A method for synthesizing 1,3-arylamines compounds by way of electrocatalysis

Abstract

The present application relates to a kind of aryl cyclopropane aryl amination reaction research, by electrocatalysis aryl cyclopropane compound and p-phenylenedinitrile and pyrazole reaction.Step one: aryl cyclopropane, p-phenylenedinitrile, pyrazole compound, cesium carbonate, tri (4-bromophenyl) amine and tetraethylammonium tetrafluoroborate are added in the three-port reaction bottle with magnet;Step two, under nitrogen atmosphere, slowly add ultrapure acetonitrile, graphite is used as positive and negative electrode material, reaction is carried out under the condition of room temperature and constant current 5mA, stirring reaction is carried out at room temperature, and the reaction is monitored by TLC, after aryl cyclopropane completely reacts, stop the reaction;Step three, the mixture obtained in step two is transferred to the reaction bottle, the solvent is concentrated using rotary evaporator, the obtained crude product is separated and purified using silica gel column, and the corresponding aryl amination product is obtained.Relative to traditional synthesis method, the method has mild reaction condition, can occur reaction at room temperature and has good yield and chemical selectivity, and the reaction uses indirect electrochemical oxidation, transfers the reaction from electrode to solution, and simultaneously utilizes the coupling effect of anodic oxidation and cathodic reduction.

Description

Technical Field

[0001] The present invention belongs to the field of organic chemistry, and particularly relates to a method for synthesizing 1,3-arylamine compounds by electrocatalysis. Background Art

[0002] 1,3-Arylaminated compounds are widely present in nature and have broad application prospects in a wide range of fields, including biomedicine and organic chemistry. There are two main methods for the ring-opening synthesis of 1,3-difunctionalized products from non-activated cyclopropanes. One relies on transition metal oxidative addition, but these reactions are limited to ring-opening rearrangements or cycloadditions and require specific directing groups for regioselective ring-opening functionalization. The other relies on electrophilic activation with Lewis acidic species, and most transformations are limited to electrophilic addition reactions. In summary, these methods for synthesizing 1,3-difunctionalized products have certain disadvantages, such as harsh reaction conditions, low product yields, long reaction times, the use of toxic reagents, and low regioselectivity. This method utilizes electrocatalysis, arylcyclopropanes, terephthalonitrile, and pyrazole derivatives as raw materials, and effectively synthesizes 1,3-arylnitrile pyrazole compounds with a single configuration. Furthermore, this method utilizes highly stable reagents, does not require a redox agent, and offers advantages such as high yields and a wide range of applicability. Summary of the Invention

[0003] The present invention aims to provide an effective method for synthesizing 1,3-arylamination compounds. This method, through electrocatalysis, overcomes the shortcomings of conventional synthesis methods, such as the need for transition metal catalysts or Lewis acids during the reaction process and poor chemical selectivity. This method, using arylcyclopropanes, terephthalonitriles, and pyrazole derivatives as raw materials, effectively synthesizes 1,3-arylamination compounds with a single configuration. Furthermore, the method utilizes highly stable reagents, does not require the addition of additional catalysts or oxidants during the reaction, can autonomously adjust the oxidation potential, and has a wide range of reaction applications.

[0004] In order to solve the technical problem of the present invention, the proposed technical solution is: a method for synthesizing 1,3-arylamine compounds by electrochemical means, comprising the following steps:

[0005] Step 1: Add an arylcyclopropane derivative (Formula 1), terephthalonitrile (Formula 2), pyrazole and its derivatives (Formula 3), and tetraethylammonium tetrafluoroborate into a dry bottle containing a magnet, and add a graphite positive electrode and a graphite negative electrode;

[0006] Step 2: slowly add ultra-dry acetonitrile solution under nitrogen atmosphere, apply DC power and stir the reaction at room temperature until the arylcyclopropane derivative (Formula 1) is completely reacted, and then stop the reaction;

[0007] Step three, the mixture obtained in step two is transferred to a reaction bottle, the filtrate of the reaction is spin-dried under low pressure by a rotary evaporator, and finally the obtained crude product is separated and purified by a silica gel column to obtain the corresponding 1, 3-aryl nitrile pyrazole compound (formula four);

[0008] The specific reaction route is as follows:

[0009]

[0010] wherein R 1 is: alkyl, alkoxy, halogen; R 2 is: methyl; R 3 is: H, methyl; R 4 is: halogen, methyl.

