CN111270259A - Method for electrochemically synthesizing hexafluoroisopropoxyaniline compound - Google Patents
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Abstract
The invention discloses a method for electrochemically synthesizing hexafluoroisopropoxy aniline compound, which comprises the following steps: respectively putting 0.5mmol of aniline, 1.5 equivalents of alkali and 0.5 equivalents of electrolyte into a 10mL three-neck round-bottom flask, adding 7mL of solvent for dissolution, using Reticular Vitreous Carbon (RVC) as an anode and a platinum sheet as a cathode, carrying out stirring reaction at room temperature under a constant current of 10-20mA, monitoring the reaction process by adopting thin-layer chromatography, wherein the reaction time is 10-15 hours, extracting the mixture by using 10mL of ethyl acetate after the reaction is finished, drying an organic layer by using anhydrous sodium sulfate, carrying out decompression and spin-drying on the solvent, and eluting and purifying residues by using column chromatography to obtain the required product. The method has mild reaction conditions, and the prepared hexafluoroisopropoxy aniline compound has good antitumor activity through in vitro antitumor activity screening.
Description
Technical Field
The invention relates to chemical synthesis, in particular to a method for electrochemically synthesizing hexafluoroisopropoxyaniline compounds.
Background
Aniline is an important chemical raw material, a very useful building block for the preparation of bioactive molecules, polymers, pharmaceuticals, agrochemicals, dyes and other functional products (chem.rev.,2009,109,259; j.med.chem.,2012,55, 3923; Synthetic Chemistry of Ureas and Amides, Springer: Berlin, 2012). Hexafluoroisopropoxy-containing compounds have a variety of biological and therapeutic activities and have been used in the treatment of hepatitis c, cancer, dyslipidemia, inflammation, and diabetes (bioorg.med.chem.lett.,2006,16, 1638; pharmacol.,2010,77, 228; ACS chem.biol.,2010,5, 1029; j.org.chem.,2014,79, 3684; medchemcom., 2016,7, 1672; org.biomol.chem.,2017,15, 6441). Furthermore, they can also be used for the preparation of polymers (Polymer,2003,44, 6431; polymer.j., 2011,43,325.), ligands (org.lett.,2010,12, 2520; j.am.chem.soc.,2012,134,11185; angelw.chem., int.ed.,2014,53,8765.) and the development of chemical sensors (Carbon,2010,48, 1262; Analyst,2010,135,368.) and the synthesis of spiroalkanes (j.org.chem.,2015,80, 3280; j.am.chem.soc.,1979,101,1591).
Molecules containing hexafluoroalkoxy groups have become an important class of compounds in the fields of medicine, pesticides and material science because the introduction of a hexafluoroalkoxy group into an organic compound generally improves the thermal, chemical, metabolic stability, lipophilicity and bioavailability of the parent molecule. Despite the great advances in late fluorination, hexafluoroalkylation and perfluoroalkyl sulfurization of (hetero) aromatics, the simple synthesis of hexafluoroalkoxylated (hetero) aromatic compounds remains an unsolved problem in synthetic organic chemistry.
The strategies reported to date for the preparation of hexafluoroisopropoxyanilines are very limited, and therefore, it remains a very valuable task to develop a process for the direct synthesis of hexafluoroisopropoxyanilines starting from commercial starting materials.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a method for electrochemically synthesizing hexafluoroisopropoxyaniline compounds. The method has mild reaction conditions, and the prepared hexafluoroisopropoxy aniline compound has good antitumor activity through in vitro antitumor activity screening.
The technical scheme for realizing the purpose of the invention is as follows:
a method for electrochemically synthesizing hexafluoroisopropoxyaniline compound, which is different from the prior art in that the general formula of the synthesis method is as follows:
in the general formula, O, S, R is aromatic or aliphatic, and the electrolyte is: tetrabutylammonium iodide or tetrabutylammonium hexafluorophosphate or tetrabutylammonium tetrafluoroborate, and the solvent is: hexafluoroisopropanol or a mixed solution of hexafluoroisopropanol and dichloromethane, wherein the alkali is: potassium carbonate or cesium carbonate or potassium tert-butoxide.
The method for electrochemically synthesizing the hexafluoroisopropoxyaniline compound comprises the following steps:
respectively putting 0.5mmol of aniline, 1.5 equivalents of alkali and 0.5 equivalents of electrolyte into a 10mL three-neck round-bottom flask, adding 7mL of solvent for dissolution, using Reticular Vitreous Carbon (RVC) as an anode and a platinum sheet as a cathode, carrying out stirring reaction at room temperature under a constant current of 10-20mA, monitoring the reaction process by adopting thin-layer chromatography, wherein the reaction time is 10-15 hours, extracting the mixture by using 10mL of ethyl acetate after the reaction is finished, drying an organic layer by using anhydrous sodium sulfate, carrying out decompression and spin-drying on the solvent, and eluting and purifying residues by using column chromatography to obtain the required product.
