Preparation method of trifluoroethyl compound
阅读说明：本技术 一种三氟乙基类化合物的制备方法 (Preparation method of trifluoroethyl compound ) 是由 张新刚 李学飞 徐志雄 童绍丰 葛建飞 赵恒军 于 2019-09-16 设计创作，主要内容包括：本发明公开一种三氟乙基类化合物的制备方法,以直接利用廉价丰富的工业原料2-氯-1,1,1-三氟乙烷和卤代物为原料,来合成三氟乙基类化合物,在采用便宜易得的碱金属镍盐催化剂和吡啶类配体的催化体系作用下,在极性溶剂中搅拌,在温和的反应条件下50℃-90℃,反应时间为12-24h生成三氟乙基类化合物,实现三氟乙基向芳环基团或杂环芳基的高效引入,从而制备获得三氟乙基类化合物。本方法不仅反应条件温和、操作简洁、原料和催化剂成本低,而且底物官能团兼容性好、反应规模易于扩大、产物分离简单,具有适于工业化生产的优势。(The invention discloses a preparation method of trifluoroethyl compounds, which is characterized in that cheap and abundant industrial raw materials 2-chloro-1, 1, 1-trifluoroethane and halogenated substances are directly utilized as raw materials to synthesize the trifluoroethyl compounds, the trifluoroethyl compounds are stirred in a polar solvent under the action of a cheap and easily-obtained alkali metal nickel salt catalyst and a pyridine ligand catalytic system, the trifluoroethyl compounds are generated under mild reaction conditions of 50-90 ℃ and the reaction time of 12-24h, and the efficient introduction of trifluoroethyl to aromatic groups or heterocyclic aryl is realized, so that the trifluoroethyl compounds are prepared and obtained. The method has the advantages of mild reaction conditions, simple operation, low cost of raw materials and catalysts, good compatibility of substrate functional groups, easy enlargement of reaction scale, simple product separation and suitability for industrial production.)
1. A preparation method of trifluoroethyl compounds is characterized in that under the action of a catalytic system, 2-chloro-1, 1, 1-trifluoroethane represented by a structural formula A and a halide represented by a structural formula B are subjected to coupling reaction to obtain trifluoroethyl compounds represented by a structural formula C; wherein the general formula of the halide is R-X, R is aryl or heterocyclic aryl, and X is selected from Cl and Br.
2. The production method according to claim 1, wherein, before the coupling reaction is carried out, 2-chloro-1, 1, 1-trifluoroethane is introduced into a reaction solvent so that the concentration of 2-chloro-1, 1, 1-trifluoroethane in the reaction solvent is 0.05 to 0.5mol/L, and then the coupling reaction is carried out under a reaction temperature, a reaction solvent and an inert gas atmosphere.
3. The method according to claim 1 or 2, wherein the reaction temperature of the coupling reaction is 50 ℃ to 90 ℃ and the reaction time of the coupling reaction is 12 to 24 hours.
4. The method of claim 1, wherein the catalytic system comprises a nickel salt catalyst and a pyridine ligand.
5. The method according to claim 4, wherein the nickel salt catalyst is a divalent nickel salt catalyst or a zero-valent nickel salt catalyst.
6. The method of claim 5, wherein the divalent nickel salt catalyst comprises NiBr2、NiQ2·mH2O、NiLnCl2、NiLnBr2、NiLnI2Or NiLn(OH)2(ii) a Wherein Q is nitrate radical, acetate radical, trifluoroacetic radical or halogen, m is more than or equal to 0 and less than or equal to 10, 0<n<3, L is triphenylphosphine, o-methoxytriphenylphosphine, o-methyltriphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, triamantalkylphosphine, 1, 2 bis (diphenylphosphine) ethane (dppe), 1, 3-bis (diphenylphosphine) propane (dppp), 1, 4-bis (diphenylphosphine) butane (dppb), 1' -bis (diphenylphosphine)Phenylphosphine) ferrocene (dppf), bis-diphenylphosphinomethane (dppm), 1, 2-bis-triphenylphosphine benzene (dppbz), dimethyl ethylene glycol Diether (DME), diethylene glycol dimethyl ether (Diglyme), substituted or unsubstituted 1, 10-phenanthroline, substituted or unsubstituted bipyridine, or substituted or unsubstituted terpyridine.
