An E-type beta-methyl enamide compound and a preparation method thereof

Abstract

The application provides an E-type beta-methyl enamide compound with a structure shown in formula (I): the compound contains both a methyl group and an enamide important biological core skeleton, and has important application value in candidate drug research and development. A preparation method comprises the following steps: stirring and mixing an enamide, an organic peroxide, a catalyst and a solvent, and performing a beta-C(sp 2 )-H methylation reaction under heating to obtain the E-type beta-methyl enamide compound. The preparation method has the advantages of simple reaction operation, easy-to-obtain raw materials, high chemical selectivity and stereoselectivity, and wide substrate range.

Description

TECHNICAL FIELD

[0001] One or more embodiments of the present specification relate to the technical field of organic synthesis, and in particular, to an E-type β-methyl enamide compound and a preparation method thereof. BACKGROUND

[0002] Methyl is a ubiquitous structural unit, which is widely present in drugs and bioactive molecules. As a bioisostere of hydrogen, methyl can significantly affect the physicochemical properties, biological activities and pharmacokinetic characteristics of bioactive molecules and biological macromolecules. This "magic methyl effect" has become a frontier topic in medical research and is widely used in pharmacological research of candidate drugs. Therefore, the research on methylation reaction has attracted widespread attention. On the other hand, enamide is a key organic synthesis building block. The direct β-(sp 2 )-H functionalization reaction of enamide has made many important progress in recent years. However, the method for the direct β-(sp 2 )-H methylation reaction of enamide is still to be studied. Considering the importance of methyl and enamide structural units, it is of great significance to develop a simple and efficient method to synthesize β-methyl enamide compounds.

[0003] C-H functionalization reaction catalyzed by transition metal does not require pre-functionalization of the reaction substrate, and is an efficient, safe and simple operation synthesis method. In this context, the present application uses the method of C-H functionalization reaction catalyzed by transition metal to synthesize β-methyl enamide compounds. SUMMARY

[0004] The present application aims to solve the problems presented in the background art, and the purpose of one or more embodiments of the present specification is to propose an E-type β-methyl enamide compound and a preparation method thereof.

[0005] To achieve the above purpose, one or more embodiments of the present specification provide an E-type β-methyl enamide compound, characterized in having a structure shown in formula (I):

[0006]

[0007] wherein, R 1 is aryl or alkyl; R 2 is benzyl, substituted benzyl, methyl, acyl or tert-butyloxycarbonyl.

[0008] Preferably, the E-type β-methyl enamide compound includes:

[0009]

[0010] According to the preparation method of the embodiment of the present application, the E-type β-methyl enamide compound is prepared by the following steps:

[0011] The enamide, the organic peroxide, the catalyst and the solvent are stirred and mixed, and the β-C(sp 2 )-H methylation reaction is carried out under heating to obtain the E-type β-methyl enamide compound.

[0012] The enamide has the structure shown in formula (II):

[0013]

[0014] The organic peroxide has the structure shown in formula (III):

[0015]

[0016] More preferably, the methylation reaction is carried out under heating, the heating temperature is 60-140°C, and the reaction time of the methylation is 6-24h.

[0017] More preferably, the catalyst is any one of cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, cupric chloride, cupric oxide, cupric acetate, cupric acetate monohydrate, cupric sulfate, ferric chloride, ferrous chloride, ferrous sulfate and ferrous acetate, and the amount of the catalyst is 2-20mol%.

[0018] More preferably, the solvent is any one or a mixture of several of trifluoroethanol, methanol, ethanol, isopropanol, tert-butanol, N,N-dimethylformamide, chlorobenzene, dichloromethane, dichloroethane and water, and the volume of the solvent is 1.0-3.0mL.

[0019] More preferably, the temperature of the methylation reaction is 120°C, and the time is 18h.

[0020] More preferably, the solvent is tert-butanol, and the volume is 2.0mL.

[0021] More preferably, the molar ratio of the enamide to the organic peroxide is 1.0:(1.0-4.0).

[0022] More preferably, the enamide and the organic peroxide are used as the reaction substrates, mixed with the solvent, and then the E-type β-methyl enamide derivative is generated under the catalysis of copper or iron.

[0023] More preferably, the methylation reaction further includes separation and purification, and the separation and purification is carried out by column chromatography, liquid chromatography, distillation or recrystallization.