[0011] Preferably, the cyclopropane derivative is selected from aromatic cyclopropane.

[0012] Preferably, the terephthalonitrile is selected from terephthalonitrile

[0013] Preferably, the pyrazole and its derivatives are pyrazole nucleophiles.

[0014] Preferably, the reaction temperature is 30 degrees; the reaction time is 6 h.

[0015] Preferably, the reaction molar ratio is aryl cyclopropane derivative: terephthalonitrile: pyrazole and its derivatives = 3:1:3

[0016] Preferably, the electrode is a graphite positive electrode and a graphite negative electrode.

[0017] Preferably, in step two, a 5 mA direct current power supply is passed at 30 degrees and the reaction is stirred.

[0018] The specific experimental scheme of the present application is as follows:

[0019] The method for electrocatalytic synthesis of 1, 3-aryl nitrile pyrazole compounds is as follows:

[0020] Step one: aryl three-membered ring formula one (0.6 mmol, 3 equiv), terephthalonitrile formula two (0.2 mmol, 1 equiv), pyrazole compound formula three (0.6 mmol, 3 equiv), cesium carbonate (0.6 mmol, 3 equiv), tris(4-bromophenyl)amine (30 mol %, 0.03 mmol), and tetraethylammonium tetrafluoroborate (0.2 mmol, 1 equiv) are placed in a three-necked bottle with a magnet, and graphite is used as the positive and negative electrode materials;

[0021]

[0022] Step two, under the atmosphere of nitrogen, slowly add 4 ml of super dry acetonitrile solution, pass 5 mA direct current at room temperature and stir the reaction, until the arylcyclopropane derivative (formula one) is completely reacted, stop the reaction;

[0023] Step three, transfer the mixture obtained in step two to the reaction bottle, then dry the filtrate of the reaction with a rotary evaporator under low pressure, and finally separate and purify the obtained crude product with a silica gel column to obtain the corresponding 1,3-aryl nitrile pyrazole compound as shown in formula four.

[0024]

[0025] R1 in formula one, formula three is: alkyl, methoxy, halogen.

[0026] R2 in formula two, formula three is: halogen, phenyl, ester group.

[0027] In step two, the reaction is monitored by TLC plate, and the reaction time is 6 h.

[0028] The 1,3-arylamination compound obtained in step three is a single configuration product.

[0029] Compared with the prior art, the beneficial effects of the present application are:

[0030] 1. The reaction system of the present application is simple, the selected substrate is stable and easy to obtain, and the preparation cost is low.

[0031] 2. The reaction system of the present application is clean, the conversion rate is high, and the product is easy to separate.

[0032] 3. The method used in the present application is widely applicable, most common pyrazole derivatives are applicable to this method, the substrate has wide applicability, and a series of 1,3-arylamination compounds can be prepared according to this method.

[0033] 4. The 1,3-arylamination compound synthesized by the present application is a novel compound, which has broad prospects in drug and material research and development. BRIEF DESCRIPTION OF DRAWINGS

[0034] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiment or prior art description.

