Preparation method of vinyl tetrahydroisoquinolyl carbazolone compound

Abstract

The invention discloses a preparation method of a vinyl tetrahydroisoquinolyl carbazole ketone compound. According to the method, palladium is used as a catalyst, and a corresponding compound is generated through reaction in an organic solvent at the temperature of 80-100 DEG C under the action of alkali, a ligand and a reducing agent. According to the method, a series of indole substrates are synthesized by using simple and easily available raw materials, the intramolecular allyl dearomatization reaction of indole under the catalysis of palladium is realized, and various ring-fused indoline products are obtained under mild conditions. The method has the advantages of mild reaction conditions, simplicity and convenience in operation, high yield, excellent enantioselectivity, easiness in separation of target products and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing vinyl tetrahydroisoquinoline carbazole ketone compounds. Background Art

[0002] The dearomatization reaction of heterocyclic aromatic compounds catalyzed by transition metals has gradually attracted the attention of chemists. Indoline is the core skeleton of many biologically active natural products and drug molecules, and is also an important intermediate in the synthesis of complex natural products. Therefore, the efficient synthesis of these two types of compounds using transition metals has important research value. Polycyclic indoline derivatives are widely present in biologically active molecules and natural products such as alkaloids (-)-Communesin F, (+)-hinckdentine A, (-)-Isatisine A. Its structure is as follows:

[0003]

[0004] Using allyl palladium chloride dimer as a catalyst, 3-nitroindole was subjected to asymmetric allylic dearomatization (AngewandteChemie International Edition, 2018, 57, 2134-2138.). The asymmetric [3+2] cycloaddition reaction of 3-nitroindole and vinylaziridine enantioselectively generated indoline skeleton products. (Chemistry-an Asian Journal, 2018, 13, 959-963.). By synthesizing a new π-allylruthenium (IV) catalyst precursor, the enantioselective and stereoselective allylic dearomatization reaction of indole was achieved, and finally an indole-3-one skeleton compound containing an ortho-quaternary carbon center was obtained. (Chemistry-AEuropean Journal, 2023, 29, e202203243.). Transition metal-catalyzed asymmetric dearomatization of indoles provides an efficient and rapid synthetic route for these skeletons. Although some progress has been made, the allylic dearomatization reaction using the C2 position of indole as a nucleophilic site has not been reported. Therefore, we hope to use the driving force of enol interconversion to enhance the nucleophilicity of the C2 position of indole, thereby nucleophilically attacking the allylic site and finally achieving the intramolecular allylic dearomatization reaction of indole derivatives catalyzed by palladium. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing a vinyl tetrahydroisoquinoline carbazole compound

[0006] In order to achieve the above objectives, the following technical solutions are proposed:

[0007] A method for preparing a vinyl tetrahydroisoquinoline carbazole compound comprises the following steps: using a compound as shown in formula (1) as a raw material, using a palladium compound as a catalyst, adding a basic compound and a reducing agent in an organic solvent, reacting through the action of a ligand L, and after the reaction is completed, post-treating to obtain a carbazole derivative as shown in formula (2). The reaction process is as follows:

[0008]

[0009] In formula (1), the substituent R 1 is selected from hydrogen, alkyl, substituted alkyl, substituted alkoxy or halogen; the substituent R 2 is selected from hydrogen, alkyl or halogen; the substituent R 3 Selected from hydrogen, alkyl, substituted alkyl or halogen

[0010] The structural formula of ligand L is as follows:

[0011] Furthermore, the substituent R 1 is selected from one of hydrogen, tert-butyl, methyl, chlorine, trifluoromethyl and trifluoromethoxy; the substituent R 2 is selected from hydrogen, methyl, ethyl or chlorine; the substituent R 3 One selected from hydrogen, methyl, chlorine and trifluoromethyl.

[0012] Furthermore, the organic solvent is selected from any one of tetrahydrofuran, N,N-dimethylformamide or acetonitrile, and the volume ratio of the organic solvent to the molar ratio of the compound represented by formula (1) is 1 to 100:1, the volume unit is milliliter, and the molar unit is millimole.

[0013] Furthermore, the palladium catalyst is selected from any one of palladium acetate, palladium chloride and palladium pivalate.

[0014] Furthermore, the alkaline compound is selected from any one of potassium carbonate, sodium carbonate and lithium tert-butoxide, and the reducing agent is triethylamine.

