Synthetic method of isoxazoline compound
By using a blue LED light source in an air environment to initiate the reaction of compound 1 with ethyl acrylate, the synthetic challenge of fused bicyclic isoxazoline was solved, achieving green synthesis and providing a new synthetic route for complex molecules.
Patent Information
- Application Number
- CN202511466431.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-10-14
- Publication Date
- 2026-01-02
AI Technical Summary
Existing technologies make it difficult to stereospecifically synthesize fused bicyclic isoxazolines by controlling reaction conditions, and there are also issues with the presence of residual traditional metal catalysts.
Compound 1 and ethyl acrylate were reacted with tert-butyl nitrite, alkali and K2S2O8 in dichloroethane. The mixture was stirred in air for 12 hours using a 35 W blue LED light source. The solvent was then removed under reduced pressure and silica gel column chromatography was performed to obtain isoxazoline compounds.
Green synthesis of isoxazoline compounds has been achieved, avoiding the residue of traditional metal catalysts, providing a new route for the synthesis of complex molecules, and deriving structures such as β-lactams and β-amino alcohols.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing isoxazoline compounds. Background Technology
[0002] Isoxazoline is a class of five-membered heterocyclic compounds containing nitrogen and oxygen atoms. Its structure has important applications in many fields, especially in agriculture, medicine and chemical synthesis.
[0003] Isoxazoline compounds achieve highly effective insecticidal effects by regulating the GABA-Cl channel in pests, and their unique mechanism makes it difficult for pests to develop resistance. Compared with traditional insecticides (such as abamectin), isoxazoline compounds are safer for crops, and no phytotoxicity has been recorded in field trials, providing a new solution to the problem of resistant pests. In addition, these compounds can also be used to derive herbicides (such as benzoxazine) and fungicides, demonstrating broad-spectrum agricultural application potential.
[0004] In the pharmaceutical field, isoxazoline skeletons are key structures in antiparasitic drugs (such as afurazone and loteranar), providing continuous protection against ectoparasites in dogs and cats for up to 12 weeks with a single dose. Its derivatives, such as sulfamethoxazole, serve as skeletons for antibiotics or antidiabetic drugs, further expanding their clinical applications. Furthermore, isoxazoline natural product fragments possess antiviral, antibacterial, and anticancer activities, providing diverse templates for drug development. For example, spirocyclic isoxazolines designed by introducing spirozyzine dibenzofuran groups can significantly enhance drug activity and selectivity.
[0005] As key intermediates, isoxazolines can be derived into structures such as β-lactams and β-amino alcohols, providing new pathways for the synthesis of complex molecules. In the field of chemical synthesis of isoxazoline compounds, photocatalytic olefin synthesis of isoxazolines (such as Cu...) ᴵᴵ Catalytic radical cyclization reaction generates α-nitro radicals through the single-electron oxidation of nitro compounds, achieving efficient and green framework construction. This technology avoids the residue problems of traditional metal catalysts; however, how to stereospecifically synthesize fused bicyclic isoxazolines by controlling reaction conditions remains a technical challenge. Summary of the Invention
[0006] To overcome the shortcomings of the prior art, this invention provides a method for synthesizing isoxazoline compounds. In this invention, compound 1 and ethyl acrylate are dissolved in dichloroethane (DCE), followed by the addition of tert-butyl nitrite (TBN), a base, and K₂S₂O₈. The reaction is carried out in air, irradiated with a 35 W blue LED light source, and stirred at room temperature for 12 hours. After the reaction is complete, the solvent is removed under reduced pressure, and the crude product is then subjected to silica gel column chromatography to obtain the product, which is the isoxazoline compound. This synthetic method avoids the residual problems of traditional metal catalysts, providing a new paradigm for the green synthesis of isoxazoline compounds. As a key intermediate, isoxazoline can derive structures such as β-lactams and β-amino alcohols, providing new pathways for the synthesis of complex molecules.
[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows: This invention provides a method for synthesizing isoxazoline compounds, comprising the following steps: Compound 1 and ethyl acrylate were dissolved in dichloroethane, and then tert-butyl nitrite, alkali and K2S2O8 were added. The reaction was carried out in air, irradiated with a blue LED light source and stirred. After the reaction was completed, the solvent was removed under reduced pressure, and the crude product was subjected to silica gel column chromatography to obtain the product, which is an isoxazoline compound.
