CN113666859B - 一种氮杂环取代的三氟甲基烯烃及其迈克尔加成产物的制备方法 - Google Patents

一种氮杂环取代的三氟甲基烯烃及其迈克尔加成产物的制备方法 Download PDF

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CN113666859B
CN113666859B CN202110973437.3A CN202110973437A CN113666859B CN 113666859 B CN113666859 B CN 113666859B CN 202110973437 A CN202110973437 A CN 202110973437A CN 113666859 B CN113666859 B CN 113666859B
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substituted trifluoromethyl
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CN113666859A (zh
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陈淑杰
李嘉慧
陈国术
李相睿
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Guangzhou University
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Abstract

本发明属于有机合成领域，公开了一种氮杂环取代的三氟甲基烯烃及其迈克尔加成产物的制备方法。所述的氮杂环取代的三氟甲基烯烃的制备方法如下：在氮气或惰性气体保护下，通过式II所示的含N‑H的氮杂环和式III所示的三氟甲基烯基锍盐在碱的促进下于溶剂中发生反应，即得到氮杂环取代的三氟甲基烯烃。反应路线如下所示。本发明所制得的氮杂环取代的三氟甲基烯烃具有出色的反应活性，能够作为迈克尔受体参与反应，比如氮杂迈克尔加成反应，从而构建氮上带有三氟烷基的氮杂环化合物。所制得的氮杂环取代的三氟甲基烯烃及其迈克尔加成产物具有抗菌、杀菌活性。因此在医药、农药等领域具有很好的应用前景。

Description

一种氮杂环取代的三氟甲基烯烃及其迈克尔加成产物的制备方法
技术领域
本发明属于有机合成领域，特别涉及一种氮杂环取代的三氟甲基烯烃及其迈克尔加成产物的制备方法。
背景技术
含氮杂环广泛存在于医药、农药分子中，例如大约有59％的小分子药物含有至少一个氮杂环(J.Med.Chem.2014,57,10257；J.Med.Chem.2014,57,5845)。另一方面，含三氟甲基化合物在医药农药领域的应用越来越广泛，研究表明，将三氟甲基引入生物活性分子的适当位置可以显著提高其活性和代谢稳定性(J.Fluorine Chem.2014,167,37)。例如，细胞色素P450对烷基胺的氧化代谢导致药效降低的重要因素，在氮原子的α位引入CF3是提高烷基胺代谢稳定性的一种重要策略(New J.Chem.2004,28,1401)；此外，三氟乙基的拉电子效应还能降低胺的碱性，进而提高化合物的生物利用度(Bioorg.Med.Chem.Lett.2006,16,1985)。这些优点已经被应用到许多上市的药品中，如偏头痛用药Ubrogepant，杀虫剂Fluralaner，类风湿关节炎用药Upadacitinib，治疗忧虑和紧张的Halazepam。
氮杂环衍生的烯胺是有机合成中的重要中间体，可参与后续反应来构建结构复杂的含氮杂环的医药、农药分子。探索氮杂环的烯基化反应是有机合成中的一个长期任务。现有的方法只能实现含NH的杂环化合物的普通烯基化(J.Org.Chem.2009,74,16,6371)，而氮杂环的三氟烯基化仍然缺乏有效手段。因此，研究氮杂环的三氟烯基化反应，并探索其合成用途具有重要的应用价值和研究意义。
发明内容
为了克服上述现有技术的缺点与不足，本发明的首要目的在于提供一种氮杂环取代的三氟甲基烯烃。
