Mechanochemistry-directed ligand design for enhanced reactivity and enantioselectivity in solvent-less palladium-catalyzed conjugate arylations

Abstract

Mechanochemical organic transformations catalyzed by transition-metal catalysts have emerged as efficient, solventminimized, and sustainable approaches for the synthesis of valuable molecules. Notably, these reactions often exhibit enhanced reaction rates that are not achievable in traditional solution-based systems, highlighting the unique benefits of mechanochemistry. Yet, the heterogeneous solid-state reaction environment often poses challenges to achieving high catalytic activity and stereoselectivity when catalytic systems developed for solution are applied under mechanochemical conditions. Herein, we report the development of a bipyridine ligand bearing a poly(ethylene)glycol (PEG) chain to enable highly efficient mechanochemical palladium-catalyzed conjugate addition of arylboronic acids. Traditional bipyridine ligands, originally developed for solution, show poor performance under mechanochemical conditions, highlighting the effectiveness of the PEGylated ligand. Furthermore, we discovered that a chiral pyridine-oxazoline ligand with a PEG chain enables mechanochemical asymmetric conjugate addition to chromone derivatives with superior yield and enanti-oselectivity compared to conventional chiral ligands optimized for solution. The present study represents the first example of mechanochemistry-directed ligand design for an enantioselective reaction. This approach is expected to accelerate the development of transition-metal-catalyzed reactions that are otherwise difficult to accomplish with ligands developed for solution-based chemistry.