Process for the preparation of alpha-chloroketone derivatives from styrenic compounds

Abstract

This invention belongs to the technical field of organic compound synthesis, specifically relating to a method for preparing α-chloroketone derivatives from styrene-based compounds. The α-chloroketone derivatives of this invention have the general structural formula: [formula omitted], where R is an electron-withdrawing, electron-donating, or sterically hindered group. The method for preparing α-chloroketone derivatives includes the following steps: first, adding a chlorine source, a compound of general formula 1, and an organic solvent to a reaction vessel; reacting at 60-70°C; and then separating and purifying the reaction solution to obtain the α-chloroketone derivative. The method for preparing α-chloroketone derivatives from styrene-based compounds provided by this invention requires no metal catalyst, avoids the use of oxygen or hazardous reagents, operates under mild conditions, is safe to operate, and is low in cost. The prepared α-chloroketone derivatives have high purity and high yield.

Description

Technical Field

[0001] This invention belongs to the technical field of organic compound synthesis, specifically relating to a method for preparing α-chloroketone derivatives from styrene compounds. Background Technology

[0002] α-Chloroaryl ketones are an important structural unit in organic synthesis, especially as key intermediates widely used in the construction of natural products and complex molecules. Traditionally, these compounds are prepared by α-chlorination of the corresponding ketones. However, considering the availability and cost of raw materials, alkenes (especially styrene compounds) are more advantageous than ketones, particularly in large-scale industrial production. Therefore, developing efficient and safe methods for synthesizing α-chloroaryl ketones using alkenes as direct raw materials is of great significance.

[0003] Currently, the main routes for preparing α-chloroketones from alkenes can be classified into the following categories:

[0004] Photo / electrocatalytic oxidative chlorination: For example, Chinese patents CN114539040A and CN116023202A disclose methods for reacting olefins with halides to produce α-haloketones in the presence of oxygen under photocatalysis or metal catalysis. Other methods utilize cobalt chloride or manganese chloride as catalysts to achieve the conversion of styrene derivatives to α-chloroacetophenone through an electrochemically driven oxygen reduction reaction (ORR). These methods share the commonality of relying on noble metal or transition metal catalysts and requiring oxygen as an oxygen source. In production, they suffer from problems such as high catalyst costs, safety hazards associated with oxygen use, and the need for specialized photocatalytic or electrocatalytic reaction devices.

[0005] Metal-catalyzed stepwise conversion: A two-step method catalyzed by ferric chloride first converts styrene into an intermediate with a specific structure, followed by nucleophilic substitution to obtain the target product. Although this method avoids the direct use of oxygen, the steps are relatively long, and the atom economy needs to be improved.

[0006] Highly toxic or hazardous reagents are involved: To avoid metal catalysts, some methods use highly reactive or highly toxic reagents. For example, the carcinogen CrO3 is used as an oxidant in combination with Me3SiCl to achieve the chloroketation of olefins. Alternatively, unstable chloric acid (HClO2) or chlorine dioxide (ClO2) is used to react with styrene. These reagents are highly reactive and easily decompose to produce toxic chlorine gas, posing significant safety risks and challenges to operation, storage, and industrial production. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to overcome the above-mentioned defects of the prior art and provide a method for preparing α-chloroketone derivatives from styrene compounds. This method does not require metal catalysts, avoids the use of oxygen or high-risk reagents, operates under mild conditions, is safe to operate, and is inexpensive. The α-chloroketone derivatives prepared have high purity and high yield.

[0008] The α-chloroketone derivatives of this invention have the following general structural formula: , where R is an electron-withdrawing, electron-donating, or sterically hindered group.

[0009] The method for preparing α-chloroketone derivatives from styrene compounds includes the following steps: first, adding a chlorine source, a compound of general formula 1, and an organic solvent to a reaction vessel, reacting at 60-70°C, and then separating and purifying the reaction solution to obtain the α-chloroketone derivative;

[0010] The compound of general formula 1 is any one of the following:

[0011] .

[0012] The chlorine source is CFBSA, with the structural formula [insert structural formula here]. .

[0013] The reaction is carried out at 60-70℃ for 6-12 hours.

