Saturated Heterocyclic Chemistry Volume 4

A Review of the Literature Published during 1974

By M. F. Ansell, G. Pattenden

The Royal Society of Chemistry

Copyright © 1977 The Chemistry Society
All rights reserved.
ISBN: 978-0-85186-592-8

Contents

Chapter 1 Three-membered Rings By D. J. Maitland, 1,
Chapter 2 Four-membered Rings By B. J. Walker, 89,
Chapter 3 Five- and Six-membered Rings and Related Fused Systems By A. E. A. Porter, 132,
Chapter 4 Medium-sized Rings By C. J. Harris, 229,
Chapter 5 Bridged Heterocyclics By J. M. Mellor, 307,
Author Index, 344,

CHAPTER 1

Three-membered Rings

BY D. J. MAITLAND

1 Introduction

The number of papers consulted in the preparation of this chapter is approximately double that of Volume 3. As a result even more selectivity has been necessary than in the past, and the depth of treatment given to reviewing of individual papers has been reduced. A review covering the chemistry of three- and four-membered heterocyclic compounds with a single heteroatom in the ring has been published in ‘Rodd’s Chemistry of Carbon Compounds’.

2 Oxirans

Formation. — Direct Insertion. Oxygen atom insertion. The preferred routes to oxirans during the period of coverage of this volume have involved the addition of oxygen to alkenes, using either peracid or peracid–metal–metal salt techniques. A small group of techniques, however, have successfully employed singlet oxygen, molecular oxygen, or ozone. When the isomeric cycloheptatrienecarboxylates (1) — (4) are oxygenated with singlet oxygen generated by photosensitization or microwave discharge, only isomer (1) is reported to form oxygen adducts. Photosensitized oxygenation affords a mixture of (5) and the bis-diepoxide (6). The latter is the major product and is thought to be formed via (5), which is the only product on oxygenation by microwave discharge.

Ground-state (3P) O atoms generated by the mercury-photosensitized decomposition of nitrous oxide react in the gas phase with buta-1,3-diene to produce inter alia 3,4-epoxybut-1-ene. It has also been reported that conjugated dienones and diene esters are readily epoxidized at the C=C double bonds by molecular oxygen when heated in solvents which have readily abstractable hydrogen atoms. For example, when a xylene solution of the dienone (7) is heated at 120 — 130°C for 21 h in the presence of air, the oxiran (8) is formed in 65 — 70% yield. Although the products are usually similar to those obtained with m-chloro-perbenzoic acid, the reaction in comparison is highly stereoselective. Isolated double bonds or singly conjugated systems are not oxidized, as would be the case with the peracid. A free-radical chain mechanism is suggested.

Epoxides and heterocyclic compounds are reported 5 to be formed when 3-alkyl-2-benzyl-1,4-napthqquinones are treated with ethanolic t-butylamine in air at room temperature. Thus 2-benzyl-3-methyl-1,4-naphthoquinone afforded the epoxides (9a; 28%) and (10; 9%), and the naphtho[2,3-c]pyrrole (11a; 2%). Similarly 2,3-dibenzyl-1,4-naphthoquinone gave (9b; 15%) and the naphtho[2,3c]furan (11b; 1% ). These products may arise through the intennediacy of a hydroperoxide formed by reaction of a benzylic anion with oxygen.

A paper has appeared which describes the first reported synthesis of pure 4,5-epoxy-4,5-dihydropyrene (15), a compound of significance in cancer research. Ozonization of a dilute solution of pyrene in dichloromethane at –70°C affords the ozonide (12), which on reduction with sodium iodide in glacial acetic acid yields the lactone (13) and phenanthrene-4,5-dicarboxaldehyde (14). The latter when refluxed with tris(dimethylamino)phosphine in dry benzene is converted into (15).

7,7′-Binorbornylidene (16), prepared by the reaction of 7,7-dibromonorbornane with magnesium via carbenoid dimerization, when treated with ozone at –78°C or m-chloroperbenzoic acid at 0°C affords 2,2,3,3-bis-(1,4-cyclohexylene)oxiran (17). Photosensitized oxidation with molecular oxygen, however, produces the oxiran (17) and 3,3,4,4-bis-(1,4-cyclohexylene)-1,2-dioxetan (18). There is a 28.5-fold range in the ratio of (17) to (18), depending on the solvent used and the concentration. This ratio, however, does not parallel the polarity of the solvent nor the capability of the solvent as a substrate for Baeyer–Villiger reaction.

