A method for preparing acrylamide compounds

Abstract

The present invention discloses a method for preparing acrylamide compounds, and belongs to the technical field of organic synthesis. The present invention uses α-trifluoromethylstyrene, aliphatic amine, and water as raw materials, and a defluorination coupling substitution reaction occurs under the action of a catalyst to generate an acrylamide compound. The acrylamide compound synthesized by the method of the present invention has an acryloyl functional group and can be used as a synthetic precursor for many drugs and functional materials. The method of the present invention has very wide substrate adaptability, the starting raw materials α-trifluoromethylstyrene and aliphatic amine for the reaction are cheap and easily available, the reaction feeding process is simple, the post-reaction processing steps are simple, and it is suitable for industrial large-scale synthesis. It can provide a new method and new goal for the synthesis of drugs and the development of new materials.

Description

Technical Field

[0001] The invention relates to a method for preparing an acrylamide compound, and belongs to the technical field of organic synthesis. Background Art

[0002] Acrylamide derivatives are an increasingly important class of compounds, found widely in natural products, bioactive molecules, and functionalized materials. Hydrogels synthesized from acrylamide compounds have applications in tissue engineering, contact lenses, wound dressings, and artificial tendons, with the most prominent application being in biopharmaceutical drug delivery systems. Small-molecule monomer hydrogels synthesized from acrylamide compounds have been used as drug delivery systems in diverse medical fields, ranging from cardiology, oncology, immunology, and wound healing to pain management. Compared to natural hydrogels, artificial hydrogels synthesized from acrylamide exhibit superior durability and chemical strength.

[0003] Therefore, an important goal of organic synthesis is to efficiently and economically synthesize organic compounds containing acrylamide groups. At present, different methods for constructing acrylamide compounds have been developed. For example, patents CN 102241673 B, CN109456219 B, CN 107011206 B, CN 111440172 B, CN 113636989 B, etc. all describe the preparation process of acrylamide compounds. However, the process for preparing acrylamide compounds in the above patents has strict requirements on reaction conditions, such as low temperature, or requires dangerous experimental reagents, and the experimental implementation process is complicated. Another commonly used method is still based on the acrylonitrile hydration method, but this method is limited by the range of substrates. Compared with existing methods for synthesizing acrylamide compounds, the method of the present invention does not require the use of dangerous chemical reagents and avoids the use of acyl chloride compounds. In terms of production and life, the present invention has a short reaction time, simple feeding, high safety, and is suitable for promotion and use in industrial production. Summary of the Invention

[0004] In view of the problems of the prior art methods for synthesizing acrylamide compounds, the present invention provides a method for preparing acrylamide compounds, which comprises the following specific steps:

[0005] α-Trifluoromethylstyrene, aliphatic amine, water, a base and a catalyst are added to a solvent to obtain a reaction system, and the reaction is carried out under heating to 60° C. for 2 hours. The solvent is removed by distillation under reduced pressure, and the mixture is separated and purified by column chromatography to obtain an acrylamide compound.

[0006] Preferably, the molar ratio of α-trifluoromethylstyrene, fatty amine, water, base, catalyst and solvent is 1:(2-4):10:3:(0.01-0.05):(10-200).

[0007] Preferably, the column chromatography separation and purification conditions are: silica gel column chromatography, the eluent is ethyl acetate: petroleum ether, the volume ratio is 1:3 to 1:20.

[0008] Preferably, the structural formula of the α-trifluoromethylstyrene is as shown in Formula II:

[0009]

[0010] Where: R 1 It is one of H, Me, OMe, CF3, F, Cl, Br, and CN.

[0011] Preferably, the fatty amine structural formula is as shown in Formula III:

[0012]

[0013] Where: R 1 is one of H, Me, Et, n-Pr, i-Pr, Bn, etc.; R 2 It is one of Me, Et, n-Pr, i-Pr, Cy, Bn, t-Bu, and Ph.

[0014] Preferably, the base is cesium carbonate (Cs2CO3), potassium carbonate (K2CO3), potassium tert-butoxide (K t Bu), sodium tert-butoxide (NaO t Bu), sodium acetate (NaOAc), sodium fluoride (NaF);

[0015] Preferably, the catalyst is one of bis(triphenylphosphine)palladium chloride (PdCl2(PPh3)2), bis(triphenylphosphine)nickel dichloride (NiCl2(PPh3)2), and triphenylphosphine rhodium chloride (RhCl(PPh3)3).

[0016] Preferably, the solvent is one of acetonitrile (MeCN), 1,4-dioxane, tetrahydrofuran (THF), dichloromethane (DCM), N,N-dimethylformamide (DMF) or dimethyl sulfoxide (DMSO).

[0017] The prepared acrylamide compound has a structural formula as shown in formula I.

[0018]

[0019] Where: R 1 is one of H, Me, OMe, CF3, F, Cl, and CN; R 2 is one of H, Me, Et, n-Pr, i-Pr, Bn, etc.; R 3It is one of Me, Et, n-Pr, i-Pr, Cy, Bn, and t-Bu.

