阅读说明：本技术 一种通过还原偶联制备单氟烷基取代芳香化合物的方法 (Method for preparing monofluoroalkyl substituted aromatic compound through reduction coupling ) 是由 杨义 罗根 李幼林 童霞 贺萌萌 蒋燕 刘应乐 舒雨玫 郑玉彬 陆文杰 赵延川 于 2019-11-11 设计创作，主要内容包括：本发明公开了一种通过还原偶联制备单氟烷基取代芳香化合物的方法。所述制备方法以单氟烷基卤代烃和未活化的(杂)芳基亲电试剂为原料,通过便宜易得的镍催化剂、含氮配体为催化体系,金属锰粉作还原剂,实现单氟烷基卤代烃与未活化的(杂)芳基亲电试剂的高效偶联,经后处理得到单氟烷基取代芳香化合物。本方法反应条件温和,安全性好,产物分离简单,底物普适性广。(The invention discloses a method for preparing monofluoroalkyl substituted aromatic compound by reduction coupling. The preparation method takes monofluoroalkyl halohydrocarbon and unactivated (hetero) aryl electrophilic reagents as raw materials, realizes the high-efficiency coupling of monofluoroalkyl halohydrocarbon and unactivated (hetero) aryl electrophilic reagents by taking cheap and easily-obtained nickel catalyst and nitrogen-containing ligand as a catalytic system and metal manganese powder as a reducing agent, and obtains the monofluoroalkyl substituted aromatic compounds through post-treatment. The method has the advantages of mild reaction conditions, good safety, simple product separation and wide substrate universality.)

1. A method for preparing monofluoroalkyl substituted aromatic compounds through reduction coupling is characterized in that monofluoroalkyl halohydrocarbon and an unactivated (hetero) aryl electrophilic reagent Ar-X are used as raw materials, a metal simple substance is used as a reducing agent under the action of a nickel catalyst and a nitrogen-containing ligand catalytic system, an activating auxiliary agent is added, the mixture is fully stirred and reacted in a reaction solvent at 50-100 ℃ in a nitrogen atmosphere, and after the reaction reaches the end point, the monofluoroalkyl substituted aromatic compounds are obtained through separation and purification.

2. The method according to claim 1, wherein the monofluoroalkyl halohydrocarbon is any one of 1-fluoro-2-iodoethane, 1-fluoro-2-bromoethane, 1-fluoro-2-iodocyclohexane, 1-bromo-2-fluorocyclohexane or (2-bromo-1-fluoro) ethylbenzene.

3. The method of claim 1, wherein Ar of the non-activated (hetero) aryl electrophile Ar-X is phenyl, alkyl-substituted phenyl of C1-C4, C1-C4 alkoxy-substituted phenyl, C1-C4 acyl-substituted phenyl, C1-C4 alkoxyacyl-substituted phenyl, cyano-substituted phenyl, nitro-substituted phenyl, naphthyl, or pyridyl; x of the unactivated (hetero) aryl electrophilic reagent Ar-X is any one of iodine radical, bromine radical, chlorine radical, p-toluenesulfonic acid radical or trifluoromethanesulfonic acid radical; the alkyl of C1-C4 is methyl, ethyl, propyl, isopropyl, butyl or tert-butyl; the alkoxy of C1-C4 refers to methoxy, ethoxy or tert-butoxy; the acyl group of C1-C4 is formyl, acetyl, propionyl, formyl acetonitrile, butyryl or benzoyl; the C1-C4 alkoxy acyl refers to methoxyacyl, ethoxyacyl, propoxycarbonyl or butoxyacyl.

4. The method of claim 1, wherein the nickel catalyst is Ni (cod)₂、NiCl₂、NiBr₂、NiI₂Or Ni (acac)₂Any one of the above.

5. The method according to claim 1, wherein the nitrogen-containing ligand is any one of pyridine, 4-dimethylaminopyridine, 2' -bipyridine, 4' -dimethyl-2, 2' -bipyridine, 4' -dimethoxy-2, 2' -bipyridine, 4' -di-tert-butyl-2, 2' -bipyridine, 6 ' -dimethyl-2, 2' -bipyridine, or phenanthroline.

