3-Bromotetrazine: A Versatile Precursor for the Synthesis of 3-Monosubstituted s-Tetrazines and the Labelling of Macromolecules

We report the synthesis of the novel precursor 3-bromotetrazine and its successful use in the synthesis of various families of 3-monosubstituted s-tetrazines. A remarkable functional group selectivity is utilized to site-selectively functionalize different complex molecules. The unexpected stability of 3- bromotetrazine in aqueous media facilitated the development of a protocol for protein functionalization in- stalling a tetrazine unit as a bio-orthogonal handle for inverse electron demand Diels-Alder reactions. Addi- tionally, a novel tetrazine-based chemical probe was developed and its application in the context of thiol- targeted natural product isolation and labelling of mammalian cells is demonstrated.