrated in Scheme 13. 1 , l -Dimetalloalkenes have been prepared and characterized, and shown to behave as new alkenylidene and alkenyl transfer agents.34 I i, ii /

I Reagents: i. 2 B U ' M ~ C I - ( ~ ~ - C ~ H , ) , T ii,~Me1 CI~;

Scheme 13

Titanium tetrachloride continues to be a popular Lewis acid catalyst in synthesis. Of the many examples quoted in this years' literature, several have attracted our attention. a -Methoxyurethanes, for example, react with trimethyls i l y l ~ y a n i d eor ~ ~ phenyli~ocyanide~~ in the presence of TiC14 to give aaminocyanides or amino-acid derivatives, respectively, in very high yields. The initial a-methoxy urethanes are derived easily, and in quantity, by anodic oxidation of the corresponding urethanes in methanol (Scheme 14). A full paper R2

R.tNJI , C0,Me

- \NAOMe-2e

MeOH

R2

R'

I

R2

R < NI A C O N H P h

C0,Me

CO,Me

A+

RZ R'\ N A C O , H H Scheme 14 32

33

3*

35 36

(a) B. Weidmann and D. Seebach, Helu. Chim. Acta, 1980,63, 2451; (6) B. Weidmann, L. Widler, A. G. Olivero, C. D. Maycock, and D. Seebach, Helu. Chim. Acta, 1981,64, 357. B. Weidmann, C. D. Maycock, and D. Seebach, Helu. Chim. Acta, 1981, 64, 1552. e.g. ( a ) F. Sato, H. Ishikawa, H. Watanabe, T. Miyake, and M. Sato, J. Chem. SOC.,Chem. Commun., 1981, 718; (6) T. Yoshida and E.4. Negishi, J. A m . Chem. SOC.,1981, 103, 1276; (c) C. L. Rand, D. E. Van Horn, M. W. Moore, and E-i. Negishi, J. Org. Chem., 1981, 46, 4093; (d) M. D. Schiavelli, J. J. Plunkett, and D. W. Thompson, J. Org. Chem., 1981, 46, 807. V. Asher, C. Becu, M. J. 0. Anteunis, and R. Callens, Tetrahedron Lett., 1981, 22, 141. T. Shono, Y. Matsumura, and K. Tsubata, Tetrahedron Lett., 1981, 22, 2411.

General and Synthetic Methods

226 / OMe OMe

/

PhCH=CHCH

b M g B r . W & r B

TiCI,

OMe / /OMe PhCH=CHCH

\OMe

\CH2CH=CH2

Scheme 15

on the reaction of acetals with Grignard reagents in the presence of TiC14 to give ethers, has also appeared (Scheme 15).37 A (trimethylsily1)cyclopentene annulation method has been developed that leads to a regiocontrolled approach to the synthesis of five-membered rings.38 Thus, it was shown that (trimethylsily1)allenes could be persuaded to react at -78 "C with unsaturated carbonyl compounds in the presence of titanium tetrachloride (Scheme 16). The methodology is presently being applied to polyquinane natural product synthesis. SiMe,

\

Scheme 16

Cross-coupling techniques are always useful, especially when either high selectivity or novelty of product are achieved, as for example in the regioselective allylation of Grignard reagents by nickel and palladium phosphine complexes. It turns out that the regiochemistry of the product is entirely dependent on the catalyst used (Scheme 17).39An adequate explanation for these observations must await further work. -OSiEt,

+ PhMgBr

+

Ph

+

/yPh

NiC12(dppf) 12 : 88 PdC12(dppf) 96 : 4 Scheme 17

The preparation of 2-substituted butadienes by palladium(0)-catalysed cross coupling of Grignard reagents with alkyl or aryl iodides, although following standard procedures, could well have applications where novel Diels-Alder addends are req~ired.~'Other highly selective synthesis of allylated arenes and as diarylmethanes uia Pd-catalysed cross couplings have been in~estigated,~' have the couplings of cis -vinyl cuprates with aryl halides to afford geometrically pure Owing to the fact that benzyl ketones are useful building blocks for a number of syntheses, a new mild method of preparation involving cross coupling of benzyl bromides with acyl chlorides in the presence of zinc and catalytic quantities of Pdo complexes might well prove 37

38 39 'O

41

42

H. Ishikawa, T. Mukaiyama, and S. Ikeda, Bull. Chem. SOC. Jpn., 1981,54, 776. R. L. Danheiser, D. J. Carini, and A. Basak, J. Am. Chem. SOC.,1981,103,1604. T.Hayashi, M. Konishi, K.-i. Yokota, and M. Kumada, J. Chem. SOC.,Chem. Commun., 1981,313. S. Nunomoto, Y.Kawakami, and Y. Yamashita, Bull. Chem. SOC.,Jpn., 1981,54,2831. E.4. Negishi, H. Matsushita, and N. Okukado, Tetrahedron Lett., 1981,22,2715. N. Jabri, A. Alexakis, and J. F. Normant, Tetrahedron Lett., 1981,22,3851. T. Sato, K.Naruse, M. Enokiya, and T. Fujisawa, Chem. Lett., 1981,1135.

Organometallics in Synthesis

227

Organocuprates, as in previous years, continue to play a crucial role in synthesis. The chemistry of so-called high-order mixed organocuprates have been discussed, by which it is now possible to effect substitution reactions at unactivated secondary centres.44 Obviously, this process is very important and opens up many new possibilities. Good experimental details are reported for the preparation of appropriate reagents. Typically, the alkyl-lithium (2 equiv.) is reacted with CuCN in tetrahydrofuran at 0 "C to give a tan-coloured solution, which is cooled to -78 "C and used in the normal way (Scheme 18).The generally far greater reactivity of these cuprates brings into question the aggregate nature of these species. O T ,6 h ___*

d2 CuLi 42 Cu(CN)Li,

23 ?!o 90%

Scheme 18

Conjugate additions to polysubstituted a,p -unsaturated aldehydes using conventional cuprate reagents such as MezCuLi often proceed in poor yield, if at all. However, the use of the Me5Cu2Li2circumvents this problem and leads to excellent yields of products from conjugate addition with only negligible amounts of 1,2-addition being noticed (i.e. ~ 1 . 5 % ) . ~ ' The R3Cu2Mspecies has been recommended as a convenient cuprate for the conversion of 1-alkynes to l - a l k e n e ~ . ~ ~ 1,4-Additions of PhCu.BF3, n-Bu"BF3, and MeCuBF3 to trans -8-phenylmethylenolates are shown to proceed with high chiral induction. Saponification of the resulting adducts leads to enantiomerically pure /3 -substituted alkanoic acids (Scheme 19).47

Scheme 19 B. H. Lipshutz, R. S. Wilhelm, and D. M. Floyd, J. A m . Chem. Soc., 1981, 103,7672. D. L. J. Clive, V. Farina, and P.Beaulieu, J. Chem. Soc., Chem. Commun., 1981, 643. " H. Westmize, H. Kleijn, J. Meyer, and P. Vermeer, Red. Trau. Chim. Pays-Bas, 1981, 100, 98. 47 W. Oppolzer and H. J. Loher, Hefu. Chim.A d a , 1981,64, 2808. 44

General and Synthetic Methods

228

In a similarly interesting manner, conjugate additions to optically active a,@-ethylenic sulphoxides have been st~died.~' The transfer of chirality from

the sulphoxide sulphur atom to the p-carbon during the addition, followed by reductive removal of the sulphur, produces p -alkylcarboxylicesters in reasonable optical purity (Scheme 20). The preparation of chiral p -substituted cyclopentanones by the method is particularly useful. Ar

Reagents: i, R',CuLi; ii, Al/Hg

R'

Scheme 20

In an effort to discover new enolonium ion equivalents, it has been shown that allylically-substituted enolates react with organometallic species (mainly cuprates) in one of two ways, either sN2 or sN2' depending on the reaction conditions (Scheme 21).49

6

MelCuLi

_____*

0

/

Me

MepJ 97 %

Me

93 %

Scheme 21

Over the years, allylsilanes have been developed as synthetically useful regiospecific carbon nucleophiles. However, there is still a need for a general and regiospecific preparation of these species. An attractive and versatile solution to some of the difficulties encountered in the previous methodology, has been recently described. Ketone derivatives are first transformed into allylic acetates by conventional means. These then react with [PhSi(CH3)&uLi to afford allylsilanes directly (Scheme 22).50The method is limited as secondary allylic acetates do not give allylsilanes when treated with the silylcuprate reagent. Aryl-, alkenyl-, and alkyl-mercurials react by cross-coupling with primary and secondary alkyl- and alkenyl-cuprate reagents to provide the first truly general G.H. Posner, J. P. Mallarno, and K. Miura, J. Am. Chem. Soc.. 1981,103,2886. P. A. Wender, J. M. Erhardt, and L. J. Letendre, J. Am. Chem. Soc., 1981,103,2114. '' I. Fleming and D. Marchi, jun., Synthesis, 1981, 560. 48

*9

Organometallics in Synthesis

229 R3

R4 [PhSiMe2I2CuLi

Ri

L .

R’‘R2 &,C02H

R3

R4

Scheme 22

method for the alkylation of a wide variety of organomercurial specie^.'^ This process complements many of the previously discussed cross-coupling reactions. The introduction of the trifluoromethyl substituent into aromatic substrates in a regiospecific way is often important to those designing novel physiologically active compounds. Consequently, the very simple process involvingdisplacement of aromatic iodides using copper(1)iodide and sodium trifluoroacetate as reagents will undoubtedly find immediate application^.^^ Many new and useful biaryl syntheses have been reported during 1981.s3 One of these was nicely used in the first synthesis of the natural product alnusone(6) (Scheme 23).’’“

Scheme 23

The use of arylamines in the Pdo-catalysed coupling with olefins has been reported.’* This modification of the classical Heck procedure further extends the utility of the method. A study of the regiochemistry of the cycloaddition of substituted trimethylenemethanepalladiurncomplexes is necessary if they are to be generally adopted in synthesis. Reaction of cyclopentenone with a methylsubstituted trimethylenemethane species afforded a single stereoisomeric product, which was converted to a precursor of the natural product chrysomelidial (Scheme 24).5’ Since previous work on the unsubstituted system suggested a ” ” s3

54

R, C. Larock and D. R. Leach, Tetrahedron Lett., 1981,22,3435. K. Matsui, E. Tobita, M. Ando, and K. Kondo, Chem. Len., 1981,1719. e.g. (a) M. F. Semmelhack, P. Helquist, L. D. Jones, L. Keller, L. Mendelson, L. S. Ryono, J. G. Smith, and R. D. Stauffer, J. Am. Chem. Soc., 1981, 103, 6460;( b ) N. Miyaura, P. Yanagi, A. Suzaki, Synth. Commun., 1981,11,513; ( c ) M. A . Tius, Tetrahedron Lett., 1981,22,3335;( d ) A . D. Ryabov, S. A . Dieko, A. K. Yatsimirsky, and I. V. Berezin, Tetrahedron Lett., 1981,22,3793. K. Kikukawa, K. Maemura, Y. Kiseki, F. Wada, T. Matsuda, and C. S. Giam, J. Org. Chem., 1981,

46,4885. ”

B. M.Trost and D. M. T. Chan, J. Am. Chem. SOC.,1981 103,5972.

230

General and Synthetic Methods

Scheme 24

dipolar structure of the complex in which the cycloaddition involves a Michaeltype addition followed by ring closure, these new results demonstrate that the carbon bearing the methyl group initiates attack on the acceptor. Assuming that the most electron-rich carbon initiates this attack, leads one to the incredible conclusion that the normally electron-releasing methyl group prefers to be on the most electron-rich carbon of the trimethylenemethane complex. Several neutral alkylations of vinyl epoxides in the presence of Pdo catalysts provide us with useful new meth~dology.'~ The reactions are shown to proceed from the same face as the epoxide oxygen in a conjugate manner using soft nucleophiles (Scheme 25). C0,Me

-

(Ph$'),Pd

6

CH (CO Me), Scheme 25

Milder and more efficient conditions than the Heck process have been developed and used very effectively in the construction of carbomycin model compounds (Scheme 26)." 0

0

PdCI,(MeCN), _____*

MeCN, 25 "C

Scheme 26

The introduction of bridged binuclear complexes, the so-called Tebbe reagents, to achieve alkylidene transfer to carbonyl species was a useful discovery. However, developments of these systems such that substituted examples could also be prepared was necessary. Recently, substituted alkylidene-bridged zirconium reagents have been prepared and briefly examined as suitable transfer reagents. 5 8 Iron ethylene transfer reagents such as [Cp(CO)(L)Fe=CHMe]' can be prepared, characterized, and reacted with a limited range of alkenes to give 56

57

B. M. Trost and G. A. Molander, J. A m . Chem. SOC.,1981,103,5969. F. E.Ziegler, U. R. Chakraborty, and R. B. Weisenfeld, Tetrahedron, 1981,37,4035. F. W. Hartner, jun., and J. Schwartz, J. Am. Chern. SOC.,1981,103,4979.

Organornetallics in Synthesis

23 1

cyclopropanyl derivative^.'^ These species are reported to be easily prepared, surprisingly stable and transfer carbenes to alkenes efficiently (Scheme 27). Other improved cyclopropanation procedures have also appeareda6' H +

Cp(CO),Fe=C

/

Scheme 27

99%

A full paper on the use of tricarbonyliron-stabilized pentadienyl cation complexes in the target-oriented synthesis of tricothecene analogues has been published. The initial complexes in the sequence react with the potassium enolate of 2-oxocyclopentanecarboxylateto afford a mixture of diasteromeric complexes, both of which can be elaborated to the final target molecules (Scheme 28).61 Similar tricarbonyliron complexes have also been used in an approach to the total synthesis of steroids.62

M'ozc.o 0-

-+ OMe

CO,Mc Scheme 20

Tricarbonyliron diene complexes have been used in a simple stereospecific synthesis of insect pheromone^.^^ The basis of this synthesis relies on the Friedel-Crafts acylation of various diene complexes. The strategy is illustrated with a preparation of the pheromone (7) from the red bollworm moth (Scheme 29). Phase-transfer-catalysed reactions of allenes with dicobalt octacarbonyl, methyl iodide, and carbon monoxide, at room temperature and atmospheric pressure, afford unsaturated hydroxy ketones and die none^.^^ Although the yields are not high, the method constitutes a simple 'one-pot' procedure for the synthesis of an interesting class of compounds not easily accessible by other means. 59 6o

61 62

&i

M. Brookhart, J. R. Tucker, and G. R. Husk, J. A m . Chem. SOC., 1981,103,979. ( a ) M. Suda, Synthesis, 1981,714; ( b ) M. P. Doyle, W. H. Tamblyn, W. E. Buhro, and R. L. Dorow, Tetrahedron Lett., 1981,22, 1783. A. J. Pearson and C. W. Ong, J. A m . Chem. SOC.,1981,103,6686. A. J. Pearson and G. C. Heywood, Tetrahedron Lett., 1981,22, 1645. G. R. Knox and I.G. Thorn, J. Chem. SOC., Chem. Commun., 1981,373. S. Gambarotta and H. Alper, J. Org Chem., 1981,46.2142.

General and Synthetic Methods

232

Reagents: i, AICI,-LiAIH,,; ii, Ac20; iii, Me,NO

Scheme 29

A whole range of potentially useful products can be derived from titanium ally1 complexes upon treatment with various insertable ligands followed by an aqueous work-up (Scheme 30).65 R Cp,Ti I Me

Me2c=Y

* Cp2Ti

I

CH,=CHCH(R)COMe

CH, =CHCH(R)CMe20H

R

1

Y=CHPh Ph R

PhNCO

lH.0

Cp,Ti

A,+& I

Ph

,Ph

CH, =CHCH(R)CO,H

CH,= CHCH(R)CH(Ph)NHPh U

CH, =CHCH(R)CONHPh Scheme 30

Finally in this Section on carbon-carbon bond formation, we report on the preparation of ketones from S- 2-pyridyl thiolates or acyl chlorides. S-2-Pyridyl thiolates react in excellent yields with dialkylcuprates to afford ketones when the reaction is carried out in a nitrogen atmosphere. However, in the presence of oxygen, esters are produced.66 Acyl halides, on the other hand, react with stoicheiometric amounts of organomanganous reagents to give ketones under very mild conditions and in the presence of various other potentially reactive functional groups (Scheme 31).67 67

B. Klei, J. H. Teuben, and H. J. de Liefde Meijer, J. Chem. Soc., Chem. Commun., 1981, 342. S. Kim, J. I. Lee, and B. Y. Chung, J. Chem. Soc., Chem. Commun., 1981,1231. G. Cahiez, Tetrahedron Lett., 1981.22. 1239.

Organometallics in Synthesis

233

i. (COCI),

Scheme 31

6 Synthesis of Heterocycles The synthesis of heterocyclic compounds using transition-metal species is a growing area of interest. A new synthesis of pyrroles from 1-amino-3-alkyn-2-01s has been reported involving Pd" as a catalyst. The yields are fairly good and the starting materials are easily accessible from conjugated ynones (Scheme 32).68 0

OH

Reagents: i, Me,SiCN; ii, LiAIH,; iii, PdCI,

Scheme 32

High yields of pyrrole derivatives have also been obtained by reaction of 5,6-dihydro-4H-1,2-oxazines with iron carbonyls. As the oxazenes in this study were prepared from a -bromo-oximes and enamines, a convenient 'one-pot' procedure was developed (Scheme 33).69 R'

Scheme 33 a -Cyanoallylic acetates undergo palladium-catalysed rearrangement to y acetoxy-cu,P -unsaturated nitriles. After hydrolysis, followed by treatment with di-isobutylaluminium hydride and acid work-up a new route to furan derivatives was realized (Scheme 34)." This simple procedure could well be applied to natural product synthesis. Furans are also obtained in one-step from 2-but-2ene- 1,4-diols by oxidation with pyridinium chloro~hromate.'~This route is versatile as the butene-diols can be prepared by various methods. The lack of regiocontrol during the hydration of triple bonds in substituted but-2-yne-1,4-diols has meant that they are not especially useful for the construc69 'O

"

K. Utimoto, H. Miwa. and H. Nozaki, Tetrahedron Letr., 1981,22.4277. S. Nakanishi, Y. Shirai, K. Takahashi, and Y . Otsuji, Chem. Lert., 1981,869. T. Mandai, S. Hashio, J. Goto, and M. Kawada, Tetrahedron Lett., 1981, 22,2187. H. Nishiyama, M. Sasaki, and K. Itoh, Chem. Left., 1981,1363.

General and Synthetic Methods

234

CCN +sphb JN

OAc

OAc

Reagents: i, (Ph,P),Pd; ii, -OH; iii, Dibal

Scheme 34

tion of furanone derivatives. However, a recent report provides a solution to this p r ~ b l e m . ~The ' process entails a selective monoacetylation followed by an Ag'-catalysed acetoxyl migration and cyclization sequence. The beauty of the method was demonstrated by a concise synthesis of the anti-tumour furanone geiparavarin (8) (Scheme 35).

. ..

OH

'3

"

+

I

I

O

W

O

0

m / o

____, 111

(8) Reagents: i, Ac,O-py; ii, Ag(C10,); iii, DDQ

Scheme 35

Dienes, after regiospecific epoxidation, react readily with pentacarbonyl iron to afford tricarbonyliron lactone complexes. These complexes can then be smoothly oxidized by ceric ammonium nitrate to give predominantly alkenylsubstituted p -propiolactones (Scheme 36).73The stereochemical integrity of the initial complexes is reflected in the structures of the oxidation products. A novel route to bicyclic p-lactams has been discovered. The reaction involves treatment of azirines with (Ph3P)4Pd in the presence of carbon monoxide.74 Yields of up to 63% were reported for this unusual process (Scheme 37). 72

73

74

H. Sairnoto, T. Hiyarna, and H. Nozaki, J. A m . Chem. SOC.,1981, 103,4975. G. D. Annis, S. V. Ley, C. R. Self, and R. Sivaramakrishnan, J. Chem. SOC.,Perkin Truns. I , 1981, 270. H. Alper, C. P. Perera, and F. R. Ahmed, J. A m . Chem. SOC.,1981,103, 1289.

Organometallics in Synthesis

235

R'

R' Fe (CO), Reagents: i, RC0,H; ii, Fe(CO),; iii, Ce'"

Scheme 36

Scheme 37

7 Miscellaneous Reactions During the first synthesis of a parent [lOIannulene, the important last step entailed a bis-decarbonylation reaction.'' This was achieved in 88YO yield using two equivalents of tris(triphenylphosphine)rhodium(I) chloride in benzene at 80 "C(Scheme 38).A similar decarbonylation process proved to be a key reaction in a short stereoselective synthesis of a steroidal C-D ring fragment.76

CHO Scheme 38

Throughout the year, several rhodium-catalysed decomposition reactions of -diazoesters have appeared. However, a particularly interesting example is its application to the preparation of cis -2-enoates (Scheme 39).77 We anticipate that this reaction will become commonly used in synthesis. (Y

Scheme 39

The conjugate addition of trialkylstannyl copper reagents to a,B -acetylenic , ~ ~ to the stereoselective preparation of esters7' or /3 -substituted a c r y l a t e ~ leads potentially useful stannyl acrylates. The stereochemical course of the conjugate addition to a,@-acetylenic esters was shown to be dependent on the constitution of the reagent and upon the structure of the 75

76 77

79

T. L. Gilchrist, D. Tuddenham, R. McCague, C. J. Moody, and C. W. Rees, J. Chem. SOC., Chem. Commun., 1981,657. T. Takahashi, Y.Naito, and J. Tsuji, J. Am. Chem. SOC., 1981, 103, 5261. N. Ikota, N. Takarnura, S. D. Young, and B. Ganern, Tetrahedron Lett., 1981, 22,4163. E. Piers, J. M. Chong, and H. E. Morton, Tetrahedron Lett., 1981,22,4906. D. E. Seitz and S.-H. Lee, Tetrahedron Lett., 1981, 22, 4905.

General and Synthetic Methods

236

cis- or trans -Stereoselective palladium-catalysed 1,4-diacetoxylation of cyclic 1,3-dienes can be achieved by relatively small changes in the reaction conditions (Scheme 40).80 It would be interesting to know how these processes would translate into more complicated systems. OAc

0:

AcO

AcO

OAc

Reagents: i, Pd(OAc),-benzophenone-HOAc-LiOAc; ii, LiCl

Scheme 40

Further examples of amination reactions of 7r -allylpalladium intermediates have been reported.81 Of particular note are the syntheses of amino-sugar derivatives e.g. a -D-forosaminide (Scheme 41).81"*b BzNHMe

--

,

Pd(Ph3P),

AcO

OMe

BzNMe

OMe

Me,N

OMe (9)

Scheme 41

Tricarbonyl(v 6-1-methylindole)chromium(O)can be lithiated by butyl-lithium at C-2, whereas the 2-trimethylsilyl analogues was lithiated predominantly at C-7. This selective C-7 lithiation permits substitution at this position in the indole nucleus by a range of functionalized electrophiles.82 1,4-Epiperoxides (endoperoxides), which are key substances in many chemical and biochemical transformations, react with 5 mol.% (Ph,P),Pd to give 4hydroxy-ketones and 1,4-diols as m,ijor Prostaglandin endoperoxides (PGH2 methyl ester) likewise undergo conversion to primary prostaglandin derivatives (PGD2, PGE2, PGF2a, and HHT). Part 11: Main Group Elements by P. F. Gordon and A. J. Nelson

1 Group1 Selective Lithiation.-In recent years chiral auxiliary groups have been used extensively as agents for the introduction of new or additional chiral centres 81

'* 83

J.-E. Backvall and R. E. Norberg, J. A m . Chem. Soc., 1981,103,4959. ( a ) H. H. Baer and Z. S. Hanna, Carbohydrate Res., 1981,94.43;( b ) H. H. Baer and Z. S. Hanna, Can. J. Chem., 1981,59,889;( c ) S. A.Godleski, J. D. Meinhart, D. J. Miller, and S. van Wallendael, Tetrahedron Lett., 1981,22, 2247. G. Nechvatal, D. A. Widdowson, and D. J. Williams, J. Chem. Soc., Chem. Commun., 1981,1260. M. Suzuki, R. Noyori, and N. Hamanaka, J. A m . Chem. Soc., 1981,103,5606. e.g.

237

Organometallics in Synthesis

into a lithiated molecule. Several further examples of this approach have been reported this year, and some of these are highlighted below. For example, by making use of either L-valine or S-O,O-dimethyl-a-methyldopaas chiral auxiliarly groups, Schollkopf and his co-workers have prepared R-a-amino-acids (1)from glycine.'"-d The strategy is the same for both auxiliaries and proceeds via the lithiated dihydropyrazine (2), prepared from L-valine and glycine (for 2a) and a-methyldopa and glycine (for 2b) (Scheme 1). Alkylation of (2) followed by hydrolysis gives the chiral amino-acids (1) in 47-90% chemical yield and 70-95% enantiomeric excess (e.e.). In both cases the chiral auxiliary can be separated and re-used.

(a)

R~ = Pri, R~ = H

I

\

OMe

H

R' *! R,&/N-voMe R Z q N Y o iii

1 .

R'

I.

-

.-I

7

1

1

OMe

H

NH,

R'

NH,

(1) Reagents: i, COCI,; ii, Gly. OEt; iii, Me,bBF,; iv, Bu"Li; v, RX; vi, H,O'

Scheme 1

The same authors have made use of a similar reaction sequence to prepare R,R-methylserine esters (3) from ketones (R'R2CO) and the lithio derivative of dihydropyrazine (4).2" Once again the dihydropyrazine is prepared from a chiral amino-acid (2 moles L-alanine). Alternatively, if alkyl halides are reacted with the lithio derivative of (4) then chiral homologues of L-valine are obtained.26 In a related application, the chiral amino-acid derivative L-N-ethoxycarbonyl-

' ( a ) U. Schollkopf, U. Groth, and C. Deng, Angew. Chem., Int. Ed. Engl., 1981, 20, 798; ( 6 ) U. Schollkopf and U. Groth, ibid., p. 977; ( c ) U. Schollkopf, W. Hartwig, K.-H. Popischil, and H. Kehne, Synthesis, 1981, 966; ( d )U. Schollkopf, U. Groth, K . - 0 . Westphalen, and C. Deng, ibid., p. 969. ( a )U. Schollkopf, U. Groth, and W. Hartwig, Liebigs Ann. Chem., 1981,2407; ( 6 )U. Schollkopf, W. Hartwig, U. Groth, and K . - 0 . Westphalen, ibid., p. 696.

238

General and Synthetic Methods

alanine reacts with phenyl-lithium (3 moles) to give the corresponding aaminopropiophenones ( 5 ) with complete retention of stereochemical i n t e g r i t ~ . ~

/

Ph

HA

H*N

OMe

Chiral amines, e.g. S-(6), can also be used as auxiliaries by conversion to the Once formed, these imines can then be converted to S-2imine, e.g. (7).4a*b alkylcyclohexanones ( n = 1, 87- 100% e.e.) and 2,6-dimethylcyclohexanone ( n = 1, 85% e.e.) by sequential lithiation, alkylation, and hydroly~is.~" Furthermore, for larger-ring analogues of (7; n = 5 , 7 or 10) it has been shown that kinetic metallation followed by alkylation and hydrolysis gives 2-alkylcycloalkanones of absolute configuration opposite to that formed under thermodynamic condition^.^^ Thus, S- (-)- 2- methylcyclododecanone is formed in 60% e.e. with kinetic control, and R- (+)- 2-methylcyclododecanone in 80% e.e. with thermodynamic control. The ability of oxazolines to co-ordinate with a lithium cation, and therefore direct lithiation-alkylation, has been widely exploited, especially by Meyers. His group has further illustrated this feature by the highly diastereoselective addition of organometallics, RM (M = Li or MgBr), to the 3-oxazolinylpyridine (8) yielding dihydropyridines (9).' However, other authors have found that allyllithium reagents add to a,P-unsaturated oxazolines (10) with a stereoselectivity opposite to that expected on the basis of Meyer's arguments, although alkyllithium reagents do behave in the predicted manner.6 The lithium enolate of R,R-tartrate acetonide (11)is another easily accessible chiral molecule and has been alkylated by reactive electrophiles (allyl and benzyl halides) with excellent stereospecificity (>80%).'" This approach has been used in the synthesis of piscidic acid (12). Similarly, the dioxolanones (13) (from pivalaldehyde and S-lactic acid) and (14) (from mandelic acid), and the T. F. Buckley, I11 and H. Rapaport, J. Am. Chem. Soc., 1981,103,6157. ( a ) A. I. Meyers, D. R. Williams, G. W. Erickson, S. White, and M. Druelinger, J. Am. Chem. Soc., 1981,103,3081; ( 6 )A. I. Meyers, D. R. Williams, S. White, and G. W. Erickson, ibid., p. 3088. A. I. Meyers, N. R. Natale, D. G. Wettlaufer, S. Rafii, and J. Clardy, Tetrahedron Lett., 1981, 22, 5123. F. E. Ziegler and P. J. Gilligan, J. Org. Chem., 1981,46, 3874. ' ( a ) R. Naef and D. Seebach, Angew. Chem., Int. Ed. Engf., 1981, 20, 1030; (6) D. Seebach and R. Naef, Helu. Chim. Actu, 1981,64,2704; ( c ) G. Frater, U. Muller, and W. Gunther, Tetrahedron Lett., 1981, 22,4221.

239

Organometallics in Synthesis

oxazolinone (15) (from S-proline) furnish chiral enolates of the type (16). Once formed, they then react with alkyl halide^,'^.' aldehyde^,'^ and ketones7' to give enantiomerically enriched products. This particular strategy has provided a convenient route to S-(+)-atrolactic acid ( 17).7'

C0,H (12)

w: X

Bu' H

(13) R

=

Me

R

=

Ph

(14)

LiO

MR2

"y"

Bu' H

OH Ar+Me C0,H (17)

(15)

The rare sugar D-ribulose has been prepared from the chiral aldehyde (18) as shown in Scheme 2.' An important feature of this synthesis is the first step in which 2-lithiofuran can be added with very high specificity (>95%) to (19) in the presence of zinc iodide, whereas in its absence little specificity is observed. It is therefore presumed that addition actually takes place to a zinc chelate of (18). Chiral sulphoxides have again been used, via their lithium salts, to induce chirality into a molecule. For instance, the chiral formyl anion equivalent (19) reacts with benzaldehyde and phenylacetaldehyde,'" and at the @-position of cyclopentenonesgbto give adducts with a high level of diastereoselective control.

* K. Suzuki, Y. Yuki, andT. Mukaiyama, Chem. Lett., 1981,1529. ' ( a ) L. Colombo, C. Gennari, C. Scolastico, G. Guanti, and E. Narisano, J. Chem. SOC.,Perkin Trans. 1 , 1981, 1278; ( b ) C. Colombo, C. Gennari, G. Resnati, and C. Scolastico, J. Chem. SOC., Perkin Trans. 1 , 1981, 1284; (c) D. R. Williams, J. G. Phillips, and J. C. Huffman, J. Org. Chem., 1981,46,4101.

General and Synthetic Methods

240 H

xo+,9

X0TCH0

.. ... + 11-111

pH

0

0

Reagents: i,

Li-ZnI,; ii, Br,; iii, 0,-NaBH,; iv, H,O+

Scheme 2

Similarly, the lithiosulphoxide (20) adds to achiral aldehydes to give the alcohols (21).9' In this latter example both the configuration at the @-positionand the chirality of the sulphoxide play an important role in determining the diastereoselectivity of addition, a fact which has been substantiated by a study of the other possible configurational isomers of (20). Another route to chiral alcohols from achiral aldehydes involves the addition of organolithium reagents in the presence of a chiral catalyst. In this reaction best enantiomeric excesses (up to 92%)were observed with the diamine (22) as catalyst, and with reactants

(22)

Several interesting papers have appeared which describe further studies into the selective preparation of erythro- and threo-hydroxycarbonyl compounds. High ratios of threo-a,P-djhydroxyestersare obtained from lithiated aalkoxypropionic esters [CH3C(OR)C02R'-Li'] and aldehydes when R' is sterically bulky and R = CH2Ph. In contrast, erythro-products are obtained when R' = Me and R is a methyl or a methoxyethoxymethoxy group.''n Similarly, threo-P-hydroxy esters are obtained in high yield from propionates (CH3CH2C02R') and aldehydes provided that the R' group is once again sterically bulky."b However, erythro-ketones (23) are formed in preference to the threo-isomer when benzaldehyde and the lithio-ketone lo

l1

J.-P.Mazaleyrat and D. J. Cram, J. Am. Chem. SOC.,1981,103,4585. ( a ) C. H. Heathcock, J. P. Hagen, E. T. Jarvi, M. C. Pirrung, and S. D. Young, J. Am. Chem. Soc., 1981, 103, 4972; ( b ) C. H. Heathcock, M. C. Pirrung, S. H. Montgomery, and J. Lampe, Tetrahedron, 1981,37,4087; ( c ) C. T. White and C. H. Heathcock, J. Org. Chem., 1981,46, 191; ( d ) F. Saurioi-Lord and T. B. Grindley, J. Org. Chem., 1981,46,2831.

24 1

Organornetallies in Synthesis

[CH3CHC(0)CMe20TMS.Li+]"' are reacted together, and the erythro-amide (24) is produced preferentially on reaction of epoxides (R-CH-CHI)

with

'0'

a-lithio carboxamides.'ld In this latter case, highest erythro :threo ratios are observed when R2 and R3 are sterically bulky groups.

(23)

(24)

A useful new procedure for assembling the cholestane 20-oxopregnanes has recently been reported.12 The route regiospecific and sequential lithiation-alkylation of the organolithium reagent (25) (Scheme 3). In the same vein, the

side-chain from relies upon the dipole-stabilized dipole-stabilized HO Me,Si

iMe,

5I

+ L i (25) e-SPh

SPh

;p 1

7

1

Reagents: i, Bu'Li; ii, Pr'I

Scheme 3

carbanions (26),13 (27),14 and (28)15 are all formed regiospecifically. Subsequent addition of (26) to ketones (R'R2CO) gives amino-alcohols [R'R*C(OH)CH(R)NHCH,R], and (27) reacts with various electrophiles (E') to give the corresponding allylamines [ECH2(Me2NCH2)CH=CH2]in good yield. Likewise, (28) reacts with electrophiles to give 2-substituted cyclic amines after hydrolysis of the trityl ketone group. Lithiation and alkylation of the oxazine (29) may also be controlled to give regiospecific attack either at the L i t 0

.AN K,,

R

I

CH,R (26) l2 l3 l4

''

w

Ph3CC- N L(CH2)"

(27)

(28)

Li +- NMe,

O+Li

1117

O J (

K. S. Kyler and D. S. Watt, J. Org. Chern., 1981, 46, 5182. D. B. Reitz, P. Beak, and A. Tse, J. Org. Chem., 1981,46,4316. J. J. Fitt and H. W. Gschwend, J. Org. Chern., 1981,46, 3349. W. Wykypiel, J.-J. Lohmann, and D. Seebach, Helu. Chirn. Acru, 1981, 64, 1337.

Me (29)

242

General and Synthetic Methods

methyl group (hindered base) or at the allylic methylene position (LiNMe2).16 Either product may then be elaborated further to provide differently substituted a-methylene ketones. Scheme 4 illustrates how regiospecific lithiation and alkylation of the alkoxy cyclopentenone (30) eventually leads to methylenomycin.17

0

4)

Me

0

-

. SPh Me

iii-vii

Me

CO,H

0

(30) Reagents: i, LiN(TMS),; ii, ICH,SPh; iii, LDA-CH,O; iv, MeLi; v, HCl; vi, [O]; vii, NaHCO, Scheme 4

The methoxymethoxy group (CH30CH20-) has again been used to direct lithiation, in this instance at the ortho position of a phenyl ring.18 The ortholithiated derivative then reacts with various electrophiles, e.g. DMF, COz, AczO, PhNCO, RX, to give the corresponding o-functionalized arylether. The hexafluoroamylalcohol group (CF,),C(OH)- also directs lithiation at the ortho position, a feature that has been used in the preparation of hypervalent sulphur, phosphorus, and silicon c o m p ~ u n d s . Similarly, '~ the lithium salt of phenylacetylene (PhCGCLi) is lithiated further, specifically at the ortho position, and reacts with halogens, trimethylsilyl chloride, and dimethyl disulphide to give the corresponding o-substituted phenylacetylenes.20".6Finally, the conjugate addition of lithium acetylides to propenyltritylketone is reported to be regiospecific for purely steric reasons.'* Alkenyl Anions and Synthetic Equivalents.-The a-lithio unsaturated compounds (31) have proven utility for the introduction of an alkenyl group, and several.papers this year have exemplified the use of such anions. Thus, the 2-lithioacrolein equivalent [31, X = CH(OEt),, R, R' = HI has been prepared and reacts with ketones and aldehydes to give 2-hydroxyalkylacroleins after deprotection.'* In this way (k)-Z-chloronuciferal and (*)-I5 nuciferol have been prepared in satisfactory yield. Similarly, the organolithium (31, X = CO,Et, R, R' = Ph) reacts with electrophiles, such as CO,, RCHO, and RI, to give the corresponding 2-substituted a~rylates.'~"The same authors have also studied competitive metallation in the related systems (32) and (33) and have noted l6

l9

2o

21

22

23

R. Lidor and S. Shatzmiller, J. Am. Chem. SOC.,1981, 103, 5916. M. Koreeda and Y. P. Liang Chen, Tetrahedron Lett., 1981,22,15. C. A. Townsend and L. M. Bloom, Tetrahedron Lett., 1981, 22,3923. E. F. Perozzi, R. S. Michalak, G. D. Figuly, W. H. Stevenson, 111, D . B. Dess, M. R. Ross, and J. C. Martin, J. Org. Chem., 1981, 46, 1049. ( a ) H. Hommes, H. D. Verkruijsse, and L. Brandsma, J. Chem. SOC., Chem. Commun., 1981, 366; (6)H. Hommes, H. D. Verkruijsse, and L. Brandsma, Tetrahedron Lett., 1981, 22, 2495. R. Locher and D . Seebach, Angew. Chem., Znt. Ed. Engl., 1981,20,569. J. C. Depezay and Y. Le Merrer, Bull. SOC.Chim. Fr., 1981, 306. ( a ) B. A. Feit, U. Melamed, R. R. Schmidt, and H. Speer, J. Chem. Soc.. Perkin Trans. 1, 1981, 1329; (6) R. R.Schmidt and H. Speer, Tetrahedron Lett, 1981,22,4259.

Organometa llics in Synthesis

‘‘I:,0

,fcN

C0,Me

Me, N

R

I C0,Me

(32)

(31)

,f

Rx.Mz:e (34)

243

X (36) X

(33)

=

MeorEt

that specific-a-metallation occurs under thermodynamically controlled conditions, whereas p-metallation occurs under kinetically controlled conditions.z3b Alternatively, methyl 3-N,N-dimethylaminopropionateavoids the direct use of species such as (31, X = C0,Me) since it can be sequentially lithiated and alkylated (RX) to give amino esters (34), which are then quaternized and pyrolysed to give 2-substituted a ~ r y l a t e s A . ~similar ~ ~ strategy has been used to Apart from convert the aminopropionate into a-methylene-y-butyrola~tones.~~~ the previously mentioned methods the acrylate unit can also be introduced via the hydrazones ( 3 9 , as shown in Scheme 5, in which the acrylate derivative is generated after a Shapiro reaction, followed by addition of a ketone.25a.”The Shapiro reaction is also used in the preparation of 3-methylenetetrahy-

Reagents: i, BuLi; ii, RRR4C0

Scheme 5

New acyl anion equivalents have proved to be popular targets for research and this year is no exception. For example anion (37) reacts with aldehydes (R’CHO) to give acrylates (38),26and amidrazones (39) provide access to the acyl anion equivalents (40).27The latter undergo electrophilic attack to yield ketones [RCH,C(O)E] after unmasking, Similarly, 1,4-diketones are obtained from the addition products of acyl anion equivalent (41) and a,@-unsaturated ketones.28 Cyclic a,P-unsaturated ketones (42) are in turn formed by addition of the @-acylanion equivalent (43) to e l e c t r ~ p h i l e sThe . ~ ~ 5-oxocyclopentenyl equivalent (44, X = Li) is generated’in three steps from the cyclopentenone

RH

0 OR It I X,P-C-CO,Me (37) 24

25

26

27 2A 29

(38)

A

YNNHS0,Ar (39)

(40)

( a ) L.-C. Yu and P. Helquist, J. Org. Chem., 1981,46,4536;(6) L.-C. Yu and P. Helquist, Synth. Commun., 1981,11,591. ( a ) R. M. Adlington and A . G. M. Barrett, J. Chem. SOC.,Chem. Commun., 1981, 65; (6) R. M. Adlington and A. G. M. Barrett, Tetrahedron, 1981, 37, 3935; (c) R. M. Adlington and A. G. M. Barrett, 1. Chem. SOC.,Perkin Trans. 1, 1981, 2848. E. Nakamura, Tetrahedron Lett., 1981, 22, 663. J. E. Baldwin and J. C. Bottaro, J. Chem. SOC.,Chem. Commun., 1981, 1121. N. Seuron, L. Wartski, and J. Seyden-Penne, Tetrahedron Lett., 1981, 22, 2175. C. Shih and J. S. Swenton, Tetrahedron Lett., 1981, 22, 4217.

General and Synthetic Methods

244

(45) and reacts with electrophiles (RX) to give (44, X = R). Selective cleavage of the silyl protecting group and oxidation of the allylic alcohol then yields cyclopentenones (46) in which an overall 1,3-carbonyl transposition (from 45) has occurred.30The new acetaldehyde equivalent (47, X = Li) is also generated by lithium halogen exchange (from 47, X = Br) and is stable for 20 hours at -70" C.31 Further reaction with ketones and aldehydes leads to p-hydroxyaldehydes after cleavage of the trimethylsilyl group. OSiMe 3 B ~ '

OSiMe,Bu'

Q-"

QCl

&R

j0'"S

X 0

THPO

(44)

(45)

THPO (46)

(47)

Aldehydes (RCHO) react with 1-diazo- 1-lithioacetone to give a-diazo-@hydroxyketones (48). These latter compounds can then be converted to pdiketones by the addition of rhodium(I1) acetate; a procedure which has been applied in the synthesis of p-darnas~one.~' 1,6,6A4-Trithiapentalene and a metal salt catalyse the lithiation of unactivated alkenes to alkenyl-lithiums by lithium constituting a very useful method for preparing such compounds since in the past the preparation of alkenyl-lithium from lithium metal has been confined to alkenes containing relatively acidic protons. Finally, the allenyllithium reagent (49) can be converted to various functionalized allenes by simple electrophile~.~~ Miscellaneous.-Several useful lithium-based synthetic procedures have been reported this year which involve the preparation or further functionalization of carbonyl compounds. For example aldehydes can be prepared by reaction of an organolithium, RLi, with the formylpiperidine (50).35 Unsymmetrically 30 31

32 33 34

35

M. Gill, H. P. Bainton, and R. W. Rickards, Tetrahedron Lett., 1981, 22, 1437. L. Duhamel and F. Tombret, J. Org. Chem., 1981,46, 3741. R. Pellicciari, R. Fringuelli, E. Sisani, and M. Curini, J. Chem. SOC.,Perkin Trans. 1, 1981, 2566. B. Bogodnovic and B. Wermeckes, Angew. Chzm., Int. Ed. Engl., 1981,20,684. J.-C. Clinet and G. Linstrumelle, Synthesis, 1981, 875. G. A. Olah and M. Arvanaghi, Angew. Chem., Znt. Ed. Engl., 1981, 20, 878.

245

Organometallics in Synthesis

0 Scheme 6

Reagents: i, N H 2 0 H ; ii, Bu"Li; iii. E'; iv, Bu'Li; v, E"; vi, [HI

Scheme 7

substituted ketones36and @-diketone$' are also accessible as shown in Schemes 6 and 7. Moreover, a-ketoe~ters~!" and a-imino-orthoesters3xa7'are readily available from triethoxyacetonitrile and organolithium reagents. Another synthesis of an a ketoester is shown in Scheme 8 and is claimed to be the first 'one-pot' preparation of such a compound from a carboxylic acid.39 Similarly, 3-cyclohexen-1-ones (51) are prepared in a 'one-pot' procedure by the addition of the organolithium [R'R2C(Li)CN] to 2-substituted b~ta-1,4-dienes.~'

H

A new carboxylic ester synthesis involves the addition of lithium dialkylcuprates to S-2-pyridylthioates in the presence of oxygen, whereas in its absence very good yields of ketones are Additionally, ketones (52) react with 2-lithioesters (53)to give a&unsaturated esters (54), which can be elaborated to A2-butenolides by acidification and r e d u ~ t i o n . ~ ~ Interestingly, cyclic products ( 5 5 ) are obtained when cyclohexanones (56) are treated with lithiated propargyl alcohols, L ~ C E C C H ( R ) O L ~The . ~ ~regio- and stereo-specificity observed in this cyclopentannulation reaction has been 36 37

38

39 40 41

42 43

P. Knochel and D. Seebach, Tetrahedron Lett., 1981,22,3223. D.J. Brunelle, Tetrahedron Lett., 1981,22,3699. ( a ) G.P. Axiotis, Tetrahedron Left., 1981,22, 1509;( b ) W.Kantlehner and J. J. Kapassakalidis, Synthesis, 1981,480. D. G. Hangauer, jun., Tetrahedron Lett., 1981,22,2439. K. Takabe, S. Ohkawa, and J. Katagiri, Chem. Lett., 1981,489. S . Kim, J. I. Lee, and B. Y. Chung, J. Chem. SOC.,Chem. Commun., 1981,1231. M.Larcheveque, Ch. Legueut, A. Debal, and J. Y. Lallemand, Tetrahedron. Lett., 1981,22,1595. T.Hiyama, M. Shinoda, H. Saimoto, and H. Nozaki, Bull. Chem. SOC.Jpn., 1981,54,2747.

246

General and Synthetic Methods

R2

(53) X

(51)

=

SiMe30rP(OEt)2

(54)

explained by assuming conrotatory ring closure of the thermodynamically most favoured hydroxypentadienyl anion. Similarly, the annulation of six-membered rings onto benzene rings has been achieved via the lithium salt of phthalides (57).44a9bIf Michael acceptors ( 5 8 ) are used then 4-hydroxytetralones or 1naphthols result, whereas if benzynes are used then anthraquinones are obtained. Lithium reagents are also involved in the synthesis of substituted benzenes. Thus, unsymmetrical biaryls (59) are obtained in the reaction between the masked P-ketoaldehyde (60) and the lithium reagent, LiCH2HC=CHSiMe3.45

Q o

R'

R (55)

0' R

(56)

Me

R

\

G(57)

Li Z

( 5 8 ) R' = H, R ' Me, or C02Me

X = CNorC02Me

Surprisingly, it appears that the preparation of imidazoles via organometallics has not been exploited. To remedy this, Iddon and his c o - w ~ r k e rhave s ~ ~ reported their studies on the preparation and reaction of 5-lithioimidazole (61) and 4-lithioimidazole (62). From these simple intermediates various 4- and 5 substituted imidazoles have been prepared by treatment with electrophiles such as RS-SR, DMF, and CO,. Finally, the in situ protection of aromatic aldehydes using N-lithiomorpholide has been and doubly labelled diethyl malonate, Et02C-13CH213 C02Et, has been prepared using doubly labelled ethyl-lithium acetate, Li13CH213C02Et, and ethyl c h l o r ~ f o r m a t e . ~ ~ 2 Group I1

Magnesium.-As is the case with the lithium cation, magnesium readily chelates with oxygen and nitrogen donors in a molecule. This forms the basis for the 44

45 46

47 48

( a ) D. J. Dodsworth, M.-C. Calcagno, E. U. Ehrmann, B. Devadas, and P. G. Sammes, J. Chem. SOC., Perkin Trans. 1, 1981, 2120; (6) N. P. J. Broom and P. G . Sammes, J. Chem. SOC.,Perkin Trans. 1, 1981,465. M. A. Tius, Tetrahedron Lett., 1981, 22,2335. B. Iddon and B. L. Lim, J. Chem. SOC., Chem. Commun., 1981,1095. D. L. Comins and J. D. Brown, Tetrahedron Lett., 1981, 22,4213. M. E. Mueller and E. Leete, J. Org. Chem., 1981,46,3151.

Organometallics in Synthesis

247

specific introduction of groups into a molecule via chelated organomagnesium reagents. Scheme 9 clearly illustrates such a strategy in the enantioselective synthesis of cycloalkylaldehydes using L-leucine t-butyl ester as a chiral auxi~iary.~’ But

Yc

N’

f‘

b

,H ‘C0,Bu‘

-

1

iii, i

*\

Reagents: i, H,O’; ii, KH-R’X; iii, R’X-HMPA

Scheme 9

In a similar manner, threo-P-hydroxy-a-amino-acids (63) can be prepared in reasonable optical purity (43-70%) and with good specificity (92 : 8 threo :erythro) from the butyl ester of glycine using 3-hydroxy-2-phenylbutan-2one as the chiral auxiliary agent.” The specificity is rationalized by the intermediacy of the magnesium chelate (64), which is metallated (LDA) and reacted with aldehydes (RCHO) to give (63). High optical purity is also attainable by Michael addition of Grignard reagents (R’MgBr) to the chiral acrylamides (65) giving chiral carboxylic acids (66) after hydrolysis.” 1,4-Addition of vinyl magnesium bromide, catalysed by ZnBr2, to S-(+)-(67) followed by the addition of alkyl halides (R’X) also results in high asymmetric induction in the resulting cyclopentanones (6QS2 The further utility of Grignard reagents can be seen in the metal-catalysed regioselective addition of phenylmagnesium bromide to alkyl compounds (69, X = OH, OR, or Cl).” Alkyl derivatives (69a, X = Ph) are formed from (69a,

49 50

”

’’

”

H. Kogen, K. Tomioka, S.-I. Hashimoto, and K. Koga, Tetrahedron, 1981, 37, 3951. T. Nakatsuka, T. Miwa, and T. Mukaiyama, Chem. Lett., 1981, 279. T. Mukaiyama and N. Iwasawa, Chem. Left., 1981, 913. G . H. Posner, M. Hulce, J. P. Mallamo, S. A. Dexler, and J. Clardy, J. Urg. Chem., 1981,46,5244. T. Hayashi, M. Konishi, K.-i. Yokota, and M. Kumada, J. Chem. Soc., Chem. Commun., 1981,313.

General and Synthetic Methods

248

\\ (68)

(69) a; R = Alky1,R' = H b; R = H , R L = Alkyl

ClMg (70)

X = OH, OR, or C1) and (69b, X = OH, OR, or C1) with Pd catalysis whereas Ni catalysis gives the isomer (69b, X = Ph) from (69a, X = OH, OR, or Cl). catalyses the reaction of Bu'MgC1 with The titanium complex, (7 5-C5H5)2TiC12, propargyl alcohols to give Grignard reagents (70), which can then be converted to substituted alkyl Alcohols (71) are also obtained by the stepwise addition of two different vinyl magnesium reagents to a-chlorocycloalkanones;55 the resulting alcohols (71) can then be further converted to medium- and large-ring compounds via an oxy-Cope rearrangement.

c

( )"

R2 R3 - R'

R' R 2-NMe2 (72)

"3

MSR3 N

R2 R'

SR3 (73)

/ \ / \

(74)

(71)

Aminoalkenes (72) are readily prepared from dimethylaminopropyl chloride, magnesium, and the corresponding ketones (R'R2CO) in a 'one-pot' procedure which is reported to result in higher yields than those obtained by a stepwise r n e t h ~ d . 'Another ~ 'one-pot' method involves the reaction between an alkyl halide (R'R'CHX), magnesium, and CS, followed by LDA-R3X to yield ketenthioace tals (73).57 In recent years Grignard reagents have been used for the preparation of carbonyl-containing functional groups. This year has proved to be no exception. For instance, the aza-compound (74) reacts with Grignard reagents, RMgBr, to give aldehydes (RCHO) in good yields,58and the authors point out that (74) is a much cheaper reagent than currently used formylating agents. Grignard reagents, ArMgBr, yield aryl-a-ketoesters when added to the carbonyl compounds ( 7 3 , whereas alkyl-a-ketoesters are prepared in rather poor yield from the same carbonyl derivative (75) and alkyl Grignard reagentss9 On the other hand, excellent yields of both alkyl and aryl alkadienoic acids (76) are obtained

F. Sato, H. Ishikawa, H. Watanabe, T. Miyake, and M. Sato, J. Chem. SOC., Chem. Commun., 1981,718. 55 D. A. Holt, Tetrahedron Lett., 1981, 22,2243. " A. Miodownik, J. Kreisberger, M. Nussim, and D. Avnir, Synth. Commun., 1981, 11, 241. " R. Kaya and N. R. Beller, Synthesis, 1981, 814. s8 J. T. Gupton and D. E. Polk, Synth. Commun., 1981, 11, 571. 59 J. S. Nimitz and H. S. Mosher, J. Org. Chem., 1981,46, 211. 54

Organometa llics in Synthesis

249

by treatment of P-ethynyl-P-propiolactone with alkyl and aryl Grignard reagents. 6o The addition of 2 moles of the Grignard reagent, R'MMgBr, to a-chloro acid chlorides, R'R'C(C1)COCl results in the formation of alkenes R'R'C=CR3, in creditable yields,61and excellent yields of y,bunsaturated ketones are obtained by the addition of vinylmagnesium bromide to imidoyl chlorides."' Finally, unsymmetrical alcohols, R'R'CHOH are prepared in a convenient 'one-pot' procedure by the stepwise addition of R'MgX and R'MgX to 2(N-formyl-Nmet hy1amin0)pyridine.~~ Zinc and Mercury.-Activity in the organozinc area appears to have been at a low level once again. The Reformatsky reagents derived from ethyl bromofluoroacetate and ethyl 2-bromopropionate add with very high selectivity to the carbonyl group in the ketone (77) in a re (equatorial) manner.64 The addition products can then be degraded into useful citric acid derivatives. An improved synthesis of P , y-unsaturated ketones also makes use of organozinc intermediates, R'R'C=CCH,ZnBr, which add to nitriles (RCN) to give (78) in yields of 67-80% ,65 Similarly, good yields of y-butyrolactones are possible by the zinc-promoted reaction between dirnethyl maleates and ketones with isopropyl iodide as catalyst.66

0 (77)

OMe

0 (78)

Three very detailed papers concerning solvomercuration and demercuration have appeared,67a- and Barluenga and co-workers have published several papers dealing with aminomercuration and demercuration of alkenes, the chemistry of which is summarized in Scheme These authors have also shown that propargyl alcohol may be aminomercurated to give either 1,2-diimines or 2-aminopr0pionamidines.~~

3 Group111 Boron.-Some new hydroborating agents have appeared this year which further extend the versatility of these useful reagents. Dilongifolylborane (79) produces 6o 61 62

63 64

65

66

'' 68

69

T. Sato, M. Kawashima, and T. Fijisawa, Tetrahedron Lett., 1981, 22, 2375. J. Barluenga, M. Yus, J. M. Concellon, and P. Bernad, J. Org. Chem., 1981, 46, 2721. K. S. Ng and H. Alper, J. Org. Chem., 1981, 46, 1039. D. L. Cornins and W. Dernell, Tetrahedron Lett., 1981, 22, 1085. S. Brandange, 0. Dahlman, and L. Morch, J. A m . Chem. Soc., 1981,103,4452. G. Rousseau and J. M. Conia, Tetrahedron. Lett., 1981, 22, 649. T. Shono, H. Harnaguchi, I. Nishiguchi, M. Sasaki, T. Miyarnoto, M. Miyamoto, and S. Fujita, Chem. Lett., 1981, 1217. ( a ) H. C . Brown and G. J. Lynch, J. Org. Chem., 1981, 46, 930; ( b ) ibid., p. 531; H. C. Brown, P. J. Geoghegen, jun., and J. T. Kurek, ibid., p. 3810. ( a ) J. Barluenga, C. Jimenez, C. Najera, and M. Yus, Synthesis, 1981, 201; ( 6 ) J. Barluenga, N. Villamana, and M. Yus, ibid., p. 375; ( c ) J. Barluenga, L. Alonso-Cires, and G . Asensio, ibid., p. 376; ( d ) J. Barluenga, C. Jimenez, C. Najera, and M. Yus, J. Chem. Soc., Chem. Commun., 1981, 1178; ( e ) ibid., p. 670. J. Barluenga, F. Aznar, and R. Liz, J. Chem. Soc., Chem. Commun., 1981, 1181.

