On the importance of an acid additive in the synthesis of pyrido[1,2-a]benzimidazoles by direct copper-catalyzed amination.
On the importance of an acid additive in the synthesis of pyrido[1,2-a]benzimidazoles by direct copper-catalyzed amination.
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DOI：
10.1002/chem.201100574
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发表时间：
2011-05
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通讯作者：
Kye-Simeon Masters;Tom R. M. Rauws;A. Yadav;W. Herrebout;B. J. van der Veken;B. Maes
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作者：
Kye-Simeon Masters;Tom R. M. Rauws;A. Yadav;W. Herrebout;B. J. van der Veken;B. Maes
吡啶并[1，2-a]苯并咪唑1，2a从药物化学2 -7（溶解性，7 DNA嵌入3）和材料化学8（荧光）的角度来看都是令人感兴趣的化合物。在前者中值得注意的是抗生素药物利福昔明，5它含有这种杂芳核。组装吡啶并[1，2-a]苯并咪唑的经典合成方法是通过在C2处含有亚甲基的苯并咪唑与适当的双亲电试剂的[3+3]环缩合。2a然而，这些方法通常产率低，涉及间接/冗长的序列，和/或提供有限范围的产物，主要提供具有位于吡啶环上的取代基的衍生物（A环，方案1）。2 -4理论上，通过分子内过渡金属催化的N-环中CN键的形成，可以获得合成苯环（C环）上具有取代基的吡啶并[1，2-a]苯并咪唑的良好替代合成方法。（2-氯芳基）吡啶-2-胺，基于我们研究小组最近开发的化学。9这些底物本身很容易通过SNAr或选择性Pd获得。用2-氯苯胺催化2-氯吡啶的胺化10。11如果能够开发一种不需要预先活化2-氯芳氨基实体的2-位的合成方法，这将是更有效的，因为苯胺比2-氯苯胺更容易商购。因此，探索了通过过渡金属催化的分子内CH胺化方法从N-芳基吡啶-2-胺（3）合成吡啶并[1，2-a]苯并咪唑（4）（方案1）。
Pyrido[1,2-a]benzimidazoles1, 2a are interesting compounds both from the viewpoint of medicinal chemistry2–7 (solubility,7 DNA intercalation3) and materials chemistry8 (fluorescence). Of note among the former is the antibiotic drug Rifaximin,5 which contains this heteroaromatic core. The classical synthetic approach for the assembly of pyrido[1,2-a]benzimidazoles is by [3+3] cyclocondensation of benzimidazoles containing a methylene group at C2 with appropriate bielectrophiles.2a However, these procedures are often low-yielding, involve indirect/lengthy sequences, and/or provide access to a limited range of products, primarily providing derivatives with substituents located on the pyridine ring (A ring, Scheme 1).2–4 Theoretically, a good alternative synthetic method for the synthesis of pyrido[1,2-a]benzimidazoles with substituents in the benzene ring (C ring) should be accessible by intramolecular transition-metal-catalyzed CN bond formation in N-(2-chloroaryl)pyridin-2-amines, based on chemistry recently developed in our research group.9 These substrates themselves are easily available through SNAr or selective Pd-catalyzed amination10 of 2-chloropyridine with 2-chloroanilines.11 If a synthetic procedure that eliminated the need for preactivation of the 2-position of the 2-chloroarylamino entity could be developed, this would be even more powerful, as anilines are more readily commercially available than 2-chloroanilines. Therefore the synthesis of pyrido[1,2-a]benzimidazoles (4) by a transition-metal-catalyzed intramolecular CH amination approach from N-arylpyridin-2-amines (3) was explored (Scheme 1).