Selective direct fluoroalkylation method of 3-methyl-4-nitro-5-styryl isoxazole compound

Abstract

The invention relates to a direct fluoroalkylation method of a 3-methyl-4-nitro-5-styryl isoxazole compound, which comprises the following steps: taking substituted 3-methyl-4-nitro-5-styryl isoxazole and sodium fluoroalkyl sulfinate as raw materials, carrying out selective free radical addition under the action of a photocatalyst, nitrogen atmosphere and LED (light-emitting diode) blue light irradiation, and carrying out direct fluoroalkylation on the 3-methyl-4-nitro-5-styryl isoxazole compound to obtain the 3-methyl-4-nitro-5-styryl isoxazole compound. And directly carrying out 1, 6-fluoroalkylation to generate the 5-(fluoroalkyl-2-phenylpropyl)-3-methyl-4-nitroisoxazole product, namely the 5-(fluoroalkyl-2-phenylpropyl)-3-methyl-4-nitroisoxazole. The raw materials are easy to prepare, and the photocatalysis method is green, simple and convenient.

Description

Technical Field

[0001] This invention relates to a direct fluoroalkylation method for 3-methyl-4-nitro-5-styrylisoxaazole compounds, and particularly to a photocatalytic 1,6-trifluoro / difluoro / monofluoromethyl radical addition reaction method for such compounds. Background Technology

[0002] Fluoroalkyl-containing organic compounds are widely used in various fields, such as pharmaceuticals, agrochemicals, and materials. Trifluoromethyl / difluoromethyl / monofluoromethyl groups are important fluoroalkyl groups, frequently found in many drug and pesticide molecules. Therefore, developing a simple, efficient, and mild synthetic method to introduce these fluoromethyl groups into organic molecules is of great significance. Isoxazole is an important heterocyclic compound, and its derivatives exhibit a wide range of biological activities, including antibacterial, anticancer, antifungal, antiviral, antituberculosis, and anti-inflammatory effects [Zhu J., Mo J., Lin H.-Z., Chen Y., Sun H.-P.]. Bioorg. Med. Chem. 2018, 26 [3065-3075]. Therefore, studying the synthetic methods of isoxazole by combining it with fluorine-containing groups is of great significance. 3-Methyl-4-nitro-5-styrylisoxaazole has a γ,δ-unsaturated olefin skeleton and is an excellent 1,6-Mike acceptor, readily undergoing addition reactions with soft, stable nucleophiles. Its nucleophilic 1,6-addition reactions have been reported extensively [Baschieri A., Bernardi L., Ricci A., et al.]. Angew. Chem. Int. Ed. 2009, 48 , 9342-9345; Chew RJ, Huang Y., Li Y., ea al Adv. Synth. Catal. 2013, 355 , 1403-1408; Bai Y.-J., Hu X.-M., Zheng X.-H., et al Tetrahedron Lett. 2021, 101 [132511], but its radical 1,6-addition has not been reported. Since common fluoroalkyl anions, such as the trifluoro / difluoromethyl anion generated from trifluoro / difluoromethyltrimethylsilane, are hard nucleophiles, their reaction with 3-methyl-4-nitro-5-styrylisoxaazole occurs at the 5-position of the substrate, making 1,6-addition difficult [Kawai H., Tachi K., Tokunaga E., Shiro M., et al, 132511], however, its radical 1,6-addition reaction has not been reported. Angew. Chem. Int. Ed. 2011, 50 , 7803-7806; Wang X., Tokunaga E., Shibata N., ScienceOpen Research 2014, 0(0) , 1-7. DOI: 10.14293 / S2199-1006.1.SOR-CHEM.AD1QVW.v2]. This patent utilizes the fluoroalkyl radical reagent fluoroalkyl sulfinate to undergo a radical addition reaction, thereby resolving the 1,6-fluoroalkylation of 3-methyl-4-nitro-5-styrylisoxazole, as described below. Summary of the Invention

[0003] The problem to be solved by the present invention is to provide a direct 1,6-trifluoro / difluoro / monofluoromethylation method for 3-methyl-4-nitro-5-styrylisoxaazole compounds. The method uses inexpensive and readily available fluoroalkyl sulfinates as raw materials and employs photocatalysis for fluoroalkyl radical addition reaction. The operation is simple and the conditions are mild.

