Green Synthesis of 1,4-Dihydropyridines through Catalyst-Free Multicomponent Hantzsch Reaction in an Undergraduate Teaching Laboratory

Multicomponent reactions (MCRs) are fascinating chemical processes where three or more starting materials come together to form a single product. By exploring various MCRs, second-year undergraduate students learn about the synergy between different functional groups and how they influence reactivity, the power of the streamlined approach compared to conventional stepwise reactions, and the critical thinking of MCR mechanisms. Herein, we introduce a valuable synthetic method for constructing heterocyclic compounds through a multiple-component condensation/cycloaddition process. Specifically, we focus on 1,4-dihydropyridine (1,4-DHP), a privileged N-heterocyclic scaffold widely used in medicinal chemistry, particularly for 4-aryl-3,5-dicarboxylated derivatives. The experiment provides an excellent opportunity for students to explore the concept of green chemistry while synthesizing structurally interesting and useful molecules using readily available materials. Specifically, we achieve this through the condensation reaction between 2-furaldehyde (furfural), acetoacetic acid tert-butyl ester, and ammonium acetate. Key features of this teaching experiment include the following. (1) Multicomponent reaction: The method involves a concise, multicomponent reaction with a short reaction time. (2) Catalyst-free: Notably, the reaction proceeds without the need for solvents or catalysts. (3) Visually striking reaction system: The change in the reaction system is visually evident, enhancing the learning experience. (4) Useful methodology for drug synthesis: The approach has practical implications for drug synthesis. We successfully implemented this experiment proposal across five parallel student groups, involving approximately 150 participants. The experimental procedures encompass organic synthesis, thin-layer chromatography (TLC), and nuclear magnetic resonance (NMR) analysis.