7. The method of claim 6, wherein the substituted or unsubstituted bipyridine is
8. The method according to claim 5, wherein the zero-valent nickel salt catalyst is Ni (COD)2，Ni(PPh3)4。
9. The process according to claim 1, wherein the halide has the formula wherein R is a substituted or unsubstituted C3～C15Aryl group of (1).
10. The method according to claim 9, wherein the halide has the formula wherein R is a substituted or unsubstituted C5～C14Aryl group of (1).
11. The method according to claim 10, wherein the halide has a general formula in which R is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or a substituted or unsubstituted phenanthryl group.
12. The method according to claim 11, wherein the substituted phenyl group is a 2, 4-tert-butylphenyl group, a 3-tert-butylphenyl group, a 4-phenylphenyl group, a 3-methoxyphenyl group, a 3-benzyloxyphenyl group, a 3-trimethylsilylphenyl group, a 4-trimethylsilylphenyl group, a,
13. The method of claim 11, wherein the substituted naphthyl group is
14. The process according to claim 1, wherein the halide is represented by the formula wherein R is a C substituted or unsubstituted C having 1 to 3 hetero atoms and oxygen, sulfur or nitrogen as the hetero atom2～C15The heterocyclic aryl group of (1).
15. The method according to claim 14, wherein the halogen-substituted compound has a general formula in which R is C having 1 hetero atom and is oxygen, sulfur or nitrogen3～C10The heterocyclic aryl group of (1).
16. The method according to claim 15, wherein the halide is represented by the formula wherein R is a substituted or unsubstituted pyridyl group, a substituted or unsubstituted quinolyl group, a substituted or unsubstituted isoquinolyl group, or a substituted or unsubstituted indolyl group.
17. The method of claim 16, wherein the unsubstituted pyridyl group is a 2-pyridyl group, a 3-pyridyl group, or a 4-pyridyl group.
18. The method according to claim 1, wherein the loading of the catalytic system is 2 mol% to 12 mol%.
19. The process according to claim 1, wherein the molar ratio of the 2-chloro-1, 1, 1-trifluoroethane to the halide is (1-2): (1-2).
20. The process according to claim 1 or 19, characterized in that the molar ratio between the 2-chloro-1, 1, 1-trifluoroethane and the halide is 1: (1-2).
Technical Field
The invention discloses a preparation method of a trifluoroethyl compound. The product prepared by the preparation method of the invention has wide application in the aspects of biological medicine, pesticide, material science and the like.
Background
The aryl, heterocyclic aryl-2, 2, 2-trifluoroethyl compound and the derivative building block thereof have wide application in the aspects of biomedicine, pesticide, material science and the like. The traditional preparation method for synthesizing the compound is to react different trifluoromethyl precursors, excessive copper powder, cuprous iodide and the like to generate trifluoromethyl copper species and benzyl bromide. (e.g., (a) Kobayashi, Y.; Yamamoto, K.; Kumadaki, I.tetrahedron Lett.1979, 20, 4071; (b) Kondratenko, N.V.; Vechirko, E.P.; Yagupolski, L.M.Synthesis.1980, 1980, 932; (c) Chen, Q.Y.; Duan, J.X.J.Chem.Soc., Chem.Commun.1993, 1389; (d) Kim, J.Shreeve, J.M.Org.Biomol.Chem.2004, 2, 2728; (e) Kawai H.; Furukawa, T.T.; Nomura Y.; Tokunaga, E.E.; Shibata N.Org.Lett.13, 2011). Most of the synthetic preparation methods require harsh conditions such as high temperature, excessive transition metal, long reaction time and the like, and have low reaction yield, limited substrates and poor functional group compatibility, which seriously limit the application of the preparation methods.
