Electrochemical synthesis of fluorine and trifluoromethyl containing compounds

Abstract

The present application relates to a kind of electrochemical synthesis method of fluorine-containing and trifluoromethyl compound, which uses cheap chemical olefin, trifluoromethyl sulfinic acid salt and triethylamine trifluoride as raw material, carries out catalytic fluorination of olefin, trifluoromethylation without exogenous oxidant and transition metal, synthesizes fluorine-containing and trifluoromethyl compound, provides active molecule with atom economy, step simplicity, low price and wide application range High efficiency, green and environmentally friendly synthesis route, to meet the requirements of industrial application, the synthesis method of the present application is more green, environment-friendly and wide application range.

Description

Technical Field

[0001] This invention relates to an electrochemical synthesis method for fluorine-containing and trifluoromethyl compounds, belonging to the field of electrochemical organic synthesis technology. Background Technology

[0002] Fluorine and trifluoromethyl compounds are widely used in the pharmaceutical field (such as Xtandi and Aprepitant) because their unique "polyfluorine effect" can significantly improve drug absorption, solubility, bioavailability, metabolism and excretion. Therefore, developing new synthetic strategies that simultaneously introduce fluorine and trifluoromethyl groups is of great significance and development potential.

[0003] Bifunctionalization strategies involving the fluorination and trifluoromethylation of inexpensive and diverse olefins can conveniently introduce two fluorine-containing groups simultaneously. In 2018, Li et al. [Z.Liu,H.Chen,Y.Lv,X.Tan,H.Shen,HZYu,C.Li,J.Am.Chem.Soc.,2018,140,6169-6175] reported an organic synthesis method for fluorine- and trifluoromethyl compounds. This method uses a copper complex as a catalyst, olefins as raw materials, S-(trifluoromethyl)dibenzothiophene tetrafluoroborate as the trifluoromethyl source, and cesium fluoride as the fluorine atom source, preparing fluorine- and trifluoromethyl compounds through a radical reaction. However, the high cost of metal catalysts and trifluoromethylating reagents (784 RMB / gram, Sigma-Aldrich) increases the reaction cost. In addition, the trifluoromethylating reagent used will generate dibenzo[B,D]thiophene waste after releasing trifluoromethyl groups, resulting in low atom economy and easy environmental pollution.

[0004] Chinese patent document CN110452078A discloses a method for preparing an ethylene compound containing both fluorine and trifluoromethyl groups. The method utilizes a copper trifluoromethyl complex as both a fluorine source and a trifluoromethyl source, and adds it to an alkyne under the action of an organic base to obtain the target product. This method uses a copper trifluoromethyl complex to trifluoromethylate and fluorinate the alkyne. However, the copper trifluoromethyl complex is expensive, resulting in high production costs and low reaction efficiency.

[0005] Therefore, finding synthetic routes that are widely applicable and do not involve transition metal catalysts and inexpensive trifluoromethylating agents, thereby reducing preparation costs, is of great significance for the preparation of fluorine-containing and trifluoromethyl compounds. Summary of the Invention

[0006] In view of the shortcomings of existing technologies, especially the problems of high cost, complex reaction system and operation, narrow applicability, low atomic efficiency and environmental unfriendliness of existing preparation methods, this invention provides an electrochemical synthesis method for fluorine-containing and trifluoromethyl compounds. Invention Overview:

[0008] The method of this invention uses inexpensive chemicals such as olefins, trifluoromethyl sulfinates, and triethylamine trihydrofluoride as raw materials. It catalyzes the fluorination and trifluoromethylation of olefins without exogenous oxidants or transition metals, synthesizing fluorinated and trifluoromethyl compounds. This provides a highly efficient, green, and environmentally friendly synthetic route for bioactive molecules that is atom-economical, simple in procedure, inexpensive, and widely applicable, thus meeting the requirements of industrial applications. The synthetic method of this invention is more green, environmentally friendly, and has a wider range of applications. Detailed description of the invention:

[0010] This invention is achieved through the following technical solution:

[0011] An electrochemical synthesis method for fluorine-containing and trifluoromethyl compounds includes the following steps:

[0012] Solvent, electrolyte, olefin, fluorinating agent, trifluoromethylating agent, cathode, and anode were added sequentially to a diaphragm-free electrolytic cell. The mixture was stirred at room temperature and reacted under constant current conditions. After the reaction was completed, the reaction solution was concentrated, and the organic phase was separated and purified to obtain fluorine-containing and trifluoromethyl compounds.

[0013] The olefin has the structure shown in formula (I):

[0014]

[0015] In formula (I), R is selected from tert-butyl, trifluoromethyl, hydrogen atom, trifluoromethoxy, ester group, trimethylsilane, fluorine, and chlorine.

[0016] According to a preferred embodiment of the present invention, the cathode is a platinum sheet electrode and the anode electrode is a carbon rod.

