CN107628926A - A kind of preparation method of single fluoro ethyl substituted aromatic compound - Google Patents
A kind of preparation method of single fluoro ethyl substituted aromatic compound Download PDFInfo
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Abstract
The present invention provides a kind of preparation method of single fluoro ethyl substituted aromatic compound, belongs to fluorine-containing organic molecule preparing technical field.The preparation method is under reaction dissolvent and nitrogen atmosphere, aryl boric acid using the iodoethane of 1 fluorine 2 and after weak base activates is raw material, under the effect of the catalyst system and catalyzing of Raney nickel and bipyridyliumses part, after heating response reaches terminal, single fluoro ethyl substituted aromatic compound is obtained through separating, purifying.Preparation method of the present invention uses cheap and easily-available Raney nickel and bipyridyliumses part as catalyst system and catalyzing, realizes that single fluoro ethyl introduces to the orientation of aromatic group, so as to efficiently prepare single fluoro ethyl substituted aromatic compound.Not only reaction condition is gentle for this method, and raw material sources are wide, cost is low, and reactions steps are succinct, and reaction scale is easy to amplify, and product separation is easy, has the advantage suitable for industrialized production.
Description
Technical field
The invention belongs to fluorine-containing organic molecule preparing technical field, specially a kind of single fluoro ethyl substituted aromatic compound
Preparation method.
Background technology
The fluorine element maximum as electronegativity in the periodic table of elements, has extremely strong electron-withdrawing power, less atom body
Product and low polarizability, can significantly regulate and control the physics, chemistry and biological property of organic molecule, " A is described as by region of chemistry
Small Atom with Big Ego".Currently, it is seen everywhere fluorine in the key core materials such as medicine, material, space flight military project
The figure of atom.It may be said that fluorochemical has a deep effect on the production and life of current people.Especially medical and agricultural
Field of chemicals, fluorinated organic compound about occupies the 20% and 30% of listing sum respectively, and proportion is also presented
Go out gradual increased trend.
Although fluorinated organic compound occupies important seat with its unique function in all trades and professions, in nature
Naturally occurring organic fluorocompound type and quantity are extremely rare, and substantial amounts of organic fluorocompound must be by artificial synthesized
Mode is obtained, and fluorine atom or fluoro-containing group are efficiently incorporated into the certain bits of hydrocarbon organic molecule precursor by organic synthesis
Point has become the manually modified and various functional fluoropolymer organic molecule of composite structure important means.
In numerous fluorine-containing modification synthesis strategies, the β positions of aromatic ring ethyl side chains are incorporated fluorine atoms into prepare single fluorine second
Base substituted aromatic compound enjoys organic chemist and Pharmaceutical Chemist to pay close attention to all the time, and this is because of single fluoro ethyl fragment in medicine
Thing bioactive molecule modifies the important function in field.
In view of the significant application value of single fluoro ethyl substituted aromatic compound, chemists, which do not turn off, sends all kinds of synthesis lists
The ways and means of fluoro ethyl substituted aromatic compound.At present existing method be concentrated mainly on using beta-hydroxyethyl aromatic compound as
Precursor carries out nucleophilic fluorination reaction and prepared, and specific preparation principle is as follows：
Existing preparation method has the disadvantages that：(1) previously-introduced beta-hydroxyethyl fragment is needed；(2) hydroxyl directly enters
, it is necessary to use expensive nucleophilic fluorination reagent (diethyl amido sulfur trifluoride, DAST) or tetrafluoride when row nucleophilic fluorination reacts
The high poison reagents such as sulphur (SF4)；(3) it is anti-by fluorine anion nucleophilic displacement of fluorine again to be first converted into leaving group (OTs or OTf) for hydroxyl
Complex steps, side reaction are more, yield is low etc. then be present in the scheme that should obtain product.Therefore, further development is succinct, high
Effect, safety, single fluoro ethyl substituted aromatic compound technology of preparing suitable for large-scale production have important research meaning.
The content of the invention
It is an object of the invention in order to overcome above-mentioned deficiency, there is provided a kind of cost is cheap, simple process, production safety can
The preparation method of the single fluoro ethyl substituted aromatic compound leaned on.
The object of the invention is realized by following technical proposals：
A kind of preparation method of single fluoro ethyl substituted aromatic compound, the preparation method are in reaction dissolvent and blanket of nitrogen
Under enclosing, using the fluoro- 2- iodoethane of 1- and the aryl boric acid after alkali activates as raw material, in urging for Raney nickel and bipyridyliumses part
Under the effect of change system, after heating response reaches terminal, single fluoro ethyl substituted aromatic compound is obtained through separating, purifying.
As an a kind of specific embodiment of the preparation method of single fluoro ethyl substituted aromatic compound of the present invention, institute
Preparation method is stated to comprise the following steps：
1) under nitrogen atmosphere, alkali, reaction dissolvent are added into aryl boric acid, and stir；
2) 1- fluoro- 2- iodoethane, bipyridyliumses part and Raney nickel are added into above-mentioned solution successively, through adding after sealing
Heat, it is stirred to up to after reaction end, reaction solution is cooled to room temperature；
3) reaction solution after cooling is produced to single fluoro ethyl substituted aromatic compound after separating, purifying.
As an a kind of specific embodiment of the preparation method of single fluoro ethyl substituted aromatic compound of the present invention, institute
It is 1 to state the ratio between amount of the fluoro- 2- iodoethane of 1- and aryl boric acid material：1~2.2；The Raney nickel and the fluoro- 2- iodoethane things of 1-
The ratio between amount of matter is 1~15.0：100；The ratio between amount of the bipyridyliumses part and the fluoro- 2- iodoethane materials of 1- is 1~20.0：
100；The ratio between amount of the alkali and the fluoro- 2- iodoethane materials of 1- is 1.5~4.0：1；The amount of the fluoro- 2- iodoethane materials of 1- with
The ratio between volume of reaction dissolvent is 1：1~20molL-1。
As an a kind of specific embodiment of the preparation method of single fluoro ethyl substituted aromatic compound of the present invention, institute
The Ar groups of aryl boric acid are stated to take for phenyl, the alkyl-substituted phenyl of C1~4, the alkoxy substituted phenyl of C1~4, the acyl group of C1~4
For phenyl, the alkoxy acyl substituted-phenyl of C1~4, cyano group substituted-phenyl, naphthyl, pyridine radicals, quinolyl, dibenzofuran group, two
One or more in benzothienyl.
As an a kind of specific embodiment of the preparation method of single fluoro ethyl substituted aromatic compound of the present invention, institute
The alkyl for C1~4 stated is base, ethyl, propyl group, isopropyl, butyl, the tert-butyl group；The alkoxy of C1~4 is methoxyl group, second
Epoxide, tert-butoxy；The acyl group of C1~4 is formoxyl, acetyl group, propiono, bytyry；The alcoxyl of described C1~4
Acyl group is methoxy acyl group, ethoxy acyl group, the third oxygen acyl group, fourth oxygen acyl group.
