A method for the synthesis of 2-alkyl indoles

Abstract

2-alkyl indole due to the unique heterocyclic structure and potential biological activity plays an important role in pharmaceutical chemistry and pharmaceutical industry. The drugs based on alkyl indole skeleton have been reported, which have significant effect in antioxidant, antitumor, antifungal and antibacterial aspects. Its importance is self-evident, because of the wide application of indole skeleton in these aspects, researchers have introduced many selective and economic methods to synthesize this kind of heterocyclic ring, such as phenylhydrazine method, aniline method, o-aminoethyl benzene method, o-chloromethyl benzene method and the like, but these methods have respective defects, such as two-step reaction leading to low yield, catalyst needed for synthesis is not easy to obtain, transition metal catalysis, reaction temperature is far below 0 DEG C and the like, which cannot meet the actual needs. The application develops a general method for synthesizing indole from simple 2-fluorobenzene acetonitrile compound and various alkyl grignard reagent, which is not involved with transition metal and has mild reaction condition.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a synthesis method of 2-alkyl indole. BACKGROUND

[0002] 2-alkyl indole plays an important role in pharmaceutical chemistry and pharmaceutical industry due to its unique heterocyclic structure and potential biological activity. There are numerous drugs based on alkyl indole skeleton reported, which have significant effects in oxidation resistance, anti-tumor, anti-fungal and anti-bacterial, etc. Its importance is self-evident. Because of the wide application of indole skeleton in these aspects, researchers have introduced many selective and economical methods to synthesize this kind of heterocyclic ring, such as phenylhydrazine method, aniline method, o-aminoethyl benzene method, o-chloromethyl benzene method, etc. However, these methods have their own shortcomings, such as two-step reaction leading to low yield, need of catalyst which is not easy to obtain, need of transition metal catalyst, reaction temperature far below 0℃, etc., which cannot meet the actual needs. Therefore, it is of great significance to develop a synthesis method of 2-alkyl indole which can be mass-produced without transition metal participation. SUMMARY

[0003] The present application aims to provide a synthesis method of 2-alkyl indole which can solve the above problems, has simple synthesis method, is more widely applicable and suitable for large-scale production. Herein, a general method for synthesizing indole from simple 2-fluorobenzene acetonitrile compound and various alkyl Grignard reagent is reported, which is free of transition metal participation and has mild reaction conditions. The specific scheme is as follows:

[0004]

[0005] A synthesis method of 2-aryl indole compound, 2-fluorobenzene acetonitrile compound shown in formula 1 and alkyl Grignard reagent shown in formula 2 are mixed in an organic solvent to synthesize 2-alkyl indole compound shown in formula 3. Wherein R1 is selected from hydrogen or methoxy, and R2 is selected from methyl, ethyl, propyl, butyl, hexyl, octyl, isopropyl, alkenyl and cyclopropyl. The method of the present application generates indole compound by one-pot method, which reduces the reaction steps and thus can improve the yield of product. The raw materials used in the synthesis method are simple and economical, and no transition metal catalyst is used, which is more economical and green. In the present application, R1 and R2 can be selected in a variety of ways, which has wider applicability.

[0006] Preferably, R1 is selected from hydrogen and methoxy, and more preferably, R1 is selected from hydrogen, and R2 is selected from methyl, ethyl, propyl, butyl, octyl, ethenyl and cyclopropyl. Even more preferably, R1 is selected from hydrogen, and R2 is selected from ethyl and ethenyl.

[0007] 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℃.

[0008] Preferably, the reaction temperature is 100℃~120℃.

[0009] Preferably, the reaction temperature is 110℃.

[0010] Preferably, the concentration of the alkyl Grignard reagent is 1–3 mol / L.

[0011] More preferably, the concentration of the alkyl Grignard reagent is 1 mol / L.

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

[0013] Preferably, the synthesis takes place in the presence of an organic solvent.

[0014] Preferably, the organic solvent is tetrahydrofuran or toluene.

[0015] More preferably, the organic solvent is toluene.

[0016] Preferably, using the method of the present invention, 2-arylindole compounds with the following structures can be synthesized:

[0017]

[0018] A pre-prepared alkyl Grignard reagent rapidly attacks a nitrile to yield a metal imine intermediate. The resulting metal imine intermediate undergoes intramolecular aromatic nucleophilic substitution for cyclization, followed by isomerization to give a 2-alkylindole compound.

[0019] The technical solution of the present invention can achieve at least one of the following beneficial effects:

[0020] This invention provides a novel method for synthesizing substituted indole. This method does not use bases or transition metal catalysts and has a mild reaction temperature, making it more economical and more suitable for industrial application.

[0021] 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.

