CN112479969B - 1, 3-di (1H-indole) group-1-fluorine-1-propylene derivative and synthetic method thereof - Google Patents
1, 3-di (1H-indole) group-1-fluorine-1-propylene derivative and synthetic method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of pharmaceutical chemicals, and discloses a 1, 3-di (1H-indole) group-1-fluoro-1-propylene derivative and a synthesis method thereof. The structural formula of the 1, 3-di (1H-indole) group-1-fluorine-1-propylene derivative is shown in formula I. The synthesis method of the 1, 3-di (1H-indole) group-1-fluoro-1-propylene derivative comprises the following steps: in alkali and organic solvent, indole compounds and trifluoromethyl olefin compounds react, and subsequent treatment is carried out to obtain the 1, 3-di (1H-indole) group-1-fluorine-1-propylene derivative. The synthesis method of the invention does not use a catalyst, and the used raw materials are nontoxic, cheap and easy to obtain; the reaction has good adaptability to functional groups, wide adaptability to substrates, high product yield and good regioselectivity; the method is simple and safe to operate, mild in reaction condition, insensitive to water and air, and good in industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to 1, 3-di (1H-indole) yl-1-fluoro-1-propylene and a synthesis method thereof.
Background
Diindole and dicarbazole derivatives play an important role in the pharmaceutical and agrochemical industries, being present in many drug molecules, agrochemical molecules and natural products. For example, compound i is a CDK4/cyclin D1 inhibitor, which has a major role in regulating the eukaryotic cell division cycle and is useful as a drug for the treatment of cancer (Aubry, c.; Wilson, a.j.; Emmerson, D.; Murphy, e.; Chan, y.y.; Dickens, m.p.; Garc i a, m.d.; Jenkins, p.r.; Mahale, s.; Chaudhuri, b.bioorg.med.chem.2009,17,6073.). Compound II has antifungal activity and can be used as a medicine for treating fungal (such as Candida albicans) infection (Pooja.; Prasher, P.; Singh, P.; Pawar, K.; Vikramdeo, K.S.; Mondal, N.; Komah, S.S.Eur.J.Med.Chem.2014,80,325). The compound III has selective targeted inhibition on the activity of dihydrofolate reductase of prokaryotes, and can be used as an anti-tumor agent (Kaur, J.; Kaur, S.; Singh, P.Bioorg.Med.chem.Lett.2016,26,1936). Compound IV has anti-breast cancer activity (Kelly, P.M.; Bright, S.A.; Fayne, D.; Pollock, J.K.; Zister, D.M.; Williams, D.C.; Meegan, M.J.Bioorg.Med.chem.2016,2,4075.). Compound V inhibits proliferation of human lung cancer cells by inducing apoptosis and inhibiting cell migration, and has anti-tumor angiogenesis effect (Ma, Q.; Chen, W.; Chen, W.Tumor biol.2016,37,6107.). Compound VI acts as a novel selective non-nucleoside deoxyribonucleotide methyltransferase (DNMTs) inhibitor and is useful as an anti-cancer active agent (Chen, S.; Wang, Y.; Zhou, W.; Li, S.; Peng, J.; Shi, Z.; Hu, J.; Liu, Y.; Ding, H.; Lin, Y.; Li, L.; Cheng, S.; Liu J.; Lu, T.; Jiang, H.; Liu, B.; Zheng, M.; Luo, C.J.Med.chem.2014,57,9028.). Therefore, the development of a new method for efficiently synthesizing diindole and dicarbazole derivatives is a very important issue in the pharmaceutical and chemical fields.
In the compounds I-VI, the linkers between the diindolyl groups are different, and abundant biological activity is shown. However, the method for synthesizing bisindole derivatives having a fluoroalkenyl group as a linker has not been reported yet. Therefore, the development of a method for efficiently synthesizing a bisindole derivative (1, 3-bis (1H-indole) yl-1-fluoro-1-propene) having a fluoroalkenyl group as a linker is still a challenging research topic.
Disclosure of Invention
In order to overcome the defects and shortcomings in the prior art, the invention mainly aims to provide a 1, 3-di (1H-indole) yl-1-fluoro-1-propylene derivative.
Another object of the present invention is to provide a method for synthesizing the above 1, 3-bis (1H-indole) yl-1-fluoro-1-propene derivative.
The purpose of the invention is realized by the following technical scheme:
a1, 3-di (1H-indole) yl-1-fluoro-1-propene derivative having the formula I:
wherein R is hydrogen, methyl, methoxyl, fluorine, chlorine, bromine, iodine, trifluoromethyl or cyano; r1Is phenyl, p-fluorophenyl, naphthyl, p-methylphenyl, p-chlorophenyl, p-methoxyphenyl, p-bromophenyl, p-trifluoromethylphenyl, p-morpholinophenyl, p-carbazolylphenyl, cyclohexenyl or thienyl.
