Photo-catalytic synthesis method of gem-difluoroketone without participation of photocatalyst

Abstract

The invention discloses a gem-difluoroketone photocatalytic synthesis method without participation of a photocatalyst. The synthesis method of gem-difluoroketone comprises the following steps: S1, dissolving a compound A and a compound B in a solvent, and adding an electron donor to form an electron donor-acceptor EDA compound; s2, enabling the electron donor-acceptor EDA compound to react for 3-48 hours under the irradiation of visible light; and after the reaction is finished, concentrating the reaction liquid, and separating and purifying (column chromatography can be carried out) to obtain the gem-difluoroketone compound C. The reaction is realized through direct optical excitation of the electron donor-acceptor EDA compound, a catalyst does not need to be introduced, the raw material cost is remarkably reduced, and the problem of subsequent treatment of catalyst separation and residues is solved.

Description

Technical Field

[0001] The present invention relates to the technical field of gem-difluoro ketone synthesis, and particularly relates to a photocatalytic synthesis method of gem-difluoro ketone without the participation of a photocatalyst. Background Art

[0002] In recent years, visible-light photocatalysis technology, as an important part of green chemical synthesis, has shown significant advantages in the field of organic synthesis. Currently, the visible-light photocatalysis field mainly relies on photocatalysts in the reaction system to enter the excited state under visible-light excitation, and then initiate a continuous radical reaction by interacting with the substrate to achieve the photocatalytic reaction. Although this process can achieve the transformation of various functional groups under mild conditions, it also has corresponding limitations: First, noble-metal photocatalysts have the problems of high cost and the possibility of metal residue after the reaction; second, the inherent problems of poor stability and short excited-state lifetime of organic photosensitizers; and moreover, the energy matching requirement between the substrate and the catalyst is relatively strict. (ROMERO NA, NICEWICZ DA. Organic Photoredox Catalysis[J]. Chemical Reviews. 2016, 116(17): 10075-10166.; HOLMBERG-DOUGLAS N, NICEWICZ DA. Photoredox-Catalyzed C-H FunctionalizationReactions[J]. Chemical Reviews. 2022, 122(2): 1925-2016.)

[0003] Fluorinated organic compounds occupy an irreplaceable strategic position in the fields of drug R & D, agrochemicals, and functional materials due to the unique thermodynamic stability of the C-F bond and the significant electronic effects brought about by the strong electronegativity. In the field of medicinal chemistry, the introduction of fluorine atoms can significantly enhance biological activity by regulating molecular lipophilicity, pKa value, and metabolic stability. Among them, the gem-difluoro ketone unit exists in a variety of bioactive molecules.(GIROUD M, HARDER M, KUHN B, et al. FluorineScan of Inhibitors of the Cysteine Protease Human Cathepsin L: Dipolar and Quadrupolar Effects in the pi-Stacking of Fluorinated Phenyl Rings on Peptide Amide Bonds[J]. ChemMedChem. 2016, 11(10): 1042-1047.; CHANDRA G, MAHTO B, SINGH VR, et al. Fluorescent fluorinated materials: A novel material for application in photodynamic therapy and designing chemical sensors[J]. Journal of Photochemistry and Photobiology C: Photochemistry Reviews. 2024, 60-61: 100677.; BRADEN RPJ, KLAUKE E. Fluorine-containing intermediates for pesticides[J]. Pesticide Science. 1986, 17(4): 418-429.; HUGHES G, DEVINE PN, NABER JR, et al. Diastereoselective reductive amination of aryl trifluoromethyl ketones and α-amino esters[J]. Angewandte Chemie International Edition. 2007, 46(11): 1839-1842.; PURSER S, MOORE PR, SWALLOW S, et al. Fluorine in medicinal chemistry[J]. Chemical Society Reviews. 2008, 37(2): 320-330.)。

