A method for preparing 1-alkoxy-1-arylpropanone compounds

Abstract

This invention discloses a method for preparing 1-alkoxy-1-arylacetone compounds, belonging to the field of organic synthesis technology. The method uses geminitrofluorocyclopropane and alcohols as raw materials, and reacts them in a nitrogen atmosphere at 80-100°C for 12-24 hours under a catalytic system consisting of a rhodium catalyst, a phosphine ligand, and a silver additive, to efficiently synthesize the target product. This method has advantages such as readily available raw materials, simple operation, good selectivity, and few byproducts. It is compatible with various substituents such as phenyl, naphthyl, alkyl, and halogen, and is suitable for the synthesis of structurally diverse 1-alkoxy-1-arylacetone compounds, showing promising application prospects in the preparation of drug molecules and functional materials.

Description

Technical Field

[0001] This invention relates to a method for preparing 1-alkoxy-1-arylacetone compounds, belonging to the field of organic synthesis technology. Background Technology

[0002] Gem-difluorocyclopropanes, as a class of three-membered ring compounds possessing both unique high ring strain and rigidity, demonstrate significant application value in organic synthesis due to the strong electron-withdrawing effect of fluorine atoms and the unique ring-opening reactivity of cyclopropanes. As key synthetic building blocks for constructing fluorine-containing functional molecules, they have been widely used in cutting-edge fields such as drug development and materials science.

[0003] Transition metal catalysis remains the most crucial method for the conversion of gem-difluorocyclopropane. While significant progress has been made in palladium catalysis, certain limitations still exist. For example, in 2015, Fu Yao's group reported the reaction of gem-difluorocyclopropane with alcohols using a Pd(OTFA)2 / tBu-XPhos catalytic system; however, this method only synthesizes 2-fluoroallyl ethers, exhibiting a single product type and linear selectivity (Angew. Chem., Int. Ed. 2015, 54, 8231-8235). Subsequently, in 2025, Feng Huangdi's team developed the Pd(TFA)2 / XPhos catalytic system, which achieved the bifluorination and bifunctionalization reaction of gem-difluorocyclopropane. However, this reaction was limited to the preparation of alkoxy / aryloxy functionalized allyl ethers and failed to obtain ketone products. Furthermore, it lacked reactivity with phenolic substrates containing strong electron-withdrawing groups (J.Org. Chem. 2025, 90, 17576-17581).

[0004] In contrast, rhodium catalysis exhibits significant advantages in the allylation and cycloaddition of gem-difluorocyclopropanes due to its unique coordination activation ability and excellent selectivity. In 2021, Xia Ying's team reported a rhodium-catalyzed direct allylation reaction of gem-difluorocyclopropanes with simple aromatic hydrocarbons. This study successfully utilized gem-difluorocyclopropanes as a highly efficient allylation reagent, overcoming the limitations of traditional allylic sources (Angew. Chem., Int. Ed. 2021, 60, 10626-10631). In 2022, the team further optimized the catalyst system, achieving regioselective regulation of reactions with olefins and successfully constructing fluoroallylic compounds with branched or straight-chain selectivity (ACS Catal. 2022, 12, 88857-8867). However, existing research on rhodium-catalyzed geminitrocyclopropane mainly focuses on coupling or cyclization reactions with substrates such as aromatics, alkenes, and indoles. Research on reactions with oxygen-containing nucleophiles such as alcohols is still relatively scarce, and the types of organic reactions in this field still need to be further enriched and improved. Summary of the Invention

[0005] The purpose of this invention is to provide a simple and efficient method for preparing 1-alkoxy-1-arylacetone compounds, in order to solve the problems of poor reaction selectivity and numerous byproducts in traditional synthesis methods.

[0006] This method uses gem-difluorocyclopropane (Formula I) and alcohol (Formula II) as raw materials, employing a catalytic system consisting of a rhodium catalyst, phosphine ligand, and silver additive. Under a nitrogen atmosphere, by controlling the ratio of components in the catalytic system, reaction temperature, and reaction time, 1-alkoxy-1-arylacetone compounds (Formula III) are synthesized. The general reaction formula is as follows: ; In the formula, R 1 It is one of 2-naphthyl, 4-phenylphenyl, 4-cyclopropylphenyl, 4-tert-butylphenyl, 4-phenoxyphenyl, 3-methylphenyl, 3,5-dimethylphenyl, phenyl, 2-methylphenyl, 4-chlorophenyl, or 1-naphthyl; R 2 It is one of the ethyl or methyl groups.

