CN110590722B - Synthetic method of 2-trifluoromethylbenzofuran derivatives - Google Patents

Abstract

The invention relates to a method for synthesizing 2-trifluoromethylbenzofuran derivatives, comprising the following steps: using 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-ene- 1-base) benzene is a reaction substrate, potassium hydroxide is an oxygen source, potassium phosphate is used as an alkali, cuprous iodide is used as a catalyst, 1,10-phenanthroline is used as a ligand, and dimethyl sulfoxide is used as a solvent. Under nitrogen conditions at -100°C, the reaction was stirred for 10-12 hours. The method has the advantages of mild reaction conditions, simple and easy-to-obtain raw materials, novel preparation process, less pollution and low energy consumption.

Description

Synthetic method of 2-trifluoromethylbenzofuran derivative

technical field

The invention relates to a preparation method of 2-trifluoromethylbenzofuran derivatives.

Background technique

Benzofuran derivatives widely exist in natural products and unnatural compounds with biopharmacological potential (J.Nat.Prod.2016,79,784-79; J.Med.Chem.2013,56,832-842; J.Med. Chem.2005,48,5279-5294), showing a wide range of activities, including antiviral, antibacterial, anti-inflammatory, antiangiogenic and antimitotic activities (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 activities of compounds (Adv.Synth.Catal, 2010, 352, 2745-2750; Angew.Chem.2012,51,8950-8958; Chem.Rev.2015,115,650-682), therefore, trifluoromethyl-containing benzofuran compounds have considerable pharmacological potential. Although there have been many reports on the synthesis of trifluoromethyl-substituted benzofuran compounds, as in 2013, Anxionnat et al. reported an iridium-catalyzed hydrogen transfer reaction in the presence of p-benzoquinone: Synthesis of substituted benzofuran from benzyl alcohol Furan, benzothiophene and indole derivatives (Org. Lett. 2013, 15, 3876-3879). In 2014, Yuan et al reported the synthesis of 2,3-disubstituted benzofuran derivatives in moderate yields by the reaction of palladium-catalyzed alkynyl-substituted benzynes and aryl halides (Org.Lett.2014,16,193-195) . In 2014, Murakami et al. reported a practical, modular, and general synthesis of benzofurans by extending the Pummerer ring/cross-coupling strategy (Angew. Chem. Int. Ed. 2014, 53, 7510-7513). The above traditional methods are troubled by multi-step reactions, and the economy is not high. Most of them are provided by the direct trifluoromethylation reaction of benzofuran with free radicals or electrophiles, and have the defects of low yield and poor regioselectivity.

Contents of the invention

Aiming at the deficiencies existing at the present stage, the present invention provides a reaction method using 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)benzene and potassium hydroxide Raw materials, a method for preparing 2-trifluoromethylbenzofuran derivatives with simple technical process, high yield, less pollution, and environmental protection and safety.

In order to achieve the above object, the technical scheme adopted in the present invention is:

The synthetic method of 2-trifluoromethyl benzofuran derivative comprises the following steps: using 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)benzene As the reaction substrate, potassium hydroxide is the oxygen source, sodium carbonate, cesium carbonate, potassium tert-butoxide or potassium phosphate are used as the base, cuprous chloride, cuprous bromide, copper thiophene-2-formate or cuprous iodide are used as Catalyst, 1,10-phenanthroline as ligand, acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide as solvent, stirring and reacting at 80°C-110°C for 10-12 hours, the chemical reaction formula as follows:

The -R is one of hydrogen, 4-methyl, 5-methyl, 5-methoxy, 4-fluoro, 4-chloro, 5-chloro, 5-bromo, 5-trifluoromethyl.

The preparation method adopted in the present invention is to synthesize 2-trifluoro The methylbenzofuran derivative has a simple process and does not need to use special instruments or methods. It is very suitable for those skilled in the art to operate, and has the advantages of simple operation and easy-to-obtain products.

In a further setting of the present invention, the catalyst is cuprous iodide.

According to a further setting of the present invention, the alkali is potassium phosphate.

