Method for synthesizing 1, 3, 4-oxadiazole compound from 1, 2-dihydrazide compound

Abstract

The invention discloses a method for synthesizing a 1, 3, 4-oxadiazole compound from a 1, 2-dihydrazide compound, and the specific implementation process is as follows: taking the 1, 2-dihydrazide compound as shown in a formula (I) as a raw material, sequentially adding alkali and a solvent into the raw material, reacting in the atmosphere of cyclizing agent gas SO2F2, and carrying out post-treatment after the reaction to prepare the 1, 3, 4-oxadiazole compound as shown in a formula (II). The invention discloses a 1, 2, 4-oxadiazole compound and a preparation method thereof, and the reaction process is as follows: in a # imgabs0 # formula, a substituent group R1 on a benzene ring is substituted or not substituted, during substitution, the substituent group R1 is fluorine, chlorine, bromine, methyl or methoxyl, and a substituent group R2 is methyl, isopropyl, tert-butyl or phenyl. According to the method, the reaction conditions are mild, the cyclizing agent which is low in cost and easy to obtain is used, and preparation of the 1, 3, 4-oxadiazole compound is efficiently promoted.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and specifically relates to a method for synthesizing 1,3,4-oxadiazole compounds from 1,2-diacylhydrazide compounds. Background Art

[0002] Nitrogen-containing heterocycles, especially five-membered rings, have attracted great interest due to their presence in natural products and frequent use in medicinal chemistry. Among these heterocycles, the 1,3,4-oxadiazole group is of particular interest in materials science, agricultural chemistry, and medicinal chemistry because it can be used as a bioelectronic alternative to acid, ester, and amide functional groups.

[0003] Many synthetic methods for preparing 1,3,4-oxadiazoles have been developed over the years, among which the cyclodehydration reaction of 1,2-diacylhydrazide is the most commonly used. To promote this transformation, cyclizing agents are used, including SOCl2, POCl3, Burgess reagent, 2-chloro-1,3-dimethylimidazolinium chloride, some of which are expensive and not available on a large scale, and most of them are hygroscopic, moisture sensitive, highly toxic or thermally unstable, which sometimes hinders their use. Summary of the invention

[0004] In view of the above problems, the object of the present invention is to provide a method for synthesizing 1,3,4-oxadiazole compounds from 1,2-diacylhydrazide compounds.

[0005] The specific technical solutions are as follows:

[0006] A method for synthesizing a 1,3,4-oxadiazole compound from a 1,2-diacylhydrazine compound comprises the following steps: using a 1,2-diacylhydrazine compound as shown in formula (I) as a raw material, sequentially adding a base and a solvent into the reaction, reacting in an atmosphere of a cyclizing agent gas SO2F2, and performing post-treatment after the reaction to obtain a 1,3,4-oxadiazole compound as shown in formula (II), wherein the reaction process is as follows:

[0007]

[0008] In the formula, the substituent R1 on the benzene ring is substituted or unsubstituted. When substituted, the substituent R1 is fluorine, chlorine, bromine, methyl or methoxy, and the substituent R2 is methyl, isopropyl, tert-butyl or phenyl.

[0009] Furthermore, the base is tripotassium phosphate, potassium carbonate or cesium carbonate.

[0010] Furthermore, the solvent is toluene, ethylene dichloride or acetone.

[0011] Furthermore, the molar ratio of the 1,2-diacylhydrazine compound represented by formula (I) to the base is 1.0:1.5 to 1.0:4.0.

[0012] Furthermore, the reaction temperature is 70°C to 110°C, and the reaction time is 4h to 12h.

[0013] Furthermore, the post-treatment method of the reaction solution is to add dichloromethane to fully dissolve after the reaction is completed, filter the membrane, concentrate the organic phase, and then separate the organic phase by column chromatography, and concentrate to obtain the 1,3,4-oxadiazole compound shown in formula (II).

[0014] The beneficial effects of the present invention are:

[0015] 1) The reaction conditions are mild, and a cheap and readily available cyclizing agent is used to efficiently promote the preparation of 1,3,4-oxadiazole compounds;

[0016] 2) The substrate has wide adaptability and can obtain the corresponding 1,3,4-oxadiazole compounds in good yield;

[0017] 3) The operation process is simple and efficient. DETAILED DESCRIPTION

[0018] The present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited thereto.

