CN115611764A - 一种多氟芳烃的邻位选择性c-f键活化官能化反应方法 - Google Patents
一种多氟芳烃的邻位选择性c-f键活化官能化反应方法 Download PDFInfo
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Abstract
本发明涉及一种多氟芳烃的邻位选择性C‑F键活化官能化反应方法，以多氟芳烃化合物和格氏试剂为原料，氮气气氛、搅拌条件下，在非均相的可循环双金属MOF催化剂和溶剂存在下发生Kumada偶联反应，实现一系列多氟芳烃的邻位选择性官能化反应，从而高效地构建邻位官能化的多氟芳烃化合物。
Description
技术领域
本申请属于无机-有机化学催化合成技术领域，具体涉及以双金属有机框架(MOF)为催化剂，异相催化Kumada偶联反应来实现邻位选择性C-F键活化官能化反应，进而制备一系列多氟芳烃衍生物。
背景技术
多氟芳烃衍生物在有机合成中是一种重要的含氟化合物，同时在医药和功能材料方面也具有重要的应用。作为廉价易得的含氟芳烃，多氟芳烃衍生物常被选用于制备各种重要含氟化合物的氟化原料。因此，选择性C-F键活化官能化也一直是有机化学工作者研究的热点。其中通过金属催化的偶联反应来实现选择性C-F键活化，从而实现C-C键的构筑，是一条行之有效的方法。近些年来，化学家主要发展了利用贵金属尤其是Pd为催化剂催化的各种C-F键活化官能化反应(Angew.Chem.Int.Ed.2013,52,5813–5817；Organometallics2021,40,2246-2252；)。然而，从原子经济性和绿色环保角度考虑，金属Pd并不是一种理想的催化剂。价格昂贵，回收难度大，且易造成金属在产物中的残留等问题是目前阻碍该类反应发展和大规模合成的主要因素。因此，如何利用廉价易得的试剂，发展绿色无毒，操作简单的方法，从而高转化率地获得多氟芳烃衍生物是一项极具挑战性又亟待解决的问题。
发明内容
为解决上述问题，申请人对多氟芳烃参与的选择性C-F键活化展开了深入的研究，并成功发展了双金属有机框架(MOF)催化的选择性C-F键活化官能化反应，即选择性Kumada偶联反应。该方法不同于传统的金属催化，其催化过程属于异相催化，催化效率高，且反应结束后可通过离心手段将催化剂回收并循环使用。此外，该反应操作过程简单，同时避免了贵重金属催化剂的使用，便于工业化应用生产；此方法还可以轻易的扩大至克级，为此类化合物的大规模合成应用提供了可能。
为实现上述目的，本发明采用如下技术方案：
氮气氛围下，向干燥的Schlenk反应瓶中加入式(I)所示的双金属有机框架材料、式(II)所示的多氟芳烃化合物和溶剂，随后将反应瓶至于一定温度下边搅拌边逐滴加入式(III)所示的格氏试剂，经TLC监测反应进程，至原料完全反应后，经后处理得到式(IV)所示的官能化的多氟芳烃化合物。
所述双金属有机框架材料的结构如式(I)所示：
所述多氟芳烃化合物的结构式如式(II)所示:
所述的芳基格氏试剂的结构如式(III)所示：
所述的邻位官能化的多氟芳烃产物的结构如式(IV)所示：
反应式如下：
本发明中，可选用的后处理过程包括：萃取，洗涤，硅胶拌样，经柱层析纯化得到偶联产物。
作为优选，R1为氢、C5-C10烷基、C2～C10酰基；
作为优选，R2为C1～C3烷基、C1～C4烯基、C5～C10芳基；
作为优选，X为氯、溴、碘
上述各R1-R2取代基中的具有所述碳原子数目的芳基、烷基和烷氧基任选地被取代基取代，所述的取代基选自氢、卤素、C1-C5烷基、C5-C10芳基、C1-C4烷氧基。
作为优选，以摩尔量计，多氟芳烃:格氏试剂＝1.0:1.0～1.0:3.0。作为进一步的优选，以摩尔量计，卤代芳烃:芳基格氏试剂＝1.0:1.3。
作为优选，所述的反应的时间为12～24小时，反应时间过长过短都会影响反应的产率，优选为15小时。
作为优选，所述的一定温度为0～50℃，优选为25℃。
作为优选，所述的双金属有机框架催化剂(MOF)的金属组合为NiFe，MnFe或CoFe中的一种，优选为MnFe。
作为优选，所述的双金属有机框架催化剂(MOF)的用量为0％-20mol％，优选为10mol％。
作为优选，所述的有机溶剂为乙醚、四氢呋喃、二氧六环和甲基叔丁基醚中的任意一种，优选为四氢呋喃。
在本发明的反应中，所述的溶剂用量为1-6mL。优选为4mL.
