Rhodium(i)-catalyzed C6-selective C-H alkenylation and polyenylation of 2-pyridones with alkenyl and conjugated polyenyl carboxylic acids.

Haoqiang Zhao,Lijin Xu,Lei Cao,Huanrong Li,Patrick J Walsh,Qinghua Fan,Xin Xu,Zhenli Luo,Bohan Li

doi:10.1039/c9sc03672e

Abstract

A versatile Rh(i)-catalyzed C6-selective decarbonylative C-H alkenylation of 2-pyridones with readily available, and inexpensive alkenyl carboxylic acids has been developed. This directed dehydrogenative cross-coupling reaction affords 6-alkenylated 2-pyridones that would otherwise be difficult to access using conventional C-H functionalization protocols. The reaction occurs with high efficiency and is tolerant of a broad range of functional groups. A wide scope of alkenyl carboxylic acids, including challenging conjugated polyene carboxylic acids, are amenable to this transformation and no addition of external oxidant is required. Mechanistic studies revealed that (1) Boc2O acts as the activator for the in situ transformation of the carboxylic acids into anhydrides before oxidative addition by the Rh catalyst, (2) a decarbonylation step is involved in the catalytic cycle, and (3) the C-H bond cleavage is likely the turnover-limiting step.

Highlights

The 2-pyridone motif is found in numerous naturally occurring molecules and synthetic organic compounds that possess a broad spectrum of bioactivities.[1]
A58365A, isolated from the fermentation broth of a soil bacterium, serves as an angiotensin-converting enzyme inhibitor;1f fredericamycin A, isolated from Streptomyces griseus, is a potent antitumor antibiotic;1g ciclopirox is a widely used synthetic antifungal agent;1h and milrinone is a phosphodiesterase 3 inhibitor used to treat heart failure (Fig. 1).1i 2-Pyridones are valued as building blocks, because they can be converted to pyridines, piperidines, quinolizidines and indolizidines.1j As a result of their widespread utility, the construction of 2-pyridones has been a vibrant research area in the synthetic community, and numerous methods for their synthesis are available.[2,3]
We were pleased to discover that the reaction of 1a and trans-cinnamic acid (2a) in the presence of [Rh(CO)2Cl]2 (1.0 mol%) and Boc2O (1.5 equiv.) at 130 C in 1,4-dioxane, provided the desired product 3aa in Recent studies have revealed that catalytic systems based on Rh(III), Ru(II) and Pd(II) complexes perform well in directed alkenylation of relatively inertarene and alkene C–H bonds.[13]

Summary

Introduction

The 2-pyridone motif is found in numerous naturally occurring molecules and synthetic organic compounds that possess a broad spectrum of bioactivities.[1]. Edge Article tolerance (Scheme 1a).8a Very recently, the group of Hirano and Miura reported Rh(III)-catalyzed (10 mol%) C6-selective alkenylation of 1-(2-pyridyl)-2-pyridones with acrylates and styrenes (Scheme 1b).8b Catalyzed alkenylation of 1a with styrylboronic acids did not afford the desired alkenylation product (Scheme 2c and ESI, Table S2†).7o

Results

Conclusion