A method for synthesizing tetrahydroquinoline using amino acids and derivatives as substrates

By using amino acids and derivatives as substrates and combining Pd/Cu synergistic catalysis methods, the safety, applicability and economical problems of tetrahydroquinoline synthesis in the prior art are solved, and efficient and low-cost tetrahydroquinoline synthesis is achieved, providing a new synthesis method.

CN116354930BActive Publication Date: 2025-06-24MINZU UNIVERSITY OF CHINA
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Patent Information

Application Number
CN202310320155.2
Authority / Receiving Office
CN · China
Patent Type
Patents(China)
Current Assignee / Owner
Filing Date
2023-03-29
Publication Date
2025-06-24
Estimated Expiration
2043-03-29

AI Technical Summary

Technical Problem

The prior art has constraints on operating safety, substrate suitability, step economy and atomic economy when synthesizing tetrahydroquinoline skeleton molecules, and lacks a synthetic method that is easy to obtain raw materials, simple steps, safe and efficient.

Method used

The efficient synthesis of tetrahydroquinoline was achieved under mild conditions by using amino acids and derivatives as substrates and the Pd/Cu synergistic catalysis method. The process includes reacting an amide substrate with ortho-halogenated bromine aromatic hydrocarbon, the catalyst is Pd(OAc)2 and CuI, the additive is Ag2CO3, and the reaction solvent is a mixed solvent of toluene and tert-amanol.

Benefits of technology

The synthesis of tetrahydroquinolines with easy raw materials, simple operation, mild conditions and wide application range of substrates is achieved, and tetrahydroquinoline derivatives with multiple chiral centers can be efficiently and at low cost, providing a new synthesis method of 1,2,3,4-tetrahydroquinoline and 2 chiral substituted tetrahydroquinolines.

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Abstract

The present invention relates to a method for synthesizing chiral substituted tetrahydroquinolines and belongs to the field of chemical synthesis. The present invention provides a method for synthesizing tetrahydroquinolines using amino acids and derivatives as substrates. Compared with the prior art, the method of the present invention has easily available raw materials, simple operation, mild conditions, a wide range of applicable substrates, and can efficiently synthesize tetrahydroquinoline derivatives with multiple chiral centers in one step, providing a new method for the synthesis of 1,2,3,4-tetrahydroquinolines and 2-chiral substituted tetrahydroquinolines.
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Description

Technical Field

[0001] The present invention relates to a method for synthesizing tetrahydroquinoline using amino acids and derivatives as substrates. Background Art

[0002] Tetrahydroquinoline compounds are commonly found in the structures of many natural products and drug molecules. In particular, the 2-substituted-tetrahydroquinoline molecular skeleton is a key molecular skeleton of many natural alkaloids and drug molecules, showing rich medicinal value and biological activities in aspects such as anti-cancer, antibacterial, antiviral, anti-Alzheimer's disease, and diabetes [1]. The efficient synthesis of this type of molecular skeleton is of great significance for drug research and development. Currently, there are usually three main methods for synthesizing tetrahydroquinoline skeleton molecules: (A) direct reduction of quinoline [2], usually preparing tetrahydroquinoline derivatives by catalytic hydrogenation reduction of quinoline with noble metals; (B) reductive intramolecular cyclization [3], catalytic hydrogenation reduction with palladium on carbon; (C) intermolecular cycloaddition reaction [4], cycloaddition reaction of aromatic imine and alkene.

[0003] These methods for synthesizing tetrahydroquinoline skeleton molecules have various restrictive factors in terms of operation safety, substrate applicability, step economy, and atom economy. Therefore, developing a new method for synthesizing tetrahydroquinoline molecules with easily available raw materials, simple steps, and being safe and efficient is urgently needed in the field of organic synthesis of tetrahydroquinoline-related compounds. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a method for synthesizing tetrahydroquinoline using amino acids and derivatives as substrates.

[0005] Technical Solution

[0006] A method for synthesizing tetrahydroquinoline using amino acids and derivatives as substrates, the steps include,

[0007]

[0008] R is selected from alkyl, trifluoromethyl, -CO2R3 (R3 = alkyl, benzyl, aryl), -CH2OR4 (R4 = ester group, silyl);

[0009] R1 is selected from -H, alkyl, trifluoromethyl-substituted methylene;

[0010] R2 is selected from -H, methyl, tert-butoxy and other groups;

[0011] X is selected from bromine, iodine;

[0012] Ar is an aromatic ring with a benzene ring structure.