[0014] The molar ratio of the chlorine source to the compound of general formula 1 is 2.5~2.6:1.

[0015] The organic solvent is acetonitrile and water.

[0016] The molar volume ratio of the compound of general formula 1 to acetonitrile is 1 mmol: 2.0~2.4 mL, and the molar volume ratio of the compound of general formula 1 to water is 1 mmol: 0.5~0.6 mL.

[0017] The specific operation of separating and purifying the reaction solution is as follows: diluting the reaction solution with water, extracting, washing, drying, concentrating under reduced pressure, and then separating by silica gel column separation or reduced pressure distillation.

[0018] Silica gel column separation uses a mixed solvent of eluent (petroleum ether) and developing solvent (dichloromethane) with a volume ratio of 4:1 to 2:1, or a mixture of petroleum ether and ethyl acetate, or a mixed solvent of petroleum ether / ethyl acetate / acetic acid = 40 / 20 / 1.

[0019] The vacuum distillation temperature is 70~90℃.

[0020] The synthetic reaction formula of this invention is as follows: .

[0021] The reaction mechanism for preparing 2-chloro-1-phenylethyl ketone using general formula 1a as a starting material in this invention is as follows:

[0022] Styrene 1a reacts with CFBSA (3) in a solvent to generate chloroium ions 4. Subsequently, water molecules attack 4 to generate intermediate 5. Intermediate 5 continues to react with another molecule of CFBSA (3) to generate 6. 6 is then reacted with PhSO2NF - After the anion removes a proton, it generates 7. 7 is unstable when heated and releases one molecule of hydrogen chloride to form the final product 2a.

[0023] Compared with the prior art, the beneficial effects of the present invention are:

[0024] (1) The preparation method of the present invention does not require the participation of metals, which reduces the cost of synthesis. It uses water instead of oxygen as the oxygen source, which is safer and suitable for industrial production. The chlorination reagent used is inexpensive, the synthesis steps are simple, and the synthesis time is short.

[0025] (2) The α-chloroaryl ketone derivatives synthesized by the synthesis method of the present invention can reach a maximum yield of 89%, and still have good yields for alkenes containing electron-withdrawing or sterically hindered groups, generally above 60%. Attached Figure Description

[0026] Figure 1 The image shows the hydrogen spectrum of the product from Example 1.

[0027] Figure 2 The carbon spectrum of the product of Example 1 is shown.

[0028] Figure 3 This is the mass spectrum of the product from Example 3.

[0029] Figure 4 The image shows the hydrogen spectrum of the product from Example 3.

[0030] Figure 5 The image shows the carbon spectrum of the product from Example 3.

[0031] Figure 6 The fluorine spectrum of the product of Example 3 is shown.

[0032] Figure 7 The image shows the hydrogen spectrum of the product from Example 4.

[0033] Figure 8 The carbon spectrum of the product of Example 4 is shown.

[0034] Figure 9 The image shows the hydrogen spectrum of the product from Example 5. Detailed Implementation

[0035] The present invention will be further described below with reference to specific embodiments.

[0036] The raw materials and additives used in the following examples are all commercially available.

[0037] The CFBSA used in Examples 1 to 10 was prepared according to the following steps: 10.6 g of chloramine B was added to 200 mL of water, followed by the addition of 20.5 g of a selective fluorine reagent (1-chloromethyl-4-fluoro-1,4-diaza-bridged bicyclo[2.2.2]octane ditetrafluoroborate). The mixture was stirred overnight at room temperature. After reacting for 12 h, 50 mL of dichloromethane was added to extract the product CFBSA. The dichloromethane was then evaporated to obtain CFBSA with a purity ≥98%. The preparation process was as follows: .

[0038] The CFBSA used in Examples 11 to 22 was prepared according to the following steps: 10.6 g of chloramine B was added to 200 mL of acetonitrile, and then 20% F2 / N2 gas (fluorine gas accounted for 20% of the volume of the mixed gas) was introduced for reaction at a gas flow rate of 1.0 L / min. After reacting for 1 h, the acetonitrile was removed by distillation at 85 °C. 50 mL of dichloromethane and 50 mL of water were added, and the product CFBSA was extracted into the organic phase. Then, the dichloromethane was distilled away at 60 °C to obtain CFBSA with a purity ≥98%. The preparation process is as follows:

[0039] .

