Late-stage Functionalization Approaches for Dihydropyrimidinone Scaffolds: Recent Methods and Biological Relevance

Abstract

3,4-Dihydropyrimidin-2(1H)-ones (DHPMs), synthesized via the classic Biginelli condensation, have emerged as pivotal heterocyclic frameworks with broad medicinal and synthetic relevance. Their intrinsic versatility enables downstream transformations that furnish a diverse spectrum of novel scaffolds. Although multicomponent-reaction-driven derivatizations of DHPMs are well documented, post-synthetic modifications remain comparatively underexplored. This review offers a comprehensive strategy for DHPM post-derivatization reported from 2000-25, organized by the specific site of functionalization on the pyrimidinone core, namely N1, N3, C2, C4, C5, and C6 positions. We discuss key strategies encompassing oxidative and reductive reactions, cyclizations, and a range of miscellaneous reactions such as Suzuki-Miyaura cross-couplings, Diels-Alder cycloadditions, and Eschenmoser sulfide-contraction couplings that afford regioselective access to functionalized DHPM derivatives. The highlighted methodological advances underscore the central role of DHPMs in expanding the heterocyclic chemical space. Finally, we summarize the biological applications of these post-modification products, including antibacterial, antifungal, antiviral, anti-inflammatory, anticancer, and antioxidant activities, illustrating how strategic functionalization translates into enhanced pharmacological profiles. This overview aims to inspire further innovation in DHPM chemistry and to facilitate the integration of these scaffolds into drug-discovery studies.