The synthesis method of the 1, 3-di (1H-indole) group-1-fluoro-1-propylene derivative comprises the following steps:
in alkali and organic solvent, indole compound
With trifluoromethyl olefin compounds
Reacting and performing subsequent treatment to obtain the 1, 3-di (1H-indole) group-1-fluorine-1-propylene derivative.
The alkali is more than one of cesium carbonate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide and sodium methoxide.
The organic solvent is more than one of dimethyl sulfoxide and N, N-dimethylformamide.
The reaction temperature is-10-25 ℃, and preferably-10-0 ℃.
The reaction time is 5 minutes to 2 hours, preferably 20 minutes to 2 hours; the reaction is carried out under air or oxygen atmosphere.
The molar ratio of the indole compound to the trifluoromethyl olefin compound is (2-4): 1
The molar ratio of the added alkali to the indole is (0.5-2): 1.
And the subsequent treatment comprises the steps of adding water and an organic solvent after the reaction is finished, extracting a reaction solution, carrying out reduced pressure rotary evaporation on an organic layer to remove the solvent to obtain a crude product, and carrying out column chromatography separation and purification to obtain the 1, 3-di (1H-indole) yl-1-fluoro-1-propylene derivative.
The column chromatography purification refers to column chromatography purification of mixed solvent eluent of petroleum ether or petroleum ether and ethyl acetate with the volume ratio of (10-100): 1.
The reaction formula of the synthesis method is as follows:
the preparation method and the obtained product have the following advantages and beneficial effects:
(1) the synthesis method of the invention does not use a catalyst, and the used raw materials are nontoxic, cheap and easy to obtain; the reaction has good adaptability to functional groups, wide adaptability to substrates, high product yield and good regioselectivity;
(2) the synthetic method provided by the invention is simple and safe to operate, mild in reaction conditions, insensitive to water and air, and good in industrial application prospect.
Drawings
FIG. 1 is a hydrogen spectrum of a 1, 3-bis (1H-indole) yl-1-fluoro-1-propene derivative obtained in examples 1 to 10;
FIG. 2 is a carbon spectrum of a 1, 3-bis (1H-indole) yl-1-fluoro-1-propene derivative obtained in examples 1 to 10;
FIG. 3 is a fluorine spectrum of the 1, 3-bis (1H-indole) yl-1-fluoro-1-propene derivative obtained in examples 1 to 10.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
Example 1
The synthesis method of 1, 3-bis (1H-indole) yl-1-fluoro-1-propene of this embodiment specifically includes the following steps:
adding 1.2 mmol of indole, 4 ml of N, N-dimethylformamide, 0.4 mol of trifluoromethyl olefin and 1.2 mol of cesium carbonate into a 25 ml test tube in sequence, stirring and reacting at-5 ℃ for 0.5 h, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether serving as a column chromatography eluent is used to obtain the product with the yield of 54 percent and the Z/E of 13: 1.
Example 2
The synthesis method of 1, 3-bis (1H-indole) yl-1-fluoro-1-propene of this embodiment specifically includes the following steps:
adding 1.2 mmol of indole, 4 ml of N, N-dimethylformamide, 0.4 mol of trifluoromethyl olefin and 1.2 mol of lithium tert-butoxide into a 25 ml test tube in sequence, stirring and reacting for 0.5 h at-5 ℃, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether serving as a column chromatography eluent is used to obtain the product with the yield of 94% and the Z/E of 9: 1.
Example 3
The synthesis method of 1, 3-bis (1H-indole) yl-1-fluoro-1-propene of this embodiment includes the following specific synthesis steps:
adding 1.2 mmol of indole, 4 ml of N, N-dimethylformamide, 0.4 mol of trifluoromethyl olefin and 1.2 mol of sodium tert-butoxide into a 25 ml test tube in sequence, stirring and reacting for 0.5 hour at-5 ℃, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-distilling to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether is used as eluent of the column chromatography to obtain the product with the yield of 92 percent and the Z/E of 13: 1.
Example 4
The synthesis method of 1, 3-bis (1H-indole) yl-1-fluoro-1-propene of this embodiment specifically includes the following steps:
adding 1.2 mmol of indole, 4 ml of N, N-dimethylformamide, 0.4 mol of trifluoromethyl olefin and 2.4 mol of sodium tert-butoxide into a 25 ml test tube in sequence, stirring and reacting for 2 hours at-10 ℃, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether serving as a column chromatography eluent is used to obtain the product with the yield of 90 percent and the Z/E ratio of 11: 1.
