CN107628926B - Preparation method of monofluoroethyl substituted aromatic compound - Google Patents
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Abstract
The invention provides a preparation method of a monofluoroethyl substituted aromatic compound, belonging to the technical field of preparation of fluorine-containing organic molecules. The preparation method comprises the steps of taking 1-fluoro-2-iodoethane and aryl boric acid activated by weak base as raw materials under the atmosphere of a reaction solvent and nitrogen, heating to react under the action of a nickel catalyst and a bipyridine ligand catalytic system to reach an end point, and then separating and purifying to obtain the monofluoroethyl substituted aromatic compound. The preparation method adopts a cheap and easily-obtained nickel catalyst and bipyridine ligands as a catalytic system to realize the directional introduction of monofluoroethyl to aromatic groups, thereby efficiently preparing and obtaining monofluoroethyl substituted aromatic compounds. The method has the advantages of mild reaction conditions, wide raw material source, low cost, simple reaction steps, easy amplification of reaction scale, simple and convenient product separation and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of preparation of fluorine-containing organic molecules, and particularly relates to a preparation method of a monofluoroethyl substituted aromatic compound.
Background
Fluorine is used as the element with the largest electronegativity in the periodic table of elements, has strong electron-withdrawing ability, smaller volume of original molecules and low polarizability, can remarkably regulate and control the physical, chemical and biological properties of organic molecules, and is known as 'ASmall Atom with Big Ego' by the chemical community. At present, the figure of fluorine atoms is seen everywhere in key core materials of medicine, materials, aerospace, military industry and the like. It can be said that fluorine-containing compounds profoundly affect the production and life of people today. Particularly in the fields of medicines and agrochemicals, the fluorine-containing organic compounds occupy approximately 20% and 30% of the total number on the market, respectively, and the proportion thereof also shows a tendency to increase gradually.
Although the fluorine-containing organic compound occupies an important seat in various industries with unique functions, the types and the number of the naturally occurring fluorine-containing organic compounds in the nature are extremely rare, a large amount of fluorine-containing organic compounds must be obtained by artificial synthesis, and the efficient introduction of fluorine atoms or fluorine-containing groups into specific sites of hydrocarbon organic molecule precursors by organic synthesis becomes an important means for artificial modification and synthesis of fluorine-containing functional organic molecules with various structures.
Among a plurality of fluorine-containing modification synthetic strategies, the preparation of monofluoroethyl substituted aromatic compounds by introducing fluorine atoms to β th position of aromatic ring ethyl side chains is always concerned by organic chemists and medicinal chemists, and is due to the important role of monofluoroethyl segments in the field of modification of pharmaceutically active molecules.
In view of the important application value of monofluoroethyl substituted aromatic compounds, chemists are constantly developing various methods and means for synthesizing monofluoroethyl substituted aromatic compounds, the current methods mainly focus on the preparation of β -hydroxyethyl aromatic compounds as precursors by nucleophilic fluorination, and the specific preparation principle is as follows:
the existing preparation method has the following defects that (1) β -hydroxyethyl fragments need to be introduced in advance, (2) expensive nucleophilic fluoride reagent (diethylaminosulfur trifluoride, DAST) or sulfur tetrafluoride (SF4) and other high-toxicity reagents need to be used when hydroxyl directly carries out nucleophilic fluoride reaction, and (3) the scheme that hydroxyl is firstly converted into leaving groups (OTs or OTf) and then products are obtained through fluorine anion nucleophilic substitution reaction has the problems of complicated steps, more side reactions, low yield and the like.
Disclosure of Invention
The invention aims to overcome the defects and provide a preparation method of a monofluoroethyl substituted aromatic compound, which has low cost, simple and convenient process and safe and reliable production.
The purpose of the invention is realized by the following technical scheme:
a preparation method of a monofluoroethyl substituted aromatic compound comprises the steps of taking 1-fluoro-2-iodoethane and aryl boric acid activated by alkali as raw materials under the atmosphere of a reaction solvent and nitrogen, heating to react to reach an end point under the action of a nickel catalyst and a bipyridine ligand catalytic system, and then separating and purifying to obtain the monofluoroethyl substituted aromatic compound.
As a specific example of the method for preparing a monofluoroethyl-substituted aromatic compound according to the present invention, the method comprises the steps of:
1) adding alkali and a reaction solvent into the arylboronic acid under the nitrogen atmosphere, and uniformly stirring;
2) sequentially adding 1-fluoro-2-iodoethane, bipyridyl ligand and nickel catalyst into the solution, sealing, heating, stirring to reach the reaction end point, and cooling the reaction solution to room temperature;
3) and separating and purifying the cooled reaction liquid to obtain the monofluoroethyl substituted aromatic compound.
As a specific example of the method for producing a monofluoroethyl-substituted aromatic compound of the present invention, the amount ratio of the 1-fluoro-2-iodoethane to the arylboronic acid substance is 1: 1 to 2.2, the amount ratio of the nickel catalyst to the 1-fluoro-2-iodoethane substance is 1 to 15.0: 100, the amount ratio of the bipyridine-based ligand to the 1-fluoro-2-iodoethane substance is 1 to 20.0: 100, the amount ratio of the base to the 1-fluoro-2-iodoethane substance is 1.5 to 4.0: 1, and the amount ratio of the 1-fluoro-2-iodoethane substance to the volume of the reaction solvent is 1: 1 to 20mol L-1。
As an embodiment of the method for preparing a monofluoroethyl substituted aromatic compound according to the present invention, the Ar group of the arylboronic acid is one or more of phenyl, C1-4 alkyl substituted phenyl, C1-4 alkoxy substituted phenyl, C1-4 acyl substituted phenyl, C1-4 alkoxy acyl substituted phenyl, cyano substituted phenyl, naphthyl, pyridyl, quinolyl, dibenzofuranyl, and dibenzothiophenyl.
As a specific example of the preparation method of the monofluoroethyl substituted aromatic compound, the C1-4 alkyl is a group, an ethyl group, a propyl group, an isopropyl group, a butyl group or a tert-butyl group; the alkoxy of C1-4 is methoxy, ethoxy, tert-butoxy; the acyl of C1-4 is formyl, acetyl, propionyl and butyryl; the C1-4 alkoxy acyl is methoxyacyl, ethoxyacyl, propoxyl and butoxyacyl.
As a specific example of the preparation method of a monofluoroethyl substituted aromatic compound according to the present invention, the reaction solvent is one or more of tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, toluene, dimethyl sulfoxide, N-dimethylformamide, and N, N-dimethylacetamide. Preferably ethylene glycol dimethyl ether or diethylene glycol dimethyl ether.
As a specific example of the preparation method of a monofluoroethyl substituted aromatic compound according to the present invention, the base is one of sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium phosphate, potassium phosphate, cesium fluoride, potassium fluoride, sodium tert-butoxide, and potassium tert-butoxide. Potassium phosphate is preferred.
As a specific example of the preparation method of the monofluoroethyl substituted aromatic compound according to the present invention, the nickel catalyst is Ni (cod)2、NiCl2、NiBr2、NiCl2(DME)、NiBr2(DME)、Ni(acac)2One kind of (1). Preferably NiBr2。
As a specific example of the preparation method of a monofluoroethyl substituted aromatic compound, the bipyridine ligand is one of 2,2 ' -bipyridine, 4 ' -dimethyl-2, 2 ' -bipyridine, 4 ' -di-tert-butyl-2, 2 ' -bipyridine, 4 ' -dimethoxy-2, 2 ' -bipyridine, phenanthroline, and α -terpyridine, preferably 4,4 ' -dimethoxy-2, 2 ' -bipyridine.
