Method for simply, conveniently and efficiently synthesizing beta-alkylated alkenyl amide and derivative thereof

Abstract

The invention discloses a novel method for simply, conveniently and efficiently synthesizing beta-alkylated alkenyl amide and derivatives thereof, which comprises the following steps: at a certain temperature, under the action of a cobalt catalyst and an oxidizing agent, taking alkenyl amide compounds 1 containing different substituent groups and 4-alkyl substituted 1, 4-dihydro-2, 6-dimethyl-3, 5-dipicolinic acid diethyl ester 2 as initial raw materials, and reacting at a certain temperature under the action of the cobalt catalyst and the oxidizing agent, thereby obtaining the beta-alkylated alkenyl amide and derivatives thereof. A carbon-hydrogen bond direct alkylation reaction is carried out in an organic solvent, and a series of beta-alkylated alkenyl amides and derivatives 3 thereof are efficiently synthesized; the raw materials involved in the invention can be directly purchased or simply prepared, the post-treatment process flow is simple to operate, the environmental pollution risk is avoided, the product is easy to separate and purify, related products are provided for the fields of biology, medicine, photoelectric functional materials and the like, and the method has good market potential and practical application value.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthetic chemistry and relates to a method for simply and efficiently synthesizing beta-alkylated enamide and derivatives thereof. Background Art

[0002] As we all know, enamides are an important type of structural unit that exists in many pesticides, medicines, natural products, and physiologically active molecules, showing excellent antibacterial and anticancer activities. In addition, enamides are also an extremely important type of synthetic building blocks that are widely used in synthetic chemistry research and have achieved a series of important synthetic transformations. However, it should be pointed out that the catalytic reaction systems reported so far have many defects, such as: excessive use of precious metal catalysts, harsh reaction conditions, narrow substrate range, excessive use of additives, etc., which greatly limit the widespread application of such reactions.

[0003] Therefore, exploring and developing an efficient, highly selective and simple and practical synthesis method to achieve efficient conversion of enamide compounds has important research value and industrial application prospects. In the reported carbon-hydrogen bond alkylation reactions involving enamide substrates, expensive transition metal catalysts such as palladium, rhodium, and iridium are usually required, and heavy metal residues also greatly limit the synthetic application of such reactions. Therefore, it is urgent to explore and develop 3d metal-catalyzed carbon-hydrogen bond alkylation of enamide substrates that are naturally abundant, cheap, easy to obtain, and low in toxicity. Cobalt-catalyzed organic reactions with abundant natural reserves are one of the hot topics in the field of synthetic chemistry research. Various cobalt-catalyzed organic synthesis reactions have been reported one after another, such as carbon-carbon coupling reactions, carbon-heteroatom coupling reactions, intramolecular reactions, multi-component reactions, etc. The present invention utilizes cheap metal cobalt catalysis to develop a carbon-hydrogen bond alkylation reaction of enamide substrates involving 4-alkyl-substituted Hans esters. Summary of the invention

[0004] The purpose of the present invention is to provide a method for simply and efficiently synthesizing β-alkylated enamide and its derivatives. The method is simple to operate, the raw materials are readily available, the products are easily separated, and high-purity products are provided for related fields such as biology, medicine, and optoelectronic functional materials, and the method has good market application potential.

[0005] The technical solution of the present invention is: at a certain temperature, in the presence of a cobalt catalyst and an activator, using olefin amide compounds 1 with different substituents and 4-alkyl-substituted hans ester 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester 2 as starting materials, an alkylation reaction is carried out in an organic solvent, and the reaction is monitored by thin layer chromatography to synthesize a series of β-alkylated olefin amides and their derivatives 3.

[0006] The reaction equation is as follows: Wherein, R is: hydrogen, methyl, ethyl, isopropyl, tert-butyl, methoxy, benzyloxy, thiomethoxy, trifluoromethoxy, (hetero)aryl, halogen (fluorine, chlorine, bromine, iodine), and is monosubstituted, disubstituted or even trisubstituted; R 1 is acetyl, propionyl, isobutyryl, benzoyl; R 2 It is methyl, ethyl, benzyl, isopropyl and allyl.

[0007] The catalyst is any one of cobalt chloride, cobalt bromide, cobalt acetate, cobalt trifluoromethanesulfonate, cobalt acetylacetonate (II) and cobalt acetylacetonate (III), and the amount thereof is 5-20 mol% of the enamide compound 1.

[0008] Furthermore, cobalt chloride has the best reaction effect, and its dosage is 10 mol% of the enamide compound 1.

