A method for preparing indolines based on electro-organic synthesis

Abstract

The application discloses a preparation method of an indoline compound based on organic electrosynthesis, and belongs to the technical field of pharmaceutical chemical engineering and related chemistry. The method uses simple arylamine and halogenated olefin as raw materials, and prepares the indoline compound under the electrolysis of an electrode, so that green and efficient synthesis of the indoline compound is realized. The method has the advantages of low cost, high selectivity, mild reaction condition, good functional group compatibility, wide substrate range and environmental friendliness. The indoline compound is an important organic synthesis intermediate, and has a very wide application in the fields of fine chemical engineering and pharmacy. The preparation method has great application value and social and economic benefits.

Description

Technical Field

[0001] This invention relates to the fields of pharmaceutical and chemical intermediates and related chemical technologies, and to a method for preparing indoline compounds based on the cyclization reaction of aromatic amine compounds and haloolefins using organic electrosynthesis and haloolefin compounds as raw materials. Background Technology

[0002] Indoline compounds are an important class of intermediates for the synthesis of natural products, pharmaceuticals, or functional molecules, and have a wide range of applications in organic synthesis. Indoline compounds, especially in the synthesis of pharmaceuticals and pesticides, demonstrate enormous potential, making their synthesis a current research hotspot. With increasing attention to sustainable development and human health, green and precise synthesis, characterized by high efficiency, low pollution, and atom economy, are gaining increasing interest. However, among the reported synthetic reactions of indoline compounds, there are no reports of organic electrolytic synthesis of indoline compounds using aromatic amines and haloalkenes as raw materials. Summary of the Invention

[0003] To address the problems existing in the prior art, this invention provides a method for synthesizing indoline compounds using an organoelectrosynthesis reaction of aromatic amines and haloolefins. This method offers advantages such as readily available and inexpensive raw materials, high selectivity and yield, mild reaction conditions, and high atom economy, and is of significant importance. The method uses aromatic amines and haloolefins as raw materials to achieve the organoelectrosynthesis reaction of aromatic amines and haloolefins to synthesize indoline compounds. This method has advantages such as readily available and inexpensive raw materials, good selectivity, mild conditions, good atom economy, environmental friendliness, and ease of industrialization. This invention has significant application value and socio-economic benefits.

[0004] The technical solution adopted in this invention is as follows: a method for preparing indoline compounds based on organic electrosynthesis, using simple aromatic amines and haloalkenes as raw materials, and completing the cyclization reaction of aromatic amines and haloalkenes through the electrolysis of electrodes to synthesize a series of indoline compounds. The method includes the following steps:

[0005] The synthesis route is as follows:

[0006]

[0007] Where: R 1 = Hydrogen, C 1-6 Straight-chain or branched alkyl, alkoxy, hydroxy, alkoxyformyl, halogen, R 2 = Hydrogen, C 1-6 Straight-chain or branched alkyl groups, R 3 = Hydrogen, C 1-6 Straight-chain or branched alkyl groups, where X = chlorine, bromine, or iodine;

[0008] (1) Aromatic amine compounds, ammonium electrolyte, and solvent are added sequentially to an electrolytic cell. Halogenated olefin compounds are added or olefin gas is introduced. Anode and cathode electrodes are inserted, and a DC power supply is connected. The reaction is carried out under constant current at room temperature for 2 to 48 hours. The molar ratio of aromatic amine compounds to olefin compounds is 1:1 to 1:4, the molar ratio of aromatic amine compounds to electrolyte is 1:0.1 to 1:2, and the current density is 1.5 mA to 60 mA.

[0009] (2) After the reaction is complete, disconnect the power supply, remove the solvent by vacuum distillation, and use the eluent for silica gel column separation to obtain indoline compounds.

