Dihydrothiazines, rearrangement

The dihydropyrimidinethione 30 has been obtained by microwave-induced rearrangement of a dihydrothiazine, using silicon carbide as a passive heating element <06JOC4651>. 

A possible mechanism for the observed photochemical rearrangement of dihydrothiazine (56) to dihydrothiazine (59) is shown in Scheme 22. It involves a... 

One notable advance in this chemistry since the publication of CHEC-II(1996) is the use of enantiomerically enriched 3,6-dihydro-l,2-thiazine 1-oxides in the rearrangement sequence. For instance, iV-Cbz-protected bicyclic 1,2-dihydrothiazine 44 undergoes ring opening upon treatment with phenylmagnesium bromide (Scheme 16). The synthesis of allylic amino alcohol 129 is completed in excellent yield upon exposure of the intermediate sulfoxide 130 to trimethyl phosphite and methanol at 80 °C <2002TA2407, 2000TL3743>. 

The goal of this section is to update and extend previous accounts on this subject in CHEC( 1984) and CHEC-11(1996). In particular, rearrangement and degradation of the cephalosporin core as well as dihydrothiazine ring cleavage, which were not included in CHEC-II(1996) <1996CHEC-II(1B)591> are to be presented herein. 

Another useful reaction of these Diels-Alder adducts is shown in equation (54). Dihydrothiazine oxide (123) from ( . )-2,4-hexadiene can be opened with a Grignard reagent to allylic sulfoxide (124) which undergoes a stereoselective 2,3-sigmatropic rearrangement via the envelope-like transition state conformation shown, having a quasi-equatorial methyl group to afford sulfenate ester (125). Desulfurization of (125) provides E)-threo smino alcohol derivative (126) in excellent overall yield. If ( ,Z)-2,4-hexadiene is used, the E)-erythro epimer of (126) is formed cleanly. 

Weinreb and coworkers have examined some reactions of dihydrothiazine imines and have developed a new approach to vicinal diamines using these intermediates. Their method is outlined in Scheme 18. Cycloaddition of ( -2,4-hexadiene with the tosyl bis-imine gives a 1.1 1 mixture of epimeric dihydrothiazine imines (140) and (144). Subsequent transformations of these adducts took two different courses. In one, adduct (140) could be opened to allylic sulfilimine (141) which underwent a stereoselective 2,3-sigmatiopic rearrangement to sulfenamide (142) (cf. equation 54). Desulfurization of (142) yielded E)-threo vicinal sulfonamide (143). Adduct (144), which presumably exists in conformation... 

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,... 

A number of rearrangements are known in which new dihydrothiazines are formed from existing derivatives. One example, in which the ring skeleton remains unaltered, is provided by the conversion of compound 169 into 172 in the presence of lithium aluminum hydride presumably the intermediate dihydrothiazinol 170 undergoes dehydration to the thiazine 171, which cyclizes to the product. 

By contrast, the chemistry of dihydro-1,4-thiazines is in a much healthier state. The abundance of syntheses, particularly for the derivation of the 3,4-dihydro tautomers, is in large measure responsible for this situation. It is clear that dihydrothiazines possess some interesting and unusual patterns of reactivity, particularly in their ability to undergo molecular rearrangements, which are of general organic chemical interest. It is also apparent that such compounds are versatile precursors of both known and rare heterocyclic systems. 

Since 3,6-dihydrothiazine 1-imines exist in conformations having a quasi-axial S—N bond, these imines are properly disposed stereoelectronically for such a pericyclic process. This reaction is essentially irreversible, similar to the equilibrium in a [2,3]-sigmatropic rearrangement of allylic sulfilimines (55), which lies to the side of the sulfenamide (56) (Scheme 11). There is a clean transfer of stereochemistry from C-6 of the dihydrothiazine (52) to C-4 of the thiadiazolidine (53), leading to the (E)-erythro-vicinal diamine derivative (54). In a similar fashion, thermolysis of the epimeric imine (57) gives the thiadiazolidine (58), which can be converted into the Z)-threo-vicinal diamine... 

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. 

This transformation presumably proceeds with initial formation of allylic sulfilimine 55, which rearranges via an envelope-like transition state to sulfenamide 56 (cf. Scheme 1-XIU). Interestingly, NMR analysis showed that this [2,3]-sigmatropic rearrangement lies totally on the side of this sulfenamide, unlike the allylic suUbxide-sulfenate ester system, which lies predominantly to the side of the sulfoxide. Similarly, C-3 epimeric dihydrothiazine imine 58 can be converted by an identical pathway to E-erythrp vicinal diamine 59 in an efficient and totally stereoselective manner [Eq. (28)]. 

Dihydrothiazine oxide 44 was also stereoselectively converted to sulfide 53, as outlined in Scheme l-XIV.56 Treatment of 44 with trimethylsi-lylmethylmagnesium chloride afforded a sulfoxide which was converted to a sulfonium salt. On treatment with potassium terf-butoxide, this intermediate underwent a [2,3]-sigmatropic rearrangement via an envelopelike transition rate (cf. Scheme 1-XIII) to yield compound 53 in good overall yield. 

New rearrangements of 2-imino-2//-l-benzopyran-3-carboxamides, on their treatment with anthranilic acid, have been revealed. 4-Quinazolinones (72) have been prepared by rearrangement of 4-imino-4//-3,l-benzoxazines (71) via amidine carboxamides, while dihydrothiazines such as (73) which are disubstituted at C(7) have been observed to undergo a cyclization-ring contraction reaction with substituted acrylic acids to yield pyrroles (74). This interesting transformation has been accounted for by the route outlined in Scheme 23. 

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