Electrochemical synthesis method and application of N-aroyl amide compounds

Abstract

The present invention belongs to the technical field of organic synthesis, and provides an electrochemical synthesis method for N-aroyl amide compounds, which comprises the following steps: (1) in an electrochemical reaction device containing an aromatic hydrocarbon compound, an electrolyte and a nitrile solvent, a pre-oxidant is added, and then the anode and the cathode are assembled for electrolysis reaction; (2) after the reaction is completed, a saturated NaHCO3 solution is slowly added dropwise directly into the electrochemical reaction device for hydrolysis reaction to obtain the required N-aroyl amide compounds, wherein the pre-oxidant is selected from any one or more of acids, sulfates or persulfates. The electrochemical synthesis method of the present invention does not require the introduction of a directing group or pre-functionalization of the substrate, avoids the use of metal catalysts and the application of stoichiometric oxidants, has the advantages of greenness, high efficiency, high atom economy, etc., can be used for the synthesis of drug acetanilide, and has certain practical application value.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to an electrochemical synthesis method and application of N - arylamide compounds. Background Art

[0002] N - arylamide is a structure widely present in natural products, bioactive molecules and some functional compounds. Therefore, how to efficiently construct the C(sp 2 ) - N bond has always been a research frontier in organic synthesis. Since the presence of an electron - withdrawing group on the benzene ring will lead to an increase in the oxidation potential and make it difficult to activate the C(sp 2 ) - H bond of the benzene ring, resulting in low reactivity and poor selectivity, it is very challenging to achieve the direct amination reaction of C(sp 2 ) - H containing an electron - withdrawing group on the benzene ring.

[0003] Mei Tiansheng et al. reported an electrochemical copper - catalyzed amination reaction of aromatic C(sp 2 ) - H bond, which requires an amide as a directing group and nBu4NI as a redox mediator (J. Am. Chem. Soc. 2018, 140, 11487–11494.). Xu Haichao et al. reported a dual - catalytic system composed of acridinium dye and TEMPO to achieve the dehydrogenative cross - coupling reaction of electron - rich aromatics and azoles (ChemElectroChem. 2021, 8, 1571 - 1573.). In the above works, the introduction of a directing group cannot be avoided, the reaction system is relatively complex, the atom economy is poor, and the substrate scope is only applicable to some electron - rich or electro - neutral aromatics. Therefore, it is very necessary to design an electrochemical synthesis method of N - arylamide compounds with a simple reaction system. Summary of the Invention

[0004] Aiming at the limitations of the above reaction system, the present invention provides an electrochemical synthesis method of N - arylamide compounds. By means of an electrochemical reaction system, the amidation reaction of aromatics is realized, and a series of N - arylamide compounds are efficiently synthesized.

[0005] The specific scheme adopted by the present invention is as follows: An electrochemical synthesis method of N - arylamide compounds, comprising the following steps:

[0006] (1) In an electrochemical reaction device containing an aromatic compound substrate, an electrolyte and a nitrile solvent, a pre - oxidant is added, and then the anode and cathode are assembled for electrolysis reaction;

[0007] (2) After the electrolysis reaction in step (1) is completed, a saturated NaHCO3 aqueous solution is slowly added dropwise to the electrochemical reaction device for hydrolysis reaction to obtain the required N - arylamide compounds;

[0008] The reaction route is as follows:

[0009]

[0010] Among them, the number of R substituents is mono-substitution, di-substitution or tri-substitution; R is selected from one or more of H or halogen atom, cyano group, nitro group, trifluoromethyl group, sulfonamide group, sulfonate group, carbonyl group, ester group;

[0011] The pre-oxidant is selected from any one or several of acids, sulfates or persulfates.

[0012] In the electrochemical synthesis method of the present invention, when an electrolysis reaction is carried out in an electrochemical reaction device, the aromatic compound substrate is first electrolyzed to obtain an aromatic radical cation intermediate, which is then nucleophilically attacked by a nitrile to carry out a Ritter-type reaction step to obtain a nitrilium ion intermediate; and then an N-aromatic amide compound is obtained through a hydrolysis reaction; the reaction route is as follows:

[0013]

[0014] According to the present invention, preferably, in step (1), the pre-oxidant is selected from one or any several of sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, sodium persulfate, potassium persulfate, ammonium persulfate, sodium sulfate, potassium sulfate, ammonium sulfate.

[0015] According to the present invention, preferably, the dosage of the pre-oxidant is 2-8 equivalents of the aromatic compound.

