CN110950739B - 一种苯酚类化合物邻位直接氟化的方法 - Google Patents
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Abstract
本发明涉及一种苯酚类化合物邻位直接氟化的方法,所述方法包括:式(1A)所示苯酚类化合物与氟化试剂在溶剂中,在光催化剂和光源的作用下于室温下进行反应,反应完全后反应混合物经分离纯化得到式(2A)所示氟化苯酚类化合物;本发明的有益效果主要体现在:本发明提供了一种有机光催化苯酚直接氟化的方法,操作过程简单,原料都已商品化容易得到,光催化剂廉价易得且环境友好,反应条件温和,位点选择性高,反应高效,只需一步便可制得氟化苯酚类衍生物。
Description
(一)技术领域
本发明涉及一种苯酚类化合物邻位直接氟化的方法。
(二)背景技术
苯酚是重要的基本有机原料,其许多下游产品涉及到众多领域,主要用于制造酚醛树脂、双酚A和己内酰胺。而苯酚的衍生物如卤代酚、硝基酚、烷基酚可用于医药、农药、油漆、染料、***、香料等的生产。苯酚类化合物广泛存在于自然界中,香料及许多天然产物中都含有苯酚结构。而传统对于苯酚类化合物修饰的方法为:首先对羟基进行保护,再在羟基的其他位点进行修饰,最后脱保护,实现修饰。这类方法条件比较苛刻,而且方法步骤多,反应收率低,这些存在的问题大大的降低了对于苯酚类化合物修饰研究的进展。因此,设计出一种更为简单高效、经济环保的方法是相当必要的。
(三)发明内容
本发明的目的是提供一种苯酚类化合物邻位直接氟化的新方法,其催化剂廉价易得且环境友好、反应条件温和、位点选择性高,反应高效,而且只需一步便可制得氟化苯酚类衍生物。
本发明采用的技术方案是:
一种苯酚类化合物邻位直接氟化的方法,所述方法包括:式(1A)所示苯酚类化合物与氟化试剂在溶剂中,在光催化剂和光源的作用下于室温下进行反应,反应完全后反应混合物经分离纯化得到式(2A)所示氟化苯酚类化合物;
所述氟化试剂为下列之一:N-氟代双苯磺酰胺(NFSI),1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)盐(Selectfluor),1-氟吡啶四氟硼酸盐(N-fluoropyridinium);
所述溶剂为下列之一:乙腈,水,醋酸水溶液,二氯甲烷,二甲基亚砜,1,2-二氯乙烷;
所述光催化剂为下列之一:三联吡啶氯化钌六水合物([Ru(bpy)3]Cl2),三(2-苯基吡啶)合铱([Ru(bpy)3]Cl2),荧光素(Fluorescein),罗丹明B(Rhodamine B),罗丹明(Rhodamine 6G),曙红Y(Eosin Y);
所述光源为下列之一:蓝光、绿光、黄光;
所述苯酚类化合物、氟化试剂与光催化剂的物质的量之比为1:1~3:0.05~0.1;
其中R为H、卤素、硝基、C1~C7烷基或C1~C7烷氧基。
优选的,所述R为H、氟、溴、氯、甲基、酯基、羟基、甲氧基或乙酰基。
具体的,所述氟化苯酚类化合物为下列之一:
苯酚类化合物、氟化试剂与光催化剂的物质的量之比优选为1:1.5:0.05。
所述氟化试剂优选为1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)盐。
所述光催化剂优选为曙红Y。
所述溶剂优选为10%醋酸水溶液。
具体的,所述分离纯化方法如下:反应混合物中加入饱和NaCl水溶液,用二乙酸乙酯烷萃取,取有机层经过无水硫酸钠干燥、过滤、常温下旋转蒸除溶剂,即得粗品;将粗品进行硅胶柱层析,以乙酸乙酯和石油醚的体积比为1:10的溶液为流动相,TLC跟踪收集Rf值为0.3~0.5的洗脱液,收集得到的洗脱液经减压除去溶剂,干燥,得到式(2A)所示氟化苯酚类化合物。
本发明的有益效果主要体现在:本发明提供了一种有机光催化苯酚直接氟化的方法,操作过程简单,原料都已商品化容易得到,光催化剂廉价易得且环境友好,反应条件温和,位点选择性高,反应高效,只需一步便可制得氟化苯酚类衍生物。
(四)附图说明
图1为化合物2A-1的核磁氢谱;
图2为化合物2A-1的碳谱;
图3为化合物2A-1的氟谱;
图4为化合物2A-2的核磁氢谱;
图5为化合物2A-2的碳谱;
图6为化合物2A-2的氟谱;
图7为化合物2A-3的核磁氢谱;
图8为化合物2A-4的核磁氢谱;
图9为化合物2A-5的核磁氢谱;
图10为化合物2A-6的核磁氢谱;
图11为化合物2A-7的核磁氢谱;
