Electrochemical synthesis method of 4 '-N-methylbenzyl-3-indole derivative

Abstract

The invention relates to the field of chemical synthesis, in particular to an electrochemical synthesis method of a 4 '-N-methylbenzyl-3-indole derivative. According to the preparation method, selected electrons are traceless oxidizing agents, the energy conversion rate is high, no catalyst is needed in the reaction, the reaction steps are few, raw materials are easy to obtain, the reaction conditions are mild, operation is easy, convenient and safe, the substrate expansion range is wide, the compound functional group tolerance is high, the product yield can reach 80% or above, and the compound can be prepared in a gram level. N-methyl N-alkylaniline or N-methylaniline is used for carrying out electrochemical oxidation reaction on indole, N-methyl provides methylene to realize connection between benzene ring para-positions of the N-methyl N-alkylaniline and N-methylaniline and the C3 position of indole, and then the 3-arylmethylindole derivative is efficiently synthesized.

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis, in particular to an electrochemical synthesis method of 4'-N-methylbenzyl-3-indole derivatives. Background Art

[0002] Indole compounds are alkaloids widely found in plants and Chinese herbal medicines, and their indole derivatives have a wide range of physiological functions and activities (Chem. Rev. 2012, 112, 3508-3549; Chem. Rev. 2010, 110, 4489-4497). The development of a variety of C3-substituted derivatives based on the indole core skeleton is the basis of many promising therapeutic drugs, which can be used as hypoglycemic drugs, antiviral drugs, antibacterial drugs, analgesics and protein kinase inhibitors (as shown below). Therefore, the development of new methods to synthesize indole derivatives is conducive to further expanding the library of potential bioactive molecules.

[0003]

[0004] Since the C3 position of indole is electron-rich and prone to electrophilic substitution and free radical substitution reactions, a variety of functional groups have been successfully introduced into this reaction site. N-methylaniline is a universal structural unit that is widely present in approved drugs, biologically active compounds and natural products. It is also a synthon widely used in synthetic chemistry (Curr. Drug Metab., 2011, 12, 35-50; Chem. Eur. J., 2019, 25, 2423-2441; Chin. J. Org. Chem., 2017, 37, 1-19; New J. Chem., 2021, 45, 14345-14359). In addition to the amine methylation reaction (Org. Lett., 2010, 12, 5214-5217), indole and N-methyl-N-alkylaniline can also undergo this type of aromatic methylation reaction in the presence of peroxides or under photocatalysis. In 2010, Zhi Zhiming's research group at the University of Hong Kong used ruthenium catalysts and peroxides to achieve the aromatic methylation reaction of indole and N-methyl-N-alkylaniline (Chem. Eur. J., 2010, 16, 5723-5735). Later, Singh's research group at the University of Allahabad, India, achieved this type of reaction using only potassium persulfate (Synlett, 2018, 29, 2306-2310). Subsequently, Weng Jianquan (Tetrahedron Lett., 2018, 59, 2945-2949; CN 108727246) of Zhejiang University of Technology, Guan Zhi and He Yanhong (Adv. Synth. Catal., 2018, 360, 762-767) of Southwest University, Chen Xiaolan and Yu Bing (Chinese J. Catal., 2023, 46, 157-166) of Zhengzhou University used photocatalysis to achieve the arylmethylation reaction of N-methyl-N-alkylaniline on the C3 position of indole. However, the above synthesis method has some shortcomings: the use of metals usually leads to metal residues in the later stage; excessive use of peroxide compounds is prone to produce chemical waste; and the photocatalytic reaction device has high requirements and requires more than 10 watts of light to irradiate the reaction for 24 hours, resulting in low energy conversion rate. Although the patent published by Weng Jianquan of Zhejiang University of Technology embodies the C3 arylmethylation reaction of indole with N-methylaniline (CN 108727246), the published article does not mention it (Tetrahedron Lett., 2018, 59, 2945-2949), which may be caused by the difficulty in separating and purifying its products. In addition, there is only one report of C3 arylmethylated indole derivatives using N-methylaniline as raw material, and formaldehyde is required to provide additional methylene (J.Org.Chem.2024, 89, 10773-10784).Based on this, an efficient and green electrochemical synthesis route was developed to realize the aromatic methylation reaction of N-methyl-N-alkylaniline and N-methylaniline on the C3 position of indole, so as to obtain indole derivatives with potential biological activity. Summary of the invention

[0005] The main purpose of the present invention is to provide an electrochemical synthesis method for 4'-N-methylbenzyl-3-indole derivatives.