[0040] The commercially available raw materials used as compounds of general formula 1 in the following examples were sourced from Bidepharm, Adamas, Meryer, Energy, and Leyan.

[0041] Example 1

[0042] Preparation of 2-chloro-1-phenylethyl ketone (compound 2a):

[0043] 1a (1.0 mmol) was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). The reaction was carried out at 60 °C for 6 h until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using petroleum ether and dichloromethane in a volume ratio of 4:1 to obtain compound 2a 132 mg, with a yield of 85%, as a white solid with a purity of 99.2%.

[0044] Hydrogen spectrum: 1H NMR (400 MHz, Chloroform-d) δ 7.93 (d, J = 7.2, 2H), 7.60 (t, J = 8.0, 1H), 7.47 (t, J = 7.2, 2H), 4.70 (s, 2H).

[0045] Example 2

[0046] Large-scale preparation of 2-chloro-1-phenylethyl ketone (compound 2a):

[0047] Add 1a (0.1 mol) to a 500 mL dry flask equipped with a magnetic stir bar, then add 240 mL acetonitrile, 60 mL water, and CFBSA (0.26 mol). After reacting at 70 °C for 12 h, the reaction is complete. After removing the solvent and water by atmospheric distillation, distill under reduced pressure at 90 °C with a pressure of 140 Pa to obtain 11.4 g of compound 2a, with a yield of 74%, as a white solid with a purity of 99.3%.

[0048] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform-d) δ 7.93 (d, J = 7.2, 2H), 7.60 (t, J = 8.0, 1H), 7.47 (t, J = 7.2, 2H), 4.70 (s, 2H).

[0049] Example 3

[0050] Preparation of 2-chloro-4'-fluoroacetophenone (compound 2b):

[0051] 1b (1.0 mmol) was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). The reaction was carried out at 70 °C for 12 h until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using petroleum ether and dichloromethane in a volume ratio of 4:1 to obtain compound 2b 117 mg, with a yield of 68%, as a white solid with a purity of 99.1%.

[0052] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform- d ) δ 7.98 (dd, J = 8.8, 5.2 Hz, 2H), 7.15 (t, J= 8.6 Hz, 2H), 4.66 (s, 2H).

[0053] Example 4

[0054] Preparation of 2-chloro-4'-chloroacetophenone (compound 2c):

[0055] 1 c (1.0 mmol) was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). The reaction was carried out at 70 °C for 12 h until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using petroleum ether and dichloromethane in a volume ratio of 4:1 to obtain compound 2 c 147 mg, with a yield of 78%, as a white solid with a purity of 99.5%.

[0056] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform- d ) δ 7.88 (d, J = 8.6 Hz, 2H), 7.45(d, J = 8.6 Hz, 2H), 4.65 (s, 2H).

[0057] Example 5

[0058] Preparation of 2-chloro-4'-bromoacetophenone (compound 2d):

[0059] Add 1d (1.0 mmol) to a 20 mL dry flask equipped with a magnetic stir bar, then add 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). After reacting at 70 °C for 12 h, the reaction is complete. The reaction mixture is diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product is then purified by silica gel column chromatography using petroleum ether and dichloromethane in a volume ratio of 4:1 to obtain compound 2d 145 mg, with a yield of 62%, as a white solid with a purity of 99.4%.

[0060] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform-d) δ 7.80 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 4.65 (s, 2H).

[0061] Example 6

[0062] Preparation of 2-chloro-4'-trifluoromethylacetophenone (compound 2e):

[0063] 1e (1.0 mmol) was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). The reaction was carried out at 70 °C for 12 h until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using petroleum ether and dichloromethane in a volume ratio of 4:1 to obtain 176 mg of compound 2e, with a yield of 79%, as a white solid with a purity of 99.2%.

[0064] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform- d ) δ 8.04 (d, J = 8.8 Hz, 2H), 7.73(d, J = 8.2 Hz, 2H), 4.72 (s, 2H).

