A method and product for realizing indole 2-alkylation using microchannel photoelectrocatalytic technology

Abstract

A method and product for the 2-position alkylation of indole using microchannel photoelectrocatalysis is disclosed. The method involves dissolving an N-pyrimidine / pyridylindole compound, methyl propionate, a photocatalyst, and an electrolyte in an organic solvent to prepare a homogeneous solution. This homogeneous solution is then pumped into a microchannel reactor equipped with a photoelectrocatalyst for reaction, yielding the 2-position alkylated indole product. This invention is the first to achieve the 2-position alkylation of indole using an N-pyrimidine / pyridylindole compound and methyl propionate as substrates. This method eliminates the need for precious metal catalysts, uses non-functionalized reagents, and operates under mild conditions with simple operation. The use of a photoelectrocatalytic microchannel reactor effectively improves the mass and heat transfer rates of the reaction, enabling precise control of the reaction process, thereby increasing the reaction rate and making the reaction safer, more efficient, and more environmentally friendly.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, specifically relating to a method and product for achieving 2-position alkylation of indole using microchannel photoelectrocatalysis technology. Background Technology

[0002] Indole and its derivatives are an important class of nitrogen-containing aromatic heterocyclic compounds, widely found in many active compounds and drug structures, possessing significant pharmacological and physiological activities. They also serve as important pharmaceutical intermediates with wide applications in fine chemicals, pharmaceuticals, pesticides, dyes, fragrances, and other related industries. Different indole derivatives can be obtained by functionalizing the indole skeleton. Over the past two decades, significant progress has been made in the 2-position alkylation of indole via directing groups. However, these methods suffer from the following problems: (1) the reaction requires noble metal catalysis, such as palladium, ruthenium, rhodium, and iridium, greatly limiting their application in organic synthesis; (2) the reaction requires high temperatures, resulting in harsh conditions and slow reaction rates; (3) alkylation reactions mostly require pre-functionalized reagents, such as halogenated compounds, alcohols, and reactive alkenes, thus greatly limiting the synthetic method and failing to meet the requirements of today's green chemistry development. Therefore, developing a new, mild, green, and efficient method for the 2-position alkylation of indole is of great significance. Summary of the Invention

[0003] Purpose of the invention: The technical problem to be solved by the present invention is to provide a method for realizing the 2-position alkylation of indole using microchannel photoelectrocatalysis technology, which addresses the shortcomings of the existing technology, such as the need for noble metal catalysts, harsh high-temperature reactions, the need for prefunctionalized reagents, and low reaction efficiency.

[0004] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0005] A method for achieving indole 2-position alkylation using microchannel photoelectrocatalysis includes the following steps:

[0006] (1) Dissolve the N-pyrimidine / pyridylindole compound shown in Formula 1, methyl propionate shown in Formula 2, photocatalyst and electrolyte in an organic solvent to prepare a homogeneous solution;

[0007] (2) The homogeneous solution described in step (1) is pumped into a microchannel reaction device equipped with photoelectrocatalysis to carry out the reaction, and the indole 2-position alkylated product shown in Formula 3 is obtained.

[0008] Among them, the N-pyrimidine / pyridylindole compounds represented by Formula 1 are:

[0009]

[0010] The methyl propionate shown in Formula 2 is:

[0011]

[0012] The indole 2-alkylated product shown in Formula 3 is:

[0013]

[0014] In the formula, R is selected from any one of hydrogen, alkyl, alkoxy, halogen or cyano;

[0015] X is selected from N or CH.

[0016] Specifically, the photocatalyst is selected from any one or a combination of two or more of cerium chloride, cerium bromide, cerium sulfate, cerium trifluoromethanesulfonate, ferric chloride, and ferric bromide; preferably cerium chloride.

[0017] Specifically, the electrolyte is selected from any one or a combination of two or more of the following: tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetraethylammonium iodide, tetraethylammonium bromide, tetraethylammonium perchlorate, tetramethylammonium iodide, tetramethylammonium bromide, ammonium iodide, sodium iodide, ammonium bromide, trifluoroacetic acid, and sodium bromide; preferably tetrabutylammonium chloride and trifluoroacetic acid.

[0018] Specifically, the organic solvent is selected from any one or a combination of two or more of acetonitrile, dichloromethane, 1,2-dichloroethane, trifluoroethanol, hexafluoroisopropanol, methanol, and ethanol, preferably acetonitrile.

[0019] Further, the concentration of the N-pyrimidindole compound shown in Formula 1 in the mixed homogeneous solution is 0.01 to 0.10 mmol / mL, preferably 0.04 mmol / mL; the concentration of the methyl propionate compound shown in Formula 2 in the mixed homogeneous solution is 0.02 to 0.30 mmol / mL, preferably 0.12 mmol / mL.

