Saturated Heterocyclic Chemistry (v. 3)

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A Specialist Periodical Report

Saturated Heterocyclic Chemistry Volume 3

A Review of the Literature Published during 1973 Sen ior Reporter

M. F. Ansell, Queen Mary College, London Reporters D. J. Maitland, University of Bradford J. M. Mellor, University of Southampton A. E. A. Porter, University of Stirling B. Walker, Queen’s University, Belfast

0 Copyright

I975

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

ISBN: 0 85186 562 3 Library of Congress Catalog Card No. 72-83454

Printed in Northern Ireland at The Universities Press, Belfast

Fore word The third volume of this Specialist Periodical Report reviews developments in the field of Saturated Heterocyclic Chemistry for the period JanuaryDecember 1973. The format of the Report follows that of Volume 2, except for the omission of the chapter on Medium-sized Rings. It is intended to remedy this unfortunate omission by including a two-year Report (1973 and 1974) in Volume 4. The production of this volume is due to the skill and patience with which the contributors have compiled their Reports and the expert assistance of the Chemical Society Editorial Staff. I express to all of them my sincere thanks. April 1975

M. F. Ansell

Contents Chapter I

Three-membered Rings

1

By D. /. Maitland

1 Introduction 2 Oxirans Formation Direct Insertion Oxygen atom insertion Carbon atom insertion Cyclization of Halohydrin Darzens Reaction Metal-cata1y sed Epoxidation Miscellaneous Reactions Ring-opening Electrophilic Nucleophilic Dipolar cycloaddition Rearrangement Ring Retention Miscellaneous 3 Aziridines Format ion Direct Insertion of Nitrogen or Carbon Atoms Cyclization Ring Contraction Formation via Azirines Reactions Ring-opening Electrophilic and nucleophilic Dipolar cycloaddition Rearrangement Ring Retention

4 Thiirans Formation Carbon Atom Insertion Sulphur Atom Insertion Cyclization Miscellaneous Episulphoxides V

1 1 1 1 1 12 16 19 22 24 28 28 28 32 40 41 45 46

49 49 49 51 59 60 62 62 62 65 69

70 73 73 73 77 77 77 79

vi

Contents Reactions Ring-opening Desulphurization Ring Expansion 5 Rings containing More than One Heteroatom Formation Diaziridines Oxaziridines Azaphosphiridines Thiadiaziridine 1,l-Dioxides Reactions Diaziridines Oxaziridines Thiadiaziridine 1,l-Dioxides

Chapter 2

Four-membered Rings By B. 1. Walker

1 Introduction 2 Physical Methods Magnetic Resonance Miscellaneous 3 Formation Oxetans Cyclization [2 21 Cycloaddition Miscellaneous Azetidines Cyclization 12 21 Cycloaddition Ring Contraction Miscellaneous Rings containing More than One Heteroatom Cyclization [2 21 Cycloaddition Miscellaneous 4 Reactions Oxetans Ring-opening Rearrangement Miscellaneous Azet idines Ring-opening Rearrangement Miscellaneous

+

+ +

80 80 81 82 82 82 82

84 84 85 85 85 87 90

92 92 92 92 94 94 94 94 96 99 100 100 103 112 113 117 117 118 121 122 122 122 125 126 127 127 128 131

vii

Contents

Chapter 3

Rings containing More than one Heteroatom Ring-opening

136 136

Five- and Six-membered Rings and Related Fused Systems

138

By A. E. A. Porter

1 Introduction 2 Conformational Analysis of Reduced Heterocycles General Oxygen-containing Rings Nitrogen-containing Rings Phosphorus-containing Rings Sulphur-containingRings

138 138 138 139 144 151 154

General Nitrones Nitrile Imines Nitrile Oxides Nitrile Ylides Azides and Diazoalkanes Miscellaneous [4 + 21 Cycloaddition Oxygen-containing Rings Nitrogen-containing Rings Rings containing both Oxygen and Nitrogen

158 158 158 159 161 161 163 165 166 166 166 168 169

4 General Chemistry of Saturated Heterocycles Oxygen containing Rings Tetrahydrofurans Dihydrofurans Lactones Miscellaneous Furanoid Derivatives 1,ZDioxolans 1,3-Dioxolans Ozonides Tetrahydropyrans Dihydropyrans Dihydropyrones Fused Pyrans 1,ZDioxans lY3-Dioxans 1,4-Dioxans Miscellaneous

170 170 170 172 174 176 177 177 179 180 181 183 184 184 185 185 185

3 Cycloaddition Reactions [3 21 Cycloaddition

+

Contents

viii Nitrogen-containing Rings Pyrrolidines Pyrrolidones Dihydropyrroles Pyrazolines Imidazolines Triazolines Tetrazolines Piperidines Piperidones Tetrahydropyridines Dihydropyridines Quinoline Derivatives Isoquinoline Derivatives Aza-steroids Fused Systems Hexahydropyridazines Tetrahydr opyridazines Dihydropyridazines Cinnoline Derivatives Phthalazine Derivatives Pyrimidine Derivatives Piperazines Dihydropyrazines Piperazinediones Fused Pyrazines 1,2,4-Triazines 1,3,5-Triazines Condensed Triazines Tetrazines Fused Tetrazines Rings containing both Oxygen and Nitrogen Isoxazole Derivatives Oxazole Derivatives Fused Oxazoles Dioxazoles Oxadiazoles 1,2-Oxazines 1,3-0xazines Fused 1,3-Oxazines 1,4-0xazines Dioxazines Oxadiazines Miscellaneous Fused Systems

186 186 189 190 194 197 200 202 202 204 205 207 208 209 210 21 1 212 212 213 213 214 214 216 217 218 221 222 223 223 224 226 226 226 229 236 236 237 238 239 241 242 243 244 245

ix

Contents

Chapter 4 Bridged Systems By 1. M. Mellor

248

1 Introduction

248

2 Physical Methods

248

3 Nitrogen Compounds Synthesis Mannich-type Reactions Routes via Electron-deficient Nitrogen Species Cycloadditions Miscellaneous Reactions Reactivity

254 255 255 256 257 264 266

4 Cryptates

272

5 Oxygen Compounds Synthesis by Cycloaddition Miscellaneous Syntheses

274 274 277

6 Sulphur Compounds

28 1 28 1 283

Synthesis by Cycloaddition Miscellaneous Syntheses

7 Miscellaneous Compounds

Author Index

286 288

1 Three-membered Rings BY D. J. MAITLAND

1 Introduction

This chapter reports on developments in the chemistry of three-membered, saturated heterocyclic ring compounds. As is usual in such Reports a certain degree of selectivity has been necessary. However, in general the author has tried to steer as neutral a course as possible, not being swayed by his own special interests, as can so easily happen. A break has been made with a pattern set in earlier Reports, in that a separate section on ‘Physical Methods’ has not been compiled. It is this author’s opinion that as such techniques are now almost routine tools in most chemical laboratories they no longer merit special attention, an opinion substantiated by the fact that almost every paper published today includes in the discussion a report on the application of various physical methods to the problem in question.

2 Oxirans In the M.T.P. review series three-membered ring compounds have been reviewed.l The synthesis, reactivity, and synthetic applications of a$epoxy-ketones have been summarized.2 Reviews have been published on the synthesis and characteristics of epoxides3 and arene oxides: selectivity in the reactions of epoxides,6 and the electrocyclic ring-opening reactions of bicyclic aziridines with oxirans.6 Formation-Direct Insertion. Oxygen atom insertion. The most common reaction in this category is the oxidation of alkenes to epoxides by organic peroxy-acids. However, some other reactions which involve either molecular D. R. Marshall, in ‘Heterocyclic Compounds’, ed. K. Schofield, M.T.P. International Review of Science, Organic Chemistry, Series One, Vol. 4, Butterworths, London, 1973, p. 1. T. Iizuka, Yuki Gosei Kagaku Kyokui Shi, 1973, 31, 271 (Chem. A h . , 1974, 80, 59 803u).

‘

Y. Tanaka, A. Okada, and I. Tomizuka, Epoxy Resins: Chem. Technol., 1973,9-134, 7 3 7 - 4 0 (Chem. Abs., 1974,80, 82 507J). D. M. Jerina, H. Yagi, and J. W. Daly, Heterocycles, 1973, 1, 267. D. N. Kirk, Chem. and Ind., 1973, 109. K. Matsumoto, Kaguku No Ryoiki, 1973, 27, 148 (Chem. A h . , 1973,79,42 253w).

1

Saturated Heterocyclic Chemistry

2

oxygen or ozone have been reported. Hexaflu~ropropylene~ has been epoxidized (79 %) by reaction with oxygen at 200 "C over a silica catalyst, activated either by pre-treatment with hexafluoropropylene or by pre-treatment with 1M hydrochloric acid8 followed by washing and treatment with hexafluoropropylene. Tetrafluoroethylene and chlorotrifluoroethylene were also successfully epoxidized at 25 "C by a variation of the same te~hnique.~ The conversion of styrene into 1-phenyl-1,2-epoxyethane, without serious competition from polymerization, has been achieved by the oxidationlo of styrene at 120 "C and 83 or 160 mmHg partial pressure of oxygen or by heating styrene, t-butyl hydroperoxide, or di-t-butyl peroxidell in chlorobenzene at 120 "C. While investigating the thermal cycloreversion of the bicyclo [3,1,O]hex-2ene system, Padwa and Brodsky12 found that when exo,exo-3,4,6-triphenylbicyclo[3,1,O]hex-2-ene (1) was heated for 48 h at reflux temperature in xylene, the major product was the oxiran (2). Similar treatment of the exo,endo-isomer (3) gave a 2:2:1 mixture of (l), (2), and the oxiran (4).

A, 02-xylene

Ph Ph'

Ph

*Ip Ph

A, 02-mesitylene

'

Ph

H35-/$;+u)+~2 Ph

(3)

(4)

Heating (1) or (3) at 160°C under nitrogen afforded a 16:l equilibrium mixture of (1) and (3). Thus the oxirans must be formed by therrnal epoxidation of the olefins by molecular oxygen, and the reactions can be rationab ized in terms of a biradical intermediate formed by cleavage of the cyclopropane ring. A continuous process for the preparation of epichlorohydrin has been G . M. Atkins, jun., U.S.P.3 775 439/1973.

* R. J. Cavanaugh, U.S.P.3 775 438/1973. * R. J. Cavanaugh and G. M. Atkins, jun., U.S.P.3 775 440/1973.

l o M. E. Pudel, L. G. Privalova, Z . K. Maizus, and I. V. Kalechits, Neftekhimiya, 1973,

13, 669 (Chem. Abs., 1974,80,95 624v). P. Koelewijn, B.P. 1 304 403/1973. l a A. Padwa and L. Brodsky, Tetrahedron Letters, 1973, 1045. l1

Three-memberedRings 3 reported. l-Chloroprop-2-ene in dimethyl phthalate containing 10-12 % acetaldehyde is oxidized13 by air in a flow system at 150-160 "C. The reaction of ozone with encumbered allenes at -78 "C in dichloromethane has recently been studied.14 1,1,3-Tri-t-butylalleneon treatment with two equivalents of ozone afforded the corresponding diepoxide (5), which rearranged to 2,2,4-tri-t-butyl-1-oxacyclobutan-3-one (6) on standing. One equivalent of ozone gave the diepoxide ( 5 ) as the principal product and the

allene oxide (7) in low yield. Neither 1,l-di-t-butylallene (8) nor 1,3-di-tbutylallene (9) gave an oxiran when treated with ozone. The allene (8) afforded di-t-butyl ketone and 2,2-di-t-butylcyclopropanonewhereas (9) gave exclusively pivaldehyde. The degree of substitution of the allene is obviously a critical factor. But

-

But

But

-c-

H

But (8)

-H

(9)

The epoxidation of allenes by organic peroxy-acids has also been studied by Crandall et a1.l5 The products are rationalized in terms of an initial epoxidation of the allene (lo), followed by competitive partitioning of the monoepoxide (1 1) between valence isomerism to the related cyclopropanone (12) and further oxidation of (11) to a dioxaspiropentane derivative (13) (Scheme 1). The cyclopropanones may react further with the peroxy-acid to yield /3-lactones (14)or undergo oxidative decarbonylation to the corresponding olefins (15), which are usually transformed into their epoxides (16) under the reaction conditions. The dioxaspiropentanes may also add carboxylic acids, yielding a-acyloxy-a'-hydroxy-ketones (17). An excess of peracetic acid in buffered methanol gave (18) and (19) as the major products from tetramethylallene. A small quantity of the lactone (20) was also detected, the a-acetoxy-ketone (18) arising by acetoxylation of the epoxyallene. Under the same conditions 1 ,l-dimethylallene gave analogous products. Under acid conditions, tetramethylallene upon epoxidation gave the amethoxy-ketone (21)as the only product (Scheme 2). Sh. K. Kazimov, A. S. Rzaeva, G. Z. Ponomareva, Khim. Prom., 1973,49,824 (Chem. Abs., 1974, 80, 70 613c). l4 J. K . Crandall and W. W. Conover, J.C.S. Chem. Comm., 1973, 340. l5 J. K. Crandall, W. H. Machleder, and S. A. Sojka, J. Org. Chem., 1973, 38, 1149. la

4

Saturated Heterocyclic Chemistry

R\A /-C-C

\o/

R

R

R,

R /c-c\R

‘**R

I

R

\c=c/ ’R

II \ IC\ /R

+ HOAc + COz

‘.R

0

Me H-C

“

I

Me

Me

I

Me

Me,

,c-c

Me

/ O \ p M ‘e

I

Me-C-C-Me

I

I 1

Me Me

Three-membered Rings

5

\iu- -n(o*c 0

0-

>=f? ) -

(11;R = Me)

\

Cyclonona-l,2-diene with excess peracetic acid in buffered methanol affords the epoxide (22), the lactone (23), cyclo-octene, and the a-acyloxya'-hydr oxy-ketone (24).

oo

4-Oxoisophorone (25) when epoxidized16with hydrogen peroxide (30 %) affords oxabicycloheptanedione (26), which with 20 % sulphuric acid yields

2-hydroxy-3,5,5-trimethylcyclohex-2-en-1,4-dione.

(25)

(26)

@-Unsaturated f-alkoxy-ketones (27) can be converted into the corresponding epoxides (28) in good yield by treatment at 40 "C (with one equivalent of alkaline hydrogen per0xide.l' Excess alkaline hydrogen peroxide effects destructive oxidation, affording formic acid, acetone, and a B-alkoxycarboxylic acid.

16

17

D. L. Roberts and B. P. Bonita, U.S.P. 3 775 437/1973. I. G. Tishchenko and V. V. Berezovskii, Vesti Akad. Navuk belarusk. S.S.R.,Ser. khim., Navuk, 1973, 113 (Chem. Abs., 1973,79,4939s).

6

Saturated Heterocyclic Chemistry

Olefins can be epoxidized in high yield and with high selectivity by hydrogen peroxide in the presence of fluoro(ha1ogeno)acetonecatalysts.l*Thus oct-1-ene was epoxidized (100 %) in the presence of hexafluoroacetone. Similarly effective were Cl,CCOCCl,F and ClF,CCOCFCl,. Propylene, ally1 alcohol, trans-stilbene, and 1,5-cyclo-octadiene were similarly epoxidized in high yield. Fluoro-oxirans have been preparedlg by the epoxidation of RCF=CF, at -20 OC with hydrogen peroxide in methanolic potassium hydroxide. Substituted cyclohexenes20with an olefinic side-chain undergo selective epoxidation with peracetic acid to afford the corresponding epoxycyclo-ol)cyclohex-1-ene (29) gave the hexane. Thus 2,6,6-trimethyl-l-(but-3-en-l epoxycyclohexane (30).

Cyclohex-3-ene-l-carboxylates(31), obtained by treatment of the appropriate cyclohexenecarboxylicacid with R1CO2CH,CH2Clin xylene containing aqueous potassium hydroxide, afford21 the corresponding oxirans (32) on treatment with 50 % peracetic acid in chloroform.

oR2 C02CH2CH20COR1

~ ~ O z C H 2 C H 2 0 C OMeC03H-CHC'3+ R 1 0

Treatment of endo-tricyclo[5,2,1,02~6]deca-3 ,8-dienes with t-butyl hydroperoxide or peracetic acid affords a mixture of epoxides22which can be separated by steam-distilling the product mixture to isolate the diepoxyendo-tricyclo[5,2,1,02*6]decane.The residual monoepoxide mixture is then distilled in the presence of 0.1 % bis-(l-naphthy1)amine to give 3,4-epoxyendo-tricyclo[5,2,1 ,02*6]dec-8-ene (33) and the 8,9-epoxy-isomer. l8 L.

Kim, Ger. Offen 2 239 681/1973 (Chem. Abs., 1973,78, 159 400n). A. Y.Zapevalov, I. P. Kolenko, and V. S. Plashkin, Zhur. org. Khim., 1973, 9, 2013 (Chem. Abs., 1974, 80,47 722d). 2o E. Kovats, G. Ohloff, E. Demole, and M. Stoll, Swiss P. 536 834/1973 (Chem. Abs., 1973,79,91 972p). a1 B. F. Pishnamazzadeand A. K. Mamishov, Zhur. org. Khim., 1973,9,715 (Chem. A h . , 1973,79, 31 748k). 29 H. Fuerst, H. G. Hauthal, and D. Schied, East Ger. P. 98 925/1973, (Chern. Abs., 1974,80,70 67th).

7

Three-membered Rings

(3 3)

Epoxidation of 1 -(p-methoxybenzyl)-2-methyl-l,2,3,4,5,6,7,8-octahydroisoquinoline (34) with performic acid23affords the isomeric epoxides (35) and (36) and the two diols (37)and (38) (Scheme 3). Hydrolysis of the epox-

CH2C6H,0Me-p (34)

I

I

CHnCsH40Me-p

CH2CsHtOMe-p

(36)

&HC) Le'

(35)

cj?-JMe

CH~C~H~OM~-~

HO

;

CHpCeH40Me-p

(37)

(38)

Scheme 3

ides (35) and (36) with 10% sulphuric acid affords quantitative conversion into the diols (37) and (38), respectively, in a ratio of 1 :15. Therefore formation of the cis-epoxide (36) predominates. Chemical evidence shows that performic acid exclusively attacks from the side cis to the 1-substituent. Interpretation of this result is difficult, but it has been shown that the aminogroup in the isoquinoline ring does not particularly participate in the formation of the epoxides, and a particular role of the ArCH, group in the transition state would be suggested. The transition state (39) for the formation of 23

2

M. Onda, Y. Sugama, H. Yokoyama, and F. Tada, Chem. and Pharm. Bull. (Japan), 1973, 21, 2359.

Saturated Heterocyclic Chemistry

(39)

(36), with intramolecular hydrogen-bonding as depicted in the formula, may depress the activation energy for ( 3 9 , leading to predominant formation of (36). The competitive reactions of (35) and (36) have also been examined. The peroxy-acid oxidation of cyclo-octatetraene oxide2* yields the bisoxirans (40), (41), and (42) and the trisoxiran (43), which is unchanged on heating at 255 "C for 20 h (Scheme 4). The oxirans (44) and (45) result on

Do+ ,00+ .o

&-

0 m-ClC6H4COf

(40)

(40)

(41)

67 %

24 %

0 (42) 9%

+ (41) + (42) + (43)

Scheme 4

thermal treatment (200 "C)of (41) and (42) respectively. Despite the requirement for high thermal activation, the bond relocations of (41) and (42) proceed entirely along symmetry-allowed pathways. The n.m.r. spectra of these compounds are discussed.

a4

A. G. Anastassiou and E. Reichmanis, J. Org. Chem., 1973, 38, 2421.

Thee-membered Rings

9

7

Me

\ c=c / \ Et

Me

I

CHzCH2O(CH2)S- C- 0

/

\

0

\

(46)

/!HZ

CH2

The epoxyoxatridecenoate (48), a pesticide,25is obtained as a mixture of (E)- and (2)-isomers by treating the unsaturated ester (47) with rn-chloroperbenzoic acid. The acetal (46), prepared from (2)-4-methylhex-3-enol and 5-bromo-2,2-ethylenedioxypentane,on acid hydrolysis followed by reaction with dimethyl methoxycarbonylmethylphosphonate affords the unsaturated ester (47). When @-unsaturated ketones are treated with peroxy-acids, attack usually occurs at the carbonyl group and epoxidation of the double bond is rare. However, it has recently been reported that oxidation of 2,3,4,5,6hexamethylcyclohexa-2,5-dienonewith m-chloroperbenzoic acid26 affords 2,3-epoxy-2,3,4,4,5,6-hexamethylcyclohex-5-enone(49) and on further oxidation cis-2,3 :5,6-diepoxy-2,3,4,4,5,6-hexamethylcyclohexanone. Irradiation of the monoepoxy-ketone (49) through a Vycor filter affords the

(49) 25 26

(50)

D. Hainaut and J. P. Demoute, Fr. Demande, 2 174 666/1973; ibid., No. 2 172 847/ 1973 (Chem. A h . , 1 9 7 4 , 8 0 , 82 617v; 82 618w). H. Hart, M. Verma, and I. Wang, J. Org. Chem., 1973, 38, 3418.

Saturated Heterocyclic Chemistry

10

single photoisomer 5-acetyl-2,3,4,4,Ppentamethylcyclopent-2-enone (50). Irradiation of the diepoxy-ketone gives only starting material. The epoxidation of acid-sensitive olefins, or olefins yielding acid-sensitive epoxides, is typically conducted in the presence of a buffer such as sodium carbonate, sodium bicarbonate, or disodium hydrogen phosphate. Such solid buffer-solid systems have proved to be unsuitable for certain compounds. For example the epoxide (52), derived from 6-methylhept-Sen-2-one (51), is known to undergo very facile rearrangement to 1,3,3-trimethyl-2,7dioxabicyclo[2,2,l]heptane (53) when heated or treated with acid. Thus

treatment of (5 1) with rn-chloroperbenzoic acid and sodium bicarbonate affords a mixture of (52) and (53). A simple procedure for the rn-chloroperbenzoic acid epoxidation of such acid-sensitive olefins2' has been reported. The method, which employs a biphasic solvent mixture of dichloromethane and 0.5M sodium bicarbonate solution, was used to epoxidize the ydunsaturated ketone (Sl), affording 85% conversion into (52) with no concurrent formation of the bicyclo-compound (53). An olefinic acetal (54) and olefins containing enol-ester moieties, Me,~CHCH,CH,C(OAc)==CH, and Me,C=CHCH,CH=C(OAc)Me, were similarly epoxidized. The system can also be used to epoxidize less reactive olefins (e.g. hex-l-ene) and shows good selectivity in the epoxidation of a trisubstituted double bond in preference to a disubstituted double bond. Limonene with one equivalent of the peroxy-acid gave 1,2-epoxy-p-rnenth-8-ene in 85 % yield. Epoxycyclopentanes (55) have been prepared by epoxidation of the appropriate cyclopentenes with monoperphthalic acid.28

(54)

27 28

(55)

W. K. Anderson and T. Veysoglu, J . Org. Chem., 1973,38,2267. S . A. Nesterenko, D. A. Pisanenko, and S. V. Zavgorodnii, Zhur. org. Khim., 1973, 9,758 (Chem. A h . , 1973,79,31 747j).

Three-memberedRings

11

MeCH=CH-CH=CHCONRlR* (56)

Me 0 x 0 Me

Reagents: i, Phthalic anhydride-H,O,-NH,CONH,EtOH

; ii, Me,CO-FeCl,

Scheme 5

Substituted amides of sorbic acid (56) when treated with phthalic anhydride-hydrogen peroxide in ethanol containing urea afford29 the corresponding epoxyhexenamides (57) (Scheme 5). Hydrogenation of 4,5-epoxyNN-diethylhex-2-enamide (57; R1 = R2 = Et) in the presence of Raney nickel gives NN-diethylhexanamide and 5-hydroxy-NN-diethylhexanamide. The epoxide (57; R1 = R2 = Et) condenses with acetone in the presence of ferric chloride to give the hexenamide cyclic acetal (58). Syntheses30 for disparlure [cis-7,8-epoxy-2-methyloctadecane(61)], a sexual attractant of the gypsy moth (Purthetria dispar L.), have been reported by two independent groups. The syntheses differ only slightly in their routes from 1-bromo-5-methylhexane to the key intermediate 2-methyloctadec-7yne (59). In one, reaction is with dodec-1-yne in the presence of sodium hydride, in the other with lithium dodecylide. Oxidation of the olefin (60) to the oxiran (61) is achieved with perphthalic acid. Sheads and Beroza31 have synthesized a tritium-labelled disparlure (~is-7,8-epoxy-2-methy1[7,8-~H,]octadecane) and report an improved method for preparing the intermediate 2-methyloctadec-7-yne. Oxiran derivatives, (62) and (63), of p-aminoacetophenone which exhibit juvenile hormone activity2 have been prepared by the reaction of N-trifluoroacetyl-p-aminoacetophenone with geranyl bromide and citronellyl L. P. Glushko, M. M. Kremlev, Yu. Yu. Samitov, and T. M. Malinovskaya, Ukrain. khim. Zhur., 1973,39, 807 (Chem. Abs., 1973,79, 126 173h). A. A. Shamshurin, M. A. Rekhter, and L. A. Vlad, Khim. prirod. Soedinenii, 1973, 9, 545 (Chem. Abs., 1974, 80, 36 927y); B. G. Kovalev, R. I. Ishchenko, V. A. Marchenko, and M. P. Filippova, Zhur. org. Khim., 1973,9,6 (Chem. Abs., 1973, 78, 84 127t). 31 R. E. Sheads and M. Beroza, J. Agric. Food Chem., 1973, 21, 751. xt2 Z. Machkova, L. Dolejs, and F. Sorm, Coil. Czech. Chem. Comm., 1973,38, 595.

29

Saturated Heterocyclic Chemistry

+ Br(CH&CHMe2

Me(CH2)gC-CLi

(59)

Me(CH2)9C-C(CH&CHMe2

Me(CHB)sCH=CH(CH2)4CHMez (60) !-HO.p

CsH 4. CO,H

bromide respectively, followed by oxidation of the resulting unsaturated derivatives with perphthalic acid in diethyl ether. Masking of the aminogroup of the intermediate N-(3,7-dimethylocta-2,6-dienyl)-p-aminoacetophenone and N-(3,7-dimet hyloct-6-enyl)-p-aminoacetophenonewith the trifluoroacetyl group is essential for successful epoxidation of the alkenyl chain, since compounds with an unprotected amino-group afford mixtures of products which are difficult to resolve. The trifluoroacetyl group is readily removed with alcoholic sodium hydroxide at 35 "C affording (62) and (63) in 57 % and 72 % yields respectively.

NHR

(62)

R

(63)

R = (CH&CHMe(CH2)2CH-CMeB

= CH2CH=CMe(CH2)2CH-CMea

\o/

'0'

Carbon atom insertion. The reactions of various sulphur-stabilized carbanions with aldehydes and ketones continue to provide useful routes to epoxides. Dimethyl sulphoximine, prepared from dimethyl sulphoxide, on dialkylation affords NN-dimethylamino- and NN-diethylamino-dimethyloxosulphonium fluoroborates as stable, white, crystalline s0lids.3~Treatment of the latter with sodium hydride in a variety of aprotic solvents, in particular dimethyl sulphoxide, gives the corresponding methylides (64; R = Et or Me). These 0 0

II 1

Me-SLMe

BF4-

NaH-DMSO,

-DMF, or -THF +

II

Me-S+CHI-

NRt C. R. Johnson and P. E. Rogers, J. Org. Chem., 1973, 38, 1793.

I

NRB

Three-memberedRings

13

ylides have proved to be effective nucleophilic methylene-transfer reagents. Reactions with aldehydes and ketones afford epoxides, whereas reactions with c$-unsaturated ketones give cyclopropyl compounds as the major products. A certain degree of selectivity is observed: diethylaminomethyloxosulphonium methylide with 4-t-butylcyclohexanonegave only the (2)-epoxide, a similar stereospecificity having previously been reported for dimethyloxosulphonium methylide, whereas dimethylsulphonium methylide gave predominantly the (E)-epoxide. A general procedure for the synthesis of epoxy-alkylated and -acylated heterocycles has been reported by Taylor et al.34The oxirans (65) (R1 = 2-

quinolyl, 4-quinolyl , 1-isoquinolyl, 4-quinazolinyl, 2-benzoxazolyl, 1,3dimethyl-2,4-dioxo-6-pyrimidinyl; R2 = Et or Ph, R3 = H; or R2 = R3 = Me) were prepared in 17-70 % yields by treating the appropriate aryl methyl sulphone (RISO,Me) or aryl chloride with diphenylmethylsulphonium tetrafluoroborate or diphenylmethylsulphonium perchlorate followed by reaction with the ketone (R2R3CO). One disadvantage of base-promoted reactions of sulphur-stabilized carbanions with aldehydes or ketones is the possibility of side-reactions (hydrolysis of the sulphonium salt or Cannizzaro or aldol reactions etc.). However, it has been reported that if a biphasic system is used these sidereactions do not occur. Thus, by stirring a heterogeneous mixture of lauryldimethylsulphonium chloride (66) and a carbonyl compound in benzeneaqueous sodium hydroxide, oxirans have been synthesized in high yields.35 Typically, acetophenone gave an 85% yield of the oxiran (67). It has also been reported that trimethylsulphonium iodide reacts with benzaldehyde in a two-phase system (dichloromethane-aqueous sodium hydroxide) to form 2-phenyloxiran in excellent yield, but only if tetrabutylanimonium iodide is present.36 The latter is considered to be acting as a phase-transfer reagent, transferring the anionic reactant from the aqueous to the organic phase. Cinnamaldehyde afforded an equally smooth conversion into 2-styryloxiran, but ketones gave only low yields (18-36 %) of oxirans. Trimethyloxosulphonium iodide and benzaldehyde afforded 2-phenyloxiran (in only 2 0 30 % yield) and 2,6-diphenyl-l,4-oxathian4-oxide (68) (12 %). With apunsaturated ketones no oxirans were formed, but instead cis-trans mixtures of cyclopropane derivatives. s4

35 s6

E. C. Taylor, M. L. Chittenden, and S. F. Martin, Heterocycles, 1973, 1, 59. Y. Yano, T. Okonogi, M. Sunaga, and W. Tagaki, J.C.S. Chem. Comm., 1973, 527. A. Merz and G. Markl, Angew. Chem. Internat. Edn., 1973,12,845.

14

Saturated Heterocyclic Chemistry Me(CH2)llS+Me&l-

I Me

NaoH-C6H6+

Me(CH ) S'CHa2111 I

\

Ph\~/r2

+ Me(CH2)11SMe

Me/'O

(67)

When 3-quin~clidinone~~ is treated with triphenyloxosulphonium iodide and sodium hydride the spiro-oxiranquinuclidine(69) is formed.

(68)

(69)

Treatment of (E)-butenylbis-sulphonium or (2)-butenylbis-sulphonium salts with a molar equivalent of an alkoxide afforded 1,3-butadienyIsulphonium salts (70), which reacted with aldehydes in the presence of alkoxides at -78 O C to form mixtures of the stereoisomeric oxirans (71) and (72), with

NaOMe, -78'C

RCHO/

(71) a1

J. R. Potaski and M.E. Freed, U.S.P. 3 775 419/1973.

(72)

Three-membered Rings

15

a 1-alkoxyprop-2-enyl ~ide-chain.~~ The diene sulphonium salt (73) did not add alcohol in the presence of alkoxide but lost a proton to give a stabilized ylide (74), which reacted with aldehydes to give the hitherto unknown oxiran derivative (75), and the diene (76), which gave a Diels-Alder reaction with tetracyanoethylene. Me2S+

Me2S+ Br’

\c/” II

\

-Ht *+H+

Me

II

/

H (73)

7

(74)

3.

(75) 70%

(76) 30%

Although the nucleophilic alkylidene transfer from a sulphur ylide to a carbonyl group is a standard method for converting an aldehyde or ketone into an oxiran, such reactions may fail (i) if the substrate is readily enolizable or (ii) if the carbonyl group is sterically hindered.39However, if such ketones are treated with phenylthiomethyl-lithium, methylthiomethyl-lithium , or a-lithiobenzyl phenyl sulphide, the corresponding p-hydroxysulphides are formed in yields of 41-100 %. Subsequent alkylation of the p-hydroxysulphides with methyl iodide or trimethyloxonium fluoroborate, followed by treatment of the resulting salts with base, affords oxirans in yields of 43-98% (Scheme 6). This sequence may also be worthy of consideration in those cases where a one-step ylide reagent would work, but where a mixture of diastereomeric epoxides results. These are often difficult to separate, but this is not usually true of the more polar diastereomericalcohols. Thus resolution of the diastereomers may be achieved at the more convenient P-hydroxysulphide stage. An alternative route to epoxides from carbonyl compounds involves reaction with diazoalkanes, a procedure which has not been very popular, possibly because of the hazardous nature of the reagents in some instances a8 39

H. Braun, G. Huber, and G. Kreszc, Tetrahedron Letters, 1973,4033. J. R. Shanklin, C. R. Johnson, J. Ollinger, and R. M. Coates, J. Amer. Chem. Suc., 1973,95,3429.

16

Saturated Heterocyclic Chemistry OH

\C---0 + PhSCH,Li % -C--I / I

CIIpSph iiii

Reagents: i, THF; ii, H'; RX,iv, base

Scheme 6

and the low selectivity achieved in others. The latter point is illustrated by the reaction of diazomethane or diazoethane40with 2,6-dichloro-p-benzoquinone (77) (Scheme 7). A diazoalkane molecule adds to each C=C group, one of the carbonyl groups is epoxidized, and both NH groups are alkylated to form (8la) and (81b). The intermediate products (78) and (79) or (80) can be isolated. Ethyl diazoacetate reacts with (77) to yield the epoxide (82), which on oxidative hydrolysis with nitric acid gives the dicarboxylic acid (83) which can be methylated with diazomethane to form the corresponding te t ramet hyl derivative. Cyclization of Halohydrin. The classical synthetic route to epoxidesfrom halohydrins and related compounds continues to be widely used, often with complete stereospecificity.2-Chloro-1-phenylpropan-1-01,MeCHClCHPhOH (84), formed by the Grignard reaction of phenylmagnesium bromide and 2-chloropropanol, when treated with potassium hydroxide in methanol yieIded trans-l,2-epoxy-l -pI~enylpropane,~~ whereas oxidation of (84) with chromic acid to the corresponding ketone followed by reduction with sodium borohydride gave a diastereomer of (84) which, when treated with methanolpotassium hydroxide, afforded cis-l,2-epoxy-l-phenylpropane. A stereospecific synthesis for the cis- and trans-2,3-epoxybutanes from the benzaldehyde acetal of meso-butane-2,3-diol (85) has been reported.42 Treatment of the acetal(85) with N-bromosuccinimide in carbon tetrachloride containing a trace of hydrogen bromide, followed by treatment of the resulting bromohydrin ester with potassium hydroxide in ethylene glycol, gave cis-2,3-epoxybutane, isomerically pure by n.m.r. (Scheme 8). Treatment of the same acetal with N-bromosuccinimide in water followed by treatment with B. Eistert, J. Riedinger, G . Kueffner, and W. Lazik, Chem. Ber., 1973, 106, 727. K. K. Mathew, P. S. Raman, and T. G . B. Antharjanam, Current Sci., 1973, 42, 17 (Chem. A h . , 1973.78, 84 1281.1). 4 2 D. A. Seeley and J. McElwee, J . Org. Chem., 1973, 38, 1691.

40

41

Three-memberedRings

17

zt

u

\

18

Saturated Heterocyclic Chemistry

-

Me% Me Ph

O y O Ph

iii

i

Ph

(8 5 )

Reagents: i, NBS-HBr-CC&; ii, Br'; iii, OH' Scheme 8

toluene-p-sulphonyl chloride, and with potassium hydroxide in ethylene glycol and 1,Zdimethoxyethane, gave trans-2,3-epoxybutane (Scheme 9). These reactions and the treatment of other cyclic acetals with NBS showed the reaction to be ionic, kinetically regiospecific, and specific for the acetal carbon. Golding, Hall, and Sakrikaf13 have investigated the mechanism, scope, and limitations of the reaction between vicinal diols and hydrogen bromide

xe

Me

Me

a

H (59 %)

O&Ph

Reagents : i, NBS-H,O; ii, H,O; iii, TsCl; iv, OH-

Scheme 9

in acetic acid and have used the reaction as a route to chiral epoxides (Scheme 10). (S)-( +)-Propan-l,2-diol [prepared by reduction of commercial (5')-(-)ethyl lactate] on treatment with hydrogen bromide in acetic acid gave a mixture of acetoxy-bromides (86), which gave optically pure (S)-( +)propylene oxide on reaction with one equivalent of potassium pentylate in pentyl alcohol. This method should also be applicable to the (R)-isomer. 43

B. T. Golding, D. R. Hall, and S. Sakrikar, J.C.S. Perkin I , 1973, 1214.

19

Three-membered Rings Me

MC

H )-COIEt

HO

J Br\

AcO

H--m

Br

Me

OAc

'0' Reagents: i, LiAlH4;ii, HBr-HOAc

Scheme 10

Epoxyacetylenes containing groups which are unstable to base have been prepared.44 For example, reaction of 2-methylbut-3-yn-2-01 with ethylmagnesium bromide at -20 O C followed by addition of 2,3-dibromobutanal gave 2-bromo-7-methyl-3,4-epoxyoct-5-yn-7-o1, which when heated with potassium carbonate afforded 2-bromo-3,4-epoxyhex-5-yne. Although the addition of mercuric salts to olefins in the presence of water to give p-hydroxyalkylmercuricsalts was discovered at the turn of the century, these compounds have received little consideration as synthetic intermediates. Recently Kretchmer et al. studied the base-catalysed decomposition of #?-hydroxyalkylmercuricchlorides45 and found that the latter compounds undergo reactions analogous to those of the corresponding 1,2-halohydrins. Thus trans-2-hydroxycyclopentylmercuricchloride and trans-2-hydroxycyclohexylmercuric chloride, in the presence of a base, e.g. potassium t-butoxide, provide convenient and high-yield sources of cyclopentene oxide and cyclohexene oxide respectively. The cycloheptyl derivative, however, affords primarily cycloheptanone, the product of a 1,2-hydride shift. Acyclic mercurials also afford the corresponding ketones. Darzens Reaction. The Darzens condensation of aldehydes and ketones may be one of the most convenient and common procedures for the one-step synthesis of 2,3-epoxyalkanoates,but little has been reported on the reactions of a-halogeno-aldehydes under such conditions. Takeda et aZ.46have studied base-catalysed Darzens-type condensations of a-haIogeno-aldehydes with methyl chloroacetate and found that aliphatic a-chloro-aldehydes afford Y . I. Kibina, Sh. Musantaeva, and A. V. Shchelkunov, Ref. Zhur., Khim., 1973, Abstr. No. 5Zh242 (Chem. Abs., 1973,79, 78 477m). 4 6 R. A. Kretchmer, R. A. Conrad, and E. D. Mihelich, J . Org. Chem., 1973, 38, 1251. A. Takeda, S. Tsuboi, and T. Hongo, Bull. Chem. SOC.Japan, 1973, 46, 1844.

44

Saturated Heterocyclic Chemistry

20

-

RIRzC-CHO

I c1

+ ClCH2C02Me NaoR-ether

Or

-CH-C

-THF, R'R2C

c1

H-C02Me

'

trans-4-chloro-2,3-epoxyalkanoates(87) in somewhat variable yields. aBromo-aldehydes reacted differently: 2-bromo-Zmethylpropanal gave a-chloro-y,y-dimethyl-Aa*p-butenolide (88) as a major product, and other 2-bromo-n-alkanals yielded mixtures of several minor products.

1

0

Moraud and C ~ m b r e have t ~ ~ reported the preparation of a new class of epoxide, namely a-alkoxy-cc,B-epoxy-esters (90). These compounds, which are stable in alcohol unlike most epoxy-esters previously reported, are prepared in 43-58 % yield at room temperature by treatment of halogenopyruvate esters (89) with an alkoxide-alcohol mixture. These epoxides provide routes to new compounds and to others difficult to make by other methods. Thus acid hydrolysis of (90) gives quantitative conversion into a-hydroxypyruvates (91), and dry hydrogen chloride-ether in an alcohol (R20H) affords acetals (92). OR2

RTH-C-C02R2

I

II

OH 0 (9 1) 47

I I

R1CH-C-C02R2

I

OH OR2 (92)

B. Moraud and J. C . Combret, Compt. rend., 1973,277, C , 523.

Three-memberedRings COAr

+

21

CICH2COrR2

NaOMe-MeCH(OMe)2

- 10°C

+ R1

"'

COzR2

A! '0'

(93)

(94)

The base-catalysed reaction of a,@-epoxy aryl ketones (93) with alkyl chloroacetates4*affords diepoxy-esters (94). Usually only one isomer, which has the aryl and the ester groups cis to the 2,3-epoxy-group, is formed. The reactiong9of 2-nitrophenacyl bromide (95) and sodium methoxide in absolute methanol affords, via a Darzens reaction, the keto-epoxide (96) and the bis-epoxide (97). The bis-epoxide results from an attack by a methoxide anion on the carbonyl carbon of (96) and a subsequent rearrangement with displacement of a bromide ion.

G/lvBr

NaOMe-MeOH,

(-J:

(95)

/

O

b

O2N (96)

+ (97)

The ability of diazomethyl ketones to undergo various base-catalysed condensation reactions similar to those of ordinary ketones is well established. However, the first example of a Darzens condensation of a diazo-ketone has only recently been reported.50 Thus reaction of 1 -chloro-3-diazopropane (98) with various aldehydes and sodium hydroxide in stoicheiometric amounts gave the Darzens-condensation products, 1-diazo-3,4-epoxybutan-2-ones (99), in 44-88 % yield. With excess benzaldehyde and base a diastereomeric mixture of a diadduct, 2-diazo-l,5-diphenyl-4,5-epoxy-l-hydroxypentan-3one (100) was also formed in addition to the monoadduct (99; R = Ph). The esterification of (R)-( -)-3,3-dimethylbutan-l ,2-dio151 with 4-bromobenzenesulphonyl chloride, followed by treatment with sodium methoxidemethanol at 0 "C, affords 3,3-dimethyl-l,2-epoxybutane, which on reaction L. S. Stanishevskii, G. I. Tishchenko, V. I. Tyvorskii, V; Yu. Glazkov, V. A. Mashenkov, and L. A. Khil'manovich, Vesrnik Beloruss. Inst., 1973, 2, 26 (Chem. Abs., 1974,80,82 522k). I9 E. Campaigne and J. H. Hutchinson, J . Heterocyclic Chem., 1973, 10, 229. 5 0 N. F. Woolsey and M. H. Khalil, J. Org. Chem., 1973, 38, 4216. 51 M. Sepulchre and A. M. Sepulchre, Bull. SOC.chim. France, 1973, 1164.

I*

22

Saturated Heterocyclic Chemistry

-)-1 -methoxy-3,3-dimethylwith methoxide-methanol at 98 “C yields (R)-( but an-2-01. The preparation of a,b-epoxy-sulphones and -sulphoxides has been reported previously by Tavares et al. Now they have reported the preparation of a,~-epoxy-~ulphides,~~ a new class of sulphur-substituted oxirans. The Darzens condensation of chloromethyl p-tolyl sulphide and benzaldehyde in the presence of potassium t-butoxide affords a poor conversion into the a$-epoxy-sulphides (101) and (102). However, in the presence of ‘Dabco’

H

SC6H4Me-p (101)

’”*-A Ph

SC6H4Me-p *H

(102)

(174-diazabicyclo[2,2,2]octane) good yields of the a,!-epoxy-sulphides are obtained. Thus it would appear that, in the absence of ‘Dabco’, the concentration of the p-tolylthiochloromethyl carbanion is low, a proposal supported by the recovery of unreacted starting material. This procedure gives a general route to this class of compound, the only previously reported a,b-epoxy-sulphide being a spiro-derivative (103). The oxiran (102) rearranges in the presence of BF3,2Et,0, affording an a-thio-aldehyde (104). 0

(103)

CHO PhCH-S-C6H4Me-p I

(104)

The latter results from a migration of the p-tolylthio-group similar to the rearrangement reported for the related sulphoxides and sulphones. Metal-catalysed Epoxidation. The use of metals or metal complexes as catalysts in the preparation of oxirans continues to receive much attention in the industrial sphere. 68

D. F. Tavares and R. E. Estep, Tetrahedron Letters, 1973, 1229.

Three-memberedRings

23

Silver of crystallite size -700-800 A, m a n ~ f a c t u r e dby~ electrodeposition ~ NaOH, from aqueous solutions containing AgNO,, Na,B,O,,lOH,O, NH,OH, and CM-cellulose as a protective colloid in an electrolytic cell, has been shown to be an effective catalyst for the oxidation of ethylene to ethylene oxide. Another procedure, in which the epoxidation reaction is not accompanied by the formation of acetaldehyde, also involves a silver catalyst.54In this instance, the oxidation reaction is carried out in the gas phase in a C-steel reaction tube coated on the inside with a nickel-phosphorus alloy. Molybdenum catalysts are also being widely used. Propylene in benzene, in the presence of the complex (NH,),MoO,F, and oxygen, is oxidized in a stainless-steel reaction vessel to propylene oxide.55Olefins can be epoxidized with >67% selectivity by carrying out the oxidation with a hydroperoxide in the presence of a molybdenum oxide catalyst containing a Group VIB metal oxide.66 Thus decene 1 ,Zoxide was obtained with 100% selectivity and 92 % hydroperoxide conversion by oxidizing dec-1-ene with t-butyl hydroperoxide in toluene in the presence of Bi,PMol,O5, on SiO,. The activity of various molybdenum-based catalysts5' has been studied for the reaction of cumene hydroperoxide with cyclohexene in cumene at 113 "C. MOO, [(NH,),MoO, ignited] alone or on carbon or aluminium oxide was only slightly active, but an active, selective, and homogeneous catalyst was prepared from MOO,-SO,. Molybdenum trioxide itself has been found to be an effective in toluene at 100 OC for the epoxidation of 1,2,3,6tetrahydrophthalic anhydride by cumene hydroperoxide. Complexes of copper, nickel, cobalt, ruthenium, or tungsten have also been successfully employed as catalysts in epoxidation reactions. Copper methoxychloride (CuClOMe) in pyridine59effected the cyclodimerization of acetone and acetophenone to give 70% and 60% yields of the epoxides (105; R = Me) and (105; R = Ph) respectively. Cyclopentanone reacted similarly.

wcoR

Me

R

(195) L. R. M. Piro and B. Notari, Ger. Offen 2 263 883/1973 (Chem. Abs., 1973, 79, 91 974r). E. Ide, T. Kumazawa and 1. Kiguchi, Ger. Offen 2 136 979/1973 (Chem. Abs., 1973, 78, 125 143). 6 6 A . A. Balepin, A. V. Bobolev, Yu. A. Buslaev, V. I. Chagin, N. M. Emanuel, and A. I. Sergeev, Ger. Offen 2235 229/1973 (Chem. Abs., 1973, 78, 125 146u). 56 J. Dahlman, E. Hoeft, H. F. Boeden, B. Castisella, and J. Scheve, Ger. Offen 2 231 374/1973 (Chem. Abs., 1974,80,27 080q). 57 L. Cerveny, A. Marhoul and V. Ruzicka, Chem. prrimysl, 1973,23, 299 (Chem. Abs., 1973,79,91 850x). 5 8 Y. M. Paushkin, D. V. Lopatik, I. P. Prokopovich, Doklady Akad. Nauk beloruss. S.S.R.,1973,17, 933 (Chem. Abs., 1974, 80, 14 791x). 6 a C. Neri and E. Perrotti, B.P. 1 331 856/1973 (Chem. Abs., 1974,80,27 081r). 59

64

3

24

Saturated Heterocyclic Chemistry

The yields of the epoxides formed by oxidation of but-l-ene, cis-but-2-ene, and isobutene were increased60by using complexes of thio-cr(or p)-diketones with nickel or cobalt as catalysts, e.g. tetrabutylammonium bis [bis-(3,4toluenedithiolato)nickelate] (106; x = 1 or 2). Styrene in benzene at 25 *C

(106)

was oxidized by t-butyl hydroperoxide to styrene oxide in the presence of dichlorotris(triphenylphosphine)ruthenium.61 Oxidation of maleic acid or its anhydride to epoxysuccinic acid by hydrogen peroxide was achieved in the presence of W03, H2W04, or its salts.62The activity of the catalyst can be increased if it is first pretreated with hydrogen peroxide. Miscellaneous. It is well known that o-hydroxymethylphenols (107), which have at least one bulky substituent, can be oxidized by periodate to monomeric spiroepoxy-2,4-cyclohexadienones(108). Recent studies.63 however,

Rq OH

OH

NaIO4

\

R

p

A

H

2

~

/

R2

R2

(107)

(108)

have shown that oxidation of benzyl-2-hydroxyphenylcarbinol (109) with sodium periodate affords the Diels-Alder dimer (1 lo), and oxidation of

H. Kawazura, Y. Yamamoto, and Y. Kariya, Japan. Kokai 73/15 808 (Chem. Abs., 1973,78, 147 768a). J. 0. Turner and J. E. Lyons, Ger. Offen 2 231 67811973 (Chem. Abs., 1973, 78, 1 1 1 925k). 62 M. Saotome, Y. Itoh and M. Terashi, Japan. Kokai 73/39 435,73139 436 (Chem. Abs., 1973,79, 78 591u, 78 592v). 63 H. D. Becker and T. Bremholt, Tetrahedron Letters, 1973, 197.

6o

25

Three-membered Rings R3

!.APh

R'

OH I

o-hydroxy-substituted diarylcarbinols and triarylcarbinols (1 11) yields cyclic catechol benzaldehyde acetals (1 12). Theoretically benzene is capable of forming five oxides, viz. benzene oxide, syn-benzene dioxide, anti-benzene dioxide, syn-benzene trioxide, and antibenzene trioxide, of which all except the anti-benzene dioxide (116) have been prepared within the past few years. The latter has now been prepared64 by treatment of the trans-l,2-diacetate (1 15) with 5 % methanolic potassium hydroxide, The intermediate (115) is formed in small yield (1 %) when the dibromoepoxide (114) is treated with acetic anhydride and sulphuric acid at room temperature or by reaction of traizs-l,2-diacetoxycyclohex-4-ene (1 13) with N-bromosuccinimide. Reaction of (1 16) with diazomethane gave a

pyrazoliiie which on U.V. irradiation afforded anti-dioxatrishomobenzene (1 17), which remained unchanged when heated at 150 "C. The analogous reaction with cis-benzene dioxide (1 18) yielded the dioxatrishomobenzene (119), which was isomerized at 150 "C to the cyclononatriene (120) (Scheme 11). An antibiotic that had earlier been assigned an anti-benzene dioxide structure was shown, as a result of detailed n.m.r. investigations in conjunction with these experiments, to have the syn-benzene dioxide structure (121). 64

E. Vogel, H. J. Altenbach, and E. Schmidbauer, Angew. Chem. Internat. Edn., 1973, 12, 838.

Saturated Heterocyclic Chemistry

26

Reagents: i, CH,N,; ii, hv; iii, 15OOC

Scheme 11

It has been established that d i o ~ q u i n o n ewhich , ~ ~ occurs in the bark of Diospyrus tricolor Hiern, is in fact an optically active naphthoquinone epoxide which must be one of the two enantiomers represented by structure (122).

L-

0

(122)

(121)

Synthetic diospyrin epoxide is the corresponding racemic compound. ( f)-2cis-4-trans-Xanthoxin (1 23) has been in eight steps, from 1 ,3,3-t rimethylcyclohex-1-en-Sone.

HO (123)

The racemic oxides (124) and (125) of methyl esters of octadec-6-enoic acids have been separated6' by the slow crystallization of the urea adducts of the racemic compound. The condensation of 5-methyl-5-(glycidoxyethoxy)hex-l-en-3-yne (126) 65

T.J. Lillie, 0. C. Musgrave, and R. H. Thomson, J.C.S. Chem. Comm., 1973,463.

66

T. Oritani and K. Yamashita, Agric. and Biol. Chem. (Japan), 1973, 37, 1215. I. L. Kuranova and L. V. Balykina, Zhur. priklad. Khim., 1973, 4 6 , 9 3 9 (Chem. Abs., 1 9 7 3 , 7 9 , 5 3 l05a).

67

Three-membered Rings

27

with hexachloropenta-l,3-diene (127) or 5,5'-dimethoxytetrachlorocyclopenta-1,3-diene leads to adducts with an endo configuration.6aThus when a mixture of (126) and (127) was heated with hydroquinone at 100°C, the adduct (128) was formed. CH2

CH20(CH&OCMe2C=C-CH= (126)

IkG;i:;;ta-l,3-diene

c1,

(127).

,Cl

b'

(128)

The base-catalysed reactionsof epichlorohydrin with alkoxynaphthenic phen~lphthalein,~~, and 4-a~etoxy-3,5,6-trimethylphenol~~ have been studied, and in each instance epoxy-groups were easily incorporated into the substrate. An ethynyl group is essential for optimal anticancer activity of carbamate esters, and bisepoxides are more potent anticancer agents than monoepoxides. These observations led to the syntheses, by an acid-catalysed reaction between epichlorohydrin and the respective acetylenic alcohol, of a series of 2[(2-propynyloxy)methyl]oxirans (129), ethynyl derivatives of ~xirans.'~It R2 I

/*\

I

R.'-C=C-C-O-CH2-CH-CHa

.

I

R3 (129) 68 69

'O

I. M. Akhrnedov, M. G . Veliev, P. B. Akhundova, and M. M. Guseinov, Azerb. khim. Zhur., 1973, 59 (Chem. Abs., 1974, 80, 47 717f). R. A. Ismailova, S. I. Sadykh-Zade, and Sh. F. Sadygov, Azerb. khim. Zhur., 1973, 56 (Chem. Abs., 1974, 1974,80,47 7 1 6 ~ ) . S. N. Satazkin, V. S. Vinogradova, and L. I. Komarova, Izvest. Akad. Nauk S.S.R., Ser. khim., 1973, 144 (Chem. Abs., 1973,78, 147 693x). L. Blaha, J. Weichet, and J. Stribrny, Czech. P. 150 020/1973 (Chem. Ahs., 1974, 80, 47 823n). R. B. Fugitt, G. S. Wu, and L. C. Martinelli, J . Pharm. Sci., 1973, 62, 1894.

Satiirated Heterocyclic Chemistry

28

was hoped that the presence of both an ethynyl group and an oxiran group in the same molecule would lead to significant anticancer activity. The screening results, however, were inconclusive.

Reactions-Ring-opening. Elecfruphilic. The reactions of a series of epoxychalcones (130; R1 = PhCH, or MeOCH,; R2 = MeO, C1, or Me; R3 = H or MeO) with acidic reagents have been in~estigated.~~ The product distribution is rationalized in terms of the sigma value of the 5’-substituent. Thus, when 0 4 0, treatment with HCI or BF,-Et,O gives the flavanon-3-01 (131), through elimination of the protective R1 group and cyclization. When Q > 0, treatment with HCl results in opening of the oxiran ring without elimination of the protective group to give the chlorohydrin (132), whereas with BF3-Et20 the isoflavone (133) is obtained.

‘OR’

(133)

Somewhat analogous and complementary results have been reported by O’Sullivan and G ~ r r n l e y who , ~ ~ have studied the reaction of 2’-tosyloxychalcone epoxides (134) with boron trifluoride (Scheme 12). Treatment of (134; R = H) affords the flavononal(l35) and the flavonal(136), but reaction with (134; R = OMe) gives the cc-formyl-desoxybenzoin (137). Treatment of the epoxide (134; R = H) with alkali at room temperature also gives flavonol whereas the epoxide (134; R = OMe) on similar treatment, or in refluxing solvent, gives 4-methoxyaurone (138; R = OMe). The latter result 7s 74

G. Litkei and R. Bognar, Acta Chim. Acad. Sci.Hung., 1973, 77, 93. T. R. Gormley and W. I. O’Sullivan, Tetrahedron, 1973, 29, 369.

29

Three-membered Rings OTs

Ph R

i ( R = OMe) -

OMe 0

O

Ph

(137)

(134)

i (R = H)

(135)

(1 36)

Reagents: i , BF3-Et20; ii, refluxing solvent

Scheme 12

indicates that an epoxide is not an intermediate in the production of flavonols from 2’-hydroxy-6’-methoxychalconeson treatment with alkaline hydrogen peroxide (Algar-Flynn-Oyamada reaction) at temperatures greater than

20 “c. The benzothiazin-4(3H)-one 1,l-dioxide (139) on treatment with hydrogen peroxide and sodium hydroxide gives rise to the epoxide (140). The latter in the presence of boron trifluoride etherate75does not yield the ring-expanded ketone (141), but the keto-aldehyde (142). The preference for phenyl migration as opposed to benzoyl migration has also been reported for the boron

NaOH-H202

0 2

76

(142) (141) H. Zinnes and J. Shavel, jun., J . Heterocyclic Chem., 1973, 10, 95.

Saturated Heterocyclic Chemistry trifluoride-catalysed rearrangement of epoxides derived from benzalacenaphthenone. The acid-catalysed rearrangements of trans- and cis-1-acetoxy-3,4-epoxypentanes and 1-acetoxy-4,5-epoxyhexanes,epoxides having neighbouring groups capable of nucleophilic participation, have been studied.76 The reactions yield cis- and trans-2-methyl-3-acetoxytetrahydrofuran and threuand erythru-2-(1-acetoxyethyl)tetrahydrofuran respectively with retention of configuration at the epoxide carbon atoms. Rearrangement of trans-l-acetoxy-3,4-epoxypentane (143) lSO-enrichedat the acetate carbonyl gave cis-3acetoxy-2-methyltetrahydrofuran(144) (21.5 % l80), which on hydrolysis 30

Me

Me

%*

OCOMe

H

(144)

-BFs /O-CH2

to the alcohol showed no significant loss of the oxygen label (20% leg). The carbonyl oxygen of the starting acetate must therefore be present as the ether or the hydroxy oxygen in the product. The known stereochemistry of the products, coupled with the labelling experiments, points to a mechanism consistent with the intermediacy of orthoesters formed by the initial attack of acetate on the epoxide with inversion of configuration. The orthoester is then cleaved to give the more stable five-membered-ring acetonium ion, which undergoes intramolecular rearrangement to form the furan ring. trans- and cis-4,5-Epoxyhexan-l-olsand 5,6-epoxyheptan-1-oh, when treated with boron trifluoride etherate in ether, show a marked preference for 78

J. M. Coxon, M. P. Hartshorn, and W. H. Swallow, J.C.S. Chem. Comm., 1973,261.

Three-rnembered Rings

31

cyclic ether formation: tetrahydrofuran > tetrahydropyran > ~ x e p a n . ' ~ The ether products arise by intramolecular hydroxyl displacement of the epoxide oxygen with inversion of configuration. Reactions of trans- and cis-epoxypentan-1-01s give a mixture of trans- and cis-2-methyltetrahydrofuran-3-01s. From each epoxide one methyltetrahydrofurar,ol must arise by nucleophilic displacement of the secondary epoxide oxygen with retention of configuration. The effect of the reaction conditions on the direction of opening of the epoxy-ring of 1,2-epoxy-3-alkoxypropane(145) on treatment with various \o/CH~OCH~CH=CH~

RC02H-A1C13 +

RCO&HCHZOCHzCH=CH2

I

CHzCl (145)

carboxylic acids in the presence of Lewis acids has been investigated.'* A carboxylate group is substituted at the 2-position and a chloro-group at the l-position. The opening of the or-oxide ring in 4,5-epoxy-3,6-diphenyl-NN'-diethoxycarbonylhexahydropyrazine (146) in the presence of gaseous hydrogen chloride in methanol79gives an unidentified product (35 %) and 3,5-diphenyl4-hydroxy-6-chloro-NN'-diethoxycarbonylhexahydropyridazine(147) (37 %). Ph

Ph dry HCI-MeOH +

Ho+T'cozEt Ph/u"\co,,,

c1

(147)

The oxiran (146), therefore, not only undergoes a ring-opening reaction but also the 6 4 5 migration of a phenyl group. Treatmentso of the nitroepoxyketones (148; R = p-MeCsH4, p-PhC6H4, p-clccH4, m-PhC6H4, or pN0,C6H4) with hydrogen chloride gives the corresponding a-chloro-phydroxy-ketone (149) in excellent yield. CMezNOz

Rco-iJ-

?y

RCOCHClCH(OH)CMe2N@2 (149)

(148) J. M. Coxon, M. P. Hartshorn, and W. H . Swallow, Austral. J . Chem., 1973,26, 2521. B. F. Pishnamazzade and A. Kh. Mamishov, Zhur. org. Khim., 1973, 9, 1365 (Chem. Abs., 1973,79, 115 376a). 79 Y. S . Shaborov and L. D. Sychkova, Zhur. obshchei Khim., 1973, 43,883 (Chern. Abs., 1973,79,66 281e). 8o V. F. Belyaev and V. P. Prokopovich, Vesti Akad. Navuk belarusk. S.S.R., Ser. khim. Nauuk, 1973, No. 5, 78 (Chem. Abs., 1973, 79, 146 106s).

77 78

32

Saturated Heterocyclic Chemistry

Ethylene oxide and 1,2-epoxycyclohexane each react with dichlorocarbenesl to form the corresponding chloro-oxirans, which when treated with hydrogen bromide give 2-bromoethanal and 2-bromocyclohexanone respectively. Sulphur trioxide is reporteds2 to react with perfluoropropylene oxide (150) at 150 "C in 10 h, affording a 1 : 3 mixture of the dioxathiolan (151) and

(151)

CF3COCF20S0,F (152), along with 5 % of CF3COCF,0S020S0,F. The dioxathiolan (151) is difficult to hydrolyse and is apparently unchanged by heating to 2OO0C or by contact with potassium fluoride, sulphur trioxide, or triethylamine. Therefore (152) must be formed independently, and not through (151), by opening of the epoxide ring by attack by sulphur trioxide at the C-F bond. If the reaction is conducted in the presence of sodium chloride, it also yields CF,COCF,Cl, confirming this proposal. Nucleophilic. Oxirans have been shown to be useful precursors in syntheses of heterocyclic compounds, Thus the epoxychalcones (153) reacts3 with toluene in the presence of aluminium chloride to give indenes (154), with monosubstituted hydrazines (R3NHNH2)to yield pyrazolines (155), and with hydroxylamine to afford isoxazoles (156) (Scheme 13). However, treatment with primary or secondary amines (R4R5NH)results in a nucleophilic substitution reaction at the carbon atom to the carbonyl group, with concurrent opening of the epoxide ring to give the compound (157). The epoxyvalerates (158; R1 = H or Me; RZN = NMe,, NEt2, piperidino, or morpholino), prepared by amination of the appropriate diepoxyvalerate, when reduced with lithium aluminium hydride afford ring-opened products (159) which can be cyclized with toluene-p-sulphonic acids4 to yield tetrahydrofuran derivatives (160). Diepoxyazabicyclononanes (161 ;R = S0,Ph or CHO) when heated with methylamine, 2,6-diaza-adamantadiols (162; R = S0,Ph or CHO). Nitrogen-containing 2,3-dihydrobenzofuran derivatives (164, 165; R = Me,N or piperidino), sedatives, are formed when methylmerancin (163) is treated with dimethylamine or piperidine.86The structure of the product M. M. Movsumzade, A. L. Shavanov, A. S. Kyazimov and N. G. Kerimova, Ref. Zhur. Khim., 1973, Abstr. No. 10Zh262 (Chem. Abs., 1974,80,95 623u). 8a I. L. Knunyants, V. V. Shokina, and E. I. MYSOV, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1973, 2725 (Chem. Abs., 1974, 80,95 151p). 83 A. Sammour, M. Selin, and A. A. Hamed, Egypt. J. Chem., 1973, 16, 101. 84 L. S. Stanishevskii, I. G. Tishchenko, V. I. Tyvorskii, L. A. Khil'manovich, A. S. Zakharevskii, and A. V. Miklevich, Khim. geterotsikl. Soedinenii, 1973, 1443 (Chem. A h . , 1974,80,70 624g). 8 5 R. E. Portmann and C. Ganter, Helu. Chim. Acra, 1973, 56, 1986. 86 M. Murayama, H. Murai, K. Sempuku, T. Suminokura, and M. Ozaki, Japan. Kokai 73/00 822 (Chem. A h . , 1973,78, 136 047p).

Three-mernbered Riiigs

33 R1

i

(155)

p-R'CsHaCOCH(OH)CH3CijH4R2-p 1 NR4R5 (157) Reagents i, RSNHNH,; ii, MePh-AICI,; iii, NH,OH; iv, R4R6NH Scheme 13

ti 0

R$NCH,CRl(OH)

COzCHMez

Me LiAIH,

(li8)

R~NCHKR1(OH)CMe(OH)CHzCHzOH (159) p-MeCaH4SOsH

34

Saturated Heterocyclic Chemistry

I

OH M $c*e

OMe

OiMe

Me/ /

0

OH

COR (165)

reflects the reaction conditions. Thus (163) and excess 40 % aqueous dimethylamine in methanol at 40 O C for 30 h afford (164; R = NMe,), whereas (163) and dimethylamine in benzene at 125 O C for 7 h give (165; R = NMe2). Some reactions of epoxides with nitrogen-containing compounds afford acyclic products. For example the amination reactionss7 of mono- and diepoxy-alcohols have been reported to give l-amino-2,4-diols as the major products. The reactions of oxirans with alcohols have received little attention during this period. Treatment of b-chloroethyl glycidyl ether (1 66) with alcohols in the presence of SnC1,,ss followed by cyclization with sodium hydroxide, gives 2-alkoxymethyl-p-dioxans(167) in 55-93 % yield. Acyloxiranssa

E. F. Marchik, V. I. Pansevich-Kolyada, V. I. Makhnach, and G . S. Bychkova, Vesti Akad. Navuk belarusk. S.S.R., Ser. khim. Navuk, 1973, No. 2 , 106; I. A. Shnyp, V. I. Pansevich-Kolyada, N. A. Glazkova, and L. N. Falaleeva, ibid., 1973, No. 3 , 107 (Chern. Abs., 1973,79, 5184d; 66 106b). 8 8 B. F. Pishnamazzade and A. Kh. Mamishov, Khim. geterotsikl. Soedinenii, 1973, 161 (Chem. Abs., 1973,78, 124 518e). se I. G. Tishchenko, 0. N. Bubel, and G. S. Chertov, Vesti Akad. Navuk belarusk. S.S.R.,Ser. khim. Navuk, 1973, No. 5, 82 (Chem. Abs., 1973,79, 137 0572).

Three-memberedRings

35

are reported to give 2-acyl-p-dioxans on reaction with alcohols followed by

cyclization with sodium. An interesting reaction is the alcoholysisgoof 2,3epoxycyclohexan-l-one with ROH (R = Me, Et, or PhCH2), which affords 2-alkoxycyclohex-2-en-1-ones. The reaction of Wittig-type reagents with oxirans to form cyclopropanecarboxylic acid derivatives has been well documented. Both ethoxycarbonylmethylenephosphoranes and phosphonate anions have been successfully utilized. There has, however, been some disagreement concerning the overall mechanisms, mainly as to whether the products arise by a direct collapse of the phosphonate ester (169) or by a stepwise decomposition (Scheme 14).

(EtO)ePOCHCO,Et

Rl** R4 R3

(168)

(EtO)2PO’

1 \

0P(0Et)s

1 COzEt

3

/(OEt)2

-0

P

R4--v R2

major product

6OzEt minor product

Scheme 14

In order to clarify the situation, Izydore and Ghirardelligl have studied the reaction of the triethylphosphonoacetate anion (168) with optically active trans-2,3-dimethyloxiran and with cis-2,3-dimethyloxiran. They conclude that the major products in each reaction must result from an even number of inversions of the initial epoxide, and are therefore consistent with Denney’s stepwise mechanism (process a). The minor products, which require only one inversion, arise by a direct collapse of the cyclophosphonate ester (1 69) (process 6). so

N. S. Kozlov and V. N. Kovaleva, Zhur. org. Khim., 1973, 9, 1984 (Chem. Abs.

O1

1974, 80, 26 803v). R. A. Izydore and R. G. Ghirardelli, J . Org. Chem., 1973, 38, 1790.

Saturated Heterocyclic Chemistry

36

HO

4Q

The epoxy-p-bromobenzenesulphonate (170; n = 1) on reaction with sodium sulphideg2in DMSO affords exo-2-hydroxy-4-thiatricyclo [4,2,1,03*7]nonane (172; n = 1) in 60% yield. The reaction is thought to proceed via the intermediate (171) which results from initial displacement of the p-bromobenzenesulphonyl group. The other possible ring-opened product (173 ; n = 1) was not formed. Similarly the epoxy-p-bromobenzenesulphonate (170; It = 2) gave exo-2-hydroxy-4-thiatricyclo[4,3,1 ,03n7]decane (172; n = 2). Such conformationally rigid organosulphur molecules are extremely useful substrates in studies pertaining to stereochemistry and intramolecular interactions. Hydrogen sulphide, hydrogen cyanide, and 1H-benzimidazole, nucleophiles containing a labile hydrogen, are reportedg3to give a regiospecific cleavage of the oxiran ring of trans-2-ethoxy-3,4-epoxytetrahydropyran (174), affording (f)-threo-tetrahydropyranols (175; R = CN, SH, and

HR

(174)

1H-benzimidazol-1-yl) respectively. A new mild procedure for the conversion at room temperature of epoxides into allylic alcohols has been reported.94 The procedure is based on the observation that alkyl phenyl selenoxides 92

93 94

C. R. Johnson and W. D. Kingsbury, J. Org. Chem., 1973, 38, 1803. V. B. Mochalin, A. N. Kornilov, and B. V. Unkovskii, Khim. geterotsikl. Soedinenii, 1973, 867 (Chern. Abs., 1973,79, 126 233c). K. B. Sharpless and R. F. Lauer, J. Amer. Chem. SOC.,1973, 95, 2697.

Three-mernberedRings

37

bearing a ,%hydrogen undergo syn-elimination to form olefins under much milder conditions than the corresponding sulphoxides. Thus 4,5-epoxyoctane reacted with PhSe- (prepared from diphenyl selenide and sodium borohydride) to give trans-oct-3-en-4-01(Scheme 15). It is of note that elimination

Reagents: i, EtOH, 2h; ii, excess H202, 0-25 "C;i i i , room temp., 10 11

Scheme 15

occurs away from the hydroxy-group in the decomposition of the &hydroxyselenide, a phenomenon which appears to be general from the examples studied. The reactions of oxirans with organolithium compounds continue to attract much attention, a high degree of selectivity often being found. It has been shown that the epoxide bridge of epoxynitriles can be selectively opened tc to the nitrile group by using lithium dimethylcuprate-lithium iodide.95 Thus the dimethylepoxynitrile (176; R1 = R2 = Me) upon treatment in ether at - 1 O O C gave four products (178)-(lsl), in 5 % , 20%, SO%, and 25 % yield respectively. The product distribution can be manipulated by altering the cuprate :oxiran ratio or by the addition of acetone to the reaction mixture. If R1 or R2 is Ph, degradation also occurs, affording ketones (R1COR2),particularly when R1 = R2 = Ph. The key intermediate in the reaction is thought to be the complex (177).

