Rearrangement benzothiazines

The sulfide 92, prepared by treatment of jV-methyl-3-methylindole with 2-nitrobenzenesulfenyl chloride, was converted to the rearranged benzothiazine 93 by treatment with triethyl phosphite under nitrogen.137... 

The most widely used variant of the Gabriel-Colman is the conversion of saccharine derivatives to benzothiazine derivatives. The reaction has been extensively studied as benzothiazines are important pharmacophores, particularly in the oxicam class of antiinflammatories. The first reported instance of this transformation was in 1956 where 43 was treated with sodium methoxide to provide 44. The rearrangement also works with esters " and some amides " in addition to ketones. 

The benzothiazine equivalent of a 1,7 naphthyridine (58) has also been prepared. The reaction did not work in alcoholic solvents, but when DMF was used 57 rearranged to provide the desired product in moderate yield. 

The l,3,4-oxadiazin-6-one (240) undergoes cycloaddition followed by a remarkable rearrangement to give the triazole A(-imine 241 and an open-chain product (136). Cycloadditions have also been carried out with the following ring systems 1,2-dihydroisoquinoline (242) (137) dihydro-1,3-oxazine (243) (138,139), 2H-, 3-benzothiazine (244) (140,141), and 27/-l-pyran-2-thione (245) (142). 

Finally, recent work has disproved the originally proposed structure 226303 of the product from addition of DMAD to benfothiazole. McKillop and Sayer304 have shown that a first-formed adduct 227 can give a fused thiazole 228 by addition of a second DMAD molecule, or rearrange to the benzothiazine 229 in the presence of water. The structure of 229 was established by X-ray crystallography.305... 

A similar pathway seems operative in the 2-substituted benzo[6]thiophene case also <79JCS(Pi 13207). Here, however, the spiro intermediate rearranges to both the benzothiazine (258) and benzothiazole (259), the two products being isolated in almost equal amounts (Scheme 70). The dihydrobenzo[6]thiophene unit present in (259) does not seem to be dehydrogenated as the dihydrothiophene unit does (Scheme 69). 

Attempts to acylate 2-unsubstituted thiazolylium salts with dialkylacylphosphonates under basic conditions yield an intermediate (72) which rearranges with ring expansion affording a 1,4-thiazine (73 Scheme 38). Under the same reaction conditions, 2-unsubstituted benzothiazolylium salts give 1,4-benzothiazines of type (74 Scheme 39). 

Benzothiazines (542) may rearrange into benzothiazoles (543) by oxidation in the presence of a base (Scheme 291). This type of synthesis was prompted by the suggestion that the biosynthesis of firefly luciferin (544) could result from a similar rearrangement of the benzothiazine formed by the condensation of p-benzoquinone and cysteine (75CC42). The... 

Amino-3,l-benzoxazin-4-one (1, X = O) and 2-amino-3,l-benzothiazin-4-one (1, X = S) undergo a facile rearrangement to furnish quinazolin-2,4(li/,3i/)-diones and 2-thioxo-2,3-dihy-droquinazolin-4(]7T)-ones 2. respectively, under relatively mild conditions on heating in acidic solution or on standing for a longer time in dilute alkali (cf. p 142). ... 

Dimroth rearrangement involving migration of an alkyl or aryl substituent from N3 to the amino or imino group at position 4 or 2 is the main type of rearrangement with retention of ring size in the quinazoline series. Although transformations of 2-amino-3,l-benzoxazin-4-ones and 2-amino-3,l-benzothiazin-4-ones to quinazolines also represent, from the mechanistic viewpoint, a Dimroth-type reaction, they are treated in Section 6.3.1.1.2.3. 

An investigation of the oxidation of melanin precursors in the presence of azide radicals using pulse radiolysis has been reported (2J9. Thus, dopa and cysteinyldopa yielded first the unstable semiquinones that disproportionated to a quinone-quinol complex. The quinones decayed to more stable products dopaquinone produced dopachrome while cystei-nyldopa-quinones rearranged to benzothiazine isomers. 

When 4//-l,3-benzothiazine-4-thiones react with propargylamine imidazoles form in 53-72% yields by way of an amidine intermediate <87LA103>. Oxidation of the dehydration product of creatine gives creatone (205) with concurrent Dimroth rearrangement (Scheme 138) <82BCJ1912, 87BCJ4115>. 

An interesting rearrangement was observed35,36 during the preparation of4-hydroxy-JV-(5-methyl-3-isoxazolyl)-2-methyl-2/M,2-benzothiazine-3-carboxamide 1,1-dioxide (43) (Eq. 9). Sodium methoxide cleaved the benziso-thiazoline derivative 40 to the expected benzoate ester 41, but this was cyclized by base to a 4-hydroxy-2//-1,2-benzothiazine (42) with simultaneous conversion of the isoxazole moiety to an oxadiazole. Compound 42 was N-methylated by methyl iodide and the product converted to the desired amide 43 by treatment with triethylamine in xylene, a process which simultaneously reconverts the oxadiazole side chain to an isoxazole. 

Direct rearrangement of benzisothiazoline amides, such as compound 8 (R = NHPh), to the l,2-benzothiazine-3-carboxamide 44 has been accomplished37 in dimethyl sulfoxide using sodium methoxide. 

The nitrogen atom of 31 is readily alkylated. The 2-phenacyl derivative (38) rearranges to 2-benzoyl-2//-l,3-benzothiazin-4(3//)-one (39) in mild base,51 illustrating once again the ease with which the S—N bond is broken. 

Benzothiazines have been reported to undergo a number of rearrangement reactions, one of the most commonly encountered involving ring contraction. Thus among the products of autoxidation of 1,4-benzothiazines are benzo-thiazoline derivatives.137,141,167 For example, the benzothiazine 135 on treatment with oxygen in acidified cyclohexane gave the acyl derivative 136. 

The last reaction can be compared with the Grignard reagent-induced conversion of the l,4-benzothiazin-3-one 145 to the dihydro-1,4-benzothiazine 146. The a,/ -unsaturated ketone 147 was postulated as an intermediate to account for this rearrangement.52... 

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