CN114507867B - Preparation method of fluoroamide derivative - Google Patents
Preparation method of fluoroamide derivative Download PDFInfo
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- CN114507867B CN114507867B CN202210198259.6A CN202210198259A CN114507867B CN 114507867 B CN114507867 B CN 114507867B CN 202210198259 A CN202210198259 A CN 202210198259A CN 114507867 B CN114507867 B CN 114507867B
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Abstract
The invention relates to the field of preparation methods of fluoroamide derivatives, and discloses a preparation method of fluoroamide derivatives. The invention aims to solve the technical problems of environmental pollution, high energy consumption and high cost caused by the high-temperature high-pressure metal catalysis condition required by the conventional method for synthesizing the fluoroamide derivative. The method comprises the following steps: uniformly mixing a trifluoromethyl amide compound, a boron reagent, an electrolyte and an organic solvent, putting the mixture into two electrodes for electrocatalytic reaction, removing the solvent by rotary evaporation, and then separating and purifying the mixture by silica gel column chromatography to obtain the product, namely the fluoroamide derivative. The method can react at normal temperature and normal pressure, has mild reaction conditions, does not need transition metal catalysis, has the highest yield of 77 percent, and has the advantages of simple operation, no pollution, safety, environmental protection and low cost. The invention is applied to the field of organic synthesis. The invention is used for preparing the fluoro-amide derivative.
Description
Technical Field
The present invention relates to the field of processes for the preparation of fluoroamide derivatives.
Background
A difluoromethyl group (CF) 2 H) The physicochemical and biological properties can be adjusted by incorporating into natural products or bioactive molecules. For example, such hydrofluorides enhance the solubility and bioavailability of the film by enhancing hydrogen bonding and lipophilicity. Thus, containing difluoromethyl (CF) 2 H) Molecules have been widely used in the fields of medicinal chemistry, chemical biology, and material science due to the unique physical and biological properties of fluorine atoms. In view of these characteristics, many chemists have great interest and have endeavored to establish general methods for synthesizing these target molecules. Over the past several decades, many monofluoroalkylated and difluoroalkylated precursors, as well as fluorination reagents and strategies, have shown great utility. From readily available trifluoromethyl (CF) 3 ) Starting from the starting materials, the functionalization of C-F bonds has also proven to be an effective way, in particular for synthesis challenges or the likeProducts which cannot be realized by other methods. However, it is difficult to continuously replace two fluorine atoms having various functions while maintaining high chemical selectivity. The strength of the C-F bond decreases as the defluorination proceeds, resulting in thorough defluorination. The strategy to solve this problem is to utilize inexpensive CF 3 It would be highly desirable if the starting materials provided a particularly economical and valuable route to difluoro and monofluoro products.
Disclosure of Invention
The invention provides a preparation method of a fluoroamide derivative, aiming at solving the technical problems of environmental pollution, high energy consumption and high cost caused by the high-temperature high-pressure metal catalysis condition required by the prior method for synthesizing the fluoroamide derivative.
A preparation method of a fluoroamide derivative specifically comprises the following steps:
1. uniformly mixing a trifluoromethyl amide compound, a boron reagent, an electrolyte and an organic solvent, adding silica gel, and uniformly stirring to obtain a mixed solution;
2. putting two electrodes into the mixed solution obtained in the first step, switching on a power supply, and carrying out electrocatalytic reaction under the conditions of room temperature and air atmosphere with stirring to obtain a reaction mixture;
3. distilling the reaction mixture obtained in the step two under reduced pressure to remove the solvent, adding silica gel, and uniformly stirring to obtain a crude product;
4. and (4) purifying the crude product obtained in the third step by silica gel column chromatography to obtain the fluoroamide derivative, thus completing the preparation.
Further, in the first step, the structural formula of the trifluoromethyl amide compound is:
wherein R is aryl, heteroaryl, alkyl, halogen or hydrogen.
Further, in the first step, the boron reagent is 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane) -benzonitrile.
The invention has the beneficial effects that:
the invention provides a simple one-step method for synthesizing a fluoroamide derivative, which solves the problems of complex synthesis steps, low yield and poor environmental protection of the conventional fluoroamide derivative, can be used for reaction at normal temperature and normal pressure, has mild reaction conditions, uses a magnesium rod as an anode sacrificial electrode, does not need transition metal catalysis, has the yield of 40-77 percent, has wide substrate universality and has great value in application. Moreover, the method also has the advantages of simple operation, no pollution, safety, environmental protection, low cost and the like.
