A method for the palladium-catalyzed preparation of 2-fluoro-1,2-diphenyl-ethanone compounds and products thereof

Abstract

The application discloses a kind of palladium catalytic preparation 2-fluoro-1,2-diphenyl ethanone compound and its product, belong to organic synthesis technical field, the compound structure is as shown in formula I, its preparation method includes the following steps: (1) palladium catalyst, ligand, base and solvent are mixed uniformly, then join fluorine-containing block and bromoaromatic hydrocarbon are stirred, after reaction, quenching by water, again after extraction, washing, liquid separation, drying, remove solvent, obtain crude product;(2) the crude product is separated and purified by column chromatography, to obtain the 2-fluoro-1,2-diphenyl ethanone compound.The application also discloses the 2-fluoro-1,2-diphenyl ethanone compound prepared by the above preparation method.The application is constructed fluorine-containing aromatic ketone by fluorine-containing block, without directly using fluorination reagent, easy to operate, high yield;And, the application is suitable for a variety of bromoaromatic hydrocarbon substrates, and the universality is wide.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and in particular to a method for preparing 2-fluoro-1,2-diphenyl ethyl ketone compounds by palladium catalysis and the products thereof. Background Technology

[0002] Fluorine-containing drugs are widely used, accounting for about 30% of all drugs, and their use is showing an increasing trend year by year. Common fluorine-containing drugs include Prozac for treating depression, Roflunarizine for treating bronchitis, fluphenazine with sedative effects, norfloxacin with bactericidal effects, trifluralin as a herbicide, and efavirenz, an anti-HIV-1 drug. Therefore, the synthesis of biologically active organofluorine compounds has become a key research focus in synthetic chemistry.

[0003] Selectively introducing fluorine atoms into organic molecules to replace hydrogen atoms or hydroxyl groups can alter the molecule's polarity, pharmacokinetics, and efficacy. In aryl ketones, replacing the carbonyl α-hydrogen atom with a fluorine atom can inhibit carbonyl enolization, improve drug metabolic stability, and compounds containing this functional group have unique medicinal value. Examples include the potassium ion channel agent flulindokalner and the potent antibacterial agent solithromycin.

[0004]

[0005] In recent years, researchers have developed a variety of fluorinating reagents or fluorinated building blocks, making it easier for synthetic chemists to obtain α-fluorocarbonyl organic compounds. For example, the Guo group used bifunctional squamamide as a chiral catalyst and employed electrosynthesis to achieve the asymmetric alkylation reaction of fluorinated geminal alcohols [8] with detrifluoroacetic acid, obtaining a wide variety of chiral α-fluoroaryl ketones (Chang, X.; Zhang, JY; Guo, C. et al. Angew Chem Int Ed, 2020, 59, 18500-18504).

[0006] Therefore, how to prepare α-fluorocarbonyl organic compounds using fluorinating reagents or fluorinated building blocks is a technical problem that urgently needs to be solved by those skilled in the art. Summary of the Invention

[0007] The purpose of this invention is to provide a method for preparing 2-fluoro-1,2-diphenyl ethyl ketone compounds by palladium catalysis and the products thereof, so as to solve the problems existing in the prior art.

[0008] To achieve the above objectives, the present invention provides the following solution:

[0009] A method for preparing 2-fluoro-1,2-diphenyl ethyl ketone compounds using palladium catalysis includes the following steps:

[0010] (1) The palladium catalyst, ligand, base and solvent are mixed and stirred, then fluorine-containing building blocks and bromoaromatic hydrocarbons are added and stirred to react. After the reaction is completed, water is added to quench the reaction, and then the solvent is removed by extraction, washing, separation and drying to obtain crude product.

[0011] (2) The crude product was purified by column chromatography to obtain the 2-fluoro-1,2-diphenyl ethyl ketone compound.

[0012] Beneficial effects: such as Figure 1 As shown, the reaction principle of this invention is as follows: First, the ligand L is complexed with Pd(II) to generate active L2Pd(0), which then undergoes an oxidative addition reaction with the CX bond in the aryl halide. At the same time, the fluorinated building block generates an enol anion in situ under the action of alkali, and acts as a nucleophile to perform ligand exchange on the intermediate [Pd(II)](Ar)(X). The intermediate [Pd(II)](Ar)(Enolate) formed after the exchange undergoes a reductive elimination reaction to generate 2-fluoro-1,2-diphenyl ethyl ketone compounds, and at the same time, L2Pd(0) is obtained again to complete the catalytic cycle.

