A method for preparing indolo[2,3-b]quinolines in aqueous phase mediated by iodine

Abstract

The application discloses a preparation method of indolo[2,3-b]quinoline compounds in water phase. 2 The C-N coupling / dehydrogenation aromatization reaction is used to prepare the indolo[2,3-b]quinoline compounds. The method does not need to protect the free amino group in the substrate, can completely avoid adding any organic solvent in the reaction, and does not need to additionally add a base additive, and has the characteristics of easy preparation of raw materials, mild reaction conditions, simple operation, wide applicable range of substrates, easy expansion of reaction scale and the like, and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic chemistry, specifically to a method for preparing iodine-mediated indodo[2,3-b]quinoline compounds in an aqueous phase. Background Technology

[0002] Indo[2,3-b]quinoline derivatives are widely found in many natural products and drug molecules, exhibiting a wealth of biological and pharmaceutical activities, such as antibacterial, antitumor, antimalarial, and hypoglycemic activities (Curr. Org. Chem., 2011, 5, 1036–1057; Eur. J. Org. Chem., 2014, 7979–8003; Curr. Top. Med. Chem., 2015, 15, 1683–1707). Therefore, synthetic chemists and pharmacologists have been actively researching new methods for the efficient synthesis of these compounds.

[0003] In recent years, iodine-mediated intramolecular coupling reactions have attracted widespread attention from chemists and pharmacologists as a metal-free strategy. This is because the methods involved typically offer advantages such as mild reaction conditions and simple experimental operation, providing a commonly used and efficient means for the green and efficient construction of some pharmaceutical intermediates and bioactive molecular skeletons. Currently, there are only a few reported methods for synthesizing indodo[2,3-b]quinoline derivatives via iodine-mediated intramolecular reactions under metal-free conditions: In 2016, Sekar et al. used sulfonyl-protected aromatic amines as substrates and acetonitrile as solvent, and achieved the synthesis of such substances by using a stoichiometric combination of iodine and cesium carbonate at 60 °C (Org. Biomol. Chem., 2016, 14, 2297–2305). However, this method has the following shortcomings: (1) It relies on organic solvents as the reaction medium, and there is still much room for improvement from the perspective of green chemistry; (2) It requires the free amino groups of aromatic amines in the substrate to be protected with sulfonyl groups and then removed through aromatization in the reaction, resulting in insufficient economic efficiency of the reaction steps; (3) It relies on the use of stoichiometric base additives (cesium carbonate), and the substrate application range is relatively limited, and cesium carbonate is expensive and unsafe.

[0004] Patent application number 202110572773.7 discloses a method for preparing indo[2,3-b]quinoline compounds, using o-aminostyrene or 3-methyl-6-vinylaniline as substrates, elemental iodine as catalyst, and DMSO as organic solvent, reacting in an oil bath at 70-90℃ to obtain indo[2,3-b]quinoline compounds. This reaction requires both oil bath heating and reaction in an organic solvent, resulting in high synthesis costs and failing to meet the requirements of green chemistry. Furthermore, this method has low yields, a very limited substrate range, and narrow functional group tolerance. Since the target product is obtained through the dimerization of o-aminostyrene, the synthesized indo[2,3-b]quinoline products have very limited substituent positions, making it difficult to obtain indo[2,3-b]quinoline compounds with other substituent positions. Therefore, a green method that does not rely on alkali additives, is safe, low-cost, and does not use organic solvents is needed for a simpler and more efficient synthesis of indo[2,3-b]quinoline derivatives. Summary of the Invention

[0005] To address the aforementioned limitations of the prior art, the objective of this invention is to provide a method for preparing iodine-mediated indo[2,3-b]quinoline compounds in an aqueous phase. This invention uses an amino-containing indole derivative as a substrate, elemental iodine as an oxidant, and water as a solvent, through intramolecular sp... 2 CN coupling / dehydrogenation aromatization reaction was used to prepare indodo[2,3-b]quinoline compounds.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] This invention provides a method for preparing iodine-mediated indo[2,3-b]quinoline compounds in an aqueous phase, wherein the preparation method comprises:

[0008] Using an amino-containing indole derivative as a substrate, iodine as an oxidant, and water as a solvent, the reaction was carried out under stirring at room temperature to obtain indole[2,3-b]quinoline compounds.

[0009] Preferably, the structural formula of the amino-containing indole derivative is shown in Formula I:

[0010]

[0011] Among them, R 1 It can be hydrogen, bromine, methyl, methoxy, ester, amide, or trifluoromethyl; R 2 It is hydrogen, methyl, allyl, isopropyl, or phenyl; R 3 It is hydrogen, bromine, methyl, or methoxy; R 4 It can be hydrogen, methyl, or phenyl.

[0012] Preferably, the ratio of the added substrate, oxidant and solvent is 1 mmol: 2 mmol: 10 mL.

[0013] Preferably, the reaction time is 12 to 24 hours.