The invention is used for preparing the fluoro-amide derivative.
Drawings
FIG. 1 shows the product obtained in example one 1 H NMR spectrum;
FIG. 2 shows the product obtained in example one 13 C NMR spectrum;
FIG. 3 shows the product obtained in the first example 19 F NMR spectrum;
fig. 4 is a partially enlarged view of fig. 3.
Detailed Description
The technical solution of the present invention is not limited to the specific embodiments listed below, and includes any combination of the specific embodiments.
The first embodiment is as follows: the preparation method of the fluoroamide derivative of the present embodiment specifically includes the following steps:
1. uniformly mixing a trifluoromethyl amide compound, a boron reagent, an electrolyte and an organic solvent, adding silica gel, and uniformly stirring to obtain a mixed solution;
2. putting two electrodes into the mixed solution obtained in the step one, switching on a power supply, and carrying out electrocatalytic reaction under the conditions of room temperature and air atmosphere with stirring to obtain a reaction mixture;
3. distilling the reaction mixture obtained in the second step under reduced pressure to remove the solvent, adding silica gel, and uniformly stirring to obtain a crude product;
4. and (4) purifying the crude product obtained in the third step by silica gel column chromatography to obtain the fluoroamide derivative, thus completing the preparation.
Detailed description of the inventionThe second method comprises the following steps: the first difference between the present embodiment and the specific embodiment is: step one the structural formula of the trifluoromethyl amide compound is:
wherein R is aryl, heteroaryl, alkyl, halogen or hydrogen. The rest is the same as the first embodiment.
The third concrete implementation mode: the first or second difference between the present embodiment and the specific embodiment is: step one the boron reagent is 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane) -benzonitrile. The other is the same as in the first or second embodiment.
The fourth concrete implementation mode is as follows: the difference between this embodiment and one of the first to third embodiments is: in the first step, the organic solvent is a mixture of acetonitrile and water, and the volume ratio of acetonitrile to water is 4. The others are the same as in one of the first to third embodiments.
The fifth concrete implementation mode: the difference between this embodiment and one of the first to fourth embodiments is: step one, the electrolyte is tetrabutylammonium tetrafluoroborate. The rest is the same as one of the first to fourth embodiments.
The sixth specific implementation mode: the difference between this embodiment and one of the first to fifth embodiments is: step one the molar ratio of the trifluoromethyl amide compound, boron reagent and electrolyte is 1. The other is the same as one of the first to fifth embodiments.
The seventh embodiment: the difference between this embodiment and one of the first to sixth embodiments is: and step two, the two electrodes are respectively a magnesium rod electrode and a carbon rod electrode. The rest is the same as one of the first to sixth embodiments.
The specific implementation mode is eight: the present embodiment differs from one of the first to seventh embodiments in that: and step two, carrying out electrocatalysis reaction, controlling the current to be 10mA, and controlling the electrolysis time to be 6-7 h. The other is the same as one of the first to seventh embodiments.
The specific implementation method nine: the present embodiment differs from the first to eighth embodiments in that: and step three, the temperature of the reduced pressure distillation is 25 ℃, and the pressure is 0.1MPa. The rest is the same as the first to eighth embodiments.
The detailed implementation mode is ten: the present embodiment differs from one of the first to ninth embodiments in that: the eluent adopted by the step four silica gel column chromatography is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the ethyl acetate to the petroleum ether is 1 (100-10). The other is the same as one of the first to ninth embodiments.
The following examples were used to demonstrate the beneficial effects of the present invention:
the first embodiment is as follows:
the preparation method of the fluoroamide derivative of the present embodiment specifically includes the following steps:
1. sequentially adding 0.4mmol 2, 2-trifluoro-substituted derivative 2, trifluoro-N-phenylacetamide, 1.2mmol 4-cyanophenylboronic acid pinacol ester, 0.5mmol tetrabutylammonium tetrafluoroborate and an organic solvent into a 25mL three-necked flask, and uniformly mixing to obtain a mixed solution; the organic solvent is 4mL acetonitrile and 0.05mL water;
2. putting two electrodes into the mixed solution obtained in the first step, switching on a power supply, carrying out electrocatalytic reaction under the conditions of room temperature and air atmosphere along with stirring, wherein the two electrodes are respectively a magnesium rod electrode and a carbon rod electrode, the diameter of the magnesium rod is 6mm, the diameter of the carbon rod is 4mm, the distance between the two electrodes is 2cm, the power supply is a constant potential rectifier, the current is constant current, the control current is 10mA, and the electrolysis time is 6h, so as to obtain a reaction mixture;
3. distilling the reaction mixture obtained in the step two under reduced pressure to remove the solvent, adding silica gel, stirring uniformly, controlling the temperature of reduced pressure distillation at 25 ℃ and the pressure at 0.1MPa, and obtaining a crude product;
4. and (3) purifying the crude product obtained in the third step by silica gel column chromatography, wherein an eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the ethyl acetate to the petroleum ether is 1.