[0013] Preferably, the molar ratio of the palladium catalyst, ligand, fluorinated building block, bromoaromatic hydrocarbon and base in step (1) is (0.05-0.1):(0.1-0.2):1:(2-3):(3-4);

[0014] The mass-to-volume ratio of the fluorinated block to the solvent is 1 g:(30-100) mL.

[0015] Beneficial effects: Under this ratio, the catalyst in this invention has the highest catalytic conversion rate and the highest atom economy of the reaction.

[0016] Preferably, the palladium catalyst in step (1) is one of palladium acetate, palladium trifluoroacetate, and tris(dibenzylacetone)palladium;

[0017] The ligand is one of triphenylphosphine, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, tris(o-methylphenyl)phosphine, and 2-di-tert-butylphosphine-2'-methylbiphenyl;

[0018] The alkali is one of sodium carbonate, potassium carbonate, and sodium hydroxide;

[0019] The solvent is one of toluene, xylene, and trimethylbenzene;

[0020] The bromoaromatic hydrocarbon is one of bromobenzene, bromotoluene, p-bromofluorobenzene, and o-chlorobromobenzene.

[0021] Beneficial effects: By adjusting the above process parameters and raw material selection, the present invention can achieve a product yield of over 70%.

[0022] Preferably, the fluorinated building block is a 2,4,4,4-tetrafluoro-3,3-dihydroxy-1-phenyl-1-butanone building block, the structure of which is shown in formula (I):

[0023]

[0024] Wherein, the R 1 It is selected from one of -H, C1-C5 alkyl, C1-C5 alkoxy, -F, -Cl and -Br.

[0025] Beneficial effects: The method for preparing fluorinated blocks provided by this invention is simple and has high stability.

[0026] Preferably, the mixing temperature in step (1) is room temperature, and the mixing time is 10 min;

[0027] The stirring reaction temperature is 100-140℃, and the reaction time is 5h-9h.

[0028] Beneficial effect: At this temperature, the fluorinated building blocks of the present invention readily react with alkali to form active intermediates.

[0029] Preferably, the extraction in step (2) is performed using an organic solvent, wherein the organic solvent is ethyl acetate and / or diethyl ether;

[0030] Beneficial effects: Under the above conditions, the oil and water phases can be well separated, and the separation operation is simple.

[0031] Preferably, the washing is performed using saturated saline solution;

[0032] The drying process is performed using anhydrous sodium sulfate and / or anhydrous magnesium sulfate.

[0033] Beneficial effects: Under the above conditions, water in the solution can be effectively removed by drying with the adsorbent.

[0034] Preferably, in the column chromatography process described in step (3), petroleum ether and ethyl acetate with a volume ratio of (50-100):1 are used as eluents.

[0035] Beneficial effects: Under the above conditions, the present invention can efficiently separate products from impurities.

[0036] A 2-fluoro-1,2-diphenyl ethyl ketone compound, the structure of which is shown in Formula II:

[0037]

[0038] Wherein, the R 1 Selected from one of -H, C1-C5 alkyl, C1-C5 alkoxy, -F, -Cl and -Br;

[0039] R 2 It is selected from one of -H, C1-C5 alkyl, C1-C5 alkoxy, -F, -Cl, -Br, -CF3, -CN and -Ph.

[0040] This invention discloses a method for preparing 2-fluoro-1,2-diphenyl ethyl ketone compounds and their products by palladium catalysis. This invention constructs fluorinated aromatic ketones through fluorinated building blocks, eliminating the need for direct use of fluorinating reagents. The method is simple to operate and yields high results. Furthermore, this invention is applicable to a variety of brominated aromatic substrates and has broad applicability. Attached Figure Description

[0041] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0042] Figure 1 This is a schematic diagram illustrating the reaction principle for the palladium-catalyzed preparation of 2-fluoro-1,2-diphenylethyl ketone compounds in this invention. Detailed Implementation

[0043] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0044] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0045] In this embodiment of the invention, the specific chemical reaction equations are as follows:

[0046]

[0047] The instrument used to test the obtained product in this embodiment of the invention is a Bruker ARX 400MHz nuclear magnetic resonance spectrometer (CDCl3 as solvent, TMS as internal standard). The test methods in the following embodiments are the same as those in this embodiment.

[0048] In this embodiment of the invention, 2,4,4,4-tetrafluoro-3,3-dihydroxy-1-phenyl-1-butanone was synthesized in the laboratory according to the literature. (The literature is: Saidalimu, I.; Fang, X.; Wu, F.-H. et al. Angew Chem Int Ed., 2013, 52, 5566-5570)

[0049] The 1,1'-binaphthyl-2,2'-bis(diphenylphosphine), xylene, and other reagents used in the embodiments of this invention were purchased from Aladdin.

