CN105085129B - Compound containing difluoromethyl and preparation method thereof - Google Patents
Compound containing difluoromethyl and preparation method thereof Download PDFInfo
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- CN105085129B CN105085129B CN201410192590.2A CN201410192590A CN105085129B CN 105085129 B CN105085129 B CN 105085129B CN 201410192590 A CN201410192590 A CN 201410192590A CN 105085129 B CN105085129 B CN 105085129B
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Abstract
The invention discloses compound containing difluoromethyl and preparation method thereof.The invention provides a kind of compound R CF containing difluoromethyl2H preparation method, comprises the following steps：Under inert gas shielding, in organic solvent, under conditions of palladium catalyst, part and alkali are present, compound R X and trimethyl difluoromethyl silicon are subjected to coupling reaction, the compound R CF containing difluoromethyl is obtained2H.The difluoromethylization reaction of the present invention can be realized realizes difluoromethyl with a variety of aryl halides aryl iodide, aryl bromide and natural products (such as oestrone or vitamin E), such reaction condition is gentle, raw material is cheap and easy to get, reaction conversion ratio is high, group is compatible good, with good market application foreground.RX+TMSCF2H→RCF2H。
Description
Technical field
The present invention relates to compound containing difluoromethyl and preparation method thereof.
Background technology
It can be very good to strengthen its fat-soluble and metabolic stability by introducing fluorine atom and fluoroalkyl into drug molecule
Property, being introduced into fluorine atom and fluoroalkyl into molecule in the last few years becomes the developing direction in the compounding design of drug molecule.
In numerous fluoroalkyls, difluoromethyl is because it can simulate hydroxyl or sulfydryl on physiologically active and become drug molecule
The important fluoroalkyl group of a class in design.Therefore difluoromethyl is introduced into molecule becomes pharmaceutical chemistry and organic fluorine chemistry
In an important topic.But the direct fewer (background document of difluoromethyl method that the transition metal of known report is participated in
It is as follows：a)Fier,P.S.；Hartwig,J.F.J.Am.Chem.Soc.2012,134,5524；b)Li,Z.-J.；Cui,Z.-
L.；Liu,Z.-Q.Org.Lett.2013,15,406；c)Prakash,G.K.S.；Ganesh,S.K.；Jones,J.P.；
Kulkarni,A.；Masood,K.；Swabeck,J.K.；Olah,G.A.Angew.Chem.Int.Ed.2012,51,12090；
d)Fujikawa,K.；Fioka,Y.；Kobayashi,A.；Amii,H.Org.Let.2011,13,5560；e)Fujiwara,
Y.；Dixon,J.A.；Rodriguez,R.A.；Baxter,R.D.；Dixon,D.D.；Collins,M.R.；Blackmond,
D.G.；Baran, P.S.J.Am.Chem.Soc.2012,134,1494.), and the method and step of report is cumbersome, substrate is applicable
Narrow range, reaction conversion ratio are low, production cost is high, be not suitable for industrialized production.For example, U.S. chemical abstract
(J.Am.Chem.Soc.2012,134,5524-5527) report what is existed using the cuprous halide of 1-3 equivalents in cesium fluoride in
Under the conditions of, 120 DEG C, 4- butyl iodobenzene and TMSCF2H carries out reaction and prepares the compound containing difluoromethyl.But the reaction halogenation
Cuprous consumption is big, and reaction temperature is high, and the reaction time is long, and applicable substrate spectrum is narrow, is not suitable for industrialized production.Therefore,
Find that a kind of suitable substrates scope is wide, reaction method is simple, reaction condition is gentle, high conversion rate, raw material is cheap and easy to get, be suitable for
The method of the introducing difluoromethyl of industrialized production is current urgent problem.
The content of the invention
The technical problems to be solved by the invention be in order to overcome in the prior art carry difluoromethyl compound synthesis
Method and step is cumbersome, route length, conversion ratio is low, cost of material is expensive, production cost is high, be not suitable for the defects such as industrialized production,
And there is provided a kind of compound containing difluoromethyl and preparation method thereof.The difluoromethylization reaction that the present invention is reported can be realized
Difluoromethyl is realized with a variety of aryl halides aryl iodide, aryl bromide and natural products (such as oestrone or vitamin E),
Such reaction condition is gentle, and raw material is cheap and easy to get, reaction conversion ratio is high, group is compatible good, before the application of good market
Scape.
The invention provides a kind of compound R CF containing difluoromethyl2H preparation method, it comprises the following steps：Inertia
Under gas shield, in organic solvent, under conditions of palladium catalyst, part and alkali are present, by compound R X and trimethyl difluoro
Methyl silicon carries out coupling reaction, obtains the compound R CF containing difluoromethyl2H；
RX+TMSCF2H→RCF2H
Wherein, X is bromine or iodine, and R is C5~C30Aryl (preferably C5~C10Aryl, described " C5~C10Aryl "
It is preferred that phenyl or naphthyl, described phenyl is further preferred Described " naphthyl " is preferably )、C5~C30The heteroaryl (C that preferably hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1~35
~C10Heteroaryl, the described " C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1~35~C10Heteroaryl " it is excellent
Pyridine radicals is selected, described pyridine radicals is preferred)、OrN is 2,3 or 4, R10And R11Various regions are independently methyl, second
Base, propyl group or isopropyl, described " C5~C30Aryl " or described " C5~C30Heteroaryl " in hydrogen atom can be by
One or more of substituents are replaced：Halogen (such as fluorine, chlorine, bromine or iodine), C1~C12Alkyl (described " C1
~C12Alkyl " preferably C1~C6Alkyl, described " C1~C6Alkyl " such as methyl, ethyl, propyl group, isopropyl, positive fourth
Base, isobutyl group, the tert-butyl group, 1- amyl groups, 2- amyl groups, 3- amyl groups, 1- hexyls, 2- hexyls or 3- hexyls), C5~C10Aryl (institute
" the C stated5~C10Aryl " preferably phenyl), halogen substitution C5~C10Aryl (described " the C of halogen substitution5~C10's
" C described in aryl "5~C10Aryl " preferably phenyl, described " phenyl " preferably 3- phenyl or 4- phenyl, described " halogen
The C of element substitution5~C10Aryl " described in " halogen " such as fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, described " halogen
The number preferably 1~2 of element ", the described " C of halogen substitution5~C10Aryl " preferred 4- bromo- phenyl),C4~C15Heteroaryl (preferably hetero atom is the C that oxygen, sulphur or nitrogen-atoms, hetero atom number are 1~24
~C12Heteroaryl, it is described that " hetero atom is the C that oxygen, sulphur or nitrogen-atoms, hetero atom number are 1~24~C12Heteroaryl " preferably
Pyrrole radicals, benzothiazolyl or 9- azepine tablet held before the breast by officials bases, described " pyrrole radicals " preferably 1- pyrrole radicals, described " benzothiazolyl " are excellent
ChoosingDescribed " 9- azepine tablets held before the breast by officials base " is preferably)、C3~C12Heterocyclylalkyl (preferably hetero atom be oxygen, sulphur or
Nitrogen-atoms, hetero atom number is the C of 1~33~C5Heterocyclylalkyl, it is described that " hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom
Number is the C of 1~33~C5Heterocyclylalkyl " preferably) or " C1~C12Alkyl-substituted C3~C12Heterocycle alkane
Base " (described " C1~C12Alkyl-substituted C3~C12Heterocyclylalkyl " described in " C1~C12Alkyl " preferably C1~C6
Alkyl, described " C1~C6Alkyl " such as methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, 1- penta
Base, 2- amyl groups, 3- amyl groups, 1- hexyls, 2- hexyls or 3- hexyls；Described " C1~C12Alkyl-substituted C3~C12Heterocycle
" C described in alkyl "3~C12Heterocyclylalkyl " preferably hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is the C of 1~33
~C5Heterocyclylalkyl, it is described that " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is the C of 1~33~C5Heterocycle alkane
Base " is preferablyIt is described " by C1~C12The C that is replaced of alkyl3~C12Heterocyclylalkyl " further preferably
)。R1For C1~C6Alkyl (described " C1~C6Alkyl " for example methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group,
The tert-butyl group, 1- amyl groups, 2- amyl groups, 3- amyl groups, 1- hexyls, 2- hexyls or 3- hexyls).R2For C1~C20Alkyl (described " C1
~C20Alkyl " preferably C1~C10Alkyl, described " C1~C10Alkyl " such as methyl, ethyl, propyl group, isopropyl, just
Butyl, isobutyl group, the tert-butyl group, 1- amyl groups, 1- hexyls, 1- heptyl, 1- octyl groups, 1- nonyls or 1- decyls), C5~C10Aryl
(described " C5~C10Aryl " preferably phenyl), " C5~C10Aryl substitution C1~C20Alkyl " (described " C5~C10
Aryl substitution C1~C20Alkyl " described in " C5~C10Aryl " preferably phenyl；Described " C5~C10Aryl take
The C in generation1~C20Alkyl " described in " C1~C20Alkyl " preferably C1~C10Alkyl, described " C1~C10Alkyl "
Such as methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, 1- amyl groups, 1- hexyls, 1- heptyl, 1- octyl groups, 1-
Nonyl or 1- decyls；Described " C5~C10Aryl substitution C1~C20Alkyl " preferred benzyloxy) or " C3~C10Cycloalkanes
The C of base substitution1~C20Alkyl " (described " C3~C10Cycloalkyl substitution C1~C20Alkyl " described in " C1~C20
Alkyl " preferably C1~C10Alkyl, described " C1~C10Alkyl " for example methyl, ethyl, propyl group, isopropyl, normal-butyl,
Isobutyl group, the tert-butyl group, 1- amyl groups, 1- hexyls, 1- heptyl, 1- octyl groups, 1- nonyls or 1- decyls；Described " C3~C10Cycloalkanes
The C of base substitution1~C20Alkyl " described in " C3~C10Cycloalkyl " preferably C3~C6Cycloalkyl, described " C3~C6
Cycloalkyl " preferably cyclopropyl；Described " C3~C10Cycloalkyl substitution C1~C20Alkyl " preferably)。R3、
R4、R5、R6、R7And R8It is independently each C1~C12Alkyl (described " C1~C12Alkyl " preferably C1~C6Alkyl, institute
" the C stated1~C6Alkyl " such as methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, 1- amyl groups, 2- penta
Base, 3- amyl groups, 1- hexyls, 2- hexyls or 3- hexyls) or C5~C10Aryl (described " C5~C10Aryl " preferably phenyl).
R9For C3~C12Heterocyclylalkyl (described " C3~C12Heterocyclylalkyl " preferably hetero atom be oxygen, sulphur or nitrogen-atoms, hetero atom
Number is the C of 1~33~C5Heterocyclylalkyl, it is described that " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is the C of 1~33
~C5Heterocyclylalkyl " preferred morpholinyl, described " morpholinyl " is preferably).M is 1,2,3,4,5,6,7,8,9 or 10.
In the present invention, the further preferably following any substituents of described R：
In the present invention, described RCF2The further preferably following any compounds of H,
In the present invention, " inert gas " described in described " inert gas shielding " can be the generic operation in this area
GPF (General Protection False gas, the one or more in the present invention preferably in helium, neon, argon gas and nitrogen.
In the present invention, described organic solvent can be the conventional organic solvent of such coupling reaction in this area, this hair
One kind or many in bright in particularly preferred ether solvent, halogenated hydrocarbon solvent, amide solvent, nitrile solvents and aromatic hydrocarbon solvent
Kind.The preferred dioxane of described ether solvent, tetrahydrofuran, glycol dimethyl ether and one kind in diethylene glycol dimethyl ether or
It is a variety of；The preferred dichloromethane of described chlorinated hydrocarbon solvent and/or 1,2 ,-dichloroethanes；The preferred N of described amide solvent,
Dinethylformamide and/or DMAC N,N' dimethyl acetamide；The preferred acetonitrile of described nitrile solvents；Described aromatic hydrocarbon solvent is excellent
Select toluene.
In the present invention, described organic solvent is preferably except the organic solvent of deoxidation.Organic solvent can except the operation of deoxidation
With according to the routine operation of organic solvent deoxygenation in this area, such as bubbling deoxygenation.
In the present invention, described organic solvent and described RX Molar are than preferred 1mL/mmol~100mL/
mmol。
In the present invention, described TMSCF2H and described RX molar ratio preferably 5~1.
