Synthesis method of 8-acylquinoline derivative
阅读说明：本技术 一种8-酰基喹啉衍生物的合成方法 (Synthesis method of 8-acylquinoline derivative ) 是由 邹亮华 邵泽宇 李炜 马成伟 宋盈盈 于 2020-12-09 设计创作，主要内容包括：本发明公开了一种8-酰基喹啉衍生物的合成方法,属于有机合成领域。本发明以式Ι所示的2,1-苯并异恶唑衍生物、式II所示的苯乙醛衍生物为底物,在铜催化剂作用下进行反应,得到式III所示的8-酰基喹啉衍生物。本发明方法原料便宜,催化剂廉价易得,高效绿色,条件温和,而且底物范围广、产率高,操作简单,具有非常广阔的应用前景。(The invention discloses a synthesis method of an 8-acyl quinoline derivative, belonging to the field of organic synthesis. The method takes a 2, 1-benzisoxazole derivative shown in a formula I and a phenylacetaldehyde derivative shown in a formula II as substrates, and the 2, 1-benzisoxazole derivative and the phenylacetaldehyde derivative react under the action of a copper catalyst to obtain the 8-acylquinoline derivative shown in a formula III. The method has the advantages of cheap raw materials, cheap and easily-obtained catalyst, high efficiency, greenness, mild conditions, wide substrate range, high yield, simple operation and very wide application prospect.)
1. A method for synthesizing 8-acyl quinoline derivatives is characterized in that 2, 1-benzisoxazole derivatives shown in formula I and aldehyde derivatives shown in formula II are used as substrates and react under the action of a copper catalyst to obtain 8-acyl quinoline derivatives shown in formula III;
wherein R is1Selected from: hydrogen, halogen, C1-C8Alkyl radical, C1-C8Cycloalkyl radical, C1-C8Alkoxy radical, C1-C8A haloalkyl group;
R2selected from: hydrogen, C1-C8Alkyl radical, C1-C8Cycloalkyl, aryl substituted or unsubstituted by a substituent, heterocyclic aryl substituted or unsubstituted by a substituent; substituents include halogen, C1-C8Alkyl radical, C1-C8Alkoxy radical, C1-C8Cycloalkyl radical, C1-C8A haloalkyl group;
R3selected from: aryl substituted or unsubstituted with a substituent; substituents include halogen, C1-C8Alkyl radical, C1-C8Cycloalkyl radical, C1-C8Alkoxy radical, C1-C8A haloalkyl group.
2. The method of claim 1, wherein the copper catalyst comprises copper powder, copper acetate, copper bromide, copper oxide, cuprous iodide, and copper triflate.
3. The method according to claim 1, wherein the molar ratio of the 2, 1-benzisoxazole derivative represented by formula I to the copper catalyst is 1: (0.1-0.3).
4. The method according to claim 1, wherein the molar ratio of the 2, 1-benzisoxazole derivative represented by formula I to the aldehyde derivative represented by formula II is 1: 1.5-2.5.
5. The method of claim 1, further comprising adding a silver additive comprising silver triflate, silver oxide, silver nitrate, silver carbonate.
6. The method according to claim 1, wherein the molar ratio of the 2, 1-benzisoxazole derivative represented by formula I to the silver additive is 1: (0.025 to 0.2).
7. The method according to claim 1, wherein the reaction is carried out by dissolving the substrate in an organic solvent; the addition amount of the organic solvent to the 2, 1-benzisoxazole derivative shown in the formula I is 5-15 mL/mmol.
8. The method of claim 1, wherein the method is carried out under an oxygen atmosphere.
9. The method of claim 1, further comprising adding water.
10. The method according to claim 1, wherein the molar ratio of the 2, 1-benzisoxazole derivative represented by formula I to water is 1: (5.0-20.0).
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthetic method of an 8-acyl quinoline derivative.
Background
The polysubstituted 8-acyl quinoline is a core skeleton structure of bioactive substances, synthetic drugs and natural drugs, can be further modified into other bioactive drug molecules on the basis of the ortho-position aldehyde group, can also be modified and reformed to synthesize other important ligands for ortho-position aldehyde group quinoline compounds, and has wide application in biological and pharmacological research.
The methods for synthesizing the aldehyde quinoline compound are not limited, and the method for oxidizing methyl and hydroxy methylene on quinoline is adopted in the prior art, and bromine atoms on quinoline are converted into aldehyde. Most of the existing methods need to add strong acid and even extremely toxic reagent, and the reaction conditions are relatively harsh, the cost is high, and the serious environmental pollution is generated. In the case of 8-hydroxyquinolines, the functional groups available in conventional methods for obtaining such compounds are limited. Therefore, it is very important to develop a new synthesis method for synthesizing 8-hydroxyquinoline compound.
