CN108530481B - 一种吲哚酮膦酰肼化合物及其衍生物的制备方法 - Google Patents
一种吲哚酮膦酰肼化合物及其衍生物的制备方法 Download PDFInfo
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- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
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Abstract
本发明涉及一种吲哚酮膦酰肼化合物及其衍生物的制备方法。以膦氧基化合物、3‑重氮吲哚酮为原料,在无金属试剂和无碱性试剂催化的条件下,3‑重氮吲哚酮与膦氧基化合物通过亲电加成进而得到吲哚酮膦酰肼衍生物。本发明采用无催化剂催化、一步直接构建N‑P键的路线,反应条件温和,操作简单且能实现克量级反应,能快速简单的合成出一系列吲哚酮膦酰肼衍生物,提供多样性的化合物骨架,对新药筛选和制药工艺有很大的意义。
Description
技术领域
本发明涉及一种吲哚酮膦酰肼化合物及其衍生物的制备方法,该吲哚酮膦酰肼衍生物具有光学活性,属于药物合成化学技术领域。
背景技术
近期的研究发现,有机膦化合物表现出特别的生物活性和化学性质(Org.Lett.2006,8(23),5291-5293),在有机合成、材料化学和药物化学上有广泛的应用。此外,吲哚骨架是许多常见的具有值得关注的药物价值和生物活性的天然物结构的重要组成部分(J.Med.Chem.1996,39,143-148)。最近,有文章报道,还有N-P键的膦酰胺衍生物显示出对抗HIV-1实质性效力以及显著抑制疱疹病毒复制的活性(J.Med.Chem.2017,60,7876-7896)。尽管现如今能够高效合成芳基和杂芳基有机膦化合物,但是,吲哚酮膦酰肼衍生物的构建方法目前还鲜少有报道。
3-重氮吲哚酮化合物在合成化学中具有多样的反应性和巨大的潜在可能性(Chem.Res.2013,46,236-247),但主要研究有金属卡宾前体,1,3-偶极以及碳-亲核试剂等领域,以3-重氮吲哚酮化合物作为亲电试剂的研究较少。冯小明教授研究团队报道了3-重氮吲哚酮化合物作为亲电试剂发生亲电加成,构建氮-碳(N-C)键的反应(J.Am.Chem.Soc.2011,133,15268–15271)。在报道之后,其他研究团队也对3-重氮吲哚酮化合物的亲电性进行了研究,然而使用的催化剂通常为贵金属催化剂或是强碱性催化剂。然而,以3-重氮吲哚酮化合物作为亲电试剂在不使用金属催化剂或碱性催化剂的条件下发生亲电加成构建氮-磷(N-P)键还未有报道。
发明内容
本发明的目的是公开一种原料价廉易得,操作简单,高收率的吲哚酮膦酰肼化合物。
为了实现上述目的,本发明采用了以下技术方案:
一种吲哚酮膦酰肼化合物及其衍生物的制备方法,用3-重氮吲哚酮化合物和苯基膦氧基化合物在无金属催化剂和无碱性催化剂的条件下,发生亲电加成反应生成N-P键,得到吲哚酮膦酰肼化合物及其衍生物,具体步骤如下:
(1)先称取1.0当量的3-重氮吲哚酮化合物,将3-重氮吲哚酮化合物溶解于有机溶剂中,浓度控制为0.125~0.350mol/L,得到重氮溶液;
(2)在一个圆底烧瓶中加入1.0~2.0当量的膦氧基化合物,加入有机溶剂,控制溶液中膦氧基化合物的浓度为0.125~0.350mol/L;
(3)将3-重氮吲哚酮溶液缓慢滴加入圆底烧瓶中,在0.5~1.0小时滴加结束,通过TLC监测反应进程,反应结束后浓缩得到粗产物;
(4)将粗产物用体积比为乙酸乙酯:石油醚=1:1的溶液进行柱层析,或是将粗产物过滤并用正己烷冲洗得到所述吲哚酮膦酰肼化合物及其衍生物。
所述有机溶剂为甲苯。
所述3-重氮吲哚酮化合物由相应的吲哚和对甲苯磺酰肼得到(请参阅Org.Lett.2016,18,1358-1361)。
本发明所用的有机溶剂和制备重氮的原料以及催化剂都可在市场购得。
与现有技术相比较,本发明具备的有益效果:
本发明公开了一种通过2-酮-3-重氮吲哚以及膦氧基化合物作为反应底物,合成一系列吲哚酮膦酰肼衍生物的新型合成策略。在这个反应中,膦氢化合物对2-酮-3-重氮吲哚的重氮的末端氮原子进行亲电加成。这个方法的特色就是提供一种无金属催化剂和无碱性催化剂催化,一步直接构建N-P键的路线。该反应具有操作简易,反应条件温和且能实现克量级反应。
本发明所用的原料,3-重氮吲哚酮化合物、膦氢化合物、有机溶剂和催化剂廉价易得,因此本发明合成膦氧基吲哚衍生物成本低廉。
本发明合成路线简单,一步构建目标产物。
本发明具有高选择性,高收率,环境友好等优点,符合绿色化学的要求。
