CN110590722A - Synthesis method of 2-trifluoromethyl benzofuran derivative - Google Patents
Synthesis method of 2-trifluoromethyl benzofuran derivative Download PDFInfo
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- CN110590722A CN110590722A CN201911007778.4A CN201911007778A CN110590722A CN 110590722 A CN110590722 A CN 110590722A CN 201911007778 A CN201911007778 A CN 201911007778A CN 110590722 A CN110590722 A CN 110590722A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
Abstract
The invention relates to a synthetic method of a 2-trifluoromethyl benzofuran derivative, which comprises the following steps: taking 1-bromo-2- (2-chloro-3, 3, 3-trifluoropropyl-1-en-1-yl) benzene as a reaction substrate, potassium hydroxide as an oxygen source, potassium phosphate as a base, cuprous iodide as a catalyst, 1, 10-phenanthroline as a ligand and dimethyl sulfoxide as a solvent, and stirring for reaction for 10-12 hours at 80-100 ℃ under the condition of nitrogen. Has the advantages of mild reaction conditions, simple and easily obtained raw materials, novel preparation process, less pollution and low energy consumption.
Description
Technical Field
The present invention relates to a process for the preparation of 2-trifluoromethylbenzofuran derivatives.
Background
Benzofuran derivatives are widely present in natural products and non-natural compounds with biopharmacological potential (J.Nat.Prod.2016,79,784-79; J.Med.chem.2013,56, 832-52842; J.Med.chem.2005,48,5279-5294) and show a wide range of activities including antiviral, antibacterial, anti-inflammatory, anti-angiogenic and anti-mitotic activities, etc. (ACS Comb.Sci.2017,19, 370-376; J.Med.chem.2015,97, 561-581). It is well known that the introduction of trifluoromethyl groups into molecules can significantly alter the solubility, metabolic stability, polarity, lipophilicity and chemical and biological activity of compounds (adv. synth. catal,2010,352, 2745-. Although there have been many reports on the synthesis of trifluoromethyl substituted benzofuran compounds, as in 2013, axionnat et al reported an iridium-catalysed hydrogen transfer reaction in the presence of p-benzoquinone: substituted benzofuran, benzothiophene and indole derivatives (org. Lett.2013,15,3876-3879) were synthesized from benzyl alcohol. In 2014 Yuan et al reported palladium-catalyzed reaction of alkynyl substituted phenylalkynes and aryl halides to synthesize 2, 3-disubstituted benzofuran derivatives (org. Lett.2014,16,193-195) in moderate yields. In 2014, Murakami et al reported a practical, modular, and general synthetic scheme for benzofuran by extending the Pummerer loop/cross-coupling strategy (Angew. chem. int. Ed.2014,53, 7510-. The traditional method has the trouble of multi-step reaction, is not high in economy, is mostly provided by direct trifluoromethylation of benzofuran and free radical or electrophilic reagent, and has the defects of low yield and poor regioselectivity.
Disclosure of Invention
Aiming at the defects existing in the prior stage, the invention provides the method for preparing the 2-trifluoromethyl benzofuran derivative, which takes 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene and potassium hydroxide as reaction raw materials, and has the advantages of simple technical process, high yield, less pollution, environmental protection and safety.
In order to achieve the purpose, the invention adopts the technical scheme that:
the synthesis method of the 2-trifluoromethyl benzofuran derivative comprises the following steps: taking 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene as a reaction substrate, potassium hydroxide as an oxygen source, sodium carbonate, cesium carbonate, potassium tert-butoxide or potassium phosphate as alkali, cuprous chloride, cuprous bromide, thiophene-2-copper formate or cuprous iodide as a catalyst, 1, 10-phenanthroline as a ligand, and acetonitrile, N-dimethylformamide or dimethyl sulfoxide as a solvent, and stirring at 80-110 ℃ for reaction for 10-12 hours, wherein the chemical reaction formula is as follows:
and the-R is one of hydrogen, 4-methyl, 5-methoxyl, 4-fluorine, 4-chlorine, 5-bromine and 5-trifluoromethyl.
The preparation method adopted by the invention is to synthesize the 2-trifluoromethyl benzofuran derivative by catalyzing the reaction of 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene and potassium hydroxide, has simple process, does not need to use special instruments or modes, is very suitable for the operation of people in the field, and has the advantages of simple and convenient operation, easy obtaining of products and the like.
In a further arrangement of the invention, the catalyst is cuprous iodide.
In a further development of the invention, the base is potassium phosphate.
In a further embodiment of the present invention, the solvent is dimethyl sulfoxide.
According to a further development of the invention, the reaction is carried out in a nitrogen atmosphere.
The method can directly synthesize the target product, does not need to separate intermediate products, can obtain the target product only by stirring and reacting under normal pressure, can eliminate the interference of oxygen under the condition of nitrogen, has the highest yield of 65 percent, greatly simplifies the process engineering, reduces the energy consumption and has excellent yield; in addition, the waste solution is less in the reaction process, and other polluted gases and liquid are not discharged, so that the method reduces the discharge of the waste solution, and has the advantages of protecting the environment and ensuring the health of operators; in addition, a series of 2-trifluoromethyl benzofuran derivatives can be prepared, and the method has better substrate universality. Therefore, the invention fills the blank of the method for preparing the 2-trifluoromethyl benzofuran derivative at the present stage, promotes the development of the polysubstituted 2-trifluoromethyl benzofuran derivative and provides a powerful guarantee for developing the biological medicine containing the 2-trifluoromethyl benzofuran.
