Racemization of sulphoxides

Resolution and Racemization of Sulphoxides.—Resolution of sulphoxides into enantiomers usually requires the presence of an acidic or basic grouping that can be used for diastereoisomeric salt formation with a chiral acid or base sulphoxides without such handles may be partially resolved (4.4— 14.5% optical purity) by stereospecific inclusion into jS-cyclodextrin. ... 

The mechanism of the racemization of sulphoxides by halide ions in acid solution, and the concurrent reduction to the sulphide, is established by rate studies to involve the conversion of the O-protonated sulphoxide into the halogenosulphonium ion in the rate-determining step. Chlorinolysis of a sulphoxide in AcOH gives the products obtained by chlorinolysis of the corresponding sulphide ArSR, where R is a group capable of independent carbonium ion stability, together with products of the Pummerer reaction e.g. PhCHO, PhSH) ... 

Quadricovalent sulphur intermediates should also be considered eligible to account for the racemization of sulphoxides ... 

Racemization of sulphoxides in non-aqueous solvents containing HCl involves an... 

Some limitations of the subject surveyed have been necessary in order to keep the size of the chapter within the reasonable bounds. Accordingly, to make it not too long and readable, the discussion of the methods of the sulphoxide synthesis will be divided into three parts. In the first part, all the general methods of the synthesis of sulphoxides will be briefly presented. In the second one, methods for the preparation of optically active sulphoxides will be discussed. The last part will include the synthetic procedures leading to functionalized sulphoxides starting from simple dialkyl or arylalkyl sulphoxides. In this part, however, the synthesis of achiral, racemic and optically active sulphoxides will be treated together. Each section and subsection includes, where possible, some considerations of mechanistic aspects as well as short comments on the scope and limitations of the particular reaction under discussion. 

A different non-classical approach to the resolution of sulphoxides was reported by Mikolajczyk and Drabowicz269-281. It is based on the fact that sulphinyl compounds very easily form inclusion complexes with /1-cyclodextrin. Since /1-cyclodextrin as the host molecule is chiral, its inclusion complexes with racemic guest substances used in an excess are mixtures of diastereoisomers that should be formed in unequal amounts. In this way a series of alkyl phenyl, alkyl p-tolyl and alkyl benzyl sulphoxides has been resolved. However, the optical purities of the partially resolved sulphoxides do not exceed 22% after... 

A new approach to the resolution of sulphoxides 242 was recently reported by T oda and coworkers282. It takes advantage of the fact that some sulphoxides form crystalline complexes with optically active 2,2 -dihydroxy-l, 1-binaphthyl 243. When a two-molar excess of racemic sulphoxide 242 was mixed with one enantiomeric form of binaphthyl 243 in benzene-hexane and kept at room temperature for 12 h, a 1 1 complex enriched strongly in one sulphoxide enantiomer was obtained. Its recrystallization from benzene followed by chromatography on silica gel using benzene-ethyl acetate as eluent gave optically pure sulphoxide. However, methyl phenyl sulphoxide was poorly resolved by this procedure and methyl o-tolyl, methyl p-tolyl, s-butyl methyl and i-propyl methyl sulphoxides did not form complexes with 243. 

Bohman and Allenmark resolved a series of sulphoxide derivatives of unsaturated malonic acids of the general structure 228. The classical method of resolution via formation of diastereoisomeric salts with cinchonine and quinine has also been used by Kapovits and coworkers " to resolve sulphoxides 229, 230, 231 and 232 which are precursors of chiral sulphuranes. Miko/ajczyk and his coworkers achieved optical resolution of sulphoxide 233 by utilizing the phosphonic acid moiety for salt formation with quinine. The racemic sulphinylacetic acid 234, which has a second centre of chirality on the a-carbon atom, was resolved into pure diastereoisomers by Holmberg. Racemic 2-hydroxy- and 4-hydroxyphenyl alkyl sulphoxides were separated via the diastereoisomeric 2- or 4-(tetra-0-acetyl-D-glucopyranosyloxy)phenyl alkyl sulphoxides 235. The optically active sulphoxides were recovered from the isolated diastereoisomers 235 by deacetylation with base and cleavage of the acetal. Racemic 1,3-dithian-l-oxide 236... 

This chiral column has been shown successfully to resolve enantiomeric mixtures (or racemates) of aromatic alcohols including l,l -bi-2-naphthol and its analogues (p. 836), aromatic hydroxy (or alkoxy) carboxylic esters and amides, amino acid derivatives, sulphoxides, cyclic imides and amides, lactones, etc. Even this list should not be regarded as limiting. The potential of this method, coupled with the simplicity of operation will undoubtedly be extensively developed and explored in the coming years. 

The same workers have also studied the racemization of (+)-methyl />-tolyI sulphoxide in acetic acid and in nitrobenzene reaction is catalysed by the chloride ion, and a chlorsulphonium ion is suggested as an intermediate. The racemization can occur by the reaction... 

The halide-catalysed racemization of ( +)-2-methylsulphinylbenzoic acid follows complex kinetics in acid solution, possibly indicating anchimeric assistance by carboxyl. Iodide ion reduction and chloride ion racemization of isopropyl phenyl sulphoxide have been studied in H2SO4 in comparison with HCIO4, and the greater relative rate of racemization in H2SO4 suggests a shift towards general-acid catalysis. Both reactions involve the same intermediate R2S-X (X = Cl or I), but the reduction process is known to be a specific-acid-catalysed reaction. 