图12为化合物2A-8的核磁氢谱;
图13为化合物2A-9的核磁氢谱;
图14为化合物2A-10的核磁氢谱;
图15为化合物2A-11的核磁氢谱;
图16为化合物2A-12的核磁氢谱。
(五)具体实施方式
下面结合具体实施例对本发明进行进一步描述,但本发明的保护范围并不仅限于此:
实施例1:化合物2A-1的制备
将1mmol对3-氟苯酚加入4ml的10%(v/v)醋酸水溶液中,向其中加入1.5mmolSelectfluor,0.05mmol Eosin Y,室温下12W蓝光照射反应6小时,反应结束后,反应液中加入饱和NaCl水溶液,用二氯甲烷萃取,取有机层经过无水硫酸钠干燥、过滤、减压蒸干,即得化合物粗品。将化合物粗品进硅胶柱层析,以乙酸乙酯和石油醚的体积比为1:9的溶液为流动相,TLC跟踪收集Rf值为0.3~0.5的洗脱液,收集得到的洗脱液经减压除去溶剂,干燥,得到式2A-1所示的化合物纯品100mg(收率70%),其核磁氢谱、碳谱、氟谱参见图1~图3。1HNMR(500MHz,CDCl3)δ7.09(tt,J=4.6,3.0Hz,2H),7.06–7.01(m,1H),5.58(s,1H).13C NMR(126MHz,CDCl3)δ156.41(s),130.79(s),123.93(s),122.79(s),118.83(s),114.27(s).19F NMR(376MHz,CDCl3)δ-133.85(d,J=6.6Hz).HRMS(ESI+):Calculated forC6H4BrFO:[M+H]+190.9430,found 190.9433.
实施例2:化合物2A-2的制备
将1mmol对苯酚加入4ml的10%醋酸水溶液中,向其中加入1.5mmol Selectfluor,0.05mmol Eosin Y,室温下12W蓝光照射反应6小时,反应结束后,反应液中加入饱和NaCl水溶液,用二氯甲烷萃取,取有机层经过无水硫酸钠干燥、过滤、减压蒸干,即得化合物粗品。将化合物粗品进硅胶柱层析,以乙酸乙酯和石油醚的体积比为1:9的溶液为流动相,TLC跟踪收集Rf值为0.3-0.5的洗脱液,收集得到的洗脱液经减压除去溶剂,干燥,得到式2A-2所示的化合物纯品90mg(收率77%),其核磁氢谱、碳谱、氟谱参见图4~图6。1H NMR(500MHz,CDCl3)δ7.13(dt,J=8.2,1.4Hz,1H),7.03(ddd,J=9.9,8.4,1.4Hz,1H),6.83(td,J=8.3,5.5Hz,1H),5.55(s,1H).13C NMR(126MHz,CDCl3)δ152.34(s),150.40(s),140.62(d,J=14.7Hz),124.76(d,J=3.5Hz),120.32(d,J=7.7Hz),114.81(d,J=18.3Hz).19F NMR(471MHz,CDCl3)δ-134.62(s).HRMS(ESI+):Calculated for C6H4ClFO:[M+H]+146.9935,found 146.9931.
实施例3:化合物2A-3的制备
将1mmol 2-叔丁基苯酚加入4ml的10%醋酸水溶液中,向其中加入1.5mmolSelectfluor,0.05mmol Eosin Y,室温下12W蓝光照射反应6小时,反应结束后,反应液中加入饱和NaCl水溶液,用二氯甲烷萃取,取有机层经过无水硫酸钠干燥、过滤、减压蒸干,即得化合物粗品。将化合物粗品进硅胶柱层析,以乙酸乙酯和石油醚的体积比为1:9的溶液为流动相,TLC跟踪收集Rf值为0.3-0.5的洗脱液,收集得到的洗脱液经减压除去溶剂,干燥,得到式2A-3所示的化合物纯品120mg(收率73%),其核磁氢谱参见图7。1H NMR(500MHz,DMSO)δ9.33(s,1H),7.06–6.93(m,2H),6.72(td,J=8.0,5.6Hz,1H),1.35(s,9H).13C NMR(126MHz,DMSO)δ151.20(s),143.02(d,J=14.6Hz),138.80(s),121.55(d,J=2.5Hz),118.45(d,J=7.6Hz),113.15(d,J=19.0Hz),29.28(s).19F NMR(376MHz,DMSO)δ-136.65(s).HRMS(ESI+):Calculated for C10H13FO:[M+H]+169.0950,found 169.0944.
