Amidinothioureas 1,2,4-thiadiazoles

A variation using thioacylguanidines affords 5-substituted-3-amino-l,2,4-thiadiazoles. If an amidinothiourea is oxidized, 5-amino-l,2,4-thiadiazoles are obtained. A recent example of this type of synthesis has been reported the amidinothiourea 87 was oxidized to the 1,2,4-thiadiazolium salt 88 on treatment with bromine (Equation 25) <2003SC2053>. 

The oxidative cyclization of amidinothioureas, which is probably the most frequently used variation of this synthesis, provides 3,5-diamino-1,2,4-thiadiazoles with varying degrees of substitution. 

The oxidation of amidinothioureas by a range of oxidizing agents to give 3,5-diimino derivatives is still one of the most versatile methods for the synthesis of N-linked derivatives (see Section 5.08.9.4). An alternative method which gives symmetrical derivatives is the oxidation of A-arylthioureas to produce Hector s bases which readily isomerize to give 3,5-diamino-l,2,4-thiadiazoles (see Section 5.08.9.2). 

Reactions of 1,2,4-thiadiazoles with radicals and electron-deficient species are virtually unknown. Catalytic and dissolving metal reductions usually cleave the nucleus at its N—S bond by a reaction that may be regarded as the reverse of its synthesis by the oxidative cyclization of amidinothiono structures (Section 4.08.9.4). For example, reduction of the diamino compound (37) gives the amidinothiourea (38) from which it may be prepared by oxidation (Equation (8)). 

Di(alkyl or aryl)amino-l,2,4-thiadiazoles (90 R,R = alkyl or aryl) are similarly obtainable in 60-85% yields from the appropriate disubstituted amidinothioureas (89 R,R = alkyl or aryl).56,57 The preparation of the latter from monosubstituted guanidines (87) and isothiocyanate esters (88) might conceivably yield the isomeric ami-... 

Amongst oxidizing reagents, arylsulfonyl chlorides in pyridine simultaneously cyclize and acylate amidinothiourea (and its 2V-phenyl and AT -diphenylhomologs), producing moderate yields of sulfonyl derivatives of 3,5-diamino-l,2,4-thiadiazoles in one step.116... 

The oxidative cyclization of amidinothioureas has been utilized in the preparation of further examples of 1,2,4-thiadiazole derivatives 38.112,113.118-122... 

Arylamino-3-nitroamino-l,2,4-thiadiazoles are crystalline solids which explode at their melting points. They are monobasic acids, remarkably stable to alkalis and to the action of boiling sodium plumbite. Mild reduction by sulfur dioxide reconverts 5-anilino-3-nitroamino-l,2,4-thiadiazole into its parent amidinothiourea from which it arises by oxidation. Attempts to reduce 3-nitroamino compounds to the corresponding 3-hydrazines were not successful.141... 

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... 

The ease with which two molecules of thioureas are joined by an S—S link to form dithioformamidine salts (37) under the influence of the most diverse oxidizing agents3,34 makes it plausible that these disulfides (37) are the primary products of most, if not all, oxidation processes. Moreover, the disulfides (37) yield, on further oxidation, the same 1,2,4-thiadiazole derivatives as the thioureas from which they are derived.3 Their role as the initial intermediates in the synthesis of the 1,2,4-thiadiazole ring system from thioureas is therefore generally accepted. In solution, dithioformamidine salts deposit elementary sulfur spontaneously and produce monothioformamidines (38) or amidinothioureas (39). The latter tend to predominate, and to become the sole products under more stringent conditions (e.g., on boiling). These amidinothioureas and the final 1,2,4-thiadiazoles are reversibly con-... 

The scope of this mechanism for the reaction of a series of nucleophiles with hydroperoxides has been reviewed and a linear free-energy plot of ogkz against logArj derived for acid-catalysed oxidations. The reaction of l-aIkyl-3-aryl-thioureas with HgOa yields 1,2,4-thiadiazoles which rearrange in acidic solutions to thiazolyl-guanidines. The formation of amidinothioureas as precursors of the thiadiazoles has, however, been established. 

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