The alkali is potassium carbonate or cesium carbonate or potassium tert-butoxide.
The electrolyte is tetrabutylammonium iodide or tetrabutylammonium hexafluorophosphate or tetrabutylammonium tetrafluoroborate.
The solvent is hexafluoroisopropanol or a mixed solution of hexafluoroisopropanol and dichloromethane.
The eluent used for the column chromatography is silica, petroleum ether/ethyl acetate 8-4: 1.
in the technical scheme, a series of hexafluoroisopropoxyaniline compounds are synthesized by reacting aniline with hexafluoroisopropanol under mild electrochemical conditions, and the compounds are found to have better antitumor activity by in vitro antitumor activity screening.
The method has mild reaction conditions, and the prepared hexafluoroisopropoxy aniline compound has good antitumor activity through in vitro antitumor activity screening.
Detailed Description
The present invention will be further illustrated with reference to the following examples, but is not limited thereto.
Example 1:
preparation and characterization of N- (2- ((1,1,1,3,3, 3-hexafluoropropan-2-yl) oxy) -4-methoxyphenyl) acetamide (2 a):
0.5mmol of N- (4-methoxyphenyl) acetamide, 1.5 equivalents of potassium carbonate and 0.5 equivalents of ammonium tetrabutyliodide as an electrolyte were placed in a 10mL three-necked round-bottomed flask, respectively, dissolved by adding 7mL of hexafluoroisopropanol, stirred at room temperature with Reticulated Vitreous Carbon (RVC) as an anode and a platinum sheet as a cathode at a constant current of 10mA, the reaction progress was monitored by thin-layer chromatography for 10 hours, after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, the solvent was spin-dried under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate ═ 8: 1) to give the desired product.
The product was characterized as:
White soild(104.6mg,63％).mp:85.6–86.3℃.1H NMR(400MHz,CDCl3)δ8.23–8.12(m,1H),7.33(s,1H),6.72–6.65(m,1H),6.61–6.54(m,1H),4.88–4.78(m,1H),3.79(s,3H),2.18(s,3H).13C NMR(100MHz,CDCl3)δ168.14,156.56,147.28,123.27,122.44,122.44,119.45,109.02,102.56,55.72,24.43.HRMS(m/z)(ESI):calcd for C12H12F6NO3[M+H]+332.0721,found 332.0736。
example 2:
preparation and characterization of N- (2- ((1,1,1,3,3, 3-hexafluoropropan-2-yl) oxy) -4-methoxyphenyl) benzamide (2 b):
0.5mmol of aniline, 1.5 equivalents of cesium carbonate and 0.5 equivalents of tetrabutylammonium hexafluorophosphate are placed in a 10mL three-necked round-bottomed flask, respectively, 7mL of hexafluoroisopropanol are added to dissolve with dichloromethane (4: 3), a stirred reaction is carried out at room temperature with Reticulated Vitreous Carbon (RVC) as anode and platinum sheet as cathode at a constant current of 15mA, the progress of the reaction is monitored by thin-layer chromatography for 12 hours, after completion of the reaction, the mixture is extracted with 10mL of ethyl acetate, the organic layer is dried over anhydrous sodium sulfate, the solvent is spin-dried under reduced pressure, and the residue is purified by column chromatography (silica, petroleum ether/ethyl acetate ═ 6-4: 1) to give the desired product.
The product was characterized as:
White soild(116.5mg,59％).mp:102.3–102.6℃.1H NMR(400MHz,Acetone-d6)δ8.80(s,1H),8.01–7.85(m,3H),7.60–7.41(m,3H),6.96–6.88(m,1H),6.82–6.66(m,1H),6.13–5.93(m,1H),3.77(s,3H).13C NMR(100MHz,Acetone-d6)δ165.89,158.49,150.08,135.85,132.46,129.45,127.97,126.44,122.78,109.89,102.82,75.43(quint,J＝33.1Hz),56.06.HRMS(m/z)(ESI):calcd for C17H14F6NO3Na[M+Na]+416.0697,found416.0692。
example 3:
preparation and characterization of N- (2- ((1,1,1,3,3, 3-hexafluoropropan-2-yl) oxy) -4-methoxyphenyl) pivaloamide (2 c):
0.5mmol of aniline, 1.5 equivalents of potassium tert-butoxide and 0.5 equivalents of tetrabutylammonium tetrafluoroborate are placed in a 10mL three-necked round-bottomed flask, 7mL of hexafluoroisopropanol are added, a Reticular Vitreous Carbon (RVC) is used as the anode and a platinum sheet is used as the cathode, the reaction is stirred at 20mA constant current at room temperature, the progress of the reaction is monitored by thin-layer chromatography for 15 hours, after completion of the reaction, the mixture is extracted with 10mL of ethyl acetate, the organic layer is dried over anhydrous sodium sulfate, the solvent is dried under reduced pressure, and the residue is purified by column chromatography (silica, petroleum ether/ethyl acetate ═ 4: 1 elution) to give the desired product.
