A method for synthesizing a pyrrolo-tetrahydroquinoline compound containing a perfluoroalkane structure

Abstract

The present application relates to the technical fields of organic medicine synthesis, and discloses a synthesis method of a perfluoroalkane structure-containing pyrrolo-tetrahydroquinoline compound. The synthesis method is as follows: under the protection of inert gas, 1.7-alkenyl alkyne, di-tert-butyl diazepinone, perfluoroiodoalkane, a palladium catalyst, a ligand and a base are added into an organic solvent in a certain proportion, and then reacted at a heating temperature; after the reaction, the perfluoroalkane structure-containing pyrrolo-tetrahydroquinoline compound shown in the following formula is prepared; and after the reaction is completed, the target product is separated. The present application uses di-tert-butyl diazepinone as a nitrogen source and perfluoroiodoalkane as a fluorine source, and has the advantages of simple method and novelty, and can synthesize a series of perfluoroalkane structure-containing pyrrolo-tetrahydroquinoline compounds and derivatives thereof with extremely high efficiency.

Description

Technical Field

[0001] This invention relates to the field of organic drug synthesis technology, and in particular to a method for synthesizing pyrrolotetrahydroquinoline compounds containing perfluoroalkane structures. Background Technology

[0002] Pyrrolotetrahydroquinoline compounds and their derivatives are an important class of heterocycles found in many natural products and bioactive molecules (as shown in the figure below). Therefore, the synthesis and application of pyrrolotetrahydroquinoline compounds and their derivatives are receiving increasing attention. Meanwhile, the introduction of fluorine atoms plays a significant role in various bioactive molecular structures. Therefore, we aim to synthesize a series of novel pyrrolotetrahydroquinoline compounds containing perfluoroalkane structures by using polyfluoroalkyl iodoalkanes as the fluorine source and di-tert-butyldiaziridinone as the nitrogen source.

[0003] Summary of the Invention

[0004] The technical problem to be solved by this invention is to overcome the shortcomings of the prior art and provide a method for synthesizing pyrrolotetrahydroquinoline compounds containing perfluoroalkane structures. This invention uses di-tert-butyldiaziridinone as a nitrogen source and perfluoroiodoalkane as a fluorine source. Under conditions of palladium catalyst as catalyst, cesium carbonate as base, and various phosphorus ligands as ligands, a series of pyrrolotetrahydroquinoline compounds containing perfluoroalkane structures can be obtained by reacting 1,7-enyne compounds with perfluoroiodoalkane and di-tert-butyldiaziridinone.

[0005] The technical solution adopted by this invention to solve its technical problem is:

[0006] A method for synthesizing pyrrolotetrahydroquinoline compounds containing perfluoroalkane structures involves, under the protection of an inert gas, adding 1,7-enyne 1, di-tert-butyldiazepinene 2, perfluoroiodoalkane 3, palladium catalyst, ligand and base in an organic solvent in a certain proportion, reacting under heating conditions, and separating the target product, pyrrolotetrahydroquinoline compounds containing perfluoroalkane structures, after the reaction is completed.

[0007] Equation (1):

[0008]

[0009] Furthermore, in the 1,7-enyne 1 represented by formula (1), R 1 Selected from one of hydrogen atom, 4-Cl, 4-F, 4-methyl, 5-methyl, 5-F, 5-chloro, 5-trifluoromethoxy, and 4,6-dimethyl; R 2 Selected from one of methyl, ethyl, and benzyl; R 3It is selected from one of phenyl, 4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 3-fluorophenyl, 3-methylphenyl, thiophene group, and pyridine group; the polyfluoroiodoalkane 3 is one of perfluoroiodopropane, perfluoroiodobutane, or perfluoroiodohexane.

[0010] Furthermore, the polyfluoroiodoalkane 3 represented by formula (1) is one of perfluoroiodopropane, perfluoroiodobutane, and perfluoroiodohexane.

[0011] Further, the molar ratio of 1,7-enyne 1, di-tert-butyldiazepinene 2, perfluoroiodoalkane 3, base, palladium catalyst, and ligand is 1:(1-3):(1-3):2:(0.025-0.2):(0.05-0.2).

[0012] Furthermore, the organic solvent is selected from one or more of toluene, 1,2-dichloroethane, dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, n-hexane, diethyl ether, and ethyl acetate, with n-hexane being preferred.

