Selective N1/N4 1,4-Cycloaddition of 1,2,4,5-Tetrazines Enabled by Solvent Hydrogen Bonding

An
unprecedented 1,4-cycloaddition (vs 3,6-cycloaddition) of 1,2,4,5-tetrazines
is described with preformed or in situ generated aryl-conjugated enamines
promoted by the solvent hydrogen bonding of hexafluoroisopropanol
(HFIP) that is conducted under mild reaction conditions (0.1 M HFIP,
25 °C, 12 h). The reaction constitutes a formal [4 + 2] cycloaddition
across the two nitrogen atoms (N1/N4) of the 1,2,4,5-tetrazine followed
by a formal retro [4 + 2] cycloaddition loss of a nitrile and aromatization
to generate a 1,2,4-triazine derivative. The factors that impact the
remarkable change in the reaction mode, optimization of reaction parameters,
the scope and simplification of its implementation through in situ
enamine generation from aldehydes and ketones, the reaction scope
for 3,6-bis­(thiomethyl)-1,2,4,5-tetrazine, a survey of participating
1,2,4,5-tetrazines, and key mechanistic insights into this reaction
are detailed. Given its simplicity and breath, the study establishes
a novel method for the simple and efficient one-step synthesis of
1,2,4-triazines under mild conditions from readily accessible starting
materials. Whereas alternative protic solvents (e.g., MeOH vs HFIP)
provide products of the conventional 3,6-cycoladdition, the enhanced
hydrogen bonding capability of HFIP uniquely results in promotion
of the unprecedented formal 1,4-cycloaddition. As such, the studies
represent an example of not just an enhancement in the rate or efficiency
of a heterocyclic azadiene cycloaddition by hydrogen bonding catalysis
but also the first to alter the mode (N1/N4 vs C3/C6) of cycloaddition.