General and Synthetic Methods

250 0

I1 R3 R4CNH-fR2 (ref. 68e) R3

<

h4e$CH2X NR2R3

(ref. 68a)

, , , Y C O 2 M e . R ' , R 2= H 111 I V II

v-vii

TSNHCHR'CH R* (ref. 68d)

1

R'

=

Ar( R4)NCH,CH ,CO, Me (ref. 68b)

H

Rj
R3

ORS

(ref. 68c)

Reagents: i, R2R3NH-Hg(OAc),; ii, NaBH,-NaOH; iii, Hg(OAc),; iv, ArNHR4; v, Hg0.2HBF4; vi, PhNH,; vii, R'OH; viii, TsNH,; ix, Hg(NO,),; x, R4CONHz

Scheme 10

alcohols having predominantly the ( R)-configuration with enantiomeric excesses in the range 60-78% (after hydroboration-oxidation of prochiral ole fin^).^' The new THF- 1-pyrrolylborane complex is reported to have regioselectivity , ~ ~the hydroboration behaviour of some comparable to that of t h e ~ y l b o r a n eand well known BH3 complexes containing nitrogen and phosphorus ligands such as pyridine and Ph3P has been studied, particularly with regard to the effects of solvent and added MeI.72 Organoboranes can also be prepared by reaction of B-H-9-BBN with di-alkyl and -arylcopper lithium reagents R,CuLi; the resulting B-R-9-BBN compounds are formed in 80-93% yield.73

@?l2BH (79)

(5 c5 0 II

(80)

Cbz 1 (81)

The sulphur and nitrogen heterocycles and (81)75have been prepared by hydroboration-carbonylation of bis-olefinic precursors, and the latter case is reported to be the first example of such a synthesis in the presence of a reducible functional group. Another hydroboration-carbonylation sequence has been used in the preparation of methylene cycloalkanes from cycloalkenes, and is shown in Scheme 11.76 70 71 72

73 74 75

76

P. K. Jadhav and H. C. Brown, J. Org. Chem., 1981,46,2988. M. Anez, G. Uribe, L. Mendoza, and R. Contreras, Synthesis, 1981,214. A. Pelter, R. Rosser, and S. Mills, J. Chem. SOC.,Chem. Commun., 1981, 1014. C. G. Whiteley, J. Chem. SOC.,Chem. Commun., 1981,s. M. E. Garst and J. N. Bonfiglio, Synth. Commun., 1981, 11, 231. M. E. Garst and J. N. Bonfiglio, Tetrahedron Lett., 1981, 22, 2075. H. C. Brown and T. M. Ford, J. Org. Chem., 1981.46. 647.

25 1

Organornetallics in Synthesis U

H Reagents: i, C B H ; ii, CO-H ; iii, LiAIH,; iv, PhCHO

Scheme 11

Several papers have appeared describing the synthesis of alkyl halides from organoboranes. Alkyl chlorides are obtained by the reaction of trialkylboranes with dichloramine-T, and in somewhat lower yield with N,N-dichl~rourethane,~~ whereas alkyl bromides are produced in excellent yield when the boranes derived from terminal alkenes and dicyclohexylborane are treated with either Br2 or BrCL7' Alkyl iodides are obtained from the same boranes by the use of ICIN ~ O A Cor~iodide ~ " ion-~hloramine-T,'~~ and this latter method has been applied to the radioiodination of olefins (with Na1251).79cVinyl iodides result from treatment of vinylboronic acids (from acetylenes and catecholborane) with IC1-NaOAc,XOand primary alkylamines are produced from the reaction of trialkylboranes with NH,OH-NaOCLX' One of the most active areas of organoborane chemistry this year has been the application of boron enolates to enantioselective aldol condensations. Thus the enolate (82), derived from (S)-valinol, reacts with aldehydes R'CHO to give, after cleavage of the oxazolidinone residue with R20H,the alcohols (83) with an erythro : threo selectivity greater than 140: 1, whereas the enolate (84), obtained from (lS,2R)-norephedrine, gives alcohols (85) with a selectivity of at least 500 : 1."' Somewhat lower levels of selectivity are observed with the azaenolates (86) and (87) which give predominantly threo- and erythro-alcohols (88) and (89), re~pectively.'~

Me

R J C O , M e

OH

.$-

C0,Me

OH

(88)

77 78 79

81

'*

83

V. B. Jigajinni, W. E. Paget, and K. Smith, J. Chem. Res., (S), 1981,376. G. W. Kabalka, K. A. R. Sastry, H. C. Hsu, and M. D. Hylarides, J. Org. Chem., 1981, 46, 3113. ( a ) E. E. Gooch and G . W. Kabalka. Synrh. Commun., 1981, 11, 521; ( b ) G. W. Kabalka and E. E. Gooch, J. Org. Chem., 1981, 46, 2582; (c) G. W. Kabalka and E. E. Gooch, J. Chem. Soc., Chem. Commun., 1981, 1011. G. W. Kabalka, E. E. Gooch, and H. C. Hsu, Synrh. Commun., 1981,11,247. G. W. Kabalka, K. A. R. Sastry, G. W. McCollum, and H. Yashioka, J. Org. Chem., 1981,46,4296. D. A. Evans, J. Bartroli andT. L. Shih, J. Am. Chem. Soc., 1981, 103, 2127. A. I. Meyers and Y. Yamamoto, J. A m . Chem. SOC.,1981,103,4278.

General and Synthetic Methods

252

Commercially available ( S ) -and (R)-mandelic acids have been used to prepare the boron enolates (90) and (91), which react with aldehydes RCHO to give [in the case of (90)] products (92) and (93) in which (92) predominates by a factor of at least 75 : l.84In the case of aldehydes with an a-substituent greatest selectivity is observed when R = 9-BBN in (90) and (91), whereas the corresponding dicyclohexyl boron enolate is recommended for aldehydes without an a-substituent.

XRO

-+sio I

H

Using these reagents 6-deoxyerythronolide B (94) possessing 10 asymmetric centres in a 14-membered ring has been assembled with an overall stereoselectivity of 85% using four successive aldol reaction^.^^ The enolates (90) and (91) have also been used in an enantioselective synthesis of P-hydroxyisobutyric acid.86 The enolate CH2=C(SBu')OBBun2, prepared from CH3C(0)SBu' and CF3S020BBun2reacts with imines to give P-amino-acid derivatives in high yield,87 and boron enolates, (95), obtained from the stabilized anion (96) and methyl benzoate, have been applied to the preparation of P-hydroxy ketones via an aldol reaction.88 0

0

9

B

?'

B I

Ph-C=CHCH,R (95)

R-cH,--\-H

Li+

(96)

A high-yield synthesis of the macrocyclic spermidine alkaloids (97) involves the boron-template cyclization of the aminoborane intermediate (98),89 and S. Masamune, W. Choy, F. A . J. Kerdesky, and B. Imperiali, J. Am. Chem. SOC., 1981,103,1566. S. Masamune, M. Hirama, S. Mori, S. A. Ali, and D. S. Garvey, J. Am. Chem. SOC.,1981,103,1568. " W.Choy, P. Ma, and S. Masamune, TetrahedronLett., 1981,22, 3555. 13' M.Otsuka, M. Yoshida, S. Kobayashi, M. Ohno, Y. Umezawa, and H. Morishima, Tetrahedron Lett., 1981,22, 2109. " T. Mukaiyama, M. Murakami, T. Oriyama, and M. Yamaguchi, Chem. Lett., 1981,1193. 89 H. Yamamoto and K. Maruoka, J. Am. Chem. SOC.,1981,103,6133. 84

Organometallics in Synthesis

253 Ph

Ph

aminoboranes (99) are produced by reaction of ethyl p-nitrobenzenesulphonoxycarbamate with trialkylboranes; on hydrolysis they give urethanes RNHC02Et.90 Some further extensions of the chemistry of alkenylboranes include their copper-mediated reaction with bromoacetylenes to give conjugated enynes," a palladium-catalysed carbonylation of vinyl boronic acids to a,@-unsaturated carboxylic estersg2and stereospecific coupling, again catalysed by palladium, of 2-1-alkenylboranes with unsaturated halidesg3 2-Allylboranes give predominantly erythro-alcohols on reaction with aldehydes, whereas threo-alcohols are obtained from the corresponding Eisomers, and some new applications of this reaction giving variously substituted alcohols have been de~cribed.~~"" Four co-ordinate lithium borates have again been used in several synthetic sequences, an example of which is the ketone synthesis shown in Scheme 12.95 Other reactions include the alkylation of borates R13BHC=CHRZLi' with benzo-1,3-dithiolium fluoroborate to give a#-unsaturated aldehyde^,^^" addition of the same borates to a,&unsaturated esters to give 6-keto esters or y,g-unsaturated and a synthesis of secondary alcohols that proceeds uia a lithium borate intermediate.97 i ii

p

3

iii iv

MeO(Br)C=CHOMe k MeOC=CHOMe 4 R-C-CH2R'

II

0 Reagents: i, BuLi; ii, R,B; iii, R'OS0,F; iv, H'

Scheme 12

The reagent system BBr3-NaI-15-crown-5 cleaves primary and secondary aliphatic methyl ethers in good yield,98 and a synthesis of sulphides from aldehydes or ketones and thiols is effected by the pyridine-BH3 complex in trifluoroacetic acid.99 YO

91 y2

93 94

95 96

y7 98

99

I. Akirnoto and A . Suzuki, Synth. Commun., 1981, 11, 475. H. C. Brown and G. A. Molander, J. Org. Chem., 1981,46,645. N. Miyaura and A. Suzuki, G e m . Lett., 1981, 879. N. Miyaura, H. Suginome, and A. Suzuki, Tetrahedron Lett., 1981, 22, 127. ( a ) D. J. S . Tsai and D. S. Matteson, Tetrahedron Lett., 1981, 22, 2751; ( 6 ) R. W. Hoffmann and B. Kernper, Tetrahedron Lett., 1981,22, 5263; ( c ) Y. Yarnamoto, H. Yatagai, and K. Maruyarna, J. A m . Chem. SOC.,1981,103,3229. T. Yogo, J. Koshino, and A. Suzuki, Chem. Lett., 1981, 1059. ( a )A. Pelter, P. Rupani, and P. Stewart, J. Chem. SOC., Chem. Commun., 1981, 164; ( b )A. Pelter and J. M. Rao, Tetrahedron Lett., 1981, 22, 797. D. Uguen, Bull. SOC.Chim. Fr., 1981, 99. H. Niwa, T. Hida, and K. Yarnada, Tetrahedron Lett., 1981, 22,4239. Y. Kikugawa, Chem. Lett., 1981, 1157.

General and Synthetic Methods

254

Amongst the applications of borohydride reducing agents reported this year is the use of chiral alkoxyamine-borane complexes for the asymmetric reduction of aromatic ketones, giving the corresponding alcohols in up to 60% enantiomeric excess.'oo Triaryloxyborohydrides chemoselectively reduce aldehydes in the presence of ketones in excellent yield,"' and a stereoselective synthesis of erythro-a,P-epoxyalcoholsby reduction of the corresponding ketones with zinc borohydride has been reported."' Finally, the reagent system cobalt phthalocyanine-NaBH4 in ethanol at 20 "C reduces nitro, oxime, and nitrile functionalities, and the double bond of conjugated esters.'03 Aluminium and Thallium.-The course of two well-known rearrangement reactions (Beckmann and Claisen) can be modified by means of organoaluminium reagents. Thus, imines (100) result from treatment of oxime sulphonates (101) with R3Al in a rearrangement which is conventional in that the group anti to the sulphonate migrate^."^ In the Claisen rearrangement of (102) to (103) with R3Al it was found that an alkenyl or alkynyl group was introduced preferentially when using mixed aluminium alkyls, whereas with tri-isobutyl and (to a lesser extent) triethyl aluminium the R group in the product (103) was hydrogen. Aldehydes rather than alcohols resulted when the reagents Et,AlSPh or Et2A1C1PPh3 were used.los

Diethylaluminium amides R,NAlEt, add to epoxides to give, after hydrolysis, trans- 1,2-amino-alcohols'06 and Scheme 13 shows the result of addition of dialkylaluminium benzenethiolates to a$-unsaturated epoxides; the major product is that in which the R groups have ~ i s - s t e r e o c h e m i s t r y . ~ ~ ~ R'

R2

R' i, Et,AISPh

PhS X

O

H

+

PhS

Scheme 13

The coupling reactions of organoaluminium reagents have again received attention, and have been extended to cover for example the substituted enol phosphates (104), which react with R3Al [catalysed by Pd(O)] to give, after hydrolysis, ketones (105).'08 Similar methodology has been used to effect 1,2- and 1,3-carbonyl transpositions with concomitant alkylation. The scope of loo lo' lo'

'03 lo4

A. Hirao, S. Itsuno, S. Nakahama, and N. Yamazaki, J. Chem. SOC.,Chem. Commun., 1981,315. S. Yamaguchi, K. Kabuto, and F. Yasuhara, Chem. Lett., 1981,461. T. Nakata, T. Tanaka, and T. Oishi, Tetrahedron Lett., 1981,22,4723. H. Eckert and Y. Kiesel, Angew. Chem., Int. Ed. Engl., 1981,20,473. K. Hattori, Y. Matsumura, T. Miyazaki, K. Maruoka, and H. Yamamoto, J. A m . Chem. SOC.,

1981,103,7368.

K.Takai, I. Mori, K. Oshima, and H. Nozaki, Tetrahedron Lett., 1981,22,3985. L.E.Overman and L. A. Flippin, Tetrahedron Lett., 1981,22, 195. lo'

A. Yasuda, M. Takahashi, and H. Takaya, Tetrahedron Lett., 1981,22, 2413. M. Sato, K. Takai, K. Oshima, and H. Nozaki, Tetrahedron Lett., 1981,22,1609.

Organometa llics in Synthesis

255

the palladium-catalysed coupling of aluminium alkyls .with allylic electrophiles has been studied, and the order of reactivity found to be halogen, OAc > 0 II

OAlMe2 > OP(OR):! > OSiR3;lo9alkenyl aluminiums, prepared for example by the carboalumination of acetylenes,"' participate in this reaction with retention of stereochemistry to give 1,4-dienes."' Aryl phosphates are found to have a reactivity similar to that of aryl chlorides in their reaction with organoaluminium reagents, and have been used to prepare alkyl, alkenyl, and aryl benzenes in a nickel-catalysed reaction."2 0 II

H

R 1CH ,COR (10 5 )

Me.)-

Ph

(104)

Lithium aluminium hydride modified with some chiral 1,2-aminodiols, for example (106), gives enantiomeric excesses of up to 82% in the reduction of aromatic ketone^,"^ and lithium tris[(3-ethyl-3-pentyl)oxy]aluminiumhydride has been introduced as a chemoselective reagent (98-1 00%) for the reduction of aldehydes in the presence of ketones.'14 Finally, the reagents AlC1,-EtSH and AlBr3-EtSH have found further application in the cleavage of esters and lactones. '' The electrophilic substitution of aromatics by allyl-silanes, -germanes, and -stannanes has been achieved by an in situ transformation to the allyl cationic species (107) with thallium(rI1) trifiuoroacetate. This represents a reactivity umpolung of these conventionally nucleophilic reagents, and gives allylsubstituted aromatics in good yield."6 4 GroupIV

Silicon.-C -C Bond Formation. Allylsilanes are versatile intermediates, reacting regiospecifically with a wide range of electrophiles, and several new methods for their preparation have been described this year. For example, reaction of the silylcuprate reagent ( PhSiMeJ2CuLi with tertiary allylic acetates (Scheme 14) gives allyl silanes, which may have substituents both a and p to the silyl group, providing a useful alternative to the Wittig route to these Another approach involves the cross-coupling of enol phosphates with trimethylsilylmethylmagnesium halides catalysed by either nickel or palladium 109

110

Ill

112 113

114 115

116 117

E. Negishi, S. Chatterjee, and H. Matsushita, Tetrahedron Lett., 1981, 22, 3737. C. L. Rand, D. E. Van Horn, M. W. Moore, and E. Negishi, J. Org. Chem., 1981,46,4093. H. Matsushita and E. Negishi, J. A m . Chern. SOC.,1981,103,2882. T. Hayashi, Y. Katsuro, Y. Okamoto, and M. Kumada, Tetrahedron Lett., 1981, 22,4449. J . D. Morrison, E. R. Grandbois, S. I. Howard, and G . R. Weisman, Tetrahedron Lett., 1981, 22, 2619. S. Krishnamurthy, J. Org. Chem., 1981, 46, 4628. ( a ) M. Node, K. Nishide, M. Sai, K. Fuji, and E. Fujita, J. Org. Chem., 1981, 46, 1991; ( 6 ) M. Node, K. Nishide, M. Ochiai, K. Fuji, and E. Fujita, J. Org. Chem., 1981, 46, 5163. M. Ochiai, M. Arimoto, and E. Fujita, Tetrahedron Lett., 1981, 22, 4491. I . Fleming and D. Marchi, jun., Synthesis, 1981, 560.

General and Synthetic Methods

256

SiMe2Ph (PhSiMe,),CuLi,

R'

R'

R2

R4

R3f

R2

Scheme 14

and gives variously substituted allyl silanes in good yields."8 The dienolate acid (108) can be alkyanions derived from 3-trimethylsilylmethylbut-3-enoic lated at either the a (Li anion) or y (Cu anion) positions, and subsequent decarboxylation of the a -substituted products gives 3-alkylated allylsilanes (109).119Alternatively, titanium-catalysed reductive silylation of 2-alkenyloxysilanes (obtained from allylic alcohols) using Me3SiC1-Li gives the thermodynamically more stable isomer of the resulting allylsilanes.120 The first of two syntheses of the prenylation reagent (110) starts from 3methylbut- 1-yn-3-01, which is commercially available and cheap, and proceeds in 47% overall yield.12' Alternatively, insertion of photochemically-generated dimethylsilylene into the allylic carbon-oxygen single bond of allyl methyl ethers has given the same compound.'22 Me,Si&R

Me3Si&C02H a

(108)

(109)

(110)

Among the applications of allyl silanes reported this year their reaction with phenylselenyl chloride and subsequent oxidation of the resulting allyl selenides to allylic has been used in the sequence outlined in Scheme 15. 3-Bromoallyltrimethylsilane therefore behaves as a hydroxypropenyl ~ y n t h 0 n . I ~ ~ Nitroalkenes react with allylsilanes to give, after hydrolysis, y,&unsaturated ketones, and a synthesis of substituted cyclopentenones based on this procedure has been d e ~ c r i b e d . 'Ally1 ~ ~ trimethylsilyl ethers undergo a palladium-promoted coupling with aryl iodides to give p-aryl-a,@-unsaturatedketones,126 and palladium also catalyses the reaction of various aryl bromides with trimethylsilyl acetylene to produce ethynylated aromatics. 127 BrMg

-

OAc

.VR4 R'

Reagents: i,

R3

R4

OH

R'.

; ii,

Ac,O-py; iii, PhSeC1; iv, SnCl,; v, H,O,-py

Scheme 15

I2O

123

124

12' 126

12'

T. Hayashi, T. Fujiwa, Y. Okamoto, Y. Katsuro, and M. Kumada, Synthesis, 1981,1001. H. Nishiyama, K. Itagaki, K. Takahashi, and K. Itoh, Tetrahedron Lett., 1981,22,1691. C. Biran, J. Dunogues, R. Calas, J. Gerval, and T. Tskhovrebachvili, Synthesis, 1981,220. B. Bennetau, J.-P. Pillot, J. Dunogues, and R. Calas, J. Chem. SOC.,Chem. Commun., 1981,1094. D. Tzeng and W. P. Weber, J. Org. Chem., 1981,46,693. H. Nishiyama, K. Itagaki, K. Sakuta, and K. Itoh, Tetrahedron Lett., 1981,22, 5285. H. Nishiyama, S. Narimatsu, and K. Itoh, Tetrahedron Lett., 1981,22, 5289. M.Ochiai, M. Arimoto, and E. Fujita, Tetrahedron Lett., 1981,22,1115. T.Hirao, J. Enda, Y.Ohshiro, and T. Agawa, Chem. Lett., 1981,403. W.B.Austin, N. Bilow, W. J. Kelleghan, and K. S. Y. Lau, J. Org. Chem., 1981,46,2280.

Organometallics in Synthesis

257

Vinylsilanes are another class of organosilicon compounds that have found wide application in organic synthesis, and reaction of the allyltrimethylsilyl anion with various electrophiles constitutes a new route to some functionalized derivatives of these useful intermediates.'** An elegant application of vinylsilane chemistry reported this year is the clean and stereospecific iminium ion-vinylsilane cyclization to dendrobatid toxin 25 1 D shown in Scheme 16,129and a spiroannulation synthesis has been described in which the final stage is Lewis-acid-catalysed cyclization of (111)to (1l2).l3'

Reagents: i. paraformaldehyde; ii, d-1 0-carnphorsuJphonic acid

Scheme 16

(111)

(112)

A new synthesis of unsaturated aldehydes (113) makes use of the vinylsilane (114) in a sequence that includes a well precedented rearrangement of silicon of silyl and sulphoxide groups in from carbon to ~ x y g e n . ' ~Cycloelimination ' compounds such as (115) gives ynones in a reaction that has no conventional analogue in the absence of a silyl group. Similarly in silanes (116, X = SiMe3) elimination of the two groups proceeds more rapidly than in the corresponding sulphoxide (116, X = H). However, when there is a choice between a silyl group and hydrogen in the molecule the hydrogen a to the silyl group is eliminated, although more rapidly than in the absence of a silyl group.13*The P-silylenone (117) behaves as an a3d2synthon (118) and the ynone (119) as a 2a3d2synthon (120). Thus (121) has been prepared from (117) and (122) from (119).'33 Several papers have appeared this year describing the oxidation of trimethylsilyl enol ethers leading to various different products depending on the reagent used. M00~(acac)~-Bu'OOH, for example, results in cleavage of the C-C bond and formation of two carboxylic acids (or a ketone and an acid in the case of a trisubstituted enol ether).'34 A method for the a-hydroxylation of ketones I 2n 129

130

I31 132

133 134

R. J. P. Corriu, C. Guerin, and J. M'Boula, Tetrahdron Lett., 1981, 22, 2985. L. E. Overman and K. L. Bell, J. A m . Chem. Soc., 1981,103, 1851. S. D. Burke, C. W. Murtiashaw, M. S. Dike, S. M. S. Strickland, and J. 0. Saunders, J. Org. Chem., 1981,46,2400. I. Cutting and P. J. Parsons, Tetrahedron Lett., 1981, 22, 2021. I. Fleming and D. A. Perry, Tetrahedron Lett., 1981, 22, 5095. I. Fleming and D. A. Perry, Tetrahedron, 1981, 37, 4027. K. Kaneda, N. Kii, K. Jitsukawa, and S . Teranishi, Tetrahedron Lett., 1981, 22, 2595.

258

General and Synthetic Methods

1

1

consists of formation of the trimethylsilyl enol ether followed by treatment with Os04-N-methylmorpholine-N-oxide.'35Sequential treatment of trimethylsilyl enol ethers with a silver carboxylate-iodine and then fluoride affords high yields of the corresponding a-acyloxycarbonyl and the action of MCPBA on trimethylsilyl keten acetals provides a-hydroxy Carbon-to-carbon bond-forming reactions involving trimethylsilyl enol ethers include the use of 3-chloro-2-(trimethylsiloxy)-l-propene as an electrophilic acetonyl eq~ivalent,',~ and an application of this method is shown in Scheme 17.

n

Reagents: i, Bu"Li;ii,

0

ccy3; iii, hydrolysis

Scheme 17

1,2-bis(Trimethylsiloxy)cycloalkenes react with chloromethyl methyl ether and Z ~ / C U - ( C H ~ ) ~ CtoHgive I intermediates which rearrange to 1,3-cycloalkadiones on treatment with KHS04.'39 1,3-Diketones are also obtained by the action of acetyl tetrafluoroborate on trimethylsilyl enol ethers.140 Sequential treatment of a$-unsaturated ketones with Me3SiSePh, R'CH(OR2),, and H 2 0 2 constitutes a new procedure for a-alkoxylation of such compounds, and proceeds J. P. McCorrnick, W. Tomasik, and M. W. Johnson, Tetrahedron Lett., 1981, 22, 607. G. M. Rubottom, R. C. Mott, and H. D. Juve, jun., J. Org. Chem., 1981,46, 2717. 137 G. M. Rubottom and R. Marrero, Synth. Commun., 1981, 11,505. 13* A. Hosorni, A. Shirahata, Y. Araki, and H. Sakurai, J. Org. Chem., 1981, 46,4631. L39 I. Nishiguchi and T. Hirashima, Chem. Lett., 1981, 551. 14" I. Kopka and M. W. Rathke, J. Org. Chem., 1981,46, 3771.

13'

13'

Organometallics in Synthesis

259

uia a trimethylsilyl enol ether inte~nediate.'~'Acetyl cyanide reacts with trimethylsilyl enol ethers in a titanium-catalysed process, giving selectively protected p-diketones and P-ketoaldehydes, as shown in Scheme 18,142and the ratio of 2 :E olefin produced by the reaction in Scheme 19 can be controlled by choice of the Lewis acid used; TiCI4 gives high 2 : E ratios, whereas AIC13 gives a high E : 2 ratio.'43

Scheme 18

OMe

Lewis Acid+

OTMS

RHSiMe,

HO

RCHo

R

C0,Me

- LC 0 , M c

Scheme 19

Silicon-stabilized anions can be put to various uses, among which is the formation of olefins (Peterson reaction), and the l-phenylthio-l-trimethylsilylalkanes required as precursors can also be used in a synthesis of aldehydes, Some of the chemistry reported this year relating to such compounds is shown in Schemes 20 and 21.144a--c

-

Li

R

L S P h

Rco2Y

phShSiMe,

0

Scheme 20

R

R'

R SPh

=/

& R

CH~R'

R

PhShSiMe,

ix=

=

CH,R1

SiMe,

=/

RCHO

Reagents: i, Li naphthalenide; ii, Me,SiCI; iii, R'R'CO; iv, R'Li; v, PhSCl

Scheme 21 14' 142

143 144

M. Suzuki, T. Kawagishi, and R. Noyori, Tetrahedron Let[., 1981, 22, 1809. G. A. Kraus and M. Shimagaki, Tetrahedron Left., 1981, 22, 1171. I. Matsuda and Y. Izumi, Tetrahedron Letr., 1981, 22, 1805. (a) D. J. Ager, Tetrahedron Lett., 1981, 22, 587; ( h ) ibid., p. 2803; ( c ) ihid., p. 2923.

260

General and Synthetic Methods

The anion from a-trimethylsilylacetate reacts with aldehydes to give a,& unsaturated esters, and it has been found that by employing magnesium as the counter-ion pure E-isomers are Another application of siliconstabilized anions involves the addition of lithiated trimethylsilyl methane [produced in situ from tributyl(trimethylsilylmethy1)tin and Bu"Li] to acid halides to give silylmethyl ketones,146and the cyclization by Bu4N'F- of (123) to (124) avoids the problems arising from the corresponding base-induced reaction in the absence of silicon.'47 Tertiary alcohols with a y-silyl group generally undergo a simple carbonium ion rearrangement in acid giving a single alkene product with loss of the silyl group; the reaction is cleaner than the corresponding pinacol rearrangement and several of the products have a quaternary carbon, as shown in Scheme 22.14* a-Silyl aldehydes such as (125) behave as stereoselective vinyl cation equivalents in their reaction with carbon nucleophiles to give, for example, the P,y-unsaturated ketones (126).14'

Scheme 22

Siloxylated butadienes have been popular for some time as the diene component in Diels-Alder reactions and numerous applications have been reported this year. Examples of their use in the synthesis of highly functionalized aromatics are given in Scheme 23, which shows the immediate result of cyclization in each case. Included with the products obtained in this way are d e r r n ~ g l a u c i n , ' ~ ~ ~ * ~ p3 and ~ - D o p a . They l ~ ~ have also d a ~ n o m y c i n o n e s ,a~ milbemycin ~~~*~ played a key part in the synthesis of the saturated carbocyclic systems fomannosin (127),"' coriolin (128),lS6and seychellene (129).lS7trans-1-Benzenesulphonyl2-(trimethylsily1)ethylene (130)is a useful dienophile in the Diels-Alder reaction 145 146

lo7

149

15"

152

153 154

156

15'

M. Larcheveque and A. Debal, J. Chem. Soc., Chem. Commun., 1981,877. D . E. Seitz and A. Zapata, Synthesis, 1981, 557. D . B. Grotjahn and N. H. Andersen, J. Chem. Soc., Chem. Commun., 1981,306. I. Fleming and S. K. Patel, Tetrahedron Lett., 1981, 22, 2321. P. F. Hudrlik and A . K. Kulkarni, J. A m . Chem. SOC.,1981, 103, 6251. ( a )G. Roberge and P. Brassard, J. Org. Chem., 1981, 46,4161; (6) G. Roberge and P. Brassard, Synthesis, 1981, 381. ( a )D. A. Jackson and R. J. Stoodley, J. Chem. SOC.,Chem. Commun., 1981,478; (6) K. Krohn, Liebigs Ann. Chem., 1981, 2285. S. V. Attwood, A. G. M. Barrett, and J.-C. Florent, J. Chem. SOC.,Chem. Commun., 1981, 556. S. Danishefsky and T. A. Craig, Tetrahedron, 1981,37,4081. J. A. Kloek,J. Org. Chem., 1981, 46, 1951. M. F. Semmelhack and S. Tomoda, J. A m . Chem. SOC.,1981,103,2427. S. Danishefsky, R. Zamboni, M. Kahn, and S. J. Etheredge J. A m . Chem. SOC., 1981, 103, 3460. M. E. Jung, C. A. McCombs, Y. Takeda, and Y.-G. Pan, J. A m . Chem. Soc., 1981,103,6677.

26 1

Organametallics in Synthesis OH

OH

0

OSiMe,

OH

Me

0

0

0

R'

Me,SiO

R3 = H

=

R'

-

OMe

H

RZ = Me

1 S0,Ph

C0,CH ,Ph

Me,SiO

0

SiMe,

CO,CH,Ph M e , S i O u S p h

'

II

0

'"Q

Scheme 23

HO

\

(127)

in that the a-sulphonyl carbanion can be alkylated before elimination, thus providing a synthetic equivalent to substituted Scheme 24 depicts a synthesis of functionalized trisubstituted olefins from [(trimethylsilyl)acetyl] trimethyl~ilane;'~~" this intermediate and other related acylsilanes can be prepared from silylacetylenes via a hydroboration-oxidation sequence.lS9' A stereoselectivesynthesis of 8-nitro- (and subsequently@-amino-) alcohols reported this year proceeds as shown in Scheme 25, although the same 0-silylated nitroalcohol intermediates can be obtained by the addition of aldehydes R'CHO to silyl nitronates R2CH=N02SiR3.16' These latter com'58

lS9

M'

L. A. Paquette and R. V. Williams, Tetrahedron Lett., 1981, 22,4643. (a) J. A. Miller and G. Zweifel, J. Am. Chem. SOC.,1981, 103, 6217; ( 6 ) J. A. Miller and G . Zweifel, Synthesis, 1981, 288. D. Seebach, A. K. Back, F. Lehr, T. Weller, and E. Colvin, Angew. Chern., Int. Ed. Engl., 1981, 20. 397.

General and Synthetic Methods

262 0

SiMe,

II

i, iii

Me,SiCH ,CSiMe, 0 Reagents: i, LDA; ii, L

B

r ; iii,

w , o

9

Scheme 24

Reagents: i, base; ii, Bu‘SiMe,CI; iii, H’; iv, H,-Ni; v, F

Scheme 25

pounds can be alkylated in dilute THF solution by organolithium reagents to give ketoximes,161 and their preparation by silylation of nitroalkenes with F3CS020SiMe3has been described. 16* Aminosilanes RNHSiMe, can be alkylated in the presence of sodium methoxide to give secondary amines se1ecti~ely.l~~

Silicon-bused Reagents. Cyclopropyl and ketones (including vinylogous cyclopropyl ketones)16’ are cleaved by trimethylsilyl iodide to give ring-opened iodides, and in the case of cyclopropyl esters the initially formed products recyclize to y-butyrolactones on treatment with base (Scheme 26). The reagent

system Me,SiCl-Zn deoxygenates aliphatic and aromatic sulphoxides, 166 and with the addition of sodium iodide deoxygenates alcohols and ethers (to alkane^)'^' or aromatic N-oxides.168An alternative method for the cleavage of primary and secondary methyl, benzyl, trityl, and tetrahydropyranyl ethers to the corresponding primary and secondary alcohols is to use MeSiC1,-NaI, although tertiary alkylmethyl ethers still give the iodides with this 161

E. W. Colvin, A. D. Robertson, D. Seebach, and A. K. Beck, J. Chem. Soc., Chem. Commun., 1981,952.

16*

163

165

166 16’ 16’ 169

H. Feger and G. Simchen, Synthesis, 1981, 378. W. Ando and H. Tsumaki, Chem. Lett., 1981, 693. S. P. Brown, B. S. Bal, and H. W. Pinnick, Tetrahedron Lett., 1981, 22, 4891. R. D. Miller and D. R. McKean, J. Org. Chem., 1981, 46, 2413. A. H. Schmidt and M. Russ, Chem. Ber., 1981,114,822. T. Morita, Y. Okamoto, and H. Sakurai, Synthesis, 1981, 32. T. Morita, K. Kuroda, Y. Okamoto, and H. Sakurai, Chem. Lett., 1981, 921. G. A. Olah, A. Husain, B. G. B. Gupta, and S. C. Narang, Angew. Chem., Int. Ed. Engl., 1981, 20, 690.

Organometallics in Synthesis

263

Further applications of Me,SiCN reported this year include the SnC14-catalysed cyanation of tertiary alkyl chlorides, avoiding the more usual elimination of HCl in such cases,17oand the exchange of an alkoxy for a cyano group in acetals and or tho ester^.'^' The related system NaCN-Me3SiC1-NaI converts primary, secondary, and tertiary alcohols into the corresponding nitriles in high yield.'72 Trimethylsilyl triflate can be prepared in situ from allyltrimethylsilane and trifluoromethanesulphonic acid; the reagent so obtained has been used for the preparation of trimethylsilyl derivatives of ketones, alcohols, thiols, and carboxylic acids. 173a*b The reagent also activates benzyl and ally1 ethers, which then react with disulphides to give S-benzyl or -ally1 sulphonium species.'74 Several new protecting groups based on silicon have been introduced this year. For instance, the chlorosilane (131) reacts with primary amines to give derivatives (132), which are stable to alkyl-lithiums and amide bases, and yet which regenerate the amine under conditions such as 0.1 N HCl, 75% aq. AcOH, or 1 N KOH.'75 Hydroxyl functions can be protected with the reagent 2(trimethylsily1)ethylchlor~formate.'~~ The resulting derivatives are formed in high yield and can be cleaved with either tetrabutylammonium fluoride or zinc halides. Fluoride ion (from pyridium hydrofluoride) is also used to remove the di-t-butylsilylene group from 1,3-diols that have been protected in this way,177 and HF is recommended as the reagent of choice for the cleavage of silyl ether^.'^' Treatment of the lactone (133)with Me,SiCl-NaI generates the double bond in (134).'79 The reverse reaction can be accomplished with for example PhSeCl (X = SePh), and as the process has a predictable stereochemicaloutcome it constitutes a method for the protection of a double bond and an attached nucleophile.

(131)

(132)

(133)

(134)

Three approaches to the problem of preparing t-butyldimethylsilyl derivatives have appeared this year, two of which make use of silyl enol ether derivatives. Both (135)18' and (136, R = CH3, OCH3)"la give silylated products under mild '71 171

'71 '71

174

175 176

lR"

M. T. Reetz and I. Chatziiosifidis, Angew. Chem., Int. Ed. Engf., 1981,20, 1017. K. Utirnoto, Y. Wakabayashi, Y. Shishiyama, M. Inoue, and H. Nozaki, Tetrahedron Lett., 1981,

22,4279. R. Davis and K. G. Untch, J. Org. Chem., 1981,46,2985. ( a ) T.Morita, Y. Okamoto, and H. Sakurai, Synthesis, 1981,745; ( b ) G. A. Olah, A. Hussain, B. G. B. Gupta, G. F. Salem, and S. C. Narang, J. Org. Chem., 1981,46,5212. E. Vedejs and J. Eustache, J. Org. Chem., 1981,46,3353. S.Djuric, J. Venit, and P. Magnus, Tetrahedron Lett., 1981,22,1787. C.Gioeli, N. Balgobin, S. Josephson, and J. B. Chattopadhyaya, Tetrahedron Lerr., 1981,22, 969. B. M. Trost and C. G. Caldwell, Tetrahedron Lett., 1981,22,4999. R. F. Newton, D . P. Reynolds, C. F. Webb, and S. M. Roberts, J. Chem. SOC.,Perkin Trans. 1, 1981,2055. D. L.J. Clive and V. N. Kale, J. Org. Chem., 1981,46,231. Y. Kita, J. Haruta, T. Fujii, J. Segawa, and Y. Tamura, Synthesis, 1981,451. ( a )T. Veysoglu and L. A. Mitscher, Tetrahedron Len., 1981,22,1299;( b ) ibid., p. 1303.

264

General and Synthetic Methods

conditions, and the latter system is also useful for the introduction of a trimethylsilyl group (using the corresponding trimethylsilyl enol ether) without any A third method makes use of t-butyldimethylsilyl triflate, catalytic prepared from the silyl chloride and trifluoromethanesulphonic acid. This reagent converts tertiary alcohols to their silylated derivatives under mild conditions, and the use of tri-isopropylsilyl triflate as a silylating agent for primary and secondary alcohols has also been described.Ig2 Finally the reagent (137) is particularly useful for the preparation of trimethylsilyl esters of thermally unstable diacids such as (138).'83 OCH, H2c<

I

osi

I (135)

+

c0' di+

n OKNSiMe3

R

(136)

O

0 (137)

C

,C02H H \ CO,H

(138)

Tin and Lead.-A novel application of allyltin chemistry in which 3-substituted butadienes are formed by thermal elimination of Bu3SnOH is shown in Scheme 27.lg4 The intermediate alkenes can be isolated and have Z : E ratios of up to 96 :4. Tributyltin formate is a useful alternative to tributyltin hydride in the preparation of trialkylallylstannanes from allyl sulphones, and has also been used to prepare these compounds from allyl sulphides and mercaptobenztriazole~.'~~ T o l S 0 2 p

- .eFB'3

+ c r ; u 3

R

OH

-%

R<

R

T0lS02 Reagents: i, BuLi; ii, (CH20), ; iii, Bu,SnH; iv, A, 160 "C

Scheme 27

Scheme 28 shows a stereoselective eDoxide synthesis, which proceeds by way of a tin eno1ate.lg6Similarly, the tin enolates derived from triphenyltin chloride and lithium enolates, R'HC=C(OLi)R2 react with alkyl and aryl aldehydes R3CH0 without the necessity for a catalyst to give mainly the erythro-products (139) in good yield."' OSnF,Br p h Brh RBr 1

SnF2b

[ p h k R ' ]

lhVR] SyF2Br

Ph%Rz

Br

R'

Scheme 28

Two syntheses of P-trialkylstannyl acrylates (140) reported this year make use of trialkylstannyl copper reagents. The first uses a,P-acetylenic esters as 18*

lS3

E. J. Corey, H. Cho, C. Rucker, and D. H. Hua, Tetrahedron Lett., 1981, 22, 3455. C. Palomo, Synthesis, 1981, 809. Y. Ueno, H. Sano, S. Aoki, and M. Okawara, Tetrahedron Lett., 1981, 22, 2675. J. Nokami, T. Sudo, H. Nose, and R. Okawara, Tetrahedron Lett, 1981, 23, 2899. S. Shoda and T. Mukaiyama, Chem. Lett., 1981, 723. Y. Yamamoto, H. Yatagai, and K. Muruyama, J. Chem. SOC.,Chem. Commun., 1981, 162.

Organometallics in Synthesis

265

R2

R3

R' (139)

R*,Sn( R2)C=CHC0, R (140)

starting materials and gives either 2-[(Me3SnCuSPh)Li] or E(Me3SnCu-LiBr-Me2S) products, although if the P-substituent of the acetylene is bulky (e.g. t-butyl) then only 2-isomers result.188aIn the second method the isomer produced is largely determined by the stereochemistry of the starting &substituted (halide, tosylate) acrylate.188b Reaction of tetrasubstituted tin derivatives with acid chlorides is a useful method for the synthesis of ketones, and some further variations have been described this year. The stannylethynyl ether (141, R2 = Me, Ph) reacts with acid chlorides and ketenes such as Bu'(CN)C=C=O to give the corresponding a$-acetylenic ketones,lg9 and similarly the stannylethynyl amine (142) gives aminoethynyl ketones.lgo a-Haloalkyl trialkylstannanes are prepared by halogenation of the corresponding alcohol, and when treated with Bu"Li give symmetrical 1,2-dialkylethylene~.~~~ SnR', I

SnR', I

lil

Ill I

(141)

(142)

I OR'

N R ~ R ~

Tributyltin hydride replaces the nitro group of tertiary (and some secondary) and nitroalkanes with hydrogen in a variation of the Kornblum reaction,192a3b in the case of vicinal dinitro-compounds or P-nitrosulphones produces 01efins.'~~ The reagent also deoxygenates primary alcohols (via several thiocarbonyl derivative~).~~~ When treated with an aryl-lead triacetate in DMSO, nitroalkanes undergo a-arylation in good yield, 195 and BF3*Et,O-Pb(OAc), converts acetophenones to methylarylacetates in a version of the Willegerodt-Kindler reaction.lQ6 5 GroupV

Phosphorus.-A large proportion of the publications in this area have, as usual, been concerned with some aspect of the Wittig reaction or related processes. Ally1 formates, for example have been reacted with phosphoranes to give ally1 lS8

lR9 190

19' 192

19' 194

19'

( a ) E. Piers, J. M. Chong, and H. E. Morton, Tetrahedron Lett., 1981,22,4905;( 6 ) D.E. Seitz and S.-H. Lee, Tetrahedron Lett., 1981,22,4909. G. Himbert and L. Henn, TetrahedronLett., 1981,22,2637. G.Himbert, M. Feustel, and M. Jung, Liebigs Ann. Chem., 1981,1907. T. Torisawa, M. Shibasaki, and S. Ikegami, TetrahedronLett., 1981,22,2397. ( a )D.D. Tanner, E. V. Blackburn, and G. E. Diaz, J. Am. Chem. Soc., 1981,103, 1557;( b ) N. Ono, H. Miyaka, R. Tamura, and A. Kaji, Tetrahedron Lett., 1981,22,1705. N. Ono, H. Miyake, R. Tamura, I. Hamamoto, and A. Kaji, Chem. Left., 1981,1139. D.H.R. Barton, W. B. Motherwell, and A. Stange, Synthesis, 1981,743. R.P. Kozyrod and J. T. Pinhey, Tetrahedron Lett., 1981,22,783. B. Myrboh, H. Ila, and H. Junjappa, synthesis, 1981,126.

General and Synthetic Methods

266

vinyl ethers,19' and cyclic phosphoranes such as (143) are useful in that after reaction with a carbonyl compound they retain the diphenylphosphine oxide moiety, which is then available for further elaboration via a Horner ~ e a c t i 0 n . l ~ ~ A new route to 2-ethoxybutadienes (144) involves the reaction of aldehydes R3CH0 with the phosphorane (145); acylation with R4COCl before double bond formation gives (146).'99 R' R Z R4 R' Rz

0

Ph

/ P\

Ph

(143)

R g

I I R3CH=C-C=CH I OEt

PPh3 R 2

(144)

R3CH=(!-c=(k< I OEt

(145)

0

(146)

N-(Acety1)thioamides react regioselectively at the thiocarbonyl function with methyl(triphenylphosphorany1idine) acetate giving, after hydrolysis, &amino acids.'" The reagent (147) has found application in prostaglandin synthesis for the chain extension of aldehydes,"' and the preparation of 1-(triphenylphosphorany1idine)-3-methoxy-2-propanone and its application in the preparation of benz[ 14lannulenes has been describeda202Several isocyanide-containing phosphonates and phosphine oxides of general formula (148) have been reported together with their application in the functionalization of the 17-ketone in ~ ~ r t i ~ ~ ~ t the e r synthesis ~ i d ~ ,of' phosphorus ~ ~ analogues of a - a m i n ~ - a c i d s , ' ~ ~ ~ * ~ and in the preparation of 3-substituted isocyanoacrylates.204' 0

0

(149)

Intramolecular Wittig-type cyclizations have been used successfully in many ring-synthesis applications, and some further examples reported this year include the preparation of chromones by cyclization of the carbonate ( 149)205a*b and an indole synthesis from 0-acyl benzyltriphenylphosphonium salts.'06 The bicyclo[3.3.0]oct-A'.2-en-3-one ring system lacking substituents at C-2 and C-5 is produced by ring closure of the phosphonates (150),207aalthough in the case of the parent member of the series (150, R' = R' = H) a novel dimer is formed '91 198

199

2oo 20 1 '02

203 2 04

'05

206 207

M. Suda, Chem. Leu., 1981, 967. J. M. Muchowski and M. C. Venuti, J. Org. Chem., 1981, 46,459. H.-J. Bestmann and K. Roth, Angew. Chem., Inf. Ed. Engl., 1981, 20, 575. M. Slopianka and A. Gossauer, Liebigs Ann. Chem., 1981,2258. J. Brugidou, J. Poncet, C.-T. B. Huong, and H. Christol, Tetrahedron Left., 1981, 22,4709. T. W. Bell and F. Sondheimer, J. Org. Chem., 1981, 46, 217. D. H. R. Barton, W. B. Motherwell, and S. Z. Zard, J. Chem. Soc., Chem. Commun., 1981, 774. ( a ) J. Rachon and U. Schollkopf, Liebigs Ann. Chem., 1981, 1186; ( b ) ibid., p. 1693; ( c ) ibid., p. 99. ( a ) H. Takeno and M. Hashimoto, J. Chem. SOC.,Chem. Commun., 1981, 282; ( 6 ) H. Takeno, M. Hashimoto, Y. Koma, H. Horiai, and H. Kikuchi, J. Chem. SOC., Chem. Commun., 1981,474. M. Le Corre, A. Hercouet, and H. Le Baron, J. Chem. Soc., Chem. Commun., 1981, 14. ( a ) M. J. Begley, K. Cooper, and G. Pattenden, Tetrahedron, 1981, 37, 4503; ( 6 ) M. J. Begley, K. Cooper, and G. Pattenden, Tetrahedron Lett., 1981, 22, 257.

267

Organometallics in Synthesis

in 52% yield.207bAcylation of Ph,P=CHCN with perfluorinated acid chlorides gives the phosphoranes (15l ) , which lose triphenylphosphine oxide when thermolysed at reduced pressure, forming perfluoro-2-alkynenitriles, again by an intramolecular Wittig reaction, 2"8 The phosphorane (152) behaves as a vinyl anion equivalent in its reaction with electrophiles producing substituted fumarate and Scheme 29 shows an a-aminomethyl ketone synthesis from a-amino-substituted diphenylphosphine oxides.'"

0

Scheme 29

The quaternary ammonium urethanes produced by N-acylation of pyridines'"" and isoquinolines'l'' with chloroformates react with trialkylphosphites to give the phosphonates (153) and (154), respectively. Wittig-Horner reaction with aldehydes and subsequent re-aromatization then gives the corresponding alkylated heterocycles. The first of three new methods of aryl phosphonate formation involves cyclization of the triene (155) followed by oxidation.2122-Hydroxyarylphosphonates are formed by treatment of aryl phosphates with a strong base such as LDA or KNH', and in substituted aromatics the isomer produced correlates with the ease of metallation at the positions ortho to the phosphate group.213The third

'08 209

'lo 211

''' 213

Y. Z. Huang, Y. Shen, W. Ding, and J. Zheng, Tetrahedron Lett., 1981, 22, 5283. M. P. Cooke, jun., Tetrahedron Lett., 1981, 22, 381. N. L. J. M. Broeckhof and A. van der Gen, TefrahedronLett., 1981, 22,2799. ( a ) K. Akiba, H. Matsuoka, and M. Wada, Tetrahedron Lett., 1981, 22, 4093; ( b ) K. Akiba, Y. Negishi, K. Kurumaya, N. Ueyama, and N. Inamoto, Tetrahedron Lett., 1981,22,4977. D. Cooper and S. Trippett, J. Chem. SOC.,Perkin Trans. 1, 1981, 2127. L. S. Melvin, Tetrahedron Lett., 1981, 22, 2375.

268

General and Synthetic Methods

route involves palladium-catalysed coupling of aryl halides with dialkylphosphites, and gives arylphosphonates in good yield.214 Other organophosphorus-based chemistry reported this year includes the reaction of allylic alcohols with aldehydes and triphenylphosphine in the presence of P d ( a ~ a c to ) ~give substituted 1 , 3 - d i e n e ~ , and ~ l ~ the regiospecific substitution reactions of allylic phosphates with soft bases such as I-, PhS-, etc216 Dialkyl acylphosphonates are efficient acylating agents of a l ~ ~ h o (to l ~give ~ ~esters) ~ " and e n 0 1 a t e s ~ ~(to ~ ' give P-diketones and P-ketoesters), and aminoalkylphosphonic acids, known for their pesticidal properties, are synthesized by reaction of the corresponding methoxy derivative (156) with a trialkyl phosphite in the presence of a Lewis acid."' 1,2-Dialkylhydrazines have been prepared by the stepwise alkylation of the diphenylphosphinoyl derivative shown in Scheme 30.2'9 Finally, consecutive reaction of an aryl acid and an aryl amine with PhOP(O)(N,)NHPh results in the formation of N,N'-disubstituted aryl ureas by way of a modified Curtius reaction.220

Reagents: i, R'Br; ii, MeCOCl; iii, R'Br; iv, HCI

Scheme 30

Arsenic and Bismuth.-The syntheses of some new triarylpyridines involving phenacylidinetriphenylarsenanes have been described (Scheme 31)."l The related arsonium ylides Ph,As=CHR have been found to react in a stereospecific manner with aldehydes leading to trans-epoxides, and with substituted cyclohexanones to give (157,R = H, Among the reactions of the new arsoranylidene keten (158) is that with the pyrrole (159) leading to the bicyclic system (160).223

'h3AshR f), x0+aR2

R2

Ph,As+ R'

NH40Ac,

R3

R' 0 0

R'

N

R3

Scheme 31

'14 '15

'I6

*I7

'I9 'O

*"

''' 223

T. Hirao, T. Masunaga, Y. Ohshiro, and T. Agawa, Synthesis, 1981,56. M.Moreno-Manas and A. Trius, Tetrahedron Lett., 1981,22,3109. S.Araki, K. Minami, and Y. Butsugan, Bull. Chem. SOC.Jpn., 1981,54,629. ( a )M.Sekine, A. Kume, and T. Hata, Tetrahedron Lett., 1981,22,3617;(b) M. Sekine, A. Kume, M. Nakajima, andT. Hata, Chem. Lett., 1981,1087. T. Shono, Y.Matsumura, and K. Tsubata, Tetrahedron Lett., 1981,22,3249. M. Kluba and A. Zwierzak, Synthesis, 1981,537. A. Arrieta and C. Palomo, Tetrahedron Lett., 1981,22, 1729. K. C. Gupta, N. Srivastava, and R. K. Nigam, J. Organornet. Chem., 1981,204,55. W.C. Still and V. J. Novack, J. Am. Chem. SOC.,1981,103,1283. H.J. Bestmann and R. K. Bansal, Tetrahedron Lett., 1981,22,3839.

Organometallics in Synthesis

269

Although bismuth reagents have received scant attention this year, it has been reported that a-glycols are smoothly cleaved to carbonyl compounds by a catalytic amount of triphenylbismuth in the presence of potassium carbonate and a little water, using N-bromosuccinimide for the regeneration of Biv.224 Phenols are converted to diary1 ethers with tetraphenylbismuth monofluoroacetate,225and one hydroxy group of a glycol can be selectively phenylated with triphenylbismuth diacetate.226 6 GroupVI

Sulphur.-Continued interest has been shown in sulphoxide-stabilized anions, and Scheme 32 illustrates some of the useful transformations carried out this year, ranging from the synthesis of cyclopropanes (161)to potent dienophiles

(162).227a4 C02Me

(ref.227a) R

(ref.227e)

(162)

y=

SMe

C02Mc

vlll

R

=

Ph

II

R=Me R'

=

H

0

A

0

(161)

'R' To1S

To1S+ 0

\

(ref.227c)

HC It 0 Reagents: i, RC(CH2),CI; I1 ii, ClPPh,; iii, I,; iv, R'Li; v, 0,; vi, viii, NaH-ZnC1,

R'

R4$

'*fR1

; vii,

0 R1,k,,R3

R3

;

R3

Scheme 32 224

225 226 227

D. H. R. Barton, W. B. Motherwell, and A. Stobie, J. Chem. SOC.,Chem. Commun., 1981,1232. D. H.R.Barton, J.-C. Blazejewski, B. Charpiot, and W. B. Motherwell, J. Chem. Soc., Chem. Commun., 1981,503. S . David and A. Thieffry, Tetrahedron Lett., 1981,22, 5063. (a) M. Madesclaire, D. Roche, and D. Chatonier, Synthesis, 1981,828;( b ) E.Vedejs, H. Mastalerz, G. P. Meier, and D. W. Powell, J. Org. Chem., 1981,46,5253;(c) L.Colombo, C. Gennari, G. Resnati, and C. Scolastico, Synthesis, 1981,74;( d )J. Nokami, T. Mandai, Y.Imakura, K. Nishiuchi, M. Kawada, and S . Wakabayashi, Tetrahedron Lett., 1981, 22, 4489; ( e ) Q. B. Cass, A. A. Jaxa-Chamiec, and P. G. Sammes, J. Chem. SOC., Chem. Commun., 1981,1248.

General and Synthetic Methods

270

The sulphoxide (163) undergoes a Pummerer rearrangement when treated with TFA to give (164),which then participates in an ene reaction with 1-alkenes (RCH2CH=CH2)to eventually give, after elimination of the sulphoxide moiety, E,E-alka-2,4-dienoic esters (165).'" These latter compounds are also obtained when the allylthioacetate dianion (166) is treated with alkyl halides (R'X) and LDA, followed by elimination of s~lphur.''~Further syntheses of E,E-alkene2,4-dienoic derivatives, e.g. (167a)230aand ( 167b),2306involve Claisen rearrangement of the sulphoxide (168) and the sulphide (169), respectively. Sulphoxide (168) is prepared in situ from the corresponding alcohol and the sulphoxide, CF,CH,S(O)Ph; it undergoes a very facile rearrangement at ambient temperature. The sulphide (169) is also conveniently prepared, from the ynamine ArSCGCNR, and the corresponding ally1 alcohol. 0 MeSCH,CO,Et II [MeSdHC02Et] R -2 C0,R' /3&HC02R1

,

(163)

(164)

(165)

(166)

0

I1

NR

R 2 v c 0 R 3

R'

a; R ~ = O H

,FSPh

o

0F S P h

-R'

U R2

R2

(167) b; R3=NR2

R

RCH,SO, R '

'

(170)

(169)

(168)

The sodium salt of the sulphone (170, R=SMe, R'=Me) provides easy access to carboxylic esters (RCO'Me) from alkyl bromides (RBr).231In this case the sodium salt is generated in a phase-transfer-catalysed reaction, and the initial adduct [RCH2(SMe)S02Me]is then converted to the methyl ester in excellent yield with SOzClzfollowed by methanol. The sodium salt of the sulphone [170, R = C(0)R2, R' = Toll is generated more conveniently by addition of sodium methoxide, and attacks alkyl bromides to give y,S-unsaturated ketones after cleavage of the sulphonyl group.232This method has been used in the synthesis of the anti-ulcer drug gefornate. In the sulphone (171) base promotes an isomerization to lactones (172) involving incorporation of the side-chain of (171) into the ring,233whereas bromination followed by a Ramberg-Backlund rearrangement of the cyclic sulphones (173) results in ring opening to give y,Sunsaturated acids (174).234

To O -( H 228 229

230

231

232 233 234

S0,Ph (171)

L

0 " + 4

O

(172)

b:

HO,C(CH,),CH=CHR (1 74)

(173)

Y. Tamura, H.-D. Choi, H. Maeda, and M. Ishibashi, Tetrahedron Lett., 1981, 22, 1343. K. Tanaka, M. Terauchi, and A. Kaji, Chem. Lett., 1981,315. ( a ) T. Nakai, K. Tanaka, K. Ogasawara, and N. Ishikawa, Chem. Left., 1981, 1829; ( b )T. Nakai, H. Setoi, and Y. Kageyama, Tetrahedron Lett., 1981,22,4097. K. Ogura, J.-i. Watanabe, and H. Iida, Tetrahedron Lett., 1981, 22, 4499. K. Sato, S. Inoue, and T. Sakamoto, Synthesis, 1981, 796. V. Bhat and R. C. Cookson, J. Chem. SOC.,Chem. Commun., 1981,1123. D. Scholz, Chem. Ber., 1981,114,909.

271

Organometallics in Synthesis

The use of carbon nucleophiles stabilized by ‘SR’ groups has been a feature of sulphur chemistry for many years now, and this year has seen additional uses for these versatile reagents. Thus the carbanion cH(SPh), adds in a 1,2-manner to 2-methylacrolein giving the ally1 alcohol (175), which is then converted to the activated diene (176) by standard methodology.z35The latter has been used in studies towards the total synthesis of the Rubradirin antibiotics. The related anion ArC(SPh)2 also adds to a,p-unsaturated systems; however, in the case of lactone (177) conjugate addition is observed. If the initial ion from (177) is trapped with benzylic bromides then trans-butyrolactones (178) are obtained in good yield.236

Another example of the addition of sulphur-stabilized carbanions to carbonyl groups is shown in the synthesis of a-sulphenylated aldehydes (179) from ketones (RR’CO) and PhScHOMe,z37and of vinyl sulphides or thioacetals from ketones and R’C(SR), or C(SR),, respectively.23xa-Sulphenylated aldehydes are also formed by electrolysis of vinyl sulphides as in the conversion of PhC=CSR’ to PhCH(SR’)CH0.239The carbanion PhSeH, adds specifically to the ketone in (180) to provide methylenecyclohexenes by further elaboration as shown in Scheme 33.240 0

II

0

CH,SPh

CH,SPh I

(180) Reagents: i, LiCHzSPh; ii, H,O’; iii, NaIO,

Scheme 33

A new synthesis of 2-alkylcyclopentenones has appeared which relies upon the introduction of the ‘CHSPh’ fragment into the a-position of a cyclopentanone, followed by oxidation and elimination of PhSOH (Scheme 34).24’ A major advantage of this synthesis is that basic conditions are avoided, and so base-sensitive groups can be present in the cyclopentanone. Sulphur has also been used in the formation of carbon-carbon bonds by direct extrusion of sulphur, as in the preparation of the alkenes (181) from the sulphide 235

A. P. Kozikowski, K. Sugiyama, and E. Huie, Tetrahedron Lett., 1981, 22, 3381.

’” A. Pelter, P. Satyanarayana, and R. S. Ward, Tetrahedron Lett., 1981, 22, 1549.

