Overriding the Expected Reactivity in C–H Bond Functionalization: Chemoselective C(sp2)–H Arylation of Enolizable Aryl Alkyl Ketones and Mechanistic Insight

Abstract

The functionalization of aryl alkyl ketones in the alkyl group via enolate chemistry is well-known. Pd-catalyzed cross-coupling reactions of these substrates usually lead to C(sp3)–C bonds via coupling of an enolate and an organic halide (α-arylation). In contrast to this expected reactivity, we report here the selective Pd-catalyzed direct arylation of aryl alkyl ketones on the aromatic ring via C(sp2)–H activation. A variety of acetophenones and alkyl aryl ketones can be functionalized in this way, leaving the methyl(alkyl) group untouched. The key to this selectivity is the use of a cooperating bipyridone ligand that lowers the barrier for C–H activation and the use of a set of reaction conditions that keeps a low concentration of the ionic enolate species in the catalytic cycle. This is supported by a combination of experimental and computational studies, including microkinetic simulations, and analysis of primary and equilibrium kinetic isotope effects (KIEs).