Sulfoxidation of methyl p-tolyl

A weak (-i-)-NLE was observed [41] for the allylic oxidation of cyclohexe-none in the presence of a peroxide and a carboxylic acid, which was catalyzed by a combination of proline, anthraquinone, and Cu(OAc)2. Asymmetric sulfoxidation of methyl p-tolyl sulfide by a hydroperoxide in the presence of a titani-um/BINOL/water catalyst also gives some asymmetric amplification [42]. 

Oxidation of sulfides has been performed by TBHP in anhydrous conditions with an excess of diethyl tartarate (4 equivalents) [59]. Modena used 1,2-dichloroethane or toluene as solvent at -20°C. Some examples are listed in Table 1.3. As with the Kagan reagent, a high ee (88%) is obtained for the sulfoxidation of methyl p-tolyl sulfide in 1,2-dichloroethane, but the ee drops to 64% in toluene. 

An optically active sulfoxide may often be transformed into another optically active sulfoxide without racemization. This is often accomplished by formation of a new bond to the a-carbon atom, e.g. to the methyl carbon of methyl p-tolyl sulfoxide. To accomplish this, an a-metallated carbanion is first formed at low temperature after which this species may be treated with a large variety of electrophiles to give a structurally modified sulfoxide. Alternatively, nucleophilic reagents may be added to a homochiral vinylic sulfoxide. Structurally more complex compounds formed in these ways may be further modified in subsequent steps. Such transformations are the basis of many asymmetric syntheses and are discussed in the chapter by Posner and in earlier reviews7-11. 

AS -8 to +4 e.u. Even though the racemization rate constants differ slightly, their distinct dependence on the steric and to a lesser extent on the electronic effects of the substituents bonded to the sulfinyl sulfur atom was noted. It deserves adding that the activation volume for racemization of methyl p-tolyl sulfoxide 41, A F 0 ml/mol, is also consistent with the pyramidal inversion mechanism (249). 

Both enantiomers of methyl p-tolyl sulfoxide are available from the above procedure by selection of the appropriate diethyl tartrate. This procedure describes the preparation of (S)-(-)-methyl p-tolyl sulfoxide which is not easy to prepare by the Andersen method " using (+)-raenthol. 

Little work has been done in this area with Ru catalysts. CM-A-[Ru(0)(py)(bpy)3] V water-CH3CN was used for the stoicheiometric oxidation of methyl-p-tolyl sulfide to (R)-methyl-p-tolyl sulfoxide with an e.e. of ca 15% [121],... 

A new enantiopure, bidentate ligand (35, 45 )-2,2,5,5-tetramethyl-3,4-hexanediol [(35, 45)-186] was developed by Yamanoi and Imamoto and investigated as asymmetric inductor in the titanium-catalyzed sulfoxidation reaction with various hydroperoxides as oxygen donors (Scheme 107). The catalytically active species was then prepared in situ from Ti(OPr-/)4 and ligand (35,45)-186. The most efficient hydroperoxide in terms of enantio-selectivity turned out to be cumyl hydroperoxide (95% ee compared to 30% ee in the case of methyl p-tolyl hydroperoxide), and molecular sieves 4 A had a beneficial effect on the... 

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. 

Catalytic oxidations of sulfides were carried out in 1,2-dichloroethane with cumyl hydroperoxide by using 10 mol % of the catalyst. The best enantioselectivity was achieved with complex 6c. However, sulfone was always produced as byproduct of the reaction. Even with a limited amount of hydroperoxide, the sulfone formation could not be avoided. For example, the reaction of methyl p-tolyl sulfide using 0.5 mol equiv. of cumyl hydroperoxide with respect to sulfide gave a 62 38 mixture of the corresponding (.S j-sulfoxide and sulfone. The reaction of benzyl phenyl sulfide led to the formation of (5)-sulfoxide (84% ee) and sulfone ([sulfox-ide]/[sulfone] = 77 23). It was established that sulfone was produced from the early stages of the reaction. It was also demonstrated that some kinetic resolution of the sulfoxide cooperated with the enantioselective oxidation of the sulfide. A unique feature of this oxidation system, as compared to those using various Ti(IV)/(DET) complexes, is the insensitivity of the enantioselectivity (40-60% ee at 0°C) to the nature of the alkyl group of sulfides Ar-S-alkyl. 

Uemura et al. [49] found that (R)-1,1 -binaphthol could replace (7 ,7 )-diethyl tartrate in the water-modified catalyst, giving good results (up to 73% ee) in the oxidation of methyl p-tolyl sulfoxide with f-BuOOH (at -20°C in toluene). The chemical yield was close to 90% with the use of a catalytic amount (10 mol %) of the titanium complex (Ti(0-i-Pr)4/(/ )-binaphthol/H20 = 1 2 20). They studied the effect of added water and found that high enantioselectivity was obtained when using 0.5-3.0 equivalents of water with respect to the sulfide. In the absence of water, enantioselectivity was very low. The beneficial effect of water is clearly established here, but the amount of water needed is much higher than that in the case of the catalyst with diethyl tartrate. They assumed that a mononuclear titanium complex with two binaphthol ligands was involved, in which water affects the structure of the titanium complex and its rate of formation. 

