Indoline[2,1-a]isoquinoline derivatives, preparation methods and applications

Abstract

The present invention belongs to the field of organic synthesis, and particularly relates to indolizino[2,1-a]isoquinoline derivatives, a preparation method and applications thereof. The indolizino[2,1-a]isoquinoline derivative has the structural formula: wherein, R 1 includes an alkyl group, an alkoxy group, hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano; R 2 includes an aryl group, an alkoxy group, hydrogen, chlorine or bromine; R 3 includes an aryl group, an alkoxy group, hydrogen, chlorine or bromine; R 4 includes an electron-withdrawing group; R 1 is located at the C8, C9, C10 or C11 position of the indolizino[2,1-a]isoquinoline derivative; R 2 or R 3 is located at the C2 or C3 position of the corresponding indolizino[2,1-a]isoquinoline derivative, and the said R 2 or R 3 can be the same or different. The product of the present invention is a novel product. The preparation method is green and efficient, the preparation conditions are mild, the requirements for equipment are low, the operation is simple, the substrate scope of application is wide, the raw materials are low in price, the production cost is low, the yield is relatively high, and it can be mass-produced industrially, thus having broad application prospects.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and specifically relates to a dihydroindole [2,1-a] isoquinoline derivative, a preparation method and an application thereof. Background Art

[0002] Condensed-ring indoles and their derivatives are an extremely important class of nitrogen-containing heterocyclic compounds, found in numerous natural products. Most of these compounds possess unique physicochemical properties and biological activities, and have important applications in organic synthetic chemistry, materials chemistry, and medicinal chemistry. Consequently, their synthesis has attracted considerable attention.

[0003] Among them, indoloisoquinoline derivatives, an important class of polycyclic indole derivatives, have demonstrated promising pharmacological activity in the treatment of multiple sclerosis and hepatitis C, as well as in anti-breast cancer cell proliferation and antiviral activities. They are promising candidates for the development of novel drug lead molecules. Currently reported methods for constructing fused-ring indoloisoquinoline skeletons often suffer from long steps, harsh reaction conditions, and the presence of heavy metal residues. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a novel dihydroindole [2,1-a] isoquinoline derivative, a preparation method and an application thereof.

[0005] In order to solve the above technical problems, the present invention provides a technical solution: a dihydroindole [2,1-a] isoquinoline derivative, the structural formula of the dihydroindole [2,1-a] isoquinoline derivative is:

[0006]

[0007] Among them, R 1 including alkyl, alkoxy, hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano; R 2 including aryl, alkoxy, hydrogen, chlorine or bromine; R 3 including aryl, alkoxy, hydrogen, chlorine or bromine; R 4 Including electron-withdrawing groups; R 1 Located at C8, C9, C10, C11 of dihydroindole[2,1-a]isoquinoline derivatives; R 2 or R 3 Located at the C2 and C3 positions of the indoline[2,1-a]isoquinoline derivative, R 2 or R 3 Can be the same or different.

[0008] Further, R 1 The alkyl groups include C1-C8 alkyl groups, R 1 The alkoxy group includes C1-C8 alkoxy groups; R 2The aryl group includes phenyl or various aryl groups containing electron-donating and electron-withdrawing groups, R 2 The alkoxy group of R includes alkoxy groups with 1 to 8 carbon atoms; R 3 The aryl group includes phenyl or various aryl groups containing electron-donating and electron-withdrawing groups, R 3 The alkoxy group of R includes alkoxy groups with 1 to 8 carbon atoms; R 4 The electron-withdrawing group includes cyano group and alkoxycarbonyl groups with 1 to 8 carbon atoms.

[0009] Furthermore, R 1 The C1-C8 alkyl group of R includes tert-butyl, methyl, ethyl, isopropyl or n-butyl, R 1 The C1-C8 alkoxy group of R includes methoxy or ethoxy; R 2 The C1-C8 alkoxy group of R includes methoxy, ethoxy; R 3 The C1-C8 alkoxy group of R includes methoxy or ethoxy.

