2-(cyanomethyl) benzoyl fluoride compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of organic chemical industry, and particularly relates to a 2-(cyanomethyl) benzoyl fluoride compound as well as a preparation method and application thereof, the preparation method comprises the following steps: mixing a 2-azido-2-fluoro-2, 3-dihydro-1H-indene-1-ketone derivative serving as a reaction raw material with activated silica gel, and carrying out rearrangement reaction; and after the reaction is finished, carrying out negative pressure suction filtration and rotary evaporation concentration to obtain the 2-(cyanomethyl) benzoyl fluoride compound. Compared with the prior art, the invention overcomes the defects that the synthesis of benzoyl fluoride compounds in the prior art involves toxic reagents and harsh conditions, is limited by other substituent groups on a ring and is harmful to the environment. According to the scheme, the 2-(cyanomethyl) benzoyl fluoride compound can be obtained through one-step rearrangement reaction, and the synthesis process is mild in reaction condition, high in yield and high in purity.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic chemical industry, and particularly relates to a 2-(cyanomethyl)benzoyl fluoride compound and a preparation method and application thereof. BACKGROUND

[0002] Benzoyl fluoride compounds (Ar-COF) have excellent stability and unique reactivity, are general intermediates in organic synthesis, and can directly obtain a series of high-value products under the action of nucleophilic reagents. Due to the influence of fluorine atoms, it can well balance stability and reactivity, at present, it is widely used as the equivalent of anhydrous fluoride ions, phenyl and benzoyl, therefore, it is of great significance to develop a new preparation method thereof.

[0003] On the one hand, acyl fluoride groups have been successfully used in many challenging amidation and esterification reactions; on the other hand, transition metal-catalyzed, non-decarbonylation and decarbonylation transformations of acyl fluoride compounds have also been widely developed. But because of the lack of safe and selective direct methods to obtain benzoyl fluoride compounds, they have not been effectively applied in the market. The industrial methods currently used for the synthesis of benzoyl fluoride compounds generally have the disadvantages of involving toxic reagents, harsh conditions, being limited by other substituents on the ring, and being harmful to the environment.

[0004] The existing direct preparation method of benzoyl fluoride compounds generally needs relatively complex conditions.

[0005] Socrates B. Munoz, Huong Dang, Xanath Ispizua-Rodriguez, Thomas Mathew, G. K. Surya Prakash. Direct Access to Acyl Fluorides from Carboxylic Acids Using a Phosphine / Fluoride Deoxyfluorination Reagent System [J]. Organic Letters, 2019, 21(6): 1659-1663. reported a reagent system composed of triphenylphosphine (PPh3), N-bromosuccinimide (NBS) and triethylamine trihydrofluoride (Et3N-3HF), which realized the deoxyfluorination of carboxylic acid through acyloxyphosphonium salt intermediate. But the cost of triphenylphosphine and N-bromosuccinimide is high, the former is toxic and easy to oxidize, and the latter may produce bromine-containing by-products, which may be limited in economy in large-scale production.

[0006] Zhongfeng Luo, Hongxiang Wu, Yue Li, Yuwen Chen, Jingyi Nie, Siqi Lu, Yulin Zhu, Zhuo Zeng. Cesium Fluoride and Copper-Catalyzed One-Pot Synthesis of Benzoxazoles via a Site-Selective Amide C-N Bond Cleavage[J]. Advanced Synthesis & Catalysis, 2019, 361(17): 4117-4125. Benzamide can be converted to benzoyl fluoride by cesium fluoride (CsF) in acetonitrile system at 100℃ for 10 hours, but cesium fluoride (CsF) is expensive and difficult to purchase in large quantities, increasing the cost of synthesis.

[0007] So far, there are few related patents about 2-(cyanomethyl) benzoyl fluoride compounds at home and abroad: patent CN115710200B discloses a preparation method of benzoyl fluoride containing a substituted group. The method is to mix cyclohexadienone compound and difluoromethyl 2-pyridyl sulfone to form a mixture under a protective atmosphere, then add potassium tert-butoxide in N, N-dimethylformamide and mix for reaction; then the obtained mixture is acidified to obtain the substituted benzoyl fluoride compound. But the reaction needs to be carried out at very low temperature (-50℃ to -78℃); and difluoromethyl 2-pyridyl sulfone may be a custom chemical, the synthesis steps are complex, the market supply is limited, and there is no market application prospect. Therefore, its limitations mainly lie in the harsh conditions, cost and insufficient substrate universality, which need to be further optimized to meet the needs of industrialization or complex molecule synthesis.