In the present invention, described palladium catalyst is excellent in the palladium catalyst commonly used in coupling reaction in this area, the present invention
Select (dibenzalacetone) palladium (Pd (dba)2), three (dibenzalacetone) two palladium (Pd2(dba)3), tetrakis triphenylphosphine palladium (Pd
(PPh3)4), palladium bichloride (PdCl2), palladium bromide (PdBr2), palladium iodide (PdI2), palladium (Pd (OAc)2), palladium trifluoroacetate
(Pd(TFA)2), a hydration trifluoromethanesulfonic acid palladium (Pd (OTf)2(H2O)), four acetonitriles close trifluoromethanesulfonic acid palladium (Pd (OTf)2
(MeCN)4), four acetonitrile p-methyl benzenesulfonic acid palladium (Pd (OTs)2(MeCN)4), diacetonitrile close palladium bichloride (PdCl2(MeCN)2), hexichol
Nitrile closes palladium bichloride (PdCl2(PhCN)2), tetramino close palladium bichloride (PdCl2(NH3)4), two (triphenylphosphine) palladium bichloride (PdCl2
(PPh3)2), four acetonitriles close fluoboric acid palladium (Pd (BF4)2(MeCN)4), palladium nitrate (Pd (NO3)2), double (diphenylphosphines) two of 1,1'-
Luxuriant iron palladium chloride ((dppf) PdCl2) and diacetyl acetone palladium (Pd (acac)2) in one or more.
In the present invention, the molar ratio preferably 0.0001~0.1 of described palladium catalyst and described RX.
In the present invention, described alkali is the conventional alkali being engaged in this area during coupling reaction with palladium catalyst, the present invention
In preferably inorganic base, the preferred sodium tert-butoxide (NaO of described inorganic basetBu), potassium tert-butoxide (KOtBu), Methanaminium, N,N,N-trimethyl-, fluoride
(Me4NF), tetrabutyl ammonium fluoride (TBAF), potassium fluoride (KF), sodium fluoride (NaF), rubidium fluoride RbF (RuF), cesium fluoride (CsF), uncle
Butanol lithium (LiOtBu), the one or more in sodium methoxide (NaOMe), lithium methoxide (LiOMe) and potassium methoxide (KOMe).
In the present invention, described alkali and compound R X molar ratio preferably 5~1.
In the present invention, described part is preferred in the conventional ligands coordinated with Metal Palladium in this area, the present invention
Double (diphenylphosphine) ferrocene (dppf) of 1,1'-, double diphenylphosphine methane (dppm), 1,2 pairs of (diphenylphosphine) ethane (dppe),
Double (diphenylphosphine) propane (dppp) of 1,3-, 1,1'- dinaphthalenes -2,2'- double diphenyl phosphine (Binap), triphenylphosphine (PPh3), three uncles
Butyl phosphine (PtBu3), tricyclohexyl phosphine (PCy3), 4,5- double diphenylphosphine -9,9- dimethyl xanthene (Xantphos), double (2-
Diphenylphosphine phenyl) ether (DPEPhos), (2- dicyclohexyl phosphino- -3,6- dimethoxys -2', 4', 6'- tri-terts -1,1'-
Biphenyl) [2- (2- amino-ethyls phenyl)] palladium (II) (BrettPhos), the phenyl -1'- of 1,2,3,4,5- penta (di-t-butyl phosphorus base)
Ferrocene (Q-Phos), (R) -1- [(S) -2- (dicyclohexyl phosphino-) ferrocenyl] ethyl dicyclohexylphosphontetrafluoroborate (Josiphos),
Isosorbide-5-Nitrae-bis- (diphenylphosphine) butane (dppb), 1,10 Féraud beautiful jades (1,10-phen), 2,2- bipyridyls (Bypyridine) and tetramethyl
One or more in base ethylenediamine (TMEDA).
In the present invention, described part and the molar ratio of palladium catalyst preferably 3~0.5.
In the present invention, preferably 25 DEG C~150 DEG C of described coupling reaction temperature.
In the present invention, described coupling reaction process can use in this area traditional test methods (such as TLC,
HPLC or NMR) it is monitored, as reaction end when typically being disappeared using compound R X, preferably 1 hour~48 hours reaction time.
In the present invention, described coupling reaction can be carried out under conditions of additive presence, and described additive is this
Double (2, the 6- diisopropyl benzenes of preferably 1,3- in the conventional additives used cooperatively in field with palladium catalyst, the present invention
Base) -4,5- glyoxalidine silver chlorate (SIPrAgCl), double (2,6- the diisopropyl phenyl)-imidazoles silver chlorates of 1,3-
(IPrAgCl), double (2,4,6- the trimethylphenyls) -4,5- glyoxalidine silver chlorates (SIMesAgCl) of 1,3-, the double (2,4,6- of 1,3-
Trimethylphenyl)-imidazoles silver chlorate (ImesAgCl), 1,3- dicyclohexyls-imidazoles silver chlorate (ICyAgCl), pivalic acid silver
(AgOPiv), silver nitrate (AgNO3), silver trifluoromethanesulfonate (AgOTf), hexafluorophosphoric acid silver (AgPF6), silver hexafluoroantimonate
(AgSbF6), silver tetrafluoroborate (AgBF4), silver acetate (AgOAc), silver carbonate (Ag2CO3), silver oxide (Ag2O), silver fluoride
(AgF), stannous chloride (CuCl), cuprous bromide (CuBr), cuprous iodide (CuI), copper sulphate (CuSO4), copper nitrate (Cu
(NO3)2), iron chloride (FeCl3), frerrous chloride (FeCl2) and ferrous sulfate (FeSO4) in one or more.
In the present invention, when described coupling reaction is carried out under conditions of additive presence, described additive and institute
The RX stated molar ratio preferably 0.001~1.
In the present invention, when X is iodine, it is preferred to use following reaction condition：
In the present invention, " inert gas " described in described " inert gas shielding " can be the generic operation in this area
GPF (General Protection False gas, the one or more in the present invention preferably in helium, neon, argon gas and nitrogen.
In the present invention, described organic solvent can be the conventional organic solvent of such coupling reaction in this area, this hair
One kind or many in bright in particularly preferred ether solvent, halogenated hydrocarbon solvent, amide solvent, nitrile solvents and aromatic hydrocarbon solvent
Kind.The preferred dioxane of described ether solvent, tetrahydrofuran, glycol dimethyl ether and one kind in diethylene glycol dimethyl ether or
It is a variety of, further preferred dioxane and/or tetrahydrofuran.The preferred chlorinated hydrocarbon solvent of described halogenated hydrocarbon solvent；It is described
The preferred dichloromethane of chlorinated hydrocarbon solvent and/or 1,2 ,-dichloroethanes；The preferred N of described amide solvent, N- dimethyl methyls
Acid amides and/or DMAC N,N' dimethyl acetamide；The preferred acetonitrile of described nitrile solvents；The preferred toluene of described aromatic hydrocarbon solvent.Institute
The further preferred dioxane of organic solvent stated, tetrahydrofuran, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, first
Benzene, dioxane and the mixed solvent of tetrahydrofuran, the mixed solvent or dioxane and ethylene glycol of dioxane and acetonitrile
The mixed solvent of dimethyl ether.When using dioxane and tetrahydrofuran mixed solvent when, described dioxane with it is described
Tetrahydrofuran volume ratio preferably 1~5, further preferred 1~3.When using dioxane and acetonitrile mixed solvent
When, the volume ratio preferably 1~5, further preferred 1~3 of described dioxane and described acetonitrile.When using dioxane
With glycol dimethyl ether mixed solvent when, the volume ratio of described dioxane and described glycol dimethyl ether is preferred
1~5, further preferred 1~3.
In the present invention, described organic solvent and described RX Molar are than preferred 1mL/mmol~100mL/
Mmol, further preferred 1mL/mmol~10mL/mmol.
In the present invention, described TMSCF2H and described RX molar ratio preferably 5~1, further preferred 5~2, then
Further preferred 2.4~2.
In the present invention, described palladium catalyst is excellent in the palladium catalyst commonly used in coupling reaction in this area, the present invention
Select (dibenzalacetone) palladium (Pd (dba)2), three (dibenzalacetone) two palladium (Pd2(dba)3), tetrakis triphenylphosphine palladium (Pd
(PPh3)4), palladium bichloride (PdCl2), palladium bromide (PdBr2), palladium iodide (PdI2), palladium (Pd (OAc)2), palladium trifluoroacetate
(Pd(TFA)2), a hydration trifluoromethanesulfonic acid palladium (Pd (OTf)2(H2O)), four acetonitriles close trifluoromethanesulfonic acid palladium (Pd (OTf)2
(MeCN)4), four acetonitrile p-methyl benzenesulfonic acid palladium (Pd (OTs)2(MeCN)4), diacetonitrile close palladium bichloride (PdCl2(MeCN)2), hexichol
Nitrile closes palladium bichloride (PdCl2(PhCN)2), tetramino close palladium bichloride (PdCl2(NH3)4), two (triphenylphosphine) palladium bichloride (PdCl2
(PPh3)2), four acetonitriles close fluoboric acid palladium (Pd (BF4)2(MeCN)4), palladium nitrate (Pd (NO3)2), double (diphenylphosphines) two of 1,1'-
Luxuriant iron palladium chloride ((dppf) PdCl2) and diacetyl acetone palladium (Pd (acac)2) in one or more.Further preferably (two
BENZYLIDENE ACETONE) palladium (Pd (dba)2), three (dibenzalacetone) two palladium (Pd2(dba)3), tetrakis triphenylphosphine palladium (Pd
(PPh3)4), palladium bichloride (PdCl2) and double (diphenylphosphine) ferrocene palladium chloride ((dppf) PdCl of 1,1'-2) in one kind or
It is a variety of, still further preferably (dibenzalacetone) palladium (Pd (dba)2) and/or three (dibenzalacetone) two palladium (Pd2
(dba)3)。
In the present invention, the molar ratio preferably 0.0001~0.1 of described palladium catalyst and described RX, further preferably
0.01~0.1, still further preferably 0.02~0.1.
In the present invention, described alkali is the conventional alkali being engaged in this area during coupling reaction with palladium catalyst, the present invention
In preferably inorganic base, the preferred sodium tert-butoxide (NaO of described inorganic basetBu), potassium tert-butoxide (KOtBu), Methanaminium, N,N,N-trimethyl-, fluoride
(Me4NF), tetrabutyl ammonium fluoride (TBAF), potassium fluoride (KF), sodium fluoride (NaF), rubidium fluoride RbF (RuF), cesium fluoride (CsF), uncle
Butanol lithium (LiOtBu), the one or more in sodium methoxide (NaOMe), lithium methoxide (LiOMe) and potassium methoxide (KOMe), further
It is preferred that sodium tert-butoxide (NaOtBu), Methanaminium, N,N,N-trimethyl-, fluoride (Me4NF) and the one or more in cesium fluoride (CsF), it is further excellent
Select sodium tert-butoxide (NaOtBu)。
In the present invention, described alkali and compound R X molar ratio preferably 5~1, further preferred 3~1.
In the present invention, described part is preferred in the conventional ligands coordinated with Metal Palladium in this area, the present invention
Double (diphenylphosphine) ferrocene (dppf) of 1,1'-, double diphenylphosphine methane (dppm), 1,2 pairs of (diphenylphosphine) ethane (dppe),
Double (diphenylphosphine) propane (dppp) of 1,3-, 1,1'- dinaphthalenes -2,2'- double diphenyl phosphine (Binap), triphenylphosphine (PPh3), three uncles
Butyl phosphine (PtBu3), tricyclohexyl phosphine (PCy3), 4,5- double diphenylphosphine -9,9- dimethyl xanthene (Xantphos), double (2-
Diphenylphosphine phenyl) ether (DPEPhos), (2- dicyclohexyl phosphino- -3,6- dimethoxys -2', 4', 6'- tri-terts -1,1'-
Biphenyl) [2- (2- amino-ethyls phenyl)] palladium (II) (BrettPhos), the phenyl -1'- of 1,2,3,4,5- penta (di-t-butyl phosphorus base)
Ferrocene (Q-Phos), (R) -1- [(S) -2- (dicyclohexyl phosphino-) ferrocenyl] ethyl dicyclohexylphosphontetrafluoroborate (Josiphos),
Isosorbide-5-Nitrae-bis- (diphenylphosphine) butane (dppb), 1,10 Féraud beautiful jades (1,10-phen), 2,2- bipyridyls (Bypyridine) and tetramethyl
One or more in base ethylenediamine (TMEDA).Further preferred 1,1'- double (diphenylphosphine) ferrocene (dppf), double hexichol
Base methane diphosphonate (dppm), 1,2 pairs of (diphenylphosphine) ethane (dppe), double (diphenylphosphine) propane (dppp) of 1,3-, 1,1'- connection
The double diphenyl phosphines (Binap) of naphthalene -2,2'-, 4,5- double diphenylphosphine -9,9- dimethyl xanthene (Xantphos), double (2- diphenyl
Phosphorus phenyl) one or more in ether (DPEPhos) and Isosorbide-5-Nitrae-bis- (diphenylphosphines) butane (dppb), still further preferably 1,
Double (diphenylphosphine) ferrocene (dppf) of 1'-, the double diphenylphosphine -9,9- dimethyl xanthenes (Xantphos) of 4,5- and double (2-
Diphenylphosphine phenyl) one or more in ether (DPEPhos), optimal is double (diphenylphosphine) ferrocene (dppf) of 1,1'-.