[0004] Traditional methods for constructing gem-difluoroketones, such as the gem-difluorination of ketones using the fluorination reagent diethylaminosulfur trifluoride (DAST) (KOMILOV A M, SOROCHINSKYA E, KUKHAR V P. Stereoselective synthesis of 14,14-difluorocoriolic acid[J]. Tetrahedron: Asymmetry. 1994, 5(6):1015-1018.; NEDER KM, FRENCH S A, MILLER S P F. Synthesis and inhibitory activity of difluoroketone substrate analogs of N-myristoyltransferase[J]. Tetrahedron. 1994, 50(33):9847-9864.), the derivatization of molecules containing three additives and obtaining the gem-difluoroketone structure by Claisen rearrangement (AUDOUARD C, GARAYT M R, KéROURéDAN E, et al. A direct and rapid route to α,α-difluoroacylsilanes from trifluoroethanol[J]. Journal of Fluorine Chemistry. 2005, 126(4):609-621.; KOLB M, NEISES B. Synthesis of fluorinated α-amino ketones. Part II: α-acylaminoalkyl α′,α′-difluoroalkyl ketones[J]. Tetrahedron Letters. 1986, 27(37):4437-4440.), the use of transition metal catalysis to connect molecules containing the gem-difluoroketone structure with other fragments (BOSCH M P, PEREZ R, LAHUERTA G, et al. Difluoropalmitic acids as potential inhibitors of the biosynthesis of the sex pheromone of the Egyptian armyworm Spodoptera littoralis--IV[J]. Bioorganic & Medicinal Chemistry. 1996, 4(3):467-472.; LEFEBVRE O, BRIGAUD T, PORTELLA C.Mixed organofluorine-organosilicon chemistry. 8. One-pot synthesis of 2,2-difluoro-1,5-diketones from acylsilanes, trifluoromethyltrimethylsilane and enones, and their annulation reaction[J]. Tetrahedron. 1998, 54(22): 5939-5948.), there are problems such as strong reagent toxicity, poor substrate adaptability, harsh reaction conditions, and relatively high catalyst cost. Summary of the Invention

[0005] In view of the current situation in the above-mentioned prior art that lacks a method for photocatalytic decarboxylation to generate gem-difluoro ketones without using a photocatalyst, the present invention provides a method for photocatalytic synthesis of gem-difluoro ketones without the participation of a photocatalyst. The synthesis method of gem-difluoro ketones provided by the present invention is simple to operate, low in cost, does not require the use of expensive or difficult-to-synthesize catalysts, and is applicable to a variety of functional groups.

[0006] The object of the present invention can be achieved by the following technical solutions:

[0007] <First aspect>

[0008] A method for synthesizing gem-difluoro ketones without the participation of a photocatalyst, comprising the following steps:

[0009] S1. Dissolve compound A and compound B in a solvent, add an electron donor to form an electron donor-acceptor (EDA) complex;

[0010] S2. React the electron donor-acceptor (EDA) complex under visible light irradiation for 3-48 hours; after the reaction is completed, concentrate the reaction solution and separate and purify (by column chromatography if possible) to obtain the gem-difluoro ketone compound C;

[0011] The structural formula of the compound A is shown in formula (1);

[0012]

[0013] Wherein, R 1 is selected from one or more of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, and an isopropyl group; R 2 is selected from one or more of a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group, a benzyl group and their corresponding derivatives.

[0014] The structural formula of the compound B is shown in formula (2);

[0015]

[0016] Among them, R 3 is selected from one or more of methyl, ethyl, propyl, isopropyl, tert-butyl, and benzyl.

[0017] Among them, R 4 is selected from one or more of a hydrogen atom, a fluorine atom, a chlorine atom, methyl, ethyl, propyl, and isopropyl.

[0018] Furthermore, the compound A is selected from one or more of 1,3-dioxoisoindol-2-yl cyclohexanecarboxylate, 1,3-dioxoisoindol-2-yl tetrahydro-2H-pyran-4-carboxylate, 4,5,6,7-tetrachloro-1,3-dioxoisoindol-2-yl tetrahydro-2H-pyran-4-carboxylate, 1,3-dioxoisoindol-2-yl pivalate, 1,3-dioxoisoindol-2-yl-2-(4-fluorophenyl)acetate, 1,3-dioxoisoindol-2-yl-2-(2-methoxyphenyl)acetate, and 4,5,6,7-tetrachloro-1,3-dioxoisoindol-2-yl-4-phenylbutyrate.

[0019] Preferably, the compound A is selected from one of 1,3-dioxoisoindol-2-yl cyclohexanecarboxylate, 1,3-dioxoisoindol-2-yl tetrahydro-2H-pyran-4-carboxylate, and 4,5,6,7-tetrachloro-1,3-dioxoisoindol-2-yl tetrahydro-2H-pyran-4-carboxylate.

[0020] More preferably, the compound A is selected from 1,3-dioxoisoindol-2-yl tetrahydro-2H-pyran-4-carboxylate.

[0021] Preferably, the compound B is selected from one or more of ((2,2-difluoro-1-phenylethenyl)oxy)triethylsilane, ((2,2-difluoro-1-(p-tolyl)ethenyl)oxy)triethylsilane, ((2,2-difluoro-1-(4-fluorophenyl)ethenyl)oxy)trimethylsilane, ((2,2-difluoro-1-phenylethenyl)oxy)trimethylsilane, and ((2,2-difluoro-1-phenylethenyl)oxy)triethylsilane.

[0022] Furthermore, the compound B is selected from one of ((2,2-difluoro-1-(4-fluorophenyl)ethenyl)oxy)trimethylsilane, ((2,2-difluoro-1-phenylethenyl)oxy)trimethylsilane, and ((2,2-difluoro-1-phenylethenyl)oxy)triethylsilane.

