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.

1,2,3 - 三嗪和1,2,3,5 - 四嗪与脒迅速、高效且选择性地反应形成嘧啶/1,3,5 - 三嗪，展现出与基于1,2,4,5 - 四嗪的共轭化学正交的反应性。虽然异构的1,2,4 - 三嗪和1,2,4,5 - 四嗪与烯烃的反应机理已被充分理解，但1,2,3 - 三嗪/1,2,3,5 - 四嗪 - 脒反应的机理及其内在反应性仍未得到充分研究。通过使用¹⁵N标记、动力学研究和动力学同位素效应研究，并辅以大量的计算研究，我们表明该反应通过加成/ N₂消除/环化途径进行，而不是通常预期的协同或分步的狄尔斯 - 阿尔德/逆狄尔斯 - 阿尔德序列。这种转化中的限速步骤是脒对嗪C4的初始亲核进攻，与不利的狄尔斯 - 阿尔德环加成物分步形成相比，随后的N₂消除步骤在能量上是有利的。所提出的反应机理与实验和计算结果一致，这解释了所观察到的1,2,3 - 三嗪和1,2,3,5 - 四嗪与脒的反应性。