[0024] According to the above, the present application includes the following beneficial effects:

[0025] The present application provides a method for synthesizing E-type beta-methyl enamide compounds, which has the advantages of simple and safe operation, easy availability of raw materials, high chemical selectivity and stereoselectivity, wide substrate range, etc., and has important application value in the development of candidate drugs. BRIEF DESCRIPTION OF DRAWINGS

[0026] In order to more clearly illustrate the technical solutions in the one or more embodiments of the present specification or the prior art, the drawings needed to be used in the embodiment or prior art description will be briefly introduced below. Obviously, the drawings in the following description are only one or more embodiments of the present specification, and other drawings can also be obtained by those skilled in the art without creative labor on the basis of these drawings.

[0027] Figures 1-2 NMR hydrogen spectrum and carbon spectrum of the product prepared in Example 1 in the present application;

[0028] Figures 3-4 NMR hydrogen spectrum and carbon spectrum of the product prepared in Example 2 in the present application;

[0029] Figures 5-6 NMR hydrogen spectrum and carbon spectrum of the product prepared in Example 3 in the present application;

[0030] Figures 7-8 NMR hydrogen spectrum and carbon spectrum of the product prepared in Example 4 in the present application;

[0031] Figures 9-10 NMR hydrogen spectrum and carbon spectrum of the product prepared in Example 5 in the present application;

[0032] Figures 11-12 NMR hydrogen spectrum and carbon spectrum of the product prepared in Example 6 in the present application;

[0033] Figures 13-15 NMR hydrogen spectrum, carbon spectrum and fluorine spectrum of the product prepared in Example 7 in the present application;

[0034] Figures 16-17 NMR hydrogen spectrum and carbon spectrum of the product prepared in Example 8 in the present application;

[0035] Figures 18-19 NMR hydrogen spectrum and carbon spectrum of the product prepared in Example 9 in the present application;

[0036] Figures 20-21 NMR hydrogen spectrum and carbon spectrum of the product prepared in Example 10 in the present application;

[0037] Figures 22-23The nuclear magnetic hydrogen spectrum and carbon spectrum diagram of the product prepared in Example 11 in the application;

[0038] Figures 24-25 The nuclear magnetic hydrogen spectrum and carbon spectrum diagram of the product prepared in Example 12 in the application. DETAILED DESCRIPTION

[0039] In order to make the purpose, technical scheme and advantages of the present disclosure clearer, the present disclosure is further described in detail below in combination with specific embodiments.

[0040] One or more embodiments of the present specification provide an E-type β-methyl enamide compound having a structure shown in formula (I):

[0041]

[0042] wherein, R 1 is aryl or alkyl; R 2 is benzyl, substituted benzyl, methyl, acyl or tert-butoxycarbonyl;

[0043] As an improved scheme of the above scheme, the E-type β-methyl enamide compound comprises:

[0044]

[0045] The preparation method of the E-type β-methyl enamide compound proposed in the embodiment of the present application comprises the following steps:

[0046] The enamide, organic peroxide, catalyst and solvent are stirred and mixed, and the β-C(sp 2 )-H methylation reaction is carried out under heating conditions to obtain the E-type β-methyl enamide compound.

[0047] The enamide has a structure shown in formula (II):

[0048]

[0049] wherein, R 1 is aryl or alkyl; R 2 is benzyl, substituted benzyl, methyl, acyl or tert-butoxycarbonyl;

[0050] The organic peroxide has a structure shown in formula (III):

[0051]

[0052] As an improved scheme of the above scheme, the methylation reaction is carried out under heating conditions, the temperature of the heating is 60-140℃, and the reaction time of the methylation is 6-24h.

[0053] As an improved scheme of the above scheme, the catalyst is any one of cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, cupric chloride, cupric oxide, cupric acetate, cupric acetate monohydrate, cupric sulfate, ferric chloride, ferrous chloride, ferrous sulfate, ferrous acetate and ferrous acetate, and the amount of the catalyst is 2-20 mol%.

[0054] As an improved scheme of the above scheme, the solvent is any one or mixture of several of trifluoroethanol, methanol, ethanol, isopropanol, tert-butanol, N,N-dimethylformamide, chlorobenzene, dichloromethane, dichloroethane and water, and the volume of the solvent is 1.0-3.0 mL.

