Journal of Organic Chemistry Research
Vol. 07  No. 04 ( 2019 ), Article ID: 33480 , 6 pages
10.12677/JOCR.2019.74014

HMA Catalyzed Friedel-Crafts Reaction of Indole and 1-Vinylpyrrolidin-2-One at Ambient Temperature

Jianpeng Li, Shiqi Zhang, Tianming Gao, Yongfei Zhang, Yun Wang, Jialiang Xia, Bing Han, Yonghai Hui*

Key Laboratory of Clean Energy Materials Chemistry of Guangdong Higher Education Institute, College of Chemistry and Chemical Engineering, Lingnan Normal University, Zhanjiang Guangdong

Received: Nov. 25th, 2019; accepted: Dec. 10th, 2019; published: Dec. 17th, 2019

ABSTRACT

Heteropoly acid (HMA and HWA) catalyst was found to be a highly efficient catalyst for the rapid and convenient synthesis of Friedel-Crafts alkylations through indoles and 1-vinylpyrrolidin-2- one in water at room temperature, and the reaction proceeded smoothly with good results under the catalysis of HMA (up to 98% yield). All the corresponding products were characterized by NMR. The approach exhibits the advantages of simple operation and mild reaction conditions, which provides a convenient method for the formation of carbon-carbon band in organic synthesis.

Keywords:Heteropoly Acid, Indole, Enamides, Friedel-Crafts Reaction

磷钼酸室温催化吲哚与1-乙烯基吡咯烷-2-酮的傅克反应研究

李建鹏,张世奇,高天明,张永飞,王赟,夏加亮,韩冰,惠永海*

岭南师范学院化学化工学院,清洁能源材料化学广东普通高校重点实验室,广东 湛江

收稿日期:2019年11月25日;录用日期:2019年12月10日;发布日期:2019年12月17日

摘 要

以杂多酸(磷钼酸和磷钨酸)为催化剂,在水相中对吲哚和1-乙烯基吡咯烷-2-酮进行了Friedel-Crafts反应的催化研究。经过条件筛选,发现在室温下磷钼酸能够更有利于使反应进行,产率可达98%。所有目标产物通过NMR进行了结构表征。该方法具有操作简单和反应条件温和等优点,为碳碳键的形成提供了便捷的方法。

关键词 :杂多酸,吲哚,烯酰胺,傅克反应

Copyright © 2019 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

1. 引言

吲哚的烃基化傅克反应是构成碳–碳键的重要反应之一 [1],构成的吲哚单元结构广泛存在于天然产物和药物分子中,并且许多吲哚衍生物具有重要的生物活性和药理活性。 [2] 烯酰胺也存在于药理活性试剂和天然产物中,目前被广泛用于药物分子结构设计中,如,脑血管病药物Nefiracetam [3] 和治疗癫痫药物Levetiracetam [4] 等。为了设计出较高活性的有机分子,研究者将吲哚单元和烯酰胺环引入到同一个化合物结构中,如,Nefiracetam [5]、Almotriptan [6] 和Melatonin [7] 等药物分子均有两个特征片段。最近几年,人们发现碘 [8]、路易斯酸 [9] [10] [11] [12] 和布朗斯特酸 [13] [14] [15] 等催化剂能够很好地催化吲哚与烯酰胺的反应。但在后续的研究中,寻找简单易得和原子经济型的催化剂依然是人们追求的目标。

杂多酸(HPA)是由杂原子(如P、Si、Fe和Co等)和多原子(如Mo、W和V等)按一定结构通过氧原子配位桥联的含氧多酸,是一种双功能绿色催化剂。本课题组前期报道过杂多酸催化Friedel-Crafts反应 [16]、Mannich反应 [17]、迈克加成反应 [18] 和缩合反应 [19] 等,并取得了很好的结果。在这里,我们以杂多酸为催化剂,在水相室温条件下高效催化了吲哚与1-乙烯基吡咯烷-2-酮的傅克反应,高效地合成了一系列吲哚酰胺类衍生物,最高产率可达98% (图1)。

Figure 1. The Friedel-Crafts reaction of Indole and 1-Vinylpyrrolidin -2-one

图1. 吲哚与1-乙烯基吡咯烷-2-酮的傅克反应

2. 实验部分

2.1. 试剂与仪器

Varian inova-400型核磁共振仪(TMS为内标,CDCl3为溶剂,单位为ppm);RV10型旋转蒸发仪;X-4数字显示显微熔点测定仪;ZF-2型三用紫外仪;柱层析用硅胶(200~300目,青岛海洋化工厂);所用试剂及溶剂均从Adamas-Beta试剂公司订售,用前未经处理。