[0035] Figure 1 is the nuclear magnetic resonance spectrum of compound 1 in the embodiment of the present application 1 H spectrum of the present application;

[0036] Figure 2 is the nuclear magnetic resonance spectrum of compound 1 in the embodiment of the present application13 C spectrum;

[0037] Figure 3 is the nuclear magnetic resonance of compound 2 in the embodiment of the present invention 1 H spectrum;

[0038] Figure 4 is the nuclear magnetic resonance of compound 2 in the embodiment of the present invention 13 C spectrum

[0039] Figure 5 is the nuclear magnetic resonance of compound 6 in the embodiment of the present invention 1 H spectrum;

[0040] Figure 6 is the nuclear magnetic resonance of compound 6 in the embodiment of the present invention 13 C spectrum;

[0041] Figure 7 is the nuclear magnetic resonance of compound 7 in the embodiment of the present invention 1 H spectrum;

[0042] Figure 8 is the nuclear magnetic resonance of compound 7 in the embodiment of the present invention 13 C spectrum;

[0043] Figure 9 is the nuclear magnetic resonance of compound 8 in the embodiment of the present invention 1 H spectrum;

[0044] Figure 10 is the nuclear magnetic resonance of compound 8 in the embodiment of the present invention 13 C spectrum; DETAILED DESCRIPTION

[0045] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0046] Example 1

[0047] This example is used to prepare 4-(1-(4-methoxyphenyl)-3-methyl-3-(1H-pyrazol-1-yl)butyl)benzonitrile. The specific steps are as follows:

[0048]

[0049] 1-(2,2-Bismethylcyclopropyl)-4-methoxybenzene (0.6 mmol, 3.0 eq.), pyrazole (0.6 mmol, 3.0 eq.), terephthalonitrile (0.2 mmol, 1.0 eq.), anhydrous cesium carbonate (0.6 mmol, 3.0 eq.), tris(4-bromophenyl)amine (0.03 mmol, 30 mol %), and tetraethylammonium tetrafluoroborate (0.2 mmol, 1.0 eq.) were weighed sequentially into a dry 25 mL three-necked reaction flask. 4 mL of ultrapure acetonitrile was added. Graphite electrodes were fixed to rubber stoppers and inserted into the reaction flask. A constant current of 5 mA was set. After the reaction reached the endpoint as determined by TLC, the reaction solution was filtered using a fritted funnel. The silica gel was rinsed three times with dichloromethane. The filtrate was then rotary evaporated under reduced pressure to obtain the crude product, which was then separated by column chromatography using ethyl acetate / petroleum ether as the eluent to obtain the pure product.

[0050] For 4-(1-(4-methoxyphenyl)-3-methyl-3-(1H-pyrazol-1-yl)butyl)benzo

[0051] The results of H NMR spectrum of nitrile are 1 H NMR (400 MHz, Chloroform-d)

[0052] 6.77 (d, J =8.7 Hz, 2H), 6.13 (t, J = 2.1 Hz, 1H), 3.74 (s, 3H), 3.56 (d, J = 13.3 Hz, 1H), 2.76 (dd, J = 14.4, 6.3 Hz, 1H), 2.60 (dd, J = 14.4, 7.0 Hz, 1H), 1.47(d, J = 9.4 Hz, 6H).

[0053] For 4-(1-(4-methoxyphenyl)-3-methyl-3-(1H-pyrazol-1-yl)butyl)benzo

[0054] The results of the C-NMR spectra of -nitrile are 13C NMR (101 MHz, Chloroform-d) δ158.29, 151.09, 139.16, 135.61, 132.25, 128.71, 128.37, 126.60, 119.10,114.18, 109.63, 104.76, 60.80, 55.28, 48.07, 46.81, 29.60, 27.59.

