Method for preparing amide from imine compound

Abstract

The invention relates to the field of organic synthesis methodology, in particular to a method for preparing amide through an imine compound. The method for preparing the amide from the imine compound comprises the following step: under the combined action of visible light irradiation, a catalyst and a deoxidizing reagent, acetic acid and the imine compound are subjected to a free radical addition reaction in an organic solvent to generate the amide compound. The amide compound is stable in structure and has certain biological activity. The amide functional group is not only an important constituent part for forming a living substance (such as protein), but also widely exists in many active drug intermediates (such as colchicine) or artificial materials (nylon), and plays an indispensable role. A traditional method for preparing an amide compound is characterized in that a carboxylic acid derivative (acyl halide or anhydride) and amine are mixed and react to prepare the amide compound. Compared with the prior art, the method has the remarkable advantages that the use of dangerous acyl halide reagents and the emission of corrosive and volatile gases are avoided; the experiment operation is simple. Therefore, the method for preparing the amide from the imine compound has important significance.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis methodology, and in particular relates to a method for preparing amides through imine compounds. Background Art

[0002] Amide compounds have stable structures and certain biological activities. Amide functional groups are not only an important component of life substances (such as proteins), but also widely exist in many active drug intermediates (such as colchicine) or artificial materials (nylon), playing an indispensable role. The traditional method for preparing amide compounds is to prepare them by mixing carboxylic acid derivatives (acyl halides or acid anhydrides) with amines, but its disadvantages are significant: the use of dangerous acyl halide reagents, the emission of corrosive and volatile gases, the difficulty of experimental operation, and the generation of a large amount of waste. (Ke, F.; Xu, YW; et al. Electrochemical N-acylation synthesis of amides under aqueous conditions. Green Chem. 2019, 21, 4329-4333.) For example, the steps for synthesizing amides in patent CN 116462601 A are cumbersome and undergo three-step transformation, which greatly reduces the synthesis efficiency. Dangerous acyl chloride intermediates are involved, which poses certain safety hazards. With the further implementation of national safety and environmental protection policies, traditional synthesis methods have gradually failed to meet the requirements of current green chemistry. Therefore, it is of great theoretical value to develop a new method for preparing amides with mild reaction conditions, safe process, environmental friendliness, and cheap and readily available catalysts. Summary of the invention

[0003] The primary purpose of the present invention is to provide a method for preparing amides from imine compounds. The method uses visible light to induce a free radical addition reaction of imines to obtain amide compounds in one step without a free radical initiator and a sacrificial agent. The present invention provides a general approach to obtain amides from two easily available materials in one step, without the need for highly reactive reagents and harsh conditions, broadens the substrate range, and improves the practicality of the reaction.

[0004] In order to achieve the above-mentioned invention object, the present invention adopts the following technical scheme:

[0005] The present invention provides a method for preparing amides by using imine compounds, comprising: under the joint action of visible light irradiation, a catalyst and a deoxidation agent, acetic acid and the imine compound undergo free radical addition reaction in an organic solvent to generate an amide compound.

[0006] Among them, the imine compounds involved in this patent are all indole series compounds, and their general structural formula is:

[0007]

[0008] Furthermore, in a preferred embodiment of the present invention, R 1 is one of methoxy, tert-butyl, hydrogen, phenyl, bromine, trifluoromethyl, ester, and cyano, R 2 It is one of methyl and hydrogen.

[0009] Furthermore, in a preferred embodiment of the present invention, the visible light is purple LED light with a wavelength of 415nm, and the lamp barrel power is 30W.

[0010] Furthermore, in a preferred embodiment of the present invention, the catalyst is thioxanthone (TX).

[0011] Furthermore, in a preferred embodiment of the present invention, the deoxygenation agent is triphenylphosphine (PPh3).

[0012] Furthermore, in a preferred embodiment of the present invention, the organic solvent is anhydrous 1,2-dichloroethane (DCE).

[0013] Furthermore, in a preferred embodiment of the present invention, the reaction should be carried out under an argon atmosphere for 36 hours.

[0014] Preferably, the reaction conditions include: the concentration of the indole series substrate used is 0.2M, PPh3 is 1.5 equivalents, TX is 5 mol%, acetic acid is 5 equivalents, and acetic acid and anhydrous DCE are evaporated and used.

