A method for synthesizing 3-indolyl benzoquinone compounds

Abstract

The present application belongs to the technical field of organic compound synthesis, and relates to a method for synthesizing 3-indolyl benzoquinone compounds, which is used to solve the technical problems that the preparation of the existing 3-indolyl benzoquinone compounds needs additional oxidants or a large amount of hydroquinone by-products is inevitably generated in the reaction system due to the use of more than 2 equivalents of benzoquinone compounds. The method is that: in an oxygen or air environment, a C2 substituted indole compound and a hydroquinone compound are reacted in a mixed solution of water and an organic solvent with Salcomine as a catalyst to generate a 3-indolyl benzoquinone compound. The catalyst system of the present application is simple, the reaction selectivity is excellent, the by-products are few, and the reaction efficiency is high; the synthesis process is simple, the waste is little, the environment is friendly, and the present application has a strong industrial application prospect.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic compound synthesis, and relates to a method for synthesizing 3-indolyl benzoquinone compounds. BACKGROUND

[0002] The 3-indolyl benzoquinone skeleton is widely present in many natural products with significant biological activity. For example, asterriquinones and demethylasterriquinones have a broad spectrum of biological activity, and exhibit good anticancer activity and HIV reverse transcription inhibition capacity. Asterriquinone A1 (such as formula 1) is found to be able to block the G1 phase of the cell cycle and promote apoptosis death, and can also be used as a non-peptide oral insulin substitute, and is expected to be used for the treatment of diabetes. Due to the broad application prospect, the selective and efficient synthesis of 3-indolyl benzoquinone compounds, especially the symmetrical and asymmetrical bisindolyl benzoquinone skeleton, has attracted more and more attention of chemists.

[0003]

[0004] The existing related synthesis methods mostly use the coupling reaction of C2-substituted indole compounds and p-benzoquinone compounds catalyzed by protonic acid or Lewis acid to realize. For example, [Michael C. Pirrung et al., J. Org. Chem., 2002, 67, 8374-8388; J. S. Yadav et al., Tetrahedron Lett., 2003, 44, 9121-9124; Hai-Bo, Zhang et al., Eur. J. Org. Chem., 2006, 869-873; Michael C. Pirrung et al., J. Comb. Chem., 2007, 9, 844-854] and the like. However, such a reaction system faces some unavoidable shortcomings, such as the need for additional stoichiometric oxidants or more than 2 equivalents of benzoquinone compounds, and the inevitable generation of a large amount of hydroquinone by-products in the system.

[0005] Since polyphenolic compounds are widely present in nature and have abundant reserves, it is more concise and efficient to synthesize such compounds by catalytic aerobic oxidation coupling of p-dihydroxybenzene compounds and C2-substituted indole compounds, and has great attraction and application value. So far, the only report on the synthesis of such compounds using p-dihydroxybenzene compounds as the substrate is the Fe3O4 / PVP-PWA catalysis and Ag2O / H2O2 oxidation reaction system [Sumit B. Kamble et al., ACS Omega, 2017, 2, 2238-2247]. However, there is no systematic research report on the efficient synthesis of such compounds by catalytic aerobic oxidation coupling of p-dihydroxybenzene compounds and C2-substituted indole compounds. SUMMARY

[0006] In order to solve the technical problems of needing additional oxidants or inevitably generating a large amount of hydroquinone byproducts in the reaction system due to using more than 2 equivalents of benzoquinone compounds in the preparation of 3-indolyl benzoquinone compounds, the present application provides a method for synthesizing 3-indolyl benzoquinone compounds.

[0007] In order to achieve the above-mentioned purpose, the technical scheme of the present application is as follows:

[0008] A method for synthesizing 3-indolyl benzoquinone compounds, wherein C2-substituted indole compounds and hydroquinone compounds are reacted in a mixed solvent of water and an organic solvent in the presence of a catalyst under an oxygen or air environment to generate 3-indolyl benzoquinone compounds.

[0009] The catalyst is bis-salicylamide ethyl cobalt.

[0010] The C2-substituted indole compounds are substituted at the C2 position and have no substituent at the C3 position.

[0011] The C2-substituted indole compounds are indole derivatives substituted at the C2 position and having no substituent at the C3 position and substituted at the C4, C5, C6 or C7 position.

[0012] The C2-substituted indole compounds have a substituent at the C2 position, which is methyl, ethyl, tert-butyl or phenyl, etc., have no substituent at the C3 position, and have a substituent at the C4, C5, C6 or C7 position, which is methyl, fluorine, chlorine, bromine, alkoxy or acetylenic group, etc., and the N1 position is unsubstituted or substituted with an alkyl group such as methyl or ethyl.

[0013] The 3-indolyl benzoquinone compounds have the following structural formula:

[0014]

[0015] etc.

[0016] The hydroquinone compounds are hydroquinone, substituted hydroquinone, 1,4-dihydroxynaphthalene or substituted 1,4-dihydroxynaphthalene.

[0017] The organic solvent is any one of acetonitrile, tetrahydrofuran, methanol, ethanol, dimethyl sulfoxide or N,N-dimethylformamide.

[0018] The molar ratio of the C2-substituted indole compounds to the hydroquinone compounds is (1-3):1.

[0019] The amount of the catalyst is 0.01-10% of the mole number of the hydroquinone compound; and the volume of the mixed solvent is 10-200 times of the mass of the hydroquinone compound.

[0020] The oxygen partial pressure of the reaction is 0.1-1.0 MPa, the reaction temperature is 25-100℃, and the reaction time is 4-60 h.

[0021] In the present application, the bis-salicylamide ethyl cobalt used for the catalyst can be directly used by purchasing corresponding chemical products.

[0022] In the use process of the present application, the reaction effect is improved with the increase of the amount of the catalyst, when the amount of the catalyst exceeds a certain value, other side reactions occur, resulting in the decrease of the yield of the target product. Moreover, the production cost is also increased with the increase of the amount of the catalyst, and the excessive catalyst will bring about separation difficulty. Therefore, the amount of the catalyst is 0.01-10% of the mole number of the hydroquinone compound, preferably 1-7%.

