A method for the synthesis of 2-arylindoles

Abstract

2-Arylindoles unique heterocyclic structure and recorded biological activity makes it has great application value in medicinal chemistry and pharmaceutical industry. Indole drugs are known to have antioxidant, antitumor, antifungal and antibacterial properties. Because of its wide application, many selective and high economic benefit of synthesis method has been introduced. Such as phenylhydrazine method, aniline method, o-aminoethyl benzene method, o-chlorotoluene method, etc., but these methods have their own shortcomings, such as two-step reaction leading to low yield, synthesis needs catalyst not easy to get, need transition metal catalysis, reaction temperature is far below 0 DEG C, not easy to scale production, etc. The purpose of the present application is to provide a kind of solution to the above problems, simple, economic and more widely applicable or suitable for scale production of 2-arylindole compound synthesis method. Here, we report a general method for the synthesis of indole from simple 2-fluorobenzene acetonitrile compound and various aryl Grignard reagent, which does not involve transition metal and the reaction condition is mild.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and specifically relates to a method for synthesizing 2-arylindole. Background Technology

[0002] The unique heterocyclic structure and recorded biological activities of 2-arylindole make it highly valuable in medicinal chemistry and the pharmaceutical industry. Indole drugs are known to possess antioxidant, antitumor, antifungal, and antibacterial properties. Due to their wide application, many selective and cost-effective synthetic methods have been developed, such as the phenylhydrazine method, the aniline method, the o-aminoethylbenzene method, and the o-chlorotoluene method. However, these methods all have their own drawbacks, such as requiring two-step reactions leading to low yields, the need for readily available catalysts, the requirement of transition metal catalysis, and reaction temperatures far below 0°C. Therefore, developing a transition metal-free synthetic method for the large-scale production of 2-arylindole is of great significance.

[0003] The main synthetic methods for 2-arylindole compounds without the involvement of transition metals are as follows:

[0004] The first method uses 2-methylaniline as a starting material, yielding 2-arylindole compounds through a two-step reaction (ABSmith, III, M. Visnick, J. N. Haseltine, PA. Sprengerler, Tetrahedron 1986, 42, 2957-2969). This reaction requires two steps, with the second step requiring a temperature of -78°C, making the conditions harsh and limiting its application to large-scale production. Furthermore, the yield is only 62%.

[0005]

[0006] The second method involves adding an organolithium reagent to styrene, followed by condensation with a nitrile at -78°C to generate a carbanion, thereby obtaining a 2-arylindole compound (CMColeman, DFO'Shea, J. Am. Chem. Soc. 2003, 125, 4054-4055). This method requires challenging low temperatures and further hydrolysis to obtain 2-arylindole compounds, making it difficult to prepare on a large scale.

[0007] Summary of the Invention

[0008] The purpose of this invention is to provide a synthetic method for 2-arylindole compounds that solves the above problems, is simple to synthesize, has wider economic applicability, or is suitable for large-scale production. Here, we also report a general method for synthesizing indole from simple 2-fluorophenylacetonitrile compounds and various aryl Grignard reagents. This method involves no transition metals and uses mild reaction conditions. The specific scheme is as follows:

[0009]

[0010] A method for synthesizing 2-arylindole compounds is disclosed, comprising mixing a 2-fluorophenylacetonitrile compound of Formula 1 with an aryl Grignard reagent of Formula 2 and an organic solvent, and reacting to synthesize the 2-arylindole compound of Formula 3. R1 is selected from hydrogen, halogen, methyl, methoxy, or phenyl, and R2 is selected from phenyl, substituted phenyl, thiophene, benzofuran, or benzothiophene, wherein the substituent of the phenyl group is selected from methyl, tert-butyl, methoxy, trifluoromethyl, or halogen. This invention provides a one-pot synthesis of indole compounds, reducing reaction steps and thus increasing product yield. The raw materials used in the synthesis are simple and economical, and no transition metal catalyst is required, making it more economical and environmentally friendly. Furthermore, R1 and R2 in this invention can be selected from various options, broadening its applicability.

[0011] Preferably, R1 is selected from hydrogen, methoxy, phenyl, or halogen group; more preferably, R1 is selected from hydrogen, and R2 is selected from p-tert-butylphenyl, p-methoxyphenyl, benzofuranyl, or 2-naphthyl. More preferably, R1 is selected from hydrogen, and R2 is selected from phenyl or p-methylphenyl.

