Synthesis of Four-membered Rings

Cyclobutanes.—Condensation of 1,3-dibromobutane with alkaline salts of phenyl-acetonitrile is syn-stereoselective in media of low dielectric constant. The influence of the reaction conditions on the ratio of product (172a) and (172b) has been examined in some detail and it has been reported that a similar reaction with 1,2-dibromopro-pane affords 2-methyl-1-phenylcyclopropyl cyanides.  

Stork and Cohen have shown that whereas epoxynitriles of type (173 =R = 

H) generally undergo cyclization by carbanion attack at the unsubstituted end of the oxiran, with equal substitution at both ends of the epoxide, cyclobutanes are always 

Ranfaing, B. Galas, J. M. Fabre, and L. Giral, Tetrahedron Letters, 1974,1439 see also M. Larcheveque. A. Debal, and T. Cuvigny, Bull. Soc. chim. France, 1974,1710. 

Cyclobutane has been found amongst the reduction and alkylation products formed when 1,4-dihalogenoalkanes are heated with alkali-metal naphthalenes. Treatment of the tosylate (174) with methanohc potash gives either the cyclobutyl ether (175 X = OMe) or cyclohexenone (176), depending on the reaction times. Similarly, with KCN in DMSO (174) affords (175 X = CN) and (177).  

The base promoted cyclization of yb-epoxysulphones affords a route to cyclo-butanes. Treatment of the epoxides (27a—-d) with butyl-lithium in THF gave first the cyclopropyl carbinols (28). Dehydration of these alcohols and epoxidation of the resultant vinylcyclopropanes gave the epoxides (29), Further treatment with butyl-lithium then gave the bicyclo[l,l,0]butanes (30). These compounds are quite stable, but react readily with iodine to give the corresponding di-iodides (31). 

Corbel and Durst have shown that the choice of base is important in controlling the size of the ring formed in this type of cyclization. With methyl-lithium or lithium di-isopropylamide, the epoxysulphones (32a—c) cyclize to cyclopropanes (33). With methylmagnesium iodide, however, the cyclization takes the alternative pathway giving rise to the cyclobutanols (34). In other examples presented, in which the 

Control of the size of the ring formed in this way is also applicable to the cyclization of yS-epoxynitriles. Thus the nitriles (35a and b) have been converted into either the cyclopropyl alcohols (36), or into the cyclobutanols (37) by application of either lithium di-isopropylamide or methylmagnesium bromide. 

Photochemical [2+ 2] cycloadditions remain the most widely used method for the formation of cyclobutanes. The dimerization of maleic anhydride in carbon tetrachloride solution gave the anti-dimer (43). The same structure is produced by irradiation of maleic anhydride in the solid phase. Irradiation of trans,trans-dibenzyli-dene acetone in benzene solution gave the head to head truxinic type of dimer (44). The photodimerization of 2-penten-4-oIide in acetonitrile solution led to the formation of three isomeric dimers. The structures of all have been established the major product was the head to tail dimer (45). 

Unusual modes of dimerization of cinnamic acids have been found in the solid state photodimerization of the octadecyl esters of these acids. Bolt and co-workers have crystallized this ester of cinnamic acid in three different forms, one of which cyclized to an a-truxilic acid type of dimer, one of which was photo-inert, and one of which gave the 6-truxinic acid dimer. Two crystal forms of the ester of trans-p-chloro-cinnamic acid were isolated, one of which cyclized to an a-truxillic acid, the other being photo-inert. The long-chain ester group presumably modifies the crystal structure, and use of orienting groups of this type may allow the formation of other dimers not usually obtained in solid state dimerizations. 

Cyclobutanes.— The low-temperature (128 K) reaction of cyclopropane with liquid diazomethane is reported to yield cyclobutanes. This reaction has been observed before in matrices at 20 K. Cyclobutylmethylmagnesium halides are formed by the reaction of allylmagnesium halides with olefins at elevated temperatures. Reaction of E- or Z-but-2-enylmagnesium chloride with oct-l-ene gave, after hydrolysis, the trisubstituted cyclobutane (14) as a mixture of stereoisomers, and the reaction of 3-methylbut-2-enylmagnesium chloride gave a mixture of the two possible orientation products (15) and (16). 