[0019] Example 1: 2-Methyl-5-phenyl-1,3,4-oxadiazole

[0020]

[0021] In a 100 mL single-necked flask, 1.78 g (10 mmol) of N'-acetylbenzohydrazide, 4.24 g (20 mmol) of tripotassium phosphate and 40 mL of toluene were added in sequence as solvent, and stirred at 70 ° C for 4 h in a sulfuryl fluoride gas atmosphere. After the reaction, 50 mL of dichloromethane was added to fully dissolve the mixture. After filtering the membrane, the organic phase was concentrated and separated by column chromatography (developing solvent: PE:EA=5:1). After concentration, 1.44 g of 2-methyl-5-phenyl-1,3,4-oxadiazole was obtained with a purity of 99% and a yield of 90%.

[0022] H NMR: (400 MHz, Chloroform-d) δ8.10-8.01 (m, 2H), 7.53 (d, J=7.5 Hz, 3H), 2.64 (s, 3H).

[0023] Example 2: 2-Isopropyl-5-phenyl-1,3,4-oxadiazole

[0024]

[0025] In a 100 mL single-necked flask, 2.06 g (10 mmol) of N'-isobutyrylbenzoylhydrazine, 2.76 g (20 mmol) of potassium carbonate and 40 mL of dichloroethane were added in sequence as a solvent, and stirred at 80 ° C for 5 h in a sulfuryl fluoride gas atmosphere. After the reaction, 50 mL of dichloromethane was added to fully dissolve the mixture. After filtering through a membrane, the organic phase was concentrated and separated by column chromatography (developing solvent: PE: EA = 5:1). After concentration, 1.73 g of 2-isopropyl-5-phenyl-1,3,4-oxadiazole was obtained with a purity of 99% and a yield of 92%.

[0026] H NMR: (400 MHz, Chloroform-d) δ8.04 (dd, J=7.7, 1.8 Hz, 2H), 7.50 (q, J=5.5 Hz, 3H), 3.27 (p, J=7.0 Hz, 1H), 1.46 (s, 3H), 1.45 (s, 3H).

[0027] Example 3: 2-tert-butyl-5-phenyl-1,3,4-oxadiazole

[0028]

[0029] In a 100 mL single-necked flask, 2.20 g (10 mmol) of N'-pivaloylbenzohydrazide, 6.52 g (40 mmol) of cesium carbonate and 40 mL of acetone were added in sequence as solvent, and stirred at 90 ° C for 6 h in a sulfuryl fluoride gas atmosphere. After the reaction, 50 mL of dichloromethane was added to fully dissolve the mixture. After filtering the membrane, the organic phase was concentrated and separated by column chromatography (developing solvent: PE:EA=5:1). After concentration, 1.84 g of 2-tert-butyl-5-phenyl-1,3,4-oxadiazole was obtained with a purity of 99% and a yield of 91%.

[0030] H NMR: (400 MHz, Chloroform-d) δ8.01 (dd, J=7.6, 2.0 Hz, 2H), 7.50-7.43 (m, 3H), 1.46 (s, 9H).

[0031] Example 4: 2-(4-Fluorophenyl)-5-methyl-1,3,4-oxadiazole

[0032]

[0033] In a 100 mL single-necked flask, 1.96 g (10 mmol) of N'-acetyl-4-fluorobenzoic acid hydrazide, 6.36 g (30 mmol) of tripotassium phosphate, and 40 mL of toluene were added in sequence as solvent, and stirred at 100 ° C for 7 h in a sulfuryl fluoride gas atmosphere. After the reaction, 50 mL of dichloromethane was added to fully dissolve the mixture. After filtering the membrane, the organic phase was concentrated, and then the organic phase was separated by column chromatography (developing solvent: PE:EA=5:1). After concentration, 1.60 g of 2-(4-fluorophenyl)-5-methyl-1,3,4-oxadiazole was obtained with a purity of 99% and a yield of 90%.

[0034] H NMR: (400 MHz, Chloroform-d) δ8.01 (dd, J=8.9, 5.3 Hz, 2H), 7.17 (t, J=8.7 Hz, 2H), 2.60 (s, 3H).