[0012] Preferably, the molar ratio of the 2-fluorophenylacetonitrile compound shown in Formula 1 to the aryl Grignard reagent shown in Formula 2 is 1:(2-4), and the reaction temperature is 90℃-130℃.

[0013] Preferably, the reaction temperature is 100℃~120℃.

[0014] Preferably, the reaction temperature is 110℃.

[0015] Preferably, the concentration of the aryl Grignard reagent is 1–3 mol / L.

[0016] More preferably, the concentration of the aryl Grignard reagent is 1 mol / L.

[0017] Preferably, the reaction is carried out under the protection of an inert gas, and preferably, the inert gas is nitrogen or argon.

[0018] Preferably, the synthesis takes place in the presence of an organic solvent.

[0019] Preferably, the organic solvent is tetrahydrofuran or toluene.

[0020] More preferably, the organic solvent is toluene.

[0021] Preferably, using the method of the present invention, 2-arylindole compounds with the following structures can be synthesized:

[0022]

[0023]

[0024] A pre-prepared aryl Grignard reagent attacks a nitrile to yield a metal imine intermediate. The resulting metal imine intermediate undergoes intramolecular S... N Ar (aromatic nucleophilic substitution reaction) cyclization and isomerization yield indole.

[0025] The technical solution of the present invention can achieve at least one of the following beneficial effects:

[0026] This invention provides a novel method for synthesizing substituted indole that does not use bases or transition metal catalysts, making it more economical and suitable for industrial application.

[0027] This invention employs a one-pot synthesis method, which reduces the loss of raw materials and increases the yield of the product due to fewer reaction steps.

[0028] The operation steps required by this invention are relatively simple, without the need for extreme heating or cooling, making it easier to operate and control;

[0029] In this invention, R1 and R2 can be chosen in various ways, thus making the method of this invention more widely applicable and capable of synthesizing a variety of 2-arylindole compounds, which has a significant impact on the synthesis of indole compounds.

[0030] Instruction manual illustrations

[0031] Figures 1 to 14 are the nuclear magnetic resonance spectra of the products of Examples 1 to 14, respectively.

[0032] In the spectrum of the product of each embodiment, A is the proton NMR spectrum of the product of the corresponding embodiment, and B is the carbon NMR spectrum of the product of the corresponding embodiment. Specific Implementation

[0033] To facilitate understanding by those skilled in the art, the concept of the present invention will be further explained below with reference to embodiments. All raw materials mentioned in the specification were purchased commercially or synthesized through simple methods. Other pharmaceuticals were purchased from Sigma-Aldrich, Acros, Alfa Aesar, TCI China, Adamas-beta, or J&K. The nuclear magnetic resonance spectrometer was a Bruker 400M.

[0034] Example 1

[0035] A dried microwave tube equipped with a magnetic stirrer was placed in a glove box under an argon atmosphere. 2-fluorophenylacetonitrile (27.0 mg, 0.2 mmol) and dried toluene (1.2 mL) were added. The microwave tube was sealed with a cap containing a rubber diaphragm and removed from the glove box. 0.6 mL of phenylmagnesium bromide (0.6 mmol, 1 M in THF) was added dropwise using a 1 mL syringe at room temperature, followed by stirring for 2 hours at room temperature. Next, the reaction was heated in an oil bath at 110 °C for 4 hours. The microwave tube was removed from the oil bath, cooled to room temperature, exposed to air, and then 3 drops of water were added. The reaction mixture was then washed and filtered through a short silica gel column with an additional 6 mL of ethyl acetate (3 × 2 mL). The filtered solution was concentrated under vacuum, and the concentrated crude product was loaded onto a silica gel column for purification and centrifugation using petroleum ether:ethyl acetate = 20:1 as the eluent to obtain 2-phenylindole (35.2 mg, 91% yield) as a light gray solid. The proton and carbon NMR spectra of the product are as follows: Figure 1A and Figure 1B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ: 8.30 (brs, 1H), 7.69-7.63 (m, 3H), 7.46 (m, 2H), 7.42-7.37 (m, 1H), 7.37-7.31(m, 1H), 7.27-7.20(m, 1H), 7.20-7.13(m, 1H), 6.90-6.81(m, 1H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 138.0, 136.9, 132.5, 129.4, 129.2, 127.9, 125.3, 122.5, 120.8, 120.4, 111.1, 100.1ppm.