[0020] Beneficial effects of the present invention

[0021] (1) The bimolecular nucleophilic substitution reaction of α-trifluoromethylstyrene, aliphatic amine, and water is achieved under heating conditions in an efficient and easy-to-operate scheme. Due to the presence of the phenyl group, the remaining position has little steric hindrance, and different atoms or functional groups with specific effects can be introduced into the benzene ring to change the physical and chemical properties of the compound. At the same time, the variety of aliphatic amines also expands the practical utility of the invention. These characteristics give the invention a wide substrate range and good functional group tolerance.

[0022] (2) The synthetic raw materials used in the present invention, α-trifluoromethylstyrene and its derivatives, have introduced halogen atoms, methyl groups, methoxy groups, cyano groups, trifluoromethyl groups, and other groups. The introduced chlorine atoms and cyano groups enhance the expansive properties of the acrylamide, allowing the synthesis of more complex acrylamides; the introduced fluorine atoms and trifluoromethyl groups improve the durability of the compound, and the introduced methylmethoxy groups enhance the activity of the compound. By modifying these acrylamide compounds with different functional groups, they can be converted into hydrogels or molecular probes with different functions.

[0023] (3) The acrylamide compounds prepared by the present invention contain an olefin functional group with two hydrogen atoms at one end. Other functional groups can be introduced into the phenyl group for molecular modification, and the phenyl group can be replaced with different fatty amines. This greatly enhances the potential of such compounds in synthetic applications. The acrylamide compounds prepared by the present invention can be used to synthesize hydrogels, adhesives, multifunctional molecular probes, adsorbents, coatings, etc.

[0024] (4) Compared with existing acrylamide compounds, the present invention can introduce corresponding elements according to product requirements to improve product performance. For example, acrylamide compounds with fluorine atoms introduced into the phenyl group can produce products with good corrosion resistance and durability. Before preparing acrylamide compounds, different fatty amines can be selected as needed to change the compound's solubility, cell membrane permeability, and metabolic stability. DETAILED DESCRIPTION

[0025] The present invention will be further described in detail below in conjunction with specific embodiments, but the scope of protection of the present invention is not limited to the above contents. Where specific techniques or conditions are not specified in the examples, the techniques or conditions described in the literature in this field or the product specifications are used. Where the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be purchased.

[0026] Example 1

[0027] The preparation of 2-(4-chlorophenyl)-1-(pyrrolidin-1-yl)prop-2-en-1-one 4a comprises the following steps:

[0028] (1) 1-Chloro-4-(3,3,3-trifluoropropyl-1-en-2-yl)benzene 1a (0.3 mmol), pyrrolidine 2a (0.9 mmol), water 3a (3 mmol), cesium carbonate (0.9 mmol), triphenylphosphine rhodium chloride (3 mol%), and acetonitrile (30 mmol) were added to a dry test tube in a molar ratio of 1:3:10:3:0.03:100.

[0029] (2) The test tube was sealed and the mixture was stirred for 2 hours under the condition of heating to 60° C. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a crude reaction product.

[0030] (3) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:20) to obtain compound 2-(4-chlorophenyl)-1-(pyrrolidin-1-yl)prop-2-en-1-one 4a in a yield of 70%.

[0031] The reaction equation is as follows:

[0032]

[0033] The NMR spectrum characterization data of the product are as follows: 1 HNMR (600MHz, CDCl3) δ7.35 (d, J=8.7Hz, 2H), 7.29 (d, J=8.8Hz, 2H), 5.68 (s, 1H), 5.41 (s, 1 H), 3.56 (t, J=7.0Hz, 2H), 3.19 (t, J=6.8Hz, 2H), 1.91–1.85 (m, 2H), 1.80 (p, J=6.8Hz, 2H); 13 CNMR (151MHz, CDCl3) δ168.80, 145.18, 134.38, 134.15, 129.02, 127.33, 115.17, 48.24, 45.59, 26.04, 24.50; HRMS (ESI)calcd for C 13 H 15 ClNO[(M+H) + ]:236.0842, found 236.0835.

[0034] Example 2

[0035] The preparation of 2-(3-chlorophenyl)-1-(pyrrolidin-1-yl)prop-2-en-1-one 4b comprises the following steps:

[0036] (1) 1-Chloro-3-(3,3,3-trifluoropropyl-1-en-2-yl)benzene 1b (0.3 mmol), pyrrolidine 2a (0.9 mmol), water 3a (3 mmol), sodium fluoride (0.9 mmol), triphenylphosphine rhodium chloride (3 mol%), and tetrahydrofuran (60 mmol) were added to a dry test tube in a molar ratio of 1:3:10:3:0.03:200.

[0037] (2) The test tube was then sealed and the mixture was stirred for 2 hours while heating to 60° C. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a crude reaction product.

[0038] (3) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:18) to obtain compound 2-(3-chlorophenyl)-1-(pyrrolidin-1-yl)prop-2-en-1-one 4b in a yield of 65%.

[0039] The reaction equation is as follows:

[0040]

[0041] The NMR spectrum characterization data of the product are as follows: 1 HNMR (500MHz, CDCl3) δ7.37 (dd, J=2.5, 1.5Hz, 1H), 7.26–7.20 (m, 3H), 5.66 (s, 1H), 5.40 (s, 1H) , 3.52 (t, J=6.9Hz, 2H), 3.16 (t, J=6.7Hz, 2H), 1.84 (dt, J=13.3, 6.6Hz, 2H), 1.80–1.73 (m, 2H); 13 CNMR (126MHz, CDCl3) δ168.54, 145.15, 137.58, 134.80, 130.10, 128.56, 126.07, 124.27, 115.95, 48.28, 45.61, 26.05, 24.49; HRMS (ESI): calcd for C 13 H 15 ClNO[(M+H) + ]:236.0842, found 236.0841.

