Synthesis method of N, N-dimethyl-3-phenyl-4-(2-thienyl) butyramide compound

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of an N, N-dimethyl-3-phenyl-4-(2-thienyl) butyramide compound. The preparation method comprises the following steps: mixing an N, N-dimethyl cinnamamide compound as shown in a formula 1 and a 2-methylthiophene compound as shown in a formula 2 with an organic solvent (N, N-dimethyl formamide) in the presence of a catalytic amount of lithium bis (trimethylsilyl) amide and cesium bis (trimethylsilyl) amino, and reacting to synthesize the N, N-dimethyl cinnamamide compound as shown in a formula 3. The structural formula of the N, N-dimethyl-3-phenyl-4-(thiophene-2-yl) butyramide compound is shown in the specification. According to the invention, a catalytic amount of Bronsted base (LiN (SiMe3) 2 / CsN (SiMe3) 2) is adopted to realize the 1, 4-addition reaction of extremely weak acidic benzyl C (sp3)-H bond of 2-methylthiophene and N, N-dimethyl cinnamamide, and the alkali metal catalyst shows obvious selectivity.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing N,N-dimethyl-3-phenyl-4-(2-thienyl)butanamide compounds. Background Art

[0002] The conjugate addition reaction of nucleophiles to electron-deficient olefins is one of the most important methods for achieving CH bond functionalization. By introducing thiophene derivatives into more complex organic molecules, compounds with pharmacological activity or other practical uses can be obtained. Amides and their derivatives, as a class of organic compounds with various biological activities, are widely used in medicine. Since α, β-unsaturated amides are carboxylic acid derivatives with the least electron deficiency, the carbon double bond therein has the lowest reactivity to nucleophilic addition, and therefore they are rarely used to catalyze asymmetric conjugate addition reactions. The present invention uses a catalytic amount of Bronsted base (LiN(SiMe 3 ) 2 / CsN(SiMe 3 ) 2 ) realized the extremely weak acidity of 2-methylthiophene benzyl C(sp 3 )-H bond to N,N-dimethylcinnamamide 1,4-addition reaction products, alkali metal catalysts show obvious selectivity. Summary of the invention

[0003] The present invention provides a reaction for synthesizing a variety of N,N-dimethyl-3-phenyl-4-(2-thienyl)butanamide compounds with biological activity and medicinal value from N,N-dimethylcinnamamide compounds and 2-methylthiophene compounds. The synthesis method is convenient and efficient. The specific scheme is as follows:

[0004]

[0005] A method for synthesizing N,N-dimethyl-3-phenyl-4-(2-thienyl)butanamides, comprising mixing an N,N-dimethylcinnamamide compound shown in Formula 1 and a 2-methylthiophene compound shown in Formula 2 with an organic solvent in the presence of a Bronsted base to react and synthesize an N,N-dimethyl-3-phenyl-4-(2-thienyl)butanamide compound shown in Formula 3;

[0006] Where R 1 is selected from phenyl, 4-methoxyphenyl, 4-fluorophenyl, benzo[d][1,3]dioxolane, thiophene, furan, R 2 Selected from hydrogen, methyl, thiophene.

[0007] The method of the present invention uses a catalytic amount of Bronsted base (LiN (SiMe 3 ) 2 / CsN(SiMe3 ) 2 ) realizes the one-pot synthesis of butyramide compounds, reduces the reaction steps, and thus can improve the product yield; the N, N-dimethylcinnamamide compounds and 2-methylthiophene compounds used in the synthesis method are convenient and economical; R in the present invention 1 , R 2 There are many options for wider applicability.

[0008] Preferably, the reaction is carried out under the protection of an inert gas, and preferably, the inert gas is nitrogen.

[0009] Preferably, the Brønsted base is lithium bis(trimethylsilyl)amide (LiN(SiMe 3 ) 2 ) and cesium bis(trimethylsilyl)amide (CsN(SiMe 3 ) 2 ), while CsN(SiMe 3 ) 2 Can be made by LiN(SiMe 3 ) 2 It was obtained by the method of exchange with cesium salt (O′Hara, CT et al, Inorg. Chem. 2016, 55, 5719).

[0010] Preferably, the organic solvent is N,N-dimethylformamide.

