Methyl aryl sulfides

An achiral reagent cannot distinguish between these two faces. In a complex with a chiral reagent, however, the two (phantom ligand) electron pairs are in different (enantiotopic) environments. The two complexes are therefore diastereomeric and are formed and react at different rates. Two reaction systems that have been used successfully for enantioselective formation of sulfoxides are illustrated below. In the first example, the Ti(0-i-Pr)4-f-BuOOH-diethyl tartrate reagent is chiral by virtue of the presence of the chiral tartrate ester in the reactive complex. With simple aryl methyl sulfides, up to 90% enantiomeric purity of the product is obtained. 

The use of furylhydroperoxides[1] has facilitated an operationally simple procedure, alternative to the one reported by Kagan[2]. Oxidation takes place rapidly and very high e.e.s have been obtained, especially in the case of aryl methyl sulfides, while overoxidation to sulfone can be reduced to a great extent (<3 %) under the proposed experimental conditions. 

In the oxidation of aryl methyl sulfides catalyzed by chloroperoxidase from Caldariomyces fumago with racemic 1-phenylethyl hydroperoxide instead of H2O2 as oxygen donor, it was found that (k)-sulfoxides, the (S)-hydroperoxides and the corresponding (k)-alcohol are produced in moderate to good enantiomeric excesses by double stereodifferentiation of the substrate and oxidant (Eq. 2, Table 3) [68]. 

Table 3. CPO-catalyzed oxidations of aryl methyl sulfides with racemic hydroperoxides... 

Preparation of various enantiomerically pure sulfoxides by oxidation of sulfides seems feasible in the cases where asymmetric synthesis occurs with ee s in the range of 90% giving crystalline products which can usually be recrystallized up to 100% ee. Aryl methyl sulfides usually give excellent enantioselectivity during oxidation and are good candidates for the present procedure. For example, we have shown on a 10-mmol scale that optically pure (S)-(-)-methyl phenyl sulfoxide [a]p -146 (acetone, o 1) could be obtained in 76% yield after oxidation with cumene hydroperoxide followed by flash chromatographic purification on silica gel and recrystallizations at low temperature in a mixed solvent (ether-pentane). Similarly (S)-(-)-methyl o-methoxyphenyl sulfoxide, [a]p -339 (acetone, o 1.5 100% ee measured by HPLC), was obtained in 80% yield by recrystallizations from hexane. 

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... 

Stereoselective catalytic oxidation of Aryl methyl sulfides. 300... 

ASYMMETRIC SULFOXIDATION OF ARYL METHYL SULFIDES WITH HYDROGEN PEROXIDE IN WATER... 

STEREOSELECTIVE CATALYTIC OXIDATION OF ARYL METHYL SULFIDES... 

The procedure is very easy to reproduce and the asymmetric sulfoxidation may be applied to a relatively large range of aryl methyl sulfides (Table 9.7). Remarkable features are (i) easy isolation of the enantioenriched products from the catalyst by simple diethyl ether/water-SDS two phase separation (ii) use of green and... 

Chiral sulfoxides (12, 92). Kagan et al.3 have reviewed the asymmetric oxidation of sulfides by a water-modified Sharpless reagent. Optical yields are generally highest in the oxidation of aryl methyl sulfides (—75-90%). 

The Schiff base-oxovanadium(IV) complex formulated as 19 was found to catalyze the asymmetric oxidation of sulfides with cumene hydroperoxide (Scheme 6C.8) [70]. Various aryl methyl sulfides were used for this process (room temperature in dichloromethane and 0,1 mol equiv. of the catalyst). Chemical yields were excellent, but enantioselectivities were not higher than 40% for the resulting methyl phenyl sulfoxide, Complex 16a, where [Ti] was replaced by VO, was also examined in the oxidation of sulfides, but the reactions gave only racemic sulfoxides [68],... 

Biological oxidation of sulfides involves cytochromes P-450 or flavin-dependent oxygenases. A chiral flavin model was prepared by Shinkai etal. and used as the catalyst in the oxidation of aryl methyl sulfides [87]. Flavinophane 30 (Scheme 6C.10) is a compound with planar chirality. It catalyzes the oxidation of sulfides with 35% H202 in aqueous methanol at -20°C in the dark. 

The use of Mn-salen catalysts for asymmetric epoxidation has been reviewed.30 Oxo(salen)manganese(V) complexes, generated by the action of PhIO on the corresponding Mn(III) complexes, have been used to oxidize aryl methyl sulfides to sulfoxides.31 The first example of C—H bond oxidation by a (/i-oxo)mangancsc complex has been reported.32 The rate constants for the abstraction of H from dihydroanthracene correlate roughly with O—H bond strengths. 

Also of significant preparative potential is the kinetic resolution of chiral hydroperoxides in the presence of sulfides or guaiacol [253-261]. The reaction has been shown to occur with CPO, HRP and CiP and provides good to excellent results for a multitude of different substrates. Whereas usually the back-reaction of Compound I to the resting state is used for organic synthesis, Compound I is formed upon the stereoselective decomposition of alkylhydroperoxides here. Scheme 2.20 illustrates the first example described in the literature [253] where CPO and different aryl methyl sulfides have been employed and where it has been found that mainly the R-form of the chiral hydroperoxide is reduced to the corresponding alcohol. 