[0010] Aromatic amines include those containing hydrogen and those containing C. 1-6 Straight-chain or branched alkyl groups, containing alkoxy groups, containing hydroxyl groups, containing alkoxyformyl groups, or containing halogens; haloalkenes including those containing hydrogen and C. 1-6 Straight-chain or branched alkyl groups of chloroethylene, bromoethylene, or iodoethylene. The R on aniline. 1 It is hydrogen, C 1-6 Straight-chain or branched alkyl groups, alkoxy groups, hydroxyl groups, alkoxyformyl groups, halogens; R groups on haloalkenes 2 It is hydrogen, C 1-6 Straight-chain or branched alkyl groups; R on haloolefins 3 It is hydrogen, C 1-6 Straight-chain or branched alkyl groups; the X on the haloalkene is chlorine, bromine, or iodine; the molar ratio of aromatic amines to haloalkenes is 1:1 to 1:4.

[0011] The reaction time ranges from 2 hours to 48 hours, preferably from 4 hours to 12 hours.

[0012] The current density is 1.5mA to 120mA, preferably 6mA to 40mA.

[0013] The ammonium electrolyte is selected from ammonium chloride, ammonium fluoride, ammonium iodide, ammonium hexafluorophosphate, ammonium tetrafluoroborate, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium fluoride, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium fluoride, tetra-n-propylammonium chloride, tetra-n-propylammonium bromide, tetra-n-propylammonium fluoride, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium fluoride, tetra-n-butylammonium iodide, tetra-n-butylammonium hexafluorophosphate, tetra-n-butylammonium tetrafluoroborate, tetra-n-hexylammonium hexafluorophosphate, tetra-n-hexylammonium tetrafluoroborate, trimethylbenzylammonium chloride, and trimethylbenzylammonium bromide.

[0014] The anode electrode material is selected from graphite, glassy carbon, platinum, and lead dioxide.

[0015] The cathode electrode material is selected from platinum, nickel, zinc, copper, and stainless steel.

[0016] The amount of organic solvent is 1 to 500 mL, and the organic solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, trifluoroethanol, 1,2-ethylene glycol, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, sulfolane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dimethyl carbonate, diethyl carbonate, methyl ethyl carbonate, and water.

[0017] The molar ratio of aromatic amine compounds to electrolytes is 1:0.1 to 1:2.

[0018] The molar ratio of aromatic amines to halogenated olefins is 1:1 to 1:4.

[0019] The beneficial effects of this invention are as follows: The method for preparing indoline compounds of this invention has the advantages of inexpensive and readily available raw materials, high selectivity, mild reaction conditions, wide substrate applicability, and environmental friendliness. Specifically:

[0020] (1) This method is for the cyclization reaction of aromatic amines with haloalkenes. In the prior art, the synthesis of indoline compounds from aromatic amines generally requires the presence of an oxidant, high temperature, and expensive metal catalysis to proceed smoothly. The reaction conditions are harsh and the catalyst cost is high. In this application, due to the use of an organic electrosynthesis method, the cyclization reaction of aromatic amines with haloalkenes can be achieved under mild and simple conditions.

[0021] (2) This method uses organic electrosynthesis, which does not require the addition of an external oxidant, has high atom economy, and the post-reaction processing is simple.

[0022] (3) High selectivity and high yield. In summary, this method is an organic electrosynthetic method for indoline compounds with high selectivity, mild reaction conditions, high atom economy, and high yield. Since indoline compounds are important organic synthesis intermediates with very wide applications in the fields of medicine, pesticides, and materials, this invention has significant application value and socio-economic benefits. Attached Figure Description

[0023] Figure 1 For compound 3a 1 H-NMR.

[0024] Figure 2 For compound 3a 13 C-NMR.

[0025] Figure 3 For compound 3b 1 H-NMR.

[0026] Figure 4 For compound 3b 13 C-NMR.

[0027] Figure 5 For compound 3c 1 H-NMR.

[0028] Figure 6 For compound 3c 13 C-NMR.

[0029] Figure 7 For compound 3d 1 H-NMR.

[0030] Figure 8 For compound 3d 13 C-NMR.

[0031] Figure 9 For compound 3e 1 H-NMR.

[0032] Figure 10 For compound 3e 13 C-NMR.

[0033] Figure 11 For compound 3f 1 H-NMR.

[0034] Figure 12 For compound 3f 13 C-NMR.

[0035] Figure 13 3g of compound 1 H-NMR.