[0013] Further, the steps include:

[0014]

[0015] Furthermore, the steps include:

[0016]

[0017] Furthermore, the steps include:

[0018]

[0019] Furthermore, the catalyst is selected from Pd / Cu co - catalysis.

[0020] Furthermore, the catalyst is selected from Pd(OAc)2 and CuI.

[0021] Furthermore, the reaction system also includes Ag2CO3 as an additive, and one or more of K3PO4, K2CO3, NaOAc and KOAc as the base, preferably NaOAc, and the reaction solvent is selected from the mixed solvent of toluene and tert - amyl alcohol.

[0022] Furthermore, when the amide substrate in the reaction system is 1.0 equivalent, the dosage of the catalyst Pd(OAc)2 is 0.1 equivalent, the dosage of the catalyst CuI is 0.1 equivalent, and the dosage of Ag2CO3 is 1.0 equivalent.

[0023] Furthermore, the solvent is selected from xylene, chlorobenzene, o - dichlorobenzene and alcohols, such as ethanol, isopropanol, tert - amyl alcohol solvents, preferably the mixed solvent of toluene and tert - amyl alcohol, and the preferred volume ratio of toluene to tert - amyl alcohol is 9:1.

[0024] Furthermore, the reaction temperature is 80 - 160 °C, preferably 140 °C.

[0025] Furthermore, the steps include: adding the reaction substrate amide, base, and catalyst into the reaction tube, adding the organic solvent, then injecting the o - halo - bromoarene, and after the heating reaction is completed, purifying by column chromatography to obtain the tetrahydroquinoline compound.

[0026] Furthermore, the reaction time is 1 - 48 hours, preferably 24 hours.

[0027] Beneficial effects

[0028] The method of the present invention has easily available raw materials, simple operation, mild conditions and a wide range of substrate applicability, and can efficiently and low - cost synthesize tetrahydroquinoline derivatives with multiple chiral centers through chiral amino acid derivatives in a one - step method, providing a new method for the synthesis of 1,2,3,4 - tetrahydroquinoline and 2 - chiral - substituted tetrahydroquinoline. Description of the drawings

[0029] Figure 1 is the HNMR analysis spectrum of compound 3a;

[0030] Figure 2 It is the CNMR analysis spectrum of compound 3a;

[0031] Figure 3 It is the HNMR analysis spectrum of compound 3b;

[0032] Figure 4 It is the CNMR analysis spectrum of compound 3b;

[0033] Figure 5 It is the HNMR analysis spectrum of compound 3c;

[0034] Figure 6 It is the HNMR analysis spectrum of compound 3d. Specific Embodiments

[0035] The present invention will be further described below in conjunction with specific embodiments and the accompanying drawings.

[0036]

[0037] Synthesis steps: Add Pd(OAc)2 (4.5 mg, 10 mol%), CuI (7.8 mg, 10 mol%), Ag2CO3 (55 mg, 1 equiv) and NaOAc (65.6 mg, 4 equiv) to a 25 mL dry reaction tube equipped with a magnetic stir bar. Inject a mixed solution of the amide substrate (0.2 mmol) and the substituted o-bromoiodobenzene (0.3 mmol) dissolved in 1 mL of toluene and tert-amyl alcohol (9:1) into the reaction tube. Seal the reaction tube mouth with a reverse rubber stopper. Place it on a magnetic stirrer and react at 140 °C in an oil bath for 3 h. After the reaction is completed, cool the reaction tube to room temperature, dip the reaction solution with a capillary tube, spot and develop the plate by thin layer chromatography (TLC), and select and determine a suitable developing agent (usually the volume ratio of petroleum ether to ethyl acetate is 3:1). Evacuate the solvents toluene and tert-amyl alcohol, add an appropriate amount of ethyl acetate to dissolve, transfer to a round bottom flask, add an appropriate amount of silica gel, and rotary evaporate to dryness to obtain a powdery crude product. Separate by column chromatography, and separate the target product with a mixed solvent of petroleum ether / ethyl acetate (volume ratio 6:1 - 3:1 - 1:1) as the mobile phase. For the reaction formula and yield, please refer to the above Method IV.

[0038] Using the above synthesis steps, the nuclear magnetic and other detection information of the prepared compounds is as follows:

[0039]

[0040] 11H NMR (600 MHz, CDCl3) δ 8.43 (d, J = 3.7 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.25 (dd, J = 10.9, 4.9 Hz, 1H), 7.13 (d, J = 7.3 Hz, 1H), 7.00 (t, J = 7.3 Hz, 1H), 6.85 (s, 1H), 6.58 (s, 1H), 5.18 (d, J = 6.8 Hz, 1H), 4.52 (s, 1H), 3.74 (s, 3H), 3.10 (dd, J = 14.4, 6.9 Hz, 1H), 2.91–2.71 (m, 1H), 1.15 (s, 9H).

