Method for preparing 2-amino-1,3,4-oxadiazole derivatives by electrocatalysis

Abstract

The present invention belongs to the technical field of preparation of oxadiazole derivatives. The present invention provides a method for preparing 2-amino-1,3,4-oxadiazole derivatives by electrocatalysis, comprising the following steps: adding 0.2mmol of benzoylhydrazide compounds, 0.4mmol of tetrabutylammonium iodide, 0.4mmol of 1,4-diazabicyclo[2.2.2]octane, 0.4mmol of sodium bicarbonate, and 6mL of acetonitrile to an electrolytic cell; then adding 0.3mmol of phenyl isothiocyanate compounds dropwise; reacting under a DC constant current between an electrode anode and an electrode cathode. The present invention adopts electrocatalysis with benzoylhydrazide and phenyl isothiocyanate as reaction substrates, acetonitrile and other cheap and less toxic reagents as solvents, and passing current to replace the oxidant in conventional reactions, thereby synthesizing oxadiazole compounds 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 various fields. For example, in drug development, certain 2-amino-1,3,4-oxadiazole derivatives have demonstrated significant anticancer activity. For example, podophyllotoxin derivatives can inhibit microtubule polymerization and prevent cancer cell division, demonstrating anti-tumor potential. Furthermore, they have been shown to modulate the immune system in anti-inflammatory settings, alleviating inflammatory symptoms by inhibiting the secretion of tumor necrosis factor α (TNF-α). In agricultural applications, these compounds are being studied as pesticides. Some derivatives have antifungal properties, effectively combating crop diseases. Furthermore, some 2-amino-1,3,4-oxadiazole compounds are being developed as plant growth regulators, enhancing crop stress resistance and growth rate. In materials science, 2-amino-1,3,4-oxadiazole derivatives are used as organic semiconductor materials, serving as electron-conducting layers in OLED (organic light-emitting diodes) and organic photovoltaic (OPV) devices. Furthermore, they can serve as fluorescent probes in bioimaging, enabling 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 has developed a simple KHSO4-catalyzed method 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 a thiourea intermediate catalyzed by KHSO4 in DMSO under room temperature stirring.

[0004]

[0005] The Dilep-Kumar Sigalapalli research group has developed a new microwave-assisted, TBHP-mediated, one-pot method for the synthesis of 2-amino-1,3,4-oxadiazoles in an aqueous phase. This method involves the reaction of isothiocyanates with hydrazines in aqueous solution under microwave irradiation, without the need for a catalyst. The reaction proceeds through the formation of a transition state thiourea intermediate, followed by a cyclodesulfurization reaction, ultimately yielding 2-amino-1,3,4-oxadiazoles.

[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 present invention provides a method for preparing 2-amino-1,3,4-oxadiazole derivatives by electrocatalysis, comprising the following steps: adding 0.2 mmol of a 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 an electrolytic cell; then dropwise adding 0.3 mmol of a phenyl isothiocyanate compound; 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 embodiment, 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 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 with benzoylhydrazide and phenyl isothiocyanate as reaction substrates, acetonitrile and other cheap and low-toxic reagents as solvents, and the passage of electric current to replace the oxidant in the conventional reaction, thereby synthesizing oxadiazole compounds 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 The compound of Example 1 13C NMR spectrum.

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

[0021] Figure 4 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] Figure 9 is the compound of Example 5 1 H NMR spectrum.

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

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

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

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

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

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

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

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

[0035] Figure 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: Compound 1 (0.3-0.6 mmol), compound 2 (0.2-0.4 mmol), electrolyte (0.4-0.8 mmol), additive (0.8-1.6 mmol), acetonitrile (5-6 mL) are sequentially added to an electrolytic cell. A magnetic particle is added, and a constant DC current is passed between the anode and cathode electrodes. The reaction is allowed to proceed for 4 hours under a constant temperature condition. The reaction progress is monitored by thin-layer chromatography until the reaction is complete. Finally, the compound is separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate) to obtain a compound of formula 3. 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] Example 1:

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

[0043] Benzoylhydrazide compound 2 (0.2 mmol), tetrabutylammonium iodide (0.4 mmol), 1,4-diazabicyclo[2.2.2]octane (0.4 mmol), sodium bicarbonate (0.4 mmol), acetonitrile (6 mL), and a magnetic particle were added sequentially to the electrolytic cell. Finally, phenyl isothiocyanate compound 1a (0.3 mmol) was added dropwise. A platinum sheet and a carbon rod were used as the cathode and anode, respectively. A constant current of 10 mA was passed between the anode and cathode electrodes. The reaction was allowed to proceed at 25°C for 4 h. The reaction progress was monitored by thin-layer chromatography until the reaction was complete. Finally, compound 3a was separated and purified 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] Example 2:

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

[0050] Benzoylhydrazide compound 2 (0.2 mmol), tetrabutylammonium iodide (0.4 mmol), 1,4-diazabicyclo[2.2.2]octane (0.4 mmol), sodium bicarbonate (0.4 mmol), acetonitrile (6 mL), and a magnetic particle were added sequentially to the electrolytic cell. Finally, phenyl isothiocyanate compound 1b (0.3 mmol) was added dropwise. A platinum sheet and a carbon rod were used as the cathode and anode, respectively. A constant current of 10 mA was passed between the anode and cathode electrodes. The reaction was allowed to proceed at 25°C for 4 h. The reaction progress was monitored by thin-layer chromatography until the reaction was complete. Finally, compound 3b was separated and purified by silica gel column chromatography to obtain compound 3b 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] Example 3:

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

[0057] Benzoylhydrazide compound 2 (0.2 mmol), tetrabutylammonium iodide (0.4 mmol), 1,4-diazabicyclo[2.2.2]octane (0.4 mmol), sodium bicarbonate (0.4 mmol), acetonitrile (6 mL), and a magnetic particle were added sequentially to the electrolytic cell. Finally, phenyl isothiocyanate compound 1c (0.3 mmol) was added dropwise. A platinum sheet and a carbon rod were used as the cathode and anode, respectively. A constant current of 10 mA was passed between the anode and cathode electrodes. The reaction was allowed to proceed at 25°C for 4 h. The reaction progress was monitored by thin-layer chromatography until the reaction was complete. Finally, compound 3c was isolated and purified by silica gel column chromatography to obtain compound 3c in a 72% yield. 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] Example 4:

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

[0063] Benzoylhydrazide compound 2 (0.2 mmol), tetrabutylammonium iodide (0.4 mmol), 1,4-diazabicyclo[2.2.2]octane (0.4 mmol), sodium bicarbonate (0.4 mmol), acetonitrile (6 mL), and a magnetic particle were added sequentially to the electrolytic cell. Finally, phenyl isothiocyanate compound 1d (0.3 mmol) was added dropwise. A platinum sheet and a carbon rod were used as the cathode and anode, respectively. A constant current of 10 mA was passed between the anode and cathode electrodes. The reaction was allowed to proceed at 25°C for 4 h. The reaction progress was monitored by thin-layer chromatography until completion. Finally, compound 3d was isolated and purified by silica gel column chromatography to obtain compound 3d in an 85% yield. 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] Example 5:

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

[0070] Benzoylhydrazide compound 2 (0.2 mmol), tetrabutylammonium iodide (0.4 mmol), 1,4-diazabicyclo[2.2.2]octane (0.4 mmol), sodium bicarbonate (0.4 mmol), acetonitrile (6 mL), and a magnetic particle were added sequentially to the electrolytic cell. Finally, phenyl isothiocyanate compound 1e (0.3 mmol) was added dropwise. A platinum sheet and a carbon rod were used as the cathode and anode, respectively. A constant current of 10 mA was passed between the anode and cathode electrodes. The reaction was allowed to proceed at 25°C for 4 h. The reaction progress was monitored by thin-layer chromatography until the reaction was complete. Finally, compound 3e was separated and purified by silica gel column chromatography to obtain compound 3e in a 62% yield. 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] Example 6:

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

[0077] Benzoylhydrazide compound 2 (0.2 mmol), tetrabutylammonium iodide (0.4 mmol), 1,4-diazabicyclo[2.2.2]octane (0.4 mmol), sodium bicarbonate (0.4 mmol), acetonitrile (6 mL), and a magnetic particle were added sequentially to the electrolytic cell. Finally, phenyl isothiocyanate compound 1f (0.3 mmol) was added dropwise. A platinum rod and a carbon rod were used as the cathode and anode, respectively. A constant current of 10 mA was passed between the anode and cathode electrodes. The reaction was allowed to proceed at 25°C for 4 h. The reaction progress was monitored by thin-layer chromatography until the reaction was complete. Finally, compound 3f was separated and purified by silica gel column chromatography to obtain compound 3f in a 76% yield. 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] Example 7:

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

[0084] To the electrolytic cell, 2g (0.2mmol) of a benzoylhydrazide compound, tetrabutylammonium iodide (0.4mmol), 1,4-diazabicyclo[2.2.2]octane (0.4mmol), sodium bicarbonate (0.4mmol), and acetonitrile (6mL) were added sequentially. A magnetic particle was then added, and finally, phenyl isothiocyanate compound 1a (0.3mmol) was added dropwise. A platinum sheet and a carbon rod were used as the cathode and anode, respectively. A constant current of 10mA was passed between the anode and cathode electrodes. The reaction was allowed to proceed at 25°C for 4h, and the reaction progress was monitored by thin-layer chromatography until complete. Finally, the compound was separated and purified by silica gel column chromatography to obtain 3g of the compound with an 88% yield. 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] Example 8:

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

[0091] Benzoylhydrazide compound 2h (0.2 mmol), tetrabutylammonium iodide (0.4 mmol), 1,4-diazabicyclo[2.2.2]octane (0.4 mmol), sodium bicarbonate (0.4 mmol), acetonitrile (6 mL), and a magnetic particle were added sequentially to the electrolytic cell. Finally, phenyl isothiocyanate compound 1a (0.3 mmol) was added dropwise. A platinum sheet and a carbon rod were used as the cathode and anode, respectively. A constant current of 10 mA was passed between the anode and cathode electrodes. The reaction was allowed to proceed at 25°C for 4 h. The reaction progress was monitored by thin-layer chromatography until the reaction was complete. Finally, compound 3h was separated and purified by silica gel column chromatography to obtain compound 3h 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] Example 9:

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

[0098] Benzoylhydrazide compound 2i (0.2 mmol), tetrabutylammonium iodide (0.4 mmol), 1,4-diazabicyclo[2.2.2]octane (0.4 mmol), sodium bicarbonate (0.4 mmol), acetonitrile (6 mL), and a magnetic particle were added sequentially to the electrolytic cell. Finally, phenyl isothiocyanate compound 1a (0.3 mmol) was added dropwise. A platinum sheet and a carbon rod were used as the cathode and anode, respectively. A constant current of 10 mA was passed between the anode and cathode electrodes. The reaction was allowed to proceed at 25°C for 4 h. The reaction progress was monitored by thin-layer chromatography until the reaction was complete. Finally, compound 3i was isolated and purified 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) δ10.68 (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 involves adding benzoylhydrazide (1.46 mmol), phenyl isothiocyanate (1.50 mmol), and 3 mL of dimethyl sulfoxide (DMSO), stirring at room temperature for 30 minutes, adding potassium bisulfate (8.75 mmol), and continuing the reaction at room temperature for 6 hours. After completion of the reaction, 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 present invention has a simple reaction process and mild conditions, which solves the tedious reaction process and reduces the reaction time. In addition, it does not require the highly toxic solvent DMSO, making it 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 to the electrolytic cell; Then 0.3 mmol of phenyl isothiocyanate compound was added dropwise; React under a DC constant current between the electrode anode and the electrode cathode; The chemical equation of the reaction is: ; The R 1 is hydrogen, methyl, methoxy, fluorine, ethyl or phenyl; The R 2 is phenyl, pyrazinyl, o-aminophenyl or 4-tert-butylphenyl; The DC constant current is 10 mA.

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

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

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

5. The method for electrocatalytically preparing 2-amino-1,3,4-oxadiazole derivatives according to claim 1, characterized in that: The reaction time is 4 h.

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