Pd/Cu Dual Metal-Catalyzed Regioselective 2 + 2 + 2 Cycloaddition of Malononitriles with Alkynes to Densely Substituted Pyridines

Transition metal-catalyzed 2 + 2 + 2 cycloaddition of nitriles and two alkynes is an efficient method for assembling pyridines. However, examples employing palladium catalysis have rarely been disclosed, and the processes of reactivity and selectivity remain unclear. We report here a palladium/copper dual metal-catalyzed 2 + 2 + 2 cycloaddition of diynyl-tethered malononitriles and terminal alkynes to synthesize densely substituted pyridines. This method features a good substrate scope, synthetically useful yields, and perfect regioselectivity. The derivatization of the pyridine products demonstrates the potential application of this method in synthesizing heterocycles and as ligands in photocatalysis. Preliminary mechanistic studies suggest that the reaction undergoes aza-oxidative cycloaddition of Pd(0) with nitrile and alkyne, followed by alkyne insertion and reductive elimination. The presence of copper is crucial to its reactivity and regioselectivity.