Method for preparing 2-amino-1, 3, 4-oxadiazole derivative through electro-catalysis

Abstract

The invention belongs to the technical field of preparation of oxadiazole derivatives. The invention provides a method for preparing a 2-amino-1, 3, 4-oxadiazole derivative through electro-catalysis, which comprises the following steps: adding 0.2 mmol of benzoyl hydrazine compound, 0.4 mmol of tetrabutylammonium iodide, 0.4 mmol of 1, 4-diazabicyclo [2.2. 2] octane, 0.4 mmol of sodium bicarbonate and 6 mL of acetonitrile into an electrolytic tank; then, 0.3 mmol of a phenyl isothiocyanate compound is added dropwise; the reaction is carried out under a direct-current constant current between the electrode anode and the electrode cathode. According to the method, benzoyl hydrazine and phenyl isothiocyanate are taken as reaction substrates through electro-catalysis, reagents such as acetonitrile which is low in price and low in toxicity are taken as solvents, an oxidizing agent in a conventional reaction is replaced by a mode of introducing current, and the oxadiazole compound is synthesized under mild and green conditions.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation of oxadiazole derivatives. Background Art

[0002] 2-amino-1,3,4-oxadiazole compounds have important applications in many fields. For example, in drug development, some 2-amino-1,3,4-oxadiazole derivatives show significant anticancer activity, such as Podophyllotoxin derivatives that can inhibit microtubule polymerization, prevent cancer cell division, and show anti-tumor potential; at the same time, they also show the role of regulating the immune system in the anti-inflammatory field, by inhibiting the secretion of tumor necrosis factor α (TNF-α), relieving symptoms caused by inflammation. In agricultural applications, this type of compound is studied as a pesticide, some of which have antifungal effects and can effectively prevent and control crop diseases. In addition, some 2-amino-1,3,4-oxadiazole compounds have been developed as plant growth regulators to improve the stress resistance and growth rate of crops. In materials science, 2-amino-1,3,4-oxadiazole derivatives are used as organic semiconductor materials and are used in OLED (organic light-emitting diodes) and organic photovoltaic (OPV) devices as materials for the electron conduction layer; in addition, they can also be used as fluorescent probes in biological imaging for the detection and quantitative analysis of intracellular components. Finally, in catalytic reactions, 2-amino-1,3,4-oxadiazole compounds showed excellent catalytic performance as green catalysts in aqueous phase reactions, promoting the research of environmentally friendly chemical reactions.

[0003] Binyu Long's research group proposed a simple method based on KHSO4 catalysis for the synthesis of 2-amino-1,3,4-oxadiazole derivatives. This method successfully synthesized 2-amino-1,3,4-oxadiazole derivatives by desulfurization of thiourea intermediates catalyzed by KHSO4 under room temperature stirring conditions in DMSO.

[0004]

[0005] Dilep-Kumar Sigalapalli's research group proposed a new method for synthesizing 2-amino-1,3,4-oxadiazoles in an aqueous phase in a one-pot manner based on microwave assistance and TBHP (tert-butyl hydroperoxide). This method uses microwave radiation in an aqueous phase to react isothiocyanates with hydrazines without the need for a catalyst. The reaction generates a transition state thiourea intermediate, followed by a cyclodesulfurization reaction, and finally synthesizes 2-amino-1,3,4-oxadiazole compounds.

[0006]

[0007] However, in the process of synthesizing such oxadiazole compounds, conventional synthesis methods require the use of highly toxic reaction solvents and strong oxidants, have long reaction times, harsh conditions, and are not suitable for mass production. Summary of the invention

[0008] The invention provides a method for preparing 2-amino-1,3,4-oxadiazole derivatives by electrocatalysis, comprising the following steps: adding 0.2 mmol of benzoyl hydrazide compounds, 0.4 mmol of tetrabutylammonium iodide, 0.4 mmol of 1,4-diazabicyclo[2.2.2]octane, 0.4 mmol of sodium bicarbonate and 6 mL of acetonitrile into an electrolytic cell; then adding 0.3 mmol of phenyl isothiocyanate compounds dropwise; and reacting under a direct current constant current between an electrode anode and an electrode cathode.

