A method for synthesizing tetrahydroquinoline and its derivatives

Abstract

The present invention belongs to the technical field of organic chemical preparation, and particularly relates to a method for synthesizing tetrahydroquinoline and its derivatives. In this method, in an organic solvent, using Hansch ester 1,4-dihydropyridine as a hydrogen source, and using N-aryl propargylamine as a starting material, under the action of a metal catalyst, tetrahydroquinoline and its derivatives are directly prepared in one step through a tandem reaction of intramolecular hydroarylation and transfer hydrogenation of alkynes. The present invention provides a synthesis method with mild reaction conditions, simple operation, few reaction steps, a wide substrate scope, and capable of directly obtaining tetrahydroquinoline and its derivatives through one-step reaction. The present invention overcomes the defects of the raw materials in the preparation of tetrahydroquinoline and its derivatives in the prior art, selects simple and easily preparable N-aryl propargylamine as the starting material, and can obtain the desired tetrahydroquinoline and its derivatives through one-step reaction.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemical preparation, and particularly relates to a method for synthesizing tetrahydroquinoline and its derivatives. Background Art

[0002] Azaheterocyclic compounds are one of the most important classes of compounds in the pharmaceutical and agrochemical industries. In particular, the tetrahydroquinoline ring is a very common structural unit and is found in many bioactive natural products and pharmacologically relevant therapeutic agents. Due to the importance of these structural units in drug discovery and medicinal chemistry, the development of new methods for synthesizing tetrahydroquinoline derivatives remains a very active research area. Currently, the main method for synthesizing the tetrahydroquinoline ring is through the hydrogenation of quinoline and its derivatives, but the sources of its raw materials quinoline and its derivatives are severely limited. Summary of the Invention

[0003] Aiming at the deficiencies of the above-mentioned existing technologies, the present invention provides a method for synthesizing tetrahydroquinoline and its derivatives; the present invention overcomes the defects of the raw materials in the preparation of tetrahydroquinoline and its derivatives in the prior art, selects simple and easily preparable nitrogen aryl propargylamine as the starting material, and can obtain the desired tetrahydroquinoline and its derivatives through a one-step reaction.

[0004] To achieve the above object, the technical solution of the present invention is as follows:

[0005] A method for synthesizing tetrahydroquinoline and its derivatives, comprising the following steps:

[0006] In an organic solvent, using Hantzsch ester 1,4-dihydropyridine as a hydrogen source, and using nitrogen aryl propargylamine as a starting material, under the action of a metal catalyst, tetrahydroquinoline and its derivatives are obtained through a tandem reaction of intramolecular hydroarylation and transfer hydrogenation of alkynes in one step; the present invention screened the hydrogen source, and the results showed that only when Hantzsch ester 1,4-dihydropyridine was used as the hydrogen source, the yield was relatively high. Therefore, in this application, only Hantzsch ester 1,4-dihydropyridine is provided as the hydrogen source. In order not to affect the technical solution of this application, the applicant did not write the control data into the technical solution of this application;

[0007] The synthesis route is as follows:

[0008]

[0009] Wherein, R 1 is selected from: H, alkyl, benzyl, aryl or tosyl;

[0010] R 2 is selected from one of 4-alkyl, 4-aryl, 4-alkoxy, 4-benzyloxy, 4-halogen atom, 4-acetyl, 3-alkyl.

[0011] Preferably, the R 1 is selected from one of H, Me, Bn, Ph, Ts, and R 2 is selected from one of 4-Me, 4-Ph, 4-OMe, 4-OBn, 4-F, 4-Br, 4-Ac, 3-Me.

[0012] Preferably, the metal catalyst is a gold complex, which is selected from one of chloro(triphenylphosphine)gold(I), bis(trifluoromethanesulfonimide)(triphenylphosphine)gold(I), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl)gold(I), bis(trifluoromethanesulfonyl)(2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl)gold(I), gold(I) hexafluoroantimonate(1-) (acetonitrile)[(2-biphenyl)di-tert-butylphosphine].

[0013] Preferably, the organic solvent is selected from one of hexafluoroisopropanol, trifluoroethanol, methanol, toluene, 1,4-dioxane, 1,2-dichloroethane.

