A method for synthesizing highly efficient polysubstituted pyrrolo[2,1-a]isoquinoline compounds

Abstract

The application relates to a synthesis method of high-efficiency polysubstituted pyrrolo[2,1-a]isoquinoline compounds, and discloses that 2-(3,4-dihydroisoquinoline-2(1H)-yl) malononitrile compounds, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are used as oxidants, substituted isocyanoacetate is used, and polysubstituted pyrrolo[2,1-a]isoquinoline compounds are synthesized under the action of a catalyst. The starting material used in the method is cheap, the reaction condition is mild, the experimental operation is simple, the input of funds and labor can be saved, and a simple and efficient preparation method of polysubstituted pyrrolo[2,1-a]isoquinoline compounds is provided.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to an efficient method for synthesizing polysubstituted pyrrolo[2,1-a]isoquinoline compounds. Background Technology

[0002] Pyrrolo[2,1-a]isoquinolines, whose structure comprises two structural units, isoquinoline and pyrrole, are an important class of heterocyclic compounds. They are found in many natural products and pharmaceutically active molecules, exhibiting a variety of effective pharmacological activities, and their synthetic methods have received widespread attention and development. This invention creatively synthesizes polysubstituted pyrrolo[2,1-a]isoquinolines by sequentially adding 2-(3,4-dihydroisoquinoline-2(1H)-yl)malonadionitrile compounds, substituted isocyanate esters, and catalysts to an organic solvent. This method uses inexpensive starting materials, has mild reaction conditions, broad substrate applicability, and simple experimental operation, saving both financial and labor costs. It provides a concise and efficient preparation method for polysubstituted pyrrolo[2,1-a]isoquinolines. Therefore, this invention has outstanding practical value, which can actively promote the process development of similar and downstream products and improve the economic efficiency of industrial production. Summary of the Invention

[0003] The purpose of this invention is to overcome the shortcomings of existing production technologies and provide a simple and mild method for synthesizing polysubstituted pyrrolo[2,1-a]isoquinoline compounds.

[0004] The technical solution of this invention is as follows: Substrate, catalyst, and oxidant are placed in a test tube, a solvent is added, and polysubstituted pyrrolo[2,1-a]isoquinoline compounds are synthesized under argon protection and room temperature conditions. The reaction formula is as follows:

[0005]

[0006] (1)R 1 Selected from nitro, chloro, bromo, fluorine, methyl, methoxy, 1,3-dioxolane, phenyl, naphthalene, and thiophene;

[0007] (2)R 2 Selected from methyl carboxylate, ethyl carboxylate, tert-butyl carboxylate, and p-toluenesulfonyl groups;

[0008] (3) The catalyst is selected from silver carbonate, silver oxide, silver fluoride, silver trifluoromethanesulfonate, etc., with silver carbonate being preferred;

[0009] (4) The solvent is selected from one or more of 1,4-dioxane, tetrahydrofuran, acetonitrile, and 1,2-dichloroethane, preferably 1,4-dioxane;

[0010] (5) the temperature is 0-80°C and the maintenance time is 24-72 hours, preferably room temperature and 36 hours;

[0011] (6) the molar ratio of each substance in the reactants is: 2-(3,4-dihydroisoquinolin-2(lH)-yl)propanedinitrile compound: isocyanoacetate: catalyst: base = 1:1.2:0-2:0-2, preferably 1:1.2:1.2:1.2. BRIEF DESCRIPTION OF DRAWINGS

[0012] 1. Figure 1 is a reaction formula for the preparation of compound I1;

[0013] 2. Figure 2 is a reaction formula for the preparation of compound I2;

[0014] 3. Figure 3 is a reaction formula for the preparation of compound I3;

[0015] 4. Figure 4 is a reaction formula for the preparation of compound I4;

[0016] 5. Figure 5 is a reaction formula for the preparation of compound I5;

[0017] 6. Figure 6 is a reaction formula for the preparation of compound I6;

[0018] 7. Figure 7 is a reaction formula for the preparation of compound I7;

[0019] 8. Figure 8 is a reaction formula for the preparation of compound I8;

[0020] 9. Figure 9 is a reaction formula for the preparation of compound I9;

[0021] 10. Figure 10 is a reaction formula for the preparation of compound I10;

[0022] 11. Figure 11 is a reaction formula for the preparation of compound I11;

[0023] 12. Figure 12 is a reaction formula for the preparation of compound I12;

[0024] 13. Figure 13 is a reaction formula for the preparation of compound I13;

[0025] 14. Figure 14 is a reaction formula for the preparation of compound I14;

[0026] 15. Figure 15 is a reaction formula for the preparation of compound I15;

[0027] 16. Figure 16 The reaction formula for the preparation of compound I16;

[0028] 17. Figure 17 The reaction formula for the preparation of compound I17;

[0029] 18. Figure 18 The reaction formula for the preparation of compound I18;

[0030] 19. Figure 19 The reaction formula for the preparation of compound I19;

[0031] 20. Figure 20 This is the reaction formula for the preparation of compound I20. Detailed Implementation

[0032] The present invention will be further described below through specific embodiments, but it should not be construed as limiting the scope of the subject matter of the present invention to the following embodiments. All technologies implemented based on the above content of the present invention are within the scope of the present invention.