[0055] As an improved scheme of the above scheme, the temperature of the methylation reaction is 120-130℃, and the time is 18 h.

[0056] As an improved scheme of the above scheme, the solvent is tert-butanol, and the volume is 2.0 mL.

[0057] As an improved scheme of the above scheme, the molar ratio of the enamide to the organic peroxide is 1.0: (1.0-4.0).

[0058] As an improved scheme of the above scheme, the enamide and the organic peroxide are used as the reaction substrates, mixed with the solvent, and then reacted under the catalysis of copper or iron to generate the E-type β-methyl enamide compound.

[0059] In the present application, the preparation process of the E-type β-methyl enamide compound is as follows:

[0060]

[0061] As an improved scheme of the above scheme, the separation and purification method is selected from any one or more of column chromatography, liquid chromatography, distillation and recrystallization.

[0062] The present application does not have special limitations on the conditions of the preparation process of the E-type β-methyl enamide compound, and in the embodiments of the present application, the enamide and the organic peroxide are dissolved in tert-butanol, a catalyst is added at room temperature for reaction, extraction, concentration and purification are performed after the reaction is completed to obtain the E-type β-methyl enamide derivative.

[0063] Example 1

[0064] An E-type β-methyl enamide compound has the structure shown in formula I-1:

[0065]

[0066] Preparation method: take enamide compound N-benzyl-N-(1-phenylvinyl)acetamide (0.3 mmol, 75.4 mg), diisopropylbenzene peroxide (0.6 mmol, 162.2 mg), copper catalyst copper acetate monohydrate (5 mol%, 2.99 mg) or iron catalyst ferrous chloride (5 mol%, 1.9 mg), then add solvent tert-butyl alcohol (2.0 mL), stir in an oil bath at 120°C for 18 h. After the reaction is completed, pour the obtained reaction solution into 15 mL of water, extract with ethyl acetate (3×15 mL). Wash the combined organic phase with 15 mL of saturated brine, dry the organic phase with anhydrous sodium sulfate, concentrate to remove the solvent with a rotary evaporator, separate by column chromatography (the volume ratio of petroleum ether to ethyl acetate is 12:1) to obtain the target product, a light yellow liquid, the yield of copper catalysis is 80%, and the yield of iron catalysis is 76%.

[0067] The structure of the obtained product is characterized by nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum as shown in Figure 1 and Figure 2 The structure characterization data are as follows:

[0068] 1H NMR (400 MHz, CDCl3) δ 7.42-7.32 (m, 3H), 7.29-7.22 (m, 5H), 7.21-7.18 (m, 2H), 5.43 (q, J = 7.3 Hz, 1H), 4.49 (s, 2H), 2.21 (s, 3H), 1.76 (d, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.8, 139.1, 137.5, 134.6, 128.7, 128.6, 128.4, 128.3, 128.1, 127.0, 126.7, 48.9, 22.0, 14.3.

[0069] Example 2

[0070] An E-type β-methyl enamide compound has the structure shown in formula I-2:

[0071]

[0072] Preparation method: take enamide compound N-benzyl-N-(1-(p-tolyl)vinyl)acetamide (0.3 mmol, 79.6 mg), diisopropylbenzene peroxide (0.6 mmol, 162.2 mg), copper catalyst copper acetate monohydrate (5 mol%, 2.99 mg) or iron catalyst ferrous chloride (5 mol%, 1.9 mg), then add solvent tert-butanol (2.0 mL), stir in an oil bath at 120°C for 18 h. After the reaction is completed, pour the obtained reaction solution into 15 mL of water, extract with ethyl acetate (3×15 mL). Wash the combined organic phase with 15 mL of saturated brine, dry the organic phase with anhydrous sodium sulfate, concentrate to remove the solvent with a rotary evaporator, separate by column chromatography (the volume ratio of petroleum ether to ethyl acetate is 12:1) to obtain the target product, a light yellow liquid, the yield of copper catalysis is 85%, and the yield of iron catalysis is 77%.

