CN115725986A

CN115725986A - Method for electrochemically synthesizing substituted indole by gamma-hydroxylamine continuous flow under microscale

Info

Publication number: CN115725986A
Application number: CN202211590532.6A
Authority: CN
Inventors: 郭凯; 袁成成; 刘成扣; 卢熠; 管文静; 黄祥兴; 姚逸飞; 刘冠汝
Original assignee: Nanjing Tech University
Current assignee: Nanjing Tech University
Priority date: 2022-12-12
Filing date: 2022-12-12
Publication date: 2023-03-03

Abstract

The invention discloses a method for electrochemically synthesizing substituted indole by gamma-hydroxylamine continuous flow under microscale, which comprises the steps of dissolving a compound shown in a formula 1 in a solvent to be used as a reaction solution A; mixing an organic additive, an organic electrolyte and a solvent to obtain a reaction solution B; respectively pumping the reaction liquid A and the reaction liquid B into a micro mixer at the same time, uniformly mixing, and then feeding the mixture into a micro-channel reactor with a cathode and an anode for continuous electrolytic reaction; and collecting the reaction liquid flowing out of the microchannel reactor to obtain the substituted indole shown in the formula 2. The invention combines the electric synthesis method with the micro-flow field continuous flow synthesis reaction technology, and the continuous flow electrochemical synthesis of the substituted indole greatly shortens the reaction time and improves the conversion rate of the reaction; compared with the traditional reaction method, the method does not need alkali and toxic and harmful substances, and is more green and efficient. Compared with the traditional reaction mode, the method has excellent amplification result, can realize continuous production, and has good industrial utilization value.

Description

Method for electrochemically synthesizing substituted indole by gamma-hydroxylamine continuous flow under microscale

Technical Field

The invention belongs to the field of medicinal chemistry and fine chemistry synthesis, and particularly relates to a method for synthesizing substituted indole by gamma-hydroxylamine continuous flow electrochemistry under microscale.

Background

The electrochemical synthesis method is to connect a positive electrode and a negative electrode into an electrolyte solution to make the reaction substance particles lose electrons in the solution on the surface of the anode, which is an oxidation reaction; in the cathode solution, the reactive species particles combine with electrons, which is a reduction reaction. Electrochemistry can be divided into two categories, according to its oxidation mechanism: one is direct oxidation, where the reactant species is oxidized by losing electrons directly at the anode; the second is indirect oxidation, which is to generate a catalyst on the anode, which has a strong oxidizing power, and then to separate the intermediate from the reactant, thereby oxidizing it. The process has the advantages of small occupied area and convenient operation, but the reaction yield is low, and the process is easily influenced by various factors such as pH value, electrode materials, electrolytes and the like.

The micro-flow field continuous flow electrochemical synthesis reaction technology can improve the mass and heat transfer efficiency and the reaction rate by 2-3 orders of magnitude and reduce the reaction online volume by thousands of times through the micro-scale effect, and improves the reaction selectivity and reduces the side reaction through continuous flow and low back mixing, thereby effectively realizing the greening of the chemical process.

The microchannel is used as a flow unit of the electrochemical reactor, so that the ion migration distance is greatly shortened, the Joule heat of the reaction is reduced, and the supported electrolyte can be removed from the reaction system. In addition, the electric field in microchannels equipped with parallel electrodes is more uniform, and the short distance between the electrodes results in a stable internal laminar flow, thereby improving control over the reactant contact sequence. The combination of the electrosynthesis method and the microfluidic continuous flow electrochemical synthesis reaction technology is used as an important component of a flow chemical system, and has great application potential in the chemical industry. Advantages of electrosynthesis microreactors include atomic economy, green and safe processing, and ease of scale-up, which is considered to be a common area for the realization of the fields of chemistry and chemical engineering. The distance between electrodes is reduced, the area of the electrodes is increased, the ion transport resistance is effectively reduced, controllable electrosynthesis is realized, the defects of the traditional batch reactor are overcome, and the industrialization of electrosynthesis technology can be promoted.

Disclosure of Invention

The invention aims to: the invention aims to solve the technical problem of the prior art, and provides a method for electrochemically synthesizing substituted indole by gamma-hydroxylamine continuous flow at a microscale so as to solve the problems of low reaction efficiency and incapability of realizing large-scale amplification reaction in the prior art.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

a method for continuous flow electrochemical synthesis of substituted indole from gamma-hydroxylamine at microscale comprises the following steps:

(1) Dissolving a compound shown in a formula 1 in a solvent to obtain a reaction solution A; mixing an organic additive, an organic electrolyte and a solvent to obtain a reaction solution B;

(2) Respectively pumping the reaction liquid A and the reaction liquid B in the step (1) into a micro mixer at the same time, uniformly mixing, and then feeding the mixture into a micro-channel reactor with a cathode and an anode for continuous electrolytic reaction;

(3) Collecting the reaction liquid flowing out of the microchannel reactor in the step (2) to obtain the substituted indole shown in the formula 2;

the above reaction formula is as follows:

wherein R is ¹ Selected from electron donating group hydrogen, alkyl with 1-4C, or substituted phenyl with electron donating group hydrogen, methyl and methoxyl;

R ² selected from electron-donating group hydrogen, alkyl with 1-4C, substituted phenyl with electron-withdrawing group halogen, or substituted phenyl with electron-donating group hydrogen, methyl and methoxyl;

r is selected from alkyl with 1-4C, alkyl with electron-donating group hydrogen, alkyl with 1-4C, thiophene, substituted phenyl of methoxyl, or substituted phenyl with electron-withdrawing group halogen.

