Method for preparing difluorocoumarin derivative by photocatalysis of iodine-containing phosphonium salt

Abstract

The method comprises the following steps: adding a coumarin compound as shown in a formula (I), a difluoromethyl triphenyl phosphonium iodide salt compound as shown in a formula (II) and alkali into a reaction solvent, carrying out stirring reaction under the conditions of nitrogen protection and blue light illumination, and after the reaction is finished, carrying out filtering, washing and drying to obtain the difluorocoumarin derivative. The reaction solution is subjected to post-treatment to obtain the target compound difluoromethylated coumarin derivative with antifungal activity as shown in formula (III), and the reaction equation is as follows: # imgabs0 #, wherein the substituent R1 is selected from H, methyl, halogen, methoxyl or hydroxyl; the substituent R2 is selected from H, hydroxyl, methoxyl or halogen, the substituent R3 is selected from H, methoxyl, alkylene or halogen, and the substituent R4 is selected from H or methyl. The preparation method of the difluoromethylated coumarin derivative has the advantages of simple operation process, cheap and easily available raw materials, mild reaction conditions, greenness and environmental protection, and is a difluoromethylated coumarin derivative with antifungal activity.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemical synthesis, and particularly relates to a method for preparing difluorocoumarin derivatives by photocatalytic iodonium salt containing iodine. Background Art

[0002] Coumarin (benzopyran-2-one, or chromene-2-one) compounds are an important class of oxygen-containing heterocyclic compounds with pyranone skeletons, and have a leading structural framework with high bioavailability and low toxicity natural activity. Based on their excellent pharmacological activities, some derivatives of coumarin have been approved for clinical treatment. On the one hand, coumarin derivatives can be used as additives in cosmetics and food, perfumes and fragrances, and agricultural chemicals; on the other hand, they also have various biological activities, such as anti-tumor, antioxidant, anti-fungal (Org. Lett. 2018, 20, 6901-6905.) and anti-HIV. Therefore, the development of direct and effective synthetic methods for related compounds with potential drug-active coumarin leading structural frameworks has received extensive attention.

[0003]

[0004] On the other hand, due to the unique properties of fluorine, organofluorine compounds have become increasingly important in drugs, agricultural chemicals, and functional materials. The unique effects of introducing fluorine-containing groups on lipophilicity, metabolic stability, and bioavailability have made organofluorine chemistry a key part of drug development. Approximately 20-25% of commercially available drugs contain at least one fluorine atom. In addition, direct C(sp 2 )-H fluoroalkylation of (hetero)aromatic compounds can provide atom economy by eliminating the need for pre-functionalization in conventional methods. In recent years, other chemists have worked hard to establish advanced synthetic methods for constructing fluorinated heteroaromatic compounds: from using stoichiometric amounts of peroxides and fluoroalkyl reagents, to using metal catalysts (copper, palladium, silver, nickel), homogeneous / transition metal photocatalysts (ruthenium, iridium, rhodium, and organic dyes), and heterogeneous semiconductor photocatalysts (g-C3N4). The use of 2-10 mol% of the catalyst eliminates the need for large amounts of peroxides. However, the demand for low levels of ruthenium, rhodium, iridium, and platinum-based metals, the problem of metal residues, and the cost of catalyst procurement have stimulated researchers to explore economical, safe, and environmentally friendly fluoroalkylation strategies. Based on previous work on radical coupling, a visible light-induced photocatalyst-free difluoromethylation reaction of coumarin and difluoromethyltriphenylphosphonium iodide is proposed here to construct difluoromethylated coumarin compounds with antifungal activity. Summary of the Invention

[0005] Aiming at the above technical problems existing in the prior art, the purpose of the present invention is to provide a method for preparing coumarin derivatives with antifungal activity by photocatalytic iodonium salt, which has the advantages of simple operation, mild reaction conditions, high product purity and green method.

