Asymmetric aryl alkyl sulfide

SCHEME 106. Titanium-catalyzed asymmetric oxidation of aryl alkyl sulfides using a chiral tetradentate trialkanolamine ligand... 

In combination with H2O2 (salen)Mn(III) complexes 173a, b, i-n have also been employed by Jacobsen and coworkers as catalysts for the asymmetric oxidation of sulfides to sulfoxides, without a need for additives. From the structurally and electronically different Mn-salen catalysts screened, 173i turned out to be the most active and selective one (equation 58) . While dialkyl sulfides underwenf uncafalyzed oxidation with H2O2, aryl alkyl sulfides were oxidized only slowly compared wifh fhe cafalyzed pathway. Using... 

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... 

Recently, Feng and co-workers reported an asymmetric sulfide oxidation" catalyzed by titanium complexes bearing HydrOx ligands, for example, 576 (Scheme 8.199). ° Enantioselectivities approached a level of synthetic utility for oxidation of aryl alkyl sulfides 632 although the yields of the sulfoxide 633 were poor due to overoxidation to the sulfone 634. The overoxidation is especially significant for reactions with high enantioselectivity. 

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]. 

After the first discovery of the asymmetric sulfoxidation by Kobayashi et al. [226], it could be shown that a large number of aryl alkyl sulfides are oxygenated with enantiomeric excesses higher than 98% [227-229]. Other peroxidases also catalyze this reaction. Interestingly, the plant peroxidase HRP [230] yields the (S)-sulfoxide, whereas mammalian myeloperoxidase [223] and lactoperoxidase [231] catalyze the formation of the R-enantiomers. The stereospecific sulfoxidation of aryl alkyl sulfides by purified toluene dioxygenase (TDO) from P. putida was also studied in this context [232] and showed that sulfoxidation yielded the (S)-sulfoxides in 60-70% yield, whereas CPO under the same conditions yielded 98% (R)-sulfoxides (Scheme 2.15). CPO is thus again an exception from the rule in that it produces R-enantiomeric sulfoxides, besides its bacterial origin [227]. The reason for this behavior lies in the... 

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. 

A similar (salen)manganese(III) catalyst was used by Katsuki for asymmetric sulfide oxidations [35]. Chiral complex 20 bears additional asymmetric carbons in the salicylidene part of the salen. In this system, hydrogen peroxide, which was the preferred oxidant in the Jacobsen procedure, turned out to be inefficient. Instead, iodosylbenzene was chosen, and in the presence of only 1 mol % of catalyst several aryl alkyl sulfides were oxidized in acceptable yields having enantiomeric excesses in the range of 8% to 90%. As in the Jacobsen-KatsuJd-epoxida-tion, the presence of additives such as pyridine N-oxide has a beneficial effect on chemical and optical yields. In addition, such co-ligands suppress the overoxidation of sulfoxides to the corresponding sulfones so that a sulfoxide sulfone ratio of 47 1 can be achieved. Consequentely, as shown for the case of thioanisole. 

It is known that cydodextrins have a hydrophobic cavity (a binding site for aromatics) and a hydrophilic external surface. A template-directed asymmetric sulfoxidation has been attempted with various aryl alkyl sulfides. [91]. Oxidations were performed by using metachlo-roperbenzoic add in water in the presence of an excess of p-cyclodextrin. The best ee (33%) was attained for mem-(r-butyl)phenyl ethyl sulfoxide. The decrease in the amount of P-cyclodex-trin below 1 mol equiv. causes a sharp decrease in enantioselectivity because of competition with oxidation of free substrate by the oxidant. Similarly, Drabowicz and Mikolajczyk observed modest asymmetric induction (27% ee) in the oxidation of Ph-S-n-Bu with H2O2 in the presence of P-cyclodextrin [92]. 

The Aggarwal group has used chiral sulfide 7, derived from camphorsulfonyl chloride, in asymmetric epoxidation [4]. Firstly, they prefonned the salt 8 from either the bromide or the alcohol, and then formed the ylide in the presence of a range of carbonyl compounds. This process proved effective for the synthesis of aryl-aryl, aryl-heteroaryl, aryl-alkyl, and aryl-vinyl epoxides (Table 1.2, Entries 1-5). 

According to this correlation model, in which the principles of steric control of asymmetric induction at carbon (40) are applied, the stereoselectivity of oxidation should depend on the balance between one transition state [Scheme 1(a)] and a more hindered transition state [Scheme 1(6)] in which the groups and R at sulfur face the moderately and least hindered regions of the peroxy acid, respectively. Based on this model and on the known absolute configuration of (+)-percamphoric acid and (+)-l-phenylperpropionic acid, the correct chirality at sulfur (+)-/ and (-)-5 was predicted for alkyl aryl sulfoxides, provided asymmetric oxidation is performed in chloroform or carbon tetrachloride solution. Although the correlation model for asymmetric oxidation of sulfides to sulfoxides is oversimplified and has been questioned by Mislow (41), it may be used in a tentative way for predicting the chirality at sulfur in simple sulfoxides. 

Optically active sulfoxides can also be prepared by asymmetric oxidation of sulfides. However, numerous papers have reported very low enantioselectivity." Only one report, " using a modified Sharpless reagent, H20/Ti(0Pr )4/diethyl tartrate/BuKX)H, described asymmetric oxidation of alkyl aryl sulfoxides with good enantiomeric excesses 75 to 95%. 

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]. 

A chiral Ti complex formed in situ by reacting Ti(0 Pr)4, (J ,P)-diphenylethane-1,2-diol, and water was reported to be effective for asymmetric oxidation of aryl alkyl and aryl benzyl sulfides using TBHP as the oxidant to obtain optically active sulfoxides in good yields and high enantiomeric excesses [274] (Scheme 14.115). 

Steric and electronic effects have been investigated for the Cu(acac)2-catalysed asymmetric oxidation of aryl benzyl, aryl alkyl and alkyl benzyl sulfides with H2O2 in presence of hexane/MeOH and the ligand 4-chloro-2-[( )-[( 17 )-l-(hydroxymethyl)-2,2-dimethyl-propyl]iminomethyl]phenol. High enantioselectivity is dependent on the attachment of an aryl group to the sulfur and was highest, with up to 97% ee, for 2-naphthyl benzyl sulfoxide. Cu-mediated oxidation of substituted aryl benzyl sulfides shows modest steric and electronic effects. ... 

The complex (70) is the most efficient catalyst in the titaniumsalan-catalysed asymmetric oxidations of bulky aryl benzyl sulfides and small alkyl phenyl sulfides by H2O2 in CH2CI2 to corresponding sulfoxides with 77% ee. The kinetics suggest that a direct attack of the sulfide on the electrophilic active oxygen species occurs... 

A new catalytic procedure for the asymmetric oxidation of aryl alkyl and aryl benzyl sulfides to optically active sulfoxides by TBHP is mediated by a chiral titanium complex formed in situ by reacting Ti( -PrO)4, (R, / )-diphenylethane-l,2-diol, and water. The results were largely unaffected by the nature of the phenyl substituents, suggesting that the same mechanism operates in all cases. Only the / -N02 substituent on the aryl ring caused a considerable loss of enantioselectivity and this is attributed to the electron-withdrawing power of this group or, more likely, its coordinating ability. ... 

SCHEME 48.1. Asymmetric sulfoxidation of aryl alkyl and dialkyl sulfides 1 with the Ti(IV)/diethyltartrate (DET)7H20 system developed by Kagan et al. leading to enantioenriched sulfoxides 2. 

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