[0004]

[0005] To achieve the purpose of the invention, the technical solution adopted by the present invention is as follows: The synthetic method of this invention uses substituted 3-methyl-4-nitro-5-styrylisoxaazole and sodium fluoroalkyl sulfinate as raw materials, adds a photocatalyst, and directly performs 1,6-fluoroalkylation under blue light irradiation in a nitrogen atmosphere to generate a 5-(fluoroalkyl-2-phenylpropyl)-3-methyl-4-nitroisoxaazole derivative. The specific reaction formula is as follows:

[0006] Preferably, the above reaction replaces 3-methyl-4-nitro-5-styrylisoxaazole, wherein R1 = hydrogen, methyl, halogen, trifluoromethyl, nitro, tert-butyl, methoxy, and the substituent group is in any position (ortho, meta, para) on the benzene ring.

[0007] Preferably, the catalyst is, for example, fluorescein, 10-methyl-9-trimethylammonium acridine perchlorate, eosin Y, rose red, or fac-Ir(ppy)3.

[0008] Preferably, the additives include acetic acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, and oxalic acid.

[0009] Preferably, the power of the blue radiating LED is 6-60W.

[0010] Preferably, the solvent is NMP, DMF, CCl4, toluene, DMSO, or acetone.

[0011] Preferably, the reaction temperature is 25-150℃.

[0012] Preferably, the reaction time is 6-48 hours.

[0013] This invention provides a simple, green free radical addition reaction method for synthesizing 5-(fluoroalkyl-2-phenylpropyl)-3-methyl-4-nitroisoxazole derivatives. The starting materials are readily available, the reaction conditions are mild, and the yield can reach up to 90%. Detailed Implementation

[0014] The present invention will be further described below with reference to the embodiments, but the scope of protection of the present invention is not limited thereto.

[0015] Example 1: In a Schlenk reaction tube, a magnetic stir bar, (E)-5-(4-fluorostyryl)-3-methyl-4-nitroisoxazole (0.4 mmol), CF2HSO2Na (0.8 mmol), and 10-methyl-9-trimethylmethylacridine perchlorate (5 mol%) were added. The reaction tube was evacuated and purged with argon (repeated three times). Acetone (5 ml) and trifluoroacetic acid (0.4 mmol) were injected into the tube using a syringe. The reaction tube was sealed and reacted under LED blue light for 24 hours. After the reaction, the mixture was extracted three times with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by column chromatography to obtain product 1 with a yield of 78%. Its structure and characterization data are as follows: 5-(3,3-Difluoro-2-(4-fluorophenyl)propyl)-3-methyl-4-nitroisoxazole (1)

[0016]

[0017] Yellow liquid. 1 H NMR (400MHz, CDCl3) δ7.27–7.23(m,2H),7.04–7.00(m,2H),6.21–5.73(m,1H),3.79–3.71(m,3H),2.49(s,3H). 13 C NMR(101MHz, CDCl3)δ171.5,162.7(d,J=248.1Hz),155.6,130.6,130.2(d,J=8.2Hz),130.0–129.7(m ,1C),116.3(t,J=246.3Hz),116.1(d,J=21.6Hz),46.3(t,J=20.6Hz),26.8(dd,J=6.3,4.0Hz),11.6. 19FNMR(376MHz, CDCl3)δ-111.7–-116.0(m,1F),-118.1(ddd,J=63.8,55.9,9.3Hz,1F),-124.7(ddd,J=74.4,55.8,16.9Hz,1F).HRMS(ESI):m / z calcd.for C 13 H 10 F3N2O3(MH) + 299.0644, found299.0644.

[0018] Example 2: In a Schlenk reaction tube, a magnetic stir bar, (E)-5-(4-chlorostyryl)-3-methyl-4-nitroisoxazole (0.4 mmol), CF₂HSO₂Na (0.8 mmol), and eosin Y (5 mol%) were added. The reaction tube was evacuated and purged with argon (repeated three times). Acetone (5 ml) and THF (0.4 mmol) were injected into the tube using a syringe. The reaction tube was sealed and reacted under LED blue light irradiation for 48 hours. After the reaction, the product was extracted three times with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by column chromatography to obtain product 2, with a yield of 90%. Its structure and characterization data are as follows:

[0019] 5-(2-(4-Chlorophenyl)-3,3-difluoropropyl)-3-methyl-4-nitroisoxazole(2)

[0020]

[0021] Yellow liquid. 1 H NMR (400MHz, CDCl3) δ7.32(d,J=8.5Hz,2H),7.22(d,J=8.5Hz,2H),5.96(td,J=56.3,2.8Hz,1H),3.79–3.70(m,3H),2.50(s,3H). 13 C NMR (101MHz, CDCl3) δ171.3, 155.7, 134.7, 132.6 (dd, J = 5.8, 2.1Hz), 130.6, 129.9 ,129.3,116.2(t,J=246.5Hz),46.5(t,J=20.7Hz),26.7(dd,J=6.2,4.0Hz),11.6. 19F NMR (376MHz, CDCl3) δ-119.9 (dd, J=276.9, 55.7Hz, 1F), -126.3 (dd, J=280.8, 56.1Hz, 1F). HRMS (ESI): m / zcalcd.for C 13 H 10 ClF2N2O3(MH) + 315.0348, found 315.0349.

