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Saturated Heterocyclic Chemistry Volume 3
A Review of the Literature Published During 1973
By M. F. Ansell
The Royal Society of ChemistryCopyright © 1975 The Chemical Society
All rights reserved.
BY D. J. MAITLAND
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.
In the M.T.P. review series three-membered ring compounds have been reviewed. The synthesis, reactivity, and synthetic applications of α, β-epoxy-ketones have been summarized. Reviews have been published on the synthesis and characteristics of epoxides and arene oxides, selectivity in the reactions of epoxides, and the electrocyclic ring-opening reactions of bicyclic aziridines with oxirans.
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 oxygen or ozone have been reported. Hexafluoropropylene has been epoxidized (79%) by reaction with oxygen at 200 °C over a silica catalyst, activated either by pre-treatment with hexafluoropropylene or by pretreatment with 1M hydrochloric acid followed by washing and treatment with hexafluoro-propylene. Tetrafluoroethylene and chlorotrifluoroethylene were also successfully epoxidized at 25 °C by a variation of the same technique.
The conversion of styrene into 1-phenyl-1,2-epoxyethane, without serious competition from polymerization, has been achieved by the oxidation10 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 peroxide in chlorobenzene at 120 °C.
While investigating the thermal cycloreversion of the bicyclo [3,1,0]hex-2ene system, Padwa and Brodsky12 found that when exo,exo-3,4,6-triphenyl-bicyclo[3,l,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 (1), (2), and the oxiran (4).
Heating (1) or (3) at 160 °C under nitrogen afforded a 16:1 equilibrium mixture of (1) and (3). Thus the oxirans must be formed by thermal epoxidation of the olefins by molecular oxygen, and the reactions can be rationalized in terms of a biradical intermediate formed by cleavage of the cyclopropane ring.
A continuous process for the preparation of epichlorohydrin has been reported. 1-Chloroprop-2-ene in dimethyl phthalate containing 10 — 12% acetaldehyde is oxidized 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. 1,1,3-Tri-t-butylallene on 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 1,1-di-t-butylallene (8) nor 1,3-di-t-butylallene (9) gave an oxiran when treated with ozone. The allene (8) afforded di-t-butyl ketone and 2,2-di-t-butylcyclopropanone whereas (9) gave exclusively pivaldehyde. The degree of substitution of the allene is obviously a critical factor.
The epoxidation of allenes by organic peroxy-acids has also been studied by Crandall et al. The products are rationalized in terms of an initial epoxidation of the allene (10), followed by competitive partitioning of the monoepoxide (11) 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 β-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 α-acyloxy-α'-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 α-acetoxy-ketone (18) arising by acetoxylation of the epoxyallene. Under the same conditions 1,1-dimethylallene gave analogous products. Under acid conditions, tetramethylallene upon epoxidation gave the α-methoxy-ketone (21) as the only product (Scheme 2).
Cyclonona-1,2-diene with excess peracetic acid in buffered methanol affords the epoxide (22), the lactone (23), cyclo-octene, and the α-acyloxy-α'-hydroxy-ketone (24).
4-0xoisophorone (25) when epoxidized with hydrogen peroxide (30%) affords oxabicycloheptanedione (26), which with 20% sulphuric acid yields 2hydroxy-3,5,5-trimethylcyclohex-2-en-1,4-dione.
αβ-Unsaturated β'-alkoxy-ketones (27) can be converted into the corresponding epoxides (28) in good yield by treatment at 40 °C (with one equiva lent of alkaline hydrogen peroxide. Excess alkaline hydrogen peroxide effects destructive oxidation, affording formic acid, acetone, and a, β-alkoxy-carboxylic acid.
Olefins can be epoxidized in high yield and with high selectivity by hydrogen peroxide in the presence of fluoro(halogeno)acetone catalysts. Thus oct-1-ene was epoxidized (100%) in the presence of hexafluoroacetone. Similarly effective were Cl3CCOCC12F and ClF2CCOCFC12. Propylene, allyl alcohol, trans-stilbene, and 1,5-cyclo-octadiene were similarly epoxidized in high yield.
Fluoro-oxirans have been prepared 19 by the epoxidation of RCF=CF2 at -20 °C with hydrogen peroxide in methanolic potassium hydroxide.
Substituted cyclohexenes 20 with an olefinic side-chain undergo selective epoxidation with peracetic acid to afford the corresponding epoxycyclohexane. Thus 2,6,6-trimethyl-1-(but-3-en-1-ol)cyclohex-1-ene (29) gave the epoxycyclohexane (30).
Cyclohex-3-ene-1-carboxylates (31), obtained by treatment of the appropriate cyclohexenecarboxylic acid with R1CO2CH2CH2Cl in xylene containing aqueous potassium hydroxide, afford the corresponding oxirans (32) on treatment with 50% peracetic acid in chloroform.
Treatment of endo-tricyclo [5,2,l,02·6]deca-3 ,8-dienes with t-butyl hydroperoxide or peracetic acid affords a mixture of epoxides22 which can be separated by steam-distilling the product mixture to isolate the diepoxy-endo-tricyclo [5,2,l,02·6]decane. The residual monoepoxide mixture is then distilled in the presence of 0.1% bis-(1-naphthyl)amine to give 3,4epoxy-endo-tricyclo[5,2,l,02·6]dec-8-ene (33) and the 8,9-epoxy-isomer.
