A method for preparing a bisindole methane alkaloid and derivatives thereof using a recyclable photocatalyst

Abstract

The application discloses a preparation method of a bisindole methane type alkaloid and derivatives thereof by using a recyclable photocatalyst, and comprises the following steps: dissolving the photocatalyst in acetonitrile, adding aniline derivatives, indole compounds and organic acids in a molar ratio of 1:(2-3):(2-3), and irradiating under sunlight, a white light, a single wavelength 456nm or 427nm blue light source in an air or oxygen atmosphere, maintaining room temperature for 0.5-6h to obtain the bisindole methane type alkaloid and derivatives thereof; compared with the prior art, the application has the advantages of mild reaction conditions, reaction under sunlight in air, easy availability of the photocatalyst which can be recycled and used repeatedly, environmental protection of the solvent, high reaction yield, low cost of raw materials and simple operation.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis preparation, and particularly relates to a preparation method of a bisindole methane type alkaloid and a derivative thereof catalyzed by a recyclable photocatalyst. BACKGROUND

[0002] An indole group is a common mother nucleus in organic synthesis, and is widely used in the fields of organic chemistry and natural drug chemistry to construct complex organic molecules with biological activity. Among them, bisindole methane has physiological activities such as bacteriostasis, oxidation resistance, anti-inflammatory and anti-tumor. Although the methods for preparing bisindole methane compounds are reported more, there are still some problems in the preparation of bisindole methane compounds, such as long reaction time, high reaction temperature, complex catalyst preparation and the like. Therefore, it is of certain practical significance to find a simple operation, mild reaction condition and high yield synthesis method.

[0003] Metal-free reaction, green solvent, recyclable catalyst and photocatalysis are all important methods to realize "green chemistry". Among them, the use of recyclable catalysts is not only green and environmentally friendly, but also can save costs, which has attracted widespread attention of industrial production.

[0004] Although the heterogeneous catalysts that can be recycled have been developed, there are always problems of poor reactivity and selectivity in the reaction. In contrast, homogeneous catalysts have better reaction activity, but it is difficult to separate and recycle them, which wastes catalysts and increases production costs.

[0005] Visible light-mediated photoredox reactions have attracted increasing interest. Compared with traditional photocatalysts, uranyl salt photocatalysts are an ideal water-soluble photoredox catalyst, which is also soluble in some organic solvents. Uranyl salt catalysts have a high redox potential (E = +2.6 V vs. standard hydrogen electrode) under the excitation of visible light. 99.3% of natural uranium is composed of non-fissile isotopes with little radioactivity 238 U group, which is the main by-product of uranium enrichment. Only 5% of this material is reused.

[0006] Visible light-induced aerobic oxidative cross-coupling of glycine derivatives with indoles: a facile access to 3,3' bisindolylmethanes. Yuan Zhang*, Xiaorong Yang, Huang Zhou,, Shilin Li, Yin Zhu, and Ying Li*. Org. Chem. Front. 2018, 5, 2120-2125. reported a visible light-induced aerobic oxidative cross-coupling of glycine derivatives with indoles to synthesize 3,3'-bisindolylmethanes (BIMs). The reaction proceeds smoothly under mild conditions with good functional group tolerance. However, the reaction needs 36 h. The method only reports the ester-substituted aniline, benzyl, and alkyl-substituted aniline. The scope of the substituent of indole is also less reported. Moreover, the catalyst cannot be recycled and the reaction time is long. SUMMARY

[0007] The purpose of the present application is to provide a preparation method of bisindole methane type alkaloids and derivatives thereof catalyzed by a recyclable photocatalyst. The photocatalyst used in the method does not use noble metals and can be recycled. The reaction conditions are mild.

