CN106905227A - The preparation method of aryl-linking compound - Google Patents
The preparation method of aryl-linking compound Download PDFInfo
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- CN106905227A CN106905227A CN201710014409.2A CN201710014409A CN106905227A CN 106905227 A CN106905227 A CN 106905227A CN 201710014409 A CN201710014409 A CN 201710014409A CN 106905227 A CN106905227 A CN 106905227A
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
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Abstract
The invention provides a kind of preparation method of aryl-linking compound.Under catalytic action of the preparation method including catalyst, substrate A and organic zinc reagent B are carried out into cross-coupling reaction, obtain aryl-linking compound；Wherein, the chemical constitution of substrate A isThe chemical constitution of organic zinc reagent B is
Description
Technical field
The present invention relates to technical field of organic synthesis, in particular to a kind of preparation method of aryl-linking compound.
Background technology
Transition metal-catalyzed cross-coupling reaction is the important method for realizing carbon carbon bonding, is widely used in medicine, agriculture
In the synthesis of medicine, dyestuff, functional material, spices and natural products.Especially for the preparation of aryl-linking compound, using phenols
Cross-coupling reaction between compound is also conventional synthetic method.
Typically, first by phenolic compound be converted into corresponding methanesulfonates (OMs), triflate (OTf) or
P-methyl benzenesulfonic acid ester (OTs), then reacts, you can realize phenolic compound cross-coupling reaction with organometallic reagent
(J.Am.Chem.Soc.1984,106,4630.；Chem.Soc.Rev.2011,40,4963.；Chem.-Eur.J.2011,17,
1728.).But the reactivity of aryl methanesulfonates, triflate and p-methyl benzenesulfonic acid ester is generally relatively low, synthesize cost
Compare high.And, catalyst is made using Metal Palladium in existing cross-coupling reaction, considerably increase reaction cost.
For these reasons, it is necessary to which a kind of low cost, the preparation method of the aryl-linking compound of high income are provided.
The content of the invention
It is a primary object of the present invention to provide a kind of preparation method of aryl-linking compound, to solve to join in the prior art
The problem that aryl compound preparation cost is high, yield is low.
To achieve these goals, according to an aspect of the invention, there is provided a kind of preparation side of aryl-linking compound
Method, it is under the catalytic action of catalyst, substrate A and organic zinc reagent B to be carried out into cross-coupling reaction, obtains biaryl
Compound；Wherein, shown in formula I, the chemical constitution of organic zinc reagent B is as shown in Formula II for the chemical constitution of substrate A：
Catalyst is one or more of nickel salt, mantoquita and cobalt salt；
In Formulas I, n is 0~1；Each X is each independently selected from C, N, S or O；Y is fluosulfonic acid ester group, methanesulfonic acid ester group, trifluoro
Any one in methanesulfonic acid ester group, p-methyl benzenesulfonic acid ester group and halogen atom；R1、R2、R3And R4It is each independently selected from H, alkane
Base, aryl, ester group, itrile group, alkoxy or halogen atom, or, R1、R2、R3And R4Two of middle arbitrary neighborhood are one group, and
At least one set of bonding；
In Formula II, m is 0~1；Each H is each independently selected from C, N, S or O；Z is ZnCl, ZnBr or ZnI；R5, R6, R7, R8
H, alkyl, aryl, ester group, itrile group, alkoxy or halogen atom are each independently selected from, or, R5, R6, R7, R8In any phase
Adjacent two are one group, and bonding between at least one set.
Further, nickel salt is NiCl2、NiBr2、NiI2、Ni(OAc)2、Ni(acac)2、NiCl2(PPh3)2、NiBr2
(PPh3)2、Ni(PCy3)Cl2、NiCl2(dppf)、NiCl2(dppe)、NiCl2(dppp)、Ni(Py)2Cl2In one kind or many
Kind；Mantoquita is CuI, CuBr, CuCl, Cu (OAc)2、Cu(acac)2、Cu(OTf)2、CuBr2、CuCl2And CuSO4In one kind or
It is various；Cobalt salt is CoCl2、CoBr2、Co(acac)2And Co (acac)3In one or more.
Further, during cross-coupling reaction, the mol ratio of substrate A and organic zinc reagent B is 1:1~3.
Further, during cross-coupling reaction, substrate A is 30~60 with the mol ratio of catalyst:1.
Further, during cross-coupling reaction, to part is added in reaction system, part is amine ligand and/or phosphorus
Part；It is preferred that amine ligand is one or more in TMEDA, DMEDA, EDA, bipyridyl and Phen；It is preferred that phosphorus part is
PPh3、PCy3、P(t-Bu)3, dppf, the one kind or many in BINAP, dppb and Xantphos of dppe, dppp, optics or racemization
Kind.
Further, during cross-coupling reaction, part is 1~3 with the mol ratio of catalyst:1.