[0042] Example 3

[0043] The preparation of 2-(2-chlorophenyl)-1-(pyrrolidin-1-yl)prop-2-en-1-one 4c comprises the following steps:

[0044] (1) 1-Chloro-2-(3,3,3-trifluoropropyl-1-en-2-yl)benzene 1c (0.3 mmol), pyrrolidine 2a (1.2 mmol), water 3a (3 mmol), sodium acetate (1.2 mmol), bis(triphenylphosphine)palladium chloride (5 mol%), and N,N-dimethylformamide (30 mmol) were added to a dry test tube in a molar ratio of 1:4:10:3:0.05:100.

[0045] (2) The test tube was then sealed and the mixture was stirred for 2 hours while being heated to 60° C. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a crude reaction product.

[0046] (3) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:20) to obtain compound 2-(2-chlorophenyl)-1-(pyrrolidin-1-yl)prop-2-en-1-one 4c in a yield of 45%.

[0047] The reaction equation is as follows:

[0048]

[0049] The NMR spectrum characterization data of the product are as follows: 1 HNMR (500MHz, CDCl3) δ7.35–7.32(m, 1H), 7.29–7.26(m, 1H), 7.21–7.14(m, 2H), 5.73(s, 1H ), 5.62 (s, 1H), 3.47 (t, J = 6.5Hz, 2H), 3.27 (t, J = 6.1Hz, 2H), 1.77 (dt, J = 20.7, 6.4Hz, 4H).; 13 CNMR (126MHz, CDCl3) δ168.10, 144.39, 137.12, 132.33, 131.10, 129.86, 129.47, 127.24, 122.71, 48.88, 46.27, 26.37, 24.37; HRMS (ESI): calcd for C 13 H 15 ClNO[(M+H) + ]:236.0842, found 236.0847.

[0050] Example 4

[0051] The preparation of 2-phenyl-1-(pyrrolidin-1-yl)prop-2-en-1-one 4d comprises the following steps:

[0052] (1) (3,3,3-Trifluoropropyl-1-en-2-yl)benzene 1d (0.3 mmol), pyrrolidine 2a (0.9 mmol), water 3a (3 mmol), cesium carbonate (0.9 mmol), bis(triphenylphosphine)nickel dichloride (5 mol%), and dimethyl sulfoxide (15 mmol) were added to a dry test tube in a molar ratio of 1:3:10:3:0.05:50.

[0053] (2) The test tube was then sealed and the mixture was stirred for 2 hours while heating to 60° C. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a crude reaction product.

[0054] (3) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:5) to obtain compound 2-phenyl-1-(pyrrolidin-1-yl)prop-2-en-1-one 4d in a yield of 40%.

[0055] The reaction equation is as follows:

[0056]

[0057] The NMR spectrum characterization data of the product are as follows: 1 HNMR (600MHz, CDCl3) δ7.41 (d, J=7.5Hz, 2H), 7.33 (t, J=7.4Hz, 2H), 7.29 (t, J=7.2Hz, 1H), 5.70 (s, 1H ), 5.41 (s, 1H), 3.58 (t, J = 7.0Hz, 2H), 3.20 (t, J = 6.8Hz, 2H), 1.91–1.84 (m, 2H), 1.80 (p, J = 6.7Hz, 2H); 13 CNMR (151MHz, CDCl3) δ169.30, 146.36, 135.65, 128.84, 128.50, 125.97, 114.67, 48.19, 45.55, 26.06, 24.53; HRMS (ESI): calcd for C 13 H 16 NO[(M+H) + ]:202.1232, found 202.1224.

[0058] Example 5

[0059] The preparation of 1-(pyrrolidin-1-yl)-2-(p-tolyl)prop-2-en-1-one 4e comprises the following steps:

[0060] (1) 1-Methyl-4-(3,3,3-trifluoropropyl-1-en-2-yl)benzene 1e (0.3 mmol), pyrrolidine 2a (0.9 mmol), water 3a (3 mmol), sodium tert-butoxide (0.9 mmol), bis(triphenylphosphine)nickel dichloride (5 mol%), and dichloromethane (30 mmol) were added to a dry test tube in a molar ratio of 1:3:10:3:0.05:100.

[0061] (2) The test tube was sealed and the mixture was stirred for 2 hours under the condition of heating to 60° C.; after the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a crude reaction product.

[0062] (3) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:3) to obtain compound 1-(pyrrolidin-1-yl)-2-(p-tolyl)prop-2-en-1-one 4e in a yield of 40%.

