CN114890912B - 一种氟代环戊烯并茚满酮化合物的制备方法 - Google Patents

一种氟代环戊烯并茚满酮化合物的制备方法 Download PDF

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CN114890912B
CN114890912B CN202210553239.6A CN202210553239A CN114890912B CN 114890912 B CN114890912 B CN 114890912B CN 202210553239 A CN202210553239 A CN 202210553239A CN 114890912 B CN114890912 B CN 114890912B
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孔望清
平媛媛
潘琪
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Abstract

本发明公开了一种氟代环戊烯并茚满酮化合物的制备方法，属于有机合成技术领域。本发明以相应的2‑溴‑N‑丙烯酰基苯甲酰胺和三氟甲基烯烃为原料，通过金属镍络合物的催化，实现2‑溴‑N‑丙烯酰基苯甲酰胺的一系列串联反应，得到氟代环戊烯并茚满酮化合物。该方法通过简单原料在廉价的镍催化剂和锰还原剂的共同作用下，经济高效地制备各种官能团化的氟代环戊烯并茚满酮化合物。

Description

一种氟代环戊烯并茚满酮化合物的制备方法
技术领域
本发明属于有机合成技术领域，具体涉及一种氟代环戊烯并茚满酮化合物的制备方法。
背景技术
环戊烯并茚满酮骨架广泛存在于具有生物活性的天然产物和药物分子中，与此同时，含氟基团的引入可以显着改善有机分子的理化性质和生物活性，已广泛应用于药物的合成和开发。因此，发展合成氟代环戊烯并茚满酮的方法学具有重要的意义。然而，现有对氟代环戊烯并茚满酮化合物合成的研究尚未得到发展。
发明内容
本发明的目的在于提供一种氟代环戊烯并茚满酮化合物的制备方法。本发明以2-溴-N-丙烯酰基苯甲酰胺与三氟甲基烯烃为原料，通过镍催化的串联环化/交叉偶联/β-F消除过程生成偕二氟烯烃中间体，随后酰基的α-碳亲核进攻高度极化的偕二氟烯烃，β-F消除，最后缩环以得到氟代环戊烯并茚满酮产物。
本发明的目的通过下述技术方案实现：
一种氟代环戊烯并茚满酮化合物的制备方法，其合成反应式如下，包括下述步骤：式A所示的2-溴-N-丙烯酰基苯甲酰胺和式B所示的三氟甲基烯烃，通过金属镍络合物催化，在70-90℃下反应得到式C所示的氟代环戊烯并茚满酮化合物。
Figure BDA0003651445090000011
式中，Ar为取代的芳基或杂芳基；R1为正丁基、甲基或苄基；R2为甲基或苯基；R3为取代的芳基或杂芳基。
进一步地，Ar中，所述的芳基具有一个选自卤素、-OMe或甲基的取代基，所述的杂芳基为吲哚基。R3中，所述的芳基具有一个选自-CN，-(C＝O)OEt、-(SO2)Me、-(C＝O)Me、甲酸薄荷酯或呋喃果糖的取代基，所述的杂芳基为喹啉基。
进一步地，式A所示的2-溴-N-丙烯酰基苯甲酰胺选自如下结构：
Figure BDA0003651445090000021
式B所示的三氟甲基烯烃选自如下结构：
Figure BDA0003651445090000022
进一步地，所述的金属镍络合物由金属镍和配体络合得到，所述的金属镍优选为乙酰丙酮镍；所述的配体优选为三联吡啶。
在一些实施方案中，所述的氟代环戊烯并茚满酮化合物的制备方法，包括下述步骤：将式A所示的2-溴-N-丙烯酰基苯甲酰胺、式B所示的三氟甲基烯烃、金属镍、配体、锰、路易斯酸、
Figure BDA0003651445090000023
分子筛加到有机溶剂中，在惰性气体保护和密闭条件下，在70-90℃下反应，得到式C所示的氟代环戊烯并茚满酮化合物。其中，所述的金属镍优选为乙酰丙酮镍，所述的配体优选为三联吡啶；所述的路易斯酸优选为溴化锰；所述的有机溶剂优选为二甲基亚砜和四氢呋喃的混合溶剂，两者体积比优选为1:1；式A所示的2-溴-N-丙烯酰基苯甲酰胺、式B所示的三氟甲基烯烃、金属镍络合物、锰、路易斯酸的最佳摩尔比为1.0:2.0:0.1:3.0:2.0；式A所示的2-溴-N-丙烯酰基苯甲酰胺浓度为0.025mol/L；所述的惰性气体优选为氩气；所述的反应的时间优选为48-96小时。