The mechanism of the invention is as follows: taking 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene 1a as an example, first, the substrate 1a is eliminated in the presence of a base to obtain o-bromophenylpropyne A. And (3) carrying out oxidative addition on the intermediate A and CuI to provide B, and carrying out ligand exchange and reductive elimination on the B and KOH to obtain an intermediate C. In the intermediate C, a carbon-carbon triple bond is coordinated with copper salt, and then the coordination is performed with phenol oxygen anion to perform intramolecular nucleophilic addition reaction, so as to obtain a cyclic intermediate D. And further adding the intermediate D with another molecule of o-bromophenyl propyne A to form an intermediate vinyl copper E. Finally, the protonation of the vinyl copper E gives the product 2a and regenerates the Cu (I). Possible reaction mechanisms the chemical reaction formula is as follows:
Detailed Description
The invention discloses a synthesis method of a 2-trifluoromethyl benzofuran derivative, which comprises the following steps of taking 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene as a reaction substrate, potassium hydroxide as an oxygen source, sodium carbonate, cesium carbonate, potassium tert-butoxide or potassium phosphate as alkali, cuprous chloride, cuprous bromide, thiophene-2-copper formate or cuprous iodide as a catalyst, 1, 10-phenanthroline as a ligand, and acetonitrile, N-dimethylformamide or dimethyl sulfoxide as a solvent, and carrying out stirring reaction for 10-12 hours at 80-110 ℃ under the condition of nitrogen; the chemical reaction formula is as follows:
the-R is one of hydrogen, 4-methyl, 5-methoxyl, 4-fluorine, 4-chlorine, 5-bromine and 5-trifluoromethyl; after the reaction, filtering, washing the filtrate with saturated sodium chloride solution, extracting with ethyl acetate, performing rotary evaporation on the combined organic layers by using a rotary evaporator, and removing the solvent to obtain a residue. Eluting the residue with petroleum ether eluent through silica gel column, collecting eluate according to actual gradient, detecting by TLC, mixing the eluates containing the target product, removing solvent by rotating the mixed eluates with rotary evaporator, and vacuum drying to obtain the target product.
The first embodiment is as follows: 57.0 mg (0.2mmol) of 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4mmol) of potassium hydroxide, 3.8 mg (0.02mmol) of cuprous iodide, 7.2 mg (0.04mmol) of 1, 10-phenanthroline, 42.4 mg (0.2mmol) of potassium phosphate are added to 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 100 ℃ under nitrogen for 12 hours. Cooling after the reaction, filtering the reaction solution to obtain filtrate, washing with saturated sodium chloride solution, extracting with ethyl acetate, and mixingThe organic layer was rotary evaporated using a rotary evaporator to remove the solvent to obtain a residue, the residue was subjected to silica gel column chromatography, rinsed with petroleum ether solution, the effluent was collected according to a practical gradient, checked by TLC, the effluent containing the product was combined, the solvent was distilled off using a rotary evaporator, and dried in vacuo to obtain 28.3 mg of (E) -3- (1- (2-bromophenyl) -3,3, 3-trifluoroprop-1-en-2-yl) -2- (trifluoromethyl) benzofuran in 65% yield as a white solid.1H NMR(400MHz,CDCl3)δ7.85(s,1H),7.67(d,J＝8.0Hz,1H),7.61(d,J＝8.4Hz,2H),7.53(d,J＝8.0Hz,1H),7.42(t,J＝7.2Hz,1H),7.12(t,J＝9.2Hz,1H)，7.00(t,J＝7.6Hz,1H)，6.91(d,J＝8.0Hz,1H)；13C NMR(125MHz,CDCl3)δ154.2,140.0(q,JC-F＝37.5Hz),138.6(q,JC-F＝3.8Hz),133.2,132.9,130.7,130.5(q,JC-F＝41.3Hz),129.2,127.7,127.2,127.1,124.7,124.3,126.6(q,JC-F＝3.8Hz),122.7(q,JC-F＝271.3Hz),121.9(q,JC-F＝250.0Hz),121.5,112.3；19F NMR(470MHz,CDCl3)δ-63.7(s,3F),-65.8(s,3F)。
The second embodiment is as follows: 59.9 mg (0.2mmol) of 2-bromo-1- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) -4-methylbenzene, 22.4 mg (0.4mmol) of potassium hydroxide, 3.8 mg (0.02mmol) of cuprous iodide, 7.2 mg (0.04mmol) of 1, 10-phenanthroline and 42.4 mg (0.2mmol) of potassium phosphate are added to 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 100 ℃ under nitrogen for 12 hours. After the reaction, the reaction solution was cooled, filtered to obtain a filtrate, washed with a saturated sodium chloride solution, extracted with ethyl acetate, the combined organic layers were subjected to rotary evaporation using a rotary evaporator to remove the solvent to obtain a residue, the residue was subjected to silica gel column