Fluorine-containing carboxylic acid compound and preparation method thereof
阅读说明：本技术 一种含氟羧酸类化合物及其制备方法 (Fluorine-containing carboxylic acid compound and preparation method thereof ) 是由 余达刚 李静 颜思顺 吴东山 叶剑衡 龚莉 曾昕 冉川昆 贵永远 于 2019-04-02 设计创作，主要内容包括：本发明提供了一种含氟羧酸类化合物及其制备方法和应用,制备方法包括：将含氟烯烃类化合物与CO<Sub>2</Sub>在铜催化剂、配体、碱和硼试剂的存在下于溶剂中发生反应,反应温度为50-100℃,反应时间为2-28h,制得。本发明所用原料来源广泛,反应条件温和,并且避免了有毒物质及贵金属的使用,同时为温室气体的合理高效利用开辟了一条重要的途径。(The invention provides a fluorine-containing carboxylic acid compound and a preparation method and application thereof, wherein the preparation method comprises the following steps: reacting a fluorine-containing olefin compound with CO 2 Reacting in a solvent in the presence of a copper catalyst, a ligand, alkali and a boron reagent at the temperature of between 50 and 100 ℃ for 2 to 28 hours to obtain the catalyst. The invention has wide source of raw materials and mild reaction conditions, avoids the use of toxic substances and noble metals, and opens up an important way for the reasonable and efficient utilization of greenhouse gases.)
1. A fluorine-containing carboxylic acid compound is characterized by having a structural general formula:
wherein R is1Is aryl, heteroaryl, ester group, alkenyl and derivatives thereof, R2Is H, alkyl, aryl or derivatives thereof, R3Is H, halogen, methoxy, cyano, alkyl, carbonyl, ester, aryl and heteroaryl and derivatives thereof.
2. The fluorocarboxylic acid compounds of claim 1, wherein the alkyl group is a straight-chain alkyl group, a branched-chain alkyl group, or a cyclic alkyl group having 1 to 20 carbon atoms; aryl is an aryl group having 6 to 20 carbon atoms; heteroaryl is heteroaryl having 6 to 20 carbon atoms.
3. The fluorocarboxylic acid-based compound according to claim 1 or 2, wherein the specific structural formula is:
4. the method for producing fluorocarboxylic acid compounds according to any one of claims 1 to 3, which comprises the steps of: reacting a fluorine-containing olefin compound with CO2Reacting in a solvent in the presence of a copper catalyst, a ligand, alkali and a boron reagent at the temperature of between 50 and 100 ℃ for 2 to 28 hours to obtain the catalyst.
5. The method for producing fluorocarboxylic acid compounds according to claim 4, which comprises the steps of: difluoroolefin compounds and CO2In the presence of a copper catalyst, a ligand, a base and a boron reagentReacting in a solvent at 50-100 ℃ for 2-28h to obtain the fluoroacrylic acid compound; wherein the molar ratio of the difluoroolefin compound to the copper catalyst is 40:1-5:1, the molar ratio of the difluoroolefin compound to the ligand is 40:1-5:1, the molar ratio of the difluoroolefin compound to the base is 1:1-1:6, and the molar ratio of the difluoroolefin compound to the boron reagent is 1:1-1:5, and the reaction formula is as follows:
6. the method for producing fluorocarboxylic acid compounds according to claim 5, wherein the molar ratio of the difluoroolefin compound to the copper catalyst is 20:1, the molar ratio of the difluoroolefin compound to the ligand is 20:1, the molar ratio of the difluoroolefin compound to the base is 1:3.5, and the molar ratio of the difluoroolefin compound to the boron reagent is 1: 1.5.
7. The method for producing fluorocarboxylic acid compounds of claim 5 or 6, wherein the copper catalyst is cuprous thiophene-2-carboxylate, cuprous acetate, cuprous chloride, cuprous bromide or cuprous iodide; the ligand is 4, 5-bis (diphenylphosphino) -9, 9-dimethyl xanthene, bis (2-diphenylphosphinophenyl) ether, 4, 6-bis (diphenylphosphino) phenazine, bis (diphenylphosphinoethane) or bis (diphenylphosphinobutane); the base is potassium fluoride, cesium fluoride, potassium methoxide, potassium acetate, lithium tert-butoxide or potassium tert-butoxide; the boron reagent is diboron pinacol ester, diboron neopentyl glycol ester, diboron o-diphenol ester or bis (2, 4-dimethyl-2, 4-pentanediol) borate; the solvent is o-xylene, N-dimethylformamide or N-methylpyrrolidone.