(178) (179) (1 80) (1 81) 95

1

R'R2C=CHCN RlR*C(OH)CH,CN R1R2C(OH)CHMeCN R'R2C(OH)CH(CN)CR'R20H

J. M. Normant, Compt. rend., 1973,277, C,1045.

38

Saturated Heterocyclic Chemistry

General synthetic routes for the preparation of a-hydroxyallenes are rare, considering their presence in a number of natural products and their value as a replacement for allylic and acetylenic alcohols in pharmaceuticals. Therefore, a recently reported reaction,96 in which a-acetylenic epoxides (182) when treated with lithium dialkylcuprate reagents afford a-hydroxyallenes (183) in good to moderate yield, should find a wide application. The addition R4

of lithium acetylides to a-halogenocarbonyl compounds followed by epoxidation with m-chloroperbenzoic acid affords the acetylenic epoxides (182), which react with either lithium dimethylcuprate or di-n-butylcuprate in diethyl ether at -20 to -30 'C.The reaction is extremely sensitive to variations in the reaction conditions, a change in temperature, for example, promoting the formation of side products. The reactions of lithium dimethylcuprate with a series of oxirans containing neighbouring oxygen-containing substituents (HO, MeO, AcO, or Et02C) have been studied.97The results suggest that the degree of selectivity observed earlier with ethyl 2,3-epoxybutyrate, which gives an a-methylated product in good yield, will not prove to be a generally useful feature of the reactions of glycidic esters and that the product distribution will largely be the result of conformational control. It is further suggested that substituent-metal complex formation is not a significant feature of these reactions. Lithium trialkylvinylborates (184) react with oxiran~,~* affording complexes (185) which on oxidative work-up with alkaline hydrogen peroxide give, by a novel and convenient route, 1,4-diols (186) in excellent yields.

RCH(CH&CHR1

I

OH

I

H202 4

OH

P. R. Ortiz de Montellano, J.C.S. Chem. Comnt., 1973, 709. B. C. Hartman, T. Livinghouse, and B. Rickborn, J. Org. Chem., 1973, 3 8 , 4 3 4 6 . 9 8 K. Urimoto, K. Uchida, and H. Nozaki, Tetrahedron Letters, 1973, 4527.

96

97

Three-memberedRings 39 Koebrich et aLg9have studied the behaviour of 2-chloro-1-t-butyl-1-phenyloxiran towards nucleophiles. The oxiran is inert to secondary amines and lithium methoxide but reacts with several organolithiums (R = Bun, But, Ph, or BuCH,CPh,) to afford the corresponding 2-alkyl-1-t-butyl-1-phenyloxiran. Lithium piperidide, however, opens the oxiran ring, affording 3,3dimethyl-2-phenylbutan-2-01-1 -al. A new synthesis for the dihydro-y-pyrone system (187) which involves the addition of 2-lithio-2-(2,2-dimethoxyethyl)1,3-dithian to epoxides has been reported.loOThe near quantitative addition to the epoxide occurs at the least hindered carbon. Conversion of (187a) into (187b) involves three further steps.

(187b)

( I 37a)

When 2-lithiated isocyanides (1S9), prepared from alkyl isocyanides (188) and butyl-lithium, are treated with epoxides (190), 5,6-dihydro-4H1,3-oxazines (193), without a substituent at position 2, or 8-amino-alcohols R1CH2NC

R'CHNC

I

(-CdH1O)

Li

(188) NC

OH

I

RICH-CH

I

CHR3

R2-

(IS9)

\

* R*I

CH-CH R2- C HR3

I

NC

OLi (191)

HNX (194) X = CHO (195)

X

=

H H R2 (193)

Reagents: i, BuLi; ii,R2

)"(

H

(190); iii,

Y'; iv,H30+-HeO;v, CuzO-NaOEt; vi, MeOH

R3

Scheme 16 99 G. Koebrich, W. Werner, and J. Grosser, Chem. Ber., 1973, 106,2620. l o o F. Sher, J. L. Isidor, H. R. Taneja, and R. M. Carlson, Tetrahedron Letters, 1973, 577.

4

40

Saturated Heterocyclic Chemistry

are formed in good yield (Scheme 16).lo1 Unsymmetrically substituted epoxides are attacked preferentially or exclusively at the least hindered carbon atom. The primary product (191) of the reaction can be isolated as an 8cyano-alcohol (192) by addition of one equivalent of acetic acid. Depending upon the experimental conditions, acid hydrolysis of these products yields either y-formylamino-alcohols (194) or p-amino-alcohols (1 95). 5,6-Dihydro4H-1,3-oxazines are formed by allowing ethanolic solutions of the primary adducts (191) to stand or by warming the p-isocyano-alcohol (192) with cuprous oxide and sodium ethoxide. Dipolar cycloaddition. On heating equimolar amounts of 1,l-dicyano-2aryloxirans (196; R = CN) or l-cyano-l-ethoxy-2-aryloxirans(196; R = C0,Et) with substituted benzylideneanilines (197), oxazolidines (1 98) are

formed102 in yields of ca. 60%. With the former only one stereoisomer is formed, whereas with the latter two isomers which do not epimerize under the reaction conditions are isolated. It is proposed that the products must arise by a regiospecific addition of an epoxide-derived ylide to the imine. The influence of ylide substituents and imine substituents on the reaction may be rationalized on the basis of frontier orbital analysis. The reaction of thiourea with 1,l-dicyano-2-aryloxirans (196; R = CN) at room temperature affordslo3a useful route to 2-amino-4-thiazolines (1 99). Spectral data show that the latter exist predominantly in the amino-form. Reaction with 1,ldicyano-2-alkyl-2-aryIoxirans, as one would expect, does not result in ringopening but yields 1-cyano-1-thiocarbamyl-2-alkyl-2-aryloxirans. The treatment of oxirans with phenyl isocyanate or methyl isocyanate in the presence of lithium chloride affords a high-yield synthesislogof N-alkyland N-aryl-2-oxazolidinones (200) in one step. Although the isocyanate oxiran reaction is known to produce both C-4 and C-5 substitution products 101 U.Schollkopf and R. Jentsch, Angew. Chem. Internat. Edn., 1973,12, 323. lorA. Robert, J. J. Pommeret, E. Marchand, and A. Foucard, Tetrahedron, 1973, 29, 463. M. Ferrey, A. Robert, and A. Foucard, Compt. rend., 1973, 277, C, 1153. l o pR. B. Fugitt and C. L. Martinelli, J . Pharm. Sci., 1973, 62, 1013.

Three-membered Rirgs

41 R2

I

/O\

R1C-C-C-O-CH,-CiI-cIr2 I

+ PhNCO

k3

(200)

through the breaking of either the C-1-0 or C-2-0 epoxide bonds, only the C-5 product was formed in these reactions. 1,3-Dioxolans (202; R = Ph, C&&k, C6H4Cl, or Me,C6H,) can be preparedlo5 in 46-81 % yield by condensation of the appropriate epoxide (201) with acetone in the presence of boron trifluoride etherate. Me

\

CHZR

/

The use of triphenylphosphine and its derivatives as deoxygenating reagents is well established. The versatility of these reagents has recently been extended by the discovery that triphenylphosphine selenide and trifluoroacetic acid constitute an effective and mild combination of reagents for carrying out a stereospecific deoxygenation of epoxides to olefins.lo6 The olefin is thought to arise by the extrusion of selenium from the corresponding episelenide (Scheme 17), an unusual process for which, however, there is precedent in the stereospecific thermolyses of episulphides.

Scheme 17

Rearrangement. The Julia-Johnson rearrangement of cyclopropylcarbinols is a most useful reaction for the stereoselective synthesis of trisubstituted olefins. One disadvantage of the sequence, however, is the formation of a terminally functionalized homoallylic system, which is unsuited for the synthesis of 2- or 3-methylalk-2-en-1-01s (the terminal unit of isoprene). M. M. Guseinov, M. S. Salakhov, 0. A. Zutitkova, and S. Yu. Mamedalieva, Arerb. Nefr. Khoz., 1973, 53, 32 (Chem. Abs., 1973, 79, 53 206j). lo6D. L. Clive and C. V. Denyer, J.C.S. Cliem. Comm., 1973, 253. lo5

42

Saturated Heterocyclic Chemistry

A novel adaptation of this synthesis which overcomes this disadvantage has now been reported.lo7 Treatment of the cyclopropyloxiran (203; R1 = H, R2 = Me) with 48 % hydrobromic acid at 0 "Caffords (E)-5-bromo-2-methylpent-2-en-1-01 with 96 % stereoselectivity, whilst treatment with sodium iodide in acetic acid-propionic acid-sodium acetate at -18 OC affords the corresponding (E)-iodo-compound. The isomeric oxiran (203 ; R1 = Me, R2 = H) on reaction with zinc bromide in ether gives (E)-5-bromo-3-methylpent-2-en-1-01. The stereoselectivity of these reactions is rationalized on the basis of a concerted process via the transition state (204). X-

H+ (204)

(203)

Addition of dicyanoacetylene or dimethyl acetylenedicarboxylate to the oxiran (205) affords the adducts (206) and (207), respectively.1°8 When (206) is treated with sodium iodide in acetone at room temperature the adduct (208) (53%) and the isomer (209) (25%) are formed. In the dehalogenation of (207) the only product formed corresponds to the isomer (209). Contrary to expectation, thermolysis of (208) does not lead to liberation of benzoxiren by Alder-Rickert cleavage. Instead, a quantitative arene oxide-arene oxide rearrangement takes place quantitatively at 80-100 "C,yielding (209). The isomerization of (208) to (209), constituting a suprafacial 1,5-sigmatropic shift, is symmetry-allowed.

RC-CR 7

Br (206) R = CN (207) R = COzMe

(208) (209) Nakamura, H. Yamamoto, and H. Nozaki, Tetrahedron Letters, 1973, 1 1 1. loB F. G. Flaerner and E. Vogel, Angew. Chem. Znternat. Edn., 1973, 12, 840.

lo' H.

43

Three-memberedRings

Reaction of trans-1-benzoyl-2-phenylcyclopropaneswith dimethylsulphonium methylide results in an inseparable mixture of two cyclopropyl epoxide isomers (210). When these are heated,lo9 alone or in toluene, at 100 O C for 10-15 min, a novel rearrangement occurs affording 3,6-dihydro2H-pyrans (211) quantitatively. The mechanism of this rearrangement is thought to involve adventitious acid-catalysed opening of the epoxide ring, followed by intramolecular attack on the resulting homoallyl cation (Scheme 18). This procedure should prove a most useful synthetic route to 2-aryl-3,6dihydro-2H-p yrans.

(21 1) Scheme 18

A re-examinationl10 of the isomerization of 1,1'-epoxybicyclohexyl-2-one (212) to spiro-diketoneshas confirmed that reaction with antimony pentachloride in liquid sulphur dioxide affords cycloheptanespirohexa-2,ir-dione as previously reported. However, in earlier work there was some doubt as to the identity of the thermal-rearrangement product. This has now been shown to be cycloheptanespirocyclohexane-2,2'-dione (213). The isomerization probably involves a radical reaction, similar to that suggested for the phot olytic conversion of a,/3-epoxy-ketones into spiro-1,3-diketones (Scheme 19).

(2 13)

Scheme 19 looJ. O'Grady, J.C.S. Perkin I , 1973, 2030. G. E. Hawkins and R. Large, J.C.S. Perkin I , 1973, 2169.

44

Saturated Heterocyclic Chemistry

The photolysis of phenanthrene oxide (214) is wavelength-dependent.lll Irradiation at 300-350 nm in dichloromethanc affords 9-phenanthrol (50%), phenanthrene (1 1%), and the oxepin (215) (0.5%). At 207-235 nm 9-phenanthrol is still the major product (56%); the yield of phenanthrene drops to 0.2%whilst that of the oxepin increases to 3 %, and a small amount of fluorene (0.2 %) is isolated. Irradiation at 250-290 nm affords 9-phenanthrol (8 %), the oxepin (2&30%), fluorene (3 %), and a dimer (25 %). In contrast to the extensive investigation of the photochemistry of u,Pepoxy-ketones, p, y-epoxy-ketones have received relatively little at tent ion. One point which is emerging, however, is that photodecarbonylation to a greater or lesser extent is a typical reaction of such compounds. Treatment of hexamethylbenzobicyclo[2,2,2]octadienone (216; R = Me) with m-chloroperbenzoic acid gives the epoxy-ketone (217; R = Me), which on irradiation in ether112througha Corex filter affords the unsaturated oxiran (218 ;R = Me) in 95 % yield. Irradiation of (217; R = H) also results in photodecarbonylation and gives (218; R = H) in 75 % yield. The photoproducts are thought to result from the biradical (219) followed by formal 1,6-hydrogen shifts.

CH2=CH U

(219)

R

(2 18)

K. Shudo and T. Okamoto, Chem. and Pharm. Bull. (Japan), 1973,21,2809. 112 R. K. Murray, jun., T. K. Morgan, H. Hart, and J. V.Hul1, J . Org. Chem., 1973,38,3805.

Three-memberedRings 45 Irradiation113 of an ether solution of 2,2,4,4-tetramethyl-7-oxabicyclo[4,1,O]heptan-3-one (220), however, in striking contrast to the previous report ,112 does not lead to photodecarbonylation, but photoisomerization occurs to give 2,2-dimethyl-4-(2-methylprop-1 -enyl) butanolide (221) and 2,2,6-trimethyl-4-oxohept-5-enal (222) The photoproducts are readily accounted for by initial Norrish Type I bond cleavage of (220) to give the biradical (223), which undergoes subsequent ring-opening to provide the biradical (224). Ring closure of (224) affords (221), and a 1,4-hydrogen shift in (224) gives (222).

1

The photoproducts resulting from the irradiation of (220) are analogous to those obtained in the photoisomerizations of 2-0xiranyl-cycloalkanones.~~~ The latter (225), like their cyclopropyl counterparts, undergo a three-atom photochemical ring expansion via the sequence (225) +(226), affording macrolides, in good yield, as the major products. Indeed, these results suggest that such photoisomerizations are the characteristic reactions of 7-oxabicyclo[4,1 ,O]heptane-3-ones and that photodecarbonylation only becomes a major process in such systems when specific skeletal constraints prevent similar photoisomerizations from occurring. Ring Retention. It is well known that organomagnesium compounds always attack epoxy-nitriles at the nitrile group. It has recently been shown,l15 however, that selective attack at either the nitrile or the epoxide group can be achieved using organolithium compounds at -78°C. The position of attack depends on the ‘basicity’ of the lithium reagent. Weakly basic compounds attack the nitrile group whereas strongly basic compounds remove the naR. K. Murray, jun. and D. L. Goff,J.C.S. Chem. Comm., 1973, 881. 11* R. G. Carlson, J. H.-A. Huber, and D. E. Henton, J.C.S. Chem. Comm., 1973, 223. 116 J. M. Normant, Tetrahedron Letters, 1973, 4253.

46

Saturated Heterocyclic Chemistry

proton a to the nitrile group. Thus the dimethyl epoxy-nitrile (227) with RLi (R = Me, Ph, or CH,CN) at -78 "C gave in 7 0 4 3 0 % yield the oxirans (228; R = Me or Ph). The corresponding imines can be prepared if a nonacidic hydrolysis of the intermediate lithium complexes is employed. The strongly basic lithium reagents RLi (R = Bu, CH,CI, CHCI,, or CH=CH,) afford in 15-70% yield in the diepoxide (229). This results from reaction of the intermediate carbanion with a further molecule of the epoxide (227), reaction occurring at the nitrile group. Butyl-lithium and 3-cyano-2,2diphenyloxiran give the diepoxy-ketimine (230) in 80 % yield. Me

RLi-HzO,

wHc,R

Me Me

II

0 (228)

0 (227)-H20

Ph

H

Miscellaneous. Soluble low-valence transition-metal complexes are now well recognized as important agents for effecting structural transformations in

Three-membered Rings

47

organic substrates. Numerous catalytic reactions have been reported involving transition-metal activation of organic substrates containing carbonhalogen bonds, carbon r-bonds, and strained a-bonds, but little has been reported about similar reactions with carbon-oxygen bonds. It has recently been shown,l16 however, that nickel(0) complexes are excellent catalysts for the formation of alkylene carbonates from epoxides and carbon dioxide. Thus epoxyethane and carbon dioxide at 100°C in benzene containing (Ph,P),Ni gave ethylene carbonate in >95 % selectivity. 2-Methyl-l,2epoxypropane and 1-chloro-2,3-epoxypropane reacted similarly. Bis(tricyd ohexylphosphine)nickel a1so cata1ysed a1kylene carbonate formation. The photochemical bromination of oxiranY1l7 methyloxiran, trimethyloxiran (23l), tetramethyloxiran, and epoxycyclohexane (232) with N-bromosuccinimide in CCI, at 15 "C yields bromo-oxiran, l-bromo-2,3-epoxypropane, 1-bromo3-methyl-2,3-epoxybutane, 1-bromo-2,3-dimethyl-2,3-epoxybutane , and l-bromo-2,3-epoxycyclohexane respectively. Bromotrichloromethane in CCl, at 0 "C with (231) and (232) afforded the a-bromo-ketones 2-bromo2-methylbutan-2-one and 2-bromocyclohexan-l-one respectively. Monobromourea and (232) at 0 "C also gave 1-bromo-2,3-epoxycyclohexane,

The bromochlorination of olefin-oxiran mixtures has been studied.ll8 Oxiran and bromine chloride in carbon tetrachloride at -30 "C, on treatment with ethene, cyclohexene, and cyclopentene, give the ethers [233; R1 = R2= H; R1R2= (CH2)4; and R1R2= (CH,),] respectively. Similarly 1,2-epoxycyclohexane and bromine chloride with ethene, propene, cyclohexene, and cyclopentene yielded the chlorocyclohexanes [234; R1= R2 = H; R1 = Me, R2 = H; R1R2= (CH2)4; and R1R2 = (CH,),] respectively.

A,

B,.Cy

C1CH2CH20CHRTHR?Br (233)

(234) u6 R. J. D e Pasquale, J.C.S. Chem. Comm., 1973, 157. u7 M. M. Movsumzade, A. L. Shabanov, and N. V. Petrova, Azerb. khim. Zhur., 1973, 35 (Chem. Abs., 1974,80, 108 268j). 11* M. M. Movsumzade, A. L. Shabanov, R. A. Garbanov, and R. G . MovsuIn-Zade, Zhur. org. Khim., 1973, 9, 1998 (Chem. Abs., 1974,80,47 721c).

48

Saturated Heterocyclic Chemistry OH O H

I

I

OR OH I I RlR2R3C-C=_C-CrC-C-C-R4

I

t

R5 H (237)

The reaction of magnesium derivatives of diacetylenic alcohols with chloro-ketones, followed by alkaline dehydrochlorination, affords a general route119 to diacetylenic epoxides (235). Thermal decomposition of (235) is reported to afford monosubstituted diacetylenic epoxides. Hydration of the epoxides (235) yields a-diols (236), whilst treatment with alcohols and boron trifluoride etherate gives a1koxydiacetylenes (237). A new route to functionalized allenes has been reported by Brown et ~1.120 They found that 3,4-epoxybut-l-yne derivatives (238; R = H or Me) give, when treated with organoboranes (239; R1 = Et or cyclopropyl) in the presence of oxygen, allenic alcohols (240) by a free-radical mechanism. Thus, tricyclopentylborane and (238; R = H) were mixed in benzene under nitrogen, air was introduced at 0.5 ml mi&, and the solution was stirred for 6 h at room temperature, affording, after alkaline hydrolysis, (240; R1 = cyclopentyl) in 62% yield.

3,4-Epoxy-2,3,4,5-tetrahydrothiophen1,l -dioxide reacts121 with sulphur tetrafluoride in dichloromethane at 100 “C to give 3,4-difluoro-2,3,4,5tetrahydrothiophen 1,l-dioxide, which on treatment with aqueous sodium carbonate affords 3-fluoro-2,3-dihydrothiophen 1,l-dioxide. The mass 119T. I.

Kupriyanov and V. Tatarchuk, Ref. Zhur. Khim., 1973, Abstr. No. 4Zh279 (Chem. Abs., 1973, 78, 91 849d); ibid., 1973, Abstr. No. 9Zh308 (Chem. Abs., 1974, 80,70 61 2b). 12oA. Suzuki, N. hliyaura, M. Itoh, H. C. Brown, and P. Jacob, tert., Synthesis, 1973, 305. 1ZlV. I. Golikov, A. M. Aleksandrov, L. A. Alekseeva, T. E. Bezmenova, and L. M. Yagupol’skil, Zhur. org. Khim., 1973,9,2428 (Chem. Abs., 1974,80,47 745p).

Tlree-membered Rings

49

spectrometry of 3-fluoro-5,6-epoxy-steroids has been studied.122The influence of the fluorine atom on the fragmentation pattern could not be precisely defined, but it is certain that the stereochemistry of the epoxide plays a prominent role in the fragmentation. Hexafluoropropylene oxide is known to form difluorocarbene and tetrafluoroacetaldehyde on pyrolysis. It has now been found that this reaction is re~ersib1e.l~~ Related polfluorinated epoxides (241; X = H or Cl; n = 2 - 4 , when heated for 4-8 h at 100-150 "C in the presence of antimony pentafluoride, i s o m e r i ~ evia , ~ an ~ ~ionic mechanism, to the corresponding fluoro-ketones (242) in 85-96 % yield.

3 Aziridines

Formation.-Direct Insertion of Nitrogen or Carbon Atoms. The reactions of amino-nitrenes with olefins to form N-aminoaziridines still attracts some attention. The reaction of N-aminonaphthalimide with cyclob~tene'~~ and with cis-3,4-dichlorocyclobutenein the presence of lead tetra-acetate gives 2-phthalimidyl-(243) and 2-phthaIimidyl-4,5-dichloro-(244)5-azabicyclo-

(243) R (244) R

=

H

=

C1

[2,1,O]pentane in yields of 18-22 % and 9-12 % respectively. The lH n.m.r. spectrum of (244) indicated the presence of the exo- (245) and the endo- (246) isomers in the ratio 4 : 1. The isomer ratio is consistent with the expectation

N-N /

H

:@tJJJ 34-N

c1

CI

0

(245)

/

0

(246)

J. L. Borgna, A. Guida, and L. Fonzes, Org. Mass Spectrometry, 1973, 7 , 133. W. Mahler and P. R. Resnick, J . Fluorine Chem., 1973, 3 , 451 (Chem. Abs., 1974, 80, 47 370n). lZ4 A. Ya. Zapevalov, I. P. Kolenko, V. S. Plashkin, and P. G. Niefel'd, Zhur. Vsesoyuz. Khim, obshch. im D . I . Mendeleeua, 1973, 18, 592 (Chem. Abs., 1974, 80, 26 713m). A. G. Anderson, jun. and D. R. Fagerburg, Tetrahedron, 1973,29,2973. lz2

laS

50

Saturated Heterocyclic Chemistry

that steric repulsion between the chlorine substituents and the aminophthalimide in the transition state for the formation of (246)would favour (245)as the major product. Stable l-alkoxyaziridine invertonxrs have been reported by Ioffee and Koroleva.126 A series of alkoxy-amines (247; R = Me, Et, or Pri) was oxidized with lead tetra-acetate in the presence of olefins, affording, by way of the respective O-nitrene, l-alkoxyaziridines (248)-(251) in yields of R' R3

OR (348) R1 = R2 = H, R3 = Me (239) R1 = Me, R2 = Rz = H (250) R1 = R? = Me, K3 = H (251) R1 = Rz = R3 = fine

9-35 %. The l-alkoxy-2,2,3-trimethylaziridines(250) were mixtures of two stereoisomers which did not interconvert at room temperature. The mixtures (250) were separated by g.1.c. and the configurations of these invertomers assigned from IH n.m.r. data. N-Unsubstituted aziridines (254) can be prepared12' by the reaction of 3,3-pentamethyleneoxaziridine(252)with olefins (253). Treatment of cyclohexanone with ammonia and sodium hypochlorite affords the oxaziridine (252). Thus indene and (252) when refluxed in chlorobenzene gave the Nphenylcarbamoyl derivative (254;R1 = R2 = o-C,H,CH,, R8 = H).

(252)

(253)

(254)

Dichlorocarbene, generated by treatment of chloroform in hexane with potassium t-butoxide, reacts12* with azomethines (255) to afford diphenylethyleneimines (256).

(255) 12s

B. V. Ioffee and E. V. Koroleva, TefruhedronLetters,1973,619. Schmitz and K. Jachnisch, Ger. Offen 230952911973 (Chem. Abs., 1973, 79, 136 973h). N. S. Kozlov, V. D. Pak, V. V. Mashevskii, and P. N. Plaksina, Khim. Farm. Zhur., 1973,7, 15 (Chem. As., 1973,79,78 47811).

le7E.

12*

(256)

Three-membered Rings

51

Cyclizatian. Brown and Levy129have reported that 2-iodoalkyl azides (257),

which are now readily available with known stereochemistry, undergo a facile reaction with aryl- and alkyl-dichlsroboranes, affording 8-iodo secondary amines. These amines without isolation undergo a ring-closure reaction with base, providing the corresponding N-aryl- and N-alkyl-aziridines (258) in good yields (73-94 %). Significantly, the stereochemistry of the original 2-iodoalkyl azide is maintained, providing for the first time a synthesis of N-aryl- and N-alkyl-aziridines in which the stereochemistry of the ring substituents may be easily defined. Furthermore, as previous work has the N-alkyl groups must retain the original stereochemistry of the group attached to boron. This procedure, therefore, shows exceptional promise as a relatively simple direct route to aziridines with well defined stereochemistry.

(257)

(258)

Ring closure of organo-azidescan also be achieved with cobalt dibromide.131 Thus the 10-mesylate derivative of methyl 1l-azido-l0-hydroxy-7-ethyl-3,11dimethyltrideca-2,6-dienoate gave methyl lO,ll-imino-7-ethyl-3,11 -dimethyltrideca-2,6-dienoate. Cromwell et al. have extended their investigation of the reaction of 2,3dibromo-3-phenylindanone (259) with cyclohexyl- and methyl-amine, which affords 1-alkyl-6-(alkylimino)-l, 1a,6,6a-tetrahydro-l a-phenylindeno[1,241azirines (261), to reactions with ethyl-, isopropyl-, t-butyl-, and benzylarnine.l3, All of these, with the exception of t-butylamine, which results only in the dehalogenation of (259) to 2-bromo-3-phenylindenone (260), gave the respective polycyclic aziridine (261 ; R = Et, Pri, or PhCH,). The behaviour of t-butylamine is attributed to the steric bulk of the t-butyl group, particularly in light of the fact that benzylamine, a weaker base, did react readily to produce an aziridinyl Schiff base. It has also been established that the Schiffbase formation is catalysed by the presence of the amine hydrobromide in the reaction mixture. Methods which may be used for hydrolysis of the iminogroup are severely limited by the reactivity and facile opening of the aziridine ring. However, in this instance, column chromatography on silica gel of the Schiff base (261) afforded an almost quantitative conversion into the previously unknown tricyclic aziridinyl ketones (262), a class of ketone characterized by great instability to air and light. The ethyl aziridinyl ketone (262; R = Et) undergoes a thermally disallowed valence tautomerism. This was shown by trapping the carbonyl ylide in a 1,3-dipolar cycloaddition reaction B. Levy and H. C. Brown, J. Amer. Chem. SOC.,1973,95,4067. H. C. Brown, M. M. Midland, and A. B. Levy, J . Amer. Chem. SOC.,1973,95,2394. R.J. Anderson, C. A. Henrick, and J. B. Siddall, U.S.P.3 179 666/1973 (Chem. A h . , 1973,78,136 03911). lgaD. L. Garling and N. H. Cromwell, J. Org. Chem., 1973,38,654. la@ A.

lgO lal

52

Saturated Heterocyclic Chemistry

(259)

(263) R1 = C02Me

with dimethyl fumarate. A mixture of isomers is obtained in which the endoproduct (263) appears to predominate. Ethyleneimine has been prepared, by a somewhat analogous procedure,l= by heating 1 ,ZdichIoroethane and ammonia for 30 min at 80 *C in the presence of 1,8-diazabicyclo[5,4,O]undec7-ene. Conversely, instead of treating an c+dihalogeno-alkane with an amine, it is possible to use NN-dihalogeno-amides and electron-deficient olefins. Thus, a series of sulphonamides (264) was brominated and the resulting NN-dibromo-compounds were heated with acrylic or methacrylic compounds in chloroform.l= Treatment of the resultant bromo-derivatives (265) with sodium hydroxide gave the respective aziridines (266). 133 134

F. Matsuda, T. Takahashi, and N. Ogiya, Japan. Kokai 74/14 456 (Chern. A h . , 1974, 80, 95 702u). M. Kojima and T. Kawakita, Japan. Kokai 73/36 148 (Chern. Abs., 1973,79,42 320r).

Three-membered Rings

53

1

R2CI-I=CR3 Y

R'

R1~ ( C H 2 h S 0 , N H C H R 2 C R 3 B r Y (265)

The cis- and trans-aziridinylphosphonates (268; R = H), related to phosphonomycin, have been prepared135by heating diethyl 1-bromopropene1-phosphonate (267) with liquid ammonia in a sealed tube. Treatment of (268; R = H) with phenyl isocyanate gave the corresponding aziridine (268; R = PhNHCO). Attempts to hydrolyse either cis- or trans-(268; R = H or PhNHCO) to the exact nitrogen analogue of phosphonomycin resulted in extensive polymerization.

R

MeCH=CBrP(0)(OEt)z

a Me

(267)

I N (268)

Oxirans can sometimes be used with advantage in the synthesis of aziridines, For example, cis-Zbutylene oxide on treatment with ammonia in methanol gives threo-3-aminobutan-2-01, which reacts with sodium hydrooxide to give ~is-2,3-dimethylaziridine.~~~ trans-Dimethylaziridine can be similarly prepared. Ethylene oxide137reacts with l-(N-methylamino)-3-arylpropanes (269) to afford ,9-hydroxy-amines (270), which on chlorination with thionyl chloride give N-(p-halogenoalky1)-N,a-dimethylarylethylamines (271). These on treatment with sodium hydroxide and sodium 2,4,6-trinitrobenzenesulphonate or silver perchlorate give the aziridinium salts [272 ; R = H, C1, or F; X = 2,4,6-(O,N),C6H,S0; or ClOa].

/"\ p-RCGH4CH2CHMeNHMe (269)

n

R (

185 ias 187

CH2CH2 +

p-RCdhCH&HMeN( Me)CH2CH20H (270)

A

\tCH2CHMe6(l

I

X-

B~-RCBH~CH~CHM~N(M~)CH~CH~C~

Me (272) (271) D. K. Berlin and S. Rengaraju, Proc. Oklahoma Acad. Sci., 1973,53,73 (Chem. Abs., 1973,79, 136 9181.1). C. A. Rowe, jun. and E. L. Stagryn, U.S.P. 3 717 628/1973, E. Zara-Kaczian, G. Deak, J. Hasko-Breur, and A. Neszmelyi, Acta Chim. h a d . Sci. Hung., 1973,79,433 (Chem. Abs., 1974,80, 82 524n).

Saturated Heterocyclic Chemistry

54

0 (274) R = H,Br, or Cl

(273)

A new synthesis for N-acylated aziridones (274) which have a chiral centre at C-3,from the corresponding L-acylamino-acids, has been described.13* The 3-substituted-1-benzyloxycarbonylaziridin-2-ones(274) and related compounds are prepared from the corresponding benzyloxycarbonyl Lamino-acids (273) by using a dehydrating agent, such as phosgene, thionyl chloride, or phosphorus oxychloride. The reaction must be carried out in THF at -20 to -30 OC,using triethylamine to neutralize the reaction solution exactly. A reaction mechanism is discussed. An advantage of this route is the fact that it does not involve abstraction from the asymmetric carbon during the cyclization reaction; therefore optical activity is retained in the product. With optically active aziridinones obtained by dehydrohalogenation of a-halogeno-amides, abstraction of halide occurs from the asymmetric carbon atom, and therefore partial racemization is possible. A somewhzt similar procedure, which does not utilize a dehydrating agent, has been used to prepare peptides containing an aziridine ring.139 Thus the peptide (275; Tos = 4-MeOC,H,S02) was cyclized, by heating it for 21 h at 60 OC with triethylamine in THF, to give the aziridine (276) in 94% yield. PhCH202CNHCH2CO-NH

XH-CONHCHXC02CHd'h

I I

H-C-OTos

Me (275)

I

Et3N-THF 60 "C, 21 h

PhCH202CNHCHeCO-N-CH-CONHCHKO2CH2Ph

\/

(276)

Lithium aluminium hydride is known to reduce certain substituted cyclohexanone oximes to amines. However, it has been reported140that 2-benzylidenecyclohexanone oximes (277), on reduction with lithium aluminium hydride, afford the corresponding 1-benzyl-l,2-epiminocyclohexanes(278), 138 13# 140

M. Miyoshi, Bull. Chem. SOC.Japan, 1973, 46, 212. K. Okawa, Japan. Kokai 73/36 158 (Cliem. Abs., 1973,79,42 848u). J. R. Dimock, W. A. Turner, P. J. Smith, and R. G. Sutherland, Cunud. J . Chern., 1973, 51,427.

Three-memberedRings

55

'OH (277) a; b; c; d;

R R R

=H = 2-CI = 4-C1

R = 4-NMe2

\

(279) a; R = H

LiAID4

(R = H)

I

H (283)

not the corresponding amines (279). Similarly reduction of 2-benzylidenecyclohexanone oxime (277a) with lithium aluminium deuteride gives the epiminocyclohexane (280), which contains two deuterium atoms. A possible reaction mechanism for the synthesis of the deuteriated product (280) is depicted in Scheme 20. Attempts to prepare the N-acetylaziridine (281) by acetylation of (278) with acetic anhydride gave 3-acetamido-2-benzylcyclohexl-ene (283). Formation of (283) from (278) presumably arises by pyrolytic cis elimination of the N-acetylaziridine via the transition state (282). The stereochemistry of the reduction of ap-unsaturated cyclohexene oximes by lithium aluminium hydride has been studied:" to establish (a) whether the formation of aziridines occurs when the olefinic bond is not substituted by L.Ferrero, M. Decouzon, and M. Azzaro, Tetrahedron Letters, 1973,4151. 6

Saturated Heterocyclic Chemistry

56

(277; R = H)

I

(280)

Scheme 20

a phenyl group (as was the case in all previous investigations) and (b) whether the configuration of the hydroxy-group of the oxime with respect to the conjugated system is a contributory factor. Reduction of E-2-methylcyclohex2-en-1-one oxime (284) gave the aziridine (285) (58%) as the major product, the azacycloheptane (286) (10 %), 1-methyl-6-aminocyclohex-1-ene(287) (19 %), and 7-aminoheptan-2-one (289) (13 %), which presumably arises by

Me

I -+I

c=o

(CH2)5

I

(285)

(286)

(287)

(288)

NH2 (289)

hydrolysis of the enamine (288). Reduction of Z-3-methylcyclohex-2-en-l-one oxime (290) gave the aziridines (291) (35%), (292) (35%), l-methyl-3aminocyclohex-1-ene (293) (13 %), and saturated amines (17 %). A 1:1 mixture of the 2-and E-oximes (290), since the E-oxime could not be isolated on its own, also gave a mixture of the aziridines (291) (27 %) and (292) (27 %), the amine (293) (17%), and saturated amines (29%). Thus it was concluded that in the reaction of lithium aluminium hydride with up-unsaturated cyclohexenone oximes (a) aziridine formation predominates over amine formation

Three-membered Rings

57

OH

I

O 'N

+

-

(290)

saturated amines

(293)

LiAIH1-THF

(290)

".i'

H

+

+ 'H (292)

and (b) ring closure to form the aziridine occurs in the direction of the carboncarbon double bond. It would also appear that the stereochemistry of the hydroxy group with respect to the C=C-C=N system is only of minor significance, a slightly increased yield of aziridines being obtained when the hydroxy-group was cis to the carbon-carbon double bond. A similar study has been made of the lithium aluminium hydride reduction of oximes of a-ethylenic carbonyl compounds.142Reduction of the Z-transoidoximes of pent-3-en-2-one (294; R = Me) and 4-phenylbut-3-en-2-one (294; R = Ph) gives the corresponding aziridines (295) and the amines (296). Reduction of the E-transoid-oximes (297; R = Me or Ph) gives in addition the corresponding aziridines (298) and the saturated amines (299). E-cisoid-2-

(294)

R C-N

/

\OH

-

(295)

(296)

R (295)

+ (296) +

+R\NH2

NH (298)

(297)

(299)

Cyclopentylidenecyclopentanoneoxime (300) also gives an aziridinereduction product (301), as well as a ring-expanded 2-cyclopentyl-3,4,5,6-tetrahydropyridine and 2-cyclopentylpiperidine.The formation of aziridines fromZ-oximes

+w

/N 142

Ho (300) (301) G. Ricart, D. Couturier, and C. Glacet, Compt. rend., 1973,277, C,519.

58

Saturated Heterocyclic Chemistry

was found to be independent of solvent polarity and temperature, but aziridine formation from E-oximes increased with temperature and solvent polarity. The preparation of fatty-acid derivatives containing an internal aziridine function continues to be a subject of interest. A procedure utilizing the stereospecificaddition of iodine azide to the unsaturated compound, followed by reductive cyclization to the aziridine, has been r e ~ 0 r t e d . For l ~ ~ the latter step, unlike the work of Brown and Levy129discussed earlier in this section, several hydride reducing agents and also direct hydrogenation over metal catalysts were investigated as ways of forming the aziridine. A comparison of the various reagents studied, namely lithium aluminium hydride, sodium bis-(2-methoxyethoxy)aluminium hydride, diborane, and catalytichydrogenation, showed that the best yields (59 %) of epimino-derivativeswere obtained with lithium aluminium hydride. Direct hydrogenation gave the poorest yield (2 %). Thus reduction of methyl threo-9-azido-10-iodo-octadecanoate with lithium aluminium hydride produced the cis-9,lO-epimino-derivativeof octadecanol by concomitant reduction of the ester function. The versatility of the b-iodo-azides as precursors in organic chemistry is illustrated by their reactions with trialkyl phosphites. The iodo-azides (302) react immediately with trimethyl phosphite in hexane, affording the dimethylphosphonoaziridines (303). Since this rearrangement involves one inversion at carbon, the aziridines (303) have a cis geometry.

I

Me0

OMe

(303) a; R1 = R2 = C8H17 b; R1 = C8HI7,R2 = C7HI4CO2Me

Treatment of exo-lY4-dihydro-l,4-methanonaphthalene with nitrosyl chloride yields the dimer (304), which is reducedlMwith lithium aluminium hydride to the em-cis-1a ,2,7,7a-tetrahydro-1H-2,7-methano [2,3-b]aziridinonaphthalene (305; R = H). Treatment of (305; R = H) with toluene-psulphonyl chloride gives both the exo- and endo-l,2,3,4-tetrahydro-2-@tosylamido)-l,4-methanonaphthalenes and the aziridine (305; R = pMeC,H,SO,).

148

T. A. Foglia, P. A. Barr, and 1. Schmeltz, J. Amer. Oil. Chemists’ SOC.,1973,50, 290. S. J. Dominianni, U.S.P.3 715 262/1973 (Chem. A h . , 1973,78,136 040f).

Three-membered Rings

59

(306)

(307)

Reaction of cyclohexene with ethyl NN-dibromoaminoformate affords a mixture of the trans-bromocyclohexylaminoformate(306) and its cis-isomer. Reduction of this mixture145 with lithium aluminium hydride gives the Nmethylaziridine (307) (90 %) and cyclohexylmethylamine(10 %). Cycloheptene gives a similar series of reactions. Ring Contraction. Organic azides often undergo 173-dipolarcycloaddition to strained cyclic olefins to give A2-triazolines, which on decomposition yield aziridines. For example, the photodecompositions of the exo-A2-triazoline adducts derived from a series of bicyclo[2,2,1]heptenes are known to result in the loss of nitrogen with stereospecific formation of the corresponding exo-3-azatricyclo-octanes.The reactions of a series of bicyclo[2,2,l]heptadienes (308) with phenyl azide have now been examined146and the resultant A2-triazolines(309) and (310) characterized. Photolysis of these compounds, (309) and (310), provides a convenient route, with good yields, to several exo- and endo-azatricyclo-octenes(3 11) and (312).

(309)

ihV R'

0.Cervinka, V. Dudek, and V. Senft, 2.Chem., 1973,13, 176. B. Halton and A. D. Woolhouse, Austral. J. Chern., 1973,26, 619.

lP6

lP6

1".

60 Saturated HeterocycZic Chemistry A more convenient synthesis of the indano [1,2-b]aziridin-6-onesystem (315) has been re~0rted.l~'The key intermediate is an indano [2,1-d]triazoline, which can be easily converted into aziridines. Indenone (313), prepared by an improved method, was treated with phenyl azide at 0 *C in the dark for 3 days and gave the A2-1,2,3-triazoline (314). Triazolines of this type containing an electron-withdrawing group in the 4-position are frequently unstable or exist in an equilibrium with the isomeric amino-azo-compound, but no such difficulties were experienced with the adduct (314). Photolysis in benzene gave the aziridine (315) (65 %). Ph

(3 14)

(3 13)

(315)

lY2-Diphenylazaspiro [2,2]pentane (3 17), a nitrogen analogue of the oxaspiropentanes that have been the subject of much interest, has been prepared148 by irradiation at 3100 in dichIoromethane of the A2-1,2,3-triazoline(316), the thermal adduct of phenyl azide and benzylidenecyclopane. Although (317) is stable at 0 'C, thermal rearrangement occurs at 100 O , affording the imine (318), a process which is analogous to the oxaspiropentane-cyclobutanone isomerization. The spiroaziridine (317) reacts readily with methanol to give the solvent adduct (319).

?[ TAPh <:: hv

Ph (316)

Ph

hat,

:

Ph (3 17)

(3 18)

Ph (3 19)

Formation via Azirines. The 3-phenyl-2H-azirines (321; R = Ph or H) undergo 1,3-dipolar cycloaddition reactions with N-(pnitrobenzy1)benzimidoyl chloride (320) in benzene, at 0 "C in the dark under nitrogen, yielding149 14' 149

P. E. Hansen and K. Undheim, Acta Chem. Scand., 1973,27,1112. J. K. Crandall and W. W. Conover, J.C.S. Chem. Comm., 1973,33. N. S. Narasimhan, H. Heimgartner, J. H. Hansen, and H. Schmid, Helu. Chim. Actu, 1973,56, 1351.

Three-memberedRings

61

c1

+ P

’-NH h F C‘H

OINCL

‘NHCOPh

2- ( p i trophenyl)-4,5-diphenyl-1,3-diazabicyclo[3 ,1,O] hex-3-enes (322). Under the basic conditions of the reaction, (322; R = Ph) and (322; R = H) are partially converted into 2- (p-nit rophenyl)-4,5-diphenyl-1,6-dihydropyrimidines (323), which are oxidized to the corresponding pyrimidines (324). Only when R = Ph is the aziridine (325) also formed. The 3-phenyl-2Hazirines (321), on heating with 2,4-diphenyl-A2-oxazolin-5-one (326) in xylene at 145 *C,give 4-(aziridin-2’-yl)-2,4-diphenyl-A2-oxazolin-5-ones (327). The aziridines (327) arise by an ene reaction of the enol form of (326) with the azirine (321).

(327)

It is well known that the reaction of Grignard reagents with oximes usually affords aziridines, and it has been postulated that such reactions proceed by way of azirine intermediates. In the case of acetophenone oxime Laurent et claim to have isolated the intermediate 2-phenylazirines. They have 160

R. Chaabouni, A. Laurent, and P. Mison, Tetrahedron Letters, 1973, 1343.

Saturated Heterocyclic Chemistry

62

/ / (328) a; R = Ph b; R = Me

cis-(329) a; 75% b; 60%

cis

P

trans

trans-(330) a; 25% b; 40%

(331)

also the reactions of E-2-phenyl- and E-2-methyl-cyclohexanone oximes (328; R = Ph or Me) with methylmagnesium bromide. Each reaction gave only two major products, the cis- and the trans- bycyclic aziridines (329) and (330). No aziridines of the type (331) were detected, thus confirming the regiospecificity and stereospecificityof this reaction. The configurations and conformations of (329) and (330) were determined from their l H and lSC n.m.r. spectra. Treatment of cyclohexanone oxime with methyl- or ethylmagnesium bromide affords the corresponding 1-methyl- or 1-et hyl-7-azabicyclo [4,1 ,O]heptane, but treatment with phenylmagnesiumbromide gives only cyclohexanone and aniline.151However, when cyclohexanone oxime is treated with phenyl-lithium, 1-phenyl-7-azabicyclo[4,1 ,O]heptane (332) (59 %) and N-phenyl-(l-pheny1)cyclohexylamine (334) (33 %) are formed. The products are thought to arise by two competitive reactions (Scheme 21). The intermediate ketimine (333) would explain both the formation of the amine (334) and that of aniline in the reaction with phenylmagnesium bromide, hydrolysis of the imine affording cyclohexanone and aniline. Reactions.-Ring-opening. Electrophilic and nucleophilic. Dichlorocarbene, prepared in situ from chloroform and potassium t-butoxide, is reportedls2 to react with N-benzylaziridine to give l-(t-butoxy)-2-(N-benzylamino)ethane and its N-formyl derivative. No N to C rearrangement products were detected. The products are rationalized in terms of reactions subsequent to ylide lS1 lS2

R. Chaabouni and A. Laurent, BUN.SOC.chim. France, 1973,2680. A. G . Giumanini, Boll. Chim. Farm., 1973, 112, 6.

Three-membered Rings

63

1

(332)

u (333) N ’ p h (334) Reagents: i, 2PhLi; ii, PhLi; iii, Ha0

Scheme 21

formation. N-Cyclohexyl-1-alkylaziridines(335; R = Me or H) on the other hand153react with dichlorocarbene, generated by refluxing sodium trichloro- . acetate in glyme, to give dichloromethanimine (336) (30-40 %). R

(335)

036)

Vaultier et aZ.lMhave reported that the reactions of nucleophiles with aziridines, potential azomethine ylides, may in some instances be catalysed by acid. For example, the aziridine (337; R1 = R2 = C02Me)when treated with trifluoroacetic acid ring-opened to give the immonium salt (338), but the aziridine (R1= H, R2 = C02Me)gave the amine (341). The immonium salts, which were not isolated but detected by lH n.m.r., reacted readily with potassium cyanide, methylmagnesium iodide, or potassium borohydride to give the amino-esters (340; R = CN, Me, or H). Formation of the immonium salt (338) or the amino-ester (339) depended on the strength of the nucleophile A-. Two ring-opening reactions are therefore possible when aziridines are treated with acid and these are summarized in the sequence (337)-(341). The selective methylation of 2,2-dimethyl-4-phenyl-6-p-nitrophenyl-1,3diazabicyclo[3,1,O]hex3-ene (342) by trimethyloxonium tetrafluoroborate to form 2,2,3 t rimeth y l 4 p hen yl-6-p-nitrophenyl- 1-aza-3-azoniabicyclo [3,1,0]hex-3-ene tetrafluoroborate (343) has been achieved.155When the tetrafluoroborate (343) is treated with diazomethane a novel transformation occurs,

-

153 15*

ls6

V. I. Markov and A. E. Polyakov, Zhur. org. Khim. 1973,9,1759 (Chem. Abs., 1973, 79, 126 175k). M. Vaultier, R. Danion-Bougot, D. Danion, J. Hamelin, and R. Carrib, Tetrahedron Letters, 1973, 2883. H. W. Heine, T. A. Newton, G. J. Blosick, K. C. Irving, C. Meyer, and G. B. Corcoran, tert., J., Org. Chem., 1973,38,651.

64

Saturated Heterocyclic Chemistry

PhCH-CR'R2 N ''

-. PhCH CR'RB \b/

I

I Ph

Pi1

(337)

Hf PhCH CHR1R2,A'

PhCH-CR1R2, A-

\&/

\&I I

/ \H

Ph

Ph

(338)

1

J/' \-

PhCH-CRlR2

I

A

PhCH-NAHR'R'

I

I

NHPh

A

(341)

t

PhCH-NAHR'R*

I

R

Ph

I

Ph

(340)

(339)

affording the ring-opened compound (345), presumably via the intermediate aziridinium ion (344). The intermediacy of (344) seems quite reasonable, since it is well known that addition of diazomethane to ternary iminium salts is a general method for the preparation of aziridinium salts. H

H

(342)

ArCH=NCH=C

/Ph

\

Ye

(343)

c-

CH2y=CMe2 BF;

(345)

(344)

The novel tricyclic system 2-azatricyclo[2,2,1,01a6]heptane(346) is formed156 when 4- (aminomethyl)cyclopentene is oxidized with lead tetra-acet ate in refluxing benzene. The aziridine (346) is rather unstable and is best converted 156

P. S . Portoghese and D. T. Sepp, Tetrahedron, 1973,29,2253.

Three-memberedRings

65

Pb(OAc)4- bznzene

8

,

H (349)

+ Me1

I

I

H

hl\e

OAc

(348)

without isolation into its methiodide salt (347) which is quite stable. Reaction of (347) with potassium acetate in refluxing ethanol gives N-methyl-exo-6acetoxy-2-azabicyclo[2,2,l]heptane (348), which on reduction with lithium aluminium hydride gives the exo-alcohol (349). Equilibration of (349) with aluminium isopropoxide gives an exo:endo ratio (83 :17) similar to that obtained with norborneol (80:20), indicating that the steric requirements of the N lone pair are similar to those of CH. DipoZar cydoaddition. 2 ,2-Dimethyl-4-phenyl-6-p-nitrophenyl-1,3-diazabicyclo[3,1,O]hex3-ene 3-oxide (350), formed when 2,2-dimethyl-4-pheny1-6p-nitrophenyl-l,3-diazabicyclo [3,1,0]hex-3-ene, (342) is treated with rnchloroperbenzoicacid in benzene at room temperature, forms an azomethine ylide when heated.155 In refluxing toluene with N-phenylmaleimide and diethyl azodicarboxylate, (350) gives the cycloadducts (351) and (352), respectively. Interestingly, irradiation of a benzene solution of (350) and

66

Saturated Heterocyclic Chemistry

diethyl azodicarboxylatealso gives (352) identical in all respects to the product from the thermal reaction. It has been reported15' that N-alkoxyaziridines react with nitriles in the presence of boron trifluoride etherate, thus affording a new route to 2imidazolines. The N-alkoxycarbonylaziridines (353a) and (353b) with acetonitrile or benzonitrile give the corresponding l-alkoxycarbonyl-2-imidazolines, (354ax), (354ay), and 354bx). The imidazolines obtained by the reaction of N-ethoxycarbonyl-2,3-tetramethyleneaziridine (353c) with acetonitrile or benzonitrile are labile and are readily hydrolysed to trans-cyclohexan-l,2diamine derivatives (355cx) or (355cy). The mechanism of the reaction, since

'>

C02R3 R1

N --COzR3

R1

\

I

R4CN-BF3,Et20

R2

(353) a; R* = H, R2 = Ph, R3 = Me, b; R1,R2= +CH2CH2CH=CHCH&H2)-, R3 = Et R3 = Et C; R',R2 = dCH&-, x; RJ = Me v; R4 = Ph

(354)

(355)

82%

the presence of a Lewis acid is necessary, is not thought to involve direct nucleophilic attack by the nitriles. Boron trifluoride is thought to co-ordinate to the oxygen atom of the carbonyl group, whilst the nitrile attacks the aziridine ring to afford a zwitterion, which subsequently cyclizes to the 2-imidazoline (Scheme 22). The stereochemistry suggests an S,Ztype mechanism.

0

IJ-

COzEt

BF3

i.

I

Scheme 22

By contrast, N-tosylaziridine reacts with methyl or ethyl 2-cyanoacetates (356; R = Me or Et), in the presence of the corresponding alkoxide, affording the 3-alkoxycarbonyl-2-amino-1-tosyl-2-pyrrolines (357; R = Me or Et) in yields of 42 and 23 %, respective1y.lm 15' lS8

T. Hiyama, H. Koide, S. Fujita, and H. Nozaki, Tetrahedron, 1973,29,3137. J. Lehmann and H. Wamhoff, Synthesis, 1973, 546.

Three-membered Rings

67

v+

Gco2"

C82R

I

((Ha

RO',

NH2

I

N fl

40s

Tos

(356)

(357)

Texier et al. have studied the cycloaddition reactions of 2-cyano-3-phenylaziridines to some alkynes and activated a l k e n e ~ The . ~ ~erythro-aziridines ~ (358 ; R = cyclohexyl or PhCH,) reacted with dimethyl acetylenedicarboxylate in boiling toluene to give pyrrolines which spontaneously eliminated hydrogen cyanide to afford the pyrroles (359) in quantitative yield. Under similar conditions the aziridines (358) reacted stereospecificallywith activated w

Ph---\-/--CN N

MeO2C-CEC--CO2Me

0

2

M

e

~

I

I

Ph

R

R (359)

(358)

olefins (360; X = H, CN or C0,Me; Y = C0,Me or CN; Z = CO,Me, CN, Ph, p-ClC6H4, or p-MeOC6H,) to give pyrrolidines, primarily (361) Ph, XYC=CHZ

f

,cN ,

'v'

(360)

toluene

(358)

Meo2ck-F Meo C02Me

Ph

16@

CO2Me

Ph

b

r3

(366) (365) F. Texier, J. Guenzet, and B. Merah, Compt. rend., 1973,277, C, 1371.

Saturated Heterocyclic Chemistry

68

and (362), with smaller amounts, if any, of (363) and (364). The pyrrolidines (361) and (362) when R = cyclohexyl, X = H, and Y = 2 = C02Me eliminated hydrogen cyanide during their purification to give (365) and (366) respectively. Aziridines are known to react with alkylidenephosphoranes, yielding 3pyrrolines. It has now been shown160that such reactions are kinetically controlled, and that the mechanism of a reaction depends on the structure of the phosphorane, which can behave either as a reactive nucleophile or as a dipolarophile. The type of product formed also depends, as one might expect, on the class of ylideused. When the aziridine (367), dissolved in either benzene, THF, or a THF-DMSO mixture, is treated at room temperature with sulphide or sulphoxide ylides (368 and 369; R1 = H, R2 = H, CO,Me, CO,Et, Bz; R1, R2 = fluorenyl) the isomeric azetidines (370) and (371) are formed in

N

I

Ph (367)

(370)

(368) Me2S=C

(371)

/R1

\ R2

' R 2

quantitative yield.161The reaction is immediate and accompanied by the formation of dimethyl sulphide or dimethyl sulphoxide. The azetidines are thought to be formed (Scheme 23) by the addition of the sulphur ylide to the azoPhkH (367)

R1 $Me2 \I3

C(C02Me)?

\"

I Ph

w

R2-;:

7C02Me)2

Ph x y N , C (

I

(3 72)

J J;:73,

(370)

+

(371)

Scheme 23 l60

M. Vaultier, R. Danion-Bougot, D. Danion, J. Hamelin, and R. Carrie, Compr. rend., 1973,277, C, 1041. M. Vaultier, R. Danion-Bougot, D. Danion, J. Hamelin, and R. Carrib, Tetrahedron Letters, 1973, 1923.

Three-memberedRings 69 methine ylide (372),which is in equilibrium with the aziridine (367)at room temperature. The betaine (373) thus formed cyclizes with elimination of dimethyl sulphide or dimethyl sulphoxide, depending on the ylide used. Although several a-lactams have been prepared, few reactions of these compounds have been studied in detail. Previous studies have shown that the thermal decomposition of all a-lactams involves fragmentation to a carbonyl compound and an isocyanide, and, depending on the conditions, other unidentified products have also been observed. A detailed study has now been made162 of the pyrolysis of 1,3-di-(1 -adamantyl)aziridin-2-one (374;R = 1-adamantyl) in a sealed tube at 115-160 "C. The ring-expansion product, 1,3-di-(l-adamantyl)4-(l-adamantylimino)-2-azetidinone(378),was the major product isolated but the aldehyde (376)and the isocyanide (377) were also detected. When equimolar mixtures of (374)and (377)were heated, the same ring-expandedproduct (378)was produced. This observation suggests that the azetidinone is produced by cycloaddition of (377) to either (374) or an isomer obtained by thermal rearrangement of (374), which may be the elusive imino-oxiran (375).

1 (375)

(374)

(376)

(378)

Rearrangement. The acetolysis reactions of a series of benzenesulphonylbenzobicycloheptaneaziridines,prepared by the action of benzenesulphonyl azide on the corresponding substituted benzobicycloheptanes, have been studied.ls3For example the aziridine (380), prepared by treating the benzonorbornene (379)with benzenesulphonyl azide in anhydrous benzene, although a somewhat unstable oil gave spectral data consistent with its structure and the expected exo stereochemistry. Acetolysis was accomplished by heating the compound to 100°C in glacial acetic acid. Under these conditions the ring opened with rearrangement to afford the products (381)and (382)in the ratio 94:6. For these products to be formed the aziridine ring must open E. R. Talaty, A. E. Dupuy, jun., C. M. Utermoehlen, and L. H. Stekol1,J.C.S. Chern. Comm., 1973,48. le3 K. Wiesner, Ho Pak-Tsun, R. C. Jain, S. F. Lee, S. Oida, and A. Philipp, Cunad. J . Chem., 1973, 51, 1448. 162

Saturated Heterocyclic Chemistry

70

COpMe

I

P h S 0 2 N H m

COzMe

AcO

-

(381) 947;

(379)

A

AcOH

c

+O

m

PhS02NH-

(382) 6 %

with rearrangement and the resulting carbonium ion react with acetic acid. This process is depicted by arrows in formula (380) and leads to the product (381). An exactly analogous process initiated by opening of the second carbon-nitrogen bond yields the product (382). Product (381) predominates since the formation of compound (382) requires the development of a carbonium ion adjacent to a carbonyl group, a situation known to be energetically unfavourable. The influence of various substitution patterns on the direction of the aziridine rearrangement is also discussed, and it is shown that the rearrangements may be used as a suitable approach to the synthesis of ring B-bridged diterpenoid a1kaloids In the presence of small amounts of ammonium bromide, the cyclic imidic ester 3,4,5,6-tetrahydro-7-methoxy-2H-azepine (383 ; It = 3) undergoes a mild exothermic reaction with the aziridines (384; R = H or Me) to yield l-iminomethyl-substitutedaziridines (385).f64When heated with iodine in acetone, the aziridines (385; R = H or Me) rearrange to 1,8-diazabicyclo[5,3,0]dec-7-enes (386). These strongly basic compounds can be used as dehydrohalogenation reagents. Ring Retention. 2-Methoxy-l-pyrroline (383 ; n = 1) and ethyl N-phenylforminidate, in the presence of ammonium bromide,ls4 also give exothermic reactions with aziridine (see previous section), yielding the aziridines (387) and (388) respectively. No rearrangement reactions were reported. The carbamate (389), prepared by reaction of p-methoxycarbonylphenyl chloroformate with an excess of p-aminophenol, gives the phosphorodichloridate (390) in almost quantitative yield when treated with equivalent amounts of phosphorus oxychloride and triethylamine. The aziridines (391 ;R = H or Me) couple with the dichloridate (390) at - 10 to - 15 *Cto givels6 bis-(l-aziridiny1)phosphinyl alkylating agents (392) which contain O-phenyl N-phenylcarbamate side-chains. By conducting the reactions at these low temperatures transamidation of the carbamyl groups, a major sidereaction at 0 "C,is avoided.

.

1G4

D. Bormann, Angew. Chern. Internut. Edn., 1973, 12,768.

1e6

Y.Y. Hsiao and T.J. Bardos,J. Medicin. Chem., 1973,16,391.

71

Three-membered Rings

(383)

I

- MeOH = 1 (384; R = H)

Ph-N=C,

/

-&OH

'OEt

(389)

6

(384; R = H)

'

Ph-N=C,

/ \

P

72

Saturated Heterocyclic Chemistry

Carboxylic acid P-(N-ethy1eneimino)ethylamides (394; n = 0, 1-4, or 8 ) are reported to be formed166when the corresponding diallyl dicarboxylates (393) are treated with ethyleneimine at 50-95 "C in the presence of triethylamine or sodium ethoxide. The diamides (394) polymerize at their melting point owing to opening of the aziridine ring. H~C=CHCH202C(CH&COzCHzCH=CHa

(393)

0 0 ~-CH2CHpNflC(CH2),CNHCH&Hp-N II II

3

(394)

The photochemical or thermal reactions of the hexacarbonyls of chromium, molybdenum, and tungsten with aziridine (in), in THF, yield the complexes (395; n = 1, 2, or 3).ls7 The cis-bis(aziridine)tetracarbonylmetal compounds M(CO)s

3

+ nHN

3

M(CO)s-n(HN

)n

(395) (395; n = 2) in the presence of protic solvents yield the chelate complexes (396) with N-(2-aminoethyl)aziridine (diin) as the ligand. A possible sequence of events which would account for the formation of the complexes (396) is depicted in Scheme 24.

a'7

H

H

'.3 +

(c0)4M,q/

/ H N \ 4

(CO),M

-.NJ/

NHzCHzCHz

/

H (395;n = 2)

/o.

/ (396) Scheme 24

lB6 16'

V. N. Andronov, V. A. Aleksandrova, V. G. Avakyan, and D. S. Zhuk, Zzuest. Akad. Nauk S.S.S.R.,Ser. khim., 1973,140 (Chem.Abs., 1973,78,147 696a). R.Hoefer, W. Beck, and A. Engelmann, Chem. Ber., 1973,106,2590.

Three-membered Rings 73 The preparation of (r-MeC,H,)Mn(CO),(in) and of (m-MeC,H,)(CO),Mn(diin)Mn(CO),(r-MeC,H,) is also reported, and the structure and bonding of each complex are discussed on the basis of its i.r. spectrum. 2-Methylaziridine is reported to react with paraforma1dehydel6*in the presence of Triton B to give (N-2-methylaziridiny1)methanol(397;R = OH)

(86 %). In the presence of potassium carbonate, the reaction yields the same aziridine (397; R = OH) (77%) and di-(2-methylaziridinyl)methane (5%). The aziridine (412; R = OH) reacts with amines to give the amino-derivat ives (397; R = piperidino, 2,6-dimethylpiperidino, 2,2,6,6-tetramethylpiperidino, morpholino, or ;dicyclohexylamino), of which (397; R = 2,6dimethylpiperidino or dicyclohexylamino) react with acetyl chloride to give 1-acetyl-2-methylaziridine and] RCH,CI, whereas 2,2,2-trichloro-l -(N-aziridinyl)ethanol(398)reactswith dialkyl chlorophosphites16gin the presenceof triethylamine to form the corresponding esters (399;R = Et, Pr”, Pri, or Bu).

cc13

(399)

(398)

4 Thiirans

Formation.-Carbon Atom Insertion. Compounds which contain a thiocarbony1 group can often be converted into the corresponding thiiran when treated with diazoalkanes. The scope of this reaction has been investigated and a reaction mechanism proposed. With diazomethane170 in ether at - 5 ‘C, aliphatic thioketones give thiirans as the principal products, plus methylthioalkeneswhich, interestingly, have the least substituted double bond. For example, 3-methylbutan-2thione (400) affords the thiiran (401) and the methylthioalkene (402). The latter must arise via 3-methylbut-l-ene-2-thiol. Under the same conditions 3-methylbut-2-ene-2-thiolyields almost quantitatively 3-methyl-2-(methylthio)but-2-ene. When the thioketone cannot enolize, a thiiran is the only 16*

160 170

G. Zinner and W. Kilwing, Chem.-Ztg., 1973, 97, 156. N. P. Grechkin and N. L. Grishina, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1973, 1883 (Chem. A h . , 1974,80,47 725g). J. M. Beiner, D. Lecadet, D. Paquer, A. Thuillier, and J. Vialle, Bull. SOC.chirn. France, 1973, 1979.

Saturated Heterocyclic Chemistry

74 Me

I

SMe

Me

Me--C--C-Me SI I HI

CH%N2,

hk,,c>\7

(400)

Me

&/-Me

\H (402) 25%

(401)70%

product. For example phenyl t-butyl thioketone yields 2-phenyl-2-t-butylthiiran, which decomposes readily on heating to 2,2-dimethyl-3-phenyIbut-3ene. The aliphatic dithioesters (403; R = Me, Et, or Pr') afford the methylthiothiirans (404; R1 = R2 = H), which on heating lose sulphur to yield methylthioalkenes (405; R1 = R2 = H). Methyl dithiobenzoate and thionoesters, however, give cis- and trans-lY3-dithiolansand 1,2,3-thiadiazolinesY respectively, as the principal products, no thiirans being detected. S

Rd-SMe

R1R2cN2,

"x,h:l

MeS (403)

(404)

R MeS (405)

With diazoethane and 2-diazopropane,171 3,3-dimethylbutan-2-thione affordsthe thiirans (406; R = H or Me) and the alkylthioalkenes (407;R = H or Me). With the non-enolizable thioketone t-butyl phenyl thioketone (408), the thiirans (409; R = H or Me) and their decomposition products (410; R = H or Me) are formed. With diazoethane the aliphatic dithioesters (403; R = Me, Et, Pr', or Bu:) yield the methylthiothiirans (404; R1 = Me, R2 = H) and their decomposition products (405; R1 = Me, R2 = H); analogous products are obtained when the dithioesters (403; R = Me or But) are treated with 2-diazopropane. In contrast to the results obtained with

171

J. M.Beiner, D. Lecadet, D. Paquer, and A. Thuillier, Bull. SOC.chim. France, 1973, 1983.

Three-memberedRings

- lhTA:e R20

R1-C--OR2

II S

75

+

H S R 1 - CI - C II4 R 2

I

R

\ R20

Me (when R1 = Ra = Me)

\

R' /c=cHMe

Scheme 25

diazomethane, both diazoethane and 2-diazopropane react with thionoesters to give thiirans. For example, the thionoesters (411; R1 = R2 = Me; R1 = Ph, R2 = Me) afford the corresponding thiirans plus decomposition products (Scheme 25). Although it is possible to rationalize the formation of the thiirans in terms of carbene cycloaddition reactions, this possibility was ruled out by the isolation and/or detection of thiadiazolines in many of the reactions; especially when the reactions were carried out at -70 "Crather than the usual -5 "C. Therefore it was concluded that the formation of thiirans, by the action of diazoalkanes on thiocarbonyl derivatives, proceeds via intermediate A2-1,2,3thiadiazolines and/or A3-l ,3,4-thiadiazoliies (Scheme 26). S

II

R' 4 - R 2

.1" R2 R1W

.R3

R

4

Scheme 26

Met~nerl'~has studied the reactions of up-ethylenic thioketones with diazoalkanesin ether. The typeof product formed depends on the diazoalkane, the reaction temperature, and the order of addition of the reactants. When 3,6,6-trimethylcyclohex-2-en-l-thione (412) was treated with diazodiphenylmethane and diazophenylmethane at 20 OC the spiro-thiirans (413; R = Ph 179

P. Metzner, Bull. SOC.chim. France, 1973, 2297.

Saturated Heterocyclic Chemistry

76

(4 12)

(413)

or H) were formed in 70% and 50% yields, respectively. SimiIarly 3,5,5trimethylcyclohex-2-en-1-thione(414) gave, when treated at 20 "C with diazodiphenylmethane, the thiiran (415; R = Ph) (75 %). However, at 20 "C the thione (414) gave the dithiolan (417) (85%) when treated with diazomethane. The thiiran (415; R = H) (45%) and the olefin (416) (20%) were formed when a reaction temperature of -60 "C was used.

A

dR+ A P

(R (R =RzCNz Ph, H, -60°C) 20 "C)

,

(414)

I

I

CHzN2,20 "C

s-s

Perchlorothiiran (418; R = C1) can be prepared by the reaction of phenylmercury bromodichloromethane with sulphur or thiophosgene, in benzene at 70 "C under an atmosphere of nitrogen.173Thiophosgene is thought to be an intermediate in the reaction with sulphur. Similarly, diphenyl thioketone gave the thiiran (418; R = Ph). A cycloaddition reaction of dichlorocarbene, formed by thermolysis of the phenylmercury trihalogenomethane, would account for the products formed. PhHgCClzBr

+

S or

$'$"+

csc12 or Ph&=S 173

wi

C1

+ PhHgBr

C1

(418) R = C1 or Ph

D. Seyferth and W. Tronich, U.S.P. 3 717 660/1973 (Chern. A h . , 1973,78,125 128q).

Three-membered Rings 77 Sulphur Atom Insertion. A unique and useful route to thiirans involves the reaction of an oxiran with thiocyanate ion. Thus, the insecticidal thiiran (419), ethyl 10,l l-epithio-3,7,1l-trimethyldodeca-2,4-dienoate,was preEt O2CCH=CMeCH=CHCH2CHMeCHzCHz

: M =

(4 19)

pared174 by treating the corresponding oxiran with aqueous potassium thiocyanate. The oxiran was synthesized by epoxidizing ethyl lrans-3,7,11t rimethyldodeca-2,4,1O-trienoate with m-chloroperbenzoic acid. Cyclization. The addition of acetyl chlorosulphide to the unsaturated esters or amides (420; R1, R2,RS = H or Me; X = OMe, NHPh, OH, or OEt) is reported175to afford mixtures of the p-halogeno-a-S-acetyl disulphides (421) and (422). The isomer (422) was predominant except in reactions with anilides of methacrylic acid and esters of 3-methylbut-2-enoic acid, which gave only isomer (421). Removal of the acetyl groups from isomer (421) with alcoholic hydrogen chloride gave a p-chloromercaptan and free sulphur. With sodium bicarbonate the mercaptan cyclized to the thiiran (423).

-

R2

\ /R3 AcSCl R'/"="\ cox (420)

AcS2CR'R2CCIR3COX (422)

+ CICR1R2CR3(COX)SpAc (j;l&Aic

HCl

1

(423)

Miscellaneous. The cycloadduct (424; R = Ph), obtained from methyl isot hiocyanate and 3-benzyl-4-methyl-5-(2-hydroxy)ethyl thiazolium ylide, with liquid ammonia in a sealed tube at room temperature for 20 h yields the t hiiran 3-phenyl-6,8-dimethyl-2,9-dithia-4,6,8-triazatricyclo [3,3,0,11*5]o~t-3ene (425; R = Ph) (83%).176The reaction of the p-nitrobenzyl derivative (424; R = p-N0,C,H4) with liquid ammonia is complete within 3 h, but the 174

175

176

J. B. Siddall and C. A. Henrick; (a) U.S.P. 3 723 462/1973; (b) U.S.P. 3 775 432/1973 (Chem. A h . , 1974,80,59 849p). N. M. Karimova, M. G . Lin'kova, 0. V. Kil'disheva, and I. L. Knunyants; ( a ) U.S.S.R.P. 376 378/1973 (Chem. A h . , 1973, 79, 78 594x); (b) Zzuest. Akad. Nauk S.S.S.R., Ser. khim., 1973, 1788 (Chem. Abs., 1974,80, 70 619j). A. Takamizawa and S. Matsumoto, Chem. and Pharm. Bull. (Japan), 1973,21,1300.

