A mild and atom-efficient four-component cascade strategy for the construction of biologically relevant 4-hydroxyquinolin-2(1 H)-one derivatives

Abstract

A mild and atom-economical four-component cascade reaction has been developed, enabling the efficient and selective synthesis of previously inaccessible 4-hydroxyquinolin-2(1H)-one derivatives. Utilizing readily available 6-halo-4-hydroxyquinolinones, aromatic aldehydes, Meldrum's acid, and alcohols under ʟ-proline catalysis, the reaction proceeds via in situ formation of arylidene-substituted Meldrum acids followed by sequential Michael-type addition and subsequent cascade transformations. This versatile one-pot protocol delivers structurally diverse open-chain 3-arylpropanoate esters in moderate to good yields (46-69%), while cyclic pyranoquinolinones are formed under kinetically controlled conditions. Subsequent transformations afford isopropyl and cyclohexyl analogues via hydrolysis-esterification. A preliminary biological evaluation revealed low cytotoxicity and modest antibacterial activity against Escherichia coli ΔtolC strains. This sustainable synthetic approach constitutes the first direct access to scarcely explored open-chain quinolinone esters, expanding the medicinal chemistry toolbox with promising scaffolds for drug discovery.

Keywords: 4-hydroxyquinolin-2(1H)-one; Meldrum’s acid; Michael addition; antibacterial activity; multicomponent reaction; ʟ-proline catalysis.

Figure 1

Examples of biologically active quinolin-2(1H)-ones.

Figure 2

Structures obtained via rational design aimed at enhancing antibacterial activity.

Scheme 1

Previously reported and newly developed 3-(4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-3-arylpropanoic acid derivatives.

Scheme 2

Retrosynthetic analysis: two alternative approaches to target compounds.

Scheme 3

Two-stage synthesis A) and one-stage one-pot synthesis B) of 6-halogen-4-hydroxyquinoline-2(1H)-ones 2a–c.

Scheme 4

Previous synthetic attempts toward the target chemotype using various approaches.

Scheme 5

Four-component synthesis of 3-(6-halo-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-3-(3,4-dimethoxyphenyl)propanoic acid esters 9 and 10.

Scheme 6

The proposed mechanism of the four-component reaction.

Scheme 7

Synthesis of isopropyl (12a–c) and cyclohexyl (13а–с) esters of 3-(4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-3-phenylpropanoic acids 11а–с and pyranoquinolines 14a–c and product scope.

Figure 3

In vitro antibacterial activity studies. А) In vitro antibacterial activity using the E. coli ΔtolC strain with modified reflux system; B) in vitro antibacterial activity using the E. coli lptD mut strain with modified cell membrane; ery – erythromycin, lev – levofloxacin.