阅读说明：本技术 一种α,β-不饱和酰胺的制备方法 (Preparation method of alpha, beta-unsaturated amide ) 是由 黄子俊 李跃辉 易兵 于 2021-09-15 设计创作，主要内容包括：本发明揭示了一种α,β-不饱和酰胺化合物的制备方法,该制备方法包括如下步骤：在反应容器中加入催化剂、炔烃、铵盐及溶剂,通入一氧化碳(CO)并加热反应,反应完成后分离得到产物α,β-不饱和酰胺。本发明使用易于操作的铵盐能有效降低设备要求,所用的铵盐廉价易得,反应过程无需添加配体,有利于节约成本。本制备方法具有优秀的底物实用性,其操作步骤简捷,反应条件温和易控,原料廉价易得,产品收率及产品纯度高,适于大规模工业化生产。(The invention discloses a preparation method of an alpha, beta-unsaturated amide compound, which comprises the following steps: adding a catalyst, alkyne, ammonium salt and a solvent into a reaction vessel, introducing carbon monoxide (CO), heating for reaction, and separating to obtain the product alpha, beta-unsaturated amide after the reaction is finished. The method can effectively reduce the equipment requirement by using the ammonium salt which is easy to operate, the used ammonium salt is cheap and easy to obtain, and a ligand is not required to be added in the reaction process, so that the cost is saved. The preparation method has excellent substrate practicability, simple and direct operation steps, mild and easily-controlled reaction conditions, cheap and easily-obtained raw materials, high product yield and product purity, and is suitable for large-scale industrial production.)

1. A process for the preparation of an α, β -unsaturated amide, characterized in that said process comprises the steps of: adding a catalyst, alkyne, ammonium salt and a solvent into a reaction vessel, introducing carbon monoxide (CO), heating for reaction, and separating to obtain the alpha, beta-unsaturated amide after the reaction is finished, wherein the ammonium salt is an ionic compound consisting of ammonium ions and acid radical ions.

2. The method of claim 1, wherein the alkyne includes one of a terminal alkyne or an internal alkyne, and the number of carbon atoms in the alkyne is an integer from 2 to 30.

3. The α, β -unsaturated acyl of claim 1A process for the preparation of an amine, characterized in that: the transition metal catalyst is selected from FeCl₃、FeCl₂、Fe(CO)₅、Fe₂(CO)₉、Fe₃CO₁₂、Fe、NiCl₂、Ni(COD)₂、Ni、CoCl₂、Co₂(CO)₈、Cr(CO)₆、Mo(CO)₆、W(CO)₆、RuCl₃、Ru₃CO₁₂、ZnCl₂、Zn、MnCl₂、Mn、Mn₂(CO)₁₀One or more of (a).

4. The method for producing an α, β -unsaturated amide according to claim 1, characterized in that: the reaction does not require a ligand.

5. The method for producing an α, β -unsaturated amide according to claim 1, characterized in that: the ammonium salt is selected from NH₄F、NH₄Cl、NH₄Br、NH₄I、NH₄OAc、NH₄PF₆、NH₄HCO₃、(NH₄)₂CO₃、HCOONH₄One or more of (a).

6. The method for producing an α, β -unsaturated amide according to claim 1, characterized in that: carbon monoxide is used as a reaction raw material.

7. The method for producing an α, β -unsaturated amide according to claim 1, characterized in that: the reaction solvent is one or more selected from tetrahydrofuran, 1, 4-dioxane, toluene, acetonitrile, 1, 2-dichloroethane and N, N-dimethylformamide.

8. The method for producing an α, β -unsaturated amide according to claim 1, characterized in that: the dosage of the ammonium salt is 1-50 molar equivalents of the dosage of alkyne.

9. The method for producing an α, β -unsaturated amide according to claim 1, characterized in that: the molar ratio of the alkyne to the transition metal catalyst is 1: (0.001-0.5).

10. The method for producing an α, β -unsaturated amide according to claim 1, characterized in that: the reaction temperature is 60-160 ℃.