chromatography, rinsed with a petroleum ether solution, an effluent was collected according to a practical gradient, subjected to TLC detection, and combined with an effluent containing the product, subjected to distillation using a rotary evaporator to remove the solvent, and dried under vacuum to obtain a white solid, (E) -3- (1- (2-bromophenyl) -3,3, 3-trifluoroprop-1-en-2-yl) -2- (trifluoromethyl) benzofuran in an amount of 18.9 mg, with a yield of 41%.1H NMR(400MHz,CDCl3)δ7.78(s,1H),7.50(d,J＝8.0Hz,1H),7.41(d,J＝12.0Hz,2H),7.22(d,J＝8.0Hz,1H),6.78(s,2H),2.54(s,3H),2.56(s,3H)；13C NMR(125MHz,CDCl3)δ154.7,141.3,140.2(q,JC-F＝40.0Hz),138.5,132.1(q,JC-F＝5.0Hz),135.8(q,JC-F＝5.0Hz),133.3,130.2,128.9,128.6(q,JC-F＝42.5Hz),128.1,126.2,124.7,124.4,122.8(q,JC-F＝271.3Hz),121.0,119.1(q,JC-F＝258.8Hz),112.2,21.8,20.8；19F NMR(470MHz,CDCl3)δ-63.7(s,3F),-65.8(s,3F)。
The third concrete embodiment: 59.9 mg (0.2mmol) of 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) -4-methylbenzene, 22.4 mg (0.4mmol) of potassium hydroxide, 3.8 mg (0.02mmol) of cuprous iodide, 7.2 mg (0.04mmol) of 1, 10-phenanthroline and 42.4 mg (0.2mmol) of potassium phosphate are added to 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 100 ℃ under nitrogen for 12 hours. After the reaction, the reaction solution was cooled, and the reaction solution was filtered to obtain a filtrate, washed with a saturated sodium chloride solution, extracted with ethyl acetate, the combined organic layers were subjected to rotary evaporation using a rotary evaporator to remove the solvent to obtain a residue, the residue was subjected to silica gel column chromatography, eluted with a petroleum ether solution, the effluent was collected in a real gradient, subjected to TLC detection, and the effluent containing the product was combined, subjected to distillation using a rotary evaporator to remove the solvent, and dried in vacuo to obtain 24.1 mg of (E) -3- (1- (2-bromo-5-methylphenyl) -3,3, 3-trifluoroprop-1-en-2-yl) -5-methyl-2- (trifluoromethyl) benzofuran in 52% yield.1HNMR(400MHz,CDCl3)δ7.79(s,1H),7.41-7.43(m,3H),7.31(d,J＝7.2Hz,1H),6.91(d,J＝8.4Hz,1H),6.77(s,1H),2.51(s,3H),1.99(s,3H)；13C NMR(125MHz,CDCl3)δ152.6,141.0(q,JC-F＝40.0Hz),138.6(q,JC-F＝5.0Hz),137.1,134.4,133.0,132.4,131.5,131.3(q,JC-F＝5.0Hz),130.1,129.5(q,JC-F＝43.8Hz),129.1,127.3,122.7(q,JC-F＝272.5Hz),121.0,120.7,119.2(q,JC-F＝268.8Hz),111.6,21.3,20.5；19F NMR(470MHz,CDCl3)δ-63.7(s,3F),-65.9(s,3F)。
The fourth concrete embodiment: 63.1 mg (0.2mmol) of 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) -4-methoxybenzene, 22.4 mg (0.4mmol) of potassium hydroxide, 3.8 mg (0.02mmol) of cuprous iodide, 7.2 mg (0.04 mm) of copper (I) iodideol)1, 10-phenanthroline, 42.4 mg (0.2mmol) of potassium phosphate is added into 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 100 ℃ under nitrogen for 12 hours. After the reaction, the reaction solution was cooled, and the reaction solution was filtered to obtain a filtrate, washed with a saturated sodium chloride solution, extracted with ethyl acetate, the combined organic layers were subjected to rotary evaporation using a rotary evaporator to remove the solvent to obtain a residue, the residue was subjected to silica gel column chromatography, eluted with a petroleum ether solution, the effluent was collected in a real gradient, subjected to TLC detection, and the effluent containing the product was combined, subjected to distillation using a rotary evaporator to remove the solvent, and dried in vacuo to obtain 25.2 mg of (E) -3- (1- (2-bromo-5-methoxyphenyl) -3,3, 3-trifluoroprop-1-en-2-yl) -5-methoxy-2- (trifluoromethyl) benzofuran in 51% yield.1H NMR(400MHz,CDCl3)δ7.74(s,1H),7.44-7.38(m,2H),7.05(d,J＝9.2Hz,1H),6.95(s,1H),6.64(d,J＝8.8Hz,1H),6.44(s,1H),3.83(s,3H),3.26(s,3H)；13C NMR(125MHz,CDCl3)δ158.4,157.3,149.1,141.5(q,JC-F＝40.0Hz),138.6(q,JC-F＝5.0Hz),133.8,133.4,133.3(q,JC-F＝36.3Hz),131.8(q,JC-F＝2.5Hz),127.7,122.7(q,JC-F＝271.3Hz),119.1(q,JC-F＝268.8Hz),118.2,117.7,114.5,113.5,112.9,102.2,55.9,54.8；19F NMR(470MHz,CDCl3)δ-63.5(s,3F),-66.0(s,3F)。