Specifically, in the step (1), the organic additive is selected from one or a combination of more than two of trifluoroacetic acid, methanesulfonic acid, acetic acid and p-toluenesulfonic acid; preferably acetic acid or p-toluenesulfonic acid; further preferred is p-toluenesulfonic acid.

In the step (1), the organic electrolyte is selected from one or a combination of more than two of tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroiodide and tetrabutylammonium tetrafluoroperchlorate; preferably one or a combination of more than two of tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate and lithium perchlorate; further preferably tetrabutylammonium hexafluorophosphate or tetrabutylammonium tetrafluoroborate; still more preferred is tetrabutylammonium tetrafluoroborate.

In the step (1), the solvent is selected from any one or the combination of more than two of dichloroethane, N-dimethylformamide, dimethyl sulfoxide, trifluoroethanol, acetonitrile, hexafluoroisopropanol, trichloroethylene or N, N-dimethylaniline and tetrahydrofuran; preferably any one or the combination of more than two of dimethyl sulfoxide, trifluoroethanol, acetonitrile, hexafluoroisopropanol, trichloroethylene, N-dimethylaniline and tetrahydrofuran; more preferably, it is any one or a combination of two or more of trifluoroethanol, acetonitrile and hexafluoroisopropanol; further preferred is a mixed solution of trifluoroethanol and acetonitrile in a volume ratio of 3.5.

Specifically, in the step (2), the reaction molar ratio of the compound of formula 1 to the organic additive is 1; the molar ratio of the compound of formula 1 to the organic electrolyte is 1.

Specifically, in the step (2), the concentration of the compound of formula 1 in the reaction solution A is 0.04-0.16 mmol/mL, preferably 0.06mmol/mL; the concentration of the organic additive in the reaction liquid B is 0.06-0.24 mmol/mL, preferably 0.09mmol/mL; the concentration of the organic electrolyte in the reaction liquid B is 0.04-0.16 mmol/mL, preferably 0.06mmol/mL; pumping the reaction solution A and the reaction solution B into a micro mixer at the same flow rate of 0.1-0.3 mL/min for uniform mixing.

Specifically, the micro mixer adopts a T-shaped mixer; the injection pumps of the reaction liquid A and the reaction liquid B are connected to the front end of the T-shaped mixer in a parallel mode, and the rear end of the T-shaped mixer is connected with the microchannel reactor;

the microchannel reactor takes a graphite plate as an anode and a platinum sheet plate as a cathode, and an electrochemical micro-reaction pipeline is arranged between the anode plate and the cathode plate; the distance between the two electrode plates is 0.5-2 mm, and the height of the electrode is 2-6 mm; the length of the electrochemical micro-reaction pipeline is 400-800 mm, and the volume is 0.33-9 mL.

Specifically, the current intensity in the microchannel reactor is 20-100 mA, preferably 20-60 mA, and more preferably 50mA; the reaction time of the reaction solution in the microchannel reactor is 5 to 15 minutes, preferably 10 minutes.

Further, in the step (3), the effluent reaction solution is extracted to obtain an organic phase, and then the organic phase is concentrated and subjected to column chromatography to obtain a pure product of the substituted indole.

Preferably, the extraction is carried out by using ethyl acetate and saturated aqueous sodium chloride solution;

the column chromatography adopts a silica gel column, and an eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate according to the volume ratio of 1.

Has the beneficial effects that:

(1) The invention combines the electrosynthesis method with the micro-flow field continuous flow synthesis reaction technology, and the substituted indole is electrochemically synthesized by the gamma-hydroxylamine continuous flow under the microscale, so that the reaction time is greatly shortened, the conversion rate of the reaction is improved, the operation is simple, and the safety factor is high; compared with the traditional reaction method, the method does not need alkali and toxic and harmful substances, and is more green and efficient.

(2) Compared with the traditional electric reaction device, the method can separate the target product from the reaction system in time, and avoid the further electrolysis of the final product, thereby improving the selectivity of the reaction and the quality of the product.

(3) Compared with the traditional reaction mode, the method has excellent amplification result, can realize continuous production, and has good industrial utilization value.

Drawings

The foregoing and/or other advantages of the invention will become further apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings.

FIG. 1 is a reaction scheme for the continuous flow electrochemical synthesis of substituted indoles of the present invention.

FIG. 2 is a schematic diagram of a microchannel reactor apparatus used in the present invention.

FIG. 3 is a NMR spectrum of product 2a of example 1.

FIG. 4 is a NMR carbon spectrum of product 2a of example 1.

FIG. 5 is a NMR spectrum of product 2b of example 2.

FIG. 6 is a NMR carbon spectrum of product 2b of example 2.

FIG. 7 is a NMR spectrum of product 2c of example 3.

FIG. 8 is a NMR carbon spectrum of product 2c of example 3.

FIG. 9 is a NMR spectrum of product 2d of example 4.

FIG. 10 is a NMR carbon spectrum of product 2d of example 4.

FIG. 11 is a NMR spectrum of product 2e of example 5.