实施例4:化合物2A-4的制备
将1mmol间甲基苯酚加入4ml的10%醋酸水溶液中,向其中加入1.5mmolSelectfluor,0.05mmol Eosin Y,室温下12W蓝光照射反应6小时,反应结束后,反应液中加入饱和NaCl水溶液,用二氯甲烷萃取,取有机层经过无水硫酸钠干燥、过滤、减压蒸干,即得化合物粗品。将化合物粗品进硅胶柱层析,以乙酸乙酯和石油醚的体积比为1:9的溶液为流动相,TLC跟踪收集Rf值为0.3-0.5的洗脱液,收集得到的洗脱液经减压除去溶剂,干燥,得到式2A-4所示的化合物纯品96mg(收率76%),其核磁氢谱参见图8。1H NMR(500MHz,CDCl3)δ6.81–6.72(m,2H),6.69(ddd,J=9.9,7.6,2.3Hz,1H),5.74(s,2H).13C NMR(126MHz,CDCl3)δ152.45(s),150.56(s),145.46(d,J=3.9Hz),131.51(s),120.22(d,J=8.8Hz),111.36(d,J=2.8Hz),107.75(d,J=18.4Hz).19F NMR(471MHz,CDCl3)δ-138.61(s).HRMS(ESI+):Calculated for C6H5FO2:[M+H]+129.0274,found 129.0271.
实施例5:化合物2A-5的制备
将1mmol对溴苯酚加入4ml的10%醋酸水溶液中,向其中加入1.5mmolSelectfluor,0.05mmol Eosin Y,室温下12W蓝光照射反应6小时,反应结束后,反应液中加入饱和NaCl水溶液,用二氯甲烷萃取,取有机层经过无水硫酸钠干燥、过滤、减压蒸干,即得化合物粗品。将化合物粗品进硅胶柱层析,以乙酸乙酯和石油醚的体积比为1:9的溶液为流动相,TLC跟踪收集Rf值为0.3-0.5的洗脱液,收集得到的洗脱液经减压除去溶剂,干燥,得到式2A-5所示的化合物纯品130mg(收率68%),其核磁氢谱参见图9。1H NMR(500MHz,CDCl3)δ7.25(dd,J=10.0,2.3Hz,1H),7.21–7.12(m,1H),6.91(t,J=8.9Hz,1H),5.44(s,1H).13CNMR(126MHz,CDCl3)δ151.87(s),149.95(s),142.85(d,J=14.0Hz),127.94(d,J=3.7Hz),119.12(s),118.95(s),118.59(d,J=2.2Hz),111.62(d,J=8.1Hz).19F NMR(471MHz,CDCl3)δ-137.33(s).HRMS(ESI+):Calculated for C6H4BrFO:[M+H]+190.9430,found190.9433.
实施例6:化合物2A-6的制备
将1mmol对氯苯酚加入4ml的10%醋酸水溶液中,向其中加入1.5mmolSelectfluor,0.05mmol Eosin Y,室温下12W蓝光照射反应6小时,反应结束后,反应液中加入饱和NaCl水溶液,用二氯甲烷萃取,取有机层经过无水硫酸钠干燥、过滤、减压蒸干,即得化合物粗品。将化合物粗品进硅胶柱层析,以乙酸乙酯和石油醚的体积比为1:9的溶液为流动相,TLC跟踪收集Rf值为0.3-0.5的洗脱液,收集得到的洗脱液经减压除去溶剂,干燥,得到式2A-6所示的化合物纯品125mg(收率85%),其核磁氢谱参见图10。1H NMR(500MHz,CDCl3)δ7.11(dd,J=10.3,2.4Hz,1H),7.03(ddd,J=8.7,2.3,1.4Hz,1H),6.95(t,J=8.9Hz,1H),5.39(s,1H).13C NMR(126MHz,CDCl3)δ151.65(s),149.74(s),142.29(d,J=14.1Hz),125.04(dd,J=12.7,6.3Hz),118.05(d,J=2.4Hz),116.34(s),116.17(s).19FNMR(471MHz,CDCl3)δ-137.42(s).HRMS(ESI+):Calculated for C6H4ClFO:[M+H]+146.9935,found 146.9931.