A synthesis of racemic trans-3,4-dihydroxy-3,4-dihydrobenzoic acid (27), which utilizes epoxide intermediates, has been reported (Scheme 1). Epoxidation of trans-1,2-dihydrophthalic acid (19) with excess m-chloroperbenzoic acid in ethyl acetate gives the bis-epoxide (20) in 84% yield, whereas reaction of (19) with singlet oxygen and thermal rearrangement of the endoperoxide affords the bisoxiran (21); epoxidation of (19) with 1 equivalent of m-chloroperbenzoic acid gives (22) in high yield. Trifluoroacetic anhydride converts (20) into the anhydride (23) which readily affords the ester (24) on reaction with methanol. Decarboxylation of (24) is effected by Barton’s procedure of irradiation after treatment with t-butyl hypoiodite and leads to the iodide (25). Reaction of (25) with zinc dust and triethylamine then affords the methyl ester (26) which is easily hydrolysed to trans-3,4-dihydroxy-3,4-dihydrobenzoic acid (27).

It has been shown that 1,4,4a,8b-tetrahydrobiphenylene (28), prepared from buta-1,3-diene and benzocyclobutadiene, reacts with m-chloroperbenzoic acid in chloroform to give a 9: 1 mixture of the isomeric epoxides (29a) and (29b) (Scheme 2). The epoxide (29a) on bromination with N-bromosuccinimide affords the dibromide (30), which on dehydrobromination with potassium t-butoxide at –3°C yields 2,3-epoxybiphenylene (31), a new arene oxide.

6-Methylenepentacyclo[5,3,0,02.5, 03.9, 04.8]decane (32) when oxidized with m-chloroperbenzoic acid affords in high yield the corresponding isomeric epoxides (33) and (34), which can be reduced with lithium aluminium hydride to the alcohols (35) and (36) (Scheme 3). The isomer distribution of the epoxides (33) and (34) is assumed to be the same (56:44) as that of the alcohols (35) and (36) since the reduction step is essentially quantitative.

The effect of the solvent properties on the stereoselectivity of the epoxidation of (+)-trans-p-menth-2-ene (37) with m-chloroperbenzoic acid has been studied. The yield of 2α,3α-epoxy-trans-p-menthane (38) increased in the range 67.1 — 73.6% as the dielectric constant of the solvent increased.

5,8-Dihydro-α-naphthol (39) can be isomerized with sodium hydroxide to give a mixture of isomers which react with m-chloroperbenzoic acid to afford a mixture of the epoxides (40) and (41). The oxiran ring in (41) can be opened with perchloric acid to afford the naphthalenetriol (42). The epoxides (40) and (41) can also be cleaved with methanol to give methoxy-substituted naphthalenediols, with sodium azide to give azidonaphthalenediols which are reduced to aminonaphthalenediols, or with amines to give (alkylamino)naphthalenediols. The naphthol (39) can also be converted into the corresponding benzyl ether or acetate and the above reactions can then be repeated to give benzyloxy- and acetoxy-naphthalene derivatives.

Another method has been published for the stereoselective synthesis of disparlure [(Z)-7,8-epoxy-2-methyloctadecane (43)], the sex attractant of the gypsy moth (Porthetria dispar L.). The procedure, which involves inter alia a different method of formation of the double bond than previously used, is summarized in Scheme 4.

Piperolide (44), a naturally ylidenetetronic acid derivative, when treated with m-chloroperbenzoic acid in boiling chloroform 14 yields the pyranodione (45; 54%) and the cinnamoylf uranone (46) as a by-product. The epoxide (47) is proposed as the key intermediate.

Gunstone and Corey have each suggested, at different times in the past, that epoxy-polyunsaturated fatty acids might be intermediates in the enzymatic cyclization of polyunsaturated fatty acids to prostaglandins. Two reports have now appeared in which this proposal has been put to the test. In the first of these reports, non-8-ynoic acid was treated with ethylmagnesium bromide and 3-bromoprop-1-yne to give dodeca-8,11-diynoic acid which was then converted into a di-Grignard reagent and coupled with 1-bromo-cis-oct-2-ene. The resulting cis-eicos-14-ene-8,11-diynoic acid was epoxidized with peracetic acid and the product hydrogenated over Lindlar’s catalyst to give ([+ or -])-eicosa-cis-14,15-epoxy-cis-8,11-dienoic acid (48). When the epoxide (48) was incubated in a prostaglandin-synthesizing system of bovine origin (BSVM) no significant quantity of PGE1 (49) was detectable. Instead (48) was converted into eicosa-14, 15-dihydroxy-cis-8,11-dienoic acid (50). In the second report p-nitrophenyl cis-eicosa-8,11,14-trienoate was epoxidized with 1 equivalent of m-chloroper-benzoic acid to give, after hydrolysis, 60% of a mixture of mono-epoxy-acids (48), (51), and (52). The radioactive [1-14C]-analogues of these were similarly prepared and it was found that the mono-epoxy-acids (48), (51), and (52) were not intermediates in the prostaglandin synthase system from sheep seminal vesicle. These observations, therefore, would suggest that cis-epoxy-poly-unsaturated fatty acids are unlikely to be free biosynthetic prostaglandin intermediates in the mammalian system.

