A 3-indolenone compound and its synthesis method

Abstract

This invention belongs to the field of organic compound preparation technology, specifically relating to a 3-indoleenone compound and its synthesis method. The synthesis method of the 3-indoleenone compound involves placing an indole compound, a palladium catalyst, a base, a solvent, a catalyst promoter, and 1-chloro-3,3,3-trifluoropropene into a high-pressure reactor for reaction. Carbon monoxide is then introduced into the reactor, and the reaction is carried out under heating conditions. After the reaction is complete, the solvent is removed using a rotary evaporator. Dichloromethane is added to the reaction flask, and silica gel is added and stirred until a powdery solid is obtained. This solid is then separated and purified using a column chromatography to obtain the 3-indoleenone compound. This invention features a simple method with low energy consumption; the use of halides as promoters effectively stabilizes the activity and lifetime of the palladium catalyst, thereby achieving C-H activation at the 3-position of indole, resulting in high selectivity and stability of the reaction; no additional oxidant is required, the reaction conditions are mild, the reaction system is simple, the synthesis cost is low, and it is environmentally friendly.

Description

Technical Field

[0001] This invention belongs to the field of organic compound preparation technology, specifically relating to a 3-indolenone compound and its synthesis method, particularly a palladium-catalyzed synthesis method for 3-indolenone compounds. Background Technology

[0002] Indole compounds are found in many natural products and are important organic raw materials and chemical products, playing a wide range of roles in the chemical and medical fields. Among the known indole natural products, more than 40 indole compounds have been found as therapeutic drugs, such as 3,5-disubstituted indoletriptans for treating migraines, antidepressants like indopine, and indomethacin for treating rheumatism or rheumatoid arthritis. Substituted indoles, especially C-3 substituted indoles, are the parent structures of some natural products and drugs, possessing strong pharmacological activity. Indole acylation is an important pathway for the direct functionalization of indole C-3, and the introduction of a carbonyl group at the C-3 position of indole is one of the important ways to derive indole as a valuable structural pillar.

[0003] Currently, there are two conversion methods for C-3 acylation of indole: Lewis acid / Brønsted acid catalysis and toxic transition metal catalysis. However, these methods suffer from problems such as harsh conditions, low selectivity, poor functional group tolerance, and excessive consumption of expensive noble metal catalysts. Furthermore, unless aromatic hydrocarbons containing directional groups are used, achieving good versatility and regioselectivity in direct carbonylation remains a challenge. Fluorine-containing molecules have wide applications, used in pharmaceuticals, agrochemicals, refrigerants, as well as in smartphone LCD displays, photovoltaic solar cells, Teflon tapes, and coatings for textiles and buildings. Introducing trifluoromethyl groups can significantly improve the chemical and metabolic stability, lipophilicity, and cell membrane permeability of organic molecules, thereby altering their activity, toxicity, and stability. Introducing trifluoromethyl groups into organic molecules can significantly change various properties of the target molecule. Organic compounds containing trifluoromethyl groups have broad application value in the synthesis of pharmaceuticals, pesticides, and liquid crystal materials. Under mild reaction conditions, introducing trifluoromethyl groups into organic compounds has been a research hotspot. Summary of the Invention

[0004] The purpose of this invention is to provide a 3-indoleenone compound and a method for its synthesis, particularly a palladium-catalyzed method for synthesizing 3-indoleenone compounds. This invention uses palladium as a catalyst to achieve the synthesis of fluorinated indoleenone compounds at the 3-position under relatively mild conditions.

[0005] The implementation process of this invention is as follows:

[0006] A method for synthesizing a 3-indolenone compound involves placing an indole compound, a palladium catalyst, a base, a solvent, a catalyst promoter, and 1-chloro-3,3,3-trifluoropropene into a high-pressure reactor for reaction. Carbon monoxide is then introduced into the reactor, and the reaction is carried out under heating conditions. After the reaction is complete, the catalyst is filtered out, the solvent is removed using a rotary evaporator, and dichloromethane is added to the reaction flask along with silica gel. The mixture is stirred to obtain a powdered solid, which is then separated and purified using a chromatography column to obtain the 3-indolenone compound.

[0007] Furthermore, the mass ratio of the indole compound, palladium catalyst, base, solvent, catalyst promoter and 1-chloro-3,3,3-trifluoropropene is 1:0.02:2:2:1.5:0.03.