[0010] Among them, the indoline[2,1-a]isoquinoline derivatives include:

[0011]

[0012]

[0013] The present invention also includes a second technical solution, a preparation method of indoline[2,1-a]isoquinoline derivatives, including: using N-arylisoquinoline and organic nitriles as raw materials, and carrying out a photoelectric co-catalyzed reaction at room temperature to obtain indoline[2,1-a]isoquinoline derivatives; the reaction formula in the synthesis process is:

[0014]

[0015] Among them, the indoline[2,1-a]isoquinoline derivative is compound 4; R 1 includes alkyl, alkoxy, hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano group; R 2 includes aryl, alkoxy, hydrogen, chlorine or bromine; R 3 includes aryl, alkoxy, hydrogen, chlorine or bromine; R 4 includes an electron-withdrawing group; R 1 is located at the C8, C9, C10 or C11 position of the indoline[2,1-a]isoquinoline derivative; R 2 or R 3 is located at the C2 or C3 position of the indoline[2,1-a]isoquinoline derivative, R 2 or R 3 can be the same or different.

[0016] Among them, the photo-electro-cocatalysis includes photocatalysis and electrocatalysis. The photocatalysis uses visible light catalysis; the electrocatalysis uses an electrode pair without bias voltage, and the anode of the electrode pair includes a BiVO4 photoanode or a composite photoanode of BiVO4.

[0017] Among them, the counter electrode of the electrode pair includes platinum.

[0018] Among them, the composite of BiVO4 includes BiVO4 and an FTO, ITO or conductive ceramic layer on the surface of BiVO4.

[0019] Among them, the electrolyte for the photo-electro-cocatalysis reaction includes any one or a mixture of several of Et4NBr, Et4NCl, n-Bu4NBr, n-Bu4NCl, KCl or NH4Cl.

[0020] Among them, the light source for the visible light catalysis includes white light or monochromatic light.

[0021] Among them, the reaction time is 4 - 12 hours. The reaction time can be determined by TLC or GC-MS detection according to the difference in reaction activity, and no specific limitation is made here. The provided reaction time of 4 - 12 hours is the set range of the reaction time under normal circumstances.

[0022] Among them, the solvent for the reaction includes alcohol; preferably, the solvent includes any one or several of ethanol, methanol, and isopropanol. The solvent used in the present invention is alcohol, which is of low toxicity, ensuring that the reaction can proceed greenly.

[0023] Among them, the organic nitrile source includes malononitrile, methyl cyanoacetate, ethyl cyanoacetate, n-propyl cyanoacetate or isopropyl cyanoacetate.

[0024] The present invention also includes a third technical solution, a compound applied to medicine, including the above-mentioned indolizino[2,1-a]isoquinoline derivative.

[0025] Beneficial effects:

[0026] (1) The indolizino[2,1-a]isoquinoline derivative, the cyano-substituted indolizino[2,1-a]isoquinoline, or the indolizino[2,1-a]isoquinoline co-substituted by cyano and other electron-withdrawing groups (such as ester groups) of the present invention is a class of novel compounds and can have wide applications in organic chemistry, material chemistry and medicinal chemistry.

[0027] (2) The preparation method of the indoline[2,1-a]isoquinoline derivative of the present invention is a novel preparation method. Without applying an external bias voltage and without heating, under room temperature conditions, visible light-induced photoelectrocatalysis can achieve the coupling / ring closure of cheap and easily available N-aryl tetrahydroisoquinoline and organic nitriles, and various indoline[2,1-a]isoquinoline compounds can be obtained in one pot with high efficiency. This method has good substrate and functional group tolerance, and the catalyst can be recycled multiple times. The preparation method of the present invention is green and efficient, has mild preparation conditions, low requirements for equipment, simple operation, wide substrate applicability, low raw material prices, low production costs, high yields, and can be industrially produced in large quantities, thus having broad application prospects.

[0028] (3) The preparation method of the indoline[2,1-a]isoquinoline derivative of the present invention uses photoelectro-cocatalysis, and the catalyst used is BiVO4 or a composite containing BiVO4. The bismuth vanadate photoanode is cheap and has good stability. Its band gap is 2.4 eV, has good response to visible light, and its potential matches the potential of substances. Using BiVO4 or a composite containing BiVO4 as the photoanode can also be used as a catalyst at the same time, so that under visible light irradiation, without applying an external bias voltage and without heating, catalysis can be carried out at room temperature, and at the same time, it can also act as a photoanode to carry out electrocatalysis, that is, the photoanode can generate hole-electron pairs under visible light excitation, and the photogenerated electrons are transferred to the counter electrode through a wire. On the one hand, it can reduce the coupling of electron-hole pairs and accelerate the reaction rate; on the other hand, it separates the oxidation and reduction reactions in the photoreaction and promotes the reaction. The BiVO4 photoanode catalyst used in the preparation method of the present invention has low cost, is easy to prepare, easy to recycle, and can be reused.

