CN115947683A - Synthesis method of tetrahydroquinoline and derivatives thereof - Google Patents

Synthesis method of tetrahydroquinoline and derivatives thereof Download PDF

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CN115947683A
CN115947683A CN202211709128.6A CN202211709128A CN115947683A CN 115947683 A CN115947683 A CN 115947683A CN 202211709128 A CN202211709128 A CN 202211709128A CN 115947683 A CN115947683 A CN 115947683A
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tetrahydroquinoline
aryl
propargylamine
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易年年
易兵
方正军
熊依
刘雅琦
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Hunan Institute of Engineering
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Abstract

The invention belongs to the technical field of organic chemical preparation, and particularly relates to a method for synthesizing tetrahydroquinoline and derivatives thereof. In an organic solvent, 1, 4-dihydropyridine hanster is used as a hydrogen source, nitrogen aryl propargylamine is used as an initial raw material, and tetrahydroquinoline and derivatives thereof are prepared in one step through a series reaction of hydroarylation and transfer hydrogenation in alkyne molecules under the action of a metal catalyst. The invention provides a synthesis method which has mild reaction conditions, simple operation, few reaction steps and wide substrate application range and can directly obtain tetrahydroquinoline and derivatives thereof through one-step reaction. The invention overcomes the defects of raw materials in the preparation process of tetrahydroquinoline and derivatives thereof in the prior art, and the required tetrahydroquinoline and derivatives thereof can be obtained by one-step reaction by selecting simple and easily prepared nitrogen aryl propargylamine as the starting raw material.

Description

Synthesis method of tetrahydroquinoline and derivatives thereof
Technical Field
The invention belongs to the technical field of organic chemical preparation, and particularly relates to a method for synthesizing tetrahydroquinoline and derivatives thereof.
Background
Azaheterocyclic compounds are the most important class of compounds in the pharmaceutical and agrochemical industries, and in particular the tetrahydroquinoline ring is a very common building block found in many biologically active natural products and pharmacologically relevant therapeutic agents. Due to the importance of these building blocks in drug discovery and pharmaceutical chemistry, the development of new methods for synthesizing tetrahydroquinoline derivatives remains a very active research area. At present, the main method for synthesizing tetrahydroquinoline ring is realized by hydrogenation of quinoline and its derivatives, but the source of quinoline and its derivatives as raw materials is greatly limited.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a method for synthesizing tetrahydroquinoline and derivatives thereof; the invention overcomes the defects of raw materials in the preparation process of tetrahydroquinoline and derivatives thereof in the prior art, and the required tetrahydroquinoline and derivatives thereof can be obtained by one-step reaction by selecting simple and easily prepared nitrogen aryl propargylamine as the starting raw material.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for synthesizing tetrahydroquinoline and derivatives thereof comprises the following steps:
in an organic solvent, taking Hans ester 1, 4-dihydropyridine as a hydrogen source, taking nitrogen aryl propargylamine as an initial raw material, and preparing tetrahydroquinoline and derivatives thereof in one step through a series reaction of hydroarylation and transfer hydrogenation in alkyne molecules under the action of a metal catalyst; according to the invention, hydrogen sources are screened, and the result shows that the yield is higher when only hanster 1, 4-dihydropyridine is used as the hydrogen source, so that the application only provides hanster 1, 4-dihydropyridine as the hydrogen source, and in order not to influence the technical scheme of the application, the applicant does not write reference data into the technical scheme of the application;
the synthetic route is as follows:
Figure BDA0004026790120000021
wherein R is 1 Selected from the group consisting of: H. alkyl, benzyl, aryl or p-toluenesulfonyl;
R 2 selected from: 4-alkyl, 4-aryl, 4-alkoxy, 4-benzyloxy, 4-halogen atom, 4-acetyl, 3-alkyl.
Preferably, said R is 1 One selected from H, me, bn, ph and Ts, R 2 Is selected from one of 4-Me, 4-Ph, 4-OMe, 4-OBn, 4-F, 4-Br, 4-Ac and 3-Me.
