Thiosemicarbazides 1.3.4- thiadiazoles

Thiosemicarbazides are useful in forming 1,3,4-thiadiazoles, a class of compounds having herbicidal activity. 

Acylation of thiosemicarbazide with propionyl chloride, interestingly, does not stop at the acylated product (124). Instead, this intermediate cyclizes to the thiadiazole, 125, under the reaction conditions. Hydrolysis then affords the heterocyclic amine, 126. Acylation by 88 followed by removal qf the acetyl group affords sulfaethidole (116) variation of thle acid chloride used in the preparation of the heterocycle leads to 117 and 118. 

The microwave-assisted solid-supported synthesis of 1,3,4-thiadiazoles was described applying from acid and thiosemicarbazide on acidic aliunina... 

A somewhat different scheme is used to gain entry to the alternate symmetrical 1,3,4-thiadiazole ring system. Reaction of thiosemicarbazide with isovaleric acid affords the ring system (217) in one step. The reaction may be rationalized by positing acylation to intermediate 216 as the first step. Sulfonylation of the amino group of 217 with p-methoxybenzenesulfonyl chloride affords the oral... 

Amino-l,3,4-thiadiazol-2-yl)-l,2,5-oxadiazole-3-amine 175 was formed with a yield of more than 75% in a condensation of 3-amino 4-cyano-l,2,5-oxadiazole 174 with thiosemicarbazide in trifluoroacetic acid (Equation 30)... 

The reaction of 2,5-dimercapto-l,3,4-thiadiazolidine 34 with dialkylamines under Mannich reaction conditions gave N,S-aminomethylated thiadiazoles in 69-70% yields (Equation 24) <1998CHE1431>. With urea, thiourea, semicarbi-zide, or thiosemicarbazide, thiadiazolidine 34 gave N,N-aminomethylated thiadiazoles in 89-98% yields (Equation 25). 

Monothiodiacylhydrazines 127, derived from the acylation of thiosemicarbazides or as intermediates in the reactions of (1) thiohydrazides with carboxylic acids and their derivatives (see Section 5.10.9.2.2(i)) or (2) hydrazides with thiocarbonyl compounds (see Section 5.10.9.2.3(i)), cyclize in the presence of an acid catalyst to give 1,3,4-thiadiazoles 128 (Equation 39, Table 4). 

The reaction of the trichloromethylarenes 146 with thiosemicarbazide 138 in a boiling methanol-pyridine mixture afforded the 2-amino-5-aryl-l,3,4-thiadiazoles, while under similar conditions trichloromethylarenes 146 were converted to the diaryl-1,3,4-thiadiazoles with thiobenzhydrazide 147 (Equation 52, Table 7) <1996RCB1185>. 

The reaction of imines with thiohydrazides gives 1,3,4-thiadiazole via a thioacylimidohydrazine intermediate. The imidoyl chloride 148 when treated with the IV-phenyl thiosemicarbazide 149 gave the 1,3,4-thiadiazole hydrochloride 150 (Equation 53) <2002MI1241>. 

Alkyl and aryl nitriles 151 react with thiosemicarbazide 138 under acidic conditions to give 1,3,4-thiadiazoles (Scheme 14 and Table 8) <1995BML1995, 1996IJB273, 1997IJB394>. The acidic conditions promote the elimination of ammonia from the intermediate iminothioacylhydrazine 152. 

The 2-[4-aryl(thiocarbamoylhydrazino)]-5-phenyl[l,3,4]thiadiazoles 51 can react in two ways. Upon heating, reaction leads to cyclized 6-phenyl[l,2,4]triazolo[3,4-A][l,3,4]thiadiazole-3(27f)thiones 52 and, on the other hand, the thiosemicarbazides 51 undergo cyclodesulfurization affording [l,2,4]triazolo[3,4-A][l,3,4]thiadiazoles 53 when treated with dicyclohexylcarbodiimide (Scheme 5) <1986JHC1339>. 

The synthesis of numerous thiadiazoles substituted in the 5-position with carbamoyl or heteroaryl moieties and hydroxyl or amino groups in the 2-position (Scheme 20), was achieved by reacting dithioesters with semicarbazide or thiosemicarbazide and cyclizing the resulting acylated sem-... 

