Method for dearylation of indole through light induction
Through the light-induced method, a specific compound is used to carry out photocatalytic reaction under blue light and separated by silica gel column chromatography, the problem of expensive catalysts and complex reactions in asymmetric dearomization of indole compounds is solved, and efficient indole dearomylation is achieved, which is suitable for biomedical synthesis.
Patent Information
- Application Number
- CN202510561426.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-30
- Publication Date
- 2025-08-05
AI Technical Summary
In the asymmetric dearamification reaction of existing indole compounds, the catalyst is expensive and the reaction environment is complex.
Using a light-induced method, photocatalytic reaction was carried out using ethyl 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid, dibenzylamine, catalyst, Lewis acid and diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridine dicarboxylic acid in a 450 nm blue light, and then separated and purified by reduced pressure distillation and silica gel column chromatography.
Dearylation of indole with high yield and high purity under mild conditions is achieved, with a yield of up to 89% and a purity of up to 99%, providing an ideal method for biomedical synthesis.
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Figure CN120424072A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of organic synthesis. Background Art
[0002] Indoline and its derivatives are important organic compounds that are widely found or used in a variety of fields, including drug molecules, medicines, pesticides, dyes, and materials. In organic synthesis, polycyclic indolines are considered to be privileged skeletons in pharmaceutically relevant molecules and alkaloid natural products. The synthesis of polycyclic indolines with good functional group tolerance has become a hot topic in the field of organic chemistry. In recent years, the catalytic asymmetric dearomatization (CADA) reaction of indoles has developed into an important strategy for the synthesis of diverse chiral polycyclic indolines, but it has the problems of expensive catalysts and complex reaction environment. Summary of the Invention
[0003] The present invention aims to solve the problems of expensive catalysts and complex reaction environment in the existing asymmetric dearomatization of indole compounds, and further provides a method for light-induced dearomatization of indole.
[0004] A method for photoinduced dearylation of indole is carried out according to the following steps:
[0005] In a nitrogen atmosphere, at room temperature, under irradiation with a 450 nm blue light lamp and stirring, 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid ethyl ester, dibenzylamine, a catalyst, a Lewis acid, 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester and an organic solvent are uniformly mixed to obtain a mixture, and then in a nitrogen atmosphere, at room temperature, under irradiation with a 450 nm blue light lamp and stirring, the mixture is subjected to a photocatalytic reaction. After the reaction, the solvent is removed by distillation under reduced pressure, and then separated and purified by silica gel column chromatography to obtain an indole derivative, thereby completing the method for photoinduced indole dearylation;
[0006] The structural formula of the 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid ethyl ester is
[0007] The molar ratio of the ethyl 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylate to dibenzylamine is 1:(1.0-1.5); the molar ratio of the ethyl 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylate to the catalyst is 1:(0.01-0.03); the molar ratio of the ethyl 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylate to Lewis acid is 1:(0.2-0.5); and the molar ratio of the ethyl 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylate to diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate is 1:(1.5-2.0).
[0008] The beneficial effects of the present invention are:
[0009] The present invention provides a method for light-induced dearylation of indole under mild conditions. The method has good application prospects in biopharmaceutical synthesis. The reaction conditions are simple and mild, the raw materials are readily available, the yield can reach 89%, and the purity can reach 99%. It is an ideal and practical method for dearylation of indole.
[0010] The present invention is used for a method for light-induced dearylation of indole. BRIEF DESCRIPTION OF THE DRAWINGS
[0011] Figure 1 The indole derivative prepared in Example 1 1 H NMR spectrum;
[0012] Figure 2 The indole derivative prepared in Example 1 13 C NMR spectrum;
[0013] Figure 3 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid ethyl ester prepared in Example 1 1 H NMR spectrum;
[0014] Figure 4 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid ethyl ester prepared in Example 1 13 C NMR spectrum. DETAILED DESCRIPTION
[0015] Specific embodiment 1: This embodiment provides a method for light-induced dearylation of indole, which is carried out according to the following steps:
[0016] In a nitrogen atmosphere, at room temperature, under irradiation with a 450 nm blue light lamp and stirring, 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid ethyl ester, dibenzylamine, a catalyst, a Lewis acid, 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester and an organic solvent are uniformly mixed to obtain a mixture, and then in a nitrogen atmosphere, at room temperature, under irradiation with a 450 nm blue light lamp and stirring, the mixture is subjected to a photocatalytic reaction. After the reaction, the solvent is removed by distillation under reduced pressure, and then separated and purified by silica gel column chromatography to obtain an indole derivative, thereby completing the method for photoinduced indole dearylation;
[0017] The structural formula of the 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid ethyl ester is
[0018] The molar ratio of the ethyl 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylate to dibenzylamine is 1:(1.0-1.5); the molar ratio of the ethyl 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylate to the catalyst is 1:(0.01-0.03); the molar ratio of the ethyl 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylate to Lewis acid is 1:(0.2-0.5); and the molar ratio of the ethyl 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylate to diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate is 1:(1.5-2.0).