As a specific example of the preparation method of a monofluoroethyl substituted aromatic compound according to the present invention, the separation and purification steps include: filtering insoluble substances in the reaction solution, washing the insoluble substances with diethyl ether, and collecting filtrate; adding water into the filtrate, extracting the water phase with diethyl ether, combining the organic phases, washing the organic phase with water and saturated sodium chloride aqueous solution successively, drying with anhydrous sodium sulfate, filtering, rotary evaporating to remove the solvent, and recrystallizing or separating the residue with silica gel column chromatography to obtain the monofluoroethyl substituted aromatic compound.
Compared with the prior art, the invention has the following beneficial effects:
the invention takes 1-fluoro-2-iodoethane and aryl boric acid which are commercialized, easy to obtain, safe and stable as raw materials, under the action of a base metal nickel catalyst/bipyridine ligand catalytic system, aryl boric acid is activated by using inorganic weak base, and is stirred in an ethylene glycol dimethyl ether solvent to generate a monofluoroethyl substituted aromatic compound. The preparation method of the invention has the advantages that:
1. the preparation method of the invention does not need to prepare β -hydroxyethyl aromatic compound in advance like the existing preparation method, and then carry out nucleophilic fluorination reaction for converting hydroxyl into fluorine, but directly realizes the connection of aromatic groups and monofluoroethyl fragments, the reaction strategy is simple and clear, and the selectable range of the aromatic groups is wide;
2. the preparation method of the invention adopts base metal nickel as the catalyst and bipyridine ligand as the supporting ligand, and the catalyst system has high efficiency and low cost.
3. The preparation method has the advantages of mild reaction conditions, good substrate functional group compatibility, easy enlargement of reaction scale, simple product separation and suitability for industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The method for preparing a monofluoroethyl substituted aromatic compound according to the present invention will be described in detail with reference to the specific principles and procedures.
A preparation method of a monofluoroethyl substituted aromatic compound comprises the steps of taking 1-fluoro-2-iodoethane and aryl boric acid activated by weak base as raw materials under the atmosphere of a reaction solvent and nitrogen, heating to react to reach an end point under the action of a nickel catalyst and a bipyridine ligand catalytic system, and then separating and purifying to obtain the monofluoroethyl substituted aromatic compound.
The reaction equation of the monofluoroethyl substituted aromatic compound of the present invention is as follows:
the preparation method of the monofluoroethyl substituted aromatic compound uses 1-fluoro-2-iodoethane and aryl boric acid as raw materials, under the action of a base metal nickel catalyst/bipyridine ligand catalytic system, uses inorganic weak base to activate the aryl boric acid, and stirs the aryl boric acid in an ethylene glycol dimethyl ether solvent to generate the monofluoroethyl substituted aromatic compound.
In the preparation method, the reaction solvent is used for providing a favorable reaction environment, and has the functions of dilution and dispersion, so that side reactions caused by overhigh local concentration are avoided. The nitrogen is inert gas (does not react with a reaction substrate and a catalyst), and under the protection of the inert gas, the quenching inactivation caused by the oxidation of transition metal catalytic species can be effectively prevented. The weak base provides lone pair electrons, can coordinate with an empty p orbit of a boron atom on the aryl boric acid to form a complex, and is beneficial to the transmetalation of aryl groups. The metal nickel catalyst provides a catalytic reaction active center, and the bipyridine ligand can obviously regulate and control and improve the reaction effect after being coordinated with the metal nickel.
Further, the preparation method of the monofluoroethyl substituted aromatic compound comprises the following steps:
1) adding weak base and a reaction solvent into the arylboronic acid under the nitrogen atmosphere, and uniformly stirring;
2) sequentially adding 1-fluoro-2-iodoethane, bipyridyl ligand and nickel catalyst into the solution, sealing, heating, stirring to reach the reaction end point, and cooling the reaction solution to room temperature;
3) and separating and purifying the cooled reaction liquid to obtain the monofluoroethyl substituted aromatic compound.
In the specific preparation process of the preparation method of the monofluoroethyl substituted aromatic compound, weak base and reaction solvent are added into aryl boric acid serving as a raw material in a nitrogen atmosphere, and the aryl boric acid is subjected to weak base reaction in a weak alkaline environmentActivating, adding 1-fluoro-2-iodoethane and catalytic system, reacting 1-fluoro-2-iodoethane with arylboronic acid under the action of catalytic system under the condition of oil bath heating and stirring, and performing fluorine nuclear magnetic resonance spectrum (F:)19F NMR) monitoring the reaction liquid to determine the reaction end point, and then cooling, separating and purifying the reaction liquid in sequence to obtain the monofluoroethyl substituted aromatic compound. The 1-fluoro-2-iodoethane in the reaction raw materials has low boiling point and is easy to volatilize and lose, the 1-fluoro-2-iodoethane needs to be added in the presence of a system solvent, and if the 1-fluoro-2-iodoethane is added together with a weak base, a reaction solvent or arylboronic acid, the conversion rate is reduced. The adding sequence and the preparation steps of each reactant in the preparation method are obtained by combining the yield and the product purity through long-term experiments, and the product yield and the product purity can be effectively improved.
Further, the ratio of the amount of the 1-fluoro-2-iodoethane to the amount of the arylboronic acid substance is 1: 1 to 2.2, the ratio of the amount of the nickel catalyst to the amount of the 1-fluoro-2-iodoethane substance is 1 to 15.0: 100, the ratio of the amount of the bipyridine ligand to the amount of the 1-fluoro-2-iodoethane substance is 1 to 20.0: 100, the ratio of the amount of the weak base to the amount of the 1-fluoro-2-iodoethane substance is 1.5 to 4.0: 1, and the ratio of the amount of the 1-fluoro-2-iodoethane substance to the volume of the reaction solvent is 1: 1 to 20mol L-1.
Further, Ar groups of the arylboronic acid are one or more of phenyl, alkyl substituted phenyl of C1-4, alkoxy substituted phenyl of C1-4, acyl substituted phenyl of C1-4, alkoxy substituted phenyl of C1-4, cyano substituted phenyl, naphthyl, pyridyl, quinolyl, dibenzofuranyl and dibenzothienyl. Furthermore, the C1-4 alkyl is a radical, ethyl, propyl, isopropyl, butyl or tert-butyl; the alkoxy of C1-4 is methoxy, ethoxy, tert-butoxy; the acyl of C1-4 is formyl, acetyl, propionyl and butyryl; the C1-4 alkoxy acyl is methoxyacyl, ethoxyacyl, propoxyl and butoxyacyl.
Further, the reaction solvent is one or more of tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, toluene, dimethyl sulfoxide, N-dimethylformamide and N, N-dimethylacetamide. The reaction solvent serves to provide a favorable site and atmosphere for the interaction of the reaction substrate with the catalyst, and may serve to dissolve the reaction substrate and dilute the concentration to reduce side reactions.
Further, the weak base is one of sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium phosphate, potassium phosphate, cesium fluoride, potassium fluoride, sodium tert-butoxide and potassium tert-butoxide. The weak base can promote the boron removal and the transmetallization of the arylboronic acid substrate, and greatly accelerate the catalytic reaction speed of the transition metal.
Further, the nickel catalyst is Ni (cod)2、NiCl2、NiBr2、NiCl2(DME)、NiBr2(DME)、Ni(acac)2One kind of (1). The preferred nickel bromide catalyst belongs to a base metal catalyst, has low price, can stably exist in the air, and has the effects of reducing the cost of the reaction catalyst and simple and convenient weighing and feeding procedures compared with the noble metal palladium catalyst of the same family.
