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.

中文翻译：

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通过 Pd/NBE 协同催化对 2-吡啶酮进行位点选择性 C–H 芳基化

4-芳基-2-吡啶酮支架被认为是一种特殊的药效基团。其衍生物的多样性合成是药物化学领域的迫切需求。在此，我们报道了通过钯/降冰片烯协同催化对 2-吡啶酮进行位点选择性 C-H 芳基化。这项研究的成功基于2-吡啶酮中C5位置所表现出的亲核性和金属化特性，2-吡啶酮是一种活化的降冰片烯，用于捕获C5-钯化中间体并将其转移到C4位置，从而产生高度特异性的C –2-吡啶酮在 C4 位的氢芳基化。该方法展示了与现成的 2-吡啶酮和芳基溴的显着相容性，能够有效合成各种具有显着位点选择性的功能性 4-芳基-2-吡啶酮支架（46 个示例），这对于药物发现非常有用。此外，该方法已成功用于经济可行的 perlolidine 类似物的合成。密度泛函理论计算揭示了 2-吡啶酮中 C5 位优先发生 C-H 键激活。此外，对该机制的深入了解表明，芳基溴的氧化加成和还原消除是转化中的关键步骤。