Preferably, the metal catalyst is a gold complex selected from one of triphenylphosphine gold chloride, triphenylphosphine bis (trifluoromethanesulfonimide) gold, 2-dicyclohexylphosphine-2 ',4',6 '-triisopropylbiphenyl gold chloride, 2-dicyclohexylphosphine-2', 4',6' -triisopropylbiphenyl-bis (trifluoromethanesulfonyl) gold imide, and (acetonitrile) [ (2-biphenyl) di-tert-butylphosphine ] gold hexafluoroantimonate.
Preferably, the organic solvent is one selected from hexafluoroisopropanol, trifluoroethanol, methanol, toluene, 1, 4-dioxane and 1, 2-dichloroethane.
Preferably, the specific synthetic steps of the tetrahydroquinoline and the derivative thereof are as follows:
adding nitrogen aryl propargylamine, a metal catalyst, a hydrogen source and an organic solvent into a reactor together, vacuumizing to replace nitrogen, stirring and reacting for 24 hours at 25-80 ℃ under a sealed condition, and purifying by column chromatography after the reaction is finished to obtain tetrahydroquinoline and a derivative thereof.
Preferably, the mass ratio of the nitrogen aryl propargylamine to the hydrogen source is 1:1-1.5, the dosage of the metal catalyst is 2-5mol%, and the dosage of the metal catalyst is based on nitrogen aryl propargylamine.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention adopts the nitrogen aryl propargylamine as the starting material, and compared with the common starting material of quinoline, the raw material is simpler and easier to obtain.
2. The method has the advantages of mild reaction conditions, simple operation, few reaction steps, wide substrate application range and particularly good compatibility with halogen and acetyl.
3. The invention takes Hans ester 1, 4-dihydropyridine as hydrogen source, nitrogen aryl propargylamine as initial raw material, and tetrahydroquinoline and derivatives thereof are prepared by one step of cascade reaction of hydrogen arylation and transfer hydrogenation in alkyne molecules under the action of metal catalyst, and the specific principle is as follows:
Figure BDA0004026790120000031
drawings
FIG. 1 is a hydrogen spectrum of N-benzyl-tetrahydroquinoline obtained in example 1 of the present invention;
FIG. 2 is a chart showing the carbon spectrum of N-benzyl-tetrahydroquinoline obtained in example 1 of the present invention.
Detailed Description
The following detailed description of specific embodiments of the invention is provided, but it should be understood that the scope of the invention is not limited to the specific embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention. The experimental methods described in the examples of the present invention are all conventional methods unless otherwise specified.
The following experimental methods and detection methods, unless otherwise specified, are all conventional methods; the following reagents and starting materials are all commercially available unless otherwise specified.
