Preparation method of 3-haloindole derivatives

Abstract

The present invention belongs to the field of organic synthesis, and specifically relates to a method for preparing a 3-halogenated indole derivative. Acetonitrile is used as a solvent, indole or substituted indole is used as a substrate, and cuprous halide is used as a halogenating agent and a catalyst. N Using ‑fluorobisbenzenesulfonamide as the oxidant, a series of C3 halogenated indole derivatives can be obtained simply and in high yield at room temperature. It has the characteristics of easy availability of raw materials, wide substrate adaptability, short reaction time, simple operation and easy scale-up.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing a 3-halogenated indole derivative. Background Art

[0002] Compounds containing indole skeletons appear in a large number of natural products and drugs, mainly used for anti-inflammatory, anti-depressant, and anti-rheumatic effects, especially the anti-tumor activity of indole compounds. A large number of studies have shown that by introducing halogen (F, Cl, Br, I) atoms into the indole nucleus and modifying the structure of the lead compound, the properties of the compound can be improved, thereby obtaining better biological activity. Research on indole halogenation has attracted great interest among chemists, especially the halogenation reaction at the C3 position of indole.

[0003] Regarding the halogenation reaction of the C3 position of indole, the methods reported in the literature are mainly: using N-halogenated succinimide, dihalogenated hydantoin, halogen element, sodium halide salt, etc. as the halogen source, thiourea, nickel, methylene chloride, copper manganese oxide, sulfuric acid as the catalyst, and assisted by the action of an oxidant to achieve C3 chlorination and bromination; the iodination reaction uses iodine element or N-iodosuccinimide as the halogen source, and is carried out in a high boiling point solvent (N,N-dimethylformamide), which makes post-processing difficult.

[0004] There are two general methods for achieving chlorination, bromination and iodination: 1. N-halogenated succinimide and substrate react in DMF, and the final product is obtained through two steps of neutralization and extraction; 2. Sodium / potassium halide and substrate are reacted with high-valent iodobenzene to obtain the corresponding halogenated product. These methods are difficult to post-process, the product is difficult to purify, or the amount of oxidant and halogenating agent used far exceeds the theoretical amount, resulting in serious pollution. Summary of the invention

[0005] The purpose of the present invention is to find a method for preparing a 3-halogenated indole derivative which has low cost, simple post-treatment, convenient and readily available raw materials and is universal for halogenation of the C3 position of indole.

[0006] The present invention provides a method for preparing a 3-halogenated indole derivative, and the specific reaction equation is as follows (Scheme 1):

[0007]

[0008] The steps are as follows: in the presence of an oxidant and an organic solvent, an indole compound 1 and a cuprous halide are used to synthesize a 3-halogenated indole derivative 2 by autocatalysis (both as a catalyst and a halogen source). R is H, C1-C6 alkyl, cycloalkyl, acyl or sulfonyl, R 1 is H, C1-C6 alkyl, cycloalkyl, nitro, cyano, methoxy, F, Cl, Br, or aromatic group, R 2is H, CH3, CF3, OCH3, NO2 or CN. Wherein R is preferably C1-C4 alkyl, acyl or sulfonyl; preferably R 1 is H, C1-C6 alkyl, cycloalkyl, nitro, cyano, methoxy, R 2 It is H, CH3, OCH3.

[0009] Specifically, the reaction solvent is selected from one or more solvents of toluene, chlorobenzene, N,N'-dimethylformamide, tetrahydrofuran, 1,4'-dioxane, dichloromethane, dichloroethane, water, ethylene glycol dimethyl ether, acetonitrile, and acetic acid; the reaction solvent is preferably acetonitrile and water; more preferably acetonitrile.

[0010] The feeding amounts of cuprous halide and oxidant may be slightly excessive, and the feeding molar ratio of compound 1, cuprous halide and oxidant is 1:1.0-2.0:1.0-2.0; preferably 1:1.0-1.5:1.0-1.5.

[0011] The reaction temperature is 0°C to 130°C; the reaction temperature is preferably 25°C to 80°C; the reaction temperature is more preferably 25°C to 40°C;

[0012] The oxidant used is one of oxygen, hydrogen peroxide, iodophenyl diacetic acid, silver oxide, bis(trifluoroacetoxy)iodobenzene, NADH, and N-fluorobisbenzenesulfonamide, preferably N-fluorobisbenzenesulfonamide.

