CN111205255A - 一种含CMe2CF3基团的黄酮类化合物的合成方法 - Google Patents

一种含CMe2CF3基团的黄酮类化合物的合成方法 Download PDF

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CN111205255A
CN111205255A CN201911126089.5A CN201911126089A CN111205255A CN 111205255 A CN111205255 A CN 111205255A CN 201911126089 A CN201911126089 A CN 201911126089A CN 111205255 A CN111205255 A CN 111205255A
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刘妙昌
吴键
刘玮
黄小波
高文霞
周云兵
吴华悦
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Abstract

本发明属于化学合成领域，具体涉及一种含CMe2CF3基团的黄酮类化合物的合成方法，本发明具有操作简单、功能组兼容性好等特点，反应得到的含CMe2CF3基团的黄酮类化合物具有广阔的应用前景。

Description

一种含CMe2CF3基团的黄酮类化合物的合成方法
技术领域
本发明属于化学合成领域，具体涉及一种含CMe2CF3基团的黄酮类化合物的合成方法。
背景技术
氟原子对有机分子的化学和生物性质具有独特的影响，氟化化合物已广泛应用于制药、农药、高级功能材料等领域。氟的特殊性质可以增强许多药代动力学和/或药效学性质，包括增加膜渗透性和改善代谢稳定性。这些物理性质和选择性反应活性的变化对它们的生物活性、稳定性和亲脂性有着深刻的影响。考虑到三氟甲基(CF3)在许多生物活性化合物中的重要作用，将其引入有机分子是一个有意义的课题。特别是CMe2CF3作为亲脂性、体积大的“CF3”源，在生物化学和药物化学领域引起了广泛的关注。
黄酮类化学物是天然药物中一类重要的活性化合物。合成含CMe2CF3基团的黄酮类化合物的方法研究对黄酮类化合物的改性以及作为中间产物合成活性药物具有重要意义。
发明内容
本发明的目的是为了克服现有技术存在的缺点和不足，而提供一种含 CMe2CF3基团的黄酮类化合物的合成方法。
本发明所采取的技术方案如下：一种含CMe2CF3基团的黄酮类化合物的合成方法，化学反应式如下：
Figure RE-GDA0002450129320000011
上式中X为O或N-Tf，R2和R3分开为单独的甲基或合起来为-CH2CH2CH2-，上述反应中加入氧化剂。
优选地，所述氧化剂为过硫酸盐。包括过硫酸钾、过硫酸钠、过硫酸铵等常见的过硫酸盐。
优选地，所述氧化剂为过硫酸铵。
反应在体积比为2:1的DMSO/H2O的溶剂体系中反应。
反应在氮气保护下进行。
本发明的有益效果如下：本发明具有操作简单、功能组兼容性好等特点，反应得到的含CMe2CF3基团的黄酮类化合物具有广阔的应用前景。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚，下面将对本发明作进一步地详细描述。
实施例1：
在烧瓶中加入3,3,3-三氟-2,2-二甲基丙酸(0.6mmol)和2-(烯丙基)苯甲醛(0.2mmol)的混合物，在DMSO/H2O(v/v＝2/1,3mL)中加入(NH4)2S2O8(0.6mmol)和 K3PO4(0.06mmol)，在氮气保护下。反应在90℃下搅拌24h，反应完成后，将反应混合物在真空下浓缩。采用石油醚/EtOAc(40:1-8:1)硅胶柱层析法对产物进行纯化，得到相应的产物。化学式如下：
Figure RE-GDA0002450129320000021
对上述反应式进行优化，具体优化如表1所示：
表1为3,3,3-三氟-2,2-二甲基丙酸和2-(烯丙基)苯甲醛的优化a
Figure RE-GDA0002450129320000022
Figure RE-GDA0002450129320000031
aReaction conditions unless specified otherwise:1a(0.2mmol),2a(0.6mmol), (NH4)2S2O8(0.6mmol),K3PO4(0.6mmol),solvent(3mL,v/v＝2:1for mixedsolvent),90℃,under N2,24h.bIsolated yield.cSolvent with a radio of 3:1.dSolvent with a radio of 1:1.eUnder air.fAt 100℃.