The product was characterized as:
White soild(129.1mg,69％).mp:97.0–98.0℃.1H NMR(400MHz,CDCl3)δ8.40–8.16(m,1H),7.77(s,1H),6.78–6.63(m,1H),6.61–6.46(m,1H),4.94–4.80(m,1H),3.79(s,3H),1.30(s,9H).13C NMR(100MHz,CDCl3)δ176.59,156.32,147.29,122.85,122.64,108.72,102.09,76.62(quint,J＝33.1Hz),55.87,40.00,27.55.HRMS(m/z)(ESI):calcdfor C15H18F6NO3[M+H]+374.1191,found 374.1185。
example 4:
preparation and characterization of N- (3- ((1,1,1,3,3, 3-hexafluoropropan-2-yl) oxy) naphthalen-2-yl)) acetamide (2 d):
0.5mmol of aniline, 1.5 equivalents of potassium carbonate and 0.5 equivalents of tetrabutylammonium iodide were placed in a 10mL three-necked round-bottomed flask, respectively, 7mL of a solvent of hexafluoroisopropanol and dichloromethane mixed solution (4: 3) was added to dissolve, a reaction was carried out with stirring at room temperature with a mesh vitreous carbon (RVC) as an anode and a platinum sheet as a cathode at a constant current of 10mA, the progress of the reaction was monitored by thin layer chromatography for 10 hours, after completion of the reaction, the mixture was extracted with 10mL of ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, the solvent was spin-dried under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate ═ 8: 1) to obtain the desired product.
The product was characterized as:
White soild(94.8mg,54％).mp:95.1–95.5℃.1H NMR(400MHz,Acetone-d6)δ8.80(s,1H),8.06-8.00(m,1H),7.91–7.81(m,2H),7.76–7.69(m,1H),7.58–7.45(m,2H),5.85–5.65(m,1H),2.14(s,3H).13C NMR(100MHz,Acetone-d6)δ169.78,144.15,133.23,128.93,127.92,127.72,126.87,126.67,125.63,121.66,76.54(quint,J＝32.0Hz),23.73.HRMS(m/z)(ESI):calcd for C15H12F6NO2[M+H]+352.0772,found 352.0768。
example 5:
preparation and characterization of N- (2- ((1,1,1,3,3, 3-hexafluoropropan-2-yl) oxy) -4- (methylthio) phenyl) acetamide (2 e):
0.5mmol of aniline, 1.5 equivalents of cesium carbonate and 0.5 equivalents of tetrabutylammonium hexafluorophosphate are placed in a 10mL three-necked round-bottomed flask, respectively, 7mL of hexafluoroisopropanol are added to dissolve, a Reticular Vitreous Carbon (RVC) is used as an anode and a platinum sheet is used as a cathode, the reaction is carried out with stirring at room temperature under a constant current of 15mA, the progress of the reaction is monitored by thin-layer chromatography for 12 hours, after completion of the reaction, the mixture is extracted with 10mL of ethyl acetate, the organic layer is dried over anhydrous sodium sulfate, the solvent is dried under reduced pressure, and the residue is purified by column chromatography (silica, petroleum ether/ethyl acetate ═ 6: 1 elution) to give the desired product.
The product was characterized as:
White soild(69.6mg,40％).mp:91.3–91.6℃.1H NMR(400MHz,CDCl3)δ8.26–8.16(m,1H),7.92(s,1H),7.21–7.11(m,1H),7.02–6.91(m,1H),4.80–4.69(m,1H),2.42(s,3H),2.22(s,3H).13C NMR(100MHz,CDCl3)δ168.51,153.93,134.50,128.52,122.83,120.79,116.65,76.74(quint,J＝33.3Hz),24.77,18.29.HRMS(m/z)(ESI):calcd for C12H12F6NO2S[M+H]+348.0493,found 348.0489。
and (3) verifying the pharmacological activity of the compound:
in order to verify the antitumor activity of hexafluoroisopropoxyaniline compounds synthesized according to the synthesis method of this example, compounds 2a-2e were screened for their in vitro inhibitory activity against 4 cancer cell lines (MGC-803, T-24, HepG-2 and HeLa) using MTT. The 5-FU is used as a positive control, and the experimental result shows that most compounds have good inhibitory activity on tumor cell strains. IC of Compound 2c against T-24 as shown in Table 150The value was 19.5. + -. 0.9. mu.M; IC of Compound 2d for T-24 and HeLa50The values were divided into 20.4. + -. 0.8. mu.M and 22.8. + -. 1.6, indicating that the compound obtained by introducing hexafluoroisopropoxy group to the aniline skeleton has good resistanceThe antitumor activity of most compounds is better than that of the commercialized 5-FU compound.