[0022] 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;

[0023] In this invention, R1 and R2 can be chosen from a variety of options, thus making the method of this invention more widely applicable and capable of synthesizing a variety of 2-alkylindole compounds, which has a significant impact on the synthesis of indole compounds.

[0024] Instruction manual illustrations

[0025] Figures 1 to 11 are the nuclear magnetic resonance spectra of the products of Examples 1 to 11, respectively.

[0026] 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

[0027] 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-bem, or J&K. The nuclear magnetic resonance spectrometer was a Bruker-400M and a JEOL 400M.

[0028] Example 1

[0029] 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 methylmagnesium 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 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 eluent was petroleum ether:ethyl acetate = 40:1, yielding 2-methylindole (18.9 mg, 72% yield) as a brown solid. The proton NMR and carbon NMR spectra of the product were as follows: Figure 1A and Figure 1B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ: 7.74 (brs, 1H), 7.59-7.52 (m, 1H), 7.30-7.26 (m, 1H), 7.17-7.08 (m, 2H), 6.29-6.21 (m, 1H), 2.48-2.40 (m, 3H)ppm. 13 C{ 1H} NMR (101MHz, CDCl3) δ: 136.2, 135.3, 129.2, 121.1, 119.8, 110.5, 100.5, 13.8ppm.

[0030] By changing the two raw materials in Example 1, the following 11 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 2-11 correspond to the sequence numbers of the respective examples.

[0031] The table lists the structural formulas of the corresponding products in each of the 1-11 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.

[0032]

[0033]

[0034] The following are the products of each of the embodiments 2-11. 1 H and 13 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.

[0035] Example 2

[0036] 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 ethyl 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 = 40:1 as the eluent to obtain 2-ethyl-1H-indole (22.1 mg, 76% yield) as a brown solid. The proton and carbon NMR spectra of the product are as follows: Figure 2A and Figure 2B The spectral data is as follows: 1H NMR (400MHz, CDCl3) δ: 7.80 (brs, 1H), 7.60-7.53 (m, 1H), 7.33-7.27 (m, 1H), 7 .17-7.08(m,2H), 6.31-6.24(m,1H), 2.85-2.73(m,2H), 1.41-1.31(m,3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 141.6, 136.0, 128.9, 121.1, 119.9, 119.7, 110.5, 98.8, 21.5, 13.4ppm.

[0037] Example 3

[0038] 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 n-propylmagnesium 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 = 40:1 as the eluent to obtain 2-propyl-1H-indole (22.0 mg, 69% yield) as a brown liquid. 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: 7.77 (brs, 1H), 7.60-7.57 (m, 1H), 7.31-7.28 (m, 1H), 7.19-7.11 (m , 2H), 6.30-6.28(m, 1H), 2.75-2.71(m, 2H), 1.82-1.72(m, 2H), 1.05(t, J=7.4Hz, 3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 140.04, 135.96, 128.99, 121.05, 119.90, 119.72, 110.50, 99.62, 30.42, 22.63, 14.07ppm.

[0039] Example 4

[0040] 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 n-butylmagnesium 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 = 40:1 as the eluent to obtain 2-butyl-1H-indole (25.3 mg, 73% yield) as a yellow liquid. 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: 7.75 (brs, 1H), 7.65-7.59 (m, 1H), 7.32-7.28 (m, 1H), 7.22-7.14 (m, 2H), 6.37 -6.26 (m, 1H), 2.76 (t, J=7.6Hz, 2H), 1.78-1.70 (m, 2H), 1.56-1.42 (m, 2H), 1.03 (t, J=7.3Hz, 3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ140.3, 136.0, 129.0, 121.0, 119.9, 119.7, 110.6, 99.5, 31.5, 28.1, 22.6, 14.1ppm.

[0041] Example 5

[0042] 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 n-hexylmagnesium 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 = 40:1 as the eluent to obtain 2-hexyl-1H-indole (28.6 mg, 71% yield) as a yellow liquid. 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: 7.76 (brs, 1H), 7.63-7.56 (m, 1H), 7.32-7.28 (m, 1H), 7.20-7.12 (m, 2H), 6.29 (dd, J=2.2, 1.0, 1H), 2.77-2.72 (m, 2H), 1.78-1.71 (m, 2H), 1.46-1.36 (m, 6H), 0.99-0.94 (m, 3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 140.3, 136.0, 129.0, 121.0, 119.9, 119.7, 110.5, 99.5, 31.8, 29.3, 29.2, 28.40, 22.79, 14.30ppm.