Finally, iron catalysts based on salen-type ligands have been used. These iron(III)-salen complexes were regarded as enzyme models, using PhIO as oxidant (Scheme 3.52) [162]. Initially, the corresponding active iron-oxo complexes were formed by reaction with PhIO and isolated before use. A stoichiometric amount of the iron-oxo complex allowed the efficient oxidation of a variety of aryl methyl sulfides in moderate to good yields. 

Non-heme Fe11 complexes of pentadentate ligands with pyrrolidinyl moieties have also been described for the oxidation of aryl methyl sulfides (Table 3.11) [167]. This system showed high selectivity in the formation of sulfoxides, but provided low... 

In the same year, Fujita s group63 reported the asymmetric oxidation of aryl methyl sulfide by hydroperoxides (TBHP, CHP) and an optically active catalyst formed by a Schiff base-oxovanadium(IV) complex 32, giving (S)-sulfoxides in low ee (up to 40%) (Fig. 4). Later, they developed64 a more promising approach using 33, a binuclear Schiff base-titanium(IV) complex (4 mol% equiv) to catalyze the asymmetric oxidation of methyl phenyl sulfide by trityl hydroperoxide in methanol at 0 °C. The (ft)-methyl phenyl sulfoxide was obtained with 60% ee. 

Arylboronic acids, (ArB(OH)2, react with thiols and copper(II) acetate to give the corresponding alkyl aryl sulfide. " Arylboronic acids also react with N-methylthiosuccinimide, with a copper catalyst, to give the aryl methyl sulfide. " " In the presence of a palladium catalyst, thiophenols react with diaryliodonium salts. 

Methylation of aryl thiols. PTC methylation of l C-aryl thiols with methyl Iodide (2 ) Is very useful for microscale synthesis of C-labeled aryl methyl sulfides (2j ). The reaction, using tetrabutylammonlum hydrogensulfate as catalyst and sodium hydroxide as base In methylene chloride and water, proceeds at ambient temperature In 50-100Z yield. 

Nucleophilic substitution reactions. Nucleophilic displacement of a halogen In compounds such as 2-acetamldo-4-chloromethylthlazole under reflux of an alkaline ethanol solution Is a straight foreward reaction (219). Nucleophilic aromatic substitution reactions are more complex but under certain conditions they can be used for single step synthesis of aryl methyl sulfides. A number of 4-methylthlo-polychlorobiphenyls were synthesized from... 

In summary, we have presented a variety of metal-based catalysts which are able to mediate the asymmetric oxidations of sulfides to the corresponding sulfoxides and sulfimides. Although very different approaches relying on distinct metal complexes are known, there is still a demand for an appropriate system which would allow the transformation of any sulfide to occur with high enantioselec-tivity. Especially the rational design of chiral complexes able to selectively oxidize substrates, in particular, those compounds other than aryl methyl sulfides is still a major challenge. 

Arenethiols. Sodium t-butanethiolate is useful for demethylation of aryl methyl sulfides. 

The methyl groups of the resulting aryl methyl sulfides 198 consistently showed an emissive CIDNP signal, while the aromatic protons were unpolarized. This was interpreted to signify that the sulfide was formed as an intermediate result of the primary photochemical event, by the escape path of [the radical pair 195/84] [31]. The sulfinyl radical was said to (1) transfer its O-... 

The first example of FB oxidation of sulfides dates back to 1995 dibenzothiophene and diphenyl stdfide gave the corresponding sulfones in low yields (1.4% and 10%, respectively) upon treatment with O2 at 100 °C in the presence of a not fully characterized perfluorocarbon-soluble iron—phthalocyanine [19]. Following this earlier report, Co(ll)—tetraarylporphyrin Co-5 and Co(I I [—phthalocyanine Co-12 (cf Stmcture) were tested as catalysts for the FB oxidation of methyl phenyl sulfide and para-substituted aryl methyl sulfides with O2 and a sacrificial aldehyde (Table 3) [20]. 

Tabled Catalytic oxidation of aryl methyl sulfides with PhIO catalyzed by achiral (salen)manganese(lll) complexes. ...

Oxidation of 1,7-heptanediol with chlorine and 3% cross-linked polystyrene-bound aryl methyl sulfide (DF 0.07-0.13) gave selective formation of the monoaldehyde, but only 50% yield (Equation 9) ( 1. 

The Sharpless epoxidation of allylic alcohols by hydroperoxides uses as mediator [45] or as catalyst [46] a chiral titanium complex obtained from the combination Ti(OPr )4/diethyl tartrate (DET) in 1 1 ratio. Kinetic resolution of P-hydroxysulfides was also observed, but without diastereoselectivity for the product P-hydroxysulfoxides [47]. We found that the Sharpless reagent deactivated by 1 equivalent of water allows the enantioselective oxidation of aryl methyl sulfides into sulfoxides to be performed with ee s up to 90% [4S-50]. The best reagent combination proved to be Ti(0Pr )4/DET/H20 = 1 2 1. Independently, Modena et al. obtained similar enantioselectivities with the combination Ti(OPr )4/DET in 1 4 ratio [51]. These two combinations are sometimes referred to as the Kagan reagent and the Modena reagent, respectively. They will be considered successively. 

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]. 

Among the less eommon methods of asymmetrie oxidation of sulfides is electrochemieal oxidation, which can be carried out by various modified electrodes. The first example was reported by Firht and Miller [115] in 1976. In spite of several improvements, the enantiomeric excess remained below 3% for the oxidation of aryl methyl sulfides. 

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