Further, cross-coupling reaction is carried out in organic solvent, and organic solvent is tetrahydrofuran, 2- methyl tetrahydrochysene furans
Mutter, 1,4- dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, benzene,toluene,xylene, N,N-dimethylformamide,
DMAC N,N' dimethyl acetamide, N, N- DEFs, 1-METHYLPYRROLIDONE, dimethyl sulfoxide (DMSO), acetonitrile, methyl alcohol, ethanol and
One or more in isopropanol.
Further, the reaction temperature of cross-coupling reaction is 60~80 DEG C.
Further, after carrying out cross-coupling reaction, crude product is obtained；Then crude product is quenched, purified, obtained
Aryl-linking compound.
Further, purified using extractant, extractant be ethyl acetate, dichloromethane, methyl tertiary butyl ether(MTBE) and
One or more of 2- methyltetrahydrofurans.
Using the preparation method of aryl-linking compound of the invention, using one or more of nickel salt, mantoquita and cobalt salt as
Catalyst, carrying out cross-coupling reaction using substrate A and organic zinc reagent B carries out the preparation of aryl-linking compound.Compared to it
His noble metal catalyst such as metal palladium catalyst, the cost of nickel salt, mantoquita and cobalt salt is relatively low, can substantially reduce biaryl chemical combination
The reaction cost of thing.Meanwhile, aromatic yl sulphonate or halogenated aryl hydrocarbon shown in substrate A have stronger electrophilic performance, are excellent performances
Different electrophilic reagent, many advantages, such as with easy preparations, low cost, activity height, good stability, using itself and organic zinc reagent B
The yield of cross-coupling reaction, generation aryl-linking compound, and the reaction can occur in the presence of nickel salt, mantoquita or cobalt salt
It is higher.
Specific embodiment
It should be noted that in the case where not conflicting, the feature in embodiment and embodiment in the application can phase
Mutually combination.The present invention is described in detail below in conjunction with embodiment.
The application is described in further detail below in conjunction with specific embodiment, these embodiments are it is not intended that limit this
Apply for scope required for protection.
As described by background section, it is low to there is high cost, yield in the preparation of existing aryl-linking compound
Problem.In order to solve this problem, the invention provides a kind of preparation method of aryl-linking compound, it is characterised in that urging
Under the catalytic action of agent, substrate A and organic zinc reagent B are carried out into cross-coupling reaction, obtain aryl-linking compound；Wherein,
Shown in formula I, the chemical constitution of organic zinc reagent B is as shown in Formula II for the chemical constitution of substrate A：
Catalyst is one or more of nickel salt, mantoquita and cobalt salt；In Formulas I, n is 0~1；Each X be each independently selected from C,
N, S or O；Y is appointing in fluosulfonic acid ester group, methanesulfonic acid ester group, TFMS ester group, p-methyl benzenesulfonic acid ester group and halogen atom
Meaning is a kind of；R1、R2、R3And R4H, alkyl, aryl, ester group, itrile group, alkoxy or halogen atom are each independently selected from, or,
R1、R2、R3And R4Two of middle arbitrary neighborhood are one group, and at least one set of bonding；In Formula II, m is 0~1；Each H is independently of one another
Selected from C, N, S or O；Z is ZnCl, ZnBr or ZnI；R5, R6, R7, R8Be each independently selected from H, alkyl, aryl, ester group, itrile group,
Alkoxy or halogen atom, or, R5, R6, R7, R8Two of middle arbitrary neighborhood are one group, and at least one set of bonding.
Using the preparation method of aryl-linking compound of the invention, using one or more of nickel salt, mantoquita and cobalt salt as
Catalyst, carrying out cross-coupling reaction using substrate A and organic zinc reagent B carries out the preparation of aryl-linking compound.Compared to it
His noble metal catalyst such as metal palladium catalyst, the cost of nickel salt, mantoquita and cobalt salt is relatively low, can substantially reduce biaryl chemical combination
The reaction cost of thing.Meanwhile, aromatic yl sulphonate or halogenated aryl hydrocarbon shown in substrate A have stronger electrophilic performance, are excellent performances
Different electrophilic reagent, many advantages, such as with easy preparations, low cost, activity height, good stability, using itself and organic zinc reagent B
The yield of cross-coupling reaction, generation aryl-linking compound, and the reaction can occur in the presence of nickel salt, mantoquita or cobalt salt
It is higher.
In addition, for above-mentioned preparation method of the invention is compared to traditional aryl-linking compound preparation method, route
Shorter, reaction condition is more gentle.Meanwhile, the species of the substrate A for using is more, in application preferably to industrialized production.
