A method for preparing an organofluorine compound

Abstract

This invention discloses a method for preparing organofluorine compounds. The specific process involves using an alcohol compound as shown in formula (I) as a raw material, adding thiosulfonyl imidazolium salt A, a base, a fluorinating reagent, and a solvent, and reacting the mixture. After the reaction is complete, post-treatment yields an organofluorine compound as shown in formula (II). The reaction formula is as follows: where one H atom on the benzene ring is replaced by a substituent R1, where R1 is an aromatic group, cyano group, sulfonyl group, ester group, nitro group, or aldehyde group, and R2 is a hydrogen group or alkyl group. This invention uses inexpensive, readily available, and environmentally friendly alcohols as substrates, enabling efficient and rapid fluorination reactions to produce the corresponding fluorinated products with high yields and high functional group tolerance. Using non-toxic, convenient, and environmentally friendly thiosulfonyl imidazolium salt A as a deoxygenating reagent effectively avoids the use of SO2F2 gas, efficiently promoting further reaction between the alcohol and the fluorinating reagent, and generating the corresponding fluorinated products in a shorter time.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and specifically relates to a method for preparing organofluorine compounds. Background Technology

[0002] Organofluorine compounds play an important role in medicine, pesticides, and materials chemistry due to the unique properties of fluorine. Incorporating highly electronegative fluorine atoms into organic molecules can greatly enhance biological activity, metabolic stability, interaction, and alter the physical properties of drug candidates.

[0003] To date, various methods have been developed for the synthesis of fluorides, such as nucleophilic fluorination, electrophilic fluorination, and radical fluorination. Due to the abundance, availability, and versatility of alcohols, deoxyfluorination of alcohols has become an important tool for constructing CF bonds. Ritter's group reported a method for deoxyfluorination of alcohols with Alkyl Fluor in the presence of KF to obtain different fluorides (NW Woldberg, X. Shen, J.-K. Li, T. Ritter, Org. Lett., 2016, 18, 6102.). Furthermore, Hu's group reported their development and use of N-toluenesulfonyl-4-chlorobenzenesulfonylimide fluoride (SulfoxFluor) as a novel deoxyfluorinating agent for the rapid conversion of various alcohols into alkyl fluorides (J.-K.Guo, C.-W.Kuang, J.Rong, L.-C.Li, C.-F.Ni, J.-B.Hu, Chem.Eur.J.2019, 25, 7259.). Lin and Xiao's group described a method for the efficient dehydroxylation of tertiary alcohols using Selectfluor (W.Zhang, Y.-C.Gu, J.-H.Lin, Z.-C.Xiao, Org.Lett.2020, 22, 6642.). Recently, Ding's group reported a mild dehydroxylation strategy using SO2F2, employing inexpensive and readily available raw materials and converting various primary, secondary, and tertiary (hetero)aryl alcohols. However, the use of the greenhouse gas SO2F2 has limited its widespread application due to drawbacks such as potential safety issues caused by leakage during operation and unsatisfactory reactivity with some substrates. In 2018, Dong and Sharpless reported a fluorothionyl imidazole salt A, for "F-SO2 +"The donor is a fluorosulfatating agent with better reactivity, selectivity, and range than SO2F2 (T. Guo, G. Meng, X. Zhan, Q. Yang, T. Ma, L. Xu, K. B. Sharpless and J. Dong, Angew. Chem., Int. Ed., 2018, 57, 2605). It is envisioned that the alkylated imidazole structure can serve as a good leaving group and provide 'F-SO2'." + "Fragmentation, introducing this substance into the fluorination system, will effectively overcome the disadvantages of using SO2F2." Summary of the Invention

[0004] To address the aforementioned problems, the present invention aims to provide an efficient, rapid, and economical method for preparing organofluorine compounds. The present invention uses inexpensive and readily available alcohols and fluorothioimidazolium salt A as raw materials, and triethylamine hydrofluoric acid salt as a fluorinating reagent to generate organofluorine compounds under the action of an alkali.