Step one, the 2, trifluoro-N-phenylacetamide is prepared by adding trifluoroacetic anhydride into aniline and dichloromethane serving as a solvent at 0 ℃ and stirring.
The reaction equation in this example is:
the fluoroamide derivative obtained in this example was 99% pure and 64.0% yield, and the NMR data analysis showed: 1 H NMR(400MHz,CDCl 3 )δ8.11(s,1H),7.57(d,J＝7.6Hz,2H),7.37(t,J＝8.0Hz,2H),7.21(t,J＝7.4Hz,1H),6.01(t,J＝54.4Hz,1H)； 13 C NMR(100MHz,CDCl3)δ160.8(t,J＝24.4Hz),135.7,129.3,125.9,120.5,106.0(t,J＝252.2Hz)； 19 F NMR(CDCl 3 ,376MHz):δ-125.5(2F,d,J＝54.5Hz).
the second embodiment:
the preparation method of the fluoroamide derivative of the present embodiment specifically includes the following steps:
1. sequentially adding 0.4mmol 2, 2-trifluoro-substituted derivative 2, trifluoro-N- (p-tolyl) acetamide, 1.2mmols 4-cyanophenylboronic acid pinacol ester, 0.5mmol tetrabutylammonium tetrafluoroborate and an organic solvent into a 25mL three-necked flask, and uniformly mixing to obtain a mixed solution; the organic solvent is 4mL acetonitrile and 0.05mL water;
2. putting two electrodes into the mixed solution obtained in the first step, switching on a power supply, carrying out electrocatalytic reaction under the conditions of room temperature and air atmosphere along with stirring, wherein the two electrodes are respectively a magnesium rod electrode and a carbon rod electrode, the diameter of the magnesium rod is 6mm, the diameter of the carbon rod is 4mm, the distance between the two electrodes is 2cm, the power supply is a constant potential rectifier, the current is constant current, the control current is 10mA, and the electrolysis time is 6h, so as to obtain a reaction mixture;
3. distilling the reaction mixture obtained in the step two under reduced pressure to remove the solvent, adding silica gel, stirring uniformly, controlling the temperature of reduced pressure distillation at 25 ℃ and the pressure at 0.1MPa, and obtaining a crude product;
4. and (3) purifying the crude product obtained in the third step by silica gel column chromatography, wherein an eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the ethyl acetate to the petroleum ether is 1.
Step one, the 2, trifluoro-N- (p-tolyl) acetamide is prepared by adding trifluoroacetic anhydride into 4-methylaniline and dichloromethane serving as a solvent at 0 ℃ and stirring.
The reaction equation of this embodiment is:
the fluoroamide derivative of example two was prepared in 99% purity and 77.0% yield, and the NMR data analysis was: 1 H NMR(400MHz,CDCl 3 )δ7.89(s,1H),7.45(d,J＝8.4Hz,2H),7.17(d,J＝8.0Hz,2H),6.01(t,J＝54.4Hz,1H),2.34(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ160.5(t,J＝24.1Hz),135.7,133.1,129.8,120.4,106.1(t,J＝252.6Hz),21.0； 19 F NMR(CDCl 3 ,376MHz):δ-125.5(2F,d,J＝54.9Hz).