The fifth concrete embodiment: 60.7 mg (0.2mmol) of 2-bromo-1- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) -4-fluorobenzene, 22.4 mg (0.4mmol) of potassium hydroxide, 3.8 mg (0.02mmol) of cuprous iodide, 7.2 mg (0.04mmol) of 1, 10-phenanthroline, and 42.4 mg (0.2mmol) of potassium phosphate were added to 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 100 ℃ under nitrogen for 12 hours. Cooling after the reaction is finished, filtering the reaction liquid to obtain filtrate, washing the filtrate by using saturated sodium chloride solution, extracting the filtrate by using ethyl acetate, carrying out rotary evaporation on combined organic layers by using a rotary evaporator to remove the solvent to obtain residues, carrying out silica gel column chromatography on the residues, eluting the residues by using petroleum ether solution, collecting effluent according to actual gradient, detecting by TLC, combining the effluent containing the product, distilling the effluent by using the rotary evaporator to remove the solvent, and drying in vacuum to obtain white solid, (E) -3- (1- (2-bromo-4-fluorophenyl)28.7 mg of (E) -3,3, 3-trifluoroprop-1-en-2-yl) -6-fluoro-2- (trifluoromethyl) benzofuran in 61% yield.1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.54-7.51(m,1H),7.31(d,J＝4.0Hz,1H),7.28(d,J＝8.0Hz,1H),7.16-7.12(m,1H),6.83-6.80(m,1H),6.73-6.69(m,1H)；13C NMR(125MHz,CDCl3)δ162.7(d,JC-F＝246.3),162.6(d,JC-F＝253.8Hz),154.3,141.6(q,JC-F＝36.3Hz),137.8(q,JC-F＝5.0Hz),130.2,129.3,125.8(q,JC-F＝3.8Hz)，124.8(d，JC-F＝8.8Hz),123.2，122.5(q,JC-F＝271.3Hz)，122.2(q,JC-F＝10.0Hz)，121.1(q,JC-F＝221.3Hz),120.9(q,JC-F＝33.8Hz),120.4,114.8(d,JC-F＝21.3Hz),113.9(d,JC-F＝25.0Hz),100.1；19F NMR(500MHz,CDCl3)δ-63.9(s,3F),-65.9(s,3F),-108.4(s,1F),-111.0(s,1F)。
The sixth specific embodiment: adding 64.0 mg (0.2mmol) of 2-bromo-4-chloro-1- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4mmol) of potassium hydroxide, 3.8 mg (0.02mmol) of cuprous iodide, 7.2 mg (0.04mmol) of 1, 10-phenanthroline and 42.4 mg (0.2mmol) of potassium phosphate into 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 100 ℃ under nitrogen for 12 hours. After the reaction, the reaction solution was cooled, and the reaction solution was filtered to obtain a filtrate, which was washed with a saturated sodium chloride solution, extracted with ethyl acetate, the combined organic layers were subjected to rotary evaporation using a rotary evaporator to remove the solvent to obtain a residue, the residue was subjected to silica gel column chromatography, rinsed with a petroleum ether solution, effluent was collected in a real gradient, subjected to TLC detection, and the effluent containing the product was combined, subjected to distillation using a rotary evaporator to remove the solvent, and dried in vacuo to obtain 31.2 mg of (E) -3- (1- (2-bromo-4-chlorophenyl) -3,3, 3-trifluoroprop-1-en-2-yl) -6-chloro-2- (trifluoromethyl) benzofuran in 62 mg yield.1H NMR(400MHz,CDCl3)δ7.77(s,1H),7.64-7.62(m,2H),7.56(d,J＝8.4Hz,1H),7.42(d,J＝8.4Hz,1H),7.03(d,J＝8.4Hz,1H),6.80(d,J＝8.4Hz,1H)；13C NMR(125MHz,CDCl3)δ154.2,141.6(q,JC-F＝40.0Hz),137.9(q,JC-F＝5.0Hz),136.2,134.1，132.8,131.6,131.2(q,JC-F＝3.8Hz),129.7,128.1(q,JC-F＝30.0Hz),127.8,125.9,125.6,124.6,122.4(q,JC-F＝272.5Hz),122.0,118.8(q,JC-F＝267.5Hz),113.0；19F NMR(500MHz,CDCl3)δ-63.8(s,3F),-66.0(s,3F)。
The seventh specific embodiment: adding 64.0 mg (0.2mmol) of 1-bromo-4-chloro-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4mmol) of potassium hydroxide, 3.8 mg (0.02mmol) of cuprous iodide, 7.2 mg (0.04mmol) of 1, 10-phenanthroline and 42.4 mg (0.2mmol) of potassium phosphate into 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 100 ℃ under nitrogen for 12 hours. After the reaction, the reaction solution was cooled, and the reaction solution was filtered to obtain a filtrate, which was washed with a saturated sodium chloride solution, extracted with ethyl acetate, the combined organic layers were subjected to rotary evaporation using a rotary evaporator to remove the solvent to obtain a residue, the residue was subjected to silica gel column chromatography, eluted with a petroleum ether solution, the effluent was collected in a real gradient, subjected to TLC detection, and the effluent containing the product was combined, subjected to distillation using a rotary evaporator to remove the solvent, and dried in vacuo to obtain 30.2 mg of (E) -3- (1- (2-bromo-5-chlorophenyl) -3,3, 3-trifluoroprop-1-en-2-yl) -5-chloro-2- (trifluoromethyl) benzofuran in 60% yield as a pale yellow oily liquid.1H NMR(400MHz,CDCl3)δ7.75(s,1H),7.64(s,1H),7.58-7.50(m,3H),7.12(d,J＝8.4Hz,1H),6.88(s,1H)；13C NMR(125MHz,CDCl3)δ152.5,142.4(q,JC-F＝41.3Hz),138.0(q,JC-F＝5.0Hz),134.5,134.0,133.6(q,JC-F＝3.8Hz),133.3,130.8,130.7,129.1,128.5,128.1,122.4(q,JC-F＝231.3Hz),121.8,120.9,118.7(q,JC-F＝268.8Hz),113.5,130.8(q,JC-F＝43.8Hz)；19F NMR(500MHz,CDCl3)δ-63.8(s,3F),-66.1(s,3F)。