[0036] By changing the two raw materials in Example 1, the following 14 sets of experimental examples were designed, where the first set of experiments is Example 1, and the corresponding NMR spectrum of the product is shown in Figure 1. The NMR spectra of the products in the remaining sets 2-14 correspond to the sequence numbers of the respective examples.

[0037] The table lists the structural formulas of R1, R2 and the corresponding products in each of the 1-14 embodiments. The last column lists the yield of the products in each embodiment and indicates the specific implementation conditions of each embodiment. The specific meaning of the implementation conditions of each embodiment is shown below the table.

[0038]

[0039]

[0040] The following are the products of each of the embodiments 2-14. 1 H and 13 The results of nuclear magnetic resonance (NMR) spectrum data of C, as well as melting point Mp, infrared (IR) spectrum, and high-resolution mass spectrometry (HRMS) data of some products.

[0041] Example 2

[0042] A dried microwave tube equipped with a magnetic stirrer was placed in a glove box under an argon atmosphere. 2,6-Difluorophenylacetonitrile (30.6 mg, 0.2 mmol) and dried toluene (1.2 mL) were added. The microwave tube was sealed with a cap containing a rubber diaphragm and removed from the glove box. 0.6 mL of phenylmagnesium bromide (0.6 mmol, 1 M in THF) was added dropwise using a 1 mL syringe at room temperature, followed by stirring for 2 hours at room temperature. Next, the reaction was heated in an oil bath at 110 °C for 4 hours. The microwave tube was removed from the oil bath, cooled to room temperature, exposed to air, and then 3 drops of water were added. The reaction mixture was then washed and filtered through a short silica gel column with an additional 6 mL of ethyl acetate (3 × 2 mL). The filtered solution was concentrated under vacuum, and the concentrated crude product was loaded onto a silica gel column for purification and centrifugation using petroleum ether:ethyl acetate = 20:1 as the eluent to obtain 4-fluoro-2-phenyl-1H-indole (36.3 mg, 86% yield) as a yellow solid. The proton and carbon NMR spectra of the product are as follows: Figure 2A and Figure 2B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ: 8.42 (brs, 1H), 7.68-7.65 (m, 2H), 7.49-7.44 (m, 2H), 7.38-7.34 (m, 1 H), 7.20-7.18 (m, 1H), 7.14-7.09 (m, 1H), 6.91 (dd, J=2.3, 0.9Hz, 1H), 6.84-6.79 (m, 1H)ppm. 13 C{ 1 H}NMR (101MHz, CDCl3) δ: 156.5 (d, J 1 C-F =247.9Hz), 139.4 (d, J) 4 C-F =11.2Hz), 138.0, 132.0, 129.3, 128.2, 125.4, 122.9 (d, J 5 C-F =7.7Hz), 118.6 (d, J) 2 C-F =22.5Hz), 107.1 (d, J)6 C-F =3.6Hz), 105.2 (d, J) 3 C-F =19.0Hz), 96.0ppm.

[0043] Example 3

[0044] A dried microwave tube equipped with a magnetic stirrer was placed in a glove box under an argon atmosphere. 2-fluoro-5-chlorophenylacetonitrile (33.8 mg, 0.2 mmol) and dried toluene (1.2 mL) were added. The microwave tube was sealed with a cap containing a rubber diaphragm and removed from the glove box. 0.6 mL of phenylmagnesium bromide (0.6 mmol, 1 M in THF) was added dropwise using a 1 mL syringe at room temperature, followed by stirring for 2 hours at room temperature. Next, the reaction was heated in an oil bath at 110 °C for 4 hours. The microwave tube was removed from the oil bath, cooled to room temperature, exposed to air, and then 3 drops of water were added. The reaction mixture was then washed and filtered through a short silica gel column with an additional 6 mL of ethyl acetate (3 × 2 mL). The filtered solution was concentrated under vacuum, and the concentrated crude product was loaded onto a silica gel column for purification and centrifugation using petroleum ether:ethyl acetate = 20:1 as the eluent to obtain 5-chloro-2-phenyl-1H-indole (36.0 mg, 79% yield) as a yellow solid. The proton and carbon NMR spectra of the product are as follows: Figure 3A and Figure 3B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ: 8.37 (brs, 1H), 7.66-7.63 (m, 2H), 7.59 (d, J=2.0Hz, 1H), 7.48-7.44(m, 2H), 7.37-7.30(m, 2H), 7.16-7.13(m, 1H), 6.77-6.76(m, 1H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 139.4, 135.2, 132.0, 130.5, 129.2, 128.3, 126.0, 125.4, 122.7, 120.1, 112.0, 99.7ppm.