What deserves to be explained is, above-mentioned R1、R2、R3And R4Two of middle arbitrary neighborhood are one group, and at least one set of bonding contains
Justice is R1、R2、R3And R4In adjacent two, such as R1And R2, constitute many yuan of rings between the X corresponding to the two, such as five-membered ring,
Hexatomic ring etc., and many yuan of rings can be carbocyclic ring, or heterocycle.Illustrate：8- fluosulfonic acid esters quinoline is made
It is substrate A, n is 1, R1、R2It is H, R3, R4Between bonding, and form hexa-member heterocycle between the C on corresponding substitution position.Class
As, R5, R6, R7, R8In adjacent two be one group, and at least one set of bonding also has same implication.
Preferably, R1、R2、R3And R4It is each independently selected from alkyl, the aryl of C6~C12, the C1~C10 of H, C1~C10
Ester group, itrile group, the alkoxy or halogen atom of C1~C10；R5, R6, R7, R8It is each independently selected from the alkane of H, C1~C10
Base, the aryl of C6~C12, the ester group of C1~C10, itrile group, the alkoxy or halogen atom of C1~C10.
The aryl of above-mentioned C6~C12 can be the aryl, or biaryl of substitution.The alkyl of above-mentioned C1~C10 can
Being branched-chain or straight-chain alkyl.
The catalyst used in above-mentioned preparation technology is one or more in nickel salt, mantoquita and cobalt salt.Specific salt
Species can be inorganic salts, or organic salt.Nickel salt is included but is not limited in a preferred embodiment
NiCl2、NiBr2、NiI2、Ni(OAc)2、Ni(acac)2、NiCl2(PPh3)2、NiBr2(PPh3)2、Ni(PCy3)Cl2、NiCl2
(dppf)、NiCl2(dppe)、NiCl2(dppp)、Ni(Py)2Cl2In one or more；Mantoquita include but is not limited to CuI,
CuBr、CuCl、Cu(OAc)2、Cu(acac)2、Cu(OTf)2、CuBr2、CuCl2And CuSO4In one or more；Cobalt salt includes
But it is not limited to CoCl2、CoBr2、Co(acac)2And Co (acac)3In one or more.Compared on other kinds of salt
State listed nickel salt, mantoquita and cobalt salt higher to the catalysis activity of above-mentioned cross-coupling reaction, product can not only be improved
Yield, also advantageously improve reaction rate, shorten the reaction time.Meanwhile, the wide material sources of these catalyst, price is relatively
It is low, it is more suitable for extensive use.
Above-mentioned cross-coupling reaction actually carbon-to-carbon bonding process, in theory between substrate A and organic zinc reagent B mole
Than being 1:1.Certainly, in specific building-up process, can also be adjusted according to specific reaction efficiency etc..A kind of preferred
Implementation method in, the mol ratio of substrate A and organic zinc reagent B during above-mentioned cross-coupling reaction is 1:1~3.The bottom of by
The mol ratio control of thing A and organic zinc reagent B within the above range, on the one hand can improve the conversion ratio of substrate A, improve biaryl
The yield of based compound；On the one hand it is more beneficial for improving the speed of reaction.
The addition of specific catalyst can also be adjusted according to the efficiency more factor of reaction.In a kind of preferred reality
Apply in mode, during above-mentioned cross-coupling reaction, substrate A is 30~60 with the mol ratio of catalyst:1.Use the addition
Catalyst, can further improve the efficiency and yield of reaction.
It is highly preferred that during above-mentioned cross-coupling reaction, while to part is added in reaction system, part is amine ligand
And/or phosphorus part.The purpose for adding part is, in order to pass through coordination, to stablize the Organometallic obtained by oxidized addition and close
Thing intermediate, meanwhile, accelerate reaction rate.It is preferred that amine ligand include but is not limited to TMEDA (tetramethylethylenediamine), DMEDA (N,
N '-dimethyl ethylenediamine), EDA (ethylenediamine), one or more in bipyridyl and Phen；It is preferred that phosphorus part include but
It is not limited to PPh3(triphenyl phosphorus), PCy3(thricyclohexyl phosphorus), P (t-Bu)3(tri-tert phosphorus), dppf (1,1 '-bis- (diphenyl
Phosphorus) ferrocene), dppe (1,2- double (diphenylphosphine) ethane), dppp (1,3- double (diphenylphosphine) propane), optics or racemization
BINAP (1,1 '-dinaphthalene -2,2 '-bis- hexichol phosphorus), dppb (double (diphenylphosphine) butane of 1,4-) and Xantphos (4,5- double two
Phenyl phosphorus -9,9- dimethyl xanthene) in one or more.It is highly preferred that part is 1~3 with the mol ratio of catalyst:1.
