A method for synthesizing a lignin-based indole derivative

Abstract

The application discloses a synthesis method of a lignin-based indole derivative and belongs to the technical field of organic synthesis. The method uses a lignin beta-O-4 model compound and an N-methyl pyrrole-2-vinyl ketone compound as reaction raw materials, heats the reaction in a solvent under the action of a titanium catalyst and a 1,10 phenanthroline ligand under an air atmosphere for a certain time, and finally obtains the lignin-based indole derivative. The synthesis method for preparing the indole derivative has the advantages of green and renewable raw materials, simple operation, mild reaction conditions, high product selectivity and the like, and provides a green new way for the preparation of indole compounds.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing lignin-based indole derivatives. Background Technology

[0002] Indole and its derivatives are important fine chemical raw materials and chemical products, with wide-ranging applications in industry, agriculture, and medicine. Indole compounds, as an important class of heterocyclic compounds, possess a wide range of biological activities. Patents (CN101516366) and (CN102307868A) report various indole derivatives exhibiting excellent in vitro activity and in vivo antitumor effects. Due to their significant biopharmacological activity and unique plastic structure, the synthesis of indole derivatives has attracted widespread attention from chemists.

[0003] Currently, there are several methods for the preparation of indole derivatives (Chem.Rev.,2012,112,3508; Chem.Rev.,2006,106,2875). Among these methods, the preparation of indole derivatives from pyrrole derivatives via the construction of benzene rings is one of the rapid and efficient ways to obtain structurally diverse indole derivatives. Related preparation methods include: 1) intramolecular cyclization reaction of functionalized pyrrole derivatives (J. Am. Chem. Soc. 2006, 128, 7436); 2) intermolecular cycloaddition reaction of functionalized pyrrole with alkenes (J. Org. Chem. 2006, 71, 5249); 3) cycloaddition reaction of pyrrole with diazonenones (Angew. Chem. Int. Ed. 2014, 53, 4076); 4) oxidative cyclization reaction of pyrrole derivatives with two molecules of alkynes or β-chloroketones (J. Org. Chem. 2009, 74, 7481; Org. Chem. Front. 2015, 2, 1361). However, these methods have limitations such as non-renewable raw materials, relatively low yields, and complex operations. It is of great significance to research and develop a novel, efficient, low-energy, environmentally friendly, easy-to-operate, and green method for synthesizing indole derivatives. Summary of the Invention

[0004] To address the problems existing in the prior art, the purpose of this invention is to provide a method for preparing indole derivatives from lignin model compounds. This method has advantages such as green and renewable raw materials, simple operation, mild reaction conditions, and high product selectivity, providing a green new route for the preparation of indole compounds.

[0005] The objective of this invention is achieved through the following means:

[0006] A method for synthesizing a lignin-based indole derivative mainly includes the following steps: adding lignin β-O-4 model compound 1, N-methylpyrrole-2-vinyl ketone compound 2, titanium catalyst, and 1,10-phenanthroline to a solvent and stirring the mixture under air atmosphere for a certain time; after separation and purification, carbazole derivative 3 is obtained; the general reaction formula is:

[0007]

[0008] The R 1 and R 2 It is an alkyl, alkoxy, or hydrogen atom with 1-3 carbon atoms; R 3 It is an alkyl group having 1-3 carbon atoms, a substituted benzene ring, an aromatic heterocycle, or hydrogen; R 4 It can be methyl or hydrogen.

[0009] Furthermore, in the above technical solution, the titanium catalyst is one or more of titanium tetrachloride, titanium dioxide, titanium acetylacetonate, and titanium triisopropoxychloride.

[0010] Furthermore, in the above technical solution, the solvent is one or more of toluene, 1,4-dioxane, acetonitrile, ethanol, isopropanol, dimethyl sulfoxide, and dimethylformamide.

[0011] Furthermore, in the above technical solution, the reaction conditions are: temperature controlled at 30-150℃, and reaction time is 2-24h.

[0012] Furthermore, in the above technical solution, the molar ratio of the lignin β-O-4 model compound 1 and the N-methylpyrrole-2-vinyl ketone compound 2 is 1:1 to 5:1, preferably 2:1 to 4:1; the molar ratio of the titanium catalyst and the N-methylpyrrole-2-vinyl ketone compound 2 is 0.01:1 to 0.3:1, preferably 0.05:1 to 0.2:1; and the molar ratio of 1,10-phenanthroline and the N-methylpyrrole-2-vinyl ketone compound 2 is 0.015:1 to 0.45:1, preferably 0.015:1 to 0.3:1.