[0015] Furthermore, the molar ratio of the compound represented by formula (1), the palladium catalyst, the ligand L, the alkaline compound and the reducing agent is 100:10:12:150:500.

[0016] Furthermore, the reaction temperature is 80-100°C, and the reaction time is 12-24h, preferably 12h.

[0017] Furthermore, the post-treatment steps are as follows: after the reaction is completed, the reaction system is diluted with water and ethyl acetate, the aqueous phase is extracted with ethyl acetate, the combined organic phase is treated with brine, the organic phase is separated, and then dried with anhydrous sodium sulfate, filtered, and the filtrate is taken to remove the solvent by rotary evaporation and then separated by column chromatography to obtain the target product.

[0018] The beneficial effects of the present invention are:

[0019] The invention synthesizes a series of indole substrates from raw materials, and utilizes the driving force of enol interconversion under the joint action of palladium catalyst, ligand, base, etc. to enhance the nucleophilicity of the C2 position of indole, thereby nucleophilically attacking the allylic site, and finally realizing the dearomatization reaction of the allylic group in the indole derivative molecule under palladium catalysis. The reaction conditions are mild, the operation is simple, the yield is high, the enantioselectivity is excellent, and the target product is easy to separate. DETAILED DESCRIPTION

[0020] The present invention is further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0021]

[0022] The structural formula of the ligand L used in the following examples is shown below:

[0023]

[0024] The compounds synthesized by catalysis in the examples are shown in Table 1.

[0025] Example 1

[0026] Under the protection of nitrogen, palladium pivalate (10 mol% of compound 1a, 3.09 mg), ligand L (12 mol% of compound 1a, 5.11 mg), K2CO3 (1.5 eq. 20.73 mg), Et3N (5.0 eq. 0.07 ml.), the compound shown in formula 1a (0.1 mmol, R1, R2 and R3 are all H) were added to a dry Shrek bottle, and then tetrahydrofuran (3.0 ml) was added through a syringe. The reaction mixture was stirred at 80°C and reacted for 12 hours. After the reaction was completed, the solution was rinsed with water, the aqueous phase was extracted with ethyl acetate, the combined organic phase was treated with brine, the organic phase was separated, and then dried with anhydrous sodium sulfate and filtered. The filtrate was taken to remove the solvent by rotary evaporation, and the target product compound 2a was separated by column chromatography with a yield of 64% and 85% ee.

[0027] 1H NMR (400MHz, CDCl3) δ7.45(d,J=7.6Hz,1H),7.41-7.31(m,3H),7.29-7.28(m,2H),7.16(d,J=7.2Hz,1H),6.79(t,J=7.6Hz,1H),6.65(d,J=8.4H z,1H),6.30(s,1H),5.45-5.361(m,1H),4.74-4.67(m,4H),3.77(d,J=6 .8Hz,1H),2.51-2.47(m,2H),2.14-2.09(m,1H),2.00-1.92(m,1H).13C NMR (100MHz, CDCl3) δ197.2,166.1,155.7,135.7,135.3,134.5,131.3,129.5,127.5,12 7.5,126.5,123.3,123.2,118.3,116.8,113.5,107.4,67.5,51.7,45.7,32.8,32.2.HRMS m / z(ESI+):Calculated for C22H20NO+([M+H]+):314.1540,found 314.1537.

[0028] Example 2

[0029] Under the protection of nitrogen, palladium pivalate (10 mol% of compound 1a, 3.09 mg), ligand L (12 mol% of compound 1a, 5.11 mg), K2CO3 (1.5 eq. 20.73 mg), Et3N (5.0 eq. 0.07 ml.), and the compound shown in formula 1b (0.1 mmol, R1 is CF3, R2 and R3 are H) were added to a dry Shrek bottle, and then N, N-dimethylformamide (3.0 ml) was added through a syringe. The reaction mixture was stirred at 80°C and reacted for 12 hours. After the reaction was completed, the solution was rinsed with water, the aqueous phase was extracted with ethyl acetate, the combined organic phase was treated with brine, the organic phase was separated, and then dried with anhydrous sodium sulfate and filtered. The filtrate was taken to remove the solvent by rotary evaporation, and the target product compound 2b was separated by column chromatography with a yield of 38% and 82% ee.