Example 5
The synthesis method of 1, 3-bis (1H-indole) yl-1-fluoro-1-propene of this embodiment specifically includes the following steps:
adding 1.2 mmol of indole, 4 ml of N, N-dimethylformamide, 0.4 mol of trifluoromethyl olefin and 0.6 mol of sodium tert-butoxide into a 25 ml test tube in sequence, stirring and reacting for 2 hours at 25 ℃, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary evaporating to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether serving as a column chromatography eluent is used to obtain the product with the yield of 41 percent and the Z/E ratio of 10: 1.
Example 6
The synthesis method of 1, 3-bis (1H-indole) yl-1-fluoro-1-propene of this embodiment specifically includes the following steps:
adding 1.2 mmol of indole, 4 ml of N, N-dimethylformamide, 0.3 mol of trifluoromethyl olefin and 1.2 mol of sodium tert-butoxide into a 25 ml test tube in sequence, stirring and reacting for 10 minutes at-5 ℃, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether serving as a column chromatography eluent is used to obtain the product with the yield of 76 percent and the Z/E ratio of 13: 1.
Example 7
The synthesis method of 1, 3-bis (1H-indole) yl-1-fluoro-1-propene of this embodiment specifically includes the following steps:
adding 1.2 mmol indole, 4 ml N, N-dimethylformamide, 0.4 mol trifluoromethyl olefin and 1.2 mol potassium tert-butoxide into a 25 ml test tube in sequence, stirring and reacting for 0.5 h at-5 ℃, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, separating and purifying by column chromatography to obtain a target product, and using petroleum ether as eluent of the column chromatography to obtain the product with the yield of 92%.
Example 8
The synthesis method of 1, 3-bis (1H-indole) yl-1-fluoro-1-propene of this embodiment specifically includes the following steps:
adding 1.2 mmol of indole, 4 ml of N, N-dimethylformamide, 0.6 mol of trifluoromethyl olefin and 1.2 mol of potassium tert-butoxide into a 25 ml test tube in sequence, stirring and reacting for 0.5 h at-5 ℃, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether serving as a column chromatography eluent is used to obtain the product with the yield of 81 percent and the Z/E of 7: 1.
Example 9
The synthesis method of 1, 3-bis (1H-indole) yl-1-fluoro-1-propene of this embodiment specifically includes the following steps:
adding 1.2 mmol of indole, 4 ml of N, N-dimethylformamide, 0.4 mol of trifluoromethyl olefin and 1.2 mol of sodium methoxide into a 25 ml test tube in sequence, stirring and reacting at-5 ℃ for 0.5 h, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary evaporating to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether serving as a column chromatography eluent is used to obtain the product with the yield of 36 percent and the Z/E ratio of 8: 1.
Example 10
The synthesis method of 1, 3-bis (1H-indole) yl-1-fluoro-1-propene of this embodiment specifically includes the following steps:
adding 1.2 mmol of indole, 4 ml of dimethyl sulfoxide, 0.4 mol of trifluoromethyl olefin and 1.2 mol of cesium carbonate into a 25 ml test tube in sequence, stirring and reacting at-5 ℃ for 0.5 hour, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary evaporating to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether serving as eluent of the column chromatography is used to obtain the product with the yield of 50 percent and the Z/E of 13: 1.
The hydrogen, carbon and fluorine spectra of the major isomers of the products obtained in examples 1-10 above are shown in FIGS. 1, 2 and 3, respectively. Structural characterization data:
1H NMR(400MHz,CDCl3)δ7.85(d,J＝7.6Hz,1H),7.70–7.73(m,2H),7.64(d,J＝8.4Hz,1H),7.33–7.50(m,5H),7.14–7.220(m,3H),6.90–6.95(m,3H),6.65(d,J＝3.2Hz,1H),6.57(d,J＝3.2Hz,1H),5.47(d,J＝2.8Hz,2H)；
13C NMR(101MHz,CDCl3)δ147.0(d,1JF-C＝264.1Hz),136.2,135.9(d,3JF-C＝3.8Hz),133.8(d,3JF-C＝3.6Hz),128.9,128.7,128.6,128.2,128.1(d,3JF-C＝3.0Hz),128.0,127.4,123.4,121.9,121.7,121.1(d,3JF-C＝3.3Hz),119.7,111.5(d,3JF-C＝2.9Hz),111.2(d,2JF-C＝25.7Hz),109.6(d,4JF-C＝1.8Hz),105.7,101.8,45.4(d,3JF-C＝2.9Hz)；
19F NMR(376MHz,CDCl3)δ-87.9(d,J＝1.8Hz,1F)；
IR(KBr):3050,2937,1695,1604,1461,1000,751cm-1；
HRMS(ESI,m/z):[M+H]+C25H19FN2+ H, theory 367.1611; measured, 367.1609.