[0008] Therefore, a simple, environmentally friendly and easy-to-industrialize method is needed to synthesize such compounds. SUMMARY

[0009] The purpose of the present application is to solve at least one of the above problems by providing a 2-(cyanomethyl) benzoyl fluoride compound and a preparation method and application, to solve the synthesis of benzoyl fluoride compounds in the prior art, which involves toxic reagents, harsh conditions, limitations on other substituents on the ring, and environmental hazards. The present application can obtain 2-(cyanomethyl) benzoyl fluoride compound by one-step rearrangement reaction, and the synthesis process has mild reaction conditions, high yield and high purity.

[0010] The purpose of the present application is achieved by the following technical solutions:

[0011] The first aspect of the present application discloses a preparation method of 2-(cyanomethyl) benzoyl fluoride compound, comprising the following steps:

[0012] The 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one derivative as a reaction raw material is mixed with the activated silica gel and rearrangement reaction is carried out;

[0013] After the reaction is completed, negative pressure filtration and rotary evaporation concentration are carried out to obtain the 2-(cyanomethyl)benzoyl fluoride compound.

[0014] Preferably, the 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one derivative has the following formula II:

[0015]

[0016] In the formula, R is 4-chloro, 4-tert-butyl, 4-methyl, 4-methoxy, 5-methyl, 5-methoxy, 4,5-dimethoxy or no substituent.

[0017] Preferably, the mass ratio of the reaction raw material to the activated silica gel is 1:1.5-2.5.

[0018] Preferably, the reaction raw material and the activated silica gel are infiltrated by petroleum ether or a mixture of petroleum ether and ethyl acetate.

[0019] Preferably, in the mixture of petroleum ether and ethyl acetate, the volume ratio of petroleum ether to ethyl acetate is 50-60:1.

[0020] Preferably, the rearrangement reaction is carried out in a silica gel column: the 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one derivative is filled into the silica gel column, left to stand and rearranged, and then eluted to obtain the crude product of the 2-(cyanomethyl)benzoyl fluoride compound.

[0021] Preferably, the reaction temperature of the rearrangement reaction is 15-25℃, and the reaction time of the rearrangement reaction is 2-3h.

[0022] Preferably, in the process of the rearrangement reaction, the reaction progress is monitored by the way of thin layer chromatography spot plate.

[0023] The second aspect of the present application discloses a 2-(cyanomethyl)benzoyl fluoride compound prepared by the preparation method of any one of the above;

[0024] The 2-(cyanomethyl)benzoyl fluoride compound has the following formula I:

[0025]

[0026] In the formula, R is 4-chloro, 4-tert-butyl, 4-methyl, 4-methoxy, 5-methyl, 5-methoxy, 4,5-dimethoxy or no substituent.

[0027] The application discloses a 2-(cyanomethyl)benzoyl fluoride compound in a transition metal catalytic reaction.

[0028] Compared with the prior art, the application has the following beneficial effects:

[0029] The synthetic process provided by the application successfully realizes efficient preparation of 2-(cyanomethyl)benzoyl fluoride compounds by innovatively adopting a one-step rearrangement reaction strategy. The process overcomes the problems, such as harsh conditions (such as ultralow temperature and high temperature), dependence on expensive / toxic reagents (such as cesium fluoride and triphenylphosphine / NBS), complicated steps and substrate limitations, which are generally present in the prior art. The reaction condition is mild (usually performed at room temperature to moderate temperature), the operation is simple and controllable (TLC can be used for convenient monitoring), the reaction time is short (a few hours), the yield is high, the raw materials used are easy to obtain, safe and environmentally friendly, and the process is suitable for large-scale production.