[0023] The method of the present application is carried out in a mixed solvent of water and an organic solvent, and the increase of the amount of the solvent will reduce the viscosity of the reaction liquid and improve the stirring effect, thereby improving the reaction effect, but the excessive amount of the solvent will reduce the concentration of the catalytic system and reduce the reaction efficiency and increase the energy consumption. Therefore, the amount of the solvent is 10-200 times of the mass of the hydroquinone compound, preferably 50-120 times. The proportion of water in the mixed solvent is 0-95%, preferably 5-50%.

[0024] In the present application, the post-treatment process after the synthesis reaction is not particularly limited, and the product separation and purification can be carried out by the following two methods according to the reactivity of different substrates and the solubility of the product: a) after the reaction is completed, the product is cooled by placing, diluted by adding water, extracted, concentrated, and the remaining solid is recrystallized with isopropyl alcohol / water, filtered, and dried; b) after the oxidation reaction is completed, the product is cooled by placing, diluted by adding water, extracted, concentrated, and the remaining solid is purified by column chromatography and dried.

[0025] The synthesis route of the 3-indolyl benzoquinone compound in the present application is shown in formula 2:

[0026]

[0027] The present application has the following beneficial effects:

[0028] The present application uses Salcomine as a catalyst to react C2-substituted indole compounds with hydroquinone compounds in a mixed solvent of water and an organic solvent in an oxygen or air environment to generate 3-indolyl benzoquinone compounds. No additional stoichiometric oxidant is needed, and the catalyst system of the present application is simple, has excellent reaction selectivity, has few by-products, has high reaction efficiency, can prepare a series of 3-indolyl benzoquinone compounds, the yield of the prepared 3-indolyl benzoquinone compounds can be up to 98%, and the purity is 94%-98%. The synthesis process provided by the present application is simple, has few wastes, is environmentally friendly, and has strong industrial application prospects. BRIEF DESCRIPTION OF DRAWINGS

[0029] In order to more clearly illustrate the technical solutions of the embodiments of the present application or the prior art, the drawings needed to be used in the embodiments or the prior art description will be briefly introduced. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative effort on the basis of these drawings.

[0030] Figure 1 The HNMR spectrum (400MHz, 298K, d-DMSO) of 2-(2-methylindole)-1,4-benzoquinone prepared for the present application embodiment 1 is shown in Figure 1. 1 HNMR spectrum (400MHz, 298K, d-DMSO).

[0031] Figure 2 The HNMR spectrum (400MHz, 298K, d-DMSO) of 2-(2-methylindole)-1,4-benzoquinone prepared for the present application embodiment 1 is shown in Figure 1. 13 CNMR spectrum (100MHz, 298K, d-DMSO).

[0032] Figure 3 The HNMR spectrum (400MHz, 298K, d-DMSO) of 2-(2-methylindole)-1,4-benzoquinone prepared for the present application embodiment 1 is shown in Figure 1. 1 HNMR spectrum (400MHz, 298K, d-DMSO).

[0033] Figure 4 The HNMR spectrum (400MHz, 298K, d-DMSO) of 2-(2-methylindole)-1,4-benzoquinone prepared for the present application embodiment 1 is shown in Figure 1. 13 CNMR spectrum (100MHz, 298K, d-DMSO).

[0034] Figure 5The 2,5-dibromo-3-(2-methylindolyl)-6-(2,5-dimethylindolyl)-1,4-benzoquinone prepared in Example 16 of the present application was used in the following reaction 1 HNMR spectrum (400 MHz, 298 K, d-DMSO).

[0035] Figure 6 The 2,5-dibromo-3-(2-methylindolyl)-6-(2,5-dimethylindolyl)-1,4-benzoquinone prepared in Example 16 of the present application was used in the following reaction 13 CNMR spectrum (100 MHz, 298 K, d-DMSO). DETAILED DESCRIPTION

[0036] The technical solutions in the embodiments of the present application will be described clearly and completely below in conjunction with the drawings in the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, but not all the embodiments. Based on the embodiments in the present application, all the other embodiments obtained by those of ordinary skill in the art without any creative effort belong to the scope of protection of the present application.

[0037] Example 1

[0038] Synthesis of 2-(2-methylindolyl)-1,4-benzoquinone:

[0039] In a 150 mL reaction kettle, 2.62 g of 2-methylindole, 2.20 g of hydroquinone, 65 mg of bis-salicyl amide ethyl cobalt, 40 mL of water and 60 mL of methanol were put in; under stirring, the temperature was heated to 30°C, oxygen was introduced, the pressure in the reaction kettle was kept at 0.5 MPa, the reaction was stopped after 30 h, and cooled to room temperature, 80 mL of saturated brine was added, 3x50 mL of ethyl acetate was extracted, the ethyl acetate layer was combined, the ethyl acetate was removed by rotary evaporation, the remaining solid was recrystallized with isopropanol / water, suction filtered and dried to obtain 4.22 g of blue solid.

[0040] The product was determined by NMR (see attached Figure 1 and 2 ), HRMS and other methods to have the structure of 2-(2-methylindolyl)-1,4-benzoquinone, with a yield of 89%, and the product purity was 95% analyzed by liquid chromatograph, as shown in Table 1.

[0041] 1HNMR (400 MHz, DMSO-D6): δ = 2.37 (s, 3H), 6.75 (d, J = 2.56 Hz, IH), 6.89 (dd, J = 10.08, 2.56 Hz, IH), 6.96 (d, J = 10.08 Hz, IH), 7.01 (td, J = 8.00, 1.00 Hz, IH), 7.08 (td, J = 8.04, 1.04 Hz, IH), 7.33 (d, J = 7.92 Hz, IH), 7.37 (d, J = 7.84 Hz, IH), 11.59 (s, IH).

[0042] 13 CNMR (100 MHz, DMSO-D6): δ = 13.25, 105.69, 110.94, 118.89, 119.86, 121.25, 127.24, 130.95, 135.49, 136.16, 137.18, 138.08, 142.13, 186.76, 187.56.