6. The method according to claim 1, wherein the reducing agent is any one of Mn, Zn, Cu, Al, or Fe.

7. The method of claim 1, wherein the co-activator is any one of potassium iodide, sodium iodide, tetrabutylammonium iodide, trimethylchlorosilane, lithium chloride, zinc chloride, or magnesium chloride.

8. The method according to claim 1, wherein the reaction solvent is any one of dioxane, ethylene glycol dimethyl ether, N-methyl pyrrolidone, N-dimethylformamide or N, N-dimethylacetamide/N, N-dimethylpropylurea or a mixture thereof.

9. The method according to claim 1, wherein the separation and purification steps are as follows: after the reaction end point is determined by fluorine spectrum monitoring, insoluble substances in the reaction solution are filtered, and a small amount of ether is washed; pouring the filtrate into water, extracting the water phase by using ether, combining the organic phases, washing the organic phase by using water and a saturated ammonium chloride aqueous solution in turn, drying the organic phase by using anhydrous sodium sulfate, filtering the organic phase, removing the solvent by rotary evaporation, and separating the residue by recrystallization or silica gel column chromatography to obtain the monofluoroalkyl substituted aromatic compound.

10. The method of any one of claims 1-9, wherein the amount of monofluoroalkyl halocarbon to unactivated (hetero) aryl electrophile Ar-X species is in a ratio of (1-2.0): 1; the amount ratio of the nickel catalyst to the non-activated (hetero) aryl electrophile Ar-X is (1-20.0): 100; the amount ratio of the nitrogen-containing ligand to the non-activated (hetero) aryl electrophile Ar-X is (1-20.0): 100; the amount ratio of the reducing agent to the non-activated (hetero) aryl electrophile Ar-X is (1-4.0): 1.0; the amount ratio of the activating auxiliary agent to the non-activated (hetero) aryl electrophilic reagent Ar-X substance is (1.0-20.0): 10.0; the ratio of the quantity of the substance of the non-activated (hetero) aryl electrophilic reagent Ar-X to the volume of the reaction solvent is 1: 1-20 mol.L^-1。

Technical Field

The invention belongs to the technical field of preparation of fluoroalkyl-substituted aromatic hydrocarbon, and mainly relates to a method for preparing a monofluoroalkyl-substituted aromatic compound through reduction coupling.

Background

Fluorine, being the most electronegative element in nature, due to its extremely strong electron-withdrawing ability and atomic volume next to hydrogen atoms, participating in the construction of organic molecules will significantly change the physical, chemical and biological properties of the molecules. A large number of drug modification practices show that the introduction of precisely controlled fluorine atoms has obvious improvement effect on improving the pharmacological properties such as lipophilicity, metabolic stability, binding affinity and the like of candidate compounds. Therefore, the development of a high-efficiency and specific synthesis method of the organofluorine compound is of great significance. In contrast to the great challenge of directly fluorinating unactivated C-H bonds on aliphatic, transition metal catalyzed fluoroalkylation is a relatively simple and efficient method for introducing pre-modified fluoroalkyl groups into organic compounds, and has been widely applied to the preparation of fluorine-containing functional organic molecules. Despite the significant advances made in the field of polyfluoroalkylation and perfluoroalkylation reaction development (Science,2010, 328, 1679-.