[0030] As one of acyl fluoride compounds (RCOF), 2-(cyanomethyl)benzoyl fluoride compounds can be used as a general building block in a transition metal catalytic reaction through a unique acyl C-F bond activation mechanism. For example, in a catalytic coupling reaction system, the compound can selectively play a triple function as an acyl donor to participate in a C-C bond construction reaction, as a decarbonylation precursor to realize an R group transfer reaction, and as a fluorination reagent to provide a fluorine source. In particular, it is worth pointing out that benzoyl fluoride compounds exhibit excellent chemical stability and controllable reactivity due to the synergistic effect of their unique electronic effect and steric hindrance, and they are often used as anhydrous fluoride ion sources or as equivalents of carbonyl and phenyl groups. Therefore, the one-step preparation method of 2-(cyanomethyl)benzoyl fluoride compounds proposed in the application has broad prospects in the preparation of 2-(cyanomethyl)benzoyl fluoride compounds and their application in transition metal catalytic reactions due to its simple reaction, low cost, and non-toxicity and harmlessness. DETAILED DESCRIPTION

[0031] The application will be described in detail below in conjunction with specific embodiments, but is by no means limited to the application. The embodiments are implemented on the premise of the technical solutions of the application, and detailed implementation modes and specific operation processes are given.

[0032] In the following description, if not specifically stated, the reagents used are conventional commercially available products, and the methods used are well-known means in the art, and the remaining matters can be implemented by using the prior art.

[0033] A preparation method of 2-(cyanomethyl)benzoyl fluoride compounds comprises the following steps:

[0034] The raw material 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one derivative is mixed with activated silica gel, and then the mixture is left to stand to perform a rearrangement reaction, and the reaction progress is monitored by thin layer chromatography. After the reaction is completed, the silica gel is removed by negative pressure filtration through a Buchner funnel, and the obtained filtrate is concentrated by rotary evaporation under reduced pressure, to obtain a white solid, i.e. the corresponding target compound A, which has a chemical structural formula as shown in formula (1):

[0035]

[0036] The reaction formula is shown in formula (2):

[0037]

[0038] In the formula, R is 4-chloro, 4-tert-butyl, 4-methyl, 4-methoxy, 5-methyl, 5-methoxy, 4,5-dimethoxy, or no substituent.

[0039] In an embodiment of the present application, the mass ratio of the raw material to silica gel is 1:1.5-2.5.

[0040] In an embodiment of the present application, the silica gel system (silica gel + raw material) needs to be infiltrated with petroleum ether or petroleum ether and ethyl acetate (volume ratio 50-60:1).

[0041] In an embodiment of the present application, the rearrangement reaction is performed at a reaction temperature of 15-25°C for 2-3 hours.

[0042] In an embodiment of the present application, the rearrangement reaction is performed in a silica gel column: the 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one derivative is filled into a silica gel column to stand and rearrange, and then elution solvent is used for rapid elution, to obtain the corresponding target product.

[0043] The method can obtain 2-(cyanomethyl)benzoyl fluoride compounds through one-step rearrangement reaction, and has the advantages of mild reaction conditions, high yield, and high purity.

[0044] Acyl fluoride compounds (RCOF) can be used as universal building blocks in transition metal catalyzed reactions through their unique acyl C-F bond activation mechanism. For example, in a catalytic coupling reaction system, the compounds can selectively play three functions according to the reaction conditions: participate in C-C bond construction reaction as an acyl donor, realize R group transfer reaction as a decarboxylation precursor, and provide fluorine source as a fluorinated reagent. In particular, benzoyl fluoride compounds exhibit excellent chemical stability and controllable reactivity due to the synergistic effect of their unique electronic effect and steric hindrance, and they are often used as anhydrous fluoride ion sources or as equivalents of carbonyl and phenyl groups.

[0045] The apparatus used in the following examples is that which is conventional in the art unless otherwise stated; the reagents used are those which are commercially available or prepared by conventional methods in the art unless otherwise stated. The preparation of 2-azido-2-fluoro-2,3-dihydro-lH-inden-l-one derivatives is described below.

[0046] Example 1

[0047] Synthesis of compound 2-(cyanomethyl)benzoyl fluoride.

