A method for preparing a photocatalytic polysubstituted indole compound

Abstract

The application belongs to the technical field of organic chemistry, and particularly relates to a preparation method of photocatalytic polysubstituted indole compounds. 1 H NMR, 13 C NMR, HRMS, single crystal X-ray diffraction and other methods are used for characterization and confirmation. The method of the application is that, in the presence of a proton acid, 2-indole methanol is de- aromatized to form an imine cation intermediate, then the intermediate is reacted with alkyl radicals generated by hydrogen atom transfer (HAT) of alkane under the catalysis of tetrabutylammonium decatungstate (TBADT) to obtain 2,3-dialkyl substituted indole compounds I through isomerization. The method has the advantages of simple reaction, high efficiency, few side reactions, high product purity, easy separation and purification, mild conditions, wide application range of substrates, simple raw materials, low cost, applicability to large-scale preparation and good application prospect.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic chemistry, and particularly relates to a preparation method of a photocatalytic polysubstituted indole compound. BACKGROUND

[0002] The indole skeleton is one of common heterocyclic structures, and exists in a plurality of drug molecules with significant biological activity. Some typical indole core skeletons are disclosed in the prior art, including: a drug molecule Panobinostat, which can be used as a histone deacetylase inhibitor (J.M. Annemieke, A.H. Gennip, H.N. Caron, S. Kemp, Biochemical Journal, 2003, 370, 737-49.); Macimorelin acetate, which can be used for treating adult growth hormone deficiency (J.M. Garcia, R. Swerdloff, C. Wang, M. Kyle, M. Kipnes, B.M.K. Biller, D. Cook, K.C J Yuen, V. Bonert, A. Dobs, M.E. Molitch, G.R. Merriam, J Clin Endocrinol Metab, 2013, 98, 2422-2429); Indomethacin, which can be used for treating migraine and the like, antipyretic analgesic (H. El-Shattawy, A. Kassem, S. Omar, A. Sami, A.E.D. Yassin, Drug Development and Industrial Pharmacy, 1994 20, 901-909.); due to the wide biological activity and potential application of indole compounds, chemists continue to develop new structures based on the indole skeleton and new synthesis methods thereof.

[0003] Hydrogen atom transfer (HAT) is a basic reaction in radical reactions, and provides a favorable means for structural modification of natural skeleton compounds with potential biological activity. At present, conversion of alkanes through photocatalytic HAT is a research hotspot in the field of organic chemistry. Based on this, the present application utilizes photocatalytic hydrogen atom transfer to alkylate 2-indolylmethanol, and provides a new technology for efficiently synthesizing polysubstituted indole compounds. SUMMARY

[0004] The present application aims to provide a simple and efficient preparation method of polysubstituted indole compounds.

[0005] The application provides a preparation method of a polysubstituted indole compound, which is alkane functionalization on a third position of 2-indole methanol through hydrogen atom transfer under photocatalysis, and provides a high-efficiency synthesis of a polysubstituted indole compound.

[0006] Specifically, the method is an indole alkylation reaction of 2-indole methanol and alkane under ultraviolet light irradiation in an organic solvent (such as acetonitrile) using TBADT (tetrabutylammonium decatungstate) as a catalyst in the presence of a proton acid (such as p-toluenesulfonic acid), and a polysubstituted indole compound I is efficiently prepared, and the reaction formula is as follows:

[0007]

[0008] R 1 is an H atom, an electron-donating or electron-withdrawing substituent; the electron-donating substituent is an alkyl group, a methoxy group, an acyloxy group, an amido group or the like; the electron-withdrawing substituent is a halogen atom, an ester group, a nitro group, a cyano group or the like;

[0009] R 2 , R 3 is a phenyl group, an aromatic substituent containing an electron-donating group or an electron-withdrawing group, or an alkyl group; the aromatic substituent containing the electron-donating group is a meta-methylphenyl group, a para-methylphenyl group, an ortho-methoxyphenyl group, a para-methoxyphenyl group or the like; the aromatic substituent containing the electron-withdrawing group is a meta-fluorophenyl group, a para-fluorophenyl group, a para-chlorophenyl group, a para-bromophenyl group or the like;

[0010] R 4 is an alkyl group;

[0011] R 5 is an H atom or an alkyl group.

