CN108047128B - 一种合成(e)-2-甲基-4-苯基-6-苯乙烯基取代吡啶化合物的方法 - Google Patents

一种合成(e)-2-甲基-4-苯基-6-苯乙烯基取代吡啶化合物的方法 Download PDF

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CN108047128B
CN108047128B CN201711398046.3A CN201711398046A CN108047128B CN 108047128 B CN108047128 B CN 108047128B CN 201711398046 A CN201711398046 A CN 201711398046A CN 108047128 B CN108047128 B CN 108047128B
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刘建明
岳园园
赵淑芳
闫旭洋
王智贤
王智玥
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Abstract

本发明公开了一种合成(E)‑2‑甲基‑4‑苯基‑6‑苯乙烯基取代吡啶化合物的方法，属于有机化学技术领域。以(2E,3E)‑4‑苯基丁‑3‑烯‑2‑酮‑O‑乙酰肟类化合物为原料，在亚硫酸氢钠和溴化亚铜存在下，反应溶剂中加热反应得到(E)‑2‑甲基‑4‑苯基‑6‑苯乙烯基取代吡啶化合物。本发明利用两分子(2E,3E)‑4‑苯基丁‑3‑烯‑2‑酮‑O‑乙酰肟，一步反应即可构建功能性多取代吡啶类化合物，反应收率高，底物适用范围广泛。

