Direct Synthesis of Ketones from Methyl Esters by Nickel-Catalyzed Suzuki-Miyaura Coupling

Abstract

The direct conversion of alkyl esters to ketones has been hindered by the sluggish reactivity of the starting materials and the susceptibility of the product towards subsequent nucleophilic attack. We have now achieved a cross-coupling approach to this transformation using nickel, a bulky N-heterocyclic carbene ligand, and alkyl organoboron coupling partners. 65 alkyl ketones bearing diverse functional groups and heterocyclic scaffolds have been synthesized with this method. Catalyst-controlled chemoselectivity is observed for C(acyl)-O bond activation of multi-functional substrates bearing other bonds prone to cleavage by Ni, including aryl ether, aryl fluoride, and N-Ph amide functional groups. Density functional theory calculations provide mechanistic support for a Ni⁰ /Ni^II catalytic cycle and demonstrate how stabilizing non-covalent interactions between the bulky catalyst and substrate are critical for the reaction's success.

Keywords: Suzuki-Miyaura reactions; cross-coupling; esters; ketones; nickel.