In recent years, palladium-catalyzed reactions of aryl boronic acid substrates with 1, 1, 1-trifluoro-2-iodoethane or 2, 2, 2-trifluoroethanol derivatives have been reported (e.g., (a) Zhao, y.; Hu, j.angelw.chem.int.ed.2012, 51, 1033; (b) Leng, f.; Wang, y.; Li, h.; Li, j.; Zou, d.; Wu y.; Wu y.chem.commu.2013, 49, 10697; (c) Liang, a.; Li, x.; Liu d.; Li, j.; Zou, d.; Wu y. chem.com.2012, 48, 8273) and excess of copper powder participating aryl iodide and 1, 1-trifluoro-2-iodoethane (e.g., Xu, h.; 11, h.; 11 j.; 11 h.; 11 j.; 11 h. (a). Although these methods have been a great improvement over the previous methods, they still have some disadvantages, such as the economic efficiency of the catalytic system needs to be improved, the yield is not high, the substrate is limited, and the functional group compatibility is poor. And the reaction raw material 1, 1, 1-trifluoro-2-iodoethane or 2, 2, 2-trifluoroethanol derivative and the like are derived from 2-chloro-1, 1, 1-trifluoroethane.
Because of strong carbon-chlorine bond energy, the synthesis of the compound by directly utilizing industrial raw material 2-chloro-1, 1, 1-trifluoroethane is very difficult. Currently, coupling of aryl-formatted reagents is limited to Ohtsuka, Y.; Yamakawa, T.J.fluorineneChem.2016, 185, 96), but the preparation method has very limited substrate and functional group types. It is not suitable for substrates containing heterocyclic rings, active hydrogen, aldehyde groups, carbonyl groups, ester groups, etc.
Therefore, the development of a mild and efficient catalytic system with wide substrate application range and good functional group compatibility for synthesizing aryl and heterocyclic aryl-2, 2, 2-trifluoroethyl compounds and derivatives thereof by directly utilizing cheap and rich industrial raw material A (2-chloro-1, 1, 1-trifluoroethane) has important significance.
Disclosure of Invention
The invention aims at overcoming the defects of the prior art and synthesizing the trifluoroethyl compound by directly utilizing cheap and abundant 2-chloro-1, 1, 1-trifluoroethane; the invention also aims to modify the structures of the existing drug molecules and bioactive molecules by directly utilizing the preparation method to carry out fluorine-containing modification on the drug molecules. The applicant of the invention finds a preparation method for synthesizing an aryl or heterocyclic aryl-2, 2, 2-trifluoroethyl compound by a coupling reaction of 2-chloro-1, 1, 1-trifluoroethane, aryl or heterocyclic aryl halide under the action of a catalytic system comprising a nickel salt catalyst and a pyridine ligand.
The present invention solves the above-mentioned problems by the following technical means.
A preparation method of trifluoroethyl compounds comprises the steps of carrying out coupling reaction on 2-chloro-1, 1, 1-trifluoroethane represented by a structural formula A and a halide represented by a structural formula B under the action of a catalytic system to obtain trifluoroethyl compounds represented by a structural formula C; wherein the general formula of the halide is R-X, R is aryl or heterocyclic aryl, and X is selected from Cl and Br.
Preferably, before the coupling reaction is performed, 2-chloro-1, 1, 1-trifluoroethane is introduced into a reaction solvent so that the concentration of 2-chloro-1, 1, 1-trifluoroethane in the reaction solvent is 0.05 to 0.5mol/L, and then the coupling reaction is performed under a reaction temperature, a reaction solvent and an inert gas atmosphere.
And further, introducing 2-chloro-1, 1, 1-trifluoroethane gas into the reaction solvent, and performing coupling reaction after the concentration is determined by a nuclear magnetic internal standard method.
Preferably, the reaction temperature of the coupling reaction is 50-90 ℃, and the reaction time of the coupling reaction is 12-24 h.
