A kind of synthetic method of tetrahydroquinoline

Abstract

This invention discloses a method for synthesizing tetrahydroquinoline. Using toluene as a solvent, p-trifluoromethylaniline as an additive, and pinacolborane as a hydrogen source, under a nitrogen atmosphere, various quinolines are used as raw materials. Through the co-catalysis of bis(trimethylsilylaminoyttrium) and tris(pentafluorophenyl)borane, quinoline compounds undergo hydrogen transfer reduction reactions, thereby achieving the synthesis of structurally diverse tetrahydroquinoline compounds. The preparation method involved in this invention has the advantages of high selectivity, high yield, controllable selectivity, mild reaction conditions, and wide applicability.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically a method for synthesizing tetrahydroquinoline. Background Technology

[0002] Tetrahydroquinolines are structural motifs commonly found in naturally occurring alkaloids and many bioactive compounds, and are also important components of drug synthesis, agrochemical synthesis, and materials science. Metal-catalyzed catalytic hydrogenation of quinolines with hydrogen molecules is a common method for preparing tetrahydroquinolines (Advanced Synthesis & Catalysis. 2016, 358, 3039). Tetrahydroquinolines can also be prepared by catalytic hydrogen transfer hydrogenation (Organic Chemistry Frontiers. 2021, 8(18), 5002-5007). Tetrahydroquinolines can also be synthesized by palladium-catalyzed amination to form aryl carbon-nitrogen bonds (Organic Letter. 2003, 5(13), 2311-2314). However, these reactions have certain limitations due to drawbacks such as cumbersome catalyst preparation, harsh reaction conditions, narrow substrate range, low functional compatibility, poor chemoselectivity, and the generation of large amounts of toxic waste. Summary of the Invention

[0003] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for synthesizing tetrahydroquinoline. By using the co-catalytic action of bis(trimethylsilylaminoyttrium) and tris(pentafluorophenyl)borane, quinoline compounds undergo hydrogen transfer reduction reactions, thereby achieving the synthesis of tetrahydroquinoline compounds with diverse structures, improving the selectivity and yield of tetrahydroquinoline, and with mild reaction conditions.

[0004] The objective of this invention is achieved through the following technical solution: a method for synthesizing tetrahydroquinoline, which uses bis(trimethylsilylaminoyttrium) and tris(pentafluorophenyl)borane as catalysts to catalyze quinoline to obtain tetrahydroquinoline.

[0005] As one possible embodiment, the molar ratio of bis(trimethylsilylaminoyttrium) to tris(pentafluorophenyl)borane is 1:1.

[0006] As one possible embodiment, the reaction uses trifluoromethylaniline as an additive, toluene as a solvent, and pinacol borane as a hydrogen source.

[0007] As one possible embodiment, the molar ratio of quinoline, bis(trimethylsilylaminoyttrium), tri(pentafluorophenyl)borane, p-trifluoromethylaniline and pinacolborane is 1:0.1:0.1:0.1:5.0.

[0008] The reaction formula for the synthesis of tetrahydroquinoline is as follows:

[0009]

[0010] As one possible embodiment, R is any one of hydrogen, 2-methyl, 3-methyl, 4-methyl, 6-methoxy, 6-bromo, or 8-methyl, and 2, 3, 4, 6, and 8 are the positions of substituents.

[0011] The beneficial effects of this invention are: under the catalytic system of bis(trimethylsilylaminoyttrium) and tris(pentafluorophenyl)borane, quinoline compounds undergo hydrogen transfer reduction reactions, thereby achieving the synthesis of structurally diverse tetrahydroquinolines. This invention has the following beneficial effects:

[0012] (1) The raw materials of this invention are widely available, the operation is simple, the applicability is broad, the post-processing is convenient, the selectivity is high, and the environmental protection and substrate applicability are significantly improved.

