A fluorine-containing dihydronaphthone derivative, a preparation method and application thereof

Abstract

The present application relates to a kind of fluorine-containing dihydronaphthalenone derivative and its preparation method and application, the fluorine-containing dihydronaphthalenone derivative obtained by visible light induced phosphine catalysis difluoroacetophenone derivative and the radical addition cyclization reaction of a variety of olefins in series compared with prior art, the preparation method of the present application has the advantages of high efficiency, short reaction time, high yield, mild condition etc., its structural motif is important in pharmaceutical and agrochemical products;The synthetic method for preparing fluorine-containing dihydronaphthalenone and its derivative of the present application is completely new, and the fluorine-containing dihydronaphthalenone compound synthesized is used in various organic synthesis reactions.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a fluorinated dihydronaphthone derivative, its preparation method, and its application. Background Technology

[0002] Naphthone derivatives have wide applications in synthetic chemistry, medicinal chemistry, and agrochemicals, and have a long research history. For example, 6-methoxy-α-naphthone is an important intermediate in the production of the steroidal oral contraceptive dl-18-methylethynone and trienolone. 5-methoxynaphthone is the main raw material for the synthesis of the glaucoma treatment drug levobunolol; 2-methoxy-6-propionylnaphthalene is a key intermediate in the synthesis of the nonsteroidal anti-inflammatory analgesic drug naproxen (S)-(+)-2-(6-methoxy-2-naphthyl)propionic acid; 6-methoxy-2-naphthylethylone is an important intermediate in the synthesis of the nonsteroidal anti-inflammatory analgesic naproxen; nabumetone is a popular nonsteroidal anti-inflammatory drug because its anti-inflammatory and analgesic effects are significantly better than naproxen, and it has a longer duration of action, fewer side effects, and a simpler synthesis method than naproxen and ibuprofen, without the need for complex enantiomeric separation.

[0003] Furthermore, naphthone compounds are important organic chemical raw materials, used to synthesize many other important chemical products such as naphthyl ethers, anthraquinones, halogenated phenols, and nitrophenols, especially fused-ring aromatic compounds and steroidal compounds, which are important intermediates in pharmaceuticals, pesticides, and dyes. However, methods involving the direct synthesis of bio-related ring scaffolds containing difluoroacyl groups are rare and still in great need.

[0004] In recent years, tandem radical fluoroalkylation and cyclization with different fluorinating agents has become an effective route for preparing fluorinated heterocyclic compounds. With the continuous development of fluorinated organic chemical synthesis methodologies, chemists have effectively introduced fluorine atoms or fluorine-containing groups into organic compound molecules, developing various fluorine-related reactions that significantly enhance the physical, chemical, and physiological properties of organic compounds or drugs compared to their parent molecules. Therefore, exploring and developing economical and highly reactive dihydronaphthone ethyl ketone derivatives and establishing effective synthetic methodologies using dihydronaphthone derivatives is crucial.

[0005] In 1995, M. Médebielle et al. reported the synthesis of difluoroacyl heterocyclic compounds via electrochemical radical cyclization using N-heteroarylchlorodifluoromethyl ketone as a fluorinating agent. The formula is shown below:

[0006]

[0007] In 2015, Chem. Commun et al. reported a cyclization reaction using 2-bromo-2,2-difluoroaryl ketones and olefins as starting materials under visible light as a catalyst. The equation is shown below:

[0008]

[0009] In 2022, Zhen Liu et al. reported in their article "A concise method for cyclic gem-difluoroacylscaffolds via visible-light-mediated redox-neutral cascade radical cyclization of alkenes" the preparation of cyclic gem-difluoroacylscaffolds using visible-light-mediated redox-neutral cascade radical cyclization of alkenes. The formula is shown below:

[0010]

[0011] α,α-Difluoroketones have long been a focus of attention in synthetic chemistry and drug development projects due to their high electrophilicity. However, methods involving the direct synthesis of bio-related ring scaffolds containing difluoroacyl groups are scarce and remain in great need. In recent years, tandem radical fluoroalkylation cyclization with different fluorinating agents has become an effective route for the preparation of fluorinated heterocyclic compounds. Therefore, there is a need to develop more fluorinated building blocks to participate in radical cyclization reactions to construct different fluorinated ring molecules. Summary of the Invention

[0012] The purpose of this invention is to address the problems existing in the prior art by providing a fluorinated dihydronaphthone derivative, its preparation method, and its applications. This application describes a visible light-induced phosphine ligand-catalyzed free radical addition cyclization reaction of a difluoroacetophenone derivative and various alkenes to obtain the fluorinated dihydronaphthone derivative. In this application, bis(diphenylphosphine)methane is used as the ligand, and sodium carbonate is used as the inorganic base. Then, a 2-bromo-2,2-difluoroacetophenone derivative and various alkenes, including active and inactive alkenes, are dissolved in tetrahydrofuran (THF) and added to a reaction tube. The reaction is stirred at 0-90°C under 18W blue light and nitrogen protection until complete. The resulting reaction solution is extracted and separated to obtain the fluorinated dihydronaphthone derivative. The preparation method of this invention has advantages such as high efficiency, short reaction time, high yield, and mild conditions. Its structural motif is important in pharmaceutical and agrochemical products. The synthetic method for preparing the fluorinated dihydronaphthone derivative is novel, and the synthesized fluorinated dihydronaphthone compound can be used in various organic synthesis reactions.

[0013] The objective of this invention can be achieved through the following technical solutions:

[0014] The first objective of this invention is to provide a method for preparing a fluorinated dihydronaphthone derivative, the specific steps of which are as follows:

[0015] S1. Mix the phosphine ligand with an inorganic base to obtain the first mixture;

[0016] S2. Dissolve the 2-bromo-2,2-difluoroacetophenone derivative of the structure shown in formula (II) and the olefin of the structure shown in formula (III) in a solvent to obtain a second mixture;

[0017] S3. Add the second mixture obtained in step S2 to the first mixture obtained in step S1 to react and obtain a reaction solution;

[0018] S4. The reaction solution obtained in step S3 is post-treated to obtain a fluorinated dihydronaphthone derivative with the structure shown in formula (I).

[0019] The structural formulas (I) to (III) are shown below:

[0020]

[0021] R1 and R2 are selected from any one of phenyl, substituted aryl, alkyl, or heterocyclic compounds.

[0022] R f This refers to monofluorine or difluorine structures bonded to carbon atoms.

[0023] In one embodiment of the present invention, the molar ratio of 2-bromo-2,2-difluoroacetophenone derivative: olefin: phosphine ligand: inorganic base is (1.0-2.0): (0.5-1.0): (0.1-0.15): (1.5-2.5).

[0024] In one embodiment of the present invention, in step S1, the phosphine ligand is selected from any one or more of bis(diphenylphosphinemethane) (dppm), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene), 1,1-binaphthyl-2,2-bis(diphenylphosphine), 1,3-bis(diphenylphosphine)propane, 1,2-bis(diphenylphosphino)benzene, triphenylphosphine, 1,1-bis(diphenylphosphine)ferrocene, or bis(diphenylphosphine)binaphthyl, and the phosphine ligand participates in the reaction as a ligand.

[0025] As a preferred technical solution, the phosphine ligand is bis(diphenylphosphinemethane) (dppm) with the structure shown in formula (Ⅳ), and the general structural formula (Ⅳ) is as follows:

[0026]

[0027] In one embodiment of the present invention, in step S1, the inorganic base is selected from any one or more of K2CO3, Cs2CO3, Na2CO3, KOH, NaOH, t-BuOK, Et3N, TMEDA or KOAC, and the inorganic base is used to initiate the reaction.

[0028] In one embodiment of the present invention, in step S2, the olefin includes active olefin and inactive olefin.

[0029] In one embodiment of the present invention, in step S2, the solvent is selected from any one or more of ethylene glycol dimethyl ether, tetrahydrofuran (THF), dichloromethane (DCE), methanol, 1,4-dioxane, dimethyl sulfoxide, diethyl ether, cyclopentyl methyl ether, or acetonitrile.

[0030] In one embodiment of the present invention, in step S3, the reaction temperature is 0-90°C and the reaction time is 0.5-12h.

[0031] As a preferred technical solution, the reaction temperature is room temperature.

[0032] In one embodiment of the present invention, in step S3, the reaction solution is reacted under nitrogen protection conditions.

[0033] In one embodiment of the present invention, in step S3, the reaction solution needs to be illuminated by a blue LED to initiate the reaction, and the blue LED is selected from any one or more of 10W, 18W, 20W, 40W, 50W, 70W, 80W or 100W.

[0034] In one embodiment of the present invention, in step S4, the post-processing is extraction followed by separation and purification.

[0035] In one embodiment of the present invention, the extraction process is carried out using an extraction solution, and the extraction is performed 2-3 times.

[0036] In one embodiment of the present invention, the extract is pure dichloromethane, and the volume ratio of the extract to the reaction solution is 1:(1-1.5).

[0037] In one embodiment of the present invention, during the separation and purification process, an eluent is used to separate and purify the material in a chromatography column, and the elution time is 1-2 hours.

[0038] In one embodiment of the present invention, the eluent is petroleum ether.

