Method for synthesizing β-aminoketone compounds by titanocene / Brønsted acid synergistic catalysis

Abstract

The invention discloses a method for synthesizing β-aminoketone compounds by titanocene / Brønsted acid synergistic catalysis, using dichlorodiphenyltitanate as a Lewis acid catalyst, 2,3-quinolinedicarboxylic acid as an acid ligand, and dichloromethane as a solvent, and using a one-pot method to make aromatic aldehydes, aromatic amines and cyclohexanone three components carry out carbonyl protonation, amines undergo nucleophilic addition to carbonyl groups, deprotonation, electron transfer on nitrogen, and water departure at room temperature to obtain an iminium ion intermediate; iminium ions, as electrophilic reagents, attack the enol structure containing active hydrogen compounds, lose protons, and obtain β-aminoketone compounds. The present invention has low cost, extremely mild reaction conditions, simple operation, short reaction time, high selectivity of catalysts, and the product only needs simple column chromatography separation after the reaction is completed. The synthesized β-aminoketone compounds have diverse biological and pharmacological activities.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis of beta-amino ketone compounds, and particularly relates to a method for synthesizing beta-amino ketone compounds by using titanocene / Brønsted acid to synergistically catalyze aromatic aldehydes, aromatic amines and cyclohexanone. Background Art

[0002] β-aminoketone is an important class of biologically active substances, with a variety of biological activities such as antitussive, antibacterial, anti-inflammatory, anticancer, antiviral, sedative, analgesic, antihypertensive, edema inhibition, anticoagulation, etc., and it has a wide range of pharmacological activities, which is mainly due to the presence of two different functional groups in its molecules - keto group and amino group. A slight change in the structure of aminoketone will cause a change in pharmacological action.

[0003] Since the anti-tumor activity of dichlorotitacenes was proposed in 1979, the synthesis of titanocene complexes has received more and more attention. Since titanocene complexes are stable to air and water and show high activity in organic catalysis, they are highly favored. The method for preparing β-aminoketones is the Mannich reaction synthesis method: aromatic aldehydes, aromatic amines and cyclohexanone undergo condensation reactions to generate β-aminoketone compounds. Due to the medicinal and synthetic value of these compounds, many scientists around the world are working hard to develop other synthetic methods, which use a variety of catalysts, such as aluminum p-aminobenzenesulfonate, phosphotungstic acid, copper trifluoromethanesulfonate, aminosulfonic acid and other catalysts.

[0004] In the invention patent application with publication number CN104045573A, when aminophenol ligands are used to cooperate with dichlorobis(pentachloro)tantalum to synthesize cyclohexanone, although the yield reaches 85% and the selectivity is 9:91, it needs to react for 4 hours at 50°C. In the invention patent application with publication number CN105085582A, the isolating titanocenes of salicylic acid and 3-thiophenecarboxylic acid are used as catalysts to catalyze the synthesis of β-aminoketone compounds from cyclohexanone. This method requires the synthesis of the titanocenes first and then uses them in the reaction, and the steps are relatively cumbersome. In the invention patent application with publication number CN104140374A, polyaminophenol and dichlorobis(pentachloro)tantalum are used to heterogeneously catalyze the synthesis of β-aminoketone compounds. The advantage is that the reaction is heterogeneous and the catalyst can be recycled, but the reaction takes 7 hours, which is too long, and the reaction conditions change with different substrates. Some reactions need to be heated to 50°C. In the invention patent application with publication number CN103467321A, salicylic acid was used as a ligand, and the yield of cyclohexanone was 78% after one hour of reaction. After another hour of reaction, the yield reached 84% with a selectivity of 9:91. The yield still needs to be improved.

[0005] Acid catalysts and metal-based Lewis acid catalysts will complement each other. The synergistic effect of the two will promote the reaction. Each component is very important for improving the activity and selectivity of chemical reactions. Therefore, more different types of titanocene complexes are developed to solve problems such as selectivity, economic cost, environmental pollution, and green chemistry. Summary of the invention

[0006] The invention aims to provide a method for synthesizing β-amino ketone compounds with extremely mild conditions, simple operation, short reaction time, good substrate applicability and high efficiency.

[0007] In view of the above purpose, the technical solution adopted by the present invention is: using a one-pot method, the aromatic aldehyde shown in formula I, the aromatic amine shown in formula II and the cyclohexanone shown in formula III are added to dichloromethane, and dichlorotitanocene is added as a catalyst and 2,3-quinolinedicarboxylic acid is added as a ligand, and the reaction is carried out at room temperature. After the reaction is completed, the product is separated and purified to obtain a β-amino ketone compound shown in formula IV.

[0008]

[0009] In formula I, R1 represents any one of nitro, alkoxy, halo, and H, such as nitro, methoxy, H, F, Cl, Br, etc.; R2 represents any one of alkyl, halo, nitro, and H, such as methyl, ethyl, H, nitro, Cl, etc.

[0010] In the above synthesis method, the molar ratio of the aromatic aldehyde, aromatic amine and cyclohexanone is preferably 1:1.1-1.3:2.0-2.5.

[0011] In the above synthesis method, preferably, the added amount of the dichlorotitanocene is 4% to 6% of the molar amount of the aromatic aldehyde, and the added amount of 2,3-quinolinedicarboxylic acid is 4% to 6% of the molar amount of the aromatic aldehyde.

[0012] In the above-mentioned synthesis method, it is further preferred to carry out the reaction at room temperature for 2 hours.