[0016] According to the present invention, preferably, in step (1), the concentration of the aromatic compound substrate is 0.05-0.5 mol / L.

[0017] According to the present invention, preferably, in step (1), the electrolyte is selected from one or any several of quaternary ammonium perchlorate, quaternary ammonium tetrafluoroborate, quaternary ammonium hexafluorophosphate, quaternary ammonium trifluoromethanesulfonate, lithium perchlorate, lithium tetrafluoroborate.

[0018] According to the present invention, preferably, in step (1), the concentration of the electrolyte is 0.03-0.2 mol / L.

[0019] According to the present invention, preferably, the nitrile solvent is selected from one or any several of acetonitrile, deuterated acetonitrile, butyronitrile, isobutyronitrile.

[0020] According to the present invention, preferably, in step (1), the anode material is selected from one or any several of platinum, graphite, carbon fiber, carbon felt, carbon paper, glassy carbon, foamed glassy carbon, conductive glass, and preferably platinum;

[0021] The cathode material is one or any combination of platinum, nickel, graphite, carbon fiber, carbon felt, carbon paper, glassy carbon, foam glassy carbon, and conductive glass, preferably platinum.

[0022] According to the present invention, preferably, in step (1), the electrolysis method can be constant current or constant voltage electrolysis; when using constant current electrolysis, the current density is 4 mA / mmol - 40 mA / mmol, preferably 4 mA / mmol - 20 mA / mmol; alternatively, when using constant voltage electrolysis, the voltage is 2 V - 10 V, preferably 3 V - 6 V.

[0023] According to the present invention, preferably, in step (1), the reaction temperature is 0 - 40 °C, preferably 0 - 30 °C.

[0024] According to the present invention, preferably, in step (1), the electricity consumption is 2 - 10 F / mol, preferably 2 - 8 F / mol.

[0025] According to a preferred embodiment of the present invention, the electrolytic cell is a diaphragmless electrolytic cell or a divided electrolytic cell.

[0026] It should be noted that the progress of the electrolysis reaction is judged according to the consumption of raw materials. In the present invention, the electrolysis reaction time is preferably 8 - 12 h.

[0027] The present invention also provides an application of the above electrochemical synthesis method (Ritter-type C(sp 2 )-H amination reaction system) in the preparation of the drug acetanilide.

[0028] Compared with the prior art, the synthesis method of amide compounds provided by the present invention has the following beneficial effects:

[0029] (1) By means of an electrochemical reaction system, the present invention realizes the amidation reaction of aromatic hydrocarbons. The raw materials are widely sourced, inexpensive, and can be obtained on a large scale commercially, without the need for multi-step preparation and synthesis.

[0030] (2) In the electrochemical synthesis method of the present invention, the amount of pre-oxidant used is relatively small, and there is no need to use expensive oxidants, noble metal catalysts, etc., and the reaction cost is low.

[0031] (3) The synthesis method of the present invention uses electrolysis to replace oxidants and reductants, avoiding the use of stoichiometric oxidants. The reaction system is simple, green and environmentally friendly, has high production efficiency, and low three-waste emissions;

[0032] (4) The synthesis method of the present invention is also very suitable for challenging electron-deficient aromatic hydrocarbon substrates, avoiding the introduction of directing groups or pre-functionalization of the substrates in the reaction substrates, and having a certain atom economy.

[0033] (5) The electrochemical synthesis method described in the present invention can be used for the synthesis of the drug acetanilide, which has certain practical application value. Detailed implementation manners

[0034] To better understand the present invention, the content of the present invention will be further clarified below in conjunction with embodiments. However, the present invention is not limited to the following embodiments.

[0035] In the following embodiments, where specific technologies or conditions are not indicated, they shall be in accordance with the technologies or conditions described in the literature in the field or in accordance with the product specifications; for the reagents or instruments whose manufacturers are not indicated, they are all conventional products that can be obtained by purchase.

[0036] Example 1

[0037] This example provides an electrochemical synthesis method for N - arylamide compounds. The specific steps are as follows: Add the electrolyte tetrabutylammonium tetrafluoroborate (98.78 mg, 0.3 mmol), 4 - bromobenzonitrile (90.48 mg, 0.5 mmol) and acetonitrile (3 mL) into an electrochemical reaction device. In this step, the concentration of the electrolyte is 0.1 mol / L. Slowly add sulfuric acid (108 μL, 2 mmol), and the usage amount of sulfuric acid is 4 equivalents. Stir at 25°C and perform constant - current electrolysis at 10 mA / mmol for 12 hours, and the electricity consumption is 3.8 F / mol.