[0008] Furthermore, compound 1 is one of the following structural formulas: .
[0009] Furthermore, the molar ratio of compound 1, ethyl acrylate, tert-butyl nitrite, alkali and K2S2O8 is 1:1~2:2~4:0.5:1~2.
[0010] Furthermore, the molar ratio of compound 1, ethyl acrylate, tert-butyl nitrite, alkali, and K2S2O8 is 1:1.5:3:0.5:1.5.
[0011] Further, the base is any one of 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine (Et3N), and triethylenediamine (DABCO).
[0012] Furthermore, the base is 4-dimethylaminopyridine.
[0013] Furthermore, the power of the blue LED light source is 35 W.
[0014] Furthermore, the stirring reaction is carried out at room temperature.
[0015] Furthermore, the stirring reaction is carried out for 12 hours.
[0016] Compared with the prior art, the beneficial effects of the present invention are: This invention involves dissolving compound 1 and ethyl acrylate in dichloroethane, then adding tert-butyl nitrite, a base, and K₂S₂O₈. The reaction is carried out in air, irradiated with a 35 W blue LED light source, and stirred at room temperature for 12 hours. After the reaction is complete, the solvent is removed under reduced pressure, and the crude product is then subjected to silica gel column chromatography to obtain the product, which is an isoxazoline compound. This synthetic method avoids the residue problems of traditional metal catalysts, providing a new paradigm for the green synthesis of isoxazoline compounds. As a key intermediate, isoxazoline can derive structures such as β-lactams and β-amino alcohols, providing new pathways for the synthesis of complex molecules. Detailed Implementation
[0017] The specific embodiments of the present invention will be further described below. It should be noted that these descriptions are for the purpose of aiding understanding the present invention, but do not constitute a limitation thereof. Furthermore, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.
[0018] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods, and the experimental materials used in the following embodiments are all available through conventional commercial channels.
[0019] Example 1: A method for synthesizing an isoxazoline compound 4a 0.5 mmol of compound 1a and 0.75 mmol of ethyl acrylate were dissolved in 1 mL of dichloroethane. Then, 1.5 mmol of tert-butyl nitrite, 0.25 mmol of 4-dimethylaminopyridine and 0.75 mmol of K2S2O8 were added. The reaction was carried out in air, irradiated with a 35 W blue LED light source and stirred at room temperature for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. The crude product was then subjected to silica gel column chromatography to obtain a yellow oily product, namely isoxazoline compound 4a, with a yield of 76%.
[0020] The structural formula of compound 1a is: The reaction equation is: The NMR detection data of compound 4a are as follows: Rf = 0.35 (EtOAc / cyclohexane = 1 / 15). 1 H NMR (400 MHz, CDCl3) δ 8.12(d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 5.16 (dd, J = 11.3, 8.0 Hz,1H), 4.27 (q, J = 7.1 Hz, 2H), 3.76-3.55 (m, 2H), 2.41 (s, 3H), 1.32 (t, J =7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 184.9, 169.2, 156.9, 145.0, 132.9, 130.5, 129.2, 78.8, 62.2, 38.6, 21.7, 14.1.
[0021] The mass spectrometry data for compound 4a are as follows: HRMS (ESI) m / z: [M+Na] + Calcd for C 14 H 15 NNaO4 + 284.0893; Found284.0894.
[0022] Example 2: A method for synthesizing an isoxazoline compound 4a The difference between Example 2 and Example 1 is that the amounts of raw materials used in Example 2 are: 0.6 mmol ethyl acrylate and 1 mmol K2S2O8, while the rest remain the same as in Example 1. The final yield of isoxazoline compound 4a was 47%.
[0023] Example 3: A method for synthesizing an isoxazoline compound 4a The difference between Example 3 and Example 1 is that the amount of raw material used in Example 3 is 1 mmol K2S2O8, while the rest remains the same as in Example 1. The final yield of isoxazoline compound 4a was 61%.
[0024] Example 4: A method for synthesizing an isoxazoline compound 4a The difference between Example 4 and Example 1 is that the amounts of raw materials used in Example 4 are: 1 mmol ethyl acrylate and 1 mmol K2S2O8, while the rest remain the same as in Example 1. The final yield of isoxazoline compound 4a was 59%.