A series of papers has appeared in which the kinetics and mechanism of the epoxidation of alkenes by peracetic acid are discussed.

Epoxidation of the allyl ether (53) with peracetic acid is reported to afford the butenyloxiran (54; R = CH2 = CHCH2) which can be hydrogenated with one or two equivalents of hydrogen to give (54; R = Prn) or the butyloxiran (55) respectively. The (alkyloxymethyl)oxiran (57) is similarly prepared from the alkyl ether (56).

The epoxy-esters (58) — (60) have been prepared by oxidation with peracetic acid of the corresponding cyclohexene carboxylates, for which syntheses are described.

It is reported that 1,4,5,8-tetrahydronaphthalene, when treated at 15°C with peracetic acid in dichloromethane containing sodium acetate, affords 4a,8a-epoxy-1,4,5,8-tetrahydronaphthalene (61). The oxiran (61) on bromination with bromine in ether at -70 to -78°C yields the bromo-oxiran (62), which on refluxing with sodium methoxide in ether gives the epoxyannulene (63) in good yield.

The 5,6-epoxyperhydroisoindolines (65) — (67) have been synthesized stereo-specifically (Scheme 5). The oxirans (66) and (67) were prepared by oxidizing the appropriate 2-benzoyl-3a,4,7,7a-tetrahydroisoquinoline with peracetic acid, and the oxiran (65) was formed when (3aRS,5SR,6SR, 7aSR)-2-benzoyl-6-brornohexahydroisoindolin-5-ol (64) was dehydrobrominated with sodium hydroxide.

Allene oxides, cyclopropanones, and 1,4-dioxaspiro[2,2]pentanes (spirodioxides) have been proposed as reactive intermediates in the peracid oxidation of allenes. In an attempt to substantiate such proposals Candall et al. have studied the peracid oxidation of several highly hindered allenes (68) — (71), and have succeeded in isolating the stable allene oxides (72) and the spirodioxides (73).

The reactions of arylidene derivatives of cycloalkeneaza-arenes with perbenzoic acid have been studied. 1-Benzylidene-1,2,3,4-tetrahydroacridine, 1,4-dibenzylidene-1,2,3,4-tetrahydrophenazine, and 1,6-dibenzylidene- and 1,4,6,9-tetrabenzylidene-1,2,3,4,6,7,8,9-octahydrophenazine afford the corresponding spiro-oxirans, e.g. (74). 1-Benzylidene-1,2,3,4-tetrahydrophenazine and 1,6-dibenzylidene-1,2,3,4,6,7,8,9-octahydrophenazine give the spiro-oxiran oxides (75) and (76), respectively.

The epoxidation of cholest-5-ene-3β,4β-, -3β,4α-, -3α,4α-, and -3α,4β-diol with perbenzoic acid in ether, benzene, or chloroform gives mixtures of the respective 5α,6α- and 5β,6β-epoxy-compounds. The formation of intermolecular hydrogen bonds between the peracid and the hydroxy-groups and intramolecular hydrogen-bonding in the cholestenediols, as well as solvation of hydroxy-groups and the peracid, influences the ratio of the isomers formed as well as the reaction rate.

Stereoisomeric 5-methyl-3a,4,5,7a-tetrahydroindanes (77) can be prepared from trans-deca-1,4,9-triene via deca-1,6,8-triene by alkaline and thermal routes. The trans-3a,7a-form occurring as the sole component in the alkaline cyclization, and as a main component in the thermal cyclization, represents the energetically favoured stereoisomer. Epoxidation of (77) with perbenzoic acid yields six stereoisomeric epoxy-derivatives (78). Amongst the epoxytetrahydroindanes with the trans-3a,7a structure, those configurations are formed preferentially in which the 5-methyl group is orientated trans to the oxiran ring. The molecular configurations of the various stereoisomeric compounds (77) and (78) are discussed and assigned on the basis of 1H. n.m.r. spectroscopic data of the olefinic and the oxiran-ring proton signals.