As an a kind of specific embodiment of the preparation method of single fluoro ethyl substituted aromatic compound of the present invention, institute
Reaction dissolvent is stated as tetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, TRIGLYME, first
One or more in benzene, dimethyl sulfoxide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide.Preferably glycol dinitrate
Ether or diethylene glycol dimethyl ether.
As an a kind of specific embodiment of the preparation method of single fluoro ethyl substituted aromatic compound of the present invention, institute
Alkali is stated as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium phosphate, potassium phosphate, cesium fluoride, potassium fluoride, the tert-butyl alcohol
One kind in sodium, potassium tert-butoxide.Preferably potassium phosphate.
As an a kind of specific embodiment of the preparation method of single fluoro ethyl substituted aromatic compound of the present invention, institute
It is Ni (cod) to state Raney nickel2、NiCl2、NiBr2、NiCl2(DME)、NiBr2(DME)、Ni(acac)2In one kind.Preferably
NiBr2。
As an a kind of specific embodiment of the preparation method of single fluoro ethyl substituted aromatic compound of the present invention, institute
Bipyridyliumses part is stated as bipy 2,2' bipyridyl, 4,4 '-dimethyl-bipy 2,2' bipyridyl, 4,4 '-di-t-butyl -2,2 '-connection pyrrole
Pyridine, 4,4 '-dimethoxy-bipy 2,2' bipyridyl, Phen, α, α, one kind in α-terpyridyl.Preferably 4,4 '-diformazan
Epoxide-bipy 2,2' bipyridyl.
As an a kind of specific embodiment of the preparation method of single fluoro ethyl substituted aromatic compound of the present invention, institute
Stating separating-purifying step is：The insoluble matter in reaction solution is filtered out, and insoluble matter is washed with ether, collects filtrate；Add into filtrate
Enter water, with ether aqueous phase extracted, merge organic phase, organic phase washed with water, saturated sodium-chloride water solution washing, then through anhydrous
Sodium sulphate is dried, and rotary evaporation removes solvent after filtering, finally by residue through recrystallizing or isolated with silica gel column chromatography
Single fluoro ethyl substituted aromatic compound.
Compared with prior art, the invention has the advantages that：
The present invention is easy to get using commercialization and the fluoro- 2- iodoethane of the 1- of safety and stability and aryl boric acid is raw materials, in base metal
Under the catalyst system and catalyzing effect of Raney nickel/bipyridyliumses part, aryl boric acid is activated using inorganic weak bases, in glycol dimethyl ether
Stirring generates single fluoro ethyl substituted aromatic compound in class solvent.Preparation method of the present invention, which has the advantage that, to be embodied in：
1st, preparation method of the present invention is without the previously prepared beta-hydroxyethyl aromatic compound as existing preparation method, then enters
Row hydroxyl is converted into the nucleophilic fluorination reaction of fluorine, but is directly realized by the connection of aromatic group and single fluoro ethyl fragment, reacts plan
Slightly brevity and lucidity, the selectable range of aromatic group are wide；
2nd, preparation method of the present invention uses base metal nickel as catalyst, and bipyridyliumses part is to support part, catalyst system and catalyzing
Efficiency high, cost are low.
3rd, preparation method reaction condition of the present invention is gentle, the compatible good, reaction scale of substrate functional group is easily enlarged, product
Separation is simple, has the advantage suitable for industrialized production.
Embodiment
In order to make the purpose , technical scheme and advantage of the present invention be clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
With reference to concrete principle and preparation process to a kind of preparation side of single fluoro ethyl substituted aromatic compound of the present invention
Method is described in detail.
A kind of preparation method of single fluoro ethyl substituted aromatic compound, the preparation method are in reaction dissolvent and blanket of nitrogen
Under enclosing, using the fluoro- 2- iodoethane of 1- and the aryl boric acid after weak base activates as raw material, in Raney nickel and bipyridyliumses part
Under catalyst system and catalyzing effect, after heating response reaches terminal, single fluoro ethyl substituted aromatic compound is obtained through separating, purifying.
The reaction equation of the single fluoro ethyl substituted aromatic compound of the present invention is as follows：
The preparation method of the single fluoro ethyl substituted aromatic compound of the present invention is using the fluoro- 2- iodoethane of 1- and aryl boric acid as original
Material, under the catalyst system and catalyzing effect of base metal nickel catalyst/bipyridyliumses part, aryl boric acid is activated using inorganic weak bases,
Stirring generates single fluoro ethyl substituted aromatic compound in glycol dinitrate ethers solvent.Preparation method of the present invention is without as existing system
The equally previously prepared beta-hydroxyethyl aromatic compound of Preparation Method, then the nucleophilic fluorination reaction that hydroxyl is converted into fluorine is carried out, but directly
Connect the connection for realizing aromatic group and single fluoro ethyl fragment, response strategy brevity and lucidity, the selectable range of aromatic group is wide.
In preparation method of the present invention, the effect of reaction dissolvent is to provide favourable reaction environment, and plays dilution and divide
Effect is dissipated, avoids the too high generation side reaction of local concentration.Nitrogen is that inert gas (is not made with reaction substrate, catalyst
With), under inert gas shielding, it can effectively prevent the oxidation of transition metal-catalyzed species and cause inactivation is quenched.Weak base provides
Lone pair electrons, it can be coordinated to form complex with the empty p tracks of boron atom on aryl boric acid, turn metal beneficial to aromatic yl group
Change.MetalNicatalyst provides catalytic reaction activity center, and bipyridine ligand is with that after metallic nickel coordination, significantly can regulate and control and improve
Reaction effect.
Further, a kind of preparation method of single fluoro ethyl substituted aromatic compound of the present invention, comprises the following steps：
1) under nitrogen atmosphere, weak base, reaction dissolvent are added into aryl boric acid, and stir；
2) 1- fluoro- 2- iodoethane, bipyridyliumses part and Raney nickel are added into above-mentioned solution successively, through adding after sealing
Heat, it is stirred to up to after reaction end, reaction solution is cooled to room temperature；
3) reaction solution after cooling is produced to single fluoro ethyl substituted aromatic compound after separating, purifying.
In a kind of specific preparation process of single fluoro ethyl substituted aromatic compound preparation method of the present invention, in nitrogen atmosphere
Under, weak base, reaction dissolvent are added into starting aryl boric acid, aryl boric acid is activated in weakly alkaline environment, Ran Houzai
The fluoro- 2- iodoethane of 1- and catalysis system are added, under oil bath heating stirring condition, the fluoro- 2- iodoethane of 1- and aryl boric acid is existed
Reacted under catalyst system and catalyzing effect, compose through fluorine nmr (19F NMR) monitoring reaction solution determine reaction end after, will react
Liquid is cooled and separated successively, purify after obtain the single fluoro ethyl substituted aromatic compound of the present invention.1- in reaction raw materials of the present invention
Fluoro- 2- iodoethane low boiling point, is easy to volatilization loss, need to be added in the presence of system solvent, if with weak base, reaction
Solvent or aryl boric acid add together, can reduce conversion ratio.In preparation method of the present invention the addition sequence of each reactant and
Preparation process is that inventor passes through long-term experiment, and combination yield and product purity optimize what is obtained, can effectively improve production
Thing yield and purity.
