Method for synthesizing tetrahydroquinoline compound by catalyzing reaction of allyl ester and substituted aniline through one-pot method

Abstract

The invention relates to a method for synthesizing tetrahydroquinoline compounds by catalyzing reaction of allyl ester and substituted aniline through a one-pot method, and belongs to the technical field of organic synthesis. Allyl ester and substituted aniline are used as raw materials, tris (pentafluorophenyl) boron is used as a catalyst, trimethylsilyl trifluoromethanesulfonate is used as an additive, reaction is carried out for 24-48 hours at the temperature of 80-140 DEG C, and polysubstituted tetrahydroquinoline products are obtained. The method is characterized in that transition metal and an external oxidant are not needed, N, N-dialkyl arylamine substituted by vinyl at the ortho-position does not need to be prepared in advance, and the tetrahydroquinoline compound is synthesized in a one-pot oxidation-reduction neutral mode. The raw materials used in the method are simple and easy to obtain, the operation is simple, the selected catalyst is green and environment-friendly, the substrate application range is wide, and the yield is good; and meanwhile, the method also shows excellent atom economy.

Description

Technical Field

[0001] The invention relates to a method for preparing a tetrahydroquinoline compound, and in particular to a method for synthesizing the tetrahydroquinoline compound by catalyzing the reaction of allyl ester and substituted aniline in a one-pot process. Background Art

[0002] Nitrogen-containing heterocyclic compounds are an indispensable class of compounds that constitute the human body and nature. They play an indispensable role in various fields. In the field of medicine, drugs containing nitrogen heterocyclic skeletons account for more than half of all drugs and play a core role in modern drug design. 1,2,3,4-Tetrahydroquinoline (THQ) is a very valuable N-heterocyclic skeleton that exists in a large number of natural products and bioactive molecules. It has many very interesting pharmacological activities (J.Carlos et al., Chem.Rev.2019,119,5057-5191). Therefore, it is necessary to develop efficient methods to synthesize tetrahydroquinoline derivatives.

[0003] At present, there are many methods to construct the tetrahydroquinoline skeleton, such as hydrogenation reduction of quinoline compounds, intramolecular cyclization, Povarov reaction, etc. Tetrahydroquinoline derivatives are synthesized by intramolecular or intermolecular cyclization of activated olefins with aniline. Most of these methods use precious transition metals or add external oxidants, which inevitably produce metal residues and are not in line with the development of green chemistry. In 2020, Kang's research group reported an iron-catalyzed synthesis of a series of tetrahydroquinoline derivatives from tertiary amines and electron-deficient olefins (Kang E.-J. et al., Org. Lett. 2020, 22, 16-21). The reaction uses oxygen as an oxidant and iron-catalyzed activation of α-amino C (sp 3 )-H bond to form an α-aminoalkyl radical, which is then coupled with an electron-deficient olefin to obtain a tetrahydroquinoline derivative without the need for precious metals, verifying the feasibility of using abundant metals as catalysts. Nevertheless, transition metals and activated olefins are still required for subsequent cyclization, which is not very environmentally friendly.

[0004] Constructing the tetrahydroquinoline skeleton without using transition metals is also a major difficulty in this field. In 2019, Wang's team reported that tri(pentafluorophenyl)borane can be used as a catalyst to grab the α-H of the nitrogen atom and act as a temporary hydride acceptor to catalyze the transfer of hydride from ortho-olefin-substituted N,N-dialkylarylamines and then undergo intramolecular cyclization to synthesize tetrahydroquinoline derivatives. However, it is still necessary to prepare ortho-olefin-substituted N,N-dialkylarylamines in advance (Wang X.-C. et al., ACS Catal. 2019, 9, 295-300). In 2022, Ma's team reported a method for tri(pentafluorophenyl)borane-catalyzed redox cyclization of neutral N-alkylamines with electron-deficient alkynes to obtain tetrahydroquinoline derivatives (Ma C. et al., Chem. Sci. 2022, 13, 775-780).

[0005] In summary, the development of a method for preparing tetrahydroquinoline compounds by the reaction of olefins and substituted anilines without transition metal catalysis has very important theoretical research value and practical significance. This patent hopes to use green and efficient catalysts to achieve Friedel-Crafts alkylation and oxygen reduction neutral cyclization in one pot, providing a method for the precise synthesis of tetrahydroquinoline skeletons. Summary of the invention

[0006] In view of the above problems, the present invention provides a method for synthesizing tetrahydroquinoline compounds by catalyzing the reaction of allyl ester with substituted aniline in one pot.

