3, 3-bisindole dialkyl compound and synthesis method thereof

Abstract

The invention discloses a 3, 3-bisindole dialkyl compound and a synthesis method thereof, and the synthesis method comprises the following steps: (1) putting indole and a derivative thereof, a palladium catalyst, a ligand, alkali, a solvent and 3-bromo-3, 3-difluoropropylene into a reaction bottle, and carrying out a heating reaction at 80-100 DEG C for 6-12 h; and (2) after the reaction is finished, cooling to room temperature, extracting, removing the solvent by rotary evaporation, then adding dichloromethane into a reaction flask, adding silica gel, uniformly stirring to obtain a powdery solid, and finally separating and purifying by using a chromatographic column to obtain the 3, 3-bisindole dialkyl compound. According to the 3, 3-bisindole dialkyl compound and the synthesis method thereof, the fluorine-containing olefin with strong electron-withdrawing capability and the C-3 site of indole are more easily subjected to electrophilic substitution, the method has higher reaction activity and a wide application range, the temperature required by the reaction is lower, the reaction time is shorter, the reaction yield is considerable, the highest reaction yield can reach 88%, and the method is suitable for industrial production. The method has positive significance on green chemical synthesis.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, in particular to a 3,3-bisindoledialkyl compound and a synthesis method thereof, in particular to a method for synthesizing the 3,3-bisindoledialkyl compound with palladium catalysis. Background Art

[0002] Indole and its derivatives are widely used in the fields of medicine and pesticides, such as indomethacin, acemetacin, tolmetin, plant growth regulators, fungicides, etc. It is a very important type of functional group transformation skeleton in organic synthetic chemistry and can undergo a variety of chemical transformations.

[0003] The electron cloud density at the C-3 position of indole is higher and the nucleophilicity is stronger. Indole dialkyl compounds synthesized by CC coupling at its C-3 position are a class of organic molecules with important biological activity, which are of great significance for drug development and biochemical research. It has multiple pharmacological effects such as anti-cancer, anti-inflammatory and antioxidant, and can be used to treat various diseases, such as cancer, inflammatory diseases and nervous system diseases. There are many methods for synthesizing such compounds, among which the most commonly used method is to prepare them through the condensation reaction of indole with aldehydes, ketones, olefins, ethers and carboxylic acid compounds, but the reaction efficiency of its preparation process is low and the selectivity of the obtained product is also low. Therefore, in the process of synthesizing 3,3-bisindole dialkyl compounds, selecting suitable reaction conditions and catalysts is crucial for the efficiency and selectivity of the reaction. Summary of the invention

[0004] The purpose of the present invention is to provide a 3,3-bisindole dialkyl compound and a synthesis method thereof, so as to solve the problems of low reaction efficiency and low product selectivity of the current method for preparing 3,3-bisindole dialkyl compounds. The present invention uses transition metal to catalyze indole and fluorine-containing olefins to achieve the synthesis of 3,3-bisindole dialkyl compounds, and the fluorine-containing olefins with strong electron-withdrawing ability are more likely to undergo electrophilic substitution with the C-3 position of indole. This method has high reaction activity and a wide range of applications, and the reaction temperature required is low, the reaction time is short, and the reaction yield is considerable, up to 88%, which has positive significance for green chemical synthesis.

[0005] To achieve the above object, the first aspect of the present invention provides a 3,3-bisindole dialkyl compound, the general structural formula of the 3,3-bisindole dialkyl compound is:

[0006]

[0007] Wherein X=H or -CH3, Y=H or Br, Z=H or Br.

[0008] The second aspect of the present invention provides a method for synthesizing a 3,3-bisindoledialkyl compound, comprising the following steps:

[0009] (1) Indole and its derivatives, palladium catalyst, ligand, base, solvent and 3-bromo-3,3-difluoropropene are placed in a reaction bottle and heated at 80-100° C. for 6-12 hours.