本发明另一目的在于提供氮杂环取代的三氟甲基烯烃的制备方法。该方法底物适用性好，能够兼容各种类型的氮杂环，反应条件温和，无需过渡金属催化剂。
本发明的再一目的在于提供一种上述氮杂环取代的三氟甲基烯烃制备含三氟烷基的氮杂环化合物的方法。
本发明的再一目的在于提供上述方法制备的含三氟烷基的氮杂环化合物。
本发明的再一目的在于提供上述含三氟烷基的氮杂环化合物的应用。
本发明的目的通过下述方案实现：
一种氮杂环取代的三氟甲基烯烃，该类三氟甲基烯烃的特征是三氟甲基的α位上带有一个氮杂环取代基，其结构如下式I所示：
Figure BDA0003226520170000021
其中氮杂环
Figure BDA0003226520170000022
为芳香氮杂环、非芳香氮杂环中的任一种；可以是环状酰亚胺、环状磺酰胺、吲哚环、环状硫代酰胺、哒嗪酮、尿嘧啶、吲唑、吡唑、三氮唑、苯并三唑、四氮唑、嘌呤中的任一种。
优选的，所述的氮杂环取代的三氟甲基烯烃的结构优选为以下结构中的一种：
Figure BDA0003226520170000031
一种上述的氮杂环取代的三氟甲基烯烃的制备方法，包括以下步骤：在氮气或惰性气体保护下，通过式II所示的含N-H的氮杂环和式III所示的三氟甲基烯基锍盐在碱的促进下于溶剂中发生反应，即得到氮杂环取代的三氟甲基烯烃。
具体反应通式如下所示：
Figure BDA0003226520170000032
所述的式III所示的三氟甲基烯基锍盐可按照以下文献方法合成(Org.Lett.2010,12,2548)。
所述的碱优选为三乙胺、DMAP、碳酸钠、碳酸钾、氢氧化钠、叔丁醇钾、DBU、碳酸铯中的至少一种；优选为三乙胺。
所述的溶剂为水、叔丁醇、乙酸乙酯、二氯甲烷、乙腈、四氢呋喃、氯苯、二甲苯、甲苯、乙醇、氯仿、环己烷、丁酮、丙酮、石油醚、正辛烷、环己烷、乙醚、二甲基亚砜、N,N-二甲基甲酰胺中的至少一种，优选为二氯甲烷/二甲亚砜的混合溶剂(体积比为DCM/DMSO＝1:1-5:1)。
所述的式II所示的含N-H的氮杂环、式III所示的三氟甲基烯基锍盐以及碱的物质的量之比为：(1-1.2):1:(1-2)，优选为1:1:1。
所述的反应的温度为室温；所述的反应时间为12-24h，优选为24h。
所述的反应结束后还包括一个纯化步骤，具体如下：反应结束后，减压浓缩再直接硅胶柱层析分离，以乙酸乙酯和石油醚的体积比为1:4的洗脱液，分离得到氮杂环取代的三氟甲基烯烃(式I)。
一种含三氟烷基的氮杂环化合物，其是由上述氮杂环取代的三氟甲基烯烃作为迈克尔受体参与氮杂迈克尔加成制备得到，具体包括以下步骤：式I所示的氮杂环取代的三氟甲基烯烃和式IV所示的胺在溶剂中反应，即得到含三氟烷基的氮杂环化合物。
具体反应通式如下所示：
Figure BDA0003226520170000041
式IV所示的胺中，R1可以是烷基、环烷基、芳基、取代芳基的任一种；R2可以是烷基、环烷基、芳基、取代芳基、H的任一种；其中R1、R2之间可以相互连接成环或者不连接。
所述的溶剂为水、叔丁醇、乙酸乙酯、二氯甲烷、乙腈、四氢呋喃、氯苯、二甲苯、甲苯、乙醇、氯仿、环己烷、丁酮、丙酮、石油醚、正辛烷、环己烷、乙醚、二甲基亚砜、N,N-二甲基甲酰胺中的至少一种，优选为四氢呋喃。
所述的式I所示的氮杂环取代的三氟甲基烯烃与式IV所示的胺的物质的量之比为：1:(1-2)，优选为1:2。
所述的反应是指在室温下反应12-24h；
所述的反应结束后还包括纯化步骤，具体如下：反应结束后将反应液减压浓缩后经硅胶柱层析分离(乙酸乙酯/石油醚洗脱)。
所述的含三氟烷基的氮杂环化合物，其结构式优选为如下所示结构中的一种：
Figure BDA0003226520170000051
上述的氮杂环取代的三氟甲基烯烃以及其合成的含三氟烷基的氮杂环化合物在医药以及农药领域中的应用，尤其是在制备抗植物病原菌药物中的应用。
本发明相对于现有技术，具有如下的优点及有益效果：