In a further setting of the present invention, the solvent is dimethyl sulfoxide.

In a further configuration of the present invention, the reaction is carried out in a nitrogen atmosphere.

The method of the present invention can directly synthesize the target product without separating the intermediate product, and the target product can be obtained only by stirring the reaction under normal pressure, and the interference of oxygen can be eliminated under the nitrogen condition, and the yield can reach up to 65%, which greatly simplifies the process engineering , the energy consumption is reduced, and the yield is excellent; and the waste solution is less in the reaction process, and other polluting gases and liquids are not discharged, so the present invention 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-trifluoromethylbenzofuran derivatives can be prepared, and this method has better substrate universality. In this way, the present invention supplements the blank of the method for preparing 2-trifluoromethylbenzofuran derivatives at the present stage, promotes the development of multi-substituted 2-trifluoromethylbenzofuran derivatives, and provides a basis for the development of 2-trifluoromethylbenzofuran derivatives. Benzofuran biopharmaceuticals provide strong protection.

The mechanism of the present invention is as follows: Taking 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)benzene 1a as an example, at first, the base is eliminated in the presence of a base Compound 1a, o-bromophenylpropyne A was obtained. Oxidative addition of intermediate A to CuI provides B, which undergoes ligand exchange with KOH and reductive elimination to yield intermediate C. In the intermediate C, the carbon-carbon triple bond coordinates with the copper salt, and then undergoes an intramolecular nucleophilic addition reaction with the phenolic oxyanion to obtain the cyclic intermediate D. The intermediate D is further added to another molecule of o-bromophenylpropyne A to form the intermediate vinyl copper E. Finally, vinyl copper E was protonated to give product 2a and regenerated Cu(I). The possible reaction mechanism chemical reaction formula is as follows:

Detailed ways

The invention discloses a synthesis method of 2-trifluoromethylbenzofuran derivatives, which uses 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl) Benzene is the reaction substrate, potassium hydroxide is the oxygen source, sodium carbonate, cesium carbonate, potassium tert-butoxide or potassium phosphate is the base, cuprous chloride, cuprous bromide, copper thiophene-2-carboxylate or cuprous iodide As a catalyst, 1,10-phenanthroline as a ligand, acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide as a solvent, stirred and reacted at 80-110°C under nitrogen for 10-12 hours; The chemical reaction formula is as follows:

The -R is one of hydrogen, 4-methyl, 5-methyl, 5-methoxy, 4-fluoro, 4-chloro, 5-chloro, 5-bromo, 5-trifluoromethyl; After the reaction was completed, it was filtered, the filtrate was washed with saturated sodium chloride solution, and then extracted with ethyl acetate. The combined organic layer was rotary evaporated with a rotary evaporator, and the solvent was removed to obtain a residue. The residue was rinsed with petroleum ether eluent through a silica gel column, the effluent was collected according to the actual gradient, detected by TLC, and the effluent containing the target product was combined, and the combined effluent was rotated to remove the solvent with a rotary evaporator. Vacuum drying yielded the target product.

Specific embodiment one: with 57.0 milligrams (0.2mmol) 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl) benzene, 22.4 milligrams (0.4mmol) hydrogen Potassium oxide, 3.8 mg (0.02 mmol) of cuprous iodide, 7.2 mg (0.04 mmol) of 1,10-phenanthroline, and 42.4 mg (0.2 mmol) of potassium phosphate were added to 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 100°C under nitrogen for 12 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, merging the effluent containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain a white solid, (E)-3-(1- (2-bromophenyl)-3,3,3-trifluoroprop-1-en-2-yl)-2-(trifluoromethyl)benzofuran 28.3 mg, yield 65%. ¹ H NMR ( 400MHz, CDCl ₃ )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); ¹³ C NMR (125MHz, CDCl ₃ ) δ154.2, 140.0 (q, J _CF = 37.5Hz), 138.6 (q, J _CF = 3.8Hz), 133.2, 132.9, 130.7, 130.5 (q, J _CF = 41.3Hz), 129.2, ¹⁹ _{F NMR _} (470MHz, CDCl ₃ ) δ-63.7(s, 3F), -65.8(s, 3F).