example three:
the preparation method of the fluoroamide derivative of the present embodiment specifically includes the following steps:
1. sequentially adding 0.4mmol 2, 2-trifluoro-substituted derivative 2, trifluoro-N- (4-isopropylphenyl) acetamide, 1.2mmol 4-cyanophenylboronic acid pinacol ester, 0.5mmol tetrabutylammonium tetrafluoroborate and an organic solvent into a 25mL three-neck flask, and uniformly mixing to obtain a mixed solution; the organic solvent is 4mL acetonitrile and 0.05mL water;
2. putting two electrodes into the mixed solution obtained in the first step, switching on a power supply, carrying out electrocatalysis reaction along with stirring at room temperature and in an air atmosphere, wherein the two electrodes are a magnesium rod electrode and a carbon rod electrode respectively, the diameter of the magnesium rod is 6mm, the diameter of the carbon rod is 4mm, the distance between the two electrodes is 2cm, the power supply is a constant potential rectifier, the current is constant current, the control current is 10mA, and the electrolysis time is 6h, so as to obtain a reaction mixture;
3. distilling the reaction mixture obtained in the second step under reduced pressure to remove the solvent, adding silica gel, stirring uniformly, and controlling the temperature of the reduced pressure distillation to be 25 ℃ and the pressure to be 0.1MPa to obtain a crude product;
4. and (3) purifying the crude product obtained in the third step by silica gel column chromatography, wherein an eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the ethyl acetate to the petroleum ether is 1.
Step one, the 2, trifluoro-N- (4-isopropylphenyl) acetamide is prepared by adding trifluoroacetic anhydride into 4-isopropylaniline and dichloromethane serving as a solvent at the temperature of 0 ℃ and stirring.
The reaction equation in this example is:
the fluoroamide derivative of example three was prepared in 99% purity and 55.0% yield, and the NMR data analysis was: 1 H NMR(400MHz,CDCl 3 )δ7.85(s,1H),7.49-7.47(m,2H),7.25-7.23(m,2H),6.01(t,J＝54.4Hz,1H),2.94-2.87(m,1H),1.26-1.24(m,6H)； 13 C NMR(100MHz,CDCl 3 )δ160.2(t,J＝26.2Hz),146.7,133.3,127.2,120.4,106.1(t,J＝252.7Hz),33.7,24.0； 19 F NMR(CDCl 3 ,376MHz):δ-125.5(2F,d,J＝54.1Hz).
example four:
the preparation method of the fluoroamide derivative of the present embodiment specifically includes the following steps:
1. sequentially adding 0.4mmol 2, 2-trifluoro-substituted derivative 2, trifluoro-N- (4-fluorophenyl) acetamide, 1.2mmol 4-cyanophenylboronic acid pinacol ester, 0.5mmol tetrabutylammonium tetrafluoroborate and an organic solvent into a 25mL three-necked flask, and uniformly mixing to obtain a mixed solution; the organic solvent is 4mL acetonitrile and 0.05mL water;
2. putting two electrodes into the mixed solution obtained in the first step, switching on a power supply, carrying out electrocatalysis reaction along with stirring at room temperature and in an air atmosphere, wherein the two electrodes are a magnesium rod electrode and a carbon rod electrode respectively, the diameter of the magnesium rod is 6mm, the diameter of the carbon rod is 4mm, the distance between the two electrodes is 2cm, the power supply is a constant potential rectifier, the current is constant current, the control current is 10mA, and the electrolysis time is 6h, so as to obtain a reaction mixture;
3. distilling the reaction mixture obtained in the step two under reduced pressure to remove the solvent, adding silica gel, stirring uniformly, controlling the temperature of reduced pressure distillation at 25 ℃ and the pressure at 0.1MPa, and obtaining a crude product;
4. and (3) purifying the crude product obtained in the third step by silica gel column chromatography, wherein an eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the ethyl acetate to the petroleum ether is 1.
The 2, trifluoro-N- (4-fluorophenyl) acetamide is prepared by adding trifluoroacetic anhydride into 4-fluoroaniline and dichloromethane serving as a solvent at the temperature of 0 ℃ and stirring.
The reaction equation in this example is:
the fluoroamide derivative prepared in example IV had a purity of 99% and a yield of 52.0%, and the NMR data analysis showed: 1 H NMR(400MHz,CDCl 3 )δ7.96(s,1H),7.56-7.53(m,2H),7.07(t,J＝8.6Hz,2H),6.02(t,J＝54.2Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ161.5(d,J＝244.4Hz),160.4(t,J＝24.5Hz),131.7(d,J＝2.8Hz),122.3(d,J＝8.0Hz),116.0(d,J＝22.7Hz),106.0(t,J＝252.7Hz)； 19 F NMR(CDCl 3 ,376MHz):δ-125.6(2F,d,J＝54.5Hz).