[0013] (2) The tetrahydroquinoline compounds obtained by the reaction of the present invention are of high quality and have high yield, with a reaction yield of over 80%;

[0014] (3) This invention is an important supplement to the preparation of tetrahydroquinoline compounds and provides important ideas for the synthesis of bioactive compounds. Attached Figure Description

[0015] Figure 1 The proton NMR spectrum of Example 1;

[0016] Figure 2 The carbon NMR spectrum of Example 1;

[0017] Figure 3 The proton NMR spectrum of Example 2;

[0018] Figure 4 The nuclear magnetic resonance carbon spectrum of Example 2;

[0019] Figure 5 The 1H NMR spectrum of Example 3;

[0020] Figure 6 The carbon NMR spectrum of Example 3;

[0021] Figure 7 The proton NMR spectrum of Example 4;

[0022] Figure 8 The carbon NMR spectrum of Example 4;

[0023] Figure 9 The proton NMR spectrum of Example 5;

[0024] Figure 10 The carbon NMR spectrum of Example 5;

[0025] Figure 11 The 1H NMR spectrum of Example 6;

[0026] Figure 12 The carbon NMR spectrum of Example 6;

[0027] Figure 13 The 1H NMR spectrum of Example 7;

[0028] Figure 14 The carbon NMR spectrum of Example 7;

[0029] Figure 15 The proton NMR spectrum of Example 8;

[0030] Figure 16 The carbon NMR spectrum is shown in Example 8. Detailed Implementation

[0031] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings, but the scope of protection of the present invention is not limited to the following description.

[0032] Example 1

[0033] The preparation of tetrahydroquinoline, with the following structural formula:

[0034]

[0035] The specific method includes the following steps:

[0036] 0.5 mmol quinoline, 0.05 mmol bis(trimethylsilyl)yttrium, 0.05 mmol tris(pentafluorophenyl)borane, 0.05 mmol p-trifluoromethylaniline, 2.5 mmol pinacolborane, and 1.5 mL toluene were reacted at 50 °C for 12 hours.

[0037] The product separation yield was 82%. The product was analyzed, and the results are as follows: Figures 1-2 .

[0038] 1 H NMR (500MHz, CDCl3) δ7.03-6.89 (m, 2H), 6.63 (t, J = 7.4Hz, 1H), 6.49 (d, J = 7.9Hz, 1H),3.77(brs,1H),3.39-3.24(m,2H),2.79(t,J=6.4Hz,2H),2.03-1.89(m,2H); 13 CNMR (101MHz, CDCl3) δ144.9,129.6,126.8,121.6,117.1,114.3,42.1,27.09,22.3.

[0039] Example 2

[0040] The preparation of 2-methyltetrahydroquinoline, with the following structural formula:

[0041]

[0042] The specific method includes the following steps:

[0043] 0.5 mmol 2-methylquinoline, 0.05 mmol bis(trimethylsilyl)yttrium, 0.05 mmol tris(pentafluorophenyl)borane, 0.05 mmol p-trifluoromethylaniline, 2.5 mmol pinacolborane, and 1.5 mL toluene were reacted at 100 °C for 24 hours.

[0044] The product separation yield was 85%. The product was analyzed, and the results are as follows: Figures 3-4 .

[0045] 1 H NMR (400MHz, CDCl3) δ6.98(t,J=6.2Hz,2H),6.62(t,J=7.2Hz,1H),6.49(d,J=8.1Hz,1H),3.48-3.32(m,1H),2.86(ddd,J =16.9,11.6,5.7Hz,1H),2.78-2.68(m,1H),1.94(ddt,J=12.2,5.9,3.1Hz,1H),1.68-1.53(m,1H),1.22(d,J=6.3Hz,3H); 13 C NMR (101MHz, CDCl3) δ144.9,129.4,126.8,121.3,117.1,114.2,47.3,30.2,26.7,22.7.

[0046] Example 3

[0047] The preparation of 3-methyltetrahydroquinoline, with the following structural formula:

[0048]

[0049] The specific method includes the following steps:

[0050] 0.5 mmol 3-methylquinoline, 0.05 mmol bis(trimethylsilyl)yttrium, 0.05 mmol tris(pentafluorophenyl)borane, 0.05 mmol p-trifluoromethylaniline, 2.5 mmol pinacolborane, and 1.5 mL toluene were reacted at 100 °C for 24 hours.

[0051] The product separation yield was 82%. The product was analyzed, and the results are as follows: Figures 5-6 .

