Thiosemicarbazones 1.3.4- thiadiazoles, 2-amino

Alkyl and aryl thiohydrazide derivatives react with orthoesters and trihalomethyls to afford 1,3,4-thiadiazoles. The reactions proceed via a thiosemicarbazone intermediate which cyclizes to eliminate either alcohol or hydrogen chloride. Treatment of the iV-thiohydrazide pyrazole 143 with triethyl orthoformate in acetic acid at reflux gave the 5-acetamido-l,3,4-thiadiazol-2-ylpyrazole 144 (Equation 51), and in the absence of acetic acid the 5-amino-l,3,4-thiadiazol-2-ylpyrazole 145 in 76% yield <2000JCM544>. 

Proton, C, and N NMR spectroscopy has been employed to demonstrate the existence of ring-chain tautomerism between protonated forms of thiosemicarbazones and protonated 2-aryl-5-amino-2,3-dihydro-1,3,4-thiadiazoles <92KGS1689>. The use of NMR in various solvents, indicates that the isoxazoline (28) contains between 24% and 34% of the thiadiazoline (29) <85KGS1001>. Tautomerism was also discussed in Sections 4.10.2 <90BCJ2991> and 4.10.3.3 <83HCA1755>. 

The sulfonylurea hypoglycemic agents, as noted in Chapter 2, also trace their ancestry to the sulfonamides. It is of interest that activity is retained when a substituted 2-amino-1,3,4-thiadiazole replaces the urea function. Reaction of isobutyryl chloride (123-1) with thiosemicarbazone (123-2) leads initially to the transient 1,2-diacyUiydrazine (123-3). This apparently cyclizes spontaneously to thiadiazine (123-4) under reaction conditions. Acylation with p-methoxysulfonyl chloride (123-5) affords the oral hypoglycemic agent isobuzole (123-6) [134]. 

Amino-5-phenyl-l,3,4-thiadiazole is reduced by sodium amalgam to benzaldehyde thiosemicarbazone, but the 5-H and 5-methyl analogs do not react (68AHC(9)165, p. 197) (see also Scheme 9 for LAH reduction). 

Sodium amalgam reduced 2-amino-5-phenyl-1,3,4-thiadiazole (38) to benzaldehyde thiosemicarbazone, whereas the 5-H and 5-methyl analogs were unaffected. The latter compounds could not be reduced polarographically, whereas 38 gave a half wave potential of —1.940 volts. 

The product obtained from phenylthiosemicarbazide (92 R = H) and phosgene, described as 2-amino-4-phenyl-l,3,4-thiadiazolin-5-one (93 R = H), is in fact a mixture. Conditions have now been specified for the successful preparation of this compound (93 R = H) by this route. Oxidation of thiosemicarbazones. The oxidative cyclization of benzalthio-semicarbazones and of acetone thiocarbohydrazone is a well-known route to the 1,3,4-thiadiazole ring system. 4-Arylthiosemicarbazones of ketones (99) have now been shown to cyclize in this manner on being stirred in benzene in contact with suspended manganese dioxide, giving satisfactory yields of 5-imino-A -l,3,4-thiadiazolines (101). Ring-closure over alumina in chloroform slowly yields the isomeric l,2,4-triazoline-5-thiones (100). Bicyclo[3,3,l]non-2-en-9-one 4-phenylthiosemicarbazone... 

Ferric chloride 2-Amino-1,3,4-thiadiazoles and 2-imino-Zl -1,3,4-thiadiazolines from thiosemicarbazones... 

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