[0041] 13 13C NMR (151 MHz, CDCl3) δ 169.6, 168.7, 154.0, 148.9, 137.7, 136.7, 129.6, 128.8, 126.3, 125.0, 124.8, 124.3, 74.9, 68.3, 62.4, 52.0, 34.7, 28.4.

[0042] HRMS (ESI): found: 369.1811 ([M+H] + ), calcd. Chemical Formula: C 21 H 25 N2O4, Exact Mass: 369.1814.

[0043]

[0044] 1 1H NMR (600 MHz, CDCl3) δ 8.49 (d, J = 3.7 Hz, 1H), 7.66 (t, J = 7.2 Hz, 1H), 7.48 (s, 1H), 7.27–7.21 (m, 1H), 7.12 (d, J = 7.4 Hz, 1H), 6.98 (t, J = 7.3 Hz, 1H), 6.85 (s, 1H), 6.54 (s, 1H), 5.04 (d, J = 3.5 Hz, 1H), 4.35 (s, 1H), 3.11 (dd, J = 13.9, 8.6 Hz, 1H), 2.83 (d, J = 13.0 Hz, 1H), 1.46 (s, 9H), 1.20 (s, 9H).

[0045] 1313C NMR (151 MHz, CDCl3) δ 168.6, 168.1, 154.3, 149.1, 137.5, 136.6, 129.3, 128.7, 126.1, 124.6, 124.5, 124.0, 81.4, 74.8, 67.9, 62.1, 34.5, 28.3, 28.2.

[0046] HRMS (ESI): found: 411.2286 ([M+H] + ), calcd. Chemical Formula: C 24 H 31 N2O4, Exact Mass: 411.2284.

[0047]

[0048] 1 1H NMR (600 MHz, CDCl3) δ 8.40 (s, 1H), 7.69 (s, 1H), 7.59–7.49 (m, 1H), 7.25 (s, 1H), 7.14 (d, J=7.3 Hz, 1H), 6.99 (s, 1H), 6.83 (s, 1H), 6.46 (s, 1H), 4.76 (d, J=7.8 Hz, 1H), 3.74 (d, J=6.9 Hz, 3H), 2.74 (dd, J=14.2, 3.6 Hz, 1H), 2.62 (t, J=12.3 Hz, 1H), 2.07 (d, J=25.1 Hz, 1H), 1.41 (s, 3H).

[0049] HRMS (ESI): found: 311.1393 ([M+H] + ), calcd. Chemical Formula: C 18 H 19 N2O3, Exact Mass: 311.1396.

[0050]

[0051] 11H NMR (600 MHz, CDCl3) δ 8.46 (s, 1H), 7.60 (s, 1H), 7.30 (s, 1H), 7.21 (s, 1H), 7.15 (d, J = 7.4 Hz, 1H), 7.00 (t, J = 7.0 Hz, 1H), 6.84 (s, 1H), 6.49 (s, 1H), 4.97 (s, 1H), 3.70–3.58 (m, 1H), 3.37–3.28 (m, 4H), 2.82–2.72 (m, 2H), 2.42 (s, 1H), 1.77 (s, 1H).

[0052] HRMS (ESI): found: 311.1397 ([M+H] + ), calcd. Chemical Formula: C 18 H 19 N2O3, Exact Mass: 311.1396.

[0053]

[0054] 1 1H NMR (600 MHz, CDCl3) δ 8.54 (d, J = 4.6 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.21 (dd, J = 14.6, 6.9 Hz, 2H), 7.13 (d, J = 7.4 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 6.77 (t, J = 7.7 Hz, 1H), 6.43 (d, J = 8.0 Hz, 1H), 4.27 (dddt, J = 17.9, 14.3, 10.8, 7.2 Hz, 2H), 3.94–3.82 (m, 1H), 3.24 (dd, J = 19.5, 7.8 Hz, 1H), 2.97–2.83 (m, 1H), 2.61 (d, J = 14.5 Hz, 1H), 2.41–2.26 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H).

[0055] 19 19F NMR (565 MHz, DMSO-d6) δ -58.72.