[0011] Preferably, in the reaction, the ratio of N,N-dimethylcinnamamide shown in Formula 1, 2-methylthiophene shown in Formula 2 and Bronsted base is 1:1 to 5:64.5; and the reaction temperature is 110°C.

[0012] Preferably, the method of the present invention can be used to synthesize N,N-dimethyl-3-phenyl-4-(2-thienyl)butanamide compounds of the following structure:

[0013]

[0014]

[0015] N, N-dimethylcinnamamide compounds and 2-methylthiophene compounds are used in the presence of a catalytic amount of Bronsted base (LiN(SiMe 3 ) 2 / CsN(SiMe 3 ) 2 ) in the presence of , and mixed with an organic solvent (N, N-dimethylformamide) to react, and finally synthesize N, N-dimethyl-3-phenyl-4-(2-thienyl)butanamide compounds.

[0016] The technical solution of the present invention can achieve at least one of the following beneficial effects:

[0017] The raw materials used in the synthesis method of the present invention are cheap and readily available;

[0018] The synthesis method of the present invention does not use transition metal catalysts and is green and environmentally friendly;

[0019] The present invention adopts a one-pot synthesis method, which reduces the loss of raw materials and improves the yield of the product due to fewer reaction steps;

[0020] The operation steps required by the present invention are relatively simple, and no extreme heating or cooling is required. The reaction can be performed at normal pressure, which is safe and convenient.

[0021] In the present invention, R 1 , R 2 There are many options, so the method of the present invention has wider applicability and can synthesize a variety of butanamide compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The accompanying drawings are hydrogen and carbon nuclear magnetic resonance spectra of the products of each embodiment. The serial numbers of the accompanying drawings correspond to the serial numbers of the embodiments. Figure A is a hydrogen nuclear magnetic resonance spectrum, and Figure B is a carbon nuclear magnetic resonance spectrum. Figure 1A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 1, Figure 1B The carbon nuclear magnetic resonance spectrum of the product obtained in Example 1; Figure 2A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 2, Figure 2B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 2; Figure 3A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 3, Figure 3B The carbon nuclear magnetic resonance spectrum of the product obtained in Example 3; Figure 4A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 4, Figure 4B The carbon nuclear magnetic resonance spectrum of the product obtained in Example 4; Figure 5A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 5, Figure 5B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 5; Fig. 6A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 6, Figure 6B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 6; Fig. 7A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 7, Figure 7B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 7; Fig. 8A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 8, Figure 8B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 8; Fig. 9A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 9, Fig. 9B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 9; Fig. 10A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 10, Fig. 10B The carbon nuclear magnetic resonance spectrum of the product obtained in Example 10 is shown in FIG. Specific embodiments

[0023] In order to facilitate the understanding of those skilled in the art, the concept of the present invention is further described below in conjunction with the embodiments. The specific description of the following embodiments is not a limitation of the present invention, but is only for the convenience of those skilled in the art to understand the technical solution. Various raw materials involved in the specification are purchased from the market, or through simple synthesis, other drugs are purchased from Anaiji, Bi De, Sigma-Aldrich, Acros, Alfa Aesar, Adamas-beta or J&K., and the nuclear magnetic resonance spectrometer model is Bruker 400M.

[0024] Example 1

[0025] In a glove box filled with nitrogen, LiN(SiMe 3 ) 2 (1.7 mg, 0.01 mmol), CsN(SiMe 3 ) 2 (2.9 mg, 0.01 mmol), N, N-dimethylcinnamamide (17.5 mg, 0.1 mmol), 2-methylthiophene (0.05 mL, 0.5 mmol) and DMF (0.6 mL) were added, the microwave tube was sealed with a lid, and it was taken out of the glove box. The reaction mixture was heated in an oil bath at 110 ° C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then three drops of water were slowly added to quench the reaction. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3 x 1 mL), and the combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluted with petroleum ether: ethyl acetate = 5: 1) to give the product (22.4 mg, 82% yield) as a yellow solid. 1 H NMR (400 MHz, CHCl 3 )δ: 7.28-7.23 (m, 2H), 7.23-7.13 (m, 3H), 7.01dd, J=5.2, 1.2Hz, 1H), 6.81 (dd, J=5.1, 3.4Hz, 1H), 6.67-6.62 (m, 1H) , 3.60-3.48 (m, 1H), 3.27 (dd, J=14.7, 6.5Hz, 1H), 3.19-3.09 (m, 1H), 2.82 (d, J=14.3Hz, 6H), 2.65 (d, J=7.0Hz, 2H).13 C NMR (101 MHz, CDCl 3 )δ: 171.1, 143.6, 142.2, 128.2, 127.5, 126.4, 126.3, 125.4, 123.2, 43.9, 38.9, 37.0, 36.0, 35.2ppm.