[0020] Further, the concentration of the electrolyte in the mixed homogeneous solution is 0.01 to 0.15 mmol / mL, preferably 0.06 mmol / mL; the concentration of the photocatalyst in the mixed homogeneous solution is 0.001 to 0.01 mmol / mL, preferably 0.002 mmol / mL.

[0021] Specifically, the microchannel reaction device equipped with photocatalysis includes a feed pump, an anode plate, a cathode plate, an LED light source, a microchannel reactor, and a receiver; wherein, the anode plate and the cathode plate are respectively arranged on both sides of the reaction channel of the microchannel reactor and connected to an external power source; the LED light source surrounds the microchannel reactor and is arranged along the reaction channel; the feed pump, the microchannel reactor, and the receiver are connected in series through pipes.

[0022] Furthermore, the anode sheet is a graphite carbon electrode, a platinum electrode, a nickel electrode, or a stainless steel electrode, preferably a graphite carbon electrode.

[0023] Furthermore, the cathode sheet is a graphite carbon electrode, a platinum electrode, a nickel electrode, or a stainless steel electrode, preferably a platinum electrode.

[0024] Furthermore, the homogeneous solution is pumped into the microchannel reaction device at a flow rate of 50–500 μL / min (preferably 100 μL / min), and the reaction temperature is controlled at 22–50 °C (preferably 40 °C), and the reaction residence time is 1–10 min, preferably 5 min.

[0025] Furthermore, in the microchannel reaction device, the current supplied is controlled to be 3-25mA, preferably 5mA; and the wavelength of the blue light used for illumination is controlled to be 390-470nm, preferably 400nm.

[0026] Furthermore, the present invention also claims protection for the indole 2-position alkylated product of Formula 3 obtained by the above method.

[0027] Beneficial effects:

[0028] (1) This invention is the first to achieve alkylation of indole at the 2-position using N-pyrimidine / pyridylindole compounds and methyl propionate as substrates. This method does not require noble metal catalysts and uses non-functionalized reagents. The conditions are mild and the operation is simple.

[0029] (2) The present invention uses a photoelectric microchannel reaction device, which can effectively improve the mass transfer and heat transfer rate of the reaction, realize precise control of the reaction process, thereby improving the reaction rate and making the reaction safer, more efficient and environmentally friendly.

[0030] (3) The present invention prepared an indole 2-alkylated product with potential drug activity and physiological activity. Attached Figure Description

[0031] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0032] Figure 1This is a reaction pathway diagram of the present invention.

[0033] Figure 2 This is an indole 2-alkylated product synthesized by the method of the present invention.

[0034] Figure 3 The hydrogen and carbon spectra are for 3a.

[0035] Figure 4 The 1H and 1C spectra are for 3b.

[0036] Figure 5 The hydrogen and carbon spectra are for 3C.

[0037] Figure 6 The 3D proton and carbon spectra are shown.

[0038] Figure 7 The hydrogen and carbon spectra of 3e are shown.

[0039] Figure 8 The 3f hydrogen and carbon spectra are shown.

[0040] Figure 9 The hydrogen and carbon spectra are for 3g.

[0041] Figure 10 The following are the proton and carbon spectra over 3 hours.

[0042] Figure 11 The hydrogen and carbon spectra of 3i are shown.

[0043] Figure 12 The hydrogen and carbon spectra of 3j are shown.

[0044] Figure 13 The hydrogen and carbon spectra are at 3k.

[0045] Figure 14 The hydrogen and carbon spectra of 3L are shown.

[0046] Figure 15 The 3m hydrogen and carbon spectra are shown.

[0047] Figure 16 The hydrogen and carbon spectra are for 3n.

[0048] Figure 17 The hydrogen and carbon spectra are for 30°.

[0049] Figure 18 The 3p hydrogen and carbon spectra are shown. Detailed Implementation

[0050] The present invention can be better understood from the following embodiments.

[0051] The photoelectrocatalytic microchannel reactor used in the following embodiments includes a feed pump, a microchannel reactor, an anode plate, a cathode plate, an LED light source, and a receiver. The microchannel reactor has an anode plate (graphite carbon sheet) and a cathode plate (platinum sheet) on both sides of the reaction channel. The reaction channel of the microchannel reactor is irradiated with blue light at a wavelength of 400nm. The feed pump, microchannel reactor, and receiver are connected in series. The series piping is made of polytetrafluoroethylene (PTFE). The microchannel reactor is named "the Asia Flux module," manufactured by Syrris Ltd, and its model number is 2200554.