[0063] The reaction equation is as follows:

[0064]

[0065] The NMR spectrum characterization data of the product are as follows: 1 HNMR (600MHz, CDCl3) δ7.31 (d, J=8.1Hz, 2H), 7.14 (d, J=8.0Hz, 2H), 5.65 (s, 1H), 5.35 (s, 1H), 3. 58 (t, J=7.0Hz, 2H), 3.20 (t, J=6.8Hz, 2H), 2.33 (s, 3H), 1.91–1.84 (m, 2H), 1.79 (p, J=6.7Hz, 2H); 13 CNMR (151MHz, CDCl3) δ169.49, 146.21, 138.43, 132.79, 129.52, 125.84, 113.65, 48.14, 45.51, 26.04, 24.53, 21.30; HRMS (ESI): calcd for C 14 H 18 NO[(M+H) + ]:216.1388, found 216.1383.

[0066] Example 6

[0067] The preparation of 2-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)prop-2-en-1-one 4f comprises the following steps:

[0068] (1) 1-Methoxy-4-(3,3,3-trifluoropropyl-1-en-2-yl)benzene 1f (0.3 mmol), pyrrolidine 2a (0.9 mmol), water 3a (3 mmol), sodium tert-butoxide (0.9 mmol), bis(triphenylphosphine)palladium dichloride (5 mol%), and dichloromethane (30 mmol) were added to a dry test tube in a molar ratio of 1:3:10:3:0.05:100;

[0069] (2) sealing the test tube and stirring the mixture under heating to 60° C. for 2 hours; after the reaction is completed, removing the solvent by distillation under reduced pressure to obtain a crude reaction product;

[0070] (3) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:3) to obtain compound 2-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)prop-2-en-1-one 4f in a yield of 51%.

[0071] The reaction equation is as follows:

[0072]

[0073] The NMR spectrum characterization data of the product are as follows: 1 HNMR (500MHz, CDCl3) δ7.35 (d, J=8.8Hz, 2H), 6.86 (d, J=8.8Hz, 2H), 5.59 (s, 1H), 5.28 (s, 1H), 3.79 ( s, 3H), 3.58 (t, J=6.9Hz, 2H), 3.21 (t, J=6.6Hz, 2H), 1.88 (dt, J=13.1, 6.5Hz, 2H), 1.84–1.76 (m, 2H); 13 CNMR (126MHz, CDCl3) δ169.62, 159.86, 145.77, 128.24 (s), 127.28, 114.20, 112.53, 55.40, 48.19, 45.53, 26.07, 24.57; HRMS (ESI): calcd for C 14 H 18 NO2[(M+H) + ]:232.1337, found 232.1334.

[0074] Example 7

[0075] The preparation of 4 g of 1-(pyrrolidin-1-yl)-2-(4-(trifluoromethyl)phenyl)prop-2-en-1-one comprises the following steps:

[0076] (1) 1-Trifluoromethyl-4-(3,3,3-trifluoropropyl-1-en-2-yl)benzene 1 g (0.3 mmol), pyrrolidine 2a (0.9 mmol), water 3a (3 mmol), potassium tert-butoxide (0.9 mmol), bis(triphenylphosphine)nickel dichloride (3 mol%), and acetonitrile (30 mmol) were added to a dry test tube in a molar ratio of 1:3:10:3:0.03:100;

[0077] (2) sealing the test tube and stirring the mixture under heating to 60° C. for 2 hours; after the reaction is completed, removing the solvent by distillation under reduced pressure to obtain a crude reaction product;

[0078] (3) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:3) to obtain 4 g of the compound 1-(pyrrolidin-1-yl)-2-(4-(trifluoromethyl)phenyl)prop-2-en-1-one in a yield of 59%.

[0079] The reaction equation is as follows:

[0080]

[0081] The NMR spectrum characterization data of the product are as follows: 1 HNMR (600MHz, CDCl3) δ7.58 (d, J=8.4Hz, 2H), 7.54 (d, J=8.3Hz, 2H), 5.79 (s, 1H), 5.52 (s , 1H), 3.58 (t, J=7.0Hz, 2H), 3.20 (t, J=6.7Hz, 2H), 1.92–1.86 (m, 2H), 1.85–1.78 (m, 2H); 13 CNMR (151MHz, CDCl3) δ168.43, 145.15, 139.23, 130.34 (q, J=32.6Hz), 126.37, 125.81 ( q, J=3.7Hz), 125.05–121.25(m), 116.92, 48.30, 45.65, 26.04, 24.47; HRMS (ESI): calcd for C 14 H 15 F3NO[(M+H) + ]: 270.1105, found270.1008.

[0082] Example 8

[0083] The preparation of 2-(4-fluorophenyl)-1-(pyrrolidin-1-yl)prop-2-en-1-one 4h comprises the following steps:

[0084] (1) 1-Fluoro-4-(3,3,3-trifluoropropyl-1-en-2-yl)benzene 1h (0.3 mmol), pyrrolidine 2a (0.9 mmol), water 3a (3 mmol), sodium tert-butoxide (0.9 mmol), bis(triphenylphosphine)nickel dichloride (3 mol%), and tetrahydrofuran (30 mmol) were added to a dry test tube in a molar ratio of 1:3:10:3:0.03:100.

[0085] (2) The test tube was sealed and the mixture was stirred for 2 hours under the condition of heating to 60° C.; after the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a crude reaction product.

[0086] (3) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:10) to obtain the compound 2-(4-fluorophenyl)-1-(pyrrolidin-1-yl)prop-2-en-1-one 4h with a yield of 50%.