[0035] Example 5: 2-(4-chlorophenyl)-5-methyl-1,3,4-oxadiazole

[0036]

[0037] In a 100 mL single-necked flask, 2.12 g (10 mmol) of N'-acetyl-4-chlorobenzoyl hydrazide, 4.14 g (30 mmol) of potassium carbonate and 40 mL of dichloroethane were added in sequence as solvent, and stirred at 100 °C for 7 h in a sulfuryl fluoride gas atmosphere. After the reaction, 50 mL of dichloromethane was added to fully dissolve the mixture. After filtering the membrane, the organic phase was concentrated and separated by column chromatography (developing solvent: PE:EA=5:1). After concentration, 1.81 g of 2-(4-chlorophenyl)-5-methyl-1,3,4-oxadiazole was obtained with a purity of 99% and a yield of 93%.

[0038] H NMR: (400 MHz, Chloroform-d) δ7.95 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 2.61 (s, 2H).

[0039] Example 6: 2-(3-chlorophenyl)-5-methyl-1,3,4-oxadiazole

[0040]

[0041] In a 100 mL single-necked flask, 2.12 g (10 mmol) of N'-acetyl-3-chlorobenzoyl hydrazide, 9.77 g (30 mmol) of cesium carbonate and 40 mL of acetone were added in sequence as solvent, and stirred at 70 ° C for 9 h in a sulfuryl fluoride gas atmosphere. After the reaction, 50 mL of dichloromethane was added to fully dissolve the mixture. After filtering the membrane, the organic phase was concentrated and separated by column chromatography (developing solvent: PE:EA=5:1). After concentration, 1.77 g of 2-(3-chlorophenyl)-5-methyl-1,3,4-oxadiazole was obtained with a purity of 99% and a yield of 91%.

[0042] H NMR: (400 MHz, Chloroform-d) δ8.00 (d, J = 1.6 Hz, 1H), 7.91 (dt, J = 7.6, 1.4 Hz, 1H), 7.50-7.46 (m, 1H), 7.42 (t, J = 7.8 Hz, 1H), 2.61 (s, 3H).

[0043] Example 7: 2-(2-chlorophenyl)-5-methyl-1,3,4-oxadiazole

[0044]

[0045] In a 100 mL single-necked flask, 2.12 g (10 mmol) of N'-acetyl-2-chlorobenzoyl hydrazide, 8.47 g (40 mmol) of tripotassium phosphate and 40 mL of toluene were added in sequence as solvent, and stirred at 80 °C for 10 h in a sulfuryl fluoride gas atmosphere. After the reaction, 50 mL of dichloromethane was added to fully dissolve the mixture. After filtering the membrane, the organic phase was concentrated and separated by column chromatography (developing solvent: PE:EA=5:1). After concentration, 1.79 g of 2-(2-chlorophenyl)-5-methyl-1,3,4-oxadiazole was obtained with a purity of 99% and a yield of 92%.

[0046] H NMR: (400 MHz, Chloroform-d) δ7.92 (dd, J = 7.7, 1.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 2.62 (s, 3H).

[0047] Example 8: 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazole

[0048]

[0049] In a 100 mL single-necked flask, 2.56 g (10 mmol) of N'-acetyl-4-bromobenzohydrazide, 5.52 g (40 mmol) of potassium carbonate and 40 mL of dichloroethane were added in sequence as solvent, and stirred at 90 °C for 11 h in a sulfuryl fluoride gas atmosphere. After the reaction, 50 mL of dichloromethane was added to fully dissolve the mixture. After filtering the membrane, the organic phase was concentrated and separated by column chromatography (developing solvent: PE:EA=5:1). After concentration, 2.15 g of 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazole was obtained with a purity of 99% and a yield of 90%.

[0050] H NMR: (400 MHz, Chloroform-d) δ7.90 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 2.63 (s, 3H).

[0051] Example 9: 2-(4-methylphenyl)-5-methyl-1,3,4-oxadiazole

[0052]

[0053] In a 100 mL single-necked flask, 1.92 g (10 mmol) of N'-acetyl-4-methylbenzohydrazide, 13.03 g (40 mmol) of cesium carbonate and 40 mL of acetone were added in sequence as solvent, and stirred at 100 °C for 12 h in a sulfuryl fluoride gas atmosphere. After the reaction, 50 mL of dichloromethane was added to fully dissolve the mixture. After filtering the membrane, the organic phase was concentrated and separated by column chromatography (developing solvent: PE:EA=5:1). After concentration, 2.15 g of 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazole was obtained with a purity of 99% and a yield of 992%.