[0036] Figure 14 3g of compound 13 C-NMR.

[0037] Figure 15 For compound 3h 1 H-NMR.

[0038] Figure 16 For compound 3h 13 C-NMR.

[0039] Figure 17 For compound 3i 1 H-NMR.

[0040] Figure 18 For compound 3i 13 C-NMR.

[0041] Figure 19 For compound 3j 1 H-NMR.

[0042] Figure 20For compound 3j 13 C-NMR. Detailed Implementation

[0043] The method for preparing indoline compounds based on organic electrosynthesis described in this invention has the advantages of inexpensive and readily available raw materials, good reaction selectivity, mild reaction conditions, environmental friendliness, and high atom economy, showing good application prospects.

[0044] The present invention will be further illustrated below with reference to specific embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Simple substitutions or modifications made to the present invention by those skilled in the art are all within the scope of the technical solutions protected by the present invention.

[0045]

[0046] Example 1: Synthesis of indoline (3a)

[0047]

[0048] Accurately weigh aniline (93 mg, 1.0 mmol), vinyl iodide (308 mg, 2.0 mmol), and tetrabutylammonium bromide (161 mg, 0.5 mmol) and add them sequentially to a 10 mL electrolytic cell. Add acetonitrile (3.0 mL), insert a graphite anode and a nickel cathode, connect a DC power supply, and control the constant current at 20 mA. Electrolyze the reaction at room temperature for 3 h. After the reaction is complete, remove the solvent by vacuum distillation. Use petroleum ether / ethyl acetate (v / v 30:1) as the eluent and separate by silica gel column chromatography. The product, indoline, is in 96% yield. 1 HNMR (600)

[0049] MHz, CDCl3) δ7.21(d,J=7.2Hz,1H),7.11(t,J=7.6Hz,1H),6.80(t,J=7.3

[0050] Hz,1H),6.72(d,J=7.8Hz,1H),3.78(s,1H),3.61(t,J=8.4Hz,2H),3.11(t,J=8.4Hz,2H). 13 C NMR (151MHz, CDCl3) δ151.7,129.4,127.3,124.7,118.7,109.5,47.4,29.9.

[0051] Example 2: Synthesis of 2-methylindoline (3b)

[0052]

[0053] Aniline (466 mg, 5.0 mmol), 1-bromopropene (726 mg, 6.0 mmol), and tetramethylammonium chloride (219 mg, 2.0 mmol) were accurately weighed and added sequentially to a 50 mL electrolytic cell. Ethanol (10.0 mL) was added, and a graphite anode and stainless steel cathode were inserted. A DC power supply was connected, and the constant current was controlled at 40 mA. The electrolysis reaction was carried out at room temperature for 8 h. After the reaction was completed, the solvent was removed by vacuum distillation. Petroleum ether / ethyl acetate (v / v 30:1) was used as the eluent, and the product 2-methylindoline was separated by silica gel column chromatography. The yield of 2-methylindoline was 91%. 1 H NMR (600MHz, CDCl3) δ7.19(d,J=7.3Hz,1H),7.13(t,J=7.6Hz,1H),6.81(t,J=7.4Hz,1H),6.70(d,J=7.8Hz,1H),4 .11-4.02(m,1H),3.81(s,1H),3.24(dd,J=15.4,8.5Hz,1H),2.74(dd,J=15.4,7.8Hz,1H),1.38(d,J=6.3Hz,3H). 13 CNMR (151MHz, CDCl3) δ151.1,129.0,127.3,124.8,118.6,109.3,55.3,37.9,22.4.

