A method for preparing a halogenated indole compound

Abstract

The present invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of haloindole compounds. The preparation method provided by the present invention comprises the following steps: mixing an indole compound having the structure shown in Formula 1, a phase transfer catalyst, an alkali metal halide salt, and a polar solvent to obtain a mixed solution; inserting an anode and a cathode into the mixed solution, and passing a constant current to carry out a halogenation reaction to obtain a haloindole compound having the structure shown in Formula 2. The preparation method provided by the present invention completes the synthesis of haloindole compounds by organic electrochemistry without using a transition metal catalyst, avoids heavy metal pollution, and conforms to the development concept of "green chemistry"; moreover, the preparation method provided by the present invention has simple steps, easily available raw materials, and low synthesis cost of haloindole compounds, which is helpful for the synthesis and industrial application of haloindole compounds with a core molecular structure having high activity against plant diseases and insect pests.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of haloindole compounds. Background Art

[0002] Indole compounds are compounds formed by a pyrrole in which a nitrogen atom replaces a carbon atom on the pyrrole ring and is fused with benzene. As one of the important nitrogen-containing heterocyclic compounds, the unique skeleton structure of indole compounds is the advantage of this type of compound. At its 1-position, 2-position, 3-position, etc., different functional groups can be substituted, so that the compound has different drug effects, and thus its derivatives have very excellent biological and pharmacological activities. Therefore, researchers often use it for the creation of heterocyclic drugs and have very wide applications in pesticides and other fields.

[0003] As one of the important indole compounds, haloindole compounds have good bactericidal, insecticidal and disease-resistant effects and are the core skeletons of many pesticide molecules. They have important applications in the field of plant pest control. Coupled with their characteristics of high efficiency, greenness and low toxicity, they have been widely studied.

[0004] At present, the synthesis methods of haloindole compounds either need to use expensive chemical reagents, such as transition metal catalysts, or have many synthesis steps, long reaction times resulting in high energy consumption, or need to meet harsh reaction conditions. Therefore, the current synthesis methods of haloindole compounds have high costs and are not conducive to expanding the application scope of haloindole compounds and their derivatives. Summary of the Invention

[0005] The purpose of the present invention is to provide a preparation method of haloindole compounds. The preparation method provided by the present invention uses an organic electrochemical method for halogenation reaction, with simple steps, easily available raw materials, and low synthesis costs of haloindole compounds.

[0006] In order to achieve the above purpose, the present invention provides the following technical solutions:

[0007] The present invention provides a preparation method of haloindole compounds, comprising the following steps:

[0008] Mix an indole compound having the structure shown in Formula 1, a phase transfer catalyst, an alkali metal halide salt, and a polar solvent to obtain a mixed solution;

[0009] Insert an anode and a cathode into the mixed solution, and pass a constant current for halogenation reaction to obtain

[0010] a haloindole compound having the structure shown in Formula 2;

[0011]

[0012] R1 in Formula 1 and Formula 2 includes H, CN, Br, I, F, Cl, NO2, CH3, CHO or OCH3;

[0013] X in Formula 2 includes Br, I, F or Cl.

[0014] Preferably, the indole compounds of the structure shown in Formula 1 include: indole, 5-bromoindole, 5-nitroindole, 4-cyanoindole, 4-aldehyde indole, 4-bromoindole, 5-cyanoindole, 5-methoxyindole or 6-chloroindole.

[0015] Preferably, the alkali metal halide salt is an alkali metal bromide salt.

[0016] Preferably, the polar solvent is dimethyl carbonate and water; the volume ratio of dimethyl carbonate to water is 2:3.

[0017] Preferably, the constant current is 0.02 - 0.05 A.

[0018] Preferably, the molar ratio of the indole compound of the structure shown in Formula 1 to the alkali metal halide salt is 1:5.

[0019] Preferably, the phase transfer catalyst is tetrabutylammonium bromide; the molar ratio of the indole compound of the structure shown in Formula 1 to the phase transfer catalyst is 1:0.5.

[0020] Preferably, the temperature of the halogenation reaction is room temperature, and the halogenation reaction is carried out in an air environment.