[0017] According to a preferred embodiment of the present invention, the solvent is acetonitrile.

[0018] According to a preferred embodiment of the present invention, the electrolyte is tetrabutylammonium hexafluorophosphate.

[0019] According to a preferred embodiment of the present invention, the trifluoromethylating agent is sodium trifluoromethyl sulfinate.

[0020] According to a preferred embodiment of the present invention, the fluorinating agent is triethylamine trihydrofluoride.

[0021] According to a preferred embodiment of the present invention, the molar concentration of the electrolyte in the solvent is 0.05–1.0 mol / L. Too high or too low a concentration will result in a decrease in yield.

[0022] According to a preferred embodiment of the present invention, the molar ratio of olefin to electrolyte is 1:(1-3).

[0023] According to a preferred embodiment of the present invention, the molar ratio of olefin, fluorinating agent, and trifluoromethylating agent is 1:(1-3):(1-3).

[0024] The most preferred molar ratio of olefin, fluorinating agent, and trifluoromethylating agent is 1:2:2.

[0025] According to a preferred embodiment of the present invention, the magnitude of the constant current is 3 to 7 mA. Excessive or insufficient current will lead to a decrease in yield.

[0026] According to a preferred embodiment of the invention, the reaction temperature is 20-30°C. Excessively high temperatures will lead to a decrease in yield. Preferably, the reaction is carried out under nitrogen atmosphere.

[0027] According to a preferred embodiment of the present invention, the reaction time is 6 to 12 hours.

[0028] According to a preferred embodiment of the present invention, the separation and purification method is as follows: the solvent is removed by rotary evaporation, and the residue is purified by silica gel column chromatography, wherein the eluent for the silica gel column is ethyl acetate: petroleum ether = 1:5 to 1:50.

[0029] A preferred embodiment of the present invention:

[0030] An electrochemical synthesis method for fluorine-containing and trifluoromethyl compounds includes the following steps:

[0031] (1) 0.4 mmol of 4-ethylenebiphenyl compound, 0.5 mmol of tetrabutylammonium hexafluorophosphate, 0.8 mmol of trifluoromethyl sulfinate, 0.8 mmol of triethylamine trihydrofluoride, and 8 mL of acetonitrile were added sequentially to a three-necked flask. A carbon rod was used as the anode and a platinum electrode was used as the cathode. The reaction was carried out under nitrogen atmosphere at 25 °C with a constant current of 5 mA for 12 h. The reaction was monitored by TLC.

[0032] (2) After the reaction is complete, the solvent of the reaction solution is removed by rotary evaporator. The residue is purified by rapid silica gel column chromatography to obtain the product. The eluent used for silica gel column chromatography purification is ethyl acetate: petroleum ether = 1:5 to 1:50.

[0033] A fluorine-containing and trifluoromethyl compound was prepared by the above method.

[0034] Fluorine-containing and trifluoromethyl compounds have the structure shown in formula (II):

[0035]

[0036] In equation (II), R has the same meaning as in equation (I).

[0037] The reaction route of this invention is as follows:

[0038]

[0039] Technical features and advantages of the present invention:

[0040] 1. This invention employs an electrochemical method for synthesizing fluorine-containing and trifluoromethyl compounds. The raw materials for this method are readily available, require no metal catalysts or chemical oxidants, and do not require expensive fluorination and trifluoromethylation reagents. It does not cause safety issues or heavy metal residue problems, is simple to operate, has a considerable yield, is environmentally friendly, and has good application prospects.

[0041] 2. The electrode used in this invention is a general inert electrode, which does not require electrode modification, avoids the use of oxidants and toxic and expensive catalysts, has a high reaction yield, and the reaction system is simple and safe.

[0042] 3. This invention not only avoids the use of metal catalysts, greatly reducing reaction costs, but also has the advantage of simple operation; at the same time, it avoids the use of expensive trifluoromethylating reagent S-(trifluoromethyl)dibenzothiophene tetrafluoroborate (784 RMB / g, Maclean's Reagent Company), by using inexpensive sodium trifluoromethyl sulfinate (2.58 RMB / g) as the trifluoromethylating reagent, which saves costs and avoids the pollution of the environment by the byproducts of the trifluoromethylating reagent after it takes effect. Attached Figure Description

[0043] Figure 1 The 4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 1 of this invention 1 H NMR spectrum.

[0044] Figure 2 The 4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 1 of this invention 13 C NMR spectrum.

[0045] Figure 3 The 4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 1 of this invention 19 F NMR spectrum.

[0046] Figure 4 The 3',5'-di-tert-butyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 2 of this invention 1 H NMR spectrum.

[0047] Figure 5 The 3',5'-di-tert-butyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 2 of this invention 13 C NMR spectrum.