[0026] The raw materials in Example 1 were changed, and the following 10 groups of experimental examples were designed, wherein the first group of experiments was Example 1, and the corresponding nuclear magnetic resonance spectrum of the product was shown in Figure 1. The serial numbers of the nuclear magnetic resonance spectra of the remaining groups 2-10 of products correspond to the serial numbers of the corresponding examples.

[0027] The table lists the structural formulas of the products in Examples 1-10, the last column lists the yields of the products in each Example, and indicates the specific implementation conditions of each Example. The specific meanings of the implementation conditions of each Example are shown below the table.

[0028]

[0029] Example 2

[0030] In a glove box filled with nitrogen, LiN(SiMe 3 ) 2 (1.7 mg, 0.01 mmol), CsN(SiMe 3 ) 2 (2.9 mg, 0.01 mmol), 3-(4-methoxyphenyl)-N,N-dimethylacrylamide (20.6 mg, 0.1 mmol), 2-methylthiophene (0.05 mL, 0.5 mmol) and DMF (0.6 mL) were added, the microwave tube was sealed with a lid, and it was taken out of the glove box. The reaction mixture was heated in an oil bath at 110 ° C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then three drops of water were slowly added to quench the reaction. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3 x 1 mL), and the combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluted with petroleum ether: ethyl acetate = 5: 1) to give the product (20.6 mg, 68% yield) as a yellow solid. 1 HNMR (400 MHz, CHCl 3)δ: 7.13-7.09 (m, 2H), 7.03 (d, J=4.0Hz, 1H), 6.83-6.79 (m, 3H), 6.67-6.64 (m, 1H), 3.76 (s, 3H), 3.53-3.45 (m, 1H), 3.25 (dd, J=14.7, 6.4Hz, 1H), 3.11 (dd, J=14.7, 8.4Hz, 1H), 2.84 (d, J=10.9Hz, 6H), 2.62 (d, J=7.0Hz, 2H). 13 C{ 1 H}NMR (101 MHz, CDCl 3 )δ: 171.5, 158.3, 142.6, 135.9, 128.7, 126.6, 125.6, 123.5, 113.8, 55.3, 43.4, 39.4, 37.3, 36.5, 35.5ppm.

[0031] Example 3

[0032] In a glove box filled with nitrogen, LiN(SiMe 3 ) 2 (2.1mg, 0.0125mmol), CsN (SiMe 3 ) 2 (3.6 mg, 0.0125 mmol), 3-(benzo[d][1,3]dioxolan-5-yl)-N,N-dimethylacrylamide (21.9 mg, 0.1 mmol), 2-methylthiophene (0.05 mL, 0.5 mmol) and DMF (0.6 mL) were added, the microwave tube was sealed with a lid, and it was taken out of the glove box. The reaction mixture was heated in an oil bath at 110 ° C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then three drops of water were slowly added to quench the reaction. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3 x 1 mL), and the combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluted with petroleum ether: ethyl acetate = 5: 1) to give the product (23.8 mg, 75% yield) as a yellow solid. 1 H NMR (400 MHz, CHCl 3)δ: 7.07-6.99 (m, 1H), 6.82 (dd, J = 5.1, 3.4Hz, 1H), 6.73-6.60 (m, 4H), 5.88 (s, 2H), 3.51-3.39 (m, 1 H), 3.20 (dd, J=14.7, 6.5Hz, 1H), 3.06 (dd, J=14.7, 8.4Hz, 1H), 2.86 (s, 6H), 2.59 (d, J=7.0Hz, 2H). 13 C{ 1 H}NMR (101 MHz, CDCl 3 )δ: 171.1, 147.5, 146.0, 142.2, 137.6, 126.4, 125.4, 123.4, 120.7, 108.1, 107.8, 100.7, 43.7, 39.2, 37.2, 36.4, 35.4ppm.