11. The method for producing an α, β -unsaturated amide according to claim 6, characterized in that: the pressure of the CO in the reaction vessel is 1-60 bar.

12. The method for producing an α, β -unsaturated amide according to claim 1, characterized in that: the reaction time is 1-48 h.

13. The method for producing an α, β -unsaturated amide according to claim 1, characterized in that: the reaction product is straight-chain alpha, beta-unsaturated amide.

Technical Field

The invention belongs to the technical field of synthesis of amide organic compounds, and particularly relates to a preparation method of alpha, beta-unsaturated amide.

Background

The alpha, beta-unsaturated amide is an important chemical, is widely applied to the chemical industry and the fine chemical production industry, and has important application in the aspects of food, medicine, pesticide, materials and the like. The traditional preparation method of alpha, beta-unsaturated amide comprises the following steps: 1) based on carboxylic acid derivatives and acyl chlorides on aminesNucleophilic substitution; 2) in the presence of an activating reagent, carboxylic acid derivatives and amine are subjected to cyclization reaction to obtain alpha, beta-unsaturated amide (R.M. de Figueiredo, J. -S. Suppo, J. -M. Campagne, Chem. Rev.,2016, 116, 12029). The amination and carbonylation reaction has been the focus of research in many carbonylation reactions of nitrogen-oxygen-containing compounds, and the reaction directly synthesizes alpha, beta-unsaturated amide compounds by using an 'one-step method' by using unsaturated compounds (such as alkene, alkyne and the like), carbon monoxide and amine as raw materials.

At present, transition metal catalyzed aminic carbonylation reactions have been reported to produce α, β -unsaturated amide compounds that require the use of noble metals, expensive complex ligands, oxidizing agents, ammonia gas or organic amines (s. Zhang, h. Neumann, m. beller. Synthesis of α, β -unsaturated carbonyl reactions).Chem. Soc. Rev., 2020, 49, 3187). These factors increase the reaction cost of the amination carbonylation reaction, which is not favorable for industrial production; meanwhile, the method also has the defects of increased cost for treating the subsequent three wastes, overhigh equipment depreciation rate and the like, and the defects can bring adverse effects on industrial application.

For example, chinese patent No. CN103232357A discloses a method for synthesizing α, β -unsaturated amide, which uses iron salt as a catalyst, uses an oxidizing agent, and uses a cinnamic acid compound and a formamide compound as reactants to synthesize the α, β -unsaturated amide. The method uses oxidant to increase preparation cost, and the range of reaction substrates is limited, which is not beneficial to application.

Therefore, it is necessary to develop a novel preparation method for synthesizing the alpha, beta-unsaturated amide, which uses a cheap catalyst, has cheap and easily available raw materials, high product yield, simple reaction process, safety, environmental protection and good substrate universality.

Disclosure of Invention

The invention aims to enrich the preparation method of alpha, beta-unsaturated amide, and provides a novel preparation method for preparing alpha, beta-unsaturated amide from alkyne.

In order to achieve the purpose, the technical scheme provided by the invention is as follows:

a process for the preparation of an α, β -unsaturated amide, said process comprising the steps of: adding a catalyst, alkyne, ammonium salt and a solvent into a reaction vessel, introducing CO, heating for reaction, and separating to obtain the alpha, beta-unsaturated amide after the reaction is finished, wherein the ammonium salt is an ionic compound consisting of ammonium ions and acid radical ions.

Further, the number of carbon atoms of the alkyne is an integer from 2 to 30, and the alkyne includes one of a terminal alkyne or an internal alkyne.

Further, the transition metal catalyst is selected from FeCl₃、FeCl₂、Fe(CO)₅、Fe₂(CO)₉、Fe₃CO₁₂、Fe、NiCl₂、Ni(COD)₂、Ni、CoCl₂、Co₂(CO)₈、Cr(CO)₆、Mo(CO)₆、W(CO)₆、RuCl₃、Ru₃CO₁₂、ZnCl₂、Zn、MnCl₂、Mn、Mn₂(CO)₁₀One or more of (a).