[0045] Example 4

[0046] A dried microwave tube equipped with a magnetic stirrer was placed in a glove box under an argon atmosphere. 2-Fluoro-6-methylphenylacetonitrile (29.8 mg, 0.2 mmol) and dried toluene (1.2 mL) were added. The microwave tube was sealed with a cap containing a rubber diaphragm and removed from the glove box. 0.6 mL of phenylmagnesium bromide (0.6 mmol, 1 M in THF) was added dropwise using a 1 mL syringe at room temperature, followed by stirring for 2 hours at room temperature. Next, the reaction was heated in an oil bath at 110 °C for 4 hours. The microwave tube was removed from the oil bath, cooled to room temperature, exposed to air, and then 3 drops of water were added. The reaction mixture was then washed and filtered through a short silica gel column with an additional 6 mL of ethyl acetate (3 × 2 mL). The filtered solution was concentrated under vacuum, and the concentrated crude product was loaded onto a silica gel column for purification and centrifugation using petroleum ether:ethyl acetate = 20:1 as the eluent to obtain 4-methyl-2-phenyl-1H-indole (25.7 mg, 62% yield) as a deep yellow solid. The proton and carbon NMR spectra of the product are as follows: Figure 4A and Figure 4B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ: 8.35 (brs, 1H), 7.70-7.67 (m, 2H), 7.50-7.41 (m, 2H), 7.36-7.31 (m, 1H), 7.27-7.24 (m, 1H), 7.12 (t, J=7.6Hz, 1H), 6.97-6.90 (m, 1H), 6.89-6.84 (m, 1H), 2.60 (s, 3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 137.4, 136.6, 132.6, 130.4, 129.3, 129.2, 127.7, 125.2, 122.6, 120.5, 108.6, 98.7, 18.9ppm.

[0047] Example 5

[0048] A dried microwave tube equipped with a magnetic stirrer was placed in a glove box under an argon atmosphere. 2-fluoro-5-methoxyphenylacetonitrile (33.0 mg, 0.2 mmol) and dried toluene (1.2 mL) were added. The microwave tube was sealed with a cap containing a rubber diaphragm, removed from the glove box, and 0.6 mL of phenylmagnesium bromide (0.6 mmol, 1 min THF) was added dropwise using a 1 mL syringe at room temperature. The reaction mixture was then stirred at room temperature for 2 hours. Next, the reaction was heated in an oil bath at 110 °C for 4 hours. The microwave tube was removed from the oil bath, cooled to room temperature, exposed to air, and 3 drops of water were added. The reaction mixture was then washed and filtered through a short silica gel column with an additional 6 mL of ethyl acetate (3 × 2 mL). The filtered solution was concentrated under vacuum, and the concentrated crude product was loaded onto a silica gel column for purification and centrifugation using petroleum ether:ethyl acetate = 20:1 as the eluent to obtain 5-methoxy-2-phenyl-1H-indole (36.6 mg, 82% yield) as a yellow solid. The proton and carbon NMR spectra of the product are as follows: Figure 5A and Figure 5B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ: 8.24 (brs, 1H), 7.65-7.58 (m, 2H), 7.45-7.38 (m, 2H), 7.33-7.23 (m, 2H), 7.08 (d, J=2.5Hz, 1H), 6.85 (dd, J=8.8, 2.5Hz, 1H), 6.78-6.71 (m, 1H), 3.85 (s, 3H)ppm. 13 C{ 1 H} NMR (101 MHz, CDCl3) δ: 154.6, 138.7, 132.5, 132.1, 129.8, 129.1, 127.8, 125.2, 112.7, 111.8, 102.4, 99.9, 56.0ppm.