[0025] Example 5: A method for synthesizing an isoxazoline compound 4a The difference between Example 5 and Example 1 is that the amount of raw materials used in Example 5 is 2 mmol tert-butyl nitrite and 1 mmol K2S2O8, while the rest remains the same as in Example 1. The yield of the final isoxazoline compound 4a is 60%.
[0026] Example 6: A method for synthesizing an isoxazoline compound 4a The difference between Example 6 and Example 1 is that the amount of raw material used in Example 6 is 0.5 mmol K2S2O8, while the rest remains the same as in Example 1. The final yield of isoxazoline compound 4a was 56%.
[0027] Example 7: A method for synthesizing an isoxazoline compound 4a The difference between Example 7 and Example 1 is that the base in Example 7 is 1,8-diazabicyclo[5.4.0]undec-7-ene, while the rest remains the same as in Example 1. The final yield of isoxazoline compound 4a was 65%.
[0028] Example 8: A method for synthesizing an isoxazoline compound 4a The difference between Example 8 and Example 1 is that the base in Example 8 is triethylamine, while the rest is the same as in Example 1. The final yield of isoxazoline compound 4a was 72%.
[0029] Example 9: A method for synthesizing an isoxazoline compound 4a The difference between Example 9 and Example 1 is that the base in Example 9 is triethylenediamine, while the rest is the same as in Example 1. The final yield of isoxazoline compound 4a was 54%.
[0030] Comparative Example 1: A method for synthesizing an isoxazoline compound 4a The difference between Comparative Example 1 and Example 1 is that the amounts of raw materials used in Comparative Example 1 are: 0.42 mmol ethyl acrylate, 1.25 mmol tert-butyl nitrite, and 0.84 mmol K₂S₂O₈, while the rest remain the same as in Example 1. The yield of the final isoxazoline compound 4a was 39%.
[0031] Comparative Example 2: A method for synthesizing an isoxazoline compound 4a The difference between Comparative Example 2 and Example 1 is that the amounts of raw materials used in Comparative Example 2 are: 1 mmol tert-butyl nitrite and 1 mmol K2S2O8, while the rest are the same as in Example 1. The final yield of isoxazoline compound 4a was 34%.
[0032] Comparative Example 3: A method for synthesizing an isoxazoline compound 4a The difference between Comparative Example 3 and Example 1 is that K2S2O8 was not added in Comparative Example 3, while the rest remained the same as in Example 1. The final yield of isoxazoline compound 4a was 42%.
[0033] Comparative Example 4: A method for synthesizing an isoxazoline compound 4a The difference between Comparative Example 4 and Example 1 is that the base in Comparative Example 4 is sodium hydroxide, while the rest is the same as in Example 1. The final yield of isoxazoline compound 4a was 37%.
[0034] Comparative Example 5: A method for synthesizing an isoxazoline compound 4a The difference between Comparative Example 5 and Example 1 is that 4-dimethylaminopyridine was not added in Comparative Example 5, while the rest remained the same as in Example 1. The final yield of isoxazoline compound 4a was 21%.
[0035] Comparative Example 6: A method for synthesizing an isoxazoline compound 4a The difference between Comparative Example 6 and Example 1 is that the amounts of raw materials used in Comparative Example 6 are: 0.33 mmol ethyl acrylate, 1 mmol tert-butyl nitrite, and 0.5 mmol K2S2O8, while the rest remain the same as in Example 1. The final yield of isoxazoline compound 4a was 43%.
[0036] Comparative Example 7: A method for synthesizing an isoxazoline compound 4a The difference between Comparative Example 7 and Example 1 is that the amount of raw material used in Comparative Example 7 was 0.5 mmol of ethyl acrylate, and the reaction was carried out under dark conditions, i.e., without blue LED light source irradiation. Otherwise, the results were the same as in Example 1. The final yield of isoxazoline compound 4a was 52%.
[0037] Comparative Example 8: A method for synthesizing an isoxazoline compound 4a The difference between Comparative Example 7 and Example 1 is that Comparative Example 7 was reacted under dark conditions, i.e., without blue LED light source illumination, while the rest remained the same as Example 1. The final yield of isoxazoline compound 4a was 15%.