[0014] Preferably, the specific synthesis steps of the tetrahydroquinoline and its derivatives are as follows:

[0015] The nitrogen aryl propargylamine, metal catalyst, hydrogen source, and organic solvent are jointly added to a reactor. After evacuating and replacing with nitrogen, the mixture is stirred and reacted at 25-80 °C for 24 h under sealed conditions. After the reaction is completed, it is purified by column chromatography to obtain the tetrahydroquinoline and its derivatives.

[0016] Preferably, the mass ratio of the nitrogen aryl propargylamine to the hydrogen source is 1:1-1.5, and the dosage of the metal catalyst is 2-5 mol%, with the dosage of the metal catalyst being based on the nitrogen aryl propargylamine.

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0018] 1. The present invention uses nitrogen aryl propargylamine as the starting material. Compared with the commonly used starting material quinoline, the raw materials are simpler and more easily available.

[0019] 2. The reaction conditions of the present invention are mild, the operation is simple, the reaction steps are few, and the substrate scope is wide. In particular, the compatibility with halogen and acetyl group is very good.

[0020] 3. The present invention uses Hansch ester 1,4-dihydropyridine as the hydrogen source, uses nitrogen aryl propargylamine as the starting material, and under the action of a metal catalyst, the tetrahydroquinoline and its derivatives are prepared in one step through a tandem reaction of intramolecular hydroarylation and transfer hydrogenation of alkynes. The specific principle is as follows:

[0021] BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 1H NMR spectrum of N-benzyl-tetrahydroquinoline prepared in Example 1 of the present invention;

[0023] Figure 2 13C NMR spectrum of N-benzyl-tetrahydroquinoline prepared in Example 1 of the present invention. Detailed Description of the Invention

[0024] The following is a detailed description of the specific embodiments of the present invention. However, it should be understood that the protection scope of the present invention is not limited by the specific embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts belong to the scope of protection of the present invention. The experimental methods described in the embodiments of the present invention are conventional methods unless otherwise specified.

[0025] The following experimental methods and detection methods are conventional methods unless otherwise specified; the following reagents and raw materials are commercially available unless otherwise specified.

[0026] Embodiment

[0027] The general preparation steps for Examples 1-26 of the present invention are as follows: Add nitrogen aryl propargylamine, metal catalyst, hydrogen source, and organic solvent into a reaction tube, such that the organic solvent dissolves the nitrogen aryl propargylamine, metal catalyst, and hydrogen source. After evacuating and replacing with nitrogen, seal it and place it in an oil bath for stirring reaction for 24 h. After the reaction is completed, purify by column chromatography to obtain tetrahydroquinoline and its derivatives. Table 1 below shows the specific experimental parameters for Examples 1-26 of the present invention, and the experimental operations are carried out according to the following experimental parameters:

[0028] Table 1 Reactants, gold catalysts, hydrogen sources, solvents, and temperature parameters for Examples 1-26

[0029]

[0030]

[0031]

[0032]

[0033] After carrying out the experimental operations using the experimental parameters of Examples 1-26 of the present invention, the product structural formulas and yields are shown in Table 2:

[0034] Table 2 Product structural formulas and yields for Examples 1-26

[0035]

[0036]

[0037]

[0038] The prepared compounds were characterized as follows:

[0039] 1 1H NMR (400 MHz, CDCl3): δ (ppm) 7.31 - 7.19 (m, 5H), 6.97 - 6.94 (m, 2H), 6.58 - 6.55 (m, 1H), 6.50 (d, J = 8.0 Hz, 1H), 4.46 (s, 2H), 3.35 (t, J = 4.0 Hz, 2H), 2.81 (t, J = 6.0 Hz, 2H), 2.02 - 1.98 (m, 2H); 13 13C NMR (100 MHz, CDCl3): 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. The hydrogen spectrum and carbon spectrum of... are as follows Figure 1 and Figure 2 shown below;

[0040] 1 1H NMR (400 MHz, CDCl3): δ (ppm) 6.97 - 6.93 (m, 2H), 6.61 - 6.58 (m, 1H), 6.47 (d, J = 8.0 Hz, 1H), 3.80 (s, 1H), 3.31 (t, J = 5.4 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H), 1.97 - 1.91 (m, 2H); 13 13C NMR (100 MHz, CDCl3): δ (ppm) 144.7, 129.5, 126.7, 121.3, 116.9, 114.1, 42.1, 26.9, 22.2.

