A method for synthesizing alpha-aryl propionate compounds

Abstract

Coupling reaction is an important type of reaction for constructing carbon-carbon bonds or carbon-hetero bonds. Usually, this type of reaction needs to be carried out under the catalysis of transition metals and has good substrate tolerance. It is commonly used in the synthesis of various natural products and drug molecules. Drugs such as naproxen and ibuprofen with α-aryl propionate as the basic skeleton are an important class of non-steroidal anti-inflammatory drugs. This type of drug has the advantages of small toxic side effects and strong efficacy. For α-aryl propionate compounds, traditional synthesis methods include Friedel-Crafts alkylation and α-methylation reaction. However, these methods are cumbersome to operate, the functional group compatibility of the substrate is poor, and they are not conducive to industrial-scale production. With the development of transition metal-catalyzed coupling reactions, there are more and more ways to synthesize α-aryl propionate compounds. In 2020, our research group reported the synthesis of such compounds under the synergistic catalytic system of transition metal nickel and visible light. Compared with traditional methods, this method has good substrate tolerance and uses green and environmentally friendly visible light. However, this method requires the use of nickel and visible light, and under their synergistic catalytic action, a certain amount of reducing agent and photocatalyst are added to react to obtain such compounds. However, the present invention, under the catalytic system of a single transition metal cobalt, takes advantage of the substrate Grignard reagent itself as a reducing agent, and can synthesize such compounds by adding a small amount of phosphine ligand.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing alpha-aryl propionate compounds. Background Art

[0002] Coupling reaction is an important reaction for building carbon-carbon bonds or carbon-hetero bonds. Usually, such reactions need to be carried out under the catalysis of transition metals and have good substrate tolerance. They are commonly seen in the synthesis of various natural products and drug molecules. Drugs such as naproxen and ibuprofen with α-aryl propionate as the basic skeleton are an important class of non-steroidal anti-inflammatory drugs. Such drugs have the advantages of low toxicity and side effects and strong efficacy.

[0003] For α-aryl propionate compounds, traditional synthesis methods include Friedel-Crafts alkylation, α-methylation reaction, etc. However, these methods are cumbersome to operate, the functional group compatibility of the substrate is poor, and they are not conducive to industrial-scale production.

[0004] With the development of transition metal-catalyzed coupling reactions, there are more and more ways to synthesize α-aryl propionate compounds. In 2020, our research group reported the synthesis of such compounds under the synergistic catalytic system of transition metal nickel and visible light. Compared with traditional methods, this method has good substrate tolerance and uses green and environmentally friendly visible light. However, this method must use nickel and visible light, and under their synergistic catalytic action, a certain amount of reducing agent and photocatalyst must be added to react to obtain such compounds. In the present invention, only under the catalytic system of a single transition metal cobalt, with the advantage of the substrate Grignard reagent itself as a reducing agent, by adding a small amount of phosphine ligand, such compounds can be synthesized. Summary of the invention

[0005] The present invention provides a transition metal-catalyzed reductive cross-coupling reaction of tert-butyl acrylate with tert-butyl iodide and an aryl Grignard reagent, which can obtain a variety of α-aryl propionate compounds with biological activity and medicinal value, and chemically selectively construct carbon-carbon bonds in a direct and high-atomic utilization method. The synthesis method is simple and efficient. The specific scheme is as follows:

[0006]

[0007] A method for synthesizing o-arylbenzamide compounds, wherein tert-butyl acrylate shown in formula 1, tert-butyl iodide shown in formula 2, and an aryl Grignard reagent shown in formula 3 are mixed with an organic solvent in the presence of a cobalt catalyst and a phosphine ligand to undergo a reduction cross-coupling reaction to synthesize an α-aryl propionate compound shown in formula 4. The cobalt catalyst is cobalt chloride, cobalt bromide, cobalt iodide, [1,2-bisdiphenylphosphine ethane] cobalt dichloride; the phosphine ligand is trifuranylphosphine, tris(2,4,6-trimethoxyphenyl)phosphine, 1,2-bis(dicyclohexylphosphine)-ethane;

[0008] Wherein R is selected from phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 3-methylphenyl, 4-tert-butylphenyl, 4-trifluoromethylphenyl, 4-biphenyl, benzodihydrofuran, 4-N,N-dimethylphenyl, 2-naphthyl, benzothiophene.

[0009] The method of the invention can realize the one-pot method for generating α-aryl propionate compounds, thereby reducing the reaction steps and improving the product yield; the raw materials used in the synthesis method are simple and economical; and R in the invention can be selected from a variety of options, and has wider applicability.

[0010] Preferably, R is selected from phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 3-methylphenyl, 4-tert-butylphenyl, 4-trifluoromethylphenyl, 4-biphenyl, benzodihydrofuran, 4-N,N-dimethylphenyl, 2-naphthyl, and benzothiophene.

[0011] More preferably, R is selected from phenyl, 4-fluorophenyl, 4-chlorophenyl.

[0012] Preferably, the reaction is carried out under the protection of an inert gas, and preferably, the inert gas is nitrogen.