本发明能快速简单的合成出一系列吲哚酮膦酰肼衍生物,提供多样性的化合物骨架,对新药筛选和制药工艺有很大的意义。
具体实施方式
实施例1
称取二苯基膦氧(121.3mg,0.6mmol)于含有搅拌子的圆底烧瓶中,加入1.2mL甲苯,至于60℃油浴中;再取1-苯基-3-重氮二氢吲哚-2-酮(74.8mg,0.3mmol)溶于1.2mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,将反应液浓缩再通过柱层析(石油醚:乙酸乙酯=1:1)分离得到产物3a。收率86%。
1H NMR(600MHz,Chloroform-d)δ11.96(d,J=30.0Hz,1H),7.98–7.90(m,4H),7.59–7.54(m,2H),7.53–7.45(m,5H),7.34–7.23(m,5H),7.22–7.16(m,1H),7.02–6.96(m,1H),6.74(d,J=6.0Hz,1H),4.91(s,2H);13C NMR(151MHz,Chloroform-d)δ161.46,141.58,135.55(d,J=12.1Hz),135.14,132.60(d,J=3.0Hz),132.29(d,J=10.6Hz),130.22,130.20(d,J=129.9Hz),128.93,128.74(d,J=13.6Hz),127.93,127.29,123.14,120.80,120.26,109.61,43.25;31P NMR(243MHz,Chloroform-d)δ22.76.
实施例2
称取二(4-氟苯基)膦氧(142.9mg,0.6mmol)于含有搅拌子的圆底烧瓶中,加入1.2mL甲苯,至于60℃油浴中;再取1-苯基-3-重氮二氢吲哚-2-酮(74.8mg,0.3mmol)溶于1.2mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,将反应液浓缩再通过柱层析(石油醚:乙酸乙酯=1:1)分离得到产物3b。收率71%。
1H NMR(600MHz,Chloroform-d)δ11.95(d,J=24.0Hz,1H),8.00–7.89(m,4H),7.46(d,J=6.0Hz,1H),7.35–7.23(m,5H),7.24–7.16(m,5H),7.00(t,J=7.6Hz,1H),6.76(d,J=6.0Hz,1H),4.91(s,2H);13C NMR(151MHz,Chloroform-d)δ165.57(dd,J=252.2,3.0Hz),161.45,141.71,135.97(d,J=13.6Hz),135.03,134.90(dd,J=10.5,9.1Hz),130.48,128.95,127.99,127.30,126.02(dd,J=135.9,3.0Hz),123.24,120.83,120.06,116.24(dd,J=21.1,14.4Hz),109.70,43.30;31P NMR(243MHz,Chloroform-d)δ21.10;19FNMR(565MHz,Chloroform-d)δ-105.30.
实施例3
称取二(3,5-双三氟甲基苯基)膦氧(284.5mg,0.6mmol)于含有搅拌子的圆底烧瓶中,加入1.2mL甲苯,至于60℃油浴中;再取1-苯基-3-重氮二氢吲哚-2-酮(74.8mg,0.3mmol)溶于1.2mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,将反应液浓缩再通过柱层析(石油醚:乙酸乙酯=1:1)分离得到产物3c。收率80%。
1H NMR(600MHz,Chloroform-d)δ12.19(d,J=24.0Hz,1H),8.44(dd,J=12.0,1.6Hz,4H),8.14(s,2H),7.45–7.40(m,1H),7.34(dd,J=8.3,6.0Hz,2H),7.32–7.26(m,4H),7.05(t,J=6.0Hz,1H),6.80(d,J=6.0Hz,1H),4.94(s,2H);13C NMR(151MHz,Chloroform-d)δ161.45,142.31,138.20(d,J=13.6Hz),134.66,132.91,132.76(d,J=19.6Hz),132.50(dd,J=10.6,4.5Hz),132.03,131.51,129.02,128.14,127.36,127.05–126.91(m),123.64,122.65(d,J=273.3Hz),121.02,119.34,110.07,43.51;31P NMR(243MHz,Chloroform-d)δ16.33;19F NMR(565MHz,Chloroform-d)δ-62.98.