FIG. 12 is a NMR carbon spectrum of product 2e of example 5.

FIG. 13 is a NMR spectrum of product 2f of example 6.

FIG. 14 is a NMR carbon spectrum of product 2f of example 6.

FIG. 15 is a NMR chart of 2g of the product of example 7.

FIG. 16 is a NMR carbon spectrum of 2g of the product of example 7.

FIG. 17 is a NMR spectrum of product 2h of example 8.

FIG. 18 is the NMR carbon spectrum of product 2h from example 8.

FIG. 19 is a NMR spectrum of product 2i in example 9.

FIG. 20 is a NMR carbon spectrum of product 2i of example 9.

FIG. 21 is a NMR spectrum of product 2j of example 10.

FIG. 22 is a NMR carbon spectrum of product 2j of example 10.

FIG. 23 is a NMR spectrum of product 2k in example 11.

FIG. 24 is a NMR carbon spectrum of product 2k from example 11.

FIG. 25 is a NMR spectrum of 2m, a product of example 12.

FIG. 26 is a NMR carbon spectrum of 2m, the product of example 12.

FIG. 27 is a NMR spectrum of product 2n in example 13.

FIG. 28 is a NMR carbon spectrum of product 2n of example 13.

Detailed Description

The invention will be better understood from the following examples.

As shown in FIGS. 1 and 2, the microchannel reactor device used in the present invention comprises a syringe pump, a T-type mixer and a microchannel reactor. The injection pumps of the reaction liquid A and the reaction liquid B are connected to the front end of the T-shaped mixer in a parallel mode, and the rear end of the T-shaped mixer is connected with the microchannel reactor.

The synthesis steps of the invention are as follows:

(3) And (3) collecting the reaction liquid flowing out of the microchannel reactor in the step (2), and purifying to obtain the substituted indole shown in the formula 2.

The invention synthesizes 13 substituted indole compounds shown in the following table 1 by the method.

TABLE 1

Example 1

Dissolving N- (2- (1-hydroxy-1-phenylethyl) phenyl) cyclopropanesulfonamide (95.1mg, 0.3mmol,1 equivalent) in 5ml of ACN/TCE (6.5 + 3.5) mixed solvent to obtain reaction liquid A; p-toluenesulfonic acid (77.5mg, 0.45mmol,1.5 equiv.) and tetrabutylammonium tetrafluoroborate (987.8mg, 0.3mmol,1 equiv.) were dissolved in 5ml of ACN/TCE (6.5 + 3.5) to obtain a reaction solution B. Injecting the reaction solution A and the reaction solution B at 70 ℃ at an injection flow rate of 0.1mL/min, respectively, and applying a current of 50mA; the reaction volume of the microchannel reactor is V =2mL, and the reaction time is 10min; after one cycle of reaction in the microchannel reactor, the reaction liquid was collected and the solvent was removed in vacuo. The product was separated with petroleum ether and ethyl acetate 10 eluent and dried in vacuo for 4h. Product 2a conversion was 84%.

The nmr hydrogen spectrum of the product 2a is shown in fig. 3, and the nmr carbon spectrum is shown in fig. 4.

1H NMR(400MHz,DMSO-d6)δ7.98(dt,J＝8.3,1.0Hz,1H),7.91(dt,J＝7.8,1.0Hz,1H),7.86(s,1H),7.77-7.72(m,2H),7.54-7.48(m,2H),7.48-7.44(m,1H),7.44-7.37(m,2H),3.18-3.10(m,1H),1.34-1.28(m,2H),1.14-1.05(m,2H).13C NMR(101MHz,DMSO-d6)δ135.32,132.64,129.03,128.14,127.65,127.44,124.88,123.88,123.62,121.75,120.28,113.53,31.01,5.82；HRMS(EI-TOF)Calcd for C17H15NO2S[M]+:297.0818；found:297.0818.

Example 2

Dissolving N- (2- (2-hydroxyhex-2-yl) phenyl) -4-methylbenzenesulfonamide (104.1mg, 0.3mmol,1 equivalent) in 5ml of mixed solvent of ACN/TCE (6.5 + 3.5) to obtain reaction liquid A; p-toluenesulfonic acid (77.5mg, 0.45mmol,1.5 equiv.) and tetrabutylammonium tetrafluoroborate (987.8mg, 0.3mmol,1 equiv.) were dissolved in 5ml of ACN/TCE (6.5 + 3.5) to obtain a reaction solution B. Injecting the reaction liquid A and the reaction liquid B at 70 ℃ at an injection flow rate of 0.1mL/min respectively; the applied current was 50mA; the reaction volume of the microchannel reactor is V =2mL, and the reaction time is 10min; after one cycle of reaction in the microchannel reactor, the reaction liquid was collected and the solvent was removed in vacuo. The product was separated with petroleum ether and ethyl acetate 10 eluent and dried in vacuo for 4h. Product 2b conversion was 82%.

The nmr hydrogen spectrum of the product 2b is shown in fig. 5, and the nmr carbon spectrum is shown in fig. 6.

