Dihydro-1,4-thiazines synthesis

Imidazo[4,5-fi][l,3]thiazine, 6-amino-2-bromo-l,5-dihydro-synthesis, 5, 664... 

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>. 

In comparison with the 1,3-oxazines, much less attention has been paid to the synthesis of cycloalkane-fused 1,3-thiazines. Only a few 2-thioxo-, 2-imino-, and 2,4-dioxotetrahydro derivatives are known. The most versatile method for the synthesis of the dihydro derivatives is cycloaddition. 

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>. 

A facile synthesis of 2,4-disubstitued-tetrahydro-l,3-thiazines 40 involves reduction of the 5,6-dihydro-4//-l,3-thiazine 130 with NaBH3CN to give the ty -isomers (Equation 5) <2004TL1503>. 

The one-step synthesis of further tri- and tetracyclic pteridine derivatives from 2-aminopyrazine 153 has also been described <2001JHC1173>. Cyclic analogues of A -[bis(methylthio)methylene]amino reagents such as 2-(methylthio)-2-thiazoline, 5,6-dihydro-2-(methylthio)-4//-l,3-thiazine, 2-(methylthio)-2-imidazoline, 2-(methylthio)-l,4,5,6-tetrahydro-pyrimidine, 2-(methylthio)-2-pyrazine, and 2-chloropyrimidine reacted with aminopyrazine 153 to afford thiazolo/thia-zino[2,3-3]- 159 ( = 1 (53%), n = 2 (42%)), imidazo/pyrimidino[2,l-/ ]- 160 ( = 1 (53%), = 2 (57%)), pyrazino[2,l-/ ]-161 (21%), and pyrimido[2,l-/ ]-pteridine 162 (42%) derivatives, respectively. 

H,3 H-Oxazolo[4,3-c][ 1,4]thiazine-6-carboxylic acid, 8,8a-dihydro-3,3-dimethyl-methyl ester X-ray diffraction, 6, 647 Oxazolo[2,3-h]thiazol-3(2H) -one 1,1-dioxide synthesis, 6, 1005... 

The described synthesis of l,4-thiazino[3,2-6][l,4]thiazine (305) <87JA4308> starts with the reaction of aqueous glyoxal (302) with iV-methylguanidinium chloride (303) in water (pH 8). The resulting 2-amino-4,5-dihydro-4,5-dihydroxy-l-methylimidazolium chloride (304) is treated with 2-amino-ethane thiol in H20 (pH 8-9) to give either (305) or (306). The NMR spectrum of the product supports both of the structures (305) and (306) there is only one diastereomer <87JA4308>. 

The hetero-DielsAlder reaction of A-sulfinyl 141 (X = 0 or NR) or thionitrosoarene 144 dienophiles with dienes 142 is the main method for the formation of 3,6-dihydro-2//-l,2-thiazine 1-oxides 143 or 3,6-dihydro-2//-1,2-thiazines 145 (Scheme 73) . The mechanistic and stereochemical aspects of this reaction are covered in detail in GHEC-II . In general, thionitrosoarenes 144 are transient in nature, rather difficult to prepare, and thus have a limited role in the synthesis of 1,2-thiazines. On the other hand, A-sulfinyl compounds 141 and related sulfur diimines are more stable and are isolable species. The common method of preparation of the A-sulfinyl compounds involves treatment of an amine or amide with SOCl2 and base. 

Dihydro-1,2-thiazines as intermediates in the synthesis of polyfunctional aliphatic compounds 88ACR313. 

A method involving the facile addition of mercaptoacetic acid across the double bond of an azomethine for the one-step preparation of 4-thiazolidinones has been used in the synthesis of thiazolo[2,3-c][l,4]thiazine-3(2//)-one. Thus, 2f/-3,4-dihydro-1,4-thiazines (138) react with alkyl mercaptoacetic acid at 100°C under nitrogen to give thiazolo[2,3-c][l,4]thiazin-3(2//)-ones (139) Similarly, 7/f-hexahydro-l,4-benzothia-zine[138, RR = (CH2)4] condenses with mercaptoacetic acid to yield 139 [RR = (CH2)4, R = R = H] (64M1335) (Scheme 30). 

Although the subject of brief surveys, " the chemistry of mono-cyclic 1,4-thiazines has not previously been discussed in a comprehensive manner. The aim of this review is to consider the synthesis, reactivity, and physicochemical properties of these compounds and their dihydro derivatives. 

Although the precise pathway involved in the aforementioned synthesis has not been established, it is clear that 3,4-dihydro-2//-l, 4-thiazines are formed in preference to thiazolidines, which, in turn, are preferred to 5,6-dihydro-2if-1,4-thiazines. The dihydrothiazines are probably produced from a-mercaptoketones, formed by the action of elemental sulfur upon the ketones, and aziridine. It seems likely that the thiazolidines arise from the reactions of the ketones with )3-mercaptoethyIamine, produced from aziridine and hydrogen sulfide a competing reaction of the a-mercaptoketone with sulfur is probably responsible for the generation of hydrogen sulfide. 

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