Further, the reaction temperature of the coupling reaction was 80 ℃.
Preferably, the catalytic system further comprises a reducing agent and an additive.
Further, the reducing agent is zinc powder or manganese powder.
Further, the reducing agent is zinc powder.
Furthermore, the using amount of the zinc powder is 1.8-3.4 equivalent.
Furthermore, the using amount of the zinc powder is 2.0-3.0 equivalent.
Preferably, the nickel salt catalyst is a divalent nickel salt catalyst or a zero-valent nickel salt catalyst.
Further, the divalent nickel salt catalyst includes NiBr2、NiQ2·mH2O、NiLnCl2、NiLnBr2、NiLnI2Or NiLn(OH)2(ii) a Wherein Q is nitrate radical, acetate radical, trifluoroacetic radical or halogen, m is more than or equal to 0 and less than or equal to 10, 0<n<3, L is triphenylphosphine, o-methoxytriphenylphosphine, o-methyltriphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, triamantylphosphine, 1, 2 bis (diphenylphosphine) ethane (dppe), 1, 3-bis (diphenylphosphine) propane (dppp), 1, 4-bis (diphenylphosphine) butane (dppb), 1' -bis (diphenylphosphine) ferrocene (dppf), bis-diphenylphosphinomethane (dppm), 1, 2-bis-triphenylphosphine benzene (dppbz), dimethyl ethylene glycol Diether (DME), diethylene glycol dimethyl ether (Diglyme), substituted or unsubstituted 1, 10-phenanthroline, substituted or unsubstituted bipyridine, or substituted or unsubstituted terpyridine.
Further, the substituted or unsubstituted bipyridine is
Further, the zero-valent nickel salt catalyst is Ni (COD)2，Ni(PPh3)4。
Preferably, in the general formula of the halogenated compound, R is substituted or unsubstituted C3～C15Aryl group of (1).
Further, in the general formula of the halogenated compound, RIs substituted or unsubstituted C5～C14Aryl group of (1).
Further, in the general formula of the halogenated compound, R is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl or substituted or unsubstituted phenanthryl.
Further, the substituted phenyl group is 2, 4-tert-butylphenyl, 3-tert-butylphenyl, 4-phenylphenyl, 3-methoxyphenyl, 3-benzyloxyphenyl, 3-trimethylsilylphenyl, 4-trimethylsilylphenyl,
further, the substituted naphthyl is
Preferably, in the general formula of the halogenated compound, R is substituted or unsubstituted C, wherein the heteroatom is oxygen, sulfur or nitrogen atom, and the number of the heteroatoms is 1-32～C15The heterocyclic aryl group of (1).
Further, in the general formula of the halogenated compound, R is C with heteroatom of oxygen, sulfur or nitrogen atom and 1 heteroatom3～C10The heterocyclic aryl group of (1).
Further, in the general formula of the halogenated compound, R is substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted isoquinolyl or substituted or unsubstituted indolyl.
Further, the unsubstituted pyridyl group is a 2-pyridyl group, a 3-pyridyl group or a 4-pyridyl group.
Preferably, the pyridine ligand is a pyridine derivative ligand selected from
Further, the pyridine ligand is 4, 4' -dtbbpy.
Preferably, the reaction solvent is selected from one or a combination of several of N, N-Dimethylformamide (DMF), N-Diethylformamide (DMA), N-Dimethylpropyleneurea (DMPU), NMP (N-methylpyrrolidone), pyridine (pyridine).
Further, the reaction solvent is selected from DMA, DMF.
Preferably, the additive is selected from Et3N·HCl，CF3CO2H，FeBr2，TMSCl，Bu4NI，NaI，KI，TMEDA，MgCl2，Mg(OTf)2，MgSO4，MgSO4·7H2O，Mg(OAc)2，LiCl，KCl，CaCl2One or more of them.