[0009] Wherein, the activator is any one of sodium bromate, potassium bromate, sodium persulfate, potassium persulfate, and ammonium persulfate, and its usage is 1.0 to 3.0 times the equivalent of the enamide compound 1.

[0010] Furthermore, potassium bromate has the best reaction effect, and its dosage is 2.0 times the equivalent of the enamide compound 1.

[0011] Wherein, the organic solvent is: benzene, toluene, acetonitrile, ethanol, acetone, dichloromethane, tetrahydrofuran, dimethyl sulfoxide, ethyl acetate, 1,2-dichloroethane, N , N -dimethylformamide, 1,4-dioxane, and the amount of the organic solvent used is 2 mL / mmol based on the amount of the enamide compound 1.

[0012] Furthermore, tetrahydrofuran has the best reaction effect.

[0013] The amount of the enamide compound 1,4-alkyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester 2 is 2.0 to 3.0 times the amount used.

[0014] Furthermore, the best effect is achieved when the amount of the enamide compound 1,4-alkyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester 2 is 2.0 times the equivalent.

[0015] Among them, the reaction temperature is 60~120 ° C, and the reaction time is 24 hours.

[0016] Furthermore, the reaction effect is best at 80 °C.

[0017] The developing solvent used for thin layer chromatography monitoring the reaction was: petroleum ether: ethyl acetate = 5:1, V / V.

[0018] The post-treatment method of the reaction solution is as follows: after the reaction is completed, dichloromethane is added to dilute, the organic phase is washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure, and then separated by silica gel column chromatography to obtain a series of β-alkylated enamides and their derivatives 3.

[0019] Furthermore, the eluent of the silica gel column chromatography is: petroleum ether: ethyl acetate = 5:1, V / V.

[0020] The advantages of the present invention are: 1. Under the catalysis of cheap metal cobalt, structurally diverse 4-alkylated hans esters participate in the carbon-hydrogen bond alkylation reaction of enamide substrates to accurately and efficiently prepare a series of β-alkylated enamides and their derivatives.

[0021] 2. Under the catalysis of cheap metal cobalt, eneamide compounds with different substituents are reacted with 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester containing different 4-alkyl substitutions to construct structurally diverse β-alkyl substituted eneamides and their derivatives, providing a new synthetic method for the precise synthesis of functionally diverse eneamides and their derivatives, enriching the preparation methods of such compounds.

[0022] 3. Using 4-alkylated Hans ester as an alkylating agent, the carbon-hydrogen bond alkylation reaction of enamide substrates was achieved, and structurally diverse β-alkylated enamides and their derivatives were accurately synthesized.

[0023] 4. The starting materials, reaction reagents, etc. involved in the present invention can be obtained from the market or through simple preparation. The reaction has many characteristics such as a simple catalytic system, convenient reaction operation, and easy separation of products. A series of β-alkylated eneamide target compounds can be obtained with high efficiency and high yield. It is particularly suitable for the preparation and synthesis of various functionalized β-alkylated eneamide compounds and for large-scale industrial production.