Microbiological oxidation is the easiest procedure because it uses the intact cells. Scheme 6C. 11 shows results obtained by using Aspergillus Niger [101], Enantioselectivity can be very high but experiments are performed on a small scale, which results in a low yield of sulfoxides. Both enantiomers of methyl p-tolyl sulfoxide were prepared by Sih et al. with Mortierella isabellina NRRL 1757, giving (/ )-sulfoxide with 100% ee in 60% yield or with Helminthosporium sp NRRL 4671, giving (S)-sulfoxide with 100% ee in 50% yield [104], A similar result was obtained for ethyl p-tolyl sulfide. A predictive model for sulfoxidation by Helminthosporium sp NRRL 4671 was proposed by Holland et al. [105], which was based on the analysis of more than 90 biotransformations of sulfides. 

The best results were obtained with (S)-(-)-phenylethyl hydroperoxide 47 at -20 °C in CC14, which afforded (S)-sulfoxides with low to modest enantioselectivity and low yield. A time profile of the oxidation of methyl p-tolyl sulfide with 47 showed that the asymmetric induction in the sulfoxidation was rather low (< 20%), demonstrating that the enantioselectivity obtained is related to a concomitant kinetic resolution of the sulfoxide formed. 

It was also reported that using methyJJithium instead of the methyl Grignard could give some racemization of methyl p-tolyl sulfoxide as a result of methyl group exchange via a methylene sulfine intermediate. ... 

Both enantiomers of methyl p-tolyl sulfoxide are also prepared from diacetyl D-glucose giving, with mesyl chloride, and according to the base used, the (S)-methyl sulfinate with diisopropylethy-lamine or the (J )-methyl sulfinate with pyridine, which are then transformed with p-tolyhnagnesium bromide into the corresponding (5)- or (f )-methyl p-tolyl sulfoxide (eq 3). ... 

It was shown recently that chloroperoxidase-catalyzed oxidation of methyl p-tolyl sulfide, using Hydrogen Peroxide or t-BuOOH as the stoichiometric oxidant, afforded the corresponding (+)-(J )-sulfoxide in 99% ee. ... 

It was also shown in the enantioselective synthesis of the macrolide patulolide that the anion of methyl p-tolyl sulfoxide was more reactive towards the imidazolide, prepared from the hemi ethyl sebacate, than the ester group (eq 7). 

The original Sharpless reagent, a mixture of tetraisopropyl orthotitan-ate, (i ,/ )-diethyl tartrate, and tert-butyl hydroperoxide in the ratio 1 1 2 in dry dichloromethane or 1,2-dichloroethane [1025, is modified by adding 1 mol of water 224, 1029]. Such a reagent gives higher enantiomeric excesses. Of many sulfide oxidations that have been carried out, the conversion of methyl p-tolyl sulfide into the sulfoxide is shown in equation 565. 

It was known that photoracemization of optically active sulfoxides can be induced upon sensitization with naphthalene [13]. Hence, by using (/ )-A -acetyl-1-naphthylethylamine 26 as a chiral sensitizer, the first photoderacemization of methyl p-tolyl sulfoxide 25a was performed to give an ee of 2.25% at the apparent photostationary state (pss) after prolonged irradiation [14]. However, more detailed examination, starting with 25a of 3.2% ee and 5.1% led to the conclusion that the ultimate value at the pss is 4.1% ee. With more a bulky substrate 25b, a higher ee of 12% was obtained upon photosensitization with (-f-)-W(trifluoro-methyl)-l-naphthylethylamine 27 [15]. 

The most important example of stoichiometric asymmetric oxidation is probably the titanium-catalysed conversion of sulfides into sulfoxides by cumene hydroperoxide in the presence of stoichiometric diethyl tartrate. A simple example is the efficient asymmetric synthesis of methyl p-tolyl sulfoxide 162, an important starting material for much sulfoxide-controlled asymmetric synthesis.30... 

Figure 16.8-1. Oxidation of methyl p-tolyl sulfide to methyl p-tolyl sulfoxide by a monooxygenase. The product can either be of the R- or 5-configuration depending on the monooxygenase used.

A quite general method of access to optically pure sulfoxides is due to Andersen [96-98] a menthyl sulfinate ester is reacted with a Grignard reagent. Both enantiomers of menthyl p-toluenesulfinate are commercially available. A large-scale preparation of (-)-menthyl (S)-p-toluenesulfinate as well as that of (/ )-(+)-methyl p-tolyl sulfoxide is described [99] by Solladie et at. Other related approaches are presented and discussed in [86]. 

---