[0049] Example 6

[0050] A dried microwave tube equipped with a magnetic stirrer was placed in a glove box under an argon atmosphere. 2-fluoro-4-phenylacetonitrile (42.2 mg, 0.2 mmol) and dried toluene (1.2 mL) were added. The microwave tube was sealed with a cap containing a rubber diaphragm and removed from the glove box. 0.6 mL of phenylmagnesium bromide (0.6 mmol, 1 min THF) was added dropwise using a 1 mL syringe at room temperature, followed by stirring for 2 hours at room temperature. Next, the reaction was heated in an oil bath at 110 °C for 4 hours. The microwave tube was removed from the oil bath, cooled to room temperature, exposed to air, and then 3 drops of water were added. The reaction mixture was then washed and filtered through a short silica gel column with an additional 6 mL of ethyl acetate (3 × 2 mL). The filtered solution was concentrated under vacuum, and the concentrated crude product was loaded onto a silica gel column for purification and centrifugation using petroleum ether:ethyl acetate = 20:1 as the eluent to obtain 2,4-diphenyl-1H-indole (41.5 mg, 77% yield) as a white solid. The proton and carbon NMR spectra of the product are as follows: Figure 6A and Figure 6B The spectral data is as follows: 1 H NMR (400MHz, DMSO-d6) δ: 11.66 (brs, 1H), 7.94-7.86 (m, 2H), 7.71-7.60 (m, 4H), 7.50-7.44 (m, 4H), 7.37-7.30 (m, 3H), 6.98-6.91 (m, 1H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 141.6, 138.5, 137.8, 134.0, 132.1, 129.0, 128.9, 128.2, 127.5, 126.7, 126.6, 125.0, 120.5, 118.9, 109.2, 98.7ppm.

[0051] Example 7

[0052] A dried microwave tube equipped with a magnetic stirrer was placed in a glove box under an argon atmosphere. 2-fluorophenylacetonitrile (27.0 mg, 0.2 mmol) and dried toluene (1.2 mL) were added. The microwave tube was sealed with a cap containing a rubber diaphragm, removed from the glove box, and 0.6 mL of p-methylphenyl magnesium bromide (0.6 mmol, 1 M inTHF) was added dropwise using a 1 mL syringe at room temperature. The reaction mixture was then stirred at room temperature for 2 hours. Next, the reaction was heated in an oil bath at 110 °C for 4 hours. The microwave tube was removed from the oil bath, cooled to room temperature, exposed to air, and 3 drops of water were added. The reaction mixture was then washed and filtered through a short silica gel column with an additional 6 mL of ethyl acetate (3 × 2 mL). The filtered solution was concentrated under vacuum, and the concentrated crude product was loaded onto a silica gel column for purification and centrifugation using petroleum ether:ethyl acetate = 20:1 as the eluent to obtain 2-(p-tolyl)-1H-indole (37.7 mg, 91% yield) as a yellow solid. The proton and carbon NMR spectra of the product are as follows: Figure 7A and Figure 7B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ: 8.26 (brs, 1H), 7.61 (d, J=7.8Hz, 1H), 7.57-7.46 (m, 2H) , 7.36 (d, J=8.0Hz, 1H), 7.26-7.08 (m, 4H), 6.86-6.68 (m, 1H), 2.38 (s, 3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 138.2, 137.8, 136.8, 129.8, 129.7, 129.4, 125.2, 122.2, 120.6, 120.3, 110.9, 99.5, 21.4ppm.

[0053] Example 8

[0054] A dried microwave tube equipped with a magnetic stirrer was placed in a glove box under an argon atmosphere. 2-fluorophenylacetonitrile (27.0 mg, 0.2 mmol) and dried toluene (1.2 mL) were added. The microwave tube was sealed with a cap containing a rubber diaphragm, removed from the glove box, and 0.6 mL of p-tert-butylphenyl magnesium bromide (0.6 mmol, 1 M inTHF) was added dropwise using a 1 mL syringe at room temperature. The reaction mixture was then stirred at room temperature for 2 hours. Next, the reaction was heated in an oil bath at 110 °C for 4 hours. The microwave tube was removed from the oil bath, cooled to room temperature, exposed to air, and then 3 drops of water were added. The reaction mixture was then washed and filtered through a short silica gel column with an additional 6 mL of ethyl acetate (3 × 2 mL). The filtered solution was concentrated under vacuum, and the concentrated crude product was loaded onto a silica gel column for purification. The developing solvent was petroleum ether:ethyl acetate = 20:1, yielding 2-(4-(tert-butyl)phenyl)-1H indole (38.9 mg, 78% yield), a yellow solid. The proton NMR and carbon NMR spectra of the product are as follows: Figure 8A and Figure 8B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ: 8.32 (brs, 1H), 7.66-7.60 (m, 3H), 7.50-7.47 (m, 2H) , 7.42-7.40(m, 1H), 7.23-7.13(m, 2H), 6.83-6.82(m, 1H), 1.39(s, 9H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 150.9, 138.0, 136.8, 129.6, 129.4, 126.0, 124.9, 122.2, 120.6, 120.2, 110.9, 99.5, 34.7, 31.3ppm.