[0054] Example 3: Synthesis of 2,3-dimethylindoline (3c)

[0055]

[0056] Aniline (186 mg, 2.0 mmol), 2-chloro-2-butene (272 mg, 3.0 mmol), and tetrahexylammonium hexafluorophosphate (300 mg, 0.6 mmol) were accurately weighed and added sequentially to a 20 mL electrolytic cell. Dimethyl sulfoxide (4.0 mL) was added, and a platinum anode and zinc cathode were inserted. A DC power supply was applied, and the reaction was carried out at a constant current of 6 mA for 6 h at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation. Petroleum ether / ethyl acetate (v / v 30:1) was used as the eluent, and the product 2,3-dimethylindoline was separated by silica gel column chromatography in 89% yield. 1 H NMR (600MHz, CDCl3) δ7.13 (dd, J=14.3, 7.4Hz, 2H), 6.83 (t, J=7.4Hz, 1H), 6.69 (d, J=7.7 Hz,1H),3.81(s,1H),3.54-3.51(m,1H),2.97-2.85(m,1H),1.40(dd,J=6.6,3.3Hz,6H). 13C NMR (151MHz, CDCl3) δ150.6,134.4,127.4,123.3,118.7,109.2,64.0,44.4,20.6,17.3.

[0057] Example 4: Synthesis of 5-methylindoline (3d)

[0058]

[0059] Accurately weigh 107 mg (1.0 mmol) of 4-methylaniline, 462 mg (3.0 mmol) of vinyl iodide, and 56 mg (0.2 mmol) of tetrabutylammonium chloride, and add them sequentially to a 10 mL electrolytic cell. Add 3.0 mL of tetrahydrofuran, insert a graphite anode and a zinc cathode, connect a DC power supply, and control the constant current at 15 mA. React at room temperature for 6 h. After the reaction is complete, remove the solvent by vacuum distillation. Use petroleum ether / ethyl acetate (v / v 30:1) as the eluent and separate by silica gel column chromatography. The product, 5-methylindoline, is obtained in 98% yield. 1 H NMR (600MHz, CDCl3) δ7.02(s,1H),6.90(d,J=7.8Hz,1H),6.63(d,J=7.8Hz,1 H),3.63(brs,1H),3.58(t,J=8.3Hz,2H),3.06(t,J=8.3Hz,2H),2.33(s,3H). 13 CNMR (151MHz, CDCl3) δ149.2,129.8,128.1,127.6,125.5,109.5,47.6,30.0,20.8.

[0060] Example 5: Synthesis of 2,5-dimethylindoline (3e)

[0061]

[0062] Accurately weigh 643 mg (6.0 mmol) of 4-methylaniline, 968 mg (8.0 mmol) of 1-bromopropene, and 329 mg (1.0 mmol) of tetrabutylammonium tetrafluoroborate, and add them sequentially to a 50 mL electrolytic cell. Add 8.0 mL of N,N-dimethylacetamide, insert a platinum anode and a copper cathode, connect a DC power supply, and control the constant current at 60 mA. React at room temperature for 16 h. After the reaction is complete, remove the solvent by vacuum distillation. Use petroleum ether / ethyl acetate (v / v 30:1) as the eluent and separate by silica gel column chromatography. The product 2,5-dimethylindoline is obtained in 90% yield. 1H NMR (600MHz, CDCl3) δ6.96(s,1H),6.87(d,J=7.8Hz,1H),6.57(d,J=7.8Hz,1H),4.03-3.98(m,1H),3.55( brs,1H),3.15(dd,J=15.3,8.4Hz,1H),2.65(dd,J=15.3,7.8Hz,1H),2.29(s,3H),1.33(d,J=6.2Hz,3H). 13 CNMR (151MHz, CDCl3) δ148.5,129.3,128.0,127.5,125.6,109.3,55.5,37.9,22.3,20.8.

[0063] Example 6: Synthesis of 5-hydroxyindoline (3f)

[0064]

[0065] Accurately weigh 218 mg (2.0 mmol) of 4-aminophenol, 616 mg (4.0 mmol) of vinyl iodide, and 103 mg (0.5 mmol) of tetrapropylammonium fluoride, and add them sequentially to a 10 mL electrolytic cell. Add 6.0 mL of 1,4-dioxane, insert a graphite anode and a zinc cathode, connect a DC power supply, and control the constant current at 3 mA. React at room temperature for 4 h. After the reaction is complete, remove the solvent by vacuum distillation. Use petroleum ether / ethyl acetate (v / v 5:1) as the eluent and separate by silica gel column chromatography. The product, 5-hydroxyindoline, is obtained in 85% yield. 1 H NMR (600MHz, DMSO) δ6.60 (dd, J=1.7, 1.0Hz, 1H), 6.44 (d, J=1.8Hz, 2H), 3.43-3.39 (m, 2H), 2.88 (dd, J=12.2, 4.4Hz, 2H). 13 C NMR (151MHz, DMSO) δ150.3, 143.6, 131.0, 113.3, 112.3, 110.4, 47.4, 30.2.

