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 is developed and reported in this study. Under optimized conditions, twenty-eight (28) heteroarylated ketones were prepared in this study to demonstrate the substrate scope of this reaction. 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.

A set of unsymmetrical heteroaryl 1,2-diketones were synthesized by a heteroarylation/oxidation sequence with up to 65% isolated yields. Palladium catalyst XPhos Pd G4 and SeO 2 were the key reagents used in this methodology, and microwave irradiation was utilized to facilitate an efficient and ecofriendly process. The application of heteroaryl 1,2-diketones is demonstrated through the synthesis of an unsymmetrical 2-phenyl-3-(pyridin-3-yl)quinoxaline ( 5a ) from 1-phenyl-2-(pyridin-3-yl)ethane-1,2-dione ( 4a ). The lowest energy conformations of 4a and 5a were located using Density Functional Theory (DFT) at the M06-2X/def2-TZVP level of theory. Two lowest energy conformations of 4a differ with respect to the position of the N atom in the pyridyl ring and 0.27 kcal/mol energy difference between them corresponds to 60.4 and 39.6% at 50 °C in toluene. Four lowest energy conformations for 5a have the energy differences of 0.01, 0.03 and 0.07 kcal/mol that corresponds to 26.0, 25.7, 24.9 and 23.4%, respectively. A comparison of 4a and 5a to the less hindered analogs (oxalyl chloride and oxalic acid) is used to investigate the structural features and bonding using Natural Bond Orbital (NBO) analysis.

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