[0023] Furthermore, the compound B includes ((2,2-difluoro-1-phenylethenyl)oxy)trimethylsilane.

[0024] The structural formula of the said compound C is as shown in formula (3);

[0025]

[0026] wherein, R 2 is selected from one or more of methyl, ethyl, propyl, isopropyl, tert-butyl, benzyl and their corresponding derivatives.

[0027] wherein, R 4 is selected from one or more of hydrogen atom, fluorine atom, chlorine atom, methyl, ethyl, propyl, isopropyl.

[0028] The said compound C is selected from one or more of 2-cyclohexyl-2,2-difluoro-1-phenylethan-1-one, 2,2-difluoro-1-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one, 2,2-difluoro-2-(tetrahydro-2H-pyran-4-yl)-1-(p-tolyl)ethan-1-one, 2,2-difluoro-1-(4-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one, 2,2-difluoro-3,3-dimethyl-1-phenylbutan-1-one, 2,2-difluoro-3-(4-fluorophenyl)-1-phenylpropan-1-one, 2,2-difluoro-3-(2-methoxyphenyl)-1-phenylpropan-1-one, 2,2-difluoro-1,5-diphenylpentan-1-one.

[0029] Preferably, the said compound C includes 2,2-difluoro-1-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one, 2,2-difluoro-3,3-dimethyl-1-phenylbutan-1-one, 2-cyclohexyl-2,2-difluoro-1-phenylethan-1-one.

[0030] More preferably, the said compound C includes 2,2-difluoro-1-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one.

[0031] The synthesis method of the gem-difluoro ketone provided by the present invention has the following synthesis route:

[0032]

[0033] The dosage of the said compound B is 1.0 - 10.0 equivalents of compound A (for example, 1.0 equivalent means the molar ratio of compound B to compound A is 1:1).

[0034] The said solvent is one or more of N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, N,N-dimethylacetamide, N-methylpyrrolidone, ethyl acetate, dichloromethane, dichloroethane.

[0035] The electron donor is one or more of triethylamine, diisopropylethylamine, dimethylamine, diethylamine, triphenylamine, benzenethiol, and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.

[0036] The dosage of the electron donor is 0.1 - 2.0 equivalents of compound A (the molar ratio of the electron donor to compound A ranges from 0.1:1 to 2.0:1).

[0037] The wavelength of the visible light irradiation is 420 - 550 nm, and the light source intensity is 10 - 40 W.

[0038] In S2, the reaction time is 3 - 48 hours.

[0039] <Second aspect>

[0040] The gem-difluoro ketone prepared by the synthesis method as described above also belongs to the protection scope of the present invention.

[0041] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0042] 1. Traditional photocatalytic methods rely on noble metals (such as iridium and ruthenium complexes) or organic photosensitizers, which have problems such as high cost, risk of metal residue, and poor stability of photosensitizers. The reaction of the present invention is achieved through direct photoexcitation of an electron donor-acceptor (EDA) complex, without the need to introduce a catalyst, significantly reducing the raw material cost and eliminating the subsequent treatment problems of catalyst separation and residue. The yield of this method is not significantly different from that of the prior art, and this greatly reduces the cost of carrying out the reaction and also avoids the use of heavy metals.

[0043] 2. The prior art has limitations in the derivatization of benzyl carboxylic acid NHPI ester substrates, while this method shows good tolerance to primary / secondary / tertiary alkyl, benzyl, and substrates with substituents such as fluorine and methoxy. For example, gem-difluoro ketone compounds with complex structures such as cyclohexyl, tetrahydropyranyl, and fluorophenyl were successfully synthesized in the examples (such as Examples 2, 4, and 6), providing a precise tool for the late-stage functional modification of drug molecules.

[0044] 3. Visible light (420 - 550 nm) is used as the energy source, the light source intensity is low (10 - 40 W), and the reaction temperature can be controlled at room temperature, avoiding the use of high temperature, strong oxidants, or highly toxic fluorination reagents (such as DAST) in traditional methods, which is in line with the development trend of green chemical synthesis. Description of the Drawings

[0045] By reading the detailed description of the non-limiting examples with reference to the following drawings, other features, purposes, and advantages of the present invention will become more obvious:

[0046] Figure 11H NMR spectrum of 2-cyclohexyl-2,2-difluoro-1-phenyl ethan-1-one prepared in Example 1 1 ;

[0047] Figure 2 19F NMR spectrum of 2-cyclohexyl-2,2-difluoro-1-phenyl ethan-1-one prepared in Example 1 19 ;