Between two electrophiles catalyzed by transition metalsThe reductive cross-coupling reaction of (a) is a powerful tool for carbon-carbon bond building in recent years. Unlike traditional coupling reactions that rely on the combination of a nucleophilic carbon reagent and an electrophilic carbon reagent, reductive cross-coupling reactions can achieve bonding between two electrophilic carbon reagents under the action of a catalyst and a reducing agent. For example, wang jun shou group has recently developed a nickel-catalyzed reductive coupling of halogenated aromatic hydrocarbons with gem-difluoroalkyl halides to achieve efficient introduction of mono-fluoroalkyl groups into aromatic rings, and to successfully prepare benzyl fluoride (ArCHFR) (angew. chem. int.ed.2018,57,7634). High benzyl fluoride (ArCH)₂CH₂F) As benzyl fluoride (ArCH)₂F) The homologue of (A) is far superior to benzyl fluoride in chemical stability, so that the homologue gradually shows important application value in the modification of drug molecules (see figure 1).

In view of the high benzyl fluoride (ArCH)₂CH₂F) The structural unit has important application prospect in drug development, and develops CH₂CH₂Efficient methods for introducing F groups into various aromatic ring structures are in the spotlight. Although Yankee et al have achieved the coupling of arylboronic acids (nucleophilic carbon reagents) with ortho-difluorohalohydrocarbons (electrophilic carbon reagents) by the traditional coupling reaction model (Suzuki reaction), the innovative development of highly benzylfluorides (ArCH)₂CH₂F) The synthesis method of (org. chem. front.2019,6, 1463-1470). However, the method has the following limitations that the preparation of arylboronic acid containing complex sensitive structural units requires complicated synthetic steps, the addition of base in the reaction causes poor functional group tolerance, and the competitive boron removal protonation side reaction of arylboronic acid caused by an alkaline activator is serious. Therefore, the traditional Suzuki coupling mode of aryl boric acid (nucleophilic carbon reagent) and o-difluorohalohydrocarbon (electrophilic carbon reagent) is bypassed, and the more available reduction coupling reaction mode of aryl halide (electrophilic carbon reagent) and o-difluorohalohydrocarbon (electrophilic carbon reagent) is adopted to realize the reduction coupling of the aromatic ring and CH₂CH₂The precise butt joint of F little fluoroalkyl has important research significance for promoting and developing the preparation technology of the monofluoroalkyl substituted aromatic compound which is concise, efficient, good in tolerance and suitable for large-scale production.

Disclosure of Invention

The technical problem to be solved by the invention is as follows: provides a preparation method of the monofluoroalkyl substituted aromatic compound, which has low cost, simple and convenient process and wide substrate universality.

The technical scheme of the invention is as follows:

a method for preparing a monofluoroalkyl-substituted aromatic compound by reductive coupling, comprising:

the preparation method comprises the steps of taking monofluoroalkyl halohydrocarbon (I) and non-activated heteroaryl electrophilic reagents Ar-X (II) as raw materials, taking a metal simple substance as a reducing agent under the action of a nickel catalyst and a nitrogen-containing ligand catalytic system, adding an activating auxiliary agent, fully stirring and reacting in a reaction solvent at 50-100 ℃ in a nitrogen atmosphere, and separating and purifying to obtain a monofluoroalkyl substituted aromatic compound after the reaction reaches an end point.

The reaction equation is as follows:

alternatively, the monofluoroalkyl halohydrocarbon (I) may be any one of 1-fluoro-2-iodoethane, 1-fluoro-2-bromoethane, 1-fluoro-2-iodocyclohexane, 1-bromo-2-fluorocyclohexane or (2-bromo-1-fluoro) ethylbenzene.

Optionally, Ar of the unactivated heteroaryl electrophile Ar-X (II) is phenyl, C1-C4 alkyl-substituted phenyl, C1-C4 alkoxy-substituted phenyl, C1-C4 acyl-substituted phenyl, C1-C4 alkoxyacyl-substituted phenyl, cyano-substituted phenyl, nitro-substituted phenyl, naphthyl, or pyridyl. The alkyl of C1-C4 is methyl, ethyl, propyl, isopropyl, butyl or tert-butyl; the alkoxy of C1-C4 refers to methoxy, ethoxy or tert-butoxy; the acyl group of C1-C4 is formyl, acetyl, propionyl, formyl acetonitrile, butyryl or benzoyl; the C1-C4 alkoxy acyl refers to methoxyacyl, ethoxyacyl, propoxycarbonyl or butoxyacyl.