本发明提出在碱的促进下，以含N-H的杂环化合物和氮杂环取代的三氟甲基烯烃为原料，合成氮杂环取代的三氟甲基烯烃。该方法解决了氮杂环三氟烯基化的难题。所用原料容易获取；反应条件相对温和，操作简单，无需昂贵的过渡金属催化剂、氧化剂以及高温条件；能够合成现有方法不易得到的氮杂环取代三氟甲基烯烃。所合成的氮杂环取代三氟甲基烯烃展现出出色的反应活性，例如可作为迈克尔受体参与氮杂迈克尔加成，构建含三氟烷基的氮杂环化合物。所制得的氮杂环取代的三氟甲基烯烃及其迈克尔加成产物具有抗菌、杀菌活性。考虑到含氮杂环以及三氟甲基分子在医药农药领域的广泛运用，本发明所涉及的结构和制备方法在医药、农药等领域具有很好的应用前景。
附图说明
图1为实施例1中制备的式I-9所示氮杂环取代的三氟甲基烯烃的核磁氢谱图；
图2为实施例1中制备的式I-9所示氮杂环取代的三氟甲基烯烃的核磁碳谱图；
图3为实施例1中制备的式I-9所示氮杂环取代的三氟甲基烯烃的核磁氟谱图。
具体实施方式
下面结合实施例和附图对本发明作进一步详细的描述，但本发明的实施方式不限于此。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
实施例中所用试剂如无特殊说明均可从市场常规购得。实施例中所述的式III-1所示的三氟甲基烯基锍盐可按照以下文献方法合成(Org.Lett.2010,12,2548)。
实施例1
式I-1所示氮杂环取代的三氟甲基烯烃的合成：
Figure BDA0003226520170000061
在氮气保护下，往10mL反应管中依次加入琥珀酰亚胺II-1(19.8mg,0.20mmol)、三氟甲基烯基锍盐III-1(86mg,0.20mmol)，二氯甲烷(1ml)/二甲亚砜(0.2ml)、三乙胺(10mg,0.20mmol)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/5)得式I-1 25.1mg，产率65％。1H NMR(400MHz,CDCl3)δ6.32(dt,J＝2.5,1.2Hz,1H),5.73(dt,J＝2.7,1.3Hz,1H),2.86(d,J＝1.0Hz,4H).13C NMR(101MHz,CDCl3)δ174.75,128.47(q,J＝37.4Hz),126.15(q,J＝4.0Hz),120.14(q,J＝275.7Hz),28.57.
实施例2:
式I-2所示氮杂环取代的三氟甲基烯烃的合成：
Figure BDA0003226520170000071
在氮气保护下，往10mL反应管中依次加入II-2(43.0mg,0.20mmol)、三氟甲基烯基锍盐III-1(86mg,0.20mmol)，二氯甲烷(1ml)/二甲亚砜(0.2ml)、三乙胺(10mg,0.20mmol)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/5)得式I-2 45.7mg，产率74％。GC-MS(EI):309。
实施例3:
式I-3所示氮杂环取代的三氟甲基烯烃的合成：
Figure BDA0003226520170000072
在氮气保护下，往10mL反应管中依次加入II-3(37.8mg,0.20mmol)、三氟甲基烯基锍盐III-1(86mg,0.20mmol)，二氯甲烷(1ml)/二甲亚砜(0.2ml)、三乙胺(10mg,0.20mmol)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/5)得式I-3 43.6mg，产率77％。1H NMR(400MHz,CDCl3)δ8.22(dt,J＝4.7,2.9Hz,1H),7.86(s,1H),7.39–7.29(m,3H),6.35(d,J＝0.7Hz,1H),5.95–5.90(m,1H),4.40(q,J＝7.1Hz,2H),1.42(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ＝164.52,137.67,133.50(q,J＝36Hz),133.34,126.35,124.10,122.91,121.96,121.15(q,J＝30Hz),120.49(q,J＝273Hz),110.80,110.55,60.12,14.51.19F NMR(377MHz,CDCl3)δ＝-68.85.