[0029] (4) The preparation method of the indoline[2,1-a]isoquinoline derivative of the present invention has a low preparation time and can improve the preparation efficiency. Description of the Drawings

[0030] Figure 1 It is the yield diagram of the product obtained by repeatedly testing with BiVO4 / FTO as the photoanode in an embodiment of the present invention. Detailed Embodiments

[0031] The following are specific embodiments of the present invention, which are only used for explaining the present invention and not for limiting it. The improvements and adjustments made by those skilled in the art in the application of reagents according to the present invention still fall within the protection scope of the present invention.

[0032] The embodiments of the present invention provide indoline[2,1-a]isoquinoline derivatives, and the structural formula of the indoline[2,1-a]isoquinoline derivative is:

[0033]

[0034] Among them, R 1 includes alkyl, alkoxy, hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano; R 2 includes aryl, alkoxy, hydrogen, chlorine or bromine; R 3 includes aryl, alkoxy, hydrogen, chlorine or bromine; R 4 includes an electron-withdrawing group; R 1 is located at the C8, C9, C10 or C11 position of the indoline[2,1-a]isoquinoline derivative; R 2 or R 3 is located at the C2 or C3 position of the indoline[2,1-a]isoquinoline derivative, R 2 or R 3 can be the same or different.

[0035] Furthermore, R 1 's alkyl includes C1-C8 alkyl, R 1 's alkoxy includes C1-C8 alkoxy; R 2 's aryl includes phenyl or various aryls containing electron-donating and electron-withdrawing groups, R 2 's alkoxy includes C1-C8 alkoxy; R 3 's aryl includes phenyl or various aryls containing electron-donating and electron-withdrawing groups, R 3 's alkoxy includes C1-C8 alkoxy; R 4 's electron-withdrawing group includes cyano, C1-C8 alkanoate group.

[0036] Furthermore, R 1 's C1-C8 alkyl includes tert-butyl, methyl, ethyl, isopropyl or n-butyl, R 1 's C1-C8 alkoxy includes methoxy or ethoxy; R 2 's C1-C8 alkoxy includes methoxy or ethoxy; R 3 's C1-C8 alkoxy includes methoxy or ethoxy.

[0037] The present invention also includes a second technical solution, a preparation method of indoline[2,1-a]isoquinoline derivative, including: using N-aryl tetrahydroisoquinoline and organic nitriles as raw materials, at room temperature, adopting a photoelectric co-catalyzed reaction to obtain the indoline[2,1-a]isoquinoline derivative; the reaction formula of the synthesis process is:

[0038]

[0039] Among them, the indoline[2,1-a]isoquinoline derivative is compound 4; R 1 includes alkyl, alkoxy, hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano; R 2 includes aryl, alkoxy, hydrogen, chlorine or bromine; R3 including aryl, alkoxy, hydrogen, chlorine or bromine; R 4 including an electron-withdrawing group; R 1 being located at the C8, C9, C10 or C11 position of the dihydroindolo[2,1-a]isoquinoline derivative; R 2 or R 3 being located at the C2 or C3 position of the dihydroindolo[2,1-a]isoquinoline derivative, R 2 or R 3 may be the same or different.

[0040] Specifically, when R 3 in the preparation method of the present invention is hydrogen, the reaction formula of the synthesis process is

[0041]

[0042] Among them, the photoelectro-cocatalysis includes photocatalysis and electrocatalysis. The photocatalysis uses visible light catalysis; the electrocatalysis has an electrode pair without bias voltage, and the anode of the electrode pair includes a BiVO4 photoanode or a composite photoanode of BiVO4.

[0043] Among them, the counter electrode of the electrode pair includes platinum.

[0044] Among them, the composite of BiVO4 includes BiVO4 and an FTO, ITO or conductive ceramic layer located on the surface of BiVO4.

[0045] Among them, the electrolyte for the photoelectro-cocatalytic reaction includes any one or a mixture of several of Et4NBr, Et4NCl, n-Bu4NBr, n-Bu4NCl, KCl or NH4Cl.

[0046] Among them, the light source for visible light catalysis includes white light or monochromatic light. For example, the monochromatic light can be blue light, green light, etc.