[0013] Furthermore, as a catalyst, the palladium catalyst is selected from one or more of palladium acetate, palladium trifluoroacetate, palladium chloride, palladium iodide, palladium nitrate, palladium acetylacetone, and palladium tetraphenylphosphine, preferably palladium acetate.

[0014] Furthermore, the alkali is cesium carbonate or potassium carbonate.

[0015] Further, the ligand is a phosphine ligand, which is one of PPh3, (o-OMe-Ph)3P, (pF-Ph)3P, (2-thienyl)3P, (2-furyl)3P, PPh2Cy, PPhCy2, PCy3, (C6F5)3P, dppm, dppb, and dppf. PPhCy2(L1) is preferably selected as the ligand, and its structure is as follows:

[0016]

[0017] The selected di-tert-butyldiazidionone has the following structure:

[0018]

[0019] Furthermore, the reaction temperature is 70–140°C, preferably 90°C.

[0020] The prepared pyrrolotetrahydroquinoline compounds containing perfluoroalkane structures were separated by column chromatography.

[0021] The synthetic mechanism of this invention is as follows: First, the substrate 1,7-enyne (1a) and polyfluoroiodobutane (3) form a cyclic palladium intermediate through a free radical reaction. Then, the cyclic palladium intermediate and di-tert-butyldiazidionone (2) undergo an N-N bond insertion reaction and a reductive elimination reaction to finally obtain a pyrrolotetrahydroquinoline compound containing a perfluoroiodoalkyl group. The specific synthetic mechanism is shown in the figure below.

[0022]

[0023] The beneficial effects of this invention are as follows: This invention is rationally designed. By using a palladium catalyst as a catalyst and various phosphine ligands as ligands, under alkaline conditions, 1,7-enyne compounds react with perfluoroiodoalkanes and di-tert-butyldiazidimone to efficiently obtain the corresponding pyrrolotetrahydroquinoline compounds and their derivatives (i.e., pyrrolotetrahydroquinoline compounds containing perfluoroalkane structures). This synthetic method is simple in steps, easy to operate, and has high synthetic efficiency. Attached Figure Description

[0024] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0025] Figure 1 The 1-(tert-butyl)-3,5-dimethyl-3-(5,5,5,5,5,5,5,5,5-nonafluoro-5λ synthesized in Example 1 12 -penta-2,4-diyn-1-yl)-2-phenyl-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 4a) 1 H NMR spectrum;

[0026] Figure 2 The 1-(tert-butyl)-3,5-dimethyl-3-(5,5,5,5,5,5,5,5,5-nonafluoro-5λ synthesized in Example 1 12 -penta-2,4-diyn-1-yl)-2-phenyl-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 3a) 13 C NMR spectrum;

[0027] Figure 3 The 1-(tert-butyl)-5-ethyl-3-methyl-3-(5,5,5,5,5,5,5,5,5-nonafluoro-5λ synthesized in Example 2 12-penta-2,4-diyn-1-yl)-2-phenyl-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 4b) 1 H NMR spectrum;

[0028] Figure 4 The 1-(tert-butyl)-5-ethyl-3-methyl-3-(5,5,5,5,5,5,5,5,5-nonafluoro-5λ synthesized in Example 2 12 -penta-2,4-diyn-1-yl)-2-phenyl-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 4b) 13 C10 NMR spectrum.

[0029] Figure 5 The 5-benzyl-1-(tert-butyl)-3-methyl-3-(5,5,5,5,5,5,5,5-nonafluoro-5λ synthesized in Example 3 12 -penta-2,4-diyn-1-yl)-2-phenyl-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 4c) 1 H NMR spectrum;

[0030] Figure 6 The 5-benzyl-1-(tert-butyl)-3-methyl-3-(5,5,5,5,5,5,5,5-nonafluoro-5λ synthesized in Example 3 12 -penta-2,4-diyn-1-yl)-2-phenyl-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 4c) 13 C10 NMR spectrum.

[0031] Figure 7 The 1-(tert-butyl)-8-chloro-3,5-dimethyl-3-(5,5,5,5,5,5,5,5,5-nonafluoro-5λ synthesized in Example 4 12 -penta-2,4-diyn-1-yl)-2-phenyl-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 4d) 1 H NMR spectrum;

[0032] Figure 8 The 1-(tert-butyl)-8-chloro-3,5-dimethyl-3-(5,5,5,5,5,5,5,5,5-nonafluoro-5λ synthesized in Example 4 12 -penta-2,4-diyn-1-yl)-2-phenyl-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 4d) 13 C10 NMR spectrum.

