Department of Chemistry, The University of Texas at San Antonio, San Antonio, Texas 78249, United States.
Laboratorio de Biotecnologia Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, 88710 Reynosa, Mexico.
J Am Chem Soc. 2023 Jun 21;145(24):13059-13068. doi: 10.1021/jacs.3c01347. Epub 2023 Jun 9.
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 N 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 NaBH 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.
1,2,3-三嗪与亲二烯体最重要的反应之一是逆电子需求 Diels-Alder（IEDDA）环加成，该反应通过三嗪的亲核加成进行，随后是 N 损失和环化，生成杂环。加成的位置要么在对称取代的三嗪核的 4-位，要么在 6-位。虽然已知三嗪加核试剂的具体实例，但尚未有全面的了解，亲核加成的首选位置未知且未被探索。由于可以获得不对称 1,2,3-三嗪-1-氧化物及其脱氧 1,2,3-三嗪化合物，我们报告了在 1,2,3-三嗪和 1,2,3-三嗪-1-氧化物框架上的 C-, N-, H-, O- 和 S-亲核加成，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，加成的位置在两个杂环体系的 C-6 位，但 1,2,3-三嗪-1-氧化物的产物形成速度更快。其他 N-亲核试剂与三嗪 1-氧化物的反应表明，加成发生在三嗪 1-氧化物环的 4-位或 6-位，但亲核攻击仅发生在三嗪的 6-位。来自 NaBH4 的氢化物在三嗪的 6-位和三嗪 1-氧化物核上发生加成。烷氧基化物对三嗪 1-氧化物的 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上的 6-位发生亲核加成，而在三嗪 1-氧化物的 4-位发生加成。这些亲核加成在温和的反应条件下进行，并显示出对功能基团的高容忍度。计算研究阐明了亲核加成和氮排除步骤的作用以及立体和电子因素对不同亲核试剂反应结果的影响。