同现有技术相比较，本发明的有益效果在于：
(1)相对于传统的均相过渡金属催化剂，非均相MOF催化剂廉价且易于制备，更重要的是，反应结束后易与产物分离，且可循环利用，从而最大化的降低了产物中的金属残留，降低了生产成本；
(2)相较于其他金属有机框架催化有机反应体系而言，该发明工艺简单，转化率高，化学选择性高，异相催化剂无需修饰即可直接用于催化Kumada偶联反应，此方法还可轻易地扩大至克级，为Kumada偶联反应的绿色、便捷、规模化催化应用提供了可能。
附图说明
图1为实施例1得到的产物的核磁共振氢谱；
图2为实施例1得到的产物的核磁共振碳谱；
图3为实施例1得到的产物的核磁共振氟谱；
具体实施方式
为了使本发明所述的内容更加清晰，下面将结合具体实施例，对本发明进行进一步详细的描述，但本发明并不局限于此。
下述实施例中所述实验方法，如无特殊说明，均为常规方法；所述试剂和原料，如无特殊说明，均可以从商业途径获得和/或根据已知的方法制备获得。
实施例1-8为反应条件优化实验。
实施例1
向充满氮气且干燥的Schlenk瓶中加入式1a所示的多氟芳基酰胺化合物(0.8mmol)，[MnFe(tda)H2O](10mol％)，四氢呋喃(4mL),然后将式2a所示的乙烯基溴化镁(1.04mmol,1.3equiv)逐滴加入上述溶液，反应器在氮气气氛、25℃条件下搅拌反应，经TLC监测反应进程至原料消失(反应时间为15小时)，反应完成后，将反应液用饱和氯化铵水溶液淬灭，随后用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤并减压浓缩除去溶剂，将残余物经柱层析分离(洗脱溶剂为：乙酸乙酯/石油醚)得到目标产物I-1(96％yield)：1H NMR(400MHz,Chloroform-d)δ7.83(d,J＝8.0Hz,1H),7.30(d,J＝4.4Hz,2H),7.00(dt,J＝8.4,4.4Hz,1H),3.42(s,3H).13C NMR(101MHz,CDCl3)δ158.8,143.9,143.4(dm,J＝257.1Hz),141.6(dm,J＝257.1Hz),137.1(dm,J＝254.1Hz),140.6,130.5,129.4,129.0(m),112.0(m),97.7,37.1.19F NMR(377MHz,Chloroform-d)δ-134.21,-137.15,-151.74(t,J＝20.8Hz),-159.82(td,J＝22.0,9.0Hz),-161.07(s).HRMS(ESI-TOF):m/z calculated forC14H8F4INONa+[M+Na]+:431.9479,found:431.9492.