From the above data it is concluded that the structure of the major isomer in the product obtained in this example is:
example 11
The synthesis method of 1, 3-bis (1H-indole) yl-1-fluoro-1-propene of this embodiment specifically includes the following steps:
adding 1.2 mmol of 5-methylindole, 4 ml of N, N-dimethylformamide, 0.4 mol of trifluoromethyl olefin and 1.2 mol of sodium tert-butoxide into a 25 ml test tube in sequence, stirring and reacting for 0.5 hour at-5 ℃, stopping stirring, adding ethyl acetate and water to extract a reaction solution, carrying out reduced pressure rotary evaporation to remove a solvent, and carrying out column chromatography separation and purification to obtain a target product, wherein the petroleum ether is used as an eluent of the column chromatography to obtain the product with the yield of 90%, and the Z/E is 10: 1.
Structural characterization data for the product obtained in this example:
1H NMR(400MHz,CDCl3)δ7.35–7.38(m,2H),7.25–7.30(m,2H),7.04(dd,J＝8.4,1.2Hz,1H),6.94–7.02(m,4H),6.88(d,J＝3.2Hz,1H),6.64–6.69(m,3H),6.31(d,J＝2.8Hz,1H),6.26(d,J＝3.2Hz,1H),5.21(d,J＝2.8Hz,2H),2.43(s,3H),2.37(s,3H)；
13C NMR(101MHz,CDCl3)δ147.2(d,1JF-C＝263.9Hz),134.6,134.2(d,3JF-C＝3.9Hz),134.0(d,3JF-C＝3.4Hz),131.1,129.2,129.0,128.9,128.6,128.3,128.1(d,3JF-C＝3.1Hz),127.9,127.5,124.9,123.5,120.9,120.8,111.2(d,3JF-C＝3.0Hz),111.2(d,2JF-C＝25.9Hz),109.3(d,4JF-C＝1.8Hz),105.4,101.2,45.5(d,3JF-C＝2.9Hz),21.5(d,3JF-C＝2.6Hz),21.4(d,3JF-C＝2.7Hz)；
19F NMR(471MHz,CDCl3)δ-88.2(s,1F)；
IR(KBr):3025,2921,1694,1473,1384,713cm-1；
HRMS(ESI,m/z):[M+H]+C27H23FN2+ H, theoretical calculation 395.1924; measured, 395.1924.
From the above data it is concluded that the structure of the major isomer in the product obtained in this example is:
example 12
The synthesis method of 1, 3-bis (1H-indole) yl-1-fluoro-1-propene of this embodiment specifically includes the following steps:
adding 1.2 mmol of 4-chloroindole, 4 ml of N, N-dimethylformamide, 0.4 mol of trifluoromethyl olefin and 1.2 mol of sodium tert-butoxide into a 25 ml test tube in sequence, stirring and reacting for 0.5 hour at-5 ℃, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary evaporating to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether is used as eluent of the column chromatography to obtain the product with the yield of 87 percent and the Z/E of 15: 1.
Structural characterization data for the product obtained in this example:
1H NMR(400MHz,CDCl3)δ7.31–7.35(m,1H),7.24(d,J＝7.6Hz,1H),6.96–7.12(m,7H),6.92(d,J＝3.2Hz,1H),6.76(d,J＝3.2Hz,1H),6.66(d,J＝7.2Hz,2H),6.51(d,J＝3.2Hz,1H),6.48(d,J＝3.2Hz,1H),5.24(d,J＝2.4Hz,2H)；
13C NMR(101MHz,CDCl3)δ147.0(d,1JF-C＝263.8Hz),136.8,136.5(d,3JF-C＝3.6Hz),133.1(d,3JF-C＝3.2Hz),128.8,128.4,127.9(d,3JF-C＝3.0Hz),127.9(d,3JF-C＝7.5Hz),126.4(d,3JF-C＝3.9Hz),124.1,122.5,121.6,119.6,111.8(d,2JF-C＝25.0Hz),110.0(d,4JF-C＝2.7Hz),108.3(d,4JF-C＝2.0Hz),104.2,100.6,45.8(d,3JF-C＝2.7Hz)；
19F NMR(376MHz,CDCl3)δ-88.2(s,1F)；
IR(KBr):3058,2937,1698,1442,1328,742cm-1；
HRMS(ESI,m/z):[M+H]+C25H17Cl2FN2+ H, theory 435.0831; measured, 435.0830.