[0043] In the present application, since ethyl and methyl groups are similar, the C2-ethyl substituted compound is not listed, but the C2-ethyl substituted compound can be prepared by replacing the corresponding raw material with the method of the C2-methyl substituted compound disclosed in the present application.

[0044] Example 2

[0045] Synthesis of 2-(1,2-dimethylindolyl)-1,4-benzoquinone:

[0046] Into a 150 mL reaction kettle, 2.24 g of 1,2-dimethylindole, 1.70 g of hydroquinone, 50 mg of bis-salicyl amide ethyl cobalt, 55 mL of water and 15 mL of acetonitrile were put; under stirring, the temperature was raised to 80°C, oxygen was introduced, the pressure in the reaction kettle was kept at 0.8 MPa, the reaction was stopped after 9 h, and cooled to room temperature, 80 mL of saturated brine was added, 3 x 50 mL of ethyl acetate was extracted, the ethyl acetate layer was combined, the ethyl acetate was removed by rotary evaporation, the remaining solid was recrystallized with isopropanol / water, suction filtered and dried to obtain 3.76 g of blue solid.

[0047] The product was determined by NMR, HRMS and other methods to have the structure of 2-(1,2-dimethylindolyl)-1,4-benzoquinone, the yield was 97%, and the product purity was 97% analyzed by liquid chromatograph, see Table 1.

[0048] 1HNMR (400 MHz, DMSO-D6): δ = 2.35 (s, 3H), 3.73 (s, 3H), 6.73 (d, J = 2.56 Hz, IH), 6.90 (dd, J = 10.12, 2.56 Hz, IH), 6.97 (d, J = 10.12 Hz, IH), 7.05 (td, J = 7.84, 0.68 Hz, IH), 7.15 (td, J = 8.00, 0.88 Hz, IH), 7.38 (d, J = 7.88 Hz, IH), 7.47 (d, J = 8.16 Hz, IH).

[0049] 13 CNMR (100 MHz, DMSO-D6): δ = 12.01, 29.78, 105.65, 109.70, 118.86, 120.16, 121.31, 126.34, 131.59, 136.18, 136.67, 137.20, 139.04, 141.95, 186.74, 187.57.

[0050] Example 3

[0051] Synthesis of 2-(2-phenylindol)-l,4-benzoquinone:

[0052] Into a 150 mL reaction kettle, 5.21 g of 2-phenylindole, 1.98 g of hydroquinone, 410 mg of disalicyl amide ethyl cobalt, 15 mL of water and 50 mL of DMF were put in; under stirring, the temperature was raised to 100°C, oxygen was introduced, the pressure in the reaction kettle was kept at 1.0 MPa, the reaction was stopped after 16 h, and cooled to room temperature, 80 mL of saturated brine was added, 3 x 50 mL of ethyl acetate was extracted, the ethyl acetate was removed by rotary evaporation, the remaining solid was recrystallized with isopropanol / water, suction filtered and dried to obtain 4.78 g of blue solid.

[0053] The product was determined by NMR, HRMS and other methods to have the structure of 2-(2-phenylindol)-l,4-benzoquinone, the yield was 89%, and the product purity was 95% by liquid chromatograph, as shown in Table 1.

[0054] 1 HNMR (400 MHz, DMSO-D6): δ = 6.86-6.89 (m, 2H), 6.93 (dd, J = 10.16, 2.56 Hz, IH), 7.11 (t, J = 7.72 Hz, IH), 7.20 (t, J = 7.68 Hz, IH), 7.33-7.53 (m, 7H), 12.00 (br, IH).

[0055] 13CNMR (100 MHz, DMSO-D6): δ = 105.22, 111.75, 118.88, 120.44, 122.43, 127.62, 128.04, 128.16 (2C), 128.72 (2C), 132.31, 133.00, 136.33, 136.64, 136.98, 138.96, 142.60, 186.09, 187.28.

[0056] Synthesis of 2-(2-tert-butylindol)-1,4-benzoquinone:

[0057] Into a 150 mL reaction kettle, 3.35 g of 2-methyl-5-chloroindole, 0.62 g of hydroquinone, 38 mg of bis-salicyl amide ethyl cobalt, 15 mL of water and 35 mL of acetonitrile were put in; under stirring, the temperature was raised to 25°C, oxygen was introduced, the pressure in the reaction kettle was kept at 0.2 MPa, the reaction was stopped after 24 h, cooled to room temperature, 80 mL of saturated brine was added, 3 x 50 mL of ethyl acetate was extracted, the ethyl acetate layer was combined, the ethyl acetate was removed by rotary evaporation, the remaining solid was recrystallized with isopropyl alcohol / water, suction filtered and dried to obtain 1.22 g of blue solid.

[0058] The product was determined by NMR, HRMS and other methods to have the structure of 2-(2-methyl-5-chloroindol)-1,4-benzoquinone, the yield was 80%, and the product purity was 94% analyzed by liquid chromatograph, as shown in Table 1.

[0059] 1 HNMR (400 MHz, DMSO-D6): δ = 2.37 (s, 3H), 6.75 (d, J = 2.56 Hz, 1H), 6.88 (dd, J = 10.12, 2.56 Hz, 1H), 6.95 (d, J = 10.12 Hz, 1H), 7.07 (dd, J = 8.56, 2.04 Hz, 1H), 7.33 (d, J = 8.56 Hz, 1H), 7.37 (d, J = 1.96 Hz, 1H), 11.75 (br, 1H).

[0060] 13 CNMR (100 MHz, DMSO-D6): δ = 13.07, 105.61, 112.34, 118.46, 121.04, 124.40, 128.48, 131.65, 133.88, 136.04, 137.26, 139.43, 141.45, 186.59, 187.64.

