A copper-catalyzed cascade borylation/Petasis reaction for synthesis of regioselective 2H-chromenes under catalytic amine conditions

Abstract

Achieving regioselective synthesis of 2-phenyl-2H-chromenes via sustainable catalytic strategies remains a significant challenge in synthetic chemistry. Traditional methods have several drawbacks, including multi-step protocols, equivalent levels of reagents, and high catalyst loadings, which compromise both environmental and economic efficiency. We report herein a green, one-pot approach for constructing 2-phenyl-2H-chromenes with excellent regiocontrol through a copper-catalyzed cascade process. Trace amounts of CuO (0.5 mol%) catalyze the generation of phenyl vinylboronate esters from alkynes in situ, followed by a catalytic amine-mediated Petasis reaction to assemble the 2H-chromene scaffold. This strategy eliminates the need for expensive ligands, equivalent levels of amines, or harsh conditions while significantly enhancing atom and step economy, aligning with green chemistry principles. The scope of the protocol is demonstrated by 33 examples, including four bioactive molecules and successful gram-scale synthesis. This work establishes a sustainable platform for accessing bioactive chromenes and provides a successful example of boron-mediated multicomponent reactions in heterocycle synthesis.