Cooperative Pd Catalysis Enabled Enantioselective Tandem Narasaka‐Heck Cyclization/Cacchi Coupling Reaction

Comprehensive Summary The enantioselective construction of bis‐heterocyclic frameworks containing pyrroline and indole motifs is achieved through a cooperative palladium‐catalyzed tandem process. This methodology efficiently couples oxime esters and 2‐alkynylanilines via a sequential Narasaka‐Heck cyclization/Cacchi coupling reaction, providing direct access to complex chiral architectures in high yields with excellent enantioselectivity. The protocol demonstrates broad substrate scope and functional group tolerance. A diverse range of oxime esters, bearing both electron‐donating and electron‐withdrawing groups, as well as heterocyclic and polyarene substituents, undergo the transformation smoothly, delivering the desired products in 80%–96% yields and up to 98% ee. The reaction also accommodates various ortho ‐alkynylanilines with para ‐, meta ‐, and even sterically demanding ortho ‐substituents, yielding products with high stereocontrol. Preliminary mechanistic investigations reveal that the reaction is facilitated by a single palladium catalyst operating in synergy with two distinct supporting ligands. The system features two concurrent catalytic cycles: a Pd/Sadphos cycle that drives the enantioselective Narasaka‐Heck cyclization of the oxime ester to form the pyrroline ring, and a Pd/Xantphos cycle that mediates the anti‐aminopalladation (Cacchi reaction) of the 2‐alkynylaniline to construct the indole core. A key transmetallation step between the alkyl‐Pd(II) and alkenyl‐Pd(II) intermediates from the respective cycles enables the coupling, followed by reductive elimination to furnish the final bis‐heterocyclic product. The synthetic utility is highlighted by a gram‐scale synthesis without erosion of yield or enantioselectivity, and the product could be readily derivatized to other valuable chiral nitrogen‐containing scaffolds. This work establishes a streamlined and efficient route to enantioenriched bis‐heterocycles, showcasing the power of single‐metal, dual‐ligand cooperative catalysis in complex molecule synthesis.