1H NMR(400MHz,DMSO-d6)δ8.08(d,J＝7.8Hz,1H),7.64(d,J＝8.4Hz,2H),7.49(d,J＝6.6Hz,1H),7.38-7.26(m,4H),3.01(t,J＝7.4Hz,2H),2.32(s,3H),2.17(s,3H),1.69(dt,J＝15.1,7.6Hz,2H),0.96(t,J＝7.4Hz,3H)；13C NMR(101MHz,DMSO-d6)δ145.03,136.82,135.76,134.89,131.07,130.14,126.01,124.27,123.63,118.84,117.04,114.55,27.59,23.41,20.98,13.60,8.73；HRMS(EI-TOF)Calcd for C19H21NO2S[M]+:327.1288；found:327.1299.

Example 3

Dissolving N- (2- (1-hydroxy-2- (4-methoxyphenyl) -1-phenylethyl) phenyl) -4-methylbenzenesulfonamide (141.9mg, 0.3mmol and 1 equivalent) in 5ml of mixed solvent of ACN/TCE (6.5 + 3.5) to obtain reaction liquid A; p-toluenesulfonic acid (77.5mg, 0.45mmol,1.5 equiv.) and tetrabutylammonium tetrafluoroborate (987.8mg, 0.3mmol,1 equiv.) were dissolved in 5ml of ACN/TCE (6.5 + 3.5) to obtain a reaction solution B. Injecting the reaction liquid A and the reaction liquid B at 70 ℃ at an injection flow rate of 0.1mL/min respectively; the applied current was 50mA; the reaction volume of the microchannel reactor is V =2mL, and the reaction time is 10min; after one cycle of reaction in the microchannel reactor, the reaction liquid was collected and the solvent was removed in vacuo. Separate with petroleum ether and ethyl acetate 10 eluent, and dry the resulting product in vacuo for 4h. Product 2c conversion was 80%.

The nmr hydrogen spectrum of product 2c is shown in fig. 7, and the nmr carbon spectrum is shown in fig. 8.

1H NMR(400MHz,DMSO-d6)δ8.24(d,J＝8.4Hz,1H),7.47–7.41(m,1H),7.40-7.37(m,3H),7.34-7.23(m,6H),7.22-7.16(m,2H),7.14 -7.09(m,2H),6.92 -6.86(m,2H),3.78(s,3H),2.29(s,3H)；13C NMR(101MHz,DMSO-d6)δ159.40,145.20,136.62,134.39,133.06,132.10,129.93,129.75,129.63,128.44,127.21,126.47,125.29,124.51,123.72,122.53,119.64,115.57,112.91,55.12,21.07；HRMS(EI-TOF)Calcd for C28H23NO3S[M]+:453.1393；found:453.1387.

Example 4

Dissolving N- (2- (1-hydroxy-1- (m-tolyl) ethyl) phenyl) -4-methylbenzenesulfonamide (114.3mg, 0.3mmol,1 equivalent) in 5ml of mixed solvent of ACN/TCE (6.5 + 3.5) to obtain reaction liquid A; p-toluenesulfonic acid (77.5mg, 0.45mmol,1.5 equiv.) and tetrabutylammonium tetrafluoroborate (987.8mg, 0.3mmol,1 equiv.) were dissolved in 5ml of ACN/TCE (6.5 + 3.5) to obtain a reaction solution B. Injecting the reaction liquid A and the reaction liquid B at 70 ℃ at an injection flow rate of 0.1mL/min respectively; the applied current was 50mA; the reaction volume of the microchannel reactor is V =2mL, and the reaction time is 10min; after one cycle of reaction in the microchannel reactor, the reaction liquid was collected and the solvent was removed in vacuo. The product was separated with petroleum ether and ethyl acetate 10 eluent and dried in vacuo for 4h. Product 2d conversion 81%.

The nmr hydrogen spectrum of the product 2d is shown in fig. 9, and the nmr carbon spectrum is shown in fig. 10.

1H NMR(400MHz,DMSO-d6)δ8.09(s,1H),8.06(d,J＝8.3Hz,1H),7.99(d,J＝8.4Hz,2H),7.87(d,J＝7.8Hz,1H),7.58(s,1H),7.54(d,J＝7.7Hz,1H),7.48-7.36(m,5H),7.25(d,J＝7.5Hz,1H),2.43(s,3H),2.36(s,3H)；13C NMR(101MHz,DMSO-d6)δ145.59,138.24,134.79,134.02,132.24,130.28,128.86,128.49,128.24,128.21,126.89,125.06,124.71,123.90,123.53,123.07,120.46,113.50,21.03；HRMS(EI-TOF)Calcd for:C22H19NO2S[M]+:361.1131；found:361.1136.

Example 5

Dissolving N- (2- (1- (4-chlorophenyl) -1-hydroxyethyl) phenyl) -4-methylbenzenesulfonamide (120.3mg, 0.3mmol,1 equivalent) in 5ml of mixed solvent of ACN/TCE (6.5 + 3.5) to obtain reaction liquid A; p-toluenesulfonic acid (77.5mg, 0.45mmol,1.5 equiv.) and tetrabutylammonium tetrafluoroborate (987.8mg, 0.3mmol,1 equiv.) were dissolved in 5ml of ACN/TCE (6.5 + 3.5) to obtain a reaction solution B. Injecting the reaction liquid A and the reaction liquid B at the injection flow rate of 0.1mL/min respectively at 70 ℃; the applied current was 50mA; the reaction volume of the microchannel reactor is V =2mL, and the reaction time is 10min; after one cycle of reaction in the microchannel reactor, the reaction liquid was collected and the solvent was removed in vacuo. The product was separated with petroleum ether and ethyl acetate 10 eluent and dried in vacuo for 4h. Product 2e conversion was 79%.