Disclosure of Invention
Aiming at the research of the prior bioactive medicament molecular quinoline compound, the invention aims to provide a synthesis method of a novel 8-acyl quinoline derivative, which has the advantages of low raw material price, environmental protection, small catalyst consumption and wide applicable substrate range. The invention reports a novel polysubstituted 8-acyl quinoline derivative for the first time, and realizes a conversion strategy from aldehyde to quinoline aldehyde.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method of synthesizing 8-acylquinoline derivatives: taking a 2, 1-benzisoxazole derivative shown in a formula I and an aldehyde derivative shown in a formula II as substrates, and reacting under the action of a copper catalyst to obtain an 8-acyl quinoline derivative shown in a formula III;
wherein R is1Selected from: hydrogen, halogen, C1-C8Alkyl radical, C1-C8Cycloalkyl radical, C1-C8Alkoxy radical, C1-C8A haloalkyl group;
R2selected from: hydrogen, C1-C8Alkyl radical, C1-C8Cycloalkyl, aryl substituted or unsubstituted by a substituent, heterocyclic aryl substituted or unsubstituted by a substituent; substituents include halogen, C1-C8Alkyl radical, C1-C8Alkoxy radical, C1-C8Cycloalkyl radical, C1-C8A haloalkyl group; the aryl group includes a benzene ring or a naphthalene ring; heterocyclic aromatic groups include C3-C6 aromatic ring groups containing at least one of the heteroatoms N, S, O;
R3selected from: aryl substituted or unsubstituted with a substituent; substituents include halogen, C1-C8Alkyl radical, C1-C8Cycloalkyl radical, C1-C8Alkoxy radical, C1-C8A haloalkyl group; the aryl group includes a benzene ring or a naphthalene ring.
In one embodiment of the invention, R1H, OMe, F, Br, Cl.
In one embodiment of the invention, R2H, Me is,
In one embodiment of the invention, R3Is phenyl,
In one embodiment of the invention, the method comprises dissolving the substrate in an organic solvent and reacting the substrate with a catalyst. The organic solvent is toluene, trifluorotoluene, o-xylene, m-xylene, etc.
In one embodiment of the invention, the addition amount of the organic solvent to the 2, 1-benzisoxazole represented by formula I is 5 to 15 mL/mmol.
Preferably, the amount of the organic solvent added is 6-14 mL/mmol based on the amount of the 2, 1-benzisoxazole shown in formula I.
In one embodiment of the invention, the process is carried out under an oxygen atmosphere.
In one embodiment of the invention, the copper catalyst comprises copper powder, copper acetate, copper bromide, copper oxide, cuprous iodide, and copper triflate.
In one embodiment of the present invention, the molar ratio of the 2, 1-benzisoxazole derivative represented by formula i to the copper catalyst is 1: (0.1-0.3); preferably 1: (0.15-0.25).
In one embodiment of the invention, the method further comprises adding a silver additive comprising silver triflate, silver oxide, silver nitrate, silver carbonate.
In one embodiment of the present invention, the molar ratio of the 2, 1-benzisoxazole derivative represented by formula i to the silver additive is 1: (0.025-0.2) preferably; 1: (0.05-0.15).
In one embodiment of the present invention, the reaction temperature is 70-130 ℃ and the reaction time is 3-30 hours.
In one embodiment of the present invention, the ratio of the amount of the 2, 1-benzisoxazole derivative represented by formula I to the amount of the aldehyde derivative represented by formula II is 1:1.5 to 2.5.
In one embodiment of the present invention, the method further comprises adding water, and the molar ratio of the 2, 1-benzisoxazole derivative shown in formula i to water is 1: (5.0-20.0).
In one embodiment of the invention, the ratio of the 2, 1-benzisoxazole derivative shown in formula I to the copper catalyst, the silver additive and the water additive is 1: 0.15-0.25: 0.05-0.15: 5.0-20.0.
In one embodiment of the present invention, after the reaction is completed, the product is purified by silica gel column chromatography.
In one embodiment of the present invention, the purification method is: and after the reaction is finished, adding column chromatography silica gel, distilling under reduced pressure to remove the solvent, spinning to dry until the silica gel adsorbs a product powder, loading the product powder onto a column, and eluting by using a mixed solution of petroleum ether and ethyl acetate to collect the quinoline derivative.
Has the advantages that:
the invention reports a method for synthesizing a novel 8-acyl quinoline derivative for the first time. The process of converting the aldehyde into the quinoline aldehyde is realized, the quinoline aldehyde can be modified into other important bioactive molecules for synthesizing other medical intermediates taking the quinoline as a framework, and the method has important application value in the aspect of ligands. In addition, the catalyst adopted by the method is cheap and easy to obtain, the dosage of the catalyst is small (as low as 10 mol%), the reaction efficiency is high (as high as 70%), and the target compound of the 8-acylquinoline derivative can be generated only in a few hours.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to the following specific examples.
The starting material 2, 1-benzisoxazole used in the present invention can be prepared on its own according to the existing literature, for example, the literature Wang, f.; xu, p.; wang, s.y.; ji, s.j.org.lett.2018,20,2204.