[0007] Preferably, the molar ratio of the geminitrofluorocyclopropane to the alcohol is 1:64.6 or 1:32.3.

[0008] Preferably, the rhodium catalyst is rhodium dicarbonylacetylacetone.

[0009] Preferably, the phosphine ligand is tris(pentafluorophenyl)phosphine.

[0010] Preferably, the silver additive is silver hexafluoroantimonate.

[0011] Preferably, the amount of the rhodium catalyst is 4% of the molar amount of the reactant geminocyclopropane.

[0012] Preferably, the amount of the phosphine ligand is 8% of the molar amount of the reactant gem-difluorocyclopropane.

[0013] Preferably, the amount of silver additive used is 5% of the molar amount of the reaction raw material gem-difluorocyclopropane.

[0014] Preferably, the amount of silver additive used is 10% of the molar amount of the reaction raw material gem-difluorocyclopropane.

[0015] Preferably, the reaction temperature is 80-100°C. o C, the reaction time is 12-24h.

[0016] Under a nitrogen atmosphere, the above-mentioned proportions of raw materials, catalytic system and solvent are loaded into a reaction flask and mixed. The mixture is stirred at 80-100 °C for 12-24 hours. After stirring, the mixture is purified by silica gel column chromatography to obtain 1-alkoxy-1-arylacetone compounds.

[0017] Compared with the prior art, the beneficial effects of the present invention are: 1) This invention is innovative in its reaction mode. It uses a rhodium catalytic system to realize the reaction of gem-difluorocyclopropane with an alcohol oxygen nucleophile and successfully constructs ketone products, providing a new route for the synthesis of 1-alkoxy-1-arylacetone compounds. 2) The raw material gem-difluorocyclopropane is widely available and easy to synthesize, and is compatible with phenyl, naphthyl, and electronically diverse substituents such as alkyl, halogen, and alkoxy groups; the alcohol compounds can be simple alcohols such as methanol and ethanol, which are suitable for constructing a diverse library of bioactive molecules. 3) The technical solution of the present invention is innovative, economical and practical, and shows important application potential in the fields of drug synthesis and materials science. Attached Figure Description

[0018] Figure 1 The 1H NMR spectrum of compound 3aa in Example 1 of this invention; Figure 2 The carbon NMR spectrum of compound 3aa in Example 1 of this invention; Figure 3 The above is the 1H NMR spectrum of compound 3ba in Example 2 of this invention; Figure 4 The carbon NMR spectrum of compound 3ba in Example 2 of this invention; Figure 5 The 1H NMR spectrum of compound 3ca in Example 3 of this invention; Figure 6 The carbon NMR spectrum of compound 3ca in Example 3 of this invention; Figure 7 The 1H NMR spectrum of compound 3da in Example 4 of this invention; Figure 8 The carbon NMR spectrum of compound 3da in Example 4 of this invention; Figure 9 The 1H NMR spectrum of compound 3ea in Example 5 of this invention; Figure 10 The carbon NMR spectrum of compound 3ea in Example 5 of this invention; Figure 11 The 1H NMR spectrum of compound 3fa in Example 6 of this invention; Figure 12 The carbon NMR spectrum of compound 3fa in Example 6 of this invention; Figure 13 The 1H NMR spectrum of compound 3ga in Example 7 of this invention; Figure 14 The carbon NMR spectrum of compound 3ga in Example 7 of this invention; Figure 15 The 1H NMR spectrum of compound 3ha in Example 8 of this invention; Figure 16 The carbon NMR spectrum of compound 3ha in Example 8 of this invention; Figure 17 The 1H NMR spectrum of compound 3ia in Example 9 of this invention; Figure 18 The carbon NMR spectrum of compound 3ia in Example 9 of this invention; Figure 19 The above is the 1H NMR spectrum of compound 3ja in Example 10 of this invention; Figure 20 The carbon NMR spectrum of compound 3ja in Example 10 of this invention; Figure 21 The 1H NMR spectrum of compound 3ka in Example 11 of this invention; Figure 22 The carbon NMR spectrum of compound 3ka in Example 11 of this invention; Figure 23 The 1H NMR spectrum of compound 3ab in Example 12 of this invention; Figure 24 This is the carbon NMR spectrum of compound 3ab in Example 12 of the present invention. Detailed Implementation