[0033] Figure 9 The 1-(tert-butyl)-7-fluoro-3,5-dimethyl-3-(5,5,5,5,5,5,5,5,5-nonafluoro-5λ synthesized in Example 5 12 -penta-2,4-diyn-1-yl)-2-phenyl-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 4e) 1 H NMR spectrum;

[0034] Figure 10 The 1-(tert-butyl)-7-fluoro-3,5-dimethyl-3-(5,5,5,5,5,5,5,5,5-nonafluoro-5λ synthesized in Example 5 12 -penta-2,4-diyn-1-yl)-2-phenyl-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 4e) 13 C10 NMR spectrum.

[0035] Figure 11 The 1-(tert-butyl)-3,5-dimethyl-3-(5,5,5,5,5,5,5,5,5-nonafluoro-5λ synthesized in Example 6 12 -penta-2,4-diyn-1-yl)-2-(p-tolyl)-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 4f) 1 H NMR spectrum;

[0036] Figure 12 The 1-(tert-butyl)-3,5-dimethyl-3-(5,5,5,5,5,5,5,5,5-nonafluoro-5λ synthesized in Example 6 12 -penta-2,4-diyn-1-yl)-2-(p-tolyl)-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 4f) 13 C10 NMR spectrum.

[0037] Figure 13 The 1-(tert-butyl)-2-(4-chlorophenyl)-3,5-dimethyl-3-(5,5,5,5,5,5,5,5,5-nonfluorinated-5λ) synthesized in Example 7 12 -penta-2,4-diyn-1-yl)-1,5-dihydropyrrole[4,3,2-de]quinoline-4(3H)-one (structural formula 4g) 1 H NMR spectrum;

[0038] Figure 14The 1-(tert-butyl)-2-(4-chlorophenyl)-3,5-dimethyl-3-(5,5,5,5,5,5,5,5,5-nonfluorinated-5λ) synthesized in Example 7 12 -penta-2,4-diyn-1-yl)-1,5-dihydropyrrole[4,3,2-de]quinoline-4(3H)-one (structural formula 4g) 13 C10 NMR spectrum.

[0039] Figure 15 The 1-(tert-butyl)-2-(3-fluorophenyl)-3,5-dimethyl-3-(5,5,5,5,5,5,5,5,5-nonafluoro-5λ synthesized in Example 8 12 -penta-2,4-diyn-1-yl)-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 4h) 1 H NMR spectrum;

[0040] Figure 16 The 1-(tert-butyl)-2-(3-fluorophenyl)-3,5-dimethyl-3-(5,5,5,5,5,5,5,5,5-nonafluoro-5λ synthesized in Example 8 12 -penta-2,4-diyn-1-yl)-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 4h) 13 C10 NMR spectrum. Detailed Implementation

[0041] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of this application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains.

[0042] It should be noted that the terminology used herein is for the purpose of describing particular implementations only and is not intended to limit the exemplary implementations according to this application. As used herein, the singular form includes the plural form unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this description, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0043] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0044] Example 1: 1-(tert-butyl)-3,5-dimethyl-3-(5,5,5,5,5,5,5,5,5-nonafluoro-5λ) 12 Synthesis of penta-2,4-diyn-1-yl)-2-phenyl-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 4a)

[0045]

[0046] Under argon protection, Pd(OAc)2 (0.0045g, 0.020mmol), Cy2PPh(L1) (0.011g, 0.040mmol), Cs2CO3 (0.2607g, 0.8mmol), 1,7-enyne with structural formula 1a (0.1101g, 0.4mmol), nonafluoroiodobutane 3 (0.2767g, 0.8mmol), 1.0mL of n-hexane, and di-tert-butyldiazidimide 2 (0.1362g, 0.80mmol) were added sequentially to the reactor. After purging the reaction flask with nitrogen, the flask was sealed with the cap. After reacting at 90°C for 24 hours, the mixture was cooled to room temperature for column chromatography. The specific conditions were: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 50:1, yielding a white solid (0.1761 g, 78% yield) mp. 109.7-112.3°C.