[0039] As a preferred technical solution, the inorganic base is Na2CO3, the solvent is tetrahydrofuran (THF), the blue LED is 18W blue light, and the reaction formula for the preparation method of the fluorinated dihydronaphthone derivative is shown below:

[0040]

[0041] A second objective of this invention is to provide a fluorinated dihydronaphthone derivative, which is prepared by the above-described preparation method and has the chemical structure shown in general formula (I):

[0042]

[0043] in,

[0044] R1 and R2 are each selected from phenyl, substituted aryl, alkyl, or heterocyclic compounds.

[0045] R f This refers to monofluorine or difluorine structures bonded to carbon atoms.

[0046] In one embodiment of the present invention, the substituent in the substituted aryl group is selected from any one or more of phenyl, fluorine, bromine, chlorine, C1-C4 alkyl, nitro, methoxy or trifluoromethyl.

[0047] In one embodiment of the present invention, the heterocycle is selected from any one or more of thiophene, furan, indole, pyrrole, thiophene homologues, furan homologues, indole homologues, or pyrrole homologues.

[0048] In one embodiment of the present invention, the fluorinated dihydronaphthone derivative is selected from any one or more compounds represented by the following structural formulas:

[0049]

[0050]

[0051] A third objective of this invention is to provide an application of a fluorinated dihydronaphthone derivative as a compound in organic synthesis reactions.

[0052] The fourth objective of this invention is to provide an application of a fluorinated dihydronaphthone derivative in medicinal chemistry.

[0053] The fifth objective of this invention is to provide an application of a fluorinated dihydronaphthone derivative in agrochemicals.

[0054] Compared with the prior art, the present invention has the following beneficial effects:

[0055] 1. The preparation method of fluorinated dihydronaphthylone derivatives provided by this invention uses a metal-free photocatalyst, while the prior art uses tri(2-phenylpyridine)iridium as a catalyst. The metal-free photocatalyst provided by this invention is cheaper and more readily available than tri(2-phenylpyridine)iridium, with a price difference of hundreds of times. At the same time, it has higher catalytic activity. Compared with the yield of about 40% of metal photocatalysts, this invention has a higher yield. In addition, the metal-free photocatalyst has stronger oxidation properties and better stability than catalysts such as tri(2-phenylpyridine)iridium and [Ir(dFppy)2(dtbbpy)]PF6.

[0056] 2. The preparation method of the present invention uses safe and highly regioselective bis(diphenylphosphine)methane as a ligand, which has the advantages of high efficiency, short reaction time, high yield and mild conditions, and has good prospects for industrial production.

[0057] 3. The structural motifs of fluorinated dihydronaphthone derivatives are important in pharmaceutical and agrochemical products, and have wide applications in fields such as medicinal chemistry and agrochemicals. Synthesized fluorinated dihydronaphthone compounds are used in various organic synthesis reactions.

[0058] 4. Fluorine-containing dihydronaphthone derivatives were obtained by visible light-induced free radical addition cyclization reactions of 2-bromo-2,2-difluoroacetophenone derivatives and various alkenes in series.

[0059] 5. In the prior art, fluorinated dihydronaphthone derivatives are prepared by using metal catalysts such as copper and tri(2-phenylpyridine)iridium or by electrochemical methods. However, there is no information on the use of phosphine ligands in the preparation of fluorinated dihydronaphthone derivatives. Therefore, the preparation method of fluorinated dihydronaphthone derivatives provided by this invention is novel and provides a new direction for the synthesis of fluorinated dihydronaphthone derivatives. Detailed Implementation

[0060] The present invention will now be described in detail with reference to specific embodiments. These embodiments are based on the technical solution of the present invention and provide detailed implementation methods and specific operating procedures. However, the scope of protection of the present invention is not limited to the following embodiments.

[0061] Unless otherwise specified, all reagents used in the following embodiments are commercially available reagents; and all detection methods and techniques used are conventional detection methods and techniques in the art.

[0062] Example 1

[0063] This embodiment provides (3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetic acid methyl ester and its preparation method.

[0064] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2,2-difluoroacetophenone (282.03 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 144.91 mg, yield 95%) was obtained, namely methyl (3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate.

[0065] The chemical structural formula of methyl (3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment is shown below:

[0066]

[0067] The NMR data of (3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetic acid methyl ester prepared in this embodiment are as follows:

[0068] 1 H NMR (400MHz, CDCl3): δ8.13(d,J=8.0Hz,1H),7.67(t,J=8.0Hz,1H),7.51-7.43 (m,2H),4.52-4.35(m,2H),3.67-3.56(m,1H),2.79-2.55(m,2H),2.09(s,3H).

[0069] 13C NMR (100MHz, CDCl3): δ184.84 (t, J = 26.0Hz), 170.78, 142.00, 135.45, 130.14, 129.11, 128.36, 12 8.16, 113.26 (t, J = 246.0Hz), 66.08 (d, J = 2.0Hz), 35.49 (t, J = 5.0Hz), 34.52 (t, J = 22.0Hz), 20.82. 19 F NMR (376MHz, CDCl3): δ-104.4~-108.1 (m, 2F).

[0070] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 13 H 12 F2O3+H,255.0893; found,255.0897.

[0071] Example 2

[0072] This embodiment provides 4-benzyl-2,2-difluoro-3,4-dihydronaphth-1(2H)-one and its preparation method.

[0073] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2,2-difluoroacetophenone (282.03 mg, 1.2 mmol, 2.0 equiv) and allylbenzene (70.83 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 156.84 mg, yield 96%) was obtained, namely 4-benzyl-2,2-difluoro-3,4-dihydronaphthyl-1(2H)-one.

[0074] The chemical structural formula of the 4-benzyl-2,2-difluoro-3,4-dihydronaphthyl-1(2H)-one prepared in this embodiment is shown below:

[0075]

[0076] The NMR data of the 4-benzyl-2,2-difluoro-3,4-dihydronaphthyl-1(2H)-one prepared in this embodiment are as follows:

[0077] 1 H NMR (400MHz, CDCl3): δ8.20(d,J=8.0Hz,1H),7.69(t,J=8.0Hz,1H),7.51-7.29(m, 7H),3.60-3.55(m,1H),3.38-3.33(m,1H),2.95(t,J=12Hz,1H),2.54-2.40(m,2H).

[0078] 13 C NMR (100MHz, CDCl3): δ185.43 (t, J = 25.0Hz), 146.16, 138.65, 135.35, 129.62, 129.43, 128.92, 128.87, 128.54, 1 27.87, 126.93, 113.75 (t, J = 246.0Hz), 42.23 (d, J = 3.0Hz), 38.02 (dd, J1 = 6.0Hz, J2 = 3.0Hz), 35.36 (t, J = 22.0Hz).

[0079] 19 F NMR (376MHz, CDCl3): δ-102.4~-106.7 (m, 2F).

[0080] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 17 H 14 F2O+H,273.1086; found,273.1090.

[0081] Example 3

[0082] This embodiment provides 2,2-difluoro-4-(phenoxymethyl)-3,4-dihydronaphth-1(2H)-one and its preparation method.

[0083] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2,2-difluoroacetophenone (282.03 mg, 1.2 mmol, 2.0 equiv) and (allyloxy)benzene (80.51 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 166.06 mg, yield 96%) was obtained, namely 2,2-difluoro-4-(phenoxymethyl)-3,4-dihydronaphthyl-1(2H)-one.

[0084] The chemical structural formula of the 2,2-difluoro-4-(phenoxymethyl)-3,4-dihydronaphthyl-1(2H)-one prepared in this embodiment is shown below:

[0085]

[0086] The NMR data of 2,2-difluoro-4-(phenoxymethyl)-3,4-dihydronaphthyl-1(2H)-one prepared in this embodiment are as follows:

[0087] 1 H NMR (400MHz, CDCl3): δ8.20(d,J=4.0Hz,1H),7.69(t,J=8.0Hz,1H),7.50-7.29(m, 7H),3.60-3.55(m,1H),3.38-3.33(m,1H),2.95(t,J=12Hz,1H),2.54-2.40(m,2H).

[0088] 13C NMR (100MHz, CDCl3): δ185.43 (t, J = 25.0Hz), 146.16, 138.65, 135.35, 129.62, 129.43, 128.92, 128.87, 128.54, 127.87, 126 .93, 113.75 (t, J = 246.0Hz), 77.29 (t, J = 32.0Hz), 42.22 (d, J = 2.0Hz), 38.02 (dd, J1 = 6.0Hz, J2 = 3.0Hz), 34.36 (t, J = 22.0Hz).

[0089] 19 F NMR (376MHz, CDCl3): δ-102.4~-106.7 (m, 2F).

[0090] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 17 H 14 F2O2+H,289.1035; found,289.1039.

[0091] Example 4

[0092] This embodiment provides methyl (3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)heptanoate and its preparation method.

[0093] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2,2-difluoroacetophenone (282.03 mg, 1.2 mmol, 2.0 equiv) and allyl heptaate (102.15 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 186.84 mg, yield 96%) was obtained, namely methyl (3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)heptanoate.