[0052] In the following examples, the following steps were followed: (1) the prepared homogeneous mixed solution was added to the syringe pump; (2) the required current and wavelength were adjusted; (3) after the reaction was completed in the photoelectric microchannel reactor, the effluent was collected, and the yield was calculated by separating the products by column chromatography. The reaction route diagram is shown below. Figure 1 As shown.

[0053] Among them, such as Figure 2 The indole 2-alkylated products shown are all products and yields obtained by the method of this invention, and have been confirmed by NMR characterization.

[0054] Example 1: Synthesis of Compound 3a

[0055] 0.4 mmol N-pyrimidindole, 1.2 mmol methyl propionate, 0.6 mmol tetrabutylammonium chloride, 0.4 mmol trifluoroacetic acid, and 0.02 mmol cerium chloride were dissolved in 10 mL acetonitrile to obtain a homogeneous solution, which was then pumped into a microchannel reaction apparatus at a flow rate of 100 μL / min. The reaction was carried out at a current intensity of 5 mA and a reaction temperature of 40 °C under 400 nm blue light (25 W) irradiation for 5 min. The eluent was collected, washed with water, extracted, dried, filtered, and then separated by column chromatography to obtain product 3a with a yield of 95%. The proton and carbon spectra of product 3a are shown below. Figure 3 The characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ8.71(d,J=4.8Hz,2H),8.54(d,J=8.4Hz,1H),7.64(d,J=7.6Hz,1H),7.36-7.25 (m,2H),7.05(t,J=4.8Hz,1H),6.72(s,1H),4.63(q,J=7.2Hz,1H),3.63(s,3H),1.74(d,J=7.2Hz,3H); 13CNMR (100MHz, CDCl3): δ174.6,158.1,157.8,139.7,136.9,129.1,123.4,122.1,120.3,116.8,115.0,107.1,51.9,40.8,17.2; HRMS (ESI): m / z calcd for C 16 H 16 N3O2[M+H] + 282.1237, found 282.1246.

[0056] The screening process for reaction conditions is as follows:

[0057] A homogeneous solution was prepared by dissolving 0.4 mmol N-pyrimidindole, 1.2 mmol methyl propionate, 0.6 mmol electrolyte, 0.4 mmol trifluoroacetic acid, and 0.02 mmol photocatalyst in 10 mL of solvent. This solution was pumped into a microchannel reaction apparatus at a flow rate of 100 μL / min. A specific current intensity and reaction temperature were set, and the reaction was carried out under blue light irradiation at a specific wavelength for 5 min. The effluent was collected, washed with water, extracted, dried, filtered, and then separated by column chromatography to obtain product 3a. The yields under different parameters during the screening process are shown in Table 1.

[0058] Table 1

[0059]

[0060]

[0061] Example 2 Synthesis of compound 3b

[0062] 0.4 mmol of 3-methylN-pyrimidindole, 1.2 mmol of methyl propionate, 0.6 mmol of tetrabutylammonium chloride, 0.4 mmol of trifluoroacetic acid, and 0.02 mmol of cerium chloride were dissolved in 10 mL of acetonitrile to obtain a homogeneous solution, which was then pumped into a microchannel reaction apparatus at a flow rate of 100 μL / min. The reaction was carried out at a current intensity of 5 mA and a reaction temperature of 40 °C under irradiation with 400 nm blue light (25 W) for 5 min. The eluent was collected, washed with water, extracted, dried, filtered, and then separated by column chromatography to obtain product 3b in 93% yield. The proton and carbon spectra of product 3b are shown below. Figure 4 The characterization data are as follows: 1H NMR (400MHz, CDCl3): δ8.70(d,J=4.8Hz,2H),8.58(d,J=8.0Hz,1H),7.59(d,J=8.0Hz,1H),7.36-7.26 (m,2H),7.06(t,J=4.8Hz,1H),4.41(q,J=7.2Hz,1H),3.59(s,3H),2.37(s,3H),1.55(d,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3): δ174.0,157.8,157.6,136.1,134.9,130.4,123.6,121.9,118.3,116.3,115.0,114.9,51.8,38.3,16.6,9.0; HRMS (ESI): m / z calcd forC 17 H 18 N3O2[M+H] + 296.1394, found 296.1402.

