Experimental and Theoretical Studies on Ru(II)-Catalyzed Oxidative C–H/C–H Coupling of Phenols with Aromatic Amides Using Air as Oxidant: Scope, Synthetic Applications, and Mechanistic Insights

We
herein illustrate the dual chelation-assisted strategy for a
Ru­(II)-catalyzed oxidative ortho-C–H/C–H
cross-coupling of phenols with (hetero)­aromatic amides with the aid
of Zn­(OTf)2, which enables to rapidly assemble a rich library
of 2′-hydroxybiphenyl-2-carboxylic acid derivatives. This protocol
features broad substrate scope, excellent functional group tolerance,
air as the terminal oxidant, low molar ratio of coupling partners,
and scale-up synthesis. Particularly, this methodology is tolerant
of more complex natural product derivatives, thus providing an opportunity
for late-stage functionalization. This protocol is also used as a
key step for the concise synthesis of Palomid 529, a drug in development
for the treatment of glioblastoma and neovascular age-related macular
degeneration. With a combination of experimental and theoretical methods,
we get more insight into the essential issues of strategy determining
the reaction process. The stronger coordinating ability of 2-aryloxypyridine
and the less steric hindrance of amide are pivotal to the high chemoselectivity
of cross-coupling over homocoupling. The first C–H bond activation
step takes place at the amide substrate, and the following C–H
bond activation at 2-aryloxypyridine is involved in the rate-determined
step.