Further, the ratio between amount of the fluoro- 2- iodoethane of the 1- and aryl boric acid material is 1：1~2.2；The Raney nickel
It is 1~15.0 with the ratio between the amount of the fluoro- 2- iodoethane materials of 1-：100；The bipyridyliumses part and the fluoro- 2- iodoethane materials of 1-
The ratio between amount be 1~20.0：100；The ratio between amount of the weak base and the fluoro- 2- iodoethane materials of 1- is 1.5~4.0：1；The 1-
The ratio between the amount of fluoro- 2- iodoethane material and the volume of reaction dissolvent are 1：1~20molL-1.In the addition of above-mentioned various materials
Measure under setting ratio, the atom utilization of each raw material is higher, and material waste is few, and economic value is high.
Further, the Ar groups of the aryl boric acid are phenyl, the alkyl-substituted phenyl of C1~4, the substitution of the alkoxy of C1~4
The alkoxy acyl substituted-phenyl of the acyl group substituted-phenyl of phenyl, C1~4, C1~4, cyano group substituted-phenyl, naphthyl, pyridine radicals, quinolyl,
One or more in dibenzofuran group, dibenzothiophenes base.Further, the alkyl of described C1~4 be base, ethyl,
Propyl group, isopropyl, butyl, the tert-butyl group；The alkoxy of C1~4 is methoxyl group, ethyoxyl, tert-butoxy；C1~4
Acyl group is formoxyl, acetyl group, propiono, bytyry；The alkoxy acyl of described C1~4 is methoxy acyl group, ethoxy acyl group, third
Oxygen acyl group, fourth oxygen acyl group.
Further, the reaction dissolvent is tetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, three
One or more in glycol dimethyl ether, toluene, dimethyl sulfoxide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide.Instead
Answer solvent to play and reaction substrate and the favourable places and atmosphere of catalyst interaction are provided, and dissolving reaction bottom can be played
Thing and concentration dilution are to reduce the effect of side reaction.
Further, the weak base is sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium phosphate, potassium phosphate, fluorine
Change one kind in caesium, potassium fluoride, sodium tert-butoxide, potassium tert-butoxide.Weak base can promote aryl boric acid substrate boron removal and turn metallization
Effect, greatly accelerate transition-metal catalysis speed.
Raney nickel described further is Ni (cod)2、NiCl2、NiBr2、NiCl2(DME)、NiBr2(DME)、Ni
(acac)2In one kind.Preferable bromination Raney nickel belongs to base metal catalysts, cheap, can stablize deposit in atmosphere
There is the effect for reducing catalysts cost and weighing charging process simplicity compared to precious metals palladium catalyst of the same clan.
Further, the bipyridyliumses part is 2,2 '-bipyridyl, 4,4 '-dimethyl -2,2 '-bipyridyl, 4,4 '-two
The tert-butyl group-bipy 2,2' bipyridyl, 4,4 '-dimethoxy-bipy 2,2' bipyridyl, Phen, α, α, one kind in α-terpyridyl.
Bipyridyliumses part plays the effect at stable nickel metal catalytic activity center as support part, effectively adjusts transition metal-catalyzed
Each primitive steps such as middle oxidation addition, ligand exchange, reduction elimination.
Further, the separating-purifying step is：The insoluble matter in reaction solution is filtered out, and insoluble matter is washed with ether, is received
Collect filtrate；Water is added into filtrate, with ether aqueous phase extracted, merges organic phase, organic phase washed with water, saturated sodium-chloride are water-soluble
Liquid washs, and then through anhydrous sodium sulfate drying, rotary evaporation removes solvent after filtering, finally by residue through recrystallizing or using silicon
The isolated single fluoro ethyl substituted aromatic compound of plastic column chromatography.The step of separating-purifying of the present invention is according to the list being prepared
What the characteristic of fluoro ethyl aromatic compound was designed, those skilled in the art preferably other can efficiently separate method of purification
To realize the separating-purifying to product, as long as the purpose of product separating-purifying of the present invention can be realized.
Have with reference to specific embodiment to a kind of preparation method of single fluoro ethyl substituted aromatic compound of the present invention
Body explanation.
The preparation of the compound β of example 1-fluoro ethyl benzene
The chemical equation of this example prepare compound β-fluoro ethyl benzene is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, sequentially added in tube sealing phenyl boric acid (1.829g, 15.0mmol), acetic anhydride potassium (2.944g,
30.0mmol), add solvents tetrahydrofurane (30mL) stir after, sequentially add the fluoro- 2- iodoethane of 1- (1.739g,
10mmol), 2,2 '-bipyridyl (0.312g, 2.0mmol) and Ni (cod)2(0.275g, 1.0mol), in 80 DEG C of oil after sealing
Stirring reaction 12 hours in bath, cooling reaction solution to room temperature, benzotrifluoride is added, reaction end is monitored using fluorine spectrum internal standard method,
And determine that it is 21% (β-fluoro ethyl benzene low boiling point, do not carry out distilation) to react thick yield.
The preparation of the compound β of example 2-fluoro ethyl benzene
The chemical equation of this example prepare compound β-fluoro ethyl benzene is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, sequentially added in tube sealing phenyl boric acid (1.585g, 13.0mmol), anhydrous phosphoric acid potassium (7.429g,
35.0mmol), add solvent dioxane (20mL) stir after, sequentially add the fluoro- 2- iodoethane of 1- (1.739g,
10.0mmol), 2,2 '-bipyridyl (0.156g, 1.0mmol) and NiCl2(0.130g, 1.0mmol), in 80 DEG C of oil after sealing
Stirring reaction 12 hours in bath, cooling reaction solution to room temperature, benzotrifluoride is added, reaction end is monitored using fluorine spectrum internal standard method,
And determine to react thick yield as 48%.
The preparation of the compound β of example 3-fluoro ethyl benzene
The chemical equation of this example prepare compound β-fluoro ethyl benzene is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, sequentially added in tube sealing phenyl boric acid (1.585g, 13.0mmol), sodium carbonate (2.332g,
22.0mmol), add solvent DMF (24mL) stir after, sequentially add the fluoro- 2- iodoethane of 1- (1.739g,
10.0mmol), α, α, α-terpyridyl (0.434g, 1.0mmol) and Ni (acac)2(0.257g, 1.0mmol), after sealing
Stirring reaction 20 hours in 80 DEG C of oil bath, cooling reaction solution to room temperature, benzotrifluoride is added, it is anti-using fluorine spectrum internal standard method monitoring
Terminal is answered, and determines to react thick yield as 24%.
The preparation of the compound β of example 4-fluoro ethyl benzene
The chemical equation of this example prepare compound β-fluoro ethyl benzene is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, sequentially added in tube sealing phenyl boric acid (2.195g, 18.0mmol), Carbon Dioxide caesium (6.516g,
20.0mmol), after addition solvent DMA (20mL) stirs, the fluoro- 2- iodoethane of 1- is sequentially added
(1.739g, 10.0mmol), Phen (0.180g, 1.0mmol) and NiBr2(DME) (0.309g, 1.0mmol), after sealing
Stirring reaction 12 hours in 80 DEG C of oil bath, cooling reaction solution to room temperature, benzotrifluoride is added, monitored using fluorine spectrum internal standard method
Reaction end, and determine to react thick yield as 18%.