[0008] In order to achieve the above purpose, the technical scheme adopted by the present application is as follows:

[0009] The first aspect of the present application provides a preparation method of bisindole methane type alkaloids and derivatives thereof catalyzed by a recyclable photocatalyst, comprising the following steps:

[0010] The photocatalyst is dissolved in acetonitrile, and aniline derivatives, indole compounds, and organic acids are added in a molar ratio of 1:(2-3):(2-3) (preferably 1:2.1:2). The reaction is carried out under air or oxygen atmosphere, irradiated by sunlight, white light, single wavelength 456 nm or 427 nm blue light source, and maintained at room temperature for 0.5-6 h to obtain bisindole methane type alkaloids and derivatives thereof.

[0011] The photocatalyst is uranyl oxy cation salt, such as uranyl nitrate hexahydrate, wherein the molecular formula of uranyl nitrate hexahydrate is (UO2(NO3)2·6H2O), or uranyl acetate dihydrate, etc.

[0012] The organic acid is trifluoroacetic acid, citric acid, acetic acid, etc.

[0013] The molar ratio of the photocatalyst to the indole compound is (0.015-0.04):1 (preferably 0.02:1).

[0014] said aniline derivative is selected from one of the following compounds:

[0015]

[0016] wherein,

[0017] R1is selected from hydrogen, C1-C5alkyl, C1-C5alkoxy, phenoxy, benzyloxy, phenyl;

[0018] R2is selected from C1-C5alkyl, phenyl, benzyl,

[0019] R3is selected from C1-C5alkyl, phenyl,

[0020]

[0021] R 10 selected from hydrogen, C1-C5alkyl, C1-C5alkoxy, -CF3;

[0022] R 11 selected from hydrogen, C1-C5alkyl, C1-C5alkoxy, -CF3;

[0023] R 12 selected from hydrogen, C1-C5alkyl, C1-C5alkoxy, -CF3;

[0024] R 13 selected from hydrogen, C1-C5alkyl, C1-C5alkoxy, -CF3;

[0025] R 14 selected from hydrogen, C1-C5alkyl, C1-C5alkoxy, -CF3;

[0026] said indole compound has the following structure:

[0027] wherein,

[0028]

[0029] R4is selected from hydrogen, C1-C5alkyl, benzyl, phenyl,

[0030] R5is selected from hydrogen, C1-C5alkyl, benzyl, phenyl,

[0031] R6is selected from hydrogen, C1-C5alkyl, C1-C5alkoxy, halogen, nitro;

[0032] R7is selected from hydrogen, C1-C5alkyl, C1-C5alkoxy, halogen, nitro;

[0033] R8is selected from the group consisting of hydrogen, C1-C5alkyl, C1-C5alkoxy, halogen, nitro;

[0034] R9is selected from the group consisting of hydrogen, C1-C5alkyl, C1-C5alkoxy, halogen, nitro.

[0035] In the aniline derivatives,

[0036] R1is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, n-butyl, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, phenoxy, benzyloxy, phenyl;

[0037] R2is selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, n-butyl, phenyl, benzyl,

[0038] R3is selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, n-butyl, phenyl,

[0039]

[0040] R 10 selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, n-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy, -CF3;

[0041] R 11 selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, n-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy, -CF3;

[0042] R 12 selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, n-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy, -CF3;

[0043] R 13 selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, n-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy, -CF3;

[0044] R 14 selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, n-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy, -CF3.

[0045] The aniline derivatives are selected from one of the following compounds:

[0046]

[0047] In the indole compounds,

[0048] R4is selected from the group consisting of hydrogen, methyl, ethyl, benzyl, phenyl,

[0049] R5 is selected from hydrogen, methyl, ethyl, benzyl, phenyl,

[0050] R6 is selected from hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, nitro;

[0051] R7 is selected from hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, nitro;

[0052] R8 is selected from hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, nitro;

[0053] R9 is selected from hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, nitro.

[0054] The indole compound is selected from one of the following compounds:

[0055]

[0056] The photocatalyst can be recycled and used at least four times.

