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Hans Journal of Chemical Engineering and Technology
Vol. 12  No. 03 ( 2022 ), Article ID: 51993 , 7 pages
10.12677/HJCET.2022.123027

电化学催化1,4-萘醌的双官能团化反应构建 碘代氨基萘醌化合物

徐雪，何永辉*

云南民族大学民族医药学院，云南 昆明

收稿日期：2022年4月25日；录用日期：2022年5月24日；发布日期：2022年5月31日

摘要

氨基萘醌类化合物是一类具有重要生理活性的杂环化合物，广泛存在于天然产物的结构中。因此，高效构建该类化合物具有重要的意义。本文以碘化钠为媒介，在电化学条件下实现了1,4萘醌的双官能团化反应，以33%~70%的收率得到了8种含不同取代基的碘代氨基萘醌类化合物，并通过自由基捕获实验验证该反应可能涉及自由基机理。

关键词

1,4萘醌，双官能团化，电催化

Synthesis of Iodoaminonaphthoquinone Compounds by Electrochemically Catalyzed Bifunctionalization of 1,4-Naphthoquinone

Xue Xu, Yonghui He*

School of Ethnic Medicine, Yunnan Minzu University, Kunming Yunnan

Received: Apr. 25th, 2022; accepted: May 24th, 2022; published: May 31st, 2022

ABSTRACT

Aminonaphthoquinones widely exist in natural products and have good biological activities. The synthesis of this kind of compounds has always been a hotspot for scientists. In this work, iodoaminonaphthoquinones with different substituents were synthesized by the bifunctionalization of 1,4-naphthoquinone in the medium of sodium iodide under electrochemical conditions. Through oxidation additions, eight iodoaminonaphthoquinones with different substituents were synthesized in 33%~70% yield under the optimal conditions. The free radical capture experiment verified that the reaction may involve the free radical mechanism.

Keywords:1,4-Naphthoquinone, Bifunctionalization, Electrocatalysis

Copyright © 2022 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

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

1. 引言

氨基萘醌类化合物是一类广泛存在于天然产物结构中的杂环化合物，具有重要的生理活性，常常被用来做抗肿瘤剂、抗疟剂和抗菌剂等 [1] - [6]。因此，氨基萘醌类化合物的合成备受关注。传统的合成方法有两种，一是利用胺与醌为反应底物的1,4-加成反应，另一种是卤代醌为底物的亲核取代反应 [7]。最近的研究发现，采用金属催化或分子碘催化均可获得氨基萘醌类化合物，且收率比较好 [7] - [13]。然而，这些方法往往存在反应条件苛刻、使用有毒化学试剂(如单质碘等)并伴随有副反应发生等不足。因此，发展不使用有毒化学试剂(如单质碘)，并在较温和反应条件下能高效发生反应的合成方法，符合绿色化学的要求，对于合成方法学具有十分重要的意义。

由于采用电子为氧化还原试剂、不使用金属催化剂即可使反应发生，电化学催化法一直是研究人员关注的焦点。该方法因不使用金属催化剂，可减少反应后处理带来的环境污染等问题，是一种绿色的合成方法 [14] [15] [16] [17] [18]。至今，电化学催化法在高效构建碳碳键、碳杂键方面的应用比较广泛。比如，李金恒老师课题组成功利用直接电化学方法实现了吩噻嗪类化合物的间位氨化反应，构建了C-N键 [19]。

基于本课组前期研究工作基础，本工作利用碘化钠作为催化剂，采用有机电化学催化合成法，在零度条件下合成了一系列的碘代氨基萘醌类化合物。该反应避免使用分子碘、金属催化剂等，且操作简便，因此是一种很好的构建碘代氨基萘醌类化合物的合成方法。

2. 实验部分

2.1. 主要仪器与试剂

目标产物的1H NMR和13C NMR检测采用产自德国布鲁克公司的核磁共振仪Bruker-400、目标产物的高分辨质谱检测采用产自德国布鲁克公司的高分辨质谱仪Bruker microTOF-Q II，电化学合成所用仪器为产自德国IKA公司的ElectraSyn2.0。