Cross-coupling reaction is generally carried out in dicyandiamide solution.Consider the originals such as substrate A, organic zinc reagent B, catalyst
The dispersiveness and solubility property of material, preferable organic solvent include but is not limited to tetrahydrofuran, 2- methyltetrahydrofurans, Isosorbide-5-Nitrae-dioxy
Six rings, glycol dimethyl ether, diethylene glycol dimethyl ether, benzene,toluene,xylene, N,N-dimethylformamide, N, N- dimethyl second
Acid amides, N, in N- DEFs, 1-METHYLPYRROLIDONE, dimethyl sulfoxide (DMSO), acetonitrile, methyl alcohol, ethanol and isopropanol one
Plant or various.These solvents can provide the environment of more stable homogeneous for reaction, meanwhile, substrate A and organic zinc reagent B are at this
Activity higher can be shown in a little dicyandiamide solutions, so as to be conducive to further improving the yield of product.
Preparation method in the present invention because using special substrate A and catalyst, for more traditional cross-coupling reaction,
Process conditions are gentleer.In a preferred embodiment, the reaction temperature of above-mentioned cross-coupling reaction is 60~80 DEG C.
In specific operating process, in order to obtain purer aryl-linking compound product, preferably cross-coupling is being carried out
After reaction, crude product is obtained；Then crude product is quenched, purified, obtained aryl-linking compound.Specifically it is quenched and purifies
Process can be using the usual way in organic synthesis.Preferably, crude product can be placed in frozen water, be quenched using pure water
Go out reaction.Then, after stratification, water is mutually extracted using extractant, extraction times can be controlled voluntarily.Finally merge
Organic phase, you can obtain more pure product.Preferably, the extractant of use includes but is not limited to ethyl acetate, dichloromethane
One or more in alkane, methyl tertiary butyl ether(MTBE) and 2- methyltetrahydrofurans.
Beneficial effects of the present invention are further illustrated by the following examples：
Embodiment 1
In a nitrogen atmosphere, to added in the Schlenk pipes of 15mL dried and cleans 2- pyridine fluosulfonic acid ester (354.3mg,
2.0mmol), nickel chloride (5.2mg, 0.04mmol), triphenylphosphine (21.0mg, 0.08mmol), tetrahydrofuran (2.0mL) and benzene
The tetrahydrofuran solution (7.2mL, 0.42mol/L, 3.0mmol) of base zinc chloride.Then, Schlenk pipes are placed in 65 DEG C of oil baths
Middle reaction 6 hours, now TLC displays raw material reaction is complete.Then, Schlenk pipes are placed in ice-water bath cooling, and in pipe
2.0mL purified waters are added in reaction system to carry out that reaction is quenched.After being stirred at room temperature 15 minutes, stratification obtains water
Phase and organic phase.After water is mutually extracted with ethyl acetate (3mL × 3), the extraction phase being obtained by extraction and foregoing organic phase merge, and are used in combination
After anhydrous sodium sulfate drying, filtrate is filtrated to get.After filtrate is concentrated, through silica gel column chromatography, oily liquids product is finally given
295mg, yield 95%.
The nuclear-magnetism spectrum of the product for obtaining is as follows：1H NMR (500MHz, CDCl3) δ=8.65 (d, J=4.6Hz, 1H),
8.03-7.91 (m, 2H), 7.67-7.54 (m, 2H), 7.42 (t, J=7.5Hz, 2H), 7.36 (t, J=7.3Hz, 1H), 7.10
(ddd, J=6.7,4.8,1.6Hz, 1H)
Embodiment 2
In a nitrogen atmosphere, to addition 5- methyl -2- pyridine fluosulfonic acid esters in the Schlenk pipes of 15mL dried and cleans
(382.3mg, 2.0mmol), nickelous bromide (14.6mg, 0.067mmol), triphenylphosphine (35.2mg, 0.067mmol), tetrahydrochysene furan
Mutter (2.0mL) and tetraphenylphosphonium chloride zinc tetrahydrofuran solution (14.4mL, 0.42mol/L, 6.0mmol).Then, by Schlenk
Pipe is placed in heating response 6 hours in 60 DEG C of oil baths, and now TLC displays raw material reaction is complete.Then, Schlenk pipes are placed in ice
Water-bath is cooled down, and to adding 2.0mL purified waters in reaction system carrying out that reaction is quenched.It is quiet after being stirred at room temperature 15 minutes
Layering is put, water phase and organic phase is obtained.After water is mutually extracted with ethyl acetate (3mL × 3), the extraction phase that is obtained by extraction and foregoing have
Machine mutually merges, and with anhydrous sodium sulfate drying after, be filtrated to get filtrate.After filtrate is concentrated, through silica gel column chromatography, finally give
Oily liquids product 307mg, yield 91%.
