A method for preparing 2,3-indole imine compounds
Through electrochemical synthesis methods and 2,2,6,6-tetramethylpiperidine oxide catalysis, the problem of using toxic reagents and transition metals in the prior art is solved, and the gentle controllable preparation and efficient separation of 2,3-indoleimine compounds is achieved, which is in line with the concept of green chemistry and has broad application prospects.
Patent Information
- Application Number
- CN202210483403.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-05-05
- Publication Date
- 2025-04-22
- Estimated Expiration
- 2042-05-05
AI Technical Summary
The existing synthesis method of 2,3-indoleimine compounds uses toxic and harmful reagents and transition metals, which violates the concept of green chemistry, and the reaction conditions are not gentle, making it difficult to separate the product.
Using electrochemical synthesis method, 2,2,6,6-tetramethylpiperidine oxide was used as a catalyst, and the target product was obtained by adding specific compounds and solvents to a pre-dried flask, and electrochemical reaction was performed using platinum sheets and graphite sheet electrodes, and finally the target product was separated by column chromatography.
It has achieved efficient preparation of 2,3-indoleimine compounds, with mild and controllable reaction conditions, easy separation of products, avoiding the use of toxic and harmful reagents and transition metals, conforming to the concept of green chemistry, and has high potential value in the fields of medicine and pesticides.
Smart Images
Figure CN114807985B_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of chemical synthesis, in particular to a method for preparing 2,3-indole imine compounds. Background Art
[0002] Indole and its derivatives are widely present in nature, most of which have biological activity and are widely used in the fields of medicine, pesticides, feed, dyes, etc., and have high application value. The existing synthesis methods of 2,3-indole imine compounds use some toxic and harmful reagents and transition metals as catalysts, which does not conform to the concept of green chemistry. Therefore, it is urgent to propose a preparation method of 2,3-indole imine compounds. The present invention adopts an electrochemical synthesis method, which has the characteristics of mild conditions, controllable reaction, and easy separation of products, and uses 2,2,6,6-tetramethylpiperidinyl oxide as a reaction catalyst, which replaces the use of some toxic and harmful reagents and transition metals, which is more in line with the concept of green chemistry. Summary of the invention
[0003] The object of the present invention is to provide a method for preparing 2,3-indole imine compounds to solve the problems raised in the above background technology.
[0004] To achieve the above object, the present invention provides the following technical solutions:
[0005] A method for preparing 2,3-indole imine compounds comprises the following steps:
[0006] To a diaphragmless three-necked flask dried in an oven in advance, o-aminophenylacetylene compounds, aniline, lithium perchlorate, tetrabutylammonium iodide, 2,2,6,6-tetramethylpiperidinoxide, and a mixture of acetonitrile and water are added in sequence as a solvent; a platinum sheet electrode in the device is used as an anode, and a graphite sheet electrode is used as a cathode. After the reaction is completed, the reaction solution is evaporated and concentrated, and then separated by column chromatography to obtain the target product.
[0007] As a further solution of the present invention: the molar ratio of the o-aminophenylacetylene compound to aniline is 1:0.1-10.
[0008] As a further solution of the present invention: the molar ratio of the o-aminophenylacetylene compound to lithium perchlorate can be 1:0.1-10.
[0009] As a further solution of the present invention: the molar ratio of the o-ethynylaniline to the tetrabutylammonium iodide is 1:0.1-10.
[0010] As a further embodiment of the present invention: the addition amount of the 2,2,6,6-tetramethylpiperidinyl oxide is 0.1-20 mol%.
[0011] As a further embodiment of the present invention: the volume ratio of water to acetonitrile in the solvent is 1:1-10.
[0012] As a further scheme of the present invention: the reaction temperature is 10-150°C, the reaction current is 0.1-10mA; the reaction time is 1-72h; the rotary evaporation temperature is 36-40°C, the vacuum degree can be 0.08-0.12Mpa, the chromatography adopts 200 mesh column chromatography silica gel, and the developing agent is a mixed solution of petroleum ether and ethyl acetate.