[0056] 1313C NMR (151 MHz, CDCl3) δ 171.9, 169.7, 154.3, 149.6, 137.6, 136.3, 133.4, 127.2, 127.1, 126.5, 126.3, 125.3, 125.2, 124.5, 123.4, 63.2, 62.4, 37.5 (q, J = 3 Hz), 35.1, 25.3, 14.2.

[0057] HRMS (ESI): found: 393.1430 ([M+H] + ), calcd. Chemical Formula: C 20 H 20 F3N2O3, Exact Mass: 393.1426.

[0058]

[0059] 1 1H NMR (600 MHz, CDCl3) δ 8.52 (s, 1H), 7.57 (s, 1H), 7.22 (s, 1H), 7.14 (d, J = 7.0 Hz, 1H), 6.97 (t, J = 7.2 Hz, 1H), 6.78 (t, J = 7.3 Hz, 1H), 6.46 (d, J = 7.6 Hz, 1H), 3.78 (s, 3H), 3.10 (t, J = 12.9 Hz, 1H), 2.64 (d, J = 14.2 Hz, 1H), 2.38 (d, J = 13.5 Hz, 1H), 1.78 (d, J = 14.0 Hz, 4H).

[0060] 13 13C NMR (151 MHz, CDCl3) δ 174.1, 168.8, 154.6, 149.5, 137.9, 136.4, 134.6, 127.2, 126.3, 126.2, 125.1, 124.5, 123.6, 63.6, 52.8, 39.2, 25.9, 23.5.

[0061] HRMS (ESI): found: 311.1398 ([M+H] + ), calcd. Chemical Formula: C 18 H 19 N2O3, Exact Mass: 311.1396.

[0062]

[0063] 11H NMR (600 MHz, CDCl3) δ 8.50 (s, 1H), 7.75 (s, 1H), 7.58 (s, 1H), 7.30 (s, 1H), 7.27 (s, 1H), 7.12 (d, J = 7.1 Hz, 1H), 7.03 (s, 1H), 6.91 (s, 1H), 4.53 (d, J = 11.2 Hz, 1H), 4.24 (s, 1H), 3.92 (t, J = 10.5 Hz, 1H), 3.16 (dd, J = 17.1, 6.9 Hz, 1H), 2.73 (dd, J = 17.3, 10.2 Hz, 1H), 2.02 (s, 3H), 1.20 (s, 9H).

[0064] 13 13C NMR (151 MHz, CDCl3) δ 171.1, 168.4, 154.8, 148.8, 136.8, 129.2, 128.6, 126.0, 125.7, 125.1, 124.6, 123.7, 74.8, 65.6, 60.3, 33.9, 28.3, 21.1.

[0065] HRMS (ESI): found: 383.1967 ([M+H] + ), calcd. Chemical Formula: C 22 H 27 N2O4, Exact Mass: 383.1971.

[0066]

[0067] 1 1H NMR (600 MHz, CDCl3) δ 8.47 (s, 1H), 7.76 (s, 1H), 7.60 (s, 1H), 7.29 (s, 1H), 7.26–7.25 (m, 1H), 7.12 (d, J = 7.3 Hz, 1H), 7.02 (s, 1H), 6.89 (s, 1H), 4.43 (s, 1H), 4.32 (d, J = 6.6 Hz, 1H), 3.93 (d, J = 10.6 Hz, 1H), 3.21 (dd, J = 17.3, 7.4 Hz, 1H), 2.74 (dd, J = 17.4, 9.8 Hz, 1H), 1.23 (s, 9H), 1.14 (s, 9H).

[0068] 1313C NMR (151 MHz, CDCl3) δ 178.4, 168.2, 154.9, 148.6, 136.9, 129.3, 128.8, 125.9, 125.5, 125.0, 124.6, 123.9, 74.8, 65.6, 60.3, 38.8, 34.2, 28.4, 27.3. HRMS (ESI): found: 425.2445 ([M+H] + ), calcd. Chemical Formula: C 25 H 33 N2O4, Exact Mass: 425.2440.

[0069]

[0070] 1 1H NMR (600 MHz, CDCl3) δ 8.68 (s, 1H), 7.94 (t, J=7.2 Hz, 1H), 7.81 (s, 1H), 7.47 (s, 1H), 7.44 (s, 1H), 7.26 (t, J=17.6 Hz, 3H), 4.47 (s, 1H), 4.00 (d, J=24.0 Hz, 1H), 3.65 (s, 1H), 3.31 (dd, J=16.9, 7.3 Hz, 1H), 2.84 (dd, J=16.5, 10.3 Hz, 1H), 1.37 (s, 9H), 0.98 (s, 9H), 0.05 (s, 3H), -0.00 (s, 3H).

