A one-pot, metal-free three-component reaction has been developed for the synthesis of fluorinated isoindolin-1-one derivatives under room temperature conditions. This method employs readily available 2-formylbenzoic acid, primary amines, and fluorinated dialkyl malonates, which takes place smoothly in a mild system of ethanol at room temperature and avoids the impact of metal contamination on the products. The transformation proceeds via a sequential condensation/Michael addition/in situ lactamization process, efficiently constructing the isoindolin-1-one core while precisely introducing a fluorine atom in one step to enhance the drug-likeness of the target products. Meanwhile, a malonate ester functionality is introduced, providing convenience for further structural diversification of the molecules. The reaction exhibits good functional group compatibility with a variety of aromatic and aliphatic amines, and electron-rich aromatic amines as well as benzylamine derivatives afford the corresponding 3-(fluoromalonate)-substituted isoindolin-1-ones in moderate to excellent yields (up to 90%). This metal-free, mild-condition multicomponent strategy might provide a direct and versatile new approach for constructing structurally diverse fluorinated bioactive compound libraries based on the privileged isoindolin-1-one scaffold.

Key words: isoindolin-1-one, three-component reaction, fluorination, lactamization, synthesis