[0048] Figure 3 13C NMR spectrum of 2-cyclohexyl-2,2-difluoro-1-phenyl ethan-1-one prepared in Example 1 13 ;

[0049] Figure 4 1H NMR spectrum of 2,2-difluoro-1-phenyl-2-(tetrahydro-2H-pyran-4-yl) ethan-1-one prepared in Example 2 1 ;

[0050] Figure 5 19F NMR spectrum of 2,2-difluoro-1-phenyl-2-(tetrahydro-2H-pyran-4-yl) ethan-1-one prepared in Example 2 19 ;

[0051] Figure 6 13C NMR spectrum of 2,2-difluoro-1-phenyl-2-(tetrahydro-2H-pyran-4-yl) ethan-1-one prepared in Example 2 13 ;

[0052] Figure 7 1H NMR spectrum of 2,2-difluoro-2-(tetrahydro-2H-pyran-4-yl)-1-(p-tolyl) ethan-1-one prepared in Example 3 1 ;

[0053] Figure 8 19F NMR spectrum of 2,2-difluoro-2-(tetrahydro-2H-pyran-4-yl)-1-(p-tolyl) ethan-1-one prepared in Example 3 19 ;

[0054] Figure 9 13C NMR spectrum of 2,2-difluoro-2-(tetrahydro-2H-pyran-4-yl)-1-(p-tolyl) ethan-1-one prepared in Example 3 13 ;

[0055] Figure 101H NMR spectrum of 2,2-difluoro-1-(4-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one prepared in Example 4 1 ;

[0056] Figure 11 19F NMR spectrum of 2,2-difluoro-1-(4-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one prepared in Example 4 19 ;

[0057] Figure 12 13C NMR spectrum of 2,2-difluoro-1-(4-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one prepared in Example 4 13 ;

[0058] Figure 13 1H NMR spectrum of 2,2-difluoro-3,3-dimethyl-1-phenylbutan-1-one prepared in Example 5

[0059] Figure 14 19F NMR spectrum of 2,2-difluoro-3,3-dimethyl-1-phenylbutan-1-one prepared in Example 5 19 ;

[0060] Figure 15 13C NMR spectrum of 2,2-difluoro-3,3-dimethyl-1-phenylbutan-1-one prepared in Example 5 13 ;

[0061] Figure 16 1H NMR spectrum of 2,2-difluoro-3-(4-fluorophenyl)-1-phenylpropan-1-one prepared in Example 6

[0062] Figure 17 19F NMR spectrum of 2,2-difluoro-3-(4-fluorophenyl)-1-phenylpropan-1-one prepared in Example 6 19 ;

[0063] Figure 18 13C NMR spectrum of 2,2-difluoro-3-(4-fluorophenyl)-1-phenylpropan-1-one prepared in Example 6 13 ;

[0064] Figure 19 1H NMR spectrum of 2,2-difluoro-3-(2-methoxyphenyl)-1-phenylpropan-1-one prepared in Example 7 1 ;

[0065] Figure 20 is the fluorine nuclear magnetic resonance spectrum ( 19 19 F NMR) of 2,2-difluoro-3-(2-methoxyphenyl)-1-phenylpropan-1-one prepared in Example 7;

[0066] Figure 21 is the carbon nuclear magnetic resonance spectrum ( 13 13 C NMR) of 2,2-difluoro-3-(2-methoxyphenyl)-1-phenylpropan-1-one prepared in Example 7;

[0067] Figure 22 is the proton nuclear magnetic resonance spectrum ( 1 1 H NMR) of 2,2-difluoro-1,5-diphenylpentan-1-one prepared in Example 8;

[0068] Figure 23 is the fluorine nuclear magnetic resonance spectrum ( 19 19 F NMR) of 2,2-difluoro-1,5-diphenylpentan-1-one prepared in Example 8;

[0069] Figure 24 is the carbon nuclear magnetic resonance spectrum ( 13 13 C NMR) of 2,2-difluoro-1,5-diphenylpentan-1-one prepared in Example 8. Detailed Description of the Invention

[0070] The present invention will be described in detail below with reference to the embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but do not limit the present invention in any form. It should be noted that those of ordinary skill in the art can make several adjustments and improvements without departing from the concept of the present invention. These all fall within the protection scope of the present invention.

[0071] The raw materials and reagents used in the present invention are all commercially available or synthesized by referring to known methods.

[0072] Among them, the sources of the raw material compound A and compound B involved in each embodiment are shown in Table 1 and Table 2.

