电化学条件下磺酰肼与烯醇硅醚自由基偶联反应合成β-羰基砜化合物
Synthesis of β-Carbonyl Sulfone Compounds by the Free Radical Coupling Reaction of Sulfonyl Hydrazide and Enol Silyl Ether under Electrochemical Conditions

作者: 王杨丽 , 周 烨 , 曾东文 , 何永辉 :云南民族大学,民族医药学院,云南 昆明;

关键词: β-羰基砜电催化自由基偶联反应β-Carbonyl Sulfone Electrocatalysis Radical Coupling Reaction

摘要: β-羰基砜是一类重要的有机合成砌块,合成该类化合物一直是研究热点。本文以四丁基碘化铵为媒介,在电化学条件下实现烯醇硅醚与各种取代的磺酰肼发生自由基磺酰化反应,经自由基加成和氧化,在最优条件下以55%~76%的收率合成了8种具有不同取代基的β-羰基砜类化合物。采用核磁共振和质谱等手段对产物结构进行表征,并提出了可能的反应机理。

Abstract: β-carbonyl sulfone is a kind of important organic synthesis block, and the synthesis of this kind of compounds has been a research hotspot. In this paper, β-carbonyl sulfones with different substi-tuents were synthesized by the free radical sulfonation of enol silyl ethers with various substituted sulfonyl hydrazides in the medium of tetrabutylammonium iodide under electrochemical conditions. Through radical addition and oxidation, eight β-carbonyl sulfones with different subs-tituents were synthesized in 55%~76% yield under the optimal conditions. The products were characterized by NMR and MS, and the possible reaction mechanism was proposed.

1. 引言

砜基化合物具有广谱生物活性,包括抗菌、抗炎和抗肿瘤等 [1]。此外,砜基化合物还被广泛用于除虫、除草等农药应用领域 [2]。β-羰基砜是一类重要的有机合成砌块,被广泛用于制备不饱和化合物炔烃和烯烃、多官能化的4H-吡喃化合物和光学活性的β-羟基砜等产物 [3] [4] [5] [6]。因此,β-羰基砜类化合物的合成备受关注,常见的合成方法为采用磺酰自由基和烯烃的分子间加成来实现。磺酰自由基的来源包括亚砜、亚磺酸、磺酰肼、磺酰氯化物和磺酰叠氮化合物等 [7] - [15]。最近,以烯醇硅醚为自由基受体的磺酰自由基加成反应也被应用于β-羰基砜化合物的合成 [16]。然而,这些方法往往存在反应条件比较苛刻、产率不够高以及存在一些副反应等不足。因此,发展反应条件温和、操作更加简便和更高选择性的绿色合成方法具有十分重要的意义。

电化学催化法用电子作为氧化还原试剂,避免使用金属催化剂,减少了合成反应后处理带来的环境污染等问题,符合绿色化学发展的需要,受到广泛的关注 [17] [18]。至今,电化学催化法已被广泛应用于C-C、C-O、C-N和C-S键的构建。例如,通过电化学氧化磺酰肼的N-S键断裂生成磺酰自由基,黄精美教授课题组成功构建了C-S键。

在前期研究工作的基础上,本文以四丁基碘化铵为催化剂,采用电化学催化法,使磺酰肼与烯醇硅醚发生自由基偶联反应,在室温条件下合成了一系列的β-羰基砜化合物。该反应具有反应条件温和、操作简便和避免使用有毒催化剂等优点,更加绿色环保。

2. 实验部分

2.1. 主要仪器与试剂

Bruker-400型核磁共振仪(CDCl3为溶剂,TMS为内标)、BrukermicroTOF-Q II型高分辨质谱仪(国布鲁克公司),电化学合成仪ElectraSyn2.0 (德国IKA)。

柱分离用200~300目硅胶、溶剂和试剂均为市售分析纯;乙腈(分析纯,南京化学试剂股份有限公司);试验所用苯乙酮、碘化钠、三乙胺、三甲基氯硅烷、磺酰肼和四丁基碘化铵均购自北京伊诺凯科技有限公司。

2.2. 实验方法

烯醇硅醚类化合物的合成:在50 mL充满氩气的三口烧瓶中加入10 mmol苯乙酮类化合物、15 mmol (4.5 g)碘化钠和10 mL干燥的乙腈,室温下搅拌反应5 min;加入15 mmol (4.2 mL)三乙胺和15 mmol (3.82 mL)三甲基氯硅烷,于40℃搅拌反应12 h;用薄层色谱法(TLC)监测反应到完全后,加入50 mL冰水淬灭反应。随后加入正戊烷(15 mL × 3)进行萃取;合并有机相,用饱和食盐水洗涤、硫酸镁干燥,经柱层析分离(石油醚/乙酸乙酯体积比30:1),得到烯醇硅醚类化合物。

