## 2 General Methods for the Synthesis of 1,2,4,5-tetrazines
### Modified Pinner Synthesis Using Carbonitriles  
The classical Pinner reaction, which originally employed iminoesters, has been modified to use carbonitriles and hydrazine in the presence of activating agents such as Lewis acids, elemental sulfur, or appropriate thiols and sulfides (Scheme 5). The reaction mechanism is not fully understood; however, it is postulated that elemental sulfur added to hydrazine enhances its nucleophilic properties and facilitates the attack of the lone electron pair located on the central nitrogen atom of the carbonitrile group. This sulfur-based method works well for aromatic carbonitriles; however, aliphatic carbonitriles are generally non-reactive, and the final products are obtained in low yields [19; 64]. An alternative to elemental sulfur as the activating agent includes thiols, sulfides, or certain Lewis acids derived from zinc or nickel, such as Zn(OTf)\({}_{2}\) and Ni(OTf)\({}_{2}\)[35]. For thiols (e.g., \(N\)-acetylcysteine) as activating agents, a different mechanism has been proposed involving the formation of the appropriate amidrazone. The latter is transformed into the corresponding dihydro-1,2,4,5-tetrazine (**1**), with the activating sulfur compound being regenerated [36; 65; 66]. Table 2 summarizes reagents and conditions applied in modified Pinner synthesis, leading to the corresponding 1,2,4,5-tetrazines (**2**). \begin{table}
\begin{tabular}{c c c c c c} \hline
**Entry** & \(\mathbf{R^{1},R^{2}}\) & **Reagents** & **Conditions** & **Product** & **Ref.** \\ \hline \multicolumn{8}{c}{**Pinner**} \\ \hline
1 & CH\({}_{3}\) & R\({}^{1}\)CN, N\({}_{2}\)H\({}_{4}\) (excess) & N\({}_{2}\)H\({}_{4}\), [Ox] &
\begin{tabular}{c} Symmetrical \\ disubstituted \\ 1,2,4,5-tetrazines \\ \end{tabular} & [31; 67] \\ \hline
2 & CH\({}_{3}\), C\({}_{6}\)H\({}_{5}\), C\({}_{6}\)H\({}_{5}\), CH\({}_{2}\)C\({}_{6}\)H\({}_{5}\) & R\({}^{1}\)CN, R\({}^{2}\)CN & N\({}_{2}\)H\({}_{4}\), [Ox] &
\begin{tabular}{c} Symmetrical \\ unsymmetrical \\ disubstituted \\ 1,2,4,5-tetrazines \\ \end{tabular} & [31; 67] \\ \hline \multicolumn{8}{c}{**Devaraj**} \\ \hline
3 & CH\({}_{3}\), C\({}_{6}\)H\({}_{4}\)CH\({}_{2}\)NHBoc, C\({}_{6}\)H\({}_{4}\)CH\({}_{2}\)NHBoc, C\({}_{6}\)H\({}_{4}\)OH, C\({}_{6}\)H\({}_{4}\), nC\({}_{5}\)H\({}_{11}\) & R\({}^{1}\)CN, R\({}^{2}\)CN & Zn(OTf)\({}_{2}\) or Ni(OTf)\({}_{2}\), N\({}_{2}\)H\({}_{4}\), [Ox] & Unsymmetrical \\
4 & CH\({}_{2}\)C\({}_{6}\)H\({}_{5}\), n-C\({}_{5}\)H\({}_{11}\), C(CH\({}_{3}\))\({}_{3}\), NHBoc, & R\({}^{1}\)CN & Zn(OT)\({}_{2}\) or Ni(OTf)\({}_{2}\), N\({}_{2}\)H\({}_{4}\), [Ox] & Monosubstituted \\
5 & C\({}_{6}\)H\({}_{5}\), (CH\({}_{2}\))\({}_{2}\)OH, CH\({}_{3}\), 4-Br-C\({}_{6}\)H\({}_{4}\) & R\({}^{1}\)CN, R\({}^{2}\)CN & 3-Sulfanylpropanoic acid, N\({}_{2}\)H\({}_{4}\)\(\cdot\)H\({}_{2}\)O, EtOH, [Ox] & Unsymmetrical \\
6 & CH\({}_{2}\)COOH, COOH, CH\({}_{2}\)OH, CN, Br, CH\({}_{3}\) & CH\({}_{2}\)Cl\({}_{2}\) & MW, [Ox] & 1,2,4,5-tetrazines \\ \hline \end{tabular}
\end{table} 
Table 2: Modified Pinner synthesis—reagents and conditions. **Scheme 5. ** A modified Pinner synthesis using carbonitriles, hydrazine, and activating agent. Another method for synthesizing 1,2,4,5-tetrazine derivatives is the condensation of imidoyl chlorides with hydrazine (Scheme 6) [39; 40]. The transformation is selective because specific structural elements are connected prior to cyclization. This eliminates the risk of forming a mixture of symmetrical and unsymmetrical 1,2,4,5-tetrazine derivatives and avoids difficulties in separating the reaction products. The method is particularly effective for synthesizing difficult-to-obtain unsymmetrical derivatives with alkyl substituents. The starting reagents, acid chlorides (or less frequently esters), react with hydrazine to form the corresponding hydrazides.