[0047] Among them, the reaction time is 4 - 12 hours. The reaction time can be determined by TLC or GC-MS detection according to the difference in reaction activity, and no specific limitation is made here. The provided reaction time of 4 - 12 hours is the set range of the reaction time under normal circumstances.

[0048] Among them, the reaction solvent includes alcohol; preferably, the solvent includes any one or several of ethanol, methanol, and isopropanol. The solvent used in the present invention is alcohol, which is low in toxicity, ensuring that the reaction can proceed greenly.

[0049] Among them, the organic nitrile source includes malononitrile, methyl cyanoacetate, ethyl cyanoacetate, n-propyl cyanoacetate or isopropyl cyanoacetate.

[0050] To facilitate the understanding of the above technical solution, the present invention further provides specific embodiments for its illustration, but the present invention is not limited to the following specific embodiments.

[0051] Example 1

[0052] The present invention provides a dihydroindolo[2,1-a]isoquinoline derivative, specifically 12,12(6H)-dicyano-5,12a-dihydroindolo[2,1-a]isoquinoline (4a), and its structural formula is:

[0053]

[0054] The preparation method of the dihydroindolo[2,1-a]isoquinoline derivative of the present invention includes:

[0055] In a quartz reaction tube, 0.2 mmol of N-aryl tetrahydroisoquinoline and 0.3 mmol of malononitrile are sequentially added as raw materials, and ammonium chloride (0.1 M) and 5 mL of ethanol solution are added. Using BiVO4 / FTO as the photoanode and a platinum sheet as the counter electrode, the reaction is carried out under visible light irradiation without an external bias voltage. After the reaction is completed, the electrode is rinsed with dichloromethane, and the reaction solution is extracted successively with dichloromethane (5 mL × 3 times) and saturated brine (5 mL × 2 times). The organic phase is dried with anhydrous Na2SO4. After separation and purification by column chromatography (eluent: ethyl acetate / petroleum ether 1 / 30 - 1 / 10, v / v), the product can be obtained with a yield of 72%. Among them, the raw materials used in the embodiments of the present invention are shown in Table 1 of the raw materials, the structural formula of the obtained product is shown in Table 1 of the product, and the yield of the obtained product is shown in Table 1 of the yield.

[0056] The reaction formula of the synthesis process is:

[0057]

[0058] Among them, R 3 is hydrogen, R 2 is hydrogen, R 1 is hydrogen, R 4 is a nitrile group.

[0059] The results of the product structure characterization are:

[0060] 5,12a-dihydroindolo[2,1-a]isoquinoline-12,12(6H)-dicarbonitrile(4a)White solid(39.2mg,72%).mp.125 - 126℃. 11H NMR (400 MHz, CDCl3): δ 7.66 - 7.45 (m, 2H), 7.40 - 7.21 (m, 4H), 6.92 (t, J = 7.5 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 5.19 (s, 1H), 3.91 - 3.76 (m, 1H), 3.27 - 3.10 (m, 2H), 2.94 - 2.82 (m, 1H). 13 13C NMR (100 MHz, CDCl3): δ 149.5, 135.6, 132.2, 129.7, 129.6, 128.9, 127.2, 125.6, 124.9, 122.0, 120.5, 115.1, 112.2, 109.6, 72.0, 42.6, 42.5, 28.7. HRMS (ESI), calcd. for C 18 H 14 N3 (M + H) + : 272.1182, found: 272.1183.

[0061] In the implementation of the above synthesis method, the reaction time can be determined by those skilled in the art according to the difference in the reaction activity of the substrates through TLC or GC - MS detection, and no specific limitation is made here. Generally, the reaction time can be considered to be set to 4 - 12 hours.

[0062] In the examples of this application, the electrolyte is ammonium chloride. In other examples, the electrolyte can also be selected from including Et4NBr, Et4NCl, n - Bu4NBr, n - Bu4NCl or KCl; the solvent in the examples of this application is ethanol. In other examples, the solvent can also be selected from methanol or isopropanol.

[0063] The indolizino[2,1 - a]isoquinoline derivative prepared in the examples of this application is 12,12(6H)-dicyano - 5,12a - dihydroindolizino[2,1 - a]isoquinoline, which can be applied in the fields of medicine, organic chemistry and materials chemistry.