实施例2
溶剂用乙醚代替四氢呋喃，其余条件同实施例1，得到目标产物I-1的收率为89％。
实施例3
催化剂用量提升至20mol％，其余条件同实施例1，得到目标产物I-1的收率为96％。
实施例4
反应温度升高至50℃，其余条件同实施例1，得到目标产物I-1的收率为83％。
实施例5
将乙烯基溴化镁用量降低至1.0当量，其余条件同实施例1，得到目标产物I-1的收率为79％。
实施例6
催化剂用[NiFe(tda)H2O]代替[MnFe(tda)H2O],其余条件同实施例1，得到目标产物I-1的收率为90％。
实施例7
催化剂用[CoFe(tda)H2O]代替[MnFe(tda)H2O],其余条件同实施例1，得到目标产物I-1的收率为88％。
实施例8
催化剂用MnCl2代替[MnFe(tda)H2O],其余条件同实施例1，得到目标产物I-1的收率为39％。
由上述实施例1-8可以看出，最佳的催化剂为实施例1的反应条件，即溶剂为四氢呋喃，所用催化剂为[MnFe(tda)H2O],温度为25℃。在获得最佳反应条件的基础上，发明人进一步在该条件下，选择不同取代的多氟芳烃和格氏试剂为底物发展高效的Kumada偶联催化方法。
实施例9
向充满氮气且干燥的Schlenk瓶中加入式1a所示的多氟芳基酰胺化合物(0.8mmol)，MOF(Mn-Fe)催化剂(10mg,10mol％)，四氢呋喃(4mL),然后将式2b所示的乙烯基溴化镁(1.04mmol,1.3equiv)逐滴加入上述溶液，反应器在氮气气氛、25℃条件下搅拌反应，经TLC监测反应进程至原料消失(反应时间为15小时)，反应完成后，将反应液用饱和氯化铵水溶液淬灭，随后用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤并减压浓缩除去溶剂，将残余物经柱层析分离(洗脱溶剂为：乙酸乙酯/石油醚)得到目标产物I-2(84％yield)：1H NMR(400MHz,CDCl3)δ5.88(s,1H),3.55–3.44(m,2H),1.88(d,J＝1.1Hz,3H),1.62(d,J＝1.9Hz,3H),1.54(d,J＝6.8Hz,3H),1.47(d,J＝6.8Hz,3H),1.13(d,J＝6.7Hz,3H),1.03(d,J＝6.7Hz,3H).13C NMR(101MHz,CDCl3)δ162.0,144.6(dm,J＝249.0Hz),143.0,142.9(dm,J＝245.2Hz),140.5(dm,J＝253.4Hz),139.3(dm,J＝253.9Hz),122.3(m),119.7(dt,J＝16.5,4.1Hz),113.2,51.5,46.5,25.7,21.0,20.5,20.32,20.28,20.2.19F NMR(377MHz,CDCl3)δ-136.55–-138.01(m),-144.09(dd,J＝22.9,12.7Hz),-156.36(t,J＝20.7Hz),-156.66–-157.57(m).HRMS(ESI-TOF):m/z calculated forC17H22F4NO+[M+H]+:332.1632,found:332.1640.
实施例10
向充满氮气且干燥的Schlenk瓶中加入式1a所示的多氟芳基酰胺化合物(0.8mmol)，MOF(Mn-Fe)催化剂(10mg,10mol％)，四氢呋喃(4mL),然后将式2c所示的苯基溴化镁(1.04mmol,1.3equiv)逐滴加入上述溶液，反应器在氮气气氛、25℃条件下搅拌反应，经TLC监测反应进程至原料消失(反应时间为15小时)，反应完成后，将反应液用饱和氯化铵水溶液淬灭，随后用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤并减压浓缩除去溶剂，将残余物经柱层析分离(洗脱溶剂为：乙酸乙酯/石油醚)得到目标产物I-3(91％yield)；
1H NMR(400MHz,CDCl3)δ7.48–7.44(m,2H),7.43–7.40(m,3H),3.50–3.40(m,1H),3.27–3.20(m,1H),1.47(d,J＝6.8Hz,3H),1.11(d,J＝6.8Hz,3H),1.03(d,J＝6.7Hz,3H),0.50(d,J＝6.6Hz,3H).13C NMR(101MHz,CDCl3)δ161.4,144.9(dm,J＝249.0Hz),143.6(dm,J＝246.8Hz),140.7(dm,J＝256.5Hz),139.8(dm,J＝257.9Hz),130.4(d,J＝1.2Hz),130.2,129.1,128.5,123.02(dd,J＝18.3,3.6Hz),122.69(dt,J＝14.8,4.0Hz),51.4,46.4,21.0,20.5,20.0,19.6.19F NMR(377MHz,CDCl3)δ-140.81(dd,J＝20.9,12.1Hz),-143.20(dd,J＝21.9,12.1Hz),-152.88–-157.08(m).HRMS(ESI-TOF):m/z calculated forC19H20F4NO+[M+H]+:354.1476,found:354.1485.