[0087] The reaction equation is as follows:

[0088]

[0089] The NMR spectrum characterization data of the product are as follows: 1 HNMR (600MHz, CDCl3) δ7.39 (dd, J=8.7, 5.4Hz, 2H), 7.01 (t, J=8.6Hz, 2H), 5.63 (s, 1H), 5.37 (s, 1H), 3.56 (t, J=7.0Hz, 2H), 3.20 (t, J=6.7Hz, 2H), 1.91–1.85 (m, 2H), 1.83–1.77 (m, 2H); 13 CNMR (151MHz, CDCl3) δ169.07, 162.88 (d, J=248.2Hz), 145.21, 131.84 (d, J=3.3Hz), 127.81 (d, J=8. 2Hz), 115.80 (d, J=21.7Hz), 114.47 (d, J=1.5Hz), 48.26, 45.59, 26.06, 24.52; HRMS (ESI): calcdforC 13 H 15 FNO[(M+H) + ]: 220.1137, found 220.1144.

[0090] Example 9

[0091] The preparation of 4-(3-oxo-3-(pyrrolidin-1-yl)prop-1-en-2-yl)benzonitrile 4i comprises the following steps:

[0092] (1) 4-(3,3,3-Trifluoropropyl-1-en-2-yl)benzonitrile 1i (0.3 mmol), pyrrolidine 2a (0.9 mmol), water 3a (3 mmol), sodium tert-butoxide (0.9 mmol), triphenylphosphine rhodium chloride (3 mol%), and dimethyl sulfoxide (15 mmol) were added to a dry test tube in a molar ratio of 1:3:10:3:0.03:50.

[0093] (2) The test tube was sealed and the mixture was stirred for 2 hours under the condition of heating to 60° C.; after the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a crude reaction product.

[0094] (3) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:10) to obtain compound 4-(3-oxo-3-(pyrrolidin-1-yl)prop-1-en-2-yl)benzonitrile 4i in a yield of 40%.

[0095] The reaction equation is as follows:

[0096]

[0097] The NMR spectrum characterization data of the product are as follows: 1 HNMR (600MHz, CDCl3) δ7.64 (d, J=8.3Hz, 2H), 7.54 (d, J=8.3Hz, 2H), 5.83 (s, 1H), 5.57 (s , 1H), 3.58 (t, J=7.0Hz, 2H), 3.22 (t, J=6.7Hz, 2H), 1.95–1.88 (m, 2H), 1.87–1.81 (m, 2H); 13 CNMR (151MHz, CDCl3) δ168.04, 144.81, 140.15, 132.72, 126.74, 118.72, 117.84, 112.07, 48.43, 45.73, 26.10, 24.52; HRMS (ESI): calcd forC 14 H 15 N2O[(M+H) + ]: 227.1184, found 227.1180.

[0098] Example 10

[0099] The preparation of 2-(4-chlorophenyl)-N,N-dimethylacrylamide 5a comprises the following steps:

[0100] (1) 1-Chloro-4-(3,3,3-trifluoropropyl-1-en-2-yl)benzene 1a (0.3 mmol), dimethylamine 2b (0.9 mmol), water 3a (3 mmol), sodium tert-butoxide (0.9 mmol), bis(triphenylphosphine)nickel dichloride (5 mol%), and dimethyl sulfoxide (30 mmol) were added to a dry test tube in a molar ratio of 1:3:10:3:0.05:100.

[0101] (2) The test tube was sealed and the mixture was stirred for 2 hours under the condition of heating to 60° C.; after the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a crude reaction product.

[0102] (3) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:8) to obtain compound 2-(4-chlorophenyl)-N,N-dimethylacrylamide 5a in a yield of 70%.

[0103] The reaction equation is as follows:

[0104]

[0105] The NMR spectrum characterization data of the product are as follows: 1 HNMR (600MHz, CDCl3) δ7.34 (d, J=8.8Hz, 2H), 7.30 (d, J=8.8Hz, 2H), 5.71 (s, 1H), 5.35 (s, 1H), 3.05 (s, 3H), 2.88 (s, 3H); 13 CNMR (151MHz, CDCl3) δ170.36, 144.00, 134.40, 133.98, 128.98, 126.99, 114.56, 38.52, 34.65; HRMS (ESI)calcd for C 11 H 13 ClNO[(M+H) + ]: 210.0685, found 210.0690.

[0106] Example 11

[0107] The preparation of 2-(4-chlorophenyl)-N,N-diethylacrylamide 5b comprises the following steps:

[0108] (1) 1-Chloro-4-(3,3,3-trifluoropropyl-1-en-2-yl)benzene 1a (0.3 mmol), diethylamine 2c (0.9 mmol), water 3a (3 mmol), potassium tert-butoxide (0.9 mmol), bis(triphenylphosphine)nickel dichloride (5 mol%), and N,N-dimethylformamide (30 mmol) were added to a dry test tube in a molar ratio of 1:3:10:3:0.05:100.

[0109] (2) The test tube was sealed and the mixture was stirred for 2 hours under the condition of heating to 60° C.; after the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a crude reaction product.

[0110] (3) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:8) to obtain compound 2-(4-chlorophenyl)-N,N-diethylacrylamide 5b in a yield of 65%.