[0019] The technical solution of the present invention will be further described below with reference to specific embodiments, but is not limited thereto. The raw materials involved in the embodiments, geminitrofluorocyclopropane (Formula I) and alcohol compounds (Formula II), can be synthesized by known methods or obtained commercially. The product structures are determined by nuclear magnetic resonance hydrogen spectroscopy (NMR spectroscopy). 1 H NMR, carbon spectrum ( 13 Confirmed by C NMR.

[0020] Example 1 The preparation method of compound 3aa is shown in the following formula: To a 4 mL screw-top vial equipped with a magnetic stirrer, add 2-(2,2-difluorocyclopropyl)naphthalene (40.8 mg, 0.2 mmol), Rh(acac)(CO)₂ (4 mol%, 2.0 mg), (C₆F₅)₃P (8 mol%, 8.6 mg), and AgSbF₆ (5 mol%, 3.4 mg) sequentially. After replacing N₂, add EtOH (0.8 mL). Place the reaction mixture at 80 °C. o The mixture was heated and stirred on a magnetic stirrer for 12 hours. After the reaction was completed, it was cooled to room temperature and filtered with ethyl acetate through a rapid silica gel adsorption column. The filtrate was concentrated by a rotary evaporator and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1, Pt / L value 0.32) to obtain a colorless oily product 3aa (37.8 mg, yield 83%).

[0021] 1 H NMR(400 MHz, CDCl3) δ 7.90 (s, 1H), 7.87 -7.82 (m, 3H), 7.52 - 7.46(m, 3H), 4.91 (s, 1H), 3.59 - 3.54 (m, 2H), 2.15 (s, 3H), 1.31 (t, J = 7.0Hz, 3H). 13 C NMR(101 MHz, CDCl3) δ 207.3, 133.8, 133.3, 133.2, 128.6, 128.0,127.7, 126.4, 126.3, 126.2, 124.2, 87.8, 65.1, 25.1, 15.2. Example 2 The preparation method of compound 3ba is shown in the following formula: To a 4 mL screw-top vial equipped with a magnetic stirrer, add 4-(2,2-difluorocyclopropyl)-1,1'-biphenyl (46.0 mg, 0.2 mmol), Rh(acac)(CO)₂ (4 mol%, 2.0 mg), (C₆F₅)₃P (8 mol%, 8.6 mg), and AgSbF₆ (5 mol%, 3.4 mg) sequentially. After replacing N₂, add EtOH (0.8 mL). Place the reaction mixture at 80 °C. oThe mixture was heated and stirred on a magnetic stirrer for 12 hours. After the reaction was completed, it was cooled to room temperature and filtered with ethyl acetate through a rapid silica gel adsorption column. The filtrate was concentrated by a rotary evaporator and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, Pt / L value 0.32) to obtain a yellow oily product 3ba (33.1 mg, yield 65%).

[0022] 1 H NMR(400 MHz, CDCl3) δ 7.59 (t, J = 7.3 Hz, 4H), 7.45 (dd, J = 16.7,8.1 Hz, 4H), 7.37-7.33 (m,1H), 4.79 (s, 1H), 3.61-3.50 (m,2H), 2.17 (s, 3H),1.30 (t, J = 7.0 Hz, 3H). 13 C NMR(101 MHz, CDCl3) δ 207.4, 141.4, 140.5, 135.3, 128.8, 127.49,127.46, 127.2, 127.1, 87.5, 65.2, 25.1, 15.2. Example 3 The preparation method of compound 3ca is shown in the following formula: To a 4 mL screw-top vial equipped with a magnetic stirrer, add Rh(acac)(CO)₂ (4 mol%, 2.0 mg), (C₆F₅)₃P (8 mol%, 8.6 mg), and AgSbF₆ (5 mol%, 3.4 mg) sequentially. After replacing N₂, add EtOH (0.8 mL) and 1-cyclopropyl-4-(2,2-difluorocyclopropyl)benzene (38.8 mg, 0.2 mmol). Place the reaction mixture at 80 °C. o The mixture was heated and stirred on a magnetic stirrer for 12 hours. After the reaction was completed, it was cooled to room temperature and filtered with ethyl acetate through a rapid silica gel adsorption column. The filtrate was concentrated by a rotary evaporator and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, Pt / L value 0.34) to obtain a yellow oily product 3ca (34.9 mg, yield 80%).