[0048] Figure 6The 3',5'-di-tert-butyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 2 of this invention 19 F NMR spectrum.

[0049] Figure 7 The 3'-tert-butyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 3 of this invention 1 HNMR image.

[0050] Figure 8 The 3'-tert-butyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 3 of this invention 13 CNMR image.

[0051] Figure 9 The 3'-tert-butyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 3 of this invention 19 FNMR image.

[0052] Figure 10 The 4'-methyl acetate-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 4 of this invention 1 H NMR spectrum.

[0053] Figure 11 The 4'-methyl acetate 4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 4 of this invention 13 C NMR spectrum.

[0054] Figure 12 The 4'-methyl acetate-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 4 of this invention 19 F NMR spectrum.

[0055] Figure 13 The 3'-trifluoromethyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 5 of this invention 1 H NMR spectrum.

[0056] Figure 14 The 3'-trifluoromethyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 5 of this invention 13 C NMR spectrum.

[0057] Figure 15 The 3'-trifluoromethyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 5 of this invention 19 F NMR spectrum.

[0058] Figure 16 The 4'-trifluoromethyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 6 of this invention 1 H NMR spectrum.

[0059] Figure 17 The 4'-trifluoromethyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 6 of this invention 13 C NMR spectrum.

[0060] Figure 18 The 4'-trifluoromethyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 6 of this invention 19 F NMR spectrum.

[0061] Figure 19 The 4'-fluoro-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 7 of this invention 1 HNMR image.

[0062] Figure 20 The 4'-fluoro-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 7 of this invention 13 CNMR image.

[0063] Figure 21 The 4'-fluoro-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 7 of this invention 19 FNMR image.

[0064] Figure 22 The 3'-chloro-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 8 of this invention 1 HNMR image.

[0065] Figure 23 The 3'-chloro-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 8 of this invention 13 CNMR image.

[0066] Figure 24 The 3'-chloro-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 8 of this invention 19 FNMR image.

[0067] Figure 25 The 2'-chloro-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 9 of this invention 1 HNMR image.

[0068] Figure 26 The 2'-chloro-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 9 of this invention 13 CNMR image.

[0069] Figure 27 The 2'-chloro-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 9 of this invention 19 FNMR image.

[0070] Figure 28 The 4'-(1'-fluoro-2'-trifluoromethyl)ethyl-4-phenylpyridine prepared in Example 10 of this invention 1 H NMR spectrum.

[0071] Figure 29 The 4'-(1'-fluoro-2'-trifluoromethyl)ethyl-4-phenylpyridine prepared in Example 10 of this invention 13 C NMR spectrum.

[0072] Figure 30 The 4'-(1'-fluoro-2'-trifluoromethyl)ethyl-4-phenylpyridine prepared in Example 10 of this invention 19 F NMR spectrum.

[0073] Figure 31 The 4'-trimethylsilyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 11 of this invention 1 H NMR spectrum.

[0074] Figure 32 The 4'-trimethylsilyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 11 of this invention 13 CNMR image.

[0075] Figure 33 The 4'-trimethylsilyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl prepared in Example 11 of this invention 19 FNMR image. Detailed Implementation

[0076] The present invention will be further described below through specific embodiments, but these are not intended to limit the scope of the invention.

[0077] The raw materials used in the examples are commercially available or can be prepared using existing technologies.

[0078] Example 1: Preparation of 4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl

[0079]

[0080] In a 10 mL three-necked flask, 0.4 mmol of 4-vinyl-1,1'-biphenyl, 0.5 mmol of tetrabutylammonium hexafluorophosphate, 0.8 mmol of trifluoromethyl sulfinate, 0.8 mmol of triethylamine trihydrofluoride, and 8 mL of acetonitrile were added sequentially. Using a carbon rod as the anode and a platinum electrode as the cathode, the reaction was carried out at 25 °C with a constant current of 5 mA for 12 h, monitored by TLC. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was purified by rapid silica gel column chromatography (petroleum ether as the mobile phase) to obtain the product in 70% yield.

[0081] product 1 H NMR spectrum, 13 C NMR spectrum, 19 See F NMR image Figures 1-3 As shown.

[0082] 1 H NMR (CDCl3, 400MHz): δ7.66 (d, J = 8.0Hz, 2H), 7.61 (d, J = 7.4Hz, 2H), 7.52-7.45 (m, 3H), 7.44-7.37(m,2H),5.83(dd,J=47.8,6.7Hz,1H),2.97-2.84(m,1H),2.70-2.52(m,1H).

[0083] 13 C NMR (CDCl3, 101MHz): δ142.14 (d, J = 2.0Hz), 140.22, 140.21, 136.72 (d, J = 20.2Hz), 128.86, 127.70, 127.51, 127.37, 127. 09, 126.22, 126.16, 125.91 (d, J = 7.0Hz), 125.11 (q, J = 275.7Hz), 87.89 (dq, J = 172.7, 4.0Hz), 41.31 (qd, J = 28.3, 25.3Hz).