[0014] After the reaction was completed, a saturated sodium thiosulfate solution was added for quenching. The mixture was extracted with ethyl acetate, the organic phases were combined and dried with anhydrous sodium sulfate, filtered and concentrated under vacuum, and the crude product was purified by column chromatography.

[0015] The beneficial effects of this invention are:

[0016] (1) This invention uses amino-containing indole derivatives as raw materials, elemental iodine as an oxidant, and water as a solvent to obtain indole[2,3-b]quinoline compounds by stirring at room temperature. The starting materials involved in this preparation method are all commercially available, simple, readily available, and widely sourced.

[0017] (2) The method provided by the present invention does not require protection of the free amino groups in the substrate, can completely avoid the addition of any organic solvent during the reaction, and does not require the addition of any additional alkali additives. It has the characteristics of easy preparation of raw materials, mild reaction conditions, simple operation, wide range of applicable substrates, and easy expansion of reaction scale, and is suitable for industrial production. Attached Figure Description

[0018] Figure 1 The 1H NMR spectrum of the target product obtained in Example 1;

[0019] Figure 2 The carbon NMR spectrum of the target product obtained in Example 1;

[0020] Figure 3 The 1H NMR spectrum of the target product obtained in Example 2;

[0021] Figure 4 The carbon NMR spectrum of the target product obtained in Example 2;

[0022] Figure 5 The 1H NMR spectrum of the target product obtained in Example 3;

[0023] Figure 6 The carbon NMR spectrum of the target product obtained in Example 3;

[0024] Figure 7 The 1H NMR spectrum of the target product obtained in Example 6;

[0025] Figure 8 The carbon NMR spectrum of the target product obtained in Example 6;

[0026] Figure 9 The 1H NMR spectrum of the target product obtained in Example 7;

[0027] Figure 10The carbon NMR spectrum of the target product obtained in Example 7;

[0028] Figure 11 The 1H NMR spectrum of the target product obtained in Example 11;

[0029] Figure 12 The carbon NMR spectrum of the target product obtained in Example 11;

[0030] Figure 13 The 1H NMR spectrum of the target product obtained in Example 14;

[0031] Figure 14 The carbon NMR spectrum of the target product obtained in Example 14;

[0032] Figure 15 The 1H NMR spectrum of the target product obtained in Example 16;

[0033] Figure 16 The image shows the carbon NMR spectrum of the target product obtained in Example 16. Detailed Implementation

[0034] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of this application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains.

[0035] As introduced in the background section, iodine-mediated intramolecular coupling reactions have attracted widespread attention from chemists and pharmacists as a metal-free strategy. However, currently, the synthesis of indodo[2,3-b]quinoline derivatives via iodine-mediated intramolecular reactions all require organic solvents and depend on the use of stoichiometric bases, which also presents technical limitations in terms of reaction steps, economy, and substrate applicability.

[0036] Therefore, the purpose of this invention is to provide a method for preparing iodine-mediated indole[2,3-b]quinoline compounds in aqueous phase. This invention uses an amino-containing indole derivative as a substrate, elemental iodine as an oxidant, and water as a solvent, through intramolecular sp... 2 CN coupling / dehydrogenation aromatization reaction was used to prepare indodo[2,3-b]quinoline compounds. The synthetic route is shown below:

[0037]

[0038] Water, as a non-toxic and pollution-free solvent, is considered an ideal solvent in laboratory and industrial processes. In this invention, the organic compounds in the aqueous phase exhibit hydrophobicity. This hydrophobicity increases the interaction between the hydrophobic substrate and the hydrophobic reaction reagent (iodine), increasing the probability of effective intermolecular collisions and promoting the improvement of reaction rate and yield.

[0039] To enable those skilled in the art to better understand the technical solution of this application, the technical solution of this application will be described in detail below with reference to specific embodiments.

[0040] Note: All water used in the examples was distilled water; the effect of other types of water on the reaction was not tested.

[0041] The test materials used in the embodiments of this invention are all conventional test materials in the art and can be purchased through commercial channels.

[0042] Example 1: Preparation of 6-methyl-6H-indole[2,3-b]quinoline

[0043]

[0044] 2-[(1-methyl-1H-indol-3-yl)methyl]aniline (0.2 mmol, 47.2 mg), 2 mL of water, and iodine (0.4 mmol, 101.6 mg) were added sequentially to a reaction tube equipped with a magnetic stir bar. The mixture was stirred at room temperature for 12 hours, and the reaction progress was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with saturated Na₂S₂O₃ solution, and then the mixture was extracted with ethyl acetate (5 mL * 4). The organic phases were combined and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified and separated by column chromatography to obtain a white solid product with a yield of 98%. The 1H NMR spectrum of the target product obtained in Example 1 is shown below. Figure 1 As shown, the carbon NMR spectrum is as follows: Figure 2 As shown.