[0073] Table 1

[0074]

[0075]

[0076] Table 2

[0077]

[0078]

[0079]

[0080] Example 1

[0081] A method for preparing 2-cyclohexyl-2,2-difluoro-1-phenylacet-1-one, comprising the following steps:

[0082] Dissolve compound 1,3-dioxoisoindol-2-yl cyclohexanecarboxylate (54.7 mg, 0.2 mmol) and compound ((2,2-difluoro-1-phenylethenyl)oxy)triethylsilane (189.3 mg, 0.7 mmol) in N,N-dimethylformamide (2 mL) completely. Add triphenylamine (4.9 mg, 0.02 mmol), and then react under light conditions (400 - 410 nm, 20 W) for 3 h. Concentrate the reaction solution, and after column chromatography and concentration, a colorless liquid is obtained, namely 2-cyclohexyl-2,2-difluoro-1-phenylacet-1-one (38.1 mg, 80%).

[0083]

[0084] The basic parameters of this compound are as follows:

[0085] 1 H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 2.34–2.14 (m, 1H), 1.90–1.75 (m, 4H), 1.74–1.64 (m, 1H), 1.38–1.10 (m, 5H). The spectrum is as Figure 1 ;

[0086] 19 F NMR (376 MHz, CDCl3): δ -108.440 (d, J = 13.5 Hz, 2F). The spectrum is as Figure 2 ;

[0087] 13 C NMR (101 MHz, CDCl3): δ 190.5 (t, J = 30.1 Hz), 134.1, 132.9, 130.0 (t, J = 3.6 Hz), 128.7, 120.4 (t, J = 255.4 Hz), 42.2 (t, J = 21.9 Hz), 25.9, 25.5, 24.8 (t, J = 4.3 Hz). The spectrum is as Figure 3 .

[0088] Example 2

[0089] Preparation method of 2,2-difluoro-1-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one, comprising the following steps:

[0090] Compound 1,3-dioxoisoindol-2-yl tetrahydro-2H-pyran-4-carboxylate (55.0 mg, 0.2 mmol) and compound ((2,2-difluoro-1-phenylethenyl)oxy)triethylsilane (324.5 mg, 1.2 mmol) were added to dimethyl sulfoxide (3 mL) and dissolved thoroughly. Triethylamine (10.1 mg, 0.1 mmol) was added, and then the reaction was carried out under light conditions (420 - 430 nm, 45 W) for 10 hours. The reaction solution was concentrated, and after column chromatography and concentration, a pale yellow liquid, namely 2,2-difluoro-1-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one (45.6 mg, 95%), was obtained.

[0091]

[0092] The basic parameters of this compound are as follows:

[0093] 1 H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 7.6 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 8 Hz, 2H), 4.08–4.00 (m, 2H), 3.48–3.34 (m, 2H), 2.66–2.47 (m, 1H), 1.75–1.66 (m, 4H). The spectrum is as shown in Figure 4 ;

[0094] 19 F NMR (376 MHz, CDCl3): δ -108.42 (d, J = 12.0 Hz, 2F). The spectrum is as shown in Figure 5 ;

[0095] 13 C NMR (101 MHz, CDCl3): δ 189.5 (t, J = 30.9 Hz), 134.4, 132.5 (t, J = 1.8 Hz), 130.1 (t, J = 3.7 Hz), 128.8, 119.3 (t, J = 256.2 Hz), 67.1, 39.2 (t, J = 22.3 Hz), 24.9 (t, J = 4.4 Hz). The spectrum is as shown in Figure 6 .

[0096] Example 3

[0097] Preparation method of 2,2-difluoro-2-(tetrahydro-2H-pyran-4-yl)-1-(p-tolyl)ethan-1-one, comprising the following steps:

[0098] Compound 4,5,6,7-tetrachloro-1,3-dioxoisoindol-2-yl tetrahydro-2H-pyran-4-carboxylate (82.6 mg, 0.2 mmol), compound ((2,2-difluoro-1-(p-tolyl)vinyl)oxy)triethylsilane (113.8 mg, 0.4 mmol) were added to N,N-dimethylformamide (1.5 mL) and dissolved thoroughly. Diisopropylethylamine (7.8 mg, 0.06 mmol) was added, and then the reaction was carried out under light conditions (540 - 550 nm, 10 W) for 24 hours. The reaction solution was concentrated, and after column chromatography and concentration, a colorless liquid was obtained, namely 2,2-difluoro-2-(tetrahydro-2H-pyran-4-yl)-1-(p-tolyl)ethan-1-one (38.1 mg, 75%).

[0099]

[0100] The basic parameters of this compound are as follows:

[0101] 1 H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 4.03 (d, J = 11.2 Hz, 2H), 3.50–3.30 (m, 2H), 2.64–2.46 (m, 1H), 2.43 (s, 3H), 1.77–1.62 (m, 4H). The spectrum is as Figure 7 ;

[0102] 19 F NMR (376 MHz, CDCl3): δ -108.49 (d, J = 12.8 Hz, 2F). The spectrum is as Figure 8 ;

[0103] 13 C NMR (101 MHz, CDCl3): δ 189.1 (t, J = 30.6 Hz), 145.6, 130.2 (t, J = 3.8 Hz), 130.0 (t, J = 2.0 Hz), 129.5, 119.3 (t, J = 256.3 Hz), 67.1, 39.3 (t, J = 22.6 Hz), 24.9 (t, J = 4.3 Hz), 21.8. The spectrum is as Figure 9 .