Saturated HeterocycZic Chemistry

78

"'Q.

isolated yield of the thiiran (425; R =p-NO,C,H,) varies from 15 to 30% because of the unstable nature of the product. In this case the 5'4minoderivative (426; R = p-N0,C6H4) is also formed. The imino-compound (426) is the only product when the cycloadduct (424; R = H) is treated with ammonia. Reaction of liquid ammonia with the p-methoxybenzyl derivative (424; R =p-MeOC,H,) gives only a trace amount of the thiiran (425; R =p-MeOC,H,). When the thiirans (425) are heated in toluene at 100 O C , sulphur is readily lost to give quantitatively the corresponding 2-aryl-4,6dimethyldihydroimidazo[4,5-d]thiazole-5-thiones(427). A possibIe mechanism for this unique decomposition is depicted in Scheme 27.

-H+,

R/C"

Three-mem bered Rings

79

Alkyl thioglycidyl sulphides (428; R = C4-ro n-alkyl) can be prepared1'' in 34-53 % yields by treatment of thioepichlorohydrin with n-alkanethiols at 60 O C in the presence of 27 % aqueous sodium hydroxide.

Episufphoxides. Methods for the synthesis of episulphoxides using metaperiodate or perbenzoic acids in dichloromethane, the thermal decomposition of episulphoxides and the trapping of sulphur monoxide with conjugated olefins, the addition reactions of episulphoxides with thioketones, and the thermal decomposition of episulphoxides substituted with alkyl groups have been re~iewed?'~ The normal reaction of sulphines with diazoalkanes is reported to involve a concerted 1,3-dipolar cycloaddition to give A3-1 ,3,4thiadiazoline 1-oxides. However, the introduction of bulky substituents into either of the reactants appears to hinder this cyclization sterically and gives rise to alternative reaction routes, of which the non-stereospecificformation of episulphoxides is the most interesting Thus, the isomeric mesityl phenylsulphonyl sulphines (429a) and (429b) reacted easily with 2-diazopropane in benzeneether (1 :1) at - 10 *C to give a 1:1 mixture of diastereomeric episulphoxides in 72.5 % yield, irrespective of which sulphine isomer was used. The product mixture 0

a

\S

\S02Ph

MezCN2,

PhS02,

\

(429)

[or the Z-isomer (429b)I

t

\

Scheme 28 177 176

17@

A. M. Kuliev, K. Byashimov, and F. N. Mamedov, Doklady Akad. Nauk Azerb. S.S.R., 1973, 29, 33 (Chem. Abs., 1973, 79, 91 854b). A, Negishi, Yuki Gosei Kagaku Kyokai Shi, 1973, 31, 331 (Chem. Abs., 1974, 80, 59 804v). L. Thijs, A. Wagenaar, E. M. M. van Rens, and B. Zwanenburg, Tetrahedron Letters, 1973, 3589.

Saturated Heterocyclic Chemistry

80

could not be separated as the compounds would not withstand extensive chromatography. Oxidation of the products with rn-chloroperbenzoic acid in ether at 20 "C gave 1-mesityl-Zmethyl-1-phenylsulphonylprop-1-ene (oxidation to the episulphone with subsequent loss of SO,). It is suggested that the episulphoxides are formed as the result of a two-step process. An initial nucleophilic attack of the diazo-carbon at the sulphine sulphur provides a zwitterionic diazonium compound and an internal 1,3-displacement of nitrogen then produces the episulphoxide (Scheme 28). Bonini and Maccagnanilgohave reported a similar series of reactions. They found that aromatic sulphines such as diphenyl sulphine and t hiofluorenone S-oxide react with phenyl- and p-tolyl-diazomethanes to give triaryl-substituted episulphoxides as a mixture of diastereomers (2:E ratio ranging from 1:4 to 2:3 depending on the aryl substituents). Once again a nonstereospecific formation of the three-membered ring was observed. Any attempt to separate the two components by normal chromatographic methods resulted in the loss of sulphur monoxide to give the olefinic derivatives. Reactions.-Ring-opening. Sulphurated sodium borohydride has been found to react with thiiranslS1in a manner similar to that observed for oxiran, to give polymeric disulphide dithiols, which on treatment with lithium aluminium hydride afford lY2-dithiols.The yield of the 1,Zdithiol can vary rather widely, depending mainly upon the structure and stability of the starting thiiran. For example, with (430; R1 = H, R2 = Ph or PhOCH,) the sulphuration reactions took place as expected, affording the lY2-dithiols(431). The thiiran (430; R1 = R2 = H) gave only polymeric material whilst trans-2,3-diphenylthiiran (430; R1 = R2 = Ph) afforded trans-stilbene as the only product.

The thioglycidic acid derivatives (432; X = OMe, NH,, NHPh, or NMe,) undergo ring-opening at -30 to -40 OC in the presence of methyl chlorosulphide or acetyl chlorosulphide to give mixtures of the corresponding #.I-halogenodisulphides(433) and (435) in 85-96 % total yield,ls2 with (433) predominating. The /?-halogenodisulphides (433; R = Me, X = NH,, NHPh, or NMe,) undergo partial isomerization to the respective (435) after 10h at 100°C, eia the intermediate episulphonium ion (434). The rate of isomerization decreases in the stated order of X. Bonini and G . Maccagnani, Tetrahedron Letters, 1973, 3585. Lalancette and M. LalibertC, Tetrahedron Letters, 1973, 1401. N. M. Karimova, M. G . Lin'kova, 0. V. Kildisheva, and I. L. Knunyants, Khim. geterotsikl. Soedinenii, 1973, 8 (Chem. Abs., 1973, 78, 123 970j).

looB. F. 181 J. M. la'

Three-membered Rings

81

yAcrx

RSSCHoCMeCICOX

(435)

ClCH2CMe(SSR)COX

(433)

+

(432)

(434)

Desulphurization. The desulphurization of cis- and trans-2,3-dimethylt hiirans with n-butyl-lithium, nonacarbonyldi-iron, and dodecacarbonyltriiron has been studied.183The reactions proceed with complete stereospecificity: for example, the trans-isomer with n-butyl-lithium produced only trans-but2-ene in 83 % yield, a 2-6 % crossover in the cases of the iron carbonyls being attributable to subsequent alkene isomerization. Approximately 15 years ago, Bordwell suggested two possible mechanisms for the n-butyllithium reaction (Scheme 29). In the first, the concerted process (a), fragmentation occurs via a sulphurane (436). The second, the carbanion mechanism (b), requires that elimination must be 30-60 times faster than inversion and bond-rotation. The intermediacy of 2-lithio-3-alkylthiobutanes (437)

Li+

H\ISIIMe+

Me'

-

RSLi

RLi

'H

-?

H

I

crythro-(437)

' y

threo-(437)

/

1 + RSLi

>

-t RSLi

(R=Bu")

Scheme 29 u3 B. M. Trost and S. D. Ziman, J . Org. Chem., 1973,38,932.

82

Saturated Heterocyclic Chemistry

for the n-butyl-lithium reaction can now be excluded, as independent generation of these species shows considerable loss of stereochemistry under the conditions of the thiiran desulphurizations. The loss of stereochemistry is a function of the thioether leaving group, the loss being considerably less for thiophenoxide than for ethyl thiolate. The major process in the photolytic decomposition of thiiran is desulphurization. The photolysis of 2,2,3,3-tetraphenylthiiran(438) has recently been investigatedlS4in order to discover what effect uic aryl substitution, a parameter known to alter the photochemical behaviour of oxirans and cyclopropanes, might have on the photolytic reactions of thiirans. Photolysis of the thiiran (438) in pentane until decomposition is complete (ca. 30 h) gives 9,lO-diphenylphenanthrene (440) (98 %), hydrogen sulphide, and sulphur. A possible transition state for the conversion of (438) into (440)is depicted in diagram (439). From this study it would appear that tetraphenyl substitution Ph

(438)

(439)

in thiiran does not alter the photolytic behaviour of thiiran; the decomposition is characterized by sulphur elimination. This conforms to the general behaviour of organosulphur compounds which exhibit a marked reluctance to undergo transformations in which the carbon-sulphur single bond is converted into a double bond. Ring Expansion. The methylthiothiirans (441; R = Me or Et) undergo a cycloaddition reaction with carbon disulphide in the presence of potassium methoxide to afford 1,3-dithiolan-2-thiones (442) and 1,3-dithiolen-2-thiones

(443).”0

n

8

5 Rings containing More than One Heteroatom

Formation.-Diaziridines. The addition of alkanals to chloramine in methanolic ammonia, the Schmitz reaction, affords 2,4,6-trialkyl-1,3,5-triazabicyclo[3,1,0]hexanes (445; R = alkyl or Ph) with trans stereochemistry of the (2-2, R. C. Petterson, A. L. Hebert, G. W. Griffin, I. Sarkar, 0. P. Strausz, and J. Font,J. Heterocyclic Chem., 1973, 10, 879.

Three-membered Rirrgs

83

C-4 substituents, whereas oxidation of the 2,4,6-trialkyl-1,3,5-hexahydrotriazines (444)with t-butyl hypochlorite in methanol at -40 "C gives the corresponding cis-diaziridines (445; R = Me, Et, or Pr) and trans-diaziridines (445; R = alkyl group larger than Pr).lS5Similarly (444;R = Pr') gives a mixture of cis- and trans-(445). The cis-isomers are quantitatively epirnerized to the trans-isomers when heated in methanol at 25 "C for 48 h. The epirnerization is believed to occur so rapidly in compounds having larger alkyl groups (larger than isopropyl) that the cis-isomers cannot be isolated under the reaction conditions used. The reaction of benzylideneanilineor benzylidine-p-toluidinewith hydroxyamino-O-sulphonic acid in the presence of aniline or p-toluidine does not yield the expected diaziridines but benzaldehyde phenyl- or p-tolyl-hydrazones.lS6Under the same conditions, however, Schiff bases of non-aromatic amines do give diaziridines. Although the existence of stereoisomers of such diaziridines, due to slow nitrogen inversion, has previously been reported, the stereochemistry has not bsen fully investigated. Thus an X-ray crystalstructure analysis of an invertomer was undertaken and the configuration of 1-cyclohexyl-3-(p-bromophenyl)diaziridine found to be trans with respect to the 1-cyclohexyl and the 3-@-bromopheny1)groups. Treatment of several of the l-cyclohexyl-3-aryldiaziridineswith phenyl isocyanate afforded l-cyclo-

hexyl-2-(anilinoformyl)-3-aryldiaziridines.

A series of diaziridines (447) having antibacterial properties has been prepared by treating substituted guanidines (446)with base.ls7 For example, the guanidine (446; R1 = R2 = Me) on treatment with methanolic sodium hydroxide gave the diaziridine Schiff base (447; R1 = R2 = Me). lE6

A. T. Nielsen, R. L. Atkins, D. W. Moore, D. Mallory, and J. M. La Berge, Tetrahedron Letters, 1973, 1167. A. Nabeya, Y.Tamura, I. Kodama, and Y. Iwakura, J . Org. Chern., 1973,38,3758.

T. Konotsune, T. Yauchi, and M. Suzuki, Japan. Kokai 73/85 565 (Chern. A h . , 1974, 80,47 968p).

lE7

84 Saturated Heterocyclic Chemistry Oxaziridines. Oxidation of unstrained imino-ethers (448; R = H or But), readily prepared by the alkylation of amides with trimethyloxonium fluoroborate, with rn-chloroperbenzoicacid in dichloromethane at -20 "Caffords188 oxaziridines (449; R = H or But). These are hydrolysed in aqueous acid to give esters (450; R = H or But) and N-t-butylhydroxylamine. With strained imino-ethers the type of product depends on the ring size. 1-Aza-2ethoxycyclopentene (451) affords 5-ethoxy-1-aza-6-oxabicyclo[3,1 ,O]hexane (452) (66%), which decomposes on heating to give the trimer of ethyl 4-iminobutanoate (453), probably by way of a radical chain mechanism. With 2-

R

R

I1 But/N (448)

m-CICsH4CO3H

R \C/OMe yoMe 11 + BU~NHOH

/

I0 N'

%Of,

0

But

(449)

(450)

\

COiEt I

methoxyazetines the novel 1-aza-5-oxabicyclo[2,1,O]pentanes can not be isolated, but l-aza-5-oxa-2,2-dimethylbicyclo [2,1 ,O]pentane can be detected by low-temperature n.m.r. It has been reported189that N-unsubstituted oxaziridines, which tend to be rather unstable, can be stabilized by saturating an ethereal solution of the oxaziridine with carbon dioxide. Azaphosphiridines. The 1 ,2L5-azaphosphiridines (455; R = MeO, EtO, or MqN) have been synthesizedlWin 57-96 % yield by treating hexafluoroacetoneazine (454) with phosphorous esters or tris(dimethy1amino)phosphine in

(455) D. Thomas and D. H. Aue, Tetrahedron Letters, 1973, 1807. lEs Y . Kobayashi, Japan. Kokai 73/10 062 (Chem. Abs., 1973, 78, 11 1 284a). no K. Burger, J. Fehn, and W. Thenn, Angew. Chem. Internat. Edn., 1973,12,502.

Three-memberedRings

85

anhydrous hexane at 0 "C. These compounds (455) have considerablethermal stability and werecharacterized bytheir1H,19F,and 13Cn.m.r.andmassspectra. Thiadiaziridine 1,l Dioxides. The second example of a stable three-membered ring system composed entirely of heteroatoms, the thiadiaziridine dioxides (458), has been reported.lg1-lg3The oxadiaziridines were the first system of this type. Although the thiadiaziridine dioxides (458) are not strictly organic heterocyclic compounds, their novel structure merits their inclusion in this Report. The thiadiaziridine dioxides (458; R1 = R2 = But, ButCH2CMe,, or adamantyl; or R1 = But, R2 = ButCH,CMe2) are conveniently prepared in good yield by treating the corresponding dialkylsulphamide (456) with sodium hydride in pentane to give the sodium salt (457), which on treatment with t-butyl hypochlorite yields the thiadiaziridine dioxide. These compounds show remarkable thermal and chemical stability.

Reactions.-Diaziridines. It has been observed that in contrast to aziridines, which have been shown to addto anumber of acetylenes to give N-vinylaziridines, diaziridines usually react with electrophilic acetylenes to give products in which the diaziridine ring is no longer For example, addition of lY3-dialkyl-and 1,3,3-trialkyl-diaziridines(459) to dibenzoylacetylene in benzene at room temperature affords 2-(alkylidenehydrazino)-l,4-diphenylbut-2-en-174-diones(460). Only the 1,2-unsubstituted diaziridine 3,3-pentamethylenediaziridine [459; R1 = H, R2,R3 = -(CH,),-] reacted with dibenzoylacetyleneor ethyl propiolate to give addition products in which the Bz =CHBz

F

diaziridine ring was still intact. The adduct with dibenzoylacetylene,however, on gentle heating in 95% ethanol rapidly rearranged to [460; R1 = H, R2,R3 = -(CH2),--]. The products (460), formed when the 1,3-dialkyl- and 1,3,3-trialkyl-diaziridines(459) react with dibenzoylacetylene, are thought J. W. Timberlake and M. L. Hodges, J . Amer. Chem. SOC.,1973,95,634. W. Timberlake, M. L. Hodges, and A. W. Garner, Tetrahedron Letters, 1973, 3843. l g 3H. Quast and F. Kees, Tetrahedron Letters, 1973, 1655. lD4H . W. Heine,T. R. Hoye, P. G. Williard, and R. C. Hoye,J. Org. Chem., 1973,38,2984. lS1

lea J.

Saturated Heterocyclic Chemistry

86

(460)

t-

Scheme 30

to arise by a Michael-type addition of the N-alkylated nitrogen of the diaziridine to the alkyne linkage (Scheme 30). 3,3-Pentamethylenediaziridine[459; R1 = H, R2,R3 = -(CH,),-] is also reported to undergo a Ugi four-component condensation reaction,ls5 with formaldehyde, cyclohexyl isocyanide, and ammonia as the nucleophilic compound, to give the tetrazolyl derivative (461) (13 %). The latter, on acid hydrolysis with hydrochloric acid, ring-opened to give the salt (462). Under the same reaction conditions, the less stable N-methyl derivative [459; R1 = Me, R2,RS = -(CH&-] gave the hydrazine (463) as the only product, but with water as the nucleophilic compound the hydrazine (464)and 1 -hydroxy-N-cyclohexylcyclohexanamide(465) were produced, possibly by way of N-methylhydrazine and cyclohexanone.

4

Me\N-N
/

R4CH2

CHzR4

wH<>

R4

C-NH

0 (464) G.Zinner and W.Bock, Arch. Pharm., 1973, 306,94.

(465)

Three-membered Rings

87

n

The reactions of 1-cyclohexyl-2-(anilinoformyl)-3-phenyldiaziridines(466 ; R = Me or H) with p-phenetidine at 100 "C under nitrogen have been investigated.186 The diaziridine (466; R = H) afforded a mixture of l-cyclohexyl-4-phenylsemicarbazide,benzylidene-p-phenetidine,and a small amount of l-(p-ethoxyphenyl)-3-phenylurea.Similarly (466; R = Me) gave the same semicarbazide and a-methylbenzylidene-p-phenetidine,plus an appreciable amount of an unknown compound (467). Thesamecompound wasalso formed when (466; R = Me) was heated at 100°C for 1 h. Analysis showed (466; R = Me) and (467) to be isomeric. The structure of (467) is tentatively proposed as l-cyclohexyl-4,5-diphenyl-5-methyl-l,2,4-triazolidin-3-one, which would be formed as the result of the cleavage of the C-N bond of the diazirine ring of (466; R = Me), possibly via the intermediacy of a stabilized 1,3dipole. The formation of the benzylidene-p-phenetidinesand lcyclohexyl-4phenylsemicarbazide by the reaction of p-phenetidine with (466; R = H or Me) may be considered to proceed via the ring-opened addition product as shown in Scheme 3 1. A study has been made of the reduction of di-t-butyldiaziridinone under electron-transfer conditions.1s6 Reduction by both electrochemical and chemical methods (t-butyl-lithium or sodium naphthalenide) gave 1,3-di-tbutylurea, indicating that the preferred mode of reduction of the diaziridinone under such conditions is cleavage of the N-N bond. Mechanisms for the reactions are discussed. Oxuziridines. As a starting point in a search for synthetic routes to thiaziridines, Black and WatsonlQ7treated oxaziridines with sulphur-containingnucleophiles, an analogous procedure to that used for the mild conversion of oxirans into thiirans. The stable bicyclic oxaziridines (468; R = Ph, Me, H, or But) each gave the corresponding pyrroline (469) when treated with thiourea in refluxing ethanol ; no thiaziridines were isolated. Similarly the monocyclic oxaziridines (470; R = Ph or p-C,H,NO,) were deoxygenated to give the ls8 lS7

7

A. J. Fry, W. E. Britton, R. Wilson, F. D. Greene, and J. G. Pacifici, J . Org. Chem., 1973, 38,2620. D. St. C. Black and K. G. Watson, Austral. J. Chem., 1973,26,2159.

Saturated Heterocyclic Chemistry

88 Ph

\C-N RN \’’

+

E t O O N k h

-

I

CONHPh

I Scheme 31

NH~CSNHZ-E~OH Me

’ Me

Me

But \ /H N-C ‘0’ \R (470)

NHtCSNHZ-EtOM,

+ s

But -N=C

R‘ (471)

R = Ph or p-CsH,NOz

imines (471) and sulphur. Treatment of the oxaziridine (468; R = Ph) with potassium t hiocyanate, potassium ethylxanthate, potassium selenocyanate, or triphenylphosphine sulphidetrifluoroaoetic acid afforded the pyrroline (469; R = Ph) with about the same facility as did thiourea. The results obtained from these studies would support the proposal that the deoxygenation is effected by conversion of the oxaziridines into thiaziridines, followed by rapid loss of sulphur. A mechanism for the reaction of oxaziridines with thiocyanate ion which invakes such a proposal is depicted in Scheme 32.

Three-memberedRings

89

Scheme 32

IrradiatioxP of the cis-oxaziridine (472) at 254nm in benzene afforded 5,5-dimethyl4-phenylpyrrolidin-2-one(473) and 2,2-dimethyl-3-phenyl-lpivaloylazetidine (474). The rearrangement of the oxaziridine (472) probably proceeds with homolytic cleavage of the N-0 bond to form a biradical which can then rearrange via two alternative pathways as shown. In all previously reported photo-rearrangementsof analogous oxaziridines the ringcontraction pathway was preferred. In this instance the t-butyl radical must be sufficiently stable to allow its formation to compete successfully with ring contraction, and also to be able to provide a hydrogen atom necessary for the formation Ph M e p b , B u t

A M

e

b

Me

Me k 0

(472) \

I

y

-

Me

N-c-BUt

.

Ph \

1

Me2C=CH2

(468; R = H) 108

(473)

D.St. C. Black and K.G . Watson, Austral. J . Chem., 1973,26,2505.

II o

Saturated Heterocyclic Chemistry

90

I \

(477)

H

(476)

of the pyrrolidin-Zone (473). It is of note that 2-methylpropene has been observed as a product in related reactions of other oxaziridines. Under similar conditions, photochemical irradiation of the oxaziridine (475) gave solely 2,2,4,4-tetramethylazetidine-l-carbaldehyde(476). Once again the homolytic cleavage of the N-0 bond must be the first step of the rearrangement reaction, followed, rather surprisingly, it would appear by a cleavage of the C4-C-5 bond to give a tertiary alkyl radical. This is the only reported example of this type of reaction in which carbon-carbon bond cleavage is preferred to carbon-hydrogen bond cleavage. Irradiation of 3,3-pentamethyleneoxaziridine,lggin ether at 0 "C in the presence of benzyl phenyl ketone, with a 250 W high-pressure mercury lamp afforded hexanamide (54 %) with 89 % selectivity. The ferrous-ion-catalysed reactions of five oxaziridines have been reported.20° The oxaziridines (470; R = But or Me) were converted into N-tbutylfomamide and N-t-butylacetamide, respectively. The bicyclic oxaziridines (468; R = H) and (472) both gave the lactam (473), whilst the bicyclic oxaziridine (475) afforded the lactam (477) together with other, unidentified products. The reactions are discussed in terms of three mechanisms postulated by Emmons, some years ago, in the first major report on the reactions of oxaziridines

.

Thiadiaziridine 1.1-Dioxides. The thermal and chemical properties of the thiadiaziridine 1 ,l-dioxides (478a-c) are discussed in the papers of Timberlake et uZ?91*192Of particular interest is the chemical reactivity of (478) towards lithium and Grignard reagents. These reactions are depicted in Scheme 33 and proably reflect the differences in nucleophilicity versus the complexing ability of the reagents. A complete mechanistic interpretation, however, must await further experimental results. Y. Kobayashi, Japan. Kokai 73/05 711 (Chem. Abs., 1973, 78, 124 077k). D. St. C. Black and K. G. Watson, Austral. J . Chern., 1973, 26, 2515.

lQU

Three-memberedRings

91 R

I

[

R-w +

N-R :

]

eRMgX

(478)

R.= But b; R = ButCH2CMe2 c; . R = adamantyl a;

*

2 Four-membered Rings BY B. 1. WALKER

1 Introduction Reviews of recent advances in penicillin chemistry' and the structure and rearrangement of penicillin sulphoxides and penicillin-cephalosporin interconversion2 have appeared. The chemistry and biology of cephalosporins and penicillins are discussed in a new

2 Physical Metbods

Magnetic Resonance.-A five-bond coupling of ca. 1 Hz has been observed between H-4 and H-7in the sulphone ester (1) and is suggested to have potential diagnostic use for abnormal C-4 stereochemistry in cepham compound^.^ The stereochemistry and configuration of the oxetans (2), obtained from photocycloaddition of benzophenone to furan and thiophen derivatives, has been determined5from Nuclear Overhauser Effect measurements. The variable-temperature n.m.r. spectra of NN-bisethoxycarbonyl-3,3,4,4tetramethoxy-1,Zdiazetidine show a single coalescence between -40 and -20 'C, which is explained by a slow interconversion of the three N-CO rotational isomers (3). No evidence for slow nitrogen inversion could be obtained even at -120 oC.8N.m.r. spectroscopy has also been used to distinguish the rapidly interconverting 1,2-diazetidinone epimers (4) and ( 5 ) through diastereomeric association complexes with ( +)-0203-dibenzoyltartaric acid.' The rate of interconversion can also be obtained by a study of the coalescence of the separate signals of the epimers. R. J. Stoodley, Progr. Org. Chem., 1973,8,102; D. H. R. Barton, Pure Appl. Chem., 1973,33, 1.

R . D. G. Cooper, L. D. Hatfield, and D. 0. Spry, AccounrsChem. Res., 1973, 6 , 32. 'Cephalosporins and Penicillins. Chemistry and Biology', ed. E. H. Flynn, Academic Press, New York, 1972. D. 0. Spry, Tetrahedron Letters, 1973, 165. T. Nakano, C. Rivas, C. Perez, and K. Tori, J.C.S. Perkin Z, 1973, 2322. E. H. Carlson, A. P. Schaap, and M. Raban, J. Org. Chem., 1973,38, 1605. A. Mannschreck, V. Jonas, and B. Kolb, Angew. Chem. Znternat. Edn., 1973,12,583.

92

Four-membered Rings

93 PhOCHeCOH

0

X

=

(3

OorS

Me0

,,0>n<:::

EtoY-?koEf 0

0

Me0

EtoltN-N7+o 0

OEt

OEt

1

EtO

(7)

OEt

Saturated Heterocyclic Chemistry

94

Miscellaneous.-The photoelectron spectrum of oxetan has been interpreted and the highest occupied orbital is shown to be essentially non-bonding;8 in the same report the relative conformational preferences of cyclobutyland 3-oxetanyl-carbinyl cations are calculated. The luminescence of (6) in the gas phase decays by first-order kinetics and is quenched by triplet quenchers. A mechanism involving formation of carbon trioxide is p r o p o ~ e d . ~ Electron diffraction measurements show that the ring of azetidine has a 37' dihedral angle between the CCC and CNC planes, similar to cyclobutane, but very different from oxetan.l0 The insecticidal oxetan (7) hasll a dihedral angle of 16' between the planes formed by 0-1, C-2, and C-3 and by 0-1, C-4, and C-3,again much less than that of azetidines or cyclobutanes. The y-irradiation of benzylpenicillin in aqueous solution12has been studied. 3 Formation

0xetans.-Cyclization. Typical of the use of cyclization methods is the synthesis of the oxetanyl acetylenes (8) through dehydrochlorination of the corresponding ch10rohydrin.l~ Dehydrobromination of the 7a-bromo-5ahydroxy-6-keto-steroids (9) gave the corresponding oxetans in fair yield ; as might be expected, higher yields of the same oxetans were obtained from the 7P-e~irner.l~

* P. D. Mollere, Tetrahedron Letters, 1973,2791. * J. Stauff, W. Jaeschke, and G. Schloegl, 2. Naturforsch., 1972,27b,1434 (Chem. Abs., lo l1 la l5 l4

1973,78,159 496y). 0 . V. Dorofeeva, V. S. Mastryukov, L. V. Vilkov, and I. Hargittai, J.C.S. Chem. Comm., 1973,772. G . Holan, C.Konala, and J. A. Wunderlich, J.C.S. Chem. Comm., 1973,34. G.0.Phillips, D. M. Power, and C. Robinson, J.C.S. Perkin 11, 1973,575. Y.Portnyagin, V. V. Sova, and N. E. Pak, Khim. Atsetilena, Trudy Vses. Konf., 3rd. 1968,249 (Chem. A h . , 1973,79,5190~). R. Hanna, G. Maalouf, B. Muckensturm, and A. Cherry, Tetrahedron, 1973, 29, 2297.

Four-membered Rings

95 ROH-RONa

’‘

R3

crL6(NMe2)2

R3

A new synthesis of 3,3-dialkyloxetans has been achieved through the reaction of the diols (10) with hexamethylphosphoramidite and carbon tetrachloride followed by base treatment.15The intermediate alkoxyphosphonium salts were not purified. t-Butylcyanoketen in the presence of small amounts of triethylamine slowly dimerizes to the p-lactone (11). However,le in the presence of larger amounts of base, both the keten and the dimer (11) give 1,3-di-t-butyl-l,3dicyanoallene (12). The mechanism outlined in Scheme 1 is suggested.

NC’

NC’

t 11

1

”1” 11

NC

Scheme 1 l6

B. Castro and C. Selve, Tetrahedron Letrers, 1973, 4459. H. W. Moore and W. G. Duncan, J . Org. Chem., 1973,38, 156.

Saturated Heterocyclic Chemistry

96

+

[2 21 Cycloaddition. Oxetans have been obtained from the photocycloaddition of ketones to norbornadiene and quadricyclane,17thiophen,18 and N-acylated ind01es.l~Most aromatic heterocvcles do not react with benzophenone on irradiation and the formation of i13) is thought to be due to the

0+ Ph2CO

I

7

COR

conjugation of the nitrogen lone pair with the carbonyl group hindering quenching of the excited-state ketone.lg Even in experiments where olefin isomerization was small, mixtures of cis- and trans-oxetans were obtained from the photocycloaddition of acetone to cis-but-Zene. Quenching experiments suggest a triplet mechanism,2O with the reaction probably proceeding via the biradical (14), which must have

(14)

sufficient lifetime to undergo rotation. The relative amounts of the various possible isomeric oxetans formed in the photoaddition of aryl aldehydes to both cis- and trans-but-2-ene have been determined and the preferences explained in terms of favourable conformations of the biradical transition states.21An intermediate triplet 1,4-biradical (15) explains the products from the photoaddition of tetramethylethylene to acetone.22This mechanism is further supported by reactions with deuterioacetone, although these latter results contradict an earlier report.23 The photoaddition of olefins to biacetyl to form oxetans proceeds with higher orientational selectivity than does the addition to m0noketones.2~ The excited biacetyl triplet is suggested to attack the olefin to give a biradical (1 6), which can undergo cyclization or disproportionation, the product proportions being controlled by steric factors. A. A. Gorman, R. L. Leyland, M. A. J. Rodgers, and P. G. Smith, Tetrahedron Letters, 1973, 5085. l 8 C. Rivas and R. A. Bolivar, J . Heterocyclic Chem., 1973, 10, 967. l9 D. R. Julian and G . W. Tringham, J.C.S. Chem. Comm.,1973, 13. 2o H . A . J. Carless, Tetrahedron Letters, 1973, 3173. 21 N. C. Yang, M. Kimura, and W. Eisenhardt, J . Amer. Chem. SOC.,1973, 95, 5058. 22 H . A. J. Carless, J.C.S. Chem. Comm.,1973, 316. 23 S. M. Japar, J. A. Davidson, and E. W. Abrahamson, J . Phys. Chem., 1972,76,478. 28 H. S. Ryang, K. Shima, and H. Sakurai, J. Org. Chem., 1973,38,2860. l7

Four-membered Rings

97 1

',' 'I +

R1 R2

MeKO

+

R3

disproportionat ion

cycliution

+ oxetan

Irradiation of the charge-transfer complexes of dimethylmaleic, phthalic, and naphthalic anhydrides with indenes and benzofuran gives mixtures of oxetans and cycl~butanes.~~ Oxetans are not expected in the maleic case since irradiation of maleic anhydride derivatives with olefins normally gives cyclobutanes exclusively. Formation of a complex with substantial chargetransfer character has been shown, on the basis of kinetic and quantum studies and secondary isotope effects, to be the initial step in the reaction of the benzophenone triplet with alkenes.2*The kinetics of the photoaddition of benzophenone to several ketenimines to give mixtures of oxetans (17) and (18) have been extensively investigated?' Ph2CO

+

R1R2C=C=NR3

+

-% R1$$

*;PI, Ph

R2

Ph

Ph (17)

(18)

Photoaddition of tetramethylethylene to esters gave the olefins (19) and (20) in addition to the oxetan, while an oxetan with the unexpected orientation (22) was the only product from a similar reaction with the vinyl ether (21).28

The novel fused oxetan (24) has been obtained from the photoaddition of the thermally unstable oxetan (23) to ben~aldehyde.~~ The analogous cis-l,6dimethyl-2,5-dioxabicyclo[2,2,0]hexane (26) is formed on irradiation of M

L7 pa

as

S. Farid and S. E. Shealer, J.C.S. Chem. Comm., 1973, 296. R. A. Caldwell, G . W. Sovocool, and R. P. Gajewski, J. Amer. Chem. SOC.,1973, 95, 2549. L. A. Singer, R. E. Brown, and G . A. Davis, J . Amer. Chem. SOC.,1973, 95, 8638. T. S. Cantrell, J.C.S. Chem. Comm., 1973, 468. L. E. Friedrich and J. D. Bower, J . Amer. Chem. SOC.,1973, 95, 6869.

98 RCOzMe

+

1-

Saturated Heterocyclic Chemistry

If

Me0

+

xoMe Aph4toMe (20)

(19)

OMe

PhCOzMe

+

Me0

Me0 (22)

.(2 1)

Me

I

PhCHO

+

hv

-780~7 I.

PhCHO -78°C

Ph

ph

Me

(26)

(25)

3-methyl4oxahex-5-en-2-one (25), probably uia intramolecular addition in the excited singlet state, since (25) does not Several reports of oxetanol formation on irradiation of ketones have appeared. Irradiation of either isomeric ketone (27) or (28) gives the acetone photodimer (29):l which readily undergoes acid-catalysed hydrolysis to (30). Similar irradiation of the 3-methoxy-chromone (3 1) gives the oxetanol dimer

(29)

I.+

MeCOCMe2CH20H (30) 30

31

J. C. Dalton and S. J. Tremont, Tetrahedron Letters, 1973, 4025. J. Kagan and J. T. Przybytek, Tetrahedron, 1973, 29, 1163.

Four-membered Rings

99

1 (32).32The all-cis ketone (33) gives an oxetan and the cyclobutanol (35) on irradiation; both products are thought to be formed via the biradical (34).= Similar isomeric ketones gave very different products on irradiation. Miscellaneous. The p-lactone (36) is among the products formed on peracid

oxidation of tetramethylallene:the allene oxide is the favoured intermediate.34 The same group reports35that the allene dioxide (37), prepared by ozonolysis of the corresponding allene, rearranges on standing to the oxetanone (38). 0

3a

33 34

S. C. Gupta and S. K. Mukerjee, Tetrahedron Letters, 1973, 5073. J. R. Scheffer, K. S. Bhandari, Y.-M. Ngan, and D. K. Schmidt, TetrahedronLetters, 1973, 1413. J. K. Crandall, W. H. Machleder, and S. A. Sojka, J . Org. Chem., 1973, 38, 1149. J. K. Crandall and W. W. Conover, J.C.S. Chem. Comm., 1973, 340.

100 Saturated Heterocyclic Chemistry Oxetans are amongst the products formed in the photochemical reaction of cholesterol with hypoiodite: a complex mechanistic scheme has been proposeds6 Azetidines.--The synthesis of /?-lactamshas been reviewed?' Cyclization. A new, simple high-yield route to dl-azetidine-2-carboxylic acid from y-butyrolactone has been reported;% several derivatives of the acid were prepared. The methyl ester loses methanol at room temperature to give the diketopiperazine (39). ~-Azetidine-2-carboxylic acid has been synthesizedSDby acid cleavage of N-tosyl-L-homoserinelactone to give (40) followed by recyclization and detosylation.

aco2Me +-L 0

2

+

0

Me

0 \

/

(39)

S02NHCHCHzCH&r

I

COzEt (40)

Cyclization of the corresponding 3-aminopropanol by triphenylphosphine dibromide and base is said to provide a new route to N-aryla~etidines;~~ however, no yields were reported. A number of other products are also formed and the method is restricted to compounds not having aryl substituents in other ring positions! /?-Lactamsare conveniently ~ r e p a r e d ~by l n cyclization ~~ of 2-amino-esters, obtained by either a Reformatsky reaction41or reduction of the corresponding Prolonged heating of cyanomalonamic acid esters (41) gives the tautomeric 2,4-dioxo-3-azetidinecarbonitriles(43). Surprisingly, the cyanomalondiamides (42) appear to be intermediates and can be isolated when CN HC-CONHR I

HvcN

CN

b,

~Q<>o=O+oH

I COZEt

a4 ST

38

40 41 48

R

R

H. Suginome and W. Kato, Tetrahedron Letters, 1973,4139. A. K. Mukerjee and R. C. Srivastava, Synthesis, 1973, 327. B. A. Phillips and N. H. Cromwell, J. Heterocyclic Chem., 1973, 10, 795. M. Mujoshi, H. Sugano, T. Fujii, T. Ishihara, and N. Yoneda, Chem. Letters, 1973, 5 (Chem. Abs., 1973, 78, 97401~). V. N. Gogte, S. B. Kulkarni, and B. D. Tilak, Tetrahedron Letters, 1973, 1867. F. Dardoize, J. L. Moreau, and M. Gaudemar, Bull. SOC.chim. France, 1973, 1668. L. Fontanella, G. Pifferi, E. Testa, and P. Consonni, Farmaco, Ed. Sci., 1973, 28, 105 (Chem. Abs., 1973,78, 124 364b).

Four-membered Rings

101

shorter reaction times are used.43A similar mechanism is presumably involved in the formation of the 4-(t-butylimino)-2-azetidinone (44) by ethanol quenching of a trifluoroacetic anhydride-t-butyl isocyanide reaction mixture in carbon tetrachloride.M B U ~BN lJ$F3OH

(44)

Virtually quantitative yields of the isomeric azetines (46)have been obt ained by the react ion of 1,2-diphenyl-3,3-di(methoxycarbonyl)aziridinewith sulphonium or sulphoxonium ylide~.*~ In all cases the cis-azetine is the major isomer and the reaction is thought to proceed uia the azomethine ylides (45).

PhCH-C(COnMeh

PhCH

C ( C 0 N e h ,,-r-orrn,

R T H y

Ph

(45)

(46)

A possible scheme for the biosynthesis of p-lactam antibiotics involves formation of the &lactam ring through cyclization of the thioaldehyde (47);4s such a route is supported by the ease of oxidation of cystinylvaline and cysteinyldehydrovaline derivatives to isothiazolidinones. Both (2RS,3S)-[4J3C]valine4' and (2S,3S)-[4-13C]valine (48)48 have been synthesized and converted into cephalosporin C and penicillin N by Cephalosporium acremonium. The penicillin (49) was strongly labelled at the a-methyl carbon and had no significantlabel at the p-methyl, and therefore formed with retention of configuration at the labelled isopropyl group.48 Other workers L. Capuano and R. Zander, Chem. Ber., 1973,106, 3670. P. Krivinka and J. Honzl, Coll. Czech. Chem. Comm., 1972, 37, 4035 (Chem. Abs., 1973,78, 84 132v). M. Vaultier, R. Danion-Bougot, D. Danion, J. Hamelin, and R. Carrie, Tetrahedron Lerters, 1973, 1923. J. E. Baldwin, S. B. Haber, and J. Kitchin, J.C.S. Chem. Comm., 1973,790. J. E. Baldwin, J. Loliger, W. Rastetter, N. Neuss, L. L. Huckstep, and N. De La Higuera, J . Amer. Chem. SOC.,1973, 95, 3796; N. Neuss, C. H . Nash, J. E. Baldwin, P. A. Lemke, and J. B. Grutzner, J. Amer. Chem. SOC.,1973,95, 3797. H. Kluender, C. H. Bradley, C . J. Sih, P. Fawcett. and E. P. Abraham, J . Amer. Chem. SOC.,1973, 95,6150.

Ia 44 46

** 47

**

Saturated Heterocyclic Chemistry

102

0

COZR'

(4 7)

xx

RTONH H H

0

'COZ R'

H~N--~--H CO2H

have prepared (2RSY3S)-[4,4,4-2H,]valine (50) for an alternative approach to similar studies.49 The photolysis of diazo-compounds has been used by several workers to form #?-lactamrings, presumably via insertion of the initially formed carbene. Thus the oxa-penam (51), which is unusually susceptible to nucleophilic cleavage, has been prepared by photolysis of N-(ethoxycarbony1)diazoacetyl4,4-dimethyloxazolidine50and a similar cyclization has been used in the

'@

D. J. Aberhart and L. J. Lin, J . Amer. Chem. SOC.,1973,95, 7859. B. T.Golding and D. R. Hall, J.C.S. Chem. Cornrn., 1973, 293.

103

Four-membered Rings H

P h C H K O H N T d 0

CO2R (52)

at tempted preparation of homopenicillin derivatives [eg. (52)].61Presumably a related reaction is involved in the formation of 1,2-diazabicyclo[3,2,0]heptan-6-ones (54) on treatment of the A5-pyrazolines (53) with acetyl chloride.62Carbenes, or carbenoids, are also involved in the thermolysis of the organomercury derivative (55) to give the @-lactam(56).63 Several penicillin analogues without gern-dimethyl groups have been prepared by photoisomerization of 2-oxoamides (57).64

Ac

(53)

(54)

(55) X = Br or C1

(56)

R

(57)

X = S, SO,.or SO2 R=MeorH

[2 + 21 Cycluadditiun. The base-catalysed cycloaddition of acid chlorides and imines remains a popular route to /I-lactams. Azido-acid chlorides have 61 s2 63 64

8

G. Lowe and M. V. J. Ramsey, J.C.S. Perkin I, 1973,479.

F. B. Culp, K. Kurita, and J. A. Moore, J . Org. Chem., 1973, 38, 2945. N. G. Johansson, Acta Chem. Scand., 1973,27, 1417. K. R. Henery-Logan and C. G . Chen., Tetrahedron Letters, 1973, 1103.

Saturated Heterocyclic Chemistry

104

(58) R1 = H,R2 =

AC

(59) R1 = OMe,R2 = CON&

been extensively used since they provide a convenient pathway to the 6amido function required in penicillin synthesis. Racemic cephalothin (58)55 and cefoxitin (59)56 have been synthesized in this way. However, attempts to

463) (61) X = PhO (62)

X

= PhOCH,CONH

Reagents: i, Pt-Hz; ii, PhOCHzCOCl-Et3N

Scheme 2

convert the 6-azido-penam (60) into the penicillin V analogue (62) via hydrogenation and reaction with phenoxyacetyl chloride gave instead the 6-phenoxy-derivative (61).57 The reaction may involve scission of the initially formed amine to the thiazoline (63), which can undergo cycloaddition of the phenoxyacetyl chloride (Scheme 2). Similar cycloadditionshave been used to prepare aza-analogues of cepham (64),684-carboxy-&lactams(65),694-mercapto-2-azetidinones(66)(Scheme3),*0

Ar6 + PhOCHzCOCl

(64) 66 68

67 68

8O

R. W. Ratcliffe and B. G. Christensen, Tetrahedron Letters, 1973,4649. R. W.Ratcliffe and B. G. Christensen, Tetrahedron Letters, 1973,4653. M. S. Manhas, J. S. Chib, and A. K. Bose, J . Org. Chem., 1973,38, 1238. A. K. Bose, J. C. Kapur, J. L. Fahey, and M. S. Manhas, J . Org. Chem., 1973,38, 3437. A. K. Bose, M. Tsai, J. C. Kapur, and M. S. Manhas, Tetrahedron, 1973,29, 2355. R. Lattrell, Angew. Chem. Internat. Edn., 1973, 12,925.

Four-membered Rings

105 H,

Ph

pi’vco2Me + N

PhOCHzCOCl

\Ar

0

CHSCPh3

i-iii

II

____)

N

+ RCH&OCl

\

CH-CMe2SMe

I

C02Me Reagects: i, Et&; ii, Hg(OAc),; iii,

11~s Scheme 3

wMe

Me0

x,

Me! I

1

(67) X = M e 0 , P h 0 , 0 r N 3

and the new bicyclic B-lactams (67).61The preparation of a-amido-#&lactams directly by this method normally fails, since a-acylamino-acid chlorides preferentially cyclize to aza-lactones; however, this does not happen with Nalkoxycarbonyl glycyl chlorides, and a variety of cis-amido-B-lactams have been prepared.62An alternative route to a-amido-/?-lactamsinvolves cycloaddition of diacid chloride followed by treatment with sodium azide and Curtius rearrangement to the isocyanate (68) (Scheme 4); the initial addition is apparently stereospecifi~.~~ Replacement of the acid chlorides by acid anhydrides has no advantages since isomeric mixtures of #l-lactams are formed.64 qoc1 p O=C=N, R

Xl\fPh

+

PhCH(COC1)2

N

‘Ph

Phg:h ‘‘a

0

h; tNJ- -J-hp

0 (68) R = Hor SMe

Reagents: i, Et3N;ii, NaN3;iii, heat

61 68

Scheme 4 A. K. Bose, J. L. Fahey, and M. S. Manhas, J . Heterocyclic Chern., 1973, 10, 791. A. K. Bose, H. P. S. Chawla, B. Dayal, and M. S. Manhas, Tetrahedron Letters, 1973, 2503.

A. K. Bose, J. C. Kapur, B. Dyal, and M. S. Manhas, Tetrahedron Letters, 1973, 3797. 1 3 ~A. K. Bose, J. C. Kapur, S. D. Sharma, and M. S. Manhas, Tetrahedron Letters, 1973, 63

23 19.

Saturated Heterocyclic Chemistry

106

Y

Y

rJNQj YI

= Tos, COPh, or COzR

The cycloaddition of ketens to (lH)-l ,Zdiazepines gives the bicyclic b-lactams (70), the cyclization of the suggested intermediate dipole (69) being stereoselecti ~ e . ~ ~ The highly reactive N-chlorosulphonylisocyanate(CSI)has again been extensively used in cycloaddition reactions with alkenes. Thus reaction with vinyl thioetherP and indene6' gives the corresponding b-lactams (71) and (72).

A similar reaction with benzonorbornene followed by treatment with sodium sulphite (Scheme 5 ) gives exo-3-aza-4-ketobenzotricyclo [4,2,1 ,02*5]non-7-ene (73), which undergoes photoinduced ring-expansion to (74) in methanol.68 66 66

13'

68

J. P. Luttringer and J. Streith, Tetrahedron Letters, 1973,4163. K.Hirai, H. Matsuda, and Y. Kishida, Chem. and Pharm. Bull. (Japan), 1973, 21, 1090 (Chem. A h . , 1973,79,66 291h). E. Dunkelblum and A. Shaviv, Israel J . Chem., 1972,10,971;A. De Sousa Gomes and A. M. Figueiredo, Org. Prep. Proced. Internat., 1973,5 , 13 (Chem. Abs., 1973, 79, 53 114c). H.L. Ammon, P. H. Mazzocchi, W. J. Kopecky, H. J. Tamburin, and P. H. Watts, J. Amer. Chem. SOC.,1973,95, 1968.

Four-membered Rings

1 07

\

OMt

(73)

(74)

Reagents: i, CSI; ii, NatSOI

Scheme 5 The/?-lactams (75) and (76), prepared from the corresponding olefins, do not undergo rearrangement to isomeric cyclopropanes on heating, although in at least one case these would be thermodynamically favoured.69

(7 5 )

(76)

Paquette and others have continued to study the reactions of CSI with multicyclic olefins. The y-lactam (79)is obtained from the reaction of bicyclo[4,2,2]deca-2,4,7,9-tetraene(77) with CSI.'O Formation of the product is

(79) 69 'O

D. H. Aue, H. Iwahashi, and D. F. Shellhamer, Tetrahedron Letters, 1973, 3719. L. A. Paquette and M. J. Broadhurst, J . Org. Chem., 1973, 38, 1886.

Saturated Heterocyclic Chemistry

108

__+

(82)

rationalized in terms of initial formation of a N-chlorosulphonyl-B-lactam, which undergoes rearrangement to the 1,4-bis-hornotropylium zwitterion (78). A similar reaction with 9-methylenebarbaralane (80) does not appear to go via the homoaromatic intermediate (82), but rather via the localized cation (81) to give a &lactam as the final product.'l The reactions of CSI with bicyclo [6,1,O]nonatrienes and cyclononenes are

OH -

NSOzCI

CSI

-

71

H

/

H

L. A. Paquette and M. J. Broadhurst, J . Org. Chern., 1973,38, 1893.

Four-memberedRings 109 highly stereospe~ific.'~cis-Bicyclo[6,1 ,O]nonatriene (83) gives the traizs-8lactam (84), while trans- and cis-cyclononene give the trans (85) and the cis (86) fused /Llactam respectively.In the case of 9-substitutedbicyclononatriene, while the anti-derivative (87) undergoes ready addition, the syn-derivative (88) does not react : 1,3-bishomotropylium ions (89) are the suggested intermediates.

8..

cr-Pinene reacts with CSI to give initially the b-lactam (go), ~ h i ~ h ~ ~ overnight at room temperature readily rearranges to the y-lactam (91).

CSI &

-78 "C

(90)

(911

/I-Pinene also gives an initial adduct (92), but this decomposes in a few minutes to give a complex mixture of products from which the 7-Iactam (93) can be isolated in low yield.'* The reactions of camphene and related olefins were also investigated.

72

73 74

L. A. Paquette, M. J. Broadhurst, C. Lee, and J. Clardy, J . Amer. Chem. Soc., 1973, 95,4647. G.T.Furst, M. A. Wachsman, J. Pieroni, J. G. White, and E. J. Moriconi, Tetrahedron, 1973,29,1675. T. Sasaki, S. Eguchi, and H. Yamada, J . Org. Chem., 1973,38, 679.

Saturated Heterocyclic Chemistry

110

h

&Lactams have been obtained from the reaction of CSI with a variety of allenes. Paquette has ~uggested'~that the reactions with isobutenylidenecyclopropanes (94) involve dipolar intermediates and that initial attack of the electrophilic CSI can be at C-4 or C-5 (to give ultimately 7- or 8-lactams) depending on the electronic and steric effects existing in the allene. Gompper and L a ~ have h ~ obtained ~ similar results, isolating the 8-lactam (96) from

CSI ___)

(94)

' 4 R

Rf

\

y-lactam

reactions with the isobutenylidenecyclopropane (95) and the y-lactam (98) from (97). In the latter case cyclization at oxygen to give the tetrahydrofuran (99) was also observed. A similar reaction of the allene (100) with phenyl isocyanate gave the p-lactam (101).77 In contrast to an earlier report,78 ketenimines are now shown to undergo [2 21 cycloaddition with isocyanates at elevated temperatures to give 4-iminoazetidinones (102).79

+

D. J. Pasto, A. Fu-Tai Chen, G. Ciurdaru, and L. A. Paquette, J . Org. Chern., 1973, 38, 1015. 76 R. Gompper and D. Lach, Tetrahedron Letters, 1973, 2683. 7 7 R. W. Saalfrank, Tetrahedron Letters, 1973, 3985. 78 G. R. Krow, Angew. Chem. Internat. Edn., 1971, 83, 455. ? @ Naser-ud-din, J. Riegl, and L. Skattebd, J.C.S. Chern. Cornrn., 1973, 271. 75

Four-membered Rings

p Ph

C

<

+

CISOzNCO

111

-----, Ph N

(97)

ClSOZ

SOzCl

(98)

(99)

112 Saturated Heterocyclic Chemistry The photoaddition of furan to (103) to give the azetine (104) probably takes place via an excited triplet, since (104) was not formed in the presence of a triplet quencher.80

R;C=C=N

0

+

140 "C R2NC0 ___,

Ring Contraction. a-Keto-y-lactams (105) can be converted into @-lactamsin moderate yields by treatment with periodate.81 The adduct (106) from the cycloaddition of tosyl isocyanate and keten loses sulphur dioxide at room temperature in chloroform to give the azetidinedione (107).82 H02C

0 periodatc

R

0

(105)

*O 81

82

0. Tsuge, K. Oe, and M. Tashiro, Tetrahedron, 1973, 29, 41. D. R. Bender, L. F. Bjeldanes, D. R. Knapp, D. R. McKean, and H. Rapoport, J . Org. Chem., 1973, 38, 3439. J. M. Bohen and M. M. JoulliC, J . Org. Chern., 1973,38, 2652.

Four-membered Rings

113 The Wolff rearrangement of the diazodione (108) has been used in a new synthesis of la lac tarn^,^^ the intermediate keten (109) being trapped with t-butylcarbazate. Similar reactions with the bicyclic diazadione (110) suggest that the method may not be useful in penicillin synthesis since the product (111) is rather unstable. The same rearrangement has been used8$to prepare the B-lactam (1 12) for studies of the structural basis for antibiotic properties.

PhCHzCOHN

tl k02R

(112)

Miscellaneous. /3-Lactams are the products of oxidative ring-expansion of the tosylhydrazidecyclopropanoneadduct (113) with manganese di0xide.8~The ,8-lactam structure was confirmed by an independent synthesis from the

84 8b

G. Lowe and D. D. Ridley, J.C.S. Chem. Comm.,1973,328; G. Lowe and D. D. Ridley, J.C.S. Perkin I, 1973, 2024. G. Lowe and H. W. Yeung, J.C.S. Perkin I , 1973,2907. F. D. Greene, R. L.Camp, V. P. Abegg, and G. 0. Pierson, Tetrahedron Letters, 1973, 4091.

114

Saturated Heterocyclic Chemistry HO<4N

HS02Ar

t

Bu(

But'

,J

But

But'

But' 0

4 ' n l l t

Reagents: i, Mn0,-CHCl,, 25 O C ; ii, Et,N+N;-CHCI,, ivy MeSO,NH,; v, ArS0,CI Scheme 6

A ; iii, DME-NaH;

cyclopropanone (1 14), again via a ring-expansion (Scheme 6). An alternative ring-expansion procedure has been reporteds6 and involves tosylation of the hydroxylamine (11 9 , prepared from cyclopropanone, which results in smooth rearrangement to the B-lactam (1 16). Pyrolysis of the b-lactam (117) gives the OH I

HoXocoMe RCH(CN)NHOH

+ CHaCOaH

c-

(114)

@-lactam(1 19), which was independently synthesized from di-(l-adamanty1)carbodi-imide and l-adamantylketen.8' The mechanism is thought to involve formation of the isocyanide (118), which adds to the ct-lactam to give (119). 2-Phenylazetene (120), prepared by thermolysis of 1-phenylcyclopropyl azide, can be converted into azetidines by lithium aluminium hydride or lithium alkyls.882-Methoxyazetenes (121) are oxidized by peracids to l-aza5-oxabicyclo[2,1,O]pentanes (122), which, although they can be detected at 86

87 88

H, H. Wassermann, E. A. Glazer, and M. J. Hearn, Tetrahedron Letters, 1973, 4855. E. R. Talaty, A. E. Dupuy, C. M. Utermoehlen, and L. H. Stekoll, J.C.S. Chern. Cornm., 1973,48. G. Szeimes, U. Siefken, and R. Rinck, Angew. Chern. Internut. Edn., 1973, 12, 161.

Four-membered Rings

115-160°C

H$NR

.'.I

115

R

H

R

R (117) R = 1-adamantyl

1

ANR

7

-1

L

RCHO

I

+

R - k e (118)

C0,H

low temperature by n.m.r. measurements, rapidly undergo further oxidation.89 1,2-Dicyclohexyl-6,7-dimethixycarbonyl- 23-diphenyl-3,8-dihydroazetidino- [3,Zb]pyridines (123) have been prepared by the reaction of 1,2-dihydropyrazineswith dimethyl acetylenedicarboxylate?oThe mechanism shown in Scheme 7 is supported by experiments with the deuterio-analogue (124). 2,2-Dimethyl-3-phenyl-l-pivaloylazetidine (125) is among the products formed on photo-rearrangement of 6-oxa-1-azabicyclo[3,1,O]he~ane;~l D. Thomas and D. H. Aue, Tetrahedron Letters, 1973, 1807.

J. M.Lown and M. H. Akhtar, Tetrahedron Letters, 1973,3727. O1

D. St. C. Black and K. G. Watson, Austral. J . Chem., 1973,26, 2505.

Saturated Heterocyclic Chemistry

116

/

Ph

Scheme 7

similarly (126) gives 2,2,4,4-tetramethylazetidine-l-carboxaldehydeas the only product. The dirner obtained from irradiation of 2-phenylazirine and previously reported as azabicyclo[2,1,0]pentane (127), is now shown to be (128).92A reportg3that isomeric azetidines (130) are formed from the indole (129) in refluxing pyridine is now on the basis of n.m.r. and chemical evidence, to be in error. The products are suggested to be diastereomericforms of *a s3 94

A. Padwa, M. Dharan, J. Smolanoff, and S. I. Wetmore, J . Amer. Chem. SOC.,1973, 95, 1954. K. Takayama, M. Isobe, K. Harano, and T. Taguchi, Tetrahedron Letters, 1973, 365. V. Dave, J. B. Stothers, and E. W. Warnhoff, Tetrahedron Letters, 1973, 4229.

117

Four-membered Rings

Ph

(1 2s)

1

q$ ArCO

'

the indolene-substituted indole (13l), arising through restricted rotation about the C-N bond indicated. Restricted rotation about the amide bond was excluded both on the basis of the higher barrier to rotation in (131) (AG* > 30 kcal mol-l) and on the observation that different products are obtained from each isomer on reduction of the carbonyl group to methylene. Rings containing More than One Heteroatom.-C'clization.

4-Methyl-3,3pentamethylene-1,Zdioxetan has been prepareds5from ethylidenecyclohexane (132) via the bromohydroperoxide (133). However, the authors were unable to isolate the dioxetan from the ozonization of (132), in contrast to a previous report.96 The reported synthesesg7 of 1,2,3-0xadiazetines (134) from the

O5

O6 O7

K. R. Kopecky, P. A. Lockwood, J. E. Filby, and R. W. Reid, Canad. J . Chem., 1973, 51,468; see also P. S. Bailey, T. P. Carter, C. M. Fischer, and J. A. Thompson, ibid., 1972,50, 1278. P. R. Story, E. A. Whited, and J. A. Alford, J. Amer. Chem. SOC.,1972, 94, 2143. K. Eiter, Ger. Offen, 1914 366 (Chem. A h . , 1970, 73, 120 688j); ibid, 1919 679 (Chern. A h . , 1971,74, 13 128a).

Saturated Heterocyclic Chemistry

118 OH

I

(132)

(133) R1N -CHR3ORa

RIN-NORe I I O-CHR3

I

N=O

(134)

(135)

diazotization of amino-alcohols in the presence of aldehydes are now showng8 to be erroneous, the products being alkoxymethyl alkylnitrosamines (135).

+

[2 23 Cycloaddition. The vinyl keten (137), generated by photolysis of (136), undergoes cycloaddition to azobenzene to give the 1,Zdiazetidinone (138).99 Dimethylketen and Z-azobenzene undergo a similar addition to COMe

\ (136)

v I

(137)

.-. CNf

W

(138)

give the diazetidinone (139), but E-azobenzene does not react with ketens, probably because of steric factors.100Rather than form a diazetidinone, the diazabicycloheptene (140) reacts with dimethylketen to give the 2: 1 adduct (141); the difference from the reaction of Z-azobenzene may be due to the

Q8

S. Yanagida, D. J. Barsotti, G . W. Harrington, and D. Swern, Tetrahedron Letters,

1973, 2671. A. C . Day and A. N. McDonald, J.C.S. Chem. Comm., 1973,247. looG . Brooks, M. A. Shah, and G. A. Taylor, J.C.S. Perkin I, 1973, 1297. Q9

Four-membered Rings

119

ring-strain involved in the products. AttemptslOl to obtain a seven-membered ring by 1,5-addition of vinylcyclopropane to 4-phenyl-l,2,4triazoline-3,5dione gave instead the diazetidine (142). However, a seven-membered lactam (145) was obtained from the reaction of chlorosulphonyl isocyanate with 2-isopropenyl-1-phenylcyclopropane(143), probably owing to the stability of the benzylic cation (144).

1

Q

6. NS02Cl

NSOzCl

t

Ph

- CH2-C.&

0

(14)

(145)

1,3-Diazetidinones (146) have been prepared by the reaction of O-methyl caprolactim ether with aryl isocyanates.lo21,3-Diazetidinesare obtained from the spontaneous dimerization of the hydrazone (147), prepared from

0

(CFa)zC=NF

lol lo2

9

+

MezNH

-

(146) (CF3)2C=NNMe2

(CF3),C=NNMe2 (147)

D. J. Pasto and A. Fu-Tai Chen, Tetrahedron Letters, 1973, 713. U. Kraatz, Tetrahedron Letters, 1973, 1219.

(CF3)2 -”Mez

* Me2”

1 -J(CF&

Saturated Heterocyclic Chemistry

120

+ (CH2COC1)2 +

2Ar--N=C=N--Ar (148)

f +

Q

R (149) bistrifluoromethyl-N-fluoroimine and dimethylamine,103and from the dimerization of the carbodi-imide (148) in the presence of succinoyl chloride.lW Oxazetidines have been synthesized from the reaction of nitroso-compounds with both alleneslo5and alkenes.lo6The reaction to give (149) is claimed10gto be the fist example of the formation of a non-fluorinated oxazetidine ring. Two recent publications provide evidence for an intermediate preceding dioxetan formation in the reaction of alkenes with singlet oxygen. Solventincorporation products, e.g. (152), formed on sensitized photo-induced

c

hv + MeOH lo2

"C

-78

'

R*C=CRZ

-

-0

7

hv.02'

-1

(1 53) R,C = 2-adamantylidene lo3 C. D. Wright and J. L. Zollinger, J . Org. Chem., 1973,38, 1075. lo4 G.Zinner and R. Vollrath, Chem.-Zrg., 1973,97,38 (Chern. A s . , 1973,78,97523u). loS D. H. Coy, R. N. Haszeldine, M. J. Newlands, and A. E. Tipping, J.C.S. Perkin I, lo6

1973, 1561. 0. Tsuge and A. Torii, Bull. Chem. SOC.Japan, 1972,45,3187.

Four-membered Rings

121

reaction of dienes with oxygen in methanol107were not formed on irradiation of the dioxetan (151); thus an intermediate, probably the perepoxide (150), must be involved. Trapping with pinacolone to give t-butyl acetate and the epoxide (153) provides the first direct evidence for the formation of perepoxides in the reactions of singlet oxygen with alkenes.lo8

(1 54)

(155)

The styryl ethers (154) appear to undergo 1,4-~ycloadditionof singlet oxygen to give (155), rather than the more usual 1,2-addition to give dioxetans.loS Singlet oxygen generated by a newly developed polymer-based Rose Bengal sensitizer has been shown1l0 to give all the normal reactions with alkenes, including formation of 1,Zdioxetans, with identical product distributions to other sensitizers. Miscellaneous. Diazetidines (158) are the stable end-products from the reaction of the cyclopentadienone (156) with azo-esters.lll The initially formed adducts (157) can be isolated but readily rearrange to (158); the final 0

Ph

PI1

110

N. M. Hasty and D. R. Kearns, J . Amer. Chem. SOC.,1973, 95, 3380. A. P. Schaap and G. R. Faler, J . Amer. Chem. SOC.,1973, 95, 3381. C. S. Foote, S. Mazur, P. A. Burns, and D. Lerdal, J . Amer. Chem. SOC.,1973,95,586. E. Blossey, D. C. Neckers, A. L. Thayer, and A. P. Schaap, J. Amer. Chem. Suc.,

ll1

D.Mackay, C.W. Pilger, and L. L. Wong, J. Org. Chem., 1973,38, 2043.

lo’

loS lo9

1973, 95, 5828.

122

Saturated Heterocyclic Chemistry 0-

0

(159)

(161)

rearrangement is reversed in photo-irradiation. Irradiation of the nitronyl nitroxide (159) gives the relatively stable radicals (160) and (161), probably via an oxaziridine nitroxide.l12 4 Reactions

Oxetans.-Ring-apeni. The reaction of the oxetans (1 62) with mines, hydrogen sulphide, or hydrogen halides gives the ring-cleavage product!; (163).l13 The same method has been developed into a new synthesis of 3, 5-dialkylpyridines.11" CHzOH

& R

I -

R-C-CH2X

I

CHZOH

Dichloro-oxetan-2-ones(164) undergo cleavage by nucleophiles to give acid derivatives (165).l16 The rate of the reaction depends on the nucleophilicity of the reagent used, and the exclusive acyl-oxygen cleavage is probably due to electronegative substituents increasing the electrophilicity of the carbony1 carbon. A similar cleavageof the intermediate oxetan-2-one (166) is thought to 11' 118 114 116

E. F. Ullman, L. Calli, and S. S. Tseng, J . Amer. Chem. SOC.,1973, 95, 1677. H. Reiff, D. Dieterich, and R. Braden, Annalen, 1973, 365. D. Dieterich, H. Reiff, H. Ziemann, and R. Braden, Annalen, 1973, 1 1 1 . W. T. Brady and A. D. Patel, J . Heterocyclic Chern., 1973, 10, 239.

Four-membered Rings

123

.;ho-

R'R2C(OH)CC1&OX

C1 CI

(165) X = Me2N,MeQ,orOH

(164)

X

ClCHa

COzH

be involved in the formation of (167) on reaction of ethoxide with 3-chloro2,2-dimethylpropionic acid.l16 p-Propiolactone undergoes117 ring-opening on reaction with trimethylsilyl azide to give the silyl ester (168),while a similar reaction with keten dimer gives a mixture of isomeric isocyanates (169). In acetic acid, keten dimer is reportedll* to react with monosubstituted sulphonamides to give 2-alkyl-5methyl-2H-l,2,6-thiadiazin-3-(6H)-one1,l-dioxides (170), while in alkaline solution the reaction gives the acetoacetyl derivative (171), which rapidly cyclizes to (172). Thermal cleaveage of oxetans has been investigated and shown to be regiospecific in the opposite sense to their photoformation.llg Usually t hermolysis appears to cause initial breaking of the weakest carbon-oxygen

L A

+

Me3SiN3

--+

N3CH2CH2C02SiMe3 (168)

m P. Y. Johnson and J. Zitsman, J . Org. Chem., 1973, 38, 2346. 11' H.R. Kricheldorf, Chem. Ber., 1973,106, 3765. 11* J. Diez, G. Garcia-Muiioz,R. Madrofiero, and M. Stud, J . Heterocyclic Chem., 1973,

10,469. G.Jones, S. B. Schwartz, and M. T. Marton, J.C.S. Chem. Comm., 1973, 374.

Saturated Heterocyclic Chemistry

124

RNH

I

S02NHCOCH,COMe

-

I

R (171)

(172)

bond. Thus oxetan (173) gives methyl 3-methylbutenoate and presumably (174), although this latter product was shown to be unstable under the reaction conditions. The photochemical reaction of benzoic acid with olefins has been stwdied.l2O The isobutyrophenone formed, in moderate yield, from. benzoic acid and tetramethylethylene is thought to arise via [2 21 cleavage. of the intermediate oxetan (175). A similar intramolecular cleavage of the oxetan intermediate (176) is one possible pathway for energy transfer in the: 'nn" 3 ~ conversion ~ * postulated in the photochemical decomposition of 5-hexenal.121

+

+

COzMe

H

-+

y C O z M e

+

[A

COzMe

COzMe

(173)

(174)

COzH

la0 T. S. Cantrell, J . Ainer. Cliem. SOC.,1973, lS1 D. A. Hansen and E. K. C. Lee, J . Amer.

95, 2714. Chem. SOC.,1973,95,7900.

Four-membered Rings

(177)

125

.

The photochemical decomposition of the /I-lactone (177), prepared by photolysis of pyran-2-one, has become a popular route to cyclobutadiene. Cyclobutadiene122and various deuteriated cyc10butadienes~~~J~~ have been generated in, an argon matrix by this method for use in spectroscopic and mechanistic studies. In fact, although it is a primary product of the photolysis of a-pyrone, the p-lactone (177) is formed much more slowly than the isomeric ketens (178);125however, unlike the keten formation, the formation of (177) is irreversible and so it becomes the only product. A /3-lactone intermediate (179) is suggested in the reaction of bis(trifluoromethy1)keten with cyclopropenones to give triafulvenes.126

(179)

Rearrangement. Irradiation of O-(l-alky1-2-phenylethyl)thioben~oates~~~ gives styrenes and 2-alkyl-2-hydroxy-l-phenylethyl phenyl thioketones (181). The reaction proceeds via the oxetan (180), which is stable at -78 "C but rapidly rearranges above -20 'C. /%Lactones are readily isomerized to unsaturated acids or dienes by catalytic amounts of Pd" salts,128the products depending on the nature of the solvent used. lee 0. L. Chapman, C. L. McIntosh, and J. Pacansky, J . Amer. Chem. SOC.,1973,95,614. l P 3 A. Krantz, C. Y. Lin, and M. D. Newton, J . Amer. Chem. SOC.,1973, 95, 2744.

0. L. Chapman, D. De La Cruz, R. Roth, and J. Pacansky, J. Amer. Chem. SOC., 1973,95, 1337. l a 6 0. L. Chapman, C. L. McIntosh, and J. Pacansky, J . Amer. Chem. Soc., 1973, 95, 244; R. G. S. Ping and J. S. Shirk, ibid., p. 248. la6 I. Agranat and M. R. Pick, Tetrahedron Letters, 1973, 4079. D. H. R. Barton, M. Bolton, P. D. Magnus, and P. J. West, J.C.S. PerkinI, 1973,1580. lea A. Noels and P. Lefebvre, Tetrahedron Letters, 1973, 3035. le4

Saturated Heterocyclic Chemistry

126 R Ph

I v 2 0

I

-

hv

A

HS

+ PhCH=CHR

Ph

Miscellaneous. 2,2,4-Trimethylpent-3-en-3-olide (182) undergoes addition12s of dichlorocarbeneto the exocyclic double bond to give the spirolactone (183). Aluminium chloride-catalysed rearrangement of (1 83) gave the pentan-4olide (184). 3-Allyloxyoxetan is isomerized by t-butoxide to almost pure cis-3-propenoxyoxetan (185),130which can be hydrolysed by acid to the parent oxetan-3-01. Thermal, photochemical, or free-radical initiation of the reaction between oxetan and dimethyl acetylenedicarboxylate gives the cis- and the transisomers of each of the 1:l adducts (186) and (187). The mechanism wa:s shown to be a free-radical chain process in each case.131 High-temperature thermolysis of spiro(bicyc1o[2,2,l]hept-5-en-2,2’-oxetan)(188) has been reported to give a high yield of 2-meth~1eneoxetan.l~~

129

130 131

133

E. S. Olson and A. J. Whitehead, J.C.S. Perkin I, 1973, 1242. J. A. Wojtowicz and R. J. Polak, J . Org. Chem., 1973, 38, 2061. G. Ahlgren, J . Org. Chem., 1973, 38, 1369. J. Haslouiii and F. Rouessac, Compt. rend. 1973, 276, C, 1691.

Four-membered Rings

127

[711

-I-McO,CC~CCO,hle

\., R.

lhv M e O & y iMeO2C? MeOzC

-k “.02C,fl

hk0,Cf

COzMe

MeOzC (187)

Me0& (186)

The reductive cleavage of polycyclic oxetans under a variety of conditions has been investigated.l% In general, these reactions lead to alcohols, e.g. (189), or alcohol mixtures, depending on the conditions. Oxetan and thioxetan react with singlet carbon atoms to give principally cyclopropane and propylene.13*Experiments with substituted oxetans and thioxetans indicate a mechanism involving a biradical (190), which collapses directly to products; excited-state cyclopropanes are not involved.

(189) Q+C1-

-A . + A + T (190)

+

cx Azetidines.-Ring-opening.

Azetidinones give the expected aminoethylketones (191) on reaction with Grignard reagents.135

133 134

135

R. R. Sauers, W. Schinski, M. M. Mason, E. O’Hara, and B. Byrne, J . Org. Chem., 1973, 38, 642. P. S. Skell, K. J. Klabunde, J. H. Plonka, J. S. Roberts, and D. L. Williams-Smith, J . Amer. Chem. SOC.,1973, 95, 1547. B. Panaiotova, B. A. Pencheva, and A. W. Spasov, Doklady Bolg. Akad. Nauk, 1972, 25, 787 (Chern. Abs., 1973,78, 84 134t).