本发明的优点和有益效果：本发明提供了一种有效的以2-溴-N-丙烯酰基苯甲酰胺与三氟甲基烯烃为原料，金属镍络合物为催化剂，在氩气保护条件下制备各种氟代环戊烯并茚满酮化合物的方法。该方法可适用于多种含不同取代基的2-溴-N-丙烯酰基苯甲酰胺与三氟甲基烯烃，反应条件温和，操作简便，官能团兼容性强，底物适用性广，原料廉价易得，是一种高效、绿色、廉价合成氟代环戊烯并茚满酮化合物的方法。
具体实施方式
下面结合实施例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1
Figure BDA0003651445090000031
在氩气气氛下向装有磁子的反应管中加入乙酰丙酮镍(2.6mg,0.01mmol)、三联吡啶(4.7mg,0.02mmol)、锰(16.5mg,0.3mmol)、溴化锰(43.0mg,0.2mmol)、
Figure BDA0003651445090000032
分子筛(20mg)、2-溴-N-丁基-N-甲基丙烯酰苯甲酰胺1a(32.3mg,0.1mmol)、三氟甲基烯烃2a(39.4mg,0.2mmol)、二甲基亚砜(2mL)和四氢呋喃(2mL)，封闭反应管，80℃下反应48小时，浓缩，快速柱层析，得无色液体产物3(27.4mg,68％yield)。
1H NMR(600MHz,CDCl3)δ7.82(d,J＝7.7Hz,1H),7.73(t,J＝7.5Hz,1H),7.62(d,J＝7.8Hz,1H),7.58(d,J＝8.6Hz,2H),7.52(d,J＝8.6Hz,2H),7.48(t,J＝7.8Hz,1H),7.36(t,J＝5.3Hz,1H),3.38(dt,J＝13.0,6.7Hz,2H),3.32(dd,J＝14.9,6.6Hz,1H),3.03(dd,J＝14.9,4.7Hz,1H),1.64(s,3H),1.60-1.52(m,2H),1.43-1.36(m,2H),0.94(t,J＝7.4Hz,3H)；13C NMR(151MHz,CDCl3)δ201.0,165.7(d,J＝3.3Hz),160.9,154.6(d,J＝295.0Hz),136.6,136.5(d,J＝5.3Hz),133.1,132.1,128.9,127.6(d,J＝7.4Hz),124.3(d,J＝88.4Hz),118.7,116.0(d,J＝2.2Hz),111.1(d,J＝1.8Hz),73.4(d,J＝18.4Hz),50.2(d,J＝5.8Hz),42.6(d,J＝4.7Hz),39.5,31.4,24.8,20.0,13.7；19F NMR(565MHz,CDCl3)δ-115.75(t,J＝5.9Hz)；HRMS(m/z):[M+H]+calcd.for C25H24FN2O2 +,403.1816；found,403.1809.
实施例2
Figure BDA0003651445090000033
在氩气气氛下向装有磁子的反应管中加入乙酰丙酮镍(2.6mg,0.01mmol)、三联吡啶(4.7mg,0.02mmol)、锰(16.5mg,0.3mmol)、溴化锰(43.0mg,0.2mmol)、
Figure BDA0003651445090000034
分子筛(20mg)、2-溴-N-甲基-N-甲基丙烯酰苯甲酰胺1b(28.1mg,0.1mmol)、三氟甲基烯烃2a(39.4mg,0.2mmol)、二甲基亚砜(2mL)和四氢呋喃(2mL)，封闭反应管，80℃下反应48小时，浓缩，快速柱层析，得无色液体产物4(29.5mg,82％yield)。
1H NMR(400MHz,CDCl3)δ7.80(d,J＝7.7Hz,1H),7.72(t,J＝8.0Hz,1H),7.61(d,J＝7.8Hz,1H),7.57(d,J＝8.6Hz,2H),7.51(d,J＝8.6Hz,2H),7.46(t,J＝7.4Hz,1H),7.31-7.27(m,1H),3.31(dd,J＝15.0,6.7Hz,1H),3.03(dd,J＝15.0,4.9Hz,1H),2.92(d,J＝4.8Hz,3H),1.63(s,3H)；13C NMR(151MHz,CDCl3)δ200.8,166.4(d,J＝3.2Hz),160.9,154.4(d,J＝294.9Hz),136.6,136.4(d,J＝5.3Hz),133.1,132.1,128.9,127.6(d,J＝7.4Hz),124.6,123.9,118.6,116.1(d,J＝2.2Hz),111.1,73.4(d,J＝18.4Hz),50.2(d,J＝5.8Hz),42.6(d,J＝4.7Hz),26.5,24.7；19F NMR(376MHz,CDCl3)δ-115.58(t,J＝5.5Hz)；HRMS(m/z):[M+H]+calcd.for C22H18FN2O2 +,361.1346；found,361.1343.