Lehmkuhl, D. Reinehr, D. Hennenberg, G. Schomberg, and G. Schroth, Annalen, 1975,119. 

Stork has demonstrated that the readily available protected cyanohydrins of aldehydes are useful acyl carbanion equivalents, and has now applied these in the preparation of small rings. Treatment of the ethoxyethyl-protected cyanohydrin of 4-chlorobutyraldehyde (17) with sodium hexamethyldisilazide gives the cyclo-butanone cyanohydrin derivative (18) in high yield. The cyanohydrin derivative is easily hydrolysed to the ketone, or may be reduced with lithium aluminium hydride to the P-amino-ether (19), which is also a useful synthetic intermediate. 

The size of the rings formed in the Stork epoxy-nitrile cyclization appears to be a function of the stereochemistry of the epoxide ring. Treatment of the cis-epoxy-nitrile (20) with sodium amide in THF gave a mixture of the epimeric cyclobutane cyano-alcohols (21). Cyclization of the rrons-epoxy-nitrile (22) under the same conditions gave both cyclobutane and cyclopentane cyano-alcohols (21) and (23) in a ratio of 28 72. The ratio of cyclobutane to cyclopentane products was not markedly affected by changing the alkyl substituent on the epoxide ring. 

Depazay, and J. d Angelo, Tetrahedron Letters, 1975, 389. J. Y. Lallemand 2ind M. Onanga, Tetrahedron Letters, 1975, 585. 

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D. The Synthesis of Four-membered Ring Sulfoxides and Sulfones. . . 444... 

Although four-membered rings are highly strained and not very stable heterocycles, there are some examples (Fig. 3.5) for the preparation of heterocycles of this type on solid supports. Different /9-lactams (229-230) have been synthesized employing different synthetic pathways [133, 275, 306-309] such as the addition of ketenes (Scheme 3.34) [306], or ester enolates to imines [133]. Also the synthesis of four-membered rings with two heteroatoms has been reported [310]. 

The stereoselective or stereospecific formation of these compounds and their interaction with butyllithium was studied with the help of NMR. Paquette and Freeman first applied asymmetric induction to the synthesis of four-membered rings, especially with the sulfene-enamine 2 -F 2 cycloaddition. The in situ generation of sulfene 68 by dehydrochlorination with butyllithium of the sulfonyl chloride allowed the formation of cycloadduct 69 in 88 % yield. In a variation, the sulfene may be generated by base-induced... 

SYNTHESIS OF FOUR-MEMBERED RINGS WITH TWO HETEROATOMS 467... 

In an indirect synthesis of four-membered rings, xof-bipyridylnickelacyclopentane (3) was synthesized in 83% yield from bis(cycloocla-1,5-dtene)nickel(0), ,x -bipyridyl and 1,4-dibromobu-tane. The treatment of x.a -bipyridylnickeiacyclopentane (3) with either methyl acrylate or maleic anhydride triggered a reductive elimination process which gave cyclobutane in 57 and 75% yield,... 

Most important, from a preparative point of view, for the synthesis of four-membered rings are the Wolff rearrangement of mono- or polycyclic x-diazocyclopentanones, the Favorskii rearrangement of polycyclic x-halocyclopentanones and, to a lesser extent, various rearrangements including cationic intermediates. 

The synthesis of four-membered ring metallacycles was initially driven by the recognition that low-valent transition metals could mediate cyclopropane carbon-carbon bond cleavage and by the extensive attention devoted to reactivity patterns thought to be relevant to olefin metathesis. More recently, however, organometallic and organic researchers... 

Just occasionally a Pd reaction with an alkyl o-complex is successful. One instance is the remarkable synthesis of four-membered ring lactones 109 from styrene oxide 107 with 1.6% Pd in 63% yield.30 Probably the OH group on the same carbon as the [3-Hs in 108 inhibits 3-elimination. 

The great utility of [2 + 2] photocycloadditions for the synthesis of four-membered rings continues to be demonstrated, and several examples are featured in a review.Oppolzer and Pattenden " and their respective co-workers have reported further on intramolecular photocycloadditions involving cyclic 1,3-dione enol esters and the ring expansions that the adducts can undergo (Scheme 3). 

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