[0005] The specific technical solution of the present invention is as follows:

[0006] A method for preparing an organofluorine compound, the method comprising the following steps:

[0007] Using the alcohol compound shown in formula (I) as a raw material, fluorothioimidazolium salt A, a base, a fluorinating agent, and a solvent are added, and the reaction is carried out. After the reaction is completed, the organofluorine compound shown in formula (II) is obtained through post-treatment. The base is one of the following: 1,8-diazabicycloundec-7-ene (DBU), triethylamine (Et3N), or diisopropylethylamine (DIPEA); the fluorinating agent is triethylamine hydrofluoric acid salt; the solvent is one of the following: dichloromethane, acetonitrile, or dimethyl sulfoxide, and the reaction formula is as follows:

[0008]

[0009] In this process, one H atom on the benzene ring is replaced by a substituent R1, which can be an aromatic group, cyano group, sulfonyl group, ester group, nitro group, or aldehyde group, and R2 can be a hydrogen group or an alkyl group.

[0010] Furthermore, the molar ratio of thiosulfonyl imidazole salt A to the alcohol compound shown in formula (I) is 1.5 to 2:1.

[0011] Furthermore, the molar ratio of the base to the alcohol compound shown in formula (I) is 2 to 3:1.

[0012] Furthermore, the molar ratio of the fluorinating reagent to the alcohol compound shown in formula (I) is 1.5 to 2:1.

[0013] Furthermore, the reaction temperature is 25℃, and the reaction time is 1 to 6 hours.

[0014] Furthermore, the post-processing procedure is as follows: after the reaction is completed, the reaction solution is purified and separated by column chromatography.

[0015] The beneficial effects of this invention are as follows:

[0016] 1) This invention uses inexpensive, readily available, and environmentally friendly alcohols as substrates to efficiently and rapidly carry out fluorination reactions, generating the corresponding fluorinated products in high yield and with high functional group tolerance.

[0017] 2) This invention uses non-toxic, convenient, and environmentally friendly thiosulfonyl imidazole salt A as a deoxygenating agent, which effectively avoids the use of SO2F2 gas and efficiently promotes the further reaction of alcohol and fluorinating agent.

[0018] 3) Compared to previous technologies, this technology can generate the corresponding fluorinated products in a shorter time;

[0019] 4) The excellent yield and functional group tolerance make this method applicable to the fluorination process of small molecule natural products and suitable for large-scale preparation. Detailed Implementation

[0020] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0021]

[0022] Example 1: Preparation of 4-fluoromethylbiphenyl

[0023] 4-Phenylacetyl alcohol (R1 = Ph, R2 = H) (1.0 mmol, 1.0 equivalent), fluorothioimidazolium salt A (2.0 mmol, 2.0 equivalent), Et3N(HF)3 (2.0 mmol, 2.0 equivalent), Et3N (3.0 mmol, 3.0 equivalent), and DCM (2.0 mL, 0.5 M) were sequentially added to a 15 mL oven-dried reaction tube equipped with a stir bar. The reaction tube was then sealed with a plastic stopper and reacted at 25 °C for 3 h. The reaction solution was then diluted with water and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were then washed with brine, dried over anhydrous Na2SO4, and concentrated to dryness. The product was purified by silica gel column chromatography to obtain 158.2 mg of 4-fluoromethylbiphenyl (Formula II-1), in 85% yield.

[0024] 1H NMR spectrum (500MHz, Chloroform-d) (δ,ppm): δ 7.79–7.60 (m, 4H), 7.50 (td, J = 6.6, 3.2 Hz, 4H), 7.46–7.35 (m, 1H), 5.47 (d, J = 47.9 Hz, 2H).

[0025] Carbon NMR spectrum: (126MHz, Chloroform-d)(δ,ppm): δ 141.73, 140.60, 135.15 (d, J = 16.38), 128.81, 128.03 (d, J = 5.04), 127.52, 127.35 (d, J = 1.26), 127.14, 84.36 (d, J = 166.30).

[0026] fluorine NMR spectrum: (565MHz, Chloroform-d)δ-206.19 (t, J=47.9Hz, 1F).

[0027] Mass spectrometry: HRMS (EI-TOF) calcd for C 13 H 11 F:186.0845; Found:186.0851.

[0028]

[0029] Example 2: Preparation of 1-fluoromethyl-4-nitrobenzene

[0030] 4-Nitrobenzyl alcohol (R1 = NO2, R2 = H) (1.0 mmol, 1.0 equivalent), fluorothioimidazolium salt A (1.5 mmol, 1.5 equivalent), Et3N(HF)3 (1.5 mmol, 1.5 equivalent), Et3N (3.0 mmol, 3.0 equivalent), and DCM (2.0 mL, 0.5 M) were sequentially added to a 15 mL oven-dried reaction tube equipped with a stir bar. The reaction tube was covered with a plastic stopper and reacted at 25 °C for 4 h. The reaction solution was then diluted with water and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were then washed with brine, dried over anhydrous Na2SO4, and concentrated to dryness. The product was purified by silica gel column chromatography to obtain 139.5 mg of 1-fluoromethyl-4-nitrobenzene (Formula II-2), with a yield of 90%.