实施例3
Figure BDA0003651445090000041
在氩气气氛下向装有磁子的反应管中加入乙酰丙酮镍(2.6mg,0.01mmol)、三联吡啶(4.7mg,0.02mmol)、锰(16.5mg,0.3mmol)、溴化锰(43.0mg,0.2mmol)、
Figure BDA0003651445090000043
分子筛(20mg)、2-溴-N-苄基-N-甲基丙烯酰苯甲酰胺1c(35.7mg,0.1mmol)、三氟甲基烯烃2a(39.4mg,0.2mmol)、二甲基亚砜(2mL)和四氢呋喃(2mL)，封闭反应管，80℃下反应48小时，浓缩，快速柱层析，得无色液体产物5(30.4mg,69％yield)。
1H NMR(600MHz,CDCl3)δ7.80(d,J＝7.7Hz,1H),7.73(t,J＝7.5Hz,1H),7.68(t,J＝5.4Hz,1H),7.62(d,J＝7.9Hz,1H),7.58(d,J＝8.5Hz,2H),7.52(d,J＝8.5Hz,2H),7.47(t,J＝7.4Hz,1H),7.36-7.30(m,4H),7.29-7.27(m,1H),4.67-4.49(m,2H),3.33(dd,J＝14.9,6.6Hz,1H),3.04(dd,J＝14.9,4.7Hz,1H),1.65(s,3H)；13C NMR(151MHz,CDCl3)δ200.7,165.9(d,J＝3.2Hz),160.8,154.3(d,J＝294.9Hz),137.6,136.7,136.4(d,J＝5.2Hz),133.0,132.1,128.9,128.7,127.6(d,J＝7.5Hz),127.6,127.5,124.6,124.0,118.6,116.2(d,J＝2.1Hz),111.1(d,J＝2.4Hz),73.4(d,J＝18.3Hz),50.3(d,J＝5.6Hz),43.7,42.6(d,J＝4.5Hz),24.8；19F NMR(376MHz,CDCl3)δ-115.60(t,J＝5.5Hz)；HRMS(m/z):[M+H]+calcd.for C28H22FN2O2 +,437.1659；found,437.1652.
实施例4
Figure BDA0003651445090000042
在氩气气氛下向装有磁子的反应管中加入乙酰丙酮镍(2.6mg,0.01mmol)、三联吡啶(4.7mg,0.02mmol)、锰(16.5mg,0.3mmol)、溴化锰(43.0mg,0.2mmol)、
Figure BDA0003651445090000044
分子筛(20mg)、2-溴-N-甲基-N-(2-苯基丙烯酰基)苯甲酰胺1d(34.3mg,0.1mmol)、三氟甲基烯烃2a(39.4mg,0.2mmol)、二甲基亚砜(2mL)和四氢呋喃(2mL)，封闭反应管，80℃下反应48小时，浓缩，快速柱层析，得无色液体产物6(16.4mg,39％yield)。
1H NMR(600MHz,CDCl3)δ7.87(d,J＝7.6Hz,1H),7.63(d,J＝8.3Hz,1H),7.61(bs,4H),7.57-7.51(m,1H),7.46(t,J＝7.5Hz,1H),7.39(d,J＝7.9Hz,1H),7.27(d,J＝7.4Hz,2H),7.19(t,J＝7.3Hz,1H),7.06(d,J＝7.4Hz,2H),4.20(dd,J＝14.5,6.7Hz,1H),3.37(dd,J＝14.5,4.5Hz,1H),2.69(d,J＝4.8Hz,3H)；13C NMR(151MHz,CDCl3)δ201.2,165.9(d,J＝3.3Hz),159.4,155.0(d,J＝295.8Hz),141.2,136.8,136.4(d,J＝5.4Hz),133.0,132.2,129.0,128.7,128.2,127.7(d,J＝7.2Hz),127.1,126.3,125.1,124.5,118.6,115.5(d,J＝2.1Hz),111.3(d,J＝2.2Hz),75.2(d,J＝18.5Hz),58.1(d,J＝5.4Hz),39.3(d,J＝4.3Hz),26.2；19F NMR(376MHz,CDCl3)δ-115.93(t,J＝5.6Hz)；HRMS(m/z):[M+H]+calcd.for C27H20FN2O2 +,423.1503；found,423.1505.