[0013] The reaction time is 0.5 to 24 hours; preferably, the reaction time is 0.5 to 5 hours.

[0014] Furthermore, the preparation method of the above 3-haloindole derivatives also includes concentrating the product under reduced pressure, separating and purifying it by column chromatography, and the eluent consists of petroleum ether and dichloromethane or petroleum ether and ethyl acetate.

[0015] After process optimization, the present invention provides a simple and efficient method for preparing 3-halogenated indole compounds, using acetonitrile as solvent, indole or substituted indole as substrate, cuprous halide as halogenating agent and catalyst, and N-fluorobisbenzenesulfonamide oxidation, a series of C3 halogenated indole derivatives can be obtained simply and in high yield at room temperature. The results show that the beneficial effects of the technical solution are as follows:

[0016] (1) The yield of halogenated products is generally high, and the yield does not decrease after being magnified 10 times;

[0017] (2) The raw materials are relatively economical, and the amount of halogenation reagent used is 1.1 equiv;

[0018] (3) The reaction time is 0.5 to 5 hours;

[0019] (4) The reaction temperature is room temperature;

[0020] (5) The halogenation process was scaled up to the gram level, and the structures of most compounds were confirmed by H-NMR spectroscopy. This strategy has the advantages of easy availability of raw materials, wide substrate adaptability, short reaction time, simple operation and easy scale-up. DETAILED DESCRIPTION

[0021] The present invention will be further described below in conjunction with embodiments, but is not limited thereto.

[0022] Example 1

[0023] 3-Chloro-1H-indole

[0024] 3-chloro-1H-indole

[0025]

[0026] Indole (117 mg, 1.0 mmol), cuprous chloride (109 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 1 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: dichloromethane = 3:1 to 1:1) to obtain 145.5 mg of a white powdery solid with a yield of 96.0%.

[0027] 1 H NMR (400MHz, CDCl3) δ (ppm): 8.08 (s, 1H), 7.68 (dd, J = 7.7, 1.2Hz, 1H), 7.42-7.37 (m, 1H), 7.33-7.16 (m, 3H).

[0028] Example 2

[0029] 3-Bromo-1H-indole

[0030] 3-bromo-1H-indole

[0031]

[0032] Indole (117 mg, 1.0 mmol), cuprous bromide (158 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 1 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: dichloromethane = 3:1 to 1:1) to obtain 160.2 mg of a white powdery solid with a yield of 81.7%.

[0033] Example 3

[0034] 3-Iodo-1H-indole

[0035] 3-iodo-1H-indole

[0036]

[0037] Indole (117 mg, 1.0 mmol), cuprous iodide (210 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 1 h. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: dichloromethane = 3:1 to 1:1) to obtain 199.0 mg of a white powdery solid with a yield of 81.9%.

[0038] 1 H NMR (400MHz, CDCl3) δ8.08 (s, 1H), 7.65 (d, J = 7.5Hz, 1H), 7.59 (t, J = 7.7Hz, 1H), 7.15 (t, J = 7.5Hz, 1H), 6.94 (d, J = 7.9Hz, 1H).

[0039] Example 4

[0040] 3-Chloro-1-methyl-indole

[0041] 3-chloro-1-methyl-1H-indole

[0042]

[0043] 1-Methyl-indole (131 mg, 1.0 mmol), cuprous chloride (109 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 0.5 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: dichloromethane = 10:1 to 4:1) to obtain 158.0 mg of a white liquid with a yield of 95.4%.

[0044] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.66 (dt, J=7.9, 1.0Hz, 1H), 7.37-7.29 (m, 2H), 7.22 (ddd, J=7.9, 6.6, 1.4Hz, 1H), 7.05 (s, 1H), 3.79 (s, 3H).

[0045] Example 5

[0046] 3-Bromo-1-methyl-indole

[0047] 3-bromo-1-methyl-1H-indole

[0048]

[0049] 1-Methyl-indole (131 mg, 1.0 mmol), cuprous bromide (158 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 0.5 h. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: dichloromethane = 5:1 to 2:1) to obtain 201.8 mg of a slightly yellow liquid with a yield of 96.1%.

[0050] 1 H NMR (400MHz, CDCl3) δ7.63-7.57(m,1H),7.36-7.29(m,2H),7.23(ddd,J=8.1,6.6,1.4Hz,1H),7.10(s,1H),3.81(s,3H).