[0084] 19 F NMR (CDCl3, 376MHz) δ -64.83 (d, J = 7.7Hz), -175.61 (q, J = 7.8Hz).

[0085] Example 2: Preparation of 3',5'-di-tert-butyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl

[0086]

[0087] In a 10 mL three-necked flask, 0.4 mmol of 3',5'-di-tert-butyl-4-vinyl-1,1'-biphenyl, 0.5 mmol of tetrabutylammonium hexafluorophosphate, 0.8 mmol of trifluoromethyl sulfinate, 0.8 mmol of triethylamine trihydrofluoride, and 8 mL of acetonitrile were added sequentially. Using a carbon rod as the anode and a platinum electrode as the cathode, the reaction was carried out at 25 °C with a constant current of 5 mA for 12 h, monitored by TLC. After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by rapid silica gel column chromatography (using petroleum ether as the mobile phase) to obtain the product in 75% yield. 1 H NMR spectrum, 13 C NMR spectrum, 19 See F NMR image Figures 4-6 As shown.

[0088] 1 H NMR (CDCl3, 400MHz): δ7.64 (d, J = 7.9Hz, 2H), 7.48-7.46 (m, 1H), 7.44 (s, 1H), 7.43-7.38 ( m,3H),5.82(dd,J=47.8,6.8Hz,1H),2.99-2.81(m,1H),2.70-2.49(m,1H),1.39(s,18H).

[0089] 13 C NMR (CDCl3, 101MHz): δ151.31, 143.53 (d, J = 2.0Hz), 139.75, 136.39 (d, J = 20.2Hz), 127.89, 125.81 (q, J = 7.1Hz), 125.13(q,J=278.7Hz),121.88,121.65,87.99(dq,J=171.7,4.0Hz),41.48(qd,J=29.29,25.25Hz),34.99,31.51.

[0090] 19 F NMR (CDCl3, 376MHz) δ-64.13 (d, J = 8.0Hz), -174.67 (q, J = 7.9Hz).

[0091] Example 3: Preparation of 3'-tert-butyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl

[0092]

[0093] In a 10 mL three-necked flask, 0.4 mmol of 3'-tert-butyl-4-vinyl-1,1'-biphenyl, 0.5 mmol of tetrabutylammonium hexafluorophosphate, 0.8 mmol of trifluoromethyl sulfinate, 0.8 mmol of triethylamine trihydrofluoride, and 8 mL of acetonitrile were added sequentially. Using a carbon rod as the anode and a platinum electrode as the cathode, the reaction was carried out at 25 °C with a constant current of 5 mA for 12 h, monitored by TLC. After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by rapid silica gel column chromatography (using petroleum ether as the mobile phase) to obtain the product in 76% yield. 1 H NMR spectrum, 13 C NMR spectrum, 19 See F NMR image Figures 7-9 As shown.

[0094] 1 H NMR (CDCl3, 400MHz): δ7.64(d,J=8.0Hz,2H),7.54(d,J=8.3Hz,2H),7.49(d,J=8.4Hz,2H),7.42( d,J=7.9Hz,2H),5.81(dd,J=47.8,6.9Hz,1H),2.98-2.81(m,1H),2.70-2.49(m,1H),1.37(s,9H).

[0095] 13 C NMR (CDCl3, 101MHz): δ150.82, 142.06 (d, J = 2.0Hz), 137.32, 136.41 (d, J = 20.2Hz), 128.49, 127.40, 126.77, 125.88 ( d, J=7.1Hz), 125.83, 125.12 (q, J=276.7Hz), 87.96 (dq, J=171.2, 4.04Hz), 41.45 (qd, J=29.3, 26.3Hz), 34.57, 31.32.

[0096] 19 F NMR (CDCl3, 376MHz) δ -64.18 (d, J = 7.9Hz), -174.76 (q, J = 7.9Hz).

[0097] Example 4: Preparation of 4'-methyl acetate-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl

[0098]

[0099] In a 10 mL three-necked flask, 0.4 mmol of 4'-methyl acetate-4-vinyl-1,1'-biphenyl, 0.5 mmol of tetrabutylammonium hexafluorophosphate, 0.8 mmol of trifluoromethyl sulfinate, 0.8 mmol of triethylamine trihydrofluoride, and 8 mL of acetonitrile were added sequentially. Using a carbon rod as the anode and a platinum electrode as the cathode, the reaction was carried out at 25 °C with a constant current of 5 mA for 12 h, monitored by TLC. After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by rapid silica gel column chromatography (using petroleum ether as the mobile phase) to obtain the product in 60% yield. 1 H NMR spectrum, 13 C NMR spectrum, 19 See F NMR image Figures 10-12 As shown.