实施例5
Figure BDA0003651445090000051
在氩气气氛下向装有磁子的反应管中加入乙酰丙酮镍(2.6mg,0.01mmol)、三联吡啶(4.7mg,0.02mmol)、锰(16.5mg,0.3mmol)、溴化锰(43.0mg,0.2mmol)、
Figure BDA0003651445090000053
分子筛(20mg)、2-溴-N-甲基丙烯酰基-N,4-二甲基苯甲酰胺1e(29.6mg,0.1mmol)、三氟甲基烯烃2a(39.4mg,0.2mmol)、二甲基亚砜(2mL)和四氢呋喃(2mL)，封闭反应管，80℃下反应48小时，浓缩，快速柱层析，得无色液体产物7(19.4mg,52％yield)。
1H NMR(400MHz,CDCl3)δ7.72-7.65(m,1H),7.61-7.48(m,4H),7.40-7.37(m,1H),7.37-7.33(m,1H),7.29-7.24(m,1H),3.29(dd,J＝14.9,6.7Hz,1H),3.02(dd,J＝14.9,4.8Hz,1H),2.92(d,J＝4.8Hz,3H),2.48(s,3H),1.62(s,3H)；13C NMR(151MHz,CDCl3)δ200.3(d,J＝2.7Hz),166.6(d,J＝3.2Hz),161.4,154.8(d,J＝295.0Hz),136.6(d,J＝5.3Hz),132.1,130.8,130.2,127.6(d,J＝7.4Hz),124.4(d,J＝22.4Hz),118.7,115.9(d,J＝2.1Hz),111.0(d,J＝2.1Hz),73.6(d,J＝18.3Hz),50.0,42.5(d,J＝4.7Hz),26.4,24.8,22.4；19F NMR(376MHz,CDCl3)δ-115.45(t,J＝6.0Hz)；HRMS(m/z):[M+H]+calcd.forC23H20FN2O2 +,375.1498；found,375.1503.
实施例6
Figure BDA0003651445090000052
在氩气气氛下向装有磁子的反应管中加入乙酰丙酮镍(2.6mg,0.01mmol)、三联吡啶(4.7mg,0.02mmol)、锰(16.5mg,0.3mmol)、溴化锰(43.0mg,0.2mmol)、
Figure BDA0003651445090000054
分子筛(20mg)、2-溴-4-氟-N-甲基丙烯酰基-N-甲基苯甲酰胺1f(30.0mg,0.1mmol)、三氟甲基烯烃2a(39.4mg,0.2mmol)、二甲基亚砜(2mL)和四氢呋喃(2mL)，封闭反应管，80℃下反应48小时，浓缩，快速柱层析，得无色液体产物8(23.8mg,63％yield)。
1H NMR(600MHz,CDCl3)δ7.85-7.82(m,1H),7.61-7.57(m,2H),7.53-7.50(m,2H),7.33-7.29(m,1H),7.26-7.24(m,1H),7.19-7.15(m,1H),3.31(dd,J＝15.0,6.7Hz,1H),2.99(dd,J＝15.0,4.7Hz,1H),2.93(d,J＝4.8Hz,3H),1.64(s,3H)；13C NMR(151MHz,CDCl3)δ199.0(d,J＝2.9Hz),168.2(d,J＝259.6Hz),166.1(d,J＝3.2Hz),164.0(d,J＝9.3Hz),154.3(d,J＝294.9Hz),136.2(d,J＝5.1Hz),132.2,129.4,127.6(d,J＝7.4Hz),127.3(d,J＝10.5Hz),118.6,117.5(d,J＝23.9Hz),116.0(d,J＝2.4Hz),111.3(d,J＝2.3Hz),111.0(d,J＝22.8Hz),73.6(d,J＝18.4Hz),50.1(d,J＝5.5Hz),42.4(d,J＝4.7Hz),26.5,24.6；19F NMR(565MHz,CDCl3)δ-96.94(m),-115.64(t,J＝5.9Hz)；HRMS(m/z):[M+H]+calcd.forC22H17F2N2O2 +,379.1247；found,379.1253.
实施例7
Figure BDA0003651445090000061
在氩气气氛下向装有磁子的反应管中加入乙酰丙酮镍(2.6mg,0.01mmol)、三联吡啶(4.7mg,0.02mmol)、锰(16.5mg,0.3mmol)、溴化锰(43.0mg,0.2mmol)、
Figure BDA0003651445090000062
分子筛(20mg)、2-溴-N-甲基丙烯酰基-5-甲氧基-N-甲基苯甲酰胺1g(31.2mg,0.1mmol)、三氟甲基烯烃2a(39.4mg,0.2mmol)、二甲基亚砜(2mL)和四氢呋喃(2mL)，封闭反应管，80℃下反应48小时，浓缩，快速柱层析，得无色液体产物9(25.7mg,66％yield)。
1H NMR(400MHz,CDCl3)δ7.60-7.55(m,2H),7.54-7.47(m,3H),7.32-7.28(m,1H),7.25-7.21(m,1H),7.20(d,J＝2.5Hz,1H),3.84(s,3H),3.26(dd,J＝14.9,6.7Hz,1H),2.97(dd,J＝15.0,4.9Hz,1H),2.92(d,J＝4.8Hz,3H),1.61(s,3H)；13C NMR(151MHz,CDCl3)δ200.7,166.5(d,J＝3.1Hz),160.3,154.5(d,J＝294.8Hz),153.8,136.5(d,J＝5.2Hz),134.3,132.1,127.6(d,J＝7.5Hz),126.1,124.8,118.7,115.9(d,J＝1.9Hz),111.1(d,J＝2.2Hz),105.3,74.0(d,J＝18.2Hz),55.8,49.6(d,J＝5.6Hz),42.4(d,J＝4.6Hz),26.5,24.9；19F NMR(376MHz,CDCl3)δ-115.62(t,J＝6.1Hz)；HRMS(m/z):[M+H]+calcd.forC23H20FN2O3 +,391.1444；found,391.1453.