Further, the additive is MgCl2。
Preferably, the loading of the catalytic system is 2mol percent to 12mol percent
Further, the loading of the catalytic system was 10 mol%.
Preferably, the molar ratio of the 2-chloro-1, 1, 1-trifluoroethane to the halide is (1-2): (1-2).
Further, the molar ratio of the 2-chloro-1, 1, 1-trifluoroethane to the halide is 1: (1-2).
Compared with the prior art, the invention has the beneficial effects that:
(1) the method provided by the invention provides a convenient and low-cost method for synthesizing the trifluoroethyl compound shown in the structural formula C, and avoids the use of expensive and unstable trifluoromethyl reagent.
(2) The trifluoroethyl compound is synthesized by directly utilizing cheap and rich industrial raw materials, namely 2-chloro-1, 1, 1-trifluoroethane and halogenated substances, and is stirred in a polar solvent under the action of an alkali metal nickel salt catalyst and a pyridine ligand catalytic system, and the trifluoroethyl compound is generated under the mild reaction condition of 50-90 ℃ and the reaction time of 12-24 h.
(3) The method has the advantages of mild reaction conditions, simple operation, low cost of raw materials and catalysts, good compatibility of substrate functional groups, easy enlargement of reaction scale, simple product separation and suitability for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental preparation methods, in which specific conditions are not specified, in the following examples were selected according to conventional preparation methods and conditions, or according to commercial instructions. Unless otherwise indicated, percentages and parts are by weight.
Preparation example 1
The coupling reaction of 2-chloro-1, 1, 1-trifluoroethane and (heterocyclic aryl) aryl bromide is used as the preparation method of the general trifluoroethyl compound.
To an argon, anhydrous oxygen-free protected 25mL Schlenk reaction flask were added anhydrous magnesium chloride (0.4mmol, 38.2mg, 1.0 equiv.), nickel bromide (0.04mmol, 8.8mg, 0.1 equiv.), ligand 4, 4 '-di-tert-butyl-2, 2' -bipyridine (0.04mmol, 10.8mg, 0.1 equiv.), bromobenzene or its derivative (0.6mmol, 1.5 equiv.), followed by DMA (4mL) and a DMA solution of 2-chloro-1, 1, 1-trifluoroethane (0.4mmol, 1.0 equiv.). If the reaction is on the 0.2mmol scale, all reagents are reduced in amount by half.
The reaction mixture is heated to 80 degrees and stirred for 12 hours (or other temperature for some time). Then cooling the mixture to room temperature, adding 100mL of ethyl acetate for dilution, washing the diluted mixture with water and a proper amount of saturated saline solution in sequence, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, and distilling the concentrated organic phase under reduced pressure or performing silica gel column chromatography to obtain a target product.
Preparation example 2
The coupling reaction of 2-chloro-1, 1, 1-trifluoroethane and (heterocyclic aryl) aryl chloride is general purpose preparation method of trifluoroethyl compound.
To an argon, anhydrous oxygen-free protected 25mL Schlenk reaction flask were added anhydrous magnesium chloride (0.6mmol, 57.2mg, 1.5 equivalents), nickel bromide (0.04mmol, 8.8mg, 0.1 equivalents), ligand 4, 4 '-di-tert-butyl-2, 2' -bipyridine (0.04mmol, 10.8mg, 0.1 equivalents), chlorobenzene or its derivative (0.8mmol, 1.5 equivalents) in sequence, followed by DMA (4mL) and a DMA solution of 2-chloro-1, 1, 1-trifluoroethane (0.4mmol, 1.0 equivalents). If the reaction is on the 0.2mmol scale, all reagents are reduced in amount by half.
The reaction mixture is heated to 80 degrees and stirred for 12 hours (or other temperature for some time). Then cooling the mixture to room temperature, adding 100mL of ethyl acetate for dilution, washing the diluted mixture with water and a proper amount of saturated saline solution in sequence, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, and distilling the concentrated organic phase under reduced pressure or performing silica gel column chromatography to obtain a target product.
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