[0104] Example 4

[0105] A preparation method of 2,2-difluoro-1-(4-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one, comprising the following steps:

[0106] Compound 4,5,6,7-tetrachloro-1,3-dioxoisoindol-2-yl tetrahydro-2H-pyran-4-carboxylate (82.6 mg, 0.2 mmol) and compound ((2,2-difluoro-1-phenylethenyl)oxy)triethylsilane (197.0 mg, 0.8 mmol) were added to N,N-dimethylacetamide (2 mL) and dissolved thoroughly. Diisopropylethylamine (38.8 mg, 0.3 mmol) was added, and then the reaction was carried out under light conditions (550 - 560 nm, 20 W) for 20 hours. The reaction solution was concentrated, and after column chromatography and concentration, a colorless liquid was obtained, namely 2,2-difluoro-1-(4-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one (41.3 mg, 80%).

[0107]

[0108] The basic parameters of this compound are as follows:

[0109] 1 H NMR (400 MHz, CDCl3): δ 8.14 (dd, J = 8.8 Hz, 5.2 Hz), 7.17 (dd, J = 8.4 Hz, 8.4 Hz), 4.04 (dt, J = 11.2 Hz, 3.2 Hz, 2H), 3.48–3.34 (m, 2H), 2.64–2.45 (m, 1H), 1.75–1.64 (m, 4H). The spectrum is as shown in Figure 10 ;

[0110] 19 F NMR (376 MHz, CDCl3): δ -101.94–-102.09 (m, 1H), -108.03 (d, J = 13.5 Hz, 2F). The spectrum is as shown in Figure 11 ;

[0111] 13 C NMR (101 MHz, CDCl3): δ 187.9 (t, J = 31.8 Hz), 166.4 (d, J = 259.0 Hz), 133.1 (dt, J = 9.7 Hz, 3.3 Hz), 128.8 (d, J = 2.6 Hz), 119.2 (t, J = 256.1 Hz), 116.1 (d, J = 22.2 Hz), 67.1, 39.1 (t, J = 22.3 Hz), 22.9 (t, J = 4.3 Hz). The spectrum is as shown in Figure 12 .

[0112] Example 5

[0113] A preparation method of 2,2-difluoro-3,3-dimethyl-1-phenylbutan-1-one, comprising the following steps:

[0114] Compound 1,3-dioxoisoindol-2-yl pivalate (49.4 mg, 0.2 mmol) and compound ((2,2-difluoro-1-phenylethenyl)oxy)triethylsilane (270.4 mg, 1 mmol) were added to N,N-dimethylacetamide (4 mL) and dissolved thoroughly. Diethylamine (7.2 mg, 0.1 mmol) was added, and then the reaction was carried out under light conditions (480 - 490 nm, 25 W) for 36 hours. The reaction solution was concentrated, and after column chromatography and concentration, a colorless liquid, namely 2,2-difluoro-3,3-dimethyl-1-phenylbutan-1-one (38.2 mg, 90%), was obtained.

[0115]

[0116] The basic parameters of this compound are as follows:

[0117] 1 H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 7.6 Hz, 2H), 7.60 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 8.0 Hz, 2H), 1.15 (s, 9H). The spectrum is as Figure 13 ;

[0118] 19 F NMR (376 MHz, CDCl3): δ -108.65 (s, 2F). The spectrum is as Figure 14 ;

[0119] 13 C NMR (101 MHz, CDCl3): δ 190.5 (t, J = 31.3 Hz), 134.2, 133.5, 129.9 (t, J = 4.4 Hz), 128.2, 121.6 (t, J = 258.8 Hz), 37.5 (t, J = 21.9 Hz), 23.8 (t, J = 4.3 Hz). The spectrum is as Figure 15 .

[0120] Example 6

[0121] A method for preparing 2,2-difluoro-3-(4-fluorophenyl)-1-phenylpropan-1-one, comprising the following steps:

[0122] The compound 1,3-dioxoisoindol-2-yl 2-(4-fluorophenyl)acetate (59.8 mg, 0.2 mmol) and the compound ((2,2-difluoro-1-phenylethenyl)oxy)triethylsilane (162.2 mg, 0.6 mmol) were added to dimethyl sulfoxide (2 mL) and dissolved thoroughly. Then benzenethiol (26.4 mg, 0.24 mmol) was added, and the reaction was carried out under light conditions (420 - 430 nm, 10 W) for 40 hours. The reaction solution was concentrated, and after column chromatography and concentration, a white solid was obtained, namely 2,2-difluoro-3-(4-fluorophenyl)-1-phenylpropan-1-one (34.3 mg, 65%).