实施例8
Figure BDA0003651445090000071
在氩气气氛下向装有磁子的反应管中加入乙酰丙酮镍(2.6mg,0.01mmol)、三联吡啶(4.7mg,0.02mmol)、锰(16.5mg,0.3mmol)、溴化锰(43.0mg,0.2mmol)、
Figure BDA0003651445090000074
分子筛(20mg)、2-溴-6-氟-N-甲基丙烯酰基-N-甲基苯甲酰胺1h(30.0mg,0.1mmol)、三氟甲基烯烃2a(39.4mg,0.2mmol)、二甲基亚砜(2mL)和四氢呋喃(2mL)，封闭反应管，80℃下反应48小时，浓缩，快速柱层析，得无色液体产物10(25.0mg,66％yield)。
1H NMR(400MHz,CDCl3)δ7.75-7.65(m,1H),7.62-7.49(m,4H),7.45-7.36(m,1H),7.34-7.29(m,1H),7.14-7.03(m,1H),3.32(dd,J＝15.0,6.7Hz,1H),3.03(dd,J＝15.0,4.9Hz,1H),2.92(d,J＝4.8Hz,3H),1.64(s,3H)；13C NMR(151MHz,CDCl3)δ197.2,166.0(d,J＝3.2Hz),162.8,159.1(d,J＝267.3Hz),155.1,153.2,138.5(d,J＝8.3Hz),136.2(d,J＝5.3Hz),132.1,127.6(d,J＝7.4Hz),121.3(d,J＝12.5Hz),119.8(d,J＝3.9Hz),118.6,116.3(d,J＝2.2Hz),115.7(d,J＝18.9Hz),111.3(d,J＝2.4Hz),73.6(d,J＝18.5Hz),50.3(d,J＝5.5Hz),42.7(d,J＝4.7Hz),26.5,24.7；19F NMR(376MHz,CDCl3)δ-112.70(dd,J＝9.0,4.6Hz),-115.52(t,J＝5.9Hz)；HRMS(m/z):[M+H]+calcd.for C22H17F2N2O2 +,379.1245；found,379.1253.
实施例9
Figure BDA0003651445090000072
在氩气气氛下向装有磁子的反应管中加入乙酰丙酮镍(2.6mg,0.01mmol)、三联吡啶(4.7mg,0.02mmol)、锰(16.5mg,0.3mmol)、溴化锰(43.0mg,0.2mmol)、
Figure BDA0003651445090000073
分子筛(20mg)、3-溴-N-甲基丙烯酰基-N,1-二甲基-1H-吲哚-2-甲酰胺1i(33.4mg,0.1mmol)、三氟甲基烯烃2a(39.4mg,0.2mmol)、二甲基亚砜(2mL)和四氢呋喃(2mL)，封闭反应管，80℃下反应48小时，浓缩，快速柱层析，得无色液体产物11(21.5mg,52％yield)。
1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.1Hz,1H),7.60–7.51(m,4H),7.46(t,J＝7.7Hz,1H),7.39(d,J＝8.5Hz,1H),7.24(d,J＝7.9Hz,1H),7.06(d,J＝4.5Hz,1H),3.93(s,3H),3.20(dd,J＝5.8,2.8Hz,2H),2.93(d,J＝4.8Hz,3H),1.79(s,3H)；13C NMR(151MHz,CDCl3)δ189.3(d,J＝3.1Hz),166.8(d,J＝3.0Hz),156.8,154.8,150.0,145.4,136.7(d,J＝5.0Hz),134.8,132.0,128.0,127.6(d,J＝7.5Hz),121.7,121.1,120.8,118.7,115.3(d,J＝2.4Hz),111.6,110.9(d,J＝2.2Hz),78.6(d,J＝17.6Hz),45.9(d,J＝6.0Hz),40.6,30.3,26.5,24.3；19F NMR(376MHz,CDCl3)δ-116.43(t,J＝5.6Hz)；HRMS(m/z):[M+H]+calcd.for C25H21FN3O2 +,414.1612；found,414.1601.