From the above data it is concluded that the structure of the major isomer in the product obtained in this example is:
example 13
The synthesis method of 1, 3-bis (1H-indole) yl-1-fluoro-1-propene of this embodiment specifically includes the following steps:
adding 1.2 mmol of 4-fluoroindole, 4 ml of N, N-dimethylformamide, 0.4 mol of trifluoromethyl olefin and 1.2 mol of sodium tert-butoxide into a 25 ml test tube in sequence, stirring and reacting for 0.5 hour at-5 ℃, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary evaporating to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether is used as eluent of the column chromatography to obtain the product with the yield of 87 percent and the Z/E of 17: 1.
Structural characterization data for the product obtained in this example:
1H NMR(400MHz,CDCl3)δ7.23(d,J＝8.0Hz,1H),7.07–7.15(m,3H),6.94–7.03(m,3H),6.86(d,J＝3.2Hz,1H),6.79(d,J＝7.6Hz,1H),6.77(d,J＝7.6Hz,1H),6.65–6.70(m,3H),6.48(dd,J＝3.2,0.8Hz,1H),6.44–6.46(m,1H),5.24(d,J＝2.8Hz,2H)；
13C NMR(101MHz,CDCl3)δ156.6(d,1JF-C＝245.8Hz),156.2(d,1JF-C＝246.5Hz),146.6(d,1JF-C＝267.3Hz),138.8(d,2JF-C＝11.6Hz),138.3(dd,JF-C＝8.9,3.6Hz),133.2(d,3JF-C＝3.2Hz),128.7,128.3,128.2,128.0(d,3JF-C＝3.0Hz),127.4,124.5(d,3JF-C＝7.7Hz),122.5(d,3JF-C＝7.6Hz),117.9(d,2JF-C＝15.1Hz),117.7(d,2JF-C＝16.4Hz),112.0(d,2JF-C＝25.4Hz),107.5,106.8(d,2JF-C＝18.8Hz),105.8,104.7(d,2JF-C＝19.0Hz),101.6,97.9,45.8(d,3JF-C＝2.2Hz)；
19F NMR(471MHz,CDCl3)δ-88.4(s,1F),-121.4–-121.3(m,1F),-121.7–-121.6(m,1F)；
IR(KBr):3055,2937,1700,1433,1319,738cm-1；
HRMS(ESI,m/z):[M+H]+C25H17F3N2+ H, theory 403.1422; measured, 403.1412.
From the above data it is concluded that the structure of the major isomer in the product obtained in this example is:
example 14
The synthesis method of 1, 3-bis (1H-indole) yl-1-fluoro-1-propene of this embodiment includes the following specific synthesis steps:
adding 1.2 mmol of 4-bromoindole, 4 ml of N, N-dimethylformamide, 0.4 mol of trifluoromethyl olefin and 1.2 mol of sodium tert-butoxide into a 25 ml test tube in sequence, stirring and reacting for 0.5 hour at-5 ℃, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary evaporating to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether is used as eluent of the column chromatography to obtain the product with the yield of 80 percent and the Z/E of 18: 1. Structural characterization data for the product obtained in this example:
1H NMR(400MHz,CDCl3)δ7.60(s,2H),7.42(d,J＝8.4Hz,1H),7.33(d,J＝8.4Hz,1H),7.24(d,J＝8.4Hz,1H),7.20(d,J＝8.0Hz,1H),6.99–7.09(m,3H),6.89(d,J＝2.4Hz,1H),6.70(d,J＝8.0Hz,3H),6.35(s,1H),6.32(d,J＝2.4Hz,1H),5.24(s,2H)；
13C NMR(101MHz,CDCl3)δ146.5(d,1JF-C＝263.7Hz),136.9,136.5(d,3JF-C＝3.8Hz),133.1(d,3JF-C＝3.4Hz),128.9,128.8,128.4,128.0,128.0,127.7,127.6,125.2,123.1,122.4,122.3,117.2,115.6,114.6(d,3JF-C＝3.3Hz),112.7(d,3JF-C＝2.2Hz),111.3(d,2JF-C＝24.9Hz),105.8,102.1,45.7(d,3JF-C＝2.7Hz)；
19F NMR(376MHz,CDCl3)δ-88.9(s,1F)；
IR(KBr):3055,2932,1692,1450,1329,717cm-1；
HRMS(ESI,m/z):[M+H]+C25H17Br2FN2+ H, theory 522.9821; measured, 522.9814.
From the above data it is concluded that the structure of the major isomer in the product obtained in this example is:
example 15
The synthesis method of 1, 3-bis (1H-indole) yl-1-fluoro-1-propene of this embodiment includes the following specific synthesis steps:
adding 1.2 mmol of 4-trifluoromethyl indole, 4 ml of N, N-dimethylformamide, 0.4 mol of trifluoromethyl olefin and 1.2 mol of sodium tert-butoxide into a 25 ml test tube in sequence, stirring and reacting for 0.5 hour at-5 ℃, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether is used as eluent of the column chromatography, the yield of the product is 85%, and Z/E is more than 30: 1.
