Penicillin sulfoxide rearrangement

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).

The nature of the products produced in a penicillin sulfoxide rearrangement are determined, in part, by the nature of the 3-substituent. In the normal acid-catalyzed rearrangement of a penicillin sulfoxide ester... 

Sila-Morin-Rearrangement of Penicillin Sulfoxides to Cephalosporins... 

Rearrangements involving sulfoxides have played an important role in the development of the chemistry of sulfoxides. It is therefore not surprising that all major literature surveys on sulfoxides " , or their sulfenate precursors , also include a discussion of this subject. However, while excellent and detailed coverage exists for certain rearrangements of general mechanistic and synthetic interest, such as, for example, the Pummerer " or the related penicillin sulfoxide-cephalosporin " rearrangement, the treatment of all... 

Mata et al. also described a new and robust protocol for the solid-phase synthesis of 2(3-methyl substituted penam derivatives using Merrifield resin as support [210]. The work begins with immobilization of 6,6-dibromopenicillanic acid (171) onto Merrifield resin followed by oxidation with m-chloroperbenzoic acid (MCPBA) to obtain the resin-bound sulfoxide (173). The key-step involves the thermal rearrangement of the corresponding penicillin sulfoxide (Scheme 49). 

Sulfenic acids (45) are generally quite unstable they easily dimerise and eliminate water to form thiol sulfinates (46) (Scheme 28). Several sulfenic acids have, however, been isolated and many of these are stabilised by hydrogen bonding to a carbonyl or amino group. The first sulfenic acid to be isolated was the anthraquinone derivative (47) in 1912. Sulfenic acids have been postulated as transient intermediates in many chemical and biochemical processes, e.g. the oxidation of thiol groups in proteins and the thermolysis of sulfoxides, including the acid-catalysed rearrangement of penicillin sulfoxides (48) to cephalosporins (49) (Scheme 29)... 

Although the dehydrogenation of dihydrothiazines of type lib, which are readily available compounds (Section V,B), may provide a useful route to thiazines, few examples have been reported. However, studies in the author s laboratory have shown that the compound 18a was converted into the thiazine 19 in good yield by lead tetraacetate in benzene. A further example is provided by the transformation, in boiling toluene, of the dihydrothiazine 18b into the bis(thiazine) 20 the product, however, was isolated only in 12% yield. The formation of the thiazinium chloride 23, from the reaction of the penicillin sulfoxide 21 with phenylacetyl chloride in acetone exposed to the air, constitutes a remarkable oxidative rearrangement. It seems likely that the dihydrothiazine 22, formed by the route suggested in Scheme 1,... 

The reaction is unusual in that sulfoxides processing an a-hydrogen atom normally undergo a Pummerer reaction under these conditions to form the acetoxy sulfide. The reaction can be compared with the Morin rearrangement of penicillin sulfoxide to cephalosporins.121... 

An extremely interesting and potentially useful rearrangement of penicillin sulfoxides has recently been reported (11) (Figure 7). Penicillin V sulfoxide... 

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