A 3-trifluoromethyltetrahydroquinoline compound and its preparation method

Abstract

The invention discloses a kind of 3 trifluoromethyl tetrahydroquinoline compound and its preparation method, belong to the field of organic synthesis technology. The present invention introduces trifluoromethyl group directly into tetrahydroquinoline compound, combines the important medicinal value of tetrahydroquinoline compound and the characteristic that trifluoromethyl can enhance the biological activity of compound. The present invention also provides a kind of preparation method of 3 trifluoromethyl tetrahydroquinoline compound, with N alkenyl aniline as raw material, with cheap and easily available CF3Br as trifluoromethyl source, under the action of visible light induction and photocatalyst and alkali, by the intramolecular free radical tandem cyclization reaction of olefin, one-step synthesis contains trifluoromethyl tetrahydroquinoline compound, and obtains mainly 3 trifluoromethyl tetrahydroquinoline compound, simultaneously with the characteristics such as simple reaction steps, high atom utilization rate, simple operation, mild reaction conditions and high reaction yield.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a 3-trifluoromethyltetrahydroquinoline compound and a preparation method thereof. Background Art

[0002] Tetrahydroquinolines are an important class of nitrogen-containing heterocyclic compounds, whose structural units are often found in natural products, pharmaceuticals, and bioactive molecules. Due to their excellent biological activity and potential therapeutic potential, they have attracted the attention of numerous organic chemists and biologists in recent years. For example, compounds with the following chemical structures A-H:

[0003]

[0004] Studies have shown that compound A, Benzastatin C, is an alkaloid containing a 1,2,3,4-tetrahydroquinoline structure isolated from Streptomyces. The compound exhibits inhibitory activity against glutamate toxicity and lipid peroxidation (J. Heterocycl. Chem. 1998, 35, 279); compound B, Martinic acid, is a tetrahydroquinoline alkaloid isolated from the root of the tropical plant Martinella iquitosensis and has antimalarial activity (Planta Med. 2002, 68, 68); compounds C and D, as a targeted drug with antibacterial activity, are mainly used to treat DNA gyrase and methoxy-tRNA synthetase (Bioorg. Med. Chem. 2009, 17, 660); compound E is mainly used for neuronal Na + Compound F is an antagonist of the NMDA (autoimmune encephalitis) receptor glycine site and has attracted widespread attention as a potential candidate for treating nicotine craving (J. Med. Chem. 1996, 39, 3248); Compound G is a retinoic acid receptor that can interact with intracellular receptors (J. Med. Chem. 1999, 42, 3602); and Compound H is an antipsychotic compound (Bioorg. Med. Chem. Lett. 2005, 15, 4560). To further explore the potential applications of tetrahydroquinoline derivatives, it is crucial to explore various new methods for their efficient synthesis.

[0005] Currently, the preparation methods of tetrahydroquinoline compounds are mainly achieved through hydrogenation reduction of quinoline, Friedel-Crafts alkylation of allylaniline, Povarov reaction, and intermolecular free radical tandem cyclization reaction of aromatic amine derivatives. The specific methods are as follows:

[0006] (1) Preparation of tetrahydroquinoline by hydrogenation reduction reaction of quinoline

[0007] In 2016, Zhang Xumu's research group proposed a hydrogenation reduction reaction of quinoline using rhodium metal and chiral ligands as catalysts and 40 atm hydrogen as a reducing agent at room temperature. The reaction yielded a series of tetrahydroquinoline compounds with yields up to 99% and enantiomeric excess values ​​>99% (Chem. Sci. 2016, 7, 3047). Although this reaction can obtain the corresponding tetrahydroquinoline compounds with high yields and high ee values, the use of noble metals (rhodium) and high pressure conditions (40 atm) limit the application of this reaction. The reaction formula is:

[0008]

[0009] (2) Preparation of tetrahydroquinoline by Friedel-Crafts alkylation of allylaniline

[0010] In 2012, the Thibaudeau group proposed a novel intramolecular Friedel-Crafts alkylation reaction using HF (hydrofluoric acid) / SbF5 (antimony pentafluoride) as initiators and N-allylaniline as the starting material, resulting in a yield of up to 92% for polysubstituted tetrahydroquinolines (Chem. Commun., 2012, 48, 5877). Notably, this reaction not only produces the tetrahydroquinoline product but also the byproduct dihydroindoline, as shown in the following equation:

[0011]

[0012] (3) Preparation of tetrahydroquinoline by Povarov reaction

[0013] In 2009, Zhu Jieping's research group proposed a Povarov reaction of aromatic amines, aldehydes, and electron-rich olefins catalyzed by chiral phosphoric acid, resulting in a series of chiral tetrahydroquinoline compounds with yields up to 90% and ee values ​​of 92-99% (J.Am.Chem.Soc., 2009, 131, 4598). In this reaction, the aromatic amine and aldehyde first undergo a condensation reaction to form an imine, which then undergoes a Povarov reaction with the electron-rich olefin under the action of a chiral catalyst to obtain the corresponding target product. Because this reaction requires the preparation of the imine first, there are cumbersome steps, which limits its further widespread industrial application. The reaction formula is:

[0014]

[0015] (4) Preparation of tetrahydroquinoline via intermolecular free radical tandem cyclization reaction of aromatic amine derivatives

[0016] In 2024, the Hashmi group proposed a tandem cyclization reaction of N-homoallylaniline with bromoalkanes under visible light-induced and precious metal gold catalysis conditions to prepare a series of N-Boc-protected tetrahydroquinoline compounds (J.Am.Chem.Soc.,2024,146,14521). It is worth noting that in this reaction, the authors only prepared four tetrahydroquinoline products, and the highest yield was only 61%. At the same time, this method uses expensive precious metal gold as a catalyst, which limits its wider preparation application. Its reaction formula is:

[0017]

[0018] In summary, existing technologies can synthesize tetrahydroquinoline compounds through hydrogenation of quinoline, Friedel-Crafts alkylation of allylaniline, Povarov reaction, and intermolecular free radical tandem cyclization of aromatic amine derivatives. However, each method has its own drawbacks and limitations. On the other hand, the introduction of a trifluoromethyl group into an organic compound, a common fluorinated group, can significantly alter the chemical, physical, and biological properties of the parent compound, such as acidity and alkalinity, bioavailability, metabolic stability, lipid solubility, and protein binding ability. However, there are few reports on the direct introduction of a trifluoromethyl group into the 3-position of tetrahydroquinoline. Therefore, considering the important pharmaceutical value of tetrahydroquinoline compounds and the fact that the introduction of a trifluoromethyl group into heterocyclic compounds can enhance the biological activity of the compound, it is highly desirable to provide a novel, efficient, and simple method for directly introducing a trifluoromethyl group into the 3-position of tetrahydroquinoline to prepare 3-trifluoromethyltetrahydroquinoline compounds. Summary of the Invention

[0019] To address the above technical problems, the present invention provides a 3-trifluoromethyltetrahydroquinoline compound and a method for its preparation. The preparation method provided by the present invention is environmentally friendly and safe, with readily available and inexpensive raw materials, high atom economy, good regioselectivity, mild reaction conditions, high yield, and easy product purification, thus representing a green synthesis.

[0020] To achieve the above objectives, the present invention provides the following technical solutions:

[0021] The present invention provides a 3-trifluoromethyltetrahydroquinoline compound, the general structural formula of which is:

[0022]

[0023] In the formula, R is any one of benzenesulfonyl (PhSO2), p-toluenesulfonyl (Ts), and tert-butyloxycarbonyl (Boc).

[0024] The present invention directly introduces a trifluoromethyl group into a tetrahydroquinoline compound, combining the important medicinal value of the tetrahydroquinoline compound with the property that the trifluoromethyl group can enhance the biological activity of the compound.

[0025] The present invention also provides a method for preparing the 3-trifluoromethyltetrahydroquinoline compound described in the above technical solution, comprising the following steps: in the presence of visible light, a photocatalyst and a base, CF3Br and N-alkenylaniline undergo a free radical tandem cyclization reaction in an organic solvent to obtain the 3-trifluoromethyltetrahydroquinoline compound.

