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 9.5 μM) had good promise against Plasmodium falciparum in the in vitro culture. Compound 3g was found to be the most potent on the basis of both in
vitro antiplasmodial activity [IC50 9.5 μM (Pf3D7) and 11.9 μM (PfINDO), resistance
index 1.25] and in silico studies.