2.5- Disubstituted 1,3,4-thiadiazoles

A new, simple, high yielding synthetic route to 3,5-disubstituted 1,2,4-thiadiazoles 75 was described by Passmore and co-workers which involved the reaction of nitriles with S (AsF6)2 in liquid S02 <99CC1801>. 

The mass spectra of 3,5-disubstituted 1,2,4-thiadiazoles follow two general fragmentation pathways (a and b) which are illustrated in Scheme 2 <84CHEC-I(6)463>. 

The thermal decomposition of some 3,5-disubstituted 1,2,4-thiadiazoles has been studied and some nonisothermal kinetic parameters have been reported <86MI 408-02). Polarographic measurements of a series of methylated 5-amino-1,2,4-thiadiazoles show that thiadiazoles are not reducible in methanolic lithium chloride solution, while thiadiazolines are uniformily reduced at 0 5= —1.6 + 0.02 V. This technique has been used to assign structures to compounds which may exist theoretically as either thiadiazoles or thiadiazolines <84CHEC-I(6)463>. The photoelectron spectrum for 1,2,4-thiadiazole has been published <84CHEC-I(6)463>. 

The oxidation of thioacylamidines (220) (R = alkyl, aryl) and thioacylguanidines (220) (R = NR 2) affords a wide range of 3,5-disubstituted 1,2,4-thiadiazoles (221). A wide variety of oxidizing agents have been used for this conversion (Equation (34)) <82AHC(32)285). 

The 1,3-dipolar cycloaddition reaction of nitrile sulfides with nitriles yields 3,5-disubstituted 1,2,4-thiadiazoles of unequivocal structure. This method has received considerable attention in recent years. Electron deficient nitriles such as tosyl cyanide afford high yields of 5-tosyl derivatives (341) (Equation (53) see also Scheme 61) <93JHC357). 

Cyanodithioimidocarbonate salts have become very useful reagents for the preparation of many 3,5-disubstituted 1,2,4-thiadiazoles. Dipotassium cyanodithioimidocarbonate (314) is readily prepared from cyanamide and carbon disulfide under alkaline conditions and is readily converted into the reactive thiadiazoles (315), (316), (317), (318) and (319), as shown in Scheme 112 (71JOC14). Alkylation of (314) produces derivatives of type (320) which react with chlorine or sulfuryl chloride to yield 5-alkylthio-3-chloro-l,2,4-thiadiazoles... 

Hofmann s classical synthesis of 3,5-disubstituted 1,2,4-thiadiazoles by the oxidation of thioamides (1869)3 continues to be further exemplified. The oxidants employed include iodine,9-11 bromine,12 chlorine,13 and nitrous acid,14 as well as /V-chlorobenzamidine (which is recovered as benzamidine)15 and IV-sulfinyl-p-toluenesulfonamide (which evolves sulfur dioxide in the process).16 Irradiation with UV light in the presence of oxygen effects the same reaction, but has not been used on a preparative scale.17... 

The study of mass spectra and fragmentation patterns of 1,2,4-thiadiazoles has provided a background of information capable of helping in solving structural problems. Fragmentation of 3,5-disubstituted 1,2,4-thiadiazoles (362) occurs with loss of nitrile from the molecular ion, followed by extrusion of sulfur, and formation of nitrilium ion.262... 

Cheng, D., and Chen, Z. (2002). Hypervalent iodine in synthesis. 84. Facile synthesis of 3,5-disubstituted 1,2,4-thiadiazoles by oxidative dimerization of thioamides using polymer-supported iodobenzene diacetate. Synth. Commun., 32, 2155-2159. 

Type G Syntheses [C—N—S + C—N]. Nitrile sulphides R—C N->S have recently become available as reactive intermediates in the thermolysis (at ca. 190 °C) of 5-substituted l,3,4-oxathiazol-2-ones they may be trapped by 1,3-dipolar cycloadditions, e.g. with acetylenes, resulting in S,N-heterocycles. Cycloaddition of nitrile sulphides R CNS to nitriles R CN provides a new general synthesis of 3,5-disubstituted 1,2,4-thiadiazoles (62). Yields are moderate, but are satisfactory when electrophilic nitriles are used in conjunction with aromatic nitrile sulphides. Minor amounts of (63) are formed as by-products. 

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