[0010] (2) After the reaction is completed, the mixture is cooled to room temperature, extracted, and the solvent is removed by rotary evaporation. Then, dichloromethane is added to the reaction flask, and silica gel is added and mixed to obtain a powdery solid. Finally, a chromatography column is used for separation and purification to obtain a 3,3-bisindoledialkyl compound.

[0011] The reaction bottle used in the present invention is a thick-walled pressure-resistant tube.

[0012] Preferably, the mass ratio of indole and its derivatives, base and 3-bromo-3,3-difluoropropene is 1:(1-2):(1-3); and the molar ratio of palladium catalyst and ligand is 1:2.

[0013] Preferably, indole and its derivatives are any one of 1-methylindole, 5-bromo-1-methylindole, 6-bromo-1-methylindole, indole and 5-bromoindole.

[0014] Preferably, the palladium catalyst is any one of bis(triphenylphosphine)palladium dichloride, bis(benzonitrile)palladium dichloride, bis(diphenylphosphine phenyl ether)palladium dichloride, tetrakis(triphenylphosphine)palladium, bis(dibenzylideneacetone)palladium, and palladium(II) trifluoroacetate.

[0015] Preferably, the ligand is any one of tricyclohexylphosphine, 2-dicyclohexylphosphine-2′,6′-diisopropoxy-1,1′-biphenyl, 2-(dicyclohexylphosphine)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl, tri(2-furyl)phosphine, tricyclohexylphosphine tetrafluoroborate, and methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II).

[0016] Preferably, the base is any one of potassium bicarbonate, potassium carbonate, dipotassium hydrogen phosphate, sodium bicarbonate, sodium carbonate, sodium acetate, sodium tert-butoxide, and 1,8-diazabicycloundec-7-ene.

[0017] Preferably, the solvent is any one of 1,4-dioxane, acetonitrile and N,N-dimethylformamide.

[0018] Preferably, the particle size of the silica gel is 100-200 mesh.

[0019] Therefore, the present invention adopts the above-mentioned 3,3-bisindole dialkyl compound and its synthesis method, which has the following beneficial effects:

[0020] (1) The present invention uses transition metal to catalyze the reaction of indole with fluorinated olefins to achieve the synthesis of 3,3-bisindole dialkyl compounds. The fluorinated olefins with strong electron-withdrawing ability are more likely to undergo electrophilic substitution with the C-3 position of indole. This method has high reactivity and a wide range of applications. The reaction temperature required is low, the reaction time is short, and the reaction yield is considerable, up to 88%, which has positive significance for green chemical synthesis.

[0021] (2) The synthesis of 3,3-bisindoledialkyl compounds is a challenging field. The present invention combines traditional synthesis methods with novel organic synthesis strategies to more effectively synthesize 3,3-bisindoledialkyl compounds with important biological activity and potential application value, thereby promoting progress in drug development and biochemistry.

[0022] (3) The present invention uses a thick-walled pressure-resistant tube as a reactor, which changes the traditional feeding method, is easy to operate, has low reaction energy consumption, and a simple preparation method.

[0023] (4) The present invention uses a phosphine ligand to effectively adjust the catalytic activity of the palladium catalyst, thereby achieving CC coupling at the 3-position of indole, thereby achieving high selectivity and high yield of the reaction.

[0024] The technical solution of the present invention is further described in detail below through the accompanying drawings and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the H NMR spectrum of the target product in Example 1;

[0026] Figure 2 This is the NMR carbon spectrum of the target product of Example 1. DETAILED DESCRIPTION

[0027] The present invention will be further described below. It should be noted that this embodiment is based on the technical solution and provides a detailed implementation method and a specific operation process, but the present invention is not limited to this embodiment.

[0028] Example 1

[0029] A method for synthesizing a 3,3-bisindoledialkyl compound, specifically comprising:

[0030] 1-Methylindole (131.17 mg / 1 eq), bis(triphenylphosphine)palladium dichloride (28.08 mg / 4 mol%), tricyclohexylphosphine (22.44 mg / 8 mol%), potassium bicarbonate (200.23 mg / 2 eq), 1,4-dioxane (4 mL) and 3-bromo-3,3-difluoropropene (313.92 mg / 2 eq) were placed in a thick-walled pressure tube for reaction. The reaction time was 6 h and the reaction temperature was 80°C.