[0019] The 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester described in this specific embodiment is a reducing agent.
[0020] The 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid ethyl ester described in this specific embodiment was prepared with reference to the following literature: M, Zhu, H. Xu, X. Zhang, C. Zheng, and S. You.. Visible-Light-Induced Intramolecular Double Dearomative Cycloaddition of Arenes. Angew. Chem. Int. Ed. 2021, 60, 7036-7040.
[0021] The preparation route of the 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid ethyl ester is:
[0022]
[0023] The preparation route of the indole derivatives is:
[0024]
[0025] The indole derivatives prepared in this specific embodiment are important raw materials for the synthesis of monoterpene indole alkaloids (-)-Goniomitine and Vincamine with anti-cancer activity. This method can greatly shorten the synthesis route of the above drug molecules. The drug molecule (-)-Goniomitine has excellent anti-tumor activity. Studies have shown that it may exert its anti-tumor effects through various mechanisms, such as inducing tumor cell apoptosis, inhibiting tumor cell proliferation and invasion, and interfering with the signal transduction pathways of tumor cells. Vincamine can selectively act on cerebral blood vessels, relax cerebral vascular smooth muscle, increase cerebral blood flow, and improve blood supply to the brain. Especially in cases of cerebral arteriosclerosis and cerebral ischemia, it helps to improve blood perfusion of brain tissue and alleviate various symptoms caused by insufficient blood supply to the brain.
[0026] The beneficial effects of this specific embodiment are:
[0027] This specific embodiment provides a method for light-induced dearylation of indole under mild conditions. This method has good application prospects in biopharmaceutical synthesis. The reaction conditions of this specific embodiment are simple and mild, the raw materials are readily available, the yield can reach 89%, and the purity can reach 99%. It is an ideal and practical method for dearylation of indole.
[0028] Specific embodiment 2: This embodiment differs from specific embodiment 1 in that the catalyst is 4Cz-IPN, Ir(dFCF3ppy)2dtbpyPF6, Ir(dFppy)2bpyPF6, Ir(dFCF3ppy)2bpyPF6 or Ir(dFppy)2dtbpyPF6. Other components are the same as specific embodiment 1.
[0029] Specific embodiment 3: This embodiment differs from specific embodiment 1 or 2 in that the Lewis acid is trifluoroacetic acid, boron trifluoride etherate, lithium chloride, sodium trifluoromethanesulfonate, sodium tetrafluoroborate or p-toluenesulfonic acid. Other aspects are the same as specific embodiment 1 or 2.
[0030] Specific embodiment 4: This embodiment differs from specific embodiments 1 to 3 in that the organic solvent is acetonitrile, anhydrous acetonitrile, anhydrous dichloroethane, toluene, N,N-dimethylformamide or anhydrous trifluorotoluene. Other aspects are the same as specific embodiments 1 to 3.
[0031] Specific embodiment 5: This embodiment differs from Specific embodiments 1 to 4 in that the molar ratio of ethyl 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylate to the volume ratio of the organic solvent is 1 mmol:(5-10) mL. Other aspects are the same as Specific embodiments 1 to 4.
[0032] Specific embodiment 6: This embodiment differs from specific embodiments 1 to 5 in that the solvent used for separation and purification by silica gel column chromatography is a mixed solvent of petroleum ether and ethyl acetate. Other aspects are the same as specific embodiments 1 to 5.
[0033] Specific embodiment 7: This embodiment differs from specific embodiments 1 to 6 in that the volume ratio of petroleum ether to ethyl acetate is (10-15): 1. Other aspects are the same as specific embodiments 1 to 6.
[0034] Specific embodiment eight: This embodiment differs from specific embodiments one to seven in that: 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid ethyl ester, dibenzylamine, a catalyst, a Lewis acid, 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester, and an organic solvent are mixed for 20 to 24 hours under nitrogen atmosphere, room temperature, and stirring at a speed of 200 to 300 rpm. Other steps are the same as specific embodiments one to seven.