The nuclear-magnetism spectrum of the product for obtaining is as follows：1H NMR (500MHz, CDCl3) δ=8.53 (d, J=4.5Hz, 1H),
7.58 (d, J=7.6Hz, 1H), 7.55-7.48 (m, 2H), 7.45 (dd, J=10.9,3.7Hz, 2H), 7.42-7.35 (m,
1H), 7.18 (dd, J=6.4,5.0Hz, 1H), 2.36 (s, 3H)
Embodiment 3
In a nitrogen atmosphere, to added in the Schlenk pipes of 15mL dried and cleans 2- pyridine fluosulfonic acid ester (354.3mg,
2.0mmol), dichloride copper (4.44mg, 0.033mmol), tri-tert phosphorus (20.2mg, 0.1mmol), glycol dimethyl ether
The ethylene glycol dimethyl ether solution (4.8mL, 0.42mol/L, 2.0mmol) of (3.0mL) and tetraphenylphosphonium chloride zinc.Then, by Schlenk
Pipe is placed in heating response 5 hours in 70 DEG C of oil baths, and now TLC displays raw material reaction is complete.Then, Schlenk pipes are placed in ice
Water-bath is cooled down, and to adding 2.0mL purified waters in reaction system carrying out that reaction is quenched.It is quiet after being stirred at room temperature 15 minutes
Layering is put, water phase and organic phase is obtained.After water is mutually extracted with ethyl acetate (3mL × 3), the extraction phase that is obtained by extraction and foregoing have
Machine mutually merges, and with anhydrous sodium sulfate drying after, be filtrated to get filtrate.After filtrate is concentrated, through silica gel column chromatography, finally give
Oily liquids product 263mg, yield 85%.
The nuclear-magnetism spectrum of the product for obtaining is as follows：Ibid embodiment 1
Embodiment 4
In a nitrogen atmosphere, to addition 4- methyl -2- pyridine fluosulfonic acid esters in the Schlenk pipes of 15mL dried and cleans
(382.3mg, 2.0mmol), copper sulphate (4.8mg, 0.03mmol), tetramethylethylenediamine (14mg, 0.12mmol), benzene
The benzole soln (6mL, 0.42mol/L, 2.5mmol) of (3.0mL) and tetraphenylphosphonium chloride zinc.Then, Schlenk pipes are placed in 55 DEG C of oil
Heating response 5 hours in bath, now TLC displays raw material reaction is complete.Then, Schlenk pipes are placed in into ice-water bath to cool down, and to
2.0mL purified waters are added in reaction system to carry out that reaction is quenched.After being stirred at room temperature 15 minutes, stratification obtains water phase
And organic phase.After water is mutually extracted with ethyl acetate (3mL × 3), the extraction phase being obtained by extraction and foregoing organic phase merge, and use nothing
After aqueous sodium persulfate is dried, filtrate is filtrated to get.After filtrate is concentrated, through silica gel column chromatography, oily liquids product is finally given
263mg, yield 78%.
The nuclear-magnetism spectrum of the product for obtaining is as follows：1H NMR (500MHz, CDCl3) δ=8.55 (d, J=4.9Hz, 1H),
7.97 (d, J=7.3Hz, 2H), 7.54 (s, 1H), 7.46 (t, J=7.5Hz, 2H), 7.40 (t, J=7.3Hz, 1H), 7.05
(d, J=4.5Hz, 1H), 2.41 (s, 3H)
Embodiment 5
In a nitrogen atmosphere, to added in the Schlenk pipes of 15mL dried and cleans 2- pyridine fluosulfonic acid ester (354.3mg,
2.0mmol), cobalt chloride (5.2mg, 0.04mmol), N, N '-dimethyl ethylenediamine (10.57mg, 0.12mmol), toluene
The benzole soln (7.1mL, 0.35mol/L, 2.5mmol) of (3.0mL) and p-methylphenyl zinc chloride.Then, Schlenk pipes are put
Heating response 8 hours in 65 DEG C of oil baths, now TLC displays raw material reaction is complete.Then, Schlenk pipes are placed in ice-water bath
Cooling, and to adding 2.0mL purified waters in reaction system carrying out that reaction is quenched.After being stirred at room temperature 15 minutes, stand and divide
Layer obtains water phase and organic phase.After water is mutually extracted with dichloromethane (3mL × 3), the extraction phase being obtained by extraction and foregoing organic phase
Merge, and with anhydrous sodium sulfate drying after, be filtrated to get filtrate.After filtrate is concentrated, through silica gel column chromatography, finally give pale yellow
Color oily liquids product 270mg, yield 80%.
The nuclear-magnetism spectrum of the product for obtaining is as follows：1H NMR (500MHz, CDCl3) δ=8.64 (d, J=4.6Hz, 1H),
7.88 (d, J=8.1Hz, 2H), 7.69-7.49 (m, 2H), 7.23 (d, J=8.0Hz, 2H), 7.17-6.96 (m, 1H), 2.34
(s,3H).
