Palladium-catalyzed synthesis of β-hydroxy compounds via a strained 6,4-palladacycle from directed C-H activation of anilines and C-O insertion of epoxides

A palladium-catalyzed C-H activation of acetylated anilines (acetanilides, 1,1-dimethyl-3-phenylurea, 1-phenylpyrrolidin-2-one, and 1-(indolin-1-yl)ethan-1-one) with epoxides usingO-coordinating directing groups was accomplished. This C-H alkylation reaction proceedsviaformation of a previously unknown 6,4-palladacycle intermediate and provides rapid access to regioselectively functionalized beta-hydroxy products. Notably, this catalytic system is applicable for the gram scale mono-functionalization of acetanilide in good yields. The palladium-catalyzed coupling reaction of theortho-C(sp(2)) atom ofO-coordinating directing groups with a C(sp(3)) carbon of chiral epoxides offers diverse substrate scope in good to excellent yields. In addition, further transformations of the synthesized compound led to biologically important heterocycles. Density functional theory reveals that the 6,4-palladacycle leveraged in this work is significantly more strained (>10 kcal mol(-1)) than the literature known 5,4 palladacycles.