Saturated Heterocyclic Chemistry (v. 3)

A Specialist Periodical Report Saturated Heterocyclic Chemistry Volume 3 A Review of the Literature Published during ...

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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


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


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


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


(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.


(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.


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


+ 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)


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


-

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


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


-)-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


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.


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


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


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


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.


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


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


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


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


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


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


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


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)


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


(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).


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).


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


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


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


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).


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 ns5o166 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


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.


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


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


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.


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.


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


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


(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


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.


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


(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


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.


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.


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.


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


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


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.


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


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


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


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


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.


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.


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


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.


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


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


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.


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.


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).


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


(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.


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.


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

:

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