Three-Component Synthesis of Tetra-substituted Pyridines

Significance

An unprecedented TMSCl-mediated three-component [3+2+1] coupling of functionalized enamines, DMF-diethyl acetal and acetylene dicarboxylate esters is reported. Two equiva-lents of TMSCl is required, as one equivalent leads to only 13% yield and other conditions (TMSI, TMSOTf, no additive) failed. The reaction affords tetrasubstituted 2,3,4,5-pyridines in yields ranging from moderate to excellent. The substrate scope was well studied for the enamine component, but only two different and activated alkynes were utilized neither of which was unsymmetrical. The enamines were synthesized beforehand in moderate to excellent yields, as shown. No mechanism was suggested but one can envisage TMSCl-­mediated attack of DMF-acetal on the acetylene followed by typical enamine condensation and cyclization to form the pyridine nucleus.