[0024] 5. The carbon-hydrogen bond alkylation reaction of olefin amide substrates with the participation of 4-alkylated 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester under the catalysis of cheap metal cobalt has the characteristics of high catalytic efficiency, mild reaction conditions and high reaction selectivity, which makes it particularly suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 for N -Benzyl- N -(1,4-diaryl-1-butenyl)acetamide 3a 1H-NMR spectrum; Figure 2 for N -Benzyl- N -(1,4-diaryl-1-butenyl)acetamide 3a 13 C-NMR spectrum; Figure 3 for N -Benzyl- N -(1,4-diaryl-1-butenyl)acetamide 3b 1 H-NMR spectrum; Figure 4 for N -Benzyl- N -(1,4-diaryl-1-butenyl)acetamide 3b 13 C-NMR spectrum; Figure 5 for N -Benzyl- N -(1,4-Diaryl-1-butenyl)acetamide 3c 1 H-NMR spectrum; Figure 6 for N -Benzyl- N -(1,4-Diaryl-1-butenyl)acetamide 3c 13 C-NMR spectrum; Figure 7 for N -Benzyl- N -(1,4-diaryl-1-butenyl)acetamide 3d 1 H-NMR spectrum; Figure 8 for N -Benzyl- N -(1,4-diaryl-1-butenyl)acetamide 3d 13 C-NMR spectrum; Fig. 9 for N -Benzyl- N -(1,4-diaryl-1-butenyl)acetamide 3e 1 H-NMR spectrum; Fig.10 for N -Benzyl- N -(1,4-diaryl-1-butenyl)acetamide 3e 13 C-NMR spectrum; Fig.11 for N -Benzyl- N -(1,4-Diaryl-1-butenyl)acetamide 3f 1H-NMR spectrum; Fig.12 for N -Benzyl- N -(1,4-Diaryl-1-butenyl)acetamide 3f 13 C-NMR spectrum; Fig.13 for N -Benzyl- N -(1,4-diaryl-1-butenyl)acetamide 3g 1 H-NMR spectrum; Fig.14 for N -Benzyl- N -(1,4-diaryl-1-butenyl)acetamide 3g 13 C-NMR spectrum; Fig.15 for N -Benzyl- N -(1,4-diaryl-1-butenyl)acetamide 3h 1 H-NMR spectrum; Fig.16 for N -Benzyl- N -(1,4-diaryl-1-butenyl)acetamide 3h 13 C-NMR spectrum; Fig.17 for N -Benzyl- N -(1,4-diaryl-1-butenyl)acetamide 3i 1 H-NMR spectrum; Fig.18 for N -Benzyl- N -(1,4-diaryl-1-butenyl)acetamide 3i 13 C-NMR spectrum; Fig.19 for N -Benzyl- N -(1,4-diaryl-1-butenyl)acetamide 3j 1 H-NMR spectrum; Fig. 20 for N -Benzyl- N -(1,4-diaryl-1-butenyl)acetamide 3j 13 C-NMR spectrum; DETAILED DESCRIPTION

[0026] With different substituents N -Benzyl- N-(1-phenylethyl)acetamide, and 4-phenylethyl substituted Hans ester were used as examples to prepare a series of β-alkylated enamides and their derivatives. The following specific examples will help to further illustrate the content of the present invention, but should not be construed as limiting the technical solution.

[0027] Example 1: Synthesis N -Benzyl- N -(1,4-diaryl-1-butenyl)acetamide derivative 3a preparation: In a 25 mL glass reaction tube with magnetic stirring, add N -Benzyl- N -(1-phenylvinyl)acetamide 1a (0.126 g, 0.5 mmol), 4-phenylethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester 2 (0.357 g, 1.0 mmol), cobalt chloride (0.0065 g, 0.05 mmol), potassium bromate (0.167 g, 1.0 mmol) and tetrahydrofuran (2.0 mL) were stirred evenly and reacted in an oil bath at 80 °C under argon protection for 24 h. The product was purified by thin layer chromatography (developing solvent V 石油醚 : V 乙酸乙酯 = 5:1) to monitor the reaction progress; after the reaction, the reaction solution was poured into saturated brine (15 mL), extracted with dichloromethane (3 × 10 mL), the organic phases were combined and washed with water (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain an oily liquid, which was separated by silica gel column chromatography (eluent: V 石油醚 : V 乙酸乙酯 = 5:1); it was confirmed to be the target product 3a by nuclear magnetic resonance and high-resolution mass spectrometry, with a yield of 78%.

[0028] Spectral analysis data 3a: light yellow solid, 1 H NMR (500 MHz, CDCl3) δ 7.39-7.32 (m, 3H), 7.31-7.23 (m, 3H), 7.23-7.12 (m, 7H), 6.96 (d, J = 6.7 Hz, 2H), 5.32 (t, J = 7.6Hz, 1H), 4.45 (s, 2H), 2.62 (t, J = 7.3 Hz, 2H), 2.54-2.46 (m, 3H), 2.06 (s,3H); 13C NMR (101 MHz, CDCl3) δ 170.69, 140.50, 138.86, 137.46, 134.71,131.36,128.75, 128.43, 128.41, 128.25, 128.10, 127.00, 125.94, 48.80, 35.20, 29.93,21.88.HRMS (ESI-TOF) [M+K] + calculated for C 25 H 25 NOK: 394.1568, found: 394.1570. Example 2: 1a in Example 1 was replaced by 1b, and the yield was 76%.