A study has been made of the action of 4-nitroperbenzoic acid on the Diels–Alder addition products (79) in a diterpenic series. It was concluded that the type of product formed, an oxiran (80), a ketone (81), or a lactone (82), depends on both the steric and electronic effects of the substituents R1 and R2. Possible mechanisms are discussed.

It has been found that methyl 3,7,11-trimethyldodeca-2,4,6,10-tetraenoate, when treated with one equivalent of perphthalic acid in ether for 3 days at 0°C, affords methyl 10,11-epoxy-3,7, 11-trimethyldodeca-2,4,6-trienoate, whereas treatment with two equivalents of oxidant leads to methyl 4,5,10,11-diepoxy-3,7,l1-trimethyldodeca-2,6-dienoate.

Hex-3-enoic acid treated successively with diazomethane and perphthalic acid affords methyl trans-3,4-epoxyhexanoate. Treatment of the latter with hydrogen bromide then leads to a 5: 1 mixture of methyl 4-bromo-3-hydroxyhexanoate and 4-bromo-5-ethyltetrahydrofuran-2-one.

Epoxidation of p-mentha-1,4-diene (83) by superoxybenzimidic acid in methanol is reported to give in 60% yield the monoepoxides (84) and (85), which can be reduced by lithium aluminium hydride to yield the menthenols (86) and (87) (Scheme 6). Epoxidation of the same terpinene (83) with an excess of superoxybenzimidic acid, prepared in situ from cyanobenzene and 50% hydrogen peroxide, affords a 92% yield of a cis–trans mixture of the dioxirans (88; 79%) and (89; 21%); perbenzoic acid gave a 69% yield of a mixture of (88; 56%) and (89; 44%).

An improved procedure for the synthesis of ethyl glycidate has been described. Ethyl prop-2-enoate is epoxidized with trifluoroperacetic acid to give ethyl glycidate (50%) and ethyl 3-trifluoroacetoxy-2-hydroxypropanoate (48%). The latter is then cyclized with sodium hydride to yield ethyl glycidate.

A study of the mechanism of the epoxidation of allyl bromide by permaleic acid suggests that intermolecular hydrogen-bond formation is involved. In the presence of dimethylformamide, the allyl bromide initiates the decomposition of the permaleic acid, and the decomposition is first-order in allyl bromide and is also affected by the DMF concentration.

The epoxidation of ethene, propene, and 2-methylbut-2-ene with organic peracids has been studied in ten solvents. In aprotic non-basic solvents the rate constants correlate with the ET values. In basic solvents the rate is independent of the polarity. The results are discussed in connection with the Bartlett mechanism.

A peracid resin, prepared from polystyrene by successive chloromethylation, oxidation, and treatment with hydrogen peroxide, can be used to oxidize alkenes to oxirans. For example, treatment of methylcyclohexene with two equivalents of the resin affords the corresponding oxiran in 65% yield. The resin is not impact sensitive.

The epoxidation of αβ-unsaturated sulphones by hydrogen peroxide in alkaline media is known to be non-stereospecific, yielding the same epoxide from either stereoisomeric reactant. For example, treatment of cis– or trans-1-phenyl-2 -(toluene-p-sulphonyl)ethene with alkaline hydrogen peroxide in aqueous acetone at 45°C affords the trans-epoxy-sulphone (92). It has now been reported 35 that epoxidation of cis-1-phenyl-2-(toluene-p-sulphonyl)ethene (90) with potassium hypochlorite in aqueous dioxan results in exclusive formation of the cis-epoxysulphone (91). Epoxidation of (90) with m-chloroperbenzoic acid gives mainly (91) and ≤ 53 of the trans-epoxy-sulphone (92), but (90) with hydrogen peroxide or t-butyl hydroperoxide gives a 1:9 mixture of (91) and (92). The stereochemistry of the epoxidation of (90), therefore, seems to depend on the nature of the epoxidizing nucleophile. Such findings may have useful synthetic implications.

(Continues…)Excerpted from Saturated Heterocyclic Chemistry Volume 4 by M. F. Ansell, G. Pattenden. Copyright © 1977 The Chemistry Society. Excerpted by permission of The Royal Society of Chemistry.
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