[0030] 1H NMR (400MHz, CDCl3) δ7.66(s,1H),7.58(d,J=8.8Hz,1H),7.38-7.30(m,3H),7.17(d,J=7.2Hz,1H),6.66(d,J=8.4Hz,1H),6.33(s,1H),5.43(dd d,J=16.8,10.0,7.2Hz,1H),4.80-4.67(m,4H),3.79(d,J=7.2Hz,1H),2 .53-2.49(m,2H),2.18(ddd,J=12.0,4.0,2.8Hz,1H),2.04-1.96(m,1H). 13 C NMR (100MHz, CDCl3) δ196.8,163.9,156.7,135.4,134.7,131.3(q,J=3.0Hz),130.7,129.7,127.7,127.7,126.4,124 .6(q,J=269Hz)123.1,120.5(q,J=4.0Hz),120.0(q,J=32Hz),117.7,114.9,106.8,68.1,51.4,45.2,32.7,31.9.HRMS m / z(ESI+):Calculated for C 23 H 19 F3NO + ([M+H] + ):382.1413,found382.1409.

[0031] Example 3

[0032] Under the protection of nitrogen, palladium acetate (10 mol% of compound 1a, 2.25 mg), ligand L (12 mol% of compound 1a, 5.11 mg), K2CO3 (1.5 eq. 20.73 mg), Et3N (5.0 eq. 0.07 ml.), the compound shown in formula 1c (0.1 mmol, R1 is OCF3, R2 and R3 are H) were added to a dry Shrek bottle, and then tetrahydrofuran (3.0 ml) was added through a syringe. The reaction mixture was stirred at 80°C and reacted for 12 hours. After the reaction was completed, the solution was rinsed with water, the aqueous phase was extracted with ethyl acetate, the combined organic phase was treated with brine, the organic phase was separated, and then dried with anhydrous sodium sulfate and filtered. The filtrate was taken to remove the solvent by rotary evaporation, and the target product compound 2c was separated by column chromatography with a yield of 43% and 84% ee.

[0033] 1H NMR (400MHz, CDCl3) δ7.38-7.30(m,3H),7.26-7.20(m,2H),7.14(d,J=7.2Hz,1H),6.58(d,J=8.8Hz,1H),6.26(s,1H), 5.41-5.35(m,1H),4.76-4.65(m,4H),3.75(d,J=7.2Hz,1H),2.49-2.45(m,2H),2.13-2.08(m,1H),2.00-1.93(m,1H). 13 CNMR (100MHz, CDCl3) δ196.8,164.4,154.0,141.1,135.4,135.0,130.9,129.6,127.7,127.6,127.6,126.5,12 3.8,120.7(q,J=254Hz),117.3,116.1,114.7,107.5,68.2,51.7,45.8,32.7,32.2.HRMSm / z(ESI+):Calculated for C 23 H 19 F3NO2 + ([M+H] + ):398.1363, found 398.1364.

[0034] Example 4

[0035] Under the protection of nitrogen, palladium pivalate (10 mol% of compound 1a, 3.09 mg), ligand L (12 mol% of compound 1a, 5.11 mg), Na2CO3 (1.5 eq. 15.9 mg), Et3N (5.0 eq. 0.07 ml.) were added to a dry Shrek bottle, as shown in formula 1d (0.1 mmol, R1 is t Bu, R2 and R3 are H), and then tetrahydrofuran (3.0 ml) is added through a syringe. The reaction mixture is stirred at 100°C and reacted for 12 hours. After the reaction is completed, the solution is rinsed with water, the aqueous phase is extracted with ethyl acetate, the combined organic phase is treated with brine, the organic phase is separated, and then dried with anhydrous sodium sulfate and filtered. The filtrate is taken and the solvent is removed by rotary evaporation. The target product compound 2d is separated by column chromatography with a yield of 54% and 87% ee.