[0023] 1 H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.1 Hz, 2H), 7.06 (d, J= 8.2 Hz,2H), 4.71 (s, 1H), 3.54-3.44 (m,2H), 2.10 (s, 3H), 1.91-1.85 (m,1H), 1.26 (t, J = 7.0 Hz, 3H), 0.99-0.94 (m,2H), 0.71-0.67 (m,2H). 13 C NMR (101 MHz, CDCl3) δ 207.5, 144.6, 133.4, 126.9, 126.1, 87.6, 65.0, 25.2, 15.32, 15.26, 9.6, 9.5. Example 4 The preparation method of compound 3da is shown in the following formula: To a 4 mL screw-top vial equipped with a magnetic stirrer, add Rh(acac)(CO)₂ (4 mol%, 2.0 mg), (C₆F₅)₃P (8 mol%, 8.6 mg), and AgSbF₆ (5 mol%, 3.4 mg) sequentially. After replacing N₂, add EtOH (0.8 mL) and 1-tert-butyl-4-(2,2-difluorocyclopropyl)benzene (42.0 mg, 0.2 mmol). Place the reaction mixture at 80 °C. o The mixture was heated and stirred on a magnetic stirrer for 12 hours. After the reaction was completed, it was cooled to room temperature and filtered with ethyl acetate through a rapid silica gel adsorption column. The filtrate was concentrated by a rotary evaporator and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, Pt / L value 0.38) to obtain a yellow oily product 3da (32.4 mg, yield 69%).

[0024] 1 H NMR (400 MHz, CDCl3) δ 7.40-7.30 (m,4H), 4.73 (s, 1H), 3.54-3.47 (m,2H), 2.13 (s, 3H), 1.31 (s, 9H), 1.27 (t, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 207.7, 151.5, 133.3, 126.6, 125.8, 87.6, 65.1, 34.7, 31.4, 25.2, 15.3. Example 5 The preparation method of compound 3ea is shown in the following formula: To a 4 mL screw-top vial equipped with a magnetic stirrer, add Rh(acac)(CO)₂ (4 mol%, 2.0 mg), (C₆F₅)₃P (8 mol%, 8.6 mg), and AgSbF₆ (5 mol%, 3.4 mg) sequentially. After replacing N₂, add EtOH (0.8 mL) and 1-(2,2-difluorocyclopropyl)-4-phenoxybenzene (51.2 mg, 0.2 mmol). Place the reaction mixture at 80 °C. o The mixture was heated and stirred on a magnetic stirrer for 12 hours. After the reaction was completed, it was cooled to room temperature and filtered with ethyl acetate through a rapid silica gel adsorption column. The filtrate was concentrated by a rotary evaporator and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, Pt / L value 0.32) to obtain a yellow oily product 3da (25.8 mg, yield 46%).