实施例11
向充满氮气且干燥的Schlenk瓶中加入式1a所示的多氟芳基酰胺化合物(0.8mmol)，MOF(Mn-Fe)催化剂(10mg,10mol％)，四氢呋喃(4mL),然后将式2d所示的均三甲苯基溴化镁(1.04mmol,1.3equiv)逐滴加入上述溶液，反应器在氮气气氛、25℃条件下搅拌反应，经TLC监测反应进程至原料消失(反应时间为19小时)，反应完成后，将反应液用饱和氯化铵水溶液淬灭，随后用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤并减压浓缩除去溶剂，将残余物经柱层析分离(洗脱溶剂为：乙酸乙酯/石油醚)得到目标产物I-4(62％yield)；1H NMR(400MHz,CDCl3)δ6.92(s,1H),6.86(s,1H),3.63–3.57(m,1H),3.29–3.22(m,1H),2.29(s,3H),2.16(s,3H),2.01(s,3H),1.44(d,J＝6.8Hz,3H),1.13(d,J＝6.6Hz,3H),0.94(d,J＝6.8Hz,3H),0.88(d,J＝6.6Hz,3H).13C NMR(101MHz,CDCl3)δ161.0,144.9(dm,J＝245.5Hz),143.7(dm,J＝252.4Hz),140.2(dm,J＝256.7Hz),139.7(dm,J＝256.6Hz),139.1,138.8,136.0,128.8,127.6,126.5,122.9(dd,J＝18.4,2.4Hz),122.1(dt,J＝19.2,4.0Hz),50.9,46.3,21.3,21.2,21.0,20.9,20.2,20.2,19.6.19F NMR(377MHz,CDCl3)δ-137.89(dd,J＝22.0,12.2Hz),-141.84(dd,J＝22.1,12.0Hz),-155.42–-155.59(m),-155.67(t,J＝21.0Hz).HRMS(ESI-TOF):m/z calculated for C22H26F4NO+[M+H]+:396.1945,found:396.1946.
实施例12
向充满氮气且干燥的Schlenk瓶中加入式1a所示的多氟芳基酰胺化合物(0.8mmol)，MOF(Mn-Fe)催化剂(10mg,10mol％)，四氢呋喃(4mL),然后将式2e所示的芳基基溴化镁(1.04mmol,1.3equiv)逐滴加入上述溶液，反应器在氮气气氛、25℃条件下搅拌反应，经TLC监测反应进程至原料消失(反应时间为18小时)，反应完成后，将反应液用饱和氯化铵水溶液淬灭，随后用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤并减压浓缩除去溶剂，将残余物经柱层析分离(洗脱溶剂为：乙酸乙酯/石油醚)得到目标产物I-5(55％yield)；1H NMR(400MHz,CDCl3)δ7.34(d,J＝8.6Hz,2H),6.71(d,J＝7.0Hz,2H),3.48–3.42(m,1H),3.29–3.23(m,1H),2.97(d,J＝2.1Hz,6H),1.49(d,J＝6.7Hz,3H),1.22(d,J＝6.8Hz,3H),1.01(d,J＝6.6Hz,3H),0.50(d,J＝6.6Hz,3H).13C NMR(101MHz,CDCl3)δ161.9,150.8,144.8(dm,J＝246.7Hz),143.6(dm,J＝245.5Hz),140.7(dm,J＝252.7Hz),139.1(dm,J＝254.8Hz),131.2,123.1(dt,J＝14.5,3.9Hz),122.8(dd,J＝17.8,2.5Hz),117.6,111.9,51.3,46.3,40.4,21.0,20.5,20.0,19.8.19F NMR(377MHz,CDCl3)δ-141.69(dd,J＝22.2,12.0Hz),-144.08(dd,J＝22.6,12.0Hz),-156.36(t,J＝21.3Hz),-157.53(t,J＝21.5Hz).HRMS(ESI-TOF):m/z calculated for C21H25F4N2O+[M+H]+:397.1898,found:397.1904.