实施例4:
式I-4所示氮杂环取代的三氟甲基烯烃的合成：
Figure BDA0003226520170000081
在氮气保护下，往10mL反应管中依次加入II-4(22.2mg,0.20mmol)、三氟甲基烯基锍盐III-1(86mg,0.20mmol)，二氯甲烷(1ml)/二甲亚砜(0.2ml)、三乙胺(10mg,0.20mmol)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/5)得式I-4 21.3mg，产率52％。GC-MS(EI):205。
实施例5:
式I-5所示氮杂环取代的三氟甲基烯烃的合成：
Figure BDA0003226520170000082
在氮气保护下，往10mL反应管中依次加入II-5(19.2mg,0.20mmol)、三氟甲基烯基锍盐III-1(86mg,0.20mmol)，二氯甲烷(1ml)/二甲亚砜(0.2ml)、三乙胺(10mg,0.20mmol)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/5)得式I-5 31.5mg，产率83％。1H NMR(400MHz,CDCl3)δ7.84(dd,J＝3.7,1.6Hz,1H),7.24(dd,J＝9.6,3.8Hz,1H),7.00(dd,J＝9.6,1.6Hz,1H),6.34(d,J＝1.1Hz,1H),6.06–5.97(m,1H).13C NMR(100MHz,CDCl3)δ＝159.65,136.99,136.20(q,J＝36Hz),131.86,131.11,122.88(q,J＝3Hz),120.35(q,J＝273Hz).19F NMR(377MHz,CDCl3)δ＝-67.11.
实施例6:
式I-6所示氮杂环取代的三氟甲基烯烃的合成：
Figure BDA0003226520170000091
在氮气保护下，往10mL反应管中依次加入II-6(22.4mg,0.20mmol)、三氟甲基烯基锍盐III-1(86mg,0.20mmol)，二氯甲烷(1ml)/二甲亚砜(0.2ml)、三乙胺(10mg,0.20mmol)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/5)得式I-6 14.8mg，产率36％。1H NMR(400MHz,CDCl3)δ7.68(d,J＝6.8Hz,1H),6.09(d,J＝6.8Hz,1H),5.34-5.27(m,1H),4.84(dd,J＝10.4,2.5Hz,1H),4.79–4.72(m,1H).13C NMR(101MHz,CDCl3)δ159.81,159.54,154.95,123.12(q,J＝284.8Hz),109.20,66.71(q,J＝3.0Hz),55.06(q,J＝35.4Hz).