β-羰基砜类化合物的合成:于25 mL的三颈圆底烧瓶中加入38.5 mg烯醇硅醚1 (0.2 mmol),37.2 mg磺酰肼2 (0.2 mmol),36.9 mg四丁基碘化铵(0.1 mmol),15 ml乙腈,混合均匀,15 mm * 15 mm铂片为正极和负极,室温下以9 mA电流通电5小时。反应完全后,混合物减压脱溶,得残余物,柱层析(石油醚/乙酸乙酯体积比60:1)纯化得到产物。

1-phenyl-2-tosylethan-1-one (3aa): white solid; 1H NMR (400 MHz, CDCl3) δ: 7.95 (d, J = 7.6 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 4.70 (s, 2H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 188.0, 145.1, 135.5, 135.4, 134.1, 129.5, 129.1, 128.6, 128.4, 63.4, 21.4; HRMS m/z (ESI) calcd for C15H15O3S (M+H)+ 275.3414, found 275.3423.

1-(p-tolyl)-2-tosylethan-1-one (3ab): white solid; 1H NMR (400 MHz, CDCl3) δ: 7.84 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 4.66 (s, 2H), 2.43 (s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ:187.2, 145.2, 145.0, 135.5, 133.0, 129.4, 129.2, 129.1, 128.2, 63.2, 21.4, 21.2; HRMS m/z (ESI) calcd for C16H17O3S (M+H)+ 289.3684, found 289.3692.

1-(4-fluorophenyl)-2-tosylethan-1-one (3ac): white solid; 1H NMR (400 MHz, CDCl3) δ: 8.01-7.97 (m, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.17-7.11 (m, 2H), 4.65 (s, 2H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 186.3, 166.2 (d, J = 256.2 Hz), 145.3, 135.4, 132.0 (d, J = 2.4 Hz), 131.9, 129.6, 128.3, 116.0(d,J =22.4 Hz), 63.5, 21.4; HRMS m/z (ESI) calcd for C15H14O3S (M+H)+ 293.0642, found 293.0638.

1-(naphthalen-2-yl)-2-tosylethan-1-one (3ad): white solid; 1H NMR (400 MHz, CDCl3) δ: 8.40 (s, 1H), 8.00-7.92 (m, 2H), 7.88-7.81 (m, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.62-7.48 (m, 2H), 7.25 (d, J = 7.6 Hz, 2H), 4.81 (s, 2H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 188.0, 145.1, 135.5, 135.3, 133.0, 132.0, 132.0, 129.7, 129.5, 129.0, 128.5, 128.2, 127.4, 127.0, 123.6, 63.4, 21.4; HRMS m/z (ESI) calcd for C19H17O3S (M+H)+325.0893, found 325.0884.

1-m-tolyl-2-tosylethanone (3af): white solid;1H NMR (400 MHz, CDCl3) δ: 7.75-7.73 (m, 2H), 7.71-7.65 (m, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.31 (dd, J = 17.5, 7.6 Hz, 3H), 4. 68 (s, 2H), 2. 41 (s, 3H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 188.0, 145.1, 138.6, 135.6, 135.6, 135.0, 129.5, 129.3, 128.5, 128.4, 126.4, 63.3, 21.5, 21.1; HRMS m/z (ESI) calcd for C16H17O3S (M+H)+ 289.0892, found 289.0883.

2-((4-methoxyphenyl)sulfonyl)-1-phenylethan-1-one (3ba): white solid; 1H NMR (400 MHz, CDCl3) δ: 7.94 (dd, J = 8.0, 1.1 Hz, 2H), 7.81-7.75 (m, 2H), 7.63-7.56 (m, 1H), 7.50-7.45 (m, 2H), 7.00-6.92 (m, 2H), 4.68 (s, 2H), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 187.5, 163.4, 135.1, 133.5, 130.1, 129.5, 128.6, 128.1, 114.0, 63.2, 55.3; HRMS m/z (ESI) calcd for C15H15O4S (M+H)+ 291.0685, found 291.0693.