Preferably, the transition metal catalyst is selected from Fe (CO)₅、Fe₂(CO)₉、Fe₃CO₁₂、CoCl₂、Co₂(CO)₈、Mo(CO)₆、W(CO)₆、Ru₃CO₁₂、Mn₂(CO)₁₀One or more of Fe, Ni, Zn and Mn.

Further, the reaction does not require a ligand.

Further, the ammonium salt is selected from NH₄Cl、NH₄F、NH₄Br、NH₄I、NH₄OAc、NH₄PF₆、NH₄HCO₃、(NH₄)₂CO₃、HCOONH₄One or more of (a).

Further, carbon monoxide is used as a reaction raw material.

Further, the reaction solvent is one or more selected from tetrahydrofuran, 1, 4-dioxane, toluene, acetonitrile, 1, 2-dichloroethane, and N, N-dimethylformamide.

Further, the amount of the ammonium salt is 1-50 molar equivalents of the amount of the alkyne.

Further, the molar ratio of alkyne to transition metal catalyst is 1: (0.001-0.5).

Further, the reaction temperature is 60-160 ℃.

Preferably, the reaction temperature is 100-.

Further, the pressure of CO in the reaction vessel is 1-60 bar.

Preferably, the pressure of CO in the reaction vessel is between 10 and 40 bar.

Further, the reaction time is 1-48 h.

Preferably, the reaction time is 12 to 30 hours.

Further, the reaction product is a linear alpha, beta-unsaturated amide.

Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:

1. the invention uses cheap transition metal as a catalyst system to catalyze alkyne and ammonium salt to carry out amination and carbonylation reaction to prepare the alpha, beta-unsaturated amide, and the reaction does not need ligand, and has mild reaction condition, higher activity, short time and high yield.

2. Compared with the prior art, the method disclosed by the invention uses a small amount of catalyst, shortens the multi-step reaction into one-step reaction, is simple to treat, is beneficial to the purification of the product, and more importantly, avoids the use of volatile ammonia gas or organic amine with irritant odor.

3. The catalyst system disclosed by the invention has universality for various types of alkynes.

4. The raw materials used by the invention are wide in source, cheap and easily available, and the reaction process is simple and controllable, so that the method is suitable for large-scale industrial production.

Detailed Description

The invention claims a preparation method of alpha, beta-unsaturated amide, which comprises the following steps: adding a catalyst, alkyne, ammonium salt and a solvent into a reaction container under the nitrogen atmosphere, heating to 60-160 ℃ under the CO pressure of 1-60 bar, reacting for 1-48 h, and slowly releasing the pressure of the reaction container at room temperature after the reaction is finished. The product in the reaction liquid is separated to obtain alpha, beta-unsaturated amide, and the yield is determined by characterization or by methods of an internal standard method and a gas chromatography.

The general reaction of this reaction is as follows:

the following examples 1-10 are specific examples of the preparation of organic carboxylic acids, as shown below:

example 1

Under nitrogen atmosphere, Co is added₂(CO)₈（0.01 mmol, 3.4 mg）, NH₄Cl (3 mmol, 160 mg) and magnetons were added to a 5 mL glass tube. Tetrahydrofuran (2 mL), phenylacetylene (1 mmol, 102 mg) was then added. The reaction tube was placed in a reaction vessel, the reaction vessel was sealed, the air in the reaction vessel was removed and washed three times with carbon monoxide, and finally the carbon monoxide was pressurized to 35 bar. After the addition, the reaction kettle is placed in a metal module preheated to 140 ℃ in advance, and stirred for 24 hours. After the reaction is finished, cooling the reaction system to room temperature and slowly releasing the pressure. After the reaction, the solvent was distilled off, and the product (126 mg) was obtained by simple column chromatography (eluent was a mixed solvent of petroleum ether (60-90 ℃) and ethyl acetate) after concentration with a yield of 86%. The nuclear magnetic data are:¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J = 15.7 Hz, 1H), 7.51 – 7.42 (m, 2H), 7.39 – 7.35 (m, 3H), 6.47 (d, J = 15.7 Hz, 1H), 5.89 (br, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 168.1, 142.5, 134.5, 130.0, 128.9, 127.9, 119.6。