[0050] Example 1

[0051] A method for preparing 2-fluoro-1,2-diphenyl ethyl ketone compounds via palladium catalysis, specifically 2-fluoro-1,2-diphenyl ethyl ketone, the preparation method comprising the following steps:

[0052] Under nitrogen protection, Pd(OAc)₂ (0.01 mmol), BINAP (0.02 mmol), K₂CO₃ (0.6 mmol), and xylene (3 mL) were added sequentially to a Schlenk flask. The mixture was stirred at room temperature for 10 min, followed by the addition of 2,4,4,4-tetrafluoro-3,3-dihydroxy-1-phenyl-1-butanone (0.2 mmol) and bromobenzene (0.4 mmol). The mixture was heated to 130 °C and stirred for 7 h. After the reaction was completed, the mixture was cooled to room temperature, and then extracted three times with distilled water (20 mL) and diethyl ether (10 mL). The combined organic phases were washed twice with saturated brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1) to obtain 2-fluoro-1,2-diphenyl ethyl ketone in 94% yield as a white solid.

[0053] The product test data are as follows:

[0054] 1 HNMR (400MHz, CDCl3) δ: 7.94 (d, J = 7.6Hz, 2H), 7.54 (t, J = 7.2Hz, 1H), 7.49~7.48 (m, 2H), 7.44~7.38 (m, 5H), 6.81 (d, J = 48.8Hz, 1H);

[0055] 19 FNMR (376MHz, CDCl3) δ: -175.9 (d, J = 47.7Hz, 1F);

[0056] 13 CNMR (100MHz, CDCl3) δ: 194.3 (d, 2 J C-C-F=21.2Hz),134.2(d,J=19.8Hz),134.0,133.7,129.6(d,J=2.3Hz),129.1,129.0,128.7,127.4(d,J=5.3Hz),93.8(d, 1 J C-F =185.1Hz).

[0057] Example 2

[0058] A method for preparing 2-fluoro-1,2-diphenyl ethyl ketone compounds via palladium catalysis, specifically 2-fluoro-1-phenyl-2-(p-tolyl)ethyl ketone, comprising the following steps:

[0059] Under nitrogen protection, Pd(OAc)₂ (0.01 mmol), BINAP (0.02 mmol), K₂CO₃ (0.6 mmol), and xylene (3 mL) were added sequentially to a Schlenk flask. The mixture was stirred at room temperature for 10 min, followed by the addition of 2,4,4,4-tetrafluoro-3,3-dihydroxy-1-phenyl-1-butanone (0.2 mmol) and p-bromotoluene (0.4 mmol). The mixture was heated to 130 °C and stirred at this temperature for 7 h. After the reaction was completed, the mixture was cooled to room temperature, and then extracted three times with distilled water (20 mL) and diethyl ether (10 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1) to obtain 2-fluoro-1-phenyl-2-(p-tolyl)ethyl ketone in 80% yield as a white solid.

[0060] The product test data are as follows:

[0061] 1 HNMR (400MHz, CDCl3) δ: 7.92 (d, J = 7.2Hz, 2H), 7.53 (t, J = 7.6Hz, 1H), 7.44-7.36 (m, 4H), 7.20 (d, J = 8.0Hz, 2H), 6.50 (d, J = 48.8Hz, 1H), 2.33 (s, 3H);

[0062] 19 FNMR (376MHz, CDCl3) δ: -174.1 (d, J = 47.7Hz, 1F);

[0063] 13 CNMR (100MHz, CDCl3) δ: 194.3 (d, 2 J C-C-F=21.3Hz), 133.9 (d, J = 25.0Hz), 133.6, 131.1, 129.8 (d, J = 1.5Hz), 129.1 (d, J = 2.2Hz), 129.0 (d, J = 3.1Hz), 128.7, 127.6 (d, J = 4.6Hz), 93.7 (d, 1 J C-F =184.5Hz),21.2.