[0094] The chemical structural formula of methyl (3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)heptanoate prepared in this embodiment is shown below:

[0095]

[0096] The NMR data of methyl (3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)heptanoate prepared in this embodiment are as follows:

[0097] 1 H NMR (400MHz, CDCl3): δ8.10(d,J=8.0Hz,1H),7.72(t,J=8.0Hz,1H),7.48-7.40(m,2H),4.48-4.31(m,2H),3.65 -3.53(m,1H),2.32(t,J=7.0Hz,2H),2.19-1.94(m,2H),1.66(t,J=19.0Hz,2H),1.33-1.30(m,4H),0.88(s,3H).

[0098] 13C NMR (100MHz, CDCl3): δ 185.46 (t, J = 25.0Hz), 173.58, 141.69 (t, J = 23.0Hz), 133.39, 133.01 (t, J = 3.0Hz), 129.52 (t, J = 2.0Hz), 129.09, 1 28.25,115.59,113.45,111.31,68.24(t,J=2.0Hz),37.40(t,J=8.0Hz),36.57(t,J=22.0Hz),34.44,31.55,28.57,25.80,22.69,14.07.

[0099] 19 F NMR (376MHz, CDCl3): δ-103.6~-107.2 (m, 2F).

[0100] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 18 H 22 F2O3+H,325.1610; found,325.1615.

[0101] Example 5

[0102] This embodiment provides methyl (3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)3-oxobutyrate and its preparation method.

[0103] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2,2-difluoroacetophenone (282.03 mg, 1.2 mmol, 2.0 equiv) and allyl 3-oxobutyrate (85.29 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 172.43 mg, yield 97%) was obtained, namely methyl (3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)3-oxobutyrate.

[0104] The chemical structural formula of methyl (3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)3-oxobutyrate prepared in this embodiment is shown below:

[0105]

[0106] The NMR data of methyl (3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)3-oxobutyrate prepared in this embodiment are as follows:

[0107] 1 H NMR (400MHz, CDCl3): δ7.86(d,J=8.0Hz,1H),7.68(t,J=8.0Hz,1H),7.42-7.35(m,2H),4.44(d,J =4.0Hz,2H),3.54(s,2H),3.45-3.40(m,1H),2.88-2.76(m,1H),2.60-2.48(m,1H),2.27(s,3H).

[0108] 13C NMR (100MHz, CDCl3): δ201.69, 185.46 (t, J = 25.0Hz), 168.44, 141.64 (t, J = 13.0Hz), 133.39, 133.01 (t, J = 3.0Hz), 129.52 (t, J =2.0Hz), 129.09, 128.25, 115.59, 113.45, 111.31, 68.06 (t, J = 2.0Hz), 49.89, 37.32 (t, J = 8.0Hz), 36.57 (t, J = 21.0Hz), 29.50.

[0109] 19 F NMR (376MHz, CDCl3): δ-106.3~-110.2 (m, 2F).

[0110] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 15 H 14 F2O4+H,297.0933; found,297.0937.

[0111] Example 6

[0112] This embodiment provides 2,2-difluoro-4-(4-methoxybenzyl)-3,4-dihydronaphthyl-1(2H)-one and its preparation method.

[0113] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2,2-difluoroacetophenone (282.03 mg, 1.2 mmol, 2.0 equiv) and 1-allyl-4-methoxybenzene (88.93 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 175.95 mg, yield 97%) was obtained, namely 2,2-difluoro-4-(4-methoxybenzyl)-3,4-dihydronaphthyl-1(2H)-one.

[0114] The chemical structural formula of the 2,2-difluoro-4-(4-methoxybenzyl)-3,4-dihydronaphthyl-1(2H)-one prepared in this embodiment is shown below:

[0115]

[0116] The NMR data of 2,2-difluoro-4-(4-methoxybenzyl)-3,4-dihydronaphthyl-1(2H)-one prepared in this embodiment are as follows:

[0117] 1 H NMR (400MHz, CDCl3): δ7.89(d,J=8.0Hz,1H),7.42-7.35(m,3H),7.14-7.11(m,2H),6.82(t,J=4.0Hz,1H),6.80(t,J=4 .0Hz,1H),3.78(s,3H),3.36-3.31(m,1H),3.16-3.11(m,1H),3.07-3.02(m,1H),2.86-2.73(m,1H),2.61-2.49(m,1H).

[0118] 13C NMR (100MHz, CDCl3): δ185.35(t,J=26.0Hz),158.62,143.29(t,J=13.0Hz),133.48(t,J=2.0Hz),132.87,130.40,129.57(t,J= 2.0Hz), 129.07, 128.27, 115.71, 113.86, 113.56, 111.42, 55.32, 40.08 (t, J = 2.0Hz), 38.63 (t, J = 22.0Hz), 36.19 (t, J = 8.0Hz).

[0119] 19 F NMR (376MHz, CDCl3): δ-101.8~-105.4 (m, 2F).

[0120] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 18 H 16 F2O2+H,303.1191; found,303.1195.

[0121] Example 7

[0122] This embodiment provides 4-(4-(tert-butoxy)benzyl)-2,2-difluoro-3,4-dihydronaphthyl-1(2H)-one and its preparation method.

[0123] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2,2-difluoroacetophenone (282.03 mg, 1.2 mmol, 2.0 equiv) and 1-allyl-4-(tert-butoxy)benzene (114.17 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 200.44 mg, yield 97%) was obtained, namely 4-(4-(tert-butoxy)benzyl)-2,2-difluoro-3,4-dihydronaphthyl-1(2H)-one.

[0124] The chemical structural formula of the 4-(4-(tert-butoxy)benzyl)-2,2-difluoro-3,4-dihydronaphthyl-1(2H)-one prepared in this embodiment is shown below:

[0125]

[0126] The NMR data of the 4-(4-(tert-butoxy)benzyl)-2,2-difluoro-3,4-dihydronaphthyl-1(2H)-one prepared in this example are as follows:

[0127] 1 H NMR (400MHz, CDCl3): δ7.89 (d, J = 8.0Hz, 1H), 7.42-7.36 (m, 3H), 7.16-7.14 (m, 2H), 6.83-6.80 (m, 2H), 3. 36-3.31(m,1H),3.16-3.11(m,1H),3.07-3.03(m,1H),2.83-2.73(m,1H),2.61-2.49(m,1H),1.30(s,9H).

[0128] 13C NMR (100MHz, CDCl3): δ185.35 (t, J = 26.0Hz), 154.21, 143.29 (t, J = 13.0Hz), 133.48 (t, J = 2.0Hz), 133.29, 130.17, 129.58 (t, J = 2.0Hz) ,129.07,128.27,120.45,115.71,113.56,113.56,111.42,77.46,40.07(t,J=2.0Hz),38.63(t,J=22.0Hz),36.19(t,J=8.0Hz),28.50.

[0129] 19 F NMR (376MHz, CDCl3): δ-99.8~-103.4 (m, 2F).

[0130] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 21 H 22 F2O2+H,345.1661; found,345.1665.

[0131] Example 8

[0132] This embodiment provides 4,4-difluoro-9b-methyl-3a,9b-dihydronaphtho[1,2-b]furan-2,5(3H,4H)-dione and its preparation method.

[0133] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2,2-difluoroacetophenone (282.03 mg, 1.2 mmol, 2.0 equiv) and prop-1-en-2-yl propionate (68.48 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 146.79 mg, yield 97%) was obtained, namely 4,4-difluoro-9b-methyl-3a,9b-dihydronaphtho[1,2-b]furan-2,5(3H,4H)-dione.

[0134] The chemical structural formula of the 4,4-difluoro-9b-methyl-3a,9b-dihydronaphtho[1,2-b]furan-2,5(3H,4H)-dione prepared in this embodiment is shown below:

[0135]

[0136] The NMR data of the 4,4-difluoro-9b-methyl-3a,9b-dihydronaphtho[1,2-b]furan-2,5(3H,4H)-dione prepared in this embodiment are as follows:

[0137] 1 H NMR (400MHz, CDCl3): δ8.00 (d, J = 8.0Hz, 1H), 7.61-7.58 (m, 1H), 7.54-7.52 (m, 1H), 7. 30-7.27(m,1H),3.63-3.50(m,1H),2.85-2.81(m,1H),2.48-2.44(m,1H),1.76(s,3H),

[0138] 13C NMR (100MHz, CDCl3): δ 188.01 (t, J = 26.0Hz), 176.81 (t, J = 24.0Hz), 141.93 (t, J = 13.0Hz), 132.03 (t, J = 4.0Hz), 131.05, 128.37, 128 .36(t,J=2.0Hz),125.01,116.77,114.63,112.48,89.50(t,J=8.0Hz),45.68(t,J=22.0Hz),33.67(t,J=8.0Hz),24.44(t,J=2.0Hz).

[0139] 19 F NMR (376MHz, CDCl3): δ-106.7~-111.1(m,2F).

[0140] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 13 H 10 F2O3+H,253.0671; found,253.0675.

[0141] Example 9

[0142] This embodiment provides 2,2-difluoro-4-(pyridin-4-ylmethyl)-3,4-dihydronaphth-1(2H)-one and its preparation method.

[0143] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2,2-difluoroacetophenone (282.03 mg, 1.2 mmol, 2.0 equiv) and 4-allylpyridine (71.50 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 159.05 mg, yield 97%) was obtained, namely 2,2-difluoro-4-(pyridin-4-ylmethyl)-3,4-dihydronaphth-1(2H)-one.