1-phenyl-2-((4-(trifluoromethyl)phenyl)sulfonyl)ethan-1-one (3bb): white solid; 1H NMR (400 MHz, CDCl3) δ: 8.03 (d, J = 8.0 Hz, 2H), 7.90 (dd, J = 8.0, 1.2 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.65-7.60 (m, 1H), 7.46 (t, J = 8.0 Hz, 2H), 4.76 (s, 2H); 13C NMR (100 MHz, CDCl3) δ:187.3, 141.5, 135.5, 135.0 (d, J = 15.8Hz), 134.0 129.0 129.0, 128.6 126.6 (q, J = 3.0 Hz), 123.0 (q, J = 268.0 Hz), 62.6; HRMS m/z (ESI) calcd for C15H12F3O3S (M+H)+ 329.0453, found 329.0460.

1-phenyl-2-(m-tolylsulfonyl)ethanone (3bc): white solid; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.6 Hz, 2H), 7.67 (s, 2H), 7.60 (t, J= 7.6 Hz, 1H), 7.45-7.41 (m, 4H), 4.71 (s, 2H), 2.42 (s, 3H);13C NMR (100 MHz, CDCl3) δ: 188.1, 139.5, 138.4,135.6, 135.1, 134.1, 129.0, 129.0, 128.7, 128.6, 125.5, 63.5, 21.2; HRMS m/z (ESI) calcd for C15H15O3S (M+H)+ 275.0736, found 275.0732.

3. 结果与讨论

3.1. 反应条件的筛选

以烯醇硅醚1a (0.2 mmol)和磺酰肼2a (0.2 mmol)为底物,以四丁基碘化铵(0.1 mmol)为催化媒介的反应为模型,我们探讨了催化媒介的类型、溶剂的种类、电流的大小以及反应温度对模型反应产率的影响(表1)。

首先探讨催化媒介对反应的影响(表1,entries 1~4)。从表中可以看出,无催化媒介条件下不能发生反应;使用碘化铵、溴化铵均不如四丁基碘化铵的产率高;增加催化媒介的量不能提高反应产率。对溶剂进行了筛选,发现溶剂甲醇、乙醇和DMSO均会使产率有所下降(表1,entries 5~7),这可能与碘化铵的溶解度有关。随后对电流进行筛选,研究表明没有电流时,反应不能发生;电流为8 mA和12 mA时,产率均有所下降,说明10 mA电流为最合适的电流(表1,entries 8~10)。最后,对反应温度进行了考察(表1,entries 11~13),结果表明提高或降低反应温度不能使产率提高。因此,此反应的最优反应条件为:以四丁基碘化铵为媒介、乙腈为溶剂、10 mA电流,室温下反应5小时。

Table 1. Optimization of reaction conditions

表1. 反应条件的优化

3.2. 目标产物的普适性研究

根据上述建立的最优反应条件(表1,entries 2),得到了中等产率的目标化合物。我们对该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,烯醇硅醚的苯环对位上无论带有强吸电子基团还是给电子基团,都能很好的发生反应,以中等产率得到目标化合物(表2,entries 1~3);而在邻位有给电子基团时,也能很好的发生反应(表2,entries 4);但在邻位有吸电子基团时,反应难以发生(表2,entries 5)。此外,在磺酰肼的苯环对位无论是吸电子基还是给电子基,反应均能较好的发生(表2,entries 7~8)。同时,在间位为甲基时,以中等产率得到目标产物(表2,entries 6, 9)。因此,该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

以模型反应为研究对象,在最优反应条件下对反应机理进行探讨。当反应中加入0.2 mmol自由基抑制剂2, 2, 6, 6-四甲基哌啶氮氧化物时,反应受到抑制。参考文献16,提出如下图1所示的反应机理:电化学条件下,碘负离子在阳极被氧化成碘自由基,该自由基进攻磺酰肼,导致磺酰肼脱氢,并进一步脱氮气,生成磺酰自由基。然后,磺酰自由基进攻烯基硅醇的末羰双键,生成自由基中间体,经单电子转移并脱氢和脱三甲基碘硅烷后得到目标化合物3。

Figure 1. Plausible mechanism for synthesis of compound 3

图1. 合成化合物3可能的反应机理

4. 结论

采用碘盐媒介的电化学催化磺酰肼活化得到磺酰基,在室温下实现了烯醇硅醚和磺酰肼的自由基偶联反应合成β-羰基砜化合物。该反应条件简单,底物的普适性较好,在温和的条件下以中等收率获得了一系列的β-羰基砜化合物。该反应避免使用金属、碘等,且副产物为氮气和氢气,绿色环保。

NOTES

*通讯作者。

文章引用: 王杨丽 , 周 烨 , 曾东文 , 何永辉 (2021) 电化学条件下磺酰肼与烯醇硅醚自由基偶联反应合成β-羰基砜化合物。 合成化学研究, 9, 1-7. doi: 10.12677/SSC.2021.91001

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