A method for synthesizing an amide compound

Abstract

The present invention discloses a synthetic method for preparing amide compounds by coupling aldehydes with secondary amines. An aldehyde having the structure of formula (I) and a secondary amine compound having the structure of formula (II) are used as a medium in an organic solvent, and an amide compound having the structure of formula (III) is prepared under the action of a metal oxide, a base and light. The synthetic method of the present invention has high reaction efficiency, mild reaction conditions, simple operation, easy separation of the amide product, and the metal oxide catalyst can be recycled, which is easy to realize industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of photocatalytic synthesis of amides, and relates to a synthesis method for coupling aldehydes with primary amines to prepare amide compounds, and particularly relates to a method for photocatalytically coupling aldehydes with primary amines using metal oxides to prepare amide compounds. Background Art

[0002] Amides are common industrial raw materials and synthetic intermediates, and the amide functional group is an important chemical unit in natural products, therapeutic drugs, and synthetic polymers. Amides are present in more than 25% of drug molecules, and the green, economic, and efficient preparation of amides has always been a problem to be solved urgently. The synthesis methods of amide bonds include: condensation method, acyl halide method, mixed anhydride method, and acyl azide method. These methods face some problems in actual production, such as the use of coupling agents making subsequent separation and purification inconvenient, and by-products being difficult to separate; the acyl halide method will cause equipment corrosion and environmental pollution, limit subsequent reactions, have poor atomic economy, and is not conducive to large-scale industrial production. For decades, new chemical methods have been developed for amide synthesis, including new acylation reactions of amines, oxidative amidation of alcohols or aldehydes with amines, transamidation reactions, and visible light-mediated C-H amidation. In particular, oxidative amidation of aldehydes with amines has recently received increasing attention because it provides an attractive alternative to traditional amide synthesis. However, most reported oxidative amides involve the use of transition noble metals and stoichiometric oxidants. Patent CN 104418762A discloses a method for synthesizing amides by thermally catalyzing the reaction of aldehydes and amines, using a metal iridium complex catalyst, and the reactants need to be carried out at 120 °C, and water needs to be evaporated during the reaction process. Such methods require high reaction temperatures, inert atmospheres, and / or anhydrous organic solvents.

[0003] Therefore, great interest has been aroused in the development of new methods for oxidative amidation under mild reaction conditions. Aldehydes and secondary amines can form amides in the presence of eosin tetrachloride photocatalyst. However, this method is only applicable to secondary amines, and it is difficult to separate the catalyst from the reaction solution (Leung K C, Cui J F, Hui T W, et al. Photooxidative Amidation of Aldehydes with Amines Catalyzed by Rose Bengal[J]. Asian Journal of Organic Chemistry, 2015, 4(6):533-536.). It has been reported in the literature that aldehydes can react with amines to obtain amides under the action of copper sulfate and tert-butyl hydroperoxide. The reaction conditions of this method are relatively mild, but an excessive amount of tert-butyl hydroperoxide must be used during the reaction process, and the use of transition metal salts is not conducive to subsequent separation (Ghosh S C, Ngiam J, Seayad A M, et al. Copper-Catalyzed Oxidative Amidation of Aldehydes with Amine Salts: Synthesis of Primary, Secondary, and Tertiary Amides[J]. Journal of Organic Chemistry, 2012, 77(18):8007-8015). The coupling of aldehydes and amines to prepare amides undergoes oxidative amination through a homogeneous Fe catalyst and carbene catalysis to form amides. However, this method requires a high reaction temperature, and there is a problem of difficult separation of the homogeneous catalyst from the reaction solution. Moreover, this synthesis method is only applicable to the reaction with aromatic aldehydes as raw materials (Singh A, Azad C S, Narula A K. Oxidative Amidation of Aldehydes with Amines Catalysed by Fe(II)-Hydride Complex and N-Heterocyclic Carbenes (NHC)[J]. ChemistrySelect, 2020, 5(30):9417-9423.). The photocatalytic selective oxidation technology generally operates at room temperature, uses a heterogeneous catalyst, the catalyst is easy to separate and can be reused, and the photocatalysis uses oxygen or air as the oxidant. Its reaction conditions are mild, and the selectivity for amides is high, which is conducive to the green synthesis of amides. SUMMARY OF THE INVENTION

[0004] The present invention provides a method for synthesizing amide compounds, aiming to avoid technical problems such as high-temperature reactions and environmental pollution caused by high-content phosphine ligands.