[0045] 1 H NMR (400MHz, CDCl3) δ8.33(s,1H),8.08(d,J=8.5Hz,1H),7.89(d,J=7.6Hz,1H),7.79(d,J=8.1Hz,1H) ,7.64(t,J=7.6Hz,1H),7.43(t,J=7.6Hz,1H),7.34(t,J=7.4Hz,1H),7.19–7.13(m,2H),3.72(s,3H).

[0046] 13C NMR(101MHz, CDCl3)δ152.5(s),146.6(s),142.6(s),128.7(s),128.5(s),127.9(s),127.4(s) ,127.1(s),124.0(s),122.8(s),121.2(s),120.2(s),119.8(s),118.0(s),108.5(s),27.5(s).

[0047] Example 2: Preparation of 9-bromo-6-methyl-6H-indole[2,3-b]quinoline

[0048]

[0049] 2-[(5-bromo-1-methyl-1H-indol-3-yl)methyl]aniline (0.2 mmol, 62.8 mg), 2 mL of water, and iodine (0.4 mmol, 101.6 mg) were added sequentially to a reaction tube equipped with a magnetic stir bar. The mixture was stirred at room temperature for 12 hours, and the reaction progress was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with saturated Na₂S₂O₃ solution, and then the mixture was extracted with ethyl acetate (5 mL * 4). The organic phases were combined and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a white solid product with a yield of 80%.

[0050] The proton NMR spectrum of the target product obtained in Example 2 is as follows: Figure 3 As shown, the carbon NMR spectrum is as follows: Figure 4 As shown.

[0051] 1 H NMR (400MHz, CDCl3) δ8.55(s,1H),8.16(s,1H),8.11(d,J=8.4Hz,1H),7.94(d,J=8.1Hz,1H),7.72 (t,J=7.6Hz,1H),7.62(d,J=8.5Hz,1H),7.45(t,J=7.4Hz,1H),7.20(d,J=8.5Hz,1H),3.89(s,3H).

[0052] 13C NMR(101MHz, CDCl3)δ152.6(s),147.2(s),141.5(s),130.7(s),129.4(s),128.8(s),128.0(s) ,127.7(s),124.2(s),124.2(s),123.3(s),122.1(s),117.1(s),112.6(s),110.2(s),27.9(s).

[0053] Example 3: Preparation of 6,7-dimethyl-6H-indole[2,3-b]quinoline

[0054]

[0055] 2-[(1,7-dimethyl-1H-indol-3-yl)methyl]aniline (0.2 mmol, 50.0 mg), 2 mL of water, and iodine (0.4 mmol, 101.6 mg) were added sequentially to a reaction tube equipped with a magnetic stir bar. The mixture was stirred at room temperature for 12 hours, and the reaction progress was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with saturated Na₂S₂O₃ solution, and then the mixture was extracted with ethyl acetate (5 mL * 4). The organic phases were combined and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a white solid product with a yield of 85%.

[0056] The proton NMR spectrum of the target product obtained in Example 3 is as follows: Figure 5 As shown, the carbon NMR spectrum is as follows: Figure 6 As shown.

[0057] 1 H NMR (400MHz, CDCl3) δ8.58(s,1H),8.14(d,J=8.5Hz,1H),7.96(d,J=7.9Hz,2H),7.72(t,J=7.6Hz, 1H), 7.45 (t, J = 7.4Hz, 1H), 7.27 (d, J = 7.0Hz, 1H), 7.17 (t, J = 7.4Hz, 1H), 4.24 (s, 3H), 2.84 (s, 3H).

[0058] 13C NMR(101MHz, CDCl3)δ153.3(s),146.9(s),141.3(s),131.3(s),128.8(s),128.5(s),127.6(s),127 .0(s),124.3(s),122.9(s),121.0(s),120.8(s),120.1(s),119.3(s),118.3(s),30.9(s),19.9(s).

[0059] Example 4: Preparation of 9-methoxy-6-methyl-6H-indole[2,3-b]quinoline

[0060]

[0061] 2-[(5-methoxy-1-methyl-1H-indol-3-yl)methyl]aniline (0.2 mmol, 53.2 mg), 2 mL of water, and iodine (0.4 mmol, 101.6 mg) were added sequentially to a reaction tube equipped with a magnetic stir bar. The mixture was stirred at room temperature for 15 hours, and the reaction progress was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with saturated Na₂S₂O₃ solution, and then the mixture was extracted with ethyl acetate (5 mL * 4). The organic phases were combined and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a pale yellow solid product with a yield of 86%.

[0062] 1 H NMR (600MHz, CDCl3) δ8.56 (s, 1H), 8.12 (d, J = 8.4Hz, 1H), 7.94 (d, J = 7.8Hz, 1H), 7.71 (t, J = 6.9Hz, 1H), 7. 58(s,1H),7.43(t,J=6.8Hz,1H),7.23(d,J=8.5Hz,1H),7.17(d,J=8.0Hz,1H),3.92(s,3H),3.88(s,3H).