Structural characterization data for the product obtained in this example:
1H NMR(400MHz,CDCl3)δ7.59(d,J＝8.4Hz,1H),7.50(d,J＝8.4Hz,1H),7.41(t,J＝6.4Hz,2H),7.19–7.27(m,2H),6.97–7.04(m,4H),6.86(d,J＝3.2Hz,1H),6.69(d,J＝6.8Hz,2H),6.60(d,J＝11.2Hz,2H),5.31(d,J＝2.4Hz,2H)；
13C NMR(101MHz,CDCl3)δ146.4(d,1JF-C＝263.7Hz),136.7,136.3(d,3JF-C＝3.6Hz),133.1(d,3JF-C＝3.3Hz),130.0,129.1,129.0,128.6,128.0(d,3JF-C＝3.0Hz),125.2(m),125.2(q,1JF-C＝270.5Hz),124.7(q,1JF-C＝270.5Hz),122.9,122.5(q,2JF-C＝32.5Hz),122.4(q,2JF-C＝32.1Hz),121.2,119.3(q,3JF-C＝4.7Hz),117.5(q,3JF-C＝4.8Hz),114.9(d,4JF-C＝1.9Hz),113.2,112.3(d,2JF-C＝25.0Hz),104.5,101.0,45.7(d,3JF-C＝3.0Hz)；
19F NMR(376MHz,CDCl3)δ-61.1(s,3F),-88.1(s,1F)；
IR(KBr):3059,2938,1700,1513,1070,742cm-1；
HRMS(ESI,m/z):[M+H]+C27H17F7N2+ H, theory 503.1358; found, 503.1356.
From the above data it is concluded that the structure of the major isomer in the product obtained in this example is:
example 16
The synthesis method of 1, 3-bis (1H-indole) yl-1-fluoro-1-propene of this embodiment specifically includes the following steps:
adding 1.2 mmol of 5-iodoindole, 4 ml of N, N-dimethylformamide, 0.4 mol of trifluoromethyl olefin and 1.2 mol of sodium tert-butoxide into a 25 ml test tube in sequence, stirring and reacting for 0.5 hour at-5 ℃, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-evaporating to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether is used as eluent of the column chromatography to obtain the product with the yield of 85 percent and the Z/E of more than 30: 1.
Structural characterization data for the product obtained in this example:
1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.90(s,1H),7.52–7.56(m,2H),7.27–7.30(m,1H),7.20(d,J＝8.4Hz,1H),7.01–7.16(m,3H),6.95(d,J＝2.8Hz,1H),6.77(d,J＝3.2Hz,1H),6.73(d,J＝7.6Hz,2H),6.40(d,J＝2.8Hz,1H),6.36(d,J＝3.2Hz,1H),5.31(s,2H).
13C NMR(101MHz,CDCl3)δ146.4(d,1JF-C＝264.4Hz),135.1,134.9(d,3JF-C＝3.6Hz),133.2(d,3JF-C＝3.3Hz),131.8,131.4,131.0,130.1,129.9,129.0,128.8,128.3,128.1(d,4JF-C＝2.0Hz),127.9(d,3JF-C＝3.1Hz),113.2(d,3JF-C＝2.8Hz),111.5(d,2JF-C＝25.3Hz),111.5(d,4JF-C＝1.8Hz),105.0,101.2,85.6,83.5,45.6(d,3JF-C＝2.5Hz)；
19F NMR(376MHz,CDCl3)δ-88.3(s,1F)；
IR(KBr):3062,2923,1694,1451,1325,707cm-1；
HRMS(ESI,m/z):[M+H]+C25H17FI2N2+ H, theory 618.9538; measured, 618.9537.
From the above data it is concluded that the structure of the major isomer in the product obtained in this example is:
example 17
The synthesis method of 1, 3-bis (1H-indole) yl-1-fluoro-1-propene of this embodiment specifically includes the following steps:
adding 1.2 mmol of indole, 4 ml of N, N-dimethylformamide, 0.4 mol of alpha-trifluoromethyl-p-tert-butylstyrene and 1.2 mol of sodium tert-butoxide into a 25 ml test tube in sequence, stirring and reacting for 0.5 h at-5 ℃, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-distilling to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used eluent of the column chromatography is petroleum ether, the yield of the product is 90%, and Z/E is 19: 1.