[0009] In a specific embodiment, the anode is a carbon rod.

[0010] In a specific embodiment, the cathode is a platinum sheet.

[0011] In a specific implementation manner, the DC constant current is 10 mA.

[0012] In a specific embodiment, the reaction temperature is 25°C.

[0013] In a specific embodiment, the reaction time is 4 hours.

[0014] In a specific embodiment, the benzoylhydrazide compound has the following structural formula: Among them, R 2 It is phenyl, pyrazinyl, o-aminophenyl or 4-tert-butylphenyl.

[0015] In a specific embodiment, the phenyl isothiocyanate compound has the following structural formula:

[0016] Among them, R 1 is hydrogen, methyl, methoxy, fluorine, ethyl or phenyl.

[0017] The present invention adopts electrocatalysis, uses benzoyl hydrazide and phenyl isothiocyanate as reaction substrates, uses acetonitrile and other cheap and low-toxic reagents as solvents, and replaces the oxidant in the conventional reaction by passing electric current, and synthesizes the oxadiazole compound under mild and green conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 is the compound of Example 1 1 H NMR spectrum.

[0019] Figure 2 is the compound of Example 1 13C NMR spectrum.

[0020] Figure 3 is the compound of Example 2 1 H NMR spectrum.

[0021] Figure 4 is the compound of Example 2 13 C NMR spectrum.

[0022] Figure 5 is the compound of Example 3 1 H NMR spectrum.

[0023] Figure 6 is the compound of Example 3 13 C NMR spectrum.

[0024] Figure 7 is the compound of Example 4 1 H NMR spectrum.

[0025] Figure 8 is the compound of Example 4 13 C NMR spectrum.

[0026] Fig. 9 is the compound of Example 5 1 H NMR spectrum.

[0027] Fig.10 is the compound of Example 5 13 C NMR spectrum.

[0028] Fig.11 is the compound of Example 6 1 H NMR spectrum.

[0029] Fig.12 is the compound of Example 6 13 C NMR spectrum.

[0030] Fig.13 is the compound of Example 7 1 H NMR spectrum.

[0031] Fig.14 is the compound of Example 7 13 C NMR spectrum.

[0032] Fig.15 is the compound of Example 8 1 H NMR spectrum.

[0033] Fig.16 is the compound of Example 8 13 C NMR spectrum.

[0034] Fig.17 is the compound of Example 9 1 H NMR spectrum.

[0035] Fig.18 is the compound of Example 9 13 C NMR spectrum. DETAILED DESCRIPTION

[0036] The raw materials include benzoyl hydrazide compounds, phenyl isothiocyanate compounds, tetrabutylammonium iodide, 1,4-diazabicyclo[2.2.2]octane, sodium bicarbonate and acetonitrile.

[0037] The experimental equipment includes a carbon rod electrode (Φ=6 mm), a platinum sheet electrode (1.0 cm×1.0 cm×0.1 cm), a 20 mL electrolytic cell, a DC regulated power supply, and a magnet.

[0038] Reaction process: Add the compound of general formula 1 (0.3-0.6mmol), compound 2 (0.2-0.4mmol), electrolyte (0.4-0.8mmol), additive (0.8-1.6mmol), acetonitrile (5-6mL) and magnet in the electrolytic cell in sequence, pass a DC constant current between the electrode anode and the electrode cathode, react for 4h under a certain temperature condition, and monitor the reaction progress with thin layer chromatography until the reaction is complete. Finally, separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate) to obtain a compound of general formula 3, and the reaction equation is as follows:

[0039]

[0040] Where: R 1 is selected from hydrogen, methyl, methoxy, fluorine, ethyl, phenyl; R 2 Selected from phenyl, pyrazinyl, o-aminophenyl, 4-tert-butylphenyl.