实施例7:
式I-7所示氮杂环取代的三氟甲基烯烃的合成：
Figure BDA0003226520170000092
在氮气保护下，往10mL反应管中依次加入II-7(23.6mg,0.20mmol)、三氟甲基烯基锍盐III-1(86mg,0.20mmol)，二氯甲烷(1ml)/二甲亚砜(0.2ml)、三乙胺(10mg,0.20mmol)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/5)得式I-7 22.9mg，产率54％。GC-MS(EI):212。
实施例8:
式I-8所示氮杂环取代的三氟甲基烯烃的合成：
Figure BDA0003226520170000101
在氮气保护下，往10mL反应管中依次加入II-8(23.6mg,0.20mmol)、三氟甲基烯基锍盐III-1(86mg,0.20mmol)，二氯甲烷(1ml)/二甲亚砜(0.2ml)、三乙胺(10mg,0.20mmol)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/5)得式I-8 23.7mg，产率56％。GC-MS(EI):212。
实施例9:
式I-9所示氮杂环取代的三氟甲基烯烃的合成：
Figure BDA0003226520170000102
在氮气保护下，往10mL反应管中依次加入II-9(29.2mg,0.20mmol)、三氟甲基烯基锍盐III-1(86mg,0.20mmol)，二氯甲烷(1ml)/二甲亚砜(0.2ml)、三乙胺(10mg,0.20mmol)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/5)得式I-9 45.6mg，产率95％。1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.65(s,1H),6.09(p,J＝2.0Hz,1H),5.78(d,J＝1.4Hz,1H).13C NMR(100MHz,CDCl3)δ＝142.41,134.71,128.93,120.12(q,J＝272Hz),110.46,96.28.19F NMR(377MHz,CDCl3)δ＝-66.75.具体核磁图分别如图1-3所示。
实施例10:
式I-10所示氮杂环取代的三氟甲基烯烃的合成：
Figure BDA0003226520170000111
在氮气保护下，往10mL反应管中依次加入II-10(28.8mg,0.20mmol)、三氟甲基烯基锍盐III-1(86mg,0.20mmol)，二氯甲烷(1ml)/二甲亚砜(0.2ml)、三乙胺(10mg,0.20mmol)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/5)得式I-10 28.6mg，产率60％。GC-MS(EI):238。
实施例11:
式I-11所示氮杂环取代的三氟甲基烯烃的合成：
Figure BDA0003226520170000112
在氮气保护下，往10mL反应管中依次加入II-11(13.8mg,0.20mmol)、三氟甲基烯基锍盐III-1(86mg,0.20mmol)，二氯甲烷(1ml)/二甲亚砜(0.2ml)、三乙胺(10mg,0.20mmol)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/5)得式I-11 8.8mg，产率27％。GC-MS(EI):163。
实施例12:
式I-12所示氮杂环取代的三氟甲基烯烃的合成：
Figure BDA0003226520170000121
在氮气保护下，往10mL反应管中依次加入II-12(29.0mg,0.20mmol)、三氟甲基烯基锍盐III-1(86mg,0.20mmol)，二氯甲烷(1ml)/二甲亚砜(0.2ml)、三乙胺(10mg,0.20mmol)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/5)得式I-12 17.2mg，产率36％。1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.80–7.75(m,2H),7.43–7.31(m,3H),6.31(p,J＝2.1Hz,1H),5.81(d,J＝2.2Hz,1H).13C NMR(101MHz,CDCl3)δ149.59,134.92(q,J＝36.4Hz),133.47,129.39,129.09,129.02,126.36,119.81(q,J＝273.7Hz),110.01(q,J＝4.0Hz).
