Regioselective Hydroxylation of Unsymmetrical Ketones Using Cu, H 2 O 2 , and Imine Directing Groups via Formation of an Electrophilic Cupric Hydroperoxide Core.

Herein, we describe the regioselective functionalization of unsymmetrical ketones using imine directing groups, Cu, and H 2 O 2 . The C-H hydroxylation of the substrate-ligands derived from 2-substituted benzophenones occurred exclusively at the γ-position of the unsubstituted ring due to the formation of only one imine stereoisomer. Conversely, the imines derived from 4-substituted benzophenones produced E / Z mixtures that upon reacting with Cu and H 2 O 2 led to two γ-C-H hydroxylation products. Contrary to our initial hypothesis, the ratio of the hydroxylation products did not depend on the ratio of the E / Z isomers but on the electrophilicity of the reactive [LCuOOH] 1+ . A detailed mechanistic analysis suggests a fast isomerization of the imine substrate-ligand binding the CuOOH core before the rate-determining electrophilic aromatic hydroxylation. Varying the benzophenone substituents and/or introducing electron-donating and electron-withdrawing groups on the 4-position of pyridine of the directing group allowed for fine-tuning of the electrophilicity of the mononuclear [LCuOOH] 1+ to reach remarkable regioselectivities (up to 91:9 favoring the hydroxylation of the electron-rich arene ring). Lastly, we performed the C-H hydroxylation of alkyl aryl ketones, and like in the unsymmetrical benzophenones, the regioselectivity of the transformations (sp 3 vs sp 2 ) could be controlled by varying the electronics of the substrate and/or the directing group.