[0029] In a 25 mL glass reaction tube with magnetic stirring, add N -Benzyl- N -(1-(4-tert-butyl)phenylvinyl)acetamide 1b (0.153 g, 0.5 mmol), 4-phenylethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester 2 (0.357 g, 1.0 mmol), cobalt (III) acetylacetonate (0.0089 g, 0.025 mmol), potassium bromate (0.167 g, 1.0 mmol) and 1,4-dioxane (2.0 mL) were stirred and reacted in an oil bath at 80 °C under argon protection for 24 h. The product was purified by thin layer chromatography (developing solvent V 石油醚 : V 乙酸乙酯 = 5:1) to monitor the reaction progress; after the reaction, the reaction solution was poured into saturated brine (15 mL), extracted with dichloromethane (3 × 10 mL), the organic phases were combined and washed with water (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain an oily liquid, which was separated by silica gel column chromatography (eluent: V 石油醚 :V 乙酸乙酯 = 5:1); it was confirmed to be the target product 3b by nuclear magnetic resonance and high-resolution mass spectrometry, with a yield of 76%.

[0030] Spectral analysis data 3b: light yellow solid, 1 H NMR (400 MHz, CDCl3)δ 7.37 (d, J = 6.5 Hz,2H), 7.31-7.26 (m, 3H), 7.24-7.16 (m, 5H), 7.11 (d, J= 6.5 Hz, 2H), 6.99 (d, J =8.0 Hz, 2H), 5.28 (t, J = 7.1 Hz, 1H), 4.46 (s, 2H), 2.62 (t, J = 7.2 Hz, 2H),2.53 (q, J = 7.3 Hz, 2H), 2.07 (s, 3H), 1.35 (s, 9H); 13 C NMR (101 MHz, CDCl3)δ170.92, 151.63, 140.78, 138.88, 137.72,131.80, 131.10, 128.95, 128.40,128.38, 128.24, 128.19, 127.07, 126.06, 125.43, 49.01, 35.44, 34.66, 31.23,30.15, 22.02;HRMS (ESI-TOF) [M+K] + calculated for C 29 H 33 NOK: 450.2194, found:450.2190. Example 3: 1c was used to replace 1a in Example 1, and the yield was 70%.

[0031] In a 25 mL glass reaction tube with magnetic stirring, add N -Benzyl- N -(1-(4-chloro)phenylvinyl)acetamide 1c (0.143 g, 0.5 mmol), 4-phenylethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester 2 (0.357 g, 1.0 mmol), cobalt chloride (0.013 g, 0.10 mmol), potassium bromate (0.251 g, 1.5 mmol) and toluene (2.0 mL) were stirred evenly and reacted in an oil bath at 60 °C under argon protection for 24 h. The product was purified by thin layer chromatography (developing solvent V 石油醚 : V 乙酸乙酯 = 5:1) to monitor the reaction progress; after the reaction, the reaction solution was poured into saturated brine (15 mL), extracted with dichloromethane (3 × 10 mL), the organic phases were combined and washed with water (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain an oily liquid, which was separated by silica gel column chromatography (eluent: V 石油醚 : V乙酸乙酯 = 5:1); it was confirmed to be the target product 3c by nuclear magnetic resonance and high-resolution mass spectrometry, with a yield of 70%.

[0032] Spectral analysis data 3c: white solid, 1 H NMR (500 MHz, CDCl3)δ 7.32-7-27 (m, 5H),7.21 (t, J = 7.1 Hz, 2H), 7.18-7.13 (m, 3H), 7.02 (d, J = 8.4 Hz, 2H), 6.98-6.92(m, 2H), 5.34 (t, J = 7.7 Hz, 1H), 4.44 (s, 2H), 2.62 (t, J = 7.2 Hz, 2H), 2.47(q, J = 7.4 Hz, 2H), 2.02 (s, 3H); 13 C NMR (101 MHz, CDCl3)δ 170.74, 140.44,138.10, 137.36, 134.37, 133.35, 132.03, 129.85, 128.82, 128.77, 128.44,128.35, 128.27, 127.22, 126.17, 49.03, 35.21,30.10, 21.95;HRMS (ESI-TOF) [M+K] + calculated for C 25 H 24 ClNOK: 428.1178, found: 428.1177. Example 4: 1d was used to replace 1a in Example 1, and the yield was 76%.

[0033] In a 25 mL glass reaction tube with magnetic stirring, add N -Benzyl- N-(1-(4-bromo)phenylvinyl)acetamide 1d (0.165 g, 0.5 mmol), 4-phenylethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester 2 (0.534 g, 1.5 mmol), cobalt acetate (0.0088 g, 0.05 mmol), potassium bromate (0.167 g, 1.0 mmol) and dimethyl sulfoxide (2.0 mL) were stirred evenly and reacted in an oil bath at 100 °C under argon protection for 24 h. The product was purified by thin layer chromatography (developing solvent V 石油醚 : V 乙酸乙酯 = 5:1) to monitor the reaction progress; after the reaction, the reaction solution was poured into saturated brine (15 mL), extracted with dichloromethane (3 × 10 mL), the organic phases were combined and washed with water (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain an oily liquid, which was separated by silica gel column chromatography (eluent: V 石油醚 : V 乙酸乙酯 = 5:1); it was confirmed to be the target product 3d by nuclear magnetic resonance and high-resolution mass spectrometry, and the yield was 76%.