实施例13:
式I-13所示氮杂环取代的三氟甲基烯烃的合成：
Figure BDA0003226520170000122
在氮气保护下，往10mL反应管中依次加入II-13(23.8mg,0.20mmol)、三氟甲基烯基锍盐III-1(86mg,0.20mmol)，二氯甲烷(1ml)/二甲亚砜(0.2ml)、三乙胺(10mg,0.20mmol)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/5)得式I-13 30.2mg，产率71％。19F NMR(376MHz,CDCl3)δ-67.49.GC-MS(EI):213。
实施例14:
式I-14所示氮杂环取代的三氟甲基烯烃的合成：
Figure BDA0003226520170000131
在氮气保护下，往10mL反应管中依次加入II-14(13.8mg,0.20mmol)、三氟甲基烯基锍盐III-1(86mg,0.20mmol)，二氯甲烷(1ml)/二甲亚砜(0.2ml)、三乙胺(10mg,0.20mmol)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/5)得式I-14 17.9mg，产率55％。GC-MS(EI):163。
实施例15:
式I-15所示氮杂环取代的三氟甲基烯烃的合成：
Figure BDA0003226520170000132
在氮气保护下，往10mL反应管中依次加入II-15(14.0mg,0.20mmol)、三氟甲基烯基锍盐III-1(86mg,0.20mmol)，二氯甲烷(1ml)/二甲亚砜(0.2ml)、三乙胺(10mg,0.20mmol)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/5)得式I-15 19.7mg，产率60％。GC-MS(EI):164。
实施例16:
式I-16所示氮杂环取代的三氟甲基烯烃的合成：
Figure BDA0003226520170000133
在氮气保护下，往10mL反应管中依次加II-16(29.2mg,0.20mmol)、三氟甲基烯基锍盐III-1(86mg,0.20mmol)，二氯甲烷(1ml)/二甲亚砜(0.2ml)、三乙胺(10mg,0.20mmol)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/5)得式I-16 38.9mg，产率81％。1H NMR(400MHz,CDCl3)δ8.18–8.10(m,2H),7.48–7.40(m,3H),6.53(p,J＝2.1Hz,1H),6.11(d,J＝2.6Hz,1H).
实施例17:
式I-17所示氮杂环取代的三氟甲基烯烃的合成：
Figure BDA0003226520170000141
在氮气保护下，往10mL反应管中依次加入II-17(23.2mg,0.20mmol)、三氟甲基烯基锍盐III-1(86mg,0.20mmol)，二氯甲烷(1ml)/二甲亚砜(0.2ml)、三乙胺(10mg,0.20mmol)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/5)得式I-17 29.4mg，产率70％。1H NMR(400MHz,CDCl3)δ6.67(dq,J＝3.5,1.8Hz,1H),6.52(dd,J＝2.8,0.9Hz,1H),3.94(s,3H).13C NMR(101MHz,CDCl3)δ164.98,129.99(q,J＝37.4Hz),122.93(q,J＝4.0Hz),119.41(q,J＝275.7Hz),35.08.
实施例18:
式I-18所示氮杂环取代的三氟甲基烯烃的合成：
Figure BDA0003226520170000142
在氮气保护下，往10mL反应管中依次加入II-18(30.8mg,0.20mmol)、三氟甲基烯基锍盐III-1(86mg,0.20mmol)，二氯甲烷(1ml)/二甲亚砜(0.2ml)、三乙胺(10mg,0.20mmol)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/5)得式I-18 43.6mg，产率88％。1H NMR(400MHz,CDCl3)δ8.84(s,1H),8.28(s,1H),6.47(s,2H).13C NMR(100MHz,CDCl3)δ＝153.09,152.08,143.15,131.46,129.12,128.75,120.88(q,J＝4Hz),119.86(q,J＝272Hz).19F NMR(377MHz,CDCl3)δ＝-68.42.
实施例19:
式V-1所示三氟烷基化氮杂环化合物的合成：
Figure BDA0003226520170000151
往10mL反应管中依次加入I-11(16.3mg,0.10mmol)、IV-1(27.4mg,0.20mmol)，四氢呋喃(1ml)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/8)得式V-1 8mg，产率27％。1H NMR(400MHz,CDCl3)δ7.77(d,J＝1.1Hz,1H),7.71–7.69(m,1H),7.14–7.09(m,2H),6.85–6.80(m,2H),5.29–5.19(m,1H),3.78(s,3H),3.74–3.66(m,2H),3.52(dd,J＝13.5,9.5Hz,1H),3.29(dd,J＝13.5,4.0Hz,1H).13C NMR(101MHz,CDCl3)δ＝159.03,134.43,131.05,129.34,123.96,123.09(q,J＝282.8Hz),114.04,62.04(q,J＝30.3Hz),55.36,52.72,45.99(q,J＝2.0Hz).
