Synthesis, Characterization, and Cycloaddition Reactivity of a Monocyclic Aromatic 1,2,3,5-Tetrazine

Herein
we disclose the synthesis and full characterization of the
first monocyclic aromatic 1,2,3,5-tetrazine, 4,6-diphenyl-1,2,3,5-tetrazine.
Initial studies of its cycloaddition reactivity, mode, regioselectivity,
and scope illustrate that it participates as the 4π-component
of well-behaved inverse electron demand Diels–Alder reactions
where it preferentially reacts with electron-rich or strained dienophiles.
It was found to exhibit an intrinsic reactivity comparable to that
of the isomeric 3,6-diphenyl-1,2,4,5-tetrazine, display a single mode
of cycloaddition with reaction only across C4/N1 (no N2/N5 cycloaddition
observed), proceed with a predictable regioselectivity (dienophile
most electron-rich atom attaches to C4), and manifest additional reactivity
complementary to the isomeric 1,2,4,5-tetrazines. It not only exhibits
a remarkable cycloaddition reactivity, surprisingly good stability
(e.g., stable to chromatography, long-term storage, presence of H2O even as reaction co-solvent), and broad cycloaddition scope,
but it also displays powerful orthogonal reactivity with the 1,2,4,5-tetrazines.
Whereas the latter reacts at extraordinary cycloaddition rates with
strained dienophiles (tetrazine ligation), the new and isomeric 1,2,3,5-tetrazine
displays similarly remarkable cycloaddition rates and efficiencies
with amidines (1,2,3,5-tetrazine/amidine ligation). The crossover
reactivities (1,2,4,5-tetrazines with amidines and 1,2,3,5-tetrazines
with strained dienophiles) are sufficiently low to indicate they may
be capable of use concurrently without competitive reactions.