实施例13
向充满氮气且干燥的Schlenk瓶中加入式1b所示的多氟芳基酰胺化合物(0.8mmol)，MOF(Mn-Fe)催化剂(10mg,10mol％)，四氢呋喃(4mL),然后将式2f所示的4-甲氧基苯基溴化镁(1.04mmol,1.3equiv)逐滴加入上述溶液，反应器在氮气气氛、25℃条件下搅拌反应，经TLC监测反应进程至原料消失(反应时间为15小时)，反应完成后，将反应液用饱和氯化铵水溶液淬灭，随后用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤并减压浓缩除去溶剂，将残余物经柱层析分离(洗脱溶剂为：乙酸乙酯/石油醚)得到目标产物I-6(92％yield)；1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.32(d,J＝8.5Hz,2H),7.02(d,J＝8.8Hz,2H),3.79(s,3H),1.11(s,9H).13C NMR(101MHz,DMSO-d6)δ159.8,159.7,144.5(dm,J＝241.3Hz),143.3(dm,J＝244.0Hz),139.6(dm,J＝250.5Hz),138.4(dm,J＝251.2Hz),130.9,123.8(dd,J＝18.7,2.3Hz),123.5(dt,J＝14.8,4.1Hz),122.2,113.7,55.2,51.1,28.0.19F NMR(377MHz,CDCl3)δ-141.77(dd,J＝23.5,12.0Hz),-144.31(dd,J＝24.2,12.0Hz),-157.01(t,J＝22.4Hz),-158.07(t,J＝22.7Hz).HRMS(ESI-TOF):m/zcalculated for C18H18F4NO2 +[M+H]+:356.1268,found:356.1280.
实施例14
向充满氮气且干燥的Schlenk瓶中加入式1c所示的多氟芳基酰胺化合物(0.8mmol)，MOF(Mn-Fe)催化剂(10mg,10mol％)，四氢呋喃(4mL),然后将式2f所示的4-甲氧基苯基溴化镁(1.04mmol,1.3equiv)逐滴加入上述溶液，反应器在氮气气氛、25℃条件下搅拌反应，经TLC监测反应进程至原料消失(反应时间为15小时)，反应完成后，将反应液用饱和氯化铵水溶液淬灭，随后用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤并减压浓缩除去溶剂，将残余物经柱层析分离(洗脱溶剂为：乙酸乙酯/石油醚)得到目标产物I-7(83％yield)；1H NMR(400MHz,CDCl3)δ7.29(d,J＝8.4Hz,2H),6.94(d,J＝8.3Hz,2H),3.80(s,3H),3.59–3.46(m,3H),3.40–3.35(m,1H),3.25–3.20(m,1H),3.10–3.05(m,1H),2.84–2.77(m,2H).13C NMR(101MHz,CDCl3)δ161.3,160.4,144.8(dm,J＝248.1Hz),143.7(dm,J＝248.9Hz),141.0(dm,J＝255.3Hz),139.5(dm,J＝255.5Hz),130.9,123.0(dt,J＝14.8,3.6Hz),122.0,120.0(dd,J＝17.0,3.3Hz),114.1,66.2,55.2,46.6,41.9.19F NMR(377MHz,CDCl3)δ-140.81(dd,J＝21.7,12.3Hz),-141.26–-141.95(m),-153.32–-155.00(m),-155.69(t,J＝21.3Hz).HRMS(ESI-TOF):m/z calculated for C18H16F4NO3 +[M+H]+:370.1061,found:370.1070.
实施例15
向充满氮气且干燥的Schlenk瓶中加入式1d所示的多氟芳基酰胺化合物(0.8mmol)，MOF(Mn-Fe)催化剂(10mg,10mol％)，四氢呋喃(4mL),然后将式2a所示的乙烯基溴化镁(1.04mmol,1.3equiv)逐滴加入上述溶液，反应器在氮气气氛、25℃条件下搅拌反应，经TLC监测反应进程至原料消失(反应时间为12小时)，反应完成后，将反应液用饱和氯化铵水溶液淬灭，随后用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤并减压浓缩除去溶剂，将残余物经柱层析分离(洗脱溶剂为：乙酸乙酯/石油醚)得到目标产物I-8(83％yield)；1H NMR(400MHz,CDCl3)δ6.43(dd,J＝17.8,11.6Hz,1H),5.78(d,J＝17.8Hz,1H),5.59(d,J＝11.7Hz,1H),2.76–2.71(m,1H),1.34(s,9H),1.07(d,J＝7.0Hz,2H),0.74–0.72(m,2H).13C NMR(101MHz,CDCl3)δ165.1,152.5,145.9(dm,J＝246.5Hz),141.0(dm,J＝246.5Hz),139.4(dm,J＝254.9Hz),125.9(d,J＝2.5Hz),123.6(dd,J＝8.5,2.0Hz),122.5(dt,J＝16.5,3.6Hz),119.6(dt,J＝12.8,3.9Hz),84.2,27.7,9.4.19F NMR(377MHz,CDCl3)δ-141.26(ddd,J＝20.2,11.6,3.4Hz),-144.70(dd,J＝22.1,11.7Hz),-155.32(t,J＝20.1Hz),-156.33–-159.86(m).HRMS(ESI-TOF):m/z calculated for C17H18F4NO3 +[M+H]+:360.1217,found:360.1230.