[0048]

[0049] Take a 5 ml beaker and add the starting material 2-azido-2-fluoro-2,3-dihydro-lH- inden-l-one (0.033 g, 0.20 mmol). Take another 0.049 g of silica gel (chromatographic grade, 200-300 mesh) and place it in a muffle furnace for activation at 120 °C for 2 hours. Cool it to room temperature and keep it ready for use. Add the activated silica gel to the beaker containing the starting material and stir well until the mixture is homogeneous. Add petroleum ether to the above powder mixture while stirring until the mixture is completely wetted and appears as a homogeneous paste. Place the beaker in a room temperature (25 ± 2 °C) environment and allow it to stand (usually 2-3 hours are required for standing). Monitor the progress of the reaction by thin layer chromatography (TLC) (eluent: petroleum ether / ethyl acetate = 4:1 v / v; silica gel plate GF254; UV 254 nm). Observe the disappearance of the starting material spot (Rf ~ 0.7) and the stable appearance of the target product spot (Rf ~ 0.6) and conclude that the reaction is complete. After completion of the reaction, transfer the reaction mixture to a Buchner funnel containing filter paper. Connect a vacuum pump and apply a negative pressure of about 0.09 MPa to perform suction filtration. Wash the beaker and the filter cake with a small amount of ethyl acetate several times. Collect all the filtrate and washings. Transfer the resulting filtrate to a 100 ml rotary evaporating flask. Perform the concentration under reduced pressure using a rotary evaporator: set the water bath temperature to 40 °C and control the vacuum to 0.08-0.09 MPa. Evaporate until no fraction is distilled out to obtain a white solid with a yield of 91% and a purity of 99.4%.

[0050] The basic parameters of this compound are as follows:

[0051] 1 H NMR (401 MHz, Chloroform-d) δ 8.11 (d, J = 7.9 Hz, 1H), 7.75 (q, J = 8.9, 8.3 Hz, 1H), 7.55 (t, J = 7.4 Hz, 1H), 4.22 (s, 2H).

[0052] 13C NMR (101 MHz, Chloroform-d): δ 156.05 (d, 1JC-F = 345.7 Hz), 135.92, 134.74 (d, 3JC-F = 8.1 Hz), 133.27, 130.66 (d, 3JC-F = 4.1 Hz), 129.05, 122.79 (d, 2JC-F = 58.0 Hz), 116.92, 23.19.

[0053] 19 F NMR (377 MHz, Chloroform-d): δ 27.81. (s, 1F).

[0054] HRMS (ESI) m / z calcd [M+H]+ = for C9H7FNO: 164.0512, found: 164.0512.

[0055] Example 2

[0056] Synthesis of compound 2-(cyanomethyl)benzoyl fluoride.

[0057]

[0058] Take a 10 ml beaker, add the starting material 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one 1.63 g (10 mmol). Take another 2.45 g of silica gel (chromatographic grade, 200-300 mesh) and place it in a muffle furnace for activation at 120 °C for 2 hours, cool to room temperature and reserve. Take the same procedure as in Example 1, obtaining a white solid with a yield of 84% and a purity of 98.6%.

[0059] The basic parameters of this compound are as follows:

[0060] 1 H NMR (401 MHz, Chloroform-d) δ 8.11 (d, J = 7.9 Hz, 1H), 7.75 (q, J = 8.9, 8.3 Hz, 1H), 7.55 (t, J = 7.4 Hz, 1H), 4.22 (s, 2H).

[0061] 13 C NMR (101 MHz, Chloroform-d): δ 156.05 (d, 1JC-F = 345.7 Hz), 135.92, 134.74 (d, 3JC-F = 8.1 Hz), 133.27, 130.66 (d, 3JC-F = 4.1 Hz), 129.05, 122.79 (d, 2JC-F = 58.0 Hz), 116.92, 23.19.

[0062] 19 F NMR (377 MHz, Chloroform-d): δ 27.81 (s, IF).

[0063] HRMS (ESI) m / z calcd [M+H]+ = for C9H7FNO: 164.0512, found: 164.0512.

[0064] Example 3

[0065] Synthesis of compound 2-(cyanomethyl)-5-methoxybenzoyl fluoride.