’” A. de Groot and B. J. M. Jansen, Tetrahedron Lett., 1981, 22, 887. 238 239 240 24 1

J. N. Denis, S. Desauvage, L. Hevesi, and A. Krief, Tetrahedron Left., 1981, 22, 4009. A. Matsumoto, K. Suda, and C. Yijima, J. Chem. Soc., Chem. Commun., 1981, 263. A. de Groot, B. J. M. Jansen, J. T. A. Reuvers, and E. M. Tedjo, Tetrahedron Lett., 1981,22,4137. N. Ono, H. Miyake, and A. Kaji, Synthesis, 1981, 1003.

6

272

OTMS A

p: bR

General and Synthetic Methods

ii, iii

,

c1 I

Reagents: i, PhSCHR; ii, [O], A; iii, H 3 0 + Scheme 34

( ~ 2 ) . ’ ~Similarly, ’ extrusion of methyl mercaptan from the sulphonium salt (183) also gives rise to a carbon-carbon 3ond-forming reaction to yield cyclopropanes (184).243

5‘

A report of the use of azidomethylphenylsulphide, PhSCH2N3, as a synthon for ‘NH2’ has appeared in which metal aryls add to PhSCH2N3 to give the corresponding aniline after hydroly~is.’~~ In contrast, the lithium salt of methyl 2-methylpropionate adds to PhSCH2N3to give the heterocycle (185), which is converted to amino carbonamide (186)on treatment with ammonium hydroxide. Another new sulphur reagent (187) activates carboxylic acids to nucleophilic attack and is used in peptide synthesis as a coupling reagent.245

$N-SPh N=NI

XcoNHCHzSPh NH2

Selenium.-The past decade has seen a vast increase in the use of selenium reagents, to the extent that they now play an important role in many synthetic schemes. For example, a recently reported synthetic study of prostacyclins utilizes the propensity for selenium to induce intramolecular cyclizations onto a double The reagent of choice here is phenylselenyl bond, i.e. (188) + (189).246”*b chloride, which has also been used in the synthesis of (f)-m~ltifidene.~~’ Important elements of this latter synthesis are the stereocontrolled introduction of the phenylselenyl group, from PhSeC1, a to the masked aldehyde functionality in (190). This is followed by a selenium-induced and stereocontrolled addition of ethylmagnesium bromide with subsequent elimination of ‘PhSe’ to give the epoxide (191) from which multifidene is prepared by deoxygenation. 242

243

244

245 246

247

J.-C. Pommelet, C. Nyns, F. Lahousse, R. Merenyi, and H. G . Viehe, Angew. Chem., Inr. Ed. Engl., 1981, 20, 585. T. Uyehara, T. Ohnuma, T. Saito, T. Kato, T. Yoshida, and K. Takahashi, J. Chem. Soc., Chem. Commun., 1981,127. B. M . Trost and W. H. Pearson, J. A m . Chem. SOC.,1981,103,2483. M. Wakselman and F. Acher, J. Chem. SOC.,Chem. Commun., 1981, 632. ( a ) K. C. Nicolaou, W. E. Barnette, and R. L. Magolda, J. A m . Chem. SOC.,1981, 103, 3486; (6) ibid., p. 3480. G. D. Crouse and L. A. Paquette, J. Org. Chem., 1981,46,4272.

273

Organometallics in Synthesis

RO’ OR

RO

OR (189)

(188) X = SACor OH

(=J...e H

H (190)

H

Sequential addition of methyl-lithium and phenylselenyl chloride to the double bond in (192) results in the selenyl derivative (193), which when treated with bromine and hydrogen peroxide yields (+)-Prelog-D jerassi lactonic acid (194).248Similarly, addition of a methyl group to (195), by LiMe,Cu, and oxidative elimination of the phenylselenyl group provides a useful route to dihydrojasmone and cis-jasmone as shown in Scheme 35.249

(195)

(193)

(194)

Me

Me

R= -(CH2)4Meor MeCH2-z-CH2-

Reagents: i, LiMe,Cu; ii, RX; iii, H202

Scheme 35

The synthetic utility of selenium reagents is not only limited to complicated synthetic schemes but is equally applicable to smaller and simpler molecules. This has been illustrated in a series of papers by Krief et al.,250Q--e who have investigated the preparation of unsaturated cyclopropanes from 1-substituted selenopropanes (Scheme 36). 248

249 250

M. Isobe, Y. Ichikawa, and T. Goto, TetrahedronLett., 1981, 22, 4287. D. Liotta, C. S. Barnum, and M. Saindane, J. Org. Chem., 1981,46, 4301. ( a ) S. Halazy, W . Durnont, and A. Krief, Tetrahedron Lett., 1981, 22, 4737; ( 6 ) S. Halazy and A. Krief, ibid., p. 1833; ( c ) ibid., p. 1829; ( d ) ibid., p. 2135; ( e ) ibid. p. 4341.

274

General and Synthetic Methods 0

R'

=

SeMe

.

..

R 1 SeMe

Me,Si

X

SeMe

R3*R4

1

viii

X

Li

R2 R3

R4

R3

R4

SiMe,

I

iv

Me,Si

SiMe,

X

CHO

SiMe,

Ph ; v, R5R6CO;vi, P h 3 k H R 3 R 4 ;vii, NaIO,;

Reagents: i, BuLi; ii, Me,SiCl; iii, DMF, iv, viii, E' Ph

Scheme 36

The addition of selenium to unsaturated carbon-carbon bonds has already been described (refs. 246 and 247), and a further application can be found in the addition of ArS0,SePh to the acetylenic bond of R 1 ~ Rto2give trans-alkenes (196) in 45-93% yield.251The same reagent, TolSO,SePh, also adds to alkenes (with BF,Et,O catalysis) to give the corresponding selenoalkane, which may then be oxidized and thermolysed to provide excellent yields of vinyl sulphones ( 197).252Excellent yields of a-halo-a$-unsaturated ketones are obtained by the addition of the more conventional selenium reagents PhSeCl and PhSeBr to the corresponding a,P-unsaturated ketones followed by oxidative elimination of the selenyl moiety.253 The excellent leaving ability of oxidized selenium (PhSe02) just described, is exploited in the preparation of ethylenic [RC(O)(CH,),C=CR'] and acetylenic [RC(O)(CH2),C~CR']ketones from the cyclohexanes (198) and cyclohexenes (199), re~pectively.~'~

(196) R,R' = H, Ph, alkyl, or C02Me 2s1

(197)

T. G . Back and S. Collins, Tetrahedron Lett., 1981,22,5111.

*" T.G.Back and S. Collins, J. Org. Chem., 1981,46,3249. 2s3 254

S. V. Ley and A. J. Whittle, Tetrahedron Lett., 1981,22,3301. M. Shimizu, R. Ando, and I. Kuwajirna, J. Org. Chem., 1981,46,5246.

275

Organometallics in Synthesis

The usefulness of selenium reagents for the introduction of further unsaturation has long been recognized and has already been exemplified above. However, the following examples further demonstrate the diversity and flexibility of selenium in synthesis. For instance, unsaturated /3-dicarbonyls (200, R = alkyl) are easily prepared by addition of selenium metal to the sodium enolate of the P-dicarbonyl(201); this is followed by methylation and oxidative removal of the selenium.2ss The advantage here is that the intermediate conversion of selenium into an organoselenium reagent is avoided. A very similar method is used in the preparation of vinyl phosphonates from selenium metal and the in the lithium salt of the corresponding saturated p h ~ s p h o n a t e In . ~ contrast, ~~ synthesis of unsaturated ketoaldehydes (200, R = H)2s7and n i t r o a l k e n e ~an~ ~ ~ organoselenium reagent, PhSeX, is used and is added to the P-ketoaldehyde (201, R = H) and nitroalkane, respectively. In common with the other methods, removal of the selenium group provides the carbon-carbon double bond. In the case of the nitroalkenes the whole sequence is in 'one-pot' and does, in fact, give far superior yields to a stepwise approach.

~

3

y

R R

3

v

RZ

R2 (200)

R

pR' OR }-YR1 (202)

(203)

(201)

The oxidative elimination of selenium also accompanies the preparation of ally1 ethers (202) from alkenes (203).259This reaction sequence uses an electrochemical method rather than a chemical oxidizing agent to complete the removal of the phenylselenyl group. The less usual selenium reagent, PhSeNEt,, adds at the a-position of an aldehyde (RCH2CHO) without requiring the presence of base to give a-phenylselenoaldehydes, RCH(SePh)CHO, under very mild conditions.260Presumably, this could form the basis for a preparation of a,P-unsaturated aldehydes. The introduction of a double bond is not limited to the oxidative elimination of selenium; P,y-unsaturated ketones can be prepared by the action of MeSO2C1Et,N on ketoselenides (204), which are in turn prepared by addition of phenyl selenoacetaldehyde to ketones, RC(0)CH2R1.261 New methods for preparing known selenium reagents are always interesting. For example, phenyl selenocyanate is readily prepared by addition of trimethylsilylcyanide to phenylselenyl chloride.262 Two new preparations of sodium phenylselenide have also appeared. In the first, selenide ion is photolysed in the presence of i ~ d o b e n z e n e , ,whereas ~~ the second preparation involves 255

256 257

258 259

260 261

262

263

D. Liotta, M. Saindane, and C. Barnurn, Tetrahedron Leu. 1981, 22, 3043. M. Mikolajczyk, S. Gnejsznak, and K. Korbacz, Tetrahedron Lett., 1981, 22, 3097. D. Liotta, C. Barnurn, R. Puleo, G. Zirna, C. Bayer, and H. S. Kezar, 111, J. Org. Chem., 1981, 46, 2920. T. Sakakibara, I. Takai, E. Ohara, and R. Sudoh, J. Chem. Soc., Chem. Commun., 1981, 261. S. Torii, K. Uneyama, M. Ono, and T.Bannou, J. Am. Chem. SOC.,1981,103,4606. J. Jefson and J. Meinwald, Tetrahedron Lett., 1981, 22, 3561. D. L. J. Clive and C. G. Russell, J. Chem. SOC.,Chem. Commun., 1981,434. S . Tomoda, Y.Takeuchi, and Y. Nomura, Chem. Lett., 1981, 1069. R. A. Rossi and A. B. Penenory, J. Org. Chem., 1981,46,4580.

276

General and Synthetic Methods

reductive cleavage of diphenyldiselenide by sodium h ~ d r i d e This . ~ ~ ~latter method is also used for the preparation of potassium phenylselenide from KH; the phenylselenide anion in the second case is found to be highly nucleophilic. The new selenium reagent (205) is prepared directly from diphenylselenide, Ph2Se, and trifluoroacetic anhydride, and has been used for biomimetic oxidations of amines and amino-a~ids.~~’ OH

0

OCOCF, Ph. ..

R1 (204)

(206)

SePh

I

P A e OCOCF,

(207)

The well known oxidizing reagent benzeneseleninic anhydride has now been used to dehydrogenate steroidal-3-ketones in high yield.266The efficiency and economy of the method is greatly enhanced by generating the anhydride in situ from catalytic amounts of diphenyldiselenide and rn-iodylbenzoic acid. Finally, a further application of N-phenylselenophthalimideis in the transformation of alkyl alcohols into alkylphenylselenides directly thus avoiding the use of the more odoriferous reagent, phenyl~elenocyanate.~~’

Tellurium.-As in previous years activity in the organotellurium field has remained comparatively low, However, some useful transformations have been carried out using tellurium reagents, as in the trans- to cis-isomerization of alkenes facilitated by the presence of tellurium(1v) chloride.268 The new organotellurium reagent (206) has been used as an aldol catalyst and is efficient in the conversion of 2,2’-diacetylbiphenyl to biphenyl (207), a transformation that has resisted previous attempts with conventional catalysts.269In common with sulphur and selenium, tellurium can be oxidatively eliminated to give the corresponding alkene; the oxidizing agent of choice here is chloramine-T.270

264

265

266

267

268 269

270

P. Dowd and P. Kennedy, Synth. Commun., 1981, 11, 935. J. P. Marino and R. D. Larsen, jun., J. Am. Chem. SOC.,1981,103,4642. D. H. R. Barton, J. W. Morzycki, W. B. Motherwell, andS. V. Ley, J. Chem. SOC.,Chem. Commun., 1981,1044. P. A. Grieco, J. Y. Jaw, D . A. Claremon, and K. C. Nicolaou, J. Org. Chem., 1981,46, 1215. J. E. Backvall and L. Engman, Tetrahedron Lett., 1981, 22, 1919. L. Engman and M. P. Cava, Tetrahedron Lett., 1981, 22, 5251. T. Otsubo, F. Ogura, and H. Yamaguchi, Chem. Lett., 1981,447.

7 Saturated Carbocyclic Ring Synthesis BY D. W. KNIGHT

1 Three-membered Rings General Methods.-Modifications of cyclopropanation reactions involving carbenoids continue to be developed. Thus, non-activated terminal olefins can be converted into cyclopropanes using ethereal diazomethane in the presence of Pd(OAc)2,' whereas the photochemical version of the Simmons-Smith reaction is especially suitable for the cyclopropanation of hindered olefins.2 Methylcyclopropanes (2) can be prepared from olefins using iron complexes such as (l).3 These reagents, and perhaps their higher homologues, could be very valuable as, in general, 'free' alkyl- and dialkyl-carbenes are not synthetically useful because of their rapid isornerization to olefins. R2

R

CpFe(CO),CH-S

'

Me FS03-

R'

'Me

(2)

(1)

PhACI (3)

A

Ph

(4)

Ph

R+qR2 R3

R'

(51

Full details have been given for the preparation of chloro(pheny1)carbene (3), from the corresponding diazirine, and for its subsequent trapping by P-methylstyrene, leading to the cyclopropene (4) after dehydro~hlorination.~ An excellent new catalyst for the synthesis of cyclopropanecarboxylates (3,from olefins and diazoesters, is the rhodium cluster compound, Rh6(C0),6.5 In general, good yields of ( 5 ) are only obtained if a large excess of olefin is used, but other work

' M. Suda, Synthesis, 1981, 714. P. J. Kropp, N. J. Pienta, J. A. Sawyer, and R. P. Polniaszek, Tetrahedron, 1981,37, 3229. K. A. M. Kremer, P. Helquist, and R. C. Kerber, J. A m . Chem. SOC., 1981, 103, 1862; M. Brookhart, J. R. Tucker, and G. R. Husk, ibid., p. 979. A. Padwa, M. J. Pulwer, andT. J. Blacklock, Org. Synth., 1981,60,53. M. P. Doyle, W. H. Tamblyn, W. E. Buhro, and R. L. Dorow, Tetrahedron Lett., 1981, 22, 1783.

277

General and Synthetic Methods

278

has shown that this is not necessary if the diazoester is added slowly to the reaction mixture.6 A full account has been given of the preparation of cyclopropylmethanols or cyclobutanols from y-epoxysulphones (Scheme l).’This useful method can also be applied to the synthesis of cyclopentanols from S-epoxysulphones. The same idea has been used by Gaoni in a simple synthesis of bicyclo[l.l.O]butanes (6).8 a,@-Unsaturatedsulphones (7) undergo Michael attack by a-metallated nitriles leading to the cyclopropanes (8);9 as yet the method is limited to cases where R = Ph or SR’.

Scheme 1 Ar02S

-SO,Ph

(8)

Chiral cyclopropanes, such as (9), have been obtained by degradation of (+)-a-pinene using a sequence of reactions that features a stereocontrolled ring contraction of a cyclobutanol derivative.” The iron carbonyl complex (10) has been resolved, and used to prepare the optically active cyclopropanes (1l).”

+C02Me H H’ (-> (9)

,Fe(C0)3 M e 0 , C v C H O

MeO, C k H c H 0

,

--+

Me0,C’ (10)

.

H

(11) R = H or C 0 2 M e

Gassman and co-workers have reported” that electrolysis of the tosylates (12) and (14) results in the very efficient formation of the cyclopropanes (13) and (15), respectively. The method is related to some older work of Stork et al., who used Li-NH3 to effect similar transformations but in lower yield, and can also be used to prepare hydrindanes. Cyclohexenones also serve as starting materials in a new and efficient version of the ‘bicycloannulation’ technique involving a double Michael addition (Scheme 2).13

‘ M. P. Doyle, D. van Leusen, and W. H. Tamblyn, Synthesis, 1981,787.

’ J. M. Decesare, B. Corbel, T. Durst, and J. Blount, Can. J. Chem., 1981,59, 1415.

l3

Y. Gaoni, Tetrahedron Lett., 1981, 22, 4339. T. Agawa, Y. Yoshida, M. Komatsu, and Y. Ohshiro, J. Chem. SOC., Perkin Trans. 1 , 1981, 751. M. Karpf and C. Djerassi, J. A m . Chem. SOC., 1981, 103, 302; see also J. P. Kutney, M. K. Choudhury, J. M. Decesare, H. Jacobs, A. K. Singh, and B. R. Worth, Can. J. Chem., 1981, 59, 3162. A. Monpert, J. Martelli, R. GrCe, and R. CarriC, Tetrahedron Lett., 1981, 22, 1961. P. G. Gassman, 0. M. Rasmy, T. P. Murdock, and K. Saito, J. Org. Chem., 1981,46, 5455. R. M. Corey, P. C. Anderson, F. R. McLaren, and B. R. Yamamoto, J. Chem. SOC.,Chem. Commun., 1981, 73.

279

Saturated Carbocyclic Ring Synthesis

m -,-130 /OTs

0

0

0

OLi

OLi

Scheme 2

The thermal hexa- 1,4-diene S 1-methyl-2-vinylcyclopropane('homo-ene') equilibrium usually lies well to the left, presumably because of ring strain, but by the simple expedient of incorporating a hydroxy substituent in the hexadiene (16), cyclopropyl aldehydes (17) can be obtained in good ~ i e 1 d s . lIn ~ related work, Dauben et al. have shown that medium-sized cyclic trienes can be thermally isomerized to tricyclic compounds e.g. (18).15 H

(16)

(17)

(18)

Enamines (19; It = 3-12) undergo nucleophilic attack by succinimide to give the fused cyclopropanes (20); subsequently, the two heterocyclic substituents can be displaced by various nucleophiles. ''

.N $

SMez

0

FSOq-

Natural Cyc1opropanes.-A useful review of the synthesis of pyrethroid acids has been published which includes a discussion of general methods for cyclopropane ring formation." F.-G. Klarner, W. Rungler, and W. Maifeld, Angew. Chem., Int. Ed. Engl., 1981, 20, 595. W. G. Dauben, D. M. Michno, and E. G. Olsen, J. Org. Chem., 1981, 46, 687; W. G. Dauben and D. M. Michno, Tetrahedron, 1981, 37,3263. 16 E. Vilsmaier, C. M. Klein, W. Troger, and D. Dausmann, Synthesis, 1981, 724; E. Vilsmaier, C. M. Klein, and D. Dausmann, ibid., p. 726; E. Vilsmaier and C. M. Klein, ibid., p. 206; E. Vilsmaier and W. Troger, ibid., p. 207. " D. Ark, M. Jautelat, and R. Lantzsch, Angew. Chem., Inf. Ed. Engl., 1981, 20, 703. l4

''

280

General and Synthetic Methods

In an extension of previous work, it has been found that Pd(0)-catalysed intramolecular cyclization of allylic acetates (21) can be used to prepare the chrysanthemic acid analogues (22).’* The potentially useful cis-cyclopropane (23) can be simply obtained by base-induced addition of cyanoacetate to ethyl 2-bromo-3,3-dimethylacrylatefollowed by decarb~xylation;~’oddly, a similar reaction using malonate fails to give a cyclopropane. Optically pure ‘dichloro’ cis-chrysanthemic acid (26) has been obtained by a Favorskii rearrangement of the chiral cyclobutanone (25) prepared from the keten (24) by sequential [2 + 2]cycloaddition, cine-rearrangement, and resolution (Scheme 3).20

ACU

R2

R2

’

_.

(22)

(21) R1,R2= C02R3,S02Ph, or CN

(23)

It

0

(24) Scheme 3

2 Four-membered Rings

Full details have been reported for the conversion of cyclopropylmethanol into cyclobutanone (27) in 31-35% overall yield” together with an improved route to the useful a-phenylthio derivative (28).22 Variations on the theme of [2 + 2lcycloaddition reactions as a route to cyclobutanes continue to be developed. 1,2-Diynylcyclobutanes (29) can be prepared by triplet-sensitized photochemical dimerization of the corresponding enynes; in general, this method cannot be used for the efficient synthesis of more highly substituted c y c l ~ b u t a n e s .Similar ~~ photochemical methods have also been used to prepare a range of substituted cis-l,2-diaminocyclobutanes (30),24and the tricyclic compounds (31), which can serve as precursors to the tricyclo[4.2.0.0’*4]octanes (32) via the Wolff rea~rangernent.~~

’* J. P. Gen6t and F. Piau, J. Org. Chem., 1981,46,2414. l9 2o

21 22

23

24

2s

J. H. Babler and B. J. Invergo, Tetrahedron Lett., 1981,22, 2743;see also S. Hiinig and M. Oller, Chem. Ber., 1981,114,959. P. Martin, H. Greuter, and D. BelluS, Helu. Chim. Acta., 1981,64, 64;P. Martin, H. Greuter, G. Rihs, T. Winkler, and D. BelluS, ibid., p. 2571;G. Greuter, J. Dingwall, P. Martin, and D. BelluS, ibid., p. 2812. M. Krumpolc and J. Rocek, Org. Synth., 1981,60,20. T. Cohen, D. Ouellette, K. Pushpananda, A. Senaratne, and L.-C. Yu, Tetrahedron Lett., 1981, 22, 3377. L. Eisenhuth, H. Siegel, and H. Hopf, Chem. Ber., 1981, 114, 3772; for a review of such photosensitized reactions, see A. Albini, Synthesis, 1981,249. K.-H. Scholz, J. Hinz, H.-G. Heine, and W. Hartmann, Liebigs Ann. Chem., 1981,248. S. Wolff and W. C. Agosta, J. Org. Chem., 1981,46,4821; J. Chem. SOC.,Chem. Commun., 1981, 118;see also W.Kirmse and P. Sandkuhler, Liebigs Ann. Chem., 1981,1394.

28 1

Saturated Carbocyclic Ring Synthesis R

(32)

(31)

Ethyl buta-2,3-dienoate reacts readily with various olefins in the presence of AlC1, to provide cyclobutylideneacetic esters (33), largely as the E-isomers, in a wide range of yields (14-95'/0).~~ The utility of ketens in such cycloadditions is further exemplified by the regioselective addition of dichloroketen to conjugated silyl enol ethers (34), to give cyclobutanones (3S).27In addition, the novel keten (36),adds to cyclopentadiene leading [via (37)] to the useful prostaglandin precursor (38).28A review

of the chemistry of t-butylcyanoketen has been published that includes a discussion of its use in the preparation of the cyclobutanones (39).29Highly reactive ketiminium salts (40) undergo facile cycloaddition reactions with simple a,@unsaturated carbonyl compounds or alkenes to give cyclobutanones (41) and (42), re~pectively.~"

;;

...._) f u t CN

(39) 26 2'

*' 29

30

R3floRz +[ c 1'- (;n;z +NMe2

..-

--*

R'

0

/

C\

R'

(41)

R'

R2

(42)

(40)

H. M. R. Hoffmann, Z. M. Ismail, and A. Weber, Tetrahedron Lett., 1981,22, 1953. W. T. Brady and R. M. Lloyd, J. Org. Chem., 1981, 46, 1322; for a review of chloroketen chemistry, see W. T.Brady, Tetrahedron, 1981,37,2949. S. Goldstein, P. Vannes, C. Houge, A . M. Frisque-Hesbain, C. Wiaux-Zamar, L. Ghosez, G. Germain, J. P. Declerq, M. Van Meerssche, and J. M. Arrieta, J. A m . Chem. Soc., 1981,103,4616. H.W.Moore and M. D Gheorghiu, Chem. SOC.Reu., 1981,10,289. H.-G. Heine and W. Hartmann, Angew. Chem., Znt. Ed. Engl., 1981,20, 782; J.-B. Falmagne, J. Escudero, S. Taleb-Sahraoui, and L. Ghosez, ibid., p. 879.

General and Synthetic Methods

282

The oxaspiropentane -+ cyclobutanone rearrangement has been used to prepare the previously unknown 2-acylcyclobutanones (43) and their mono-acetal derivatives (acetal of side-chain ketone),31 while a related rearrangement of cyclopropylmethanols (44) provides an entry into 2-vinylcyclobutanones (45).32 Chiral 2-methylcyclobutanones have been obtained from 1,3-dibromopropanes by condensation with an optically active TosMIC d e r i v a t i ~ e . ~ ~

The utility of o-quinodimethanes as very reactive diene components in DielsAlder reactions has stimulated interest in the synthesis of benzocyclobutanes, their most commonly used precursors. A full account has been given of the preparation of benzocyclobutanols (47) from o-halostyrene oxides (46),34 whereas a related Parham-type cyclization can be used to convert bromoethylbenzenes (48) into benzocyclobutanes (49).35Two rather different approaches

R' (46) R2 = H o r M e

involve flash vacuum pyrolysis of acid chlorides (50), leading to (5 1) in moderate yield,36and the conversion of cycloheptatriene (52) into the bromocyclobutane (53) (26% yield) using bromoform and K2C03in the presence of 18-crown-6.37

31 32 33 34

35

36

37

F. Huet, A . Lechevallier, and J.-M. Conia, Chem. Lett., 1981, 1515. T. Cohen and J. R. Matz, Tetrahedron Lett., 1981,22,2455. D. van Leusen, P. H. F. M. Rouwette, and A . M. van Leusen, J. Org. Chem., 1 9 8 1 , 4 6 , 5 1 5 9 . E. Akgiin, M. B. Glinski, K. L. Ohawan, andT. Durst, J. Org. Chem., 1981,46, 2730. C. K. Bradsher and K. J. Edgar, J. Org. Chem., 1981, 4 6 , 4 6 0 0 ; C. K. Bradsher and D. A . Hunt, ibid., p. 4608. B. L. Chenard, C. Slapak, D. K. Anderson, and J. S. Swenton, J. Chem. Soc., Chem. Commun., 1981, 179. M. R. Decamp and L. A. Viscogliosi, J. Org. Chem., 1981,46, 3918.

283

Saturated Carbocyclic Ring Synthesis

3 Five-membered Rings A modification of the Dieckmann reaction using the thiol-ester (54) gives only the cyclopentanone (55).38This could be of considerable value in the cyclization of unsymmetrical adipates given that such precursors can be prepared regioselectively. An alternative way to achieve such a regioselective cyclization is to use a dithioester (56) which gives only (57); the alternative Dieckmann product undergoes cine -rearrangement to (57)under the reaction condition^.^^ Attempts

to convert keto-acetals such as (58) into cyclopentenones (59) by sequential deprotection and aldol cyclization are usually very inefficient, but by using an ion-exchange resin containing both acidic and basic beads, yields of ca. 50% can be a~hieved.~' A new dihydrojasmone (61) synthesis involves sequential treatment of the enone (60) with bromine and aqueous NaOH and could be of some generality in the absence of other olefinic groups in the e n ~ n e . A ~ ' further example of the synthetic utility of bis-Grignard reagents is their reaction with esters leading to cyclopentanols in high yield (Scheme 4).42 This annulation method seems to be useful only for the preparation of five-membered rings.

4 R

O

U( 5 8 )

RC0,Et

+ BrMg(CH,),MgBr Scheme 4

+

gH

A neat procedure for effecting intramolecular cyclizations of mono-thioacetals of dicarbonyl compounds is to use the corresponding 2-silyldithianes (62) and to generate the required anion by fluoride-induced desilylation, leading to (63,

'* 39 40 41

42

Y. Yamada, T. Ishii, M. Kimura, and K. Hosaka, Tetrahedron Lett., 1981,22, 1353. H.-J. Liu and H. K.Lai, Synth. Commun., 1981,11,65. J. C. Stowell and H. F. Hauck, jun., J. Org. Chem., 1981,46, 2428. T. Fujisawa and K. Sakai, Chem. Lett., 1981,5 5 ; see also T.-L. Ho, Synth. Commun., 1981,11, 7; D. J. Goldsmith and J. K. Thottathil, Tetrahedron Left., 1981,22, 2447. P. Canonne, D. BClanger, and G. Lemay, Tetrahedron Lett., 1981,22, 4995;P. Canonne, D. BClanger, G. Lemay, and G. B. Foscoles, J. Org. Chem., 1981,46, 3091.

284

General and Synthetic Methods

n = 2-4 only).43 Similarly, the useful masked cyclopentanone (65) can be obtained from the enone (64) by an intramolecular Michael cyclization.

Ally1 vinyl ethers (66) undergo [ 1,3]rearrangements to give cyclopentanones (67) when heated with Pd' catalysts,44in vivid contrast to the uncatalysed thermal rearrangement of compounds such as (66), which results in the formation of cycloheptenones. The recently developed oxyanionic Cope rearrangement of cyclononatrienols has been used by Paquette and Crouse as the key step in a brief synthesis of (*)-multifidene (68).45Highly substituted alkylcyclopentenes may be prepared by [3 + 2]cycloadditions between ally1 cations and 01efins.~~

Some syntheses of useful chiral cyclopentane derivatives have been reported and the this year. For example, (69) has been obtained from (-)-quinic hexa-acetate (70) from unsaturated sugar derivative^.^^ The diene (7l),of.36% optical purity, results from a thermal hetero-ene reaction of a chiral allene aldehyde.49 Gill and Rickards have reported full details for the resolution of the cyclopentenone (72), derived from phenol."

n

s

A C H O

\

BzO (69)

43

44

4s

46

47

48 49

Ac&

OAc

,CO,Me

(CHOAc),CH,OAc

(71)

D. B. Grotjahn and N. H. Anderson, J. Chem. SOC.,Chem. Commun., 1981,306. B. M. Trost and T. A . Runge, J. A m . Chem. SOC.,1981,103,7550,7559,2485. L. A . Paquette and G . D. Crouse, Tetrahedron, 1981, 37 (Suppl. l), 281; J. Org. Chem., 1981, 46,4272. H. Klein and H. Mayr, Angew. Chem., Znt. Ed. Engl., 1981, 20, 1027. J.-C. Barritre, A. Chiaroni, J. ClCophax, S. D. Giro, C. Riche, and M. Vuilhorgne, Helu. Chim. A m , 1981,64, 1140. D. Horton and T. Machinami, J. Chem. Soc., Chem. Cornmun., 1981.88. M. Bertrand, M. L. Roumestant, and P. Sylvestre-Panthet, Tetrahedron Lett., 1981, 22, 3589. M. Gill and R. W. Richards, Ausr. J. Chem., 1981, 34, 1063, 2587, and refs. therein.

Saturated Carbocyclic Ring Synthesis

285

Ring-cleavage reactions have been used to control stereochemistry in preparations of the racemic cyclopentanes (73)'l and (74).52 0

-sio +I

6

GC,

CO, H

(73)

(72)

(74)

Methylenomycin B (75) has been prepared by a route, which is notable for the simplicity of the classical methods whereas a synthesis of (*)methylenomycin A (76) involves the application of more modern r e a g e n t ~ . ' ~ Total syntheses of the related (*)-xanthocidin (77),55and of the unique isonitrile (78)56have also been achieved.

Fused Five-membered Rings.-An

attractive general method for the elaboration of fused five-membered rings, as well as monocyclic cyclopentane derivatives, involves a [3 + 2lcycloaddition of readily available silylallenes to enones (Scheme 5).57 Yields are usually high, and the method can also be used to prepare spirocyclic systems e.g. (79) -+ (80).

91% '

+

- - - - - - ~ 2

R3>=,<SiMe3

R4

TiCI,,

,

R5

,%

SiMe,

-.RZ*

H

R ~ R ~

Scheme 5

(79) 51

52

53 54

(80)

A. K. Saksena, A. T. McPhail, and K. D . Onan, Tetrahedron Lert., 1981,22,2067; A. K. Saksena and A. K. Ganguly, ibid., p. 5227. P. Camps and C. Jaime, Can. J. Chem., 1981,59,2848. R. F . Newton, D . P. Reynolds, and T. Eyre, Synth. Commun., 1981,11, 527. Y. Takahashi, K. Isobe, H. Hagiwara, H. Kosugi, and H. Uda, J. Chem. Soc., Chem. Commun., 1981,714.

55 56 57

D . Boschelli and A. B. Smith, 111, Tetrahedron Lett., 1981, 22, 3733. T. Fukuyama and Y. M. Yung, Tetrahedron Lett., 1981, 22,3759. R. L. Danheiser, D . J. Carini, and A. Basak, J. Am. Chem. Soc., 1981,103, 1604.

General and Synthetic Methods

286

Smith's group has reported in full on the Lewis-acid promoted annulation of unsaturated diazoketones leading to cyclopentenones in variable, but often good, yields (Scheme 6).58The method can also be applied to polyene cyclizations as in the conversion of diazoketone (81) to (82) in 43% yield (cf. refs. 71, 92, and

Scheme 6

93). The alternative mode of reaction of diazoketones, that of carbene formation, has been used to prepare a hydrindane derivative (Scheme 7).59The second step of this sequence, a vinylcyclopropane -+cyclopentane rearrangement, can be carried out under much milder conditions if the cyclopropane carries an alkoxide substituent.60

Scheme 7

A full report has been published on the annulation of the P-keto-ester (83) by the cyclopropylphosphonium salt (84) leading to (85);61 hydrolysis of the intermediate vinyl sulphide was effected by an iodolactonization procedure, as standard methods failed. An alternative annulation method (Scheme 8) involves the acylation of vinyl cuprates by unsaturated acid chlorides followed by Nazarov cyclization;62 Me,SiI can sometimes serve as a good reagent for this step. Nazarov-type cyclizations using acetylenic acetals have also been employed in

58

59

60

A. B. Smith, 111, B. H. Toder, S. J. Branca, and R. K. Dieter, J. Am. Chem. SOC., 1981, 103, 1996;A. B. Smith, 111, and R. K. Dieter, ibid.,pp. 2009 and 2017; Tetrahedron, 1981,37,2407. T. Hudlicky, F. J. Koszyk, D . M. Dochwat, and G . L. Cantrell, J. Org. Chem., 1981,46,2911. R.L.Danheiser, C. Martinez-Davila, R. J. Auchus, and J. T. Kadonaga, J. Am. Chem. SOC.,1981,

103,2443. " 62

J. P. Marino and M. P. Ferro, J. Org. Chem., 1981,46,1828. J. P.Marino and R. J. Linderman, J. Org. Chem., 1981,46,3696.

Saturated Carbocyclic Ring Synthesis

287

syntheses of compounds (86) and (87).63An alternative cyclization procedure is the 1,3-dipolar cycloaddition of nitrones [(88); n = 1 or 21, which can be used to prepare cyclopentene aldehydes (89), for example.64

Scheme 8

(86)

A full report has been published on the chemistry of the highly functionalized bicyclo[3.2.0]heptene (90), reaction of which with diazoethane gives a mixture (ca. 7 : 3) of the useful ring-expanded products (91) and (92).“5A synthesis of

another potential precursor (93) of polycyclopentanoids has also been reported.66

In another full report, details are given of the preparation of (95a) by an intramolecular Wadsworth-Emmons reaction of the phosphonate (94);67”this method constitutes a key step in a synthesis of 6a-carbaprostaglandin 12,67hA related Wittig reaction using a phosphonium salt derived from a chiral phosphine has been used to obtain (96) in high optical purity.68 Bicyclo-AlV2-octenone D. R. Williams, A . Abbaspour, and R. M. Jacobson, Tetrahedron Lett., 1981,22,3565; T. Hiyarna, M.Shinoda, H. Sairnoto, and H. Nozaki, Bull. Chem. SOC. Jpn, 1981,54,2747. 64 S. Takahashi, T. Kusumi, Y. Sato, Y. Inouye, and H. Kakisawa, Bull. Chem. SOC. Jpn., 1981,54, 1777. I. Fleming and B.-W. Au-Yeung, Tetrahedron, 1981,37 (Suppl. l), 13; see also I. Fleming and R. V. Williams, J. Chem. SOC.,Perkin Trans. I , 1981,684. 66 L. A . Paquette, E. Farkas, and R. Galemmo, J. Org. Chem., 1981,46, 5434. ” ( a ) M.J. Begley, K. Cooper, and G. Pattenden, Tetrahedron, 1981,37, 4503;(6) P. A . Aristoff, J. Org. Chem., 1981,46,1954. B. M. Trost and D. P. Curran, Tetrahedron Lett., 1981,22, 4929. 63

‘’

288

General and Synthetic Methods

(95b), the simplest member of this series is produced in only low yield by the intramolecular Wadsworth-Emmons Other methods e.g. from (97; cf. Scheme 6),58(98; by a l d ~ l )and , ~ ~(99, by cobalt ~atalysis)~' lead to better yields of (95b). 0 11

( 9 5 ) a, R = Me; b, R =

(94)

H

(97)

Another o,xample of the acid-catalysed intramolecular cyclization of diazoketones (cf. refs. 58, 92, 93) is a high-yielding preparation of polycyclic enones (101) from diazoketones Further reports have appeared on the preparation of fused cyclopentanones by condensations between acetonedicarboxylate and a-diketones; yields are higher if the substituents on the latter substrates are An alternative approach to polycyclopentanoids, consisting of successive additions of propargyl alcohol anions to cyclopentanones followed by 'double dehydrative cyclization' and hydrogenation, has been used to prepare the potential dodecahedrane precursor (102)73(cf. ref. 63). The cage compound (103), obtained from 1,4-naphthoquinones and cyclopentadiene, produces the polycyclopentanoid (104) under acyloin condensation c o n d i t i o n ~ . ~ ~

4 0

(102) 69

70 71

72

73

74

D. K. Klipa and H. Hart, J. Org. Chem., 1981,46, 2815. N. E. Schore and M. C. Croudace, J. Org. Chem., 1981,46, 5436; see also ibid., p. 5357. G. 0. S. V. Satyanarayana, P. R. Kanjilal, and U. R. Ghatak, J. Chem. SOC.,Chem. Commun., 1981,746. A. Gawish, R. Mitschka, J. M. Cook, and U. Weiss, Tetruhedron Lett., 1981, 22, 211; K. Avasthi, M. N. Deshpande, W.-C. Han, J. C. Cook, and U. Weiss, ibid., p. 3475; R. Mitschka, J. Oehldrich, K. Takahashi, J. M. Cook, U. Weiss, and J. V. Silverton, Tetrahedron, 1981, 37,4521. M. A. McKervey, P. Vibuljan, G. Ferguson, and P. Y. Sew, J. Chem. SOC.,Chem. Commun., 1981, 912; see also P. Deslongchamps and P. Soucy, Tetrahedron, 1981, 37, 4385; P. E. Eaton, R. S. Sidhu, G. E. Langford, D. A. Cullison, and C.:L. Pietruszewski, ibid., p. 4479. G. Mehta, K. S. Rao, M. M. Bladbhade, and K. Venkatesan, J. Chem. SOC.,Chem. Commun., 1981.755.

Saturated Carbocyclic Ring Synthesis

q g

289

H'

(103)

0

Naturally Occurring Fused Cyc1opentanoids.-Activity in this area continues to be intense. Little et aL7' have used the rather low-yielding intramolecular 1,3-diyl trapping procedure in syntheses of A9"*'-capnellene (105) and the isomeric hirsutene (106), whereas in an alternative route to (105), sequential Nazarov and aldol cyclizations are used to build up the three ring ~ystem.'~ Pyrolysis of the cage compound (107), derived from cyclopentadiene and 2,5-dimethylbenzoquinone, leads to the hirsutene precursor (108) in high yield.77The preparation of another potential precursor (110) to the hirsutanes by intramolecular [2 + 2lphotoaddition of (109) has been detailed in

. presented ~ ~ in full their syntheses of (*)-coriolin (111) Danishefsky et ~ 1 have and (*)-coriolin-B, which feature the cyclopentenone-annulationprocedure (112) + (113) at the outset. Japanese workers8" have also achieved total syntheses of (k)-coriolin in which one key step is the conversion of 1,3-cyclo-oc75

76

77

78 79

R. D. Little and G. L. Carroll, Tetrahedron Lett., 1981, 22, 4389; R. D. Little and G. W. Muller, J. Am. Chem. SOC.,1981, 103, 2744; see also R. D. Little, G. W. Muller, M. G. Venegas, G. L. Carroll, A. Bukhari, L. Patton, and K. Stone, Tetrahedron, 1981, 37,4371. K. E. Stevens and L. A. Paquette, Tetrahedron Lett., 1981, 22,4393. G. Mehta and A. V. Reddy, J. Chem. SOC.,Chem. Commun., 1981,756; G. Mehta, A . Srikrishna, A. V. Reddy, and M. S. Nair, Tetrahedron, 1981, 37,4543. J. S. H. Kueh, M. Mellor, and G. Pattenden, J. Chem. SOC.,Perkin Trans. 1, 1981, 1052; see also J. B. Stothers, Pure Appl. Chem., 1981, 53, 1241. S. Danishefsky, R. Zamboni, M. Kahn, and S. J. Etheredge, J. A m . Chem. SOC.,1981, 103,3460; S. Danishefsky and M. Kahn, Tetrahedron Lett., 1981, 22,489. K. Iseka, M. Yamazaki, M. Shibasaki, and S. Ikegami, Tetrahedron, 1981, 37,4411; K.Tatsuta, K. Akimoto, and M. Kinoshita, ibid., p. 4365; see also M: Yamazaki, M. Shibasaki, and S. Ikegami, Chem. Lett., 1981, 1245.

290

General and Synthetic Methods

tadiene into (114). Trost and Currang’ have used a novel annulation procedure in an approach to coriolin that involves the intramolecular cyclization of an allyl silane. A closely related intermolecular version of this idea can be used to convert cyclopentenones, e.g. (115) into the bicyclic derivatives, e.g. (117) by Pdo-catalysed coupling with the allyl silane (116).82

Detailed accounts of several total syntheses of the tricyclic hydrocarbon isocomene (118) have been In an interesting and very brief approach to a dehydroisocomene, Wender and Dreyer have used an intramolecular [1,3]photoaddition of an olefin to a benzene ring as a key This photoreaction has also been exploited in a synthesis of (*)-a-cedrene (121);86 thus, photolysis of the anisole (119) leads to a mixture of cycloadducts (120), which is converted into (121) following sequential cleavage of the cyclopropane ring by bromination, debromination (Bu,SnH), and finally Wolff-Kishner reduction. An alternative approach to the cedrene carbon skeleton, which has resulted in a synthesis of (*)-a-cedrol, has the conjugate addition of Me2CuLi to a tricyclo[3.3.0.02~8]octan-3-oneas a key The related tricyclic compound (122), a precursor to the zizaene sesquiterpenoids, has been synthesized by an intramolecular [2 + 2lcycloaddition followed by Grob fragmentation.88 Notable total syntheses of pentalenolactone E methyl ester (123)89and quadrone ( 124)90 have also been reported. B. M. Trost and D. P. Curran, J. A m . Chem. SOC.,1981,103,7380. B. M. Trost and D. M. T. Chan, J. A m . Chem. SOC.,1981,103, 5972. M. C. Pirrung, J. A m . Chem. SOC., 1981, 103, 82; L. A. Paquette, and Y.-K. Han, ibid., p. 1835, see also W. G. Dauben and D. M. Walker, J. Org. Chem., 1981,46, 1103. 84 W. Oppolzer, K. Battig, and T. Hudlicky, Tetrahedron, 1981, 37, 4359. ” P. A. Wender and G. B. Dreyer, Tetrahedron, 1981,37,4445. 86 P. A. Wender and J. J. Howbert, J. A m . Chem. SOC.,1981,103,688. P. Yates and K. E. Stevens, Tetrahedron, 1981, 37, 4401. (See also P. Callant, H. DeWilde, and M. Vanderwalle, Tetrahedron, 1981, 37, 2079; P. Callant, R. Ongena, and M. Vandenvalle, ibid., p. 2085). A. J. Barker and G. Pattenden, Tetrahedron Lett., 1981, 22, 2599. 89 L. A. Paquette, H. Schostarez, and G. D. Annis, J. A m . Chem. SOC.,1981, 103, 6526; see also K. Sakai, T. Ohtsuka, S. Misumi, H. Shirahama, and T. Matsumoto, Chem. Lett., 1981, 355. 90 W. K. Bornack, S. S. Bhagwat, J. Ponton, and P. Helquist, J. A m . Chem. SOC., 1981, 103, 4647; S. Danishefsky, K. Vaughan, R. Gadwood, and K. Tsuzuki, ibid., p. 4136; see also L. A. Paquette, G. D. Annis, H. Schostarez, and J. F. Blount, J. Org. Chem., 1981, 46, 3768.

82

83

’’

Saturated Carbocyclic Ring Synthesis

29 1 OMe

h

0

New methods for the elaboration of the gibbane carbon skeleton and related structures continue to be developed. Chiral gibbane derivatives can be prepared by asymmetric aldol condensations using L-proline as catalyst, or by building up the carbon skeleton from a chiral p r e c u r ~ o rExamples .~~ have already been qu~ted”*’~ which bear witness to the considerable synthetic potential of acidcatalysed intramolecular cyclizationsof olefinic diazoketones. Mander et al. have given full details of their studies in this area with anisole derivatives such as (125) and (128). Cyclization occurs para to a methoxy substituent, leading to (126) and (129), respectively, which rearrange under the reaction conditions to (127) and (130).92 This type of cyclization procedure has been used by Nicolaou

91

92

S. Takano. C. Kasahara, and K. Ogasawar, J. Chem. SOC.,Chem. Commun., 1981, 635, 637. D. W. Johnson, L. N. Mander, and T. J. Masters, Aust. J. Chem., 1981, 34, 1243; I. A. Blair, L. N. Mander, P. H. C. Mundill, and S. G . Pyne, ibid., p. 1887; L. N Mander and S. G. Pyne, ibid., p. 1899; L. N. Mander, G. J. Potter, S. G. Pyne, and M. Woolias, ibid., p. 1913; B. Basu, S. K. Maityiand D. Mukherjee, Synth. Commun., 1981,11, 803.

General and Synthetic Methods

292

+ Me0

Me0

0 (129)

(128)

(130)

and Zipkin in an attractive synthesis of the potential aphidicolin precursor (131) (Scheme 9).93 Further notable syntheses of aphidicolin itself ( 132),94and a biomimetic route to maritmol (133),95a member of the related stemodane group,

8

0

N2$ I

OMe

Reagents: i, CF,CO,H; ii, W

AcO

O

A

c

; SnC1,-CH,Cl,,

0 "C

Scheme 9

HO'

(133)

(132)

have also been reported. The instability of diazoketones has prompted the development of an efficient alternative for effecting such cyclizations based on a Pummerer rearrangement of P-ketosulphoxides, (134) + ( 135).96 Buchi's approach to bicyclo[3.2. lloctanes based on the acid-catalysed or photochemical addition of p-quinone monoacetals to olefins has been used in a 93 94

9s

96

K. C. Nicolaou and R. E. Zipkin. Angew. Chem., Znt. Ed-Engl., 1981,20, 785. R. E. Ireland, J. D. Godfrey, and S. Thaisrivongs, J. A m . Chem. SOC.,1981, 103,2446; J. E. McMurry, A. Andrus, G. M. Ksander, J. H. Musser, and M. A. Johnson, Tetrahedron, 1981, 37 (Suppl. l), 319; see also, R. L. Cargill, D. F. Bushey, J. R. Dalton, R. S. Prasad, R. D. Dyer, and 3. Bordner, J. Org. Chem., 1981, 46, 3389; T. Kametani, T. Honda, Y.Shiratori, H. Matsumoto, and K. Fukumoto, J. Chem. SOC.,Perkin Trans. 1, 1981, 1386. E. E. van Tamelen, J. G. Carlson, R. K. Russell, and S. R. Zawacky, J. A m . Chem. SOC.,1981, 103,4615. L. N. Mander and P. H. C. Mundill, Synthesis, 1981, 620.

Saturated Carbocyclic Ring Synthesis

293

short synthesis of gymnomitrol (136),97which has also been prepared by Paquette and Han98by a route that features the use of a vinyl silane as an acetaldehyde enolate equivalent.

have reported syntheses of the unusual hydrocarSeveral research bon modhephene (137); a feature of work in this area is the failure of many standard and normally facile reactions owing to extreme steric hindrance effects. A total synthesis of (*)-albene (138) includes an alternative method for converting a succinic anhydride derivative into a cyclopentenone.lo* A useful review has been published on the synthesis and chemistry (mainly rearrangement reactions) of longifolene (139).lo3

4 Six-membered Rings

Diels-Alder Reactions.-Cyclopentenone is a notoriously poor dienophile, but its a-phenylthio-derivative (140) reacts cleanly with excess butadiene (catalysed or uncatalysed) to give (141) or (142) after appropriate desulphuri~ations.'~~ Thus, in the latter case, (140) acts as a cyclopentynone equivalent. The ring opening of cyclobutenes (143) to the corresponding 1,3-dienes is greatly accelerated by the addition of BunLi.lo5A synthesis of the useful diene (144) has been reported; Diels-Alder reaction of (144) with 2-acetoxyacrylonitrile followed by hydrolysis then leads to (145).lo6 As predicted, @-nitroenones such as (146) are active dienophiles that react with the reverse G. Buchi and P.-S. Chu, Tetrahedron,1981,37,4509;C.-P. Mak and G. Buchi, J. Org. Chem,,1981, 46, 1; T. R. Hoye, Tetrahedron Lett., 1981, 33, 2523. L. A. Paquette and Y.-K. Han, J. Am. Chem. Soc., 1981,103,1831. 99 A. B. Smith, I11 and P. J. Jerris, J. Am. Chem. Soc., 1981, 103, 194. '"o W. Oppolzer and F. Marazza, Helu. Chim. Actu, 1981, 64, 1575; W. Oppolzer and K. Battig, ibid., p. 2489. lo' H. Schostarez and L. A. Paquette, J. Am. Chem. SOC.,1981, 103, 722; Tetrahedron, 1981, 37, 4431; see also M. Karpf and A. S. Dreiding, Helo. Chim. Acta., 1981, 64, 1123. lo2 J. E. Baldwin and T. C. Barden, J. Org. Chem., 1981,46,2442. lo3 S . Dev, Fortschr. Chem. Org. Nuturst., 1981,40,49. lo' S . Knapp, R. Lis, and P. Michna, J. Org. Chem., 1981, 46, 624; see also H. J. Reich, W. W. Willis, jun., and P. D. Clark, ibid., p. 2775 and L. A. Paquette and R. V. Williams, Tetrahedron Lett., 1981,22,4643. lo' T. Kametani, M. Tsubuki, H. Nemoto, and K. Suzuki, J. Am. Chem. Soc., 1981,103, 1256. M. R. Bell, J. L. Herrmann, and V. Akullian, Synthesis, 1981, 357. 97

294

General and Synthetic Methods

regiochemistry relative to the unsubstituted enones. lo’ For example, the enedione (147) can be obtained from (146) by reaction with 2-trimethylsilyloxybuta-1,3-diene.

An examination of the Diels-Alder reactions of dieneones, such as (148), with penta-1,3-diene has revealed that the stereochemistry of the products is remarkably dependent on the reaction conditions (Scheme 10).lo* The quinone (149) preferentially undergoes Diels-Alder reactions at the ‘internal’ double bond; for example, the tricyclic derivative (150) is formed in high yield with butadiene.log

Jp

SnCI,

*-

(148) Scheme 10

H

OH

The utility of cyclopentadienes as reactive dienophiles continues to be exploited. Glutaconic anhydride has been shown to exist largely as the anhydride rather than the tautomeric hydroxy-pyrone in non-polar solvents, and as such reacts smoothly with cyclopentadiene to give the useful ‘prostanoid precursor lo’

E. J. Corey and H. Estreicher, TetrahedronLett., 1981, 22, 603. D. Liotta, M. Saindane, and C. Barnum, J. Am. Chem. SOC.,1981, 103, 3224; see also H.-J. Liu and E. N. C. Browne, Can. J. Chem., 1981,59,601. M. Oda and Y. Kanao, Chem. Lett., 1981,1547.

Saturated Carbocyclic Ring Synthesis

295

(15 1).' l o Allenic esters react with cyclopentadiene to give mainly the endo-isomer (152) in the presence of AICl,."' Very extensive studies"* of the Lewis acidcatalysed reaction between cyclopentadiene and chiral acrylic esters have resulted in an optimum optical yield of 93% in favour of endo-(R)-(153), which are obtained from the initial adducts by reduction with lithium aluminium hydride. Although (trimethoxymethy1)cyclopentadiene exists as mixtures of the 1- and 2-isomers, it reacts with several dienophiles to give largely the product arising from the 2-isomer, e.g. (154) from dimethyl acetylenedicarboxylate."3 Similarly, isomers of methyl (trimethylsily1)cyclopentadiene give largely (155), on BF,catalysed cycloaddition to methyl acrylate.' l4 Some cyclohexadienones have also been found to undergo stereoselective cycloadditions with simple dienophile~."~

(154)

The beneficial effects of Lewis acids on Diels-Alder reactions are well known. A similarly dramatic rate acceleration is also observed when a radical cation species such as Ar3NSbC1i is used as catalyst."6 For example, the uncatalysed dimerization of cyclohexa-l,3-diene, which requires 20 h at 200 "C,can be carried out at 0 "Cin 0.25 h with this catalyst. The development of heteroatom-substituted buta-1,3-dienes has added another dimension to the utility of the Diels-Alder reaction. Such reactions 'lo

S. P. Briggs, D. I. Davies, R. F. Newton, and D. P. Reynolds, J. Chem. SOC., Perkin Trans, 1,

1981, 146, 150. Z . M. Ismail and H. M. R. Hoffmann, J. Org. Chem., 1981,46, 3549. '12 W. Oppolzer, M. Kurth, D. Reichlin, and F. Moffatt, Tetrahedron Lett., 1981, 22, 2545; W. Oppolzer, M. Kurth, D. Reichlin, C. Chapius, M. Mohnhaupt, and F. Moffatt, Helv. Chim. Acta., 1981, 64, 2802; see also G. Helmchen and R. Schmierer, Angew. Chem., Inr. Ed. Engl., 1981, 20,205 and J. Bachner, U. Huber, and G. Buchbauer, Monatsh. Chem., 1981,112,679. P. Yates and I. Gupta, J. Chem. SOC.,Chem. Commun., 1981,449; see also G. Grundke and H. M. R. Hoffmann,J. Org. Chem., 1981,46,5428. 'I4 W. R. Roush and T. E. D'Ambra, J. Org. Chem., 1981, 46, 5045; see also J. D. White, T. Matsui, and J. A. Thomas, ibid., p. 3376. l YH. 5 Auksi and P. Yates, Can. J. Chem., 1981, 59, 2510; for related work, see P. Yates and G. E. Langford, ibid., p. 344. D. J. Bellville, D. D. Wirth, and N. L. Bauld, J. A m . Chem. SOC.,1981, 103, 718. *''For reviews, see M. Petrzilka and J. I. Grayson, Synthesis, 1981, 753; S. Danishefsky, Acc. Chem. Res., 1981, 14,400; see also S. Danishefsky, J. Morris, and L. A. Clizbe, J. A m . Chem. SOC.1981, 103,1602. 'I1

296

General and Synthetic Methods

using trialkylsilyloxybuta-1,3-dienes form key steps in approaches to (*)formannosin,' '' cyathin diterpenes,"' perhydrohistrionicotoxin,12' anthraquinones,'21 and cyclohexane epoxide precursors.'22 A neat use of the residual silyl enol ether functionalityresulting from this type of reaction is shown Diels-Alder reactions of the in a synthesis of (*)-seychellene (Scheme 1l).123 related 1-acetoxybuta-1,3-dienes have been used to prepare trichothecene precursors.124

fi3

OSiMe3

+ A p & o

-h0 Tic14

0

H Scheme 11

Full accounts have been given of the Diels-Alder reactions of 1-acylaminodienes (156),12' salient features of which are their wide application (even with reluctant dienophiles such as cyclohexenone), their generally good endo-selectivity, and their high regioselectivity with unsymmetrical dienophiles. Full details have also been given of the Diels-Alder reactions of the silyl-dienes (157), which are useful precursors of cyclic ally1 silanes.'26 R'

+I NC

C0,Et

In efforts towards a synthesis of eremolactone, the dienolate (158) has been found to react with the cyano-ester (159) to give (160) (probable stereochemistry shown) most likely via a double Michael a d d i t i ~ n rather '~ than a Diels-Alder reaction.12' Highly substituted cyclohexanes have been prepared by cycloadditions between cyclohexa-1,3-dienes and nitroso-compounds followed by N - 0 and olefinic bond cleavage (Scheme 12).12' 118 119

120 121

122 123 124

12s

lZ6 '21

M. F. Semmelhack and S. Tomoda, J. A m . Chem. Soc., 1981,103,2427. W. A. Ayer, D. E. Ward, L. M. Browne, L. T. J. Delbaere, and Y. Hoyano, Can. J. Chem., 1981, 59,2665. T. Ibuka, Y.Mitsui, K. Hoyashi, H. Minakata, and Y. Inubushi, Tetrahedron Lett., 1981.22.4425. G. Roberge and P. Brassard, Synthesis, 1981, 381; see also A. P. Kozikowski, K. Sugiyama, and J. P. Springer, I. Org. Chem., 1981,46,2426. R. H. Schlessinger and A. Lopes, J. Org. Chem., 1981,46, 5252. M. E. Jung, C. A. McCombs, Y. Takeda, and Y.-G. Pan, J. A m . Chem. Soc., 1981,103, 6677. R. E. Banks, J. A. Miller, M. J. Nunn, P. Stanley, T. J. R. Weakley, and Z. Ullah, J. Chem. SOC., Perkin Trans. 1, 1981, 1096. L. E. Overman, R. L. Freerks, C. B. Petty, L. A. Clizbe, R. K. Ono, G. F. Taylor, and P. J. Jessup, J. A m . Chem. SOC.,1981, 103, 2816; L. E. Overman and R. L. Freerks, J. Org. Chem., 1981.46.2833: R. R. Schmidt and A. Wagner, Synthesis, 1981,273. M. J..CaAer, I. kleming, and A. Percival, .f Chem. SOC.,Perkin Trans. 1, 1981, 2415. A. S. Narula and A. J. Birch, Tetrahedron Lett., 1981, 22, 591. G. Kresze and E. Kysela, Liebigs Ann. Chem., 1981, 202; G. Kresze, E. Kysela, and W. Dittel, ibid., p. 210; G. Kresze, W. Dittel, and H. Melzer, ibid., p. 224; G. Kresze and W. Dittel, ibid., p. 610.