[0034] Spectrum analysis data 3d: white solid, 1 H NMR (500 MHz, CDCl3)δ 7.47 (d, J = 8.4 Hz,2H), 7.26 (dd, J = 14.6, 6.5 Hz, 3H), 7.21 (t, J = 7.2 Hz, 2H), 7.19-7.11 (m,3H), 6.95 (d, J = 8.5 Hz, 4H), 5.35 (t, J = 7.7 Hz, 1H), 4.44 (s, 2H), 2.61 (t, J =7.3 Hz, 2H), 2.46 (q, J = 7.4 Hz, 2H), 2.02 (s, 3H); 13 C NMR (101 MHz, CDCl3)δ170.73, 140.41, 138.13, 137.33, 133.81,132.09, 131.72, 130.11, 128.81,128.43, 128.35, 128.26, 127.21, 126.16, 122.58, 49.02, 35.18, 30.10, 21.94;HRMS (ESI-TOF) [M+K] +calculated for C 25 H 24 BrNOK: 472.0673, found: 472.0672. Example 5: 1e was used to replace 1a in Example 1, and the yield was 78%.

[0035] In a 25 mL glass reaction tube with magnetic stirring, add N -Benzyl- N -(1-(4-iodo)phenylvinyl)acetamide 1e (0.188 g, 0.5 mmol), 4-phenylethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester 2 (0.357 g, 1.0 mmol), cobalt chloride (0.0065 g, 0.05 mmol), sodium bromate (0.226 g, 1.5 mmol) and tetrahydrofuran (2.0 mL) were stirred evenly and reacted in an oil bath at 120 °C under argon protection for 24 h. The product was purified by thin layer chromatography (developing solvent V 石油醚 : V 乙酸乙酯 = 5:1) to monitor the reaction progress; after the reaction, the reaction solution was poured into saturated brine (15 mL), extracted with dichloromethane (3 × 10 mL), the organic phases were combined and washed with water (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain an oily liquid, which was separated by silica gel column chromatography (eluent: V 石油醚 : V 乙酸乙酯 = 5:1); it was confirmed to be the target product 3e by nuclear magnetic resonance and high-resolution mass spectrometry, with a yield of 78%.

[0036] Spectral analysis data 3e: yellow solid, 1 H NMR (500 MHz, CDCl3)δ 7.67 (d, J = 8.5 Hz,2H), 7.27 (dd, J = 10.6, 7.8 Hz, 3H), 7.23-7.12 (m, 5H), 6.95 (d, J = 7.0 Hz,2H), 6.81 (d, J = 8.4 Hz, 2H), 5.34 (t, J = 7.7 Hz, 1H), 4.44 (s, 2H), 2.61 (t, J =7.3 Hz, 2H), 2.46 (q, J= 7.4 Hz, 2H), 2.02 (s, 3H); 13 C NMR (126 MHz, CDCl3)δ170.73, 140.38, 138.18, 137.65, 137.30,134.36, 132.15, 130.24, 128.79,128.41, 128.34, 128.25, 127.19, 126.15, 94.35, 48.99, 35.18, 30.10, 21.94;HRMS (ESI-TOF) [M+K] + calculated for C 25 H 24 INOK: 520.0534, found: 520.0539. Example 6: 1f was used to replace 1a in Example 1, and the yield was 67%.

[0037] In a 25 mL glass reaction tube with magnetic stirring, add N -Benzyl- N -(1-(4-methoxy)phenylvinyl)acetamide 1f (0.140 g, 0.5 mmol), 4-phenylethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester 2 (0.357 g, 1.0 mmol), cobalt chloride (0.0065 g, 0.05 mmol), sodium bromate (0.15 g, 1.0 mmol) and acetonitrile (2.0 mL) were stirred evenly and reacted in an oil bath at 100 °C under argon protection for 24 h. Thin layer chromatography (developing solvent V 石油醚 : V 乙酸乙酯 = 5:1) to monitor the reaction progress; after the reaction, the reaction solution was poured into saturated brine (15 mL), extracted with dichloromethane (3 × 10 mL), the organic phases were combined and washed with water (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain an oily liquid, which was separated by silica gel column chromatography (eluent: V 石油醚 : V 乙酸乙酯 = 5:1); it was confirmed to be the target product 3f by nuclear magnetic resonance and high-resolution mass spectrometry, with a yield of 67%.

