Indole Synthesis via Palladium-Catalyzed Intramolecular Cyclization of Alkynes and Imines
Indole Synthesis via Palladium-Catalyzed Intramolecular Cyclization of Alkynes and Imines
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DOI：
10.1021/ja000390p
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发表时间：
2000-05
影响因子：
15
通讯作者：
A. Takeda;and Shin Kamijo;Yoshinori Yamamoto
中科院分区：
文献类型：
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作者：
A. Takeda;and Shin Kamijo;Yoshinori Yamamoto
吲哚是多种天然生物碱中最基本的单元之一，开发构建这种结构框架的新方法已引起人们的广泛关注。 1 在使用过渡金属催化剂的方法中，2 钯催化的吲哚环结构已得到广泛研究。 3 以前的方法分为以下三种类型：2-炔基苯胺的分子内环化（方案1中的a），2-卤代-N-烯丙基-3e或乙烯基苯胺的3a-d Heck型环化（b）、3f、g以及2-卤代苯胺和内部炔烃的分子间环加成（c）。 3h-j 因此，在N和C-2之间(a)、C-3和C-芳基之间(b)、以及N和C-2之间以及C-3和C-芳基之间(c)形成吲哚环。我们报道了一种全新的钯催化吲哚合成方法，其中 2-(1-炔基)-N-亚烷基苯胺 1 以良好的产率生成 2-取代的-3-(1-烯基)吲哚 2 (eq 1)。此处，键形成发生在 C-2 和 C-3 之间 (d)。 4 结果总结于表 1 中。当 N-亚苄基-2-(1-戊炔基)苯胺 (1a) 在 1, 4-二恶烷中的 5 mol% 乙酸钯和 20 mol% 三正丁基膦存在下于 100°C 加热 25 小时时，在 1, 4-二恶烷中形成 3-((E)-1-丁烯基)-2-苯基吲哚 (2a) 88% NMR 收率（条目 1）。众所周知，2-或3-烯基吲哚是不稳定的5，实际上一开始我们很难分离出纯形式的2a。然而，我们发现纯 2a 可以用 Al2O3 柱色谱（己烷-AcOEt 50-20/1）分离，产率 58%（条目 1）。 2a 用 H2/Pd-C 氢化得到 3-丁基-2-苯基吲哚，产率 60%，明确证实了 2a 的结构。对硝基苯基取代的底物1b在7小时内顺利反应，得到2b，收率70%。 4-吡啶基1c、2-噻吩基1d和2-(5-甲基呋喃基)衍生物1e分别以良好的产率提供相应的吲哚2c-e（条目3-5）。环己基衍生物1f以良好的收率提供了β,β-二取代的乙烯基吲哚2f。不仅是乙基取代的衍生物，而且官能团取代的1g-i也以中等分离产率得到相应的吲哚2g-i。制备烷基取代的亚胺的尝试因所得亚胺缺乏稳定性而失败。 6 因此，我们尝试从 2-炔基苯胺 3 和环己烷甲醛原位形成亚胺，然后进行环化。该试验进展顺利，并以 52% 的产率获得了 2j（eq 2）。在
Indole is one of the most basic units among a wide variety of naturally occurring alkaloids, and much attention has been paid to developing a new methodology for the construction of this structural framework. 1 Among the approaches employing transition metal catalysts, 2 the palladium-catalyzed ring construction of indole has been investigated widely. 3 The previous methods are categorized under the following three types: the intramolecular cyclization of 2-alkynylanilines (a in Scheme 1), 3a-d Heck-type cyclization of 2-halo-N-allyl-3e or vinylanilines (b), 3f, g and intermolecular cycloaddition of 2-haloanilines and internal alkynes (c). 3h-j Therefore, the indole ring is formed between N and C-2 (a), between C-3 and C-aryl (b), and between N and C-2 and between C-3 and C-aryl (c). We report an entirely new palladiumcatalyzed indole synthesis in which 2-(1-alkynyl)-N-alkylideneanilines 1 give 2-substituted-3-(1-alkenyl) indoles 2 in good yields (eq 1). Here the bond formation takes place between C-2 and C-3 (d). 4 The results are summarized in Table 1. When N-benzylidene-2-(1-pentynyl) aniline (1a) was heated at 100 C for 25 h in the presence of 5 mol% palladium acetate and 20 mol% tri-n-butylphosphine in 1, 4-dioxane, 3-((E)-1-butenyl)-2-phenylindole (2a) was formed in 88% NMR yield (entry 1). It is known that 2-or 3-alkenylindoles are unstable, 5 and actually at the beginning we had difficulty isolating 2a in a pure form. However, we found that pure 2a could be isolated with Al2O3 column chromatography (hexane-AcOEt 50-20/1) in 58% yield (entry 1). The hydrogenation of 2a with H2/Pd-C gave 3-butyl-2-phenylindole in 60% yield, confirming the structure of 2a unambiguously. The p-nitrophenyl-substituted substrate 1b reacted smoothly within 7 h to give 2b in 70% yield. 4-Pyridyl 1c, 2-thienyl 1d, and 2-(5-methylfuryl) derivatives 1e afforded the corresponding indoles 2c-e, respectively, in good yields (entries 3-5). Cyclohexyl derivative 1f afforded the β, β-disubstituted vinylindole 2f in a good yield. Not only ethyl-substituted derivatives but also the functional group-substituted 1g-i gave the corresponding indoles 2g-i in moderate isolated yields. An attempt to prepare alkylsubstituted imines failed because of lack of stability of the resulting imines. 6 Accordingly, we attempted the in situ formation of the imine from the 2-alkynylaniline 3 and cyclohexanecarboxaldehyde followed by subsequent cyclization. This trial proceeded well and 2j was obtained in 52% yield (eq 2). The in