实施例4
称取二(2-甲基苯基)膦氧(138.1mg,0.6mmol)于含有搅拌子的圆底烧瓶中,加入1.2mL甲苯,至于60℃油浴中;再取1-苯基-3-重氮二氢吲哚-2-酮(74.8mg,0.3mmol)溶于1.2mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,将反应液浓缩再通过柱层析(石油醚:乙酸乙酯=1:1)分离得到产物3d。收率71%。
1H NMR(600MHz,Chloroform-d)δ11.94(d,J=30.0Hz,1H),7.72–7.66(m,2H),7.53(dd,J=6.0,1.0Hz,1H),7.49–7.44(m,2H),7.36–7.23(m,9H),7.23–7.18(m,1H),7.05–7.00(m,1H),6.76(d,J=6.0Hz,1H),4.94(s,2H),2.57(d,J=1.0Hz,6H);13C NMR(151MHz,Chloroform-d)δ161.50,142.69(d,J=10.6Hz),141.46,135.19,134.83(d,J=13.6Hz),133.47(d,J=12.1Hz),132.59,131.90(d,J=12.1Hz),129.99,128.96(d,J=125.3Hz),128.93,127.92,127.29,125.69(d,J=13.6Hz),123.14,120.74,120.49,109.58,43.28,21.80(d,J=4.5Hz);31P NMR(243MHz,Chloroform-d)δ26.87.
实施例5
称取二(4-甲氧基苯基)膦氧(157.3mg,0.6mmol)于含有搅拌子的圆底烧瓶中,加入1.2mL甲苯,至于60℃油浴中;再取1-苯基-3-重氮二氢吲哚-2-酮(74.8mg,0.3mmol)溶于1.2mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,将反应液浓缩再通过柱层析(石油醚:乙酸乙酯=1:1)分离得到产物3e。收率77%。
1H NMR(600MHz,Chloroform-d)δ11.85(d,J=30.0Hz,1H),7.87–7.81(m,4H),7.50(dd,J=6.0,1.0Hz,1H),7.34–7.30(m,2H),7.29–7.26(m,3H),7.22–7.17(m,1H),7.03–6.97(m,5H),6.74(d,J=6.0Hz,1H),4.92(s,2H),3.85(s,6H);13C NMR(151MHz,Chloroform-d)δ162.93,161.43,141.46,135.21,135.03(d,J=13.6Hz),134.17(d,J=12.1Hz),129.97,128.09(d,J=247.6Hz),127.89,123.05,122.13,121.22,120.73,120.42,114.26(d,J=143.6Hz),109.51,55.38,43.22;31P NMR(243MHz,Chloroform-d)δ23.36.
实施例6
称取苯基膦酸乙酯(102.1mg,0.6mmol)于含有搅拌子的圆底烧瓶中,加入1.2mL甲苯,至于60℃油浴中;再取1-苯基-3-重氮二氢吲哚-2-酮(74.8mg,0.3mmol)溶于1.2mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,将反应液浓缩再通过柱层析(石油醚:乙酸乙酯=1:1)分离得到产物3f。收率50%。
1H NMR(600MHz,Chloroform-d)δ11.62(d,J=30.0Hz,1H),8.00–7.93(m,2H),7.58–7.53(m,2H),7.50–7.45(m,2H),7.33–7.24(m,5H),7.23–7.19(m,1H),7.04(t,J=6.0Hz,1H),6.74(d,J=6.0Hz,1H),4.92(d,J=1.0Hz,2H),4.37–4.27(m,2H),1.44(t,J=6.0Hz,3H);13C NMR(151MHz,Chloroform-d)δ161.16,141.63,135.21,134.53(d,J=13.6Hz),132.55(d,J=3.0Hz),131.91(d,J=10.6Hz),130.11,128.91(d,J=154.0Hz),128.89,128.43(d,J=15.1Hz),127.89,127.35,123.01,120.41,120.35,109.62,62.04(d,J=7.6Hz),43.26,16.40(d,J=6.0Hz);31P NMR(243MHz,Chloroform-d)δ16.74.
实施例7
称取二苯基膦氧(121.3mg,0.6mmol)于含有搅拌子的圆底烧瓶中,加入1.2mL甲苯,至于60℃油浴中;再取1-苯基-3-重氮-5-甲基二氢吲哚-2-酮(79.0mg,0.3mmol)溶于1.2mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,将反应液浓缩再通过柱层析(石油醚:乙酸乙酯=1:1)分离得到产物3g。收率73%。
1H NMR(600MHz,Chloroform-d)δ11.97(d,J=24.0Hz,1H),7.97–7.91(m,4H),7.59–7.54(m,2H),7.53–7.47(m,4H),7.33–7.23(m,6H),7.01–6.97(m,1H),6.62(d,J=6.0Hz,1H),4.89(s,2H),2.23(s,3H);13C NMR(151MHz,Chloroform-d)δ161.53,139.42,135.82(d,J=13.6Hz),135.24,132.80,132.56(d,J=3.0Hz),132.30(d,J=9.1Hz),130.69,130.30(d,J=166.0Hz),128.90,128.73(d,J=12.1Hz),127.87,127.26,121.36,120.23,109.39,43.24,20.95;31P NMR(243MHz,Chloroform-d)δ22.45.
