Synthesis of new thiophene-based heterocyclic compounds with 1,2,4-triazole ring

Abstract

Some chemical modifications of the 2-amino-thiophenes prepared via Gewald method were established. A number of new substituted thienotriazolopyrimidines, thienotriazoles and thiophenyl-triazolothiadiazine were obtained. This study provides new approaches to the construction of substituted 1 H -1,2,4-triazoles bearing thiophene core and allows to use data in medical chemistry for further drug discovery. The obtained compounds could have significant potential for biological research, in particular, to discover new anticancer drugs. The ethyl thiophene-3-carboxylate, formed in deamination reaction of 2-aminothiophene, was converted to 4-amino-[1,2,4]triazole-3-thiol. Alkylation of the last with chloroacetamide and subsequent cyclization of the product in excess of POCl 3 resulted in the previously unknown thienyl substituted [1,2,4]triazolo[3,4- b ][1,3,4]thiadiazine formation. Moreover, 2-aminothiophenes were studied in a three-component reaction with hydrazides and orthoester leading to the thieno[2,3- e ][1,2,4]triazolo[1,5- c ]pyrimidines in high yields. Thus, 2-aminothiophene reacting with triethylorthoformiate forms an appropriate ethoxymethylene-aminothiophene, which undergoes an attack by the nucleophilic nitrogen atom of the hydrazide molecule. Further cascade cyclization leads to the formation of thieno[2,3- e ][1,2,4]triazolo [1,5- c ]pyrimidines. Finally, the properties of previously obtained thienopyrimidines were studied and it was found that heating a mixture of 2,3-diaminothieno[2,3- d ]pyrimidine with benzaldehyde and sulphur in DMF afford fused thieno[2,3- d ][1,2,4]triazolo[1,5- a ]pyrimidine. A number of new substituted thienyl-1,2,4-triazoles, 3-(thiopen-3-yl)-triazolo[3,4- b ] [1,3,4]thiadiazines, thieno[2,3- e ][1,2,4]triazolo[1,5- c ]pyrimidines, thieno[2,3- d ][1,2,4]triazolo [1,5- a ]pyrimidine were obtained. New heterocyclic compounds that combine thiophene and 1,2,4-triazole cycles in one molecule were synthesized and are of considerable interest as potential biologically active substances, in particular, anti-tumor agents. Кеу words: 2-aminothiophene, 1,2,4-triazole, thieno[2,3- e ][1,2,4]triazolo[1,5- c ] pyrimidine, thieno[2,3- d ][1,2,4]triazolo[1,5- a ]pyrimidine, [1,2,4]triazolo[3,4- b ][1,3,4] thiadiazine