[0041] Embodiment 1:

[0042] The preparation method of this embodiment comprises the following steps:

[0043] Benzoyl hydrazide compound 2 (0.2mmol), tetrabutylammonium iodide (0.4mmol), 1,4-diazabicyclo[2.2.2]octane (0.4mmol), sodium bicarbonate (0.4mmol), acetonitrile (6mL), and magnetic particles were added to the electrolytic cell in sequence, and finally phenyl isothiocyanate compound 1a (0.3mmol) was added dropwise. Platinum sheet and carbon rod were used as cathode and anode respectively, and a constant current of 10mA was passed between the electrode anode and the electrode cathode. The reaction was allowed to proceed at 25°C for 4h, and the reaction progress was monitored by thin layer chromatography until the reaction was complete. Finally, compound 3a was obtained by separation and purification by silica gel column chromatography with a yield of 82%. The reaction equation is as follows:

[0044]

[0045] Compound spectrum data:

[0046] 1 H NMR (400MHz, DMSO-d6) δ10.68(s,1H),7.93-7.90(m,2H),7.65-7.57(m,5H),7.40-7.36(m,2H),7.05-7.01(m,1H).

[0047] 13 C NMR (101MHz, DMSO-d6) δ160.4,158.2,139.1,131.4,129.8,129.6,126.0,124.3,122.4,117.5.

[0048] Embodiment 2:

[0049] The preparation method of this embodiment comprises the following steps:

[0050] Benzoyl hydrazide compound 2 (0.2mmol), tetrabutylammonium iodide (0.4mmol), 1,4-diazabicyclo[2.2.2]octane (0.4mmol), sodium bicarbonate (0.4mmol), acetonitrile (6mL), and magnetic particles were added to the electrolytic cell in sequence, and finally phenyl isothiocyanate compound 1b (0.3mmol) was added dropwise. Platinum sheet and carbon rod were used as cathode and anode respectively, and a constant current of 10mA was passed between the electrode anode and the electrode cathode. The reaction was allowed to proceed at 25°C for 4h, and the reaction progress was monitored by thin layer chromatography until the reaction was complete. Finally, compound 3b was obtained by separation and purification by silica gel column chromatography with a yield of 59%. The reaction equation is as follows:

[0051]

[0052] Compound spectrum data:

[0053] 1 H NMR (400MHz, DMSO-d6) δ9.71 (s, 1H), 7.95-7.92 (m, 2H), 7.84 (d, J = 9.6Hz, 1H),7.63-7.61(m,3H),7.30-7.27(m,2H),7.12-7.08(m,1H),2.36(s,3H).

[0054] 13C NMR (101MHz, DMSO-d6) δ161.6,158.5,137.1,131.3,131.1,129.8,129.5,127.0,125.9,124.4,124.3,121.5,18.4.

[0055] Embodiment 3:

[0056] The preparation method of this embodiment comprises the following steps:

[0057] Benzoyl hydrazide compound 2 (0.2mmol), tetrabutylammonium iodide (0.4mmol), 1,4-diazabicyclo[2.2.2]octane (0.4mmol), sodium bicarbonate (0.4mmol), acetonitrile (6mL), and magnetic particles were added to the electrolytic cell in sequence, and finally phenyl isothiocyanate compound 1c (0.3mmol) was added dropwise. Platinum sheet and carbon rod were used as cathode and anode respectively, and a DC constant current of 10mA was passed between the electrode anode and the electrode cathode. The reaction was carried out at 25°C for 4h, and the reaction progress was monitored by thin layer chromatography until the reaction was complete. Finally, compound 3c was obtained by separation and purification by silica gel column chromatography with a yield of 72%. The reaction equation is as follows:

[0058]

[0059] Compound spectrum data: 1 H NMR(400MHz,DMSO-d6)δ10.72(s,1H),7.92-7.89(m,2H),7.60-7.57(m,3H),7.33(t,J =2.4Hz,1H),7.27(t,J=8.0Hz,1H),7.17-7.15(m,1H),6.62-6.59(m,1H),3.77(s,3H);

[0060] 13 C NMR (101MHz, DMSO-d6) δ160.4,160.3,158.2,140.3,131.4,130.4,129.8,126.0,124.3,110.1,107.7,103.6,55.5.