Further, the bipyridine ligand is one of 2,2 ' -bipyridine, 4 ' -dimethyl-2, 2 ' -bipyridine, 4 ' -di-tert-butyl-2, 2 ' -bipyridine, 4 ' -dimethoxy-2, 2 ' -bipyridine, phenanthroline and α -terpyridine, and the bipyridine ligand is used as a supporting ligand to play a role in stabilizing the nickel metal catalytic active center, so that the elementary steps of oxidation addition, ligand exchange, reduction elimination and the like in transition metal catalysis are effectively regulated.
Further, the separation and purification steps are as follows: filtering insoluble substances in the reaction solution, washing the insoluble substances with diethyl ether, and collecting filtrate; adding water into the filtrate, extracting the water phase with diethyl ether, combining the organic phases, washing the organic phase with water and saturated sodium chloride aqueous solution successively, drying with anhydrous sodium sulfate, filtering, rotary evaporating to remove the solvent, and recrystallizing or separating the residue with silica gel column chromatography to obtain the monofluoroethyl substituted aromatic compound. The steps of the separation and purification of the invention are designed according to the characteristics of the prepared monofluoroethyl aromatic compound, and those skilled in the art can preferably select other effective separation and purification methods to realize the separation and purification of the product, so long as the purpose of the separation and purification of the product of the invention can be realized.
The following will specifically explain a method for producing a monofluoroethyl-substituted aromatic compound of the present invention with reference to specific examples.
EXAMPLE 1 preparation of β -fluoroethylbenzene Compound
This example prepared compound β -fluoroethylbenzene according to the following chemical reaction:
the preparation process comprises the following steps:
under nitrogen atmosphere, phenylboronic acid (1.829g,15.0mmol), anhydrous potassium acetate (2.944g, 30.0mmol) were sequentially added to a sealed tube, solvent tetrahydrofuran (30m L) was added, and after stirring, 1-fluoro-2-iodoethane (1.739g, 10mmol), 2' -bipyridine (0.312g, 2.0mmol), and Ni (cod) were sequentially added2(0.275g, 1.0mol), sealing, stirring in an oil bath at 80 ℃ for 12 hours, cooling the reaction solution to room temperature, adding trifluorotoluene, monitoring the reaction endpoint by using a fluorine spectrum internal standard method, and determining that the crude yield of the reaction is 21% (β -fluoroethylbenzene has a low boiling point and is not purified by distillation).
EXAMPLE 2 preparation of β -fluoroethylbenzene Compound
This example prepared compound β -fluoroethylbenzene according to the following chemical reaction:
the preparation process comprises the following steps:
under nitrogen atmosphere, phenylboronic acid (1.585g,13.0mmol) and anhydrous potassium phosphate (7.429g, 35.0mmol) were sequentially added to a sealed tube, solvent dioxane (20m L) was added, and after stirring, 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 2' -bipyridine (0.156g, 1.0mmol) and NiCl were sequentially added2(0.130g, 1.0mmol), and a silica gelAfter sealing, stirring the mixture in an oil bath at the temperature of 80 ℃ for reaction for 12 hours, cooling the reaction liquid to room temperature, adding benzotrifluoride, monitoring the reaction end point by using a fluorine spectrum internal standard method, and determining that the crude yield of the reaction is 48 percent.
EXAMPLE 3 preparation of β -fluoroethylbenzene Compound
This example prepared compound β -fluoroethylbenzene according to the following chemical reaction:
the preparation process comprises the following steps:
under nitrogen atmosphere, phenylboronic acid (1.585g,13.0mmol) and sodium carbonate (2.332g, 22.0mmol) were sequentially added into a sealed tube, solvent DMF (24m L) was added, and after stirring well, 1-fluoro-2-iodoethane (1.739g, 10.0mmol), α -terpyridine (0.434g, 1.0mmol) and Ni (acac)2(0.257g, 1.0mmol), sealing, stirring in an oil bath at 80 ℃ for 20 hours, cooling the reaction solution to room temperature, adding trifluorotoluene, monitoring the end point of the reaction by using a fluorimetry internal standard method, and determining that the crude yield of the reaction is 24%.
EXAMPLE 4 preparation of β -fluoroethylbenzene Compound
This example prepared compound β -fluoroethylbenzene according to the following chemical reaction:
the preparation process comprises the following steps:
under the atmosphere of nitrogen, phenylboronic acid (2.195g,18.0mmol) and anhydrous cesium carbonate (6.516g, 20.0mmol) are sequentially added into a sealed tube, solvent N, N-dimethylacetamide (20m L) is added, the mixture is uniformly stirred, and then 1-fluoro-2-iodoethane (1.739g, 10.0mmol), phenanthrene (0.180g, 1.0mmol) and NiBr are sequentially added2(DME) (0.309g, 1.0mmol), sealed and stirred in an oil bath at 80 ℃ for 12 hours, the reaction solution was cooled to room temperature, trifluorotoluene was added, the end of the reaction was monitored by the fluorimetry internal standard method, and the crude yield of the reaction was determined to be 18%.
EXAMPLE 5 preparation of β -fluoroethylbenzene Compound
This example prepared compound β -fluoroethylbenzene according to the following chemical reaction:
the preparation process comprises the following steps:
under nitrogen atmosphere, phenylboronic acid (1.829g,15.0mmol) and anhydrous potassium carbonate (3.455g,25.0mmol) are sequentially added into a sealed tube, solvent dimethyl sulfoxide (22m L) is added, the mixture is uniformly stirred, and then 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 2' -bipyridine (0.156g, 1.0mmol) and NiBr are sequentially added2(DME) (0.309g, 1.0mmol), sealed and stirred in an oil bath at 80 ℃ for 12 hours, the reaction solution was cooled to room temperature, trifluorotoluene was added, the end of the reaction was monitored by the fluorimetry internal standard method, and the crude yield of the reaction was determined to be 56%.
EXAMPLE 6 preparation of β -fluoroethylbenzene Compound
This example prepared compound β -fluoroethylbenzene according to the following chemical reaction:
the preparation process comprises the following steps:
under nitrogen atmosphere, phenylboronic acid (1.829g,15.0mmol) and anhydrous potassium fluoride (1.740g,30.0mmol) are sequentially added into a sealed tube, a solvent of diethylene glycol dimethyl ether (15m L) is added, the mixture is uniformly stirred, and then 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 2' -bipyridine (0.156g, 1.0mmol) and NiCl are sequentially added2(DME) (0.220g, 1.0mmol), sealed and stirred in an oil bath at 80 ℃ for 24 hours, the reaction was cooled to room temperature, trifluorotoluene was added, the end of the reaction was monitored by the fluorimetry internal standard method, and the crude yield of the reaction was determined to be 24%.
EXAMPLE 7 preparation of β -fluoroethylbenzene Compound
This example prepared compound β -fluoroethylbenzene according to the following chemical reaction:
the preparation process comprises the following steps:
under nitrogen atmosphere, phenylboronic acid (1.829g,15.0mmol) and anhydrous potassium phosphate (4.245g,20.0mmol) were sequentially added into a sealed tube, a solvent ethylene glycol dimethyl ether (50m L) was added, and after stirring uniformly, 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 2' -bipyridine (0.172g, 1.1mmol) and NiBr were sequentially added2(0.219g, 1.0mmol), sealing, stirring in an oil bath at 80 ℃ for 24 hours, cooling the reaction solution to room temperature, adding trifluorotoluene, monitoring the reaction end point by using a fluorimetry internal standard method, and determining that the crude yield of the reaction is 80%.
EXAMPLE 8 preparation of β -fluoroethylbenzene Compound
This example prepared compound β -fluoroethylbenzene according to the following chemical reaction:
the preparation process comprises the following steps:
under nitrogen atmosphere, phenylboronic acid (1.829g,15.0mmol) and anhydrous potassium phosphate (6.368g,30.0mmol) were sequentially added into a sealed tube, a solvent ethylene glycol dimethyl ether (50m L) was added, and after stirring uniformly, 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 2' -bipyridine (0.172g, 1.1mmol) and NiBr were sequentially added2(0.219g, 1.0mmol), sealing, stirring in an oil bath at 80 ℃ for 24 hours, cooling the reaction solution to room temperature, adding trifluorotoluene, monitoring the end point of the reaction by using a fluorimetry internal standard method, and determining that the crude yield of the reaction is 84%.