[0033] Example 4

[0034] In a glove box filled with nitrogen, LiN(SiMe 3 ) 2 (1.7 mg, 0.01 mmol), CsN(SiMe 3 ) 2 (2.9 mg, 0.01 mmol), 3-(4-fluorophenyl)-N, N-dimethylacrylamide (19.3 mg, 0.1 mmol), 2-methylthiophene (0.05 mL, 0.5 mmol) and DMF (0.6 mL) were added, the microwave tube was sealed with a lid, and it was taken out of the glove box. The reaction mixture was heated in an oil bath at 110 ° C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then three drops of water were slowly added to quench the reaction. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3x1 mL), and the combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluted with petroleum ether: ethyl acetate = 5: 1) to give the product (22.4 mg, 82% yield) as a white solid. 1 HNMR (400 MHz, CHCl 3)δ: 7.27-7.18 (m, 1H), 7.04 (dd, J=5.1, 1.2Hz, 1H), 6.98 (d, J=7.7Hz, 1H), 6.92-6.81 (m, 3H), 6.68-6.63 (m, 1H), 3 .63-3.51 (m, 1H), 3.25 (dd, J=14.7, 6.6Hz, 1H), 3.11 (dd, J=14.6, 8.2Hz, 1H), 2.87 (s, 6H), 2.64 (d, J=6.9Hz, 2H).1 3 C{ 1 H}NMR (101 MHz, CDCl 3 )δ: 170.7, 163.9, 161.5, 146.5 (d, J=6.8Hz), 141.7, 129.7 (d, J=8.2Hz), 126.5, 125.5, 123. 5, 114.3 (d, J = 21.2Hz), 113.3 (d, J = 21.0Hz), 43.7 (d, J = 1.9Hz), 38.6, 37.0, 36.1, 35.3ppm.

[0035] Example 5

[0036] In a glove box filled with nitrogen, LiN(SiMe 3 ) 2 (4.3mg, 0.025mmol), CsN(SiMe 3 ) 2 (7.3 mg, 0.025 mmol), 3-(1-naphthylphenyl)-N,N-dimethylacrylamide (22.5 mg, 0.1 mmol), 2-methylthiophene (0.05 mL, 0.5 mmol) and DMF (0.6 mL) were added, the microwave tube was sealed with a lid, and it was taken out of the glove box. The reaction mixture was heated in an oil bath at 110 ° C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then three drops of water were slowly added to quench the reaction. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3 x 1 mL), and the combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluted with petroleum ether: ethyl acetate = 5: 1) to give the product (13.9 mg, 43% yield) as a yellow solid. 1 HNMR (400 MHz, CHCl 3)δ: 8.12 (d, J=8.5Hz, 1H), 7.70 (d, J=8.1Hz, 1H), 7.58 (d, J=8.0Hz, 1H), 7.41-7.36 (m, 1H), 7.34-7.23 (m, 3H), 6.85 (d, J=5 .0Hz, 1H), 6.68-6.61(m, 1H), 6.57-δ.52(m, 1H), 4.42(p, J=7.0Hz, 1H), 3.31-3.22(m, 2H), 2.69(s, 3H), 2.66-2.58(m, 5H). 13 CNMR (101MHz, CDCl 3 )δ: 171.1, 142.0, 139.8, 133.8, 131.6, 128.6, 126.9, 126.3, 125.9, 125.5, 125.3, 125.0, 123.2, 123.0, 38.3, 37.4, 36.9, 35.2.

[0037] Example 6

[0038] In a glove box filled with nitrogen, LiN(SiMe 3 ) 2 (3.4 mg, 0.02 mmol), CsN(SiMe 3 ) 2 (5.8 mg, 0.02 mmol), 3-thienyl-N, N-dimethylacrylamide (18.1 mg, 0.1 mmol), 2-methylthiophene (0.05 mL, 0.5 mmol) and DMF (0.6 mL) were added, the microwave tube was sealed with a lid, and it was taken out of the glove box. The reaction mixture was heated in an oil bath at 110 ° C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then three drops of water were slowly added to quench the reaction. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3 x 1 mL), and the combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluted with petroleum ether: ethyl acetate = 5: 1) to give the product (19.0 mg, 68% yield) as a yellow solid. 1 HNMR (400 MHz, CHCl 3)δ: 7.05 (dd, J=5.1, 1.2Hz, 1H), 6.99 (dd, J=5.2, 1.2Hz, 1H), 6.79 (ddd, J=13.5, 5.1, 3.4Hz, 2H), 6.72 (d, J=3.5Hz, 1H), 6.66-6.62 (m, 1H), 3.88-3.76 (m, 1H), 3.23 (dd, J=15.0, 5.9Hz, 1H), 3.10 (dd, J=14.6, 7.9Hz, 1H), 2.81 (d, J=8.7Hz, 6H), 2.60 (dd, J=6.8, 2.5Hz, 2H). 13 C{ 1 H}NMR (101 MHz, CDCl 3 )δ: 170.7, 147.4, 141.6, 126.5, 126.4, 125.7, 124.3, 123.6, 123.1, 39.6, 39.3, 37.2, 37.1, 35.4ppm.

