Diversity-oriented functionalization of 2-pyridones and uracils

• Published in: Nature communications Vol. 12; no. 1; pp. 2988 - 11
• Main Authors: Shang, Yong, Wu, Chenggui, Gao, Qianwen, Liu, Chang, Li, Lisha, Zhang, Xinping, Cheng, Hong-Gang, Liu, Shanshan, Zhou, Qianghui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.05.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 140/131; 140/58; 639/638/403/605; 639/638/403/933; Alkylation; Alkynes; Bromides; Catalysis; CD3 antigen; Chemistry, Pharmaceutical - methods; Deuterium; Drug Discovery - methods; Feasibility Studies; Fenofibrate; Halides; Humanities and Social Sciences; multidisciplinary; Norbornanes - chemistry; Palladium; Palladium - chemistry; Pharmaceutical Preparations - chemistry; Pharmaceutical sciences; Pharmacology; Pharmacophores; Pyridones - chemistry; Reagents; Science; Science (multidisciplinary); Thymine; Uracil; Uracil - chemistry
• ISSN: 2041-1723; 2041-1723
• 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/DCO 2 Na, boronic acid/ester, terminal alkene and alkyne are compatible with this protocol. Thus, a large number of valuable 2-pyridone derivatives, including deuterium/CD 3 -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. Diversity-oriented synthesis of 2-pyridone and uracil derivatives is in urgent need in medicinal chemistry as they are useful pharmacophores. Here the authors show that palladium/norbornene cooperative catalysis enabled dual-functionalization of iodinated 2- pyridones and uracils.