Divergent Synthesis of 3-(Indol-2-yl)quinoxalin-2-ones and 4-(Benzimidazol-2-yl)-3-methyl(aryl)cinnolines via Polyphosphoric Acid (PPA)-Mediated Intramolecular Rearrangements of 3-(Methyl/aryl(2-phenylhydrazono)methyl)quinoxalin-2-ones,The Journal of Organic Chemistry

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Divergent Synthesis of 3-(Indol-2-yl)quinoxalin-2-ones and 4-(Benzimidazol-2-yl)-3-methyl(aryl)cinnolines via Polyphosphoric Acid (PPA)-Mediated Intramolecular Rearrangements of 3-(Methyl/aryl(2-phenylhydrazono)methyl)quinoxalin-2-ones
The Journal of Organic Chemistry ( IF 3.3 ) Pub Date : 2023-11-30 , DOI: 10.1021/acs.joc.3c01626
Vakhid A Mamedov ₁ , Liliya V Mustakimova ₁ , Zheng-Wang Qu ₂ , Hui Zhu ₂ , Victor V Syakaev ₁ , Venera R Galimullina ₁ , Leisan R Shamsutdinova ₁ , Il'dar Kh Rizvanov ₁ , Aidar T Gubaidullin ₁ , Oleg G Sinyashin ₁ , Stefan Grimme ₂

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Herein, we report a polyphosphoric acid (PPA)-mediated divergent metal-free operation to access a diverse collection of 3-(indol-2-yl)quinoxalin-2-ones and 4-(benzimidazol-2-yl)-3-methylcinnolines in moderate to excellent overall yields. The described process involves two distinct, and competing rearrangements of 3-(methyl(2-phenylhydrazono)methyl)quinoxalin-2-ones, namely [3,3]-sigmatropic Fischer rearrangement with the formation of an indole ring to produce 3-(indol-2-yl)-quinoxalin-2-ones, and Mamedov rearrangement with simultaneous construction of benzimidazole and cinnoline rings to form the new biheterocyclic system─4-(benzimidazol-2-yl)-3-methylcinnolines. The reaction mechanism of both rearrangement channels is explored by extensive dispersion-corrected DFT calculations. It is partcularly remarkable that when 3-(aryl(2-phenylhydrazono)methyl)quinoxalin-2-ones is used, instead of 3-(methyl(2-phenylhydrazono)methyl)quinoxalin-2-ones, reactions proceed regioselectively with the formation of only rearrangement products─4-(benzimidazol-2-yl)-3-arylcinnolines with high yields. This operationally simple protocol enables a rapid access to these scaffolds and is compatible with a wide scope of starting materials. In addition, the new rearrangement found features a promising approach for the design of unique compound libraries for drug design and discovery programs.

中文翻译：

3-(吲哚-2-基)喹喔啉-2-酮和4-(苯并咪唑-2-基)-3-甲基(芳基)肉啉通过多磷酸(PPA)介导的3-(甲基)分子内重排的发散合成/芳基(2-苯基亚肼基)甲基)喹喔啉-2-酮

在此，我们报告了一种多磷酸（PPA）介导的不同的无金属操作，以获得多种3-（吲哚-2-基）喹喔啉-2-酮和4-（苯并咪唑-2-基）-3-甲基肉啉的总产率中等至优异。所描述的过程涉及 3-(甲基(2-苯基亚肼基)甲基)喹喔啉-2-酮的两个不同且竞争的重排，即 [3,3]-sigmatropic Fischer 重排，形成吲哚环以产生 3-(吲哚-2-基)-喹喔啉-2-酮，以及Mamedov重排同时构建苯并咪唑和肉桂啉环，形成新的双杂环体系─4-(苯并咪唑-2-基)-3-甲基肉啉。通过广泛的色散校正 DFT 计算探索了两个重排通道的反应机制。特别值得注意的是，当使用 3-(芳基(2-苯基亚肼基)甲基)喹喔啉-2-酮代替 3-(甲基(2-苯基亚肼基)甲基)喹喔啉-2-酮时，反应会区域选择性地进行并形成唯一的重排产物─4-(苯并咪唑-2-基)-3-芳基肉啉，产率高。这种操作简单的方案可以快速访问这些支架，并且与多种起始材料兼容。此外，新的重排发现了一种有前途的方法，用于设计用于药物设计和发现项目的独特化合物库。

更新日期：2023-11-30

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