柱分离用硅胶(200~300目)产自青岛海洋化工有限公司，本合成所用的底物(1,4-萘醌、胺)、催化剂(碘化钠、碘化铵、四丁基碘化铵等)、支持电解质(高氯酸锂)、溶剂(乙腈、甲醇、乙醇、DMSO和DMF)均为分析纯，购自北京伊诺凯科技有限公司。

2.2. 实验方法

碘代氨基萘醌类化合物的合成：于25 mL的三颈圆底烧瓶中加入反应底物1,4-萘醌(0.2 mmol, 31.6 mg)，苄胺(0.2 mmol, 21.4 mg)，催化剂碘化钠(0.1 mmol, 14.9 mg)，溶剂乙腈(15 ml)，并加入磁力搅拌子，待混合均匀后，插入10 mm * 10 mm铂片为正极和负极，0度下以10 mA (电压为3.1 V)电流通电4小时。待该电化学催化反应完全后，将所得到的混合物经减压蒸馏后得残余物，然后利用柱层析(石油醚/乙酸乙酯体积比60:1)纯化最后得到目标产物。

2-Iodo-3-(benzylamino)naphthalene-1,4-dione (3a): Yield 62%. Red solid, 1H NMR (CDCl3): δ 8.15 (dd, J = 1.2 Hz, 7.8 Hz 1H), 8.04 (dd, J = 2.0 Hz, J = 7.6 Hz 1H), 7.68 (dt, J = 1.4 Hz, J = 7.6 Hz 1H), 7.64 (dt, J = 2.0 Hz, 8.0 Hz 1H), 7.43~7.32 (m, 5H), 6.24 (brs, 1H), 5.13 (d, J = 5.6 Hz, 2H); 13C NMR (CDCl3): δ 179.1, 178.2 (1C), 151.7, 138.4, 134.9, 132.6, 131.1, 131.0, 129.2, 128.9, 127.9, 128.4, 127.1, 78.0, 51.0; HRMS (ESI-TOF) m/z. Calcd for C17H13INO2 [M + H]+ 389.9985, found 389.9989.

2-Iodo-3-(benzylamino)naphthalene-1,4-dione (3b): Yield 58%. Red solid, 1H NMR (CDCl3): δ 8.05 (d, J = 1.2 Hz, 7.8 Hz 1H), 8.01 (d, J = 2.0 Hz, J = 7.6 Hz 1H), 7.66 (t, J = 1.4 Hz, J = 7.6 Hz 1H), 7.54 (t, J = 2.0 Hz, 8.0 Hz 1H), 7.20 (d, J = 7.8 Hz 2H), 7.12 (d, J = 7.6 Hz 2H), 5.84 (brs, 1H), 4.71 (d, J = 5.6 Hz, 2H); 13C NMR (CDCl3): δ 181.1, 180.2, 161.7, 136.4, 134.9, 132.6, 131.1, 131.0, 129.2, 128.9, 127.9, 128.4, 127.1, 77.6, 46.0, 24.3; HRMS (ESI-TOF) m/z. Calcd for C18H15INO2 [M + H]+ 404.0142, found 404.0151.

2-(4-chlorobenzylamino)-3-iodonaphthalene-1,4-dione (3c): Yield 59%. Red solid, 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 7.8 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 5.868 (s, 1H), 4.62 (d, J = 6.2 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 183.7, 182.3, 145.8, 137.3, 134.2, 133.4, 133.3, 132.0, 130.3, 129.1, 128.1, 126.0, 125.8, 77.9, 48.4; HRMS (ESI-TOF) m/z. Calcd for C17H12ClINO2 [M+H]+ 423.9595, found 423.9590.

2-Iodo-3-(methylamino)naphthalene-1,4-dione (3d): Yield 56%. Red solid; 1H NMR (CDCl3): δ 8.23 (d, J = 7.2 Hz 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.78 (t, J = 7.8 Hz 1H), 7.66 (t, J = 7.2 Hz 1H), 6.18 (brs, 1H), 3.49 (d, J = 6.2 Hz, 3H); 13C NMR (CDCl3): δ 179.9, 177.7, 150.9, 134.9, 132.5, 131.6, 129.9, 127.7, 126.9, 78.2, 42.3; HRMS (ESI-TOF) m/z Calcd for C11H9INO2 [M + H]+ 313.9672, found 313.9664.