The preparation of the compound β of example 5-fluoro ethyl benzene
The chemical equation of this example prepare compound β-fluoro ethyl benzene is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, sequentially added in tube sealing phenyl boric acid (1.829g, 15.0mmol), Anhydrous potassium carbonate (3.455g,
25.0mmol), add solvent dimethyl sulfoxide (22mL) stir after, sequentially add the fluoro- 2- iodoethane of 1- (1.739g,
10.0mmol), 2,2 '-bipyridyl (0.156g, 1.0mmol) and NiBr2(DME) (0.309g, 1.0mmol), 80 after sealing
DEG C oil bath in stirring reaction 12 hours, cooling reaction solution to room temperature, add benzotrifluoride, use fluorine spectrum internal standard method monitoring reaction
Terminal, and determine to react thick yield as 56%.
The preparation of the compound β of example 6-fluoro ethyl benzene
The chemical equation of this example prepare compound β-fluoro ethyl benzene is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, sequentially added in tube sealing phenyl boric acid (1.829g, 15.0mmol), anhydrous potassium fluoride (1.740g,
30.0mmol), after addition solvent diethylene glycol dimethyl ether (15mL) stirs, the fluoro- 2- iodoethane of 1- is sequentially added
(1.739g, 10.0mmol), 2,2 '-bipyridyl (0.156g, 1.0mmol) and NiCl2(DME) (0.220g, 1.0mmol), it is close
It is honored as a queen stirring reaction 24 hours in 80 DEG C of oil bath, cooling reaction solution to room temperature, adds benzotrifluoride, uses fluorine spectrum internal standard method
Reaction end is monitored, and determines to react thick yield as 24%.
The preparation of the compound β of example 7-fluoro ethyl benzene
The chemical equation of this example prepare compound β-fluoro ethyl benzene is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, sequentially added in tube sealing phenyl boric acid (1.829g, 15.0mmol), anhydrous phosphoric acid potassium (4.245g,
20.0mmol), after addition solvent ethylene glycol dimethyl ether (50mL) stirs, the fluoro- 2- iodoethane of 1- is sequentially added
(1.739g, 10.0mmol), 2,2 '-bipyridyl (0.172g, 1.1mmol) and NiBr2(0.219g, 1.0mmol), after sealing
Stirring reaction 24 hours in 80 DEG C of oil bath, cooling reaction solution to room temperature, benzotrifluoride is added, it is anti-using fluorine spectrum internal standard method monitoring
Terminal is answered, and determines to react thick yield as 80%.
The preparation of the compound β of example 8-fluoro ethyl benzene
The chemical equation of this example prepare compound β-fluoro ethyl benzene is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, sequentially added in tube sealing phenyl boric acid (1.829g, 15.0mmol), anhydrous phosphoric acid potassium (6.368g,
30.0mmol), after addition solvent ethylene glycol dimethyl ether (50mL) stirs, the fluoro- 2- iodoethane of 1- is sequentially added
(1.739g, 10.0mmol), 2,2 '-bipyridyl (0.172g, 1.1mmol) and NiBr2(0.219g, 1.0mmol), after sealing
Stirring reaction 24 hours in 80 DEG C of oil bath, cooling reaction solution to room temperature, benzotrifluoride is added, it is anti-using fluorine spectrum internal standard method monitoring
Terminal is answered, and determines to react thick yield as 84%.
The preparation of the compound β of example 9-fluoro ethyl benzene
The chemical equation of this example prepare compound β-fluoro ethyl benzene is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, sequentially added in tube sealing phenyl boric acid (1.829g, 15.0mmol), anhydrous phosphoric acid potassium (6.368g,
30.0mmol), after addition solvent ethylene glycol dimethyl ether (50mL) stirs, the fluoro- 2- iodoethane of 1- is sequentially added
(1.739g, 10.0mmol), 4,4 '-dimethyl -2,2 '-bipyridyl (0.203g, 1.1mmol) and NiBr2(0.219g,
1.0mmol), stirring reaction 24 hours, cooling reaction solution add benzotrifluoride, made to room temperature in 80 DEG C of oil bath after sealing
Reaction end is monitored with fluorine spectrum internal standard method, and determines to react thick yield as 88%.
The preparation of the compound β of example 10-fluoro ethyl benzene
The chemical equation of this example prepare compound β-fluoro ethyl benzene is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, sequentially added in tube sealing phenyl boric acid (1.829g, 15.0mmol), anhydrous phosphoric acid potassium (6.368g,
30.0mmol), after addition solvent ethylene glycol dimethyl ether (50mL) stirs, the fluoro- 2- iodoethane of 1- is sequentially added
(1.739g, 10.0mmol), 4,4 '-di-t-butyl -2,2 '-bipyridyl (0.295g, 1.1mmol) and NiBr2(0.219g,
1.0mmol), stirring reaction 24 hours, cooling reaction solution add benzotrifluoride, made to room temperature in 80 DEG C of oil bath after sealing
Reaction end is monitored with fluorine spectrum internal standard method, and determines to react thick yield as 90%.
The preparation of the compound β of example 11-fluoro ethyl benzene
The chemical equation of example prepare compound β-fluoro ethyl benzene is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, sequentially added in tube sealing phenyl boric acid (1.829g, 15.0mmol), anhydrous phosphoric acid potassium (6.368g,
30.0mmol), after addition solvent ethylene glycol dimethyl ether (50mL) stirs, the fluoro- 2- iodoethane of 1- is sequentially added
(1.739g, 10.0mmol), 4,4 '-dimethoxy -2,2 '-bipyridyl (0.238g, 1.1mmol) and NiBr2(0.219g,
1.0mmol), stirring reaction 24 hours, cooling reaction solution add benzotrifluoride, made to room temperature in 80 DEG C of oil bath after sealing
Reaction end is monitored with fluorine spectrum internal standard method, and determines to react thick yield as 92%.
The preparation of the compound β of example 12-fluoro ethyl benzene
The chemical equation of this example prepare compound β-fluoro ethyl benzene is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, sequentially added in tube sealing phenyl boric acid (1.829g, 15.0mmol), anhydrous phosphoric acid potassium (6.368g,
30.0mmol), after addition solvent diethylene glycol dimethyl ether (50mL) stirs, the fluoro- 2- iodoethane of 1- is sequentially added
(1.739g, 10.0mmol), 4,4 '-dimethoxy -2,2 '-bipyridyl (0.238g, 1.1mmol) and NiBr2 (0.219g,
1.0mmol), stirring reaction 24 hours, cooling reaction solution add benzotrifluoride, made to room temperature in 80 DEG C of oil bath after sealing
Reaction end is monitored with fluorine spectrum internal standard method, and determines to react thick yield as 95%.