[0073] The structure of the obtained product is characterized by nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum as shown in Figure 3 and Figure 4 The structure characterization data are as follows:

[0074] 1H NMR (400 MHz, CDCl3) δ 7.29-7.23 (m, 3H), 7.22-7.20 (m, 2H), 7.20 (s, 2H), 7.17-7.15 (m, 2H), 5.38 (q, J = 7.3 Hz, 1H), 4.48 (s, 2H), 2.38 (s, 3H), 2.20 (s, 3H), 1.76 (d, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.9, 139.1, 138.2, 137.6, 131.7, 129.1, 128.7, 128.5, 128.1, 126.9, 126.1, 48.9, 22.0, 21.1, 14.3.

[0075] Example 3

[0076] An E-type β-methyl enamide compound has the structure shown in formula I-3:

[0077]

[0078] Preparation method: take enamide compound N-benzyl-N-(1-(o-tolyl)vinyl)acetamide (0.3 mmol, 79.6 mg), diisopropylbenzene peroxide (0.6 mmol, 162.2 mg), copper catalyst copper acetate monohydrate (5 mol%, 2.99 mg) or iron catalyst ferrous chloride (5 mol%, 1.9 mg), then add solvent tert-butanol (2.0 mL), stir in an oil bath at 120°C for 18 h. After the reaction is completed, pour the obtained reaction solution into 15 mL of water, extract with ethyl acetate (3×15 mL). The combined organic phase is washed with 15 mL of saturated brine, dried with anhydrous sodium sulfate, concentrated to remove the solvent with a rotary evaporator, and separated by column chromatography (the volume ratio of petroleum ether to ethyl acetate is 12:1) to obtain the target product, a light yellow liquid, with a copper-catalyzed yield of 68% and an iron-catalyzed yield of 72%.

[0079] The structure of the obtained product is characterized by nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum as shown in Figure 5 and Figure 6 The structure characterization data are as follows:

[0080] 1H NMR (400 MHz, CDCl3) δ 7.28-7.17 (m, 7H), 7.13 (m, 3H), 5.56 (q, J = 7.1 Hz, 1H), 4.40 (s, 2H), 2.37 (s, 3H), 2.11 (s, 3H), 1.52 (d, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.9, 138.4, 137.7, 137.3, 133.8, 130.6, 129.3, 128.4, 128.1, 128.0, 126.8, 126.0, 125.8, 48.2, 22.2, 19.5, 14.2.

[0081] Example 4

[0082] An E-type β-methyl enamide compound has the structure shown in formula I-4:

[0083]

[0084] Preparation method: Take enamide compound N-(1-([1,1'-biphenyl]-4-yl)vinyl)-N- benzylacetamide (0.3 mmol, 98.2 mg), diisopropylbenzene peroxide (0.6 mmol, 162.2 mg), copper catalyst copper acetate monohydrate (5 mol%, 2.99 mg) or iron catalyst ferrous chloride (5 mol%, 1.9 mg), then add solvent tert-butanol (2.0 mL), stir in an oil bath at 120°C for 18 h. After the reaction is completed, pour the obtained reaction solution into 15 mL of water, extract with ethyl acetate (3 x 15 mL). Wash the combined organic phase with 15 mL of saturated brine, dry the organic phase with anhydrous sodium sulfate, concentrate to remove the solvent with a rotary evaporator, and separate by column chromatography (the volume ratio of petroleum ether to ethyl acetate is 12:1) to obtain the target product, a light yellow liquid, with a yield of 77% under copper catalysis and a yield of 76% under iron catalysis.

[0085] The structure of the obtained product was characterized by nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum as shown in Figure 7 and Figure 8 The structure characterization data are as follows:

[0086] 1H NMR (400 MHz, CDCl3) δ 7.65 (m, 4H), 7.48 (m, 2H), 7.38 (m, 3H), 7.32-7.24 (m, 5H), 5.49 (q, J = 7.3 Hz, 1H), 4.58 (s, 2H), 2.25 (s, 3H), 1.84 (d, J = 7.4 Hz, 3H);13C NMR (101 MHz, CDCl3) δ 170.8, 141.0, 140.0, 138.8, 137.5, 133.5, 129.6, 128.9, 128.7, 128.0, 127.5, 127.0, 127.0, 126.9, 126.8, 49.0, 22.0, 14.4.