[0026] The invention uses N-alkenylaniline as a raw material and cheap and easily available CF3Br as a trifluoromethyl source. Under the induction of visible light and the action of a photocatalyst and a base, a tetrahydroquinoline compound containing a trifluoromethyl group is synthesized in one step through a tandem cyclization reaction of intramolecular free radicals of olefins, and the obtained compounds are mainly 3-trifluoromethyltetrahydroquinoline compounds.

[0027] Preferably, the reaction formula of the free radical tandem cyclization reaction is:

[0028]

[0029] The reaction mechanism of the free radical tandem cyclization reaction is as follows (using 4CzIPN as the catalyst and sodium bicarbonate as the base for illustration):

[0030]

[0031] First, under light conditions, the photocatalyst 4CzIPN is excited to the excited state 4CzIPN*, and the excited state photocatalyst undergoes single electron transfer with trifluorobromomethane to generate a trifluoromethyl radical and a bromine anion; then, the trifluoromethyl radical undergoes a radical addition reaction with N-alkenylaniline (1) to obtain a stable tertiary carbon radical intermediate I; then, the tertiary carbon radical intermediate I attacks the aromatic ring, undergoes an intramolecular radical addition cyclization reaction, and obtains a radical intermediate II; the radical intermediate II is then oxidized by the photocatalyst to obtain a carbon cation intermediate III; finally, the carbon cation intermediate III undergoes a deprotonation reaction under the action of a base to obtain a 3-trifluoromethyltetrahydroquinoline compound (3).

[0032] The reaction mechanism described above demonstrates that when the trifluoromethyl radical generated in the radical tandem cyclization reaction undergoes radical addition to the carbon-carbon double bond in the substrate molecule, a stable tertiary carbon radical is preferentially generated, rather than a less stable secondary carbon radical. Furthermore, because this step is a directed reaction, the trifluoromethyl group is introduced into the 3-position of the tetrahydroquinoline in the product molecule generated after the subsequent ring-closure reaction, resulting in the production of primarily 3-trifluoromethyltetrahydroquinoline compounds. This demonstrates the high regioselectivity of the preparation method provided by the present invention.

[0033] Preferably, the CF3Br is added in the form of CF3Br gas; the pressure of the CF3Br gas is 1.0 atm, and the amount added is excessive.

[0034] The CF3Br in the present invention is a non-toxic, odorless, cheap and readily available industrial raw material. Compared with other fluorination reagents, it has the advantages of low price, easy availability and high atom economy.

[0035] More preferably, the structural formula of the N-alkenylaniline is:

[0036]

[0037] In the formula, R is any one of benzenesulfonyl (PhSO2), p-toluenesulfonyl (Ts), and tert-butyloxycarbonyl (Boc).

[0038] Preferably, the photocatalyst comprises a noble metal catalyst or an organic dye catalyst; the amount of the photocatalyst used is 1.0 to 3.0 mol %, more preferably 2.0 to 3.0 mol %, of the amount of the N-alkenylaniline used.

[0039] Preferably, the noble metal catalyst includes (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate ([Ir(ppy)2(dtbbpy)]·PF6); the organic dye catalyst includes 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN) or 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (3DPA2FBN), and is further preferably 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN).

[0040] Preferably, the molar ratio of the N-alkenylaniline to the base is 1:(0-3.0), more preferably 1:(2.0-3.0).

[0041] Preferably, the base includes any one of NaHCO3, Na2CO3, and 2,6-lutidine, and more preferably NaHCO3.

[0042] Preferably, the visible light is blue light with a wavelength of 390 to 460 nm and a power of 5 to 20 W; more preferably, it is blue light with a power of 10 to 20 W.

[0043] Preferably, the organic solvent includes any one of acetonitrile (CH3CN), dichloromethane (DCM), and dimethyl sulfoxide (DMSO), and is more preferably acetonitrile (CH3CN).

[0044] More preferably, the amount of the organic solvent used is 2 mL.

[0045] Preferably, the free radical tandem cyclization reaction time is 12 to 36 hours, and the free radical tandem cyclization reaction temperature is room temperature;

[0046] More preferably, the free radical tandem cyclization reaction time is 24 to 36 hours.

[0047] More preferably, the free radical tandem cyclization reaction further includes spin drying and purification; the purification method is column chromatography; the column chromatography uses silica gel as the stationary phase and petroleum ether and ethyl acetate as eluents; the volume ratio of petroleum ether and ethyl acetate is 8:1.

