CN109942459B - Method for synthesizing 3-difluoromethyl-3-acrylonitrile compounds - Google Patents
Method for synthesizing 3-difluoromethyl-3-acrylonitrile compounds Download PDFInfo
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Abstract
The invention discloses a synthesis method of a 3-difluoromethyl-3-acrylonitrile compound, which takes acetonitrile B and a difluorodicarbonyl compound C as raw materials, takes cesium carbonate as a catalyst, and fully reacts for 10 hours at 120 ℃ under the condition that excess acetonitrile is taken as a solvent. After the reaction, the reaction solution was cooled, and the cooled reaction solution was extracted with an ethyl acetate-saturated saline solution system, the aqueous phase was removed, and the organic phase was concentrated and then subjected to column chromatography using petroleum ether-ethyl acetate 15: the pure 3-difluoromethyl-3-acrylonitrile compound A can be obtained by separating the system 1 after chromatography. The method has the advantages of simple and safe process operation, high reaction conversion rate, economical and practical raw materials, less three wastes and environmental friendliness, does not need to treat additional organic solvents, and is a new application for synthesizing the compounds.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a method for synthesizing a 3-difluoromethyl-3-acrylonitrile compound from acetonitrile and a difluorodicarbonyl compound.
Background
Difluoromethylaryl compounds are very important as basic constituents of organic synthesis, pharmaceuticals and functional materials. Therefore, the development of an efficient method for introducing difluoromethyl has been a focus of research in recent years. Among them, the catalytic electrophilic substitution reaction of potassium difluorobromoacetate with aryl compounds has become one of the most important methods in the synthesis of difluoromethylaryl compounds. Difluoromethyl as a solubilizing group may also enhance the ability of the compound to penetrate cells. In recent years, introduction of difluoromethyl group in two steps through addition reaction of unsaturated bond has attracted great attention. This process allows for more efficient synthesis and the reaction products can be recovered. Various reagents such as phenylolefin reagents, e.g., styrene, phenylpropylene, aryl aldehyde reagents, e.g., phenylpropylaldehyde, etc., are successfully introduced into difluoromethyl. This method has also been successfully used for difluoromethylation of most unsaturated bonds and selectively results in various terminal difluoro-substituted aryl compounds which can be used as effective drugs for the treatment of cancer, AIDS, heart disease and allergy. The aryl unsaturated compound reagent can react under the catalysis of sodium bicarbonate, diethylamine compounds and the like to introduce difluoromethyl. The aryl alkene and the aryl aldehyde are widely distributed in nature, many natural compounds contain aryl unsaturated bonds, and the life activity is closely related to certain aryl unsaturated compounds, so the aryl alkene and the aryl aldehyde are organic unsaturated compounds with great medical research value.
For example:
document 1(Kitamura T., Muta K., Oyamada J., et al., Hypervalve Iodine-media fluoride of Styrene Derivatives: Stoichimetric and Catalytic Transformation to 2, 2-Difluoroethylenes [ J ]. J. Org.Chem.,2015,80(21), 10431-channel 10436) this method was published by Paterick, Timothyl B. and Qian S. on Organic letters in 2000, which method is intended to be more primitive, and the mechanisms used by the other latter methods are essentially based on this method, as follows:
document 2(Levesque E., Difluoroiodomethyl [ J ]. e-EROS Encyclopedia of Reagents for Organic Synthesis, 1-3; 2014.) discloses a benzyldifluoromethylated product obtained by reacting a benzyl halide with a Difluoroiodomethane, and a benzyldifluoromethylated product obtained by substitution reaction of a Difluoroiodomethane with a benzyl halide under cadmium-catalyzed conditions, as disclosed in e-EROS Encyclopedia of Reagents for Organic Synthesis in 2014. Cadmium, cuprous bromide and the like are used as catalysts in the reaction, difluoroiodomethane is added for reaction, the reaction temperature is 25 ℃, the reaction time is 6 hours, the yield can basically reach more than 80%, and the reaction formula is as follows:
reference 3(Levin V., Zemtsov A., Structure kova M., et al., reaction of organic reagents with potassium bromide [ J ]. Journal of fluoride Chemistry 171, 97-101; 2015) has been made by a number of researchers, and we have selected a relatively representative one of the articles published in Journal of fluoride Chemistry 2015. The reaction is mild, and the reaction yield is high when the tetrahydrofuran solution of tetraethylammonium bromide is added at room temperature by stirring, but the reaction conditions are harsh. Therefore, although the yield is high, the method is difficult to apply, and the reaction formula is as follows:
reference 4(Dolbier W., Okamoto M., et al.: preparation of 1,1-difluoroalkanes from aldehyde via 1,1-bistriflates: Advantageous use of HF-Lewis base reagents [ J ]. Journal of Fluorine Chemistry,167, 96-100; 2014.) an article published by Okamoto, Masamune in 2, 6-dimethylpyridine catalyzed reaction of trifluoromethanesulfonic anhydride with phenylacetaldehyde to give difluoromethyl benzyl difluoride compounds in the 2014 by the reaction of trifluoromethanesulfonic anhydride with phenylacetaldehyde to introduce difluoromethyl groups on benzyl groups, Dolbier, William R.Jr., and Okamoto. The reaction is carried out under the condition of no metal catalysis and has quite good selectivity and yield of more than 50 percent basically by taking 2, 6-dimethyl pyridine as a catalyst, triethylamine as an additive and dichloromethane as a solvent at the temperature of 0 ℃, and the reaction formula is as follows:
however, the above methods have some disadvantages:
(1) the use of high purity difluoroiodomethane or some other fluorine-containing reagent can create serious environmental concerns and safety concerns;
(2) the surplus solvent can not be reused, and a large amount of discharged solvent can pollute the environment, thus being not in accordance with the development direction of green chemistry;
(3) expensive catalysts are used in part of the reactions, so that the experimental cost is too high and the economic principle is not met.
Therefore, in order to find a more suitable difluoromethyl introduction source, a reagent which has a large influence on the environment is not used for participating in the reaction, and the reduction of the reaction cost has very important practical significance for the reaction result.
Disclosure of Invention
The invention aims to provide a method for synthesizing 3-difluoromethyl-3-acrylonitrile compounds from acetonitrile and difluorodicarbonyl compounds, which has the advantages of reasonable process, low toxicity, good product quality and low cost.
The technical scheme for realizing the invention is as follows:
a novel synthetic method of a 3-difluoromethyl 2-alkene nitrile compound comprises the following steps: acetonitrile B
And difluorodicarbonyl compound C
Reacting under the catalysis of cesium carbonate and the condition of acetonitrile as a solvent at 120 ℃, and separating and purifying reaction liquid to obtain the 3-difluoromethyl-3-acrylonitrile compound A
In the formulae A and C, Ar1Selected from one of the following: phenyl, 4-fluorophenyl, 4-methylphenyl, 4-bromophenyl.
The reaction formula is as follows:
further, the molar ratio of acetonitrile B to difluorodicarbonyl compound C is 5:1 to 20:1, preferably 10: 1.
Further, the molar ratio of the dosage of the catalyst cesium carbonate to the dosage of the difluoro dicarbonyl compound C is 1: 1.
further, the amount of acetonitrile as a solvent is 5 to 20 times, preferably 10 times, the molar amount of the difluorodicarbonyl compound C.
Further, the reaction temperature is 100-150 ℃, preferably 120 ℃.
Further, the reaction time required is 8 to 12 hours, preferably 10 hours.
Further, the method for separating and purifying the reaction liquid comprises the following steps: after the reaction, the reaction mixture was diluted with ethyl acetate, washed with saturated brine for 3 times, separated to obtain an organic layer, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to remove the solvent. And separating the crude product by column chromatography (eluent is a mixed solution of petroleum ether and ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate is 15:1) to obtain the 3-difluoromethyl-3-acrylonitrile compound shown in the formula A.
Compared with the prior art, the invention has the following remarkable advantages:
(1) the invention avoids using dangerous raw materials such as difluoro iodomethane, xenon difluoride and the like, has less three wastes and is environment-friendly.
(2) The invention has few kinds of catalysts and avoids the direct use of transition metals.