2.2. 目标化合物3a-3m的合成结构分析

目标化合物的合成(以1a的合成为例):将吲哚(0.1 mmol,11.7 mg)、1-乙烯基吡咯烷-2-酮(0.1 mmol,11.1 mg)和磷钼酸(0.005 g)溶于水(0.5 mL)中,室温搅拌4 h,TLC检测反应。反应完毕后,柱层析(乙酸乙酯:石油醚 = 1:5洗涤)分离纯化得目标产物。目标化合物的表征如下:

3a [8] :1-(1-(1H-吲哚-3-基)乙基)吡咯烷-2-酮,白色固体,m.p.165~167℃;1H NMR (400 MHz,CDCl3) d:8.26 (s,1H),7.63 (d,J = 8.0 Hz,1H),7.37 (d,J = 8.0 Hz,1H),7.22~7.18 (m,1H),7.13~7.10 (m,2H),5.78 (dd,J = 20.0,4.0 Hz,1H),3.31~3.25 (m,1H),2.90~2.86 (m,1H),2.44~2.42 (m,2H),1.93~1.88 (m,1H),1.84~1.79 (m,1H),1.60 (d,J = 8.0 Hz,3H)。

3b [8] :1-(1-(1-甲基-1H-吲哚-3-基)乙基)吡咯烷-2-酮,黄色油状物;1H NMR (400 MHz,CDCl3) d: 7.63~7.60 (m,1H),7.32~7.17 (m,2H),7.12~7.08 (m,1H),6.97 (d,J = 0.8 Hz,1H),5.79~5.74 (m,1H),3.77 (s,3H),3.29~3.21 (m,1H),2.92~2.86 (m,1H),2.45~2.40 (m,2H),1.93~1.70 (m,2H),1.58 (d,J = 7.0 Hz,3H)。

3c [12] :1-(1-(1-苄基-1H-吲哚-3-基)乙基)吡咯烷-2-酮,无色油状物,1H NMR (400 MHz,CDCl3) d:7.64 (d,J = 7.9 Hz,1H),7.34~7.30 (m,1H),7.31~7.27 (m,2H),7.26 (q,J = 2.3 Hz,1H),7.24 (s,1H),7.21~7.16 (m,1H),7.10 (tdd,J = 4.9,3.8,1.1 Hz,3H),7.04 (d,J = 0.6 Hz,1H),5.80 (q,J = 6.9 Hz,1H),5.30 (s,2H),3.31~3.23 (m,1H),2.89 (td,J = 9.0,5.6 Hz,1H),2.48~2.41 (m,2H),1.97~1.76 (m,2H),1.58 (d,J = 7.0 Hz,3H)。

3d [8] :1-(1-(2-甲基-1H-吲哚-3-基)乙基)吡咯烷-2-酮,白色固体,m.p.175~176℃;1H NMR (400 MHz,CDCl3) d:8.11 (s,1H),7.70 (dd,J = 7.1,1.2 Hz,1H),7.30~7.26 (m,1H),7.16~7.02 (m,2H),5.75 (q,J = 7.3 Hz,1H),3.59~3.50 (m,1H),3.18~3.07 (m,1H),2.48 (s,3H),2.43~2.31 (m,2H),1.98~1.78 (m,2H),1.72 (d,J = 7.3 Hz,3H)。

3e [14] :1-(1-(5-氯-1H-吲哚-3-基)乙基)吡咯烷-2-酮,白色固体,158~159℃,1H NMR (400 MHz,CDCl3) d:8.28 (s,1H),7.30~7.27 (m,1H),7.27 (s,1H),7.17 (s,1H),6.94 (td,J = 9.0,2.5 Hz,1H),5.73~5.66 (m,1H),3.27 (dd,J = 8.4,5.8 Hz,1H),2.90~2.84 (m,1H),2.46 (t,J = 8.0 Hz,2H),1.91 (dd,J = 7.7,5.1 Hz,1H),1.86~1.79 (m,1H),1.58 (d,J = 7.0 Hz,3H)。

3f [12] :1-(1-(6-硝基-1H-吲哚-3-基)乙基)吡咯烷-2-酮,白色固体,m.p.249~251℃;1H NMR (400 MHz,DMSO) d:11.80 (s,1H),8.31 (d,J = 1.9 Hz,1H),7.88 (dd,J = 8.8,2.1 Hz,1H),7.80 (d,J = 2.5 Hz,1H),7.59 (d,J = 8.8 Hz,1H),5.56 (q,J = 7.1 Hz,1H),3.31~3.26 (m,1H),2.71 (td,J = 8.9,5.6 Hz,1H),2.35~2.15 (m,2H),1.90~1.60 (m,2H),1.54 (d,J = 7.1 Hz,3H)。