[0013] As a further embodiment of the present invention, the structure of the o-aminophenylacetylene compound is as shown in Formula I:
[0014] Formula I:
[0015] The R group in Formula I includes but is not limited to substituted methyl, halogen, ester group, methoxy, trifluoromethyl, etc., and the halogen is one of fluorine, chlorine, and bromine; the R1 group in Formula I includes but is not limited to substituted benzenesulfonyl and phenylmethylsulfonyl, and the substituted benzenesulfonyl includes but is not limited to methyl, methoxy, trifluoromethyl, nitro and halogen.
[0016] As a further solution of the present invention: the structure of the aniline is shown in Formula II:
[0017] Formula II: Ar-NH2;
[0018] The Ar group in Formula II includes, but is not limited to, a phenyl group and a substituted phenyl group. The substituted phenyl group includes, but is not limited to, a methyl group, a phenyl group, a tert-butyl group, an ester group, and a halogen group.
[0019] As a further solution of the present invention: the structure of the 2,3-indole imine compound is shown in Formula III:
[0020] Formula III:
[0021] Compared with the prior art, the present invention has the following beneficial effects:
[0022] (1) The present invention provides a novel method for preparing 2,3-indole imine compounds under electrochemical conditions;
[0023] (2) The method of the present invention does not require the use of toxic and harmful oxidants and transition metals, the reaction conditions are mild and controllable, the product is easy to separate, and the environmental pollution is small;
[0024] (3) The product of the present invention and its derivatives have high potential value in the fields of medicine, pesticides, etc. and have good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS
[0025] Figure 1This is the H NMR spectrum of the compound in Example 1.
[0026] Figure 2 This is the NMR spectrum C of the compound in Example 1.
[0027] Figure 3 This is the H spectrum of the NMR spectrum of the compound in Example 2.
[0028] Figure 4 This is the NMR spectrum C of the compound in Example 2.
[0029] Figure 5 This is the H spectrum of the NMR spectrum of the compound in Example 3.
[0030] Figure 6 This is the NMR spectrum C of the compound in Example 3. DETAILED DESCRIPTION
[0031] The technical solution of this patent is further described in detail below in conjunction with specific implementation methods.
[0032] Example 1
[0033] A preparation method of 2,3-indole imine compounds comprises the following steps: in a pre-dried 10 mL three-necked flask without a diaphragm, N-(2-ethynylphenyl)-4-toluenesulfonamide (83 mg, 0.3 mmol) and aniline (110 μL, 1.2 mmol) are added in sequence, and then lithium perchlorate (83 mg, 0.75 mmol), tetrabutylammonium iodide (23 mg, 0.06 mmol), 2,2,6,6-tetramethylpiperidinoxide (2.2 mg, 5 mol%), water (1 mL) and acetonitrile are added; (5mL) was mixed as a solvent and electrolyzed at room temperature at a constant current of 1.2mA for 48h. After the reaction solution was stirred, it was extracted three times with ethyl acetate. The organic phases extracted several times were combined into a 100mL eggplant-shaped bottle. A Heidolph rotary evaporator was used at a speed of 100-200rpm, a temperature of 38-40°C, and a vacuum degree of 0.08-0.12Mpa for 3-5min. Then, a 200-mesh column chromatography silica gel was used for column chromatography. The developing solvent was petroleum ether: ethyl acetate = 20:1. The target compound was isolated. The yield of the target compound was 89.3mg, and the yield was 66%. The NMR spectrum shape, signal, noise, etc. showed that the product had extremely high purity.
[0034] The structure of the 2,3-indole imine compound obtained in this example is shown below:
[0035]
[0036] The structural characterization data of the product are:
[0037] 1 1H NMR (600 MHz, CDCl3) δ 8.24 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 6.5 Hz, 2H), 7.44 (t, J = 7.9 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.28 (t, J = 7.7 Hz, 2H), 7.22 (t, J = 7.6 Hz, 2H), 7.09 (t, J = 7.4 Hz, 1H), 6.98 (t, J = 7.3 Hz, 1H), 6.81 (t, J = 7.6 Hz, 1H), 6.74 (d, J = 5.5 Hz, 2H), 6.59 (d, J = 7.7 Hz, 3H), 2.47 (s, 3H).
[0038] 13 13C NMR (150 MHz, CDCl3) δ 149.7, 147.5, 145.6, 145.3, 145.0, 135.5, 134.0, 129.44, 129.42, 128.8, 128.5, 126.3, 124.6, 123.7, 123.2, 118.8, 116.7, 115.5, 21.8.