Embodiment 6
In a nitrogen atmosphere, to added in the Schlenk pipes of 15mL dried and cleans 2- pyridine fluosulfonic acid ester (354.3mg,
2.0mmol), stannous chloride (3.95mg, 0.04mmol), tetramethylethylenediamine (14mg, 0.12mmol), N, N- dimethyl formyls
Amine (3.0mL) and the benzole soln (7.1mL, 0.35mol/L, 2.5mmol) to cyano-phenyl zinc chloride.Then, Schlenk is managed
Heating response 7 hours in 65 DEG C of oil baths are placed in, now TLC displays raw material reaction is complete.Then, Schlenk pipes are placed in frozen water
Bath cooling, and to adding 2.0mL purified waters in reaction system carrying out that reaction is quenched.After being stirred at room temperature 15 minutes, stand
Layering obtains water phase and organic phase.After water is mutually extracted with dichloromethane (3mL × 3), the extraction phase that is obtained by extraction and foregoing organic
Mutually merge, and with anhydrous sodium sulfate drying after, be filtrated to get filtrate.After filtrate is concentrated, through silica gel column chromatography, finally give white
Color solid product 306mg, yield 85%.
The nuclear-magnetism spectrum of the product for obtaining is as follows：1H NMR (500MHz, CDCl3) δ=8.74 (d, J=4.1Hz, 1H),
8.12 (d, J=8.4Hz, 2H), 7.82 (td, J=7.8,1.7Hz, 1H), 7.77 (d, J=8.4Hz, 3H), 7.36-7.29 (m,
1H).
Embodiment 7
In a nitrogen atmosphere, to added in the Schlenk pipes of 15mL dried and cleans 2- pyridine fluosulfonic acid ester (354.3mg,
2.0mmol)、NiCl2(dppf) (13.7mg, 0.02mmol), 1,10 Phens (3.6mg, 0.02mmol), N, N- dimethyl
The benzole soln (7.1mL, 0.35mol/L, 2.5mmol) of acetamide (3.0mL) and p-methoxyphenyl zinc chloride.Then, will
Schlenk pipes are placed in heating response 10 hours in 65 DEG C of oil baths, and now TLC displays raw material reaction is complete.Then, by Schlenk
Pipe is placed in ice-water bath cooling, and to adding 2.0mL purified waters in reaction system carrying out that reaction is quenched.It is stirred at room temperature 15 points
Zhong Hou, stratification obtains water phase and organic phase.After water is mutually extracted with dichloromethane (3mL × 3), the extraction phase that is obtained by extraction and
Foregoing organic phase merges, and with anhydrous sodium sulfate drying after, be filtrated to get filtrate.After filtrate is concentrated, through silica gel column chromatography, most
White solid product 277mg, yield 75% are obtained eventually.
The nuclear-magnetism spectrum of the product for obtaining is as follows：1H NMR(500MHz,CDCl3) δ=8.65 (ddd, J=4.8,1.7,
0.9Hz, 1H), 8.01-7.92 (m, 2H), 7.68 (tdd, J=7.9,7.4,1.4Hz, 2H), 7.16 (ddd, J=7.1,4.8,
1.3Hz,1H),7.03–6.95(m,2H),3.85(s,3H).
Embodiment 8
In a nitrogen atmosphere, to added in the Schlenk pipes of 15mL dried and cleans 2- pyridine fluosulfonic acid ester (354.3mg,
2.0mmol), CuI (3.8mg, 0.02mmol), bipyridyl (6.4mg, 0.04mmol), 1-METHYLPYRROLIDONE (3.0mL) and 4-
The benzole soln (7.1mL, 0.35mol/L, 2.5mmol) of fluorophenyl zinc chloride.Then, Schlenk pipes are placed in 65 DEG C of oil baths
Heating response 8 hours, now TLC displays raw material reaction is complete.Then, Schlenk pipes are placed in ice-water bath cooling, and to reaction
2.0mL purified waters are added in system to carry out that reaction is quenched.After being stirred at room temperature 15 minutes, stratification obtains water phase and has
Machine phase.After water is mutually extracted with dichloromethane (3mL × 3), the extraction phase being obtained by extraction and foregoing organic phase merge, and use anhydrous sulphur
After sour sodium is dried, filtrate is filtrated to get.After filtrate is concentrated, through silica gel column chromatography, light yellow attached body product is finally given
249mg, yield 72%.
The nuclear-magnetism spectrum of the product for obtaining is as follows：1H NMR(500MHz,CDCl3) δ=8.64 (s, 1H), 8.06-7.87 (m,
2H),7.78–7.55(m,2H),7.22–7.02(m,3H)；19F NMR(377MHz,CDCl3) δ=- 113.58.