[0031] 1H NMR spectrum: (500MHz, Chloroform-d)(δ,ppm): δ8.27 (d,J=8.2Hz,2H), 7.68 (d,J=8.2Hz,2H), 5.61 (d,J=46.8Hz,2H).

[0032] Carbon NMR spectrum: (126MHz, Chloroform-d)(δ,ppm): 147.40, 143.75 (d,J=17.64), 127.81 (d,J=6.3), 123.60, 82.87 (d,J=165.07).

[0033] fluorine NMR spectrum: (565MHz, Chloroform-d)δ-215.65 (t, J=46.9Hz, 1F).

[0034] Mass spectrometry: HRMS (EI-TOF) calcd for C7H6NO2F: 155.0383; Found: 155.0381.

[0035]

[0036] Example 3: Preparation of 1-fluoromethyl-4-cyanobenzene

[0037] 4-Cyanobenyl alcohol (R1 = CN, R2 = H) (1.0 mmol, 1.0 equivalent), fluorothioimidazolium salt A (2.0 mmol, 2.0 equivalent), Et3N(HF)3 (2.0 mmol, 2.0 equivalent), Et3N (3.0 mmol, 3.0 equivalent), and DCM (2.0 mL, 0.5 M) were sequentially added to a 15 mL oven-dried reaction tube equipped with a stir bar. The reaction tube was covered with a plastic stopper and reacted at 25 °C for 4 h. The reaction solution was then diluted with water and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were then washed with brine, dried over anhydrous Na2SO4, and concentrated to dryness. The product was purified by silica gel column chromatography to obtain 121.5 mg of 1-fluoromethyl-4-cyanobenzene (Formula II-3), in 90% yield.

[0038] 1H NMR spectrum: (500MHz, Chloroform-d)(δ,ppm): δ 7.84-7.62 (m, 2H), 7.49 (dt, J = 7.8, 1.3Hz, 2H), 5.47 (d, J = 46.9Hz, 2H).

[0039] Carbon NMR spectrum: (126MHz, Chloroform-d)(δ,ppm): δ 141.66 (d,J=17.64), 132.43, 126.99 (d,J=6.3), 118.48, 112.40 (d,J=2.52), 83.13 (d,J=171.36).

[0040] fluorine NMR spectrum: (565MHz, Chloroform-d)δ-215.13 (t, J=46.9Hz, 1F).

[0041] Mass spectrometry: HRMS (EI-TOF) calcd for C8H6NF: 135.0484; Found: 135.0480.

[0042]

[0043] Example 4: Preparation of 1-fluoromethyl-4-methanesulfonylbenzene

[0044] 4-Methanesulfonylbenzyl alcohol (R1 = SO2Me, R2 = H) (1.0 mmol, 1.0 equivalent), fluorothioimidazolium salt A (2.0 mmol, 2.0 equivalent), Et3N(HF)3 (2.0 mmol, 2.0 equivalent), DBU (3.0 mmol, 3.0 equivalent), and DCM (2.0 mL, 0.5 M) were sequentially added to a 15 mL oven-dried reaction tube equipped with a stir bar. The reaction tube was covered with a plastic stopper and reacted at 25 °C for 2 h. The reaction solution was then diluted with water and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were then washed with brine, dried over anhydrous Na2SO4, and concentrated to dryness. The product was purified by silica gel column chromatography to obtain 121.5 mg of 1-fluoromethyl-4-methanesulfonylbenzene (Formula II-4), in 90% yield.

[0045] 1H NMR spectrum: (500MHz, DMSO-d6) (δ,ppm): δ 7.98 (d,J=7.9Hz,2H), 7.57 (d,J=7.9Hz,2H), 5.50 (d,J=46.9Hz,2H), 3.07 (s,3H).

[0046] Carbon NMR spectrum: (126MHz, DMSO-d6) (δ,ppm): δ 142.41 (d,J=17.64), 140.55, 127.72, 127.22 (d,J=7.56), 83.07 (d,J=170.1), 44.48.