从表1所示，以磷酸钾为基础反应***可以成功促进反应，有24％的收益率(反应2)，采用磷酸钠(反应3)、碳酸钠(反应4)、碳酸钾(反应5)均比不上磷酸钾。研究不同溶剂体系下的反应(反应6-11)，发现体积比为2:1的 DMSO/H2O的溶剂体系为最佳。对Ag2O、Ag2CO3、AgOAc等几种Ag盐进行筛选，结果显示AgNO3的结果最好(表1，反应12-14)。进一步地，可以发现无 Ag盐催化作用下的反应收率更高，可以达到45％。缺少氧化剂反应无法进行(反应16)，说明氧化剂在反应过程中为不可或缺的，进一步地，对氧化剂进行优化筛选，表明过硫酸铵为最佳选择(反应18)。当反应在空气中进行时，产量明显下降(反应19)。而将反应温度提高100℃并没有提高收率(反应20)。综上所述，反应18的反应条件为最优。
其中，底物1a的合成过程如下：
Figure RE-GDA0002450129320000032
将水杨醛(5mmol)和碳酸钾(7.5mmol)分别放入50mL圆底烧瓶中，加入15 mL DMF，室温下继续搅拌。在搅拌溶液中加入丙烯基溴(7.5mmol)。反应混合物在室温下搅拌15小时。反应完成后，反应混合物在真空下浓缩。采用石油醚 /EtOAc(20:1)硅胶柱层析法对产物进行了纯化，得到了O-(烯丙基)苯甲醛1a。
实施例2：
根据实施例中反应18的反应条件进行不同烯烃和3,3,3-三氟-2,2-二甲基丙酸反应的探索，具体如表2所示：
表2反应底物烯烃的探索
Figure RE-GDA0002450129320000041
Figure RE-GDA0002450129320000051
Figure RE-GDA0002450129320000061
Figure RE-GDA0002450129320000071
其中，底物1p的合成过程如下：
Figure RE-GDA0002450129320000072
将2-氟苯甲醛(5mmol)、烯丙基硫醇(10mmol)、碳酸钾(10mmol)加入DMF (10ml)。将反应混合物加热至55℃过夜。冷却至室温后，将反应倒入水中，用乙酸乙酯萃取。有机萃取物先用水冲洗一次，再用盐水冲干(MgSO4)浓缩。采用石油醚/乙氧基乙酸(20:1)硅胶柱层析法对产物进行纯化，得到2-(烯丙基硫)苯甲醛1p。
底物1q的合成过程如下：
Figure RE-GDA0002450129320000073
在100mL圆底烧瓶中投入2-甲酰基苯硼酸(5mmol)、烯丙基溴(6mmol)、 THF(25mL)。然后加入PdCl2(PPh3)2(0.125mmol)和aq.Na2CO3(1M,10mmol) 溶液。反应混合物回流加热3-4h,H2O淬灭反应混合物，CH2Cl2萃取三次。结合后的有机层用H2O洗涤，在MgSO4上干燥，真空浓缩。采用石油醚/乙氧基乙酸乙酯(30:1)硅胶柱层析法对产物进行纯化，得到所需的2-烯丙基苯甲醛1q。
底物1r的合成过程如下：
Figure RE-GDA0002450129320000081
室温下，将四价(三苯基膦)钯(0.15mmol)和2-溴苯甲醛(5mmol)置于二甲氧基乙烷(50mL)中搅拌10min。在乙醇(6ml)中加入(2-乙烯基苯基)硼酸溶液7.5 mmol，在水中加入(6ml)碳酸钠溶液10mmol。搅拌18小时后回流，减压浓缩。用石油醚在硅胶上进行闪蒸色谱纯化，得到2'-乙烯基联苯-2-乙醛1r。
实施例3：
根据实施例中反应18的反应条件进行不同烯烃和1-三氟甲基环丁基甲酸反应的探索，具体如表3所示：
Figure RE-GDA0002450129320000082
Figure RE-GDA0002450129320000091
从表3可以看出，1-三氟甲基环丁基甲酸可以作为反应物得到含有系列的含 CF3的黄酮类化合物，且收率良好。
实施例4：
反应物3a用于合成TRPV1前体：
Figure RE-GDA0002450129320000101
上述反应式中，Conditions A的反应条件如下:1a(0.2mmol),2a(0.6mmol),(NH4)2S2O8(0.6mmol),K3PO4(0.6mmol),DMSO/H2O(v/v＝2:1,3mL),90℃,N2保护下,24h.