[0100] 1 H NMR (CDCl3, 400MHz): δ7.62 (d, J = 8.0Hz, 2H), 7.55 (d, J = 8.1Hz, 2H), 7.43 (d, J = 7.9Hz, 2H), 7.37 (d, J = 7.7Hz, 2H), 5.81 (dd, J=46.5, 10.6Hz, 1H), 3.72 (s, 3H), 3.69 (d, J=4.3Hz, 2H), 2.97-2.81 (m, 1H), 2.67-2.49 (m, 1H).

[0101] 13 C NMR (CDCl3, 101MHz): δ171.88, 141.73 (d, J = 3.0Hz), 139.10, 136.73 (d, J = 20.2Hz), 133.51, 129.79, 127.46, 127.29, 126.47, 125.91(d,J=6.1Hz), 125.08(q,J=276.7Hz), 87.89(dq,J=171.7,3.0Hz), 61.06, 52.10, 41.41(qd,J=29.29,25.25Hz), 40.75.

[0102] 19 F NMR (CDCl3, 376MHz) δ -64.14 (d, J = 7.8Hz), -175.06 (q, J = 7.8Hz).

[0103] HRMS (ESI) + ): Calculated for C 18 H 16 F4O2 + [M+H] + :341.1160; found:341.1158.

[0104] Example 5: Preparation of 3'-trifluoromethyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl

[0105]

[0106] In a 10 mL three-necked flask, 0.4 mmol of 3'-trifluoromethyl-4-vinyl-1,1'-biphenyl, 0.5 mmol of tetrabutylammonium hexafluorophosphate, 0.8 mmol of trifluoromethyl sulfinate, 0.8 mmol of triethylamine trihydrofluoride, and 8 mL of acetonitrile were added sequentially. Using a carbon rod as the anode and a platinum electrode as the cathode, the reaction was carried out at 25 °C with a constant current of 5 mA for 12 h, monitored by TLC. After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by rapid silica gel column chromatography (using petroleum ether as the mobile phase) to obtain the product, with a yield of 67%. 1 H NMR spectrum, 13 C NMR spectrum, 19 See F NMR image Figures 13-15 As shown.

[0107] 1 H NMR (CDCl3, 400MHz): δ7.83 (s, 1H), 7.77 (d, J = 7.6Hz, 1H), 7.70-7.62 (m, 3H), 7.58 (t, J = 7.7Hz, 1H),7.47(d,J=7.9Hz,2H),5.83(dd,J=47.7,6.5Hz,1H),2.97-2.81(m,1H),2.69-2.52(m,1H).

[0108] 13 C NMR (CDCl3, 101MHz): δ141.06, 140.71 (d, J = 2.0Hz), 137.62 (d, J = 20.0Hz), 131.32 (d, J = 32.2Hz), 130.41, 129.38, 127.67, 126.11 (d ,J=7.1Hz), 125.57(q,J=277.8Hz), 124.17(q,J=46.5Hz), 124.13(q,J=46.5Hz), 87.82(d,J=176.8Hz), 41.43(qd,J=29.3,26.2,Hz).

[0109] 19 F NMR (CDCl3, 376MHz) δ -62.66 (d, J = 8.2Hz), -64.12 (d, J = 7.9Hz), -175.88 (q, J = 7.8Hz).

[0110] Example 6: Preparation of 4'-trifluoromethyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl

[0111]

[0112] In a 10 mL three-necked flask, 0.4 mmol of 4'-trifluoromethyl-4-vinyl-1,1'-biphenyl, 0.5 mmol of tetrabutylammonium hexafluorophosphate, 0.8 mmol of trifluoromethyl sulfinate, 0.8 mmol of triethylamine trihydrofluoride, and 8 mL of acetonitrile were added sequentially. Using a carbon rod as the anode and a platinum electrode as the cathode, the reaction was carried out at 25 °C with a constant current of 5 mA for 12 h, monitored by TLC. After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by rapid silica gel column chromatography (using petroleum ether as the mobile phase) to obtain the product, with a yield of 61%. 1 H NMR spectrum, 13 C NMR spectrum, 19 See F NMR image Figures 16-18 As shown.

[0113] 1 H NMR (CDCl3, 400MHz): δ7.74-7.62(m,6H),7.47(d,J=8.0Hz,2H),5.84(dd,J=47.7,6.5Hz,1H),3.02-2.76(m,1H),2.74-2.47(m,1H).

[0114] 13 C NMR (CDCl3, 101MHz): δ143.76, 140.70 (d, J = 2.1Hz), 137.78 (d, J = 19.8Hz), 129.80 (d, J = 32.4Hz), 129.23 (d, J = 6.1Hz), 129.21 (q, J = 218.2Hz), 1 24.2(q,J=272.7Hz),126.09(d,J=6.1Hz),125.83(q,J=4.0Hz),125.05( q, J=278.8Hz), 87.80 (dq, J=176.8, 2.0Hz), 41.43 (qd, J=29.4, 26.4Hz).