[0005] To achieve the above object, an embodiment of the present invention provides a method for synthesizing an amide compound,

[0006] reacting an aldehyde having the structure of formula (I) with an amine compound having the following formula through photocatalysis to obtain an amide compound having the structure of formula (III);

[0007]

[0008] Wherein, in the aldehyde having the structure of formula (I), the R 1 is C6-C 20 aryl, C4-C 20 heterocyclic arene, C1-C 10 alkyl and C2-C 10 alkenyl; in the amine compound having the structure of formula (II), the R 2 is C1-C 20 alkyl, C3-C 20 cycloalkyl, C2-C 20 alkenyl, C2-C 20 alkynyl, C6-C 20 aryl.

[0009] Further, the R 1 is C6-C 12 aryl, C4-C6 heterocyclic arene, C4-C8 alkyl and C4-C9 alkenyl; the R 2 is C1-C 12 alkyl, C3-C 12 cycloalkyl, C2-C 12 alkenyl, C2-C 12 alkynyl, C6-C 12 aryl, or the N atom to which they are attached together forms a C1-C6 heterocyclic group.

[0010] Furthermore, the substituents of the alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclic arene and heterocyclic group are optionally mono-substituted by halogen, hydroxyl, cyano, nitro, alkoxy or aryl, or poly-substituted with the same or different groups.

[0011] Further, the R 1 is phenyl, 4-methylphenyl, 4-methoxyphenyl, furyl, pyridyl, thienyl, naphthyl, hexadienyl; the R 2 is methyl, ethyl, butyl, octyl, cyclohexyl, phenyl, or naphthyl, or together with the attached N atom forms azepan-1-yl or pyrrolidin-1-yl.

[0012] Furthermore, the molar ratio of the aldehyde to the amine compound is 1:1 to 2.

[0013] Further, the organic solvent is one or more of toluene, cyclohexane, xylene, benzene, n-hexane, ether, 1,4-dioxane, tetrahydrofuran, dichloromethane, dichloroethane, carbon tetrachloride, acetone or petroleum ether.

[0014] Further, the photocatalytic reaction is carried out in the presence or absence of a base.

[0015] Still further, the base is one or more of potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium isopropoxide;

[0016] Further, the molar ratio of the aldehyde to the base is 1:0.1 - 3.

[0017] Further, the metal oxide is one or more of Co3O4, WO3, CuO, TiO2, Mn3O4, Ru2O3, SnO2, Fe3O4, Ag2O, Ni2O3.

[0018] Further, the specific process of the synthesis method includes the following steps:

[0019] (1) Put the aldehyde, secondary amine compound, photocatalyst, base and organic solvent into a reactor;

[0020] (2) Continuously stir and react under the irradiation of a 15W - 100W light source to obtain an amide compound.

[0021] Further, the reaction time in step (2) is 1 - 10h.

[0022] Further, the light source is one or more of a xenon lamp, a light-emitting diode, a mercury lamp, a metal halide lamp.

[0023] The above solution of the present invention has the following beneficial effects:

[0024] (1) The present invention uses photocatalysis to prepare amides from aldehydes and amines, which has the advantages of high catalytic efficiency and mild reaction conditions. It not only avoids the high temperature, precious metal catalysts and excessive oxides used as oxidants required in the existing process of preparing amides from aldehydes and amines, but also has a wide substrate applicability.

[0025] (2) The method for preparing amides by reacting aldehydes and amines under photocatalytic conditions in the present invention reacts at room temperature in an air or oxygen atmosphere, has high catalytic selectivity, high purity and yield of the obtained product, avoids the production of by-product imines, and the by-product in the preparation process is water, which is environmentally friendly and has high atom economy.

[0026] (3) The present invention uses photocatalysis to prepare amides from aldehydes and amines, and the catalyst used is a common transition metal oxide, which not only has low cost, but also is easy to separate and recycle from the product and can be reused, meeting the requirements of green chemistry.

[0027] (4) The aldehyde and amine of the present invention react under photocatalytic conditions to prepare amides. The products are easy to separate, the operation is simple, and it is easy to realize industrial application. Description of the Drawings

[0028] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required to be used in the embodiments. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0029] Figure 1 is the 1 HNMR spectrum of N-benzylbenzamide prepared in Example 1 of the present invention;

[0030] Figure 2 is the 1 H NMR spectrum of N-butyl-2-naphthamide prepared in Example 2;

[0031] Figure 3 is the mass spectrum of N-benzylhepta-2,4-dienamide prepared in Example 3;

[0032] Figure 4 is the 1 H NMR spectrum of N-(thiophen-2-ylmethyl)benzamide prepared in Example 4;

[0033] Figure 5 is the 1 HNMR spectrum of (5-methylpyridin-2-yl)(pyrrolidin-1-yl)methanone prepared in Example 5;

[0034] Figure 6 is the 1 H NMR spectrum of N-(2-(cyclohex-1-en-1-yl)ethyl)-1-naphthamide prepared in Example 6 Detailed Embodiments

[0035] In order to make the technical problems, technical solutions and advantages to be solved by the present invention clearer, the following will be described in detail with reference to the drawings and specific embodiments.