[0013] The beneficial effects of the present invention are as follows:

[0014] The present invention uses dichlorotitanocene as a Lewis acid catalyst and 2,3-quinolinedicarboxylic acid as a Bronsted acid ligand, adopts a one-pot method, and does not require any gas protection at room temperature to catalyze the carbonyl protonation of aromatic aldehydes, aromatic amines and cyclohexanone, the nucleophilic addition of amines to carbonyls, deprotonation, electron transfer on nitrogen, and water departure to obtain an iminium ion intermediate; the iminium ion, as an electrophilic reagent, attacks the enol structure of the active hydrogen-containing compound, loses protons, and obtains β-amino ketone compounds. The present invention has low cost, extremely mild reaction conditions, simple operation, short reaction time, and no need to heat up or extend the reaction time in the substrate expansion part, the catalyst has high selectivity, and the product only needs simple column chromatography separation after the reaction. The synthesized β-amino ketone compounds have diverse biological and pharmacological activities. The present invention was funded by Guyuan Science and Technology Plan Project 2020GYKYF004 and Ningxia Natural Science Foundation Project 2022AAC03322. DETAILED DESCRIPTION

[0015] The present invention is further described in detail below with reference to the embodiments, but the scope of the present invention is not limited to these embodiments.

[0016] Example 1

[0017] Synthesize 2-((4-nitrophenyl)(phenylamino)methyl)cyclohexane-1-one having the following structural formula

[0018]

[0019] To a 20 mL scintillation vial, 0.1511 g (1 mmol) of p-nitrobenzaldehyde, 110 μL (1.2 mmol) of aniline, 207 μL (2 mmol) of cyclohexanone, 0.0124 g (0.05 mmol) of dichlorotantalum, 0.0108 g (0.05 mmol) of 2,3-quinolinedicarboxylic acid, and 2 mL of dichloromethane were added, and the mixture was stirred at room temperature for 2 hours. The reaction was stopped, and the mixture was separated by column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:20) to obtain 2-((4-nitrophenyl)(phenylamino)methyl)cyclohexane-1-one with a yield of 98.0% and a dr of 9:91.

[0020] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1H NMR(400MHz,Chloroform-d)δ8.22–8.09(m,2H),7.61–7.55(m,2H),7.12–7.04(m,2H),6.70–6.64(m,1H),6.53–6.47(m,2H),4.87(s,1H),4.71 (d,J=5.2Hz,1H),2.86(dt,J=10.5,5.2Hz,1H),2.46–2.38(m,1H),2.37 –2.26(m,1H),2.07–1.98(m,2H),1.97–1.90(m,1H),1.81–1.69(m,3H); 13 C NMR (101MHz, Chloroform-d) δ211.89,149.99,147.20,146.81,129.42,128.39,123.83,118.28,113.64,57.96,57.21,42.57,32.19,27.92,24.65.

[0021] Example 2

[0022] Synthesize 2-((2-nitrophenyl)(phenylamino)methyl)cyclohexane-1-one having the following structural formula

[0023]

[0024] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal molar amount of o-nitrobenzaldehyde, and the other steps were the same as in Example 1 to obtain 2-((2-nitrophenyl)(phenylamino)methyl)cyclohexane-1-one with a yield of 94.3% and a dr of 13:87.

[0025] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1H NMR(400MHz,Chloroform-d)δ7.93(dd,J=8.2,1.4Hz,1H),7.75(dd,J=7.9,1.5Hz,1H),7.52(td,J =7.6,1.4Hz,1H),7.37(ddd,J=8.5,7.4,1.5Hz,1H),7.11–7.05(m,2H),6.68(ddt,J=8.5,7.3,1.1H z,1H),6.56–6.51(m,2H),5.61(d,J=4.4Hz,1H),4.65–3.84(m,1H),3.00–2.92(m,1H),2.45(dp,J= 14.2,2.3,1.9Hz,1H),2.37–2.30(m,1H),2.10–2.06(m,1H),1.96–1.91(m,1H),1.69–1.57(m,4H); 13 C NMR (101MHz, Chloroform-d) δ210.33,146.82,137.35,133.25,128.13,125.26,118.48,114.09,55.48,52.27,42.50,28.53,27.47,25.18.

[0026] Example 3

[0027] Synthesize 2-(((4-ethylphenyl)amino)(4-nitrophenyl)methyl)cyclohexane-1-one having the following structural formula

[0028]

[0029] In Example 1, the aniline used was replaced by an equal molar amount of 4-ethylaniline, and the other steps were the same as in Example 1 to obtain 2-(((4-ethylphenyl)amino)(4-nitrophenyl)methyl)cyclohexane-1-one with a yield of 99.0% and a dr of 8:92.

[0030] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1H NMR(400MHz,Chloroform-d)δ8.20–8.11(m,2H),7.62–7.54(m,2H),6.97–6.87(m,2H),6.47–6.40(m,2H),4.95–4.70(m,1H),4.68(s,1 H),2.85–2.80(m,1H),2.48(q,J=7.6Hz,2H),2.44–2.30(m,2H),2.04–1.92(m,3H),1.75(dt,J=15.9,5.6Hz,3H),1.13(t,J=7.6Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ211.59,149.89,146.86,144.36,133.80,128.4 1,128.11,123.49,113.45,57.85,56.93,42.20,31.74,27.65,24.28,15.57.

[0031] Example 4

[0032] Synthesize 2-((4-nitrophenyl)((4-nitrobenzene)amino)methyl)cyclohexane-1-one having the following structural formula:

[0033]

[0034] In Example 1, the aniline used was replaced by an equimolar amount of p-nitroaniline, and the other steps were the same as in Example 1 to obtain 2-((4-nitrophenyl)((4-nitrobenzene)amino)methyl)cyclohexane-1-one with a yield of 91.7% and a dr of 28:72.