-

Saturated Carbocyclic Ring Synthesis -&Rl

0:;

297 A

c

oNHAcr * :

~

~

~

II

+

'\R3

AcO.

R2

OAc

Scheme 12

Many of the studies on the intramolecular version of the Diels-Alder reaction carried out in 1981 have focused attention on its stereochemical aspects. Previous work by Sutherland has revealed that the conversion (161) + (162) requires a temperature of 190°C, suggesting that the enone group in (161) is forced out of conjugation. By using bulky acetal or alcohol derivatives of (161), thus removing any secondary orbital interactions and disflavouring an endo-transition state, the stereoselectivity can be reversed in favour of the trans-fused isomer of (162).'*' Related work resulting in the synthesis of (163),I3Olargely as the cis-fused isomer, and (164)l" and related has led to the suggestion that such reactions may be concerted but non-synchronous. Three research groups have used the largely stereoselective cyclization (165) + (166) as a

prelude to total syntheses of antibiotic X-14547A.'33 Intramolecular cycloadditions of methyl 2,8,10-undecatrienoates lead to isomeric mixtures of decalins, the proportions of which are independent of the dienophile s t e r e o c h e r n i ~ t r y . ~ ~ ~ Reactions similar to (161) + (162) form key steps in syntheses of (&)-a-and 12'

13" 13' 132

133

134

M. E. Jung and K. M. Halweg, Tetrahedron Lett., 1981,22, 3929;S. A. Bal and P. Helquist, ibid., p. 3933. D. F. Taber, C. Campbell, B. P. Gunn, and I.-C. Chiu, Tetrahedron Lett. 1981,22, 5141. W. R. Roush and S. M. Peseckis, J. A m . Chem. SOC., 1981,103,6696. J. D.White and B. G . Sheldon, J. Org. Chem., 1981,46,2273. M. P.Edwards, S. V. Ley, and S. G. Lister, Tetrahedron Lett., 1981,22, 361;K. C. Nicolaou, D. P. Papahatjis, D. A. Cameron, and R. E. Dolle, 111, J. A m . Chem. SOC..1981,103,6967: K.C. Nicolaou and R. L. Magolda, J. Org. Chem., 1981,46,1506;W.R.Roush and A. G. Myers, ibid., p. 1509. W. R. Roush and S. E. Hall, J. A m . Chem. SOC., 1981,103,5200.

General and Synthetic Methods

298

and an erroneously assigned strucP-himachalenes, 13' (&)-coronafacic ture of (&)-chil~scyphone.'~~ The novel features of these schemes are the ways in which the appropriate trienes are built up rather than the Diels-Alder reactions. A synthesis of sativene includes an in situ formation of a silyloxycyclopentadiene under standard conditions (ZnCl,-TMSCl-Et,N, 110 "C) (Scheme 13),138the overall yield for this step being a spectacular 94'/0, while in a synthesis of (-)-patchouli alcohol (168), a preformed triene (167) is used; the cyclization only proceeds in the presence of a trace of K O B U ' . ' ~ ~

Scheme 13

4

& 0

Me0

OH

A range of simple lactones, e.g. (169), have been prepared by intramolecular cycloadditions involving benzocy~lobutenes'~~ (cf. refs. 159-16 1).Oppolzer has summarized much of his group's work on intramolecular cyclizations, including ene and [2 + 2]types, as well as Diels-Alder reaction^.'^' Other Six-membered Ring Synthesis.-The course of intramolecular aldol condensation of heptane-2,6-diones can be completely changed by varying the reaction conditions (Scheme 14).14*

J+J)+Q 0

i

b Z 0 2 R 1*C0,R' Reagents: i, HCI-Me,SiCl-CHCl,,

16 h, 25 "C; ii,

6)

-AcOH-C,H,,

R2

C0,R'

12 h, A

H

Scheme 14

13'

139

140

w.Oppolzer, R. L. Snowden, and D. P. Simmons, Helu. Chim. Acta, 1981,64,2002; W. Oppolzer, R. L. Snowden, and P. H. Briner, ibid., p. 2022; W. Oppolzer and R. L. Snowden, ibid., p. 2592. M. E. Jung and K. M. Halweg, Tetrahedron Lett., 1981,22, 2735. J.-L. Gras, J. Org. Chem. 1981,46, 3738. R. L. Snowden, Tetrahedron Lett., 1981,22, 97, 101. F. Naf, R. Decorzant, W. Giersch, and G. Ohloff, Helu. Chim. Acta, 1981,64, 1387. T. Kametani, T. Honda, H. Matsumoto, and K. Fukumoto, J. Chem. Soc., Perkin Trans. I , 1981, 1383.

W. Oppolzer, Pure A p p l . Chem., 1981, 53, 1181. W. Kreiser and P. Below, Tetrahedron Lett., 1981, 22, 429.

Saturated Carbocyclic Ring Synthesis

299

A rapid if not very efficient ( 2 3 4 6 % yields) entry to cyclohex-3-en-1-ones Two (170) is by condensations between a-lithio-nitriles and b~ta-1,3-dienes.'~~ closely related methods involving Michael additions of 2-(2-lithiophenyl)ethyl halides leading to tetralin derivatives have been reported. Thus, condensation of (171) with the diester (172) results in the formation of the lignan precursor (173),144 while the aryl-lithium (174) reacts similarly with unsaturated sulphones (175; It = 1 or 2) to give (176) in high ~ i e 1 d s . IA~ ~further example of the 0

g

C0,Et

6

a

/' C0,Et

g e B r +

Me0

(171)

R

R2

r

'

(174)

'

Li

S02Bu'

o C02Et 2E

Me0

R:q OMe

b)n -

+

,

+

OMe OMe

(172)

c

(173)

)n

R;SiO (175)

RjSiO (176)

accelerating effect that an alkoxy substituent can have on sigmatropic rearrangem e n d 0 is the facile conversion of vinylcyclobutanoxides (177) to cyclohexenols (178);'46 the method looks to have a broad generality. Allenyl cations derived from a-chloroacetylenes add to cycloalka-l,3-dienes to give the [2 + 4]cycloadducts (179) in variable yields,14' and photoadducts of

143 144

147

K. Takabe, S. Ohkawa, and T. Katagiri, Chem. Lett., 1981,489; see also Synthesis, 1981, 359. A. S. Kende, M. L. King, and D. P. Curran, J. Org. Chem., 1981,46, 2826. I. Ponton, P. Helquist, P. C. Conrad, and P. L. Fuchs, J. Org. Chem., 1981,46, 118. R. L. Danheiser, C. Martinez-Davila, and H. Sard, Tetrahedron, 1981, 37,3943. H. Mayr and F. Schutz, Tetrahedron Lett., 1981, 22, 925.

300

General and Synthetic Methods

allene and cyclohexenones undergo HgC10,-catalysed rearrangements leading to bicyclo[2.2.2]octanones ( 180).14s

The reported structure of cycloseychellene has been shown to be erroneous by a total synthesis that features intramolecular versions of the Claisen rearrangement and Prins reaction (Scheme 15).149 Robinson annulations using methyl vinyl ketone can sometimes be effected more efficiently and with greater stereoselectivity by using acid rather than base catalysis.150The same type of reaction, when used to prepare the WielandMiescher ketone from 2-methylcyclohexan-l,3 -dione and methyl vinyl ketone, can be effected in 80% yield simply by heating the reactants together at 185 OC.lS1 A neat route has been developed for the synthesis of useful analogues of the Wieland-Miescher ketone that have oxygenated angular substituents, e.g. (181).lS2The related octalone (183) is available from condensation between the dianion (182) and ethyl 4-bromobutanoate followed by decarboxylation.1s3 Adducts (184) of vinyl ketones and cyclic P-keto-thiolesters can also be cyclized to angularly substituted octalones (185)using suitable conditions (Scheme l6).ls4

Rq

@ )n

0

ii

1"

+

'

0

R (185)

(184) n

=

1 or 2

-

&Et 0

R

n

Reagents: i, p-MeC,H,SO,H; ii, H2S04-C6H6, 0 "C

Scheme 16 14* 149

151

D . K. M. Duc, M. Fetizon, I. Hanna, and A. Olesker, Tetrahedron Lett., 1981,22,3847. S. C. Welch, J. M. Gruber, C.-Y. Chou, M. R. Willcott, and R. Inners, J. Org. Chem., 1981,46, 4816;M. R.Willcott, P. A . Morrison, J.-M. Assercq, S. C. Welch, and R. Inners, ibid., p. 4819. P.A . Zoretic, J. A. Golen, and M. D. Saltzman, J. Org. Chem., 1981,46,3554. J. A . Findlay, D. N. Desai, and J. B. Macaulay, Can. J. Chem., 1981,59, 3303. L. N.Mander and R. J. Hamilton, Tetrahedron Lett., 1981,22,4115. K.G. Bilyard and P. J. Garratt, Tetrahedron Lett.. 1981,22. 1755. H.-J. Liu, L.-K. Ho, and H. K. Lai, Can. J. Chem., 1981,59, 1685.

Saturated Carboc yclic Ring Synthesis

301

Treatment of the enone (185; n = 2, R = H) with Me2CuLi results in the formation of (187); this rarely observed reaction involving replacement of a ketone oxygen by two methyl groups presumably proceeds via the lactone (186). Further work from Vollhardt's group on cobalt-catalysed cycloadditions of olefins and acetylenes has led to a synthesis of cyclohexadiene derivatives (188; a = 0-2) by addition of w-enynes to trimethyl silyla~etylenes;'~~ the reactions can also be carried out in an intramolecular sense, leading to tricyclic comp o u n d ~The . ~ ~novel ~ tricyclic compound (189) has been obtained from naphthoquinone by a [2 + 2laddition of 1,l-bis(silylmethy1)ethylene followed by treatment with a Lewis acid.l5' A key step in the first total synthesis of a decipiene diterpene is the formation of tricyclic ketone (190) by an intramolecular aldol condensation, which required the use of methanolic barium oxide."'

Steroids.-Intramolecular Diels-Alder reactions of o-quinodimethanes,'40 generated by thermolysis of the corresponding benzocyclobutanes, continue to form the basis of many steroid s y n t h e ~ e s , ' ' ~including ~ estradiol derivatives,159b18hydroxye~trone,'~~" (+)-chenodeoxycholic acid,lSYdand des-A-ring Two alternative ways to obtain o-quinodimethanes, by photoenolization of o-methylphenyl ketones'60 or by a fluoride-ion-induced elimination reaction [(191) + (192)1,161 have been utilized in syntheses of 19-nor-steroids and 0methyl estrone (193), respectively.

Is*

C.-A. Chang, J. A . King, jun., and K. P. C. Vollhardt, J. Chem. SOC.,Chem. Commun., 1981, 53. T. R. Gadek and K. P. C. Vollhardt, Angew. Ckem.. Int. Ed. Engf., 1981,20, 802. M. Ochiai, M. Arimoto, and E. Fujita, J. Chem. SOC.,Chem. Commun., 1981, 460. M. L. Greenlee, I. A m . Chem. SOC.,1981,103, 2425. ( a ) T . Kametani and H. Nemoto, Tetrahedron, 1981, 37, 3 ; ( b ) T. Kametani, M. Aizawa, and H. Nemoto, ibid., p. 2547, ( c ) J. Tsuji, H. Okumoto, Y. Kobayashi, and T. Takahashi, Tetrahedron Lett., 1981, 22, 1357; ( d ) T. Kametani, K. Suzuki, and H. Nemoto, J. A m . Chem. SOC.,1981, 103, 2890; ( e )T. Kametani, H. Matsumoto, T. Honda, M. Nagai, and K. Fukumoto, Tetrahedron, 1981.37.2555.

G. Quinkert, W.-D. Weber; U. Schwartz, H. Stark, H. Baier, and G. Durner, Liebigs Ann. Chem., 1981,2335. 16'

V. Ito, M. Nakatsuka, and T. Saegusa, J. A m . Chem. SOC.,1981,103,476.

302

General and Synthetic Methods 0

An attractive route to an estrone precursor consists of Cope rearrangement of a protected cyanohydrin followed by an extremely facile polyene cyclization (Scheme 17).'" Certainly the briefest synthesis of estrone, although not the most efficient (8.4% yield), has the tandem Michael-Michael ring-closure sequence, outlined in Scheme 18, as the key Another practical and highly convergent approach to A-ring aromatic steroids has been developed. 164 Also of note, is an elegant approach to 11-oxygenated steroids, such as 11ketotestosterone, developed by Stork et ~ 1 . l ~ ~

Scheme 17

Me0

Me0

Scheme 18

Anthracyc1ines.-Diels-Alder reactions continue to be a dominant feature in many approaches to the anthracycline antibiotics. The rather unreactive dienophile (194) takes part in such reactions with o-quinodimethanes to provide

'64

l''

F. E. Ziegler and T.-F. Wang, Tetrahedron Lett., 1981, 22, 1179;see also E. E. van Tamelen, Pure Appl. Chem., 1981,53,1259. G . H.Posner, J. P. Mallamo, and A. Y. Black, Tetrahedron, 1981,37,3921. L. N. Mander and J. V. Turner, Tetrahedron Lett., 1981,22,3683. G.Stork, G. Clark, and C. S. Shiner, J. A m . Chem. Soc., 1981,103,4948.

303

Saturated Carbocy c lic Ring Synthesis

an inefficient but useful synthesis of functionalized tetralins (e.g. 195) (Scheme 19).166This approach can apparently by improved by using the more reactive 3-aryloxycarbonyl analogues of (194).16'

WH KBr 0

Me0

Me0

M e 3 s i 0 7 p

+

Me0

Me0

(194)

Br

Scheme 19

(195)

Cycloadditions between naphthoquinones and a 1,2-dirnethylidenecyclohexane derivative have been used to prepare pentacyclic compounds, e.g. ( 196),'68 while a related cycloaddition between isobenzofurans and benzoquinone monoacetal derivatives occurs regioselectively leading to anthracycline derivatives such as (197).'"'

(197)

A study of the regioselectivity of Diels-Alder reactions between electron-rich dienes and methoxy- or methyl-substituted quinones has provided data that will be of use in designing syntheses in this area."' In an extension of earlier work, intermediates for the synthesis of 6-deoxyanthracyclines have been prepared from naphthoquinones using the novel diene ( 198).171The precursor (200) of 4-demethoxydaunomycin, which is one of the clinically more promising anthracyclines, has been obtained from the quinone (199) by a Diels-Alder reaction with Danishefsky's diene.I7' OSiMe,

(198) . .

9

9

0

0

(199)

(200)

R. J. Ardecky, F. A. J. Kerdesky, and M. P. Cava, J. Org. Chem., 1981, 46, 1483; F. A. J. Kerdesky, R. J. Ardecky, M. V. Lakshmikanthan, and M. P. Cava, J. A m . Chem. SOC.,1981,103, 1992. '" J. Tamariz and P. Vogel, Helu. Chim. Acta, 1981, 64, 188. '" L. K. Bee and P. J. Garratt, J. Chem. Res. ( S ) , 1981, 368. 169 R. N. Warrener. B. C. Hammer, and R. A. Russell, J. Chem. Soc., Chem. Commun., 1981, 942. I7O 1.-M. Tegmo-Larsson, M. D. Rozeboom, and K. N. Houk, Tetrahedron Lett., 1981, 33, 2043; 1.-M. Tegmo-Larsson, M. D. Rozeboom, N. G. Rondan, and K. N. Houk, ibid., p. 2047. 17' J.-P. Gesson, J.-C. Jacquesy and M. Mondon, Tetrahedron Left., 1981, 22, 1337; see also S. V. Ley, W. L. Mitchell, T. V. Radhaknshnan, and D.H. R. Barton, J. Chem. SOC., Perkin Trans. 1, 1981,1582. 17* D. A. Jackson and R. J. Stoodley, J. Chem. SOC.,Chem. Commun., 1981,478.

'61

General and Synthetic Methods

304

An approach to an anthracycline, 8,lO-dideoxycarminomycinone(204), which does not involve a Diels-Alder reaction, is by base-induced addition of the nitro-acetal (202) to the anthraquinone (201) resulting in the regioselective formation of (203), which is then converted to (204) using relatively standard m e t h ~ d o l o g y . 'Also ~ ~ of considerable interest in this area are several different total syntheses of aklavinone (205).'74 OH

HO

NO,

OH

0

OMe

HO

0

OH

'OH

---b

Hb

0

OH (204)

HO

0

OH

OH

(205)

5 Polyene Cyclizations

Simple mono-olefinic derivatives (206) of P-diketones or p-keto-esters can be cyclized efficiently using SnC1,; the method can also be applied to the synthesis of bicyclic and spiro-cyclic systems. 17' A closely related cyclization using monoacetylenes, e.g. (207) also works well to give (208), a potential precursor of the clerodin d i t e r p e n e ~ . ' ~ ~

The allylic alcohol (209) has been found to undergo stereoselective acidcatalysed cyclization to give a mixture of the hydrindene (210) and the decalene 173

174

'76

A. E. Ashcroft and J. K. Sutherland, J. Chem. SOC.,Chem. Commun., 1981, 1075;see also, A.S. Kende and S. D. Boettger, J. Org. Chem., 1981,46,2799. A. S. Kende and J. P. Rizzi, J. Am. Chem. SOC.,1981,103,4247; B. A.Pearlman, J. M. McNamara, I. Hasan, S. Hatakeyama, H. Sekizaki, and Y. Kishi, ibid., p. 4248; P. N. Confalone and G. Pizzolato, ibid., p. 4251;Z . Ahmed and M. P. Cava, Tetrahedron Lett., 1981,22, 5239;T.Li and T. C. Walsgrove, ibid., p. 3741;K.Krohn, ibid., p. 3219. M. T.Reetz, I. Chatziiosifidis, and K. Schwellnus, Angew. Chem., Int. Ed. Engl., 1981,20, 687. W. P. Jackson and S. V. Ley, J. Chem. SOC.,Perkin Trans. 1 , 1981,1516;see also Y.Kojima and N. Kato, Tetrahedron, 1981,37,2527;J. M. Luteijn and A. De Groot, J. Org. Chem., 1981,46,

3448.

Saturated Carboc yclic Ring Synthesis

305

(21l);l” the 2-geometrical isomer of (209) also reacts stereoselectively to give similar products, which are isomeric at C”.The allylic alcohol (212) undergoes a remarkably clean dimerization to give (213) in up to 80% yield when treated with p-toluenesulphonic acid in H,O-pentane. Related acid-catalysed cyclizations of dienes constitute key steps in total syntheses of the sesquiterpenoids oplopanone (214)”’ and norambreinolide (215).

A full account has been given of the use of the TiC1,-PhNHMe complex in cyclizations of 2-allylic alcohoIs.’I3’ The vinylcyclobutanone (216, R = H) undergoes acid-catalysed rearrangement to the decalin (217); if the C-2 position of the cyclobutanone is blocked however by an alkyl group, then the major products are spiro-cyclopentenones (218)18’(cf. ref. 146).

The use of heteroatomic groups to initiate olefin cyclizations continues to be exploited. Trimethylsilyl enol ethers (219) can be annulated as shown on treat~ ~ yields are ment with dimethyl(methy1thio)sulphonium f l u o r ~ b o r a t e . ’Good 17’

17’

E.-J. Brunke, F.-J. Hamrnerschmidt, and H. Struwe, Tetrahedron Lett., 1981, 22, 5259; Terruhedron, 1981, 37, 1033. H. M. R. Hoffmann and H. Vathke-Emst, Chem. Ber., 1981, 114, 1182 (see also ibid., pp. 1464, 1548).

”” IR2

IR3

F.-H. Koster and H. Wolf, Tetrahedron Lett., 1981, 22, 3937. A. Saito, H. Matsushita, Y. Tsujino, and H. Kaneko, Chem. Lett., 1981, 757. A. Itoh, T. Saito, K. Oshima, and H. Nozaki, Bull. Chem. SOC.Jpn., 1981, 54, 1456. J. R. Matz and T. Cohen, Tetrahedron Lett., 1981,22,2459; see also E. Lee-Ruff,A. C. Hopkinson, and L. H. Dao, Can. J. Chem., 1981,59,1675. B. M. Trost and E. Murayarna, J. Am. Chem. Soc., 1981,103,6529.

306

General and Synthetic Methods

obtained when n = 1 + 3. Lewis acid-catalysed C-cyclizations of a-phenylseleno-P-keto-esters, e.g. (220) + (221) occur with migration of the PhSe group184(cf. refs. 175 and 176). Although care is needed with the choice of the Lewis acid and the conditions used, as competing 0-cyclization can take place, this method can be applied to the preparation of a wide range of useful, polyfunctionalized carbocycles. Selenium-assisted cyclizations have also been used to prepare several cyclic terpenoid derivatives. 185~186 0

,&CO,Me

R

SePh

(219)

(220)

(221)

In contrast to (Lewis) acid-catalysed annulations of P-keto-esters such as (222), which lead to decalins (cf.refs. 175,176), mercuric ion-induced cyclization of (222) leads instead to the pyran (223).18' Further examples of the ability of a carbon-tin bond to provide a specific nucleophilic site in TiC1,-catalysed cyclizations of allylic alcohols have been reporfed,l8' together with a full account of the use of an imino group to initiate polyene cyclization~;'~~ annulations of imines that carry a chiral substituent result in moderate chiral inductions.

6 Seven-membered Rings Syntheses if two potentially useful seven-membered-ring natural product precursors have been developed. The cycloheptenone (225) can be obtained efficiently, on a large scale if necessary, by thermal rearrangement of the divinylcyclopropane (224),l9' whereas the pseudoguaiane precursor (226) has been

W. P. Jackson, S. V. Ley, and J. A. Morton, Tetrahedron Lett., 1981, 22, 2601; M. Alerdice and L. Weiler Can. J. Chem., 1981,59,2239. A. Rouessac, F. Rouessac, and H. Zamarlik, Tetrahedron Lett., 1981, 22, 2641; F. Rouessac and H. Zamarlik, ibid., p. 2643; A. Rouessac and F. Rouessac, Tetrahedron, 1981, 37, 4165. lS6 T. Kametani, K. Fukumoto, H. Kurobe, and H. Nemoto, Tetrahedron Letr., 1981, 22, 3653; T. Kametani, H. Kurobe, and H. Nemoto, J. Chem. SOC.,Perkin Trans. 1, 1981, 756. "'T. R.Hoye, A. J. Caruso, and M. J. Kurth, J. Org. Chem., 1981,46, 3550. T. L. Macdonald and S . Mahalingam, Tetrahedron Lett., 1981, 22, 2077; T. L. Macdonald, S. Mahalingam, and D. E. O'Dell, J. A m . Chem. Soc., 1981,103,6767. la9 G. Demailly and G. Solladie, J. Org. Chem., 1981,46, 3102. ' 9 0 J. P. Marino and M. P. Ferro, J. Org. Chem., 1981,46, 1912. lE4

Saturated Carbocyclic Ring Synthesis

307

prepared by relatively standard procedure^.'^^ Seebach et al. have reported an interesting route to cycloheptanone (227) that features a rarely used TiffeneuDemyanov rearrangement (Scheme 20). 192

NaNO

2_

(22 H’

O w 0

Scheme 20

(227)

7 Ring-expansion Methods

In an extension of known methodology, Conia et al. have shown that ketones can be expanded by one carbon to 2-methylenones [i.e. (228) -+ (229)] by the addition of chloro(methy1) carbene to the trimethylsilyl enol ether derived from (228), followed by elimination of trimethylsilyl ch10ride.l~~ A somewhat related approach can be used to ring-expand the acyloin condensation products (230) to 1,3-diones (231).’94

Versions of the Cope rearrangement are featured in several ring expansion methods. An approach to the germacrane skeleton (234) involves an extremely facile oxy-Cope rearrangement of the diene (232) followed by thermal electrocyclic ring opening of the intermediate cyclobutene (233).19’ A closely related procedure can be used to prepare the homologous bridgehead olefins (235); subsequent oxidative cleavage of the double bond leads to large mono cycle^.'^" Also of note is the development of a simple route to unsymmetrical 1,2divinylcycloalkanols, the required precursors for many, useful oxy-Cope rearrangements. 19’ A higher homologue (236) of these compounds has been found to undergo a facile vinylogous oxy-Cope rearrangement leading to (237). It is not clear whether this eight-carbon ring expansion occurs via a single [5,5]- or 19’

193 194

19’

196 197

J. J. Cristie, T. E. Varkey, and J. A, Whittle, I. Org. Chem., 1981,46,3590. D. Seebach, T. Weller, G. Protschuk, A. K. Beck, and M. S. Hoekstra, Helu. Chim. Actu, 1981, 64,716;T.Weller, D.Seebach, R. E. Davis, and B. B. Laird, ibid., p. 736. L. Blanco, P. Amice, and J.-M. Conia, Synthesis, 1981, 289; see also W. Kraus, H. Patzelt, H. Sadlo, G. Sawitzki, and G. Schwinger, Liebigs Ann. Chem., 1981,1826; I. Nishiguchi, T. Hirashima, T. Shono, and M. Sasaki, Chem. Lett., 1981,$54. S. L. Schreiber and C. Santini, Tetrahedron Lett., 1981, 22, 4651;see also W. G. Dauben and D. M. Michno, J. Am. Chem. Soc., 1981,103,2284. S. G. Levine and R. L. McDaniel, jun., I.Org. Chem., 1981,46,2199. D.A. Holt, TetrahedronLett., 1981,22, 2243.

General and Synthetic Methods

308

two consecutive [3,3]-sigmatropic rearrangement^.'^^ A tandem Cope-Claisen rearrangement can be used to prepare E,E-cyclodeca-l,6-dienes(Scheme 21).199 The Claisen step is facilitated by using the enolate version of this reaction.

-22

25 ‘C

180°C

H

b

Scheme 21

Improved conditions have been found for the synthesis of cycloalkynones by Eschenmoser fragmentation of bicyclic epoxy-ketones.200 Various cyclodecene derivatives have been prepared from the Diels-Alder adduct of cyclo-octyne and furan-3,4-dicarbo~ylates,~~~ and some simple cyclodecanones have been obtained from 9-decalinols by radical-induced ring cleavage.2o2 The remarkable ‘zip’ reaction, previously used for the ring expansion of N-aminoalkylated lactams, can also be applied to appropriate carbocyclic systems, e.g. (238) + (239).’03

O5

C0,Me

1

C0,Me (239)

(238) 199

’O0

”*

’02

’03

P. A. Wender, S . McN. Sieburth, J. J. Petraitis, and S . K. Singh, Tetrahedron, 1981,37, 3967; P.A.Wender and S. McN. Sieburth, Tetrahedron Lett., 1981,22,2471. S . Raucher, J. E. Burks, jun.,K.-J. Hwang, andD. P. Svedberg,J.Arn. Chem. Soc., 1981,103,1853. C. B. Reese and H. P. Sanders, Synthesis, 1981,276. W.Tochtermann, and P. Rosner, Chem. Ber., 1981,114,3725. T.L.Macdonald and D . E. O’Dell, J. Org. Chem., 1981,46,1501. Y.Nakashita and M. Hesse, Angew. Chem., Int. Ed. Engl., 1981,20, 1021.

309

Saturated Carbocyclic Ring Synthesis

8 Medium and Large Rings 2,Z-Cyclodeca- 1,6-dienes have been prepared from the bis-allylic bromide (240) (Scheme 22) by coupling with dimethyl malonate or the formaldehyde dianion equivalent, TosMIC; yields are around 60%, when high-dilution condiIn related work, it has been shown that 2-(o-bromoalkyl) tions are malonic esters can be cyclized intramolecularly in moderate yield using EtOK and 18-crown-6 in very dilute DMSO s01utions.~~~ M

e

o

2

C

o

CH,(CO,Me),

TosMIC

Me0,C (240) Scheme 22

Useful bis-phosphoranes can be obtained from a,o-dinitriles by an unusual sequence, involving reduction followed by coupling with a phosphorane (Scheme 23); a subsequent Wittig reaction with a dialdehyde leads to isomeric mixtures of cyclic tetraenes in good yield.Z06

Reagents: i, DIBAL; ii, CH,=PPh,; iii, OHC(CH,),CHO

Scheme 23

Intramolecular alkylation of the protected cyanohydrin (24 1)can be effected in good yield using NaN(SiMe,), in THF under moderately dilute A full account has been given of the preparation of biphenyls (242) by intramolecular Ullmann coupling, catalysed by zerovalent nickel complexes.208 This mild method, which has a wide application to many ring sizes containing a wide range of functional groups, has been used to synthesize the natural biphenyl, alnusone. RO

RO (242) 204 205

206

'O'

208

M.S.Frazza and B. W. Roberts, TetrahedronLett., 1981,22,4193. M.A. Casadei, C. Galli, and L. Mandolini, J. Org. Chem., 1981,46,3127. B. BogdanoviC, A. Hullen, S. KonstantinoviC, B. Krawiecka, and R. Mynott, Chem. Ber., 1981, 114,2261. T. Takahashi, T. Nagashima, and J. Tsuji, TetrahedronLett., 1981,22,1359;see also T. Takahashi, H. Ikeda, and J. Tsuji, ibid., p. 1363 and T. Kumagai, F. Ise, T. Uyehara, and T. Kato, .Chem. Lett., 1981,25. M. F. Semmelhack, P. Helquist, L. D. Jones, L. Keller, L. Mendelson, L. S. Ryono, J. G. Smith, and R. D. Stauffer, J. A m . Chem. SOC.,1981,103,6460.

310

General and Synthetic Methods

9 Spiro-ring Compounds A rather unusual synthesis of spiro[2.3]hexanols (244) consists of treatment of the tertiary propargylic alcohols (243, R1,R2= Me, Et, or Ph) with the Simmons-Smith reagent.209

The spiro[4S]decane (246) has been prepared by a novel reductive cleavage (Li-NH3) of the chloromethylcyclobutane (245), which in turn is obtained by an intramolecular [2 + 2]photoadditi0n.~~'This type of cleavage can also be effected by a Norrish Type 2 fragrnentation2l1 An alternative and potentially very useful entry into the spiro[4S]decane system involves an intramolecular decarboxylative alkylation, e.g. (247) -+ (248).212This method, which can be applied to other cyclic and spiro-cyclic systems, is very efficient and has the additional advantage of relatively easily prepared starting materials. Other approaches to this spiro-ring system feature an intramolecular acylation of a vinyl silane (249),213and an acid-catalysed fragmentation-cyclization sequence (Scheme 24).214

Scheme 24 209 'lo

'I1 212 'I3

'14

C. Dumont, M. Zoukal, and M. Vidal, Tetrahedron Lett., 1981, 22, 5267. W. Oppolzer, L. Gorrichon, and T. C. G. Bird, Helu. Chim. Acta, 1981,64, 186. D . D . K. Manh, J, Ecoto, M. Fetizon, H. Colin, and>.-C. Diez-Masa, J. Chem. SOC., Chem. Commun., 1981,953. R. G. Eilerman and B. J. Wallis, J. Chem. SOC.,Chem. Commun., 1981, 30. S. D . Burke, C. W. Murtiashaw, M. S. Dike, S. M. S. Strickland, and J. 0. Saunders, J. Org. Chem., 1981,46, 2400. A. Murai, S. Sato, and T. Masamune, Tetrahedron Lett., 1981, 22, 1033; J. Chem. SOC.,Chem. Commun., 1981,904.

311

Saturated C arboc y c lic Ring S y n thesis

An intramolecular cycloaddition of an a-diazoketone, a reaction which has featured prominently this year,58.71.92,93 forms the key step, (250) + (251), in a synthesis of s ~ l a v e t i v o n e By . ~ ~contrast, ~ intramolecular cycloadditions of carbenoids derived from a-diazoketones have been used in total synthesis of (&)-a-chamigreneand (-)-acorenone B; in the latter case, (+)-limonene was used as the chiral precursor.216 OH

f

COCHNz

Q 0

Spir0[4S]decanes and spiro[SS]undecanes (253) can be prepared in a stereoselective manner from enol lactones (252) by reaction with ~ n a m i n e s . ~ ”

(252) ( n

=

1 or 2)

0

215*C.Iwata, T. Fusaka, T. Fujiwara, K. Tomita, and M. Yarnada, J . Chem. SOC.,Chem. Commun.,

1981,463. 216

217

J. F. Ruppert and J. D. White, J. A m . Chem. SOC., 1981, 103, 1808; J. D. White, J. F. Ruppert, M. A . Avery, S. Torii, and J. Nokami, ibid., p. 1813. J. Ficini, G. Revial, and J. P. GenCt, Tetrahedron Lett., 1981, 22, 629, 633.

Saturated Heterocyclic Ring Synthesis BY R.C.BROWN

1 Oxygen-containing Heterocycles 0xirans.-Numerous syntheses of oxirans have appeared this year. Examples include the production of the heterocycle as an end product per se, and as a useful intermediate, especially for natural product synthesis. A total of six diastereomeric tri-oxirans of bicyclo[4.2.0]octa-2,4,7-triene are possible and the research group led by Adam has reported the preparation of three of them [i.e. (2)-(4)]. The starting material, endoperoxide (l),was prepared by addition of singlet oxygen to the triene, as reported last year. The unexpected endo-attack leading to (2) was explained on stereoelectronic grounds. Steric requirements also preclude endo- attack on (1)and, therefore, the exo- epoxide is obtained on the 4-membered ring.’ Other strategies need to be developed for the synthesis of the remaining diastereomers (Scheme 1). 0-?

1

iv

Reagents: i,

1.

lo2; ii, A, benzene; iii, m-CIC,H,CO,H;

Vii,

iv, m-CIC,H,CO,H-NaHCO,;

v, A; vi, Ph,P;

m- CIC6H.,COpH-NaHCO3

Scheme 1 W. Adam, 0. Cueto, 0. D e Lucchi, K. Peters, E.-M. Peters, and H. G . von Schnering, Angew. Chem., Int. Ed. En& 1981,20, 580.

3 12

313

Saturated He terocy c lic R ing Synthesis

Sharpless and co-workers* have utilized their recently discovered method for epoxidation of olefinic alcohols in a highly enantioselective manner to prepare the chiral epoxy-alcohols (3,(6), and (7), key intermediates for the synthesis of methymycin, erythromycin, and leukotriene C- 1, respectively. The first stages in these reactions were described last year’ but the work-up procedures have now been modified to avoid problems with water-soluble products.

The first examples of epoxidation of olefins using oxaziridines have been d e ~ c r i b e dby , ~ heating a two-fold excess of the alkene with 2-arenesulphonyl-3aryloxaziridines (8) -+ (9). This particular reagent and method of aprotic oxygen transfer has been used before for the preparation of sulphoxides and amine oxides from sulphides and amines respectively, but olefins react considerably slower.

0 ArS02-dl..Ar

+

-+

)&

+ArSO,N=CHAr

(9)

A useful method’ for the direct epoxidation of carbonyl compounds involves reaction of an unstabilized arsonium ylide (10) with an aldehyde or ketone, analogous to the reactions of sulphur ylides. Unlike previous methods, the reaction of (10) to form (11) proceeds with a high degree of stereochemical control, and most aldehydes react cleanly giving trans- oxirans. Drawbacks to the method are: (i) the toxicity of arsenic, and (ii) the fact that since Ph3As is C -HO

H

+

base

d

less nucleophilic than the phosphorus analogue, a simple synthesis of the necessary arsonium salts is difficult. Along similar lines, Japanese workers6 have investigated the use of selenium ylides. The reaction of (12) with carbonyl

’

B. E. Rossiter, T. Katsuki, and K. B. Sharpless, J. A m . Chem. SOC., 1981,103,464. T.Katsuki and K. B. Sharpless, J. Am. Chem. Soc., 1980,102,5974. F.A.Davis, N. F. Abdul-Malik, S. B. Awad, and M. E. Harakal, Tetruhedron Left., 1981,22,917. W. C. Still and V. J. Novack, J. Am. Chem. SOC.,1981,103,1283. K. Takaki, M. Yasamura, and K. Negoro, Angew. Chem., Inf. Ed. Engl., 1981,20,671.

General and Synthetic Methods

3 14

compounds gives oxirans (13j in high yields, but the ylide has to be generated in situ owing to its instability. Me

0

PhSe / +

\

CH,-

+

+

"9+

PhSeMe

R2

RlKRz

0xetans.-Relatively few examples of new chemistry involving this ring system have appeared, but Picard et al.7 have improved the usual two-step method of synthesis from 1,3-glycols, by tosylation and then base-induced cyclization, to a one-pot procedure. Their method involves the generation of a mono-lithium salt from the 1,3-glycol, followed by tosylation, and then addition of a second mole of butyl-lithium to effect cyclization [e.g. (14) + (15)]. i, BuLi

R3

R4

R5

(14)

ii, TsCl iii, BuLi

' R ZR3

R4

(15)

Oxetes have been postulated as reactive intermediates in many types of reactions and in most cases are unstable, although fluorine-substituted derivatives are exceptions. 3-Phenyloxete has been shown' to have more stability. The alcohol (16) can be prepared by photolysis of a-methoxy acetophenone, then converted to the corresponding tosylate (17). Base treatment of (17) gave the 3-phenyloxete (18),which in air slowly decomposed to the unsaturated aldehyde. The tosylation route was unsuccessful for the synthesis of the parent compound (20), which can be obtained via the selenoxide (19).

01

Five-membered Rings.-Examples of this group of compounds occur widely in natural products, and their syntheses have occupied chemists for many years. A useful synthesis of 2,2-disubstituted 3(2H)-furanones (22) has been published which is based on the reaction of ketones with the lithium salt of propynal

' P. Picard, D. Leclercq, J.-P. Bats, and J. Moulines, Synthesis, 1981, 550. L. E. Friedrich and P. Y.-S. Lam, J. Org. Chem., 1981,46, 306.

Saturated Heterocye fie Ring Synthesis '>O

R

315

+ LiCrC-CH(OEt),

diethylacetal (21), followed by acid work-up.' Hydration of the triple bond and deacetalization occur spontaneously at the acidification stage, and the tertiary hydroxyl group is not lost by dehydration. Williams et a1.I' have produced acetylenic alcohols by a similar route (23) -+ (24) and obtained good yields of furanones by treatment with BF,.Et20 in ethanol containing a trace of HgO and trichloroacetic acid. The authors speculate on Hg2+ ion assistance €or hydration of the triple bond.

The well known route to furanones from acetylenic diols (25) has been improved," by incorporation of a degree of selectivity for hydration of the triple bond, The two routes developed are outlined below. Route A involves monoacetylation of the least-hindered hydroxyl group in (25), Ag' ion-catalysed cyclization, and acetyl migration followed by hydrolysis to give (26). The furanone (27) was produced directly using Hg2'-polymer catalysis in which

1 (26)

l1

T. Hiyama, M. Shinoda, H. Saimoto, and H. Nozaki, Heterocycles, 1981, 15, 263. D. R. Williams, A. Abbaspour, and R. M. Jacobson, Tetrahedron Lett., 1981, 22, 3565. H. Saimoto, T. Hiyama, and H. Nozaki, J. A m . Chem. SOC.,1981, 103,4975.

General and Synthetic Methods

316

work-up follows the very simple procedure associated with reactions involving polymeric reagents. As part of a programme directed towards the synthesis of the macrocyclic diterpene Jatrophone, Smith's have developed the route shown in Scheme 2, for the synthesis of the furanone (28).

Reagents: i, LDA; ii, RCHO; iii, oxidation; iv, Hi

Scheme 2

3-Methylenetetrahydrofuran-2-ones (e.g. 32) have been the subject of much synthetic activity in recent years. B a r ~ e t t has ' ~ ~shown that the Shapiro reaction may be used to prepare these useful compounds by a one-pot process. The well documented severe limitations of the Shapiro reaction have been partially overcome by structural modifications. The dianion (29) reacts with ketones forming a new dianion that was converted to the trianion (30), which on warming evolves nitrogen to give (31) and that, upon treatment with CO, followed by N-TS

- q3R4 N-TS

N-TS

R

R ' N'

5 N' 4

RZ0-

RZ

3

o-R4

R2

(32)

(31)

acidic work-up, provides the required compounds. The method works well, has been applied to several aldehydes and ketones, and may be adapted for the preparation of various ring sizes. In a similar fashion 1-1ithio-oxy- l-lithio-aminoallene derivatives (33) have been converted to 3-methylene tetrahydrofuran-2ones (34).13b

R2CH=C=C,

/

N-R' (33) l2

l3

R2

do

Me0

0-

+

I

(34)

( a ) A . B. Smith, 111, M. A. Guaciaro, S. R. Schow, P. M. Wovkulich, B. H. Toder. and T. W. Hall, J. A m . Chem. SOC.,1981, 103, 219; ( b ) A. B. Smith, 111, P. A . Levenberg, P. J. Jerris, R. M. Scarborough, jun., and P. M. Wovkulich, J. A m . Chem. SOC.,1981, 103, 1501. ( a ) R. M. Adlington and A . G. M. Barrett, J. Chem. SOC., Perkin Trans. 1, 1981, 2848; (6) R. M. Adlington and A. G . M. Barrett, J. Chem. SOC.,Chem. Commun., 1981, 65.

317

Saturated Heterocyclic Ring Synthesis

5-Substituted furanones (37) have been ~ b t a i n e d by ' ~ the reaction of E-3(phenylthio)prop-2-enoic acid and its 2-methyl homologue with aldehydes and ketones in a facile one-step synthesis. The reaction, which is carried out in THF, provides good yields and the dianion (36), which is stable at room temperature, reacts with acetic anhydride to give the hydroxyfuranone (38). The mono-anion (35) of the corresponding ester does not react with ketones. PhS? / C0,Me

Li

(35)

r

!ICH0-

1 (37) A synthesis of 2,s-disubstituted tetrahydrofurans, which may be of interest

to those concerned with ionophore antibiotics, has been developed using the anions of crotonaldimines (39)." These anions normally alkylate at the aposition but it has been found that y-alkylation can be achieved if steric bulk is sufficient and the correct solvent, HMPT, is used. These intermediates then cyclize to the corresponding tetrahydrofuran derivatives (40), accompanied by an equal amount of a-alkylated product.

By analogy with some earlier reports, the reaction of unactivated imines bearing cinnamoyl groups with BuLi has been investigated.I6Benzofurans were l4 l6

Y. Takahashi, H. Hagiwara, H. Uda, and H. Kosugi, Heterocycles, 1981,15, 225. K. Takabe, N. Nagaoka, T. Endo, and T. Katagiri, Chem. Ind., 1981,540. 0. Tsuge, K. Ueno, and K. Oe, Chem. Len., 1981,135.

318

General and Synthetic Methods

obtained as a mixture of products in low yield from (41).The pyrrolo-benzopyran derivative (42) was formed via an aza-ally1 anion, whereas (43) and (44) are derived from the ally1 anion. The corresponding acetylenic imine (45) gave a good yield of the benzoxepin (46).

+

i, BuLi ii, H,O

(43)

(44)

The synthesis of some naturally occurring fused tetrahydrofurans has been elaborated" using the well-known thallium reagent. Compounds of this type (47) exhibit a number of inhibitory actions and are prepared in reasonable yield by oxidative dimerization of p- alkoxycinnamic acids.

Six-memberedRings.-Olah and his colleagues have reported the facile preparation of several cyclic ethers from a,u-diols, and the yields are good for rings containing up to 8 members.'* Cyclization (48) + (49) is achieved using Nafion H resin, a solid superacidic perfluorinated resin sulphonic acid. The alkylene chain may be substituted, and benzo-analogues are available using an extension l7

E. C. Taylor, J. G. Andrade, G. J. H. Rall, K. Steliou, G. E. Jagdmann, jun., and A. McKillop, J. Org. Chem., 1981,46,3078. G.A. Olah, A. P. Fung, and R. Malhotra, Synthesis, 1981,474.

Saturated Heterocyclic Ring Synthesis

319

of the Parham cyclization. l9 By careful variation of reaction temperature the cyclization (50) -+ (51) was achieved where n = 2, 3,4, and 5 . ,CH,OH (CH,)"

- p - bO\ F H 2 \

(CH2)"

\

\

CH20H (48)n = 2 , 3 , 4 or 5 0 -(C

R'

2).

-Br

Br

CH2 (49)

BuLi

((342)"

R'

( 5 1)

(50)

The pyran ring features extensively in natural product chemistry, and methods for its formation are legion; only a few further examples and modifications will be described here. 5,6-Dihydropyran-3(4H)-ones(53) are good precursors of 3-hydroxy-4H- pyran-4-ones which in turn are potent flavouring materials. Sat0 . shown ~ ~ that they are readily prepared from 3-methyleneheptan-2,6et ~ 1have dione, according to Scheme 3. The overall yield by this circuitous route was quite good, but when a more straightforward cyclization was attempted only furans of type (52) were obtained.

1

iii

O

D

M

e

y-Jye y-y] fi

OH

0

(53) Reagents: i, PPh,; ii, HOCH,CH,OH-H'-toluene;

iii, NaBH,; iv, p-TsOH-(MeO),CH-MeOH; v,

0 3

Scheme 3

(52)

A novel method21a for introduction of isoprenyl groups into phenols has been described, and the method has been reported in several publications.21bsc Phenols l9 2o

C. K. Bradsher and D. C . Reames, J. Org. Chem., 1981,46, 1384. K. Sato, S. Inoue, T. Tanami, and M. Ohasi, J. Chem. SOC.,Perkin Trans. 1, 1981, 1015. ( a )V. K. Ahluwalia and K. K. Arora, Tetrahedron, 1981, 37, 1437; (6) V. K. Ahluwalia, K. K. Arora, and R. S. Jolly, Synthesis, 1981, 527; (c) V. K. Ahluwalia, F. A . Ghazanfari, and K. K. Arora, Synthesis, 1981, 526.

320

General and Synthetic Methods

and isoprene react directly in the presence of a catalytic amount of phosphoric acid to give good yields of dimethyldihydrobenzopyrans [e.g. (54) + ( 5 5 ) + (56)].Good yields of dihydropyran-2-ones may be had by a TiC1,-catalysed Knoevenagel reaction of p- keto esters.22

Under the influence of LDA 5-formyl-1,3,6-trimethyluracil forms a stabilized salt which can participate in cycloaddition reactions. Hence, with aldehydes, pyrano[4,3-d ]pyrimidines are obtained,23with high regio-and stereo-specificity. Since the Diels-Alder reaction occurs in a ‘disrotatory’manner (thermal) R and OH are cis to each other in (57).

Isochroman-1,4-dione is an extremely interesting and potentially useful heterocycle, but exploration of its chemistry has been limited owing to lack of a suitable method for the preparation of substituted examples [e.g. (58)]. A method utilizing substituted phthalic anhydrides as a starting point 24 could now open the way for more interesting reactions.

Me 0

22

23 24

G. Falsone and B. Spur, Liebigs Ann. Chem., 1981,565. K. Hirota, T. Asao, I. Sugiyama, and S. Senda, Heterocycles, 1981,16, 289. M.Ishikawa and Y. Eguchi. Heterocycles, 1981, 16.25.

321

Saturated Heterocyclic Ring Synthesis

Several syntheses of di- and tri-oxans have appeared, but limitations of space permit only the more synthetically useful to be described here. The Prins reaction for 1,3-dioxan formation generally only works well with formaldehyde but now a general method utilizing the ubiquitous cation-exchange resin is a ~ a i l a b l e . ~ ~ Various aliphatic and aromatic aldehydes may be used and yields are good [e.g. (59)]. Long reaction times are involved however, and strongly acidic sulphonic acid resins give the best results.

An intermediate of potential use in the synthesis of macrocyclic antibiotics has been obtained26 starting from allylic and homo-allylic alcohols. The anions generated with BuLi react with carbon dioxide to give the transient anion (60) which cyclizes in the presence of iodine. Functionalization of the double bond is highly regioselective and the equatorial stereochemistry of the 6-membered example (61, n = 1)has been established by n.m.r. spectroscopy.

(60)

(61) n

= 0 or

1

Bloodworth et uL2’ have extended their peroxymercuration method with dienes to cyclic analogues in order to prepare peroxides (62), but substantial amounts of bicyclic ethers are also formed. Finally, a new method has been added to the limited number available for trioxan (63) synthesis, which involves cyclization of a-hydroxyhydroperoxidesn2’ The method is widely applicable using easily prepared reagents.

2 Nitrogen-containing Heterocycles

Three-membered Rings.-Because of the limited number of methods available to the synthetic chemist for the preparation of aziridine rings, additions to the R. E. Gharbi. M. Delmas, and A. Gaset, Synthesis, 1981, 361. G. Cardillo, M. Orena, G. Porzi, and S. Sandri, J. Chem. SOC.,Chem. Commun., 1981,465. ” A. J. Bloodworth, J. A. Khan, and M. E. Loveitt, J. Chem. SOC., Perkin Trans. l . , 1981,621. M. Miura, M. Nojima, and S. Kusabayashi, J. Chem. SOC.,Chem. Commun., 1981, 581.

” 26

General and Synthetic Methods

322

armoury are always welcome. Hence the oxidation of 2,4-dinitrobenzenesulphenamide with lead tetra-acetate in the presence of electron-rich alkenes gives the corresponding a z i r i d i n e ~ The . ~ ~ nitrene does not react with deactivated double bonds and of a number of aromatic sulphenamides tried only nitrosubstituted examples gave successful aziridine formation [e.g. (64)].

(641

Schustov and c o - ~ o r k e r have s ~ ~ discovered that the accessibility of substituted diaziridines depends upon the conformational mobility of carbonyl groups in the substituents. They have developed two useful routes (Scheme 4) to these interesting molecules which will supersede the previous methods. The compounds obtained are fairly stable and are amenable to derivatization. RCH,O,C

RCH,O,C

>=",

RCH20?C

6 OTs

-0,c

RCH20,C RCH,O,C

RCH,O,C

H

-0,c

N

Reagents: i, RCH,ONH,-CH,CN; ii, KOH-MeOH; iii, Bu'OCI-CH,CN

Scheme 4

Four-membered Rings.-This Section will include examples of p- lactam synthesis since these molecules serve as interesting intermediates for the preparation of antibiotics, both natural and synthetic, and as fascinating molecules in their own right. Methylene transfer for conversion of aziridines into azetidines has been little explored. The reaction of dimethyloxosulphonium methylide with 29

R. S. Atkinson and B. D. Judkins, J. Chem. SOC.,Perkin Trans. I , 1981,2615.

30

G.V.Schustov, N. B. Tavakalyan, and R. G. Kostyanovsky, A n g e w . Chem., Znt. Ed. Engl., 1981, 20,200.

323

Saturated Heterocyclic Ring Synthesis

certain N- arylsulphonyl aziridines leads to useful yields of the target molecules (66).31Variation of the aryl group confers susceptibility to nucleophiles, and hence easy removal of the group from nitrogen. The intermediacy of azomethine ylides (67) in this reaction was ruled out by the authors on the basis of the failure of the aziridines to react with dimethylacetylene dicarboxylate. S0,Ar I

&

Ph

0

-a’ t

S0,Ar

S02Ar

I

N

Me2S - CH2

/+\

Ph (66)

CH - - Ph (67)

A new procedure for the production of azetidine which promises to improve its commercial availability has now been developed.32The procedure incorporates the familiar Staudinger reaction for preparation of the alcohol (68), (Scheme 5).

Reagents: i, NaN,-AcOH; ii, NaBH,; iii,

R,P; iv, A Scheme 5

Two papers have appeared describing the cycloaddition reactions of ketens which, ultimately, lead to p-lactams. In the diphenyl keten is generated in situ, and by reaction with Schiff’sbases affords fair yields of N-alkylazetidinones (69). In the second example,34 [2 + 2lcycloaddition of iminothiadiazoles (70) with ketenes gave spiro-substituted /3- lactams (7 l), which were readily desulphurized with Raney nickel or by reflux with DMF.

31

32

U. K. Nadir and V. K. Koul, J. Chem. SOC.,Chem. Commun., 1981,417. J. Szmuszkovicz, M. P. Kane, L. G . Laurian, C. G . Chidester, and T. A . Scahill, J. Org. Chem., 1981,46,3562.

33 34

K. N. Mehrotra and S. B. Singh, Bull. Chem. SOC.Jpn., 1981,54, 1838. I. Yamamoto, I. Abe, M. Nozawa, J . Motoyoshiya, and H. Gotoh, Synthesis, 1981, 813.

324

General and Synthetic Methods

Some work published by Barrett and his group,35related to that mentioned earlier, describes how 3-methylene-azetidin-2-ones (73) may be formed from 1-1ithio-oxy-1-lithio-aminoallene derivatives (72) by reaction with aldehydes followed by manipulation as shown in Scheme 6.

/

H,C=C=C

\

N-R'

.I, .. II

iii, iv, ii, v

B: R'

0

0-

(72)

(73)

Reagents: i, R'CHO; ii, H,O; iii, BuLi; iv, TsCl; v, NaH

Scheme 6

Ring expansion of smaller heterocycles or ring contraction of larger ones is an attractive method of p-lactam formation, owing to the ready accessibility of starting materials. One publication concerning the former36 adds another example to the many fascinating metal complex induced ring-opening reactions of azirines. The Pdo-catalysed carbonylation (74) + ( 7 9 , possibly uiu a pathway involving 7r-ally1 complexes has been disclosed. Thermal or photochemical ring contractions are powerful methods for the formation of 4-membered rings. Me

(74)

+ co

(75)

Brennan for example, has shown that irradiation of 4-methyl-2-pyridone at 3 10 nm gives rise to the azabicyclohexane derivative (76), further manipulation of which led to 6-lactams (77).37Similarly, the readily prepared isoxazolidines (78) ring contract under thermal or photochemical stimulation to give the isomeric p-lactams (79) and (go), re~pectively.~~

"

R. M. Adlington, A. G . M. Barrett, P. Quayle, and A. Walker, J. Chem. Soc., Chem. Commun.,

1981,404. H. Alper, C. P. Perern, and F. R. Ahmed, J. A m . Chem. Soc., 1981,103,1289. " J. Brennan, J. Chem. Soc., Chem. Commun., 1981,880. A. Padwa, K. F. Koehler, and A. Rodriguez, J. A m . Chem. Soc., 1981,103,4974.

36

Saturated Heterocyclic Ring Synthesis

325

Y

Bu' I

P h y N 'o

lA (80)

Finally, thermolysis or photolysis of pyrrolinones bearing an azido group3' produces mono- or bi-cyclic P-lactams depending upon the substituents (i.e. 81 + 82; 83 -+ 84). This new synthetic method does have its limitations in that although it is general in the monocyclic case, it does not work where n = 0 in (83),leading instead to open-chain products. 0 R

OEt

CN

Two other routes that avoid the cyclization of open-chain precursors are now available for p- lactam construction. Readily available azetidine-2-carboxylic (85) + (86), and the recently reported acids have been modified as synthesis of 'stable' 2,3-dihydroazete-l-oxideshas led to investigations of their isomerism to p-lactams. The effective method seems to be treatment with lead i. LDA iii, H20

HOzC (85)

R

R (86)

tetra-acetate in benzene41 as shown in (87) + (88) since treatment with base causes ring expansion to the isoxazolidines (89) and reaction with acid causes ring opening. The attraction of this method lies in the stereochemistry of the products. 39

H. W. Moore, L. Hernandez, jun., D. M. Kunert, F. Mercer, and A. Sing, I. A m . G e m . SOC.,

*'

H . H. Wasserman, B. H. Lipshutz, A. W. Tremper, and J. S. Wu, I. Org. Chem., 1981,46,2991. M. L. M. Pennings and D. N. Reinhoudt, Tetrahedron Lett., 1981,22, 1153.

