Sulfoxide sulfenate equilibrium

Treatment of allyl p-tolyl sulfoxide with LDA followed by addition of HMPA (4.4 mol equiv.) and chiral 2-methylalkanal (3 mol equiv.) at -78 C gave a mixture of readily separable a- and y-adducts, where the a y regioisomer ratios are markedly higher than those obtained in Ae reaction with aromatic aldehydes. Exposure of the a-adduct to an excess of a thiophile (trimethyl phosphite or dimethylamine in MeOH) results in quenching of the allylic sulfoxide-sulfenate equilibrium and affords diastereoisomeric mixtures of the syn- and anti-diols (Scheme 18), for which some yields and product ratios are shown in Table 3. 

NMR measurements indicate that the equilibrium constant varies with the polarity of the solvent and temperature. The more polar the solvent, the greater the fraction of sulfoxide at equilibrium which is consistent with the greater dipole moment of the sulfoxide as compared with the sulfenate. Increasing temperature results in a reverse effect, due to the steric hindrance in the sulfoxide which becomes more marked at higher temperatures. These results are the first published evidence for the reversibility of the sulfenate-sulfoxide rearrangement and illustrate the occurrence of the rearrangement unsuccessfully attempted by Cope39. 

Owing to the reversible nature of the allylic sulfenate/allylic sulfoxide interconversion, the stereochemical outcome of both processes is treated below in an integrated manner. However, before beginning the discussion of this subject it is important to point out that although the allylic sulfoxide-sulfenate rearrangement is reversible, and although the sulfenate ester is usually in low equilibrium concentration with the isomeric sulfoxide, desulfurization of the sulfenate by thiophilic interception using various nucleophiles, such as thiophenoxide or secondary amines, removes it from equilibrium, and provides a useful route to allylic alcohols (equation 11). 

In the stereoselective total synthesis of ( )-14-deoxyisoamijiol by G. Majetich et al., the last step was the epimerization of the C2 secondary allylic alcohol functionality. The Mitsunobu reaction resulted only in a poor yield (30%) of the inverted product, so the well-established sulfoxide-sulfenate rearrangement was utilized. The allyic alcohol was first treated with benzenesulfenyl chloride, which afforded the thermodynamically more stable epimeric sulfenate ester via an allylic sulfoxide intermediate. The addition of trimethyl phosphite shifted the equilibrium to the right by consuming the desired epimeric sulfenate ester and produced the natural product. 

The [2,3]-sigmatropic interconversion of sulfoxides and sulfenate esters is easily reversible, and this is why chiral allylic sulfoxides typically racemize at room temperature. The sulfoxide-sulfenate ester equilibrium usually favors the sulfoxide. If a reactive thiophile that cleaves the O-S bond of the sulfenate ester is introduced into the reaction mixture, then the equilibrium is displaced and the allylic alcohol is formed with the possibility of transfer of chirality (Figure 10.10). Starting from... 

Even though the sulfilimine (83) undergoes a [2,3]-sigmatropic rearrangement, unlike the sulfoxide/sulfenate rearrangement the equilibrium here lies toward the sulfenamide (84) (Scheme 14). This difference in reactivity plays a very critical role in the stereochemical outcome in the conversion of some dihydrothiazine imines to vicinal diamines. 

Penicillin sulfoxides can be epimerized by heat to afford thermal equilibrium mixtures of a- and /3-sulfoxides, the position of the equilibrium depending on the C(6) side chain (Scheme 5). Deuterium incorporation studies support a sulfenic acid, e.g. (18), as the intermediate in these transformations. This mechanism is also supported by the finding that when an a-sulfoxide epimerizes to a /3-sulfoxide there is a simultaneous epimerization at C(2) (71JCS(C)3540). With irradiation by UV light it is possible to convert a more thermodynamically stable /3-sulfoxide to the a-sulfoxide (69JA1530). 

In order to account for the unusually facile thermal racemization of optically active allyl p-tolyl sulfoxide (15 R = p-Tol) whose rate of racemization is orders of magnitude faster than that of alkyl aryl or diaryl sulfoxides as a result of a comparably drastically reduced AH (22kcalmol- ), Mislow and coworkers44 suggested a cyclic (intramolecular) mechanism in which the chiral sulfoxide is in mobile equilibrium with the corresponding achiral sulfenate (equation 10). 