The eighth embodiment: 72.9 mg (0.2mmol) of 1, 4-dibromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4mmol) of potassium hydroxide, 3.8 mg (0.02mmol) of cuprous iodide, 7.2 mg (0.04mmol) of 1, 10-phenanthroline and 42.4 mg (0.2mmol) of potassium phosphate are added to 2 ml of a solvent, namely dimethyl sulfoxide. The reaction was stirred at 100 ℃ under nitrogen for 12 hours. Cooling after the reaction is finished, and filtering the reaction liquidThe filtrate was obtained and washed with saturated sodium chloride solution and extracted with ethyl acetate, the combined organic layers were rotary evaporated using a rotary evaporator to remove the solvent to obtain a residue, the residue was chromatographed on silica gel column, rinsed with petroleum ether solution, the effluent was collected in real gradient, checked by TLC, the product-containing effluent was combined, the solvent was distilled off using a rotary evaporator and dried in vacuo to give 36.8 mg of (E) -5-bromo-3- (1- (2, 5-dibromophenyl) -3,3, 3-trifluoroprop-1-en-2-yl) -2- (trifluoromethyl) benzofuran in 62% yield.1HNMR(400MHz,CDCl3)δ7.79(s,1H),7.73(s,1H),7.64(d,J＝8.8Hz,1H),7.51(d,J＝8.8Hz,1H),7.46(d,J＝8.4Hz,1H),7.26(d,J＝8.8Hz,1H),7.02(s,1H)；13C NMR(125MHz,CDCl3)δ152.9,142.2(q,JC-F＝41.3Hz),137.9(q,JC-F＝5.0Hz),134.9,134.5(q,JC-F＝3.8Hz),134.2,133.7,132.7(q,JC-F＝52.5Hz),132.1,131.2,128.7,124.0,122.2(q,JC-F＝271.3Hz),122.5,120.9,118.7(q,JC-F＝268.8Hz),118.1,114.0；19F NMR(500MHz,CDCl3)δ-63.8(s,3F),-66.1(s,3F)。
The specific embodiment is nine: 70.7 mg (0.2mmol) of 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) -4- (trifluoromethyl) benzene, 22.4 mg (0.4mmol) of potassium hydroxide, 3.8 mg (0.02mmol) of cuprous iodide, 7.2 mg (0.04mmol) of 1, 10-phenanthroline, 42.4 mg (0.2mmol) of potassium phosphate are added to 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 100 ℃ under nitrogen for 12 hours. After the reaction, the reaction solution was cooled, and the reaction solution was filtered to obtain a filtrate, washed with a saturated sodium chloride solution, extracted with ethyl acetate, the combined organic layers were subjected to rotary evaporation using a rotary evaporator to remove the solvent to obtain a residue, the residue was subjected to silica gel column chromatography, eluted with a petroleum ether solution, the effluent was collected in a real gradient, subjected to TLC detection, and the effluent containing the product was combined, subjected to distillation using a rotary evaporator to remove the solvent, and dried in vacuo to obtain 23.1 mg of (E) -3- (1- (2-bromo-5- (trifluoromethyl) phenyl) -3,3, 3-trifluoroprop-1-en-2-yl) -2, 5-bis (trifluoromethyl) benzofuran in 40% yield.1H NMR(400MHz,CDCl3)δ7.83(d,J＝8.4Hz,1H),7.74-7.68(m,3H),7.61(s,1H),7.53(d,J＝8.0Hz,1H),7.39(d,J＝8.8Hz,1H)；13C NMR(125MHz,CDCl3)δ159.5,142.8(q,JC-F＝33.8Hz),136.0(q,JC-F＝6.3Hz),133.2,132.2，130.6(q,JC-F＝25.0Hz),129.5(q,JC-F＝27.2Hz),130.2(q,JC-F＝2.5Hz),129.9(q,JC-F＝32.5Hz),129.4(q,JC-F＝6.3Hz),129.1(q,JC-F＝3.8Hz),128.6,127.9,127.5(q,JC-F＝3.8Hz),127.4(q,JC-F＝3.8Hz),123.4(q,JC-F＝261.3Hz),122.2,122.1(q,JC-F＝272.5Hz),121.1(q,JC-F＝245.0Hz),118.7(q,JC-F＝273.8Hz)；19F NMR(500MHz,CDCl3)δ-61.9(s,3F),-62.4(s,3F),-62.9(s,3F),-63.5(s,3F)。
The specific embodiment ten: 67.1 mg (0.2mmol) of 2-bromo-3- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) naphthalene, 22.4 mg (0.4mmol) of potassium hydroxide, 3.8 mg (0.02mmol) of cuprous iodide, 7.2 mg (0.04mmol) of 1, 10-phenanthroline, 42.4 mg (0.2mmol) of potassium phosphate were added to 2 ml of solvent dimethyl maple. The reaction was stirred at 100 ℃ under nitrogen for 12 hours. Cooling after the reaction is finished, filtering the reaction liquid to obtain filtrate, washing the filtrate by using saturated sodium chloride solution, extracting the filtrate by using ethyl acetate, carrying out rotary evaporation on combined organic layers by using a rotary evaporator to remove the solvent to obtain residues, carrying out silica gel column chromatography on the residues, eluting the residues by using petroleum ether solution, collecting effluent according to actual gradient, carrying out TLC detection, combining the effluent containing the product, distilling the mixture by using the rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain yellow solid, (E) -3- (1- (3-bromonaphthalene-2-yl) -3,3, 3-trifluoroprop-1-en-2-yl) -2- (trifluoromethyl) naphtho [2,3-b ]]24.1 mg of furan, 45% yield.1H NMR(400MHz,CDCl3)δ8.50(s,1H),8.31(d,J＝8.8Hz,1H),7.96-7.90(m,3H),7.85(d,J＝8.4Hz,2H),7.69-7.66(m,2H),7.65-7.60(m,2H),7.55(d,J＝8.8Hz,1H),7.50(d,J＝8.4Hz,1H)；13C NMR(125MHz,CDCl3)δ154.8,141.1(q,JC-F＝32.5Hz),137.6(q,JC-F＝5.0Hz),136.3,134.2,131.9,130.7(q,JC-F＝2.5Hz),130.0,128.3,128.2,128.1,127.7,127.6,127.5,127.4,127.2,127.1,126.5,126.2,125.9,125.0,122.7(q,JC-F＝272.5Hz),123.6,122.9,128.5(q,JC-F＝30.0Hz),118.8(q,JC-F＝275.0Hz)；19F NMR(500MHz,CDCl3)δ-61.0(s,3F),-63.7(s,3F)。