The nmr hydrogen spectrum of the product 2e is shown in fig. 11, and the nmr carbon spectrum is shown in fig. 12.

1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),8.03-7.99(m,1H),7.98-7.93(m,2H),7.84-7.73(m,1H),7.57-7.50(m,2H),7.47-7.37(m,2H),7.37-7.32(m,1H),2.31(s,3H)；13C NMR(101MHz,DMSO-d6)δ145.70,134.73,133.97,132.14,131.29,130.32,129.40,128.97,128.14,126.95,125.22,124.13,124.02,121.64,120.29,113.53,21.02；HRMS(EI-TOF)Calcd for C21H16ClNO2S[M]+:381.0585；found:381.0593.

Example 6

Dissolving 4- (tert-butyl) -N- (2- (1-hydroxy-1-phenylethyl) phenyl) benzenesulfonamide (122.7mg, 0.3mmol,1 equivalent) in 5ml of mixed solvent of ACN/TCE (6.5 + 3.5) to obtain reaction solution A; p-toluenesulfonic acid (77.5mg, 0.45mmol,1.5 equiv.) and tetrabutylammonium tetrafluoroborate (987.8mg, 0.3mmol,1 equiv.) were dissolved in 5ml of ACN/TCE (6.5 + 3.5) to obtain a reaction solution B. Injecting the reaction liquid A and the reaction liquid B at 70 ℃ at an injection flow rate of 0.1mL/min respectively; the applied current was 50mA; the reaction volume of the microchannel reactor is V =2mL, and the reaction time is 10min; after one cycle of reaction in the microchannel reactor, the reaction liquid was collected and the solvent was removed in vacuo. Separate with petroleum ether and ethyl acetate 10 eluent, and dry the resulting product in vacuo for 4h. Product 2f conversion was 83%.

The nmr hydrogen spectrum of the product 2f is shown in fig. 13, and the nmr carbon spectrum is shown in fig. 14.

1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),8.05(d,J＝8.3Hz,1H),8.02-7.98(m,2H),7.84(d,J＝7.9Hz,1H),7.75-7.68(m,2H),7.65-7.58(m,2H),7.51-7.47(m,2H),7.46-7.38(m,3H),1.25(s,9H).13C NMR(101MHz,DMSO-d6)δ157.96,134.77,134.26,132.33,129.00,128.38,127.66,127.59,126.85,126.81,125.16,123.95,123.61,122.84,120.45,113.47,35.05,30.52；HRMS(EI-TOF)Calcd for C24H23NO2S[M]+:389.1444；found:389.1438.

Example 7

Dissolving N- (2- (1-hydroxy-1-phenethyl) phenyl) -4-iodobenzenesulfonamide (143.7mg, 0.3mmol,1 equivalent) in 5ml of a mixed solvent of ACN/TCE (6.5 + 3.5) to obtain a reaction solution A; p-toluenesulfonic acid (77.5mg, 0.45mmol,1.5 eq), tetrabutylammonium tetrafluoroborate (987.8mg, 0.3mmol,1 eq) were dissolved in 5ml ACN/TCE (6.5 + 3.5) to afford reaction solution B. Respectively injecting the reaction liquid A and the reaction liquid B at the flow rate of 0.1mL/min at 70 ℃; the applied current was 50mA; the reaction volume of the microchannel reactor is V =2mL, and the reaction time is 10min; after one cycle of reaction in the microchannel reactor, the reaction liquid was collected and the solvent was removed in vacuo. The product was separated with petroleum ether and ethyl acetate 10 eluent and dried in vacuo for 4h. Product 2g conversion 80%.

The NMR spectrum of the product 2g is shown in FIG. 15, and the NMR spectrum is shown in FIG. 16.

1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),8.02-8.00(m,1H),7.98-7.92(m,2H),7.86-7.78(m,3H),7.74-7.68(m,2H),7.53-7.46(m,2H),7.46-7.29(m,3H)；13C NMR(101MHz,DMSO-d6)δ138.80,136.33,134.76,132.22,129.02,128.56,128.33,127.74,127.71,125.33,124.21,123.59,123.48,120.53,113.52,103.95；HRMS(EI-TOF)Calcd for C20H14INO2S[M]+:458.9784；found:458.9787.

Example 8

Dissolving N- (2- (1-hydroxy-1-phenylethyl) phenyl) thiophene-2-sulfonamide (107.7mg, 0.3mmol,1 equivalent) in 5ml of mixed solvent of ACN/TCE (6.5 + 3.5) to obtain reaction liquid A; p-toluenesulfonic acid (77.5mg, 0.45mmol,1.5 equiv.) and tetrabutylammonium tetrafluoroborate (987.8mg, 0.3mmol,1 equiv.) were dissolved in 5ml of ACN/TCE (6.5 + 3.5) to obtain a reaction solution B. Injecting the reaction liquid A and the reaction liquid B at the injection flow rate of 0.1mL/min respectively at 70 ℃; the applied current was 50mA; the reaction volume of the microchannel reactor is V =2mL, and the reaction time is 10min; after one cycle of reaction in the microchannel reactor, the reaction liquid was collected and the solvent was removed in vacuo. Separate with petroleum ether and ethyl acetate 10 eluent, and dry the resulting product in vacuo for 4h. The 2h conversion of the product was 77%.