[0144] The chemical structural formula of the 2,2-difluoro-4-(pyridin-4-ylmethyl)-3,4-dihydronaphthyl-1(2H)-one prepared in this embodiment is shown below:

[0145]

[0146] The NMR data of 2,2-difluoro-4-(pyridin-4-ylmethyl)-3,4-dihydronaphth-1(2H)-one prepared in this embodiment are as follows:

[0147] 1 H NMR (400MHz, CDCl3): δ8.53(d,J=8.0Hz,2H),7.90-7.88(m,1H),7.42-7.35(m,3H),7.17(d,J=8.0Hz ,1H),3.36-3.31(m,1H),3.20-3.16(m,1H),3.03-2.99(m,1H),2.87-2.74(m,1H),2.62-2.49(m,1H).

[0148] 13C NMR (100MHz, CDCl3): δ185.35(t,J=26.0Hz),149.69,147.41,143.26(t,J=13.0Hz), 133.48(t,J=2.0Hz), 129.58(t,J=2 .0Hz), 1290.07, 128.29, 124.00, 115.71, 113.56, 111.42, 39.81 (t, J = 2.0Hz), 38.63 (t, J = 22.0Hz), 36.19 (t, J = 8.0Hz).

[0149] 19 F NMR (376MHz, CDCl3): δ-104.6~-107.6 (m, 2F).

[0150] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 16 H 13 F2NO+H,274.1038; found,274.1042.

[0151] Example 10

[0152] This embodiment provides 2,2-difluoro-4-(thiophen-2-ylmethyl)-3,4-dihydronaphthyl-1(2H)-one and its preparation method.

[0153] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2,2-difluoroacetophenone (282.03 mg, 1.2 mmol, 2.0 equiv) and 2-allylthiophene (74.52 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 160.31 mg, yield 96%) was obtained, namely 2,2-difluoro-4-(thiophene-2-ylmethyl)-3,4-dihydronaphthyl-1(2H)-one.

[0154] The chemical structural formula of the 2,2-difluoro-4-(thiophen-2-ylmethyl)-3,4-dihydronaphthyl-1(2H)-one prepared in this embodiment is shown below:

[0155]

[0156] The NMR data of 2,2-difluoro-4-(thiophen-2-ylmethyl)-3,4-dihydronaphthyl-1(2H)-one prepared in this embodiment are as follows:

[0157] 1 H NMR (400MHz, CDCl3): δ7.89 (d, J = 8.0Hz, 1H), 7.42-7.35 (m, 3H), 7.22-7.20 (m, 1H), 6.95-6.93 (m, 1 H),6.71-6.69(m,1H),3.45-3.40(m,1H),3.18-3.08(m,2H),2.87-2.75(m,1H),2.61-2.49(m,1H).

[0158] 13C NMR (100MHz, CDCl3): δ 185.35 (t, J = 26.0Hz), 143.11 (t, J = 13.0Hz), 140.74, 133.48 (t, J = 3.0Hz), 129.59 (t, J = 2.0Hz), 129. 07,128.29,127.33,126.98,125.42,115.70,113.56,111.42,38.91(t,J=22.0Hz),37.73(t,J=2.0Hz),36.14(t,J=8.0Hz).

[0159] 19 F NMR (376MHz, CDCl3): δ-105.9~-107.9 (m, 2F).

[0160] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 15 H 12 F2OS+H,279.0650; found,279.0654.

[0161] Example 11

[0162] This embodiment provides methyl (3,3-difluoro-7-methoxy-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate and its preparation method.

[0163] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2,2-difluoro-4-methoxyacetophenone (318.06 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 165.44 mg, yield 97%) was obtained, namely methyl (3,3-difluoro-7-methoxy-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate.

[0164] The chemical structural formula of methyl (3,3-difluoro-7-methoxy-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment is shown below:

[0165]

[0166] The NMR data of (3,3-difluoro-7-methoxy-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetic acid methyl ester prepared in this embodiment are as follows:

[0167] 1 H NMR (400MHz, CDCl3): δ8.13(d,J=8.0Hz,1H),6.98(d,J=8.0Hz,1H),6.89(t,J=4.0Hz,1H) ,4.48-4.37(m,2H),3.92-3.87(m,3H),3.58-3.51(m,1H),2.72-2.58(m,2H),2.11(s,3H).

[0168] 13C NMR (100MHz, CDCl3): δ183.38 (t, J = 15.0Hz), 170.78, 165.26, 144.55, 131.83, 123.44, 114.64, 11 3.24,112.68,77.13(t,J=32.0Hz),66.05(d,J=2.0Hz),55.80,35.67,34.63(t,J=22.0Hz),20.88.

[0169] 19 F NMR (376MHz, CDCl3): δ-104.1~-107.5 (m, 2F).

[0170] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 14 H 14 F₂O₄ + H, 285.0933; found, 285.0937. Example 12

[0171] This embodiment provides methyl (3,3-difluoro-4-oxo-7-(pyridin-4-yl)-1,2,3,4-tetrahydronaphth-1-yl)acetate and its preparation method.

[0172] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2,2-difluoro-1-(4-(pyridin-4-yl)phenyl)ethane-1-one (374.53 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 192.83 mg, yield 97%) was obtained, namely methyl (3,3-difluoro-4-oxo-7-(pyridin-4-yl)-1,2,3,4-tetrahydronaphth-1-yl)acetate.

[0173] The chemical structural formula of methyl (3,3-difluoro-4-oxo-7-(pyridin-4-yl)-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment is shown below:

[0174]

[0175] The NMR data of methyl (3,3-difluoro-4-oxo-7-(pyridin-4-yl)-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment are as follows:

[0176] 1 H NMR (400MHz, CDCl3): δ8.79-8.78(m,2H),8.00(d,J=4.0Hz,1H),7.64-7.59(m,4H),4. 51-4.45(m,2H),3.46-3.41(m,1H),2.88-2.76(m,1H),2.63-2.50(m,1H),2.05(s,3H).

[0177] 13 C NMR (100MHz, CDCl3): δ185.52(t,J=25.0Hz),171.41,149.98,145.22,141.73,141.68,141.60,141.47,131.94(t,J=3.0Hz),130 .29(t,J=2.0Hz),128.71,127.80,121.73,115.96,113.81,111.67,67.23(t,J=2.0Hz),36.76(t,J=8.0Hz),36.52,36.30,20.79.

[0178] 19 F NMR (376MHz, CDCl3): δ-104.9~-107.1 (m, 2F).

[0179] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 18 H 15 F2NO3+H,332.1093; found,332.1097.

[0180] Example 13

[0181] This embodiment provides (7-chloro-3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetic acid methyl ester and its preparation method.

[0182] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-1-(4-chlorophenyl)-2,2-difluoroethane-1-one (323.36 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W BlueLED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 169.74 mg, yield 98%) was obtained, namely methyl (7-chloro-3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate.

[0183] The chemical structural formula of methyl (7-chloro-3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment is shown below:

[0184]

[0185] The NMR data of (7-chloro-3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetic acid methyl ester prepared in this embodiment are as follows:

[0186] 1 H NMR (400MHz, CDCl3): δ7.87(d,J=4.0Hz,1H),7.45-7.39(m,2H),4.47(d,J=4.0 Hz,2H),3.47-3.43(m,1H),2.88-2.75(m,1H),2.63-2.50(m,1H),2.31(s,3H).

[0187] 13C NMR (100MHz, CDCl3): δ184.89(t,J=25.0Hz), 171.41, 139.61(t,J=13.0Hz), 136.31, 131.89(t,J=3.0Hz), 130.19(t ,J=2.0Hz),128.99,128.57,115.94,113.80,111.65,67.23(t,J=2.0Hz),36.74(t,J=8.0Hz),36.52,36.30,20.79.

[0188] 19 F NMR (376MHz, CDCl3): δ-104.1~-107.3 (m, 2F).

[0189] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 13 H 11 ClF2O3+H,289.0438; found,289.0441.

[0190] Example 14

[0191] This embodiment provides methyl (7-bromo-3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate and its preparation method.

[0192] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-1-(4-bromophenyl)-2,2-difluoroethane-1-one (376.70 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W BlueLED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 193.88 mg, yield 97%) was obtained, namely methyl 7-bromo-3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate.

[0193] The chemical structural formula of methyl (7-bromo-3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment is shown below:

[0194]

[0195] The NMR data of (7-bromo-3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetic acid methyl ester prepared in this embodiment are as follows:

[0196] 1 H NMR (400MHz, CDCl3): δ7.82(d,J=8.0Hz,1H),7.56(d,J=4.0Hz,1H),7.52-7.50(m,1H),4 .51-4.45(m,2H),3.41-3.36(m,1H),2.88-2.75(m,1H),2.63-2.50(m,1H),2.24(s,3H).

[0197] 13C NMR (100MHz, CDCl3): δ 184.99 (t, J = 26.0Hz), 171.41, 139.15 (t, J = 13.0Hz), 132.90, 132.56 (t, J = 3.0Hz), 131.38, 130. 53(t,J=2.0Hz),126.00,115.94,113.80,111.65,67.23(t,J=2.0Hz),36.74,36.63,36.52(t,J=3.0Hz),36.30,20.79.