实施例7:化合物2A-7的制备
将1mmol 2-溴-苯酚加入4ml的10%醋酸水溶液中,向其中加入1.5mmolSelectfluor,0.05mmol Eosin Y,室温下12W蓝光照射反应6小时,反应结束后,反应液中加入饱和NaCl水溶液,用二氯甲烷萃取,取有机层经过无水硫酸钠干燥、过滤、减压蒸干,即得化合物粗品。将化合物粗品进硅胶柱层析,以乙酸乙酯和石油醚的体积比为1:9的溶液为流动相,TLC跟踪收集Rf值为0.3-0.5的洗脱液,收集得到的洗脱液经减压除去溶剂,干燥,得到式2A-7所示的化合物纯品140mg(收率74%),其核磁氢谱参见图11。1H NMR(500MHz,CDCl3)δ7.11(dd,J=10.3,2.4Hz,1H),7.03(ddd,J=8.7,2.3,1.4Hz,1H),6.95(t,J=8.9Hz,1H),5.39(s,1H).13C NMR(126MHz,CDCl3)δ151.65(s),149.74(s),142.29(d,J=14.1Hz),125.04(dd,J=12.7,6.3Hz),118.05(d,J=2.4Hz),116.34(s),116.17(s).19FNMR(471MHz,CDCl3)δ-137.42(s).HRMS(ESI+):Calculated for C6H4ClFO:[M+H]+146.9935,found 146.9931.
实施例8:化合物2A-8的制备
将1mmol 2-氯苯酚加入4ml的10%醋酸水溶液中,向其中加入1.5mmolSelectfluor,0.05mmol Eosin Y,室温下12W蓝光照射反应6小时,反应结束后,反应液中加入饱和NaCl水溶液,用二氯甲烷萃取,取有机层经过无水硫酸钠干燥、过滤、减压蒸干,即得化合物粗品。将化合物粗品进硅胶柱层析,以乙酸乙酯和石油醚的体积比为1:9的溶液为流动相,TLC跟踪收集Rf值为0.3-0.5的洗脱液,收集得到的洗脱液经减压除去溶剂,干燥,得到式2A-8所示的化合物纯品112mg(收率77%),其核磁氢谱参见图12。1H NMR(500MHz,CDCl3)δ7.27(dt,J=8.2,1.4Hz,1H),7.07(ddd,J=9.8,8.3,1.3Hz,1H),6.78(td,J=8.2,5.3Hz,1H).13C NMR(126MHz,CDCl3)δ127.69(d,J=3.5Hz),121.09(d,J=7.5Hz),115.45(d,J=18.4Hz).19F NMR(471MHz,CDCl3)δ-133.77(s).HRMS(ESI+):Calculated forC6H4BrFO:[M+H]+190.9430,found 190.9433.
实施例9:化合物2A-9的制备
将1mmol邻苯二酚加入4ml的10%醋酸水溶液中,向其中加入1.5mmolSelectfluor,0.05mmol Eosin Y,室温下12W蓝光照射反应6小时,反应结束后,反应液中加入饱和NaCl水溶液,用二氯甲烷萃取,取有机层经过无水硫酸钠干燥、过滤、减压蒸干,即得化合物粗品。将化合物粗品进硅胶柱层析,以乙酸乙酯和石油醚的体积比为1:9的溶液为流动相,TLC跟踪收集Rf值为0.3-0.5的洗脱液,收集得到的洗脱液经减压除去溶剂,干燥,得到式2A-9所示的化合物纯品60mg(收率47%),其核磁氢谱参见图13。1H NMR(500MHz,CDCl3)δ6.81–6.72(m,2H),6.69(ddd,J=9.9,7.6,2.3Hz,1H),5.74(s,2H).13C NMR(126MHz,CDCl3)δ152.45(s),150.56(s),145.46(d,J=3.9Hz),131.51(s),120.22(d,J=8.8Hz),111.36(d,J=2.8Hz),107.75(d,J=18.4Hz).19F NMR(471MHz,CDCl3)δ-138.61(s).HRMS(ESI+):Calculated for C6H5FO2:[M+H]+129.0274,found 129.0271.