[0055] Example 2

[0056] This example is used to prepare 4-(1-(4-methoxyphenyl)-3-methyl-3-(4-methyl-1H-pyrazol-1-yl)butyl)benzonitrile. The specific steps are as follows:

[0057]

[0058] 1-(2,2-Bismethylcyclopropyl)-4-methoxybenzene (0.6 mmol, 3.0 eq.), 4-methylpyrazole (0.6 mmol, 3.0 eq.), terephthalonitrile (0.2 mmol, 1.0 eq.), anhydrous cesium carbonate (0.6 mmol, 3.0 eq.), tris(4-bromophenyl)amine (0.03 mmol, 30 mol %), and tetraethylammonium tetrafluoroborate (0.2 mmol, 1.0 eq.) were weighed sequentially into a 25 mL dry three-necked reaction flask. 4 mL of ultrapure acetonitrile was added. Graphite electrodes were fixed to rubber stoppers and inserted into the reaction flask. A constant current of 5 mA was set. After the reaction reached the endpoint as determined by TLC, the reaction solution was filtered using a fritted funnel. The silica gel was rinsed three times with dichloromethane. The filtrate was rotary evaporated under reduced pressure to obtain the crude product, which was then separated by column chromatography using ethyl acetate / petroleum ether as the eluent to obtain the pure product.

[0059] The results of H NMR spectrum determination of 4-(1-(4-methoxyphenyl)-3methyl-3-(4-methyl-1H-pyrazol-1-yl)butyl)benzonitrile are 1H NMR (400 MHz, Chloroform-d) δ 7.45 (d,J = 8.6 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 7.06 – 7.02 (m, 3H), 6.78 (d, J =8.8 Hz, 2H), 3.75 (s, 3H), 3.65 (t, J = 6.7 Hz, 1H), 2.74 (dd, J = 14.4, 6.6Hz, 1H), 2.56 (dd, J = 14.4, 6.9 Hz, 1H), 1.98 (s, 3H), 1.46 (d, J = 5.8 Hz, 6H). The results of the carbon NMR spectrum of 4-(1-(4-methoxyphenyl)-3methyl-3-(4-methyl-1H-pyrazol-1-yl)butyl)benzonitrile are 13 C NMR (101 MHz, Chloroform-d) δ 158.37,151.11, 139.40, 135.80, 132.20, 128.75, 128.48, 125.59, 119.13, 115.24,114.22, 109.65, 60.46, 55.35, 48.24, 46.90, 29.57, 27.57, 8.97.

[0060] Example 3

[0061] In this example, 4-(1-(4-(tert-butyl)phenyl)-3-methyl-3-(1H-pyrazol-1-yl)butyl)

[0062] The preparation of benzonitrile is as follows:

[0063]

[0064] 1-(2,2-Dimethylcyclopropyl)-4-tert-butylbenzene (0.6 mmol, 3.0 eq.), pyrazole (0.6 mmol, 3.0 eq.), terephthalonitrile (0.2 mmol, 1.0 eq.), anhydrous cesium carbonate (0.6 mmol, 3.0 eq.), tris(4-bromophenyl)amine (0.03 mmol, 30 mol %), and tetraethylammonium tetrafluoroborate (0.2 mmol, 1.0 eq.) were weighed sequentially into a 25 mL dry three-necked reaction flask. 4 mL of ultrapure acetonitrile was added. Graphite electrodes were fixed to rubber stoppers and inserted into the reaction flask. A constant current of 5 mA was set. After the reaction reached its endpoint as determined by TLC, the reaction solution was filtered using a fritted funnel. The silica gel was rinsed three times with dichloromethane. The filtrate was then rotary evaporated under reduced pressure to obtain the crude product, which was then separated by column chromatography using ethyl acetate / petroleum ether as the eluent to obtain the pure product.

[0065] For 4-(1-(4-(tert-butyl)phenyl)-3-methyl-3-(1H-pyrazol-1-yl)butyl)benzo

[0066] The results of H NMR spectrum of nitrile are 1 H NMR (400 MHz, Chloroform-d) δ 7.48(d, J = 2.3 Hz, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 1.7 Hz, 1H), 7.24(d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 7.03 (d, J = 8.3 Hz, 2H), 6.11 (t, J = 2.1 Hz, 1H), 3.62 (t, J = 6.6 Hz, 1H), 2.80 (dd, J = 14.4, 7.1 Hz,1H), 2.64 (dd, J = 14.4, 6.3 Hz, 1H), 1.49 (d, J = 2.9 Hz, 6H), 1.26 (s, 9H).