[0115] 19 F NMR (CDCl3, 376MHz) δ -62.48, -64.13 (d, J = 7.8Hz), -175.93 (q, J = 7.8Hz).

[0116] Example 7: Preparation of 4'-fluoro-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl

[0117]

[0118] In a 10 mL three-necked flask, 0.4 mmol of 4'-fluoro-4-vinyl-1,1'-biphenyl, 0.5 mmol of tetrabutylammonium hexafluorophosphate, 0.8 mmol of trifluoromethyl sulfinate, 0.8 mmol of triethylamine trihydrofluoride, and 8 mL of acetonitrile were added sequentially. Using a carbon rod as the anode and a platinum electrode as the cathode, the reaction was carried out at 25 °C with a constant current of 5 mA for 12 h, monitored by TLC. After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by rapid silica gel column chromatography (using petroleum ether as the mobile phase) to obtain the product in 71% yield. 1 H NMR spectrum, 13 C NMR spectrum, 19 See F NMR image Figures 19-21 As shown.

[0119] 1 H NMR (CDCl3, 400MHz): δ7.59 (d, J = 8.0Hz, 2H), 7.55 (dd, J = 8.7, 5.3Hz, 2H), 7.43 (d, J = 7.9Hz, 2 H),7.15(t,J=8.7Hz,2H),5.82(dd,J=47.8,6.6Hz,1H),2.98-2.80(m,1H),2.70-2.49(m,1H).

[0120] 13 C NMR (CDCl3, 101MHz): δ162.69 (d, J = 248.5Hz), 141.23 (d, J = 2.0Hz), 136.76 (d, J = 20.2Hz), 136.37 (d, J = 3.0Hz), 129.48, 128.72 (d, J = 8.0H z), 127.44, 125.98 (d, J = 6.1Hz), 125.07 (q, J = 276.7Hz), 115.78 (d, J = 21.2Hz), 87.88 (dq, J = 172.7, 3.0Hz), 41.46 (qd, J = 29.29, 26.26Hz).

[0121] 19 F NMR (CDCl3, 376MHz) δ-64.13 (d, J = 7.7Hz), -114.98, -175.16 (q, J = 7.4Hz).

[0122] Example 8: Preparation of 3'-chloro-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl

[0123]

[0124] In a 10 mL three-necked flask, 0.4 mmol of 3'-chloro-4-vinyl-1,1'-biphenyl, 0.5 mmol of tetrabutylammonium hexafluorophosphate, 0.8 mmol of trifluoromethyl sulfinate, 0.8 mmol of triethylamine trihydrofluoride, and 8 mL of acetonitrile were added sequentially. Using a carbon rod as the anode and a platinum electrode as the cathode, the reaction was carried out at 25 °C with a constant current of 5 mA for 12 h, monitored by TLC. After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by rapid silica gel column chromatography (using petroleum ether as the mobile phase) to obtain the product in 71% yield. 1 H NMR spectrum, 13 C NMR spectrum, 19 See F NMR image Figures 22-24 As shown.

[0125] 1 H NMR (CDCl3, 400MHz): δ7.61 (d, J = 8.0Hz, 2H), 7.57 (s, 1H), 7.47-7.32 (m, 5H), 5.82 (dd, J = 47.7, 6.6Hz, 1H), 2.98-2.79 (m, 1H), 2.71-2.48 (m, 1H).

[0126] 13 C NMR (CDCl3, 101MHz): δ142.07, 140.76, 140.75, 137.40 (d, J = 20.2Hz), 134.79, 130.11, 129.17, 127.72, 127.56, 127. 27,126.01(d,J=6.1Hz), 125.27,125.04(q,J=275.7Hz), 87.81(dq,J=173.7,3.0Hz), 41.47(qd,J=28.28,26.26Hz).

[0127] 19 F NMR (CDCl3, 376MHz) δ-64.11 (d, J = 8.0Hz), -175.67 (q, J = 7.9Hz).

[0128] Example 9: Preparation of 2'-chloro-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl

[0129]

[0130] In a 10 mL three-necked flask, 0.4 mmol of 2'-chloro-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl, 0.5 mmol of tetrabutylammonium hexafluorophosphate, 0.8 mmol of trifluoromethyl sulfinate, 0.8 mmol of triethylamine trihydrofluoride, and 8 mL of acetonitrile were added sequentially. Using a carbon rod as the anode and a platinum electrode as the cathode, the reaction was carried out at 25 °C with a constant current of 5 mA for 12 h, monitored by TLC. After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by rapid silica gel column chromatography (using petroleum ether as the mobile phase) to obtain the product, with a yield of 67%. 1 H NMR spectrum, 13 C NMR spectrum, 19 See F NMR image Figures 25-27 As shown.