[0006] To achieve the above object, the present invention proposes the following technical solutions:

[0007] A method for preparing difluorocoumarin derivatives by photocatalytic iodonium salt, comprising the following steps: adding a coumarin compound represented by formula (I), a difluoromethyltriphenylphosphonium iodide compound represented by formula (II), and a base into a reaction solvent, protecting with nitrogen, stirring and reacting under blue light irradiation. After the reaction is completed, the reaction solution is post-treated to obtain the target compound, a difluoromethylated coumarin derivative with antifungal activity represented by formula (III), and its reaction equation is as follows:

[0008]

[0009] The substituent R1 is selected from H, methyl, halogen, methoxy or hydroxy; the substituent R2 is selected from H, hydroxy, methoxy or halogen, the substituent R3 is selected from H, methoxy, alkenyl or halogen, and the substituent R4 is selected from H or methyl.

[0010] The reaction mechanism is as follows:

[0011] Under visible light irradiation, the difluoromethyl iodonium salt undergoes a single electron transfer (SET) process through a photoinduced intramolecular charge transfer complex, generating a difluoromethyl radical and an iodine radical, and releasing the by-product PPh3 at the same time. Subsequently, the difluoromethyl radical attacks the C-3 position of the coumarin compound, and the generated intermediate undergoes a SET process with the iodine radical and combines with the deprotonation of the base to finally form a difluoromethylated coumarin compound.

[0012] Furthermore, the reaction solvent is selected from acetone or dichloromethane, preferably dichloromethane.

[0013] Furthermore, the type of base is selected from N,N,N',N'-tetramethylethylenediamine (TMEDA) or N,N,N,N',N'-pentamethyldiethylenetriamine (PMDETA), preferably N,N,N',N'-tetramethylethylenediamine (TMEDA).

[0014] Furthermore, the molar ratio of the coumarin compound represented by formula (I) to the difluoromethyltriphenylphosphonium iodide compound represented by formula (II) is 1:1.0 - 3.0, preferably the molar ratio is 1:2.0.

[0015] Further, the post-treatment process of the reaction solution is as follows: saturated brine is added to the reaction solution for washing, followed by extraction with ethyl acetate. The organic layers are combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product is separated and purified by a chromatographic column to obtain the target compound. The eluent for chromatographic column separation and purification is a mixed solvent of petroleum ether / ethyl acetate with a volume ratio of 5-10:1.

[0016] Further, in a reaction tube equipped with magnetic stirring, a coumarin compound represented by formula (I), a difluoromethyltriphenylphosphonium iodide compound represented by formula (II), a base, and a reaction medium are added. After replacing the nitrogen three times, the reaction system is placed under light irradiation and stirred at 30-40 °C for reaction. After the reaction is completed, saturated brine is added for washing, and the mixture obtained after washing is extracted with ethyl acetate. The organic layers are combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product is separated and purified by a chromatographic column to obtain the target compound, a difluoromethylated coumarin compound with antifungal activity represented by formula (III).

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0018] 1) The present invention can realize the synthesis of difluoromethylated coumarin compounds with antifungal activity only by means of blue light source irradiation conditions, without adding any photocatalyst, avoiding the use of oxidants, transition metal catalysts, and specific ligands in conventional technologies, and effectively controlling the cost of the reaction;

[0019] 2) The present invention uses a one-step synthesis method to prepare the target compound. Compared with conventional technologies, this method is simple to operate and does not require pre-functionalization of the reaction substrate;

[0020] 3) The present invention has the advantages of simple operation, mild reaction conditions, simple post-treatment, and antifungal activity, conforms to the development concept of green chemistry, and is suitable for industrial promotion and application. Specific Embodiments

[0021] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0022] Example 1 3-(Difluoromethyl)-2H-chromen-2-one

[0023]

[0024] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-a) coumarin (29.2 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), and TMEDA (46.5 mg, 0.4 mmol). Add dichloromethane (3.0 mL) to the mixture. After displacing the air with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 48 hours. After the reaction is completed, add saturated brine to the reaction solution, extract it with ethyl acetate, combine the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 10:1 to obtain the target product with a yield of 65% and an HPLC purity of 98.5%.

[0025] 1 H NMR(600MHz,CDCl3)δ8.07(s,1H),7.63(t,1H),7.60(d,J=7.8Hz,1H),7.39(d,J=8.4Hz,1H),7.36(t,J=7.6Hz,1H),6.76(t,J=54.7Hz,1H).

[0026] 13 C NMR(151MHz,CDCl3)δ=158.6(t,J C-F =6.0Hz),154.2,141.3(t,J C-F =6.0Hz),133.5,129.1,125.1,121.7(t,J C-F =24.2Hz),117.8,117.0,110.1(t,J C-F =240.1Hz).

