Metal-catalyzed one-pot synthesis of tetrazines directly from aliphatic nitriles and hydrazine.

Abstract

There is rapidly growing interest in the use of 1,2,4,5-tetrazines as bioorthogonal coupling agents.[1-3] Recent applications of tetrazine cycloadditions include intracellular small molecule imaging, genetically targeted protein tagging, post-synthetic DNA labeling, nanoparticle based clinical diagnostics, and in-vivo imaging.[4-7] In addition, tetrazines have seen significant use in materials science[8,9], coordination chemistry, [10,11] and specialty explosives research.[12,13] They are also valuable synthetic intermediates, and have been elegantly deployed on route to several natural product syntheses.[14-16] Despite the promise of tetrazines, the lack of convenient synthetic methods is a significant roadblock to their broader use and study by the scientific community.[17] Here we report that Lewis acid transition metal catalysts, most notably divalent nickel and zinc salts, can catalyze the formation of 1,2,4,5-tetrazines directly from nitriles. To our knowledge, this is the first method utilizing homogenous catalysis to directly synthesize tetrazines from a wide range of unactivated aliphatic nitriles and hydrazine. Symmetric and asymmetric tetrazines were conveniently prepared from multiple precursors including alkyl nitriles, aromatic nitriles, and formamidine salts. This methodology should greatly improve the accessibility of tetrazines and lead to further exploration of their applications, particularly with respect to bioorthogonal conjugations.