[0033] Implementation Case 1 uses 2-(3,4-dihydroisoquinoline-2(1H)-yl)malononitrile substrate A1 and isocyanate substrate B1 as starting materials (Reaction Formula 1).

[0034]

[0035] A magnetic stir bar, A1 (0.2 mmol, 39.4 mg, 1.0 equiv.), and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was reacted at room temperature for 1 hour. The reaction was monitored by TLC. After the reactants were consumed, the solvent in the reaction system was removed using a rotary evaporator. Then, B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), and Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was carried out at room temperature for 36 hours. After the reaction was completed, the system was filtered through diatomaceous earth and washed with dichloromethane. The filtrate was collected and concentrated under vacuum using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain product I1.

[0036] The product test data are as follows:

[0037] White solid, yield 82%, melting range 158-160℃.

[0038] 1 H NMR (400 MHz, CDC13): δ 8.12 - 8.12 (m, 1H), 7.30 - 7.27 (m, 2H), 7.24 - 7.22 (m, 1H), 5.04 (s, 2H), 4.35 (q, J = 7.2 Hz, 2H), 3.95 (t, J = 6.8 Hz, 2H), 3.05 (t, J = 6.4 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H).

[0039] 13 C NMR (100 MHz, CDC13): δ 164.6, 147.2, 135.4, 133.5, 129.0, 128.5, 127.6, 126.7, 126.4, 113.7, 99.0, 88.5, 60.2, 42.5, 29.0, 14.2.

[0040] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 16 N3O2282.1237; Found: 282.1232.

[0041] Case two was performed with 2-(3,4-dihydroisoquinolin-2(lH)-yl)propanedinitrile substrate A2, isocyanoacetate substrate B1 as starting materials (Reaction Scheme 2)

[0042]

[0043] To a pre-dried 10 mL reaction tube, a magnetic stir bar, A2 (0.2 mmol, 48.4 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added and dissolved using acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. TLC monitoring of the reaction, after the completion of the consumption of the raw material, the solvent of the reaction system was removed using a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), Ag2CO3(0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved using 1,4-dioxane (3 mL), and the reaction was carried out at room temperature for 36 hours. After the reaction was completed, the reaction system was filtered through diatomite and washed with dichloromethane, and the filtrate was collected and concentrated under vacuum using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain product I2.

[0044] The product detection data are as follows:

[0045] Bright yellow solid, yield 59%, melting point 223-225 °C.

[0046] 1 H NMR (400 MHz, CDC13): δ 9.08 (s, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 5.17 (s, 2H), 4.40 (q, J = 7.2 Hz, 2H), 4.04 (t, J = 6.4 Hz, 2H), 3.18 (t, J = 6.4 Hz, 2H), 1.37 (t, J = 6.8 Hz, 3H).

[0047] 13 C NMR (100 MHz, CDC13): δ 164.3, 147.5, 147.1, 140.2, 132.6, 128.6, 127.8, 123.6, 123.3, 113.0, 99.9, 89.5, 60.9, 42.1, 29.2, 14.1.

[0048] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 15 N4O4327.1088; Found: 327.1078.

[0049] Case three was performed with 2-(3,4-dihydroisoquinolin-2(lH)-yl)propanedinitrile substrate A3, isocyanoacetate substrate B1 as starting materials (Reaction Scheme 3)

[0050]

[0051] To a pre-dried 10 mL reaction tube, a magnetic stir bar, A3 (0.2 mmol, 43.0 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added and dissolved using acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. TLC monitoring of the reaction, after the completion of the consumption of the starting material, the solvent of the reaction system was removed using a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), Ag2CO3(0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved using 1,4-dioxane (3 mL), and the reaction was carried out at room temperature for 36 hours. After the completion of the reaction, the system was filtered through celite and washed with dichloromethane, and the filtrate was collected and concentrated under vacuum using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain product I3.

[0052] Product assay data is as follows:

[0053] Bright yellow solid, yield 82%, melting range 175-177 °C.

[0054] 1 H NMR (400 MHz, CDC13): δ 7.93 (dd, J = 10.8, 2.8 Hz, 1H), 7.18 (dd, J = 8.4, 5.6 Hz, 1H), 7.01 - 6.96 (m, 1H), 5.08 (s, 2H), 4.36 (q, J = 7.2 Hz, 2H), 3.97 - 3.94 (m, 2H), 3.02 (t, J = 6.8 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H).

[0055] 13 C NMR (100 MHz, CDC13): δ 164.4, 161.4 (d, J = 241.7 Hz), 147.2, 134.2 (d, J = 2.8 Hz), 129.1 (d, J = 3.1 Hz), 128.8 (d, J = 8.1 Hz), 128.0 (d, J = 9.6 Hz), 115.7 (d, J = 6.8 Hz), 115.5 (d, J = 10.5 Hz), 113.4, 99.4, 89.0, 60.4, 42.8, 28.3, 14.1.