[0047] The structural verification results are as follows: 1 H NMR (400MHz, CDCl3) δ7.50-7.32(m,6H),7.14(t,J=7.6Hz,1H),6.55(d,J=7.6Hz,1 H),3.45(s,3H),3.05-2.85(m,.1H),2.20-2.00(m,1H),1.55(s,9H),1.43(m,3H); 13 C NMR (100MHz, CDCl3) δ173.5,136.2,135.3(d,J=0.6Hz),134.0,133.4,133.0,132.0(d,J=3.3Hz),129.0,127 .8,127.7,122.5,115.1,112.3,110.3,101.3,60.0,42.4(d,J=2.1Hz),39.8(t,J=18.2Hz),32.2,30.4,29.3.

[0048] Example 2: 1-(tert-butyl)-5-ethyl-3-methyl-3-(5,5,5,5,5,5,5,5,5-nonafluoro-5λ) 12Synthesis of penta-2,4-diyn-1-yl)-2-phenyl-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 4b)

[0049]

[0050] Under argon protection, Pd(OAc)2 (0.0045 g, 0.020 mmol), Cy2PPh(L1) (0.011 g, 0.040 mmol), Cs2CO3 (0.2607 g, 0.8 mmol), 1,7-enyne with structural formula 1b (0.1158 g, 0.4 mmol), nonafluoroiodobutane 3 (0.2767 g, 0.8 mmol), 1.0 mL of n-hexane, and di-tert-butyldiazidimide 2 (0.1362 g, 0.80 mmol) were added sequentially to the reactor. After purging the reaction flask with nitrogen, the flask was sealed with the cap. After reacting at 90°C for 24 hours, the mixture was cooled to room temperature for column chromatography. The specific conditions were: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 50:1, yielding a yellow solid (0.1145 g, 50% yield) at mp. 35.2-37.3°C.

[0051] The structural verification results are as follows: 1 H NMR (400MHz, CDCl3) δ7.49-7.32(m,6H),7.14(t,J=8.0Hz,1H),6.57(d,J=7.6Hz,1H),4.27-4.15(m,1H), 3.96-3.85(m,1H),3.04-2.86(m,1H),2.18-2.01(m,1H),1.55(s,9H),1.42(s,3H),1.29(t,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3) δ172.8,136.2,135.3(d,J=1.3Hz),134.2,133.0,132.2,132.0(d,J=3.4Hz),129.0,127.8, 127.7, 122.6, 115.3, 112.4, 110.1, 101.2, 60.0, 42.4 (d, J = 1.8Hz), 39.9 (t, J = 18.3Hz), 37.2, 32.1, 30.3, 12.1.

[0052] Example 3: 5-Benzyl-1-(tert-butyl)-3-methyl-3-(5,5,5,5,5,5,5,5-nonafluoro-5λ) 12 Synthesis of penta-2,4-diyn-1-yl)-2-phenyl-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 4c)

[0053]

[0054] Under argon protection, Pd(OAc)2 (0.0045 g, 0.020 mmol), Cy2PPh(L1) (0.011 g, 0.040 mmol), Cs2CO3 (0.2607 g, 0.8 mmol), 1,7-enyne with the structural formula 1C (0.1406 g, 0.4 mmol), nonafluoroiodobutane 3 (0.2767 g, 0.8 mmol), 1.0 mL of n-hexane, and di-tert-butyldiazidimide 2 (0.1362 g, 0.80 mmol) were added sequentially to the reactor. After purging the reaction flask with nitrogen, the flask was sealed with the cap. After reacting at 90°C for 24 hours, the mixture was cooled to room temperature for column chromatography. The specific conditions were: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 50:1, yielding a white solid (0.1717 g, 67% yield) at mp. 135.7-137.8°C.

[0055] The structural verification results are as follows: 1 H NMR (400MHz, CDCl3) δ7.52-7.38(m,5H),7.36-7.26(m,5H),7.25-7.19(m,1H),7.02(t,J=8.0Hz,1H),6. 48(d,J=7.6Hz,1H),5.31-5.19(m,2H),3.11-2.95(m,1H),2.24-2.07(m,1H),1.54(s,9H),1.48(s,3H); 13 C NMR (100MHz, CDCl3) δ173.8,137.4,136.2,135.4,134.2,133.0,132.7,132.0(d,J=3.7Hz),129.0,128.7,127.9,127.7,127 .15,127.06(d,J=1.7Hz),122.5,115.2,112.3,110.3,102.4,60.1,46.3,42.8(d,J=2.0Hz),39.7(t,J=18.4Hz),32.2,30.8.