实施例8
称取二苯基膦氧(121.3mg,0.6mmol)于含有搅拌子的圆底烧瓶中,加入1.2mL甲苯,至于60℃油浴中;再取1-苯基-3-重氮-6-氟二氢吲哚-2-酮(80.2mg,0.3mmol)溶于1.2mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,将反应液浓缩再通过柱层析(石油醚:乙酸乙酯=1:1)分离得到产物3h。收率84%。
1H NMR(600MHz,Chloroform-d)δ11.85(d,J=30.0Hz,1H),7.97–7.91(m,4H),7.61–7.55(m,2H),7.54–7.48(m,4H),7.46–7.41(m,1H),7.36–7.32(m,2H),7.33–7.25(m,3H),6.71–6.66(m,1H),6.48(dd,J=6.0,1.0Hz,1H),4.89(s,2H).13C NMR(151MHz,Chloroform-d)δ164.17(d,J=249.2Hz),161.65,143.04(d,J=12.1Hz),134.63,134.55(d,J=1.5Hz),132.67(d,J=1.5Hz),132.29(d,J=10.6Hz),130.04(d,J=120.8Hz),129.06,128.77(d,J=13.6Hz),128.15,127.28,122.34(d,J=10.6Hz),116.20(d,J=1.5Hz),109.85(d,J=22.7Hz),98.45(d,J=28.7Hz),43.45;31P NMR(243MHz,Chloroform-d)δ22.81;19F NMR(565MHz,Chloroform-d)δ-107.36.
实施例9
称取二苯基膦氧(121.3mg,0.6mmol)于含有搅拌子的圆底烧瓶中,加入1.2mL甲苯,至于60℃油浴中;再取1-苯基-3-重氮-7-氟二氢吲哚-2-酮(80.2mg,0.3mmol)溶于1.2mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,将反应液浓缩再通过柱层析(石油醚:乙酸乙酯=1:1)分离得到产物3i。收率90%。
1H NMR(600MHz,Chloroform-d)δ11.98(d,J=24.0Hz,1H),7.96–7.90(m,4H),7.61–7.56(m,2H),7.54–7.49(m,4H),7.35–7.29(m,4H),7.28(dd,J=6.0,1.0Hz,2H),7.01–6.91(m,2H),5.06(s,2H).13C NMR(151MHz,Chloroform-d)δ161.19,147.62(d,J=244.7Hz),136.23,134.82(dd,J=12.1,4.5Hz),132.71(d,J=21.5Hz),132.29(d,J=9.1Hz),129.94(d,J=113.3Hz),128.83,128.75(d,J=3.0Hz),127.90,127.83,127.55–127.51(m),123.86(d,J=6.0Hz),123.13(d,J=4.5Hz),118.08(d,J=19.6Hz),116.72–116.66(m),45.08(d,J=4.5Hz);31P NMR(243MHz,Chloroform-d)δ22.99;19F NMR(565MHz,Chloroform-d)δ-133.64.
实施例10
称取二苯基膦氧(121.3mg,0.6mmol)于含有搅拌子的圆底烧瓶中,加入1.2mL甲苯,至于60℃油浴中;再取1-苯基-3-重氮-4-氯二氢吲哚-2-酮(85.1mg,0.3mmol)溶于1.2mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,将反应液浓缩再通过柱层析(石油醚:乙酸乙酯=1:1)分离得到产物3j。收率83%。
1H NMR(600MHz,Chloroform-d)δ12.03(d,J=24.0Hz,1H),8.01–7.95(m,4H),7.61–7.54(m,2H),7.54–7.46(m,4H),7.34–7.29(m,2H),7.29–7.23(m,3H),7.09(t,J=6.0Hz,1H),6.97(d,J=6.0Hz,1H),6.64(d,J=6.0Hz,1H),4.92(s,2H);13C NMR(151MHz,Chloroform-d)δ160.76,142.49,134.84,133.31(d,J=13.6Hz),132.51(d,J=3.0Hz),132.29(d,J=10.6Hz),130.20,130.19(d,J=129.9Hz),128.94,128.67,128.51(d,J=13.6Hz),127.99,127.22,124.66,117.28,107.88,43.33;31P NMR(243MHz,Chloroform-d)δ25.00.