[0198] 19 F NMR (376MHz, CDCl3): δ-103.6~-106.1(m,2F).

[0199] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 13 H 11 BrF2O3+H,332.9932; found,332.9936.

[0200] Example 15

[0201] This embodiment provides (3,3-difluoro-7-iodo-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetic acid methyl ester and its preparation method.

[0202] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2,2-difluoro-1-(4-iodophenyl)ethane-1-one (433.10 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL). Stir the reaction mixture at 25 °C under 18 W BlueLED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 221.24 mg, yield 97%) was obtained, namely methyl (3,3-difluoro-7-iodo-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate.

[0203] The chemical structural formula of methyl (3,3-difluoro-7-iodo-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment is shown below:

[0204]

[0205] The NMR data of (3,3-difluoro-7-iodo-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)methyl acetate prepared in this embodiment are as follows:

[0206] 1 H NMR (400MHz, CDCl3): δ7.75-7.33(m,2H),7.67(d,J=4.0Hz,1H),4.51-4.45( m,2H),3.45-3.40(m,1H),2.88-2.75(m,1H),2.63-2.50(m,1H),2.29(s,3H).

[0207] 13C NMR (100MHz, CDCl3): δ190.90 (t, J = 26.0Hz), 171.42, 138.63 (t, J = 13.0Hz), 137.66, 137.33, 133.65 (t, J = 3.0Hz), 130 .16(t,J=2.0Hz),117.13,114.99,112.85,95.67,67.37(t,J=2.0Hz),42.04(t,J=8.0Hz),30.26(t,J=21.0Hz),20.79.

[0208] 19 F NMR (376MHz, CDCl3): δ-103.9~-106.1(m,2F).

[0209] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 13 H 11 F2IO3+H,380.9794; found,380.9797.

[0210] Example 16

[0211] This embodiment provides methyl (7-ethyl-3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl) acetate and its preparation method.

[0212] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-1-(4-ethylphenyl)-2,2-difluoroethane-1-one (315.70 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 165.99 mg, yield 98%) was obtained, namely methyl (7-ethyl-3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate.

[0213] The chemical structural formula of methyl (7-ethyl-3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment is shown below:

[0214]

[0215] The NMR data of (7-ethyl-3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetic acid methyl ester prepared in this embodiment are as follows:

[0216] 1 H NMR (400MHz, CDCl3): δ7.80 (d, J = 8.0Hz, 1H), 7.32-7.25 (m, 2H), 4.51-4.45 (m, 2H),3.39-3.35(m,1H),2.88-2.76(m,1H),2.67-2.50(m,3H),1.23(t,J=8.0Hz 3H).

[0217] 13C NMR (100MHz, CDCl3): δ185.38(t,J=26.0Hz), 171.41, 146.78, 140.44(t,J=13.0Hz), 130.47(t,J=4.0Hz), 130.18(t,J=2.0Hz) ,128.53,127.50,115.95,113.81,111.66,67.23(t,J=2.0Hz),36.80(t,J=8.0Hz),36.52(t,J=20.0Hz),20.87,20.79,15.63.

[0218] 19 F NMR (376MHz, CDCl3): δ-102.7~-105.4 (m, 2F).

[0219] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 15 H 16 F2O3+H,283.1140; found,283.1144.

[0220] Example 17

[0221] This embodiment provides methyl (3,3-difluoro-4-oxo-7-(trifluoromethyl)-1,2,3,4-tetrahydronaphth-1-yl)acetate and its preparation method.

[0222] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2,2-difluoro-1-(4-(trifluoromethyl)phenyl)ethane-1-one (363.64 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 187.54 mg, yield 97%) was obtained, namely methyl (3,3-difluoro-4-oxo-7-(trifluoromethyl)-1,2,3,4-tetrahydronaphth-1-yl)acetate.

[0223] The chemical structural formula of methyl (3,3-difluoro-4-oxo-7-(trifluoromethyl)-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment is shown below:

[0224]

[0225] The NMR data of methyl (3,3-difluoro-4-oxo-7-(trifluoromethyl)-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment are as follows:

[0226] 1 H NMR (400MHz, CDCl3): δ7.88 (d, J = 4.0Hz, 1H), 7.79-7.77 (m, 1H), 7.69-7.68 (m, 1H), 4. 51-4.45(m,2H),3.41-3.37(m,1H),2.88-2.76(m,1H),2.63-2.50(m,1H),2.20(s,3H).

[0227] 13C NMR (100MHz, CDCl3): δ185.36 (t, J = 26.0Hz), 171.41, 141.86, 141.85, 141.83, 141.8 2,141.72,141.59,135.53(d,J=24.0Hz),133.95(t,J=4.0Hz),130.23(t,J=3.0Hz),1 27.21,126.52(d,J=4.0Hz),125.37(d,J=19.0Hz),125.06,122.92,120.78,115.94, 113.80, 111.65, 67.23 (t, J = 2.0Hz), 36.88 (t, J = 8.0Hz), 36.52 (t, J = 22.0Hz), 20.79.

[0228] 19 F NMR (376MHz, CDCl3): δ-104.7~-107.8 (m, 2F).

[0229] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 14 H 11 F5O3+H,323.0701; found,323.0705.

[0230] Example 18

[0231] This embodiment provides methyl (3,3-difluoro-7-methyl-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate and its preparation method.

[0232] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2,2-difluoro-1-(p-tolyl)ethane-1-one (298.86 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL). Stir the reaction mixture at 25 °C under 18 W BlueLED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 156.13 mg, yield 97%) was obtained, namely methyl (3,3-difluoro-7-methyl-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate.

[0233] The chemical structural formula of methyl (3,3-difluoro-7-methyl-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment is shown below:

[0234]

[0235] The NMR data of (3,3-difluoro-7-methyl-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)methyl acetate prepared in this embodiment are as follows:

[0236] 1 H NMR (400MHz, CDCl3): δ7.76 (d, J = 8.0Hz, 1H), 7.22-7.19 (m, 2H), 4.51-4.45 ( m,2H),3.37-3.32(m,1H),2.88-2.76(m,1H),2.62-2.50(m,1H),2.31(s,3H).

[0237] 13C NMR (100MHz, CDCl3): δ185.51(t,J=26.0Hz),171.41,130.69(t,J=3.0Hz),129.56(t,J=1.0Hz),128.57,1 15.95, 113.81, 111.66, 67.23 (t, J = 2.0Hz), 36.88 (t, J = 8.0Hz), 36.52 (t, J = 22.0Hz), 21.05 (d, J = 27.0Hz).

[0238] 19 F NMR (376MHz, CDCl3): δ-104.9~-107.4 (m, 2F).

[0239] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 14 H 14 F2O3+H,269.0984; found,269.0988.

[0240] Example 19

[0241] This embodiment provides methyl (3,3-difluoro-5-methyl-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate and its preparation method.

[0242] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2,2-difluoro-1-(o-tolyl)ethane-1-one (298.86 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL). Stir the reaction mixture at 25 °C under 18 W BlueLED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 156.13 mg, yield 97%) was obtained, namely methyl (3,3-difluoro-5-methyl-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate.

[0243] The chemical structural formula of methyl (3,3-difluoro-5-methyl-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment is shown below:

[0244]

[0245] The NMR data of (3,3-difluoro-5-methyl-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)methyl acetate prepared in this embodiment are as follows:

[0246] 1 H NMR (400MHz, CDCl3): δ7.30-7.22(m,3H),4.51-4.45(m,2H),3.37-3.32(m,1H),2.88-2.76(m,1H),2.62-2.50(m,1H),2.44(s,3H).

[0247] 13 C NMR (100MHz, CDCl3): δ 190.44 (t, J = 25.0Hz), 171.41, 138.45 (t, J = 2.0Hz), 136.35 (t, J = 13.0Hz), 131.72, 130.41 (t, J = 3. 0Hz), 127.22, 115.10, 112.96, 110.82, 67.23 (t, J = 2.0Hz), 36.52 (t, J = 22.0Hz), 36.32 (t, J = 8.0Hz), 20.51 (d, J = 28.0Hz).

[0248] 19 F NMR (376MHz, CDCl3): δ-104.3~-107.7 (m, 2F).

[0249] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 14 H 14 F2O3+H,269.0984; found,269.0988.

[0250] Example 20

[0251] This embodiment provides methyl (3,3-difluoro-6-methyl-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate and its preparation method.

[0252] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2,2-difluoro-1-(m-tolyl)ethane-1-one (298.86 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL). Stir the reaction mixture at 25 °C under 18 W BlueLED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 156.13 mg, yield 97%) was obtained, namely methyl (3,3-difluoro-6-methyl-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate.

[0253] The chemical structural formula of methyl (3,3-difluoro-6-methyl-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment is shown below:

[0254]

[0255] The NMR data of (3,3-difluoro-6-methyl-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetic acid methyl ester prepared in this embodiment are as follows:

[0256] 1 H NMR (400MHz, CDCl3): δ7.68 (d, J = 8.0Hz, 1H), 7.33-7.31 (m, 1H), 7.19-7.16 (m, 1H), 4.45 (d,J=8.0Hz,2H),3.48-3.44(m,1H),2.88-2.76(m,1H),2.60-2.48(m,1H),2.37(s,3H).