[0051] Example 6

[0052] 3-Iodo-1-methyl-indole

[0053] 3-iodo-1-methyl-1H-indole

[0054]

[0055] 1-Methyl-indole (131 mg, 1.0 mmol), cuprous iodide (210 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 0.5 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 4:1 to 2:1) to obtain 242.5 mg of a colorless liquid with a yield of 94.3%.

[0056] 1 H NMR (400MHz, CDCl3) δ7.49 (dt, J=8.0, 1.0Hz, 1H), 7.36-7.30 (m, 2H), 7.25 (ddd, J=8.0, 5.6, 2.6Hz, 1H), 7.16 (s, 1H), 3.83 (s, 3H).

[0057] Example 7

[0058] tert-Butyl 3-chloro-indolecarbonate

[0059] tert-butyl 3-chloro-1H-indole-1-carboxylate

[0060]

[0061] In a 25 ml reaction bottle, add tert-butyl indoleate (217 mg, 1.0 mmol), cuprous chloride (109 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile, and stir at room temperature for 0.5 h. After filtering the reaction solution, concentrate under reduced pressure to obtain a crude product, which is separated by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain 220.2 mg of a white powdery solid with a yield of 87.5%.

[0062] Example 8

[0063] tert-Butyl 3-bromo-indolecarbonate

[0064] tert-butyl 3-bromo-1H-indole-1-carboxylate

[0065]

[0066] In a 25 ml reaction bottle, add tert-butyl indole carbonate (217 mg, 1.0 mmol), cuprous bromide (158 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile, and stir at room temperature for 0.5 h. After filtering the reaction solution, concentrate under reduced pressure to obtain a crude product, which is separated by column chromatography (eluent: petroleum ether: dichloromethane = 20:1-15:1) to obtain 263.0 mg of a light yellow liquid with a yield of 88.8%.

[0067] Example 9

[0068] tert-Butyl 3-iodo-indolecarbonate

[0069] tert-butyl 3-iodo-1H-indole-1-carboxylate

[0070]

[0071] In a 25 ml reaction bottle, add tert-butyl indole carbonate (217 mg, 1.0 mmol), cuprous iodide (210 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile, and stir at room temperature for 0.5 h. After filtering the reaction solution, concentrate under reduced pressure to obtain a crude product, which is separated by column chromatography (eluent: petroleum ether: dichloromethane = 6:1 to 3:1) to obtain 307.8 mg of a light yellow liquid with a yield of 89.7%.

[0072] Example 10

[0073] 3-Chloro-4-nitro-indole

[0074] 3-chloro-4-nitro-1H-indole

[0075]

[0076] 4-Nitro-indole (162 mg, 1.0 mmol), cuprous chloride (109 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 5 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain 171.0 mg of a yellow powdery solid with a yield of 87.0%.

[0077] 1 H NMR (400MHz, CDCl3) δ8.60(s,1H),7.82(dd,J=7.8,0.9Hz,1H),7.66(dd,J=8.2,0.9Hz,1H),7.45(d,J=2.8Hz,1H),7.32(t,J=8.0Hz,1H).

[0078] Embodiment 11

[0079] 3-Bromo-4-nitro-indole

[0080] 3-bromo-4-nitro-1H-indole

[0081]

[0082] 4-Nitro-indole (162 mg, 1.0 mmol), cuprous bromide (158 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 5 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1 to 3:1) to obtain 205.3 mg of a yellow solid with a yield of 85.2%.

[0083] 1 H NMR (400MHz, CDCl3) δ8.74 (s, 1H), 7.79 (d, J = 7.8Hz, 1H), 7.67 (d, J = 8.2Hz, 1H), 7.50 (d, J = 2.7Hz, 1H), 7.32 (t, J = 8.0Hz, 1H).

[0084] Example 12

[0085] 3-Iodo-4-nitro-indole

[0086] 3-iodo-4-nitro-1H-indole

[0087]

[0088] 4-Nitro-indole (162 mg, 1.0 mmol), cuprous iodide (210 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 5 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1 to 3:1) to obtain 273.9 mg of a yellow solid with a yield of 95.1%.

[0089] 1 H NMR (400MHz, DMSO) δ11.98(s,1H),8.07(dd,J=8.0,0.8Hz,1H),7.91(dd,J=7.9, 0.9Hz, 1H), 7.78 (d, J = 3.0Hz, 1H), 7.31 (t, J = 8.0Hz, 1H), 7.05 (d, J = 3.0Hz, 1H).