[0048] Compared with the prior art, the present invention has the following advantages and technical effects:

[0049] (1) The present invention synthesizes 3-trifluoromethyltetrahydroquinoline compounds for the first time by adopting an intramolecular free radical tandem cyclization reaction involving N-alkenylaniline. While constructing the tetrahydroquinoline ring, the trifluoromethyl group is directly introduced into the tetrahydroquinoline compound, providing a new method for the synthesis of tetrahydroquinoline compounds with trifluoromethyl substitution.

[0050] (2) This invention is the first to use trifluorobromomethane in an intramolecular free radical tandem cyclization reaction involving N-alkenylaniline to construct a trifluoromethyl-substituted tetrahydroquinoline compound.

[0051] (3) The preparation method provided by the present invention has a high regioselectivity, that is, the main products obtained are 3-trifluoromethyltetrahydroquinoline compounds. It also has the characteristics of simple reaction steps, high atom utilization, simple operation, mild reaction conditions and high reaction yield. At the same time, visible light irradiation is used to generate free radicals, realizing green synthesis.

[0052] (4) 3-trifluoromethyltetrahydroquinoline compounds prepared by the present invention, 1 H NMR, 13 C NMR, 19 F NMR high-resolution mass spectrometry detection showed that the obtained product was a pure target compound with high purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] The accompanying drawings, which constitute part of this application, are intended to provide a further understanding of this application. The exemplary embodiments and descriptions of this application are intended to explain this application and do not constitute an improper limitation on this application. In the accompanying drawings:

[0054] Figure 1 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) prepared in Example 1 1 H NMR spectra;

[0055] Figure 2 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) prepared in Example 1 13 C NMR spectrum;

[0056] Figure 3 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) prepared in Example 1 19 F NMR spectrum;

[0057] Figure 4 This is a high-resolution mass spectrometry monitoring diagram of 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) prepared in Example 1;

[0058] Figure 5 1-(p-Toluenesulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3b) prepared in Example 2 1 H NMR spectra;

[0059] Figure 6 1-(p-Toluenesulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3b) prepared in Example 2 13 C NMR spectrum;

[0060] Figure 7 1-(p-Toluenesulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3b) prepared in Example 2 19 F NMR spectrum;

[0061] Figure 8 This is a high-resolution mass spectrometry monitoring diagram of 1-(p-toluenesulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3b) prepared in Example 2;

[0062] Figure 9 1-(tert-Butyloxycarbonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3c) prepared in Example 3 1 H NMR spectra;

[0063] Figure 10 1-(tert-Butyloxycarbonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3c) prepared in Example 3 13 C NMR spectrum;

[0064] Figure 11 1-(tert-Butyloxycarbonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3c) prepared in Example 3 19 F NMR spectrum;

[0065] Figure 12 This is a high-resolution mass spectrum monitoring chart of 1-(tert-butoxycarbonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3c) prepared in Example 3. DETAILED DESCRIPTION

[0066] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall within the scope of protection of the present invention.

[0067] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the present invention is further described in detail below with reference to the accompanying drawings and specific embodiments.

[0068] The room temperature in the embodiments of the present invention refers to "25±2°C".

[0069] Unless otherwise specified, the raw materials in the examples of the present invention were purchased from commercial sources.

[0070] Example 1

[0071] A method for preparing 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a), the synthetic route is:

[0072]

[0073] A 50 mL Schlenk flask was charged with N-(4-methoxyphenyl)-N-(3-methyl-2-buten-1-yl)benzenesulfonamide 1a (33.1 mg, 0.1 mmol, 1.0 equiv), 4CzIPN (1.58 mg, 2.0 mol%), NaHCO (16.8 mg, 0.2 mmol, 2.0 equiv), and 2 mL of CHCN. The Schlenk flask was evacuated and then filled with CFBr gas three times, with the pressure in the Schlenk flask maintained at 1.0 atm (observed by a barometer). The reaction mixture was stirred at room temperature for 36 h under 10 W blue light. After the reaction, the reaction mixture was concentrated by spin drying the solvent and then purified by column chromatography using silica gel as the stationary phase and petroleum ether and ethyl acetate as eluents (PE:EA = 8:1, volume ratio) to obtain 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) as a white solid, 33.1 mg, with a yield of 83%.

