Sauvage Center for Molecular Sciences, Engineering Research Center of Organosilicon Compounds & Materials (Ministry of Education), College of Chemistry and Molecular Sciences, and The Institute for Advanced Studies, Wuhan, China.
Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui, China.
Nat Commun. 2021 May 20;12(1):2988. doi: 10.1038/s41467-021-23058-3.
Heterocycles 2-pyridone and uracil are privileged pharmacophores. Diversity-oriented synthesis of their derivatives is in urgent need in medicinal chemistry. Herein, we report a palladium/norbornene cooperative catalysis enabled dual-functionalization of iodinated 2-pyridones and uracils. The success of this research depends on the use of two unique norbornene derivatives as the mediator. Readily available alkyl halides/tosylates and aryl bromides are utilized as ortho-alkylating and -arylating reagents, respectively. Widely accessible ipso-terminating reagents, including H/DCONa, boronic acid/ester, terminal alkene and alkyne are compatible with this protocol. Thus, a large number of valuable 2-pyridone derivatives, including deuterium/CD-labeled 2-pyridones, bicyclic 2-pyridones, 2-pyridone-fenofibrate conjugate, axially chiral 2-pyridone (97% ee), as well as uracil and thymine derivatives, can be quickly prepared in a predictable manner (79 examples reported), which will be very useful in new drug discovery.
杂环 2-吡啶酮和尿嘧啶是特权药效团。在药物化学中，非常需要对它们的衍生物进行多样性导向合成。在此，我们报告了一种钯/降冰片烯协同催化方法，该方法可实现碘化 2-吡啶酮和尿嘧啶的双官能化。这项研究的成功取决于使用两种独特的降冰片烯衍生物作为介体。可大量获得的烷基卤化物/对甲苯磺酸盐和芳基溴化物分别用作邻位烷基化和芳基化试剂。该方案与许多易得的反位终止试剂兼容，包括 H/DCONa、硼酸/酯、末端烯烃和炔烃。因此，可以快速以可预测的方式制备大量有价值的 2-吡啶酮衍生物，包括氘/CD 标记的 2-吡啶酮、双环 2-吡啶酮、2-吡啶酮-非诺贝特缀合物、轴手性 2-吡啶酮（97%ee）以及尿嘧啶和胸腺嘧啶衍生物（79 个实例），这在新药发现中非常有用。