[0038] Example 10: A method for synthesizing an isoxazoline compound 4b The difference between Example 10 and Example 1 is that in Example 10, compound 1b is used instead of compound 1a, and the structure of compound 1b is as follows: The structural formula of the synthesized compound 4b is: Compound 4b is a yellow oil with a yield of 78%.
[0039] The NMR data for compound 4b are as follows: Rf = 0.35 (EtOAc / cyclohexane = 1 / 15). 1 H NMR (400 MHz, CDCl3) δ 8.01(d, J = 7.8 Hz, 2H), 7.42 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 5.18(dd, J = 11.2, 8.0 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.81-3.48 (m, 2H), 2.42(s, 3H), 1.33 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 185.6, 169.2,156.9, 138.3, 135.5, 134.7, 130.7, 128.4, 127.7, 78.9, 62.2, 38.6, 21.3,14.1.
[0040] The mass spectrometry data for compound 4b are as follows: HRMS (ESI) m / z: [M+Na] + Calcd for C 14 H 15 NNaO4 +284.0893; Found284.0895.
[0041] Example 11: A method for synthesizing an isoxazoline compound 4c The difference between Example 11 and Example 1 is that in Example 11, compound 1c is used instead of compound 1a, and the structure of compound 1c is as follows: The structural formula of the synthesized compound 4c is: Compound 4c is a yellow oil with a yield of 75%.
[0042] The NMR detection data of compound 4c are as follows: Rf = 0.35 (EtOAc / cyclohexane = 1 / 15). 1 H NMR (400 MHz, CDCl3) δ 7.77(dd, J = 5.8, 3.2 Hz, 1H), 7.43 (td, J = 7.6, 1.2 Hz, 1H), 7.35-7.19 (m, 2H), 5.22 (dd, J = 10.8, 8.4 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.64 (dd, J = 9.6,2.8 Hz, 2H), 2.46 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3)δ 189.0, 169.1, 157.7, 138.4, 135.9, 132.0, 131.5, 130.8, 125.4, 79.8, 62.3,37.7, 20.6, 14.1.
[0043] The mass spectrometry data for compound 4c are as follows: HRMS (ESI) m / z: [M+Na] + Calcd for C 14 H 15 NNaO4 + 284.0893; Found284.0893.
[0044] Example 12: A method for synthesizing isoxazoline compound 4d The difference between Example 12 and Example 1 is that in Example 12, compound 1d is used instead of compound 1a, and the structure of compound 1d is as follows: The structural formula of the synthesized compound 4d is: Compound 4d is a yellow oil with a yield of 76%.
[0045] The NMR data for compound 4d are as follows: Rf = 0.33 (EtOAc / cyclohexane = 1 / 15). 1 H NMR (400 MHz, CDCl3) δ 8.27-8.12 (m, 2H), 7.67-7.57 (m, 1H), 7.54-7.43 (m, 2H), 5.20 (dd, J = 11.1, 8.1Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.79-3.56 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 185.5, 169.1, 156.9, 135.4, 133.9, 130.4,128.5, 79.0, 62.2, 38.5, 14.1.
[0046] Example 13: A method for synthesizing an isoxazoline compound 4e The difference between Example 13 and Example 1 is that in Example 13, compound 1e is used instead of compound 1a, and the structure of compound 1e is as follows: The structural formula of the synthesized compound 4e is: Compound 4e is a yellow oil with a yield of 84%.
[0047] The NMR detection data for compound 4e are as follows: Rf = 0.36 (EtOAc / cyclohexane = 1 / 8). 1 H NMR (400 MHz, CDCl3) δ 8.34-8.21 (m, 2H), 7.06-6.89 (m, 2H), 5.17 (dd, J = 11.5, 7.8 Hz, 1H), 4.30 (q, J= 7.1 Hz, 2H), 3.90 (s, 3H), 3.76-3.57 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H). 13 CNMR (101 MHz, CDCl3) δ 183.6, 169.3, 164.4, 156.9, 132.9, 128.3, 113.8, 78.7, 62.2, 55.6, 38.9, 14.1.
[0048] The mass spectrometry data for compound 4e are as follows: HRMS (ESI) m / z: [M+Na] + Calcd for C 14 H 15 NNaO5 + 300.0842; Found 300.0839.