In the present invention, described part and compound R X molar ratio preferably 0.01~1, further preferred 0.025~
0.5, still further preferably 0.05~0.3, optimal is 0.1~0.15.
In the present invention, preferably 25 DEG C~150 DEG C of the temperature of described coupling reaction, further preferred 60 DEG C~100 DEG C, then
Further preferred 70 DEG C~100 DEG C, optimal is 80 DEG C~90 DEG C.
In the present invention, the process of described coupling reaction can use in this area traditional test methods (such as TLC,
HPLC or NMR) it is monitored, as reaction end when typically being disappeared using compound R X, preferably 1 hour~48 hours reaction time,
Further preferred 2 hours~30 hours, still further preferably 3 hours~4 hours.
In the present invention, described coupling reaction can be carried out under conditions of additive presence, and described additive is this
Double (2, the 6- diisopropyl benzenes of preferably 1,3- in the conventional additives used cooperatively in field with palladium catalyst, the present invention
Base) -4,5- glyoxalidine silver chlorate (SIPrAgCl), double (2,6- the diisopropyl phenyl)-imidazoles silver chlorates of 1,3-
(IPrAgCl), double (2,4,6- the trimethylphenyls) -4,5- glyoxalidine silver chlorates (SIMesAgCl) of 1,3-, the double (2,4,6- of 1,3-
Trimethylphenyl)-imidazoles silver chlorate (ImesAgCl), 1,3- dicyclohexyls-imidazoles silver chlorate (ICyAgCl), pivalic acid silver
(AgOPiv), silver nitrate (AgNO3), silver trifluoromethanesulfonate (AgOTf), hexafluorophosphoric acid silver (AgPF6), silver hexafluoroantimonate
(AgSbF6), silver tetrafluoroborate (AgBF4), silver acetate (AgOAc), silver carbonate (Ag2CO3), silver oxide (Ag2O), silver fluoride
(AgF), stannous chloride (CuCl), cuprous bromide (CuBr), cuprous iodide (CuI), copper sulphate (CuSO4), copper nitrate (Cu
(NO3)2), iron chloride (FeCl3), frerrous chloride (FeCl2) and ferrous sulfate (FeSO4) in one or more.Further preferably
1,3- double (2,6- diisopropyl phenyl) -4,5- glyoxalidine silver chlorates (SIPrAgCl), 1,3- double (2,4,6- trimethylphenyls) -
Double (2,4,6- the trimethylphenyls)-imidazoles silver chlorates (ImesAgCl) of 4,5- glyoxalidine silver chlorate (SIMesAgCl), 1,3-, spy
Valeric acid silver (AgOPiv), silver nitrate (AgNO3), silver trifluoromethanesulfonate (AgOTf), silver hexafluoroantimonate (AgSbF6), silver tetrafluoroborate
(AgBF4), the one or more in stannous chloride (CuCl) and cuprous iodide (CuI), still further preferably 1,3- double (2,6- bis-
Isopropyl phenyl) -4,5- glyoxalidine silver chlorate (SIPrAgCl), double (2,4,6- trimethylphenyl) -4, the 5- glyoxalidine of 1,3-
Silver chlorate (SIMesAgCl), silver nitrate (AgNO3) and silver hexafluoroantimonate (AgSbF6) in one or more, most preferably 1,3- is double
(2,6- diisopropyl phenyl) -4,5- glyoxalidine silver chlorate (SIPrAgCl).
In the present invention, when described coupling reaction is carried out under conditions of additive presence, described additive and institute
The RX stated molar ratio preferably 0.025~1, further preferred 0.08~1, still further preferably 0.1~1.
In the present invention, when X is bromine, it is preferred to use following reaction condition：
In the present invention, " inert gas " described in described " inert gas shielding " can be the generic operation in this area
Conventional inert gas, the one or more in the present invention preferably in helium, neon, argon gas and nitrogen.
In the present invention, described organic solvent can be the conventional organic solvent of such coupling reaction in this area, this hair
One kind or many in bright in particularly preferred ether solvent, halogenated hydrocarbon solvent, amide solvent, nitrile solvents and aromatic hydrocarbon solvent
Kind.The preferred dioxane of described ether solvent, tetrahydrofuran, glycol dimethyl ether and one kind in diethylene glycol dimethyl ether or
It is a variety of, further preferred dioxane and/or tetrahydrofuran.The preferred chlorinated hydrocarbon solvent of described halogenated hydrocarbon solvent；It is described
The preferred dichloromethane of chlorinated hydrocarbon solvent and/or 1,2 ,-dichloroethanes；The preferred N of described amide solvent, N- dimethyl methyls
Acid amides and/or DMAC N,N' dimethyl acetamide；The preferred acetonitrile of described nitrile solvents；The preferred toluene of described aromatic hydrocarbon solvent.Institute
The mixing of the further preferred dioxane of organic solvent, tetrahydrofuran, dichloromethane, toluene, toluene and the tetrahydrofuran stated is molten
Agent, the mixed solvent of dioxane and toluene, the mixed solvent or toluene and glycol dimethyl ether of toluene and acetonitrile mixing it is molten
Agent.When the mixed solvent using toluene and tetrahydrofuran, the volume ratio preferably 1 of described toluene and described tetrahydrofuran
~5, further preferred 1~3.When the mixed solvent using dioxane and toluene, described dioxane and described first
The volume ratio of benzene preferably 1~5, further preferred 1~3.When using toluene and acetonitrile mixed solvent when, described dioxy
The volume ratio preferably 1~5, further preferred 1~3 of six rings and described glycol dimethyl ether.When using toluene and second two
During the mixed solvent of diethylene glycol dimethyl ether, the volume ratio preferably 1~5 of described toluene and described glycol dimethyl ether, further
It is preferred that 1~3.
In the present invention, described organic solvent and described RX Molar are than preferred 1mL/mmol~100mL/
Mmol, further preferred 1mL/mmol~10mL/mmol.
In the present invention, described TMSCF2H and described RX molar ratio preferably 5~1, further preferred 5~2, then
Further preferred 3~2, optimal is 2.4.
In the present invention, described palladium catalyst is excellent in the palladium catalyst commonly used in coupling reaction in this area, the present invention
Select (dibenzalacetone) palladium (Pd (dba)2), three (dibenzalacetone) two palladium (Pd2(dba)3), tetrakis triphenylphosphine palladium (Pd
(PPh3)4), palladium bichloride (PdCl2), palladium bromide (PdBr2), palladium iodide (PdI2), palladium (Pd (OAc)2), palladium trifluoroacetate
(Pd(TFA)2), a hydration trifluoromethanesulfonic acid palladium (Pd (OTf)2(H2O)), four acetonitriles close trifluoromethanesulfonic acid palladium (Pd (OTf)2
(MeCN)4), four acetonitrile p-methyl benzenesulfonic acid palladium (Pd (OTs)2(MeCN)4), diacetonitrile close palladium bichloride (PdCl2(MeCN)2), hexichol
Nitrile closes palladium bichloride (PdCl2(PhCN)2), tetramino close palladium bichloride (PdCl2(NH3)4), two (triphenylphosphine) palladium bichloride (PdCl2
(PPh3)2), four acetonitriles close fluoboric acid palladium (Pd (BF4)2(MeCN)4), palladium nitrate (Pd (NO3)2), double (diphenylphosphines) two of 1,1'-
Luxuriant iron palladium chloride ((dppf) PdCl2) and diacetyl acetone palladium (Pd (acac)2) in one or more.Further preferably (two
BENZYLIDENE ACETONE) palladium (Pd (dba)2), three (dibenzalacetone) two palladium (Pd2(dba)3), tetrakis triphenylphosphine palladium (Pd
(PPh3)4) and double (diphenylphosphine) ferrocene palladium chloride ((dppf) PdCl of 1,1'-2) in one or more, further
It is preferred that (dibenzalacetone) palladium (Pd (dba)2) and/or three (dibenzalacetone) two palladium (Pd2(dba)3)。
In the present invention, the molar ratio preferably 0.0001~0.1 of described palladium catalyst and described RX, further preferably
0.01~0.1, still further preferably 0.05~0.1.
In the present invention, described alkali is the conventional alkali being engaged in this area during coupling reaction with palladium catalyst, the present invention
In preferably inorganic base, the preferred sodium tert-butoxide (NaO of described inorganic basetBu), potassium tert-butoxide (KOtBu), Methanaminium, N,N,N-trimethyl-, fluoride
(Me4NF), tetrabutyl ammonium fluoride (TBAF), potassium fluoride (KF), sodium fluoride (NaF), rubidium fluoride RbF (RuF), cesium fluoride (CsF), uncle
Butanol lithium (LiOtBu), the one or more in sodium methoxide (NaOMe), lithium methoxide (LiOMe) and potassium methoxide (KOMe), further
It is preferred that sodium tert-butoxide (NaOtBu), Methanaminium, N,N,N-trimethyl-, fluoride (Me4NF) and the one or more in cesium fluoride (CsF), it is further excellent
Select sodium tert-butoxide (NaOtBu)。
In the present invention, described alkali and compound R X molar ratio preferably 5~1, further preferred 3~1.
In the present invention, described part is preferred in the conventional ligands coordinated with Metal Palladium in this area, the present invention
Double (diphenylphosphine) ferrocene (dppf) of 1,1'-, double diphenylphosphine methane (dppm), 1,2 pairs of (diphenylphosphine) ethane (dppe),
Double (diphenylphosphine) propane (dppp) of 1,3-, 1,1'- dinaphthalenes -2,2'- double diphenyl phosphine (Binap), triphenylphosphine (PPh3), three uncles
Butyl phosphine (PtBu3), tricyclohexyl phosphine (PCy3), 4,5- double diphenylphosphine -9,9- dimethyl xanthene (Xantphos), double (2-
Diphenylphosphine phenyl) ether (DPEPhos), (2- dicyclohexyl phosphino- -3,6- dimethoxys -2', 4', 6'- tri-terts -1,1'-
Biphenyl) [2- (2- amino-ethyls phenyl)] palladium (II) (BrettPhos), the phenyl -1'- of 1,2,3,4,5- penta (di-t-butyl phosphorus base)
Ferrocene (Q-Phos), (R) -1- [(S) -2- (dicyclohexyl phosphino-) ferrocenyl] ethyl dicyclohexylphosphontetrafluoroborate (Josiphos),
Isosorbide-5-Nitrae-bis- (diphenylphosphine) butane (dppb), 1,10 Féraud beautiful jades (1,10-phen), 2,2- bipyridyls (Bypyridine) and tetramethyl
One or more in base ethylenediamine (TMEDA).Further preferred 1,1'- double (diphenylphosphine) ferrocene (dppf), double hexichol
Base methane diphosphonate (dppm), 1,2 couples of (diphenylphosphine) ethane (dppe), 1,1'- dinaphthalenes -2,2'- double diphenyl phosphine (Binap), 4,5-
Double diphenylphosphine -9,9- dimethyl xanthenes (Xantphos), double (2- diphenylphosphines phenyl) ethers (DPEPhos) and 1,4- are double
One or more in (diphenylphosphine) butane (dppb), double (diphenylphosphine) ferrocene (dppf) of still further preferably 1,1'-,
In the double diphenylphosphine -9,9- dimethyl xanthenes (Xantphos) of 4,5- and double (2- diphenylphosphines phenyl) ethers (DPEPhos)
One or more, optimal is double (diphenylphosphine) ferrocene (dppf) of 1,1'-.
In the present invention, described part and compound R X molar ratio preferably 0.01~1, further preferred 0.025~
0.5, still further preferably 0.1~0.3.
In the present invention, preferably 25 DEG C~150 DEG C of described coupling reaction temperature, further preferred 60 DEG C~100 DEG C, then enter
Preferably 70 DEG C~100 DEG C of one step, optimal is 80 DEG C~90 DEG C.