[0007] The present invention adopts the following technical solutions:

[0008] A one-pot catalytic reaction method for synthesizing tetrahydroquinoline compounds by catalyzing the reaction of allyl ester and substituted aniline, wherein allyl ester and substituted aniline are used as raw materials, tri(pentafluorophenyl)boron is used as a catalyst, and the allyl ester and substituted aniline are dissolved in a solvent and reacted at 80 to 140° C. for 12 to 24 hours to obtain a Friedel-Crafts alkylation intermediate, and then trimethylsilyl trifluoromethanesulfonate is added and reacted at 80 to 140° C. for 12 to 36 hours to obtain a tetrahydroquinoline product, wherein the general structural formula of the tetrahydroquinoline product is as follows:

[0009]

[0010] Among them, R 1 is any of an alkyl group and a benzyl group; R 2 is any one of H and alkyl; R 3 is any of an alkyl group and an alkoxy group, R 4 is any one of H, methyl, methoxy and halogen; R 5 is any one of H and methoxy; Ar is any one of phenyl, substituted phenyl and aromatic heterocycle.

[0011] Furthermore, the molar ratio of allyl ester, substituted aniline, tris(pentafluorophenyl)boron and trimethylsilyl trifluoromethanesulfonate is 1:(1-1.5):(0.01-0.1):(0.2-1).

[0012] Further, the general structural formula of the allyl ester is as follows:

[0013]

[0014] Furthermore, the general structural formula of the substituted aniline is as follows:

[0015]

[0016] Furthermore, the solvent is any one or more of toluene, m-xylene, dichloromethane, 1,2-dichloroethane, 1,4-dioxane, acetonitrile and tetrahydrofuran.

[0017] After adopting the above technical solution, the present invention has the following advantages compared with the prior art:

[0018] 1. The present invention utilizes tri(pentafluorophenyl)borane to catalyze the activation of allyl ester, so that it undergoes Friedel-Crafts alkylation reaction with tertiary amine and then undergoes redox neutral cyclization reaction to obtain tetrahydroquinoline compounds in one pot. The reaction substrate range is wide.

[0019] 2. The present invention does not require the use of transition metals or the addition of external oxidants, and does not require the advance preparation of N,N-dialkyl aromatic amines containing vinyl substitutions at the ortho position, thus meeting the requirements of green chemistry and demonstrating excellent step economy and atom economy.

[0020] 3. The catalyst and raw materials of the present invention are simple and easy to obtain, the operation is simple, and the atomic utilization rate is high.

[0021] The present invention is described in detail below with reference to the accompanying drawings and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 It is a schematic diagram of the process of the method of the present invention;

[0023] Figure 2 Schematic diagram of the synthesis process of Examples 1-5 of the present invention;

[0024] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of the product prepared in Example 1 of the present invention;

[0025] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of the product prepared in Example 2 of the present invention;

[0026] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of the product prepared in Example 3 of the present invention;

[0027] Figure 6 This is the hydrogen nuclear magnetic resonance spectrum of the product prepared in Example 4 of the present invention;

[0028] Figure 7 This is the hydrogen nuclear magnetic resonance spectrum of the product prepared in Example 5 of the present invention;

[0029] Figure 8 This is the X-ray single crystal diffraction structure of the product prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0030] The principles and features of the present invention are described below in conjunction with the accompanying drawings. The examples given are only used to explain the present invention and are not used to limit the scope of the present invention.

[0031] like Figure 1 As shown, a one-pot method for synthesizing tetrahydroquinoline compounds by catalyzing the reaction of allyl ester and substituted aniline, wherein allyl ester and substituted aniline are used as raw materials, tri(pentafluorophenyl)boron is used as a catalyst, and the allyl ester and substituted aniline are dissolved in a solvent and reacted at 80 to 140° C. for 12 to 24 hours to obtain a Friedel-Crafts alkylation intermediate, and then trimethylsilyl trifluoromethanesulfonate is added and reacted at 80 to 140° C. for 12 to 36 hours to obtain a tetrahydroquinoline product, wherein the general structural formula of the tetrahydroquinoline product is as follows:

[0032]

[0033] Among them, R 1 is any of an alkyl group and a benzyl group; R 2 is any one of H and alkyl; R 3 is any of an alkyl group and an alkoxy group, R 4 is any one of H, methyl, methoxy and halogen; R 5 is any one of H and methoxy; Ar is any one of phenyl, substituted phenyl and aromatic heterocycle.