[0074] 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) obtained in Example 1 was reacted with 1 HNMR, 13 CNMR, 19 FNMR and high-resolution mass spectrometry detection, the results are shown in Figure 1-Figure 4 ,from Figure 1-Figure 4 It can be concluded that the product obtained in Example 1 is a pure target compound.

[0075] The characterization data of the product are:

[0076] 1 H NMR (400MHz, CDCl3) δ7.78 (d, J=9.2Hz, 1H), 7.60-7.54 (m, 3H), 7.47-7.42 (m, 2H), 6.82 (td, J=9.2, 2.8Hz, 2H), 4.41 (dd ,J=14.8,3.2Hz,1H),3.82(s,3H),3.33(dd,J=14.4,12.0Hz,1H),1.85-1.74(m,1H),1.21(q,J=2.0Hz,3H),0.99(s,3H).

[0077] 13 C{ 1 H}NMR(150MHz, CDCl3)157.8,139.8,139.0,133.2,129.2,127.5,127.4,127.3,126.9,126.4(q,J C-F=280.5Hz),55.4,45.3(q,J C-F =24.0Hz),42.7(q,J C-F =3.0Hz),35.4,30.0(q,J C-F =1.5Hz),26.0(q,J C-F =3.0Hz).

[0078] 19 F NMR (376MHz, CDCl3) δ, -63.81 (d, J = 11.3Hz).

[0079] HRMS(ESI):m / z calcd for C 19 H 21 O3NF3S[M+H] + 400.11888,found 400.11908.

[0080] Example 2

[0081] A method for preparing 1-(p-toluenesulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3b), the synthetic route is:

[0082]

[0083] A 50 mL Schlenk flask was charged with N-(4-methoxyphenyl)-N-(3-methyl-2-buten-1-yl)-p-toluenesulfonamide 1b (34.5 mg, 0.1 mmol, 1.0 equiv), 4CzIPN (1.58 mg, 2.0 mol%), NaHCO (16.8 mg, 0.2 mmol, 2.0 equiv), and 2 mL of CHCN. The Schlenk flask was evacuated and then filled with CFBr gas three times, with the pressure in the Schlenk flask maintained at 1.0 atm (observed by a barometer). The reaction mixture was stirred at room temperature for 36 h under 10 W blue light. After the reaction, the reaction mixture was concentrated by spin drying the solvent and then purified by column chromatography using silica gel as the stationary phase and petroleum ether and ethyl acetate as eluents (PE:EA = 8:1, volume ratio) to obtain 1-(p-toluenesulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3b) as a white solid, 31.4 mg, with a yield of 76%.

[0084] 1-(p-Toluenesulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3b) obtained in Example 2 was reacted with 1 HNMR,13 CNMR, 19 FNMR and high-resolution mass spectrometry were used for the detection and results were shown in Figure 5-Figure 8 ,from Figure 5-Figure 8 It can be concluded that the product obtained in Example 2 is a pure target compound.

[0085] The characterization data of the product are:

[0086] 1 H NMR (400MHz, CDCl3) δ7.77(d,J=8.8Hz,1H),7.42(d,J=8.4Hz,1H),7.27-7.22(m,2H),6.83-6.79(m,2H),4.40(dd,J=14.8, 3.2Hz,1H),3.82(s,3H),3.31(dd,J=14.4,12.0Hz,1H),2.39(s,3H),1.91-1.83(m,1H),1.21(d,J=2.0Hz,3H),1.01(s,3H).

[0087] 13 C{ 1 H}NMR(150MHz,CDCl3)157.7,144.2,139.8,136.1,129.8,127.6,127.4,126.9,126.5(q,J C-F =279.0Hz),112.6,112.2,55.4,45.3(q,J C-F =24.0Hz),42.7(q,J C-F =3.0Hz),35.4,30.0(q,J C-F =3.0Hz),26.1(d,J C-F =1.5Hz),21.5.

[0088] 19 F NMR (376MHz, CDCl3) δ, -63.87 (d, J = 7.5Hz).