[0049] Example 14: A method for synthesizing an isoxazoline compound 4f The difference between Example 14 and Example 1 is that in Example 14, compound 1f is used instead of compound 1a, and the structure of compound 1f is as follows: The structural formula of the synthesized compound 4f is: Compound 4f is a yellow solid with a yield of 78%.
[0050] The NMR data for compound 4f are as follows: Rf = 0.38 (EtOAc / cyclohexane = 1 / 15). 1 H NMR (400 MHz, CDCl3) δ 8.42-8.20 (m, 2H), 7.75-7.70 (m, 2H), 7.68-7.64 (m, 2H), 7.52-7.47 (m, 2H), 7.46-7.40 (m, 1H), 5.22 (dd, J = 11.1, 8.2 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.79-3.59 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 184.9,169.2, 157.0, 146.6, 139.7, 134.1, 131.0, 129.0, 128.4, 127.3, 127.1, 79.0,62.3, 38.6, 14.1.
[0051] The mass spectrometry data for compound 4f are as follows: HRMS (ESI) m / z: [M+Na] + Calcd for C 19 H 17 NNaO4 + 346.1050; Found346.1052.
[0052] Example 15: A method for synthesizing 4g of an isoxazoline compound The difference between Example 15 and Example 1 is that in Example 15, compound 1g is used instead of compound 1a, and the structure of compound 1g is as follows: The structural formula of the synthesized compound 4g is: The compound, 4g, was a yellow oil with a yield of 70%.
[0053] The NMR detection data of compound 4g are as follows: Rf = 0.33 (EtOAc / cyclohexane = 1 / 15). 1 H NMR (400 MHz, CDCl3) δ 8.35-8.16 (m, 2H), 7.23-7.06 (m, 2H), 5.19 (dd, J = 11.2, 8.0 Hz, 1H), 4.28 (q, J= 7.1 Hz, 2H), 3.77-3.54 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 183.7, 169.1, 166.3 (d, J = 256.6 Hz), 156.9, 133.3, 133.2, 131.7 (d, J = 2.9 Hz) 115.7 (d, J = 21.9 Hz), 79.0, 62.3, 38.4, 14.1. 19 F NMR (376MHz, CDCl3) δ -103.47.
[0054] The mass spectrometry data for compound 4g are as follows: HRMS (ESI) m / z: [M+Na] + Calcd for C 13 H 12 FNNaO4 + 288.0643; Found288.0645.
[0055] Example 16: A method for synthesizing an isoxazoline compound 4h The difference between Example 16 and Example 1 is that in Example 16, compound 1h is used instead of compound 1a, and the structure of compound 1h is as follows: The structural formula of the synthesized compound 4h is: The compound was a yellow oil after 4 hours, with a yield of 73%.
[0056] The NMR data of compound 4h are as follows: Rf = 0.33 (EtOAc / cyclohexane = 1 / 15). 1 H NMR (400 MHz, CDCl3) δ 8.21-8.06 (m, 2H), 7.54-7.40 (m, 2H), 5.33-5.08 (m, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.80-3.51 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 184.1, 169.0, 156.9, 140.6, 133.6, 131.8, 128.8, 79.1, 62.3, 38.3, 14.1.
[0057] The mass spectrometry data of the compound after 4 hours are as follows: HRMS (ESI) m / z: [M+Na] + Calcd for C 13 H 12 ClNNaO4 + 304.0347; Found304.0348.
[0058] Example 17: A method for synthesizing an isoxazoline compound 4i The difference between Example 17 and Example 1 is that in Example 17, compound 1i is used instead of compound 1a, and the structure of compound 1i is as follows: The structural formula of the synthesized compound 4i is: Compound 4i is a yellow oil with a yield of 69%.
[0059] The NMR data for compound 4i are as follows: Rf = 0.33 (EtOAc / cyclohexane = 1 / 15). 1 H NMR (400 MHz, CDCl3) δ 8.19-8.00 (m, 2H), 7.71- 7.56 (m, 2H), 5.20 (dd, J = 11.1, 8.3 Hz, 1H), 4.29 (q, J= 7.1 Hz, 2H), 3.74-3.54 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 184.3, 169.0, 156.9, 134.1, 131.9, 131.8, 129.4, 79.1, 62.3, 38.3, 14.1.
[0060] The mass spectrometry data for compound 4i are as follows: HRMS (ESI) m / z: [M+Na] + Calcd for C 13 H 12 BrNNaO4 + 347.9842; Found347.9843.