[0036] Unless otherwise defined, all the technical terms used hereinafter have the same meaning as commonly understood by those skilled in the art. The technical terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the protection scope of the present invention.

[0037] Unless otherwise specified, all raw materials, reagents, instruments, and equipment used in the present invention can be obtained through market purchases or can be prepared by existing methods.

[0038] The present invention provides a method for synthesizing amide compounds in view of existing problems.

[0039] All parts and percentages in the examples refer to mass unless otherwise specified.

[0040] Example 1

[0041] Add 2.6811 g of benzaldehyde (with a content of 99%) to a 250 mL reaction flask, add 100 mL of cyclohexane as a solvent, then add a total of 1 g of sodium hydride (with a content of 60%) in two portions, add 2.7061 g of benzylamine (with a content of 99%), add 60 mg of Co3O4, and react for 6 hours under normal temperature and 30 W LED light irradiation conditions to obtain a light yellow solid. The reaction mixture is filtered, washed with alcohol, the filtrate is concentrated by rotary evaporation, 10 mL of water is added for dissolution, the pH is adjusted to 7 with 0.1 mol / L HCl, and then washed with water to obtain 4.9120 g of a white solid. Through analysis and detection, the yield of N-benzylbenzamide based on benzaldehyde is 93.2%.

[0042] The white solid is directly characterized, and its 1 1H NMR spectrum is as Figure 1 shown:

[0043] δ 2.50 is the solvent peak, δ: 0.70 (t, 3H), 4.66 (d, 2H), 6.53 (s, 1H), 7.33 (m, 5H), 7.43 (t, 2H), 7.51 (d, 1H), 7.81 (d, 2H), and its chemical shift is consistent with the hydrogen on the target product N-benzylbenzamide.

[0044] Comparative Example 1

[0045] Add 2.7322 g of benzaldehyde (with a content of 99%) to a 100 mL reaction flask, add 5 mL of toluene as a solvent, then add a total of 1.1 g of sodium hydroxide (with a content of 99%) in two portions, add 2.7061 g of benzylamine (with a content of 99%), add 50 mg of CoCl3, and add 1.7363 g of tert-butyl hydroperoxide with a content of 70%. React for 6 hours under normal temperature and 30 W LED light irradiation conditions to obtain a black liquid. Through analysis and detection, N-benzylbenzamide is not obtained.

[0046] Example 2

[0047] 3.9442 g of 2-naphthaldehyde (with a content of 99%) was added to a 250 mL reaction flask, 100 mL of toluene was added as a solvent, then 2.8571 g of potassium tert-butoxide (with a content of 98%) was added, 1.8471 g of n-butylamine (with a content of 99%) was added, and then 100 mg of Fe3O4 was added. The reaction was carried out at room temperature under 15 W LED light irradiation for 4 hours. After the reaction, it was filtered, washed with alcohol, the filtrate was dried by rotary evaporation, 10 mL of water was added to dissolve it, and the pH was adjusted to 7 with 0.1 mol / L HCl. After washing with water, 5.0804 g of yellow solid was obtained. Through analysis and detection, the yield of N-butyl-2-naphthamide based on naphthaldehyde was 89.4%.

[0048] Recovery performance test of Fe3O4 catalyst: After filtration and washing with water, the above catalyst Mn3O4 was recovered, dried at 120 °C, and after being reused 5 times, its catalytic effect did not decrease significantly.

[0049] The yellow solid was directly characterized, and its 1 1H NMR spectrum was as Figure 2 shown:[[]]END]]

[0050] δ 2.50 was the solvent peak, δ: 0.91 (t, 3H), 1.32 (m, 2H), 1.52 (m, 2H), 3.29 (t, 2H), 7.58 (m, 2H), 7.94 (m, 4H), 8.44 (d, 1H), 8.62 (t, 1H). It was confirmed as the product N-butyl-2-naphthamide.

[0051] Comparative Example 2

[0052] 3.9442 g of 2-naphthaldehyde (with a content of 99%) was added to a 250 mL reaction flask, 100 mL of toluene was added as a solvent, then 2.8571 g of potassium tert-butoxide (with a content of 98%) was added in batches, 1.8471 g of n-butylamine (with a content of 99%) was added, and then 2.7363 g of tert-butyl hydroperoxide (with a content of 70%) was added. The reaction was carried out at room temperature under 15 W LED light irradiation for 10 hours. Through analysis and detection, the target product N-butyl-2-naphthamide was not obtained.