[0071] 13 13C NMR (151 MHz, CDCl3) δ 168.6, 155.6, 148.6, 136.8, 129.0, 129.0, 125.9 124.8, 124.2, 123.8, 74.64 (s), 65.62 (s), 58.63 (s), 34.26 (s), 28.41 (s), 26.00 (s), 18.33 (s), -5.38 (s), -5.55 (s).

[0072] HRMS (ESI): found: 455.2735 ([M+H] + ), calcd. Chemical Formula: C 26 H 39 N2O3Si, Exact Mass: 455.2730.

[0073]

[0074] 11H NMR (600 MHz, CDCl3) δ 8.47 (s, 1H), 7.59 (s, 1H), 7.26–7.25 (m, 1H), 7.20 (s, 1H), 7.13 (d, J = 7.4 Hz, 1H), 6.97 (t, J = 6.7 Hz, 1H), 6.81 (s, 1H), 6.46 (s, 1H), 4.77 (s, 1H), 3.87 (dd, J = 9.7, 4.1 Hz, 1H), 3.66 (s, 1H), 2.74 (d, J = 5.0 Hz, 2H), 2.37 (s, 1H), 1.86 (dd, J = 12.6, 7.1 Hz, 1H), 0.76 (s, 9H), -0.02 (d, J = 11.6 Hz, 6H).

[0075] 13 13C NMR (151 MHz, CDCl3) δ 168.5, 155.0, 149.1, 136.3, 127.5, 126.0, 125.9, 125.05, 124.20 123.5, 63.8, 54.9, 26.0, 25.8, 18.2, -5.3, -5.4.

[0076] HRMS (ESI): found: 383.2153 ([M+H] + ), calcd. Chemical Formula: C 22 H 31 N2O2Si, Exact Mass: 383.2155.

[0077]

[0078] 1 1H NMR (600 MHz, CDCl3) δ 8.46 (s, 1H), 7.66 (s, 1H), 7.41 (d, J = 48.2 Hz, 1H), 7.24 (s, 1H), 7.17 (d, J = 7.5 Hz, 1H), 7.03 (s, 1H), 6.83 (s, 1H), 6.40 (s, 1H), 4.48–4.00 (m, 3H), 2.94–2.75 (m, 2H), 2.11–1.93 (m, 5H), 1.84–1.69 (m, 2H).

[0079] 1313C NMR (151 MHz, CDCl3) δ 171.2, 171.1, 168.2, 164.1, 154.8, 149.7, 148.9, 148.1, 137.6, 136.5, 128.2, 126.4, 126.1, 125.3, 124.3, 123.6, 122.4, 61.7, 61.6, 44.7, 33.8, 21.1, 21.1.

[0080] HRMS (ESI): found: 325.1548 ([M+H] + ), calcd. Chemical Formula: C 19 H 21 N2O3, Exact Mass: 325.1552.

[0081]

[0082] 1 1H NMR (600 MHz, CDCl3) δ 8.53 (d, J = 4.3 Hz, 1H), 8.49 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 7.4 Hz, 1H), 7.85 (t, J = 7.7 Hz, 1H), 7.60 (s, 1H), 7.46–7.39 (m, 1H), 7.29 (s, 1H), 7.22 (s, 1H), 7.15 (d, J = 7.4 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H), 6.84 (s, 1H), 6.55 (s, 1H), 4.39–4.30 (m, 1H), 4.19 (t, J = 6.2 Hz, 1H), 2.82–2.69 (m, 1H), 2.43 (s, 1H), 2.05 (s, 1H), 1.94 (tt, J = 14.8, 7.3 Hz, 1H), 1.54 (s, 1H), 1.32 (d, J = 6.6 Hz, 1H), 1.28 (d, J = 6.4 Hz, 2H).

[0083] 13 13C NMR (151 MHz, CDCl3) δ 171.1, 168.0, 163.7, 155.0, 150.0, 149.0, 149.0, 148.0, 137.4, 137.4, 136.4, 127.8, 126.2, 126.2, 126.1, 125.9, 125.1, 124.2, 123.4, 122.3, 61.7, 49.5, 43.0, 35.4, 21.0, 20.9.

[0084] HRMS(ESI): found: 253.1343 ([M+H] + ), calcd. Chemical Formula: C 16 H 17 N2O, Exact Mass: 253.1341.