实施例11
称取二苯基膦氧(121.3mg,0.6mmol)于含有搅拌子的圆底烧瓶中,加入1.2mL甲苯,至于60℃油浴中;再取1-苯基-3-重氮-6-氯二氢吲哚-2-酮(85.1mg,0.3mmol)溶于1.2mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,将反应液浓缩再通过柱层析(石油醚:乙酸乙酯=1:1)分离得到产物3k。收率91%。
1H NMR(600MHz,Chloroform-d)δ11.89(d,J=24.0Hz,1H),7.96–7.91(m,4H),7.61–7.56(m,2H),7.54–7.48(m,4H),7.40(dd,J=6.0,2.0Hz,1H),7.34(t,J=6.0Hz,2H),7.32–7.24(m,3H),7.00–6.96(m,1H),6.75(d,J=1.0Hz,1H),4.89(s,2H);13C NMR(151MHz,Chloroform-d)δ161.4,142.45,135.94,134.63,134.54(d,J=13.6Hz),132.69(d,J=3.0Hz),132.28(d,J=10.6Hz),129.98(d,J=111.7Hz),129.07,128.77(d,J=12.1Hz),128.14,127.23,123.27,121.70,118.73,110.20,43.40;31P NMR(243MHz,Chloroform-d)δ22.92.
实施例12
称取二苯基膦氧(121.3mg,0.6mmol)于含有搅拌子的圆底烧瓶中,加入1.2mL甲苯,至于60℃油浴中;再取1-苯基-3-重氮-7-氯二氢吲哚-2-酮(74.8mg,0.3mmol)溶于1.2mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,将反应液浓缩再通过柱层析(石油醚:乙酸乙酯=1:1)分离得到产物3l。收率88%。
1H NMR(600MHz,Chloroform-d)δ11.94(d,J=30.0Hz,1H),7.95–7.89(m,4H),7.61–7.55(m,2H),7.54–7.47(m,4H),7.43(dd,J=6.0,1.0Hz,1H),7.31(dd,J=6.0,6.0Hz,2H),7.28–7.16(m,4H),6.95(t,J=6.0Hz,1H),5.37(s,2H);13C NMR(151MHz,Chloroform-d)δ161.88,137.21,136.71,134.34(d,J=13.6Hz),132.72(d,J=1.5Hz),132.43,132.28(d,J=9.1Hz),129.89(d,J=110.2Hz),128.82,128.73(d,J=1.5Hz),127.49,126.46,124.04,123.15,119.23,116.07,44.36;31P NMR(243MHz,Chloroform-d)δ23.02.
实施例13
称取二苯基膦氧(121.3mg,0.6mmol)于含有搅拌子的圆底烧瓶中,加入1.2mL甲苯,至于60℃油浴中;再取1-苯基-3-重氮-4-溴二氢吲哚-2-酮(98.5mg,0.3mmol)溶于1.2mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,将反应液浓缩再通过柱层析(石油醚:乙酸乙酯=1:1)分离得到产物3m。收率93%。
1H NMR(600MHz,Chloroform-d)δ12.07(d,J=24.0Hz,1H),8.02–7.96(m,4H),7.59–7.54(m,2H),7.52–7.47(m,4H),7.30(dd,J=6.0,6.0Hz,2H),7.28–7.23(m,3H),7.13(d,J=12.0Hz,1H),6.99(t,J=6.0Hz,1H),6.68(d,J=6.0Hz,1H),4.90(s,2H);13C NMR(151MHz,Chloroform-d)δ160.79,142.64,134.84,133.57(d,J=13.6Hz),132.54(d,J=3.0Hz),132.35(d,J=10.6Hz),130.30,130.19(d,J=129.9Hz),128.96,128.55(d,J=13.6Hz),128.01,127.85,127.25,118.92,115.97,108.45,43.27;31P NMR(243MHz,Chloroform-d)δ25.23.
实施例14
称取二苯基膦氧(121.3mg,0.6mmol)于含有搅拌子的圆底烧瓶中,加入1.2mL甲苯,至于60℃油浴中;再取1-苯基-3-重氮-6-溴二氢吲哚-2-酮(74.8mg,0.3mmol)溶于1.2mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,将反应液浓缩再通过柱层析(石油醚:乙酸乙酯=1:1)分离得到产物3n。收率80%。
1H NMR(600MHz,Chloroform-d)δ11.91(d,J=30.0Hz,1H),7.97–7.89(m,4H),7.61–7.55(m,2H),7.55–7.47(m,4H),7.36–7.31(m,3H),7.31–7.24(m,3H),7.14(dd,J=6.0,1.0Hz,1H),6.90(d,J=6.0Hz,1H),4.88(s,2H);13C NMR(151MHz,Chloroform-d)δ161.28,142.50,134.63,134.54,132.70(d,J=3.0Hz),132.27(d,J=10.6Hz),129.97(d,J=129.9Hz),129.07,128.78(d,J=13.6Hz),128.14,127.22,126.18,123.90,121.92,119.18,112.92,43.38;31P NMR(243MHz,Chloroform-d)δ22.91.