[0022] Example 3: In a Schlenk reaction tube, a magnetic stir bar, (E)-5-(4-bromostyryl)-3-methyl-4-nitroisoxazole (0.4 mmol), CF₂HSO₂Na (0.8 mmol), and fluorescein (5 mol%) were added. The reaction tube was evacuated and purged with argon (repeated three times). DMF (5 ml) and acetic acid (0.4 mmol) were injected into the tube using a syringe. The reaction tube was sealed and reacted under LED blue light irradiation for 40 hours. After the reaction, the product was extracted three times with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by column chromatography to obtain product 3, with a yield of 70%. Its structure and characterization data are as follows:

[0023] 5-(2-(4-Bromophenyl)-3,3-difluoropropyl)-3-methyl-4-nitroisoxazole(3)

[0024]

[0025] Yellow liquid. 1 H NMR (400MHz, CDCl3) δ7.47(dd,J=8.1,1.3Hz,2H),7.16(d,J=8.4Hz,2H),5.96(td,J=55.9,2.7Hz,1H),3.83–3.70(m,3H),2.49(s,3H). 13 C NMR (101MHz, CDCl3) δ171.3, 155.7, 133.1 (dd, J = 5.7, 2.2Hz), 132.3, 130.6, 130.2 ,122.8,116.1(t,J=246.4Hz),46.5(t,J=20.6Hz),26.6(dd,J=6.2,4.0Hz),11.6. 19F NMR(376MHz, CDCl3)δ-118.2(ddd,J=280.0,55.5,10.3Hz,1F),-124.4(ddd,J=279.3,55.6,17.2Hz,1F).HRMS(ESI):m / z calcd.for C 13 H 10 BrF₂N₂O₃(MH) + 358.9843, found 358.9836.

[0026] Example 4: In a Schlenk reaction tube, a magnetic stir bar, (E)-5-(3-bromostyryl)-3-methyl-4-nitroisoxazole (0.4 mmol), CFH2SO2Na (0.8 mmol), and 10-methyl-9-trimethylmethylacridine perchlorate (5 mol%) were added. The reaction tube was evacuated and purged with argon (repeated three times). Acetone (5 ml) and trifluoroacetic acid (0.4 mmol) were injected into the tube using a syringe. The reaction tube was sealed and reacted under LED blue light for 48 hours. After the reaction, the mixture was extracted three times with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product 4 was obtained by column chromatography with a yield of 44%. Its structure and characterization data are as follows: 5-(2-(3-Bromophenyl)-3-fluoropropyl)-3-methyl-4-nitroisoxazole (4)

[0027]

[0028] Yellow liquid. 1 H NMR (400MHz, CDCl3) δ7.41(dd,J=5.7,2.6Hz,2H),7.23–7.17(m,2H),4.71–4.48(m,2H),3.73–3.53(m,3H),2.52(s,3H). 13 C{1H}NMR(101MHz,CDCl3)δ172.3,155.7,140.1(d,J=5.5Hz),131.2,130.8,130.6,13 0.5, 126.3, 123.0, 85.5 (d, J = 176.4Hz), 43.7 (d, J = 19.1Hz), 30.0 (d, J = 5.1Hz), 11.6. 19 F NMR (376MHz, CDCl3) δ-219.6 (td, J=47.1, 18.5Hz, 1F). HRMS (ESI): m / z calcd.for C 13 H 11 BrFN2O3[MH]+ 340.9937, found 340.9937.