EXAMPLE 9 preparation of β -fluoroethylbenzene Compound
This example prepared compound β -fluoroethylbenzene according to the following chemical reaction:
the preparation process comprises the following steps:
under the atmosphere of nitrogen, 1.829g,15.0mmol of phenylboronic acid is added into a sealed tube in sequence,Anhydrous potassium phosphate (6.368g,30.0mmol), solvent ethylene glycol dimethyl ether (50m L) was added and stirred uniformly, and then 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 4 '-dimethyl-2, 2' -bipyridine (0.203g, 1.1mmol) and NiBr were added in this order2(0.219g, 1.0mmol), sealing, stirring in an oil bath at 80 ℃ for 24 hours, cooling the reaction solution to room temperature, adding trifluorotoluene, monitoring the end point of the reaction by using a fluorimetry internal standard method, and determining that the crude yield of the reaction is 88%.
EXAMPLE 10 preparation of β -fluoroethylbenzene Compound
This example prepared compound β -fluoroethylbenzene according to the following chemical reaction:
the preparation process comprises the following steps:
under nitrogen atmosphere, phenylboronic acid (1.829g,15.0mmol) and anhydrous potassium phosphate (6.368g,30.0mmol) were sequentially added into a sealed tube, a solvent ethylene glycol dimethyl ether (50m L) was added, and after stirring uniformly, 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 4 '-di-tert-butyl-2, 2' -bipyridine (0.295g, 1.1mmol) and NiBr were sequentially added2(0.219g, 1.0mmol), sealing, stirring in an oil bath at 80 ℃ for 24 hours, cooling the reaction solution to room temperature, adding trifluorotoluene, monitoring the end point of the reaction by using a fluorimetry internal standard method, and determining that the crude yield of the reaction is 90%.
EXAMPLE 11 preparation of β -fluoroethylbenzene Compound
An exemplary chemical reaction for the preparation of compound β -fluoroethylbenzene is as follows:
the preparation process comprises the following steps:
under nitrogen atmosphere, phenylboronic acid (1.829g,15.0mmol) and anhydrous potassium phosphate (6.368g,30.0mmol) were sequentially added to a sealed tube, a solvent ethylene glycol dimethyl ether (50m L) was added thereto, the mixture was stirred uniformly, and then 1-fluoro-2-iodoethane (1.739g, 10.0mmol) and 4,4 '-dimethoxy-2, 2' -bipyridine (0.238g, 1.1 mm) were sequentially added theretool) and NiBr2(0.219g, 1.0mmol), sealing, stirring in an oil bath at 80 ℃ for 24 hours, cooling the reaction solution to room temperature, adding trifluorotoluene, monitoring the end point of the reaction by using a fluorimetry internal standard method, and determining that the crude yield of the reaction is 92%.
EXAMPLE 12 preparation of β -fluoroethylbenzene Compound
This example prepared compound β -fluoroethylbenzene according to the following chemical reaction:
the preparation process comprises the following steps:
phenylboronic acid (1.829g,15.0mmol) and anhydrous potassium phosphate (6.368g,30.0mmol) were sequentially added to a sealed tube under a nitrogen atmosphere, a solvent diethylene glycol dimethyl ether (50m L) was added and stirred uniformly, then 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 4 '-dimethoxy-2, 2' -bipyridine (0.238g, 1.1mmol) and NiBr2(0.219g, 1.0mmol) were sequentially added and stirred in an oil bath at 80 ℃ after sealing for 24 hours, the reaction solution was cooled to room temperature, benzotrifluoride was added, the end point of the reaction was monitored by the internal standard method of fluorine spectrum, and the crude yield of the reaction was determined to be 95%.
EXAMPLE 13 preparation of β -fluoroethylbenzene Compound
This example prepared compound β -fluoroethylbenzene according to the following chemical reaction:
the preparation process comprises the following steps:
under nitrogen atmosphere, phenylboronic acid (1.829g,15.0mmol) and anhydrous potassium phosphate (6.368g,30.0mmol) were sequentially added to a sealed tube, a solvent, diethylene glycol dimethyl ether (50m L), was added, and after stirring, 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 4 '-dimethoxy-2, 2' -bipyridine (0.119g, 0.55mmol) and NiBr were sequentially added2(0.110g, 0.5mmol), sealing, stirring in 80 deg.C oil bath for 36 hr, cooling the reaction solution to room temperature, adding trifluorotoluene, monitoring the reaction end point by using fluorimetry internal standard method, and determiningThe crude yield of the reaction was 91%.
EXAMPLE 14 preparation of β -fluoroethylbenzene Compound
This example is a comparative example to example 13, which differs from example 13 in that no weak base anhydrous potassium phosphate activated with p-phenylboronic acid was added, and the effect of the addition of the weak base on the yield of the product was investigated the chemical reaction formula for this example to produce compound β -fluoroethylbenzene is as follows:
the preparation process comprises the following steps:
under nitrogen atmosphere, phenylboronic acid (1.829g,15.0mmol) and diethylene glycol dimethyl ether (50m L) as solvent are sequentially added into a sealed tube, and after uniform stirring, 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 4 '-dimethoxy-2, 2' -bipyridine (0.119g, 0.55mmol) and NiBr are sequentially added2(0.110g, 0.5mmol), sealing, stirring in an oil bath at 80 ℃ for reaction for 36 hours, cooling the reaction solution to room temperature, adding trifluorotoluene, monitoring the reaction endpoint by using a fluorimetry internal standard method, and determining that the crude yield of the reaction is 2%.
EXAMPLE 15 preparation of β -fluoroethylbenzene Compound
This example is a comparative example to example 13, which differs from example 13 in that the bipyridine ligand 4,4 '-dimethoxy-2, 2' -bipyridine was not added and the effect of the addition of the bipyridine ligand on the yield of the product was investigated the chemical reaction formula for the preparation of compound β -fluoroethylbenzene in this example is as follows:
the preparation process comprises the following steps:
under nitrogen atmosphere, phenylboronic acid (1.829g,15.0mmol), anhydrous potassium phosphate (6.368g,30.0mmol) and diethylene glycol dimethyl ether (50m L) were added in sequence to a sealed tube, and after stirring, 1-fluoro-2-iodoethane (1.739g, 10.0mmol) and NiBr were added in sequence2(0.110g, 0.5mmol), sealing, stirring in an oil bath at 80 ℃ for 36 hours,the reaction solution was cooled to room temperature, benzotrifluoride was added, the reaction end point was monitored by the internal standard method of fluorine spectrum, and the crude yield of the reaction was determined to be 6%.
EXAMPLE 16 preparation of β -fluoroethylbenzene Compound
This example is a comparative example to example 13, which differs from example 13 in that no nickel catalyst, NiBr, was added2The chemical reaction formula for this example to produce compound β -fluoroethylbenzene is as follows:
the preparation process comprises the following steps:
under nitrogen atmosphere, phenylboronic acid (1.829g,15.0mmol), (b) anhydrous potassium phosphate (6.368g,30.0mmol) and diethylene glycol dimethyl ether (50m L) are added into a sealed tube in sequence, after uniform stirring, 1-fluoro-2-iodoethane (1.739g, 10.0mmol) and 4,4 '-dimethoxy-2, 2' -bipyridine (0.119g, 0.55mmol) are added into the sealed tube in sequence, after sealing, the mixture is stirred in an oil bath at 80 ℃ for reaction for 36 hours, the reaction liquid is cooled to room temperature, benzotrifluoride is added, the end point of the reaction is monitored by using a fluorine spectrum internal standard method, and the crude yield of the reaction is determined to be 0% (no product is generated).
