A method for synthesizing a compound of the formula (I) by electrocatalysis

Abstract

This invention relates to the field of compound synthesis technology, specifically disclosing a method for synthesizing aromatic ring geminal difluoroallyl compounds using electrocatalysis. This invention develops a novel electrochemical synthesis method that uses the cathode and anode of an electrolytic cell instead of traditional metal catalysts to catalyze the reaction of aryl diazonium salts and α-(trifluoromethyl)styrene, thereby achieving the synthesis of aromatic ring geminal difluoroallyl compounds. The synthesis method provided by this invention is economical and efficient, requires no expensive transition metal catalysis, leaves no heavy metal residues, and meets the requirements of green chemical development.

Description

Technical Field

[0001] This invention relates to the field of compound synthesis technology, and specifically to a method for synthesizing aromatic ring geminopropyl compounds using electrocatalysis. Background Technology

[0002] The aromatic ring geminal difluoroallyl structure, due to its unique structure, possesses physicochemical properties such as stability, polarity, and lipophilicity, and is therefore widely used in the modification of drug molecules, pesticide molecules, and material molecules. In synthetic chemistry, aromatic ring geminal difluoroolefins can also serve as valuable multifunctional precursors for fluorine-containing molecules, transforming them into other fluorine-containing structures, such as monofluoroolefins, difluoromethyl products, and trifluoromethyl products. Therefore, developing efficient and convenient geminal difluoroallylation methods for constructing geminal difluoroolefins is of great significance, and the research on such synthetic methods has received continuous attention over the past few decades.

[0003] In 2008, Tomoya Miura et al. reported the reaction of arylborates with α-(trifluoromethyl)styrene using the noble metal rhodium catalyst [RhCl(COD)]2 and methylmagnesium chloride (MeMgCl) to obtain the aromatic ring geminal difluoroallyl structure. In 2022, Pan Yi's group reported the electrochemical reaction of iodoaryl hydrocarbons with α-(trifluoromethyl)styrene catalyzed by transition metal nickel complexes to generate the aromatic ring geminal difluoroallyl structure. In the same year, Frederic W. Patureau's group developed a photocatalytic reaction of aryl sulfonium salts with α-(trifluoromethyl)styrene using the noble metal ruthenium catalyst [Ru(bpy)3](PF6)2 to obtain the aromatic ring geminal difluoroallyl structure. Although the above methods can successfully construct the target framework, there are still obvious limitations: ruthenium catalysts are expensive (about 250 yuan / gram), and the synthesis of nickel complexes is complicated and expensive; and all of them inevitably introduce transition metal residues, which seriously restricts their large-scale application in the chemical and pharmaceutical fields.

[0004] Therefore, developing novel synthetic strategies that are green, economical, and free of metal residues is of significant research value and application importance for the preparation of aromatic ring geminodifluoroallyl compounds. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a method for the electrocatalytic synthesis of aromatic ring geminal difluoroallyl compounds. This invention utilizes the cathode and anode of an electrolytic cell instead of traditional metal catalysts to catalyze the reaction of aryl diazonium salts and α-(trifluoromethyl)styrene, thereby achieving the synthesis of aromatic ring geminal difluoroallyl compounds.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: A method for electrocatalytic synthesis of aromatic ring geminopropyl compounds, the method comprising the following steps: Compound 1, compound 2, electrolyte and organic solvent were added to a reaction flask and an electrocatalytic reaction was carried out under a nitrogen atmosphere. After the reaction was completed, the compound was separated and purified to obtain aryl ring difluoroallyl compound 3. R1 is selected from hydrogen, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, methyl, methoxy, or aryl; R2 is selected from hydrogen, fluorine, chlorine, bromine, aryl, alkyl, carboxylic acid ester, or aryl.

[0007] In the technical solution disclosed in this invention, compound 1 is synthesized according to existing literature methods, wherein the synthetic route of compound 1 is as follows: R1 is selected from hydrogen, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, methyl, methoxy, or aryl.

[0008] In the technical solution disclosed in this invention, the molar ratio of compound 1 and compound 2 is 1-3:1. For example, 1:1, 1.5:1, 2:1, 2.5:1, and 3:1 can be selected, but are not limited to the listed values. Other unlisted values ​​within the range are also applicable.

[0009] In the technical solution disclosed in this invention, the electrolyte is selected from tetrabutylammonium perchlorate.