Embodiment 9
In a nitrogen atmosphere, to added in the Schlenk pipes of 15mL dried and cleans 8- fluosulfonic acid esters quinoline (44.3mg,
2.0mmol)、Co(acac)3(7.2mg, 0.02mmol), Ni (OAc)2(4.96mg, 0.02mmol), 1-METHYLPYRROLIDONE
The benzole soln (7.1mL, 0.35mol/L, 2.5mmol) of (3.0mL) and tetraphenylphosphonium chloride zinc.Then, Schlenk pipes are placed in 65 DEG C
Heating response 8 hours in oil bath, now TLC displays raw material reaction is complete.Then, Schlenk pipes are placed in ice-water bath cooling, and
To adding 2.0mL purified waters in reaction system carrying out that reaction is quenched.After being stirred at room temperature 15 minutes, stratification obtains water
Phase and organic phase.After water is mutually extracted with dichloromethane (3mL × 3), the extraction phase being obtained by extraction and foregoing organic phase merge, and are used in combination
After anhydrous sodium sulfate drying, filtrate is filtrated to get.After filtrate is concentrated, through silica gel column chromatography, finally give light yellow attached body and produce
Thing 266mg, yield 65%.
The nuclear-magnetism spectrum of the product for obtaining is as follows：1H NMR(500MHz,CDCl3) δ=8.92 (s, 1H), 8.12 (d, J=
8.1Hz, 1H), 7.75 (d, J=7.9Hz, 1H), 7.69 (d, J=7.0Hz, 3H), 7.54 (t, J=7.2Hz, 1H), 7.47 (t,
J=7.0Hz, 2H), 7.39 (t, J=6.9Hz, 1H), 7.36-7.29 (m, 1H)
Embodiment 10
In a nitrogen atmosphere, to addition 5- Chloro-2-Pyridyle fluosulfonic acid esters in the Schlenk pipes of 15mL dried and cleans
(44.3mg, 2.0mmol), Co (acac)3(7.2mg, 0.02mmol), Ni (OAc)2(4.96mg, 0.02mmol), N- methyl pyrroles
The benzole soln (7.1mL, 0.35mol/L, 2.5mmol) of pyrrolidone (3.0mL) and tetraphenylphosphonium chloride zinc.Then, Schlenk pipes are put
Heating response 8 hours in 65 DEG C of oil baths, now TLC displays raw material reaction is complete.Then, Schlenk pipes are placed in ice-water bath
Cooling, and to adding 2.0mL purified waters in reaction system carrying out that reaction is quenched.After being stirred at room temperature 15 minutes, stand and divide
Layer obtains water phase and organic phase.After water is mutually extracted with dichloromethane (3mL × 3), the extraction phase being obtained by extraction and foregoing organic phase
Merge, and with anhydrous sodium sulfate drying after, be filtrated to get filtrate.After filtrate is concentrated, through silica gel column chromatography, white is finally given
Solid 226mg, yield 73%.
The nuclear-magnetism spectrum of the product for obtaining is as follows：1H NMR(500MHz,CDCl3) δ=8.62 (d, J=2.0Hz, 1H), 7.93
(d, J=7.3Hz, 2H), 7.65 (dd, J=8.5,2.4Hz, 1H), 7.61 (d, J=8.4Hz, 1H), 7.45 (t, J=7.3Hz,
2H), 7.40 (t, J=7.2Hz, 1H)
As can be seen from the above description, the above embodiments of the present invention realize following technique effect：
Aryl-linking compound is prepared for using different substrate As and organic zinc reagent B in the embodiment of the present invention 1 to 10, respectively
Embodiment to prepare yield higher.Especially in embodiment 1 to 3, each raw material dosage relation and technique bar in preparation process
Part is within the scope of specific so that the yield of target product is higher.
In a word, the preparation method that the present invention is provided, is substrate A using aromatic yl sulphonate, halogenated aryl hydrocarbon being readily synthesized etc.,
With nickel salt cheap and easy to get, mantoquita and cobalt salt as catalyst, the cross-coupling reaction with arylzinc reagent is realized.Reaction condition
Gently, good yield, wide application range of substrates can be obtained to a series of substrate As containing different substituents.Meanwhile, it is also big
The big heavy-metal residual reduced in product, reduces the risk and cost of post-reaction treatment and three-protection design.The present invention is virtue
The cross-coupling reaction preparation technology of base aryl-linking compound provides an environment-friendly, economical and practical high effective way.
The preferred embodiments of the present invention are the foregoing is only, is not intended to limit the invention, for the skill of this area
For art personnel, the present invention can have various modifications and variations.It is all within the spirit and principles in the present invention, made any repair
Change, equivalent, improvement etc., should be included within the scope of the present invention.