The NMR spectrum of the product 2h is shown in FIG. 17, and the NMR spectrum is shown in FIG. 18.

1H NMR(400MHz,DMSO-d6)δ8.07-7.95(m,4H),7.85(dt,J＝7.9,1.0Hz,1H),7.77-7.67(m,2H),7.55-7.44(m,3H),7.43-7.34(m,2H),7.18(dd,J＝5.0,3.9Hz,1H)；13C NMR(101MHz,DMSO-d6)δ136.42,136.24,134.85,132.17,129.07,128.63,128.52,127.77,127.74,125.40,124.34,123.85,123.33,120.60,113.68.HRMS(EI-TOF)Calcd for C18H13NO2S2[M]+:339.0382；found:339.0386.

Example 9

Dissolving methyl 4- (N- (2- (1-hydroxy-1-phenylethyl) phenyl) sulfamoyl) benzoate (123.3mg, 0.3mmol,1 equivalent) in 5ml of mixed solvent of ACN/TCE (6.5 + 3.5) to obtain reaction liquid A; p-toluenesulfonic acid (77.5mg, 0.45mmol,1.5 equiv.) and tetrabutylammonium tetrafluoroborate (987.8mg, 0.3mmol,1 equiv.) were dissolved in 5ml of ACN/TCE (6.5 + 3.5) to obtain a reaction solution B. Injecting the reaction liquid A and the reaction liquid B at the injection flow rate of 0.1mL/min respectively at 70 ℃; the applied current was 50mA; the reaction volume of the microchannel reactor is V =2mL, and the reaction time is 10min; after one cycle of reaction in the microchannel reactor, the reaction liquid was collected and the solvent was removed in vacuo. Separate with petroleum ether and ethyl acetate 10 eluent, and dry the resulting product in vacuo for 4h. Product 2i conversion was 78%.

The nmr hydrogen spectrum of the product 2i is shown in fig. 19, and the nmr carbon spectrum is shown in fig. 20.

1H NMR(400MHz,DMSO-d6)δ8.27–8.23(m,2H),8.16(s,1H),8.14–8.05(m,3H),7.87(d,J＝7.9Hz,1H),7.79–7.73(m,2H),7.58–7.31(m,5H),3.86(s,3H).13CNMR(101MHz,DMSO-d6)δ164.66,140.38,134.79,132.12,130.45,129.00,128.59,127.74,127.36,125.38,124.28,123.71,123.52,120.53,113.50,52.70；HRMS(EI-TOF)Calcd for C22H17NO4S[M]+:391.0873；found:391.0887.

Example 10

Dissolving N- (2- (1-hydroxy-1-phenylethyl) phenyl) -2-methylbenzenesulfonamide (110.1mg, 0.3mmol,1 equivalent) in 5ml of mixed solvent of ACN/TCE (6.5 + 3.5) to obtain reaction liquid A; p-toluenesulfonic acid (77.5mg, 0.45mmol,1.5 equiv.) and tetrabutylammonium tetrafluoroborate (987.8mg, 0.3mmol,1 equiv.) were dissolved in 5ml of ACN/TCE (6.5 + 3.5) to obtain a reaction solution B. Injecting the reaction liquid A and the reaction liquid B at 70 ℃ at an injection flow rate of 0.1mL/min respectively; the applied current was 50mA; the reaction volume of the microchannel reactor is V =2mL, and the reaction time is 10min; after one cycle of reaction in the microchannel reactor, the reaction liquid was collected and the solvent was removed in vacuo. The product was separated with petroleum ether and ethyl acetate 10 eluent and dried in vacuo for 4h. Product 2j conversion was 83%.

The nmr hydrogen spectrum of the product 2j is shown in fig. 21, and the nmr carbon spectrum is shown in fig. 22.

1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),8.05(dd,J＝8.1,1.3Hz,1H),7.89-7.84(m,1H),7.78-7.70(m,3H),7.60(td,J＝7.5,1.3Hz,1H),7.49(qt,J＝7.6,1.6Hz,3H),7.42-7.30(m,4H),3.37(s,3H)；13C NMR(101MHz,DMSO-d6)δ137.50,136.08,134.82,134.67,133.40,132.39,129.35,129.09,128.25,127.82,127.64,127.21,125.06,124.14,123.89,121.77,120.61,113.15,19.79；HRMS(EI-TOF)Calcd for C21H17NO2S[M]+:347.0975；found:347.0979.

Example 11

Dissolving 2-bromo-N- (2- (1-hydroxy-1-phenylethyl) phenyl) benzenesulfonamide (129.3mg, 0.3mmol,1 equivalent) in 5ml of mixed solvent of ACN/TCE (6.5 + 3.5) to obtain reaction solution A; p-toluenesulfonic acid (77.5mg, 0.45mmol,1.5 equiv.) and tetrabutylammonium tetrafluoroborate (987.8mg, 0.3mmol,1 equiv.) were dissolved in 5ml of ACN/TCE (6.5 + 3.5) to obtain a reaction solution B. Injecting the reaction liquid A and the reaction liquid B at 70 ℃ at an injection flow rate of 0.1mL/min respectively; the applied current was 50mA; the reaction volume of the microchannel reactor is V =2mL, and the reaction time is 10min; after one cycle of reaction in the microchannel reactor, the reaction liquid was collected and the solvent was removed in vacuo. The product was separated with petroleum ether and ethyl acetate 10 eluent and dried in vacuo for 4h. Product 2k conversion 85%.