[0025] 1 H NMR (400 MHz, CDCl3) δ 7.34 (t, J = 8.0 Hz, 4H), 7.13 (d, J = 7.4 Hz,1H), 7.03-6.97 (m, 4H), 4.73 (s, 1H), 3.56-3.48 (m, 2H), 2.14 (s, 3H), 1.28(t, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 207.6, 157.7, 156.8, 131.0, 129.9, 128.4,123.7, 119.3, 118.9, 87.3, 65.2, 25.1, 15.4. Example 6 The preparation method of compound 3fa is shown in the following formula: To a 4 mL screw-top vial equipped with a magnetic stirrer, add Rh(acac)(CO)₂ (4 mol%, 2.0 mg), (C₆F₅)₃P (8 mol%, 8.6 mg), and AgSbF₆ (5 mol%, 3.4 mg) sequentially. After replacing N₂, add EtOH (0.8 mL) and 1-(2,2-difluorocyclopropyl)-3-methylbenzene (33.6 mg, 0.2 mmol). Place the reaction mixture at 80 °C. oThe mixture was heated and stirred on a magnetic stirrer for 12 hours. After the reaction was completed, it was cooled to room temperature and filtered with ethyl acetate through a rapid silica gel adsorption column. The filtrate was concentrated by a rotary evaporator and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, Pt / L value 0.48) to obtain a pale yellow oily product 3fa (19.4 mg, yield 51%).

[0026] 1 H NMR (400 MHz, CDCl3) δ 7.27-7.19 (m, 3H), 7.13 (d, J = 7.4 Hz, 1H), 4.72 (s, 1H), 3.54-3.47 (m, 2H), 2.35 (s, 3H), 2.12 (s, 3H), 1.27 (t, J = 7.0Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 207.6, 138.6, 136.4, 129.3, 128.7, 127.6,124.0, 87.8, 65.1, 25.2, 21.5, 15.3. Example 7 The preparation method of compound 3ga is shown in the following formula: To a 4 mL screw-top vial equipped with a magnetic stirrer, add Rh(acac)(CO)₂ (4 mol%, 2.0 mg), (C₆F₅)₃P (8 mol%, 8.6 mg), and AgSbF₆ (5 mol%, 3.4 mg) sequentially. After replacing N₂, add EtOH (0.8 mL) and 1-(2,2-difluorocyclopropyl)-3,5-dimethylbenzene (36.4 mg, 0.2 mmol). Place the reaction mixture at 80 °C. o The mixture was heated and stirred on a magnetic stirrer for 12 hours. After the reaction was completed, it was cooled to room temperature and filtered with ethyl acetate through a rapid silica gel adsorption column. The filtrate was concentrated by a rotary evaporator and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, Pt / L value 0.45) to obtain a yellow oily product 3ga (21.9 mg, yield 53%).

[0027] 1 H NMR (400 MHz, CDCl3) δ 6.98 (d, J= 19.3 Hz, 3H), 4.68 (s, 1H), 3.53 –3.46 (m, 2H), 2.31 (s, 6H), 2.12 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 207.6, 138.5, 136.3, 130.2, 124.7, 87.9, 65.1, 25.2, 21.4, 15.3. Example 8 The preparation method of compound 3ha is shown in the following formula: To a 4 mL screw-top vial equipped with a magnetic stirrer, add Rh(acac)(CO)₂ (4 mol%, 2.0 mg), (C₆F₅)₃P (8 mol%, 8.6 mg), and AgSbF₆ (10 mol%, 6.8 mg) sequentially. After replacing N₂, add 1,4-dioxane (0.4 mL), EtOH (0.4 mL), and (2,2-difluorocyclopropyl)benzene (30.6 mg, 0.2 mmol). Place the reaction mixture at 80 °C. o The mixture was heated and stirred on a magnetic stirrer for 12 hours. After the reaction was completed, it was cooled to room temperature and filtered with ethyl acetate through a rapid silica gel adsorption column. The filtrate was concentrated by rotary evaporation and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, Pt / L value 0.32) to obtain a pale yellow oily product of 3 ha (18.3 mg, yield 51%).

[0028] 1 H NMR(400 MHz, CDCl3) δ 7.42-7.26 (m, 5H), 4.75 (s, 1H), 3.57-3.47(m, 2H), 2.12 (s, 3H), 1.28 (t, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 207.4, 136.4, 128.7, 128.4, 126.8, 87.7, 65.1, 25.0, 15.2. Example 9 The preparation method of compound 3ia is shown in the following formula: To a 4 mL screw-top vial equipped with a magnetic stirrer, add Rh(acac)(CO)₂ (4 mol%, 2.0 mg), (C₆F₅)₃P (8 mol%, 8.6 mg), and AgSbF₆ (10 mol%, 6.8 mg) sequentially. After replacing N₂, add 1,4-dioxane (0.4 mL), EtOH (0.4 mL), and 1-(2,2-difluorocyclopropyl)-2-methylbenzene (33.6 mg, 0.2 mmol). Place the reaction mixture in a 100 mL container. o The mixture was heated and stirred on a magnetic stirrer for 24 hours. After the reaction was completed, it was cooled to room temperature and filtered with ethyl acetate through a rapid silica gel adsorption column. The filtrate was concentrated by a rotary evaporator and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, Pt / L value 0.30) to obtain a pale yellow oily product 3ia (20.5 mg, yield 53%).