The invention provides a synthesis method which comprises the following steps:
o-nitrobenzaldehyde (3 mmol) and stannous chloride anhydrous (9 mmol) were added to a reaction flask equipped with magnetic stirring, a solution of methanol and ethyl acetate (1:1,20mL) was prepared, added to the reaction flask, and stirred at room temperature for 24 hours. The reaction was complete, quenched with saturated sodium bicarbonate solution (20mL), extracted with ethyl acetate (3 × 10mL), the organic phase washed with water (20mL), saturated brine (20mL), the organic phase dried over anhydrous sodium sulfate, left to stand, filtered and concentrated by evaporation, purified by column chromatography petroleum ether: purification of ethyl acetate 30:1 afforded the product.
The synthetic route is as follows:
R1h, OMe, F and Br.
The phenylacetaldehyde with substituents used in the present invention can be prepared by itself according to known methods, for example, the documents n.eleftheidis, h.poelman, n.g.j.leus, b.honrath, c.g.neochoritis, a.dolga, a.F.J.Dekker,Eur. J.Med.Chem.2016,122,786.
The invention provides a synthesis method which comprises the following steps:
a250 mL single-neck flask was charged with dessimutant reagent (9.6mmol), dissolved in dichloromethane (70mL), and the corresponding alcohol substrate (commercially available) (8mmol) was added dropwise and stirred at room temperature for 18 hours. After the reaction was completed, the reaction was quenched by adding a saturated thiosulfate solution (50mL) to the reaction solution, washed with a saturated sodium bicarbonate solution (60mL), washed with brine (60mL), dried over anhydrous sodium sulfate, left to stand, filtered and concentrated by evaporation, and purified by column chromatography petroleum ether: ethyl acetate 20:1 purification afforded the substituted aldehyde of formula II.
The synthetic route is as follows:
R3is phenyl,
Example 1
This example prepares an 8-acylquinoline derivative having the following structural formula:
the preparation method comprises the following steps: 2, 1-benzisoxazole (0.3mmol,44.7mg), phenylacetaldehyde (0.6mmol,72.0mg), copper powder (0.06mmol,3.8mg), silver trifluoromethanesulfonate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were charged into a 25mL Schlenk tube, and the reaction tube was purged with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 55%. This material was a yellow solid with a melting point of 163.2-164.6 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ11.32(d,J＝0.6Hz,1H),8.41-8.37(m,2H),8.21 (dd,J＝8.2,1.4Hz,1H),7.92(dd,J＝8.4,1.2Hz,2H),7.82-7.32(m,9H)；13C NMR(101MHz, CDCl3)δ194.5,192.4,157.0,145.2,137.4,137.2,136.0,135.0,134.0,133.8,131.7,130.5,129.7, 129.0,128.8,128.6,128.3,128.1,127.8；HR-MS(ESI-TOF)calcd for C23H15NO2(M+H)+ 338.1175，found 338.1175.
example 2
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 6-methoxy-2, 1-benzisoxazole (0.3mmol,44.7mg), phenylacetaldehyde (0.6mmol,72.0mg), copper powder (0.06mmol,3.8mg), silver triflate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 55%. This material is a yellow solid with a melting point of 181.7-182.8 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ11.14(s,1H),8.74(s,1H),8.40(d,J＝8.3Hz,1H), 7.92-7.90(m,2H),7.58(dd,J＝10.5,4.3Hz,1H),7.43(ddd,J＝6.6,5.5,4.8Hz,4H),7.38-7.32 (m,3H),7.08(d,J＝8.3Hz,1H),4.14(s,3H)；13C NMR(101MHz,CDCl3)δ194.8,191.4,160.2, 157.0,146.3,137.5,136.0,134.0,133.8,132.7,131.7,130.5,129.0,128.8,128.5,128.2,125.1, 119.9,105.4,56.4；HRMS m/z(ESI-TOF)calcdforC24H17NO3(M+H)+368.1281,found 368.1281.
example 3
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 6-bromo 2, 1-benzisoxazole (0.3mmol,59.4mg), phenylacetaldehyde (0.6mmol,72.0mg), copper powder (0.06mmol,3.8mg), silver triflate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 53%. This material was a yellow solid with a melting point of 197.3-198.9 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ11.27-11.25(m,1H),8.72-8.71(m,1H),8.23(d,J＝7.9Hz,1H),8.10(dd,J＝7.9,0.5Hz,1H),7.89(dd,J＝8.3,1.2Hz,2H),7.61(ddd,J＝8.7,3.0, 1.8Hz,1H),7.47-7.43(m,4H),7.40-7.37(m,3H)；13C NMR(101MHz,CDCl3)δ194.1,191.7, 157.6,145.5,137.0,136.7,136.0,135.7,134.0,131.7,131.2,130.4,129.7,129.1,128.9,128.9, 128.6,128.6,127.5；HRMS m/z(ESI-TOF)calcd for C23H14BrNO2(M+H)+416.0281,found 416.0284.