[0063] 13 C NMR(101MHz, CDCl3)δ154.2(s),153.0(s),146.9(s),137.5(s),128.9(s),128.6(s),127.4(s),127 .3(s),123.8(s),122.7(s),120.7(s),118.2(s),116.1(s),109.3(s),105.5(s),56.2(s),27.7(s).

[0064] Example 5: Preparation of methyl 6-methyl-6H-indole[2,3-b]quinoline-9-carboxylic acid

[0065]

[0066] Methyl 3-(2-aminobenzyl)-1-methyl-1H-indole-5-carboxylic acid (0.2 mmol, 58.8 mg), 2 mL of water, and iodine (0.4 mmol, 101.6 mg) were added sequentially to a reaction tube equipped with a magnetic stir bar. The mixture was stirred at room temperature for 15 hours, and the reaction progress was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with saturated Na₂S₂O₃ solution, and then the mixture was extracted with ethyl acetate (5 mL * 4). The organic phases were combined and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a white solid product with a yield of 73%.

[0067] 1 H NMR (400MHz, CDCl3) δ8.70(s,1H),8.58(s,1H),8.20(d,J=8.5Hz,1H),8.09(d,J=8.5Hz,1H),7.92(d,J=8 .1Hz,1H),7.71(t,J=7.6Hz,1H),7.45(t,J=7.4Hz,1H),7.27(d,J=9.0Hz,1H),3.97(s,3H),3.87(s,3H).

[0068] 13 C NMR(101MHz, CDCl3)δ167.5(s),153.0(s),147.0(s),145.6(s),129.8(s),129.3(s),128.7(s),127.9(s) ,127.7(s),124.4(s),123.5(s),123.4(s),121.8(s),120.2(s),117.7(s),108.2(s),52.2(s),27.9(s).

[0069] Example 6: Preparation of N,6-dimethyl-N-phenyl-6H-indole[2,3-b]quinoline-9-carboxamide

[0070]

[0071] 3-(2-aminobenzyl)-N,1-dimethyl-N-phenyl-1H-indole-5-carboxamide (0.2 mmol, 73.8 mg), 2 mL of water, and iodine (0.4 mmol, 101.6 mg) were added sequentially to a reaction tube equipped with a magnetic stir bar. The mixture was stirred at room temperature for 12 hours, and the reaction progress was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with saturated Na₂S₂O₃ solution, and then the mixture was extracted with ethyl acetate (5 mL * 4). The organic phases were combined and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified and separated by column chromatography to obtain a white solid product with a yield of 81%. The 1H NMR spectrum of the target product obtained in Example 6 is shown below. Figure 7 As shown, the carbon NMR spectrum is as follows: Figure 8 As shown.

[0072] 1 H NMR (600MHz, CDCl3) δ8.55(s,1H),8.25(s,1H),8.10(d,J=8.4Hz,1H),7.97(d,J=8.1Hz,1H),7.71(t, J=7.5Hz,1H),7.49–7.42(m,2H),7.24(t,J=7.5Hz,2H),7.16–7.09(m,4H),3.89(s,3H),3.59(s,3H).

[0073] 13 C NMR(151MHz, CDCl3)δ170.9(s),153.1(s),147.0(s),145.8(s),143.6(s),129.5(s),129.4(s),129.2(s),128.7(s),127.8(s) ,127.7(s),127.5(s),127.1(s),126.5(s),124.3(s),123.3(s),123.2(s),119.9(s),118.0(s),107.6(s),39.0(s),27.9(s).

[0074] Example 7: Preparation of 6-methyl-8-trifluoromethyl-6H-indole[2,3-b]quinoline

[0075]

[0076] 2-[(1-methyl-6-trifluoromethyl-1H-indol-3-yl)methyl]aniline (0.2 mmol, 60.8 mg), 2 mL of water, and iodine (0.4 mmol, 101.6 mg) were added sequentially to a reaction tube equipped with a magnetic stir bar. The mixture was stirred at room temperature for 12 hours, and the reaction progress was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with saturated Na₂S₂O₃ solution, and then the mixture was extracted with ethyl acetate (5 mL * 4). The organic phases were combined and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified and separated by column chromatography to obtain a white solid product with a yield of 82%. The 1H NMR spectrum of the target product obtained in Example 7 is shown below. Figure 9 As shown, the carbon NMR spectrum is as follows: Figure 10 As shown.

[0077] 1 H NMR (600MHz, CDCl3) δ8.73(s,1H),8.18(d,J=7.8Hz,1H),8.14(d,J=8.5Hz,1H),8.00(d,J=8.0Hz, 1H), 7.76 (t, J = 7.5Hz, 1H), 7.62 (s, 1H), 7.55 (d, J = 7.9Hz, 1H), 7.49 (t, J = 7.3Hz, 1H), 3.99 (s, 3H).

