An Overview of Synthetic Approaches towards 1,2,3-Triazoles

Abstract

Nitrogen-containing heterocyclic compounds, including triazoles, play a crucial role as building blocks for essential biomolecules such as nucleotides, amino acids, and more.1 Triazoles are five-membered heteroaromatic ring struc tures with two carbon atoms and three nitrogen atoms, having two isomers: 1,2,3 and 1,2,4. These isomers exhibit a broad range of biological activities, including anticancer, antibacterial, antiviral, anti-inflammatory, antimalarial, and more, making them useful in lead development for drug design and synthesis. With its ease of synthesis in the laboratory, 1,2,3-triazole derivatives have garnered signifi cant attention in the field of organic chemistry.2 Click chemistry, particularly the Rolf Huisgen cycloaddition reac tion3 continues to be a prominent method for the synthesis of 1,2,3-triazole compounds. Copper-catalyzed and copper free versions have been developed to minimize toxicity and enhance the reaction’s efficiency. These methods have al lowed for the synthesis of diverse triazole-containing com pounds with applications in medicinal chemistry. Until the late 1960s, the synthetic route towards 1,2,3-triazoles was limited (Scheme 1).4 But in the late 1970s and early 1980s, after the investigation of the mechanistic approach to this reaction through frontier molecular orbital (FMO) analysis,5 significant momentum was gained in advancing the syn thesis of triazole derivatives. In 2002, Meldal6 and Sharp less7 independently worked and subsequently reported their findings on the copper-catalyzed azide and terminal alkyne [3+2] cycloaddition, a reaction that would later be come renowned as the ‘click reaction’. Further Bertozzi8 has made significant contributions to bioorthogonal chemistry by developing bioorthogonal reactions that allow for the se lective and efficient labeling of biomolecules in complex bi ological systems, advancing the field of chemical biology and enabling new avenues of research in medicine and di agnostics. In acknowledgement of their pioneering efforts in the field of click chemistry, Morten P. Meldal, K. B. Sharp less, and C. R. Bertozzi were collectively awarded the Nobel Prize in 2022 for the development of ‘click’ and ‘bioorthogo nal’ chemistry.