[0056] 19 F NMR (376 MHz, CDC13) δ -114.84.

[0057] HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 16 H 15 FN3O2300.1143; Found: 300.1133.

[0058] Case four was implemented with 2-(3,4-dihydroisoquinolin-2(lH)-yl)malononitrile substrate A4, isocyanoacetate substrate B1 as raw materials (reaction formula 4)

[0059]

[0060] A 10 mL reaction tube previously dried was charged with a magnetic stir bar, A4 (0.2 mmol, 46.2 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) dissolved using acetonitrile (2 mL). The system was left to react under stirring at room temperature for 1 h. The reaction was monitored by TLC and once the consumption of the starting material was complete, the solvent of the reaction system was removed using a rotary evaporator. Subsequently, B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μί, 1.2 equiv.), Ag2C03(0.24 mmol, 66.2 mg, 1.2 equiv.) were added dissolved using 1,4-dioxane (3 mL) and left to react at room temperature for 36 h. Once the reaction was complete, the system was filtered through celite and washed with dichloromethane, the filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by column chromatography on silica gel (PE:EA = 10:1) to obtain the product I4.

[0061] Product test data are as follows:

[0062] Bright yellow solid with a yield of 78% and a melting range of 133-135 °C.

[0063] 1 H NMR (400 MHz, CDC13): δ 8.18 (d, J = 2.0 Hz, 1H), 7.29 (dd, J = 8.0, 2.0 Hz,

[0064] 1H), 7.20 (d, J = 8.0 Hz, 1H), 5.17 (s, 2H), 4.39 (q, J = 7.2 Hz, 2H), 3.99 (t, J = 6.4

[0065] Hz, 2H), 3.05 (t, J = 6.6 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H).

[0066] 13 C NMR (100 MHz, CDC13): δ 164.4, 147.4, 133.6, 132.5, 131.8, 128.7, 128.6, 128.4, 127.9, 113.3, 99.3, 89.0, 60.4, 42.5, 28.5, 14.1.

[0067] HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 16 H 15 ClN3O2316.0847; Found: 316.0838.

[0068] Case five was carried out with 2-(3,4-dihydroisoquinolin-2(lH)-yl)malononitrile substrate A5, isocyanoacetate substrate B1 as starting materials (Reaction Scheme 5)

[0069]

[0070] To a pre-dried 10 mL reaction tube, a magnetic stir bar, A5 (0.2 mmol, 55.2 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added and dissolved using acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. TLC monitoring of the reaction, after the completion of the consumption of the starting material, the solvent of the reaction system was removed using a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), Ag2CO3(0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved using 1,4-dioxane (3 mL), and the reaction was carried out at room temperature for 36 hours. After the completion of the reaction, the system was filtered through celite and washed with dichloromethane, and the filtrate was collected and concentrated under vacuum using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain product I5.

[0071] The product detection data are as follows:

[0072] Bright yellow solid, yield 79%, melting range 148-150 °C.

[0073] 1 H NMR (400 MHz, CDC13): δ 8.27 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.0, 2.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 5.13 (s, 2H), 4.35 (q, J = 7.2 Hz, 2H), 3.96 - 3.93 (m, 2H), 2.99 (t, J = 6.4 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H).

[0074] 13 C NMR (100 MHz, CDC13): δ 164.5, 147.5, 133.4, 132.3, 131.6, 131.3, 129.0, 128.2, 120.4, 113.4, 99.3, 89.1, 60.4, 42.5, 28.5, 14.2.

[0075] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 15BrN3O2360.0342; Found: 360.0328.

[0076] Case six was carried out with 2-(3,4-dihydroisoquinolin-2(lH)-yl)malononitrile substrate A6, isocyanoacetate substrate B1 as starting materials (Reaction Scheme 6)

[0077]

[0078] To a pre-dried 10 mL reaction tube, a magnetic stir bar, A6 (0.2 mmol, 55.2 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added and dissolved using acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. TLC monitoring of the reaction, after the completion of the consumption of the starting material, the solvent of the reaction system was removed using a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), Ag2CO3(0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved using 1,4-dioxane (3 mL), and the reaction was carried out at room temperature for 36 hours. After the completion of the reaction, the system was filtered through celite and washed with dichloromethane, and the filtrate was collected and concentrated under vacuum using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain product I6.

[0079] The product detection data are as follows:

[0080] Bright yellow solid, yield 64%, melting range 149-151 °C.

[0081] 1 H NMR (600 MHz, CDC13) δ 8.03 (d, J = 9.0 Hz, 1H), 7.43 (dd, J = 6.4, 1.8 Hz, 1H), 7.40 (s, 1H), 5.03 (s, 2H), 4.35 (q, J = 7.2 Hz, 2H), 3.97 - 3.95 (m, 2H), 3.04 (t, J = 6.6 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H).