example 2

Under nitrogen atmosphere, Fe₃(CO)₁₂（0.01 mmol, 5 mg），NH₄HCO₃ (5 mmol, 400 mg) and magnetons were added to a 5 mL glass tube. Tetrahydrofuran (2 mL), 3-chlorophenylacetylene (1 mmol, 136 mg) was then added. The reaction tube was placed in a reaction vessel, the reaction vessel was sealed, the air in the reaction vessel was removed and washed three times with carbon monoxide, and finally the carbon monoxide was pressurized to 30 bar. After the addition, the reaction kettle is placed in a metal module preheated to 140 ℃ in advance, and stirred for 18 hours. After the reaction is finished, cooling the reaction system to room temperature and slowly releasing the pressure. After the reaction, the solvent was distilled off, and the product (146 mg) was obtained by simple column chromatography (eluent was a mixed solvent of petroleum ether (60-90 ℃) and ethyl acetate) after concentration, with a yield of 81%. The nuclear magnetic data are:¹H NMR (400 MHz, DMSO) δ 7.63 (s, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.43 (s, 2H), 7.39 (s, 1H), 7.19 (s, 1H), 6.70 – 6.66 (m, 1H). ¹³C NMR (101 MHz, DMSO) δ 166.8, 138.0, 137.7, 134.1, 131.2, 129.5, 127.6, 126.5, 124.6。

example 3

FeCl is added under nitrogen atmosphere₂（0.02 mmol, 2.6 mg）， NH₄HCO₃(3 mmol, 240 mg) and magnetons were added to a 5 mL glass tube. 1, 4-dioxane (2 mL), 4-cyanophenylacetylene (1 mmol, 127 mg) was then added. The reaction tube was placed in a reaction vessel, the reaction vessel was sealed, the air in the reaction vessel was removed and washed three times with carbon monoxide, and finally the carbon monoxide was pressurized to 30 bar. After the addition, the reaction kettle was placed in a metal block preheated to 130 ℃ in advance, and stirred for 18 hours. After the reaction is finished, the reaction kettle is used for reaction,the reaction was cooled to room temperature and the pressure was slowly released. The yield was determined by gas chromatography working curve using dodecane as internal standard to be 58%.

Example 4

Under nitrogen atmosphere, ZnCl is added₂（0.02 mmol, 2.7 mg），HCOONH₄(3 mmol, 189 mg) and magnetons were added to a 5 mL glass tube. Tetrahydrofuran (2 mL), 2-methoxyphenylacetylene (1 mmol, 132 mg) was then added. The reaction tube was placed in a reaction vessel, the reaction vessel was sealed, the air in the reaction vessel was removed and washed three times with carbon monoxide, and finally the carbon monoxide was pressurized to 25 bar. After the addition, the reaction kettle is placed in a metal module preheated to 130 ℃ in advance, and stirred for 24 hours. After the reaction is finished, cooling the reaction system to room temperature and slowly releasing the pressure. After the reaction, the solvent was distilled off, and the product (155.8 mg) was obtained by simple column chromatography (eluent was a mixed solvent of petroleum ether (60-90 ℃) and ethyl acetate) after concentration with a yield of 88%. The nuclear magnetic data are:¹H NMR (400 MHz, DMSO) δ 7.67 (d, J = 16.0 Hz, 1H), 7.51 (d, J = 7.0 Hz, 2H), 7.35 (t, J = 7.7 Hz, 1H), 7.06 (d, J= 8.0 Hz, 2H), 6.97 (t, J = 7.4 Hz, 1H), 6.63 (d, J = 16.0 Hz, 1H), 3.85 (s, 3H). ¹³C NMR (100 MHz, DMSO) δ 167.0, 157.5, 134.2, 130.7, 127.7, 123.3, 122.6, 120.6, 111.7, 55.5, 40.1。

