Diversification of Thieno[2,3-d]pyrimidin 4-one Scaffold via Regioselective Alkylation Reactions

The 2-aryl-2,3,5,6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidin-4(1H)-ones and 2-aryl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-ones were diversified by alkylation reactions, applying benzylchlorides and 2-chloro-N-R-acetamides as the alkylating agents. Under the found uniform conditions the substitution direction does not depend on the structure of the alkylating agent and gives monoalkylated products in high yields with simple workup. The alkylation of the 2,3-dihydropyrimidin-4(1H)-one derivatives proceeds onto the N1-position, however, in the case of pyrimidin-4(3H)-ones the O-alkylated products are formed selectively. An alternative strategy for the synthesis of the N1-benzyl-2,3-dihydropyrimidin-4(1H)-one derivatives is also developed. It applies the reaction of N2-substituted Gewald’s amides with aromatic aldehydes and allows simple introduction of various substituents in the final molecule (Dzhavakhishvili S.G. et al. J. Comb. Chem. 2009, 11, pp. 508–514)