[0061] Example 18: A method for synthesizing an isoxazoline compound 4j The difference between Example 18 and Example 1 is that in Example 18, compound 1j is used instead of compound 1a, and the structure of compound 1j is as follows: The structural formula of the synthesized compound 4j is: Compound 4j is a yellow oil with a yield of 61%.
[0062] The NMR data for compound 4j are as follows: Rf = 0.33 (EtOAc / cyclohexane = 1 / 15). 1 H NMR (400 MHz, CDCl3) δ 8.07(ddd, J = 7.8, 1.6, 1.0 Hz, 1H), 7.94 (ddd, J = 9.5, 2.7, 1.6 Hz, 1H), 7.48(td, J = 8.0, 5.6 Hz, 1H), 7.34 (tdd, J = 8.3, 2.7, 1.0 Hz, 1H), 5.22 (dd, J= 10.8, 8.5 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 3.78-3.56 (m, 2H), 1.36 (t, J= 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 184.1, 169.0, 162.5 (d, J = 247.7Hz), 156.8, 137.2 (d, J = 6.9 Hz), 130.1 (d, J = 7.6 Hz), 126.3 (d, J = 3.0Hz), 120.9 (d, J = 21.4 Hz), 117.1 (d, J = 23.3 Hz), 79.2, 62.3, 38.2, 14.1. 19 F NMR (376 MHz, CDCl3) δ -111.80.
[0063] The mass spectrometry data for compound 4j are as follows: HRMS (ESI) m / z: [M+Na] + Calcd for C 13 H 12 FNNaO4 + 288.0643; Found288.0644.
[0064] Example 19: A method for synthesizing an isoxazoline compound 4k The difference between Example 19 and Example 1 is that in Example 19, compound 1k is used instead of compound 1a, and the structure of compound 1k is as follows: The structural formula of the synthesized compound 4k is: Compound 4K is a yellow oil with a yield of 63%.
[0065] The NMR detection data for compound 4k are as follows: Rf = 0.33 (EtOAc / cyclohexane = 1 / 15). 1 H NMR (400 MHz, CDCl3) δ 8.36(t, J = 1.8 Hz, 1H), 8.19 (ddd, J = 7.9, 1.7, 1.1 Hz, 1H), 7.75 (ddd, J =8.0, 2.0, 1.1 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 5.22 (dd, J = 10.9, 8.5 Hz,1H), 4.31 (q, J = 7.1 Hz, 2H), 3.76-3.54 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H). 13CNMR (101 MHz, CDCl3) δ 184.0, 169.0, 156.8, 137.0, 136.7, 133.1, 130.0,129.1, 122.7, 79.2, 62.4, 38.2, 14.1.
[0066] The mass spectrometry data for compound 4k are as follows: HRMS (ESI) m / z: [M+Na] + Calcd for C 13 H 12 BrNNaO4 + 347.9842; Found347.9841.
[0067] Example 20: A method for synthesizing an isoxazoline compound 4l The difference between Example 20 and Example 1 is that in Example 20, compound 11 is used instead of compound 1a, and the structure of compound 11 is as follows: The structural formula of the synthesized compound 4l is: Compound 4l is a yellow oil with a yield of 46%.
[0068] The NMR detection data of compound 4l are as follows: Rf = 0.38 (EtOAc / cyclohexane = 1 / 5). 1 H NMR (400 MHz, CDCl3) δ 8.33(d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 5.24 (t, J = 9.7 Hz, 1H), 4.32(q, J = 7.1 Hz, 2H), 3.75-3.55 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H). 13 C NMR (101MHz, CDCl3) δ 184.1, 168.8, 156.8, 138.5, 132.2, 130.8, 117.8, 117.0, 79.5,62.4, 37.9, 14.1.
[0069] The mass spectrometry data for compound 4l are as follows: HRMS (ESI) m / z: [M+Na] + Calcd for C 14 H 12 N2NaO4 +295.0689; Found295.0688.
[0070] Example 21: A method for synthesizing an isoxazoline compound 4m The difference between Example 21 and Example 1 is that in Example 21, compound 1m is used instead of compound 1a, and the structure of compound 1m is as follows: The structural formula of the synthesized compound 4m is: Compound 4M is a yellow oil with a yield of 52%.