[0041] 1 1H NMR (400 MHz, CDCl3): δ (ppm) 7.08 - 7.05 (m, 1H), 6.94 (d, J = 4.0 Hz, 1H), 6.62 - 6.59 (m, 2H), 3.21 (t, J = 4.0 Hz, 2H), 2.88 (s, 3H), 2.76 (t, J = 4.0 Hz, 2H), 2.00 - 1.95 (m, 2H); 1313C NMR (100 MHz, CDCl3): δ (ppm) 146.7, 128.9, 127.1, 123.0, 116.3, 111.1, 51.3, 39.2, 27.8, 22.5.

[0042] 1 1H NMR (400 MHz, CDCl3): δ (ppm) 7.33 (t, J = 8.0 Hz, 2H), 7.22 (d, J = 4.0 Hz, 2H), 7.10 - 7.02 (m, 2H), 6.92 (t, J = 6.0 Hz, 1H), 6.75 - 6.67 (m, 2H), 3.62 (t, J = 6.0 Hz, 2H), 2.84 (t, J = 6.0 Hz, 2H), 2.06 - 2.00 (m, 2H); 13 13C NMR (100 MHz, CDCl3): 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.

[0043] 1 1H NMR (400 MHz, CDCl3): δ (ppm) 7.78 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.19 - 6.98 (m, 5H), 3.80 (t, J = 6.0 Hz, 2H), 2.44 (t, J = 6.0 Hz, 2H), 2.38 (s, 3H), 1.68 - 1.59 (m, 2H); 13 13C NMR (100 MHz, CDCl3): 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.

[0044] 1 1H NMR (400 MHz, CDCl3): 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); 1313C NMR (100 MHz, CDCl3): 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.

[0045] 1 1H NMR (400 MHz, CDCl3): 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 13C NMR (100 MHz, CDCl3): 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.

[0046] 1 1H NMR (400 MHz, CDCl3): 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 13C NMR (100 MHz, CDCl3): 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.

[0047] 11H NMR (400 MHz, CDCl3): 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 13C NMR (100 MHz, CDCl3): 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.

[0048] 1 1H NMR (400 MHz, CDCl3): 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 13C NMR (100 MHz, CDCl3): 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.

[0049] 1 1H NMR (400 MHz, CDCl3): 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 = 6.0Hz, 2H), 2.00 - 1.94 (m, 2H); 13 13C NMR (100 MHz, CDCl3): 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.

[0050] 1 H NMR(400 MHz, CDCl3): 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, CDCl3): 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.

[0051] 1 H NMR(400MHz, CDCl3): 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, CDCl3): 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.

[0052] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention is also intended to include these modifications and variations.

Claims

1. A method for synthesizing tetrahydroquinoline and its derivatives, characterized in that: The steps include: In an organic solvent, using hans ester 1,4-dihydropyridine as a hydrogen source and nitrogen aryl propargylamine as a starting material, tetrahydroquinoline and its derivatives are prepared in one step through a tandem reaction of intramolecular hydrogen arylation and transfer hydrogenation in the presence of a metal catalyst. The synthetic route is as follows: Among them, R 1 Selected from H; R 2 selected from 4-halogen atoms; The metal catalyst is a gold complex, which is selected from triphenylphosphine gold chloride, triphenylphosphine bis(trifluoromethanesulfonyl imide) 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] gold hexafluoroantimonate.

2. The method for synthesizing tetrahydroquinoline and its derivatives according to claim 1, wherein: The R 1 Selected from H, R 2 One selected from 4-F and 4-Br.

3. The method for synthesizing tetrahydroquinoline and its derivatives according to claim 1, wherein: The organic solvent is selected from one of hexafluoroisopropanol, trifluoroethanol, methanol, toluene, 1,4-dioxane, and 1,2-dichloroethane.

4. The method for synthesizing tetrahydroquinoline and its derivatives according to claim 1, wherein: The specific synthesis steps of the tetrahydroquinoline and its derivatives are: A nitrogen aryl propargylamine, a metal catalyst, a hydrogen source, and an organic solvent are added to a reactor. After evacuation to replace nitrogen, the mixture is stirred and reacted at 25-80° C. under sealed conditions for 24 hours. After the reaction is completed, the mixture is purified by column chromatography to obtain tetrahydroquinoline and its derivatives.

5. The method for synthesizing tetrahydroquinoline and its derivatives according to claim 1, wherein: The mass ratio of the nitrogen aryl propargyl amine to the hydrogen source is 1:1-1.5, and the amount of the metal catalyst is 2-5 mol%, with the amount of the metal catalyst being based on the nitrogen aryl propargyl amine.

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