1981,103,1769.

General and Synthetic Methods

326

k%'

+ p-

G--Me

Pb(OAc),

Ph

CONEtz

Ph

CONEt, (89)

CONEtz

Ph

A large number of papers have appeared concerned with the formation of

p- lactams from readily available open-chain precursors, using inexpensive reagents for the cyclization processes. Activation of phenoxyacetic acid (90) with cyanuric chloride to give (91) and protection of the N-terminal of aminoacids with p- dicarbonyl compounds followed by reaction with imines [i.e. (92) + (93)] for example may be carried out on a large scale, cheaply and without hazard, in a stereospecific PhO

W

Ph

(93)

p- Amino-acids have been cyclized under phase-transfer c ~ n d i t i o n sconven,~~ tional base treatment,45and using the Ph,P-(pyS), reagent.46Similarly, y-amidoor amino-alcohols have been cyclized using Ph3P-NEt3,47 or Ph3P-DEAD.48 Each method claims one or more advantages over existing routes and whether it be ease of reaction, expense, availability of starting materials, stereoselectivity, compatibility of other substituents or whatever, space does not permit a detailed individual discussion. Rather, it remains for each researcher to make his own conclusion from the above publications and three other isolated example^.^^-^'

"t M. S. Manhas, A. K. Bose, and M. S. Khajavi, Synthesis, 1981,209. 43

"" 45 46

A. K. Bose, M. S. Manhas, J. M. Van Der Veen, S. G. Amin, I. F. Fernandez, K. Gala, R. Gruska, J. C. Kapur, M. S. Khajavi, J. Kreder, L. Mukkavilli, B. Ram, M. Sugiura, and J. E. Vincent, Tetrahedron, 1981, 37, 2321. Y. Watanabe and T. Mukaiyama, Chem. Lett., 1981,443. K. Ikeda, Y. Terao, and M. Sekiya, Chem. Pharm. Bull. (Jpn.), 1981,29, 1747. S. Kobayashi, T. Tirnori, T. Izawa, and M. Ohno, J. Am. Chem. Soc., 1981,103,2406. P. G. Mattingly and M. J. Miller, J. Org. Chem., 1981,46, 1557. A. K. Bose, D. P. Sahu, and M. S. Manhas, J. Org. Chem., 1981, 46, 1229. H. Aoyama, M. Sakamoto, and Y. Omote, J. Chem. SOC., Perkin Trans. 1, 1981, 1357. H. Takahata, V. Ohnishi, H. Takehara, K. Tsuritani, and T. Yamazaki, Chem. Pharm. Bull. (Jpn.), 1981,29,1063. T. Okawara, Y. Noguchi, T. Matsuda, and M. Furukawa, Chem. Lett., 1981,185.

"' 49

51

Saturated Heterocyclic Ring Synthesis

327

Five-membered Rings.-The occurrence of pyrroles, pyrrolines, and pyrrolidines is widespread throughout the field of natural products, and they are also useful precursors to many other interesting ring systems. Hence, the large number of new synthetic methods and modifications of existing molecules precludes a detailed discussion of them all. A few examples will illustrate the general trend this year. Cycloaddition of azomethine ylides (94)with alkeness2 provides adducts that can be desulphurized to give pyrrolidines (95), and N- allyldiazoacetamides, which are unstable at 20 "C, undergo intramolecular 1,3-dipolar c y ~ l o a d d i t i o n ~ ~ to give cis- hexahydrop~rrolo[3,4-c]pyrazoles(97). It was found that the amide derivatives (96, R' = C02Et) react faster but that the isostere (98)fails to react.

A

QCOX H (95) (X = OEt or Me, A

=

electron withdrawing group)

Stamm and his c o - w ~ r k e r shave ~ ~ shown that pyrrolidones can be. obtained from aziridines by reaction with sodium enolates of simple esters, and if R1or R2 = H in (99),then further amidoethylation can result.

'kR2

+EN-COY

-0 OAlk (99)

-+

I COY

H

H

G . A. Kraus and J. 0. Nagy, Tetrahedron Lett., 1981,22, 2727. H. Sturm, K.-H. Ongania, J. J. Daly, and W. Klotzer, Chem. Ber., 1981, 114, 190. '' H. Stamm, A. Woderer, and W. Wiesert, Chem. Ber., 1981, 114, 32; H. Stamm and V. Gailius, Chem. Ber., 1981, 114, 3599. 52

53

328

General and Synthetic Methods

have elaborated upon the recently reported conSome Japanese trolled Dieckmann cyclization of disymmetric dithio-esters; mixtures were not obtained, and hence this method should have wide synthetic utility, (100) -b (101). 0

f-‘COSEt X-CO

NaH (1.3 eq)

,Et

THF

(101)

(100)

X

= S or NC0,Et

The susceptibility of the amide bond of azetidinones to nucleophiles has been utilized for the synthesis of many heterocycles. Pyrrolidinones (103) may be obtained by treatment of the epoxide (102) with amine~,’~ whereas a paper by Crockett et aL5’ draws attention to the long known but little used preparation of imides [e.g. (104)] by heating di-acids or anhydrides with urea. It is claimed that the reaction is easily managed on a large scale and that yields are often better than those of other procedures.

(102) U

-

-YNH

[;oANp]

Ph

(103)

Two reactions which should lend themselves to the synthesis of pyrrolidines with a wide variety of substituents have been published this year. In the first method Blake and co-w~rkers’~ have improved the versatility of a well known pyrrolidine synthesis from arylcyclopropyl ketones. By reaction with formamide in the presence of MgCl,, alkylcyclopropyl ketones (105) give good yields of pyrrolidines (106). The second method details the reaction of Schiff’s bases of trimethylsilyl methylamine with acyl halides in the presence of alkenes and

x

R

- x -mR R

CN

+ R’MgX

COR’

MeNHCHO MgCl,

(105)

N R’ Me (106)

Y. Yamada, T. Ishii, M. Kimara, and K. Hosaka, TetrahedronLett.. 1981,22,1353. S. Kano, S. Shibuya, and T. Ebata, J. Heterocycl. Chem., 1981,18,1239. ” G.C. Crockett, B. J. Swanson, D. R. Anderson, and T. H. Koch, Synrh. Commun., 1981,11,447. K. W. Blake, I. Gillies, and R. C. Denney, J. Chem. SOC.,Perkin Trans. I , 1981,700.

” 56

329

Saturated Heterocyclic Ring Synthesis

alkynes to give (107) and (108), respecti~ely.~’ In the absence of these reagents imidazolidines (109) are formed. Cl

Me,SiCH,N=CHPh

+ RCOCl

1

/

YCH=CHCO,Me

YCEEC-CO~MC

Y

C0,Me

ytjp.Me N Ph COR

COR (108)

(107)

Me, SiCH

2-jPh

N I COPh (109)

Ph

Flitsch and Wernsmann6’ have described the synthesis of one of the more simple members of the vast array of pyrrolizidine alkaloids, and have shown that the reaction of the phosphonium salt (110) with imides is a general one, e.g. formation of (111)-(113). Reinhoudt and his group61 have obtained the pyrrolizine (114) from enamines by reaction with DMAD, by the simple

CN. 9/ C0,Et

@ 0

(111)

Et0,C

X

YPh,

BF 4 (110)

w

C0,Et

0 (112)

59

6o 61

<

!oOo

C0,Et

0 N I CHO

(113)

K. Achiwa and M. Sekiya, Chem. Lett., 1981, 1213. W.Flitsch and P. Wernsmann, Tetrahedron Lett., 1981,22,719. W.Verboom, G. W. Visser, W. P. Trompenaars, D. N. Reinhoudt, S. Harkema, and G. J. Van Hummel, Tetrahedron, 1981,37,3525.

General and Synthetic Methods

330

expedient of using a polar solvent. Similarly, the synthesis of indole and its derivatives has been the subject of considerable synthetic effort this year. K a m e t a d 2 has extended the work reported earlier concerning the intramolecular nucleophilic aromatic substitution of aryl ethylamines to give indolines [e.g. (117)]. The reaction, which is thought to proceed via the intermediate (116) has the advantage that it can be used to make oxindoles and indoles with electron-donating groups, and also that the starting materials (115) are easily prepared.

" ' m NBr R 3 R2 (115)

[ R Y ! N - R ]

Ry!T R3

Br ......Cu (116)

(117)

A new route to isoindolines and isoindolinones has been developed by Bradsher's g r o ~ p . It~ is~ known ~ , ~ that in the presence of organo-lithium reagents, N-substituted imines without a-hydrogens undergo simple addition to the imine bond. By using aryl-lithiums having an electrophilic centre adjacent to the site of lithiation cyclization occurs (118) + (119). Slight variations in starting materials can lead to isoindolinones (120) or isobenzofuran derivatives (121).

62

63

T. Kametani, T. Ohsawa, and M. Ihara, J. Chem. SOC.,Perkin Trans. 1, 1981,290. ( a ) C. K. Bradsher and D. A. Hunt, J. Org. Chem., 1981,46, 327; (6)W.E. Parham, C. K. Bradsher, and D. C. Reames, J. Org. Chem., 1981,46,4804.

Saturated Heterocyclic Ring Synthesis

331

The Diels-Alder reaction of 1-azadienes has been used to construct indolizines and homologous Hence, acyl azadienes (122), prepared by thermal elimination of acetic acid from N-acyl-0- acetyl-N- allylhydroxylamines, undergo intramolecular Diels-Alder cyclization to form indolizidine (123) and related ring systems. A closely related paper6** describes the synthesis of the indolizine ring system (124) by utilization of an imino Diels-Alder cyclization.

L

0

0 (122)

OAc

Katritzky et ~ 1 have . corrected ~ ~ an earlier report concerning the reaction of pyridinium carbamoyl methylide [generated from the salt (125) with base] with chalcone which leads to indolizine derivatives (126) rather than pyridones (127). There are many such reactions known, although dehydrogenation to indolizines usually occurs. Ph

H

CONH, Ph

Five-membered Rings with two or more Nitrogen Atoms.-Conventional syntheses of imidazolines (128) normally require nitriles or imino-ethers as starting materials. Only in selected cases can ethylene diamines and acids or esters lead to the required products. The use of thiols and nitriles66 goes some way to circumventing the problems, but under the conditions described by Neef and c o - w ~ r k e r s a, ~wide ~ range of esters is readily transformed to imidazolines and their benzo-analogues (Scheme 7). ( a )Y.-S. Cheng, F. W. Fowler, and A. T. Lupo, jun., J. A m . Chem. SOC.,1981,103, 2090; ( b ) N. A. Khatri, H. F. Schmitthenner, J. Shringarpure, and S. M. Weinreb, J. A m . Chem. SOC.,1981, 103,6387. A. R. Katritzky, N. E. Grzeskowiak, and J. Alvarez-Bailla, J. Chem. SOC.,Perkin Trans. 1 , 1981, 1181. G. Levesque, J.-C. Gressier, and M. Proust, Synthesis, 1981, 963. G. Neef, U. Eder, and G , Sauer, J. Org Chem., 1981,46, 2824.

General and Synthetic Methods

332

i

R1

S-R2

R1-C, /p

y-z R

OR

H Scheme 7

Carbodi-imides can effect the 1,2- or 1,3-ring opening of amino-azirines, depending upon the nature of substituents, with the subsequent formation of zwitterions (129). These intermediates can be usefully converted into a variety of imidazolines6' by reduction, thiolysis, hydrolysis, and aminolysis (Scheme 8). R'N=C=NR~

+

--*

\

NMez R 2

J

NR

0 S Scheme 8 68

E. Schaumann and S. Grabley, Liebigs Ann. Chem., 1981,290.

Saturated Heterocyclic Ring Synthesis

333

In what the authors suggest might be the first example of a [l + 3ldipolar cycloaddition, mesoionic-4-thiazolones (130) give imidazolinones (132) upon reaction with ethyl azidoformate, in a multistep process which may proceed via the strained bicycle (131).69 A similar loss of sulphur occurred during an attempted synthesis of the thienodiazepinone (133), the isolated product being the pyrrolo[ 1,242 ]imidaz-2(3H)-one derivative (134).” Ar

l$i2

+ N3C0,Et

Ph

(130)

L

C0,Et (131)

A

&

“-6”’

(133)

(134)

Two papers from G n i ~ h t e l ” “ ~ demonstrate ~ the utility of oximes of aaminoketones [e.g. (135)] for preparing small heterocycles [e.g. (136)-(138)]. In both examples imidazoline N-oxides can be formed if the anti-forms of the oximes are reacted with carbonyl compounds as shown. 69 ’O

71

T. Sheradsky and D. Zbaida, Tetrahedron Lett., 1981,22,1639. D.Binder and P. Stanetty, J. Chem. Res. (S), 1981,102. ( a ) H.Gnichtel and M. Beier, Liebigs Ann. Chem., 1981, 312; ( b ) H.Gnichtel and B. Moller, Chem. Ber., 1981,114,3170.

334

General and Synthetic Methods phcH2pNH2 N HO’

COCI,,

0

3

OH anti

Nq

Ph

I

h

-o’yyNO R

OYNO Me

Me

(137)

The first report of the reaction of 2H-1-benzopyran (139) with various 1,3-dipoles has appeared.” Good yields of single cycloaddition products (140) were obtained upon reaction with nitrile-imines, whereas nitrile oxides gave 1 : l mixtures of the regioisomers (141) and (142). The reactions with diazomethane gave rather inconclusive results, and phenyl azide and diphenyl nitrone failed to react. Similar types of reactions have been carried out using a variety of en one^^^ in which the overall conclusion appears to be that simple aliphatic or alicyclic enones produce mixtures of regioisomers upon reaction with nitrile oxides and nitrile iminesrwhereas enones of the chalcone type show only one product. Experts in FMO theory will probably declare these results

(139) \ArCNO

L

0-N I

\\

U o J 72

73

+

T. Shimizu, Y. Hayashi, K. Yamada, T. Nishio, and K. Teramura, Bull. Chem. SOC.Jpn., 1981, 54,217. G.Biachi, R. Gandolfi, and C. De Micheli, J. Chem. Res. (S), 1981,6.

335

Saturated Heterocyclic Ring Synthesis

obvious. Further, some Japanese have discovered an unexpected outcome of the reaction of nitrile imines with 1,2-dibenzoylethenes. Only careful exclusion of water led to the expected pyrazoline (143). Excellent yields of the pyrazole (144) may be obtained by reaction of (143) with H,O-NEt,. The authors propose initial attack of water at the carbonyl group of the 5-substituent as the first step of the reaction, followed by in situ oxidation.

+

Ar>N--NHAr2 CI

Ar3

\If=-coAr’ 0

lNEfl

Ar

Ar’

NEt-+-H,O

XJ:;

*

‘

3JCoAr3 N

Ar

Ar

(143)

(144)

Diazomethane reacts in a 1,3-dipolar fashion across the C=C of thioketene S-oxides to give good yields of the 1: 1 adducts (145).75In contrast, thioketenes are known to react across the C=S bond.

R‘

>c=s”

R2

0

+

CHzNz

-

s’p

11 H (14.51

In a series of papers S c h ~ l t and z ~ his ~ ~co-workers ~ have studied the DielsAlder reaction of dialkylaminopyrroles. As well as the expected benzene derivatives, pyrazolines (146) are obtained to the extent of 30%. They suggest the in situ formation of a nitrene followed by an ‘ene’ reaction to generate an ylide, which subsequently undergoes thermal disrotatory cyclization (Scheme 9). The reaction has been used as part of the synthetic scheme to Juncusol. An investigation of the reactions of vinyl azides with enamines has been p~blished,~’ in which the results are given extensive discussion with consideration 74 75

76

”

T. Oida, T. Shimizu, Y. Hayashi, and K. Teramura, Bull. Chem. SOC.Jpn., 1981,54, 1429. E. Schaumann, H. Behr, G. Adiwidjaja, A. Tangerman. B. H. M. Lammerink, and B. Zwanenburg. Tetrahedron, 1981,37, 219. ( a ) A. G . Schultz, M. Shen, and R. Ravichandran, Tetrahedron Lett., 1981,22, 1767;( b ) A. G. Schultz and R. Ravichandran, Tetrahedron Lett., 1981,22, 1771. ( c ) A. G.Schultz and M. Shen, Tetrahedron Lett., 1981,22, 1775. Y. Nomura, Y. Takeuchi, S. Tomoda, and M. M. Ito, Bull. Chem. SOC.Jpn., 1981,54,261.

General and Synthetic Methods

336 NMe, I

Me I

Q

MefrMe Me

Me

DMAq M e 0 , C

C0,Me

+ Me$co2Me Me Me

C0,Me

C0,Me Scheme 9

of FMO theory. The overall outcome is that triazolines (147) are formed by 1,3-dipolar cycloaddition. The well known reaction of azide ion with alkenes and alkynes has been modified by attaching the azide group to the double bond,78 followed by reaction with sulphur ylides. 1,2,3-Triazolines (148) are obtained in high yield and pyrolysis affords a good route to aziridines (149).

Six-membered Rings.-A reaction, which may be especially suited to natural product synthesis, provides a facile route to l-azaspirocycles.79Cyclization via a T-ally1 palladium complex occurs in almost quantitative yield in some cases, A. Hassner, B. A. Belinka, jun., M. Haber, and P. Munger, Tetrahedron Lett., 1981, 22, 1863.

’’ S. A. Godleski, J. A. Meinhart, D. J. Miller, and S. Van Wallendoel, Tetrahedron Lett., 1981, 22, 2247.

Saturated Heterocyclic Ring Synthesis

337

(150) -+(151). Another route by which reduced bicyclic pyridine derivatives may be obtained begins with 4-cyanopyridine." OAc

The pyrrole derivative (152) was converted to the tricyclic compound (153) upon treatment with base, via isomerization to the enamine. The yields, however, are disappointing. The isomer (154) failed to give a tricyclic product, probably because of the non-formation of the enamine owing to the acidity of the inter-ring methylene protons.

In general piperazine-2,5-diones (155) are not difficult to prepare; indeed their ease of formation can sometimes be irritating. Mono-N- alkyl derivatives, however, are more of a challenge. An improved synthesis of l-methyl-23piperazinedione has been achieved" and this is outlined in Scheme 10. Me

Reagents: i, HCI-EtOH; ii, C1CH,COCI-NEt3-CH,CI,; iii, NH40H

H

(155)

Scheme 10

The bis-Schiff's base (156) offers considerable promise as a synthon for a number of heterocycles. It reactss2 with various ketones and the type of product [i.e. (157) or (158)]obtained depends greatly upon the structure of this carbonyl component, as shown. Alternatively, heteroatoms on aryl groups of the Schiff's base can enter into the reaction producing a variety of heterocyclic products [e.g. (159) and (160)]. A note which appeared last year has now been followed up with a full paperR3 and concerns the formation of aminoanthraquinones, which are important as

R3

J. Bosch, D. Mauleon, and R. Granados, Heterocycles, 1981,16,1665. T.D.Harris, T. J . Reilly, and J. A. Del Principe, J. Heterocycl. Chem., 1981,18,423. T.Takajo and S. Kambe, Synthesis, 1981,151. T. Takei, M. Matsuoka. and T. Kitao, Bull. Chem. SOC.Jpn., 1981,54,2735.

338

General and Synthetic Methods

\

Ph'

Ph

(156)

phwp HN

/

NH

Ph

4".+ OH

N7 Ph

1 R'

Ph

$-.-.

R'

\

OAPh

(159)

dyes or dye intermediates. The reaction of 1,4-dihydroxyanthraquinone(161) with primary amines in the presence of cupric chloride led to cyclic products (162) in good yields.

0 (161)

OH

0

OH

(162)

As usual, a large number of papers concerning reduced quinoline and isoquinoline derivatives have appeared. Some of the more interesting and useful examples will be discussed in the following Section. MeyersE4has continued his work with oxazolines and has developed what promises to be an extremely valuable route 84

A. I. Meyers, M. Reuman, and R. A. Gabel, J. Org. Chem., 1981,46,783.

Saturated Heterocyclic Ring Synthesis

339

to benzo-fused heterocycles. The well known ability of oxazolines to activate ortho- methoxy groups to displacement by nucleophiles is utilized in a synthesis of (163), the starting materials being available from cheap simple compounds. from Also, a new, practical synthesis of 5-hydroxy-3,4-dihydrocarbostyryl(l65) cyclohexane-1,3-dione has been d e ~ e l o p e d It . ~ involves ~ a conversion to the enamine (164) with ammonia and its reaction with acrylic acid. The method

'

OMe

X

(X = OH or NH2, n

(163) =

2, 3, or 4)

provides a straightforward route to a useful but otherwise difficultly accessible compound and was prompted by its use as an intermediate for the synthesis of /3- adrenergic blocking compounds. Another method of great potential involves intramolecular cyclization of arylalkyl hydroxylamines,86by Lewis acid activation. Aluminium chloride and stannic chloride both effect the cyclization (166) + (167) but yields vary with the amount of catalyst and solvent. Protic acids such as CF3C02Htend to give better yields, and the method would appear to be general for the synthesis of a variety of fused heterocycles. In order to determine the mechanism of the reaction (a nitrenium ion or a concerted process), 0-,rn-, and p- methoxy-analogueswere studied. Because of the product distribution (168) and (169) illustrated, the spiro-intermediate (170) was postulated. Opp01zer~~ has published an elegant synthesis of racemic lysergic acid in which the reduced quinoline moiety within the molecule is constructed using an intramolecular Diels-Alder reaction of an in situ generated diene across the

OAc

(166) 85 86

T. Shono, Y. Matsumura, and S. Kashimura, J. Org. Chem., 1981,46,3719. M. Kawase and Y. Kikugawa, Chem. Phurm. Bull (Jpn.), 1981, 29, 1615. W. Oppolzer, E. Francotte, and K. Battig. Helu. Chim. Acru, 1981,64, 478.

340

Meomo($-

General and Synthetic Methods

+

HN

rn

I

OAc

Me6

Me0

03,

(169)

HN I OAc

C=N of an imine, i.e. (171)-(172). Good results were only achieved by careful maintenance of the concentration of the generated diene.

A + 200°C

Magnus and his groups8 have discovered a new method of cyclization via quinodimethane intermediates, which avoids the problems associated with the well known methods involving benzocyclobutenes, dihydrothiophen dioxides, etc. The discovery was made after the observation that when the trimethylsilyl derivative (173) was treated with fluoride ion cyclization did not occur, only (174) was isolated. The cyclization to (175) is affected in good yield by heating (174) with acetic anhydride, and although the method is being developed for synthesis of Aspidosperma alkaloids, it promises to have much wider application. What might be described as an aza-equivalent of the last reaction has been employed for the construction of a ~ a - s t e r o i d s(176) , ~ ~ + (177), whereas a more straightforward approach concerns the reaction of aminoquinoline derivatives (178) with p-keto-e~ters.'~Although there are many examples of this latter " 89 90

T. Gallagher and P. Magnus, Tetrahedron, 1981, 37, 3889. Y. Ito, S. Miyata, M. Nakatsaka, and T. Saegusa, J. A m . Chem. SOC.1981, 103, 5250. K. Matoba, E. Ishigami, H. Takahata, and T. Yamazaki, Chem. Pharm. Bull. (Jpn.), 1981,29,651.

Saturated Heterocyclic Ring Synthesis

w

34 1

Me 0 (177)

x

reaction, they mostly proceed in low yield. Finally, as a follow-up to previous reports regarding annelation reactions of lactim ethers, two paper^,"^** describe the synthesis of various diazasteroids. Although mixtures are obtained in some cases, the method appears to be general and promising, e.g. (179) + (180) + (181) + (182). The usefulness of lactim ethers has been further demonstrated by the conversion of homophthalic anhydride (183)to quinolizines (184).92Again the reaction is general, proceeding with various ring sizes and with heterosubstitution. Two 91

97

( a ) H. Takahata, M. Ishikura, K. Nagai, M. Nagata, and T. Yamazaki, Chem, Pharm. Bull. (Jpn.), 1981,29, 366. (6)H.Takahata, A. Tomoguchi, and T. Yamazaki. Chem. Pharm. Bull. (Jpn.), 1981,29,2526. G. M. Coppola, J. Heferocycl. Chem., 1981,18,767.

342

General and Synthetic Methods

0

(183)

(X = 0 or S , n

=

1 or 2)

1 0 (184)

other reactions that produce quinolizine derivatives have been published. In the homo-allylic alcohols gave the expected cycloadditionproducts (185) when heated with nitrones; conversion to quinolizine derivatives (186) then followed. The second paper94 describes the unexpected formation of the quinolizine OBz

0 R'

OMe

Ho@oMe M " O e0 m

+

i, MsCI-pyridine toluene

0-

I+

0 93

94

S. Takano and K. Shishido, I. Chem. SOC.,Chem. Commun., 1981,940. G . Kalaus, P. Gyory, M. Kajtar-Peredy, L. Radics, L. Szabo, and C. Szantay, Chem. Ber., 1981, 114,1476.

343

Saturated Heterocyclic Ring Synthesis

derivative (188), as a mixture of isomers, from the reaction of 2-ethoxycarbonyltryptamine (187) with a y-formyl ester. The authors expected the initially formed Schiff’sbase to fail to react with the indole ring owing to steric hindrance. Subsequent hydrolysis and decarboxylation, however, gave a mixture of the lactams (188).

According to Tamura and his c o - ~ o r k e r s the , ~ ~easily prepared methylsulphinyl substituted amides (189) may be cyclized by treatment with toluene sulphonic acid. Similarly, the methylthio-substituted halides (190), prepared from the same precursor, cyclize to the same products under influence of a Lewis acid. These methods are mild and proceed in good yields and, when n = 0, provide a useful synthesis of the oxindoles (191).

J

MeSCH,COCI

SMe

1

SMe (190)

s

OM ‘Me

(189)

Intramolecular amidomethylation, i.e. (192)+(193), is the basis of a new, facile synthesis of 1,4-dihydro-3(2H)- isoquin~linones.~~ The reaction may be accomplished using polyphosphoric acid, but under certain conditions dimeric 95 96

Y. Tamura, J.-I. Uenishi, H.Maeda, H.-D. Choi, and H. Ishibashi, Synrhesis, 1981, 534. Y. Watanabe, Y.Kamochi, and T. Miyazaki, Heterocycles, 1981,16,609.

General and Synthetic Methods

344

I

(193)

OH (192)

amides were obtained. 1-Isoquinolinones (195) have been obtained from 3substituted indanones (194) by treatment with butylnitrite and base." Interestingly, where R = H only the isonitroso-derivative (196) was obtained.

R2w R3

0

R' \

/

R

(195)

BuONO NaOMe

R' R2@ (194)

R

\

R=H

R2&$NoH R'

The photocyclization of a series of suitably substituted enamides [e.g. (197)] has been used to create spiro-substituted isoquinolin-1-ones (198) a ring system present in a range of natural Although a great variety of products is available by this route, compounds lacking =N-CH2Ph do not cyclize.

(197)

(198)

Isomeric thienopyridinones are also available using a method described by Satake and c o - w ~ r k e r s ,in~ ~which the amino-acid derivatives (199) and (200) were cyclized as shown. Conventional Friedel-Crafts reactions failed. The Bischler-Napieralski reaction, one of the classic methods of isoquinoline synthesis, still attracts attention. In a method''' claimed to proceed under much milder conditions than the conventional process that uses P0Cl3, trifluoroacetic anhydride has been used as the condensing agent. The reaction was carried out J. N. Chatterjea, C. Bhakta, A. K. Sinha, H. C. Jha, and F. Zilliken, Liebigs Ann. Chem., 1981, 52. 98 J.-C. Gramain. Y. Troin, and D. Vallee, J. Chem. SOC., Chem. Commun., 1981,832. 99 H.Satake, T. Imai, M. Kimura, and S.Morosawa, Heterocycles, 1981,16,1271. '00 S.Nagubandi and G. Fodor, Heterocycles, 1981.15, 165. 97

345

Saturated Heterocyclic Ring Synthesis

in a step-wise manner with formation of the imidoyl trifluoroacetates or sulphonates, followed by cyclization by heating in uacuo. A variety of diazaphenalene derivatives has been made available following the work of Schwan."' In an extension of some earlier work the bis-aminoalcohol derivatives (201) have been cyclized using 48% HBr or polyphosphoric acid. The naphthalene compounds (202) offer a degree of flexibility since by judicious use of blocking groups cyclization can be achieved across normally disfavoured positions. The series has also been extended to include reduced forms. Lastly, the Mannich reaction has been employed"* to construct triazaphenalene derivatives (203) and intermediary products, albeit in low yield.

ph&Me

102

T. J. Schwan, Heterocycles, 1981,15,469. J. Aritomi and H. Nishimura, Chem. Pharm. Bull. (Jpn.), 1981, 29, 1193.

General and Synthetic Methods

346

""'me

-

h4e02c)/&Me

MeNH2.HCI (CHzO),

Me Me

Ph C 0 , M e \

Me

Me

+

M *eJM Fe

Ph C 0 , M e \

-

3 Sulphur containing Heterocycles Thiirans, Thietans, and Thiophen Derivatives.-These classes of compounds have been grouped together since very few papers have app3ared describing useful synthetic procedures. Apart from exchange reactions from oxirans, thiirans tend to be formed by roundabout routes. The dioxides (204) for instance may be prepared from diazoalkanes by reaction with sulphur dioxide.lo3The reaction produces trans- isomers accompanied by the dihydrothiadiazoledioxides (205).The formation of the thiiran, however, is favoured in polar solvents.

(204)

(205)

A knowledge of the rules for conservation of orbital symmetry allows one to predict the stereochemistry of products of concerted cycloaddition reactions. In the case of two-step reactions, however, a knowledge of the conformation of' the intermediate is necessary. A paper by Schaumann et ~ 1 . " ~attempts to make such a prediction and rationalize the stereochemistry obtained in the products of reaction of aryl isothiocyanates and vinyl ethers. Thietanimines (206) are obtained in good yield. X-Ray and n.m.r. spectroscopy were used to determine the configuration in the cycloadducts and the authors have proposed that there is orthogonal approach of reactants with only slight steric interactions. It is also suggested that this model could be of general importance for dipolar cycloadditions of hetero-allenes.

RimR3 ~2

OR^

R~-E;-OR~ + R o S 0 2 ~ = C = S ---+ R O S 0 2 " (206)

lo3

lo4

H. Quart and F. Kees, Chem. Ber., 1981,114,787. E. Schaurnann, H.-G. Bauch, and G. Adiwidjaja, AngQv..Chem., Int. Ed. Engl., 1981, 20, 613.

347

Saturated Heterocyclic Ring Synthesis

A method of thietan (207) formation that promises to be widely applicable concerns the reaction of chalcones, which are available with a tremendous variety of substituents, and diethyl hydrogen phosphodithioate. lo5 A possible drawback is that &/trans mixtures are obtained. There are very few examples of additions to non-activated alkynes; an intramolecular example has now been shownlo6to lead to thietan oxides (208) as well as larger sulphur heterocycles. Ar'-CH=CH-CO

+

Ar

Ar2

lp:r z

\

S

II (Et0)2PSH

(208) n

= 1, 2,

3, or 4

2,5 -Dihydrothiophens are readily available by Birch reduction of thiophens, and they may be alkylated adjacent to activating substituents. lo' Subsequent removal of sulphur provides a useful route to substituted butadienes. Finally in this Section the preparation of 1,2-dithiolo[3,4-d]pyrimidine-3-thionesmerits a mention."' The reaction of 6-arylaminouracils with carbon disulphide in the presence of sodium hydroxide and dimethyl sulphate gives good yields of the expected pyrimido[4,5-b]quinolines (2 10). However, upon acid work-up in the absence of Me2S04the reaction follows a different course. The amino-function is lost and the sulphur heterocycles (209) are obtained. 0

i, NaOHCS,/

'R

Me (209) '06

'"I

U . Ueno, L. D. S. Yadav, and M. Okawara, Synrhesis, 1981, 547. R. Bell, P. D . Cottam, J. Davies, and D. N. Jones, J. Chem. SOC.,Perkin Trans. I , 1981, 2106. K. Kosugi, A. V. Anisimov, H. Yamamoto, R. Yarnashiro, K. Shirai, and T. Kumamoto, Chem. Len., 1981, 1341. Y. Tominaga. H. Okuda, M. Tochiki, Y. Matsuda, and G. Kabayashi, Heterocycles, 1981, 15,679.

General and Synthetic Methods

348

Thiapyran Derivatives.-Several papers have appeared detailing the synthesis of reduced thiapyranone derivatives and they essentially follow the same sort of approach. Generally, the methods available for the preparation of 2-arylpyran-4-ones are not applicable to their sulphur analogues. Chen and cow o r k e r ~ ' ~ have ~ " * ~developed two useful routes, although isomeric mixtures are obtained. Mazza and Reinecke"' adopted a slightly different approach in that the ring formation was carried out after the sulphur atom was in place, rather than the ring formation by insertion of sulphur favoured by Chen et al. The base-catalysed conjugate addition of H,S to a,& unsaturated ketones is well known. Sometimes the y-ketosulphides so obtained undergo facile intramolecular aldol condensation to give tetrahydrothiopyranols (211).

R' O H 0

%

R-CH=CH-COR~

Vinyl sulphones have been shown to react with a-lithiated nitriles to give 3-oxothian-l,l-dioxides or cyclopropanes according to the nature of the starting material.11' The sulphonyl group plays a dual role, i.e. as an electron-withdrawing group and as a leaving group. Generally if R' or R2 = aryl the cyclopropane (212) is obtained but when R' or R2 = H or alkyl the thian (213) is formed in yields approaching 90%. Ph \

S0,Me

+ R' >CN

- vp.

R'

R2

Ph

or O

4 OS$ P h 0

0

The increased interest in hetero steroid analogues stems from the desire to modify or temper the wide ranging physiological activity present in these systems. As we have seen earlier in this Chapter, nitrogen analogues are well known, and now the first synthesis of a pentacyclic dithiasteroid [i.e. (214)] has been achieved,'12 from isothiochroman-4-one as shown. The interesting tricyclic sulphur-containing heterocycle (215 ) has also been prepared' l 3 by a versatile cycloaddition route, which would seem to offer great opportunity for extending the ring system. lo9 'lo

'" '12 '13

( a )C H. Chen, J. J. Doney, and G. A. Reynolds, J. Org. Chem., 1981,46,4604;( 6 ) C. H.Chen, G. A. Reynolds, and B. C. Cossar, J. Org. Chem., 1981,46,2752. D. D. Mazza and M. G. Reinecke, J. Org. Chem., 1981.46, 128. T.Agawa, Y. Yoshida, M. Komatsu, and Y. Ohshiro, J. Chem. SOC.,Perkin Trans. I , 1981,751. M. V.Krishna and S. R. Ramadas, Heterocycles, 1981,16,405. H.Ohmura and S. Motoki, Chem. Letr., 1981,235.

Saturated Heterocyclic Ring Synthesis

349

1

0

t

4 Ring systems of more than Six Members Containing Heteroatoms of One Type w

Benzoxepins.-The chemistry and biological activity of this ring system has not been fully explored; this situation may now change following the publication of a short efficient The compounds (216) have been linked with amines to provide molecules of potential as hypotensives.

Meo -Meo Me + TFA

Me0

+

Me0

EtOq kH,Br

Me0

BrCH,CH(OEt),

<

Br

Rings Containing Nitrogen.-The a-position of saturated nitrogen heterocycles may be activated to subsequent C-C bond formation through anodic oxidation, and this method makes tropone alkaloid precursors (2 17) readily accessible.11s The synthesis of various 8- and 9-membered lactams is now possible from '14

'"

( a ) R. E. Ten Brink and J. M. McCall, J. Heterocycl. Chem., 1981, 18, 821; ( b ) R. E. Ten Brink, J. M. McCall, D. T. Pals, R. B. McCall, S. J. Humphrey, and M. G. Wendling, J. Med. Chem., 1981,24,64. T. Shono, Y. Matsumura, and K. Tsubata, J. Am. Chem. SOC.,1981,103,1172.

350

General and Synthetic Methods

suitably substituted oxaziridine derivatives."' Oxaziridines, formed by photorearrangement of the isomeric nitrones, are known to cleave in the presence of Fe" sulphate to afford oxamides. This reaction also proceeds with tricyclic oxaziridines to give the macrocyclic lactams. C0,Me

-bo /

TiCI,-CH,CI,

W

M I

e

M

e

oxidation

o I

C 0 , Me

w Me

C0,Me

(217)

Macrocyclic polyazaheterocycles include the well known spermidine alkaloids, the synthesis of which has attracted a great deal of attention over the past few years. An efficient 6-step total ~ y n t h e ~ i ~of ' " the dihydroperiphylline system (218), which has recently been isolated from plant sources, has been reported. 0

The method involves successive ring expansion of smaller heterocyclic units. Another paper describes' l8 boron-templated cyclizations of small units for the construction of macrocyclic lactams [e.g.(219)l. The fact that the reactions occur

(219) '16 1' 'la

D. St. C. Black and L. M. Johnstone, Angew. Chem., Int. Ed. Engl., 1981, 20, 669,670. H. J. Wasserman and H. Matsuyama, J. A m . Chem. Soc., 1981, 103,461. H. Yamamoto and K. Maruoka, J. A m . Chem. Soc., 1981,103,6133.

Saturated Heterocyclic Ring Synthesis

35 1

with high selectivity supports the mechanism whereby the acyclic amino-ester becomes covalently attached to boron before the final cyclization step. The first report' l 9 of an intermolecular amino-alkylation has been published (220). The reaction occurs with the synthesis of 3-aryl-4-azidohomo-adamantane in yields in excess of go%, presumably via an imine intermediate, and does not proceed without A1C13.

By far the greater proportion of papers concerning heterocycles of this general category, deal with the chemistry of azepines, diazepines, and their benzoanalogues, for the simple reason that they have demonstrated a broad spectrum of biological activity. The little known formation of azepines from divinyl aziridines has been extended12' to the monovinyl compounds (22l),which are themselves readily formed from azirines. Reaction proceeds with a variety of alkynes and alkenes although the latter react more slowly. The pharmacologically active 5-phenylbenzazepine derivatives (222) have been synthesizedl'l along lines published in the previous two years.

Ph

- phcH

)"+ iiMgBr

Ph The novel reaction of 2,5-dimethylbenzoxazole with DMAD for two weeks in the absence of light gives an azepine derivative among a mixture of products.'22 12" 12'

lZ2

D . Margosian and P. Kovacic, J. Org. Chem., 1981,46,877. A. Hassner, R. D'Costa, A. T. McPhail, and W. Butler, Tetrahedron Lett., 1981,22, 3691. D.Berney and K. Schuh, Helv. Chim.Actu, 1981,64,373. N. Nawahara, M. Katsayarna, T. Itoh, and H. Ogura, Heterocycles, 1981,16,235.

General and Synthetic Methods

352

Pyrrolo[2,3-b]azepin-4-ones(223)have been prepared by a Dieckmann cyclization of the appropriately substituted pyrrole, as potential antineoplastic and antimalarial agents.123 Et02C NaH

Me

I C0,Et

C0,Et

\

C0,Et (223)

Diazepine derivatives, because of their interesting chemistry and great potential as therapeutic agents, still attract a great deal of synthetic activity each year; 1981 is no exception. A simple procedure has been developed'24for the preparation of monocyclic azepine derivatives. The imidate (224)and N- methylethylenediamine form the bridged diamidine salt (225, R = H) in ethanol, and this has been used for a variety of transformations. N,N'- Dimethylethylene diamine, however, fails to react in this way and instead straight-forward seven-membered condensation products (226) are produced, which may be further elaborated to bicyclic derivatives (227). MeHN

nN H M e

HN

Me

Yj E'onoEt +

+

HN

NH

Me

Me

NH

Me

(225)

The well known palladium-catalysed insertion of carbon monoxide into substituted aryl halides has been elaborated to provide a useful synthesis of benzodia~epinones,'~'and the reaction of 1,2-diamines with allenic nitriles has been lZ3 124

12'

M. M. Vora, C. S. Yi, and C. D. Blanton, jun., Heterocycles, 1981,16,399. H. Meyer, Liebigs Ann. Chem., 1981,1545. M.Mori, M. Ishikura, T. Ikeda, and Y. Ban, Heterocycles, 1981,16.1491.

Saturated Heterocyclic Ring Synthesis

353

reported to give imidazolines by a double Michael addition. If the diamine unit is incorporated into an aromatic ring, however, the reaction follows the pathway leading to the seven-membered ring (229) to the exclusion of the benzimidazoles. l Z 6This reaction probably proceeds through (228)via a 7-exo-trigmode of ring closure.

Details have appearedI2’ of a method of benzodiazepinone formation that claims to be an improvement on established procedures. The precursor amides (230)are heated with a small excess of hexamine in acetonitrile forming the salt (231)quantitatively. From this the pure diazepinone (232)may be isolated in 90% yield. A simple procedure has also been developed for the preparation of indenodiazepines,128 again involving the use of hexamine, (233)+ (234). The triketone (233)is also a useful starting point for the synthesis of pyrrole and pyridazine derivatives.

Ar

Ar (231)

-0K;Cc J

\

\

Ph

0 (233)

(232)

N

H

0 (234)

Several nitrogen-containing tetracycles incorporating an azepine unit have ~ technique employed involves the been prepared by Atkinson et ~ l . ” The generation of N- nitrenes in close proximity to an electron-rich aromatic moiety. Thus, oxidation of 3-amino-2-(arylalkyl)quinazolones(235)with lead tetraacetate yields N-nitrenes, which are trapped by the adjacent aryl group provided that there is an electron-donating group para to the point of insertion. The corresponding benzyl analogues show no nitrene trapping products only deamination, thus indicating the preference for a 7-membered transition state. lZ6

”* 12’

J. Ackroyd and F. Scheinmann, J. Chem. SOC.,Chem. Commun., 1981,339. T. Kovac, B. Belin, T. Fajdiga, and V. Sunjic, J. Heterocycl. Chem., 1981,18,59. P. V. Padmanabhan, K. J. J. Rao, D. V. Ramana, and S. R. Ramadas, Heterocycles, 1981, 16, 1. R. S. Atkinson, J. R. Malpass, and K. L. Woodthorpe, J. Chem. SOC.,Chem. Commun., 1981,160.

General and Synthetic Methods

354

OMe (235)

OMe

Lastly in this Section two papers concerning the formation of nitrogen containing rings of more then seven members deserve a mention. Until recently there was no direct synthesis of 1,4-diazocines and 1,4-diazonines available but this gap has now been filled13' with the publication of a simple reaction leading to their reduced derivatives. The sodium salts of di-anils (236), formed by electron transfer, react with a,o-dihaloalkanes giving the required compounds (237) in good yield. An annulated example of a tetrahydrobenzodiazocinehas also been synthesi~ed.'~'These two methods may well provide a much needed stimulus in the search for CNS-active compounds in this area. Cl

-

A

Ar'

/

2Na

Ether

A Ar

(237) n

=

4 or 5

Rings Containing Sulphur.-A successful synthesis of medium-sized sulphurcontaining rings which avoids the high-dilution techniques previously thought necessary, has appeared.'32 Yields are good, with a,w- dibromoalkanes affording 7-13-membered rings (238). Br -(CH2), - Br

+

Na,S

10-'M

(CH2),

W (238)

Last year an interesting ring-expansion process was described in which benzothiazepinone derivatives were formed from benzothiapyranones. This process has now been extended to embrace the isoelectronic sulphenium methylides 130

G. Singh and K. N. Mehrotra, Heterocycles, 1981,16,1341.

13'

E.Aiello, G. Dattolo, G. Cirrincione, A. M. Americo, and I. D'Asdia, I. Heferocyl. Chem., 1981,

13'

A. Singh, A. Mehrotra, and S. L. Regen, Synth. Commun., 1981,11,409.

18,1153.

Saturated Heterocyclic Ring Synthesis

355

(239) such that tetrahydro- l-benzothiepin-5-ones are obtained in good yield^.'^^".^ The details are shown in Scheme 11.

a \ Reagents: i, N,C(C02Me),-CuS0,;

t iii

@ \

C0,Me C0,Me

CO2H ii, NEt,; iii, H'-H,O

Scheme 11

5 Heterocycles Containing Both Oxygen and Nitrogen

Three-membered Rings.-As has been mentioned earlier, oxaziridines are readily formed by photochemical isomerization of nitrones. A purely chemical method has been discovered by some Japanese workers during the course of their work with ethyl 3-hydroxypyrrole-2-carboxylates(240). 134 They have found that the esters produce oxaziridines (241) upon reaction with nitrous acid rather than the expected nitroso derivatives. Ring expansion may occur via a push-pull mechanism and is also seen upon reaction of (240) with aryl diazonium salts, when diaziridines (242) are formed if the pH of the reaction is carefully controlled.

0 Rz

2

E

(240)

1

ArA,CI-

PH 7-8

0

t

1

(242) 133

134

(a)Y.Tamura, Y. Takebe, C. Mukai, and M. Ikeda, J. Chem. SOC.,Perkin Trans. 1, 1981, 2978; (6)Y.Tamura, Y.Takebe, C. Mukai, and M. Ikeda, Heterocycles, 1981,15, 875. T. Momose, T. Tanaka, T. Yokota, N. Nagamoto, H. Kobayashi, and S. Takano, Heterocycles, 1981, 15, 843.

356

General and Synthetic Methods

Five-membered Rings.-Oxazolidines (243) are obtained by the fusion of pamino-alcohols with aromatic a1deh~des.l~' If the carbonyl component used is in a higher oxidation state then oxazolines are obtained. A new method for the 'one-pot' synthesis of these very useful activating and protecting groups has been deve10ped.l~~ The reaction requires the appropriate carboxylic acid (244), three equivalents of PPh, and NEt,, excess CC14, all in CH,CN-pyridine 1: 1. The quoted yields for both reactions are good but the most important feature is their versatility since amino-alcohols, amino-mercaptans, and diamines of various chain lengths can be used to produce a great variety of heterocycles.

ArCHO

+

RHco2Et RHco +

HO

NH,

Et

OyNH Ar (243)

R'

Oxazolines (246) have also been prepared by the ring transformation of tetrahydropyrimidines (245), which can be readily metallated and ring opened to give intermediates which, with a further equivalent of butyl-lithium form a dianion. These can now react with carbonyl groups followed by ring closure through oxygen to give o x a ~ o l i n e s . 'Another ~~ useful ring conversion has been achieved by reaction of alkylisocyanates with amino-azirine~.~~' 3 : 1 Cyclic adducts (247) are obtained when R = Me, whereas when R = But only 1: 1 adduct formation occurs owing to steric hindrance.

n , n +nN, - -n N,

N-NLTs

N?N\Ts

CN

Ts

CN

(245)

13'

13' 13' 138

Ts

M. Z. A. Badr, M. M. Aly, A. M. Fahmy, and M. E. Y. Mansour, Bull. Chem. SOC.Jpn. 1981,

54,1844. H. Vorbruggen and K. Krolikewicz, Tetrahedron Lett., 1981,22, 4471. I. Hoppe and U. Schollkopf, Liebigs A n n . Chem. 1981,103. E.Schaumann, S. Grabley, and G. Adiwidjaja, Liebigs A n n . Chem., 1981,264.

Saturated Heterocyclic Ring Synthesis

357

The well known fluoride ion-induced liberation of carbanions from silyl compounds has been applied to trimethyl isothiocyanate for generation of the carbanion a- to nitrogen.I3' The method of Hoppe is unsuitable for the direct reaction of methyl isothiocyanate.The carbanion (248) then reacts with carbonyl compounds to form oxazolidines very smoothly at room temperature.

Bun NF

Me3SiCH2NC+ S + Me3SiCH2NC=S 4 [CH2NCS] (248')

i,R,CO

kH20

R

Rt\ OKNH 0

Imidazo[2,1-b]oxazolines, a novel class of heterocycle, can be obtained by reaction of dinitro-imidazoles with e p o x i ~ l e s [e.g. ' ~ ~ (249) -+ (250)l and phenyl azidoformates give benzoxazolones when pyrolysed.14' The authors have determined that this reaction does not proceed uia a spiro-intermediate since mixtures of compounds were not obtained.

H

(249)

H (250)

Cycloaddition reactions lend themselves very well to formation of molecules of this type and starting materials are readily available. N-Acylketenimines (251), prepared from acyl isocyanates and a phosphorane, react readily with isonitriles producing oxazolimines (252).'41 A similar reaction with carbodiimides gives the 6-membered heterocycles (253). Intra- and inter-molecular cycloadditions of nitrones are frequently applied in synthesis and further examples have appeared. 143 The authors have extensively investigated the scope of the reaction and from a large number of reactions the overall conclusion is that the butenyl group is most favourable for cyclization; the method has been utilized for a high yielding synthesis of the azulene derivative (254). Cycloaddition of nitrones with DMAD is a good route to oxa~olines.~*~ The reaction of 139

14' 143

144

T. Hirao, A. Yamada, Y. Ohshiro, and T. Agawa, Angew. Chem., Int. Ed. Engl., 1981,20, 126. R. K. Sehgal, M. W. Webb, and K. C. Agrawal, J. Med. Chem., 1981,24,601. 0. Meth-Cohn and S. Rhouati, J. Chem. Soc., Chem. Commun., 1981,241. L. Capuano and K. Djokar, Chem. Ber., 1981,114,1976. S . Takahashi, T. Kusumi, Y. Sato, Y. Inouye, and H. Kakisawa, Bull. Chem. SOC.Jpn., 1981,54, 1777. H.Gnichtel, B. Schmitt, and G. Schunk, Chem. Ber., 1981,114,2536.

General and Synthetic Methods

358 0 PPh,

I1

+ R-C-NCO

+

Et 0 , C

M, EtO,C

C =N-

COR

(251) AN=c=NRI

Eto2cYMe

Me I

N- hydroxyureas with dihalomethanes gives good yields of 1,2,4-oxadiazolidin-3ones (256).14'The reaction with formaldehyde, however, follows a different course and the dioxadiazocine derivatives (25 5) are formed. Me

7HO

MeN

/O7

Me N'

ArN\[i 'OH 0 CH2/

Ar -N

Y-BrcHzc'

roi LOTAr (255)

14'

R. Becker and W. Rohr, Liebigs Ann. Chern., 1981,191.

Saturated Heterocyclic Ring Synthesis

359

Six-membered Rings.-The versatility of 1,3-dipolar cycloadditions and of hetero-Diels-Alder reactions is, once again, used to great effect for the synthesis of 1,2-oxazine derivatives. Useful, multifunctionalized heterocycles are obtained by reaction of nitrile oxides with sulphoxonium allylides, followed by conversion of the initially formed furans (257) to oxazines (258) by treatment with tosic Treatment with NEt3 causes migration of the alkoxycarbonyl group forming the pyrrolone (259).

*p-

0I N+ 111 + R O 2 C A o R 1

, +

CO R 1

-

+s40 Me'

'Me

TsOt6

/c R0,C

"OH

(257)

'OZR'

R0,C

RO,C

do C0,R'

NEt,

H

(258)

(259)

As one would expect, oximes and nitroso-compounds are frequently encountered starting materials throughout the chemistry of this group of heterocycles. Further examples of their reactions have appeared. Reaction with enol ethers14' produces dihydro-oxazines (260), which may be converted to pyridine N- oxides upon treatment with HCl. Dihydro-oxazines are also obtained upon treatment of y,S- unsaturated p- dicarbonyl compounds with nitrous Thermolysis of these products leads to nitrones (261).

I 0--

(261) 146

14'

14'

Y. Nakada, T. Hata, C. Tamura, T. Iwaska, M. Kondo, and J. Ide, Tetrahedron Left., 1981,22,473. T. L. Gilchrist, G. M. Iskander, and A. K. Yagoub, J. Chem. Soc., Chem. Commun., 1981,696. G. Deshayes and S. Gelin, Tetrahedron Lett., 1981,22, 2 5 5 7 .

360

General and Synthetic Methods

Nitroso-alkenes are useful synthons since they combine the features of an electron-deficientalkene and a hetero-substituted diene. The mode of cycloaddition depends upon substitution on the double bond. 149 When either R2or R3 = H the compound functions as a 47r component in reaction with cyclopentadiene and oxazine derivatives (262) are formed, otherwise the nitroso-group behaves as a dienophile forming the bridged compounds (263). Halonitroso-compounds are also useful for the formation of functionalized cyclohexenes of known stereochemistry.

R3 I

I

A

(263)

An unusual reaction of an azo-compound has been shown"' to lead to benzoxazinones. The azo phenoxy acid derivatives (264) react with thionyl chloride to produce the chlorinated benzoxazinones (265) by intramolecular electrophilic transfer of chlorine to the anilino-ring. The reaction appears to be

N II

-0

SOCI,

Me

NH I

(265)

Is'

E. Francotte, R. Merenyi, B. Vandenbulcke-Coyette, and H.-G. Viehe, Helu. Chirn. Acta, 1981, 64,1208. ( a ) G. Kresze and E. Kysela, Liebigs Ann. Chem., 1981, 202; ( b ) G. Kresze, E. Kysela. and W. Dittel, Liebigs Ann. Chern., 1981, 210; ( c ) G. Kresze, W. Dittel, and H. Melzer, Liebigs Ann. Chern., 1981,224; ( d ) G. Kresze and W. Dittel, Liebigs Ann. Chem., 1981,611. M. Byers, A. R. Forrester, I. L. John, and R. H. Thomson,J. Chem. Soc., Perkin Trans. I , 1981, 1092.

Saturated Heterocyclic Ring Synthesis

361

general for azo-acids in which the B ring has a vacant ortho-position. A new synthesis of 2,2-disubstituted benzoxazinones from salicylamides has been deve10ped.l~~ The amides react with aldehydes and ketones under base catalysis to give the benzoxazinones (266); enamines also react but yields are poorer. Salicylamides and salicylhydroxamic acids may also be cyclized with 1,l‘carbonyldi-imidazole to produce 1,3-benzo~azine-2,4-diones,~~~ rather than the isomeric benzodioxan derivatives or benzoxazoles.

(266)

Ried and his have continued their work with benzo[b]thiophen derivatives, and have shown that they may be converted to a number of heterocycles [e.g. (267) and (268)]upon reaction with dicyclohexyl carbodi-imide and cyanamides. Some Japanese have followed up an earlier report concerning nitroquinolines with an interesting reaction in the naphthalene series. The potassium salt (269), which is formed from 2-nitronaphthalene cyclizes on treatment with HCl to give naphtho-1,3-oxazines (270), and these in turn can be further modified.

DCC ___,

1

R’NCN

Finally, hydrazinolysis of the phthalimide derivative (271) has been to give 2H-1,5,6-benzodioxazonines(272), a new ring system, whereas the attempted direct cyclization of the halide (273) with hydroxylamine failed.

Is’

I56

R. B. Gammill, J. Org. Chem., 1981,46,3340. D. Geffken, Liebigs Ann.Chem., 1981,1513. W. Ried, G. Oremek, and R. Guryn, Liebigs Ann. Chem., 1981,612. T. Ohshima, Y. Tomioka, and M. Yamazaki, Chem. Pharm. Bull. (Jpn.), 1981.29, 1292. E.J. Browne, Heterocycles, 1981,16,881.

General and Synthetic Methods

362

0

I

i, N,H.,.H,O ii, HCI

6 Heterocycles Containing Both Oxygen and Sulphur Four-membered Rings.-Open-chain sulphinate esters are readily prepared but their cyclic analogues are less easily come by. [2 + 2lCycloadditions involving SOz are limited to a few specialized examples, and it has been ~uggested'~'that it is this mode of reaction that leads to the initially formed adduct (274) between SO, and ketenimines. These compounds are unstable and rearrange to thiazetidine S-oxides (275) in 90% yield. A versatile approach has been Me2C=C=NR

+

-O\

+

s-0

/+

-0

SLN I I

/

R

Me0 -Me

developed by another group15* in which p- hydroxysulphoxides are cyclized under oxidative conditions. Loss of sulphur dioxide from the sultines (276) occurs by concerted stereospecific cis elimination, analogous to f i e loss of COz from p- lactones. Is'

A. Dondoni, P. Giorgianni, and A. Battaghia, J. Chem. SOC.,Chem. Commun., 1981, 350. M. D. M. Gray, D. R. Russel, D. J. H. Smith, T.Durst, and B. Gimbarzevsky, J. Chem. SOC., Perkin Truns. 1, 1981, 1826:

363

Saturated Heterocyclic Ring Synthesis

Me 'Me'"

Six-membered Rings.-The cycloadducts (277) are formed in good yield by reaction of sulphene with open-chain enaminones bearing a phenyl group at the 2-position. lS9 The conversion of 2-chloro-oxirans to 6-membered heterocycles has been described.16' The reaction with bidentate nucleophiles is most interesting, leading to mixed heterocycles such as (278). Tropone also reacts with 2-mercapto-ethanol to give a 95 : 5 mixture of the cyclohepta[l,2-6]- 1,4oxathiins (279),161which could be separated by h.p.1.c. NR2

+

7 Heterocycles Containing Both Nitrogen and Sulphur

Three- and Four-membered Rings.-Thiaziridine- 1,1-dioxides (280) have been prepared162by the reaction of diazoalkanes with N- sulphonylamines. The compounds are stable at -30°C but lose SOz to form aldimines on warming. Elimination of halogen from a-halosulphonamides and from N- chlorosulphonamides failed to give the required products. Only a few three-membered 'sI 161 j6*

A. Bargagna, F. Evangelisti, and P. Schenone. J. Heterocycl. Chem., 1981,18, 111. C. Herzig and J. Gasteiger, Chem. Ber., 1981, 114, 2348. M. Cavazza, G. Morganti, A. Guerriero, and F. Pietra, J. Chem. SOC.,Perkin Trans. 1, 1981, 1868. H. Quast and F. Kees, Chem. Eer., 1981, 114, 774.