[0027] 19 F NMR(565MHz,CDCl3)δ=-119.4.

[0028] Example 2 3-(Difluoromethyl)-6-methoxy-2H-chromen-2-one

[0029]

[0030] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-b) 6-methoxycoumarin (35.2 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), TMEDA (46.5 mg, 0.4 mmol). Add dichloromethane (3.0 mL) to the mixture. After purging with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 48 hours. After the reaction is completed, add saturated brine to the reaction solution, then extract with ethyl acetate. Combine the organic layers. After washing the organic phase with saturated NaCl solution, separate the layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 10:1 to obtain the target product with a yield of 68% and an HPLC purity of 98.6%.

[0031] 1 H NMR(600MHz,CDCl3)δ8.02(t,J=1.7Hz,1H),7.31(d,J=9.1Hz,1H),7.20(dd,J=9.1,3.0Hz,1H),7.01(d,J=2.9Hz,1H),6.86-6.60(m,1H),3.87(s,3H).

[0032] 13 C NMR(151MHz,CDCl3)δ=158.8(t,J C-F =4.5Hz),156.5,148.6,141.1(t,J C-F =6.0Hz),121.9(t,J C-F =24.2Hz),121.4,118.1,118.0,110.7,110.2(t,J C-F =240.1Hz),55.9. 19 F NMR(565MHz,CDCl3)δ=-119.4.

[0033] Example 3 6,8-Dibromo-3-(difluoromethyl)-2H-chromen-2-one

[0034]

[0035] Into a reaction flask equipped with magnetic stirring, add compound (Ⅰ-c) 6,8-dibromocoumarin (60.4 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), and TMEDA (46.5 mg, 0.4 mmol). Add dichloromethane (3.0 mL) to the mixture. After displacing the air with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 48 hours. After the reaction is completed, add saturated brine to the reaction solution, extract with ethyl acetate, combine the organic layers, dry over anhydrous Na2SO4, and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 10:1 to obtain the target product with a yield of 58% and an HPLC purity of 98.7%.

[0036] 1 H NMR(600MHz,CDCl3)δ7.98(d,J=2.2Hz,1H),7.95(s,1H),7.69(d,J=2.2Hz,1H),6.75(t,J=54.4Hz,1H).

[0037] 13 C NMR(151MHz,CDCl3)δ=157.0,150.0,139.7(t,J C-F =6.0Hz),138.9,130.5,123.5(t,J C-F =22.6Hz),120.0,117.6,111.6,109.6(t,J C-F =240.1Hz).

[0038] 19 F NMR(565MHz,CDCl3)δ=-119.8.

[0039] Example 4 3-(Difluoromethyl)-6-hydroxy-4-methyl-2H-chromen-2-one

[0040]

[0041] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-d) 4-methyl-6-hydroxycoumarin (35.2 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), TMEDA (46.5 mg, 0.4 mmol). Add dichloromethane (3.0 mL) to the mixture. After displacing the air with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 48 hours. After the reaction is completed, add saturated brine to the reaction solution, extract with ethyl acetate, combine the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 5:1 to obtain the target product with a yield of 63% and an HPLC purity of 98.8%.

[0042] 1 H NMR (600 MHz, CDCl3) δ 9.88 (s, 1H), 7.50 - 6.94 (m, 4H), 2.57 (s, 3H).

[0043] 13 C NMR (151 MHz, CDCl3) δ=158.4 (t, J C-F =4.5 Hz), 154.4, 154.1, 145.8, 121.7, 119.8, 117.6, 116.8 (t, J C-F =21.1 Hz), 112.3 (t, J C-F =235.6 Hz), 110.4, 14.5.

[0044] 19 F NMR (565 MHz, DMSO-d6) δ=-109.0.

[0045] Example 5 3-(Difluoromethyl)-7-hydroxy-4-methyl-2H-chromen-2-one

[0046]

[0047] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-e) 4-methyl-7-hydroxycoumarin (35.2 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), and TMEDA (46.5 mg, 0.4 mmol). Add dichloromethane (3.0 mL) to the mixture. After displacing the air with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 48 hours. After the reaction is completed, add saturated brine to the reaction solution, extract with ethyl acetate, combine the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 5:1 to obtain the target product with a yield of 74% and an HPLC purity of 98.5%.