[0061] Embodiment 4:

[0062] The preparation method of this embodiment comprises the following steps:

[0063] Benzoyl hydrazide compound 2 (0.2mmol), tetrabutylammonium iodide (0.4mmol), 1,4-diazabicyclo[2.2.2]octane (0.4mmol), sodium bicarbonate (0.4mmol), acetonitrile (6mL), and magnetic particles were added to the electrolytic cell in sequence, and finally phenyl isothiocyanate compound 1d (0.3mmol) was added dropwise. Platinum sheet and carbon rod were used as cathode and anode respectively, and a DC constant current of 10mA was passed between the electrode anode and the electrode cathode. The reaction was carried out at 25°C for 4h, and the reaction progress was monitored by thin layer chromatography until the reaction was complete. Finally, compound 3d was obtained by separation and purification by silica gel column chromatography with a yield of 85%. The reaction equation is as follows:

[0064]

[0065] Compound spectrum data:

[0066] 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.37-8.34(m,1H),8.10(d,J=8.0Hz,1H),7.99-7.93(m,3H),7.73(d,J=8.4Hz,1H),7.61-7.55(m,6H).

[0067] 13 C NMR (101MHz, DMSO-d6) δ161.8,158.7,134.4,134.3,131.4,129.8,128.7,126.7,126.4,126.3,126.3,126.0,124.4,124.2,122.7,117.1.

[0068] Embodiment 5:

[0069] The preparation method of this embodiment comprises the following steps:

[0070] Benzoyl hydrazide compound 2 (0.2mmol), tetrabutylammonium iodide (0.4mmol), 1,4-diazabicyclo[2.2.2]octane (0.4mmol), sodium bicarbonate (0.4mmol), acetonitrile (6mL), and magnetic particles were added to the electrolytic cell in sequence, and finally phenyl isothiocyanate compound 1e (0.3mmol) was added dropwise. Platinum sheet and carbon rod were used as cathode and anode respectively, and a DC constant current of 10mA was passed between the electrode anode and the electrode cathode. The reaction was carried out at 25°C for 4h, and the reaction progress was monitored by thin layer chromatography until the reaction was complete. Finally, compound 3e was obtained by separation and purification by silica gel column chromatography with a yield of 62%. The reaction equation is as follows:

[0071]

[0072] Compound spectrum data:

[0073] 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.18-8.13(m,1H),7.95-7.92(m,2H),7.61-7.58(m,3H),7.34-7.25(m,2H),7.15-7.11(m,1H).

[0074] 13 C NMR (101MHz, DMSO-d6) δ160.7,158.8,152.8(d,J=243.4Hz,1C),131.5,129.8,127.0(d,J=11.3Hz,1C),126.0,125.2(d,J=3.6Hz,1C),124.1,124.0 121.2,116.0(d,J=18.8Hz,1C).

[0075] Embodiment 6:

[0076] The preparation method of this embodiment comprises the following steps:

[0077] Benzoyl hydrazide compound 2 (0.2mmol), tetrabutylammonium iodide (0.4mmol), 1,4-diazabicyclo[2.2.2]octane (0.4mmol), sodium bicarbonate (0.4mmol), acetonitrile (6mL), and magnetic particles were added to the electrolytic cell in sequence, and finally phenyl isothiocyanate compound 1f (0.3mmol) was added dropwise. Platinum rod and carbon rod were used as cathode and anode respectively, and a DC constant current of 10mA was passed between the electrode anode and the electrode cathode. The reaction was carried out at 25°C for 4h, and the reaction progress was monitored by thin layer chromatography until the reaction was complete. Finally, compound 3f was obtained by separation and purification by silica gel column chromatography with a yield of 76%. The reaction equation is as follows:

[0078]

[0079] Compound spectrum data:

[0080] 1 H NMR (400MHz, DMSO-d6) δ10.59 (s, 1H), 7.92-7.90 (m, 2H), 7.59-7.54 (m, 5H), 7.21 (d, J = 8.8Hz, 2H), 2.60-2.55 (m, 2H), 1.18 (t, J = 7.6Hz, 3H).

[0081] 13C NMR (101MHz, DMSO-d6) δ160.5,158.1,137.8,136.8,131.4,129.8,128.8,126.0,124.4,117.7,28.0,16.2.

[0082] Embodiment 7:

[0083] The preparation method of this embodiment comprises the following steps:

[0084] Add 2g (0.2mmol) of benzoyl hydrazide compound, tetrabutylammonium iodide (0.4mmol), 1,4-diazabicyclo[2.2.2]octane (0.4mmol), sodium bicarbonate (0.4mmol), acetonitrile (6mL), add a magnetic particle, and finally add phenyl isothiocyanate compound 1a (0.3mmol) dropwise into the electrolytic cell. Use platinum sheet and carbon rod as cathode and anode respectively, pass a DC constant current of 10mA between the electrode anode and the electrode cathode, react at 25℃ for 4h, and monitor the reaction progress by thin layer chromatography until the reaction is complete. Finally, separate and purify by silica gel column chromatography to obtain compound 3g with a yield of 88%. The reaction equation is as follows:

[0085]

[0086] Compound spectrum data:

[0087] 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),9.28(s,1H),8.81-8.79(m,2H),7.63(d,J=8.0Hz,2H),7.41-7.37(t,2H),7.05(t,J=7.2Hz,1H).

[0088] 13 C NMR (101MHz, DMSO-d6) δ161.3,156.4,146.3,145.2,143.1,139.9,138.7,129.6,122.7,117.7.

[0089] Embodiment 8:

[0090] The preparation method of this embodiment comprises the following steps:

[0091] Benzoyl hydrazide compound 2h (0.2mmol), tetrabutylammonium iodide (0.4mmol), 1,4-diazabicyclo[2.2.2]octane (0.4mmol), sodium bicarbonate (0.4mmol), acetonitrile (6mL), and magnetic particles were added to the electrolytic cell in sequence, and finally phenyl isothiocyanate compound 1a (0.3mmol) was added dropwise. Platinum sheet and carbon rod were used as cathode and anode respectively, and a DC constant current of 10mA was passed between the electrode anode and the electrode cathode. The reaction was carried out at 25°C for 4h, and the reaction progress was monitored by thin layer chromatography until the reaction was complete. Finally, compound 3h was obtained by separation and purification by silica gel column chromatography with a yield of 85%. The reaction equation is as follows:

[0092]

[0093] Compound spectrum data:

[0094] 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),7.63(d,J=8.0Hz,2H),7.54(d,J=8.0Hz,1H),7.37(t,J= 7.6Hz, 2H), 7.24-7.20 (m, 1H), 7.01 (t, J = 7.2Hz, 1H), 6.88 (d, J = 8.4Hz, 1H), 6.69-6.65 (m, 3H).

[0095] 13 C NMR (101MHz, DMSO-d6) δ158.8,158.7,147.6,139.2,131.9,129.6,126.9,122.3,117.5,116.1,115.9,105.1.

