Accessing Functionalized Tetrazines as Click Chemistry Tools: A Synthesis Guide for Chemists and Chemical Biologists

Abstract

AbstractSince the first report that 1,2,4,5‐tetrazines undergo a bioorthogonal reaction with dienophiles in the form of an inverse electron‐demand Diels‐Alder reaction, the demand for high‐yielding synthetic approaches towards them grew steadily. Despite this significant interest, tetrazines were predominantly accessed via the Pinner synthesis or other Pinner‐like reactions, significantly limiting available substrates. In particular, the synthesis of unsymmetrically substituted s‐tetrazines for the selective conjugation to another species presented a major challenge. To tackle these challenges, new and innovative high‐yielding transformations have been developed to widen the scope of accessible symmetric and unsymmetric tetrazines. For instance, Ni(II), Zn(II), and sulphur‐catalysed reactions between two nitriles and hydrazine were developed, which provide access to a wide range of (un‐)symmetric aryl s‐tetrazines. Also, amidines and orthoesters give tetrazines with alkyl substituents, whereas the usage of CH2Cl2 yields valuable H‐monosubstituted tetrazines. Methods using thiocarbohydrazides, terminal fluoroolefins, oxetane esters, or tosyl hydrazones are among the recent additions. Due to the high interest in tetrazine click‐chemistry approaches, some of which reach beyond inverse electron‐demand Diels‐Alder reactions, we expect this overview of synthetic routes to aid the exploration for further applications of tetrazines. Ultimately, we hope to provide a guide for chemists and chemical biologists for accessing functional s‐tetrazines.