EXAMPLE 17 preparation of the Compound 1- (2-fluoroethyl) -4-methoxybenzene
This example prepared the compound 1- (2-fluoroethyl) -4-methoxybenzene according to the following chemical reaction:
the preparation process comprises the following steps:
under nitrogen atmosphere, sequentially adding p-methoxyphenylboronic acid (2.279g,15.0mmol) and anhydrous potassium phosphate (6.368g,30.0mmol) into a sealed tube, adding diethylene glycol dimethyl ether (50m L) as a solvent, uniformly stirring, and sequentially adding 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 4 '-dimethoxy-2, 2' -bipyridine (0.238g, 1.1mmol) and NiBr2(0.219g, 1.0mmol), sealed and stirred in an oil bath at 80 ℃ for reaction 24After the reaction solution was cooled to room temperature, insoluble matter in the reaction solution was filtered off with a celite core funnel, and washed with a small amount of ether, and the filtrate was collected, 60m L of water was added to the filtrate, the aqueous phase (40m L× 3) was extracted with ether, the organic phases were combined, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, and the solvent was recovered by rotary evaporation, and the residue was separated by silica gel column chromatography to give 1.311g of the product, with a yield of 85%.
The structural data for the product prepared in this example are characterized as follows:
1H NMR(600MHz,CDCl3)7.08(d,J＝8.5Hz,2H),6.79(d,J＝8.5Hz,2H),4.56(t,J＝6.7Hz,1H),4.48(t,J＝6.7Hz,1H),3.72(s,3H),2.88(dt,J＝22.8,6.6Hz,2H)；13C NMR(101MHz,CDCl3)158.62,130.08,129.25(d,J＝6.7Hz),114.18,84.44(d,J＝168.9Hz),55.41,36.21(d,J＝20.3Hz).
EXAMPLE 18 preparation of the Compound 1-benzyloxy-4- (2-fluoroethyl) benzene
This example prepared the compound 1-benzyloxy-4- (2-fluoroethyl) benzene according to the following chemical reaction:
the preparation process comprises the following steps:
under nitrogen atmosphere, sequentially adding p-benzyloxy phenylboronic acid (3.421g,15.0mmol) and anhydrous potassium phosphate (6.368g,30.0mmol) into a sealed tube, adding diethylene glycol dimethyl ether (50m L) as a solvent, stirring uniformly, and sequentially adding 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 4 '-dimethoxy-2, 2' -bipyridine (0.238g, 1.1mmol) and NiBr2(0.219g, 1.0mmol), sealing, stirring in an oil bath at 80 ℃ for 24 hours for reaction, cooling the reaction liquid to room temperature, filtering insoluble substances in the reaction liquid by using a diatomite sand core funnel, washing with a small amount of diethyl ether, collecting filtrate, adding 60m L water into the filtrate, extracting an aqueous phase (40m L× 3) by using diethyl ether, combining organic phases, washing the organic phases with water and saturated saline solution successively, drying with anhydrous sodium sulfate, filtering, recovering the solvent by rotary evaporation, and separating residues by using a silica gel column chromatography to obtain 2.050g of a product, wherein the yield is 89%.
The structural data for the product prepared in this example are characterized as follows:
1H NMR(600MHz,CDCl3)7.34(d,J＝7.3Hz,2H),7.30(t,J＝7.5Hz,2H),7.24(t,J＝7.3Hz,1H),7.06(d,J＝8.6Hz,2H),6.87–6.82(m,2H),4.96(s,2H),4.54(t,J＝6.6Hz,1H),4.46(t,J＝6.6Hz,1H),2.87(dt,J＝22.9,6.6Hz,2H)；13C NMR(151MHz,CDCl3)156.61,136.03,128.93,128.33(d,J＝6.7Hz),127.54,126.90,126.42,113.91,83.25(d,J＝168.9Hz),68.99,35.01(d,J＝20.2Hz).
EXAMPLE 19 preparation of the Compound 6- (2-fluoroethyl) -2, 3-dihydrobenzo [ b ] [1,4] dioxane
This example prepared the compound 6- (2-fluoroethyl) -2, 3-dihydrobenzo [ b ] [1,4] dioxane according to the following chemical reaction:
the preparation process comprises the following steps:
under the atmosphere of nitrogen, 2, 3-dihydrobenzo [ b ] is added into a sealed tube in sequence][1,4]Dioxane-6-boric acid (2.700g,15.0mmol) and anhydrous potassium phosphate (6.368g,30.0mmol) are added into solvent diethylene glycol dimethyl ether (50m L) and stirred evenly, and then 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 4 '-dimethoxy-2, 2' -bipyridine (0.238g, 1.1mmol) and NiBr are added into the mixture in sequence2(0.219g, 1.0mmol), sealing, stirring in an oil bath at 80 ℃ for 24 hours for reaction, cooling the reaction solution to room temperature, filtering insoluble substances in the reaction solution by using a diatomite sand core funnel, washing with a small amount of diethyl ether, collecting filtrate, adding 60m L water into the filtrate, extracting an aqueous phase (40m L× 3) by using diethyl ether, combining organic phases, washing the organic phase by using water and saturated saline water successively, drying by using anhydrous sodium sulfate, filtering, recovering the solvent by rotary evaporation, and separating residues by using a silica gel column chromatography to obtain 1.694g of a product, wherein the yield is 93%.
The structural data for the product prepared in this example are characterized as follows:
1H NMR(600MHz,CDCl3)6.73(d,J＝8.1Hz,1H),6.67(s,1H),6.62(d,J＝8.0Hz,1H),4.50(dt,J＝47.1,6.4Hz,2H),4.16(s,4H),2.83(dt,J＝22.8,6.3Hz,2H)；13C NMR(151MHz,CDCl3)143.46,142.36,130.27(d,J＝6.8Hz),121.90,117.67,117.29,84.21(d,J＝168.9Hz),64.40,64.34,36.19(d,J＝20.4Hz).
EXAMPLE 20 preparation of the Compound 4- (2-fluoroethyl) -1, 1' -biphenyl
This example prepared the compound 4- (2-fluoroethyl) -1, 1' -biphenyl according to the following chemical formula:
the preparation process comprises the following steps:
under nitrogen atmosphere, 4-biphenylboronic acid (2.970g,15.0mmol) and anhydrous potassium phosphate (6.368g,30.0mmol) are sequentially added into a sealed tube, a solvent diethylene glycol dimethyl ether (50m L) is added, the mixture is uniformly stirred, and then 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 4 '-dimethoxy-2, 2' -bipyridine (0.238g, 1.1mmol) and NiBr are sequentially added2(0.219g, 1.0mmol), sealing, stirring in an oil bath at 80 ℃ for 24 hours for reaction, cooling the reaction liquid to room temperature, filtering insoluble substances in the reaction liquid by using a diatomite sand core funnel, washing with a small amount of diethyl ether, collecting filtrate, adding 60m L water into the filtrate, extracting an aqueous phase (40m L× 3) by using diethyl ether, combining organic phases, washing the organic phases with water and saturated saline solution successively, drying with anhydrous sodium sulfate, filtering, recovering the solvent by rotary evaporation, and separating residues by using a silica gel column chromatography to obtain 1.882g of a product, wherein the yield is 94%.