Conditions B的反应条件如下:3a(1mmol),盐酸羟胺(1.5mmol),甲酸胺(9mmol),Zn粉(3mmol),甲醇(5mL),回流,过夜。
通过上述反应过程，可以成功得到TRPV1前体，总收率为42％，得到的 TRPV1前体由两个非对映异构体组成，比例为3:1。
以下为上述实施例中产物的结构分析数据：
(S)-3-(3,3,3-trifluoro-2,2-dimethylpropyl)chroman-4-one
Figure RE-GDA0002450129320000102
按照一般步骤，使用石油醚/AcOEt(40：1)作为洗脱剂，得到无色油状物 (收率78％)。1H NMR(500MHz,CDCl3)δ7.90-7.89(m,1H),7.50-7.46(m,1H), 7.04-7.01(m,1H),6.97-6.96(m,1H),4.54-4.50(dd,J＝11.5Hz,J＝5.5Hz,1H), 4.20-4.15(m,1H),2.88-2.83(m,1H),2.38-2.34(dd,J＝15.0Hz,J＝4.0Hz,1H), 1.36-1.32(dd,J＝14.5Hz,J＝5.0Hz,1H),1.18(s,3H),1.17(s,3H)；13C NMR (125MHz,DMSO-d6)δ194.1,162.0,136.4,128.1,122.0,121.0,118.2,71.9,42.2, 40.5(q,JC-F＝25.0Hz),31.2,22.1,20.7；19F NMR(470MHz,CDCl3):δ[ppm]＝-78.1.
(S)-7-methyl-3-(3,3,3-trifluoro-2,2-dimethylpropyl)chroman-4-one
Figure RE-GDA0002450129320000111
按照一般步骤，使用石油醚/AcOEt(40：1)作为洗脱剂，得到白色污垢(收率69％)，熔点：73-74℃。1H NMR(500MHz,CDCl3)δ7.78(d,J＝8.0Hz,1H), 6.84(d,J＝8.0Hz,1H),6.76(s,1H),4.51-4.47(dd,J＝11.0Hz,J＝5.0Hz,1H), 4.17-4.12(m,1H),2.83-2.78(m,1H),2.36(s,3H),2.35-2.31(m,1H),1.36-1.31(dd, J＝14.5Hz,J＝5.0Hz,1H),1.18(s,3H),1.17(s,3H)；13C NMR(125MHz,CDCl3) δ193.8,162.0,147.9,130.0,123.4,118.8,118.2,71.9,42.2,40.55(q,JC-F＝23.8Hz), 31.2,22.4,22.1,20.7；19F NMR(470MHz,CDCl3):δ[ppm]＝-78.0.
(S)-6-methyl-3-(3,3,3-trifluoro-2,2-dimethylpropyl)chroman-4-one
Figure RE-GDA0002450129320000112
按照一般步骤，使用石油醚/AcOEt(40：1)作为洗脱剂，得到无色油状物 (产率为75％)。1H NMR(500MHz,CDCl3)δ7.66(s,1H),7.29-7.27(m,1H), 6.86-6.84(m,1H),4.49-4.46(dd,J＝11.0Hz,J＝5.0Hz,1H),4.16-4.11(m,1H), 2.83-2.78(m,1H),2.35-2.33(m,1H),2.30(s,3H),1.35-1.31(dd,J＝11.0Hz,J＝ 5.5Hz,1H),1.17(s,3H),1.16(s,3H)；13CNMR(125MHz,CDCl3)δ194.4,160.0, 137.5,131.4,127.6,120.6,118.0,71.9,42.3,40.6(q,JC-F＝23.8Hz),31.2,22.1, 20.9,20.7；19F NMR(470MHz,CDCl3):δ[ppm]＝-78.0.
(S)-7-chloro-3-(3,3,3-trifluoro-2,2-dimethylpropyl)chroman-4-one
Figure RE-GDA0002450129320000121
按照一般步骤，使用石油醚/AcOEt(40：1)作为洗脱液，得到白色污垢(66％收率)，mp：63-64℃。1H NMR(500MHz,CDCl3)δ7.82(d,J＝8.0Hz,1H), 7.01-7.00(m,2H),4.55-4.51(dd,J＝11.5Hz,J＝5.0Hz,1H),4.20-4.15(m,1H), 2.87-2.81(m,1H),2.35-2.31(dd,J＝11.5Hz,J＝5.0Hz,1H),1.36-1.31(dd,J＝ 15.0Hz,J＝5.5Hz,1H),1.18(s,3H),1.17(s,3H)；13C NMR(125MHz,CDCl3)δ 193.1,162.3,142.3,129.3,122.8,119.6,118.4,72.1,42.1,40.8,40.5(q,JC-F＝25.0 Hz),31.2,22.2(q,JC-F＝2.5Hz),20.7；19F NMR(470MHz,CDCl3):δ[ppm]＝ -78.0.
