Copper-Catalyzed Oxidative Coupling of β-Keto Esters with N-Methylamides for the Synthesis of Symmetrical 2,3,5,6-Tetrasubstituted Pyridines

A copper-catalyzed oxidative formal [2+2+1+1] cycloaddition for the synthesis of symmetrical tetrasubstituted pyridines was first demonstrated. The reaction is involved in a domino cross-dehydrogenative coupling (CDC) of beta-keto esters and N-methylamides, the C-N bond cleavage, the Michael addition, and a condensation and oxidative aromatization process. Multiple C-C and C-N bonds were constructed in one pot via the C-H and C-N cleavage of N-methylamides, which were employed as the carbon source of pyridines. The preliminary mechanistic studies revealed that the C(sp(3))-H bond cleavage of N-methylamides was the rate-determining step.