[0038] Spectral analysis data 3f: light yellow solid, 1 H NMR (500 MHz, CDCl3)δ 7.31-7.24 (m, 3H),7.23-7.14 (m, 5H), 7.07 (d,J = 8.8 Hz, 2H), 6.97 (d, J = 6.7 Hz, 2H), 6.88 (d, J =8.8 Hz, 2H), 5.24 (t, J = 7.5 Hz, 1H), 4.45 (s, 2H), 3.83 (s, 3H), 2.61 (t, J =7.3 Hz, 2H), 2.49 (q, J = 7.4 Hz, 2H), 2.04 (s, 3H); 13 C NMR (101 MHz, CDCl3)δ170.87, 159.58, 140.75, 138.62, 137.64,130.25, 129.86, 128.86, 128.37,128.36, 128.19, 127.07, 126.04, 113.84, 55.27, 48.86, 35.39, 30.11, 21.99;HRMS (ESI-TOF)[M+H] + calculated for C 26 H 28 NO2: 386.2115, found: 386.2099. Example 7: 1g was used to replace 1a in Example 1, and the yield was 66%.

[0039] In a 25 mL glass reaction tube with magnetic stirring, add N -Benzyl- N -(1-(4-phenyl)phenylvinyl)acetamide 1g (0.163 g, 0.5 mmol), 4-phenylethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester 2 (0.357 g, 1.0 mmol), cobalt chloride (0.0065g, 0.05 mmol), potassium persulfate (0.27 g, 1.0 mmol) and 1,2-dichloroethane (2.0 mL) were stirred evenly and reacted in an oil bath at 120 °C under argon protection for 24 hours. Thin layer chromatography (developing solvent V 石油醚 : V 乙酸乙酯= 5:1) to monitor the reaction progress; after the reaction, the reaction solution was poured into saturated brine (15 mL), extracted with dichloromethane (3 × 10 mL), the organic phases were combined and washed with water (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain an oily liquid, which was separated by silica gel column chromatography (eluent: V 石油醚 : V 乙酸乙酯 = 5:1); it was confirmed by nuclear magnetic resonance and high-resolution mass spectrometry to be 3 g of the target product with a yield of 66%.

[0040] Spectral analysis data 3g: light yellow solid, 1 H NMR (500 MHz, CDCl3)δ 7.60 (dd, J = 14.2,7.7 Hz, 4H), 7.46 (t, J = 7.7 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.33-7.24 (m,3H), 7.24-7.14 (m, 7H), 6.99 (d, J = 7.0 Hz, 2H), 5.35 (t, J = 7.5 Hz, 1H), 4.50(s, 2H), 2.65 (t, J = 7.3 Hz, 2H), 2.56 (q, J = 7.4 Hz, 2H), 2.08 (s, 3H); 13 C NMR(126 MHz, CDCl3)δ 170.89, 141.24, 140.62, 140.16, 138.69, 137.56, 133.70,131.67, 128.95, 128.88,128.83, 128.39, 128.37, 128.21, 127.61, 127.14,127.12, 126.97, 126.08, 49.06, 35.34, 30.18, 22.02;HRMS (ESI-TOF) [M+H] + calculated for C 31 H 29 NO: 432.2322, found: 432.2334. Example 8: 1a in Example 1 was replaced by 1h, and the yield was 78%.

[0041] In a 25 mL glass reaction tube with magnetic stirring, add N -Benzyl- N -(1-(3-methyl)phenylvinyl)acetamide 1h (0.132 g, 0.5 mmol), 4-phenylethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester 2 (0.357 g, 1.0 mmol), cobalt chloride (0.0032 g, 0.05 mmol), potassium bromate (0.25 g, 1.5 mmol) and N , N -dimethylformamide (2.0 mL), stirred evenly, and reacted in an oil bath at 100 °C for 24 h under argon protection. 石油醚 : V 乙酸乙酯 = 5:1) to monitor the reaction progress; after the reaction, the reaction solution was poured into saturated brine (15 mL), extracted with dichloromethane (3 × 10 mL), the organic phases were combined and washed with water (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain an oily liquid, which was separated by silica gel column chromatography (eluent: V 石油醚 :V 乙酸乙酯 = 5:1); it was confirmed to be the target product 3h by nuclear magnetic resonance and high-resolution mass spectrometry, with a yield of 78%.