实施例15
称取二苯基膦氧(121.3mg,0.6mmol)于含有搅拌子的圆底烧瓶中,加入1.2mL甲苯,至于60℃油浴中;再取1-苯基-3-重氮-5-甲氧基二氢吲哚-2-酮(83.8mg,0.3mmol)溶于1.2mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,将反应液浓缩再通过柱层析(石油醚:乙酸乙酯=1:1)分离得到产物3o。收率78%。
1H NMR(600MHz,Chloroform-d)δ12.03(d,J=30.0Hz,1H),7.97–7.91(m,4H),7.60–7.55(m,2H),7.54–7.48(m,4H),7.31(t,J=6.0Hz,2H),7.26(d,J=6.0Hz,3H),7.08(d,J=3.0Hz,1H),6.75(dd,J=6.0,3.0Hz,1H),6.63(d,J=12.0Hz,1H),4.88(s,2H),3.69(s,3H);13C NMR(151MHz,Chloroform-d)δ161.52,156.28,135.98,135.36,135.19,132.62(d,J=3.0Hz),132.27(d,J=10.6Hz),130.19(d,J=131.4Hz),128.92,128.77(d,J=12.1Hz),127.90,127.25,121.08,116.53,110.41,106.14,55.90,43.28;31P NMR(243MHz,Chloroform-d)δ22.56.
实施例16
称取二苯基膦氧(121.3mg,0.6mmol)于含有搅拌子的圆底烧瓶中,加入1.2mL甲苯,至于60℃油浴中;再取1-甲基-3-重氮二氢吲哚-2-酮(52.0mg,0.3mmol)溶于1.2mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,将反应液浓缩再通过柱层析(石油醚:乙酸乙酯=1:1)分离得到产物3p。收率89%。
1H NMR(600MHz,Chloroform-d)δ11.94(d,J=30.0Hz,1H),7.95–7.88(m,4H),7.60–7.54(m,2H),7.53–7.45(m,5H),7.35–7.28(m,1H),7.07–7.01(m,1H),6.84(dd,J=6.0,6.0Hz,1H),3.24(s,3H);13C NMR(151MHz,Chloroform-d)δ161.48,142.36,135.66(d,J=12.1Hz),132.55,132.25(d,J=10.6Hz),130.30(d,J=129.9Hz),130.24,128.70(d,J=13.6Hz),123.11,120.72,120.12,108.63,25.51;31P NMR(243MHz,Chloroform-d)δ22.68.
实施例17
称取二苯基膦氧(121.3mg,0.6mmol)于含有搅拌子的圆底烧瓶中,加入1.2mL甲苯,至于60℃油浴中;再取1-叔丁氧羰基-3-重氮二氢吲哚-2-酮(77.8mg,0.3mmol)溶于1.2mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,将反应液浓缩再通过柱层析(石油醚:乙酸乙酯=1:1)分离得到产物3q。收率79%。
1H NMR(600MHz,Chloroform-d)δ11.80(d,J=30.0Hz,1H),7.93–7.87(m,4H),7.83(d,J=6.0Hz,1H),7.61–7.56(m,2H),7.54–7.48(m,5H),7.37–7.33(m,1H),7.16–7.12(m,1H),1.65(s,9H);13C NMR(151MHz,Chloroform-d)δ160.23,148.54,138.69,133.68(d,J=13.6Hz),132.70(d,J=1.5Hz),132.26(d,J=9.1Hz),130.47,129.92(d,J=129.9Hz),128.75(d,J=13.6Hz),124.81,120.62,120.30,115.27,85.26,28.09;31P NMR(243MHz,Chloroform-d)δ23.29.
实施例18
称取二苯基膦氧(121.3mg,0.6mmol)于含有搅拌子的圆底烧瓶中,加入1.2mL甲苯,至于60℃油浴中;再取3-重氮二氢吲哚-2-酮(47.7mg,0.3mmol)溶于1.2mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,将反应液浓缩再通过柱层析(石油醚:乙酸乙酯=1:1)分离得到产物3r。收率63%。
1H NMR(600MHz,Chloroform-d)δ11.90(d,J=30.0Hz,1H),9.25(s,1H),7.96–7.88(m,4H),7.60–7.54(m,2H),7.53–7.46(m,4H),7.29(d,J=6.0Hz,1H),7.17–7.12(m,1H),6.88(t,J=6.0Hz,1H),6.83(d,J=12.0Hz,1H);13C NMR(151MHz,Chloroform-d)δ162.95,140.43,136.41(d,J=12.1Hz),132.64,132.28(d,J=9.1Hz),130.31,129.99(d,J=139.9Hz),128.79,122.64,120.69,120.63,110.80;31P NMR(243MHz,Chloroform-d)δ23.59.
