New pathways for substituted pyrimidines: Influence of tantalum catalysis on the chemoselectivity of alkyne-nitrile reactions

Substituted pyrimidines exhibit a wide range of biological activities, including antiviral, anticancer, antihistaminic, antimicrobial, antitubercular, and anti-inflammatory properties, driving continuous interest in developing novel synthetic routes. Methods for the direct construction of the pyrimidine ring from alkynes and nitriles using metal complex catalysis are of particular interest. While previous titanium-catalyzed systems (e.g., Cp2TiCl2) were effective for terminal acetylenes but limited in their applicability to disubstituted acetylenes, the transition to a tantalum-based system offers a significant breakthrough. In this work, we report a selective one-pot synthesis of 4,5-dialkyl-2,6-diarylpyrimidines via the reaction of dialkyl-substituted acetylenes with aromatic nitriles in the presence of EtAlCl2 (4 eq.), magnesium, and catalytic amounts of TaCl5 (10 mol.%) in a THF/toluene mixture (5:1 v/v) at 60oC. A key finding of this study is the unexpected shift in chemoselectivity: replacing Cp2TiCl2 with TaCl5 fundamentally alters the reaction pathway, leading to the formation of pyrimidines instead of pyrroles. This transformation is attributed to the reduction of TaCl5 by magnesium to TaCl4, which subsequently undergoes ionization in the presence of EtAlCl2 to form a highly electrophilic TaCl3+
cation. This species facilitates the activation of the nitrile group, enabling the efficient construction of the pyrimidine core. The target pyrimidines were obtained in yields ranging from 30–58%.