A method for synthesizing 1,3,4-oxadiazoles from 1,2-dihydrazides
By using the inexpensive cyclizing agent SO2F2 in the presence of a base and solvent, 1,3,4-oxadiazole compounds were synthesized, solving the problems of expensive and unstable cyclizing agents in the prior art, and realizing the efficient and readily available synthesis of 1,3,4-oxadiazole compounds.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-10
- Publication Date
- 2026-03-24
AI Technical Summary
In the prior art, the cyclizing agents used in the cyclization and dehydration reaction of 1,2-diacylhydrazine are expensive, moisture-sensitive, highly toxic, or thermally unstable, which limits the synthesis efficiency and large-scale production of 1,3,4-oxadiazole compounds.
Using the inexpensive and readily available cyclizing agent SO2F2, 1,2-diacylhydrazide compounds were cyclized in the presence of a base and solvent to generate 1,3,4-oxadiazole compounds. The reaction conditions were mild, and the post-processing was carried out by column chromatography for separation and purification.
The method achieves efficient synthesis of 1,3,4-oxadiazole compounds under mild reaction conditions, with broad substrate adaptability, high yield, simple operation, and readily available cyclizing agents.
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Figure CN119431269B_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the technical field of organic chemical synthesis, and particularly relates to a method for synthesizing 1,3,4-oxadiazole compounds from 1,2-dihydrazide compounds. BACKGROUND
[0002] Nitrogen-containing heterocycles, particularly five-membered rings, have attracted great interest due to their presence in natural products and their frequent use in medicinal chemistry. Among these heterocycles, the 1,3,4-oxadiazolyl group has particular value in materials science, agrochemistry and medicinal chemistry as it can be used as a bioisostere of acid, ester and amide functionalities.
[0003] Over the years, many synthetic methods for preparing 1,3,4-oxadiazoles have been developed, among which the cyclodehydration of 1,2-dihydrazides is the most commonly used. To facilitate this transformation, cyclizing agents have been used, including SOCl2, POCl3, Burgess reagent, 2-chloro-1,3-dimethylimidazolinium chloride, some of which are expensive, not available on a large scale, and most of which have hygroscopicity, moisture sensitivity, toxicity or thermal instability, which sometimes hinders their use. SUMMARY
[0004] In view of the above problems, the purpose of the present application is to provide a method for synthesizing 1,3,4-oxadiazole compounds from 1,2-dihydrazide compounds.
[0005] The specific technical solutions are as follows:
[0006] A method for synthesizing 1,3,4-oxadiazole compounds from 1,2-dihydrazide compounds, comprising the following steps: taking 1,2-dihydrazide compounds as shown in formula (I) as raw materials, adding alkali and solvent into a reactor in sequence, and reacting in a SO2F2 gas atmosphere, and after the reaction is completed, post-treatment is carried out to obtain 1,3,4-oxadiazole compounds as shown in formula (II), and the reaction process is as follows:
[0007] ,
[0008] In the formula, the substituent R1 on the benzene ring is substituted or not substituted, when substituted, the substituent R1 is fluorine, chlorine, bromine, methyl or methoxy, and the substituent R2 is methyl, isopropyl, tert-butyl or phenyl.
[0009] Further, the alkali is potassium phosphate, potassium carbonate or cesium carbonate.
[0010] Further, the solvent is toluene, dichloroethane or acetone.
[0011] Further, the 1,2-dihydrazide compound shown in formula (I) and the base are in a molar ratio of 1.0:1.5-1.0:4.0.
[0012] Further, the reaction temperature is 70-110 DEG C, and the reaction time is 4-12 h.
[0013] Further, the reaction liquid post-treatment method is as follows: after the reaction is completed, dichloromethane is added to fully dissolve, and after filtration, the organic phase is concentrated, and then the organic phase is separated by column chromatography, and concentrated to obtain the 1,3,4-oxadiazole compound shown in formula (II).
[0014] The present application has the following beneficial effects:
[0015] 1) The reaction condition is mild, a cheap and readily available cyclization agent is used, and the preparation of the 1,3,4-oxadiazole compound is promoted efficiently;
[0016] 2) The substrate has wide adaptability, and the corresponding 1,3,4-oxadiazole compound can be obtained in a good yield;
[0017] 3) The operation process is simple and efficient. DETAILED DESCRIPTION
[0018] The present application will be further described below in combination with examples, but the protection scope of the present application is not limited to this.