[0013] Preferably, the cobalt catalyst is cobalt chloride, cobalt bromide, cobalt iodide, or [1,2-bis(diphenylphosphine)ethane]cobalt dichloride.

[0014] More preferably, the cobalt catalyst is [1,2-bis(diphenylphosphine)ethane]cobalt dichloride.

[0015] Preferably, the phosphine ligand is trifuranylphosphine, tri(2,4,6-trimethoxyphenyl)phosphine, or 1,2-bis(dicyclohexylphosphine)-ethane.

[0016] More preferably, the phosphine ligand is tris(2,4,6-trimethoxyphenyl)phosphine.

[0017] Preferably, the organic solvent is 2-methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, isopropyl ether, tetrahydrofuran.

[0018] More preferably, the organic solvent is tetrahydrofuran and ethylene glycol dimethyl ether.

[0019] Preferably, in the reaction, the molar ratio of tert-butyl acrylate shown in Formula 1, tert-butyl iodide shown in Formula 2, aromatic Grignard reagent shown in Formula 3, phosphine ligand and cobalt catalyst is: 1:2-6:2:0.05-0.2:0.05-0.2.

[0020] More preferably, the molar ratio is 1:4:2:0.2:0.2;

[0021] Preferably, the reaction temperature is -20°C to 20°C.

[0022] More preferably, the reaction temperature is 0°C.

[0023] Preferably, the method of the present invention can be used to synthesize α-aryl propionate compounds with the following structure:

[0024]

[0025]

[0026] The Grignard reagent first reduces the divalent metallic cobalt to a low-valent state, and the low-valent metallic cobalt undergoes a single electron transfer process with tert-butyl iodide to generate a tert-butyl free radical. Subsequently, the tert-butyl free radical undergoes a free radical addition reaction with tert-butyl acrylate to obtain a corresponding free radical intermediate. The metallic cobalt then undergoes transmetallation with the Grignard reagent, and undergoes an oxidative addition and reductive elimination process with the above-mentioned free radical intermediate to prepare an α-aryl propionate ester compound.

[0027] The technical solution of the present invention can achieve at least one of the following beneficial effects:

[0028] The raw materials used in the synthesis method of the present invention are cheap and readily available;

[0029] The present invention adopts a one-pot synthesis method, which reduces the loss of raw materials and improves the yield of the product due to fewer reaction steps;

[0030] The operation steps required by the present invention are relatively simple, and no extreme heating or cooling is required. The reaction can be performed at normal pressure, which is safe and convenient.

[0031] R in the present invention can be selected from a variety of options, so that the substrate of the present invention has a wide range of applicability and can be used to synthesize a variety of α-aryl propionate compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The accompanying drawings are hydrogen and carbon nuclear magnetic resonance spectra of the products of each embodiment. The serial numbers of the accompanying drawings correspond to the serial numbers of the embodiments. Figure A is a hydrogen nuclear magnetic resonance spectrum, and Figure B is a carbon nuclear magnetic resonance spectrum. Figure 1Ais the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 1, Figure 1B The carbon nuclear magnetic resonance spectrum of the product obtained in Example 1; Figure 2A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 2, Figure 2B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 2; Figure 3A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 3, Figure 3B The carbon nuclear magnetic resonance spectrum of the product obtained in Example 3; Figure 4A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 4, Figure 4B The carbon nuclear magnetic resonance spectrum of the product obtained in Example 4; Figure 5A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 5, Figure 5B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 5; Fig. 6A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 6, Figure 6B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 6; Fig. 7A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 7, Figure 7B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 7; Fig. 8A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 8, Figure 8B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 8; Fig. 9A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 9, Fig. 9B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 9; Fig. 10A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 10, Fig. 10B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 10; Fig.11A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 11, Fig. 11B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 11; Fig. 12A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 12, Fig. 12B This is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 12. Specific embodiments

[0033] In order to facilitate the understanding of those skilled in the art, the concept of the present invention is further described below in conjunction with the embodiments. The specific description of the following embodiments is not a limitation of the present invention, but is only for the convenience of those skilled in the art to understand the technical solution. Various raw materials involved in the specification are purchased from the market, or through simple synthesis, other drugs are purchased from Anaiji, Bi De, Sigma-Aldrich, Acros, Alfa Aesar, Adamas-beta or J&K., and the nuclear magnetic resonance spectrometer model is Bruker 400M.