[0057] Due to the adoption of the above technical solutions, the present application has the following advantages and beneficial effects:

[0058] The present application has the following advantages and beneficial effects:

[0059] Compared with the prior art, the present application has the following advantages and beneficial effects:

[0060] In the present application, the photocatalyst can be recycled and used at least four times, and the conversion rate is high. Moreover, the reaction time is greatly shortened compared with the prior art, and the reaction can be completed within 3 hours, saving manpower and resources.

[0061] Compared with the method reported in the prior art, the present application is not limited to ester aniline, but can also react with alkyl and aryl aniline, which greatly improves the substrate range and can directly synthesize natural alkaloids such as turbomycin A, turbomycin B, vibrindole A, arsindoline A, streptindole, and their derivatives. The present application can efficiently and greenly implement a kilogram-scale reaction, and is more practical. DETAILED DESCRIPTION

[0062] In order to make the present application clearer, further description will be made to the present application with reference to preferred embodiments. It should be understood by those skilled in the art that the following description is illustrative rather than limiting and is not intended to limit the scope of the present application.

[0063] Example 1

[0064] In a 4 mL glass bottle, add uranyl nitrate hexahydrate (0.002 mmol, 1 mg), where the molecular formula of uranyl nitrate hexahydrate is (UO2(NO3)2·6H2O), add 1 mL of acetonitrile, then add 0.1 mmol of trifluoroacetic acid, 0.05 mmol of aniline derivative and 0.105 mmol of indole compound, irradiate under sunlight or turn on white light or single wavelength 456 nm blue light source, irradiate the reaction under uniform stirring, and maintain room temperature using a fan. The reaction is completed after 3 h, spin dry the solvent, add 1 mL of water and 2 mL of organic solvent (ethyl acetate or dichloromethane, etc.) to extract 3 times, combine the organic phase, spin dry using a rotary evaporator, and freeze dry the water layer for standby. Purify the organic phase by column chromatography, use petroleum ether: ethyl acetate (3:1 v / v) as the mobile phase, obtain the reaction product, and the conversion rate and the structure of each substance are shown in Table 1.

[0065] Table 1

[0066]

[0067]

[0068]

[0069] As can be seen from Table 1, the selectivity of the catalytic reaction system is high. Among them, the yield of the ester group p-methoxy aniline reaction is higher than that of the alkyl p-methoxy aniline The yield of the electron-donating group indole reaction is higher than that of the electron-withdrawing group indole .

[0070] Example 2

[0071] Stability of uranyl nitrate hexahydrate photocatalyst:

[0072] In a 4 mL glass bottle, add uranyl nitrate hexahydrate (0.002 mmol, 1 mg), where the molecular formula of the uranyl nitrate hexahydrate is (UO2(NO3)2·6H2O), add 1 mL of acetonitrile, then add 0.1 mmol of trifluoroacetic acid, 0.05 mmol of 2-[(4-methoxyphenyl)amino]acetic acid ethyl ester and 0.105 mmol of indole, turn on the blue light source of single wavelength 456 nm, irradiate the reaction under uniform stirring, and maintain room temperature using a fan. The reaction is completed after 3 h, the solvent is spin-dried, 1 mL of water and 2 mL of organic solvent (ethyl acetate or dichloromethane, etc.) are added for extraction three times, the organic phases are combined, the aqueous phase is reserved, and the aqueous phase is freeze-dried for preparation for testing the stability of the uranyl nitrate hexahydrate photocatalyst. The organic phase is spin-dried using a rotary evaporator. Column chromatography is used for separation and purification, and the mobile phase uses petroleum ether: ethyl acetate (3:1 v / v) to obtain the product.