实施例16
向充满氮气且干燥的Schlenk瓶中加入式1e所示的多氟芳烃化合物(0.8mmol)，MOF(Mn-Fe)催化剂(10mg,10mol％)，四氢呋喃(4mL),然后将式2f所示的4-甲氧基苯基溴化镁(1.04mmol,1.3equiv)逐滴加入上述溶液，反应器在氮气气氛、25℃条件下搅拌反应，经TLC监测反应进程至原料消失(反应时间为17小时)，反应完成后，将反应液用饱和氯化铵水溶液淬灭，随后用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤并减压浓缩除去溶剂，将残余物经柱层析分离(洗脱溶剂为：乙酸乙酯/石油醚)得到目标产物I-9(86％yield)；1HNMR(500MHz,CDCl3)δ:7.27(d,J＝9.5Hz,1H),7.12(d,J＝7.0Hz,1H),7.04(d,J＝8.0Hz,1H),6.99(d,J＝7.5Hz,1H),6.74(d,J＝22.5Hz,1H),6.67(d,J＝7.5Hz,1H),3.76(s,3H),3.51(d,J＝9.5Hz,1H),3.38(d,J＝9.5Hz,1H),3.11(d,J＝15.5Hz,1H),2.69-2.56(m,3H),2.20(d,J＝10.5Hz,6H),1.26(s,3H),1.19(s,3H)；13C NMR(125MHz,CDCl3)δ:177.8,158.4,137.6,137.2,137.0,133.0,129.7,128.6,128.3,121.6,117.7,113.1,112.0,59.7,55.3,49.1,41.4,39.3,38.2,24.0,21.0,20.0,19.2；HRMS m/z(ESI)calcd for C23H28NO2([M+H]+)350.2115,found 350.2117。
实施例17
向充满氮气且干燥的Schlenk瓶中加入式1f所示的多氟芳烃化合物(0.8mmol)，MOF(Mn-Fe)催化剂(10mg,10mol％)，四氢呋喃(4mL),然后将式2f所示的4-甲氧基苯基溴化镁(1.04mmol,1.3equiv)逐滴加入上述溶液，反应器在氮气气氛、25℃条件下搅拌反应，经TLC监测反应进程至原料消失(反应时间为15小时)，反应完成后，将反应液用饱和氯化铵水溶液淬灭，随后用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤并减压浓缩除去溶剂，将残余物经柱层析分离(洗脱溶剂为：乙酸乙酯/石油醚)得到目标产物I-10(78％yield)；1HNMR(400MHz,CDCl3)δ7.27(d,J＝8.7Hz,2H),6.95(d,J＝8.7Hz,2H),4.16(t,J＝9.6Hz,2H),3.88(t,J＝9.6Hz,2H),3.84(s,3H).13C NMR(101MHz,CDCl3)δ160.0,158.2,146.0(ddt,J＝252.3,11.1,3.6Hz),144.9(dddd,J＝245.6,10.0,3.5,1.6Hz),141.5(dddd,J＝256.9,16.4,12.1,4.1Hz),139.6(dddd,J＝257.3,16.5,12.6,3.5Hz),130.7,126.1(dd,J＝15.3,2.5Hz),123.0,114.2(dt,J＝13.3,2.9Hz),113.9,67.9,55.3.19F NMR(377MHz,CDCl3)δ-138.80(ddd,J＝22.0,12.5,4.9Hz),-140.95(dd,J＝22.7,12.4Hz),-152.62(td,J＝21.6,5.3Hz),-156.63(td,J＝20.8,2.7Hz).HRMS(ESI-TOF):m/z calculated forC16H12F4NO2 +[M+H]+:326.0799,found:326.0815.