[0021] Preferably, the halogenation reaction is carried out in a diaphragm-free electrolytic reaction vessel; the material of the anode is platinum, and the material of the cathode is carbon.

[0022] Preferably, the halogenation reaction obtains a halogenation reaction solution, and further includes: mixing and extracting the halogenation reaction solution, an organic solvent and water to obtain an extraction organic phase; subjecting the extraction organic phase to column chromatography to obtain a halogenated indole compound of the structure shown in Formula 2; the elution solvent used for the column chromatography is a mixed solvent of petroleum ether and ethyl acetate.

[0023] The present invention provides a method for preparing halogenated indole compounds, comprising the following steps: mixing an indole compound having the structure shown in Formula 1, a phase transfer catalyst, an alkali metal halide salt, and a polar solvent to obtain a mixed solution; inserting an anode and a cathode into the mixed solution, and introducing a constant current to carry out a halogenation reaction to obtain a halogenated indole compound having the structure shown in Formula 2. The preparation method provided by the present invention completes the synthesis of halogenated indole compounds by organic electrochemistry without using a transition metal catalyst, avoiding heavy metal pollution and conforming to the development concept of "green chemistry"; moreover, the preparation method provided by the present invention has simple steps, easily available raw materials, and a low synthesis cost of halogenated indole compounds, which is helpful for the synthesis and industrial application of halogenated indole compounds with a core molecular structure of high-activity anti-plant diseases and insect pests pesticides. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 1H-NMR spectrum of 3,5-dibromoindole prepared in Example 2 of the present invention; 1 1H-NMR spectrum;

[0025] Figure 2 13C-NMR spectrum of 3,5-dibromoindole prepared in Example 2 of the present invention; 13 13C-NMR spectrum;

[0026] Figure 3 1H-NMR spectrum of 3-bromo-5-nitroindole prepared in Example 3 of the present invention; 1 1H-NMR spectrum;

[0027] Figure 4 13C-NMR spectrum of 3-bromo-5-nitroindole prepared in Example 3 of the present invention; 13 13C-NMR spectrum;

[0028] Figure 5 1H-NMR spectrum of 3-bromo-5-cyanoindole prepared in Example 4 of the present invention; 1 1H-NMR spectrum;

[0029] Figure 6 13C-NMR spectrum of 3-bromo-5-cyanoindole prepared in Example 4 of the present invention; 13 13C-NMR spectrum;

[0030] Figure 7 1H-NMR spectrum of 3-bromo-4-cyanoindole prepared in Example 4 of the present invention; 1 1H-NMR spectrum;

[0031] Figure 8 13C-NMR spectrum of 3-bromo-4-cyanoindole prepared in Example 4 of the present invention; 13 13C-NMR spectrum;

[0032] Figure 9 Flow chart for the preparation of halogenated indole compounds provided in the examples of the present invention;

[0033] Figure 10 It is the preparation flow chart of 3-bromo-indole provided by Embodiment 1 of the present invention. Detailed implementation manners

[0034] The present invention provides a preparation method of a haloindole compound, comprising the following steps:

[0035] Mix an indole compound with the structure shown in Formula 1, a phase transfer catalyst, an alkali metal halide salt, and a polar solvent to obtain a mixed solution;

[0036] Insert an anode and a cathode into the mixed solution, and pass a constant current to carry out a halogenation reaction to obtain

[0037] A haloindole compound with the structure shown in Formula 2;

[0038]

[0039] R1 in Formula 1 and Formula 2 includes H, CN, Br, I, F, Cl, NO2, CH3, CHO or OCH3;

[0040] X in Formula 2 includes Br, I, F or Cl.

[0041] In the present invention, unless otherwise specified, all preparation raw materials / components are commercially available products well-known to those skilled in the art.

[0042] The present invention mixes an indole compound with the structure shown in Formula 1, a phase transfer catalyst, an alkali metal halide salt, and a polar solvent to obtain a mixed solution;

[0043]

[0044] In the present invention, R1 in Formula 1 includes H, CN, Br, I, F, Cl, NO2, CH3, CHO or OCH3, and more preferably includes H, CN, Br, I, F, Cl or NO2.

