Methyl alkyl sulfoxides

A major problem with the sulfoxide synthesis using menthyl sulfmates is its failure to produce optically pure dialkyl sulfoxides. The prerequisite menthyl alkanesulfinates are oils which have resisted separation into the individual epimers. The menthyl phenyl methanesulfmates are an exception the R epimer is crystalline . One solution to this problem, at least for preparing methyl alkyl sulfoxides, was achieved using cholesteryl methanesulfmates (27) . Both epimers were crystalline and could be separated by fractional crystallization, although in poor yield. Treatment of the epimers with n-propyl, n-butyl, isobutyl, p-tolyl and benzyl magnesium halides yielded the respective methyl alkyl sulfoxides (28) in greater than 95% e.e. and in 32 to 53% yields. 

Nevertheless, correlations have been found in four j3-hydroxyesters (107), eight aminoesters (108), primary a-deuterioalcohols (109), and secondary carbinols (110). Even in a closely related series, exceptions have been found (110) in search of a predictable pattern. A study of nonequivalence in methyl alkyl sulfoxides with CLSR 54c (48) revealed a diminution of nonequivalence on increasing alkyl bulk with an inversion of sense between n-propyl and isopropyl. Changes in nonequivalence sense in several cases with different CSA-solute ratios were also observed. Presently, these CLSR configurational correlations remain totally empirical. 

An alternative route to enantiomeric methyl alkyl sulfoxides (95) is based on the reaction of aliphatic Grignard reagents with the dia-... 

Methyl alkyl sulfoxides that do not contain other strongly perturbing groups have negative Cotton effects centered at the strong absorption band near 200 nm and have the (i > configuration. 

It must be stressed, however, that the methyl alkyl sulfoxide rule is not valid for alkyl benzyl and alkyl allyl sulfoxides (222-224), where the electronic, steric, and solvent effects exert influences on the chiroptical phenomena in a way that is difficult to rationalize. This rule was found to be satisfactory and was used for the assignment of absolute configurations of steroidal (200,201,225), penicillin (226), and amino acid (227-230) sulfoxides. 

Cyclodextrins, toroidal molecules composed of 6, 7 and 8 D-glucose units, are now commercially available at reasonable cost. They form inclusion compounds with a variety of molecules and often differentially include sulfoxide enantiomers29,30. This property has been used to partially resolve some benzyl alkyl, phenyl alkyl and p-tolyl alkyl sulfoxides. The enantiomeric purities after one inclusion process ranged from 1.1 % for t-butyl p-tolyl sulfoxide to 14.5% for benzyl r-butyl sulfoxide. Repeating the process on methyl p-tolyl sulfoxide (10) increased its enantiomeric purity from 8.1% to 11.4% four recrystallizations raised the value to 71.5%. The use of cyclodextrins in asymmetric oxidations is discussed in Section II.C.l and in the resolution of sulfmate esters in Section II.B.l. 

Carbanions formed from methyl methylthiomethyl sulfoxide 94 and ethyl ethylthio-methyl sulfoxide 95 were shown to be alkylated in excellent yields126,127. Treatment of 94 with rc-BuLi or KH and subsequent reaction with 1, n-dihalo- or bis(tosyloxy)alkane gave 3-, 4-, 5- and 6-membered 1-methylsulfmyl-l-methylthiocycloalkanes128"130. Upon hydrolyses of these products, the corresponding aldehydes and ketones are obtained. 

For methyl phenyl sulfoxide it was found that 25% of the adduct decomposes to give phenyl radical and methane sulfinic acid, while 75% of the adduct leads to methyl radical and benzene sulfinic acid. For heavier alkyl groups the formation of the benzene sulfinic acid is even more dominant, 96% for R = Et and 100% for R = C2H4C1 or i-Pr. 

The seleno derivative 1374, which can be readily prepared by reduction of di-phenyldiselenide with sodium borohydride then alkylation with chloromethyltri-methylsilane, is alkylated to 1375 to give, on oxidative hydrolysis, aldehydes 1376 in high yields, PhSe02H-H20 1377 [104], and 7 (Scheme 8.44). Alkylation of the commercially available methyl thiomethyl sulfoxide 1378 leads to mono- or dialkyl... 

Pedersen and coworkers studied the El mass spectra of several alkyl 2-hydroxyphenyl sulfoxides (10) and found that, contrary to methyl phenyl sulfoxide and the corresponding sulfones , they do not show any abundant skeletal rearrangement ions (see Section III). This is obviously due to an ortho effect as shown in structure 10. 

Recently, optically active (+)-(R)-methyl tolyl sulfoxide 102, R = H was alkylated with a very high diastereoselectivity The sulfoxide was treated with either lithium diisopropy-... 

This (Sj-rich methyl phenyl sulfoxide was subjected to the inclusion with the enantiomer (1 ) as summarized in Scheme 1. In this procedure, (.S )-methyl phenyl sulfoxide was obtained with high enantioselectivity. It is noteworthy that racemic methyl phenyl sulfoxide can be recovered from the washings. Thus, two enantiomers of methyl phenyl sulfoxide can be obtained by the use of the dipeptide (1) and its enantiomer (1 ). It should be noted that the present procedure can be applicable to other alkyl phenyl sulfoxides. 

Chiral sulfoxides. The Sharpless reagent lor asymmetric epoxidation also effects asymmetric oxidation of prochiral sulfides to sulfoxides. The most satisfactory results are obtained for the stoichiometry Ti(0-(-Pr)4/L DET/H20/(CH,),C00H = 1 2 1 2 for I equiv. of sulfide. In the series of alkyl p-tolyl sulfides, the (R)-sulfoxide is obtained in 41-90% ee the enantioselectivity is highest when the alkyl group is methyl. Methyl phenyl sulfide is oxidized to the (R)-sulfoxide in 81% ee. Even optically active dialkyl sulfoxides can be prepared in 50-71% ee the enantioselectivity is highest for methyl octyl sulfoxide. 

---