[0019] Example 1: 2-methyl-5-phenyl-1,3,4-oxadiazole
[0020]
[0021] In a 100 mL single-necked flask, N'-acetylbenzhydrazide 1.78 g (10 mmol) and potassium phosphate 4.24 g (20 mmol) were sequentially added, 40 mL of toluene was used as a solvent, and stirring was carried out under a sulfuric fluoride gas atmosphere at 70 DEG C for 4 h. After the reaction was completed, 50 mL of dichloromethane was added to fully dissolve, and after filtration, the organic phase was concentrated, and then the organic phase was separated by column chromatography (developing agent: PE:EA = 5:1), and concentrated to obtain 2-methyl-5-phenyl-1,3,4-oxadiazole 1.44 g, purity 99%, yield 90%.
[0022] Nuclear magnetic resonance hydrogen spectrum: (400 MHz, Chloroform-d) δ 8.10-8.01 (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, N'-isobutyrylbenzoyl hydrazine 2.06 g (10 mmol), potassium carbonate 2.76 g (20 mmol), 40 mL dichloroethane as solvent were sequentially added, stirred in a sulfuric fluoride gas atmosphere, 80 ℃ for 5 h, after the reaction was completed, 50 mL dichloromethane was added to dissolve completely, after filtering membrane, the organic phase was concentrated, and then separated by column chromatography (eluent: PE:EA = 5:1), and concentrated to obtain 2-isopropyl-5-phenyl-1,3,4-oxadiazole 1.73 g, purity 99%, yield 92%.
[0026] Nuclear magnetic resonance hydrogen spectrum: (400 MHz, Chloroform-d) δ 8.04 (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, N'-isobutyrylbenzoyl hydrazine 2.06 g (10 mmol), potassium carbonate 2.76 g (20 mmol), 40 mL dichloroethane as solvent were sequentially added, stirred in a sulfuric fluoride gas atmosphere, 80 ℃ for 5 h, after the reaction was completed, 50 mL dichloromethane was added to dissolve completely, after filtering membrane, the organic phase was concentrated, and then separated by column chromatography (eluent: PE:EA = 5:1), and concentrated to obtain 2-isopropyl-5-phenyl-1,3,4-oxadiazole 1.73 g, purity 99%, yield 92%.
[0030] Nuclear magnetic resonance hydrogen spectrum: (400 MHz, Chloroform-d) δ 8.04 (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).
[0031] Example 4: 2-(4-fluorophenyl)-5-methyl-1,3,4-oxadiazole
[0032]
[0033] In a 100 mL single-necked flask, N'-acetyl-4-fluorobenzohydrazide 1.96 g (10 mmol), potassium phosphate 6.36 g (30 mmol), 40 mL of toluene as solvent, were added in sequence, stirred at 100 °C for 7 h in a sulfuryl fluoride gas atmosphere, after the reaction was completed, 50 mL of dichloromethane was added to dissolve completely, after filtering membrane, the organic phase was concentrated, and then separated by column chromatography (eluent: PE:EA = 5:1), and concentrated to obtain 2-(4-fluorophenyl)-5-methyl-1,3,4-oxadiazole 1.60 g, purity 99%, yield 90%.
[0034] Nuclear magnetic resonance hydrogen spectrum: (400 MHz, Chloroform-d) δ 8.01 (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, N'-acetyl-4-chlorobenzohydrazide 2.12 g (10 mmol), potassium carbonate 4.14 g (30 mmol), 40 mL of dichloroethane as solvent, were added in sequence, stirred at 100 °C for 7 h in a sulfuryl fluoride gas atmosphere, after the reaction was completed, 50 mL of dichloromethane was added to dissolve completely, after filtering membrane, the organic phase was concentrated, and then separated by column chromatography (eluent: PE:EA = 5:1), and concentrated to obtain 2-(4-chlorophenyl)-5-methyl-1,3,4-oxadiazole 1.81 g, purity 99%, yield 93%.
[0038] Nuclear magnetic resonance hydrogen spectrum: (400 MHz, Chloroform-d) δ 7.95 (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, N'-acetyl-3-chlorobenzohydrazide 2.12 g (10 mmol), cesium carbonate 9.77 g (30 mmol), 40 mL of acetone as solvent were added in turn, stirred at 70 ℃ for 9 h in the atmosphere of sulfuryl fluoride gas, after the reaction was completed, 50 mL of dichloromethane was added to dissolve completely, after filtering membrane, the organic phase was concentrated, and then separated by column chromatography (developing agent: PE:EA = 5:1), and concentrated to obtain 2-(3-chlorophenyl)-5-methyl-1,3,4-oxadiazole 1.77 g, purity 99%, yield 91%.
[0042] Nuclear magnetic resonance hydrogen spectrum: (400 MHz, Chloroform-d) δ 8.00 (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, N'-acetyl-2-chlorobenzohydrazide 2.12 g (10 mmol), potassium phosphate 8.47 g (40 mmol), 40 mL of toluene as solvent were added in turn, stirred at 80 ℃ for 10 h in the atmosphere of sulfuryl fluoride gas, after the reaction was completed, 50 mL of dichloromethane was added to dissolve completely, after filtering membrane, the organic phase was concentrated, and then separated by column chromatography (developing agent: PE:EA = 5:1), and concentrated to obtain 2-(2-chlorophenyl)-5-methyl-1,3,4-oxadiazole 1.79 g, purity 99%, yield 92%.