[0008] Furthermore, the indole compound is selected from any one of 1-methylindole, 5-fluoro-1,2-dimethylindole, 7-aza-1-methylindole, 5-trifluoromethyl-1-methylindole, and 1,2-dimethylindole.

[0009] Furthermore, the palladium catalyst is selected from any one of palladium acetate, palladium acetylacetonate, palladium bis(triphenylphosphine) chloride, palladium dichlorobis(triphenylphosphine) chloride, palladium tetra(triphenylphosphine) chloride, palladium dicyanophenyl dichloride, and palladium dichloroallyl chloride dimer.

[0010] Furthermore, the alkali is selected from any one of potassium carbonate, sodium carbonate, potassium tert-butoxide, cesium carbonate, sodium acetate, triethylamine, sec-butylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, and disodium hydrogen phosphate.

[0011] Furthermore, the solvent is selected from any one of acetonitrile, toluene, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and 1,2-dichloroethane.

[0012] Furthermore, the catalyst additive is selected from any one of sodium chloride, potassium chloride, sodium iodide, potassium iodide, potassium bromide, and sodium bromide.

[0013] Furthermore, the heating conditions are in the range of 80℃ to 120℃, and the reaction time is 12 h.

[0014] Furthermore, the carbon monoxide pressure is 10–40 atm, and the silica gel is 100–200 mesh.

[0015] The 3-indolenone compound obtained by the above method.

[0016] The positive effects of this invention:

[0017] (1) The design of using a high-pressure reactor in this invention changes the traditional feeding method and realizes a simple method for synthesizing indole-enone with low reaction energy consumption.

[0018] (2) In this invention, halides are used as promoters to effectively stabilize the activity and lifetime of the palladium catalyst, thereby achieving CH activation at the 3-position of indole and realizing high selectivity and stability of the reaction.

[0019] (3) This invention does not require the addition of an oxidant, the reaction conditions are mild, the reaction system is simple, the synthesis cost is low, and it is relatively environmentally friendly. Detailed Implementation

[0020] The present invention will now be described in detail with reference to specific embodiments.

[0021] This invention starts with indole and studies the carbonylation of fluorinated olefins involved by indole. Under the catalysis of transition metal palladium, fluorinated olefins and indole compounds are synthesized in one step to fluorinated indole ketones. The mechanism is preliminarily explored. This method has the advantages of simple synthesis, high efficiency and wide substrate range, thus opening up a new route for synthesizing 3-indole ketones containing trifluoromethyl compounds. Example 1

[0022]

[0023] 1 g of 1-methylindole, 0.02 g of tetraphenylphosphine palladium catalyst, 2 g of potassium carbonate, 2 g of acetonitrile, 1.5 g of sodium chloride catalyst, and 0.03 g of 1-chloro-3,3,3-trifluoropropene were placed in an autoclave for reaction. Carbon monoxide was then introduced into the autoclave at 20 atm, and the reaction was carried out at 100°C for 12 h. After the reaction, the catalyst was filtered off, and the solvent was removed using a rotary evaporator. Dichloromethane was added to the reaction flask, and 200-mesh silica gel was added and stirred until a powdery solid was obtained. The solid was then purified by column chromatography to obtain the target product, 3-indoleenone, in 70% yield. The 1H, 1C, and 1F NMR spectra of the target product are as follows:

[0024] 1 H NMR (400 MHz, d 6 -Acetone) δ 8.51 (s, 1 H), 8.38 (d, J = 6.8 Hz, 1H), 7.65 (dd, J = 15.4, 2.1 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.40 – 7.25(m, 2H), 6.94 – 6.76 (m, 1H), 3.97 (s, 3H).

[0025] 13C NMR (101 MHz, d 6 -Acetone) δ 205.96, 180.12, 138.88, 138.14,134.14, 134.08, 134.03, 133.97, 126.53, 126.28, 125.94, 125.60, 125.26,124.98, 123.86, 122.79, 122.24, 116.27, 110.52, 33.05.