[0035] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ8.23–8.15(m,2H),8.06–7.96(m,2H),7.55(d,J=8.6Hz,2H),6.48(ddd,J=9.2,5.5,2.7Hz,2H), 5.84–5.57(m,1H),5.30(s,1H),3.02–2.90(m,1H),2.43–2.31(m,2H),2.11(d,J=9.9Hz,2H),1.96(s,1H),1.82–1.51(m,5H); 13C NMR (101MHz, Chloroform-d) δ211.90,152.28,148.19,147.55,139.10,128.12,126.46,124.12,112.11,58.18,56.79,42.99,33.07,28.13,25.01.

[0036] Example 5

[0037] Synthesize 2-((2-methoxyphenyl)(phenylamino)methyl)cyclohexane-1-one having the following structural formula

[0038]

[0039] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal mole of 2-methoxybenzaldehyde, and the other steps were the same as in Example 1 to obtain 2-((2-methoxyphenyl)(phenylamino)methyl)cyclohexane-1-one with a yield of 90.1% and a dr of 3:97.

[0040] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ7.39–7.34(m,1H),7.17(d,J=8.1Hz,1H),7.07(dt,J=8.1,4.9Hz, 2H),6.87(dd,J=7.8,3.7Hz,2H),6.65–6.60(m,1H),6.59–6.54(m,2H),5.25(t,J=4.0Hz,1H),4 .45(s,1H),3.88(d,J=2.6Hz,3H),2.91(p,J=5.4Hz,1H),2.46–2.39(m,1H),2.32(dd,J=13.7,5 .6Hz,1H),2.12–2.05(m,1H),2.04–1.97(m,1H),1.88(dt,J=8.0,4.2Hz,1H),1.72–1.60(m,3H); 13 C NMR(101MHz,Chloroform-d)δ213.87,157.34,147.50,129.58,129.17,128.36,128.1 7,120.95,117.34,113.55,110.33,56.13,55.51,52.62,41.99,31.88,28.35,23.79.

[0041] Example 6

[0042] Synthesize 2-((4-methoxyphenyl)(phenylamino)methyl)cyclohexane-1-one having the following structural formula

[0043]

[0044] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal mole of 4-methoxybenzaldehyde, and the other steps were the same as in Example 1 to obtain 2-((4-methoxyphenyl)(phenylamino)methyl)cyclohexane-1-one with a yield of 93.5% and a dr of 7:93.

[0045] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR (400MHz, Chloroform-d) δ7.28(d,J=8.3Hz,2H),7.06(t,J=7.7Hz,2H),6.83(d,J=8.3Hz,2H),6.63(t,J=7.3Hz,1H),6.54(d,J=7.9Hz,2H),4.72(d,J=4 .6Hz,1H),4.59(d,J=7.2Hz,1H),3.77(s,3H),2.72(q,J=7.2Hz,1H),2.44(dt ,J=12.6,5.9Hz,1H),2.37–2.30(m,1H),1.94–1.82(m,4H),1.71–1.64(m,2H); 13 C NMR (101MHz, Chloroform-d) δ213.20,158.82,133.63,129.18,128.45,117.76,114.02,57.70,55.46,55.34,41.83,31.24,28.00,23.69.

[0046] Example 7

[0047] Synthesize 2-((3-chlorophenyl)(phenylamino)methyl)cyclohexane-1-one having the following structural formula

[0048]

[0049] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal molar amount of 3-chlorobenzaldehyde, and the other steps were the same as in Example 1 to obtain 2-((3-chlorophenyl)(phenylamino)methyl)cyclohexane-1-one with a yield of 96.2% and a dr of 6:94.

[0050] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1H NMR(400MHz,Chloroform-d)δ7.37(t,J=1.9Hz,1H),7.30–7.26(m,1H),7.24(d,J =7.7Hz,1H),7.21–7.17(m,1H),7.11–7.06(m,2H),6.65(tt,J=7.2,1.1Hz,1H),6. 54–6.49(m,2H),4.75(s,1H),4.58(d,J=6.4Hz,1H),2.79–2.72(m,1H),2.44–2.3 8(m,1H),2.34(tdd,J=7.9,5.0,1.2Hz,1H),1.99–1.87(m,3H),1.81–1.67(m,3H); 13 C NMR(101MHz,Chloroform-d)δ212.48,147.09,144.32,134.53,129.85,129.29,127. 51(d,J=1.4Hz),125.67,117.89,113.66,57.83,57.41,42.23,31.78,28.00,24.17.

[0051] Example 8

[0052] Synthesize 2-((3-bromophenyl)(phenylamino)methyl)cyclohexane-1-one having the following structural formula

[0053]

[0054] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal molar amount of 3-bromobenzaldehyde, and the other steps were the same as in Example 1 to obtain 2-((3-bromophenyl)(phenylamino)methyl)cyclohexane-1-one with a yield of 97.1% and a dr of 7:93.

[0055] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1H NMR (400MHz, Chloroform-d) δ7.53–7.48(m,1H),7.36–7.29(m,2H),7.16(tt,J=7.8,1. 9Hz,1H),7.09(ddq,J=9.8,4.5,2.3Hz,2H),6.67(t,J=7.3Hz,1H),6.55–6.48(m,2H),4. 74(d,J=4.3Hz,1H),4.57–4.41(m,1H),2.78(tt,J=10.1,6.4Hz,1H),2.48–2.38(m,1H) ,2.32(dt,J=13.7,6.8Hz,1H),2.10–1.98(m,2H),1.94–1.88(m,1H),1.68–1.55(m,3H); 13 C NMR(101MHz,Chloroform-d)δ212.47,147.08,144.62,130.42(d,J=3.6Hz),130.16, 129.30,126.14,122.82,117.90,113.66,57.83,57.43,42.25,31.82,28.00,24.19.