General and Synthetic Methods

364

rings lacking carbon are known; thiadiaziridine-1,l-dioxides (282) have now been prepared'63 by treating dialkylsulphamides (281) with sodium hydride followed by t-butyl hypochlorite. Great care must be exercised over the reaction temperature and the stability of the products depends on the steric demands of the alkyl groups. The [2 + 2lcycloaddition of N- sulphinylsulphonamides with ketenimines has been to give thiazetidine-1-oxides (283) rather than thiadiazetidine-1-oxides (284). The proof for the structure was obtained from spectroscopicevidence and from further chemical modification.

Me2C=C=N-Ph

N,

Five-membered Rings.-In a series of papers Cambie and c o - w o r k e r ~ ' ~ ~ ~ * ~ have shown that iodoisothiocyanates (285) will react with carbon and other nucleophiles to form a variety of 2-substituted-2-thiazolines(286). The yields are good and the products useful since protons attached to the 2-substituents are acidic, thus offering the opportunity for further modification. Also, thiones 163

165

J. W. Timberlake, J. Alender, A . W. Garner, M. L. Hodges, C. Ozmeral, S. Szilagyi, and J. 0. Jacobus, I. Org. Chem., 1981,46,2082. G. L'Abbe, A. Van Asch, and J.-P. Dekerk, Tetrahedron Lett., 1981,22, 583. ( a ) R. C. Cambie, D . Chambers, P. S. Rutledge, and P. D . Woodgate, J. Chem. Soc., Perkin Trans. 1, 1981,40; ( b ) R. C. Cambie, G. D . Meyer, P. S. Rutledge, and P. D . Woodgate, J. Chem. Soc., Perkin Trans. I , 1981, 52.

Saturated Heterocyclic Ring Synthesis

365

derived from the products (286,R = SR') are useful reagents for production of thiirans from oxirans. Ring transformations of isothiazoles have received little attention compared with their isoxazole counterparts. Production of the thiazolinone (288)by reaction of the isothiazolinethione (287)with DMAD proceeds in high yield.'66

o* d-*.>R "N

"NCS

(285)

H (286)

3-Amino-2-arylazo-2-butenoic acids (289)have been prepared by two pathwith bligomeric ways from acetoaceticesters. The reaction of these cornp~unds'~' a-mercapto-aldehydes leads to substituted thiazoleacetic esters (290), which appear to be useful intermediates for the synthesis of penicillin analogues. Most syntheses of 2,4-dioxa-1,3-thiazolidines(292),which show an interesting spectrum of biological activity, involve oxidation of thiol precursors. A new method'68 uses readily available dihydropyrimidine thiones in reaction with chloro-acetic acid. The reaction does not proceed if R = H in (291).

166

.T.Nishiwaki, E. Kawamura, N. Abe, H. Kochi, Y.Sasoaka, and K. Soneda, Heterocycles, 1981,

16'

16, 595. J. Gasteiger and U. Strauss, Chem. Ber., 1981,114, 2336. H. Singh, P. Singh, and K. Deep, Chem. I d . , 1981,252.

168

General and Synthetic Methods

366

The reaction of thioketens and amino-azirines proceeds by C=N cleavage'69 to give the dipolar species (293) or ketenimines (294), depending upon substitution; hydrolysis of the latter leads to 2-thiazolin-5-ones (295). There are few general routes to 1,3,4-thiadiazolines and a new method, 170 discovered accidentally, provides the derivatives (296) which, since they have amidine characteristics, will probably prove to be useful synthons. Thiadiazolidine diones are readily available171from metallated N-(trimethylsilyl) alkylamines.

rPh

Ar

N

i, (NH,),C=S

A

ii, NaOH

Ar

CI

The anti-fungal and anti-bacterial properties of 1,2-benzisothiazol-3(2H)ones has caused much synthetic activity to be focused upon them and two new routes have been published this year,'72 from the 0-acylhydroxylamines (297) and the sulphinylbenzamides (298). As one would expect, spirocyclic benzothiazolines are readily prepared'73 from o-aminothiophenols and cyclic

I 'Me -0

169

''O

172

E. Schaumann, S. Grabley, F.-F. Grabley, E. Kausch, and G. Adiwidjaja, Liebigs Ann. Chem., 1981,277. S . H. Askari, S. F. Moss, and D. R. Taylor, J. Chem. Soc., Perkin Trans. 1, 1981, 360. R. Neidlein and W. Lehr, Chem. Ber., 1981, 114, 80. Y. Uchida and S. Kozuka, J. Chem. Soc., Chem. Commun., 1981,510. F. Sauter, P. Stanetty, and A . Blaschke, J. Chem. Res., ( S ) 1981,98.

367

Saturated Heterocyclic Ring Synthesis

ketones; spiro[3H- indole-3,2'-thiazolidine]-2,4'-( 1H)-diones (299) may be obtained from isatin as These compounds show a broad spectrum of biological activity.

a H

I

i, ArNH, ii. HS"CO~H

Six-membered Rings.-Diels-Alder cyclizations using heterodienophiles provide a useful route to 1,2-thiazine derivatives; immonium salts (300) derived from N- sulphinylmethylamine react across the N=S g r 0 ~ p i n g . I ~1,3~ Thiazinones are prepared176by reaction of thia-acylisocyanates (301) with enamines and enol ethers, and the formation of this ring system is also possible by reaction of N- monosubstituted dithiocarbamates with a,& unsaturated acid chloride~.'~' The reaction involves a series of equilibria, N- to S-transacylation, and cyclization reactions.

K. C. Joshi, R. Patni, and P. Chaud, Heterocycles, 1981,16,1555. G. Kresze and M. Rossert, Liebigs Ann. Chem., 1981,58. 176 J. G.Goerdeler, M.-L. Tiedt, and K. Nandi, Chem. Ber., 1981,114,2713. "' W.Hanefeld and G. Glaeske, Liebigs Ann. Chem., 1981,1388. 174

General and Synthetic Methods

368

Azabutadienes have been s h o ~ n ’ ’to~ react in a [4 + 2lcycloaddition across the C=S of aryl isothiocyanates, to give a new synthesis of imino-2,3-dihydro1,3-thiazines (302). Cyclization does not occur if the steric requirements of R2 are too large. The new ring system (303) has been f ~ r m e d ”by ~ reaction of cyclic thioureas with 2-chloro-3-cyanopyridine.

R:

R’

S=C=N-Ar

N-Ar

n Cheap and convenient syntheses of carbonyl di-isothiocyanate (304) and of carbonyl isocyanate isothiocyanate (305) have been reported.’*’ Their reactions with water, H2S, HCl, and various nucleophiles lead to a variety of thiadiazine derivatives.

NCS (304)

0

’” 179

Y. Ohshiro, T. Hirao, N. Yamada, and T. Agawa, Synthesis, 1981,896. G. M. Coppola and M. J. Shapiro, J. Heterocycl. Chem., 1981,18,495. R. Bunnenberg and J. C. Jochims, Chem. Ber., 1981,114,2064,2075.

Saturated Heterocyclic Ring Synthesis

369

Acheson and his group'" have continued their work on the reactions of DMAD, and have shown that the products (307) and (308) obtained from benzimidazolin-2-thione(306)are dependent upon the solvent used. The benzothiazoline ring system has also been included in the search for potential antibiotics, with the synthesis of (309) from 4-acetoxyazetidinone.la* a ' > S N (306)

+ MeO,CC=CCO,Me Y O H

ON& '

/&CN

Np&CO,Me

TJN ->S

'

N&C02Me

0

0 (307)

(308)

O

H q

b

(309)

Seven-membered Rings.-In an earlier Section, the ring expansion of 2,3dihydrobenzothiapyran-4-ones was discussed. A preliminary report in which benzothiazepinones were obtained has been followed by the full paperla3 in which the further scope of this transformation is discussed. The first example of a [2 + 2lcycloaddition of benzisothiazoles with vinyl ethers has been reported.lS4Ring expansion to 1,4-benzothiazepine analogues (310) occurs in 80% yield. In a similar study'*' benzothiazoles have been shown to react in a regioand stereo-selective manner to give the 1,5benzothiazepine derivatives (311).

(310)

hP>;Jf

+

R?y; - aN$: s

R'

R4 (311) 18'

le3

R. M. Acheson and J. D. Wallis, J. Chem. Soc., Perkin Trans. 1, 1981,415. M. Shibuya and S. Kubota, Heterocycles, 1981, 15,489. Y. Tamura, Y. Takebe, S. M. M. Bayomi, C. Mukai, M. Ikeda, M. Murase, and M. Kise, J. Chem. Soc., Perkin Trans. 1 , 1981, 1037. M. Sinder-Kulyk and D. C. Neckers, Tetrahedron Lett., 1981,22, 529. M. Sinder-Kulyk and D. C. Neckers, Tetrahedron Lett., 1981. 22, 2081.

370

General and Synthetic Methods

8 Heterocycles Containing Nitrogen, Oxygen, and Sulphur Relatively few papers have appeared concerning heterocycles which fall into this category, and only a small number of them merit discussion. Nitrile sulphides and can be generated by thermal decarboxylation of 1,3,4-oxathiazo1-2-ones, if this is done in the presence of dipolarophiles new heterocycles are formed. Reactions of this type are known to occur with alkenes, alkynes, and nitriles, and they have now been shown to occur186with activated aldehydes and ketones. This provides a new route to 1,3,4-oxathiazolines (3 12) which were previously rather inaccessible. Silylated thioketones (313)are unstable but may be prepared and reacted in situ to provide routes to a variety of new heterocycles, depending upon the dipolar species R'

R2

A new method has been reported188 for the preparation of 1,2,3benzoxathiazine-2,2-dioxides (314). Finally, 1,2,5-benzoxathiazepines (315) have been prepared through a novel rearrangement of the unstable adducts of The compound obtained sulphene with N- ben~ylidene-2-hydroxyanilides.~~~ was identical with that produced unambiguously by an alternative route.

-OH

(314)-

+

OH

0,s = C H 2

1

A. M. Damas, R. 0. Gould, M. M. Harding, J. F. Ross, and J. Crosby, J. Chem. SOC.,Perkin Trans. 1 , 1981, 2991. B. F. Bonini, G. Mazzanti, S. Sarti, P. Zanirato, and G. Maccagnani, J. Chem. SOC., Chem. Commun., 1981,822. "'A. Kamal and P. B. Sattur, Synthesis, 1981, 272. lS9 M. Rai and B. Kaur, J. Chem. SOC.,Chem. Commun., 1981,971.

9 Highlights in Total Synthesis of Natural Products BY A. P. JOHNSON

1 Introduction Most of the trends which were apparent in previous years have continued to manifest themselves. The feverish activity directed towards the synthesis of the hirsutane class of sesquiterpenes has not abated and other natural products containing annulated cyclopentane rings have also proved popular synthetic targets. In the field of steroid synthesis, Stork and his co-workers have developed an outstandingly elegant approach to 1l-oxygenated steroids. Work concerned with providing solutions to the difficult stereochemical problems encountered in the synthesis of the macrolide and polyether antibiotics continues, and in this field pride of place must go to the total synthesis of erythromycin which has been completed by the collaborators of the late R. B. Woodward.

2 Terpene and Other Carbocyclic Systems The previously established biosynthetic relationship between fomannosin (1) and illudol(2) provides the key element in the strategy behind the total synthesis of (1)by Semmelhack and Tomoda.' Thus a stereospecific Diels-Alder reaction provided (3) which was converted to (4) in several steps. Silyl ether cleavage brought about a spontaneous translactonization to yield ( 5 ) which was readily converted to (1).

(1)

I

OH (2)

The upsurge of interest in the synthesis of natural products containing two or more fused cyclopentane rings shows no signs of abating. Three different of total syntheses of (k)-isocomene (6) have now appeared, two of

' M. F. Semmelhack and S. Tomoda,J. Am. Chem. SOC.,1981,103,2427. M. C. Pirrung, J. Am.Chem. Suc., 1981, 103, 82. L. A. Paquette and Y.-K. Han, J. Am. Chem. Suc., 1981,103, 1835. W. G. Dauben and D. M. Walker, J. Org. Chem., 1981,46,1103.

371

General and Synthetic Methods

372

E which provide details of previously published work. Pirrung's modification (Scheme 1)of his earlier route provides a particularly efficient and elegant entry into this system.

6

3

@ I

ChJ-

TsOH-benzene, A

CH,=PPh,,DMSO,

$g

Scheme 1

(6)

Four syntheses of the related sesquiterpene, modhephene (9) have also been r e p ~ r t e d One . ~ ~of these also proceeds uia a [2 + 2]photocycloaddition route to give (7) followed by an acid-catalysed Cargill rearrangement to (8), which was converted to modhephene (9) by conventional methods. The bulk of the work in this area continues to be directed at the synthesis of sesquiterpenes of the hirsutane group. Details have appeared of the previously reported synthesis

(7)

(10) A. B. Smith and P. J. Jervis, J. Am. Chem. Soc., 1981,103, 194.

' H. Schostarez and L. A. Paquette, J. A m . Chem. Soc., 1981,103,722. ' W. Oppolzer and F. Marazza. Helu. Chim. Acra, 1981,64, 1575; W. Oppolzer and K. Battig, Helu. Chim. Actu, 1981, 64, 2489. M. Karpf and A. S. Dreiding, Helu. Chim. Acru, 1981, 64, 1123.

Highlights in Total Synthesis of Natural Products

373

of coriolin and hirsutene (11)" and new syntheses of both of these compounds have also appeared. "J A' novel olefin metathesis sequence (Scheme 2) is used to construct the hirsutane nucleus in one of these new approaches," whereas another makes use of a cyclopentane annulation12[(12) + (13)]. The

* 0

0

Scheme 2

tricycle (13) promises to be a useful key intermediate for the synthesis of other members of this class of sesquiterpenes. The synthesis of A9""-capnellene (16) has been achieved by two groups. Little and Carr011'~have again exploited an intramolecular cycloaddition to a thermally generated diyl[(l4) 3 (15)] though unfortunately in this case the reaction showed very little stereoselectivity. The conversion of (15) to A9('2)-capnellene(16) was readily achieved. The alternative synthesis was more ~traightforward,'~ one ring being constructed by a Nazarov

lo

'' l3

S. Danishefsky, R. Zamboni, M. Kahn, and S. J. Etheredge, J. A m . Chem. SOC.,1981,103, 3460. R. D. Little and G. W. Muller, J. A m . Chem. SOC.,1981,103, 2744. G. Mehta and A. V. Reddy, J. Chem. SOC.,Chem. Commun., 1981,756. B. M. Trost and D . P. Curran, J. A m . Chem. SOC.,1981,103.7380. R. D. Little and G. L. Carroll, Tetrahedron Lett., 1981, 22, 4389. K. E. Stevens and L. A. Paquette, Tetrahedron Lett., 1981,22,4393.

374

General and Synthetic Methods

cyclization [(17) + (18)] and another by an ozonolysis followed by an aldol condensation [(19) + (20)]. Paquette and his co-workers have also completed a synthesis of (*)-pentalactone E-methyl ester (24)." The key intermediate, (21), (whose synthesis had been reported previously) was converted to the vinyl iodide (22) via the corres-

a 0

H

BQ (22) R (23) R

= =

I C02Me

ponding hydrazone. The nickel carbonyl-sodium methoxide reagent smoothly converted (22) to (23), which in turn was readily converted to (24). Details have appeared of Danishefsky's synthesis of quadrone (25),16whose synthesis has now also been reported by Helquist et al.17 Although the two syntheses show considerable overlap in the overall strategy, the latter achieved greater regioselectivity in the lactone synthesis by constructing the

I-IV

,

fH-C02Me

Qk

0 0

(25) Reagents: i, PhSCHLiCO,Me, -60 "C-35 "C; ii, CH,=O; iii, NaBH,; iv, (CH,),C(OMe),-TsOH; v, Li-NH, Scheme 3

17

L. A. Paquette, H. Schostarez, and G. D . Annis, J. Am. Chem. SOC., 1981, 103,6526. S. Danishefsky, K. Vaughan, R. Gadwood, and K. Tsuzuki, J. Am. Chem. Soc., 1981, 103, 4136. W. K. Bornack, S. S. Bhagwat, J. Pouton, and P. Helquist, J. Am. Chem. Soc., 1981, 103,4647.

Highlights in Total Synthesis of Natural Products

375

elements of the lactone ring by a conjugate addition-enolate trapping sequence (Scheme 3). The meta- or 1,3-photoaddition of olefins to arenes [(26) + (27) -* (28)] is potentially a very useful synthetic reaction since it proceeds from readily available starting materials with the formation of three rings and up to six stereocentres. However, since its discovery in 1966 it has not been used to any extent for the synthesis of natural products, perhaps because a large number of isomeric products might result from the reaction of unsymmetrical arenes. However, as

Wender and Howbert have now pointed out,'* the constraints imposed by an intramolecular reaction greatly reduce the number of possible isomers, thus permitting this reaction to be used as the pivotal step in their very elegant synthesis of cedrene (29) (Scheme 4).

(29)

Scheme 4

The anti-leukaemic and anti-tumour compound eriolanin (30) has been synthesized by Schlessinger and Roberts by a route in which the key step is a base-induced fragmentation of (31) to (32).19 ?H

MeOlC,

MOM0 H

(31) l8

P. A. Wender and J. J. Howbert, J. A m . Chem. SOC.,1981,103,688.

*' M.R. Roberts and R. H . Schlessinger, J. A m . Chem. SOC..1981,103,724.

I

!

(32)

General and Synthetic Methods

376

X-14547A (33) is an unusual ionophore antibiotic in that its structure includes a tetrahydroindan system. There has been considerable synthetic interest20-22 in this compound which has culminated in a total ~ynthesis.'~ Not surprisingly, the intramolecular Diels-Alder reaction proved a popular choice for the construction of the tetrahydroindan unit. The synthesis of highly functionalized decalins continues to attract interest, with syntheses reported of walburganal (34),24drimenin (35),25polygodial (36),25 cinnamodial (37),26and compactin (41).27Compactin is of some pharmacological interest since it is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-controlling enzyme in cholesterol biosynthesis. A major problem in the synthesis of (41) was the stereoselective introduction of the axial methyl substituent. This was finally achieved by conjugate addition

@ H

(33)

H

i

(34)

(35)

WCHO wo PhCH20

QCHO

PhCH2O

(37)

PhCH20 & 0 0 y 0 ~ P h C HCH2OH 20

;

Y'

I

__ PhC 20 21

22

23

(41) M. P. Edwards, S. V. Ley, and S. G. Lister, Tetrahedron Lett., 1981,22,361. K.C. Nicolaou and R. L. Magolda, J. Org. Chem., 1981.46,1506. W. R. Roush and A. G. Myers, J. Org. Chem., 1981,46,1509. K . C . Nicolaou, D . P. Papahatjis, D. A. Claremon, and R. E. Dolle, J. Am. Chem. SOC.,1981, 103,6967;K.C. Nicolaou, D . A. Claremon, D. P. Papahatjis, and R. L. Magolda, I. Am. Chem. Soc.. 1981,103,6969.

24

25

26 2'1

S . V.Ley and M. Mahon, Tetrahedron Lett., 1981,22,3909. M. Jallali-Naini, G. Boussac, P. Lemaitre, M. Larcheveque, D. Guillerm, and J.-Y.Lallemand, Tetrahedron Lett., 1981.22,2995. L. P. J. Burton and J. D . White, J. A m . Chem. Soc., 1981,103,3226. N.-Y. Wang. C.-T. Hsu, and C. J. Sih, J. Am. Chem. Soc., 1981,103,6538.

Highlights in Total Synthesis of Natural Products

377

to enone (38) followed by enolate trapping by formaldehyde to give (39). Dehydration of (39)followed by hydrogenation in the presence of pyridine gave (40).

The first total synthesis of trihydroxydecipiadiene (45),28 a member of the structurally unique decipiene diterpenes, has been reported. A route involving cycloaddition of dichloroketen and reductive dehalogenation led to (42) which was found to undergo a stereospecific aldol reaction to give (43) under carefully controlled conditions. As expected, catalytic hydrogen was stereospecific giving the desired isomer (44), which in turn was converted to (45) in several steps,

I

r C H O

(43)

(44)

Jatrophone (46) is an attractive synthetic target, not only because of its interesting macrocyclic structure, but also because of its significant activity as an inhibitor of certain cancers. The normethyl derivative (50) has now succumbed to the efforts of Smith and his c o - w ~ r k e r s The . ~ ~ key element in the synthetic

OSiMe3 OSiMe3 (46) R (50) R

= =

Me H

I (48) 29

+ (49)

M. L. Greenlee, J. A m . Chem. SOC., 1981, 103,-2425. A. B. Smith, 111, M. A. Guaciaro, S. R . Schow, P. M. Workulich, B. H. Toder, and T. W. Hall, J. Am. Chem. SOC.,1981,103,219.

General and Synthetic Methods

378

strategy was the construction of the oxaspirocyclic system (49) by an aldol reaction between (47) and (48) followed by oxidation. The formation of the macrocyclic ring of (50) proved troublesome but was eventually achieved by the Mukaiyama aldol reaction (TiC1,-promoted condensation of an acetal with an enol silyl ether). A new synthesis of (+)-aphidicolin (54) has been r e p ~ r t e d . ~A' key step in the projected synthesis was the photo-induced conversion of (51) to (53). In practice, photolysis led exclusively to (52) despite strenuous attempts to trap the keten intermediate with methoxide. Fortunately, (52) proved to be rather CHzSiMe3

J=H2SiMes

do dH J-:" C W C

O

(53) (53)

unstable and chromatography on silica gel brought about a smooth conversion to (53)which was then converted to (54) in several steps. The structurally related compound, maritimol ( 5 9 , has also been synthesized, by a route that has some parallels with the probable b i o g e n e ~ i s . ~ ~ HO

HO'H

HO

; A

CHzOH

(55)

(54)

A

o*o

O u O

Hwp M

I

CO, Me

Me0

Me0

OMe OMe (56)

30 31

OMe (57)

R. E. Ireland, J. D. Godfrey, and S. Thaisrivongs,J. A m . Chem. Soc., 1981, 103,2446. E. E. van Temelen, J. G. Carlson, R. K. Russell, and S. R. Zawacky, J. A m . Chem. Soc., 1981, 103,4615.

379

Highlights in Total Synthesis of Natural Products

A new synthesis of the antineoplastic compound, podophyllotoxin (57), has been It scores over previous approaches in that the problem of epimerization of the C-2 carboxyl group is avoided by the use of the acetonide protecting group in the key intermediate (56). This controlling element forces (56) into a conformation with axial phenyl and equatorial ester, thus removing the usual driving force for epimerization at C-2.

3 Steroids Kametani has reviewed the synthesis of steroids via intramolecular cycloaddit i ~ and n ~has ~ also employed a reaction of this type as the key step [(SS) + (SS)] in a synthesis of chenodeoxycholic acid (60).34A variant on this theme, [(61) + (62)] is employed in a new stereoselective synthesis of e s t r ~ n e . ~ ' Stork and his co-workers have reported an exceptionally elegant route for the synthesis of 1l-oxygenated steroids.36The key step is a highly stereoselective, intramolecular Diels-Alder reaction that is undergone by (63) to give tetracyclic but non-steroidal(64). However, ozonolysis of (64) followed by aldol cyclization gave the 11-ketosteroid (65) in excellent yield.

&co2H HO'*

'OH

H (60)

@-..#

Me0

"Me3

I-

Me0 (61)

32 33 34

'' 36

\

(62)

D. Rajapaksa and R. Rodrigo, J. Am. Chem. Soc., 1981, 103,6208. T. Kametani and H. Nemoto, Tetrahedron, 1981, 37, 3. T. Kametani, K. Suzuki, and H. Nemoto, J. Am. Chem. Soc.. 1981,103, 2890. Y. Ito, M. Nakatsuka, and T. Saegusa, I. Am. G e m . Soc., 1981,103,476. G. Stork, G . Clark, and C. S. Shiner, J. Am. Chem. Soc., 1981,103,4948.

p

General and Synthetic Methods

380

OSi

+

I

osi +

@+

I

H

I

I

H

H

0

(63)

(64)

4 Anthracyclinones

Aklavinone (66),the aglycone of aclacinomycin A has proved to be a popular synthetic target with no less than four total syntheses The various approaches to the construction of the ring nucleus are outlined in Scheme 5.

I

I

OSi

f0?+

0I

+

+-+

OMe

Me

Me

C02Me

i, Zn-NaOH ii, (CF3CO)20

T

\

OMe 0

OMe ref. 37

(66)

C02Me

0

OH

OH

0

CO2Me

0 1

C02Me

+ + (66)

ref. 38 ” 38

39 40

A. S. Kende and J. P. Rizzi, 3. Am. Chem. SOC.,1981,103,4247. €3. A. Perlman, J. M. McNamara, I. Hasan, S. Hatakeyama, H. Sekizaki, and Y. Kishi, J. Am. Chem. SOC.,1981, 103,4248. P. N. Confalone and G. Pizzolato, J. A m . Chem. SOC.,1981. 103, 4251. T. Li and Y. L. Wu, J. A m . Chem. SOC., 1981, 103, 7007.

381

Highlights in Total Synthesis of Natural Products

Me0

”

0

Me0

0

OH

+ + (66)

ref. 40 Scheme 5

Details have appeared of the Hauser total synthesis of daunomycinone (71).4’ Swenton and his co-workers have also reported a synthesis of this compound in which a key step is the coupling of the ‘Hauser’ anion (69) with (68) to give (70).42The monoacetal(68) was prepared by a highly selective hydrolysis of the bis-acetal (67). Apparently this selectivity is entirely caused by the effect of the neighbouring methoxy group in (67)since the corresponding desmethoxy compound showed no similar selectivity. M e 0 OMe

M e 0 OMeOMe

41

42

Me0 OMe

S02Ph

Me

Me

F. M. Hauser and S. Prasanua, J. A m . Chem. SOC.,1981,103,4378. M.G.Dolson, B. L. Chenard. and J. S. Swenton, J. A m . Chem. Sac., 1981,103,5263.

382

General and Synthetic Methods

Variations on previously developed methodology have led to syntheses of the deoxyanthracyclines (72),43(73),44and (74).45 addiTownsend and his co-workers have exploited the previously tion of a phthalide anion to a benzyne in their neat synthesis of averufin (78).47 Thus, in the presence of a strong base, (75) and (76) underwent a regiospecific addition to give (77), the regiospecificity presumably resulting from the inductive and chelating effectsof the o-methoxymethyl group in (75). 0

R2 COMe

(72) R' = H, R2 = H, R3 = OH (73) R' = Me, R2 = H, R3 = OH (74) R' = Me, R2 = H, R3 = H

(77) R = CH20Me (78) R = H

(75)

5 Alkaloids

Perhydroindole and perhydroquinoline alkaloids continue to attract the attention of synthetic chemists, frequently serving as suitable vehicles for the exploitation of new methodology. For example, Overman and Mendelson have shown that thermolysis of (79) brings about a stereospecific rearrangement to yield (81).48 Presumably the first step is an aza-Cope rearrangement proceeding via a 'chair' transition state to yield (80),which rapidly undergoes a Mannich-type cyclization to (81).This methodology provides an entry to the amaryllidacae alkaloids since compounds related to (81) are key intermediates in earlier syntheses of these

4 Ph

.N

I

kHPh2 (79) 43 44

45 46

47

48

@

CHPh2

A. S. Kende and S. D. Boettger, J. Org. Chem., 1981,46,2799. S. D. Kimball, D. R. Walt, and F. Johnson, J. A m . Chem. SOC., 1981,103,1561. J. Yadav, P. Corey, C.-T. Hsu. K. Perlman, and C. J. Sih, Tetrahedron Lett., 1981,22, 811. N.J. P. Broom and P. G. Sammes, J. Chem. SOC., Chem. Commun., 1978,162;P. G.Sammes and D . J. Dodsworth, J. Chem. SOC.,Chem. Commun., 1979,33. C. A. Townsend, S. G . Davis, S. B. Christensen, J. C. Link, and C. P. Lewis, J. A m . Chem. SOC., 1981,103,6885. L. E. Overman and L. T. Mendelson, J. A m . Chem. Soc., 1981,103,5579.

3 83

Highlights in Total Synthesis of Natural Products

alkaloids. An alternative route to these alkaloids is provided by Keck and Webb,49who have exploited the intramolecular 'ene' reaction of the acylnitroso compound (82) to give (83), which in turn is readily converted to crinane (84). /-0

n H-

'

(0

OH

(84)

(83)

An iminium ion-vinylsilane cyclization (Scheme 6) provides the basis for a very short synthesis of dendrobatid toxin 251D (85) as reported by Overman and Bell.50A related iminium ion cyclization [(86) -* (87)] is a key step in a new synthesis of gephyrotoxin (88).'*

Me H

&Me

SiMe I,

CH,=O

A

ii, H '

cqH Me

**OH Me

Scheme 6

bH \

0

HO 49 50

51

G . E. Keck and R. R. Webb, 111, J. Am. Chem. Soc., 1981,103,3173. L. E. Overman and K. L. Bell, J. Am. Chem. Soc., 1981,103, 1851. D. J. Hart, J. Org. Chem.. 1981, 46, 3576.

H

384

General and Synthetic Methods

A novel variation of the Beckmann rearrangement has been used by Yamamoto and his co-workers in the course of an extremely short synthesis of pumiliotoxin C (89).’* As shown in Scheme 7, trialkylaluminium catalyses the Beckmann rearrangement and then serves to alkylate the intermediate nitrilium species.

-

I

Pr,AI

N-OTS

@+

PrJAl

(89)

Scheme 7

Details of the synthesis of gliotoxin (90) and related compounds have been reported by Kishi and his c o - ~ o r k e r s . ’ ~ The intramolecular Diels-Alder reaction has served as the key step [(91) -* (92)] in a synthesis of lycorine (93).54 An aza-variant of the same reaction

A

(92) 52

(93)

K. Hattori, Y. Matsumura, T. Miyazaki, K. Maruoka, and H. Yamamoto, J. A m . Chem. SOC.,1981,

103,7368.

’’ T.Fukuyama, S. Nakasuka, and Y. Kishi, Tetrahedron, 1981,37,2045. 54

S.F. Martin and C.-Y.Tu, J. Org. Chem., 1981,46,3763.

385

Highlights in Total Synthesis of Natural Products

[(94) + (931 performs the same function in the Oppolzer synthesis of lysergic acid (96).” COzMe

CO2H

&Me \

&\b M e

HN

HN (94)

(96)

(95)

Dehydrosecodine (97) is believed to be a key intermediate in the biosynthesis of the Aspidosperma and Iboga alkaloids.The dihydro-derivative,secodine (102), has now been synthesized by a route involving a Claisen ortho ester rearrangement [(98) + (99) -* (loo)] and in situ elimination of methanol [(loo) + ( 101)].~~

X

(101) R = C02C(Me)2CC12, X (102) R = H, X = H2

=o

The photo-induced 1,3-acyl shift of enamides has been used to provide an entry to both Strychnos and Aspidosperma alkaloids (Scheme 8).” The utility of the process is exemplified by the synthesis of quebrachamine (103). A new synthesis of colchicine (108) utilizes the trifluoroacetic acid-induced conversion of (104) to (107) in 92% yield.” This process probably proceeds via intermediates (105) and (106), which can be isolated when alternative reaction conditions are employed. ”

W. Oppolzer, E. Francotte, and K. Battig, Helv. Chim. Acta, 1981, 64,478.

”

Y. Ban, K. Yoshida, J. Goto, and T. Oishi, I. A m . Chem. SOC., 1981,103,6990. D. A. Evans, S. P. Tains, and D. J. Hart, J. A m . Chem. Soc., 1981,103, 5813.

’‘ S. Raucher, J. E. Macdonald, and R. F. Lawrence, J. A m . Chem. SOC.,1981,103,2419.

General and Synthetic Methods

386

JJ

0

Scheme 8

Me0 Me0 Me0 M e 0 OMe

_--

CO2Me M e 0 \

Me0 Me0

I

O2Me

OMe OMe

Me0 0

0

(107)

(106)

Me0 Me0

3 87

Highlights in Total Synthesis of Natural Products

6 Stereochemically-complex Oxygen Heterocycles Methods for the preparation of optically active compounds have been re~iewed.'~ Still and his co-workers recently developed the hydroboration of acyclic 1,4dienes as a method for the controlled creation of stereocentres. Two groups have now exploited this method in a short synthesis of the Prelog-Djerassi The key step in both routes is the hydroboration-oxidation lactone (111).60*61 of (109) to (110) that is highly stereoselective with respect to three of the four stereocentres of (110).

Several of the anthracycline antibiotics are highly effective against a wide variety of tumours, but possess a toxicity that severely limits dosage. In consequence considerable efforts have been directed towards modification of structure, and in one case lowering of toxicity has been achieved by replacing the carbohydrate moiety L-daunosamine (115) by its C-4 epimer L-acosamine (116). A chiral synthesis of both these compounds has now been reported.62The key step is an intramolecular nitrone-olefin cycloaddition [(112) + (113) and (114) in a ratio of 82 : 181 in which the chiral side-chain exerts considerable asymmetric induction. The major isomer (1 13) could be converted to either (115) or (116) by conventional means.

*'NH2 0

(115)

(112) (113)

"14'

R'

(116)R'

= =

OH,R2 = H H,R2 = OH

The utilization of sugars as a source of cheap, chiral starting materials continues to flourish. Thus, D-glucose serves as the starting material in syntheses of tirandamycic acid (117),63tylonolide (118),64and carbomycin B (1 19y5 and leucomycin A3 (120).65 Masamune and his collaborators have contributed much to the development of the stereoselective aldol condensation. Through the use of chiral boron 59

6o 61

62

63

65

S. Terashima, Yukuguku Zasshi, 1981,100, 1171. D. J. Morgans, Tetrahedron Lett., 1981, 22, 3721. W. C. Still and K. R. Show, Tetrahedron Lett., 1981,22,3725. P. M. Woukulich and M. R. UskokoviC, J. Am. Chem. SOC., 1981,103,3956. R. E. Ireland, P. G . M. Wuts, and B. Ernst, J. A m . Chem. SOC.,1981,103, 3205. K. Tatsuta, Y. Amemiya, Y. Kanemura. and M. Kinoshita, Tetrahedron Lerr., 1981, 22, 3997. K. C. Nicolaou, S. P. Seitz, and M. R. Pavia, J. Am. Chem. SOC., 1981, 103, 1222; ibid., 1224.

General and Synthetic Methods

388

Jr

HO2C

R'

NMe2

Me

OCOCH2CHMe2

(119) R' = OH, R2 = H (120) R', R2 = 0

enolates they have now developed a highly enantioselective variation of the reaction [e.g. (121) + (122) + (123) -B (124), with enantioselectivity 100: 1].66 This methodology is extensively exploited in the Masamune synthesis of 6deoxyerythronolide B (1 2 5 y 7 a common biosypthetic precursor of all the currently known erythromycins. 1

"

S. Masamune, W. Choy,F. A . J. Kerdesky, and B. Imperiali, J. A m . Chem. Soc., 1981,103,1566. S.Masamune, M. Hirama, S. Mori, S. A. Ali, and D. S. Gamey, J. A m . Chem. SOC.,1981,103,1568.

Highlights in Total Synthesis of Natural Products

389

Finally, a fitting memorial to the late R. B. Woodward is provided by the publication of three papers describing the total synthesis of erythromycin (126).68”” A key element in the synthetic strategy is the use of the dithiadecalin (127) as a source of the C-3-C-8 and C-9-C-13 portions of the seco-acid (128). The dithiadecalin (127) was synthesized by an enantioselective aldol cyclization, catalysed by D-proline [(129) + (130)], followed by dehydration, sodium borohydride reduction, osmium tetroxide oxidation, and acetamide formation. Closure of the seco-acid (128) to the 14-membered lactone could not be achieved by any of the multitude of methods that have been developed for this purpose in recent years. However, subjection of the close relative (131) to the Corey procedure did bring about a smooth lactonization, presumably because (131)adopts a conformation more conducive to lactonization than that adopted by (128). The synthesis was concluded by the attachment of Ddesosamine and L-cladinose to the appropriate sites. Me

*PMe2 w Me

HO

OMe

Me Me

Jfe

MeOCH20

OCHzPh

%

Me Me0

(127)

Me

(126)

11

Me

Me

Me

/s+s\ n

Me

___H _

Me

Me

Me

1 4 0 n**H I ‘-H 1 0

68aR. B. Woodward, E. Logusch, K.P. Nambiar, K. Sakan, D. E. Ward, B.-W. Au-Yeung, P. Balaram, L. J. Browne, P. J. Card, C. H. Chen, R. B. Chenevert, A. Fliri, K. Frobel, H.-J. Gais, D. G. Garratt, K. Hayakawa, W. Heggie, D. P. Hesson, D. Hoppe, I. Hoppe, J. A. Hyatt, D. Ikeda, P. A. Jacobi, K. S. Kim, Y. Kobuke, K.Jojima, K. Krowicki, V. J. Lee, T. Leutert, S. Malchenko, J. Martens, R. S. Matthews, B. S. Ong, J. B. Press, T. V. Rajan Babu, G. Rousseau, H. M. Sauter, M. Suzuki, K. Tatsuta, L. M. Tolbert, E. A. Truesdale, I. Uchida, Y. Ueda, T. Uyehara, A. T. Vasella, W. C. Vladuchick, P. A. Wade, R. M. Williams, and H. N . 4 . Wong, J. Am. Chem. Soc., 1981,103,3210; ibid.,1981, 103,9213; ibid., 1981, 103, 3215.

Reviews on General and Synthetic Methods COMPILED BY G. PAlTENDEN AND G. M. ROBERTSON

1 Olefins P. J. Kocienski, ‘A New and Useful Olefin Synthesis based on Sulphones’, Chem. Ind., 1981, 548. R. F. Heck, ‘Palladium-catalysed Synthesis of Conjugated Polyenes’, Pure Appl. Chem., 1981,53,2332. J. F. Normant and A. Alexakis, ‘Carbometallation, C-Metallation of Alkynes, Stereospecific Synthesis of Alkenyl Derivatives’, Synthesis, 1981, 841.

2 Aldehydes and Ketones T. A. Hase and J. K. Koshimies, ‘A Compilation of References of Formyl and Acyl Anion Synthons’, Aldrichimica Acta, 1981,14, 73. F. A. J. Meskens, ‘Methods for the Preparation of Acetals from Alcohols, or Oxiranes and Carbonyl Compounds’, Synthesis, 1981, 501.

3 Nitrogen-containing Functional Groups S. Rajappa, ‘Nitroenamines. Preparation, Structure and Synthetic Potential’, Tetrahedon, 1981, 37, 1453. H. W. Moore and M. D. Gheorghiu, ‘Cyanoketenes: Synthesis and Cycloadditions’, Chem. SOC.Rev., 1981, 10, 289. 4 Organometallics

Boron H. C . Brown and J. B. Campbell, ‘Synthesis and Applications of Vinylic Organoboranes’, Aldrichimica Acta, 1981,14, 3. Silicon E. W. Colvin, ‘Silicon in Organic Synthesis’, Butterworth Publishers Inc., Massachusetts, 1981. I. Fleming, ‘Some uses of Silicon Compounds in Organic Synthesis’, Chem.Soc.Rev., 1981, 10, 83. A. H. Schmidt, ‘Bromotrimethylsilane and Iodotrimethylisane-Versatile Reagents for Organic Synthesis’, Aldrichimica Acta, 1981, 14, 31. Tin M. Pereyre and J.-P. Quintard, ‘Organotin Chemistry for Synthetic Applications’, Pure A p p l . Chem., 1981, 53,2401. 390

Reviews on General and Synthetic Methods

391

Transition Elements B. M. Trost, ‘Transition Metal Templates for Selectivity in Organic Synthesis’, Pure Appl. Chem., 1981, 53, 2357. Y. H. Lai, ‘Organic Reductive Coupling with Titanium and Vanadium Chlorides’, Org. Prep. Proc. Int., 1980, 12, 361. E. Negishi, ‘Bimetallic Catalytic Systems Containing Ti, Zr, Ni and Pd. Their Applications to Selective Organic Synthesis’, Pure Appl. Chem., 1981, 53, 2333. 5 Ring Synthesis

G. Illuminati and L. Mandolini, ‘Ring Closure Reactions of Bifunctional Chain Molecules’, Acc. Chem. Res., 1981, 14, 95. A. Padwa, T. J. Blacklock, and W. F. Rieker, ‘Synthesis of Polycyclic Ring Systems via Intramolecular [2 + 21-Cycloaddition Reactions of Cyclopropene Derivatives’, Isr. J. Chem., 1981, 21, 157. A. Viola, J. J. Collins, and N. Filipp, ‘Intramolecular Pericyclic Reactions of Acetylenic Compounds’, Tetrahedron, 1981, 37, 3765. W. Oppolzer, ‘Regio-and Stero-selective Synthesis of Cyclic Natural Products by Intramolecular Cycloaddition-and Ene-reactions’,Pure Appl. Chem., 1981, 53, 1181. S. Danishefsky, ‘Siloxydienesin Total Synthesis’,Acc. Chem. Res. 1981,14,400.

6 Heterocycles K. Matsumoto, T. Uchida, and R. M. Acheson, ‘The Synthesis and Reactions of Heterocycles under High Pressures’, Chem. Sac. Rev., 1981,16, 1367. C. Wentrup, ‘Carbenes and Nitrenes in Heterocyclic Chemistry. Intramolecular Reactions’, A d v . Heterocycl. Synth, 1981, 28, 232. V. Snieckus and J. Streith, ‘1,2-Diazepines. A New Vista in Heterocyclic Chemistry’, Acc. Chem. Res., 1981, 14, 348. M. R. Grimmett, ‘Advances in Imidazole Chemistry’, A d v . Heterocyl. Chem., 1981, 27, 1. T. Mukai, T. Kumagai, and Y. Yamashita, ‘Cyclization and Cyloaddition Reactions of Heteroepins, Conjugated Seven-membered Heterocyclic Comunds’, Heterocycles, 1981, 15, 1569. R. Barone and M. Chanon, ‘Synthesis of Elliptecine. Review and Computer Suggestions’, Chem. SOC.Rev., 1981, 16, 1357. I. Ninomiya and T. Naito, ‘Enamide Photocyclization and its Application to the Synthesis of Heterocycles’, Heterocycles, 1981,15, 1433. W. Freidrichesen and A. Bottcher, ‘Recent Developments in the Chemistry of o -Benzoquinone-diimines’,Heterocycles, 1981, 16, 1009. M. Petrzilka and S. I. Grayson, ‘Preparations and Diels-Alder Reactions of Hetero-substituted 1,3-Dienes,’ Synthesis, 1981, 753. I. Murata and K. Nakasuji, ‘Recent Advances in Thiepin Chemistry’, Top. Curr. Chem., 1981,97,33.

392

General and Synthetic Methods 7 Photochemical Methods

G. R. Lenz, ‘Photocycloaddition Reactions of Conjugated Enones’, Reu. Chem. Intermed, 1981, 4, 369. A. Albini, ‘Photosensitizationin Organic Synthesis’, Synthesis, 1981, 249. S. W. Baldwin, ‘Synthetic Aspect of 2 + 2 Cycloadditions of a,P-Unsaturated Carbonyl Compounds’, in ‘Organic Photochemistry,’ ed. A. Padwa, Dekker, New York, 1980, Vol. 5. J. Grimshaw and A. P. de Silva, ‘Photochemistry and Photocyclization Aryl Halides’, Chem. SOC.Reu., 1981, 10, 181. P. H. Mazzocchi, ‘The Photochemistry of Imides’, in ‘Organic Photochemistry’, ed. A. Padwa, Dekker, New York, 1980, Vo1.5. H. G. Jones, ‘SyntheticApplications of the Paterno-Buchi Reaction’, in ‘Organic Photochemistry’, ed. A. Padwa, Dekker, New York, 1980, Vol. 5 .

8 Oxidation H. H. Wasserman and J. L. Ives, ‘Singlet Oxygen in Synthesis’, Tetrahedron, 1981,37, 1825. P. S. Bailey, ‘Ozonation in Organic Chemistry’, Academic Press, New York, 1982, Vol. 2. V. Kamojitzby, ‘Oxidation of Ketones by Molecular Oxygen’, Russ. Chem. Reu., 1981, 50, 888.

9 Asymmetric Synthesis G. H. Posner, J. P. Mallarno, and M. Hulce, ‘Asymmetric Synthesis using Organometallic Reagents and Optically Pure Vinylic Sulphoxides’,Pure A p p l . Chem., 1981,53,2307. G. SolladiC, ‘Asymmetric Synthesis using Nucleophilic Reagents Containing Chiral Sulphoxide Groups’, Synthesis, 1981, 185. H. C. Brown, P. K. Jadhav, and A. K.Mandal, ‘AsymmetricSynthesis via Chiral Organoborane Reagents’, Tetrahedron, 1981,37, 3547. V. Caplar, G. Comisso, and V. Smijic, ‘HomogeneousAsymmetric Hydrogenation’, Synthesis, 1981, 85.

10 Polymer Supports in Synthesis ‘Polymer Supported Reactions in Organic Synthesis’, ed. P. Hodge and D. C. Sherington, Wiley-Interscience,New York, 1980. W. R. Scheidt and C. A. Reed, ‘Applications of Functionalised Polymers in Organic synthesis’, Chem Rev., 1981, 81,557. A. Akelah, ‘Heterogeneous Organic Synthesis using Functionalised Polymers’, Synthesis, 1981, 413.

11 Protecting Groups T. W. Greene, ‘Protective Groups in Organic Synthesis’, Wiley-Interscienc 2, New York, 1981.

Reviews on General and Synthetic Methods

393

J. M. F. Frkchet, ‘Synthesis and Applications of Organic Polymers as Supports and Protecting Groups’, Tetrahedron, 1981, 37,663.

12 Natural Product Synthesis E. Wenkert, ‘Alkaloid Synthesis’, Pure Appl. Chem., 1981, 53, 1271. G. D. Pandey and K. P. Trivari, ‘On the Use of Lactones as Building Blocks in the Alkaloid Synthesis-A Review’, Heterocycles, 1981, 16, 449. A, P. Kozikowski, ‘Synthesis of 4-Substituted Indoles and the Elaboration to the Ergot Alkaloids’, Heterocycles, 1981, 16,267. R. P. Evstigneeva, ‘Advances and Perspectives of Porphyrin Synthesis’, Pure Appl. Chem., 1981, 53, 1129. T. Kametani and K. Nemoto, ‘Recent Advances in the Total Synthesis of Steroids via Intramolecular Cycloaddition Reactions’, Tetrahedron, 1981, 37,3. B. Lythgoe, ‘Synthetic Approaches to Vitamin D and its Relatives’, Chem. SOC. Rev., 1980, 9,449. A. F. Thomas and Y. Bessiere, ‘The Synthesis of Monoterpenes’, in ‘The Total Synthesis of Natural Products’, ed. J. ApSimon, Wiley-Interscience, New York, 1981, Vol. 4. R. K. Razdan, ‘The Total Synthesis of Cannabinoids’, in ‘The Total Synthesis of Natural Products’, ed. J. ApSimon, Wiley-Interscience, New York, 1981 VOl. 4. J. S. Bindra, ‘The Synthesis of Prostaglandins’, in, ‘The Total Synthesis of Natural Products’, ed. J. ApSimon, Wiley-Interscience, New York, 1981, VOl. 4. W. Wierenga, ‘The Total Synthesis of Ionophores’, in, ‘The Total Synthesis of Natural Products’, ed. J. ApSimon, Wiley-Interscience, New York, 1981, VOl. 4. K. Mori, ‘The Synthesis of Insect Pheromones’, in, ‘The Total Synthesis of Natural Products’, ed. J. ApSimon, Wiley-Interscience, New York, 1981, VOl. 4.

13 General H. Alper, ‘Phase Transfer Catalysis in Organometallic Chemistry’, Adu. Organomet. Chem., 1981, 19, 183. H. J. Schafer, ‘Anodic and Cathodic C-C Bond Formation, Angew. Chem., Int. Ed. Engl., 1981, 20, 911. D. H. R. Barton and W. Motherwell, ‘New and Selective Reactions and Reagents in Carbohydrate Chemistry’, Pure A p p l . Chem., 1981, 53, 15. D. H. R. Barton and W. Motherwell, ‘New and Selective Reactions and Reagents in Natural Product Chemistry’, Pure Appl. Chem., 1981, 53, 1081. A. L. Lapidus and Y. Y. Ping, ‘Organic Synthesis Based on Carbon Dioxide’, Russ. Chem. Rev., 1981, 50, 63. Oka, ‘Some Applications of Thionyl Chloride in Organic Synthesis’, Synthesis, 1981,661. A. J. Mancuso and D. Swern, ‘Activated Dimethylsulphoxide, Useful Reagents for Synthesis’, Synthesis, 1981, 165.

394

General and Synthetic Methods

Y. Nagai, ‘Hydrosilanesas Reducing Agents’, Org. Prep. Proc. Knt., 1980,12,13. R. 0 . Hutchins and F. Cistone, ‘Utility and Applications Borane Dimethylsulphide in Organic Synthesis’, Org. Prep. Proc. Int., 1981, 13, 225. 14 Miscellaneous D. Arlt, M. Jautelat, and R. Lantzoch. ‘Synthesis of Pyrethroid Acids’, Agnew. Chem., Int. Ed. Engl., 1981, 20, 703. . Kappe and W. Stadlbauer, ‘Isatoic Anhydrides and Their Uses in Synthesis’, A d v . Heterocycl. Synth, 1981, 28, 127. M. Balci, ‘Bicyclic Endoperoxides and Synthetic Applications’, Chem. Rev., 1981, 81, 91. W. T. Brady, ‘Synthetic Applications involving Halogenated Ketenes’, Tetrahe‘dron, 1981,37, 2949. A. K. Bhattacharya and G. Thyagarajam, ‘The Michaelis-Arbuzov Rearrangement’, Chem. Rev., 1981,81,415. J. Yoshimura, ‘StereoselectiveSynthesis of Branched Chain Sugar Derivatives’, Pure Appl. Chem., 1981, 53, 113. G. Cainelli and G. Cardillo, ‘Some Aspects of the Stereospecific Synthesis of Terpenoids by Means of Isoprene Units’, Ace. Chem. Res., 1981,14, 89. F. Freeman, ‘Reactions of Malononitrile Derivatives’, Synthesis, 1981, 925, A. L. J. Beckwith, ‘Regio-selectivityand Stereo-selectivityin Radical Reactions’, Tetrahedron, 1981,87,307. 0. Mitsimobu, ‘The Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Products,’ Synthesis, 1981, 1. Yu. V. Belkin and N. A. Pclezhaeva, ‘The Chemistry of Stabilised Sulphonium Ylides’, Russ. Chem. Rev., 1981, 50, 481. G. R. Krow, ‘Nitrogen Insertion Reactions of Bridged Bicyclic Ketones. Regioselective Lactam Formation’, Tetrahedron, 198 1, 37, 1283. A. B. Smith and R. K.Dieter, ‘The Acid Promoted Decomposition of a-Diazo Ketones’, Tetrahedron, 1981, 37, 2407.