[0085]

[0086] 1 H NMR (600 MHz, CDCl3) δ 8.36 (s, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.23 (t, J=7.9 Hz, 2H), 7.09 (dd, J=14.8, 7.4 Hz, 1H), 6.90 (t, J=7.5 Hz, 1H), 6.57 (s, 1H), 5.66–5.55 (m, 1H), 2.83 (d, J=4.7 Hz, 2H), 2.73–2.63 (m, 1H), 2.01 (dt, J=16.1, 8.2 Hz, 1H).

[0087] 19 F NMR (565 MHz, Chloroform-d) δ -73.96.

[0088] 13 C NMR (151 MHz, CDCl3) δ 168.5, 153.7, 148.7, 138.1, 136.5, 134.4, 127.3, 126.7, 126.3, 126.0, 124.6, 123.7, 52.6, 25.36 (d, J=19.7 Hz).

[0089] HRMS(ESI): found: 307.1055 ([M+H] + ), calcd. Chemical Formula: C 16 H 14 F3N2O, Exact Mass: 307.1058.

[0090]

[0091] 11H NMR (600 MHz, CDCl3) δ 8.46 (s, 1H), 7.67 (s, 1H), 7.48 (s, 1H), 7.25 (s, 1H), 6.69 (s, 1H), 6.36 (s, 2H), 5.19 (s, 1H), 4.53 (s, 1H), 3.73 (d, J = 6.0 Hz, 6H), 3.06 (s, 1H), 2.82 (dd, J = 14.4, 2.0 Hz, 1H), 1.16 (s, 9H).

[0092] 13 13C NMR (151 MHz, CDCl3) δ 169.5, 168.2, 156.9, 154.0, 148.9, 136.7, 131.0, 125.6, 124.6, 124.2, 114.1, 111.6, 74.9, 68.2, 62.2, 55.4, 51.9, 35.0, 28.4. HRMS (ESI): found: 399.1921 ([M+H] + ), calcd. Chemical Formula: C 22 H 27 N2O5, Exact Mass: 399.1920.

[0093]

[0094] 1 1H NMR (600 MHz, CDCl3) δ 8.47 (d, J = 2.7 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.50 (d, J = 6.4 Hz, 1H), 7.26 (d, J = 5.9 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.80 (d, J = 7.4 Hz, 1H), 6.34 (s, 1H), 5.16 (d, J = 6.6 Hz, 1H), 4.48 (s, 1H), 3.75 (s, 3H), 3.06 (dd, J = 14.3, 6.9Hz, 1H), 2.80 (d, J = 14.4 Hz, 1H), 1.99 (s, 3H), 1.16 (s, 9H).

[0095] 1313C NMR (151 MHz, CDCl3) δ 169.6, 168.6, 154.1, 148.9, 137.2, 136.7, 135.9, 128.5, 126.3, 125.8, 125.4, 124.6, 124.2, 74.9, 68.2, 62.2, 52.0, 34.2, 28.4, 21.1. HRMS (ESI): found: 383.1975 ([M+H] + ), calcd. Chemical Formula: C 22 H 27 N2O4, Exact Mass: 383.1971.

[0096]

[0097] 1 1H NMR (600 MHz, CDCl3) δ 8.38 (d, J=3.7 Hz, 1H), 7.77 (t, J=7.6 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.40 (s, 1H), 7.33–7.28 (m, 1H), 7.13 (d, J=8.1 Hz, 1H), 6.69 (s, 1H), 5.20 (d, J=6.8 Hz, 1H), 4.62 (s, 1H), 3.75 (s, 3H), 3.10 (dd, J=14.6, 6.2 Hz, 1H), 2.92 (d, J=14.6 Hz, 1H), 1.15 (s, 9H).

[0098] 19 19F NMR (565 MHz, Chloroform-d) δ -62.10.

[0099] 13 13C NMR (151 MHz, CDCl3) δ 169.2, 168.6, 153.0, 148.7, 141.1, 137.1, 130.1, 127.1, 126.9,126.8, 126.6, 126.4, 126.0, 125.9, 125.9, 125.9, 125.34, 125.1, 124.7, 124.6, 123.4, 123.4, 123.4, 123.4, 123.3, 75.2, 67.8, 62.7, 52.1, 34.8, 28.4. HRMS (ESI): found: 437.1684 ([M+H] + ), calcd. Chemical Formula: C 22 H 24F3N2O4, Exact Mass: 437.1688.