The reaction of 1,4,2-dithiazolium salts with amines also leads to thiadiazoles. Thus treatment of the A,A-diethylamino dithiazolium salt (177) with an excess of hydrazine (Scheme 32) afforded 2,5-bis(diethylamino)-l,3,4-thiadiazole (180) together with thiobenzamide. The mechanism postulated is as follows in the first step, hydrazine causes rupture of the ring to liberate A,A-diethyl-thiosemicarbazide (178) which in turn reacts with another molecule of (177) to give the intermediate... 

Amino-5-alkyl- or 5-phenyI-l,3,4-thiadiazoles are prepared most conveniently from thiosemicarbazide. For example, benzalthiosemicarbazone by oxidation with iron(III) chloride gives the 5-phenyl derivative. Thiosemicarbazide is also used in the synthesis of 2-amino-5-mercapto-l,3,4-thiadiazole by reaction with carbon disulfide. The product may be alkylated to yield the 5-alkylthio derivatives using a variety of alkylating agents (58MI11201). 

A substrate-dependent transformation to either thiadiazoles 41 or oxadiazoles 40 occurred upon cyclodehydration of thiosemicarbazides and the selectivity of the reaction was found to be highly dependent on the electronic... 

The synthesis of 1,3,4-thiadiazoIes is discussed in terms of the number of bonds being formed and by ring transformation. Thiadiazole synthesis by one-bond formation is exemplified by the cyclization of an acylated thiosemicarbazide as shown in Scheme 16. The most common two bond formation takes place via 1,3-dipolar cycloadditions presented in Scheme 23. 

The reaction of oxalyl hydrazide with aryl isothiocyanate gives the bis(thiosemicarbazide) (162) which under acidic conditions cyclizes to the bis(l,3,4-thiadiazole) (163). Under alkaline conditions the 5-mercapto-l,2,4-triazole (164) is obtained (77BSB399). 

The parent molecule, 1,3,4-thiadiazole (174), was first synthesized in 1956 by a four-step reaction sequence starting from thiosemicarbazide. A second procedure utilizes hydrazine and potassium dithioformate. A later procedure is shown in Scheme 19. Dehydration of DMF with thionyl chloride or phosgene gives the formamidoyl chloride (172) which on... 

Various 3,5-disubstituted 1,2,4-triazoles 593 have been prepared in good yields by the reaction of nitriles 591 with acylhydrazides 592 in the presence of catalytic potassium carbonate under microwave heating (Scheme 266) <2005TL3429, CHEC-III(5.02.9.2)182>. Likewise, alkyl and aryl nitriles 594 react with thiosemicarbazide 595 under acidic conditions to give 1,3,4-thiadiazoles 596 (Scheme 267) <1995BML1995, CHEC-III(5.10.9.2.2)595>. 

Horclois et al.239 have suggested the use of NMA as a solvent for the reaction of thiosemicarbazide with carbon disulfide to produce 2-amino-5-mercapto-l,3,4-thiadiazole. The reaction proceeds at a lower pressure (atmospheric) and at a lower temperature than the comparable reaction in water. Campbell240 has described the polymerization of acrylonitrile by BF3 in amide solvents including NMA. 

Trifluoroacetic acid or trifluoroacetic acid anhydride reacts with hydrox-amic acid amides, thiosemicarbazide, and 1,2-diaminopyridine to yield herbicidal active 1,2,4-oxadiazoles [78GEP(0)2801509], fungicidal-active 1,3,4-thiadiazoles (80USP4264616), and 2-trifluoromethyltriazolo[l,5-alpyridines [80JFC(15)179. 2-Trifluoromethyl-L-histidine was obtained from L-histidine on treatment with benzoyl chloride/sodium hydroxide and subsequent ring closure with trifluoroacetic anhydride (78JOC3403) (Scheme 41). 

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... 

By cyclizing thiosemicarbazide with iV,iV -diphenylcarbodiimide, Goodfrey and Kurzer obtained 2-amino-5-anilino-l,3,4-thiadiazole (57) with the thiocarbamidoaminoguanidine (56) as intermediate. 57 and similar compounds (59), also with alkylamino groups, have... 

Alkoxy-5-amino-1,3,4-thiadiazoles (41) are not particularly stable to hydrolysis. They were hydrolyzed by hot hydrochloric acid, first to 2-amino-l,3,4-thiadiazolin-5(4)-one (108) (or the tautomeric imine) and then to thiosemicarbazide. On diazotization in hydrochloric acid 41 gave 2-chloro-l,3,4-thiadiazolin-5(4)-one (107), and by hot alkali it was cleaved to 1-alkoxythiocarbonylsemicarbazide (109). ... 

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