[0034] Example 1

[0035] In a glove box filled with nitrogen, [1,2-bis(diphenylphosphinoethane)cobalt dichloride (0.02mmol, 0.0106g) and tri(2,4,6-trimethoxyphenyl)phosphine (0.02mmol, 0.0106g) were added to a dry microwave tube equipped with a magnet, followed by 0.5mL tetrahydrofuran and 0.5mL ethylene glycol dimethyl ether. The color of the solution was dark green. Stir and coordinate for about 15min, add tert-butyl acrylate (0.1mmol, 14μL, 1.0 equivalent) and tert-butyl iodide (0.4mmol, 46μL, 4.0 equivalent) to the microwave tube, then seal and remove from the glove box. Next, slowly add 0.2mL phenylmagnesium bromide solution (0.2mmol, 2.0 equivalent, dissolved in THF to make a 1mol / L solution) using a 1mL syringe at 0℃. At this time, the color of the solution changes from dark green to brown-black. Seal the microwave tube with a sealing film and continue to stir the reaction at 0°C for 10 hours. After the reaction is completed, take out the microwave tube, return to room temperature and open it in the air. Then pass the reaction mixture through a short chromatographic column containing a small amount of silica gel and wash it three times with 6mL of dichloromethane (3×2mL). Then remove the solvent by vacuum rotary evaporation, load the obtained crude product onto a silica gel column, and elute it with an eluent of petroleum ether: ethyl acetate = 80:1 to obtain a white solid (19.1mg, 73% yield). The hydrogen spectrum and carbon spectrum nuclear magnetic resonance spectra of the product are respectively Figure 1A and Figure 1B , the spectrum data is: 1 H NMR (401 MHz, CDCl 3 )δ: 7.31-7.26 (m, 4H), 7.23-7.18 (m, 1H), 3.59-3.46 (m, 1H), 2.27 (dd, J=14.0, 9.4Hz, 1H), 1.50 (d, J=3.3Hz, 1H), 1.36 (s, 9H), 0.90 (s, 9H). 13 C NMR (101 MHz, CDCl 3 )δ: 174.01, 141.77, 128.55, 126.76, 80.42, 49.34, 47.27, 31.14, 29.58, 27.93ppm.

[0036] The raw materials in Example 1 were changed to design the following 12 groups of experimental examples, wherein the first group of experiments is Example 1, and the corresponding nuclear magnetic resonance spectrum of the product is shown in Figure 1. The serial numbers of the nuclear magnetic resonance spectra of the remaining groups 2-12 of products correspond to the serial numbers of the corresponding examples.

[0037] The table lists the structural formulas of the products in Examples 1-12. In the 12 examples, only the types of aromatic Grignard reagents are different, and other raw materials, amounts, conditions, etc. are kept consistent. The last column lists the yields of the products in each example.

[0038]

[0039] Example 2

[0040] In a glove box filled with nitrogen, [1,2-bis(diphenylphosphinoethane)cobalt dichloride (0.02mmol, 0.0106g) and tri(2,4,6-trimethoxyphenyl)phosphine (0.02mmol, 0.0106g) were added to a dry microwave tube equipped with a magnet, followed by 0.5mL tetrahydrofuran and 0.5mL ethylene glycol dimethyl ether. The color of the solution was dark green. Stir and coordinate for about 15min, add tert-butyl acrylate (0.1mmol, 14μL, 1.0 equivalent) and tert-butyl iodide (0.4mmol, 46μL, 4.0 equivalent) to the microwave tube, then seal and remove from the glove box. Next, slowly add 0.2mL 4-fluorophenylmagnesium bromide solution (0.2mmol, 2.0 equivalent, dissolved in THF to make a 1mol / L solution) using a 1mL syringe at 0℃. At this time, the color of the solution changes from dark green to brown-black. Seal the microwave tube with a sealing film and continue to stir the reaction at 0°C for 10 hours. After the reaction is completed, take out the microwave tube, return to room temperature and open it in the air. Then pass the reaction mixture through a short chromatographic column containing a small amount of silica gel and wash it three times with 6mL of dichloromethane (3×2mL). Then remove the solvent by vacuum rotary evaporation, load the obtained crude product onto a silica gel column, and elute it with an eluent of petroleum ether: ethyl acetate = 80:1 to obtain a white solid (19.6mg, 70% yield). The hydrogen spectrum and carbon spectrum nuclear magnetic resonance spectra of the product are respectively Figure 2A and Figure 2B , the spectrum data is: 1 HNMR (400MHz, Chloroform-d) δ: 7.25 (t, J=6.9Hz, 3H), 6.96 (t, J=8.7Hz, 2H), 3.49 (dd, J=9. 2, 3.6Hz, 1H), 2.22 (dd, J=14.0, 9.2Hz, 1H), 1.46 (d, J=3.6Hz, 1H), 1.35 (s, 9H), 0.88 (s, 9H). 13C NMR (101MHz, Chloroform-d) δ: 173.91, 162.55 (d, J=245.6Hz), 137.41 (d, J=3.2Hz), 12 9.22 (d, J=7.9Hz), 115.34 (d, J=21.3Hz), 80.60, 48.57, 47.27, 31.13, 29.58, 27.91ppm.