[0006] The technical solution adopted by the present invention is specifically as follows:

[0007] An electrochemical synthesis method of 4'-N-methylbenzyl-3-indole derivatives, the structural formula of the 4'-N-methylbenzyl-3-indole derivatives is shown in Formula I

[0008]

[0009] Wherein: R1, R3 and R5 are any one of hydrogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 perfluoroalkyl, halogen, C2-C6 alkylcarbonyl, C6-C12 aryl, benzyl, C2-C6 ester, C2-C8 alkenyl-containing substituent, C2-C8 alkynyl-containing substituent, C2-C10 heterocyclic group, silicon group, and amino group;

[0010] R2 and R4 are any one of hydrogen, amino, C1-C6 alkyl, C1-C6 perfluoroalkyl, C2-C6 alkylcarbonyl, C6-C12 aryl, benzyl, C2-C8 alkenyl-containing substituent, C2-C8 alkynyl-containing substituent, C2-C10 heterocyclic group, sulfonyl, and alkoxycarbonyl;

[0011] The synthesis method is shown in Formula II:

[0012]

[0013] In the formula, the preparation steps of compound I are:

[0014] S1. Compound II, compound III, electrolyte and additives are placed in an organic solvent, and after installing an anode and a cathode, a constant direct current is passed to react;

[0015] S2. After compound II disappears completely, removing the organic solvent from the reaction mixture under reduced pressure;

[0016] S3. Use silica gel column chromatography to elute to obtain compound I.

[0017] The molar ratio of the compound II to the compound III is II:III=1.0:2.0-10.0.

[0018] The anode is an electrode made of graphite sheet, graphite rod, mesh glassy carbon, glassy carbon, foamed carbon, platinum sheet or platinum wire.

[0019] The cathode is an electrode made of graphite sheet, graphite rod, carbon paper, carbon cloth, mesh glassy carbon, glassy carbon, various graphite felts, foamed carbon, platinum sheet, platinum wire, nickel, iron, stainless steel, aluminum, zinc, tin, titanium, lead, molybdenum, niobium or tantalum.

[0020] The electrolyte is a mixture of one or more of tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium perchlorate, tetrabutylammonium iodide, tetraethylammonium tetrafluoroborate, tetraethylammonium hexafluorophosphate, tetraethylammonium p-toluenesulfonate, sodium benzoate, lithium perchlorate, lithium bromide, tetraethylammonium chloride, tetrabutylammonium tetrafluoroborate, ammonium hexafluorophosphate, tetramethylammonium acetate, tetrabutylammonium hydrogen sulfate, tetraethylammonium perchlorate, and tetrabutylammonium chloride hydrate.

[0021] The additive is any one of ferrocene, triphenylamine, 2,2,6,6-tetramethylpiperidinoxide, bipyridine, and 2,6-di-tert-butyl-p-cresol.

[0022] The organic solvent is any one of benzene, xylene, ethyl chloride, ethylene dichloride, 1,2-dichloropropane, 1,4-dioxane, carbon tetrachloride, ethyl acetate, acetonitrile, dimethylformamide or dimethylacetamide.

[0023] The co-solvent is any one of acetic acid, propionic acid, butyric acid, dichloroacetic acid, difluoroacetic acid, trichloroacetic acid, isobutyric acid and pivalic acid.

[0024] The eluent used in the column chromatography is a mixture of petroleum ether and ethyl acetate, and the volume ratio V petroleum ether:V ethyl acetate=20:1-1:1.

[0025] The beneficial effects of the present invention are as follows: (1) The present invention provides an electrochemical synthesis method for 4'-N-methylbenzyl-3-indole derivatives, and can retain the active hydrogen in the N-methylphenyl fragment in the product.

[0026] (2) The preparation method of the present invention uses electric current as a traceless oxidant, has a high energy conversion rate, does not require a catalyst, has a small number of reaction steps, has readily available raw materials, has mild reaction conditions, is simple and safe to operate, has a wide range of substrate expansion, and has a high tolerance for compound functional groups. The product yield can reach up to 87%.