[0042] Spectral analysis data 3h: light yellow solid, 1 H NMR (400 MHz, CDCl3)δ 7.33-7.13 (m, 10H),7.02-6.92 (m, 3H), 6.89 (s, 1H), 5.31 (t, J = 7.6 Hz, 1H), 4.45 (s, 2H), 2.62(t, J = 7.1 Hz, 2H), 2.50 (q, J = 7.3 Hz, 2H), 2.33 (s, 3H), 2.07 (s, 3H); 13 C NMR(101 MHz, CDCl3)δ 170.88, 140.72, 139.18, 138.21, 137.67,134.78, 131.27,129.29, 128.97, 128.86, 128.40, 128.38, 128.33, 128.19, 127.08, 126.04,125.84, 49.01, 35.37, 30.14, 22.04, 21.44;HRMS (ESI-TOF) [M+K]+ calculated for C 26 H 27 NOK: 408.1724, found: 408.1726. Example 9: 1a in Example 1 was replaced by 1i, and the yield was 76%.

[0043] In a 25 mL glass reaction tube with magnetic stirring, add N -Benzyl- N -(1-(1,3-dioxolane)phenylvinyl)acetamide 1i (0.128 g, 0.5 mmol), 4-phenylethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester 2 (0.357 g, 1.0 mmol), cobalt chloride (0.0065 g, 0.05 mmol), potassium bromate (0.25 g, 1.5 mmol) and dichloromethane (2.0 mL) were stirred evenly and reacted in an oil bath at 60 °C under argon protection for 24 h. The product was purified by thin layer chromatography (developing solvent V 石油醚 : V 乙酸乙酯 = 5:1) to monitor the reaction progress; after the reaction, the reaction solution was poured into saturated brine (15 mL), extracted with dichloromethane (3 × 10 mL), the organic phases were combined and washed with water (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain an oily liquid, which was separated by silica gel column chromatography (eluent: V 石油醚 : V 乙酸乙酯 = 5:1); it was confirmed to be the target product 3i by nuclear magnetic resonance and high-resolution mass spectrometry, with a yield of 76%.

[0044] Spectral analysis data 3i: light yellow solid, 1 H NMR (500 MHz, CDCl3)δ 7.31-7.25 (m, 3H),7.24-7.14 (m, 5H), 6.98 (d, J = 7.4 Hz, 2H), 6.79 (d, J = 8.0 Hz, 1H), 6.63 (d, J =9.7 Hz, 1H), 6.58 (s, 1H), 5.99 (s, 2H), 5.23 (t, J = 7.5 Hz, 1H), 4.45 (s,2H), 2.61 (t, J = 7.3 Hz, 2H), 2.49 (q, J= 7.4 Hz, 2H), 2.03 (s, 3H); 13 C NMR (126MHz, CDCl3)δ 170.78, 147.80, 147.70, 140.65, 138.58, 137.56, 130.64, 128.84,128.66, 128.38, 128.36, 128.20,127.10, 126.07, 122.62, 108.64, 108.24,101.31, 48.86, 35.32, 30.14, 21.93;HRMS (ESI-TOF) [M+K] + calculated for C 26 H 25 NO3K: 438.1466, found: 438.1472. Example 10: 1j was used to replace 1a in Example 1, and the yield was 65%.

[0045] In a 25 mL glass reaction tube with magnetic stirring, add N -Benzyl- N -(1-naphthylene)acetamide 1j (0.151 g, 0.5 mmol), 4-phenylethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester 2 (0.357 g, 1.0 mmol), cobalt chloride (0.0065 g, 0.05 mmol), potassium bromate (0.167 g, 1.0 mmol) and tetrahydrofuran (2.0 mL) were stirred evenly and reacted in an oil bath at 100 °C under argon protection for 24 h. The product was purified by thin layer chromatography (developing solvent V 石油醚 : V 乙酸乙酯 = 5:1) to monitor the reaction progress; after the reaction, the reaction solution was poured into saturated brine (15 mL), extracted with dichloromethane (3 × 10 mL), the organic phases were combined and washed with water (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain an oily liquid, which was separated by silica gel column chromatography (eluent: V 石油醚 : V 乙酸乙酯 = 5:1); it was confirmed to be the target product 3j by nuclear magnetic resonance and high-resolution mass spectrometry, with a yield of 65%.