[0015] Wherein, the thioxanthone, triphenylphosphine, 1,2-dichloroethane and acetic acid described in the present invention are all commercially available.

[0016] In addition, in the present invention, conventional organic synthesis operations such as extraction and spin drying of solvents, including the final silica gel column chromatography separation to obtain the corresponding amide compound, belong to the prior art. The extractants and eluents used therein also have ready-made technical support. Those skilled in the art can select appropriate reagents according to the properties of the final product.

[0017] Compared with the prior art, the present invention has the following beneficial effects:

[0018] Through visible light-induced free radical addition reaction of imine, an amide compound is obtained in one step without free radical initiator and sacrificial agent. The amide preparation method of the present invention has high reaction activity, short reaction time and can be carried out at room temperature, high yield of target product, compatibility with multiple functional groups, universality for various types of substrates, simple synthesis operation, cheap and easy to obtain reaction raw materials, and has excellent application prospects. DETAILED DESCRIPTION

[0019] The present invention is described in detail below with reference to the examples. The examples are only preferred embodiments of the present invention and are not intended to limit the present invention.

[0020] Example 1

[0021]

[0022] In a clean, dry, sealed reaction vessel, 1a (0.2mmol, 37.8mg), TX (0.01mmol, 2.1mg), triphenylphosphine (0.3mmol, 78.9mg), anhydrous acetic acid (1mmol, 57μL), anhydrous 1,2-dichloroethane (10mL) were added in sequence under an argon atmosphere, and placed in a purple LED lamp bucket (wavelength 415nm, power 30W). After reacting at room temperature for 36h, a TLC plate was used to confirm that the reaction was complete (developing agent was PE / EA=4:1). Subsequently, the solvent was removed by a rotary evaporator, and the resulting crude product was separated by silica gel column chromatography (eluent was PE / EA=5:1) to obtain a slightly yellow solid product 2a with a yield of 88%. The product was characterized by nuclear magnetic resonance as follows:

[0023] 1 H NMR(400MHz, CDCl3) δ8.06(brs,1H),6.87(td,J=8.8,2.8Hz,1H),6.81(d,J=8.0Hz,1H),4.51 (brs,0.2H),4.00(brs,0.8H),2.28(s,3H),1.31(s,3H),1.21(s,3H),1.17(d,J=6.4Hz,3H).

[0024] Example 2

[0025]

[0026] In a clean, dry, sealed reaction vessel, 1b (0.2mmol, 34.5mg), TX (0.01mmol, 2.1mg), triphenylphosphine (0.3mmol, 78.9mg), anhydrous acetic acid (1mmol, 57μL), anhydrous 1,2-dichloroethane (10mL) were added in sequence under an argon atmosphere, and placed in a purple LED lamp bucket (wavelength 415nm, power 30W). After reacting at room temperature for 36h, a TLC plate was used to confirm that the reaction was complete (developing agent was PE / EA=4:1). Subsequently, the solvent was removed by a rotary evaporator, and the resulting crude product was separated by silica gel column chromatography (eluent was PE / EA=5:1) to obtain a slightly yellow solid product 2b with a yield of 79%. The product was characterized by nuclear magnetic resonance as follows:

[0027] 1H NMR (400MHz, CDCl3) δ7.97 (brs, 1H), 7.01 (d, J = 8.0Hz, 1H), 6.92 (brs, 1H), 4. 49(brs,0.3H),3.97(s,0.7H),2.49–2.16(m,6H),1.31(s,3H),1.19(brs,6H).