[0045] In the present invention, the indole compound with the structure shown in Formula 1 preferably includes: indole, 5-bromoindole, 5-nitroindole, 4-cyanoindole, 4-aldehyde indole, 4-bromoindole, 5-cyanoindole, 5-methoxyindole or 6-chloroindole, and more preferably is indole, 5-bromoindole, 5-nitroindole, 4-cyanoindole, 4-bromoindole or 5-cyanoindole.

[0046] In the present invention, the phase transfer catalyst is preferably tetrabutylammonium bromide (TBAB).

[0047] In the present invention, the molar ratio of the indole compound with the structure shown in Formula 1 to the phase transfer catalyst is preferably 1:0.5.

[0048] In the present invention, the alkali metal halide salt is preferably an alkali metal bromide salt, and more preferably potassium bromide.

[0049] In the present invention, the molar ratio of the indole compound of the structure shown in Formula 1 to the alkali metal halide salt is preferably 1:5.

[0050] In the present invention, the polar solvent is preferably dimethyl carbonate and water.

[0051] In the present invention, the water is preferably purified water.

[0052] In the present invention, the volume ratio of dimethyl carbonate to water is preferably 2:3.

[0053] In the present invention, the mass ratio of the indole compound of the structure shown in Formula 1 to the volume of the polar solvent is preferably 500 mg: 25 mL.

[0054] In the present invention, the mixing preferably includes the following steps: dissolving the indole compound of the structure shown in Formula 1 in a polar solvent to obtain an indole compound solution; mixing the indole compound solution, the alkali metal halide salt and a phase transfer catalyst.

[0055] In the present invention, the mixing is preferably carried out under stirring, and the stirring is specifically preferably magnetic stirring. The temperature of the stirring is preferably room temperature.

[0056] After obtaining the mixed solution, in the present invention, an anode and a cathode are inserted into the mixed solution, and a constant current is passed through to carry out a halogenation reaction to obtain a halogenated indole compound of the structure shown in Formula 2;

[0057]

[0058] In the present invention, R1 in Formula 2 includes H, CN, Br, I, F, Cl, NO2, CH3, CHO or OCH3, and preferably includes H, CN, Br, I, F, Cl or NO2.

[0059] In the present invention, X in Formula 2 includes Br, I, F or Cl, and is preferably Br.

[0060] In the present invention, the material of the anode is platinum.

[0061] In a specific embodiment of the present invention, the anode is specifically preferably a platinum plate. The size of the platinum plate is 10 mm × 10 mm × 0.2 mm.

[0062] In the present invention, the material of the cathode is carbon.

[0063] In a specific embodiment of the present invention, the cathode is preferably a carbon plate. The size of the carbon plate is 10mm×10mm×0.2mm.

[0064] In the present invention, the constant current is preferably 0.02 - 0.05 A.

[0065] In the present invention, the temperature of the halogenation reaction is preferably room temperature.

[0066] In the present invention, the halogenation reaction is preferably carried out in an air environment.

[0067] In the present invention, the halogenation reaction is preferably carried out in a diaphragm-free electrolytic reaction vessel.

[0068] In the present invention, during the halogenation reaction, thin layer chromatography (TCL) is preferably used to sample and monitor the reaction. In a specific embodiment of the present invention, the halogenation reaction is preferably sampled and monitored by thin layer chromatography (TCL) every 0.5 h. When the indole compound of the structure shown in Formula 1 disappears or there is no change in the raw material concentration / product concentration in two samplings, it represents the end of the halogenation reaction.