Description

一种合成(E)-2-甲基-4-苯基-6-苯乙烯基取代吡啶化合物的 方法
技术领域
本发明属于有机合成技术领域，具体涉及一种合成(E)-2-甲基-4-苯基-6-苯乙烯基取代吡啶化合物的方法。
背景技术
吡啶作为一种重要的含氮杂环，存在于多种重要的化合物中，包括吖嗪、维生素烟酸、吡哆醇。它不仅是化学品和药物的前体，也是重要的助染剂和变性剂。吡啶衍生物是众多化合物的母体或片段结构，其构成了天然产物、功能材料、药物化学中的一类重要组成部分。正是由于其在各领域中的潜在应用前景，从而引起了科学家的重视与关注，并对此进行了大量研究，取得了众多有价值的科研成果。
吡啶衍生物的合成，尤其是取代的吡啶化合物，通常采用传统的交叉偶联反应，如金属催化的吡啶卤化物的反应，现有技术中已有诸多相关报道。传统的方法或工艺中均或多或少的存在诸多缺陷，例如：(1)采用昂贵的金属有机试剂、特殊的膦配体等，成本高昂，不利于工业化生产；(2)需要高温、多步反应，条件苛刻，限制了反应的实际应用；(3)产率、选择性仍不够高，有待进一步改进等等。因此，对于开发一种采用廉价催化剂、操作简便、成本低、收率高的取代吡啶衍生物的合成工艺，成为广大科研工作者的目标所在，其不但具有迫切的研究价值，也具有良好的经济效益和工业应用潜力。
发明内容
为了克服上述所指出的诸多缺陷，进而寻求合成取代吡啶化合物的简便方法，本发明公开了一种简单、有效、便捷合成(E)-2-甲基-4-苯基-6-苯乙烯基取代吡啶化合物的方法。从简单易得的试剂出发，经由简便的操作步骤，在温和的反应条件下，经过一步反应即可得到(E)-2-甲基-4-苯基-6-苯乙烯基取代的吡啶化合物的方法，避免了传统合成方法原料复杂、条件苛刻等弊端，成功合成了多官能化吡啶。
一种合成(E)-2-甲基-4-苯基-6-苯乙烯基取代吡啶化合物的方法，本发明采用的技术方案，其特征在于，包括以下操作：将(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟1、在铜催化剂和亚硫酸氢钠存在下，有机溶剂中加热反应得到(E)-2-甲基-4-苯基-6-苯乙烯基取代吡啶化合物2。
Figure BDA0001518938230000021
其中：
Ar选自苯基、4-甲基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-叔丁基苯基、2,4-二甲基苯基、3,4-二甲基苯基、2,4,6-三甲基苯基、3-甲基苯基、3-甲氧基苯基，3-氟苯基、3-氯苯基、2-甲氧基苯基，2-氟苯基、2-氯苯基、联苯基、噻吩基、苯并噻吩基、呋喃基、苯并呋喃基。
进一步地，所述铜催化剂为溴化亚铜。所述加热反应时，温度控制在60-150℃，优选80-120℃。
进一步地，所述反应溶剂选自1,4-二氧六环、甲苯、氯苯、乙腈、THF、DMAC、DMF或NMP；进一步地，在使用1-4当量的亚硫酸氢钠做为还原剂时，反应能达到很好的促进效果。
进一步地，反应在惰性气体保护下进行，优选氮气保护。
进一步地，为了更好的理解本发明，以Ar＝苯基为底物进行条件优化为例：在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟1、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA(恒温磁力搅拌器)中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2,收率68％，改变其它反应条件时，结果如下：
Figure BDA0001518938230000031
在上述反应中，改变反应条件时，结果如下：
1)将溴化亚铜的量更换至0.015mmol和0.06mmol时，分离收率分别为39％和52％。
2)将亚硫酸氢钠的量更换至0.6mmol和1.2mmol时，分离收率分别为45％和57％。采用亚硫酸钠替换亚硫酸氢钠时，没有检测到反应产物。
3)采用氯化亚铜、碘化亚铜、溴化铜、醋酸铜、乙酰丙酮铜或溴化亚铜体系时，分离收率分别为45％、46％、52％、30％、47％、68％。
4)采用其它反应溶剂，如甲苯、氯苯、乙腈、1,4-二氧六环、THF、DMAC、DMF或NMP时，产率分别为45％、59％、43％、68％、54％、47％、55％、29％。
5)反应温度为80℃、90℃、120℃、130℃时，反应收率分别对应为40％，64％，41％和45％。
为了进一步理解反应机理，做了如下对比试验：
Figure BDA0001518938230000041
推测反应机理如下：
Figure BDA0001518938230000042
一分子反应物(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟化合物在铜催化剂的条件下，N-O键断裂形成氮自由基，含氮自由基前体进攻另一分子的不饱和键受体，然后通过还原消除，氧化加成得到目标产物。
发明有益效果：
1)本发明方法实验步骤少，技术难度低，条件温和，易于操作。本发明方法避免了使用多步反应的过程，反应一步即可完成。
2)本发明实现了一种反应物既可以做自由基前体，又可以做自由基受体，解决了含氮自由基进攻不饱和键的环加成选择性加成。
具体实施例：
通过以下实例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下实例，凡基于本发明上述内容实现的技术均属于本发明的范围。
本实施例1-9研究了多种苯环被吸电子基和供电子基取代，以及萘和杂环取代的(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟化合物自身偶联反应。
根据以上实验可以发现，该反应对苯环的烷基、甲氧基、氟代、氯代、溴代等取代基以及杂环均有广泛的底物适应性，得到了较高产率的对应目标产物。
代表性反应过程操作如下：
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟化合物1、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA(恒温磁力搅拌器)中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2a-2i。反应方程式如下：
Figure BDA0001518938230000051
Figure BDA0001518938230000061
续表
Figure BDA0001518938230000071
实施例1：(E)-2-甲基-4-苯基-6-苯乙烯基吡啶2a
Figure BDA0001518938230000072
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟类化合物1a、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2a(68％)。该化合物的表征数据如下：1H NMR(600MHz,CDCl3)：7.65(dd,J＝12.0,6.0Hz,3H),7.60(d,J＝6.0Hz,2H),7.49(t,J＝9.0Hz,2H),7.43(t,J＝6.0Hz,2H),7.37(t,J＝6.0Hz,2H),7.29(t,J＝6.0Hz,1H),7.24(dd,J＝12.0,6.0Hz,2H),2.65(s,3H)；13C NMR(101MHz,CDCl3)：158.8,155.7,149.3,138.7,136.8,132.6,129.0,128.9,128.7,128.5,128.2,127.1,127.1,119.9,117.2,24.8；HRMS,calculated for C20H18N(M+H+):272.1434,found:272.1433.
实施例2：(E)-2-甲基-6-(4-甲基苯乙烯基)-4-对甲苯基吡啶2b
Figure BDA0001518938230000081
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟类化合物1b、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2b(59％)。
实施例3：(E)-4-(4-甲氧基苯基)-2-(4-甲氧基苯乙烯基)-6-甲基吡啶2c
Figure BDA0001518938230000091