[0078] 13 C NMR(151MHz, CDCl3)δ153.1(s),147.5(s),142.4(s),123.0(s),129.8(s),128.8(s),128.8(s),127.8(s),124.7(q, J=272.3Hz), 124.3(s), 123.5(s), 123.3(s), 121.7(s), 117.1(s), 116.8(q, J=3.8Hz), 105.9(q, J=3.9Hz), 28.0(s).

[0079] Example 8: Preparation of 6H-indole[2,3-b]quinoline

[0080]

[0081] 2-[(1H-indol-3-yl)methyl]aniline (0.2 mmol, 44.4 mg), 2 mL of water, and iodine (0.4 mmol, 101.6 mg) were added sequentially to a reaction tube equipped with a magnetic stir bar. The mixture was stirred at room temperature for 12 hours, and the reaction progress was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with saturated Na₂S₂O₃ solution, and then the mixture was extracted with ethyl acetate (5 mL * 4). The organic phases were combined and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a white solid product with a yield of 85%.

[0082] 1 H NMR (600MHz, DMSO-d6) δ11.72(s,1H),9.06(s,1H),8.26(d,J=5.6Hz,1H),8.11(d,J=6.8 Hz,1H),7.98(d,J=7.3Hz,1H),7.78–7.68(m,1H),7.57–7.42(m,3H),7.32–7.20(m,1H).

[0083] 13 C NMR(151MHz,DMSO-d6)δ152.8(s),146.1(s),141.4(s),128.7(s),128.7(s),128.2(s),127 .7(s),126.8(s),123.6(s),122.8(s),121.8(s),120.3(s),119.7(s),118.0(s),111.0(s).

[0084] Example 9: Preparation of 6-phenyl-6H-indole[2,3-b]quinoline

[0085]

[0086] 2-[(1-phenyl-1H-indol-3-yl)methyl]aniline (0.2 mmol, 59.6 mg), 2 mL of water, and iodine (0.4 mmol, 101.6 mg) were added sequentially to a reaction tube equipped with a magnetic stir bar. The mixture was stirred at room temperature for 20 hours, and the reaction progress was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with saturated Na₂S₂O₃ solution, and then the mixture was extracted with ethyl acetate (5 mL * 4). The organic phases were combined and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a white solid product with a yield of 80%.

[0087] 1H NMR (400MHz, CDCl3) δ8.80 (s, 1H), 8.22 (d, J = 7.6Hz, 1H), 8.08 (d, J = 8.5Hz, 1H), 8.03 (d, J = 8. 1Hz, 1H), 7.78 (d, J = 7.7Hz, 2H), 7.72–7.63 (m, 3H), 7.55–7.46 (m, 4H), 7.36 (t, J = 6.9Hz, 1H).

[0088] 13 C NMR(101MHz, CDCl3)δ152.8(s),147.0(s),142.7(s),136.5(s),129.7(s),128.9(s),128.4(s),128.3(s), 128.3(s),127.6(s),127.6(s),127.5(s),124.8(s),123.5(s),121.6(s),121.0(s),118.5(s),110.3(s).

[0089] Example 10: Preparation of 6-allyl-6H-indole[2,3-b]quinoline

[0090]

[0091] 2-[(1-allyl-1H-indol-3-yl)methyl]aniline (0.2 mmol, 52.4 mg), 2 mL of water, and iodine (0.4 mmol, 101.6 mg) were added sequentially to a reaction tube equipped with a magnetic stir bar. The mixture was stirred at room temperature for 24 hours, and the reaction progress was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with saturated Na₂S₂O₃ solution, and then the mixture was extracted with ethyl acetate (5 mL * 4). The organic phases were combined and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a white solid product with a yield of 96%.

[0092] 1 H NMR (400MHz, CDCl3) δ8.72(s,1H),8.15(t,J=7.8Hz,2H),8.01(d,J=8.1Hz,1H),7.72(t,J=7.6Hz,1H),7.56(t,J=7. 5Hz,1H),7.47(t,J=7.3Hz,1H),7.41(d,J=8.1Hz,1H),7.31(t,J=7.4Hz,1H),6.16–6.03(m,1H),5.25–5.13(m,4H).

[0093] 13C NMR (101MHz, CDCl3) δ152.4(s),146.9(s),142.3(s),132.8(s),128.9(s),128.6(s),128.1(s),127.8(s) ,127.5(s),124.4(s),123.1(s),121.6(s),120.7(s),120.2(s),118.3(s),117.0(s),109.7(s),43.8(s).

[0094] Example 11: Preparation of 6-isopropyl-6H-indole[2,3-b]quinoline

[0095]

[0096] 2-[(1-isopropyl-1H-indol-3-yl)methyl]aniline (0.2 mmol, 52.4 mg), 2 mL of water, and iodine (0.4 mmol, 101.6 mg) were added sequentially to a reaction tube equipped with a magnetic stir bar. The mixture was stirred at room temperature for 18 hours, and the reaction progress was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with saturated Na₂S₂O₃ solution, and then the mixture was extracted with ethyl acetate (5 mL * 4). The organic phases were combined and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a yellow oily product with a yield of 87%.

