“Overview of Synthetic Approaches to Commercially Successful Drugs with Small-Ring Heterocyclicâ€

Small-ring heterocycles are essential building blocks in pharmaceutical chemistry, widely found in approved drugs due to their unique reactivity and biological activity. This review summarizes recent synthetic strategies for constructing three- and four-membered rings such as aziridines, β-lactams, and azetidines. These rings exhibit high ring strain, enabling versatile transformations like cycloaddition and nucleophilic substitution. Chalcones are helpful building blocks for making various nitrogen-containing compounds, like pyrroles and triazoles, and eco-friendly methods like microwave and ultrasound treatment often improve this process. Oxygen-containing rings such as tetrahydropyrans and isoxazolines are synthesized via organocatalytic oxa-Michael reactions. Additionally, ring-closing metathesis and copper-catalyzed 1,3-dipolar cycloaddition offer efficient access to five- and six-membered heterocycles under mild, eco-friendly conditions. Thiosemicarbazides are known for synthesizing N-, O-, and S-containing heterocycles but remain underutilized in small-ring construction and biological evaluation. Ternary condensation strategies also yield bioactive fused heterocycles. Future efforts should focus on expanding structural diversity and understanding structure–activity relationships.