[0038] After the reaction is completed, slowly drop the saturated NaHCO3 solution into the reaction system until no bubbles are generated.

[0039] Extract the substances in the reaction system with ethyl acetate (10 mL * 3). After combining the organic phases, wash them with water (10 mL) and saturated brine (10 mL) respectively, and then dry with anhydrous Na2SO4. Remove the organic solvent by distillation under reduced pressure for concentration. The concentrate is purified by silica gel column chromatography to obtain the final product N - (2 - bromo - 5 - cyanophenyl)acetamide with high purity. The structural formula is as shown in formula (Ⅰ), the property is a light yellow crystal, and the total yield is 64%.

[0040] In this example, the electrochemical reaction device uses a diaphragm - free electrolytic cell, and both the anode material and the cathode material are made of platinum.

[0041]

[0042] Perform nuclear magnetic resonance hydrogen spectrum, carbon spectrum and mass spectrum characterization and analysis on the product prepared in this example. The nuclear magnetic resonance hydrogen spectrum, carbon spectrum and mass spectrum data are as follows, which can indicate that the prepared product is acetanilide.

[0043] 11H NMR (400 MHz, Chloroform-d) δ 8.77 - 8.72 (m, 1H), 7.70 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.29 - 7.21 (m, 1H), 2.28 (s, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 168.48, 136.71, 133.20, 127.91, 124.51, 117.87, 117.81, 112.54, 24.90. HRMS (EI): exact mass calculated for C9H7BrN2O [M]+ require m / z = 237.9742, found m / z = 237.9740。

[0044] Examples 2 - 9

[0045] The N - arylamide compounds were prepared according to the electrochemical synthesis method described in Example 1, except that different pre - oxidants were used, and the reaction products were characterized and analyzed. The specific pre - oxidants used and the corresponding reaction results are shown in Table 1 below.

[0046] Table 1 Reaction Results of Different Pre - oxidants

[0047] Example Pre-oxidant Yield (%) 2 Trifluoroacetic acid 58 3 Trifluoromethanesulfonic acid 55 4 Sodium sulfate 32 5 Potassium sulfate 30 6 Ammonium sulfate 34 7 Sodium persulfate 62 8 Potassium persulfate 60 9 Ammonium persulfate 58

[0048] The experimental results in Table 1 show that in Examples 2 - 9, by using different pre - oxidants, they can all be applied to this reaction and good yields are obtained.

[0049] Examples 10 - 15

[0050] The N - arylamide compounds were prepared according to the method described in Example 1, except that different amounts of sulfuric acid were used. Compared with the substrate, different equivalents of sulfuric acid were used in the reaction, and the reaction products were characterized and analyzed. The reaction results are shown in Table 2 below.

[0051] Table 2 Reaction Results of Different Equivalents of Pre - oxidants

[0052] Example Sulfuric acid (eq.) Yield (%) 10 2 48 11 3 57 12 5 64 13 6 62 14 7 60 15 8 60

[0053] The reaction results in Table 2 show that in Examples 10 - 15, by using different amounts of sulfuric acid, they can all be well applied to this reaction. When the reaction equivalent is between 2 - 8, good yields are obtained; and when the amount of sulfuric acid is 4 - 6 equivalents, the reaction has more excellent effects.

[0054] Examples 16 - 20

[0055] The N - arylamide compounds were prepared by the method described in Example 1, except that different electrolytes were used, and the reaction products were characterized and analyzed. The reaction results are shown in Table 3 below.

[0056] Table 3 Reaction Results of Different Electrolytes

[0057] Example Electrolyte Yield (%) 16 Tetrabutylammonium perchlorate 56 17 Tetrabutylammonium hexafluorophosphate 55 18 Tetrabutylammonium trifluoromethanesulfonate 53 19 Lithium perchlorate 62 20 Lithium tetrafluoroborate 50

[0058] From the reaction results in Table 3, it can be seen that in Examples 16 - 20, different electrolytes were used, and they could all be well applied to this reaction, and good yields were obtained. And it was found that when the electrolytes were ammonium tetrabutylborate and lithium perchlorate, they had more excellent reaction results compared to other electrolytes.

[0059] Examples 21 - 24

[0060] The N - arylamide compounds were prepared by the method described in Example 1. Different amounts of ammonium tetrabutylborate as the electrolyte were used, and the reaction results are shown in Table 4 below.