The first specific embodiment: 57.0 mg (0.2mmol) of 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4mmol) of potassium hydroxide, 3.8 mg (0.02mmol) of cuprous iodide, 7.2 mg (0.04mmol) of 1, 10-phenanthroline, 21.2 mg (0.2mmol) of sodium carbonate were added to 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 100 ℃ under nitrogen for 12 hours. After the reaction, the reaction solution was cooled, filtered to obtain a filtrate, washed with a saturated sodium chloride solution, extracted with ethyl acetate, the combined organic layers were subjected to rotary evaporation using a rotary evaporator to remove the solvent to obtain a residue, the residue was subjected to silica gel column chromatography, rinsed with a petroleum ether solution, effluent liquid was collected according to a practical gradient, subjected to TLC detection, the effluent liquid containing the product was combined, subjected to distillation using a rotary evaporator to remove the solvent, and dried in vacuum to obtain a white solid, (E) -3- (1- (2-bromophenyl) -3,3, 3-trifluoroprop-1-en-2-yl) -2- (trifluoromethyl) benzofuran in an amount of 15.7 mg with a yield of 36%.
The specific example twelve: 57.0 mg (0.2mmol) of 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4mmol) of potassium hydroxide, 3.8 mg (0.02mmol) of cuprous iodide, 7.2 mg (0.04mmol) of 1, 10-phenanthroline, 65.2 mg (0.2mmol) of cesium carbonate were added to 2 ml of a solvent, dimethyl sulfoxide. The reaction was stirred at 100 ℃ under nitrogen for 12 hours. After the reaction, the reaction solution was cooled, filtered to obtain a filtrate, washed with a saturated sodium chloride solution, extracted with ethyl acetate, the combined organic layers were subjected to rotary evaporation using a rotary evaporator to remove the solvent to obtain a residue, the residue was subjected to silica gel column chromatography, rinsed with a petroleum ether solution, an effluent was collected according to a practical gradient, subjected to TLC detection, and combined with an effluent containing the product, subjected to distillation using a rotary evaporator to remove the solvent, and dried in vacuum to obtain 25.2 mg of (E) -3- (1- (2-bromophenyl) -3,3, 3-trifluoroprop-1-en-2-yl) -2- (trifluoromethyl) benzofuran as a white solid in 58% yield.
The specific example thirteen: 57.0 mg (0.2mmol) of 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4mmol) of potassium hydroxide, 3.8 mg (0.02mmol) of cuprous iodide, 7.2 mg (0.04mmol) of 1, 10-phenanthroline, 22.4 mg (0.2mmol) of potassium tert-butoxide are added to 2 ml of the solvent dimethyl sulfoxide. The reaction was stirred at 100 ℃ under nitrogen for 12 hours. After the reaction, the reaction solution was cooled, filtered to obtain a filtrate, washed with a saturated sodium chloride solution, extracted with ethyl acetate, the combined organic layers were subjected to rotary evaporation using a rotary evaporator to remove the solvent to obtain a residue, the residue was subjected to silica gel column chromatography, rinsed with a petroleum ether solution, an effluent was collected according to a practical gradient, subjected to TLC detection, and combined with an effluent containing the product, subjected to distillation using a rotary evaporator to remove the solvent, and dried in vacuum to obtain a white solid, (E) -3- (1- (2-bromophenyl) -3,3, 3-trifluoroprop-1-en-2-yl) -2- (trifluoromethyl) benzofuran in 22.6 mg with a yield of 52%.
The specific embodiment fourteen: 57.0 mg (0.2mmol) of 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4mmol) of potassium hydroxide, 2.0 mg (0.02mmol) of cuprous chloride, 7.2 mg (0.04mmol) of 1, 10-phenanthroline, 42.4 mg (0.2mmol) of potassium phosphate are added to 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 100 ℃ under nitrogen for 12 hours. After the reaction, the reaction solution was cooled, filtered to obtain a filtrate, washed with a saturated sodium chloride solution, extracted with ethyl acetate, the combined organic layers were subjected to rotary evaporation using a rotary evaporator to remove the solvent to obtain a residue, the residue was subjected to silica gel column chromatography, rinsed with a petroleum ether solution, an effluent was collected according to a practical gradient, subjected to TLC detection, and combined with an effluent containing the product, subjected to distillation using a rotary evaporator to remove the solvent, and dried in vacuum to obtain 25.2 mg of (E) -3- (1- (2-bromophenyl) -3,3, 3-trifluoroprop-1-en-2-yl) -2- (trifluoromethyl) benzofuran as a white solid in 58% yield.