[0073] The reserved freeze-dried residue of the aqueous phase is directly used, 0.05 mmol of 2-[(4-methoxyphenyl)amino]acetic acid ethyl ester and 0.105 mmol of indole are added, a blue light source of single wavelength 456 nm is turned on, the reaction is irradiated under uniform stirring, and room temperature is maintained using a fan. The reaction is completed after 3 h, the solvent is spin-dried, 1 mL of water and 2 mL of organic solvent (ethyl acetate or dichloromethane, etc.) are added for extraction three times, the organic phases are combined, the aqueous phase is reserved, and the aqueous phase is freeze-dried. The organic phase is spin-dried using a rotary evaporator. Column chromatography is used for separation and purification, and the mobile phase uses petroleum ether: ethyl acetate (3:1 v / v) to obtain the product. The next reaction is carried out according to the above reaction procedure, and the cycle is repeated four times in turn, and the stability of the catalyst is shown in Table 2:

[0074] Table 2

[0075] Cycle number Illumination time Conversion rate (%) 1 3 93 2 3 90 3 3 85 4 3 73

[0076] As shown in Table 2, the uranyl nitrate hexahydrate can still achieve similar conversion rates by extending the time when it is used for four cycles, which indicates that the uranyl nitrate hexahydrate used in the application has good stability as a catalyst in photocatalytic reactions.

[0077] Example 3

[0078]

[0079] Table 3

[0080]

[0081]

[0082] In Table 3, other conditions are the same as in Example 1, and the best conditions are screened by changing different conditions.

[0083] The photocatalyst in Example 1 was replaced by uranyl acetate dihydrate compound, and other conditions were the same as in Example 1, and the conversion rate was only 57%. No photocatalyst was added in Example 1, and it was found that the reaction could not be completed. The acetonitrile in Example 1 was replaced by water and ethanol respectively, and other conditions were the same as in Example 1, and the conversion rates were 20% and 45% respectively. The trifluoroacetic acid in Example 1 was replaced by citric acid, and other conditions were the same as in Example 1, and the conversion rate was 25%. If no trifluoroacetic acid was added, the conversion rate was 18%. When the amount of trifluoroacetic acid added in Example 1 was 1 equivalent, the conversion rate was only 48%.

[0084] The above is obtained by screening the catalyst, organic acid, and solvent to obtain the optimal reaction conditions of the application.

[0085] Example 4

[0086] A method for preparing a biindolylmethane derivative on a gram scale:

[0087]

[0088] Bromoacetic acid (5.18 mmol, 714.5 mg) and 40 mL of dichloromethane were added to a round-bottom flask equipped with a magnetic stirring bar and argon protection. Cholesterol (5.18 mmol, 2.0 g), dicyclohexyl carbodiimide (6.22 mmol, 1.28 g), and 4-dimethylaminopyridine (0.26 mmol, 31.7 mg) were added to the mixture. The reaction mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure, and column chromatography was used for separation and purification, with petroleum ether: ethyl acetate (3:1 v / v) as the mobile phase, to obtain the product, with a yield of 91%.

[0089]

[0090] p-Methoxyaniline (3.0 mmol, 369.2 mg,) and α-bromocholesterol acetate (3.6 mmol, 1.8 g) were added to a round-bottom flask equipped with a magnetic stirring bar, and 60 mL of acetonitrile was added. The mixture was stirred at 60°C for 12 hours. The solvent was evaporated under reduced pressure, and column chromatography was used for separation and purification, with petroleum ether: ethyl acetate (1:1 v / v) as the mobile phase, to obtain the product, with a yield of 94%.

[0091]

[0092] In a 200 mL glass bottle, add uranyl nitrate hexahydrate (0.073 mmol, 36.4 mg), where the molecular formula of uranyl nitrate hexahydrate is (U02(N03)2-6H20), 37 mL of acetonitrile, 3.82 mmol of trifluoroacetic acid, 1.82 mmol of p-methoxyaniline cholesteryl ester, and 3.82 mmol of indole. Turn on the blue light source at a single wavelength of 456 nm and irradiate the reaction under uniform stirring, using a fan to maintain room temperature. The reaction is complete after 3 h, spin dry the solvents, add 40 mL of water and extract 3 times with 80 mL of organic solvent (ethyl acetate or dichloromethane, etc.), combine the organic phases and reserve the aqueous phase. Dry the organic phase using a rotary evaporator. Purify by column chromatography using petroleum ether: ethyl acetate (1 : 1 v / v) as the mobile phase to obtain the product in 88% yield.

