Enantioselective Michael addition of 3-hydroxy-2-pyridone to nitroolefins using cinchona-derived bifunctional organocatalysts†

Abstract

Despite the extensive use of N-heteroarenes in pharmaceuticals and natural products, efficient methods for selective alkylation at the C-4 position of 2-pyridone are scarce. We developed an enantioselective Michael addition of 3-hydroxy-2-pyridone to nitroolefins at the C-4 position using cinchona-derived bifunctional squaramide organocatalysts, achieving up to 95% yield and >99% ee. This selectivity is driven by the bifunctional organocatalysts’ hydrogen bonding interactions with 3-hydroxy-2-pyridone and nitroolefins under mild conditions. This method demonstrates the Michael reaction's versatility with various nitroolefins, providing a sustainable approach for synthesizing chiral N-heteroarenes with high enantioselectivity and regioselectivity under environmentally friendly conditions.