[0056] Example 4: 1-(tert-butyl)-8-chloro-3,5-dimethyl-3-(5,5,5,5,5,5,5,5,5-nonafluoro-5λ) 12 Synthesis of penta-2,4-diyn-1-yl)-2-phenyl-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 4d)

[0057]

[0058] Under argon protection, Pd(OAc)2 (0.0045g, 0.020mmol), Cy2PPh(L1) (0.011g, 0.040mmol), Cs2CO3 (0.2607g, 0.8mmol), 1,7-enyne with the structural formula 1d (0.1239g, 0.4mmol), nonafluoroiodobutane 3 (0.2767g, 0.8mmol), 1.0mL of n-hexane, and di-tert-butyldiazidimide 2 (0.1362g, 0.80mmol) were added sequentially to the reactor. After purging the reaction flask with nitrogen, the flask was sealed with the cap. After reacting at 90°C for 24 hours, the mixture was cooled to room temperature for column chromatography. The specific conditions were: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 50:1, yielding a white solid (0.1386 g, 58% yield) mp. 149.1-153.0°C.

[0059] The structural verification results are as follows: 1 H NMR (400MHz, CDCl3) δ7.45-7.38(m,4H),7.38-7.34(m,1H),7.22(d,J=8.0Hz,1H),6.52(d, J=8.0Hz,1H);3.43(s,3H),3.08-3.92(m,1H),2.28-2.12(m,1H),1.60(s,9H),1.41(s,3H) 13 CNMR(100MHz, CDCl3)δ172.9,138.3(d,J=1.4Hz),136.5,133.0,132.3,132.0,131.2(d,J=3.1Hz),128.8,128 .1,128.0,126.6,118.2,113.7,112.5,103.7,60.3,42.0(d,J=2.1Hz),40.1(t,J=17.9Hz),34.5,30.4,29.6.

[0060] Example 5: 1-(tert-butyl)-7-fluoro-3,5-dimethyl-3-(5,5,5,5,5,5,5,5,5-nonafluoro-5λ) 12 Synthesis of penta-2,4-diyn-1-yl)-2-phenyl-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 4e)

[0061]

[0062] Under argon protection, Pd(OAc)2 (0.0045 g, 0.020 mmol), Cy2PPh(L1) (0.011 g, 0.040 mmol), Cs2CO3 (0.2607 g, 0.8 mmol), 1,7-enyne with the structural formula 1e (0.1173 g, 0.4 mmol), nonafluoroiodobutane 3 (0.2767 g, 0.8 mmol), 1.0 mL of n-hexane, and di-tert-butyldiazidimide 2 (0.1362 g, 0.80 mmol) were added sequentially to the reactor. After purging the reaction flask with nitrogen, the flask was sealed with the cap. After reacting at 90°C for 24 hours, the mixture was cooled to room temperature for column chromatography. The specific conditions were: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 30:1, yielding a white solid (0.1966 g, 84% yield) mp. 137.9-140.5°C.

[0063] The structural verification results are as follows: 1 H NMR(400MHz, CDCl3) δ7.47-7.35(m,5H),7.05(dd,J=11.6,1.6Hz,1H),6.38(dd,J=10.8, 2.0Hz,1H),3.40(s,3H),2.99-2.83(m,1H),2.16-2.00(m,1H),1.51(s,9H),1.42(s,3H); 13 C NMR (100MHz, CDCl3) δ 173.7, 160.4 (d, J = 232.7Hz), 136.9, 135.4 (d, J = 4.1Hz), 133.7 (d, J = 13.8Hz), 133.00, 132.98 (d, J = 14.0Hz), 132.0 (d, J = 3. 3Hz),129.1,127.9,127.8,112.3,111.3,96.4(d,J=28.8Hz),92.0(d,J= 30.9Hz), 60.2, 42.4 (d, J = 2.0Hz), 39.9 (t, J = 18.0Hz), 32.0, 30.3, 29.5.

[0064] Example 6: 1-(tert-butyl)-3,5-dimethyl-3-(5,5,5,5,5,5,5,5,5-nonafluoro-5λ) 12 Synthesis of -penta-2,4-diyn-1-yl)-2-(p-tolyl)-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structural formula 4f)

[0065]

[0066] Under argon protection, Pd(OAc)2 (0.0045 g, 0.020 mmol), Cy2PPh(L1) (0.011 g, 0.040 mmol), Cs2CO3 (0.2607 g, 0.8 mmol), 1,7-enyne with structural formula 1f (0.1158 g, 0.4 mmol), nonafluoroiodobutane 3 (0.2767 g, 0.8 mmol), 1.0 mL of n-hexane, and di-tert-butyldiazidimide 2 (0.1362 g, 0.80 mmol) were added sequentially to the reactor. After purging the reaction flask with nitrogen, the flask was sealed with the cap. After reacting at 90°C for 24 hours, the mixture was cooled to room temperature for column chromatography. The specific conditions were: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 50:1, yielding a yellow solid (0.1907 g, 82% yield) mp. 148.4-150.3°C.