Specific example two: 59.9 mg (0.2 mmol) of 2-bromo-1-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-4-methylbenzene, 22.4 mg (0.4mmol) potassium hydroxide, 3.8mg (0.02mmol) cuprous iodide, 7.2mg (0.04mmol) 1,10-phenanthroline, 42.4mg (0.2mmol) potassium phosphate add 2ml solvent dimethyl sulfoxide middle. The reaction was stirred at 100°C under nitrogen for 12 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, merging the effluent containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain a white solid, (E)-3-(1- (2-bromophenyl)-3,3,3-trifluoroprop-1-en-2-yl)-2-(trifluoromethyl)benzofuran 18.9 mg, yield 41%. ¹ H NMR ( 400MHz, CDCl ₃ )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); ¹³ C NMR (125MHz, CDCl ₃ ) δ154.7, 141.3, 140.2(q, J _CF ＝40.0Hz), 138.5, 132.1(q ,J _CF ＝5.0Hz),135.8(q,J _CF ＝5.0Hz),133.3,130.2,128.9,128.6(q,J _CF ＝42.5Hz),128.1,126.2,124.7,124.4,122.8(q,J _CF = 271.3 Hz), 121.0, 119.1 (q, J _CF = 258.8 Hz), 112.2, 21.8, 20.8; ¹⁹ F NMR (470 MHz, CDCl ₃ ) δ -63.7 (s, 3F), -65.8 (s, 3F).

Specific example three: 59.9 mg (0.2 mmol) of 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-4-methylbenzene, 22.4 mg (0.4mmol) potassium hydroxide, 3.8mg (0.02mmol) cuprous iodide, 7.2mg (0.04mmol) 1,10-phenanthroline, 42.4mg (0.2mmol) potassium phosphate add 2ml solvent dimethyl sulfoxide middle. The reaction was stirred at 100°C under nitrogen for 12 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, merging the effluent containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain a white solid, (E)-3-(1- (2-Bromo-5-methylphenyl)-3,3,3-trifluoroprop-1-en-2-yl)-5-methyl-2-(trifluoromethyl)benzofuran 24.1 mg , Yield 52%. ¹ HNMR (400MHz, CDCl ₃ ) 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); ¹³ C NMR(125MHz, CDCl ₃ ) δ152.6, 141.0(q, J _CF ＝40.0Hz), 138.6 (q,J _CF ＝5.0Hz),137.1,134.4,133.0,132.4,131.5,131.3(q,J _CF ＝5.0Hz),130.1,129.5(q,J _CF ＝43.8Hz),129.1,127.3,122.7( q, J _CF = 272.5Hz), 121.0, 120.7, 119.2 (q, J _CF = 268.8 Hz), 111.6, 21.3, 20.5; ¹⁹ F NMR (470MHz, CDCl ₃ ) δ-63.7(s, 3F), -65.9 (s, 3F).

Specific example four: 63.1 mg (0.2 mmol) of 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-4-methoxybenzene, 22.4 mg (0.4 mmol) potassium hydroxide, 3.8 mg (0.02 mmol) cuprous iodide, 7.2 mg (0.04 mmol) 1,10-phenanthroline, 42.4 mg (0.2 mmol) potassium phosphate were added to 2 ml solvent dimethyl methylene in sulfone. The reaction was stirred at 100°C under nitrogen for 12 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, combining the effluent containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain a yellow oily liquid, (E)-3-(1 -(2-Bromo-5-methoxyphenyl)-3,3,3-trifluoroprop-1-en-2-yl)-5-methoxy-2-(trifluoromethyl)benzo Furan 25.2 mg, yield 51%. ¹ H NMR (400MHz, CDCl ₃ ) 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); ¹³ CNMR(125MHz,CDCl ₃ )δ158.4,157.3, 149.1, 141.5(q, J _CF ＝40.0Hz), 138.6(q, J _CF ＝5.0Hz), 133.8, 133.4, 133.3(q, J _CF ＝36.3Hz), 131.8(q, J _CF ＝2.5Hz), 127.7, 122.7(q, J _CF ＝271.3Hz), 119.1(q, J _CF ＝268.8Hz), 118.2, 117.7, 114.5, 113.5, 112.9, 102.2, 55.9, 54.8; ¹⁹ F NMR (470MHz, CDCl ₃ )δ -63.5(s,3F),-66.0(s,3F).