[0048] 1 H NMR(600MHz,CDCl3)δ10.89(s,1H),7.79(d,J=8.9Hz,1H),7.12(t,J=53.4Hz,1H),6.87(dd,J=8.8,2.4Hz,1H),6.73(d,J=2.4Hz,1H),2.59(s,3H).

[0049] 13 C NMR(151MHz,CDCl3)δ=162.8,158.8(t,J C-F =4.5Hz),155.2,154.6,128.0,113.7,112.6(t,J C-F =22.6Hz),112.6(t,J C-F =241.6Hz),111.5,102.1,14.4.

[0050] 19 F NMR(565MHz,CDCl3)δ=-108.0.

[0051] Example 6 6-(Difluoromethyl)-9-methoxy-7H-furo[3,2-g]chromen-7-one

[0052]

[0053] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-f) methoxsalen (43.2 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), TMEDA (46.5 mg, 0.4 mmol). Add dichloromethane (3.0 mL) to the mixture. After displacing the air with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 48 hours. After the reaction is completed, add saturated brine to the reaction solution, extract with ethyl acetate, combine the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 10:1 to obtain the target product with a yield of 61% and an HPLC purity of 98.4%.

[0054] 1 H NMR(600MHz,DMSO-d6)δ8.38(s,1H),8.05(d,J=2.4Hz,1H),7.42(d,J=2.4Hz,1H),7.34(s,1H),6.91(t,J=54.4Hz,1H),4.29(s,3H).

[0055] 13 C NMR(151MHz,DMSO-d6)δ=158.8,157.7(t,J C-F =3.0Hz),152.0,150.5,146.1,137.7(t,J C-F =6.0Hz),116.2(t,J C-F =22.6Hz),112.2,111.9(t,J C-F =241.6Hz),105.7,104.2,93.0,60.2.

[0056] 19 F NMR(565MHz,DMSO-d6)δ=-117.6.

[0057] Example 7 3-(Difluoromethyl)-7-methoxy-8-(3-methylbut-2-en-1-yl)-2H-chromen-2-one

[0058]

[0059] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-g) osthole (48.8 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), and TMEDA (46.5 mg, 0.4 mmol). Add dichloromethane (3.0 mL) to the mixture. After displacing the air with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 48 hours. After the reaction is completed, add saturated brine to the reaction solution, extract with ethyl acetate, combine the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 8:1 to obtain the target product with a yield of 60% and an HPLC purity of 98.9%.

[0060] 1 H NMR(600MHz,CDCl3)δ7.95(s,1H),7.39(d,J=8.6Hz,1H),6.89(d,J=8.6Hz,1H),6.73(t,J=55.1Hz,1H),5.25-5.12(m,1H),3.94(s,3H),3.52(d,J=7.4Hz,2H),1.83(s,3H),1.66(s,3H).

[0061] 13 C NMR(151MHz,CDCl3)δ=161.6,159.2(t,J C-F =6.0Hz),153.0,141.7(t,J C-F =6.0Hz),133.0,127.8,120.7,118.1,117.7(t,J C-F =24.2Hz),111.8,110.6(t,J C-F =238.6Hz),108.1,56.2,25.8,22.0,17.9.

[0062] 19 F NMR(565MHz,CDCl3)δ=-118.4.

[0063] Example 8 3-(Difluoromethyl)-6-methyl-2H-chromen-2-one

[0064]

[0065] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-h) 6-methylcoumarin (32.0 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), TMEDA (46.5 mg, 0.4 mmol). Add dichloromethane (3.0 mL) to the mixture. After displacing with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 48 hours. After the reaction is completed, add saturated brine to the reaction solution, then extract with ethyl acetate. Combine the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 10:1 to obtain the target product with a yield of 70% and an HPLC purity of 98.7%.

[0066] 1 H NMR(600MHz,CDCl3)δ8.00(s,1H),7.43(dd,J=8.5,2.1Hz,1H),7.37(d,J=2.1Hz,1H),7.27(d,J=8.5Hz,1H),6.74(t,J=54.8Hz,1H),2.43(s,3H).