8. The method for producing fluorocarboxylic acids according to claim 4, which comprises α -trifluoromethylstyrene-based compound and CO2Reacting in solvent in the presence of copper catalyst, ligand, alkali and boron reagent at 50-100 deg.CAnd the reaction time is 2-28h, α -difluoro crotonate compounds are prepared, wherein the molar ratio of the α -trifluoromethyl styrene compound to the copper catalyst is 40:1-5:1, the molar ratio of the α -trifluoromethyl styrene compound to the ligand is 40:1-5:1, the molar ratio of the α -trifluoromethyl styrene compound to the alkali is 1:1-1:6, the molar ratio of the α -trifluoromethyl styrene compound to the boron reagent is 1:1-1:5, and the reaction formula is as follows:
9. the method for producing fluorocarboxylic acid compounds of claim 8, wherein the molar ratio of α -trifluoromethylstyrene compound to copper catalyst is 10:1, the molar ratio of α -trifluoromethylstyrene compound to ligand is 10:1, the molar ratio of α -trifluoromethylstyrene compound to base is 1:3.0, and the molar ratio of α -trifluoromethylstyrene compound to boron reagent is 1: 1.5.
10. The method for producing fluorocarboxylic acid compounds according to claim 8 or 9, wherein the copper catalyst is cuprous thiophene-2-carboxylate, cupric acetylacetonate, cuprous acetate, cupric acetate, cuprous chloride, cupric fluoride, cupric bromide, or cupric chloride; the ligand is 4, 5-bis (diphenylphosphino) -9, 9-dimethyl xanthene, bis (2-diphenylphosphinophenyl) ether, 4, 6-bis (diphenylphosphino) phenazine, bis (diphenylphosphinoethane) or bis (diphenylphosphinobutane); the base is potassium fluoride, cesium carbonate, potassium methoxide, sodium methoxide, lithium tert-butoxide or potassium tert-butoxide; the boron reagent is diboron pinacol ester, diboron neopentyl glycol ester, diboron o-diphenol ester or bis (2, 4-dimethyl-2, 4-pentanediol) borate; the solvent is N, N-dimethylformamide or N, N-methylpyrrolidone.
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to a fluorine-containing carboxylic acid compound and a preparation method thereof.
Background
The organofluorine compounds are irreplaceable in medicines, agricultural chemicals, fluorine-containing aromatic intermediates, and the like. In medicine, introduction of fluorine-containing groups can effectively improve metabolic pathways and speed of medicines, so that the medicines have better bioavailability and biological selectivity, and molecules containing alpha-fluorocarboxyl structures play an important role in medicines and active molecules. The following are all drug molecules containing an α -fluorocarboxyl structure:
however, the existing method for synthesizing the compounds often has the defects of complicated steps, poor functional group compatibility, narrow substrate application range and selectionTherefore, the introduction of fluorine-containing building blocks, the formation of carboxyl groups and the use of equivalent reagents greatly limit the application of the reaction, and the construction of numerous important α -fluorocarboxylic acid compounds from widely-sourced perfluoro or polyfluoro molecules by direct selective carboxylation reaction of inert C-F has important academic significance and application prospect in modern organic synthesis and pharmaceutical chemistry2Coupling carboxylation reaction.
On the other hand, with environmental and resource problems becoming more prominent in recent years, fossil resources are consumed enormously, resources are in short supply, and a large amount of CO is generated2The emission of exhaust gas causes greenhouse effect, resulting in global sea level elevation. But also can recycle and regenerate, cheap and easily obtained CO without toxicity2Not only is a greenhouse gas, but also is a good C1 resource, and the organic matter prepared by the method has important academic and environmental protection values. But CO2Its own properties become a challenge for its utilization. In CO2In the various chemical conversions, chemists have correspondingly developed various COs2Participate in a new way of synthesizing high value-added chemicals and obtain a plurality of kinds of chemicals. Albeit at CO2A great deal of research has been carried out on chemical conversion, but CO is achieved under mild conditions2There are still many challenges to the transformation utilization of (c).
Disclosure of Invention
In order to solve the above problems in the prior art, the present invention provides a fluorocarboxylic acid compound, which is produced by reacting a fluorocarboxylic acid compound with CO2Under the mild condition, the α -fluorocarboxylic acid compound is prepared from the difluoro olefin and the α -trifluoromethyl styrene compound, the raw material source is wide,the reaction condition is mild, the use of toxic substances and noble metals is avoided, and an important way is opened up for the reasonable and efficient utilization of greenhouse gases.
In order to achieve the purpose, the technical scheme adopted by the invention for solving the technical problems is as follows:
a fluorine-containing carboxylic acid compound has a general structural formula:
wherein R is1Is aryl, heteroaryl, ester group, alkenyl and derivatives thereof, R2Is H, alkyl, aryl or derivatives thereof, R3Is H, halogen, methoxy, cyano, alkyl, carbonyl, ester, aryl and heteroaryl and derivatives thereof.