example 4
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 5-methoxy 2, 1-benzisoxazole (0.3mmol,44.7mg), phenylacetaldehyde (0.6mmol,72.0mg), copper powder (0.06mmol,3.8mg), silver triflate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 55%. This material was a yellow solid with a melting point of 166.5-167.9 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ11.25-11.24(m,1H),8.25-8.23(m,1H),8.03(d,J＝ 2.9Hz,1H),7.93(d,J＝7.9Hz,2H),7.59(t,J＝7.4Hz,1H),7.48-7.34(m,8H),4.03(s,3H)；13C NMR(101MHz,CDCl3)δ194.6,192.1,158.6,154.3,141.1,137.5,136.2,136.1,135.5,133.6, 132.9,130.5,129.9,128.9,128.7,128.5,128.2,121.1,112.1,56.1；HRMS m/z(ESI-TOF)calcd for C24H17NO3(M+H)+368.1281,found 368.1286.
example 5
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 5-fluoro-2, 1-benzisoxazole (0.3mmol,41.1mg), phenylacetaldehyde (0.6mmol,72.0mg), copper powder (0.06mmol,3.8mg), silver triflate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 51%. This material was a yellow solid with a melting point of 104.6-105.9 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ11.25(d,J＝3.1Hz,1H),8.32(s,1H),8.13(dd,J＝ 8.4,2.9Hz,1H),7.91(dd,J＝8.2,1.1Hz,2H),7.82(dd,J＝8.1,2.9Hz,1H),7.62-7.58(m,1H), 7.45(t,J＝7.8Hz,2H),7.37(ddd,J＝7.1,5.2,2.8Hz,5H)；13C NMR(101MHz,CDCl3)δ194.2, 191.0,162.3,159.8,156.4(d,JF-C＝2.9Hz),142.2,136.8,136.6(d,JF-C＝5.4Hz),135.8,134.0, 133.9,133.8,130.4,129.6(d,JF-C＝9.3Hz),128.9(d,JF-C＝7.4Hz),128.6,128.5,119.3(d,JF-C＝ 26.4Hz),116.9(d,JF-C＝22.1Hz)；19F NMR(376MHz,CDCl3)δ-109.37；HRMS m/z(ESI-TOF) calcd for C23H14FNO2(M+H)+356.1081,found 356.1087.
example 6
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 5-bromo 2, 1-benzisoxazole (0.3mmol,59.4mg), phenylacetaldehyde (0.6mmol,72.0mg), copper powder (0.06mmol,3.8mg), silver triflate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 58%. This material was a yellow solid with a melting point of 142.5-143.7 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ11.23(s,1H),8.42-7.62(m,6H),7.45(t,J＝7.7Hz, 2H),7.39-7.34(m,5H)；13C NMR(101MHz,CDCl3)δ194.2,191.0,157.3,143.6,136.7,136.3, 135.9,135.7,135.5,134.0,133.0,132.8,130.4,129.6,128.9,128.9,128.7,128.6,122.3。
example 7
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 3-phenyl-5-chloro-2, 1-benzisoxazole (0.3mmol,68.9mg), phenylacetaldehyde (0.6mmol,72.0mg), copper powder (0.06mmol,3.8mg), silver triflate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was purged with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 60%. This material was a yellow solid with a melting point of 148.1-149.2 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ7.91-7.74(m,4H),7.64(td,J＝5.8,3.1Hz,3H), 7.50(t,J＝7.7Hz,2H),7.43(d,J＝7.0Hz,2H),7.38(d,J＝2.4Hz,1H),7.32(dd,J＝5.2,1.9Hz, 3H),7.23(s,1H),6.46(d,J＝8.5Hz,1H),6.11(s,1H)；13C NMR(101MHz,CDCl3)δ197.0, 169.8,144.8,138.7,137.8,135.6,134.2,134.0,133.3,133.0,132.0,131.2,130.9,130.8,130.3, 129.1,128.9,128.7,128.6,128.5,127.5,126.4,91.2；HRMS m/z(ESI-TOF)calcd for C29H18ClNO2(M+H)+448.1098,found 448.1103.
example 8
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 3-methyl-2, 1-benzisoxazole (0.3mmol,40.0mg), phenylacetaldehyde (0.6mmol,72.0mg), copper powder (0.06mmol,3.8mg), silver triflate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 65%. This material is a yellow solid with a melting point of 120.5-121.5 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ8.35-8.32(m,1H),8.11-8.06(m,2H),7.94-7.92(m, 2H),7.70(d,J＝7.3Hz,1H),7.59(t,J＝7.4Hz,1H),7.47-7.34(m,7H),2.79(s,3H)；13C NMR (101MHz,CDCl3)δ202.8,194.4,155.9,143.1,139.0,137.6,137.3,136.2,134.6,133.7,131.6, 130.9,130.5,129.0,128.8,128.5,128.2,127.8,33.0；HRMS m/z(ESI-TOF)calcd for C29H18ClNO2(M+H)+352.1332,found 352.1332.