[0090] Embodiment 13

[0091] 3-Chloro-5-nitro-indole

[0092] 3-chloro-5-nitro-1H-indole

[0093]

[0094] 5-Nitro-indole (162 mg, 1.0 mmol), cuprous chloride (109 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 5 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 9:1 to 3:1) to obtain 195.8 mg of a yellow powdery solid with a yield of 99.6%.

[0095] 1 H NMR (400MHz, CDCl3) δ8.66(d,J=2.2Hz,1H),8.48(s,1H),8.20(dd,J=9.0,2.2Hz,1H),7.46(d,J=9.0Hz,1H),7.38(d,J=2.6Hz,1H)

[0096] Embodiment 14

[0097] 3-Bromo-5-nitro-indole

[0098] 3-bromo-5-nitro-1H-indole

[0099]

[0100] 5-Nitro-indole (162 mg, 1.0 mmol), cuprous bromide (158 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 5 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 20:1 to 15:1) to obtain 211.1 mg of a yellow powdery solid with a yield of 87.6%.

[0101] 1 H NMR (400MHz, DMSO) δ12.29-12.13(m,1H),8.32(d,J=2.3Hz,1H),8.07(dd,J=9.0,2.3Hz,1H),7.88(s,1H),7.64(d,J=9.0Hz,1H).

[0102] Embodiment 15

[0103] 3-Iodo-5-nitro-indole

[0104] 3-iodo-5-nitro-1H-indole

[0105]

[0106] 5-Nitro-indole (162 mg, 1.0 mmol), cuprous iodide (210 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 5 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 20:1 to 15:1) to obtain 249.7 mg of a yellow powdery solid with a yield of 86.7%.

[0107] 1 H NMR (400MHz, CDCl3) δ8.72 (s, 1H), 8.48 (d, J = 2.2Hz, 1H), 8.19 (dd, J = 9.0, 2.2Hz, 1H), 7.50-7.45 (m, 2H).

[0108] Example 16

[0109] 3-Chloro-6-nitro-indole

[0110] 3-chloro-6-nitro-1H-indole

[0111]

[0112] 6-Nitro-indole (162 mg, 1.0 mmol), cuprous chloride (109 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 5 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 6:1 to 3:1) to obtain 168.9 mg of a yellow powdery solid with a yield of 85.9%.

[0113] 1 H NMR (400MHz, CDCl3) δ8.63 (s, 1H), 8.40 (d, J = 2.0Hz, 1H), 8.13 (dd, J = 8.8, 2.0Hz, 1H), 7.74 (d, J = 8.8Hz, 1H), 7.51 (d, J = 2.7Hz, 1H).

[0114] Embodiment 17

[0115] 3-Bromo-6-nitro-indole

[0116] 3-bromo-6-nitro-1H-indole

[0117]

[0118] 6-Nitro-indole (162 mg, 1.0 mmol), cuprous bromide (158 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 5 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: dichloromethane = 10:1 to 5:1) to obtain 204.1 mg of a yellow powdery solid with a yield of 84.7%.

[0119] 1 H NMR (400MHz, DMSO) δ12.28-12.17(m,1H),8.38(d,J=2.1Hz,1H),8.01(s,1H),7.99(dd,J=8.8,2.1Hz,1H),7.61(d,J=8.8Hz,1H).

[0120] Embodiment 18

[0121] 3-Iodo-6-nitro-indole

[0122] 3-iodo-6-nitro-1H-indole

[0123]

[0124] 6-Nitro-indole (162 mg, 1.0 mmol), cuprous iodide (210 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 5 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain 266.7 mg of a yellow powdery solid with a yield of 92.6%.

[0125] 1 H NMR (400MHz, CDCl3) δ8.87 (s, 1H), 8.41 (d, J = 2.1Hz, 1H), 8.13 (dd, J = 8.8, 2.0Hz, 1H), 7.64-7.53 (m, 2H).

[0126] Embodiment 19

[0127] 3-Chloro-7-nitro-indole

[0128] 3-chloro-7-nitro-1H-indole

[0129]

[0130] 7-Nitro-indole (162 mg, 1.0 mmol), cuprous chloride (109 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 5 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: dichloromethane = 6:1 to 2:1) to obtain 188.3 mg of a yellow powdery solid with a yield of 95.8%.