[0010] In the technical solution disclosed in this invention, the organic solvent is selected from anhydrous acetonitrile.

[0011] In the technical solution disclosed in this invention, the anode of the electrocatalytic reaction is selected from a magnesium sheet electrode, and the cathode is selected from a platinum sheet electrode.

[0012] In the technical solution disclosed in this invention, the current of the electrocatalytic reaction is 4-6 mA and the electrolysis time is 6-10 h.

[0013] More preferably, the current for the electrocatalytic reaction is 5 mA and the electrolysis time is 8 h.

[0014] In the technical solution disclosed in this invention, separation and purification are carried out by column chromatography, recrystallization, thin-layer chromatography or vacuum distillation.

[0015] In a further preferred embodiment, when using column chromatography for separation and purification, petroleum ether and ethyl acetate are used as eluents, with a volume ratio of petroleum ether to ethyl acetate of 10:1.

[0016] Compared with the prior art, the present invention has the following beneficial effects: This invention develops a novel electrochemical synthesis method that utilizes the cathode and anode of an electrolytic cell instead of traditional metal catalysts to catalyze the reaction of aryl diazonium salts and α-(trifluoromethyl)styrene, thereby achieving the synthesis of aromatic ring geminal difluoroallyl compounds. The synthesis method provided by this invention is economical and efficient, requires no expensive transition metal catalysis, leaves no heavy metal residues, and meets the requirements of green chemical development. Attached Figure Description

[0017] Figure 1 The NMR spectrum of the compound synthesized in Example 1 of this invention; Figure 2 The NMR spectrum of the compound synthesized in Example 2 of this invention; Figure 3 This is the NMR spectrum of the compound synthesized in Example 3 of the present invention. Detailed Implementation

[0018] The present invention will be further described in detail below through specific preferred embodiments, but the present invention is not limited to the following embodiments.

[0019] It should be noted that, unless otherwise specified, all chemical reagents involved in this invention were purchased through commercial channels.

[0020] This invention synthesizes diazonium salt compounds according to existing literature methods, and the synthetic route is as follows: R1 is selected from hydrogen, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, methyl, methoxy, or aryl.

[0021] Taking the synthesis of phenyltetrafluoroborate diazonium salt as an example: 4.65 g (50 mmol) of aniline, 15 ml of deionized water, and 30 ml of fluoroboric acid (40% wt) were weighed into a 250 ml round-bottom flask. A stir bar was added and the mixture was stirred. After 15 min in an ice bath, 3.45 g (55 mmol) of sodium nitrite and 10 ml of deionized water were weighed into a 25 ml constant-pressure dropping funnel. The sodium nitrite solution was slowly added dropwise to the reaction system. After the addition was complete, the mixture was stirred in an ice bath for another 60 min. The mixture was then filtered, and the filter cake was collected. The filter cake was transferred to a round-bottom flask and recrystallized with acetone / ether. The mixture was then filtered again, and the filter cake was washed three times with ether. The filter cake was then dried in a vacuum oven at 40 ℃ for 3 h to obtain pure, dry phenyltetrafluoroborate diazonium salt.

[0022] Example 1 A method for the electrocatalytic synthesis of aromatic ring geminopropyl compounds includes the following steps: In a single-necked flask (25 mL) equipped with a stir bar, weigh out 576 mg (3 mmol) of phenyltetrafluoroborate diazonium salt and 248 mg (1 mmol) of 4-(3,3,3-trifluoroprop-1-en-2-yl)-1,1'-biphenyl. n Add Bu4NClO4 (341 mg, 1 mmol), and add 10 mL of anhydrous MeCN. Insert a magnesium electrode (10 × 10 mm) into the reaction flask. 2 As a sacrificial anode, a platinum sheet electrode (10 × 10 mm) 2 The reaction mixture was used as the cathode. Electrolysis of the reaction mixture under nitrogen atmosphere with constant current stirring at 5 mA for 8 h was performed. After the reaction was complete, the solution was extracted with ethyl acetate and water. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was removed by rotary evaporator, and column chromatography was performed on silica gel using petroleum ether and ethyl acetate as eluents (10:1) to obtain the target product in 73% yield.