[0027] (3) The efficient and green synthesis method of the present invention uses N-methyl as an additional methylene source and generates an aromatic methylated product through an oxidative coupling tandem reaction, thereby avoiding the addition of other reagents to introduce methylene groups and can also prepare 4'-N-methylbenzyl-3-indole derivatives on a gram scale. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is the NMR spectrum (hydrogen spectrum) of the product Ⅰ-2 obtained in the example of the present invention;

[0029] Figure 2 This is the NMR spectrum (carbon spectrum) of the product Ⅰ-2 obtained in the example of the present invention;

[0030] Figure 3 This is the NMR spectrum (hydrogen spectrum) of the product Ⅰ-4 obtained in Example 1 of the present invention;

[0031] Figure 4 This is the NMR spectrum (carbon spectrum) of the product Ⅰ-4 obtained in the example of the present invention;

[0032] Figure 5 This is the NMR spectrum (hydrogen spectrum) of the product Ⅰ-6 obtained in the example of the present invention;

[0033] Figure 6 This is the NMR spectrum (carbon spectrum) of the product Ⅰ-6 obtained in the example of the present invention. DETAILED DESCRIPTION

[0034] The technical solution of the present invention is further described below with reference to the accompanying drawings and through specific embodiments:

[0035] The following is the best embodiment of the preparation of the compounds of the present invention. In all the following examples, the nuclear magnetic spectrum was detected by Bruker 500, and the instrument was obtained in CDCl3. The δ value is the internal standard relative value (CHCl3 calibration δ7.261H NMR and 77.1613CNMR. The high-resolution mass spectrum (HRMS) was obtained by a 4G quadrupole time-of-flight (QTof) mass spectrometer.

[0036] Example 1

[0037] The reaction formula of Example 1, the specific structures of the compounds II-1, III-1 and the product I-1 used are as follows. Experiments show that the preferred anode of the present invention is a platinum sheet, the preferred cathode is a graphite sheet, the preferred electrolyte is tetrabutylammonium tetrafluoroborate, the preferred co-solvent is acetic acid, the preferred direct current is 6 mA, the preferred organic solvent is dimethylformamide, the highest yield of the reaction product is 80%, the best raw material molar ratio is the molar ratio of compound II and compound III is II:III=1:5, wherein compound II should be an equivalent value, and the optimal reaction concentration is 0.06M.

[0038]

[0039] The specific experimental steps are: 35 mg (0.30 mmol, 1.0 equivalent) of compound II-1, 182 mg (1.5 mmol, 5.0 equivalent) of compound III-1 and 2.0 mL of acetic acid are dissolved in 3.0 mL of dimethylformamide, loaded with a graphite anode and a nickel cathode and replaced with a nitrogen atmosphere, and reacted at room temperature for 4 hours under a direct current of 6 mA. After the reaction, the reaction mixture is poured into a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate, and the collected organic phase is dehydrated with anhydrous sodium sulfate and then rotary evaporated under reduced pressure of a water pump to remove the organic solvent. The residue is chromatographed on a 200-300 mesh silica gel column with an eluent (volume ratio V petroleum ether: V ethyl acetate = 20:1 to 5:1) to obtain the compound shown in Ⅰ-1, and the product is identified by nuclear magnetic resonance (hydrogen spectrum, carbon spectrum) and high-resolution mass spectrometry.

[0040] ((1H-indol-3-yl)methyl)-N,N-dimethylaniline(54mg, Yield=72%, Rf=0.40 (PE / EA=5:1)) was isolated as a white solid.1H NMR (500MHz, CDCl3) δ7.92(s,1H),7.57(d,J=7.9Hz,1H),7.35(d,J=8.1Hz,1H),7.21–7.16(m 13C NMR (125MHz, CDCl3) δ149.21,136.57,129.59,129.40,127.65,122.29,122.02,11 9.36,119.34,116.85,113.17,111.11,41.10,30.63.HRMS(ESI)m / z:[M+H]+Calcd for C17H19N2 250.1470; found250.1472.

[0041] Example 2

[0042] The reaction formula of Example 2, the specific structures of the compounds II-2, III-1 and the product I-2 used are as follows. Experiments show that the preferred anode of the present invention is a platinum sheet, the preferred cathode is a graphite sheet, the preferred co-solvent is acetic acid, the preferred direct current is 6 mA, the preferred organic solvent is dimethylformamide, the highest yield of the reaction product is 87%, the best raw material molar ratio is the molar ratio of compound II and compound III is II:III=1:5, wherein compound II should be an equivalent value, and the optimal reaction concentration is 0.06M.

