1.2.5- Thiadiazole S-oxide

Usually, N-sulfinyl compounds (59) behave as thionyl transfer reagents, similar to, but milder than, thionyl chloride. For example, o-diamines with A-sulfinylbenzeneamine (59 R = Ph) afford fused 1,2,5-thiadiazoles, as in Scheme 8a.77 The advantage of using Af-sulfinyl compounds, rather than thionyl chloride itself, is that concomitant chlorinations and oxidations are avoided. This is of particular importance in the synthesis of 2,1-benzisothia-zoles (Section V,B,6). Singerman s reagent, N-sulfinylmethanesulfonamide (60) is especially valuable 78 it was used very successfully in the synthesis of a series of benzobis(isothiazoles).79... 

Thiadiazoles can be prepared by the oxidative cyclisation of 1,2-diamines or aminocarboxamides. Condensation of snlfamide (S02(NH2)2) with 1,2-diketones gives 1,2,5-thiadiazole 1,1-dioxides. A good general method is the reaction of trithiazyl trichloride with activated alkenes and alkynes this method is also useful for the fusion of a 1,2,5-thiadiazole onto other heterocycles, such as pyrroles. The reaction possibly proceeds via cycloaddition to an N-S-N unit in the trithiazine ring. "... 

A review on the ehemistry of the 1,2,4-thiadiazoles has appeared in a book <04MI277>. A novel method is reported to convert 1,3,5-oxathiazine-S-oxides 239 into 1,2,4-oxathiazoles 241 under thermal conditions. Lewis acid promoted reaction of 241 furnishes 1,2,4-thiadiazoles 243 <04HAC175>. 

Lumma, W.C., Jr., Anderson, P.S., Baldwin, J.J., Bolhofer, W.A., Habecker, C.N., etal. (1982) Inhibitors of gastric acid secretion 3,4-diamino-1,2,5-thiadiazole 1-oxides and 1,1-dioxides as urea equivalents in a series of histamine H2-receptor antagonists. J. Med. Chem. 25 207 -210. 

Reactions of 1,2,4-thiadiazoles with radicals and carbenes are virtually unknown. Catalytic hydrogenations and dissolving metal reductions usually cleave the N-S bond in a reversal of the oxidative cyclization procedures used in synthesis of 1,2,4-thiadiazoles (see Section 5.08.9.4). 

Diamino-1,2,4-thiadiazoles 66, also known as Hector s bases, are the oxidation products from iV-arylthioureas 65 a large number of examples of this type of reaction are known. Typical oxidants that give good yields are acidic hydrogen peroxide, nitrous acid, and iron(m) chloride (Equation 20) <1996CHEC-II(4)307>. 

The preparations of 1,2,4-thiadiazoles and 1,2,4-thiadiazolidines from thioureas are well known and have been summarized in three reviews those of Bambas,188 Sherman,189 and Kurzer.170 Contained in these reviews are discussions of the controversies that surrounded some of the products, notably Hector s bases, which resulted from oxidation of substituted thioureas.171,172 Subjects covered in the above reviews, but too extensive to outline in detail here, are the oxidation of amidinothioureas to 3,5-diamino-1,2,4-thiadiazoles (71),173,174 the oxidation of phenylthiourea175 and of substituted amidinothioureas176 to 3,5-diimino-l,2,4-thiadiazolidines (72, Hector s bases), the reaction of thiopseudoureas with trichloromethanesulfenyl chloride to form 3-alkylthio-5-chloro-l,2,4-thiadiazoles (73),177 the reaction of thiopseudoureas with sodium thiocyanate and bromine178 and the oxidation... 

Reactions of 1,2,4-thiadiazoles with radicals and electron deficient species are virtually unknown. Catalytic and dissolving metal reductions usually result in S—N bond cleavage. For example, the 5-anilino-3-hydroxy derivative (51) gives a good yield of l-phenyl-2-thiobiuret (52) on Zn-HCl reduction (Scheme 27). Reduction of the diamino derivative (53) gives amidinothiourea (54) from which it may be prepared by oxidation (Scheme 28). Under similar conditions, cleavage of the 3,5-diphenyl derivative (55) results in loss of sulfur and formation of benzylbenzamidine (56 Scheme 29). Reduction of 5-alkylamino-or 5-arylamino-3-alkylthio derivatives (57) with H2S in pyridine-triethylamine or sodium in liquid ammonia yields 1-substituted dithiobiurets (58 Scheme 30). 

Moderate yields of thiadiazoles (255) also have been obtained by the thermolysis of mixtures of thioamides (253) and A-sulfinylsulfonamides (259 Scheme 91) (62AG135). The manner in which the proposed intermediate (260) is converted into (255) has not been discussed and the mechanism of this reaction deserves further study. TV-Arylthioureas (261) form 1,2,4-thiadiazole derivatives (73) ( Hector s bases ) in good yields when oxidized with acidic hydrogen peroxide or other oxidizing agents (nitrous acid, iron(III) chloride) as indicated in Scheme 92 (65AHC(5)119). Evidence for the intermediate formation of dithio-... 

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