example five:
the preparation method of a fluoroamide derivative of this example specifically includes the following steps:
1. sequentially adding 0.4mmol 2, 2-trifluoro-substituted derivative 2, trifluoro-N- (4-chlorphenyl) acetamide, 1.2mmols 4-cyanophenylboronic acid pinacol ester, 0.5mmol tetrabutylammonium tetrafluoroborate and an organic solvent into a 25mL three-neck flask, and uniformly mixing to obtain a mixed solution; the organic solvent is 4mL acetonitrile and 0.05mL water;
2. putting two electrodes into the mixed solution obtained in the first step, switching on a power supply, carrying out electrocatalysis reaction along with stirring at room temperature and in an air atmosphere, wherein the two electrodes are a magnesium rod electrode and a carbon rod electrode respectively, the diameter of the magnesium rod is 6mm, the diameter of the carbon rod is 4mm, the distance between the two electrodes is 2cm, the power supply is a constant potential rectifier, the current is constant current, the control current is 10mA, and the electrolysis time is 6h, so as to obtain a reaction mixture;
3. distilling the reaction mixture obtained in the step two under reduced pressure to remove the solvent, adding silica gel, stirring uniformly, controlling the temperature of reduced pressure distillation at 25 ℃ and the pressure at 0.1MPa, and obtaining a crude product;
4. and (3) purifying the crude product obtained in the third step by silica gel column chromatography, wherein an eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the ethyl acetate to the petroleum ether is 1.
Step one, the 2, trifluoro-N- (4-chlorphenyl) acetamide is prepared by adding trifluoroacetic anhydride into 4-chloroaniline and dichloromethane serving as a solvent at the temperature of 0 ℃ and stirring.
The reaction equation of this embodiment is:
the fluoroamide prepared in example five had a purity of 99% and a yield of 40.0%, and the NMR data analysis was: 1 H NMR(400MHz,CDCl 3 )δ7.93(s,1H),7.53(d,J＝8.8Hz,2H),7.34(d,J＝8.8Hz,2H),6.02(t,J＝54.2Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ160.3(t,J＝24.6Hz),134.2,131.1,129.4,121.6,108.5(t,J＝252.9Hz)； 19 F NMR(CDCl 3 ,376MHz):δ-125.5(2F,d,J＝54.5Hz).
example six:
the preparation method of the fluoroamide derivative of the present embodiment specifically includes the following steps:
1. sequentially adding 0.4mmol 2, 2-trifluoro-substituted derivative 2, trifluoro-N- (4-methoxyphenyl) acetamide, 1.2mmol 4-cyanophenylboronic acid pinacol ester, 0.5mmol tetrabutylammonium tetrafluoroborate and an organic solvent into a 25mL three-neck flask, and uniformly mixing to obtain a mixed solution; the organic solvent is 4mL acetonitrile and 0.05mL water;
2. putting two electrodes into the mixed solution obtained in the first step, switching on a power supply, carrying out electrocatalytic reaction under the conditions of room temperature and air atmosphere along with stirring, wherein the two electrodes are respectively a magnesium rod electrode and a carbon rod electrode, the diameter of the magnesium rod is 6mm, the diameter of the carbon rod is 4mm, the distance between the two electrodes is 2cm, the power supply is a constant potential rectifier, the current is constant current, the control current is 10mA, and the electrolysis time is 6h, so as to obtain a reaction mixture;
3. distilling the reaction mixture obtained in the step two under reduced pressure to remove the solvent, adding silica gel, stirring uniformly, controlling the temperature of reduced pressure distillation at 25 ℃ and the pressure at 0.1MPa, and obtaining a crude product;
4. and (3) purifying the crude product obtained in the third step by silica gel column chromatography, wherein an eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the ethyl acetate to the petroleum ether is 1.
Step one, the 2, trifluoro-N- (4-methoxyphenyl) acetamide is prepared by adding trifluoroacetic anhydride into 4-methoxyaniline and dichloromethane serving as a solvent at the temperature of 0 ℃ and stirring.