[0061] Table 4 Influence of Different Amounts of Electrolyte on Reaction Results

[0062]

[0063] In Examples 21 - 24, different amounts of ammonium tetrabutylborate were used, and they could all be well applied to this reaction, obtaining good yields; and when the electrolyte concentration in the electrochemical reaction device was 0.1 - 0.167 mol / L, more excellent reaction effects were achieved.

[0064] Examples 25 - 27

[0065] The N - arylamide compounds were prepared by the method described in Example 1. Different concentrations of substrates were used, and the reaction results are shown in Table 5 below.

[0066] Table 5 Influence of Different Substrate Concentrations on Reaction Results

[0067] Example Substrate concentration Yield (%) 25 0.05 mol / L 56 26 0.25 mol / L 60 27 0.5 mol / L 59

[0068] From the experimental results shown in Table 5, it can be seen that in the above - mentioned examples, different concentrations of substrates were used, and they could all be well applied to this reaction, obtaining good yields.

[0069] Examples 28 - 42

[0070] The N - arylamide compounds were prepared by the method described in Example 1. Different anode materials and cathode materials were used, and the reaction results are shown in Table 6 below.

[0071] Table 6 Influence of Different Anode-Cathode Materials on Reaction Results

[0072]

[0073]

[0074] In Examples 28 - 42, different anode materials and cathode materials were used, and all could be applied to this reaction; however, when both the anode material and the cathode material were platinum, the reaction effect was the best.

[0075] Examples 43 - 49

[0076] Prepare N - arylamide compounds according to the method described in Example 1, except that the electrolysis method is different. The electrolysis method and its corresponding reaction results are shown in Table 7 below.

[0077] Table 7 Influence of Different Electrolysis Conditions on Reaction Results

[0078] Example Current density / Voltage Yield (%) 43 4 mA / mmol 44 44 20 mA / mmol 41 45 40 mA / mmol 38 46 2V 55 47 3V 59 48 6V 63 49 10V 42

[0079] It can be seen from the reaction results in Table 7 that different electrolysis methods have a relatively obvious influence on the corresponding results. In the examples described in the present invention, different current densities or voltages can be well applied to this reaction to obtain good yields. Among them, when constant - current electrolysis is used, when the current density is 4 - 20 mA / mmol, a more excellent reaction effect is obtained; when constant - voltage electrolysis is used, when the voltage is 3 - 6 V, a relatively more excellent reaction effect can be obtained.

[0080] Examples 50 - 53

[0081] Prepare N - arylamide compounds according to the method described in Example 1. Different from that, different electrolysis reaction temperatures are adopted. The reaction results at different reaction temperatures are shown in Table 8 below.

[0082] Table 8 Influence of Different Electrolysis Reaction Temperatures on the Reaction

[0083]

[0084]

[0085] In Examples 50 - 53, different reaction temperatures were used, and all could be well applied to this reaction to obtain good yields. And when the reaction temperature is 0 - 30 °C, a relatively more excellent reaction effect can be obtained.

[0086] Examples 54 - 57

[0087] The N - arylamide compounds were prepared by the method described in Example 1, except that different amounts of electricity were selected in the electrolysis reaction step, and the reaction results are shown in Table 9 below.

[0088] Table 9 Influence of Different Amounts of Electricity in Electrolysis Reaction on the Reaction

[0089] Example Power consumption Yield (%) 54 2 F / mol 57 55 3 F / mol 60 56 8 F / mol 59 57 10 F / mol 46

[0090] It can be seen from the experimental results in Table 9 that in Examples 54 - 57, different amounts of electricity were used, and all of them could be well applied to this reaction to obtain good yields. Moreover, when the amount of electricity ranged from 2 - 8 F / mol, relatively excellent technical effects were achieved.

[0091] Example 58

[0092] The N - arylamide compounds were prepared by the method described in Example 1, except that a divided electrolytic cell was used instead, and the reaction yield was 55%, which could also be well applied to this reaction.

[0093] Examples 59 - 61

[0094] The N - arylamide compounds were prepared by the method described in Example 1, except that different nitrile solvents were used instead. The products obtained in each example were characterized by 1H NMR, 13C NMR and mass spectrometry. The structural formulas and yield results of the different N - arylamide compounds are shown in Table 10 below.

[0095] Table 10 Reaction Results of Different Nitrile Solvents

[0096]

[0097] In Examples 59 - 61, different nitrile solvents were used, and different amide products could be obtained in good yields.

[0098] Examples 62 - 81

[0099] The N - arylamide compounds were prepared by the method described in Example 1, except that different substrates were used instead. The products obtained in each example were characterized by 1H NMR, 13C NMR and mass spectrometry. The structural formulas and yield results of the different N - arylamide compounds are shown in Table 11 below.