[0087] Example 5

[0088] An E-type β-methyl enamide compound has the structure shown in formula I-5:

[0089]

[0090] Preparation method: take enamide compound N-benzyl-N-(1-(3- methoxyphenyl)vinyl)acetamide (0.3 mmol, 84.4 mg), diisopropylbenzene peroxide (0.6 mmol, 162.2 mg), copper catalyst copper acetate monohydrate (5 mol%, 2.99 mg) or iron catalyst ferrous chloride (5 mol%, 1.9 mg), then add solvent tert-butanol (2.0 mL), stir in an oil bath at 120°C for 18 h. After the reaction is completed, pour the obtained reaction solution into 15 mL of water, extract with ethyl acetate (3×15 mL). Wash the combined organic phase with 15 mL of saturated brine, dry the organic phase with anhydrous sodium sulfate, concentrate to remove the solvent with a rotary evaporator, separate by column chromatography (the volume ratio of petroleum ether to ethyl acetate is 12:1) to obtain the target product, a light yellow liquid, the yield of copper catalysis is 76%, and the yield of iron catalysis is 70%.

[0091] The structure of the obtained product was characterized by nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum as shown in Figure 9 and Figure 10 The structure characterization data are as follows:

[0092] 1H NMR (400 MHz, CDCl3) δ 7.33-7.18 (m, 7H), 6.90-6.84 (m, 2H), 6.77-6.75 (m, 1H), 5.43 (q, J = 7.3 Hz, 1H), 4.49 (s, 2H), 3.77 (s, 3H), 2.18 (s, 3H), 1.77 (d, J = 5.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.8, 159.6, 139.1, 137.6, 136.1, 129.4, 128.8, 128.1, 127.0, 126.9, 121.1, 114.4, 113.5, 55.1, 49.1, 22.0, 14.4.

[0093] Example 6

[0094] An E-type β-methyl enamide compound has the structure shown in formula I-6:

[0095]

[0096] Preparation method: Take enamide compound N-benzyl-N-(1-(2,4-dimethoxyphenyl)vinyl)acetamide (0.3 mmol, 93.4 mg), diisopropylbenzene peroxide (0.6 mmol, 162.2 mg), copper catalyst copper acetate monohydrate (5 mol%, 2.99 mg) or iron catalyst ferrous chloride (5 mol%, 1.9 mg), then add solvent tert-butanol (2.0 mL), stir in an oil bath at 120°C for 18 h. After the reaction is completed, pour the obtained reaction solution into 15 mL of water, extract with ethyl acetate (3×15 mL). Wash the combined organic phase with 15 mL of saturated brine, dry the organic phase with anhydrous sodium sulfate, concentrate to remove the solvent with a rotary evaporator, and separate by column chromatography (the volume ratio of petroleum ether to ethyl acetate is 12:1) to obtain the target product, a light yellow liquid, with a copper-catalyzed yield of 59% and an iron-catalyzed yield of 71%.

[0097] The structure of the obtained product was characterized by nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum as shown in Figure 11 and Figure 12 The structure characterization data are as follows:

[0098] 1H NMR (400 MHz, CDCl3) δ 7.20 (m, 5H), 6.93 (d, J = 8.2 Hz, 1H), 6.47-6.42 (m, 2H), 5.41 (q, J = 7.1 Hz, 1H), 4.42 (s, 2H), 3.81 (s, 3H), 3.72 (s, 3H), 2.26 (s, 3H), 1.54 (d, J = 7.1 Hz, 3H);13C NMR (101 MHz, CDCl3) δ 171.3, 161.1, 158.7, 138.1, 137.1, 132.4, 128.4, 127.9, 126.6, 126.4, 115.8, 104.0, 98.4, 55.2, 55.0, 48.2, 22.2, 14.1.

[0099] Example 7

[0100] An E-type β-methyl enamide compound has the structure shown in formula I-7:

[0101]

[0102] Preparation method: take enamide compound N-benzyl-N-(1-(4-fluorophenyl)vinyl)acetamide (0.3 mmol, 80.8 mg), diisopropylbenzene peroxide (0.6 mmol, 162.2 mg), copper catalyst copper acetate monohydrate (5 mol%, 2.99 mg) or iron catalyst ferrous chloride (5 mol%, 1.9 mg), then add solvent tert-butanol (2.0 mL), stir in an oil bath at 130°C for 18 h. After the reaction is completed, pour the obtained reaction solution into 15 mL of water, extract with ethyl acetate (3×15 mL). Wash the combined organic phase with 15 mL of saturated brine, dry the organic phase with anhydrous sodium sulfate, concentrate to remove the solvent with a rotary evaporator, and separate by column chromatography (the volume ratio of petroleum ether to ethyl acetate is 12:1) to obtain the target product, white solid, the yield of copper catalysis is 59%, and the yield of iron catalysis is 56%.

