Synthesis of Pyridin-2(1 H )-ones and Isoquinolin-1(2 H )-ones Using Calcium Carbide as an Acetylene Source under Redox-Neutral Conditions

Abstract

Presented herein is a synthesis of pyridin-2(1H)-ones and isoquinolin-1(2H)-ones based on Rh(III)-catalyzed C–H bond activation-initiated cascade reactions of N-methoxyacrylamides or N-methoxybenzamides with calcium carbide. The formation of products involves an initial vinyl or aryl C(sp2)–H bond metalation, insertion of the in situ-generated acetylene into the C–Rh bond, and reductive elimination, followed by oxidative insertion of the in situ-formed Rh(I) species into the N–O bond and proto-demetalation. On the basis of this method, a number of pyridin-2(1H)-one and isoquinolin-1(2H)-one derivatives, including some hybrid products containing the essential skeleton of probenecid, ataluren, or adapalene, were obtained. Moreover, the analogue of natural alkaloid doryanine and a key intermediate for the preparation of MK-1220 (inhibitor of hepatitis C virus NS3/4A protease) were also prepared via simple structural derivations of the products thus obtained. In general, this protocol features simple and economical substrates, a safe and convenient acetylene source, the absence of an external oxidant, good compatibility with labile functional groups, excellent step and atom economy, and ready scalability. Moreover, some products possess strong anticancer activities.