[0046] Spectrum analysis data 3j: light yellow solid, 1 H NMR (400 MHz, CDCl3)δ 7.83 (t, J= 7.3 Hz,2H), 7.76 (d, J = 9.6 Hz, 1H), 7.55-7.47 (m, 3H), 7.29 (d, J = 6.8 Hz, 3H), 7.25-7.16 (m, 6H), 6.97 (d, J = 6.5 Hz, 2H), 5.42 (t, J = 7.5 Hz, 1H), 4.49 (s, 2H), 2.66 (t, J = 7.6 Hz, 2H), 2.57 (q, J = 6.9 Hz, 2H), 2.12 (s, 3H); 13 C NMR (101 MHz, CDCl3)δ 170.99, 140.67, 139.13, 137.59, 133.06, 132.96, 132.21, 131.79,128.85, 128.46, 128.43, 128.26, 128.18, 127.62, 127.15, 126.67, 126.49,126.11, 125.79, 49.06, 35.36, 30.27,22.13;HRMS (ESI-TOF) [M+K] + calculated for C 29 H 27 NOK: 444.1724, found: 444.1727. The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent transformation or modification made according to the spirit of the present invention should be included in the protection scope of the present invention.

[0047] The above embodiments 1-10 are summarized in the following Table 1:

Claims

1. A simple and efficient method for synthesizing β-alkylated enamide and its derivatives, characterized in that: At a certain temperature, in the presence of a cobalt catalyst and an oxidant, alkylation reaction takes place in an organic solvent using olefin amide compounds 1 with different substituents and 4-alkyl-substituted 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester 2 as starting materials. The reaction progress is monitored by thin layer chromatography (TLC) to synthesize a series of β-alkylated olefin amides and their derivatives 3. The reaction equation is as follows: Among them, R is: hydrogen, methyl, ethyl, isopropyl, tert-butyl, methoxy, benzyloxy, thiomethoxy, trifluoromethoxy, (hetero)aryl, halogen (fluorine, chlorine, bromine, iodine), which is monosubstituted, disubstituted or even trisubstituted; R1 is acetyl, propionyl, isobutyryl, benzoyl; R2 is methyl, ethyl, benzyl, isopropyl, allyl.

2. A method for synthesizing β-alkylated enamide and its derivatives in a simple and efficient manner according to claim 1, characterized in that the catalyst is any one of cobalt chloride, cobalt bromide, cobalt acetate, cobalt trifluoromethanesulfonate, cobalt acetylacetonate (II) and cobalt acetylacetonate (III), and its amount is 5-20 mol% of the enamide compound 1.

3. A simple and efficient method for synthesizing β-alkylated enamide and its derivatives according to claim 1, characterized in that The activator is any one of sodium bromate, potassium bromate, sodium persulfate, potassium persulfate and ammonium persulfate, and its usage is 1.0 to 3.0 times the equivalent of the enamide compound 1.

4. A method for synthesizing β-alkylated enamides and their derivatives in a simple and efficient manner according to claim 1, characterized in that the organic solvent is any one of benzene, toluene, acetonitrile, ethanol, acetone, dichloromethane, tetrahydrofuran, dimethyl sulfoxide, ethyl acetate, 1,2-dichloroethane, N,N-dimethylformamide, and 1,4-dioxane, and the amount of the organic solvent used is 2 mL / mmol based on the amount of the enamide compound 1.

5. A simple and efficient method for synthesizing β-alkylated enamide and its derivatives according to claim 4, characterized in that: Tetrahydrofuran has the best reaction effect.

6. The method for synthesizing β-alkylated enamide and its derivatives simply and efficiently according to claim 1, characterized in that: The amount of the enamide compound 1,4-alkyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester 2 is 2.0 to 3.0 times the amount used.

7. The method for synthesizing β-alkylated enamide and its derivatives simply and efficiently according to claim 1, characterized in that: The reaction temperature is 60~120 °C and the reaction time is 24 hours.

8. A simple and efficient method for synthesizing β-alkylated enamide and its derivatives according to claim 1, characterized in that The developing solvent used for TLC monitoring of the reaction was: petroleum ether: ethyl acetate = 5:1, V / V.

9. A simple and efficient method for synthesizing β-alkylated enamide and its derivatives according to claim 1, characterized in that The post-treatment method of the reaction solution is: after the reaction is completed, dichloromethane is added to dilute, the organic phase is washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure, and then separated by silica gel column chromatography to obtain a series of β-alkylated enamides and their derivatives 3.

10. A simple and efficient method for synthesizing β-alkylated enamide and its derivatives according to claim 9, characterized in that The eluent for the silica gel column chromatography is: petroleum ether:ethyl acetate = 5:1, V / V.

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