A method for synthesizing N-methyl-2-phenylindole

Abstract

The present invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing N-methyl-2-phenylindole. A methyl benzoate compound represented by Formula 1 and an N-methyl-o-toluidine compound represented by Formula 2 are mixed with an organic solvent (methyl tert-butyl ether) in the presence of a strong base (lithium bis(trimethylsilyl)amide) and a cesium salt additive (cesium fluoride) to synthesize N-methyl-2-phenylindole represented by Formula 3. The raw materials used in the present invention are simple and readily available, and a one-pot method for synthesizing N-methyl-2-phenylindole is constructed. This method has the advantages of a simple synthesis method, economical and environmentally friendly operation, and a wide range of applications.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing N-methyl-2-phenylindole. Background Art

[0002] Indole is a special heterocyclic compound that is a key component of biologically active molecules. 2-Aryl indole moieties have been widely extracted, isolated, or chemically synthesized for use in research fields such as pharmaceuticals, pesticides, fragrances, and dyes, such as NK1 receptor antagonists (A), 3-thiocyanate-indole (B), and 3-selenocyanate-indole (C). As a result, many new methods for preparing indole systems are reported every year, but most of them are usually based on transition metal catalysis. These methods are very useful, but they all have problems such as the use of toxic or expensive catalysts, the generation of heavy metal waste, and harsh reaction conditions. Therefore, there is a need to continuously explore more economical and efficient design and synthesis routes for various indole derivatives.

[0003] Summary of the Invention

[0004] The present invention provides a one-pot synthesis of N-methyl-2-phenylindole from methyl benzoate and N-methyl-o-toluidine, which can produce a variety of N-methyl-2-phenylindoles with biological activity and medicinal value. The synthesis method is simple and efficient. The specific scheme is as follows:

[0005]

[0006] A method for synthesizing an N-methyl-2-phenylindole compound comprises: using a methyl benzoate compound represented by Formula 1 and an N-methyl-o-toluidine compound represented by Formula 2, mixed with an organic solvent in the presence of a strong base and a cesium salt additive, to react and synthesize N-methyl-2-phenylindole represented by Formula 3;

[0007] Wherein R1 is selected from 4-methylphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 2-pyridine, etc., R2 is selected from methyl, phenyl, etc., and R3 is selected from methyl, methoxy, halogen, etc.

[0008] The method of the present invention can realize the one-pot process of preparing N-methyl-2-phenylindole compound, reducing the reaction steps, thereby improving the product yield; the raw materials used in the synthesis method are simple and economical; R1, R2, and R3 in the present invention can be selected from multiple options, and the applicability is wider.

[0009] Preferably, R1 is selected from 4-methylphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 2-pyridine, etc., R2 is selected from methyl, phenyl, etc., and R3 is selected from methyl, methoxy, halogen, etc.

[0010] Preferably, the reaction is carried out under the protection of an inert gas, and preferably, the inert gas is nitrogen.

[0011] Preferably, the synthesis occurs in the presence of a strong base, a cesium salt additive and an organic solvent.

[0012] Preferably, the strong base is lithium bis(trimethylsilyl)amide; and the cesium salt additive is cesium fluoride.

[0013] Preferably, the organic solvent is methyl tert-butyl ether.

[0014] Preferably, the molar ratio of methyl benzoate shown in Formula 1, N-methyl-o-toluidine shown in Formula 2, strong base and cesium salt additive in the reaction is: 1-2:1-2:1-4; and the reaction temperature is 110°C.

[0015] Preferably, the method of the present invention can be used to synthesize N-methyl-2-phenylindole having the following structure:

[0016]

[0017]

[0018] Methyl benzoate and N-methyl-o-toluidine are reacted in the presence of a strong base (lithium bis(trimethylsilyl)amide) and a cesium salt additive (cesium fluoride) in a mixture with an organic solvent (methyl tert-butyl ether) to finally synthesize N-methyl-2-phenylindole.