[0052] 1H NMR (500MHz, CDCl3) δ6.99(dd,J=15.1,7.5Hz,2H),6.63(t,J=7.4Hz,1H),6.51(d,J=8.0Hz,1H),3.84(brs,1H),3.34-3.23(m,1H),2. 92(t,J=10.3Hz,1H),2.80(dd,J=16.1,3.8Hz,1H),2.46(dd,J=16.0,10.3Hz,1H),2.08(dd,J=10.3,4.4Hz,1H),1.07(d,J=6.6Hz,3H); 13 C NMR (101MHz, CDCl3) δ144.4,129.6,126.8,121.2,117.0,114.0,49.0,35.6,27.3,19.1.

[0053] Example 4

[0054] The preparation of 4-methyltetrahydroquinoline, with the following structural formula:

[0055]

[0056] The specific method includes the following steps:

[0057] 0.5 mmol 4-methylquinoline, 0.05 mmol bis(trimethylsilyl)yttrium, 0.05 mmol tris(pentafluorophenyl)borane, 0.05 mmol p-trifluoromethylaniline, 2.5 mmol pinacolborane, and 1.5 mL toluene were reacted at 100 °C for 24 hours.

[0058] The product separation yield was 87%. The product was analyzed, and the results are as follows: Figures 7-8 .

[0059] 1 H NMR (400MHz, CDCl3) δ7.06(d,J=7.6Hz,1H),6.97(t,J=7.6Hz,1H),6.64(t,J=7.3Hz,1H),6.48(d,J=7.8Hz,1H ),3.42-3.24(m,2H),2.92(d,J=6.8Hz,1H),2.08-1.92(m,1H),1.75-1.62(m,1H),1.29(dd,J=7.0,2.1Hz,3H); 13 C NMR (126MHz, CDCl3) δ144.4,128.6,126.8,117.1,114.3,100.1,39.2,30.4,30.0,22.8.

[0060] Example 5

[0061] The preparation of 2-phenyltetrahydroquinoline, with the following structural formula:

[0062]

[0063] The specific method includes the following steps:

[0064] 0.5 mmol 2-phenylquinoline, 0.05 mmol bis(trimethylsilyl)yttrium, 0.05 mmol tris(pentafluorophenyl)borane, 0.05 mmol p-trifluoromethylaniline, 2.5 mmol pinacolborane, and 1.5 mL toluene were reacted at 100 °C for 24 hours.

[0065] The product separation yield was 80%. The product was analyzed, and the results are as follows: Figures 9-10 .

[0066] 1 H NMR (400MHz, CDCl3) δ7.25 (dddd, J=15.1, 12.5, 9.1, 4.9Hz, 5H), 6.94 (t, J=7.3Hz, 2H), 6.63-6.54 (m, 1H), 6.46 (d, J=7.6Hz, 1H), 4.36 (dd, J=9.3,3.2Hz,1H),3.96(brs,1H),2.85(ddd,J=16.3,10.7,5.5Hz,1H),2.66(dt,J=16.4,4.7Hz,1H),2.12-1.99(m,1H),2.00-1.82(m,1H); 13 C NMR (126MHz, CDCl3) δ144.9,144.8,129.4,128.7,127.5,127.0,126.6,121.0,117.2,114.1,56.3,31.1,26.5.

[0067] Example 6

[0068] The preparation of 8-methyltetrahydroquinoline, with the following structural formula:

[0069]

[0070] The specific method includes the following steps:

[0071] 0.5 mmol 8-methylquinoline, 0.05 mmol bis(trimethylsilyl)yttrium, 0.05 mmol tris(pentafluorophenyl)borane, 0.05 mmol p-trifluoromethylaniline, 2.5 mmol pinacolborane, and 1.5 mL toluene were reacted at 100 °C for 24 hours.

[0072] The product separation yield was 85%. The product was analyzed, and the results are as follows: Figures 11-12 .

[0073] 1 H NMR (400MHz, CDCl3) δ6.92 (ddd, J=9.3, 8.0, 4.1Hz, 2H), 6.61 (t, J=7.4Hz, 1H), 3.69 (brs, 1H), 3. 43(dd,J=6.9,4.1Hz,2H),2.84(t,J=6.4Hz,2H),2.13(s,3H),2.00(dtd,J=8.7,6.4,4.1Hz,2H); 13 C NMR (126MHz, CDCl3) δ142.8,128.0,127.5,121.3,121.0,116.52,42.5,27.4,22.3,17.3.