In the present invention, described coupling reaction process can use in this area traditional test methods (such as TLC,
HPLC or NMR) it is monitored, as reaction end when typically being disappeared using compound R X, preferably 1 hour~48 hours reaction time,
Further preferred 2 hours~30 hours, still further preferably 3 hours~16 hours, optimal was 4 hours~12 hours.
In the present invention, described coupling reaction can be carried out under conditions of additive presence, and described additive is this
Double (2, the 6- diisopropyl benzenes of preferably 1,3- in the conventional additives used cooperatively in field with palladium catalyst, the present invention
Base) -4,5- glyoxalidine silver chlorate (SIPrAgCl), double (2,6- the diisopropyl phenyl)-imidazoles silver chlorates of 1,3-
(IPrAgCl), double (2,4,6- the trimethylphenyls) -4,5- glyoxalidine silver chlorates (SIMesAgCl) of 1,3-, the double (2,4,6- of 1,3-
Trimethylphenyl)-imidazoles silver chlorate (ImesAgCl), 1,3- dicyclohexyls-imidazoles silver chlorate (ICyAgCl), pivalic acid silver
(AgOPiv), silver nitrate (AgNO3), silver trifluoromethanesulfonate (AgOTf), hexafluorophosphoric acid silver (AgPF6), silver hexafluoroantimonate
(AgSbF6), silver tetrafluoroborate (AgBF4), silver acetate (AgOAc), silver carbonate (Ag2CO3), silver oxide (Ag2O), silver fluoride
(AgF), stannous chloride (CuCl), cuprous bromide (CuBr), cuprous iodide (CuI), copper sulphate (CuSO4), copper nitrate (Cu
(NO3)2), iron chloride (FeCl3), frerrous chloride (FeCl2) and ferrous sulfate (FeSO4) in one or more.Further preferably
1,3- double (2,6- diisopropyl phenyl) -4,5- glyoxalidine silver chlorates (SIPrAgCl), 1,3- double (2,4,6- trimethylphenyls) -
Double (2,4,6- the trimethylphenyls)-imidazoles silver chlorates (ImesAgCl) of 4,5- glyoxalidine silver chlorate (SIMesAgCl), 1,3-, spy
Valeric acid silver (AgOPiv), silver nitrate (AgNO3), silver trifluoromethanesulfonate (AgOTf), silver carbonate (Ag2CO3) and stannous chloride
(CuCl) double (2,6- diisopropyl phenyl) -4,5- glyoxalidine silver chlorates of the one or more in, still further preferably 1,3-
(SIPrAgCl), double (2,4,6- the trimethylphenyls) -4,5- glyoxalidine silver chlorates (SIMesAgCl) of 1,3- and silver nitrate
(AgNO3) in one or more, optimal is double (2,6- diisopropyl phenyl) -4,5- glyoxalidine silver chlorates of 1,3-
(SIPrAgCl)。
In the present invention, when described coupling reaction is carried out under conditions of additive presence, described additive and institute
The RX stated molar ratio preferably 0.001~1, further preferred 0.01~1, still further preferably 0.1~0.2.
Present invention also offers compound R CF2H, wherein, R is defined as above described.
Present invention also offers described compound R CF2H is in the medicine for preparing drug molecule or fluorine-containing difluoromethyl
Application in mesosome, described medicine includes medicine and agricultural chemicals.The compound of fluorine-containing difluoromethyl is preparing drug molecule or doctor
The situation that application such as documents below in medicine intermediate is reported：a)Kirsch,P.Modern Fluoroorganic
Chemistry:Synthesis,Reactivity,Applications；Wiley–VCH:Weinheim,2004.b)Hiyama,
T.Organofluorine Compounds:Chemistry and Properties；Springer-Verlag:Berlin,
2000.c)Uneyama,K.Organofluorine Chemistry；Blackwell:Oxford,U.K.,2006.(d)O’
Hagan,D.Chem.Soc.Rev.2008,37,308.d)Leroux,F.；Jeschke,P.；Schlosser,
M.Chem.Rev.2005,105,827.e)Ma,J.-A.；Cahard,D.Chem.Rev.2004,104,6119；f)Ma,J.-
A.；Cahard,D.Chem.Rev.2008,108,PR1；g)Nie,J.；Guo,H.-C.；Cahard,D.；Ma,J.-
A.Chem.Rev.2011,111,455.g)Tozer,M.J.；Herpin,T.F.Tetrahedron,1996,52,8619；h)
Shimizu,M.；Hiyami,T.Angew.Chem.Int.Ed.2005,44,214；i)Hu,J.-B.；Zhang,W.；Wang,
F.Chem.Commun.2009,7465.j)Markovski,L.N.；Pahinnik,V.E.；Kirsanov,
A.V.Synthesis1973,787；k)Kuroboshi,M.；Hiyama,T.Synlett1991,909.
In the present invention, when not specifying, described " alkyl " is to include with specified carbon number purpose branch
The saturated aliphatic hydrocarbons of chain or straight chain；Such as in " C1~C20Have defined in alkyl " to be included in straight chain or branched structure
1st, 2,3,4,5,6,7,8,9,11,11,12,13,14,15,16,17, the 18, group of 19 or 20 carbon atoms.For example, " C1
~C10Alkyl " specifically include methyl, ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, amyl group, hexyl, heptyl,
Octyl group, nonyl and decyl etc..
In the present invention, when not specifying, described " cycloalkyl " refers to that full carbon is monocyclic or polycyclic moiety, wherein often
Individual ring can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Such as 3~20 carbon
The cycloalkyl of 1~3 ring formed, the cycloalkyl of 1 ring of 3~12 carbon formation is for example：Cyclopropyl, cyclobutyl, ring penta
Base, cyclohexyl, suberyl, cyclooctyl, cyclodecane and cyclo-dodecyl.
In the present invention, when not specifying, described " aryl " refer to any stabilization in each ring may be up to 7
The monocyclic or bicyclic carbocyclic of individual atom, wherein at least one ring is aromatic rings；The example of above-mentioned aryl unit includes phenyl, naphthalene
Base, tetralyl, indanyl, xenyl, phenanthryl, anthryl or acenaphthenyl (acenaphthyl).It is appreciated that
In the case of aryl substituent is two ring substituents, and one of ring is non-aromatic ring, connection is carried out by aromatic ring.
In the present invention, when not specifying, described " heteroaryl " represents in each ring the steady of up to 7 atoms
Order ring or two rings, wherein at least one ring are aromatic rings and the hetero atoms selected from O, N and S containing 1-4；Define herein
In the range of heteroaryl include but is not limited to：Acridinyl, carbazyl, cinnolines base, quinoxalinyl, pyrazolyl, indyl, benzo three
Oxazolyl, furyl, thienyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyls, indoles
Base, pyrazinyl, pyridazinyl, pyridine radicals, pyrimidine radicals, pyrrole radicals, tetrahydroquinoline." heteroaryl " is it should also be understood that be to include any contain
The N- oxide derivatives of azepine aryl.Wherein heteroaryl substituent be two ring substituents and a ring be non-aromatic ring or
Person do not include it is heteroatomic in the case of, it will be understood that connection is carried out by aromatic ring or by hetero atom comprising ring respectively.
In the present invention, when not specifying, described " Heterocyclylalkyl " is herein individually or as another group
A part in use, referring to 4~12 unit monocycles or many for including 1~4 hetero atom (one or more in such as nitrogen, oxygen and sulphur)
Cyclic group, wherein each ring can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.
In addition, any heterocycloalkyl ring can be condensed on cycloalkyl, aryl, heteroaryl or heterocycloalkyl ring.Within the range defined herein
Heterocyclylalkyl include but is not limited to：Oxazoline, oxygen cyclobutyl, pyranose, THP trtrahydropyranyl, azetidinyl, 1,4- bis-
Oxane base, hexahydro azatropylidene base, piperazinyl, piperidyl, pyrrolidinyl, morpholinyl, thio-morpholinyl, dihydrofuran base, dihydro
Imidazole radicals, indolinyl, dihydro-isoxazole base, dihydro isothiazolyl, Er Qing oxadiazolyls, dihydro-oxazole base, dihydro pyrazine
Base, pyrazoline base, dihydropyridine base, dihydro-pyrimidin base, pyrrolin base, dihydro tetrazole radical, thiodiazoline base, dihydro thiophene
Oxazolyl, dihydro-thiophene base, dihydro triazolyl, dihydro azetidinyl, tetrahydrofuran base and tetrahydro-thienyl and its N- oxidations
Thing.Heterocyclylalkyl can be attached through carbon atom therein or hetero atom with other groups.
In the present invention, when not specifying, described " halogen " represents fluorine, chlorine, bromine, iodine or astatine.
In the present invention, the described " C that carbon number range is determinedx1~Cy1" substituent (x1 be with y1 integers), such as " Cx1
~Cy1" alkyl, " Cx1~Cy1" alkoxy, " Cx1~Cy1" aryl, " Cx1~Cy1" heteroaryl or " Cx1~Cy1" alkane
Epoxide carbonyl, represents not include the carbon number of substituent, such as C1~C20Alkyl represents not include the C of substituent1~C20Alkyl.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and produce the present invention each preferably
Example.
Agents useful for same and raw material of the present invention are commercially available.
In the present invention, described room temperature refers to environment temperature, is 10 DEG C~35 DEG C.
The positive effect of the present invention is：The difluoromethylization reaction of the present invention can be realized and aryl iodide, aryl
A variety of aryl halides bromine and natural products (such as oestrone or vitamin E) realize difluoromethyl, such reaction condition
Gently, raw material is cheap and easy to get, reaction conversion ratio is high, group is compatible good, with good market application foreground.
Embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Apply among a scope.The experimental method of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product specification is selected.
The difluoromethyl repercussion study for the iodo aromatic hydrocarbon (RI) that the palladium of embodiment 1 is participated in
Under conditions of argon gas, by 4- phenyl iodobenzene (0.1mmol), trimethyl difluoromethyl silicon, palladium catalyst, addition
Agent, part and alkali are dissolved in dry deoxygenation solvent with corresponding ratio in form, are heated to the temperature listed in form, reaction
To after the time listed by form, the benzotrifluoride of equal proportion is added as internal standard, yield is determined by fluorine spectrum.Urged for palladium
The screening of agent is shown in Table 1, and the screening for additive is shown in Table 2, and the screening for alkali is shown in Table 3, and the screening for solvent is shown in Table 4,
Screening for part is shown in Table 5, and the screening for reaction temperature is shown in Table 6, and the screening for the reaction time is shown in Table 7, is urged for palladium
The screening of agent dosage is shown in Table 8, and the screening for additive dosage is shown in Table 9, and the screening for part dosage is shown in Table 10,
For TMSCF2Screening with alkali dosage is shown in Table 11.
Under conditions of argon gas, the trimethyl difluoromethyl silicon of 4- phenyl iodobenzene and 2.4 equivalents (2.4eq) be coupled instead
Should, using 2.0 equivalent sodium tert-butoxides as alkali, using dioxane as solvent, Molar ratio is 10L/mol (described Molars
Than the ratio for referring to solvent volume and the mole of 4- phenyl iodobenzenes), the palladium catalyst that mol ratio is 5% is added, mol ratio is
10% part dppf, mol ratio is 20% additive SIPrAgCl, 80 DEG C, is reacted 4 hours, it is specific that palladium catalyst is screened
Data are shown in Table 1.
The screening table of the palladium catalyst of table 1
| Numbering | The species of palladium catalyst | Fluorine spectrum (19FNMR) yield (%) |
| 1 | Pd(dba)2 | 90 |
| 2 | Pd2(dba)3 | 85 |
| 3 | Pd(PPh3)4 | 56 |
| 4 | PdCl2 | 43 |
| 5 | PdBr2 | 10 |
| 6 | PdI2 | 7 |
| 7 | Pd(OAc)2 | 12 |
| 8 | Pd(TFA)2 | 16 |
| 9 | Pd(OTf)2(H2O) | ＜ 5 |
| 10 | Pd(OTf)2(MeCN)4 | 15 |
| 11 | Pd(OTs)2(MeCN)4 | 11 |
| 12 | PdCl2(MeCN)2 | 9 |
| 13 | PdCl2(PhCN)2 | ＜ 5 |
| 14 | PdCl2(NH3)4 | 7 |
| 15 | PdCl2(PPh3)2 | 11 |
| 16 | Pd(BF4)2(MeCN)4 | ＜ 5 |
| 17 | Pd(NO3)2 | 23 |
| 18 | (dppf)PdCl2 | 45 |
| 19 | Pd(acac)2 | 6 |
Under conditions of argon gas, 4- phenyl iodobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, work as with 2
Amount sodium tert-butoxide is alkali, using dioxane as solvent, and Molar ratio is that (described Molar ratio refers to solvent to 10L/mol
The ratio of volume and the mole of 4- phenyl iodobenzenes), the palladium catalyst Pd (dba) that addition mol ratio is 5%2, mol ratio is
10% part dppf, mol ratio is 20% additive, 80 DEG C, is reacted 4 hours, the specific data of selection of additives are shown in Table 2.
