Palladium-Catalyzed C8-Selective C–H Arylation
of Quinoline <i>N</i>‑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 <i>N</i>-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 <i>N</i>-oxides
are highly C2 selective. The reaction exhibits a broad synthetic scope
with respect to quinoline <i>N</i>-oxides and iodoarenes
and can be significantly accelerated to subhour reaction times under
microwave irradiation. The C8-arylation method can be carried out
on a 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
