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 using
O-coordinating directing groups was accomplished. This C–H alkylation reaction proceeds
via formation of a previously unknown 6,4-palladacycle intermediate and provides rapid access to regioselectively functionalized β-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 the
ortho-C(sp
2) atom of
O-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.The combined experimental and computational study on palladium-catalyzed regioselective C–H functionalization of
O-coordinating directing groups with epoxides is described.
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