Examples
The general preparation steps of the embodiments 1-26 of the invention are as follows: adding nitrogen aryl propargylamine, a metal catalyst, a hydrogen source and an organic solvent into a reaction tube together, dissolving the nitrogen aryl propargylamine, the metal catalyst and the hydrogen source in the organic solvent, vacuumizing to replace nitrogen, hermetically placing the mixture in an oil bath, stirring and reacting for 24 hours, and purifying by column chromatography to obtain tetrahydroquinoline and derivatives thereof after the reaction is finished, wherein the following table 1 shows specific experimental parameters of examples 1-26 of the invention, and experimental operations are carried out according to the following experimental parameters:
TABLE 1 reactants, gold catalyst, hydrogen source, solvent, temperature parameters for examples 1-26
Figure BDA0004026790120000041
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Figure BDA0004026790120000051
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Figure BDA0004026790120000061
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Figure BDA0004026790120000071
The product structures and yields obtained after experimental operations using the experimental parameters of examples 1-26 of the present invention are shown in table 2:
TABLE 2 structural formulae and yields of the products of examples 1-26
Figure BDA0004026790120000072
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Figure BDA0004026790120000081
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Figure BDA0004026790120000091
The compounds prepared were characterized as follows:
Figure BDA0004026790120000092
1 H NMR(400MHz,CDCl 3 ):δ(ppm)7.31-7.19(m,5H),6.97-6.94(m,2H),6.58-6.55(m,1H),6.50(d,J＝8.0Hz,1H),4.46(s,2H),3.35(t,J＝4.0Hz,2H),2.81(t,J＝6.0Hz,2H),2.02-1.98(m,2H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)145.7,139.0,129.1,128.7,127.3,126.9,126.7,122.4,116.0,111.1,55.3,50.0,28.3,22.5./>
Figure BDA0004026790120000101
the hydrogen spectrum and the carbon spectrum of the compound are shown in FIG. 1 and FIG. 2; />
Figure BDA0004026790120000102
1 H NMR(400MHz,CDCl 3 ):δ(ppm)6.97-6.93(m,2H),6.61-6.58(m,1H),6.47(d,J＝8.0Hz,1H),3.80(s,1H),3.31(t,J＝5.4Hz,2H),2.77(t,J＝6.4Hz,2H),1.97-1.91(m,2H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)144.7,129.5,126.7,121.3,116.9,114.1,42.1,26.9,22.2.
Figure BDA0004026790120000103
1 H NMR(400MHz,CDCl 3 ):δ(ppm)7.08-7.05(m,1H),6.94(d,J＝4.0Hz,1H),6.62-6.59(m,2H),3.21(t,J＝4.0Hz,2H),2.88(s,3H),2.76(t,J＝4.0Hz,2H),2.00-1.95(m,2H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)146.7,128.9,127.1,123.0,116.3,111.1,51.3,39.2,27.8,22.5.
Figure BDA0004026790120000104
1 H NMR(400MHz,CDCl 3 ):δ(ppm)7.33(t,J＝8.0Hz,2H),7.22(d,J＝4.0Hz,2H),7.10-7.02(m,2H),6.92(t,J＝6.0Hz,1H),6.75-6.67(m,2H),3.62(t,J＝6.0Hz,2H),2.84(t,J＝6.0Hz,2H),2.06-2.00(m,2H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)148.4,144.5,129.4,126.4,124.7,124.6,123.6,118.3,115.8,50.9,27.8,22.8.
Figure BDA0004026790120000105
1 H NMR(400MHz,CDCl 3 ):δ(ppm)7.78(d,J＝8.4Hz,1H),7.49(d,J＝8.0Hz,2H),7.19-6.98(m,5H),3.80(t,J＝6.0Hz,2H),2.44(t,J＝6.0Hz,2H),2.38(s,3H),1.68-1.59(m,2H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)143.4,136.8,136.7,130.5,129.4,128.9,127.0,126.4,124.87,124.84,46.4,26.5,21.5,21.4.
Figure BDA0004026790120000111
1 H NMR(400 MHz,CDCl 3 ):δ(ppm)7.31-7.20(m,5H),6.80(s,1H),6.77(d,J＝8.0 Hz,1H),6.42(d,J＝8.0 Hz,1H),4.43(s,2H),3.31(t,J＝6.0 Hz,2H),2.77(t,J＝6.0 Hz,2H),2.19(s,3H),2.02-1.96(m,2H)； 13 C NMR(100 MHz,CDCl 3 ):δ(ppm)143.5,139.3,129.8,128.6,127.6,126.73,126.71,125.0,122.4,111.3,55.5,50.0,28.2,22.6,20.2.
Figure BDA0004026790120000112
1 H NMR(400 MHz,CDCl 3 ):δ(ppm)7.32-7.20(m,5H),6.60-6.55(m,2H),6.45(d,J＝8.0 Hz,1H),4.40(s,2H),3.70(s,3H),3.28(t,J＝6.0 Hz,2H),2.79(t,J＝6.0 Hz,2H),2.02-1.96(m,2H)； 13 C NMR(100 MHz,CDCl 3 ):δ(ppm)151.0,140.4,139.4,128.6,126.82,126.76,123.9,115.3,112.5,112.4,56.1,55.8,50.0,28.4,22.6.