[0029] 1 H NMR(400 MHz, CDCl3) δ 7.45-7.41 (m, 1H), 7.26-7.16 (m, 3H), 4.94(s, 1H), 3.52-3.45 (m, 2H), 2.37 (s, 3H), 2.12 (s, 3H), 1.26 (t, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 206.9, 136.7, 134.7, 130.9, 128.3, 127.1,126.3, 85.1, 64.9, 25.2, 19.5, 15.2. Example 10 The preparation method of compound 3ja is shown in the following formula: To a 4 mL screw-top vial equipped with a magnetic stirrer, add Rh(acac)(CO)₂ (4 mol%, 2.0 mg), (C₆F₅)₃P (8 mol%, 8.6 mg), and AgSbF₆ (10 mol%, 6.8 mg) sequentially. After replacing N₂, add 1,4-dioxane (0.4 mL), EtOH (0.4 mL), and 1-chloro-4-(2,2-difluorocyclopropyl)benzene (37.6 mg, 0.2 mmol). Place the reaction mixture in a 100 mL container. oThe mixture was heated and stirred on a magnetic stirrer for 12 hours. After the reaction was completed, it was cooled to room temperature and filtered with ethyl acetate through a rapid silica gel adsorption column. The filtrate was concentrated by a rotary evaporator and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, Pt / L value 0.49) to obtain a yellow oily product 3ja (17.0 mg, yield 40%).

[0030] 1 H NMR (400 MHz, CDCl3) δ 7.35 (s, 4H), 4.71 (s, 1H), 3.51 (q, J = 7.0Hz, 2H), 2.13 (s, 3H), 1.28 (t, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 207.4, 135.0, 134.4, 129.0, 128.1, 87.1, 65.4, 25.0, 15.3. Example 11 The preparation method of compound 3ka is shown in the following formula: To a 4 mL screw-top vial equipped with a magnetic stirrer, add Rh(acac)(CO)₂ (4 mol%, 2.0 mg), (C₆F₅)₃P (8 mol%, 8.6 mg), and AgSbF₆ (10 mol%, 6.8 mg) sequentially. After replacing N₂, add 1,4-dioxane (0.4 mL), EtOH (0.4 mL), and 1-(2,2-difluorocyclopropyl)naphthalene (40.8 mg, 0.2 mmol). Place the reaction mixture in a 100 mL container. o The mixture was heated and stirred on a magnetic stirrer for 24 hours. After the reaction was completed, it was cooled to room temperature and filtered with ethyl acetate through a rapid silica gel adsorption column. The filtrate was concentrated by a rotary evaporator and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1, Pt / L value 0.28) to obtain a yellow oily product of 3 kJ (24.8 mg, yield 54%).

[0031] 1 H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 7.7 Hz, 1H), 7.88-7.84 (m, 2H), 7.69 (d, J= 7.0 Hz, 1H), 7.56 – 7.48 (m, 3H), 5.38 (s, 1H), 3.62-3.49 (m, 2H), 2.09 (s, 3H), 1.28 (t, J = 7.0 Hz, 3H). 13 C NMR(101 MHz, CDCl3) δ 206.6, 134.1, 132.4, 131.1, 129.4, 128.8,126.8, 126.2, 126.1, 125.4, 124.2, 86.2, 65.2, 25.3, 15.4. Example 12 The preparation method of compound 3ab is as follows: To a 4 mL screw-top vial equipped with a magnetic stirrer, add 2-(2,2-difluorocyclopropyl)naphthalene (40.8 mg, 0.2 mmol), Rh(acac)(CO)₂ (4 mol%, 2.0 mg), (C₆F₅)₃P (8 mol%, 8.6 mg), and AgSbF₆ (5 mol%, 3.4 mg) sequentially. After replacing N₂, add MeOH (0.8 mL). Place the reaction mixture at 80 °C. o The mixture was heated and stirred on a magnetic stirrer for 12 hours. After the reaction was completed, it was cooled to room temperature and filtered with ethyl acetate through a rapid silica gel adsorption column. The filtrate was concentrated by a rotary evaporator and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1, Pt / L value 0.25) to obtain a yellow oily product 3ab (35.0 mg, yield 82%).