[0082] 13 C NMR (150 MHz, DMSO-d6) δ 164.1, 147.5, 136.9, 133.7, 130.6, 130.0, 129.3, 125.4, 121.9, 114.0, 98.1, 88.1, 59.9, 42.0, 27.9, 14.2.

[0083] HRMS (ESI-TOF) m / z: [M + H]+ Calcd for C 16 H 15 BrN3O2360.0342; Found: 360.0338.

[0084] Example Seven

[0085] Using 2-(3,4-dihydroisoquinolin-2(lH)-yl)propanedinitrile substrate A7, isocyanoacetate substrate Bl as starting materials (Reaction Scheme 7)

[0086]

[0087] To a pre-dried 10 mL reaction tube, add a magnetic stir bar, A7 (0.2 mmol, 55.2 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.), and dissolve using acetonitrile (2 mL). Stir the system at room temperature for 1 hour. Monitor the reaction by TLC, and after the starting material is consumed, remove the solvent of the reaction system using a rotary evaporator. Then add Bl (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μί, 1.2 equiv.), Ag2C03(0.24 mmol, 66.2 mg, 1.2 equiv.), and dissolve using 1,4-dioxane (3 mL), and react at room temperature for 36 hours. After the reaction is complete, filter the system through celite and rinse with dichloromethane, collect the filtrate, and concentrate under vacuum using a rotary evaporator. Purify the crude product by silica gel column chromatography (PE:EA = 10: 1) to obtain product I7.

[0088] Product detection data are as follows:

[0089] Bright yellow solid, yield 85%, melting range 150-152 °C.

[0090] 1 H NMR (400 MHz, CDC13): δ 8.05-8.04 (m, 1H), 7.53 (dd, J = 8.0, 0.8 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 5.04 (s, 2H), 4.33 (q, J = 7.2 Hz, 2H), 3.95-3.93 (m, 2H), 3.20 (t, J = 6.6 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H).

[0091] 13C NMR (100 MHz, CDC13): δ 164.4, 147.2, 134.3, 133.1, 133.0, 128.3, 127.8, 127.7, 123.3, 113.4, 99.4, 88.8, 60.3, 42.1, 28.6, 14.2.

[0092] HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 16 H 15 BrN3O2360.0342; Found: 360.0345.

[0093] Example Eight

[0094] Using 2-(3,4-dihydroisoquinolin-2(lH)-yl)malononitrile substrate A8, isocyanoacetate substrate B1 as starting materials (Reaction Scheme 8)

[0095]

[0096] To a pre-dried 10 mL reaction tube, a magnetic stir bar, A8 (0.2 mmol, 42.3 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added and dissolved using acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. TLC monitoring of the reaction showed that the starting material was consumed after 1 hour. The solvent of the reaction system was removed using a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), Ag2CO3(0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved using 1,4-dioxane (3 mL), and the reaction was carried out at room temperature for 36 hours. After the reaction was completed, the system was filtered through celite and washed with dichloromethane, and the filtrate was collected and concentrated under vacuum using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain product I8.

[0097] The product detection data are as follows:

[0098] Bright yellow solid, yield 73%, melting range 158-160 °C.

[0099] 1H NMR (400 MHz, CDC13): δ 7.92 (s, 1H), 7.11 (s, 2H), 5.07 (s, 2H), 4.35 (q, J = 7.2 Hz, 2H), 3.94 - 3.91 (m, 2H), 2.99 (t, J = 6.8 Hz, 2H), 2.36 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H).

[0100] 13 C NMR (100 MHz, CDC13): δ 164.7, 147.4, 136.2, 135.5, 130.6, 129.7, 129.1, 127.4, 126.3, 113.7, 98.9, 88.5, 60.1, 42.8, 28.6, 21.2, 14.2.

[0101] HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 17 H 18 N3O2296.1394; Found: 296.1389.

[0102] Case nine was performed with 2-(3,4-dihydroisoquinolin-2(lH)-yl)malononitrile substrate A9, isocyanoacetate substrate B1 as starting materials (reaction scheme 9)

[0103]

[0104] To a pre-dried 10 mL reaction tube, a magnetic stir bar, A9 (0.2 mmol, 45.5 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added and dissolved using acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. TLC monitoring of the reaction, after the completion of the consumption of the starting material, the solvent of the reaction system was removed using a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), Ag2CO3(0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved using 1,4-dioxane (3 mL), and the reaction was carried out at room temperature for 36 hours. After the completion of the reaction, the system was filtered through celite and washed with dichloromethane, and the filtrate was collected and concentrated under vacuum using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain the product I9.

[0105] The product detection data are as follows:

[0106] White solid, yield 70%, melting range 137-139 °C.

[0107] 1 H NMR (400 MHz, CDC13): δ 7.78 (d, J = 2.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.84 (dd, J = 8.4, 2.4 Hz, 1H), 5.04 (s, 2H), 4.36 (q, J = 7.2 Hz, 2H), 3.93 (t, J = 6.0 Hz, 2H), 3.82 (s, 3H), 2.97 (t, J = 6.4 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H).