[0100]

[0101] 1 H NMR (600 MHz, CDCl3) δ 8.38 (d, J=3.8 Hz, 1H), 7.75 (t, J=7.6 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.29 (d, J=6.1 Hz, 1H), 7.14 (d, J=8.2 Hz, 1H), 6.87 (d, J=8.2 Hz, 1H), 6.43 (s, 1H), 5.19 (d, J=6.8 Hz, 1H), 4.60 (s, 1H), 3.75 (s, 3H), 3.07 (dd, J=14.6, 6.3 Hz, 1H), 2.86 (d, J=14.5 Hz, 1H), 1.15 (s, 9H).

[0102] 19 F NMR (565 MHz, Chloroform-d) δ -58.16.

[0103] 13 C NMR (151 MHz, CDCl3) δ 169.2, 168.6, 153.0, 148.8, 147.1, 138.8, 137.0, 129.6, 128.2, 125.2, 124.5, 121.1, 119.4, 117.9, 117.8, 75.1, 67.9, 62.4, 52.1, 34.3, 28.4.

[0104] HRMS (ESI): found: 453.1639 ([M+H] + ), calcd. Chemical Formula: C 22 H 24 F3N2O5, Exact Mass: 453.1637.

[0105]

[0106] 11H NMR (600 MHz, CDCl3) δ 8.41 (s, 1H), 7.73 (t, J = 7.3 Hz, 1H), 7.60 (s, 1H), 7.27 (s, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.57 (s, 1H), 6.43 (s, 1H), 5.20 (d, J = 5.7 Hz, 1H), 4.62 (s, 1H), 3.74 (s, 3H), 3.03 (dd, J = 14.4, 5.3 Hz, 1H), 2.86 (d, J = 14.5 Hz, 1H), 1.14 (s, 9H).

[0107] 19 19F NMR (565 MHz, Chloroform-d) δ -117.85.

[0108] 13 13C NMR (151 MHz, CDCl3) δ 169.3, 168.3, 160.8, 159.2, 153.5, 148.7, 136.9, 132.0, 126.1, 125.0, 124.5, 115.6, 115.4, 113.3, 113.1, 75.0, 68.0, 62.6, 52.0, 34.9, 29.8, 28.5.

[0109] HRMS (ESI): found: 387.1723 ([M+H] + ), calcd. Chemical Formula: C 21 H 24 F N2O4, Exact Mass: 387.1720.

[0110]

[0111] 1 1H NMR (600 MHz, CDCl3) δ 8.42 (s, 1H), 7.76 (d, J = 7.4 Hz, 1H), 7.66 (d, J = 6.9 Hz, 1H), 7.32 (d, J = 3.8 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.59 (s, 1H), 5.17 (d, J = 6.2 Hz, 1H), 4.59 (s, 1H), 3.74 (s, 3H), 3.06–2.94 (m, 1H), 2.83 (d, J = 14.6 Hz, 1H), 1.14 (s, 9H).

[0112] 1313C NMR (151 MHz, CDCl3) δ 169.2, 168.3, 153.1, 148.6, 138.7, 137.1, 131.4, 129.7, 128.0, 125.2, 125.0, 124.7, 124.5, 75.0, 67.8, 62.5, 52.1, 34.3, 28.4. HRMS (ESI): found: 403.1423 ([M+H] + ), calcd. Chemical Formula: C 21 H 24 ClN2O4, Exact Mass: 403.1425.

[0113]

[0114] 1 1H NMR (600 MHz, CDCl3) δ 8.42 (s, 1H), 7.76 (t, J=7.5 Hz, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.30 (dd, J=12.6, 6.5 Hz, 2H), 7.23–7.21 (m, 1H), 6.99 (s, 1H), 6.44 (s, 1H), 5.17 (s, 1H), 4.58 (s, 1H), 3.74 (s, 3H), 3.02 (dd, J=14.6, 6.1 Hz, 1H), 2.86 (d, J=14.4 Hz, 1H), 1.15 (s, 9H).

[0115] 13 13C NMR (151 MHz, CDCl3) δ 169.2, 168.1, 153.2, 148.6, 137.2, 131.9, 131.6, 129.3, 126.1, 125.2, 124.6, 118.2, 75.1, 67.9, 62.5, 52.1, 34.6, 28.4.

[0116] HRMS (ESI): found: 447.0921 ([M+H] + ), calcd. Chemical Formula: C 21 H 24 BrN2O4, Exact Mass: 447.0919.