The synthesis method of the embodiment does not need metal and oxidant, is environment-friendly, has better atom economy, and the synthesized compound has good inhibition activity on tumor cells, which shows that hexafluoroisopropoxy aniline compound obtained by introducing hexafluoroisopropoxy on aniline skeleton has good anti-tumor activity.
TABLE 1 IC of Compounds on 2a-2e Strain cell lines50Value (. mu.M).
| Compounds | MGC-803 | T-24 | HepG-2 | HeLa |
| 2a | 29.7±0.9 | 28.4±1.8 | 37.5±0.9 | 30.2±1.3 |
| 2b | 26.9±0.7 | 25.0±1.2 | 30.1±1.7 | 29.2±0.9 |
| 2c | 20.4±1.0 | 19.5±0.9 | 29.7±0.9 | 28.1±0.5 |
| 2d | 25.6±1.5 | 20.4±0.8 | 30.3±1.1 | 22.8±1.6 |
| 2e | 26.4±0.8 | 22.1±1.6 | 32.5±0.6 | 28.0±0.4 |
| 5-FU | >40 | 30.6±1.3 | >40 | 34.9±0.5 |
。
Claims (6)
1. A method for electrochemically synthesizing hexafluoroisopropoxyaniline compounds, which is characterized in that the general formula of the synthesis method is as follows:
in the general formula, O, S, R = aromatic or aliphatic group, the electrolyte is: tetrabutylammonium iodide or tetrabutylammonium hexafluorophosphate or tetrabutylammonium tetrafluoroborate, and the solvent is: hexafluoroisopropanol or a mixed solution of hexafluoroisopropanol and dichloromethane, wherein the alkali is: potassium carbonate or cesium carbonate or potassium tert-butoxide.
2. The method for electrochemically synthesizing a hexafluoroisopropoxyaniline compound according to claim 1, wherein the method comprises:
respectively putting 0.5mmol of aniline, 1.5 equivalents of alkali and 0.5 equivalents of electrolyte into a 10mL three-neck round-bottom flask, adding 7mL of solvent for dissolution, using Reticular Vitreous Carbon (RVC) as an anode and a platinum sheet as a cathode, carrying out stirring reaction at room temperature under a constant current of 10-20mA, monitoring the reaction process by adopting thin-layer chromatography, wherein the reaction time is 10-15 hours, extracting the mixture by using 10mL of ethyl acetate after the reaction is finished, drying an organic layer by using anhydrous sodium sulfate, carrying out decompression and spin-drying on the solvent, and eluting and purifying residues by using column chromatography to obtain the required product.
3. The method for electrochemically synthesizing a hexafluoroisopropoxyaniline compound according to claim 2, wherein the base is potassium carbonate or cesium carbonate or potassium tert-butoxide.
4. The method for electrochemically synthesizing a hexafluoroisopropoxyaniline compound according to claim 2, wherein the electrolyte is tetrabutylammonium iodide or tetrabutylammonium hexafluorophosphate or tetrabutylammonium tetrafluoroborate.
5. The method for electrochemically synthesizing a hexafluoroisopropoxyaniline compound according to claim 2, wherein the solvent is hexafluoroisopropanol or a mixed solution of hexafluoroisopropanol and dichloromethane.
6. The method for electrochemically synthesizing a hexafluoroisopropoxyaniline compound according to claim 2, wherein the eluent used for the column chromatography is silica, petroleum ether/ethyl acetate = 8-4: 1.
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| CN111170924A (en) * | 2020-02-18 | 2020-05-19 | 广西师范大学 | Method for electrochemically synthesizing hexafluoroisopropoxy indole compound |
| CN112080755A (en) * | 2020-09-02 | 2020-12-15 | 昆明海关技术中心 | Method for electrocatalytic hydrolysis of chiral imine |
| CN114481173A (en) * | 2022-03-01 | 2022-05-13 | 哈尔滨工业大学（深圳） | Preparation method of aniline derivative |
| CN115961298A (en) * | 2022-12-31 | 2023-04-14 | 广西师范大学 | Electrochemical mediated vinylaniline and alcohol synthesis 2,3-dialkoxy substituted indoline compound, synthesis method and application |
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