Further, the alkyl group is a straight-chain alkyl group, a branched-chain alkyl group, a cyclic alkyl group having 1 to 20 carbon atoms, such as methyl, ethyl, isopropyl, n-butyl, cyclopentyl, etc.; aryl is aryl having 6 to 20 carbon atoms, such as phenyl, benzyl, naphthyl, etc.; heteroaryl is heteroaryl having 6 to 20 carbon atoms, such as quinoline, isoquinoline, pyridine, thiophene, and the like.
Further, the specific structural formula of the fluorine-containing carboxylic acid compound is as follows:
the preparation method of the fluorine-containing carboxylic acid compound comprises the following steps: reacting a fluorine-containing olefin compound with CO2Reacting in a solvent in the presence of a copper catalyst, a ligand, alkali and a boron reagent at the temperature of between 50 and 100 ℃ for 2 to 28 hours to obtain the catalyst.
The preparation method of the compound of the formula 1 comprises the following steps: difluoroolefin compounds and CO2In the presence of a copper catalyst, a ligand, a base and a boron reagentReacting in a solvent at 50-100 ℃ for 2-28h to obtain the fluoroacrylic acid compound; wherein the molar ratio of the difluoroolefin compound to the copper catalyst is 40:1-5:1, the molar ratio of the difluoroolefin compound to the ligand is 40:1-5:1, the molar ratio of the difluoroolefin compound to the base is 1:1-1:6, and the molar ratio of the difluoroolefin compound to the boron reagent is 1:1-1:5, and the reaction formula is as follows:
further, the molar ratio of the difluoroolefin compound to the copper catalyst was 20:1, the molar ratio of the difluoroolefin compound to the ligand was 20:1, the molar ratio of the difluoroolefin compound to the base was 1:3.5, and the molar ratio of the difluoroolefin compound to the boron reagent was 1: 1.5.
Further, the copper catalyst is an organic copper catalyst, such as cuprous thiophene-2-carboxylate (CuTc) or cuprous acetate (CuOAc); and inorganic copper catalysts such as cuprous chloride (CuCl), cuprous bromide (CuBr), or cuprous iodide (CuI); preferably, cuprous thiophene-2-carboxylate (CuTc).
Further, the ligand is a bisphosphine ligand such as 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (xanthphos), bis (2-diphenylphosphinyl) ether (DPEphos), 4, 6-bis (diphenylphosphino) phenazine (nixantpos), bis diphenylphosphinoethane (dppe), bis diphenylphosphinobutane (dppb), etc.; preferably 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (Xantphos), bis (2-diphenylphosphinophenyl) ether (DPEphos), 4, 6-bis (diphenylphosphino) phenazine (Nixantphos); more preferably 4, 5-bis diphenylphosphino-9, 9-dimethylxanthene (xanthphos).
Further, the base is a strong base or a weak base, such as potassium fluoride (KF), cesium fluoride (CsF), potassium methoxide (KOMe), potassium acetate (KOAc), lithium tert-butoxide (LiO)tBu), potassium tert-butoxide (KO)tBu), and the like; lithium tert-butoxide (LiO) is preferredtBu)。
Further, the boron reagent is pinacol diboron (B)2Pin2) Bis (boroxine) bis (boroxine B)2nep2) The biboric acid o-catechol ester,Bis (2, 4-dimethyl-2, 4-pentanediol) borate, and the like; preferably pinacol ester diborate (B)2Pin2)。
Further, the solvent is a nonpolar solvent or a strongly polar organic solvent, such as o-xylene (o-xylene), N-Dimethylformamide (DMF), N-methylpyrrolidone (NMP), etc.; n, N-Dimethylformamide (DMF) is preferred.
In the preparation of the compound of formula 1, methoxy, phenoxy, cyano, halogen substituted ortho-, meta-, or para-substrates are all well compatible when substituents are present on the phenyl ring in the substrate. In the case of the naphthalene ring-substituted difluoroolefin compound, the reaction proceeds smoothly at both the 1-position and the 2-position, but when R is present2When the substrate is a substrate with larger methyl equipotential resistance, the reaction performance is poorer compared with a substrate with smaller steric hindrance. In addition, the target product can be obtained with a good yield by the substrate of the heteroaromatic ring, and the C-F bond carboxylation of the aryl difluoroolefin can be realized specifically by the reaction when the aryl difluoroolefin and the alkyl difluoroolefin exist in the substrate at the same time, but the product obtained by the carboxylation of the alkyl difluoroolefin functional group is not detected, so that the chemical selectivity of the reaction is shown.