[0066] Example 7: Synthesis of 5-(methoxyformyl)indoline (3g)

[0067]

[0068] Accurately weigh methyl 4-aminobenzoate (151 mg, 1.0 mmol), vinyl iodide (231 mg, 1.5 mmol), and tetrabutylammonium bromide (65 mg, 0.2 mmol) and add them sequentially to a 10 mL electrolytic cell. Add isopropanol (3.0 mL), insert a platinum anode and zinc cathode, connect a DC power supply, and maintain a constant current of 40 mA. React at room temperature for 24 h. After the reaction is complete, remove the solvent by vacuum distillation. Use petroleum ether / ethyl acetate (v / v 10:1) as the eluent and separate by silica gel column chromatography. The product 5-(methoxyformyl)indoline yield is 87%. 1 H NMR (600MHz, CDCl3) δ7.77(dd,J=4.0,2.7Hz,2H),6.55(d,J=8.6Hz,1H),4.30(brs,1H),3.86(s,3H),3.66(t,J=8.6Hz,2H),3.07(t,J=8.5Hz,2H). 13 CNMR (151MHz, CDCl3) δ167.5,156.0,130.7,128.7,126.1,119.6,107.4,51.5,47.3,28.9.

[0069] Example 8: Synthesis of 6-methylindoline (3h)

[0070]

[0071] Accurately weigh 107 mg (1.0 mmol) of 3-methylaniline, 462 mg (3.0 mmol) of vinyl iodide, and 97 mg (0.3 mmol) of tetrabutylammonium bromide, and add them sequentially to a 10 mL electrolytic cell. Add 3.0 mL of dimethyl carbonate, insert a graphite anode and a copper cathode, connect a DC power supply, and control the constant current at 3 mA. React at room temperature for 8 h. After the reaction is complete, remove the solvent by vacuum distillation. Use petroleum ether / ethyl acetate (v / v 30:1) as the eluent and separate by silica gel column chromatography. The yield of 6-methylindoline is 81%. 1 H NMR (600MHz, CDCl3) δ7.09(d,J=7.3Hz,1H),6.62(d,J=7.3Hz,1H),6.56(s,1H),3.69(s,1H),3.60(t,J=8.3Hz,2H),3.06(t,J=8.3Hz,2H),2.36(s,3H). 13 CNMR (151MHz, CDCl3) δ151.9,137.1,126.5,124.3,119.4,110.5,47.6,29.6,21.5.

[0072] Example 9: Synthesis of 6-hydroxyindoline (3i)

[0073]

[0074] Accurately weigh 218 mg (2.0 mmol) of 3-aminophenol, 2.5 mmol of vinyl iodide, and 145 mg (1.0 mmol) of ammonium iodide, and add them sequentially to a 10 mL electrolytic cell. Add 3.0 mL of trifluoroethanol, insert a glassy carbon anode and a copper cathode, connect a DC power supply, and control the constant current at 1.5 mA. React at room temperature for 12 h. After the reaction is complete, remove the solvent by vacuum distillation. Use petroleum ether / ethyl acetate (v / v 5:1) as the eluent and separate by silica gel column chromatography. The product, 6-hydroxyindoline, is obtained in 92% yield. 1 H NMR (600MHz, DMSO) δ8.75 (s, 1H), 6.76 (d, J = 7.8Hz, 1H), 5.9-5.934 (m, 2H), 5.33 (s, 1H), 3.36 (t, J = 8.3Hz, 2H), 2.76 (t, J = 8.3Hz, 2H). 13 C NMR (151MHz, DMSO) δ157.4,154.2,124.7,119.4,104.0,97.0,47.4,28.9.

