Palladium-catalyzed oxidative cyclization of N-aryl enamines:: From anilines to indoles
Palladium-catalyzed oxidative cyclization of N-aryl enamines:: From anilines to indoles
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DOI：
10.1002/anie.200802482
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Glorius, Frank
中科院分区：
文献类型：
--
作者：
Wuertz, Sebastian;Rakshit, Souvik;Glorius, Frank
吲哚环是天然产物和药物中最丰富和最相关的杂环之一尽管存在许多合成和衍生吲哚的方法，但开发新的、更有效的方法是非常重要的。在这种情况下，通过选择性激活两个CÀH键[3]直接氧化CÀC偶联是一种很有前途的合成策略。[4,5]与已建立的交叉偶联方法（如Suzuki-Miyaura偶联）相比，不需要对反应中心进行预官能化。例如，富电子苯胺底物可以在酸性条件下通过亲电芳钯化活化和功能化，得到吲哚醌类或咔唑类。[8,9]然而，这些反应的范围有限，钯络合物的化学计量量的频繁要求，以及通常观察到的低产率限制了这些方法的实用性。此外，在这些酸性条件下不能制备简单的无环吲哚。在此，我们报道了一种由钯催化的分子内氧化偶联从市售苯胺有效合成功能化吲哚的方法。由于这种环化不是通过亲电芳钯化进行的，因此在这种反应中可以使用多种苯胺。我们的研究开始于甲基(Z)-3-（苯胺）- 2-烯酸酯（1a）的环化，得到相应的吲哚2a。在优化反应的实验中，DMF中以Pd (OAc) 2、Cu (OAc) 2为氧化剂、K2CO3为碱的催化量时，反应效果最佳（表1，条目1）。在这些条件下，在808C下，转化在3小时内完成（分离产物收率的72%），或者在1408C下，即使只使用5mol %的Pd (OAc) 2（未示出），也在不到15分钟内完成。氧化剂（表1，条目3-6）、碱（表1，条目7和8）或溶剂（表1，条目9-11）的变化导致了
The indole unit is one of the most abundant and relevant heterocycles in natural products and pharmaceuticals.[1] Despite the existence of numerous methods for the synthesis and derivatization of indoles,[2] the development of new, more efficient methods is of great importance. In this context, direct oxidative CÀC coupling by the selective activation of two CÀH bonds [3] is a promising synthetic strategy.[4, 5] In contrast to established cross-coupling methods,[6] such as the Suzuki–Miyaura coupling, prefunctionalization of the reaction centers is not required. For example, electron-rich aniline substrates can be activated and functionalized by electrophilic aromatic palladation under acidic conditions to give indolequinones [7] or carbazoles.[8, 9] However, the limited scope of these reactions, the frequent requirement of a stoichiometric amount of a palladium complex, and the low yields often observed limit the usefulness of these methods. Furthermore, simple non-annulated indoles could not be prepared under these acidic conditions.Herein, we report an efficient synthesis of functionalized indoles from commercially available anilines by palladiumcatalyzed, intramolecular oxidative coupling. As this cyclization does not proceed through electrophilic aromatic palladation, a large variety of anilines can be used in this reaction. Our investigation commenced with the cyclization of methyl (Z)-3-(phenylamino) but-2-enoate (1a) to give the corresponding indole 2a. In experiments to optimize the reaction, the best results were obtained with a catalytic amount of Pd (OAc) 2, Cu (OAc) 2 as the oxidant, and K2CO3 as the base in DMF (Table 1, entry 1). Under these conditions, conversion was complete within 3 h at 808C (72% yield of the isolated product), or within less than 15 min at 1408C, even when only 5 mol% of Pd (OAc) 2 was used (not shown). Variation of the oxidant (Table 1, entries 3–6), the base (Table 1, entries 7 and 8), or the solvent (Table 1, entries 9–11) led to a decrease in