12s

Saturated Heterocyclic Chemistry

Various N-substituted azetidinones (192) have been allowed to react with methyl 3-amino-3-methylbutyratein an attempt to develop a new route to sterically hindered B-amino-acid pep tide^.^^^ Although in some cases products were obtained, the method is generally unsatisfactory. The kinetics of the aminolysis of some N-aryl-lactams have been investigated.13’Reactions with 1-p-nitrophenylazetidin-2-one(193) show a marked general base catalysis, and the effect of ring-strain in the B-lactam is noted in that the overall rate of reaction of piperidine with (193) is a thousand times greater than with ylactam (194). --+

(193)

RNHCMe2CH2CONHCMe2CH2C02Me

(194)

Hydrolysis of 6-epihetacillin (195) in neutral aqueous solution for several hours gave 6-epiampicillin (196); however, after five days (196) has undergone cyclic rearrangement to the dioxopiperazine (197).lm Rearrangement.The acid-catalysed rearrangement of aryl-substituted azetidin2-ones has been investigated, and the route followed was shown to be determined by the substituents on the azetidinone and the solvent used.139Protoncatalysed reaction of (198) gives the cyclized product (199), but the use of boron trifluoride in toluene on the azetidinone (200) gives the adduct with toluene (201), possibly involving electrophilic substitution of toluene by the intermediate (202). Penicillin /I-sulphoxide acid (203)undergoes ring-expansion to the 2H-1,4thiazinium chloride (204)on stirring with phenylacetyl chloride in acetone.lm The structure (204) was confirmed by X-ray crystallography.

138

C. N. C. Drey, J. Lowbridge, and R. J. Ridge, J.C.S. Perkin I, 1973, 2001. M. G. Blackburn and J. D. Plackett, J.C.S. Perkin 11, 1973, 981. E. E. Roets, A. J. Vlietinck, G. Janssen, and H. Vanderhaeghe, J.C.S. Chem. Comm.,

139 140

1973,484. P. G. Bird and W. J. Irwin, J.C.S. Perkin I, 1973, 2664. R. Thomas and D. J. Williams, J.C.S. Chem. Cornm., 1973, 226.

136 13’

Four-membered Rings

129

kOzH (195)

*C02H

0-

0

130

Saturated Heterocyclic Chemistry

1

H

Stoodley and Kitchin have used141a route involving a Favorskii rearrangement to prepare the monodeuteriated aziridine (205) for studies of the 1,3sulphur migration to give (206). Transition states (207) are suggested on the basis of rearrangement of the labelled species. The base-catalysed epimerization at C-6 of N-trimethylsilyl derivatives of phenoxymethylpenicillin benzyl ester (208) in the presence of DBN (1,5diazabicyclo[4,3,O]non-5-ene) and triethylamine has been investigated.142 DBN gave mixtures of C-6 epimers as the only isolable products, but with triethylamine the 1,4-thiazepine (209) was also obtained. 6-Epiphenoxymethyl- and 6-epibenzyl-penicillin have been prepared by deoxygenation of the corresponding 6-episulphoxides, which were in turn obtained by epimerization of the normal sulphoxides with various bases.143Epimerization at C-6 lal

143

J. Kitchin and R. J. Stoodley, J.C.S. Perkin I, 1973,2460; J. Kitchin and R. J. Stoodley, J . Amer. Chem. SOC.,1973, 95, 3439. A. Vlientinck, E. Roets, P. Claes, G. Jansen, and H. Vanderhaeghe, J.C.S. Perkin I, 1973. 937. P. Claes, A. Vlientinck, E. Roets, H. Vanderhaeghe, and S. Toppet, J.C.S. Perkin I, 1973,932.

Four-membered Rings Me$i

131

BB

&!I Y PhOCH2CO/

0

1

COaCHpPh

2.5PriNLi

’

of penicillin bearing a secondary amide side-chain [formation of (21 l)], previously excluded-by formation of the amide anion, has now been achieved14$ by the use of more than two equivalents of base, presumably via the dianion (210). Miscellaneous. The carbon analogues of penicillin V (212) and phenylpenicillin (213) have been synthesized from benzyl 6-oxopenicillinate by a Wittig

(212) R = CHzOPh (213) R = Ph G . A. Koppel, TetrahedronLetters, 1973, 4233.

132

Saturated Heterocyclic Chemistry

602H

kO2H

C02H

R = NHCOCHZPh (215)

(214)

(216)

reaction followed by h y d r o g e n a t i ~ n .Nuclear ~~~ analogues of 7-methyl-. cephalosporins (214)-(216) have been synthesizedlg6by a route previously usedlq7for penicillin and cephalosporin analogues. The thiazolidine ring in penicillins has been removed without affecting the p-lactam ring, or its other substituents, by a series of reactions in one of which the key step is removal of the sulphonyl side-chain in (217).la

(217)

Metallation of N-substituted B-lactams to give (218) followed by reaction with various electrophilesprovides a new route to 3-substituted lac lac tarn^.^^^

The hydrolysis of the 3-tosyl-substituted /?-lactams (219) and (220) has been reported150to be completely stereospecific. The order of the rates of hydrolysis of (219) and (220) and the non-linearity of the Arrhenius plot for the hydrolysis of (220) have been explained in terms of anchimeric assistance leading to

J. C. Sheehan and Y. S. Lo, J . Org. Chem., 1973, 38, 3228. D. M. Brunwin and G. Lowe, J.C.S. Perkin I , 1973, 1321. 14' G. Lowe and J. Parker, Chem. Comm., 1971, 577; D. M. Brunwin, G . Lowe, and J. Parker, J . Chem. SOC.( C ) , 1971, 3756. l P 8J. C. Sheehan and C. A. Panetta, J . Org. Chem., 1973, 38, 940; J. C. Sheehan, D. Ben-Ishai, and J. U. Piper, J . Amer. C'hem. Soc., 1973, 95, 3064. 140 T. Durst and M. J. Labelle, Canad. J . Chem., 1972, 50, 3196. 150 R. H. Higgins and N. H. Cromwell, J . Amer. Chem. SOC.,1973, 95, 120.

146

146

Four-membered Rings

133

(221)

intermediate l-azabicyclo [1,1,O]butonium ions (221) as the exclusive mechanism by which (219) undergoes hydrolysis, and at least an important mechanism by which (220) undergoes hydrolysis. 2-Alkoxy- and 2-acyloxy-derivativesof azetidinones have been prepared by the Lewis-acid-catalysed reaction of the 2-chloro-derivative (222) with n u ~ l e o p h i l e sand , ~ ~ an ~ elimination-addition mechanism was suggested. Peracid oxidation of the acid chloride p-lactams (223) gives the cis-@lactams (224)152 rather than the 3-hydroxy-2-azetidinonesexpected on the basis of the analogous oxidation of simple acid ch10rides.l~~ Decarboxylation of the carboxylic acid may be involved, although this is not established on the basis of the evidence presented. The Moffatt oxidation has been used as the final step in the synthesis of N-unsubstituted lac lac tam^.^^*

COzMe

COaMe

cis or trans

(222) R = CsHa(C0)2N X = ORorOCOR

V

F

Alkylation of anions of SchiiT bases has again been a popular route to penicillins and related derivatives.155A new stereospecific synthesis of C-6methoxy-penicillins and C-7-methoxy-cephalosporinsinvolves initial thiomethylation of the Schiff-base anion, e.g. (225).15sA similar route involving 151

15* 153 lS4

lS6 156

S. Wolfe and M. P. Goeldner, Tetrahedron Letters, 1973, 5131. A. K. Bose and J. C. Kapur, Tetrahedron Letters, 1973, 1811. D. B. Denney and N. Sherman, J. Org. Chem., 1965,30, 3760. A. K. Bose, M. Tsai, S. D . Sharma, and M. S. Manhas, Tetrahedron Letters, 1973, 3851. E. H. W. Bohme, H. E. Applegate, J. B. Ewing, P. T. Funke, M. S. Puar, and J. E. Dolfini, J . Org. Chem., 1973, 38, 230. W. A. Spitzer and T. Goodson, Tetrahedron Letters, 1973, 273; T . Jen, J. Frazer, and J. R. E. Hoover, J , Org. Chem., 1973, 38,2857.

134

Saturated Heterocyclic Chemistr-y

addition of anions to activated olefins has been used to prepare a variety of C-6(C-7)-substituted penicillins and c e p h a l o ~ p o r i n s and , ~ ~ ~various heteroatom derivatives have been prepared by the addition of the appropriate electrophilic reagent to anions of Schiff bases (225) and (226).158

A direct one-step method for the introduction of the 6-methoxy-group into penicillins has been developed by Baldwin and c o - w o r k e r ~through l~~ reaction with t-butyl hypochlorite and methanol; acylimine intermediates, e.g. (227),,

c1

PhOCH,CQNA ButOCl

O M e O H , sodium borate 0°C

-

H I 1

0

are thought to be involved. However, this route requires protection of the sulphur when applied to penicillins. An alternative but very similar method, which involves formation of the amide anion (with LiOMe) before treatment with t-butyl hypochlorite, does not require protection of sulphur and thus has considerable merit.leOVarious minor modifications of the same method have been used to prepare 6-a-hydroxy-, alkoxy-, and formyloxy-penicillins161 and the spiro-derivative (228).162A related method involving halogenation of G. H. Rasrnussan, G . F. Reynolds, and G . E. Arth, Tetrahedron Letters, 1973, 145. W. A. Slusarchyk, H. E. Applegate, P. Funke, W. Koster, M. S. Puar, M. Young, and J. E. Dolfini, J . Urg. Chem., 1973, 38, 943. lSs J. E. Baldwin, F. J. Urban, R. D. G. Cooper, and F. L. Jose, J . Amer. Chem. Suc., 1973,95,2401. 160 G . A. Koppel and R. E. Koehler, J. Ainer. Chem. SOC., 1973, 95, 2403. 161 R. A. Firestone and B. G. Christensen, J . Org. Chern., 1973, 38, 1436. lS2 G . A. Koppel and R. E. Koehler, Tetrahedron Letters, 1973, 1943.

16'

16*

Four-membered Rings

135

2

U3&OCONHZ

0

0 COzR (228)

the Schiff-base anion (229), followed by treatment with methanol, has been developed163to give stereospecifically a-methoxy-penicillins and -cephalosporins. The iminium salt (230) is the suggested intermediate, to which methanol adds from the least hindered side. PhCH=N

p---&- p-----Br H

PhCH=N

H

I

0

I

0

&OR

kOR

(229)

[PhCH=fip1]

P h C H =OMe N p l t

0

N.,

0

N\

(230)

Heating penicillin $-oxides causes equilibration with the corresponding sulphenic acids (23 l), which have been trapped with thi01s,l~~ acetylenes>s5o166 and 01efins.l~~

163 164 166

L. D. Cama and B. G . Christensen, Tetrahedron Letters, 1973, 3505. R. D. Allan, D. H. R. Barton, M. Girijavallabhan, P. G . Sammes, and M. V. Taylor, J.C.S. Perkin I, 1973, 1 1 82. I. Ager, D. H. R. Barton, D. G . T. Greig, G. Lucente, P. G . Sammes, M. V. Taylor, G . H . Hewitt, B. E. Looker, A. Mowatt, C. A. Robson, and W. G. E. Underwood, J.C.S. Perkin I, 1973, 1187. D. H. R. Barton, I. H. Coates, P. G . Sammes, and C. M. Cooper, J.C.S. Chem. Comm. 1973, 303.

10

136

Saturated Heterocyclic Chemistry

Rings containing More than One Heteroatom.-Ring-opening. The thermal decompositionof tetramethyl-1,Zdioxetan is greatly accelerated in the absence of oxygen, since oxygen deactivates the triplet acetone so rapidly that it cannot sensitize the decomposition of the d i 0 ~ e t a n .This l ~ ~ is thought to be the first example of a reaction in which the chain decomposition of a molecule occurs as the direct result of interaction with its electronically excited cleavage products. The large solvent effects in methanol for the thermal decomposition of tetramethyl-l,2-dioxetanhave now been shown to be due to a competitive 'dark' process caused by trace impurities.168 The kinetics of thermolysis of tetramethyl-l,2-dioxetanin various solvents have been studied,169and the enthalpies of thermolysis of the dioxetan in the solid state and in butyl phthalate solution have been determined as 70 and 61 kcal mol-l, respe~tive1y.l~~ Acetone phosphorescence has been observed for the first time by conventional spectrophotoluminescence techniques in fluid solution by the thermolysis of tetramethyl-1,2-dioxetan.171 Energy transfer between identical molecules in solution has been studied by irradiating tetramethyl-1,Zdioxetan in PH,]acetone under conditions where the acetone produced was not excited by the direct absorption of light.172 Selective trapping of singlet and triplet acetone and analysis of the extent of deuteriation indicates that on average singlet acetone makes one energy exchange per lifetime, whereas triplet acetone makes fourteen. That photolysis of the dioxetan gives excited acetone has also now been demonstrated.17:' Trimethyl-1,Zdioxetan has been used as the source of excited states for energy transfer without the use of irradiation.17" The technique was used to carry out a variety of 'photochemical' reactions. A rare example of a biphonic process (a reaction involving two electronically excited states) has been observed175during biacetyl-sensitized photolysis of tetramethyl-1,Zdioxetan and valerophenone to give acetone and acetophenone. No reaction took. place in the absence of the dioxetan, and excited biacetyl has only 56 kcal mot1, compared with the 74 kcal mol-l required for valerophenone excitation; thus the results can only be explained by energy transfer from excited acetone to valerophenone.

167

P. Lechtken, A. Yekta, and N. J. Turro, J. Amer. Chem. SOC.,1973, 95,3027. T. Wilson, M. E. Landis, A. L. Baumstark, and P. D. Bartlett, J. Amer. Chem. SOC., 1973,95,4765. C. Steinmetzer, P. Lechtken, and N. J. Turro, Annalen, 1973, 1984; N. J. Turro and P. Lechtken, J. Amer. Chem. SOC.,1973, 95, 264. P. Lechtken and G. Hohne, Angew. Chem. Internat. Edn., 1973, 12, 772. N. J. Turro, H. C. Steinmetzer, and A. Yekta, J. Amer. Chem. SOC.,1973, 95, 6468. P. Lechtken and N. J. Turro, Angew. Chem. Internat. Edn., 1973, 12, 314.

16ri H. 170 171

17p 173 17*

N. J. Turro, P. Lechtken, A. Lyons, R. R. Hautala, E. Carnahan, and T. J. Katz, J . Amer. Chem. SOC.,1973, 95,2036. E. H. White, P. D. Wildes, J. Wiecko, H. Doshan, and C. C. Wei, J. Amer. Chem. SOC.,

175

N. J. Turro and P. Lechtken, Tetrahedron Letters, 1973, 565.

1973,95,7050.

Four-membered Rings

137 0

EtS

\ /SEt /"="\

EtS

hv

I

(EtS)ZCO

+ EtSCOCOSEt + EtSSEt Est*Et

SEt

H

Et (2331

Sensitized photo-oxidation of tetrathioethylethylene (232) gives either the corresponding dioxetan or the perepoxide (233), which fragments via a biradical to the products shown.176Although substituted allenes did not react with the singlet oxygen precursors, triphenyl phosphite-ozone and aqueous potassium perchromate, reaction with singlet oxygen generated by sensitization did occur to give carbon dioxide and the corresponding ketones.177On the basis of similar reactions with alkenes, the spirodioxetan (234) is presumably the intermediate. The effect of ring-strain on [2 21 addition of singlet oxygen to alkenes has been investigated through reactions of various aryl-substituted cyclopropene~.~~~ The reaction of tetramethyl-l,2-dioxetan with triphenylphosphine gives the phosphorane (235), which decomposes above 55 'C to give phosphine oxide and tet ramethylethylene oxide.170

+

PhsPO

R'-

(234)

(235)

Both heterocycles (236) and (237)give polymers when heated,lsOpossibly via the common intermediate diazetidinone (238). HN-N

W. Ando, J. Suzuki, T. Arai, and T. Migita, Tetrahedron, 1973, 29, 1507. T. Greibrokk, Tetrahedron Letters, 1973, 1663. 178 I. R. Politzer and G. W. Griffin, Tetrahedron Letters, 1973, 4775. 179 P. D. Bartlett, A. L. Baumstark, and M. E. Landis, J . Amer. Chem. SOC.,1973, 95, 6486. lSoT. Hirata, H. B. Wood, and J. S. Driscoll, J.C.S. Perkin I, 1973, 1209. 176

177

3

Five- and Six-membered Rings and Related Fused Systems BY A. E. A. PORTER

1 Introduction As has been the case in previous years this chapter is written in three sections dealing with (i) conformational analysis of reduced heterocyclic systems, (ii) cycloaddition reactions used for the synthesis of reduced heterocyclic systems, and (iii) the general chemistry of reduced heterocyclic systems. Included under the first heading are systems containing sulphur an'd phosphorus, although these compounds are not included in the other twlo sections. Aside from these limitations material that is within the scope clf other Specialist Periodical Reports has been excluded, and within these boundaries an attempt has been made to present a comprehensive review. General criticisms of the material covered include the failure of authors to adopt SI units, in spite of stated editorial policy; the failure of the abstract of a paper to state clearly or concisely the content of the paper; and a tendency to spread a given piece of work over more papers than is necessary. 2 Conformational Analysis of Reduced Heterocycles General.-A review on the application of thermochemical techniques to the determination of conformational equilibria has been presented.l Application of Wolfe's rule2 to a large number of 1,2-disubstitutedethane derivatives leads to the wrong prediction concerning the relative stabilities of the gauche- and trans-conformers. Phillips and Wray3 have observed that if the energy difference (AEY-,) between the gauche- and trans-forms of 1,2disubstituted ethanes in the gas phase is considered solely in terms of the polar nature of the substituents, then, for a given series, a linear relationship exists between (AEY',) and the sum of the Huggins electronegativities of the polar substituents (X).Values calculated using the equation

a

K. Pihlaja and E. Taskinen, Phys. Methods Heterocyclic Chem., 1973,6,199. S. Wolfe, A. Rauk, L. M. Tel, and I. G. Csizmadia, J. Chem. SOC.(B), 1971, 136. L. Phillips and V. Wray, J.C.S. Chem. Comm., 1973, 90.

138

Five- and Six-membered Rings and Related Fused Systems 139 show that as the sum of the electronegativities increases, the trans-conformer becomes less stable. 1,2-Dioxygenated ethane derivatives have a value of CE of 7.0, and, since solvents play an important part in determining the point at which the gauche-conformer becomes the more stable, this concept readily explains the preferred formation of the thermodynamically stable (1) rather than the sterically favoured (2) during the reaction of formaldehyde with D-arabinitol. Conformer (2) has three trans oxygen-oxygen interactions, whilst (1) can adopt a conformation (lb) in which only gauche oxygenoxygen interactions occur. CHPOH

I

(2)

This concept also appears to have important implications in normal electrophilicaddition to double bonds, since as the electronegativity difference between the two ‘halves’ of the electrophilic species increases, the overall preference for trans addition decreases. Badderlf has attempted to extend Wolfe’s generalizations in terms of ‘bonding into anti-bonding orbitals.’ Oxygen-containing Rings.-The R-value method has served as an important source of structural information for six-membered heterocycles, but application of this method to five-membered rings such as tetrahydrofuran leads to a considerable overestimation5 of torsional angles. The 300 MHz spectra of 2-substituted-4-halogenomethyl-1,3-dioxans(3) have been examined and permit a convenient distinction6=between the cisand trans-isomers. On the basis of coupling constants between protons at positions 4 and 5 , a number of predictable conformations have been proposed. In the case of the trifluoromethyl compound (3; R = CF,) anomalous 5J(F,H) couplings across oxygen are observed.6b G. Badderly, Tetrahedron Letters, 1973, 1645. J. B. Lambert, J. J. Papay, E. S. Magyar, and M. K. Neuberg, J. Amer. Chern. SOC., 1973, 95,4458.

(a) F. Borremans, M. Anteunis, and F. Anteunis-de-Ketelaere, Org. Magn. Resonance, 1973,5,299; (b) M. Anteunis, R. Van Cauwenberghe, and C. Becu, Bull. SOC.chim. belges, 1973, 82, 591.

Saturated Heterocyclic Chemistry

I40

H (3)

(4)

lH N.m.r spectra of the cis- and trans-forms of 2,5-disubstituteddioxolan-4ones (4) show long-range coupling between protons at the 2- and 5-positions, confirming that the presence of such couplings7 is not diagnostic of a cis relationship. Variable-temperature lH n.m.r. studies* on the spirodioxolans (5) and (6) indicate that the former (5; R = H) displays a conformational preference for the O-axial conformation (5a) in non-polar solvents, but for the 0equatorial conformation (5b) in polar solvents. The latter, however, prefers the O-axial conformation (6a) regardless of solvent polarity. In the case of

(64

(6b)

the dimethyl analogue (5; R = Me) the O-equatorial conformation is preferred, a reversal of the predicted trend. Clarification of these results awaits further work. Conflicting results on the relative energies of twelveg conformers of the cis- and trans-but-Zene ozonide (7) have been obtained using EHT and

R. Brettle and I. D. Logan, J.C.S. Perkin ZZ, 1973, 687. R. A. Y. Jones, A, R. Katritzky, D. J. Nichol, and R. Scattergood, J.C.S. Perkin ZZ, 1973, 337. R. A. Rouse, J. Amer. Chem. SOC.,1973,95, 3460.

Five- and Six-membered Rings and Related Fused Systems 141 CND0/2 methods. Similar calculations when applied to ethylene ozonide demonstrate that the CND0/2 method accurately predicts the experimental conformation and is probably more reliable. Conformational equilibria in a series of cis- and tram-2-alkoxy-4-phenyl2,3-dihydropyrano[2,3-c]pyrazoles (8) have been investigated using graphical methodslO and although complex have been rationalized in terms of steric interactions between the 4- and 5-substituents and the anomeric effect. Application of the R-value method to a number of substituted six-membered anhydridesll supports X-ray findings12that these compounds exist in a sofa conformation in which small deformations due to steric effects of the substituents occur. Examination of the lH n.m.r. spectrum of the dihydropyran (9) in the presence of Eu(fod), has permitted the evaluation of all coupling constants, and on the basis of the values obtained13 the half-chair conformer (9) appears probable.

(9)

1 ,2-Dioxacyclohexene (10) displays similar conformational properties to cyclohexene. The value of 54.4 kJ mol-l for the ring-inversion barrier14 is much higher than in cyclohexene, and this high figure has been attributed to unfavourable van de Waals repulsions, 0-0 torsional interactions, and electrostatic effects in the intermediate boat conformation (Scheme 1).

Scheme 1

Conformational properties of 1,3-dioxans have been widely studied. Using a microcalorimetric method the Stirling group15have determined the enthalpy change for the chair-twist-chair conversion of 1,3-dioxan as 37.3 kJ mol-l. lo l1 la l3 l4 l5

G.Desimoni, L. Astolfi, M. Cambieri, A. Gamba, and G . Jacconi, Tetrahedron, 1973, 29, 2627. F. J. Koer, T. M. W. van Asbeck, and C. Altona, Rec. Trav. chim., 1973, 92,1003. F. J. Koer, A. J. de Kok, and C. Romers, Rec. Trau. chim., 1973,91,691. A. De Boer, Org. Magn. Resonance, 1973, 5 , 7 . M. L. Kaplan and G. N. Taylor, Tetrahedron Letters, 1973,295. R. M.Clay, G. M. Kellie, and F. G . Riddell, J. Amer. Chem. SOC.,1973,95, 4632.

142

Saturated Heterocyclic Chemistry

Eliel and HoferlGhave observed that the position of equilibrium for 2isopropyl-5-alkoxy-ly3-dioxans is dependent on solvent polarity; thus in polar solvents the conformer with the axial alkoxy-group is preferred, consistent with the observations of Phillips and Wray. Empirical values for the chemical shifts of protons in the 1,3-dioxan ring have been calculated1’ and these values applied to substituted dioxans. As substituents tend to alter the conformational properties of the system, the initial assumption of a preferred conformation may lead to erroneous assignments, although in the case of methyl substituents the results appear to be consistent. lJC3C,H) Values in a number of lY3-dioxansappear to be dependent on the orientation of the ring protons relative to the oxygen atoms. Using trans-2-methyl-5-t-butyl-1,3-dioxanthe lJ(13C,H) coupling constant was shown to be 158 Hz,whereas the cis-isomers have a value of 166 Hz. In the: systems studied, this result was diagnostic.18 Anteunis and co-workers have demon~tratedl~ that the spirodioxans, [ l l ; X = (CH,),] exhibit similar conformational preferences to the spiro-, dioxolans ( 5 ) . However, as the ring size increases the preference for conformation (1 la) decreases, and when X is (CH,), or (CH,), (1 1b) is preferred. R

dl

X

The reasons for this difference are far from clear and the authors claim that the difference is ‘inherent’ in the system. Work by this group on the related system (12) has revealed20 the highest known barrier to inversion of 1,3dioxans in a non-annelated system and this high valuehas been attributed to a double inversion (12a -+ 12c) brought about by unfavourable steric interactions in the intermediatd(l2b). Chair-chair equilibria in trans-4,5,5trimethyl-6-alkyl-lY3-dioxans show a marked preference for the conformer in which the 6-alkyl substituent

E. L. Eliel and 0. Hofer, J . Amer. Chem. SOC.,1973, 95, 8041. P. Maroni, L. Cazaux, J. P. Gorrichon, P. Tisnes, and J. G. Wolf, Org. Magn. Resonance, 1973, 5 , 517,523. K. Bock and L. Wiebe, Acta Chem. Scand., 1973, 27, 2676. A. K. Bhatti and M. Anteunis, Tetrahedron Letters, 1973, 71. ao D. Tavernier, M. Anteunis, and N. Hosten, TetrahedronLetters, 1973, 75.

l6

Five- and Six-membered Rings and Related Fused Systems

143

f

occupies the equatorial position.21 However, trans-4-methyl-6-alky1-ly3dioxans exhibit unusual behaviour in that equatorial preference for the 6alkyl substituent decreases in the order Pri > Et > Pr” w Bu’ w neopentyl M Me. Clearly, steric factors22are not the most important and reasons for this trend remain unclear. Results for trans-4-vinyl-6-rnethyl-l,3-dioxan clearly demonstrate that the vinyl group prefers the axial position. This axial preference seems overriding since in cis-4-vinyl-2,5-dimethyl-l,3-dioxan the trans-dia~ial~~ conformer (1 3) is preferred.

(13)

Conformational properties of the 4-oxo-l,3-dioxan ring are limited by the planarity of the ester function. The Finnish group have conducted a detailed study of substituent effects on this ~ y s t e m . ~ Three * - ~ ~ principal conformations (14-16) have been identified and it has been demonstrated that the conformational properties of the system are markedly dependent on substituents. Axial 2- and 6-substituents give rise to the 2,5-twist-boat as do 5,5,6- and

21 2a

23 24 25

26

27

28 30

D. Tavernier and M. Anteunis, Bull. SOC.chim. beiges, 1973, 82, 405. M. Anteunis, D. Tavernier, and G. Swaelens, Rec. Trav. cliim., 1973, 92, 531. M. Anteunis and M. Coryn, Bull. Soc. chim. belges, 1973, 82, 413. P. Ayras and K. Pihlaja, Suomen Kem., 1973, 46, 167. P. Ayras and K. Pihlaja, Tetrahedron, 1973, 29, 3369. P. Ayras, Suomen Ken2., 1973, 46, 151. P. Ayras and K. Pihlaja, Tetrahedron, 1973, 29, 1311. P. Ayras and K. Pihlaja, Acta Chem. Scand., 1973, 27, 2511. P. Ayras, Acta Chem. Scand., 1973, 27, 2887. P. Ayras, Adu. Mol. Relaxation Processes, 1973, 5 , 219.

Saturated Heterocyclic Chemistry

144

cis-2,5,6,6-substitution;2-, 2,5-,and trans-2,5,6,6-substitutionfavour the half-chair conformation. Determination of the barrier to ring inversion31 of 1,4-dioxen using lH n.m.r. methods gives a value of 31.69 kJ mol-l, a value which agrees with that obtained from far-infrared studies. A twist angle of 39.3' was obtained from proton-proton coupling constants. This value differs appreciably from ihat obtained by the i.r. method, which relies on a number of assumptions and must be regarded as suspect. A crystal-structuredeterminati01-1~~ of glyceraldehyde dimer (1 7) shows that it exists in the chair conformation with all substituents in equatorial positions. Two of the five possible isomers of 2,3,5,6-tetramethyl-l,4-dioxanhave been isolated33and their structures assigned as (18) and (19) on the basis of their lH n.m.r. spectra.

(17)

(18)

(19)

Electron diffraction studies34 of 2,4,6-trimethyl-1,3,5-trioxan in the gas phase show that the ring exists in the chair form with all three methyl groups possessing the equatorial orientation. Accurate bond lengths and angles are reported. Nitrogen-containing Rings.-Examination of the lH n.m.r. spectra of model cis and trans symmetrical 2,5-disubstituted pyrrolidines has led to the conclusion35that the ct-protons of the cis-isomer always appear at higher field than those of the corresponding trans-isomer. The Portsmouth group has inve~tigated~~ a number of perhydro-7amethyloxazolo[3,4-c]oxazoles, obtained by classical synthesis. Molecular models suggest that a number of relatively flexible cis-fused conformations are possible, which are interconvertible with the trans-fused system through nitrogen inversion. Variable-temperature lH n.m.r. studies within the range -85 to +llO"C show that the conformational properties do not alter appreciably in this range, and a distorted cis-fused structure (20) is proposed on the basis of coupling constants. When R = Me the value of JQemfor the N-CH, protons is -8.0 Hz, the largest value on record for this arrangement in a five-membered ring. Substitution at other positions alters the ring conformation but not to a marked extent. 3L 32 33 34

36 36

R. H . Larkin and R. C. Lord, J. Amer. Chem. Soc., 1973,95, 5129. M. Senona, Z. Tiari, K. Osaki, and T. Taga, J.C.S. Chem. Comm., 1973, 880. Y . Sumi and F. Kametani, Chem. and Pharm. Bull. (Japan), 1973, 21, 1103. E. E. Astrup, Acta Chem. Scand., 1973, 27, 1345. E. Breuer and D. Melumad, J. Org. Chem., 1973, 38, 1601. T. A. Crabb, M. J. Hall, and R. 0. Williams, Tetrahedron, 1973, 29, 3389.

Five- and Six-mernbered Rings and Related Fused Systems

145

+

I CO,Me

Proton displacements3' observed by the addition of Eu(fod), to A1-pyrazolines are consistent with the shift reagent approaching the a~o-groupin the plane of the ring. A'-Pyrazolines carrying substituents at the 3- or 4-positions usually exist in the envelope form, e.g. (21) or (22), the position of the equilibrium depending on the nature of the substituents. Using the t-butyl group to hold the c o n f o r m a t i ~ na~folding ~ of 36' has been estimated for (21). 1,2-Diphenyl-4-t-butylpyrazoline exists in an envelope c o n f ~ r m a t i o nin~ ~ which rapid nitrogen inversion results in a net shielding of the protons H1 (23) and deshielding of H2.

(234

(23W

Barriers to rotation about the Ar-N bond in l-arylhydantoins (24) and thiohydantoins** indicate that an ortho-methyl group restricts rotation to a greater extent than an ortho-chlorine. In the case of the isomeric 3-arylhydantoins (25) the reverse is observed and this difference has been attributed to electrostatic repulsion between the chlorine and the carbonyl oxygens in the torsional transition state.

38

M. Franck-Neumann and M. Sedrati, Org. Magn. Resonance, 1973,5, 217. R. Danion-Bougot and R. Carrie, Org. Magn. Resonance, 1973,5 , 453.

38

K.Berg-Nielsen, Acta Chem. Scand., 1973, 27, 1092.

40

L. D.Colebrook, H. G. Giles, A. Granata, S. Icli, and J. R. Fehlner, Canad. J . Chem.,

37

1973,51,3635.

Saturated Heterocyclic Chemistry

146

In contrast to the perhydro-oxazolederivatives (20), the octahydroimidazo[I ,S-alpyridines have been assigned41the trans-fused structure (26) on the basis of their l H n.m.r. spectra and the appearance of Bohlmann bands in the i.r. spectra. t-Butyl hypochlorite oxidation of 2,4,6-trialkylhexahydro-l,3,5-triazines produces the unusual42 1,3,5-triazabicyclo[3,1 ,O]hexenes (27). With small alkyl groups the labile cis-isomers (27a) are produced, which undergo isomerization to the trans-isomers (27b) in methanol at 25 'C. When bulky groups are present the trans-isomers are preferentially formed.

R' (27a)

R'

(27b)

The crystal structure43 of 1 ,4-dimethyl-5-ethyl-5-hydroxy-A2-1 ,2,3-tri-azoline shows that this ring adopts an envelope conformation with the: hydroxy-group in the pseudo-axial position and the alkyl groups pseudo-, equatorial. The anticipated surge of 13C data on piperidine and alkylpiperidine~~**~' has provided supporting information for the known conformational preferences of such systems. 13CShifts induced by the protonation of piperidine derivative^^^ confirm the predictions of Pople4' that the electrons normally associated with the hydrogen atoms at C-2 and C-6 are partly delocalized through the carbon skeleton to the positively charged nitrogen. Crystalstructure data on piperidinium p - t o l ~ a t eshow ~ ~ that the piperidinium ion adopts a normal chair conformation in the solid state. The Norwich group has developed49computer programs which permit calculation of ring geometry, including vector angles for dipole moment components and energy minimization of bond and torsional angle strain. Data obtained for 1 -alkylpiperidines support previous conclusions. Stereochemical orientation during alkylation of N-substituted piperidines is a complex problem.50The Norwich group51has examined benzylation of 'l

T. A. Crabb, P. J. Chivers, and R. F. Newton, Org. Magn. Resonance, 1973, 5 , 397, T. Nielsen, R. L. Atkins, and D. W. Moore, Tetrahedron Letters, 1973, 1167. K.Kaas, Acta Cryst., 1973,B29, 1458. H.Booth and D. V. Griffiths, J.C.S. Perkin 11, 1973, 842. D.Wendisch, H. Feltkamp, and U. Scheidegger, Org. Magn. Resonance, 1973,5,129. I. Morishirna, K. Yoshikawa, K. Okada, T. Yonezawa, and K. Goto, J. Amer. Chem. SOC.,1973,95, 165. J. A. Pople and M. S. Gordon, J. Amer. Chem. SOC., 1967, 89,4253. S. Kashino, Acta Cryst., 1973,B29, 1836. I. D. Blackburne, R. P. Duke, R. A. Y. Jones, A. R. Katritzky, and K. A. F. Record J.C.S. Perkin 11, 1973, 332. R. V. Smith, F. W. Benz, and J. P. Long, Canad. J. Chem., 1973,51, 171. R. P. Duke, R. A. Y. Jones, and A. R. Katritzky, J.C.S. Perkin ZZ, 1973, 1553.

r a A. 43

44 45

46

47 48 49

so 51

Fiue- and Sixmembered Rings and Related Fused Systems 147 1-methyl-4-phenylpiperidinesin several solvents, using benzyl halides , benzyl tosylate, and ring-substituted derivatives. Whereas benzyl chloride and its 4-nitro-derivativereact by equatorial approach, p-methoxybenzyl chloride attacks axially. X-Ray supports these observations but no satisfactory explanation for these differences in behaviour has been put forward. Lyle and Pridgen53have demonstrated that 3-axial or branched-chain 3equatorial substituents have an anisotropic effect on the benzylic methylene protons of l-benzylpiperidines, resulting in their appearance as an AB quartet. This effect has some precedent in that 3-axial substituents introduce anomalous effects in the 0.r.d. curves of six-membered cyclic ketones. On the basis of an N-benzyl singlet it has been possible to cdnfirm the structural assignment54 of the piperidine (28) previously prepared by Casy and coworkers.

PhCH\

(28)

A synthesis of cis- and trans-4-substituted pipecolic esters55 has been reported and the stereochemical assignments rest on their lH n.m.r. spectra. Epimerization studies suggest that the conformational preference of the ethoxycarbonyl group is less than would be expected from comparison with cyclohexane carboxylates and this difference has been attributed to dipolar repulsion between the axial ethoxycarbonyl and the nitrogen lone pair. Intramolecular hydrogen-bonding appears to play an important part in determining conformational preferences. 1.r. studies on 3-hydroxypiperidine~~~ prepared by hydroboration of the corresponding 3-piperideines5' indicate a preference for the O-axial conformer in which intramolecular hydrogen-bonding with N-1 stabilizes5*the structure. The physio1ogical properties of 4-phenyl-4-h y dr oxypiperidines render the conformational properties in terms of structureactivity relationships of this 52 53 54 55

56 67

R. J. Carruthers, W. Fedeli, F. Mazza, and A. Viciago, J.C.S. Perkin 11, 1973, 1558. R.E. Lyle and L. N. Pridgen, J . Org. Chem., 1973, 38, 1628. A. F. Casy, A. B. Simmonds, and D. Staniforth, J. Org. Chem., 1972,37,3189. D.E. Caddy and J. H. P. Utley, J.C.S. Perkin IZ, 1973, 1258. S. Vasickova, A. Vitek, and M. Tichy, Coll. Czech. Chem. Comm., 1973, 38, 1791. M. Ferles, T. Stern, P. Trska, and F. Vysata, Coll. Czech. Chem. Comm., 1973, 38, 1206. R. E. Lyle, D. H. McMahon, W. E. Krueger, and C. K. Spicer, J . Org. Chem., 1966, 31,4164.

148

Saturated Heterocyclic Chemistry OAc

I

(29)

system of some importance. 13CN.m.r.59*60 and X-rayG1studies on the 1,2,6trimethyl derivative (29) support a chair conformation with the acetylated hydroxy-function at the axial position. E.p.r. is a very sensitive tool for the study of paramagnetic species and has been applied to a study of piperidine nitroxidesG2over a temperature range -100 to +35 'C. Computer simulation confirms a rapid chair-chair equilibrium and yields accurate values for the associated activation parameters. The observed variation of coupling constants of protons at C-2 and C-6 may be rationalized in terms of rapid nitrogen inversion. In continuation of their studies of bicyclic systems the Portsmouth groupG3 have investigated the conformational properties of the cyclic amides (30) and (31) and the perhydro-oxazines (32) and (33).64The preferred conformation

0

(30)

(31)

.(34

(33)

of oxazolo [3,6c]oxazines (32) varies according to substitution; thus the unsubstituted molecule adopts conformation (34) whereas substitution at position 8 results in a mixture of conformers (35) and (36). Oxazino-oxazines prefer the unexceptional chair-chair conformation (37) and conformational preferences in this series are rationalized in terms of minimization of dipolar interactions arising from the 1,3-arrangement of the heteroatoms. 13C, lH, and lQFn.m.r. studiesG5on N-substituted cis-decahydroquinolines (38) have revealed that when R = H or Me conformer (38b) is favoured, but as the size of R increases to e.g. CD2CH3or CD2CF3,conformer (38a) becomes more favoured. Newman projections along the N-C-8a bond show 69

A. 5. Jones, A. F. Casy, and K. M. J. McErlane, Canad. J . Chem., 1973, 51, 1782, 1790.

6o

61 62

63 O5

A. F. Jones, A. F. Casy, and K . M. J. McErlane, J.C.S. Perkin 1, 1973,2576. K. Hayakawa and M. N. G . James, Canad. J. Chem., 1973,51, 1535. R. E. Rolfe, K. D. Sales, and J. H . P. Utley, J.C.S. PerkinU, 1973, 1171. R. Cahill and T. A. Crabb, Org. Mugn. Resonance, 1973, 5, 295. T. A. Crabb and M. J. Hall, J.C.S. Perkin 11, 1973, 1379. H. Booth and D. V. Griffiths, J.C.S. Chem. Comm., 1973, 666.

Fiue- and Six-membered Rings and Related Fused Systems

149 _”-

(37)

that when R = H the repulsive interaction which dominates is the C-2-C-8 repulsion (39a), which leads to a preference for (38b). As R increases in size the interaction R-C-8 (39b) becomes dominant, leading to a preference for (38a).

(394

(39b)

Bernath and co-workers66have investigated the conformational properties of a number of cis- and trans-1,3-oxazolin-2-ones (40) and (41). The transisomers (41a and b) preferentially adopt a diequatorial conformation. For the cis-isomers (40a and b), however, the preferred conformational form depends upon the value of n ; thus when n = 4 the heteroatom-axial conformers (42) are favoured, but when n = 5 the heteroatom-equatorial conformer (43) is favoured. A crystal structure of the dihydro-oxazine (44) has been reported in which the anticipated half-chair conformation is observed?’ 66

67

P. Sohar and G. Bernath, Org. Magn. Resonance, 1973, 5 , 159; G. Bernath, G. Gondos, K. Kovacs, and P. Sohar, Tetrahedron, 1973, 29, 981. F. Garbassi and L. Giarda, Acta Cryst., 1973, B29, 1190.

150

Saturated Heterocyclic Chemistry

I;r

H (41) a: Y = N H , X = 0 b; Y = 0 , X = NH

Ph (43)

(3 4)

A synthesis of tetrahydro-l,4,Zdioxazineshas been published.68 Lowtemperature lH n.m.r. studies indicate the existence of two conformers (45a and b). A conformational free energy difference of 4.4 kJ mol-l has been observed for (45; R = H) and is intermediate between values obtained for 3-methyltetrahydro-1,3-oxazine and 2-methyltetrahydro-1,Zoxazine. The observation of both (45a and b) shows that both nitrogen and ring inversion are slow on the n.m.r. time-scale.

Photoelectron spectroscopy permits a quantitative determination of the interaction between molecular orbitals, and in the case of hydrazine derivat i v e the ~ ~ extent ~ of the interaction varies with the dihedral angle between the lone pairs of electrons on adjacent nitrogen atoms (46). Using model systems of fixed geometry, it has been possible to construct calibration figures?O Application of the data to the controversial conformational properties of l ,2-dimethylhexahydropyridazinesuggests that Anderson's claim'l that a single conformer (47) exists at -120 OC needs some 68

BD 70

71

R. A. Y. Jones, A. R. Katritzky, A. R. Martin, and S. Saba, J.C.S. Chem. Comm., 1973,908. P. Rademacher, Angew. Chem. Internat. Edn., 1973,12,408. S. F. Nelsen and J. M. Buschek, J . Amer. Chem. SOC.,1973,95, 2011. J. E.Anderson, J . Amer. Chem. SOC.,1969,91, 6374.

151

Five- and Six-membered Rings and Related Fused Systems

(47)

(49)

revision. The presence of three conformers (47), (48), and (49) has been established, with (47) predominating, supporting the earlier work of K a t r i t ~ k y . ~ ~ Calculation of the conformer populations of a number of reduced heterocycles by dipole moment methods has been carried out by the Norwich Figures were based on calculated dipole moments of expected conformers and assume that vector addition may be applied. In contrast to piperidines and piperazines the N-H protons of hexahydropyrimidines, tetrahydro-l,3-oxazines, and tetrahydro-l,3-thiazinesprefer the axial orientation. This is considered to be due to attractive forces between a lone pair and the N-H proton and/or dipolar forces between two adjacent lone pairs in the N-H equatorial conformer. Hall and H ~ r s f a lhave l ~ ~ applied the dipole moments method to the determination of the conformational properties of lY3-dinitrohexahydropyrimidines. X-Ray studies75have confirmed the results of earlier lHn.m.r. work in showing that piperazine-2,s-dionescontaining phenylalanine or tyrosine have the aromatic ring folded over the piperazine ring. In the case of 3-(4-hydroxybenzyl)piperazine-2,5-dione the piperazine ring assumes a boat conformation, but in the case of 3-(4-hydroxybenzyl)-6-hydroxymethylpiperazine-2,5-dione the ring is almost planar. have 15N--15NCoupling constants in hexahydro-l,3,5-trinitro-l,3,5-triazine been determined as 9 H z . ~ ~ With the advent of a convenient method of preparation of alkyl-substituted triazinesY7'the conformational properties of mixed isopropyl- and t-butyland methyl- and t-butyl-hexahydrotriazines have been examined by the dipole moment method. In the case of the t-butyl and isopropyl compounds the equilibrium mixtures contain mainly triequatorial and monoaxialdiequatorial species. With methyl- and ethyl-substituted compounds the equilibrium is essentially between the monoaxial-diequatorial and diaxialmonoequatorial conformers. Phosphorus-containing R i n g ~ . - ~ ~ c - ~Coupling ~P constants for 2-methyl substituents in 2-phospholen are larger78than for the isomeric 3-methylphospholen offering a useful differentiation between these two series. 72

73 74 75 76

77

78

R. A. Y . Jones, A. R. Katritzky, and R. Scattergood, Chem. Comm.,1971, 644. M. J. Cook, R. A. Y . Jones, A. R. Katritzky, M. M. Manas, A. C . Richards, A. J. Sparrow, and D. L. Trepanier, J.C.S. Perkin II, 1973, 325. P. G. Hall and G. S. Horsfall, J.C.S. Perkin IZ, 1973, 1280. C. F. Lin and L. E. Webb, J. Amer. Chem. SOC.,1973,95, 6803. S. Bulusu, J. R. Autera, and T. Axenrod, J.C.S. Chem. Comm.,1973, 602. R. P. Duke, A. R. Katritzky, R. Scattergood, and F. G. Riddell, J.C.S. PerkinII, 1973, 2109. L. D. Quin, S. G . Borleske, and R. C. Stocks, Org. Mugn. Resonance, 1973,5, 161.

11

152

Saturated Heterocyclic Chemistry

Reaction of phenylphosphorus dichloride with diethyl malonate in thr: presence of amines produces an unusual compound79which contains two covalently bound phosphorus atoms in different oxidation states. The structure of this compound has been shown to be (50) by X-ray methods and the ring approximates to a half-chair conformation.

COzEt P-P

/ Ph

/P 'h OEt

19FN.m.r. studiess0 have given barriers to pseudorotation for the 1,3,2-, dioxaphospholan (51) of 42-50 kJ mol-l. This value is consistent with a large difference in apicophilicity between the dialkylamino- and phenoxy-groups. High-resolution l H n.m.r. studiess1 on the cis- and trans-Zchloro- and -2-phenyl-5-methyl-l,3,2-oxathiaphospholans(52) suggest that the transisomer exists as an equilibrium mixture of two envelope conformers with C-5 out of the plane of the ring, whereas the cis-isomer exists as a single envelope conformer. Similar conclusions have been drawn for related systems.82-84 OH I

I

Me

(54)

Quin and Feathermans5have used the cis- and trans-4-phosphorinols (53) and (54) of known stereochemistry to obtain 13C chemical shift assignments and have applied the values obtained to structural assignments in related systems;86thus 1-methylphosphorinanexists as a 2: 1 equatorial-axial mixture at -130 "C (cf. 99% equatorial for cyclohexane at -110 "C). Extrapolation W. Saenger, J . Org. Chem., 1973,38, 253. S. Trippett and P. J. Whittle, J.C.S. Perkin I, 1973, 2302. 81 K.Bergesen and M. Bjorsy, Acta Chem. Scand., 1973,27, 3477. 82 M. Revel and J. Navech, Bull. SOC.chim. France, 1973, 1195. a3 K.Bergesen and M. Bjorsy, Acta Chem. Scand., 1973,27, 1103. J. P. Albrand, D. Gagnaire, J. Martin, and J.-B. Robert, Org. Magn. Resonance, 1973, 5 , 33. 85 S. I. Featherman and L. D. Quin, Tetrahedron Letters, 1973, 1955. 86 S. I. Featherman and L. D. Quin, J. Amer. Chem. SOC.,1973,95, 1699. 79

Five- and Six-mpmbered Rings and Related Firsed Systems

153

I

Me

(55)

to 25'C suggests that the axial conformer (55) is preferred, with AGZ5of 1.42 kJ mol-l. The known preference of 2-methoxy-l,3,2-dioxaphosphorinan for the 0-axial chair conformation (56) has been utilized by Haemers and coworkerss7in making 13C n.m.r. chemical shift assignments for the geometric isomers (57) and (58). Both the 13Csignals of C-4 and C-6 and the 31P signals appear at 3-4 p.p.m. higher field for (57) than for (58). These differences are

+

believed to be associated with 1,3-syn-diaxialinteractionsss and are diagnostic. Consideration of JP-O-Meleads to an insight into rotamer populations of the methoxy-group in both axial and equatorial conformers. Oxidation of 2methoxy-l,3,2-dioxaphosphorinansproceedsagwith retention of configuration at phosphorus. Hydrolysis of 2-chloro-4-methyl-l,3,2-dioxaphosphorinans(59) gives a mixture of products (60) and (61). The major productg0has been shown to be

(60) by X-ray crystall~graphy,~~ offering support to earlierg2observations. l H N.m.r. studies on related systems have appeared.93

** 89

e0

91 92

93

M. Haemers, R. Ottinger, D. Zimmermann, and J. Reisse, Tetrahedron Letters, 1973, 2241. M. Haemers, R. Ottinger, D. Zimmermann, and J. Reisse, Tetrahedron, 1973,29,3539. J . A . Mosbo and J. G . Verkade, J . Amer. Chem. Sac., 1973,95,4659. C. L. Bodkin and P. Simpson, J.C.S.Perkin 11, 1973, 676. W. Saenger and M. Mikolajczyk, Chem. Ber., 1973, 106, 3519. J. A. Mosbo and J. G . Verkade, J. Amer. Chem. SOC.,1973, 95, 204. J. P. Majoral, C. Bergounhou, J. Navech, P. C. Maria, L. Elegant, and M. Azzaro, Bull. SOC.chim. France, 1973, 3142.

Saturated Heterocyclic Chemistry

154

Unusual stereochemical results have been observerg4during nucleophilic substitution of the phosphochloridate (62).Using lH n.m.r. assignments based on the model compounds (63) and (64) of known ~ t r u c t u r e the , ~ ~stereochemical fate of (62)may be assessed during substitution reactions. Both (63) and (64) are conformationally rigid and do not undergo inversion at 200 "C. Using nitrogen nucleophiles such as piperidine, t-butylamine, or aniline lit has been demonstrated that inversion occurs during substitution. When the nucleophile is phenoxide, however, products of mixed stereochemistry result, indicating retention and inversion. The ratio of products depends markedly on the basicity of the nucleophile; thus p-cresol gives a ratio of 1 :1 of retention to inversion, whereas the ratio for p-nitrophenol is 94:t;. Added saltsg6dramatically influence the ratio, favouring inversion. These

(64)

(65)

results have been interpreted in terms of an S,2(P) mechanism in which the leaving group preferentially leaves from an apical position, rather than a dissociative mechanism. Conformational properties of the related cis- and trans-2-dimethylamino-5-t-butyl-1,3,2-dioxaphosphorinanshave been in,vestigated using 13C, 19F,and 31Pn.m.r.97 A crystal structure of the principal metaboliteg8 of the antineoplastic substance cyclophosphamide has confirmed its structure as the 4-ketoderivative (65). Sulphur-containing Rings.-The dubious comparison of the proton-proton coupling constantsg9of the conformationally rigid bicyclic system (66)with. Qp g6

Q6 Q7 g8

W. S. Wadsworth, S. Larsen, and H. L. Horton, J. Org. Chem., 1973, 38, 256. R. E. Wagner, W. Jensen, W. S. Wadsworth, and Q. Johnson, Acta Cryst., 1973., B29, 2160. W. S. Wadsworth, J. Org. Chem., 1973, 38, 2921. W. G. Bentrude and H. W. Tan, J. Amer. Chem. SOC.,1973, 95, 4666. N. Cameraman and A. Cameraman, J. Amer. Chern. SOC.,1973, 95, 5038. A. Garbesi, G. Barbarella, and A. Fava, J.C.S. Chem. Cornm., 1973, 155.

Five- and Six-membered Rings and Related Fused Systems H4

155

,9 A

i Me (66)

(67)

those of the mobile thiacyclopentylmethylsulphonium iodide (67) has been cited as evidence for a preference for the half-chair conformer in the latter system. Rates of exchange of a-protons in (66) and (67) have been studied and in the case of (67) the protonsloocis to the S-methyl group exchange twelve times faster than those trans to it. A complete first-order analysislOl of the lH n.m.r. spectrum due to the protons of the sulphur-containing ring in (66) has been carried out, and unambiguous assignments have been made. The kinetics of deuterium exchange for H-1 to H-4 reveal relative rates of 200 :3 :3 :1,again demonstrating a large preference for the exchange of a cis-proton. Since the torsional angle between the lone pair on sulphur and the lone pair formed by removal of H-1 is in the order of 120°, whereas removal of H-4 results in eclipsed lone pairs, the reactivity difference between these two protons is hardly surprising and thegauche effect may be invoked. However, the difference in reactivity between H-1 and H-3 has proven difficult to rationalize and further work is needed to clarify these results. Green and Hellierlo2have examined the lHn.m.r. and i.r. spectra of a number of cyclic sulphites. In all cases it has been possible to analyse the spectra, and chemical shift additivity is observed. A single stable conformation is believed to exist in solution. Conformational preferences in a number of substituted lY3-dithiolanshave been examined by lH n.m.r. and chemical equilibration methods.lo3 Free energy differences are small, suggesting that the dithiolan ring is flexible, like the 1,3-dioxan ring. The ring appears to possess steric demands of its own which exceed normal steric requirements of all but the largest of substituents. Long-range proton-proton couplings have been observedlo4in lY3-dithiolan 1,1,3,3-tetroxides (68) which are not observed in the parent lY3-dithiolans or oxygen analogues. A number of possible sources of this effect are discussed. cis- and trans-4-chlorothian l-oxide show a marked preference for the S-0-axial conformation.lo5In the former a ratio of 74: 26 (axia1:equatorial) loo 0. Hofer

lol

and E. L. ElieI, J. Arner. Chern. Suc., 1973, 95, 8045. G . Barbarella, A. Garbesi, A. Boicelli, and A. Fava, J. Arner. Chern. Soc., 1973, 95, 805 1.

H. Green and D. G . Hellier, J.C.S.Perkin 11, 1973, 243. Keskinen, A. Nikkila, and K. Pihlaja, J.C.S. Perkin II, 1973, 1376. lo* L. A. Sternson and A. W. Sternson, Tetrahedron Letters, 1973, 1315. lo5 G. Wood, C. C. Barker, and A. Klingerman, Cunud. J. Chem., 1973,51, 3328. lo2 C.

lo3 R.

156

Saturated Heterocyclic Chemistry

(68)

was observed whilst the latter exists almost exclusively (96:4) in the axial form. The cis-isomer exhibits additive behaviour whereas there is a large deviation for the trans-isomer, consistent with a 1,4-dipolar interaction. a-Halogenation of cyclic sulphoxides has been the subject of extensive investigations.lo6Chlorination has beeen shown to occur when the sulphinyl oxygen is equatorial and the halogen is introduced cis to the sulphinyl oxygen. Mechanistically, a tetrahedral chlorosulphonium ion is believed to be formed followed by a trans-diaxial elimination of hydrogen chloride. The resulting 'inverted ylide' undergoes axial chloride-ion attack, giving the observed products (Scheme 2).

I

I c__+

Scheme 2

Alkylation of thian 1-oxides gives productslo7formed by the addition of the alkyl group trans to the sulphinyl oxygen. Deuteriation studies have produced somewhat more complex results. Generally, when no a-substituents are present deuterium exchange occurs trans to the sulphinyl oxygen, but when or-substituents are present steric effects determine the course of the reaction. Further work is needed to clarify reported observations. Conformational free energy differenceslo8of a number of stereoisomeric methyl-l,3-oxathians have been correlated with the ionization appearance S. Iriuchijima, M. Ishibashi, and G. Tsuchihashi, Bull. Chem. SOC.Japan, 1973, 46, 921 ;E. Casadevall and M. M. Bouisset, Tetrahedron Letters, 1973,2975; S . Iriuchijima and G. Tsuchihashi, Bull. Chem. SOC.Japan, 1973, 46, 929; J. Klein and H . Stollar, J . Amer. Chem. SOC.,1973, 95, 7437. lo' S. Bory and A. Marquet, Tetrahedron Letters, 1973, 4155. lo* J. Jalonen, P. Pasanen, and K. Pihlaja, Org. Mass Spectrometry, 1973, 7 , 949. Io6

Five- and Six-membered Rings and Related Fused Systems

157

potentials of M+ and ( M - CH3)+in the mass spectra. 13CN.m.r. data on this system have been reported.log A synthesis of 1,3,2-dioxathianshas been reportedY1l0 and low-temperature lH n.m.r. studies have given a barrier to ring inversion of 46.9 kJ mol-l for 4,4,6,6-tetradeuterio-ly3 ,2-dioxathian. This value is considerably higher than for six-membered rings not possessing vicinal electron pairs, supporting the observation that electron pairs on adjacent atoms increase the barrier to rotation about the bond joining them, 13C N.m.r. studies on the related sulphite (69) have been interpreted in terms of the molecule adopting a chair and/or twist-chair conformation. Shielding at C-4 and C-6 give an insight into conformational changes.ll1

0

(69)

(704

(70b)

The barrier to ring inversion of 1,4-dithiin (70a + 70b) has been calculated as 26.8 kJ mol-l, casting doubt112 on the reported existence of two stable stereoisomers of (71)113 with markedly differingphysical properties. Examination of the two ‘stereoisomers’revealed that they are (71) and (72).

asD S

(71)

(72)

In contrast to thian l-oxides, lY3-dithian1-oxides114 exist preferentially with the S-0 bond in the equatorial position. The axial and equatorial isomers (75) and (74) are formed in a 10:90 ratio by periodate oxidation of the parent (73). Structural assignments were based on their dipole moments and

t (73) log

112 113

(74)

(75)

K. Pihlaja and P. Pasanen, Suomen Kem., 1973, 46, 273. G . Wood, R. M. Srivastava, and B. Adlam, Canad. J . Chem., 1973,51, 1200. G . W. Buchanan, J. B. Stothers, and G . Wood, Canad. J . Chem., 1973,51, 3746. R. M. Moriaty, C. C. Chien, and C. W. Jefford, Tetrahedron Letters, 1973, 4429. M. M. Kreevoy, J . Amer. Chem. SOC.,1958, 80, 5543. M. J. Cook and A. P. Tonge, Tetrahedron Letters, 1973, 849.

Saturated Heterocyclic Chemistry

158

220 MHz spectra, and the equatorial preference has been attributed to intramolecular dipole-dipole interactions. A-stereoselective synthesis of cis-l,4- and cis-l,3-dimethylisothiochromans and their 2,2-dioxides has been described,l15 and crystallographic studies indicate a preferred boat conformation. 3 Cycloaddition Reactions

+

+

[3 21 Cyc1oaddition.-General. [3 21 Cycloaddition reactions have been studied extensively and this section is covered in terms of the individual 1,3-dipole types. The stereochemistry of 1,3-dipolar addition reactions hati been reviewed116 and the role of solvents discussed.l17 The consensus of opinion favours a concerted mechanism and considerable work has been carried out to support this view.ll* Considerable predictive powers are associated with the frontier-orbital approach, discussed by Houk and co-workers. Using experimental values for ionization potentials (IP) and electron affinities, a set of frontier-orbita I energies for 1,3-dipoles and dipolarophiles has been calculated.11g On the basis of these calculations the unidirectional addition of many 1,3-dipoles tcb monosubstituted dipolarophiles should no longer be observed when the: dipole is made highly electron deficient.120Reaction of the nitrone (76) withi Me

monosubstituted alkenes gives only 5-substituted isoxazolines, a general reaction which depends little on the nature of the substituents. However, with methyl propriolate a 42: 58 mixture of 4- and 5-substituted isoxazolines is obtained. The loss or reversal of stereoselectivity is associated with the highest occupied (HO) orbital energy of the propriolate (IP = 10.72eV). Cyanoacetylene (IP = 11.81 eV), a more electron-deficient dipolarophile, gives a larger proportion of reversed isomers (50:50), indicating that as the IP increases the formation of reversed, i.e. 4-substituted, product is favoured. 115 116

117 llS

ll9 lZo

D. A. Pullman and D. A. Whiting, J.C.S. Perkin I, 1973, 410. R. R. Schmidt, Angew. Chem. Internat. Edn., 1973, 12, 212; J. Bastide, J. Hamelin, F. Texier, and Y. V. Quang, Bull. SOC.chim. France, 1973, 2555. P. K. Kadaba, Synthesis, 1973, 71. M. Cristl and R. Huisgen, Chem. Ber., 1973, 106, 3345; J. Bastide, N. El Ghandour, and 0. H. Rousseau, Bull. SOC. chim. France, 1973, 2290. K. N. Houk, J. Sims, R. E. Duke, R. W. Strozier,and J. K. George, J. Amer. Chem. SOC., 1973,95, 7287. J. Sims and K. N. Houk, J . Amer. Chem. SOC.,1973,95, 5800.

Fiue- and Six-membered Rings and Related Fused Systems 159 In general terms the dipole-LU-dipolarophile-HO interactions strongly favour the formation of 5-substitutedproducts, whereas dipole-HO-dipolarophile-LU interactions only weakly favour the formation of the 4-substituted adducts (LU signifies lowest unoccupied orbital). As a consequence, not until the latter interaction is much stronger than the former will a reversal of regioselectivity occur. It is suggested that monosubstituted alkenes with IP > 11.2 eV show partial or total reversal of regioselectivity with nitrones, nitrile oxides, and nitrile imines. 14C Primary isotope effects support a concerted rather than a biradical mechanism.121 Nitrones. The 1,3-dipolar character of nitrones is well established and further examples of their reactions support existing precedent.122Reaction of 5,5dimethyl-A1-pyrrolidine l-oxide with t h i ~ k e t o n e s lgives ~ ~ rise (Scheme 3) to S

(77) Scheme 3

(78)

the thermally labile oxathiazolidines (77). Photolysis of (77) results in the formation of the thiopyrrolidone (78), possibly by way of an intermediate thiaziridine. The reaction of 5 ,5-dimethyl- Al-pyrrolidine 1-oxide with phenyl is~thiocyanatel~~ results in predominant addition to the C=N bond;

Scheme 4

however, substituted phenyl isothiocyanates add to the C=S bond, giving unstable adducts which decompose to the thioamide (78) and ArNCO. The aryl isocyanate then reacts with excess of nitrone (Scheme 4). Formation of (78) is also observed during the reaction of the nitrone with CS,.12j 121

lZ2 123

lZ4

B. M. Benjamin and C . J. Collins, J . Amer. Chem. SOC., 1973, 95, 6145. M. Joulcla, D. Gree, and J. Hamelin, Tetrahedron, 1973, 29, 2315; M. Masui, K. Suda, M. Yamauchi, and C . Yijima, Chem. and Pharm. Buff.(Japan), 1973, 21. 160% D. St.C. Black and K. G. Watson, Austral. J . Chem., 1973, 26, 2491. D. St.C. Black and K. G. Watson, Austral. J. Chem., 1973, 26, 2473. D. St.C. Black and K. G. Watson, Austral. J. Chem., 1973, 26, 2177.

Saturated Heterocyclic Chemistry

160

Scheme 5

The interesting intramolecular reaction outlined is Scheme 5 , a stage in the synthesis of pseudotropine, has been reported.126 Synthesis of olefins by thermal decomposition of amine oxides is a well established procedure; however, dimethyldodecylamine oxide12' at 125 O C gives only small quantities of the olefin, the major product being 2-methyl-5decylisoxazoline. This anomalous product is believed to be due to the initial cycloelimination to yield the olefin, followed by oxidation of the hydroxylamine by-product to a nitrone and subsequent addition (Scheme 6). This

-0 \+/

r;i Me

Scheme 6

reaction appears to be general, and treatment of dimethylhydroxylaminewith olefins gives isoxazolines, suggesting a disproportionation to dimethylamine, methyl nitrone, and water. Nitronic esters function as 1,3-dipole~,1~~ and addition of acetylenic dipolarophiles to the cyclic nitronic ester (79) occurs readily with concomitant loss of HNO,, yielding dihydro-oxazine derivatives129(80) in high yields. OMe

I

CHCOR RC53ZH-MeOH

(79) 126 12'

lZ8 129

(80)

J. J. Tufariello and E. J. Trybulski, J.C.S. Chem. Comm., 1973, 720. R. G . Laughlin, J . Amer. Chem. SOC.,1973, 95, 3295. R. Gree, F. Tonnard, and R. Carrie, Tetrahedron Letters, 1973,453. I. E. Chlenov, I. L. Sokolova, S. S. Novikov, and V. A. Tartakovskii, Izvest. Aknd. Nauk S.S.S.R., Ser. khim., 1973, 960 (Chem. Abs., 1973, 7 9 , 5 2 341).

Five- and Six-mernbered Rings and Related Fused Systems

161

Nitrile Imities. General methods of synthesis of nitrile imines have been reviewed.130 The conseq~encel~~ of 1,3-dipolar addition of nitrile imines to indoles is dependent on substituents at positions 1, 2, and 3 of the indole ring. Three different product types (81-83) may be formed, and the presence of adducts of type (82) strongly supports the intermediacy of dipolar intermediates. COR'

COR'

'\

H

\

Ph

(84)

Fliege and H ~ i s g e n have l ~ ~ examined the addition of nitrile imines to norbornene. Only products of exo addition are observed (84; R = H) and ex0 addition is also preferred in apobornene (84; R = Me) in spite of considerable steric hindrance from the 7-methyl group. On the basis of these observations the authors suggest a modification of Brown's hypothesis133 correlating the ex0 and endo addition ratios with the nature of the transition state. The reaction of nitrile imines with cyclo-octatetraene gives unexcept ional p r 0 d ~ c t s . l ~ ~ NitriZe Oxides. Dondoni and B a r b a r ~ have l ~ ~ examined p-values for the cycloaddition of benzonitrile oxides to substituted styrenes. Observed variations of p are small and have been interpreted in terms of a concerted mechanism, although the evidence presented does not rule out a two-step mechanism. Other attempts at drawing mechanistic conclusions by examination 130 131

132 133 134

135

C. G.Stuckwische, Synthesis, 1973, 469. M. Ruccia, N.Vivona, G . Cusmano, M. L. Marino, and F. Piozzi, Tetrahedron, 1973, 29, 3159. W. Fliege and R. Huisgen, Annalen, 1973, 2038. H. C. Brown and J. H. Kawakami, J . Amer. Chem. SOC., 1970,92,201. G . Bianchi, R. Gandolfi, and P. Grunanger, Tetrahedron, 1973, 29, 2405. A. Dondoni and G. Barbaro, J.C.S. Perkin ZZ, 1973, 1769.

162

Saturated Heterocyclic Chemistry PI1

d- Ph% .Ph

0 (85)

(87)

Scheme 7

of product ratios136led to ambiguous results. Reactions of benzonitrile oxide with he~amethyl-Dewar-benzene,~~~ cyclopropene derivatives,13* cyclic imidates and i m i d a z ~ l i n e s ,and ~ ~ ~styreneslg0have been reported to yield the anticipated products. Reaction of benzonitrile oxide with 4-arylideneisoxazol-5-ones results in mixtures of spiroisoxazolone derivatives (85) and (86),141 together with small quantities of the spirane (87) derived from phenylnitrosocarbene (Scheme 7). Aqueous nitrosation of primary a-carbonyl-diazo-compounds, e.g. ethyl diazoacetate, diaxoacetone, etc., yields a-carbonyl-nitrile oxides, 136

13' 13* 139

140

M. Cristl, R. Huisgen, and R. Sustmann, Chem. Ber., 1973, 106, 3275; K. Bast, M. Cristl, R. Huisgen, and W. Mack, ibid., p. 3312; G . Bianchi, C. D. Micheli, R. Gandolfi, P. Grunanger, P. V. Finza, and 0. V. de Pava, J.C.S. Perkin I, 1973, 1148. G. Bruntrup and M. Cristl, Tetrahedron Letters, 1973, 3369. J. P. Visser and P. Smael, Tetrahedron Letters, 1973, 1139. K. H . Magosch, Ger. Offen 2 155 753 (Chenr. A h . , 1973,79,42 516). K. Bast, hl. Cristl, R. Huisgen, W. Mack, and R. Sustmann, Chem. Ber., 1973, 106, 3258.

141

G. L. Vecchio, G . Grassi, F. Risitano, and F. Foti, Tetrahedron Letters, 1973, 3777.

Five- and Six-membered Rings and Related Fused Systems

163

+

RCOCGN-~, which have been trapped142in 1,3-dipolar addition reactions. In the absence of dipolarophiles furoxans are formed.

+

from formhydroximoyl iodide143and triethylGeneration of HC-N-6 aminehas beenreported. Observedcycloadditionsgiverise give to products with the expected orientation, although with weak dipolarophiles oligomerization competes with cyclization. The resultant 2-isoxazolines, unsubstituted at position 3, suffer base-catalysed ring-opening (Scheme 8), resulting in a nett addition of HOCN to the dipolarophile. +

H-CEN-0

B :3 H

-

-

4-

CHFCHR

OH

Ti?-

I

+ eCH2CHR

R Scheme 8

Nitrile Ylides. Methods of generating specific nitrile ylides include thermolysis of the dihydro-l,3,5-oxazaphosphole(88)144and of the aziridine (89)lg5 and photolysis of the azetidine

phvCr:

7

PhCH=G-C(C02Me)2 I

I

Ph

Ph

hv ---+

- + (CF&C-N%Ph

+

C,H,,NC

F,CF3C gC : 6Hl (90) 143 144

14j 146

H. Dahn, B. Favre, and J. P. Leresch, Helv. Cliim. Acta, 1973, 56,457. R. Huisgen and M. Cristl, Chem. Ber., 1973, 106, 3291. K. Burger and K. Einhellig, Chem. Ber., 1973, 106, 3421. F. Texier and R. Carrie, Bull. SOC.chim. France, 1973, 3437. K. Burger, W. Thenn, and E. Muller, Angew. Chem. Internat. Edn., 1973, 12, 155.

164 Saturated Heterocyclic Chemistry General methods of nitrile ylide synthesis have centred around arylazirines. Photolysis of ary1azirinesl4' in inert solvents results in the formation of 1,3-diazabicyclo[3,1 ,O]hex-3-ene derivatives. This reaction has been shown to involve the initial opening of the arylazirine to a nitrile ylide followed by [3 + 21 cycloaddition with the unchanged arylazirine. In the presence of good dipolarophiles the ylide may be trapped as a A1-pyrroline. Padwa and c o - ~ o r k e r s lhave ~ ~ shown that during irradiation of phenylazirine and diphenylazirine at 3130& 95% of the incident light is absorbed by the diphenylazirine,which results in its conversion into the nitrile ylide. Reaction

Scheme 9

of this ylide (Scheme 9) occurs preferentially with phenylazirine. Basecatalysed oxidative rearrangement of the resultant 2,4,5-triphenyl-l,3diazabicyclo[3,1,0]hex-3-enes yields 2,4,6-triphenylpyrimidine. 2,4,6-Triphenyl-1,3-diazabicyclo[3,1 ,O]hex-3-ene (91) is itself thermally giving fused systems in the presence of dipolarophiles (Scheme lo),

phTLc NxN

Ph

\

-

Ph

H

H

/A

Ph

H

Scheme 10

although the anticipated product differences between thermal and photochemical reactions are not observed. A number of plausible explanations for these observations exist.