example 9
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 3-Furan-2, 1-benzisoxazole (0.3mmol,55.5mg), phenylacetaldehyde (0.6mmol,72.0mg), copper powder (0.06mmol,3.8mg), silver triflate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 55%. This material was a yellow solid with a melting point of 185.5-186.7 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ8.32(s,1H),8.08-8.06(m,1H),7.90-7.84(m,3H), 7.75-7.71(m,1H),7.52(dd,J＝12.2,4.0Hz,2H),7.37-7.32(m,7H),6.95(d,J＝3.5Hz,1H),6.46 (dd,J＝3.5,1.6Hz,1H)；13C NMR(101MHz,CDCl3)δ194.0,184.4,156.1,153.4,147.1,143.4, 138.5,137.6,137.2,136.0,135.1,133.4,130.6,130.3,129.4,128.9,128.7,128.3,128.1,127.9, 127.5,120.4,112.3；HRMS m/z(ESI-TOF)calcd for C27H17NO3(M+H)+404.1281,found 404.1281.
example 10
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 3-thiophene-2, 1-benzisoxazole (0.3mmol,60.4mg), p-methylphenylacetal (0.6mmol,80.4mg), copper powder (0.06mmol,3.8mg), silver triflate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was purged with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing a target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 70%. This material was a yellow solid with a melting point of 225.5-226.7 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ8.33-8.32(m,1H),8.06(m,1H),7.88(dd,J＝7.0,1.2Hz, 1H),7.83(d,J＝7.2Hz,2H),7.74(dd,J＝7.9,7.3Hz,1H),7.66(dd,J＝4.9,0.9Hz,1H),7.50(t, J＝7.4Hz,1H),7.37-7.26(m,8H),7.05(dd,J＝4.7,4.0Hz,1H)；13C NMR(101MHz,CDCl3)δ193.8,189.3,156.0,145.3,143.3,139.4,137.7,137.3,135.9,135.4,135.2,134.5,133.3,130.6, 129.8,128.9,128.8,128.7,128.2,128.1,128.0,127.9,127.5.
example 11
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 2, 1-benzisoxazole (0.3mmol,44.7mg), p-methylphenylacetal (0.6mmol,80.5mg), copper powder (0.06mmol,3.8mg), silver triflate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 61%. This material was a yellow solid with a melting point of 180.6-181.7 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ11.31(d,J＝0.6Hz,1H),8.36(dd,J＝7.2,1.5Hz,1H), 8.33(s,1H),8.18(dd,J＝8.2,1.4Hz,1H),7.83-7.22(m,7H),7.15(d,J＝7.9Hz,2H),2.42-2.33 (m,6H)；13C NMR(101MHz,CDCl3)δ194.3,192.5,157.3,145.1,144.9,138.2,137.2,134.9, 134.3,134.0,133.6,131.7,130.7,129.6,129.4,129.3,128.8,128.2,127.6,21.9,21.2；HRMS m/z (ESI-TOF)calcd for C25H19NO2(M+H)+366.1488,found 366.1493.
example 12
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 2, 1-benzisoxazole (0.3mmol,44.7mg), p-methoxyphenylacetaldehyde (0.6mmol,90.1 mg), copper powder (0.06mmol,3.8mg), silver triflate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 57%. This material was a yellow solid with a melting point of 158.8-159.5 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ11.33(s,1H),8.36-7.88(m,5H),7.76(t,J＝7.7Hz,1H), 7.35(d,J＝8.7Hz,2H),6.89(dd,J＝11.5,8.8Hz,4H),3.87(s,3H),3.79(s,3H)；13CNMR(101 MHz,CDCl3)δ193.5,192.5,164.1,159.7,157.5,145.1,136.9,134.4,133.9,132.9,131.6,130.2, 129.5,129.3,129.0,128.2,127.5,114.3,113.9,55.6,55.3；HRMS m/z(ESI-TOF)calcd for C25H19NO4(M+H)+398.1386,found 398.1391.
example 13
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 2, 1-benzisoxazole (0.3mmol,44.7mg), p-tert-butylacetal (0.6mmol,105.7 mg), copper powder (0.06mmol,3.8mg), silver triflate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 57%. This material was a yellow solid with a melting point of 217.9-218.3 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ11.33(s,1H),8.38-8.36(m,2H),8.20(dd,J＝8.2, 1.4Hz,1H),7.89-7.87(m,2H),7.78(t,J＝7.7Hz,1H),7.47-7.45(m,2H),7.36(d,J＝2.0Hz,4H), 1.35(s,9H),1.30(s,9H)；13C NMR(101MHz,CDCl3)δ194.2,192.6,157.5,157.2,151.2,145.0, 137.3,135.0,134.3,134.0,133.6,131.7,130.5,129.4,128.7,128.2,127.6,125.8,125.5,35.3,34.6, 31.3,31.1；HRMS m/z(ESI-TOF)calcd for C31H31NO2(M+H)+450.2427,found 450.2431.