[0063] Example 3 Synthesis of compound 3c

[0064] 0.4 mmol of 3-chloroN-pyrimidindole, 1.2 mmol of methyl propionate, 0.6 mmol of tetrabutylammonium chloride, 0.4 mmol of trifluoroacetic acid, and 0.02 mmol of cerium chloride were dissolved in 10 mL of acetonitrile to obtain a homogeneous solution, which was then pumped into a microchannel reaction apparatus at a flow rate of 100 μL / min. The reaction was carried out at a current intensity of 5 mA and a reaction temperature of 40 °C under irradiation with 400 nm blue light (25 W) for 5 min. The eluent was collected, washed with water, extracted, dried, filtered, and then separated by column chromatography to obtain product 3c in 90% yield. The proton and carbon spectra of product 3c are shown below. Figure 5 The characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ8.71(d,J=4.8Hz,2H),8.62(d,J=8.4Hz,1H),7.67(d,J=7.2Hz,1H),7.41 -7.32(m,2H),7.12(t,J=4.8Hz,1H),4.63(q,J=7.2Hz,1H),3.58(s,3H),1.59(d,J=7.2Hz,3H); 13C NMR (100MHz, CDCl3): δ173.0,157.7,157.4,135.1,134.6,126.9,124.7,122.7,118.1,117.1,115.4,112.0,51.9,38.2,15.9; HRMS (ESI): m / z calcd for C 16 H 15 ClN3O2[M+H] + 316.0847, found 316.0856.

[0065] Example 4 Synthesis of compound 3d

[0066] 0.4 mmol of 4-methoxy-N-pyrimidindole, 1.2 mmol of methyl propionate, 0.6 mmol of tetrabutylammonium chloride, 0.4 mmol of trifluoroacetic acid, and 0.02 mmol of cerium chloride were dissolved in 10 mL of acetonitrile to obtain a homogeneous solution, which was then pumped into a microchannel reaction apparatus at a flow rate of 100 μL / min. The reaction was carried out at a current intensity of 5 mA and a reaction temperature of 40 °C under irradiation with 400 nm blue light (25 W) for 5 min. The eluent was collected, washed with water, extracted, dried, filtered, and then separated by column chromatography to obtain product 3d, with a yield of 94%. The proton and carbon spectra of product 3d are shown below. Figure 6 The characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ8.71(d,J=4.8Hz,2H),8.08(d,J=8.4Hz,1H),7.28-7.21(m,1H),7.08(t,J=4.8Hz,1H) ,6.83(s,1H),6.69(d,J=7.2Hz,1H),4.58(q,J=6.8Hz,1H),3.97(s,3H),3.58(s,3H),1.71(d,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3): δ174.6,158.1,157.8,152.6,138.2,138.1,124.1,119.4,116.9,108.2,103.9,102.3,55.4,51.9,40.7,17.1; HRMS (ESI): m / z calcdfor C 17 H 18 N3O3[M+H] + 312.1343, found 312.1354.

[0067] Example 5 Synthesis of compound 3e

[0068] 0.4 mmol of 5-bromo-N-pyrimidindole, 1.2 mmol of methyl propionate, 0.6 mmol of tetrabutylammonium chloride, 0.4 mmol of trifluoroacetic acid, and 0.02 mmol of cerium chloride were dissolved in 10 mL of acetonitrile to obtain a homogeneous solution, which was then pumped into a microchannel reaction apparatus at a flow rate of 100 μL / min. The reaction was carried out at a current intensity of 5 mA and a reaction temperature of 40 °C under irradiation with 400 nm blue light (25 W) for 5 min. The eluent was collected, washed with water, extracted, dried, filtered, and then separated by column chromatography to obtain product 3e, with a yield of 91%. The proton and carbon spectra of product 3e are shown below. Figure 7 The characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ8.72(d,J=4.8Hz,2H),8.39(d,J=8.8Hz,1H),7.71(d,J=1.6Hz,1H),7.38-7.35 (m,1H),7.13(t,J=4.8Hz,1H),6.62(s,1H),4.59(q,J=7.2Hz,1H),3.60(s,3H),1.69(d,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3): δ174.3,157.8,140.9,135.6,130.8,126.1,122.7,117.1,116.7,115.2,106.3,52.0,40.8,17.1; HRMS (ESI): m / z calcd for C 16 H 15 BrN3O2[M+H] + 360.0342, found 360.0356.

[0069] Example 6 Synthesis of compound 3f

[0070] 0.4 mmol of 5-methyl-N-pyrimidindole, 1.2 mmol of methyl propionate, 0.6 mmol of tetrabutylammonium chloride, 0.4 mmol of trifluoroacetic acid, and 0.02 mmol of cerium chloride were dissolved in 10 mL of acetonitrile to obtain a homogeneous solution, which was then pumped into a microchannel reaction apparatus at a flow rate of 100 μL / min. The reaction was carried out at a current intensity of 5 mA and a reaction temperature of 40 °C under irradiation with 400 nm blue light (25 W) for 5 min. The eluent was collected, washed with water, extracted, dried, filtered, and then separated by column chromatography to obtain product 3f in 86% yield. The proton and carbon spectra of product 3f are shown below. Figure 8 The characterization data are as follows: 1H NMR (400MHz, CDCl3): δ8.71(d,J=4.8Hz,2H),8.42(d,J=8.4Hz,1H),7.39(s,1H),7.14-7.06 (m,2H),6.62(s,1H),4.59(q,J=7.2Hz,1H),3.60(s,3H),2.48(s,3H),1.71(d,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3): δ174.7,158.1,157.7,139.6,135.2,131.5,129.3,124.8,120.1,116.5,114.8,106.9,51.9,40.9,21.3,17.1; HRMS (ESI): m / z calcd for C 17 H 18 N3O2[M+H] + 296.1394, found 296.1398.