实施例18
向充满氮气且干燥的Schlenk瓶中加入式1g所示的多氟芳烃化合物(0.8mmol)，MOF(Mn-Fe)催化剂(10mg,10mol％)，四氢呋喃(4mL),然后将式2f所示的4-甲氧基苯基溴化镁(1.04mmol,1.3equiv)逐滴加入上述溶液，反应器在氮气气氛、25℃条件下搅拌反应，经TLC监测反应进程至原料消失(反应时间为18小时)，反应完成后，将反应液用饱和氯化铵水溶液淬灭，随后用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤并减压浓缩除去溶剂，将残余物经柱层析分离(洗脱溶剂为：乙酸乙酯/石油醚)得到目标产物I-11(64％yield)；1HNMR(400MHz,CDCl3)δ7.34–7.30(m,2H),7.08–7.01(m,1H),6.97–6.93(m,2H),3.83(s,3H),3.65–3.50(m,3H),3.45–3.39(m,1H),3.30–3.24(m,1H),3.16–3.10(m,1H),2.91–2.83(m,2H).13C NMR(101MHz,CDCl3)δ162.2(t,J＝2.8Hz),160.1,154.8(ddd,J＝247.5,9.4,2.7Hz),149.2(ddd,J＝253.5,14.5,12.3Hz),143.5(ddd,J＝246.5,13.6,4.0Hz),131.1(d,J＝1.8Hz),126.5(dd,J＝16.9,3.1Hz),123.2,123.0(ddd,J＝18.6,4.6,2.2Hz),114.1,106.4(dd,J＝29.2,20.7Hz),66.41,66.38,55.4,46.8,42.0.19F NMR(377MHz,CDCl3)δ-116.27(dd,J＝16.4,6.7Hz),-133.17(ddd,J＝23.0,9.6,3.6Hz),-144.54(ddd,J＝22.2,15.0,6.5Hz).HRMS(ESI-TOF):m/z calculated for C18H17F3NO3 +[M+H]+:352.1155,found:352.1169.
实施例19
催化剂循环实验
根据表1的条件，向充满氮气且干燥的Schlenk瓶中加入式1a所示的多氟芳基酰胺化合物(236.0mg,0.8mmol)，[MnFe(tda)H2O](10mol％)，四氢呋喃(4mL),然后将式2a所示的4-甲氧基苯基溴化镁(1.04mmol,1.3equiv)逐滴加入上述溶液，反应器在氮气气氛、一定温度条件下搅拌反应，经TLC监测反应进程至原料消失(反应时间为15小时)，反应完成后，将反应液用饱和氯化铵水溶液淬灭，随后用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤并减压浓缩除去溶剂，将残余物经柱层析分离(洗脱溶剂为：乙酸乙酯/石油醚)得到目标产物I-12(89％yield)。。所得无机相加入去离子水和乙醇洗涤，后经离心处理，可回收相应的催化剂。所得催化剂经干燥后，再投入下次催化循环。结果表明，催化剂可循环四次，且产率并没有明显的降低。1H NMR(400MHz,CDCl3)δ7.39(d,J＝7.7Hz,2H),6.92(d,J＝8.8Hz,2H),3.81(s,3H),3.48–3.38(m,1H),3.30–3.19(m,1H),1.47(d,J＝6.8Hz,3H),1.16(d,J＝6.8Hz,3H),1.01(d,J＝6.7Hz,3H),0.51(d,J＝6.6Hz,3H).13C NMR(101MHz,CDCl3)δ161.5,160.2,144.8(dm,J＝248.1Hz),143.5(dm,J＝245.5Hz),140.8(dm,J＝257.5Hz),139.4(dm,J＝257.1Hz),131.7(d,J＝1.2Hz),122.9(dd,J＝18.2,3.5Hz),122.5(m,overlapping,1C),122.4,113.9,55.4,51.3,46.3,20.9,20.4,20.1,19.7.19F NMR(377MHz,CDCl3)δ-141.16(dd,J＝21.6,12.3Hz),-143.59(dd,J＝22.2,12.2Hz),-155.98(t,J＝21.0Hz),-156.30(t,J＝21.3Hz).HRMS(ESI-TOF):m/z calculated for C20H22F4NO2 +[M+H]+:384.1581,found:384.1589.
