α-Arylated carbonyl compounds are ubiquitous substructures in organic synthesis, and the diverse bioactivity of such molecules is exemplified by familiar blockbuster drugs, such as Naproxen and Ibuprofen. Current methods to acess this scaffold either require strong base (enolate α-arylation) or lengthy functional group manipulation (Suzuki-type). To overcome these limitation, the palladium-catalyzed, α-selective hydroarylation of acrylates and acrylamides, proceeding via an interrupted hydrodehalogenation pathway, has been developed. Under optimized conditions, this method is highly tolerant of a wide range of substrates including those with base sensitive functional groups and/or multiple enolizable carbonyl groups. A detailed mechanistic study was undertaken using reaction progress kinetic analysis (RPKA), NMR studies, and control experiments. The high selectivity of this transformation was shown to be enabled by the formation of a [PdII(Ar)(H)] intermediate, which performs selective hydride insertion into the β-position of α,β-unsaturated carbonyl compounds.

Interrupting palladium-catalyzed hydrodehalogenation to access α-arylated amides and esters

ACS Spring 2022

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