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

Abstract

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.

Keywords

Narasaka-heck cyclization / Cacchi coupling / Pd catalysis / Indole / Pyrroline / Sadphos / Synergistic effect / Tandem reaction

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2025 SIOC, CAS, Shanghai, & WILEY-VCH GmbH