Heteroaryl compounds are valuable building blocks in medicinal chemistry and chemical industry. A palladium-catalyzed direct α-C(sp3) heteroarylation of ketones under microwave irradiation has been recently developed. The ground-state optimized structure of Pd(0) active catalyst with 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) in toluene, and the products of its reaction with 3-bromopyridine and acetophenone were studied using all-atom density functional theory. This study provided insightful information for palladium catalytic system design to generate heteroaryl compounds. Palladium catalysis is used in a wide range of coupling reactions. The understanding of the mechanistic steps involved in the catalytic cycle is very important for mechanism-driven reaction design. Although the mechanistic steps are not clear and still need further investigation, it has been proposed that the catalytic cycle for Pd-catalyzed (hetero)arylation typically involves the following steps: 1) oxidative addition of (hetero)aryl halides to generate the Pd(II) intermediate, 2) transmetallation with enolates, and 3) reductive elimination to form the α-(hetero)arylation product and regenerate the Pd(0) active catalyst. The (hetero)aryl-Pd(II) enolate was considered as the reactive intermediate. We first reexamined the ground-state structure of the XPhos Pd(0) active catalyst. The lowest-energy rotamer of XPhos Pd(0) has a C1-C2-P-Pd dihedral angle of −157° and an asymmetrical Pd η2-arene interaction of the nonphosphine-containing ring of the ligand with Pd−C(ortho) and Pd−C(meta) distances of 2.23 and 2.42 Å, respectively. The Pd(0) active catalyst undergoes oxidative addition reaction with 3-bromopyridine to produce a palladium(II) intermediate. The trans isomer with the Br ligand to the P atom is more stable than the cis isomer by 5.6 kcal/mol. The XPhos Pd(II) oxidative addition product subsequently reacts with the sodium enolate to afford the (hetero)aryl-Pd(II) enolate. The lowest-energy isomer of the transmetallation products is a Pd(II) η1-alkyl complex. The η3-Pd(II) complex is 4.4 kcal/mol higher in energy, and the Pd(II) η1-oxo complex is 9.6 kcal/mol higher in energy.

Mechanistic investigation of palladium-catalyzed heteroarylation of acetophenone with 3-Bromopyridine

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.