[0071] The NMR data for compound 4m are as follows: Rf = 0.39 (EtOAc / cyclohexane = 1 / 10). 1 H NMR (400 MHz, CDCl3) δ 8.35-8.22 (m, 2H), 8.19-8.09 (m, 2H), 5.22 (dd, J = 10.7, 8.6 Hz, 1H), 4.30 (q, J= 7.2 Hz, 2H), 3.97 (s, 3H), 3.68 (d, J = 3.4 Hz, 1H), 3.65 (d, J = 1.2 Hz, 1H), 1.35 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 185.0, 169.0, 166.2,156.9, 138.7, 134.4, 130.28, 130.25, 129.5, 125.8, 79.3, 62.3, 52.5, 38.1,14.1.
[0072] The mass spectrometry data for compound 4m are as follows: HRMS (ESI) m / z: [M+Na] + Calcd for C 15 H 15 NNaO6 + 328.0792; Found328.0792.
[0073] Example 22: A method for synthesizing an isoxazoline compound 4n The difference between Example 22 and Example 1 is that in Example 22, compound 1n is used instead of compound 1a, and the structure of compound 1n is as follows: The structural formula of the synthesized compound 4n is: Compound 4n is a yellow oil with a yield of 78%.
[0074] The NMR detection data of compound 4n are as follows: Rf = 0.40 (EtOAc / cyclohexane = 1 / 15). 1 H NMR (400 MHz, CDCl3) δ 7.74(d, J = 8.2 Hz, 1H), 7.09 (d, J = 7.8 Hz, 2H), 5.21 (dd, J = 11.2, 8.0 Hz,1H), 4.30 (q, J = 7.1 Hz, 2H), 3.75-3.52 (m, 2H), 2.46 (s, 3H), 2.38 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 188.4, 169.2, 157.8,142.9, 139.0, 133.0, 132.4, 131.5, 126.1, 79.5, 62.2, 38.0, 21.5, 20.8, 14.1.
[0075] The mass spectrometry data for compound 4n are as follows: HRMS (ESI) m / z: [M+Na] + Calcd for C 15 H 17 NNaO4 + 298.1050; Found298.1048.
[0076] Example 23: A method for synthesizing an isoxazoline compound 4o The difference between Example 23 and Example 1 is that in Example 23, compound 1o is used instead of compound 1a, and the structure of compound 1o is as follows: The structural formula of the synthesized compound 4o is: Compound 4o is a yellow oil with a yield of 76%.
[0077] The NMR detection data of compound 4o are as follows: Rf = 0.40 (EtOAc / cyclohexane = 1 / 15). 1H NMR (400 MHz, CDCl3) δ 7.55(s, 1H), 7.24 (dd, J = 7.8, 1.2 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 5.22 (dd,J = 10.9, 8.4 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.63 (dd, J = 9.6, 3.2 Hz, 2H), 2.41 (s, 3H), 2.36 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 189.2, 169.1, 157.7, 135.9, 135.2, 134.9, 132.8, 131.4, 131.1, 79.7, 62.2, 37.8, 20.9, 20.1, 14.1.
[0078] The mass spectrometry data for compound 4o are as follows: HRMS (ESI) m / z: [M+Na] + Calcd for C 15 H 17 NNaO4 + 298.1050; Found298.1050.
[0079] Example 24: A method for synthesizing an isoxazoline compound 4p The difference between Example 24 and Example 1 is that in Example 24, compound 1p is used instead of compound 1a, and the structure of compound 1p is as follows: The structural formula of the synthesized compound 4p is: Compound 4p is a yellow oil with a yield of 70%.
[0080] The NMR detection data for compound 4p are as follows: Rf = 0.45 (EtOAc / cyclohexane = 1 / 15). 1 H NMR (400 MHz, CDCl3) δ 6.88(s, 2H), 5.24 (t, J = 9.4 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.59 (d, J = 9.4Hz, 2H), 2.31 (s, 3H), 2.20 (s, 6H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR (101MHz, CDCl3) δ 193.8, 168.9, 158.1, 139.7, 135.8, 134.4, 128.5, 80.4, 62.2,36.4, 21.2, 19.5, 14.1.
[0081] The mass spectrometry data for compound 4p are as follows: HRMS (ESI) m / z: [M+Na] + Calcd for C 16 H 19 NNaO4 + 312.1206; Found312.1209.