The specific embodiment fifteen: 57.0 mg (0.2mmol) of 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4mmol) of potassium hydroxide, 2.9 mg (0.02mmol) of cuprous bromide, 7.2 mg (0.04mmol) of 1, 10-phenanthroline, 42.4 mg (0.2mmol) of potassium phosphate are added to 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 100 ℃ under nitrogen for 12 hours. After the reaction, the reaction solution was cooled, filtered to obtain a filtrate, washed with a saturated sodium chloride solution, extracted with ethyl acetate, the combined organic layers were subjected to rotary evaporation using a rotary evaporator to remove the solvent to obtain a residue, the residue was subjected to silica gel column chromatography, rinsed with a petroleum ether solution, effluent liquid was collected according to a practical gradient, subjected to TLC detection, the effluent liquid containing the product was combined, subjected to distillation using a rotary evaporator to remove the solvent, and dried in vacuum to obtain 27.0 mg of (E) -3- (1- (2-bromophenyl) -3,3, 3-trifluoroprop-1-en-2-yl) -2- (trifluoromethyl) benzofuran in 62% yield.
The specific embodiment is sixteen: 57.0 mg (0.2mmol) of 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4mmol) of potassium hydroxide, 3.8 mg (0.02mmol) of thiophene-2-copper formate, 7.2 mg (0.04mmol) of 1, 10-phenanthroline, 42.4 mg (0.2mmol) of potassium phosphate are added to 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 100 ℃ under nitrogen for 12 hours. After the reaction, the reaction solution was cooled, filtered to obtain a filtrate, washed with a saturated sodium chloride solution, extracted with ethyl acetate, the combined organic layers were subjected to rotary evaporation using a rotary evaporator to remove the solvent to obtain a residue, the residue was subjected to silica gel column chromatography, rinsed with a petroleum ether solution, an effluent was collected according to a practical gradient, subjected to TLC detection, and combined with an effluent containing the product, subjected to distillation using a rotary evaporator to remove the solvent, and dried in vacuum to obtain a white solid, (E) -3- (1- (2-bromophenyl) -3,3, 3-trifluoroprop-1-en-2-yl) -2- (trifluoromethyl) benzofuran in an amount of 26.1 mg with a yield of 60%.
Specific example seventeen: 57.0 mg (0.2mmol) of 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4mmol) of potassium hydroxide, 3.8 mg (0.02mmol) of cuprous iodide, 7.2 mg (0.04mmol) of 1, 10-phenanthroline, 42.4 mg (0.2mmol) of potassium phosphate are added to 2 ml of acetonitrile solvent. The reaction was stirred at 100 ℃ under nitrogen for 12 hours. After the reaction, the reaction solution was cooled, filtered to obtain a filtrate, washed with a saturated sodium chloride solution, extracted with ethyl acetate, the combined organic layers were subjected to rotary evaporation using a rotary evaporator to remove the solvent to obtain a residue, the residue was subjected to silica gel column chromatography, rinsed with a petroleum ether solution, effluent liquid was collected according to a practical gradient, subjected to TLC detection, the effluent liquid containing the product was combined, subjected to distillation using a rotary evaporator to remove the solvent, and dried in vacuum to obtain a white solid, (E) -3- (1- (2-bromophenyl) -3,3, 3-trifluoroprop-1-en-2-yl) -2- (trifluoromethyl) benzofuran in 16.5 mg with a yield of 38%.
The specific embodiment eighteen: 57.0 mg (0.2mmol) of 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4mmol) of potassium hydroxide, 3.8 mg (0.02mmol) of cuprous iodide, 7.2 mg (0.04mmol) of 1, 10-phenanthroline, 42.4 mg (0.2mmol) of potassium phosphate were added to 2 ml of a solvent of N, N-dimethylformamide. The reaction was stirred at 100 ℃ under nitrogen for 12 hours. After the reaction, the reaction solution was cooled, filtered to obtain a filtrate, washed with a saturated sodium chloride solution, extracted with ethyl acetate, the combined organic layers were subjected to rotary evaporation using a rotary evaporator to remove the solvent to obtain a residue, the residue was subjected to silica gel column chromatography, rinsed with a petroleum ether solution, an effluent was collected according to a practical gradient, subjected to TLC detection, and combined with an effluent containing the product, subjected to distillation using a rotary evaporator to remove the solvent, and dried in vacuum to obtain a white solid, (E) -3- (1- (2-bromophenyl) -3,3, 3-trifluoroprop-1-en-2-yl) -2- (trifluoromethyl) benzofuran in an amount of 11.7 mg, with a yield of 27%.