[0043]

[0044] The specific experimental steps are: 43mg (0.30mmol, 1.0 equivalent) of compound II-2, 182mg (1.5mmol, 5.0 equivalent) of compound III-1 and 2.0mL of acetic acid are dissolved in 3.0mL of dimethylformamide, loaded with a graphite anode and a nickel cathode and replaced with a nitrogen atmosphere, and reacted at room temperature for 4 hours under a direct current of 6 mA. After the reaction is completed, the reaction mixture is poured into a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate, and the collected organic phase is dehydrated with anhydrous sodium sulfate and then rotary evaporated under reduced pressure of a water pump to remove the organic solvent. The residue is chromatographed on a 200-300 mesh silica gel column with an eluent (volume ratio V petroleum ether: V ethyl acetate = 20:1 to 5:1) to obtain the compound shown in Ⅰ-2, and the product is identified by nuclear magnetic resonance (hydrogen spectrum, carbon spectrum).

[0045] 4-((1,2-dimethyl-1H-indol-3-yl)methyl)-N,N-dimethylaniline (73 mg, Yield=87%, Rf=0.50 (PE / EA=5:1)) was isolated as a white solid.1H NMR (500MHz, CDCl3) δ7.45(d,J=7.8Hz,1H),7.25(d,J=8.3Hz,1H),7.14(t,J=7.6Hz,1H),7.09(d,J=8.5Hz 13C NMR (125MHz, CDCl3) δ149.07,136.72,133.44,130.44,128.84,128.15,120 .53,118.82,118.54,113.19,110.60,108.53,41.12,29.66,29.40,10.52.

[0046] Example 3

[0047] The reaction formula of Example 3, the specific structures of the compounds II-3, III-1 and the product I-3 used are as follows. Experiments show that the preferred anode of the present invention is a platinum sheet, the preferred cathode is a graphite sheet, the preferred co-solvent is acetic acid, the preferred direct current is 6 mA, the preferred organic solvent is dimethylformamide, the highest yield of the reaction product is 50%, the best raw material molar ratio is the molar ratio of compound II and compound III is II:III=1:5, wherein compound II should be an equivalent value, and the optimal reaction concentration is 0.06M.

[0048]

[0049] The specific experimental steps are: 58 mg (0.30 mmol, 1.0 equivalent) of compound II-3, 182 mg (1.5 mmol, 5.0 equivalent) of compound III-1 and 2.0 mL of acetic acid are dissolved in 3.0 mL of dimethylformamide, loaded with a graphite anode and a nickel cathode and replaced with a nitrogen atmosphere, and reacted at room temperature for 7 hours under a direct current of 6 mA. After the reaction is completed, the reaction mixture is poured into a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The collected organic phase is dehydrated with anhydrous sodium sulfate and then the organic solvent is removed by rotary evaporation under reduced pressure of a water pump. The residue is chromatographed on a 200-300 mesh silica gel column with an eluent (volume ratio V petroleum ether: V ethyl acetate = 20:1 to 5:1) to obtain the compound shown in Ⅰ-3, and the product is identified by nuclear magnetic resonance (hydrogen spectrum, carbon spectrum).

[0050] N,N-dimethyl-4-((2-phenyl-1H-indol-3-yl)methyl)aniline (49mg, Yield=50%, Rf=0.30 (PE / EA=5:1)) was isolated as a brown oil.1H NMR(500MHz, CDCl3)δ8.19(s,1H),7.56–7.53(m,2H),7.48(d,J=7.9Hz,1H),7.46–7.42(m,2H),7.40(d,J=8.1Hz,1H),7.38 13C NMR (125MHz, CDCl3) δ148.02,136.14,135.35,133.09,129.68,129.05,128.97,1 27.92,127.75,122.41,119.80,119.79,114.21,111.71,110.89,41.73,29.52(1C is merged with other peaks).

[0051] Example 4

[0052] The reaction formula of Example 4, the specific structures of the compounds II-1, III-2 and the product I-4 used are as follows. Experiments show that the preferred anode of the present invention is a platinum sheet, the preferred cathode is a graphite sheet, the preferred co-solvent is acetic acid, the preferred direct current is 6 mA, the preferred organic solvent is dimethylformamide, the highest yield of the reaction product is 44%, the best raw material molar ratio is the molar ratio of compound II and compound III is II:III=1:5, wherein compound II should be an equivalent value, and the optimal reaction concentration is 0.06M.