[0028] Example 3

[0029]

[0030] In a clean, dry, sealed reaction vessel, 1c (0.2mmol, 31.8mg), TX (0.01mmol, 2.1mg), triphenylphosphine (0.3mmol, 78.9mg), anhydrous acetic acid (1mmol, 57μL), anhydrous 1,2-dichloroethane (10mL) were added in sequence under an argon atmosphere, and placed in a purple LED lamp bucket (wavelength 415nm, power 30W). After reacting at room temperature for 36h, the reaction was confirmed to be complete using a TLC plate (developing agent PE / EA=4:1). Subsequently, the solvent was removed using a rotary evaporator, and the resulting crude product was separated by silica gel column chromatography (eluent PE / EA=5:1) to obtain a slightly yellow solid product 2c with a yield of 87%. The product NMR characterization is as follows:

[0031] 1 H NMR (400MHz, CDCl3) δ8.11(brs,1H),7.20(t,J=7.6Hz,1H),7.12(d,J=7.6Hz,1H),7.05(t,J=7.6Hz, 1H), 4.49 (s, 0.3H), 3.98 (s, 0.7H), 2.30 (brs, 3H), 1.33 (s, 3H), 1.20 (s, 3H), 1.16 (d, J = 6.4Hz, 3H).

[0032] Example 4

[0033]

[0034] In a clean, dry, sealed reaction vessel, 1d (0.2mmol, 41.7mg), TX (0.01mmol, 2.1mg), triphenylphosphine (0.3mmol, 78.9mg), anhydrous acetic acid (1mmol, 57μL), anhydrous 1,2-dichloroethane (10mL) were added in sequence under an argon atmosphere, and placed in a purple LED lamp bucket (wavelength 415nm, power 30W). After reacting at room temperature for 36h, the reaction was confirmed to be complete using a TLC plate (developing agent PE / EA = 4:1). Subsequently, the solvent was removed using a rotary evaporator, and the resulting crude product was separated by silica gel column chromatography (eluent PE / EA = 5:1) to obtain a white solid product 2d with a yield of 89%. The product was characterized by nuclear magnetic resonance as follows:

[0035] 1 H NMR(400MHz, CDCl3)δ8.16(brs,0.7H),7.57(d,J=7.6Hz,2H),7.47–7.38(m,3H),7.35–7.27(m,2H),7.14(br s,0.3H),4.53(brs,0.3H),4.02(brs,0.7H),2.31(brs,3H),1.38(s,3H),1.24(s,3H),1.20(d,J=4.0Hz,3H); 13 C NMR (101MHz, CDCl3) majorconformation: δ168.2,141.0,140.6,139.3,137.2,128.7,126.8,126.5,120.6,118.1,68.2,43.4,31.1,23.2,20.2,16.7; minor conformation: δ168.2,141.0,140.6,139.3,137.2,128.7,126.8,126.5,122.0,115.1,67.2,43.4,31.1,24.1,20.2,15.1.

[0036] Example 5

[0037]

[0038] In a clean, dry, sealed reaction vessel, 1e (0.2mmol, 47.6mg), TX (0.01mmol, 2.1mg), triphenylphosphine (0.3mmol, 78.9mg), anhydrous acetic acid (1mmol, 57μL), anhydrous 1,2-dichloroethane (10mL) were added in sequence under an argon atmosphere, and placed in a purple LED lamp bucket (wavelength 415nm, power 30W). After reacting at room temperature for 36h, a TLC plate was used to confirm that the reaction was complete (developing agent was PE / EA = 4:1). Subsequently, the solvent was removed by a rotary evaporator, and the resulting crude product was separated by silica gel column chromatography (eluent was PE / EA = 5:1) to obtain a white solid product 2e with a yield of 89%. The product was characterized by nuclear magnetic resonance as follows:

[0039] 1 H NMR (400MHz, CDCl3) δ7.98 (brs, 1H), 7.30 (dd, J = 8.4, 1.6Hz, 1H), 7.20 (s, 1H), 4.45 (brs ,0.2H),3.98(brs,0.8H),2.28(s,3H),1.30(s,3H),1.19(s,3H),1.15(d,J=6.0Hz,3H).; 13 C NMR (101MHz, CDCl3) δ168.3,142.3,139.0,130.4,125.2,119.4,116.4,68.1,43.5,30.9,23.2,20.0,16.6.