[0067] For 4-(1-(4-(tert-butyl)phenyl)-3-methyl-3-(1H-pyrazol-1-yl)butyl)

[0068] The carbon spectrum of benzonitrile is 13C NMR (101 MHz, Chloroform-d) δ 150.79,149.64, 140.65, 139.16, 132.30, 128.58, 127.31, 126.60, 125.78, 119.18,109.76, 104.81, 60.84, 48.11, 47.33, 34.49, 31.43, 29.42, 27.84.

[0069] Example 4

[0070] In this example, 4-(1-(4-cyclopropylphenyl)-3-methyl-3-(1H-pyrazol-1-yl)butyl)

[0071] The preparation of benzonitrile is as follows:

[0072]

[0073] 1-(2,2-Dimethylcyclopropyl)-4-cyclopropylbenzene (0.6 mmol, 3.0 eq.), pyrazole (0.6 mmol, 3.0 eq.), terephthalonitrile (0.2 mmol, 1.0 eq.), anhydrous cesium carbonate (0.6 mmol, 3.0 eq.), tris(4-bromophenyl)amine (0.03 mmol, 30 mol %), and tetraethylammonium tetrafluoroborate (0.2 mmol, 1.0 eq.) were weighed sequentially into a dry 25 mL three-necked reaction flask. 4 mL of ultrapure acetonitrile was added. Graphite electrodes were fixed to rubber stoppers and inserted into the reaction flask. A constant current of 5 mA was set. After the reaction reached the endpoint as determined by TLC, the reaction solution was filtered using a fritted funnel. The silica gel was rinsed three times with dichloromethane. The filtrate was rotary evaporated under reduced pressure to obtain the crude product, which was then separated by column chromatography using ethyl acetate / petroleum ether as the eluent to obtain the pure product.

[0074] For 4-(1-(4-cyclopropylphenyl)-3-methyl-3-(1H-pyrazol-1-yl)butyl)

[0075] The results of Benzonitrile H NMR spectrum are 1H NMR (400 MHz, Chloroform-d) δ7.50 (d, J = 2.5 Hz, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 3.1 Hz, 1H), 7.17 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.16 – 6.11 (m, 1H), 3.59 (t, J = 6.6 Hz, 1H), 2.79 (dd, J = 14.4, 6.5 Hz,1H), 2.62 (dd, J = 14.4, 6.8 Hz, 1H), 1.82 (ddd, J = 13.5, 8.4, 5.1 Hz, 1H), 1.48 (d, J = 6.4 Hz, 6H), 0.94 – 0.90 (m, 2H), 0.65 – 0.60 (m, 2H).

[0076] For 4-(1-(4-cyclopropylphenyl)-3-methyl-3-(1H-pyrazol-1-yl)butyl)

[0077] The results of Benzonitrile C-NMR spectrometry are as follows: 13 C NMR (101 MHz, Chloroform-d) δ150.97, 142.64, 140.69, 139.19, 132.30, 128.51, 127.69, 126.60, 126.16,109.79, 104.82, 60.90, 48.08, 47.36, 29.64, 27.68, 15.07, 9.32.

[0078] Example 5

[0079] This example is used to prepare 4-(1-(3-bromo-4-methoxyphenyl)-3-methyl-3-(1H-pyrazol-1-yl)butyl)benzonitrile. The specific steps are as follows:

[0080]

[0081] 1-(2,2-Dimethylcyclopropyl)-3-bromo-4-cyclopropylbenzene (0.6 mmol, 3.0 eq.), pyrazole (0.6 mmol, 3.0 eq.), terephthalonitrile (0.2 mmol, 1.0 eq.), anhydrous cesium carbonate (0.6 mmol, 3.0 eq.), tris(4-bromophenyl)amine (0.03 mmol, 30 mol %), and tetraethylammonium tetrafluoroborate (0.2 mmol, 1.0 eq.) were weighed sequentially into a dry 25 mL three-necked reaction flask. 4 mL of ultrapure acetonitrile was added. Graphite electrodes were fixed to rubber stoppers and inserted into the reaction flask. A constant current of 5 mA was set. After the reaction reached its endpoint as determined by TLC, the reaction solution was filtered using a fritted funnel. The silica gel was rinsed three times with dichloromethane. The filtrate was rotary evaporated under reduced pressure to obtain the crude product, which was then separated by column chromatography using ethyl acetate / petroleum ether as the eluent to obtain the pure product.