2-Iodo-3-(ethylamino)naphthalene-1,4-dione (3e): Yield 69%. Red solid; 1H NMR (CDCl3): δ 8.15 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 7.8 Hz 1H), 7.72 (dt, J = 1.5 Hz, 7.6 Hz 1H), 7.66 (dt, J = 1.5 Hz, 7.5 Hz 1H), 5.99 (brs, 1H), 3.98~3.92 (m, 2H) 1.39 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3): δ 179.9, 177.7, 150.9, 134.9, 132.5, 131.6, 129.9, 127.7, 126.9, 78.2, 41.7, 16.2; HRMS (ESI-TOF) m/z Calcd for C12H11INO2 [M + H]+ 327.9829, found 327.9838.

2-Iodo-3-(propylamino)naphthalene-1,4-dione (3f): Yield 70%. Red solid; 1H NMR (CDCl3): δ 8.17 (dd, J = 1.6 Hz, 8.2 Hz 1H), 8.06 (dd, J = 1.0 Hz, 7.6 Hz 1H), 7.78 (dt, J = 1.0 Hz, 7.6 Hz 1H), 7.68 (dt, J = 1.5 Hz, 7.5 Hz 1H), 6.09 (brs, 1H), 5.89 (q, J = 7.6 Hz, 2H), 1.82~1.70 (m, 2H), 1.051 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3): δ 179.2, 178.8, 151.5, 135.7, 133.6, 131.2, 129.9, 128.5, 127.7, 78.2, 46.6, 247, 11.9; HRMS (ESI-TOF) m/z Calcd for C13H13INO2 [M+H]+ 341.9985, found 341.9981.

2-Iodo-3-(butylamino)naphthalene-1,4-dione (3g): Yield 68%. Red solid; 1H NMR (CDCl3): δ 8.18 (dd, J = 1.5 Hz, 8.0 Hz 1H), 8.06 (dd, J = 1.5 Hz, 8.0 Hz 1H), 7.79 (dt, J = 1.6 Hz, 7.8 Hz 1H), 7.69 (dt, J = 1.5 Hz, 7.6 Hz 1H), 6.21 (brs, 1H), 3.99 (q, J = 6.6 Hz, 2H), 1.78~1.63 (m, 2H), 1.54~1.42 (m, 2H), 1.01 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3): δ 179.9, 177.8, 150.9, 135.5, 133.3, 132.7, 131.8, 129.9, 128.4, 127.3, 78.2, 45.9, 32.9, 19.8, 13.8; HRMS (ESI-TOF) m/z Calcd for C14H15INO2 [M + H]+ 356.0142, found 356.0135.

2-Iodo-3-(hexylamino)naphthalene-1,4-dione (3h): Yield 33%. Red solid; 1H NMR (CDCl3): δ 8.18 (dd, J = 1.2 Hz, 8.2 Hz 1H), 8.09 (dd, J = 1.5 Hz, 7.8 Hz 1H), 7.79 (dt, J = 1.0 Hz, 7.8 Hz 1H), 7.72 (dt, J = 1.6 Hz, 8.2 Hz 1H), 6.08 (brs, 1H), 3.98 (q, J = 6.6 Hz, 2H), 1.77~1.68 (m, 2H), 1.49~1.40 (m, 2H), 1.36~1.32 (m, 4H), 0.93 (t, J = 7.6 Hz, 3H). 13C NMR (CDCl3): δ 180.1, 178.2, 151.8, 135.5, 133.3, 132.1, 131.4, 129.9, 128.3, 127.8, 78.2, 46.7, 32.3, 31.4, 27.9, 23.6, 14.7. HRMS (ESI-TOF) m/z Calcd for C16H19INO2 [M + H]+ 384.0455, found 384.0464.