[0096] Embodiment 9:

[0097] The preparation method of this embodiment comprises the following steps:

[0098] Benzoyl hydrazide compound 2i (0.2mmol), tetrabutylammonium iodide (0.4mmol), 1,4-diazabicyclo[2.2.2]octane (0.4mmol), sodium bicarbonate (0.4mmol), acetonitrile (6mL), and magnetic particles were added to the electrolytic cell in sequence, and finally phenyl isothiocyanate compound 1a (0.3mmol) was added dropwise. Platinum sheet and carbon rod were used as cathode and anode respectively, and a DC constant current of 10mA was passed between the electrode anode and the electrode cathode. The reaction was carried out at 25°C for 4h, and the reaction progress was monitored by thin layer chromatography until the reaction was complete. Finally, compound 3i was obtained by separation and purification by silica gel column chromatography with a yield of 76%. The reaction equation is as follows:

[0099]

[0100] Compound spectrum data:

[0101] 1 H NMR (400MHz, DMSO-d6) δ 10.68 (s, 1H), 7.85 (d, J = 8.4Hz, 2H), 7.65-7.60 (m, 4H), 7.39-7.36 (m, 2H), 7.04-7.00 (m, 1H), 1.33 (s, 9H).

[0102] 13 C NMR (101MHz, DMSO-d6) δ160.2,158.2,154.3,139.2,129.6,126.6,125.9,122.3,121.6,117.5,35.2,31.3.

[0103] Comparative Example:

[0104] The existing method for preparing 2-amino-1,3,4-oxadiazole compounds is to add benzoyl hydrazide (1.46 mmol), phenyl isothiocyanate (1.50 mmol), and 3 mL of dimethyl sulfoxide (DMSO), respectively, stir at room temperature for 30 minutes, add potassium hydrogen sulfate (8.75 mmol), and continue to react at room temperature for 6 hours. After the reaction is completed, 30 mL of water is added, filtered, and the solid is dried and purified by column chromatography to obtain the final compound.

[0105]

[0106] Compared with this method, the reaction process of the present invention is simple, the conditions are mild, the cumbersome reaction process is solved, the reaction time is reduced, and the highly toxic solvent DMSO is not required, which is green and environmentally friendly.

Claims

1. A method for preparing 2-amino-1,3,4-oxadiazole derivatives by electrocatalysis, characterized in that: The steps include: Add 0.2 mmol of benzoyl hydrazide compound, 0.4 mmol of tetrabutylammonium iodide, 0.4 mmol of 1,4-diazabicyclo[2.2.2]octane, 0.4 mmol of sodium bicarbonate, and 6 mL of acetonitrile into the electrolytic cell; Then, 0.3 mmol of phenyl isothiocyanate compound was added dropwise; The reaction takes place under a constant direct current between the anode and cathode electrodes.

2. The method for preparing 2-amino-1,3,4-oxadiazole derivatives by electrocatalysis according to claim 1, characterized in that: The anode is a carbon rod.

3. The method for preparing 2-amino-1,3,4-oxadiazole derivatives by electrocatalysis according to claim 1, characterized in that: The cathode is a platinum sheet.

4. The method for preparing 2-amino-1,3,4-oxadiazole derivatives by electrocatalysis according to claim 1, characterized in that: The DC constant current is 10 mA.

5. The method for preparing 2-amino-1,3,4-oxadiazole derivatives by electrocatalysis according to claim 1, characterized in that: The temperature of the reaction was 25°C.

6. The method for preparing 2-amino-1,3,4-oxadiazole derivatives by electrocatalysis according to claim 1, characterized in that: The reaction time is 4 hours.

7. The method for preparing 2-amino-1,3,4-oxadiazole derivatives by electrocatalysis according to claim 1, characterized in that: The benzoylhydrazide compound has the following structural formula: Among them, R 2 It is phenyl, pyrazinyl, o-aminophenyl or 4-tert-butylphenyl.

8. The method for preparing 2-amino-1,3,4-oxadiazole derivatives by electrocatalysis according to claim 1, characterized in that: The phenyl isothiocyanate compound has the following structural formula: Among them, R 1 is hydrogen, methyl, methoxy, fluorine, ethyl or phenyl.

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