[0061] Example 5

[0062] Synthesis of 2-(2-tert-butylindol)-1,4-benzoquinone:

[0063] In a 150 mL reaction kettle, 1.81 g of 2-tert-butylindole, 0.95 g of hydroquinone, 140 mg of disalicyl amide ethyl cobalt, 7 mL of water and 70 mL of methanol were put in; the temperature was heated to 25°C under stirring, oxygen was introduced, the pressure in the reaction kettle was kept at 0.5 MPa, the reaction was stopped after 36 h, cooled to room temperature, 80 mL of saturated brine was added, 3 x 50 mL of ethyl acetate was extracted, the ethyl acetate layer was combined, the ethyl acetate was removed by rotary evaporation, the remaining solid was recrystallized with isopropanol / water, suction filtered and dried to obtain 1.45 g of blue solid.

[0064] The product was determined by NMR, HRMS and other methods to have a structure of 2-(2-tert-butylindole)-1,4-benzoquinone, with a yield of 60%, and a purity of 95% by liquid chromatography, as shown in Table 1.

[0065] 1 HNMR (400 MHz, DMSO-D6): δ = 1.31 (s, 9H), 6.80 (d, J = 2.2 Hz, 1H), 6.93 (td, J = 7.12, 0.80 Hz, 1H), 6.98 (dd, J = 10.16, 2.2 Hz, 1H), 7.02 (d, J = 10.08 Hz, 1H), 7.07 (td, J = 7.00, 1.04 Hz, 1H), 7.17 (d, J = 7.84 Hz, 1H), 7.35 (d, J = 8.04 Hz, 1H), 11.12 (s, 1H).

[0066] 13 CNMR (100 MHz, DMSO-D6): δ = 30.56 (3C), 33.35, 102.80, 110.78, 117.71, 119.14, 121.09, 128.50, 134.70, 135.47, 136.80, 136.97, 144.79, 145.52, 187.65, 187.76.

[0067] Example 6

[0068] Synthesis of 2-(2-methyl-4-bromoindole)-1,4-benzoquinone:

[0069] In a 150 mL reaction kettle, 0.42 g of 2-methyl-4-bromoindole, 0.28 g of hydroquinone, 2 mg of disalicyl amide ethyl cobalt, 1 mL of water and 15 mL of ethanol were put in; the temperature was heated to 40°C under stirring, the air in the reaction system was replaced every 2 h, the reaction was stopped after 60 h, cooled to room temperature, 30 mL of saturated brine was added, 3 x 20 mL of ethyl acetate was extracted, the ethyl acetate layer was combined, the ethyl acetate was removed by rotary evaporation, the remaining solid was recrystallized with isopropanol / water, suction filtered and dried to obtain 0.50 g of blue solid.

[0070] The product was determined to be 2-(2-methyl-4-bromoindole)-1,4-benzoquinone by NMR, HRMS, etc. The yield was 62%, and the product purity was 95% by liquid chromatograph analysis, as shown in Table 1.

[0071] 1 HNMR (600 MHz, DMSO-D6): δ = 2.32 (s, 3H), 6.76 (d, J = 2.64 Hz, 1H), 6.95 (dd, J = 10.14, 2.64 Hz, 1H), 6.99 (t, J = 7.92 Hz, 1H), 7.04 (d, J = 10.08 Hz, 1H), 7.15 (dd, J = 7.56, 0.60 Hz, 1H), 7.37 (d, J = 8.04 Hz, 1H), 11.75 (br, 1H).

[0072] 13 CNMR (150 MHz, DMSO-D6): δ = 11.72, 105.86, 110.63, 111.92, 122.15, 123.34, 126.43, 133.53, 136.45, 136.57, 137.14, 137.28, 143.25, 187.52, 187.83.

[0073] This method is suitable for Br / Cl substituted indole, which can be derivatized to obtain alkynyl substituted substrate by simple coupling reaction.

[0074] Example 7

[0075] Synthesis of 2-(2-methyl-6-bromoindole)-1,4-benzoquinone:

[0076] In a 150 mL reaction kettle, 0.93 g of 2-methyl-6-bromoindole, 0.51 g of hydroquinone, 5 mg of disalicyl amide ethyl cobalt, 1 mL of water and 25 mL of ethanol were added; under stirring, the temperature was heated to 70°C, oxygen was introduced, the pressure in the reaction kettle was kept at 0.3 MPa, the reaction was stopped after 48 h, and cooled to room temperature, 40 mL of saturated brine was added, 3×30 mL of ethyl acetate was extracted, the ethyl acetate layer was combined, the ethyl acetate was removed by rotary evaporation, the remaining solid was recrystallized with isopropanol / water, suction filtered and dried to obtain blue solid 1.14 g.

[0077] The product was determined to be 2-(2-methyl-6-bromoindole)-1,4-benzoquinone by NMR, HRMS, etc. The yield was 62%, and the product purity was 95% by liquid chromatograph analysis, as shown in Table 1.

[0078] 1HNMR (600 MHz, DMSO-D6): δ = 2.36 (s, 3H), 6.75 (d, J = 2.64 Hz, IH), 6.90 (dd, J = 10.08, 2.58 Hz, IH), 6.96 (d, J = 10.14 Hz, IH), 7.13 (dd, J = 8.46, 1.80 Hz, IH), 7.31 (d, J = 8.52 Hz, IH), 7.50 (d, J = 1.74 Hz, IH), 11.73 (br, IH).

[0079] 13 CNMR (150 MHz, DMSO-D6): δ = 13.08, 105.88, 113.39, 113.64, 120.86, 122.55, 126.35, 131.61, 136.13, 136.31, 137.22, 138.83, 141.51, 186.57, 187.59.

[0080] Example 8

[0081] Synthesis of 2-(2,7-dimethylindolyl)-1,4-benzoquinone:

[0082] Into a 150 mL reaction kettle, 1.75 g of 2,7-dimethylindole, 0.65 g of hydroquinone, 96 mg of bis-salicyl amide ethyl cobalt, 6 mL of water and 100 mL of methanol were put in; under stirring, the temperature was raised to 85°C, oxygen was bubbled, the pressure in the reaction kettle was kept at 0.5 MPa, the reaction was stopped after 32 h, cooled to room temperature, 80 mL of saturated brine was added, 3 x 50 mL of ethyl acetate was extracted, the ethyl acetate layer was combined, the ethyl acetate was removed by rotary evaporation, the remaining solid was recrystallized with isopropyl alcohol / water, suction filtered and oven dried to obtain 1.60 g of blue solid.