[0026] 19 F NMR (376 MHz, d 6 -Acetone) d -65.5 (s, 3 F). Example 2

[0027]

[0028] 1 g of 1,2-dimethylindole, 0.02 g of palladium acetate catalyst, 2 g of disodium hydrogen phosphate, 2 g of toluene, 1.5 g of potassium iodide catalyst, and 0.03 g of 1-chloro-3,3,3-trifluoropropene were placed in an autoclave for reaction. Carbon monoxide was then introduced into the autoclave at 10 atm, and the reaction was carried out at 80°C for 12 h. After the reaction, the catalyst was filtered off, and the solvent was removed using a rotary evaporator. Dichloromethane was added to the reaction flask, along with 100-mesh silica gel, and the mixture was stirred until a powdery solid was obtained. This powder was then purified by column chromatography to obtain the target product, 3-indoleenone, in 75% yield. The 1H, 1C, and 1F NMR spectra of the target product are as follows:

[0029] 1 H NMR (400 MHz, d 6 -Acetone) δ 8.03 (d, J = 8.9 Hz, 1H), 7.77 – 7.56(m, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.21 (q, J = 5.2, 3.8 Hz, 2H), 6.76 (dq, J= 14.0, 7.0 Hz, 1H), 3.08 (s, 3H), 2.78 (s, 3H).

[0030] 13 C NMR (101 MHz, d 6-Acetone) δ 206.64, 183.77, 146.63, 146.48,137.62, 137.56, 137.51, 137.45, 136.30, 136.14, 123.45, 122.88, 121.50,114.65, 112.21, 15.25.

[0031] 19 F NMR (376 MHz, d 6 -Acetone) δ -65.23 (s, 3 F). Example 3

[0032]

[0033] 1 g of 5-trifluoromethyl-1-methylindole, 0.02 g of palladium acetylacetone catalyst, 2 g of sodium acetate, 2 g of 1,4-dioxane, 1.5 g of sodium bromide catalyst, and 0.03 g of 1-chloro-3,3,3-trifluoropropene were placed in a high-pressure reactor for reaction. Carbon monoxide was then introduced into the reactor at 30 atm, and the reaction was carried out at 120°C for 12 h. After the reaction, the catalyst was filtered off, and the solvent was removed using a rotary evaporator. Dichloromethane was added to the reaction flask, and 150-mesh silica gel was added and stirred until a powdery solid was obtained. The solid was then purified by column chromatography to obtain the target product, 3-indoleenone compound, in 68% yield. The 1H, 1C, and 1F NMR spectra of the target product are as follows:

[0034] 1 H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 8.3 Hz, 1H), 7.91 (s, 1H), 7.64 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.40 – 7.28 (m, 1H), 6.85 (dq, J =13.5, 6.7 Hz, 1H), 3.95 (s, 3H).

[0035] 13C NMR (101 MHz, CDCl3) δ 180.88, 138.14, 136.85, 132.34, 132.29,132.23, 132.18, 128.81, 128.53, 128.18, 127.83, 127.48, 126.65, 126.33,125.93, 124.23, 123.45, 119.93, 116.75, 107.55, 33.98.

[0036] 19 F NMR (376 MHz, CDCl3) δ -65.03. (s, 3 F). Example 4

[0037]

[0038] 1 g of 7-aza-1-methylindole, 0.02 g of bis(triphenylphosphine)palladium catalyst, 2 g of cesium carbonate, 2 g of tetrahydrofuran, 1.5 g of potassium bromide catalyst, and 0.03 g of 1-chloro-3,3,3-trifluoropropene were placed in an autoclave for reaction. Carbon monoxide was then introduced into the autoclave at 40 atm, and the reaction was carried out at 110 °C for 12 h. After the reaction, the catalyst was filtered off, and the solvent was removed using a rotary evaporator. Dichloromethane was added to the reaction flask, and 200-mesh silica gel was added and stirred until a powdery solid was obtained. The solid was then purified by column chromatography to obtain the target product, 3-indoleenone, in 54% yield. The 1H, 1C, and 1F NMR spectra of the target product are as follows:

[0039] 1 H NMR (400 MHz, d 6 -Acetone) δ 8.68 (s, 1H), 8.59 (dd, J = 7.8, 1.5Hz, 1H), 8.41 (dd, J = 4.7, 1.4 Hz, 1H), 7.66 (dd, J = 15.4, 2.1 Hz, 1H), 7.31 (dd, J = 7.8, 4.7 Hz, 1H), 6.89 (dq, J = 14.2, 7.1 Hz, 1H), 3.96 (s,3H).

[0040] 13 C NMR (101 MHz, d 6-Acetone) δ 205.70, 180.43, 148.88, 144.92,138.74, 133.36, 133.30, 133.25, 133.19, 130.35, 126.89, 126.54, 126.20,125.86, 124.84, 122.16, 118.76, 118.67, 114.49.

