De Novo Synthesis of α-Ketoamides via Pd/TBD Synergistic Catalysis

Abstract Precise control on the product selectivity of a reaction is an important objective in organic synthesis. α-ketoamides are vital intermediates in chemical transformation and privileged motifs in numerous drugs, natural products and biologically active molecules. The selective synthesis of α-ketoamides from feedstock chemicals in a safe and operationally simple manner under mild conditions is a long-standing challenge in catalysis. Herein we disclose an unprecedented TBD-switched Pd-catalyzed double isocyanide insertion reaction of (hetero)aryl halides or pseudohalides for the assembly α-ketoamides in aqueous DMSO under mild conditions. The effectiveness and utility of this protocol are demonstrated by diverse substrate scope (85 examples), late-stage modification of pharmaceuticals, scalability in large-scale synthesis, transformations of functional groups, as well as the synthesis of pharmaceutically active molecules. Mechanistic studies indicate that TBD is a key ligand to modulate the Pd-catalyzed double isocyanide insertion process, thus selectively providing the desired α-ketoamides in a unique manner. In addition, imidoylpalladium(II) complex and α-ketoimine amide are successfully isolated and determined by X-ray analysis, proving them the probable intermediates in the catalytic pathway.