[0041] Example 3

[0042] In a glove box filled with nitrogen, [1,2-bis(diphenylphosphinoethane)cobalt dichloride (0.02mmol, 0.0106g) and tri(2,4,6-trimethoxyphenyl)phosphine (0.02mmol, 0.0106g) were added to a dry microwave tube equipped with a magnet, followed by 0.5mL tetrahydrofuran and 0.5mL ethylene glycol dimethyl ether. The color of the solution was dark green. Stir and coordinate for about 15min, add tert-butyl acrylate (0.1mmol, 14μL, 1.0 equivalent) and tert-butyl iodide (0.4mmol, 46μL, 4.0 equivalent) to the microwave tube, then seal and remove from the glove box. Next, slowly add 0.2mL 4-chlorophenylmagnesium bromide solution (0.2mmol, 2.0 equivalent, dissolved in THF to make a 1mol / L solution) using a 1mL syringe at 0℃. At this time, the color of the solution changes from dark green to brown-black. Seal the microwave tube with a sealing film and continue to stir the reaction at 0°C for 10 hours. After the reaction is completed, take out the microwave tube, return to room temperature and open it in the air. Then pass the reaction mixture through a short chromatographic column containing a small amount of silica gel and wash it three times with 6mL of dichloromethane (3×2mL). Then remove the solvent by vacuum rotary evaporation, load the obtained crude product onto a silica gel column, and elute it with an eluent of petroleum ether: ethyl acetate = 80:1 to obtain a white solid (20.2mg, 68% yield). The hydrogen spectrum and carbon spectrum nuclear magnetic resonance spectra of the product are respectively Figure 3A and Figure 3B , the spectrum data is: 1 HNMR (400MHz, Chloroform-d) δ: 7.24 (dd, J=8.2, 4.3Hz, 4H), 3.48 (dd, J=9.2, 3.6Hz, 1H ), 2.21 (dd, J=14.0, 9.2Hz, 1H), 1.44 (dd, J=14.0, 3.7Hz, 1H), 1.35 (s, 9H), 0.88 (s, 9H). 13CNMR (101MHz, Chloroform-d) δ: 173.65, 140.19, 132.60, 129.14, 128.69, 80.73, 48.75, 47.17, 31.15, 29.58, 27.90ppm.

[0043] Example 4

[0044] In a glove box filled with nitrogen, [1,2-bis(diphenylphosphinoethane)cobalt dichloride (0.02mmol, 0.0106g) and tri(2,4,6-trimethoxyphenyl)phosphine (0.02mmol, 0.0106g) were added to a dry microwave tube equipped with a magnet, followed by 0.5mL tetrahydrofuran and 0.5mL ethylene glycol dimethyl ether. The color of the solution was dark green. Stir and coordinate for about 15min, add tert-butyl acrylate (0.1mmol, 14μL, 1.0 equivalent) and tert-butyl iodide (0.4mmol, 46μL, 4.0 equivalent) to the microwave tube, then seal and remove from the glove box. Next, slowly add 0.2mL 4-methylphenylmagnesium bromide solution (0.2mmol, 2.0 equivalent, dissolved in THF to make a 1mol / L solution) using a 1mL syringe at 0℃. At this time, the color of the solution changes from dark green to brown-black. Seal the microwave tube with a sealing film and continue to stir the reaction at 0°C for 10 hours. After the reaction is completed, take out the microwave tube, return to room temperature and open it in the air. Then pass the reaction mixture through a short chromatographic column containing a small amount of silica gel and wash it three times with 6mL of dichloromethane (3×2mL). Then remove the solvent by vacuum rotary evaporation, load the obtained crude product onto a silica gel column, and elute it with an eluent of petroleum ether: ethyl acetate = 80:1 to obtain a white solid (18.2mg, 66% yield). The hydrogen spectrum and carbon spectrum nuclear magnetic resonance spectra of the product are respectively Figure 4A and Figure 4B , the spectrum data is: 1 H NMR (401MHz, Chloroform-d) δ: 7.17 (d, J=8.1Hz, 2H), 7.08 (d, J=8.1Hz, 2H), 3.48 (dd, J=9.4, 3.3H z, 1H), 2.30 (s, 3H), 2.24 (dd, J=14.0, 9.5Hz, 1H), 1.47 (d, J=3.3Hz, 1H), 1.36 (s, 9H), 0.89 (s, 9H). 13 C NMR (101MHz, Chloroform-d) δ: 174.22, 136.30, 129.25, 129.08, 128.47, 127.58, 80.33, 48.88, 47.39, 31.13, 29.59, 27.94, 21.13ppm.