[0066]

[0067] Take a 5 ml beaker, add the starting material 2-azido-2-fluoro-6-methoxy-2,3-dihydro-1 H- inden-1-one 0.039 g (0.20 mmol). Take another 0.058 g of silica gel (chromatographic grade, 200-300 mesh) and place it in a muffle furnace to be activated for 2 hours at 120 °C, cool to room temperature and reserve. Take the same procedure as in example 1 to prepare, obtaining a white solid with a yield of 64% and a purity of 98.4%.

[0068] The basic parameters of this compound are as follows:

[0069] 1 H NMR (401 MHz, Chloroform-d) δ 7.66-7.58 (m, 2H), 7.28 (dd, J = 8.6, 2.8 Hz, 1H), 4.14 (s, 2H), 3.91 (s, 3H).

[0070] 13 C NMR (101 MHz, Chloroform-d): δ 159.61, 155.88 (d,1JC-F = 346.3 Hz), 131.92 (d,3JC-F = 4.5 Hz), 126.33 (d,3JC-F = 7.5 Hz), 123.68 (d,2JC-F = 57.8 Hz), 121.33, 118.26, 117.27, 55.83, 22.37.

[0071] 19 F NMR (377 MHz, Chloroform-d): δ 27.70. (s, IF).

[0072] HRMS (ESI) m / z calcd [M+H]+ = for C10H9FNO2: 194.0617, found: 194.0613.

[0073] Example 4

[0074] Synthesis of compound 2-(cyanomethyl)-5-methylbenzofluoride.

[0075]

[0076] Take a 5 ml beaker, add the starting material 2-azido-2-fluoro-6-methyl-2,3-dihydro-1 H- inden-1-one 0.035 g (0.20 mmol). Take another 0.053 g of silica gel (chromatographic grade, 200-300 mesh) and place it in a muffle furnace for activation at 120 °C for 2 hours, cool to room temperature and keep ready for use. Take the same procedure as in example 1 to prepare, obtaining a white solid with a yield of 89% and a purity of 99.7%.

[0077] The basic parameters of this compound are as follows:

[0078] 1 H NMR (401 MHz, Chloroform-d): δ 7.66 (d, J = 32.7 Hz, 1 H), 7.42-7.07 (m, 1 H), 3.87 (s, 2 H), 2.15 (s, 3 H).

[0079] 13 C NMR (101 MHz, Chloroform-d) δ 156.21 (d,1JC-F = 346.8 Hz), 139.28, 136.52, 133.74, 131.66 (d,3JC-F = 7.7 Hz), 130.56 (d,3JC-F = 4.1 Hz), 122.55 (d,2JC-F = 58.1 Hz), 117.11, 22.80, 20.88.

[0080] 19 F NMR (377 MHz, Chloroform-d): δ 27.58. (s, 1 F).

[0081] HRMS (ESI) m / z calcd [M+H]+for C10H9FNO: 178.0668, found: 178.0669.

[0082] Example 5

[0083] Synthesis of compound 4-tert-butyl-2-(cyanomethyl)benzofluoride.

[0084]

[0085] A 5 ml beaker was taken and 0.044 g (0.20 mmol) of starting material 2-azido-2- fluoro-5-tert-butyl-2,3-dihydro-1 H-inden-1-one was added. Another 0.066 g of silica gel (chromatographic grade, 200-300 mesh) was taken and was activated by heating at 120 °C for 2 hours in a muffle furnace. After cooling to room temperature, it was kept ready for use. The same procedure as in example 1 was followed to obtain a white solid with a yield of 54% and a purity of 98.8%.

[0086] The basic parameters of this compound are as follows:

[0087] 1 H NMR (401 MHz, Chloroform-d): δ 8.03 (d, J = 8.3 Hz, 1H), 7.70 (d, J = 2.1 Hz, 1H), 7.53 (dd, J = 8.3, 1.9 Hz, 1H), 4.21 (s, 2H), 1.37 (s, 9H).

[0088] 13 C NMR (101 MHz, Chloroform-d): δ 160.35, 156.05 (d,1JC-F = 344.1 Hz), 134.44 (d,3JC-F = 8.5 Hz), 133.20, 127.90 (d,3JC-F = 4.2 Hz), 125.92, 119.80 (d,2JC-F = 58.1 Hz), 117.03, 35.57, 30.80, 23.31.

