Efficient and divergent synthesis of polyfunctionalized 2-pyridones from β-keto amides.

Baochang Gao,Zhigang Yuan,Jun Wang,Liwu Zu,Xu Zhang,Wenbin Liu,Yufeng Sun

doi:10.1039/c8ra05709e

Abstract

Efficient and divergent one-pot synthesis of polyfunctionalized 2-pyridones from β-keto amides based on reaction condition selection was developed. The methodology offers several significant advantages including mild conditions, ease of handling, high yields, and a relatively broad range of substrates. Based on various experiments and observations, a plausible mechanism for the selective synthesis of 2-pyridones was proposed.

Highlights

Molecules bearing 2-pyridone derivatives are used as important structural units in the synthesis of nitrogen-containing heterocycles, such as pyridines,[17] piperidines,[18] b-lactams,[19] indolizidines, and quinolizidines.[20]
A number of natural product-like heterocyclic compounds have been successfully synthesized based on b-keto amide and their derivatives
As part of our efforts to discover novel and practical synthesis methods for the construction of heterocyclic compounds, we recently developed an efficient synthesis of substituted thieno[2,3-b]pyridines from b-keto amides.[38]

Summary

Introduction

Diverse and complex heterocycles make a vital contribution to the organic synthesis and discovery of new pharmaceutical reagents.1 2-Pyridone is one of the most signi cant heteroaromatic rings in natural products, bioactive molecules, and pharmaceutical agents.[2,3,4,5] Such well-known molecules possess a wide spectrum of biological properties such as antimalarial,[6] anti-hepatitis B,7 vasorelaxant,[8] antifungal,[9] anti-epilepsy,[10] anti- brosis,[11] anti-HIV,[12] MEK-1 inhibitor,[13] antitumor,[14] anti-ulcer,[15] antioxidant, and antituberculosis activities.[16]. As the result of our continued interest in this area, we have provided an efficient and selective synthesis methodology for the construction of two libraries of 2pyridones 3 and 4 via a tandem annulation of b-keto amides 1 and malononitrile 2 in CH2Cl2 and DMF, respectively (Scheme 1). To optimize the reaction conditions, the reaction of b-keto amide derivative 1a with 2 was investigated using various bases and solvent (Table 1).

Results

Conclusion