[0082] Example 25: A method for synthesizing an isoxazoline compound 4q The difference between Example 25 and Example 1 is that in Example 25, compound 1q is used instead of compound 1a, and the structure of compound 1q is as follows: The structural formula of the synthesized compound 4q is: Compound 4q is a yellow oil with a yield of 63%.
[0083] The NMR detection data of compound 4q are as follows: Rf = 0.37 (EtOAc / cyclohexane = 1 / 10). 1 H NMR (400 MHz, CDCl3) δ 8.32(dd, J = 3.9, 1.2 Hz, 1H), 7.77 (dd, J = 4.9, 1.2 Hz, 1H), 7.18 (dd, J = 4.9,3.9 Hz, 1H), 5.21 (dd, J = 10.6, 8.8 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.63 (dd, J = 9.7, 1.6 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ176.9, 169.0, 156.6, 140.8, 136.3, 136.0, 128.5, 79.2, 62.3, 38.0, 14.1.
[0084] The mass spectrometry data for compound 4q are as follows: HRMS (ESI) m / z: [M+Na] + Calcd for C11 H 11 NNaO4S + 276.0301; Found276.0302.
[0085] Example 26: A method for synthesizing an isoxazoline compound 4r The difference between Example 26 and Example 1 is that in Example 26, compound 1r is used instead of compound 1a, and the structure of compound 1r is as follows: The structural formula of the synthesized compound 4r is: Compound 4r is a yellow oil with a yield of 49%.
[0086] The NMR detection data of compound 4r are as follows: Rf = 0.35 (EtOAc / cyclohexane = 1 / 5). 1 H NMR (400 MHz, CDCl3) δ 8.80(d, J = 4.7 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.89 (td, J = 7.8, 1.7 Hz,1H), 7.53 (ddd, J = 7.6, 4.7, 1.0 Hz, 1H), 5.23 (t, J = 9.8 Hz, 1H), 4.30 (q,J = 7.1 Hz, 2H), 3.74 (d, J = 9.6 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 185.1, 169.0, 156.4, 152.6, 149.7, 137.0, 127.3, 125.0, 79.5, 62.3, 38.4, 29.7, 14.1.
[0087] The mass spectrometry data for compound 4r are as follows: HRMS (ESI) m / z: [M+Na] + Calcd for C 12 H 12 N2NaO4 + 271.0689; Found271.0688.
[0088] The embodiments of the present invention have been described in detail above, but the present invention is not limited to the described embodiments. For those skilled in the art, various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and these variations still fall within the protection scope of the present invention.
Claims
1. A method for synthesizing isoxazoline compounds, characterized in that, Includes the following steps: Compound 1 and ethyl acrylate were dissolved in dichloroethane, and then tert-butyl nitrite, alkali and K2S2O8 were added. The reaction was carried out in air, irradiated with a blue LED light source and stirred. After the reaction was completed, the solvent was removed under reduced pressure, and the crude product was subjected to silica gel column chromatography to obtain the product, which is an isoxazoline compound.
2. The method for synthesizing an isoxazoline compound according to claim 1, characterized in that, Compound 1 is one of the following structural formulas: 。 3. The method for synthesizing an isoxazoline compound according to claim 1, characterized in that, The molar ratio of compound 1, ethyl acrylate, tert-butyl nitrite, alkali and K2S2O8 is 1:1~2:2~4:0.5:1~2.
4. The method for synthesizing an isoxazoline compound according to claim 3, characterized in that, The molar ratio of compound 1, ethyl acrylate, tert-butyl nitrite, alkali and K2S2O8 is 1:1.5:3:0.5:1.
5.
5. The method for synthesizing an isoxazoline compound according to claim 1, characterized in that, The base is any one of 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, and triethylenediamine.
6. The method for synthesizing an isoxazoline compound according to claim 5, characterized in that, The base is 4-dimethylaminopyridine.
7. The method for synthesizing an isoxazoline compound according to claim 1, characterized in that, The power of the blue LED light source is 35 W.
8. The method for synthesizing an isoxazoline compound according to claim 1, characterized in that, The stirring reaction was carried out at room temperature.
9. The method for synthesizing an isoxazoline compound according to claim 1, characterized in that, The stirring reaction was carried out for 12 hours.