Palladium-Catalyzed C8-Selective C–H Arylation of Quinoline N-Oxides: Insights into the Electronic, Steric, and Solvation Effects on the Site Selectivity by Mechanistic and DFT Computational Studies

We report herein a palladium-catalyzed C-H arylation of quinoline N-oxides that proceeds with high selectivity in favor of the C8-isomer. This site-selectivity is unusual for palladium, since all of the hitherto described methods of palladium-catalyzed C-H functionalization of quinoline N-oxides are highly C2-selective. The reaction exhibits a broad synthetic scope with respect to quinoline N-oxides and iodoarenes and can be significantly accelerated to sub-hour reaction times under microwave irradiation. The C8-arylation method can be carried out on gram scale and has excellent functional group tolerance. Mechanistic and Density Functional Theory (DFT) computational studies provide evidence for the cyclopalladation pathway and describe key parameters influencing the site-selectivity.