Hydrazino-1,3,4-thiadiazoles

AT-Benzylhydrazino)-l,3,4-thiadiazole (14) rearranges quantitatively in the presence of HC1 to 4-amino-2-benzyl-l,2,4-triazoline-3-thione (15). In HCl-HOAc, (14) gives a mixture of (15) and (16). MO calculations indicate that the rr-electron stabilization is -0.61j8 units greater for the 4-amino-1,2,4-triazoline-3-thione system than for the 2-hydrazino-1,3,4-thiadiazole system (70ZC406). 

By analogy with what is known for thiosemicarbazide, cyclizations of thiocarbohydrazide (47) could be expected to lead to hydrazino-thiadiazoles. However, a much stronger tendency toward formation of triazoles is apparent in the latter case, and thiadiazoles are formed only in special reactions. Thus 1-thiocarbamoylthiocarbohydrazide... 

Oxidation of bisaldothiocarbohydrazones (52) with ferric chloride, or cyclization of monothiocarbohydrazones (53) with thioacylating agents, leads to thiadiazolylhydrazones (54), from which hydrazino-thiadiazoles can be prepared in some cases. ... 

The enhanced reactivity of 5-halogeno-l,2,4-thiadiazoles over 3-halogeno-l,2,4-thiadiazoles has been mentioned before (see Section 5.08.7.1). Nucleophilic substitution at this center is a common route to other 1,2,4-thiadiazoles, including 5-hydroxy, alkoxy, mercapto, alkylthio, amino, sulfonamido, hydrazino, hydroxylamino, and azido derivatives. Halogens in the 3-position of 1,2,4-thiadiazoles are inert toward most nucleophilic reagents, but displacement of the 3-halogen atom can be achieved by reaction with sodium alkoxide in the appropriate alcohol <1996CHEC-II(4)307>. 

The 3-hetaryl-substituted 6-hydroxy- and 6-thiol[l,2,4]triazolo[3,4-A][l,2,4]thiadiazoles 28 and 29 on treatment with hydrazine hydrate gave the 3-hetaryl-substituted 4-amino-5-hydrazino-[l,2,4]triazoles 30 (Equation 3) <1990IJB135>. 

Acetazolamide Acetazolamide is 5-acetamido-l,3,4-thiadiazole-2-sulfonamide (9.7.5). The synthesis of acetazolamide is based on the production of 2-amino-5-mercapto-l,3, 4-thiadiazole (9.7.2), which is synthesized by the reaction of ammonium thiocyanate and hydrazine, forming hydrazino-N,N -( ji-(thiourea) (9.7.1), which cycles into thiazole (9.7.2) upon reaction with phosgene. Acylation of (9.7.2) with acetic anhydride gives 2-acetylamino-5-mercapto-l,3,4-thiadiazol (9.7.3). The obtained product is chlorinated to give 2-acetylamino-5-mercapto-l,3,4-thiadiazol-5-sulfonylchloride (9.7.4), which is transformed into acetazolamide upon reaction with ammonia (9.7.5) [24,25]. 

Hydrazino-l,2,4-thiadiazoles (124), which can be prepared by reduction of the corresponding nitrosamine (123) (Scheme 29) with LAH, are stable in acid and base and readily form hydrazone derivatives on reaction with suitable carbonyl compounds <65AHC(5)ll9>. In contrast, 3-hydrazino-1,2,4-thiadiazoles (125), which are synthesized by ring closure methods, are very sensitive to acid... 

The reduction of nitrosamines to hydrazino compounds is accomplished by lithium aluminum hydride 5-(a-methylhydrazino)-3-phenyl-l,2,4-thiadiazole has been obtained in 65% yield by this method.170... 

Treatment of the hydrazine 283 with acetylacetone yields the corresponding -substituted 3,5-dimethylpyrazole (284) incorporation of the hydrazino group into this new heterocyclic ring has a striking stabilizing effect on the 1,2,4-thiadiazole ring of the resulting compound.140... 

The 5-position in 1,2,4-thiadiazoles is most reactive in nucleophilic substitution reactions. Chlorine, for example, may be displaced by nucleophiles (Nu) such as fluoride, hydroxide, thiol, amino, hydrazino, sulfite and azido groups (Scheme 11). Active methylene compounds such as malonic, acetoacetic and cyanoactic esters as their sodio derivatives also displace the 5-halo substituent (65AHC(5)ll9). The reaction follows second-order kinetics, the rate determining step being addition of the nucleophile at C-5 followed by rapid elimination of X. 

By contrast, 3-hydrazino-l,2,4-thiadiazoles (163), which are prepared by ring closure methods, are very sensitive to acids and undergo elimination of sulfur with formation of 5-arylamino-l,2,4-triazoles (164) as indicated in Scheme 61 (63JCS4566). The mechanism of this conversion is not known but presumably involves the attack of a hard nucleophile at the 5-position followed by ring opening, loss of sulfur and recyclization as has been observed with the quaternary salts (77JCS(P1)1791) (see Schemes 22, 23, and 24). Hydrazine (163) reacts with aldehydes to produce hydrazones (165) and with dimethyl malonate to yield pyrazoles (166). Diazonium salts of type (153) have been prepared by the methods... 

Nucleophilic substitution in the thiadiazole ring could be of value as a way of preparing aminothiadiazoles corresponding to thiosemi-carbazides which are not readily available. This case does not frequently occur, but the method has been of considerable use in the preparation of hydrazinothiadiazoles. Thus, Fujii et prepared 2-hydrazino-5-phenyl-l,3,4-thiadiazole (43) by hydrazinolysis of 2-methylsulfonyl-5-phenyl-l,3,4-thiadiazole (44), and Kanaoka prepared the 5-methyl analog by hydrazinolysis of 2-chloro-5-methyl-1,3,4-thiadiazole. Both authors also obtained these compounds by... 

The 1,3,4-thiadiazole ring is rather susceptible to attack by strong nucleophiles. Thus, the parent compound is stable to acids but is readily cleaved by bases. 2-Amino- and 2-hydrazino-l,3,4-thia-diazoles can be rearranged to l,2,4-triazoline-3(2)-thiones. Goerdeler and Galinke showed that 2-amino- and 2-methylamino-1,3,4-thiadiazole (128, R = H and CH3) are rearranged by methylamine in methanol at 150° to the isomeric triazolinethiones (129). The 5-methyl... 

A patent describes the preparation of 2-amino-5-nitro-l,3,4-thiadiazole (142) by nitration of 2-amino-1,3,4-thiadiazole (4, R = H) with fuming nitric acid at 40°. However, the product has the same melting point as the 2-nitramino-1,3,4-thiadiazole (46, R = H) described by Kanaoka, which was obtained under very similar conditions. Since the structure of 46 (R = H) was demonstrated by reduction to 2-hydrazino-l,3,4-thiadiazole, the structure 142 may be viewed with some skepticism. 

Thiadiazol 5-(2-Chlor-phenyl)-2-(l-methyl-hydrazino)- El6a, 689 (Cl - NR-NH2)... 

Thiadiazol 5-(4-Methoxy-benzoylamino)-2-hydrazino-E16a, 785 (Ringschl.)... 

Thiadiazol 5-(2-Acetyl-hydrazino)-2-(2-methyl-phenyl)-E16a, 798 (N-Acylier.)... 

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