[0055] Example 9

[0056] A dried microwave tube equipped with a magnetic stirrer was placed in a glove box under an argon atmosphere. 2-fluorophenylacetonitrile (27.0 mg, 0.2 mmol) and dried toluene (1.2 mL) were added. The microwave tube was sealed with a cap containing a rubber diaphragm, removed from the glove box, and 0.6 mL of p-methoxyphenyl magnesium bromide (0.6 mmol, 1 M inTHF) was added dropwise using a 1 mL syringe at room temperature. The reaction mixture was then stirred at room temperature for 2 hours. Next, the reaction was heated in an oil bath at 110 °C for 4 hours. The microwave tube was removed from the oil bath, cooled to room temperature, exposed to air, and 3 drops of water were added. The reaction mixture was then washed and filtered through a short silica gel column with an additional 6 mL of ethyl acetate (3 × 2 mL). The filtered solution was concentrated under vacuum, and the concentrated crude product was loaded onto a silica gel column for purification and centrifugation using petroleum ether:ethyl acetate = 20:1 as the eluent to obtain 2-(4-methoxyphenyl)-1H-indole (39.3 mg, 88% yield) as a pale yellow solid. The proton and carbon NMR spectra of the product are as follows: Figure 9A and Figure 9B The spectral data is as follows: 1 H NMR (400MHz, DMSO-d6) δ: 11.41 (brs, 1H), 7.85-7.73 (m, 2H), 7.49 (d, J=7.8Hz, 1H), 7.43-7.31(m, 1H), 7.11-6.93(m, 4H), 6.80-6.71(m, 1H), 3.80(s, 3H)ppm. 13 C{ 1 H} NMR (101MHz, DMSO-d6) δ: 158.8, 137.8, 137.0, 128.9, 126.4, 125.0, 121.1, 119.7, 119.3, 114.4, 111.1, 97.4, 55.2ppm.

[0057] Example 10

[0058] A dried microwave tube equipped with a magnetic stirrer was placed in a glove box under an argon atmosphere. 2-fluorophenylacetonitrile (27.0 mg, 0.2 mmol) and dried toluene (1.2 mL) were added. The microwave tube was sealed with a cap containing a rubber diaphragm, removed from the glove box, and 0.6 mL of p-trifluoromethylphenyl magnesium bromide (0.6 mmol, 1 M inTHF) was added dropwise using a 1 mL syringe at room temperature. The reaction mixture was then stirred at room temperature for 2 hours. Next, the reaction was heated in an oil bath at 110 °C for 4 hours. The microwave tube was removed from the oil bath, cooled to room temperature, exposed to air, and 3 drops of water were added. The reaction mixture was then washed and filtered through a short silica gel column with an additional 6 mL of ethyl acetate (3 × 2 mL). The filtered solution was concentrated under vacuum, and the concentrated crude product was loaded onto a silica gel column for purification and centrifugation using petroleum ether:ethyl acetate = 20:1 as the eluent to obtain 2-(4-trifluoromethylphenyl)-1H-indole (37.1 mg, 71% yield) as a pale yellow solid. The proton and carbon NMR spectra of the product are as follows: Figure 10A and Figure 10B The spectral data is as follows: 1 H NMR (400MHz, DMSO-d6) δ: 11.76 (brs, 1H), 8.06 (d, J = 8.1Hz, 2H), 7.80 (d, J = 8.2Hz, 2H), 7.57 (d, J=7.9Hz, 1H), 7.44 (d, J=8.2Hz, 1H), 7.17-7.13 (m, 1H), 7.07-7.01 (m, 2H)ppm. 13 C{ 1 H}NMR (101MHz, DMSO-d6) δ: 137.6, 136.1, 135.9, 128.5, 127.3 (q, J 2 C-F =31.9Hz), 125.9(q, .J3) C-F =4.0Hz), 125.4, 124.4 (q, J 1 C-F =272.8Hz), 122.5, 120.6, 119.8, 111.6, 100.8ppm.

