An efficient synthesis ofs-tetrazines
by solid-phase
methods is described. This synthesis route was compatible with different
solid-phase resins and linkers and did not require metal catalysts
or high temperatures. Monosubstituted tetrazines were routinely synthesized
using thiol-promoted chemistry, using dichloromethane as a carbon
source, while disubstituted unsymmetrical aryl or alkyl tetrazines
were synthesized using readily available nitriles. This efficient
approach enabled the synthesis ofs-tetrazines in
high yields (70–94%), eliminating the classical solution-phase
problems of mixtures of symmetrical and unsymmetrical tetrazines,
with only a single final purification step required, and paves the
way to the rapid synthesis ofs-tetrazines with various
applications in bioorthogonal chemistry and beyond.