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-tetrasubstituted heterobiaryls, yet has remained scarcely explored due to significant steric constraints and challenging selectivity control. Herein, we report a novel synergistic Pd–Ag catalysis system, which enables the regioselective 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-tetrasubstituted heterobiaryl N-oxides, featuring a 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 intermediates, and DFT calculations, demonstrating the critical roles of Ag additive and DPEphos ligand for achieving high levels of reactivity and regioselectivity.