实施例20:
式V-2所示三氟烷基化氮杂环化合物的合成：
Figure BDA0003226520170000152
往10mL反应管中依次加入I-13(21.3mg,0.10mmol)、IV-2(27.0mg,0.20mmol)，四氢呋喃(1ml)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/8)得式V-2 30.1mg，产率87％。1H NMR(400MHz,CDCl3)δ8.10(dt,J＝8.3,0.7Hz,1H),7.55–7.50(m,2H),7.42(ddd,J＝8.1,5.7,2.2Hz,1H),6.98(d,J＝7.9Hz,2H),6.94–6.89(m,2H),5.38(ddd,J＝10.4,7.2,4.1Hz,1H),3.99(dd,J＝13.3,10.3Hz,1H),3.46(dd,J＝13.3,4.1Hz,1H),2.87–2.76(m,2H),2.60(t,J＝7.2Hz,2H),2.26(s,3H).13C NMR(100MHz,CDCl3)δ＝146.09,136.04,135.86,133.65,129.23,128.49,128.42,124.64,123.63(q,J＝284Hz),120.51,109.48,60.79(q,J＝3Hz),50.64,45.60,35.66,21.09.
实施例21:
式V-3所示三氟烷基化氮杂环化合物的合成：
Figure BDA0003226520170000161
往10mL反应管中依次加入I-17(21.0mg,0.10mmol)、IV-1(27.4mg,0.20mmol)，四氢呋喃(1ml)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/8)得式V-3 24.3mg，产率70％。1H NMR(400MHz,CDCl3)δ7.17–7.12(m,2H),6.86–6.80(m,2H),5.62–5.50(m,1H),3.93(s,3H),3.78(s,3H),3.77–3.63(m,2H),3.51(dd,J＝13.5,10.6Hz,1H),3.34(dd,J＝13.5,4.1Hz,1H).13C NMR(101MHz,CDCl3)δ＝166.64,158.99,131.03,129.40,123.0(q,J＝284.8Hz),114.00,57.32(q,J＝30.3Hz),55.36,52.17,45.37(q,J＝2.0Hz),35.08.
实施例22:
式V-4所示三氟烷基化氮杂环化合物的合成：
Figure BDA0003226520170000162
往10mL反应管中依次加入I-16(24.0mg,0.10mmol)、IV-3(14.2mg,0.20mmol)，四氢呋喃(1ml)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/8)得式V-4 28.6mg，产率92％。1H NMR(400MHz,CDCl3)δ8.24–8.15(m,2H),7.50(qd,J＝4.3,1.5Hz,3H),5.56(dqd,J＝10.3,6.8,3.3Hz,1H),3.76(dd,J＝13.3,10.7Hz,1H),3.20(dd,J＝13.3,3.3Hz,1H),2.66–2.56(m,2H),2.47–2.34(m,2H),1.73–1.65(m,4H).13C NMR(101MHz,CDCl3)δ165.54,130.64,128.92,127.07,126.98,122.50(q,J＝282.8Hz),64.36(q,J＝31.3Hz),53.88,52.93,23.64.
实施例23:
式V-5所示三氟烷基化氮杂环化合物的合成：
Figure BDA0003226520170000171
往10mL反应管中依次加入I-15(16.4mg,0.10mmol)、IV-2(27.0mg,0.20mmol)，四氢呋喃(1ml)，室温下搅拌24h。反应液减压浓缩后经硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝1/8)得式V-5 26.6mg，产率89％。GC-MS(EI):299.