The structural data for the product prepared in this example are characterized as follows:
1H NMR(600MHz,CDCl3)7.56(dd,J＝19.2,7.6Hz,4H),7.42(t,J＝7.4Hz,2H),7.32(dd,J＝20.5,7.5Hz,3H),4.66(dt,J＝47.1,6.5Hz,2H),3.05(dt,J＝23.4,6.4Hz,2H)；13C NMR(151MHz,CDCl3)140.93,139.74,136.23(d,J＝6.1Hz),129.44,128.81,127.36,127.26,127.10,84.11(d,J＝169.1Hz),36.60(d,J＝20.4Hz).
EXAMPLE 21 preparation of the Compound 4- (2-fluoroethyl) benzaldehyde
This example prepared the compound 4- (2-fluoroethyl) benzaldehyde according to the following chemical formula:
the preparation process comprises the following steps:
under nitrogen atmosphere, 4-formylphenylboronic acid (2.249g,15.0mmol) and anhydrous potassium phosphate (6.368g,30.0mmol) were sequentially added to a sealed tube, the solvent diethylene glycol dimethyl ether (50m L) was added, and after stirring, 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 4 '-dimethoxy-2, 2' -bipyridine (0.238g, 1.1mmol) and NiBr were sequentially added2(0.219g, 1.0mmol), sealing, stirring in an oil bath at 80 ℃ for 24 hours for reaction, cooling the reaction solution to room temperature, filtering insoluble substances in the reaction solution by using a diatomite sand core funnel, washing with a small amount of diethyl ether, collecting filtrate, adding 60m L water into the filtrate, extracting an aqueous phase (40m L× 3) by using diethyl ether, combining organic phases, washing the organic phases with water and saturated saline sequentially, drying with anhydrous sodium sulfate, filtering, recovering the solvent by rotary evaporation, and separating residues by using a silica gel column chromatography to obtain 1.126g of a product, wherein the yield is 74%.
The structural data for the product prepared in this example are characterized as follows:
1H NMR(400MHz,CDCl3)10.00(s,1H),7.84(d,J＝8.2Hz,2H),7.41(d,J＝8.1Hz,2H),4.74(t,J＝6.2Hz,1H),4.62(t,J＝6.2Hz,1H),3.10(dt,J＝24.9,6.2Hz,2H)；13C NMR(101MHz,CDCl3)191.96,144.67(d,J＝4.7Hz,),135.33,130.14,129.77,83.41(d,J＝169.9Hz),37.18(d,J＝20.6Hz).
EXAMPLE 22 preparation of the Compound 1- (4- (2-fluoroethyl) phenyl) ethanone
This example prepared the compound 1- (4- (2-fluoroethyl) phenyl) ethanone according to the following chemical formula:
the preparation process comprises the following steps:
under a nitrogen atmosphere, 4-acetylphenylboronic acid (2.460g,15.0 mmol) was added to the sealed tube in sequence) Anhydrous potassium phosphate (6.368g,30.0mmol), diethylene glycol dimethyl ether (50m L) as a solvent, and then 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 4 '-dimethoxy-2, 2' -bipyridine (0.238g, 1.1mmol) and NiBr were added in this order after stirring well2(0.219g, 1.0mmol), sealing, stirring in an oil bath at 80 ℃ for 24 hours for reaction, cooling the reaction liquid to room temperature, filtering insoluble substances in the reaction liquid by using a diatomite sand core funnel, washing with a small amount of diethyl ether, collecting filtrate, adding 60m L water into the filtrate, extracting an aqueous phase (40m L× 3) by using diethyl ether, combining organic phases, washing the organic phases with water and saturated saline solution successively, drying with anhydrous sodium sulfate, filtering, recovering the solvent by rotary evaporation, and separating residues by using a silica gel column chromatography to obtain 1.330g of a product, wherein the yield is 80%.
The structural data for the product prepared in this example are characterized as follows:
1H NMR(400MHz,CDCl3)7.91(d,J＝8.3Hz,2H),7.34(d,J＝8.2Hz,2H),4.72(t,J＝6.3Hz,1H),4.60(t,J＝6.3Hz,1H),3.07(dt,J＝24.6,6.3Hz,2H),2.59(s,3H)；13C NMR(101MHz,CDCl3)197.79,143.02(d,J＝5.0Hz),135.93,129.28,128.74,83.52(d,J＝169.7Hz),36.97(d,J＝20.6Hz),26.63.
EXAMPLE 23 preparation of the Compound methyl 4- (2-fluoroethyl) benzoate
This example prepared the compound methyl 4- (2-fluoroethyl) benzoate according to the following chemical formula:
the preparation process comprises the following steps:
under nitrogen atmosphere, 4-methoxycarbonylphenylboronic acid (2.700g,15.0mmol) and anhydrous potassium phosphate (6.368g,30.0mmol) were sequentially added to a sealed tube, a solvent of diethylene glycol dimethyl ether (50m L) was added, the mixture was stirred uniformly, and 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 4 '-dimethoxy-2, 2' -bipyridine (0.238g, 1.1mmol) and NiBr were sequentially added2(0.219g, 1.0mmol), sealing, stirring in an oil bath at 80 deg.C for 24 hr, cooling the reaction solution to room temperature, filtering off insoluble substances in the reaction solution with a diatomaceous earth sand core funnel,washing with a small amount of ether, collecting filtrate, adding 60m L water into the filtrate, extracting the aqueous phase (40m L× 3) with ether, combining the organic phases, washing the organic phase with water and saturated brine successively, drying over anhydrous sodium sulfate, filtering, recovering the solvent by rotary evaporation, and separating the residue by silica gel column chromatography to obtain 1.512g of the product with 83% yield.
The structural data for the product prepared in this example are characterized as follows:
1H NMR(400MHz,CDCl3)7.99(d,J＝8.3Hz,2H),7.31(d,J＝8.1Hz,2H),4.71(t,J＝6.3Hz,1H),4.60(t,J＝6.3Hz,1H),3.91(s,3H),3.07(dt,J＝24.3,6.3Hz,2H)；13C NMR(101MHz,CDCl3)167.08,142.78,130.00,129.12,128.88,83.60(d,J＝169.7Hz),52.16,37.04(d,J＝20.6Hz).
EXAMPLE 24 preparation of the Compound 4- (2-fluoroethyl) benzonitrile
This example prepared the compound 4- (2-fluoroethyl) benzonitrile according to the following chemical formula:
the preparation process comprises the following steps:
under nitrogen atmosphere, 4-cyanophenylboronic acid (2.204g,15.0mmol) and anhydrous potassium phosphate (6.368g,30.0mmol) were sequentially added to a sealed tube, a solvent diethylene glycol dimethyl ether (50m L) was added thereto, and after stirring the mixture uniformly, 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 4 '-dimethoxy-2, 2' -bipyridine (0.238g, 1.1mmol) and NiBr were sequentially added thereto2(0.219g, 1.0mmol), sealing, stirring in an oil bath at 80 ℃ for reaction for 36 hours, cooling the reaction liquid to room temperature, filtering insoluble substances in the reaction liquid by using a diatomite sand core funnel, washing with a small amount of diethyl ether, collecting filtrate, adding 60m L water into the filtrate, extracting an aqueous phase (40m L× 3) by using diethyl ether, combining organic phases, washing the organic phases with water and saturated saline solution in turn, drying by using anhydrous sodium sulfate, filtering, recovering the solvent by rotary evaporation, and separating residues by using a silica gel column chromatography to obtain 1.134g of a product, wherein the yield is 76%.
The structural data for the product prepared in this example are characterized as follows:
1H NMR(600MHz,CDCl3)7.61(d,J＝7.3Hz,2H),7.36(d,J＝7.3Hz,2H),4.66(d,J＝46.9Hz,2H),3.07(d,J＝25.5Hz,2H)；13C NMR(151MHz,CDCl3)143.02(d,J＝4.2Hz),132.35,129.79,118.85,110.73,83.14(d,J＝170.0Hz),36.96(d,J＝20.6Hz).