Specific example five: 60.7 mg (0.2 mmol) 2-bromo-1-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-4-fluorobenzene, 22.4 mg ( 0.4mmol) potassium hydroxide, 3.8mg (0.02mmol) cuprous iodide, 7.2mg (0.04mmol) 1,10-phenanthroline, 42.4mg (0.2mmol) potassium phosphate were added to 2ml solvent DMSO . The reaction was stirred at 100°C under nitrogen for 12 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, merging the effluent containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain a white solid, (E)-3-(1- (2-Bromo-4-fluorophenyl)-3,3,3-trifluoroprop-1-en-2-yl)-6-fluoro-2-(trifluoromethyl)benzofuran 28.7 mg, yielding Rate 61%. ¹ HNMR (400MHz, CDCl ₃ ) 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); ¹³ C NMR(125MHz, CDCl ₃ )δ162.7(d, J _CF ＝246.3 ), 162.6(d, J _CF ＝253.8Hz), 154.3, 141.6(q, J _CF ＝36.3Hz), 137.8(q, J _CF ＝5.0Hz), 130.2, 129.3, 125.8(q, J _CF ＝3.8Hz ), 124.8(d, J _CF ＝8.8Hz), 123.2, 122.5(q, J _CF ＝271.3Hz), 122.2(q, J _CF ＝10.0Hz), 121.1(q, J _CF ＝221.3Hz), 120.9( q, J _CF ＝33.8Hz), 120.4, 114.8 (d, J _CF ＝21.3Hz), 113.9 (d, J _CF ＝25.0Hz), 100.1; ¹⁹ F NMR (500MHz, CDCl ₃ ) δ-63.9 (s, 3F), -65.9(s, 3F), -108.4(s, 1F), -111.0(s, 1F).

Specific embodiment six: 64.0 mg (0.2 mmol) 2-bromo-4-chloro-1-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg ( 0.4mmol) potassium hydroxide, 3.8mg (0.02mmol) cuprous iodide, 7.2mg (0.04mmol) 1,10-phenanthroline, 42.4mg (0.2mmol) potassium phosphate were added to 2ml solvent DMSO . The reaction was stirred at 100°C under nitrogen for 12 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, combining the effluent containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain a light yellow oily liquid, (E)-3-( 1-(2-Bromo-4-chlorophenyl)-3,3,3-trifluoroprop-1-en-2-yl)-6-chloro-2-(trifluoromethyl)benzofuran 31.2 mg , Yield 62%. ¹ H NMR (400MHz, CDCl ₃ ) 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); ¹³ C NMR (125MHz, CDCl ₃ ) δ154.2, 141.6 (q, J _CF = 40.0 Hz), 137.9(q, J _CF ＝5.0Hz), 136.2, 134.1, 132.8, 131.6, 131.2(q, J _CF ＝3.8Hz), 129.7, 128.1(q, J _CF ＝30.0Hz), 127.8, 125.9, 125.6, 124.6, 122.4(q, J _CF ＝272.5Hz), 122.0, 118.8(q, J _CF ＝267.5Hz), 113.0; ¹⁹ F NMR (500MHz, CDCl ₃ ) δ-63.8(s, 3F), -66.0 (s, 3F).

