Diversity-oriented functionalization of 2-pyridones and uracils

Yong Shang,Chenggui Wu,Lisha Li,Shanshan Liu,Qianwen Gao,Hong-Gang Cheng,Qianghui Zhou,Xinping Zhang,Chang Liu

doi:10.1038/s41467-021-23058-3

Abstract

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/DCO2Na, boronic acid/ester, terminal alkene and alkyne are compatible with this protocol. Thus, a large number of valuable 2-pyridone derivatives, including deuterium/CD3-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.

Highlights

Heterocycles 2-pyridone and uracil are privileged pharmacophores
Pyridone moiety acts as the common warhead of EZH2 inhibitors, it is crucial for their EZH2 enzyme inhibition activities (Fig. 1B)
Following the success of tazemetostat, there is an urgent need from pharmaceutical industry for diversity-oriented synthesis (DOS)[18,19] of 2-pyridone derivatives library, to find new generation of EZH2 inhibitors via high-throughput biochemical screening (HTS)[14,15]

Summary

Introduction

Heterocycles 2-pyridone and uracil are privileged pharmacophores. Diversity-oriented synthesis of their derivatives is in urgent need in medicinal chemistry. 4-iodo-2-pyridone (1), electrophilic alkyl/aryl halide (2), and terminating reagent (3) would engage in sequential ortho-C–H activation (intermediate I to II), functionalization (II–IV), and Results and discussion Ortho-alkylation of 2-pyridones Reaction design and optimization.

Results

Conclusion