Sulfoxidation-kinetic resolution process

A one-pot titanium-catalyzed tandem sulfoxidation-kinetic resolution process was developed by Chan using TBHP as the oxidant This process combines asymmetric sulfoxidation (at 0°C) and kinetic resolution (at room temperature). Excellent enantiomeric excesses (up to >99.9%) and moderate to high chemical yields of sulfoxides were obtained [270] (Scheme 14.113). The effect of fluorine substitution at the backbone of BINOL on the catalytic activity in titanium-catalyzed sulfide oxidation with TBHP or cumyl hydrc en peroxide (CHP) was studied by Yudin [271]. Introduction of fluorines into the BINOL scaffold was found to increase the electrophilic character of the Lewis acidic titanium center of the catalyst The most intriguing difference between the FsBINOL and BINOL systems is the reversal in the sense of chiral induction upon fluorine substitution. A steroid-derived BINOL ligand has also been used for the same reaction [272]. 

A study on the time course of the enantiomeric excess of the sulfoxide revealed that it was highly dependent on the reaction time. In addition, as the reaction proceeded, the formation of sulfone was observed. With the gradually increasing amounts of sulfone the ee of the sulfoxide was raised. This dependence of the enantiomeric excess on time and sulfone formation indicated that a kinetic resolution process of the newly formed sulfoxide took place. Chiral recognition of the (S)-sulfoxide by the Ti(OiPr)4/(i )-BINOL complex led preferably to consumption of this enantiomer and thereby raised the enantiomeric excess of the fi j-sulfoxide. 

A new modification was recently described by Imamoto who employed a combination of (S,S)-2,2,5,5-tetramethyl-3,4-hexane diol (13) and Ti(OiPr)4 as catalyst. The active species was proposed to be monomeric with two diols and one cumyl hydroperoxide ligand leading to an octahedral coordination sphere around titanium. Under conditions similar to those reported by Kagan, p-tolyl methyl sulfoxide was obtained with 95% ee in 42% yield. Sulfone formation was a dominant, albeit beneficial side reaction giving in a kinetic resolution process (s=... 

It is noteworthy that further oxidation of the sulfoxide products was observed in the (salalen)Al 33-catalysed sulfide oxidation. Therefore, the enantiomer differentiation in the oxidation of racemic methyl phenyl sulfoxide was investigated (Scheme 19.39). It was found that the (J )-sulfoxide was oxidised preferentially into the sulfone with a relative ratio of 4.6, and the (S )-enantiomer remained selectively in the oxidation of thioanisole. This result explains the gradual increase in the enantiomeric excess of the sulfoxide as the reaction proceeds the synergistic combination of the initial highly enantioselective oxidation of the sulfide with the following oxidative kinetic resolution process is responsible for the high enantiomeric excesses observed for the sulfoxides. 

The above procedure can be exploited for the asymmetric oxidation of racemic sulfoxide1 1, and high stereoselection can be frequently observed. Moreover unreacted / -sulfoxides were always recovered as the most abundant enantiomers, kinetic resolution and asymmetric oxidation being two enantioconvergent processes. Thus, by the combined routes, higher enantioselectivity can be observed with dialkyl sulfoxides, usually obtained with poor to moderate e.e.s. 

Very recently, Lattanzi and coworkers reported on the use of enantiomericaUy pure camphor derived hydroperoxide 61 for the Ti(OPr-/)4 catalyzed chemoselective asymmetric oxidation of aryl methyl sulfides (equation 59) . The corresponding sulfoxides could be obtained in moderate yields (39-68%) and ee values up to 51%. The sulfoxidation to the sulfoxides is accompanied by further oxidation of the sulfone (kinetic resolution, yields of sulfone up to 9%). This process is stereodivergent with respect to the sulfoxidation step, which was found for the first time. Although the obtained enantioselectivities for the sulfoxides were only moderate, they proved to be among the best reported at that time with the use of enantiopure hydroperoxides as the only asymmetric inductor. The... 

Uemura and coworkers utilized (R)-binaphthol 85 as chiral ligand in place of DET in association with Ti(IV)/TBHP, which not only mediated the oxidation of sulfides to (R)-configurated sulfoxides, but also promoted the kinetic resolution of sulfoxides (equation 50). In this latter process the two enantiomers of the sulfoxide are oxidized to sulfone by the chiral reagent at different rates, with decrease of the chemical yield, but increase of the ee values. Interestingly, the presence of ortho-nilro groups on the binaphthol ligand lead to the reversal of enantioselectivity with formation of the (5 )-configurated sulfoxide. Non-racemic amino triols and simple 1,2-diols have been successfully used as chiral mediators. 

It should be noted that the related imine-oxaziridine couple E-F finds application in asymmetric sulfoxidation, which is discussed in Section 10.3. Similarly, chiral oxoammonium ions G enable catalytic stereoselective oxidation of alcohols and thus, e.g., kinetic resolution of racemates. Processes of this type are discussed in Section 10.4. Whereas perhydrates, e.g. of fluorinated ketones, have several applications in oxidation catalysis [5], e.g. for the preparation of epoxides from olefins, it seems that no application of chiral perhydrates in asymmetric synthesis has yet been found. Metal-free oxidation catalysis - achiral or chiral - has, nevertheless, become a very potent method in organic synthesis, and the field is developing rapidly [6]. 

Kinetic resolution was shown by Kunieda and coworker to be another enantioselective process of a-sulfinyl carbanions. Slight asymmetric induction was achieved in the reaction of racemic a-lithiomethyl p-tolyl sulfoxide with ethyl carboxylates in the presence of (-)-sparteine [Eq. (17)] [62]. 

Several approaches have been described for the preparation of optically active sulfoxides [5-7]. The three main routes to obtain these compounds are as follows (i) the asymmetric sulfoxidation of prochiral sulfides, (ii) nucleophilic substitution using a chiral sulfur precursor, and (iii) the kinetic resolution of racemic sulfoxides. The first of tiiese methods involves the use of various oxidants and catalysts and has been the most extensively employed. There are many examples in the scientific literature and reviews are available on this approach. In recent years, much attention has been focused on the synthesis of organic sulfoxides by emplo5dng conditions compatible with the green chemistry procedures [8-10]. For this reason, mild oxidants such as molecular oxygen or hydrogen peroxide are considered in combination with novel catalysts in order to develop a mild and environmentally friendly process. 

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