[0041] 19 F NMR (376 MHz, d 6 -Acetone) δ -65.23 (s, 3 F). Example 5

[0042]

[0043] 1 g of 5-fluoro-1,2-dimethylindole, 0.02 g of allyl palladium chloride dimer catalyst, 2 g of sec-butylamine, 2 g of N,N-dimethylformamide, 1.5 g of potassium chloride catalyst, and 0.03 g of 1-chloro-3,3,3-trifluoropropene were placed in an autoclave for reaction. Carbon monoxide was then introduced into the autoclave at 15 atm, and the reaction was carried out at 100°C for 12 h. After the reaction, the catalyst was filtered off, and the solvent was removed using a rotary evaporator. Dichloromethane was added to the reaction flask, along with 150-mesh silica gel, and the mixture was stirred to obtain a powdery solid. The solid was then purified by column chromatography to obtain the target product, 3-indoleenone, in 60% yield. The 1H, 1C, and 1F NMR spectra of the target product are as follows:

[0044] 1 H NMR (400 MHz, d 6 -Acetone) δ 7.62 (dd, J = 10.1, 2.4 Hz, 1H), 7.51(dd, J = 15.6, 2.0 Hz, 1H), 7.45 (dd, J = 8.9, 4.5 Hz, 1H), 7.02 (td, J =9.1, 2.5 Hz, 1H), 6.79 – 6.63 (m, 1H), 3.76 (s, 3H), 2.69 (s, 3H).

[0045] 13 C NMR (101 MHz, d 6-Acetone) δ 205.72, 182.87, 160.57, 158.23,147.77, 136.81, 133.59, 126.99, 126.89, 126.03, 125.69, 113.58, 113.54,111.23, 111.13, 110.32, 110.07, 105.91, 105.66.

[0046] 19 F NMR (376 MHz, d 6 -Acetone) δ -65.23 (s, 3 F). Example 6

[0047] 1 g of 1-methylindole, 0.02 g of palladium chloride catalyst, 2 g of sodium carbonate, 2 g of 1,2-dichloroethane, 1.5 g of sodium iodide catalyst, and 0.03 g of 1-chloro-3,3,3-trifluoropropene were placed in a high-pressure reactor for reaction. Then, 10 atm of carbon monoxide was introduced into the high-pressure reactor, and the reaction was carried out at 90°C for 12 h. After the reaction was completed, the catalyst was filtered out, the solvent was removed by rotary evaporator, and dichloromethane was added to the reaction flask. At the same time, 200-mesh silica gel was added and stirred to obtain a powdered solid. The solid was separated and purified by column chromatography to obtain the target product, 3-indole-enone compound. Example 7

[0048] 1 g of 1-methylindole, 0.02 g of dichloroditriphenylphosphine palladium catalyst, 2 g of potassium tert-butoxide, 2 g of acetonitrile, 1.5 g of sodium chloride catalyst, and 0.03 g of 1-chloro-3,3,3-trifluoropropene were placed in a high-pressure reactor for reaction. Then, carbon monoxide was introduced into the high-pressure reactor at 20 atm, and the reaction was carried out at 100°C for 12 h. After the reaction was completed, the catalyst was filtered out, the solvent was removed by rotary evaporator, and dichloromethane was added to the reaction flask. At the same time, 200-mesh silica gel was added and stirred to obtain a powdered solid. The solid was separated and purified by column chromatography to obtain the target product, 3-indole-enone compound. Example 8

[0049] 1 g of 1-methylindole, 0.02 g of palladium dicyanophenyl dichloride catalyst, 2 g of triethylamine, 2 g of acetonitrile, 1.5 g of sodium chloride catalyst, and 0.03 g of 1-chloro-3,3,3-trifluoropropene were placed in a high-pressure reactor for reaction. Then, carbon monoxide was introduced into the high-pressure reactor at 20 atm, and the reaction was carried out at 100°C for 12 h. After the reaction was completed, the catalyst was filtered out, the solvent was removed by rotary evaporator, and dichloromethane was added to the reaction flask. At the same time, 200-mesh silica gel was added and stirred to obtain a powdered solid. The solid was separated and purified by column chromatography to obtain the target product, 3-indole-enone compound. Example 9