[0131] 1 H NMR (400MHz, DMSO) δ12.14(s,1H),8.20(d,J=8.0Hz,1H),8.01(d,J=7.8Hz,1H),7.72(s,1H),7.35(t,J=7.9Hz,1H).

[0132] Embodiment 20

[0133] 3-Bromo-7-nitro-indole

[0134] 3-bromo-7-nitro-1H-indole

[0135]

[0136] 7-Nitro-indole (162 mg, 1.0 mmol), cuprous bromide (158 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 5 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: dichloromethane = 4:1 to 2:1) to obtain 210.4 mg of a yellow powdery solid with a yield of 87.3%.

[0137] 1 H NMR (400MHz, DMSO) δ12.24(s,1H),8.21(dd,J=8.0,1.0Hz,1H),7.94(dd,J=7.8,1.0Hz,1H),7.75(s,1H),7.36(t,J=7.9Hz,1H).

[0138] Embodiment 21

[0139] 3-Iodo-7-nitro-indole

[0140] 3-iodo-7-nitro-1H-indole

[0141]

[0142] 7-Nitro-indole (162 mg, 1.0 mmol), cuprous iodide (210 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 5 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: dichloromethane = 6:1 to 2:1) to obtain 246.8 mg of a yellow powdery solid with a yield of 85.7%.

[0143] 1 H NMR (400MHz, CDCl3) δ10.09 (s, 1H), 8.27 (d, J = 8.1Hz, 1H), 7.86 (d, J = 7.8Hz, 1H), 7.52 (d, J = 2.4Hz, 1H), 7.34 (t, J = 7.9Hz, 1H).

[0144] Embodiment 22

[0145] 3-Chloro-5-methoxy-indole

[0146] 3-chloro-5-methoxy-1H-indole

[0147]

[0148] 5-Methoxy-indole (147 mg, 1.0 mmol), cuprous chloride (109 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 1 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain 142.5 mg of a yellow powdery solid with a yield of 78.5%.

[0149] 1 H NMR (400MHz, CDCl3) δ7.99 (s, 1H), 7.26 (s, 1H), 7.17 (d, J = 2.7Hz, 1H), 7.07 (d, J = 2.5Hz, 1H), 6.93 (dd, J = 8.9, 2.5Hz, 1H), 3.91 (s, 3H).

[0150] Embodiment 23

[0151] 3-Bromo-5-methoxy-indole

[0152] 3-bromo-5-methoxy-1H-indole

[0153]

[0154] 5-Methoxy-indole (147 mg, 1.0 mmol), cuprous bromide (158 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 1 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 15:1-10:1) to obtain 183.0 mg of a khaki powdery solid with a yield of 80.9%.

[0155] Embodiment 24

[0156] 3-Iodo-5-methoxy-indole

[0157] 3-iodo-5-methoxy-1H-indole

[0158]

[0159] 5-Methoxy-indole (147 mg, 1.0 mmol), cuprous iodide (210 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 1 hour. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain 206.4 mg of an off-white powdery solid with a yield of 75.6%.

[0160] 1 H NMR (400MHz, CDCl3) δ8.28 (s, 1H), 7.28 (td, J = 3.4, 1.4Hz, 2H), 6.93 (d, J = 8.0Hz, 2H), 3.93 (s, 3H).

[0161] Embodiment 25

[0162] 3-Chloro-2-methyl-indole

[0163] 3-chloro-2-methyl-1H-indole

[0164]

[0165] 1-Methyl-indole (131 mg, 1.0 mmol), cuprous chloride (109 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 1 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 15:1 to 10:1) to obtain 125.9 mg of a khaki solid with a yield of 76.0%.

[0166] 1 H NMR (400MHz, CDCl3) δ7.87(s,1H),7.61-7.49(m,1H),7.29(s,1H),7.23-7.12(m,2H),2.46(s,3H).

[0167] Embodiment 26

[0168] 3-Bromo-2-methyl-indole

[0169] 3-bromo-2-methyl-1H-indole

[0170]

[0171] 1-Methyl-indole (131 mg, 1.0 mmol), cuprous bromide (158 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 1 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 15:1 to 8:1) to obtain 161.3 mg of a light yellow solid with a yield of 76.8%.