[0123]

[0124] The basic parameters of this compound are as follows:

[0125] 1 H NMR (400 MHz, CDCl3): δ 8.04 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.06–6.96 (m, 2H), 7.01 (t, J = 8.4 Hz, 2H), 3.49 (t, J = 17.6 Hz, 2H). The spectrum is as shown in Figure 16 .

[0126] 19 F NMR (376 MHz, CDCl3): δ -98.68 (t, J = 17.7 Hz, 2F), -114.81–-114.95 (m, 1F). The spectrum is as shown in Figure 17 .

[0127] 13 C NMR (101 MHz, CDCl3): δ 189.4 (t, J = 31.6 Hz), 162.4 (d, J = 247.2 Hz), 134.4, 132.5 (d, J = 8.2 Hz), 132.0 (t, J = 2.2 Hz), 130.2 (t, J = 2.9 Hz), 128.7, 127.1–126.9 (m), 118.2 (t, J = 225.7 Hz), 115.4 (d, J = 21.4 Hz), 39.3 (t, J = 23.3 Hz). The spectrum is as shown in Figure 18 .

[0128] Example 7

[0129] A preparation method of 2,2-difluoro-3-(2-methoxyphenyl)-1-phenylpropan-1-one, comprising the following steps:

[0130] The compound 1,3-dioxoisoindol-2-yl 2-(2-methoxyphenyl)acetate (62.3 mg, 0.2 mmol) and the compound ((2,2-difluoro-1-phenylethenyl)oxy)trimethylsilane (91.3 mg, 0.4 mmol) were added to ethyl acetate (3 mL) and dissolved thoroughly. Diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (10.1 mg, 0.04 mmol) was added, and then the reaction was carried out under light conditions (450 - 460 nm, 30 W) for 20 hours. The reaction solution was concentrated, and after column chromatography and concentration, a colorless liquid, namely 2,2-difluoro-3-(2-methoxyphenyl)-1-phenylpropan-1-one (33.2 mg, 60%), was obtained.

[0131]

[0132] The basic parameters of this compound are as follows:

[0133] 1 H NMR (400 MHz, CDCl3): δ 8.02 (d, J = 8.0 Hz, 2H), 7.59 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.34–7.22 (m, 2H), 6.94 (t, J = 7.2 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 3.59 (t, J = 17.6 Hz, 2H), 3.56 (s, 3H). The spectrum is as shown in Figure 19 .

[0134] 19 F NMR (376 MHz, CDCl3): δ -98.68 (t, J = 18.0 Hz, 2F). The spectrum is as shown in Figure 20 .

[0135] 13 C NMR (101 MHz, CDCl3): δ 189.5 (t, J = 29.6 Hz), 157.9, 134.0, 132.5, 132.4, 130.0 (t, J = 3.4 Hz), 129.2, 128.5, 120.6, 119.8 (t, J = 3.9 Hz), 118.6 (t, J = 255.1 Hz), 110.5, 55.0, 35.0 (t, J = 24.4 Hz). The spectrum is as shown in Figure 21 .

[0136] Example 8

[0137] A preparation method of 2,2-difluoro-1,5-diphenylpentan-1-one, comprising the following steps:

[0138] Compound 4,5,6,7-tetrachloro-1,3-dioxoisoindol-2-yl 4-phenylbutyrate (89.4 mg, 0.2 mmol) and compound ((2,2-difluoro-1-phenylethenyl)oxy)triethylsilane (432.6 mg, 1.6 mmol) were added to N,N-dimethylacetamide (2 mL) and dissolved thoroughly. Triphenylamine (73.6 mg, 0.3 mmol) was added, and then the reaction was carried out under light conditions (520 - 530 nm, 40 W) for 5 hours. The reaction solution was concentrated, and after column chromatography and concentration, a colorless liquid, namely 2,2-difluoro-1,5-diphenylpentan-1-one (27.4 mg, 50%), was obtained.