[0067] The structural verification results are as follows: 1 H NMR (400MHz, CDCl3) δ7.37-7.31(m,2H),7.26-7.17(m,3H),7.13(t,J=7.6Hz,1H),6.54(d,J=7.6H z,1H),3.45(s,3H),3.03-2.87(m,1H),2.45(s,3H),2.24-2.07(m,1H),1.55(s,9H),1.43(s,3H); 13 C NMR (100MHz, CDCl3) δ173.5,138.9,135.6(d,J=0.6Hz),134.0,133.3,133.0,132.9,131.8(d,J=3.2Hz),128.5, 128.4, 122.4, 115.2, 112.3, 110.3, 101.2, 60.0, 42.4 (d, J = 2.0Hz), 39.9 (t, J = 17.7Hz), 32.2, 30.3, 29.3, 21.6.

[0068] Example 7: 1-(tert-butyl)-2-(4-chlorophenyl)-3,5-dimethyl-3-(5,5,5,5,5,5,5,5,5-nonfluorinated-5λ) 12 -penta-2,4-diyn-1-yl)-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structure)

[0069] Synthesis of Formula 4g

[0070]

[0071] Under argon protection, Pd(OAc)2 (0.0045g, 0.020mmol), Cy2PPh(L1) (0.011g, 0.040mmol), Cs2CO3 (0.2607g, 0.8mmol), 1,7-enyne (0.1239g, 0.4mmol), nonafluoroiodobutane 3 (0.2767g, 0.8mmol), 1.0mL of n-hexane, and di-tert-butyldiazidimone 2 (0.1362g, 0.80mmol) were added sequentially to the reactor. After purging the reaction flask with nitrogen, the flask was sealed with the cap. After reacting at 90°C for 24 hours, the mixture was cooled to room temperature for column chromatography. The specific conditions were: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 50:1, yielding a white solid (0.1652 g, 69% yield) mp. 141.2-143.6°C.

[0072] The structural verification results are as follows: 1 H NMR (400MHz, CDCl3) δ7.43-7.38(m,3H),7.37-7.31(m,2H),7.15(t,J=7.6Hz,1H),6.56(d, J=7.6Hz,1H),3.45(s,3H),3.10-2.93(m,1H),2.16-1.99(m,1H),1.55(s,9H),1.44(s,3H); 13 CNMR(100MHz, CDCl3)δ173.2,135.2,134.7,134.22,134.15,133.7,133.4,133.2(d,J=3.5Hz),128.14,1 28.09, 122.9, 115.1, 112.8, 110.3, 101.5, 60.1, 42.4 (d, J = 2.1Hz), 40.0 (t, J = 18.0Hz), 32.2, 30.4, 29.3.

[0073] Example 8: 1-(tert-butyl)-2-(3-fluorophenyl)-3,5-dimethyl-3-(5,5,5,5,5,5,5,5,5-nonafluoro-5λ) 12 -penta-2,4-diyn-1-yl)-1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one (structure)

[0074] Synthesis of Formula 4h

[0075]

[0076] Under argon protection, Pd(OAc)₂ (0.0045 g, 0.020 mmol), Cy₂PPh(L₁) (0.011 g, 0.040 mmol), Cs₂CO₃ (0.2607 g, 0.8 mmol), 1,7-enyne with the structural formula 1h (0.1173 g, 0.4 mmol), nonafluoroiodobutane 3 (0.2767 g, 0.8 mmol), 1.0 mL of n-hexane, and di-tert-butyldiazidimidine 2 (0.1362 g, 0.80 mmol) were added sequentially to the reactor. After purging the reaction flask with nitrogen, the flask was sealed with the cap screwed on. After reacting at 90 °C for 24 hours, the mixture was cooled to room temperature for column chromatography. The specific conditions were: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 50:1, yielding a yellow solid (0.0762 g, 33% yield).