[0036] 1H NMR (400MHz, CDCl3) δ7.49-7.45(m,2H),7.34-7.29(m,4H),7.17(d,J=6.8Hz,1H),6.62(d,J=8.4Hz,1H),6.31(s,1H),5.45- 5.37(m,1H),4.74-4.69(m,4H),3.78(d,J=6.8Hz,1H),2.51-2.46(m,2H),2.10-2.07(m,1H),1.97-1.90(m,1H),1.35(s,9H). 13 C NMR (100MHz, CDCl3) δ197.1,166.6,154.1,141.6,135.7,135.5,132.4,131.5,129.4,127.5,1 27.4,126.5,122.8,119.3,116.7,112.9,107.2,67.8,51.9,46.1,34.3,32.9,32.4,31.6.HRMS m / z(ESI+):Calculated for C 26 H 28 NO + ([M+H] + ):370.2166, found 370.2163.

[0037] Example 5

[0038] Under the protection of nitrogen, palladium chloride (10 mol% of compound 1a, 1.77 mg), ligand L (12 mol% of compound 1a, 5.11 mg), K2CO3 (1.5 eq. 20.73 mg), Et3N (5.0 eq. 0.07 ml.), a compound shown in formula 1e (0.1 mmol, R2 is Et, R1 and R3 are H) were added to a dry Shrek bottle, and then tetrahydrofuran (3.0 ml) was added through a syringe. The reaction mixture was stirred at 80°C and reacted for 12 hours. After the reaction was completed, the solution was rinsed with water, the aqueous phase was extracted with ethyl acetate, the combined organic phase was treated with brine, the organic phase was separated, and then dried with anhydrous sodium sulfate and filtered. The filtrate was taken to remove the solvent by rotary evaporation, and the target product compound 2e was separated by column chromatography with a yield of 72% and 78% ee.

[0039] 1H NMR (400MHz, CDCl3) δ7.35-7.28(m,5H),7.23-7.18(m,2H),6.80(t,J=7.6Hz,1H),6.26(s,1H),5.53-5.45(m,1H),4.98(dd,J=23.2,15.2Hz,2H ),4.80-4.72(m,2H),3.76(d,J=6.8Hz,1H),3.00-2.86(m,2H),2.46-2. 42(m,2H),2.04-2.00(m,1H),1.91-1.84(m,1H),1.32(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ197.2,166.6,154.2,135.9,135.5,135.2,132.4,128.9,127.6,127.4 ,126.6,126.1,124.3,120.9,119.4,117.0,112.6,67.6,52.5,48.6,32.9,25.9,15.6.HRMS m / z(ESI+):Calculated for C 24 H 24 NO + ([M+H] + ):342.1853, found 342.1859.

[0040] Example 6

[0041] Under the protection of nitrogen, palladium pivalate (10 mol% of compound 1a, 3.09 mg), ligand L (12 mol% of compound 1a, 5.11 mg), K2CO3 (1.5 eq. 20.73 mg), Et3N (5.0 eq. 0.07 ml.), a compound shown in formula 1f (0.1 mmol, R1 and R2 are CH3, R3 is H) were added to a dry Shrek bottle, and then tetrahydrofuran (3.0 ml) was added through a syringe. The reaction mixture was stirred at 80°C and reacted for 24 hours. After the reaction was completed, the solution was rinsed with water, the aqueous phase was extracted with ethyl acetate, the combined organic phase was treated with brine, the organic phase was separated, and then dried with anhydrous sodium sulfate and filtered. The filtrate was taken to remove the solvent by rotary evaporation, and the target product compound 2f was separated by column chromatography with a yield of 43% and 84% ee.

[0042] 1H NMR (400MHz, CDCl3) δ7.33-7.26(m,4H),7.18(d,J=6.8Hz,1H),7.12(s,1H),7.00(s,1H),6.22(s,1H),5.53-5.45(m,1H),4.98(dd,J=25.2 ,15.2Hz,2H),4.80-4.73(m,2H),3.75(d,J=6.8Hz,1H),2.54(s,3H),2.45-2.41(m,2H),2.29(s,3H),2.00-1.94(m,1H),1.88-1.80(m,1H). 13 C NMR (100MHz, CDCl3) δ197.2,166.7,153.5,138.9,135.7,135.1,132.5,128.9,128.7,127.6,1 27.4,126.7,124.3,120.7,119.9,116.9,112.4,68.0,52.6,49.1,33.1,32.9,20.5,19.9.HRMS m / z(ESI+):Calculated for C 24 H 24 NO + ([M+H] + ):342.1853, found 342.1852.

