CN109627163B - 苯酚类化合物邻位直接烯烃化方法及烯烃化苯酚类化合物 - Google Patents
苯酚类化合物邻位直接烯烃化方法及烯烃化苯酚类化合物 Download PDFInfo
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- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 6
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Abstract
本发明涉及一种苯酚类化合物邻位直接烯烃化方法,以及利用该方法制备获得的烯烃化苯酚类化合物。所述方法包括:式(II)所示苯酚类化合物与式(III)所示烯烃化合物在乙酸溶剂中,在催化剂和氧化剂作用下,于20~100℃下反应10~20小时,反应结束后反应液经分离纯化得到式(I)所示烯烃化苯酚类化合物;本发明提供了一种钯催化苯酚直接烯烃化的方法,操作过程简单,原料都已商品化容易得到,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,只需一步便可制得烯烃化苯酚类衍生物。
Description
(一)技术领域
本发明涉及一种苯酚类化合物邻位直接烯烃化方法,以及利用该方法制备获得的烯烃化苯酚类化合物。
(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、炸药、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烯烃化的新方法以及利用该方法制备获得的新烯烃化苯酚类化合物,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烯烃化苯酚类衍生物。
本发明采用的技术方案是:
一种苯酚类化合物邻位直接烯烃化方法,所述方法包括:式(II)所示苯酚类化合物与式(III)所示烯烃化合物在乙酸溶剂中,在催化剂和氧化剂作用下,于20~100℃下反应10~20小时,反应结束后反应液经分离纯化得到式(I)所示烯烃化苯酚类化合物;
式(I)~(III)中,
R1为H、卤素、C1~C7的直链或支链烷基、C1~C7的直链或支链烷氧基;R2为芳基、取代芳基、C2~C8的直链烷基、氰基、C1~C7的烷基砜基、或C2~C8的烷氧羰基,所述取代芳基的取代基为一个或多个,每个取代基各自独立选自C1~C7的烷基;
所述催化剂为下列之一:醋酸钯、氯化钯、醋酸铜、氯化铜、醋酸亚铁、氯化镍或乙酰丙酮钯;
所述的氧化剂为下列之一:氧化锰、醋酸碘苯、叔丁基过氧化氢或过硫酸钾。
所述苯酚类化合物、烯烃化合物、催化剂、氧化剂物质的量之比为1:1~5:0.1~0.5:1~5。
所述的分离纯化可按照如下步骤进行:反应混合物中加入饱和NaCl水溶液,用二氯甲烷萃取,取有机层经过无水硫酸镁干燥、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,得到烯烃化苯酚类化合物(I)。
优选的,所述R1为H、氟、溴、甲基或甲氧基;R2为苯基、氰基、甲氧羰基、乙氧羰基、2,3,4,5,6-五甲基苯基、或甲基砜基。
式(I)所示烯烃化苯酚类化合物优选为下列之一:
所述催化剂为二乙酰丙酮钯。
所述氧化剂为过硫酸钾。
所述苯酚类化合物、烯烃化合物、催化剂、氧化剂物质的量之比为1:1:0.2:1。
本发明还涉及一种烯烃化苯酚类化合物,所述化合物结构如下式之一所示:
本发明还涉及上述新述化合物在制备香豆素类化合物中的应用。上述化合物可通过环合反应制备香豆素类化合物,以化合物(I-2)为例,反应式如下:
本发明还涉及所述化合物作为荧光标记物的应用。经检测,该烯烃化苯酚衍生物具有荧光结构,可作为荧光标记物应用于荧光检测中。
本发明的有益效果体现在:本发明提供了一种钯催化苯酚直接烯烃化的方法,操作过程简单,原料都已商品化容易得到,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,只需一步便可制得烯烃化苯酚类衍生物,所得烯烃化苯酚衍生物可以进一步的合成香豆素以及其他药物,且该烯烃化苯酚衍生物具有荧光结构,可作为荧光标记物应用于荧光检测中。
(四)附图说明
图1为化合物(I-2)荧光发射图谱;
图2为化合物(I-3)荧光发射图谱;
图3为化合物(I-4)荧光发射图谱;
图4为化合物(I-6)荧光发射图谱。
(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:
将1mmol对甲基苯酚加入4ml的乙酸溶剂中,向其中加入0.2mmol乙酰丙酮钯,1.0mmol丙烯酸乙酯,1.0mmol过硫酸钾,80℃下反应12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(I-1)所示的化合物纯品42mg。
化合物(I-1)NMR数据:1H NMR(400MHz,CDCl3)δ8.03(d,J=16.4Hz,1H),7.01(d,J=2.0Hz,1H),6.86(s,1H),6.76(d,J=8.0Hz,1H),6.62(d,J=16.0Hz,1H),4.29(q,J=14.0,7.6Hz,2H),2.26(s,3H),1.34(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3)δ168.7,153.5,141.0,132.2,129.7,129.4,121.4,118.0,116.3,60.7,20.4,14.3
实施例2:
将1mmol对乙基苯酚加入4ml的乙酸溶剂中,向其中加入0.2mmol乙酰丙酮钯,1.0mmol丙烯酸乙酯,1.0mmol过硫酸钾,80℃下反应12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2A-2化合物粗品。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1:8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(I-2)所示的化合物纯品48mg。
化合物(I-2)NMR数据:1H NMR(500MHz,DMSO)δ8.46(d,J=8.0Hz,1H),8.30(d,J=7.3Hz,1H),8.09(d,J=8.5Hz,1H),7.44(t,J=7.6Hz,1H),6.56(s,1H),4.03–3.96(m,2H),1.56(dd,J=14.9,7.6Hz,2H),1.33(dd,J=15.0,7.4Hz,3H),0.92(t,J=7.4Hz,3H).