Specific embodiment seven: with 64.0 milligrams (0.2mmol) 1-bromo-4-chloro-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)benzene, 22.4 milligrams ( 0.4mmol) potassium hydroxide, 3.8mg (0.02mmol) cuprous iodide, 7.2mg (0.04mmol) 1,10-phenanthroline, 42.4mg (0.2mmol) potassium phosphate were added to 2ml solvent DMSO . The reaction was stirred at 100°C under nitrogen for 12 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, combining the effluent containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain a light yellow oily liquid, (E)-3-( 1-(2-Bromo-5-chlorophenyl)-3,3,3-trifluoroprop-1-en-2-yl)-5-chloro-2-(trifluoromethyl)benzofuran 30.2 mg , Yield 60%. ¹ H NMR (400MHz, CDCl ₃ ) 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); ¹³ C NMR(125MHz,CDCl ₃ )δ152.5,142.4(q,J _CF ＝41.3Hz),138.0(q,J _CF ＝5.0Hz),134.5,134.0,133.6(q, J _CF ＝3.8Hz),133.3,130.8,130.7,129.1,128.5,128.1,122.4(q,J _CF ＝231.3Hz),121.8,120.9,118.7(q,J _CF ＝268.8Hz),113.5,130.8(q , J _CF = 43.8 Hz); ¹⁹ F NMR (500 MHz, CDCl ₃ ) δ -63.8 (s, 3F), -66.1 (s, 3F).

Specific example eight: 72.9 mg (0.2 mmol) of 1,4-dibromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)benzene, 22.4 mg (0.4 mmol) potassium hydroxide, 3.8 mg (0.02 mmol) cuprous iodide, 7.2 mg (0.04 mmol) 1,10-phenanthroline, and 42.4 mg (0.2 mmol) potassium phosphate were added to 2 ml solvent dimethyl sulfoxide. The reaction was stirred at 100°C under nitrogen for 12 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, combining the effluent containing the product, distilling off the solvent with a rotary evaporator, and drying in vacuo to obtain a white solid, (E)-5-bromo-3 -(1-(2,5-Dibromophenyl)-3,3,3-trifluoroprop-1-en-2-yl)-2-(trifluoromethyl)benzofuran 36.8 mg, yield 62%. ¹ HNMR (400MHz, CDCl ₃ ) 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); ¹³ C NMR(125MHz,CDCl ₃ )δ152.9,142.2(q,J _CF = 41.3Hz), 137.9(q, J _CF ＝5.0Hz), 134.9, 134.5(q, J _CF ＝3.8Hz), 134.2, 133.7, 132.7(q, J _CF ＝52.5Hz), 132.1, 131.2, 128.7, 124.0 , 122.2(q, J _CF ＝271.3Hz), 122.5, 120.9, 118.7(q, J _{CF ＝} ^268.8Hz ), 118.1, 114.0; 66.1(s,3F).

Specific example nine: 70.7 mg (0.2 mmol) of 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-4-(trifluoromethyl) Benzene, 22.4 mg (0.4 mmol) potassium hydroxide, 3.8 mg (0.02 mmol) cuprous iodide, 7.2 mg (0.04 mmol) 1,10-phenanthroline, 42.4 mg (0.2 mmol) potassium phosphate were added to 2 ml solvent di in methyl sulfoxide. The reaction was stirred at 100°C under nitrogen for 12 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, combining the effluent containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain a light yellow oily liquid, (E)-3-( 1-(2-Bromo-5-(trifluoromethyl)phenyl)-3,3,3-trifluoroprop-1-en-2-yl)-2,5-bis(trifluoromethyl)benzene Furan 23.1 mg, yield 40%. ¹ H NMR (400MHz, CDCl ₃ ) 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); ¹³ C NMR (125MHz, CDCl ₃ ) δ159.5, 142.8 (q, J _CF = 33.8Hz), 136.0 (q, J _CF =6.3Hz), 133.2, 132.2, 130.6(q, J _CF =25.0Hz), 129.5(q, J _CF =27.2Hz), 130.2(q, J _CF =2.5Hz), 129.9(q, J _CF = 32.5Hz), 129.4(q, J _CF ＝6.3Hz), 129.1(q, J _CF ＝3.8Hz), 128.6, 127.9, 127.5(q, J _CF ＝3.8Hz), 127.4(q, J _CF ＝3.8Hz ), 123.4(q, J _CF ＝261.3Hz), 122.2, 122.1(q, J _CF ＝272.5Hz), 121.1(q, J _CF ＝245.0Hz), 118.7(q, J _CF ＝273.8Hz); ¹⁹ F NMR (500MHz, CDCl ₃ ) δ-61.9(s, 3F), -62.4(s, 3F), -62.9(s, 3F), -63.5(s, 3F).