The screening table of the additive of table 2
| Numbering | The species of additive | Fluorine spectrum (19FNMR) yield (%) |
| 1 | SIPrAgCl | 90 |
| 2 | IPrAgCl | ＜ 5 |
| 3 | SIMesAgCl | 56 |
| 4 | IMesAgCl | 41 |
| 5 | ICyAgCl | 21 |
| 6 | AgOPiv | 49 |
| 7 | AgOTf | 36 |
| 8 | AgPF6 | ＜ 5 |
| 9 | AgSbF6 | 55 |
| 10 | AgBF4 | 36 |
| 11 | AgOAc | 18 |
| 12 | Ag2CO3 | 22 |
| 13 | Ag2O | 7 |
| 14 | AgF | 21 |
| 15 | CuCl | 35 |
| 16 | CuBr | 33 |
| 17 | CuI | 42 |
| 18 | CuSO4 | 6 |
| 19 | Cu(NO3)2 | 8 |
| 20 | FeCl3 | 6 |
| 21 | FeCl2 | 7 |
| 22 | FeSO4 | 12 |
| 23 | Nothing | 34 |
Under conditions of argon gas, 4- phenyl iodobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, 2 equivalents
Alkali, using dioxane as solvent, Molar ratio be 10L/mol (described Molar ratio refers to solvent volume and 4- benzene
The ratio of the mole of base iodobenzene), addition mol ratio is 5% palladium catalyst Pd (dba)2, mol ratio is 10% part dppf,
Mol ratio is additive 20%SIPrAgCl, 80 DEG C, is reacted 4 hours, and the specific data of alkali screening are shown in Table 3.
The screening table of the alkali of table 3
| Numbering | The species of alkali | Fluorine spectrum (19FNMR) yield (%) |
| 1 | Sodium tert-butoxide | 90 |
| 2 | Potassium tert-butoxide | 15 |
| 3 | Methanaminium, N,N,N-trimethyl-, fluoride | 36 |
| 4 | Tetrabutyl ammonium fluoride | 11 |
| 5 | Potassium fluoride | 6 |
| 6 | Sodium fluoride | 5 |
| 7 | Rubidium fluoride RbF | 7 |
| 8 | Cesium fluoride | 36 |
| 9 | Tert-butyl alcohol lithium | ＜ 5 |
| 10 | Sodium methoxide | 5 |
| 11 | Lithium methoxide | 4 |
| 12 | Potassium methoxide | 8 |
Under conditions of argon gas, 4- phenyl iodobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, work as with 2
The sodium tert-butoxide of amount is alkali, addition 5%Pd (dba)2, mol ratio is 10% part dppf, and mol ratio is 20% additive
SIPrAgCl, reacts 4 hours by 80 DEG C, and for 10L/mol, (described Molar ratio refers to the Molar added the ratio of solvent
The ratio of the mole of solvent volume and 4- phenyl iodobenzenes) the specific data of solvent screening are shown in Table 4.
The screening table of the solvent of table 4
Under conditions of argon gas, 4- phenyl iodobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, work as with 2
The sodium tert-butoxide of amount is alkali, using dioxane as solvent, and Molar ratio is that (described Molar ratio refers to molten 10L/mol
The ratio of agent volume and the mole of 4- phenyl iodobenzenes), the palladium catalyst Pd (dba) that addition mol ratio is 5%2, mol ratio is
10% part, mol ratio is 20% additive SIPrAgCl, 80 DEG C, is reacted 4 hours, the specific data of ligand screening are shown in Table
5。
The screening table of the part of table 5
| Numbering | The species of part | Fluorine spectrum (19FNMR) yield (%) |
| 1 | dppf | 90 |
| 2 | dppm | 35 |
| 3 | dppe | 46 |
| 4 | dppp | 37 |
| 5 | Binap | 42 |
| 6 | PPh3 | 9 |
| 7 | PtBu3 | ＜ 5 |
| 8 | PCy3 | 6 |
| 9 | Xantphos | 65 |
| 10 | DPEPhos | 63 |
| 11 | BrettPhos | ＜ 5 |
| 12 | Q-Phos | 7 |
| 13 | Josiphos | 6 |
| 14 | dppb | 27 |
| 15 | 1,10-phen | 15 |
| 16 | Bypyridine | 12 |
| 17 | TMEDA | 6 |
Under conditions of argon gas, 4- phenyl iodobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, work as with 2
The sodium tert-butoxide of amount is alkali, using dioxane as solvent, and Molar ratio is that (described Molar ratio refers to molten 10L/mol
The ratio of agent volume and the mole of 4- phenyl iodobenzenes), the palladium catalyst Pd (dba) that addition mol ratio is 5%2, mol ratio is
10% part, mol ratio is 20% additive SIPrAgCl, is reacted 4 hours, and the specific data of reaction temperature screening are shown in Table
6。
The screening table of the reaction temperature of table 6
| Numbering | Reaction temperature (DEG C) | Fluorine spectrum (19FNMR) yield (%) |
| 1 | 100 | 70 |
| 2 | 90 | 80 |
| 3 | 80 | 90 |
| 4 | 70 | 67 |
| 5 | 60 | 52 |
| 6 | 50 | 39 |
| 7 | 40 | 35 |
| 8 | 30 | 26 |
| 9 | 25 | 5 |
Under conditions of argon gas, 4- phenyl iodobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, work as with 2
The sodium tert-butoxide of amount is alkali, using dioxane as solvent, and Molar ratio is that (described Molar ratio refers to molten 10L/mol
The ratio of agent volume and the mole of 4- phenyl iodobenzenes), the palladium catalyst Pd (dba) that addition mol ratio is 5%2, mol ratio is
10% part dppf, mol ratio is 20% additive SIPrAgCl, and temperature is 80 DEG C, the specific data of reaction time screening
It is shown in Table 7.
The screening table in the reaction time of table 7
| Numbering | Reaction time (hour) | Fluorine spectrum (19FNMR) yield (%) |
| 1 | 2 | 60 |
| 2 | 3 | 81 |
| 3 | 4 | 90 |
| 4 | 8 | 89 |
| 5 | 12 | 90 |
| 6 | 16 | 89 |
| 7 | 20 | 90 |
| 8 | 30 | 88 |
Under conditions of argon gas, 4- phenyl iodobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, work as with 2
The sodium tert-butoxide of amount is alkali, using dioxane as solvent, and Molar ratio is that (described Molar ratio refers to molten 10L/mol
The ratio of agent volume and the mole of 4- phenyl iodobenzenes), addition palladium catalyst Pd (dba)2, mol ratio is 10% part
Dppf, mol ratio is 20% additive SIPrAgCl, 80 DEG C, is reacted for 4 times, the specific data of palladium catalyst dosage screening
It is shown in Table 8.
The screening table of the palladium catalyst dosage of table 8
| Numbering | Palladium catalyst Pd (dba)2With compound R X molar ratio | Fluorine spectrum (19FNMR) yield (%) |
| 1 | 0.1 | 86 |
| 2 | 0.05 | 90 |
| 3 | 0.02 | 81 |
| 4 | 0.01 | 24 |
| 5 | 0.005 | 9 |
| 6 | 0.001 | 7 |
| 7 | 0.0001 | 6 |
Under conditions of argon gas, 4- phenyl iodobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, work as with 2
The sodium tert-butoxide of amount is alkali, using dioxane as solvent, and Molar ratio is that (described Molar ratio refers to molten 10L/mol
The ratio of agent volume and the mole of 4- phenyl iodobenzenes), the palladium catalyst Pd (dba) that addition mol ratio is 7%2, mol ratio is
10% part dppf, SIPrAgCl is additive, 80 DEG C, is reacted 4 hours, and the specific data of the dosage screening of additive are shown in
Table 9.
The screening table of the additive dosage of table 9
| Numbering | Additive SIPrAgCl and compound R X molar ratio | Fluorine spectrum (19FNMR) yield (%) |
| 1 | 1 | 76 |
| 2 | 0.5 | 74 |
| 3 | 0.25 | 61 |
| 4 | 0.20 | 89 |
| 5 | 0.10 | 68 |
| 6 | 0.08 | 54 |
| 7 | 0.05 | 49 |
| 8 | 0.025 | 46 |
Under conditions of argon gas, 4- phenyl iodobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, work as with 2
The sodium tert-butoxide of amount is alkali, using dioxane as solvent, and Molar ratio is that (described Molar ratio refers to molten 10L/mol
The ratio of agent volume and the mole of 4- phenyl iodobenzenes), the palladium catalyst that addition mol ratio is 5%, part is dppf, mol ratio
For 20% additive SIPrAgCl, 80 DEG C, react 4 hours, the specific data of part dppf dosages screening are shown in Table 10.
The screening table of the part dppf dosages of table 10
| Numbering | Part dppf and compound R X molar ratio | Fluorine spectrum (19FNMR) yield (%) |
| 1 | 0.025 | 52 |
| 2 | 0.05 | 60 |
| 3 | 0.1 | 90 |
| 4 | 0.15 | 88 |
| 5 | 0.20 | 67 |
| 6 | 0.30 | 64 |
| 7 | 0.50 | 22 |
Under conditions of argon gas, 4- phenyl iodobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, work as with 2
The sodium tert-butoxide of amount is alkali, using dioxane as solvent, and Molar ratio is that (described Molar ratio refers to molten 10L/mol
The ratio of agent volume and the mole of 4- phenyl iodobenzenes), the palladium catalyst Pd (dba) that addition mol ratio is 5%2, mol ratio is
10% part dppf, mol ratio is 20% additive SIPrAgCl, 80 DEG C, is reacted 4 hours, alkali and TMSCF2H's adds
The specific data of amount screening are shown in Table 11.
The alkali of table 11 and TMSCF2H dosage screening table
Conclusion：By the condition optimizing of form 1~11, we determined that with the fluorine-based silicon of trimethyl two of 2.4 equivalents, mole
Than double (bis- Ya Benzyl benzylacetones for 5%) palladium, mol ratio is 10% double (diphenylphosphine) ferrocene of 1,1'-, and mol ratio is
20% SIPrAgCl, the sodium tert-butoxide of 2 equivalents is alkali, and dioxane is as solvent, and Molar ratio is that 10L/mol is (described
Mole of the Molar than referring to solvent volume and 4- phenyl iodobenzenes ratio), 4 hours of reaction are under conditions of 80 DEG C
Optimum reaction condition.
The experiment of the difluoromethyl of the iodo aromatic hydrocarbon (RI) of the palladium chtalyst of embodiment 2
Under argon gas atmosphere, by iodo aromatic hydrocarbon (0.5mmol), double (bis- Ya Benzyl benzylacetones) palladium (14.5mg, 0.025mmol),
1,1'- double (diphenylphosphine) ferrocene (28mg, 0.05mmol), additive SIPrAgCl (53.5mg, 0.1mmol), the tert-butyl alcohol
Sodium (96.1mg, 1.0mmol) is dissolved in 5mL dioxane, and 150uL trimethyl difluoro silicon is added into system.At 80 DEG C
Lower reaction is cooled to room temperature after 4 hours, and reaction is quenched in the distilled water for adding 10mL, and filtrate is extracted with dichloromethane after diatomite filtering
Take (25ml × 3), merge organic phase, anhydrous sodium sulfate drying, concentration, post separation obtains the product of corresponding difluoromethyl
1a~1l, specific yield is shown in Table 12.