The preparation method of the compound of the formula 2 comprises α -trifluoromethyl styrene compound and CO2Reacting in a solvent in the presence of a copper catalyst, a ligand, alkali and a boron reagent at the temperature of 50-100 ℃ for 2-28h to obtain α -difluorobutenoate compounds, wherein the molar ratio of the α -trifluoromethyl styrene compounds to the copper catalyst is 40:1-5:1, the molar ratio of the α -trifluoromethyl styrene compounds to the ligand is 40:1-5:1, the molar ratio of the α -trifluoromethyl styrene compounds to the alkali is 1:1-1:6, the molar ratio of the α -trifluoromethyl styrene compounds to the boron reagent is 1:1-1:5, and the reaction formula is as follows:
further, the molar ratio of the α -trifluoromethylstyrene compound to the copper catalyst was 10:1, the molar ratio of the α -trifluoromethylstyrene compound to the ligand was 10:1, the molar ratio of the α -trifluoromethylstyrene compound to the base was 1:3.0, and the molar ratio of the α -trifluoromethylstyrene compound to the boron reagent was 1: 1.5.
Further, the copper catalyst is an organic copper catalyst, such as cuprous thiophene-2-carboxylate (CuTc), cupric acetylacetonate, cuprous acetate (CuOAc), or cupric acetate (Cu (OAc)2) (ii) a And inorganic copper catalysts, such as cuprous chloride (CuCl), cupric fluoride (CuF)2) Copper bromide (CuBr)2) Or copper chloride (CuCl)2) (ii) a Cuprous chloride (CuCl) is preferred.
Further, the ligand is a bisphosphine ligand such as 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (xanthphos), bis (2-diphenylphosphinyl) ether (DPEphos), 4, 6-bis (diphenylphosphino) phenazine (nixantpos), bis diphenylphosphinoethane (dppe), bis diphenylphosphinobutane (dppb), etc.; preferably 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (Xantphos), bis (2-diphenylphosphinophenyl) ether (DPEphos), 4, 6-bis (diphenylphosphino) phenazine (Nixantphos); more preferably 4, 5-bis diphenylphosphino-9, 9-dimethylxanthene (xanthphos).
Further, the base is a strong or weak base, such as potassium fluoride (KF), cesium carbonate (Cs)2CO3) Potassium methoxide (KOMe), sodium methoxide (NaOMe), and lithium tert-butoxide (LiO)tBu), potassium tert-butoxide (KO)tBu), and the like; preferably potassium methoxide (KOMe) or lithium tert-butoxide (LiO)tBu), potassium tert-butoxide (KO)tBu); more preferably potassium methoxide (KOMe).
Further, the boron reagent is pinacol diboron (B)2Pin2) Bis (boroxine) bis (boroxine B)2nep2) O-phenylphenol diborate bisate, bis (2, 4-dimethyl-2, 4-pentanediol) borate and the like; bis (2-methyl-2, 4-pentanediol) borate is preferred.
Further, the solvent is a polar solvent such as N, N-Dimethylformamide (DMF), N-methylpyrrolidone (NMP), or the like; n-methylpyrrolidone (NMP) is preferred.
In the preparation of the compound of formula 2, when a substituent exists on a benzene ring in a substrate, methyl, phenyl, methoxy, phenoxy, ester, carbonyl, cyano and halogen substituted substrates are all compatible well. The reaction proceeds smoothly in both 1-and 2-positions of the naphthalene ring-substituted α -trifluoromethylethylene compound. The carboxylation reaction of one C-F bond is realized for all substrates, and the chemical selectivity specific to the reaction is shown.
The fluorine-containing carboxylic acid compound and the preparation method thereof provided by the invention have the following beneficial effects:
according to the invention, unsaturated bonds are added by a copper boron substance B, then beta-F elimination is carried out to form a boron intermediate D, further transmetallization is carried out on the boron intermediate D and copper, an active organic copper nucleophilic reagent E is generated, and then carbon dioxide is attacked to generate an alpha-fluorocarboxylic acid target product. The specific reaction process is as follows:
the invention realizes the construction of the alpha-fluorocarboxylic acid compound under mild conditions, and the synthesis method of the invention utilizes the greenhouse gas carbon dioxide, thereby having certain academic value and economic environmental significance. The invention has the advantages of high chemical, regional and diastereoisomer selectivity, good functional group compatibility, wider substrate range, easy realization of gram-scale and derivation and the like for synthesizing the alpha-fluoroacrylic acid and alpha-difluorobutenoate compounds, and lays a solid foundation for the application of the alpha-fluoroacrylic acid and alpha-difluorobutenoate compounds in the fields of medicines, materials and the like.
Detailed Description