[0023] Example 2 A method for the electrocatalytic synthesis of aromatic ring geminopropyl compounds includes the following steps: In a single-necked flask (25 mL) equipped with a stir bar, weigh out 666 mg (3 mmol) of 4-methoxyphenyldiazotetrafluoroborate and 248 mg (1 mmol) of 4-(3,3,3-trifluoroprop-1-en-2-yl)-1,1'-biphenyl. n Add Bu4NClO4 (341 mg, 1 mmol), and add 10 mL of anhydrous MeCN. Insert a magnesium electrode (10 × 10 mm) into the reaction flask. 2 As a sacrificial anode, a platinum sheet electrode (10 × 10 mm) 2 The reaction mixture was used as the cathode. Electrolysis of the reaction mixture under nitrogen atmosphere with constant current at 5 mA for 8 h was performed. After the reaction was complete, the solution was extracted with ethyl acetate and water. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was removed by rotary evaporator, and column chromatography was performed on silica gel using petroleum ether and ethyl acetate as eluents (10:1) to obtain the target product in 61% yield.

[0024] Example 3 A method for the electrocatalytic synthesis of aromatic ring geminopropyl compounds includes the following steps: In a single-necked flask (25 mL) equipped with a stir bar, weigh out 576 mg (3 mmol) of phenyltetrafluoroborate diazonium salt and 230 mg (1 mmol) of methyl 4-(3,3,3-trifluoroprop-1-en-2-yl)benzoate. n Add Bu4NClO4 (341 mg, 1 mmol), and add 10 mL of anhydrous MeCN. Insert a magnesium electrode (10 × 10 mm) into the reaction flask. 2 As a sacrificial anode, a platinum sheet electrode (10 × 10 mm) 2 The reaction mixture was used as the cathode. Electrolysis of the reaction mixture under nitrogen atmosphere with constant current at 5 mA for 8 h was performed. After the reaction was complete, the solution was extracted with ethyl acetate and water. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was removed by rotary evaporator, and column chromatography was performed on silica gel using petroleum ether and ethyl acetate as eluents (10:1) to obtain the target product in 84% yield.

[0025] Comparative Example 1 Compared with Example 1, Comparative Example 1 uses a different organic solvent, with anhydrous DCE replacing anhydrous MeCN.

[0026] In a single-necked flask (25 mL) equipped with a stir bar, weigh out 576 mg (3 mmol) of phenyltetrafluoroborate diazonium salt and 248 mg (1 mmol) of 4-(3,3,3-trifluoroprop-1-en-2-yl)-1,1'-biphenyl. n Add Bu4NClO4 (341 mg, 1 mmol), and add 10 mL of anhydrous DCE. Insert a magnesium electrode (10 × 10 mm) into the reaction flask. 2 As a sacrificial anode, a platinum sheet electrode (10 × 10 mm) 2 The reaction mixture was used as the cathode. Electrolysis of the reaction mixture under nitrogen atmosphere with constant current at 5 mA for 8 h was performed. After the reaction was complete, the solution was extracted with ethyl acetate and water. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was removed by rotary evaporator, and column chromatography was performed on silica gel using petroleum ether and ethyl acetate as eluents (10:1) to obtain the target product in 18% yield.

[0027] Comparative Example 2 Compared to Example 1, Comparative Example 2 uses a different electrolyte, replacing LiClO4. n Bu4NClO4.

[0028] In a single-necked flask (25 mL) equipped with a stirrer, weigh out 576 mg (3 mmol) of phenyltetrafluoroborate diazonium salt, 248 mg (1 mmol) of 4-(3,3,3-trifluoroprop-1-en-2-yl)-1,1'-biphenyl, and 329 mg (1 mmol) of LiClO4, and add anhydrous MeCN (10 mL). Insert a magnesium electrode (10 × 10 mm) into the reaction flask. 2 As a sacrificial anode, a platinum sheet electrode (10 × 10 mm) 2 The reaction mixture was used as the cathode. Electrolysis of the reaction mixture under nitrogen atmosphere with constant current at 5 mA for 8 h was performed. After the reaction was complete, the solution was extracted with ethyl acetate and water. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was removed by rotary evaporator, and column chromatography was performed on silica gel using petroleum ether and ethyl acetate as eluents (10:1) to obtain the target product in 27% yield.

[0029] Comparative Example 3 Compared with Example 1, Comparative Example 3 uses a different electrolyte. n Bu4NBF4 replacement n Bu4NClO4.