实施例24：部分氮杂环取代的三氟甲基烯烃及其迈克尔加成产物的杀菌活性测试
采用菌丝生长速率法，参照徐曙(徐曙,赵兴增,周倩等.甘草根中黄酮类化合物的提取、分离与衍生化及其抑菌活性研究[J].植物资源与环境学报,2020,29(06):32-41.)等的方法，将测试化合物溶于二甲基亚砜(DMSO)，配制成50000μg/mL母液。将马铃薯蔗糖琼脂培养基(PSA)加热融化后室温放置，当培养基冷却至55℃左右时，加入母液使其终浓度为10μg/mL，倒入直径6cm的培养皿中制成含药平板，以含等体积DMSO的PSA平板作为溶剂对照，另设PSA空白平板(不加溶剂或者药液)作为空白对照。将稻瘟菌(ATCC 64557)、黄瓜灰霉病菌(ATCC 20599)分别接种于PSA平板上，并在25℃生化培养箱中预培养。用打孔器在预培养的生长旺盛的菌落边缘取直径5mm的菌碟，并接种于空白对照、溶剂对照和含药PSA平板上，然后在25℃生化培养箱中培养至空白对照接近长满平板。采用十字交叉法测量抑菌圈直径大小(扣除菌碟直径5mm)，每个处理设置3个技术重复，实验重复3次,测试数据详见表1。
表1部分测试化合物的抗菌活性a
Figure BDA0003226520170000181
a生长抑菌区直径：<10mm(-)，10-12mm(+)，13-15mm(++)，16-20mm(+++)；菌碟直径：5mm.
从表1中的数据可以看出，测试的化合物中部分对以上两种植物病原菌都表现出不同程度的抑制作用，其抑制能力因各化合物中取代基的不同而有所差异。其中化合物I-9、I-17对稻瘟菌具有较为出色的抑制活性；化合物V-3、V-4对黄瓜灰霉病菌具有较为出色的抑制活性。总体上来说，表1中的活性测试数据表明本发明所述氮杂环取代的三氟甲基烯烃及其迈克尔加成产物具有一定抗菌活性。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (9)

1.一种氮杂环取代的三氟甲基烯烃，其特征在于结构如下式I所示：
并且式I选自以下结构中的一种：
。
2.一种根据权利要求1所述的氮杂环取代的三氟甲基烯烃的制备方法，其特征在于包括以下步骤：
在惰性气体保护下，通过式II所示的含N-H的氮杂环和式III所示的三氟甲基烯基锍盐在碱的促进下于溶剂中发生反应，即得到式I所示的氮杂环取代的三氟甲基烯烃；
具体反应路线如下所示：
。
3.根据权利要求2所述的氮杂环取代的三氟甲基烯烃的制备方法，其特征在于：
所述的碱为三乙胺、DMAP、碳酸钠、碳酸钾、氢氧化钠、叔丁醇钾、DBU、碳酸铯中的至少一种；
所述的溶剂为水、叔丁醇、乙酸乙酯、二氯甲烷、乙腈、四氢呋喃、氯苯、二甲苯、甲苯、乙醇、氯仿、丁酮、丙酮、石油醚、正辛烷、环己烷、1:1-5:1的二氯甲烷/二甲亚砜的混合溶剂。
4.根据权利要求3所述的氮杂环取代的三氟甲基烯烃的制备方法，其特征在于：
所述的碱为三乙胺。
5.根据权利要求2所述的氮杂环取代的三氟甲基烯烃的制备方法，其特征在于：
所述的式II所示的含N-H的氮杂环、式III所示的三氟甲基烯基锍盐以及碱的物质的量之比为：（1-1.2）:1:（1-2）；
所述的反应的温度为室温；所述的反应时间为12-24h。
6.根据权利要求5所述的氮杂环取代的三氟甲基烯烃的制备方法，其特征在于：
所述的式II所示的含N-H的氮杂环、式III所示的三氟甲基烯基锍盐以及碱的物质的量之比为1:1:1。
7.根据权利要求1所述的氮杂环取代的三氟甲基烯烃在制备抗植物病原菌药物中的应用。
8.一种含三氟烷基的氮杂环化合物，其特征在于其具体结构为以下结构中的一种：
。
9.根据权利要求8所述的含三氟烷基的氮杂环化合物在制备抗植物病原菌药物中的应用。
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