Structural characterization data for the product obtained in this example:
1H NMR(400MHz,CDCl3)δ7.61(d,J＝8.0Hz,1H),7.47(t,J＝6.8Hz,2H),7.38(d,J＝8.0Hz,1H),7.08–7.21(m,4H),6.98(d,J＝8.4Hz,3H),6.72(d,J＝3.2Hz,1H),6.62(d,J＝8.0Hz,2H),6.43(d,J＝2.8Hz,1H),6.35(d,J＝3.2Hz,1H),5.23(d,J＝2.4Hz,2H),1.12(s,9H)；
13C NMR(101MHz,CDCl3)δ150.9,147.1(d,1JF-C＝263.5Hz),136.3,135.9(d,3JF-C＝3.6Hz),130.8(d,3JF-C＝3.3Hz),128.9,128.8,128.2,127.7(d,3JF-C＝3.1Hz),127.6,125.5,123.4,121.8,121.6,121.0(d,3JF-C＝4.9Hz),119.7,111.6(d,3JF-C＝2.9Hz),110.7(d,2JF-C＝25.4Hz),109.7,105.7,101.8,45.5(d,3JF-C＝3.0Hz),34.5,31.2；
19F NMR(376MHz,CDCl3)δ-87.9(s,1F)；
IR(KBr):3049,2960,1692,1459,1336,742cm-1；
HRMS(ESI,m/z):[M+H]+C29H27FN2+ H, theory 423.2237; measured, 423.2236.
From the above data it is concluded that the structure of the major isomer in the product obtained in this example is:
example 18
The synthesis method of 1, 3-bis (1H-indole) yl-1-fluoro-1-propene of this embodiment specifically includes the following steps:
sequentially adding 1.2 mmol of indole, 4 ml of N, N-dimethylformamide, 0.4 mol of alpha-trifluoromethyl p-carbazolyl styrene and 1.2 mol of sodium tert-butoxide into a 25 ml test tube, stirring and reacting for 0.5 h at-5 ℃, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent petroleum ether is used to obtain the product with the yield of 40% and the Z/E ratio of more than 30: 1.
Structural characterization data for the product obtained in this example:
1H NMR(400MHz,CDCl3)δ8.03(d,J＝7.6Hz,2H),7.64(d,J＝7.6Hz,1H),7.52(d,J＝7.6Hz,1H),7.47(d,J＝8.4Hz,1H),7.27–7.34(m,4H),7.05–7.23(m,10H),6.87(d,J＝3.2Hz,1H),6.81(d,J＝8.4Hz,2H),6.49(d,J＝3.2Hz,1H),6.47(d,J＝3.2Hz,1H),5.33(d,J＝2.8Hz,2H)；
13C NMR(101MHz,CDCl3)δ147.3(d,1JF-C＝264.7Hz),140.6,137.3,136.3,135.7(d,3JF-C＝3.4Hz),132.9(d,3JF-C＝3.6Hz),129.6(d,3JF-C＝2.7Hz),129.0,128.8,128.1,127.2,127.0,126.0,123.6,123.5,122.1,121.8,121.3(d,3JF-C＝2.9Hz),120.4,120.2,119.9,111.5(d,3JF-C＝2.5Hz),110.3(d,2JF-C＝26.4Hz),109.7,109.7,106.3,102.2,45.3(d,3JF-C＝3.0Hz)；
19F NMR(471MHz,CDCl3)δ-87.1(s,1F)；
IR(KBr):3053,2928,1707,1453,745cm-1；HRMS(ESI,m/z):[M+H]+C37H26FN3+ H, theory 532.2189; measured, 532.2185.
From the above data it is concluded that the structure of the major isomer in the product obtained in this example is:
example 19
The synthesis method of 1, 3-bis (1H-indole) yl-1-fluoro-1-propene of this embodiment specifically includes the following steps:
adding 1.2 mmol of 5-iodoindole, 4 ml of N, N-dimethylformamide, 0.4 mol of alpha-trifluoromethyl p-methylstyrene and 1.2 mol of sodium tert-butoxide into a 25 ml test tube in sequence, stirring and reacting for 0.5 h at-5 ℃, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-evaporating to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether serving as a column chromatography eluent is used to obtain the product with the yield of 90 percent and the Z/E of 19: 1.