[0089] 19 F NMR (377 MHz, Chloroform-d) δ 26.83. (s, 1F).

[0090] HRMS (ESI) m / z calcd [M+H]+ = for C13H15FNO: 220.1138, found: 220.1144.

[0091] Example 6

[0092] Synthesis of compound 4-chloro-2-(cyanomethyl)benzoyl fluoride.

[0093]

[0094] Take a 5 ml beaker, add the starting material 2-azido-2-fluoro-5-chloro-2,3-dihydro-1 H- inden-1-one 0.040 g (0.20 mmol). Take another 0.059 g of silica gel (chromatographic grade, 200-300 mesh) and place it in a muffle furnace for activation at 120 °C for 2 hours, cool to room temperature and keep ready for use. Prepare it in the same way as in example 1 to obtain a white solid with a yield of 78% and a purity of 99.4%.

[0095] The basic parameters of this compound are as follows:

[0096] 1 H NMR (401 MHz, Chloroform-d): δ 8.05 (d, J = 8.5 Hz, 1 H), 7.75 (d, J = 2.0 Hz, 1 H), 7.53 (dd, J = 8.6, 2.1 Hz, 1 H), 4.21 (s, 2 H).

[0097] 13 C NMR (101 MHz, Chloroform-d): δ 155.34 (d,1JC-F = 344.9 Hz), 142.83, 136.55 (d,3JC-F = 8.3 Hz), 134.42, 130.92 (d,3JC-F = 3.9 Hz), 129.38, 121.13 (d,2JC-F = 59.6 Hz), 116.21, 23.02.

[0098] 19 F NMR (377 MHz, Chloroform-d): δ 28.19. (s, 1 F).

[0099] HRMS (ESI) m / z calcd [M+H]+for C9H6ClFNO: 198.0122, found: 198.0126.

[0100] Example 7

[0101] Synthesis of compound 2-(cyanomethyl)-4,5-dimethoxybenzoyl fluoride.

[0102]

[0103] Take a 5 ml beaker, add the starting material 2-azido-2-fluoro-5-chloro-2,3-dihydro-1 H- inden-1-one 0.040 g (0.20 mmol). Take another 0.059 g of silica gel (chromatographic grade, 200-300 mesh) and place it in a muffle furnace for activation at 120 °C for 2 hours, cool to room temperature and keep ready for use. Prepare it in the same way as in example 1 to obtain a white solid with a yield of 78% and a purity of 99.4%.

[0104] The basic parameters of this compound are as follows:

[0105] 1 H NMR (401 MHz, Chloroform-d): δ 7.48 (s, 1H), 7.26 (s, 0H), 7.11 (d, J = 1.8 Hz, 1H), 4.16 (s, 2H), 4.00 (s, 3H), 3.92 (s, 3H).

[0106] 13 C NMR (101 MHz, Chloroform-d): δ 155.89 (d,1JC-F = 341.5 Hz), 154.89, 148.59, 129.67 (d,3JC-F = 8.2 Hz), 117.25, 114.79, 114.21 (d,2JC-F = 58.9 Hz), 112.91 (d,3'JC-F = 4.5 Hz), 56.48, 56.33, 22.84.

[0107] 19 F NMR (377 MHz, Chloroform-d): δ 25.87. (s, F).

[0108] HRMS (ESI) m / z calcd [M+Na]+ = for C11H10FNO3Na: 246.0542, found: 246.0545.

[0109] Application Example 1

[0110] Synthesis of isocoumarin compounds.

[0111]

[0112] To a dry reaction flask equipped with a stir bar, was added compound 2- (cyanomethyl)benzoyl fluoride (163 mg, 1.0 mmol) and anhydrous dichloromethane (CH2Cl2, 3.0 mL) at room temperature (25 ± 2 °C) and stirred to dissolve.

