Synthesis of 4,5-dihydropyrazolo[1,5-a]thieno[3,2-e]pyrimidines

A number of new functionalized 4,5-dihydropyrazolo[1,5- a ]thieno[3,2- e ]pyrimidine derivatives were obtained by the domino reaction of thienylhydrazonyl chlorides with (1,2,4-oxadiazol-5-yl)acetonitrile. In organic synthesis, much attention has been recently paid to tandem and domino reactions. The advantage of such reactions concerns high selectivity, ease of performance, reduction of the number of intermediate steps, high atom economy. In this work, we have investigated a new domino reaction of ortho -carboxyl-containing nitrileimines with 2-(3-aryl-1,2,4-oxadiazol-5-yl)acetonitrile. In the reactions, nitrileimines are generated in situ from the corresponding hydrazonyl halides by base action. Thienylhydrazonyl chlorides 3a,b , the precursors of nitrileimines, were obtained according to the classical scheme of interaction of 2-chloro-3-oxobutanoate with the corresponding diazonium salts 2a,b . Thienylhydrazonyl chlorides 3a,b reacted with 2-(3-aryl-1,2,4-oxadiazol-5-yl)acetonitriles 4a-e in methanol solution in the presence of two equivalents of sodium methylate at room temperature. The target 5-oxo-3-(3-aryl-1,2,4-oxadiazol-5-yl)-4,5-dihydropyrazolo[1,5- a ]thieno[3,2- e ]pyrimidines 5a-e were obtained by stirring the reaction mixture for 12 h. The long reaction time caused the side reactions on the ester group of the formed pyrazolo[1,5- a ]thieno[3,2- e ]pyrimidines. Thus, in the case of using thienylhydrazonyl chloride 3a with a methyl substituent in the thiophene ring, products 5a,b were isolated from the reaction mixture, which underwent transesterification. Whereas in the case of using thienylhydrazonyl chloride 3b with a cyclohexyl substituent in the thiophene ring, a mixture of methyl and ethyl esters (which are difficult to separate into individual components) was isolated from the reaction mixture. Therefore, in this case, the reaction mixture was diluted with water, if necessary, an alkali solution was added so that the pH of the solution was 11−12, and heated until the precipitate dissolved, then the concentrated hydrochloric acid was added to the hot solution in a strongly alkaline medium, and the formed precipitate was left to crystallize, filtered off to give 3-(1,2,4-oxazol-5-yl)-5-oxo-4,5-dihydropyrrolo[1,5- a ]thieno[3,2- e ]pyrimidin-2-carboxylic acids 5c-e . The reaction proceeds according to the domino principle: at the first stage, 1,3-dipolar cycloaddition takes place with the formation of intermediate 5-amino- 1H -pyrazoles, which undergo spontaneous intramolecular cyclization with the participation of ester and amino groups to form a pyrimidine cycle. Keywords : thienylhydrazonyl chlorides, 1,2,4-oxadiazole, 4,5-dihydropyrazolo[1,5- a ]thieno[3,2- e ]pyrimidines, domino reaction, 1,3-dipolar cycloaddition.