Preparation method of photocatalytic polysubstituted indole compound

Abstract

The invention belongs to the technical field of organic chemistry, and particularly relates to a preparation method of a photocatalytic polysubstituted indole compound. The structure of the compound is characterized and confirmed by methods such as < 1 > H NMR, < 13 > C NMR, HRMS, single crystal X diffraction and the like. According to the method, tetrabutylammonium decatungstate (TBADT) is used as a catalyst in an organic solvent, in the presence of protonic acid, 2-indolyl methanol is subjected to dearomatization to form an imine cation intermediate, then the imine cation intermediate reacts with alkyl free radicals generated by alkane through hydrogen atom transfer (HAT) under the catalysis of TBADT, and the 2, 3-dialkyl substituted indole compound I is obtained through isomerization. The method is simple and efficient in reaction, few in side reaction, high in product purity and convenient to separate and purify; conditions are mild, and the application range of a substrate is wide; the raw materials are simple and easy to obtain, the cost is low, and the method can be suitable for large-scale preparation and has a very good application prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemistry, and in particular relates to a method for preparing a photocatalytic multi-substituted indole compound. Background Art

[0002] The indole skeleton is one of the common heterocyclic structures and exists in a variety of drug molecules with significant biological activity. The prior art discloses some typical indole core skeletons, including: the drug molecule Panobinostat, which can be used as a histone deacetylase inhibitor (JM Annemieke, AH Gennip, HN Caron, S. Kemp, Biochemical Journal, 2003, 370, 737-49.); Macimorelin acetate, which can be used to treat adult growth hormone deficiency (JM Garcia, R. Swerdloff, C. Wang, M. Kyle, M. Kipnes, BMB Biller, D. Cook, KC J Yuen, V. Bonert, A. Dobs, ME Molitch, GRM Merriam, J Clin Endocrinol Metab, 2013, 98, 2422-2429); Indomethacin can be used to treat migraine, antipyretic and analgesic (H. El-Shattawy, A. Kassem, S. Omar, A. Sami, AED Yassin, Drug Development and Industrial Pharmacy, 1994 20, 901-909.); Due to the wide range of biological activities and potential applications of indole compounds, chemists are constantly working to develop new structures based on the indole skeleton and new synthesis methods.

[0003] Hydrogen atom transfer (HAT) is a basic reaction in free radical reactions, which provides a favorable means for structural modification of natural skeleton compounds with potential biological activity. At present, the transformation of alkanes by photocatalytic HAT is a research hotspot in the field of organic chemistry. Based on this, the present invention utilizes photocatalytic hydrogen atom transfer to alkylate 2-indole methanol, providing a new technology for the efficient synthesis of polysubstituted indole compounds. Summary of the invention

[0004] The present invention aims to provide a simple and efficient method for preparing polysubstituted indole compounds.

[0005] The preparation method of the polysubstituted indole compound provided by the present invention is to functionalize the third position of 2-indole methanol with an alkane by hydrogen atom transfer under photocatalysis, thereby providing a highly efficient synthesis of polyalkyl substituted indole compounds.

[0006] Specifically, the method of the present invention uses TBADT (tetrabutylammonium decaprol tungstate) as a catalyst in an organic solvent (such as acetonitrile), and in the presence of a protonic acid (such as p-toluenesulfonic acid), 2-indole methanol and an alkane undergo an indole alkylation reaction under ultraviolet light to efficiently prepare a polysubstituted indole compound I, and the reaction formula is:

[0007]

[0008] Among them, R 1 is an H atom, an electron-donating or electron-withdrawing substituent; wherein the electron-donating substituent is an alkyl group, a methoxy group, an acyloxy group, an acylamino group, etc.; the electron-withdrawing substituent is a halogen atom, an ester group, a nitro group, a cyano group, etc.;

[0009] R 2 , R 3 is phenyl, an aromatic substituent containing an electron-donating group or an electron-withdrawing group, or an alkyl group; wherein the aromatic substituent containing an electron-donating group is m-, p-methylphenyl, o-, p-methoxyphenyl, etc.; the aromatic substituent containing an electron-withdrawing group is m-, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, etc.;

[0010] R 4 is an alkyl group;

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

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

[0013] (1) Adding catalyst TBADT, protonic acid, 2-indole methanol and substrate alkane or aldehyde in a reaction tube in sequence, then replacing nitrogen, adding an organic solvent, and stirring under ultraviolet light for 0.5-3 hours until the reaction is complete by TLC detection;

[0014] (2) The reaction solution is concentrated and separated by column chromatography to obtain the corresponding polysubstituted indole compounds.

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

[0016] The structure of this class of compounds 1 H NMR, 13 The product was characterized and confirmed by C NMR, HRMS, and single crystal X-ray diffraction.

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

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

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

[0020] In the present invention, based on 1.0 equivalent of 2-indole methanol, the amount of protonic acid used is 0.05-0.15 equivalent, 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 invention, the reaction temperature of the reaction system is 20-40° C. and the reaction time is 0.5-3 hours.