[0089] HRMS(ESI):m / z calcd for C 20 H 23 O3NF3S[M+H] + 414.13453, found 414.13461.

[0090] Example 3

[0091] A method for preparing 1-(tert-butoxycarbonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3c), the synthetic route is:

[0092]

[0093] A 50 mL Schlenk flask was charged with tert-butyl N-(4-methoxyphenyl)-N-(3-methyl-2-buten-1-yl)carbamate 1c (29.1 mg, 0.1 mmol, 1.0 equiv), 4CzIPN (1.58 mg, 2.0 mol%), NaHCO (16.8 mg, 0.2 mmol, 2.0 equiv), and 2 mL of CHCN. The Schlenk flask was evacuated and then filled with CFBr gas three times, with the pressure in the Schlenk flask maintained at 1.0 atm (observed by a barometer). The reaction mixture was stirred at room temperature for 36 h under 10 W blue light. After the reaction, the reaction mixture was concentrated by spin drying the solvent and then purified by column chromatography using silica gel as the stationary phase and petroleum ether and ethyl acetate as eluents (PE:EA = 8:1, volume ratio) to obtain 1-(tert-butoxycarbonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3c) as a colorless liquid, 31.2 mg, with a yield of 87%.

[0094] 1-(tert-Butyloxycarbonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3c) obtained in Example 3 was reacted with 1 HNMR, 13 CNMR, 19 FNMR and high-resolution mass spectrometry detection, the results are shown in Figures 9-12 ,from Figures 9-12 It can be concluded that the product obtained in Example 3 is a pure target compound.

[0095] The characterization data of the product are:

[0096] 1 H NMR (400MHz, CDCl3) δ7.51(d,J=9.2Hz,1H),6.85(d,J=2.8Hz,1H),6.74(dd,J=9.2,3.2Hz,1H),4.17(dd,J=13.6,4.4H z,1H),3.79(s,3H),3.59(dd,J=13.2,9.2Hz,1H),2.49-2.38(m,1H),1.51(s,9H),1.48(s,3H),1.39(d,J=1.6Hz,3H).

[0097] 13 C{ 1H}NMR(150MHz,CDCl3)156.1,153.3,138.3,126.8(q,J C-F =180.5Hz),125.4,111.4,81.3,55.4,49.3(q,J C-F =24.0Hz),41.2,35.9,30.5,28.3,25.4.

[0098] 19 F NMR (376MHz, CDCl3) δ, -64.14 (d, J = 11.3Hz).

[0099] HRMS(ESI):m / z calcd for C 18 H 24 O3NF3Na[M+Na] + 382.16005,found382.15994.

[0100] Example 4

[0101] The difference from Example 1 is that NaHCO3 (16.8 mg, 0.2 mmol, 2.0 equiv) was replaced by Na2CO3 (21.2 mg, 0.2 mmol, 2.0 equiv) to obtain 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) as a white solid, 25.5 mg, and a yield of 64%.

[0102] Example 5

[0103] The difference from Example 1 is that NaHCO3 (16.8 mg, 0.2 mmol, 2.0 equiv) is replaced by 2,6-lutidine (21.4 mg, 0.2 mmol, 2.0 equiv) to obtain 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) as a white solid, 19.6 mg, and a yield of 49%.

[0104] Example 6

[0105] The difference from Example 1 is that CH3CN is replaced by DCM to obtain 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) as a white solid, 20.0 mg, with a yield of 50%.

[0106] Example 7

[0107] The difference from Example 1 is that CH3CN is replaced by DMSO to obtain 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) as a white solid, 23.9 mg, with a yield of 60%.

[0108] Example 8

[0109] The difference from Example 1 is that NaHCO3 (16.8 mg, 0.2 mmol, 2.0 equiv) was replaced by NaHCO3 (0 mg, 0 mmol, 0 equiv) to obtain 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) as a white solid, 7.2 mg, with a yield of 18%.

[0110] Example 9

[0111] The difference from Example 1 is that NaHCO3 (16.8 mg, 0.2 mmol, 2.0 equiv) was replaced by NaHCO3 (8.4 mg, 0.1 mmol, 1.0 equiv) to obtain 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) as a white solid, 20.3 mg, and a yield of 51%.

