Recent synthesis of functionalized s-tetrazines and their application in ligation reactions under physiological conditions: a concise overview

Inverse electron demand Diels–Alder reactions have gained comprehensive attraction in recent years. Accordingly, the synthetic approaches for one of the coupling partners, namely s-tetrazine, have been extensively investigated. Generally, the main synthetic method of s-tetrazine relied on the condensation of two nitriles to give the corresponding symmetric/asymmetric tetrazines with moderate to excellent yields. However, the practical synthesis route and commercial/synthetic availability of the feedstock nitriles are still elusive. It is therefore probably worth summarizing the existing methods and typical biological applications that have been demonstrated in recent years. In brief, this overview will be split into three parts. First, we will summarize the typical approaches toward the synthesis of s-tetrazines till now. Then, we will provide the representative bio-orthogonal reactions by the combination of s-tetrazines with unsaturated compounds under physiological conditions. Eventually, we will propose a direction for the practical and efficient synthesis of s-tetrazine.