[0111] The reaction equation is as follows:

[0112]

[0113] The NMR spectrum characterization data of the product are as follows: 1 HNMR (500MHz, CDCl3) δ7.30 (d, J=8.6Hz, 2H), 7.24 (d, J=8.5Hz, 2H), 5.60 (s, 1H), 5.26 (s, 1H ), 3.42 (q, J=7.1Hz, 2H), 3.14 (q, J=7.1Hz, 2H), 1.13 (t, J=7.1Hz, 3H), 0.93 (t, J=7.1Hz, 3H); 13 CNMR (126MHz, CDCl3) δ169.76, 144.30, 134.40, 134.25, 128.97, 126.95, 113.48, 42.82, 38.85, 14.06, 12.79; HRMS (ESI)calcd for C 13 H 17 ClNO[(M+H) + ]: 238.0998, found 238.0991.

[0114] Example 12

[0115] The preparation of 2-(4-chlorophenyl)-N,N-dipropylacrylamide 5c comprises the following steps:

[0116] (1) 1-Chloro-4-(3,3,3-trifluoropropyl-1-en-2-yl)benzene 1a (0.3 mmol), dipropylamine 2d (0.9 mmol), water 3a (3 mmol), potassium tert-butoxide (0.9 mmol), bis(triphenylphosphine)palladium dichloride (3 mol%), and dimethyl sulfoxide (30 mmol) were added to a dry test tube in a molar ratio of 1:3:10:3:0.03:100.

[0117] (2) The test tube was sealed and the mixture was stirred for 2 hours under the condition of heating to 60° C.; after the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a crude reaction product.

[0118] (3) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:8) to obtain compound 2-(4-chlorophenyl)-N,N-dipropylacrylamide 5c in a yield of 65%.

[0119] The reaction equation is as follows:

[0120]

[0121] The NMR spectrum characterization data of the product are as follows: 1 HNMR (600MHz, CDCl3) δ7.35 (d, J=8.7Hz, 2H), 7.30 (d, J=8.5Hz, 2H), 5.65 (s, 1H), 5.30 (s, 1H), 3.40–3.35 (m , 2H), 3.09–3.04 (m, 2H), 1.67–1.58 (m, 2H), 1.45–1.37 (m, 2H), 0.92 (t, J=7.4Hz, 3H), 0.71 (t, J=7.4Hz, 3H); 13 CNMR (151MHz, CDCl3) δ170.28, 144.55, 134.45, 134.44, 129.04, 127.05, 113.94, 50.26, 46.09, 21.95, 20.66, 11.47, 11.19; HRMS (ESI)calcd for C 15 H 21 ClNO[(M+H) + ]: 266.1311, found266.1315.

[0122] Example 13

[0123] The preparation of 2-(4-chlorophenyl)-N,N-diisopropylacrylamide 5d comprises the following steps:

[0124] (1) 1-Chloro-4-(3,3,3-trifluoropropyl-1-en-2-yl)benzene 1a (0.3 mmol), diisopropylamine 2e (0.9 mmol), water 3a (3 mmol), sodium tert-butoxide (0.9 mmol), bis(triphenylphosphine)palladium dichloride (3 mol%), and dichloromethane (60 mmol) were added to a dry test tube in a molar ratio of 1:3:10:3:0.03:200.

[0125] (2) The test tube was sealed and the mixture was stirred for 2 hours under the condition of heating to 60° C.; after the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a crude reaction product.

[0126] (3) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:6) to obtain compound 2-(4-chlorophenyl)-N,N-diisopropylacrylamide 5d in a yield of 35%.

[0127] The reaction equation is as follows:

[0128]

[0129] The NMR spectrum characterization data of the product are as follows: 1 HNMR (600MHz, CDCl3) δ7.38 (d, J=8.7Hz, 2H), 7.32 (d, J=8.7Hz, 2H), 5.60 (s, 1H), 5.26 (s, 1H), 3.93 (dt, J=13.4, 6.7Hz, 1H), 3.42 (dt, J=13.6, 6.8Hz, 1H), 1.52 (d, J=6.8Hz, 6H), 1.01 (d, J=6.7Hz, 6H); 13 CNMR (151MHz, CDCl3) δ169.71, 145.64, 134.45, 134.41, 129.05, 127.05, 112.14, 50.86, 45.76, 20.53 (d, J=3.7Hz); HRMS (ESI)calcd for C 15 H 21 ClNO[(M+H) + ]: 266.1311, found 266.1307.

[0130] Example 14

[0131] The preparation of 2-(4-chlorophenyl)-1-(piperidin-1-yl)prop-2-en-1-one 5e comprises the following steps:

[0132] (1) 1-Chloro-4-(3,3,3-trifluoropropyl-1-en-2-yl)benzene 1a (0.3 mmol), piperidine 2f (0.9 mmol), water 3a (3 mmol), potassium carbonate (0.9 mmol), bis(triphenylphosphine)palladium dichloride (3 mol%), and tetrahydrofuran (60 mmol) were added to a dry test tube in a molar ratio of 1:3:10:3:0.03:200.

[0133] (2) The test tube was sealed and the mixture was stirred for 2 hours under the condition of heating to 60° C.; after the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a crude reaction product.

[0134] (3) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:9) to obtain compound 2-(4-chlorophenyl)-1-(piperidin-1-yl)prop-2-en-1-one 5e in a yield of 56%.