[0029] Example 5: In a Schlenk reaction tube, a magnetic stir bar, (E)-5-(2-chlorostyryl)-3-methyl-4-nitroisoxazole (0.4 mmol), CF2HSO2Na (0.8 mmol), and 10-methyl-9-trimethylmethylacridine perchlorate (5 mol%) were added. The reaction tube was evacuated and purged with argon (repeated three times). Acetone (5 ml) and acetic acid (0.4 mmol) were injected into the tube using a syringe. The reaction tube was sealed and reacted under LED blue light for 36 hours. After the reaction, the mixture was extracted three times with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product 5 was obtained by column chromatography with a yield of 77%. Its structure and characterization data are as follows: 5-(2-(2-Chlorophenyl)-3,3-difluoropropyl)-3-methyl-4-nitroisoxazole (5)

[0030]

[0031] Yellow liquid. 1 H NMR(400MHz, CDCl3) δ7.43(d,J=7.6Hz,1H),7.38(dd,J=7.7,1.6Hz,1H),7.33–7.22(m ,2H),6.04(td,J=55.7,3.0Hz,1H),4.57–4.31(m,1H),3.96–3.60(m,2H),2.50(s,3H). 13 C NMR (101MHz, CDCl3) δ171.3, 155.6, 134.6, 131.9 (dd, J = 6.5, 1.6Hz), 130.6, 130.1, 129.7 ,129.1,127.6,115.7(t,J=246.4Hz),42.6(t,J=21.2Hz),25.9(dd,J=6.2,3.9Hz),11.6. 19 F NMR (376MHz, CDCl3) δ-117.2 (ddd, J=279.6, 55.3, 10.2Hz), -125.9 (dd, J=272.4, 48.7Hz). HRMS (ESI): m / z calcd.for C 13 H 10 ClF2N2O3(MH) + 315.0348, found 315.0354.

[0032] Example 6: In a Schlenk reaction tube, a magnetic stir bar, (E)-5-(3-chlorostyryl)-3-methyl-4-nitroisoxazole (0.4 mmol), CF₂HSO₂Na (0.8 mmol), and eosin Y (5 mol%) were added. The reaction tube was evacuated and purged with argon (repeated three times). DMSO (5 ml) and trifluoroacetic acid (0.4 mmol) were injected using a syringe. The reaction tube was sealed and reacted under LED blue light irradiation for 24 hours. After the reaction, the product was extracted three times with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by column chromatography to obtain product 6, with a yield of 71%. Its structure and characterization data are as follows:

[0033] 5-(2-(3-Chlorophenyl)-3,3-difluoropropyl)-3-methyl-4-nitroisoxazole(6)

[0034]

[0035] Yellow liquid. 1 H NMR (400MHz, CDCl3) δ7.30–7.26(m,3H),7.19–7.16(m,1H),5.97(td,J=55.7,2.8Hz,1H),3.77–3.66(m,3H),2.50(s,3H). 13 C NMR (101MHz, CDCl3) δ171.3, 155.7, 136.1 (dd, J = 6.2, 1.4Hz), 134.9, 130.6, 130.4, 128.9 ,128.8,126.7,116.1(t,J=246.5Hz),46.7(t,J=20.7Hz),26.7(dd,J=6.1,4.0Hz),11.6. 19 F NMR(376MHz, CDCl3)δ-117.0–-120.0(m,1F),-123.1–-125.9(m,1F).HRMS(ESI):m / z calcd.forC 13 H 10 ClF2N2O3(MH) + 315.0348, found 315.0339.

[0036] Example 7: In a Schlenk reaction tube, a magnetic stir bar, (E)-3-methyl-4-nitro-5-(4-trifluoromethylstyrene)isoxazole (0.4 mmol), CF3SO2Na (0.8 mmol), and rose red (5 mol%) were added. The reaction tube was evacuated and purged with argon (repeated three times). Acetone (5 ml) and acetic acid (0.4 mmol) were injected into the tube using a syringe. The reaction tube was sealed and reacted under LED blue light irradiation for 48 hours. After the reaction, the mixture was extracted three times with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product 7 was purified by column chromatography in 30% yield. Its structure and characterization data are as follows:

[0037] 3-Methyl-4-nitro-5-(3,3,3-trifluoro-2-(4-trifluoromethylphenyl)propyl)isoxazole(7)

[0038]

[0039] Yellowish-brown liquid. 1 H NMR (400MHz, CDCl3) δ7.63(d,J=8.2Hz,2H),7.48(d,J=8.1Hz,2H),4.13(dd,J=6.0, 1.5Hz, 1H), 3.94 (dd, J=15.6, 9.9Hz, 1H), 3.84 (dd, J=15.6, 5.9Hz, 1H), 2.50 (s, 3H). 13 C{1H}NMR(101MHz,CDCl3)δ169.8,155.8,136.1,131.5(q,J=32.8Hz),130.7,129.6,126.1(q,J=3 .7Hz), 125.5 (q, J = 280.5Hz), 123.6 (q, J = 272.3Hz), 46.9 (q, J = 28.3Hz), 27.6 (q, J = 2.9Hz), 11.5. 19 F NMR(376MHz, CDCl3)δ-62.95(s,3F),-69.97 / -69.99(s,3F).HRMS(ESI):m / z calcd.for C 14 H9N2O3F6[MH] + 367.0518, found 367.0514.

