Synthesis, Tautomeric Behavior, and Biological Activity of 6-Unsubstituted 2-Aryl-1,4-dihydropyrimidines and 4-Unsubstituted 2-Aryl-1,6-dihydropyrimidines.

Dihydropyrimidines (DPs) show a wide range of biological activities for medicinal applications. Among DP derivatives, 2-aryl-DPs have been reported to show remarkable pharmacological properties. In this work, 6-unsubstituted, N-unsubstituted 2-aryl-1,4-DP and its 1,6-DP tautomer were synthesized using a Pd2dba3/(2-furyl)3P-catalyzed, CuCl-mediated 2-arylation and a deprotection reaction. The sequential reactions give twenty types of the 1,4-DP and the 1,6-DP tautomers in high yields. To clarify the effects of substituents on their tautomeric behavior, 1H-NMR analysis of a mixture of the tautomers was performed. The analysis revealed that not only the electronic properties of substituents at the 2-position of 1,6-DP but also the electronic properties of substituents at the 4-position of 1,4-DP affect the stability of 1,4-DP and 1,6-DP. These compounds were also assessed for their antiproliferative effect on a human promyelocytic leukemia cell line, HL-60. Five compounds showed relatively high inhibitory activity, and their IC50 values were 1.7-3.9 μM. The analysis indicates that the 2-aryl group with a para-substituent and the cyclohexyl group are related to the biological activity.