[0077] The structural verification results are as follows: 1 H NMR (400MHz, CDCl3) δ7.43-7.33(m,2H),7.29-7.24(m,1H),7.21-7.08(m,3H),6.56(d,J= 7.2Hz,1H),3.45(s,3H),3.10-2.90(m,1H),2.18-2.00(m,1H),1.56(s,9H),1.46(s,3H); 13 C NMR (100MHz, CDCl3) δ173.2, 161.9 (d, J = 246.8Hz), 138.4 (d, J = 7.8Hz), 134.2, 133.5, 129.4 (d, J = 8.4Hz), 127.98 (d, J = 3.1Hz), 127.95 (d, J = 3.0H z), 122.9, 119.9 (d, J = 20.7Hz), 116.1 (d, J = 20.6Hz), 115.1, 112.8, 110. 4,101.5,60.2,42.4(d,J=2.0Hz),39.9(t,J=17.6Hz),32.1,30.5,29.4.

[0078] In summary, this invention is rationally designed. By using a palladium catalyst and various phosphine ligands as ligands, 1,7-enyne compounds react with perfluoroiodoalkanes and di-tert-butyldiaziridinone under alkaline conditions to efficiently obtain the corresponding pyrrolotetrahydroquinoline compounds and their derivatives (i.e., pyrrolotetrahydroquinoline compounds containing perfluoroalkane structures). This synthetic method is simple, easy to operate, and has high synthetic efficiency.

[0079] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing pyrrolotetrahydroquinoline compounds containing a perfluoroalkane structure, characterized in that: Under the protection of an inert gas, 1,7-enyne 1, di-tert-butyldiazididine ketone 2, perfluoroiodoalkane 3, palladium catalyst, ligand, and base, as shown in formula (1), are added to an organic solvent in a certain proportion and reacted under heating conditions. After the reaction is completed, the target product, a pyrrolotetrahydroquinoline compound containing a perfluoroalkane structure, is separated. The base is CsCO3. The specific synthesis reaction is as follows: Equation (1): ； In the 1,7-enyne 1 represented by formula (1), R 1 Selected from one of hydrogen atom, 4-Cl, 4-F, 4-methyl, 5-methyl, 5-F, 5-chloro, 5-trifluoromethoxy, and 4,6-dimethyl; R 2 Selected from one of methyl, ethyl, and benzyl; R 3 It is selected from one of phenyl, 4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 3-fluorophenyl, 3-methylphenyl, thiophene group, and pyridine group; the polyfluoroiodoalkane 3 shown in formula (1) is one of perfluoroiodopropane, perfluoroiodobutane, and perfluoroiodohexane; The molar ratio of 1,7-enyne 1, di-tert-butyldiazididine 2, perfluoroiodoalkane 3, base, palladium catalyst, and ligand is 1:(1~3):(1~3):2:(0.025~0.2):(0.05~0.2).

2. The method for synthesizing a pyrrolotetrahydroquinoline compound containing a perfluoroalkane structure according to claim 1, characterized in that: The organic solvent is selected from one or more of toluene, 1,2-dichloroethane, dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, n-hexane, diethyl ether, and ethyl acetate.

3. The method for synthesizing a pyrrolotetrahydroquinoline compound containing a perfluoroalkane structure according to claim 1, characterized in that: The palladium catalyst is selected from one or more of palladium acetate, palladium trifluoroacetate, palladium chloride, palladium iodide, palladium nitrate, palladium acetylacetone, and tetraphenylphosphine palladium.

4. The method for synthesizing a pyrrolotetrahydroquinoline compound containing a perfluoroalkane structure according to claim 1, characterized in that: The ligand is a phosphine ligand.

5. The method for synthesizing a pyrrolotetrahydroquinoline compound containing a perfluoroalkane structure according to claim 4, characterized in that: The phosphine ligand is PPh3, ( o -OMe-Ph)3P、( p One of the following: (-F-Ph)3P, (2-thienyl)3P, (2-furyl)3P, PPh2Cy, PPhCy2, PCy3, (C6F5)3P, dppm, dppb, dppf.

6. The method for synthesizing a pyrrolotetrahydroquinoline compound containing a perfluoroalkane structure according to claim 1, characterized in that: The reaction temperature is 70~140℃.

7. The method for synthesizing a pyrrolotetrahydroquinoline compound containing a perfluoroalkane structure according to claim 1, characterized in that: The separation method is column chromatography.

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