[0053]

[0054] The specific experimental steps are: 35 mg (0.30 mmol, 1.0 equivalent) of compound II-1, 227 mg (1.5 mmol, 5.0 equivalent) of compound III-2 and 2.0 mL of acetic acid are dissolved in 3.0 mL of dimethylformamide, loaded with a graphite anode and a nickel cathode and replaced with a nitrogen atmosphere, and reacted at room temperature for 7 hours under a direct current of 6 mA. After the reaction, the reaction mixture is poured into a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The collected organic phase is dehydrated with anhydrous sodium sulfate and then the organic solvent is removed by rotary evaporation under reduced pressure of a water pump. The residue is chromatographed on a 200-300 mesh silica gel column with an eluent (volume ratio V petroleum ether: V ethyl acetate = 20:1 to 5:1) to obtain the compound shown in Ⅰ-4, and the product is identified by nuclear magnetic resonance (hydrogen spectrum, carbon spectrum) and high-resolution mass spectrometry.

[0055] 2-((4-((1H-indol-3-yl)methyl)phenyl)(methyl)amino)ethan-1-ol (37 mg, Yield=44%, Rf=0.30 (PE / EA=2:1)) was isolated as a brown oil.1H NMR(500MHz, CDCl3)δ8.00(s,1H),7.57(d,J=7.9Hz,1H),7.34(d,J=8.1Hz,1H),7.22–7.17(m,3H),7.12–7.08(m,1H),6.9 0–6.87(m,1H),6.78–6.74(m,2H),4.05(s,2H),3.78(t,J=5.6Hz,2H),3.42(t,J=5.6Hz,2H),2.92(s,3H),2.00(s,1H); 13C NMR (125MHz, CDCl3) δ148.61,136.56,130.33,129.48,127.56,122.31,121.97,119.28,1 19.27,116.53,113.64,111.15,60.08,55.90,38.97,30.60.HRMS(ESI)m / z:[M+H]+Calcd for C18H21N2O 281.1648; found281.1648.

[0056] Example 5

[0057] The reaction formula of Example 5, the specific structures of the compounds II-4, III-3 and the product I-5 used are as follows. Experiments show that the preferred anode of the present invention is a platinum sheet, the preferred cathode is a graphite sheet, the preferred electrolyte is tetrabutylammonium tetrafluoroborate, the preferred co-solvent is acetic acid, the preferred additive is 2,2,6,6-tetramethylpiperidinyl oxide, the preferred direct current is 6 mA, the preferred organic solvent is dimethylformamide, the maximum yield of the reaction product is 55%, the best raw material molar ratio is the molar ratio of compound II and compound III is II:III=1:5, wherein compound II should be an equivalent value, and the optimal reaction concentration is 0.06M.

[0058]

[0059] The specific experimental steps are: 39 mg (0.30 mmol, 1.0 equivalent) of compound II-4, 161 mg (1.5 mmol, 5.0 equivalent) of compound III-3, 49 mg of tetrabutylammonium tetrafluoroborate (nBu4NBF4, 0.15 mmol, 0.5 equivalent), 23 mg of 2,2,6,6-tetramethylpiperidinoxide (TEMPO, 0.15 mmol, 0.5 equivalent) and 2.0 mL of acetic acid are dissolved in 3.0 mL of dimethylformamide, and a graphite sheet anode and a nickel sheet cathode are loaded and replaced with a nitrogen atmosphere, and then reacted at room temperature under a direct current of 6 mA for 6 hours. After the reaction is completed, the reaction mixture is poured into a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate, and the collected organic phase is dehydrated with anhydrous sodium sulfate and then the organic solvent is removed by rotary evaporation under reduced pressure of a water pump. The residue was purified by column chromatography on 200-300 mesh silica gel with an eluent (volume ratio V petroleum ether: V ethyl acetate = 20:1-5:1) to obtain the compound Ⅰ-5, which was identified by NMR (hydrogen spectrum, carbon spectrum).