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

[0020] The raw materials used in the synthesis method of the present invention are cheap and easily available;

[0021] The synthesis method of the present invention does not use transition metal catalysts and is green and environmentally friendly;

[0022] 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 the small number of reaction steps;

[0023] 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.

[0024] R1, R2, and R3 in the present invention can be selected from a variety of options, so the method of the present invention has wider applicability and can synthesize a variety of N-methyl-2-phenylindoles.

[0025] Figures in the specification

[0026] 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. A in the figure is a hydrogen nuclear magnetic resonance spectrum, and B in the figure is a carbon nuclear magnetic resonance spectrum. Figure 1A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 1, Figure 1B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 1; Figure 2A This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 2, Figure 2B This is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 2; Figure 3A This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 3, Figure 3B This is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 3; Figure 4A This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 4, Figure 4B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 4; Figure 5A This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 5, Figure 5B This is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 5; Figure 6A This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 6, Figure 6B This is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 6; Figure 7A This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 7, Figure 7B This is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 7; Figure 8A This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 8, Figure 8B This is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 8; Figure 9A This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 9, Figure 9B This is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 9; Figure 10A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 10, Figure 10B The carbon nuclear magnetic resonance spectrum of the product obtained in Example 10 is shown in FIG. Specific embodiments

[0027] For the convenience of those skilled in the art to understand, the concept of the present invention is further described below in conjunction with the embodiments. The specific description of the following examples 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. The various raw materials involved in the description are all purchased from the market, or through simple synthesis, and other medicines 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.

[0028] Example 1

[0029] In a nitrogen-filled glove box, a dry microwave vial equipped with a magnet was charged sequentially with LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mol), methyl benzoate (12.5 μL, 0.1 mmol), N-methyl-o-toluidine (12.5 μL, 0.1 mmol), and TBME (0.5 mL). The microwave vial was sealed with a lid and removed from the glove box. The reaction mixture was heated in an oil bath at 110°C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then quenched by the slow addition of three drops of water. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3 x 1 mL). The combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluting with petroleum ether:ethyl acetate = 100:1) to afford the product (20.1 mg, 90% yield) as a white solid. 1 H NMR (401MHz, Chloroform-d) δ7.69 (d, J=7.8Hz, 1H), 7.58-7.54 (m, 2H), 7.53-7.48 (m, 2H), 7.47-7.39 (m, 2H), 7.33-7.27 (m, 1H), 7.19 (t, J=7.4Hz, 1H), 6.61 (s, 1H), 3.78 (s, 3H)ppm. 13 C NMR (101 MHz, Chloroform-d) δ 141.5, 138.3, 132.8, 129.3, 128.5, 127.9, 127.8, 121.6, 120.4, 119.8, 109.6, 101.6, 31.1ppm.

[0030] The raw materials in Example 1 were changed to design the following 10 experimental examples, wherein the first group of experiments is Example 1, and the corresponding nuclear magnetic resonance spectrum of the product is Figure 1A and Figure 1B The serial numbers of the NMR spectra of the remaining 2-10 groups of products correspond to the serial numbers of the corresponding examples.

[0031] The table lists the structural formulas of the products in Examples 1-10, and the last column lists the yields of the products in each Example, and indicates the specific implementation conditions of each Example. The specific meanings of the implementation conditions of each Example are shown below the table.

[0032]

[0033]