[0064] The photoanode used in the examples of this invention is BiVO4 / FTO with a flaky structure. In other examples, the photoanode can also be BiVO4 / ITO or BiVO4 / conductive ceramic layer. The photoanode in the examples of this invention is easily recyclable. Specifically, the recycled BiVO4 / FTO photoanode in the examples of this invention still has good cyclic catalytic ability. Therefore, the cyclic catalytic ability of the BiVO4 / FTO photoanode is further tested in the examples of this invention. The specific test conditions and test results are as follows:

[0065] After the reaction of the preparation method of indolizino[2,1-a]isoquinoline derivatives is completed, the BiVO4 / FTO photoanode is taken out from the reaction solution, washed three times with dichloromethane, and after drying, the BiVO4 / FTO photoanode is used for the above-mentioned preparation method of indolizino[2,1-a]isoquinoline derivatives and tested 10 times repeatedly. It is found that it still maintains a very high catalytic reaction ability and can convert the raw materials into the corresponding target products with a relatively high yield. Specifically, the yield of obtaining product 4 remains at 69%-73%; Figure 1 The yields of product 3a and product 4a obtained from the 10 repeated tests are given in Figure 1 , where product 4a is: 12,12(6H)-dicyano-5,12a-dihydroindolizino[2,1-a]isoquinoline (4a); product 3a is:

[0066]

[0067] wherein, R 1 and R 2 are both hydrogen, and the name of product 3a is: 2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile.

[0068] Table 1 Raw materials, products and yields of the synthesis method of indolizino[2,1-a]isoquinoline derivatives.

[0069]

[0070]

[0071]

[0072] Example 2

[0073] In the embodiment of the present invention, the indolizino[2,1-a]isoquinoline derivative has the following general structural formula:

[0074]

[0075] wherein, R 1 is tert-butyl ( t Bu) and is located at the C10 position; R 2 is hydrogen; R 3 is hydrogen; R 4 is cyano.

[0076] The embodiment of the present invention provides a preparation method of indolizino[2,1-a]isoquinoline derivatives, and the synthesis reaction formula is:

[0077]

[0078] The preparation method specifically includes: sequentially adding 0.2 mmol of 2-arylisoquinoline (raw material 1 in Example 2 of Table 2) and 0.3 mmol of organic nitrile (raw material 2 in Example 2 of Table 2) into a quartz reaction tube, and adding ammonium chloride (0.1 M) and 5 mL of ethanol solution. Using BiVO4 / FTO as the photoanode and a platinum sheet as the counter electrode, reacting under visible light irradiation without an external bias voltage. After the reaction, the electrode was rinsed with dichloromethane, and the reaction solution was extracted successively with dichloromethane (5 mL × 3 times) and saturated brine (5 mL × 2 times). The organic phase was dried with anhydrous Na2SO4. After separation and purification by column chromatography (eluent: ethyl acetate / petroleum ether 1 / 30 - 1 / 10, v / v), the product (the product in Example 2 of Table 2) could be obtained with a yield of 66%.

[0079] Example 3

[0080] The difference from Example 2 is that in the structural formula of the indolo[2,1-a]isoquinoline derivative, R 1 is ethyl (Et). The raw materials in the preparation method were the raw materials in Example 3 of Table 2, and the yield of the obtained product was 61%. Others are the same as in Example 2 and will not be elaborated here.

[0081] Example 4

[0082] The difference from Example 2 is that in the structural formula of the indolo[2,1-a]isoquinoline derivative, R 1 is methyl (Me). The raw materials in the preparation method were the raw materials in Example 4 of Table 2, and the yield of the obtained product was 68%. Others are the same as in Example 2 and will not be elaborated here.

[0083] Example 5

[0084] The difference from Example 2 is that in the structural formula of the indolo[2,1-a]isoquinoline derivative, R 1 is fluorine (F). The raw materials in the preparation method were the raw materials in Example 5 of Table 2, and the yield of the obtained product was 77%. Others are the same as in Example 2 and will not be elaborated here.

[0085] Example 6

[0086] The difference from Example 2 is that in the structural formula of the indolo[2,1-a]isoquinoline derivative, R 1 is chlorine (Cl). The raw materials in the preparation method were the raw materials in Example 6 of Table 2, and the yield of the obtained product was 77%. Others are the same as in Example 2 and will not be elaborated here.