[0117]

[0118] 11H NMR (600 MHz, CDCl3) δ 8.34 (s, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.69 (d, J = 7.9 Hz, 2H), 7.34–7.11 (m, 3H), 5.22 (d, J = 6.6 Hz, 1H), 4.63 (s, 1H), 3.73 (s, 6H), 3.11 (dd, J = 14.7, 5.9 Hz, 1H), 2.92 (d, J = 14.7 Hz, 1H), 1.13 (s, 9H).

[0119] 13 13C NMR (151 MHz, CDCl3) δ 169.2 (s), 168.5, 166.5, 153.3, 148.5, 138.0, 137.0, 135.0, 128.9, 128.4, 126.0, 125.8, 125.00, 124.6, 75.0, 67.9, 62.55 (s), 52.01 (d, J = 8.5 Hz), 34.94 (s), 28.42 (s).

[0120] HRMS (ESI): found: 427.1871 ([M+H] + ), calcd. Chemical Formula: C 23 H 27 N2O6, Exact Mass: 427.1869.

[0121]

[0122] 1 1H NMR (600 MHz, CDCl3) δ 8.35 (s, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.39–7.31 (m, 2H), 7.28 (d, J = 8.3 Hz, 1H), 5.23 (d, J = 6.6 Hz, 1H), 4.71 (s, 1H), 3.76 (s, 3H), 3.10 (dd, J = 14.8, 5.0 Hz, 1H), 2.96 (d, J = 14.8 Hz, 1H), 1.14 (s, 9H).

[0123] 1313C NMR (151 MHz, CDCl3) δ 168.9, 168.2, 152.4, 148.4, 139.1, 137.5, 135.6, 129.8, 128.4, 127.9, 125.7, 125.0, 118.6, 110.1, 75.3, 67.7, 62.9, 52.2, 35.2, 28.5. HRMS (ESI): found: 394.1763 ([M+H] + ), calcd. Chemical Formula: C 22 H 24 N3O4, Exact Mass: 394.1767.

[0124]

[0125] 1 1H NMR (600 MHz, CDCl3) δ 8.29 (s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.84 (d, J=3.4 Hz, 2H), 7.47 (s, 1H), 7.33–7.26 (m, 2H), 5.24 (d, J=6.7 Hz, 1H), 4.73 (s, 1H), 3.75 (s, 3H), 1.13 (s, 9H).

[0126] 13 13C NMR (151 MHz, CDCl3) δ 168.9, 168.3, 152.4, 148.4, 146.4, 139.0, 137.5, 137.3, 129.4, 125.7, 125.0, 119.6, 75.3, 67.6, 62.8, 52.2, 35.1, 28.4.

[0127] HRMS (ESI): found: 414.1665 ([M+H] + ), calcd. Chemical Formula: C 21 H 24 N3O6, Exact Mass: 414.1665.

Claims

1. A method for synthesizing tetrahydroquinoline using amino acids and derivatives as substrates, characterized in that the steps Comprising: ； Formula II ； Formula III R is selected from alkyl, trifluoromethyl, -CO2R3, -CH2OR4; R1 is selected from -H, alkyl, trifluoromethyl-substituted methylene; R2 is selected from -H, methyl and tert-butoxy group; R3 is selected from alkyl, benzyl; R4 is selected from ester group, silyl group; X is selected from bromine, iodine; Ar is an aromatic ring with a benzene ring structure; The catalyst is Pd(OAc)2 and CuI; The reaction system further includes Ag2CO3 as an additive; one or more of K3PO4, K2CO3, NaOAc and KOAc as a base; the reaction solvent is selected from a mixed solvent of toluene and tert-amyl alcohol; When the amide substrate in the reaction system is 1.0 equivalent, the dosage of the catalyst Pd(OAc)2 is 0.1 equivalent, the dosage of the catalyst CuI is 0.1 equivalent, and the dosage of Ag2CO3 is 1.0 equivalent.

2. The method for synthesizing tetrahydroquinoline using amino acids and derivatives as substrates according to claim 1, characterized in that, The said steps include: 。 3. The method for synthesizing tetrahydroquinoline using amino acids and derivatives as substrates according to claim 1, characterized in that, The reaction temperature is 80 - 160 °C.

4. The method for synthesizing tetrahydroquinoline using amino acids and derivatives as substrates according to claim 1, wherein The said steps include: adding the reaction substrate amide, base, catalyst into a reaction tube, adding an organic solvent, then injecting an o-haloiodoarene, and after heating the reaction to completion, purifying by column chromatography to obtain a tetrahydroquinoline compound.