[0031] After the reaction is completed, cool to room temperature, extract, remove the solvent by rotary evaporation at 40°C, then add 2 mL of dichloromethane to the reaction bottle, and add 1.5 g of silica gel and mix well to obtain a powdery solid. Finally, separate and purify with a chromatography column to obtain the target product 3,3-bisindoledialkyl compound.

[0032] The H NMR spectrum data and C NMR spectrum data of the target product are as follows, indicating that the target product 3,3-bisindole dialkyl compound in this example has been successfully synthesized. Figure 1 The target product's NMR carbon spectrum is shown in Figure 2 .

[0033] 1 H NMR (300MHz, CDCl3) δ7.73 (d, J=7.8Hz, 2H), 7.41-7.30 (m, 4H), 7.17 (t, J=8.1H z, 2H), 6.89 (s, 2H), 4.81 (q, J=6.9Hz, 1H), 3.78 (s, 6H), 1.93 (d, J=7.2Hz, 3H).

[0034] 13 C NMR (75MHz, CDCl3) δ137.41, 127.38, 126.14, 121.43, 120.40, 119.95, 118.54, 109.24, 32.70, 28.15, 22.35.

[0035] Example 2

[0036] A method for synthesizing a 3,3-bisindoledialkyl compound, specifically comprising:

[0037] 5-Bromo-1-methylindole (224.01 mg / 1 eq), bis(benzonitrile)palladium dichloride (15.32 mg / 4 mol%), 2-dicyclohexylphosphine-2′,6′-diisopropoxy-1,1′-biphenyl (37.33 mg / 8 mol%), potassium carbonate (276.42 mg / 2 eq), acetonitrile (4 mL) and 3-bromo-3,3-difluoropropene (313.92 mg / 2 eq) were placed in a thick-walled pressure tube for reaction. The reaction time was 12 h and the reaction temperature was 80°C.

[0038] After the reaction is completed, cool to room temperature, extract, remove the solvent by rotary evaporation at 40°C, then add 2 mL of dichloromethane to the reaction bottle, and add 1.5 g of silica gel and mix well to obtain a powdery solid. Finally, use a chromatography column for separation and purification to obtain the target product.

[0039] The H-NMR spectrum data of the target product are as follows, indicating that the target product 3,3-bisindoledialkyl compound in this example has been successfully synthesized.

[0040] 1 H NMR (600MHz, CDCl3) δ7.64 (d, J=1.8, 2H), 7.30-7.26 (m, 2H), 7.15 (t, J=4.2Hz, 1H) , 7.14 (s, 1H), 7.67 (s, 2H), 4.52 (q, J=7.0Hz, 1H), 3.70 (s, 6H), 1.73 (d, J=7.2, 3H).

[0041] Example 3

[0042] A method for synthesizing a 3,3-bisindoledialkyl compound, specifically comprising:

[0043] 6-Bromo-1-methylindole (224.01 mg / 1 eq), bis(diphenylphosphinophenyl ether)palladium dichloride (28.64 mg / 4 mol%), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (42.94 mg / 8 mol%), 1,8-diazabicycloundec-7-ene (304.48 mg / 2 eq), 1,4-dioxane (4 mL) and 3-bromo-3,3-difluoropropylene (313.92 mg / 2 eq) were placed in a thick-walled pressure tube for reaction. The reaction time was 12 h and the reaction temperature was 80°C.

[0044] After the reaction is completed, cool to room temperature, extract, and remove the solvent by rotary evaporation at 40°C, then add 2 mL of dichloromethane to the reaction bottle, and add 1.5 g of silica gel and mix well to obtain a powdery solid. Finally, use a chromatography column for separation and purification to obtain the target product.