14*

A. Padwa, M. Dharan, J. Smolanoff, and S. I. Wetmore, J. Amer. Chem. SOC.,1973, 95, 1954; ibid., p. 1945. A. Padwa, J. Smolanoff, and S. I. Wetmore, J. Org. Chem., 1973, 38, 1333.

14s

A. Padwa and E. Glaser, J. Org. Chem., 1973, 38, 284.

147

Five- and Six-membered Rings and Relafed Fused Systems

165

Schmid and c o - w ~ r k e r shave l ~ ~ examined the photolysis of azirine derivatives at -185 "C in a pentane-2,2-dimethylbutane matrix. Using this method benzonitrile-diphenylmethylidehas been prepared and trapped with methyl trifluoroacetate and C 0 2 . Azirines prepared by photolysis of vinylazides151 exhibit similar reactivity. Nitrile ylides may be trapped with forming 3-oxazolines, although care should be exercised, since if the nitrile ylide is generated photochemically secondary transformations of the oxazolines may The mild, non-photochemical method of preparing nitrile ylides by the dehydrohalogenation of benzimidoyl chlorides154with triethylamine is clearly a method of choice and fair yields of cycloadducts may be obtained. Azides and Diazoalkanes. Ketones undergo reaction with alkyl and aryl a ~ i d e s in l ~the ~ presence of base, forming A2-1,2,3-triazolines. The reaction probably proceeds by way of a [3 21 cycloaddition of the azide on the enolate (Scheme 11). Base-induced elimination of water results in the formation of l ,2,3-triazoles.

+

0

ll R1CHCR2

-

O-

R3Ns

"*AH

I -

R1CH=CR2

N\\ /N

N

R '3

Scheme 11

Benzylidenecy~loproane~~~ undergoes reaction with phenyl azide to form the spiro [4,2]pentane (92) which eliminates nitrogen on photolysis, giving 1,2-diphenylazaspiro[2,2 pentane (93). The structure of a 2: 1 cycloadduct (94) of diazomethane and 4-methyl-1,lbis(trifluoromethyl)-2-azabuta-1,3-diene has been confirmed by an X-ray T

p$y-ph N=N

hv,

dH 'ph

(92) 150 151

15%

lS3 154

lS5 156

Nx-f F 3 C P N

\

(93)

(94)

W. Sieber, P. Gilgen, S. Chaloupka, H. J. Hansen, and H. Schmid, Helv. Chim. Acta, 1973,56, 1679. A. Orahovats, B. Jackson, H. Heimgartner, and H. Schmid, Helv. Chim. Acta, 1973, 56,2007. H. Giezendanner, H. Heimgartner, B. Jackson, T. Winkler, H. J. Hansen, and H. Schmid, Helv. Chim. Acta, 1973, 56,2611. H. Giezendanner, H. J. Rosenkranz, H. J. Hansen, and H. Schmid, Helv. Chim. Acta, 1973, 56,2588. N . S. Narasimham, H. Heimgartner, H. J. Hansen, and H . Schmid, Helv. Chim. Acta, 1973,56, 1351. C . A. Olsen and C. Pedersen, Acta Chem. Scand., 1973, 27, 2271 ; C.A. Olsen, Acta Chem. Scand., 1973, 27, 2983. J. K. Crandall and W. W. Conover, J.C.S. Chem. Comm., 1973, 33.

166

Saturated Heterocyclic Chemistry

structure determination.15' 2-Diazoa~enaphthalenel~~ functions as a 1,3dipole in the expected way with suitable dipolarophiles. An unusual reaction is observed159between Toluene-p-sulphonylazocyclo-, hexene and maleic anhydride. Kinetic evidence suggests that two simultaneous reactions, one a first-order and one a second-order process, are occurring. The first-order process is thought to involve an ionization step to yield a diazonium salt. Collapse of this salt to the diazoalkane (95) followed by cycloaddition represents a plausible mechanism (Scheme 12).

Scheme 12

Miscellaneous. Benzylidene anilines react with 1,l-dicyano- or 1-cyano-lethoxycarbonyl-epoxides (96), forming oxazolidines.160The initial step of this reaction appears to involve the formation of a carbonyl ylide, followed by a 1,3-dipolar addition reaction (Scheme 13).

(96) R = C N or C02Et

Scheme 13 [4 + 21 Cycloaddition.--xygen-conraining Rings. 2,6-Dibenzylidenecyclohexanone reacts with electron-rich acetylenes, giving pyran derivatives which 15' 158

159

160

A. Gieren, Chem. Ber., 1973, 106, 288. 0. Tsuge, M. Koga, and I. Shinkai, Tetrahedron, 1973, 29, 259. P. de Maria, F. Gasparrini, L. Caglioti, and M. Ghedini, J.C.S. Pcrkin 11, 1973, 1922. A. Robert, J. J. Pommeret, E. Marchand, and A. Foucard, Tetrahedron, 1973, 29, 463.

Fiue- and Six-membered Rings and Related Fused Systems Ph Me

pe 6ZLt2 167

+

PI1/

Ph

Ph’

Scheme 14

undergo facile161hydrolysis to dihydropyrones (Scheme 14). Dibenzylideneacetone failed to yield a crystalline adduct, but hydrolysis of the crude product gave the lactone (97). Quinone methides (98)16aand naphthoquinone methides (99)lS3have been prepared from 2-chloromethylphenol and l-hydroxymethyl-2-naphthol. Diels-Alder reactions result in the formation of chroman derivatives.

Ph’

Photolysis of tetramethylallene in the presence of singlet oxygen has been shownlM to give 3,3,5-trimethyl-A4-1,Zdioxan, formed by the initial isomerization of the allene to 2,2,4-trimethylbuta-1,3-diene. Production of a number of A4-l ,Zdioxans by the addition of singlet oxygen to dienes has been r e ~ 0 r t e d . Reduction l~~ followed by dehydration results in the formation of furan derivatives. Two g r o ~ p P ~have * l independently ~~ demonstrated that photo-oxygenation of electron-rich or strained styrene derivatives results in [4 + 21 rather than the anticipated [2 + 21 cycloadducts. 1 ,l-Diaryl-2-methoxyethyleneresults in the formation of the adduct (100) and benzhydrylidenecyclobutane gave the adduct (101). P. L. Meyers and J. W. Lewis,J. Heterocyclic Chem., 1973, 10, 165. M. S. Chauhan, F. M. Dean, S. McDonald, and M. S. Robinson, J.C.S. Perkin I, 1973, 359. 163 M. S. Chauhan, F. M. Dean, D. Matkin, and M. L. Robinson, J.C.S. Perkin I, 1973, 120. 164 T. Greibrokk, Tetrahedron Letters, 1973, 1663. 165 K. Kondo, M. Matsumoto, and M. Hatsutani, Ger. Offen 2 262 792 (Chem. Abs., 1973,79, 78 817). lB6 G . Rio, D. Bricout, and L. Lacombe, Tetrahedron, 1973, 29, 3553. l e 7C. S. Foote, S. Mazur, P. A. Burns, and D. Lerdal, J . Amer. Chem. SOC.,1973, 95,

163

586. 12

165

Saturated Heterocyclic Chemistry

Nitrogen-containing Rings. Derivatives of tetrahydropyridine have been synthesized168 by the cycloaddition of imines derived from c$-unsaturated aldehydes with maleic anhydride. Intramolecular Diels-Alder reactions are now recognized as an important method for the construction of otherwise inaccessible molecules. Such proc:esses remove or offset unf‘avourable entropy considerations and increase the facility with which the Diels-Alder reaction occurs. Thus in the case of (102)1,

which is formally an isolated double bond and a conjugated diene,169cycloaddition occurs- in refluxing acetonitrile to give (103). When electronic: requirements associated with ‘normal’ Diels-Alder reactions are ‘built in’, mild conditions may be employed to effect the cycloaddition, and (104) undergoes cycli~ationl~~ to the isoindolone (105) at 0 ‘C.

A synthesis of diaza-~teroidsl~l employing the reaction (106) -+ (107) has been reported, again demonstrating the synthetic utility of the intramolecular. Diels-Alder reaction in offering stereochemicalcontrol during the construction of four asymmetric centres. 16* 169

Z. M. Garashchenko, G. G. Skvortsova, and L. A. Shestova, U.S.S.R. P. 370208 (Chem. A h . , 1973,79, 31 900). A. T. Babayan, K. T. Tagmazyan, and G. 0. Torosyan, Zhur. org. Khim., 1973, 9 , 1156.

170 171

H. W. Gshwend, A. 0. Lee, and H. P. Meier, J . Org. Chem., 1973,38,2169. H. W. Gshwend, Helu. Chim. Acta, 1973, 56, 1763.

Five- and Six-membered Rings and Related Fused Systems

169

n

Rings containing both Oxygen and Nitrogen. Competition between ex0 and endo transition states in the cycloaddition of 4-arylidene-5-pyrazolones(108) and vinyl ethers has been rationalized in terms of steric and electronic intera c t i o n ~ . ~Conformational '~ preferences in the resultant cycloadducts have been discussed.8 Diels-Alder reactions of nitroso-compounds have been examined by a number of groups. The reaction of 2-acetoxy-4-aryl-l,3-butadiene-l-carb o x y l a t e ~ with l ~ ~ nitrosobenzene yields the dihydro-lY2-oxazine(109), which rearranges to the pyrrole (110) on silica.

Ph

(108)

Ph

( 1 09)

Ar

(110)

(111)

Kirby and S ~ e e n yhave l ~ ~ generated nitrosocarbonyl derivatives by periodate oxidation of hydroxamic acids. The unstable nitroso-compounds were trapped with conjugated dienes giving N-acyl-3,3-dihydro-2H-lY2-oxazines. Nitrosobenzene reacts with 2,3-dimethylbuta-l,3-dieneat 0 "C to give the Diels-Alder product (111) and a second product (112), whose structure has

17a

173

174

G . Desimoni, G . Columbo, P. P. Righetti, and G . Jacconi, Tetrahedron, 1973, 29, 2635. G . Kresze and H. Hartner, Annalen, 1973, 640. G . W. Kirby and J. G . Sweeny, J.C.S. Chem. Comm., 1973,704.

170

Saturated Heterocyclic Chemistry

been determined by X-ray crystal10graphy.l~~ Formation of (112) has been rationalized in terms of an initial ‘ene’ reaction followed by oxidation (by PhNO) to the nitrone (Scheme 15) and subsequent Diels-Alder reaction. 1,3-0xazine derivatives are formed from electron-deficient a~yl-imine$~~ and electron-rich olefins (Scheme 16).

Scheme 16

4 General Chemistry of Saturated Heterocycles Oxygen-containingRings.-Tetrahydro furuns. Oxidation of aliphatic alcohols to ketones and tetrahydrofuran derivatives with lead tetra-a~etatel~~ or silver salts in the presence of bromine178has been examined by several groups. The initial step appears to involve179the formation of an alkoxy-radical, reminiscent of that formed during nitrite photolysis. Deuteriation studies have confirmed that 1,4- and 1,5-hydrogen shifts from the a-carbon occur during ketone formation. The ratio of ketone to tetrahydrofuran varies according to the solvent, the latter being favoured by neutral or weakly acidic conditions.1.80 Photolysis of nitrite esters with y-ethylenic substituentPl results in the formation of substituted tetrahydrofurans in yields ranging from 50 to 60 %. The suggested mechanism of this reaction involves intramolecular addition of an alkoxy-radical to a non-activated double bond. Lewis acid-catalysed rearrangement of 1-acetoxy-3,4-epoxypentanesarid 1-acetoxy-3,4-epoxyhexanes occurs with neighbouring-group participation of the acetoxy-function with a nett retention of relative stereochemistry at the epoxide carbon atoms. l80Studies support the intermediacylE2of the orthoester (113) in the former case (Scheme 17). Results with 4,5-epoxyh e x a n - l - 0 1 ~and ~ ~ ~5,6-epoxyheptan-l-ols are consistent with the known preference in ease of ring formation, viz. 5 > 6 > 7, and proceed with inversion of relative stereochemistry at the epoxide carbon atoms. The stereochemistry of ring c l o ~ u r of ~ *( -)-4-hydroxy-4-methylhexanlol ~ to 2-ethyl-2-methyltetrahydrofuranhas been examined. Cyclization by treatment with tosyl chloride or heating with alumina results in retention of E. Oikawa and S. Tsubaka, Bull. Chem. SOC.Japan, 1973,46, 1819. A. D. Sinitsa, B. S. Drach, and A. A. Kisilenko, Zhur. org. Khim., 1973, 9, 685. S. Milosavljevic, D. Jeremic, and M. L. Mihailovic, Tetrahedron, 1973, 29, 3547. M. L. Mihailovic, S. Gojkovic, and S. Konstantinovic, Tetrahedron, 1973, 29, 3675. M. M. Green, J. M. Moldowan, and J. G. McGrew, J.C.S. Chem. Comm., 1973, 451. l S o N. M. Roscher and E. J. Jedziniak, Tetrahedron Letters, 1973, 1049. lS1 M. P. Bertrand and J. M. Surzur, Bull. SOC.chim. France, 1973,2393. lE2 J. M. Coxon, M. P. Hartshorn, and W. H. Swallow, J.C.S. Chem. Comm., 1973, 261. lS3 J. M. Coxon, M. P. Hartshorn, and W. H. Swallow, Austral. J. Chem., 1973,26,2521. lS4 J. Jacobus, J . Org. Chem., 1973,38,402.

175

178 177 178 17s

Five- and Six-membered Rings and Related Fused Systems

171

Me

'

A,

Me Y 0 \ C H 2 0 H\

,CH, -

H

a

-

Me OEF3

Me (113)

I Me

Scheme 17

configuration at the chiral centre, whereas acid- or dimethyl sulphoxidecatalysed ring closure results in the formation of racemic products, Diallyl ethers undergo c y c l i ~ a t i o nin~ ~the ~ presence of halogeno-acids and iron halides (Scheme 18).

Scheme 18

A convenient route for the preparation of tetrahydrofurylidene acetates incorporates treatment of the dianion (1 14) with ethylene oxide.las Preferential alkylation at the y-carbon atom is observed and acid-catalysed cyclization yields (115), possessing the E stereochemistry, in good yield. The stereochemistry of the antibiotic Botrydiplodin (1 16) has been confirmed by total

Me

OH

A. A. Gevorkyan, A. N. Stepanyan, and S. 0. Badanyan, U.S.S.R.P. 372 219 (Chem. A h . , 1973,79,31 838). T. A. Bryson, J. Org. Chem., 1973,38,3428. P. M.McCurry and K. Abe, J. Amer. Chem. SOC.,1973, 95,5824.

lE5

lS6 lS7

172

Saturated Heterocyclic Chemistry

Tetrahydrofuran undergoes radical reactions at the a-position ; thus reaction with dimethyl acetylenedicarboxylate under thermal or photochemical conditionsla8yields (1 17) and (118). Similarly photolysis in the presence of SO2 results in the formation of mixtures of the sulphone (119) and sulphinic acid (120).189 NN-Dibromobenzenesulphonamide reacts with tetrahydrofuran, yielding 7-butyrolactone in modest yield:go a reaction which may be of some synthetic value. Caution should be employed when using butyl-lithium in tetrahydrofuran, since fragmentationlgl to the enolate of acetaldehyde and ethylene (Scheme 19) may result in unwanted side reactions.

Scheme 19

Thermal decomposition of 2-methyl-2-hydroperoxytetrahydrofuran(12 1) occurs in benzaldehyde at 150OC. The intervening radical (122) has been detected in a CIDNP experiment.lg2

W)

(122)

Dihydrofurans. 3-Chlor0-4,5-dihydrofuran~~~ must surely be added to the arsenal of heterocyclic synthons. Easily synthesized by dehydrochlorination of 2,3-dichlorotetrahydrofuran, it reacts with butyl-lithium to form the 2-lithio-derivative, which undergoes alkylation with suitable substrates. l a * G.

Ahlgren, J. Org. Chem., 1973, 38, 1369. H. Takeuchi, T. Nagai, and N. Tokura, BUN. Chem. SOC.Japan, 1973,46, 695. lS0 Y . Kamiya and S. Takemura, Chem. and Pharm. Bull. (Japan), 1973,21, 1401. lS1 P. Tomboulian, D. Amick, S. Beare, K. Dumke, D. Hart, R. Hites, A. Metzger, and R. Nowak, J. Org. Chem., 1973, 38, 322. lg2 A. V. Ignatenko, A. V. Glukhavstev, A. V. Kessenikh, and M. A. Nadtochii, Org. Magn. Resonance, 1973, 5 , 219. lV3 M. Schlosser, B. Schaub, B. Spahic, and G. Sleiter, Helu. Chirn. Acta, 1973, 56,2166. lBB

173

Five- and Six-membered Rings and Related Fused Systems

4

RCOCHzCHzCHzOCOMe

Scheme 20

Cleavage of the resultant alkylated product may be effected in two ways: thus reaction with sodium-potassium alloy in tetrahydrofuran (Scheme 20; path a) followed by hydrolysis generates acetylenic alcohols ;Birch reduction followed by acetolysis (Scheme 20; path b) yields y-acetoxy-ketones. The kinetics of the reaction of p-hydroxy-acetylenes in base to form dihydrofuranslg4have been examined. The rate-determining step involves addition to the triple bond, and factors which aid the formation of the alkoxide anion or which polarize the acetylenic bond facilitate the reaction. A number of syntheses of dihydrofuran derivatives have been reported. Photolysis of the diethylacetal of propargaldehydelg5in propan-2-01results in addition of propan-2-01 to the triple bond. A dark reaction ensues, yielding 2-ethoxy-4,4-dimethyl-l,4-dihydrofuran.Low yields of fused dihydrofuranslg6have been obtained by alkylation of 2-alkylthio-2-cycloalkenones with ethyl acetoacetate (Scheme 21).

&g-y--+ 0

'J

tC02Et

COaEt

COZEt

Scheme 21 ( +)-2,3-Divinyloxiranle7 undergoes a vinyl-cyclopropane rearrangement at 150 O C , forming the racemic furan (123). Reaction of a-dibromo-ketones with zinc in the presence of olefins results in the formation of dihydrofurans.lgs Dibromobenzil reacts with stilbene to give 1,2,3,4-tetraphenyl3,6dihydrofuran, the product stereochemistry being independent of the stereochemistry of the starting olefin. This reaction is believed to proceed lQ4 lQ5

loQ lS7 lQ8

F. Mercier and R. Epsztein, Bull. SOC.chim. France, 1973, 3393. E. P. Serebryakov, L. M. Kostochka, and V. F. Kucherov, Zhur. org. Khim., 1973,9, 1617. T. K. Mukayama and A. Takanobu, Japan Kokai 73126753 (Chem. Abs., 1973, 79, 5255). R. J . Crawford, V. Vukov, and H. Tokunaga, Canad. J . Chem., 1973,51, 3718. L. T. Scott and W. D. Cotton, J . Amer. Chem. SOC.,1973, 95, 5416.

Satiirated Heterocyclic Chemistry

174 Me

I

(123)

(124)

(125)

by a dipolar mechanism rather than by a carbene insertion into the olefin followed by a vinyl-cyclopropane rearrangement of the resultant benzoylcyclopropane. The rearrangement of acylcyclopropanes to 3,4-dihydrofurans has been examinedlg9 and kinetic evidence200 supports the currently accepted 1,3biradical mechanism. Pyrolysis of 2-oxabicyclo[3,3,1 Ihexenes (1 24) produce!; dienak2O1A mechanism involving the initial concerted ring-opening of the cyclopropane ring to the ylide (125) followed by a 1,4-sigmatropic shift is proposed. Lactunes. Interest in a-alkylation of butyrolactones continues and a number of routes have been reported,202usually directed towards the synthesis of or-methylenebutyrolactones. An interesting example in this latter category involves the acid-catalysed rearrangement203of the cyclopropane (126) to the lactone (127).

' kOzMe (126)

(127)

Intramolecular trapping of carbenes generated by photolysis of diazo-, esters has been shown to proceed with retention of stereochemistry; thus the: (S)-2-methylbutyl ester (128) gives the (a-lactone (129) on p h o t o l y ~ i s . ~ ~ ~

lDD

zol zo2

203 204

H. Hiraoka, Tetrahedron, 1973, 29, 2955. D. E. McGreer and J. W. McKinley, Canad. J. Chem., 1973,51, 1487; A. T. Cocks and K. W. Egger, J.C.S. Perkin II, 1973, 197. J. Wolfhugel, A. Maujean, and J. Chuche, Tetrahedron Letters, 1973, 1635. B. M. Trost and T. N. Saltzmann, J. Amer. Chem. SOC.,1973,95,6840; A. D. Harman and C. R. Hutchinson, Tetrahedron Letters, 1973, 1293; J. L. Hermann and R. H. Schlessinger, J.C.S. Chem. Comm., 1973, 711 ; P. A. Grieco and K. Hiroi, ibid., p. 500. P. Hudrlik, L. R. Rudnick, and S. H. Korzeniowski, J. Amer. Chem. SOC.,1973, 95, 6849. H . Ledon, G. Linstrumelle, and S. Julia, Tetrahedron Letters, 1973, 25.

Five- and Six-membered Riiigs and Related Fused Systems

175

The stereochemistry at the chiral centre was correlated with that of (9-2ethyl-2-methylsuccinicacid (130). Attempts to cyclize 3-hydroxymethyl-4,4-dimethylpentanoic acid to the lactone with phosphoryl chloride result in the formation of 3,3,4,4-tetramethy1butyrolact formed by rearrangement of the intermediate carbonium ion (Scheme 22).

Scheme 22

Tricarbonylcyclopentadienylmolybdenum has been used to catalyse the reaction between olefins and trichloroacetic acid.206Hex-1-ene reacts to form 2,2-dichloro-4-butylbutyrolactone,which may be reduced to 4-butyl-4butyrolactone with zinc. Trost and Arndt have applied the s p i r ~ a n n e l a t i o n ~ ~ ~ technique to the preparation of cc-spirocyclopropyl-y-bu tyrolactones. Hydroxylation of y6-unsaturated acids offers a convenient route to /3hydroxy-y-butyrolactones,2°8 and this procedure has successfully been applied to the synthesis of the dilactone epicanadens~lide~~~ (Scheme 23).

eo

Bun I

Me20C

Bun

COzMe

Scheme 23

Alternative approaches to the dilactone antibiotic avenaciolide210have been reported. Jeffs and Molina have reported2u a general synthesis of cis-octahydrobenzo [blfuranones based on Baeyer-Villiger oxidation of cyclobutanones Zo5

Pod 207 208 209

210

all

A. Deboer and J. A. Hunter, J. Org. Chem., 1973, 38, 144. Y. Mori and J. Tsuji, Jap. P. 73/15 932 (Chem. A h . , 1973, 79, 53 168). B. M. Trost and H . C. Arndt, J . Org. Chem., 1973, 38, 3410. H. Koyama, K. Kogure, K. Mori, and M. Matsui, Agric. and Biol. Chem. (Japan), 1973, 34, 915. A. Yoshikoshi, Japan Kokai 73/40 797 (Chem. A h . , 1973,79,66 337). J. L. Herrmann, M. H. Berger, and R. H. Schlessinger,J . Amer. Chem. Soc., 1973,95, 7923. P. W. Jeffs and G. Molina, J.C.S. Chem. C o r n . , 1973, 3.

176 Saturated Heterocyclic Chemistry derived from [2 21 cycloaddition of dichloroketen to cyclohexane derivatives. Asymmetric induction during the synthesis of cis-octahydrobenzo[b]furanones by the Lewis acid-catalysed ring closure of optically active esters of homogeranic acid has been observed.212

+

Miscellaneous Furanoid Derivatives. Photolysis of diazo-ketones in the presence of ketens has been developed as a general method of synthesis of butenolides213(Scheme 24), although specific approaches to this class are more

RCOCHNZ

RC=CH-N2 +

I

+c=o

R

-0 Scheme 24

Products from the photolysis of 3-substituted 2,3-dihydrobenzofuran-2ones are solvent-dependent; thus ethers are formed in protic solvents whereas hydrocarbon solvents promote the formation of styrene derivativesY2l5 consistent with the intermediacy of a quinone methide formed by decarbonylation of the intermediate biradical (Scheme 25).

Scheme 25

Interest in 3(2H)-furanones has centred around the flavouring material furaneol (131), for which three independent syntheses have been reported.216 Two more general approaches to the rational synthesis of 3(2H)-furanones have also appeared.217

212

213 214 215 216

217

S. Kunazawa, T. Kato, and Y . Kitahara, Chem. Letters, 1973, 633. W. Reid and R. Kraemer, Annalen, 1973, 1952. A. Svedsen and P. M. Boll, Tetrahedron, 1973, 29,4251. B. A. M. Oude-Alink, A. W. K. Chan, and D. C. Gutsche, J. Org. Chem., 1973,38, 1993. G. Buchi, E. Demole, and A. F. Thomas, J. Org. Chem., 1973, 38, 123; D. De Rijke and H. Boelens, Rec. Trau. chim., 1973, 92, 731; L. Re, B. Maurer, and G. Ohloff, Helv. Chim. Acta, 1973, 56, 1882. F. Sher, J. L. Isidor, H. R. Taneja, and R. M. Carlson, Tetrahedron Letters, 1973, 577; R. Noyori, Y . Hayakawa, S. Makino, N. Hayakawa, and H . Takaya, J. Amer. Chem. SOC.,1973,95,4103.

Five- and Six-membered Rings and Related Fused Systems

177 1,2-Dioxolans. Thermal decomposition of 1,2-dioxolans has been studied in detail and results indicate that the initial step involves the formation of a 1,5-biradical which collapses to ketonic products. The spiro-l,2-dioxolan (132) undergoes a novel ring-expansion2l8to 2-methyIcyclohexanone (133) with racemization at the chiral centre.

0-0 ( 132)

(133)

T h e r m o l y s i ~and ~ ~ ~photolysis220of malonyl peroxide derivatives proceeds by a two-step mechanism involving the initial formation of a 1,5-biradical followed by extrusion of CO, to give a-lactonic products. Prolonged reaction results in decarbonylation to the ketone (Scheme 26).

Scheme 26

Syntheses of the monomeric221and dimeric222peroxylactones (134) and (135) have been reported.

(134)

(135)

1,3-DioxoZans. A number of unexceptional syntheses of 1,3-dioxolan derivatives have appeared.223 The use of the ethylene acetal protecting group normally involves subsequent cleavage with aqueous acid and on occasions this treatment is 218 z20 231

222

223

W. Adam and N. Duran, J . Org. Chem., 1973, 38, 1434. M. M. Martin, F. T. Hammer, and E. Zador, J . Org. Chem., 1973,38,3422. W. Adam, J. Liu, and 0. Rodriguez, J . Org. Chem., 1973,38,2269. D . H. Gibson, H . L. Wilson, and J. T. Joseph, Tetrahedron Letters, 1973, 1289. N. A. Kartashova, E. V. Matsina, A. I. Kirillov, A. Y.Lazaris, and S. M. Schmuilovich, Zhur. org. Khim., 1973, 9 , 1625. B. Barone and W. F. Brill, U.S. P. 3 725 438 (Chem. Abs., 1973,79, 5323); E. F. Hahn, J. Org. Chem., 1973, 38, 2092; I. L. Kuranova and V. L. Lyudmirova, Zhur. org. Khim., 1973, 9 , 928; H . J. Van der Linde, Tetrahedron, 1973, 29, 2925; J. M. Kliegerman and R. K. Barnes, J . Org. Chem., 1973,38,556.

178 Saturated Heterocyclic Chemistry sufficient to destroy other sensitive functionalities. Corey and Ruden have used monobromoglycerol to protect carbonyl functions as 4-bromomethyl1 , 3 - d i o x o l a n ~The . ~ ~ketone may be regenerated by refluxing with active zinc in methanol. Under these conditions, other acetal functions or tetrahydropyranyl ethers are stable (Scheme 27).

Scheme 27

Hine and c o - ~ o r k e r shave ~ ~ ~examined the cyclization of trihalogenoacetate esters of 1,Zdiols to the 1,3-dioxolan-2-ols (136; R = H). In the cast: of 2-hydroxyethyl trifluoracetate the concentration of the cyclic form was too low to detect, but an equilibrium may be inferred on the basis that diazo,methane treatment gives the methyl derivative (136; R = Me, X = F). When several methyl groups are present or when the hydroxy- and trihalogenoacetoxy-groups are held in close proximity, as in cis-3,4-dihydroxytetrahydro,furan, ring formation is favoured.

Thermal isomerization226of 4-methylene-l,3-dioxolans(137) to the 1,3dioxoles (138) occurs at temperatures above 200 "C and as such may offer a. convenient entry into the lY3-dioxenesystem. The related system (139) has been prepared227by photolysis of 9,lO-phenanthroquinone in the presence of 1-methoxyprop-1-yne.

2z4 3a5

2z6 227

E. J. Corey and R. A. Ruden, J . Org. Chem., 1973, 38, 834. J. Hine, D. Ricard, and R. Perz, J . Org. Chem., 1973, 38, 110. A. S. Atavin, A. N. Mirskova, T. Proskurina, V. K. Voranov, and G . A. Kalabin, Khim. geterotsikl. Soedinenii, 1973, 446 (Chem. Abs., 1973, 79, 31 967). H.J. T. Bos, H. Polman, and P. F. E. van Montfort, J.C.S. Chem. Comm., 1973,188.

Fiue- and Six-membered Rings and Related Fused Systems

179 4-Isopropylidene-5,5-dimethyl-2-dimethylamino-1,3-dioxan undergoes acidcatalysed elimination of dimethylformamide to produce trialkylenols228 (Scheme 28) which are remarkably stable, enjoying lifetimes ranging from days to weeks.

I

Scheme 28

A crystal-structure determination229of the dioxolanium perchlorate (140) reveals that the ring is completely planar with the methyl groups at C-4 and C-5 eclipsed. These observations imply that the mesomeric stabilization of the three-atom r-system is larger than the repulsive forces produced by the eclipsing of two pairs of methyl groups.

H .\j.clo,

v*

R2

O%

(140)

0

(141)

1,3-Dioxolan-2,4-diones (141) (the oxygen analogues of Leuchs anhydrides) have been prepared and their general reactivity is as predicted.230 Ozonides. The great ozonolysis controversy continues. Kinetic evidence has been put forward which supports zero,231 second-, and third-order processes,232although the precise kinetics appear to be governed by the pressure at which the reaction is carried out. The presence of oxygen appears to have a marked effect on the rate of reaction. Bailey and c o - ~ o r k e r claim s ~ ~ ~that, in contrast to earlier reports, cyclohexanone and pinacolone are not oxidized to their Baeyer-Villiger products during ozonolysis of ethylidenecyclohexanein their presence. On the basis of a dubious mechanistic interpretation of the failure of the primary ozonide of trans-di-t-butylethylene to form a dioxetan on treatment with proprionaldehyde, the initial formation of a Staudinger molozonide is discarded. Other workers234favour the initial formation of a 1,2,3-trioxolan by [3 + 21 cycloaddition of ozone to the double bond., 228

H. M. R. Hofimann and E. A. Schmidt, Angew. Chem. Internat. Edn., 1973,12,239.

229

H.Paulsen and R. Dammeyer, Chem. Ber., 1973,106,2324. I. J. Smith and B. J. Tighe, Chem. and Ind., 1973,695. E. R.Altwicker and J. Basila, Tetrahedron, 1973,29, 1969.

S3O 231 232 233 834

L. A. Hull, I. C. Hisatune, and J. Heiklen, Canud. J . Chem., 1973,51, 1504. P. S. Bailey, T. P. Carter, C. M. Fischner, and J. A. Thompson, Canad. J . Chem., 1973, 51, 1278. K.R. Kopecky, P. A. Lockwood, J. C. Filby, and R. W. Reid, Canad.J. Chem., 1973, 51,468; D.R. Kerur and D. G. M. Diaper, ibid., p. 3110.

180

Saturated Heterocyclic Chemistry

Scheme 29

Murray and co-workers have developed a new method for the synthesis of o ~ o n i d e sPhotolysis .~~~ of diary1 diazo-compounds in the presence of aldehydes and oxygen results in the formation of 1,2,4-trioxolans (Scheme 29) in yields of ca. 10%. This synthesis offers direct evidence for the involvement of the Criegee zwitterion in ozonide formation. The products may be isolated in pure form and it has been possible specifically to locate an l 8 0 label in the peroxide or ether linkages. Mass spectrometric studies indicate236that no scrambling of the label occurs during this reaction. Attempts to generate tetrameth~ltetrahedrane~~' by photolysis of the ozonide (142) gave hexamethylbenzene and acetic anhydride. No evidence of the desired product was observed.

1142)

Tetrahydropyrans. Distillation of pentane-l,5-diol from amberlyst 15 ionexchange resin results in the formation of tetrahydropyran through the cycloelimination of water.238Palladium-catalysed reaction of butadiene with aldehydes results in the formation of 2-alkyl-3,6-divinyltetrahydropyrans (143). Although this reaction appears to be general for a variety of aldehydes the introduction of electron-donating or electron-withdrawing substituents into the butadiene prevents the reaction from occurring.239 235

236 237

238 239

R. W. Murray and A. Suzui, J. Amer. Cherii. SOC.,1973,95, 3343. R. W. Murray and D. P. Higley, J . Amer. Chem. SOC.,1973, 95, 7886. G. Maier and M. Schneider, Angew. Chem. Internat. Edn., 1973, 12, 162. L. T. Scott and J. 0. Naples, Synthesis, 1973, 209. A. De Smet and M. Anteunis, Org. Magn. Resonance, 1973, 5 , 589.

Five- and Six-membered Rings and Related Fused Systems 181 A number of 4-substituted t e t r a h y d r ~ p y r a n shave ~ ~ ~ been prepared by Grignard reaction of ethoxymagnesium chloride with 4-oxotetrahydropyrans. Formic acid-induced hydrolysis of the acetylated product results in the direct formation of 4-formyltetrahydropyrans. Nelson and Miller have observed an interesting fragmentation of 2ethynyltetrahydropyrans on treatment with Grignard reagents, leading to substituted allenes241(Scheme 30).

Et

Scheme 30

Dihydropyrans. Contrary to earlier report, toluene-p-sulphonic acid appears to be a better catalyst for the formation of THP ethers242than boron trifluoride etherate. Cholesterol gives the THP ether in five minutes in the presence of toluene-p-sulphonic acid. An unusual rearrangement (Scheme 31) of l-methylcyclopentyl hydroperoxide has been reported.243Treatment of (144) with sulphuric acid in chloroform results in the formation of (145) and (146).

60°Hs (144)

(146)

Scheme 31 Z4O

242

S. A. Vartanyan, A. S. Noravyan, L. S. Avertsyan, and A. P. Mkrtchyan, Armyan. khim. Zhur., 1973,26,227 (Chem. Abs., 1973,79, 66 132). D. J. Nelson and W. J. Miller, J.C.S. Chem. Comm., 1973, 444. J. N. Van Boom, J. D. M. Herschied, and C. B. Reese, Synthesis, 1973, 169. R. D. Bushick and R. W. Warren, Tetrahedron Letters, 1973,4779.

Saturated Heterocyclic Chemistry

182

Attempts244to prepare 2-methoxy-3-oxotetrahydropyranby the hydrolysis of 2-methoxy-3,3-dihalogenotetrahydropyran have failed, the observed product being 2-methoxy-3-halogeno-5,6-dihydropyran ; however, m-chloroperbenzoic acid oxidation of 5-halogeno-3,4-dihydropyrans produces modest yields of the ketone. Base-induced cyclization of propargyloxy-derivativesw5pursues a similar course to that observed with acetylenic alcohols. Cyclization of the malonate derivative (147) results in the formation of the dihydropyran derivative (148) and the tetrahydro-oxepin (149) in a ratio of 1 :1.4, a somewhat surprising result in view of the known preference for six-membered-ring formation. ,COeEt COzEt

I

CH=C-CH20CH2CH2CH

I

COaEt (147)

(1491

(148)

Taylor and Wright,246on attempting to perform an ‘ene’ reaction between hexafluoroacetone and tetramethylallene, found that the onIy observable reaction was the formation of the dihydropyran (150), presumably by way of the initial isomerization of the allene to 2,4-dimethylpenta-1,3-diene.

CFS (150)

The ‘in viuu’ conversion of loganin into secologanin prior to coupling with tryptamine has long been considered to proceed by way of the hydroxylated loganin (15 1) during indole-monoterpenoid alkaloid biosynthesis. Ringopening by a 1,3-eliminationprocess (Scheme 32) should lead to secologanin

,OGlucose COzMe

244

245 246

J. E. Roff and R.K. Brown, Canad. J . Chem., 1973,51, 3354. A. T. Bottini, J. G . Maroski, and V. Dev, J. Org. Chem., 1973,38, 1767. D. R. Taylor and D. B. Wright, J.C.S. Perkin I, 1973, 956.

Five- and Six-membered Rings and Related Fused Systems 183 (152), and the recent synthesisM7of (151) in optically active form will certainly result in the clarification of this point. A synthesis of the related antiviral agent methyl elenolate (153) has been described,248and the structures of valtratum (154) and a number of related compounds249have been reported. CO2H

1

GHO

'OCOCH2CHMe2 (154)

(153)

Dihydropyrones. lH N.m.r. studies on 'kawa lactones' (155) indicate that the C-6 substituent preferentially adopts a pseudoequatorial position250and that rotation about the arylethyl side-chain is hindered.

R 2 bC - & C H 5 2 0 ° M e 0 (155)

Reaction of aromatic aldehydes with diethyl isopr~pylidenemalonate~~~ results in the formation of dihydropyrones (157) by way of the intermediate diarylidene derivatives (Scheme 33).

,

,CO2Et

X

COzEt

ArCH=CH, NaNH2- ArCHO

ArCH=CH

,CO2Et

CH=CHAr I

X

CO2Et

(156)

(157)

Scheme 33

Photoaddition of dienes to 2,2-dimethyl-2,3-dihydro-4-pyroneresults in the formation of mixed cis- and trans-products, suggesting a radical addition rather than [2 + 21 c y ~ l o a d d i t i o n . ~ ~ ~ 248

24D 250

261

252

L. F. Tietze, Angew. Chem. Internat. Edn., 1973, 12, 757. R. C. Kelly and I. Schletter, J. Amer. Chem. SOC.,1973, 95, 7156. P. W. Thies, E. Finner, and F. Rosskopf, Tetrahedron, 1973, 29, 3226. H. Achenbach and W. Regel, Chem. Ber., 1973, 106, 2648. Y.Anghelova and C. Ivanov, Chem. Ber., 1973,106, 2643. P. Margaretha, Annalen, 1973, 727.

13

I84

Saturated Heterocyclic Chemistry

Fused Pyans. Catalytic reduction of the nitrobenzopyran (158) gives truns-2methylchroman-3-amine whereas lithium aluminium hydride reduction gives the isomeric cis-products; the stereochemical assignments rest on their l H n.m.r. spectra.253

(158)

Chromones are reduced to perhydro-derivatives over a ruthenium cata-lyst;254the carbonyl group requires protection and a side reaction results in the hydrogenolysis of the O-alkyl bond. Flavones have been reduced over palladium on the product of reduction being dependent on the: pH at which the reduction is carried out. Hamer and have prepared isochroman-4-ones by the photolysis of phenylpropane-ly2-diones(Scheme 34).

& @ ; @ /"\" 0

.

-t

Et

Me

Me

Et

Et

-Me

Scheme 34

1,2-Dioxans. Thermolysis of 1 ,2-dioxans has been to proceed by the initial formation of a 1,6-biradical by homolysis of the 0-0 bond. The tetramethyl derivative (159) appears to undergo a concerted fragmentation rather than a stepwise loss of acetone. The thermolytic and p h o t o l y t i ~ ~ ~ * decomposition of phenylmaleoyl peroxide (160) to phenylacetylene probably proceeds by a similar mechanism.

253

254 255

256 257 258

H. Booth, D. Huckle, and I. M. Lockhart, J.C.S. Perkin IZ, 1973, 277. J. A. Hirsch and G . Swartzkopf, J. Org. Chem., 1973, 38, 3534. V. Szabo and E. Antal, Tetrahedron Letters, 1973, 1659. N. K. Hamer and C. J. Samuel, J.C.S. Perkin 11, 1973, 1316. W. Adam and J. Sanabia, Angew. Chem. Internat. Edn., 1973, 12, 843. M. M. Martin and J. M. King, J . Org. Chem., 1973, 38, 1588.

Five- and Six-membered Rings and Related Fused Systems 185 1,3-Dioxans. A number of classical syntheses of 1,3-dioxans from 1,3-diols have been reported and as such warrant no further discussion. 2-Bromomethyl-l,3-dioxan has been described259and may find some use as a synthon. The carbanion derived from base treatment of 4-hydroxymethyl-4-nitro-1,3dioxan undergoes Michael addition with suitable acceptors.260Radical bromination of 1,3-dioxans results in substitution at the 4 - p o ~ i t i o n . ~ ~ ~ Treatment of cyclic a-acetal acids containing262the 1,3-dioxan or 1,3dioxolan ring with PCl, results in the formation of esters of 1,2- or 1,3chlorohydrins (Scheme 35). This reaction offers a synthetic method of preparing oxirans from 1,2-diols with the same configuration at carbon as the diol. CI -

RCOz(CH2),CHZCI

Scheme 35

Flauobacterium ~ x y d a n oxidation s ~ ~ ~ of a variety of 5,5-di(hydroxymethyl)1,3-dioxans derived from pentaerythritol results in the formation of the 5carboxy-5-hydroxymethyl derivatives. cis- and trans-Derivatives of 2,5disubstituted 1,3-dioxalan-4-0nes have been synthesized264and structures assigned by lH n.m.r. 1,4-Dioxans. Base-catalysed c y ~ l i z a t i o nof~propargyloxy-ethanols ~~ gives rise to mixed products including 1,4-dioxans. Low yields of 1,4-dioxan derivatives are produced during the reaction of phenylacetyldiazomethane266 with SO2in ethanol, The mechanism for this reaction appears obscure. The photoelectron spectra of 1,4-dioxans have been discussed.267 Miscellaneous. A substance derived from the ozonolysis of pin-2( 10)-ene which was formerly formulated as 7,7-dimethyl-3-oxabicyclo[4,1,l]octan-2one has been shown to be the 1,2,4,5tetraoxan (161).268 259

260 261

262 263 264

265 266 267 268

A. N. Volkov, A. N. Khudyakova, and K . N. Kolobugina, U.S.S.R. P. 382 620 (Chem. Abs., 1973, 79, 66 368). H . Piotrowska, T. Urbanski, and I. Kmiotek, Roczniki Chem., 1973,42,409. D. L. Rakhmankulov, V. I. Isagulyants, and S. S. Zlotskii, U.S.S.R. P. 376 369 (Chem. Abs., 1973,79, 53 337). M. S. Newman and C. H. Chen, J . Org. Chem., 1973,38, 1173. J. R. Schaeffer and R . E. Stevens, J . Org. Chem., 1973, 38, 1421. Y. Asabe, S. Takitani, and Y. Tsuzuki, BUN.Chem. SOC.Japan, 1973,46, 661. A. T. Bottini and J. G. Maroski, J . Org. Chem., 1973, 38, 1455. M. Tanaka, K. Katayama, T. Nagai, and K. Tokura, Tetrahedron Letters, 1973, 3385. T. Kobayashi and S. Nagukura, Bull. Chem. SOC.Japan, 1973,46,1558. K. H. Overton and P. Owen, J.C.S. Perkin I, 1973, 226.

186

Saturated Heterocyclic Chemistry

Nitrogen-containing Rings.-Pyrrolidines. In contrast to potassium metal, potassium hydride reacts rapidly with pyrrolidine to form the potassio-derivative, which functions as a ‘super base’.269 One of the most elegant pieces of work in the 1973 literature has appeared from the Sandoz group2‘O and describes the general synthetic utility of the intramolecular ‘ene’ reaction. Thermal cycliation of the cis-crotylamide (162) occurs at 230-280 O C to yield 1-acylpyrrolidines (163). The cis stereochemistry of (163) has been confirmed by X-ray methods. Under similar conditions the trans-crotylamides (164) gave (163) as major products with

minor quantities of the trans-isomers (165), and these products have been rationalized in terms of the relative stabilities of the transition states. When the ‘ene’ component forms part of a ring, fused pyrrolidines are formed as typified by the conversion (166) -+(167). The efficient cyclization of the diene (168) to the pyrrolidine (169) offers a stereospecific approach to spiro-systems.

K

269

C. A. Brown, J. Amer. Chem. SOC.,1973,95,982.

W. Oppolzer, E. Pfenninger, and K. Keller, Helo. Chim. Acra, 1973, 56, 1807.

Five- and Six-membered Rings and Related Fused Systems

187

COMe

(168)

(169)

Cyclic amines undergo palladium-catalysed rearrangement271to N-substituted cycloamines. The reaction is believed to involve initial dehydrogenation to the imine (Scheme 36) followed by self condensation. U

J

1

Scheme 36

Nelsen and W e i ~ r n a nhave ~ ~ ~described a one-step synthesis of tetraaklylhydrazines in which a 1,l-disubstituted hydrazine reacts with aldehydes in the presence of sodium cyanoborohydride. Using this method the pyrrolidinohydrazine (1 70) has been prepared. R' dC02Me dco2Me

cN-o %R2

0

I

CHePh

I

CH2Ph

RS

(170)

(171)

(172)

(173)

3-Substituted methylenepyrrolidones (1 71) have been prepared by dehydration of the corresponding alcohols under acidic conditions.273NAlkylpyrrolidine derivatives have been prepared in high yields by reduction of N-alkyl-2-pyrrolidoneswith diborane in THF.274This method is particularly useful as many other functionalities are unaffected; e.g. (172) gives (173) in 54% yield. 273 273

274

N. Yoshimura, I. Moritani, T. Shimamura, and S. Murahashi, J.C.S. Chem. Comm., 1973, 307. S. F. Nelsen and G. R. Weisman, Tetrahedron Letters, 1973, 2321. G. C. Helsley, C. D. Lunsford, and J. A. Richman, U.S. P. 3 732 247 (Chem. A h . , 1973, 79, 18 564). H. C. Brown and P. Heim, J . Org. Chem., 1973,38, 912.

Saturated Heterocyclic Chemistry

188

(174)

(175)

Acid-catalysed cyclization of some dialkylaminoacetylenes (1 74) results in the formation of 2-methylenepyrrolidinium salts (1 75) which possess anal-. gesic properties.275Alternative methods of preparation of NN-dialkyl-, pyrrolidinium salts have been reported.276 N-Cyanomethylpyrrolidinium salts, on treatment with base, form y l i d e ~ which ~ ~ ' undergo a [2,3] sigmatropic rearrangement (Scheme 37). Acid hydrolysis affords By-unsaturated aldehydes in yields exceeding 90%.

CN Scheme 37

N-Dealkylation represents a difficult problem in natural product synthesis. Chloroformate ester cleavage appears to give satisfactory results in many cases and has been applied to demethylation of r n e ~ e m b r i n eReinecke .~~~ and D a ~ b e r have t ~ ~ shown ~ that if a benzyl group is used to protect nitrogen, specific debenzylation occurs with trichloroethyl chloroformate. The resultant urethane may be cleaved selectively with zinc, offering a mild deprotection sequence. Unexceptional syntheses of 1 -methylpyrrolizidines (1 76),2s03aY4,9,9a-tetrahydrobenzo[flindoles (1 77),2*l and isoindoles (1 78)2s2have been reported. ,

c.,& N

(176) 275

276 277 278

27B 280

281 282

@-y

\

\

(177)

(178)

J. A. Gautier, M. Miocque, M. D. d'Engenieres, J. Maldonado, J. L. Avril, G. Raynaulde, and N. Dorme, French Demande 2 142 809 (Chem. Abs., 1973,79, 5255). R. M. Ottenbrite and G . Meyers, Canad. J . Chem., 1973, 51, 3631. L. N. Mander and J. V. Turner, J . Org. Chem., 1973, 38, 2916. P. Pfaffli and H . Hauth, Helu. Chim. Acta, 1973, 56, 347. M. G. Reinecke and R. G. Daubert, J . Org. Chem., 1973,38, 3281. N. M. Skvortsov and I. V. Antipova, Ref. Zhur. Khim., 1973, Abstr. No. 2Zh304 (Chem. Abs., 1973, 79, 78 496). U. A. De and B. F. Saha, J. Pharm. Sci., 1973,62, 1363. D. Middlemiss, Ger. Offen 2 259 498 (Chem. Abs., 1973, 79, 66 171).

Fiue- and Six-membered Rings and Related Fused Systems

189

qip @p R

R

COMe

(179)

(180)

P h o t o l y ~ iof s ~the ~ ~hexahydrocarbazole (179; R = H) results in the formation of the indolenine derivative (181; R = H) by way of the intermediate radical (180). When R = OMe a competing side reaction involves the formation of (181 ;R = COMe) through loss of formaldehyde from (182).

R

Asymmetric induction has been observed during alkylation,2m halogenationFa5and cyclization286of enamines derived from the t-butyl ester of proline. Optical yields as high as 50% have been reported. Montei1-0~~~ has published details of the total synthesis of cucurbitine (183), an uncommon amino-acid with plant-growth regulatory properties.

8°2H HI

(183)

Pyrrolidones. Numerous methods of synthesis of pyrrolidones and substituted pyrrolidones have appeared.288Specific N-acylation is accomplished in high

286

286

a07

B. Winkler-Lardelli, H. J. Rosenkranz, H. J. Hansen, H. Schmid, B. Blank, and H. Fischer, Helv. Chim. Acta, 1973, 56,2628. G . Otani and S. Yamada, Chem. and Pharm. Bull. (Japan), 1973,21,2112. H . Hiroi and S. Yamada, Chem. and Pharm. Bull. (Japan), 1973,21,41. S . Yamada, H. Shibasaki, and S. Terashima, Tetrahedron Letters, 1973, 381. H. J. Monteiro, J.C.S. Chem. Comm., 1973, 2. N. M. Tsybina, B. I. Bryantsev, N. A. Losnakova, T. V. Protopopova, G. S. Rosenberg, and A. P. Skoldinov, Zhur. org. Khim., 1973, 9, 496; G. J. Koomen, A. J. Kroon, M. F. Cabre, A. P. Goores, R. Peereboom, and U. K. Pandit, J.C.S. Perkin I, 1973, 1934; N. Kolocouris, Bull. Soc. chim. France, 1973, 1057; D. St.C. Black and K. G. Watson, Austral. J . Chem., 1973, 26, 2515; R. I. Davis, Ger. Offen 2 253 486 (Chem. A h . , 1973,79, 18 558).

190

Saturated Heterocyclic Chemistry

(186)

(185)

(184)

yields289by the reaction of the N-trimethylsilyl derivative with acid chlorides. Treatment of 1-methyl-2-pyrrolidone with phenyl isocyanate results in the formation of low yields of 1-methyl-2-iminophenylpyrrolidine(184), the major product being the pyrimidine derivative (185).2901-Alkyl-Zaminomethylpyrr~lidines~~~ have been prepared by a sequence involving reduction of the nitro-compound (186) derived from base-catalysed condensation of nitromethane with 1-alkyl-2-pyrrolidones. Treatment of the P-lactam (187) with lithium di-isopropylamideresults in ring enlargement to (188)Fg2 Diborane reduction of the morpholine enamine of the 3-pyrrolidone (1 89) followed by thermolysis yields racemic d e h y d r ~ p r o l i n e . ~ ~ ~

qPh CHzPh

0

(187)

COzEt

(188) (189)

Dihydropyrroles. In an attempt to form 1,3-diazetidinones K r a a t ~has ~~~ treated the y-butyrolactim ether (190) with aryl isocyanates. The observed product was the 3-arylcarbamoyl lactim ether (191); this may be rationalized in terms of the initial isomerization of (190) to the enamine (192). Patent literature295describes the related derivatives (193).

a

OR

28s 290

291 292

2B3

2B4 z95

6

O

R

a

CONR1R2

CONHAr

n HI o R

Et

(190) (191) (192) (193) M. Matsui, Agric. and Biol. Chem. (Japan), 1973, 37, 1139. R. Richter and H . Ulrich, J. Org. Chem., 1973, 38, 2614. S. A. Fratmann, French Demande 2 154 423 (Chem. Abs., 1973,79, 1991). R. W. Fraser, G. Boussard, I. D. Portescu, J. J. Whiting, and Y. Y. Wigfield, Canad. J. Chem., 1973, 51, 1109. R. J. Friary, J. M. Gilligan, R. P. Szajewski, K. J. Falci, and R. W. Frank, J . Org. Chem., 1973,38, 3487. U . Kraatz, Tetrahedron, 1973, 29, 3991. W. B. Dickinson and P. Lang, U.S. P. 3 732 217 (Chem. Abs., 1973,79,18 563).

Five- and Six-membered Rings and Related Fused Systems 191 Oxidation of (1 90) with rn-chloroperbenzoic a ~ i d generates ~ ~ ~ oxa* ~ ~ ~ ziridines (194), which undergo thermal decomposition to the cyclic trimer (195) a€the 4-iminobutanoate ester (196).

(195)

(194)

Alkylation of bicyclic imines by way of metallo-enamines under equilibrating conditions gives rise to products predictable on the basis of thermodynamic rather than kinetic Aln8-Hexahydroindo1e(1 97) is specifically alkylated, giving 7-substituted A1v8-hexahydroindole (198).

Schollkopf and c o - w o r k e r ~ have ~ ~ prepared ~ A1-and A2-pyrrolinederivatives by the reaction of a-isocyano-acetates or -propionates with acrylates. The intermediate a-isocyanoglutarates undergo base-catalysed cyclization to A1- or A2-pyrrolines. The reaction of tetracyanoethylene with acyclic #?-diketonesunexpectedly300 produces dihydropyrroles; thus acetylacetone reacts to form (200). The dihydrofuran (199) has been identified as an intermediate and a mechanism (Scheme 38) tentatively formulated. Bonnett and co-workers have described a synthesis of i ~ o i n d o l e . ~ ~ ~ Optical resolution of 2-ethylidene-3-methylsuccinimide (201) has been achieved302using cellulose acetate as the resolving agent. Hydrogenation of the ( +)-isomer yields a mixture of erythro-2-ethyl-3-methylsuccinimide and ( -)-threu-2S-ethyl-3S-methylsuccinimide. Reduction of the maleimides (202) to (203)has been accomplished using trialkyl p h o ~ p h i t e s .Unsymmetrical ~~~ 286

297 2g8 zg9 289

300 301

302 303

D. Thomas and D. H. Uhe, TetrahedronLetters, 1973, 1807. D. St.C. Black and K. G. Watson, Austral. J. Chem., 1973, 29, 2159. J. C. Leffingwell, J.C.S. Chem. Comm., 1973, 299. U. Schollkopf and P. H . Porsche, Chem. Ber., 1973, 106, 3382. U. Schollkopf and K. Hantke, Annalen, 1973, 1571. J. W. Ducker and M. J. Gunter, Austral. J . Chem., 1973, 26, 1551. R. Bonnett, R. F. C. Brown, and R. G. Smith, J.C.S. Perkin 1, 1973, 1432. H. Brockmann and G . Knobloch, Chem. Ber., 1973,106, 803. M. F. Chasle-Pommeret, M. Leduc, A. Foucard, M. Hassairi, and E. Marchand, Tetrahedron, 1973, 29, 1419.

Saturated Heterocyclic Chemistry

192

succinimides are reduced to mixed products ; thus a-methyl-N-benzylsuccinimide (204) is reduced to a 1.4:l mixture of (205) and (206).304 Acylimmonium salts are formed on treatment of (205) and (206) with strong acids.305

HJ-- - -Me

~2j-~o

Me

H (201)

I

I

(202)

(203)

$CH2ph

e N C H 2 P h

O

0

OH

(204)

(205)

$CHzPh 0

(206)

P h o t o l y ~ i sof~ ~the ~ imidate (207) results in the formation of the cyclopropyl urethane (209). A w-w* singlet state is invoked and the isocyanate (208) has been shown to be involved.

JAm

0

(207) 304

306

YE, YEt N==C==O

(208)

NHC02R

(209)

S. Ohki, T. Watanabe, M. Uchiyama, N. Azawa, and F. Hamaguchi, Yukuguku Zusshi, 1973, 93, 841. H. D. Bartfeld and W. Flitsch, Chem. Ber., 1973, 106, 1423. T. H . Koch, R. J. Sluski, and R. H. Moseley, J . Amer. Chem. SOC.,1973,95, 3957.

Five- and Six-membered Rings and Related Fused Systems

193 0

0

II

)-x ButC02NHC

0

N2+ 0

(211)

(210)

(2 12)

Lowe and Ridley307 have developed a photolytic route to B-lactams. Photolysis of 3-diazo-5-methylpyrrolidine-2,4-dione (210) results in a Wolff rearrangement of the intermediate carbene, generating the keten (211) which was trapped with t-butyl carbazate as (212). Periodate oxidation of the 3-0x0-2-pyrrolidines(213)results in ring contraction to the p-lactams (214).308

(2 13)

(214)

Products from the reaction of N-(4-chlorobutyryl)isatin (215) with KOH appear to be solvent-dependent.In protic solvents3092-(2-oxopyrrolidin-l-yl)phenylglyoxylic acid (216) is formed whereas in aprotic solvents 1-(3carboxypropy1)isatin (217) is formed. This reaction sequence may be rationalized in terms of Scheme 39.

0:::g. u

Protic solvent

COCO2H

0

(217) Scheme 39 307

308 309

G. Lowe and D. D. Ridley, J.C.S. Perkin I, 1973, 2024; J.C.S. Chern. Comm., 1973,

328. D. R. Bender, L. F. Bjeldanes, D. R. Knapp, P. R. McKean, and H . Rapoport, J. Org. Chem., 1973, 38, 3439. P. Lakshminarayana, K. K. Balasubramanian, and P. Shanmugam, J.C.S. Perkin I, 1973, 998.

194 Saturated Heterocyclic Chemistry Ethyl a-oxo-carboxylates react with benzaldehydeimine at 100 'C,forming 4-alkyl-5-phenylpyrrolidin-2,3-dione~.~~~ Trioxopyrrolidines (218) have been prepared311 by condensation of diethyl oxalacetate with alkyl cyanates.

R I

R

N-Alkylmaleimides oligomerize on being heated in refluxing acetonitrile in the presence of imidazole. When hydroquinone is added, trimers (219) are formed. A radical mechanism is proposed.312 Addition of maleimide to benzimidazoles produces l-benzimidazolylsuccinimides.313 Pyrazolines. Quantum yields and fluorescencedecay times for emission from 1pyrazolines have been examined. When Aex < 308 nm, l-pyrazoline decomposes with unit efficiency in less than 10 ns.314Details of mercury-sensitized decomposition of 1-pyrazolines have been reported.315 Kinetic studies on the thermal decomposition of phenyl-substituted 1-pyrazolines using dilatometric and differential thermal analysis techniques suggest that the nature of the decomposition products may be predicted from pyrazoline configuration.316 Photolysis of a number of 2,3-dia~abicyclo[3,1,O]hex-2-enes (220) offers a promising route to bicyclo[l ,1,O]butanes. A radical mechanism (Scheme 40; path a) is suggested although the alternative (Scheme 40; path b) formation of diazoalkane and carbene fragmentation cannot be ruled Treatment of the 4-methoxycarbonylpyra~oline(221) with mild base results in cyclization to the pyrazolotriazinone (222). When a strong base such as methoxide is employed fragmentation of (222) to the pyrazole (223) In contrast to these observations the pyrazoline (224) gives rise 310 311 312

313 314 315 316

317

318

C. Shin and J. Yoshimura, Tetrahedron Letters, 1973, 2615. L. Capuano, H. R. Kirn, and M. Kalweit, Chem. Ber., 1973, 106, 3677. T. Wagner-Jauregg, Q. Ahmad, and E. Pretsch, Helv. Chim. Acta, 1773, 56, 1406. Q. Ahmad, T. Wagner-Jauregg, E. Pretsch, and J. Seible, Helv. Chim. Actu, 1973,56, 1646. G. L. Loper and F. H. Dorer, J. Amer. Chem. Soc., 1973,95, 20. E. B. Klunder and R. W. Carr, J . Amer. Chem. Soc., 1973, 95, 7386. J. P. Deleux, G . Leroy, and J. Weiler, Tetrahedron, 1973, 29, 1135; J. P. Delew, G. Leroy, M. Sana, and J. Weiler, Bull. SOC.chim. belges, 1973, 82, 423. P. A. Gassman and W. J. Greenlee, J . Amer. Chem. SOC.,1973, 95, 980. F. B. Culp, A. Nebeya, and J. A. Moore, J. Org. Chem., 1973,38,2949.

19s

Five- and Six-membered Rings and Related Fused Systems ,Me

-

I(

Ph\ Ph

N 2 q , Me

:
Ph, , / -

+

ph&

Ph

\Me

Ph

Scheme 40

to the diazabicyclo[4,1 ,O]heptanone (225) under similar conditions.319 This difference in reactivity has beeen attributed to the fact that (221) shows a greater tendency to undergo isomerization of the N=N double bond into conjugation with the C02Me group, which stabilizes (222), although this suggestion requires further clarification. C02Me 0

H

The stereochemistry of cyclization of phenylhydrazones of ap-unsaturated ketones to A2-pyrazolines has been examined.320i321 A stereoselective enamine-imine tautomerism step (Scheme 41) which is temperature- and solventdependent appears to be involved. 31g 320

321

A. Nabeya, K. Kurita, and J. A. Moore, J. Org. Chem., 1973,38, 2954; F. B. Culp, K. Kurita, and J. A. Moore, ibid., p. 2945. H. Ferres, M. S. Hamdam, and W. R. Jackson, J.C.S. Perkin II, 1973, 936. J. Elguero and C. Marzin, Bull. SOC.chim. France, 1973, 3401.

196

Saturated Heterocyclic Chemistry Ph H

\

Ph

Y

P"

R

2

AcOH, 60 "C

~

I

Ph

Ph

H

J

9 P'

Scheme 41

The influence of solvent on the tautomeric form of 1-phenyl-Ah-pyrazolin5-ones (226a- 226b) has been examined.322As anticipated, in polar solvents (226a) is preferred, the preference decreasing with increasing solvent polarity.

R (226a)

(226b)

5-Hydroxy-A2-pyrazolin-4-ones and 4-halogeno-5-hydroxy-A2-pyrazolines show a strong tendency to rearrange323by acyloin or halohydrin rearrangements to produce the thermodynamically more stable A2-pyrazolin-5-ones (Scheme 42).

H

OS

P

dN-N

h

-

HO

Ph

hP*'

/

/"-"

R

R

Scheme 42

Rees and Yelland324have examined the lead tetra-acetate oxidation of A2-pyrazolin-5-one derivatives. The anticipated cyclopropanes were not obtained: the major products from the oxidation of (227) were diphenylacetylene and (228). The presence of (228) suggests that cyclopropenones are not intermediates in this reaction.

3a3

324

A. Maquestian, Y. Van Haverbeke, and R. Jacquerye, Bull. SOC.chim.belges, 1973, 82, 215. M. J. Nye and W. P. Tang, Canad. J. Chem., 1973, 51, 338. C. W. Rees and M. Yelland, J.C.S. Perkin I, 1973, 221.

Five- and Six-membered Rings and Related Fused Systems

197 ,COaMe

(227)

(228)

(229)

The 1-cyclopropylpyrrole (229) is formed during the lead tetra-acetate oxidation of 3-methoxycarbonyl-A2-pyrazoline.325 Acylation of 1-(2,2,2-trichloroethoxycarbonyl)-5,5-dimethylpyrazolin-3-onewith benzoyl chloride and Et3N results in exclusive O-acylation at room temperature.326Thermolysis of the imidate results in the formation of the N-acylated compound in high yield. 4,4’-Diphenyl-4,4’-bis-5-pyrazolones (230) form long-lived radicals on thermolysis, their relative stabilities depending on the nature and number of substituents in the phenyl ring.327A dissociation energy of 51.1 f 0.8 kJ mol-l has been determined for (230; Ar =p-N02C6H4).

Electrochemical reduction of 1-arylpyrazoles gives rise to 4,5-dihydropyrazoles as the principal products.328 Imidazolines. The stereo~hemistry,3~~ and mechanism331 of imidazoline formation from 1,Zdiamines have been reported. Suggestions concerning assignments of N-methyl groups in the lHn.m.r. spectra of imidazolines have been although unambiguous assignments appear difficult. 2-Halogenomethyl- and 2-dialkylamino-l,3-dialkylimidazolines undergo rearrangement (Scheme 43) to tetrahydropyrazines on heating at 180 “C or ab0ve.3~~ 325

326 327 3a8

32s 330

331

A. A. Akrem, E. I. Kvasyuk, and I. A. Mikhailopulo, Tetrahedron Letters, 1973,2655 C. E. Hatch and P. Y . Johnson, Tetrahedron Letters, 1973,2153. R. Huttel, M. Rosner, and D. Wagner, Chem. Ber., 1973,106,2767. J. Grimshaw and J. Trocha-Grimshaw, J.C.S. Perkin I, 1973, 1275. J. Hine and K. W. Narducy, J. Amer. Chem. SOC.,1973,95, 3362. C. Chapuis, A. Gavreau, A. Klaebe, J. J. Perie, and J. Roussel, Bull. SOC.chim. France, 1973,2676. C. Chapuis, A. Gauvreau, A. Klaebe, A. Lattes, and J. J. Perie, Bull. SOC.chim. France,

1973,977. 332 133

J. L. Aubagnac, J. Elguero, and J. L. Gilles, Bull. SOC. chim. France, 1973,228. P. Duhamel, L. Duhamel, and P. Siret, Compt. rend., 1973,276,C , 1319 (Chem. A h . , 1973,79, 18 667).

198

Saturated Heterocyclic Chemistry R

n

'R

"YRCH-X N'3

L.

R

Scheme 43

Birch and D a s t f l have used 1,3-dialkylimidazolinesderived from aromatic aldehydes as protecting groups during metal-liquid ammonia reduction; thus reduction of the imidazoline (231) followed by hydrolysis gave the aldehyde (232).

n N$/

g

*rwp *XN Me

Me

(231)

(234)

(232)

(235)

(2 3 3)

(236)

M e t h y l a t i ~ nof~the ~ ~ 1,3-diazabicycl0[3,1,O]hexane (233) occurs on N-3 to yield the salt (234), which on prolonged treatment with diazomethane undergoes carbene insertion to yield (235). Hydrolysis of (235) results in the formation of the tetrahydropyrimidine (236). l-Acylaziridines (237) undergo336boron trifluoride-catalysedreaction with

(237) 534

a35

338

(238)

Scheme 44

A. J. Birch and K. P. Dastur, Austral. J. Chem., 1973, 26, 1363. H . W. Heine, T. A. Newton, G . J. Blosick, K. C. Irving, C. Meyer, and G . B. Corcoran, J . Org. Chem., 1973, 38, 651. T. Hiyama, K. Koide, S. Fujita, and H . Nozaki, Tetrahedron, 1973, 29, 3137.

Five- and Six-membered Rings and Related Fused Systems

199

nitriles to form A2-imidazolines.Reaction of the aziridine produces the transfused A2-imidazoline (238). Scheme 44 represents a suggested mechanism, although alternative pathways may be envisaged. Approaches to the synthesis of simple337and 2-imidazolines have appeared. Cyclol formation plays an important role in the chemistry of peptides, but azacyclols are known to be unstable. Treatment of N-trimethylsilyl derivatives of lactams with acid chlorides of benzyloxycarbonyl amino-acids results in the formation of a z a c y c l o l ~such ~ ~ ~as (239; R1 = H), which form relatively stable methyl derivatives (239; R1 = Me). Treatment of (239) with HC10, results in the formation of perchlorate salts (240).

(239)

(240)

Ceder and StenhedeaO have prepared 2-alkylidene-4-imidazolidonederivatives for which four possible isomeric forms (241a-d) exist. lH N.m.r.

(241 a)

(241b)

(241c)

(241d)

evidence suggests that (241a) is the favoured tautomer and that only one geometrical isomer is present in dimethyl sulphoxide. In pyridine the situation is more complex as evidenced by the appearance of two separate vinyl proton signals, which have been attributed to the geometrical isomers of (241a). The kinetics of ring closure of hydrantoic acids (242) to hydantoins (243)

337 338

339

360

R. Riebling, K. Pressler, and J. Potel, Ger. Offen 2 150 438 (Chern. Abs., 1973, 79, 5368). L. Fontanella, E. Occelli, and A. Perazzi, Farmaco, Ed. sci., 1973,28,463; D. Kuliling, Annalen, 1973, 263. G . Lucente, G. Zaniotti, and P. Frattesi, Tetrahedron Letters, 1973, 4303. 0. Ceder and U. Stenhede, Acta Chem. Scand., 1973, 27,2221.

14

200 Saturated Heterocyclic Chemistry under aqueous acid conditions have been studied.341Results suggest that substitution at C-2 by alkyl or aryl groups accelerates the cyclization, but the degree of acceleration is not entirely predictable on the basis of the size of the substituent. A competing acceleration-inhibition mechanism resulting from substituents being able to interfere with the reaction centre or assist in the cyclization has been suggested. Alternative approaches to hydantoins,342t h i o h y d a n t o i n ~ and , ~ ~ optically active 5-pheny1hydantoinsM4have appeared. 3-Substituted hydantoins containing dimethylamino-groups in the side-chain undergo hydrolytic ringopeninP5 under mild conditions. By varying the length of the side-chain it has been demonstrated that the hydrolysis is assisted by intramolecular catalysis (Scheme 45).

RN-CONH( CH2)3&HMe2

I

CHZCOp-

Scheme 45

The rea~tivity,~' and spectroscopic properties348of parabanic acid (2,4,5-trioxoimidazoline)and its derivatives have been described. Triazolines. Cycloelimination from the anion of 1,3-dioxalans and dithiolans, resulting in olefin formation, is well documented, and examination of 1,3,4-triazolines,e.g. (244), has revealed that a similar fragmentation occurs at -60 "C

Ph

,Ph

\

H

n

...J------H

Ph

~i

H

Ph +20"C

(244) 341 342 343 344 345

346 347

348

Ph 2 7

Ph-N=N-Ph

+

&-fi-+ph

Ph

Scheme 46

Ph

,H

phLj+-J: H

,Ph

H-, Ph

H

Ph

(245)

V. Stella and T. Higuchi, J. Org. Chem., 1973, 38, 1527. H. Bredereek, G . Simchen, and H. Hoffmann, Chem. Ber., 1973, 106, 3725. R. W. Hoffmann, K. Steinbach, and B. Dittrich, Chem. Ber., 1973,106,2174. K. H . Dudley and D. L. Bius, J . Heterocyclic Chem., 1973, 10, 173. C. F. Spencer, J . Heterocyclic Chem., 1973, 10, 455. A. Haas and V. Plass, Chem. Ber., 1973, 106, 3391. H . Gross and G . Zinner, Chem. Ber., 1973, 106, 2315. D. B. Larson, J. F. Arnett, and S. P. McGlynn, J . Amer. Chem. Soc., 1973,95, 6928.