实施例3:
将1mmol对氟苯酚加入4ml的乙酸溶剂中,向其中加入0.2mmol乙酰丙酮钯,1.0mmol丙烯酸乙酯,1.0mmol过硫酸钾,80℃下反应12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1:10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(I-3)所示的化合物纯品39mg。
化合物(I-3)NMR数据:H NMR(400MHz,CDCl3)δ7.97(d,J=16.1Hz,1H),7.17(dd,J=9.1,3.0Hz,1H),6.95(td,J=8.5,3.0Hz,1H),6.79(dd,J=8.8,4.5Hz,1H),6.58(d,J=16.1Hz,1H),6.23(br s,1H),4.28(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3)δ167.7,156.0,151.1,139.0,122.8,119.7,117.9
实施例4:
将1mmol间溴苯酚加入4ml的乙酸溶剂中,向其中加入0.2mmol乙酰丙酮钯,1.0mmol丙烯酸乙酯,1.0mmol过硫酸钾,80℃下反应12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1:8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(I-4)所示的化合物纯品62mg。
化合物(I-4)NMR数据:1H NMR(400MHz,DMSO-d6):δ8.20(br,1H),7.99(d,J=16.0Hz,1H),7.34(d,J=8.0Hz,1H),6.93-6.86(m,2H),6.64(d,J=16.0Hz,1H),4.31(q,J=8.0Hz,2H),1.36(t,J=8.0Hz,3H)ppm;13C NMR(100MHz,DMSO-d6):δ169.05,156.52,140.24,136.70,19.99,120.77,120.45,118.16,116.73,61.08,14.27
实施例5:
将1mmol对甲氧基苯酚加入4ml的乙酸溶剂中,向其中加入0.2mmol乙酰丙酮钯,1.0mmol丙烯酸乙酯,1.0mmol过硫酸钾,80℃下反应12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1:10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(I-5)所示的化合物纯品57mg。
化合物(I-5)NMR数据:1H NMR(500MHz,CDCL3):δ=9.13(s,1H,OH),7.93(d,3J=15.9Hz,1H),7.53(d,3J=8.4Hz,1H),6.53-6.48(m,2H),6.47(d,J=16.2Hz,1H),4.18(q,3J=7.2Hz,2H),3.78(s,3H),1.28(t,3J=7.2Hz,3H).13C NMR(105MHz,CDCL3):δ=167.9,163.5,158.8,140.6,131.0,115.9,115.5,107.1,102.2,60.3,55.6,14.7
实施例6:
将1mmol邻甲基苯酚加入4ml的乙酸溶剂中,向其中加入0.2mmol乙酰丙酮钯,1.0mmol丙烯酸乙酯,1.0mmol过硫酸钾,80℃下反应12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1:10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,得到式所示的化合物纯品47mg。
化合物(I-6)NMR数据:1H NMR(400MHz,CDCl3)δ8.03(d,J=16.4Hz,1H),7.01(d,J=2.0Hz,1H),6.86(s,1H),6.76(d,J=8.0Hz,1H),6.62(d,J=16.0Hz,1H),4.29(q,J=14.0,7.6Hz,2H),2.26(s,3H),1.34(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3)δ168.7,153.5,141.0,132.2,129.7,129.4,121.4,118.0,116.3,60.7,20.4,14.3;
实施例7:
将1mmol苯酚加入4ml的乙酸溶剂中,向其中加入0.2mmol乙酰丙酮钯,1.0mmol丙烯酸乙酯,1.0mmol过硫酸钾,80℃下反应,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1:15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,得到式所示的化合物纯品55mg。
化合物(I-7)NMR数据:1H NMR(500MHz,CDCl3)δ8.03(d,J=15.8Hz,1H),7.46(s,1H),7.26(d,J=17.7Hz,1H),6.95–6.83(m,2H),6.63(d,J=15.9Hz,1H),4.30(s,2H),1.37(s,3H).13C NMR(126MHz,CDCl3)δ168.40(s),155.48(s),140.57(s),131.40(s),129.17(s),120.64(s),118.40(s),116.39(s),60.68(s),14.34(s).