[0034] The general structural formula of the allyl ester is as follows:

[0035]

[0036] The general structural formula of the substituted aniline is as follows:

[0037]

[0038] Example 1: Synthesis of 3-benzyl-1,6-dimethyl-4-phenyl-1,2,3,4-tetrahydroquinoline:

[0039] like Figure 2As shown in Figure a, in a glove box under anhydrous inert nitrogen atmosphere, 0.02 mmol of tri(pentafluorophenyl)borane, 0.2 mmol of (E)-1,3-diphenyl-2,2,2-trifluoroacetic acid allyl ester 1a, 0.3 mmol of 4-methyl-N,N-dimethylaniline 2a and 1.5 mL of solvent m-xylene were added to the reaction tube in sequence, and the mixture was sealed and stirred continuously at 80° C. for 24 hours, cooled to room temperature, and 0.2 mmol of trimethylsilyl trifluoromethanesulfonate was added to the reaction tube in the glove box, and the mixture was sealed and stirred continuously at 140° C. for 24 hours. After purification by silica gel column chromatography, 65.2 mg (white solid) of the target product was obtained with a yield of> 99%, 7:1 dr, as shown in Figure a. Figure 8 As shown, the X-ray single crystal diffraction structure of the product can be seen; Figure 3 As shown, it can be seen that this embodiment can successfully synthesize the corresponding tetrahydroquinoline products. 1 H NMR(400MHz,Chloroform-d)δ7.26(t,J=7.4Hz,4H),7.20-7.16(m,2H),7.13-7.09(m, 2H),7.05-7.02(m,2H),6.95(dd,J=8.4,2.2Hz,1H),6.62(d,J=8.4Hz,1H),6.59(s,1H) ,3.84(d,J=5.5Hz,1H),3.05(dd,J=11.5,3.2Hz,1H),2.85(s,3H),2.74(dd,J=12.6,5. 8Hz, 2H), 2.49 (dd, J=13.6, 9.5Hz, 1H), 2.27 (dqd, J=9.0, 5.6, 3.1Hz, 1H), 2.13 (s, 3H). 13 C NMR(101MHz,Chloroform-d)δ147.09,144.60,140.73,131.71,129.24,129.11,128.42,128.36,128.2 0,126.18,126.09,125.74,123.48,111.15,51.51,49.11,42.44,39.60,39.07,20.41.HRMS(ESI):m / z Calcd.for[C 25 H 28 N,M+H] + :342.2216;Found:342.2212.

[0040] Example 2: Synthesis of 3-benzyl-1,6-dimethyl-4-phenyl-1,2,3,4-tetrahydroquinoline:

[0041] like Figure 2 As shown in Figure b, the reaction was carried out in a glove box under an anhydrous inert nitrogen atmosphere. 0.02 mmol of tri(pentafluorophenyl)borane, 0.2 mmol of (E)-1,3-diphenyl-2,2,2-trifluoroacetic acid allyl ester 1a, 0.3 mmol of 4-methoxy-N,N-dimethylaniline 2b and 1.5 mL of solvent m-xylene were added to the reaction tube in sequence. After sealing, the tube was stirred continuously at 80°C for 24 hours, cooled to room temperature, and 0.2 mmol of trimethylsilyl trifluoromethanesulfonate was added to the reaction tube in the glove box. After sealing, the tube was stirred continuously at 140°C for 24 hours. After purification by silica gel column chromatography, 61 mg of the target product (yellow solid) was obtained with a yield of 89% and a dr of 9:1. Figure 4 As shown, it can be seen that this embodiment can successfully synthesize the corresponding tetrahydroquinoline products. 1 H NMR(400MHz,Chloroform-d)δ7.25(t,J=7.5Hz,4H),7.20-7.15(m,2H),7.12-7.08(m,2H ),7.06-7.03(m,2H),6.73(dd,J=8.9,3.0Hz,1H),6.64(d,J=8.8Hz,1H),6.36(d,J=2.9Hz ,1H),3.83(d,J=6.0Hz,1H),3.61(s,3H),3.03(dd,J=11.4,3.3Hz,1H),2.83(s,3H),2.75 (dd,J=12.6,5.9Hz,2H),2.49(dd,J=13.5,9.3Hz,1H),2.31(dqd,J=9.3,6.0,3.2Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ151.48,146.52,141.49,140.59,129.18,129.07,128.36,126.25,126.06, 125.20,117.04,113.14,112.09,55.73,52.19,49.48,42.54,39.92,39.00.HRMS(ESI):m / zCalcd.for[C 24 H 26 NO,M+H] + :344.2008;Found:344.2001.

