Site-Selective C–H Arylation of 2-Pyridones via Pd/NBE Cooperative Catalysis

The 4-aryl-2-pyridone scaffold is considered to be a privileged pharmacophore. Diversity-oriented synthesis of its derivatives is a pressing demand within the field of medicinal chemistry. Herein, we report a site-selective C–H arylation of 2-pyridones via palladium/norbornene cooperative catalysis. The success of this research is based on the nucleophilicity and metalation properties exhibited by the C5 position in 2-pyridones, an activated norbornene that was employed to capture the C5-palladation intermediate and transfer it to the C4 position, resulting in a highly specific C–H arylation of 2-pyridones at the C4 position. This methodology showcases remarkable compatibility with readily available 2-pyridones and aryl bromides, enabling the efficient synthesis of a diverse range of functional 4-aryl-2-pyridone scaffolds (46 examples) with notable site selectivity, which will be very useful in drug discovery. Furthermore, this approach was successfully utilized for the economically viable synthesis of the perlolidine analogues. Density functional theory calculations revealed a preference for C–H bond activation at the C5 position in 2-pyridones. In addition, the insights into the mechanism suggest that oxidative addition and reductive elimination of aryl bromides are crucial steps in the conversion.