由上述催化剂循环实验的顺利实施可知，该催化剂易与产物分离且可循环使用。因此该方法的发展极大地推动了异相催化的Kumada偶联反应的发展，为工业化、绿色催化合成提供了一条可供选择的方法。
以上所述实施例仅为本发明的优选实施例，而并非本发明可行实施的穷举。对于本领域技术人员而言，在不背离本发明原理和精神的前提下，对其所作出的任何显而易见的改动，都应当被认为包含在本发明的权利要求保护范围之内。
Claims (10)
1.一种多氟芳烃的邻位选择性C-F键活化官能化反应方法，其特征在于，包括以下步骤：以多氟芳烃化合物和格氏试剂为原料，氮气气氛、搅拌条件下，在双金属有机框架材料和溶剂存在下发生Kumada偶联反应，得到邻位官能化的多氟芳烃化合物；
所述双金属有机框架材料的分子式为[M(tda)H2O]；
M为NiFe，MnFe或CoFe；tda为硫代二乙酸其结构式；
所述多氟芳烃化合物的结构式如式(II)所示:
所述的格氏试剂的结构如式(III)所示：
所述的邻位官能化的多氟芳烃产物的结构如式(IV)所示：
在通式(I)、(II)和(III)中:
R1为氢、C1～C8烷基、C5～C13芳基、C2～C10酰基、C2～C10杂环；
R2为C1～C5烷基、C1～C4烯基、C5～C12芳基；Fn为芳杂环上取代的氟原子，n＝1～4；
X为卤素。
2.根据权利1要求所述的多氟芳烃的邻位选择性C-F键活化官能化反应方法，其特征在于，所述的R1为氢、甲基、乙基、叔丁基、酰基、杂环芳烃或芳基。
3.根据权利1要求所述的多氟芳烃的邻位选择性C-F键活化官能化反应方法，其特征在于，所述的R2为甲基、乙基、乙烯基、烯丙基或取代的芳基。
4.根据权利1要求所述的多氟芳烃的邻位选择性C-F键活化官能化反应方法，其特征在于，所述的X为Cl、Br或I。
5.根据权利要求1-4任一项所述的多氟芳烃的邻位选择性C-F键活化官能化反应方法，其特征在于，相对于所述的多氟芳烃化合物，双金属有机框架材料的用量为0％-20％mmol；
相对于所述的多氟芳烃化合物，所述的格氏试剂的摩尔用量为1-3当量。
6.根据权利要求1-4任一项所述的多氟芳烃的邻位选择性C-F键活化官能化反应方法，其特征在于，反应温度为0-50℃，反应时间为12-24小时。
7.根据权利要求1-4任一项所述的多氟芳烃的邻位选择性C-F键活化官能化反应方法，其特征在于，所述的溶剂为乙醚、四氢呋喃、二氧六环和甲基叔丁基醚中的任意一种。
8.根据权利要求1-4任一项所述的多氟芳烃的邻位选择性C-F键活化官能化反应方法，其特征在于，后处理操作如下：将反应完成后的反应液用饱和氯化铵淬灭，随后用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤并减压浓缩除去溶剂，将残余物经柱层析分离，洗脱溶剂为：乙酸乙酯/石油醚，得到多氟芳烃产物。
9.根据权利要求1所述的多氟芳烃的邻位选择性C-F键活化官能化反应方法，其特征在于：所述的双金属有机框架材料的制备方法如下：
将金属硝酸盐和有机配体置于N,N-二甲基甲酰胺、乙醇和水的混合溶液中，搅拌溶解，然后置于110～130℃反应1～3天，冷却至室温，乙醇洗涤，干燥，最终得到所述的双金属有机框架材料；
所述硝酸盐为钴、锰和镍的硝酸盐中的一种和铁的硝酸盐；
所述有机配体为均苯三酸和硫代二乙酸。
10.根据权利要求1所述的多氟芳烃的邻位选择性C-F键活化官能化反应方法，其特征在于：所述邻位官能化的多氟芳烃化合物为化合物I-1～I-12中的一种：
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| US6362365B1 (en) * | 1998-11-04 | 2002-03-26 | Clariant Gmbh | Preparation of trifluorobenzoic acids |
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