Overcoming Steric Constraints in C-H Arylation via Pd/Ag Dual Catalysis: A Shortcut to Ortho-Tetrasubstituted Heterobiaryl N-Oxides

Abstract

The selective C-H arylation of N-containing aromatics with sterically demanding 2,6-disubstituted arylating reagents represents a straightforward way for the modular synthesis of ortho-tetra-substituted heterobiaryls, yet has remained scarcely explored due to the significant steric constraints and challenging selectivity control. Herein, we report a novel synergistic Pd-Ag catalysis system, which enables the regio-selective C-H arylation of different types of N-heterocyclic N-oxides with diverse ortho-disubstituted aryl iodides for the first time. This protocol offers a step-economic route for the synthesis of ortho-tetra-substituted heterobiaryl N-oxides, featuring novel catalytic mode, high regioselectivity, high yields, and broad substrate scope (45 examples, >19:1 r.r. in most cases). The mechanistic details have been clarified by deuterium-labeling experiments, isolation and transformation of key intermediate, and DFT calculations, demonstrating the critical roles of Ag additive and DPEphos ligand for achieving high level of reactivity and regioselectivity.