[0045] The H-NMR spectrum data of the target product are as follows, indicating that the target product 3,3-bisindoledialkyl compound in this example has been successfully synthesized.

[0046] 1 H NMR (600MHz, CDCl3) δ7.32 (d, J=8.7, 4H), 7.25 (t, J=8.4Hz, 2H), 6.64 (s, 2H), 4.46 (q, J=7.0Hz, 1H), 3.56 (s, 6H), 1.64 (d, J=6.6, 3H).

[0047] Example 4

[0048] A method for synthesizing a 3,3-bisindoledialkyl compound, specifically comprising:

[0049] Indole (117.15 mg / 1 eq), bis(dibenzylideneacetone)palladium (23 mg / 4 mol%), tri(2-furyl)phosphine (18.57 mg / 8 mol%), sodium bicarbonate (168.02 mg / 2 eq), acetonitrile (4 mL) and 3-bromo-3,3-difluoropropene (313.92 mg / 2 eq) were placed in a thick-walled pressure tube for reaction. The reaction time was 12 h and the reaction temperature was 80°C.

[0050] After the reaction is completed, cool to room temperature, extract, and remove the solvent by rotary evaporation at 40°C, then add 2 mL of dichloromethane to the reaction bottle, and add 1.5 g of silica gel and mix well to obtain a powdery solid. Finally, use a chromatography column for separation and purification to obtain the target product.

[0051] The H-NMR spectrum data of the target product are as follows, indicating that the target product 3,3-bisindoledialkyl compound in this example has been successfully synthesized.

[0052] 1 H NMR (600MHz, CDCl3) δ7.81 (s, 2H), 7.56 (d, J=7.8Hz, 2H), 7.31 (d, J=8.4Hz, 2H), 7.15 (t, J=7.5Hz , 2H), 7.03 (t, J=7.5Hz, 2H), 6.87 (d, J=1.2Hz, 2H), 4.66 (t, J=7.0Hz, 1H), 1.79 (d, J=7.2Hz, 3H).

[0053] Example 5

[0054] A method for synthesizing a 3,3-bisindoledialkyl compound, specifically comprising:

[0055] 5-Bromoindole (196.05 mg / 1 eq), palladium (II) trifluoroacetate (13.30 mg / 4 mol%), 2-dicyclohexylphosphine-2′,6′-diisopropoxy-1,1′-biphenyl (37.33 mg / 8 mol%), 1,8-diazabicycloundec-7-ene (304.48 mg / 2 eq), 1,4-dioxane (4 mL) and 3-bromo-3,3-difluoropropene (313.92 mg / 2 eq) were placed in a thick-walled pressure tube for reaction. The reaction time was 12 h and the reaction temperature was 80°C.

[0056] After the reaction is completed, cool to room temperature, extract, and remove the solvent by rotary evaporation at 40°C, then add 2 mL of dichloromethane to the reaction bottle, and add 1.5 g of silica gel and mix well to obtain a powdery solid. Finally, use a chromatography column for separation and purification to obtain the target product.

[0057] The H-NMR spectrum data of the target product are as follows, indicating that the target product 3,3-bisindoledialkyl compound in this example has been successfully synthesized.

[0058] 1 H NMR (600MHz, CDCl3) δ7.89 (s, 2H), 7.62 (d, J=1.8Hz, 2H), 7.22 (d, J=1.8Hz, 1H), 7.21 (d, J=1.8 Hz, 1H), 7.18-7.15 (m, 2H), 6.86 (d, J=1.8Hz, 2H), 4.49 (t, J=7.2Hz, 1H), 1.72 (d, J=7.2Hz, 3H).

[0059] Example 6

[0060] The difference from Example 1 is that the ligand is tricyclohexylphosphine tetrafluoroborate.

[0061] Example 7

[0062] The difference from Example 1 is: methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II).

[0063] Comparative Example 1

[0064] The difference from Example 1 is that 3-bromo-3,3-difluoropropene is replaced by 3-bromopropene, and the electron-withdrawing ability of 3-bromopropene is smaller than that of 3-bromo-3,3-difluoropropene.