[0082] For 4-(1-(3-bromo-4-methoxyphenyl)-3-methyl-3-(1H-pyrazol-1-yl)butyl)

[0083] The results of Benzonitrile H NMR spectrum are 1 H NMR (400 MHz, Chloroform-d) δ7.50 (d, J = 1.9 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.29 (dd, J = 14.6, 2.3Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.01 (dd, J = 8.5, 2.3 Hz, 1H), 6.77 (d, J= 8.6 Hz, 1H), 6.13 (t, J = 2.1 Hz, 1H), 3.84 (s, 3H), 3.59 (t, J = 6.7 Hz,1H), 2.74 (dd, J = 14.4, 6.4 Hz, 1H), 2.64 (dd, J = 14.4, 7.0 Hz, 1H), 1.50(d, J = 3.2 Hz, 6H).

[0084] For 4-(1-(3-bromo-4-methoxyphenyl)-3-methyl-3-(1H-pyrazol-1-yl)butyl)

[0085] The results of Benzonitrile C-NMR spectrometry are as follows: 13C NMR (101 MHz, Chloroform-d) δ154.67, 150.37, 139.24, 137.17, 132.43, 128.39, 127.71, 126.55, 118.96,112.14, 111.95, 110.08, 104.90, 60.68, 56.35, 47.90, 46.59, 29.22, 28.08.

[0086] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for synthesizing 1,3-arylamine compounds by electrocatalysis, characterized in that: The following steps are involved: Step 1: Add an arylcyclopropane derivative (Formula 1), terephthalonitrile (Formula 2), a pyrazole derivative (Formula 3), and tetraethylammonium tetrafluoroborate to a dry bottle containing a magnet, and add a graphite positive electrode and a graphite negative electrode; Step 2: slowly add ultrapure acetonitrile under a nitrogen atmosphere, apply a DC power supply and stir the reaction at room temperature until the arylcyclopropane derivative (Formula 1) is completely reacted, and then stop the reaction; Step 3: Transfer the mixture obtained in step 2 to a reaction flask, dry the solvent using a rotary evaporator, and finally separate and purify the obtained crude product using a silica gel column to obtain an arylation amination reaction product of the arylcyclopropane (Formula 4); The specific reaction equation is as follows: ; where R 1 is: alkyl, alkoxy, halogen; R 2 is: methyl; R 3 is: H, methyl; R 4 For: halogen, methyl.

2. The method for synthesizing 1,3-arylamine compounds by electrocatalysis according to claim 1, characterized in that: The arylcyclopropane derivatives are selected from arylcyclopropanes with alkyl, alkoxy and halogen at the para, ortho and meta positions of the phenyl group, and the pyrazole derivatives are selected from pyrazoles with methyl or halogen at the 4 position.

3. The method for synthesizing 1,3-arylamine compounds by electrocatalysis according to claim 1, characterized in that: The reaction temperature is 30 degrees; the reaction time is 6 hours.

4. The method for synthesizing 1,3-arylamine compounds by electrocatalysis according to claim 1, characterized in that: The reaction molar ratio is arylcyclopropane derivative: terephthalonitrile: pyrazole derivative = 3:1:

3.

5. The method for synthesizing 1,3-arylamine compounds by electrocatalysis according to claim 1, characterized in that: In step 2, a 5 mA DC power supply was applied at room temperature and the reaction was stirred.

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