[0108] 13 C NMR (100 MHz, CDC13): δ 164.5, 158.3, 147.1, 135.4, 128.3, 127.2, 125.6, 114.5, 114.4, 113.7, 99.1, 88.7, 60.3, 55.4, 43.0, 28.1, 14.3.

[0109] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 17 H 18 N3O3312.1343; Found: 312.1341.

[0110] Case ten was carried out with 2-(3,4-dihydroisoquinolin-2(lH)-yl)malononitrile substrate A10, isocyanoacetate substrate B1 as raw materials (reaction formula 10)

[0111]

[0112] A 10 mL reaction tube was added with a magnetic stirrer, A10 (0.2 mmol, 45.5 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.), and acetonitrile (2 mL) was used for dissolution. The system was stirred at room temperature for 1 hour. TLC was used to monitor the reaction, and after the completion of the consumption of the raw material, the solvent of the reaction system was removed using a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added, 1,4-dioxane (3 mL) was used for dissolution, and the reaction was carried out at room temperature for 36 hours. After the completion of the reaction, the system was filtered through diatomite, washed with dichloromethane, the filtrate was collected, and vacuum concentration was carried out using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain the product I10.

[0113] Product detection data as follows:

[0114] Bright yellow solid, yield 67%, melting range 139-141 °C.

[0115] 1 H NMR (400 MHz, CDC13): δ 8.11 (d, J = 8.8 Hz, 1H), 6.81 (dd, J = 8.8, 2.6 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 5.02 (s, 2H), 4.34 (q, J = 7.2 Hz, 2H), 3.91 (t, J = 6.4 Hz, 2H), 3.83 (s, 3H), 3.01 (t, J = 6.4 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H).

[0116] 13 C NMR (100 MHz, CDC13): δ 164.6, 160.0, 147.2, 135.9, 135.6, 130.3, 119.3, 114.0, 113.2, 111.8, 98.3, 87.9, 60.1, 55.3, 42.4, 29.3, 14.2.

[0117] HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 17 H 18 N3O3312.1343; Found: 312.1339.

[0118] Case eleven was implemented with 2-(3,4-dihydroisoquinolin-2(lH)-yl)malononitrile substrate A11, isocyanoacetate substrate B1 as raw material (reaction formula 11)

[0119]

[0120] To a pre-dried 10 mL reaction tube, add a magnetic stir bar, A11 (0.2 mmol, 53.2 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) dissolved using acetonitrile (2 mL). Stir the reaction at room temperature for 1 hour. Monitor the reaction by TLC, after the starting material is consumed, remove the solvent from the reaction using a rotary evaporator. Then add B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μί, 1.2 equiv.), Ag2C03(0.24 mmol, 66.2 mg, 1.2 equiv.) dissolved using 1,4-dioxane (3 mL), and stir at room temperature for 36 hours. After the reaction is complete, filter the reaction through celite and rinse with dichloromethane, collect the filtrate and concentrate under vacuum using a rotary evaporator. Purify the crude product by silica gel column chromatography (PE:EA = 10: 1) to give product I11.

[0121] Product testing data are as follows:

[0122] Bright yellow solid, yield 65%, melting range 204-206 °C.

[0123] 1 H NMR (400 MHz, CDC13): δ 8.31 (s, 1H), 7.33 (s, 1H), 5.12 (s, 2H), 4.37 (q, J = 7.2 Hz, 2H), 3.99-3.96 (m, 2H), 3.02 (t, J = 6.4 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H).

[0124] 13 C NMR (100 MHz, CDC13): δ 164.4, 147.4, 133.3, 132.9, 132.5, 130.9, 130.2, 129.23, 126.3, 113.2, 99.5, 89.3, 60.6, 42.4, 28.4, 14.2.

[0125] HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 16 H 14 Cl2N3O2350.0458; Found: 350.0441.

[0126] Case twelve is carried out with 2-(3,4-dihydroisoquinolin-2(lH)-yl)malononitrile substrate A12, isocyanoacetate substrate B1 as raw material (reaction formula 12)

[0127]

[0128] To a pre-dried 10 mL reaction tube, add a magnetic stir bar, A12 (0.2 mmol, 51.5 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.), dissolve using acetonitrile (2 mL). Stir the system at room temperature for 1 hour. Monitor the reaction by TLC, after the completion of the consumption of the starting material, remove the solvent of the reaction system using a rotary evaporator. Then add B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.), dissolve using 1,4-dioxane (3 mL), react at room temperature for 36 hours. After the completion of the reaction, filter the system through celite, and rinse with dichloromethane, collect the filtrate, and concentrate under vacuum using a rotary evaporator. Purify the crude product by silica gel column chromatography (PE:EA = 10:1) to obtain the product I12.

[0129] The product detection data are as follows:

[0130] White solid, yield 41%, melting range 131-133 °C.