[0097] The proton NMR spectrum of the target product obtained in Example 11 is as follows: Figure 11 As shown, the carbon NMR spectrum is as follows: Figure 12 As shown.

[0098] 1 H NMR (600MHz, CDCl3) δ8.72(s,1H),8.19(d,J=7.3Hz,1H),8.14(d,J=8.4Hz,1H),8.01(d,J=7.8Hz,1H),7.72(t,J=6.9Hz,1H),7.62 (d,J=7.9Hz,1H),7.55(t,J=7.4Hz,1H),7.46(t,J=6.9Hz,1H),7.29(t,J=7.1Hz,1H),5.73–5.62(m,1H),1.79(s,3H),1.78(s,3H).

[0099] 13C NMR(101MHz, CDCl3)δ152.4(s),146.8(s),141.3(s),128.8(s),128.5(s),127.8(s),127.8(s),127 .1(s),124.1(s),122.9(s),121.7(s),121.1(s),119.5(s),118.4(s),110.9(s),45.2(s),20.6(s).

[0100] Example 12: Preparation of 2-methoxy-6-methyl-6H-indole[2,3-b]quinoline

[0101]

[0102] 4-Methoxy-2-[(1-methyl-1H-indol-3-yl)methyl]aniline (0.2 mmol, 53.2 mg), 2 mL of water, and iodine (0.4 mmol, 101.6 mg) were added sequentially to a reaction tube equipped with a magnetic stir bar. The mixture was stirred at room temperature for 15 hours, and the reaction progress was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with saturated Na₂S₂O₃ solution, and then the mixture was extracted with ethyl acetate (5 mL * 4). The organic phases were combined and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a yellow oily product with a yield of 75%.

[0103] 1 H NMR (400MHz, CDCl3) δ8.54(s,1H),8.09(d,J=7.6Hz,1H),8.03(d,J=9.2Hz,1H),7.54( d,J=7.8Hz,1H),7.37(t,J=10.5Hz,2H),7.29–7.23(m,2H),3.94(s,3H),3.92(s,3H).

[0104] 13 C NMR(101MHz, CDCl3)δ155.3(s),151.8(s),142.9(s),142.8(s),128.9(s),128.1(s),126.2(s),124 .7(s),121.5(s),121.5(s),120.3(s),119.7(s),118.3(s),108.7(s),106.4(s),55.6(s),27.8(s).

[0105] Example 13: Preparation of 3-bromo-6-methyl-6H-indole[2,3-b]quinoline

[0106]

[0107] 5-Bromo-2-[(1-methyl-1H-indol-3-yl)methyl]aniline (0.2 mmol, 62.8 mg), 2 mL of water, and iodine (0.4 mmol, 101.6 mg) were added sequentially to a reaction tube equipped with a magnetic stir bar. The mixture was stirred at room temperature for 24 hours, and the reaction progress was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with saturated Na₂S₂O₃ solution, and then the mixture was extracted with ethyl acetate (5 mL * 4). The organic phases were combined and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a white solid product with a yield of 78%.

[0108] 1 H NMR (400MHz, CDCl3) δ8.51(s,1H),8.27(s,1H),8.06(d,J=7.6Hz,1H),7.76(d,J=8.6Hz,1H),7.57 (t,J=7.7Hz,1H),7.48(d,J=8.6Hz,1H),7.35(d,J=8.0Hz,1H),7.29(t,J=7.5Hz,1H),3.89(s,3H).

[0109] 13 C NMR(101MHz, CDCl3)δ153.0(s),147.4(s),142.9(s),129.9(s),129.7(s),128.4(s),127.1(s) ,126.3(s),122.9(s),122.6(s),121.6(s),120.3(s),120.2(s),118.5(s),108.9(s),27.8(s).

[0110] Example 14: Preparation of 2,6-dimethyl-6H-indolo[2,3-b]quinoline

[0111]

[0112] 4-Methyl-2-[(1-methyl-1H-indol-3-yl)methyl]aniline (0.2 mmol, 50.0 mg), 2 mL of water, and iodine (0.4 mmol, 101.6 mg) were added sequentially to a reaction tube equipped with a magnetic stir bar. The mixture was stirred at room temperature for 15 hours, and the reaction progress was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with saturated Na₂S₂O₃ solution, and then the mixture was extracted with ethyl acetate (5 mL * 4). The organic phases were combined and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified and separated by column chromatography to obtain a white solid product with a yield of 96%. The 1H NMR spectrum of the target product obtained in Example 14 is shown below. Figure 13 As shown, the carbon NMR spectrum is as follows: Figure 14 As shown.