[0012] The specific steps of the method are as follows:

[0013] (1) catalyst TBADT, a proton acid, 2-indole methanol and a substrate alkane or aldehyde are sequentially added in a reaction tube, nitrogen is replaced, then an organic solvent is added, and stirring is performed under ultraviolet light irradiation for 0.5-3 hours until complete reaction is detected by TLC;

[0014] (2) the reaction liquid is concentrated and column chromatography is performed to separate to obtain the corresponding polysubstituted indole compound.

[0015] The reaction yield is 80-95%.

[0016] The structure of the compound is characterized and confirmed by H NMR, C NMR, HRMS and single crystal X-ray diffraction. 1 H NMR, 13 C NMR, HRMS, single crystal X-ray diffraction and the like.

[0017] In the present application, the organic solvent used in the reaction system in step (1) is MeCN, DCE, DMSO, or DCM.

[0018] In the present application, the amount of alkane used in the reaction system is 2.0-10.0 equivalents based on 1.0 equivalent of 2-indolylmethanol.

[0019] In the present application, the amount of catalyst TBADT used in the reaction system is 0.01-0.02 equivalents based on 1.0 equivalent of 2-indolylmethanol.

[0020] In the present application, the amount of protonic acid used is 0.05-0.15 equivalents based on 1.0 equivalent of 2-indolylmethanol, and the acid used in the reaction system is p-toluenesulfonic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, or benzoic acid.

[0021] In the present application, the reaction temperature of the reaction system is 20-40℃, and the reaction time is 0.5-3 hours.

[0022] The method of the present application has the advantages of simple and efficient reaction, less side reaction, high product purity, easy separation and purification, mild conditions, wide range of applicable substrates, simple and readily available raw materials, low cost, and good application prospect. DETAILED DESCRIPTION

[0023] Example 1

[0024]

[0025] At room temperature, a dry test tube was taken and a stirring bar was added, and TBADT (6.6 mg, 0.002 mmol), 2-indolylmethanol (29.9 mg, 0.1 mmol), and p-toluenesulfonic acid (1.7 mg, 0.01 mmol) were weighed and sealed, and replaced with N2 three times. Acetonitrile (1.0 mL) was used as the solvent, and cyclohexane (0.1 mL, 1 mmol) was added to the test tube. Under the condition of normal temperature and nitrogen environment, 370 nm ultraviolet light was used for irradiation and stirring, and the reaction was carried out for 0.5 h. After the reaction was completed, the product was concentrated and separated by column chromatography to obtain the corresponding indole compound Ia.

[0026] 1H NMR (400 MHz, CDC13) δ 7.76 (d, J = 7.4 Hz, 1H), 7.42 (s, 1H), 7.33-7.27 (m, 4H), 7.27-7.23 (m, 2H), 7.22-7.18 (m, 1H), 7.16-7.12 (m, 4H), 7.10-7.02 (m, 2H), 5.84 (s, 1H), 2.73 (tt, J = 12.3, 3.6 Hz, 2H), 1.96-1.85 (m, 2H), 1.81-1.74 (m, 2H), 1.71-1.63 (m, 2H), 1.32-1.20 (m, 4H). 13 C NMR (101 MHz, CDC13) δ 142.5, 135.8, 134.2, 129.1, 128.7, 127.6, 126.9, 121.0, 120.5, 118.9, 118.3, 111.0, 48.5, 36.7, 33.0, 27.4, 26.4. HRMS (ESI): Calcd for [C 27 H 27 N+H] + : 366.2222, found: 366.2220.

[0027] Example 2

[0028]

[0029] The dry test tube was taken at room temperature, and a stirring bar was added, and TBADT (6.6 mg, 0.002 mmol), 2-indolemethanol (29.9 mg, 0.1 mmol), p-toluenesulfonic acid (1.7 mg, 0.01 mmol) were weighed in, and it was sealed and replaced with N2 three times. Ethylbenzene (0.12 mL, 1 mmol) was added to the test tube using acetonitrile (1.0 mL) as the solvent. It was irradiated and stirred under the condition of room temperature and nitrogen environment using 370 nm ultraviolet light, and the reaction was carried out for 0.5 h. After the reaction was completed, it was concentrated and column chromatography was used to separate to obtain the corresponding indole compound Ib.