[0131] 1 H NMR (400 MHz, CDC13): δ 7.92 (s, 1H), 6.72 (s, 1H), 4.98 (s, 2H), 4.37 (q, J = 7.2 Hz, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 2.99 (t, J = 6.8 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H).

[0132] 13 C NMR (100 MHz, CDC13): δ 164.6, 149.7, 147.4, 147.1, 136.2, 127.0, 119.3, 113.9, 112.4, 110.6, 98.6, 88.2, 60.2, 56.1, 56.0, 42.8, 28.7, 14.5.

[0133] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 18 H 20 N3O4342.1448; Found: 342.1441.

[0134] Case thirteen is carried out with 2-(3,4-dihydroisoquinolin-2(lH)-yl)malononitrile substrate A13, isocyanate substrate B1 as raw material (reaction formula 13)

[0135]

[0136] To a pre-dried 10 mL reaction tube, a magnetic stir bar, A13 (0.2 mmol, 48.3 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added and dissolved using acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. TLC monitored the reaction and after the completion of the consumption of the starting material, the solvent of the reaction system was removed using a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), Ag2CO3(0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved using 1,4-dioxane (3 mL), and the reaction was carried out at room temperature for 36 hours. After the completion of the reaction, the system was filtered through celite and washed with dichloromethane, and the filtrate was collected and concentrated under vacuum using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain the product I13.

[0137] The product detection data are as follows:

[0138] White solid, yield 72%, melting range 210-212 °C.

[0139] 1 H NMR (400 MHz, CDC13): δ 7.65 (s, 1H), 6.70 (s, 1H), 5.98 (s, 2H), 5.02 (s, 2H), 4.35 (q, J = 7.2 Hz, 2H), 3.91-3.88 (m, 2H), 3.02-2.83 (t, J = 6.8 Hz 2H), 1.37 (t, J = 7.2 Hz, 3H).

[0140] 13 C NMR (100 MHz, CDC13): δ 164.6, 148.1, 147.2, 146.4, 135.7, 128.6, 120.2, 113.9, 109.2, 108.0, 101.4, 98.5, 88.1, 60.2, 42.6, 29.2, 14.3.

[0141] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 17 H 16 N3O4326.1135; Found: 326.1132.

[0142] Case fourteen was carried out with 2-(3,4-dihydroisoquinolin-2(lH)-yl)malononitrile substrate A14, isocyanoacetate substrate B1 as starting materials (Reaction Scheme 14)

[0143]

[0144] To a pre-dried 10 mL reaction tube, a magnetic stir bar, A14 (0.2 mmol, 54.7 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added and dissolved using acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. TLC monitoring of the reaction, after the completion of the consumption of the starting material, the solvent of the reaction system was removed using a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), Ag2CO3(0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved using 1,4-dioxane (3 mL), and the reaction was carried out at room temperature for 36 hours. After the completion of the reaction, the system was filtered through celite and washed with dichloromethane, and the filtrate was collected and concentrated under vacuum using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain the product I14.

[0145] The product detection data are as follows:

[0146] Bright yellow solid, yield 66%, melting range 181-183 °C.

[0147] 1 H NMR (400 MHz, CDC13): δ 8.41 (d, J = 1.6 Hz, 1H), 7.62-7.60 (m, 2H), 7.52 (dd, J = 7.8, 1.8 Hz, 1H), 7.45 (t, J = 7.2 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.08 (s, 2H), 4.33 (q, J = 7.2 Hz, 2H), 4.01-3.97 (m, 2H), 3.08 (t, J = 6.4 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H).

[0148] 13 C NMR (100 MHz, CDC13): δ 164.6, 147.3, 140.5, 139.8, 135.4, 132.4, 128.8, 128.0, 127.5, 127.4, 126.9, 126.8, 113.7, 99.2, 88.7, 60.3, 42.7, 29.6, 28.7, 14.1.

[0149] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 22 H 20 N3O2358.1550; Found: 358.1539.

[0150] Case fifteen was carried out with 2-(3,4-dihydroisoquinolin-2(lH)-yl)malononitrile substrate A15, isocyanoacetate substrate B1 as starting materials (Reaction Scheme 15)

[0151]

[0152] To a pre-dried 10 mL reaction tube, a magnetic stir bar, A15 (0.2 mmol, 49.5 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added and dissolved using acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. TLC monitoring of the reaction, after the completion of the consumption of the starting material, the solvent of the reaction system was removed using a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), Ag2CO3(0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved using 1,4-dioxane (3 mL), and the reaction was carried out at room temperature for 36 hours. After the completion of the reaction, the system was filtered through celite and washed with dichloromethane, and the filtrate was collected and concentrated under vacuum using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to obtain product I15.

[0153] The product detection data are as follows:

[0154] Brown solid, yield 53%, melting range 183-185 °C.