[0083] The product was determined by NMR, HRMS and other methods to have the structure of 2-(2,7-dimethylindolyl)-1,4-benzoquinone, the yield was 86%, the product purity was 95% analyzed by liquid chromatograph, see Table 1.

[0084] 1 HNMR (600 MHz, DMSO-D6): δ = 2.36 (s, 3H), 6.75 (d, J = 2.64 Hz, IH), 6.90 (dd, J = 10.08, 2.58 Hz, IH), 6.96 (d, J = 10.14 Hz, IH), 7.13 (dd, J = 8.46, 1.80 Hz, IH), 7.31 (d, J = 8.52 Hz, IH), 7.50 (d, J = 1.74 Hz, IH), 11.73 (br, IH).

[0085] 13CNMR (150 MHz, DMSO-D6): δ = 13.20, 16.68, 106.09, 116.42, 120.03, 120.18, 121.85, 126.90, 130.93, 134.92, 136.14, 137.15, 137.95, 142.29, 186.74, 187.53.

[0086] Example 9

[0087] Synthesis of 2-(2-methyl-5-methoxyindol)-l,4-benzoquinone:

[0088] Into a 150 mL reaction kettle, 3.35 g of 2-methyl-5-methoxyindole, 1.45 g of hydroquinone, 100 mg of bis-salicyl amide ethyl cobalt, 10 mL of water and 100 mL of acetonitrile were put in; under stirring, the temperature was heated to 55°C, oxygen was introduced, the pressure in the reaction kettle was kept at 0.4 MPa, the reaction was stopped after 28 h, cooled to room temperature, 80 mL of saturated brine was added, 3 x 50 mL of ethyl acetate was extracted, the ethyl acetate layer was combined, the ethyl acetate was removed by rotary evaporation, the remaining solid was recrystallized with isopropanol / water, suction filtered and dried to obtain 3.20 g of blue solid.

[0089] The product was determined by NMR, HRMS and other methods to have the structure of 2-(2-methyl-5-methoxyindol)-l,4-benzoquinone, with a yield of 91%, and the product purity was 97% analyzed by liquid chromatograph.

[0090] 1 HNMR (400 MHz, DMSO-D6): δ = 2.33 (s, 3H), 3.71 (s, 3H), 6.70-6.75 (m, 2H), 6.84-6.89 (m, 2H), 6.94 (d, J = 10.08 Hz, IH), 7.22 (d, J = 8.68 Hz, IH), 11.46 (s, IH).

[0091] 13 CNMR (100 MHz, DMSO-D6): δ = 13.40, 55.38, 101.60, 105.78, 110.79, 111.59, 127.84, 130.53, 130.63, 136.14, 137.22, 138.69, 142.30, 154.10, 186.82, 187.64.

[0092] Example 10

[0093] Synthesis of 2-acetyl-3-(2-methylindol)-l,4-benzoquinone:

[0094] Into a 150 mL reaction vessel, 2.62 g of 2-methylindole, 1.20 g of 2-acetyl hydroquinone, 26 mg of bis-salicylaldimine ethyl cobalt, 9 mL of water and 80 mL of ethanol were put; the mixture was heated to 40°C under stirring, oxygen was bubbled into the mixture, the pressure in the reaction vessel was kept at 0.8 MPa, the reaction was stopped after 16 hours, the mixture was cooled to room temperature, 80 mL of saturated brine was added, the mixture was extracted with 3 x 50 mL of ethyl acetate, the ethyl acetate layers were combined, the ethyl acetate was removed by rotary evaporation, the remaining solid was recrystallized from isopropanol / water, the mixture was filtered and dried, and 2.03 g of blue solid was obtained.

[0095] The product was determined to be 2-acetyl-3-(2-methylindole)-1,4-benzoquinone by NMR, HRMS and other methods, and the yield was 92%. The product purity was 98% as analyzed by a liquid chromatograph, as shown in Table 1.

[0096] 1 HNMR (400 MHz, DMSO-D6): δ = 1.88 (s, 3H), 2.18 (s, 3H), 6.93-6.97 (m, 2H), 7.01 (d, J = 10.12 Hz, 1H), 7.06 (td, J = 7.20, 1.04 Hz, 1H), 7.19 (d, J = 7.88 Hz, 1H), 7.31 (d, J = 8.04 Hz, 1H), 11.50 (s, 1H).

[0097] 13 CNMR (100 MHz, DMSO-D6): δ = 12.55, 30.09, 103.62, 110.83, 118.92, 119.50, 121.15, 127.66, 135.55, 136.17, 136.89, 136.90, 136.94, 142.83, 185.27, 186.75, 199.37.

[0098] Example 11

[0099] Synthesis of 2-methylformate-3-(2-methylindole)-1,4-benzoquinone:

[0100] Into a 150 mL reaction vessel, 1.56 g of 2-methylindole, 2.20 g of 2-methylformate hydroquinone, 193 mg of bis-salicylaldimine ethyl cobalt, 81 mL of water and 17 mL of DMF were put; the mixture was heated to 100°C under stirring, oxygen was bubbled into the mixture, the pressure in the reaction vessel was kept at 1.0 MPa, the reaction was stopped after 4 hours, the mixture was cooled to room temperature, 80 mL of saturated brine was added, the mixture was extracted with 3 x 50 mL of ethyl acetate, the ethyl acetate layers were combined, the ethyl acetate was removed by rotary evaporation, the remaining solid was recrystallized from isopropanol / water, the mixture was filtered and dried, and 3.67 g of blue solid was obtained.

[0101] The product was determined to be 2-methyl formate-3-(2-methyl indole)-1,4-benzoquinone by NMR, HRMS and other methods, the yield was 95%, and the product purity was 97% analyzed by liquid chromatograph, as shown in Table 1.