[0074] Example 7

[0075] The preparation of 6-methoxytetrahydroquinoline, with the following structural formula:

[0076]

[0077] The specific method includes the following steps:

[0078] 0.5 mmol 6-methoxyquinoline, 0.05 mmol bis(trimethylsilyl)yttrium, 0.05 mmol tris(pentafluorophenyl)borane, 0.05 mmol p-trifluoromethylaniline, 2.5 mmol pinacolborane, and 1.5 mL toluene were reacted at 100 °C for 24 hours.

[0079] The product separation yield was 81%. The product was analyzed, and the results are as follows: Figures 13-14 .

[0080] 1 H NMR (400MHz, CDCl3) δ6.63-6.53(m,2H),6.46(d,J=8.5Hz,1H),3.73(s,3H),3.29-3.21(m,2H),2.76(t,J=6.5Hz,2H),1.98-1.87(m,2H); 13 C NMR (126MHz, CDCl3) δ152.0,139.0,123.0,115.7,115.0,113.0,55.9,42.5,27.3,22.6.

[0081] Example 8

[0082] The preparation of 6-bromotetrahydroquinoline, with the following structural formula:

[0083]

[0084] The specific method includes the following steps:

[0085] 0.5 mmol 6-bromoquinoline, 0.05 mmol bis(trimethylsilyl)yttrium, 0.05 mmol tris(pentafluorophenyl)borane, 0.05 mmol p-trifluoromethylaniline, 2.5 mmol pinacolborane, and 1.5 mL toluene were reacted at 100 °C for 24 hours.

[0086] The product separation yield was 90%. The product was analyzed, and the results are as follows: Figures 15-16 .

[0087] 1 H NMR (400MHz, CDCl3) δ7.08-6.99(m,2H),6.34(d,J=8.3Hz,1H),3.83(brs,1H),3.36-3.20(m,2H),2.72(t,J=6.4Hz,2H),1.99-1.83(m,2H); 13 C NMR (126MHz, CDCl3) δ143.8,132.0,129.5,123.5,115.6,108.3,41.9,26.9,21.8.

[0088] Comparative Example 1

[0089] Based on Example 1, using only bis(trimethylsilylaminoyttrium) as a catalyst, the yield was 66%.

[0090] Comparative Example 2

[0091] Based on Example 1, using only tris(pentafluorophenyl)borane as a catalyst, the yield was 69%.

[0092] The above description is merely a preferred embodiment of the present invention. It should be understood that the present invention is not limited to the forms disclosed herein and should not be construed as excluding other embodiments. It can be used in various other combinations, modifications, and environments, and can be altered within the scope of the concept described herein through the above teachings or related technologies or knowledge. Modifications and variations made by those skilled in the art that do not depart from the spirit and scope of the present invention should be within the protection scope of the appended claims.

Claims

1. A method for synthesizing tetrahydroquinoline, characterized in that: Using bis(trimethylsilylaminoyttrium) and tris(pentafluorophenyl)borane as catalysts, tetrahydroquinoline was obtained by catalysis of quinoline. The reaction used trifluoromethylaniline as an additive, toluene as a solvent, and pinacol borane as a hydrogen source.

2. The method for synthesizing tetrahydroquinoline according to claim 1, characterized in that: The molar ratio of bis(trimethylsilylaminoyttrium) to tris(pentafluorophenyl)borane is 1:

1.

3. The method for synthesizing tetrahydroquinoline according to claim 1, characterized in that: The molar ratio of quinoline, bis(trimethylsilylaminoyttrium), tri(pentafluorophenyl)borane, p-trifluoromethylaniline and pinacolborane is 1:0.1:0.1:0.1:5.

0.

4. A method for synthesizing a tetrahydroquinoline compound, characterized in that: The reaction formula for the synthesis method is: Wherein, R is any one of hydrogen, 2-methyl, 3-methyl, 4-methyl, 6-methoxy, 6-bromo, or 8-methyl, and 2, 3, 4, 6, and 8 are the positions of the substituents.

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