[0064] Example 3

[0065] A method for preparing 2-fluoro-1,2-diphenyl ethyl ketone compounds via palladium catalysis, specifically 2-fluoro-1-phenyl-2-(4′-fluorophenyl)ethyl ketone, the preparation method comprising the following steps:

[0066] Under nitrogen protection, Pd(OAc)₂ (0.01 mmol), BINAP (0.02 mmol), K₂CO₃ (0.6 mmol), and xylene (3 mL) were added sequentially to a Schlenk flask. The mixture was stirred at room temperature for 10 min, followed by the addition of 2,4,4,4-tetrafluoro-3,3-dihydroxy-1-phenyl-1-butanone (0.2 mmol) and p-bromofluorobenzene (0.4 mmol). The mixture was heated to 130 °C and stirred at this temperature for 7 h. After the reaction was completed, the mixture was cooled to room temperature, and then extracted three times with distilled water (20 mL) and diethyl ether (10 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1) to obtain 2-fluoro-1-phenyl-2-(4′-fluorophenyl)ethyl ketone in 93% yield as a white solid.

[0067] The product test data are as follows:

[0068] 1 HNMR (400MHz, CDCl3) δ: 7.92 (d, J = 7.2Hz, 2H), 7.58 ~ 7.41 (m, 5H), 7.08 (t, J = 8.4Hz, 2H), 6.50 (d, J = 48.4Hz, 1H);

[0069] 19 FNMR (376MHz, CDCl3) δ: -111.1 (m, 1F), -174.3 (dd, J = 47.7Hz, 4.1Hz, 1F);

[0070] 13 CNMR (100MHz, CDCl3) δ: 194.1 (d, 2 JC-C-F =22.0Hz),163.3(dd,J=248.3Hz,3.0Hz),133.9,130.2(dd,J=20.5Hz,3.0Hz),129.5(dd, 3 J C-C-C-F =9.1Hz,5.3Hz),129.1,129.0,128.7,116.2(d, 2 J C-C-F =22.8Hz), 93.0(d, 1 J C-F =185.2Hz).

[0071] Example 4

[0072] A method for preparing 2-fluoro-1,2-diphenyl ethyl ketone compounds via palladium catalysis, specifically 2-fluoro-1-phenyl-2-(2′-chlorophenyl)ethyl ketone, the preparation method comprising the following steps:

[0073] Under nitrogen protection, Pd(OAc)₂ (0.01 mmol), BINAP (0.02 mmol), K₂CO₃ (0.6 mmol), and xylene (3 mL) were added sequentially to a Schlenk flask. The mixture was stirred at room temperature for 10 min, followed by the addition of 2,4,4,4-tetrafluoro-3,3-dihydroxy-1-phenyl-1-butanone (0.2 mmol) and o-chlorobromobenzene (0.4 mmol). The mixture was heated to 130 °C and stirred at this temperature for 7 h. After the reaction was completed, the mixture was cooled to room temperature, and then extracted three times with distilled water (20 mL) and diethyl ether (10 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1) to obtain 2-fluoro-1-phenyl-2-(2′-chlorophenyl)ethyl ketone in 85% yield as a white solid.

[0074] The product test data are as follows:

[0075] 1 HNMR (400MHz, CDCl3) δ: 7.94 (d, J = 7.2Hz, 2H), 7.54 (t, J = 7.6Hz, 1H), 7.44~7.40 (m, 4H), 7.32~7.22 (m, 2H), 7.04 (d, J = 47.2Hz, 1H);

[0076] 19 FNMR (376MHz, CDCl3) δ: -177.6 (d, J = 46.2Hz, 1F);

[0077] 13 CNMR (100MHz, CDCl3) δ: 193.3 (d, 2 J C-C-F =20.5Hz),134.0(d,J=2.2Hz),133.8(d,J=14.5Hz),132.2(d,J=20.5Hz),131.1(d,J=3.1Hz ),130.1(d,J=2.5Hz),129.5,129.4,128.8,128.7(d,J=2.3Hz),127.5(d,J=1.5Hz),89.3(d, 1 J C-F =182.2Hz).

[0078] Example 5

[0079] A method for preparing 2-fluoro-1,2-diphenyl ethyl ketone compounds via palladium catalysis, specifically 2-fluoro-1-(4′-methylphenyl)-2-(4,1′-biphenyl)ethyl ketone, the preparation method comprising the following steps:

[0080] Under nitrogen protection, Pd(OAc)₂ (0.01 mmol), BINAP (0.02 mmol), K₂CO₃ (0.6 mmol), and xylene (3 mL) were added sequentially to a Schlenk flask. The mixture was stirred at room temperature for 10 min, followed by the addition of 2,4,4,4-tetrafluoro-3,3-dihydroxy-1-(p-tolyl)but-1-one (0.2 mmol) and bromobenzene (0.4 mmol). The mixture was heated to 130 °C and stirred at this temperature for 7 h. After the reaction was completed, the mixture was cooled to room temperature, and then extracted three times with distilled water (20 mL) and diethyl ether (10 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1) to obtain 2-fluoro-1-(4′-methylphenyl)-2-(4,1'-biphenyl)ethyl ketone in 81% yield as a white solid.