[0046] Nuclear magnetic resonance hydrogen spectrum: (400 MHz, Chloroform-d) δ 7.92 (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-bromobenzoylhydrazine, 5.52 g (40 mmol) of potassium carbonate, and 40 mL of dichloroethane were added sequentially. The mixture was stirred at 90 °C for 11 h under a sulfuryl fluoride atmosphere. After the reaction was completed, 50 mL of dichloromethane was added to dissolve the mixture completely. After filtration, the organic phase was concentrated and then separated by column chromatography (developing solvent: PE:EA = 5:1). Concentration yielded 2.15 g of 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazole with a purity of 99% and a yield of 90%.
[0050] 1H NMR spectrum: (400 MHz, Chloroform-d) δ 7.90 (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-methylbenzoylhydrazine and 13.03 g (40 mmol) of cesium carbonate were added sequentially. 40 mL of acetone was used as the solvent. The mixture was stirred at 100 °C for 12 h under a sulfuryl fluoride atmosphere. After the reaction was completed, 50 mL of dichloromethane was added to dissolve the mixture completely. After filtration, the organic phase was concentrated and then separated by column chromatography (developing solvent: PE:EA = 5:1). Concentration yielded 2.15 g of 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazole with a purity of 99% and a yield of 992%.
[0054] 1H NMR spectrum: (400 MHz, Chloroform-d) δ 7.90 (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-methoxybenzoylhydrazine and 4.24 g (20 mmol) of tripotassium phosphate were added sequentially, with 40 mL of toluene as solvent. The mixture was stirred at 110 °C for 4 h under a sulfuryl fluoride atmosphere. After the reaction was completed, 50 mL of dichloromethane was added to dissolve the mixture completely. After filtration, the organic phase was concentrated and then separated by column chromatography (developing solvent: PE:EA = 5:1). Concentration yielded 2.15 g of 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazole with a purity of 99% and a yield of 90%.
[0058] 1H NMR spectrum: (400 MHz, Chloroform-d) δ 7.95 (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 100 mL single-necked flask, 2.40 g (10 mmol) of dibenzoyl hydrazine, 2.76 g (40 mmol) of potassium carbonate, and 40 mL of dichloroethane were added sequentially. The mixture was stirred at 70 °C for 5 h in a sulfuryl fluoride atmosphere. After the reaction was completed, 50 mL of dichloromethane was added to dissolve the mixture completely. After filtration, the organic phase was concentrated and then separated by column chromatography (developing solvent: PE:EA = 5:1). Concentration yielded 2.15 g of 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazole with a purity of 99% and a yield of 93%.
[0062] 1H NMR spectrum: (400 MHz, Chloroform-d) δ 8.17 (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-diachydrazides, characterized in that, The process includes the following steps: using a 1,2-diacylhydrazine compound as shown in formula (I) as a raw material, a base and a solvent are added sequentially to a reactor, and the reaction is carried out in a cyclizing agent atmosphere of SO2F2. After the reaction is completed, the 1,3,4-oxadiazole compound as shown in formula (II) is obtained. The reaction process is as follows: ， In the formula, the substituent R1 on the benzene ring may or may not be substituted. When substituted, the substituent R1 is fluorine, chlorine, bromine, methyl or methoxy, and the substituent R2 is methyl, isopropyl, tert-butyl or phenyl. The base is tripotassium phosphate, potassium carbonate, or cesium carbonate; The solvent is toluene, dichloroethane, or acetone.
2. The method for synthesizing 1,3,4-oxadiazole compounds from 1,2-diachydrazides as described in claim 1, characterized in that, The molar ratio of 1,2-diachydrazide compounds to bases, as shown in formula (Ⅰ), is 1.0:2.0 to 1.0:4.
0.
3. The method for synthesizing 1,3,4-oxadiazole compounds from 1,2-diachydrazides as described in claim 1, characterized in that, The reaction temperature is 70℃~110℃, and the reaction time is 4h~12h.
4. The method for synthesizing 1,3,4-oxadiazole compounds from 1,2-diachydrazides as described in claim 1, characterized in that, The post-treatment method of the reaction solution is as follows: after the reaction is completed, dichloromethane is added to dissolve the solution completely, the solution is filtered through a membrane, the organic phase is concentrated, and then the organic phase is separated by column chromatography and concentrated to obtain 1,3,4-oxadiazole compounds as shown in formula (II).
Citation Information
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