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟类化合物1c、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2c(63％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3)：7.63-7.53(m,5H),7.39(s,1H),7.18-7.08(m,2H),7.02-7.00(m,2H),6.91(d,J＝8.0Hz,2H),3.87(s,3H),3.84(s,3H),2.63(s,3H)；13C NMR(151MHz,CDCl3)：160.4,159.8,158.5,155.9,148.7,132.1,131.0,130.5,129.6,128.4,128.2,128.0,126.4,119.0,116.4,114.4,114.3,114.2,113.7,55.4,55.3,24.7；HRMS,calculated for C22H22NO2(M+H+):332.1645,found:332.1643.
实施例4：(E)-2-甲基-4-(萘-2-基)-6-(2-(萘-2-基)乙烯基)吡啶2d
Figure BDA0001518938230000092
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟类化合物1d、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2d(89％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3)：8.15(s,1H),7.98-7.94(m,3H),7.91-7.78(m,7H),7.62(s,1H),7.57-7.44(m,4H),7.42-7.38(m,2H),2.71(s,3H)；13C NMR(101MHz,CDCl3)：158.9,155.8,149.2,135.9,134.4,133.7,133.5,133.4,133.4,132.8,128.8,128.8,128.4,128.4,128.2,127.7,127.7,126.7,126.7,126.4,126.2,124.7,123.8,120.1,117.5,24.8；HRMS,calculated for C28H22N(M+H+):372.1747,found:372.1748.
实施例5：(E)-2-甲基-4-(噻吩-3-基)-6-(2-(噻吩-3-基)乙烯基)吡啶2e
Figure BDA0001518938230000101
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟类化合物1e、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2e(56％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3)：7.66-7.62(m,2H),7.44-7.37(m,5H),7.33-7.31(m,1H),7.20(s,1H),7.04(d,J＝16.0Hz,1H),2.61(s,3H)；13C NMR(101MHz,CDCl3)：158.8,155.8,143.5,139.9,139.7,128.3,126.9,126.7,126.3,125.9,125.2,124.1,122.8,118.9,116.1,24.7；HRMS,calculated for C16H14NS2(M+H+):284.0562,found:284.0559.
实施例6：(E)-4-三甲苯基-2-甲基-6-(2,4,6-三甲基苯乙烯基)吡啶2f
Figure BDA0001518938230000111
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟类化合物1f、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2f(52％)。
实施例7：(E)-4-(4-氟苯基)-2-(4-氟苯乙烯基)-6-甲基吡啶2g
Figure BDA0001518938230000112
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟类化合物1g、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2g(78％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3)：7.62(td,J＝8.0,4.0Hz,3H),7.56(td,J＝6.0,4.0Hz,2H),7.36(d,J＝4.0Hz,1H),7.19-7.04(m,6H),2.64(s,3H)；13C NMR(151MHz,CDCl3)：163.3(JCF＝249Hz),162.7(JCF＝248Hz),158.9,155.6,148.3,134.7(JCF＝3.0Hz),132.9(JCF＝3.0Hz),131.6,128.8(JCF＝7.6Hz),128.7(JCF＝7.6Hz),128.0(JCF＝1.5Hz),119.7,117.1,116.0(JCF＝21.1Hz),115.7(JCF＝21.1Hz),24.8；HRMS,calculated for C20H16NF2(M+H+):308.1245,found:308.1252.
实施例8：(E)-4-(呋喃-2-基)-2-(2-(呋喃-2-基)乙烯基)-6-甲基吡啶2h
Figure BDA0001518938230000121
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟类化合物1h、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2h(44％)。
实施例9：(E)-4-(苯并[b]噻吩-2-基)-2-(2-(苯并[b]噻吩-2-基)乙烯基)-6-甲基吡啶2i
Figure BDA0001518938230000122
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟类化合物1i、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2i(74％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3)：7.92(d,J＝16.0Hz,1H),7.87-7.85(m,1H),7.80(td,J＝8.0,4.0Hz,2H),7.75-7.71(m,2H),7.45(s,1H),7.39-7.37(m,3H),7.33-7.31(m,3H),7.07(d,J＝16.0Hz,1H),2.65(s,3H)；13C NMR(151MHz,CDCl3)：159.2,155.1,142.3,142.2,141.3,140.2,140.1,139.8,139.4,129.8,126.6,125.4,125.2,125.1,124.9,124.6,124.2,123.7,122.5,122.3,121.9,118.8,116.6,24.8；HRMS,calculated for C24H18NS2(M+H+):384.0875,found:384.0884.
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。

Claims (2)

1.一种合成(E)-2-甲基-4-苯基-6-苯乙烯基取代吡啶化合物的方法，其特征在于，包括以下操作：将(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟1在溴化亚铜和亚硫酸氢钠存在下，1,4-二氧六环中100℃反应得到(E)-2-甲基-4-苯基-6-苯乙烯基取代吡啶化合物2，反应方程式如下：
Figure FDA0002700594700000011
所述(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟1、溴化亚铜与亚硫酸氢钠摩尔比为1：0.05：1.5。
2.根据权利要求1所述的合成方法：所述反应在惰性气体保护下进行。
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