In addition to the synthetic applications related to the stereoselective or stereospecific syntheses of various systems, especially natural products, described in the previous subsection, a number of general synthetic uses of the reversible [2,3]-sigmatropic rearrangement of allylic sulfoxides are presented below. Several investigators110-113 have employed the allylic sulfenate-to-sulfoxide equilibrium in combination with the syn elimination of the latter as a method for the synthesis of conjugated dienes. For example, Reich and coworkers110,111 have reported a detailed study on the conversion of allylic alcohols to 1,3-dienes by sequential sulfenate sulfoxide rearrangement and syn elimination of the sulfoxide. This method of mild and efficient 1,4-dehydration of allylic alcohols has also been shown to proceed with overall cis stereochemistry in cyclic systems, as illustrated by equation 25. The reaction of trans-46 proceeds almost instantaneously at room temperature, while that of the cis-alcohol is much slower. This method has been subsequently applied for the synthesis of several natural products, such as the stereoselective transformation of the allylic alcohol 48 into the sex pheromone of the Red Bollworm Moth (49)112 and the conversion of isocodeine (50) into 6-demethoxythebaine (51)113. 

An allylic sulfenate, like 199, is known to be in equilibrium with allylic sulfoxide, like 196, although its concentration is usually low . Various allylic sulfoxides can be prepared by treatment of allylic alcohols with arenesulfenyl chlorides . Evans and coworkers prepared various allylic alcohols by treating the corresponding allylic sulfoxides with trimethyl phosphite. For example, the carbanion from a cycloalkenyl sulfoxide 201 was readily alkylated at the a-position by treatment with alkyl halide. The resulting alkylated derivative 202 was then treated with trimethyl phosphite and 3-substituted cycloalkenol was obtained. Alkylation of acyclic allylic sulfoxide 204 gave... 

Subsequently, these authors have also studied the effect of polar factors on the sulfenate-sulfoxide equilibrium and obtained similar results to those reported by Braverman and coworkers . For example, reaction of 2,4-dinitrobenzenesulfenyl chloride with lithium allyl-a-dj alcoholate gives only (or perhaps mainly ) allyl-a-d2 2,4-dinitrobenzenesulfenate, whereas the corresponding reaction with 4-nitrobenzenesul-fenyl chloride results in complete ( > 99%) rearrangement to the sulfoxide. However, when a single nitro group is located in the ortho position, the ratio (K) of sulfenate to sulfoxide approaches unity. This ratio is also affected by the polarity of the solvent and changes from 1.43 in CCI4 to 0.39 in chloroform, consistent with the results described above for the equilibrium shown in equation 9. 

The rearrangement of allylic sulfoxides to allylic sulfenates was first studied in connection with the mechanism of racemization of allyl aryl sulfoxides.272 Although the allyl sulfoxide structure is strongly favored at equilibrium, rearrangement through the achiral allyl sulfenate provides a low-energy pathway for racemization. 

The steric effect of the introduction of an cr-methyl group in the allyl portion of allyl trichloromethyl sulfoxide produces a shift in the equilibrium toward the sulfenate (Braverman and Stabinsky, 1967) that immediately brings to mind the fact that a similar structural alteration in thiolsulfinate [23] had a similar effect on the thiolsulfinate-thiolsulfoxylate equilibria in (87) and (88). 

Sulfeny I chlondes react with allyl alcohols to yield allyl sulfenates, which are in equilibrium with the allyl sulfoxides [12] (equation 9a) These products can be oxidized to the corresponding sulfones (equation 9b) Pyrolysis of the sulfoxides gives sulfines or evidence for the presence of sulfmes Pyrolysis of sulfones leads to unsaturated compounds by extrusion of sulfur dioxide [12] (equation 9c)... 

This is an unfavourable reaction, because the equilibrium lies over on the sulfoxide side. But the nucleophile traps the sulfenate ester and the methanol ensures that the alkoxide ion formed is immediately protonated so that we get another allylic alcohol. 

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