[0013] Furthermore, in the above technical solution, the lignin β-O-4 model compound 1 is selected from 1-phenyl-2-(2-methoxyphenyl)-propane-1,3-diol (1a), 1-(4-methoxyphenyl)-2-(2-methoxyphenyl)-propane-1,3-diol (1b); the N-methylpyrrole-2-vinyl ketone compound 2 is selected from N-methylpyrrole-2-phenylvinyl ketone (2a), N-methylpyrrole-2-(4-methylphenyl)vinyl ketone (2b), N-methylpyrrole-2-(4-chlorophenyl)vinyl ketone (2c), N-methylpyrrole-2-furanylvinyl ketone (2d), and N-methylpyrrole-2-cyclopropaneylvinyl ketone (2e).

[0014] The synthetic method for preparing indole compounds described in this invention has the advantages of green and renewable raw materials, simple operation, mild reaction conditions, and high product selectivity, providing a green new route for the preparation of indole compounds. Attached Figure Description

[0015] To more clearly illustrate the embodiments of the present invention, the accompanying drawings involved in the embodiments will be briefly described below.

[0016] Figure 1 1-Methyl-4,6-dibenzoylindole prepared in Example 1 1 H-NMR spectrum.

[0017] Figure 2 1-Methyl-4-(4-methoxy)benzoyl-6-benzoylindole prepared in Example 9 1 H-NMR spectrum.

[0018] Figure 3 1,2-Dimethyl-4,6-dibenzoylindole prepared in Example 14 1 H-NMR spectrum. Detailed Implementation

[0019] Lignin β-O-4 model compound 1 was prepared according to the literature (Green Chem. 2023, 25, 550-553). The preparation method for N-methylpyrrole-2-vinyl ketone compound 2 was as follows: Commercially available ethyl ketone derivative A (1 mmol), N-methylpyrrole-2-carboxaldehyde derivative B (1 mmol), and NaOH (3 mmol) were added to 5 mL of ethanol, and the mixture was stirred at room temperature for 20 h. After the reaction was stopped, the ethanol was evaporated under reduced pressure, and N-methylpyrrole-2-vinyl ketone compound 2 was obtained by column chromatography. The reaction formula is as follows:

[0020] The R 3 It is an alkyl group having 1-3 carbon atoms, a substituted benzene ring, an aromatic heterocycle, or hydrogen; R4 It is methyl or hydrogen. Compounds A and B are available from Beijing Innocare Company.

[0021] The present invention will be described in detail below with reference to the embodiments. However, the implementation of the present invention is not limited thereto. Obviously, the embodiments described below are only some embodiments of the present invention. For those skilled in the art, other similar embodiments can be obtained without creative effort and all fall within the protection scope of the present invention.

[0022] Example 1:

[0023] 1-Phenyl-2-(2-methoxyphenyl)-propane-1,3-diol 1a (110 mg, 0.4 mmol), N-methylpyrrole-2-phenylvinyl ketone 2a (42 mg, 0.2 mmol), titanium tetrachloride (TiCl4) catalyst (3.8 mg, 10 mol%), and 1,10-phenanthroline (5.4 mg, 15 mol%) were added to 5 mL of acetonitrile. The mixture was heated to 120 °C under air and stirred for 16 h. The reaction formula is shown below. After cooling to room temperature, the mixture was filtered through diatomaceous earth. 20 mL of water was added to the filtrate, and the aqueous phase was extracted with dichloromethane (2 × 15 mL), separating the organic phase. The organic phases were mixed, dried over anhydrous magnesium sulfate, and filtered. Volatile components were removed under reduced pressure, followed by separation by silica gel column chromatography (eluting buffer: petroleum ether (60-90℃) / ethyl acetate / dichloromethane, v / v / v = 250:8:20) to give a yellow solid product 3a (51 mg, 75% yield) and guaiacol 4a (45 mg, 92% yield). The target products were confirmed by NMR spectroscopy and high-resolution mass spectrometry. 1 For H-NMR characterization, please see the appendix. Figure 1 .

[0024]

[0025] Example 2

[0026] The reaction steps and operations were the same as in Example 1, except that the catalysts were titanium dioxide (TiO2) (4.8 mg, 30 mol%) and 1,10-phenanthroline (16 mg, 45 mol%). The reaction was stopped, and after post-treatment, the target product 3a (17 mg, 25% yield) was obtained. This indicates that titanium dioxide can also be used as a catalyst, but its effect is not as good as that of titanium tetrachloride.

[0027] Example 3

[0028] The reaction procedure and operation were the same as in Example 1, except that the catalyst was titanium acetylacetonate TiO(acac)₂ (0.5 mg, 1 mol%) and 1,10-phenanthroline (0.5 mg, 1.5 mol%). The reaction was stopped, and after post-treatment, the target product 3a (13 mg, yield 19%) was obtained. This indicates that titanium acetylacetonate can also be used as a catalyst, but it is not the optimal one.

[0029] Example 4

[0030] The reaction steps and operations were the same as in Example 1, except that the reaction solvent was toluene, the reaction temperature was 140°C, and the reaction time was 24 hours. The reaction was stopped, and after post-treatment, the target product 3a (53 mg, yield 78%) was obtained.

