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

TL;DR

A new chemical method efficiently creates complex quinolinone compounds that could be useful for drug development.

Contribution

A novel four-component cascade reaction enables the synthesis of previously inaccessible 4-hydroxyquinolin-2(1H)-one derivatives.

Findings

The cascade reaction produces open-chain 3-arylpropanoate esters in moderate to good yields.

Cyclic pyranoquinolinones are formed under kinetically controlled conditions.

The compounds show low cytotoxicity and modest antibacterial activity against Escherichia coli ΔtolC.

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.

Figures