Site Reversal in Nucleophilic Addition to 1,2,3-Triazine 1-Oxides.
Site Reversal in Nucleophilic Addition to 1,2,3-Triazine 1-Oxides.
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DOI：
10.1021/jacs.3c01347
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发表时间：
2023-06
影响因子：
15
通讯作者：
Luca De Angelis;Graham C. Haug;G. Rivera;Soumen Biswas;Ammar Al-Sayyed;Hadi D Arman;O. Larionov;M. Doyle
中科院分区：
文献类型：
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作者：
Luca De Angelis;Graham C. Haug;G. Rivera;Soumen Biswas;Ammar Al-Sayyed;Hadi D Arman;O. Larionov;M. Doyle
1，2，3-三嗪与亲二烯化合物的最重要的反应之一是反电子需求Diels-Alder(IEDDA)环加成反应，该反应通过三氮的亲核加成、氮气损失和环合反应生成杂环。加成部位位于对称取代的三氮杂环的4位或6位。虽然已知亲核剂与三氮杂环加成的具体例子，但尚未有全面了解的报道，亲核加成的首选位置也是未知和未被探索的。通过获得不对称的1，2，3-三嗪-1-氧化物及其脱氧的1，2，3-三嗪化合物，我们报道了1，2，3-三嗪和1，2，3-三嗪-1-氧化物骨架上的C-，N-，H-，O-和S-亲核加成反应，其中4-位和6-位可以区分。在使用C-和N-亲核试剂进行的IEDDA环加成反应中，两个杂环体系的加成中心都在C-6，但与1，2，3-三氮杂环-1-氧化物的产物形成速度更快。其他与三嗪1-氧化物的N-亲核反应在三嗪1-氧化物的4-位或6-位发生加成反应，但亲核攻击只发生在三嗪上的6-位。来自NaBH4的氢化物在三氮杂环上的6位和三氮杂环上的1-氧化物上加成。醇类化合物对三嗪1-氧化物的4位具有很高的亲核选择性。硫代酚、半胱氨酸和谷胱甘肽在三氮杂环的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，表现出较高的官能团耐受性。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决定与不同亲核试剂反应结果方面的影响。
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.