Thiosemicarbazones 1.3.4- thiadiazoles

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>. 

Thiosemicarbazone 4 reacted in a similar manner to give l,2,4-triazole-3-one 5 in good yield (1986JHC881), whereas at lower temperature (40 °C), unexpectedly, 2-methylamino-5-phenyl-l,3,4-thiadiazole 6 was isolated in low yield (Scheme 4). 

The proposed mechanism includes the addition of sulfur monochloride to the N-H bond of semicarbazone or thiosemicarbazone with the formation of an N-S-S-Cl intermediate followed by its cyclization into the triazole or thiadiazole ring with the extrusion of two sulfur atoms and HCl. 

The second method of making sulfamethizole consists of reacting 4-acetylaminobenzenesulfonyl chloride with thiosemicarbazone of acetaldehyde, and subsequent oxidative cyclization of the product (33.1.16) to the substituted 1,3,4-thiadiazole in the presence of potassium ferricyanide in base, along with the simultaneous removal of the protective acetyl group [16,17],... 

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>. 

Indian workers described the synthesis of l,3,4-thiadiazolo[3,2-a]-5-triazine-5(//)-thiones (61) by a hetero Diels-Alder reaction between 2-(arylideneamino)-5-ethylthio-l,3,4-thiadiazoles (60) and aromatic isothiocyanates (Equation (2)) <94MI 410-0I>. Thiadiazoles can be reduced with sodium amalgam to the aldehyde thiosemicarbazone while lithium aluminum hydride will reduce mesoionic thiadiazoles all the way to the hydrazine <84CHEC-I(4)545>. 

German workers have prepared a very large number of 4-acyl-2-acylamino-4,5-dihydro-l,3,4-thiadiazoles (138) by the condensation of substituted thiosemicarbazones with acid chlorides (Equation (15)) <86JPR205>. 

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]. 

Oxidation of Thiosemicarbazoles Oxidative cyclization to thiadiazoles in good yields from thiosemicarbazones can be performed using FeCl3 in benzene-water at room temperature (Scheme 3.46) [148]. 

The semicarbazone (96a), thiosemicarbazone (96b) and 2,4-dinitrophenyl hydrazone (96c) were all reacted with SOCl2 to yield 9//-l,2,3-thiadiazolo[4,5-a]-4,5,6,7-tetrahydropyrrolizine (97) <83IJC(B)822>. The reaction of varying amounts of benzylamine with 4-bromomethyl-5-benzoyl-1,2,3-thiadiazole (98) gave 5-benzyl-6-phenylpyrrolo[3,4-d]-1,2,3-thiadiazole (83) in low yields <78JHC473>. 

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). 

ACS(B)264). Thiosemicarbazones can also furnish thiadiazoles. Iron(III) chloride oxidation of (159) gives the acylated (160) which on treatment with base yields (161 Scheme 17). Thiazolines can be made in the same way (77JHC853). 

Acetylation of benzaldehyde thiosemicarbazone (165) yields the thiadiazoline (166) and not the diacyl derivative (167) as previously suggested (Scheme 18). Structural proof rests on spectroscopic data and on oxidation to the thiadiazole (168) followed by deacetylation with hydrazine to (169). Mild acid or base hydrolysis of (166) furnishes the starting (165) while methylation gives (170), a product identical to that obtained from the acetylation of (171) (80JOC1473). 

Tomchin and coworkers also described that O-methyli satin reacts with thiosemicarbazine to furnish isatin-2-thiosemicarbazone, which can undergo a cyclization reaction under acidic conditions to furnish a thiadiazanoindole derivative the kinetics of the reaction were subsequently determined. Later, Tomchin also described that isatin-2-thiosemicarbazones suffer a cleavage reaction of the five member ring, and the intermediate formed recyclizes to a thiadiazole derivative (Scheme 58). 

The chlorothiadiazoles (17) react readily with nucleophiles to give a series of 5-substituted 2-acyl-1,3,4-thiadiazoles (18-21). The structure of 17 was demonstrated by an unambiguous synthesis from p-nitrophenylglyoxal thiosemicarbazone (22). ... 

The first preparation of 1,3,4-thiadiazole aldehydes was described by Ohta and Isowa, who used the Krohnke reaction on 2,5-dimethyl- and 2-methyl-5-phenyl-l,3,4-thiadiazole. They described 2,4-dinitrophenylhydrazones and thiosemicarbazones, oxidation to acid, and acyloin condensation. Bacchetti has shown that 2-phenyl-... 

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 periodate oxidation of 165 and its derivatives gave 195, which could be transformed into a variety of derivatives (194 and 196) (80MI8) upon reaction with amines, hydrazines, semicarbazide, or thiosemicarbazide (Scheme 44). The thiosemicarbazones 196 were cyclized to the thiadiazoles 199 and thiadiazolines 198, which are of chemotherapeutic interest (80MI8). The aldehyde also affords the expected dimedone derivative 197. 

The acyclic C-nucleoside analogues of 1,3,4-thiadiazoles 247 were prepared by the oxidative cyclization of the thiosemicarbazones 248 (X = S) with iron(III) chloride (86JPR1 87BCJ3405). The respective oxadiazole analogues were prepared by the oxidation of the acetate of 248 (X = O) with iodine (72MI1). Both of the aroylhydrazones and thiosemicarbazones... 

The thiosemicarbazone 88 gave the 1,3,4-thiadiazole 89 with FeCh or the dihydrothiadiazole 90 on acetylation. Similar reactions have been reported for D-galactosyl, D-glucosyl and D-mannosyl thiosemicarbazones. Tetradentate metal ion and Pd " ) complexes of the l,2-bis(thiosemicarbazone) 91... 

Chemistry and heterocyclization of thiosemicarbazones. Synthesis of pyrrohdine, thiazole, thiazoline, thiazohdine, pyrazole, thiadiazole, oxa-(hazole, triazole, pyridazine, thiazine, and triazine derivatives and fused heterocycles 12JHC21. 

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... 

---