The nmr hydrogen spectrum of the product 2k is shown in fig. 23, and the nmr carbon spectrum is shown in fig. 24.

1H NMR(400MHz,DMSO-d6)δ8.30(dd,J＝7.9,1.7Hz,1H),8.12(s,1H),7.89-7.85(m,2H),7.77-7.67(m,4H),7.63(td,J＝7.7,1.7Hz,1H),7.54-7.49(m,2H),7.43-7.38(m,1H),7.37-7.32(m,2H).13C NMR(101MHz,DMSO-d6)δ136.45,136.22,134.39,132.30,131.90,129.04,128.85,128.27,127.76,127.60,125.04,124.98,123.98,121.29,120.54,119.78,112.99；HRMS(EI-TOF)Calcd for C20H14BrNO2S[M]+:410.9923；found:410.9925.

Example 12

Dissolving 3-chloro-N- (2- (1-hydroxy-1-phenylethyl) phenyl) benzenesulfonamide (116.1mg, 00.3mmol,1 equivalent) in 5ml of mixed solvent of ACN/TCE (6.5 + 3.5) to obtain reaction solution A; p-toluenesulfonic acid (77.5mg, 0.45mmol,1.5 equiv.) and tetrabutylammonium tetrafluoroborate (987.8mg, 0.3mmol,1 equiv.) were dissolved in 5ml of ACN/TCE (6.5 + 3.5) to obtain a reaction solution B. Injecting the reaction liquid A and the reaction liquid B at the injection flow rate of 0.1mL/min respectively at 70 ℃; the applied current was 50mA; the reaction volume of the microchannel reactor is V =2mL, and the reaction time is 10min; after one cycle of reaction in the microchannel reactor, the reaction liquid was collected and the solvent was removed in vacuo. The product was separated with petroleum ether and ethyl acetate 10 eluent and dried in vacuo for 4h. Product 2m conversion 84%.

The NMR spectrum of the product 2m is shown in FIG. 25, and the NMR spectrum is shown in FIG. 26.

1H NMR(400MHz,DMSO-d6)δ8.19(t,J＝2.0Hz,1H),8.15(s,1H),8.09-8.04(m,2H),7.83(dt,J＝7.9,1.0Hz,1H),7.78-7.70(m,3H),7.61(t,J＝8.0Hz,1H),7.53-7.43(m,3H),7.43-7.33(m,2H)；13C NMR(101MHz,DMSO-d6)δ138.55,134.80,134.74,134.47,132.20,131.88,129.02,128.56,127.75,126.46,125.71,125.40,124.28,123.74,123.54,120.54,113.57；HRMS(EI-TOF)Calcd for C20H14ClNO2S[M]+:367.0428；found:367.0428.

Example 13

Dissolving 4-chloro-N- (2- (1-hydroxy-1-phenylethyl) phenyl) benzenesulfonamide (116.1mg, 0.3mmol,1 equivalent) in 5ml of mixed solvent of ACN/TCE (6.5 + 3.5) to obtain reaction solution A; p-toluenesulfonic acid (77.5mg, 0.45mmol,1.5 equiv.) and tetrabutylammonium tetrafluoroborate (987.8mg, 0.3mmol,1 equiv.) were dissolved in 5ml of ACN/TCE (6.5 + 3.5) to obtain a reaction solution B. Injecting the reaction liquid A and the reaction liquid B at the injection flow rate of 0.1mL/min respectively at 70 ℃; the applied current was 50mA; the reaction volume of the microchannel reactor is V =2mL, and the reaction time is 10min; after one cycle of reaction in the microchannel reactor, the reaction liquid was collected and the solvent was removed in vacuo. The product was separated with petroleum ether and ethyl acetate 10 eluent and dried in vacuo for 4h. Product 2n conversion was 83%.

The nmr hydrogen spectrum of the product 2n is shown in fig. 27, and the nmr carbon spectrum is shown in fig. 28.

1H NMR(400MHz,DMSO-d6)δ8.12-8.07(m,3H),8.03(dt,J＝8.3,1.2Hz,1H),7.84(dt,J＝7.8,1.1Hz,1H),7.74-7.70(m,2H),7.69-7.65(m,2H),7.53-7.47(m,2H),7.46-7.32(m,3H)；13C NMR(101MHz,DMSO-d6)δ139.91,135.61,134.78,132.21,130.11,129.04,128.87,128.58,127.75,125.38,124.26,123.61,123.53,120.55,113.54；HRMS(EI-TOF)Calcd for C20H14ClNO2S[M]+:367.0428；found:367.0442.