example 14
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 2, 1-benzisoxazole (0.3mmol,44.7mg), p-fluorobenzaldehyde (0.6mmol,80.4mg), copper powder (0.06mmol,3.8mg), silver trifluoromethanesulfonate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 54%. This material was a yellow solid with a melting point of 135.1-136.8 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ11.31-11.30(m,1H),8.41-8.35(m,2H),8.22(dd,J＝8.2, 1.4Hz,1H),7.97-7.94(m,2H),7.82(t,JF-C＝7.7Hz,1H),7.39-7.35(m,2H),7.10(dt,J＝23.7,8.6 Hz,4H)；13C NMR(101MHz,CDCl3)δ192.76,192.06,167.46,164.90,164.03,161.55,156.37, 145.14,137.55,133.90(d,JF-C＝2.2Hz),133.18,133.13,133.08,132.28(d,JF-C＝2.9Hz),131.68, 130.68(d,JF-C＝8.3Hz),129.91,128.03(d,JF-C＝3.0Hz),115.92(d,JF-C＝21.6Hz)；19F NMR (376MHz,CDCl3)δ-103.07,-113.17；HRMS m/z(ESI-TOF)calcd for C23H12F2NO2(M+H)+ 374.0987,found 374.0994.
example 15
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 2, 1-benzisoxazole (0.3mmol,44.7mg), p-chlorobenzaldehyde (0.6mmol,92.8mg), copper powder (0.06mmol,3.8mg), silver trifluoromethanesulfonate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were charged into a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 51%. This material was a yellow solid with a melting point of 178.7-179.2 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ11.28(s,1H),8.41(dd,J＝7.2,1.4Hz,1H),8.35(s, 1H),8.22(dd,J＝8.2,1.4Hz,1H),7.90-7.88(m,2H),7.83(t,J＝7.7Hz,1H),7.46-7.43(m,2H), 7.37-7.31(m,4H)；13C NMR(101MHz,CDCl3)δ192.9,192.0,156.0,145.2,140.6,137.7,135.6, 134.7,134.2,134.0,133.9,131.8,131.7,130.2,130.1,129.1,129.1,128.2,128.1；HRMS m/z (ESI-TOF)calcd for C23H13Cl2NO2(M+H)+406.0396,found 406.0393.
example 16
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 2, 1-benzisoxazole (0.3mmol,44.7mg), p-bromophenylacetal (0.6mmol,119.4mg), copper powder (0.06mmol,3.8mg), silver trifluoromethanesulfonate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were charged into a 25mL Schlenk tube, and the reaction tube was purged with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 57%. This material was a yellow solid with a melting point of 209.1-210.2 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ11.27(d,J＝0.6Hz,1H),8.41(dd,J＝7.2,1.5Hz, 1H),8.35(s,1H),8.21(dd,J＝8.2,1.4Hz,1H),7.82(d,J＝8.6Hz,3H),7.63-7.61(m,2H), 7.52-7.50(m,2H),7.27-7.25(m,2H)；13C NMR(101MHz,CDCl3)δ193.0,191.9,155.8,145.1, 137.6,136.1,134.6,133.9,133.9,132.0,131.9,131.7,130.4,130.1,129.5,128.2,128.0,123.7, 122.9；HRMS m/z(ESI-TOF)calcd for C23H13Br2NO2(M+H)+493.9385,found 493.9379.
example 17
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 2, 1-benzisoxazole (0.3mmol,44.7mg), m-tolylacetaldehyde (0.6mmol,80.5mg), copper powder (0.06mmol,3.8mg), silver trifluoromethanesulfonate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were charged into a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 51%. This material was a yellow solid with a melting point of 123.3-124.9 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ11.33(d,J＝0.6Hz,1H),8.40-8.35(m,2H),8.20 (dd,J＝8.2,1.4Hz,1H),7.81-7.75(m,2H),7.69(d,J＝7.7Hz,1H),7.40(d,J＝7.5Hz,1H),7.32 (t,J＝7.6Hz,1H),7.22-7.14(m,3H),5.30(s,1H),2.38(s,3H),2.33(s,3H)；13C NMR(101MHz, CDCl3)δ194.8,192.5,157.2,145.2,138.5,138.4,137.3,137.2,136.1,135.0,134.6,134.0,131.7, 130.6,129.7,129.5,129.1,128.6,128.4,128.2,128.0,127.7,126.1,21.5,21.4；HRMS m/z (ESI-TOF)calcd for C23H13Br2NO2(M+H)+366.1488,found 366.1493.