[0257] 13C NMR (100MHz, CDCl3): δ 185.63 (t, J = 26.0Hz), 171.41, 140.11 (t, J = 12.0Hz), 139.15, 133.63, 131.35 (t, J = 3.0Hz), 129. 10(t,J=2.0Hz),128.13,115.45,113.31,111.17,67.27(t,J=2.0Hz),37.10(t,J=8.0Hz),36.57(t,J=22.0Hz),20.79.

[0258] 19 F NMR (376MHz, CDCl3): δ-103.9~-106.4 (m, 2F).

[0259] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 14 H 14 F2O3+H,269.0984; found,269.0988.

[0260] Example 21

[0261] This embodiment provides methyl (7-(tert-butoxy)-3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate and its preparation method.

[0262] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-1-(4-(tert-butoxy)phenyl)-2,2-difluoroethane-1-one (368.56 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 189.93 mg, yield 97%) was obtained, namely methyl 7-(tert-butoxy)-3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate.

[0263] The chemical structural formula of methyl 7-(tert-butoxy)-3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment is shown below:

[0264]

[0265] The NMR data of methyl (7-(tert-butoxy)-3,3-difluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment are as follows:

[0266] 1 H NMR (400MHz, CDCl3): δ7.84 (d, J=4.0Hz, 1H), 6.98-6.96 (m, 1H), 6.80-6.77 (m, 1H), 4.48 (d, J= 4.0Hz,1H),3.42-3.37(m,1H),2.87-2.75(m,1H),2.61-2.48(m,1H),2.01(s,3H),1.30(s,9H).

[0267] 13C NMR (100MHz, CDCl3): δ185.34(t,J=25.0Hz), 171.41, 160.66, 142.71(t,J=13Hz), 130.45(t,J=1.0Hz), 128.47(t,J=3.0Hz), 119.4 4,117.85,115.95,113.81,111.67,76.84,67.23(t,J=2.0Hz),36.88(t,J=8.0Hz),36.81(t,J=8.0Hz),36.52,36.30,28.49,20.79.

[0268] 19 F NMR (376MHz, CDCl3): δ-104.6~-107.5 (m, 2F).

[0269] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 17 H 20 F2O4+H,327.1402; found,327.1406.

[0270] Example 22

[0271] This embodiment provides methyl (3,3-difluoro-4-oxo-7-phenyl-1,2,3,4-tetrahydronaphth-1-yl)acetate and its preparation method.

[0272] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 1-([1,1'-biphenyl]-4-yl)-2-bromo-2,2-difluoroethane-1-one (373.36 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 192.25 mg, yield 97%) was obtained, namely methyl (3,3-difluoro-4-oxo-7-phenyl-1,2,3,4-tetrahydronaphth-1-yl)acetate.

[0273] The chemical structural formula of methyl (3,3-difluoro-4-oxo-7-phenyl-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment is shown below:

[0274]

[0275] The NMR data of methyl (3,3-difluoro-4-oxo-7-phenyl-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment are as follows:

[0276] 1 H NMR (400MHz, CDCl3): δ7.98 (d, J = 4.0Hz, 1H), 7.62-7.57 (m, 4H), 7.46-7.42 (m, 2H), 7.40-7.36 ( m,1H),4.51-4.45(m,2H),3.46-3.41(m,1H),2.88-2.76(m,1H),2.63-2.50(m,1H),2.01(s,3H).

[0277] 13C NMR (100MHz, CDCl3): δ185.52(t,J=25.0Hz),171.41,143.12,160.66,141.44(t,J=13Hz),140.55,131.94(t,J=3.0Hz),130.29(t,J=2.0Hz ),129.06,128.15,127.92,127.20,127.04,115.96,113.81,111.67,67.23(t,J=2.0Hz),36.76(t,J=12.0Hz),36.52(t,J=16.0Hz),20.79.

[0278] 19 F NMR (376MHz, CDCl3): δ-103.6~-106.7 (m, 2F).

[0279] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 19 H 16 F2O3+H,331.1140; found,331.1145.

[0280] Example 23

[0281] This embodiment provides (3,3-difluoro-4-oxo-1,2,3,4-tetrahydroanthracene-1-yl) methyl acetate and its preparation method.

[0282] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2,2-difluoro-1-(naphth-2-yl)ethane-1-one (342.11 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL). Stir the reaction mixture at 25 °C under 18 W BlueLED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 177.10 mg, yield 97%) was obtained, namely methyl (3,3-difluoro-4-oxo-1,2,3,4-tetrahydroanthracene-1-yl)acetate.

[0283] The chemical structural formula of (3,3-difluoro-4-oxo-1,2,3,4-tetrahydroanthracene-1-yl)acetic acid methyl ester prepared in this embodiment is shown below:

[0284]

[0285] The NMR data of (3,3-difluoro-4-oxo-1,2,3,4-tetrahydroanthracene-1-yl)methyl acetate prepared in this embodiment are as follows:

[0286] This embodiment provides (8,8-difluoro-9-oxo-7,8,9,11-tetrahydro) 1 H NMR (400MHz, CDCl3): δ8.35(d,J=4.0Hz,1H),7.99(t,J=4.0Hz,1H),7.90-7.88(m,2H),7.55-7.52(m,1H),7 .48-7.45(m,1H),4.51-4.45(m,2H),3.46-3.41(m,1H),2.88-2.76(m,1H),2.63-2.50(m,1H),2.01(s,3H).

[0287] 13C NMR (100MHz, CDCl3): δ 185.52 (t, J = 25.0Hz), 171.41, 138.72 (t, J = 13.0Hz), 136.33, 135.50, 129.61 (t, J = 3.0Hz), 129.05 (t, J = 2.0Hz) ,128.83,128.32,126.90,126.34,125.90,115.77,113.62,111.48,67.23(t,J=2.0Hz),36.72(t,J=5.0Hz),36.52(t,J=4.0Hz),20.79.

[0288] 19 F NMR (376MHz, CDCl3): δ-103.2~-106.1 (m, 2F).

[0289] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 17 H 14 F2O3+H,305.0984; found,305.0988.

[0290] Example 24

[0291] 6H-benzo[b]fluorene-6-yl)methyl acetate and its preparation method.

[0292] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-1-(9H-fluoren-2-yl)-2,2-difluoroethane-1-one (387.77 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 199.24 mg, yield 97%) was obtained, namely methyl (8,8-difluoro-9-oxo-7,8,9,11-tetrahydro-6H-benzo[b]fluorene-6-yl)acetate.

[0293] The chemical structural formula of methyl (8,8-difluoro-9-oxo-7,8,9,11-tetrahydro-6H-benzo[b]fluorene-6-yl)acetate prepared in this embodiment is shown below.

[0294]

[0295] The NMR data of (8,8-difluoro-9-oxo-7,8,9,11-tetrahydro-6H-benzo[b]fluorene-6-yl)methyl acetate prepared in this embodiment are as follows:

[0296] 1 H NMR (400MHz, CDCl3): δ8.07(s,1H),7.74(d,J=8.0Hz,1H),7.68(s,1H),7.63(d,J=4.0Hz,1H),7.36-7.28(m,2H ),4.51-4.45(m,2H),4.01-3.94(m,2H),3.50-3.45(m,1H),2.88-2.76(m,1H),2.63-2.50(m,1H),2.01(s,3H).

[0297] 13C NMR (100MHz, CDCl3): δ 185.90 (t, J = 26.0Hz), 171.41, 144.65, 143.66 (d, J = 1.0Hz), 140.59, 139.72 (t, J = 12.0Hz), 129.59 (t, J = 3.0Hz), 126.90 (d ,J=1.0Hz),125.94(t,J=1.0Hz),125.24,121.27,119.19,115.84,113.6 9,111.55,67.23(t,J=2.0Hz),36.74(t,J=8.0Hz),36.52,36.30,20.79.

[0298] 19 F NMR (376MHz, CDCl3): δ-102.2~-105.3 (m, 2F).

[0299] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 20 H 16 F2O3+H,343.1140; found,343.1144.

[0300] Example 25

[0301] This embodiment provides methyl (3,3-difluoro-4-oxo-7-(thiophen-2-yl)-1,2,3,4-tetrahydronaphth-1-yl)acetate and its preparation method.

[0302] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2,2-difluoro-1-(4-(thiophen-2-yl)phenyl)ethane-1-one (380.58 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 195.76 mg, yield 97%) was obtained, namely methyl (3,3-difluoro-4-oxo-7-(thiophen-2-yl)-1,2,3,4-tetrahydronaphth-1-yl)acetate.

[0303] The chemical structural formula of methyl (3,3-difluoro-4-oxo-7-(thiophen-2-yl)-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment is shown below:

[0304]

[0305] The NMR data of methyl (3,3-difluoro-4-oxo-7-(thiophen-2-yl)-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment are as follows:

[0306] 1 H NMR (400MHz, CDCl3): δ7.91(d,J=4.0Hz,1H),7.76-7.74(m,1H),7.64-7.63(m,1H),7.60-7.58(m,1H),7.55-7.54( m,1H),7.18-7.16(m,1H),4.51-4.45(m,2H),3.46-3.41(m,1H),2.88-2.76(m,1H),2.63-2.50(m,1H),2.01(s,3H).