Five- and Six-membered Rings and Related Fused Systems

201

-60 O C . At 20 "C the reverse reaction regenerates the triazolidine (Scheme 46), but when trans-stilbene is added the pyrrolidine (245) is formed in 20% yield.349Trapping with nitriles gives 3-imidazolines.3j0 Acid-catalysed ring closure of 1,2-diaryl-4-benzoylsemicarbazides yields 1,2,3-triaryl-A3-1,2,4-triazolin-5-0nes,3~~whereas base-induced oxidative cyclization of 4-arylsemicarbazones of aromatic aldehydes yields 3,4-diarylA2-1,2,4-triazoIin-5-0nes.3~~Phenylhydrazinium thiocyanate reacts with ketones and aldehydes to form 1-phenyl-3-alkyl-A4-1,2,4-triazoline-5-thiones in high yield.353 The synthesis of urazole and its derivatives by the reaction of hydrazines with biuret or ethyl allophanate is a complex process and the products are largely governed by experimental conditions.354Slow heating of a mixture of phenylhydrazine with biuret gives l-phenylurazole (246), whereas rapid heating gives 4-anilino-l-phenylurazole(247). A general synthesis of urazoles has appeared.355 Ph

Ph

\

I

1

H

NHPh

Oxidation of ~ r a z o l ewith ~ ~ N,04 ~ offers the first synthesis of 1,2,4-triazoline-3,5-dioneY which has been characterized by its spectroscopicproperties and its rapid reaction with cyclopentadiene. Vinyl esters react with phenyltriazolinedione (Scheme 47) to form trisubstituted u r a ~ o l e s . ~ ~ ~

.R1

Scheme 47 348

350 351

352

353 354 355

356 357

T. Kauffmann, A. Busch, K. Habersaat, and B. Scheerer, Tetrahedron Letters, 1973, 4047. T . Kauffmann, A. Busch, K. Habersaat, and E. Koppelmann, Angew. Chem. Internat. Edn., 1973, 12, 569. 0 . Tsuge and S. Kanemasa, J. Org. Chem., 1973, 38, 2972. K. Koyano and C. R. McArthur, Canad. J . Chem., 1973, 51, 333. I. Arai, Bull. Chem. SOC.Japan, 1973, 46, 2215. J. A. Lenoir and B. L. Johnson, Tetrahedron Letters, 1973, 5123. S. M. A. Hai and W. Lwowski, J . Org. Chem., 1973,38,2442. J. E. Herweh and R. M. Fantazier, Tetrahedron Letters, 1973,2101. K. B. Wagener and G. B. Butler, J . Org. Chem., 1973,38, 3070.

202 Saturated Heterocyclic Chemistry Tetrazulines. Borohydride reduction358 of 1,4,5-trisubstituted tetrazoliuni iodides results in the formation of A2-tetrazolines, which undergo thermal fragmentation (Scheme 48) to azides and imines.

Piperidines. The synthesis of piperidines by the reduction of pyridines can be complex. Borohydride reduction359of 3-substituted pyridines leads to partial and total hydrogenation; thus 3-nitropyridine gives 3-nitropiperidine in 42 % yield, but 3-cyanopyridine gives mixtures including 3-cyano-l,4,5,6-tetrahydropyridine and 3-aminomethylpyridine. Catalytic hydrogenation of collidine proceeds stereospecificallyover ruthenium on carbon360to yield allcis-2,4,6-trimethyIpiperidine. 0ther synthetic routes to piperidines have been reported.361 Lithium 2,2,6,6-tetramethylpiperidefunctions as a powerful base and has been used to generate phenylcarbene from benzyl chloride?62 Rates of reaction of p-substituted o-nitrofluorobenzene derivatives with piperidine have been studied and generally increase with increasing polarity of solvent r n e d i ~ r n . 3Water ~ ~ appears to retard the reaction and is thought to function by the solvation of piperidine. Product analysis364of the NaOH-induced solvolysis of 1-ethyl-3-chloropiperidine and 2-chloromethyl-l-ethylpyrrolidine indicates that the reactions proceed by way of the bicyclic intermediate (248) (Scheme 49). Although aziridinium species of this type are common during solvolysis of mines they are rarely observed with amides; however, Wong and H e l t ~ nhave ~ ~ob~ served that solvolysis of l-acetyl-3-tosylpiperidinesresults in a mixture of

358

sb9

361

362 363 364 365

T. Tsida, T. Akiyama, N. Mihara, S. Kozima, and K. Sisido, Bull. Chem. SOC.Japan, 1973,46, 1240. Y. Kigugawa, M. Kuramoto, I. Saito, and S. Yamada, Chem. and Pharm. Bull. (Japan), 1973, 21, 1914. R. Schubert, H. Ziemamm, and D. Wendisch, Synthesis, 1973, 220. A. Yamamoto, T. Okamoto, K. Sasajima, M. Nakao, I. Muruama, and S. Katayama, Ger. Offen 2 065 331 (Chem. A h . , 1973, 79, 18 577); L. Duhamel, P. Duhamel, and P. Siret, Bull. SOC.chim. France, 1973,2460; B. Gutkowska, Acta Polon. Pharm., 1973, 30, 109. R. A. Olofson and C. M. Dougherty, J. Amer. Chem. SOC.,1973,95,581. J. Kavalek and V. Sterba, Coll. Czech. Chem. Comm., 1973, 38, 884. C. F. Hammer, M. McC. Ali, and J. D. Weber, Tetrahedron, 1973,29, 1767. J. L. Wong and D. L. Helton, J.C.S. Chem. Comm., 1973, 353.

203

Five- and Six-membered Rings and Related Fused Systems

Products

Scheme 49

(250) and (251) in a ratio of 1.8:1, suggesting the intermediacy of (249). A similar aziridinium intermediate (252) has been invoked366to explain the lead tetra-acetate oxidation of 1-trityl-2-hydroxymethylpiperidineto 1trityl-Zdiacetoxymethylpyrrolidine.

(249)

(O*cN I

The base-induced reaction of phenylmercuric and N-(dihalogenoacety1)piperidines is strongly influenced by temperature and the nature of the base. Potassium t-butoxide prepared from equimolar amounts of potassium and t-butyl alcohol in THF at -20 to -30 "C gave the dibromocompound (253; X = Br) in ca. 80% yield. Thermolysis of (253; X = Br) gave a cisltrans mixture of the &lactams (254).

I OAc Trityl

(253)

(254)

(252)

De Koning, A. Springer-Fidder, M. J. Moolenaar, and H. 0. Huisman, Rec. Trav. chim., 1973, 92, 237. 3137 N. G. Johansson, Acta Chem. Scand., 1973,27, 1417. 3 1 3 ~H.

204

Saturated Heterocyclic Chemistry of~keto-lactams ~ (255) results in the formaPiperidones.Reductive a m i n a t i ~ n tion of amino-lactams which undergo cyclization to diazabicycloalkanes

(256).

Diethyl acetals of 1-methyl-2-piperidone-react with active methylene compounds to form 1-methy1-2-alkylidenepiperidine~?~~ With esters containing no a-hydrogen atoms acylation occurs; thus ethyl benzoate reacts to form 1-methyl-2-ethoxy-3-benzoyl-l,4,5,6-tetrahydropyridine?7~ 3-Piperidone derivatives3'l have been prepared by reaction of the ethyl ester of sarcosine with ethyl formylsuccinate. The intermediate enamine (Scheme 50) undergoes Dieckmann cyclization, forming 1-methylJ-ethoxy-

+ Reagents: i, MeNHCH2CO2Et;ii, NaCNBHS;iii, NaOEt; iv, H+-HpO; v, H'-EtOH

Scheme 50

carbonyl-3-piperidone and its diethyl acetal as the major products. The diethyl acetal appears to enjoy remarkable stability and on prolonged hydrolysis gives only low yields of the piperidone. The effect of the nitrogen atom on the n-r* carbonyl transition372in (S)-6-methyltetrahydropyridonederivatives has been reported. The nitrogen atom falls in the rear, upper-left octant and small negative Cotton effects have been observed at 300 nm. The results obtained were consistent and may be of some value in structural elucidation of natural products. 4-Substituted 4-piperidinols have been prepared by the reaction of 4piperidones under Reformatsky conditions373or with lithium a ~ e t y l i d e . ~ ~ ~ 4-Aminopiperidines have been prepared by the reduction of oximes of 368 36D 370

371

372 373

37p

H. Moehrle and R. Engelsing, Arch. Pharm., 1973,306, 325. V. G. Granik, A. G. Sukhoruchkin, N. S. Kuryatov, V. P. Pakhomov, and R. G. Glushkov, Khim. geterotsikl. Soedinenii, 1973, 954 (Chem. Abs., 1973, 79, 126 261). V. G. Granik, A. G. Sukhoruchkin, N. S. Kuryatov, V. P. Pakhomov, and R. G . Glushkov, Khim. getetosikl. Soedinenii, 1973, 958 (Chem. Abs., 1973, 79, 126 264). D. E. Nichols and C. F. Barfknecht, J . Heterocyclic Chem., 1973, 10, 339. M. M. Cook and C. Djerassi, J . Amer. Chem. Soc., 1973,95, 3679. S. A. Buskine, Belgian P. 786 613 (Chem. A h . , 1973,79, 5326). B. V. Unkovskii, Y . F. Malina, T. D. Sokolova, S. I. Gavrilova, K. I. Romanova, and Y . V. Kolosov, Khim. geterotsikl. Soedinenii, 1973, 1056 (Chem. Abs., 1973, 79, 126 255).

Five- and Six-membered Rings and Related Fused Systems

205

4-piperidones, the ratio of cis:trans isomers depending upon the reduction conditions.375 Tetrahydropyridines. 2-Alko~y-3,4,5,6-tetrahydropyridines~~~ react with aziridines by the addition-elimination mechanism to form 2-aziridinotetrahydropyridines (Scheme 51). Thermal rearrangement results in the formation of imidazoline derivatives.

I2-DMF

x

QOR

R

H

Scheme 51

Cyclic vinylogous amides have gained in importance as synthons but the difficulty associated with their synthesis has severely limited their use. Stutz and Stadle1377have developed a ‘one pot’ procedure (Scheme 52) in

AczO-EtaN

[b (5 8 I\

ACOS

0-

‘H

I

I

Scheme 52

which 1-methyl-4-piperidonemay be converted into l-methyl-4-oxo-l,4,5,6tetrahydropyridine. Tetrahydropyridine derivatives have been prepared by AICl,-catalysed addition378of imines to acrylonitrile. The resultant 2-imino-l,2,3,4-tetrahydropyridines, e.g. (257), undergo hydrolysis to the amides (258).

375

376 377

378

E. M. Urinovich, Y. S. Matyukhin, E. T. Golovin, and B. V. Unkovskii, Zhur. org. Khim., 1973, 9, 1525. D. Bormann, Angew. Chem. Internat. Edn., 1973, 12, 768. P. Stutz and P. A. Stadler, Tetrahedron Letters, 1973, 5095. W. Gomez Arander, J. Barluenga, and V. Gotor, Tetrahedron Letters, 1973, 2819.

Saturated Heterocyclic Chemistry

206

COMe

COMe

Scheme 53

N-Acetyl-enamines undergo nitrosation with butyl nitrite. The resultant hydroxy-nitroso-compounds (Scheme 53) undergo ring-expansion to amidooximes. This reaction may3'' offer some interesting possibilities in the field of peptide and macrolide antibiotics. 2-Acetyl-l,4,5,6-tetrahydropyridinehas been describedF80 the bisulphite addition compound possessing the aroma of freshly baked bread. Reaction of 1 -methyl-1,4,5,6-tetrahydronicotinamide with ethyl bromoacetate gives O-alkylati~n~~l and ring closure to the oxazolinone (259), which appears to exist in the zwitterionic form (260). Borohydride reduction of (260) followed by alkaline hydrolysis yields (262) by way of the intermediate cyclol (261).

(261)

(262)

3-Piperideines have been prepared by lithium aluminium hydride reduction382of l-alkylpyridinium salts. Under these conditions some fission of the ring occurs and sodium bis-(2-methoxyethoxy)aluminium hydride appears to be the reagent of ch0ice.3~~ Electrolytic reduction of sulphate salts appears to be somewhat less selective, resulting in piperidines and 3- or 4-pi~erideines.3~~ 37s 380 381 383 383 384

J. R. Mahajan, G. A. L. Ferreira, H . C. Araujo, and B. J. Nunes, Synthesis, 1973, 313. I. R. Hunter and M. K. Walden, U.S. P. 3 725 425 (Chem. Abs., 1973,79,5275). F. Troxler, Helu. Chim. Acta, 1973, 56, 1815. M. Ferles, P. Stern, and F. Vysata, CON.Czech. Chem. Comm., 1973, 38, 1977. M. Ferles, A. Attia, and A. Silhankova, Coll. Czech. Chem. Comm., 1 9 7 3 , 3 8 , 6 1 5 . M. Ferles and A. Attia, Coll. Czech. Chem. Comm., 1973, 38, 2747.

Five- and Six-membered Rings and Re Iated Fused System

207

R2\/COPh

Scheme 54

Ollis and c o - w o r k e r ~have ~ ~ ~observed a thermally induced rearrangement of piperideinium ylides (Scheme 54) and kinetic measurements have demonstrated that the rearrangement is considerably slower than in related acyclic systems. This difference in reactivity is thought to result from severe distortion of the m-system in the transition state for the cyclic systems and a [2,3] sigmatropic process is invoked. Enamines of 1-alkyl-4-piperidones react with acrolein to form 6-cycloalkylaminobicyclo[3,3 ,l]nonan-9-0nes.~~~ Photochemical d e c o n j ~ g a t i o n ~ ~ ~ of 1-methyl-4-methoxycarbonylmethylenepiperidinesto the methyl ester of 1-methyl-A5-piperidine4-aceticacid is a facile process and offers a convenient route to 4-functionalized-A3-piperideines. Examination of deuterium exchange during elimination reactions of lY2,4,5-tetrahydropyridiniumsalts reveals that 1,Zrather than 1,4-eIimination occurs.388 Dihydropyridines. l-Alkyl-l,4-dihydropyridine~~~~ react with gramines to give 1-alkyl-5-skatyl-l,4-dihydropyridines(Scheme 55). 1,4,5,6-Tetrahydropyri-

Scheme 55

dines have been observed to give similar results and this reaction sequence may prove of value in alkaloid synthesis. Stable crystalline complexes of Cr(C0,) with dihydropyridines have been isolated and c h a r a c t e r i ~ e d . ~ ~ ~ S. Mageswaran, W. D. Ollis, and I. 0. Sutherland, J.C.S. Chem. Comm., 1973, 656. A. Z. Britten and J. O'Sullivan, Tetrahedron, 1973, 29, 1331. 387 R. J. Sundberg, L. Lin, and F. X. Smith, J . Org. Chem., 1973, 38, 2558. 388 G. R. Wenzinger and J. A. Williams, Tetrahedron Letters, 1973, 2167. 3 8 B F. Troxler, Helv. Chim. Acta, 1973, 56, 374. 3B0 C. A. Bear, W. R. Cullen, J. P. Kutney, V. E. Ridaura, J. Trotter, and A. Zanarotti, J . Amer. Chem. Soc., 1973, 95, 3058.

385

386

208 Saturated Heterocyclic Chemistry Acheson and Paglietti391have examined the reaction of 1,2-dihydro-lphenylpyridine with dimethyl acetylenedicarboxylate. Instead of the anticipated Diels-Alder reaction the adduct (263) is formed and undergoes electrocyclic ring-opening to 1,2-dihydro-1-phenylazocine-6,6-dicarboxylate (264).

(263)

(264)

(265)

1,4-Dihydropyridines available by conventional Hantzsch synthesis have been patented392as remedies for heart conditions. The 1-methyl4methoxycarbonyl-1&dihydropyridine radical (265) decomposes by a bimolecular process which is pH-dependent ; the importance of this observation relative to the NAD-NADH system has been discussed.393 Quinoline Derivatives. A synthesis of the optically active trans-4-oxoperhydroquinoline (266)and its derivatives, involving the treatment of optically active N-2-propionyl-a-phenethylaminemethyl ester with cyclohexanone containing CF3C02H,has been described?%

H i PhCHMe

(266)

6 \.

\

0

(267)

0

(268)

Polyphosphoric acid-induced cyclization of 2-(o-nitroanilino)propionates results in the formation of 8-nitro-4-oxo-l,2,3,4-tetrahydroquinoline (267).395 Reduction of the nitro-group followed by acetylation with acetic anhydride offers a route into 4,5-dihydro-6-oxoimidazo [4,5,l-ij]quinolines (268). PhotolysisaSs of 1,2-dihydroquinoline-l-carboxylates gives rise either to allenic compounds or to products derived from solvent addition, depending 3s1 392

R. M. Acheson and G. Paglietti, J.C.S. Chem. Comm., 1973, 655. R. Kawai, M. Murakami, and T. Takenada, Japan Kokai 73/26 770 (Chem. Abs., 1973,79, 31 902).

383 3s4

395

3s6

E. M. Kosower, A, Tuerstein, and A. J. Swallow, J . Amer. Chem. SOC.,1973,95,2127. V. M. Potapov, G. K. Kiryuskina, and G. P. Tokmakov, U.S.S.R.P. 385 964 (Chem. Abs., 1973,79,92 028). J. M. Kamenka and M. N. Alam, J, Heterocyclic Chem., 1973, 10, 459. M. Ikeda, S. Matsugashita, and Y . Tamura, J.C.S. Chem. Comm., 1973,922.

Five- and Six-membered Rings and Related Fused Systems / \

\

N CN I COzEt

209

CN

\

N I CO2Et Scheme 56

NHCO2Et

on the solvent employed. The products have been rationalized in terms of the initial formation of a benzazahexatriene (Scheme 56). Isoguinoline Derivatives. Recent interest in azatwistane chemistry has led to a number of routes to cis-decahydroisoquinoline~~~~ and cis-octahydroisoq u i n o l i n e ~ Enzymatic .~~~ reduction has been employed3SSin the synthesis of (4aS),(8aR)-2-benzoyloctahydroisoquinolin-6-ones. Thus reduction of racemic 2-benzoyloctahydroisoquinolin-6-one with sporotrichurn exile QM1250 under anaerobic conditions gives the (4aS),(8aR)-alcohol (269) of ca. 70% optical purity. Reoxidation yields the ketone of the same optical purity at positions 4a and 8a, and the resultant octahydroisoquinoline(270)has been used in the synthesis of a number of alkaloids.

(269)

(270)

A number of syntheses of 1,2,3,4-tetrahydroisoquinolines have been reported, usually following classical Bischler-Napieralski or Pictet-Spengler Reaction of isoquinoline with benzyl chloride in the presence of 2-methylfuran results in the formation of the adduct (271), which may prove to be of some value in alkaloid synthesis.4o1 Oxidation of cyclic imines is known to give both oxaziridines and nitrones and it has been demonstrated that for 1 -alkyl-3,4-dihydroisoquinolines nitrone formation is favoured by the use of aprotic solvents. Kinetic studies suggest that oxaziridine formation proceeds by a two-step mechanism whereas nitrone formation involves nucleophilic attack by the imine on the peracid.402 Reaction of 1,2,3,4-tetrahydroisoquinolin-l-ylideneacetonitriles (272)with HNO, follows an unusual course.4o3Nitrosation does not occur on nitrogen, but results in the formation of the oximes (273). 3Q7 3g8

30Q 400

401 40f

403

S. Sicsic and N. T. Luong-Thi, Tetrahedron Letters, 1973, 169. H. Teufel, E. F. Jenny, and K. Heusler, Tetrahedron Letters, 1973,3413. M. R. Uskokovic, D. L. Pruess, C. W. Despreaux, S. Shiuey, G. Pizzalato, and J. Gutzwiller, Helv. Chim. Acta, 1973,56, 2834. S. F. Dyke, A. W. C. White, and D. Hartley, Tetrahedron, 1973,29, 857. A. A. Diekalo and A. K. Sheinkman, Ref. Zhur. Khim., 1972,Abstr. 8Zh423 (Chem. Abs., 1973,79,78 570). Y . Ogata and Y . Sawaki, J . Amer. Chem. SOC.,1973,95,4692. K.Harsanyi, K. Takacs, and E. Benedek, Annulen, 1973, 1606.

210

Saturated Heterocyclic Chemistry

2-Alkyl-3-phenyl-4-methyl1,2-dihydroisoquinolines have been prepared by polyphosphoric acid-catalysed cyclization of N-methyl-N-(1-phenylprop2-ynyl)ben~ylamine.~~~ Photolysis of N-benzoyl-enarnine~~~~ has received some attention by Ninomiya and co-workers and gives rise to the formation of trans-fused octahydrophenanthridonesjo6Photolysis of (274) results in the formation of (275) in 20% yield. Racemic crinane (276) has been synthesized from (275)jo7

(274)

(275)

(276)

Aza-steroids. Reaction of 2-acylcyclohexan-l,3-dione derivatives with 3,4dihydroisoquinoline N-oxide408 results in the condensation product (277) which undergoes cyclization in DMF to 8-aza-steroid derivatives (278).

404 (05

408

407

408

J. R. Brooks, D. N . Harcourt, and R. D. Waigh, J.C.S. Perkin Z, 1973, 2589. I. Ninomiya, T. Naito, and T. Mori, J.C.S. Perkin Z, 1973, 505. I. Ninomiya, T. Naito, and T. Kiguchi, J.C.S. Perkin I, 1973, 2257. I. Ninomiya, T. Naito, and T. Kiguchi, J.C.S. Perkin I, 1973, 2261. A. A. Akhrem, A. M. Moiseenkov, A, I. Poselenov, and V. A. Krivoruchko, Doklady Akad. Nauk S.S.S.R., 1973, 210, 841; A. A. Akhrem, A. M. Moiseenkov, V. A. Krivoruchko and A. I. Poselenov, Zzvest. Akad. Nauk S.S.S.R., Ser. khim., 1973, 310 (Chern. A h . , 1973, 79, 5240).

Five- and Six-membered Rings and Related Fused Systems

Me

21 1

'Me

8 , l l -diaza-2,3-dimet hoxygona-1,3,5(10) ,9 (11)- t etraene Syntheses of (279)409and 4,17a-dimethyl-4,17a-diaza-~-homo-5~-androstane dimethiodide (280), a powerful neuromuscular blocking agent ,4l0 have been reported. Fused Systems. Partial reduction of amides to enamines using di-isobutylaluminium hydride appears to offer considerable synthetic potential and Bohlmann and co-workers411 have developed a stereospecific synthesis of spartein (Scheme 57) involving reduction of the diamide (281). Syntheses of indenopiperidines (282) ,*12 1O-hydroxyperhydroacridines (283),413 and pyrrolo [3,4-b]pyridine derivatives (284)414have been reported.

Scheme 57 40D 410

411 412

413

414

M. Nagata, M. Goi, K. Matoba, T. Yamazaki, and R. N. Castle, J . Heterocyclic Chem., 1973,10,21. H. Singh, D. Paul, and V. V. Parashar, J.C.S. Perkin I, 1973,1204. F. Bohlmann, H. J. Muller, and D. Schumann, Chem. Ber., 1973,106,3026. A. Ebnoether, I. M. Bastian, and E. Rissi, Ger. Offen 2 300 617 (Chem. A h . , 1973, 79, 92 020). V. K. Gamov, T. V. Tropina, V. A. Kaminskii, and N. N. Tilichenko, Khim. geterotsikf. Soedinenii, 1973, 1145 (Chem. Abs., 1973,79, 126 281). R. Madhav, Synthesis, 1973, 609.

212

Saturated Heterocyclic Chemistry R

(282)

(283)

(284)

Hexahydrupyridazines. Ring-opening4lS of 4,5-epoxy-3,6-diphenyl-NN’-diethoxycarbonylhexahydropyridazine with gaseous HCl results in the formation of l ,2-diethoxycarbonyl-3,5-diphenyl-4-hydroxy-6-chlorohexahydropyridazine, formed by the migration of a phenyl group (Scheme 58).

Ph-

c1

c1Scheme 58

Terrahydropyridazines. Beetz and Kellogg4l6 have prepared derivatives of 3,4,5,6-tetrahydropyridazinesas outlined in Scheme 59. Under acidic conditions isomerization to 1,4,5,6-tetrahydropyridazinesoccurs. Me02C \

MeOK

/

\\

N ---N

N-N

/ iii, iv

HReagents: i, ArCOH,; ii, A; iii, MeOH-KOH;

ivy MeO,CN=NCO,Me;

v, H+

Scheme 59 416

Y. S. Shabarov and L. D. Sychkova, Zhur. obshchei Khim., 1973,43, 883. T. Beetz and R. M. Kellogg, J . Amer. Chem. SOC.,1973, 95, 7925.

213

Five- and Six-membered Rings and Related Fused Systems

Scheme 60

Thermal fragmentation of maleic hydrazide has been shown to occur by two pathways (Scheme 60).417 Dihydrupyridazines. 1,4-Dihydropyridazines have been synthesized by the zinc chloride-catalysed reaction of 1,4-dicarbonylcompounds with hydrazine derivatives.418Using this approach De Mayo and co-workers have found that reaction of hydrazine with hexane-2,5-dione419did not furnish the expected adduct, but gave the dimer (285). Treatment of (285)with butyl-lithium gave (286), which was converted into the 3,ddihydropyridazine (287). 3,4-Dihydropyridazines appear to be kinetic products and undergo [l $]hydrogen shifts to yield the thermodynamically more stable 1,6-dihydropyridazines. The spectroscopic properties of (287)have been

(285)

(286)

(287)

Cinnoline Derivatives. 2-Phenyldimedone reactsg21with hydrazine to form hexahydrocinnoline (288), which in treatment with toluene-p-sulphonyl chloride in pyridine yields the oxotetrahydrocinnoline (289). Reaction of 1-phenyl-l,2,4-triazolin-2,5-dionewith l-phenyl-l-cyclopropylethylene followed by oxidative work-up results in the formation422of the tetrahydrocinnoline (290). 0

(290) 417

418 419 420 421 422

S. C. Clough, J. C. Kang, W. R. Johnson, and T. S . Osdene, Chem. and Ind., 1973,323. K. N. Zelenin and J. Dumpis, Zhur. org. Khim., 1973,9, 1295. P. De Mayo and M. C. Usselman, Canad. J. Chern., 1973,51,1724. N. C. Baird, P. De Mayo, J. R. Swenson, and M. C. Usselman, J.C.S. Chem. Cornm., 1973, 314. K. Nagarajan and R. K. Shah, J.C.S. Chem. Comm., 1973, 926. D. J. Pasto and F. T. Chen, Tetrahedron Letters, 1973, 713.

214 Saturatzd Heterocyclic Chemistry Phthalazine Derivatives. Kametani and c o - ~ o r k e rhave s ~ ~prepared ~ a number of 1,l-disubstituted-l,2,3,4-tetrahydrophthalazinesby the reaction of benzylhydrazines with ketones under acidic conditions. Oxidation of 1,2,3,4tetrahydrophthalazine to 1,4-dihydrophthaIazine has been effected at low and formation of o-xylylene occurs during photolysis in a rigid glass at -196 *C. Pyrimidine Derivatives. The addition of NN’-di-n-butylpropane-1,3-diamine to b u t a - l , 3 - d i ~ n produces e ~ ~ ~ the allene (291) in ca. 50 % yield.

5-Amino-l,3-dibenzyl-5-methylhexahydropyrimidineundergoes oxidative ring-opening426in the presence of HCI , forming N-benzyl-2-methylpropane1,2,3-triamine. Synthesis of cyclic ureas by ureidoalkylation has been re~iewed.4~’ The photoproduct428of 1,3-dimethyIuraciland vinyl carbonate has been shown to be the [2 + 21 cycloadduct (292) in which all four hydrogen atoms at the ring junctions are cis. Reaction of 1-phenylthi~prop-l-ene~~~ with chlorosulphonyl isocyanate yields dihydrouracil derivatives (293) and (294). Ketenimines react with isocyanates yielding adducts, which after reduction with pyridinethiophenol result in the formation430of imines, e.g. (295).

423

424 425 426 427 428 42s 430

T. Kametani, K. Kigasawa, M. Hirragi, T. Urgu, and S. Haga, J.C.S. Perkin I, 1973, 471. C. R. Flynn and J. Michl, J. Amer. Chem. SOC.,1973, 95, 5802. I. B. Bystrova, I. A. Chekulaeva, A. V. Ignatenko, and V. A. Ponoamarenko, Izoest. Akad. Nnuk S.S.S.R., Ser. khim.,1973, 1163 (Chern. Abs., 1973,79, 66 294). T. Tsuji and M. Hara, Chem. andPharm. Bull. (Japan), 1973,21, 1375. H. Petersen, Synthesis, 1973, 243. C. Pascard-Billy, Acra Cryst., 1973, B29, 521. K. Hirai, H . Matsuda, and Y . Kishida, Chem. andPliarm. Bull. (Japan), 1973,21,1090. Naser-ud-din, J. Riegl, and L. Skatteberl, J.C.S. Chem. Comm., 1973, 271.

215

Five- and Six-membered Rings and Related Fused Systems

The patent literature is heavily endowed with reports on the physiological properties of 2,4,6-trioxopyrimidines and since classical approaches are used during their synthesis431a comprehensive survey would serve no real function. Caprolactam imino-ether reacts with alkyl cyanates to form 2: 1 addition compounds, e.g. (296), which on hydrolysis yield 5-(4-aminobutyl)-l,3disubstituted barbituric acids (297).432

a-Acetyl-y-butyr~lactone~~~ reacts with heterocyclic amines to form condensed pyrimidine derivatives, and this approach has been employed in the synthesis of pyrrolo [2,1-b]pyrimidin-2-ones(298), pyrimidino [2,1-a]isoindol2-ones (299), pyrimidino [1,2-a]isoindol-4-ones (300), tetrahydroimidazo[I ,2-a]pyrimidin-5-ones (301), and related systems. 0

0

Synthetic routes to cyclic guanidines (302) have appeared.4a 2-Arylaminoimidazolines435 react with 3-amino-3-chloroacryloyl chloride, forming imidazo[1,2-a]pyrimidinones (303). 431 432

43s

434 435

S. Landa, J. Burkhard, and J. Vais, Coll. Czech. Chem. Comm., 1973, 38, 2947; L. Capuano and R. Zander, Chem. Ber., 1973, 106, 3670. R. Richter and H. Ulrich, Chem. Ber., 1973, 106, 374. H. J. Willenbrock, H. Wamhoff, and F. Korte, Annalen, 1973, 103. T. B. Bosh, R. N. Hanson, J. V. Rodericks, R. A. Simpson, and H.Rapoport,J. Org. Chem., 1973, 38, 1591. H. Stahle and H. Koppe, Annalen, 1973, 1275.

15

216

Saturated Heterocyclic Chemistry 0

(302)

(303)

Lithium aluminium hydride reduction of the isoquinolinium salt (304) followed by rapid work-up results in the formation of the pyrimidino[l,2-b]-isoquinoline (305).43GThe tricyclic system (306) has been prepared by

(304)

(305) (306)

Hg(OAc), oxidation of (305), and a mechanism involving a benzodiazocine has been suggested (Scheme 6 1). Lossen rearrangements of quinoxaline-2,4diones have been reported.437

q$!! H

(305)

Hg(oAc)2 F

4

HgOAc

Scheme 61

Piperazines. The reaction of lY4-dimethylpiperazinewith hydroxylaminesulphonic has been utilized in preparing the bis-N-amino-salt (307), which has been assigned the trans structure on the basis of its lHn.m.r. 438

437 4s8

N. Finch and C. W. Gemeden, J . Org. Chem., 1973,38, 437. K. Y.Tserng, and L. Bauer, J . Org. Chem., 1973, 38, 3498. J. Epsztajn, A. R. Katritzky, E. Lunt, J. W. Mitchell, and G . Roch, J.C.S. Perkin I, 1973, 2622.

Five- and Six-membered Rings and Related Fused Systems

217

COCH2CH2Br

I

c,

(3

I

COCHzCHzBr

spectrum. A crystal-structure determination439of 1,4-di-(3-bromopropionyI)piperazine (308)has revealed considerable steric strain within the molecule which may be connected with its oncolytic acitivity. An electrochemical preparation of perfiuoropiperazine has been reported.440 Dihydropyrazines. The product of condensation of glyoxal with diaminomaleonitrile has been shown441to be the acyclic diamine (309),rather than the dihydropyrazine (310) as previously reported. Crystallization of (309)from dilute aqueous oxalic acid results in the formation of (310).

(309)

(310)

Phenacyl bromideM2reacts with benzylamine at low temperature to give 1,4-dibenzyl-l,4-dihydro-2,6-diphenyIpy1-azine (3 12; R = CH,Ph) through dimerization of the intermediate N-benzylphenacylamine (3 11). At temperatures above 50 OC (312)undergoes rearrangement to (313) by a 1,3-alkylshift. Examination of the thermal rearrangement of the dihydropyrazine (314) in degassed benzene443at 55 OC has shown that (315)is produced by a first-order process. Crossover experiments indicate that two mechanistic pathways are

I

CHZPh

43a 440

441 442 443

I

R

L. Olansky, and J. W. Moncreif, Acta Cryst., 1973, B29, 357. R. E. Banks, P. A. Carlson, and R. N. Haszeldine, J.C.S. Perkin I, 1973, 11 1 1 . F. D. Popp, Chem. and Ind., 1973, 852. J. W. Lown and M. H. Akhtar, J.C.S. Perkin I, 1973, 683. J. W. Lown and M. H. Akhtar, J.C.S. Chem. Comm., 1973, 511.

218

Saturated Heterocyclic Chemistry CH2Ph

CHaPh

Ph (3 14)

(315)

operating, a radical process to the extent of 12 f 6 % and a suprafacial 1,3shift with inversion of configuration at the chiral centre. This appears to be the first example of a 1,3-shift involving nitrogen at the migrating centre. ly4-Dihydro-l,4-dimethyl-3,6-diphenylpyrazine (312; R = Me) has been prepared under similar conditions and has been characterized. 1,2-Dihydropyrazines react with dimet hy1 acetylenedicarboxylate to form adducts (316), which undergo valence tautomerism to (317).444

(3 16)

(317)

Piperazinediones. During the past five years considerable interest has developed in the growing number and diversity of the naturally occurring piperazine-2,5-diones, and Steyn hasu6 recently reported some new examples of this class of compound. The naturally occurring compound (318) is an interesting example of a nitrogen mustard and shows promising anti-cancer activity.u6 Blaha and co-workersU7have prepared a number of pipera~ine-2~5-dione~ from one or two moles of four-, five-, or six-membered imino-acids and

(3 18) 444

445 446

447

J. W. Lown and M. H. Akhtar, Tetrahedron Letters, 1973, 3727. P. S. Steyn, Tetrahedron, 1973, 29, 107. B. H. Arison and J. L. Beck, Tetrahedron, 1973, 29,2743; T . Y.Shen, N. P. Jenses, and A. F. Wagner, Ger. Offen 2 257 542 (Chem. Abs., 1973, 79, 42 551). J. Vicar, M. Budesinsky, and K. Blaha, Coll. Czech. Chem. Comm., 1973,38, 1940.

Five- and Six-membered Rings and Related Fused System

219

examined their molecular geometry by i.r. measurements. Compounds containing one or two residues of pipecolic acid or with two proline residues of opposite chirality are virtually planar. When the imino-acids possess the same chirality, a boat conformation is preferred and the boat appears to be deepened in traversing the series pipecolic acid 4proline 3 azetidine-2carboxylic acid.448Blaha also reports that piperazine-2,5-diones in which one residue is derived from azetidine-2-carboxylicacid are formed with difficulty, although Phillips and Cr0mwe11~~ have synthesized (319) with little difficulty.

(319)

A method of peptide sequencing based on the degradation of peptides to piperazins2,5-diones and mass spectral analysis has been reported?50 In four-component condensation reactions of the Ugi type, carboxylic acids react with isocyanides and aldimines to form a-acylamino-amides, and using l-isocyano-cycloalkanecarboxylicacids (320) it has been possible to demonstrate the intermediacy of azlactones (321). Thermolysis of the azlactones results in the formation of spirodioxopiperazines (322):"

NHCH2Ph

Monoalkylidene- or arylidene-piperazine-2,5-dioneshave been prepared from 1,4-diacetylpiperazine-2,5-dionesby carefully controlled condensation with the appropriate aldeh~des.4~~ This method avoids otherwise circuitous routes. Cyclodimerization of the optically active a-lactams (323) derived from phenylmethylamine derivatives results in the formation of piperazine-2,5diones (324). Hydrolysis of (324) followed by hydrogenolysis has resulted in 448 44g 450 451

452

J. Vicar, J. Smolitkova, and K. Blaha, Coll. Czech. Chem. Comm., 1973,38, 1957. B. A. Phillips and N. H. Cromwell, J. Heterocyclic Chem., 1973, 10, 795. R. A. W. Johnstone, T. J. Povall, and J. D. Baty,J.C.S. Chem. Comm., 1973,392. D. Marquarding, Angew. Chem. Internat. Edn., 1973, 12, 79. C. Gallina and A. Liberatori, Tetrahedron Letters, 1973, 1135.

220

Saturated Heterocyclic Chemistry PhCHR

I

H

R

RCHPh

(324)

(323)

the production of alanine with an optical purity of ca. 30%.453Asymmetric induction has also been observed4% during hydrogenation of arylidenepiperazine-2,5-diones derived from glycyl-proline anhydride, with optical yields of up to 90%. 3,6-Dibenzylpiperazine-2,5-dioneon pyrolysis at 650 "C results in the formation of an observation consistent with a radical decomposit ion.455a Treatment of 1,3-dimethylpiperazine-2,5-dionewith triethyloxonium fluoroborate followed by DDQ oxidation has yielded 5-ethoxy-l,3-dimethylpyrazin-2(1H)-one (325). This compound has been used as a model for biosynthetic and undergoes facile Diels-Alder reactions with simple olefins. Surprisingly, it reacts with oxygen in the absence of light to form the oxygen adduct (326) which undergoes base-catalysed rearrangement to (327).

(325)

(326)

(327)

Imino-ethers derived from a series of prolylpiperazine-2,5-diones react with anthranilic forming tetracyclic quinazolones (Scheme 62). N 30E ol.t

m::;

Scheme 62 T. Okawara and K. Harada, Bull. Chem. SOC.Japan, 1973, 46, 1869. H. Poise1 and U. Schmidt, Chem. Ber., 1973, 106, 3408. 455 J. M. Patterson, N. F. Haidar, E. P. Papadopoulos, and W. T. Smith, J . Org. Chem., 1973, 38, 663. 4550 K. W. Blake, A. E. A. Porter, and P. G. Sammes, J.C.S. Perkin I, 1972, 2494. 456 P. J. Machin, A. E. A. Porter, and P. G. Sammes, J.C.S. Perkin I, 1973,404. 4 5 7 S. Rajappa and B. G. Advani, Tetrahedron, 1973, 29, 1299.

453

454

221

Five- and Six-mernbered Rings and Related Fused Systems

One of the major areas of interest in this field has centred around the introduction of sulphur-containing substituents into the 3- and 6-positions of piperazine-2,5-diones, in order to prepare 3,6-epidithiadiketopiperazines. Attempts to cyclize dipeptides containing protected thiol residues have Schmidt and c o - w ~ r k e r shave ~ ~ ~ prepared 3,6-epidithioproline anhydride as outlined in Scheme 63. The stereochemical changes observed during these manipulations have been examined in

iii, iv/

Reagents: i, Pb(OAc),; ii, H 3 0 + ;iii, H2S-ZnC12; iv, 12-KI

Scheme 63

Barot and E l ~ i d g e have ~ ~ l recently described a synthesis of 2,6-di-iminopiperazine derivatives which undergo palladium-catalysed dehydrogenation to 2,6-diaminopyrazines. A number of piperazine-2,6-diones have found use as antifungal agentsgs2 Fused Pyrazines. The crystalline dimer of ally1 azide has been shown to be (328) by X-ray methods.4632,3,6,7-Tetrahydro-(4H)-cyclopenta[blpyrazines (329) have been preparedgs4by the condensation of 1,Zdiamines with cyclopentenolones. R3

(328) 458 450

460

461 46rL

463 464

(329)

T. Petrzilka and C. H. Fehr, Helv. Chim. Acfa, 1973, 56, 1218. E. Ohler, F. Tataruch, and U. Schmidt, Chem. Ber., 1973, 106, 396. E. Ohler, F. Tataruch, and U. Schmidt, Chem. Ber., 1973, 106, 165. J. A. Elvidge and N. R. Barot, J.C.S. Perkin I, 1973, 606. K. Shinoda, T. Shida, S. Yamazaki, and K. Satake, Ger. Offen2 157 955 (Chem. A h . , 1973, 79,42 546). J. C. Pezzullo and E. R. Boyko, J . Org. Chem., 1973,38, 168. I. Flament, P. Sonnay, and G. Ohloff, Heh. Chim. Acta, 1973, 56, 610.

222

Saturated Heterocyclic Chemistry

(330)

(331)

Mercuric acetate oxidation465 of the octahydropyridino[1,2-a]pyrazine (330) results in the formation of the enone (331) in high yield. Syntheses of the hexahydropyrazinoindole (332)466 and di-triazopyrazine (333)467have been described.

(333)

(332)

1,2,4Triazines. Reaction of 1-methy1-(2-~hloroethyl)hydrazine with dimethylmethyleneammonium chloride followed by ba~ification*~* leads to the format ion of l ,4,4-trimethylperhydro-l ,2,4-triazinium chloride (334). 1,2,5,6-Tetrahydrotriazines (335) have been prepared by the reaction of 2-aminoethylhydrazine with carboxylic a ~ i d s . 4Hexahydro-l,2,4-triazine~~

Me

Me

(334)

(335)

(336)

(337)

3,s-diones undergo cleavage at C-5 on treatment with nitrogen nucleophiles, giving salts or amides depending upon the nature of the nu~leophile.4~~ Methylation of 2,3,4,5-tetrahydro-l,2,4-triazin-3,5-dione (336) with dimethyl sulphate in neutral media results in the formation of the betaine (337) whereas in alkaline media methylation occurs on N-2 or N-4.471This observation may be rationalized in terms of methylation of the most basic nitrogen atom under 465 466 467

468 46s 470 471

Y.Arata and Y. Nakagawa, Chem. andPharm. Bull. (Japan), 1973,21,1248. R. Jonas, R. Unger, E. Schorscher, and H. J. Schliep, Ger. Offen 2 162 422 (Chem. Abs., 1973, 79, 66 402). E. M. Burgess and J. P. Sanchez, J . Org. Chem., 1973, 38, 178. H. Bohme and F. Martin, Chem. Ber., 1973, 106, 3540. J. Perner and H. W. Eckert, Ger. Offen 2 203 666 (Chem. Abs., 1973,79,115 637). A. Novacek and J. Gut, Coll. Czech. Chem. Comm., 1973,38, 592. M. Prystas, V. Uchytilova, and J. Gut, Coll. Czech. Chem. Comm., 1973,38,934.

Fiue- and Six-membered Rings and Related Fused Systems 223 neutral conditions or methylation of the anion derived from the most acidic NH group under basic conditions. 1,3,5-Triazines. The reaction of aliphatic aldehydes with 15M aqueous ammonia at -10 "C leads to the formation of hydrated l-amino-alkanols which have been characterized by microanalysis and by their spectroscopic properties. At 0-5 O C they form 2,4,6-trialkylhexahydr0-1,3,5-triazines.4~~ The kinetics of 2,4,6-trialkylhexahydro-l,3,5-triazineformation have been reported.4732,4,6-Trimethylhexahydro-1,3,5-triazine has been isolated during vapour-phase irradiation of MeNH,, albeit in low yield.474 Formation of 1,3,5-trialkylhexahydro-1,3,5-triazines from formaldehyde and amines is catalysed by ion-exchange re~ins.4'~ Acylation of hexamethylenetetramine with acetic anhydride476results in the formation of 1,3,5triacetylhexahydro-1,3,5-triazine. 1,3,5-Triacryloylhexahydro-l,3,5-triazine has been synthesized by the reaction of 1,3,5-trioxan with acrylonitrile under acidic ~onditions.4~~ Seckinger has prepared perhydro-l,3,5-triazin-2,6-diones by the reaction of NN-dimethyl-N'-arylf~rmamidines~~~ or NN-dimethyl-N'-dimethylaminoformamidines with alkyl or aryl isocyanates. The 2:l adducts (338), on hydrolysis followed by CrOs oxidation, yield hexahydro-l,3,5-triazin-2,4,6triones (339).

502c1 (338)

(339)

(340)

(341)

Suchitzky and W a l r ~ n d ~ have ' ~ observed that chlorosulphonyl isocyanate reacts with imines to form 2 :1 adducts (340) which may be converted into the hexahydrotriazin-2,5-diones(341).

Condensed Triazines. Phenacyl derivatives of certain 7r-deficient heterocycles have been shown to undergo cyclization on treatment with h~drazine;~*O thus 3-cyano-l-phenacylpyridiniumbromide reacts to form the dihydropyridotriazine (342). 472 473

474 476

478

477 478 479

480

A. T. Nielsen, R. L. Atkins, D. W. Moore, R. Scott, D. Mallory, and J. M. Laberge, J. Org. Chem., 1973, 38, 3289. W. E. Hull, B. D. Sykes, and B. M. Baboir, J. Org. Chem., 1973,38, 2931. V. I. Stenberg, N . Kulevsky, and C. Niu, J. Org. Chem., 1973,38, 1227. I. I. Konstantinov, B. M. Tsigin, Y. I. Mashkin, and E. N. Boitsov, U.S.S.R. P. 374 31 1 (Chem. Abs., 1973,79, 53 380). M. Warman, V. I. Siele, and E. E. Gilbert, J . Heterocyclic Chetn., 1973, 10, 97. G. A. Karustis, U.S. P. 3 736 320 (Chem. Abs., 1973, 79, 66 407). K. Seckinger, Helv. Chim. Acta, 1973, 56, 776, 2061. R. E. Wairond and H. Suchitzky, J.C.S. Chem. Comm., 1973, 570. U. Habermalz and F. Krohnke, Chem. Ber., 1973,106, 1549.

Saturated Heterocyclic Chemistry

224

(342)

Attempts to prepare 2,5-dihydro-lY3,4-oxadiazine from the Diels-Alder adduct (343) resulted in the formation of the tripyridotriazine (344). This product is believed to be derived from the trimerization of the dihydropyrida~ i n e (Scheme ~ ~ l 64), and the structure has been confirmed by rational synthesis.

Scheme 64

(344)

Tefrazines. Two approaches to the synthesis of ly4,5,6-tetrahydro-l,2,3 ,4tetrazines have been reported. Seebach and c o - ~ o r k e r have s ~ ~ ~shown that the amine oxides (345-347) are formed during thermal decomposition of metallated dimethylnitrosamine, methylcyclohexylnitrosamine, and 1nitrosopiperidine. Deoxygenation yields the corresponding tetrazines. The alternative approach483involves direct oxidation of the hydrazines (348)with potassium ferricyanide or potassium permanganate.

B. K. Bandlish, J. N. Brown, J. W. Timberlake, and L. M. Trefanas, J . Org. Chem., 1973,38, 1102. u2 D. Seebach, D. Enders, B. Renger, and W. Brugel, Angew. Chem. Internat. Edn., 1973, 12,495. 483 R. Kreher and H. Wissmann, Chem. Ber., 1973, 106, 3079.

Fiue- and Six-membered Rings and Related Fused Systems

225

Alkylhydrazines undergo condensation with formaldehyde to form the corresponding hydrazones. When, however, this reaction is carried out using straight-chain hydrazines dimerization occurs rapidly,"84forming 1,4-dialkylhexahydro-l,2,4,5-tetrazines. This reaction is believed to involve a stepwise ionic mechanism rather than dimerization through an azomethine imine. A crystal-structure determination of the tetrahydro-l,2,4,5-tetrazine(349) has been rep0rted.4~~ 2,4-Diaryl-2-methylimidazolin-5-thione(350) reacts with hydrazine forming the 1,2-dihydro-l,2,4,54etrazine(351). H

(350)

(349)

(351)

1,2-Dihydro-l,2,4,5-tetrazines have also been prepared by the reaction of thione hydra~ides~~' with mercury bis(phenylacety1ide) (Scheme 65).

PhCNHNH2

II

S

(PhC=C)zHg,

,h
Ph I

Ph

Ph Scheme 65

Ph

I

1,2-Ditoluene-p-sulphonyl-1,4-dihydro-l,2,4,5-tetrazines (352) are formed during the reaction488of N-toluene-p-sulphonylhydrazidoylchlorides with triethylamine. 484 486 486

487

48a

S. Hammerum, Actu Chem. Scand., 1973, 27, 779. D. E. Williams, Actu Cryst., 1973, B29, 96. F. Asinger, D. Neuray, W. Leuchtenberger, and U. Lames, Annalen, 1973, 879. W. Ried and R. Oxenius, Chem. Ber., 1973, 106,484. S. Wawzonek and J. N. Keller, J. Org. Chem., 1973, 38, 3627.

Saturated Heterocyclic Chemistry

226

x,

p-MeC6H4-N NYN-SO2C6H4Me-p 1 1 Ar

(352)

Fused Tetrazines. 1 -Phenyl-l,3,4-triazolin-2,5-dione reacts with diazoalkanes to form azomethine imines which dimerize in the absence of suitable traps to form spiro-hexahydro-l,2,4,5-tetrazine~~~~ (Scheme 66).

/

Scheme 66

Rings containing both Oxygen and Nitrogen.-Isoxazule Deriuatiues. Syntheses of 3-iso~azolidones~~~ and 5-isoxazolidones491have appeared. Alkylation of the potassio-salt of the former leads to mixed products resulting from N- and O-alkylation. 48D 480

4Q1

W. Ried and Sok-Hun Lim, Annalen, 1973, 1141. A. D. Voitenko, J. Kastrons, and S. Hillers, Khim. geterotsikl. Soedinenii, 1973, 898 (Chem. Abs., 1973, 79, 115 480). J. Hocker and R. Merten, Ger. Offen 2 158 740 (Chem. Abs., 1973, 79,42 519).

227

Five- and Six-rnernbered Rings and Related Fused Systems

(353)

(354)

(355)

The failure of olefinic nitrones (353) to cyclize in acid medium to isoxazolinium salts (354) has been interpreted in terms of the non-involvement of such species during the formation of A2-oxazolidines from hydroxylamines and ab-unsaturated ketones.492 Low-temperature lH n.m.r. studies have demonstrated the intermediacy of hydroxylamino-ketones (e.g. 355), formed by Michael addition of the hydroxylamine to the ag-unsaturated ket0ne.4~~ Addition of nitrosyl chloride494to 1,2-diarylcyclopropeneshas been shown to result in the formation of 5-chloro-A2-isoxazolidines, which undergo elimination of HCl to form isoxazoles. Photochemical transformations of A2-isoxazolidineshave been examined in some detail. Photolysis of 3,5-diphenyl-A2-isoxazolidineyields 4,5diphenyl-A3-oxazolidine.496 Of the several mechanistic possibilities, the initial photofragmentation (Scheme 67) to benzaldehyde and 2-phenylazirine

Scheme 67

followed by photoaddition seems most likely, and it has been observed that the photolysis of a 1: 1 mixture of these compounds produces the observed product. Photolysis of the oxazabicyclo[3,2,0]hepta-2,6-diene (356) produces the 1,3-oxazepine (357) by the initial formation of the azirine (Scheme 68) followed by electrocyclic ring c l o s ~ r e . 4 ~ ~

(356)

(357) Scheme 68

482

4B3 484 495 498

A. Belly, C. Petrus, and F. Petrus, Bull. SOC.chim. France, 1973, 1390. A. Belly, F. Petrus, and J. Verduccia, Bull. SOC.chim. France, 1973, 1395.

T. N. Grigorova, K. A. Oglobin, and M. I. Komendantov, Zhur. org. Khim., 1973,9, 711. T. Matsuura and Y .Ito, TetrahedronLetters, 1973,2283. T. Mukai and H. Sukawa, Tetrahedron Letters, 1973, 1835.

228 Saturated Heterocyclic Chemistry lH N.m.r . spectra of uic-dihalogeno-2,3-0xazabicyc10 [3,2,O] hept-3-enes (358) permit an unambiguous stereochemical assignment of these compound~.~~’ In principle, 4-arylaminomethylene-3-methyl-A2-isoxazolid-5-ones are capable of existing in a number of tautomeric forms. Summers c l a i m ~ , 4on~ ~ the basis of i.r. measurements, that (359) is the major contributing form.

(359)

(358)

Alkylation of the sodium salt of 5-hydroxyisoxazoles40gresults in the formation of 2-alkyl-A3-isoxazolin-5-ones, although in some cases O-alkylation may be observed. 3,5-Dihydro~yisoxazoles~~ also undergo specific a1kylation at N-2, and with aromatic a1dehydes N-ar ylmethylideneisoxazol-5onium-3-enolates (360) are formed. 5-Hydroxyisoxazoles, however, behave somewhat differently and with aromatic aldehydes 4-arylidene-A2-isoxazolid5-ones are formed.5o1Imines follow a similar course but 2: 1 condensation products (361) are formed. The known propensity of 4-arylidene-A2-isoxa-

hp*hp

HO

Ph (360)

(361)

zolid-5-ones to undergo mild hydrolytic cleavage to the parent heterocycle is not observed502in non-polar solvents ; thus when 3-alkyl-4-benzylidene-A2isoxazolid-5-one was refluxed in benzene in the presence of triethylamine, the cinnamylidene derivative (362) was formed in 25% yield. The mechanism of this interesting transformation awaits elucidation. Catalytic hydrogenation503of A2-isoxazolid-5-ones (363) results in the formation of /?-enamino-/3’-keto-carboxylic acids which undergo thermal u7R. 498 499

Mondelli and A. Gamba, Org. Magn. Resonance, 1973, 5 , 101. L. A. Summers, Austral. J. Chem., 1973, 26, 889. L. V. Rompuy, N. Schamp, N. De Kimpe, and R. Van Parijs, J.C.S. Perkin I, 1973,

2503. 500 501

G. Zvilchovsky and U. Fotadar, J . Org. Chem., 1973, 38, 1782. A. M. Knowles and A. Lawson, J.C.S. Perkin I, 1973, 537. A. Maquestiou, Y. Van Haverbeke, and R. N. Muller, Tetrahedron Letters, 1973,4249. W. Muller, U. Kraatz, and F. Korte, Chem. Ber., 1973, 106, 332.

229

Fiue- and Six-membered Rings and Related Fused Systems

R

(364)

(363)

(3 62)

decarboxylation. Using this approach amino-chalcones (364) have been prepared. Oxazole Derivatives. Irradiation of imines in the presence of carbonyl compounds leads to the formation of o x a ~ o l i d i n e sThe . ~ ~ reaction ~ is believed to proceed by the abstraction of H*from the allylic position of the imine by the carbonyl triplet (Scheme 69). OH

PhzCO

I

-

Ph-c-Ph

lNA

hv

Ph

\

H

/+NH

Scheme 69

A synthesis of 3-butoxymethyl-4,4-dimethyl-l,3-oxazolidines506 possessing antineoplastic properties has been described. Hexafluoroacetone reacts506with glycyl peptides in dimethyl sulphoxide, forming adducts of 2: 1 stoicheiometry which have been shown to be 2,2,5,5tetra(trifluoromethyl)oxazolidines (Scheme 70). NH&HZCONH-----

-

(CF&C=NCHaCONH--

----+kHCO

3i*:

t--

""x

F3C

---

I (CF&C=N-CHCONHHO/I\CF3

CFs

CF3

Scheme 70 504

A. A. Baum and L. A. Karnischky, J. Amer. Chem. SOC.,1973, 95, 3072.

606

P. Y. Johnson and M. Davies, Tetrahedron Letters, 1973, 293. C. A. Panetta, T. G. Casanova, and C. Chu, J. Urg. Chem., 1973,38, 128.

-

--c

230 Saturated Heterocyclic Chemistry Amongst the many routes to fused @-lactamsdescribed in 1973, Golding and Hall have applied the intramoleculaflo7carbene insertion reaction to the diazo-ester (365), which results in the formation of oxapenams (366). A number of routes to 2-oxazolidones have appeared. The reaction of epoxides with urethane results in the formation of 2: 1 adducts which c y c l i ~ e ~ ~ ~ to 3,5-disubstituted oxazolid-5-ones (367).

The classical route to 2-oxazolidones, involving the reaction of 2-aminoalcohols with phosgene, may now be superseded by the use of ethyl trichloroacetate.509Reaction of the amino-alcohol with ethyl trichloroacetate results in the formation of the trichloromethylamide(Scheme 71), which on treatment with sodium methoxide results in the elimination of the trichloromethyl group as chloroform.

Scheme 71

p-Hydroxy primary amides form 2-oxazolidones on lead tetra-acetate oxidation.510The reaction proceeds with retention of configuration and a quadricovalent lead-amide complex, rather than the alternative nitrene, is believed to lead to the intermediate isocyanate. Wohi5l1 has described the synthesis of cis- and trans-4,5-dimethyl-N-phenyloxazolid-2-one from the corresponding threo- and erythro-@-bromocarbamates,through HBr elimination. Long-range couplings have been observed between substituents at C-2 and C-5 in the lH n.m.r. spectra of substituted 4-oxazolidones and geometric isomers may be distinguished on the basis of the coupling constants.512 507 608

509 510

511 512

B. T. Golding and D. R. Hall, J.C.S. Chem. Comm., 1973, 293. Z . Pasenko, E. I. Fedorchenko, A. G. Yakovenko, and K. A. Korner, U.S.S.R. P. 367 100 (Chem. Abs., 1973,79, 5325). C. Caccia, S. Gladiali, R.Vitali, and R. Gardi, J . 0 r g . Chem., 1973,38,2264. S . S. Simons, J. Org. Chem., 1973, 38, 414. R. A. Wohl, J . Org. Chem., 1973, 38, 3858. D. L. Deavenport, C. H. Harrison, and D. W. Rathburn, Org. Magn. Resonance 1973, 5, 285.

Five- and Six-membered Rings and Related Fused Systems

23 1

H0ppe51s has investigated acylation and a l k y l a t i ~ n ~of~ *173-oxazolid-2thiones (368). Acylation with acetyl chloride results specifically in N-acetylation, whereas alkylation occurs on sulphur. Base-induced fragmentation of the N-acylated derivative results in the formation of N-acetyl-anhydroamino-acid esters (369). Reaction of the anion (370) with diphenyl phosphochloridate followed by base treatment results in the N-phosphorylated product (371), which fragments to 3-substituted isothiocyanatoacrylic acids (372).515

Two methods leading to 2-imino-oxaxolidines have been described. The first, due to Pawson and Gurbaxani,''' involves the reaction of carbodiimides with ethynyl carbinols in the presence of cuprous chloride; thus di-isopropyl carbodi-imide reacts with ethylethynylcarbinol, forming the

(373)

imino-oxazolidine (373). The second method involves the reaction of 2amino-alcohols with cyanogen bromide517and results in retention of configuration about the amine and alcohol termini. 513

514 515 516

517

D. Hoppe, Angew. Chem. Internat. Edn., 1973, 12, 658. D. Hoppe, Angew. Chem. Internat. Edn., 1973, 12, 656. D. Hoppe, Angew. Chem. Internat. Edn., 1973, 12, 923. B. A. Pawson and S. Gurbaxani, J. Org. Chem., 1973,38, 1051. H. Wollweber and R. Hiltmann, Arch. Pharm., 1973, 306, 284.

16

Saturated Heterocyclic Chemistry

232

X R

C

H

3

-

+ N2 +

RCH=C:

H2O

Scheme 72

3-Nitroso-oxazolid-2-onesundergo fragmentation518on base treatment, offering a convenient source of vinylcarbenes (Scheme 72). Under similar conditions 3-nitroso-4-methyl-5,5-pentamethyleneoxazolid-2-one (374) produces a variety of products519which have been rationalized in terms of fragmentation of the diazonium salt (375).

(374) (375) Thermal rearrangement52oof N-silylated oxazolid-Zones and -2-thiones appears, at least in certain circumstances, to be a reversible process resulting in the formation of 2-silyloxyalkyl or 2-silyloxyphenyl isocyanates. A twostep rearrangement (Scheme 73) has been suggested. SiMet

I

SiMea

Scheme 73

Derivatization of Leuchs anhydrides (1,3-0xazolid-2,4-diones) is conventionally regarded as a difficult problem; however, reaction with o-nitrophenylsulphenyl chloride results in the formation of the N-o-nitrophenylsulphenyl derivatives (376). These compounds are more stable than their precursors and are crystalline solids which do not undergo polymerization. Decarboxylation occurs on melting, yielding the N-o-nitrophenylsulphenylamino-a~id.~~~ 619 620 6a1

M. S. Newman and Z. U. Din, J. Org. Chem., 1973,38, 547. M. S. Newman and V. Lee, J . Org. Chem., 1973,38,2435. H. R. Kricheldorf, Annalen, 1973, 772. H. R. Kricheldorf, Angew. Chem. Internat. Edn., 1973, 12, 73.

Five- and Six-membered Rings and Relatcd Fused Systems

233

(376)

The reaction of epoxides with nitriles results in the formation of 2-oxazolines, and Wohl and Car1nie~~2 have demonstrated that the process is stereospecific, resulting in inversion of relative stereochemistry at C-4 and C-5 ; thus trans-2,3-epoxybutanegives cis-2,5-dimethyl-2-phenyl-2-oxazoline, and the cis-isomer gives the trans-2-oxazoline on reaction with benzonitrile. The reaction of bromohydrins under similar conditions results in 2-oxazoline formation with retention of stereo~hemistry.~~~ 2-Amino-alcohols react with nitriles in the presence of zinc chloride; thus erythro-3-aminobutan-2-01 gives cis-2-oxazolines, and the threo-compound yields the trans-isorner~.~~~ Anodic oxidation525of (S)-2-acetamido-2-(3,4-dimethoxybenzyl)propionitrileresults in the formation of (4R75S)-and (4R,SR)-2-0xazolines (377) and (378) in a ratio of 3.5:l.

(377)

(378)

Schollkopf and S ~ h r o d e have r ~ ~ demonstrated ~ that phosphate derivatives of 2-oxazolines are formed during the reaction of isocyanomethylphosphonic acid diethyl ester with ketones in the presence of base (Scheme 74). The condensation of a-alkoxycarbonyl-isocyanideswith carbonyl compounds follows a similar course, and using this approach derivatives of 8-phenylserine have been prepared (Scheme 75).527 Contrary to earlier reports, 00-diethyl monothiomalonate on reaction with 2-aminoethanol forms ethyl A2-thiazolin-2-yl-acetate and not A2o~azolin-2-yl-acetate.~~~ A2-Oxazolines(379) react with methyl is0cyanate,5~~ forming fused pyrimidine derivatives (380). R. A. Wohl and J. Cannie, J . Org. Chem., 1973, 38, 1787. R. A. Wohl, J . Org. Chem., 1973,38, 3099. 524 R. A. Wohl, Angew. Chem. Internat. Edn., 1973, 12, 920. 5a5 S. H. Pines, J. Org. Chem., 1973, 38, 3854. 5 z 6 U. Schollltopf and R. Schroder, Tetrahedron Letters, 1973, 633. 527 M. Suzuki, T. Iwasaki, K. Matsumoto, and K. Okumura, G e m . and hid., 1973, 229. 628 H. Wamhoff and C. Materne, Annalen, 1973, 572. 5 2 ~ 3 R. Richter and H. Ulrich, Chem. Ber., 1973, 106, 1501.

52a

623

Saturated Heterocyclic Chemistry

234

'C

I II

EtO\I1 0

R*COR2--OEt

j

EtO/P-CH2N=C

R

I

w

R2

HI

-

O

H

E

t

I

OEt

J

Scheme 74

R

I

CEEN--CHC02Me

NaH

0

OH

(379)

(380)

Introduction of a trifluoromethyl into A3-l ,3-oxazolin-4-onerings confers unusual properties on the molecule. The reaction of (381) with thioacyl esters in the presence of triethylamine results in the formation of 2-arylthio-3-oxazolin-5-ones(382), which on thermolysis generate nitrile yIides (383). Arenesulphenyl chlorides behave in a different way, resulting in 4-substitution. When 2,4-dinitrofluorobenzene is the electrophile exclusive substitution at position 2 occurs.531 630 631

P. Gruber, L. Muller, and W. Steglich, Chem. Ber., 1973, 106, 2863. W. Steglich, B. Kubel, and P. Gruber, Chem. Ber., 1973,106,2870.

235

Fiue- and Six-membered Rings and Related Fused Systems

(381)

(382)

(383)

Cook and L a ~ s o have n ~ ~examined ~ the reaction of 2-phenyl-A2-oxazolin5-ones with 2-alkyl-A2-thiazolines.The initial step involves addition of the anion (384) to the thiazoline (Scheme 76). The subsequent course of the reaction, leading to the formation of (385;X = S,Y = NH) or (385;X = NH, Y = S), appears to be solvent-dependent. B.

JH

HN

I

(CH&YH

Ph

~$~CH&YCOCI-I2NH k l COPh

Ph (385) Scheme 76

Reaction of nucleophiles with oxazolid-5-ones under acidic conditions has been examined and normally follows second-order 2-Aryl-4arylideneoxazolid-5-onesreact with primary amines in the presence of acetic acid 634 forming 1,2-diary1-4-arylidene-2-imidazolones (Scheme 77).

" YAr'

4

0'

Xrl

A rI

Scheme 77 632

633 634

D. C. Cook and A. Lawson, J.C.S. Perkin I, 1973,465. C. Chuaqui, S. Atala, A. Marquez, and H. Rodriguez, Tetrahedron, 1973,29, 1197. A. M. Islam, A. M. Khalil, and I. I. A. El-Gawad, Austral. J. Chem., 1973, 26, 827.

Saturated Heterocyclic Chemistry

236 D

D

n

O

Scheme 78

Kirby and have developed a route to stereospecifically labelled tyrosine and phenylalanine by catalytic reduction of N-acetyl-anhydro-aminoacids derived from the hydrolysis of 4-arylidene-2-oxazolid-5-ones (Scheme 78).

4,5-Diphenyl-4-oxazolin-2-one has been used as a protecting group for amines. Reaction of benzoin with phosgene (Scheme 79) followed by the reaction of the resultant carbonate with amines results in the formation of the 4-0xazolin-2-one.~~~ Cleavage may be effected with anhydrous hydrazine, anhydrous HF, or sodium in liquid ammonia or by hydrogenolysis.

‘OH

Ph’ Scheme 79

Fused Oxazoles. A synthesis of the spiro-oxazolidone (386) has been537 reported. The unstable 3,4-dihydroxybemylmethanolamine(388)has been prepared by catalytic reduction538of the 4-oxazolin-2-one (387). Dioxazules. Ozonolysis of olefins in the presence of ammonia539results in the formation of 1,2,4-dioxazolidines (389). Nucleophilic addition of hydroxamic acidsu0to acetylenic compounds yields A2-1,4,3-dioxazolines (390). 63a

637 638 63s

G. W. Kirby and J. Michael, J.C.S. Perkin I, 1973, 115. J. C. Sheehan and F. S. Guziec, J . Org. Chem., 1973,38, 3034. M. Nakanishi, A. Katsuo, and H. Ao., U.S. P. 3 723 442 (Chem. Abs., 1973,79,5351). J: L. Neumeyer and C. B. Boyce, J . Org. Chem., 1973, 38, 2291. A. T. Menyailo, 0. R. Kaliko, G. G. Filina, and M. V. Pospelov, U.S.S.R.P. 375 932 (Chem. Abs., 1973, 79, 78 809). F. M. F. Chen and T. P. Forrest, Canad. J. Chern., 1973, 51, 1386.

237

Five- and Six-membered Rings and Related Fused Systems

F OH

Ofi

OH

Oxadiazoles. Addition of nitrosyl chloridem to vinyl ethers results in the initial formation of 1 :1 adducts, which undergo disproportionation to form 1,2,3-0xadiazoline 3-oxides (391). 1,2,4-0xadiazolid-5-ones(392) have been prepared by the addition of phenyl isocyanate to glyoxal nitrones (393).

+

RNSH-CH=NR

I

I

I

I

0-

R

Ph (391)

0-

+

(392)

(393)

This reaction is believed to involve two successive dipolar additions.M2 Amidoximes undergo condensation reactions with aldehyde^,^^ producing A2-1,2,4-oxadiazolines. The 1,2,4-oxadiazolopyridines (394) have been prepared from 3-picoline and phenyl isocyanate, although yields were low and elevated temperatures resultedu in fragmentation to Z-anih-10-3-picoline (395). Ph

(394) 641 54a 544

(395)

K. A. Oglobin and D. M. Kunovskaya, Zhur. org. Khim., 1973,9,1547. G . Zinner, 0. Hantelmann, and U. Dybowski, Chem.-Ztg., 1973,97,205. C. Malavaud, M. T. Boisdon, and J. Barrans, Bull. SOC.chim. France, 1973,2996. T . Hisano, S. Yoshikawa, and K. Muraoka, Org. Prep. Proced. Internat., 1973, 5.95.

238

Saturated Heterocyclic Chemistry ,SiMe3

Ph (397)

(396)

5-Substituted 3-trimethylsilyl-lY3 ,4-oxadiazolin-2-ones (396) have been reported to be thermally stable and do not undergo rearrangement to the isomeric 2-trimethylsilyl-l,3,4-oxadiazolesat temperatures up to 300 0C.545 Photolysis of 2,5-disubstituted 1,3,4-oxadiazoles with furan in benzene solution gives 1 :1 cycloadducts;546thus the photolysis of 2,5-diphenyloxadiazole results in the formation of (397). lY2-Oxazines.A full paper describing Eschenmoser’~~~~ elegant chloronitrone work has appeared. Reaction of olefins with the chloro-nitrone (398) in the presence of silver(1) salts (Scheme 80) yields, after cyanide work-up, the oxazines (399). Hydrolysis of the oxazines results in the formation of the a-methylbutyrolactone (400), and a fractional crystallization permits separa-

J

Reagents: i, Ag1-S02; ii, KCO

Scheme 80

tion of the C-2 epimers. Using the dichloro-nitrone (401) it has proven possible to synthesize a-methylene-butyrolactones. In contrast to earlier reports Brandman and Conleyw8have demonstrated that oximation of 7-halogeno-ketones does not furnish 4(H)-5,6-dihydro-lY2oxazines. Methyl 3-chloropropyl ketone on oximation produces the nitrone 645

546 547 648

H. R. Kricheldorf, Annalen, 1973, 1816. 0.Tsuge, K. Oe, and M. Tashiro, Tetrahedron, 1973, 29, 41. M. Petrzilka, D. Felix, and A. Eschenmoser, Helu. Chirn. A d a , 1973,56,2950. H. A. Brandman and R. T. Conley, J. Org. Chem., 1973,38,2236.

Five- and Six-membered Rings and Related Fused Systems

c'y c1

(401)

/QI 0-

239

n 0

0

*WC1 (403)

(402)

(404)

(402) as the sole product. Unequivocal synthesis of (404)was achieved by the reaction of the ethylene acetal (403) with the potassium salt of N-hydroxyurethane, followed by alkaline hydrolysis. 3-Methoxycarbonyl-4,5-dihydro6H-1,Zoxazine N-oxide (405) reacts with acetylenes to form bicyclic syst e m ~This . ~ probably ~ ~ proceeds through the intermediate [ 3 21cycloadduct (406) (Scheme 81).