[0039] HRMS-ESI (m / z) [M+H] + calculated for C27H22N3O2S 452.1427, found 452.1417.
[0040] Example 2
[0041] A preparation method of 2,3-indole imine compounds comprises the following steps: in a pre-dried 10 mL three-necked flask without a diaphragm, N-(2-ethynyl, 3-methylphenyl)-4-toluenesulfonamide (87.4 mg, 0.3 mmol) and 4-(tert-butyl)aniline (193 μL, 1.2 mmol) are added in sequence, and then lithium perchlorate (83 mg, 0.75 mmol), tetrabutylammonium iodide (23 mg, 0.06 mmol), 2,2,6,6-tetramethylpiperidinoxide (2.2 mg, 5 mol%), water ( 1mL) and acetonitrile (5mL) were mixed as solvents and added, and electrolyzed at room temperature at a constant current of 1.2mA for 48h. After the reaction solution was stirred, it was extracted three times with ethyl acetate, and the organic phases extracted several times were combined into a 100mL eggplant-shaped bottle. A Heidolph rotary evaporator was used with a speed of 100-200rpm, a temperature of 38-40°C, and a vacuum degree of 0.08-0.12Mpa for 3-5min. Then, a 200-mesh column chromatography silica gel was used for column chromatography, and the developing solvent was petroleum ether: ethyl acetate = 20:1, and the target compound was isolated. The yield of the target compound was 67.6mg, and the yield was 39%. The NMR spectrum shape, signal, noise, etc. showed that the product purity was extremely high.
[0042] The structure of the 2,3-indole imine compound obtained in this example is shown below:
[0043]
[0044] The structural characterization data of the product are:
[0045] 1 H NMR (600MHz, CDCl3) δ7.93(d,J=8.3Hz,1H),7.88(d,J=8.1Hz,2H),7.40(t,J=8.0Hz,1H),7.22(d,J=8.2Hz,2H),7.00(d,J=8. 3Hz,3H),6.94(d,J=8.2Hz,2H),6.28(d,J=8.3Hz,2H),6.25–6.15(m,2H),2.57(s,3H),2.38(s,3H),1.30(s,9H),1.28(s,9H).
[0046] 13C NMR (150MHz, CDCl3) δ150.6,147.6,147.3,146.6,144.8,144.2,144.0,138.2,135.1,132.3,129. 4,128.5,127.0,125.7,125.4,123.3,119.7,119.1,112.8,34.3,34.2,31.43,31.43,21.7,19.5.
[0047] HRMS-ESI[M+Na] + calculated for C36H39N3NaO2S 600.2655, found 600.2656.
[0048] Example 3
[0049] A preparation method of 2,3-indole imine compounds comprises the following steps: N-(2-ethynylphenyl)-4-methoxybenzenesulfonamide (87.9 mg, 0.3 mmol) and 4-(tert-butyl)aniline (193 μL, 1.2 mmol) are sequentially added into a pre-dried 10 mL three-necked flask without a diaphragm, and then lithium perchlorate (83 mg, 0.75 mmol), tetrabutylammonium iodide (23 mg, 0.06 mmol), 2,2,6,6-tetramethylpiperidinoxide (2.2 mg, 5 mol%), and a mixture of water (1 mL) and acetonitrile (5 mL) are added as a solvent, and electrolysis is performed at room temperature with a constant current of 1.2 mA for 48 h. After the reaction liquid was stirred, it was extracted three times with ethyl acetate, and the organic phases extracted several times were combined into a 100 mL eggplant-shaped bottle, and a Heidolph rotary evaporator was used at a speed of 100-200 rpm, a temperature of 38-40°C, and a vacuum degree of 0.08-0.12Mpa for 3-5 minutes, and then a 200-mesh column chromatography silica gel was used for column chromatography, and the developing solvent was petroleum ether: ethyl acetate = 10:1, and the target compound was separated. The yield of the target compound was 121.86 mg, and the yield was 70%. The NMR spectrum shape, signal, noise, etc. showed that the product purity was extremely high.