Difluoromethyl substrate applicability research of the iodine of table 12 with aromatic hydrocarbons
Compound 1a~1l Structural Identification data are as follows：
Compound 1a
H NMR(400MHz,CDCl3) δ 7.70 (d, J=8.4Hz, 2H), 7.62 (m, 4H), 7.49 (m, 2H), 7.42 (m,
1H), 6.72 (t, J=56.4Hz, 1H)；19F NMR(376MHz,CDCl3) δ -110.33 (d, J=56.4Hz)；13C NMR
(126MHz,CDCl3) δ 114.89 (t, J=239.4Hz), 126.15 (t, J=5.0Hz), 127.37,127.55,128.03,
(t, J=22.7Hz), 129.04,133.34 140.30,143.82 (t, J=2.5Hz) ppm.GC-MS (EI, m/z):204.0(M
+),183.0,152.0
Compound 1b
1H NMR(400MHz,CDCl3) δ 8.05 (d, J=8.4Hz, 2H), 7.52 (d, J=8.4Hz, 2H), 6.66 (t, J
=56.0Hz, 1H), 1.58 (s, 9H)；19F NMR(376MHz,CDCl3) δ -112.03 (d, J=56.0Hz)；13C NMR
(126MHz,CDCl3) δ 28.29,81.77,114.26 (t, J=240.1Hz), 125.58 (t, J=5.9Hz), 129.91,
(t, J=25.0Hz), 134.35,138.10 165.00ppm.HRMS (EI) for C12H14O2F2):Calcd:228.0962；
Found:228.0957.IR:=3012,2980,2935,1952,1912,1582,1511,1480,1462,1413,1396,
1371,1314,1296,1257,1222,1188,1172,1127,1111,1067,1045,1016,976,891,863,850,
833,765,753,713,664,576,515cm-1.M.P.40~43 DEG C
Compound 1c
1H NMR(400MHz,CDCl3) δ 7.45~7.35 (m, 7H), 7.03 (d, J=8.4Hz, 2H), 6.60 (t, J=
56.8Hz,1H),5.10(s,2H)；19F NMR(376MHz,CDCl3) δ -108.30 (d, J=56.8Hz)；13C NMR
(126MHz,CDCl3) δ 70.20,114.89,114.99 (t, J=238.0Hz), 127.17 (t, J=5.8Hz), 127.22,
(127.48,128.17,128.69,136.59,160.64 t, J=1.9Hz) ppm.LRMS (EI, m/z):234(M+),210,91
Compound 1d
1H NMR(300MHz,CDCl3) δ 7.48~7.42 (m, 4H), 6.64 (t, J=57.0Hz, 1H), 1.35 (s, 9H)
；19F NMR(282MHz,CDCl3) δ -110.27 (d, J=57.0Hz)；13C NMR(101MHz,CDCl3)δ31.35,34.99,
115.05 (t, J=238.2Hz), 125.45 (t, J=6.3Hz), 125.75,131.70 (t, J=21.4Hz),
154.16ppm.GC-MS(EI,m/z):184.1(M+),169.1,141.0.
Compound 1e
1H NMR(400MHz,CDCl3) δ 7.56 (d, J=8.4Hz, 2H), 7.46 (d, J=8.4Hz, 2H), 7.11 (m,
2H), 6.66 (t, J=56.8Hz, 1H), 6.37 (m, 2H)；19F NMR(376MHz,CDCl3) δ -110.13 (d, J=
56.8Hz)；13C NMR(126MHz,CDCl3) δ 111.29,114.48 (t, J=239.0Hz), 119.30,120.35,127.22
(t, J=6.1Hz), 131.55 (t, J=22.8Hz), 142.61ppm.HRMS (EI) for C10H6OF2S):Calcd:
193.0703；Found:193.0702.IR:=3143,3085,2967,1910,1618,1594,1568,1532,1475,
1437,1384,1330,1309,1230,1194,1128,1083,1067,1012,949,921,855,725,610,551,
441cm-1.M.P.86~87 DEG C
Compound 1f
1H NMR(400MHz,CDCl3) δ 7.51 (d, J=8.0Hz, 2H), 7.42 (d, J=8.0Hz, 2H), 6.64 (t, J
=56.4Hz, 1H), 3.52 (br, 2H), 3.19 (br, 2H), 1.24~1.20 (br, 3H), 1.09~1.05 (br, 3H)；19F
NMR(376MHz,CDCl3) δ -111.33 (d, J=56.4Hz)；13C NMR(126MHz,CDCl3)δ12.82,14.15,
(t, J=239.7Hz), 39.29,43.23,114.83 125.73 (t, J=6.2Hz), 126.60,134.92 (t, J=
22.6Hz),139.19,170.19ppm.HRMS(ESI)for C12H16NOF2):Calcd:228.1194；Found:
228.1196.IR:=2977,2937,2242,1628,1578,1474,1460,1433,1382,1349,1289,1 221,
1161,1098,1072,1033,911,877,834,733,647cm-1.
Compound 1g
1H NMR(400MHz,CDCl3) δ 7.47~7.42 (m, 4H), 6.63 (t, J=56.4Hz, 1H), 3.60 (s, 2H),
2.51 (q, J=2.1Hz, 4H), 1.05 (t, J=2.3Hz, 6H)；19F NMR(376MHz,CDCl3) δ -109.92 (d, J=
56.4Hz)；13C NMR(126MHz,CDCl3) δ 11.92,46.99,57.42,115.00 (t, J=238.8Hz), 125.50 (t,
), J=6.3Hz 129.09,132.93 (t, J=22.4Hz), 143.39 (t, J=2.0Hz) ppm.LCMS (ESI):214.1(M+
H).
Compound 1h
1H NMR(400MHz,CDCl3) δ 6.71 (s, 2H), 6.56 (t, J=56.8Hz, 1H), 3.87 (s, 6H), 3.85
(s,3H)；19F NMR(376MHz,CDCl3) δ -109.40 (d, J=56.8Hz, 1H)；13C NMR(101MHz,CDCl3)δ
(t, J=6.3Hz), 56.25,60.90,102.70 114.72 (t, J=239.5Hz), 129.77 (t, J=22.6Hz),
139.85,153.60ppm.HRMS(EI)for C10H12O3F2):Calcd:218.0755；Found:218.0754.IR:=
2943,2845,2253,1598,1509,1466,1425,1381,1333,1301,1241,1185,1161,1132,1090,
1025,976,911,843,759,731cm-1
Compound 1i
1H NMR(400MHz,CDCl3) δ 7.48~7.37 (m, 6H), 7.20~7.09 (m, 3H), 6.63 (t, J=
56.4Hz,1H),5.11(s,2H)；19F NMR(376MHz,CDCl3)δ-110.65(d,J1=56.4Hz)；13C NMR
(101MHz,CDCl3) δ 159.10,136.61,135.89 (t, J=22.3Hz), 130.06,128.79,128.28,127,66,
118.21 (t, J=6.3Hz), 117.44 (t, J=1.9Hz), 114.65 (t, J=239.5Hz), 111.86 (t, J=
6.1Hz),70.26ppm.HRMS(EI)for C14H12OF2):Calcd:234.0856；Found:234.0853.IR:ν/cm-1
=3250,2972,2932,1604,1497,1456,1385,1258,1180,1057,1019,8 61,795,750,831,
697.M.P.:51~52 DEG C of
Compound 1j
1H NMR(400MHz,CDCl3) δ 7.42 (d, J=8.8Hz, 2H), 6.95 (d, J=8.8Hz, 2H), 6.59 (t, J
=56.8Hz, 1H), 3.83 (d, J=3.4Hz, 2H), 1.28~1.23 (m, 1H), 0.67~0.38 (m, 2H), 0.38~0.35
(m,2H)；19F NMR(376MHz,CDCl3) δ -108.23 (d, J=56.8Hz)；13C NMR(101MHz,CDCl3)δ3.34,
(10.29,73.01,114.73,115.06 t, J=238.4Hz), 126.76 (t, J=22.8Hz), 127.21 (t, J=
6.0Hz),160.94ppm.HRMS(EI)for C11H12OF2):Calcd:198.0856；Found:198.0860.IR:=
2924,1616,1588,1519,1471,1408,1384,1307,1250,1173,1071,1011,940,913,861,
833cm-1.
Compound 1k
1H NMR(400MHz,CDCl3) δ 7.63~7.56 (m, 6H), 7.45~7.43 (m, 2H), 6.68 (t, J=
56.4Hz,1H)；19F NMR(376MHz,CDCl3) δ -110.57 (d, J=56.4Hz)；13C NMR(126MHz,CDCl3)δ
114.73 (t, J=239.3Hz), 122.42,126.30 (t, J=6.0Hz), 127.36,128.93,132.18,133.73 (t,
), J=22.4Hz 139.18,142.57 (t, J=2.0Hz) ppm.HRMS (EI) for C13H9BrF2):Calcd:281.9856；
Found:281.9859.IR:=2959,1908,1614,1587,1483,1419,1389,1366,1311,1282,1220,
1188,1070,1002,881,842,807,759,665,626,568,543,517,451cm-1.M.P.109~110 DEG C
Compound 1l
1H NMR(400MHz,CDCl3) δ 7.40 (d, J=8.4Hz, 2H), 6.92 (d, J=8.4Hz, 2H), 6.70 (t, J
=56.8Hz, 1H), 4.02 (t, J=6.4Hz, 2H), 3.70 (t, J=4.4Hz, 4H), 2.52~2.44 (m, 6H), 1.99~
1.92(m,2H)；19F NMR(376MHz,CDCl3) δ -108.11 (d, J=56.8Hz)；13C NMR(101MHz,CDCl3)δ
(26.39,53.80,55.45,66.26,67.03,114.57,114.96 t, J=237.8Hz), 126.71 (t, J=
22.8Hz), 127.12 (t, J=5.9Hz), 160.85 (t, J=1.8Hz) ppm.HRMS (EI) for C14H19NO2F2):
Calcd:271.1384；Found:271.1383.IR:=2958,2856,2814,2247,1705,1615,1589,1519,
1448,1459,1433,1383,1305,1255,1222,1176,1144,1118,1070,1020,961,911,864,836,
734,645,627,613,554cm-1
The difluoromethyl repercussion study for the aryl bromide (RBr) that the palladium of embodiment 3 is participated in
Under conditions of argon gas, by 4- phenyl bromobenzene (0.1mmol), trimethyl difluoromethyl silicon, palladium catalyst, addition
Agent, part and alkali are dissolved in dry deoxygenation solvent with corresponding ratio in form, are heated to the temperature listed in form, reaction
To after the time listed by form, the benzotrifluoride of equal proportion is added as internal standard, yield is determined by fluorine spectrum.Urged for palladium
The screening of agent is shown in Table 13, and the screening for additive is shown in Table 14, and the screening for alkali is shown in Table 15, and the screening for solvent is shown in Table
16, the screening for part is shown in Table 17, and the screening for reaction temperature is shown in Table 18, and the screening for the reaction time is shown in Table 19, right
20 are shown in Table in the screening of palladium catalyst dosage, the screening for additive dosage is shown in Table 21, for the sieve of part dosage
Choosing is shown in Table 22, for TMSCF2Screening with alkali dosage is shown in Table 23.
Under conditions of argon gas, 4- phenyl bromobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, work as with 2
Amount sodium tert-butoxide is alkali, using dioxane as solvent, and Molar ratio is that (described Molar ratio refers to solvent to 10L/mol
The ratio of volume and the mole of 4- phenyl bromobenzenes), the palladium catalyst that addition mol ratio is 5%, mol ratio is 10% part
Dppf, mol ratio is 20% additive SIPrAgCl, 80 DEG C, is reacted 4 hours, the specific data of palladium catalyst screening are shown in Table
13。
The screening table of the palladium catalyst of table 13
| Numbering | The species of palladium catalyst | Fluorine spectrum (19FNMR) yield (%) |
| 1 | Pd(dba)2 | 80 |
| 2 | Pd2(dba)3 | 75 |
| 3 | Pd(PPh3)4 | 46 |
| 4 | PdCl2 | 23 |
| 5 | PdBr2 | 8 |
| 6 | PdI2 | 6 |
| 7 | Pd(OAc)2 | 11 |
| 8 | Pd(TFA)2 | 14 |
| 9 | Pd(OTf)2(H2O) | ＜ 5 |
| 10 | Pd(OTf)2(MeCN)4 | ＜ 5 |
| 11 | Pd(OTs)2(MeCN)4 | ＜ 4 |
| 12 | PdCl2(MeCN)2 | 8 |
| 13 | PdCl2(PhCN)2 | ＜ 5 |
| 14 | PdCl2(NH3)4 | 6 |
| 15 | PdCl2(PPh3)2 | 10 |
| 16 | Pd(BF4)2(MeCN)4 | ＜ 5 |
| 17 | Pd(NO3)2 | 13 |
| 18 | (dppf)PdCl2 | 55 |
| 19 | Pd(acac)2 | 9 |
Under conditions of argon gas, 4- phenyl bromobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, work as with 2
Amount sodium tert-butoxide is alkali, using dioxane as solvent, and Molar ratio is that (described Molar ratio refers to solvent to 10L/mol
The ratio of volume and the mole of 4- phenyl bromobenzenes), the palladium catalyst Pd (dba) that addition mol ratio is 5%2, mol ratio is
10% part dppf, mol ratio is 20% additive, 80 DEG C, is reacted 4 hours, the specific data of selection of additives are shown in Table
14。
The screening table of the additive of table 14
| Numbering | The species of additive | Fluorine spectrum (19FNMR) yield (%) |
| 1 | SIPrAgCl | 80 |
| 2 | IPrAgCl | ＜ 5 |
| 3 | SIMesAgCl | 46 |
| 4 | IMesAgCl | 34 |
| 5 | ICyAgCl | 23 |
| 6 | AgOPiv | 38 |
| 7 | AgOTf | 25 |
| 8 | AgPF6 | ＜ 5 |
| 9 | AgSbF6 | ＜ 5 |
| 10 | AgBF4 | 6 |
| 11 | AgOAc | 14 |
| 12 | Ag2CO3 | 25 |
| 13 | Ag2O | 17 |
| 14 | AgF | 23 |
| 15 | CuCl | 25 |
| 16 | CuBr | 13 |
| 17 | CuI | 12 |
| 18 | CuSO4 | 16 |
| 19 | Cu(NO3)2 | ＜ 5 |
| 20 | FeCl3 | ＜ 5 |
| 21 | FeCl2 | 7 |
| 22 | FeSO4 | ＜ 5 |
| 23 | Nothing | 24 |
Under conditions of argon gas, 4- phenyl bromobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, 2 equivalents
Alkali, using dioxane as solvent, Molar ratio be 10L/mol (described Molar ratio refers to solvent volume and 4- benzene
The ratio of the mole of bromide benzene), addition mol ratio is 5% palladium catalyst Pd (dba)2, mol ratio is 10% part dppf,
Mol ratio is additive 20%SIPrAgCl, 80 DEG C, is reacted 4 hours, and the specific data of alkali screening are shown in Table 15.