Specific example ten: with 67.1 milligrams (0.2mmol) 2-bromo-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl) naphthalene, 22.4 milligrams (0.4mmol) hydrogen Potassium oxide, 3.8 mg (0.02 mmol) of cuprous iodide, 7.2 mg (0.04 mmol) of 1,10-phenanthroline, and 42.4 mg (0.2 mmol) of potassium phosphate were added to 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 100°C under nitrogen for 12 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, merging the effluent containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain a yellow solid, (E)-3-(1- (3-bromonaphthalen-2-yl)-3,3,3-trifluoroprop-1-en-2-yl)-2-(trifluoromethyl)naphtho[2,3-b]furan 24.1 mg , Yield 45%. ¹ H NMR (400MHz, CDCl ₃ ) 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); ¹³ CNMR (125MHz, CDCl ₃ ) δ154.8, 141.1 (q, J _CF = 32.5Hz), 137.6 (q, J _CF = 5.0Hz), 136.3, 134.2, 131.9, 130.7 (q, J _CF = 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, J _CF = 272.5 Hz), 123.6, 122.9, 128.5 (q, J 0 _Hz = 3 ), 118.8 (q, J _CF = 275.0 Hz); ¹⁹ F NMR (500 MHz, CDCl ₃ ) δ -61.0 (s, 3F), -63.7 (s, 3F).

Specific Example Eleven: 57.0 mg (0.2 mmol) of 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4 mmol) Potassium hydroxide, 3.8 mg (0.02 mmol) of cuprous iodide, 7.2 mg (0.04 mmol) of 1,10-phenanthroline, and 21.2 mg (0.2 mmol) of sodium carbonate were added to 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 100°C under nitrogen for 12 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, merging the effluent containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain a white solid, (E)-3-(1- (2-Bromophenyl)-3,3,3-trifluoroprop-1-en-2-yl)-2-(trifluoromethyl)benzofuran 15.7 mg, yield 36%.

Specific Example 12: 57.0 mg (0.2 mmol) of 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4 mmol) Potassium hydroxide, 3.8 mg (0.02 mmol) of cuprous iodide, 7.2 mg (0.04 mmol) of 1,10-phenanthroline, and 65.2 mg (0.2 mmol) of cesium carbonate were added to 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 100°C under nitrogen for 12 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, merging the effluent containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain a white solid, (E)-3-(1- (2-bromophenyl)-3,3,3-trifluoroprop-1-en-2-yl)-2-(trifluoromethyl)benzofuran 25.2 mg, yield 58%.

Specific Example Thirteen: 57.0 mg (0.2 mmol) of 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4 mmol) Potassium hydroxide, 3.8 mg (0.02 mmol) of cuprous iodide, 7.2 mg (0.04 mmol) of 1,10-phenanthroline, and 22.4 mg (0.2 mmol) of potassium tert-butoxide were added to 2 ml of the solvent dimethyl sulfoxide. The reaction was stirred at 100°C under nitrogen for 12 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, merging the effluent containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain a white solid, (E)-3-(1- (2-bromophenyl)-3,3,3-trifluoroprop-1-en-2-yl)-2-(trifluoromethyl)benzofuran 22.6 mg, yield 52%.

Specific Example 14: 57.0 mg (0.2 mmol) of 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4 mmol) Potassium hydroxide, 2.0 mg (0.02 mmol) of cuprous chloride, 7.2 mg (0.04 mmol) of 1,10-phenanthroline, and 42.4 mg (0.2 mmol) of potassium phosphate were added to 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 100°C under nitrogen for 12 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, merging the effluent containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain a white solid, (E)-3-(1- (2-bromophenyl)-3,3,3-trifluoroprop-1-en-2-yl)-2-(trifluoromethyl)benzofuran 25.2 mg, yield 58%.