[0113] To the above solution, triethylamine (279 μL, 2.0 mmol) was added dropwise slowly. After the addition was completed, the reaction was continued to stir at room temperature. The progress of the reaction was monitored by thin layer chromatography (TLC) (silica gel plate GF254; developing solvent: n-hexane / ethyl acetate = 3:1 v / v; UV 254 nm visualization). After about 1 hour, the disappearance of the starting material spot (Rf≈0.7) and the appearance of the target product spot (Rf≈0.4) were observed, indicating the completion of the reaction. The reaction mixture was diluted with ethyl acetate (20 mL). The diluted mixture was transferred to a separatory funnel and washed with deionized water (20 mL x 2). The organic phase was separated, and the aqueous phase was back-extracted with ethyl acetate (10 mL) once. All the organic phases were combined. The combined organic phase was transferred to a conical flask, anhydrous magnesium sulfate (MgS04, about 1.0 g) was added, and the mixture was stirred for 15 minutes to dry. The drying agent was removed by filtration, and the filter cake was washed with a small amount of ethyl acetate (about 5 mL). The filtrate and the washing were combined and transferred to a rotary evaporation flask, which was concentrated under reduced pressure (about 0.08-0.09 MPa) at a water bath temperature of 35-40 °C to remove all the solvents to obtain the crude product. The crude product was purified by silica gel column chromatography:

[0114] Stationary phase: Silica gel (200-300 mesh)

[0115] Eluent: Petroleum ether / ethyl acetate (gradient elution: starting ratio 10:1 v / v→ final ratio 3:1 v / v)

[0116] Fractions containing the target product were collected (confirmed by TLC monitoring, Rf≈0.4, developing solvent: n-hexane / ethyl acetate = 3:1 v / v). The target fractions were combined and concentrated under reduced pressure (about 0.08-0.09 MPa) at a water bath temperature of 35-40 °C to remove all the solvents. The obtained residue was dried under vacuum to obtain the white isocoumarin compound solid with biological activities such as antibacterial, anti-inflammatory, anticancer, etc. with a yield of 73% and a purity of 99.3%.

[0117] This application example fully demonstrates the role and application of the 2-(cyanomethyl)benzoyl fluoride compound in the catalytic coupling reaction.

[0118] The basic parameters of this compound are as follows:

[0119] 1 H NMR (401 MHz, Chloroform-d): δ 8.40 (d, J = 7.9 Hz, 1H), 8.07-7.95 (m, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.81-7.72 (m, 2H), 7.67 (d, J = 4.4 Hz, 2H), 7.58 (dt, J = 8.6, 4.3 Hz, 1H), 4.02 (s, 2H).

[0120] 13 C NMR (101 MHz, Chloroform-d): δ 162.68, 158.90, 136.44, 133.25, 132.70, 131.08, 130.67, 130.37, 130.18, 129.61, 129.57, 128.90, 124.80, 119.01, 116.65, 113.89, 94.87, 22.50.

[0121] HRMS (ESI) m / z calcd [M+H]+= for C18H11N2O2: 287.0821, found: 287.0818.

[0122] Particular mention: Preparation of 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one derivatives

[0123]

[0124] Take a 20 ml reaction tube, add raw material 2-bromo-2-fluoro-2,3-dihydro-1H-inden-1-one derivative (1.00 mmol, 1 eq.), tetrabutylammonium azide (1.05 eq.), dimethyl sulfoxide (5 ml). Among them, the 2-bromo-2-fluoro-2,3-dihydro-1H-inden-1-one derivative of this scheme adopts the synthesis method of 2-bromo-2-fluoro-2,3-dihydro-1H-inden-1-one derivative given in the literature Cheng Zheng, Xuhui Cui, Jingjing Wu, Pingjie Wu, Yanyan Yu, Hanwen Liu, Fanhong Wu. Synthesis and Application of Monofluoroalkyl Building Blocks: a-Halo-a-fluoroketones [J]. European Journal of Organic Chemistry. 2022 (32), e202200137. Put the reaction tube in a room temperature (25±2℃) for 1-2 hours reaction. The reaction progress is monitored by thin layer chromatography (TLC) (developing agent: petroleum ether / ethyl acetate = 3:1 v / v; silica gel plate GF254; UV 254nm). It is observed that the raw material point (Rf≈0.6) disappears and the target product point (Rf≈0.7) appears stably, and the reaction is determined to be complete. Dilute the reaction mixture with ethyl acetate (20 mL). Transfer the diluted mixture to a separatory funnel and wash twice with deionized water (20 mL x 2). Separate the organic phase, and the aqueous phase is back extracted once with ethyl acetate (10 mL). Combine all the organic phases. Transfer the combined organic phase to a conical flask, add anhydrous magnesium sulfate (MgSO4, about 1.0 g), stir and dry for 15 minutes. Filter out the drying agent and wash the filter cake with a small amount of ethyl acetate (about 5 mL). Combine the filtrate and washing liquid and transfer to a rotary evaporation flask. Concentrate under reduced pressure (about 0.08-0.09 MPa) at a water bath temperature of 35-40℃ to remove all solvents to obtain 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one derivative.