[0045] Example 5

[0046] In a glove box filled with nitrogen, [1,2-bis(diphenylphosphinoethane)cobalt dichloride (0.02mmol, 0.0106g) and tri(2,4,6-trimethoxyphenyl)phosphine (0.02mmol, 0.0106g) were added to a dry microwave tube equipped with a magnet, followed by 0.5mL tetrahydrofuran and 0.5mL ethylene glycol dimethyl ether. The color of the solution was dark green. Stir and coordinate for about 15min, add tert-butyl acrylate (0.1mmol, 14μL, 1.0 equivalent) and tert-butyl iodide (0.4mmol, 46μL, 4.0 equivalent) to the microwave tube, then seal and remove from the glove box. Next, slowly add 0.4mL 3-methylphenylmagnesium bromide solution (0.2mmol, 2.0 equivalent, dissolved in THF to make a 0.5mol / L solution) using a 1mL syringe at 0℃. At this time, the color of the solution changes from dark green to brown-black. Seal the microwave tube with a sealing film and continue to stir the reaction at 0°C for 10 hours. After the reaction is completed, take out the microwave tube, return to room temperature and open it in the air. Then pass the reaction mixture through a short chromatographic column containing a small amount of silica gel and wash it three times with 6mL of dichloromethane (3×2mL). Then remove the solvent by vacuum rotary evaporation, load the obtained crude product onto a silica gel column, and elute it with an eluent of petroleum ether: ethyl acetate = 80:1 to obtain a white solid (15.8mg, 57% yield). The hydrogen spectrum and carbon spectrum nuclear magnetic resonance spectra of the product are respectively Figure 5A and Figure 5B , the spectrum data is: 1 H NMR (400MHz, Chloroform-d) δ: 7.21-7.13 (m, 1H), 7.09 (d, J=7.2Hz, 2H), 7.02 (d, J=7.1Hz, 1H), 3.48 (dd, J=9. 6, 3.1Hz, 1H), 2.32 (s, 3H), 2.26 (dd, J=14.0, 9.7Hz, 1H), 1.47 (d, J=3.1Hz, 1H), 1.37 (s, 9H), 0.90 (s, 9H).13C NMR (101MHz, Chloroform-d) δ: 174.12, 141.70, 138.13, 128.45, 128.41, 127.51, 124.72, 80.38, 49.21, 47.41, 31.16, 29.58, 27.95, 21.56ppm.

[0047] Example 6

[0048] In a glove box filled with nitrogen, [1,2-bis(diphenylphosphinoethane)cobalt dichloride (0.02mmol, 0.0106g) and tri(2,4,6-trimethoxyphenyl)phosphine (0.02mmol, 0.0106g) were added to a dry microwave tube equipped with a magnet, followed by 0.5mL tetrahydrofuran and 0.5mL ethylene glycol dimethyl ether. The color of the solution was dark green. Stir and coordinate for about 15min, add tert-butyl acrylate (0.1mmol, 14μL, 1.0 equivalent) and tert-butyl iodide (0.4mmol, 46μL, 4.0 equivalent) to the microwave tube, then seal and remove from the glove box. Next, slowly add 0.4mL 4-tert-butylphenylmagnesium bromide solution (0.2mmol, 2.0 equivalent, dissolved in THF to make a 0.5mol / L solution) using a 1mL syringe at 0℃. At this time, the color of the solution changes from dark green to brown-black. Seal the microwave tube with a sealing film and continue to stir the reaction at 0°C for 10 hours. After the reaction is completed, take out the microwave tube, return to room temperature and open it in the air. Then pass the reaction mixture through a short chromatographic column containing a small amount of silica gel and wash it three times with 6mL of dichloromethane (3×2mL). Then remove the solvent by vacuum rotary evaporation, load the obtained crude product onto a silica gel column, and elute it with an eluent of petroleum ether: ethyl acetate = 50:1 to obtain a white solid (19.6mg, 61% yield). The hydrogen and carbon nuclear magnetic resonance spectra of the product are respectively Fig. 6A and Figure 6B , the spectrum data is: 1 H NMR (401MHz, Chloroform-d) δ7.31-7.27 (m, 2H), 7.23-7.18 (m, 2H), 3.50 (dd, J=9.9, 2.8Hz, 1H ), 2.26 (dd, J=14.0, 9.9Hz, 1H), 1.47 (d, J=2.8Hz, 1H), 1.38 (s, 9H), 1.29 (s, 9H), 0.91 (s, 9H). 13 C NMR (101MHz, Chloroform-d) δ174.24, 138.68, 127.23, 125.44, 80.34, 48.76, 34.47, 31.46, 31.14, 29.57, 27.98ppm.

[0049] Example 7

[0050] In a glove box filled with nitrogen, [1,2-bis(diphenylphosphinoethane)cobalt dichloride (0.02mmol, 0.0106g) and tri(2,4,6-trimethoxyphenyl)phosphine (0.02mmol, 0.0106g) were added to a dry microwave tube equipped with a magnet, followed by 0.5mL tetrahydrofuran and 0.5mL ethylene glycol dimethyl ether. The color of the solution was dark green. Stir and coordinate for about 15min, add tert-butyl acrylate (0.1mmol, 14μL, 1.0 equivalent) and tert-butyl iodide (0.4mmol, 46μL, 4.0 equivalent) to the microwave tube, then seal and remove from the glove box. Next, slowly add 0.4mL 4-trifluoromethylphenylmagnesium bromide solution (0.2mmol, 2.0 equivalent, dissolved in THF to make a 0.5mol / L solution) using a 1mL syringe at 0℃. At this time, the color of the solution changes from dark green to brown-black. Seal the microwave tube with a sealing film and continue to stir the reaction at 0°C for 10 hours. After the reaction is completed, take out the microwave tube, return to room temperature and open it in the air. Then pass the reaction mixture through a short chromatographic column containing a small amount of silica gel and wash it three times with 6mL of dichloromethane (3×2mL). Then remove the solvent by vacuum rotary evaporation, load the obtained crude product onto a silica gel column, and elute it with an eluent of petroleum ether: ethyl acetate = 80:1 to obtain a white solid (23.1mg, 70% yield). The hydrogen spectrum and carbon spectrum nuclear magnetic resonance spectra of the product are respectively Fig. 7A and Figure 7B , the spectrum data is: 1 H NMR (401MHz, Chloroform-d) δ: 7.54 (d, J=8.2Hz, 2H), 7.40 (d, J=7.6Hz, 2H), 3.57 (dd, J=9.2 , 3.4Hz, 1H), 2.26 (dd, J=14.0, 9.3Hz, 1H), 1.48 (d, J=3.5Hz, 1H), 1.36 (s, 9H), 0.90 (s, 9H). 13 C NMR (101MHz, Chloroform-d) δ: 173.29, 145.67, 130.86, 129.08, 128.47, 128.12, 125.59, 125.52, 81.00, 47.23, 31.22, 29.55, 27.89ppm.