[0043] Example 7

[0044] Under the protection of nitrogen, palladium pivalate (10 mol% of compound 1a, 3.09 mg), ligand L (12 mol% of compound 1a, 5.11 mg), K2CO3 (1.5 eq. 20.73 mg), Et3N (5.0 eq. 0.07 ml.), and the compound shown in formula 1g (0.1 mmol, R1 and R2 are Cl, R3 is H) were added to a dry Shrek bottle, and then N, N-dimethylformamide (3.0 ml) was added through a syringe. The reaction mixture was stirred at 80°C and reacted for 24 hours. After the reaction was completed, the solution was rinsed with water, the aqueous phase was extracted with ethyl acetate, the combined organic phase was treated with brine, the organic phase was separated, and then dried with anhydrous sodium sulfate and filtered. The filtrate was taken to remove the solvent by rotary evaporation, and the target product compound 2g was separated by column chromatography separation method with a yield of 53%, 66% ee.

[0045] 1H NMR (400MHz, CDCl3) δ7.34-7.28(m,4H),7.24(s,1H),7.13(d,J=7.2Hz,1H),6.21(s,1H),5.51-5.45(m,1H),5.44-5.4 1(m,1H),4.96-4.72(m,3H),3.71(d,J=6.8Hz,1H),2.44-2.41(m,2H),2.04(dt,J=13.2,3.6Hz,1H),1.95-1.90(m,1H). 13 C NMR (100MHz, CDCl3) δ196.8,163.2,149.5,134.9,134.7,134.5,131.8,129.0,127.6,12 7.6,127.3,126.6,123.5,121.2,117.9,115.1,114.8,68.4,52.1,47.6,32.6,32.4.HRMS m / z(ESI+):Calculated for C 22 H 18 Cl2NO + ([M+H] + ):382.076, found 382.0759.

[0046] Example 8

[0047] Under the protection of nitrogen, palladium pivalate (10 mol% of compound 1a, 3.09 mg), ligand L (12 mol% of compound 1a, 5.11 mg), K2CO3 (1.5 eq. 20.73 mg), Et3N (5.0 eq. 0.07 ml.), a compound (0.1 mmol) as shown in formula 1h, and then tetrahydrofuran (3.0 ml) were added to a dry Shrek bottle. The reaction mixture was stirred at 100°C and reacted for 12 hours. After the reaction was completed, the solution was rinsed with water, the aqueous phase was extracted with ethyl acetate, the combined organic phase was treated with brine, the organic phase was separated, and then dried with anhydrous sodium sulfate and filtered. The filtrate was taken to remove the solvent by rotary evaporation, and the target product compound 2h was separated by column chromatography with a yield of 50% and 78% ee.

[0048] 1H NMR (400MHz, CDCl3) δ7.92-7.80(m,3H),7.56-7.45(m,3H),7.39-7.33(m,2H),6.77(t,J=7.6Hz,1H),6.66(d,J=8.4Hz,1H),6.36(s,1H),5.46(dd d,J=16.8,10.4,7.2Hz,1H),4.87-4.77(m,2H),4.72-4.65(m,2H),4.51( d,J=7.2Hz,1H),2.45-2.41(m,2H),2.12-2.07(m,1H),1.97-1.89(m,1H). 13 C NMR (100MHz, CDCl3) δ197.2,166.4,155.7,134.6,134.4,133.1,131.5,130.0,129.1,129.0,127.9,12 7.1,125.9,124.4,123.4,123.3,122.3,118.3,117.7,113.7,107.5,67.7,46.4,46.3,33.5,32.2.HRMS m / z(ESI+):Calculated for C 26 H 22 NO + ([M+H] + ):364.1701,found364.1694.

[0049] Example 9

[0050] Under the protection of nitrogen, palladium pivalate (10 mol% of compound 1a, 3.09 mg), ligand L (12 mol% of compound 1a, 5.11 mg), K2CO3 (1.5 eq. 20.73 mg), Et3N (5.0 eq. 0.07 ml.), a compound shown in formula 1i (0.1 mmol, R1 and R2 are H, R3 is CH3) were added to a dry Shrek bottle, and then tetrahydrofuran (3.0 ml) was added through a syringe. The reaction mixture was stirred at 80°C and reacted for 12 hours. After the reaction was completed, the solution was rinsed with water, the aqueous phase was extracted with ethyl acetate, the combined organic phase was treated with brine, the organic phase was separated, and then dried with anhydrous sodium sulfate and filtered. The filtrate was taken to remove the solvent by rotary evaporation, and the target product compound 2i was separated by column chromatography with a yield of 61% and 88% ee.