[0131] 1 H NMR (CDCl3, 400MHz): δ7.52-7.47 (m, 3H), 7.43 (d, J = 8.0Hz, 2H), 7.35-7.28 (m,3H),5.83(dd,J=47.8,7.1Hz,1H),2.99-2.80(m,1H),2.72-2.50(m,1H).

[0132] 13 C NMR (CDCl3, 101MHz): δ140.34 (d, J = 2.0Hz), 139.61, 137.10 (d, J = 20.2Hz), 132.40, 131.24, 130.03, 129.96, 129.83, 128.89, 128.8 6,127.35,126.92,125.47,125.44(d,J=6.1Hz),125.11(q,J=277.8Hz),87.90(dq,J=172.7,3.0Hz),41.50(qd,J=29.29,26.26Hz).

[0133] 19 F NMR (CDCl3, 376MHz) δ -64.19 (d, J = 7.8Hz), -175.75 (q, J = 7.7Hz).

[0134] Example 10: Preparation of 4'-(1'-fluoro-2'-trifluoromethyl)ethyl-4-phenylpyridine

[0135]

[0136] In a 10 mL three-necked flask, 0.4 mmol of 4'-vinyl-4-phenylpyridine, 0.5 mmol of tetrabutylammonium hexafluorophosphate, 0.8 mmol of trifluoromethyl sulfinate, 0.8 mmol of triethylamine trihydrofluoride, and 8 mL of acetonitrile were added sequentially. Using a carbon rod as the anode and a platinum electrode as the cathode, the reaction was carried out at 25 °C with a constant current of 5 mA for 12 h, monitored by TLC. After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by rapid silica gel column chromatography (using petroleum ether as the mobile phase) to obtain the product, with a yield of 63%. 1 H NMR spectrum, 13 C NMR spectrum, 19 See F NMR image Figures 28-30 As shown.

[0137] 1 H NMR (CDCl3, 400MHz): δ8.69(d,J=4.6Hz,2H),7.69(d,J=8.0Hz,2H),7.50(t,J=7 .6Hz,4H),5.83(dd,J=49.0,10.7Hz,1H),2.97-2.79(m,1H),2.71-2.49(m,1H).

[0138] 13 C NMR (CDCl3, 101MHz): δ150.28, 147.44, 139.05 (d, J = 2.0Hz), 138.67 (d, J = 19.2Hz), 127.50, 126.16 (d, J=7.1Hz), 124.96 (q, J=276.7Hz), 121.60, 87.67 (dq, J=174.7, 3.0Hz), 41.45 (qd, J=28.28, 26.26Hz).

[0139] 19 F NMR (CDCl3, 376MHz) δ -64.08 (d, J = 7.8Hz), -176.61 (q, J = 7.7Hz).

[0140] HRMS (ESI) + ): Calculated for C 14 H 11 F3N + [M+H] + :251.0922; found:251.0918.

[0141] Example 11: Preparation of 4'-trimethylsilyl-4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl

[0142]

[0143] In a 10 mL three-necked flask, 0.4 mmol of 4'-trimethylsilyl-4-vinyl-1,1'-biphenyl, 0.5 mmol of tetrabutylammonium hexafluorophosphate, 0.8 mmol of trifluoromethylsulfinate, 0.8 mmol of triethylamine trihydrofluoride, and 8 mL of acetonitrile were added sequentially. Using a carbon rod as the anode and a platinum electrode as the cathode, the reaction was carried out at 25 °C with a constant current of 5 mA for 12 h, monitored by TLC. After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by rapid silica gel column chromatography (using petroleum ether as the mobile phase) to obtain the product in 54% yield. 1 H NMR spectrum, 13 C NMR spectrum, 19 See F NMR image Figures 31-33 As shown.

[0144] 1 H NMR (CDCl3, 400MHz): δ7.66-7.57(m,6H),7.43(d,J=7.6Hz,2H),5.88(dd,J=48.4,6.7Hz,1H),2.97-2.80(m,1H),2.71-2.46(m,1H),0.31(s,9H).

[0145] 13 C NMR (CDCl3, 101MHz): δ141.82 (d, J = 2.0Hz), 140.58, 136.44 (d, J = 19.2Hz), 133.91, 129.42, 127.58, 126.44, 1 25.58(d,J=7.1Hz), 125.23(q,J=221.2Hz), 87.58(dq,J=172.7,3.0Hz), 41.13(qd,J=29.29,25.25Hz), 29.36.

[0146] 19 F NMR (CDCl3, 376MHz) δ -64.18 (d, J = 8.0Hz), -175.04 (q, J = 7.9Hz).