Epoxidation of 1-(p-methoxybenzyl)-2-methyl-l,2,3,4,5,6,7,8-octahydro-isoquinoline (34) with performic acid affords the isomeric epoxides (35) and (36) and the two diols (37) and (38) (Scheme 3). Hydrolysis of the epoxides (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 1substituent. Interpretation of this result is difficult, but it has been shown that the amino-group in the isoquinoline ring does not particularly participate in the formation of the epoxides, and a particular role of the ArCH2 group in the transition state would be suggested. The transition state (39) for the formation of (36), with intramolecular hydrogen-bonding as depicted in the formula, may depress the activation energy for (39), leading to predominant formation of (36). The competitive reactions of (35) and (36) have also been examined.
The peroxy-acid oxidation of cyclo-octatetraene oxide yields the bis-oxirans (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 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.
The epoxyoxatridecenoate (48), a pesticide, is obtained as a mixture of E)- and (Z)-isomers by treating the unsaturated ester (47) with m-chloro-perbenzoic acid. The acetal (46), prepared from (Z)-4-methylhex-3enol and 5-bromo-2,2-ethylenedioxypentane, on acid hydrolysis followed by reaction with dimethyl methoxycarbonylmethylphosphonate affords the unsaturated ester (47).
When αβ-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 2,3,4,5,6-hexamethylcyclohexa-2,5-dienone with m-chloroperbenzoic acid 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 single photoisomer 5-acetyl-2 ,3,4,4,5-pentamethylcyclopent-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-5-en-2-one (51), is known to undergo very facile rearrangement to I ,3,3-trimethyl-2,7dioxabicyclo[2,2,l]heptane (53) when heated or treated with acid. Thus treatment of (51) with m-chloroperbenzoic acid and sodium bicarbonate affords a mixture of (52) and (53). A simple procedure for the m-chloroperbenzoic acid epoxidation of such acid-sensitive olefins has been reported. The method, which employs a biphasic solvent mixture of dichloromethane and 0.5M sodium bicarbonate solution, was used to epoxidize the γδ-unsaturated ketone (51), affording 85% conversion into (52) with no concurrent formation of the bicyclo-compound (53). An olefinic acetal (54) and olefins containing enol-ester moieties, Me2C=CHCH2CH2C(OAc)=CH2 and Me2C=CHCH2CH=C(0Ac)Me, were similarly epoxidized. The system can also be used to epoxidize less reactive olefins (e.g. hex-1-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 l,2-epoxy-p-menth-8-ene in 85% yield.
Epoxycyclopentanes (55) have been prepared by epoxidation of the appropriate cyclopentenes with monoperphthalic acid.
Substituted amides of sorbic acid (56) when treated with phthalic anhydride-hydrogen peroxide in ethanol containing urea afford the corresponding epoxyhexenamides (57) (Scheme 5). Hydrogenation of 4,5-epoxy-NN-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).
Syntheses for disparlure [cis-1, 8-epoxy-2-methyloctadecane (61)], a sexual attractant of the gypsy moth (Porthetria 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). ln 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 Beroza have synthesized a tritium-labelled disparlure (cis-7,8-epoxy-2-methyl[7,8-3H2]-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 activity have been prepared by the reaction of N-trifluoroacetyl-p-aminoacetophenone with geranyl bromide and citronellyl bromide respectively, followed by oxidation of the resulting unsaturated derivatives with perphthalic acid in diethyl ether. Masking of the amino-group of the intermediate N-(3, 7-dimethylocta-2,6-dienyl)-p-aminoacetophenone and N-(3,7-dimethyloct-6-enyl)-p-aminoacetophenone with 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.
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-diethylaminodimethyloxosulphonium fl.uoroborates as stable, white, crystalline solids. 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 ylides have proved to be effective nucleophilic methylene-transfer reagents. Reactions with aldehydes and ketones afford epoxides, whereas reactions with αβ-unsaturated ketones give cyclopropyl compounds as the major products. A certain degree of selectivity is observed: diethylaminomethyloxosulphonium methylide with 4-t-butylcyclohexanone gave only the (Z)-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. The oxirans (65) (R1 = 2-quinolyl, 4-quinolyl, 1-isoquinolyl, 4-quinazolinyl, 2-benzoxazolyl, 1,3 dimethyl-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 (R1SO2Me) or aryl chloride with diphenylmethylsulphonium tetrafiuoroborate 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 side-reactions do not occur. Thus, by stirring a heterogeneous mixture of lauryl-dimethylsulphonium chloride (66) and a carbonyl compound in benzene-aqueous sodium hydroxide, oxirans have been synthesized in high yields. 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 tetrabutylammonium iodide is present. 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 20 — 30% and 2,6-diphenyl-1,4-oxathian 4-oxide (68) (12%). With αβ-unsaturated ketones no oxirans were formed, but instead cis-trans mixtures of cyclopropane derivatives.
Excerpted from Saturated Heterocyclic Chemistry Volume 3 by M. F. Ansell. Copyright © 1975 The Chemical Society. Excerpted by permission of The Royal Society of Chemistry.
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Table of Contents
Front matter; Foreword; Contents; Three membered rings; Four membered rings; Five and six membered rings and related fused systems; Medium sized rings; Bridged heterocyclics; Author index