Alternatively, X of the unactivated heteroaryl electrophile Ar — X (ii) is any one of an iodo group, a bromo group, a chloro group, a p-toluenesulfonate group, or a trifluoromethanesulfonate group.

Alternatively, the nickel catalyst is Ni (cod)₂、NiCl₂、NiBr₂、NiI₂Or Ni (acac)₂Any one of the above. Preferably NiBr₂。

Alternatively, the reducing agent is any one of Mn, Zn, Cu, Al, or Fe. Mn is preferred.

Alternatively, the co-activator is any one of potassium iodide, sodium iodide, tetrabutylammonium iodide, trimethylchlorosilane, lithium chloride, zinc chloride, or magnesium chloride, and the addition of the co-activator facilitates efficient conversion of the non-activated heteroaryl electrophile Ar — X. Preferably magnesium chloride.

Alternatively, the nitrogen-containing ligand is any one of pyridine, 4-dimethylaminopyridine, 2' -bipyridine, 4' -dimethyl-2, 2' -bipyridine, 4' -dimethoxy-2, 2' -bipyridine, 4' -di-tert-butyl-2, 2' -bipyridine, 6 ' -dimethyl-2, 2' -bipyridine, or phenanthroline. Preferably 4,4 '-dimethoxy-2, 2' -bipyridine.

Alternatively, the reaction solvent is any one of dioxane, ethylene glycol dimethyl ether, N-methyl pyrrolidone, N-dimethylformamide or N, N-dimethylacetamide/N, N-dimethylpropylurea or a mixture thereof. N-methylpyrrolidone is preferred.

Optionally, the separation and purification steps are: after the reaction end point is determined by fluorine spectrum monitoring, insoluble substances in the reaction solution are filtered, and a small amount of ether is washed; pouring the filtrate into water, extracting the water phase by using ether, combining the organic phases, washing the organic phase by using water and a saturated ammonium chloride aqueous solution in turn, drying the organic phase by using anhydrous sodium sulfate, filtering the organic phase, removing the solvent by rotary evaporation, and separating the residue by recrystallization or silica gel column chromatography to obtain the monofluoroalkyl substituted aromatic compound.

Optionally, the ratio of the amount of monofluoroalkyl halocarbon to the amount of unactivated heteroaryl electrophile is (1-2.0): 1; the amount ratio of the nickel catalyst to the non-activated heteroaryl electrophile is (1-20.0): 100; the ratio of the amount of the nitrogen-containing ligand to the amount of unactivated heteroaryl electrophile speciesIs (1-20.0): 100; the amount ratio of the reducing agent to the non-activated heteroaryl electrophile is (1-4.0): 1.0; the amount ratio of the activation aid to the non-activated heteroaryl electrophile is (1.0-20.0): 10.0; the ratio of the amount of the substance of the non-activated heteroaryl electrophile to the volume of the solvent is 1: 1-20 mol.L^-1. The feeding ratio and the solvent dosage are economical and cost-saving.

Compared with the prior art, the invention has the beneficial effects that:

the preparation method comprises the steps of taking cheap and easily-obtained monofluoroalkyl halohydrocarbon (I) and an unactivated heteroaryl electrophilic reagent Ar-X (II) as raw materials, adding an activating auxiliary agent and a metal reducing agent under the action of a base metal nickel catalyst/nitrogen ligand-containing catalytic system, and stirring in a reaction solvent to generate a monofluoroalkyl substituted aromatic hydrocarbon compound. 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.

Drawings

FIG. 1 shows a structure containing CH₂CH₂The application of the benzyl fluoride of the F structural fragment in the drug screening is shown in the figure;

FIG. 2 is a schematic diagram of the reaction equation of the present invention.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it is understood that various changes or modifications may be made by one skilled in the art after reading the disclosure of the present invention, and such equivalents may fall within the scope of the invention as defined by the claims appended hereto.