A flexible and catalytic one-pot procedure for the synthesis of indoles.
A flexible and catalytic one-pot procedure for the synthesis of indoles.
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DOI：
10.1002/anie.200351345
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发表时间：
2003-07
影响因子：
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通讯作者：
H. Siebeneicher;Igor Bytschkov;S. Doye
中科院分区：
文献类型：
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作者：
H. Siebeneicher;Igor Bytschkov;S. Doye
在过去的几年里，由于筛选方法的改进，对高度灵活的合成方法的需求稳步增长。这些合成方法的主要目的是快速生成某类物质的各种衍生物。在过去，我们已经多次表明，钛催化的炔的氢胺化[1]是一种高度灵活的合成生物学上感兴趣的化合物的通用工具。[2]扩展这些研究，我们现在提出了一种高度灵活和催化的一锅法合成吲哚[3]，采用邻氯取代的1-苯基-2-烷基炔或苯基-（氨基烷基）炔作为起始原料。一锅法的一般原理如方案1所示。主要的期望是在碱性条件下，在Ti催化剂[Cp 2 TiMe 2]（Cp= C5 H5）[4]存在下在加氢胺化期间区域选择性地形成的亚胺将与相应的烯胺平衡。此外，苯环中的邻氯取代基应提供通过Pd催化的N-芳基化/环化（Buchwald-Hartwig反应）将烯胺转化为吲哚的可能性。[5]由于烯胺在该环化步骤期间从平衡中除去，因此应该可以将亚胺完全转化为吲哚。然而，据我们所知，相应的N-取代亚胺在碱性条件下，在钯催化剂的存在下的N-芳基化反应还没有报道。[6]To研究了所建议的合成策略的范围，其中包括两个C3 CN键形成步骤，我们从简单的1-氯-2-碘苯和末端炔开始，通过Sonogashira偶联[7]合成了许多邻氯取代的1-苯基-2-烷基炔（1-10，表1）。[2c]然后将可以高产率分离的炔1-10用于一锅法。为此，首先在5摩尔%[Cp 2 TiMe 2]的存在下用任意伯胺将炔氢化胺化。随后，将5摩尔%[Pd 2（dba）3]（dba=二亚苄基丙酮）、10摩尔%氯化1，3-双（2，4，6-三甲基苯基）咪唑鎓和KOtBu直接加入到反应混合物中。在将所得混合物加热至1108 ° C之后，可以以良好的产率分离大部分1，2-、1，2，5-和1，2，6-取代的吲哚11-20 [Eq. (1)，表1]。然而，4和叔丁胺的反应仅以39%的产率得到相应的吲哚14。这一适度的结果是因为[Cp 2 TiMe 2]催化的1-苯基-2-烯基炔的氢胺化的区域选择性比1-苯基-2-烷基炔的区域选择性差。[2b]
Initiated by improved screening methods, a steadily increasing demand for highly flexible synthetic procedures has evolved during the last couple of years. The major purpose of these synthetic methods is the fast generation of various derivatives of a certain class of substances. In the past, we have repeatedly shown that the titanium-catalyzed hydroamination of alkynes [1] is a versatile tool for the highly flexible synthesis of biologically interesting compounds.[2] Expanding these studies, we now present a highly flexible and catalytic one-pot procedure for the synthesis of indoles [3] employing ortho-chloro-substituted 1-phenyl-2-alkyl alkynes or phenyl-(aminoalkyl) alkynes as starting materials. The general principle of the one-pot procedure is shown in Scheme 1. The major expectation is that under basic conditions, the imines, which are regioselectively formed during the hydroamination in the presence of the Ti catalyst [Cp2TiMe2](Cp= C5H5)[4], will be in equilibrium with the corresponding enamines. In addition, an ortho-chloro-substituent in the benzene ring, should offer the possibility to convert the enamines into indoles by a Pd-catalyzed N-arylation/cyclization (Buchwald–Hartwig reaction).[5] Since the enamines are removed from the equilibrium during this cyclization step it should be possible to convert the imines completely into indoles. However, to our knowledge, corresponding N-arylations of N-substituted imines under basic conditions in the presence of Pd-catalysts have not been reported.[6]To investigate the scope of the suggested synthetic strategy, which includes two CÀN bond-forming steps, we synthesized a number of ortho-chloro-substituted 1-phenyl-2-alkyl alkynes (1–10, Table1) by Sonogashira couplings [7] starting from simple 1-chloro-2-iodobenzenes and terminal alkynes.[2c] The alkynes 1–10, which could be isolated in high yields, were then used for the one-pot procedure. For this purpose, the alkynes were first hydroaminated with an arbitrary primary amine in the presence of 5 mol%[Cp2TiMe2]. Subsequently, 5 mol%[Pd2 (dba) 3](dba= dibenzylideneacetone, 10 mol% 1, 3-bis (2, 4, 6-trimethylphenyl) imidazolium chloride, and KOtBu were added directly to the reaction mixture. After heating the resulting mixture to 1108C, most of the 1, 2-, 1, 2, 5-, and 1, 2, 6-substituted indoles 11–20 could be isolated in good yields [Eq.(1), Table1]. However, the reaction of 4 and tert-butylamine gave the corresponding indole 14 in only 39% yield. This modest result is because the regioselectivity of the [Cp2TiMe2]-catalyzed hydroamination of 1-phenyl-2-alkenyl alkynes is worse than that of 1-phenyl-2-alkyl alkynes.[2b]