[0075] Example 10: Synthesis of 7-methylindoline (3j)

[0076]

[0077] Accurately weigh 107 mg (1.0 mmol) of 2-methylaniline, 308 mg (2.0 mmol) of vinyl iodide, and 322 mg (1.0 mmol) of tetrabutylammonium bromide, and add them sequentially to a 10 mL electrolytic cell. Add 3.0 mL of ethanol, insert a graphite anode and a copper cathode, connect a DC power supply, and control the constant current at 60 mA. React at room temperature for 5 h. After the reaction is complete, remove the solvent by vacuum distillation. Use petroleum ether / ethyl acetate (v / v 30:1) as the eluent and separate by silica gel column chromatography. The product 7-methylindoline is obtained in 97% yield. 1 H NMR(600MHz, CDCl3) δ7.06(d,J=7.3Hz,1H),6.93(d,J=7.5Hz,1H),6.73(t,J=7.4 Hz,1H),3.62(t,J=8.4Hz,2H),3.52(brs,1H),3.12(t,J=8.4Hz,2H),2.20(s,3H). 13CNMR(151MHz,CDCl3)δ150.1,128.7,128.2,122.2,119.0,118.9,47.2,30.2,16.9。

Claims

1. A method for preparing indoline compounds based on organic electrosynthesis, using aromatic amines and haloalkenes as raw materials, and synthesizing a series of indoline compounds by completing the cyclization reaction of aromatic amines and haloalkenes through electrolysis of electrodes, characterized in that... The method includes the following steps: The synthesis route is as follows: ； Where: R 1 =Hydrogen, C 1-6 Straight-chain or branched alkyl, alkoxy, hydroxy, alkoxyformyl, halogen, R 2 =Hydrogen, C 1-6 Straight-chain or branched alkyl groups, R 3 =Hydrogen, C 1-6 Straight-chain or branched alkyl groups, where X = chlorine, bromine, or iodine; (1) Add aromatic amine, ammonium electrolyte and solvent to the electrolytic cell in sequence, add haloolefin, insert anode and cathode electrodes, connect DC power supply, and electrolyze at constant current for 2~48 h at room temperature; the molar ratio of aromatic amine to haloolefin is 1:1~1:4, the molar ratio of aromatic amine to electrolyte is 1:0.1~1:2, and the current is 1.5 mA~120 mA; (2) After the reaction is complete, disconnect the power supply, remove the solvent by vacuum distillation, and separate the solvent by silica gel column chromatography with eluent to obtain indoline compounds.

2. The method for preparing indoline compounds based on organic electrosynthesis according to claim 1, characterized in that: The ammonium electrolyte is selected from ammonium chloride, ammonium fluoride, ammonium iodide, ammonium hexafluorophosphate, ammonium tetrafluoroborate, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium fluoride, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium fluoride, tetra-n-propylammonium chloride, tetra-n-propylammonium bromide, tetra-n-propylammonium fluoride, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium fluoride, tetra-n-butylammonium iodide, tetra-n-butylammonium hexafluorophosphate, tetra-n-butylammonium tetrafluoroborate, tetra-n-hexylammonium hexafluorophosphate, tetra-n-hexylammonium tetrafluoroborate, trimethylbenzylammonium chloride, and trimethylbenzylammonium bromide.

3. The method for preparing indoline compounds based on organic electrosynthesis according to claim 1, characterized in that: The anode electrode is a graphite electrode, a glassy carbon electrode, a platinum electrode, or a lead dioxide electrode.

4. The method for preparing indoline compounds based on organic electrosynthesis according to claim 1, characterized in that: The cathode electrode is a platinum electrode, nickel electrode, zinc electrode, copper electrode, or stainless steel electrode.

5. The method for preparing indoline compounds based on organic electrosynthesis according to claim 1, characterized in that: The solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, trifluoroethanol, 1,2-ethylene glycol, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, sulfolane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dimethyl carbonate, diethyl carbonate, methyl ethyl carbonate, and water.

6. The method for preparing indoline compounds based on organic electrosynthesis according to claim 1, characterized in that: The structures of the starting aromatic amine, the haloolefin, and the corresponding indoline compounds are as follows: 。

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