[0022] The method of the invention has simple and efficient reaction, few side reactions, high product purity, and is easy to separate and purify; the conditions are mild, and the applicable scope of the substrate is wide; the raw materials are simple and easy to obtain, the cost is low, and it can be applied to large-scale preparation, and has very good application prospects. DETAILED DESCRIPTION

[0023] Example 1

[0024]

[0025] At room temperature, take a dry test tube and add a stirrer, weigh TBADT (6.6 mg, 0.002 mmol), 2-indole methanol (29.9 mg, 0.1 mmol), p-toluenesulfonic acid (1.7 mg, 0.01 mmol), seal it, and replace N2 three times. Use acetonitrile (1.0 mL) as solvent, add cyclohexane (0.1 mL, 1 mmol) into the test tube. Under normal temperature nitrogen environment, use 370 nm ultraviolet light to irradiate and stir, and react for 0.5 h. After the reaction is completed, concentrate and separate by column chromatography to obtain the corresponding indole compound Ia.

[0026] 1H NMR (400MHz, CDCl3) δ7.76 (d, J = 7.4Hz, 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=12.3,3.6Hz,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 (101MHz, CDCl3) δ142.5,135.8,134.2,129.1,128.7,127.6,126.9,121.0,1 20.5,118.9,118.3,111.0,48.5,36.7,33.0,27.4,26.4.HRMS(ESI):Calcdfor[C 27 H 27 N+H] + :366.2222,found:366.2220.

[0027] Example 2

[0028]

[0029] At room temperature, take a dry test tube and add a stirrer, weigh TBADT (6.6 mg, 0.002 mmol), 2-indole methanol (29.9 mg, 0.1 mmol), p-toluenesulfonic acid (1.7 mg, 0.01 mmol), seal it, and replace N2 three times. Use acetonitrile (1.0 mL) as solvent, add ethylbenzene (0.12 mL, 1 mmol) into the test tube. Under normal temperature nitrogen environment, use 370 nm ultraviolet light to irradiate and stir, and react for 0.5 h. After the reaction is completed, concentrate and separate by column chromatography to obtain the corresponding indole compound Ib.

[0030] 1 H NMR (400MHz, CDCl3) δ7.52 (s, 1H), 7.42 (d, J = 8.0Hz, 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),7.01-6.96m,1H),5.74(s,1H),4.47(q,J=7.2Hz,1H),1.64(d,J=7.3Hz,3H); 13C NMR (101MHz, CDCl3) δ145.7,142.3,142.3,135.7,135.3,129.2,129.0,128.8,128.2,127.7,127 .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] At room temperature, take a dry test tube and add a stirrer, weigh TBADT (6.6 mg, 0.002 mmol), 5-methyl-2-indole methanol (31.5 mg, 0.1 mmol), p-toluenesulfonic acid (1.7 mg, 0.01 mmol), seal it, and replace N2 three times. Use acetonitrile (1.0 mL) as solvent, add cyclohexane (0.1 mL, 1 mmol) into the test tube. Under normal temperature nitrogen environment, use 370 nm ultraviolet light to irradiate and stir, and react for 0.5 h. After the reaction is completed, concentrate and separate by column chromatography to obtain the corresponding indole compound Ic. 1 H NMR(400MHz, CDCl3)δ7.52(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=12.2,3.6Hz,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 (101MHz, CDCl3) δ142.6,134.4,134.0,129.1,128.7,128.1,127.8,126.9,1 22.6,120.1,117.9,110.7,48.5,36.7,33.0,27.4,26.4,21.8.HRMS(ESI):Calcd for[C 28 H 29 N+H] + :380.2378,found:380.2356.

Claims

1. A method for preparing a photocatalytic multi-substituted indole compound, characterized in that In an organic solvent, tetrabutylammonium decatungstate (TBADT) is used as a catalyst. In the presence of a protonic acid, 2-indole methanol dearomatizes to form an imine cation intermediate, which then reacts with an alkyl radical generated by hydrogen atom transfer (HAT) of an alkane catalyzed by TBADT, and finally isomerizes to obtain a 2,3-dialkyl substituted indole compound I. The reaction formula is: Among them, R 1 is an H atom, an electron-donating or electron-withdrawing substituent; wherein the electron-donating substituent is an alkyl group, a methoxy group, an acyloxy group, an acylamino group, etc.; the electron-withdrawing substituent is a halogen atom, an ester group, a nitro group, a cyano group, etc.; R 2 , R 3 is phenyl, an aromatic substituent containing an electron-donating group or an electron-withdrawing group, or an alkyl group; wherein the aromatic substituent containing an electron-donating group is m-, p-methylphenyl, o-, p-methoxyphenyl, etc.; the aromatic substituent containing an electron-withdrawing group is m-, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, etc.; R 4 is an alkyl group; R 5 is a H atom or an alkyl group.

2. The preparation method according to claim 1, characterized in that The specific steps are as follows: (1) Adding catalyst TBADT, protonic acid, 2-indole methanol and substrate alkane to a reaction tube in sequence, then replacing nitrogen, adding an organic solvent, and stirring under ultraviolet light for 0.5-3 hours until the reaction is complete by TLC detection; (2) The reaction solution is concentrated and separated by column chromatography to obtain the corresponding polysubstituted indole compounds.

3. The preparation method according to claim 2, characterized in that The organic solvent is MeCN, DCE, DMSO, or DCM; based on 1.0 equivalent of 2-indole methanol, 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 protonic acid is 0.05-0.15 equivalents; the acid is p-toluenesulfonic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid or benzoic acid; The light is ultraviolet light; the reaction time is 0.5-3 hours.

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