The preparation of the compound β of example 13-fluoro ethyl benzene
The chemical equation of this example prepare compound β-fluoro ethyl benzene is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, sequentially added in tube sealing phenyl boric acid (1.829g, 15.0mmol), anhydrous phosphoric acid potassium (6.368g,
30.0mmol), after addition solvent diethylene glycol dimethyl ether (50mL) stirs, the fluoro- 2- iodoethane of 1- is sequentially added
(1.739g, 10.0mmol), 4,4 '-dimethoxy -2,2 '-bipyridyl (0.119g, 0.55mmol) and NiBr2(0.110g,
0.5mmol), stirring reaction 36 hours, cooling reaction solution add benzotrifluoride, made to room temperature in 80 DEG C of oil bath after sealing
Reaction end is monitored with fluorine spectrum internal standard method, and determines to react thick yield as 91%.
The preparation of the compound β of example 14-fluoro ethyl benzene
This example is the comparative example of example 13, and the difference of itself and example 13 is not add lives to phenyl boric acid
The weak base anhydrous phosphoric acid potassium of change, study the influence of the addition of weak base to the yield of product.This example prepare compound β-fluoro ethyl
The chemical equation of benzene is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, phenyl boric acid (1.829g, 15.0mmol), solvent diethylene glycol dimethyl ether are sequentially added in tube sealing
(50mL), after stirring, sequentially add the fluoro- 2- iodoethane (1.739g, 10.0mmol) of 1-, 4,4 '-dimethoxy -2,
2 '-bipyridyl (0.119g, 0.55mmol) and NiBr2(0.110g, 0.5mmol), stirred instead in 80 DEG C of oil bath after sealing
Answer 36 hours, cooling reaction solution to room temperature, add benzotrifluoride, using fluorine spectrum internal standard method monitoring reaction end, and determine to react
Thick yield is 2%.
The preparation of the compound β of example 15-fluoro ethyl benzene
This example is the comparative example of example 13, and the difference of itself and example 13 is not add bipyridine ligand 4,
4 '-dimethoxy -2,2 '-bipyridyl, study the influence of the addition of bipyridine ligand to the yield of product.This example prepares chemical combination
The chemical equation of thing β-fluoro ethyl benzene is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, sequentially added in tube sealing phenyl boric acid (1.829g, 15.0mmol), anhydrous phosphoric acid potassium (6.368g,
30.0mmol), solvent diethylene glycol dimethyl ether (50mL), after stirring, sequentially add the fluoro- 2- iodoethane of 1- (1.739g,
10.0mmol) and NiBr2(0.110g, 0.5mmol), stirring reaction 36 hours, cooling reaction in 80 DEG C of oil bath after sealing
Liquid adds benzotrifluoride, using fluorine spectrum internal standard method monitoring reaction end, and determines to react thick yield as 6% to room temperature.
The preparation of the compound β of example 16-fluoro ethyl benzene
This example is the comparative example of example 13, and the difference of itself and example 13 is not add Raney nickel NiBr2,
Influence of the addition of research Raney nickel to the yield of product.The chemical equation of this example prepare compound β-fluoro ethyl benzene is such as
Under：
Specific preparation process is as follows：
Under nitrogen atmosphere, sequentially added in tube sealing phenyl boric acid (1.829g, 15.0mmol), anhydrous phosphoric acid potassium
(6.368g, 30.0mmol), solvent diethylene glycol dimethyl ether (50mL), after stirring, sequentially add the fluoro- 2- iodoethane of 1-
(1.739g, 10.0mmol) and 4,4 '-dimethoxy -2,2 '-bipyridyl (0.119g, 0.55mmol), at 80 DEG C after sealing
Stirring reaction 36 hours in oil bath, cooling reaction solution to room temperature, benzotrifluoride is added, using fluorine spectrum internal standard method monitoring reaction eventually
Point, and determine to react thick yield as 0% (no product generation).
The preparation of example 17 compound 1- (2- fluoro ethyls) -4- methoxybenzenes
The chemical equation of this example prepare compound 1- (2- fluoro ethyls) -4- methoxybenzenes is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, sequentially added in tube sealing to methoxyphenylboronic acid (2.279g, 15.0mmol), anhydrous phosphoric acid potassium
(6.368g, 30.0mmol), after addition solvent diethylene glycol dimethyl ether (50mL) stirs, sequentially add the fluoro- 2- iodine of 1-
Ethane (1.739g, 10.0mmol), 4,4 '-dimethoxy -2,2 '-bipyridyl (0.238g, 1.1mmol) and NiBr2
(0.219g, 1.0mmol), stirring reaction 24 hours, cooling reaction solution use diatomite to room temperature in 80 DEG C of oil bath after sealing
Sand core funnel filters out the insoluble matter in reaction solution, a small amount of washed with ether, collects filtrate.60mL water, ether extraction are added into filtrate
Phase of fetching water (40mL × 3), merge organic phase, organic phase washed with water, saturated common salt water washing, anhydrous sodium sulfate drying, filter,
Rotary evaporation recycling design, residue obtain product 1.311g, yield 85% after silica gel column chromatography separates.
The structured data that product is prepared in this example is characterized as below：
1H NMR(600MHz,CDCl3) δ 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) δ 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)
The preparation of embodiment 18 compound 1- benzyloxies -4- (2- fluoro ethyls) benzene
The chemical equation of this example prepare compound 1- benzyloxies -4- (2- fluoro ethyls) benzene is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, sequentially added in tube sealing to benzyloxy phenyl boric acid (3.421g, 15.0mmol), anhydrous phosphoric acid potassium
(6.368g, 30.0mmol), after addition solvent diethylene glycol dimethyl ether (50mL) stirs, sequentially add the fluoro- 2- iodine of 1-
Ethane (1.739g, 10.0mmol), 4,4 '-dimethoxy -2,2 '-bipyridyl (0.238g, 1.1mmol) and NiBr2
(0.219g, 1.0mmol), stirring reaction 24 hours, cooling reaction solution use diatomite to room temperature in 80 DEG C of oil bath after sealing
Sand core funnel filters out the insoluble matter in reaction solution, a small amount of washed with ether, collects filtrate.60mL water, ether extraction are added into filtrate
Phase of fetching water (40mL × 3), merge organic phase, organic phase washed with water, saturated common salt water washing, anhydrous sodium sulfate drying, filter,
Rotary evaporation recycling design, residue obtain product 2.050g, yield 89% after silica gel column chromatography separates.
The structured data that product is prepared in this example is characterized as below：
1H NMR(600MHz,CDCl3) δ 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)δ
(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)
The preparation of embodiment 19 compound 6- (2- fluoro ethyls) -2,3- dihydrobenzos [b] [1,4] dioxane
The chemical equation of this example prepare compound 6- (2- fluoro ethyls) -2,3- dihydrobenzos [b] [1,4] dioxane
It is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, 2,3- dihydrobenzos [b] [Isosorbide-5-Nitrae] dioxane -6- boric acid is sequentially added in tube sealing
(2.700g, 15.0mmol), anhydrous phosphoric acid potassium (6.368g, 30.0mmol), add solvent diethylene glycol dimethyl ether (50mL) and stir
After mixing uniformly, the fluoro- 2- iodoethane (1.739g, 10.0mmol) of 1-, 4,4 '-dimethoxy -2,2 '-bipyridyl are sequentially added
(0.238g, 1.1mmol) and NiBr2(0.219g, 1.0mmol), after sealing in 80 DEG C of oil bath stirring reaction 24 hours, it is cold
But reaction solution filters out the insoluble matter in reaction solution with diatomite sand core funnel, a small amount of washed with ether, collects filtrate to room temperature.To
60mL water is added in filtrate, ether aqueous phase extracted (40mL × 3), merges organic phase, organic phase washed with water, saturated common salt washing
Wash, anhydrous sodium sulfate drying, filter, rotary evaporation recycling design, residue obtains product after silica gel column chromatography separates
1.694g, yield 93%.