Claims (10)
1. a kind of preparation method of aryl-linking compound, it is characterised in that the preparation method includes：Make in the catalysis of catalyst
Under, substrate A and organic zinc reagent B are carried out into cross-coupling reaction, obtain the aryl-linking compound；Wherein, the substrate A
Chemical constitution shown in formula I, the chemical constitution of the organic zinc reagent B is as shown in Formula II：
The catalyst is one or more of nickel salt, mantoquita and cobalt salt；
In the Formulas I, n is 0~1；Each X is each independently selected from C, N, S or O；Y is fluosulfonic acid ester group, methanesulfonic acid ester group, trifluoro
Any one in methanesulfonic acid ester group, p-methyl benzenesulfonic acid ester group and halogen atom；R1、R2、R3And R4It is each independently selected from H, alkane
Base, aryl, ester group, itrile group, alkoxy or halogen atom, or, R1、R2、R3And R4Two of middle arbitrary neighborhood are one group, and
At least one set of bonding；
In the Formula II, m is 0~1；Each H is each independently selected from C, N, S or O；Z is ZnCl, ZnBr or ZnI；R5, R6, R7, R8
H, alkyl, aryl, ester group, itrile group, alkoxy or halogen atom are each independently selected from, or, R5, R6, R7, R8In any phase
Adjacent two are one group, and bonding between at least one set.
2. preparation method according to claim 1, it is characterised in that the nickel salt is NiCl2、NiBr2、NiI2、Ni
(OAc)2、Ni(acac)2、NiCl2(PPh3)2、NiBr2(PPh3)2、Ni(PCy3)Cl2、NiCl2(dppf)、NiCl2(dppe)、
NiCl2(dppp)、Ni(Py)2Cl2In one or more；The mantoquita is CuI, CuBr, CuCl, Cu (OAc)2、Cu
(acac)2、Cu(OTf)2、CuBr2、CuCl2And CuSO4In one or more；The cobalt salt is CoCl2、CoBr2、Co
(acac)2And Co (acac)3In one or more.
3. preparation method according to claim 2, it is characterised in that during the cross-coupling reaction, the substrate A
It is 1 with the mol ratio of the organic zinc reagent B:1~3.
4. preparation method according to claim 3, it is characterised in that during the cross-coupling reaction, the substrate A
It is 30~60 with the mol ratio of the catalyst:1.
5. preparation method according to any one of claim 1 to 4, it is characterised in that the cross-coupling reaction process
In, to part is added in reaction system, the part is amine ligand and/or phosphorus part；
It is preferred that the amine ligand is one or more in TMEDA, DMEDA, EDA, bipyridyl and Phen；
It is preferred that the phosphorus part is PPh3、PCy3、P(t-Bu)3, dppf, dppe, dppp, BINAP, dppb of optics or racemization and
One or more in Xantphos.
6. preparation method according to claim 5, it is characterised in that during the cross-coupling reaction, the part
It is 1~3 with the mol ratio of the catalyst:1.
7. preparation method according to claim 6, it is characterised in that the cross-coupling reaction enters in organic solvent
OK, the organic solvent is tetrahydrofuran, 2- methyltetrahydrofurans, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether, diethylene glycol two
Methyl ether, benzene,toluene,xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- DEFs, N- methyl
One or more in pyrrolidones, dimethyl sulfoxide (DMSO), acetonitrile, methyl alcohol, ethanol and isopropanol.
8. preparation method according to claim 7, it is characterised in that the reaction temperature of the cross-coupling reaction is 60~
80℃。
9. the preparation method according to claim 7 or 8, it is characterised in that after carrying out the cross-coupling reaction, obtains thick
Product；Then the crude product is quenched, purified, obtained the aryl-linking compound.
10. preparation method according to claim 9, it is characterised in that the purification, the extraction are carried out using extractant
Agent is ethyl acetate, dichloromethane, one or more of methyl tertiary butyl ether(MTBE) and 2- methyltetrahydrofurans.
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| CN112138718A (en) * | 2019-06-26 | 2020-12-29 | 北京工商大学 | Method for synthesizing biaryl compound by coupling covalent organic framework material photocatalysis C-C bond |
| CN116273180A (en) * | 2022-09-09 | 2023-06-23 | 浙江大学 | Catalyst of organic zinc complex and molybdenum sulfide heterostructure, preparation method and application |
| US11827610B2 (en) | 2021-09-15 | 2023-11-28 | Enko Chem, Inc. | Protoporphyrinogen oxidase inhibitors |
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| CN112138718A (en) * | 2019-06-26 | 2020-12-29 | 北京工商大学 | Method for synthesizing biaryl compound by coupling covalent organic framework material photocatalysis C-C bond |
| CN112138718B (en) * | 2019-06-26 | 2023-06-16 | 北京工商大学 | Method for synthesizing biaromatic compound by coupling covalent organic framework material with photocatalysis C-C bond |
| US11827610B2 (en) | 2021-09-15 | 2023-11-28 | Enko Chem, Inc. | Protoporphyrinogen oxidase inhibitors |
| CN116273180A (en) * | 2022-09-09 | 2023-06-23 | 浙江大学 | Catalyst of organic zinc complex and molybdenum sulfide heterostructure, preparation method and application |
| CN116273180B (en) * | 2022-09-09 | 2024-05-31 | 浙江大学 | Catalyst of organic zinc complex and molybdenum sulfide heterostructure, preparation method and application |
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