Specific Example 15: 57.0 mg (0.2 mmol) of 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4 mmol) Potassium hydroxide, 2.9 mg (0.02 mmol) of cuprous bromide, 7.2 mg (0.04 mmol) of 1,10-phenanthroline, and 42.4 mg (0.2 mmol) of potassium phosphate were added to 2 ml of solvent dimethyl sulfoxide. The reaction was stirred at 100°C under nitrogen for 12 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, merging the effluent containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain a white solid, (E)-3-(1- (2-bromophenyl)-3,3,3-trifluoroprop-1-en-2-yl)-2-(trifluoromethyl)benzofuran 27.0 mg, yield 62%.

Specific Example 16: 57.0 mg (0.2 mmol) of 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4 mmol) Potassium hydroxide, 3.8 mg (0.02 mmol) of copper thiophene-2-carboxylate, 7.2 mg (0.04 mmol) of 1,10-phenanthroline, and 42.4 mg (0.2 mmol) of potassium phosphate were added to 2 mL of the solvent dimethyl sulfoxide. The reaction was stirred at 100°C under nitrogen for 12 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, merging the effluent containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain a white solid, (E)-3-(1- (2-bromophenyl)-3,3,3-trifluoroprop-1-en-2-yl)-2-(trifluoromethyl)benzofuran 26.1 mg, yield 60%.

Specific Example 17: 57.0 mg (0.2 mmol) of 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4 mmol) Potassium hydroxide, 3.8 mg (0.02 mmol) of cuprous iodide, 7.2 mg (0.04 mmol) of 1,10-phenanthroline, and 42.4 mg (0.2 mmol) of potassium phosphate were added to 2 ml of solvent acetonitrile. The reaction was stirred at 100°C under nitrogen for 12 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, merging the effluent containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain a white solid, (E)-3-(1- (2-bromophenyl)-3,3,3-trifluoroprop-1-en-2-yl)-2-(trifluoromethyl)benzofuran 16.5 mg, yield 38%.

Specific example eighteen: 57.0 mg (0.2 mmol) 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4 mmol) Potassium hydroxide, 3.8 mg (0.02 mmol) of cuprous iodide, 7.2 mg (0.04 mmol) of 1,10-phenanthroline, 42.4 mg (0.2 mmol) of potassium phosphate were added to 2 ml of solvent N,N-dimethylformamide middle. The reaction was stirred at 100°C under nitrogen for 12 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, merging the effluent containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain a white solid, (E)-3-(1- (2-Bromophenyl)-3,3,3-trifluoroprop-1-en-2-yl)-2-(trifluoromethyl)benzofuran 11.7 mg, yield 27%.

Specific Example 19: 57.0 mg (0.2 mmol) of 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl) benzene, 22.4 mg (0.4 mmol) Potassium hydroxide, 3.8 mg (0.02 mmol) of cuprous iodide, 7.2 mg (0.04 mmol) of 1,10-phenanthroline, and 42.4 mg (0.2 mmol) of potassium phosphate were added to 2 ml of the solvent dimethyl sulfoxide. The reaction was stirred at 110°C under nitrogen for 12 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, merging the effluent containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain a white solid, (E)-3-(1- (2-bromophenyl)-3,3,3-trifluoroprop-1-en-2-yl)-2-(trifluoromethyl)benzofuran 28.3 mg, yield 52%.