[0051] Example 8

[0052] In a glove box filled with nitrogen, [1,2-bis(diphenylphosphinoethane)cobalt dichloride (0.02mmol, 0.0106g) and tri(2,4,6-trimethoxyphenyl)phosphine (0.02mmol, 0.0106g) were added to a dry microwave tube equipped with a magnet, followed by 0.5mL tetrahydrofuran and 0.5mL ethylene glycol dimethyl ether. The color of the solution was dark green. Stir and coordinate for about 15min, add tert-butyl acrylate (0.1mmol, 14μL, 1.0 equivalent) and tert-butyl iodide (0.4mmol, 46μL, 4.0 equivalent) to the microwave tube, then seal and remove from the glove box. Next, slowly add 0.4mL 4-biphenyl magnesium bromide solution (0.2mmol, 2.0 equivalent, dissolved in THF to make a 0.5mol / L solution) using a 1mL syringe at 0℃. At this time, the color of the solution changes from dark green to brown-black. Seal the microwave tube with a sealing film and continue to stir the reaction at 0°C for 10 hours. After the reaction is completed, take out the microwave tube, return to room temperature and open it in the air. Then pass the reaction mixture through a short chromatographic column containing a small amount of silica gel and wash it three times with 6mL of dichloromethane (3×2mL). Then remove the solvent by vacuum rotary evaporation, load the obtained crude product onto a silica gel column, and elute it with an eluent of petroleum ether: ethyl acetate = 80:1 to obtain a white solid (23.0mg, 68% yield). The hydrogen spectrum and carbon spectrum nuclear magnetic resonance spectra of the product are respectively Fig. 8A and Figure 8B , the spectrum data is: 1 H NMR (401MHz, Chloroform-d) δ: 7.58 (d, J=8.2Hz, 2H), 7.53 (d, J=8.1Hz, 2H), 7.42 (t, J=7.6Hz, 3H), 7.37 (d, J=8.1Hz, 2H), 7.32 (t , J=7.4Hz, 1H), 3.58 (dd, J=9.4, 3.2Hz, 1H), 2.31 (dd, J=14.0, 9.5Hz, 1H), 1.53 (dd, J=14.0, 3.1Hz, 1H), 1.39 (s, 9H), 0.93 (s, 9H). 13 CNMR (101MHz, Chloroform-d) δ: 174.01, 140.93, 140.85, 139.64, 128.84, 128.15, 127.28, 127.11, 80.56, 49.02, 47.38, 31.21, 29.62, 27.98ppm.

[0053] Example 9

[0054] In a glove box filled with nitrogen, add [1,2.bis(diphenylphosphine)ethane]cobalt dichloride (0.02mmol, 0.0106g) and tri(2,4,6-trimethoxyphenyl)phosphine (0.02mmol, 0.0106g) to a dry microwave tube equipped with a magnet, then add 0.5mL tetrahydrofuran and 0.5mL ethylene glycol dimethyl ether, and the color of the solution is dark green. Stir and coordinate for about 15 minutes, add tert-butyl acrylate (0.1mmol, 14μL, 1.0 equivalent) and tert-butyl iodide (0.4mmol, 46μL, 4.0 equivalent) to the microwave tube, then seal it with a lid and take it out of the glove box. Next, 0.4 mL of 5-magnesium bromide-2H benzofuran solution (0.2 mmol, 2.0 equivalents, dissolved in THF to make a 0.5 mol / L solution) was slowly added dropwise using a 1 mL syringe at 0 °C. At this time, the color of the solution changed from dark green to brown-black. The microwave tube was sealed with a sealing film and the reaction was continued to stir at 0 °C for 10 h. After the reaction was completed, the microwave tube was taken out, returned to room temperature and opened in the air. The reaction mixture was then passed through a short chromatographic column containing a small amount of silica gel and washed three times with 6 mL of dichloromethane (3×2 mL). The solvent was then removed by vacuum rotary evaporation, and the crude product was loaded onto a silica gel column and eluted with an eluent of petroleum ether: ethyl acetate = 20:1 to obtain a white solid (16.4 mg, 54% yield). The hydrogen and carbon nuclear magnetic resonance spectra of the product are respectively Fig. 9A and Fig. 9B , the spectrum data is 1 H NMR (401MHz, Chloroform-d) δ: 7.13 (t, J=1.5Hz, 1H), 7.07-6.96 (m, 1H), 6.75-6.58 (m, 1H), 4.53 (t, J=8.8Hz, 2H), 3.50-3.40 ( m, 1H), 3.17 (t, J=8.8Hz, 2H), 2.22 (dd, J=13.9, 9.5, 1.1Hz, 1H), 1.41 (dd, J=3.6, 2.4Hz, 1H), 1.39-1.34 (s, 9H), 0.89 (s,,9H). 13 CNMR (101MHz, Chloroform-d) δ: 174.49, 158.96, 127.40, 127.21, 124.14, 109.07, 80.29, 71.35, 48.61, 47.59, 31.12, 29.61, 27.98ppm.