The specific examples are nineteen: 57.0 mg (0.2mmol) of 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4mmol) of potassium hydroxide, 3.8 mg (0.02mmol) of cuprous iodide, 7.2 mg (0.04mmol) of 1, 10-phenanthroline, 42.4 mg (0.2mmol) of potassium phosphate are added to 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 110 ℃ under nitrogen for 12 hours. After the reaction, the reaction solution was cooled, filtered to obtain a filtrate, washed with a saturated sodium chloride solution, extracted with ethyl acetate, the combined organic layers were subjected to rotary evaporation using a rotary evaporator to remove the solvent to obtain a residue, the residue was subjected to silica gel column chromatography, rinsed with a petroleum ether solution, effluent liquid was collected according to a practical gradient, subjected to TLC detection, the effluent liquid containing the product was combined, subjected to distillation using a rotary evaporator to remove the solvent, and dried in vacuum to obtain a white solid, (E) -3- (1- (2-bromophenyl) -3,3, 3-trifluoroprop-1-en-2-yl) -2- (trifluoromethyl) benzofuran in 28.3 mg with a yield of 52%.
The specific embodiment twenty: 57.0 mg (0.2mmol) of 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4mmol) of potassium hydroxide, 3.8 mg (0.02mmol) of cuprous iodide, 7.2 mg (0.04mmol) of 1, 10-phenanthroline, 42.4 mg (0.2mmol) of potassium phosphate are added to 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 100 ℃ under nitrogen for 10 hours. After the reaction, the reaction solution was cooled, filtered to obtain a filtrate, washed with a saturated sodium chloride solution, extracted with ethyl acetate, the combined organic layers were subjected to rotary evaporation using a rotary evaporator to remove the solvent to obtain a residue, the residue was subjected to silica gel column chromatography, rinsed with a petroleum ether solution, an effluent was collected according to a practical gradient, subjected to TLC detection, and combined with an effluent containing the product, subjected to distillation using a rotary evaporator to remove the solvent, and dried in vacuum to obtain 28.3 mg of (E) -3- (1- (2-bromophenyl) -3,3, 3-trifluoroprop-1-en-2-yl) -2- (trifluoromethyl) benzofuran in 58% yield.
In the embodiment of the invention, 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene and potassium hydroxide are used as substrates, potassium phosphate is used as alkali, cuprous iodide is used as a catalyst, 1, 10-phenanthroline is used as a ligand, and dimethyl sulfoxide is used as a solvent, and the mixture is stirred and reacted for 10 to 12 hours at the temperature of 80 to 110 ℃ under the condition of nitrogen. Wherein examples one to ten are variable with Ar in 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene substituted with different substituents. It is noted that substituents and alkyl groups on the phenyl group that are strongly electron withdrawing can also be advantageously used with the process of the present invention; examples eleven to thirteen were varied with base, examples fourteen to sixteen were varied with catalyst, examples seventeen and eighteen were varied with solvent, example nineteen was varied with temperature, and example twenty was varied with time.
According to the invention, the intermediate product does not need to be separated, the target product can be directly synthesized by simple raw materials, the process is simplified, the energy consumption is low, the waste solution discharge is reduced, the environmental pollution is reduced, and the yield reaches 65% at most; in the above embodiment, a series of 2-trifluoromethylbenzofuran derivatives can be prepared by selecting 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene and reacting the benzene with potassium hydroxide, wherein the method has certain substrate universality and operation simplicity. The present invention is not limited to the above embodiments, and those skilled in the art can implement the present invention in other embodiments according to the disclosure of the present invention, or make simple changes or modifications on the design structure and idea of the present invention, and fall into the protection scope of the present invention.
Claims (6)
1. A method for synthesizing 2-trifluoromethyl benzofuran derivatives comprises the following steps: taking 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene as a reaction substrate, potassium hydroxide as an oxygen source, sodium carbonate, cesium carbonate, potassium tert-butoxide or potassium phosphate as alkali, cuprous chloride, cuprous bromide, thiophene-2-copper formate or cuprous iodide as a catalyst, 1, 10-phenanthroline as a ligand, and acetonitrile, N-dimethylformamide or dimethyl sulfoxide as a solvent, and stirring at 80-110 ℃ for reaction for 10-12 hours, wherein the chemical reaction formula is as follows:
and the-R is one of hydrogen, 4-methyl, 5-methoxyl, 4-fluorine, 4-chlorine, 5-bromine and 5-trifluoromethyl.
2. The method for synthesizing 2-trifluoromethylbenzofuran derivative according to claim 1, wherein: the catalyst is cuprous iodide.
3. The method for synthesizing 2-trifluoromethylbenzofuran derivative according to claim 1, wherein: the base is potassium phosphate.
4. The method for synthesizing 2-trifluoromethylbenzofuran derivative according to claim 1, wherein: the solvent is dimethyl sulfoxide.
5. The method for synthesizing 2-trifluoromethylbenzofuran derivative according to claim 1, wherein: and after the reaction is finished, filtering, washing the filtrate by using a saturated sodium chloride solution, extracting by using ethyl acetate, carrying out rotary evaporation on the combined organic layers by using a rotary evaporator, removing the solvent to obtain a residue, carrying out column layer separation on the residue through a silica gel column, leaching by using an eluent, collecting an effluent containing the target product, combining the effluent, and removing the solvent by vacuum concentration to obtain the target product.
6. The method for synthesizing 2-trifluoromethylbenzofuran derivative according to claim 1, wherein: the reaction was carried out under nitrogen atmosphere.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115043802A (en) * | 2022-06-06 | 2022-09-13 | 温州大学 | Synthesis method of trifluoroethyl benzofuran compound |
| CN115043802B (en) * | 2022-06-06 | 2023-05-09 | 温州大学 | Synthesis method of trifluoroethylbenzofuran compound |
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