[0039] Example 7

[0040] In a glove box filled with nitrogen, LiN(SiMe 3 ) 2 (4.3mg, 0.025mmol), CsN(SiMe 3 ) 2 (7.3 mg, 0.025 mmol), 3-furan-2-yl-N, N-dimethylacrylamide (16.5 mg, 0.1 mmol), 2-methylthiophene (0.05 mL, 0.5 mmol) and DMF (0.6 mL) were added, the microwave tube was sealed with a lid, and it was taken out of the glove box. The reaction mixture was heated in an oil bath at 110 ° C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then three drops of water were slowly added to quench the reaction. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3 x 1 mL), and the combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluted with petroleum ether: ethyl acetate = 5: 1) to give the product (14.2 mg, 54% yield) as a yellow solid. 1 HNMR (400 MHz, CHCl 3)δ: 7.39-7.30(m, 1H), 7.11-7.03(m, 1H), 6.90-6.81(m, 1H), 6.67(s, 1H), 6.35-6.20(m, 1H), 5.98(s, 1H), 3.70-3 .61 (m, 1H), 3.27-3.19 (m, 2H), 2.90 (d, J=10.0Hz, 6H), 2.70 (dd, J=15.5, 6.9Hz, 1H), 2.57 (dd, J=16.2, 6.2Hz, 1H). 13 C NMR (101 MHz, CDCl 3 )δ: 170.9, 156.4, 141.6, 141.0, 126.6, 125.6, 123.6, 110.2, 106.1, 37.5, 37.1, 36.2, 35.4, 33.7.

[0041] Example 8

[0042] In a glove box filled with nitrogen, LiN(SiMe 3 ) 2 (1.7 mg, 0.01 mmol), CsN(SiMe 3 ) 2 (2.9 mg, 0.01 mmol), N,N-dimethylcinnamamide (17.5 mg, 0.1 mmol), 2,5-dimethylthiophene (0.05 mL, 0.44 mmol) and DMF (0.6 mL), seal the microwave tube with a lid, and remove it from the glove box. The reaction mixture was heated in an oil bath at 110 ° C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then three drops of water were slowly added to quench the reaction. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3x1 mL), and the combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluted with petroleum ether: ethyl acetate = 5: 1) to give the product (22.4 mg, 78% yield) as a yellow solid. 1 H NMR (400 MHz, CHCl 3 )δ: 7.34-7.22 (m, 2H), 7.25-7.15 (m, 3H), 6.49-6.41 (m, 2H), 3.51 (p, J=7.2Hz, 1H), 3.17 (dd, J=14.7, 6.8Hz, 1H ), 3.08 (dd, J=14.7, 7.9Hz, 1H), 2.84 (d, J=10.6Hz, 6H), 2.65 (dd, J=7.0, 1.8Hz, 2H), 2.37 (d, J=1.0Hz, 3H)ppm. 13 C{1 H}NMR (101 MHz, CDCl 3 )δ: 171.3, 144.0, 140.1, 137.8, 128.3, 127.7, 126.5, 125.3, 124.5, 44.0, 39.0, 37.2, 36.4, 35.4, 15.2ppm.

