Asymmetric alkyl methyl sulfides

Table 6C. 1 lists representative results for the asymmetric oxidation of thio ethers with r-butyl hydroperoxide under the standard conditions (in dichloromethane at -20°C). Enantioselectivi-ties are especially good (80-95% ee) for the oxidation of aryl methyl sufoxides (Table 6C.1). A substantial decrease in enantioselectivity is observed for oxidation of aryl-S-alkyl-type sulfides in which an alkyl group is larger than methyl such as n-propyl an n-butyl.

Uemura described use of a Ti(OiPr)4/(i )-BINOL complex for the oxidation of alkyl aryl sulfides with aqueous ferf-butyl hydroperoxide as stoichiometric oxidant [22]. At room temperature p-tolyl methyl sulfide was converted into the corresponding sulfoxide with 96% ee in 44% yield with as little as 5 mol % of the chiral ligand. The reaction is insensitive to air, while the presence of water seems to be essential for the formation of the catalytically active species, long catalyst lifetime, and high asymmetric induction. The authors observed a large positive non-linear effect which indicates that the actual catalyst consists of a titanium species with more than one (K)-BINOL ligand (11) coordinated to the metal. 

The absolute configurations of the sulfoxides resulting from the asymmetric oxidation of sulfides are safely predicted by the method shown in Scheme 1.7. In aryl methyl sulfides, one takes aryl as the large (L) group. For methyl alkyl sulfides, it is the methyl group which is the smaller. 7t-Systems play a special role, as often encountered in asymmetric synthesis thus in the oxidation of Me— C=C—Bu", the triple bond has to be taken as the (L) group [54,55]. 

Fujita et al. used a catalytic amount of a binuclear titanium(IV) complex in an attempt to find an efficient system to oxidize sulfides with high enantioselectivity [102]. Prior to this study, they investigated other systems with several transition metals. A similar asymmetric sulfoxidation was discovered [105] using a catalytic amount of nonracemic Schiff base oxovanadium complex (Table 1.4) under atmospheric conditions at room temperature in dichloromethane. With 0.1 mol% of catalyst and cumene hydroperoxide as oxidant, oxidation produces sulfoxides in excellent yields. However, the reaction is limited to alkyl aryl sulfide substrates, and the best enantioselectivity obtained was 40% ee, for (S)-methyl p-methoxy phenyl sulfoxide. 

More recently, Katsuki et al. [109] prepared the Salen manganese complex (50) (Figure 1.6), which is efficient in the oxidation of alkyl aryl sulfide with iodosobenzene as oxidant. With 1 mol% of catalyst, they obtained the 2-nitrophenyl methyl sulfoxide in 1 h at -20°C in acetonitrile solution with 90% ee and 88% yield. This is currently one of the best results for catalytic asymmetric sulfoxidation. 

A further catalytic method for asymmetric sulfoxidation of aryl alkyl sulfides was reported by Adam s group, who utilized secondary hydroperoxides 16a, 161 and 191b as oxidants and asymmetric inductors (Scheme 114) . This titanium-catalyzed oxidation reaction by (S)-l-phenylethyl hydroperoxide 16a at —20°C in CCI4 afforded good to high enantiomeric excesses for methyl phenyl and p-tolyl alkyl sulfides ee up to 80%). Detailed mechanistic studies showed that the enantioselectivity of the sulfide oxidation results from a combination of a rather low asymmetric induction in the sulfoxidation ee <20%) followed by a kinetic resolution of the sulfoxide by further oxidation to the sulfone... 

In Studying asymmetric oxidation of methyl p-tolyl sulfide, employing Ti(OPr-/)4 as catalyst and optically active alkyl hydroperoxides as oxidants, Adam and coworkers collected experimental evidence on the occurrence of the coordination of the sulfoxide to the metal center. Therefore, also in this case the incursion of the nucleophilic oxygen transfer as a mechanism can be invoked. The authors also used thianthrene 5-oxide as a mechanistic probe to prove the nucleophilic character of the oxidant. 

Chiral (salen)Mn(III)Cl complexes are useful catalysts for the asymmetric epoxidation of isolated bonds. Jacobsen et al. used these catalysts for the asymmetric oxidation of aryl alkyl sulfides with unbuffered 30% hydrogen peroxide in acetonitrile [74]. The catalytic activity of these complexes was high (2-3 mol %), but the maximum enantioselectivity achieved was rather modest (68% ee for methyl o-bromophenyl sulfoxide). The chiral salen ligands used for the catalysts were based on 23 (Scheme 6C.9) bearing substituents at the ortho and meta positions of the phenol moiety. Because the structures of these ligands can easily be modified, substantia] improvements may well be made by changing the steric and electronic properties of the substituents. Katsuki et al. reported that cationic chiral (salen)Mn(III) complexes 24 and 25 were excellent catalysts (1 mol %) for the oxidation of sulfides with iodosylbenzene, which achieved excellent enantioselectivity [75,76]. The best result in this catalyst system was given by complex 24 in the formation of orthonitrophenyl methyl sulfoxide that was isolated in 94% yield and 94% ee [76]. 

Asymmetric imidations of aryl alkyl sulfides with [(tosylimino)iodo]ben-zene, catalyzed by various chiral (salen)manganese(III) complexes, have been investigated in some detail [31,32]. The influence of catalyst structure, solvent, temperature, 3°-amine AT-oxides, and the presence of molecular sieves on product yields and the enantioselectivity of imidation with 17 was evaluated. Enan-tioselectivities as high as 90 % ee and 97 % ee with methyl 2-nitrophenyl sulfide and methyl 2,4-dinitrophenyl sulfide, respectively, were achieved. 

Asymmetric synthesis of sulfoxides can be achieved by biocatalytic oxidation of sulfides and reduction of sulfoxides (Figure 33). i4-27s One example is the reduction of alkyl aryl sulfoxides by intact cells of Rhodobacter sphaeroides f.sp. denitrificans (Figure 33 (a)). 341 In the reduction of methyl -substituted phenyl sulfoxides, ( S )-cnanliomcrs were exclusively deoxygenated while enantiomerically pure (W)-isomcrs were recovered in good yield. For poor substrates such as ethyl phenyl sulfoxide, the repetition of the incubation after removing the toxic product was effective in enhancing the ee of recovered (f )-enantiomers to 100%. 

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. 

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