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.