example 18
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 2, 1-benzisoxazole (0.3mmol,44.7mg), m-fluorobenzaldehyde (0.6mmol,82.9mg), copper powder (0.06mmol,3.8mg), silver trifluoromethanesulfonate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing a target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 50%. This material was a yellow solid with a melting point of 160.7-161.9 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ11.30(s,1H),8.44-8.38(m,2H),8.23(dd,J＝8.2,1.3 Hz,1H),7.84(t,J＝7.7Hz,1H),7.71(d,J＝7.7Hz,1H),7.65(dd,J＝8.9,2.0Hz,1H),7.45(td,J ＝8.0,5.5Hz,1H),7.37-7.30(m,2H),7.16-7.12(m,2H),7.09-7.04(m,1H)；13C NMR(101MHz, CDCl3)δ192.7(d,JF-C＝2.3Hz),192.0,164.0(d,JF-C＝8.2Hz),161.5(d,JF-C＝8.9Hz),155.8, 145.3,139.2(d,JF-C＝7.8Hz),137.9(d,JF-C＝6.5Hz),137.8,134.0,133.8(d,JF-C＝2.1Hz),131.8, 130.4(d,JF-C＝21.5Hz),130.4(d,JF-C＝5.4Hz),130.2,128.3,128.0,126.4(d,JF-C＝3.0Hz), 124.8(d,JF-C＝3.0Hz),121.1(d,JF-C＝21.5Hz),116.8(d,JF-C＝22.5Hz),116.0(d,JF-C＝22.4 Hz),115.4(d,JF-C＝21.0Hz)；19F NMR(376MHz,CDCl3)δ-111.37,-111.91。
example 19
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 2, 1-benzisoxazole (0.3mmol,44.7mg), o-tolylacetaldehyde (0.6mmol,80.5mg), copper powder (0.06mmol,3.8mg), silver trifluoromethanesulfonate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were charged into a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 51%. This material was a white solid with a melting point of 203.1-204.5 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ11.33(s,1H),8.40(dd,J＝7.2,1.4Hz,1H), 8.20-8.15(m,2H),7.79(t,J＝7.7Hz,1H),7.43(dd,J＝7.7,1.0Hz,1H),7.34(td,J＝7.5,1.2Hz, 1H),7.21(ddd,J＝13.3,9.6,4.3Hz,3H),7.10(dt,J＝7.4,6.7Hz,3H),2.34(s,3H),2.14(s,3H)；13C NMR(101MHz,CDCl3)δ196.7,192.4,158.0,145.4,140.0,137.9,136.6,136.1,135.8,134.2, 133.8,132.0,131.8,131.8,131.7,130.1,129.7,129.6,128.4,127.8,127.7,125.6,125.00,21.0, 20.4。
example 20
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 2, 1-benzisoxazole (0.3mmol,44.7mg), o-fluorobenzaldehyde (0.6mmol,82.9mg), copper powder (0.06mmol,3.8mg), silver trifluoromethanesulfonate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing a target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 50%. This material was a white solid with a melting point of 166.8-167.4 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ11.14(s,1H),8.38-8.36(m,2H),8.20(dd,J＝8.2,1.4 Hz,1H),7.88(td,J＝7.5,1.8Hz,1H),7.80(t,J＝7.7Hz,1H),7.62-7.56(m,1H),7.50(td,J＝7.6, 1.7Hz,1H),7.40(tdd,J＝7.3,5.2,1.8Hz,1H),7.31-7.26(m,2H),7.13-7.09(m,2H)；13C NMR (101MHz,CDCl3)δ192.2,191.5,163.2,160.5(d,JF-C＝27.0Hz),157.9,155.8,145.4,138.8, 135.0(d,JF-C＝8.9Hz),133.9,131.7(d,JF-C＝3.7Hz),131.1(d,JF-C＝2.9Hz),130.4(d,JF-C＝8.2 Hz),129.8,128.5(d,JF-C＝4.0Hz),128.2,125.6(d,JF-C＝2.9Hz),125.4,124.8(d,JF-C＝3.6Hz), 124.3(d,JF-C＝3.5Hz),116.5,116.1(d,JF-C＝32.1Hz),115.7；19F NMR(376MHz,CDCl3)δ -107.37,-107.41,-115.81,-115.84。
example 21
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 2, 1-benzisoxazole (0.3mmol,44.7mg), o-fluorobenzaldehyde (0.6mmol,92.8mg), copper powder (0.06mmol,3.8mg), silver trifluoromethanesulfonate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 55%. This material was a yellow solid with a melting point of 59.8-60.2 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ11.02(s,1H),8.38(dd,J＝7.2,1.4Hz,1H),8.31(s,1H), 8.19(dd,J＝8.2,1.4Hz,1H),7.82(t,J＝7.7Hz,1H),7.63(dd,J＝7.6,1.5Hz,1H),7.50-7.42(m, 4H),7.38-7.31(m,3H)；13C NMR(101MHz,CDCl3)δ193.6,192.2,153.6,145.5,139.4,137.4, 137.0,133.9,133.0,132.9,132.8,132.4,131.9,131.5,131.0,130.2,129.9,129.6,129.6,128.6, 128.2,127.0,126.5。
example 22
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 2, 1-benzisoxazole (0.3mmol,44.7mg), o-fluorobenzaldehyde (0.6mmol,119.4mg), copper powder (0.06mmol,3.8mg), silver trifluoromethanesulfonate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 61%. This material was a yellow solid with a melting point of 69.4-70.1 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ11.00(s,1H),8.38(dd,J＝7.2,1.4Hz,1H),8.28(s,1H), 8.19(dd,J＝8.2,1.3Hz,1H),7.82(t,J＝7.7Hz,1H),7.68(dd,J＝8.0,0.8Hz,1H),7.60(dt,J＝ 7.2,2.1Hz,2H),7.47-7.28(m,5H)；13C NMR(101MHz,CDCl3)δ194.1,192.2,152.8,145.4, 139.5,139.4,139.0,134.7,133.9,133.4,132.7,132.2,131.9,131.5,130.9,130.0,129.7,128.7, 128.1,127.5,127.0,123.3,121.1。
example 23
The formula for preparing quinoline derivatives in this example is as follows:
the preparation method comprises the following steps: 2, 1-benzisoxazole (0.3mmol,44.7mg), o-bromobenzaldehyde (0.6mmol,119.4mg), copper powder (0.06mmol,3.8mg), silver triflate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the quinoline compound with the yield of 61%. This material was a yellow solid with a melting point of 69.4-70.1 ℃.