[0065] Example 7

[0066] Preparation of 2-chloro-4'-nitroacetophenone (compound 2f):

[0067] 1f (1.0 mmol) was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). The reaction was carried out at 70 °C for 12 h until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using a 2:1 volume ratio of petroleum ether and ethyl acetate to obtain 2f 64 mg of compound, with a yield of 32%, as a white solid with a purity of 99.3%.

[0068] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform- d ) δ 8.34 (d, J = 8.8 Hz, 2H), 8.13(d, J = 8.8 Hz, 2H), 4.71 (s, 2H).

[0069] Example 8

[0070] Preparation of 2-chloro-4'-bromoacetophenone (compound 2g):

[0071] 1 g (1.0 mmol) was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). The reaction was carried out at 70 °C for 12 h until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using petroleum ether and dichloromethane in a volume ratio of 2:1 to obtain 2 g (61 mg) of the compound, with a yield of 34%, as a white solid with a purity of 99.5%.

[0072] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform- d ) δ 8.03 (d, J = 8.0 Hz, 2H), 7.78(d, J = 8.4 Hz, 2H), 4.71 (s, 2H).

[0073] Example 9

[0074] Preparation of 2-chloro-4'-carboxyacetophenone (compound 2i):

[0075] 1i (1.0 mmol) was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). The reaction was carried out at 70 °C for 12 h until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using a petroleum ether / ethyl acetate / acetic acid ratio of 40 / 20 / 1 (v / v). The result was 2i 52 mg of compound 26% as a white solid with a purity of 99.1%.

[0076] Hydrogen spectrum: 1 H NMR (400 MHz, Methanol- d 4) δ 8.15 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.6 Hz, 2H), 4.98 (s, 2H).

[0077] Example 10

[0078] Preparation of 2-chloro-4'-methylacetophenone (compound 2j):

[0079] 1j (1.0 mmol) was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). The reaction was carried out at 60 °C for 6 h until it was complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using petroleum ether and dichloromethane in a volume ratio of 4:1 to obtain compound 2j 132 mg, with a yield of 78%, as a white solid with a purity of 99.2%.

[0080] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform- d ) δ 7.84 (d, J = 8.2 Hz, 2H), 7.27(d, J = 8.0 Hz, 2H), 4.67 (s, 2H), 2.41 (s, 3H).

[0081] Example 11

[0082] Preparation of 2-chloro-3'-methylacetophenone (compound 2k):

[0083] 1k (1.0 mmol) was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). The reaction was carried out at 60 °C for 6 h until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using petroleum ether and dichloromethane in a volume ratio of 4:1 to obtain compound 2k116 mg, with a yield of 69%, as a white solid with a purity of 99.3%.

[0084] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform- d ) δ 7.75 – 7.65 (m, 2H), 7.44 –7.29 (m, 2H), 4.67 (s, 2H), 2.37 (s, 3H).

[0085] Example 12

[0086] Preparation of 2-chloro-4'-methoxyacetophenone (compound 2m):

[0087] 1 mg (1.0 mmol) was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). The reaction was carried out at 60 °C for 6 h until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using petroleum ether and dichloromethane in a volume ratio of 4:1 to obtain 2 mg of compound 122 mg, with a yield of 66%, as a white solid with a purity of 99.1%.

[0088] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform- d ) δ 7.86 (d, J = 8.4 Hz, 2H), 6.89(d, J = 8.2 Hz, 2H), 4.60 (s, 2H), 3.81 (s, 3H).

[0089] Example 13

[0090] Preparation of 2-chloro-4'-tert-butylacetophenone (compound 2o):

[0091] 10 (1.0 mmol) of compound 20 O was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL of acetonitrile, 0.5 mL of water, and 2.5 mmol of CFBSA. The reaction was carried out at 60 °C for 6 h until the reaction was complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using petroleum ether and dichloromethane in a volume ratio of 4:1 to obtain 169 mg of compound 20 O, with a yield of 80%, as a white solid with a purity of 99.4%.

