Rh(III)-Catalyzed C(8)–H Functionalization of Quinolines via Simultaneous C–C and C–O Bond Formation: Direct Synthesis of Quinoline Derivatives with Antiplasmodial Potential

Here, a facile and efficient protocol for the synthesis of 3-hydroxyquinolin-8-yl propanoates via Rh(III)-catalyzed C(8)–H activation of 2-substituted quinolines has been developed. The reaction proceeds via C(8)–H activation, functionalization with acrylates, followed by intramolecular migration of the oxygen atom from quinoline N-oxides to the acrylate moiety. In this approach, N-oxide plays a dual role of a traceless directing group as well as a source of an oxygen atom for hydroxylation. This catalytic method involves simultaneous formation of new C–C and C–O bonds and is applicable only for C2-substituted quinolines. A catalytically competent five-membered rhodacycle has been characterized, thus revealing a key intermediate in the catalytic cycle. In silico docking studies against Falcipan-2 have revealed that 3a, 3b, 3g, and 3m have better scores. In vitro evaluation of selected compounds against CQ-sensitive pf3D7 and CQ-resistant pfINDO strains provided evidence that 3d (IC50 13.3 μM) and 3g (IC50...