Penicillin sulfoxide reaction with

Morin et al. showed that the reaction of penicillin sulfoxides (162) with refluxing acetic anhydride leads to formation of the ring-expanded cepham derivatives (165) and compound (166 Scheme 41). Although this transformation was effected under Pummerer conditions, it occurs by a different mechanism, hence the term Abnormal Pummerer reaction . 

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 normal acidic rearrangement of penicillin sulfoxide derivatives is the well-known one discussed at length previously (Cooper and Spry, 1972). The usage of some alternative acidic reagents has resulted in totally different reaction pathways. The reaction of penicillin sulfoxide (349) with phenylacetyl chloride furnished the thiazinium salt (350)... 

Reaction of the penicillin sulfoxide (355) with A-chloro-A -sodio-car-... 

The most important application of sulfoxide thermolysis is probably in the field of p-lactam antibiotics.6 Penicillin sulfoxide (34) by heating is converted into the more stable isomer (35). The reaction occurs via the intermediate sulfenic acid (36). This sulfenic acid, by treatment with trimethyl phosphite in glacial acetic acid, can be reduced to the thiol acetate (37), which can be isolated (Scheme 20). 

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... 

A. Reactions of Penicillin Sulfoxides with Sulfur Nucleophiles. . ... 

The sulfenic acid (19) underwent the same reactions previously associated with the thermal treatment of penicillin sulfoxide except under considerably milder conditions. Methanesulfonic acid at ambient tern-... 

More recently, an in-depth study (Chou et al., 1978) of the reaction of the penicillin sulfoxide ester (55) with a positive chlorine source (i.e., A -chlorophthalimide) aptly illustrated the capriciousness of this reaction. In the presence of traces of acid (e.g., HCI), a rapid autocatalytic reaction ensued which liberated hydrogen chloride and gave two major new products 99 and 100. On continued heating 99 was also converted to 100. A minor product (101) could be obtained as the major product if the reaction was conducted at ambient temperature. By heating in the presence of chlorine, 101 could also be converted to 99 and 100. Treatment of 101 with methanol gave the thiazoline 102. These results indicated that under certain conditions a penicillin sulfoxide could cleave at the S—C-5 bond, a previously unrecognized site for cleavage. 

The trapping of the penicillin sulfenic acid with dihydropyran has been previously discussed (Cooper and Spry, 1972). Further examples of trapping with vinyl ethers have also been disclosed (Ager et al., 1972 1973). The sulfoxide (106) reacted with isobutyl vinyl ether resulting predominantly in unstable vinyl ether (139). On treatment with a catalytic amount of p-toluenesulfonic acid in benzene, 139 afforded the dihydrothiazine (140). The reaction of 139 with methanolic hydrogen chloride resulted in a smooth transformation to the acetal (141). When 1,1-diethoxyethy-lene was used, the corresponding vinyl ether was not observed. Instead, the preferred course of the reaction was an in situ hydrolysis to the ester (142). 

A utility for this reaction was demonstrated by the reaction of the penicillin sulfoxide hydrazide derivative (143) with 2-propoxypropene to afford the enol ether (144). This was then hydrolyzed with mercuric nitrate to afford the ketone (145) (Ager et al., 1973). Ozonolysis of 145 gave the diketone (146) which on treatment with base cyclized to cepham... 

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