Figure BDA0004026790120000113
1 H NMR(400 MHz,CDCl 3 ):δ(ppm)7.41-7.20(m,10H),6.69-6.62(m,2H),6.44(d,J＝12.0 Hz,1H),4.94(s,2H),4.40(s,2H),3.28(t,J＝4.0 Hz,2H),2.79(t,J＝6.0 Hz,2H),2.02-1.96(m,2H)； 13 C NMR(100 MHz,CDCl 3 ):δ(ppm)150.2,140.6,139.4,137.9,128.6,128.5,127.7,127.5,126.80,128.76,123.8,116.4,113.6,112.2,70.8,56.0,50.0,28.4,22.6.
Figure BDA0004026790120000114
1 H NMR(400 MHz,CDCl 3 ):δ(ppm)7.50(d,J＝8.0 Hz,2H),7.36-7.18(m,10H),6.56(d,J＝8.0 Hz,1H),4.49(s,2H),3.37(t,J＝6.0 Hz,2H),2.86(t,J＝6.0 Hz,2H),2.05-1.99(m,2H)； 13 C NMR(100 MHz,CDCl 3 ):δ(ppm)145.2,141.4,138.9,128.8,128.72,128.65,127.8,126.9,126.7,126.2,125.88,125.87,122.5,111.4,55.3,50.0,28.5,22.5.
Figure BDA0004026790120000121
1 H NMR(400 MHz,CDCl 3 ):δ(ppm)7.32-7.21(m,5H),6.71-6.62(m,2H),6.39-6.36(m,1H),4.42(s,2H),3.31(t,J＝6.0 Hz,2H),2.78(t,J＝6.0 Hz,2H),2.02-1.96(m,2H)； 13 C NMR(100 MHz,CDCl 3 ):δ(ppm)154.8(d,J＝233.0 Hz),142.1,138.9,128.7,126.9,126.7,123.8(d,J＝7.0 Hz),115.5(d,J＝22.0Hz),113.1(d,J＝21.0 Hz),111.8(d,J＝7.0 Hz),55.8,49.9,28.3,22.4.
Figure BDA0004026790120000122
1 H NMR(400 MHz,CDCl 3 ):δ(ppm)7.32-7.20(m,5H),7.05-6.99(m,2H),6.30(d,J＝12.0 Hz,1H),4.43(s,2H),3.33(t,J＝6.0 Hz,2H),2.76(t,J＝6.0 Hz,2H),2.00-1.94(m,2H)； 13 C NMR(100 MHz,CDCl 3 ):δ(ppm)144.6,138.3,131.4,129.7,128.7,127.0,126.5,124.4,112.6,107.5,55.2,49.9,28.1,22.2.
Figure BDA0004026790120000123
1 H NMR(400 MHz,CDCl 3 ):δ(ppm)7.63-7.58(m,2H),7.34-7.19(m,5H),6.46(d,J＝8.0 Hz,1H),4.55(s,2H),3.44(t,J＝6.0 Hz,2H),2.83(t,J＝6.0 Hz,2H),4.45(s,3H),2.04-1.98(m,2H)； 13 C NMR(100 MHz,CDCl 3 ):δ(ppm)196.3,149.5,137.4,129.6,129.3,128.8,127.2,126.4,125.3,121.3,109.6,54.7,50.1,28.1,25.9,21.9.
Figure BDA0004026790120000131
1 H NMR(400MHz,CDCl 3 ):δ(ppm)7.33-7.19(m,5H),6.89-6.85(m,1H),6.50-6.36(m,2H),4.45(s,2H),3.33-3.29(m,2H),2.78-2.68(m,2H),2.20(s,1.36H),2.17(s,1.51H),2.06-1.94(m,2H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)145.9,145.6,139.2,139.1,136.8,136.5,129.0,128.6,126.78,126.76,126.74,126.68,126.5,120.9,119.5,118.2,116.8,111.7,109.6,56.0,55.2,49.8,49.7,28.0,24.9,22.6,22.4,21.7,20.0.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.