实施例10
Figure BDA0003651445090000081
在氩气气氛下向装有磁子的反应管中加入乙酰丙酮镍(2.6mg,0.01mmol)、三联吡啶(4.7mg,0.02mmol)、锰(16.5mg,0.3mmol)、溴化锰(43.0mg,0.2mmol)、
Figure BDA0003651445090000083
分子筛(20mg)、2-溴-N-甲基-N-甲基丙烯酰苯甲酰胺1b(28.2mg,0.1mmol)、三氟甲基烯烃2b(48.8mg,0.2mmol)、二甲基亚砜(2mL)和四氢呋喃(2mL)，封闭反应管，80℃下反应48小时，浓缩，快速柱层析，得无色液体产物12(19.6mg,48％yield)。
1H NMR(400MHz,CDCl3)δ7.99-7.92(m,2H),7.83-7.78(m,1H),7.75-7.68(m,1H),7.64-7.59(m,1H),7.52-7.42(m,3H),7.32-7.26(m,1H),4.34(q,J＝7.1Hz,2H),3.32(dd,J＝15.1,6.6Hz,1H),3.06(dd,J＝15.1,4.9Hz,1H),2.92(d,J＝4.8Hz,3H),1.63(m,3H),1.37(t,J＝7.1Hz,3H)；13C NMR(151MHz,CDCl3)δ201.0(d,J＝2.9Hz),166.7(d,J＝3.3Hz),163.6(d,J＝759.8Hz),154.3,152.3,136.5,136.3(d,J＝5.2Hz),133.2,129.5,129.5(d,J＝1.7Hz),128.8,127.0(d,J＝7.1Hz),124.5,124.0,116.8(d,J＝2.5Hz),73.5(d,J＝18.4Hz),61.0,50.1(d,J＝5.8Hz),42.8(d,J＝4.9Hz),26.4,24.8,14.3；19F NMR(376MHz,CDCl3)δ-117.47(t,J＝6.0Hz)；HRMS(m/z):[M+H]+calcd.for C24H23FNO4 +,408.1609；found,408.1606.
实施例11
Figure BDA0003651445090000082
在氩气气氛下向装有磁子的反应管中加入乙酰丙酮镍(2.6mg,0.01mmol)、三联吡啶(4.7mg,0.02mmol)、锰(16.5mg,0.3mmol)、溴化锰(43.0mg,0.2mmol)、
Figure BDA0003651445090000084
分子筛(20mg)、2-溴-N-甲基-N-甲基丙烯酰苯甲酰胺1b(28.2mg,0.1mmol)、三氟甲基烯烃2c(50.0mg,0.2mmol)、二甲基亚砜(2mL)和四氢呋喃(2mL)，封闭反应管，80℃下反应48小时，浓缩，快速柱层析，得无色液体产物13(27.2mg,66％yield)。
1H NMR(600MHz,CDCl3)δ7.89–7.83(m,2H),7.83–7.79(m,1H),7.75–7.71(m,1H),7.65–7.58(m,3H),7.50–7.44(m,1H),7.34–7.29(m,1H),3.35(dd,J＝14.9,6.4Hz,1H),3.06(dd,J＝15.0,4.6Hz,1H),3.00(s,3H),2.93(d,J＝4.6Hz,3H),1.64(s,3H)；13C NMR(151MHz,CDCl3)δ200.9(d,J＝2.8Hz),166.5,160.9,154.5(d,J＝294.9Hz),139.2,137.4(d,J＝5.1Hz),136.7,133.1,128.9,127.9(d,J＝7.1Hz),127.4,124.6,124.0,116.0,73.4(d,J＝18.5Hz),50.3(d,J＝5.6Hz),44.5,42.7(d,J＝4.4Hz),26.5,24.8；19F NMR(565MHz,CDCl3)δ-115.78(d,J＝6.1Hz)；HRMS(m/z):[M+H]+calcd.for C22H20FNO4S+,414.1170；found,414.1172.
实施例12
Figure BDA0003651445090000091
在氩气气氛下向装有磁子的反应管中加入乙酰丙酮镍(2.6mg,0.01mmol)、三联吡啶(4.7mg,0.02mmol)、锰(16.5mg,0.3mmol)、溴化锰(43.0mg,0.2mmol)、
Figure BDA0003651445090000092
分子筛(20mg)、2-溴-N-甲基-N-甲基丙烯酰苯甲酰胺1b(28.2mg,0.1mmol)、三氟甲基烯烃2d(42.8mg,0.2mmol)、二甲基亚砜(2mL)和四氢呋喃(2mL)，封闭反应管，80℃下反应48小时，浓缩，快速柱层析，得无色液体产物14(20.7mg,55％yield)。
1H NMR(400MHz,CDCl3)δ7.91-7.86(m,2H),7.81(dd,J＝7.6,1.1Hz,1H),7.75-7.69(m,1H),7.62(dd,J＝7.9,0.9Hz,1H),7.55-7.50(m,2H),7.46(td,J＝7.1,0.8Hz,1H),7.29(t,J＝4.9Hz,1H),3.33(dd,J＝15.1,6.6Hz,1H),3.06(dd,J＝15.0,4.9Hz,1H),2.93(d,J＝5.1Hz,2H),2.57(s,2H)；13C NMR(151MHz,CDCl3)δ201.0(d,J＝3.0Hz),197.5,166.7(d,J＝3.3Hz),161.1,153.6(d,J＝293.7Hz),136.6,136.6,136.5,133.2,128.8,128.4,127.3(d,J＝7.2Hz),124.6,124.0,116.7(d,J＝2.4Hz),73.5(d,J＝18.5Hz),50.2(d,J＝5.6Hz),42.8(d,J＝4.8Hz),26.6,26.5,24.8；19F NMR(565MHz,CDCl3)δ-117.21(t,J＝5.9Hz)；HRMS:(ESI)calcd for C23H20FNO3 +[M+H]+378.1500；found 378.1513.