+

r

1

0(405)

COC02Me

Scheme 81

1,3-0xazines. The Mannich reaction550of isobutyraldehyde, formaldehyde, and one equivalent of methylammonium chloride gives 6-alkoxytetrahydro5,5-dimethyl-l,3-oxazine(407) in ca. 80% yield. A similar approach551has been used to prepare 5-nitro-5-hydroxymethyl-l,3-tetrahydro-oxazines, although the more general synthesis employing l ,3-amino-alcohols and aldehydes appears to offer greater Treatment553 of N-benzyloxycarbonylamino-3-bromopropanewith triphenylphosphine results in ring closure to the 1,3-0xazinone (408). This reaction appears to be quite general. 549

560

551 552

553

I. E. Clilenov, I. L. Sokolova, S. S. Novikov, and V. A. Tartakovskii, Izcest. Akad. Nauk S.S.S.R., Ser. khim., 1973, 473 (Chem. Abs., 1973, 79, 5304). P. Y. Johnson, R. B. Silver, and M. M. Davies, J . Org. Chem., 1973,38, 3753. H. Piotrowska, T. Urbanski, and W. Sienicki, Roczniki Chem., 1973, 47, 193. I. P. Boiko, Y. E. Kazantsev, I. 0. Zhuk, and Y. Y . Samilov, Khim. gererotsikl. Soedinenii, 1973, 467 (Chem. A h . , 1973, 79, 18 652). J. K. Coward and R. Lok, J. Org. Chem., 1973,38,2546.

Saturated Heterocyclic Chemistry

240 ?Et

I

I

A number of papers describing the synthetic utility of dihydro-l,3-oxazines have appeared. 2,4,4,6-Tetramethyldihydro-l,3-oxazine (409) is conveniently prepared by the reaction of acetonitrile with 2-methylpentane-l,4-dioland sulphuric acid at 0 0C.5s4 The method of choice for cleavage of the ring involves low-temperature borohydride reduction followed by acid hydrolysis. Formation of the anion (410) is readily accomplished with PhLi or BuLi at -78OC and alkylation occurs readily. Using this approach Meyers and Nazarenko have recently synthesized j a ~ r n o n e . ~ ~ ~ Two approaches to 2-vinyl-4,4,6-trimethyldihydro-l,3-oxazines have been reported. Condensation of an appropriately substituted a c r y l ~ n i t r l ewith ~~~ 2-methylpentane-2,4-diolresults in the vinyl derivatives; alternatively reaction of the anion (410) with aldehydes may be used. Treatment of the vinyl derivatives with alkyl-lithium reagents results in alkylation, though this process occurs through ketenimines(41l)rather than by the expected 1,4-addi-

tion.556~557 Hydrolysis of the ketenimines yields ketones, whilst alkylation may be e f f e ~ t e dto ~~ yield * ~ highly ~ ~ branched ketones. A synthesis of the fused oxazine (412) has been described.56a Metallation of isocyanides followed by reaction with oxirans results in attack at the least hindered carbon atom, the products of the reaction being determined by the work-up procedure.561 Use of methanol results in the m A. I. Meyers, A. Nabeya, H. W. Adickes, I. R. Politzer, G. R. Molone,A. C. Kovelesky, R. L. Nolen, and R. C. Portnoy, J. Org. Chem., 1973,38,36. 566 A. I. Meyers and N. Nazarenko, J. Org. Chem., 1973,38, 176. 6s* A. I. Meyers, A. C. Kovelesky, and A. F. Jurjevich, J . Org. Chem.. 1973,38, 2136. 6 5 7 C. Lion and J. E. Dubois, Tetrahedron, 1973, 29, 3417. 558 A. I. Meyers, E. M. Smith, and M.S. Ao, J . Org. Chem., 1973,38, 2129. s6B C. Lion and J. E. Dubois, Bull. SOC.chim. France, 1973, 2673. 560 A. Picot and X. Lusinchi, Tetrahedron Letters, 1973, 903. U. Schollkopf and R. Jentsch, Angew. Chem. Internat. Edn., 1973, 12, 323.

Fiue- and Six-membered Rings and Related Fused Systems

241

formation of dihydro4H-l,3-oxazines (413). Silver([)-catalysed reaction of isocyanides with 3-aminopropanol results in the formation of dihydro4H1,3-oxazine (413; R1 = R2= H), the nitrogen atom and alkyl group of the isocyanide being lost as an

k”

J-3

R’

The reaction of trans-N-cinnamyl-p-nitrobemamide with bromine in acetic acid results in the formation of the oxazinium salt (414), supporting the existence of a benzylcarbonium ion intermediate, rather than a bridged bromonium ion.563 Fused 1,3-0xazines. Ba~e-catalysed~~ reaction of 1-cyanomethyIene-6,7dimethoxy-l,2,3,4-tetrahydroisoquinolinewith formaldehyde results in the formation of the oxazino [4,3-a]isoquinoline (415). The reaction of amides of phenylethylamine with phosphoryl chloride to form dihydroisoquinolinesis well known, and the corresponding cyclohexenyl derivatives (416) behave similarly. However, when polyphosphoric acid is used as the cyclizing agent spiro-oxazine derivatives (417) The spirocyclic systems (418) have been obtained by the reaction of imines of l-alkyl-4-piper idones with a,o-hydroxy-carboxylic acids!66

(417) 562 563

564 565 566

Y.Ito, Y.Inubushi, M. Zenbayashi, S. Tomita, and T. Saegusa, J . Amer. Chem. SOC., 1973,95,4447. S. P. McManus and R. A. Hames, Tetrahedron Letters, 1973, 4549. K. Harsanyi, P. Kiss, and D. Korbonits, J . Heterocyclic Chem., 1973, 10, 435. R. R. Wittekind and S. Lazarus, J. Heterocyclic Chem.. 1973,10,217. M. Nakanishi, K. Arimura, and H. Ao, Japan Kokai 73/26 018 (Chem. Abs., 1973,79, 115 562).

242

Saturated Heterocyclic Chemistry

Trimethylsilyl a ~ i d reacts e ~ ~with ~ cyclopropanedicarboxylicacid anhydride to form the isocyanate (419), which on treatment with water generates the oxazine-dione (420). A synthesis of the oxazinobenzimidazole (421)has been describedF6*

PNCO 1,4-Oxnzines. Perfluoromorpholine derivatives have been prepared using an elect1ochemical method56gand their photochemical and pyrolytic behaviour has been examined. Spectroscopic properties of some N-aryl-2,3dihydro-3-oxo-4H-l,4-oxazineshave been reported.670Aryl methyl ketones R

I

Me-C-CN

I NH

Me

Ph (422)

(423)

(424)

(425)

react with (4S,5S)-( +)-5-amino-2,2-dimethyl-4-phenyl-lY3-dioxan (422) in the presence of sodium cyanide to form the aminonitrile derivatives (423). Under acid catalysis, rearrangement to the tetrahydro-l,4-oxazin-2-ones (424)occurs and hydrolytic ring-opening results in the formation of optically active amino-a~ids.~'~ 2,4,6-Triphenyl-1,4-oxazine(425) is formed when diphena~ylaniline~~~ is treated with an excess of phosphoryl chloride. Details of the spectroscopic properties of nitrophenoxazines have ap~ e a r e d Morpholino-enamines .~~~ react with 1-nitroso-Znaphthol, forming 1:1 adducts;574thus 1-morpholinocyclohexanegives the adduct (426). 667

568 569 570

571

572

673 574

H. R. Kricheldorf and W. Regel, Chern. Ber., 1973,106, 3753. M. J. Haddadin and A. Hasner, J. Org. Chem., 1973,38,2650. R. E. Banks, A. J. Parker, M. J. Sharp, and G . F. Smith, J.C.S. Perkin I, 1973, 5. R. F. Abdulla, J. Heterocyclic Chem., 1973, 10, 347. K. Weinges and B. Stemmle, Chem. Ber., 1973, 106, 2291. J. Correle, J. Org. Chem., 1973, 38, 3433. V. Bekarek and Z . Stransky, Coll. Czech. Chem. Comm., 1973, 38, 62. J. W. Lewis, P. L. Meyers, and J. A. Ormerod, J.C.S. Perkin I, 1973, 1129.

Fiue- and Six-niembered Rings and Related Fused Systems

243

Diuxazines. Among the multitude of products obtained from formaldehyde condensation with 2,4dinitrophenylhydrazine,it has been demonstrated that the major formed with excess formaldehyde is the 1,3,5-dioxazine (427). Hassner and co-workers have observed that the reaction576of 2-phenylazirine with diphenylketen results in the formation of the labile 2: 1 adduct (428). On silica (428) rearranges to the dioxazepine (429), whereas basecatalysed rearrangement yields the oxazepine (430). These products have been rationalized in terms of ring-opening of (428)followed by the alternative modes of cyclization (Scheme 82).

PPhh o q f p h

Ph

c---

Ph

Ph (430)

Scheme 82 576

676

S. R. Johns, J. A. Lamberton, and E. R. Nelson, Austral. J. Chern., 1973, 26, 1279. M. J. Haddadin and A. Hassner, J. Org. Chem., 1973, 38, 3466; A. Hassner, M. J. Haddadin, and A. B. Levy, Tetrahedron Letters, 1973, 1015.

Saturated Heterocyclic Chemistry

244

(43 1)

Oxadiazines. Perhydro-l,3,4-oxadiazinederivatives (431) have been prepared by the reaction of ketones577with 1-aryl-l-(2-hydroxyethyl)hydrazines. and a~id-catalysed57~ rearrangement of Diels-Alder adducts The of cyclopentadiene and azodibenzoyl or diethyl azidodicarboxylateand cyclopentadienone have been investigated. The rearrangement proceeds in two stages, by a fast and reversible rearrangement to the 1,3,4-0xadiazine derivative (Scheme 83) and a slow, irreversible rearrangement to the diazetidine.

1 ihPh Scheme 83

A new class6s0of bicyclic oxadiazines (433) has been obtained by the reaction of amino-oxyacetic acid with the dihydroimidazoline (432).

n

HNpY /N,O

SH (432)

(433)

B. L. Mil'man and A. A. Potekhim, Khim. geterosikl. Soedinenii, 1973, 902 (Chem. Abs., 1973, 79, 115 540). 6 7 8 D. Mackay, C. W. Pilger, and L. L. Wong, J . Org. Chem., 1973, 38,2043. 5 7 Q C. P. R. Jennison and D. Mackay, Tetrahedron, 1973, 29, 1255. m0 C. Belzecki and J. Trojnar, Polish P. 67 024 (Chem. Abs., 1973,79,32 062). 577

Fiue- and Six-membered Rings and Related Fused Systems

245

Mercury(11)-e thylenediaminetetra-acet ate dehydrogenation of o x i m e ~ ~ ~ ~ of N-tertiary cyclic amino-compounds has been examined. Z-Amino-oximes cyclize to dihydro-oxadiazine derivatives whereas the E-oximes yield nitrones. These reactions have been interpreted in terms of dehydrogenation of the amine to the iminium salt (Scheme 84) followed by ring closure.

Scheme 84

Miscellaneous Fused Systems. Middleton and co-workers, in a continuation of their studies on the properties of hexafluoroacetone,M2have isolated the spirocyclic compound (434) from prolonged standing of the cyanhydrin of hexafluoroacetone.

(434)

(435)

4,6-Dioxa-l-azabicyclo [3,3,O]octanes (435) have been synthesizedsmby the reaction of alkyl cyanides with diethanolamines in the presence of catalytic quantities of alkoxide. Syntheses of the pyrrolo[3,4-b]pyridines (436) and the related pyrano-systems (437) have

R3 (436) s81 688 58s

584

(437)

H. Mohrle and R. Engelsing, Chem. Ber., 1973, 106, 1172. W. J. Middleton, D. Metzger, and D. C. England, J. Org. Chem., 1973, 38, 1751. K. Burzin and R. Feinauer, Angew. Chem. Internat. Edn., 1973, 12, 996. M. Baues, U. Kraatz, and F. Korte, Annulen, 1973, 1310.

246

Saturated Heterocyclic Chemistry

(438)

Scheme 85

Treatmen t of or-(o-nit robenzoy1)butyrolactone with tr ieth yl phosphite results in the formation of the spiro-indolone lactone (438). A nitrene insertion (Scheme 85) into the C-H bond has been suggested.686 Thermal rearrangement of nitrones possessing 8-hydrogen atoms to unsaturated N-hydroxy-compounds has been utilized in the synthesis of some fused heterocyclic systems;586thus the nitrone (439) on thermolysis gives the hydrobenzofuro[3 ,Zc]indole (441) by way of the intermediate hydroxylamine (440). 0-

P"

OH

OH OMe

OMe

OMe

The tetrahydropyrano [2,3 :2',3']-2,3-dihydropyrano [6,5-c]pyrazole (442) ring system undergoes equilibration between the cis- and trans-fused isomers about the ring junction in strong acid?*' Deuterium-labelling studies suggest that ring-opening to the onium species (443) occurs, followed by ring closure.

*

R

Ph

N, I

H

Ph

(442) be6 686 587

R

Ph

N m I Ph (443)

T. Kametani, F. F. Ebetino, and K. Fukamoto, Tetrahedron Letters, 1973, 5229. S. Klutchko, A. C. Sonntag, M. von Strandmann, and J. Shave], J. Org. Chern., 1973, 38, 3012. G. Desimoni, G. Cellerino, A. Gamba, P. P. Righetti, and G. Jacconi, Tetrahedron, 1973, 29, 2621.

Five- and Six-membered Rings and Related Fused Systems

247

The reaction of benzaldazine with 2,3-epoxypropyl aryl ethers588in the presence of Lewis acids results in the formation of the perhydro-oxadiazolooxadiazines (444). Diels-Alder reaction of 4,5-dimethylene-2,2-diphenyl-l,3-dioxolanwith ethyl azidodicarboxylate produces addicts (445) in modest yieldFS9 Ar

Ar (444)

(445)

In contrast to 2,3-dimethoxycarbonyl-4,5-dihydrofurans,s90 5,6-dihydro4H-pyran-2,3-dicarboxylicesters react with hydrazine to form dihydrazides which c y c l i ~ to e ~the ~ ~fused pyridazinediones (446). Base-catalysed condensation of benzaldehyde with 1-1nethyl-4-piperidone~~~ results in the formation of two dimeric products. The crystal structure593of the major product has confirmed its identity as (447).

(446)

(447)

Tetrahydro-2H-pyrano[2,3-d]pyrimidines (448) have been synthesized by the reaction of barbituric acid with tetracyan~ethylene.~~~

58B s90

5g3

693 694

M. Furakawa, M. Sugita, Y. Kogima, and S. Hayashi, Chem. and Pharm. Bull. (Japan), 1973,21,2088. G . M. Coppola and S. P. Gimelli, J. Heterocyclic Chem., 1973, 10, 323. J. Lehmann, U. Kraatz, and F. Korte, Chem. Bet., 1973, 106, 1099. J. Lehmann, U. Kraatz, and F. Korte, Chem. Ber., 1973, 106, 929. G . G. Lyle, J. J. Dziark, J. Connor, and C . S. Huber, Tetrahedron, 1973, 29, 4039. C. S. Huber, Acta Cryst., 1973, B29, 1646. H. Junek and H. Aigner, Chem. Ber., 1973,106,914.

17

4

Bridged Systems BY J. M. MELLOR

1 Introduction The material in this Report is organized in a similar manner to that of Volumes 1’ and 2.2 An analysis of the application of physical methods precedes discussion of groups of compounds divided on the basis of the nature of the heteroatom in the bridged system. In addition to the sections on nitrogen, oxygen, and sulphur compounds, a section is introduced this yearoncryptates. In the final section the growing importance of bridged carbo-silanes and -boranes is noted.

2 Physical Methods The increased availability of commercial photoelectron spectrometers equipped with heated inlets has extended the range of compounds for which information may be obtained. The most studied cases are those of lone-pairlone-pair interactions either through space or through bonds. However, interesting accounts of lone-pair interactions with a-frameworks have been presented. In a boat cyclohexane the highest occupied a-orbital3 has the symmetry shown in (1). Consequently in the 7-norbornyl cation (2) symmetry requirements preclude significant interaction between the vacant orbital and the highest occupied a-orbital. This, in part, accounts for the relative instability of the 7-norbornyl cation. In a like manner in 7-oxanorbornane (3) absence of interaction with the a-orbital of type (1) is expected. Experimental evidence

(1) 1

8 3

(2)

(3)

J. M. Mellor in ‘Aliphatic, Alicyclic, and Saturated Heterocyclic Chemistry’, ed. W. Parker (Specialist Periodical Reports), The Chemical Society, London, Vol. 1 , part 111, 1973, p. 483. J. M. Mellor in ‘Saturated Heterocyclic Chemistry,’ ed. W. Parker (Specialist Periodical Reports), The Chemical Society, London, Vol. 2, 1974, p. 353. R. Hoffmann, P. D. Mollere, and E. Heilbronner, J . Amer. Chem. Soc., 1973,95,4860.

248

249

Bridged Systems Table Compound Adiabatic Z.P. (eV) Dimethyl ether 10.04" Dimethyl sulphide 8.70 Di-isopropyl ether 9.20 Di-isopropyl sulphide 8.26b Tetrahydrofuran 9.576 Tetrahydrothiophen 8.40d 9.576 7-Oxanorbornane (3) 7-Thianorbornane (4) 8.43

a S. Cradock and R. A. Whitford, J.C.S. Faraday IZ, 1972, 68, 281; H. Bock and G . Wagner, h g e w Chem. Internat. Edn., 1972, 11, 150; A. D. Bain, J. C. Bunzli, D. C. Frost, and L. Weiler, J . Amer. Chem. SOC.,1973,95, 291 ; H. Schmidt and A. Schweig, Tetrahedron Letters, 1973, 1437.

is given by the unusual sharpness of the band associated with no and by the position of this band (see the Table). Increased substitution destabilizes no in di-isopropyl ether relative to dimethyl ether by an inductive effect. A similar effect might be expected to destabilize no in (3) relative to tetrahydrofuran. The absence of any such destabilization has been interpretedSas evidence for non-interaction in (3) between a p-type lone-pair and the highest occupied a-orbital. Similarly, in 7-thianorbornane (4) neither the p-type lone-pair n, nor the vacant d-orbitals interact significantly4 with the a-orbitals. Hence n, in 7thianorbornane is unusually stabilized. The effects are small by comparison with the more dramatic lone-pair-lone-pair interactions, Further examples that have been studied are 1 ,5-diazabicyclo[3,2,1]octane5( 5 ) and various adamantanes. In ( 5 ) different interactions are expected through the three bridges and the resultant observed splitting (0.71 eV) is much smaller than in 1,4-diazabicyclo[2,2,2]octane (2.0 eV). In urotropine (6) interactions lead6 to a single lone-pair band at ca. 8.2 eV; the spectrum of 1,3,5,7-tetrasilaadamantane (7) has also been reported.

(4)

(5)

(6)

(7)

For a number of years it has been known that the interaction of nitrogen lone-pairs with a carbonyl group modifies spectroscopic properties, e.g. red shifts observed in the n --+ T* transition of cc-amino- and p-amino-ketones. Both EHT and STO-3G calculations7on aminoacetaldehydehave established the critical conformational requirements of such interactions, and have led J. C. Bunzli, D. C. Frost, and L. Weiler, J. Arner. Chem. SOC.,1973,95, 7880. Y. Hamada, A. Y . Hirakawa, M. Tsuboi, and H. Ogata, Bull. Chem. SOC.Japan, 1973,46,2244. 13

W. Schmidt, Tetrahedron, 1973,29,2129; W. Schmidt, B. T. Wilkins, G. Fritz, and R. Huber, J. Organometallic Chem., 1973, 59, 109. C. C. Levin, R. Hoffmann, W. J. Hehre, and J. Hudec, J.C.S. Perkin IZ, 1973,210.

250 Saturated Heterocyclic Chemistry to the suggestion that the following are important in amino-ketones: through-bond coupling of the nitrogen and oxygzn lone-pairs, through-space interaction of these lone-pairs, hyperconjugation between the C-N CT* level and the carbonyl r-system, and the direct overlap of the nitrogen lone-pair with the carbonyl n-system. Through-space interactions fall off rapidly as the conformation departs from a cis coplanar orientation. This analysis suggests that the frequently observed band in the U.V. spectrum of amino-ketones at ca. 235 nm can be attributed to a second n + n* transition. The analysis adequately accounts for both the U.V. and p.e. spectra of many’bridgedamino- ketones. The anomalous spectral properties of tropanone have previously been recognized, but now in the more rigid l-azaadamantan-4-one (8) detailed spectroscopicobservations have been reported? The terminology used of ‘sigma-coupled’transitions and of ‘charge transfer’ transitions conceals the recognitition of mixing between the nitrogen lonepair and the carbonyl group. In view of the experimental observations that charge transfer in the transition at ca. 240nm is very small, an analysis avoiding this term is to be preferred. The photoelectron spectrum of (8) should be revealing. U.V. spectra have been reportedg for series of 1,3-diazaadamantan-6-ones and 3,6-diazahomoadamantan-9-ones. In (9) the observed transition at 255 nm ( E 1380) is probably an n-r* transition (the terminology ‘sigma-coupled’was again used). Other spectral and chemical properties of (9) and related compounds were also reported. COzMe I

(8)

(9)

Recently developed synthetic methods have now permitted an examination of lone-pair interactions in bridged hydrazines and diaza-compounds. In compounds (10)-(13) a lone-pair splitting of -2.36 eV was estimated.1° The observation that in azo -compounds the energy of the n --t T* transition is

*

A. W. J.D.Dekkers, J. W.Verhoeven,andW.N.Speckamp,Tetrahedron,1973,29,1691. T. Sasaki, S. Eguchi, T. Kiriyama, and Y.Sakito, J. Org. Chem., 1973, 38, 1648. lo R. J. Boyd, J. C. Bunzli, J. P. Snyder, and M. L. Heyman, J. Amer. Chem. SOC.,1973, 95, 6478.

25 1

Bridged Systems

related to the angle subtended by the azo-group has been justified'l by ab initio calculations, and is shown both by calculationll and by p.e. spectra to be due to the stability of the lone-pair (n-) rather than to any change in w* energy. As expected the series of hydrazines (14)-(18) showed a lone-pair splitting determinedlaby the magnitude of the lone-pair-lone-pair dihedral angle. The

(1 8)

(17)

largest splitting is in (17) where the lone pairs have a preferred anti-conformation. An interesting feature of this study was the poor correlation between El12(oxidation) values and first I.P. values. This unusual situation can presumably be attributed to differing conformations of the molecules in the gas phase and on an electrode. It cautions against both the extrapolation of p.e.s. results to solution chemistry and the use of Ell2values as a criterion of reactivity in non-electrochemical studies. The development of pulse Fourier-transform spectroscopy has permitted the observation of 15N-15N couplings with isotopic enrichment. Couplings were observedl3in the nitro-mine (19) and in a range of acyclic hydrazines, with a lSN enrichment of 95% at each nitrogen centre. Using similar FT techniques 31PCC13C couplings were observed14in the previously reported oxide (20) and in the novel oxide (21). Further evidence15has been presented

(19) l1

(20)

(21)

N. C. Baird, P. De Mayo, J. R. Swenson, and M. C. Usselman,J.C.S. Chem. Comm., 1973,314.

la S. F. Nelsen l 3 S. Bulusu, J.

l4 l6

and J. M. Buschek, J. Amer. Chern. SOC.,1973, 95, 2011. R. Autera, and T. Axenrod, J.C.S. Chem. Comm., 1973, 602. R. B. Wetzel and G. L. Kenyon, J.C.S. Chem. Comm., 1973,287. C . Benezra, J . Amer. Chem. Soc., 1973,95,6890.

252

Saturated Heterocyclic Chemistry 0

0

(22)

(23)

showing that a Karplus relation may be applied to 31PCCH couplings and it is now concludedf4that a Karplus relation may be applied to 31PCC13C couplings. Further lanthanide-shift studies on (22) and (23) have been reported.16 Interest in bridged nitroxide radicals continues. An X-ray study1' has been made of the previously reported nitroxide (24). In agreement with calculation, the N-0 bond was reported to be inclined towards the six-membered ring. The conformational requirements of transmission of electron spin have been further studied18in (25) and (26). Experimentally observed hyperfine splitting

(24)

(25)

(26)

constants were used to deduce that in (25) the N-0 bond is inclined over the double bond but in (26) it is inclined over the aromatic ring. The above nitroxides (24)-(26) represent cases in which the lack of symmetry might be expected to lead to the non-planarity of the C,NO grouping. Rassat and Rey19have recently examined the spectra of the nitroxide (27) attemperatures down to -150 "C. Both the spectra and calculations for this compound suggest a rapid inversion of the nitrogen with a low energy barrier (ca. 2 kcal mol-l), and a conformation of minimum energy with a deformation from planarity of about 35'. The equilibrium constants20 found for reversible dimerization of nitroxides (28) and (29) are comparable in solution but the solid-state properties are very different. Nitroxide (28) is yellow and diamagnetic, but nitroxide (29) is red and paramagnetic. Differences in packing within the crystal have been suggested as factors preventing dimerization of (29). Full details21of the previously reported irreversible dimerization of (28) via hydrogen atom abstraction have been given. Surprisingly in R. Caple, D. K. Harris, and S. C. Kuo, J . Org. Chem., 1973, 38, 381. A. Capiomont, A m Crysf.,1973, B29, 1720. l 8 I. Morishima, K. Yoshikawa, K. Bekki, M. Kohno, and K. Arita, J . Amer. Chem. SOC., l7

1973,95, 5815. l9 2o 21

A. Rassat and P. Rey, Tefruhedron,1973, 29, 1599. G.D. Mendenhall and K. U. Ingold, J . Amer. Chem. SOC.,1973,95,6390. G. D. Mendenhall and K. U. Ingold, J . Amer. Chern. SOC.,1973, 95, 6395.

253

Bridged Systems

this dimerization, which proceeds by removal of a bridgehead hydrogen, (28) is much more reactive than (29); an explanation for this is not yet available. Other intermolecular reductions of (28) and (29) have been reported.21*22 Just as measurements of hyperfine splitting constants can help to determine geometry about a nitroxide group, similar measurements might be expected to help determine the geometry of alkyl radicals. From e m . spectra reported2s for a series of 2-norbornyl radicals and 7-oxabicyclo[2,2,l]hept-2-y1 radicals it was suggested that the C-2-H bond is bent in these radicals in the endodirection; this observation would accord with the experimentally observed preference for e m attack on such radicals. In addition to compounds mentioned elsewhere in this Report, X-ray studies have been reported for compounds (30),24(31),26 (32),26and (33)27 and

OMe (30)

(32) 22

23 24 25

26

27

(33)

L. R. Mahoney, G. D. Mendenhall, and K . U. Ingold, J . Amer. Chem. Soc., 1973,95, 8610. T. Kawamura, T. Koyama, and T. Yonezawa, J . Amer. Chem. SOC.,1973, 95,3220. H.-C. Mez and G. Rihs, Tetrahedron Letters, 1973, 3417. A.Aubry, J.Protas,C. M. Thong, M. Marraud,and J.Neel,Acta Cryst.,1973,B29,2576. T. K. Bradshaw, E. W. Della, and M. R. Taylor, Acta C r p t . , 1973, B29,2637. R. L. Craig, J. Murray-Rust, P. Murray-Rust, and J. S. Roberts,J.C.S. Chem. Comm., 1973, 751.

254 Saturated Heterocyclic Chemistry mass spectra have been recorded for 7-azabicyclo[2,2,l]heptane~~~ and 9-heterobicyclo[3,3,1]non-6-en-2-0nes.~~ To assist in a rationalization of polar substituent effects the pK, values of a wide range of 4-substituted quinuclidinium perchloratesSO have been determined. Electrochemical determinations of redox potentials have been used31to estimate indirectly the pK, of the trialkylhydrazine (34). The value

obtained (>42) is exceptionally high (cf: pK, values for ammonia and methane of 33 and 40 respectively);this was attributed to lone-pair interactions destabilizing the anion. E.s.r. spectra of related trialkylhydrazyl radicalsa2 have been noted.

3 Nitrogen Compounds Emphasis here is again given to synthetic methods and to the chemical reactivity of bridged systems. However, note is taken of the preparation and antibiotic activity of 3-hydroxy- and 3-amino-quinuclidine derivatives,%the synthesis and analgesic activity of benzoxazocines (35) and (36), and the isolation35from the European ladybug of the novel alkaloid adaline (37).

28 29

30

31 3a

33 34 35

K. G. Das, P. S. Kulkarni, and S . K . Roy, Org. Mass Spectrometry, 1973, 7 , 1419. M. Dharan, A. Battisti, and A. Padwa, Indian J . Chem., 1973, 11, 549. E. Ceppi, W. Eckhardt, and C. A. Grob, Tetrahedron Letters, 1973,3627; C. A. Grob, W. Simon, and D. Treffert, Angew. Chem. Internat. Edn., 1973, 12, 319. S. F. Nelsen and R.T. Landis, J. Amer. Chem. SOC.,1973,95,5422. S. F. Nelsen and R. T. Landis, J. Amer. Chem. SOC.,1973,95, 6454. E. E. Mikhlina, K. A. Zaitseva, V. Y.Vorob’eva, M. D. Mashkovskii, and L. N. Yakhontov, Khim. Farm. Zhur., 1973, 7,20. R. K. Razdan, H. G. Pars, B. A. Zitko, V. V. Kane, and W. R. Thompson, Tetrahedron Letters, 1973, 1623. B. Tursch, J. C. Braekman, D. Daloze, C. Hootele, D. Losman, R. Karlsson, and J. M. Pasteels, Tetrahedron Letters, 1973, 201.

Bridged Systems 255 Synthesis.-This section is divided into : (a) Mannich reactions and carbonnitrogen bond formation via direct nucleophilic substitution by nitrogen, (b) routes proceeding via an electron-deficient nitrogen species, (c) cycloadditions in which carbon-nitrogen bonds are formed, and ( d ) miscellaneous reactions. Mannich-type Reactions. Reaction of cyclododecanoneS with formaldehyde and methylamine led to the three products (38)-(40). The dihydropyridin-

44 Me

QNM Me N

MeN

4-one (40) is not a by-product from (39) and it has been suggested that (40) arises by an intramolecular hydride abstraction. A further synthesis37of 1,3diaza-adamantane (41) proceeds via condensation of formaldehyde with 3,7diazabicyclo[3,3,l]nonane (42), prepared in situ from the tetrabromide (43).

& & -N

(41)

4

(42)

N

H

BrCH2-CH-CH2Br

I I

CH2

BrCH-CH-CH2Br (43)

An X-ray studyS8established the structure (45) for the product of treatment of (44) with anhydrous hydrazine. In benzene solution exposed to air (45) underwent quantitative conversion into the ozonide (46); this transformation was not accelerated by light.

s6

37 38

C . W . Thornber, J.C.S. Chem. Comm., 1973, 238. V. Galik and S. Landa, Coll. Czech. Chem. Comm.,1973, 38, 1101. E. Cuthbertson, A. D. U. Hardy, and D. D. MacNicol, J.C.S. Chem. Comm., 1973, 597.

256 Saturated Heterocyclic Chemistry The ring-opening of epoxides by nucleophilicattack of amines is well established; the analogous reaction with amides is less so. The utility of this procedure is illustrated3gin Scheme 1.

NHR

/ NHR

Reagents: i, SOCl,; ii, RNH,; iii, m-ClC,H,CO,H; iv, KOBut-ButOH; v, BnH6-THF

Scheme 1 Routes via Electron-deficientNitrogen Species. The Hofmann-Loffler-Freytag reaction has continued to provide satisfactory methods of synthesis for bridged systems. A new synthesis of 2,6-diaza-adamantanes (47) proceeds40from the readily available pseudopelletierine (48) via the bromo-amine (49) (Scheme 2).

rR2

R'N (49)

(47)

Scheme 2 3*

'*

R.J. Schultz, W. H. Staas, and L. A. Spurlock, J . Org. Chew., 1973,38,3091. R.-M. Dupeyre and A. Rassat, Tetrahedron Letters, 1973,2699.

Bridged Systems

257

DecompositionP1of thechloro-amine(50)gave a mixture of (51) and (52) (ratio 1 :4) in 96 % yieldin trifluoroacetic acid. However, in methanol (50) preferentiallygave(51).Clearlythesyntheticutilityof addition of chloro-aminesto activated olefins is considerable. A different mode of addition of amines to olefins proceeded photochemically. I r r a d i a t i ~ nof~ ~(53) gave by meta-cyclization the isomer (54) in unspecified yield. The use of nitroso-amines, an alternative

43

Ph(CH&NMez

(53).

1

(54)

to chloro-amines, in the development of bridged systemsa has been reviewed. Further details of the synthesis of 2-azabicyclo[2,2,2]0ctanes~by aluminium chloride-initiated rearrangement of dichloro-amines are now published. A novel route, which should be generally applicable, for the synthesis of 2azabicyclo[2,2,l]heptane~*~ is shown in Scheme 3. The intermediate tricyclic amine (55) is of low stability but the salt (56) is stable in the solid state.

(55)

(56)

Reagents: i, Pb(OAc),; ii, MeI; iii, KOAc-EtOH

Scheme 3

Cycloadditions. A limitation to the yield of bicyclic hydrazines obtained via cycloaddition of an azo-compound to a diene is frequently the efficiency of the hydrolytic cleavage to give the hydrazine. The problem has been avoided by R. Tadayoni, A. Heumann, R. Furstoss, and B. WaegeI1, Tetrahedron Letters, 1973, $2879. 4 2 D. Bryce-Smith, A. Gilbert, and G. Klunklin, J.C.S. Chem. Comm., 1973, 330. 4 3 Y . L. Chow, Accounts Chem. Res., 1973, 6 , 354. 4 4 R. D. Fisher, T. D. Bogard, and P. Kovacic, J. Amer. Chem. SOC.,1973,95, 3646. 4 5 P. S. Portoghese and D. T. Sepp, Tetrahedron, 1973,29,2253.

41

258

Saturated Heterocyclic Chemistry

Bridged Systems

259

use of dibenzyl azodicarboxylate. Reaction with cyclopentadiene followed by hydrogenolyticcleavage was reported to be quantitative!6 No rupture of the N-N bond was observed when a palladium catalyst was used. Improved methods of oxidation to the azoalkanes were also described. Addition of a triazolinedione to (57) gave both mono- and bis-adducts (Scheme 4). Some transformations4’ of these adducts are shown in Scheme 4a. The suggested hydrogen transfers (an intramolecular variation of a di-imide reduction) are noteworthy; the transfers correspond to the reduction of the carbon-carbon and nitrogen-nitrogen double bonds in the pathways to (58) O\

hydrolysis

ioxidat iollreducr ion

(58)

Scheme 4a (continued overleaf) 48 47

M. L. Heyman and J. P. Snyder, Tetrahedron Letters, 1973, 2859. M. Korat and D. Ginsburg, Tetrahedron, 1973,29,2373.

Saturated Heterocyclic Chemistry

260

H'

(59)

Scheme 4a (continued)

and (59) respectively. Related hydrogen transfers between two carbon-carbon double bonds in bridged systems have been reported.@The phototransformations suggest the intermediacy of biradicals. The thermal cycloaddition of thiadiazolinedione~~~ to cyclic dienes and further cycloadditions of triazolinediones to cyclopentadien~nes~~ are noted. Use of thiadiazolinediones affords another route to bridged hydrazines not involving a difficult hydrolysis but offers little advantage over the use of dibenzyl azodicarb~xylates.~~ Further examples of the use of Diels-Alder cycloadditions to introduce a single heteroatom into a bridged system are shown in Scheme 5 . The halogeno-imines (60) and (61)51and the iminourethane (62)52have sufficient stability to be used directly. Other iminourethanes were generated in situ by a BF3catalysed reaction with alkylidene bisurethanes. Addition to cyclohexa-l,3diene,53cyclohepta- 1,3-diene,54and cycloheptatrieneU gave bridged adducts &s bo

s1

K. Mackenzie, J . Chem. SOC.( C ) , 1969,1784. E. J. Corey and B. B. Snider, J . Org. Chem., 1973,38, 3632. W. Reid and S.-H. Lim, Annalen, 1973, 129. G. R. Krow, R. Rodebaugh, J. Marakowski, and K. C. Ramey, Tetrahedron Letters,

1973, 1899. T. Imagawa, K. Sisido, and M. Kawanisi, Bull. Chem. SOC.Japan, 1973, 46,2922. 6 8 G. R. Krow, R. Rodebaugh, R. Carmosin, W. Figures, H. Pannella, G. DeVicaris, and M. Grippi, J. Amer. Chem. SOC.,1973, 95, 5273. s4 G. R. Krow, R. Rodebaugh, M. Grippi, G. DeVicaris, C. Hyndman, and J. Marakowski, J. Org. Chem., 1973,38, 3094. Sa

Bridged Systems

261

“CCIB

J

n

Reagents: i, CF,CH=NTos (60); ii, CCI,CH=NTos iv, CHz=NCO*Et; v, MeCOCH=NCO&t; heptatriene

(1

(61); iii, CCI,CH=NCO,Et (62); vi, cyclohepta-1,3-diene; vii, cyclo-

Scheme 5

in low yield but cyclo-octa-l,3-diene54gave a product by an ene reaction. of the stereochemistry of the adducts led to the suggestion that there are substituent effects which influence the adduct formation, but product yields were too low to warrant any confident analysis. Paquette’s group has reported of its latest additions of chlorosulphonyl isocyanate (Scheme 6).56Associated work is discussed elsewhere (see ref. 85). Acid-catalysed dimerization5’ of the diazepine (63) gave an adduct (64)in 87% yield by a [4 21 cycloaddition in which an ‘enamine’ acted as the dienophile. The addition of cycloheptatriene to nitrosobenzene, giving the

+

66

G. Krow and R. Rodebaugh, Org. Magn. Resonance, 1973, 5,73. L.A. Paquette, M. J. Broadhurst, C. Lee, and 3. Clardy, J . Amer. Chem. Soc., 1973,

67

95,4647. B. Willig and J. Streith, Tetrahedron Letters, 1973, 4167.

262

Saturated Heterocyclic Chemistry

11 %

8%

53.5 %

5%

36 % Reagents: i, CISOzN=C =O--CH2CIZ-PhSH-C5H5N

Scheme 6

+

[6 21 adduct (65), has been reported.%Isoindole gave both e m - and endo-adducts with N-phenylmaleimide.59 Warrener et also have given extensive details of the use of [4 21 cycloadditions to sym-tetrazine to generate, inter aka, isobenzofulvenes.

+

Prinzbach and his groups1 have made extensive studies of the synthesis of 7-azanorbornadienes and of their transformation into 3-azaquadricyclanes (Scheme 7). 58 6o 61

S. Ito, S. Narita, and K. Endo, Bull. Chem. SOC.Japan, 1973, 46, 3517. R. Bonnett, R. F. C. Brown, and R. G. Smith, J.C.S.Perkin I , 1973, 1432. R. N. Warrener, J. A. Elix, and W. S. Wilson, Austral. J . Chem., 1973, 26, 389; P. L. Watson and R. N. Warrener, ibid. p. 1725. H. Prinzbach, G. Kaupp, R. Fuchs, M. Joyeux, R . Kitzing, and J. Markert, Chem. Ber., 1973, 106, 3824.

Bridged Systems

263

&2rR2 /R'

0

+RzCZCR2

-

/R'

@'

R' ' R 2

RS

Scheme 7

The range of dipolar additions of olefins to betaines has been extended by the observation that although the betaine (66) is unstable, it may be intercepted. Additions2 of styrene to (66) gave (67) in 50% yield. Both the stereospecificity and the lack of activation in the dipolarophile are noteworthy. Adducts of pyridynes with furans, e g . (68), have been reported.63

Witkop has previously shown that derivatives of N-chloroacetyltyramine undergo photoaddition to give bridged dimeric products. Convincing spectroscopic evidence recently p r e ~ e n t e dfrom , ~ ~ flash studies and isolation of adducts, shows the intermediacy of 2,4-cyclohexadienones, e.g. (69).

An elegant synthesis of pseudotropine (Scheme 8) proceeding65by cycloaddition of a nitrone was reported, although yields were not stated. N. Dennis, B. Ibrahim, A. R. Katritzky, and Y. Takeuchi, J.C.S. Chem. Comm.,1973, 292.

F. Marsais, G . Quequiner, and P. Pastour, Compt. rend., 1972,275, C, 1439. T. Iwakuma, 0.Yonemitsu, N. Kanamaru, K. Kimura, and B. Witkop, Angcw. Chum. Znternat. Edn., 1973, 12, 73. I5 J. J. Tufariello, and E. J. Trybulski, J.C.S. Chem. Comm., 1973, 720.

as

18

Saturated Heterocyclic Chemistry

264

Reagcnts: i , Zn-NH,CI-HCI; i i , A : iii, MeI; iv, LiAlHa

Scheme 8

MisceZZaireous Reactions. The synthesis of 2-azabicyclo[2,2,2]octanes53has led to their transformation66into 7-azabicyclo[3,2,l]oct-2-enes although in low yields (ca. 25%). The suggested intermediate, a cyclohexenyl cation, is shown in Scheme 9. In related photorearrangements 9-azabarbaraIanesG7 and azabullvaleness8were obtained (Scheme 10). Spectroscopic analysis showed

c -

NHC0,Et Scheme 9

Reagents: i, hv, Me,CO-Michler's ketone; ii, LiAlH,

Scheme 10 66 13' e8

G. R. Krow, R. Rodebaugh, C. Hyndman, R. Carmosin, and G. DeVicaris, Tetrahedron Letters, 1973, 2175. A. G. Anastassiou, A. E. Winston, and E. Reichmanis,J.C.S. Chern. Cornrn., 1973,779. G. R. Krow and J. Reilly, Tetrahedron Letters, 1973, 3075.

265

Bridged Systems

LJ

tl N

I

Scheme 11

the fluxional character of the barbaralanes and the preferred orientation of the dihydrobullvalenes. A series of 3-azabicyclo[3,3 ,l]nonanes has been preparedas (see Scheme 11) by addition of acrolein to enamines derived from piperidones (by a method well studied with cyclohexanones); the epimeric products were difficult to separate. An interesting approach to the construction of bridged systems has been reported by Hayward and Meth-Cohn'O and involves the use of the diamine (70) (Scheme 12). The spectra of the benzimidazolones suggest that for n < 7

// ArCHO

I

(71a)

*O

Scheme 12

(71b)

A. Z . Britten and J. O'Sullivan, Terrahedron, 1973, 29, 1331. R. J. Hayward and 0. Meth-Cohn, J.C.S. Chem. Comm., 1973, 427.

266

Saturated HeterocycIic Chemistry

the non-planar non-conjugated structure (71a) is important but for n > 7 the planar aromatic structure (71b) is adopted. Cyclizations of dihydrothiazine oxides to give, inter aka, (72)'l and (73)72 are noted. Ac

"

(72)

(73)

Reactivity.-Important synthetic studies by two Swiss groups, Ganter et al. and Heusler et al., merit considerable discussion. In addition to syntheses of various twistanes and adamantanes, they have also reported various transformations involving aza-adamantanes-a subject of developing interest.

Br

Tos N

G Br

TosN

4 (75)

Scheme 13 71 73

J. Kitchin and R. J. Stoodley, J.C.S. Perkin I, 1973, 22. J. Kitchin and R. J. Stoodley, J.C.S. Perkin I, 1973, 2464.

Bridged Systems 267 This section also includes consideration of a number of unrelated papers. The use of 1,5-cyclo-octadiene to give, by addition, functionalized 9heterobicyclo[3,3,l]nonanes has been noted previously. New routes based on this approach have been developed. The dienes (74) and (75) have been prepared ; although skeletal-rearrangement products might also have been expected they were not reported (Scheme 13). Subsequent e l a b ~ r a t i o n ' ~of* ~ ~ (74) and (75) by similar additions afforded the adamantanes (76) and (77).

BHHNa

0

(77)

(76)

Portmann and Ganter74*75 have made an extensive study of the functionalization of the dienes (74) and (75): spectra of derivatives have been interpreted and methods of conversion into (76) and (77) have been critically discussed. The reaction of the bisepoxide (78) with methylamine gave76diols (79) and (80),thus providing a route to isotwistanes and twistanes (Scheme 14). N

/

OH (79)

I

i , acetylation ii, pyrolysis

Et02C\

N

AcOHg

Scheme 14

The solvolysis of the amine (81) has been described earlier and recently the nature of the intermediates has been ~ l a r i f i e d . ~Solvolysis ~.~' proceeds as 73 74 75 76

77

H. Stetter and K. Heckel, Chem. Ber., 1973, 106, 339. R. E. Portmann and C. Ganter, Helv. Chirn. Acta, 1973,56, 1962. R. E. Portmann and C. Ganter, Helv. Chim. Acta, 1973, 56, 1986. R. E. Portmann and C. Ganter, Helu. Chim. Acra, 1973, 56, 1991. H. Teufel, E. F. Jenny, and K. Heusler, Tetrahedron Letters, 1973, 3413.

268

Saturated Heierocyclic Chemistry

shown in Scheme 15. A further case of solvolytic displacement to afford a twistane has been given7*in Scheme 16.

I \

(8 1)

McsoVOMe Scheme 15

---

-

\

H

Scheme 16

Ready availability of hexamethylenetetramine (82) has led to study of its degradation. Although acyclic products are obtained with phosphorus pentachl~ride,~~ degradation under controlled alkaline conditionss0leads to bicyclicamines.Themethod has been applieds1to tetra-azahomoadamantanes. The diaza-adamantanone (83) was transformed82by Wittig reaction into (84)

(83)

x=0

(84)

X

=

CH2

but spectroscopic properties were not reported. In view of the interesting interactions observedgin derivatives of (83) it would be of value to establish whether orbital interactions are also important between nitrogen and the double bond in (84). Stabilization of the 7-norbornenyl cation by interaction of the cationic centre with the double bond is well known. An earlier solvolytic study '13 'O

6o

S. Sicsic and N.-T. Luong-Thi, Tetrahedron Letters, 1973, 169. E. Fluck and P. Meiser, Chem. Ber., 1973, 106,69. H. Yoshida, G. Sen, and B. S. Thyagarajan, J. Heterocyclic Chem., 1973, 10, 725. J. B. Kang, G. Sen, and B. S. Thyagarajan, J . Heterocyclic Chem., 1973, 10, 439. J. Kuthan, J. Palecek, and L. Musil, Cull. Czech. Chem. Cornrn., 1973, 38, 3491.

Bridged Systems

269

indicated that the cation (85) was unstable, and recently the stabilities of (85) and (86) have beenestimateds3by CNDO calculations.Gassman and Hartmang4 have continued their studies of nitrenium ions and established an efficient method of generation from derivatives of NN-dialky1hydroxylamines with suitable leaving groups. Thus, benzoate (87) efficientlygives the nitrenium ion and hence (88) as a product. Although the decomposition of various azo-compounds is discussed elsewhereF5 some features of this process and of some cheletropic extrusions are noted here. The azo-compounds (89) and (90) were obtaineds6 by cycloaddition (Scheme 17). The em orientation of the small rings makes the loss

of nitrogen from (89) or (90) more difficultthan from endo-analogues where favourable overlap is possible. Nitroso-amines (9 1) and (92) were preparedg7 from the corresponding amines with nitrous acid, and the nitroso-amine (93) from hydrolysis of the cyanamide. Treatment of (91) or (93) with basic sodium 83 84

s6 87

W. W. Schoeller and M. E. Hendrick, Tetrahedon Letters, 1973, 2035. P. G. Gassman and G. D. Hartman, J. Amer. Chem. SOC.,1973, 95,449. J. M. Mellor in ‘Alicyclic Chemistry,’ ed. W. Parker (Specialist Periodical Reports), The Chemical Society, London, Vol. 3, 1975, Chap. 4. L. A. Paquette and M. J. Epstein, J. Amer. Chem. SOC.,1973, 95, 6717. A. G . Anastassiou and H. Yamamoto, J.C.S. Chem. Comm., 1973, 840.

270

Saturated Heterocyclic Chemistry

hydrosulphite led to efficient loss of nitrogen but this was not observed with (92). It was argueds7that the relative ease of loss of molecular nitrogen reflects a preference for a linear rather than a non-linear cheletropic reaction. The influence of other factors is as yet difficult to assess. Both dimethylketen and diphenylketen add to (10). In the case of diphenylketen88the adduct (94) was isolated. Treatment of (10) with silver Auoroborate and t-butyl iodide led to the formationsg of the salt ( 9 9 , and addition of tbutyl-lithium to (10) followed by quenching with ammonium chloride gave (96).

A mechanistic study suggests that although (96) can be autoxidized to give (97) the mechanism of this oxidation is probably via a hydrogen atom abstraction inan intermediate (98) rather than by the intermediacyof a diazenium cation. In rearrangement of (99) catalysed by ( +)-camphor-10-sulphonic acidw a very slight asymmetric induction was observed which led preferentially to

88 8'

uO

G.Brooks, M. A. Shah, and G. A. Taylor, J.C.S. Perkin I, 1973, 1297. S. F. Nelsen and R. T. Landis, J. Amer. Chew. SOC.,1973, 95, 2719. C. P. R. Jennison and D. Mackay, Tetrahedron, 1973, 29, 1255.

27 1

Bridged Systems

(100)

(99)

( -)-(loo) in chloroform. Adducts of cyclopentadienones, e.g. (101), rearranged readily. A rapid, reversible [3,3] sigmatropic rearrangement and an irreversible [1,3] sigmatropic rearrangements1 were both observed (Scheme 18).

Ph (101)

Scheme 18

Alkylation of scopolamine may be hindered by formation of amine salts by dehydrohalogenation. Alkylations in the presence of ethylene oxides2 proceed more efficiently. Although further alkylations in the tropane series have not been reported, studies of the benzylation of piperidiness3have emphasized the complexity of factors determining the stereochemistry of the products. Bellendine (102), a plant alkaloid, has been synthesizedg4from tropinone (Scheme 19).

(102) Me0 Rcagents: i . NaH-

\==<

;ii.

H~O+

Cot1

Scheme 19 O1 O3 93 94

D. Mackay, C. W. Pilger, and L. L. Wong, J . Org. Chem., 1973, 38,2043. A. Donetti and E. Bellora, Tetrahedron Letters, 1973, 3573. R. P. Duke, R. A. Y . Jones, and A. R. Katritzky, J.C.S. Perkin ZZ, 1973, 1553; J. R. Carruthers, W. Fedeli, F. Mazza, and A. Vaciago, ibid, p. 1558. I. R. C. Bick, J. B. Bremner, and J. W. Gillard, Tetrahedron Letters, 1973, 5099.

272 Saturated Heterocyclic Chemistry The olefinic quaternary salt (103) does not undergo the normal concerted [2,3]sigmatropic rearrangement; lack of reactivity has been attributed to the steric constraints imposed upon the concerted rearrangement. In contrast ,it has been reportedg5recently that rearrangement of (104) proceeds smoothly to give via the allene (105) the furan (106). It was concluded that rearrangement to the allene is not concerted; a further example was cited wherein (107) gave (108).

Br- CH,CH=CHPh

4 cryptates

Macropolycyclic ligands form stable complexes with many cations and these complexes are of great interest in a number of diverse areas. Recent progress has involved improvements in synthesis making more ligands available, crystallographic studies establishing structures of cryptates, and a number of most interesting studies hinting at possible biological implications and the use of cryptates as catalysts. Synthesis of polycyclic amides has been described using high-dilution techniques for the reaction of, for example, diamines with diacid chlorides. A rapid mixing technique, an alternative to high-dilution techniques, has been described. For the synthesis of macrocyclic systemsgsnot only must mixing be rapid and thorough and the initial condensation substantially complete during the flow time, but the cyclization steps must be sufficiently fast to compete with intermolecular reaction. If these criteria are satisfied, the process will have considerable generality. 95

W. D. Ollis, I. 0. Sutherland, and Y . Thebtaranonth, J.C.S. Chem. Comm., 1973,657. J. L. Dye, M. T. Lok, F. J. Tehan, J. M. Ceraso, and K. J. Voorhees, J . Org. Chem., 1973, 38, 1773.

Bridged Systems 273 The Strasbourg group has now defined some of its objectives in its extensive studies of cryptates and given full experimental detailsg7for thesynthesisof the amines (109)-(114); the topology of these amines with an account of nitrogen (109) m (110)m (111)m (112) rn

=.O, n = 1 = 1,n = 0 =n = 1 = 1,n = 2

inversion are described. Further studies are required before the full picture of the interaction of nitrogen inversion with other conformational processes can be assessed. A report has appearedg8on the formation of cryptates having an alkali-metal cation or alkaline earth metal cation in the cavity. There is greater rigidity in the cryptates and nitrogen inversion is less important because a conformation is adopted (endo-endo) which permits amine stabilization of the complex. Crystallographic studies have been reported for the cryptates of potassium iodideg9with (1 1 l), rubidium thiocyanateloO with (1 1 l), caesium thiocyanatelOO with (1 1 l), sodium iodidelo1with (1 1 l), lithium iodidelo2with (1 lo), cobalt(1r) thiocyanatelo3with (110), and silver nitratela with (115).

(115)

The reversible exchange of sodium cations between the cavity of (1 11) and a solution of ethylenediamine has been followed105by 23Na n.m.r. The efficient complex formation of (111) with sodium ion or potassium ion has permitted the generationlo6of highly basic solutions. Thus methyl mesitoate B. Dietrich, J. M. Lehn, J. P. Sauvage, and J. Blanzat, Tetrahedron, 1973,29, 1629. B. Dietrich, J. M. Lehn, and J. P. Sauvage, Tetrahedron, 1973,29,1647;J.C.S. Chem. Comm., 1973, 15. sg D. Moras, B. Metz, and R. Weiss, Acru Cryst., 1973, B29, 383. loo D. Moras, B. Metz, and R. Weiss, Actu Cryst., 1973,B29, 388. lol D. Moras and R. Weiss, Actu Cryst., 1973,B29, 396. lo* D. Moras and R. Weiss, Actu Cryst., 1973,B29, 400. lo3F. Mathieu and R . Weiss, J.C.S. Chem. Comm., 1973,816. lo4 R. West and R. Weiss, J.C.S. Chem. Comm., 1973,678. lo5 J. M. Ceraso and J. L. Dye, J . Amer. Chem. Soc., 1973,95,4432. l o 6 B. Dietrich and J. M. Lehn, Tetrahedron Letters, 1973, 1225. 87 98

274 Saturated Heterocyclic Chemistry was hydrolysed (70% at 25OC) by potassium hydroxide in toluene in the presence of (111). Anions of fluorene,diphenylmethane,etc. may be generated under similar conditions. The amines described above all form cryptate complexes with metal cations. An interesting development has been the synthesis of a series of tri- and tetra-cyclic amines,lo7 which not only form cryptate complexes but have sufficiently large cavities to be capable of forming molecular inclusion complexes. In preliminary studieslo8it has been established that molecular complexes are formed, but discrimination between association complexes and complexes with the host molecule actually inside the cavity has not yet been made. 5 Oxygen Compounds

Discussion is divided into two sections, one concerning synthesis by cycloaddition and the chemistry of the adducts and a second devoted mainly to the chemistry of products derived from nucleophilic attack by oxygen. Synthesis by Cyc1oaddition.-The formation of 7-0xabicyclo[2,2,1Inonenes by Diels-Alder addition is well established. An excellent review of the analogous addition of ally1cations generatingseven-memberedringslogis available, and details of the addition of the 2-methoxyalIy1cation to furadlohave been given. The related mode of cycloaddition of a,a'-dibromo-ketones to dienes in the presence of iron carbonyls has been usedlll to generate similar bicyclic adducts (Scheme 20). Tricyclic systems may also be produced efficiently from 0

96 %

Scheme 20

dihalogeno-cycloalkanones.Hydrogenation of the adducts followed by acidcatalysed cleavage of the ether bridge112 afforded a route to troponoids; with cyclododecanone (116) the bridge is sufficiently large to permit formation of (117) (Scheme 21). lo'

J. M. Lehn, J. Simon, and J. Wagner, Angew. Chem. Internat. Edn., 1973, 12, 578. M. Lehn, J. Simon, and J. Wagner, Aitgew. Chem. Internat. Edn., 1973,12, 579; M . Mellinger, J. Fischer, and R. Weiss, ibid., p. 771. H. hl. R. Hoffmann, Angew. Chem. Internat. Edn., 1973, 12, 819. A. E. Hill, G. Greenwood, and H. M. R. Hoffmann, J. Amer. Chem. SOC.,1973, 95, 1338. R. Noyori, Y.Baba, S. Makino, and H. Takaya, Tetrahedron Letters, 1973, 1741. R. Noyori, S. Makino, and H. Takaya, Tetrahedron Letters, 1973, 1745.

lo8J.

log 110 ll1

Il2

Bridged Systems

275

Reagents: H,-Pd/C; ii, BF,-Ac,O; iii, AI,O,; iv, NBS; v, LiCI-Li,CO,

Scheme 21

To probe the energy requirements of systems constrained towards having planar tetrahedral carbon atoms Helder and Wynberg1lS examined the addition of dicyanoacetylene to bridged furans. The adduct (118)wasobtained

(118,)

(118b)

and it was suggested that the saturated chain is capable of considerable conformational mobility. Adducts of furans were also reported with 1,2-dicyanoc y c l o b ~ t e n eand l ~ ~ with dimethylacetylenedi~arboxylate>~~ In the latter case the initial 1:1 adduct upon further treatment with furan gave 2: 1 adducts the nature of which were reported to be dependent on temperature and on the 113 11* 115

R. Helder and H. Wynberg, Tetrahedron Letters, 1973, 4321. D. Bellus, K. von Bredow, H. Sauter, and C. D. Weis, Helv. Chim. Acta, 1973, 56, 3004. A. W. McCulloch, D. G . Smith, and A. G . McInnes, Cunad. J . Chem., 1973,51,4125.

276

Saturated Heterocyclic Chemistry

Lewis acid catalysts present. The 1 :1 adduct (119) on either direct or acetonesensitized excitation gavells fulvene (120). Further details have been given117 of the rhodium-catalysed rearrangement of analogues of (1 19) to hydroxyfulvenes. The thermodynamic instability of endo-adducts of furan has led to difficulty in their isolation. The reactions of the endo-adduct (121) obtained fromthediacid (122),118and the dimerization of a furan by [4 21 addition1l9 to give (123), have been reported. In the irradiation of 2-isopropenylbenzophenone120trapping studies have supplemented flash photolytic evidence for the intermediacy of o-quinodimethane intermediates; adduct (124) has been

+

D.Stusche and H. Prinzbach, Chem. Ber., 1973, 106, 3817. H.Hogeveen and T. B. Middelkoop, Tetrahedron Letters, 1973,4325. 118 T . A. Eggelte, H. De Koning, and H. 0. Huisman, Tetrahedron, 1973,29,2445,2491. 119 J. L.Isidor, M. S. Brookhart, and R. L. McKee, J. Org. Chern., 1973, 38,612. lao A. K.C.Chu and M. F. Tchir, J.C.S. Chem. Comm., 1973,619. ll8

11'

Bridged Systems 277 trapped. An interesting application of the furan adducts to the stereospecific synthesis of carbohydrates involving transformations of (125) has been reported.121 Intramolecular cycloaddition of (126) afforded122the tricyclic ketone (127), but it has now been reported that the photocycloaddition of (128) generates (129) rather than (130). On heating123(131) rearranges stereospecifically to (1 32).

n =2or3 ’(128)

(130)

(129) 0

(131)

(132)

Miscellaneous Syntheses.-The extensive work by Ganter and his group on the synthesis of oxa-adamantanes and o x a t w i s t a n e ~has ~ ~ already ~ ~ ~ been noted and in a preliminary account of these studies syntheses124of (133) and (134) were described. Much of this work is based on syntheses from cycloocta-l&diene and a further route from this diene has been developed125to

121 121 123

12* 125

G . Just and A. Martel, Tetrahedron Letters, 1973, 1517. Y.Tamura, H. Ishibashi, Y.Kita, and M. Ikeda, J.C.S. Chem. Comm., 1973, 101. A. G. Anastassiou and E. Reichmanis, J. Org. Chem., 1973, 38, 2421. P. Ackermann and C. Ganter, Helv. Chim. Acta, 1973, 56, 3054. C. B. Quinn and J. R. Wiseman, J. Amer. Chem. Soc., 1973, 95, 1342.

Saturated Heterocyclic Chemistry

278

d 111

1

__+

OiSMe

HO Reagents: i, CrO,; ii, MeS0,Cl-Et,N;

(135)

iii, KOBut-ButO€I

Scheme 22

the 9-oxabicyclo[3,3,1]non-l-ene(135) (Scheme 22). Quinn and Wiseman have related the reactivity of (135) to that of other brigehead olefins. It is not exceptionally reactive, e.g. t1/2with acetic acid at 25 "C is 68 h. Rate studies of the solvolysis of 1-chloro-9-oxabicyclo[3,3,llnonane have suggested that some stabilization of the cation by oxygen is possible. Synthesis of oxa-adamantanes by cyclization of derivatives of bicyclo[3,3,l]nonane is well established. New reactions of bicyclo [3,3,llnonane3,7-di0nel~~ are shown in Scheme 23. Bicyclo[3,3,l]nonane-2,6-diol(136) in

OH

Scheme 23

concentrated sulphuric acid gavel2' 2-oxa-adamantane (137). Lithium aluminium hydride reduction128of (138), obtained from adamantan-1-01by the previously described lead tetra-acetate oxidation, gave the oxahomoadamantane (139). Although tetrahydrofurans and tetrahydropyrans are stable to reductive conditions, further strain as in polycyclic oxetans leads to enhanced reactivity. lZ7 lZ8

R. Yamaguchi, K. H. Yang, and M. Kawanisi, Bull. Chem. SOC.Japan, 1973,46,673. N. V. Averina and N. S . Zefirov, J.C.S. Chem. Comm., 1973, 197. R. Durand and P. Geneste, Compt. rend,, 1973, 277, C, 1051.

Bridged Systems

279

'0 H (136)

This is demonstrated by some of the reported transformation~l~~ shown in Scheme 24.

(b-,k,+ci, HO

Ph

0

HO

75 %

25 "/o

CH*OH

80 7; Reagents: i, H,-Ni; ii, Li-(CH,NH,),; iii, AIH,

Scheme 24

Ether formation, proceeding by addition to double bonds, has been reported in diverse cases (Scheme 25). Further transf~rmationsl~~ of cyclopentenones to give cyclic ethers have been noted. The loss of the methylene group to give (140) probably proceeds via the biradical (141). lag

R. R. Sauers, W. Schinski, M. M. Mason, E. O'Hara, and B. Byrne, J . Org. Chern., 1973, 38, 642.

280

Saturated Heterocyclic Chemistry

o'cF1zoNo+ B

Ref. 130

0

0

1

Ref. 130

Ref. 130

0

1

X#. 130

Ref. 131

0.

NaBH4-EtOH

Ref. 132

CH~OTS Na OH-MeOH

+&'

Me0

0-

O M g

o e*.

0--

Rrf. 132

Scheme 25 131

R. Nouguier and J.-M. Surzur, Bull. SOC.chim. France, 1973, 2399. P. Calinaud, J. Gelas, and S. Veyssieres-Rambaud, Bull. SOC.chim. France, 1973,

13a

H.-R. Kruger, H. Marschall, P. Weyerstahl, and F. Nerdel, Chem. Ber., 1973, 106,

lSo

2769.

2255. 133

S. Wolff and W. C. Agosta, J.C.S. Chem. Comm., 1973,502.

Bridged Systems

4

28 1

hv,PhH +

CHBOMe

6 Sulphur Compounds

Discussion in this section, as with oxygen compounds, is divided into two parts, one concerning synthesis by cycloaddition and the chemistry of the adducts and a second devoted mainly to the products of sulphur dichloride addition to olefins and to products derived from nucleophilic attack by sulphur . Synthesis by Cyc1oaddition.-Thiophosgene is known to add to cyclopentadiene. Reaction has now been extended to cyclohexa-l,3-diene, and the adduct has been reduced with lithium aluminium hydride to give (142).la Di-imide reduction of (142) gave (143), which was found to be different from the compound obtained after irradiation of the mercaptan (144). The previous report that photo-reaction of (144) gives (143) is incorrect; the product is (145). Structural assignments have been backed by 13C n.m.r. data.ls4

(142)

(143)

144)

(145)

+

Although cycloheptatriene reacted with nitrosobenzene to give a [6 21 cycloadduct,58 thiobenzophenone gave135a single [4 21 cycloadduct (146).

+

134

H. J. Reich and J. E. Trend, J. Org. Chem., 1973, 38, 2637.

135

Y.Ohnishi, Y.Akasaki, and A. Ohno, Bull. Chem. SOC.Japan, 1973, 46, 3307.

Saturhted Heterocyclic Chemistry

282

(146)

Stable adducts were obtained136J37 by addition of acetylenes to a-thiopyran 1 ,l-dioxides (Scheme 26). However, (147) decomposed136at 220 O C by two

COcMe

\ CO2Me

(147)

Scheme 26

independent pathways, to give dimethyl phthalate by loss of sulphene, and cycloheptatrienes by cheletropic loss of sulphur dioxide. A further route to cycloheptatrienes via the addition of cyclopropenes to thiophen 1,l-dioxides has been reported (Scheme 27).la A careful of the modes of

Scheme 27 136 13' 138

139

N. H. Fischer and H.-N. Lin, J. Org. Chem., 1973, 38, 3073. J. F. King and E. G. Lewars, Cunud. J . Chem., 1973, 51, 3044. D. N. Reinhoudt, P. Smael, W. J. M. van Tilborg, and J. P. Visser, Tetrahedron Letters, 1973, 3755. P. Chao and D. M. Lemal, J . Amer. Chem. SOC.,1973, 95, 920.

283

Bridged Systems

(148)

cycloaddition of sulphur monoxide to dienes has shown that addition to cyclo-octa-l,3-diene gives only the sulphoxide (148). Miscellaneous Syntheses.-The chemistry of the sulphur dichloride adduct of norbornadiene has been examined.140Substitutions via cationic intermediates proceed with sulphur participation and retention of stereochemistry.Reaction via carbanions or radicals proceeds with rearrangement (Scheme 28). Sulphur

‘S

SMe

Reagents: i, Zn-HOAc; ii, Cr(OAc)z;iii, BusSnH; iv, A1H3-6M-NaCN; v, LiCuMea

Scheme 28

participation has again been observed in the dehydrochlorination of (149) in ~ o l l i d i n eto l ~ give ~ (150) [and not (151) as reported in the Patent literature]. 140 141

S. D. Ziman and B. M. Trost, J . Org. Chem., 1973,38, 649. P. H. McCabe and C. M. Livingston, TetrahedronLetters, 1973, 3029.

284

Saturated Heterocyclic Chemistry S

S

s

(149)

(150)

(151)

Following Wiseman’s synthesis of 9-oxabicyclo[3,3 ,l]non-l-ene (135) it was to be expected that attentionwould turn to the synthesisand a study of the properties of the sulphur analogue (152). Synthesis142of this compound proceeded from the known hemiacetal (153) (Scheme 29). The vinyl sulphide

(153)

(60 7;)

(45 %)

Reagents: i, H,S; ii, Me,SO,CI-Et,N;

(65 %I

iii, KOBut

Scheme 29

(152) shows an absence of conjugative interaction in the U.V. spectrum but forms an adduct with 1,3-diphenylisobenzofuran.It is stable at room temperature. This work has been beautifully complemented by a of the sulphones. Treatment of the chlorosulphone (154) with base in the presence of 1,3-diphenylisobenzofurangave two Diels-Alder adducts ; under similar conditions the bromosulphone (155) gave a single adduct. Careful chemical and X-ray analysis of a Diels-Alder adduct led to the fascinating conclusion that two isomers of the olefin (156) exist [the 2-form (156a) and the E-form (156b)I and these are separated by a sufficiently high energy barrier to permit trapping of both types of olefin by the isobenzofuran. The much more reactive E-form gives two adducts by indiscriminate reaction but the 2-form gives a single adduct.

C. B. Quinn and J. R. Wiseman, J . Amer. Chem. SOC.,1973, 95, 6120. C. B. Quinn, J. R. Wiseman, and J. C. Calabrese,J. Amer. Chem. SOC.,1973,95,6121.

Bridged Systems

285

(1 56a)

(156b)

Sulphones (157)-(161) all dianions on treatment with n-butyllithium. However, the dianions derived from (160) and (161) were strongly coloured. In each case, the removal of two protons can be considered to generate two lone-pairs which may be considered as n, and n, combinations. Although symmetry requirements preclude substantial interaction between these lone-pair combinations and the mystems, low-energy n -+ T* transitions arepossible. The colour in anions of (160) and (161) has been attributed to such an effectand this has been substantiated by the low E values associated with these transitions and by Huckel calculations.

Full details have been published of the synthesis145of the sulphides (162) and (163) by the reaction of sodium sulphide with the epoxides (164) and

n ( 162) 144

145

4

(163)

L. A. Paquette, R. H. Meisinger, and R. Gleiter, J. Amer. Chem. SOC.,1973,95,5414. C.R. Johnson and W. D. Kingsbury, J . Org. Chem., 1973,38, 1803

Saturated Heterocyclic Chemistry

286

CHzOBs

CHZOBS (164)

(165)

(165). Transformations of (162) and (163) by oxidation are noted. Treatment of (166) with acetic anhydride-sulphuric acid under vigorous conditions gave146(167) and (168) in addition to the enol acetates.

7 Miscellaneous Compounds

Cycloaddition reactions of phospholes are exemplified by addition to tropone147to give (169) and (170) and the self-dimerization of phospholium e.g. to give (171).

(169)

(170)

(171)

The detailed study by Turnblom and Katz of the synthesis and reactivity of bridged alkylphosphoranes has now been fully reported149 (for earlier accounts see ref. 1 , p. 541, and ref. 2, p. 389). The factors which act to stabilizethe quinquevalent phosphoranes have been established and thermal and photo-transformations are described. 146

14' 148 149

P. H. McCabe and W. Routledge, Tetrahedron Letters, 1973, 3919. Y. Kashman and 0. Awerbouch, Tetrahedron, 1973, 29, 191. L. D. Quin, S. G. Borleske, and J. F. Engel, J. Org. Chem., 1973, 38, 1954. E. W. Turnblom and T. J. Katz, J . Amer. Chem. SOC., 1973, 95,4292.

Bridged Systems 287 Further novel carbo~ilanesl~~ have been prepared. In addition to the silaadamantanes previously isolated from the pyrolysis products of tetramethylsilane several new ‘silascaphanes’,e.g. (172), which have boat structures, have been obtained. Pyrolytic eliminations of 7-silanorbornadienes have been further examined and also the hydrolysis151of (173), which was found to lead to (174). Cycloadditionshave been reported152for a number of silacyclopenta-

Ph

dienes. In view of recent X-ray studies which have revealed incorrect assignments made to structures of other [4 21 adducts of silacyclopentadienes it should be noted that the present structural assignments are based on n.m.r. studies. The adduct (175) was prepared153by cycloaddition; thermolysis suggested the transient formation of (176).