3. 结果与讨论

3.1. 反应条件的筛选

以0.1 M的碘化钠为本反应的催化剂，以底物1,4-萘醌1 (0.2 mmol)和苄胺2a (0.2 mmol)的反应为模型反应，本工作首先研究了催化剂的用量及类型、溶剂的种类以及电流的大小对该合成碘代氨基萘醌反应产率的影响(表1)。

Table 1. Optimization of reaction conditions

表1. 反应条件的优化

首先，研究了催化剂碘代物对该电催化反应的影响(表1，entries 1~5)。从表1中可知，不用催化剂碘化钠时，该反应几乎不能发生(表1，entries 1)；而使用其它碘代物(如碘化铵、四丁基碘化铵等)均不如利用碘化钠的产率高(表1，entries 2~4)；增加催化碘化钠的用量并不能使反应产率显著提高(表1，entries 5)。接下来，对所用溶剂的种类进行了筛选研究，发现使用其它溶剂(如甲醇、乙醇、DMSO和DMF)均不如乙腈的效果好(表1，entries 6~9)，这可能与高氯酸锂和碘化钠在乙腈溶剂中具有良好的溶解度有关。然后，对本电催化反应所用的电流大小进行了研究。结果表明，当该反应中有电流时，反应几乎不能发生；提高或降低电流(电流为5 mA或15 mA)时，目标产物的产率均有不同程度的降低，表明10 mA电流最合适(表1，entries 10~12)。最后，对该反应所用的时间进行了研究。结果表明，缩短反应时间至2小时时，产率明显降低，而延长反应时间至6小时后，目标产物的产率变化不大。因此，此电催化合成反应的最优反应条件为：以碘化钠为催化剂、乙腈为溶剂、通电电流为10 mA，在零度条件下反应4小时。

3.2. 目标产物的普适性研究

根据上述条件筛选实验得到的最优反应条件(表1，Entries 2)，对该电催化合成碘代氨基萘醌反应的底物普适性进行了研究。结果如表2所示。从表中可以看出，当所用底物苄胺的苯环对位取代基为强吸电子基团或给电子基团，该反应都能发生，并以中等产率得到碘代氨基萘醌类化合物(表2，3b, 3c)；当以烷烃胺为氨源时，也能以较高的产率得到目标产物(表2，3d)；当烷烃链增长为4个碳时，该电催化反应均能以良好的产率得到碘代氨基萘醌类化合物(表2，3e, 3f, 3g)。而当烷烃链进一步增长时，产率明显下降(表2，3h)，可能与反应物在反应溶剂中的溶解度有关。因此，该电催化合成碘代氨基萘醌的反应体系具有较好的底物普适性。

Table 2. Investigation of substrate scope

表2. 底物普适性研究

3.3. 反应机理分析

以1,4-萘醌和苄胺为底物的模型反应作为研究对象，在条件筛选实验中获得的最优反应条件下，对该电催化反应的机理进行了研究。当该电催化合成碘代氨基萘醌的反应中加入自由基捕获剂(0.2 mmol的2,2,6,6-四甲基哌啶氮氧化物)时，该反应明显受到了抑制。参考相关文献 [13]，结合反应条件筛选结果和自由基捕获实验，提出合成碘代氨基萘醌反应的机理(如下图1所示)：首先，碘负离子在阳极铂片表面被氧化成碘自由基，发生自由基消除生成碘单质，碘单质活化1,4-萘醌。然后苄胺进攻活化的1,4-萘醌，并同时实现碘化反应，得到中间体B。中间体B进一步氧化脱氢得到目标化合物碘代氨基萘醌3a。同时，质子在负极得电子还原得氢气。

Figure 1. Plausible mechanism for synthesis of compound 3a

图1. 合成化合物3a可能的反应机理

4. 结论

采用碘化钠为催化剂的电催化1,4-萘醌的双官能团化反应，在零度条件下实现了构建了碘代氨基萘醌类化合物。该电催化合成碘代氨基萘醌的反应具有操作简便、反应底物氨的普适性较好等优点，在毕竟温和的反应条件下以中等收率获得了一系列的碘代氨基萘醌类化合物。该反应避免使用有毒试剂如单质碘等，且副产物为氢气，绿色环保。

文章引用

徐 雪,何永辉. 电化学催化1,4-萘醌的双官能团化反应构建碘代氨基萘醌化合物
Synthesis of Iodoaminonaphthoquinone Compounds by Electrochemically Catalyzed Bifunctionalization of 1,4-Naphthoquinone[J]. 化学工程与技术, 2022, 12(03): 194-200. https://doi.org/10.12677/HJCET.2022.123027

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    20. NOTES

    *通讯作者。

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