[0056] Example 9

[0057] Synthesize 2-((2-bromophenyl)(phenylamino)methyl)cyclohexane-1-one having the following structural formula

[0058]

[0059] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal molar amount of 2-bromobenzaldehyde, and the other steps were the same as in Example 1 to obtain 2-((2-bromophenyl)(phenylamino)methyl)cyclohexane-1-one with a yield of 92.6% and a dr of 17:83.

[0060] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1H NMR (400MHz, Chloroform-d) δ7.56 (dd, J=8.0, 1.3Hz, 1H), 7.47 (dd, J=7.8, 1.7Hz, 1H), 7. 25–7.20(m,1H),7.09(qd,J=7.1,1.7Hz,3H),6.69–6.64(m,1H),6.53–6.47(m,2H),5.30( d,J=3.4Hz,1H),4.36(s,1H),2.89(dt,J=12.8,4.6Hz,1H),2.52–2.45(m,1H),2.42–2.34 (m,1H),2.04(dddd,J=15.2,12.5,6.2,2.9Hz,2H),1.94–1.89(m,1H),1.72–1.58(m,3H); 13 C NMR(101MHz,Chloroform-d)δ210.65,147.25,140.16,133.34,129.79,129.15 ,128.77,127.66,123.18,118.18,114.33,55.57,54.11,42.42,27.24,25.12.

[0061] Example 10

[0062] Synthesize 2-((4-bromophenyl)(phenylamino)methyl)cyclohexane-1-one having the following structural formula

[0063]

[0064] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal molar amount of 4-bromobenzaldehyde, and the other steps were the same as in Example 1 to obtain 2-((4-bromophenyl)(phenylamino)methyl)cyclohexane-1-one with a yield of 93.5% and a dr of 16:84.

[0065] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1H NMR(400MHz,Chloroform-d)δ7.39(dd,J=10.9,7.7Hz,2H),7.25–7.16(m,2H),7.05( dt,J=11.0,7.4Hz,2H),6.62(dt,J=10.8,7.1Hz,1H),6.48(dd,J=10.9,7.5Hz,2H),4. 70(d,J=8.5Hz,1H),4.59–4.50(m,1H),2.70(dq,J=11.1,5.9Hz,1H),2.38(dq,J=10.9 ,6.9,5.5Hz,1H),2.29(dt,J=14.9,7.2Hz,1H),1.96–1.82(m,3H),1.77–1.62(m,3H); 13 C NMR (101MHz, Chloroform-d) δ 212.58, 147.06, 141.01, 131.69, 129.22 (d, J = 8.4Hz), 121.01, 117.89, 113.71, 57.65, 57.40, 42.19, 31.66, 27.97, 24.13.

[0066] Embodiment 11

[0067] Synthesize 2-(phenyl(phenylamino)methyl)cyclohexane-1-one having the following structural formula

[0068]

[0069] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal mole of benzaldehyde, and the other steps were the same as in Example 1 to obtain 2-(phenyl(phenylamino)methyl)cyclohexane-1-one with a yield of 93.5% and a dr of 10:90.

[0070] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ7.37(d,J=7.7Hz,2H),7.30(t,J=7.5Hz,2H),7.2 4–7.18(m,1H),7.06(t,J=7.7Hz,2H),6.62(t,J=7.3Hz,1H),6.53(d,J=8.0Hz, 2H),4.72(s,1H),4.63(d,J=7.0Hz,1H),2.78–2.71(m,1H),2.46–2.40(m,1H), 2.34(dt,J=13.6,6.4Hz,1H),1.95–1.84(m,4H),1.71(dd,J=11.5,7.5Hz,2H);13 C NMR (101MHz, Chloroform-d) δ 213.04, 147.31, 141.82, 129.19, 128.61, 127.34 (d, J = 8.2Hz), 117.64, 113.72, 58.09, 57.62, 41.91, 31.43, 28.03, 23.78.

[0071] Example 12

[0072] Synthesize 2-((2-methoxyphenyl)(p-toluylamino)methyl)cyclohexane-1-one having the following structural formula

[0073]

[0074] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal molar amount of 2-methoxybenzaldehyde, the aniline used was replaced by p-toluidine, and the other steps were the same as in Example 1 to obtain 2-((2-methoxyphenyl)(p-toluylamino)methyl)cyclohexane-1-one with a yield of 96.2% and a dr of 12:88.

[0075] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ7.36(dd,J=7.8,1.8Hz,1H),7.17(td,J=7.8,1.8H z,1H),6.91–6.83(m,4H),6.52–6.46(m,2H),5.20(d,J=5.2Hz,1H),4.32(s,1H), 3.87(s,3H),2.90(dt,J=11.2,5.3Hz,1H),2.46–2.39(m,1H),2.31(dd,J=12.5,6 .0Hz,1H),2.17(s,3H),2.04–1.98(m,1H),1.91–1.86(m,1H),1.75–1.57(m,4H); 13 C NMR(101MHz,Chloroform-d)δ211.66,156.47,145.29,129.30,128.81,127.64,1 20.39,113.79,110.26,55.12,54.61,51.39,42.13,28.37,27.27,24.48,20.17.