The structured data that product is prepared in this example is characterized as below：
1H NMR(600MHz,CDCl3) δ 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) δ 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)
The preparation of embodiment 20 compound 4- (2- fluoro ethyls) -1,1 '-biphenyl
The chemical equation of this example prepare compound 4- (2- fluoro ethyls) -1,1 '-biphenyl is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, 4- biphenylboronic acids (2.970g, 15.0mmol), anhydrous phosphoric acid potassium are sequentially added in tube sealing
(6.368g, 30.0mmol), after addition solvent diethylene glycol dimethyl ether (50mL) stirs, sequentially add the fluoro- 2- iodine of 1-
Ethane (1.739g, 10.0mmol), 4,4 '-dimethoxy -2,2 '-bipyridyl (0.238g, 1.1mmol) and NiBr2
(0.219g, 1.0mmol), stirring reaction 24 hours, cooling reaction solution use diatomite to room temperature in 80 DEG C of oil bath after sealing
Sand core funnel filters out the insoluble matter in reaction solution, a small amount of washed with ether, collects filtrate.60mL water, ether extraction are added into filtrate
Phase of fetching water (40mL × 3), merge organic phase, organic phase washed with water, saturated common salt water washing, anhydrous sodium sulfate drying, filter,
Rotary evaporation recycling design, residue obtain product 1.882g, yield 94% after silica gel column chromatography separates.
The structured data that product is prepared in this example is characterized as below：
1H NMR(600MHz,CDCl3) δ 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) δ 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)
The preparation of embodiment 21 compound 4- (2- fluoro ethyls) benzaldehyde
The chemical equation of this example prepare compound 4- (2- fluoro ethyls) benzaldehyde is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, 4- formylphenylboronic acids (2.249g, 15.0mmol), anhydrous phosphoric acid potassium are sequentially added in tube sealing
(6.368g, 30.0mmol), after addition solvent diethylene glycol dimethyl ether (50mL) stirs, sequentially add the fluoro- 2- iodine of 1-
Ethane (1.739g, 10.0mmol), 4,4 '-dimethoxy -2,2 '-bipyridyl (0.238g, 1.1mmol) and NiBr2
(0.219g, 1.0mmol), stirring reaction 24 hours, cooling reaction solution use diatomite to room temperature in 80 DEG C of oil bath after sealing
Sand core funnel filters out the insoluble matter in reaction solution, a small amount of washed with ether, collects filtrate.60mL water, ether extraction are added into filtrate
Phase of fetching water (40mL × 3), merge organic phase, organic phase washed with water, saturated common salt water washing, anhydrous sodium sulfate drying, filter,
Rotary evaporation recycling design, residue obtain product 1.126g, yield 74% after silica gel column chromatography separates.
The structured data that product is prepared in this example is characterized as below：
1H NMR(400MHz,CDCl3) δ 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) δ 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)
The preparation of the compound 1- of embodiment 22 (4- (2- fluoro ethyls) phenyl) ethyl ketone
The chemical equation of this example prepare compound 1- (4- (2- fluoro ethyls) phenyl) ethyl ketone is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, 4- acetylbenzenes boric acid (2.460g, 15.0mmol), anhydrous phosphoric acid potassium are sequentially added in tube sealing
(6.368g, 30.0mmol), after addition solvent diethylene glycol dimethyl ether (50mL) stirs, sequentially add the fluoro- 2- iodine of 1-
Ethane (1.739g, 10.0mmol), 4,4 '-dimethoxy -2,2 '-bipyridyl (0.238g, 1.1mmol) and NiBr2
(0.219g, 1.0mmol), stirring reaction 24 hours, cooling reaction solution use diatomite to room temperature in 80 DEG C of oil bath after sealing
Sand core funnel filters out the insoluble matter in reaction solution, a small amount of washed with ether, collects filtrate.60mL water, ether extraction are added into filtrate
Phase of fetching water (40mL × 3), merge organic phase, organic phase washed with water, saturated common salt water washing, anhydrous sodium sulfate drying, filter,
Rotary evaporation recycling design, residue obtain product 1.330g, yield 80% after silica gel column chromatography separates.
The structured data that product is prepared in this example is characterized as below：
1H NMR(400MHz,CDCl3) δ 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) δ 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.
The preparation of embodiment 23 compound 4- (2- fluoro ethyls) methyl benzoate
The chemical equation of this example prepare compound 4- (2- fluoro ethyls) methyl benzoate is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, 4- methoxycarbonyl groups phenyl boric acid (2.700g, 15.0mmol), anhydrous phosphoric acid are sequentially added in tube sealing
Potassium (6.368g, 30.0mmol), after addition solvent diethylene glycol dimethyl ether (50mL) stirs, sequentially add the fluoro- 2- of 1-
Iodoethane (1.739g, 10.0mmol), 4,4 '-dimethoxy -2,2 '-bipyridyl (0.238g, 1.1mmol) and NiBr2
(0.219g, 1.0mmol), stirring reaction 24 hours, cooling reaction solution use diatomite to room temperature in 80 DEG C of oil bath after sealing
Sand core funnel filters out the insoluble matter in reaction solution, a small amount of washed with ether, collects filtrate.60mL water, ether extraction are added into filtrate
Phase of fetching water (40mL × 3), merge organic phase, organic phase washed with water, saturated common salt water washing, anhydrous sodium sulfate drying, filter,
Rotary evaporation recycling design, residue obtain product 1.512g, yield 83% after silica gel column chromatography separates.
The structured data that product is prepared in this example is characterized as below：
1H NMR(400MHz,CDCl3) δ 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) δ 167.08,142.78,130.00,129.12,128.88,83.60 (d, J=169.7Hz), 52.16,
37.04 (d, J=20.6Hz)
The preparation of embodiment 24 compound 4- (2- fluoro ethyls) benzonitrile
The chemical equation of this example prepare compound 4- (2- fluoro ethyls) benzonitrile is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, 4- cyanophenylboronic acids (2.204g, 15.0mmol), anhydrous phosphoric acid potassium are sequentially added in tube sealing
(6.368g, 30.0mmol), after addition solvent diethylene glycol dimethyl ether (50mL) stirs, sequentially add the fluoro- 2- iodine of 1-
Ethane (1.739g, 10.0mmol), 4,4 '-dimethoxy -2,2 '-bipyridyl (0.238g, 1.1mmol) and NiBr2
(0.219g, 1.0mmol), stirring reaction 36 hours, cooling reaction solution use diatomite to room temperature in 80 DEG C of oil bath after sealing
Sand core funnel filters out the insoluble matter in reaction solution, a small amount of washed with ether, collects filtrate.60mL water, ether extraction are added into filtrate
Phase of fetching water (40mL × 3), merge organic phase, organic phase washed with water, saturated common salt water washing, anhydrous sodium sulfate drying, filter,
Rotary evaporation recycling design, residue obtain product 1.134g, yield 76% after silica gel column chromatography separates.