[0067] 13 C NMR(151MHz,CDCl3)δ=158.9(t,J C-F =6.0Hz),152.3,141.3(t,J C-F =6.0Hz),134.9,134.5,128.8,121.4,117.5,116.6,110.2(t,J C-F =240.1Hz),20.7.

[0068] 19 F NMR(565MHz,CDCl3)δ=-119.3.

[0069] Example 9 3-(Difluoromethyl)-7-methoxy-2H-chromen-2-one

[0070]

[0071] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-i) 7-methoxycoumarin (35.2 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), TMEDA (46.5 mg, 0.4 mmol). Add dichloromethane (3.0 mL) to the mixture. After displacing the air with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 48 hours. After the reaction is completed, add saturated brine to the reaction solution, then extract with ethyl acetate. Combine the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 10:1 to obtain the target product with a yield of 62% and an HPLC purity of 98.2%.

[0072] 1 H NMR(600MHz,CDCl3)δ7.99(s,1H),7.48(d,J=8.7Hz,1H),6.91(dd,J=8.7,2.4Hz,1H),6.84(d,J=2.4Hz,1H),6.73(t,1H),3.90(s,3H).

[0073] 13 C NMR(151MHz,CDCl3)δ=164.2,159.1(t,J C-F =6.0Hz),156.2,141.4(t,J C-F =6.0Hz),130.1,117.9(t,J C-F =24.2Hz),113.5,111.4,110.5(t,J C-F =238.6Hz),100.8,55.9. 19 F NMR(565MHz,CDCl3)δ=-118.5.

[0074] Example 10 3-(Difluoromethyl)-7-hydroxy-2H-chromen-2-one

[0075]

[0076] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-j) 7-hydroxycoumarin (32.4 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), PMDETA (69.3 mg, 0.4 mmol). Add dichloromethane (3.0 mL) to the mixture. After displacing with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 48 hours. After the reaction is completed, add saturated brine to the reaction solution, then extract with ethyl acetate. Combine the organic layers, dry with anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 5:1 to obtain the target product with a yield of 60% and an HPLC purity of 98.5%.

[0077] 1 H NMR (600 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.32 (s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.01 - 6.55 (m, 3H).

[0078] 13 C NMR (151 MHz, DMSO-d6) δ = 162.9, 158.2 (t, J C-F = 6.0 Hz), 155.8, 142.7 (t, J C-F = 6.0 Hz), 131.3, 115.5 (t, J C-F = 22.6 Hz), 113.9, 111.8 (t, J C-F = 237.0 Hz), 110.1, 102.1.

[0079] 19 F NMR (565 MHz, DMSO-d6) δ = -117.4.

[0080] Example 11 7-Chloro-3-(difluoromethyl)-2H-chromen-2-one

[0081]

[0082] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-k) 7-chlorocoumarin (36.0 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), TMEDA (46.5 mg, 0.4 mmol). Add acetone (3.0 mL) to the mixture. After purging with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 48 hours. After the reaction is completed, add saturated brine to the reaction solution, extract with ethyl acetate, combine the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 10:1 to obtain the target product with a yield of 33% and an HPLC purity of 98.8%.

[0083] 1 H NMR(600MHz,CDCl3)δ8.03(s,1H),7.53(d,J=8.3Hz,1H),7.40(d,J=2.0Hz,1H),7.34(dd,J=8.3,2.0Hz,1H),6.73(t,J=54.8Hz,1H).

[0084] 13 C NMR(151MHz,CDCl3)δ=157.9(t,J C-F =6.0Hz),154.4,140.5(t,J C-F =6.0Hz),139.7,129.9,125.8,121.6(t,J C-F =22.6Hz),117.4,116.3,109.9(t,J C-F =238.6Hz).

[0085] 19 F NMR(565MHz,CDCl3)δ=-119.5.

[0086] Example 12 3-(Difluoromethyl)-2H-chromen-2-one

[0087]

[0088] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-a) coumarin (29.2 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), and TMEDA (46.5 mg, 0.4 mmol). Add dichloromethane (3.0 mL) to the mixture. After displacing the air with nitrogen three times, irradiate the reaction system under white light / violet light / green light. Stir the reaction at 35 ± 5 °C for 48 hours. After that, add saturated brine to the reaction solution, extract with ethyl acetate, combine the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Detection by TLC shows that no target product is produced.