(S)-7-fluoro-3-(3,3,3-trifluoro-2,2-dimethylpropyl)chroman-4-one
Figure RE-GDA0002450129320000122
按照一般步骤，使用石油醚/AcOEt(40：1)作为洗脱剂，获得黄色油状物 (72％收率)。1H NMR(500MHz,CDCl3)δ7.93-7.89(m,1H),6.76-6.73(m,1H), 6.66-6.64(m,1H),4.55-4.52(dd,J＝11.5Hz,J＝5.0Hz,1H),4.21-4.16(m,1H), 2.86-2.81(m,1H),2.36-2.32(dd,J＝15.0Hz,J＝3.5Hz,1H),1.35-1.31(dd,J＝ 15.0Hz,J＝11.5Hz,5.5H),1.18(s,3H),1.17(s,3H)；13C NMR(125MHz,CDCl3) δ192.7,167.9(d,JC-F＝253.8Hz),163.6(d,JC-F＝13.8Hz),130.6(d,JC-F＝11.3Hz), 118.0(d,JC-F＝2.5Hz),110.4(d,JC-F＝22.5Hz),105.0(d,JC-F＝23.8Hz),72.3, 42.0,40.52(q,JC-F＝146.3Hz),31.2,22.2,20.7；19F NMR(470MHz,CDCl3):δ [ppm]＝-78.0,-100.7.
(S)-6-fluoro-3-(3,3,3-trifluoro-2,2-dimethylpropyl)chroman-4-one
Figure RE-GDA0002450129320000131
按照一般步骤，使用石油醚/AcOEt(40：1)作为洗脱剂，得到黄色油状物 (73％收率)。1H NMR(500MHz,CDCl3)δ7.55-7.53(m,1H),7.22-7.18(m,1H), 6.96-6.94(m,1H),4.53-4.49(dd,J＝11.5Hz,J＝5.5Hz,1H),4.18-4.13(m,1H), 2.87-2.81(m,1H),2.35-2.31(dd,J＝14.5Hz,J＝3.5Hz,1H),1.37-1.33(dd,J＝ 15.0Hz,J＝5.5Hz,1H)；13C NMR(125MHz,CDCl3)δ193.4,158.2,157.8(d,JC-F＝240.0Hz),124.0(d,JC-F＝25.0Hz),121.4(d,JC-F＝7.5Hz),119.9(d,JC-F＝7.5 Hz),113.0(d,JC-F＝22.5Hz),72.03,42.2,40.54(q,JC-F＝23.8Hz),22.2(q,JC-F＝ 2.5Hz),20.73(q,JC-F＝2.5Hz)；19F NMR(470MHz,CDCl3):δ[ppm]＝-78.0, -121.4.
(S)-8-fluoro-3-(3,3,3-trifluoro-2,2-dimethylpropyl)chroman-4-one
Figure RE-GDA0002450129320000132
按照一般步骤，使用石油醚/AcOEt(40：1)作为洗脱剂，得到黄色油状物 (61％收率)。1H NMR(500MHz,CDCl3)δ7.68-7.66(m,1H),7.31-7.27(m,1H), 6.99-6.94(m,1H),4.65-4.62(dd,J＝11.5Hz,J＝5.0Hz,1H),4.28-4.23(m,1H), 2.93-2.88(m,1H),2.38-2.35(dd,J＝15.0Hz,J＝4.0Hz,1H),1.38-1.34(dd,J＝ 15.0Hz,J＝5.0Hz,1H),1.19(s,3H),1.18(s,3H)；13C NMR(125MHz,CDCl3)δ 193.1,152.0(d,JC-F＝247.5Hz),150.4,150.3,123.2(d,JC-F＝3.8Hz),122.2(d,JC-F＝17.5Hz),121.4(d,JC-F＝6.3Hz),72.4,42.3,40.5(q,JC-F＝23.8Hz),31.1,22.2, 20.8；19F NMR(470MHz,CDCl3):δ[ppm]＝-78.0,-135.6.
