Enantioselective C–H Arylation for Axially Chiral Tetra- <i>ortho</i> -Substituted Heterobiaryl <i>N</i> -Oxides

The catalytic enantioselective construction of axially chiral hexatomic <i>N</i>-heterobiaryls through aromatic C-H arylation with sterically demanding arylating reagents is of great interest and importance from the viewpoint of both organic synthesis and drug discovery, but many challenges still exist in terms of reactivity and selectivity. Here, we report a synergistic Pd-Ag catalysis for the asymmetric C-H bond arylation of C3-substituted pyridine <i>N</i>-oxides with <i>ortho</i>-disubstituted aryl bromides using a commercially available chiral phosphine ligand. This protocol offers an efficient and selective route for the synthesis of otherwise challenging axially chiral tetra-<i>ortho</i>-substituted C2-arylpyridine <i>N</i>-oxides from readily accessible pyridine <i>N</i>-oxides and diverse aryl bromides, featuring high yields, high enantioselectivity, excellent regioselectivity, and broad substrate scope. Experimental and density functional theory (DFT) studies revealed the role of the silver salt and the origin of high site selectivity and enantioselectivity. This work opens a new avenue for the enantioselective C-H transformation of <i>N</i>-heterocycles, leading to the efficient and selective construction of sterically demanding axially chiral <i>N</i>-heterobiaryl scaffolds that were previously difficult to access by other means.