Claims (6)

1. A method for synthesizing tetrahydroquinoline and derivatives thereof is characterized by comprising the following steps:
in an organic solvent, taking Hans ester 1, 4-dihydropyridine as a hydrogen source, taking nitrogen aryl propargylamine as an initial raw material, and preparing tetrahydroquinoline and derivatives thereof in one step through a series reaction of hydroarylation and transfer hydrogenation in alkyne molecules under the action of a metal catalyst;
the synthetic route is as follows:
Figure FDA0004026790110000011
wherein R is 1 Selected from the group consisting of: H. alkyl, benzyl, aryl or p-toluenesulfonyl;
R 2 selected from the group consisting of: 4-alkyl, 4-aryl, 4-alkoxy, 4-benzyloxy, 4-halogen atom, 4-acetyl, 3-alkyl.
2. A compound of claim 1The synthesis method of the hydroquinoline and the derivatives thereof is characterized in that R is 1 One selected from H, me, bn, ph and Ts, R 2 Is selected from one of 4-Me, 4-Ph, 4-OMe, 4-OBn, 4-F, 4-Br, 4-Ac and 3-Me.
3. The method as claimed in claim 1, wherein the metal catalyst is a gold complex selected from the group consisting of triphenylphosphine gold chloride, triphenylphosphine bis (trifluoromethanesulfonimide) gold, 2-dicyclohexylphosphine-2 ',4',6 '-triisopropylbiphenyl gold chloride, 2-dicyclohexylphosphine-2', 4',6' -triisopropylbiphenyl-bis (trifluoromethanesulfonyl) imide gold, and (acetonitrile) [ (2-biphenyl) di-tert-butylphosphine ] hexafluoroantimonate gold.
4. The method as claimed in claim 1, wherein the organic solvent is selected from hexafluoroisopropanol, trifluoroethanol, methanol, toluene, 1, 4-dioxane, and 1, 2-dichloroethane.
5. The method for synthesizing tetrahydroquinoline and derivatives thereof as claimed in claim 1, wherein the specific steps of the synthesis of tetrahydroquinoline and derivatives thereof are as follows:
adding nitrogen aryl propargylamine, a metal catalyst, a hydrogen source and an organic solvent into a reactor together, vacuumizing to replace nitrogen, stirring and reacting for 24 hours at 25-80 ℃ under a sealed condition, and purifying by column chromatography after the reaction is finished to obtain tetrahydroquinoline and derivatives thereof.
6. The method for synthesizing tetrahydroquinoline and derivatives thereof as claimed in claim 1, wherein the mass ratio of nitrogen aryl propargylamine to hydrogen source is 1:1-1.5, wherein the dosage of the metal catalyst is 2-5mol%, and the dosage of the metal catalyst is based on nitrogen aryl propargylamine.
CN202211709128.6A 2022-12-29 2022-12-29 Synthesis method of tetrahydroquinoline and derivatives thereof Pending CN115947683A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116535404A (en) * 2023-05-09 2023-08-04 湖南工程学院 Method for efficiently synthesizing polysubstituted pyrroloquinoline compounds
CN117700423A (en) * 2024-02-05 2024-03-15 湖南工程学院 Tetrahydropyrrolo [2,1-a ] isoquinoline derivative and synthesis method thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116535404A (en) * 2023-05-09 2023-08-04 湖南工程学院 Method for efficiently synthesizing polysubstituted pyrroloquinoline compounds
CN117700423A (en) * 2024-02-05 2024-03-15 湖南工程学院 Tetrahydropyrrolo [2,1-a ] isoquinoline derivative and synthesis method thereof

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