[0071] Example 7 Synthesis of Compound 3g

[0072] 0.4 mmol of 5-cyano-N-pyrimidindole, 1.2 mmol of methyl propionate, 0.6 mmol of tetrabutylammonium chloride, 0.4 mmol of trifluoroacetic acid, and 0.02 mmol of cerium chloride were dissolved in 10 mL of acetonitrile to obtain a homogeneous solution, which was then pumped into a microchannel reaction apparatus at a flow rate of 100 μL / min. The reaction was carried out at a current intensity of 5 mA and a reaction temperature of 40 °C under irradiation with 400 nm blue light (25 W) for 5 min. The eluent was collected, washed with water, extracted, dried, filtered, and then separated by column chromatography to obtain 3 g of product, with a yield of 92%. The proton and carbon spectra of the 3 g product are shown below. Figure 9 The characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ8.79(d,J=4.8Hz,2H),8.53(d,J=8.3Hz,1H),7.92(d,J=0.8Hz,1H),7.53-7.50 (m,1H),7.23(t,J=4.8Hz,1H),6.74(s,1H),4.62(q,J=7.2Hz,1H),3.60(s,3H),1.71(d,J=7.2Hz,3H); 13C NMR (100MHz, CDCl3): δ173.9,158.0,157.5,142.1,138.6,128.8,126.3,125.2,120.2,117.8,115.7,106.6,105.1,52.1,40.6,16.9; HRMS (ESI): m / z calcd forC 17 H 15 N4O2[M+H] + 307.1190, found 307.1201.

[0073] Example 8 Synthesis of compound 3h

[0074] 0.4 mmol of 6-methyl-N-pyrimidindole, 1.2 mmol of methyl propionate, 0.6 mmol of tetrabutylammonium chloride, 0.4 mmol of trifluoroacetic acid, and 0.02 mmol of cerium chloride were dissolved in 10 mL of acetonitrile to obtain a homogeneous solution, which was then pumped into a microchannel reaction apparatus at a flow rate of 100 μL / min. The reaction was carried out at a current intensity of 5 mA and a reaction temperature of 40 °C under irradiation with 400 nm blue light (25 W) for 5 min. The eluent was collected, washed with water, extracted, dried, filtered, and then separated by column chromatography to obtain the product 3 h in 93% yield. The 1H and 1C spectra of the product 3 h are shown below. Figure 10 The characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ8.74(d,J=4.8Hz,2H),8.30(s,1H),7.50(d,J=8.0Hz,1H),7.10-7.07 (m,2H),6.65(s,1H),4.59(q,J=7.2Hz,1H),3.59(s,3H),2.53(s,3H),1.71(d,J=7.2Hz,3H); 13 CNMR (100MHz, CDCl3): δ174.6,158.1,157.7,138.9,137.3,133.2,126.8,123.6,119.9,116.6,114.8,106.9,51.9,40.7,22.1,17.1; HRMS (ESI): m / z calcd for C 17 H 18 N3O2[M+H] + 296.1394, found 296.1402.

[0075] Example 9: Synthesis of Compound 3i

[0076] 0.4 mmol of 7-bromo-N-pyrimidindole, 1.2 mmol of methyl propionate, 0.6 mmol of tetrabutylammonium chloride, 0.4 mmol of trifluoroacetic acid, and 0.02 mmol of cerium chloride were dissolved in 10 mL of acetonitrile to obtain a homogeneous solution, which was then pumped into a microchannel reaction apparatus at a flow rate of 100 μL / min. The reaction was carried out at a current intensity of 5 mA and a reaction temperature of 40 °C under irradiation with 400 nm blue light (25 W) for 5 min. The eluent was collected, washed with water, extracted, dried, filtered, and then separated by column chromatography to obtain product 3i, with a yield of 86%. The proton and carbon spectra of product 3i are shown below. Figure 11 The characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ8.88(d,J=4.8Hz,2H),7.59(d,J=7.6Hz,1H),7.39-7.33(m,2H),7.0 4(t,J=8.0Hz,1H),6.65(s,1H),4.04(q,J=7.2Hz,1H),3.52(s,3H),1.61(d,J=7.2Hz,3H); 13 CNMR(100MHz, CDCl3): δ173.3,158.5,157.4,141.3,135.0,131.4,127.6,122.4,119.9,119.8,104.8,103.4,52.2,38.1,17.1; HRMS(ESI):m / zcalcd for C 16 H 15 BrN3O2[M+H] + 360.0342, found 360.0352.