[0100] Table 11 Experimental Results of Different Reaction Substrates

[0101]

[0102]

[0103] In Examples 62 - 81, different substrates were used, and the corresponding amide products could be prepared, and good yields could be obtained. It should be noted that for Examples 63 - 68, monosubstituted aromatic compounds were used as reaction substrates, and finally two or three different aromatic amide products with the -NHCOCH3 group located at positions 1, 2, or 3 marked in the structural formula were obtained. The yields in the examples were the total yields of multiple substances. Similarly, for Examples 78 and 80, disubstituted aromatic compounds were used as reaction substrates, and finally two different aromatic amide products with the -NHCOCH3 group located at positions 1 and 2 marked in the structural formula could be obtained respectively. The yields were the total yields including the two substances.

[0104] In summary, the electrochemical synthesis method described in the present invention can be used to prepare N - aromatic amide compounds with good yields. This method has a wide range of applications and can be applied to a variety of different aromatic compound substrates. Moreover, the reaction system in the above synthesis process is simple, the conditions are mild, the atom economy is relatively high, and no transition metal catalyst and stoichiometric oxidant are required, which has certain economic efficiency and practicality.

[0105] It should be noted that the above - described embodiments should be understood as illustrative and not limiting the protection scope of the present invention. The protection scope of the present invention is subject to the claims. For those skilled in the art, without departing from the essence and scope of the present invention, some non - essential improvements and adjustments made to the present invention still fall within the protection scope of the present invention.

Claims

1. An N -electrochemical synthesis method of arylamide compounds, characterized in that The synthesis method includes the following steps: (1) In an electrochemical reaction device containing an aromatic compound substrate, an electrolyte, and a nitrile solvent, a pre-oxidant is added, and then the anode and cathode are assembled for electrolysis; (2)After the electrolysis reaction in step (1) is completed, slowly add a saturated aqueous solution of NaHCO3 to the electro-chemical reaction device to carry out a hydrolysis reaction to obtain the desired N -aryl amide compounds; The reaction route is as follows: Among them, the number of R substituents is mono-substituted, di-substituted, or tri-substituted, and R is selected from one or more of H or a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a sulfonamide group, a sulfonate group, a carbonyl group, and an ester group; the pre-oxidant is selected from one or any combination of sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, sodium persulfate, potassium persulfate, ammonium persulfate, sodium sulfate, potassium sulfate, and ammonium sulfate; The dosage of the pre-oxidant is 2-8 equivalents of the aromatic compound; the electrolyte is selected from one or any combination of quaternary ammonium perchlorate, quaternary ammonium tetrafluoroborate, quaternary ammonium hexafluorophosphate, quaternary ammonium trifluoromethanesulfonate, lithium perchlorate, and lithium tetrafluoroborate.

2. The electrochemical synthesis method according to claim 1, wherein In step (1), the concentration of the aromatic compound substrate is 0.05-0.5 mol / L.

3. The electrochemical synthesis method according to claim 1, wherein In step (1), the concentration of the electrolyte is 0.03-0.2 mol / L.

4. The electrochemical synthesis method according to claim 1, wherein The nitrile solvent is selected from one or any combination of acetonitrile, deuterated acetonitrile, butyronitrile, and isobutyronitrile.

5. The electrochemical synthesis method according to claim 1, characterized in that, The anode material is selected from one or any combination of platinum, graphite, carbon fiber, carbon felt, carbon paper, glassy carbon, foamed glassy carbon, and conductive glass; the cathode material is selected from one or any combination of platinum, nickel, graphite, carbon fiber, carbon felt, carbon paper, glassy carbon, foamed glassy carbon, and conductive glass.

6. The electrochemical synthesis method according to claim 1, wherein In step (1), the electrolysis method is constant current or constant voltage electrolysis; when using constant current electrolysis, the current density is 4 mA / mmol - 40 mA / mmol; or when using constant voltage electrolysis, the voltage is 2 V - 10 V.

7. The electrochemical synthesis method according to claim 1, wherein In step (1), the reaction temperature is 0-40°C, and the electricity consumption is 2-10 F / mol.

8. The electrochemical synthesis method according to claim 1, characterized in that, The electrochemical reaction device is an electrolytic cell, and the electrolytic cell is a diaphragm-free electrolytic cell or a partitioned electrolytic cell.

9. Use of an electrochemical synthesis method as described in any one of claims 1-8 in the preparation of the drug acetanilide.

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