[0050] The structure of the 2,3-indole imine compound obtained in this example is shown below:
[0051]
[0052] The structural characterization data of the product are:
[0053] 1H NMR (600MHz, CDCl3) δ8.23(d,J=7.8Hz,1H),8.16–7.99(m,2H),7.42(t,J=7.8Hz,1H),7.32(d,J=8.1Hz,2H),7.25(d,J=6.6Hz,2H ),6.99(d,J=8.5Hz,2H),6.87–6.74(m,3H),6.72(d,J=7.6Hz,1H),6.59(d,J=8.1Hz,2H),3.89(s,3H),1.33(s,9H),1.31(s,9H).
[0054] 13 C NMR (150MHz, CDCl3) δ164.1,147.8,147.1,146.1,145.6,144.9,144.5,133.7,131.1,130.1,126 .1,126.0,125.2,123.4,119.1,117.0,115.4,115.4,114.9,113.9,55.8,34.5,34.3,31.5,31.5.
[0055] HRMS-ESI[M+Na] + calculated for C35H37N3NaO3S 602.2448,found 602.2443.
[0056] In summary, the present invention has developed a new synthesis method for 2,3-indole imine compounds. The method adopts electrochemical conditions, has the characteristics of mild and controllable reaction, easy separation of products, and no need to use toxic and harmful oxidants and transition metals. It is more in line with the concept of green chemistry, and the product and its derivatives have high potential value in the fields of medicine, pesticides, etc., and have good application prospects.
[0057] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.
Claims
1. A method for preparing 2,3-indole imine compounds, characterized in that: The steps include: An o-aminophenylacetylene compound, an aniline compound, lithium perchlorate, tetrabutylammonium iodide, 2,2,6,6-tetramethylpiperidinoxide, and a mixture of acetonitrile and water are sequentially added to a three-necked flask without a diaphragm that has been dried in an oven in advance. A platinum sheet electrode is used as an anode, and a graphite sheet electrode is used as a cathode in the device. After the reaction is completed, the reaction solution is evaporated and concentrated, and then separated by column chromatography to obtain the target product. The o-aminophenylacetylene compound is N-(2-ethynylphenyl)-4-toluenesulfonamide; The aniline compound is aniline; The structure of the 2,3-indole imine compound is shown below: .
2. A method for preparing 2,3-indole imine compounds, characterized in that: The steps include: An o-aminophenylacetylene compound, an aniline compound, lithium perchlorate, tetrabutylammonium iodide, 2,2,6,6-tetramethylpiperidinoxide, and a mixture of acetonitrile and water are sequentially added to a three-necked flask without a diaphragm that has been dried in an oven in advance. A platinum sheet electrode is used as an anode, and a graphite sheet electrode is used as a cathode in the device. After the reaction is completed, the reaction solution is evaporated and concentrated, and then separated by column chromatography to obtain the target product. The o-aminophenylacetylene compound is N-(2-ethynyl, 3-methylphenyl)-4-toluenesulfonamide; The aniline compound is 4-tert-butylaniline; The structure of the 2,3-indole imine compound is shown below: .
3. The method for preparing a 2,3-indole imine compound according to claim 1 or 2, characterized in that: The molar ratio of the o-aminophenylacetylene compound to the aniline compound is 1:0.1-10.
4. The method for preparing a 2,3-indole imine compound according to claim 1 or 2, characterized in that: The molar ratio of the o-aminophenylacetylene compound to lithium perchlorate is 1:0.1-10.
5. The method for preparing a 2,3-indole imine compound according to claim 1 or 2, characterized in that: The addition amount of the 2,2,6,6-tetramethylpiperidinyl oxide is 0.1-20 mol %.
6. The method for preparing a 2,3-indole imine compound according to claim 1 or 2, characterized in that: The volume ratio of water to acetonitrile in the solvent is 1:1-10.
7. The method for preparing a 2,3-indole imine compound according to claim 1 or 2, characterized in that: The reaction temperature is room temperature, the reaction current is 0.1-10 mA; the reaction time is 1-72 h; the rotary evaporation temperature is 36-40°C, the vacuum degree is 0.08-0.12Mpa, the chromatography uses 200 mesh column chromatography silica gel, and the developing agent is a mixed solution of petroleum ether and ethyl acetate.