[0069] In the present invention, the halogenation reaction yields a halogenation reaction solution. The present invention preferably further includes: mixing and extracting the halogenation reaction solution, an organic solvent, and water to obtain an extraction organic phase; performing column chromatography on the extraction organic phase to obtain a halogenated indole compound of the structure shown in 2; the elution solvent used for the column chromatography is a mixed solvent of petroleum ether and ethyl acetate. In the present invention, the organic solvent is specifically preferably ethyl acetate. In the present invention, after obtaining the extraction organic phase and before performing the column chromatography, the present invention preferably dries and concentrates the extraction organic phase in sequence. In the present invention, the drying reagent for drying is preferably anhydrous sodium sulfate. After drying, the present invention preferably separates the solid and liquid to remove the drying reagent, and the solid-liquid separation is specifically preferably filtration. The present invention has no special requirements for the specific implementation process of the concentration, and operations well-known to those skilled in the art can be used, such as rotary evaporation. In the present invention, the size of the column chromatography silica gel used for the column chromatography is 300 - 400 mesh. The volume ratio of the petroleum ether to the ethyl acetate is preferably 12.5:1.

[0070] To further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below with reference to the drawings and embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0071] The experimental instruments used in the embodiments of the present invention are shown in Table 1.

[0072] Table 1 Experimental Instruments

[0073]

[0074] The experimental materials and reagents used in the embodiments of the present invention are shown in Table 2.

[0075] Table 2 Experimental Materials and Reagents

[0076]

[0077]

[0078] Example 1

[0079] According to Figure 10 The provided preparation flow chart of 3-bromo-indole:

[0080] In a clean and dried 50 mL two-necked flask, first place a magnetic stir bar, then successively add 500 mg of the corresponding substrate (indole), 10 mL of dimethyl carbonate, and 15 mL of purified water. Subsequently, turn on the magnetic stirrer, and under the action of the magnetic stir bar, dissolve the raw materials in the mixed solvent. Then add 0.5 molar equivalent of the phase transfer catalyst TBAB and 5 molar equivalents of the electrolyte potassium bromide relative to the reaction substrate. After stirring and mixing evenly, insert a 10 mm × 10 mm × 0.2 mm platinum plate as the anode and a 10 mm × 10 mm × 0.2 mm carbon plate as the cathode into the two-necked flask, and plug an uninflated balloon into the other neck of the two-necked flask. Turn on the DC power supply, and allow a constant current of 0.03 A to pass through the reaction system at room temperature.

[0081] During the reaction process, samples of the reaction are taken and monitored by thin-layer chromatography every 0.5 h. When the raw materials disappear or the raw material concentration / product concentration does not change between two samplings, it represents the end of the reaction.

[0082] After the reaction system returns to room temperature, take out the magnetic stir bar. Subsequently, extract the reaction solution with ethyl acetate and water, dry the obtained organic layer solution with anhydrous sodium sulfate, filter, concentrate, and then use silica gel (300 - 400 mesh) for column chromatography of the reaction sample. Separate and purify with a mixed solution prepared from pure petroleum ether and ethyl acetate as the eluent (the volume ratio of petroleum ether to ethyl acetate is 12.5:1) to obtain 3-bromo-indole, with a yield of 26%.

[0083] Example 2

[0084] According to Figure 9 The provided preparation flow chart of halogenated indole compounds:

[0085] The preparation method is basically the same as that of Example 1, except that: 5-bromoindole is used to replace indole in Example 1 to obtain 3,5-dibromoindole. In addition, when using silica gel as the separation packing for column chromatography, since the target product 3,5-dibromoindole has a very strong adsorption effect on silica gel and the desorption effect is poor, therefore, in order to improve the separation efficiency, triethylamine needs to be added to the column chromatography eluents petroleum ether and ethyl acetate (the volume ratio of triethylamine to petroleum ether is: triethylamine 5: petroleum ether 1000), and the sample of the obtained target compound 3-bromo-indole and the nuclear magnetic resonance spectrum will contain triethylamine components. Finally, the 1 1H-NMR spectrum ( Figure 1 ) of 3,5-dibromoindole prepared in Example 2 of the present invention; Figure 2 The 13 13C-NMR spectrum ( Figure 2 ) of 3,5-dibromoindole prepared in Example 2 of the present invention;

[0086] TLC: R f f = 0.94 (petroleum ether / ethyl acetate = 12.5:1).