+

Et,

,Et Ge

&

HB

l-B~ra-adamantanel~~ and polyb~ra-adamantanesl~~ have been prepared. The X-ray structure156of 9-borabicyclo[3,3,1]nonane (177) has been determined and further details of the p r e p a r a t i ~ nof l ~ (177) ~ and its use158in the exceptionally regiospecific addition to olefins have been described. G. Fritz, G. Marquardt, and H. Scheer, Angew. Chem. Znternat. Edn., 1973, 12, 654; G. Fritz, H. J. Dannappel, and E. Matera, 2.anorg. Chem., 1973, 399, 263. lS1 R. Maruca, R. Fischer, L. Roseman, and A. Gehring, J. Organometallic Chem., 1973, 49, 139. laaR. Balasubramanian and M. V. George, Tetrahedron, 1973, 29, 2395. T. J. Barton, E. A. Kline, and P. hl. Garvey, J. Amer. Chem. SOC., 1973, 95, 3078. 154 B. M. Mikhailov andV.N. Smirnov, Izoest. Akad. NaukS.S.S.R.,Ser.khim.,1973,2165. 155 M. P. Brown, A. K. Holliday, and G . M. Way, J.C.S. Chem. Comm., 1973, 532. lS8 D. J. Brauer and C. Kruger, Acta Cryst., 1973, B29, 1684. 15’ C.Pinazzi, J. Vassort, and D. Reyx, Bull. SOC.chim. France, 1973, 1656. 15* C. G. Scouten and H. C. Brown, J. Org. Chem., 1973, 38, 4092; P. L. Burke, E. Negishi, and H. C. Brown, J . Amer. Chem. SOC..1973,95, 3654. 150

20

Author Index

Abdulla, R. F., 242 Abe, K., 171 Abegg, V. P., 113 Aberhart, D. J., 102 Abraham, E. P., 101 Abrahamson, E. W., 96 Achenbach, H., 183 Acheson, R. M., 208 Ackermann, P., 277 Adam, W., 177,184 Adickes, H. W., 240 Adlam, B., 157 Advani, B. G., 220 Ahlgren, G., 126, 172 Ahmad, Q., 194 Ager, I., 135 Agosta, W. C., 280 Agranat, I., 125 Ahmad, Q., 194 Aigner, H., 247 Akasaki, Y., 281 Akhmedov, I., M., 27 Akhundova, P. B., 27 Akiyama, T., 202 Akhtar, M. H., 115, 217, 218 Akrem, A. A,, 197,210 Alam, M. N., 208 Albrand, J. P., 152 Aleksandrov, A. M., 48 Aleksandrova, V. A., 72 Alekseeva, L. A., 48 Alford, J. A., 117 Ali, M. McM., 202 Allan, R. D., 135 Altenbach, H. J., 25 Altona, C., 141 Altwicker, E. R., 179 Amick, D., 172 Ammon, H. L., 106 Anastassiou, A. G., 8,264, 269,277 Anderson, A. G., jun., 49 Anderson, J. E., 150 Anderson, R. J., 51 Anderson, W. K., 10 Ando, J., 137 Andronov, V. N., 72 Anghelova, Y., 183

Antal, E., 184 Anteunis-De-Ketelaere, F., 139 Anteunis, M., 139, 142, 143, 180 Antharjanam, T. G. B., 16 Antipova, I. V., 188 Ao, H., 236,241 Ao, M. S., 240 Applegate, H. E., 133, 134 Arai, I., 201 Arai, T., 137 Arata, Y., 222 Araujo, H. C., 206 Arimura, K., 241 Arison, B. H., 218 Arita, K., 252 Arnot, H. C., 175 Arnett, J. F., 200 Arth, G. E., 134 Asabe, Y., 185 Asinger, F., 225 Astolfi, L., 141 Astrup, E. E., 144 Atala, S., 235 Atauin, A. S., 178 Atkins, G. M., 2 Atkins, R. L., 83, 146,223 Attia, A,, 206 Aubagnac, J. L., 197 Aubry, A., 253 Aue, D. H., 84, 107, 115 Autera, J. R., 151, 251 Avakyan, V. G., 72 Averina, N. V., 278 Avetsyan, L. S., 181 Avril, J. L., 185 Awerbouch, O., 286 Axenrod, T., 151, 251 Ayras, P., 143 Azawa, N., 192 Azzaro, M., 55, 153 Baba, Y., 274 Babayan, A. T., 168 Baboir, B. M., 223 Badanyan, S. O., 171 Badderly, G., 139 Bailey, P. S., 117, 179

288

Baird, N. C.. 213, 251 Balasubramanian, K. K., 193 Balasubramanian, R., 287 Baldwin, J. E., 101, 134 Balepin, A. A,, 23 Balykina, L. V., 26 Bandlish, B. K., 224 Banks, R. E., 217,242 Barbarella, G., 154, 155 Barbaro, G., 161 Bardos, T. J., 70 Barfknecht, C. F., 204 Barker, C. C., 155 Barluenga, J., 205 Barnes, R. K., 177 Barone, B., 177 Barot, N. R., 221 Barr, P. A., 58 Barrans, J., 237 Barsotti, D. J., 118 Bartfeld, H. D., 192 Bartlett, P. D., 136, 137 Barton, D. H. R., 92, 125, 135 Barton, T. J., 287 Basila J., 179 Bast, K., 162 Bastian, I. M., 21 Bastide, J., 158 Battisti, A., 254 Baty, J. D., 219 Bauer, L., 216 Baues, M., 245 Baum, A. A., 229 Baumstark, A. L., 136,137 Bear, C. A., 207 Beare, S., 172 Beck, J. L., 218 Beck, W., 72 Becker, H. D., 24 Becu, C., 139 Beetz, T., 212 Beiner, J. M., 73, 74 Bekarek, V., 242 Bekki, K., 252 Bellora, E., 271 Bellus, D., 275 Belly, A., 227

Author Index Belyaev, V. F., 31 Belzecki, C., 244 Bender, D. R., 112, 193 Benedek, E., 209 Benezra, C., 251 Ben-Ishai, D., 132 Benjamin, B. M., 153 Bentrude, W. G., 154 Benz, F. W., 146 Berezovskii, V. V., 5 Berger, M. H., 175 Bergesen, K., 152 Berg-Nielsen, K., 145 Bergounhou, C., 153 Berlin, D. K., 53 Bernath, G., 149 Beroza, M., 11 Bertrand, M. P., 170 Bezmenova, T. E., 48 Bhandari, K. S., 99 Bhatti, A. K., 142 Bianchi, G., 161, 162 Bick, I. R. C., 271 Birch, A. J., 198 Bird, P. G., 128 Bius, D. L., 200 Bjeldanes, L. F., 112, 193 Bjoroey, M., 152 Black, D. St.C., 87,89,90, 115,159,189,191

Blackburn, M. G., 128 Blackburne, I. D., 146 Blaha, K., 218, 219 Blaha, L., 27 Blake, K. W., 220 Blank, B., 189 Blosick, G. J., 63, 198 Blossey, E., 121 Bobolev, A. V., 23 Bock, K., 142 Bock, W., 86 Bodkin, C. L., 153 Boeden, H. F., 23 Boelens, H., 176 Bogard, T. D., 257 Bognar, R., 28 Bohen, J. M., 110 Bohlmann, F., 211 Bohme, E. H. W., 133 Bohme, H., 222 Boicelli, A., 155 Boiko, I. P., 239 Boisdon, M. T., 237 Boitsov, E. N., 223 Bolivar, R. A., 96 Boll, P. M., 176 Bolton, M., 125 Bonini, B. F., 80 Bonita, B. P.,5 Bonnett, R., 191, 262 Booth, H., 148, 146, 184 Borgna, J. L., 49

289 Borleske, S. G., 151, 286 Bormann, D., 70,205 Borremans, F., 139 Bory, S., 156 Bos, H. J. T., 178 Bose, A. K., 104, 105, 133 Bosin, T. B., 215 Bottini, A. T., 182, 185 Bouisset, M. M., 156 Boussard, G., 190 Bower, J. D., 97 Boyce, C. B., 236 Boyd, R. J., 250 Boyko, E. R., 221 Braden, R., 122 Bradley, C. H., 101 Bradshaw, T. K., 253 Brady, W. T., 122 Braekman, J. C., 254 Brandman, H. A., 238 Brauer, D. J., 287 Braun, H., 15 Bredereek, H., 200 Bremholt, T., 24 Bremner, J. B., 271 Brettle, R., 140 Breuer, E., 144 Bricout, D., 167 Brill, W. F., 177 Britten, A. Z., 207, 265 Britton, W. E., 87 Broadhurst, M. J., 107, 108, 109,261

Brockmann, H., 191 Brodsky, L., 2 Brookhart, M. S., 276 Brooks, G., 118,270 Brooks, J. R., 210 Brown, C. A., 186 Brown, H. C., 48, 51, 161, 187,287

Brown, J. N., 224 Brown, M. P., 287 Brown, R. E., 97 Brown, R. F. C., 191, 262 Brown, R. K., 182 Brugel, W., 224 Bruntrup, G., 162 Brunwin, D. M., 132 Bryantsev, B. I., 189 Bryce-Smith, D., 257 Bryson, T. A., 171 Bubel, 0. N., 34 Buchanan, G. W., 157 Buchi, G., 176 Budesinsky, M., 218 Bulusu, S., 151, 251 Bunzli, J. C., 249, 250 Burger, K., 84, 163 Burgess, E. M., 222 Burke, P. L., 287 Burkhard, J., 215

Burns, P. A., 121, 167 Burzin, K., 245 Busch, A., 201 Buschek, J. M., 150, 251 Bushick R. D., 181 Buskine, S. A., 204 Buslaev, Yu. A., 23 Butler, G. B., 201 Byashimov, K., 79 Bychkova, G. S., 34 Byrne, B., 127, 279 Bystrova, I. B., 214 Cabre, M. F., 189 Caccia, C., 230 Caddy, D. E., 147 Caglioti, L., 166 Cahill, R., 148 Calabrese, J. C., 284 Caldwell, R. A., 97 Calinaud, P., 280 Calli, L., 122 Cama, L. D., 135 Cambieri, M., 141 Cameraman, A., 154 Cameraman, N., 154 Camp, R. L., 113 Campaigne, E., 21 Cannie, J., 233 Cantrell, T. S., 97, 124 Capiomont, A., 252 Caple, R., 252 Capuano, L., 100,194,215 Carr, R. W., 194 Carless, H. A. J., 96 Carlson, E. H., 92 Carlson, P. A., 217 Carlson, R. G., 45 Carlson, R. M., 39, 176 Carmosin, R.,260, 264 Carnahan, E., 136 Carter, T. P., 117, 179 Carrie, R., 63,68,101,145, 160, 163

Carruthers, J. R., 147, 271 Casadevall, E., 156 Casanova, T. G., 229 Castisella, B., 23 Castle, R. N., 211 Castro, B., 95 Casy, A. F., 147, 148 Cavanaugh, R. J., 2 Cazaux, L., 142 Ceder, O., 199 Cellerino, G., 246 Ceppi, E., 254 Ceraso, J. M., 272, 273 Cerveny, L., 23 Cervinka, O., 59 Chaabouni, R., 61, 62 Chagin, V. I., 23 Chaloupka, S., 165

290 Chan, A. W. K., 176 Crabb, T. A., 144,146,141 Chao, P., 282 Craig, R. L., 253 Chapman, 0. L., 125 Crandall, J. K., 2, 60, 99 Chapuis, C., 197 165 Chasle-Pommeret, M. F., Crawford, R. J., 173 191 Cristl, M., 158, 162, 163 Chauhan, M. S., 167 Cromwell, N. H., 51, 100 Chawla, H. P. S., 105 132, 219 Chekulaeva, I. A., 214 Csizmadia, I. G., 138 Chen, C. G., 103 Cullen, W. R., 207 Chen, C. H., 185 Culp, F. B., 103, 194, 195 Chen, F. M. F., 236 Cusmano, G., 161 Chen, F. T., 213 Cuthbertson, E., 255 Cherry, A., 94 Chertov, G. S., 34 Dahlman, J., 23 Chib, J. S., 104 Dahn, H., 163 Chien, C. C., 157 Daloze, D., 254 Chittenden, M. L., 13 Dalton, J. C., 98 Chivers, P. J., 146 Daly, T. W., 1 Chlenov, I. E., 160, 239 Dammeyer R., 179 Chow, Y. L., 257 Danion, D., 63, 68, 101 Christensen, B. G., 104, Danion-Bougot, R., 63, 134, 135 68, 101, 145 Chu, A. K. C., 276 Dannappel, H. J., 287 Chu, C., 229 Dardoize, F., 100 Chuaqui, C., 235 Das, K. G., 254 Chuche, J., 174 Dastur, K. P., 198 Ciurdaru, G., 110 Daubert, R. G., 188 Claes, P., 130 Dave, V., 1 16 Clardy, J., 109, 261 Davidson, J. A., 96 Clay, R. M., 141 Davies, M. M., 229, 239 Clive, D. L., 41 Davis, G. A., 97 Clough, S. C., 213 Davis, R. I., 189 Coates, I. H., 135 Day, A. C., 118 Coates, R. M., 15 Dayal, B., 105 Cocks, A. T., 174 Deak, G., 53 Colebrook, L. D., 145 Dean, F. M., 167 Collins, C.J., 159 Deavenport, D. L., 230 Columbo, G., 169 De Boer, A., 141, 175 Combret, J. C., 20 Decouzon, M., 55 Conley, R. T., 238 De Kimpe, N., 228 Connor, J., 247 Dekkers, A. W. J. D., 250 Conover, W. W., 2, 60, 99, De Kok, A. J., 141 165 De Koning, H., 203, 276 Conrad, R. A., 19 de la Cruz, D., 125 Consonni, P., 100 de la Higuera, N., 101 Cook, D. C., 235 Deleux, J. P., 194 Cook, M. J., 151, 157 Della, E. W., 253 Cook, M. M., 204 je Maria, P., 166 Cooper, C. M., 135 De Mayo, P., 251 Cooper, R. D. G., 92, 134 Demole, E., 6, 176 Coppola, G. M., 247 Demoute, J. P., 9 Corcoran, G. B., tert., 63, D’Engenieres, M. D., 185 198 Denney, D. B., 133 Corey, E. J., 178, 260 Dennis, N., 263 Correle, J., 242 Denyer, C. V., 41 Coryn, M., 143 3e Pasquale, R. J., 47 Cotton, W. D., 173 le Pava, 0. V., 162 Couturier, D., 57 De Rijke, D., 176 Coward, J. K., 239 Desimoni, G., 141, 169, Coxon, J. M., 30, 31, 170 246 Coy, D. H., 120 De Smet, A,, 180

Author Index de Sousa Gomes, A., 106 Despreaux, C. W., 209 De, U. A., 188 Dev, V., 182 De Vicaris, G., 260, 264 Dharan, M., 116, 164,254 Diaper, D. G. M., 179 Dickinson, W. B., 190 Diekalo, A. A., 209 Dietrich, B., 273 Dieterich, D., 122 Diez, J., 123 Dimock, J. R., 54 Din, Z. U., 232 Dittrich, B., 200 Djerassi, C., 204 Dolejs, L., 11 Dolfini, J. E., 133, 134 Dominianni, S . J., 58 Dondoni, A., 161 Donetti, A., 271 Dorer, F. H., 194 Doshan, H., 136 Dorme, N., 185 Dorofeeva, 0. V., 94 Dougherty, C. M., 202 Drach, B. S., 170 Drey, C. N. C., 128 Driscoll, J. S., 137 Dubois, J. E., 240 Ducker, J. W., 191 Dudek, V., 59 Dudley, K. H., 200 Duhamel, L., 197, 202 Duhamel, P., 197, 202 Duke, R. E.,jun., 158 Duke, R. P., 146, 151, 271 Dumke, K., 172 Dumdis, J., 213 Duncan, W. G., 95 Dunkelblum, E., 106 Dupeyre, R.-M., 256 Dupuy, A. E., jun., 69,114 Duran, N., 177 Durand, R., 278 Durst, T., 132 Dybowski, U., 237 Dye, J. L., 272, 273 Dyke, S. F., 209 Dziark, J. J., 247 Zbetino, F. F., 246 :bnoether, A., 21 1 Zckert, H. W., 222 Zckhardt, W., 254 Zggelte, T. A., 276 {gger, K. W., 174 {guchi, S., 109, 250 {inhellig, K., 163 {isenhardt, W., 96 {istert, B., 16 ?iter, K., 117

Author Index Elegant, L., 153 El-Gawad, 1. I. A., 235 Elguero, J., 195, 197 Eliel, E. L., 142, 155 Elix, J. A., 262 Elvidge, J. A., 221 Emanuel, N. M., 23 Enders, D., 224 Endo, K., 262 Engel, J. F., 286 Engelmann, A., 72 Engelsing, R., 204, 245 England, D. C., 245 Epstein, M. J., 269 Epsztajn, J., 216 Epsztein, R., 173 Eschenmoser, A., 238 Estep, R. E., 22 Ewing, J. B., 133 Fagerburg, D. R., 49 Fahey, J. L., 104, 105 Falaleeva, L. N., 34 Falci, K. J., 190 Faler, G. R., 121 Fantazier, R. M., 201 Farid, S., 97 Fava, A., 154, 155 Favre, B., 163 Fawcett, P., 101 Featherman, S. I., 152 Fedeli, W., 147, 271 Fedorchenko, E. I., 230 Fehlner, J. R., 145 Fehn, J., 84 Fehr, C. H., 221 Feinauer, R., 245 Felix, D., 238 Feltkamp, H., 146 Ferles, M., 147, 206 Ferreira, G. A. L., 206 Ferrero, L., 55 Ferres, H., 195 Ferrey, M., 40 Figueiredo, A. M., 106 Figures, W., 260 Filby, J. E., 117, 179 Filina, G. G., 236 Filippova, M. P., 11 Finch, N., 216 Finner, E., 183 Finza, P. V., 162 Firestone, R. A., 134 Fischer, C. M., 117, 179 Fischer, H., 189 Fischer, J., 274 Fischer, N. H., 282 Fischer, R., 287 Fisher, R. D., 257 Flaerner, F. G., 42 Flament, I., 221 Fliege, W., 161

29 1 Flitsch, W., 192 Fluck, E., 268 Flynn, C. R., 214 Foglia, T. A., 58 Font, J., 82 Fontanella, L., 100, 199 Fonzes, L., 49 Foote, C. S., 121, 167 Forrest, T. P., 236 Fotadar, U., 228 Foti, F., 162 Foucard, A., 40, 166, 191 Franck-Neumann, M., 145 Frank, R. W., 190 Fraser, R. W., 190 Fratmann, S. A., 190 Frattesi, P., 199 Frazer,.J., 133 Freed, M. E., 14 Friary, R. J., 190 Friedrich, L. E., 97 Fritz, G., 249, 287 Frost, D. C., 249 Fry, A. J., 87 Fuchs, R., 262 Fuerst, H., 6 Fugitt, R. B., 27, 40 Fujii, T., 100 Fujita, S., 66, 198 Fukamoto, K., 246, Funke, P. T., 133, 134 Furakawa, M., 247 Furst, G. T., 109 Furstoss, R., 257 Fu- Tai Chen, A., 110,119 Gagnaire, D., 152 Gajewski, R. P., 97 Galik, V., 255 Gallina, C., 219 Gamba, A., 141, 226, 228 Gamov, V. K., 21 1 Gandolfi, R., 161, 162 Ganter, C., 32, 267, 277 Garashchenko, Z. M., 168 Garbanov, R. A., 47 Garbassi, F., 149 Garbesi, A., 154, 155 Garcia-Muiioz, G., 123 Gardi, R., 230 Garling, D. L., 51 Garner, A. W., 85 Garvey, P. M., 287 Gasparrini, F., 166 Gassman, P. G., 194, 269 Gaudemar, M., 100 Gautier, J. A., 188 Gauvreau, A., 197 Gavrilova, S. I., 204 Gehring, A., 287 Gelas, J., 280 Gemeden, C. W., 216

Geneste, P., 278 George, J. K., 158 George, M. V., 287 Gevorkyan, A. A., 171 Ghandour, N. El., 158 Ghedini, M., 166 Ghirardelli, R. G., 35 Giarda, L., 149 Gibson, D. H., 177 Gieren, A., 166 Giezendanner, H., 165 Gilbert, A., 257 Gilbert, E. E., 223 Giles, H. G., 145 Gilgen, P., 165 Gillard, J. W., 271 Gilles, J. L., 197 Gilligan, J. M., 190 Gimelli, S . P., 247 Ginsburg, D., 259 Girijavallabhan, M., 135 Giumanini, A. G., 62 Glacet, C., 57 Gladiali, S., 230 Glazer, E., 164 Glazer, E. A., 114 Glazkov, V. Yu., 21 Glazkova, N. A., 34 Gleiter, R., 285 Glukhavstev, A. V., 172 Glushko, L. P., 11 Glushkov, R. G., 204 Goeldner, M. P., 133 Goff, D. L., 45 Gogte, V. N., 100 Goi, M., 211 Gojkovic, S., 170 Golding, B. T., 18, 102 230 Golikov, V. I., 48 Golovin, E. T., 205 Gomez Arander, W., 205 Gompper, R., 110 Gondos, G., 149 Goodson, T., 133 Goores, A. P., 189 Gordon, M. S., 146 Gorman, A. A., 96 Gormley, T. R., 28 Gorrichon, J. P., 142 Goto, K., 146 Gotor, V., 205 Granata, A., 145 Granik, V. G., 204 Grassi, G., 162 Grechkin, N. P., 73 Grke, R., 159, 160 Green, C. H., 155 Green, M. M., 170 Greene, F. D., 87, 113 Greenlee, W. J., 194 Greenwood, G., 274

Author Index

292 Greibrokk, T., 137, 167 Grieco, P. A., 174 Grieg, D. G. T., 135 Griffin, G. W., 82, 137 Griffiths, D. V., 146, 148 Grigorova, T. N., 227 Grimshaw, J., 197 Grippi, M., 260 Grishina, N. L., 73 Grob, C. A., 254 Gross, H., 200 Grosser, J., 39 Gruber, P., 234 Grunanger, P., 161, 162 Grutzner, J. B., 101 Gshwend, H. W., 168 Guenzet, J., 67 Guida, A., 49 Gunter, M. J., 191 Gupta, S. C., 99 Gurbaxani, S., 23 1 Guseinov, M. M., 27, 41 Gut, J., 222 Gutkowska, B., 202 Gutsche, D. C., 176 Gutzwiller, J., 209 Guziec, F. S., 236 Haas, A., 200 Haber, S. B., 101 Habermalz, U., 223 Habersaat, K., 201 Haddadin, M. J., 242,243 Haemers, M., 153 Haga, S., 214 Hahn, E. F., 177 Haidar, N. F., 220 Hai, S. M. A., 201 Hainaut, D., 9 Hall, D. R., 18, 102, 230 Hall, M. J., 144, 148 Hall, P. G., 151 Halton, B., 59 Hamada, Y., 249 Hamaguchi, F., 192 Hamdam, M. S., 195 Hamed, A. A., 32 Hamelin, J., 63, 68, 101, 158, 159

Hamer, N. K., 184 Hames, R. A., 241 Hammer, C. F., 202 Hammer, F. T., 177 Hammerum, S., 225 Hanna, R., 94 Hansen, D. A., 124 Hansen, H. J., 165, 189 Hansen, J. H., 60 Hansen, P. E., 60 Hanson, R. N., 215 Hantelmann, O., 237 Hantke, K., 191

Hara, M., 214 Harada, K., 220 Harano, K., 116 Harcourt, D. N., 210 Hardy, A. D. U., 255 Hargittai, I., 94 Harman, A. D., 174 Harrington, G. W., 1 8 Harris, D. K., 252 Harrison, C. H., 230 Harsanyi, K., 209, 24 Hart, H., 9, 44, 172 Hartley, D., 209 Hartner, H., 169 Hartman, B. C., 38 Hartman, G. D., 269 Hartshorn, M. P., 30, 31, 170

Hasko-Breuer, J., 53 Haslouin, J., 126 Hassairi, M., 191 Hassner, A., 242, 243 Hasty, N. M., 121 Haszeldine, R .N., 120,217 Hatch, C. E., 197 Hatfield, L. D., 92 Hatsutani, M.,167 Hautala, R. R., 136 Hauth, H., 188 Hauthal, H. G., 6 Hawkins, G. E., 43 Hayakawa, K., 148 Hayakawa, N., 176 Hayakawa, Y.,176 Hayashi, S., 247 Hayward, R. J., 265 Hearn, M. J., 114 Hebert, A. L., 82 Heckel, K., 267 Hehre, W. J., 249 Heiklen, J., 179 Heilbronner, E., 248 Heim, P., 187 Heimgartner, H., 60, 165 Heine, H. W., 63, 85, 198 Helder, R., 275 Hellier, D. G., 155 Helsley, G. C., 187 Helton, D. L., 202 Hendrick, M. E., 269 Henery-Logan, K. R., 103 Henton, D. E., 45 Henrick, C. A., 51, 77 Hermann, J. L., 174, 175 Herschied, J. D. M., 181 Herweh, J. E., 201 Heumann, A., 257 Heusler, K., 209, 267 Hewitt, G. H., 135 Heyman M. L., 250,259 Higgins, R. H., 132 Higley, D. P., 180

Higuchi, T., 200 Hill, A. E., 274 Hillers, S., 226 Hiltmann, R., 231 Hine, J., 178, 197 Hirai, K., 106, 214 Hirata, T., 137 Hirakawa, A. Y., 249 Hiraoka, H., 174 Hiroi, H., 189 Hiroi, K., 174 Hirragi, M., 214 Hirsch, J. A., 184 Hisano, T., 237 Hisatsune, I. C., 179 Hites, R.,172 Hiyama, T., 66, 198 Hocker, J., 226 Hodges, M. L., 85 Hoefer, R., 72 Hoeft, E., 23 Hofer, O., 142, 155 Hoffmann, H. M. R., 179, 274

Hoffmann, R., 248,249 Hoffmann, R. W., 200 Hogeveen, H., 276 Hohne, G., 136 Holan, G., 94 Holliday, A. K., 287 Hongo, T., 19 Honzl, J., 100 Hooltele, C., 254 Hoover, J. R. E., 133 Ho Pak-Tsun, 69 Hoppe, D., 231 Horsfall, G. S., 151 Horton, H. L., 154 Hosten, N., 142 Houk, K. N., 158 Hoye, R. C., 85 Hoye, T. R., 85 Hsiao, Y. Y., 70 Huber, C. S., 247 Huber, G., 15 Huber, J. H.-A., 45 Huber, R., 249 Huckle, D., 184 Huckstep, L. L., 101 Hudec, J., 249 Hudrlik, P., 174 Hsuigen, R., 158, 161, 163 Huisman, H. O., 203, 276 Hull, J. V., 44 Hull, L. A., 179 Hull, W. E., 223 Hunter, I. R., 206 Hunter, J. A., 175 Hutchinson, C. R., 174 Hutchinson, J. H., 21 Huttel, R., 197 Hyndman, C., 260,264

Author Index brahim, B., 263 cli, S., 145 de, E., 23 gnatenko, A. V., 172, 214 izuka, T., 1 keda, M., 208,277 magawa, T., 260 ngold, K. U.,252, 253 nubushi, Y., 241 offee, B. V., 50 riuchijima, S., 156 rving, K. C., 63, 198 rwin, W. J., 128 sagulyants, V. I., 185 shaand, T., 100 shibashi, H., 277 shibashi, M., 156 shchenko, R. I., 11 sidor, J. L., 39, 176, 276 slam, A. M., 235 smailova, R. A., 27 sobe, M., 116 to, S., 262 to, Y., 227, 241 toh, M., 48 toh, Y., 24 vanov, C., 183 wahashi, H., 107 wakuma, T., 263 wakura, Y.,83 [zydore, R. A., 35 Jacconi, G., 141, 169, 246 Jachnisch, K., 50 Jackson, B., 165 Jackson, W. R., 195 Jacob, P., 48 Jacobus, J., 170 Jacquerye, R., 196 Jaeschke, W., 94 Jain, R. C., 69 Jalonen, J., 156 James, M. N. G., 148 Janssen, G., 128, 130 Japar, S. M., 96 Jedziniak, E. J., 170 Jefford, C. W., 157 Jeffs, P. W., 175 Jen, T., 133 Jennison, C. P. R., 244, 270 Jensen, W., 154 Jenses, N. P., 218 Jenny, E. F., 209,267 Jentsch, R., 39, 204 Jeremic, D., 170 Jerina, D. M., 1 Johansson N. G., 103, 203 Johns, S. R., 243 Johnson, B. L., 201. Johnson C. R., 12, 15, 36, 285

293 Johnson, P. Y.,123, 197, 229, 239 Johnson, Q., 154 Johnson, R. A. W., 219 Johnson, W. R., 213 Jonas, R., 222 Jonas, V., 92 Jones, A. F., 148 Jones, G., 123 Jones, R. A. Y.,140, 146, 150, 151, 271 Jose, F. L., 134 Joseph, J. T., 177 Joulcla, M., 159 Joullik, M. M., 112 Joyeux, M., 262 Julia, S., 174 Julian, D. R., 96 Junek, H., 247 Jurjevich, A. F., 240 Just, G., 277 Kaas, K., 146 Kadaba, P. K., 158 Kagan, J., 98 Kalabin, G. A., 178 Kalechits, I. V., 2 Kaliko, 0.R., 236 Kalweit, M., 194 Kamenka, J. M., 208 Kametani, F., 144 Kametani, T., 214,246 Kaminskii, V. A., 21 1 Kamiya, Y.,172 Kanamaru, N., 263 Kane, V. V., 254 Kang, J. B., 268 Kang, J. C., 213 Kanemasa, S., 201 Kaplan, M. L., 141 Kapur, J. C., 104,105,133 Karimova, N. M., 77, 80 Kariya, Y., 24 Karlsson, R., 254 Karnischky, L. A., 229 Kartashova, N. A., 177 Karustis, G. A., 223 Kashino, S., 146 Kashman, Y., 286 Kastrons, J., 226 Katayama, K., 185, 202 Kato, T., 176 Kato, W., 100 Katritzky, A. R., 146, 150, 151,216, 263,271 Katsuo, A., 236 Katz, T. J., 136, 286 Kauffmann, T., 201 Kaupp, G., 262 Kavalek, J., 202 Kawai, R., 208

Kawaakmi, J. H., 161 Kawakita, T., 52 Kawamura, T., 253 Kawanisi, M., 260, 278 Kawazura, H., 24 Kazantsev, Y.E., 239 Kazimov, Sh. K., 2 Kearns, D. R., 121 Kees, F., 85 Keller, J. N., 225 Keller, K., 186 Kellie, G. M., 141 Kellogg, R. M., 212 Kelly, R. C., 183 Kenyon, G. L., 251 Kerimova, N. G., 32 Kerur, D. R., 179 Keskinen, R., 155 Kessenikh, A. V., 172 Khalil, A. M., 235 Khalil, M. H., 21 Khil’manovich, L. A., 21, 32 Khudyakova, A. N., 185 Kibina, Y.I., 19 Kigasawa, K., 214 Kiguchi, I., 23, 210 Kigugawa, Y., 202 Kil’disheva, 0. V., 77, 80 Kilwing, W., 73 Kim, L., 6 Kimura, K., 263 Kimura, M., 96 King, J. F., 282 King, J. M., 184 Kingsbury, W. D., 36, 285 Kirby, G. W., 169, 236 Kirillov, A. I., I77 Kiriyama, T., 250 Kirk, D. N., 1 Kirn, H. R., 194 Kiryuskina, G. K., 208 Kishida, Y., 106, 214 Kisilenko, A. A., 170 Kiss, P.,241 Kita, Y.,277 Kitahara, Y.,176 Kitchin, J., 101, 130, 266 Kitzing, R., 262 Klabunde, K. J., 127 Klaebe, A., 197 Klein, J., 156 Kliegerman, J. M., 177 Kline, E. A., 287 Klingerman, A., 155 Kluender, H., 101 Klunder, E. B., 194 Klunklin, G., 257 Klutchko, S.,246 Kmiotek, I., 185 Knapp, D. R., 112, 193

Author Index

294 Knobloch, G., 191 Knowles, A. M., 228 Knunyants, I. L., 32, 77, 80 Kobayashi, T., 185 Kobayashi, Y., 84, 90 Koch, T. H., 192 Kodama, I., 83 Koebrich, G., 39 Koehler, R. E., 134 Koelewijn, P., 2 Koer, K. J., 141 Koide, K.,198 Koga, M., 166 Kogima, Y., 247 Kogure, K., 175 Kohno, M., 252 Koide, H., 66 Kojima, M., 52 Kolb, B., 92 Kolenko, I. P., 6, 49 Kolobugina, K. N., 185 Kolocouris, N., 189 Kolosov, Y. V., 204 Komarova, L. I., 27 Komendantov, M. I., 227 Konala, C., 94 Kondo, K., 167 Konotsune, T., 83 Konstantinov, I. I., 223 Konstantinovic, S., 170 Koomen, G. J., 189 Kopecky, K. R., 117, 179 Kopecky, W. J., 106 Koppe, H., 215 Koppel, G. A., 131, 134 Koppelmann, E., 201 Korat, M., 259 Korbonits, D., 241 Korner, K. A., 230 Kornilov, A. N., 36 Koroleva, E. V., 50 Korte, F., 215, 228, 245, 247 Korzeniowski, S. H., 174 Kosower, E. M., 208 Koster, W., 134 Kostochka, L. M., 173 Kovacs, K., 149 Kovacic, P., 257 Kovalev, B. G., 11 Kovaleva, V. N., 35 Kovats, E., 6 Kovelesky, A. C., 240 Koyama, H., 175 Koyama, T., 253 Koyano, K., 201 Kozima, S., 202 Kozlov, N. S., 35, 50 Kraatz, U., 119, 190, 228, 245,247 Kraemer, R., 176

Krantz, A., 125 Kreevoy, M. M., 157 Kreher, R., 224 Kremlev, M. M., 11 Kresze, G., 15, 169 Kretchmer, R. A., 19 Kricheldorf, H. R., 123, 232,238,242 Krivinka, P., 100 Krivoruchko, V. A., 210 Krohnke, F., 223 Kroon, A. J., 189 Krow, G. R., 110, 260, 261, 264 Krueger, W. E., 147 Kruger, C., 287 Kruger, H-R., 280 Kubel, B., 234 Kucherov, V. F., 173 Kueffner, G., 16 Kuhling, D., 199 Kulevsky, N., 223 Kuliev, A. M., 79 Kulkarni, P. S., 254 Kulkarni, S. B., 100 Kumazawa, T., 23 Kunazawa, S., 176 Kunovskaya, D. M., 237 Kuo, S. C., 252 Kupriyanov, T. I., 48 Kuranova, I. L., 26, 177 Kuramoto, M., 202 Kurita, K., 103, 195 Kuryatov, N. S., 204 Kuthan, J., 268 Kutney, J. P., 207 Kvasyuk, E. I., 197 Kyazimov, A. S., 32 Labelle, M. J., 132 LaBerge, J. M., 83 Lach, D., 110 Lacombe, L., 167 Lakshmarayana, L., 193 Lalancette, J. M., 80 Lalibertt, M., 80 Lambert, J. B., 139 Lamberton, J. A., 243 Lames, U., 225 Landa, S., 215, 255 Landis, M. E., 136, 137 Landis, R. T., 254, 270 Lang, P., 190 Large, R., 43 Larkin, R. H., 144 Larsen, S., 154 Larson, D. B., 200 Lattes, A., 197 Lattrell, R., 104 Lauer, R. F., 36 Laughlin, R. G., 160 Laurent, A., 61, 62

Lawson, A., 228,235 Lazaris, A. Y., 177 Lazarus, S., 241 Lazik, W., 16 Lecadet, D., 73, 74 Lechtken, P., 136 Ledon, H., 174 Leduc, M., 191 Lee, A. O., 168 Lee, C., 109, 261 Lee, E. K. C., 124 Lee, S. F., 69 Lee, V., 232 Lefebvre, P., 125 Leffingwell, J. C., 191 Lehniann, J., 66, 247 Lehn, J. M., 273, 274 Lemal, D. M., 282 Lemke, P. A., 101 Lenoir, J. A., 201 Lerdal, D., 121, 167 Leresch, J. P., 163 Leroy, G., 194 Leuchtenberger, W., 225 Levin, C. C., 249 Levy, A. B., 5 1, 243 Lewars, E. G., 282 Lewis, J. W., 167, 242 Leyland, R. L., 96 Liberatori, A., 219 Lillie, T. J., 26 Lim, S.-H., 226,260 Lin, C. F., 151 Lin, C. Y.,125 Lin, H-N., 282 Lin, L., 207 Lin, L. J., 102 Lin’kova, M. G., 77, 80 Linstrumelle, G., 174 Lion, C., 240 Litkei, G., 28 Liu, J., 177 Livinghouse, T., 38 Livingston, C. M., 283 Lo, Y.S., 132 Lockhart, I. M., 184 Lockwood, P. A., 117, 179 Loeliger, J., 101 Logan, I. D., 140 Lok, M. T., 272 Lok, R., 239 Long, J. P., 146 Looker, B. E., 135 Lopatik, D. V., 23 Loper, G. L., 194 Lord, R. C., 144 Losman, D., 254 Losnakova, N. A., 189 Lowbridge, J., 128 Lowe, G., 103, 113, 132, 193 Lown, J. W., 115,217,218

Author Index Lyle, R. E., 147 Lyons, A., 136 Lyons, J. E., 24 Lucente, G., 135, 199 Lunsford, C. D., 187 Lunt, E., 216 Luong-Jhi, N. T.,209,268 Lusinchi, X., 240 Luttringer, J. P., 106 Lwowski, W., 201 Lyle, G. G., 247 Lyle, R. E., 147 Lyudmirova, V. L., 177 Maalouf, G., 94 McArthur, C. R., 201 McCabe, P. H., 283, 286 Maccagnani, G., 80 McCulloch, A. W., 275 McCurry, P. M., 171 McDonald, A. N., 118 MacDonald, S., 167 McElwee, J., 16 McErlane, K. M. J., 148 McGreer, D. E., 174 McGrew, J. G., 170 McGlynn, S. P., 200 Machkova, Z., 11 Machleder, W. H., 2 Machin, P. J., 220 Machleder, W. H., 99 McInnes, A. G., 275 McIntosh, C. L., 125 Mack, W., 162 Mackay, D., 121,244,270, 27 1

McKean, D. R., 112, 193 McKee, R. L., 276 Mackenzie, K., 260 MacKinley, J. W., 174 McMahon, D. H., 147 McManus, S. P., 241 MacNicol, D. D., 255 Madhav, R., 211 Madrofiero, R., 123 Maerkl, G., 13 Mageswaran, S.,207 Magnus, P. D., 125 Magosch, K. H., 162 Magyar, E. S., 139 Mahajan, J. R., 206 Mahler, W., 49 Mahoney, L. R., 253 Maier, G., 180 Maizus, Z. K., 2 Majoral, J. P., 153 Makino, S., 176, 274 Makhnach, V. I., 34 Malavaud, C., 237 Maldonado, J., 185 Mallory, D., 83, 223 Malina, Y. F.,204

295 Malinovskaya, T. M.,11 Mamedalieva, S. Yu.,41 Mamedov, F. N., 79 Mamishov, A. K., 6,31,34 Manas, M. M., 151 Mander, L. N., 188 Manhas, M. S., 104, 105, 133

Mannschreck, A., 92 Maquestian, A., 196,228 Marakowski, J., 260 Marchand, E., 40,166,191 Marchenko, V. A,, 11 Marchik, E. F., 34 Margaretha, P., 183 Marhoul, A., 23 Maria, P. C., 153 Marino, M. L., 161 Markert, J., 262 Markov, V. I., 63 Maroni, P., 142 Maroski, J. G., 182, 185 Marquarding, D., 219 Marquardt, G., 287 Marquet, A., 156,235 Marraud, M., 253 Marsais, F., 263 Marschall, H., 280 Marshall, D. R., 1 Martel, A., 277 Martin, A. R., 150 Martin, F., 222 Martin, J., 152 Martin, M. M., 177, 184 Martin, S. F., 13 Martinelli, L. C., 27, 40 Marton, M. T., 123 Maruca, R., 287 Marzin, C., 195 Mashenkov, V. A., 21 Mashevskii, V. V., 50 Mashkin, Y. I., 223 Mashkovskii, M. D., 254 Mason, M. M., 127, 279 Mastryukov, V. S., 94 Masui, M., 159 Matera, E., 287 Materne, C., 233 Mathew, K. K., 16 Mathieu, F., 273 Matkin, D., 167 Matoba, K., 211 Matsina, E. V., 177 Matsuda, F., 52 Matsuda, H., 106, 214 Matsugashita, S., 208 Matsui, M., 175, 190 Matsumoto, K., 1, 233 Matsumoto, M., 167 Matsumoto, S., 77 Matsuura, T., 227 Matyukhin, Y. S., 205

Maujean, A., 174 Maurer, B., 176 Mazur, S., 121, 677 Mazza, F., 147, 27 Mazzocchi, P. H., 106 Meier, H. P., 168 Meiser, P., 268 Meisinger, R. H., 285 Mellinger, M., 274 Mellor, J. M., 248, 269 Melumad, D., 144 Mendenhall, G. D., 252, 253

Menyailo, A. T., 236 Merah, B., 67 Mercier, F., 173 Merten, R., 226 Merz, A,, 13 Meth-Cohn, O., 265 Metz, B., 273 Metzger, A., 172 Metzger, D., 245 Metzner, P., 75 Meyers, A. I., 240 Meyers, G., 180 Meyers, P. L., 167, 242 Meyer, C., 63, 198 Mez, H.-C., 253 Michael, J., 236 Micheli, C. D., 162 Michl, J., 214 Middelkoop, T. B., 276 Middlemiss, D., 188 Middleton, W. J., 245 Midland, M. M., 51 Migita, T., 137 Mihailovic, M. L., 170 Mihara, N., 202 Mihelich, E. D., 19 Mikhlina, E. E., 254 Mikhailopulo, I. A., 197 Mikhailov, B. M., 287 Miklevich, A. V., 32 Mikolajczyk, M., 153 Miller, W. J., 181 Mil’man, B. L., 244 Milosavljevic, S., 170 Milson, P., 61 Miocque, M., 185 Mirskova, A. N., 178 Mitchell, J. W., 216 Miyaura, N., 48 Miyoshi, M., 54 Mkrtchyan, A. P., 181 Mochalin, V. B., 36 Moehrle, H., 204, 245 Moiseenkov, A. M., 210 Moldowan, J. M., 170 Molina, G., 175 Mollere, P. D., 94, 248 Molone, G. R., 240 Moncreif, J. W., 217

296 Mondelli, R., 228 Monteiro, H. J., 189 Moolenaar, M. J., 203 Moore, D. W., 83, 146, 223

Moore, J. A., 103, 194, 195 Moore, H. W., 95 Moras, D., 273 Moraud, B., 20 Moreau, J. L.,100 Morgan, T. K., 44 Mori, K., 175 Mori, T., 210 Mori, Y., 175 Moriaty, R. M., 157 Moricon, E. J., 109 Morishima, I., 146, 252 Moritani, I., 187 Mosbo, J. A,, 153 Moseley, R. H., 192 Movsumzade, M. M., 32, 47

Movsum-Zade, R. G., 47 Mowatt, A., 135 Muckensturm, B., 94 Mujoshi, M., 100 Mukai, T., 227 Mukayama, T. K., 173 Mukerjee, S. K., 99, 100 Muller, E., 163 Muller, H. J., 211 Muller, L.,234 Muller, R. N., 228 Muller, W., 228 Murahashi, S., 187 Murai, H., 32 Murakami, M., 208 Muraoka, K., 237 Murayama, M., 32 Murray-Rust, J., 253 Murray-Rust, P., 253 Murray, R. K. jun., 44, 45

Murray, R. W., 180 Muruama, I., 202 Musantaeva, Sh., 19 Musgrave, 0. C., 26 Musil, L.,268 Mysov, E. I., 32 Nabeya, A., 83, 195, 240 Nadtochii, M. A., 172 Nagai, T., 172, 185 Nagarajan, K., 213 Nagata, M., 211 Nagukura, S., 185 Naito, T., 210 Nakagawa, Y., 222 Nakamura, H., 42 Nakanishi, M., 236, 241 Nakano, T., 92 Nakao, M., 202

Author Index Naples, J. O., 180 Narasimhan, N. S., 60,165 Narducy, K. W., 197 Narita, S., 262 Naser-ud-din, 110,214 Nash, C. H., 101 Navech, J., 152, 153 Nazarenko, N., 240 Nebya, A., 194 Neckers, D. C., 121 Neel, J., 253 Negishi, A,, 79 Negishi, E., 287 Neifel’d, P. G., 49 Nelsen, S. F., 150, 187, 251, 254, 270

Nelson, D. J., 181 Nelson, E. R., 243 Nerdel, F., 280 Neri, C., 23 Nesterenko, S. A., 10 Neszmelyi, A., 53 Neuberg, M. K., 139 Neumeyer, J. L., 236 Neuray, D., 225 Neuss, N., 101 Newlands, M. J., 120 Newman, M. S., 185,232 Newton, M. D., 125 Newton, R. F., 146 Newton, T. A., 63, 198 Ngan, Y.-M., 99 Nichol, D. J., 140 Nichols, D. E., 204 Nielsen, A. T., 83, 144,223 Nikkila, A., 155 Ninomiya, I., 210 Niu, C., 223 Noels, A., 125 Nolen, R. L., 240 Noravyan, A. S., 181 Normant, J. M., 37, 45 Notari, B., 23 Nouguier, R., 280 Novacek, A., 222 Novikov, S. S., 160, 239 Nowak, R., 172 Noyori, R., 176, 274 Nozaki, H., 38,42,66, 198 Nunes, B. J., 206 Nye, M. J., 196

Ohloff, G., 6, 176,221 Ohnishi, Y., 281 Ohno, A., 281 Oida, S., 69 Oikawa, E., 170 Okada, A., 1 Okada, K., 146 Okamoto, T., 44,202 Okawa, K., 54 Okawara, T., 220 Okonogi, T., 13 Okumura, K., 233 Olansky, L., 2 17 Ollinger, J., 15 Ollis, W. D., 207, 272 Olofson, R. A., 202 Olsen, C. A., 165 Olson, E. S., 126 Onda, M., 7 Oppolzer, W., 186 Orahovats, A., 165 Oritani, T., 26 Ormerod, J. A., 242 Ortiz de Montellano, P. R., 38

Osaki, K., 144 Osdene, T. S., 213 O’Sullivan, J., 207, 265 O’Sullivan, W. I., 28 Otani, G., 189 Ottenbrite, R. M., 188 Ottinger, R.,153 Oude-Alink, B. A. M., 176 Overton, K. H., 185 Owen, P., 185 Oxenius, R., 225 Ozaki, M., 32 Pacansky, J., 125 Pacifici, J. G., 87 Padwa, A., 2,116,164,254 Paglietti, G., 208 Pak, N. E., 94 Pak, V. D., 50 Pakhomov, V. P., 204 Palecek, J., 268 Panaiotova, B., 127 Pandit, U. K., 189 Panetta, C. A., 132,229 Pannella, H., 260 Pansevich-Kolyada, V. I., 34

Occelli, E., 199 Oe, K., 112, 238 Ogata, H., 249 Ogata, Y.,209 Ogiya, N., 52 Oglobin, K. A., 227, 237 O’Grady, J., 43 O’Hara, E., 127, 279 Ohki, S., 192 Ohler, E., 221

Papadopoulos, E. P., 220 Papay, J. J., 139 Paquer, D., 73, 74 Paquette, L. A., 107, 108, 109, 110,269,285

Parashar, V. V., 211 Parker, J., 132, 242 Pars, H. G., 254 Pasanen, P., 156, 157 Pascard-Billy, C., 214

Author Index Pasenko, Z., 230 Pasteels, J. M., 254 Pasto, D. J., 110, 119, 213 Pastour, P., 263 Patel, A. D., 122 Patterson, J. M., 220 Paul, D., 211 Paulsen, H., 179 Paushkin, Y. M., 23 Pawson, B. A., 231 Pedersen, C., 165 Peereboom, R., 189 Pencheva, B. A., 127 Perazzi, A., 199 Perez, C., 92 Perie, J. J., 197 Perner, J., 222 Perrotti, E., 23 Perz, R., 178 Petersen, H., 214 Petrova, N. V., 47 Petrus, C., 227 Petrus, F., 227 Petrzilka, M., 238 Petrzilka, T., 221 Petterson, R. C., 82 Pezzullo, 3. C., 221 Pfaffli, P., 188 Pfenninger, E., 186 Philipp, A., 69 Phillips, B. A., 100, 219 Phillips, G. O., 94 Phillips, L., 138 Pick, M. R., 125 Picot, A., 240 Pieroni, J., 109 Pierson, G. O., 113 Pifferi, G., 100 Pihlaja, K., 138, 143, 155, 156, 157 Pinazzi, C., 287 Pines, S. H., 233 Ping, R. G. S., 125 Piotrowska, H., 185, 239 Piozzi, F., 161 Piper, J. U., 132 Piro, L. R. M., 23 Pisanenko, D. A., 10 Pishnamazzade, B. F., 6, 31, 34 Pizzalalato, G., 209 Plaas, V., 200 Plackett, J. D., 128 Plaksina, D. N., 50 Plashkin, V. S., 6,49 Plonka, J. H., 127 Pohlman, H., 178 Poisel, H., 220 Polak, R. J., 126 Politzer, I. R., 137, 240 Polyakov, A. E., 63 Pommeret, J. J., 40, 166

297 Ponoamarenko, V. A., 214 Ponomareva, G. Z., 2 Pople, J. A., 146 Popp, F. D., 217 Porsche, P. H., 191 Porter, A. E. A., 220 Portescu, I. D., 190 Portmann, R. E., 32,267 Portnoy, R. C., 240 Portnyagin, Y.,94 Portoghese, P. S., 64,257 Poselenov, A. I., 210 Pospelov, M. V., 236 Potapov, V. M., 208 Potaski, J. R., 14 Potekhim, A. A., 244 Potel, J., 199 Povall, T. J., 219 Power, D. M., 94 Pressler, K., 199 Pretsch, E., 194 Pridgen, L. N., 147 Prinzbach, H., 262,276 Privalova, L. G., 2 Prokopovich, I. P., 23 Prokopovich, V. P., 31 Proskurina, T., 178 Protas, J., 253 Protopopova, T. V., 189 Pruess, D. L., 207 Prystas, M., 222 Przybytek, J. T., 98 Puar, M. S., 133, 134 Pudel, M. E., 2 Pullman, D. A., 158 Quang, Y.V., 158 Quast, H., 85 Quequiner, G., 263 Quin, L. D., 151, 152,286 Quinn, C. B., 277,284 Raban, M., 92 Rademacher, P., 150 Rajappa, S., 220 Rakhmankulou, D. L., 185 Raman, P. S., 16 Ramey, K. C., 260 Ramsey, M. V. J., 103 Rapoport, H., 112, 193, 215 Rasmussan, G. H., 134 Rassat, A., 252, 256 Rastetter, W., 101 Ratcliffe, R. W., 104 Rathburn, D. W., 230 Rauk, A., 138 Raynaulde, G., 185 Razdan, R. K., 254 Re, L., 176 Record, K. A. F., 146

Rees, C. W., 196 Reese, C. B., 181 Regel, W., 183, 242 Reich, H. J., 281 Reichmanis, E., 8,264, 277 Reid, R. W., 117, 179 Reiff, H., 122 Reilly, J., 264 Reinecke, M. G., 188 Reinhoudt, D. N., 282 Reisse, J., 153 Rekhter, M. A., 11 Rengaraju, S., 53 Renger, B., 224 Resnick, P. R., 49 Revel, M., 152 Rey, P., 252 Reynolds, G. F., 134 Reyx, D., 287 Ricard, D., 178 Ricart, G., 57 Richards, A. C., 151 Richter, R., 190, 215,233 Richman, J. A., 187 Rickborn, B., 36 Ridaura, V. E., 207 Riddell, F. G., 141, 151 Ridge, R. J., 128 Ridley, D. D., 113, 193 Riebling, R., 199 Ried, W., 176, 225, 226, 260 Riedinger, J., 16 Riegl, J., 110, 214 Righetti, P. P., 169, 246 Rihs, G., 253 Rinck, R., 114 Rio, G., 167 Risitano, F., 162 Rissi, E., 211 Rivas, C., 92, 96 Robert, A., 40, 166 Roberts, D. L., 5 Roberts, J. S., 127, 253 Robert, 3.-B., 152 Robinson, C., 34 Robinson, M. L., 167 Robinson, M. S., 167 Robson, C. A., 135 Roch, G., 216 Rodebaugh, R., 260, 261, 264 Rodericks, J. V., 215 Rodgers, M. A. J., 96 Rodriguez, H., 235 Rodriguez, O., 177 Roets, E. E., 128, 130 Roff, J. E., 182 Rogers, P. E., 12 Rolfe, R. E., 148 Romanova, K. I., 204 Romers, C., 141

Author Index

298 Roinpuy, L. V., 228 Roscher, N. M., 170 Rosenberg, G. S., 189 Rosenkranz, H. J., 165, 189 Roseman, L., 287 Rosner, M., 197 Rosskopf, F., 183 Roth, R., 125 Rouessac, F., 126 Rouse, R. A., 140 Rousseau, 0. H., 158 Roussel, J., 197 Routledge, W., 286 Rowe, C. A. jun., 53 Roy, S. K., 254 Ruccia, M., 161 Ruden, R. A., 178 Rudnick, L. R., 174 Ruzicka, V., 23 Ryang, H. S., 96 Rzaeva, A. S., 2 Saalfrank, R. W., 110 Saba, S., 150 Sadygov, Sh. F., 27 Sadykh-Zade, S. I., 27 Saegusa, T., 241 Saenger, W., 152, 153 Saha, B. F., 188 Sahabia, J., 184 Saito, I., 202 Sakito, Y., 250 Sakrikar, S., 18 Sakurai, H., 96 Salakhov, M. S., 41 Salazkin, S. N., 27 Sales, K. D., 148 Saltzmann, T.-N., 174 Samitov, Yu. Yu., 11, 239 Sammes, P. G., 135,220 Sammour, A., 32 Samuel, C. J., 184 Sana, M., 194 Sanchez, J. P., 222 Saotome, M., 24 Sarkar, I., 82 Sasajima, K., 202 Sasaki, T., 109, 250 Satake, K., 221 Sauers, R. R., 127,279 Sauter, M., 275 Sauvage, J. P., 273 Sawaki, Y., 209 Scattergood, R., 140, 151 Schaap, A. P., 92, 121 Schaeffer, J. R., 185 Schamp, N., 228 Schaub, B., 172 Scheer, H., 287 Scheerer, B., 201 Scheffer, J. R., 99

Scheidegger, U., 146 Scheve, J., 23 Schied, D., 6 Schinski, W., 127, 279 Schlessinger, R. H., 174, 175 Schletter, I., 183 Schliep, H. J., 222 Schloegl, G., 94 Schlosser, M., 172 Schmeltz, I., 58 Schmid, H., 60, 165, 189 Schmidbauer, E., 25 Schmidt, D. K., 99 Schmidt, E. A., 179 Schmidt, R. R., 158 Schmidt, U., 220, 221 Schmidt, W., 249 Schmitz, E., 50 Schmuilovich, S. M., 177 Schneider, M., 180 Schoeller, W. W., 269 Schollkopf, U., 39, 191, 233,244 Schorscher, E., 222 Schroder, R., 233 Schubert, R., 202 Schultz, R. J., 256 Schumann, D., 211 Schwartz, S. B., 123 Scott, L. T., 173, 180 Scott, R., 223 Scouten, C. G., 287 Seckinger, K., 223 Sedrati, M., 145 Seebach, D., 224 Seeley, D. A., 16 Seible, J., 194 Selin, M., 32 Selve, C., 95 Sempuku, K., 32 Sen, G., 268 Senft, V., 59 Senona, M., 144 Sepp, D. T., 64, 257 Sepulchre, A. M., 21 Serebryakov, E. P., 173 Sergeev, A. I., 23 Seyferth, D., 76 Shabanov, A. L., 32, 47 Shabarov, Yu. S., 31, 212 Shah, M. A., 118,270 Shah, R . K., 213 Shamshurin, A. A., 11 Shanklin, J. R., 15 Shanmugan, P., 193 Sharma, S. D., 105, 133 Sharp, M. J., 242 Sharpless, K. B., 36 Shavel, J., 29, 246 Shaviv, A. 106 Shchelkunov, A. V., 19

Sheads, R. E., 11 Shealer, S. E., 97 Sheehan, J. C., 132, 236 Sheinkman, A. K., 209 Shellhamer, D. F., 107 Shen, T. Y., 218 Sher, F., 39, 176 Sherman, N., 133 Shestova, L. A., 168 Shibasaki, H., 189 Shida, T., 221 Shima, K., 96 Shimamura, T., 187 Shin, C., 194 Shinkai, I., 166 Shinoda, K., 221 Shirk, J. S., 125 Shiuey, S., 209 Shnyp, I. A., 34 Shokina, V. V., 32 Shudo, K., 44 Sicsic, S., 209, 268 Siddall, T. B., 51, 77 Sieber, W., 165 Siefken, U., 114 Siele, V. I., 223 Sienicki, W., 239 Sih, C. J., 101 Silhankova, A., 206 Silver, R. B., 239 Simchen, G., 200 Simmonds, A. B., 147 Simon, J., 274 Simon, W., 254 Simons, S. S.,230 Simpson, P., 153 Simpson, R. A., 215 Sims, J., 158 Singer, L. A., 97 Singh, H., 211 Sinitsa, A. D., 170 Siret, P., 197, 202 Sisido, K., 202, 260 Skattebl, L., 110, 214 Skell, P. S., 127 Skoldinov, A. P., 189 Skvortsova, G. G., 168 Skvortsov, N. M., 188 Sleiter, G., 172 Slusarchyk, W. A., 134 Sluski, R. J., 192 Smael, P., 162, 282 Smirnov, V. M., 287 Smith, D. G., 275 Smith, E. M., 240 Smith, F. X., 207 Smith, G. F., 242 Smith, I. J., 179 Smith, P. G., 96 Smith, P. J., 54 Smith, R. G., 191, 262 Smith, R. V., 146

Author Index Smith, W. T., 220 Smolanoff, J., 116, 164 Smolitkova, J., 219 Snider, B. B., 260 Snyder, J. P., 250, 259 Sojka, S. A., 2, 99 Sohar, P., 149 Sok-Hun Limy 226,260 Sokolova, I. L., 160, 239 Sokolova, T. D., 204 Sonnay, P., 221 Sonntag, A. C., 246 Sorm, F., 11 Sova, V. V., 94 Sovocool, G. W., 97 Spahic, B., 172 Sparrow, A. J., 151 Spasov, A. W., 127 Speckamp, W. N., 250 Spencer, C. F., 200 Spicer, C. K., 147 Spitzer, W. A., 133 Springer-Fidder, A., 203 Spry, D. O., 92 Spurlock, L. A., 256 Srivastava, R. C., 100 Srivastava, R. M., 157 Staas, W. H., 256 Stadler, P. A., 205 Stagryn, E. L., 53 Stahle, H., 215 Staniforth, D., 147 Stanishevskii, L. S., 21, 32 Stauff, J., 94 Steglich, W., 234 Steinbach, K., 200 Steinmetzer, H. C., 136 Stekoll, L. H., 69, 114 Stella, V., 200 Stemmle, B., 242 Stenberg, V. I., 223 Stenhede, U., 199 Stepanyan, A. N., 171 Sterba, V., 202 Stern, P., 206 Stern, T., 147 Sternson, A. W., 155 Sternson, L. A., 155 Stetter, H., 267 Stevens, R. E., 185 Steyn, P. S., 218 Stocks, R. C., 151 Stoll, M., 6 Stollar, H., 156 Stoodley, R. J., 92, 130, 266

Story, P. R., 117 Stothers, J. B., 116, 157 Stransky, Z., 242 Strausz, 0. P., 82 Streith, J., 106, 261 Stribrny, J., 27

299 Strozier, R. W., 158 Stuckwische, C. G., 161 Stud, M., 123 Stusche, D., 276 Stutz, P., 205 Suchitzky, H., 223 Suda, K., 159 Sugama, Y.,7 Sugano, H., 100 Suginome, H., 100 Sugita, M., 247 Sukawa, H., 227 Sukhoruchkin, A. G., 204 Sumi, Y., 144 Suminokura, T., 32 Summers, L. A., 228 Sunaga, M., 13 Sundberg, R. J., 207 Surzur, J. M., 170, 280 Sustmann, R., 162 Sutherland, I. O., 207, 272 Sutherland, R. G., 54 Suzuki, A., 48, 180 Suzuki, J., 137 Suzuki, M., 83, 233 Svedsen, A., 176 Swaelens, G.,143 Swallow, A. J., 208 Swallow, W. H., 30, 31, 170

Swartzkopf, G., 184 Sweeny, J. G., 169 Swenson, J. R., 213,251 Swern, D., 118 Sychkova, L. D., 31, 212 Sykes, B. D., 223 Szabo, V., 184 Szajewski, R. P., 190 Szeimes, G., 114 Tada, F., 7 Tadayoni, R., 257 Taga, T., 144 Tagaki, W., 13 Tagmazyan, K. T., 168 Taguchi, T., 116 Takacs, K., 209 Takahashi, T., 52 Takamizawa, A., 77 Takanobu, A., 173 Takaya, H., 176,274 Takayama, K., 116 Takeda, A., 19 Takemura, S., 172 Takenada, T., 208 Takeuchi, H., 172 Takeuchi, Y., 263 Takitani, S., 185 Talaty, E. R., 69, 114 Tamburin, H. J., 106 Tamura, Y., 83, 208, 277 Tan, H. W., 154

Tanaka, M., 185 Tanaka, Y., 1 Taneja, H. R., 39, 176 Tang, W. P., 196 Tartakovskii, V. A., 160, 239

Tashiro, M., 112, 238 Taskinen, E., 138 Tatarchuk, V., 48 Tataruch, F., 221 Tavares, D. F., 22 Tavernier, D., 142, 143 Taylor, D. R., 182 Taylor, E. C., 13 Taylor, G. A., 118, 270 Taylor, G. N., 141 Taylor, M. R., 253 Taylor, M. V., 135 Tchir, M. F., 276 Tehan, F. J., 272 Tel, L. M., 138 Terashi, M., 24 Terashima. S., 189 Testa, E., 100 Teufel, H., 209, 267 Texier, F., 67, 158, 163 Thayer, A. L., 121 Thebtaranonth, Y., 272 Thenn, W., 84, 163 Thies, P. W., 183 Thijs, L.,79 Thomas, A. F., 176 Thomas, D., 84, 115, 191 Thomas, R., 128 Thompson, J. A., 117, 179 Thompson, W. R., 254 Thomson, R. H., 26 Thong, C. M., 253 Thornber, C. W., 255 Thuiller, A., 73, 74 Thyagarajan, B. S., 268 Tiari, Z., 144 Tichy, M., 147 Tietze, L. F., 183 Tighe, B. J., 179 Tilak, B. D., 100 Tilichenko, N. N., 21 1 Timberlake, J. W., 85, 224 Tipping, A. E., 120 Tishchenko, I. G., 5, 21, 32, 34

Tisnes, P., 142 Tokmakov, G. P., 208 Tokunaga, H., 173 Tokura, K., 185 Tokura, N., 172 Tomita, S., 241 Tomizuka, I., 1 Tomboulian, P., 172 Tonge, A. P., 157 Tonnard, F., 160 Toppet, S., 130

300 Torii, A., 120 Tori, K., 92 Torosyan, G. O., 168 Trefanas, L. M., 224 Treffert, D., 254 Tremont, S. J., 98 Trend, J. E., 281 Trepanier, D. L., 151 Tringham, G. W., 96 Trippett, S., 152 Trocha-Grimshaw, J., 197 Trojnar, J., 244 Tronich, W., 76 Tropina, T. V., 2 11 Trost, B. M., 81, 174, 175, 283

Trotter, J., 207 Troxler, F., 206,207 Trska, P., 147 Trybulski, E. J., 160, 263 Tsai, M., 104, 133 Tseng, S. S., 122 Tserng, K. Y., 216 Tsida, T., 202 Tsigin, B. M., 223 Tsubaka, S., 170 Tsuchihashi, G., 156 Tsuboi, M., 249. Tsuboi, S., 19 Tsuge, O., 112, 120, 166, 201, 238

Tsuji, J., 175 Tsuji, T., 214 Tsuzki, Y., 185 Tsybina, N. M., 189 Tuerstein, A., 208 Tufariello, J. J., 160, 263 Turnblom, E. W., 286 Turner, J. O., 24 Turner, J. V., 188 Turner, W. A., 54 Turro, N. J., 136 Tursch, B., 254 Twasaki, T., 233 Tyvorskii, V. I., 21, 32 Uchida, K., 38 Uchiyama, M., 192 Uchytilova, V., 222 Uhe, D. H., 191 Ullman, E. F., 122 Ulrich, H., 190, 215, 233 Underwood, W. G. E., 135 Undheim, K., 60 Unger, R., 222 Unkovskii, B. V., 36, 204, 205

Urban F. J., 134 Urbanski, T., 185, 239 Urgu, T., 214 Urimoto, K., 38 Urinovich, E. M., 205

Author Index Uskokovic, M. R., 209 Usselman, M. C., 213,251 Utermoehlen, C. M., 69, 114

Utley, J. H. P., 147, 148 Vaciago, A., 271 Vais, J., 215 van Asbeck, T. M. W., 141 Van-Boom, J. H., 181 Van Cauwenberghe, R., 139

Vanderhaeghe,

H.,

128,

130

Van der Linde, H. J., 177 Van Haverbeke, Y., 196, 228

Van-Montfort, P. F. E., 178

Van Rens, E. M. M., 79 Van Parijs., R., 228 van Tilborg, W. J. M., 282 Vartanyan, S. A., 181 Vasickova, S., 147 Vassort, J., 287 Vaultier, M., 63, 68, 100 Vecchio, G. L., 162 Veliev, M. G., 27 Verduccia, J., 227 Verhoeven, J. W., 250 Verkade, J. G., 153 Verma, M., 9 Veysoglu, T., 10 Veyssieres-Rambaud, S., 280

Vialle J., 73, 74 Vicar, J., 218, 219 Viciago, A., 147 Vilkov, L. V., 94 Vinogradova, V. S., 27 Visser, J. P., 162, 282 Vitali, R., 230 Vitek, A., 147 Vivona, N., 161 Vlad, L. A., 11 Vlietinck, A. J., 128, 130 Voitenko, A. D., 226 Vogel, E., 25,42 Volkov, A. N., 185 Vollrath, R., 120 von Bredow, K., 275 von Strandmann, M., 246 Voorhees, K. J., 272 Voranov, V. K., 178 Vorob’eva, V. Y.,254 Vukov, V., 173 Vysata, F., 147,206 Wachsman, M. A., 109 Wadsworth, W. S., 154 Waegell, B., 257 Wagenaar, A., 79

Wagener, K. B., 201 Wagner, A. F., 218 Wagner, D., 197 Wagner, J., 274 Wagner, R. E., 154 Wagner-Jauregg, T., 194 Waigh, R. D., 210 Walden, M. K., 206 Walrond, R. E., 223 Wamhoff, H., 66,215,233 Wang, I., 9 Warman, M., 223 Warnhoff, E. W., 116 Warren, R. W., 181 Warrener, R. N., 262 Wassermann, H. H., 114 Watanabe, T., 192 Watson, K. G., 87, 89, 90, 115, 159, 189, 191

Watson, P. L., 262 Watts, P. H., 106 Wawzonek, S., 225 Way, G. M., 287 Webb, L. E., 151 Weber, J. D., 202 Wei, C. C., 136 Weichet, J., 27 Weiler, J., 194 Weiler, L., 249 Weinges, K., 242 Weis, C. D., 275 Weisman, G. R., 187 Weiss, R., 273, 274 Wendisch, D., 146, 202 Wenzinger, G. R., 207 Werner, W., 39 West, P. J., 125 Wetmore, S. I., 116, 164 Wetzel, R. B., 251 Weyerstahl, P., 280 White, A. W. C., 209 White, E. H., 136 White, J. G., 109 Whited, E. A,, 117 Whitehead, A. J., 126 Whiting, D. A., 158 Whiting, J. J., 190 Whittle, P. J., 152 Wiebe, L.,142 Wiecko, J., 136 Wiesner, K., 69 Wiest, R., 273 Wigfield, Y.Y.,190 Wildes, P. D., 136 Williams, D. E., 225 Williams, D. J., 128 Williams, J. A., 207 Williams, R. O., 144 Williams-Smith, D. L., 127 Williard, P. G., 85 Willig, B., 261 Wilkins, B. T., 249

Author Index Willenbrock, H. J., 215 Wilson, H. L., 177 Wilson, R., 87 Wilson, T., 136 Wilson, W. S.,262 Winkler, T., 165 Winkler-Lardelli, B., 189 Winston, A. E., 264 Wiseman, J. R., 277, 284 Wissmann, H., 224 Witkop, B., 263 Wittekind, R. R., 241 Wohl, R. A., 230, 233 Wojtowicz, J. A., 126 Wolf, J. G., 142 Wolfe, S., 133, 138, 280 Wolfhugel, J., 174 Wollweber, H., 231 Wong, J. L., 202 Wong, L. L., 121, 244, 271 Wood, G., 155, 157 Wood, H. B., 137 Woolhouse, A. D., 59 Woolsey, N. F., 21 Wray, V., 138 Wright, C. D., 120 Wright, D. B., 182 W u , G. S., 27 Wunderlich, J. A., 94 Wynberg, H., 275

301 Yagi, H., 1 Yagupol’skii, L. M., 48 Yakhontov, L. N., 254 Yakovenko, A. G., 230 Yamada, H., 109 Yamada, S., 189, 202 Yamaguchi, R., 278 Yamamoto, A., 202 Yamamoto, H., 42, 269 Yamamoto, Y., 24 Yamashita, K., 26 Yamauchi, M., 159 Yamazaki, S.,221 Yamazaki, T., 21 1 Yanagida, S., 118 Yang, K. H., 278 Yang, N. C., 96 Yano, Y.,13 Yauchi, T., 83 Yekta, A., 136 Yelland, M., 196 Yeung, H. W., 113 Yijima, C., 159 Yoneda, N., 100 Yonemitsu, O., 263 Yonezawa, T., 146, 253 Yoshida, H., 268 Yoshikawa, K., 146, 252 Yoshikawa, S., 237 Yoshikoshi, A., 175 Yokoyama, H., 7

Yoshimura, J., 194 Yoshimura, N., 187 Young, M.,134 Zador, E., 177 Zaitseva, K. A., 254 Zakharevskii, A. S., 32 Zanarotti, A., 207 Zander, R., 100,215 Zaniotti, G., 199 Zapevalov, A. Ya., 6, 49 Zara-Kaczian, E., 53 Zavgorodnii, S. V., 10 Zefirov, N. S., 278 Zelenin, K. N., 213 Zenbayashi, M., 241 Zhuk, D. S., 72 Zhuk, I. O., 239 Ziemann, H., 122, 202 Ziman, S. D., 81, 283 Zimmermann, D., 153 Zinner, G., 73, 86, 120, 200, 237 Zinnes, H., 29 Zitko, B. A., 254 Zitsman, J., 123 Zlotskii, S. S., 185 Zollinger, J. L., 120 Zutitkova, 0. A., 41 Zvilchovsky, G., 228 Zwanenburg, B., 79