EXAMPLE 25 preparation of the Compound 1- (2-fluoroethyl) naphthalene
This example prepared the compound 1- (2-fluoroethyl) naphthalene according to the following chemical reaction:
the preparation process comprises the following steps:
under nitrogen atmosphere, 1-naphthalene boric acid (2.580g,15.0mmol) and anhydrous potassium phosphate (6.368g,30.0mmol) are sequentially added into a sealed tube, a solvent diethylene glycol dimethyl ether (60m L) is added, the mixture is uniformly stirred, and then 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 4 '-dimethoxy-2, 2' -bipyridine (0.238g, 1.1mmol) and NiBr are sequentially added2(0.219g, 1.0mmol), sealing, stirring in an oil bath at 80 ℃ for 18 hours for reaction, cooling the reaction liquid to room temperature, filtering insoluble substances in the reaction liquid by using a diatomite sand core funnel, washing with a small amount of diethyl ether, collecting filtrate, adding 60m L water into the filtrate, extracting an aqueous phase (40m L× 3) by using diethyl ether, combining organic phases, washing the organic phases with water and saturated saline solution in turn, drying by using anhydrous sodium sulfate, filtering, recovering the solvent by rotary evaporation, and separating residues by using a silica gel column chromatography to obtain 1.394g of a product, wherein the yield is 80%.
The structural data for the product prepared in this example are characterized as follows:
1H NMR(600MHz,CDCl3)8.02(s,1H),7.87(s,1H),7.77(s,1H),7.60–7.46(m,2H),7.46–7.35(m,2H),4.77(d,J＝46.9Hz,2H),3.51(d,J＝20.3Hz,2H).13C NMR(151MHz,CDCl3)133.90,132.90,132.02,128.92,127.59,127.20,126.21,125.69,125.56,123.37,83.55(d,J＝169.6Hz),33.87(d,J＝20.7Hz).
EXAMPLE 26 preparation of the Compound 2- (2-fluoroethyl) naphthalene
This example prepared the compound 2- (2-fluoroethyl) naphthalene according to the following chemical reaction:
the preparation process comprises the following steps:
under nitrogen atmosphere, 2-naphthalene boric acid (2.580g,15.0mmol) and anhydrous potassium phosphate (6.368g,30.0mmol) are sequentially added into a sealed tube, a solvent of diethylene glycol dimethyl ether (60m L) is added, the mixture is uniformly stirred, and then 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 4 '-dimethoxy-2, 2' -bipyridine (0.238g, 1.1mmol) and NiBr are sequentially added2(0.219g, 1.0mmol), sealing, stirring in an oil bath at 80 ℃ for 18 hours for reaction, cooling the reaction solution to room temperature, filtering insoluble substances in the reaction solution by using a diatomite sand core funnel, washing with a small amount of diethyl ether, collecting filtrate, adding 60m L water into the filtrate, extracting an aqueous phase (40m L× 3) by using diethyl ether, combining organic phases, washing the organic phases with water and saturated saline sequentially, drying with anhydrous sodium sulfate, filtering, recovering the solvent by rotary evaporation, and separating residues by using a silica gel column chromatography to obtain 1.463g of a product, wherein the yield is 84%.
The structural data for the product prepared in this example are characterized as follows:
1H NMR(600MHz,CDCl3)7.79(s,3H),7.68(s,1H),7.47(t,J＝20.9Hz,2H),7.35(s,1H),4.71(d,J＝47.0Hz,2H),3.17(d,J＝23.2Hz,2H)；13C NMR(151MHz,CDCl3)134.63(d,J＝5.9Hz),133.58,132.37,128.22,127.69,127.57,127.50,127.34,126.15,125.61,84.10(d,J＝169.1Hz),37.11(d,J＝20.4Hz).
EXAMPLE 27 preparation of the Compound 3- (2-fluoroethyl) -2-methoxypyridine
This example prepared the compound 3- (2-fluoroethyl) -2-methoxypyridine according to the following chemical formula:
the preparation process comprises the following steps:
under the nitrogen atmosphere, 2-methoxy pyridine is sequentially added into a sealed tubePyridine-3-boric acid (2.294g,15.0mmol) and anhydrous potassium phosphate (6.368g,30.0mmol) are added into solvent diethylene glycol dimethyl ether (60m L) and stirred uniformly, and then 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 4 '-dimethoxy-2, 2' -bipyridine (0.238g, 1.1mmol) and NiBr are added in sequence2(0.219g, 1.0mmol), sealing, stirring in an oil bath at 80 ℃ for 20 hours for reaction, cooling the reaction solution to room temperature, filtering insoluble substances in the reaction solution by using a diatomite sand core funnel, washing with a small amount of diethyl ether, collecting filtrate, adding 60m L water into the filtrate, extracting an aqueous phase (40m L× 3) by using diethyl ether, combining organic phases, washing the organic phases with water and saturated saline solution in turn, drying with anhydrous sodium sulfate, filtering, recovering the solvent by rotary evaporation, and separating residues by using a silica gel column chromatography to obtain 1.195g of a product, wherein the yield is 77%.
The structural data for the product prepared in this example are characterized as follows:
1H NMR(600MHz,CDCl3)8.07(d,J＝6.4Hz,1H),7.46(d,J＝7.1Hz,1H),6.84(dd,J＝7.1,5.1Hz,1H),4.68(t,J＝6.3Hz,1H),4.60(t,J＝6.3Hz,1H),3.96(s,3H),2.98(dt,J＝23.8,6.3Hz,2H)；13C NMR(151MHz,CDCl3)161.07,144.16,138.00,118.66(d,J＝5.8Hz),115.75,81.27(d,J＝167.4Hz),52.34,30.31(d,J＝21.0Hz).
EXAMPLE 28 preparation of the Compound 3- (2-fluoroethyl) quinoline
This example prepared the compound 3- (2-fluoroethyl) quinoline according to the following chemical formula:
the preparation process comprises the following steps:
under nitrogen atmosphere, 3-quinolineboronic acid (2.595g,15.0mmol) and anhydrous potassium phosphate (6.368g,30.0mmol) were sequentially added to a sealed tube, the solvent diethylene glycol dimethyl ether (60m L) was added and stirred uniformly, and then 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 4 '-dimethoxy-2, 2' -bipyridine (0.119g, 0.55mmol) and NiBr were sequentially added2(0.110g, 0.50mmol), sealing, stirring in 80 deg.C oil bath for 24 hr, cooling to room temperature, and filtering with diatomite sand core funnelThe insoluble matter in the reaction solution was removed, the reaction solution was washed with a small amount of ether, the filtrate was collected, 60m L water was added to the filtrate, the aqueous phase (40m L× 3) was extracted with ether, the organic phases were combined, the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was recovered by rotary evaporation, and the residue was separated by silica gel column chromatography to give 1.384g of a product in 79% yield.
The structural data for the product prepared in this example are characterized as follows:
1H NMR(600MHz,CDCl3)8.82(s,1H),8.10(d,J＝8.3Hz,1H),8.04(s,1H),7.79(d,J＝7.9Hz,1H),7.70(t,J＝7.4Hz,1H),7.55(t,J＝7.2Hz,1H),4.74(d,J＝46.9Hz,2H),3.20(d,J＝25.1Hz,2H)；13C NMR(151MHz,CDCl3)151.67,147.10,135.54,130.14(d,J＝4.4Hz),129.19,129.14,128.01,127.49,126.87,83.40(d,J＝169.9Hz),34.25(d,J＝21.0Hz).