3g [10] :1-(1-(7-甲基-1H-吲哚-3-基)乙基)吡咯烷-2-酮,白色固体,m.p.167~169℃;1H NMR (400 MHz,CDCl3) d:8.06 (s,1H),7.48 (dd,J = 7.0,2.0 Hz,1H),7.13 (s,1H),7.06~7.00 (m,2H),5.76 (t,J = 6.8 Hz,1H),3.30~3.22 (m,1H),2.90~2.81 (m,1H),2.49 (s,3H),2.47~2.42 (m,2H),1.96~1.87 (m,2H),1.79 (ddd,J = 13.0,7.6,5.1 Hz,1H),1.60 (d,J = 7.0 Hz,3H)。

3. 结果与讨论

3.1. 反应条件的优化

以吲哚和1-乙烯基吡咯烷-2-酮的反应进行反应条件优化,水作为溶剂,室温条件下反应(表1)。首先进行催化剂种类筛选,在无催化剂条件下,反应无产物生成;当使用杂多酸磷钨酸(PWA)和磷钼酸(PMA)为催化剂时,反应能顺利进行,其中磷钼酸催化效果较好,反应能够得到98%的产率。同时,发现使用磷钨酸催化反应时,反应4 h就能得到98%产率的目标产物。最后考察了催化剂用量对反应产率的影响,结果显示,减少催化剂用量对反应产率影响较大(0.0025 g磷钨酸催化反应,产率下降到76%);当增加催化剂用量时,反应产率保持不变。确定的最佳反应条件为:吲哚(0.1 mmol)、1-乙烯基吡咯烷-2-酮(0.1 mmol)及PMA (0.005 g)在水(0.5 mL)中室温反应4 h。

Table 1. Different condition effect on the reaction

表1. 不同反应条件的优化a

a反应条件:吲哚(0.1 mmol),1-乙烯基吡咯烷-2-酮(0.1 mmol),PMA (0.005 g)在水(0.5 mL)中室温反应。b柱层析产率。c1.0 mL水。

3.2. 反应底物的扩展

在最优条件下研究了不同取代基吲哚与1-乙烯基吡咯烷-2-酮的傅克反应(表2)。在吲哚结构中的苯环上R取代基不论是供电子还是吸电子取代基,反应都能顺利进行,并得到很高的产率(Entries 1-7)。当R为供电子基时,如-CH3,反应均能得到90%以上的产率(Entries 4和7);当R是吸电子取代基(如,-NO2)时,反应可以得到76%的产率(Entry 6)。当吲哚N原子上的氢被烃基(如,-CH3和-CH2Ph)取代后,反应依然能够得到96%以上的产率(Entries 2和3)。最后,对反应放大量实验进行了研究,所有反应底物均放大到克级,反应产率可以保持95% (entry8)。

Table 2. Friedel-Crafts reaction by PMA

表2. 磷钼酸催化傅克反应a

a反应条件:吲哚(0.1 mmol),1-乙烯基吡咯烷-2-酮(0.1 mmol),PMA (0.005 g)在水(0.5 mL)中室温反应。b柱层析产率。c反应规模扩大100倍。

3.3. 反应机理

吲哚与1-乙烯基吡咯烷-2-酮的Friedel-Crafts反应可能机理如图2所示。根据文献 [14] 可以认为,1-乙烯基吡咯烷-2-酮在磷钼酸存在下形成质子化亚胺离子中间体,然后,吲哚与此亚胺离子中间体进行亲核加成得到最终产物。

Figure 2. Proposed reaction mechanism for the reaction

图2. 反应可能的机理

4. 结论

本文利用杂多酸(磷钼酸)作为催化剂,水相中室温下能够有效地催化吲哚和1-乙烯基吡咯烷-2-酮的Friedel-Crafts反应,最高产率可达98%。反应具有操作简单,条件温和,产物收率高等优点。

致谢

岭南师范学院人才专项基金(No. ZL1908)。

文章引用

李建鹏,张世奇,高天明,张永飞,王 赟,夏加亮,韩 冰,惠永海. 磷钼酸室温催化吲哚与1-乙烯基吡咯烷-2-酮的傅克反应研究
HMA Catalyzed Friedel-Crafts Reaction of Indole and 1-Vinylpyrrolidin-2-One at Ambient Temperature[J]. 有机化学研究, 2019, 07(04): 103-108. https://doi.org/10.12677/JOCR.2019.74014

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  20. NOTES

    *通讯作者。

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