[0092] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform- d ) δ 7.88 (d, J = 8.6 Hz, 2H), 7.49(d, J = 8.4 Hz, 2H), 4.68 (s, 2H), 1.33 (s, 9H).

[0093] Example 14

[0094] Preparation of 2-chloro-4'-phenylacetophenone (compound 2p):

[0095] 1 p (1.0 mmol) was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). The reaction was carried out at 60 °C for 6 h until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using petroleum ether and dichloromethane in a volume ratio of 4:1 to obtain compound 2 p 78 mg, with a yield of 34%, as a white solid with a purity of 99.5%.

[0096] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform- d ) δ 8.03 (d, J = 8.4 Hz, 2H), 7.71(d, J = 8.4 Hz, 2H), 7.63 (d, J = 7.2 Hz, 2H), 7.55 – 7.38 (m, 3H), 4.73 (s, 2H).

[0097] Example 15

[0098] Preparation of 2-chloro-1-(naphth-2-yl)ethane-1-one (compound 2q):

[0099] 1q (1.0 mmol) was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). The reaction was carried out at 60 °C for 6 h until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using petroleum ether and dichloromethane in a volume ratio of 4:1 to obtain compound 2q121 mg, with a yield of 59%, as a white solid with a purity of 99.1%.

[0100] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform- d ) δ 8.41 (s, 1H), 8.00 – 7.90 (m, 2H), 7.90 – 7.80 (m, 2H), 7.66 – 7.50 (m, 2H), 4.80 (s, 2H).

[0101] Example 16

[0102] Preparation of 2-chloroacetylthiophene (compound 2r):

[0103] 1r (1.0 mmol) was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). The reaction was carried out at 60 °C for 6 h until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using petroleum ether and dichloromethane in a volume ratio of 4:1 to obtain compound 2r 84 mg, with a yield of 52%, as a white solid with a purity of 99.2%.

[0104] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform- d ) δ 7.79 (dd, J = 3.8, 1.0 Hz, 1H), 7.72 (dd, J = 5.0, 1.1 Hz, 1H), 7.17 (dd, J = 5.0, 3.8 Hz, 1H), 4.60 (s, 2H).

[0105] Example 17

[0106] Preparation of α-chlorophenylacetone (compound 2s):

[0107] 1 sa (1.0 mmol) was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). The reaction was carried out at 60 °C for 6 h until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using petroleum ether and dichloromethane in a volume ratio of 4:1 to obtain compound 2s 130 mg, with a yield of 77%, as a white solid with a purity of 99.5%.

[0108] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform- d ) δ 8.01 (d, J = 7.0 Hz, 2H), 7.59(t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 5.25 (q, J = 6.6 Hz, 1H), 1.74(d, J = 6.6 Hz, 3H).

[0109] Example 18

[0110] Preparation of α-chlorophenylacetone (compound 2s):

[0111] 1 sb (1.0 mmol) was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). The reaction was carried out at 60 °C for 6 h until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using petroleum ether and dichloromethane in a volume ratio of 4:1 to obtain compound 2s126 mg, with a yield of 75%, as a white solid with a purity of 99.4%.

[0112] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J = 7.0 Hz, 2H), 7.59(t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 5.25 (q, J = 6.6 Hz, 1H), 1.74(d, J = 6.6 Hz, 3H).

[0113] Example 19

[0114] Preparation of 2-chloro-1,2,3,4-tetrahydronaphthyl-1-one (compound 2t):

[0115] 1 t (1.0 mmol) was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). The reaction was carried out at 60 °C for 6 h until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using petroleum ether and dichloromethane in a volume ratio of 4:1 to obtain 2 t 99 mg of compound, with a yield of 55%, as a white solid with a purity of 99.1%.

[0116] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform- d ) δ 8.07 (d, J = 7.8 Hz, 1H), 7.52(t, J = 7.4 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.26 (d,J = 7.6 Hz, 1H), 4.62(dd, J = 7.8, 3.8 Hz, 1H), 3.27 (ddd, J = 17.0, 8.0, 4.6 Hz, 1H), 2.99 (ddd, J =17.0, 7.0, 4.8 Hz, 1H), 2.57 (ddt, J = 16.4, 8.2, 4.2 Hz, 1H), 2.44 (dtd, J =14.2, 7.4, 4.6 Hz, 1H).