(3) The raw materials required by the invention are economical and practical.
(4) The method has the advantages of simple reaction steps, high conversion rate, easy achievement of reaction conditions, easy separation and purification and high purity of the obtained product.
Drawings
FIG. 1 is a scheme for producing 3-difluoromethyl-3-phenylacetonitrile1H NMR chart;
FIG. 2 is a scheme for producing 3-difluoromethyl-3-phenylacetonitrile13C NMR chart;
FIG. 3 is a scheme showing the preparation of 3-difluoromethyl-3- (4' -bromophenyl) acrylonitrile1H NMR chart;
FIG. 4 is a scheme showing the preparation of 3-difluoromethyl-3- (4' -bromophenyl) acrylonitrile13C NMR chart;
FIG. 5 is a scheme showing the preparation of 3-difluoromethyl-3- (4' -fluorophenyl) acrylonitrile1H NMR chart;
FIG. 6 is a scheme showing the preparation of 3-difluoromethyl-3- (4' -fluorophenyl) acrylonitrile13C NMR chart;
FIG. 7 is a scheme showing the preparation of 3-difluoromethyl-3- (4' -methylphenyl) acrylonitrile1H NMR chart;
FIG. 8 is a scheme showing the preparation of 3-difluoromethyl-3- (4' -methylphenyl) acrylonitrile13C NMR chart.
Detailed Description
For better understanding of the present invention, the technical solution of the present invention will be specifically described below by way of specific examples.
Example 1
2.60g (10mmol) of difluorodibenzoylmethane, 3.26g (10mmol) of cesium carbonate and 30ml of acetonitrile were charged in a reactor and stirred at 120 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with 100mL of ethyl acetate, washed with saturated brine for 3 times, separated to obtain an organic layer, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The crude product was isolated by column chromatography (eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 15:1) to give 1.58g of 3-difluoromethyl-3-phenylacetonitrile in 88% yield.
3-difluoromethyl-3-phenylacrylonitrile1The H NMR chart is shown in FIG. 1, 3-difluoromethyl-3-phenylacetonitrile13The C NMR chart is shown in FIG. 2.
1H NMR(500MHz,Chloroform-d)δ7.59–7.45(m,5H),6.88(t,J＝53.5Hz,0H),6.42(t,J＝54.4Hz,1H),5.95(d,J＝2.4Hz,1H),5.91(s,0H).
13C NMR(126MHz,Chloroform-d)δ152.72,129.95,128.09,126.94,126.46,114.28,113.55,111.61,109.67,100.04,99.95,99.86.
Example 2
4.18g (10mmol) of difluorobis (4' -bromo) benzoylmethane, 3.26g (10mmol) of cesium carbonate and 30ml of acetonitrile were charged into a reactor and stirred at 120 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with 100mL of ethyl acetate, washed with saturated brine for 3 times, separated to obtain an organic layer, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The crude product was isolated by column chromatography (eluent was a mixture of petroleum ether and ethyl acetate at a volume ratio of 15:1) to yield 2.20g of 3-difluoromethyl-3- (4' -bromophenyl) acrylonitrile in 85% yield.
3-difluoromethyl-3- (4' -bromophenyl) acrylonitrile1The H NMR chart is shown in FIG. 3, 3-difluoromethyl-3- (4' -bromophenyl) acrylonitrile13The C NMR chart is shown in FIG. 4.
1H NMR(500MHz,Chloroform-d)δ7.64(d,J＝8.5Hz,2H),7.43(d,J＝8.5Hz,2H),6.38(t,J＝54.3Hz,1H),5.97(t,J＝2.3Hz,1H).
13C NMR(126MHz,Chloroform-d)δ151.65,131.43,128.65,128.56,124.70,113.94,113.41,111.47,109.52,100.77,100.68,100.59.
Example 3
2.96g (10mmol) of difluorobis (4' -fluoro) benzoylmethane, 3.26g (10mmol) of cesium carbonate and 30ml of acetonitrile were charged into a reactor and stirred at 120 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with 100mL of ethyl acetate, washed with saturated brine for 3 times, separated to obtain an organic layer, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The crude product was isolated by column chromatography (eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 15:1) to yield 1.70g of 3-difluoromethyl-3- (4' -fluorophenyl) acrylonitrile in 86% yield.