实施例10:化合物2A-10的制备
将1mmol 3-甲氧基苯酚加入4ml的10%醋酸水溶液中,向其中加入1.5mmolSelectfluor,0.05mmol Eosin Y,室温下12W蓝光照射反应6小时,反应结束后,反应液中加入饱和NaCl水溶液,用二氯甲烷萃取,取有机层经过无水硫酸钠干燥、过滤、减压蒸干,即得化合物粗品。将化合物粗品进硅胶柱层析,以乙酸乙酯和石油醚的体积比为1:9的溶液为流动相,TLC跟踪收集Rf值为0.3-0.5的洗脱液,收集得到的洗脱液经减压除去溶剂,干燥,得到式2A-10所示的化合物纯品122mg(收率86%),其核磁氢谱参见图14。1H NMR(500MHz,CDCl3)δ6.95(dd,J=10.3,9.1Hz,1H),6.55(dd,J=7.3,3.0Hz,1H),6.35(dt,J=9.0,3.3Hz,1H),3.75(s,3H).13C NMR(126MHz,CDCl3)δ156.33(s),146.92(s),145.08(s),144.29(d,J=15.8Hz),115.52(d,J=19.7Hz),105.13(d,J=6.4Hz),103.28(s),55.71(s).19F NMR(376MHz,CDCl3)δ-150.96(d,J=10.3Hz).HRMS(ESI+):Calculated forC7H7FO2:[M+H]+143.0430,found 143.0432.
实施例11:化合物2A-11的制备
将1mmol对乙酰基苯酚加入4ml的10%醋酸水溶液中,向其中加入1.5mmolSelectfluor,0.05mmol Eosin Y,室温下12W蓝光照射反应6小时,反应结束后,反应液中加入饱和NaCl水溶液,用二氯甲烷萃取,取有机层经过无水硫酸钠干燥、过滤、减压蒸干,即得化合物粗品。将化合物粗品进硅胶柱层析,以乙酸乙酯和石油醚的体积比为1:9的溶液为流动相,TLC跟踪收集Rf值为0.3-0.5的洗脱液,收集得到的洗脱液经减压除去溶剂,干燥,得到式2A-11所示的化合物纯品88mg(收率57%),其核磁氢谱参见图15。1H NMR(500MHz,MeOD)δ7.75–7.63(m,2H),6.98(t,J=8.6Hz,1H),4.86(s,1H),2.52(s,3H).13C NMR(126MHz,MeOD)δ198.42(d,J=1.9Hz),153.46(s),151.78–151.45(m),130.65(d,J=4.7Hz),127.31(d,J=2.9Hz),118.32(d,J=2.9Hz),116.97(d,J=19.2Hz),26.25(s).19FNMR(376MHz,MeOD)δ-138.68(s).HRMS(ESI+):Calculated for C8H7FO2:[M+H]+155.0430,found 155.0433.
实施例12:化合物2A-12的制备
将1mmol 4-甲酸甲酯苯酚加入4ml的10%醋酸水溶液中,向其中加入1.5mmolSelectfluor,0.05mmol Eosin Y,室温下12W蓝光照射反应6小时,反应结束后,反应液中加入饱和NaCl水溶液,用二氯甲烷萃取,取有机层经过无水硫酸钠干燥、过滤、减压蒸干,即得化合物粗品。将化合物粗品进硅胶柱层析,以乙酸乙酯和石油醚的体积比为1:9的溶液为流动相,TLC跟踪收集Rf值为0.3-0.5的洗脱液,收集得到的洗脱液经减压除去溶剂,干燥,得到式2A-12所示的化合物纯品93mg(收率59%),其核磁氢谱参见图16。1H NMR(500MHz,CDCl3)δ7.78(dt,J=4.2,2.0Hz,2H),7.05(dt,J=12.4,2.5Hz,1H),6.20(s,1H),3.91(s,3H).13C NMR(126MHz,CDCl3)δ166.21(s),151.42(s),149.52(s),148.15(d,J=14.2Hz),127.10(d,J=3.2Hz),122.95(d,J=6.0Hz),117.24(s),117.07(d,J=2.2Hz),52.27(s).19F NMR(471MHz,CDCl3)δ-139.71(s).HRMS(ESI+):Calculated for C8H7FO3:[M+H]+171.0379,found 171.0379.
Claims (6)
2.如权利要求1所述的方法,其特征在于所述R为H、氟、溴、氯、甲基、酯基、羟基、甲氧基或乙酰基。
4.如权利要求2所述的方法,其特征在于所述苯酚类化合物、氟化试剂与光催化剂的物质的量之比为1:1.5:0.05。
5.如权利要求1~4之一所述的方法,其特征在于所述溶剂为10%醋酸水溶液。
6.如权利要求1~4之一所述的方法,其特征在于所述分离纯化方法如下:反应混合物中加入饱和NaCl水溶液,用二乙酸乙酯烷萃取,取有机层经过无水硫酸钠干燥、过滤、常温下旋转蒸除溶剂,即得粗品;将粗品进行硅胶柱层析,以乙酸乙酯和石油醚的体积比为1:10的溶液为流动相,TLC跟踪收集Rf值为0.3~0.5的洗脱液,收集得到的洗脱液经减压除去溶剂,干燥,得到式(2A)所示氟化苯酚类化合物。
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