One of the most important reactions of 1,2,3-triazines with a dienophile is inverse electron demand Diels–Alder (IEDDA) cycloaddition, which occurs through nucleophilic addition to the triazine followed by N₂ loss and cyclization to generate a heterocycle. The site of addition is either at the 4- or 6-position of the symmetrically substituted triazine core. Although specific examples of the addition of nucleophiles to triazines are known, a comprehensive understanding has not been reported, and the preferred site for nucleophilic addition is unknown and unexplored. With access to unsymmetrical 1,2,3-triazine-1-oxides and their deoxygenated 1,2,3-triazine compounds, we report C-, N-, H-, O-, and S-nucleophilic additions on 1,2,3-triazine and 1,2,3-triazine-1-oxide frameworks where the 4- and 6-positions could be differentiated. In the IEDDA cycloadditions using C- and N-nucleophiles, the site of addition is at C-6 for both heterocyclic systems, but product formation with 1,2,3-triazine-1-oxides is faster. Other N-nucleophile reactions with triazine 1-oxides show addition at either the 4- or 6-position of the triazine 1-oxide ring, but nucleophilic attack only occurs at the 6-position on the triazine. Hydride from NaBH₄ undergoes addition at the 6-position on the triazine and the triazine 1-oxide core. Alkoxides show a high nucleophilic selectivity for the 4-position of the triazine 1-oxide. Thiophenoxide, cysteine, and glutathione undergo nucleophilic addition on the triazine core at the 6-position, while addition occurs at the 4-position of the triazine 1-oxide. These nucleophilic additions proceed under mild reaction conditions and show high functional group tolerance. Computational studies clarified the roles of the nucleophilic addition and nitrogen extrusion steps and the influence of steric and electronic factors in determining the outcomes of the reactions with different nucleophiles.

中文翻译：

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1,2,3-三嗪 1-氧化物亲核加成中的位点反转

1,2,3-三嗪与亲二烯体最重要的反应之一是逆电子需求狄尔斯-阿尔德 (IEDDA) 环加成，该反应通过三嗪的亲核加成和 N 2_发生损失并环化生成杂环。加成位点位于对称取代的三嗪核心的 4 位或 6 位。尽管亲核试剂与三嗪加成的具体例子是已知的，但尚未报道全面的理解，并且亲核加成的优选位点未知且尚未探索。通过获得不对称 1,2,3-三嗪-1-氧化物及其脱氧 1,2,3-三嗪化合物，我们报告了 1,2 上的 C-、N-、H-、O- 和 S- 亲核加成,3-三嗪和 1,2,3-三嗪-1-氧化物骨架，其中 4- 和 6- 位可以区分。在使用 C- 和 N- 亲核试剂的 IEDDA 环加成中，两种杂环体系的加成位点均位于 C-6，但使用 1,2,3-三嗪-1-氧化物形成产物的速度更快。与三嗪 1-氧化物的其他 N-亲核反应显示在三嗪 1-氧化物环的 4-位或 6-位上发生加成，但亲核攻击仅发生在三嗪的 6-位上。NaBH 的氢化物₄在三嗪和三嗪1-氧化物核的6位上进行加成。醇盐对 1-氧化物三嗪的 4-位表现出高亲核选择性。噻吩氧化物、半胱氨酸和谷胱甘肽在三嗪核心的 6 位上进行亲核加成，而加成发生在三嗪 1-氧化物的 4 位上。这些亲核加成反应在温和的反应条件下进行，并表现出高官能团耐受性。计算研究阐明了亲核加成和氮挤出步骤的作用以及空间和电子因素在确定不同亲核试剂反应结果中的影响。