实施例1~18中,非光学活性的吲哚酮膦酰肼化合物的反应方程式是:
实施例19
称取二苯基膦氧(1.7g,8.46mmol)于含有搅拌子的圆底烧瓶中,加入8.0mL甲苯,至于60℃油浴中;再取1-苯基-3-重氮-6-氯二氢吲哚-2-酮(2.0g,7.05mmol)溶于20.0mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,反应混合物通过过滤再用正己烷冲洗,后经真空干燥,得到产物3k。收率88%。
1H NMR(600MHz,Chloroform-d)δ11.89(d,J=24.0Hz,1H),7.96–7.91(m,4H),7.61–7.56(m,2H),7.54–7.48(m,4H),7.40(dd,J=6.0,2.0Hz,1H),7.34(t,J=6.0Hz,2H),7.32–7.24(m,3H),7.00–6.96(m,1H),6.75(d,J=1.0Hz,1H),4.89(s,2H);13C NMR(151MHz,Chloroform-d)δ161.4,142.45,135.94,134.63,134.54(d,J=13.6Hz),132.69(d,J=3.0Hz),132.28(d,J=10.6Hz),129.98(d,J=111.7Hz),129.07,128.77(d,J=12.1Hz),128.14,127.23,123.27,121.70,118.73,110.20,43.40;31P NMR(243MHz,Chloroform-d)δ22.92.
实施例19中,合成大量的吲哚酮膦酰肼化合物的反应方程式是:
实施例20
称取苯基膦酸薄荷酯(56.0mg,0.2mmol)(RP/SP>99/1)于含有搅拌子的圆底烧瓶中,加入0.2mL甲苯,至于60℃油浴中;再取1-苯基-3-重氮-6-溴二氢吲哚-2-酮(32.8mg,0.1mmol)溶于0.2mL甲苯,并通过蠕动泵30分钟注入反应体系中,注入完毕后,TLC监测反应,待反应完全后,将反应液浓缩再通过柱层析(石油醚:乙酸乙酯=1:1)分离得到产物5。收率63%,dr>20:1。
1H NMR(600MHz,Chloroform-d)δ11.55(d,J=30.0Hz,1H),7.99–7.91(m,2H),7.56–7.52(m,1H),7.49–7.45(m,2H),7.36–7.30(m,3H),7.29–7.23(m,3H),7.18–7.15(m,1H),6.88(d,J=6.0Hz,1H),4.91–4.84(m,2H),4.52–4.46(m,1H),2.48–2.34(m,2H),2.10–2.01(m,1H),1.71–1.63(m,2H),1.53–1.44(m,2H),1.34–1.25(m,1H),1.06–0.98(m,1H),0.91(dd,J=12.0,6.0Hz,6H),0.71(d,J=6.0Hz,3H);13C NMR(151MHz,Chloroform-d)δ160.91,142.49,134.75,133.15(d,J=13.6Hz),132.48(d,J=3.0Hz),131.82(d,J=10.6Hz),130.22,129.01,128.39(d,J=15.0Hz),128.07,127.25,126.04,123.66,121.20,119.39,112.93,78.68(d,J=7.6Hz),48.71(d,J=7.6Hz),43.42(d,J=28.7Hz),34.04,31.65,25.34,22.89,21.94,21.21,15.56;31P NMR(243MHz,Chloroform-d)δ14.96.