[0087] Example 7

[0088] The difference from Example 2 is that in the structural formula of the indoline[2,1-a]isoquinoline derivative, R 1 is bromine (Br). The raw materials in the preparation method are the raw materials of Example 7 in Table 2, and the yield of the obtained product is 74%. Others are the same as in Example 2 and will not be elaborated here.

[0089] Example 8

[0090] The difference from Example 2 is that in the structural formula of the indoline[2,1-a]isoquinoline derivative, R 1 is trifluoromethyl (CF3). The raw materials in the preparation method are the raw materials of Example 8 in Table 2, and the yield of the obtained product is 20%. Others are the same as in Example 2 and will not be elaborated here.

[0091] Example 9

[0092] The difference from Example 2 is that in the structural formula of the indoline[2,1-a]isoquinoline derivative, R 1 is methoxy (OMe), and it is located at the C9 or C11 position. The indoline[2,1-a]isoquinoline derivatives of the embodiments of the present invention include: 12,12(6H)-dicyano-11-methoxy-5,12a-dihydroindoline[2,1-a]isoquinoline and 12,12(6H)-dicyano-9-methoxy-5,12a-dihydroindoline[2,1-a]isoquinoline. The raw materials in the preparation method are the raw materials of Example 9 in Table 2, and the yield of the obtained product is 76%. Others are the same as in Example 2 and will not be elaborated here.

[0093] Example 10

[0094] The difference from Example 2 is that in the structural formula of the indoline[2,1-a]isoquinoline derivative, R 1 is bromine (Br), and it is located at the C9 or C11 position. The indoline[2,1-a]isoquinoline derivatives of the embodiments of the present invention include: 12,12(6H)-dicyano-11-bromo-5,12a-dihydroindoline[2,1-a]isoquinoline and 12,12(6H)-dicyano-9-bromo-5,12a-dihydroindoline[2,1-a]isoquinoline. The raw materials in the preparation method are the raw materials of Example 10 in Table 2, and the yield of the obtained product is 52%. Others are the same as in Example 2 and will not be elaborated here.

[0095] Example 11

[0096] The difference from Example 2 is that in the structural formula of the indoline[2,1-a]isoquinoline derivative, R 2is bromine (Br) and is located at the C3 position. The raw materials in the preparation method are the raw materials of Example 11 in Table 2, and the yield of the obtained product is 66%. The others are the same as in Example 2 and will not be repeated here.

[0097] Example 12

[0098] The difference from Example 2 is that in the structural formula of the indoline [2,1-a]isoquinoline derivative, R 2 is bromine (Br) and is located at the C2 position. The raw materials in the preparation method are the raw materials of Example 12 in Table 2, and the yield of the obtained product is 85%. The others are the same as in Example 2 and will not be repeated here.

[0099] Example 13

[0100] The difference from Example 2 is that in the structural formula of the indoline [2,1-a]isoquinoline derivative, R 2 is chlorine (Cl) and is located at the C2 position. The raw materials in the preparation method are the raw materials of Example 13 in Table 2, and the yield of the obtained product is 65%. The others are the same as in Example 2 and will not be repeated here.

[0101] Example 14

[0102] The difference from Example 2 is that in the structural formula of the indoline [2,1-a]isoquinoline derivative, R 2 is aryl (Ph) and is located at the C2 position. The raw materials in the preparation method are the raw materials of Example 14 in Table 2, and the yield of the obtained product is 51%. The others are the same as in Example 2 and will not be repeated here.

[0103] Example 15

[0104] The difference from Example 2 is that in the structural formula of the indoline [2,1-a]isoquinoline derivative, R 2 is methoxy (MeO), and R 3 is methoxy (MeO), which are located at the C2 and C3 positions respectively. The raw materials in the preparation method are the raw materials of Example 15 in Table 2, and the yield of the obtained product is 54%. The others are the same as in Example 2 and will not be repeated here.

[0105] Example 16

[0106] The difference from Example 2 is that in the structural formula of the indoline [2,1-a]isoquinoline derivative, R 4 is methyl acetate (MeOOC). The raw materials in the preparation method are the raw materials of Example 16 in Table 2, and the yield of the obtained product is 38%. The ratio of the dextrorotatory to the levorotatory of the obtained product is 4:1. The others are the same as in Example 2 and will not be repeated here.