[0030] In a single-necked flask (25 mL) equipped with a stir bar, weigh out 576 mg (3 mmol) of phenyltetrafluoroborate diazonium salt and 248 mg (1 mmol) of 4-(3,3,3-trifluoroprop-1-en-2-yl)-1,1'-biphenyl. n Add Bu4NBF4 (329 mg, 1 mmol), and add 10 mL of anhydrous MeCN. Insert a magnesium electrode (10 × 10 mm) into the reaction flask. 2 As a sacrificial anode, a platinum sheet electrode (10 × 10 mm) 2 The reaction mixture was used as the cathode. Electrolysis of the reaction mixture under nitrogen atmosphere with constant current stirring at 5 mA for 8 h was performed. After the reaction was complete, the solution was extracted with ethyl acetate and water. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was removed by rotary evaporator, and column chromatography was performed on silica gel using petroleum ether and ethyl acetate as eluents (10:1) to obtain the target product in 54% yield.

[0031] Comparative Example 4 Compared with Example 1, Comparative Example 4 uses different electrodes, employing an iron sheet electrode as the sacrificial anode and a graphite plate electrode as the cathode.

[0032] In a single-necked flask (25 mL) equipped with a stir bar, weigh out 576 mg (3 mmol) of phenyltetrafluoroborate diazonium salt and 248 mg (1 mmol) of 4-(3,3,3-trifluoroprop-1-en-2-yl)-1,1'-biphenyl. n Add Bu4NBF4 (329 mg, 1 mmol), and add 10 mL of anhydrous MeCN. Insert an iron electrode (10 × 10 mm) into the reaction flask. 2 As a sacrificial anode, a graphite plate electrode (10 × 10 mm) 2 The reaction mixture was used as the cathode. Electrolysis of the reaction mixture under nitrogen atmosphere with constant current stirring at 5 mA for 8 h was performed. After the reaction was complete, the solution was extracted with ethyl acetate and water. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was removed by rotary evaporator, and column chromatography was performed on silica gel using petroleum ether and ethyl acetate as eluents (10:1) to obtain the target product in 38% yield.

[0033] Comparative Example 5 Compared with Example 1, Comparative Example 5 uses different electrodes, employing a nickel sheet electrode as the sacrificial anode and a graphite plate electrode as the cathode.

[0034] In a single-necked flask (25 mL) equipped with a stir bar, weigh out 576 mg (3 mmol) of phenyltetrafluoroborate diazonium salt and 248 mg (1 mmol) of 4-(3,3,3-trifluoroprop-1-en-2-yl)-1,1'-biphenyl. n Add Bu4NClO4 (341 mg, 1 mmol), and add 10 mL of anhydrous MeCN. Insert a nickel electrode (10 × 10 mm) into the reaction flask. 2 As a sacrificial anode, a graphite plate electrode (10 × 10 mm) 2 The reaction mixture was used as the cathode. Electrolysis of the reaction mixture under nitrogen atmosphere with constant current stirring at 5 mA for 8 h was performed. After the reaction was complete, the solution was extracted with ethyl acetate and water. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was removed by rotary evaporator, and column chromatography was performed on silica gel using petroleum ether and ethyl acetate as eluents (10:1) to obtain the target product in 42% yield.

[0035] Comparative Example 6 Compared with Example 1, Comparative Example 6 uses a different organic solvent, replacing anhydrous MeCN with a MeCN / DMF mixed solvent of 5:1 (volume ratio).

[0036] In a single-necked flask (25 mL) equipped with a stir bar, weigh out 576 mg (3 mmol) of phenyltetrafluoroborate diazonium salt and 248 mg (1 mmol) of 4-(3,3,3-trifluoroprop-1-en-2-yl)-1,1'-biphenyl. n Add Bu4NClO4 (341 mg, 1 mmol), and add 10 mL of mixed solvent (MeCN / DMF = 5:1). Insert a magnesium electrode (10 × 10 mm) into the reaction flask. 2 As a sacrificial anode, a platinum sheet electrode (10 × 10 mm) 2 The reaction mixture was used as the cathode. Electrolysis of the reaction mixture under nitrogen atmosphere with constant current stirring at 5 mA for 8 h was performed. After the reaction was complete, the solution was extracted with ethyl acetate and water. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was removed by rotary evaporator, and column chromatography was performed on silica gel using petroleum ether and ethyl acetate as eluents (10:1) to obtain the target product in 45% yield.

