Bromine- and iodine-mediated oxidative dimerization of cyanothioacetamide derivatives: synthesis of new functionalized 1,2,4-thiadiazoles

The ( 2E,2 ′ E )-2,2′-(1,2,4-thiadiazole-3,5-diyl) bis [3-aryl(hetaryl)-2-cyanoprop-2-entioamides] were obtained by treating ( E )-3-aryl(hetaryl)-2-cyanoprop-2-entioamides or their [4 + 2] dimerization products, 6-amino-2,4-diaryl-3,5-dicyano-3,4-dihydro-2 H -thiopyran-3-carbothioamides, with bromine or iodine in DMF. The scope and limitations of the reaction are discussed. Partial ring bromination of starting thioamide was observed only in the case of ( E )-2-cyano-3-(4-hydroxy-3-methoxyphenyl)prop-2-enethioamide. When treated with bromine in DMF, 2-cyano-2-cyclopentylideneethanthioamide gives 2,2′-(1,2,4-thiadiazole-3,5-diyl) bis [2-cyclopentylideneacetonitrile] in 69% yield. When 2-imino-7-methoxy-2 H -chromene-3-carbothioamide was brominated, 3a,4-dibromo-7-methoxy-3a,4-dihydro-3H-chromeno[2,3-c]isothiazol-3-iminium bromide was isolated instead of the expected 3,3′-(1,2,4-thiadiazole-3,5-diyl) bis (7-methoxy-4a,8a-dihydro-2 H -chromene-2-one). The structure of ( 2E,2 ′ E )-2,2′-(1,2,4-thiadiazole-3,5-diyl) bis {3-[2-(trifluoromethyl)phenyl]acrylonitrile} was confirmed by X-ray studies. Molecular docking was performed in order to find possible protein targets for the prepared new 1,2,4-thiadiazoles. One of the compound, (( 2E,2 ′ E )-2,2′-(1,2,4-thiadiazole-3,5-diyl) bis (3-(4-chlorophenyl)acrylonitrile), showed good herbicide safening effect in the experiments with sunflower seedlings. Graphical abstract