[0042] Example 3: Synthesis of 3-benzyl-7-chloro-1,6-dimethyl-4-phenyl-1,2,3,4-tetrahydro-quinoline:

[0043] like Figure 2 As shown in Figure c, the reaction was carried out in a glove box under an anhydrous inert nitrogen atmosphere. 0.02 mmol of tri(pentafluorophenyl)borane, 0.2 mmol of (E)-1,3-diphenyl-2,2,2-trifluoroacetic acid allyl ester 1a, 0.3 mmol of 3-chloro-N,N,4-trimethylaniline 2c and 1.5 mL of solvent m-xylene were added to the reaction tube in sequence. After sealing, the tube was stirred continuously at 80°C for 24 hours, cooled to room temperature, and 0.2 mmol of trimethylsilyl trifluoromethanesulfonate was added to the reaction tube in the glove box. After sealing, the tube was stirred continuously at 140°C for 24 hours. After purification by silica gel column chromatography, 65 mg of the target product (white solid) was obtained with a yield of 90% and a dr of 11:1. Figure 5 As shown, it can be seen that this embodiment can successfully synthesize the corresponding tetrahydroquinoline products. 1 H NMR(400MHz,Chloroform-d)δ7.25(dt,J=7.4,3.7Hz,4H),7.21-7.16(m,2H), 7.09(d,J=7.5Hz,2H),6.99(d,J=7.6Hz,2H),6.67(s,1H),6.60(s,1H),3.78(d ,J=5.1Hz,1H),3.05(dd,J=11.6,3.3Hz,1H),2.85(s,3H),2.73(td,J=14.2,1 3.1,5.7Hz,2H),2.48(dd,J=13.6,9.2Hz,1H),2.32-2.19(m,1H),2.14(s,3H). 13 CNMR(101MHz,Chloroform-d)δ146.54,145.58,140.43,133.15,133.12,129.15,128.86,128.43,128. 38,126.29,126.15,123.13,121.83,111.13,50.82,48.26,41.98,39.30,38.96,18.75.HRMS(ESI):m / z Calcd.for[C 24 H 25 NCl,M+H] + :362.1670;Found:362.1673.

[0044] Example 4: Synthesis of 1,3-dibenzyl-6-methyl-4-phenyl-1,2,3,4-tetrahydroquinoline:

[0045] like Figure 2As shown in Figure d, the reaction was carried out in a glove box under an anhydrous inert nitrogen atmosphere. 0.02 mmol of tri(pentafluorophenyl)borane, 0.2 mmol of (E)-1,3-diphenyl-2,2,2-trifluoroacetic acid allyl ester 1a, 0.3 mmol of N-benzyl-N,4-dimethylaniline 2d and 1.5 mL of solvent m-xylene were added to the reaction tube in sequence. After sealing, the tube was stirred continuously at 80°C for 24 hours, cooled to room temperature, and 0.2 mmol of trimethylsilyl trifluoromethanesulfonate was added to the reaction tube in the glove box. After sealing, the tube was stirred continuously at 140°C for 24 hours. After purification by silica gel column chromatography, 78 mg of the target product (white solid) was obtained with a yield of 95% and a dr of 9:1. Figure 6 As shown, it can be seen that this embodiment can successfully synthesize the corresponding tetrahydroquinoline products. 1 H NMR(400MHz,Chloroform-d)δ7.29-7.20(m,9H),7.16(t,J=7.3Hz,2H),7.10-7.06(m,2H),7 .03-6.99(m,2H),6.87(dd,J=8.3,2.2Hz,1H),6.64(s,1H),6.59(d,J=8.4Hz,1H),4.52-4.3 9(m,2H),3.88(d,J=4.5Hz,1H),3.22(dd,J=11.7,3.4Hz,1H),2.93(dd,J=11.9,4.6Hz,1H), 2.76(dd,J=13.7,6.5Hz,1H),2.57(dd,J=13.7,8.5Hz,1H),2.34-2.23(m,1H),2.13(s,3H). 13 C NMR(101MHz,Chloroform-d)δ147.00,143.38,140.66,139.28,131.92,129.15,128.89,128.57,128.39,128.32,128.2 9,126.93,126.84,126.11,126.07,125.50,122.27,111.39,55.78,49.78,48.49,42.10,39.16,20.30.HRMS(ESI):m / z Calcd.for[C 30 H 30 N,M+H] + :404.2372;Found:404.2359.