Previous studies of photoaquation of [Cr(en)a] + and [Cr(ox)s] are linked by a study of photoaquation of the mixed complexes [Cr(en)aOx]+ and [Cr(en)(ox)2] . Both of these ions photoaquate to intermediates containing unidentate monoprotonated en. These intermediates aquate further thermally, with loss of the ethylenediamine. The rate of photo-racemization of [Cr(ox)3] in water-dimethyl sulphoxide decreases as the proportion of dimethyl sulphoxide increases, since solvating water plays a vital part in the racemization mechanism. ... 

Allenmark s work on anchimerically assisted reactions of sulphoxides" continues with a study of the rates of reduction of the syn- and anti-forms of e fo-cis-3-benzenesulphinylbicyclo[2,2,l]heptane-2-carboxylic acids. The syn-was more reactive than the an/i-isomer by a factor of more than 3.2 x 10 . The relative ease of formation of the acyloxysulphonium ion resulting from nucleophilic attack by the carboxy-group on sulphur accounts for this result, and also for the relative racemization rates of jS-carboxy-substituted sulphoxides. Pummerer reaction of one enantiomer of a benzyl o-carboxyphenyl sulphoxide in the presence of DCCI leads to 2-phenyl-3,l-benzoxathian-4-one (47) in an optically active form, indicating the transfer of chirality from S to C. ... 

The purpose of the present chapter is to provide an up-to-date review of methods which may be applied for the synthesis of both achiral and chiral (racemic and optically active) sulphoxides as well as their derivatives. Since the synthesis of optically active sulphoxides is based on many special procedures, it was found necessary to separate the syntheses of achiral and racemic sulphoxides from those of optically active ones. 

II. SYNTHESIS OF ACHIRAL AND RACEMIC SULPHOXIDES A. Oxidation of Sulphides... 

Few racemic alkyl p-tolyl sulphoxides were prepared in rather low yields (16—40%) by the reaction of Grignard reagents with mixed anhydrides 108, 109 and compound HO formed in situ from p-toluenesulphinic acid and 3-phthalimidoxy-l,2-benzoisothiazole 1, 1-dioxide167 (equation 59). The mixed anhydrides 109 or 110 when reacted with cyclopen-tene and cyclohexene enamines 111 gave the corresponding a-ketocycloalkyl sulphoxides 112 in low yields (10-41%) along with small amounts of several by-products such as disulphides and thiosulphonates167 (equation 60). 

Deimination of sulphoximines 213 as a method of synthesis of racemic sulphoxides (equation 117) has no synthetic value. However, this approach has been applied for the synthesis of optically active sulphoxides and will be discussed in the next part of this chapter. 

It is well known that spontaneous resolution of a racemate may occur upon crystallization if a chiral molecule crystallizes as a conglomerate. With regard to sulphoxides, this phenomenon was observed for the first time in the case of methyl p-tolyl sulphoxide269. The optical rotation of a partially resolved sulphoxide (via /J-cyclodextrin inclusion complexes) was found to increase from [a]589 = + 11.5° (e.e. 8.1%) to [a]589 = +100.8 (e.e. 71.5%) after four fractional crystallizations from light petroleum ether. Later on, few optically active ketosulphoxides of low optical purity were converted into the pure enantiomers by fractional crystallization from ethyl ether-hexane270. This resolution by crystallization was also successful for racemic benzyl p-tolyl sulphoxide and t-butyl phenyl sulphoxide271. 

Optically active hydroperoxides 244 were found285 to oxidize prochiral sulphides into the corresponding sulphoxides in higher optical yields (up to 27%) in comparison with those observed with peracids (equation 132). Moreover, the optical purity of the sulphoxides formed may be enhanced by addition of Ti(OPr-i)4. The oxidation of racemic 2-methyl-2,3-dihydrobenzothiophene 246 with these peroxides gave a mixture of cis and trans-sulphoxides 247 (equation 133). In all cases of the oxidation with the hydroperoxide alone the formation of the trans-isomer was strongly preferred and the e.e. value (up to 42%) of the cis-isomer was always higher than that of the trans-isomer. Moreover, the addition of Ti(OPr-i)4 furthermore promoted the selective formation of the frans-sulphoxide 247 and remarkably enhanced the e.e. value of both isomers. 

The standard Sharpless reagent [Ti(OPr-i)4/(R, R)-diethyl tartrate (DET)/t-BuOOH] oxidizes methyl p-tolyl sulphide into a mixture of racemic sulphoxide and sulphone286. 

A very interesting approach to optically active sulphoxides, based on a kinetic resolution in a Pummerer-type reaction with optically active a-phenylbutyric acid chloride 269 in the presence of /V,A -dimethyIaniline, was reported by Juge and Kagan332 (equation 149). In contrast to the asymmetric reductions discussed above, this procedure afforded the recovered sulphoxides in optical yields up to 70%. Chiral a, /1-unsaturated sulphoxides 270 were prepared via a kinetic resolution elaborated by Marchese and coworkers333. They found that elimination of HX from racemic /i-halogenosulphoxides 271 in the presence of chiral tertiary amines takes place in an asymmetric way leading to both sulphoxides 270 and 271, which are optically active (optical yields up to 20%) with opposite configurations at sulphur (equation 150). 

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