[0054] H NMR: (400 MHz, Chloroform-d) δ7.90 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 2.59 (s, 3H), 2.41 (s, 3H).

[0055] Example 10: 2-(4-methoxyphenyl)-5-methyl-1,3,4-oxadiazole

[0056]

[0057] In a 100 mL single-necked flask, 2.08 g (10 mmol) of N'-acetyl-4-methoxybenzohydrazide, 4.24 g (20 mmol) of tripotassium phosphate and 40 mL of toluene were added in sequence as solvent, and stirred at 110 °C for 4 h in a sulfuryl fluoride gas atmosphere. After the reaction, 50 mL of dichloromethane was added to fully dissolve the mixture. After filtering the membrane, the organic phase was concentrated and separated by column chromatography (developing solvent: PE:EA=5:1). After concentration, 2.15 g of 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazole was obtained with a purity of 99% and a yield of 90%.

[0058] H NMR: (400 MHz, Chloroform-d) δ7.95 (d, J = 8.9 Hz, 2H), 6.98 (d, J = 8.9 Hz, 2H), 3.86 (s, 3H), 2.59 (s, 3H).

[0059] Example 11: 2,5-Diphenyl-1,3,4-oxadiazole

[0060]

[0061] In a 100mL single-necked flask, 2.40g (10mmol) of dibenzoylhydrazide, 2.76g (40mmol) of potassium carbonate and 40mL of dichloroethane were added in sequence as solvent, and stirred at 70°C for 5h in a sulfuryl fluoride gas atmosphere. After the reaction, 50mL of dichloromethane was added to fully dissolve the mixture. After filtering the membrane, the organic phase was concentrated and separated by column chromatography (developing solvent: PE:EA=5:1). After concentration, 2.15g of 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazole was obtained with a purity of 99% and a yield of 93%.

[0062] H NMR: (400 MHz, Chloroform-d) δ8.17 (dd, J=7.4, 1.9 Hz, 4H), 7.62-7.51 (m, 6H).

Claims

1. A method for synthesizing 1,3,4-oxadiazole compounds from 1,2-diacylhydrazide compounds, characterized in that: The method comprises the following steps: using a 1,2-diacylhydrazine compound as shown in formula (I) as a raw material, adding a base and a solvent to the reaction in sequence, reacting in an atmosphere of a cyclizing agent gas SO2F2, and performing post-treatment after the reaction to obtain a 1,3,4-oxadiazole compound as shown in formula (II). The reaction process is as follows: In the formula, the substituent R1 on the benzene ring is substituted or unsubstituted. When substituted, the substituent R1 is fluorine, chlorine, bromine, methyl or methoxy, and the substituent R2 is methyl, isopropyl, tert-butyl or phenyl.

2. A method for synthesizing 1,3,4-oxadiazole compounds from 1,2-diacylhydrazide compounds as claimed in claim 1, characterized in that: The base is tripotassium phosphate, potassium carbonate or cesium carbonate.

3. A method for synthesizing 1,3,4-oxadiazole compounds from 1,2-diacylhydrazide compounds as claimed in claim 1, characterized in that: The solvent is toluene, ethylene dichloride or acetone.

4. The method for synthesizing 1,3,4-oxadiazole compounds from 1,2-diacylhydrazide compounds as claimed in claim 1, characterized in that: The molar ratio of the 1,2-diacylhydrazine compound as shown in formula (I) to the base is 1.0:2.0 to 1.0:4.

0.

5. The method for synthesizing 1,3,4-oxadiazole compounds from 1,2-diacylhydrazide compounds as claimed in claim 1, characterized in that: The reaction temperature is 70°C to 110°C, and the reaction time is 4h to 12h.

6. The method for synthesizing 1,3,4-oxadiazole compounds from 1,2-diacylhydrazide compounds as claimed in claim 1, characterized in that: The post-treatment method of the reaction solution is to add dichloromethane to fully dissolve after the reaction is completed, filter the membrane, concentrate the organic phase, and then separate the organic phase by column chromatography, and concentrate to obtain the 1,3,4-oxadiazole compound shown in formula (II).

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