[0055] Example 10

[0056] In a glove box filled with nitrogen, add [1,2-bis(diphenylphosphinoethane)cobalt dichloride (0.02mmol, 0.0106g) and tri(2,4,6-trimethoxyphenyl)phosphine (0.02mmol, 0.0106g) to a dry microwave tube equipped with a magnet, then add 0.5mL tetrahydrofuran and 0.5mL ethylene glycol dimethyl ether, and the color of the solution is dark green. Stir and coordinate for about 15 minutes, add tert-butyl acrylate (0.1mmol, 14μL, 1.0 equivalents) and tert-butyl iodide (0.4mmol, 46μL, 4.0 equivalents) to the microwave tube, then seal it with a lid and take it out of the glove box. Next, 0.4 mL of 4-N,N-dimethylphenylmagnesium bromide solution (0.2 mmol, 2.0 equivalents, dissolved in THF to make a 0.5 mol / L solution) was slowly added dropwise using a 1 mL syringe at 0 °C. At this time, the color of the solution changed from dark green to brown-black. The microwave tube was sealed with a sealing film and the reaction was continued to stir at 0 °C for 10 h. After the reaction was completed, the microwave tube was taken out, returned to room temperature and opened in the air. The reaction mixture was then passed through a short chromatographic column containing a small amount of silica gel and washed three times with 6 mL of dichloromethane (3×2 mL). The solvent was then removed by vacuum rotary evaporation, and the crude product was loaded onto a silica gel column and eluted with an eluent of petroleum ether: ethyl acetate = 80:1 to obtain a white solid (16.2 mg, 53% yield). The hydrogen and carbon nuclear magnetic resonance spectra of the product are respectively Fig. 10A and Fig. 10B , the spectrum data is: 1 H NMR (401MHz, Chloroform-d) δ: 7.16 (d, J=8.6Hz, 2H), 6.67 (d, J=8.6Hz, 2H), 3.42 (dd, J=9.5, 3.3Hz, 1 H), 2.91 (s, 6H), 2.22 (dd, J=13.9, 9.6Hz, 1H), 1.44 (dd, J=14.0, 3.3Hz, 1H), 1.36 (s, 9H), 0.89 (s, 9H). 13 C NMR (101MHz, Chloroform-d) δ: 174.62, 149.47, 129.08, 128.33, 112.94, 80.12, 48.23, 47.40, 40.88, 31.08, 27.99ppm.

[0057] Embodiment 11

[0058] In a glove box filled with nitrogen, [1,2-bis(diphenylphosphinoethane)cobalt dichloride (0.02mmol, 0.0106g) and tri(2,4,6-trimethoxyphenyl)phosphine (0.02mmol, 0.0106g) were added to a dry microwave tube equipped with a magnet, followed by 0.5mL tetrahydrofuran and 0.5mL ethylene glycol dimethyl ether. The color of the solution was dark green. Stir and coordinate for about 15min, add tert-butyl acrylate (0.1mmol, 14μL, 1.0 equivalent) and tert-butyl iodide (0.4mmol, 46μL, 4.0 equivalent) to the microwave tube, then seal and remove from the glove box. Next, slowly add 0.4mL 2-naphthylmagnesium bromide solution (0.2mmol, 2.0 equivalent, dissolved in THF to make a 0.5mol / L solution) using a 1mL syringe at 0℃. At this time, the color of the solution changes from dark green to brown-black. Seal the microwave tube with a sealing film and continue to stir the reaction at 0°C for 10 hours. After the reaction is completed, take out the microwave tube, return to room temperature and open it in the air. Then pass the reaction mixture through a short chromatographic column containing a small amount of silica gel and wash it three times with 6mL of dichloromethane (3×2mL). Then remove the solvent by vacuum rotary evaporation, load the obtained crude product onto a silica gel column, and elute it with an eluent of petroleum ether: ethyl acetate = 20:1 to obtain a white solid (13.1mg, 42% yield). The hydrogen spectrum and carbon spectrum nuclear magnetic resonance spectra of the product are respectively Fig.11A and Fig. 11B , the spectrum data is: 1 H NMR (401MHz, Chloroform-d) δ: 7.84-7.75 (m, 3H), 7.72 (s, 1H), 7.44 (dtd, J=6.9, 4.3, 1.8Hz, 3H), 3.69 (dd, J=9.2, 3.3Hz, 1H), 2.35 (dd, J=14.0, 9.3Hz, 1H), 1.60 (d, J=3.3Hz, 1H), 1.36 (s, 9H), 0.93 (s, 9H). 13 C NMR (101MHz, Chloroform-d) δ: 173.96, 139.24, 133.58, 132.49, 128.20, 127.89, 127 .67, 126.27, 126.22, 126.06, 125.66, 80.57, 49.47, 47.30, 31.23, 29.63, 27.95ppm.