[0102] 1 HNMR (400MHz, DMSO-D6): δ = 2.24 (s, 3H), 3.50 (s, 3H), 6.95 (td, J = 8.00, 0.92 Hz, 1H), 6.99 (d, J = 10.12 Hz, 1H), 7.04 (d, J = 10.12 Hz, 1H), 7.05 (td, J = 8.84, 1.04 Hz, 1H), 7.22 (d, J = 7.84 Hz, 1H), 7.30 (d, J = 8.00 Hz, 1H), 11.52 (s, 1H).

[0103] 13 CNMR (100MHz, DMSO-D6) δ = 13.32, 52.88, 104.40, 111.37, 119.27, 119.95, 121.63, 128.06, 136.04, 136.41, 136.88, 137.76, 137.85, 139.90, 165.10, 184.93, 186.55.

[0104] Example 12

[0105] Synthesis of 2,5-dibromo-3-(2-methyl indole)-1,4-benzoquinone:

[0106] In a 150 mL reaction kettle, 0.77 g of 2-methyl indole, 1.57 g of 2,5-dibromo-p- benzoquinone, 20 mg of bis-salicyl amide ethyl cobalt, 30 mL of water and 30 mL of THF were put in; stirring at room temperature, replacing oxygen, keeping the pressure in the reaction kettle at 1.0 MPa, stopping the reaction after 30 h of reaction, cooling to room temperature, adding 50 mL of saturated brine, 3x40 mL of ethyl acetate extraction, combining the ethyl acetate layers, removing the ethyl acetate by rotary evaporation, recrystallizing the remaining solid with isopropanol / water, suction filtering and drying to obtain 2.27 g of blue solid.

[0107] The product was determined to be 2-methyl formate-3-(2-methyl indole)-1,4-benzoquinone by NMR (see attached Figure 3 and 4 ), HRMS and other methods, the yield was 95%, and the product purity was 97% analyzed by liquid chromatograph, as shown in Table 1.

[0108] 1HNMR (400 MHz, DMSO-D6): δ = 2.27 (s, 3H), 6.97 (t, J = 7.72 Hz, IH), 7.06 (td, J = 7.80, 0.72 Hz, IH), 7.20 (d, J = 7.80 Hz, IH), 7.32 (d, J = 8.04 Hz, IH), 7.82 (s, IH), 11.50 (s, IH).

[0109] 13 CNMR (100 MHz, DMSO-D6): δ = 13.26, 106.62, 110.88, 119.23, 119.62, 120.83, 126.66, 134.99, 135.32, 136.72, 136.82, 137.27, 142.56, 176.16, 178.09.

[0110] Example 13

[0111] Synthesis of 2-(2-methylindole)-l,4-naphthoquinone:

[0112] Into a 150 mL reaction kettle, 2.62 g of 2-methylindole, 1.60 g of 1,4- naphthoquinone, 165 mg of cobaltous bis-salicylformamide ethyl, 10 mL of water and 150 mL of ethanol were put in; under stirring, the temperature was raised to 45 °C, oxygen was bubbled, the pressure in the reaction kettle was kept at 0.3 MPa, the reaction was stopped after 40 h, and cooled to room temperature, 80 mL of saturated brine was added, 3 x 50 mL of ethyl acetate was extracted, the ethyl acetate layer was combined, and the ethyl acetate was removed by rotary evaporation, the remaining solid was recrystallized with isopropanol / water, filtered, and dried to obtain 2.30 g of blue solid.

[0113] The product was determined by NMR, HRMS and other methods to be 2-(2-methylindole)-l,4-naphthoquinone, the yield was 80%, and the product purity was 97% by liquid chromatograph, as shown in Table 1.

[0114] 1 HNMR (400 MHz, DMSO-D6): δ = 2.27 (s, 3H), 6.97 (t, J = 7.72 Hz, IH), 7.06 (td, J = 7.80, 0.72 Hz, IH), 7.20 (d, J = 7.80 Hz, IH), 7.32 (d, J = 8.04 Hz, IH), 7.82 (s, IH), 11.50 (s, IH).

[0115] 13CNMR (100 MHz, DMSO-D6): δ = 13.42, 106.22, 110.96, 119.12, 119.88, 121.24, 125.31, 126.53, 127.40, 131.79, 132.50, 133.44, 133.76, 133.98, 135.52, 138.28, 144.27, 184.17, 184.41. Example 14

[0116] Synthesis of 2,5-dibromo-3,6-bis(2-methylindol)-l,4-benzoquinone:

[0117] Into a 100 mL reaction kettle, 4.07 g of 2-methylindole, 2.68 g of 2,5-dibromo-p- benzoquinone, 39 mg of bis-salicyl amide ethyl cobalt, 26 mL of water and 9 mL of ethanol were put; under stirring, the temperature was kept at 50°C, oxygen was bubbled, the pressure in the reaction kettle was kept at 0.2 MPa, the reaction was stopped after 12 hours, cooled to room temperature, 50 mL of saturated brine was added, 3 x 50 mL of ethyl acetate was extracted, the ethyl acetate layer was combined, the ethyl acetate was removed by rotary evaporation, the remaining solid was recrystallized with isopropyl alcohol / water, suction filtered and oven dried to obtain 5.13 g of blue solid.

[0118] The product was determined by NMR (see attached Figure 3 and 4 ), HRMS and other methods to be 2,5-dibromo-3,6-bis(2-methylindol)-l,4-benzoquinone, with a yield of 98%, and the product purity was 98% by liquid chromatograph, see Table 1.

[0119] 1 HNMR (400 MHz, DMSO-D6): δ = 2.34 (s, 3H), 2.35 (s, 3H), 6.99 (t, J = 7.56 Hz, 2H), 7.08 (t, J = 7.24 Hz, 2H), 7.29-7.36 (m, 4H), 11.51 (s, 2H).