The structured data that product is prepared in this example is characterized as below：
1H NMR(600MHz,CDCl3) δ 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) δ 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)
The preparation of embodiment 25 compound 1- (2- fluoro ethyls) naphthalene
The chemical equation of this example prepare compound 1- (2- fluoro ethyls) naphthalene is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, 1- naphthalene boronic acids (2.580g, 15.0mmol), anhydrous phosphoric acid potassium are sequentially added in tube sealing
(6.368g, 30.0mmol), after addition solvent diethylene glycol dimethyl ether (60mL) stirs, sequentially add the fluoro- 2- iodine of 1-
Ethane (1.739g, 10.0mmol), 4,4 '-dimethoxy -2,2 '-bipyridyl (0.238g, 1.1mmol) and NiBr2
(0.219g, 1.0mmol), stirring reaction 18 hours, cooling reaction solution use diatomite to room temperature in 80 DEG C of oil bath after sealing
Sand core funnel filters out the insoluble matter in reaction solution, a small amount of washed with ether, collects filtrate.60mL water, ether extraction are added into filtrate
Phase of fetching water (40mL × 3), merge organic phase, organic phase washed with water, saturated common salt water washing, anhydrous sodium sulfate drying, filter,
Rotary evaporation recycling design, residue obtain product 1.394g, yield 80% after silica gel column chromatography separates.
The structured data that product is prepared in this example is characterized as below：
1H NMR(600MHz,CDCl3)δ8.02(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)δ133.90,132.90,132.02,128.92,127.59,127.20,126.21,125.69,125.56,123.37,
83.55 (d, J=169.6Hz), 33.87 (d, J=20.7Hz)
The preparation of embodiment 26 compound 2- (2- fluoro ethyls) naphthalene
The chemical equation of this example prepare compound 2- (2- fluoro ethyls) naphthalene is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, 2- naphthalene boronic acids (2.580g, 15.0mmol), anhydrous phosphoric acid potassium are sequentially added in tube sealing
(6.368g, 30.0mmol), after addition solvent diethylene glycol dimethyl ether (60mL) stirs, sequentially add the fluoro- 2- iodine of 1-
Ethane (1.739g, 10.0mmol), 4,4 '-dimethoxy -2,2 '-bipyridyl (0.238g, 1.1mmol) and NiBr2
(0.219g, 1.0mmol), stirring reaction 18 hours, cooling reaction solution use diatomite to room temperature in 80 DEG C of oil bath after sealing
Sand core funnel filters out the insoluble matter in reaction solution, a small amount of washed with ether, collects filtrate.60mL water, ether extraction are added into filtrate
Phase of fetching water (40mL × 3), merge organic phase, organic phase washed with water, saturated common salt water washing, anhydrous sodium sulfate drying, filter,
Rotary evaporation recycling design, residue obtain product 1.463g, yield 84% after silica gel column chromatography separates.
The structured data that product is prepared in this example is characterized as below：
1H NMR(600MHz,CDCl3) δ 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)δ134.63
(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)
The preparation of embodiment 27 compound 3- (2- fluoro ethyls) -2- methoxypyridines
The chemical equation of this example prepare compound 3- (2- fluoro ethyls) -2- methoxypyridines is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, 2- methoxypyridine -3- boric acid (2.294g, 15.0mmol), anhydrous is sequentially added in tube sealing
Potassium phosphate (6.368g, 30.0mmol), after addition solvent diethylene glycol dimethyl ether (60mL) stirs, sequentially add 1-
Fluoro- 2- iodoethane (1.739g, 10.0mmol), 4,4 '-dimethoxy -2,2 '-bipyridyl (0.238g, 1.1mmol) and NiBr2
(0.219g, 1.0mmol), stirring reaction 20 hours, cooling reaction solution use diatomite to room temperature in 80 DEG C of oil bath after sealing
Sand core funnel filters out the insoluble matter in reaction solution, a small amount of washed with ether, collects filtrate.60mL water, ether extraction are added into filtrate
Phase of fetching water (40mL × 3), merge organic phase, organic phase washed with water, saturated common salt water washing, anhydrous sodium sulfate drying, filter,
Rotary evaporation recycling design, residue obtain product 1.195g, yield 77% after silica gel column chromatography separates.
The structured data that product is prepared in this example is characterized as below：
1H NMR(600MHz,CDCl3) δ 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) δ 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)
The preparation of embodiment 28 compound 3- (2- fluoro ethyls) quinoline
The chemical equation of this example prepare compound 3- (2- fluoro ethyls) quinoline is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, 3- quinoline boronic acids (2.595g, 15.0mmol), anhydrous phosphoric acid potassium are sequentially added in tube sealing
(6.368g, 30.0mmol), after addition solvent diethylene glycol dimethyl ether (60mL) stirs, sequentially add the fluoro- 2- iodine of 1-
Ethane (1.739g, 10.0mmol), 4,4 '-dimethoxy -2,2 '-bipyridyl (0.119g, 0.55mmol) and NiBr2
(0.110g, 0.50mmol), stirring reaction 24 hours, cooling reaction solution use diatom to room temperature in 80 DEG C of oil bath after sealing
Native sand core funnel filters out the insoluble matter in reaction solution, a small amount of washed with ether, collects filtrate.60mL water, ether are added into filtrate
Aqueous phase extracted (40mL × 3), merge organic phase, organic phase washed with water, saturated common salt water washing, anhydrous sodium sulfate drying, mistake
Filter, rotary evaporation recycling design, residue obtain product 1.384g, yield 79% after silica gel column chromatography separates.
The structured data that product is prepared in this example is characterized as below：
1H NMR(600MHz,CDCl3) δ 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) δ 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).
The preparation of embodiment 29 compound 4- (2- fluoro ethyls) dibenzo [b, d] furans
The chemical equation of this example prepare compound 4- (2- fluoro ethyls) dibenzo [b, d] furans is as follows：
Specific preparation process is as follows：
Under nitrogen atmosphere, 4- dibenzofurans boric acid (3.180g, 15.0mmol), anhydrous phosphoric acid are sequentially added in tube sealing
Potassium (6.368g, 30.0mmol), after addition solvent diethylene glycol dimethyl ether (60mL) stirs, sequentially add the fluoro- 2- of 1-
Iodoethane (1.739g, 10.0mmol), 4,4 '-dimethoxy -2,2 '-bipyridyl (0.119g, 0.55mmol) and NiBr2
(0.110g, 0.50mmol), stirring reaction 24 hours, cooling reaction solution use diatom to room temperature in 80 DEG C of oil bath after sealing
Native sand core funnel filters out the insoluble matter in reaction solution, a small amount of washed with ether, collects filtrate.60mL water, ether are added into filtrate
Aqueous phase extracted (40mL × 3), merge organic phase, organic phase washed with water, saturated common salt water washing, anhydrous sodium sulfate drying, mistake
Filter, rotary evaporation recycling design, residue obtain product 1.885g, yield 88% after silica gel column chromatography separates.