[0051] 1H NMR (400MHz, CDCl3) δ7.42-7.33(m,2H),7.15-7.10(m,2H),6.94(s,1H),6.75(t,J=7.6Hz,1H),6.61(d,J=8.4Hz,1H),6.26(s,1 H),5.40-5.31(m,1H),4.70-4.63(m,4H),3.68(d,J=7.6Hz,1H),2.48-2.43(m,2H),2.34(s,3H),2.11-2.07(m,1H),1.95-1.90(m 1H). 13 C NMR (100MHz, CDCl3) δ197.2,166.2,155.8,137.2,135.8,135.1,134.5,130.0,128.3,128.2 ,126.4,123.3,123.2,118.2,116.6,113.4,107.5,67.6,51.8,45.6,32.9,32.3,21.1.HRMS m / z(ESI+):Calculated for C 23 H 22 NO + ([M+H] + ):328.1696,found328.1691.

[0052] Example 10

[0053] Under the protection of nitrogen, palladium pivalate (10 mol% of compound 1a, 3.09 mg), ligand L (12 mol% of compound 1a, 5.11 mg), K2CO3 (1.5 eq. 20.73 mg), Et3N (5.0 eq. 0.07 ml.), a compound shown in formula 1j (0.1 mmol, R1 and R2 are H, R3 is Cl) were added to a dry Shrek bottle, and then acetonitrile (3.0 ml) was added through a syringe. The reaction mixture was stirred at 80°C and reacted for 12 hours. After the reaction was completed, the solution was rinsed with water, the aqueous phase was extracted with ethyl acetate, the combined organic phase was treated with brine, the organic phase was separated, and then dried with anhydrous sodium sulfate and filtered. The filtrate was taken to remove the solvent by rotary evaporation, and the target product compound 2j was separated by column chromatography with a yield of 47% and 88% ee.

[0054] 1H NMR (400MHz, CDCl3) δ7.43-7.34(m,3H),7.24-7.22(m,1H),7.08(d,J=8.0Hz,1H),6.78(t,J=7.2Hz,1H),6.61(d,J=8.0Hz,1H),6.27(s,1H ),5.40-5.31(m,1H),4.72-4.61(m,4H),3.72(d,J=6.8Hz,1H),2.45(dd,J=9.2,3.6Hz,2H),2.08(dt,J=12.4,4Hz,1H),1.99-1.93(m,1H). 13 C NMR (100MHz, CDCl3) δ196.9,165.6,155.4,135.4,134.6,133.8,133.2,133.1,130.9,12 7.7,126.5,123.2,123.2,118.5,117.1,113.7,107.4,67.4,50.9,45.3,32.7,32.1.HRMS m / z(ESI+):Calculated for C 22 H 19 ClNO + ([M+H] + ):348.1155,found348.1147.

[0055] Embodiment 11

[0056] Under the protection of nitrogen, palladium pivalate (10 mol% of compound 1a, 3.09 mg) and ligand L (12 mol% of compound 1a, 5.11 mg) were added to a dry Shrek bottle. t BuOLi (1.5eq. 12.01mg), Et3N (5.0eq. 0.07ml.), a compound as shown in formula 1k (0.1mmol, R1 and R2 are H, R3 is CF3), and then tetrahydrofuran (3.0ml) was added through a syringe. The reaction mixture was stirred at 80°C and reacted for 12 hours. After the reaction was completed, the solution was rinsed with water, the aqueous phase was extracted with ethyl acetate, the combined organic phase was treated with brine, the organic phase was separated, and then dried with anhydrous sodium sulfate and filtered. The filtrate was taken and the solvent was removed by rotary evaporation. The target product compound 2k was separated by column chromatography with a yield of 53% and 85% ee.