[0120] 13 CNMR (100 MHz, DMSO-D6): δ = 13.38, 13.42, 106.91 (2C), 110.85 (2C), 119.14 (2C), 119.82, 119.86, 120.78 (2C), 126.80, 126.83, 135.35 (2C), 135.43 (2C), 136.64, 136.70, 142.46 (2C), 176.85 (2C).

[0121] Example 15

[0122] Synthesis of 2,5-dibromo-3,6-bis(2-methyl-5-chloroindol)-1,4-benzoquinone:

[0123] Into a 150 mL reaction kettle, 1.23 g of 2-methyl-5-chloroindole, 1.10 g of 2,5-dibromo-p-dihydroxybenzene, 13 mg of bis-salicyl amide ethyl cobalt, 20 mL of water and 70 mL of DMF were put; under stirring, the temperature was kept at 30°C, oxygen was bubbled, the pressure in the reaction kettle was kept at 0.1 MPa, the reaction was stopped after 48 h, cooled to room temperature, 50 mL of saturated brine was added, 3 x 40 mL of ethyl acetate was extracted, the ethyl acetate layer was combined, the ethyl acetate was removed by rotary evaporation, the remaining solid was recrystallized with isopropanol / water, suction filtered and dried to obtain 2.28 g of blue solid.

[0124] The product was determined to be 2,5-dibromo-3,6-bis(2-methyl-5-chloroindol)-1,4-benzoquinone by NMR (see attached Figure 3 and 4 ), HRMS and other methods, the yield was 94%, the product purity was 96% by liquid chromatograph, see Table 1.

[0125] 1 HNMR (400 MHz, DMSO-D6): δ = 2.34 (s, 3H), 2.36 (s, 3H), 7.19 (dt, J = 8.48, 2.24 Hz, 2H), 7.31 (d, J = 8.52 Hz, 2H), 7.56 (d, J = 1.84 Hz, 1H), 7.61 (d, J = 1.84 Hz, 1H), 11.69 (s, 2H).

[0126] 13 CNMR (100 MHz, DMSO-D6): δ = 13.24 (2C), 106.61, 106.62, 111.85, 111.89, 112.80 (2C), 121.89, 121.93, 123.18, 123.20, 128.60, 128.64, 134.07, 134.09, 136.43, 136.48, 137.93, 138.04, 141.72, 141.75, 176.76, 176.77.

[0127] Example 16

[0128] Synthesis of 2,5-dibromo-3-(2-methylindol)-6-(2,5-dimethylindol)-1,4-benzoquinone:

[0129] In a 150 mL reaction vessel, 0.79 g of 2-methylindole, 1.61 g of 2,5-dibromo-p- hydroquinone, 0.87 g of 2,5-dimethylindole, 97 mg of bis-salicylaldimine ethyl cobalt, 8 mL of water and 88 mL of ethanol were added; the mixture was stirred and heated to 40°C, and oxygen was bubbled through the mixture while maintaining the pressure in the reaction vessel at 0.3 MPa. The reaction was stopped after 43 h, the mixture was cooled to room temperature, 50 mL of saturated brine was added, and the mixture was extracted with 3 x 40 mL of ethyl acetate. The ethyl acetate layers were combined, and the solvent was removed by rotary evaporation. The remaining solid was recrystallized from isopropanol / water, filtered, and dried to yield 2.16 g of a blue solid.

[0130] The product was identified as 2,5-dibromo-3-(2-methylindole)-6-(2,5-dimethylindole)-1,4- benzoquinone by NMR (see Table 1), HRMS, and other methods. The yield was 67%, and the product was 96% pure by HPLC analysis, as shown in Table 1. Figure 3 and 4 The product was identified as 2,5-dibromo-3-(2-methylindole)-6-(2,5-dimethylindole)-1,4- benzoquinone by NMR (see Table 1), HRMS, and other methods. The yield was 67%, and the product was 96% pure by HPLC analysis, as shown in Table 1.

[0131] 1 HNMR (400 MHz, DMSO-D6): δ = 2.33 (s, 3H), 2.35 (s, 3H), 2.36 (s, 3H), 6.90 (d, J = 8.24 Hz, IH), 6.98-7.02 (m, IH), 7.06-7.13 (m, 2H), 7.23 (d, J = 8.16 Hz, IH), 7.29-7.36 (m, 2H), 11.37 (s, IH), 11.51 (s, IH).

[0132] 13 CNMR (100 MHz, DMSO-D6): δ = 13.40, 13.42, 21.29, 106.54, 106.92, 110.56, 110.86, 119.14, 119.43, 119.82, 120.78, 122.26, 126.84, 127.03, 127.06, 127.68, 127.71, 133.69, 135.36, 136.62, 136.69, 142.47, 142.61, 176.86 (2C).

[0133] Example 17

[0134] Synthesis of 2,5-dibromo-3-(2-methylindole)-6-(2-methyl-5-bromoindole)-1,4-benzoquinone:

[0135] Into a 150 mL reaction vessel, 0.95 g of 2-methylindole, 0.97 g of 2,5-dibromo-p- benzoquinone, 1.52 g of 2-methyl-5-bromoindole, 82 mg of bis-salicylaldimine ethyl cobalt, 40 mL of water and 50 mL of acetonitrile were charged; the reaction vessel was kept at 50°C with stirring, and oxygen was bubbled into the reaction vessel to maintain the pressure at 0.1 MPa. After 12 hours of reaction, the reaction was stopped, the reaction vessel was cooled to room temperature, 50 mL of saturated brine was added, and the mixture was extracted with 3 x 40 mL of ethyl acetate. The ethyl acetate layers were combined, and the ethyl acetate was removed by rotary evaporation. The remaining solid was recrystallized from isopropanol / water, filtered, and dried to obtain 0.98 g of blue solid.