[0077] Example 10 Synthesis of Compound 3j

[0078] 0.4 mmol N-pyridylindole, 1.2 mmol methyl propionate, 0.6 mmol tetrabutylammonium chloride, 0.4 mmol trifluoroacetic acid, and 0.02 mmol cerium chloride were dissolved in 10 mL acetonitrile to obtain a homogeneous solution, which was then pumped into a microchannel reaction apparatus at a flow rate of 100 μL / min. The reaction was carried out at a current intensity of 5 mA and a reaction temperature of 40 °C under 400 nm blue light (25 W) irradiation for 5 min. The eluent was collected, washed with water, extracted, dried, filtered, and then separated by column chromatography to obtain product 3j, with a yield of 91%. The proton and carbon spectra of product 3j are shown below. Figure 12 The characterization data are as follows: 1H NMR (400MHz, CDCl3): δ8.65(d,J=7.2Hz,1H),7.88(t,J=7.6Hz,1H),7.70-7.68(m,1H),7.55-7.53(m,1H),7.43-7.41 (m,1H),7.32-7.29(m,1H),7.23-7.21(m,2H),6.72(s,1H),4.38(q,J=7.2Hz,1H),3.58(s,3H),1.69(d,J=7.2Hz,3H); 13 CNMR (100MHz, CDCl3): δ174.0,151.3,149.5,139.6,138.4,137.1,128.4,122. 5,122.1,121.0,120.9,120.7,110.3,102.9,52.0,38.3,17.2; HRMS(ESI):m / z calcd for C 17 H 17 N₂O₂[M+H] + 281.1285, found 281.1292.

[0079] Example 11 Synthesis of Compound 3k

[0080] 0.4 mmol of 3-methylN-pyridinylindole, 1.2 mmol of methyl propionate, 0.6 mmol of tetrabutylammonium chloride, 0.4 mmol of trifluoroacetic acid, and 0.02 mmol of cerium chloride were dissolved in 10 mL of acetonitrile to obtain a homogeneous solution, which was then pumped into a microchannel reaction apparatus at a flow rate of 100 μL / min. The reaction was carried out at a current intensity of 5 mA and a reaction temperature of 40 °C under irradiation with 400 nm blue light (25 W) for 5 min. The eluent was collected, washed with water, extracted, dried, filtered, and then separated by column chromatography to obtain product 3k in 86% yield. The proton and carbon spectra of product 3k are shown below. Figure 13 The characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ8.65(d,J=3.6Hz,1H),7.92-7.88(m,1H),7.66-7.63(m,1H),7.55(d,J=8.0Hz,1H),7.41-7.39 (m,1H),7.33-7.28(m,1H),7.25-7.23(m,2H),4.24(d,J=7.2Hz,1H),3.68(s,3H),2.40(s,3H),1.55(d,J=7.2Hz,3H); 13C NMR (100MHz, CDCl3): δ173.8,151.5,149.6,138.3,136.2,134.9,129.5,122.5, 121.9,120.9,120.5,118.6,110.9,110.2,52.1,36.9,16.4,8.8; HRMS(ESI):m / z calcd for C 18 H 19 N₂O₂[M+H] + 295.1441, found 295.1456.

[0081] Example 12 Synthesis of Compound 3l

[0082] 0.4 mmol of 4-bromo-N-pyridylindole, 1.2 mmol of methyl propionate, 0.6 mmol of tetrabutylammonium chloride, 0.4 mmol of trifluoroacetic acid, and 0.02 mmol of cerium chloride were dissolved in 10 mL of acetonitrile to obtain a homogeneous solution, which was then pumped into a microchannel reaction apparatus at a flow rate of 100 μL / min. The reaction was carried out at a current intensity of 5 mA and a reaction temperature of 40 °C under irradiation with 400 nm blue light (25 W) for 5 min. The eluent was collected, washed with water, extracted, dried, filtered, and then separated by column chromatography to obtain product 3l, with a yield of 80%. The proton and carbon spectra of product 3l are shown below. Figure 14 The characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ8.65(d,J=4.8Hz,1H),7.93-7.89(m,1H),7.49(d,J=8.0Hz,1H),7.37-7.33(m,2H),7.3 0-7.28(m,1H),7.04(t,J=8.0Hz,1H),6.73(s,1H),4.29(q,J=7.2Hz,1H),3.56(s,3H),1.67(d,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3): δ173.6,150.9,149.7,140.3,138.6,137.4,128.9,123. 7,123.3,122.6,121.1,114.6,109.5,102.9,52.1,38.3,17.0; HRMS(ESI):m / z calcd for C 17 H 16 BrN2O2[M+H] + 359.0390, found 359.0402.

