1,3-Thiazine ring synthesi

Thiazine Ring Synthesis by Transformation of Another Heterocycle... 

The synthesis of 2,3-dihydrothieno[3,2-e]-l,3-thiazin-4-ones 184, in which the orientation of the thiophene ring toward the 1,3-thiazine ring is different, is based on a reaction between mercaptoamide 183 and various ketones (72KGS909) (Scheme 63). 

The overall sequence of carbenoid generation/ylide formation/[3-l-2]-cycloaddition or rearrangement was explored in the synthesis of a series of 1,3-triazine derivatives. Thus, 1,3-dipolar cycloaddition of the pyridinium ylide derived from 2-(3-diazo-2-oxopropylthio)pyridine gives a 1,3-thiazine ring incorporated into the polycyclic system (Scheme 21) (93JOC1144). 

Multicyclic ring systems are also found to be present in synthetic heterocyclic pharmaceuticals. These drugs may be benzo derivatives of monocyclic heterocycles or they may contain other fused-on (said to be annelated or annulated) heterocyclic rings. An important example of a dibenzo derivative, namely, a derivative of the tricyclic phe-nothiazine ring system, is the valuable antihistamine methopromazine (9.142). Its synthesis employs conventional reactions of aromatic chemistry to constmct the interior thiazine ring, as is outlined in Scheme 9.84. 

The mechanism for the synthesis of 3-aminopyrroles by ring transformation-desulphurisation of substituted 2-methylisothiazolium salts was investigated and evidence for the intermediacy of 3-aIkylideneaminothioacrylamides (30) and 27f-l,3-thiazines (31) obtained <96JCS(P1)2239>. 

Conformational analysis using the Sybyl 6.8 program was performed on the proposed transition state structure of the pyrazino[2,l-A [l,3]thiazine 288 (R =Me, R2 = H, R3 = Arg-Trp-NH2) formed by solid-phase synthesis, to rationalize the stereochemical outcome of the ring formation <2004TL6333>. 

The first synthesis of pyrazolo[5,l-c]-l,2,4-thiadiazines 116 and pyrazolo[3,4-c]-l,2-thiazines 118 was reported by Aiello and co-workers <76JHC615>. Compound 115 was heated five degrees above its melting point to afford the novel ring system 116. However, compound 117 gave compound 118 when treated with triethylamine. 

Similar ring systems were prepared <97JHC1693> by Coppo and Fawzi from the reaction of substituted ethyl 5-[methyl(methylsulfonyl)amino]-l 7/-pyrazole-4-carboxylates 119 with sodium hydride. This gave the 7-substitued 1,7-dihydro-l-methylpyrazolo[3,4-c][l, 2]thiazin-4(37/)-one 2,2-dioxides 120 in fair to good yield (Scheme 30). They also extended this synthesis by treating methyl 2-[methyl(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridinecarboxylate 121 with sodium hydride in dimethylformamide to yield l-methyl-7-(trifhioromethyl)-l//-pyrido[2,3-c][l,2]thiazin-4(3//)-one 2,2-dioxide 122 in 79% yield (Scheme 31) <98JHC499>. 

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 following section provides an update to the synthesis of the title ring systems covering material published from 1996 to 2006. Similar to CHEC-II(1996), this information is organized by the type of disconnection, beginning with the one-bond disconnections A-F, followed by [4-1-2] and [3-1-3] two-bond disconnections (Figure 23). There have been several notable advancements in the synthesis of 1,2-thiazines since the publication of CHEC-II(1996). For one,... 

A synthesis during which the pyrimidine ring of this system was formed involved the fusion of 2-mercapto-4,4,6-trimethyl-4//-l,3-thiazine (592) with anthranilic acids to give 593 (62JOC4061). 

Another approach to the synthesis of simultaneously b- and e-fused heterosystems containing l,3-thiazin-4-one fragments is based on the use of a thiazinone ring prepared in advance. Thus, 2-imino-3-amino-TA 79, obtained from hydrazide 198, was applied to the syntheses of triazolobenzo-TAs 199,200, and 201 (75MI1). Amine 201 may be obtained from hydrazide... 

Thiazine analogues have received a great deal of attention partly because they may arise by chemical transformations from penicillins (73CC226,74JCS(P1)1572>. A simple synthesis of this ring system is shown below. 

A convenient method for the synthesis of trioxo-benzothiazine 181 involves a ring expansion reaction of benzoisothiazole 180 <07H1843>. Directed ort/ o-mctalation of benzenesulfonamide 176 coupled with carboxylation gives rise to 2-carboxybenzene-sulfonamide 178 which is then converted to benzoisothiazole 179 under the TMSCl-Nal deprotective-cyclization conditions. Bromination of 179 followed by ring expansion mediated by 20% KOH according to the Abramovitch procedures furnishes the benzo-thiazine 181. Optical resolution of 181 using (-)-menthoxyacetyl chloride yields its (+) and (-) enantiomers. 

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