The reaction equation in this example is:
the fluoroamide derivative prepared in example VI had a purity of 99% and a yield of 61.0%, and the NMR data analysis was: 1 H NMR(400MHz,CDCl 3 )δ8.04(s,1H),7.46(d,J＝8.4Hz,2H),6.88(d,J＝8.8Hz,2H),5.99(td,J＝54.4Hz,1H),3.79(m,3H)； 13 C NMR(100MHz,CDCl 3 )δ160.3(t,J＝21.3Hz),157.5,128.7,122.2,114.4,108.6(t,J＝252.4Hz),55.5； 19 F NMR(CDCl 3 ,376MHz):δ-125.6(2F,dd,J＝54.1,9.4Hz).
example seven:
the preparation method of the fluoroamide derivative of the present embodiment specifically includes the following steps:
1. sequentially adding 0.4mmol 2, 2-trifluoro-substituted derivative 2, trifluoro-N- (4-ethoxyphenyl) acetamide, 1.2mmol 4-cyanophenylboronic acid pinacol ester, 0.5mmol tetrabutylammonium tetrafluoroborate and an organic solvent into a 25mL three-neck flask, and uniformly mixing to obtain a mixed solution; the organic solvent is 4mL acetonitrile and 0.05mL water;
2. putting two electrodes into the mixed solution obtained in the first step, switching on a power supply, carrying out electrocatalysis reaction along with stirring at room temperature and in an air atmosphere, wherein the two electrodes are a magnesium rod electrode and a carbon rod electrode respectively, the diameter of the magnesium rod is 6mm, the diameter of the carbon rod is 4mm, the distance between the two electrodes is 2cm, the power supply is a constant potential rectifier, the current is constant current, the control current is 10mA, and the electrolysis time is 6h, so as to obtain a reaction mixture;
3. carrying out reduced pressure distillation on the reaction mixture obtained in the step two to remove the solvent, adding silica gel, uniformly stirring, and controlling the temperature of the reduced pressure distillation to be 25 ℃ and the pressure to be 0.1MPa to obtain a crude product;
4. and (3) purifying the crude product obtained in the third step by silica gel column chromatography, wherein an eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the ethyl acetate to the petroleum ether is 1.
Step one, the 2, trifluoro-N- (4-ethoxy phenyl) acetamide is prepared by adding trifluoroacetic anhydride into 4-ethoxy aniline and dichloromethane serving as a solvent at the temperature of 0 ℃ and stirring.
The reaction equation of this embodiment is:
the fluoroamide derivative prepared in example seven had a purity of 99% and a yield of 56.0%, and the nuclear magnetic data analysis showed: 1 H NMR(400MHz,CDCl 3 )δ7.94(s,1H),7.45(d,J＝9.2Hz,2H),6.87(d,J＝9.2Hz,2H),6.00(t,J＝54.4Hz,1H),4.02(q,J＝7.0Hz,2H),1.41(t,J＝7.0Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ160.2(t,J＝24.2Hz),156.9,128.5,122.2,115.0,108.7(t,J＝252.3Hz),63.8,14.8； 19 F NMR(CDCl 3 ,376MHz):δ-125.5(2F,d,J＝54.1Hz).
example eight:
the preparation method of the fluoroamide derivative of the present embodiment specifically includes the following steps:
1. sequentially adding 0.4mmol 2, 2-trifluoro-substituted derivative 2, trifluoro-N- (4-phenoxyphenol) acetamide, 1.2mmol 4-cyanophenylboronic acid pinacol ester, 0.5mmol tetrabutylammonium tetrafluoroborate and an organic solvent into a 25mL three-neck flask, and uniformly mixing to obtain a mixed solution; the organic solvent is 4mL acetonitrile and 0.05mL water;
2. putting two electrodes into the mixed solution obtained in the first step, switching on a power supply, carrying out electrocatalytic reaction under the conditions of room temperature and air atmosphere along with stirring, wherein the two electrodes are respectively a magnesium rod electrode and a carbon rod electrode, the diameter of the magnesium rod is 6mm, the diameter of the carbon rod is 4mm, the distance between the two electrodes is 2cm, the power supply is a constant potential rectifier, the current is constant current, the control current is 10mA, and the electrolysis time is 6h, so as to obtain a reaction mixture;
3. distilling the reaction mixture obtained in the step two under reduced pressure to remove the solvent, adding silica gel, stirring uniformly, controlling the temperature of reduced pressure distillation at 25 ℃ and the pressure at 0.1MPa, and obtaining a crude product;
4. and (3) purifying the crude product obtained in the third step by silica gel column chromatography, wherein an eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the ethyl acetate to the petroleum ether is 1.
Step one, the 2, trifluoro-N- (4-phenoxyphenol) acetamide is prepared by adding trifluoroacetic anhydride into 4-phenoxyaniline and dichloromethane serving as a solvent at the temperature of 0 ℃ and stirring.