[0076] Embodiment 13

[0077] Synthesize 2-((2-bromophenyl)(p-toluylamino)methyl)cyclohexane-1-one having the following structural formula

[0078]

[0079] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal molar amount of 2-bromobenzaldehyde, the aniline used was replaced by p-toluidine, and the other steps were the same as in Example 1 to obtain 2-((2-bromophenyl)(p-toluamino)methyl)cyclohexane-1-one with a yield of 97.1% and a dr of 10:90.

[0080] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ7.56(d,J=7.9Hz,1H),7.48(dd,J=7.8,1.8Hz,1H),7.21(d, J=7.8Hz,1H),7.09(td,J=7.6,1.8Hz,1H),6.90(d,J=8.0Hz,2H),6.42(d,J=8.2Hz,2H),5 .27(d,J=3.2Hz,1H),4.13(q,J=7.1Hz,1H),2.87(dt,J=12.8,3.8Hz,1H),2.49(ddt,J=14 .2,4.6,2.4Hz,1H),2.41–2.34(m,1H),2.18(s,3H),2.06–1.88(m,3H),1.73–1.57(m,3H); 13 CNMR(101MHz,Chloroform-d)δ210.40,144.65,139.98,132.97,129.40(d,J=15.7Hz),1 28.32, 127.30, 122.83, 114.12, 55.47, 53.79, 42.09, 26.90 (d, J = 9.8Hz), 24.79, 20.18.

[0081] Embodiment 14

[0082] Synthesize 2-((3-fluorophenyl)(phenylamino)methyl)cyclohexane-1-one having the following structural formula

[0083]

[0084] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal molar amount of 3-fluorobenzaldehyde, and the other steps were the same as in Example 1 to obtain 2-((3-fluorophenyl)(phenylamino)methyl)cyclohexane-1-one with a yield of 92.6% and a dr of 9:91.

[0085] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were:1 H NMR(400MHz,Chloroform-d)δ7.32–7.27(m,1H),7.19(d,J=7.8Hz,1H),7.12(ddd,J =13.1,6.3,4.8Hz,3H),6.93(td,J=8.3,2.6Hz,1H),6.68(t,J=7.3Hz,1H),6.55(d,J =8.0Hz,2H),4.77(s,1H),4.64(d,J=6.5Hz,1H),2.78(dt,J=9.1,5.3Hz,1H),2.47– 2.41(m,1H),2.36(td,J=9.0,8.2,4.8Hz,1H),2.01–1.90(m,3H),1.82–1.69(m,3H); 13 C NMR(101MHz,Chloroform-d)δ212.50,164.35,161.90,147.10,144.86(d,J=6.2Hz),129.98(d,J=8.2Hz),129.2 2,123.08,117.81,114.32(d,J=6.3Hz),114.11(d,J=5.8Hz),113.62,57.72,57.35,42.12,31.64,27.96,24.07.

[0086] Embodiment 15

[0087] Synthesize 2-((3-bromophenyl)(p-toluylamino)methyl)cyclohexane-1-one having the following structural formula

[0088]

[0089] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal molar amount of 3-bromobenzaldehyde, the aniline used was replaced by p-toluidine, and the other steps were the same as in Example 1 to obtain 2-((3-bromophenyl)(p-toluamino)methyl)cyclohexane-1-one with a yield of 97.1% and a dr of 10:90.

[0090] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1H NMR(400MHz,Chloroform-d)δ7.54–7.47(m,1H),7.36–7.28(m,2H),7.15(td,J=7.8,2.1Hz,1H ),6.90(dd,J=8.5,2.9Hz,2H),6.50–6.40(m,2H),4.71(d,J=4.3Hz,1H),4.57–4.23(m,1H),2. 77(td,J=11.9,9.3,4.4Hz,1H),2.41(td,J=8.3,6.5,3.9Hz,1H),2.33(dt,J=9.2,4.9Hz,1H), 2.18(d,J=3.3Hz,3H),2.10–1.99(m,2H),1.92(td,J=7.6,7.1,3.9Hz,1H),1.73–1.58(m,3H); 13 C NMR(101MHz,Chloroform-d)δ211.14,144.94,144.55,134.11,132.86,131.49,130.59,1 30.41,129.72,126.44,120.97,114.34,57.34,56.66,42.57,28.75,27.21,25.06,20.50.

[0091] Example 16

[0092] Synthesize 2-((4-fluorophenyl)(phenylamino)methyl)cyclohexane-1-one having the following structural formula

[0093]

[0094] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal molar amount of p-fluorobenzaldehyde, and the other steps were the same as in Example 1 to obtain 2-((4-fluorophenyl)(phenylamino)methyl)cyclohexane-1-one with a yield of 99.0% and a dr of 8:92.

[0095] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1H NMR(400MHz,Chloroform-d)δ7.34(ddd,J=7.9,5.3,2.2Hz,2H),7.11–7.04(m,2H), 6.98(td,J=8.7,2.2Hz,2H),6.64(t,J=7.4Hz,1H),6.55–6.47(m,2H),4.72(s,1H),4 .61(dd,J=6.7,2.1Hz,1H),2.73(q,J=6.7Hz,1H),2.41(q,J=6.5,5.5Hz,1H),2.37– 2.29(m,1H),1.98–1.86(m,3H),1.84–1.76(m,1H),1.69(td,J=8.4,7.5,3.8Hz,2H); 13 C NMR(101MHz,Chloroform-d)δ212.71,163.07,160.63,147.05,137.39,129.12,128.78( d, J=8.0Hz), 117.67, 115.45, 115.23, 113.60, 57.50, 57.37, 41.98, 31.42, 27.88, 23.87.