The structured data that product is prepared in this example is characterized as below：
1H NMR(600MHz,CDCl3)δ7.93(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)δ156.05,154.81,128.08,127.17,124.45,124.12,122.92,122.78,120.99,120.95,
(120.79,119.27,82.86 d, J=168.8Hz), 31.27 (d, J=21.4Hz)
The preparation of embodiment 30 compound 4- (2- fluoro ethyls) dibenzo [b, d] thiophene
The chemical equation of this example prepare compound 4- (2- fluoro ethyls) dibenzo [b, d] thiophene is as follows：
Specific course of reaction is as follows：
Under nitrogen atmosphere, 4- dibenzothiophenes boric acid (3.421g, 15.0mmol), anhydrous phosphoric acid are sequentially added in tube sealing
Potassium (6.368g, 30.0mmol), after addition solvent diethylene glycol dimethyl ether (60mL) stirs, sequentially add the fluoro- 2- of 1-
Iodoethane (1.739g, 10.0mmol), 4,4 '-dimethoxy -2,2 '-bipyridyl (0.119g, 0.55mmol) and NiBr2
(0.110g, 0.50mmol), stirring reaction 32 hours, cooling reaction solution use diatom to room temperature in 80 DEG C of oil bath after sealing
Native sand core funnel filters out the insoluble matter in reaction solution, a small amount of washed with ether, collects filtrate.60mL water, ether are added into filtrate
Aqueous phase extracted (40mL × 3), merge organic phase, organic phase washed with water, saturated common salt water washing, anhydrous sodium sulfate drying, mistake
Filter, rotary evaporation recycling design, residue obtain product 1.888g, yield 82% after silica gel column chromatography separates.
The structured data that product is prepared in this example is characterized as below：
1H NMR(600MHz,CDCl3) δ 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) δ 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 foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
All any modification, equivalent and improvement made within refreshing and principle etc., should be included in the scope of the protection.
Claims (10)
1. a kind of preparation method of single fluoro ethyl substituted aromatic compound, it is characterised in that the preparation method is to react molten
Under agent and nitrogen atmosphere, using the fluoro- 2- iodoethane of 1- and the aryl boric acid after weak base activates as raw material, in Raney nickel and connection pyrrole
Under the catalyst system and catalyzing effect of pyridine class part, after heating response reaches terminal, single fluoro ethyl substituted aromatic is obtained through separating, purifying
Compound.
2. a kind of preparation method of single fluoro ethyl substituted aromatic compound as claimed in claim 1, it is characterised in that including following
Step：
1) under nitrogen atmosphere, alkali, reaction dissolvent are added into aryl boric acid, and stir；
2) 1- fluoro- 2 iodoethane, bipyridyliumses part and Raney nickel are added into above-mentioned solution successively, through heating, stirring after sealing
Mix after reaching reaction end, reaction solution is cooled to room temperature；
3) reaction solution after cooling is produced to single fluoro ethyl substituted aromatic compound after separating, purifying.
3. a kind of preparation method of single fluoro ethyl substituted aromatic compound as claimed in claim 1 or 2, it is characterised in that described
The ratio between amount of the fluoro- 2- iodoethane of 1- and aryl boric acid material is 1：1~2.2；The Raney nickel and the fluoro- 2- iodoethane materials of 1-
The ratio between amount be 1~15.0：100；The ratio between amount of the bipyridyliumses part and the fluoro- 2- iodoethane materials of 1- is 1~20.0：
100；The ratio between amount of the alkali and the fluoro- 2- iodoethane materials of 1- is 1.5~4.0：1；The amount of the fluoro- 2- iodoethane materials of 1- with
The ratio between volume of reaction dissolvent is 1：1~20molL-1。
4. a kind of preparation method of single fluoro ethyl substituted aromatic compound as claimed in claim 1 or 2, it is characterised in that described
The Ar groups of aryl boric acid are phenyl, the alkyl-substituted phenyl of C1~4, the alkoxy substituted phenyl of C1~4, the acyl group substitution of C1~4
The alkoxy acyl substituted-phenyl of phenyl, C1~4, cyano group substituted-phenyl, naphthyl, pyridine radicals, quinolyl, dibenzofuran group, hexichol
One or more in bithiophene base.
5. as claim 4 states a kind of preparation method of single fluoro ethyl substituted aromatic compound, it is characterised in that described C1~
4 alkyl is base, ethyl, propyl group, isopropyl, butyl, the tert-butyl group；The alkoxy of C1~4 is methoxyl group, ethyoxyl, uncle
Butoxy；The acyl group of C1~4 is formoxyl, acetyl group, propiono, bytyry；The alkoxy acyl of described C1~4 is first
Oxygen acyl group, ethoxy acyl group, the third oxygen acyl group, fourth oxygen acyl group.
6. a kind of preparation method of single fluoro ethyl substituted aromatic compound as claimed in claim 1 or 2, it is characterised in that described
Reaction dissolvent be tetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, TRIGLYME, toluene,
One or more in dimethyl sulfoxide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide.
7. a kind of preparation method of single fluoro ethyl substituted aromatic compound as claimed in claim 1 or 2, it is characterised in that described
Alkali be sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium phosphate, potassium phosphate, cesium fluoride, potassium fluoride, sodium tert-butoxide,
One kind in potassium tert-butoxide.
8. a kind of preparation method of single fluoro ethyl substituted aromatic compound as claimed in claim 1 or 2, it is characterised in that described
Raney nickel is Ni (cod)2、NiCl2、NiBr2、NiCl2(DME)、NiBr2(DME)、Ni(acac)2In one kind.
9. a kind of preparation method of single fluoro ethyl substituted aromatic compound as claimed in claim 1 or 2, it is characterised in that described
Bipyridyliumses part be bipy 2,2' bipyridyl, 4,4 '-dimethyl-bipy 2,2' bipyridyl, 4,4 '-di-t-butyl-bipy 2,2' bipyridyl,
4,4 '-dimethoxy-bipy 2,2' bipyridyl, Phen, α, α, one kind in α-terpyridyl.
10. a kind of preparation method of single fluoro ethyl substituted aromatic compound as claimed in claim 1 or 2, it is characterised in that described
Separating-purifying step is：The insoluble matter in reaction solution is filtered out, and insoluble matter is washed with ether, collects filtrate；Added into filtrate
Water, with ether aqueous phase extracted, merge organic phase, organic phase washed with water, saturated sodium-chloride water solution washing, then through anhydrous sulphur
Sour sodium is dried, and rotary evaporation removes solvent after filtering, finally by residue through recrystallizing or with the isolated list of silica gel column chromatography
Fluoro ethyl substituted aromatic compound.
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| CN109232175A (en) * | 2018-09-27 | 2019-01-18 | 四川理工学院 | A kind of preparation method of chloroethyl substituted aromatic compound |
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