[0103] The structure of the obtained product was characterized by nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum and nuclear magnetic resonance fluorine spectrum as shown in Figure 13 、 Figure 14 and Figure 15 The structure characterization data are as follows:

[0104] 1H NMR (400 MHz, CDCl3) δ 7.26-7.19 (m, 5H), 7.19-7.14 (m, 2H), 7.07 (t, J = 8.6 Hz, 2H), 5.42 (q, J = 7.3 Hz, 1H), 4.47 (s, 2H), 2.18 (s, 3H), 1.73 (d, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.7, 162.3 (d, J = 248.8 Hz), 138.30, 137.4, 130.7 (d, J = 3.3 Hz), 130.4 (d, J = 8.2 Hz), 128.7, 128.1, 127.1, 126.7, 115.5 (d, J = 21.6 Hz), 49.0, 22.0, 14.3;19F NMR (377 MHz, CDCl3) δ -112.45.

[0105] Example 8

[0106] An E-type β-methyl enamide compound has the structure shown in formula I-8:

[0107]

[0108] Preparation method: Take enamide compound N-benzyl-N-(1-(3-bromophenyl)vinyl)acetamide (0.3 mmol, 99.06 mg), diisopropylbenzene peroxide (0.6 mmol, 162.2 mg), copper catalyst copper acetate monohydrate (5 mol%, 2.99 mg) or iron catalyst ferrous chloride (5 mol%, 1.9 mg), then add solvent tert-butanol (2.0 mL), stir in an oil bath at 120°C for 18 h. After the reaction is completed, pour the obtained reaction solution into 15 mL of water, extract with ethyl acetate (3×15 mL). The combined organic phase is washed with 15 mL of saturated brine, dried with anhydrous sodium sulfate, concentrated to remove the solvent with a rotary evaporator, and separated by column chromatography (the volume ratio of petroleum ether to ethyl acetate is 12:1) to obtain the target product, a light yellow liquid, with a copper-catalyzed yield of 67% and an iron-catalyzed yield of 65%.

[0109] The structure of the obtained product was characterized by nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum as shown in Figure 16 and Figure 17 The structure characterization data are as follows:

[0110] 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.9 Hz, 1H), 7.36 (t, J = 1.7 Hz, 1H), 7.27-7.21 (m, 4H), 7.19-7.15 (m, 3H), 5.47 (q, J = 7.4 Hz, 1H), 4.48 (s, 2H), 2.17 (s, 3H), 1.76 (d, J = 7.4 Hz, 3H);13C NMR (101 MHz, CDCl3) δ 170.8, 137.9, 137.3, 136.9, 131.4, 130.0, 128.7, 128.2, 128.0, 127.3, 127.2, 122.6, 49.1, 22.1, 14.4.

[0111] Example 9

[0112] An E-type β-methyl enamide compound has the structure shown in formula I-9:

[0113]

[0114] Preparation method: take enamide compound N-benzyl-N-(1-(4-iodophenyl)vinyl)acetamide (0.3 mmol, 113.2 mg), diisopropylbenzene peroxide (0.6 mmol, 162.2 mg), copper catalyst copper acetate monohydrate (5 mol%, 2.99 mg) or iron catalyst ferrous chloride (5 mol%, 1.9 mg), then add solvent tert-butanol (2.0 mL), stir in an oil bath at 120°C for 18 h. After the reaction is completed, pour the obtained reaction solution into 15 mL of water, extract with ethyl acetate (3×15 mL). Wash the combined organic phase with 15 mL of saturated brine, dry the organic phase with anhydrous sodium sulfate, concentrate to remove the solvent with a rotary evaporator, separate by column chromatography (the volume ratio of petroleum ether to ethyl acetate is 12:1) to obtain the target product, a light yellow liquid, the yield of copper catalysis is 48%, and the yield of iron catalysis is 54%.