[0059] Example 11

[0060] A dried microwave tube equipped with a magnetic stirrer was placed in a glove box under an argon atmosphere. 2-fluorophenylacetonitrile (27.0 mg, 0.2 mmol) and dried toluene (1.2 mL) were added. The microwave tube was sealed with a cap containing a rubber diaphragm, removed from the glove box, and 0.6 mL of p-fluorophenyl magnesium bromide (0.6 mmol, 1 M in THF) was added dropwise using a 1 mL syringe at room temperature. The reaction mixture was then stirred at room temperature for 2 hours. Next, the reaction was heated in an oil bath at 110 °C for 4 hours. The microwave tube was removed from the oil bath, cooled to room temperature, exposed to air, and 3 drops of water were added. The reaction mixture was then washed and filtered through a short silica gel column with an additional 6 mL of ethyl acetate (3 × 2 mL). The filtered solution was concentrated under vacuum, and the concentrated crude product was loaded onto a silica gel column for purification and centrifugation using petroleum ether:ethyl acetate = 20:1 as the eluent to obtain 2-(4-fluorophenyl)-1H-indole (35.5 mg, 84% yield) as a white solid. The proton and carbon NMR spectra of the product are as follows: Figure 11A and Figure 11B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ: 8.25 (brs, 1H), 7.65-7.59 (m, 3H), 7.41-7.39 (m, 1H), 7.24-7.20 (m, 1H), 7.17-7.12 (m, 3H), 6.77 (d, J=2.1Hz, 1H) ppm. 13 C{ 1 H}NMR (101MHz, CDCl3) δ: 162.5 (d, J 1 C-F =248.6Hz), 137.1, 136.9, 129.4, 128.8 (d, J 4 C-F =3.3Hz), 127.0 (d, J) 3 C-F =8.1Hz), 122.5, 120.8, 120.5, 116.2 (d, J 2 C-F =21.8Hz), 111.0, 100.0 (d, J 5 C-F =1.3Hz)ppm.

[0061] Example 12

[0062] A dried microwave tube equipped with a magnetic stirrer was placed in a glove box under an argon atmosphere. 2-fluorophenylacetonitrile (27.0 mg, 0.2 mmol) and dried toluene (1.2 mL) were added. The microwave tube was sealed with a cap containing a rubber diaphragm, removed from the glove box, and 0.6 mL of thiophene-2-ylmagnesium bromide (0.6 mmol, 1 M inTHF) was added dropwise using a 1 mL syringe at room temperature. The reaction mixture was then stirred at room temperature for 2 hours. Next, the reaction was heated in an oil bath at 110 °C for 4 hours. The microwave tube was removed from the oil bath, cooled to room temperature, exposed to air, and then 3 drops of water were added. The reaction mixture was then washed and filtered through a short silica gel column with an additional 6 mL of ethyl acetate (3 × 2 mL). The filtered solution was concentrated under vacuum, and the concentrated crude product was loaded onto a silica gel column for purification and centrifugation. The developing solvent was petroleum ether:ethyl acetate = 20:1, yielding 2-(thiophene-2-yl)-1H-indole (28.3 mg, 71% yield), a pale yellow solid. The proton NMR and carbon NMR spectra of the product are as follows: Figure 12A and Figure 12B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ: 8.21 (brs, 1H), 7.62-7.57 (m, 1H), 7.41-7.32 (m, 1H), 7.30-7.28 (m, 2 H), 7.27-7.24 (m, 1H), 7.22-7.17 (m, 1H), 7.15-7.08 (m, 2H), 6.74 (dd, J=2.1, 1.0Hz, 1H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 136.6, 135.7, 132.5, 129.2, 128.0, 124.7, 123.0, 122.7, 120.7, 120.6, 110.9, 100.5ppm.