example 5

Under nitrogen atmosphere, adding Ni (COD)₂（0.01 mmol, 2.8 mg），NH₄OAc (6 mmol, 462 mg) and magnetons were added to a 5 mL glass tube. N, N-dimethylformamide (2 mL), 2-fluoroacetylene (1 mmol, 120 mg) was then added. Putting the reaction tube into a reaction kettle, sealing and reactingThe kettle was allowed to stand, the air in the kettle was removed and washed three times with carbon monoxide, and finally the carbon monoxide was pressurized to 25 bar. After the addition, the reaction kettle is placed in a metal module preheated to 120 ℃ in advance, and stirred for 25 hours. After the reaction is finished, cooling the reaction system to room temperature and slowly releasing the pressure. After the reaction, the solvent was distilled off, and the product (138.6 mg) was obtained by simple column chromatography (eluent was a mixed solvent of petroleum ether (60-90 ℃) and ethyl acetate) after concentration with a yield of 84%. The nuclear magnetic data are:¹H NMR (400 MHz, CDCl₃) δ 7.65 (d, J = 15.9 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.26 (dd, J = 13.1, 6.3 Hz, 1H), 7.05 (dt, J = 19.2, 8.1 Hz, 2H), 6.53 (d, J = 15.9 Hz, 1H), 5.76 (br, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 168.0, 162.8, 135.6, 131.4, 131.4, 129.89, 124.6, 124.5, 122.7, 116.4, 116.2。

example 6

Under nitrogen atmosphere, Co is added₂(CO)₈（0.01 mmol, 3.4 mg），HCOONH₄(3 mmol, 189 mg) and magnetons were added to a 5 mL glass tube. Toluene (2 mL), 4-tert-butylacetylene (1 mmol, 158 mg) was then added. The reaction tube was placed in a reaction vessel, the reaction vessel was sealed, the air in the reaction vessel was removed and washed three times with carbon monoxide, and finally the carbon monoxide was pressurized to 35 bar. After the addition, the reaction kettle is placed in a metal module preheated to 140 ℃ in advance, and stirred for 18 hours. After the reaction is finished, cooling the reaction system to room temperature and slowly releasing the pressure. After the reaction, the solvent was distilled off, and the product (182.7 mg) was obtained by simple column chromatography (eluent was a mixed solvent of petroleum ether (60-90 ℃) and ethyl acetate) after concentration with a yield of 90%. The nuclear magnetic data are:¹H NMR (400 MHz, DMSO) δ 7.65 – 7.32 (m, 6H), 7.08 (s, 1H), 6.59 – 6.55 (m, 1H), 1.27 (s, 10H). ¹³C NMR (100 MHz, DMSO) δ 166.8, 152.2, 139.0, 132.1, 127.3, 125.6, 121.4 34.4, 30.9。

example 7

Under nitrogen atmosphere, adding Mn₂(CO)₁₀（0.01 mmol, 3.9 mg），NH₄OAc (6 mmol, 462 mg) and magnetons were added to a 5 mL glass tube. 1,2 dichloroethane (2 mL), methyl 4-carboxylate phenylacetylene (1 mmol, 160.2 mg) was then added. The reaction tube was placed in a reaction vessel, the reaction vessel was sealed, the air in the reaction vessel was removed and washed three times with carbon monoxide, and finally the carbon monoxide was pressurized to 25 bar. After the addition, the reaction kettle is placed in a metal module preheated to 130 ℃ in advance, and stirred for 30 hours. After the reaction is finished, cooling the reaction system to room temperature and slowly releasing the pressure. After the reaction, the solvent was distilled off, and the product (166 mg) was obtained by simple column chromatography (eluent was a mixed solvent of petroleum ether (60-90 ℃) and ethyl acetate) with a yield of 81%. The nuclear magnetic data are:¹H NMR (400 MHz, DMSO) δ 7.97 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 7.61 (s, 1H), 7.47 (d, J = 15.9 Hz, 1H), 7.21 (s, 1H), 6.74 (d, J = 15.9 Hz, 1H), 3.86 (s, 3H).¹³C NMR (100 MHz, DMSO) δ 166.2, 165.8, 139.5, 137.8, 129.9, 129.7, 127.7, 125.0, 52.1。