[0087] 1 1H NMR (600 MHz, CDCl3) δ ppm: 7.23 (s, 1H), 7.26 - 7.32 (m, 2H), 7.71 (s, 1H), 9.15 (NH, s, 1H). (In the 1H nuclear magnetic resonance spectrum: the peaks at 1.2 CH3 and 3.2 CH2 are the peaks of triethyl)

[0088] 13 13C NMR (150 MHz, CDCl3) δ ppm: 90.5, 113.1, 113.8, 121.8, 124.7, 125.9, 128.6, 134.1. (In the 13C nuclear magnetic resonance spectrum: the peaks at 14 CH3 and 59 CH2 are the peaks of triethyl)

[0089] IR: (cm –1 -1): 3417, 3160, 3136, 3116, 2963, 2919, 2859, 2824, 1604, 1568, 1443, 1332, 1301, 1238, 1201, 1096, 981, 883, 793, 593, 476, 422.

[0090] Example 3

[0091] According to the Figure 9 provided preparation flow chart of halogenated indole compounds:

[0092] It is basically the same as the preparation method of Example 1, except that: 5-nitroindole is used to replace indole in Example 1 to obtain 3-bromo-5-nitroindole. Figure 3 The 1 H-NMR spectrum of 3-bromo-5-nitroindole prepared in Example 3 of the present invention Figure 3 ); Figure 4 The 13 C-NMR spectrum of 3-bromo-5-nitroindole prepared in Example 3 of the present invention Figure 4 );

[0093] TLC: R f = 0.94 (petroleum ether / ethyl acetate = 12.5:1).

[0094] 1 H NMR (400 MHz, DMSO) δ ppm: 7.60 - 7.63 (d, 1H, J = 9 Hz), 7.86 (s, 1H), 8.04 - 8.07 (m, 1H), 8.29 (s, 1H), 12.21 (NH, s, 1H).

[0095] 13 C NMR (100 MHz, DMSO) δ ppm: 91.5, 113.4, 115.4, 117.9, 126.1, 129.5, 139.0, 141.8.

[0096] IR: (cm –1 ): 3303, 3121, 3095, 3035, 2467, 1880, 1777, 1622, 1582, 1501, 1466, 1421, 1385, 1357, 1079, 889, 805, 785, 750, 734, 695, 639, 592, 417.

[0097] Example 4

[0098] According to Figure 9 The preparation flow chart of the provided haloindole compounds:

[0099] It is basically the same as the preparation method of Example 1, except that: 5-cyanoindole is used to replace indole in Example 1 to obtain 3-bromo-5-cyanoindole. Figure 5 The 1 H-NMR spectrum of 3-bromo-5-cyanoindole prepared in Example 4 of the present invention Figure 5 ); Figure 6 The 13 C-NMR spectrum of 3-bromo-5-cyanoindole prepared in Example 4 of the present inventionFigure 6 )

[0100] TLC:R f = 0.94 (petroleum ether / ethyl acetate = 12.5:1).

[0101] 1 H NMR (600 MHz, CD3OD) δ ppm: 7.35 - 7.36 (d, 1H, J = 1.6 Hz), 7.42 - 7.46 (m, 2H), 7.92 (s, 1H).

[0102] 13 C NMR (150 MHz, CD3OD) δ ppm: 91.5, 103.1, 112.6, 120.3, 124.8, 125.3, 126.0, 126.7, 137.2.

[0103] IR: (cm –1 ): 3411, 3358, 3329, 3140, 3125, 2224, 1890, 1763, 1616, 1471, 1409, 1341, 1241, 1202, 1153, 1083, 986, 912, 883, 807, 625, 605, 537, 492, 419.

[0104] Example 5

[0105] According to Figure 9 the preparation flow chart of the provided haloindole compounds:

[0106] It is basically the same as the preparation method in Example 1, except that: 4-cyanoindole is used to replace indole in Example 1 to obtain 3-bromo-4-cyanoindole, Figure 7 which is the 1 H-NMR spectrum of 3-bromo-4-cyanoindole prepared in Example 4 of the present invention Figure 7 ); Figure 8 which is the 13 C-NMR spectrum of 3-bromo-4-cyanoindole prepared in Example 4 of the present invention Figure 8 );

[0107] TLC:R f = 0.94 (petroleum ether / ethyl acetate = 12.5:1).