[0139]

[0140] The basic parameters of this compound are as follows:

[0141] 1 H NMR (400 MHz, CDCl3): 8.09 (d, J = 7.2 Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 8.0 Hz, 2H), 7.33–7.25 (m, 2H), 7.24–7.15 (m, 3H), 2.72 (t, J = 7.6 Hz, 2H), 2.30–2.13 (m, 2H), 1.98–1.84 (m, 2H). The spectrum is as Figure 22 。

[0142] 19 F NMR (376 MHz, CDCl3): -98.92 (t, J = 18.0 Hz, 2F). The spectrum is as Figure 23 。

[0143] 13 C NMR (101 MHz, CDCl3): 189.5 (t, J = 31.5 Hz), 141.2, 134.3, 132.0, 130.2 (t, J = 3.3 Hz), 128.7, 128.5, 128.4, 126.1, 119.8 (t, J = 254.2 Hz), 35.3, 33.4 (t, J = 23.1 Hz), 23.1 (t, J = 4.3 Hz). The spectrum is as Figure 24 。

[0144] The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art can make various deformations or modifications within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A method for synthesizing gem-difluoro ketones without the participation of a photocatalyst, characterized in that, It includes the following steps: S1. Dissolve compound A and compound B in a solvent, add an electron donor to form an electron donor-acceptor complex; S2. React the electron donor-acceptor complex under visible light irradiation; after the reaction is completed, concentrate the reaction solution, separate and purify to obtain gem-difluoro ketone compound C; The structural formula of the said compound A is shown as formula (1); Among them, R 1 is selected from one or more of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, and an isopropyl group; R 2 selected from one or more of methyl, ethyl, propyl, isopropyl, tert-butyl, benzyl and their corresponding derivatives; The structural formula of the said compound B is shown as formula (2); Among them, R 3 is selected from one or more of methyl, ethyl, propyl, isopropyl, tert-butyl, and benzyl. wherein, R 4 is selected from one or more of a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a propyl group, and an isopropyl group.

2. The synthesis method according to claim 1, wherein The structural formula of the said compound C is shown as formula (3): wherein R 2 is selected from one or more of methyl, ethyl, propyl, isopropyl, tert-butyl, benzyl and their corresponding derivatives. wherein R 4 is selected from one or more of a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a propyl group, and an isopropyl group.

3. The synthesis method according to claim 1, wherein The dosage of the said compound B is 1.0 - 10.0 equivalents of compound A.

4. The synthesis method according to claim 1, wherein The said solvent is one or more of N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, N,N-dimethylacetamide, N-methylpyrrolidone, ethyl acetate, dichloromethane, dichloroethane.

5. The synthesis method according to claim 1, wherein The said electron donor is one or more of triethylamine, diisopropylethylamine, dimethylamine, diethylamine, triphenylamine, benzenethiol, diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.

6. The synthesis method according to claim 1, characterized in that, The dosage of the said electron donor is 0.1 - 2.0 equivalents of compound A.

7. The synthesis method according to claim 1, characterized in that, The wavelength of the said visible light irradiation is 420 - 550 nm, and the light source intensity is 10 - 40 W.

8. The synthesis method according to claim 1, characterized in that, In S2, the said reaction time is 3 - 48 hours.

9. The synthesis method according to claim 1, characterized in that The said compound A is selected from one or more of 1,3-dioxoisoindol-2-yl cyclohexanecarboxylate, 1,3-dioxoisoindol-2-yl tetrahydro-2H-pyran-4-carboxylate, 4,5,6,7-tetrachloro-1,3-dioxoisoindol-2-yl tetrahydro-2H-pyran-4-carboxylate, 1,3-dioxoisoindol-2-yl pivalate, 1,3-dioxoisoindol-2-yl-2-(4-fluorophenyl)acetate, 1,3-dioxoisoindol-2-yl-2-(2-methoxyphenyl)acetate, 4,5,6,7-tetrachloro-1,3-dioxoisoindol-2-yl-4-phenylbutyrate; And / or, the said compound B is selected from one or more of ((2,2-difluoro-1-phenylethenyl)oxy)triethylsilane, ((2,2-difluoro-1-(p-tolyl)ethenyl)oxy)triethylsilane, ((2,2-difluoro-1-(4-fluorophenyl)ethenyl)oxy)trimethylsilane, ((2,2-difluoro-1-phenylethenyl)oxy)trimethylsilane, ((2,2-difluoro-1-phenylethenyl)oxy)triethylsilane; And / or, the compound C is selected from one or more of 2-cyclohexyl-2,2-difluoro-1-phenyl-ethan-1-one, 2,2-difluoro-1-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one, 2,2-difluoro-2-(tetrahydro-2H-pyran-4-yl)-1-(p-tolyl)ethan-1-one, 2,2-difluoro-1-(4-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one, 2,2-difluoro-3,3-dimethyl-1-phenylbutan-1-one, 2,2-difluoro-3-(4-fluorophenyl)-1-phenylpropan-1-one, 2,2-difluoro-3-(2-methoxyphenyl)-1-phenylpropan-1-one, 2,2-difluoro-1,5-diphenylpentan-1-one.

10. A gem-difluoro ketone compound prepared by the synthesis method according to any one of claims 1-9.

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