[0037] Comparative Example 7 Compared with Example 1, Comparative Example 7 uses a different organic solvent, replacing anhydrous MeCN with a MeCN / DMSO mixed solvent of 5:1 (volume ratio).

[0038] In a single-necked flask (25 mL) equipped with a stir bar, weigh out 576 mg (3 mmol) of phenyltetrafluoroborate diazonium salt and 248 mg (1 mmol) of 4-(3,3,3-trifluoroprop-1-en-2-yl)-1,1'-biphenyl. n Add Bu4NClO4 (341 mg, 1 mmol), and add 10 mL of mixed solvent (MeCN / DMSO = 5:1). Insert a magnesium electrode (10 × 10 mm) into the reaction flask. 2 As a sacrificial anode, a platinum sheet electrode (10 × 10 mm) 2 The reaction mixture was used as the cathode. Electrolysis of the reaction mixture under nitrogen atmosphere with constant current stirring at 5 mA for 8 h was performed. After the reaction was complete, the solution was extracted with ethyl acetate and water. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was removed by rotary evaporator, and column chromatography was performed on silica gel using petroleum ether and ethyl acetate as eluents (10:1) to obtain the target product in 33% yield.

[0039] Comparative Example 8 The current used in Comparative Example 8 is different from that in Example 1.

[0040] In a single-necked flask (25 mL) equipped with a stir bar, weigh out 576 mg (3 mmol) of phenyltetrafluoroborate diazonium salt and 248 mg (1 mmol) of 4-(3,3,3-trifluoroprop-1-en-2-yl)-1,1'-biphenyl. n Add Bu4NClO4 (341 mg, 1 mmol), and add 10 mL of anhydrous MeCN. Insert a magnesium electrode (10 × 10 mm) into the reaction flask. 2 As a sacrificial anode, a platinum sheet electrode (10 × 10 mm) 2 The reaction mixture was used as the cathode. Electrolysis of the reaction mixture under nitrogen atmosphere with constant current stirring at 10 mA for 4 h was performed. After the reaction was complete, the solution was extracted with ethyl acetate and water. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was removed by rotary evaporator, and column chromatography was performed on silica gel using petroleum ether and ethyl acetate as eluents (10:1) to obtain the target product in 47% yield.

[0041] Finally, it should be noted that the above embodiments do not limit the present invention in any way. Those skilled in the art can make modifications and improvements based on the present invention. Therefore, any modifications or improvements made without departing from the spirit of the present invention are within the scope of protection claimed by the present invention.

Claims

1. A method for the electrocatalytic synthesis of aromatic ring gem-difluoroallyl compounds, characterized in that, The method includes the following steps: Compound 1, compound 2, electrolyte and organic solvent were added to a reaction flask and an electrocatalytic reaction was carried out under a nitrogen atmosphere. After the reaction was completed, the compound was separated and purified to obtain aryl ring difluoroallyl compound 3. R1 is selected from hydrogen, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, methyl, methoxy, or aryl; R2 is selected from hydrogen, fluorine, chlorine, bromine, aryl, alkyl, carboxylic acid ester, or aryl.

2. The method according to claim 1, characterized in that, The molar ratio of compound 1 to compound 2 is 1-3:

1.

3. The method according to claim 1, characterized in that, The electrolyte is selected from tetrabutylammonium perchlorate.

4. The method according to claim 1, characterized in that, The organic solvent is selected from anhydrous acetonitrile.

5. The method according to claim 1, characterized in that, The anode for the electrocatalytic reaction is selected from a magnesium sheet electrode, and the cathode is selected from a platinum sheet electrode.

6. The method according to claim 1, characterized in that, The current for the electrocatalytic reaction is 4-6 mA, and the electrolysis time is 6-10 h.

7. The method according to claim 1, characterized in that, The electrocatalytic reaction uses a current of 5 mA and an electrolysis time of 8 h.

8. The method according to claim 1, characterized in that, Separation and purification were performed using column chromatography, recrystallization, thin-layer chromatography, or vacuum distillation.

9. The method according to claim 1, characterized in that, When separating and purifying the material using column chromatography, petroleum ether and ethyl acetate were used as eluents, with a volume ratio of 10:1.

Images