[0035] Specific embodiment 9: This embodiment differs from Specific embodiments 1 to 8 in that the mixture is photocatalytically reacted for 20 to 24 hours using two blue light lamps with a wavelength of 450 nm and a power of 12 to 18 W, under a nitrogen atmosphere, room temperature, and a stirring speed of 200 to 300 rpm. Other aspects are the same as Specific embodiments 1 to 8.
[0036] Specific embodiment 10: This embodiment differs from any one of specific embodiments 1 to 9 in that the structural formula of the indole derivative is The rest is the same as the specific embodiments one to nine.
[0037] The following examples are used to verify the beneficial effects of the present invention:
[0038] Example 1:
[0039] A method for photoinduced dearylation of indole is carried out according to the following steps:
[0040] Using two blue light lamps with a wavelength of 450 nm and a power of 12 W, under nitrogen atmosphere, room temperature and stirring speed of 300 r / min, 28.5 mg (0.1 mmol) of 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid ethyl ester, 23.6 mg (0.12 mmol) of dibenzylamine, 1 mg (0.001 mol) of catalyst, 3.29 mg (0.03 mmol) of Lewis acid, 37.95 mg (0.15 mmol) of mol) 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester and 1 mL of an organic solvent are mixed for 24 hours to obtain a mixture, which is then irradiated with two blue light lamps with a wavelength of 450 nm and a power of 12 W. The mixture is subjected to a photocatalytic reaction for 24 hours in a nitrogen atmosphere, at room temperature, and at a stirring speed of 300 r / min. After the reaction, the solvent is removed by distillation under reduced pressure, and then separated and purified by silica gel column chromatography to obtain an indole derivative, thereby completing the method for photoinduced indole dearylation.
[0041] The structural formula of the 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid ethyl ester is
[0042] The catalyst is 4Cz-IPN.
[0043] The Lewis acid is sodium tetrafluoroborate.
[0044] The organic solvent is anhydrous dichloroethane.
[0045] The solvent used for the silica gel column chromatography separation and purification is a mixed solvent of petroleum ether and ethyl acetate.
[0046] The volume ratio of petroleum ether to ethyl acetate is 10:1.
[0047] The prepared indole derivative is 9-(dibenzylamino)-6-oxo-6,7,8,9,9a,10-hexahydro-7,9-methanepyrimido[1,2-a]indole-10-carboxylate, with the structural formula
[0048] The preparation route of the 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid ethyl ester is:
[0049]
[0050] Among them named Indole A, named is a substituted carboxylic acid B.
[0051] The 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid ethyl ester was prepared with reference to the following literature: Zhu, ZM (2020). Visible-Light-Induced Intramolecular Double Dearomative Cycloaddition of Arenes. The preparation process is as follows: In a round-bottom flask, indole A (20 mmol) was dissolved in anhydrous acetonitrile (30.0 mL), and then substituted carboxylic acid B (10 mmol) was added, followed by the addition of DMAP (122 mg, 1.0 mmol), 2,6-lutidine (0.12 mL, 1.0 mmol) and di-tert-butyl dicarbonate (BoC)2O (5.5 mL, 25.0 mmol). After completion of the reaction (monitored by TLC), the reaction was quenched with water, and the aqueous phase was extracted with EtOAc (30 mL×3). The extracted organic phases were combined and washed with brine, dried over sodium sulfate, filtered and concentrated by rotary evaporator, and the residue was purified by silica gel column chromatography (PE / EA=10 / 1) to obtain the target product.
[0052] The preparation route of the indole derivatives in this example is:
[0053]
[0054] The Hantzsch ester is diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate.
[0055] The yield of the indole derivative prepared in this example is 89% and the purity is 99%.
[0056] Figure 1 The indole derivative prepared in Example 1 1 H NMR spectrum. Figure 2 The indole derivative prepared in Example 1 13 C NMR spectrum. The NMR data analysis of indole derivatives is:
[0057] 1H NMR (400MHz, CDCl3): δH 7.68(dd,J=7.9,1.2Hz,1H),7.29(d,J=7.1Hz,4H),7.23-7.18(m,6H),7.15-7.09(m,2H ),7.01(td,J=7.5,1.1Hz,1H),5.20(d,J=10.9Hz,1H),4.30-4.17(m,2H),4.16-4.11(m ,1H),3.90(d,J=14.6Hz,2H),3.52(d,J=14.7Hz,2H),2.70-2.54(m,2H),2.26(dd,J=10 .5,6.5Hz,1H),2.01-1.86(m,1H),1.37(dd,J=10.4,8.0Hz,1H),1.27(t,J=7.1Hz,3H).