Author Index Abatjoglou, A. G., 170 Abbaspour, A., 124, 287, 315 Abdul-Malik, N. F., 313 Abe, I., 323 Abe, N., 365 Abe, Y., 123, 152 Abushanab, E., 8 Acher, F., 272 Acheson, R. M., 369, 391 Achiwa, K., 329 Achmatowicz, O., 147 Ackroyd, J., 353 Adam, W., 6, 125, 211, 312 Adiwidjaja. G., 335, 346, 356,366 Adlington, R. M.,28, 137, 138, 144, 147, 243, 316, 324 Agawa, T., 20, 22, 78, 205, 256, 268, 278, 348, 357, 368 Ager, D. J., 62, 83, 89, 259 Agho, M. O., 200 Agosta, W. C., 110, 280 Agrawal, K. C., 357 Aguilar, M.A., 206 Ahluwalia, V. K.. 319 Ahmed, F. R., 234, 324 Ahmed. Z., 304 Aiello, E., 354 Aizawa, M., 301 Akelah, A., 392 Akermark, B., 112 Akgiin, E., 282 Akiba, K., 1, 267 Akimoto, I., 253 Akimoto, K., 289 Akiyama, T., 131 Akssira, M.,134 Akullian, V., 293 Alberts, V., 127 Albini, A., 392 Alender, J., 364 Alerdice, M., 306 Alexakis, A., 12, 38, 165, 226, 390 Ali, Sk. A., 95, 141, 252, 388 Ali, S. M., 216 Allan, R. D., 146 Alonso-Cires, L., 199, 249 Alper, H., 37, 211, 219, 231, 234,249, 324, 393 Altevogt, R., 4 Alvarez-Bailla, J., 33 1

Alvernhe, G. M.,197 Aly, M. M., 356 Amemiya, Y., 387 Americo, A. M., 354 Amice, P., 21, 69, 75, 307 Amin, S. G., 326 Amin, N. V., 207 Amino, Y., 144 Amos, R. A., 138 Amouroux, R., 197 Amstutz, R., 92 Andersen, N. H., 260, 284 Anderson, D. K., 282 Anderson, D. R., 328 Anderson, G. H., 18 Anderson, H. J., 206 Anderson, P. C., 278 Ando, K., 207 Ando, M.,229 Ando, R., 78, 274 Ando, W., 198, 262 Andrade, J. G., 132, 318 Andreu, D., 152 Andrews, G. C., 129 Andrus, A., 292 Aneja, R., 41 Anez, M.,159, 250 Anisimov, A. V., 347 Annis, G. D., 140, 234, 290, 3 74 Annunziata, R., 163, 205 Anteunis, M. J. O., 146, 203, 225 Antonioletti, R., 26, 80 Aoai, T., 32, 143 Aoki, S., 48, 189, 264 Aoyama, H., 326 Araki, K.,185 Araki, S., 33, 268 Araki, Y., 88, 258 Ardecky, R. J., 303 Arias, L. A., 211 Arimoto, M., 37, 79, 209, 255,256, 301 Arison, B. H., 197 Aristoff, P. A., 287 Aritomi, J., 345 Arlt, D., 101, 279, 394 Arora, K. K., 319 Arrieta, A., 268 Arrieta, J. M.,281 Arvanaghi, M., 2, 59, 219, 244 Arzoumanidis. G. G., 194

395

Asano, T., 215 Asao, T., 320 Asaoka, M., 134, 142 Asensio, G., 199, 249 Ashcroft, A. E., 304 Asher, V., 146, 203, 225 Askari, S. H., 366 Assercq, J.-M., 300 Atkinson, R. S., 322, 353 Attwood, S. V., 260 Auchus, R. J., 36, 286 Auksi, H., 295 Austin, W. B., 256 Au-Yeung, B.-W., 141, 287, 389 Avasthi, K., 103, 118, 288 Avery, M. A., 311 Avila, W. B., 132 Avnir, D., 201, 248 Awad, S. B., 313 Axelrad, G., 16 Axiotis, G. P., 86, 197, 245 Ayer, W.A., 296 Aznar, F., 199, 249 Azuma, Y., 144 Azzaro, M., 213 Babiak, K. A., 109, 173 Babidge, P. J., 134 Babler, J. H., 57, 58, 158, 159,280 Babu, T. V. R., 141 Bachner, J., 295 Back, T. G., 274 Backvall, J. E., 276 Bacon, B. E., 129 Bacquit, C., 24, 108 Badr, M. Z. A., 356 Backvall. J.-E., 236 Baer, H. H., 236 Battig, K., 290, 293, 339, 372, 385 Bagheri, V., 129, 222 Baier. H.. 301 Bailey, P. S., 392 Bailin, S.J., 8 Bainton, H.P., 244 Bair, K. W., 136 Baker, G. L., 150 Baker. R., 10, 191 Bal, B. S.. 130, 262 Bal, S. A., 297 Balakrishnan, P., 26, 77 Balaram, P.. 141, 389

Author Index

396 Balci, M., 394 Baldwin, J. E., 63, 136, 146, 147,243, 293 Baldwin, J. J., 197 Baldwin, S. W., 392 Balgobin, N., 111, 173, 263 Balme, G., 67 Ban, Y., 352, 385 Banks, R. E., 296 Bannou, T., 163, 275 Bansal, R. K., 38, 268 Bantick, J. R., 114 Baraldi, P. G., 24, 72, 119 Barbot, F., 59 Barco, A., 24, 72, 119 Barden, T. C., 293 Bargagna, A., 363 Barker, A. J., 290 Barlow, J. J., 173 Barluenga, J., 144, 197, 199, 249 Barnes, N. J., 101 Barnette, W. E., 272 Barnum, C., 26, 77, 275, 294 Barnum, C. S., 273 Barone, R., 391 Barrett, A. G. M., 28, 111, 137, 138, 144, 179, 243, 260, 316,324 Barriere, J.-C., 284 Barth, J., 109 Bartlett, P. A., 104 Barton, A. E., 114, 220 Barton, D. H. R., 1, 58, 72, 111, 164, 179, 265, 266, 269, 276,303, 393 Bartosevich, J. F., 217 Bartroli, J., 25 1 Basak, A., 139, 226, 285 Basu, B., 291 Batcho, A. D., 123 Bates, G. S., 89 Bats, J.-P., 314 Battaghia, A., 362 Battiste, M. A., 126 Bauch, H. G., 346 Baudouy, R., 54 Baudy, R., 195 Bauld, N. L., 295 Baxter, S. L., 185 Bayer, C., 26, 77, 275 Bayomi, S. M. M., 369 Beak, P., 61, 121, 157, 241 Beaulieu, P., 95, 227 Beck, A. K., 61, 86, 197, 261, 262, 307 Becker, R., 358 Beckwith, A. L. J., 394 Becu, C.,146, 203, 225 Bee, L. K., 303 Beebe, T. R., 58 Begley, M. J., 6, 266, 287 Behr, H., 335 Behrens, J. M., 200

Beier, M., 333 Belanger, D., 130, 283 Belin, B., 353 Belinka, B. A., jun., 336 Belkin, Yu. V., 394 Bell, K. L., 257, 383 Bell, M. R., 293 Bell, R., 347 Bell, S. C., 193 Bell, T. W., 266 Beller, N. R., 248 Belli, A., 128 BelluS, D., 35, 106, 148, 280 Bellville, D. J., 295 Below, P., 68, 118, 298 Bencivengo, D., 109 Bender, D. D., 41, 78 Benetti, S., 24, 72, 119 Benezra, C., 137 Bennetau, B., 46, 77, 256 Bennett, W., 17, 182 Berenschot, D. R., 81, 107 Berezin, I. V., 229 Berger, D. E., 123 Bergmann, K., 1 Bergstein, W., 150 Bernad, P., 249 Bernal, I., 150 Bernardi, R., 14 Bernath, G., 200 Berney, D., 351 Bertero, L., 155 Berthon, B., 109 Berti, C., 210 Bertrand, M., 284 Bestmann, H.-J., 38, 69, 156, 266, 268 Bessiere, Y., 393 Bessodes, M., 8 Bhagwat, S. S., 140, 290, 374 Bhakta, C., 344 Bhat, V., 141, 270 Bhatt, R. S., 106 Bhatt, M. V., 64, 81 Bhattacharya, A. K., 394 Biachi, G., 334 Bigi, F., 14 Bilow, N., 256 Bilyard, K. G., 300 Binder, D., 333 Bindra, J. S., 393 Binger, P., 121 Biran, C., 32, 256 Birch, A. J., 296 Bird, T. C. G., 310 Bittner, S., 141 Black, A. Y., 302 Black, D. St. C., 350 Blackburn, E. V., 2, 265 Blacklock, T. J., 277, 391 Bladbhade, M. M., 288 Blair, I. A,, 291 Blake, K. W., 328 Blanco, L., 21, 69, 75, 307

Blanton, C. D., jun., 352 Blaschek, U., 105 Blaschke, A., 366 Blazejewski, J.-C., 269 Bleicher, W., 1 Bloodworth, A. J., 321 Bloom, J. D., 201 Bloom, L. M., 242 Blount, J. F., 140, 278, 290 Blum, R. B., 136 Blum, Y.,109 Boar, R. B., 111, 179 Boche, G., 182 Bock, K., 129 Bodanszky, M., 151 Boeckman, R. K., 61 Bohrer, G., 105 Bottcher, A,, 391 Boettger, S. D., 136, 304, 382 BogodnoviC, B., 20, 244, 309 Bolin, D. R., 151 Bonfiglio, J. N., 250 Bonini, B. F., 370 Bordner, J., 292 Bornack, W. K., 140, 290, 374 Bos, H. J. T., 47, 55, 77, 142 Bosch, J., 337 Boschelli, D., 124, 129, 130, 285 Bose, A. K., 326 Bosma, R. H. A., 12 Bosnich, B., 218 Bottaro, J. C., 63, 243 Boudjouk, P., 4 Boussac, G., 132, 376 Boyer, J., 157 Bozell, J. J., 199 Bradshaw, J. S., 185 Bradsher, C. K., 282, 319, 330 Brady, W. T., 281, 394 Brandange, S., 114, 249 Bram, G., 159 Branca, S. J., 6, 286 Brandsma, L., 46, 47, 48, 55, 77, 242 Brassard, P., 260, 296 Braun, M., 116 Brecknell, D. J., 127 Brennan, J., 324 Brickner, S. J., 28, 29, 138 Briggs, S. P., 139, 295 Briner, P. H., 44, 74, 298 Brion, F., 42, 107 Brittelli, D. R., 26 Brocksom, T. J., 138 Broekhof, N. L. J. M., 84, 201, 267 Brookhart, M., 123, 231, 277 Brooks, R., 110 Broom, N. J. P., 136, 246, 382

Author Index Brown, H. C., 16, 50, 157, 160, 194, 249, 250, 253, 390, 392 Brown, J. D., 246 Brown, J. M., 101 Brown, S. P., 130, 262 Brown, T., 151 Brownbridge, P., 111, 133 Browne, E. J., 361 Browne, E. N. C., 294 Browne, L. J., 141, 389 Browne, L. M., 296 Bruce, J. M., 176 Bruce, M. R., 2 Bruck, W., 215 Bruntrup, G., 105 Brugidou, J., 266 Brunelle, D. J., 87, 245 Brunet, J.-J., 26, 184 Brunke, E.-J., 305 Brunner, H., 150 Bruza, K. J., 61 Bryant, D. R., 170 Bryant, K. E., 121 Bryce, M. R., 217 Buchbauer, G., 295 Buckley, T. F., tert., 238 Buchi, G., 293 Bugle, R. C., 103 Buhro, W. E., 110, 231, 277 Bukhari, A., 289 Bukownik, R. R., 157 Bullee, R. J., 5 5 Bullerjahn, R., 153 Bundle, D. R., 175 Bunnenberg, R., 216, 368 Buono, G., 77 Burch, M. T., 121 Burger, D. H., 200 Burger, J. J., 52 Burgoyne, W., 155 Burke, S. D., 257, 310 Burks, J. E., jun., 308 Burrows, C. J., 18 Burton, L. P. J., 135, 376 Buse, C. T., 93, 126 Bushey, D. F., 292 Buss, A. D., 9 Bussmann, W., 191 Buter, J., 190 Butler, R. N., 144 Butler, W., 351 Butsugan, Y., 33, 268 Byers, M., 360 Bystrom, S., 129 Byung Hee Han., 4 Cahiez, G., 59, 232 Cainelli, G., 187, 394 Calas, R., 32, 34, 46, 77, 79, 256 Calcagni, A., 145 Calcagno, M.-C., 246 Caldwell, C. G., 263

397 Callant, P., 290 Callens, R., 146, 203, 225 Cambie, R. C., 181, 216, 364 Cameron, D. A., 297 Campbell, C., 297 Campbell, J. B., 390 Camps, J., 52 Camps, P., 135, 202, 285 Canonne, P., 130, 134,283 Cantrell, G. L., 215, 286 Capetola, R. J., 193 eaplar, V., 149, 218, 392 Caporusso, A. M., 160 Capuano, L., 357 Caputo, R., 9 Card, P. J., 141, 389 Cardillo, G., 139, 154, 171, 321, 394 Cargill, R. L., 292 Carini, D.J., 226, 285 Carlsen, P. H. J., 98, 221 Carlson, J. G., 292, 378 Carman, R. M., 127 Caronna, T., 14 Carpenter, B. K., 18 Carpino, L. A., 105 Carrie, R., 278 Carroll, G. L., 289, 373 Carson, J. F., 150 Carter, L. G., 61, 121, 157 Carter, M. J., 296 Caruso, A. J., 135, 306 Carver, D. R., 32, 196 Casadei, M. A., 111, 309 Casiraghi, G., 14 Casnati, G., 14, 188 Cass, Q. B., 29, 122, 269 Castedo, L., 11 Castro, B., 151 Caubere, P., 26, 184 Cava, M. P., 72, 276, 303, 304 Cavazza, M., 363 CCIerier, J.-P., 87, 120, 214 Cenini, S., 215 Cha, J. K., 146 Chabaud, B., 89 Chadwick, D. J., 191 Chakraborty, U. R., 41, 78, 140, 230 Chamberlin, A. R., 127 Chambers, D., 216, 364 Chan, D. M. T., 229, 290 Chan, T.-H., 111 Chang, C.-A., 301 Chang, M. H., 211 Chang, S.-C., 5 Chang, T. C. T., 28, 35, 90, 137 Chanon, M., 391 Chantegrel, B., 137 Chao, Y. L., 98, 219 Chapius, C., 122, 295 Chapleur, Y., 139

Chapman, 0. L., 50 Charpentier, J.-P., 46 Charpiot, B., 269 Chatonier, D., 269 Chatterjea, J. N., 344 Chatterjee, A., 206 Chatterjee, S., 13, 255 Chatterjee, S. K., 206 Chattopadhyaya, J. B., 111, 173, 263 Chatziiosifidis, I., 90, 263, 304 Chaud, P., 367 Chaudhary, S. K., 175 Chen, C.-S., 139 Chen, C. H., 141, 348, 389 Chen, L.-M., 88 Chen, T. B. R. A., 52 Chen, Y. L., 213 Chen, Y. P. L., 124 Chenard, B. L., 282, 381 ChCnevert, R. B., 141, 188, 389 Cheng, Y.-S., 331 Chiaroni, A., 284 Chidester, C. G., 323 Chimiak, A., 151 Chiu, I.-C., 297 Chkir, M., 24, 108 Chmielewski, M., 222 Cho, H., 177, 264 Cho, Y.-S., 128 Choi, H.-D., 40, 270, 343 Choi, Y. M., 157, 194 Chong, J. M., 235, 265 Chou, C.-Y., 300 Choudhury, M. K., 278 Choy, W., 95, 102, 252, 388 Christensen, S. B., 382 Christie, J. J., 307 Christol, H., 89, 266 Chu, C. H., 174 Chu, P.-S., 293 Chuit, C., 165 Chujo, Y., 107, 130 Chung, B. Y., 60, 232, 245 Chwang, T. L., 106 Cinquini, M., 163, 205 Cipullo, M. J., 88 Cirrincione, G., 354 Cistone, F., 394 Citterio, A., 128 Clague, A. R., 200 Clardy, J., 97, 238, 247 Claremon, D. A., 276, 376 Clark, G., 302, 379 Clark, G. R., 206 Clark, P. D., 62, 293 Clarke, D., 216 Clarke, S. J., 193, 220 Clemo, N. G., 134 CICophax, J., 284 Cliff, G. R., 216 Cliffe, I. A., 191

Author Index

398 Clinet, J.-C., 45, 244 Clive, D. L. J., 8, 34, 79, 95, 106, 227, 263,275 Clizbe, L. A., 146, 295, 296 Clowell, A. R., 110 Cohen, B. J., 86 Cohen, T., 35, 69, 83, 280, 282, 305 Colin, H., 310 Collins, J. J., 391 Collins, S., 274 Collum, D. B., 204 Colombo, L., 82, 95, 172, 239,269 Colonna, S., 205 Colvin, E., 197, 261 Colvin, E. W., 61, 262, 390 Comins, D. L., 155, 246, 249 Comisso, G., 149, 218, 392 Concellon, J. M., 249 Concilio, C., 199 Confalone, P. N., 304, 380 Conia, J.-M., 21, 35, 69, 75, 79,249, 282, 307 Conrad, P. C., 299 Contento, M., 187 Contreras, R., 159, 250 Cook, J. C., 288 Cook, J. M., 103, 118, 288 Cooke, M. P.,jun., 29, 113, 267 Cookson, R. C., 141, 270 Cooley, G., 131 Coombs, W., 139 Cooney, C. L., 158 Cooney, J. V., 38 Cooper, C. S., 214 Cooper, D., 267 Cooper, K., 6, 266, 287 Coppola, G. M., 341, 368 Corbel, B., 278 Corbet, J.-P., 137 Cordova, R., 166 Corey, E. J., 52, 107, 114, 177, 209,220, 264,294 Corey, P., 382 Corey, R. M., 278 Corriu, R. J. P., 61, 157, 257 Cossar, B. C., 348 Costisella, B., 214 Cottam, P. D., 347 Coudert, G., 175 Couffignal, R., 85 Counotte-Potman, A., 194 Cox, R. H., 175 Coyle, S., 151 Coui, F., 163, 205 Craig, J. C., 58 Craig, T. A., 146, 260 Cram, D. J., 162, 191, 240 Crass, G., 186 Cravador, A., 30, 164 Crawford, T. C., 129 Crimmin, M. J., 147

Cristau, H.-J., 89 Crivello, J. V., 207 Crockett, G. C., 215, 328 Crosby, J., 370 Croudace, M. C., 6, 119, 288 Crouse, G. D., 272, 284 Crout, D. H. G., 147 Cueto, O., 312 Cullen, E. R., 5 Cullison, D. A., 288 Curini, M., 87, 244 Curran, D. P., 132, 287, 290, 299, 373 Cutting, I., 23, 74, 257 Czech, B., 184 Dahlman, O., 249 Dainobu, Y., 123 Dalton, J. R., 123, 292 Daly. J. J., 327 Damas, A. M., 370 D’Ambra, T. E., 295 Damin, B., 127 Danheiser, R. L., 36, 139, 226,285,286,299 Daniels, K., 221 Daniels, L., 158 Daniels, R. G., 45 Danishefsky, S., 140, 146, 260, 289, 290, 295, 373, 374,391 Dao, L. H., 305 Darling, P., 56 Darling, S. D., 19 D’Asdia, I., 354 Dattolo, G., 354 Daub, G. W., 121 Daub, J. P., 140 Dauben, W. G., 123, 279, 290, 307, 371 D’Auria, M., 26, 80 Dausmann, D., 279 Dauzonne, D., 202 Davey, P. N., 58, 159 David, S., 58, 173, 269 Davidson, A. H., 101 Davies, D. I., 139, 295 Davies, J., 347 Davis, F. A., 124, 313 Davies, J. E., 58 Davis, R., 204, 263 Davis, R. E., 307 Davis,’S. G., 382 Day, R. A., jun., 42 D’Costa, R., 351 de Araujo, H. C., 141 Debal, A., 118, 126, 134, 245,260 De Buyck, L., 127 De Camp, M. R., 282 Decesare, J. M., 278 De Chirico, G., 15 Declereq, J. P., 281 Decorzant, R., 298

Deep, K., 365 Degani, I., 58, 89 de Groot, A,, 83, 271, 304 Deiko, S. A., 229 de Jong. F., 185, 189 Dekerk, J.-P., 214, 364 De Kimpe, N., 127, 214 de Koning, J. H., 176 Delbaere, L. T. J., 296 del Bianco, C., 162 de Liefde Meijer, H. J., 232 Delmas, M., 321 Deloisy, E., 87, 120, 214 Del Principe, J. A., 337 De Lucchi, 0.. 211, 312 Demailly, G., 139, 196, 306 De March, P., 52 Demerseman, P., 7, 202, 214 De Micheli, C., 334 De Munari, S., 98 Deng, C., 145, 237 Denis, J. N., 2, 20, 80, 271 Denney, R. C., 328 de Noten, L. J., 47 Depezay, J.-C., 122, 242 Dernell, W., 155, 249 De Rosa, M., 199 Desai, D. N., 300 Desauvage, S., 20, 271 Deshayes, G., 359 Deshpande, M. N., 103, 118, 288 de Silva, A. P., 392 Deslongchamps, P., 288 Dess, D. B., 242 Deutsch, E. A., 166 Dev, S., 63, 293 Devadas, B., 246 De Ward, E. R.. 52 Dewick, P. M., 175 De Wilde, H., 118, 290 Dexler, S. A., 247 Dezube, M., 127 Diaz, E., 126 Diaz, G. E., 2, 265 Dibaji, N., 200 Dieter. R. K., 6, 84, 286, 394 Dietsche, M., 140 Diez-Masa, J.-C., 310 Dike, M. S., 257, 310 d’Incan, E., 159 Ding, W., 267 Dingwall, J., 106, 280 Dittel, W., 296, 360 Dixneuf, P. H., 7 Djerassi, C., 119, 278 Djokar, K., 357 Djuric, S., 113, 147, 263 Dochwat, D. M., 286 Dodsworth, D. J., 246, 382 Do Khac Manh Duc, 42 Dolle, R. E., tert., 297, 376 Dolson, M. G., 381 Donatelli. B. A., 48

Author Index Dondoni, A., 362 Doney, J. J., 348 Dormoy, J.-R., 151 Dorow, R. L., 110, 231, 277 Dorta, H. L., 173 Dossena, A., 188 Dougherty, D. A., 211 Dowd, P., 276 Doyle, M. P., 110, 129, 222, 231, 277,278 Drabowicz, J., 195 Drauz, K,,144 Dreiding, A. S., 293, 372 Drexler, S. A., 97 Dreyer, G. B., 290 Druelinger, M., 91, 238 Dubois, J.-E., 89 Duc, D. K. M., 300 Duckwall, L. R.,110 Diirner, G., 301 Duhamel, L., 72, 244 Dulcere, J.-P., 54, 202 Dumont, C., 310 Dumont, W., 273 Duncia, J. V., 148 Dunitz, J. D., 92 Dunoguis, J., 32, 34, 46, 77, 79, 256 Durr, H., 215 Durst, T., 278, 282, 362 Dussault, P., 127 Dyer, R. D., 292 Eaton, P. E., 288 Ebata, T., 121, 220, 328 Eckert, H., 193, 254 Ecoto, J., 310 Eder, U., 331 Edgar, K. J., 282 Edwards, M. P., 297, 376 Effenberger, F., 64, 144 Egert, E., 133 Eguchi, S., 206, 212 Eguchi, Y., 320 Ehrmann, E. U., 246 Eickhoff, D. J., 221 Eilerman, R. G., 90, 107, 310 Einhorn, J., 100 Eisenhuth, L., 280 Ekwuribe, N. N., 58 Elfehail, F. E., 208 Elferink, V. H. M., 142 Eliel, E. L., 82, 139 El-Mowafy, A. M., 7 Elsevier, C. J., 44 Emde, H., 89 Enda, J., 20, 22, 78, 256 Enders, D., 81, 170 Endo, T., 317 Engel, N., 18 Engel, P. S., 211 Engel, R., 16 Engman, L., 72, 276 Ennakova, C. M., 197

Enokiya, M.,60, 226 Ensley, H., 26, 77 Epsztein, R., 54 Erhardt, J. M., 73, 228 Erickson, A. S., 58, 207 Erickson, G. W., 91, 92, 214, 238 Ernst, B., 387 Escudero, J., 281 Esdar, M., 116 Estreicher, H., 209, 294 Etheredge, S. J., 260, 289, 373 Ethier, D., 139 Eustache, J., 263 Evangelisti, F., 363 Evans, D. A., 93, 103, 224, 251, 385 Everhardus, R. H., 46 Evstigneeva, R. P., 393 Eyre, T., 285 Fadda, A. A,, 199 Fahrmann, U., 182 Fahmy, A. M., 356 Fajdiga, T., 353 Falmagne, J.-B., 281 Falsone, G., 320 Fang, J.-M., 28, 138 Farina, V., 95, 227 Farkas, E., 287 Farrall, M. J., 56 Farrant, R. D., 131 Faustini, F., 98 Feger, H., 262 Feit, B. A., 121, 242 Fels, G., 116 Ferguson, G., 288 Feringa, B. L., 142 Fernandez, I. F., 326 Ferraboschi, P., 157 Ferreira, J. T. B., 138 Ferro, M. P., 117, 286, 306 Fetizon, M., 42, 300, 310 Feuerherd, K.-H., 215 Feustel, M., 76, 265 Fiandanese, V., 15 Fiaud, J.-C., 37, 90 Fichtner, M. W., 188 Ficini, J., 3 11 Field, L. D., 181 Fields, K. W., 25 Figuly, G. D., 242 Fijisawa, T., 249 Filipp, N., 391 Fillippo, J. S., 109 Findlay, J. A., 300 Finn, J. M., 178 Fishman, D., 72 Fitt, J. J., 200, 241 Flanagan, W. G., 106 Fleet, G. W. J., 58, 159, 193, 220

Fleming, I., 9, 22, 23, 32, 76, 89, 188, 228, 255, 257, 260, 287, 296, 390 Flippin, L. A,, 200, 254 Fliri, A., 141, 389 Flitsch, W., 329 Florent, J.-C., 260 Floyd, D. M., 5, 142, 227 Fochi, R., 58, 89 Fodor, G., 344 Forster, S., 144 Font, J., 52, 135 Ford, T. M., 16, 250 Ford, W. T., 184 Forestiere, A., 109, 127 Forrester, A. R., 360 Fortunak, J. M. D., 52, 112 G. B., 130, 283 FOSCOIOS, Foucaud, A., 142, 206 Foulon, J. P., 165 Four, P., 58, 220 Fowler, F. W., 331 Frahm, A. W., 196 Franck-Neumann, M., 42 Francotte, E., 210, 339, 360, 385 Frater, G., 68, 115, 238 Frazier, K. A., 125 Frazza, M. S., 309 Frtchet, J. M. J., 56, 393 Freeman, F., 394 Freerks, R. L., 296 Fresneda, P. M., 204 Friedrich, L. E., 314 Freidrichesen, W., 391 Fringuelli, R., 87, 244 Frisque-Hesbain, A. M., 281 Fritschel, S. J., 150 Fritz, A. W., 142 Frobel, K., 141, 389 Fronczek, F. R., 190 Fry, A. J., 81 Fry, J. L., 60, 212 Fu, C. C., 58 Fuchs, P. L., 299 Fuji, K., 99, 115, 255 Fujihara, H., 185 Fujii, T., 95, 177, 263 Fujimoto, Y., 139 Fujisawa. T., 24, 35, 46, 60, 95, 105, 140, 226, 283 Fujita, E., 37, 79, 99, 115, 143, 152, 209, 255, 256, 301 Fujita, S., 128, 249 Fujita, T., 142 Fujita, Y., 44, 187 Fujitsu, H., 158 Fujiwa, T., 33, 256 Fujiwara, T., 31 1 Fukumoto, K., 131, 292, 298, 301, 306 Fukumoto, T., 109 Fukunaga, K.,8

Author Index

400 Fukunishi, K., 184 Fukushima, A., 18, 111 Fukuyama, T., 119, 132, 285, 384 Fulop, F., 200 Fung, A. P., 74, 207, 318 Furukawa, M., 326 Furukawa, N., 185 Furukawa, Y., 144 Fusaka, T., 3 11 Fushiya, S., 147 Gabel, R. A., 198, 338 Gadek, T. R., 301 Gadreau, C., 142 Gadwood, R., 140, 290, 374 Gailius, V., 144, 327 Gais, H.-J., 141, 389 Gajda, T., 143 Gala, K., 326 Galemmo, R., 287 Gallagher, T., 340 Gallant, P., 118 Galli, C., 111, 309 Gallop, P. M., 144 Galobardes, M. R., 58, 209, 222 Galpin, I. J., 152 Gambale, R. J., 140 Gambarotta, S.,231 Gammill, R. B., 361 Gandolfi, R., 98, 334 Ganern, B., 119, 150, 197, 223,235 Ganeshpure, P. A., 132 Ganguly, A. K., 285 Gano, J., 50 Gaoni, Y.,278 Garapon, J., 127 Garcia, J. L., 206 Garcia-Luna, A., 89, 109 Garner, A. W., 364 Garratt, D. G., 141, 389 Garratt, P. J., 300, 303 Garst, M. E., 250 Garvey, D. S . , 95, 141, 252, 388 Gasagrande, F., 128 Gaset, A., 321 Gassman, P. G., 278 Gasteiger, J., 80, 363, 365 Gaviraghi, G., 211 Gawish, A., 103, 288 Gedge, D. R., 134 Geffken, D., 361 Gelin, S., 137, 359 Gemal, A. L., 159 Gendler, P. L., 215 GenQt, J. P., 280, 311 Gennari, C., 82, 95, 172, 239, 269 Geoghegen, P. J., jun., 249 Geribaldi, S., 213 Germain, G., 281

Gero, S . D., 284 Gerstenberger, M. R. C., 180 Gerth, D. B., 211 Gerval, J., 32, 256 Gesson, J.-P., 119, 303 Ghali, N. I., 210 Gharbi, R. E., 321 Ghatak, U. R., 288 Ghazanfari, F. A., 319 Gheorghiu, M. D., 281, 390 Ghera, E., 41 Ghosez, L., 281 Ghosh, S., 111 Giacornelli, G., 155, 160 Giam, C. S.,229 Giannis, A., 90 Giersch, W., 298 Gilchrist, T. L., 235, 359 Gill, M., 102, 244, 284 Gillies, I., 328 Gilligan, P. J., 129, 238 Gilpin, M. L., 38 Gimbarzevsky, B., 362 Gioeli, C., 111, 173, 263 Giordano, C., 128 Giorgianni, P., 362 , Giralt, E., 152 Girard, P., 85 Glaeske, G., 367 Glinski, M. B., 282 Gnichtel, H., 333, 357 Godfrey, C. R. A., 111, 179 Godfrey, J. D., 292, 378 Godleski, S. A., 236, 336 Godoy, J., 57, 85, 222 Goerdeler, J. G., 367 Goering, H. L., 91 Gotz, A., 89 Gohda, N., 216 Gold, P. M., 74 Golding, B. T., 41 Goldsmith, D. J., 283 Goldstein, S.,281 Golen, J. A., 300 Golinski, J., 209 Gonzalez, A., 140 Gonzalez, A. G., 173 Gooch, E. E., 17, 181, 182, 25 1 Gopal, M., 2 11 Gordon, J., 158 GorB, J., 54, 67, 134, 166 Gorrichon, L., 310 Gossauer, A., 145, 197, 266 Goto, J., 233, 385 Goto, M., 143 Goto, T., 140, 273 Gotoh, H., 212, 323 Gould, R. O., 370 Grabley, F.-F., 366 Grabley, S.,332, 356, 366 Gramain, J.-C., 344 Granados, R., 337 Grandbois, E. R., 161, 255

Grande, K. D., 8 Gras, J.-L., 298 Gray, M. D. M., 362 Grayson, J. I., 69, 295, 391 Greber, G., 185 Greci, L., 210 Grte, R., 278 Greene, T. W., 392 Greenlee, M. L., 301, 377 Gressier, J.-C., 331 Greute;, H., 106, 280 Grey, R. A., 158 Grieco, P. A., 122, 127, 276 Griesbaum, K., 80 Griesser, H., 152 Grigg, R., 198, 205,218 Grignon-Dubois, M., 34, 79 Grimaldi, J., 54 Grirnmett, M. R., 391 Grimshaw, J., 392 Grindley, T. B., 240 Gross, G., 55 Gross, H., 214 Grotemeier, G., 110, 156 Groth, U., 145, 148, 237 Grotjahn, D. B., 260, 284 Grover, E. R., 174 Gruber, H., 185 Gruber, J. M., 300 Grundke, G., 114, 295 Grundon, M. F., 161 Gruska, R., 326 Grzejszczak, S., 275 Grzeskowiak, N. E., 331 Gschwend, H. W., 200,241 Guaciaro, M. A., 24, 76, 124, 316, 377 Guanti, G., 82, 172, 239 Guerin, C., 257 Guerriero, A., 363 Guggisberg, A., 144 Guglielmetti, G., 128 Guibe, F., 58, 174, 220 Guida, W. C., 159 Guillaurnet, G., 175 Guillern, D., 132, 376 Guindon, Y.,139 Guinosso, C. J., 193 Guittet, E., 75 Gumulka, M., 135 Gunn, B. P., 297 Gunther, W., 238 Gupta, B. G. B., 89, 109, 175, 177, 186, 263, 262 Gupta, D. N., 58 Gupta, I., 295 Gupta, K. C., 268 Gupta, S. C., 81, 107 Gupton, J. T., 21, 248 Gurusiddappa, S., 152 Guryn, R., 361 Guziec, F. S.,jun., 5 Guzmln, A., 84, 126, 199 Gyory, P., 342

40 1

Author Index Haas, A., 180 Haber, M., 336 Haberfield, P., 199 Hagen, J. P., 114, 240 Hagiwara, H., 107, 285, 317 Hahajan, J. R., 141 Hahn, B., 83 Hakucho, T., 1 Halazy, S., 273 Halberstadt-Kausch, I. K., 17 Haley, N. F., 188 Hall, R., 139 Hall, S. E., 297 Hall, T. W., 24, 76, 124, 316, 377 Hallett, A., 151, 152 Halweg, K. M., 297, 298 Hamada, Y., 207 Hamaguchi, H., 128, 249 Hamamoto, I., 9, 205, 265 Hamanaka, N., 236 Hamilton, R. J., 300 Hammer, B. C., 303 Hammerschmidt, F.-J., 305 Hamper, B. C., 178 Han, W.-C., 103, 118, 288 290,293, 371 Han, Y.-K., Hancock, F. E., 152 Handa, B. K., 152 Haneda, A., 2, 183 Hanefeld, W., 367 Hanessian, S.,56, 139, 175, 180 Hangauer, D. G., jun., 245 Hanko, R., 63 Hanna, I., 42, 300 Hanna, Z. S.. 236 Hanson, G., 151, 152 Hanson, A. W., 138 Hanson, P.. 217 Hara, J., 146 Hara, T., 4 Harada, K., 150 Harada, N., 178 Harada, T., 45, 166, 167 Harakal, M. E.,313 Harbridge, J. B., 38 Harding, M. M., 370 Harding, P. J. C., 58, 159 Hardinger, S. A., 207 Harkema, S., 329 Harris, T. D., 337 Harris, T. M., 117 Harrison, I. T., 141 Harrison, J. J., 206 Hart, D. J., 383, 385 Hart, H., 6, 288 Hartmann, W., 197, 280, 281 Hartmanns, J., 3 Hartner, F. W., jun., 11, 230 Hartwig, W., 145, 237 Hartz, G., 105 Haruta, J., 177, 263

Hasan, I., 304, 380 Hase, T. A., 142, 390 Hashiko, T., 100 Hasimoto, J., 89 Hashimoto, K., 177 Hashirnoto, M., 38, 266 Hashimoto, S., 97, 114 Hashimoto, S.-I.,212, 220, 247 Hashio, S., 233 Hassner, A,, 336, 351 Hata, T., 65, 86, 111, 173, 268, 359 Hatakeda, K., 215 Hatakeyama, S., 304, 380 Hatanaka, K., 38, 86 Hatanaka, Y., 36, 166 Hattori, K., 199, 254, 384 Hattori, S., 212 Hattori, T., 2 Hauck, G., 215 Hauck, H. F., jun., 24, 67, 283 Hausberg, H., 145 Hauschka, P. V., 144 Hauser, F. M.,381 Hayakawa, K., 141, 389 Hayashi, M., 82, 124, 160 Hayashi, T., 4, 14, 33, 163, 218, 226, 247,255, 256 Hayashi, Y., 334, 335 Hayward, R. C., 181 Heathcock, C. H., 65, 92, 93, 103, 114, 126,240 Heavner, G. A., 152 Hecht, S. M., 145 Heck, R. F., 41, 78, 113, 390 Hegde, S. G., 80 Hegedus, L. S., 199 Heggie, W., 141, 389 Heidelberger, C., 106, 144 Heine, H.-G., 197, 280, 281 Heinzer, F., 35, 148 Heldrich, F. J., 42 Helgeson, R. C., 191 Hellring, S., 199 Helmchen, G., 110, 114, 156, 295 Helquist, P., 138, 140, 229, 243, 277, 290, 297, 299, 309, 374 Hendrixson, T. L., 200 Henn, L., 49, 265 Henson, E. B., 144 Hercouet, A., 266 Herlt, A. J., 144 Hermann, K.,204 Hernandez, L., jun., 325 Hernandez, O., 175 Herold, T., 169 Herrmann, J. L., 293 Herscheid, J. D. M., 149 Hershberger, S. S., 12, 43 Herzig, C., 80, 363

Hesse, M., 70, 143, 144, 308 Hesson, D. P., 141, 389 Hevesi, L., 20, 271 Heywood, G. C., 231 Hida, T., 186, 253 Higuchi, H., 9 Higuchi, T., 152 Hii, P., 58 Himbert, G., 49, 76, 265 Hinney, H. R., 207 Hinz, J., 197, 280 Hirarna, M., 95, 141, 252, 388 Hirao, A., 160, 161, 254 Hirao, T., 20, 22, 78, 256, 268, 357, 368 Hirashima, T., 18, 87, 120, 258,307 Hirata, K., 141 Hirobe, M.,123, 152 Hiroi, K., 88 Hirota, K., 320 Hiyama. T., 130, 167, 173, 224,234, 245, 287, 315 Ho, L.-K., 123, 300 Ho, T. L., 283 Hodge, P., 58 Hodges, M. L., 364 Hogberg, H.-E., 129 Hoekstra, M.S., 86, 307 Hoffmann, H. M. R., 114, 122, 281, 295, 305 Hoffmann, R. W., 169, 171, . 253 Hoffmann, W., 101 Hofheinz, W.,110 Hofmann, K., 89 Hohman, J. R., 103 Hollander, M. I., 5 Hollinshead, D. M., 111, 179 Holmberg, C., 112, 142 Holt, D. A., 248, 307 Holt, S. L., 140 Holton, R. A., 64, 200 Holy, N. L., 7 Hommes, H., 48, 242 Honda, M., 141 Honda, T., 131, 292, 298, 30 1 Hong, P., 133 Hang, S.-S. S.,81 Hopf, H., 280 Hopkins, P. B., 107 Hopkinson, A. C., 305 Hoppe, D., 63, 141 Hoppe, I., 35, 145, 148, 356, 389 Horiai, H., 38, 266 Horiuchi, C. A., 72, 80 Horton, D., 284 Hosaka, K., 68, 117, 119. 283,328 Hoshiko, T., 209 Hoshino, Y., 158

402 Hosomi, A., 36, 88, 155, 177, 186, 258 Houge, C., 281 Houk, K. N., 303 Houser, D.J., 103 Howard, S. I., 161, 255 Howarth, T. T., 38 Howbert, J. J., 290, 375 Howell, S. C., 132 Hoyano, Y., 296 Hoyashi, K., 296 Hoye, T. R., 124, 135, 140, 293,306 Hoz, S., 209 HSU,C.-T., 140, 376, 382 Hsu, H. C., 17, 181, 182, 251 Hu, H., 81, 107 Hua, D.H., 177, 264 Huang, J., 141 Huang, Y. Z., 267 Hubbard, J. S., 117 Huber, U., 295 Hudlicky, T., 286, 290 Hudrlik, P. F., 15, 85, 147, 260 Hudson, D., 152 Hudspeth, J. P., 143 Hubner, F., 90 Hunig, S., 280 Huesmann, P. L., 213 Huet, F., 282 Huttenhain, S., 90 Huffman, J. C., 172, 239 Hughes, L. R., 101 Huie, E., 271 Huisman, H. O., 52 Hulce, M., 97, 247, 392 Hullen, A., 309 Humphrey, S. J., 349 Hung, S. C., 210 Hunt, D.A., 282, 330 Hunt, P. G., 133 Huong, C.-T. B., 266 Husain, A., 89, 175, 177, 186, 262, 263 Husk, G. R., 231, 277 Hutchins, R. 0.. 155, 394 Hwang, K.-J., 308 Hyatt, J. A., 141, 389 Hylarides, M. D., 181, 251 Iame, C., 202 Ibuka, T., 296 Ichikawa, Y.,140, 143, 273 Ida, T., 142 Iddon, B., 246 Ide, J., 359 Iguchi, S., 160 Ihara, M., 330 Iida, H., 203, 270 Iida, K., 167, 224 Iijima, S., 36, 106, 155, 167, 224 Iio, H., 143

Author Index Ikariya, T., 139 Ikeda, D.,141, 389 Ikeda, H., 140, 309 Ikeda, K., 90,326 Ikeda, M., 178, 221, 355, 369 Ikeda, N., 30, 206 Ikeda, S., 186, 226 Ikeda, T., 352 Ikegami, S., 11, 265, 289 Ikota, N., 119, 235 Ila, H., 265 Illuminati, G., 391 Imagawa, T., 131 Imai, T., 344 Imai, Y., 142 Imakura, Y., 206, 269 Imamoto, T., 36, 166 Imamura, P. M., 133 Imanaka, T., 202 Imaoka, K., 185 Imperiali, B., 95, 102, 252, 388 Imuta, M., 178 Inamoto, N., 52, 267 Inanaga, J., 57, 109, 123, 141 Inners, R., 300 Inokuchi, T., 139 Inomata, K., 187 Inoue, K., 57 Inoue, M., 263 Inoue, S., 203, 270, 319 Inoue, Y., 193 Inouye, Y., 146, 287, 357 Inubushi, Y., 296 Invergo, B. J., 57, 58, 159, 280 Ireland, R. E., 104, 140, 292, 378, 387 Irving, E. M., 193, 220 Ise, F., 309 Iseka, K., 289 Isenring, H. P., 110 Ishibashi, H., 40, 343 Ishibashi, K., 134 Ishibashi, M., 270 Ishigami, E., 340 Ishiguro, M., 30, 206 Ishii, T., 68, 117, 283, 328 Ishikawa, H., 31, 165, 186, 225,226,248 Ishikawa, M., 320 Ishikawa, N., 40, 104, 119, 179, 180, 270 Ishikawa, Y., 60 Ishikura, M., 341, 352 Ishino, Y., 18, 120 Iskander, G. M., 359 Ismail, Z. M., 122, 281, 295 Isobe, K., 107, 285 Isobe, M., 140, 143, 273 Israel, M., 81 Itagaki, K., 31, 33, 107, 164, 256 Ito, K., 142

Ito, M. M., 335 Ito, S., 57, 215 Ito, V., 301 Ito, Y., 340, 379 Itoh, A,, 73, 305 Itoh, K., 29, 31, 33, 107, 124, 164, 172, 233, 256 Itoh, T., 35, 351 Itsuno, S., 160, 161, 254 Iversen, T., 175 Ives, J. L., 392 Iwabuchi, J., 178 Iwai, K.. 100, 209 Iwakuma, T., 197 Iwamoto, H., 211 Iwasawa, N., 99, 247 Iwaska, T., 359 Iwata, C., 311 Izawa, T., 326 Izurni, Y., 27, 118, 259 Jabri, N., 12, 38, 226 Jackson, A. G., 152 Jackson, D. A., 260, 303 Jackson, W. P., 118, 304, 306 Jacobi, P. A., 141, 389 Jacobs, H., 278 Jacobsen, P., 146 Jacobson, R. A., 5 Jacobson, R. M., 124, 287. 315 Jacobus, J. O., 364 Jacquesy, J.-C., 119, 303 Jadhav, P. K., 52, 160, 250, 392 Jahme, J., 101 Jagdmann, G. E., jun., 132, 318 Jaime, C., 285 Jakubke, H.-D., 153 Jallali-Naini, M., 132, 376 Jarnison, W. C. L., 210 Jansen, B. J. M.,83,271 Jarvi, E. T., 114, 240 Jautelat, M., 101, 279, 394 Jaw, J. Y., 276 Jawdosiuk, M., 26 Jaxa-Chamiec, A. A., 29, 122, 269 Jefson, J., 275 Jefson, M., 24, 84 Jenkins, R. H., 124 Jenny, C., 143 Jerris, P. J., 123, 124, 293, 316, 372 Jessup, P. J., 296 Jeuring, H. J., 213 Jha, H. C., 344 Jigajinni, V. B., 181, 251 Jieh Shyh Tsai, D.,39 Jiminez, C., 144, 197, 199, 249 Jinbo, T., 58, 219 Jirkovsky, I., 195

403

Author Index Jitsukawa, K., 101, 222, 257 Jo, S., 20, 89 Jochims, J. C., 216, 368 John, I. L., 360 Johnson, D. W., 291 Johnson, F., 136, 382 Johnson, M. A., 292 Johnson, M. W., 81, 258 Johnson, R. W., 174 Johnston, G. A. R., 146 Johnstone, L. M.. 350 Johnstone, R. A. W., 7 Jojima, K., 389 Jolly, R. S.,319 Jones, D. N., 347 Jones, H. G., 392 Jones, J. H., 151, 197 Jones, L. D., 229, 309 Jones, S. S., 174 Jorge, Z. D., 173 Josephson, S., 111, 114, 173, 263 Joshi, K. C., 367 Joukhadar, L., 111, 179 Judkins, B. D., 322 Julia, S., 75 Jung, M., 76,265 Jung, M. E., 136, 260, 296, 297, 298 Junjappa, H., 265 Jurczak, J., 222 Jurlina, J. L., 181 Just, G., 107 Juve, H. D., jun., 81, 117, 222,258 Kabalka, G. W., 1, 17, 181, 182,195,251 Kabayashi, G., 347 Kabuto, C., 135 Kabuto, K., 159, 254 Kadonaga, J. T., 36, 286 Kagan, H. B., 85 Kageyama, Y., 40, 142, 179, 270 Kagotani, M., 37, 144 Kahn, M., 260,289, 373 Kahne, D., 204 Kaiser, E. T., 151 Kaji, A., 2, 9, 24, 40, 73, 205, 207,210,265, 270,271 Kajihara, Y.,15 Kajtar-Peredy, M., 342 Kakisawa, H.,146, 287, 357 Kalaus, G., 342 Kale, V. N., 8, 106, 263 Kalinowski, H.-0.. 186 Kaloustian, M. K., 125 Kamal, A., 370 Kambe, S., 337 Kamekawa, K., 152 Kametani, T., 131, 292, 293, 298, 301, 306, 330, 379, 393

Kamochi, Y., 343 Kamojitzby, V., 392 Kanao, Y., 294 Kane, M. P., 323 Kaneda, K., 101, 202, 222, 257 Kanehira, K., 163, 218 Kaneko, H., 132, 305 Kanellis, P., 84 Kanemura, Y.,387 Kang, J., 52, 107 Kanjilal, P. R., 288 Kano, S., 328 Kantlehner, W., 86, 212, 245 Kanuma, N., 147 Kao, L.-C., 41, 78 Kapassakalidis, J. J., 86, 212, 245 Kappe, T., 394 Kapron, P., 87, 120, 214 Kapur, J. C., 326 Karmarkar, P. G., 48 Karpf, M., 119, 278, 293, 372 Karras, M., 166 Kasahara, C., 291 Kasemsri, P., 47 Kashimura, S., 339 Katagiri, T., 68, 245, 299, 317 Kataoka, H., 30, 112 Kato. J., 128 Kato, N., 304 Kato, T., 272, 309 Katritzky, A. R., 7, 84, 154, 199,331 Katsayama, M., 351 Katsuki, T., 98, 109, 123, 141, 178,220, 221,313 Katsuro, Y., 4, 33, 255, 256 Katzenellenbogen, J. A., 105, 127, 138 Kauffmann, T., 11 Kaur, B., 370 Kausch, E., 366 Kawabata, N., 89 Kawada, M., 206,233, 269 Kawagishi, T., 73, 259 Kawai, K., 178 Kawakami, Y., 226 Kawamura, A., 131 Kawamura, E., 365 Kawamura, N., 189 Kawanami, Y., 123, 141 Kawanisis, M., 131 Kawara, T., 95, 140 Kawasaki, T., 216 Kawase, M., 339 Kawashima, M., 35, 46, 105, 249 Kaya, R., 248 Kayama, M., 128 Keck, G. E., 383 Kees, F., 346, 363 Kehne, H., 145, 237 Keitel, I., 214

Kell, R. A., 200 Kelleghan, W. J., 256 Keller, L., 229, 309 Kellogg, R. M., 140, 179, 190 Kemp, D, S., 101, 151, 152 Kemper, B., 171,253 Kende, A. S., 132, 136, 299, 304, 380, 382 Kennard. O., 133 Kennedy, P., 276 Kenner, G. W., 152 Kerber, R. C., 277 Kerdesky, F. A. J., 95, 102, 252, 303, 388 Kerkman, D. J., 152 Ketari, R., 206 Keul, H., 80 Keumi, T., 202 Kezar, H.S.,tert., 26, 77, 275 Khai, B.-T., 199 Khajavi, M. S.,326 Khan, J. A., 321 Khanh, T. T., 200 Khatri, N. A., 331 Khouri, F.,125 Kibar, R., 80 Kibby, J. J., 144 Kido, F., 135 Kiesel, Y.,254 Kii, N., 101, 222, 257 Kikuchi, H., 38, 266 Kikugawa, Y.,188, 253, 339 Kikukawa, K., 229 Kim, J.-I. I., 41, 78, 113 Kim, K. S., 107, 141, 389 Kim, S., 60, 109, 123. 232, 245 Kimball, S. D., 136, 382 Kimura, K., 167, 224 Kimura, M., 68, 117, 283, 328, 344 Kimura, T., 151 Kimura, Y.,35, 79, 104, 179 King, J. A., jun., 301 King, M. L., 132, 299 King, S. W., 149 King, T. J., 38 Kinoshita, M., 83, 289, 387 Kirk, D. N., 131 Kirk, T. C., 166 Kirkpatrick, A.. 123 Kirmse, W., 280 Kirschleger, B., 80 Kise, H., 185 Kise, M., 369 Kiseki. Y., 229 Kishi, N.,79, 104, 187 Kishi, Y., 143, 304, 380, 384 Kita, Y.,177, 216, 263 Kitajama, H.,202 Kitamura, M., 143 Kitao, T., 337 Kitazume, T., 119, 180 Klamer, F.-G., 279

404 Klaubert, D. H., 193 Klayman, D. L., 217 Kleemann, A., 150 Klei, B., 232 Kleijn, H., 16, 44, 51, 227 Klein, C. M., 279 Klein, H., 284 Klein, P., 144 Klenk, H., 64 Klipa, D. K., 6, 288 Kloek, J. A,, 260 Klotzer, W., 327 Kluba, M., 268 Klug, J. T., 72 Klun, T. P., 112 Knapp, S., 293 Knight, D. W., 106 Knochel, P., 19, 208, 245 Knox, G. R., 231 Knupp, G., 196 Kobayashi, H., 211, 355 Kobayashi, K., 202 Kobayashi, N., 100, 209 Kobayashi, S., 123, 200, 252, 326 Kobayashi, T., 49, 77, 109 Kobayashi, Y., 30, 107, 112, 205, 301 Kober, H., 215 Kobuke, Y., 59, 389 Koch, T. H., 215, 328 Kochi, H., 365 Kocienski, P. J., 390 Koehler, K. F., 324 Koll, P., 3 Koeners, H. J., 173 Konig, G., 64 Konig, R., 11 Konnecke, A., 153 Koster, F.-H., 305 Koga, K., 82, 97, 124, 128, 212,247 Kogen, H., 97, 212, 247 Kogure, T., 150 Kohara, T., 66 Kohda, A.. 80 Kojima, K.. 141 Kojima, Y., 304 Kokalj, M., 191, 206 Kokuba, Y., 140 Kolb, M., 109 Koma, Y., 38,266 Komatsu, M., 205, 278, 348 Kondo, K., 229 Kondo, M., 359 Konig, K.-H., 215 Konishi, M., 14, 226, 247 KonstantinoviC, S., 309 Kopka, I., 86, 258 Kopke, B., 83 Korbacz, K., 275 Koreeda, M., 124, 242 Kornblum, N., 58, 207 Korp, J., 150

Author Index Korst, K. M.,200 Koshimies, J. K., 390 Koshino, J., 49, 65, 76, 253 Kost, A. N., 199 Kostyanovsky, R. G., 322 Kosugi, H., 107, 285, 317 Kosugi, K., 347 Koszyk, F. J., 286 Kotake, H., 187 Kotsuki, H., 131 Koul, V. K., 323 Kouwenhoven, A. P., 12 Kovac, T., 353 Kovacic, P., 351 Kowalski, C. J., 25 Koyangi, M., 109, 204 Kozikowski, A. P., 271, 296, 393 Kozuka, S., 366 Kozyrod, R. P., 265 Krageloh, K., 69 Krafft, G. A., 127 Kraus, G. A., 86, 125, 203, 259,327 Kraus, M. A., 86 Kraus, W., 307 Krawiecka, B., 309 Krebs, A., 5 Kreder, J., 326 Kreevoy, M. M., 157, 194 Kreisberger, J., 248 Kreiser, W., 68, 118, 298 Kremer, K. A. M., 277 Kresze, G., 296, 360, 367 Krief, A., 2, 20, 30, 80, 164, 271, 273 Kriesberger, J., 201 Krishna, M. V., 348 Krishnamurthy, S., 160, 255 Krogsgaard-Larsen, P., 146 Krohn, K., 260, 304 Krolikewicz, K., 356 Kropp, P. J., 277 Krow, G. R., 394 Krowicki, K., 141, 389 Kruizinga, W. H., 140, 179 Krumpolc, M., 280 Kruse, L. I., 146 Ksander, G. M., 292 Kubota, S.,369 Kubota, T., 132 Kudo, T., 193 Kueh, J. S. H., 289 Kuhl, U., 105 Kulkarni, A. K., 15, 85, 147, 260 Kumada, M., 4, 14, 33, 163, 218,226, 247,255,256 Kumagai, T., 309, 391 Kumamoto, T., 347 Kume, A., 65, 86, 111, 173, 268 Kundu, N. G., 106 Kunert, D. M., 325

Kunesch, G., 126 Kunieda, N., 83 Kunieda, T., 123, 132 Kunin, A., 8 Kurebayashi, Y., 60 Kurek, A., 135 Kurek, J. T., 249 Kurobe, H., 306 Kuroda, K., 262 Kuroki, M., 214 Kurosaki, H., 202 Kurosawa, H., 2 Kurth, M., 122, 295 Kurth, M. J., 124, 306 Kurtz, R. R., 103 Kurumaya, K., 267 Kurusu, Y.,56 Kurz, M. E., 207 Kusabayashi, S., 321 Kusumi, T., 287, 357 Kutney, J. P., 278 Kuwajima, I., 57, 78, 84, 85, 134, 177, 274 Kwan, Y. C., 206 Kyler, K. S., 241 Kysela, E., 296, 360 Labaudiniere, R., 89 L’Abbe, G., 364 Lacombe, S. M., 197 Ladika, M., 54 Laguua, B. C., 107, 150, 223 Lahouse, F., 27, 272 Lai, H. K., 68, 117, 123, 283, 300 Lai. Y. H., 391 Laird, B. B., 307 Lakshmikanthan, M. V., 303 Lallemand, J. Y.,126, 132, 134, 245, 376 Lam, P. Y.-S., 314 Lammerink, B. H. M., 335 La Monica, G., 215 Lampe, J., 93, 103, 126, 240 Lange, G. L., 135 Langford. G. E., 288, 295 Lantzsch, R., 101, 279, 394 Laosooksathit, S., 16 Lapidus, A. L., 393 LarchevCque, M., 118, 132, 134, 245, 260, 376 Lardicci, L., 155, 160 Larock, R. C., 4, 12, 43, 229 Larsen, D. S., 216 Larsen, J. J., 146 Larsen, R. D., jun., 276 Larson, G. L., 108 Latrofa, A., 65 Lau, K. S. Y., 256 Laurent, A. J., 197 Laurian, L. G., 323 Lautens, M., 135 Lawrence, R. F., 385 Lawson, J. P., 32, 196

Author Index Laycock, D. E., 219 Lazare, S.,42 Leach, D. R., 4, 229 Le Baron, H., 266 Le Breton, G. C., 210 Lechevallier, A., 282 Leclercq, D., 314 Le Corre, M., 266 Lee, C., 56, 98 Lee, D. G., 56 Lee, J. I., 60, 232, 245 Lee, P. E., 103 Lee, S.-H., 235, 265 Lee, V. J., 141, 389 Lee-Ruff, E., 305 Leete, E., 246 Leger, S.,139 Le Goff,N., 54 Legueut, Ch., 134, 245 Lehn, J.-M., 191 Lehr, F., 197, 261 Lehr, W., 366 Lelandais, D., 24, 108 Leleu, G., 109 Le Mahieu, R. A., 194 Lemaitre, P., 132, 376 Lemay, G., 130. 134, 283 Le Merrer, Y.,122, 242 Lenz, G. R., 392 Letendre, L. J., 73, 228 Leung, S.-L., 152 Leutert, T., 141, 389 Levenberg, P. A., 87, 116, 123, 316 Lever, 0. W., 63 Levesque, G., 331 Levine, S. G.. 6, 307 Lewis, C. P., 382 Lewis, W., 182 Ley, S. V., 72, 80, 118, 132, 135, 234, 274, 276, 297, 303, 304,306,376 Lhornmet, G., 87, 120, 214 Li, T., 304, 380 Liak, T. J., 175 Liang Chen, Y. P., 242 Lidon, M. J., 204 Lidor, R., 21, 74, 242 Lieberknecht, A., 152 Lim, €3. L., 246 Linderman, R. J., 25, 68, 286 Lindner, K., 145 Linfield, W. M., 26 Lingenfelter, D. S., 191 Link, J. C., 382 Linstrumelle, G., 16, 45, 182, 244

Lion, C., 89 Liotta, D., 26, 77, 99, 273, 275,294 Lipshutz, B. H., 5, 173, 227, 325 Lis, R.,293 Liso, G., 65

405 Lissel, M., 86, 176 Lister, S. G., 297, 376 Little, G. M., 213 Little, R. D., 289, 373 Liu, G.-J.. 57, 21 1 Liu, H.-J., 68, 117, 123. 157, 283, 294,300 Liz, R., 199, 249 Ljungqvist, A., 112 Lloyd, R. M., 281 Lo, V., 124 Loader, C. E., 206 Locher, R., 49, 95, 169, 242 Loher, H. J., 99, 227 Logusch, E., 141, 389 Loh, J.-P., 10 Lohmann, J.-J., 241 Lohr, K., 135 Long, N. R., 113 Lopes, A., 296 Lorenzi-Riatsch, A., 70 Lotter, H., 81, 170 Loubinoux, B., 175 Loupy, A., 159 Loveitt, M. E., 321 Lucente, G., 145 Luche, J.-L., 159 Luh, T.-Y., 1 Luis, F. R., 173 Lundt, I., 129 Lupo, A. T., jun., 331 Luteijn, J. M., 304 Lutstorf, M., 147 Lynch, G. J., 249 Lynch, J. E., 82 Lythgoe, B., 393 Lyzwa, P., 195 Ma, P., 102, 252 Maas, G., 50 Mabon, G., 42 McAlees, A. J., 101 Macaulay, J. B., 300 Maccagnani, G., 370 McCague, R., 235 McCall, J. M., 349 McCall, R. B., 349 McCleery, D. G., 161 McClure, D. E., 197 McCollurn, G. W., 195,251 McCombs, C. A., 260, 296 McComsey, D. F.,159 McCormick, J. P.. 81, 258 McCrindle, R., 101 McCulloch, A. W., 138 McDaniel, R. L., jun., 6, 307 Macdonald, J. E., 385 Macdonald, T. L., 183, 306, 308 McDowell, P., 152 McEwen, W. E., 38 McGee, L. R., 103, 224 McGhie, J. F., 111, 179

Machado-Araujo, F. W., 134 Machinami, T., 284 McInnes, A. G., 138 McKean, D. R., 262 McKervey, M. A., 288 McKillop, A., 132, 318 McLaren, F. R., 278 Maclaren, J. A., 123 McManus, S. P., 110 McMurry, J. E., 292 McNamara, J. M., 304, 380 MacNeil, P. A., 218 McPhail, A. T,, 285, 351 MacPherson, L. J., 174 Madesclaire, M., 269 Maeda, H., 40, 190, 270, 343 Maeda, M., 47 Maeda, Y., 124 Maemura, K., 229 Magid, R. M., 180 Magnus, P., 113, 147, 263, 340 Magnus, P. D., 203 Magolda, 'R. L., 272, 297, 376 Mahalingam, S., 306 Mahon, M., 132, 135, 376 Maier, W. F., 1 Maifeld, W., 279 Maillo, M.A., 135 Maitlis, P. M., 19 Maitte, P., 87, 120, 214 Maity, S. K., 291 Majestic, V. K., 190 Mak, C.-P., 293 Makaiyama, T., 128 Makami, K., 104 Makisumi, S., 144 Malacria, M., 67 Malchenko, S.,141, 389 Maleki, M., 63 Malhotra, R., 318 Mali, R. S., 142 Mallamo, J. P., 96, 97, 100, 228,247,302, 392 Malleron, J.-L., 37, 90 Malpass, J. R., 353 Mancuso, A. J., 56, 393 Mandai, T., 206, 233. 269 Mandal, A. K..160, 392 Mandell, L., 42 Mander, L. N., 67, 291, 292, 300, 302 Mandolini, L., 111, 309, 391 Manescalchi, F., 187 Mangold, D., 121, 194 Mangoni, L., 9 Manh, D. D. K., 310 Manhas, M. S.,326 Mansour, M. E. Y., 356 Marazza, R., 293, 372 Marchelli, R., 188 Marchese, G., 1s Marchi, D., jun., 32, 228, 255