[0040] Example 6

[0041]

[0042] In a clean, dry, sealed reaction vessel, 1f (0.2mmol, 45.8mg), TX (0.01mmol, 2.1mg), triphenylphosphine (0.3mmol, 78.9mg), anhydrous acetic acid (1mmol, 57μL), anhydrous 1,2-dichloroethane (10mL) were added in sequence under an argon atmosphere, and placed in a purple LED lamp bucket (wavelength 415nm, power 30W). After reacting at room temperature for 36h, the reaction was confirmed to be complete using a TLC plate (developing agent PE / EA=4:1). Subsequently, the solvent was removed using a rotary evaporator, and the resulting crude product was separated by silica gel column chromatography (eluent PE / EA=5:1) to obtain an orange solid product 2f with a yield of 87%. The product NMR characterization is as follows:

[0043] 1H NMR (400MHz, CDCl3) δ8.19(brs,1H),7.48(d,J=8.4Hz,1H),7.34(s,1H),4.08(brs,1H),2.33(s,3H),1.37(s,3H),1.23(s,3H),1.19(d,J=6.4Hz,3H); 13 C NMR (101MHz, CDCl3) δ168.7,142.7,140.7,125.9(q,J=128.4),125.3,124.3(q,J=1080.8),119.2,117.6,68.2,43.3,31.0,23.4,19.9; 19 F NMR (376MHz, CDCl3) δ-61.58.

[0044] Example 7

[0045]

[0046] In a clean, dry, sealed reaction vessel, 1g (0.2mmol, 46.4mg), TX (0.01mmol, 2.1mg), triphenylphosphine (0.3mmol, 78.9mg), anhydrous acetic acid (1mmol, 57μL), anhydrous 1,2-dichloroethane (10mL) were added in sequence under an argon atmosphere, and placed in a purple LED lamp bucket (wavelength 415nm, power 30W). After reacting at room temperature for 36h, a TLC plate was used to confirm that the reaction was complete (developing agent was PE / EA=4:1). Subsequently, the solvent was removed by a rotary evaporator, and the resulting crude product was separated by silica gel column chromatography (eluent was PE / EA=5:1) to obtain 2g of a slightly yellow solid product with a yield of 85%. The product was characterized by nuclear magnetic resonance as follows:

[0047] 1 H NMR (400MHz, CDCl3) δ8.14(brs,1H),7.95(d,J=8.0Hz,1H),7.81(s,1H),4.37(q,J=7.2Hz ,2H),4.09(brs,1H),2.35(s,3H),1.43–1.36(m,6H),1.23(s,3H),1.18(d,J=6.4Hz,3H); 13 C NMR (101MHz, CDCl3) δ168.49,166.07,143.59,140.14,129.91,125.82,123.44,116.87,68.09,60.53,42.89,30.78,23.28,19.85,16.38,14.17.

[0048] The above-mentioned embodiments merely express the implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the patent scope of the present invention. Any technical solution obtained in the form of equivalent replacement or equivalent transformation shall fall within the protection scope of the present invention.

Claims

1. A method for preparing amides by using imine compounds, characterized in that: include: Under the combined action of visible light irradiation, catalyst and deoxidation agent, acetic acid and imine compound undergo free radical addition reaction in organic solvent to generate amide compound. The imine compounds involved in this patent are all indole series compounds, and their general structural formula is: Where R 1 is one of methoxy, tert-butyl, hydrogen, phenyl, bromine, trifluoromethyl, ester, and cyano, R 2 It is one of methyl and hydrogen.

2. The method for preparing amides by using imine compounds according to claim 1, characterized in that: The visible light is purple LED light with a wavelength of 415nm, and the lamp barrel power is 30W.

3. The method for preparing amides by using imine compounds according to claim 1, characterized in that: The catalyst is thioxanthone (TX).

4. The method for preparing amides by using imine compounds according to claim 1, characterized in that: The deoxidizing agent is triphenylphosphine (PPh3).

5. The method for preparing amides by using imine compounds according to claim 1, characterized in that: The organic solvent is anhydrous 1,2-dichloroethane (DCE).

6. A method for preparing amides by using imine compounds according to claims 1-5, characterized in that: The concentration of the indole series substrates used was 0.2 M, PPh3 was 1.5 equivalents, TX was 5 mol%, acetic acid was 5 equivalents, and acetic acid and anhydrous DCE were evaporated and used.

7. The method for preparing amides by using imine compounds according to claim 1, characterized in that: The reaction should be carried out under argon atmosphere at room temperature for 36 h.

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