The screening table of the alkali of table 15
| Numbering | The species of alkali | Fluorine spectrum (19FNMR) yield (%) |
| 1 | Sodium tert-butoxide | 80 |
| 2 | Potassium tert-butoxide | 5 |
| 3 | Methanaminium, N,N,N-trimethyl-, fluoride | 16 |
| 4 | Tetrabutyl ammonium fluoride | 1 |
| 5 | Potassium fluoride | 6 |
| 6 | Sodium fluoride | 5 |
| 7 | Rubidium fluoride RbF | 7 |
| 8 | Cesium fluoride | 23 |
| 9 | Tert-butyl alcohol lithium | ＜ 5 |
| 10 | Sodium methoxide | 5 |
| 11 | Lithium methoxide | ＜ 5 |
| 12 | Potassium methoxide | 7 |
Under conditions of argon gas, 4- phenyl bromobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, work as with 2
The sodium tert-butoxide of amount is alkali, addition 5%Pd (dba)2, mol ratio is 10% part dppf, and mol ratio is 20% additive
SIPrAgCl, reacts 4 hours by 80 DEG C, and the Molar ratio that solvent is added is that (described Molar ratio refers to molten 10L/mol
The ratio of agent volume and the mole of 4- phenyl bromobenzenes), the specific data of solvent screening are shown in Table 16.
The screening table of the solvent of table 16
Under conditions of argon gas, 4- phenyl bromobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, with tertiary fourth
Sodium alkoxide is alkali, using dioxane as solvent, Molar ratio be 10L/mol (described Molar ratio refer to solvent volume with
The ratio of the mole of 4- phenyl bromobenzenes), the palladium catalyst Pd (dba) that addition mol ratio is 5%2, mol ratio matches somebody with somebody for 10%
Body, mol ratio is 20% additive SIPrAgCl, 80 DEG C, is reacted 4 hours, the specific data of ligand screening are shown in Table 17.
The screening table of the part of table 17
| Numbering | The species of part | Fluorine spectrum (19FNMR) yield (%) |
| 1 | dppf | 86 |
| 2 | dppm | 23 |
| 3 | dppe | 27 |
| 4 | dppp | 15 |
| 5 | Binap | 33 |
| 6 | PPh3 | 8 |
| 7 | PtBu3 | ＜ 5 |
| 8 | PCy3 | ＜ 5 |
| 9 | Xantphos | 72 |
| 10 | DPEPhos | 68 |
| 11 | BrettPhos | ＜ 5 |
| 12 | Q-Phos | ＜ 5 |
| 13 | Josiphos | 6 |
| 14 | dppb | 24 |
| 15 | 1,10-phen | 14 |
| 16 | Bypyridine | 11 |
| 17 | TMEDA | 8 |
Under conditions of argon gas, 4- phenyl bromobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, work as with 2
The sodium tert-butoxide of amount is alkali, using toluene as solvent, and Molar ratio is that (described Molar ratio refers to solvent body to 10L/mol
The ratio of product and the mole of 4- phenyl bromobenzenes), the palladium catalyst Pd (dba) that addition mol ratio is 5%2, mol ratio is 10%
Part, mol ratio be 20% additive SIPrAgCl, react 4 hours, reaction temperature screening specific data be shown in Table 18.
The screening table of the reaction temperature of table 18
| Numbering | Reaction temperature (DEG C) | Fluorine spectrum (19FNMR) yield (%) |
| 1 | 100 | 82 |
| 2 | 90 | 80 |
| 3 | 80 | 85 |
| 4 | 70 | 65 |
| 5 | 60 | 54 |
| 6 | 50 | 49 |
| 7 | 40 | 25 |
| 8 | 30 | 16 |
| 9 | 25 | 5 |
Under conditions of argon gas, 4- phenyl bromobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, work as with 2
The sodium tert-butoxide of amount is alkali, using toluene as solvent, and Molar ratio is that (described Molar ratio refers to solvent body to 10L/mol
The ratio of product and the mole of 4- phenyl bromobenzenes), the palladium catalyst Pd (dba) that addition mol ratio is 5%2, mol ratio is 10%
Part dppf, mol ratio be 20% additive SIPrAgCl, temperature be 80 DEG C, the reaction time screening specific data be shown in Table
19。
The screening table in the reaction time of table 19
| Numbering | Reaction time (hour) | Fluorine spectrum (19FNMR) yield (%) |
| 1 | 2 | 60 |
| 2 | 3 | 71 |
| 3 | 4 | 85 |
| 4 | 8 | 87 |
| 5 | 12 | 88 |
| 6 | 16 | 88 |
| 7 | 20 | 87 |
| 8 | 30 | 85 |
Under conditions of argon gas, 4- phenyl bromobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, work as with 2
The sodium tert-butoxide of amount is alkali, using toluene as solvent, and Molar ratio is that (described Molar ratio refers to solvent body to 10L/mol
The ratio of product and the mole of 4- phenyl bromobenzenes), addition palladium catalyst Pd (dba)2, mol ratio is 10% part dppf, is rubbed
You 80 DEG C, reacted for 6 times than the additive SIPrAgCl for 20%, and the specific data of palladium catalyst dosage screening are shown in Table 20.
The screening table of the palladium catalyst dosage of table 20
| Numbering | Palladium catalyst Pd (dba)2With compound R X molar ratio | Fluorine spectrum (19FNMR) yield (%) |
| 1 | 0.1 | 86 |
| 2 | 0.07 | 89 |
| 3 | 0.05 | 85 |
| 4 | 0.01 | 24 |
| 5 | 0.005 | 11 |
| 6 | 0.001 | 8 |
| 7 | 0.0001 | ＜ 5 |
Under conditions of argon gas, 4- phenyl bromobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, work as with 2
The sodium tert-butoxide of amount is alkali, using toluene as solvent, and Molar ratio is that (described Molar ratio refers to solvent body to 10L/mol
The ratio of product and the mole of 4- phenyl bromobenzenes), the palladium catalyst Pd (dba) that addition mol ratio is 7%2, mol ratio is 14%
Part dppf, SIPrAgCl be additive, 80 DEG C, react 6 hours, the specific data of the dosage screening of additive are shown in Table
21。
The screening table of the additive dosage of table 21
| Numbering | Additive SIPrAgCl and compound R X molar ratio | Fluorine spectrum (19FNMR) yield (%) |
| 1 | 1 | 73 |
| 2 | 0.5 | 76 |
| 3 | 0.25 | 68 |
| 4 | 0.20 | 91 |
| 5 | 0.10 | 81 |
| 6 | 0.08 | 53 |
| 7 | 0.05 | 51 |
| 8 | 0.025 | 39 |
| 9 | 0.01 | 41 |
| 10 | 0.001 | 33 |
| 11 | Nothing | 26 |
Under conditions of argon gas, 4- phenyl bromobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, work as with 2
Amount sodium tert-butoxide is alkali, using dioxane as solvent, and Molar ratio is that (described Molar ratio refers to solvent to 10L/mol
The ratio of volume and the mole of 4- phenyl bromobenzenes) palladium catalyst that mol ratio is 7% is added, part is dppf, and mol ratio is
20% additive SIPrAgCl, 80 DEG C, reacts 6 hours, the specific data of part dppf dosages screening are shown in Table 22.
The screening table of the part dppf dosages of table 22
| Numbering | Part dppf and compound R X molar ratio | Fluorine spectrum (19FNMR) yield (%) |
| 1 | 0.025 | 35 |
| 2 | 0.05 | 33 |
| 3 | 0.1 | 70 |
| 4 | 0.14 | 89 |
| 5 | 0.20 | 74 |
| 6 | 0.30 | 69 |
| 7 | 0.50 | 52 |
Under conditions of argon gas, 4- phenyl iodobenzene and 2.4eq trimethyl difluoromethyl silicon carry out coupling reaction, work as with 2
The sodium tert-butoxide of amount is alkali, using toluene as solvent, and Molar ratio is that (described Molar ratio refers to solvent body to 10L/mol
The ratio of product and the mole of 4- phenyl bromobenzenes), the palladium catalyst Pd (dba) that addition mol ratio is 7%2, mol ratio is 14%
Part dppf, mol ratio is 20% additive SIPrAgCl, 80 DEG C, is reacted 6 hours, alkali and TMSCF2H dosage sieve
The specific data of choosing are shown in Table 23.
The alkali of table 23 and TMSCF2H dosage screening table
| Compile | TMSCF2With rubbing for compound R X | Alkali sodium tert-butoxide is with compound R X's | Fluorine spectrum (19FNMR) yield (%) |
| Number | That ratio | Molar ratio | |
| 1 | 1 | 1 | 27 |
| 2 | 2 | 1 | 79 |
| 3 | 3 | 1 | 53 |
| 4 | 5 | 1 | 55 |
| 5 | 2 | 2 | 85 |
| 6 | 2.4 | 2 | 89 |
| 7 | 4 | 2 | 48 |
| 8 | 5 | 2 | 46 |
| 9 | 3 | 3 | 73 |
| 10 | 4 | 3 | 66 |
| 11 | 5 | 3 | 43 |
Conclusion：By the condition optimizing of above table 13~23, we determined that with the trimethyl two of 2.4 equivalents fluorine-based
Silicon, the double (bis- Ya Benzyl benzylacetones of palladium catalyst that mol ratio is 7%) palladium, mol ratio is 14% ligand 1, the double (diphenyl of 1'-
Phosphine) ferrocene, mol ratio is 20% additive SIPrAgCl, and the sodium tert-butoxide of 2 equivalents, toluene is used as solvent, Molar
Than for 10L/mol (ratio of mole of the described Molar than referring to solvent volume and 4- phenyl bromobenzenes), 80 DEG C of bar
It is optimal conditions that 6 hours are reacted under part.
The experiment general rule of the difluoromethyl of the aryl bromide (RBr) of the palladium chtalyst of embodiment 4
Under argon gas atmosphere, by aryl bromide (0.5mmol), double (bis- Ya Benzyl benzylacetones) palladium (20.1mg, 0.035mmol),
1,1'- double (diphenylphosphine) ferrocene (38.8mg, 0.07mmol), additive SIPrAgCl (53.5mg, 0.1mmol), tertiary fourth
Sodium alkoxide (96.1mg, 1.0mmol) is dissolved in 5mL toluene, and 150uL trimethyl difluoro silicon is added into system.At 80 DEG C
Reaction is cooled to room temperature after 6 hours, reaction is quenched in the distilled water for adding 10mL, and filtrate is extracted with dichloromethane after diatomite filtering
(25ml × 3), merge organic phase, anhydrous sodium sulfate drying, concentration, post separation, obtain corresponding difluoromethyl product 1a,
1b, 1f, 2c~2g and 2i~2n, specific yield are shown in Table 24.