[0093] Comparative Example 1

[0094] 2-[(4-methoxyphenyl)amino]ethyl acetate (0.2 mmol, 41.8 mg), rhodamine 6G (0.002 mmol, 1.0 mg), and indole (0.42 mmol, 49.2 mg) were added to dry DCE (4.0 mL) along with citric acid (0.3 mmol, 57.6 mg). The mixture was irradiated with a blue LED lamp (456 nm, 5 W) at room temperature in an air atmosphere. The reaction was monitored by TLC and upon completion the mixture was diluted with ethyl acetate and washed with water and brine, then dried over anhydrous MgS04. The organic layers were combined and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether: ethyl acetate (3: 1 v / v) as the eluent to obtain the product.

[0095] Comparative Example 2

[0096] To a dry vial equipped with a magnetic stir bar was added indole (1.71 mmol, 200.0 mg), ethyl bromofluoroacetate (3.42 mmol, 632.7 mg), diisopropylethylamine (3.42 mmol, 442.0 mg), Eosin Y (0.04 mmol, 28.8 mg), and dry DMF (2 mL). The mixture was purged with argon for 10 min and irradiated using a green LED lamp (530 nm, 18 W) for 36 h. Upon completion of the reaction (confirmed by TLC), the mixture was poured into a separatory funnel containing 50 mL of ethyl acetate / water (1 : 1 v / v), the layers were separated, and the aqueous layer was extracted twice with 15 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography using petroleum ether: ethyl acetate (3: 1 v / v) as the eluent to obtain the product.

[0097] Table 4

[0098] Yield Time Whether the photocatalyst can be recycled Example 1 96 3h Yes Comparative Example 1 95 36h No Comparative Example 2 83 36h No

[0099] The yield, reaction time of Example 1 and Comparative Example 1, Comparative Example 2 are shown in Table 4, the yield of Example 1 is not much different from that of Comparative Example 1, but the method time of the present application is greatly shortened from 36h of Comparative Example 1 to 3h, saving manpower and material resources. At the same time, in the method of the present application, the photocatalyst can be recycled at least four times. The photocatalysts of Comparative Example 1 and Comparative Example 2 cannot be recycled. The method of the present application meets the requirements of green and sustainable development.

[0100] The above only describes the preferred embodiments of the present application and does not limit the present application in any form. Although the present application has been disclosed as above with the preferred embodiments, it is not intended to limit the present application. Any person skilled in the art can make some changes or modifications to the above-mentioned technical content without departing from the scope of the technical solution of the present application, and any simple modification, equivalent change and modification of the above-mentioned embodiments made according to the technical essence of the present application still belong to the scope of the present application.

Claims

1. A method for preparing a bisindolemethane alkaloid and derivatives thereof using a photocatalyst which is recyclable, characterized by, The method comprises the following steps: The photocatalyst is dissolved in acetonitrile, aniline derivatives, indole compounds and organic acids are added in a molar ratio of 1:(2-3):(2-3), irradiation is carried out under air or oxygen atmosphere, sunlight, white light, single wavelength 456nm or 427nm blue light source, and reaction is maintained at room temperature for 0.5-6h to obtain bisindole methane alkaloids and derivatives thereof; The photocatalyst is uranyl nitrate hexahydrate; The organic acid is trifluoroacetic acid; The structures of the aniline derivatives, indole compounds, bisindole methane alkaloids and derivatives thereof are shown as follows:

2. The method for preparing a bisindolemethane alkaloid and derivatives thereof using a recoverable photocatalyst according to claim 1, characterized by, The molar ratio of the photocatalyst to the indole compound is (0.015-0.04):1.

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