[0053] Example 3

[0054] 2.7818 g of 2,4-heptadienal (with a content of 99%) was added to a 250 mL reaction flask, 100 mL of cyclohexane was added as a solvent, a total of 1.3 g of potassium hydride (with a content of 60%) was added in batches, 2.7061 g of benzylamine (with a content of 99%) was added, 50 mg of Mn3O4 hydrate (99%) was added, and the reaction was carried out for 5 hours under normal temperature and 100 W LED light irradiation to obtain a yellow liquid. The reaction mixture was filtered, washed with alcohol, the filtrate was concentrated by rotary evaporation, dissolved in 10 mL of water, and the pH was adjusted to 7 with 0.1 mol / L HCl. After washing with water, 4.2844 g of yellow liquid was obtained. The yield of N-benzylhepta-2,4-dienamide based on heptadienal was 79.6%.

[0055] The mass spectrum of the yellow liquid is as Figure 3 shown. The peak with a mass-to-charge ratio of 238.1208 in the spectrum is the [M+Na] ion peak. The theoretical molecular weight M+Na of phenyl-pyrrolidin-1-one is 238.1202, confirming that the product is N-benzylhepta-2,4-dienamide.

[0056] Example 4

[0057] 2.7330 g of benzaldehyde (with a content of 99%) was added to a 100 mL reaction flask, 50 mL of benzene was added as a solvent, and then a total of 1 g of sodium hydride (with a content of 60%) was added in two portions. 2.8578 g of thiophene-2-methylamine (with a content of 99%) was added, 40 mg of Mn3O4 (99%) was added, and the reaction was carried out for 7 hours under normal temperature and 100 W LED light irradiation to obtain a light yellow liquid. The reaction mixture was filtered, washed with alcohol, the filtrate was concentrated by rotary evaporation, dissolved in 10 mL of water, and the pH was adjusted to 7 with 0.1 mol / L HCl. After washing with water, 4.9704 g of white solid was obtained. The yield of N-(thiophen-2-ylmethyl)benzamide based on benzaldehyde was 91.5%.

[0058] The white solid was directly characterized, and its 1 1H NMR spectrum is as Figure 4 shown:

[0059] δ 2.50 is the solvent peak, δ: 4.63 (d, 2H), 6.96 (t, 1H), 7.02 (d, 1H), 7.38 (t, 1H), 7.48 (m, 3H), 7.87 (d, 2H), 9.13 (s, 1H), and its chemical shifts are consistent with the hydrogens on the target product N-(thiophen-2-ylmethyl)benzamide.

[0060] Comparative Example 4

[0061] 2.7330 g of benzaldehyde (with a content of 99%) was added to a 100 mL reaction flask, 50 mL of benzene was added as a solvent, and then a total of 1.5 g of sodium ethoxide (with a content of 60%) was added in two portions. 2.8578 g of thiophene-2-methylamine (with a content of 99%) was added, and then 0.1 g of MnCl2 (with a content of 99%) and 0.0500 g of piperidine N-oxide (TEMPO, with a content of 98%) were added. The reaction was carried out for 10 hours under normal temperature and 100 W LED light irradiation. After analysis and detection, N-(thiophen-2-ylmethyl)benzamide was not obtained.

[0062] Example 5

[0063] 3.0510 g of 5-methylpyridine-2-carbaldehyde (with a content of 99%) was added to a 100 mL reaction flask, 50 mL of n-hexane was added as a solvent, and then 1.5 g of sodium methoxide (with a content of 60%) was added in batches. 2.7061 g of benzylamine (with a content of 99%) was added, and then 40 mg of the prepared CuO was added. The reaction was carried out for 10 hours under normal temperature and 30 W LED light irradiation. The reaction mixture was filtered, washed with alcohol, the filtrate was concentrated by rotary evaporation, 10 mL of water was added to dissolve it, and the pH was adjusted to 7 with 0.1 mol / L HCl. After washing with water, 5.1309 g of a white solid was obtained, and the yield of (5-methylpyridin-2-yl)(pyrrolidin-1-yl)methanone was 90.7%.

[0064] The white solid was directly characterized, and its 1 1H NMR spectrum was as Figure 5 shown:

[0065] δ 7.26 was the solvent peak, δ: 4.47 (d, 2H), 7.21 (m, 1H), 7.29 (m, 4H), 7.79 (d, 1H), 7.95 (d, 1H), 8.49 (d, 1H), 9.26 (t, 1H). Its chemical shift was consistent with the hydrogen of (5-methylpyridin-2-yl)(pyrrolidin-1-yl)methanone.