(S)-6-bromo-7-fluoro-3-(3,3,3-trifluoro-2,2-dimethylpropyl)chroman-4-one
Figure RE-GDA0002450129320000141
按照一般步骤，使用石油醚/AcOEt(40：1)作为洗脱剂，得到黄色污垢(收率58％)，熔点：82-83℃。1H NMR(500MHz,CDCl3)δ8.10-8.08(m,1H), 6.76-6.74(m,1H),4.56-4.52(dd,J＝11.5Hz,J＝5.5Hz,1H),4.21-4.16(m,1H), 2.86-2.81(m,1H),2.34-2.30(dd,J＝15.0Hz,J＝3.5Hz,1H),1.35-1.31(dd,J＝ 14.5Hz,J＝5.0Hz,1H),1.17(s,6H)；13C NMR(125MHz,CDCl3)δ191.7,163.7 (d,JC-F＝255.0Hz),162.5(d,JC-F＝12.5Hz),133.2(d,JC-F＝3.8Hz),119.0(d,JC-F＝2.5Hz),106.4(d,JC-F＝25.0Hz),102.9(d,JC-F＝22.5Hz),72.3,41.9,40.5(q,JC-F＝25.0Hz),31.2,22.2(q,JC-F＝2.5Hz),20.7；19F NMR(470MHz,CDCl3):δ[ppm] ＝-77.8,-94.8.
(S)-6-methoxy-3-(3,3,3-trifluoro-2,2-dimethylpropyl)chroman-4-one
Figure RE-GDA0002450129320000142
按照一般步骤，使用石油醚/AcOEt(40：1)作为洗脱剂，得到无色油状物 (64％收率)。1H NMR(500MHz,CDCl3)δ7.32-7.31(m,1H),7.10-7.08(m,1H), 6.91-6.89(m,1H),4.49-4.46(dd,J＝11.0Hz,J＝5.0Hz,1H),4.16-4.12(m,1H), 3.80(s,3H),2.85-2.80(m,1H),2.35-2.31(dd,J＝11.0Hz,J＝5.0Hz,1H), 1.37-1.18(dd,J＝15.0Hz,J＝5.5Hz,1H),1.19(s,3H),1.18(s,3H)；13C NMR (125MHz,CDCl3)δ194.2,156.7,154.7,125.6,120.8,119.5,108.6,72.0,56.3,42.3, 40.6(q,JC-F＝25.0Hz),31.4,22.1,20.8；19F NMR(470MHz,CDCl3):δ[ppm]＝ -78.0.
(S)-7-methoxy-3-(3,3,3-trifluoro-2,2-dimethylpropyl)chroman-4-one
Figure RE-GDA0002450129320000151
按照一般步骤，使用石油醚/AcOEt(40：1)作为洗脱剂，得到白色污垢(55％的收率)，mp：90-91℃。1H NMR(500MHz,CDCl3)δ7.83(d,J＝8.5Hz,1H), 6.60-6.58(m,1H),6.41-6.40(m,1H),4.52-4.48(dd,J＝11.5Hz,J＝5.0Hz,1H), 4.18-4.14(m,1H),3.84(s,3H),2.81-2.76(m,1H),2.34-2.31(dd,J＝15.0Hz,J＝ 3.5Hz,1H),1.36-1.32(dd,J＝15.0Hz,J＝5.5Hz,1H),1.18(s,3H),1.17(s,3H)；13C NMR(125MHz,CDCl3)δ192.8,166.5,163.9,129.8,114.9,110.5,101.1,72.2, 56.1,41.9,40.55(q,JC-F＝25.0Hz),31.3,22.2,20.7；19F NMR(470MHz,CDCl3):δ [ppm]＝-78.0.
(S)-6-nitro-3-(3,3,3-trifluoro-2,2-dimethylpropyl)chroman-4-one
Figure RE-GDA0002450129320000152
按照一般步骤，使用石油醚/AcOEt(8：1)作为洗脱剂，得到黄色污垢(61％收率)，熔点：118-119℃。1H NMR(500MHz,CDCl3)δ8.80-8.78(m,1H), 8.34-8.32(m,J＝8.0Hz,1H),7.12-7.10(m,1H),4.68-4.64(dd,J＝11.5Hz,J＝5.5 Hz,1H),4.30-4.25(m,1H),2.95-2.92(m,1H),2.40-2.36(m,1H),1.38-1.34(dd,J＝ 15.0Hz,J＝5.0Hz,1H),1.19(s,6H)；13CNMR(125MHz,CDCl3)δ192.0,165.8, 142.8,130.7,124.7,120.6,119.6,72.2,42.0,40.5(q,JC-F＝23.8Hz),31.08,22.4, 20.7；19F NMR(470MHz,CDCl3):δ[ppm]＝-77.8.