实施例8:
将1mmol苯酚加入4ml的乙酸溶剂中,向其中加入0.2mmol乙酰丙酮钯,1.0mmol丙烯酸甲酯,1.0mmol过硫酸钾,80℃下反应12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1:5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,得到式所示的化合物纯品29mg。
化合物(I-9)NMR数据:H NMR(500MHz,CDCl3)δ8.03(d,J=16.1Hz,1H),7.48(dd,J=7.8,1.6Hz,1H),7.27–7.23(m,1H),6.94(td,J=7.6,1.1Hz,1H),6.85(dd,J=8.1,1.1Hz,1H),6.64(d,J=16.2Hz,1H),6.27–6.17(m,1H),3.84(s,3H).
实施例9:
将1mmol苯酚加入4ml的乙腈溶剂中,向其中加入0.2mmol乙酰丙酮钯,1.0mmol丙烯腈,1.0mmol过硫酸钾,80℃下反应,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1:3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,得到所示的化合物纯品33mg。
化合物(I-10)NMR数据:1H NMR(400MHz,CDCl3):δ7.62(d,J=16.8Hz,1H),7.67-7.65(dd,J=7.6,1.6Hz,1H),7.30-7.26(m,1H),6.95(dt,J1=8.0Hz,J2=1.2Hz,1H),6.84(dd,J1=8.4Hz,J2=1.2Hz,1H),6.16(d,J=16.8Hz,1H);13C NMR(100MHz,CDCl3):δ155.2,147.1,132.3,129.5,121.1,121.0,119.1,116.5,96.9。
实施例10:
将1mmol苯酚加入4ml的乙酸溶剂中,向其中加入0.2mmol乙酰丙酮钯,1.0mmol苯乙烯,1.0mmol过硫酸钾,80℃下反应12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1:3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,得到式所示的化合物纯品33mg。
化合物(I-8)NMR数据:1H NMR(400MHz,CDCl3):δ7.53(d,J=7.6Hz,3H),7.37(d,J=16.4Hz,1H),7.35(t,J=7.6Hz,2H),7.25(t,J=3.6Hz,1H),7.15(dt,J=1.6Hz,1H),7.12(d,J=16.4Hz,1H),6.95(t,J=7.6Hz,1H),6.80(d,J=8.0Hz,1H),5.00(s,1H);13CNMR(100MHz,CDCl3):δ153.0,137.7,130.3,128.7,127.7,127.3,126.6,124.8,123.1,121.3,116.0。
实施例11:
将1mmol苯酚加入4ml的乙酸溶剂中,向其中加入0.2mmol乙酰丙酮钯,1.0mmol五氟苯乙烯,1.0mmol过硫酸钾,80℃下反应12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1:3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,得到化合物纯品33mg。
化合物(I-13)NMR数据:δ7.66(s,1H),7.50(d,J=8.0Hz,1H),7.41-7.34(m,3H),7.23-7.12(m,2H),7.03(d,J=16.4Hz,1H),6.95(t,J=7.6Hz,1H),6.77(d,J=8.0Hz,1H),5.13(s,1H);13C NMR(100MHz,CDCl3):δ153.1,139.9,130.4,130.2,129.3,129.1,128.3,127.3,125.3,124.6,124.2,122.9,121.3,116.1。
实施例12:化合物(I-2)、(I-3)、(I-4)和(I-6)荧光性质检测
准确称取前述制得的化合物(I-2)、(I-3)、(I-4)和(I-6),溶解在二甲基亚砜中,配置成终浓度为10mmol的荧光母液,用移液枪吸取1ul的母液,加入到1.0mL的PBS缓冲液中,震荡5分钟,用荧光酶标仪检测其荧光信号曲线,结果见图1~4。
由图可见,化合物(I-2)、(I-3)、(I-4)和(I-6)具有荧光结构,提示可以作为荧光标记物应用于荧光检测之中。
Claims (4)
2.如权利要求1所述的方法,其特征在于所述R1为H、氟、溴、甲基或甲氧基。
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、烯烃化合物、催化剂、氧化剂物质的量之比为1: 1:0.2:1。
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