[0043] Example 6

[0044] 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 n-octylmagnesium 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 = 40:1 as the eluent to obtain 2-octyl-1H indole (29.8 mg, 65% yield) as a yellow liquid. 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, CDCl3) δ: 7.97-7.70 (m, 1H), 7.61-7.51 (m, 1H), 7.31-7.27 (m, 1H), 7.15-7.07 (m, 2H), 6 .28-6.22 (m, 1H), 2.74 (t, J=7.7, 2H), 1.68-1.76 (m, 2H), 1.39-1.28 (m, 10H), 0.93-0.89 (m, 3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 140.2, 135.9, 129.0, 121.0, 119.9, 119.7, 110.4, 99.5, 32.0, 29.6, 29.5, 29.4, 29.3, 28.4, 22.8, 14.3ppm.

[0045] Example 7

[0046] 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 isopropyl magnesium 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 = 40:1 as the eluent to obtain 2-isopropyl-1H indole (21.0 mg, 66% yield) as a brown liquid. 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: 8.01-7.80 (m, 1H), 7.58-7.53 (m, 1H), 7.32-7.29 (m, 1H), 7.15-7.08(m, 2H), 6.30-6.23(m, 1H), 3.02-3.11(m, 1H), 1.37(d, J=6.9, 6H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 146.1, 135.8, 128.7, 121.1, 120.0, 119.7, 110.5, 97.5, 27.7, 22.6ppm.

[0047] Example 8

[0048] 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 vinyl 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 = 40:1 as the eluent to obtain 2-vinyl-1H-indole (23.5 mg, 82% yield) as a pale yellow solid. The proton 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: 8.14 (brs, 1H), 7.62-7.54 (m, 1H), 7.36-7.29 (m, 1H), 7.24-7.15 (m, 1H), 7.14- 7.07 (m, 1H), 6.79-6.70 (m, 1H), 6.57-6.45 (m, 1H), 5.54 (d, J = 17.8Hz, 1H), 5.27 (d, J = 11.2Hz, 1H) ppm. 13 C{ 1 H}NMR (101MHz, CDCl3) δ: 136.7, 136.4, 128.8, 127.7, 122.9, 120.9, 120.2, 112.2, 110.8, 103.3ppm..

[0049] Example 9

[0050] 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 prop-1-en-2-ylmagnesium 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 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. The concentrated crude product was loaded onto a silica gel column for purification and centrifugation using petroleum ether:ethyl acetate = 40:1 as the developing solvent, yielding 2-(prop-1-en-2-yl)-1H-indole (26.7 mg, 85% yield) as a white solid. The proton NMR 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, CDCl3) δ: 8.14 (brs, 1H), 7.67 (d, J=7.9Hz, 1H), 7.38-7.33 (m, 1H), 7.30-7 .24(m,1H),7.21-7.15(m,1H),6.63(s,1H),5.32(s,1H),5.14(s,1H),2.25(s,3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 138.7, 136.7, 135.4, 129.0, 122.9, 121.0, 120.1, 110.9, 109.8, 101.4, 20.8ppm.

[0051] Example 10

[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 2-methylprop-1-en-1-ylmagnesium 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 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. The concentrated crude product was loaded onto a silica gel column for purification and centrifugation using petroleum ether:ethyl acetate = 40:1 as the developing solvent, yielding 2-(2-methylprop-1-en-1-yl)-1H-indole (26.0 mg, 76% yield). The product was a white solid. The proton NMR 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, CDCl3) δ: 7.89 (brs, 1H), 7.57 (d, J = 7.7Hz, 1H), 7.30 (d, J = 7.8Hz, 1H), 7.17-7.06(m, 2H), 6.44(s, 1H), 6.16(s, 1H), 2.05(s, 3H), 1.97(s, 3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 137.5, 136.4, 135.6, 129.1, 121.7, 120.2, 119.9, 116.1, 110.5, 101.6, 27.4, 20.5ppm.

[0053] Example 11

[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 cyclopropylmagnesium 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 = 40:1 as the eluent to give 2-cyclopropyl-1H-indole (24.5 mg, 78% yield) as a brown 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: 7.88 (brs, 1H), 7.58-7.52 (m, 1H), 7.30-7.26 (m, 1H), 7.18-7.09 (m, 2H), 6.21-6.17 (m, 1H), 1.99-1.91 (m, 1H), 1.02-0.96 (m, 2H), 0.82-0.77 (m, 2H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 142.0, 135.9, 128.8, 121.1, 119.9, 110.4, 97.8, 9.0, 7.5ppm.

Claims

1. A method for synthesizing indole derivatives, characterized in that: The indole derivatives shown in Formula 3 were 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 and R2 is selected from methyl, ethyl, propyl, n-butyl, n-hexyl, n-octyl, vinyl, prop-1-en-2-yl, 2-methylprop-1-en-1-yl, and cyclopropyl.

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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