[0147] Comparative experimental example:

[0148] The preparation method of 4-(1-fluoro-2-trifluoromethyl)ethyl-1,1'-biphenyl described in Example 1 differs from that in that:

[0149] 1. Replace the carbon rod with a carbon plate as the anode, and keep other conditions and parameters unchanged, and proceed according to Example 1;

[0150] 2. Replace the carbon rod with boron-doped diamond as the anode, and keep other conditions and parameters unchanged, proceeding according to Example 1;

[0151] 3. Replace the carbon rod with a platinum sheet as the anode, and keep other conditions and parameters unchanged, proceeding according to Example 1;

[0152] 4. Replace the carbon rod with an iron sheet as the anode, and keep other conditions and parameters unchanged, proceeding according to Example 1;

[0153] 5. Replace tetrabutylammonium hexafluorophosphate with 0.5 mmol of LiClO4 as the electrolyte, and keep other conditions unchanged, proceeding as in Example 1;

[0154] 6. Replace triethylamine trihydrofluoride with KF (2.0 equiv.) / PEG (2.0 equiv.) as the fluorinating agent, and keep other conditions unchanged, proceeding as in Example 1;

[0155] 7. Add 2.0 mmol of AcOH to the reaction system, and proceed as in Example 1;

[0156] 8. The reaction time was 6 hours, and other conditions remained unchanged, proceeding as in Example 1;

[0157] 9. The constant current is 8mA, and other conditions and parameters remain unchanged. The procedure is carried out according to Example 1.

[0158] The yields of the above products are shown in Table 1 below:

[0159] Table 1

[0160]

[0161]

[0162] As shown in Table 1, using carbon plates, boron-doped diamond, platinum sheets, or iron sheets instead of carbon rods as anodes resulted in product yields far lower than those of the present invention. Changing the electrolyte also led to a decrease in yield. Replacing triethylamine trihydrofluoride with KF (2.0 equiv.) / PEG (2.0 equiv.) resulted in no reaction during direct electrochemical synthesis. Excessive constant current also caused yields far lower than those of the present invention. Therefore, the fluorinating reagent, anode, constant current, and reaction time are all key factors for obtaining high yields of fluorine-containing and trifluoromethyl compounds.

Claims

1. An electrochemical synthesis method of fluorine-containing and trifluoromethyl compounds, comprising the following steps: adding a solvent, an electrolyte, an olefin, a fluorination reagent, a trifluoromethylation reagent, a cathode, and an anode in a diaphragm-free electrolytic cell in sequence, stirring at room temperature, and performing a reaction under a constant current condition; after the reaction is completed, concentrating the reaction solution, separating and purifying an organic phase, and obtaining a fluorine-containing and trifluoromethyl compound; the cathode is a platinum sheet electrode, the anode is a carbon rod, the solvent is acetonitrile, the electrolyte is tetrabutylammonium hexafluorophosphate, the fluorination reagent is triethylamine trifluoride, the constant current is 3-7 mA, the reaction temperature is 20-30 ℃, and the reaction time is 6-12 h; the olefin has a structure shown in the following formula (I): in formula (I), R is selected from a tert-butyl group, a trifluoromethyl group, a hydrogen atom, a trifluoromethoxy group, an ester group, a trimethylsilyl group, fluorine, and chlorine.

2. The electrochemical synthesis method according to claim 1, characterized in that, the trifluoromethylation reagent is sodium trifluoromethylsulfinate.

3. The electrochemical synthesis method according to claim 1, characterized in that, the molar concentration of the electrolyte in the solvent is 0.05-1.0 mol / L.

4. The electrochemical synthesis method of claim 1, wherein, the molar ratio of the olefin to the electrolyte is 1: (1-3), and the molar ratio of the olefin, the fluorination reagent, and the trifluoromethylation reagent is 1: (1-3): (1-3).

5. The electrochemical synthesis method of claim 1, wherein, the separation and purification mode is rotary evaporation to remove the solvent, and the residue is purified by silica gel column chromatography, and the eluent of the silica gel column is ethyl acetate: petroleum ether = 1: 5-1:

50.

6. An electrochemical synthesis method of fluorine-containing and trifluoromethyl compounds, comprising the following steps: (1) adding 4-vinylbiphenyl 0.4 mmol, tetrabutylammonium hexafluorophosphate 0.5 mmol, sodium trifluoromethylsulfinate 0.8 mmol, triethylamine trifluoride 0.8 mmol, and acetonitrile 8 mL in a three-necked flask in sequence, taking a carbon rod as an anode, a platinum sheet electrode as a cathode, performing a reaction under a constant current of 5 mA for 12 h at 25 ℃ under a nitrogen condition, and monitoring by TLC; (2) after the reaction is completed, removing the solvent of the reaction solution by a rotary evaporator, purifying the residue by rapid silica gel column chromatography to obtain a product, and using an eluent of ethyl acetate: petroleum ether = 1: 5-1: 50 for silica gel column chromatography.

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