[0108] 11H NMR (400 MHz, CDCl3) δ ppm: 7.23 - 7.27 (t, 1H, J = 14.32 Hz), 7.41 - 7.45 (d, 1H, 8.88 Hz), 7.51 - 7.52 (d, 1H, J = 7.16 Hz), 7.67 - 7.69 (t, 1H, J = 8.08 Hz).

[0109] 13 13C NMR (100 MHz, CDCl3 and CD3OD) δ ppm: 88.3, 101.2, 116.9, 117.8, 121.5, 124.7, 127.2, 127.5, 135.7.

[0110] IR: (cm –1 ): 3304, 2974, 2928, 2890, 2222, 1642, 1425, 1351, 1275, 1090, 1050, 975, 883, 783, 734.

[0111] Example 6

[0112] According to Figure 9 the preparation flow chart of the provided haloindole compounds:

[0113] It is basically the same as the preparation method of Example 1, except that: 4 - bromoindole is used to replace indole in Example 1 to obtain 3,4 - dibromoindole.

[0114] Example 7

[0115] According to Figure 9 the preparation flow chart of the provided haloindole compounds:

[0116] It is basically the same as the preparation method of Example 1, except that: 4 - formylindole is used to replace indole in Example 1 to obtain 3 - bromo - 4 - formylindole.

[0117] The reaction raw materials, conditions and yields of Examples 2 - 7 are shown in Table 3.

[0118] Table 3 Reaction Raw Materials, Conditions and Yields of Examples 2 - 7

[0119]

[0120] In the present invention, through an organic electrochemical method, using indole compounds as reaction substrates, tetrabutylammonium bromide (TBAB) as a phase - transfer catalyst, potassium bromide as an electrolyte, dimethyl carbonate and water as reaction solvents, a reaction occurs. After the reaction solution is subjected to extraction and column chromatography, the pure target product is obtained through nuclear magnetic resonance hydrogen spectrum ( 11H NMR), carbon nuclear magnetic resonance 13 13C NMR), and infrared spectroscopy (IR), and the results obtained after calculation showed that the hydrogen atom at the 3-position of the indole parent ring had been replaced by a bromine atom, and a halogenation reaction occurred.

[0121] Although the above embodiments have described the present invention in detail, they are only a part of the embodiments of the present invention, rather than all embodiments. Other embodiments can also be obtained according to this embodiment without creative efforts, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing a halogenated indole compound, characterized in that, The steps include: In a washed and dried 50 mL two-necked flask, first place a magnetic stir bar, then successively add 500 mg of 5-nitroindole, 10 mL of dimethyl carbonate and 15 mL of purified water. Subsequently, turn on the magnetic stirrer and dissolve the raw materials in the mixed solvent under the action of the magnetic stir bar. Then add 0.5 molar equivalent of the phase transfer catalyst tetrabutylammonium bromide and 5 molar equivalent of the electrolyte potassium bromide relative to 5-nitroindole. After stirring and mixing evenly, insert a 10 mm×10 mm×0.2 mm platinum plate as the anode and a 10 mm×10 mm×0.2 mm carbon plate as the cathode into the two-necked flask. Plug an uninflated balloon into the other neck of the two-necked flask, turn on the DC power supply, and allow a constant current of 0.04 A to pass through the reaction system at room temperature. During the reaction process, sample the reaction for monitoring by thin layer chromatography every 0.5 h. When the raw materials disappear or the concentration of the raw materials / concentration of the products does not change between two samplings, it represents the end of the reaction. After the reaction system returns to room temperature, take out the magnetic stir bar. Then extract the reaction solution with ethyl acetate and water. Dry the obtained organic layer solution with anhydrous sodium sulfate, filter, concentrate, and then perform column chromatography on the reaction sample using silica gel. The silica gel is 300-400 mesh, and the eluent is a mixed solution prepared from pure petroleum ether and ethyl acetate for separation and purification. The volume ratio of petroleum ether to ethyl acetate is 12.5:1 to obtain 3-bromo-5-nitroindole with a yield of 42.5%.

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