Ni-catalyzed enantioselective [2+2+2] cycloaddition of malononitriles with alkynes

Efficient strategies to assemble enantioenriched pyridine derivatives are highly important, given their significance in both synthetic and medicinal chemistry. Here, we report an enantioselective nickel-catalyzed intermolecular [2 + 2 + 2] cycloaddition of alkyne-tethered malononitriles with alkynes for the synthesis of densely substituted pyridines. The a-all-carbon quaternary center adjacent to pyridine is introduced by desymmetrizing the two cyano groups of disubstituted malononitriles. Notably, terminal alkynes are also tolerated with good regioselectivity to afford tetrasubstituted pyridines. Zinc halide is essential to enable the occurrence of the transformation by promoting the hetero-cyclometallation step. The reaction uses bio-renewable 2-MeTHF as the solvent and features mild reaction conditions, good functional group compatibilities, and enantioselectivities. This study offers a straightforward approach to the valuable enantioenriched heteroarenes fromfeedstock chemicals by forming three bonds and one quaternary stereocenter simultaneously in a single reaction step.

Automated summary

This study presents an efficient strategy for assembling enantioenriched pyridine derivatives by forming three bonds and one quaternary stereocenter simultaneously in a single reaction step. The reaction utilizes bio-renewable 2-MeTHF as the solvent, features mild reaction conditions, and shows good functional group compatibilities and enantioselectivities.