Sulfoxides to sulfenates

III. REARRANGEMENTS OF SULFOXIDES TO SULFENATES A. Thermal and Ionic Rearrangements... 

The facile racemization of optically active sulfoxides (enantiomerically enriched in configuration at sulfur) provided early evidence for the concerted, [2,3]-sigmatropic nature of the allylic sulfoxide-to-sulfenate rearrangement (Scheme 18.31. Mislow found that racemization occurred readily at 50-70 °C, conditions considerably milder than the 130-150 °C required for the radical-cleavage pathway associated with the corresponding benzyl sulfoxide and well below the tenperature needed for pyramidal inversion at the sulfoxide sulfur center (190-220 °C). 

A closely related stereochemical feature of the allylic sulfoxide-to-sulfenate rearrangement involves sulfur-to-carbon (S C) chirality transfer. Trapping of the sulfenate with a thiophile has the potential to relay stereochemical information from the sulfoxide chiral center to the carbinol center of the allylic alcohol product. This stereochemical transfer originates from a preference for either the exo or the endo transition state, with the latter typically predominating. Thus, as shown in Scheme 18.8. for a fixed configuration at the sulfoxide S-center and the E-alkene geometry, the exo and endo transition states provide enantiomeric... 

Finally, calculations show that the transition state for the Mislow-Evans rearrangement is sulfenate-like. This was consistent with the fact that the reaction rate in the sulfoxide-to-sulfenate direction slowed in solvents of increasing polarity, presumably because a polar solvent stabilizes the sulfoxide starting material more than the sulfenate-like transition state. Indeed, Jorgensen s calculations indicated that the sulfoxide forms a stronger hydrogen bond to water ( 10 kcal/mol) than does the sulfenate ( 6 kcal/mol). Nevertheless, in a calculation that included methanol solvation, the Mislow-Evans transition state maintained a sulfoxide-like hydrogen bond to methanol. 

In general, diastereoface selectivity in the allylic sulfoxide-to-sulfenate Mislow-Evans rearrangement is possible in cases such as 74 (Scheme 18.19). having the sulfoxide attached to a chiral center, or with substrates of type 75, where the alkene faces are rendered diastereotopic by a structural element distal from the allyl sulfoxide. These diastereoselective... 

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). 

Scheme 6 depicts a typical penicillin sulfoxide rearrangement (69JA1401). The mechanism probably involves an initial thermal formation of a sulfenic acid which is trapped by the acetic anhydride as the mixed sulfenic-acetic anhydride. Nucleophilic attack by the double bond on the sulfur leads to an episulfonium ion which, depending on the site of acetate attack, can afford either the penam (19) or the cepham (20). Product ratios are dependent on reaction conditions. For example, in another related study acetic anhydride gave predominantly the penam product, while chloroacetic anhydride gave the cepham product (7lJCS(O3540). The rearrangement can also be effected by acid in this case the principal products are the cepham (21) and the cephem (22 Scheme 7). Since these early studies a wide variety of reagents have been found to catalyze the conversion of a penicillin sulfoxide to the cepham/cephem ring system (e.g. 77JOC2887).

Recently, a simple and general synthetic method for the preparation of N-alkylisothioazolidines involving [2,3]-sigmatropic rearrangement of appropriately substituted allylic sulfoxides to corresponding sulfenates, followed by intramolecular substitution of the latter, has been described (equation 28)126. 

Analogous with the rearrangement of allylic sulfoxides is the [2,3]-sigmatropic rearrangement of propargylic sulfoxides to allenic sulfenates. This process, which has been relatively little studied so far, appears to be the first step in the facile and quantitative rearrangement of sulfoxide 98 to the hemithioacetal 101 (equation 45)167. This reaction,... 

The thermolysis of acyclic- and/or six- and larger ring sulfoxides to yield olefins and sulfenic acids is well documented . The formation of allylic sulfenic acids and thiosulfinates in the thermolysis of thiirane oxides containing hydrogen on the a-carbon of the ring substituent (which is syn to the S—O bond) has been discussed previously in terms of /i-elimination of hydrogen, which is facilitated by relief of strain in the three-membered ring (Section llI.C.l). 

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