[0040] Example 8: In a Schlenk reaction tube, a magnetic stir bar, (E)-3-methyl-4-nitro-5-(4-nitrostyryl)isoxazole (0.4 mmol), CF₂HSO₂Na (0.8 mmol), and eosin Y (5 mol%) were added. The reaction tube was evacuated and purged with argon (repeated three times). Acetone (5 ml) and trifluoroacetic acid (0.4 mmol) were injected into the tube using a syringe. The reaction tube was sealed and reacted under LED blue light irradiation for 48 hours. After the reaction, the mixture was extracted three times with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by column chromatography to obtain product 8, with a yield of 60%. Its structure and characterization data are as follows:

[0041] 5-(3,3-Difluoro-2-(4-nitrophenyl)propyl)-3-methyl-4-nitroisoxazole(8)

[0042]

[0043] Yellow liquid. 1 H NMR (400MHz, CDCl3) δ8.21(d,J=8.7Hz,2H),7.51(d,J=8.7Hz,2H),6.04(td,J=55.4,2.9Hz,1H),3.95–3.81(m,3H),2.50(s,3H). 13 C NMR (101MHz, CDCl3) δ170.6, 155.8, 148.1, 141.2 (dd, J = 5.2, 2.2Hz), 130.7, 129.8 ,124.2,115.6(t,J=246.7Hz),46.7(t,J=21.0Hz),26.7(dd,J=6.2,4.0Hz),11.5. 19 F NMR(376MHz, CDCl3)δ-119.1(ddd,J=282.0,55.1,11.9Hz,1F),-123.3(ddd,J=281.9,55.4,16.0Hz,1F).HRMS(ESI):m / z calcd.for C 13 H 10 F2N3O5(MH) + 326.0589, found 326.0589.

[0044] Example 9: In a Schlenk reaction tube, a magnetic stir bar, (E)-3-methyl-4-nitro-5-(4-tert-butylstyryl)isoxazole (0.4 mmol), CF3SO2Na (0.8 mmol), and 10-methyl-9-trimethylmethylacridine perchlorate (5 mol%) were added. The reaction tube was evacuated and purged with argon (repeated three times). Acetone (5 ml) and trifluoroacetic acid (0.4 mmol) were injected into the tube using a syringe. The reaction tube was sealed and reacted under LED blue light for 48 hours. After the reaction, the mixture was extracted three times with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by column chromatography to obtain product 9, with a yield of 18%. Its structure and characterization data are as follows: 3-Methyl-4-nitro-5-(3,3,3-trifluoro-2-(4-(tert-butyl)phenyl)propyl)isoxazole (9)

[0045]

[0046] Yellowish-brown liquid. 1 H NMR(400MHz, CDCl3) δ7.35(d,J=8.4Hz,2H),7.23(d,J=8.3Hz,2H),4.04-3.95( m,1H),3.87(d,J=9.4Hz,1H),3.82(d,J=6.2Hz,1H),2.49(s,3H),1.29(s,9H). 13 C{1H}NMR(101MHz,CDCl3)δ170.7,155.6,152.1,130.6,129.0(d,J=2.1Hz),128.3,12 5.92, 125.91 (q, J = 280.5Hz), 46.7 (q, J = 27.8Hz), 34.6, 31.2, 27.9 (q, J = 2.7Hz), 11.6. 19 F NMR(376MHz,CDCl3)δ-70.11 / -70.12(s,CF3).HRMS(ESI):m / zcalcd.for C 17 H 18 N₂O₃F₃[MH] + 355.1270, found 355.1272.

