Synthesis and heterocyclization of 3-cinnamyl-sulfanyl-4-methyl-1,2,4-triazole

In the present paper the interaction between 4-methyl-1,2,4-triazole-3-thiol (1) and trans-cinnamyl chloride (2) under various conditions (i-PrOH-КOH, i-PrOH-Na, MeOH-Na, Me2CO-K2CO3) has been studied for the first time. As a result, individual 4-methyl-3-cinnamylsulfanyl-1,2,4-triazole (3) has been synthesized. It has been found that selectivity of the alkylation reactions of compound 1 does not depend on the reaction conditions (solvent, base), however, target product 3 has been obtained in the highest yield (89 %) in the MeOH-Na system. The structure of synthesized compound 3 has been studied and proved by mass spectrometry (GC-MS), as well as ¹H, ¹³C NMR spectroscopy. General predictable directions for fragmentation of the molecular ion of S-derivative 3, which are accompanied by elimination of methyl, benzyl, and triazolylsulfide radicals, have been revealed. The evidence that alkylation reaction occurs at the sulfur atom is the presence of signals for the -SCH2- protons at δ 4.06 ppm in the 1Н NMR spectra of compound 3. Heterocyclization of 4-methyl-3-cinnamylsulfanyl-1,2,4-triazole 3 has been studied for the first time under the action of iodine and bromine in various solvents (iodination in chloroform, acetone, dichloromethane, ethanol; bromination in chloroform, dichloromethane), and at different ratios substrate : iodine (1 : 2) and substrate : bromine (1 : 1.5). It has been found that the interaction of compound 3 with iodine proceeds regioselectively, regardless of the reaction conditions, and it is accompanied by the linear annelation of the thiazinium ring and formation of a bicyclic fused heterocyclic system. As a result, new iodine-containing [1,2,4]triazolo[5,1-b][1,3]thiazinium systems have been synthesized: 6-iodo-3-methyl-7-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]thiazinium polyiodide and iodide (4, 5). In contrast to iodination reactions, the interaction of cinnamyl sulfide 3 with bromine proceeds non-regioselectively under the indicated conditions: in addition to the bromocyclization product, 6-bromo-3-methyl-7-phenyl-6,7-dihydro-5Н-[1,2,4]triazolo[5,1-b][1,3]thiazinium bromide (6), the bromine addition product, 3-[(2,3-dibromo-3-phenylpropyl)sulfanyl]-4-methyl-1,2,4-triazole (7), has been obtained. The evidence for heterocyclization reactions of compound 3 is the absence of signals for the cinnamyl protons and the presence of a more complicated splitting pattern of signals for the thiazinium ring protons in the 1H NMR spectra of heterocyclization products 4, 5, and 6. Keywords: 4-methyl-1,2,4-triazole-3-thiol, alkylation, 3-cinnamylsulfanyl-4-methyl-1,2,4-triazole, heterocyclization, iodo- and bromocyclization, iodine- and bromine-containing [1,2,4]triazolo[5,1-b]-[1,3]thiazinium systems, chromatography-mass spectrometry, 1H and 13C NMR spectroscopy, “heavy atom effect”