[0034] Example 2

[0035] In a nitrogen-filled glove box, a dry microwave vial equipped with a magnet was charged sequentially with LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mmol), methyl 4-methylbenzoate (14.2 μL, 0.1 mmol), N-methyl-o-toluidine (12.5 μL, 0.1 mmol), and TBME (0.5 mL). The microwave vial was sealed with a lid and removed from the glove box. The reaction mixture was heated in an oil bath at 110°C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, and exposed to air before being quenched by the slow addition of three drops of water. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3 x 1 mL). The combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluting with petroleum ether:ethyl acetate = 100:1) to afford the product (19.0 mg, 80% yield) as a white solid. 1 H NMR (400MHz, Chloroform-d) δ7.62 (d, J=7.7Hz, 1H), 7.42-7.32 (m, 3H), 7.29-7.20 (m, 3H), 7.17-7.09 (m, 1H), 6.53 (s, 1H), 3.72 (s, 3H), 2.42 (s, 3H)ppm. 13 C NMR (101MHz, Chloroform-d) δ 141.6, 138.2, 137.7, 129.9, 129.3, 129.2, 128.0, 121.5, 120.3, 119.8, 109.5, 101.3, 31.1, 21.3ppm.

[0036] Example 3

[0037] In a nitrogen-filled glove box, a dry microwave vial equipped with a magnet was charged sequentially with LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mmol), methyl 4-tert-butylbenzoate (19.3 μL, 0.1 mmol), N-methyl-o-toluidine (12.5 μL, 0.1 mmol), and TBME (0.5 mL). The microwave vial was sealed with a lid and removed from the glove box. The reaction mixture was heated in an oil bath at 110°C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, and exposed to air before being quenched by the slow addition of three drops of water. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3 x 1 mL). The combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluting with petroleum ether:ethyl acetate = 100:1) to afford the product (22.1 mg, 84% yield) as a white solid. 1H NMR (401MHz, Chloroform-d) δ7.63 (d, J=7.8Hz, 1H), 7.47 (q, J=8.7Hz, 4H), 7.36 (d, J=9.2H z, 1H), 7.28-7.21 (m, 1H), 7.13 (t, J=6.9Hz, 1H), 6.55 (s, 1H), 3.76 (s, 3H), 1.38 (s, 9H)ppm. 13 CNMR (101MHz, Chloroform-d) δ150.9, 141.6, 138.2, 129.9, 129.0, 128.0, 125.4, 121.5, 120.3, 119.8, 109.5, 101.3, 34.7, 31.3, 31.2ppm.

[0038] Example 4

[0039] In a nitrogen-filled glove box, a dry microwave vial equipped with a magnet was charged sequentially with LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mmol), methyl 4-fluorobenzoate (13.2 μL, 0.1 mmol), N-methyl-o-toluidine (12.5 μL, 0.1 mmol), and TBME (0.5 mL). The microwave vial was sealed with a lid and removed from the glove box. The reaction mixture was heated in an oil bath at 110°C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, and exposed to air before being quenched by the slow addition of three drops of water. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3 x 1 mL). The combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluting with petroleum ether:ethyl acetate = 100:1) to afford the product (45.0 mg, 84% yield) as a pale yellow solid. 1 H NMR (400MHz, Chloroform-d) δ7.62 (d, J=7.8Hz, 1H), 7.46-7.41 (m, 2H), 7.33 (d, J=7.3 Hz, 1H), 7.26-7.21 (m, 1H), 7.16-7.10 (m, 3H), 6.51 (d, J=0.9Hz, 1H), 3.67 (s, 3H)ppm. 13 C NMR (101MHz, Chloroform-d) δ163.8, 161.3, 140.4, 138.2, 131.1, 131.0, 128 .9, 128.8, 127.8, 121.7, 120.4, 119.9, 115.6, 115.4, 109.6, 101.7, 31.0ppm.

[0040] Example 5

[0041] In a nitrogen-filled glove box, a dry microwave vial equipped with a magnet was charged with LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mmol), methyl isonicotinate (10.0 μL, 0.1 mmol), N-methyl-o-toluidine (12.5 μL, 0.1 mmol), and TBME (0.5 mL). The microwave vial was sealed with a lid and removed from the glove box. The reaction mixture was heated in an oil bath at 110°C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, and exposed to air before being quenched by the slow addition of three drops of water. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3 x 1 mL). The combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluting with petroleum ether:ethyl acetate = 100:1) to afford the product (13.1 mg, 63% yield) as a pale yellow solid. 1 H NMR (401MHz, Chloroform-d) δ 8.72-8.66 (m, 2H), 7.65 (s, 1H), 7.46-7.41 (m, 2H), 7.38 (d, J=8. 2Hz, 1H), 7.30 (t, J=7.0Hz, 1H), 7.17 (t, J=7.4Hz, 1H), 6.71 (d, J=0.8Hz, 1H), 3.79 (s, 3H)ppm. 13 CNMR (101MHz, Chloroform-d) δ149.9, 140.4, 139.1, 138.3, 127.6, 123.3, 122.8, 121.0, 120.3, 109.8, 103.6, 31.4ppm.