Structural characterization data for the product obtained in this example:
1H NMR(400MHz,CDCl3)δ7.59(d,J＝8.0Hz,1H),7.47(t,J＝8.0Hz,2H),7.40(d,J＝8.4Hz,1H),7.22(t,J＝7.6Hz,1H),7.17(t,J＝7.6Hz,1H),7.08–7.12(m,2H),6.92(d,J＝3.2Hz,1H),6.73(d,J＝8.0Hz,2H),6.70(d,J＝3.2Hz,1H),6.56(d,J＝8.0Hz,2H),6.39(d,J＝3.2Hz,1H),6.33(d,J＝3.6Hz,1H),5.21(d,J＝2.4Hz,2H),2.06(s,3H)；
13C NMR(101MHz,CDCl3)δ146.8(d,1JF-C＝263.8Hz),137.7,136.2,135.9(d,3JF-C＝3.7Hz),130.7(d,3JF-C＝3.4Hz),129.3,128.9,128.7,128.2,127.9(d,3JF-C＝2.9Hz),127.5,123.4,121.9,121.6,121.1(d,3JF-C＝2.8Hz),119.7,111.5(d,3JF-C＝2.9Hz),111.2(d,2JF-C＝25.5Hz),109.7(d,4JF-C＝2.0Hz),105.6,101.7,45.5(d,3JF-C＝2.9Hz),21.1(d,JF-C＝2.6Hz)；
19F NMR(376MHz,CDCl3)δ-88.4(s,1F)；
IR(KBr):3047,2922,1694,1455,1332,739cm-1；
HRMS(ESI,m/z):[M+H]+C26H21FN2+ H, theory 381.1767; measured, 381.1773.
From the above data it is concluded that the structure of the major isomer in the product obtained in this example is:
the invention relates to a 1, 3-di (1H-indole) group-1-fluorine-1-propylene derivative, the structural formula of which is shown in formula I:
wherein R is hydrogen, methyl, methoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl or cyano; r1Is phenyl, p-fluorophenyl, naphthyl, p-methylphenyl, p-chlorophenyl, p-methoxyphenyl, p-bromophenyl, p-trifluoromethylphenyl, p-morpholinophenyl, p-carbazolylphenyl, cyclohexenyl or thienyl.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (8)
1. A method for synthesizing 1, 3-di (1H-indole) group-1-fluorine-1-propylene derivatives is characterized in that: the method comprises the following steps:
in alkali and organic solvent, indole compounds and trifluoromethyl olefin compounds react, and subsequent treatment is carried out to obtain 1, 3-di (1H-indole) group-1-fluorine-1-propylene derivatives;
the structure of the indole compound is
The structure of the trifluoromethyl olefin compound is
R，R1As defined in formula I;
the 1, 3-di (1H-indole) yl-1-fluoro-1-propylene derivative has a structural formula shown in a formula I:
wherein R is hydrogen, methyl, methoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl or cyano; r1Is phenyl, p-fluorophenyl, naphthyl, p-methylphenyl, p-chlorophenyl, p-methoxyphenyl, p-bromophenyl, p-trifluoromethylphenyl, p-morpholinophenyl, p-carbazolylphenyl, cyclohexenyl or thienyl.
2. The method of synthesizing the 1, 3-bis (1H-indole) yl-1-fluoro-1-propene derivative according to claim 1, wherein: the alkali is more than one of cesium carbonate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide and sodium methoxide.
3. The method of synthesizing the 1, 3-bis (1H-indole) yl-1-fluoro-1-propene derivative according to claim 1, wherein: the organic solvent is more than one of dimethyl sulfoxide and N, N-dimethylformamide.
4. The method of synthesizing the 1, 3-bis (1H-indole) yl-1-fluoro-1-propene derivative according to claim 1, wherein: the reaction temperature is-10-25 ℃.
5. The method of synthesizing the 1, 3-bis (1H-indole) yl-1-fluoro-1-propene derivative according to claim 1, wherein: the reaction temperature is-10-0 ℃.
6. The method of synthesizing the 1, 3-bis (1H-indole) yl-1-fluoro-1-propene derivative according to claim 1, wherein: the mol ratio of the indole compound to the trifluoromethyl olefin compound is (2-4) to 1;
the molar ratio of the alkali to the indole compound is (0.5-2) to 1;
the reaction time is 5 minutes to 2 hours; the reaction is carried out under air or oxygen atmosphere.
7. The method of synthesizing the 1, 3-bis (1H-indole) yl-1-fluoro-1-propene derivative according to claim 1, wherein: and the subsequent treatment comprises the steps of adding water and an organic solvent after the reaction is finished, extracting a reaction solution, carrying out reduced pressure rotary evaporation on an organic layer to remove the solvent to obtain a crude product, and carrying out column chromatography separation and purification to obtain the 1, 3-di (1H-indole) yl-1-fluoro-1-propylene derivative.
8. The method of synthesizing the 1, 3-bis (1H-indole) yl-1-fluoro-1-propene derivative according to claim 7, wherein: the column chromatography purification refers to column chromatography purification of mixed solvent eluent of petroleum ether or petroleum ether and ethyl acetate with the volume ratio of (10-100): 1.
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| CN101490045A (en) * | 2006-05-16 | 2009-07-22 | 解码遗传Ehf公司 | Process for preparing 7- (acryl0yl) -ind0les |
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