[0063] Example 13

[0064] A dried microwave tube equipped with a magnetic stirrer was placed in a glove box under an argon atmosphere. 2-fluorophenylacetonitrile (27.0 mg, 0.2 mmol) and dried toluene (1.2 mL) were added. The microwave tube was sealed with a cap containing a rubber diaphragm, removed from the glove box, and 0.6 mL of benzo[b]thiophene-5-bromine magnesium (0.6 mmol, 1 M inTHF) was added dropwise using a 1 mL syringe at room temperature. The reaction mixture was then stirred at room temperature for 2 hours. Next, the reaction was heated in an oil bath at 110 °C for 4 hours. The microwave tube was removed from the oil bath, cooled to room temperature, exposed to air, and then 3 drops of water were added. The reaction mixture was then washed and filtered through a short silica gel column with an additional 6 mL of ethyl acetate (3 × 2 mL). The filtered solution was concentrated under vacuum, and the concentrated crude product was loaded onto a silica gel column for purification. The developing solvent was petroleum ether:ethyl acetate = 20:1, yielding 2-(benzothiophene-5-yl)-1H indole (38.9 mg, 78% yield), a white solid. The proton NMR and carbon NMR spectra of the product are as follows: Figure 13A and Figure 13B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ: 8.38 (brs, 1H), 8.07 (s, 1H), 7.93 (d, J=8.4Hz, 1H), 7.69-7.64 (m, 2H), 7.53-7.47(m, 1H), 7.45-7.30(m, 2H), 7.24-7.18(m, 1H), 7.17-7.12(m, 1H), 6.88(s, 1H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 140.3, 139.2, 138.3, 136.9, 129.5, 128.9, 127.7, 124.1, 123.2, 122.4, 122.2, 120.7, 120.4, 119.9, 111.0, 100.1ppm.

[0065] Example 14

[0066] A dried microwave tube equipped with a magnetic stirrer was placed in a glove box under an argon atmosphere. 2-fluorophenylacetonitrile (27.0 mg, 0.2 mmol) and dried toluene (1.2 mL) were added. The microwave tube was sealed with a cap containing a rubber diaphragm, removed from the glove box, and 0.6 mL of benzo[b]furan-5-bromine magnesium (0.6 mmol, 1 min THF) was added dropwise using a 1 mL syringe at room temperature. The reaction mixture was then stirred at room temperature for 2 hours. Next, the reaction was heated in an oil bath at 110 °C for 4 hours. The microwave tube was removed from the oil bath, cooled to room temperature, exposed to air, and then 3 drops of water were added. The reaction mixture was then washed and filtered through a short silica gel column with an additional 6 mL of ethyl acetate (3 × 2 mL). The filtered solution was concentrated under vacuum, and the concentrated crude product was loaded onto a silica gel column for purification. The developing solvent was petroleum ether:ethyl acetate = 20:1, yielding 2-(benzofuran-5-yl)-1H-indole (38.7 mg, 83% yield), a white solid. The proton NMR and carbon NMR spectra of the product are as follows: Figure 14A and Figure 14B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ: 8.32 (brs, 1H), 7.85 (d, J=1.8Hz, 1H), 7.68-7.64 (m, 2H), 7.61 (dd, J=8.6Hz, 1.8, 1 H), 7.58-7.55 (m, 1H), 7.42-7.38 (m, 1H), 7.24-7.19 (m, 1H), 7.18-7.13 (m, 1H), 6.81 (t, J=2.4Hz, 2H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 154.8, 146.0, 138.6, 136.9, 129.5, 128.2, 127.8, 122.4, 122.2, 120.6, 120.4, 117.9, 112. 1, 111.0, 106.9, 99.7ppm.IR (neat): 3432, 1637, 1527, 1455, 1402, 1348, 1229, 1131, 1110, 1029, 885, 749, 608, 449cm -1 HRMS: calcd for C 16 H 12 NO[M+H] + 233.0841, found 233.0841.

Claims

1. A method for synthesizing indole derivatives, characterized in that: The indole derivatives shown in Formula 3 are synthesized by mixing the 2-fluorophenylacetonitrile compound shown in Formula 1 with the Grignard reagent shown in Formula 2 and an organic solvent; wherein R1 is selected from hydrogen, halogen group, methyl, methoxy or phenyl, and R2 is selected from phenyl, substituted phenyl, thienyl, benzofuranyl, benzothienyl, wherein the substituent of the substituted phenyl is selected from methyl, tert-butyl, methoxy, trifluoromethyl or halogen group.

2. The synthesis method according to claim 1, characterized in that, The reaction is carried out under nitrogen or argon protection.

3. The synthesis method according to claim 1, characterized in that, The organic solvent is toluene.

4. The synthesis method according to claim 1, characterized in that, In the reaction, the molar ratio of the 2-fluorophenylacetonitrile compound shown in Formula 1 to the Grignard reagent shown in Formula 2 is 1:(2~4), and the reaction temperature is 90℃~130℃.

5. The synthesis method according to claim 1, characterized in that, The 2-fluorophenylacetonitrile compounds, Grignard reagents, and products mentioned are one of the following:

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