[0107] Example 17

[0108] The difference from Example 2 is that in the structural formula of the indoline [2,1-a]isoquinoline derivative, R 2 is bromine (Br), located at the C2 position; R 4 is methyl acetate (MeOOC). The raw materials in the preparation method are the raw materials of Example 17 in Table 2, and the yield of the obtained product is 68%. The ratio of the dextrorotatory to the levorotatory of the obtained product is 4:1. Others are the same as in Example 2 and will not be elaborated here.

[0109] Example 18

[0110] The difference from Example 2 is that in the structural formula of the indoline [2,1-a]isoquinoline derivative, R 2 is bromine (Br), located at the C2 position; R 4 is ethyl acetate (EtOOC). The raw materials in the preparation method are the raw materials of Example 18 in Table 2, and the yield of the obtained product is 56%. The ratio of the dextrorotatory to the levorotatory of the obtained product is 4:1. Others are the same as in Example 2 and will not be elaborated here.

[0111] Example 19

[0112] The difference from Example 2 is that in the structural formula of the indoline [2,1-a]isoquinoline derivative, R 2 is bromine (Br), located at the C2 position; R 4 is n-propyl acetate ( n PrOOC). The raw materials in the preparation method are the raw materials of Example 19 in Table 2, and the yield of the obtained product is 60%. The ratio of the dextrorotatory to the levorotatory of the obtained product is 4:1. Others are the same as in Example 2 and will not be elaborated here.

[0113] Example 20

[0114] The difference from Example 2 is that in the structural formula of the indoline [2,1-a]isoquinoline derivative, R 2 is bromine (Br), located at the C2 position; R 4 is isopropyl acetate ( i PrOOC). The raw materials in the preparation method are the raw materials of Example 20 in Table 2, and the yield of the obtained product is 60%. The ratio of the dextrorotatory to the levorotatory of the obtained product is 3:1. Others are the same as in Example 2 and will not be elaborated here.

[0115] The synthesis method of the present invention has many advantages such as cheap and easily available raw materials, green reaction conditions, wide substrate applicability, high synthesis yield, and recyclable catalytic system, and has broad application prospects.

[0116] Under the teachings of the present invention and the above embodiments, those skilled in the art can easily foresee that the present invention can be implemented by each of the raw materials listed or enumerated in the present invention or their equivalent substitutes, each processing method or its equivalent substitutes, as well as the upper and lower limit values and interval values of the parameters of each raw material and processing method. Examples of implementation are not listed one by one here.

Claims

1. A method for preparing indolizino[2,1-a]isoquinoline derivatives, characterized in that, Comprising: Using N-aryl tetrahydroisoquinoline and organic nitrile as raw materials, at room temperature, through a photoelectrochemical co-catalyzed reaction, a dihydroindolo[2,1-a]isoquinoline derivative is obtained; the reaction formula for the synthesis process is: Among them, the dihydroindolo[2,1-a]isoquinoline derivative is Compound 4; R 1 is an alkyl group, an alkoxy group, hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano group; R 2 is aryl, alkoxy, hydrogen, chlorine or bromine; R 3 is aryl, alkoxy, hydrogen, chlorine or bromine; R 4 is an electron-withdrawing group; R 1 is located at the C8, C9, C10 or C11 position of the indoline[2,1-a]isoquinoline derivative; R 2 or R 3 is located at the C2 or C3 position of the indoline[2,1-a]isoquinoline derivative, and said R 2 or R 3 may be the same or different; The photoelectrochemical co-catalysis includes photocatalysis and electrocatalysis. The photocatalysis uses visible light catalysis; for the electrocatalysis, an electrode pair without bias voltage is used, and the anode of the electrode pair is a BiVO4 photoanode or a composite photoanode of BiVO4; The electrolyte for the photoelectrochemical co-catalyzed reaction includes any one or a mixture of several of Et4NBr, Et4NCl, n-Bu4NBr, n-Bu4NCl, KCl, or NH4Cl; The reaction time is 4 - 12 hours, and the solvent for the reaction is alcohol.

2. The preparation method of the indolizino[2,1-a]isoquinoline derivative according to claim 1, characterized in that, The composite of BiVO4 includes BiVO4 and an FTO, ITO, or conductive ceramic layer located on the surface of BiVO4.

3. The preparation method of the indolizino[2,1-a]isoquinoline derivative according to claim 1, characterized in that, The light source for the visible light catalysis is white light or monochromatic light.

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