[0032] 1 H NMR (400 MHz, CDCl3) δ 7.89-7.83 (m, 4H), 7.55-7.45 (m, 3H), 4.83 (s, 1H), 3.42 (s, 3H), 2.15 (s, 3H). 13 C NMR(101 MHz, CDCl3) δ 206.7, 133.5, 133.33, 133.31, 128.9, 128.1,127.9, 126.7, 126.59, 126.57, 124.3, 89.6, 57.4, 25.4. The above embodiments demonstrate that a series of 1-alkoxy-1-arylacetone compounds can be successfully prepared using the method of the present invention. This method is simple to operate, effectively solves the problems of poor reaction selectivity and numerous byproducts in traditional synthetic routes, and expands the research on the reaction of geminal difluorocyclopropane with alcohols / phenols under rhodium catalysis, thus possessing significant application value.

[0033] It should be noted that the above embodiments are only some examples of preferred embodiments of the present invention, and not all implementations. All other embodiments obtained by those skilled in the art based on the above embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

Claims

1. A method for preparing 1-alkoxy-1-arylacetone compounds, characterized in that, Using gem-difluorocyclopropane (Formula I) and alcohol (Formula II) as raw materials, and employing a catalytic system of rhodium catalyst, phosphine ligand, and silver additive, 1-alkoxy-1-arylacetone compounds (Formula III) were synthesized under nitrogen atmosphere by controlling the ratio of each raw material, reaction temperature, and reaction time. The general reaction formula is as follows: ； In the formula, R 1 It is one of 2-naphthyl, 4-phenylphenyl, 4-cyclopropylphenyl, 4-tert-butylphenyl, 4-phenoxyphenyl, 3-methylphenyl, 3,5-dimethylphenyl, phenyl, 2-methylphenyl, 4-chlorophenyl, or 1-naphthyl; R 2 It is one of the ethyl or methyl groups.

2. The method for preparing 1-alkoxy-1-arylacetone compounds according to claim 1, characterized in that, The molar ratio of the geminitrocyclopropane to the alcohol is 1:64.6 or 1:32.

3.

3. The method for preparing 1-alkoxy-1-arylacetone compounds according to claim 1, characterized in that, The rhodium catalyst is rhodium dicarbonylacetylacetone.

4. The method for preparing 1-alkoxy-1-arylacetone compounds according to claim 1, characterized in that, The phosphine ligand is tris(pentafluorophenyl)phosphine.

5. The method for preparing 1-alkoxy-1-arylacetone compounds according to claim 1, characterized in that, The silver additive is silver hexafluoroantimonate.

6. The method for preparing 1-alkoxy-1-arylacetone compounds according to claim 1, characterized in that, The amount of the rhodium catalyst used is 4% of the molar amount of the reactant gem-difluorocyclopropane.

7. The method for preparing 1-alkoxy-1-arylacetone compounds according to claim 1, characterized in that, The amount of the phosphine ligand used is 8% of the molar amount of the reaction raw material gem-difluorocyclopropane.

8. The method for preparing 1-alkoxy-1-arylacetone compounds according to claim 1, characterized in that, The amount of silver additive used is 5% of the molar amount of the reaction raw material gem-difluorocyclopropane.

9. The method for preparing 1-alkoxy-1-arylacetone compounds according to claim 1, characterized in that, The amount of silver additive used is 10% of the molar amount of the reaction raw material gem-difluorocyclopropane.

10. The method for preparing 1-alkoxy-1-arylacetone compounds according to claim 1, characterized in that, The reaction temperature is 80-100°C. o C, the reaction time is 12-24 h.

Images