[0050] 1 g of 1-methylindole, 0.02 g of palladium dicyanophenyl dichloride catalyst, 2 g of 4-dimethylaminopyridine, 2 g of acetonitrile, 1.5 g of sodium chloride catalyst, and 0.03 g of 1-chloro-3,3,3-trifluoropropene were placed in a high-pressure reactor for reaction. Then, carbon monoxide was introduced into the high-pressure reactor at 20 atm, and the reaction was carried out at 100°C for 12 h. After the reaction was completed, the catalyst was filtered out, the solvent was removed by rotary evaporator, and dichloromethane was added to the reaction flask. At the same time, 100-mesh silica gel was added and stirred to obtain a powdered solid. The solid was separated and purified by column chromatography to obtain the target product, 3-indole-enone compound. Example 10

[0051] 1 g of 1-methylindole, 0.02 g of palladium dicyanophenyl dichloride catalyst, 2 g of N,N-dimethylaniline, 2 g of acetonitrile, 1.5 g of sodium chloride catalyst, and 0.03 g of 1-chloro-3,3,3-trifluoropropene were placed in a high-pressure reactor for reaction. Then, carbon monoxide was introduced into the high-pressure reactor at 20 atm, and the reaction was carried out at 100°C for 12 h. After the reaction was completed, the catalyst was filtered out, the solvent was removed by rotary evaporator, and dichloromethane was added to the reaction flask. At the same time, 100-mesh silica gel was added and stirred to obtain a powdered solid. The solid was separated and purified by column chromatography to obtain the target product, 3-indole-enone compound.

[0052] The synthesis method of the 3-indolenone compound described in this invention is carried out in a sealed container, and the reaction is monitored by online infrared and in-situ nuclear magnetic resonance methods. After the reaction is completed, the catalyst is separated by simple filtration before removing the solvent using a rotary evaporator. The separated catalyst can be reused while maintaining essentially the same activity, and the product separation rate is high. Therefore, the preparation process of this invention is green and environmentally friendly, and has broad prospects for industrial application.

[0053] The above description, in conjunction with specific preferred embodiments, provides a further detailed explanation of the present invention. It should not be construed that the specific implementation of the present invention is limited to these descriptions. For those skilled in the art, various simple deductions or substitutions can be made without departing from the concept of the present invention, and all such modifications and substitutions should be considered within the scope of protection of the present invention.

Claims

1. A method for synthesizing a 3-indolenone compound, characterized in that: An indole compound, a palladium catalyst, a base, a solvent, a catalyst promoter, and 1-chloro-3,3,3-trifluoropropene were placed in a high-pressure reactor for reaction. Carbon monoxide was then introduced into the reactor, and the reaction was carried out under heating conditions. After the reaction was completed, the palladium catalyst was filtered out, the solvent was removed by a rotary evaporator, and dichloromethane was added to the reaction flask. Silica gel was added and stirred to obtain a powdered solid, which was then separated and purified by a chromatography column to obtain a 3-indoleenone compound. The indole compound is selected from any one of 1-methylindole, 5-fluoro-1,2-dimethylindole, 7-aza-1-methylindole, 5-trifluoromethyl-1-methylindole, and 1,2-dimethylindole; the palladium catalyst is selected from any one of palladium acetate, palladium acetylacetonate, bis(triphenylphosphine) palladium, palladium chloride, dichlorodi(triphenylphosphine) palladium, tetra(triphenylphosphine) palladium, dicyanophenyl dichloride, and allyl palladium chloride dimer; the base is selected from any one of potassium carbonate, sodium carbonate, potassium tert-butoxide, cesium carbonate, sodium acetate, triethylamine, sec-butylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, and disodium hydrogen phosphate; the catalyst promoter is selected from any one of sodium chloride, potassium chloride, sodium iodide, potassium iodide, potassium bromide, and sodium bromide.

2. The method for synthesizing the 3-indolenone compound according to claim 1, characterized in that: The mass ratio of the indole compound, palladium catalyst, base, solvent, catalyst promoter and 1-chloro-3,3,3-trifluoropropene is 1:0.02:2:2:1.5:0.

03.

3. The method for synthesizing the 3-indolenone compound according to claim 1, characterized in that: The solvent is selected from any one of acetonitrile, toluene, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and 1,2-dichloroethane.

4. The method for synthesizing the 3-indolenone compound according to claim 1, characterized in that: The heating conditions are in the range of 80℃ to 120℃, and the reaction time is 12 h.

5. The method for synthesizing the 3-indolenone compound according to claim 1, characterized in that: The carbon monoxide pressure is 10–40 atm, and the silica gel is 100–200 mesh.

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