(S)-2-(3,3,3-trifluoro-2,2-dimethylpropyl)-2,3-dihydro-1H-benzo[f]chromen-1-o
Figure RE-GDA0002450129320000161
按照一般步骤，使用石油醚/AcOEt(40：1)作为洗脱剂，得到白色污垢(收率36％)，熔点：104-105℃。1H NMR(500MHz,CDCl3)δ9.40(d,J＝9.0Hz,1H), 7.92(d,J＝9.0Hz,1H),7.75(d J＝8.0Hz,1H),7.64-7.61(m,1H),7.44-7.41(m, 1H),7.08(d,J＝9.0Hz,1H),4.63-4.60(dd,J＝11.0Hz,J＝4.5Hz,1H),4.33-4.29 (m,1H),2.93-2.88(m,1H),2.41-2.37(dd,J＝15.0Hz,J＝4.5Hz,1H),1.49-1.45 (dd,J＝15.0Hz,J＝5.5Hz,1H),1.21(s,3H),1.18(s,3H)；13C NMR(125MHz, CDCl3)δ195.3,163.7,137.9,132.2,130.1,129.8,129.0,126.1,125.4,119.0,112.5, 71.9,42.8,40.6(q,JC-F＝23.8Hz),31.8,22.2,20.7；19F NMR(470MHz,CDCl3):δ [ppm]＝-78.0.
(S)-1-tosyl-3-(3,3,3-trifluoro-2,2-dimethylpropyl)-2,3-dihydroquinolin-4(1H)-on
Figure RE-GDA0002450129320000162
按照一般步骤，使用石油醚/AcOEt(40：1)作为洗脱剂，得到黄色污垢(收率60％)，熔点：101-102℃。1H NMR(500MHz,CDCl3)δ7.98-7.96(m,1H), 7.88-7.86(m,1H),7.61-7.59(m,2H),7.58-7.54(m,1H),7.27-7.24(m,3H), 4.58-4.54(dd,J＝14.0Hz,J＝5.5Hz,1H),3.67-3.61(m,1H),2.47-2.42(m,1H), 2.39(s,3H),2.35-2.31(dd,J＝15.0Hz,J＝3.0Hz,1H),1.25-1.21(dd,J＝14.5Hz, J＝5.5Hz,1H),1.11(s,3H),1.09(s,3H)；13C NMR(125MHz,CDCl3)δ195.0, 145.1,142.8,137.3,135.1,130.5,128.9,127.4,125.7,125.1,123.7,52.5,42.1,40.5 (q,JC-F＝25.0Hz),33.2,22.0,21.7,21.0；19F NMR(470MHz,CDCl3):δ[ppm]＝ -78.1.
(R)-2-(3,3,3-trifluoro-2,2-dimethylpropyl)-2,3-dihydro-1H-inden-1-one
Figure RE-GDA0002450129320000171
按照通用程序，使用石油醚/AcOEt(40：1)作为洗脱剂，得到无色油状物 (收率72％)。1H NMR(500MHz,CDCl3)δ7.77(d,J＝7.5Hz,1H),7.61-7.58 (m,1H),7.46(d,J＝7.5Hz,1H),7.39-7.36(m,1H),3.51-3.46(dd,J＝17.0Hz,J＝8.0Hz,1H),2.89-2.85(dd,J＝17.0Hz,J＝4.5Hz,1H),2.68-2.64(m,1H),2.37(d, J＝14.5Hz,1H),1.59-1.54(dd,J＝14.5Hz,J＝10.5Hz,1H),1.23(s,6H)；13C NMR(125MHz,CDCl3)δ208.2,153.9,136.5,135.4,128.0,126.9,124.5,44.5, 40.8(q,JC-F＝25.0Hz),38.5,36.3,22.3(q,JC-F＝2.5Hz),21.5(q,JC-F＝2.5Hz)；19F NMR(470MHz,CDCl3):δ[ppm]＝-77.6.