EXAMPLE 29 preparation of the Compound 4- (2-fluoroethyl) dibenzo [ b, d ] furan
This example prepared the compound 4- (2-fluoroethyl) dibenzo [ b, d ] furan according to the following chemical formula:
the preparation process comprises the following steps:
under nitrogen atmosphere, 4-dibenzofuranboronic acid (3.180g,15.0mmol) and anhydrous potassium phosphate (6.368g,30.0mmol) are sequentially added into a sealed tube, a solvent diethylene glycol dimethyl ether (60m L) is added, the mixture is uniformly stirred, and then 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 4 '-dimethoxy-2, 2' -bipyridine (0.119g, 0.55mmol) and NiBr are sequentially added2(0.110g, 0.50mmol), sealing, stirring in an oil bath at 80 ℃ for 24 hours for reaction, cooling the reaction liquid to room temperature, filtering insoluble substances in the reaction liquid by using a diatomite sand core funnel, washing with a small amount of diethyl ether, collecting filtrate, adding 60m L water into the filtrate, extracting an aqueous phase (40m L× 3) by using diethyl ether, combining organic phases, washing the organic phases with water and saturated saline solution in turn, drying by using anhydrous sodium sulfate, filtering, recovering the solvent by rotary evaporation, and separating residues by using a silica gel column chromatography to obtain 1.885g of a product, wherein the yield is 1.885gThe content was 88%.
The structural data for the product prepared in this example are characterized as follows:
1H NMR(600MHz,CDCl3)7.93(s,1H),7.84(s,1H),7.57(s,1H),7.45(s,1H),7.33(s,2H),7.29(s,1H),4.82(d,J＝47.0Hz,2H),3.39(d,J＝22.3Hz,2H).；13C NMR(151MHz,CDCl3)156.05,154.81,128.08,127.17,124.45,124.12,122.92,122.78,120.99,120.95,120.79,119.27,82.86(d,J＝168.8Hz),31.27(d,J＝21.4Hz).
EXAMPLE 30 preparation of the Compound 4- (2-fluoroethyl) dibenzo [ b, d ] thiophene
This example prepared the compound 4- (2-fluoroethyl) dibenzo [ b, d ] thiophene according to the following chemical reaction:
the specific reaction process is as follows:
under nitrogen atmosphere, 4-dibenzothiophene boric acid (3.421g,15.0mmol) and anhydrous potassium phosphate (6.368g,30.0mmol) are sequentially added into a sealed tube, a solvent diethylene glycol dimethyl ether (60m L) is added, the mixture is uniformly stirred, and then 1-fluoro-2-iodoethane (1.739g, 10.0mmol), 4 '-dimethoxy-2, 2' -bipyridine (0.119g, 0.55mmol) and NiBr are sequentially added2(0.110g, 0.50mmol), sealing, stirring in an oil bath at 80 ℃ for reaction for 32 hours, cooling the reaction liquid to room temperature, filtering insoluble substances in the reaction liquid by using a diatomite sand core funnel, washing with a small amount of diethyl ether, collecting filtrate, adding 60m L water into the filtrate, extracting an aqueous phase (40m L× 3) by using diethyl ether, combining organic phases, washing the organic phases with water and saturated saline sequentially, drying with anhydrous sodium sulfate, filtering, recovering the solvent by rotary evaporation, and separating residues by using a silica gel column chromatography to obtain 1.888g of a product with the yield of 82%.
The structural data for the product prepared in this example are characterized as follows:
1H NMR(600MHz,CDCl3)8.06–8.01(m,1H),7.96(d,J＝7.8Hz,1H),7.79–7.74(m,1H),7.39–7.32(m,3H),7.25(d,J＝7.2Hz,1H),4.71(dt,J＝46.9,6.6Hz,2H),3.20(dt,J＝26Hz,2H)；13C NMR(151MHz,CDCl3)139.51,138.92,136.09,135.97,131.37(d,J＝6.2Hz),127.13,126.85,124.98,124.56,122.86,121.83,120.24,82.32(d,J＝169.8Hz),36.11(d,J＝21.1Hz).
the above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (4)
1. A preparation method of a monofluoroethyl substituted aromatic compound is characterized in that the compound is β -fluoroethylbenzene, and the preparation method comprises the steps of sequentially adding 1.829g of phenylboronic acid and 6.368g of anhydrous potassium phosphate into a sealed tube under a nitrogen atmosphere, adding 50m L of diethylene glycol dimethyl ether as a solvent, uniformly stirring, and sequentially adding 1-fluoro-2-iodoethane 1.739g, 4 '-dimethoxy-2, 2' -bipyridine 0.238g and NiBr20.219g, sealed, stirred in an oil bath at 80 ℃ for reaction for 24 hours, cooled to room temperature, added with trifluorotoluene, monitored for the end of the reaction by the fluorimetry internal standard method, and determined to be 95% in crude yield.
2. A preparation method of a monofluoroethyl substituted aromatic compound is characterized in that the compound is β -fluoroethylbenzene, and the preparation method comprises the steps of sequentially adding 1.829g of phenylboronic acid and 6.368g of anhydrous potassium phosphate into a sealed tube under the nitrogen atmosphere, adding 50m L of diethylene glycol dimethyl ether as a solvent, uniformly stirring, and sequentially adding 1-fluoro-2-iodoethane 1.739g, 4 '-dimethoxy-2, 2' -bipyridine 0.119g and NiBr20.110g, sealed, stirred in an oil bath at 80 ℃ for reaction for 36 hours, cooled to room temperature, added with trifluorotoluene, monitored for the end of the reaction by the internal standard method of fluorine spectrum, and determined to have a crude yield of 91%.
3. A preparation method of a monofluoroethyl substituted aromatic compound is characterized in that the compound 6- (2-fluoroethyl) -2, 3-dihydrobenzo [ b][1,4]The preparation method of the dioxane comprises the following steps: under the atmosphere of nitrogen, 2, 3-dihydrobenzo [ b ] is added into a sealed tube in sequence][1,4]Dioxonol six2.700g of cyclo-6-boric acid and 6.368g of anhydrous potassium phosphate, as well as 50m L of diethylene glycol dimethyl ether as a solvent are added and stirred uniformly, and then 1.739g of 1-fluoro-2-iodoethane, 0.238g of 4,4 '-dimethoxy-2, 2' -bipyridine and NiBr are added in sequence20.219g, sealed, stirred in an oil bath at 80 ℃ for 24 hours, cooled to room temperature, filtered to remove insoluble substances in the reaction solution by a kieselguhr sand core funnel, washed by a small amount of diethyl ether, collected, added with 60m L water, extracted by diethyl ether, combined with organic phases, washed by water and saturated saline sequentially, dried by anhydrous sodium sulfate, filtered, subjected to rotary evaporation to recover the solvent, and subjected to silica gel column chromatography to separate the residue, thus obtaining 1.694g of a product with a yield of 93%.
4. A preparation method of a monofluoroethyl substituted aromatic compound is characterized in that the compound is 4- (2-fluoroethyl) -1,1 ' -biphenyl, and the preparation method comprises the steps of sequentially adding 2.970g of 4-diphenylboronic acid and 6.368g of anhydrous potassium phosphate into a sealed tube under a nitrogen atmosphere, adding 50m of diethylene glycol dimethyl ether serving as a solvent, stirring uniformly, and sequentially adding 1.739g of 1-fluoro-2-iodoethane, 0.238g of 4,4 ' -dimethoxy-2, 2 ' -bipyridine and NiBr20.219g, sealed, stirred in an oil bath at 80 ℃ for 24 hours, cooled to room temperature, filtered off insoluble substances in the reaction solution by a diatomite sand core funnel, washed by a small amount of ether, collected, added with 60m L water, extracted by ether to obtain an aqueous phase, combined with organic phases, washed by water and saturated saline solution, dried by anhydrous sodium sulfate, filtered, subjected to rotary evaporation to recover the solvent, and separated by silica gel column chromatography to obtain 1.882g of a product with a yield of 94%.
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