Characterization data:1H NMR(400MHz,CDCl3)δ11.00(s,1H),8.38(dd,J＝7.2,1.4Hz,1H),8.28(s,1H), 8.19(dd,J＝8.2,1.3Hz,1H),7.82(t,J＝7.7Hz,1H),7.68(dd,J＝8.0,0.8Hz,1H),7.60(dt,J＝ 7.2,2.1Hz,2H),7.47-7.28(m,5H)；13C NMR(101MHz,CDCl3)δ194.1,192.2,152.8,145.4, 139.5,139.4,139.0,134.7,133.9,133.4,132.7,132.2,131.9,131.5,130.9,130.0,129.7,128.7, 128.1,127.5,127.0,123.3,121.1。
example 24
Referring to example 1, water was not added during the reaction, and other conditions were not changed, and the reaction was used to prepare quinoline compounds.
The specific process comprises the following steps: 2, 1-benzisoxazole (0.3mmol,44.7mg), phenylacetaldehyde (0.6mmol,72.0mg), copper catalyst (0.06mmol, 0.2eq) and silver triflate (0.03mmol,8.0mg) were added to a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. After the reaction is finished, adding 100-200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting by using mixed liquid of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, merging the target product eluent, and carrying out evaporation concentration to obtain the target product with the yield of 40%.
Example 25
Referring to example 1, the copper catalyst was replaced with copper powder by a different copper catalyst as shown in Table 1, and the conditions were otherwise unchanged, and used to prepare quinolines.
The specific process comprises the following steps: 2, 1-benzisoxazole (0.3mmol,44.7mg), phenylacetaldehyde (0.6mmol,72.0mg), copper catalyst (0.06mmol, 0.2eq), silver triflate (0.03mmol,8.0mg) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. And after the reaction is finished, adding 100-mesh and 200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting by using a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the target product.
The specific reaction results are shown in Table 1.
TABLE 1 results of different copper catalysts for the preparation of quinolines
Copper catalyst
Yield (%)
Cu(OAc)2
27
CuI
28
CuBr2
25
CuO
37
Cu2O
36
Cu(OTf)2
15
CuCl
38
Example 26
Referring to example 1, the amount of copper catalyst was changed from 0.06mmol (0.2 eq) to a different amount (see table 2), and the conditions were otherwise unchanged, and used to prepare quinolines.
The specific reaction results are shown in Table 2.
TABLE 2 results of preparing quinolines with varying copper catalyst levels
Amount of copper catalyst
Yield (%)
0.10eq
38
0.15eq
42
0.25eq
51
0.30eq
53
Example 27
Referring to example 1, the silver additive was replaced with other different silver additives shown in table 3 (see table 3), respectively, and the other conditions were not changed, to prepare quinoline-based compounds.
The specific process comprises the following steps: 2, 1-benzisoxazole (0.3mmol,44.7mg), phenylacetaldehyde (0.6mmol,72.0mg), copper powder (0.06mmol, 0.2eq), silver additive (0.03mmol,0.1eq) and water (3mmol,54.0mg) were added to a 25mL Schlenk tube, and the reaction tube was replaced with oxygen three times under reduced pressure. Toluene (2mL) was added and stirred at 110 ℃ for 12 hours. And after the reaction is finished, adding 100-mesh and 200-mesh column chromatography silica gel, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the crude product, eluting by using a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10:1), carrying out TLC (thin layer chromatography) elution tracking detection, collecting eluent containing the target product, combining the target product eluent, and carrying out evaporation concentration to obtain the target product.
The specific reaction results are shown in Table 3.
TABLE 3 results of different silver additives for preparing quinolines
Silver additive
Yield (%)
Ag2O
10
AgNO3
11
AgCO3
13
Example 28
Referring to example 1, the amount of silver additive was changed from 0.03mmol (0.1 eq) to a different amount (see table 4), and the conditions were otherwise unchanged, and used to prepare quinolines.
The specific reaction results are shown in Table 4.
TABLE 4 results of preparing quinolines with varying amounts of silver additive
Amount of silver additive
Yield (%)
0.025eq
44
0.05eq
48
0.15eq
51
0.20eq
50
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.