(S)-3-((1-(trifluoromethyl)cyclobutyl)methyl)chroman-4-one
Figure RE-GDA0002450129320000172
按照一般步骤，使用石油醚/AcOEt(40：1)作为洗脱剂，得到无色油状物 (81％收率)。1H NMR(500MHz,CDCl3)δ7.91-7.89(m,1H),7.49-7.46(m,1H), 7.04-7.01(m,1H),6.97-6.95(m,1H),4.54-4.51(dd,J＝11.5Hz,J＝5.0Hz,1H), 4.21-4.17(m,1H),2.86-2.80(m,1H),2.58-2.55(m,1H),2.42-2.37(m,1H), 2.35-2.30(m,1H),2.03-1.93(m,4H),1.56-1.55(m,1H)；13C NMR(125MHz, CDCl3)δ194.3,162.1,136.4,128.1,122.0,120.9,118.2,71.2,44.67(q,JC-F＝26.3 Hz),43.3,30.4,27.9(q,JC-F＝3.8Hz),26.3(q,JC-F＝2.5Hz),15.2；19F NMR(470 MHz,CDCl3):δ[ppm]＝-77.0.
(S)-7-methyl-3-((1-(trifluoromethyl)cyclobutyl)methyl)chroman-4-one
Figure RE-GDA0002450129320000181
按照一般步骤，使用石油醚/AcOEt(40：1)作为洗脱剂，得到无色油状物 (收率70％)。1H NMR(500MHz,CDCl3)δ7.79(d,J＝8.0Hz,1H),6.84(d,J＝ 8.0Hz,1H),6.77(s,1H),4.52-4.49(dd,J＝11.5Hz,J＝5.0Hz,1H),4.19-4.15(m, 1H),2.81-2.79(m,1H),2.57-2.53(dd,J＝15.0Hz,J＝3.0Hz,1H),2.41-2.30(m, 1H),2.36(s,3H),2.03-1.95(m,4H),1.61-1.55(m,2H)；13C NMR(125MHz,CDCl3) δ194.0,162.1,147.9,128.0,123.4,118.7,118.2,71.2,44.7(q,JC-F＝26.3Hz),43.3, 30.5,27.9,26.3,22.4,15.2；19F NMR(470MHz,CDCl3):δ[ppm]＝-76.7.
(S)-7-fluoro-3-((1-(trifluoromethyl)cyclobutyl)methyl)chroman-4-one
Figure RE-GDA0002450129320000182
按照通用程序，使用石油醚/AcOEt(40：1)作为洗脱剂，得到无色油状物 (73％收率)。1H NMR(500MHz,CDCl3)δ7.94-7.91(m,1H),6.77-6.73(m,1H), 6.67-6.64(m,1H),4.56-4.53(m,1H),4.23-4.19(m,1H),2.84-2.79(m,1H), 2.59-2.55(dd,J＝15.5Hz,J＝4.0Hz,1H),2.43-2.30(m,2H),2.04-1.94(m,4H), 1.58-1.54(m,1H)；13C NMR(125MHz,CDCl3)δ192.9,167.9(d,JC-F＝253.8Hz), 163.7(d,JC-F＝13.8Hz),130.6(d,JC-F＝11.3Hz),117.9(d,JC-F＝2.5Hz),110.4(d, JC-F＝22.5Hz),105.0(d,JC-F＝25.0Hz),71.6,44.6(q,JC-F＝26.3Hz),43.1,30.3, 27.9,26.3,15.2；19F NMR(470MHz,CDCl3):δ[ppm]＝-76.7,-100.6.
(S)-6-methyl-3-((1-(trifluoromethyl)cyclobutyl)methyl)chroman-4-one
Figure RE-GDA0002450129320000191
按照一般步骤，使用石油醚/AcOEt(40：1)作为洗脱剂，得到无色油状物 (74％收率)。1H NMR(500MHz,CDCl3)δ7.69(s,1H),7.29(d,J＝7.0Hz,1H), 6.87(d,J＝7.0Hz,1H),4.51-4.48(dd,J＝11.5Hz,J＝5.0Hz,1H),4.19-4.15(m, 1H),2.83-2.78(m,1H),2.56-2.52(m,1H),2.41-2.37(m,1H),2.31(s,3H),2.04-1.94 (m,4H),1.60-1.56(m,2H)；13C NMR(125MHz,CDCl3)δ194.5,160.1,137.5, 131.4,127.6,120.5,118.0,71.2,44.7(q,JC-F＝26.3Hz),43.4,30.5,27.9(q,J＝3.8 Hz),26.3(q,J＝3.8Hz),20.9,15.2；19F NMR(470MHz,CDCl3):δ[ppm]＝-76.7.
