Direct palladium-catalyzed C-2 and C-3 arylation of indoles: A mechanistic rationale for regioselectivity
Direct palladium-catalyzed C-2 and C-3 arylation of indoles: A mechanistic rationale for regioselectivity
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DOI：
10.1021/ja043273t
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发表时间：
2005-06-08
影响因子：
15
通讯作者：
Sames, D
中科院分区：
文献类型：
--
作者：
Lane, BS;Brown, MA;Sames, D
我们最近开发了钯催化的方法来直接芳基化吲哚（和其他唑），其中对游离(NH)-吲哚和(NR)-吲哚都有很高的C-2选择性。为了提供观察到的选择性（“非亲电性”区域选择性）的基本原理，进行了机制研究，使用1-甲基吲哚的苯基化作为模型系统。确定了碘苯（零级）、吲哚（一级）和催化剂（一级）的反应级数。这些动力学研究与Hammett图一起为亲电钯化途径提供了强有力的支持。此外，还测定了C-2和C-3位置的动力学同位素效应（KIEH/D）。令人惊讶的是，在没有发生取代的C-3位置（继发性KIE）发现了1.6的大值，而在C-2位置（明显的原发性KIE）发现了1.2的小值。在这些发现的基础上，提出了一种机制解释，其特征是吲哚的亲电钯化，伴随着中间钯的1,2-迁移。利用这一模式设计了吲哚C-3芳基化反应的新催化条件。在游离(NH)-吲哚的情况下，通过选择镁碱实现了芳基化反应的区域选择性（C-2与C-3）。
We have recently developed palladium-catalyzed methods for direct arylation of indoles (and other azoles) wherein high C-2 selectivity was observed for both free (NH)-indole and (NR)-indole. To provide a rationale for the observed selectivity ("nonelectrophilic" regioselectivity), mechanistic studies were conducted, using the phenylation of 1-methylindole as a model system. The reaction order was determined for iodobenzene (zero order), indole (first order), and the catalyst (first order). These kinetic studies, together with the Hammett plot, provided a strong support for the electrophilic palladation pathway. In addition, the kinetic isotope effect (KIEH/D) was determined for both C-2 and C-3 positions. A surprisingly large value of 1.6 was found for the C-3 position where the substitution does not occur (secondary KIE), while a smaller value of 1.2 was found at C-2 (apparent primary KIE). On the basis of these findings, a mechanistic interpretation is presented that features an electrophilic palladation of indole, accompanied by a 1,2-migration of an intermediate palladium species. This paradigm was used to design new catalytic conditions for the C-3 arylation of indole. In case of free (NH)-indole, regioselectivity of the arylation reaction (C-2 versus C-3) was achieved by the choice of magnesium base.