An unprecedented 1,4-cycloaddition (vs 3,6-cycloaddition) of 1,2,4,5-tetrazines is described with preformed or in situ generated enamines promoted by the solvent hydrogen bonding of hexafluoroisopropanol (HFIP) or Lewis acid ZnCl<sub>2</sub>. 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. Activation of heteroaromatic azadiene through hydrogen bonding or Lewis acid complexation with the nitrogen of 1,2,4,5-tetrazine is the key factor leading to change of the cycloaddition mode from conventional 3,6-cycloaddition to 1,4-cycloaddition. To date, aryl-conjugated aldehydes or ketones and cyclohexanone derivatives are found to exhibit this unique reactivity enabled by solvent HFIP and ZnCl<sub>2</sub>, respectively. Mechanistic studies suggested a stepwise mechanism, consisting of enamine nucleophilic attack, 6π electrocyclic rearrangement, electrocyclic cyclization, and subsequent aromatization with elimination of amine and nitrile. Given its simplicity and breath, the study establishes a novel method for the simple and efficient one-step synthesis of 1,2,4-triazines found in drugs and bioactive molecules that is conducted under mild conditions from readily accessible starting materials. The studies represent examples of not just an enhancement in the rate or efficiency of a heterocyclic azadiene cycloaddition by hydrogen bonding or Lewis acid catalysis, but also the first to alter the mode (N1/N4 vs C3/C6) of cycloaddition.

Selective N1/N4 1,4-cycloaddition of 1,2,4,5-tetrazines: Development, scope, and mechanism

ACS Spring 2022

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