[0047] fluorine NMR spectrum: (565MHz, Chloroform-d)δ-214.92 (t, J=46.9Hz, 1F).

[0048] Mass spectrometry: HRMS (EI-TOF) calcd for C8H9O2SF: 188.0307; Found: 188.0311.

[0049]

[0050] Example 5: Preparation of methyl 1-fluoromethylbenzoate

[0051] 4-Methyl benzoyl alcohol (R1 = CO2Me, R2 = H) (1.0 mmol, 1.0 equivalent), fluorothioimidazolium salt A (1.5 mmol, 1.5 equivalent), Et3N(HF)3 (2.0 mmol, 2.0 equivalent), DBU (2.0 mmol, 2.0 equivalent), and acetonitrile (2.0 mL, 0.5 M) were sequentially added to a 15 mL oven-dried reaction tube equipped with a stir bar. The reaction tube was covered with a plastic stopper and reacted at 25 °C for 4 h. The reaction solution was then diluted with water and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were then washed with brine, dried over anhydrous Na2SO4, and concentrated to dryness. The product was purified by silica gel column chromatography to obtain 139.4 mg of methyl 4-fluoromethylbenzoate (Formula II-5), in 83% yield.

[0052] 1H NMR spectrum: (500MHz, Chloroform-d)(δ,ppm): δ8.01 (d,J=7.7Hz,2H), 7.55 (d,J=7.8Hz,2H), 5.54 (d,J=47.1Hz,2H), 3.87 (s,3H).

[0053] Carbon NMR spectrum: (126MHz, Chloroform-d)(δ,ppm): δ 165.85, 141.46 (d, J = 16.38), 129.60 (d, J = 2.52), 129.32, 127.20 (d, J = 6.30), 83.40 (d, J = 163.80), 52.14.

[0054] fluorine NMR spectrum: (565MHz, Chloroform-d)δ-212.88 (t, J=47.2Hz, 1F).

[0055] Mass spectrum: HRMS(EI-TOF)calcd for C9H9OF: 168.0587; Found: 168.0582.

[0056]

[0057] Example 6: Preparation of 1-fluoromethylbenzaldehyde

[0058] 4-Methylcarbonylbenzyl alcohol (R1 = CHO, R2 = H) (1.0 mmol, 1.0 equivalent), fluorothioimidazolium salt A (2.0 mmol, 2.0 equivalent), Et3N(HF)3 (2.0 mmol, 2.0 equivalent), DIPEA (2.0 mmol, 2.0 equivalent), and acetonitrile (2.0 mL, 0.5 M) were sequentially added to a 15 mL oven-dried reaction tube equipped with a stir bar. The reaction tube was then sealed with a plastic stopper and reacted at 25 °C for 5 h. The reaction mixture was then diluted with water and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were then washed with brine, dried over anhydrous Na2SO4, and concentrated to dryness. The product was purified by silica gel column chromatography to obtain 139.4 mg of 4-fluoromethylbenzaldehyde (Formula II-6), in 83% yield.

[0059] 1H NMR spectrum: (500MHz, Chloroform-d) (δ,ppm): δ 10.05 (s, 1H), 7.93 (d, J = 7.8Hz, 2H), 7.55 (d, J = 7.7Hz, 2H), 5.50 (d, J = 47.0Hz, 2H).

[0060] Carbon NMR spectrum: (126MHz, Chloroform-d)(δ,ppm): δ191.75, 142.88 (d,J=17.64), 136.39, 130.00, 127.01 (d,J=6.3), 83.52 (d,J=170.1).

[0061] fluorine NMR spectrum: (565MHz, Chloroform-d)δ-214.30 (t, J=47.1Hz, 1F).

[0062] Mass spectrometry: HRMS (EI-TOF) calcd for C8H7OF: 138.0481; Found: 138.0487.

[0063]

[0064] Example 7: Preparation of 1-(1-fluoroethyl)-4-nitrobenzene

[0065] 1-(4-nitrophenyl)ethane-1-ol (R1 = NO2; R2 = Me) (1.0 mmol, 1.0 equivalent), fluorothioimidazolium salt A (2.0 mmol, 2.0 equivalent), Et3N(HF)3 (2.0 mmol, 2.0 equivalent), DIPEA (2.0 mmol, 2.0 equivalent), and dimethyl sulfoxide (2.0 mL, 0.5 M) were sequentially added to a 15 mL oven-dried reaction tube equipped with a stir bar. The reaction tube was then sealed with a plastic stopper and reacted at 25 °C for 1 h. The reaction mixture was then diluted with water and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were then washed with brine, dried over anhydrous Na2SO4, and concentrated to dryness. The product was purified by silica gel column chromatography to obtain 139.4 mg of 1-(1-fluoroethyl)-4-nitrobenzene (Formula II-7), in 83% yield.