(S)-1-tosyl-3-((1-(trifluoromethyl)cyclobutyl)methyl)-2,3-dihydroquinolin-4(1H)-
Figure RE-GDA0002450129320000192
按照一般步骤，使用石油醚/AcOEt(10：1)作为洗脱剂，得到黄色油状物 (68％收率)。1H NMR(500MHz,CDCl3)δ7.97-7.89(m,2H),7.56-7.54(m,3H), 7.26-7.20(m,3H),4.63-4.59(dd,J＝14.0Hz,J＝5.5Hz,1H),3.67-3.62(m,1H), 2.54-2.50(dd,J＝15.5Hz,J＝3.5Hz,1H),2.45-2.39(m,2H),2.37(s,3H), 2.27-2.21(m,1H),2.00-1.80(m,4H),1.46-1.41(dd,JC-F＝15.0Hz,JC-F＝6.0Hz)；13C NMR(125MHz,CDCl3)δ195.3,145.0,142.9,137.2,135.2,130.4,128.8,127.4, 125.7,125.2,123.9,52.0,44.7(q,JC-F＝26.4Hz),43.0,32.4,27.7,26.2,22.0,15.2；19F NMR(470MHz,CDCl3):δ[ppm]＝-76.8.
(R)-2-((1-(trifluoromethyl)cyclobutyl)methyl)-2,3-dihydro-1H-inden-1-one
Figure RE-GDA0002450129320000201
按照一般步骤，使用石油醚/AcOEt(10：1)作为洗脱剂，得到无色油状物 (77％收率)。1H NMR(500MHz,CDCl3)δ7.77(d,J＝7.5Hz,1H),7.61-7.58(m, 1H),7.46(d,J＝7.5Hz,1H),7.39-7.36(m,1H),3.50-3.45(dd,J＝17.5Hz,J＝8.0 Hz,1H),2.91-2.87(dd,J＝17.0Hz,J＝4.0Hz,1H),2.68-2.64(m,1H),2.61-2.58 (m,1H),2.46-2.41(m,1H),2.39-2.33(m,1H),2.07-2.01(m,4H),1.76-1.71(dd,,J ＝15.0Hz,J＝10.0Hz,1H)；13C NMR(125MHz,CDCl3)δ208.4,154.2,136.6, 135.4,128.0,126.9,124.5,45.0,37.3,35.5,30.2,27.9(q,JC-F＝3.9Hz),26.1,15.3；19F NMR(470MHz,CDCl3):δ[ppm]＝-76.4.
(3R,4S)-3-(3,3,3-trifluoro-2,2-dimethylpropyl)chroman-4-amine
Figure RE-GDA0002450129320000202
按照一般步骤，使用AcOEt作为洗脱剂，得到黄色油状物(55％的收率)。1H NMR(500MHz,CDCl3)δ7.74-7.73(m,1H),7.60-7.55(m,2H),7.35-7.32(m, 1H),3.94-3.91(m,2H),3.56-3.55(m,1H),2.35-2.31(m,1H),2.14-2.11(m,1H), 1.17-1.14(m,1H),1.11(s,3H),0.98(s,3H)；13C NMR(125MHz,CDCl3)δ163.8, 137.5,130.6,124.1,121.9,110.7,66.5,44.1,41.1(q,JC-F＝25.0Hz),36.4,35.9,21.9, 21.0；19F NMR(470MHz,CDCl3):δ[ppm]＝-78.2.
以上所揭露的仅为本发明较佳实施例而已，当然不能以此来限定本发明之权利范围，因此依本发明权利要求所作的等同变化，仍属本发明所涵盖的范围。

Claims (6)

1.一种含CMe2CF3基团的黄酮类化合物的合成方法，其特征在于化学反应式如下：
Figure FDA0002276855910000011
上式中X为O或N-Tf，R2和R3分开为单独的甲基或合起来为-CH2CH2CH2-，上述反应中加入氧化剂。
2.根据权利要求1所述的含CMe2CF3基团的黄酮类化合物的合成方法，其特征在于：所述氧化剂为过硫酸盐。
3.根据权利要求2所述的含CMe2CF3基团的黄酮类化合物的合成方法，其特征在于：所述氧化剂为过硫酸铵。
4.根据权利要求1所述的含CMe2CF3基团的黄酮类化合物的合成方法，其特征在于：反应在体积比为2:1的DMSO/H2O的溶剂体系中反应。
5.根据权利要求1所述的含CMe2CF3基团的黄酮类化合物的合成方法，其特征在于：反应在氮气保护下进行。
6.根据权利要求1所述的含CMe2CF3基团的黄酮类化合物的合成方法，其特征在于：反应在无金属催化剂的条件下进行。
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