[0112] Example 10

[0113] The difference from Example 1 is that NaHCO3 (16.8 mg, 0.2 mmol, 2.0 equiv) is replaced by NaHCO3 (25.2 mg, 0.3 mmol, 3.0 equiv) to obtain 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) as a white solid, 14.8 mg, and a yield of 37%.

[0114] Example 11

[0115] The difference from Example 1 is that 4CzIPN (1.58 mg, 2.0 mol%) was replaced by 4CzIPN (0.79 mg, 1.0 mol%) to obtain 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) as a white solid, 27.1 mg, with a yield of 68%.

[0116] Example 12

[0117] The difference from Example 1 is that 4CzIPN (1.58 mg, 2.0 mol%) was replaced by 4CzIPN (2.37 mg, 3.0 mol%) to obtain 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) as a white solid, 21.5 mg, with a yield of 54%.

[0118] Example 13

[0119] The difference from Example 1 is that 4CzIPN (1.58 mg, 2.0 mol%) was replaced by 3DPA2FBN (1.28 mg, 2.0 mol%) to obtain 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) as a white solid, 15.2 mg, with a yield of 38%.

[0120] Example 14

[0121] The difference from Example 1 is that 4CzIPN (1.58 mg, 2.0 mol%) was replaced by [Ir(ppy)2(dtbbpy)]PF6 (1.83 mg, 2.0 mol%) to obtain 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) as a white solid, 23.9 mg, with a yield of 60%.

[0122] Example 15

[0123] The difference from Example 1 is that 10W blue light is replaced by 5W blue light to obtain 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) as a white solid, 31.9 mg, with a yield of 80%.

[0124] Example 16

[0125] The difference from Example 1 is that 10W blue light is replaced by 20W blue light to obtain 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) as a white solid, 30.3 mg, with a yield of 76%.

[0126] Example 17

[0127] The difference from Example 1 is that the reaction mixture was stirred at room temperature for 12 h to obtain 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) as a white solid, 24.7 mg, with a yield of 62%.

[0128] Example 18

[0129] The difference from Example 1 is that the reaction mixture is stirred at room temperature for 24 h to obtain 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroquinoline (3a) as a white solid, 31.1 mg, with a yield of 78%.

[0130] The above are merely preferred embodiments of the present application, but the scope of protection of the present application is not limited thereto. Any changes or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in this application should be included in the scope of protection of the present application. Therefore, the scope of protection of the present application should be based on the scope of protection of the claims.

Claims

1. A method for preparing 3-trifluoromethyltetrahydroquinoline compounds, characterized in that: The following steps are involved: In the presence of visible light, a photocatalyst and a base, CF3Br and N-alkenylaniline undergo a free radical tandem cyclization reaction in an organic solvent to obtain the 3-trifluoromethyltetrahydroquinoline compound; The photocatalyst is a noble metal catalyst or an organic dye catalyst; the noble metal catalyst is (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate; the organic dye catalyst is 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile or 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile; the amount of the photocatalyst used is 1.0 to 3.0 mol% of the amount of the N-alkenylaniline used; The base is any one of NaHCO3, Na2CO3, and 2,6-lutidine; The visible light is blue light with a wavelength of 390 to 460 nm and a power of 5 to 20 W; The structural formula of the N-alkenylaniline is: Wherein, R is any one of benzenesulfonyl, p-toluenesulfonyl, and tert-butyloxycarbonyl; The general structural formula of the 3-trifluoromethyltetrahydroquinoline compound is: In the formula, R is any one of benzenesulfonyl, p-toluenesulfonyl, and tert-butyloxycarbonyl.

2. The preparation method according to claim 1, characterized in that The CF3Br is added in the form of CF3Br gas; the pressure of the CF3Br gas is 1.0 atm, and the amount added is excessive.

3. The preparation method according to claim 1, characterized in that The molar ratio of the N-alkenylaniline to the base is 1:(0-3.0).

4. The preparation method according to claim 1, characterized in that The organic solvent includes any one of acetonitrile, dichloromethane and dimethyl sulfoxide.

5. The preparation method according to claim 1, characterized in that The time of the free radical tandem cyclization reaction is 12 to 36 hours, and the temperature of the free radical tandem cyclization reaction is room temperature.

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