[0083] Example 13 Synthesis of compound 3m

[0084] 0.4 mmol of 5-cyano-N-pyridinylindole, 1.2 mmol of methyl propionate, 0.6 mmol of tetrabutylammonium chloride, 0.4 mmol of trifluoroacetic acid, and 0.02 mmol of cerium chloride were dissolved in 10 mL of acetonitrile to obtain a homogeneous solution, which was then pumped into a microchannel reaction apparatus at a flow rate of 100 μL / min. The reaction was carried out at a current intensity of 5 mA and a reaction temperature of 40 °C under irradiation with 400 nm blue light (25 W) for 5 min. The eluent was collected, washed with water, extracted, dried, filtered, and then separated by column chromatography to obtain product 3m, with a yield of 85%. The proton and carbon spectra of product 3m are shown below. Figure 15 The characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ8.66-8.65(m,1H),7.98-7.95(m,2H),7.48-7.33(m, 4H), 6.70 (s, 1H), 4.23 (q, J = 7.2Hz, 1H), 3.55 (s, 3H), 1.63 (d, J = 7.2Hz, 3H); 13 C NMR (100MHz, CDCl3): δ173.3,150.1,149.9,142.1,138.8,138.7,127.9,125.8,1 25.4,123.1,121.2,120.5,111.1,103.9,103.0,52.2,38.1,16.9; HRMS(ESI):m / z calcd for C 18 H 16 N3O2[M+H] + 306.1237, found 306.1248.

[0085] Example 14 Synthesis of Compound 3n

[0086] 0.4 mmol of 5-benzyloxyN-pyridinylindole, 1.2 mmol of methyl propionate, 0.6 mmol of tetrabutylammonium chloride, 0.4 mmol of trifluoroacetic acid, and 0.02 mmol of cerium chloride were dissolved in 10 mL of acetonitrile to obtain a homogeneous solution, which was then pumped into a microchannel reaction apparatus at a flow rate of 100 μL / min. The reaction was carried out at a current intensity of 5 mA and a reaction temperature of 40 °C under irradiation with 400 nm blue light (25 W) for 5 min. The eluent was collected, washed with water, extracted, dried, filtered, and then separated by column chromatography to obtain product 3n in 87% yield. The 1H and 1C spectra of product 3n are shown below. Figure 16 The characterization data are as follows: 1H NMR (400MHz, CDCl3): δ8.64(d,J=6.0Hz,1H),7.92-7.87(m,1H),7.53-7.51(m,3H),7.45-7.41(m,2H),7.38-7.28(m,3H), 7.21-7.20(m,1H),6.97-6.94(m,1H),6.61(s,1H),5.16(s,2H),4.34(d,J=7.2Hz,1H),3.58(s,3H),1.66(d,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3): δ174.0,154.1,151.4,149.5,140.1,138.4,137.7,132.4,128.9,128.6,1 27.8,127.5,121.9,120.6,112.9,111.1,104.3,102.8,70.9,52.0,38.4,17.2; HRMS(ESI):m / z calcd forC 24 H 23 N₂O₃[M+H] + 387.1703, found 387.1716.

[0087] Example 15 Synthesis of Compound 3o

[0088] 0.4 mmol of 6-chloroN-pyridinylindole, 1.2 mmol of methyl propionate, 0.6 mmol of tetrabutylammonium chloride, 0.4 mmol of trifluoroacetic acid, and 0.02 mmol of cerium chloride were dissolved in 10 mL of acetonitrile to obtain a homogeneous solution, which was then pumped into a microchannel reaction apparatus at a flow rate of 100 μL / min. The reaction was carried out at a current intensity of 5 mA and a reaction temperature of 40 °C under irradiation with 400 nm blue light (25 W) for 5 min. The eluent was collected, washed with water, extracted, dried, filtered, and then separated by column chromatography to obtain product 3o, with a yield of 91%. The proton and carbon spectra of product 3o are shown below. Figure 17 The characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ8.65-8.63(m,1H),7.96-7.92(m,1H),7.55-7.48(m,2H),7.37-7.35(m, 2H),7.15-7.13(m,1H),6.64(s,1H),4.27(q,J=7.2Hz,1H),3.56(s,3H),1.63(d,J=7.2Hz,3H); 13CNMR (100MHz, CDCl3): δ173.7,150.7,149.7,140.3,138.6,137.5,128.3,126. 8,122.5,121.5,121.4,120.9,110.3,102.8,52.1,38.2,17.0; HRMS(ESI):m / z calcd forC 17 H 16 ClN2O2[M+H] + 315.0895, found 315.0904.