[0065] The yields of the target products of the embodiments and comparative examples are shown in Table 1.

[0066] Table 1

[0067]

[0068]

[0069] Therefore, the present invention adopts a 3,3-bisindole dialkyl compound of the above structure and a synthesis method thereof, and uses transition metal to catalyze indole and fluorine-containing olefins to achieve the synthesis of the 3,3-bisindole dialkyl compound, and the fluorine-containing olefin with strong electron-withdrawing ability is more likely to undergo electrophilic substitution with the C-3 position of indole. This method has high reactivity and a wide range of applications, and the reaction temperature required is low, the reaction time is short, and the reaction yield is considerable, up to 88%, which has positive significance for green chemical synthesis.

[0070] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that they can still modify or replace the technical solution of the present invention with equivalents, and these modifications or equivalent replacements cannot cause the modified technical solution to deviate from the spirit and scope of the technical solution of the present invention.

Claims

1. A 3,3-bisindoledialkyl compound, characterized in that: The general structural formula of 3,3-bisindole dialkyl compounds is: Wherein X=H or -CH3, Y=H or Br, Z=H or Br.

2. The method for synthesizing a 3,3-bisindoledialkyl compound according to claim 1, characterized in that: The following steps are involved: (1) Indole and its derivatives, palladium catalyst, ligand, base, solvent and 3-bromo-3,3-difluoropropene are placed in a reaction bottle and heated at 80-100° C. for 6-12 hours; (2) After the reaction is completed, the mixture is cooled to room temperature, extracted, and the solvent is removed by rotary evaporation. Then, dichloromethane is added to the reaction flask, and silica gel is added and mixed to obtain a powdery solid. Finally, a chromatography column is used for separation and purification to obtain a 3,3-bisindoledialkyl compound.

3. The method for synthesizing a 3,3-bisindoledialkyl compound according to claim 2, characterized in that: The mass ratio of indole and its derivatives, base and 3-bromo-3,3-difluoropropylene is 1:(1-2):(1-3); the molar ratio of palladium catalyst and ligand is 1:

2.

4. A method for synthesizing a 3,3-bisindoledialkyl compound according to claim 2, characterized in that: Indole and its derivatives are any one of 1-methylindole, 5-bromo-1-methylindole, 6-bromo-1-methylindole, indole and 5-bromoindole.

5. The method for synthesizing a 3,3-bisindoledialkyl compound according to claim 2, characterized in that: The palladium catalyst is any one of bis(triphenylphosphine)palladium dichloride, bis(benzonitrile)palladium dichloride, bis(diphenylphosphine phenyl ether)palladium dichloride, tetrakis(triphenylphosphine)palladium, bis(dibenzylideneacetone)palladium, and palladium(II) trifluoroacetate.

6. The method for synthesizing a 3,3-bisindoledialkyl compound according to claim 2, characterized in that: The ligand is any one of tricyclohexylphosphine, 2-dicyclohexylphosphine-2′.6′-diisopropoxy-1.1′-biphenyl, 2-(dicyclohexylphosphine)-3,6-dimethoxy-2′.4′,6′-triisopropyl-1,1′-biphenyl, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl, tri(2-furyl)phosphine, tricyclohexylphosphine tetrafluoroborate, and methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II).

7. The method for synthesizing a 3,3-bisindoledialkyl compound according to claim 2, characterized in that: The base is any one of potassium bicarbonate, potassium carbonate, dipotassium hydrogen phosphate, sodium bicarbonate, sodium carbonate, sodium acetate, sodium tert-butoxide, and 1,8-di-azabicycloundec-7-ene.

8. The method for synthesizing a 3,3-bisindoledialkyl compound according to claim 2, characterized in that: The solvent is any one of 1,4-dioxane, acetonitrile and N,N-dimethylformamide.

9. The method for synthesizing a 3,3-bisindoledialkyl compound according to claim 2, characterized in that: The particle size of silica gel is 100-200 mesh.

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