3-difluoromethyl-3- (4' -fluorophenyl) acrylonitrile1The H NMR chart is shown in FIG. 5, 3-difluoromethyl-3- (4' -fluorophenyl) acrylonitrile13The C NMR chart is shown in FIG. 6.
1H NMR(500MHz,Chloroform-d)δ7.64–7.50(m,3H),7.24–7.10(m,2H),6.88(t,J＝53.4Hz,0H),6.38(t,J＝54.3Hz,1H),5.94(t,J＝2.3Hz,1H),5.87(s,0H).
13C NMR(126MHz,Chloroform-d)δ129.34,129.27,125.88,115.49,115.32,114.13,113.54,111.64,109.70,100.28.
Example 4
2.88g (10mmol) of difluorobis (4' -methyl) benzoylmethane, 3.26g (10mmol) of cesium carbonate and 30ml of acetonitrile were charged into a reactor, and stirred at 120 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with 100mL of ethyl acetate, washed with saturated brine for 3 times, separated to obtain an organic layer, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The crude product was isolated by column chromatography (eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 15:1) to give 1.70g of 3-difluoromethyl-3- (4' -methylphenyl) acrylonitrile in 88% yield.
3-difluoromethyl-3- (4' -methylphenyl) acrylonitrile1The H NMR chart is shown in FIG. 7, 3-difluoromethyl-3- (4' -methylphenyl) acrylonitrile13The C NMR chart is shown in FIG. 8.
1H NMR(500MHz,Chloroform-d)δ7.46(dd,J＝10.5,8.0Hz,3H),7.28(dd,J＝22.6,8.0Hz,3H),6.88(t,J＝53.6Hz,0H),6.41(t,J＝54.5Hz,1H),5.93–5.86(m,1H),2.41(d,J＝4.5Hz,5H).
13C NMR(126MHz,Chloroform-d)δ152.58,140.47,128.77,128.23,127.43,127.14,126.85,126.34,114.60,113.69,111.75,109.80,99.83,99.10,99.02,98.93,20.41.
The above embodiments do not limit the present invention in any way, and all technical solutions obtained by means of equivalent substitution or equivalent transformation fall within the protection scope of the present invention.
Claims (7)
1. A method for synthesizing 3-difluoromethyl-3-acrylonitrile compounds is characterized by comprising the following steps:
with acetonitrile B
And difluorodicarbonyl compound C
Taking cesium carbonate as a catalyst and acetonitrile as a solvent as raw materials, and fully reacting at 100-150 ℃ for at least 10 hours; cooling after the reaction is finished, extracting the cooled reaction solution by using an ethyl acetate-saturated saline solution system, removing a water phase, concentrating an organic phase, performing column chromatography, performing chromatography by using an eluent, and separating to obtain the 3-difluoromethyl-3-acrylonitrile compound A
A and C are represented by the formula, Ar1Selected from one of the following: phenyl, 4-fluorophenyl, 4-methylphenyl, 4-bromophenyl.
2. The process of claim 1, wherein the acetonitrile B and difluorodicarbonyl compound C are used in a molar ratio of 10: 1.
3. The method of claim 1, wherein the molar ratio of the amount of cesium carbonate catalyst to the amount of difluorodicarbonyl compound of formula C is 1: 1.
4. The process of claim 1 wherein the solvent acetonitrile is used in an amount of 10 times the molar amount of difluorodicarbonyl compound C.
5. The process of claim 1, wherein the temperature of the reaction is 120 ℃.
6. The method of claim 1, wherein the reaction solution is separated and purified by: after the reaction is finished, adding ethyl acetate into the reaction liquid for dilution, washing the reaction liquid for 3 times by using saturated saline solution, separating and taking an organic layer, drying the organic layer by using anhydrous sodium sulfate, then carrying out reduced pressure distillation to remove the solvent, and adding an eluent to carry out column chromatography separation on a crude product to obtain the 3-difluoromethyl-3-acrylonitrile compound A.
7. The method as claimed in claim 1 or 6, wherein the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 15: 1.
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