[0155] 1 H NMR (400 MHz, CDC13): δ 8.09 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.58 - 7.50 (m, 2H), 5.07 (s, 2H), 4.37 (q, J = 7.2 Hz, 2H), 4.05 (t, J = 6.4 Hz, 2H), 3.48 (t, J = 6.8 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H).

[0156] 13C NMR (100 MHz, CDC13): δ 164.7, 147.3, 135.8, 133.6, 130.5, 130.2, 128.6, 126.7, 126.6, 126.2, 125.7, 124.2, 123.5, 113.7, 99.5, 88.5, 60.3, 42.1, 24.2, 14.3.

[0157] HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 20 H 18 N3O2332.1394; Found: 332.1385.

[0158] Case sixteen was implemented with 2-(3,4-dihydroisoquinolin-2(lH)-yl)malononitrile substrate A16, isocyanoacetate substrate B1 as raw materials (reaction formula 16)

[0159]

[0160] A 10 mL reaction tube was added with a magnetic stirrer, A16 (0.2 mmol, 49.5 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.), and was dissolved with acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. TLC monitoring showed that the raw material was consumed after 1 hour. The solvent of the reaction system was removed using a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), and Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved with 1,4-dioxane (3 mL), and the reaction was carried out at room temperature for 36 hours. After the reaction was completed, the system was filtered through diatomite, washed with dichloromethane, and the filtrate was collected and concentrated under vacuum using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to obtain product I16.

[0161] The product detection data are as follows:

[0162] Brown solid, yield 51%, melting range 172-174°C.

[0163] 1H NMR (400 MHz, CDC13): δ 7.97 (d, J = 8.2 Hz, 1H), 7.86 - 7.74 (m, 2H), 7.48 - 7.34 (m, 3H), 5.07 (s, 2H), 4.24 (s, 1H), 3.90 (s, 1H), 3.78 (s, 2H), 3.29 (s, 1H), 3.00 (s, 1H), 0.47 (t, J = 7.2 Hz, 3H).

[0164] 13 C NMR (100 MHz, CDC13): δ 165.1, 146.7, 133.9, 133.5, 132.9, 130.1, 129.6, 128.0, 126.1, 125.8, 125.5, 125.4, 124.5, 113.8, 101.3, 88.8, 59.9, 42.0, 30.4, 12.8.

[0165] HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 20 H 18 N3O2332.1394; Found: 332.1384.

[0166] Case seventeen was implemented with 2-(3,4-dihydroisoquinolin-2(lH)-yl)malononitrile substrate A17, isocyanoacetate substrate B1 as raw materials (reaction formula 17)

[0167]

[0168] A 10 mL reaction tube was added with a magnetic stirrer, A17 (0.2 mmol, 41.1 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.), and was dissolved with acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. TLC monitoring showed that the raw material was consumed after 1 hour. The solvent of the reaction system was removed using a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), and Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved with 1,4-dioxane (3 mL), and the reaction was carried out at room temperature for 36 hours. After the reaction was completed, the system was filtered through diatomite, washed with dichloromethane, and the filtrate was collected and concentrated under vacuum using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain product I17.

[0169] The product detection data are as follows:

[0170] White solid, yield 43%, m.p. 118-120 °C.

[0171] 1 H NMR (400 MHz, CDC13): δ 7.93 (d, J = 5.2 Hz, 1H), 7.14 (d, J = 5.2 Hz, 1H), 5.00 (s, 2H), 4.37 (q, J = 7.2 Hz, 2H), 4.04 (t, J = 7.2 Hz, 2H), 3.19 (t, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H).

[0172] 13 C NMR (100 MHz, CDC13): δ 164.3, 146.6, 136.0, 133.8, 128.0, 127.5, 122.2, 114.0, 98.4, 88.2, 60.2, 43.3, 24.0, 14.4.

[0173] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 14 H 14 N3O2S288.0801; Found: 288.0794.

[0174] Case eighteen was implemented with 2-(3,4-dihydroisoquinolin-2(lH)-yl)malononitrile substrate Al, isocyanoacetate substrate B2 as starting materials (reaction formula 18)

[0175]

[0176] To a pre-dried 10 mL reaction tube, a magnetic stirrer was added, Al (0.2 mmol, 39.4 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were dissolved with acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. TLC monitoring reaction, after the completion of raw material consumption, using a rotary evaporator to remove the solvent of the reaction system. Then B2 (0.24 mmol, 23.8 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), Ag2CO3(0.24 mmol, 66.2 mg, 1.2 equiv.) were dissolved with 1,4-dioxane (3 mL), and the reaction was carried out at room temperature for 36 hours. After the reaction was completed, the system was filtered through celite and washed with dichloromethane, and the filtrate was collected and concentrated under vacuum using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain product I18.

[0177] Product detection data as follows:

[0178] Brown solid, yield 80%, melting range 137-139 °C.

[0179] 1 H NMR (400 MHz, CDC13): δ 8.09-8.06 (m, 1H), 7.32-7.22 (m, 3H), 5.03 (s, 2H), 3.97-3.93 (m, 2H), 3.86 (s, 3H), 3.04 (t, J = 6.4 Hz, 2H).

