Multicomponent reactions, particularly the Passerini reaction, serve as efficient tools for the synthesis of druglike molecules and the creation of compound libraries. Despite the effectiveness of the Passerini reaction, the limited alternatives to the crucial carboxylic acid component pose a structural constraint. Here, we have discovered that the phthalimide moiety and its derivatives react in the Passerini reaction as an acid component. We explored their potential in synthesizing diverse and intricate molecules. The phthalimide moiety stands out as a favorable building block due to its oxidative stability, heat-stable characteristics, and resistance to solvents. Our approach introduces a novel perspective to multicomponent reactions by incorporating NH-based acid components, addressing the ongoing need for the development of innovative molecular scaffolds.

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry and Czech Advanced Technology and Research Institute Palacký University in Olomouc 779 00 Olomouc Czech Republic

University of Groningen Department of Drug Design A Deusinglaan 1 9713 AV Groningen The Netherlands

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