example 8

Under nitrogen atmosphere, Fe₃(CO)₁₂（0.01 mmol, 5 mg），NH₄F (5 mmol, 185 mg) and magnetons were added to a 5 mL glass tube. Toluene (2 mL), 4- (trifluoromethyl) phenylacetylene (1 mmol, 170 mg) was then added. The reaction tube was placed in a reaction vessel, the reaction vessel was sealed, the air in the reaction vessel was removed and washed three times with carbon monoxide, and finally the carbon monoxide was pressurized to 25 bar. After the addition is finished, the reaction kettle is,the reaction kettle is placed in a metal module preheated to 110 ℃ in advance, and stirred for 25 hours. After the reaction is finished, cooling the reaction system to room temperature and slowly releasing the pressure. After the reaction, the solvent was distilled off, and the product (169.8 mg) was obtained by simple column chromatography (eluent was a mixed solvent of petroleum ether (60-90 ℃) and ethyl acetate) after concentration, with a yield of 79%. The nuclear magnetic data are:¹H NMR (400 MHz, DMSO) δ 7.85 – 7.70 (m, 4H), 7.62 (s, 1H), 7.49 (d, J = 15.9 Hz, 1H), 7.22 (s, 1H), 6.74 (d, J = 15.9 Hz, 1H). ¹³C NMR (101 MHz, DMSO) δ 166.2, 138.9, 137.4, 129.3, 129.0, 128.1, 125.6 (t, J = 16.0 Hz), 125.2.

example 9

Under nitrogen atmosphere, Ru₃(CO)₁₂（0.01 mmol, 6.4 mg），NH₄HCO₃(3 mmol, 240 mg) and magnetons were added to a 5 mL glass tube. 1, 4-dioxane (2 mL), diphenylacetylene (1 mmol, 178 mg) was then added. The reaction tube was placed in a reaction vessel, the reaction vessel was sealed, the air in the reaction vessel was removed and washed three times with carbon monoxide, and finally the carbon monoxide was pressurized to 25 bar. After the addition, the reaction kettle is placed in a metal module preheated to 140 ℃ in advance, and stirred for 25 hours. After the reaction is finished, cooling the reaction system to room temperature and slowly releasing the pressure. After the reaction, the solvent was distilled off, and the product (102.6 mg) was obtained by simple column chromatography (eluent was a mixed solvent of petroleum ether (60-90 ℃) and ethyl acetate) after concentration with a yield of 46%. The nuclear magnetic data are:¹H NMR (400 MHz, DMSO) δ 7.48 – 7.33 (m, 4H), 7.30 –7.26 (m, 1H), 7.20 – 7.15 (m, 5H), 7.03 – 6.94 (m, 2H), 6.86 (s, 1H). ¹³C NMR (101 MHz, DMSO) δ 169.0, 136.7, 136.6, 135.0, 133.9, 129.6, 129.3, 128.8, 128.2, 128.1, 127.8。

example 10

Under nitrogen atmosphere, Fe₂(CO)₉（0.01 mmol, 3.6 mg），(NH₄)₂CO₃(2 mmol, 192 mg) and magnetons were added to a 5 mL glass tube. Toluene (2 mL), 1-octyne (1 mmol, 110 mg) was then added. The reaction tube was placed in a reaction vessel, the reaction vessel was sealed, the air in the reaction vessel was removed and washed three times with carbon monoxide, and finally the carbon monoxide was pressurized to 35 bar. After the addition, the reaction kettle is placed in a metal module preheated to 140 ℃ in advance, and stirred for 24 hours. After the reaction is finished, cooling the reaction system to room temperature and slowly releasing the pressure. The reaction was cooled to room temperature and the pressure was slowly released. The yield was determined to be 55% by working curve of gas chromatography using dodecane as internal standard.

It should be noted that the above-mentioned preferred embodiments are merely illustrative of the technical concepts and features of the present invention, and are intended to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.