[0081] The product test data are as follows:

[0082] 1 HNMR(400MHz, CDCl3)δ:7.89(d,J=8.0Hz,2H),7.61(d,J=8.0Hz,2H),7.55(d,J=7.2Hz,4H),7.43( t,J=7.6Hz,2H),7.35(t,J=7.6Hz,1H),7.24(d,J=8.0Hz,2H),6.55(d,J=48.8Hz,1H),2.38(s,3H);

[0083] 19 FNMR (376MHz, CDCl3) δ: -175.5 (d, J = 47.8Hz, 1F);

[0084] 13 CNMR (100MHz, CDCl3) δ: 193.7 (d, 2 J C-C-F =21.2Hz), 144.8, 142.4 (d, J = 3.0Hz), 140.1, 133.3 (d, J = 19.7Hz), 131.4, 129.4, 129. 2(d,J=2.2Hz),128.8,127.9(d,J=5.3Hz),127.8(d,J=1.5Hz),127.7,127.1,93.6(d, 1 J C-F =184.5Hz), 21.7.

[0085] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A method for preparing 2-fluoro-1,2-diphenylethyl ketone compounds using palladium catalysis, characterized in that, Includes the following steps: (1) The palladium catalyst, ligand, base and solvent are mixed and stirred, then fluorine-containing building blocks and bromoaromatic hydrocarbons are added and stirred to react. After the reaction is completed, water is added to quench the reaction, and then the solvent is removed by extraction, washing, separation and drying to obtain crude product. (2) The crude product was separated and purified by column chromatography to obtain the 2-fluoro-1,2-diphenyl ethyl ketone compound; The palladium catalyst is palladium acetate; The ligand is 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; The alkali is potassium carbonate; The fluorinated building block is a 2,4,4,4-tetrafluoro-3,3-dihydroxy-1-phenyl-1-butanone type building block, and its structure is shown in formula (I): Wherein, the R 1 Selected from one of -H, C1-C5 alkyl, C1-C5 alkoxy, -F, -Cl and -Br; The 2-fluoro-1,2-diphenyl ethyl ketone compounds have the structure shown in Formula II: Wherein, the R 1 Selected from one of -H, C1-C5 alkyl, C1-C5 alkoxy, -F, -Cl, and -Br; R 2 It is selected from one of -H, C1-C5 alkyl, C1-C5 alkoxy, -F, -Cl, -Br, -CF3, -CN and -Ph.

2. The method for preparing 2-fluoro-1,2-diphenyl ethyl ketone compounds by palladium catalysis according to claim 1, characterized in that, The molar ratio of palladium catalyst, ligand, fluorinated building block, bromoaromatic hydrocarbon and base in step (1) is (0.05-0.1):(0.1-0.2):1:(2-3):(3-4); the mass-volume ratio of fluorinated building block and solvent is 1g:(30-100)mL.

3. The method for preparing 2-fluoro-1,2-diphenyl ethyl ketone compounds by palladium catalysis according to claim 2, characterized in that, The solvent is one of toluene, xylene, and trimethylbenzene; The bromoaromatic hydrocarbon is one of bromobenzene, bromotoluene, p-bromofluorobenzene, and o-chlorobromobenzene.

4. The method for preparing 2-fluoro-1,2-diphenyl ethyl ketone compounds by palladium catalysis according to claim 1, characterized in that, The mixing and stirring temperature in step (1) is room temperature, and the stirring time is 10 min; the stirring reaction temperature is 100-140℃, and the reaction time is 5-9 h.

5. The method for preparing 2-fluoro-1,2-diphenyl ethyl ketone compounds by palladium catalysis according to claim 1, characterized in that, The extraction in step (1) is performed using an organic solvent, namely ethyl acetate and / or diethyl ether.

6. The method for preparing 2-fluoro-1,2-diphenyl ethyl ketone compounds by palladium catalysis according to claim 1, characterized in that, The washing in step (1) is performed using saturated brine; the drying is performed using anhydrous sodium sulfate and / or anhydrous magnesium sulfate.

7. The method for preparing 2-fluoro-1,2-diphenyl ethyl ketone compounds by palladium catalysis according to claim 1, characterized in that, In the column chromatography process described in step (2), petroleum ether and ethyl acetate with a volume ratio of (50-100):1 are used as eluents.

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