[0113] 1 H NMR (600MHz, CDCl3) δ8.56(s,1H),8.11(d,J=7.6Hz,1H),8.05(d,J=8.6Hz,1H),7.72(s,1H) ,7.59–7.53(m,2H),7.37(d,J=8.0Hz,1H),7.29(t,J=7.4Hz,1H),3.95(s,3H),2.57(s,3H).

[0114] 13 C NMR(151MHz, CDCl3)δ152.6(s),145.4(s),142.9(s),132.4(s),131.2(s),128.0(s),127.5(s),127 .3(s),126.8(s),124.2(s),121.4(s),120.5(s),119.8(s),118.2(s),108.7(s),27.8(s),21.5(s).

[0115] Example 15: Preparation of 6,11-dimethyl-6H-indole[2,3-b]quinoline

[0116]

[0117] 2-[1-(1-methyl-1H-indol-3-yl)ethyl]aniline (0.2 mmol, 50.0 mg), 2 mL of water, and iodine (0.4 mmol, 101.6 mg) were added sequentially to a reaction tube equipped with a magnetic stir bar. The mixture was stirred at room temperature for 12 hours, and the reaction progress was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with saturated Na₂S₂O₃ solution, and then the mixture was extracted with ethyl acetate (5 mL * 4). The organic phases were combined and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a white solid product with a yield of 86%.

[0118] 1 H NMR (400MHz, CDCl3) δ8.25(d,J=7.8Hz,1H),8.21(d,J=8.5Hz,1H),8.13(d,J=8.4Hz,1H),7.72(t,J=7.6Hz,1H),7. 57(t,J=7.6Hz,1H),7.48(t,J=7.6Hz,1H),7.39(d,J=8.0Hz,1H),7.31(t,J=7.5Hz,1H),3.94(s,3H),3.14(s,3H).

[0119] 13 C NMR(101MHz, CDCl3)δ152.3(s),146.6(s),142.8(s),139.0(s),128.7(s),128.1(s),127.4(s) ,124.1(s),123.6(s),122.7(s),121.5(s),119.9(s),116.5(s),108.6(s),27.7(s),15.2(s).

[0120] Example 16: Preparation of 6-methyl-11-phenyl-6H-indole[2,3-b]quinoline

[0121]

[0122] 2-[(1-methyl-1H-indol-3-yl)(phenyl)methyl]aniline (0.2 mmol, 62.4 mg), 2 mL of water, and iodine (0.4 mmol, 101.6 mg) were added sequentially to a reaction tube equipped with a magnetic stir bar. The mixture was stirred at room temperature for 15 hours, and the reaction progress was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with saturated Na₂S₂O₃ solution, and then the mixture was extracted with ethyl acetate (5 mL * 4). The organic phases were combined and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified and separated by column chromatography to obtain a white solid product with a yield of 80%. The 1H NMR spectrum of the target product obtained in Example 16 is shown below. Figure 15 As shown, the carbon NMR spectrum is as follows: Figure 16 As shown.

[0123] 1 H NMR(400MHz, CDCl3)δ8.23(d,J=8.5Hz,1H),7.80–7.71(m,2H),7.70–7.62(m,3H),7.59–7.54(m,2H) ,7.50(t,J=7.6Hz,1H),7.42–7.36(m,2H),7.11(d,J=7.7Hz,1H),7.03(t,J=7.4Hz,1H),4.03(s,3H).

[0124] 13 C NMR (101MHz, CDCl3) δ152.5(s),146.9(s),143.0(s),142.4(s),136.7(s),129.5(s),129.2(s),128.8(s),128.6(s) ,127.8(s),127.7(s),126.5(s),123.8(s),123.1(s),122.9(s),120.7(s),119.8(s),116.0(s),108.5(s),27.8(s).

[0125] Example 17: Gram-scale Scale-up Experiment

[0126]

[0127] 2-[(1H-indol-3-yl)methyl]aniline (4.5 mmol, 1.00 g), 45 mL of water, and iodine (9.0 mmol, 2.29 g) were added sequentially to a round-bottom flask equipped with a magnetic stir bar. The mixture was stirred at room temperature for 12 hours, and the reaction progress was monitored by thin-layer chromatography (petroleum ether / ethyl acetate = 4:1). After the reaction was completed, the reaction was quenched with saturated Na₂S₂O₃ solution, and then the mixture was extracted with ethyl acetate (50 mL * 4). The organic phases were combined and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a white solid product with a yield of 96%.

[0128] The preparation method of this invention can completely convert the product in both small-scale and large-scale experiments, without any other impurities. However, when using column chromatography for purification, the loss during scale-up is relatively small due to the small amount of product adsorption on the silica gel column, resulting in a higher yield in the scale-up experiment. This indicates that the method of this invention is more suitable for industrial applications.

[0129] The characterization was performed using the same proton and carbon NMR spectra as in Example 8.

[0130] Comparative Example 1

[0131] The preparation method is the same as that of 6-methyl-6H-indole[2,3-b]quinoline in Example 1, except that the solvent water is replaced with DMSO.