[0057] 1H NMR (400MHz, CDCl3) δ7.55-7.53(m,2H),7.44(d,J=7.6Hz,1H),7.40-7.36.(m,1H),7.28(d,J=8.4Hz,1H),6.79(t,J=7.2Hz,1H),6.63(d,J=8 .0Hz,1H),6.29(s,1H),5.37(ddd,J=16.8,10.0,7.2Hz,1H),4.75-4.63(m,4H),3.82(d,J=7.2Hz,1H),2.48-2.44(m,2H),2.06-1.96(m,2H). 13 C NMR (100MHz, CDCl3) δ196.8,165.3,155.4,139.4,134.9,134.6,132.3,130.2,129.9(q,J=33Hz),124.4(q,J=4.0Hz), 124.0(q,J=188Hz),123.5(q,J=4.0Hz),123.3,123.2,118.7,117.5,113.8,107.4,67.2,51.4,45.5,32.7,32.1.HRMS m / z(ESI+):Calculated for C 23 H 19 F3NO + ([M+H] + ):382.1413, found 382.1415.

[0058] The experimental results corresponding to the synthesis methods of specific vinyl tetrahydroisoquinolyl carbazole compounds in Examples 1 to 11 are listed in Table 1:

[0059] Table 1 Palladium-catalyzed vinyl tetrahydroisoquinolyl carbazole ketone reaction results [a]

[0060]

[0061]

[0062]

[0063] [a] The reaction conditions are shown in the examples; [b] Isolated yield.

[0064] The above are only several specific embodiments of the present invention, and the description is relatively specific and detailed, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by any technician familiar with the technical field within the technical scope disclosed by the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing a vinyl tetrahydroisoquinolyl carbazole compound, characterized in that: The method comprises the following steps: using a compound as shown in formula (1) as a raw material, using a palladium compound as a catalyst, adding a basic compound and a reducing agent in an organic solvent, reacting through the action of a ligand L, and after the reaction is completed, post-processing to obtain a carbazole derivative as shown in formula (2), wherein the reaction process is as follows: In formula (1), the substituent R 1 is selected from hydrogen, alkyl, substituted alkyl, substituted alkoxy or halogen; the substituent R 2 is selected from hydrogen, alkyl or halogen; the substituent R 3 Selected from hydrogen, alkyl, substituted alkyl or halogen The structural formula of ligand L is as follows:

2. The method for preparing a vinyl tetrahydroisoquinolyl carbazolone compound according to claim 1, characterized in that: Substituent R 1 is selected from one of hydrogen, tert-butyl, methyl, chlorine, trifluoromethyl and trifluoromethoxy; the substituent R 2 is selected from hydrogen, methyl, ethyl or chlorine; the substituent R 3 One selected from hydrogen, methyl, chlorine and trifluoromethyl.

3. The method for preparing a vinyl tetrahydroisoquinolyl carbazolone compound according to claim 1, characterized in that: The organic solvent is selected from any one of tetrahydrofuran, N,N-dimethylformamide or acetonitrile, and the volume ratio of the organic solvent to the molar ratio of the compound represented by formula (1) is 1 to 100:1, the volume unit is milliliter, and the molar unit is millimole.

4. The method for preparing a vinyl tetrahydroisoquinolyl carbazolone compound according to claim 1, characterized in that: The palladium catalyst is selected from any one of palladium acetate, palladium chloride and palladium pivalate.

5. The method for preparing a vinyl tetrahydroisoquinolyl carbazolone compound according to claim 1, characterized in that: The basic compound is selected from any one of potassium carbonate, sodium carbonate and lithium tert-butoxide.

6. The method for preparing a vinyl tetrahydroisoquinolyl carbazolone compound according to claim 1, characterized in that: The reducing agent is triethylamine.

7. The method for preparing a vinyl tetrahydroisoquinolyl carbazolone compound according to claim 1, characterized in that: The molar ratio of the compound represented by formula (1), the palladium catalyst, the ligand L, the alkaline compound and the reducing agent is 100:10:12:150:

500.

8. The method for preparing a vinyl tetrahydroisoquinolyl carbazolone compound according to claim 1, characterized in that: The reaction temperature is 80-100°C, and the reaction time is 12-24h, preferably 12h.

9. The method for preparing a vinyl tetrahydroisoquinolyl carbazolone compound according to claim 1, characterized in that: The post-treatment steps are as follows: after the reaction is completed, the reaction system is diluted with water and ethyl acetate, the aqueous phase is extracted with ethyl acetate, the combined organic phase is treated with brine, the organic phase is separated, and then dried with anhydrous sodium sulfate, filtered, and the filtrate is taken to remove the solvent by rotary evaporation and then separated by column chromatography to obtain the target product.

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