[0096] Embodiment 17

[0097] Synthesis of 2-((3-bromophenyl)((4-ethylphenyl)amino)methyl)cyclohexane-1-one having the following structural formula

[0098]

[0099] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal molar amount of 3-bromobenzaldehyde, the aniline used was replaced by 4-ethylaniline, and the other steps were the same as in Example 1 to obtain 2-((3-bromophenyl)((4-ethylphenyl)amino)methyl)cyclohexane-1-one with a yield of 98.0% and a dr of 9:91.

[0100] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1H NMR(400MHz,Chloroform-d)δ7.53(t,J=1.9Hz,1H),7.34(dt,J=8.0,2.0Hz,2H),7.17(t,J =7.8Hz,1H),6.93(d,J=8.2Hz,2H),6.49–6.44(m,2H),4.54(d,J=6.5Hz,2H),2.73(dt,J=9 .6,5.6Hz,1H),2.49(q,J=7.6Hz,2H),2.44–2.38(m,1H),2.33(td,J=9.0,8.2,4.9Hz,1H), 1.89(dt,J=10.0,3.4Hz,2H),1.83–1.76(m,1H),1.74–1.66(m,2H),1.15(t,J=7.6Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ212.43,144.97,144.83,133.69,130.40(d,J=5.6Hz),130.12 ,128.58,126.18,122.80,113.77,58.05,57.45,42.14,31.65,29.01,27.96,24.11,15.91.

[0101] Embodiment 18

[0102] Synthesize 2-(((4-ethylphenyl)amino)(phenyl)methyl)cyclohexane-1-one having the following structural formula

[0103]

[0104] In Example 1, the p-nitrobenzaldehyde used was replaced by an equimolar amount of benzaldehyde, the aniline used was replaced by 4-ethylaniline, and the other steps were the same as in Example 1 to obtain 2-(((4-ethylphenyl)amino)(phenyl)methyl)cyclohexane-1-one with a yield of 97.1% and a dr of 10:90.

[0105] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1H NMR(400MHz,Chloroform-d)δ7.37(s,1H),7.33–7.28(m,2H),7.24–7.18(m,1H),6.94–6.88(m,2H),6.52–6.44(m,2H),4.60(d,J=7.3Hz,2H),2.7 7–2.69(m,1H),2.61–2.49(m,1H),2.46(t,J=7.5Hz,2H),2.33(td,J=9.1 ,4.9Hz,1H),1.96–1.80(m,4H),1.74–1.64(m,2H),1.13(t,J=7.6Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ213.02,145.24,142.05,133.39,128.54(d,J=8.2Hz),1 27.42,127.25,113.82,58.30,57.68,41.82,31.29,27.99(d,J=4.1Hz),23.70,15.92.

[0106] Embodiment 19

[0107] Synthesize 2-(phenyl(p-tolueneamino)methyl)cyclohexane-1-one having the following structural formula

[0108]

[0109] In Example 1, the p-nitrobenzaldehyde used was replaced by an equimolar amount of benzaldehyde, the aniline used was replaced by p-toluidine, and the other steps were the same as in Example 1 to obtain 2-(phenyl(p-toluylamino)methyl)cyclohexane-1-one with a yield of 96.2% and a dr of 9:91.

[0110] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ7.38–7.29(m,3H),7.19(t,J=7.3Hz,1H),6.85(d,J=8.0Hz,2H),6.44(d,J=8.0Hz,2H),4.58 (d,J=7.3Hz,2H),2.71(q,J=6.9Hz,1H),2.42(dt,J=12.4,5.9Hz,1H),2.34–2.27(m,1H),2.14(s,3H),1.91–1.65(m,6H); 13C NMR(101MHz,Chloroform-d)δ213.10,144.98,141.94,129.68,128.57,127.3 8,127.23,126.77,113.84,58.26,57.65,41.81,31.31,28.02,23.69,20.46.

[0111] Embodiment 20

[0112] Synthesize 2-((4-bromophenyl)(p-toluylamino)methyl)cyclohexane-1-one having the following structural formula

[0113]

[0114] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal molar amount of 4-bromobenzaldehyde, the aniline used was replaced by p-toluidine, and the other steps were the same as in Example 1 to obtain 2-((4-bromophenyl)(p-toluamino)methyl)cyclohexane-1-one with a yield of 95.2% and a dr of 15:85.

[0115] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ7.43(d,J=8.1Hz,2H),7.27(d,J=8.1Hz,2H),6.90(d,J=8.0Hz,2H),6.44(d,J=8.1Hz,2H),4.57(d,J=6.5Hz,2H),2 .73(p,J=5.5Hz,1H),2.46–2.40(m,1H),2.34(td,J=9.1,8.3,4.7Hz,1H ),2.19(s,3H),2.00–1.88(m,3H),1.84–1.78(m,1H),1.74–1.66(m,2H); 13 C NMR(101MHz,Chloroform-d)δ212.59,144.70,141.11,131.62,130.15,129.7 2,129.18,120.91,113.83,57.80,57.37,42.07,31.50,27.93,24.03,20.44.

[0116] Embodiment 21

[0117] Synthesize 2-((4-bromophenyl)((4-ethylphenyl)amino)methyl)cyclohexane-1-one having the following structural formula

[0118]

[0119] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal molar amount of 4-bromobenzaldehyde, the aniline used was replaced by 4-ethylaniline, and the other steps were the same as in Example 1 to obtain 2-((4-bromophenyl)((4-ethylphenyl)amino)methyl)cyclohexane-1-one with a yield of 97.1% and a dr of 10:90.

