Oxidation of sulfoxides to sulfones

Uemura et al. found that the combination Ti(OPr%/binaphthol/water in ratio 1 2 10 acts as a catalyst for oxidation of aryl methyl sulfides into the corresponding sulfoxides by Bu OOH (see also Section 1.4.1) [159]. A mechanistic study showed that the titanium complex was a sulfoxidation catalyst (initial ee -50%) as well as a catalyst for the overoxidation into sulfones, with an enhancement of the ee of the residual sulfoxides (because the minor sulfoxide enantiomer is preferentially oxidized). In a subsequent paper, the authors reported the kinetic resolution of racemic aryl methyl sulfoxides by the same catalyst [160]. A stereoselectivity factor s of 2.6 was calculated for the kinetic resolution of racemic methyl p-tolyl sulfoxide. For example, methyl p-tolyl sulfoxide ( 99% ee) could be recovered from oxidation at about 75% conversion. Using partially resolved l,l -binaphthol, a positive nonlinear effect was established. 

Biosulfoxidations are also of interest. There are many cases where nearly enantiopure sulfoxides have been prepared by this route, using either entire cells or isolated enzymes. The yields, however, are often lower than in the chemical approach, and the enantioselectivity is correlated to a narrow range of substrates. Molecular engineering of enzymes could be a useful tool for acquiring enzymes better matched to substrate structure. 

Antibody-catalyzed sulfoxidation is a very new area. One may expect in the near future that it will give rise to new generations of regio- and stereoselective catalytic antibodies for sulfoxidation. 

Morrison and H. S. Mosher, Asymmetric Organic Reactions, p. 336. Prentice-Hall, Englewood Cliffs, NJ (1971). 

Hayashi, M. Matsui, T. Koizumi, M. Shiro and K. Kuriyama, 7. Chem. Soc., Perkins Trans 1,1709 (1991). 

---

Sulfoxides are readily reduced to sulfides however, analogous to the oxidation aldehydes, the oxidation of sulfoxides to sulfones is irreversible as illustrated by the drug sulindac in Figure 5.13. 

Oxidation of a snlfide to sulfoxide is known to be an electrophilic reaction, in contrast with nncleophUic oxidation of sulfoxide to sulfone. Since 2-nitrobenzenesulfinyl chloride/KOi oxidizes sulfides to sulfoxides selectively, intermediate 48 must be the actual active intermediate. Moreover, in the presence of l,4-diazabicyclo[2.2.2.]octane (DABCO), which is a radical capturing reagent, the oxidation of methyl phenyl sulfide to the sulfoxide was inhibited. In order to further detect the intermediate 48, pure 5,5-dimethyl-l-pyrroUne-l-oxide (DMPO) was used as a trapping reagent and spin adduct was obtained. The ESR spectrum of the DMPO spin adduct was obtained by the reaction of 02 with 2-nitrobenzenesulfinyl chloride (hyperfine coupling constants, aH = 10.0 G and aN = 12.8 G). 

Diphenylphosphinic chloride reacts with the superoxide anion radical (Oi ) in CH3CN under mild conditions to form the diphenylphosphinic peroxy radical intermediate 77, which shows strong oxidizing abilities in the epoxidation of alkenes, oxidation of sulfoxides to sulfones, desulfurization of thioamides to amides and oxidation of triphenylphos-phines to triphenylphosphine oxide in good to excellent yields (equation 105). ... 

Organic hydroperoxides are generally used for the preparation of sulfoxides from sulfides, - while sulfones can be obtained in neutral organic solvents in the presence of metal catalysts such as V, Mo and Ti oxides at 50-70 C. Two polymer-supported reagents which involve peroxy acid groups and bound hypervalent vanadium(V) and molybdenum(VI) compounds have been developed for facile oxidation of sulfoxides to sulfones. 

In shaip contrast to peroxy acid oxidation the oxidation of sulfoxides to sulfones with various transi tion metal salts proceeds much faster than that of sulfides to sulfoxides and consequently sulfoxides may be selectively oxidized to sulfones in the presence of sulfides. 

Sodium permanganate monohydrate, NaMn04 H20, which is commercially available, is used for the oxidation of alkenes to carboxylic acids [834] and of alcohols to carbonyl compounds [SJ5], the conversion of sul-finic acids into sulfonic acids [836], and the selective oxidation of sulfoxides to sulfones (sulfides are not oxidized with sodium permanganate in dioxane solutions) 837. ... 

The oxidation of sulfoxides to sulfones is accomplished with air in the presence of noble metal salts [10 or with sodium permanganate [837] (equations 578 and 579). 

As noted above, the oxidation of sulfoxides to sulfones is facile, but slower than the sulfide sulfoxide conversion. The mechanism is probably similar to that for oxidation of sulfides,582 but sulfoxides are less nucleophilic than sulfides and the reaction slower.5 Sulfoxides are oxidized to sulfones using the same oxidants that converted the sulfide to a sulfoxide, but longer reaction times and/or more vigorous conditions are usually required. Direct oxidation of a sulfide to a sulfone is also easily accomplished in many cases. Oxidation of sulfide 431 with MCPBA gave sulfone 432 directly, without oxidation of the sensitive pyrrole unit.5 4 It is noted that the sulfur in a sulfone is achiral due to the presence of two oxygen atoms. 

Impressive enantioselectivities (up to >99.9% enantiomeric excess) were observed with a large range of thioethers. However, moderate yields were obtained [ca. 30-40%), which was attributed to a kinetic resolution in the oxidation of sulfoxide to sulfone, thus reducing the yield in sulfoxide. The heterogeneous nature of the catalyst was confirmed by inductively coupled plasma (ICP) spectroscopic analysis of the liquid phase (<1 ppm of titanium). The catalyst was recycled by simple filtration, and was reused at least 8 times in oxidation of thioanisole without any loss of enantioselectivity. 

Oxidation of sulfoxides to sulfones with oxygen in the presence of soluble iridium and rhodium complexes has also been reported. Metachloroperbenzoic acid has also been reported to be a good laboratory oxidizing agent for converting sulfides to sulfones. 

---