[0060] N-methyl-4-((2-methyl-1H-indol-3-yl)methyl)aniline (41mg, Yield=55%, Rf=0.40 (PE / EA=5:1)) was isolated as a brown oil.1H NMR(500MHz, CDCl3)δ7.78(s,1H),7.41(d,J=7.8Hz,1H),7.26(d,J=8.0Hz,1H),7.10–7.0 6(m,1H),7.05–6.99(m,3H),6.53–6.49(m,2H),3.97(s,2H),2.79(s,3H),2.38(s,3H); 13C NMR (125MHz, CDCl3) δ147.47,135.40,131.50,130.64,129.12,129.06,120.96,119.2 4,118.62,112.69,111.42,110.15,31.16,29.27,11.94.HRMS(ESI)m / z:[M+H]+Calcd for C17H19N2 251.1543; found251.1541.

[0061] Example 6

[0062] The reaction formula of Example 6, the specific structures of the compounds II-1, III-4 and the product I-6 used are as follows. Experiments show that the preferred anode of the present invention is a platinum sheet, the preferred cathode is a graphite sheet, the preferred electrolyte is tetrabutylammonium tetrafluoroborate, the preferred co-solvent is acetic acid, the preferred additive is 2,2,6,6-tetramethylpiperidinoxide, the preferred direct current is 6 mA, the preferred organic solvent is dimethylformamide, the maximum yield of the reaction product is 40%, the best raw material molar ratio is the molar ratio of compound II and compound III is II:III=1:5, wherein compound II should be an equivalent value, and the optimal reaction concentration is 0.06M.

[0063]

[0064] The specific experimental steps are: 35 mg (0.30 mmol, 1.0 equivalent) of compound II-1, 278 mg (1.5 mmol, 5.0 equivalent) of compound III-4, 49 mg of tetrabutylammonium tetrafluoroborate (nBu4NBF4, 0.15 mmol, 0.5 equivalent), 23 mg of 2,2,6,6-tetramethylpiperidinoxide (TEMPO, 0.15 mmol, 0.5 equivalent) and 2.0 mL of acetic acid are dissolved in 3.0 mL of dimethylformamide, and a graphite sheet anode and a nickel sheet cathode are loaded and replaced with a nitrogen atmosphere, and then reacted at room temperature under a direct current of 6 mA for 11 hours. After the reaction is completed, the reaction mixture is poured into a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate, and the collected organic phase is dehydrated with anhydrous sodium sulfate and then the organic solvent is removed by rotary evaporation under reduced pressure of a water pump. The residue was purified by column chromatography on 200-300 mesh silica gel with an eluent (volume ratio V petroleum ether: V ethyl acetate = 20:1-5:1) to obtain compound Ⅰ-6, which was identified by NMR (hydrogen spectrum, carbon spectrum) and high-resolution mass spectrometry.

[0065] 4-((1H-indol-3-yl)methyl)-3-bromo-N-methylaniline.Compound 3as(38mg,Yield=40%,Rf=0.20(PE / EA=5:1)) was isolated as a black oil.1H NMR (500MHz, CDCl3) δ7.95 (s, 1H), 7.57 (d, J = 7.3Hz, 1H), 7.36 (d, J = 8.1Hz, 1H), 7.21–7.17 (m, 1H), 7.12–7.08 (m, 1H), 6. 13C NMR (125MHz, CDCl3) δ148.76,136.53,130.99,128.64,127.58,125.27,122.72,122.08,11 9.44,119.35,115.88,115.32,112.29,111.17,30.92,30.90.HRMS(ESI)m / z:[M+H]+Calcd for C16H16BrN2 315.0491; found 315.0488.

[0066] Example 7

[0067] The reaction formula of Example 7, the structures of the compounds II-1, III-1 and the product I-1 used are as follows. Experiments show that the reaction system can be applied to gram-scale reactions.

[0068]

[0069] The specific experimental steps are: 1.17g (10mmol, 1.0 equivalent) of compound II-1, 6.05g (50mmol, 5.0 equivalent) of compound III-1 and 30mL of acetic acid are dissolved in 60mL of dimethylformamide, and a graphite sheet anode and a nickel sheet cathode are loaded and replaced with a nitrogen atmosphere, and then reacted at room temperature for 65 hours under a direct current of 12 mA. After the reaction is completed, the reaction mixture is poured into a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The collected organic phase is dehydrated with anhydrous sodium sulfate and then the organic solvent is removed by rotary evaporation under reduced pressure of a water pump. The residue is chromatographed with 200-300 mesh silica gel and an eluent (volume ratio V petroleum ether: V ethyl acetate = 20:1 to 5:1) to obtain 1.36 grams of compound Ⅰ-1, with a yield of 54%.