[0120] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ7.41(dt,J=8.3,2.8Hz,2H),7.27(s,1H),7.25(d,J=1.5Hz,1H),6.91(d d,J=8.7,2.6Hz,2H),6.44(dq,J=9.4,2.9,2.3Hz,2H),4.55(d,J=6.6Hz,1H),4.43–4.01(m,1H),2.76 –2.68(m,1H),2.55(td,J=7.1,6.7,3.6Hz,1H),2.50–2.44(m,2H),2.36–2.30(m,1H),1.91(ddt,J=16 .2,9.9,3.6Hz,3H),1.81–1.76(m,1H),1.69(td,J=9.9,8.7,4.0Hz,2H),1.13(td,J=7.6,2.4Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ212.64,144.94,141.20,140.95,131.66,129.22,1 28.57,120.95,113.80,57.83,57.44,42.10,40.48,31.53,27.96,24.05,15.93.

[0121] Embodiment 22

[0122] Synthesize 2-(((4-ethylphenyl)amino)(3-fluorophenyl)methyl)cyclohexane-1-one having the following structural formula

[0123]

[0124] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal molar amount of 3-fluorobenzaldehyde, the aniline used was replaced by 4-ethylaniline, and the other steps were the same as in Example 1 to obtain 2-(((4-ethylphenyl)amino)(3-fluorophenyl)methyl)cyclohexane-1-one with a yield of 91.0% and a dr of 14:86.

[0125] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1 H NMR(400MHz,Chloroform-d)δ7.35–7.28(m,1H),7.19(d,J=7.7Hz,1H),7.13(dt,J=9 .9,2.1Hz,1H),6.94(t,J=6.9Hz,3H),6.49(d,J=8.4Hz,2H),4.62(d,J=6.7Hz,2H),2 .80–2.71(m,1H),2.51(q,J=7.6Hz,2H),2.44(t,J=5.6Hz,1H),2.39(s,1H),2.03–1. 89(m,3H),1.87–1.81(m,1H),1.72(td,J=9.8,8.8,5.6Hz,2H),1.17(t,J=7.6Hz,3H); 13 CNMR(101MHz,Chloroform-d)δ212.58,164.39,161.94,145.10,145.00,133.64,130.03, 123.14,114.29,114.08,113.76,57.96,57.45,42.08,31.55,29.84,27.98,24.03,15.93.

[0126] Embodiment 23

[0127] Synthesize 2-((3-chlorophenyl)((4-ethylphenyl)amino)methyl)cyclohexane-1-one having the following structural formula

[0128]

[0129] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal molar amount of 3-chlorobenzaldehyde, the aniline used was replaced by 4-ethylaniline, and the other steps were the same as in Example 1 to obtain 2-((3-chlorophenyl)((4-ethylphenyl)amino)methyl)cyclohexane-1-one with a yield of 96.1% and a dr of 13:87.

[0130] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1H NMR(400MHz,Chloroform-d)δ7.37(s,1H),7.28(d,J=7.6Hz,1H),7.20(dd,J=13.5,7.7Hz,2H),6.92(d,J=8.0Hz,2H),6.47(d,J=8.0Hz,2H),4 .56(d,J=6.6Hz,2H),2.79–2.67(m,1H),2.48(q,J=7.7Hz,2H),2.43–2. 28(m,2H),1.97–1.86(m,3H),1.81–1.67(m,3H),1.14(t,J=7.6Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ212.51,144.96,144.50,134.48,133.65,129.81,128.58,127 .48(d,J=6.3Hz),125.70,113.74,58.01,57.43,42.12,31.63,29.05,27.96,24.07,15.93.

[0131] Embodiment 24

[0132] Synthesize 2-((3-chlorophenyl)(p-toluylamino)methyl)cyclohexane-1-one having the following structural formula

[0133]

[0134] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal molar amount of 3-chlorobenzaldehyde, the aniline used was replaced by p-toluidine, and the other steps were the same as in Example 1 to obtain 2-((3-chlorophenyl)(p-toluylamino)methyl)cyclohexane-1-one with a yield of 98.0% and a dr of 16:84.

[0135] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1H NMR(400MHz,Chloroform-d)δ7.34(q,J=2.3,1.9Hz,1H),7.24(s,1H),7.21(d,J=7.7Hz,1H ),7.16(dt,J=7.9,1.9Hz,1H),6.90–6.85(m,2H),6.45–6.40(m,2H),4.53(d,J=6.5Hz,2H), 2.71(dt,J=10.0,5.7Hz,1H),2.40(dt,J=13.8,5.6Hz,1H),2.36–2.29(m,1H),2.16(s,3H) ,1.89(ddt,J=16.7,10.4,3.4Hz,3H),1.80–1.75(m,1H),1.69(td,J=10.1,8.9,3.3Hz,2H); 13 CNMR(101MHz,Chloroform-d)δ212.54,144.75,144.45,134.50,129.97,129.77,127 .49(d,J=6.0Hz),125.69,113.82,58.05,57.43,42.14,31.66,27.98,24.10,20.47.

[0136] Embodiment 25

[0137] Synthesize 2-((2-nitrophenyl)(p-toluylamino)methyl)cyclohexane-1-one having the following structural formula

[0138]

[0139] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal molar amount of 2-nitrobenzaldehyde, the aniline used was replaced by p-toluidine, and the other steps were the same as in Example 1 to obtain 2-((2-nitrophenyl)(p-toluylamino)methyl)cyclohexane-1-one with a yield of 93.5% and a dr of 10:90.