[0066] Example 6

[0067] 3.9442 g of 2-naphthaldehyde (with a content of 99%) was added to a 250 mL reaction flask, 100 mL of toluene was added as a solvent, then 2.8571 g of potassium tert-butoxide (with a content of 98%) was added in batches, 3.1620 g of 2-(cyclohex-1-en-1-yl)ethan-1-amine (with a content of 99%) was added, and then 50 mg of PdO (99%) was added. The reaction was carried out for 6 hours at room temperature under xenon lamp illumination. The reaction mixture was filtered, washed with alcohol, the filtrate was concentrated by rotary evaporation, 10 mL of water was added to dissolve it, and the pH was adjusted to 7 with 0.1 mol / L HCl. After washing with water, 6.1883 g of yellow solid was obtained, and the yield of N-(2-(cyclohex-1-en-1-yl)ethyl)-1-naphthamide based on 2-naphthaldehyde was 88.6%.

[0068] The yellow solid was directly characterized, and its proton nuclear magnetic resonance spectrum was as Figure 6 shown:

[0069] δ 2.50 was the solvent peak, δ: 1.53 (m, 4H), 1.98 (m, 4H), 2.26 (t, 2H), 3.54 (m, 2H), 5.56 (s, 1H), 7.49 (m, 2H), 7.77 (m, 4H), 8.24 (s, 1H), and its chemical shift was consistent with that of the hydrogen of N-(2-(cyclohex-1-en-1-yl)ethyl)-1-naphthamide.

[0070] The above is the preferred embodiment of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for synthesizing an amide compound, characterized in that, An aldehyde having the structure of formula (I) and a secondary amine compound having the structure of formula (II) are used as a medium with an organic solvent, and an amide compound having the structure of formula (III) is prepared by a photocatalytic reaction in the presence of a catalyst metal oxide; ； Among them, in the aldehyde of the formula (I) structure, the R 1 is C6~C 20 aryl, C4~C 20 heterocyclic aryl; in the secondary amine compound of the formula (II) structure, the R 2 is C1~C 20 alkyl, C3~C 20 cycloalkyl, C2~C 20 alkenyl; The metal oxide is one or more of Co3O4, WO3, CuO, TiO2, Mn3O4, Ru2O3, SnO2, Fe3O4, Ru2O3, Ag2O, CoO, FeO, NiO, Ni2O3; The photocatalytic reaction also includes being carried out in the presence of a base; The base is one or more of potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium isopropoxide.

2. The method for synthesizing the amide compound according to claim 1, characterized in that, The R 1 is C6~C 12 aryl, C4~C6 heteroaromatic group; the R 2 is C1~C 12 alkyl, C3~C 12 cycloalkyl, C2~C 12 alkenyl.

3. The method for synthesizing the amide compound according to claim 2, characterized in that, The R 1 is phenyl, 4-methylphenyl, 4-methoxyphenyl, furyl, pyridyl, or thienyl; the R 2 is methyl, ethyl, butyl, octyl, dodecyl, cyclohexyl, phenyl, or naphthyl, or the linked N atoms together form azepan-1-yl, pyrrolidin-1-yl, and morpholinyl.

4. The synthesis method of the amide compound according to any one of claims 1 to 3, characterized in that, The molar ratio of the aldehyde to the secondary amine compound is 1:1 to 2.

5. The method for synthesizing the amide compound according to any one of claims 1 to 3, characterized in that, The organic solvent is one or more of toluene, cyclohexane, xylene, benzene, n-hexane, ether, 1,4-dioxane, tetrahydrofuran, dichloromethane, dichloroethane, carbon tetrachloride, acetone or petroleum ether.

6. The method for synthesizing the amide compound according to claim 4, characterized in that, The molar ratio of the aldehyde to the base is 1:0.1 to 3.

7. The method for synthesizing the amide compound according to claim 1, wherein The specific process of the synthesis method includes the following steps: (1) Put the aldehyde, secondary amine compound, photocatalyst, base and organic solvent into a reactor; (2) Continuously stir and react under the irradiation of a 15W - 100W light source to obtain an amide compound.

8. The method for synthesizing the amide compound according to claim 7, characterized in that, The reaction time in step (2) is 1 - 10h.

9. The method for synthesizing the amide compound according to claim 7, characterized in that, The light source is one or more of a xenon lamp, a light-emitting diode, a mercury lamp, a metal halide lamp.

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