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

A mild and atom-economical four-component cascade reaction has been developed, enabling the efficient and selective synthesis of previously inaccessible 4-hydroxyquinolin-2(1<i>H</i>)-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 <i>Escherichia coli</i> 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.