Recent Advancements in Strategies for the Synthesis of Tetrazines and Brief Overview of Their Applications

Tetrazine belongs to the heterocyclic group of compounds bearing four nitrogen atoms in the ring system, with wide applicability in analytical and optical fields, energy and catalysis, and also in biomedical research. s-Tetrazine is emerging as one of the bioorthogonal molecules among other compounds like 1,2,4-triazines, trans-cyclooctenes, and hetero-cycloheptynes. The unique arrangement of nitrogen atoms in s-tetrazine, having a planar structure, significantly enhances its stability, making it superior to the rest of the isomers. v-Tetrazines are highly unstable energetic molecules, and hence, are ideal for high-energy-density materials. Herein, we reviewed various synthetic methods of 1,2,4,5-, 1,2,3,4- and 1,2,3,5-tetrazine, involving organocatalytic approaches, various cross-coupling methods, Pinner-type reaction, one-pot methodology, cycloaddition, nucleophilic substitutions, polymerization, and solid-phase method. This work will give a peek into the formation methods of tetrazines from various substrates, which are substituted with different groups, ranging from electron-withdrawing to electron-donating substituents. Applications of the developed tetrazine derivatives are also highlighted.