The reaction equation in this example is:
the fluoroamide derivative prepared in example viii had a purity of 99% and a yield of 55.0%, and the NMR data analysis showed: 1 H NMR(400MHz,CDCl 3 )δ8.00(s,1H),7.54-7.52(m,2H),7.37-7.33(m,2H),7.12(t,J＝7.4Hz,1H),7.03-7.00(m,4H),6.02(t,J＝54.2Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ160.4(t,J＝24.4Hz),157.0,155.0,130.9,129.9,123.6,122.2,119.5,118.9,108.6(t,J＝252.5Hz)； 19 F NMR(CDCl 3 ,376MHz):δ-125.4(2F,d,J＝54.5Hz).
example nine:
the preparation method of the fluoroamide derivative of the present embodiment specifically includes the following steps:
1. sequentially adding 0.4mmol 2, 2-trifluoro-substituted derivative 2, trifluoro-N- (3-methoxyphenyl) acetamide, 1.2mmol 4-cyanophenylboronic acid pinacol ester, 0.5mmol tetrabutylammonium tetrafluoroborate and an organic solvent into a 25mL three-neck flask, and uniformly mixing to obtain a mixed solution; the organic solvent is 4mL acetonitrile and 0.05mL water;
2. putting two electrodes into the mixed solution obtained in the first step, switching on a power supply, carrying out electrocatalytic reaction under the conditions of room temperature and air atmosphere along with stirring, wherein the two electrodes are respectively a magnesium rod electrode and a carbon rod electrode, the diameter of the magnesium rod is 6mm, the diameter of the carbon rod is 4mm, the distance between the two electrodes is 2cm, the power supply is a constant potential rectifier, the current is constant current, the control current is 10mA, and the electrolysis time is 6h, so as to obtain a reaction mixture;
3. distilling the reaction mixture obtained in the step two under reduced pressure to remove the solvent, adding silica gel, stirring uniformly, controlling the temperature of reduced pressure distillation at 25 ℃ and the pressure at 0.1MPa, and obtaining a crude product;
4. and (3) purifying the crude product obtained in the third step by silica gel column chromatography, wherein an eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the ethyl acetate to the petroleum ether is 1.
Step one, the 2, trifluoro-N- (3-methoxyphenyl) acetamide is prepared by adding trifluoroacetic anhydride into 3-methoxyaniline and dichloromethane serving as a solvent at 0 ℃ and stirring.
The reaction equation in this example is:
example nine the fluoroamide derivative prepared was 99% pure and 67.0% yield, with nuclear magnetic data analysis: 1 H NMR(400MHz,CDCl 3 )δ7.91(s,1H),7.31-7.27(m,1H),7.28(d,J＝3.2Hz,1H),7.08-7.06(m,1H),6.77(dd,J＝8.4,2.2Hz,1H),6.02(t,J＝54.4Hz,1H),3.83(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ160.3(t,J＝24.2Hz),136.8,130.0,112.4,111.7,106.1,106.0(t,J＝252.9Hz),55.4； 19 F NMR(CDCl 3 ,376MHz):δ-125.5(2F,d,J＝54.1Hz).
example ten:
the preparation method of the fluoroamide derivative of the present embodiment specifically includes the following steps:
1. sequentially adding 0.4mmol of 2, 3-pentafluoro-N-phenylacrylamide, 1.2mmol of 4-cyanophenylboronic acid pinacol ester, 0.5mmol of tetrabutylammonium tetrafluoroborate and an organic solvent into a 25mL three-necked flask, and uniformly mixing to obtain a mixed solution; the organic solvent is 4mL acetonitrile and 0.05mL water;
2. putting two electrodes into the mixed solution obtained in the first step, switching on a power supply, carrying out electrocatalytic reaction under the conditions of room temperature and air atmosphere along with stirring, wherein the two electrodes are respectively a magnesium rod electrode and a carbon rod electrode, the diameter of the magnesium rod is 6mm, the diameter of the carbon rod is 4mm, the distance between the two electrodes is 2cm, the power supply is a constant potential rectifier, the current is constant current, the control current is 10mA, and the electrolysis time is 6h, so as to obtain a reaction mixture;
3. distilling the reaction mixture obtained in the step two under reduced pressure to remove the solvent, adding silica gel, stirring uniformly, controlling the temperature of reduced pressure distillation at 25 ℃ and the pressure at 0.1MPa, and obtaining a crude product;
4. and (3) purifying the crude product obtained in the third step by silica gel column chromatography, wherein an eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the ethyl acetate to the petroleum ether is 1.