[0135] The reaction equation is as follows:

[0136]

[0137] The NMR spectrum characterization data of the product are as follows: 1 HNMR (600MHz, CDCl3) δ7.35 (d, J=8.7Hz, 2H), 7.30 (d, J=8.6Hz, 2H), 5.67 (s, 1H), 5.32 (s, 1 H), 3.65 (t, J=4.8Hz, 2H), 3.29–3.24 (m, 2H), 1.59 (d, J=2.6Hz, 4H), 1.34 (d, J=4.6Hz, 2H); 13 CNMR (151MHz, CDCl3) δ168.78, 144.07, 134.46, 134.20, 129.03, 127.09, 113.94, 48.08, 42.51, 26.41, 25.68, 24.51; HRMS (ESI)calcd for C 14 H 17 ClNO[(M+H) + ]:250.0998, found 250.0992.

[0138] Example 15

[0139] The preparation of N, N-dibenzyl-2-(4-chlorophenyl)acrylamide 5f comprises the following steps:

[0140] (1) 1-Chloro-4-(3,3,3-trifluoropropyl-1-en-2-yl)benzene 1a (0.3 mmol), dibenzylamine 2 g (0.9 mmol), water 3a (3 mmol), cesium carbonate (0.9 mmol), bis(triphenylphosphine)palladium dichloride (3 mol%), and 1,4-dioxane (30 mmol) were added to a dry test tube in a molar ratio of 1:3:10:3:0.03:100.

[0141] (2) The test tube was sealed and the mixture was stirred for 2 hours under the condition of heating to 60° C.; after the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a crude reaction product.

[0142] (3) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:9) to obtain compound N,N-dibenzyl-2-(4-chlorophenyl)acrylamide 5f in a yield of 41%.

[0143] The reaction equation is as follows:

[0144]

[0145] The NMR spectrum characterization data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ7.33 (d, J=8.6Hz, 2H), 7.30–7.21 (m, 8H), 7.18 (d, J=5.0Hz , 2H), 6.99 (d, J=7.1Hz, 2H), 5.63 (s, 1H), 5.41 (s, 1H), 4.56 (s, 2H), 4.24 (s, 2H); 13 C NMR (151MHz, CDCl3) δ170.89, 143.83, 136.80, 136.04, 134.76, 134.30, 129.20, 128.96, 128.84, 128.72, 127.90, 127.81, 127.28, 127.19, 114.92, 50.93, 46.42; HRMS(ESI)calcd for C 23 H 21 ClNO[(M+H) + ]: 362.1311, found 362.1306.

[0146] Example 16

[0147] The preparation of 5 g of N-benzyl-2-(4-chlorophenyl)-N-methylacrylamide comprises the following steps:

[0148] (1) 1-Chloro-4-(3,3,3-trifluoropropyl-1-en-2-yl)benzene 1a (0.3 mmol), N-methyl-1-phenylmethanamine 2h (0.9 mmol), water 3a (3 mmol), sodium tert-butoxide (0.9 mmol), bis(triphenylphosphine)palladium dichloride (5 mol%), and dimethyl sulfoxide (30 mmol) were added to a dry test tube in a molar ratio of 1:3:10:3:0.05:100.

[0149] (2) The test tube was sealed and the mixture was stirred for 2 hours under the condition of heating to 60° C.; after the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a crude reaction product.

[0150] (3) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:5) to obtain 5 g of the compound N-benzyl-2-(4-chlorophenyl)-N-methylacrylamide with a yield of 55%.

[0151] The reaction equation is as follows:

[0152]

[0153] The NMR spectrum characterization data of the product are as follows: 1 HNMR (600MHz, CDCl3) δ7.35–7.17 (m, 8H), 6.99 (d, J=7.3Hz, 1H), 5.65 (d, J=22.9H z, 1H), 5.35 (d, J=23.4Hz, 1H), 4.49 (d, J=168.4Hz, 2H), 2.80 (d, J=112.5Hz, 3H); 13 CNMR (151MHz, CDCl3) δ170.66 (d, J=57.8Hz), 143.92 (d, J=35.8Hz), 136.48 (d, J =105.0Hz), 134.59 (d, J = 17.9Hz), 134.11 (d, J = 19.3Hz), 129.11 (d, J = 2.5Hz), 12 8.82(d, J=10.5Hz), 128.28, 127.74(d, J=16.7Hz), 127.37–126.82(m), 114.78( d, J=23.8Hz), 52.37 (d, J=637.3Hz), 34.22 (d, J=537.6Hz); HRMS (ESI): calcdfor C 17 H 17 ClNO[(M+H) + ]: 286.0998, found 286.0993.

[0154] Example 17

[0155] The preparation of 2-(4-chlorophenyl)-N-cyclohexyl acrylamide 5h comprises the following steps:

[0156] (1) 1-Chloro-4-(3,3,3-trifluoropropyl-1-en-2-yl)benzene 1a (0.3 mmol), cyclohexylamine 2i (0.9 mmol), water 3a (3 mmol), sodium tert-butoxide (0.9 mmol), bis(triphenylphosphine)nickel dichloride (3 mol%), and acetonitrile (30 mmol) were added to a dry test tube in a molar ratio of 1:3:10:3:0.03:100.