[0031] Example 5

[0032] The reaction steps and operations were the same as in Example 1, except that the reaction solvent was dimethyl sulfoxide, the reaction temperature was 150°C, and the reaction time was 2 hours. The reaction was stopped, and after post-treatment, the target product 3a (10 mg, yield 15%) was obtained.

[0033] Example 6

[0034] The reaction steps and operations were the same as in Example 1, except that the reaction solvent was ethanol, the reaction temperature was 30°C, and the reaction time was 12 hours. The reaction was stopped, and after post-processing, the target product 3a (13 mg, yield 20%) was obtained.

[0035] Example 7

[0036] The reaction procedure and operation were the same as in Example 4, except that 1-phenyl-2-(2-methoxyphenyl)-propane-1,3-diol 1a (55 mg, 0.2 mmol) was added to stop the reaction, and the target product 3a (31 mg, yield 46%) was obtained after post-treatment. This indicates that reducing the amount of 1a is detrimental to the reaction.

[0037] Example 8

[0038] The reaction procedure and operation were the same as in Example 4, except that 1-phenyl-2-(2-methoxyphenyl)-propane-1,3-diol 1a (275 mg, 1.0 mmol) was added, the reaction was stopped, and the target product 3a (50 mg, yield 76%) was obtained after post-treatment. This indicates that further increasing the amount of 1a has little effect on the reaction.

[0039] Example 9

[0040]

[0041] The reaction procedure and operation were the same as in Example 4, except that 1-(4-methoxyphenyl)-2-(2-methoxyphenyl)-propane-1,3-diol 1b (122 mg, 0.4 mmol) was added to the reaction system. The reaction was stopped, and after post-processing, the target product 3b (50 mg, yield 68%) was obtained as a pale yellow solid. The target product was confirmed by NMR spectroscopy and high-resolution mass spectrometry.

[0042] Example 10

[0043]

[0044] The reaction procedure and operation were the same as in Example 4, except that 2-enylpyrrole derivative 2b (45 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and after post-processing, the target product 3c (53 mg, 75% yield) was obtained as a pale yellow solid. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0045] Example 11

[0046]

[0047] The reaction procedure and operation were the same as in Example 4, except that the 2-enylpyrrole derivative added to the reaction system was 2c (49 mg, 0.2 mmol). The reaction was stopped, and after post-treatment, the target product 3d (54 mg, yield 72%) was obtained as a white solid. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0048] Example 12

[0049]

[0050] The reaction procedure and operation were the same as in Example 4, except that the 2-enylpyrrole derivative added to the reaction system was 2d (40 mg, 0.2 mmol). The reaction was stopped, and after post-processing, the target product 3e (44 mg, yield 67%) was obtained as a pale yellow solid. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0051] Example 13

[0052]

[0053] The reaction procedure and operation were the same as in Example 4, except that the 2-enylpyrrole derivative added to the reaction system was 2e (35 mg, 0.2 mmol). The reaction was stopped, and after post-processing, the target product 3f (34 mg, yield 56%) was obtained as a pale yellow oily liquid. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0054] Example 14

[0055]

[0056] The reaction procedure and operation were the same as in Example 4, except that the 2-enylpyrrole derivative added to the reaction system was 2f (45 mg, 0.4 mmol). The reaction was stopped, and after post-treatment, 3 g (48 mg, yield 68%) of the white solid target product was obtained. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0057] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing a lignin-based indole derivative 3, characterized in that: Lignin β-O-4 model compound 1, N-methylpyrrole-2-vinyl ketone compound 2, titanium catalyst, and 1,10-phenanthroline were added to a solvent and reacted under air atmosphere with stirring for a certain time. After separation and purification, indole derivative 3 was obtained. The reaction formula is: In the reaction formula, R 1 and R 2 It is an alkyl, alkoxy, or hydrogen atom with 1-3 carbon atoms; R 3 It is an alkyl group with 1-3 carbon atoms, a substituted benzene ring, or an aromatic heterocycle; R 4 It can be methyl or hydrogen; The titanium catalyst is one or more of titanium tetrachloride, titanium dioxide, titanium acetylacetonate, and titanium triisopropoxychloride.

2. The synthesis method according to claim 1, characterized in that, The solvent is one or more of toluene, 1,4-dioxane, acetonitrile, ethanol, isopropanol, dimethyl sulfoxide, and dimethylformamide.

3. The synthesis method according to claim 1, characterized in that, The reaction conditions are: temperature controlled at 30-150 ℃, and reaction time of 2-24 h.

4. The synthesis method according to claim 1, characterized in that, The molar ratio of the lignin β-O-4 model compound 1 to N-methylpyrrole-2-vinyl ketone compound 2 is 1:1 to 5:1; the molar ratio of the titanium catalyst to N-methylpyrrole-2-vinyl ketone compound 2 is 0.01:1 to 0.3:1; and the molar ratio of 1,10-phenanthroline to N-methylpyrrole-2-vinyl ketone compound 2 is 0.015:1 to 0.045:1.

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