[0089] Example 13 3-(Difluoromethyl)-2H-chromen-2-one

[0090]

[0091] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-a) coumarin (29.2 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (87.8 mg, 0.2 mmol), and TMEDA (46.5 mg, 0.4 mmol). Add dichloromethane (3.0 mL) to the mixture. After displacing the air with nitrogen three times, irradiate the reaction system under blue light. Stir the reaction at 35 ± 5 °C for 48 hours. After the reaction is completed, add saturated brine to the reaction solution, extract with ethyl acetate, combine the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 10:1 to obtain the target product with a yield of 23% and an HPLC purity of 98.8%.

[0092] Example 14 3-(Difluoromethyl)-2H-chromen-2-one

[0093]

[0094] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-a) coumarin (29.2 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (263.4 mg, 0.6 mmol), and TMEDA (46.5 mg, 0.4 mmol). Add dichloromethane (3.0 mL) to the mixture. After displacing the air with nitrogen three times, irradiate the reaction system under blue light. Stir the reaction at 35 ± 5 °C for 48 hours. After the reaction is completed, add saturated brine to the reaction solution, extract with ethyl acetate, combine the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 10:1 to obtain the target product with a yield of 60% and an HPLC purity of 98.2%.

[0095] The content described in this specification is only an enumeration of the implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as limited to the specific forms stated in the embodiments.

Claims

1. A method for preparing difluorocoumarin derivatives by photocatalyzing iodonium salts, characterized in that, It includes the following steps: adding the coumarin compound shown in formula (I), the difluoromethyltriphenylphosphonium iodide compound shown in formula (II), and a base into a reaction solvent, protecting with nitrogen, stirring and reacting under blue light irradiation conditions. After the reaction is completed, the reaction solution is post-treated to obtain the target compound, the difluoromethylated coumarin derivative with antifungal activity shown in formula (III), and its reaction equation is as follows: The substituent R1 is selected from H, methyl, halogen, methoxy or hydroxy; the substituent R2 is selected from H, hydroxy, methoxy or halogen, the substituent R3 is selected from H, methoxy, alkenyl or halogen, and the substituent R4 is selected from H or methyl.

2. The method for preparing difluorocoumarin derivatives by photocatalyzing iodine-containing phosphonium salts as claimed in claim 1, wherein The reaction solvent is selected from acetone or dichloromethane.

3. A method for preparing difluorocoumarin derivatives by photocatalyzing iodonium salts as described in claim 2, characterized in that, The base is selected from N,N,N',N'-tetramethylethylenediamine or N,N,N,N',N'-pentamethyldiethylenetriamine.

4. The method for preparing difluorocoumarin derivatives from photocatalytic iodine-containing phosphonium salts according to claim 3, wherein The molar ratio of the coumarin compound shown in formula (I) to the difluoromethyltriphenylphosphonium iodide compound shown in formula (II) is 1:1.0 - 3.

0.

5. The method for preparing difluorocoumarin derivatives from photocatalytic iodine-containing phosphonium salts as claimed in claim 1, wherein The process of post-treating the reaction solution is as follows: adding saturated brine to the reaction solution for washing, then extracting with ethyl acetate, combining the organic layers, drying with anhydrous Na2SO4 and concentrating under reduced pressure to obtain a crude product, and separating and purifying the crude product by column chromatography to obtain the target compound.

6. The method for preparing difluorocoumarin derivatives by photocatalytic iodine-containing phosphonium salt according to claim 5, characterized in that, The eluent for column chromatography separation and purification is a mixed solvent of petroleum ether / ethyl acetate with a volume ratio of 5 - 10:

1.

7. The method for preparing difluorocoumarin derivatives from photocatalytic iodine-containing phosphonium salts according to claim 1, characterized in that, Stir and react at 30 - 40 °C.

8. The method for preparing difluorocoumarin derivatives from photocatalytic iodine-containing phosphonium salts according to claim 4, characterized in that, The reaction solvent is dichloromethane, the base is N,N,N',N'-tetramethylethylenediamine, and the molar ratio of the coumarin compound shown in formula (I) to the difluoromethyltriphenylphosphonium iodide compound shown in formula (II) is 1:2.0.

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