[0132] Comparative Example 2

[0133] The preparation method is the same as that of 6-methyl-6H-indole[2,3-b]quinoline in Example 1, except that the solvent water is replaced with HFIP.

[0134] Comparative Example 3

[0135] The preparation method is the same as that of 6-methyl-6H-indole[2,3-b]quinoline in Example 1, except that the solvent water is replaced with CH3CN.

[0136] Comparative Example 4

[0137] The preparation method is the same as that of 6-methyl-6H-indole[2,3-b]quinoline in Example 1, except that the solvent water is replaced with DCM.

[0138] Comparative Example 5

[0139] The preparation method is the same as that of 6-methyl-6H-indole[2,3-b]quinoline in Example 1, except that the solvent water is replaced with EtOAc.

[0140] Comparative Example 6

[0141] The preparation method is the same as that of 6-methyl-6H-indole[2,3-b]quinoline in Example 1, except that the oxidizing agent elemental iodine is replaced with sodium iodate.

[0142] Comparative Example 7

[0143] The preparation method of 6-methyl-6H-indole[2,3-b]quinoline in Example 1 is the same, except that the oxidant elemental iodine is replaced with PhI(OAc)2.

[0144] Comparative Example 8

[0145] The preparation method is the same as that of 6-methyl-6H-indole[2,3-b]quinoline in Example 1, except that the oxidant elemental iodine is replaced with trimethyldodecylammonium iodide.

[0146] The product yields of Comparative Examples 1–7 are shown in Table 1.

[0147] Table 1

[0148] Comparative Example 1 58 Comparative Example 2 56 Comparative Example 3 38 Comparative Example 4 43 Comparative Example 5 39 Comparative Example 6 Trace Comparative Example 7 45 Comparative Example 8 No response

[0149] As shown in Table 1, when Comparative Examples 1-7 were replaced with some common organic solvents (including DMSO, HFIP, CH3CN, DCM, EtOAc) or oxidants, the product yields were much lower than those in Example 1. Therefore, the use of water as a solvent is key to the high yield of indole[2,3-b]quinoline compounds, which may be attributed to the promoting effect of hydrophobic effects on the reaction.

[0150] The above description is merely a preferred embodiment of this application and is not intended to limit this application. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A method for preparing iodine-mediated indo[2,3-b]quinoline compounds in an aqueous phase, characterized in that, The preparation method is as follows: Using amino-containing indole derivatives as substrates, elemental iodine as oxidant, and water as solvent, the reaction was carried out under stirring at room temperature to obtain indole[2,3-b]quinoline compounds; ； The structural formula of the amino-containing indole derivative is shown in Formula I; wherein, R 1 It can be hydrogen, bromine, methyl, methoxy, ester, amide, or trifluoromethyl; R 2 It is hydrogen, methyl, allyl, isopropyl, or phenyl; R 3 It is hydrogen, bromine, methyl, or methoxy; R 4 It can be hydrogen, methyl, or phenyl; The ratio of the added substrate, oxidant, and solvent is 1 mmol: 2 mmol: 10 mL.

2. The preparation method according to claim 1, characterized in that, The amino-containing indole derivative is selected from 2-[(1-methyl-1H-indole-3-yl)methyl]aniline, 2-[(5-bromo-1-methyl-1H-indole-3-yl)methyl]aniline, 2-[(1,7-dimethyl-1H-indole-3-yl)methyl]aniline, 2-[(5-methoxy-1-methyl-1H-indole-3-yl)methyl]aniline, methyl 3-(2-aminobenzyl)-1-methyl-1H-indole-5-carboxylic acid, 3-(2-aminobenzyl)- N ,1-Dimethyl- N 2-Phenylacetyl-1H-indole-5-carboxamide, 2-[(1-methyl-6-trifluoromethyl-1H-indole-3-yl)methyl]aniline, 2-[(1H-indole-3-yl)methyl]aniline, 2-[(1-phenyl-1H-indole-3-yl)methyl]aniline, 2-[(1-allyl-1H-indole-3-yl)methyl]aniline, 2-[(1-isopropyl-1H-indole-3-yl)methyl]aniline, 4-Methoxy-2-[(1-methyl-1H-indol-3-yl)methyl]aniline, 5-bromo-2-[(1-methyl-1H-indol-3-yl)methyl]aniline, 4-methyl-2-[(1-methyl-1H-indol-3-yl)methyl]aniline, 2-[1-(1-methyl-1H-indol-3-yl)ethyl]aniline or 2-[(1-methyl-1H-indol-3-yl)(phenyl)methyl]aniline.

3. The preparation method according to claim 1, characterized in that, The stirring reaction time is 12-24 hours.

4. The preparation method according to claim 1, characterized in that, After the stirring reaction was completed, a saturated sodium thiosulfate solution was added for quenching. The mixture was extracted with ethyl acetate, the organic phases were combined and dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography to obtain indo[2,3-b]quinoline compounds.

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