[0089] Example 16 Synthesis of compound 3p

[0090] 0.4 mmol of 7-bromo-N-pyridinylindole, 1.2 mmol of methyl propionate, 0.6 mmol of tetrabutylammonium chloride, 0.4 mmol of trifluoroacetic acid, and 0.02 mmol of cerium chloride were dissolved in 10 mL of acetonitrile to obtain a homogeneous solution, which was then pumped into a microchannel reaction apparatus at a flow rate of 100 μL / min. The reaction was carried out at a current intensity of 5 mA and a reaction temperature of 40 °C under irradiation with 400 nm blue light (25 W) for 5 min. The eluent was collected, washed with water, extracted, dried, filtered, and then separated by column chromatography to obtain product 3p in 83% yield. The 1H and 1C spectra of product 3p are shown below. Figure 18 The characterization data are as follows: 1 H NMR (400MHz, CDCl3): δ8.67(d,J=4.0Hz,1H),7.86(t,J=7.6Hz,1H),7.60(d,J=7.6Hz,1H),7. 46-7.32(m,3H),7.03-7.01(m,1H),6.64(s,1H),3.78-3.71(m,1H),3.55(s,3H),1.59(s,3H); 13 CNMR (100MHz, CDCl3): δ173.5,150.8,149.0,141.6,137.5,134.6,130.9,127. 3,126.3,123.9,121.6,119.9,103.9,102.0,52.2,37.8,17.3; HRMS(ESI):m / z calcd forC 17 H 16 BrN2O2[M+H] + 359.0390, found 359.0403.

[0091] This invention provides a method and product for the 2-position alkylation of indole using microchannel photoelectrocatalysis. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A method for achieving indole 2-position alkylation using microchannel photoelectrocatalysis, characterized in that, Includes the following steps: (1) Dissolve the N-pyrimidine / pyridylindole compound shown in Formula 1, methyl propionate shown in Formula 2, photocatalyst and electrolyte in an organic solvent to prepare a homogeneous solution; (2) The homogeneous solution described in step (1) is pumped into a microchannel reaction device equipped with photoelectrocatalysis to carry out the reaction, and the indole 2-position alkylated product shown in Formula 3 is obtained. Among them, the N-pyrimidine / pyridylindole compounds represented by Formula 1 are: ； The methyl propionate shown in Formula 2 is: ； The indole 2-alkylated product shown in Formula 3 is: ； In the formula, R is selected from any one of hydrogen, alkyl, alkoxy, halogen or cyano; X is selected from N or CH; The photocatalyst is selected from any one or a combination of two or more of cerium chloride, cerium bromide, cerium sulfate, cerium trifluoromethanesulfonate, ferric chloride, and ferric bromide; The electrolyte is selected from any one or a combination of two or more of the following: tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetraethylammonium iodide, tetraethylammonium bromide, tetraethylammonium perchlorate, tetramethylammonium iodide, tetramethylammonium bromide, ammonium iodide, sodium iodide, ammonium bromide, trifluoroacetic acid, and sodium bromide. The organic solvent is selected from any one or a combination of two or more of acetonitrile, dichloromethane, 1,2-dichloroethane, trifluoroethanol, hexafluoroisopropanol, methanol, and ethanol; The concentration of the N-pyrimidindole compound shown in Formula 1 in the mixed homogeneous solution is 0.01~0.10 mmol / mL; the concentration of the methyl propionate compound shown in Formula 2 in the mixed homogeneous solution is 0.02~0.30 mmol / mL. The concentration of the electrolyte in the homogeneous mixed solution is 0.01~0.15 mmol / mL; the concentration of the photocatalyst in the homogeneous mixed solution is 0.001~0.01 mmol / mL. The homogeneous solution was pumped into the microchannel reaction device at a flow rate of 50~500 μL / min, and the reaction temperature was controlled at 22~50℃, and the reaction residence time was 1~10 min. In the microchannel reaction device, the current is controlled to be 3~25 mA, and the wavelength of the blue light illumination is controlled to be 390~470 nm.

2. The method for achieving indole 2-position alkylation using microchannel photoelectrocatalysis according to claim 1, characterized in that, The microchannel reaction device equipped with photocatalysis includes a feed pump, an anode plate, a cathode plate, an LED light source, a microchannel reactor, and a receiver; wherein, the anode plate and the cathode plate are respectively arranged on both sides of the reaction channel of the microchannel reactor and connected to an external power source; the LED light source surrounds the microchannel reactor and is arranged along the reaction channel; the feed pump, the microchannel reactor, and the receiver are connected in series through pipes.

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