Mechanistic Insights into the Reaction of Amidines with 1,2,3-Triazines and 1,2,3,5-Tetrazines

1,2,3-Triazines and
1,2,3,5-tetrazines react rapidly, efficiently,
and selectively with amidines to form pyrimidines/1,3,5-triazines,
exhibiting an orthogonal reactivity with 1,2,4,5-tetrazine-based conjugation
chemistry. Whereas the mechanism of the reaction of the isomeric 1,2,4-triazines
and 1,2,4,5-tetrazines with alkenes is well understood, the mechanism
of the 1,2,3-triazine/1,2,3,5-tetrazine–amidine reaction as
well as its intrinsic reactivity remains underexplored. By using 15N-labeling, kinetic investigations, and kinetic isotope effect
studies, complemented by extensive computational investigations, we
show that this reaction proceeds through an addition/N2 elimination/cyclization pathway, rather than the generally expected
concerted or stepwise Diels–Alder/retro Diels–Alder
sequence. The rate-limiting step in this transformation is the initial
nucleophilic attack of an amidine on azine C4, with a subsequent energetically
favored N2 elimination step compared with a disfavored
stepwise formation of a Diels–Alder cycloadduct. The proposed
reaction mechanism is in agreement with experimental and computational
results, which explains the observed reactivity of 1,2,3-triazines
and 1,2,3,5-tetrazines with amidines.