[0042] Example 6

[0043] In a nitrogen-filled glove box, a dry microwave vial equipped with a magnet was charged sequentially with LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mmol), methyl benzoate (12.5 μL, 0.1 mmol), N,2,4-trimethylaniline (14.1 μL, 0.1 mmol), and TBME (0.5 mL). The microwave vial was sealed with a lid and removed from the glove box. The reaction mixture was heated in an oil bath at 110°C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, and exposed to air before being quenched by the slow addition of three drops of water. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3 x 1 mL). The combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluting with petroleum ether:ethyl acetate = 100:1) to afford the product (16.1 mg, 73% yield) as a pale yellow solid. 1 H NMR (401MHz, Chloroform-d) δ7.52-7.47 (m, 3H), 7.43 (t, J=7.7Hz, 2H), 7.36 (t, J=7.1 Hz, 1H), 7.14 (s, 1H), 6.97 (d, J=8.0Hz, 1H), 6.50 (s, 1H), 3.68 (s, 3H), 2.51 (s, 3H)ppm. 13 C NMR (101MHz, Chloroform-d) δ140.9, 138.8, 132.9, 131.4, 129.2, 128.4, 127.6, 125.7, 121.6, 120.1, 109.6, 101.4, 31.1, 22.0ppm.

[0044] Example 7

[0045] In a nitrogen-filled glove box, a dry microwave vial equipped with a magnet was charged sequentially with LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mmol), methyl benzoate (12.5 μL, 0.1 mmol), 4-methoxy-N,2-dimethylaniline (14.9 μL, 0.1 mmol), and TBME (0.5 mL). The microwave vial was sealed with a lid and removed from the glove box. The reaction mixture was heated in an oil bath at 110°C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, and exposed to air before being quenched by the slow addition of three drops of water. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3 x 1 mL). The combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluting with petroleum ether:ethyl acetate = 100:1) to afford the product (19.0 mg, 80% yield) as a pale yellow solid.1 H NMR (400MHz, Chloroform-d) δ7.49-7.41 (m, 4H), 7.39-7.34 (m, 1H), 7.23 (d, J=8.9Hz, 1H), 7 .09 (d, J=2.5Hz, 1H), 6.90 (dd, J=8.8, 2.5Hz, 1H), 6.48 (s, 1H), 3.85 (s, 3H), 3.68 (s, 3H)ppm. 13 C NMR (101MHz, Chloroform-d) δ 154.3, 142.1, 133.7, 132.8, 129.2, 128.4, 128.2, 127.7, 111.8, 110.3, 102.1, 101.2, 55.8, 31.2ppm.

[0046] Example 8

[0047] In a nitrogen-filled glove box, a dry microwave vial equipped with a magnet was charged sequentially with LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mmol), methyl benzoate (12.5 μL, 0.1 mmol), 4-chloro-N,2-dimethylaniline (13.6 μL, 0.1 mmol), and TBME (0.5 mL). The microwave vial was sealed with a lid and removed from the glove box. The reaction mixture was heated in an oil bath at 110°C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, and exposed to air before being quenched by the slow addition of three drops of water. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3 x 1 mL). The combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluting with petroleum ether:ethyl acetate = 100:1) to afford the product (18.1 mg, 75% yield) as a pale yellow solid. 1 H NMR (400MHz, Chloroform-d) δ7.63 (d, J=2.0Hz, 1H), 7.54-7.45 (m, 5H), 7.28 (d, J=8.7Hz, 1H), 7.22 (dd, J=8.7, 2.0Hz, 1H), 6.53 (s, 1H), 3.73 (s, 3H)ppm. 13 C NMR (101MHz, Chloroform-d) δ 142.8, 136.7, 132.2, 129.3, 128.8, 128.5, 128.1, 125.4, 121.7, 119.7, 110.6, 101.1, 31.2ppm.