The 2, 3-pentafluoro-N-phenylacrylamide is prepared by adding perfluoropropionic anhydride into aniline and dichloromethane serving as a solvent at 0 ℃ and stirring.
The reaction equation in this example is:
the fluoroamide derivative prepared in example ten had a purity of 99% and a yield of 66.0%, and the NMR data analysis showed: 1 H NMR(400MHz,CDCl 3 )δ7.99(s,1H),7.57(d,J＝8.0Hz,2H),7.38(t,J＝7.8Hz,2H),7.22(t,J＝7.4Hz,1H),7.22(t,J＝7.4Hz,1H),5.20(dq,J＝46.4,6.4Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ158.8(d,J＝17.5Hz),135.7,129.3,125.9,120.4,119.1(dd,J＝255.3,25.3Hz),84.2(dq,J＝204.1,33.7Hz)； 19 F NMR(CDCl 3 ,376MHz):δ-200.0(1F,dqd,J＝36.8,10.9,4.1Hz),-75.7(3F,dd,J＝10.5,4.1Hz)。
Claims (7)
1. the preparation method of the fluoroamide derivative is characterized by comprising the following steps of:
1. uniformly mixing a trifluoromethyl amide compound, a boron reagent, an electrolyte and an organic solvent, adding silica gel, and uniformly stirring to obtain a mixed solution;
2. putting two electrodes into the mixed solution obtained in the step one, switching on a power supply, and carrying out electrocatalytic reaction under the conditions of room temperature and air atmosphere with stirring to obtain a reaction mixture;
3. distilling the reaction mixture obtained in the step two under reduced pressure to remove the solvent, adding silica gel, and uniformly stirring to obtain a crude product;
4. purifying the crude product obtained in the third step by silica gel column chromatography to obtain a fluoroamide derivative, thereby completing the preparation;
step one the structural formula of the trifluoromethyl amide compound is:
wherein R is aryl, heteroaryl, alkyl, halogen or hydrogen;
firstly, the boron reagent is 4-cyanophenylboronic acid pinacol ester;
step one, mixing acetonitrile and water as the organic solvent;
and step two, the two electrodes are respectively a magnesium rod electrode and a carbon rod electrode.
2. The process for the preparation of fluoroamide derivatives according to claim 1, characterized in that the ratio by volume of acetonitrile to water in step one is 4.
3. The method for producing a fluoroamide derivative according to claim 1, wherein in step one, the electrolyte is tetrabutylammonium tetrafluoroborate.
4. The process for producing a fluoroamide derivative according to claim 1, wherein in step one, the molar ratio of the trifluoromethylamide compound, boron reagent, and electrolyte is 1.
5. The method for preparing fluoroamide derivative according to claim 1, wherein the electrocatalytic reaction in step two is carried out under a controlled current of 10mA for an electrolysis time of 6 to 7 hours.
6. The process for producing a fluoroamide derivative according to claim 1, wherein the temperature of the reduced pressure distillation in step three is 25 ℃ and the pressure is 0.1MPa.
7. The method for preparing fluoroamide derivative according to claim 1, wherein the eluent used in the step of silica gel column chromatography is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of ethyl acetate to petroleum ether is 1 (100 to 10).
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| CN114478609A (en) * | 2022-01-24 | 2022-05-13 | 中国科学技术大学 | Method for applying thiophenol photocatalyst to defluorination alkylation or defluorination protonation reaction |
| CN114516815A (en) * | 2022-03-02 | 2022-05-20 | 中国科学技术大学 | Controllable defluorination deuteration method for polyfluoroamide |
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| CN114478609A (en) * | 2022-01-24 | 2022-05-13 | 中国科学技术大学 | Method for applying thiophenol photocatalyst to defluorination alkylation or defluorination protonation reaction |
| CN114516815A (en) * | 2022-03-02 | 2022-05-20 | 中国科学技术大学 | Controllable defluorination deuteration method for polyfluoroamide |
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| John R. Box et al..Direct electrochemical hydrodefluorination of trifluoromethylketones enabled by non-protic conditions. Chem. Sci..2021,第10252-10258页. * |
| Zheng-Jia Shen et al..Organoboron Reagent-Controlled Selective (Deutero)Hydrodefluorination.Angew. Chem. Int. Ed..2023,e202217244第1-10页. * |
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