[0136] The product was identified by NMR (see Table 1 below), HRMS, and other methods to be 2,5-dibromo-3-(2-methylindole)-6-(2-methyl-5-bromoindole)-1,4-benzoquinone, with a yield of 45% and a purity of 97% as determined by HPLC, as shown in Table 1. Figure 3 and 4 The product was identified by NMR (see Table 1 below), HRMS, and other methods to be 2,5-dibromo-3-(2-methylindole)-6-(2-methyl-5-bromoindole)-1,4-benzoquinone, with a yield of 45% and a purity of 97% as determined by HPLC, as shown in Table 1.

[0137] 1 HNMR (400 MHz, DMSO-D6): δ = 2.35 (s, 3H), 2.37 (d, J = 4.64 Hz, 3H), 6.97-7.03 (m, 1H), 7.08 (t, J = 7.73, Hz, 1H), 7.20 (dt, J = 8.80, 1.24 Hz, 1H), 7.30-7.39 (m, 3H), 7.61 (dd, J = 16.84, 1.76 Hz, 1H), 11.51 (s, 1H), 11.70 (s, 1H).

[0138] 13 CNMR (100 MHz, DMSO-D6): δ = 13.28, 13.40, 106.62, 106.93, 110.83, 111.89, 112.79, 119.12, 119.80, 120.79, 121.93, 123.19, 126.81, 128.62, 134.08, 135.35, 135.58, 136.34, 136.54, 138.01, 141.76, 142.46, 176.79, 176, 82.

[0139] Example 18

[0140] Synthesis of 2,5-dibromo-3-(2-methylindole)-6-(2-phenylindole)-1,4-benzoquinone:

[0141] In a 150 mL reaction kettle, 1.39 g of 2-methylindole, 1.90 g of 2,5-dibromo-p- hydroquinone, 2.05 g of 2-phenylindole, 138 mg of bis-salicyl amide ethyl cobalt, 15 mL of water and 75 mL of methanol were put in; under stirring, the temperature was kept at 40°C, oxygen was bubbled in, the pressure in the reaction kettle was kept at 0.8 MPa, the reaction was stopped after 50 h, the temperature was cooled to room temperature, 50 mL of saturated brine was added, 3×40 mL of ethyl acetate was extracted, the ethyl acetate was removed by rotary evaporation, the remaining solid was recrystallized with isopropyl alcohol / water, suction filtration was performed, and drying was performed to obtain 2.19 g of blue solid.

[0142] The product was determined to have the structure of 2,5-dibromo-3-(2-methylindole)-6-(2-phenylindole)-1,4-benzoquinone by NMR (see attached Figure 3 and 4 ), HRMS and other methods, the yield was 53%, and the product purity was 96% by liquid chromatograph analysis, as shown in Table 1.

[0143] 1 HNMR (400 MHz, DMSO-D6): δ = 2.37 (d, J = 4.00 Hz, 3H), 6.98-7.12 (m, 3H), 7.21 (t, J = 7.94 Hz, 1H), 7.28-7.40 (m, 3H), 7.45-7.52 (m, 4H), 7.61-7.69 (m, 2H), 11.54 (s, 1H), 12.00 (s, 1H).

[0144] 13 CNMR (100 MHz, DMSO-D6): δ = 13.43, 106.49, 106.76, 106.97, 110.84, 110.93, 111.72, 119.19, 119.75, 120.84, 122.18, 126.86, 127.22 (2C), 128.13, 128.98, 129.02, 132.16, 134.80, 135.33, 136.17, 136.70, 136.90, 137.09, 137.46, 143.01, 143.12, 176.49, 176.73.

[0145] The reaction conditions and reaction results of the 3-indolylbenzoquinone compounds prepared under the above reaction conditions are shown in Table 1.

[0146] Table 1 shows the synthesis of various 3-indolylbenzoquinone compounds under different conditions in the examples

[0147]

[0148]

[0149] The above description is only the preferred embodiment of the present application, and is not intended to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for synthesizing 3-indolylbenzoquinone compounds, characterized in that: In the presence of an oxygen or air environment and a catalyst, C2-substituted indole compounds are reacted with hydroquinone compounds in a mixed solvent of water and organic solvents to generate 3-indolylbenzoquinone compounds. The catalyst is bis(salicylamide)ethylcobalt; The C2-substituted indole compounds are those in which the C2 position is substituted and the C3 position is unsubstituent.

2. The method for synthesizing 3-indolylbenzoquinone compounds according to claim 1, characterized in that: The C2-substituted indole compounds are indole derivatives with a substituted C2 position and no substituent at C3, or with a substituted C4, C5, C6, or C7 position.

3. The method for synthesizing 3-indolylbenzoquinone compounds according to claim 2, characterized in that: The C2-substituted indole compounds are indole derivatives in which the C2 position is substituted with methyl, ethyl, tert-butyl, or phenyl groups and the C3 position is unsubstituted, or indole derivatives in which the C4, C5, C6, or C7 positions are substituted with methyl, fluorine, chlorine, bromine, alkoxy, or alkyne groups, and the N1 position is unsubstituted or substituted with an alkyl group.

4. The method for synthesizing 3-indolylbenzoquinone compounds according to claim 3, characterized in that: The hydroquinone compounds are hydroquinone, substituted hydroquinone, and 1,4-dihydroxynaphthalene and its derivatives.

5. The method for synthesizing 3-indolylbenzoquinone compounds according to claim 1, characterized in that: The organic solvent is any one of acetonitrile, tetrahydrofuran, methanol, ethanol, dimethyl sulfoxide, or N,N-dimethylformamide.

6. The method for synthesizing 3-indolylbenzoquinone compounds according to claim 1, characterized in that: The molar ratio of the C2-substituted indole compound to the hydroquinone compound is (1-3):

1.

7. The method for synthesizing 3-indolylbenzoquinone compounds according to claim 5, characterized in that: The amount of catalyst used is 0.01-10% of the molar number of hydroquinone compounds; the volume of the mixed solvent is 10-200 times the mass of the hydroquinone compounds.

8. The method for synthesizing 3-indolylbenzoquinone compounds according to any one of claims 1-7, characterized in that: The oxygen partial pressure in the reaction is 0.1-1.0 MPa, the reaction temperature is 25-100℃, and the reaction time is 4-60 h.

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