Specific Example Twenty: 57.0 mg (0.2 mmol) of 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)benzene, 22.4 mg (0.4 mmol) Potassium hydroxide, 3.8 mg (0.02 mmol) of cuprous iodide, 7.2 mg (0.04 mmol) of 1,10-phenanthroline, and 42.4 mg (0.2 mmol) of potassium phosphate were added to 2 ml of the solvent dimethyl sulfoxide. The reaction was stirred at 100°C under nitrogen for 10 hours. Cool after the reaction, filter the reaction liquid to obtain the filtrate and wash it with saturated sodium chloride solution, then extract it with ethyl acetate, use a rotary evaporator to carry out rotary evaporation for the combined organic layer, remove the solvent to obtain the residue, and use silica gel to obtain the residue Column chromatography, washing with petroleum ether solution, collecting the effluent according to the actual gradient, TLC detection, merging the effluent containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain a white solid, (E)-3-(1- (2-bromophenyl)-3,3,3-trifluoroprop-1-en-2-yl)-2-(trifluoromethyl)benzofuran 28.3 mg, yield 58%.

The embodiment of the present invention uses 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)benzene and potassium hydroxide as substrates, potassium phosphate as base, iodide Cuprous as a catalyst, 1,10-phenanthroline as a ligand, and dimethyl sulfoxide as a solvent, the reaction is stirred for 10-12 hours at 80°C-110°C under nitrogen. In Examples 1 to 10, Ar in 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)benzene is substituted by different substituents as variables. It should be noted that the substituents and alkyl groups with strong electro-absorbing properties on the phenyl group can also use the method of the present invention well; Embodiment 11 to 13 are based on alkali as a variable, and embodiments 14 to 16 are Taking the catalyst as a variable, Examples 17 and 18 took solvent as a variable, Example 19 took temperature as a variable, and Example 20 took time as a variable.

The present invention does not need to separate intermediate products, and can directly synthesize the target product through simple raw materials, simplify the process, reduce energy consumption, reduce waste solution discharge, reduce environmental pollution, and the highest yield can reach 65%; the above embodiments use 1- Bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)benzene and the reaction of different substituents with potassium hydroxide can prepare a series of 2-trifluoromethylbenzene And furan derivatives, this method has certain substrate adaptability and easy operation. The present invention is not limited to the specific embodiments described above. Those skilled in the art can adopt various other specific embodiments to implement the present invention according to the content disclosed in the present invention, or make simple changes or All changes fall within the protection scope of the present invention.

Claims (6)

1. a synthetic method of 2-trifluoromethyl benzofuran derivatives, comprising the steps of: taking formula (I) as reaction substrate, potassium hydroxide as oxygen source, sodium carbonate, cesium carbonate, potassium tert-butoxide Or potassium phosphate as base, cuprous chloride, cuprous bromide, copper thiophene-2-carboxylate or cuprous iodide as catalyst, 1,10-phenanthroline as ligand, acetonitrile, N,N-dimethyl Formamide or dimethyl sulfoxide is used as a solvent, and the reaction is stirred at 80 ^o C-110 ^o C for 10-12 hours. The chemical reaction formula is as follows:

The -R is one of hydrogen, 4-methyl, 5-methyl, 5-methoxy, 4-fluoro, 4-chloro, 5-chloro, 5-bromo, 5-trifluoromethyl. 2. according to the synthetic method of the described 2-trifluoromethylbenzofuran derivative of claim 1, it is characterized in that: described catalyst is cuprous iodide. 3. according to the synthetic method of the described 2-trifluoromethylbenzofuran derivative of claim 1, it is characterized in that: described alkali is potassium phosphate. 4. The synthetic method of 2-trifluoromethylbenzofuran derivatives according to claim 1, characterized in that: the solvent is dimethyl sulfoxide. 5. the synthetic method of 2-trifluoromethylbenzofuran derivative according to claim 1, is characterized in that: after reaction finishes, filter, and filtrate uses saturated sodium chloride solution to wash, then carries out with ethyl acetate Extraction, the combined organic layer is rotary evaporated using a rotary evaporator, the solvent is removed to obtain the residue, the residue is subjected to column separation through a silica gel column, and the eluent is rinsed, the effluent containing the target product is collected, and the effluent is combined. solution and concentrated in vacuo to remove the solvent to obtain the target product. 6. The synthetic method of 2-trifluoromethylbenzofuran derivatives according to claim 1, characterized in that: the reaction is carried out in a nitrogen atmosphere.