[0115] The structure of the obtained product was characterized by nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum as shown in Figure 18 and Figure 19 The structure characterization data are as follows:

[0116] 1H NMR (400 MHz, CDCl3) δ 7.72-7.68 (m, 2H), 7.27-7.21 (m, 3H), 7.18-7.13 (m, 2H), 6.98 (d, J = 8.4 Hz, 2H), 5.45 (q, J = 7.3 Hz, 1H), 4.47 (s, 2H), 2.16 (s, 3H), 1.74 (d, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.8, 138.3, 137.7, 137.3, 134.3, 130.4, 128.7, 128.2, 127.5, 127.1, 94.1, 49.1, 22.1, 14.5.

[0117] Example 10

[0118] An E-type β-methyl enamide compound has the structure shown in formula I-10:

[0119]

[0120] Preparation method: take enamide compound N-benzyl-N-(1-(3-iodophenyl)vinyl)acetamide (0.3 mmol, 113.2 mg), diisopropylbenzene peroxide (0.6 mmol, 162.2 mg), copper catalyst copper acetate monohydrate (5 mol%, 2.99 mg) or iron catalyst ferrous chloride (5 mol%, 1.9 mg), then add solvent tert-butanol (2.0 mL), stir in an oil bath at 120°C for 18 h. After the reaction is completed, pour the obtained reaction solution into 15 mL of water, extract with ethyl acetate (3×15 mL). Wash the combined organic phase with 15 mL of saturated brine, dry the organic phase with anhydrous sodium sulfate, concentrate to remove the solvent with a rotary evaporator, and separate by column chromatography (the volume ratio of petroleum ether to ethyl acetate is 12:1) to obtain the target product, a light yellow liquid, with a copper-catalyzed yield of 58% and an iron-catalyzed yield of 61%.

[0121] The structure of the obtained product was characterized by nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum as shown in Figure 20 and Figure 21 The structure characterization data are as follows:

[0122] 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.8 Hz, 1H), 7.54-7.53 (m, 1H), 7.25-7.22 (m, 3H), 7.19-7.15 (m, 3H), 7.10-7.08 (m, 1H), 5.46 (q, J = 7.3 Hz, 1H), 4.47 (s, 2H), 2.16 (s, 3H), 1.74 (d, J = 7.4 Hz, 3H);13C NMR (101 MHz, CDCl3) δ 170.7, 137.8, 137.2, 137.2, 136.9, 130.0, 128.7, 128.1, 127.9, 127.8, 127.1, 94.3, 49.1, 22.1, 14.4.

[0123] Example 11

[0124] An E-type β-methyl enamide compound has the structure shown in formula I-11:

[0125]

[0126] Preparation method: take enamide compound N-benzyl-N-(1-(4- cyano phenyl) vinyl) acetamide (0.3 mmol, 82.9 mg), diisopropyl benzene peroxide (0.6 mmol, 162.2 mg), copper catalyst copper acetate monohydrate (5 mol%, 2.99 mg) or iron catalyst ferrous chloride (5 mol%, 1.9 mg), then add solvent tert-butyl alcohol (2.0 mL), stir in an oil bath at 120°C for 18 h. After the reaction is completed, pour the obtained reaction solution into 15 mL of water, extract with ethyl acetate (3×15 mL). Wash the combined organic phase with 15 mL of saturated brine, dry the organic phase with anhydrous sodium sulfate, concentrate to remove the solvent with a rotary evaporator, separate by column chromatography (the volume ratio of petroleum ether to ethyl acetate is 8:1) to obtain the target product, a light yellow liquid, the yield of copper catalysis is 74%, and the yield of iron catalysis is 65%.

[0127] The structure of the obtained product is characterized by nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum as shown in Figure 22 and Figure 23 The structure characterization data are as follows:

[0128] 1H NMR (400 MHz, CDCl3) δ 7.67-7.63 (m, 2H), 7.35-7.30 (m, 2H), 7.22-7.19 (m, 3H), 7.14-7.11 (m, 2H), 5.59 (q, J = 7.4 Hz, 1H), 4.47 (s, 2H), 2.15 (s, 3H), 1.77 (d, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.7, 139.5, 137.9, 137.0, 132.2, 129.6, 129.2, 128.7, 128.2, 127.3, 126.2, 118.3, 111.9, 49.4, 22.0, 14.5.