[0030] 1 H NMR (400 MHz, CDC13) δ 7.52 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.32-7.24 (m, 8H), 7.23-7.21 (m, 1H), 7.19-7.15 (m, 1H), 7.13-7.10 (m, 2H), 7.10-7.05 (m, 3H), 7.01-6.96 m, 1H), 5.74 (s, 1H), 4.47 (q, J = 7.2 Hz, 1H), 1.64 (d, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDC13) δ 145.7, 142.3, 142.3, 135.7, 135.3, 129.2, 129.0, 128.8, 128.2, 127.7, 127.6, 127.0, 127.0, 125.8, 121.4, 120.1, 119.3, 117.4, 110.9, 48.3, 35.2, 20.2. HRMS (ESI): Calcd for [C 29 H 25 N+H] + :388.2065, found:388.2069.

[0031] Example 3

[0032]

[0033] The dry test tube was taken at room temperature and a stir bar was added, TBADT (6.6 mg, 0.002 mmol), 5-methyl-2-indolemethanol (31.5 mg, 0.1 mmol), p-toluenesulfonic acid (1.7 mg, 0.01 mmol) were added and sealed, and replaced with N2 three times. Cyclohexane (0.1 mL, 1 mmol) was added to the test tube as the solvent. The reaction was irradiated and stirred under the condition of room temperature and nitrogen environment using 370 nm ultraviolet light for 0.5 h. After the reaction was completed, it was concentrated and column chromatography was used to separate to obtain the corresponding indole compound Ic. 1 H NMR (400 MHz, CDC13) δ 7.52 (s, 1H), 7.31-7.26 (m, 4H), 7.26-7.21 (m, 3H), 7.15-7.11 (m, 4H), 7.10-7.07 (m, 1H), 6.94-6.87 (m, 1H), 5.82 (s, 1H), 2.70 (tt, J = 12.2, 3.6 Hz, 1H), 2.44 (s, 3H), 1.95-1.83 (m, 2H), 1.81-1.73 (m, 2H), 1.70-1.62 (m, 2H), 1.31-1.21 (m, 4H); 13 C NMR (101 MHz, CDC13) δ 142.6, 134.4, 134.0, 129.1, 128.7, 128.1, 127.8, 126.9, 122.6, 120.1, 117.9, 110.7, 48.5, 36.7, 33.0, 27.4, 26.4, 21.8. HRMS (ESI): Calcd for [C 28 H 29 N+H] + :380.2378, found:380.2356.

Claims

1. A method for the preparation of a photocatalytic polysubstituted indole compound, characterized by In the presence of a proton acid and under UV irradiation, 2-indolemethanol is de- aromatized to form an imine cation intermediate using tetrabutylammonium decatungstate TBADT as a catalyst, which is then reacted with alkyl radicals generated by hydrogen atom transfer of alkane catalyzed by TBADT, and finally isomerized to obtain 2,3-dialkyl substituted indole compounds I, as shown in the reaction formula: ； Among them, R 1 It can be an H atom, an electron-donating or electron-withdrawing substituent; wherein, the electron-donating substituent is alkyl, methoxy, acyloxy, or amide; and the electron-withdrawing substituent is a halogen atom, an ester group, a nitro group, or a cyano group. R 2 , R 3 is phenyl, aromatic substituent containing an electron-donating group or an electron-withdrawing group, alkyl; wherein the aromatic substituent containing an electron-donating group is meta, para-methylphenyl, ortho, para-methoxyphenyl; the aromatic substituent containing an electron-withdrawing group is meta, para-fluorophenyl, para-chlorophenyl, para-bromophenyl; R4 is an alkyl group; R5 is an H atom or an alkyl group.

2. The method of claim 1, wherein The specific steps are as follows: (1) In a reaction tube, the catalyst TBADT, the proton acid, 2-indolemethanol and the substrate alkane are sequentially added, followed by replacement of nitrogen, and then the organic solvent is added, and stirred under UV irradiation for 0.5-3 hours until the complete reaction is detected by TLC; (2) The reaction solution is concentrated and column chromatography is used for separation to obtain the corresponding polysubstituted indole compounds.

3. The method of claim 2, wherein The organic solvent is MeCN, DCE, DMSO or DCM; the amount of 2-indolemethanol is 1.0 equivalent, the amount of alkane is 2.0-10.0 equivalents, the amount of catalyst TBADT is 0.01-0.02 equivalents, and the amount of proton acid is 0.05-0.15 equivalents; the proton acid is p-toluenesulfonic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid or benzoic acid; The reaction time is 0.5-3 hours. ​

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