[0047] Example 10: In a Schlenk reaction tube, a magnetic stir bar, (E)-5-(4-methoxyphenyl)propyl-3-methyl-4-nitroisoxazole (0.4 mmol), CF2HSO2Na (0.8 mmol), and 10-methyl-9-trimethylmethylacridine perchlorate (5 mol%) were added. The reaction tube was evacuated and purged with argon (repeated three times). Acetone (5 ml) and acetic acid (0.4 mmol) were injected into the tube using a syringe. The reaction tube was sealed and reacted under LED blue light for 24 hours. After the reaction, the mixture was extracted three times with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product 10 was obtained by column chromatography with a yield of 83%. Its structure and characterization data are as follows: 5-(3,3-Difluoro-2-(4-methoxyphenyl)propyl)-3-methyl-4-nitroisoxazole (10)

[0048]

[0049] Yellow liquid. 1 H NMR (400MHz, CDCl3) δ7.18(d,J=8.6Hz,2H),6.84(d,J=8.8Hz,2H),5.94(td,J=55.9,2.6Hz,1H),3.77(s,3H),3.81–3.68(m,3H),2.48(s,3H). 13 CNMR(101MHz,CDCl3)δ171.9,159.6,155.6,130.6,129.6,126.0(dd,J=6.1,2.3Hz),1 16.7(t,J=246.2Hz),114.4,55.2,46.3(t,J=20.3Hz),26.8(dd,J=6.2,4.0Hz),11.6. 19 F NMR(376MHz, CDCl3)δ-117.1–-118.0(m,1F),-124.95(ddd,J=279.0,56.8,18.9Hz,1F).HRMS(ESI):m / z calcd.for C 14 H 13 F2N2O4(MH) + 311.0843, found 311.0844.

[0050] Example 11: In a Schlenk reaction tube, a magnetic stir bar, (E)-3-methyl-5-(4-methylstyryl)-4-nitroisoxazole (0.4 mmol), CFH2SO2Na (0.8 mmol), and 10-methyl-9-trimethylmethylacridine perchlorate (5 mol%) were added. The reaction tube was evacuated and purged with argon (repeated three times). Acetone (5 ml) and TFA (0.4 mmol) were injected into the tube using a syringe. The reaction tube was sealed and reacted under LED blue light for 36 hours. After the reaction, the mixture was extracted three times with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product 11 was obtained by column chromatography with a yield of 48%. Its structure and characterization data are as follows: 5-(3-Fluoro-2-(p-tolyl)propyl)-3-methyl-4-nitroisoxazole (11)

[0051]

[0052] Yellow liquid. 1 H NMR (400MHz, CDCl3) δ7.11(s,4H),4.73–4.42(m,2H),3.73–3.51(m,3H),2.50(s,3H),2.31(s,3H). 13 C{1H}NMR(101MHz,CDCl3)δ173.0,155.5,137.7,134.5(d,J=6.8Hz),130.4,129. 7,127.5,86.1(d,J=175.8Hz),43.7(d,J=18.7Hz),30.3(d,J=4.5Hz),21.1,11.7. 19 F NMR(376MHz, CDCl3)δ-217.7–-218.1(m,1F).HRMS(ESI):m / zcalcd.for C 14 H 14 FN2O3[MH] + 277.0988, found 277.0987.

[0053] Those skilled in the art will recognize that various modifications, variations, and combinations can be made to the above embodiments without departing from the scope of protection of the present invention, and such modifications, variations, and combinations are considered to be within the scope of originality.

Claims

1. A synthetic method for a class of 5-(fluoroalkyl-2-phenylpropyl)-3-methyl-4-nitroisoxazole products, using substituted 3-methyl-4-nitro-5-styrylisoxazole and sodium fluoroalkyl sulfinate as raw materials, adding a photocatalyst, additives and solvent, under a nitrogen atmosphere, under LED blue light irradiation of a certain power, at a certain temperature and reaction time, selective 1,6-fluoroalkylation occurs to obtain the product. The specific reaction formula is as follows: (Where R1 = hydrogen, methyl, halogen, trifluoromethyl, nitro, tert-butyl, methoxy, and the substituent group can be in any position on the ortho, meta, or para of the benzene ring).

2. The synthesis method according to claim 1, characterized in that, The catalyst is selected from fluorescein, 10-methyl-9-trimethylammonium acridine perchlorate, eosin Y, rose red, and fac-Ir(ppy)3.

3. The synthesis method according to claim 1, characterized in that, The additives are selected from acetic acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, and oxalic acid.

4. The synthesis method according to claim 1, characterized in that, The solvent is selected from NMP, DMF, CCl4, toluene, DMSO, and acetone.

5. The synthesis method according to claim 1, characterized in that, The power of the blue radiant LED is 6-60W.

6. The synthesis method according to claim 1, characterized in that, The reaction temperature is 25-150℃.

7. The synthesis method according to claim 1, characterized in that, The reaction time is 6-48 hours.

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