实施例13
Figure BDA0003651445090000093
在氩气气氛下向装有磁子的反应管中加入乙酰丙酮镍(2.6mg,0.01mmol)、三联吡啶(4.7mg,0.02mmol)、锰(16.5mg,0.3mmol)、溴化锰(43.0mg,0.2mmol)、
Figure BDA0003651445090000094
分子筛(20mg)、2-溴-N-甲基-N-甲基丙烯酰苯甲酰胺1b(28.2mg,0.1mmol)、三氟甲基烯烃2e(44.6mg,0.2mmol)、二甲基亚砜(2mL)和四氢呋喃(2mL)，封闭反应管，80℃下反应48小时，浓缩，快速柱层析，得无色液体产物15(19.3mg,49％yield)。
1H NMR(600MHz,CDCl3)δ8.99(d,J＝2.2Hz,1H),8.04–7.96(m,2H),7.82(d,J＝7.7Hz,1H),7.72(t,J＝7.5Hz,1H),7.70–7.62(m,3H),7.50(t,J＝7.9Hz,2H),7.46(t,J＝7.7Hz,1H),3.39(dd,J＝14.9,6.5Hz,1H),3.14(dd,J＝14.9,4.7Hz,1H),2.95(d,J＝4.8Hz,3H),1.68(s,3H)；13C NMR(151MHz,CDCl3)δ200.8(d,J＝3.0Hz),166.8(d,J＝3.2Hz),161.0,153.3(d,J＝292.2Hz),149.0(d,J＝8.3Hz),146.9,136.5,133.4(d,J＝6.9Hz),133.2,129.8,129.0,128.8,128.0,127.4,127.0,125.4(d,J＝5.8Hz),124.6,124.0,114.9(d,J＝3.5Hz),73.4(d,J＝18.3Hz),50.4(d,J＝5.5Hz),42.5(d,J＝5.1Hz),26.5,24.8；19F NMR(376MHz,CDCl3)δ-117.71(t,J＝4.9Hz)；HRMS(m/z):[M+H]+calcd.forC24H20FN2O2 +,387.1503；found,387.1502.
实施例14
Figure BDA0003651445090000101
在氩气气氛下向装有磁子的反应管中加入乙酰丙酮镍(2.6mg,0.01mmol)、三联吡啶(4.7mg,0.02mmol)、锰(16.5mg,0.3mmol)、溴化锰(43.0mg,0.2mmol)、
Figure BDA0003651445090000102
分子筛(20mg)、2-溴-N-甲基-N-甲基丙烯酰苯甲酰胺1b(28.2mg,0.1mmol)、三氟甲基烯烃2f(42.5mg,0.12mmol)、二甲基亚砜(2mL)和四氢呋喃(2mL)，封闭反应管，70℃下反应48小时，浓缩，快速柱层析，得无色液体产物16(29.9mg,57％yield)。
1H NMR(400MHz,CDCl3)δ7.95(d,J＝8.1Hz,2H),7.81(d,J＝7.7Hz,1H),7.71(t,J＝7.5Hz,1H),7.61(dd,J＝7.8,2.7Hz,1H),7.47(dd,J＝16.6,7.8Hz,3H),7.27(s,1H),4.89(td,J＝10.8,4.3Hz,1H),3.32(ddd,J＝15.0,6.6,3.2Hz,1H),3.05(dd,J＝15.1,4.8Hz,1H),2.93(d,J＝4.8Hz,3H),2.10(d,J＝11.8Hz,1H),1.97–1.85(m,1H),1.71(d,J＝11.4Hz,2H),1.58–1.48(m,2H),1.30(d,J＝19.8Hz,1H),1.08(q,J＝12.1Hz,2H),0.99–0.82(m,9H),0.76(d,J＝7.7Hz,3H)；13C NMR(151MHz,CDCl3)δ201.0,166.7,165.6,161.1,153.3(d,J＝293.2Hz),136.5,136.1(d,J＝5.2Hz),133.1,129.8,129.5,128.8,127.0(d,J＝7.0Hz),124.5,124.0(d,J＝2.4Hz),116.8(d,J＝1.5Hz),74.9,73.4(d,J＝18.3Hz),50.2(d,J＝5.4Hz),47.2,42.8(d,J＝4.8Hz),40.9,34.2,31.4,26.5(d,J＝2.2Hz),24.8,23.6,22.0,20.7,16.5(d,J＝2.0Hz)；19F NMR(565MHz,CDCl3)δ-117.65–-117.81(m)；HRMS(m/z):[M+H]+calcd.for C32H37FNO4 +,518.2701；found,518.2713.