[0046] Example 5: Synthesis of 1,6-dimethyl-4-(naphthalen-2-yl)-3-(naphthalen-2-ylmethyl)-1,2,3,4-tetrahydroq-uinoline:

[0047] like Figure 2 As shown in Figure e, the reaction was carried out in a glove box under an anhydrous inert nitrogen atmosphere. 0.02 mmol of tri(pentafluorophenyl)borane, 0.2 mmol of (E)-1,3-di(naphthalene-2-yl)-2,2,2-trifluoroacetic acid allyl ester 1b, 0.3 mmol of 4-methyl N,N-dimethylaniline 2a and 1.5 mL of solvent m-xylene were added to the reaction tube in sequence. After sealing, the mixture was stirred continuously at 80°C for 24 hours, cooled to room temperature, and 0.2 mmol of trimethylsilyl trifluoromethanesulfonate was added to the reaction tube in the glove box. After sealing, the mixture was stirred continuously at 140°C for 24 hours. After purification by silica gel column chromatography, 70 mg (white solid) of the target product was obtained with a yield of 82% and a dr of 9:1. Figure 7 As shown, it can be seen that this embodiment can successfully synthesize the corresponding tetrahydroquinoline products. 1 H NMR(400MHz,Chloroform-d)δ7.81-7.73(m,6H),7.55-7.50(m,2H),7.45-7.40 (m,4H),7.27-7.22(m,2H),6.97(dd,J=8.4,2.1Hz,1H),6.66(d,J=8.3Hz,1H),6 .60(s,1H),4.03(d,J=6.4Hz,1H),3.09(dd,J=11.5,3.2Hz,1H),3.00-2.86(m, 2H),2.86(s,3H),2.64(dd,J=13.5,9.7Hz,1H),2.58-2.46(m,1H),2.11(s,3H). 13 C NMR(101MHz,Chloroform-d)δ144.79,144.11,138.09,133.60,133.42,132.32,132.17,131.72,128.29,128.24,127.99,127.81,127.75,127.7 1,127.53,127.48,127.11,126.05,126.02,125.91,125.53,125.33,12 3.87,111.30,52.34,49.69,42.19,39.65,39.23,20.37.HRMS(ESI):m / z Calcd.for[C 32 H 30 N,M+H]+ :428.2372;Found:428.2372.

[0048] In summary, the present invention provides a method for preparing tetrahydroquinoline compounds by catalyzing the reaction of olefins with substituted anilines in a one-pot process. By reacting allyl esters with substituted anilines in a solvent in the presence of a catalyst and an additive, the synthesis of the target product tetrahydroquinoline compounds can be successfully achieved.

[0049] The above is an example of the best implementation of the present invention, and the parts not described in detail are common knowledge of ordinary technicians in the field. The protection scope of the present invention shall be based on the content of the claims, and any equivalent transformation based on the technical enlightenment of the present invention is also within the protection scope of the present invention.

Claims

1. A one-pot catalytic method for synthesizing tetrahydroquinoline compounds by reacting allyl esters with substituted anilines, characterized in that: Allyl ester and substituted aniline are used as raw materials, tri(pentafluorophenyl)borane is used as a catalyst, and they are dissolved in a solvent and reacted at 80-140° C. for 12-24 hours to obtain a Friedel-Crafts alkylation intermediate, and then trimethylsilyl trifluoromethanesulfonate is added and reacted at 80-140° C. for 12-36 hours to obtain a tetrahydroquinoline product. The general structural formula of the tetrahydroquinoline product is as follows: Among them, R 1 is any of an alkyl group and a benzyl group; R 2 is any one of H and alkyl; R 3 is any of an alkyl group and an alkoxy group, R 4 is any one of H, methyl, methoxy and halogen; R 5 is any one of H and methoxy; Ar is any one of phenyl, substituted phenyl and aromatic heterocycle.

2. The method for synthesizing tetrahydroquinoline compounds by one-pot catalytic reaction of allyl ester and substituted aniline according to claim 1, characterized in that: The molar ratio of allyl ester, substituted aniline, tris(pentafluorophenyl)boron and trimethylsilyl trifluoromethanesulfonate is 1:(1-1.5):(0.01-0.1):(0.2-1).

3. The method for synthesizing tetrahydroquinoline compounds by one-pot catalytic reaction of allyl ester and substituted aniline according to claim 1, characterized in that: The general structural formula of the allyl ester is as follows:

4. The method for synthesizing tetrahydroquinoline compounds by one-pot catalytic reaction of allyl ester and substituted aniline according to claim 1, characterized in that: The general structural formula of the substituted aniline is as follows:

5. The method for synthesizing tetrahydroquinoline compounds by catalyzing the reaction of allyl ester and substituted aniline in one pot according to claim 1, characterized in that: The solvent is any one or more of toluene, m-xylene, dichloromethane, 1,2-dichloroethane, 1,4-dioxane, acetonitrile and tetrahydrofuran.

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