406 Marchiori, M. L. P. F. C., 59 Marfat, A., 107 Margosian, D., 351 Mariano, P. S., 213 Marino, J. P., 25, 68, 117, 276, 286,306 Markiewicz, W., 99 Marrero, R., 258 Marriott, D. P., 114 Martelli, J., 278 Martens, J., 141, 150, 389 Martin, J. C., 242 Martin, P., 106, 280 Martin, S. F., 384 Martin, V. S., 98, 178, 221 Martina, D., 42 Martinez, G., 6, 125 Martinez, J., 151 Martinez-Davila, C., 36, 286, 299 Maruoka, K., 143, 160, 198, 199,252, 254,350,384 Maruyama, K., 93, 167, 168, 224, 253, 264 Maruyama, T., 135 Maryanoff, B. E., 159 Masamune, S.. 95, 102, 141, 252, 388 Masamune, T.. 124, 131, 310 Mashima, K., 15 Mason, C. J., 217 Massey-Westropp, R. A., 134 Mastalerz, H., 269 Masters, T. J., 291 Masunaga, T., 268 Masuyama, Y.,56 Mathias, E., 206 Matoba, K., 340 Matsuda, I., 27, 118, 259 Matsuda, T., 229, 326 Matsuda, Y.,347 Matsueda, G. R., 151 Matsueda, R., 151 Matsui, K., 229 Matsui, T., 295 Matsumoto, A., 83. 271 Matsumoto, H., 131, 158, 292, 298, 301 Matsumoto, K., 209, 391 Matsumoto, M., 57 Matsumoto, T., 290 Matsumura, E., 158 Matsumura, Y.,134, 144, 199, 201, 225, 254, 268, 339, 349,384 Matsuoka, H., 267 Matsuoka, M., 337 Matsuoka, Y.,60 Matsushima, K., 189 Matsushita, H., 13, 132, 226, 255, 305 Matsuura, K., 131 Matsuyama, H., 143, 350 Matta, K. L., 173

Author Index Matteson, D. S., 39, 253 Matthews, R. S., 141, 389 Mattingly, P. G., 326 Matz, J. R., 35, 69, 282, 305 Mauleon, D., 337 Maybury, P. C., 158 Maycock, C. D., 160, 225 Mayer, G. D., 216 Mayr, H., 16, 17, 284, 299 Maysumoto, H., 128 Mazaleyrat, J.-P. 162, 240 Mazza, D. D., 348 Mauanti, G., 370 Mauocchi, P. H., 392 M’Boula, J., 257 Meyer, J., 227 Mehrotra. A,, 354 Mehrotra, K. N., 323, 354 Mehta, G., 288, 289, 373 Meidar, D., 88 Meier, G. P., 269 Meier, H., 50 Meijer, J., 16, 44, 51, 55 Meinhart, J. D., 236, 336 Meinwald, J., 24, 84, 141, 169, 275 Melamed, U., 121, 242 Mellor, M., 289 Melvin, L. S., 267 Melzer, H., 296, 360 Mendelson, L., 229, 309 Mendelson, L. T., 382 Mendoza, L., 159, 250 Mendoza, S., 126 Menger, F. M., 56, 98, 174 Mercer, F., 325 Merenyi, R., 27, 210, 272, 360 Merkel, T. F., 211 MCrot, P., 142 Meskens, F. A. J., 88, 390 Mesnard, D., 46 Mestres, R., 213 Mestroni, G., 162 Meth-Cohn. O., 357 Metzger, J., 3 Meyer. G. D., 364 Meyer, H., 352 Meyer. R., 148 Meyers, A. I., 32, 91, 92, 115, 132, 143, 196, 198, 199, 214,238,251, 338 Michalak, R. S.. 242, Michie, J. K., 89 Michna, P., 293 Michno, D. M., 279, 307 Midland, M. M., 103, 128, 206 Miginiac, P., 46, 59 Mihelich, E. D., 221 Mikaye, H., 205 Mikami, K., 35, 44, 79, 104, 179, 187

Mikolajczyk, M., 195, 275 Millan, A., 19 Miller, A., 63 Miller, D. J., 236 Miller, J. A., 27, 65, 89, 261, 296 Miller, M. J., 326 Miller, R. D., 262 Mills, S., 250 Mimura, T., 35, 71, 79, 104, 179 Minakata, H., 296 Minami, I., 140 Minami, K., 33, 268 Minton, M. A., 106 Miodownik, A., 201, 248 Mirbach, M. F., 65 Mirbach, M. J., 65 Misawa, H., 50 Mise, T., 133 Mislankar, D. G., 19 Misra, S. C., 111, 179 Misumi, S., 9, 290 Mitchell, M. A., 43 Mitchell, T. R. B., 198, 205, 218 Mitchell, W. L., 303 Mitscher, L. A., 177, 263 Mitschka, R., 103, 288 Mitsudo, T., 50 Mitsui, Y.,296 Mitsunobu, O., 56, 109, 394 Mitsuo, N., 1, 193 Miura, K., 96, 100, 109, 173, 228 Miura, M., 321 Miwa, H., 233 Miwa, T., 145, 247 Miyake, H., 2, 9, 24, 73, 210, 265, 271 Miyake, T., 31, 165, 225, 248 Miyamoto, M., 128, 249 Miyamoto, T., 128, 249 Miyasaka, T., 143, 152 Miyata, S., 340 Miyaura, N., 13, 27, 39, 120, 229,253 Miyazaki, T., 199, 254, 343, 384 Mizusaki, K., 144 Moberg, C., 202 Mochida, I., 158 Mochida, Y.,180 Mochizuki, H., 160, 161 Mock, W. L., 86 Moller, B., 333 Morch, L., 114 Moffatt, F., 122, 295 Mohnhaupt, M., 122, 295 Moinet, C., 42 Mol, J. C., 12 Molander, G. A., 30, 50, 230, 253 Molas, J., 202

Author Index Molina, P., 204 Momose, D., 4 Momose, T., 355 Mondon, M., 119, 303 Monpert, A., 278 Montanari, F., 184 Montgomery, S. H., 103, 240 Moody, C. J., 235 Moore, H. W., 281, 325, 390 Moore, M. W., 31, 165, 225, 255 Morch, L., 249 Moreau, J. J. E., 61 Moreno-Mafias, M., 39, 90, 268 Morey, M. C., 173 Morgan, B. A., 152 Morgan, P. J., 147 Morgans, D. J., jun., 140, 223, 387 Morganti, G., 363 Mori, I., 37, 169, 173, 254 Mori, K., 114, 120, 121, 220, 393 Mori, M., 352 Mori, S., 95, 141, 252, 388 Mori, Y., 24 Moriarty, R. M., 81, 107 Morin, J. M., 139 Morishima, H., 123, 252 Morita, K., 4 Morita, T., 1, 177, 179, 262, 263 Morito, N., 152 Moriya, H., 167, 224 Morizawa, Y.,130, 173 Morosawa, S., 344 Morris, J., 146, 295 Morrison, G. A., 216 Morrison, J. D., 161, 255 Morrison, J. J., 92 Morrison, P. A., 300 Morrocchi, S., 14 Morrow, S.D., 207 Morton, H. E., 235, 265 Morton, J. A., 118, 306 Morzycki, J. W., 72, 276 Mosher, H. S., 85, 116, 248 Moss, S. F., 366 Motherwell, R. S. H., 164 Motherwell, W. B., 1, 58, 72, 164, 179, 265, 266, 269, 276, 393 Motoki, S., 348 Motoyoshiya, J., 212, 323 Mott, R. C., 81, 117, 222, 258 Moulines, J., 314 Moynihan, P.,144 Muchowski, J. M., 44, 84, 199,266 Mudryk, B., 26 Mueller, M. E., 246 Muller, P.. 57, 85, 222

407 Miiller, W.,144 Mugrage, B., 19 Mukai, C., 355, 369 Mukai, T., 391 Mukaiyama, S., 57 Mukaiyama, T,,45, 60, 83, 94, 99, 100, 115, 145, 152, 162, 166, 167, 186, 209, 226, 239, 247, 252, 264, 326 Mukherjee, D., 291 Mukkavilli, L., 326 Mukuta, T., 142 Muller, G. W., 289, 373 Muller, U., 238 Mulzer, J., 105, 125 Mundhill, P. H. C., 67, 291, 292 Munegumi, T., 150 Munger, P., 336 Munns, M. S., 151 Munroe, J., 107 Murahashi, S., 124, 183 Murai, A., 124, 131, 310 Murakami, M., 94, 115, 252 Murase, M., 369 Murata, I., 391 Murata, S., 163, 175 Murayama, E., 67, 305 Murdock, T. P., 278 Murphy, C. J., 5 Murray, E. B., 26 Murray, R. E., 20 Murray, T. F., 138 Murtiashaw, C. W., 257, 310 Mussatto, M. C., 187 Musser, J. H., 292 Mutai, K., 202 Muzart, J., 22, 72 Myers, A. G., 297, 376 Mynott, R., 309 Myrboh, B., 265 Nadir, U. K., 323 Nadolska, B., 152 Naf, F.,298 Naef, R., 102, 113, 238 Nagai, K., 341 Nagai, M., 301 Nagai, Y.,20, 128, 133, 158, 394 Nagami, S., 160 Nagamoto, N., 355 Nagao, Y., 152 Nagaoka, H., 143 Nagaoka, N., 317 Nagashima, E., 43 Nagashima, H., 112 Nagashima, T., 68, 309 Nagasuna, K., 15 Nagata, M., 341 Nago, Y.. 143 Nagubandi, S., 344 Nagy, J. O., 327

Nahm, S.,60 Nair, M. S., 289 Nair, V., 214 Naito, T., 391 Naito, Y., 235 Najera, C., 144, 197, 199, 249 Nakada, Y.,359 Nakagawa, M., 105 Nakagawa, T., 131 Nakagawa, Y.,50 Nakahama, S.,160, 161,254 Nakai, H., 160 Nakai, T., 32, 35, 40, 44, 71, 79, 104, 142, 179, 181, 187, 270 Nakajirna, M., 86, 111, 268 Nakajima, R., 4 Nakamura, A., 15 Nakamura, E., 177, 243 Nakamura, H., 189 Nakamura, T., 189 Nakanishi, K., 178 Nakanishi, S., 233 Nakano, T., 128, 133, 135 Nakao, R., 109 Nakao, S., 18, 120 Nakashita, Y., 70, 308 Nakasuji, K., 391 Nakasuka, S., 384 Nakata, T., 254 Nakatsuji, Y.,189, 190 Nakatsuka, M., 113, 301, 340, 379 Nakatsuka, T., 145, 247 Nakatsuyama, S.,147 Nakayama, M,,107 Nakazaki, M., 47 Nambiar, K. P., 141, 389 Nanba, K., 1 Nandi, K., 367 Naota, T., 124 Narang, S. C., 88, 89, 109, 175, 177, 181, 186, 207, 262, 263 Narasimhan, S., 194 Narayanan, B. A., 183 Narimatsu, S., 31, 172, 256 Narisano, E.. 82, 172, 239 Narula, A. P. S., 196 Narula, A. S., 92, 296 Naruse, K., 60, 226 Naso, F., 15 Natale, N. R., 238 Natalie, K. J., jun., 64, 200 Nawahara, N., 351 Ndal, N. T., 199 Nechvatal, G.,236 Neckers, D. C., 369 Neef, G.,331 Negishi, E., 13, 17, 31, 52, 165, 255, 391 Negishi, E.4.. 225, 226 Negishi, Y.,267

Author Index

408 Negoro, K., 313 Neidlin, R., 366 Nelson, J. V., 93 Nemoto, H., 293, 301, 306, 379 Nemoto, K., 393 Neri, O., 9 Neuenschwander, K., 125 Neuenschwander, M., 6 Newkome, G. R., 190 Newton, R. F., 139, 178, 191, 263, 285,295 Ney-Igner, E., 121 Ng, K. S.,37, 249 Ngoviwatchai, P., 207 Nguyen, D. L., 151 Nguyen, N. H., 128 Nickel, W.-U., 5 Nicodem, D. E., 59 Nicolaou, K. C., 120, 125, 142, 272, 276, 292, 297, ‘ 376, 387 Nigam, R. K., 268 Nimitz, J. S., 85, 116,248 Ninomiya, I., 391 Nishida, I., 93 Nishida, K., 99 Nishide, K., 255 Nishiguchi, I., 18, 87, 120, 128, 249, 258, 307 Nishiki, M., 1, 193 Nishimura, H., 345 Nishio, T., 334 Nishitani, K., 17, 182 Nishiuchi, K., 206, 269 Nishiwaki, T., 365 Nishiyama, H., 29, 31, 33, 107, 164, 172, 233, 256 Nishizawa, M., 161 Nishizuka, T., 203 Niwa, H., 186, 253 Noble, P., 152 Noda, A., 95 Noda, Y., 135 Node, M., 99, 255 Noguchi, Y., 326 Nojima, M., 321 Nokami, J., 206, 264, 269, 311 Nomoto, K., 147 Nomoto, S., 150 Nomura, Y.,216, 275, 335 Norberg, R. E., 236 Norin, T., 129 Normant, J. F., 12, 38, 165, 226, 390 Nortey, S. O., 159 Norton, J. R., 138 Nose, A., 193 Nose, H., 264 Notegen, E., 141 Nott, A. P., 106 Noureldin, N. A., 56 Novack, V. J., 268, 313

Noyori, R., 73, 93, 161, 163, 175, 236,259 Nozaki, H., 37, 57, 59, 70, 73, 130, 167, 169, 173, 222, 224, 233, 234, 245, 254, 263, 287, 305, 315 Nozawa, M., 323 Nozoe, S., 147 Nurrenbach, A., 101 Nukada, T., 121 Nunn, M. J., 296 Nunomoto, S., 226 Nussim, M., 201, 248 Nyns, C., 27, 272 Oae, S.,181, 185 Obana, M., 139 O’Brien, D., 213 Ochi, M., 131 Ochiai, M., 37, 79, 99, 209, 255, 256, 301 Oda, M., 173,294 O’Dell, D. E., 183, 306, 308 O’Doherty, J., 89 Oe, K., 317 Oehldrich, J., 288 Oller, M., 280 Oesch, U., 191 Oeser, H-G., 215 Ogasawara, K., 40, 104, 129, 179, 270, 291 Ogura, F., 9, 276 Ogura, H., 351 Ogura, K., 270 Oh, H., 107 Ohara, E., 19, 208, 275 Ohasi, M., 319 Ohata, K., 119 Ohawan, K. L., 282 Ohba, N., 81 Ohfune, Y., 147 Ohgi, T., 145 Ohgo, Y., 150 Ohira, S., 107 Ohkawa, S., 68, 245, 299 Ohloff, G., 298 Ohmizu, H., 98, 141 Ohmura, H., 348 Ohnishi, K., 119, 217 Ohnishi, S., 144 Ohnishi, V., 326 Ohno, M., 123, 200, 252, 326 Ohnuma, T., 272 Ohsawa, T., 2, 183, 330 Ohshima, T., 361 Ohshiro, Y., 20, 22, 78, 205, 256, 268, 278, 348, 357, 368 Ohta, S., 123 Ohtsuka, T., 290 Ohwa, M., 160, 161 Oida, T., 38, 89, 335 Oishi, T., 2, 183, 254, 385 Ojima, I., 150

Oka, K., 80, 109, 393 Okada, H., 2 Okada, S. S., 109, 173 Okahara, M., 189, 190 Okamoto, M., 123 Okamoto, Y., 1, 4, 33, 177, 179, 255, 256, 262, 263 Okamura, Y., 107 Okano, M., 32, 38, 86, 89, 143 Okano, T., 206, 212 Okawara, M., 40, 264, 347 Okawara, R., 264 Okawara, T., 326 Okazaki, R., 52 Oku, J., 203 Okuda, H., 347 Okukado, N., 13, 226 Okumoto, H., 112, 205, 301 Olah, G. A., 2, 59, 74, 88, 89, 98, 109, 175, 177, 181, 186, 207, 219, 244, 262, 263, 318 Olesker, A., 300 Olivero, A. G., 160, 162, 225 Olsen, E. G., 279 Olson, R. E., 74 Oltvoort, J. J., 176 Omote, Y., 326 On, H. P., 20, 182 Onaka, M., 60 Onan, K. D., 285 Ong, B. S., 141, 389 Ong, C. W., 231 Ongania, K.-H., 327 Ongena, R., 290 Ono, M., 163, 275 Ono, N., 2, 9, 24, 73, 205, 207, 210, 265, 271 Ono, R. K., 296 Onwezen, Y.,185, 189 Ooi, N. S., 217 Ooi, Y., 193 0-oka, M., 52 Oppolzer, W., 44, 74, 99, 122, 227, 290, 293, 295, 298, 310, 339, 372, 385, 391 Orchin, M., 65 Oremek, G., 361 Orena, M., 139, 154, 171, 321 Oriyama, T., 94, 252 Orme-Johnson, W. H., 158 Ornstein, P. L., 7, 219 Ortiz, M., 108 Osakada, K., 139 Oshima, K., 37, 57, 59, 70, 73, 169, 222, 254, 305 Otsubo, T., 9, 276 Otsuji, Y., 233 Otsuka, M., 123, 200, 252 Ott, R. A., 60, 212 Ottenheijm, H. C. J., 149

409

Author Index Ouellette, D., 83, 280 Ourila, A., 142 Overberger, C. G., 211 Overman, L. E., 200, 254, 257, 296,382, 383 Owada, H.,32, 143 Ozawa, S., 73 Ozbal, H., 208 Ozmeral, C., 364 Pachaly, B., 2 Padmanabhan, P. V., 353 Padwa, A., 277,324,391 Paget, W. E., 181, 251 Pahde, C., 11 Pale, P., 22, 72 Palomo, C., 108, 213, 264, 268 Pals, D. T., 349 Palumbo, G., 9 Pan Y-G., 260,296 Pandey, G. D., 393 Panunzio, M., 112 Panzeri, A,, 98 Panzica, R. P., 8 Papahatjis, D. P., 297, 376 Paquette, L. A., 43, 45, 140, 261, 272, 284, 2 7, 289, 290, 293, 371, 32!, 373, 374 Paquin, R., 188 Pardo, S. N., 111 Parham, M. E., 151 Parham, W. E., 330 Parker, D., 101 Parker, J. E., 84 Parsons, P. J., 23, 74, 257 Pastuszak, J. J., 151 Pataud-Sat, M., 61 Patchornik, A., 86 Patel, B. A., 41, 78, 113 Patel, R. C., 154 Patel, S. K., 9, 89, 260 Paterson, I., 86, 88, 188 Patni, R., 367 Patrick, T. B., 215 Pattenden, G., 6, 134, 266, 287, 289, 290 Patterson, M. A. K.,102 Patton, L., 289 Patzelt, H., 307 Paust, J., 101 Pavia, M. R., 142, 387 Pclezhaeva, N. A., 394 Pearce, A., 188 Pearlman, B. A,, 304 Pearson, A. J., 231 Pearson, N. R., 51 Pearson, W. H., 193, 272 Peck, D. R., 140 Pedersen, C., 129 Pednekar, P. R., 157 Pedroso, E., 152

Pegg, W. J., 81 Pellicciari, R., 87, 244 Pelter, A., 22, 59, 65, 75, 118, 136, 156, 250, 253, 27 1 Penenory, A. B., 275 Pennanen, S. I., 135 Pennings, M. L. M., 325 Pepperman, A. B., 103 Percival, A., 296 Perera, C. P., 234, 324 Pereyre, M., 390 Perlman, B. A., 380 Perlman, K., 382 Perozzi, E. F., 242 Perry, D. A., 22, 23, 76, 257 Perumal, P. T., 64 Perz, R., 157 Peseckis, S. M., 297 Petasis, N. A., 120 Pete, J.-P., 22, 72 Peter, R., 93, 224 Peters, E.-M., 312 Peters, K., 312 Petersen, H., 50 Petraitis, J. J., 70, 308 Petrakis, K. S., 101 Petrzilka, M., 69, 295, 391 Petty, C. B., 296 Pez, G. P., 158 Pfeffer, B., 80 Phillion, D. P., 192 Phillips, J. G., 172, 239 Photis, J. M., 89, 109, 203 Phu, T. N., 65 Piancatelli, G., 26, 80 Piau, F., 280 Picard, P., 314 Pienta, N. J., 277 Pieronzyk, W., 150 Pierpoint, C., 41 Piers, E., 235, 265 Pietra, F., 363 Pietraszkiewicz, M., 147 Pietruszewski, C. L., 288 Pifferi, G., 211 Pillot, J.-P., 46, 77, 256 Pines, H., 121 Ping, Y. Y., 393 Pinhey, J. T., 265 Pinnick, H. W., 58, 130, 209, 222, 262 Pinza, M., 211 Pirkle, W. H., 178 Pirrung, M. C., 93, 103, 114, 126,240,290,371 Pittman, C. U., 65 Pizzo, C. F., 104 Piuolato, G., 304, 380 Place, P., 166 Plumerk, P., 191 Plunkett, J. J., 225 Pochat, F., 206 Pohmakotr, M., 63, 142

Poindexter, G. S., 197 Poirier, M., 157 Polaski, C. M., 21 Polk, D,E., 248 Pollet, P., 137 Polniaszek, R. P., 277 Pommelet, J.-C., 27, 272 Poncet, J., 266 Poncini, L., 59 Ponkshe, N. K., 84, 199 Pons, M., 152 Ponsati, 0.. 135 Ponton, J., 140, 290, 299 Pornet, J., 42, 46, 165 Porter, J., 175 Porzi, G., 139, 154, 171, 199, 32 1 Posner, G. H., 96, 97. 100, 109, 173, 228, 247, 302, 392 Pospischil, K.-H., 145, 257 Potter, G. J., 291 Potts, K. T., 88 Pouton, J.. 374 Powell, D. R., 5 Powell, D. W., 269 Prakash, G. K. S., 2, 98, 219 Prasad, R. S., 292 Prasanua, S., 381 Press, J. B., 141, 389 Prestwich, G. D., 128 Prevot, D., 151 Price, L. G., 86, 88 Price, M. F., 134 Price, R. T., 166 Procter, G., 101 Prokopiou, P. A., 11I , 179 Protschuk, G., 86, 307 Proust, M., 331 Pugin, B., 199 Puleo, R., 26, 77, 275 Pulwer, M. J., 140, 277 Pushpananda, K., 280 Pyne, S. G., 291 Quast, H., 346, 363 Quayle, P., 324 Quinkert, G., 301 Quintard, J.-P., 390 Raber, D. J., 159 Rachon, J., 119, 207, 266 Raddatz, P., 142 Radhakrishnan, T. V., 303 Radics, L., 342 Rafii, S., 238 Rai, M., 370 Rajan Babu, T. V., 389 Rajapaksa, D., 379 Rajappa, S., 390 Rajcoomar, V., 101 Rall, G. J. H., 132, 318

Author Index

410 Ralli, P., 88 Ram, B., 326 Ramadas, S. R., 348, 353 Ramage, R., 152 Ramana, D. V., 353 Rambaud, M., 80 Rana, S. S., 173 Rand, C. L., 31, 52, 165, 225, 255 Randrianoelina, B., 42, 59, 165 Rao, J. M., 65, 118, 156, 253 Rao, K. J. J., 353 Rao, K. S., 288 Rapoport, H., 116,215, 238 Rasmy, 0. M., 278 Rastetter, W. H., 192 Rathke, M. W., 86, 113, 258 Ratovelomanana, V., 16, 182 Rauch, F. C., 194 Raucher, S., 144, 308, 385 Ravichandran, R., 335 Raynier, B., 202 Razdan, R. K., 393 Reames, D. C., 319, 330 Reddy, A. V., 289, 373 Reddy, G. S., 81 Redeker, U., 18 Reed, C. A., 392 Rees, C. W., 235 Reese, C. B., 174, 308 Reetz, M. T., 3, 89, 90, 93, 160,224, 263, 304 Regen, S. L., 184, 354 Regitz, M., 50 Regondi, V., 58, 89 Reho, A., 65 Reich, H. J., 62, 74, 293 Reichlin, D., 122, 295 Reilly, T. J., 337 Reinecke, M. G., 348 Reinhoudt, D. N., 108, 177, 189, 325,329 Reink,ing, P., 58 Reissenweber, G., 121, 194 Reissig, H.-U., 116 Reiter, U., 145 Reitz, D. B., 241 Rene, L., 208 Resch, J. F., 169 Reshef, D., 109 Resnati, G., 95, 239, 269 Rettig, M.F., 106, 223 Reuman, M., 198, 338 Reuvers, J. T. A., 271 Revial, G., 311 Reye, C., 157 Reynolds, C. D., 217 Reynolds, D. P., 139, 178, 263, 285, 295 Reynolds, G. A., 348 Rhouati, S., 357 Richardson, W. H., 11 Riche, C., 284

Rickards, R. W., 102, 144, 244,284 Ried, W., 361 Rieker, W. F., 391 Rihs, G., 280 Risse, S., 214 Rizzi, J. P., 136, 304, 380 Roberge, G., 260, 296 Roberts, B. W., 309 Roberts, M. R., 138, 375 Roberts, N. K., 218 Roberts, S. M., 178, 263 Robertson, A. D., 61, 262 Robins, M. J., 179 Roca, M. R., 108 Rocek, J., 280 Roche, D., 269 Rodini, D. J., 166 Rodrigo, R., 379 Rodriguez, A., 324 Rodrique, A., 188 Rader, T., 156 Rosner, P., 308 Rohr, W., 358 Rokach, J., 139 Rolla, F., 2, 183 Rollinson, S. W., 138 Rondan, N. G., 303 Rose, R. K., 109, 173 Rosenblum, M., 28, 35, 90, 137 Rosenfeld, S. M., 8 Roshan-Ali, Y.,176 Ross, J. F., 370 Ross, M. R., 242 Rosseau, G., 141 Rosser, R., 250 Rossert, M., 367 Rossi, D., 145 Rossi, R. A., 275 Rossiter, B. E., 220, 313 Rossy, P., 101 Roth, B. D., 125 Roth, K., 69, 266 Roth, M., 99 Rouessac, A., 127, 306 Rouessac, F., 127, 306 Roumestant, M. L., 284 Roush, W. R., 295, 297, 376 Rousseau, G., 21, 35, 75, 79, 249, 389 Rouwette, P. H. F. M., 207, 282 Roy, D., 206 Royer, R., 202, 208, 214 Rozeboom, M. D., 303 Rubin, M. B., 42 Rubottom, G. M., 81, 117, 222,258 Ruchardt, C., 101 Riicker, C., 177,264 Ruger, W., 5 Rungeler, W., 279 Ruitenberg, K.,44, 55

Runge, T. A., 67, 223, 284 Rupani, P., 22, 75, 253 Ruppert, J. F., 311 Russ, M., 188, 262 Russel, D. R., 362 Russell, C. G., 34, 79, 275 Russell, G. A., 26 Russell, R. A., 136, 303 Russell, R. K., 292, 378 Rutledge, P. S., 181, 216, 364 Ruveda, E. A., 133 Ryabov, A. D., 229 Ryono, L. S., 229, 309 Rzeszotarska. B., 152 Sal, J. M., 11 Saba, A., 154 Saburi, M., 139 Sadlo, H., 307 Saegusa, T., 95, 113, 130, 167, 301,340, 379 Saenger, W., 145 Saft, M. S., 207 Saga, H., 202 Sagitullin, R. S., 199 Sahu, D. P., 326 Sai, M., 255 Saimoto, H., 234, 245, 287, 315 Saindane, M., 26, 77, 273, 275,294 Saint M’Leux, Y.,174 Saito, A., 132, 305 Saito, K., 278 Saito, M., 20 Saito, N., 215 Saito, 0.. 202 Saito, T., 272, 305 Sakaguchi, R., 81 Sakai, K., 24, 112, 283, 290 Sakai, Y.,118 Sakakibara, T., 19, 208, 275 Sakamoto, M., 326 Sakamoto, T., 270 Sakan, K., 141, 389 Sakata, J.. 93 Sakata, Y.,9 Saksena, A. K., 285 Sakurai, H., 1, 36, 88, 155, 177, 179, 186, 258, 262, 263 Sakuta, K., 31, 164, 256 Saleh, S. A., 29, 205 Salem, G. F., 88, 89, 109, 177,263 Salomon, R. G., 111 Saltzman, M. D., 300 Sammes, P. G., 29, 122, 136, 246,269,282 Samsel, E. G., 138 Samson, M., 150 Sanchez, I. H., 206 Sancho, J., 47 Sanders, H. P., 308

41 1

Author Index Sandkuhler, P., 280 Sandri, S., 139, 154, 171, 321 Sano, H., 40, 264 Santaniello, E., 157 Santelli, M., 54 Santiesteban, H., 99 Santini, C., 6, 307 Sard, H., 36, 299 Sarkar, T., 113 Sarti, S., 370 Sartori, G., 14 Sarussi, S. J., 158 Sasaki, K., 36, 186 Sasaki, M., 29, 87, 128, 233, 249, 307 Sasaki, T., 206, 212 Sasoaka, Y., 365 Sastry, K. A. R., 181, 195, 25 1 Satake, H., 344 Sato, F., 31, 36, 58, 106, 128, 165, 167, 219, 224, 225, 248 Sato, K., 270, 319 Sato, M., 31, 36, 58, 70, 106, 165, 167, 219, 224, 225, 248, 254 Sato, N., 188 Sato, S., 124, 310 Sato, T., 35, 46, 60, 80, 95, 105, 140, 226, 249 Sato, Y., 147, 287, 357 Satoh, J. Y.,72, 80 Satoh, T., 1, 81, 193 Sattur, P. B., 370 Satyanarayana, G. 0. S. V., 288 Satyanarayana, P., 136, 271 Sauer, G., 331 Sauerwald, M., 89 Saunders, J. O., 257, 310 Sauriol-Lord, F., 240 Saus, A., 65 Sauter, F., 366 Sauter, H. M., 141, 389 Savoia, D., 7, 193 Savu, P. M., 103 Sawitzki, G., 307 Sawyer, J. A., 277 Scahill, T. A., 323 Scarborough, R. M., jun., 123, 129, 316 Scettri, A., 26, 80 Schafer, H. J., 56, 142, 176, 222,393 Schamp, N., 127,214 Schaper, U.-A., 175 Schaumann, E., 332, 335, 346,356,366 Schaumburg, K.. 146 Scheibel, J. J., 215 Scheidt, W. R., 392 Scheinmann, F., 353 Schenone, P., 363

Schiavelli, M. D., 225 Schinzer, D., 65 Schlessinger, R. H., 138, 296, 375 Schleyer, P. von R., 1 Schmid, G., 143 Schmidt, A. H., 188, 262, 390 Schmidt, D. G., 137 Schmidt, H.-J., 56, 142, 222 Schmidt, R. R., 121, 242, 296 Schmidt, U.,140, 152 Schmierer, R., 110, 114, 156, 295 Schrnitt, B., 357 Schmitthenner, H. F., 331 Schneiders, G. E., 132 Schollkopf, U., 35, 119, 145, 148, 207,237, 266, 356 Schonhammer, B., 150 Scholten, H. P. H., 149 Scholz, D., 105, 270 Scholz, K.-H., 197, 280 Schore, N. E., 6, 119,288 Schostarez, H., 140, 290, 293, 372, 374 Schow, S. R., 24,76, 124, 316, 377 Schreiber, S. L., 6, 307 Schreifels, J. A., 158 Schreiner, J. L., 178 Schrock, R. R., 47 Schrott, U., 169 Schuchardt, U., 121 Schiitz, F., 299 Schuh, K., 351 Schultz, A. G., 122, 335 Schulz, R., 55 Schulz-Popitz, C., 50 Schumann, H., 2 Schunk, G., 357 Schuster, D. I., 196 Schustov, G. V., 322 Schwan, T. J., 345 Schwartz, J., 11, 230 Schwartz, U., 301 Schweig, A., 55 Schweizer, W.-B., 92 Schwellnus, K., 90, 304 Schwendemann, V. M., 215 Schwindeman, J. A., 203 Schwinger, G., 307 Sciacovelli, O., 15 Scolastico, C., 82, 95, 172, 239, 269 Scott, P. W., 141 Scovill, J. P., 217 Seebach, D., 19,49, 61, 63, 86, 92, 95, 102, 113, 142, 160, 162, 169, 186, 197, 208, 209, 225, 238, 241, 242, 245, 261, 262, 307 Seeley, J. H., 152 Segal, M., 145 Segawa, J., 177,263

Sehgal, R. K., 357 Seitz, B., 17 Seitz, D. E., 85, 235, 260, 265 Seitz, S. P., 120, 142, 387 Seki, K., 142 Sekine, M., 65, 86, 111, 173, 268 Sekiya, M., 43, 60, 90, 326, 329 Sekizaki, H., 304, 380 Self, C. R., 234 Selim, A., 110, 156 Selltedt. J. H., 193 Semmelhack, M. F.,28, 29, 138, 206, 229, 260, 296, 309, 371 Senaratne, A., 83, 280 Senda, S., 320 Seno, K., 152 Seno, M., 185 Serota, S., 26 Seshadri, S., 81 Seto, K., 59 Setoi, H., 40, 142, 179, 270 Seuron, N., 243 Seyden-Penne, J., 243 Shabtai, J., 121 Shah, S. K., 74 Sham, H. L., 122 Shani, A., 72 Shapiro, M. J., 368 Sharpless, K. B., 98, 178, 220, 221, 223, 313 Shatzmiller, S., 21, 74, 242 Shaw, K. R., 140 Sheldon, B. G., 131, 297 Shelton, S. R., 7 Shen, M., 122, 335 Shen, Y., 267 Sheradsky, T., 333 Shibasaki, M., 11, 265, 289 Shibuya, S,,328, 369 Shieh, H.-M., 128 Shiga, M., 189 Shih, C., 25, 243 Shih, T L., 251 Shimagaki, M., 86, 203, 259 Shimanski, M., 206 Shimizu, I., 112 Shimizu, M., 57, 78, 84, 274 Shimizu, T., 334, 335 Shin, G 149 Shiner, S., 302, 379 Shinoda, M.. 245, 287, 315 Shioiri, T., 207 Shiosaki, K., 116 Shirahama, H., 290 Shirahata, A., 88, 258 Shirai, K.,347 Shirai, Y., 233 Shiratori, Y., 292 Shishido, K., 342 Shishido, Y., 52

k.

Author Index

412 Shishiyama, Y.,203, 263 Shoda, S.-I., 83, 264 Shoenberger, D. C., 159 Shono, T., 87, 128, 134, 144, 201, 225, 249, 268, 307, 339,349 Show, K. R., 387 Shringarpure, J., 331 Shuo, Y., 109 Sibanda, S., 174 Sidhu, R. S., 288 Sidot, C., 26 Sieburth, S. McN., 70, 308 Siegel, H., 280 Sierra, M. G., 133 Siew, P. Y., 288 Sih, C. J., 139, 140, 376, 382 Sillion, B., 109, 127 Silverton, J. V., 288 Simchen, G., 69, 89, 204, 262 Simmons, D. P., 74, 298 Simmonds, K. A., 178 Simmross, F. M., 105 Simon, J. R., 26 Simon, W., 191 Simonet, J., 42 Simoni, D., 24, 72, 119 Sims, R. J., 10, 191 Sinder-Kulyk, M., 369 Sing, A., 325 Singh, A., 354 Singh, A. K., 278 Singh, G., 354 Singh, H., 365 Singh, P., 365 Singh, R. P., 63 Singh, S. B., 323 Singh, S. K., 70, 308 Sinha, A. K., 344 Sisani, E., 87, 244 Sit, S. Y., 17, 182 Sivanandaiah, K. M., 152 Sivaramakrishnan, R., 234 Slapak, C., 282 Slopianka, M., 145, 197, 266 Slougui, N., 21, 75 Smijic, V., 392 Smith, A. B., tert., 6, 24, 76, 84, 87, 116, 123, 124, 129, 130, 285, 286, 293, 316, 372, 377, 394 Smith, D. J. H., 362 Smith, J. G., 229, 309 Smith, K., 181, 251 Smith, S. S., 127 Snider, B. B., 33, 123, 148, 166 Snieckus, V., 391 Snowdon, R. L., 44, 74, 124, 298 So, S., 135 Soai, K., 139 Soga, S., 107

Sogah, G. D. Y., 191 Solas, D., 126 SolladiC, G., 95, 196, 306, 392 Sondheimer, F., 266 Soneda, K., 365 Sonoda, A., 183 Sonoda, T., 211 Sopher, D. W., 111 Soucy, P., 288 Souther, S. K., 180 Sozzani, P., 157 Speer, H., 121, 242 Speizman, D., 209 Spraul, M., 80 Springer, J. P., 296 Spur, B., 320 Srikrishna, A., 289 Srinivasan, C. V., 127 Srivastava, N., 268 Stadlbauer, W., 394 Stahl, I., 89 Stamm, H., 144, 327 Stammer, C. H., 149 Stanetty, P., 333, 366 Stanfield, C. F., 84 Stang, P. J., 18, 54, 55 Stange, A., 1, 179, 265 Stanley, P., 296 Stark, H., 301 Stauffer, R. D., 229, 309 Steglich, W., 18 Steinbach, R., 3, 160, 224 Steliou, K., 132, 318 Stella, L., 202 Stephanou, E., 144 Sternbach, D. D., 210 Stevens, K. E., 289, 290, 373 Stevenson, R., 132 Stevenson, W. H., tert., 242 Stewart, F. H. C., 152 Stewart, P., 22, 75, 253 Still, W. C., 98, 140, 141, 268, 313, 387 Stille, J. R., 150 Sto, Y., 113 Stobie, A., 58, 269 Stoh, T., 105 Stone, K., 289 Stoodley, R. J., 260, 303 Stork, G., 302, 379 Stothers, J. B., 289 Stowell, J. C., 24, 67, 283 Strauss, U., 365 Streith, J., 391 Strekowski, L., 126 Streng, K., 150 Strickland, S. M. S., 257, 310 Strijtveen, B., 179 Stringer, D. D., 124 Struwe, H., 305 Sturm, H., 327 Suau, R., 11 Subbarao, H. N., 63

Suda, K., 83, 271 Suda, M., 18, 111, 231, 266, 277 Sudo, T., 264 Sudoh, R., 19, 208, 275 Siihs, K., 156 Sueoka, H., 141 Sugimoto, T., 20, 86 Suginome, H., 39, 253 Sugiura, M., 326 Sugiyama, I., 320 Sugiyama, K., 271, 296 Sum, F. W., 119 Sumi, K., 115 Summers, S. T., 1 Sunay, U., 99 Sundberg, R. J., 201 Sunjik, V., 149, 218, 353 Surzur, J. M., 202 Sustmann, R., 4 Sutherland, I. O., 191 Sutherland, J. K., 304 Sutou, N., 20 Sutthivaiyakit, S., 198, 205 Suzukarno, G., 30, 164 Suzuki, A., 13, 27, 39, 49, 65, 76.83, 101, 120, 229, 253 Suzuki, H., 188, 217 Suzuki, K., 43, 90, 239, 293, 301, 379 Suzuki, M., 24, 73, 141, 163, 236, 259,389 Suzuki, R., 37 Suzuki, S., 1 Svedberg, D. P., 308 Swanson, B. J., 215, 328 Swartz, W. E., 158 Swenton, J. S., 25, 243, 282, 381 Swern, D., 56, 393 Sylvestre-Panthet, P., 284 Szabo, L., 342 Szajewski, R. P., 102 Szantay, C., 342 Szilagyi, S., 364 Szmuszkovicz, J., 323 Taber, D. F., 29, 205, 297 Taber, T. R., 93 Tabushi, I., 59 Taffer, I. M., 155 Tagliavini, E., 7 Tains, S. P., 385 Takabe, K., 68, 245, 299, 317 Takagi, K., 43 Takagi, M., 189 Takagaki, T., 2, 183 Takahashi, K., 33, 107, 131, 203, 233, 256, 272, 288 Takahashi, M., 30, 254 Takahashi, S., 107, 287, 357 Takahashi, T., 68, 140, 235, 301, 309

Author Index Takahashi, Y., 107, 285, 317 Takahata, H., 326, 340, 341 Takai, I., 19, 208, 257 Takai, K., 37, 57, 59, 70, 169, 222, 254 Takajo, T., 337 Takaki, K., 313 Takamura, N., 119, 235 Takano, S., 129, 291, 342, 355 Takao, S., 143 Takaya, H., 30, 254 Takebe, Y., 355, 369 Takeda, M., 197 Takeda, R., 84, 85 Takeda, T., 100, 209 Takeda, Y., 260,296 Takehara, H., 326 Takei, H., 134, 142 Takei, T I 337 Takeno, H., 38, 266 Takeshita, K., 158 Taketsuru, H., 131 Takeuchi, M., 35, 105 Takeuchi, S., 150 Takeuchi, Y., 216, 275, 335 Takimoto, S., 109 Takita, S., 81 Talaty, E. R., 200 Talbiersky, J., 152 Taleb-Sahraoui, S., 281 Talley, B. G., 180 Tamariz, J., 303 Tamaru, Y., 37, 57, 144 Tamblyn, W. H., 110, 231, 277, 278 Tamm, C., 141 Tamura, C., 359 Tamura, M., 30, 164 Tamura, N., 81 Tamura, R., 2, 9, 205, 207, 210, 265 Tamura, Y., 40, 177, 216, 263,270,343, 355, 369 Tanaka, A., 137 Tanaka, K., 40, 104, 179, 270 Tanaka, M., 49, 66, 77, 109, 204 Tanaka, T., 150, 254, 355 Tanami, T., 319 Tangerman, A., 335 Tanikaga, R., 207 Tanimoto, S., 20, 38, 86, 89 Tanner, D. D., 2, 265 Tannert, A., 11 Tarhouni, R., 80 Tarnawski, J., 152 Tarnchompoo, B., 47 Taschner, M. J., 125 Tatsuno, T., 180 Tatsuta, K., 141, 289, 387, 389 Tavakalyan, N. B., 322 Tawarayama, Y., 36. 166

413 Taya, S., 35, 44, 79, 104, 179, 187 Taylor, D. R., 366 Taylor, E. C., 132, 318 Taylor, G. F., 296 Tataki, M., 189 Tedjo, E. M., 271 Tegmo-Larsson, 1.-M., 303 Ten Brink, R. E., 349 Tenca, C., 188 Ten Hoeve, W., 199 Teramura, D. H., 121 Teramura, K., 334, 335 Teranishi, S., 101, 202, 222, 257 Terao, Y., 60, 90, 326 Terasawa, M., 202 Terashima, S., 82, 124, 387 Terauchi, M., 40, 270 Teuben, J. H., 232 Thaisrivongs, S.,292, 378 Thakar, A. A., 48 Thanabalasundrum, S., 8 Thebtaranonth, Y., 47, 206 Theodoridis, G., 88 Therien, M., 56 Thibffry, A., 58, 173, 269 Thom, I. G., 231 Thomas, A. F., 393 Thomas, J. A., 295 Thompson, D. W., 225 Thompson, J., 6, 125 Thomson, R. H., 360 Thornton, J. D., 144 Thorpe, W. D., 152 Thorsen, P. T., 157, 194 Thottathil, J. K., 283 Thulin, B., .142, 189 Thyagarajam, G., 394 Tiedt, M.-L., 367 Tigchelaar, M., 51 Tijhuis, M. W., 149 Tilley, J. W., 194 Timberlake, J. W., 364 Timori, T., 326 Tius, M. A., 229, 246 Tjoeng, F. S., 152 Tobita, E., 229 Tochiki, M., 347 Tochtermann, W., 308 Toda, T., 215 Toder, B. H., 6, 24, 76, 124, 286, 316, 377 Togo, H., 181 Toi, H., 183 Tojo, G., 11 Tokitoh, N., 52 Tokoroyama, T., 131, 132 Tolbert, L. M., 141, 389 Tornada, S., 273 Tomasik, W., 81, 258 TomaiiE, A., 41 Tombret, F., 72, 244 Tominaga, Y., 347

Tomioka, H., 57, 222 Tomioka, K., 97, 128, 212, 247 Tomioka, Y., 361 Tomita, K., 311 Tomoda, S., 216, 260, 296, 335, 371 Tomoguchi, A., 341 Tomoi, M., 184 Tongpenyai, N., 198, 218 Topalsavoglu, N., 65 Tori, M., 141 Torii, S., 32, 139, 163, 181, 275, 311 Torisawa, T., 265 Torisawa, Y., 11 Torny, G. J., 189 Toshimitsu, A., 32, 143 Towns, E., 19 Townsend, C. A., 242, 382 Traldi, P., 14 Trapani, G., 65 Traynor, S. G., 223 Tremper, A. W., 325 Trippett, S., 267 Trius, A., 39, 90, 268 Trivari, K. P., 393 Troger, W., 279 Troin, Y., 344 Trombini, C., 7, 193 Trompenaars, W. P., 329 Trost, B. M., 7, 30, 52, 57, 67, 112, 173, 193, 211, 219, 223, 229, 230, 263, 272, 284, 287, 290, 305, 373, 391 Truesdale, E. A., 141, 389 Trurnper, P. K., 140 Tsai, D. J. S., 253 Tse, A., 241 Tseng, C. C., 91 Tskhovrebachvili, T., 32, 256 TSOU,H.-R., 86 Tsubata, K., 144, 201, 225, 268, 349 Tsuboi, M., 24 Tsubuki, M., 293 Tsuda, T., 95, 107, 130 Tsuda, Y., 118 Tsuge, O., 317 Tsuhako, A., 56 Tsuji, J., 30, 68, 107, 112, 140,205, 235, 301, 309 Tsuji, S., 142 Tsujino, Y., 132, 305 Tsukube, H., 191 Tsumaki, H., 198, 262 Tsunashima, Y., 214 Tsuritani, K., 326 Tsuzuki, K., 140, 290, 374 Tu, C.-Y., 384 Tucker, J. R., 231, 277 Tuddenham, D., 235 Tundo, P., 184

A uthor Index

414 Tun Naal, N., 84 Turner, J. V., 302 Tuthill, P. A., 122 Twitchin, B., 146 Tzeng, D., 256 Uchida, I., 141, 389 Uchida, T,, 391 Uda, H., 107, 178, 285, 317 Ueda, H., 120 Ueda, K., 80 Ueda, M., 115, 142 Ueda, Y., 141,389 Uemura, S., 32, 143 Uenishi, J.-I., 343 Ueno, H., 112, 205 Ueno, K., 189, 317 Ueno, U., 347 Ueno, Y., 40, 264 Ueyarna, N., 267 Uguen, D., 156, 253 Ullah, Z., 296 Umani-Ronchi, A., 7, 193 Umezawa, Y.,123, 252 Uneyama, K., 32, 163, 181, 275 Untch, K. G., 204, 263 Urabe, H., 57, 134 Uribe, G., 159, 250 Uskokovik, M. R., 123, 387 Utarnapanya, S., 47 Utimoto, K., 203, 233, 263 Utley, J. H. P., 111 Uyehara. T., 141, 272, 309, 389 Vail, P. D., 207 Valentine, V., jun., 194 Vallee, D., 344 Vallen, S., 114 Van Asch, A., 364 Vanasse, B., 175 van Bockel, C. A. A., 176 van Boom, J. H., 173, 176 Vandenbulcke-Coyette, B., 210, 360 Vanderesse, R., 184 van der Gen, A., 84, 201, 267 van der Plas, H. C., 194 van der Stouwe, C., 176 Van Der Veen, J. M., 326 Van Derveer, D., 92 van der Ven, J., 46 van der Vondervoort, E. M., 189 Vandewalle, M., 118. 290 Van Horn, D. E., 31, 165, 225, 255 Van Hummel, G. J., 329 van Leusen, A. M., 207, 213, 282 van Leusen, D., 207, 278, 282 Van Meerssche, M., 281 Vannes, P., 281

Van Nipsen, S. P. J. M., 213 van Rijn, P. E., 46 Van Stappen, P., 214 van Tarnelen, E. E., 292, 302, 378 van Wallendael, S., 236, 336 van Zon, A.. 185, 189 Varkey, T. E., 307 Varrna, V., 138 Vasella, A., 146 Vasella, A. T., 141, 389 Vatkle, J.-M., 180 Vathke-Ernst, H., 305 Vaughan, K., 140, 290, 374 Vedejs, E., 263, 269 Venanzi, L. M., 199 Venegas, M. G., 289 Venit, J., 147, 263 Venkatesan, K., 288 Venton, D. L., 210 Venuti, M. C., 44, 266 Verardo, G., 7, 193 Verboom, W., 108, 177,329 Verdegaal, C. H. M., 173 Verht, R., 127 Verkruijsse, H. D., 47, 48, 242 Verrneer, P., 16, 44, 51, 55, 227 Vernikre, C., 166 Vernon, J. M., 217 Vevert, J. P., 104 Veysoglu, T., 177, 263 Vibuljan, P., 288 Vidal, M., 310 Videau, B., 213 Viehe, H.-G., 27, 210, 272, 360 Vigneron, J. P., 126 Vilaplana, M. J., 204 Villa, V., 98 Villarnana, J., 199 Villamana, N., 249 Villieras, J., 80 Vilsmaier, E., 279 Vincent, J. E., 326 Viola, A., 391 Viscogliosi, L. A., 282 Visser, G. W., 108, 177, 329 Visser, R. G., 55, 77, 142 Vittimberga, B. M., 14 Vladuchick, W. C., 141, 389 Voeffray, R., 146 Vogtle, F., 142, 189 Vogel, E., 93 Vogel, F. G. M., 101 Vogel, P., 303 Volante, R. P., 123, 188 Vollhardt, K. P. C., 301 von Schnering, H. G., 312 Vora, M. M., 352 Vorbruggen, H., 356 Voss, J., 83 Vuilhorgne, M., 284

Wada, F.,229 Wada, M., 94, 267 Wade, P. A., 141,207,389 Wadia, M. S., 48 Wadsworth, D. H., 48 Wagner, A., 296 Wakabayashi, S.,206, 269 Wakabayashi, Y., 203, 263 Wakselman, M., 272 Walker, A., 324 Walker, A. M., 58 Walker, D. M., 290, 371 Wallis, B. J., 310 Wallis, J. D., 369 Wallo, A., 158 Walsgrove, T. C., 304 Walt, D. R., 136, 382 Walters, C. P., 201 Walz, P., 89 Wan, T. S., 147 Wang, N.-Y., 140, 376 Wang, T.-F., 302 Wann, S. R., 157, 194 Ward, D. E., 141, 296, 389 Ward, R. S., 136, 271 Warner, P., 5 Warren, S., 9, 133 Warrener, R. N., 136, 303 Wartski, L., 243 Wasserman, H. H.,140, 143, 325, 392 Wasserman, H.J., 350 Watanabe, H., 20. 31, 50, 165, 225,248 Watanabe, J.-i., 270 Watanabe, K., 50, 95 Watanabe, Y., 50, 152, 326, 343 Watt, D. S., 241 Weakley, T. J. R., 296 Webb, C. F.,178, 263 Webb, M. W., 357 Webb, R. R., tert,, 383 Weber, A., 6, 281 Webber, W.-D., 301 Weber, W. P., 256 Weidrnann, B., 142, 160, 162, 225 Weiffen, J., 176 Weiler, L., 119, 306 Weinreb, S. M., 60, 331 Weisenfeld, R. B., 41, 78, 140, 230 Weisman, G. R., 161, 255 Weiss, U., 103, 118, 288 Welch, S. C., 10, 300 Weller, T., 86, 197, 261, 307 Wender, P. A., 70, 73, 228, 290, 308,375 Wenderoth, B., 3, 160 Wendling, M. G., 349 Wengrovius, J. H., 47 Wenkert, E., 393 Wentrup, C., 55, 391

Author Index Wermeckes, B., 20, 244 Wernsmann, P.,329 West, P. R., 50 Westermann, J., 3, 160, 224 Westmijze, H., 16, 227 Westphalen, K.-O., 145, 237 Wetter, H., 102 Wettlaufer, D. G., 238 Weyerstahl, P., 105 Wheeler, D. M.,S., 103 Wheeler, M M., 103 White, C. T., 92, 240 White, J. D., 131, 135, 295, 297, 311,376 White, K. B., 81, 107 White, M. R., 55 White, S., 91, 92, 214, 238 Whiteley, C. G., 250 Whitesell, J. K., 106 Whitesides, G. M., 102, 158 Whittle, A. J., 80, 274, 307 Wiaux-Zamar, C., 281 Wicha, J., 135 Widdowson, D. A., 236 Widler, L., 160, 225 Wierenga, W., 393 Wiesert, W., 327 Wilby, A. H., 7 Wildeman, J., 213 Wilemon, T. M., 65 Wilhelm, R. S., 5, 227 Willcott, M. R., 300 Williams, D. J., 236 Williams, D. R., 17, 91, 92, 124, 172, 182, 214, 238, 239,287, 315 Williams, J. L., 106, 223 Williams, R. M., 141, 389 Williams, R. V.,43, 261, 287, 293 Willis, B. J., 90, 107 Willis, W. W., jun., 62, 293 Wilson, D. A., 217 Wilson, J. S., 179 Wilson, J. W., 161 Winkler, T., 280 Winterfeldt, E., 142 Wirth, D. D., 295 Woderer, A., 327 Wolf, H., 305 Wolfbeis, 0. S., 214 Wolff, S., 110, 280 Wolinsky, J., 80, 126 Wong, C.-H., 158 Wong, D. H.. 56 Wong, H. N.-C., 141, 389 Woodard, S . S., 178, 221 Woodgate, P. D., 181, 216, 364 Woodgate, S. D., 216 Woodthorpe, K. L., 353 Woodward, R. B., 141, 389 Woolias, M., 291

415 Workulich, P. M., 377 Worth, B. R., 287 Worthington, P. A., 132 Wovkulich, P. M., 24, 76, 123, 124,316,387 Wrobel, J. E., 197 Wu, J. S., 325 Wu, Y. L., 380 Wulff, W., 206 wuts, P. G. M., 387 Wykpiel, W., 241 Wynn, S., 131 Yadav, J., 382 Yadav, L. D. S., 347 Yapi, M., 152 Yagoub, A. K.,359 Yamada, A., 357 Yamada, H., 187 Yamada, K.,186, 197, 253, 334 Yamada, M., 161, 311 Yamada, N., 368 Yamada, Y., 4, 57, 68, 117, 119, 178, 221,283, 328 Yamaguchi, H., 8, 9, 276 Yamaguchi, M., 57, 94, 109, 123, 128, 141, 252 Yamaguchi, S., 159, 254 Yamakado, Y., 30, 206 Yamakawa, K., 81 Yamamoto, A., 66, 202 Yamamoto, B. R., 278 Yamamoto, H., 30, 143, 160, 198, 199, 206, 252, 254. 347, 350,384 Yamamoto, I., 212, 323 Yamamoto, K.,47 Yamamoto, M., 133 Yamamoto, T., 66, 202 Yamamoto, Y., 93, 115, 144, 167, 168, 183, 224, 251, 253,264 Yamane, S., 134 Yamaoka, H., 1 Yamashiro, R., 347 Yamashita, A., 206 Yamashita, K.. 137 Yamashita, Y., 226, 391 Yamazaki, H., 133 Yamazaki, M., 289, 361 Yamazaki, N., 160, 161, 254 Yamazaki, T., 180, 326, 340, 34 1 Yanagi, P., 229 Yanagida, N., 134 Yang, F., 125 Yang, S., 109, 123 Yany, F., 6 Yasamura, M., 313 Yashioka, H., 251 Yasuda, A., 30, 254 Yasuda, H., 15, 216 Yasuda, T., 32, 181

Yasuhara, F., 159, 254 Yatagai, H., 93, 168, 253, 264 Yates, P., 290, 295 Yatsimirsky, A. K., 229 Yazawa, T., 9 5 Yi, C. S., 352 Yijima, C., 83, 271 Yobuke, Y., 141 Yogo, T., 49, 65, 76, 253 Yokatani, K.,132 Yokota, K., 1 4 Yokota, K.-i., 226, 247 Yokota, T., 355 Yokota, Y..178 Yokoyama, M., 36, 166 Yonaga, M., 129 Yoneda, N., 1 0 1 Yonezawa, Y.,149 Yoritaka, K., 139 Yoshida, J.. 8 9 Yoshida, K.,385 Yoshida, M., 123, 200, 252 Yoshida, N., 56 Yoshida, T., 17, 225, 272 Yoshida, Y., 205, 278, 348 Yoshida, Z., 37, 57, 144 Yoshikawa, S., 139 Yoshikoshi, A., 135 Yoshimura, J., 149, 394 Yoshimura, M., 211 Yoshioka, H., 195 Young, G. T., 151 Young, R. N., 139 Young, S. D., 93, 114, 119, 126, 235,240 Yu,L.-C., 83, 138, 243, 280 Yu, M., 139 Yuki, K.,239 Yung, Y. M., 1 1 9 , 2 8 5 Yus, M., 144, 197, 199, 249 Zagatti, P., 126 Zajac, W. W., jun., 208 Zamarlik. H., 127, 306 Zamboni, R., 260, 289, 373 Zanirato, P., 370 Zapata, A., 85, 260 Zard, S. Z., 266 Zassinovich, G., 162 Zawacky, S. R., 292 378 Zbaida, D., 333 Zeiss, H.-J., 169 Zheng, J., 267 Ziegler, F. E., 28. 41, 78, 129, 138, 140, 230, 238, 302 Ziffer, H., 178 Zilliken, F., 344 Zima, G., 26, 77, 275 Zimmer, H., 137 Zipkin, R. E., 292 Zippel, M., 125 Zoorov, H. H. A., 160

Author Index

416 Zoretic, P. A., 300 Zoukal, M., 310

ZupanEiE, B., 191, 206 Zwanenburg, B., 335

Zweifel, G., 20, 27, 51, 65, 182, 261 Zwierzak, A., 143, 268