[0172] 1 H NMR (400MHz, CDCl3) δ8.00 (s, 1H), 7.54-7.47 (m, 1H), 7.29 (d, J = 6.8Hz, 1H), 7.22-7.15 (m, 2H), 2.47 (s, 3H).

[0173] Embodiment 27

[0174] 3-Iodo-1-methyl-indole

[0175] 3-iodo-2-methyl-1H-indole

[0176]

[0177] 1-Methyl-indole (131 mg, 1.0 mmol), cuprous iodide (210 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 1 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 15:1 to 8:1) to obtain 223.9 mg of a light yellow solid with a yield of 87.1%.

[0178] Embodiment 28

[0179] 3-Chloro-4-nitro-indole

[0180] 3-chloro-4-nitro-1H-indole

[0181]

[0182] 4-Nitro-indole (162 mg, 1.0 mmol), cuprous chloride (109 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of toluene were added to a 25 ml reaction bottle and stirred at room temperature for 5 h. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain 151.2 mg of a yellow powdery solid with a yield of 76.9%.

[0183] Embodiment 29

[0184] 3-Chloro-4-nitro-indole

[0185] 3-chloro-4-nitro-1H-indole

[0186]

[0187] 4-Nitro-indole (162 mg, 1.0 mmol), cuprous chloride (109 mg, 1.1 mmol), iodophenyl diacetic acid (354.2 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at room temperature for 5 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain 131.5 mg of a yellow powdery solid with a yield of 66.9%.

[0188] Embodiment 30

[0189] 3-Chloro-4-nitro-indole

[0190] 3-chloro-4-nitro-1H-indole

[0191]

[0192] 4-Nitro-indole (162 mg, 1.0 mmol), cuprous chloride (109 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (349 mg, 1.1 mmol) and 10 mL of acetonitrile were added to a 25 ml reaction bottle and stirred at 80 ° C for 5 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain 165.1 mg of a yellow powdery solid with a yield of 84.0%.

[0193] Embodiment 31

[0194] 3-Chloro-4-nitro-indole

[0195] 3-chloro-4-nitro-1H-indole

[0196]

[0197] 4-Nitro-indole (1.62 g, 10 mmol), cuprous chloride (1.09 g, 11 mmol), N-fluorobisbenzenesulfonamide (3.49 g, 11 mmol) and 100 mL of acetonitrile were added to a 250 ml reaction bottle and stirred at room temperature for 5 h. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a crude product, which was recrystallized from ethanol to obtain 1.90 g of a yellow powdery solid with a yield of 96.6%.

Claims

1. A method for preparing a 3-haloindole derivative, characterized in that: The method comprises the following steps: in the presence of an oxidant and an organic solvent, an indole compound 1 and a cuprous halide with a molecular formula of CuX are reacted by self-catalysis to synthesize a 3-halogenated indole derivative 2; ； Wherein, R is H, C1~C6 alkyl, cycloalkyl, acyl or sulfonyl, R 1 is H, C1~C6 alkyl, cycloalkyl, nitro, cyano, methoxy, F, Cl, Br, or aromatic group, R 2 is H, CH3, CF3, OCH3, NO2 or CN; X is any one of Cl, Br and I; The organic solvent is acetonitrile; the oxidant is N - fluorobisbenzenesulfonamide; the reaction time of the autocatalytic reaction is 0.5~5h.

2. The method for preparing a 3-haloindole derivative according to claim 1, characterized in that: R is any one of H, C1~C4 alkyl, acyl or sulfonyl; R 1 is any one of H, C1~C6 alkyl, cycloalkyl, nitro, cyano, or methoxy; R 2 It is any one of H, CH3, or OCH3.

3. The method for preparing a 3-haloindole derivative according to claim 1, characterized in that: The feeding molar ratio of the indole compound 1, cuprous halide and oxidant is 1:1.0~2.0:1.0~2.

0.

4. The method for preparing a 3-haloindole derivative according to claim 1, characterized in that: The reaction temperature is 0℃~130℃.

5. The method for preparing a 3-haloindole derivative according to claim 1, characterized in that: The preparation method further comprises concentrating the product under reduced pressure, separating and purifying by column chromatography and / or recrystallizing the product.

6. The method for preparing a 3-haloindole derivative according to claim 5, characterized in that: The eluent for column chromatography separation and purification consists of petroleum ether and dichloromethane or petroleum ether and ethyl acetate.

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