[0058] 13 C NMR (101MHz, CDCl3): δC 173.82,171.26,141.88,139.90,130.22,128.76,128.40,127.86,126.93,124.53 ,123.22,117.73,66.77,64.18,61.70,53.14,49.89,36.06,34.39,32.33,14.26.
[0059] Figure 3 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid ethyl ester prepared in Example 1 1 H NMR spectrum. Figure 4 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid ethyl ester prepared in Example 1 13 C NMR spectrum. The NMR data analysis of ethyl 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylate is as follows:
[0060] 1 H NMR (400MHz, CDCl3): δH 8.42(dd,J=7.2,1.8Hz,1H),8.12-8.07(m,1H),8.05(s,1H),7.39-7.33(m,2H),4.37(q,J= 7.1Hz,2H),3.93-3.86(m,1H),3.69-3.61(m,2H),3.48-3.40(m,2H),1.38(t,J=7.1Hz,3H).
[0061] 13C NMR(101MHz,CDCl3):δH 201.68,171.35,163.91,136.18,129.88,127.37,126.35,125.25,121.81,116.58,115.17,77.36,77.04,76.72,60.82,51.43,28.34,14.45.
Claims
1. A method for light-induced dearylation of indole, characterized in that It is carried out in the following steps: In a nitrogen atmosphere, at room temperature, under irradiation with a 450 nm blue light lamp and stirring, 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid ethyl ester, dibenzylamine, a catalyst, a Lewis acid, 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester and an organic solvent are uniformly mixed to obtain a mixture, and then in a nitrogen atmosphere, at room temperature, under irradiation with a 450 nm blue light lamp and stirring, the mixture is subjected to a photocatalytic reaction. After the reaction, the solvent is removed by distillation under reduced pressure, and then separated and purified by silica gel column chromatography to obtain an indole derivative, thereby completing the method for photoinduced indole dearylation; The structural formula of the 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid ethyl ester is The molar ratio of the ethyl 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylate to dibenzylamine is 1:(1.0-1.5); the molar ratio of the ethyl 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylate to the catalyst is 1:(0.01-0.03); the molar ratio of the ethyl 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylate to Lewis acid is 1:(0.2-0.5); and the molar ratio of the ethyl 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylate to diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate is 1:(1.5-2.0).
2. The method for photoinduced dearylation of indole according to claim 1, wherein The catalyst is 4Cz-IPN, Ir(dFCF3ppy)2dtbpyPF6, Ir(dFppy)2bpyPF6, Ir(dFCF3ppy)2bpyPF6 or Ir(dFppy)2dtbpyPF6.
3. The method for photoinduced dearylation of indole according to claim 1, characterized in that The Lewis acid is trifluoroacetic acid, boron trifluoride etherate, lithium chloride, sodium trifluoromethanesulfonate, sodium tetrafluoroborate or p-toluenesulfonic acid.
4. The method of photoinduced dearylation of indole according to claim 1, characterized in that The organic solvent is acetonitrile, anhydrous acetonitrile, anhydrous dichloroethane, toluene, N,N-dimethylformamide or anhydrous trifluorotoluene.
5. The method for photoinduced dearylation of indole according to claim 1, characterized in that The volume ratio of the mole of 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid ethyl ester to the organic solvent is 1 mmol: (5-10) mL.
6. The method of photoinduced dearylation of indole according to claim 1, characterized in that The solvent used for the silica gel column chromatography separation and purification is a mixed solvent of petroleum ether and ethyl acetate.
7. The method of photoinduced dearylation of indole according to claim 6, characterized in that The volume ratio of petroleum ether to ethyl acetate is (10-15):
1.
8. The method of photoinduced dearylation of indole according to claim 1, characterized in that Using two blue light lamps with a wavelength of 450 nm and a power of 12 W to 18 W, 1-(3-oxocyclobutane-1-carbonyl)-1H-indole-3-carboxylic acid ethyl ester, dibenzylamine, a catalyst, a Lewis acid, 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester and an organic solvent were mixed for 20 h to 24 h in a nitrogen atmosphere, room temperature and a stirring speed of 200 r / min to 300 r / min.
9. The method of photoinduced dearylation of indole according to claim 1, characterized in that The mixture was photocatalytically reacted for 20 to 24 hours under the conditions of nitrogen atmosphere, room temperature and stirring speed of 200 to 300 r / min using two blue light lamps with a wavelength of 450 nm and a power of 12 to 18 W.
10. The method of photoinduced dearylation of indole according to claim 1, characterized in that The structural formula of the indole derivative is