[0307] 13C NMR (100MHz, CDCl3): δ185.52(t,J=25.0Hz),171.41,141.91,139.95,139.16(t,J=13.0Hz), 133.04(t,J=4.0Hz), 129.89(t,J=2.0Hz) ,128.30,126.53(t,J=1.0Hz),124.19,115.96,113.81,111.67,67.23(t,J=2.0Hz),36.77(t,J=12.0Hz),36.52(t,J=16.0Hz),20.79.

[0308] 19 F NMR (376MHz, CDCl3): δ-103.8~-106.1 (m, 2F).

[0309] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 17 H 14 F2O3S+H,337.0705; found,337.0709.

[0310] Example 26

[0311] This embodiment provides (3-fluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetic acid methyl ester and its preparation method.

[0312] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2-fluoro-1-phenylethanol-1-one (260.45 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 137.49 mg, yield 97%) was obtained, namely methyl (3-fluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate.

[0313] The chemical structural formula of methyl (3-fluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment is shown below:

[0314]

[0315] The NMR data of (3-fluoro-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)acetic acid methyl ester prepared in this embodiment are as follows:

[0316] 1 H NMR (400MHz, CDCl3): δ7.86-7.82(m,1H),7.39-7.32(m,3H),5.54-5.42(m,1H),4.45 -4.38(m,2H),3.49-3.43(m,1H),3.30-3.20(m,1H),2.12-2.03(m,1H),2.01(s,3H).

[0317] 13C NMR (100MHz, CDCl3): δ192.80 (d, J = 13.0Hz), 171.41, 143.55 (d, J = 6.0Hz), 133.48 (d, J = 2.0Hz), 133.35, 129.23 (d, J=2.0Hz),128.25(d,J=7.0Hz),90.94,88.79,66.94(d,J=1.0Hz),36.29(d,J=4.0Hz),28.86(d,J=10.0Hz),20.79.

[0318] 19 F NMR (376MHz, CDCl3): δ-186.5 (s, 1F).

[0319] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 13 H 13 FO3+H,237.0922; found,237.0926.

[0320] Example 27

[0321] This embodiment provides 4-benzyl-2-fluoro-3,4-dihydronaphth-1(2H)-one and its preparation method.

[0322] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2-fluoro-1-phenylethanol-1-one (260.45 mg, 1.2 mmol, 2.0 equiv) and allylbenzene (70.83 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 148.00 mg, yield 97%) was obtained, namely 4-benzyl-2-fluoro-3,4-dihydronaphthyl-1(2H)-one.

[0323] The chemical structural formula of the 4-benzyl-2-fluoro-3,4-dihydronaphthyl-1(2H)-one prepared in this embodiment is shown below:

[0324]

[0325] The NMR data of the 4-benzyl-2-fluoro-3,4-dihydronaphthyl-1(2H)-one prepared in this embodiment are as follows:

[0326] 1 H NMR (400MHz, CDCl3): δ7.85-7.82(m,2H),7.38-7.15(m,16H),5.52(t,J=8Hz1H),5.43(t,J=4Hz 1H),3.43-3.37(m,2H),3.12-3.02(m,4H),2.23-2.03(m,4H).

[0327] 13 C NMR (100MHz, CDCl3): δ192.76 (d, J = 14.0Hz), 144.27 (d, J = 6.0Hz), 140.41, 134.34 (d, J = 2.0Hz), 133.27, 129.33 (d, J = 2.0 Hz), 129.18, 128.70, 128.34, 128.08, 127.22, 91.09, 88.94, 39.54 (d, J = 1.0Hz), 36.44 (d, J = 4.0Hz), 31.15 (d, J = 11.0Hz).

[0328] 19 F NMR (376MHz, CDCl3): δ-186.4 (s, 1F).

[0329] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 17 H 15 FO+H,255.1180; found,255.1184.

[0330] Example 28

[0331] This embodiment provides 2-fluoro-4-(4-methoxybenzyl)-3,4-dihydronaphthyl-1(2H)-one and its preparation method.

[0332] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2-fluoro-1-phenylethanol-1-one (260.45 mg, 1.2 mmol, 2.0 equiv) and 1-allyl-4-methoxybenzene (88.93 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 165.48 mg, yield 97%) was obtained, namely 2-fluoro-4-(4-methoxybenzyl)-3,4-dihydronaphthyl-1(2H)-one.

[0333] The chemical structural formula of the 2-fluoro-4-(4-methoxybenzyl)-3,4-dihydronaphthyl-1(2H)-one prepared in this embodiment is shown below:

[0334]

[0335] The NMR data of the 2-fluoro-4-(4-methoxybenzyl)-3,4-dihydronaphthyl-1(2H)-one prepared in this embodiment are as follows:

[0336] 1 H NMR (400MHz, CDCl3): δ7.85-7.82(m,1H),7.39-7.32(m,6H),7.13-7.11(m,4H),6.82-6.80(m,4H),5.52(t,J=8Hz 1H),5.43(t,J=8Hz 1H),3.78(s,6H),3.43-3.37(m,2H),3.15-3.04(m,4H),2.25-2.03(m,4H).

[0337] 13C NMR (100MHz, CDCl3): δ192.77 (d, J = 14.0Hz), 144.28 (d, J = 6.0Hz), 140.41, 134.35 (d, J = 2.0Hz), 133.27, 129.33 (d, J = 2.0Hz) ,129.18,128.70,128.34,128.08,127.22,91.09,88.94,55.32,39.56(d,J=1.0Hz),36.45(d,J=4.0Hz),31.17(d,J=11.0Hz).

[0338] 19 F NMR (376MHz, CDCl3): δ-186.6 (s, 1F).

[0339] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 18 H 17 FO2+H,285.1285; found,285.1289.

[0340] Example 29

[0341] This embodiment provides 4-fluoro-9b-methyl-3a,9b-dihydronaphtho[1,2-b]furan-2,5(3H,4H)-dione and its preparation method.

[0342] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2-fluoro-1-phenylethanol-1-one (260.45 mg, 1.2 mmol, 2.0 equiv) and prop-1-en-2-yl propionate (68.48 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED illumination for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 136.32 mg, yield 97%) was obtained, namely 4-fluoro-9b-methyl-3a,9b-dihydronaphtho[1,2-b]furan-2,5(3H,4H)-dione.

[0343] The chemical structural formula of the 4-fluoro-9b-methyl-3a,9b-dihydronaphtho[1,2-b]furan-2,5(3H,4H)-dione prepared in this embodiment is shown below:

[0344]

[0345] The NMR data of the 4-fluoro-9b-methyl-3a,9b-dihydronaphtho[1,2-b]furan-2,5(3H,4H)-dione prepared in this embodiment are as follows:

[0346] 1 H NMR (400MHz, CDCl3): δ7.91-7.90(m,1H),7.53-7.51(m,1H),7.47-7.44(m,1H),7.31-7.28(m, 1H),4.97-4.86(m,1H),3.54-3.44(m,1H),2.80-2.76(m,1H),2.45-2.41(m,1H),1.74(s,3H).

[0347] 13C NMR (100MHz, CDCl3): δ192.02 (d, J = 13.0Hz), 176.68 (d, J = 12.0Hz), 142.82 (d, J = 6.0Hz), 131.79 (d, J = 2.0Hz), 130.85, 128.50 ,127.71(d,J=1.0Hz),125.91,85.77,85.46(d,J=4.0Hz),83.63,50.10(d,J=10.0Hz),33.26(d,J=4.0Hz),23.38(d,J=1.0Hz).

[0348] 19 F NMR (376MHz, CDCl3): δ-186.7 (s, 1F).

[0349] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 13 H 11 FO3+H,235.0765,found 235.0769.

[0350] Example 30

[0351] This embodiment provides (3-fluoro-4-oxo-7-phenyl-1,2,3,4-tetrahydronaphth-1-yl)acetic acid methyl ester and its preparation method.

[0352] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 1-([1,1'-biphenyl]-4-yl)-2-bromo-2-fluoroethane-1-one (351.77 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 181.78 mg, yield 97%) was obtained, namely methyl (3-fluoro-4-oxo-7-phenyl-1,2,3,4-tetrahydronaphth-1-yl)acetate.

[0353] The chemical structural formula of methyl (3-fluoro-4-oxo-7-phenyl-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment is shown below:

[0354]

[0355] The NMR data of (3-fluoro-4-oxo-7-phenyl-1,2,3,4-tetrahydronaphth-1-yl)acetic acid methyl ester prepared in this embodiment are as follows:

[0356] 1 H NMR (400MHz, CDCl3): δ7.83 (d, J = 4Hz 1H), 7.60-7.58 (m, 3H), 7.53-7.52 (m, 1H), 7.46-7.42 (m, 2H), 7.40-5.36 (m, 1H), 5.53 (t, J = 8Hz 1H),5.44(t,J=4Hz 1H),4.45-4.36(m,2H),3.49-3.44(m,1H),3.30-3.20(m,1H),2.12-2.03(m,1H),2.01(s,3H).