[0066] 1H NMR spectrum: (500MHz, Chloroform-d) (δ,ppm): δ 8.20 (dd, J = 26.9, 8.6Hz, 2H), 7.52 (dd, J = 11.7, 9.0Hz, 2H), 6.00-5.40 (m, 1H), 1.67 (dd, J = 24.1, 6.5Hz, 3H).

[0067] Carbon NMR spectrum: (126MHz, Chloroform-d)(δ,ppm): δ148.55, 143.79, 125.64, 123.71, 89.66 (d,J=171.36), 22.91 (d,J=25.2).

[0068] fluorine NMR spectrum: (565MHz, Chloroform-d)δ-172.57 (dq, J=47.8, 24.1Hz, 1F).

[0069] Mass spectrometry: HRMS (EI-TOF) calcd for C8H8NO2F: 169.0539; Found: 169.0544.

[0070]

[0071] Example 8: Preparation of (8S,9S,10R,13S,14S,17S)-17-(2-fluoroacetyl)-11-hydroxy-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecanohydro-3H-cyclopentadien[a]phenanthrene-3-one

[0072] (8S, 9S, 10R, 13S, 14S, 17S)-11-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecano-3H-cyclopentadiene[a]phenanthrene-3-one (1.0 mmol, 1.0 equivalent), thiosulfonyl imidazole salt A (2.0 mmol, 2.0 equivalent), Et3N(HF)3 (2.0 mmol, 2.0 equivalent), DBU (2.0 mmol, 2.0 equivalent), and dimethyl sulfoxide (2.0 mL, 0.5 M) were sequentially added to an oven-dried reaction tube (15 mL) equipped with a stir bar. The reaction tube was then covered with a plastic stopper and reacted at 25 °C for 6 h. The reaction solution was then diluted with water and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were then washed with brine, dried over anhydrous Na₂SO₄, and concentrated to dryness. The product was purified by silica gel column chromatography to obtain 138.4 mg of the corresponding fluoride (Formula II-8), with a yield of 40%.

[0073] fluorine NMR spectrum: (565MHz, DMSO-d6)δ-226.18 (t, J=47.7Hz).

[0074]

Claims

1. A method for preparing an organofluorine compound, characterized in that... Includes the following steps: Using the alcohol compound shown in formula (I) as a raw material, fluorothioimidazolium salt A, a base, a fluorinating reagent, and a solvent are added, and the reaction is carried out. After the reaction is completed, the organofluorine compound shown in formula (II) is obtained through post-treatment. The base is one of the following: 1,8-diazabicycloundec-7-ene, triethylamine, or diisopropylethylamine; the fluorinating reagent is triethylamine hydrofluoric acid salt; the solvent is one of the following: dichloromethane, acetonitrile, or dimethyl sulfoxide, and the reaction formula is as follows: ， In this process, one H atom on the benzene ring is replaced by a substituent R1, where R1 is a phenyl, cyano, sulfonyl, ester, nitro, or aldehyde group, and R2 is hydrogen. The structural formula of fluorothionyl imidazole salt A is as follows: 。 2. The preparation method according to claim 1, characterized in that... The molar ratio of fluorothioimidazolium salt A to the alcohol compound shown in formula (I) is 1.5 to 2:

1.

3. The preparation method according to claim 1, characterized in that... The molar ratio of the base to the alcohol compound shown in formula (I) is 2~3:

1.

4. The method for preparing an organofluorine compound as described in claim 1, characterized in that... The molar ratio of the fluorinating reagent to the alcohol compound shown in formula (I) is 1.5 to 2:

1.

5. The method for preparing an organofluorine compound as described in claim 1, characterized in that... The reaction temperature is 25℃ and the reaction time is 1~6 h.

6. The method for preparing an organofluorine compound as described in claim 1, characterized in that... The post-processing procedure is as follows: after the reaction is completed, the reaction solution is purified and separated by column chromatography.

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