[0048] Example 9

[0049] In a nitrogen-filled glove box, a dry microwave vial equipped with a magnet was charged sequentially with LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mmol), methyl benzoate (12.5 μL, 0.1 mmol), 2-ethyl-N-methylaniline (14.2 μL, 0.1 mmol), and TBME (0.5 mL). The microwave vial was sealed with a lid and removed from the glove box. The reaction mixture was heated in an oil bath at 110°C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then quenched by the slow addition of three drops of water. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3 x 1 mL). The combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluting with petroleum ether:ethyl acetate = 100:1) to afford the product (16.6 mg, 73% yield) as a white solid. 1 H NMR (400MHz, Chloroform-d) δ7.85-7.79(m, 1H), 7.69-7.62(m, 2H), 7.61-7.55(m, 3H), 7.53-7.42 (m, 2H), 7.37 (dd, J=6.6, 4.0Hz, 1H), 3.76 (s, 3H), 2.50 (s, 3H)ppm. 13 C NMR (101MHz, Chloroform-d) δ 137.5, 137.2, 132.1, 130.6, 128.4, 128.3, 127.7, 121.7, 119.1, 118.8, 109.2, 108.4, 30.8, 9.3ppm.

[0050] Example 10

[0051] In a nitrogen-filled glove box, a dry microwave vial equipped with a magnet was charged sequentially with LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mmol), methyl benzoate (12.5 μL, 0.1 mmol), 2-phenyl-N-methylaniline (19.7 mg, 0.1 mmol), and TBME (0.5 mL). The microwave vial was sealed with a lid and removed from the glove box. The reaction mixture was heated in an oil bath at 110°C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, and exposed to air before being quenched by the slow addition of three drops of water. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3 x 1 mL). The combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluting with petroleum ether:ethyl acetate = 100:1) to afford the product (26.0 mg, 92% yield) as a white solid. 1H NMR(400MHz,Chloroform-d)δ7.96(d,J=7.1Hz,1H),7.54-7.37(m,11H),7.30(q,J=7.6Hz,2H),3.76(s,3H)ppm. 13 C NMR(101MHz,Chloroform-d)δ137.7,137.3,135.2,131.8,131.1,129.8,128.3,128.1,128.0,126.9,125.5,122.2,120.2,119.6,115.0,109.6,30.8ppm。

Claims

1. A method for synthesizing N-methyl-2-phenylindole, characterized in that: In an inert gas environment, a methyl benzoate compound or methyl isonicotinate shown in Formula 1 and an N-methyl-o-toluidine compound shown in Formula 2 are mixed with methyl tert-butyl ether in the presence of lithium bis(trimethylsilyl)amide and cesium fluoride to synthesize N-methyl-2-phenylindole shown in Formula 3; Wherein R1 is selected from any one of phenyl, 4-methylphenyl, 4-tert-butylphenyl, 4-fluorophenyl, and 4-pyridyl, R2 is selected from any one of H, methyl, and phenyl, and R3 is selected from any one of H, methyl, methoxy, and halogen atom.

2. The synthesis method according to claim 1, wherein The inert gas is nitrogen.

3. The synthesis method according to claim 1, wherein The reaction temperature was 110°C.

4. The synthesis method according to claim 1, wherein The methyl benzoate compound or methyl isonicotinate, N-methyl-o-toluidine compound and the product N-methyl-2-phenylindole are as shown in one of the following tables:

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