[0357] 13C NMR (100MHz, CDCl3): δ192.81 (d, J = 10.0Hz), 171.41, 144.10, 141.07 (d, J = 6.0Hz), 140.55, 133.70 (d, J = 1.0Hz), 130.10 (d, J = 1.0 Hz), 129.06, 127.92, 127.60, 127.04, 126.56, 91.02, 88.88, 66.91 (d, J = 1.0Hz), 36.27 (d, J = 4.0Hz), 28.88 (d, J = 10.0Hz), 20.79.

[0358] 19 F NMR (376MHz, CDCl3): δ-186.9 (s, 1F).

[0359] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 19 H 17 FO3+H,313.1235,found 313.1239.

[0360] Example 31

[0361] This embodiment provides methyl (3-fluoro-4-oxo-7-(pyridin-4-yl)-1,2,3,4-tetrahydronaphth-1-yl)acetate and its preparation method.

[0362] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2-fluoro-1-(4-(pyridin-4-yl)phenyl)ethane-1-one (352.94 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL) to the reaction tube. Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 182.36 mg, yield 97%) was obtained, namely methyl (3-fluoro-4-oxo-7-(pyridin-4-yl)-1,2,3,4-tetrahydronaphth-1-yl)acetate.

[0363] The chemical structural formula of methyl (3-fluoro-4-oxo-7-(pyridin-4-yl)-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment is shown below:

[0364]

[0365] The NMR data of methyl (3-fluoro-4-oxo-7-(pyridin-4-yl)-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment are as follows:

[0366] 1 H NMR (400MHz, CDCl3): δ8.79-8.88 (m, 2H), 7.84 (d, J = 4Hz 1H),7.61-7.59(m,3H),7.55-7.54(m,1H),5.55-5.43(m,1H),4.45-4.36(m ,2H),3.49-3.44(m,1H),3.30-3.20(m,1H),2.12-2.03(m,1H),2.01(s,3H).

[0367] 13C NMR (100MHz, CDCl3): δ192.84 (d, J = 13.0Hz), 171.41, 149.98, 145.52, 142.44, 141.10 (d, J = 7.0Hz), 132.69 (d, J = 2.0Hz), 130 .09(d,J=1.0Hz),128.07,127.21,121.73,91.02,88.88,66.93(d,J=1.0Hz),36.27(d,J=4.0Hz),28.88(d,J=10.0Hz),20.79.

[0368] 19 F NMR (376MHz, CDCl3): δ-186.4 (s, 1F).

[0369] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 18 H 16 FNO3+H,314.1187, found 314.1191.

[0370] Example 32

[0371] This embodiment provides methyl (3-fluoro-4-oxo-7-(thiophen-2-yl)-1,2,3,4-tetrahydronaphth-1-yl)acetate and its preparation method.

[0372] Add dppm (23.06 mg, 0.06 mmol, 10% mol) and Na₂CO₃ (158.98 mg, 1.5 mmol, 2.5 equiv) to a clean reaction tube. Evacuate the reaction tube and backfill with nitrogen (repeat three times). Then, add 2-bromo-2-fluoro-1-(4-(thiophen-2-yl)phenyl)ethane-1-one (358.99 mg, 1.2 mmol, 2.0 equiv) and allyl acetate (60.07 mg, 0.6 mmol, 1.0 equiv) dissolved in DCE (5.0 mL). Stir the reaction mixture at 25 °C under 18 W Blue LED irradiation for 6 h. The reaction proceeds until the starting material is completely reacted, as monitored by TLC. After the reaction was complete, DCE was removed by rotary evaporation at 0.6-0.8 kPa. After rotary evaporation, dichloromethane (10 mL) and water (10 mL) were added to the reaction system for extraction. After extraction, the aqueous layer was extracted twice more with dichloromethane (5 mL). The aqueous layer was discarded, and the organic layers were combined. Anhydrous sodium sulfate (5 g) was added for drying (about 0.5 h). After drying, the organic solvent in the filtrate was removed by rotary evaporation. The filtrate was separated by column chromatography on silica gel column using petroleum ether as eluent (1 h). Finally, a yellow oily substance (yield 185.29 mg, yield 97%) was obtained, namely methyl (3-fluoro-4-oxo-7-(thiophen-2-yl)-1,2,3,4-tetrahydronaphth-1-yl)acetate.

[0373] The chemical structural formula of methyl (3-fluoro-4-oxo-7-(thiophen-2-yl)-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment is shown below:

[0374]

[0375] The NMR data of methyl (3-fluoro-4-oxo-7-(thiophen-2-yl)-1,2,3,4-tetrahydronaphth-1-yl)acetate prepared in this embodiment are as follows:

[0376] 1 H NMR (400MHz, CDCl3): δ7.86 (d, J=4Hz 1H),7.76-7.74(m,1H),7.60-7.54(m,2H),7.18-7.16(m,1H),5.55-5.43(m,1H),4.4 5-4.36(m,2H),3.49-3.44(m,1H),3.30-3.20(m,1H),2.12-2.03(m,1H),2.01(s,3H).

[0377] 13C NMR (100MHz, CDCl3): δ192.84(d,J=13.0Hz),171.41,141.91,140.76,138.72(d,J=7.0Hz), 133.58(d,J=2.0Hz), 129.78(d,J=1.0Hz ),128.30,126.48,125.92(d,J=7.0Hz),124.19,91.02,88.88,66.92(d,J=1.0Hz),36.31(d,J=4.0Hz),28.88(d,J=10.0Hz),20.79.

[0378] 19 F NMR (376MHz, CDCl3): δ-186.8 (s, 1F).

[0379] HRMS(APCI-QE,m / z)[M+H] + Calcd.for C 17 H 15 FO3S+H,319.0799,found 319.0803.

[0380] Table 1. Yields of fluorinated dihydronaphthone derivatives prepared with different phosphine ligands

[0381]

[0382] Table 2. Yields of fluorinated dihydronaphthone derivatives prepared with different inorganic bases

[0383]

[0384]

[0385] As shown in Tables 1 and 2, the yield is highest when the phosphine ligand is bis(diphenylphosphinemethane) and the inorganic base is Na2CO3, and is significantly higher than that of existing catalysts such as tris(2-phenylpyridine)iridium and [Ir(dFppy)2(dtbbpy)]PF6.

[0386] The above embodiments provide a method for preparing a fluorinated dihydronaphthone derivative, which has wide applications in pharmaceutical chemistry and agrochemicals.

[0387] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A method for preparing a fluorinated dihydronaphthone derivative, characterized in that, The specific steps are as follows: S1. Mix the phosphine ligand with an inorganic base to obtain a first mixture, wherein the phosphine ligand is bis(diphenylphosphinemethane) with the structure shown in formula (IV), and the inorganic base is Na2CO3; S2. Dissolve the 2-bromo-2,2-difluoroacetophenone derivative of the structure shown in formula (II) and the olefin of the structure shown in formula (III) in a solvent to obtain a second mixture; S3. Add the second mixture obtained in step S2 to the first mixture obtained in step S1 to react and obtain a reaction solution; S4. The reaction solution obtained in step S3 is post-treated to obtain a fluorinated dihydronaphthone derivative with the structure shown in formula (I). The structural formulas (I) to (IV) are shown below: R1 and R2 are selected from any one of phenyl, substituted aryl, alkyl, or heterocyclic compounds. R f It refers to the difluorine structure linked to carbon bonds.

2. The method for preparing a fluorinated dihydronaphthone derivative according to claim 1, characterized in that, In molar ratio, 2-bromo-2,2-difluoroacetophenone derivative: olefin: phosphine ligand: inorganic base = (1.0-2.0): (0.5-1.0): (0.1-0.15): (1.5-2.5).

3. The method for preparing a fluorinated dihydronaphthone derivative according to claim 1, characterized in that, In step S2, the solvent is selected from any one or more of ethylene glycol dimethyl ether, tetrahydrofuran, dichloromethane, methanol, 1,4-dioxane, dimethyl sulfoxide, diethyl ether, cyclopentyl methyl ether, or acetonitrile.

4. The method for preparing a fluorinated dihydronaphthone derivative according to claim 1, characterized in that, In step S3, the reaction temperature is 0-90℃ and the reaction time is 0.5-12h.

5. The method for preparing a fluorinated dihydronaphthone derivative according to claim 1, characterized in that, In step S3, the reaction solution is reacted under nitrogen protection.

6. The method for preparing a fluorinated dihydronaphthone derivative according to claim 1, characterized in that, In step S3, the reaction solution needs to be illuminated by a blue LED to initiate the reaction. The blue LED is selected from any one or more of 10W, 18W, 20W, 40W, 50W, 70W, 80W or 100W.

7. The method for preparing a fluorinated dihydronaphthone derivative according to claim 1, characterized in that, In step S4, the post-processing is extraction followed by separation and purification.

8. The method for preparing a fluorinated dihydronaphthone derivative according to claim 7, characterized in that, During the extraction process, an extractant solution is used, and the extraction is performed 2-3 times. The extractant solution is pure dichloromethane, and the volume ratio of the extractant solution to the reaction solution is 1:(1-1.5).

9. The method for preparing a fluorinated dihydronaphthone derivative according to claim 7, characterized in that, During the separation and purification process, an eluent is used in the chromatography column for separation and purification. The elution time is 1-2 hours, and the eluent is petroleum ether.

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