[0059] Example 12

[0060] In a glove box filled with nitrogen, [1,2.bis(diphenylphosphine)ethane]cobalt dichloride (0.02mmol, 0.0106g) and tri(2,4,6-trimethoxyphenyl)phosphine (0.02mmol, 0.0106g) were added to a dry microwave tube equipped with a magnet, followed by 0.5mL tetrahydrofuran and 0.5mL ethylene glycol dimethyl ether. The color of the solution was dark green. Stir and coordinate for about 15 minutes, add tert-butyl acrylate (0.1mmol, 14μL, 1.0 equivalent) and tert-butyl iodide (0.4mmol, 46μL, 4.0 equivalent) to the microwave tube, then seal and remove from the glove box. Next, slowly add 0.4mL 5-magnesium bromide benzothiophene solution (0.2mmol, 2.0 equivalent, dissolved in THF to make a 0.5mol / L solution) using a 1mL syringe at 0°C. At this time, the color of the solution changes from dark green to brown-black. Seal the microwave tube with a sealing film and continue to stir the reaction at 0°C for 10 hours. After the reaction is completed, take out the microwave tube, return to room temperature and open it in the air. Then pass the reaction mixture through a short chromatographic column containing a small amount of silica gel and wash it three times with 6mL of dichloromethane (3×2mL). Then remove the solvent by vacuum rotary evaporation, load the obtained crude product onto a silica gel column, and elute it with an eluent of petroleum ether: ethyl acetate = 20:1 to obtain a white solid (16.6mg, 52% yield). The hydrogen and carbon nuclear magnetic resonance spectra of the product are respectively Fig. 12A and Fig. 12B , the spectrum data is 1 H NMR (400MHz, Chloroform-d) δ: 7.81-7.73 (m, 2H), 7.41 (d, J=5.4Hz, 1H), 7.34-7.27 (m, 2H), 3.64 (dd, J =9.3, 3.4Hz, 1H), 2.33 (dd, J = 14.0, 9.3Hz, 1H), 1.54 (dd, J = 14.0, 3.4Hz, 1H), 1.36 (s, 9H), 0.92 (s, 9H). 13 C NMR (101MHz, Chloroform-d) δ: 174.15, 139.98, 138.24, 138.05, 126.73, 124.44, 123.96, 123.81, 122.52, 80.50, 49.20, 47.66, 31.21, 29.62, 27.96ppm.

[0061] Embodiment 13

[0062] The tris(2,4,6-trimethoxy)triphenylphosphine in Example 1 was replaced with trifuranylphosphine, and the conditions such as the raw materials and amounts in other steps remained unchanged, and finally the product (5.42 mg, 20.7% yield) was obtained.

[0063] Embodiment 14

[0064] The tris(2,4,6-trimethoxy)triphenylphosphine in Example 1 was replaced with 1,2-bis(dicyclohexylphosphine)-ethane, and the raw materials and dosages in other steps remained unchanged, and the product (14.46 mg, 55.2% yield) was finally obtained.

Claims

1. A method for synthesizing α-aryl propionate, characterized in that: The α-aryl propionate shown in Formula 4 is synthesized by using tert-butyl acrylate shown in Formula 1, tert-butyl iodide shown in Formula 2 and an aryl Grignard reagent shown in Formula 3 in the presence of a cobalt catalyst, adding a phosphine ligand, and mixing with an organic solvent for a reductive cross-coupling reaction; the cobalt catalyst is [1,2-bisdiphenylphosphine ethane] cobalt dichloride; the phosphine ligand is trifuranyl phosphine, tri(2,4,6-trimethoxyphenyl)phosphine, 1,2-bis(dicyclohexylphosphine)-ethane; Wherein R is selected from phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 3-methylphenyl, 4-tert-butylphenyl, 4-trifluoromethylphenyl, 4-biphenyl, benzodihydrofuran, 4-N,N-dimethylphenyl, 2-naphthyl, benzothiophene.

2. The synthesis method according to claim 1, characterized in that The reaction is carried out under the protection of an inert gas, wherein the inert gas is nitrogen.

3. The synthesis method according to claim 1, characterized in that The organic solvent is 2-methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, isopropyl ether and tetrahydrofuran.

4. The synthesis method according to claim 1, characterized in that In the reaction, the molar ratio of tert-butyl acrylate shown in formula 1, tert-butyl iodide shown in formula 2, aryl Grignard reagent shown in formula 3, phosphine ligand and cobalt catalyst is: 1:2-6:2:0.05-0.2:0.05-0.2; the reaction temperature is -20°C to 20°C.

5. The synthesis method according to claim 1, characterized in that The aryl Grignard reagent and the product α-aryl propionate are as shown in the following table:

Images