[0070] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.

[0071] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. An electrochemical synthesis method of 4'-N-methylbenzyl-3-indole derivatives, wherein the structural formula of the 4'-N-methylbenzyl-3-indole derivatives is as shown in Formula I: in: R1, R3 and R5 are any one of hydrogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 perfluoroalkyl, halogen, C2-C6 alkylcarbonyl, C6-C12 aryl, benzyl, C2-C6 ester, C2-C8 alkenyl-containing substituent, C2-C8 alkynyl-containing substituent, C2-C10 heterocyclic group, silicon group and amino group; R2 and R4 are any one of hydrogen, amino, C1-C6 alkyl, C1-C6 perfluoroalkyl, C2-C6 alkylcarbonyl, C6-C12 aryl, benzyl, C2-C8 alkenyl-containing substituent, C2-C8 alkynyl-containing substituent, C2-C10 heterocyclic group, sulfonyl, and alkoxycarbonyl; It is characterized in that the synthesis method is as shown in Formula II: In the formula, the preparation steps of compound I are: S1. Compound II, compound III, electrolyte and additives are placed in an organic solvent, and after installing an anode and a cathode, a constant direct current is passed to react; S2. After compound II disappears completely, removing the organic solvent from the reaction mixture under reduced pressure; S3. Use silica gel column chromatography to elute to obtain compound I.

2. The electrochemical synthesis method of 4'-N-methylbenzyl-3-indole derivatives according to claim 1, characterized in that: The molar ratio of the compound II to the compound III is II:III=1.0:2.0-10.

0.

3. The electrochemical synthesis method of 4'-N-methylbenzyl-3-indole derivatives according to claim 1, characterized in that: The anode is an electrode made of graphite sheet, graphite rod, mesh glassy carbon, glassy carbon, foamed carbon, platinum sheet or platinum wire.

4. The electrochemical synthesis method of 4'-N-methylbenzyl-3-indole derivatives according to claim 1, characterized in that: The cathode is an electrode made of graphite sheet, graphite rod, carbon paper, carbon cloth, mesh glassy carbon, glassy carbon, various graphite felts, foamed carbon, platinum sheet, platinum wire, nickel, iron, stainless steel, aluminum, zinc, tin, titanium, lead, molybdenum, niobium or tantalum.

5. The electrochemical synthesis method of 4'-N-methylbenzyl-3-indole derivatives according to claim 1, characterized in that: The electrolyte is a mixture of one or more of tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium perchlorate, tetrabutylammonium iodide, tetraethylammonium tetrafluoroborate, tetraethylammonium hexafluorophosphate, tetraethylammonium p-toluenesulfonate, sodium benzoate, lithium perchlorate, lithium bromide, tetraethylammonium chloride, tetrabutylammonium tetrafluoroborate, ammonium hexafluorophosphate, tetramethylammonium acetate, tetrabutylammonium hydrogen sulfate, tetraethylammonium perchlorate, and tetrabutylammonium chloride hydrate.

6. The electrochemical synthesis method of 4'-N-methylbenzyl-3-indole derivatives according to claim 1, characterized in that: The additive is any one of ferrocene, triphenylamine, 2,2,6,6-tetramethylpiperidinoxide, bipyridine, and 2,6-di-tert-butyl-p-cresol.

7. The electrochemical synthesis method of 4'-N-methylbenzyl-3-indole derivatives according to claim 1, characterized in that: The organic solvent is any one of benzene, xylene, ethyl chloride, ethylene dichloride, 1,2-dichloropropane, 1,4-dioxane, carbon tetrachloride, ethyl acetate, acetonitrile, dimethylformamide or dimethylacetamide.

8. The electrochemical synthesis method of 4'-N-methylbenzyl-3-indole derivatives according to claim 1, characterized in that: The co-solvent is any one of acetic acid, propionic acid, butyric acid, dichloroacetic acid, difluoroacetic acid, trichloroacetic acid, isobutyric acid and pivalic acid.

9. The electrochemical synthesis method of 4'-N-methylbenzyl-3-indole derivatives according to claim 1, characterized in that: The eluent used in the column chromatography is a mixture of petroleum ether and ethyl acetate, and the volume ratio V petroleum ether:V ethyl acetate=20:1-1:1.

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