Comparative example 1

Dissolving 4-chloro-N- (2- (1-hydroxy-1-phenylethyl) phenyl) benzenesulfonamide (1.161g, 3mmol,1 equivalent), p-toluenesulfonic acid (0.775g, 4.5mmol,1.5 equivalent) and tetrabutylammonium tetrafluoroborate (0.9878g, 3mmol,1 equivalent) in solvent ACN/TCE (65 + 35) mL at 70 ℃ to obtain a homogeneous solution, adding the homogeneous solution into a 250mL three-neck round-bottom flask provided with a carbon cloth (100mm x 50mm) anode and a platinum sheet (40 mm x 0.2 mm) cathode, controlling the current to be 80mA, and reacting for 3.5h; after completion of the reaction, the product was identified by TLC. The solvent was removed in vacuo. The conversion was 69%. The method has poor amplification effect and cannot generate target products in large batch.

Comparative example 2

N- (2- (but-2-en-2-yl) phenyl) -4-methylbenzenesulfonamide (2.4 g, 8.0 mmol), 10- (4- (tert-butyl) phenyl) -3, 7-dimethoxy-10H-phenothiazine (0.48 g, 1.2 mmol), and tetrabutylammonium hexafluorophosphate (3.2 g, 8.2 mmol) were charged in a beaker type cell. The flask was equipped with a rubber stopper, magneton, two pieces of reticulated vitreous carbon (100PPI, 1.2cm. Times.4.0 cm. Times.6.0 cm) as the anode and a platinum plate (5.0 mm. Times.5.0 mm) as the cathode. The resulting mixture was sealed, degassed by vacuum evacuation, and backfilled with argon three times. MeCN (160 mL) and H2O (80 mL) were added. Constant current (300 mA) electrolysis was carried out at 55 deg.C (oil bath temperature) for 1.8 hours. The reaction mixture was concentrated under reduced pressure and then extracted with dichloromethane. The combined organic solutions were concentrated under reduced pressure. Chromatography of the residue on silica gel eluting with ethyl acetate/petroleum ether gave 2, 3-dimethyl-1-tosyl-1H-indole in 71% yield (1.7 g). The method has poor amplification effect and cannot generate target products in large batch.

The present invention provides a method and a concept for continuous flow electrochemical synthesis of substituted indole from gamma-hydroxylamine at microscale, and a method and a way for implementing the technical scheme are many, and the above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should be regarded as the protection scope of the present invention. All the components not specified in the present embodiment can be realized by the prior art.

Claims

1. A method for continuous flow electrochemical synthesis of substituted indole from gamma-hydroxylamine at microscale is characterized by comprising the following steps:

the above reaction formula is as follows:

2. The method for the micro-scale continuous flow electrochemical synthesis of substituted indole from gamma-hydroxylamine according to claim 1, wherein in step (1), the organic additive is selected from one or more of trifluoroacetic acid, methanesulfonic acid, acetic acid and p-toluenesulfonic acid.

3. The method for micro-scale continuous flow electrochemical synthesis of substituted indoles from gamma-hydroxylamine according to claim 1, wherein in step (1), the organic electrolyte is selected from one or more of tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroiodide, and tetrabutylammonium tetrafluoroperchlorate.

4. The method for continuous flow electrochemical synthesis of substituted indole by gamma-hydroxylamine at microscale according to claim 1, wherein in step (1), the solvent is selected from any one or combination of two or more of dichloroethane, N-dimethylformamide, dimethyl sulfoxide, trifluoroethanol, acetonitrile, hexafluoroisopropanol, trichloroethylene, N-dimethylaniline, and tetrahydrofuran.

5. The method for continuous flow electrochemical synthesis of substituted indole by gamma-hydroxylamine at micro-scale according to claim 1, wherein in step (2), the reaction molar ratio of the compound of formula 1 to the organic additive is 1.

6. The method for the micro-scale continuous flow electrochemical synthesis of substituted indole from gamma-hydroxylamine according to claim 1, wherein in step (2), the concentration of the compound of formula 1 in the reaction solution A is 0.04-0.16 mmol/mL; the concentration of the organic additive in the reaction liquid B is 0.06-0.24 mmol/mL; the concentration of the organic electrolyte in the reaction liquid B is 0.04-0.16 mmol/mL; pumping the reaction liquid A and the reaction liquid B into a micro mixer at the same flow rate of 0.1-0.3 mL/min for uniform mixing.

7. The method for the continuous flow electrochemical synthesis of substituted indoles from gamma-hydroxylamine at the microscale of claim 1, wherein the micromixer is a T-mixer; the injection pumps of the reaction liquid A and the reaction liquid B are connected to the front end of the T-shaped mixer in a parallel mode, and the rear end of the T-shaped mixer is connected with the microchannel reactor;

8. The method for continuous-flow electrochemical synthesis of substituted indoles from gamma-hydroxylamine at the microscale of claim 1, wherein the current intensity in the microchannel reactor is 20-100 mA, and the reaction time of the reaction solution in the microchannel reactor is 5-15 minutes.

9. The method for the micro-scale continuous flow electrochemical synthesis of substituted indole from gamma-hydroxylamine according to claim 1, wherein in step (3), the effluent reaction solution is extracted to obtain an organic phase, and then the organic phase is concentrated and subjected to column chromatography to obtain a pure substituted indole product.

10. The continuous flow electrochemical synthesis of substituted indoles from gamma-hydroxylamine at microscale of claim 9, wherein the extraction is performed using ethyl acetate and saturated aqueous sodium chloride;

the column chromatography adopts a silica gel column, and an eluent for the column chromatography is a mixed solvent of petroleum ether and ethyl acetate according to a volume ratio of 1.