Programmed Heterocycle Synthesis Using Halomucononitriles as Pyridinimine Precursors
Programmed Heterocycle Synthesis Using Halomucononitriles as Pyridinimine Precursors
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DOI：
10.1021/acs.orglett.4c00547
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发表时间：
2024-04-01
期刊：
影响因子：
5.2
通讯作者：
Wilkerson-Hill，Sidney M.
中科院分区：
文献类型：
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作者：
Zahara，Adam J.;Haines，Brandon E.;Wilkerson-Hill，Sidney M.
在此，我们报告了一种将伯胺（药物库中普遍存在的基序）通过两步从已知化合物转化为咪唑并[1,2-a]吡啶或7-烷基氮杂吲哚的方法。使用卤代粘康腈试剂，我们可以通过瞬时氨基粘康腈中间体的环化，一步从伯胺直接获得 5-溴-6-亚氨基-1-烷基-1,6-二氢吡啶-2-甲腈（吡啶亚胺）（产率 25-93%）。然后，我们证明这些化合物可以使用 Sonogashira 交叉偶联条件轻松转化为 7-烷基氮杂吲哚（13 个示例，产率高达 91%）。在氧化条件下，吡啶亚胺充当 C-H 官能化反应的导向基团，得到咪唑并[1,2-a]吡啶。我们还使用 DFT 计算研究了环化事件的机制，并提出这是通过连续的碱基介导的 E/Z 异构化和环化步骤发生的。
Herein we report a method to convert primary amines, ubiquitous motifs found in pharmaceutical libraries, to either imidazo[1,2-a]pyridines or 7-alkyl azaindoles in two steps from known compounds. Using halomucononitrile reagents, we can directly access 5-bromo-6-imino-1-alkyl-1,6-dihydropyridine-2-carbonitriles (pyridinimines) in a single step from primary amines (25–93% yield) through the cyclization of transient aminomucononitrile intermediates. We then demonstrate that these compounds can be readily converted to 7-alkylazaindoles using Sonogashira cross-coupling conditions (13 examples, up to 91% yield). Under oxidative conditions, the pyridinimines serve as directing groups for C–H functionalization reactions to afford imidazo[1,2-a]pyridines. We also studied the mechanism of the cyclization event using DFT calculations and propose that this takes place via sequential base-mediatedE/Zisomerization and cyclization steps.