[0157] (2) The test tube was sealed and the mixture was stirred for 2 hours under the condition of heating to 60° C.; after the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a crude reaction product.

[0158] (3) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:5) to obtain the compound 2-(4-chlorophenyl)-N-cyclohexyl acrylamide 5h with a yield of 40%.

[0159] The reaction equation is as follows:

[0160]

[0161] The NMR spectrum characterization data of the product are as follows: 1 HNMR (600MHz, CDCl3) δ7.34 (d, J=8.8Hz, 2H), 7.31 (d, J=8.7Hz, 2H), 6.02 (d, J=0.9Hz, 1H), 5.60 (d, J=0.8Hz, 1H), 5.53 (s, 1H) , 3.92–3.82 (m, 1H), 1.97–1.88 (m, 2H), 1.72–1.54 (m, 3H), 1.36 (qt, J=14.0, 5.3Hz, 2H), 1.11 (ddd, J=26.0, 12.0, 4.7Hz, 3H); 13 CNMR (151MHz, CDCl3) δ166.39, 144.28, 135.49, 134.61, 129.39, 128.97, 121.55, 48.68, 33.06, 25.55, 24.89; HRMS (ESI): calcd for C 15 H 19 ClNO[(M+H) + ]:264.1155found 264.1162.

[0162] Example 18

[0163] The preparation of N-(tert-butyl)-2-(4-chlorophenyl)acrylamide 5i comprises the following steps:

[0164] (1) 1-Chloro-4-(3,3,3-trifluoropropyl-1-en-2-yl)benzene 1a (0.3 mmol), 2-methylpropane-2-amine 2j (0.9 mmol), water 3a (3 mmol), potassium tert-butoxide (0.9 mmol), bis(triphenylphosphine)nickel dichloride (3 mol%), and dimethyl sulfoxide (30 mmol) were added to a dry test tube in a molar ratio of 1:3:10:3:0.03:100.

[0165] (2) The test tube was sealed and the mixture was stirred for 2 hours under the condition of heating to 60° C.; after the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a crude reaction product.

[0166] (3) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:5) to obtain compound N-(tert-butyl)-2-(4-chlorophenyl)acrylamide 5i in a yield of 45%.

[0167] The reaction equation is as follows:

[0168]

[0169] The NMR spectrum characterization data of the product are as follows: 1 HNMR (600MHz, CDCl3) δ7.34–7.30 (m, 4H), 5.95 (d, J=0.8Hz, 1H), 5.55 (d, J=0.9Hz, 1H), 5.53 (s, 1H), 1.37 (s, 9H); 13 CNMR (151MHz, CDCl3) δ166.79, 145.08, 135.63, 134.48, 129.28, 128.90, 120.79, 51.76, 28.75; HRMS (ESI): calcdfor C 13 H 17 ClNO[(M+H) + ]: 238.0998, found 238.0992.

[0170] The acrylamide compounds prepared in Examples 1-18 can be used to prepare hydrogels and molecular probes. Hydrogels with different properties can be used to manufacture water-retaining materials in agriculture, water-blocking agents in industry, and as drug carriers in biopharmaceuticals. Chemically modified, these acrylamide compounds can be synthesized into multifunctional molecular probes for use as biomarkers or imaging agents. Products prepared from these acrylamide compounds exhibit long lifespans and high activity.

Claims

1. A method for preparing an acrylamide compound, characterized in that: α-Trifluoromethylstyrene, aliphatic amine, water, a base, and a catalyst are added to a solvent to obtain a reaction system, and the reaction is carried out under heating to 60°C for 2 hours. The solvent is removed by distillation under reduced pressure, and then the product is separated and purified by column chromatography to obtain an acrylamide compound. The molar ratio of α-trifluoromethylstyrene, fatty amine, water, base, catalyst and solvent is 1:(3-4):10:3:(0.03-0.05):(50-200); The prepared acrylamide compound has the structural formula shown in Formula I Where: R 1 is one of H, Me, OMe, CF3, F, Cl, and CN; R 2 is one of H, Me, Et, n-Pr, i-Pr, and Bn; R 3 is one of Me, Et, n-Pr, i-Pr, Cy, Bn, and t-Bu; The structural formula of α-trifluoromethylstyrene is shown in Formula II: Where: R 1 is one of H, Me, OMe, CF3, F, Cl, and CN; The structural formula of the fatty amine is shown in Formula III: Where: R 1 is one of H, Me, Et, n-Pr, i-Pr, and Bn; R 2 is one of Me, Et, n-Pr, i-Pr, Cy, Bn, and t-Bu; The base is one of cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium acetate, and sodium fluoride; The catalyst is one of bis(triphenylphosphine)palladium chloride, bis(triphenylphosphine)nickel dichloride and triphenylphosphine rhodium chloride.

2. The method for preparing acrylamide compounds according to claim 1, wherein: The column chromatography separation and purification conditions are as follows: silica gel column chromatography, an eluent of ethyl acetate:petroleum ether, a volume ratio of 1:3 to 1:

20.

3. The method for preparing acrylamide compounds according to claim 1, wherein: The solvent is one of acetonitrile, 1,4-dioxane, tetrahydrofuran, dichloromethane, N,N-dimethylformamide or dimethyl sulfoxide.

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