[0125] The above description of the embodiments is to facilitate those skilled in the art to understand and use the invention. Those skilled in the art can easily make various modifications to these embodiments, and apply the general principles described herein to other embodiments without having to go through creative labor. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art without departing from the scope of the invention should be within the scope of protection of the invention.

Claims

1. A method for producing a 2-(cyanomethyl)benzoyl fluoride compound, characterized by comprising the steps of, It comprises the following steps: ​ mixing 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one derivative as a reaction raw material with activated silica gel and performing rearrangement reaction; After the reaction is completed, negative pressure filtration and rotary evaporation concentration are performed to obtain the 2-(cyanomethyl)benzoyl fluoride compound.

2. The method of claim 1, wherein the 2-(cyanomethyl)benzoyl fluoride compound is prepared by the reaction of 2-halogenomethylbenzoyl fluoride with sodium cyanide in the presence of a base. The 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one derivative has the following structural formula II: In the formula, R is 4-chloro, 4-tert-butyl, 4-methyl, 4-methoxy, 5-methyl, 5-methoxy, 4,5-dimethoxy or no substituent.

3. The method of claim 1, wherein the 2-(cyanomethyl)benzoyl fluoride compound is prepared by the reaction of 2-halogenomethylbenzoyl fluoride with sodium cyanide in the presence of a base. The mass ratio of the reaction raw material to the activated silica gel is 1:1.5-2.

5.

4. The method of claim 1, wherein the 2-(cyanomethyl)benzoyl fluoride compound is prepared by the reaction of 2-halogenomethylbenzoyl fluoride with sodium cyanide in the presence of a base. The reaction raw material and the activated silica gel are infiltrated by petroleum ether or a mixture of petroleum ether and ethyl acetate.

5. The method of claim 4, wherein the 2-(cyanomethyl)benzoyl fluoride compound is prepared by the reaction of 2-halogenomethylbenzoyl fluoride with sodium cyanide in the presence of a base. In the mixture of petroleum ether and ethyl acetate, the volume ratio of petroleum ether to ethyl acetate is 50-60:

1.

6. The method for preparing a 2-(cyanomethyl)benzoyl fluoride compound according to claim 1, characterized in that, The rearrangement reaction is performed in a silica gel column: 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one derivative is filled into the silica gel column, left to stand and rearrange, and then eluted to obtain the crude product of the 2-(cyanomethyl)benzoyl fluoride compound.

7. The method of claim 1, wherein the 2-(cyanomethyl)benzoyl fluoride compound is prepared by the reaction of 2-bromomethylbenzoyl fluoride with sodium cyanide in the presence of a base. The reaction temperature of the rearrangement reaction is 15-25°C, and the reaction time of the rearrangement reaction is 2-3h.

8. The method for preparing a 2-(cyanomethyl)benzoyl fluoride compound according to claim 1, characterized in that, In the process of the rearrangement reaction, the reaction progress is monitored by the way of thin layer chromatography point plate.

9. A 2-(cyanomethyl)benzoyl fluoride compound, characterized by, Prepared by the preparation method in any one of claims 1-8; The 2-(cyanomethyl)benzoyl fluoride compound has the following structural formula I: In the formula, R is 4-chloro, 4-tert-butyl, 4-methyl, 4-methoxy, 5-methyl, 5-methoxy, 4,5-dimethoxy or no substituent.

10. Use of the 2-(cyanomethyl)benzoyl fluoride compound in claim 9 in a transition metal catalyzed reaction.

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