实施例15
Figure BDA0003651445090000111
在氩气气氛下向装有磁子的反应管中加入乙酰丙酮镍(2.6mg,0.01mmol)、三联吡啶(4.7mg,0.02mmol)、锰(16.5mg,0.3mmol)、溴化锰(43.0mg,0.2mmol)、
Figure BDA0003651445090000112
分子筛(20mg)、2-溴-N-甲基-N-甲基丙烯酰苯甲酰胺1b(28.2mg,0.1mmol)、三氟甲基烯烃2g(54.9mg,0.12mmol)、二甲基亚砜(2mL)和四氢呋喃(2mL)，封闭反应管，90℃下反应48小时，浓缩，快速柱层析，得无色液体产物17(34.8mg,56％yield)。
1H NMR(600MHz,CDCl3)δ8.02-7.96(m,2H),7.83-7.79(m,1H),7.75-7.69(m,1H),7.64-7.59(m,1H),7.54-7.43(m,3H),7.30-7.26(m,1H),4.68(dd,J＝11.8,1.1Hz,1H),4.63(dd,J＝7.9,2.7Hz,1H),4.44(dd,J＝2.6,1.0Hz,1H),4.29(dd,J＝11.8,2.0Hz,1H),4.27-4.23(m,1H),3.94(dd,J＝13.1,1.9Hz,1H),3.79(dd,J＝13.0,0.8Hz,1H),3.32(ddd,1H),3.06(ddd,J＝15.0,4.8,1.9Hz,1H),2.93(d,J＝4.8Hz,3H),1.64(s,3H),1.53(d,J＝1.9Hz,3H),1.45(d,J＝1.3Hz,3H),1.34(s,3H),1.31(d,J＝2.5Hz,3H),13C NMR(151MHz,CDCl3)δ201.0(d,J＝2.8Hz),166.7(d,J＝3.0Hz),165.4,161.1,153.6(d,J＝293.6Hz),136.6(d,J＝5.1Hz),136.5,133.2,129.8,128.9,128.8,127.1(d,J＝7.2Hz),124.6,124.0,116.7(d,J＝2.2Hz),109.2,108.8,101.6,73.5(d,J＝18.6Hz),70.8,70.5,70.1,65.2,61.3,58.5,50.2(d,J＝5.5Hz),42.8(d,J＝4.8Hz),26.5(d,J＝5.9Hz),25.9,25.5,24.8,24.0,14.1；19F NMR(565MHz,CDCl3)δ-117.14(dt,J＝17.7,5.8Hz)；HRMS(m/z):[M+H]+calcd.for C34H37FNO9 +,622.2447；found,622.2446.
以上列举的仅是本发明的几个具体实施例，显然，本发明不仅限于以上实施例，还可以有诸多变形，本领域的普通技术人员能从本发明公开的内容直接导出或间接联想到的所有变形，均应认为是本发明的保护范围。

Claims (6)

1. 一种氟代环戊烯并茚满酮化合物的制备方法，其特征在于，包括下述步骤：将式A所示的化合物、式B所示的三氟甲基烯烃、乙酰丙酮镍、三联吡啶、锰、溴化锰、4 Å分子筛加到二甲基亚砜和四氢呋喃的混合溶剂中，在惰性气体保护和密闭条件下，在70-90℃下反应，得到式C所示的氟代环戊烯并茚满酮化合物；
Figure QLYQS_1
、
Figure QLYQS_2
、
Figure QLYQS_3
式中，Ar为取代的芳基或杂芳基；R1为正丁基、甲基或苄基；R2为甲基或苯基；R3为取代的芳基或杂芳基。
2.根据权利要求1所述的制备方法，其特征在于：
Ar中，所述的芳基具有一个选自卤素、-OMe或甲基的取代基，所述的杂芳基为吲哚基；
R3中，所述的芳基具有一个选自-CN，-(C=O)OEt、-(SO2)Me、-(C=O)Me、甲酸薄荷酯或呋喃果糖的取代基，所述的杂芳基为喹啉基。
3.根据权利要求1所述的方法，其特征在于：式A所示的化合物选自如下结构：
Figure QLYQS_4
；
式B所示的三氟甲基烯烃选自如下结构：
Figure QLYQS_5
。
4. 根据权利要求1所述的制备方法，其特征在于：式A所示的化合物、式B所示的三氟甲基烯烃、乙酰丙酮镍、锰、溴化锰的摩尔比为1.0:2.0:0.1:3.0:2.0；其中式A所示的化合物浓度为0.025 mol/L。
5.根据权利要求1所述的制备方法，其特征在于：所述的惰性气体为氩气。
6.根据权利要求1所述的制备方法，其特征在于：所述的反应的时间为48-96小时。
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