[0180] 13 C NMR (100 MHz, CDC13): δ 164.9, 147.1, 135.5, 133.5, 129.1, 128.3, 127.6, 126.9, 126.4, 113.6, 98.8, 88.6, 51.1, 42.6, 29.0.

[0181] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 15 H 14 N3O2268.1081; Found: 268.1074.

[0182] Case Nineteen was carried out with 2-(3,4-dihydroisoquinolin-2(lH)-yl)malononitrile substrate Al, isocyanoacetate substrate B3 as raw materials (Reaction Formula 19)

[0183]

[0184] A 10 mL reaction tube was added with a magnetic stirrer, Al (0.2 mmol, 39.4 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.), and acetonitrile (2 mL) was used for dissolution. The system was stirred at room temperature for 1 hour. TLC was used to monitor the reaction, and after the completion of the consumption of the raw material, the solvent of the reaction system was removed using a rotary evaporator. Then B3 (0.24 mmol, 33.9 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added, 1,4-dioxane (3 mL) was used for dissolution, and the reaction was carried out at room temperature for 36 hours. After the completion of the reaction, the system was filtered through diatomite, washed with dichloromethane, the filtrate was collected, and vacuum concentration was performed using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain product I19.

[0185] Product detection data as follows:

[0186] Brown solid, yield 79%, melting point 152-154 °C.

[0187] 1 H NMR (400 MHz, CDC13): δ 8.12-8.10 (m, 1H), 7.30-7.26 (m, 2H), 7.23-7.21 (m, 1H), 5.02 (s, 2H), 3.94 (t, J = 6.4 Hz, 2H), 3.04 (t, J = 6.4 Hz, 2H), 1.58 (s, 9H).

[0188] 13 C NMR (100 MHz, CDC13): δ 164.1, 147.2, 135.2, 133.5, 128.9, 128.8, 127.5, 126.6, 126.5, 113.8, 100.4, 88.5, 81.4, 42.5, 29.1, 28.4.

[0189] HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 18 H 20 N3O2310.1550; Found: 310.1543.

[0190] Case twenty was carried out with 2-(3,4-dihydroisoquinolin-2(lH)-yl)propanedinitrile substrate Al, isocyanoacetate substrate B4 as raw materials (reaction formula 20)

[0191]

[0192] A 10 mL reaction tube was added with a magnetic stirrer, Al (0.2 mmol, 39.4 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.), and acetonitrile (2 mL) was used for dissolution. The system was stirred at room temperature for 1 hour. TLC was used to monitor the reaction, and after the completion of the consumption of the raw material, the solvent of the reaction system was removed using a rotary evaporator. Then B4 (0.24 mmol, 46.9 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added, 1,4-dioxane (3 mL) was used for dissolution, and the reaction was carried out at room temperature for 36 hours. After the completion of the reaction, the system was filtered through diatomite, washed with dichloromethane, the filtrate was collected, and concentrated under vacuum using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain product I20.

[0193] Product testing data as follows:

[0194] White solid, yield 15%, melting range 236-238 °C.

[0195] 1 H NMR (400 MHz, CDC13): δ 8.22 - 8.20 (m, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.29 - 7.24 (m, 4H), 7.20 - 7.18 (m, 1H), 5.17 (s, 2H), 3.99 (t, J = 6.4 Hz, 2H), 3.00 (t, J = 6.8 Hz, 2H), 2.38 (s, 3H).

[0196] 13 C NMR (100 MHz, CDC13): δ 145.5, 143.9, 140.6, 133.9, 133.4, 129.7, 129.6, 128.5, 127.9, 127.3, 126.0, 125.2, 112.9, 105.9, 89.4, 42.9, 28.7, 21.5.

[0197] HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 20 H 18 N3O2S 364.1114; Found: 364.1105.

Claims

1. A method for synthesizing highly efficient polysubstituted pyrrolo[2,1-a]isoquinolines, characterized in that, A, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, compound B, a catalyst and a base are sequentially added into an organic solvent to react at room temperature to synthesize a polysubstituted pyrrolo[2,1-a]isoquinoline compound, and a reaction formula is as follows: wherein R 1 selected from nitro, chloro, bromo, fluoro, methyl, methoxy, 1,3-dioxolane, phenyl, naphthalene, thiophene; R 2 selected from carboxylic acid methyl ester, carboxylic acid ethyl ester, carboxylic acid tert-butyl ester, p-toluenesulfonyl; said catalyst is selected from silver carbonate, silver oxide, silver fluoride, silver triflate.

2. The method of synthesis of claim 1, wherein: The solvent is selected from one or more of 1,4-dioxane, tetrahydrofuran, acetonitrile and 1,2-dichloroethane.

3. The method of synthesis of claim 1, wherein: The reaction time is 36 hours.

4. The method of synthesis of claim 1, wherein: The molar ratio of each substance in the reactants is: compound A: compound B: catalyst: base = 1:1.2:1.2:1.2.

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