[0117] Example 20

[0118] Preparation of 2-chloro-2-phenylacetophenone (compound 2u):

[0119] 1 u (1.0 mmol) was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). The reaction was carried out at 60 °C for 6 h until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using petroleum ether and dichloromethane in a volume ratio of 4:1 to obtain compound 2 u 159 mg, with a yield of 69%, as a white solid with a purity of 99.3%.

[0120] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform- d ) δ 7.97 (d, J = 7.8 Hz, 2H), 7.59 –7.27 (m, 8H), 6.36 (s, 1H).

[0121] Example 21

[0122] Preparation of 2-chloro-2-phenylacetophenone (compound 2u):

[0123] 1ub (1.0 mmol) was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). The reaction was carried out at 60 °C for 6 h until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using petroleum ether and dichloromethane in a volume ratio of 4:1 to obtain compound 2u161 mg, with a yield of 70%, as a white solid with a purity of 99.6%.

[0124] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform- d ) δ 7.97 (d, J = 7.8 Hz, 2H), 7.59 –7.27 (m, 8H), 6.36 (s, 1H).

[0125] Example 22

[0126] Preparation of (E)-1-chloro-4-phenylbut-3-en-2-one (compound 2v):

[0127] 1v (1.0 mmol) was added to a 20 mL dry flask equipped with a magnetic stir bar, followed by 2 mL acetonitrile, 0.5 mL water, and CFBSA (2.5 mmol). The reaction was carried out at 60 °C for 6 h until complete. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography using petroleum ether and dichloromethane in a volume ratio of 4:1 to obtain compound 2v 105 mg, with a yield of 58%, as a white solid with a purity of 99.2%.

[0128] Hydrogen spectrum: 1 H NMR (400 MHz, Chloroform- d ) δ 7.68 (d, J = 16.0 Hz, 1H), 7.60– 7.51 (m, 2H), 7.40 (d, J = 6.2 Hz, 3H), 6.95 (d, J = 16.0 Hz, 1H), 4.29 (s, 2H).

Claims

1. A method for preparing α-chloroketone derivatives from styrene compounds, characterized in that: The process includes the following steps: First, a chlorine source, a compound of general formula 1, and an organic solvent are added to the reaction vessel, and the reaction is carried out at 60-70°C. Then, the reaction solution is separated and purified to obtain an α-chloroketone derivative. The compound of general formula 1 is any one of the following: ； The chlorine source is CFBSA, with the structural formula [insert structural formula here]. The organic solvent is acetonitrile and water; The structural formula of the α-chloroketone derivative is as follows: , , , , , , , , , , , , , , , , , ,or .

2. The method for preparing α-chloroketone derivatives from styrene compounds according to claim 1, characterized in that: The reaction is carried out at 60-70℃ for 6-12 hours.

3. The method for preparing α-chloroketone derivatives from styrene compounds according to claim 1, characterized in that: The molar ratio of the chlorine source to the compound of general formula 1 is 2.5~2.6:

1.

4. The method for preparing α-chloroketone derivatives from styrene compounds according to claim 1, characterized in that: The molar volume ratio of the compound of general formula 1 to acetonitrile is 1 mmol: 2.0~2.4 mL.

5. The method for preparing α-chloroketone derivatives from styrene compounds according to claim 4, characterized in that: The molar volume ratio of the compound of general formula 1 to water is 1 mmol: 0.5~0.6 mL.

6. The method for preparing α-chloroketone derivatives from styrene compounds according to claim 1, characterized in that: The specific operation of separating and purifying the reaction solution is as follows: diluting the reaction solution with water, extracting, washing, drying, concentrating under reduced pressure, and then separating by silica gel column separation or reduced pressure distillation.

7. The method for preparing α-chloroketone derivatives from styrene compounds according to claim 6, characterized in that: Silica gel column separation uses eluent and eluent.

8. The method for preparing α-chloroketone derivatives from styrene compounds according to claim 6, characterized in that: The vacuum distillation temperature is 70~90℃.

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