[0043] Example 9

[0044] In a glove box filled with nitrogen, LiN(SiMe 3 ) 2 (1.7 mg, 0.01 mmol), CsN(SiMe 3 ) 2 (2.9 mg, 0.01 mmol), N,N-dimethylcinnamamide (17.5 mg, 0.1 mmol), 2,3-dimethyl (0.05 mL, 0.45 mmol) and DMF (0.6 mL), seal the microwave tube with a lid and remove it from the glove box. The reaction mixture was heated in an oil bath at 110 ° C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then three drops of water were slowly added to quench the reaction. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3 x 1 mL), and the combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluted with petroleum ether: ethyl acetate = 5: 1) to give the product (12.9 mg, 45% yield) as a white solid. 1 H NMR (400 MHz, CHCl 3 )δ: 7.28-7.16 (m, 5H), 6.95 (d, J=5.1Hz, 1H), 6.69 (d, J=5.1Hz, 1H), 3.54-3.44 (m, 1H), 3.19 (dd, J=14.6, 6.5Hz, 1H), 2.99 (dd, J=14.6, 8.2Hz, 1H), 2.88 (d, J=4.5Hz, 6H), 2.69 (dd, J=7.0, 3.4Hz, 2H), 2.00 (s, 3H). 13 C{ 1 H}NMR (101 MHz, CDCl 3 )δ171.3, 143.9, 135.5, 133.8, 129.6, 128.3, 127.6, 126.5, 121.6, 43.7, 38.8, 37.2, 35.4, 34.5, 13.5ppm.

[0045] Example 10

[0046] In a glove box filled with nitrogen, LiN(SiMe 3 ) 2 (1.7 mg, 0.01 mmol), CsN(SiMe 3 ) 2 (2.9 mg, 0.01 mmol), N,N-dimethylcinnamamide (17.5 mg, 0.1 mmol), 5-methyl-2,2'-thiophene (18.0 mg, 0.1 mmol) and DMF (0.6 mL) were added, the microwave tube was sealed with a lid, and it was taken out of the glove box. The reaction mixture was heated in an oil bath at 110 ° C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then three drops of water were slowly added to quench the reaction. The reaction mixture was passed through a short pad of silica and washed with an additional 3 mL of ethyl acetate (3x1 mL), and the combined solution was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column (eluted with petroleum ether: ethyl acetate = 5: 1) to give the product (28.4 mg, 80% yield) as a white solid. 1 H NMR (400 MHz, CHCl 3 )δ: 7.73 (d, J = 1.9 Hz, 1H), 7.49-7.38 (m, 5H), 7.29 (dd, J = 8.6, 1.9 Hz, 1H), 7.18 (d, J = 8.6 Hz, 1H), 6.47 (s, 1H), 3.68 (s, 3H) ppm. 13 C{ 1 H}NMR (101 MHz, CDCl 3 )δ: 142.6, 136.9, 132.2, 129.5, 129.3, 128.5, 128.2, 124.3, 122.8, 113.0, 111.0, 101.0, 31.2ppm.

Claims

1. A method for synthesizing N,N-dimethyl-3-phenyl-4-(2-thienyl)butanamide compounds, characterized in that: The N,N-dimethylcinnamamide compound shown in Formula 1 and the 2-methylthiophene compound shown in Formula 2 are mixed with an organic solvent in the presence of a Bronsted base to synthesize the N,N-dimethyl-3-phenyl-4-(2-thienyl)butanamide compound shown in Formula 3; the Bronsted base is lithium bis(trimethylsilyl)amide (LiN(SiMe3)2) and cesium bis(trimethylsilyl)amide (CsN(SiMe3)2), and CsN(SiMe3)2 can be obtained by exchanging LiN(SiMe3)2 with a cesium salt (O′Hara, CT et al, Inorg. Chem. 2016, 55, 5719); Where R 1 is selected from phenyl, 4-methoxyphenyl, 4-fluorophenyl, benzo[d][1,3]dioxolane, thiophene, furan, R 2 Selected from hydrogen, methyl, thiophene.

2. The synthesis method according to claim 1, characterized in that The reaction is carried out under the protection of an inert gas, wherein the inert gas is nitrogen.

3. The synthesis method according to claim 1, characterized in that The organic solvent is N,N-dimethylformamide.

4. The synthesis method according to claim 1, characterized in that In the reaction, the ratio of N,N-dimethylcinnamamide shown in formula 1, 2-methylthiophene shown in formula 2 and Bronsted base is 1:1 to 5:64.5; and the reaction temperature is 110°C.

5. The synthesis method according to claim 1, characterized in that The N,N-dimethylcinnamamide compounds, 2-methylthiophene compounds and the product N,N-dimethyl-3-phenyl-4-(2-thienyl)butanamide compounds are as shown in one of the following tables:

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