[0140] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1H NMR(400MHz,Chloroform-d)δ7.94(dd,J=8.1,1.4Hz,1H),7.77(dd,J=7.9,1.4Hz,1H),7.55–7.5 1(m,1H),7.38(ddd,J=8.6,7.4,1.5Hz,1H),6.94–6.88(m,2H),6.50–6.44(m,2H),5.57(d,J=4.3H z,1H),4.19(d,J=49.7Hz,1H),2.97(dt,J=12.6,4.8Hz,1H),2.59–2.52(m,1H),2.48–2.43(m,1H) ,2.39–2.34(m,1H),2.19(s,3H),2.10(d,J=8.1Hz,1H),1.95(d,J=6.4Hz,1H),1.74–1.62(m,3H); 13 C NMR(101MHz,Chloroform-d)δ210.38,149.24,144.53,137.52,133.19,131.32(d,J=7.3 Hz),129.78,128.02,125.18,114.24,55.49,52.49,42.48,28.46,27.48,25.17,20.48.

[0141] Embodiment 26

[0142] Synthesis of 2-((2-bromophenyl)((4-ethylphenyl)amino)methyl)cyclohexane-1-one having the following structural formula

[0143]

[0144] In Example 1, the p-nitrobenzaldehyde used was replaced by an equal molar amount of 2-bromobenzaldehyde, the aniline used was replaced by 4-ethylaniline, and the other steps were the same as in Example 1 to obtain 2-((2-bromophenyl)((4-ethylphenyl)amino)methyl)cyclohexane-1-one with a yield of 98.0% and a dr of 10:90.

[0145] The obtained product was characterized by a 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were: 1H NMR(400MHz,Chloroform-d)δ7.60(ddd,J=19.6,7.9,1.5Hz,2H),7.51(dd,J=7.9,1.3Hz,1H) ,7.32–7.29(m,1H),7.21–7.18(m,1H),7.04(td,J=7.7,1.7Hz,1H),6.92(d,J=8.1Hz,2H),5. 24(s,1H),4.78(d,J=4.4Hz,1H),2.93(dt,J=10.4,5.0Hz,1H),2.66(d,J=1.9Hz,1H),2.57(s ,1H),2.47(q,J=7.6Hz,2H),2.01–1.94(m,3H),1.75(t,J=6.0Hz,3H),1.13(t,J=7.6Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ213.31,144.92,141.00,138.61,134.17,130.65,129.7 3,128.61,126.95,124.04,113.50,58.07,55.47,40.80,28.99,28.21,25.14,15.91.

[0146] Embodiment 27

[0147] Synthesize 2-(((2-chlorophenyl)amino)(4-nitrophenyl)methyl)cyclohexane-1-one having the following structural formula

[0148]

[0149] In Example 1, the aniline used was replaced by o-chloroaniline, and the other steps were the same as in Example 1 to obtain 2-(((2-chlorophenyl)amino)(4-nitrophenyl)methyl)cyclohexane-1-one with a yield of 20.3% and a dr of 5:95.

[0150] The obtained product was characterized by 400 MHz nuclear magnetic resonance spectrometer, and the characterization data were as follows: 1H NMR (400 MHz, Chloroform-d) δ8.15 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.25 (dd, J = 7.8, 1.6 Hz, 1H), 7.01–6.92 (m, 1H), 6.60 (t, J = 7.6 Hz, 1H), 6.35 (d, J = 8.3 Hz, 1H), 5.52 (d, J = 8.0 Hz, 1H), 4 .80(dd,J=7.9,4.7Hz,1H),2.94(dt,J=10.6,5.1Hz,1H),2.42(dt,J=13.3,4.0Hz,1H),2.38–2. 28(m,1H),2.06(p,J=6.4,5.9Hz,2H),1.95(dd,J=6.6,3.6Hz,1H),1.77(dd,J=20.8,7.9Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ211.29,149.21,147.23,142.78,129.45,128.36,12 7.78,123.84,120.00,118.21,112.09,57.75,57.10,42.69,32.28,27.89,24.87.

Claims

1. A method for synthesizing β-amino ketone compounds by titanocene / Brønsted acid synergistic catalysis, characterized in that: A one-pot method is adopted, wherein the aromatic aldehyde represented by formula I, the aromatic amine represented by formula II and the cyclohexanone represented by formula III are added to dichloromethane, and dichlorotitanocene is added as a catalyst and 2,3-quinolinedicarboxylic acid is added as a ligand, and the reaction is carried out at room temperature. After the reaction is completed, the product is separated and purified to obtain a β-aminoketone compound represented by formula IV; In formula I, R1 represents any one of nitro, alkoxy, halo, and H; R2 represents any one of alkyl, halo, nitro, and H.

2. The method for synthesizing β-amino ketone compounds by titanocene / Brønsted acid synergistic catalysis according to claim 1, characterized in that: In the formula, R1 is any one of nitro, methoxy, H, F, Cl, and Br, and R2 is any one of methyl, ethyl, H, nitro, and Cl.

3. The method for synthesizing β-amino ketone compounds by titanocene / Brønsted acid synergistic catalysis according to claim 1, characterized in that: The molar ratio of the aromatic aldehyde, the aromatic amine and the cyclohexanone is 1:1.1-1.3:2.0-2.

5.

4. The method for synthesizing β-amino ketone compounds by titanocene / Brønsted acid synergistic catalysis according to claim 1, characterized in that: The added amount of the dichlorotitanocene is 4% to 6% of the molar amount of the aromatic aldehyde, and the added amount of the 2,3-quinolinedicarboxylic acid is 4% to 6% of the molar amount of the aromatic aldehyde.

5. The method for synthesizing β-amino ketone compounds by titanocene / Brønsted acid synergistic catalysis according to claim 1, characterized in that: The reaction was carried out at room temperature for 2 hours.

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