[0129] Example 12

[0130] An E-type β-methyl enamide compound has the structure shown in formula I-12:

[0131]

[0132] Preparation method: Take enamide compound N-(4-methylbenzyl)-N-(1-phenylvinyl)acetamide (0.3 mmol, 79.6 mg), diisopropylbenzene peroxide (0.6 mmol, 162.2 mg), copper catalyst copper acetate monohydrate (5 mol%, 2.99 mg) or iron catalyst ferrous chloride (5 mol%, 1.9 mg), and then add solvent tert-butanol (2.0 mL), stir in an oil bath at 120°C for 18 h. After the reaction is completed, pour the obtained reaction solution into 15 mL of water, extract with ethyl acetate (3 x 15 mL). Wash the combined organic phase with 15 mL of saturated brine, dry the organic phase with anhydrous sodium sulfate, concentrate to remove the solvent with a rotary evaporator, and separate by column chromatography (volume ratio of petroleum ether: ethyl acetate is 12:1) to obtain the target product, a light yellow liquid, with a yield of 72% under copper catalysis and a yield of 75% under iron catalysis.

[0133] The structure of the obtained product was characterized by nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum as shown in Figure 24 and Figure 25 The structure characterization data are as follows:

[0134] 1H NMR (400 MHz, CDCl3) δ 7.42-7.33 (m, 3H), 7.28-7.25 (m, 2H), 7.11-7.05 (m, 4H), 5.42 (q, J = 7.3 Hz, 1H), 4.44 (s, 2H), 2.31 (s, 3H), 2.19 (s, 3H), 1.77 (d, J = 7.3 Hz, 3H);13C NMR (101 MHz, CDCl3) δ 170.8, 139.1, 136.5, 134.7, 134.5, 128.8, 128.7, 128.6, 128.4, 128.3, 126.7, 48.7, 22.1, 21.0, 14.4.

[0135] One or more embodiments of the present specification are intended to cover all such alternatives, modifications and variations falling within the broad scope of the appended claims. Therefore, any omissions, modifications, equivalent replacements, improvements, etc. made in the spirit and principles of one or more embodiments of the present specification should be included in the protection scope of the present disclosure.

Claims

1. A method of manufacture, characterized by, The method comprises the following steps: mixing an enamide, an organic peroxide, a catalyst and a solvent, and performing a β-C(sp 2 )-H methylation reaction under heating to obtain an E-type β-methyl enamide compound; the compound comprises: ； The catalyst is any one of copper chloride, copper oxide, copper acetate monohydrate, copper sulfate, ferrous oxide, ferrous sulfate and ferrous acetate; The enamide has a structure shown in formula (II): ； R1 and R2 are corresponding groups in the E-type β-methyl enamide compound; The organic peroxide has a structure shown in formula (III): 。 2. The production method according to claim 1, characterized by, The methylating reaction is carried out under heating, the temperature of the heating is 60-140°C, and the reaction time of the methylating is 6-24h.

3. The preparation method according to claim 1, characterized in that, The catalyst is used in an amount of 2-20mol%.

4. The method of claim 1, wherein, The solvent is any one or mixture of several of trifluoroethanol, methanol, ethanol, isopropanol, tert-butyl alcohol, N,N-dimethylformamide, chlorobenzene, dichloromethane, dichloroethane and water, and the volume of the solvent is 1.0-3.0mL.

5. The preparation method according to claim 2, characterized in that, The temperature of the methylating reaction is 120°C, and the time is 18h.

6. The preparation method according to claim 4, characterized in that, The solvent is tert-butyl alcohol, and the volume is 2.0mL.

7. The preparation method according to claim 1, characterized in that, The molar ratio of the enamide to the organic peroxide is 1.0:(1.0-4.0).

8. The preparation method according to claim 1, characterized in that, The enamide and the organic peroxide are used as reaction substrates, mixed with the solvent, and then the mixture is subjected to the methylating reaction under the catalysis of the catalyst to generate the E-type β-methyl enamide derivative.

9. The method of claim 1, wherein, The methylating reaction further comprises separation and purification, and the separation and purification is carried out by column chromatography, liquid chromatography, distillation or recrystallization.

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