实施例20中,具有光学活性的吲哚酮膦酰肼化合物的反应方程式是:
所述singal diastereoisomer为单一非对映异构体。
Claims (5)
1.一种吲哚酮膦酰肼化合物及其衍生物的制备方法,其特征在于,用3-重氮吲哚酮化合物和膦氧基化合物在无金属试剂和无碱性试剂催化的条件下,进行亲电加成反应,得到吲哚酮膦酰肼化合物及其衍生物;
具体如下:
当所述的膦氧基化合物为二苯基膦氧时,所述的3-重氮吲哚酮化合物为1-苯基-3-重氮二氢吲哚-2-酮,反应得到产物3a;
当所述的膦氧基化合物为二(4-氟苯基)膦氧时,所述的3-重氮吲哚酮化合物为1-苯基-3-重氮二氢吲哚-2-酮,反应得到产物3b;
当所述的膦氧基化合物为二(3,5-双三氟甲基苯基)膦氧时,所述的3-重氮吲哚酮化合物为1-苯基-3-重氮二氢吲哚-2-酮,反应得到产物3c;
当所述的膦氧基化合物为二(2-甲基苯基)膦氧时,所述的3-重氮吲哚酮化合物为1-苯基-3-重氮二氢吲哚-2-酮,反应得到产物3d;
当所述的膦氧基化合物为二(4-甲氧基苯基)膦氧时,所述的3-重氮吲哚酮化合物为1-苯基-3-重氮二氢吲哚-2-酮,反应得到产物3e;
当所述的膦氧基化合物为苯基膦酸乙酯时,所述的3-重氮吲哚酮化合物为1-苯基-3-重氮二氢吲哚-2-酮,反应得到产物3f;
当所述的膦氧基化合物为二苯基膦氧时,所述的3-重氮吲哚酮化合物为1-苯基-3-重氮-5-甲基二氢吲哚-2-酮,反应得到产物3g;
当所述的膦氧基化合物为二苯基膦氧时,所述的3-重氮吲哚酮化合物为1-苯基-3-重氮-6-氟二氢吲哚-2-酮,反应得到产物3h;
当所述的膦氧基化合物为二苯基膦氧时,所述的3-重氮吲哚酮化合物为1-苯基-3-重氮-7-氟二氢吲哚-2-酮,反应得到产物3i;
当所述的膦氧基化合物为二苯基膦氧时,所述的3-重氮吲哚酮化合物为1-苯基-3-重氮-4-氯二氢吲哚-2-酮,反应得到产物3j;
当所述的膦氧基化合物为二苯基膦氧时,所述的3-重氮吲哚酮化合物为1-苯基-3-重氮-6-氯二氢吲哚-2-酮,反应得到产物3k;
当所述的膦氧基化合物为二苯基膦氧时,所述的3-重氮吲哚酮化合物为1-苯基-3-重氮-7-氯二氢吲哚-2-酮,反应得到产物3l;
当所述的膦氧基化合物为二苯基膦氧时,所述的3-重氮吲哚酮化合物为1-苯基-3-重氮-4-溴二氢吲哚-2-酮,反应得到产物3m;
当所述的膦氧基化合物为二苯基膦氧时,所述的3-重氮吲哚酮化合物为1-苯基-3-重氮-6-溴二氢吲哚-2-酮,反应得到产物3n;
当所述的膦氧基化合物为二苯基膦氧时,所述的3-重氮吲哚酮化合物为1-苯基-3-重氮-5-甲氧基二氢吲哚-2-酮,反应得到产物3o;
当所述的膦氧基化合物为二苯基膦氧时,所述的3-重氮吲哚酮化合物为1-甲基-3-重氮二氢吲哚-2-酮,反应得到产物3p;收率89%;
当所述的膦氧基化合物为二苯基膦氧时,所述的3-重氮吲哚酮化合物为1-叔丁氧羰基-3-重氮二氢吲哚-2-酮,反应得到产物3q;
当所述的膦氧基化合物为二苯基膦氧时,所述的3-重氮吲哚酮化合物为3-重氮二氢吲哚-2-酮,反应得到产物3r;
当所述的膦氧基化合物为苯基膦酸薄荷酯时,所述的3-重氮吲哚酮化合物为1-苯基-3-重氮-6-溴二氢吲哚-2-酮,反应得到产物5;
所述产物3a~3r以及产物5的结构如下:
结构式一:
结构式二:
结构式三:
结构式四:
其中:
2.如权利要求1所述的吲哚酮膦酰肼化合物及其衍生物的制备方法,其特征在于,具体步骤如下:
(1)先称取1eq3-重氮吲哚酮化合物,将3-重氮吲哚酮化合物溶解于有机溶剂中,浓度控制为0.125~0.350mol/L,得到重氮溶液;
(2)在一个圆底烧瓶中加入1.0~2.0eq的膦氧基化合物,加入有机溶剂,控制溶液中膦氧基化合物的浓度为0.125~0.350mol/L;
(3)将3-重氮吲哚酮溶液缓慢滴加入圆底烧瓶中,在0.5~1.0小时滴加结束,通过TLC监测反应进程,反应结束后浓缩得到粗产物。
3.如权利要求2所述的吲哚酮膦酰肼化合物及其衍生物的制备方法,其特征在于,还包括以下步骤:
(4)将粗产物用体积比为乙酸乙酯:石油醚=1:1的溶液进行柱层析,或是将粗产物过滤并用正己烷冲洗得到所述吲哚酮膦酰肼化合物及其衍生物。
4.如权利要求1~3任意一项所述的吲哚酮膦酰肼化合物及其衍生物的制备方法,其特征在于,所述有机溶剂为甲苯。
5.如权利要求1~3任意一项所述的吲哚酮膦酰肼化合物及其衍生物的制备方法,其特征在于,所述3-重氮吲哚酮化合物由相应的吲哚和对甲苯磺酰肼化合物制备得到。
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