The difluoromethyl substrate applicability research of the aryl bromide of table 24
Compound 2c~2g and 2i~2n Structural Identification data are as follows：
Compound 2c
1H NMR(400MHz,CDCl3) δ 7.44 (d, J=8.0Hz, 2H), 7.29 (d, J=8.0Hz, 2H), 6.64 (t, J
=56.8Hz, 1H), 2.67 (t, J=8.0Hz, 2H), 1.65~1.61 (m, 2H), 1.31 (m, 10H), 0.92 (t, J=
6.7Hz,3H)；19F NMR(376MHz,CDCl3) δ -109.67 (d, J=56.8Hz)；13C NMR(101MHz,CDCl3)δ
14.24,22.83,29.41,29.43,29.61,31.52,32.05,35.98,115.11 (t, J=239.3Hz), 125.63
(t, J=6.1Hz), 128.82,131.94 (t, J=22.6Hz), 146.01 (t, J=2.0Hz) ppm.HRMS (EI) for
C15H22F2):Calcd:240.1690；Found:240.1693.IR:ν/cm-1=2927,2856,1618,1519,1466,
1425,1378,1303,1222,1183,1073,1031,909,859,831,735,649,630,568.
Compound 2d
1H NMR(400MHz,CDCl3) δ 8.00 (s, 1H), 7.96~7.90 (m, 3H), 7.65~7.58 (m, 3H), 6.84
(t, J=56.4Hz, 1H)；19F NMR(376MHz,CDCl3) δ -109.66 (d, J=56.4Hz)13C NMR(101MHz,
CDCl3) δ 134.43 (t, J=1.4Hz), 132.67,131.73 (t, J=22.3Hz), 129.00,128.63,127.98,
(t, J=7.6Hz), 127.50,126.91,126.00 122.12 (t, J=4.8Hz), 115.20 (t, J=238.5Hz) .LRMS
(EI,m/z):178(M+),177,128,91.
Compound 2e
1H NMR(500MHz,CDCl3) δ 8.21 (d, J=8.5Hz, 1H), 7.98 (d, J=8.5Hz, 1H), 7.93 (d, J
=7.5Hz, 1H), 7.72 (dd, J=7.5,1.0Hz, 1H), 7.60 (m, 2H), 7.52 (t, J=7.5Hz, 1H), 7.16 (t, J
=56.4Hz, 1H)；19F NMR(376MHz,CDCl3) δ -110.83 (d, J=56.4Hz)；13C NMR(126MHz,CDCl3)δ
115.57 (t, J=238.1Hz), 123.68 (t, J=1.3Hz), 124.78,124.92 (t, J=8.8Hz), 126.49,
(t, J=21.4Hz), 127.29,128.90,129.67 129.84 (t, J=1.2Hz), 131.61 (t, J=2.5Hz),
133.90ppm.GC-MS(EI,m/z):178.0(M+),157.0,128.0
Compound 2f
1H NMR(400MHz,CDCl3) δ 7.70~7.65 (m, 2H), 7.56~7.50 (m, 4H), 7.16 (m, 2H), 6.72
(t, J=56.4Hz, 1H)；19F NMR(376MHz,CDCl3) δ -110.64 (d, J=56.4Hz, 2F), 114.84 (m, 1F)；13C
NMR(126MHz,CDCl3) δ 114.83 (t, J=239.7Hz), 115.95 (t, J=21.55Hz), 124.24 (t, J=
6.0Hz), 124.51 (t, J=6.0Hz), 128.91 (d, J=8.2Hz), 129.40 (d, J=3.8Hz), 129.41,135.15
(t, J=22.3Hz), 136.43 (t, J=3.4Hz), 141.00,162.88 (d, J=247.8Hz) ppm.HRMS (EI) for
C13H9F3):Calcd:222.0656；Found:222.0660.IR:=3045,2964,1607,1516,1487,1447,
1404,1369,1302,1236,1200,1221,1160,1101,1064,1032,908,838,817,797,736,699,
562,548cm-1.
Compound 2g
1H NMR(400MHz,CDCl3) δ 7.40~7.36 (m, 3H), 7.26~7.04 (m, 6H), 6.60 (t, J=
56.4Hz,1H)；19F NMR(376MHz,CDCl3) δ -110.80 (d, J=56.4Hz)；13C NMR(101MHz,CDCl3)δ
(t, J=240.4Hz), 111.83,114.21 115.56 (t, J=6.3Hz), 116.60,119.31,120.05 (t, J=
6.3Hz), 120.71 (t, J=1.9Hz), 123.91,129.95,130.21,136.13 (t, J=22.5Hz), 156.45,
157.82ppm.HRMS(EI)for C13H10OF2):Calcd:220.0700；Found:220.0698.IR:=3042,3021,
2946,1587,1489,1452,1385,1371,1257,1216,1162,1043,878,800,753,734,693cm-1.
Compound 2i
1H NMR(400MHz,CDCl3) δ 7.45~7.35 (m, 7H), 7.03 (d, J=8.4Hz, 2H), 6.60 (t, J=
56.8Hz,1H),5.10(s,2H)；19F NMR(376MHz,CDCl3) δ -108.30 (d, J=56.8Hz)；13C NMR
(126MHz,CDCl3) δ 70.20,114.89,114.99 (t, J=238.0Hz), 127.17 (t, J=5.8Hz), 127.22,
(127.48,128.17,128.69,136.59,160.64 t, J=1.9Hz) ppm.LRMS (EI, m/z):234(M+),210,
91.
Compound 2j
1H NMR(400MHz,CDCl3) δ 7.58 (d, J=8.0Hz, 2H), 7.49 (d, J=8.0Hz, 2H), 6.64 (t, J
=56.5Hz, 1H), 4.07~4.04 (m, 2H), 3.78~3.74 (m, 2H), 1.66 (s, 3H)；19F NMR(376MHz,
CDCl3) δ -110.45 (d, J=56.5Hz)；13C NMR(126MHz,CDCl3) δ 146.33 (t, J=1.9Hz), 134.07 (t,
), J=22.3Hz 125.84,125.67 (t, J=6.0Hz), 122.90,112.87 (t, J=239.1Hz), 108.63,
64.66,27.68,22.58ppm.HRMS(EI)for C10H9O2F2):Calcd:199.0571；Found:199.0569.IR:=
2990,2891,1930,1618,1418,1375,1253,1220,1201,1123,1071,1038,949,874,846,762,
736,682cm-1.
Compound 2k
1H NMR(400MHz,CDCl3) δ 7.36~7.29 (m, 6H), 7.14~7.07 (m, 8H), 6.60 (t, J=
56.8Hz,1H)；19F NMR(376MHz,CDCl3) δ -108.62 (d, J=56.8Hz)；13C NMR(126MHz,CDCl3)δ
115.05 (t, J=237.9Hz), 122.19,123.89,125.25,126.72 (t, J=5.9Hz), 127.43 (t, J=
22.6Hz),129.59,147.30,150.26ppm.HRMS(EI)for C19H15NF2):Calcd:295.1173；Found:
295.1176.IR:=3062,3035,2962,1614,1593,1515,1486,1451,1430,1382,1334,1 283,
1269,1222,1191,1176,1125,1064,1016,948,903,839,758,734,698,633,623,528,506cm-1.M.P.97~98 DEG C
Compound 2l
1H NMR(400MHz,CDCl3) δ 8.49 (s, 1H), 8.35 (s, 1H), 7.42~7.39 (m, 6H), 6.68 (t, J=
56.0Hz,1H),5.12(s,2H)；19F NMR(376MHz,CDCl3) δ -112.08 (d, J=56.0Hz)；13C NMR
(101MHz,CDCl3) δ 113.19 (t, J=241.6Hz), 118.02 (t, J=5.6Hz), 127.66,128.58,128.86,
130.63 (t, J=23.1Hz), 131.80,139.56 (t, J=7.1Hz), 141.14 (t, J=2.0Hz),
154.89ppm.HRMS(EI)for C13H11NOF2):Calcd:235.0809；Found:235.0805.IR:ν/cm-1=
3066,3036,2933,2877,1918,1816,1597,1498,1466,1456,1440,1376,1324,1288,1246,
1183,1072,1029,952,911,879,844,790,737,698,630,552.
Compound 2m
1H NMR(400MHz,CDCl3) δ 8.23 (d, J=8.0Hz, 2H), 7.80 (d, J=8.4Hz, 2H), 7.72 (d, J
=8.4Hz, 2H), 7.50~7.49 (m, 4H), 7.42~7.38 (m, 2H), 6.60 (t, J=56.4Hz, 1H)；19F NMR
(376MHz,CDCl3) δ -110.23 (d, J=56.4Hz)；13C NMR(101MHz,CDCl3) δ 109.76,114.45 (t, J=
240.5Hz), 120.50,120.56,123.75,126.27,127.32,127.45 (t, J=6.1Hz), 133.32 (t, J=
22.6Hz),140.19,140.64ppm.HRMS(EI)for C19H13NF2):Calcd:293.1016；Found:
293.1021.IR:=3047,2975,1611,1520,1480,1453,1378,1365,1336,1319,1302,1 230,
1185,1168,1150,1123,1072,1022,916,839,750,725,625cm-1.M.P.137~139 DEG C
Compound 2n
1H NMR(400MHz,CDCl3) δ 8.16 (d, J=8.0Hz, 2H), 8.09 (d, J=8.0Hz, 2H), 7.90 (d, J
=8.0Hz, 2H), 7.62 (d, J=8.0Hz, 2H), 7.49 (m, 1H), 7.40 (m, 1H), 6.70 (t, J=56.0Hz, 1H)；19F
NMR(376MHz,CDCl3) δ -111.59 (d, J=56.0Hz)；13C NMR(101MHz,CDCl3) δ 114.29 (t, J=
240.6Hz), 121.81,123.60,125.56,126.24 (t, J=6.1Hz), 126.51,127.75,135.13,135.74,
136.46 (t, J=22.7Hz), 154.17,166.72ppm.HRMS (EI) for C14H9NSF2):Calcd:261.0424；
Found:261.0425.IR:ν/cm-1=3055,2972,1918,1484,1457,1436,1418,1376,1315,1253,
1219,1185,1121,1073,1016,970,817,756,730,672,620.M.P.134~136 DEG C of
The application of the difluoromethyl of the bromo-derivative of the oestrone skeleton of the palladium chtalyst of embodiment 5
Oestrone is a kind of sex hormone and promotees sex hormone, is mainly used in treatment uterine hypoplasia, menstrual disorder, climacteric barrier
The symptom such as hinder, it is contemplated that the biological isoelectronic species property of difluoromethyl and hydroxyl, we attempt will using the method that we invent
It is as follows that difluoromethyl is incorporated into concrete operations in such molecular skeleton：Under argon gas atmosphere, by bromo substrate (164.5mg,
0.44mmol), double (bis- Ya Benzyl benzylacetones) palladium (36.1mg, 0.061mmol), double (diphenylphosphine) ferrocene of 1,1'-
(66.9mg, 0.12mmol), SIPrAgCl (93.3mg, 0.18mmol), sodium tert-butoxide (84.6mg, 0.88mmol) is dissolved in
In 2.2ml toluene, 132uL trimethyl difluoro silicon is added into system.Room temperature is cooled to after being reacted 48 hours at 80 DEG C,
Reaction is quenched in the distilled water for adding 10mL, and filtrate is extracted (25ml × 3) with dichloromethane after diatomite filtering, merges organic phase,
Anhydrous sodium sulfate drying, concentration, post separation, obtaining the product of corresponding difluoromethyl, (70%) 121mg, separation yield is.
1H NMR(400MHz,CDCl3) δ 7.38 (d, J=8.0Hz, 2H), 7.27 (d, J=8.0Hz, 2H), 7.22 (s,
1H), 6.58 (t, J=56.8Hz, 1H), 3.98~3.88 (m, 4H), 2.91~2.90 (m, 2H), 2.38~2.34 (m, 2H),
2.1~1.98 (m, 1H), 1.96~1.76 (m, 4H), 1.67~1.27 (m, 6H), 0.89 (s, 3H)；
19F NMR(376MHz,CDCl3)δ-109.80(dd,J1=56.8Hz, J2=7.1Hz)；
13C NMR(101MHz,CDCl3) δ 143.40,137.49,131.73 (t, J=22.7Hz), 126.14 (t, J=
5.1Hz), 125.86,122.75 (t, J=5.0Hz), 116.98 (t, J=238.1Hz), 65.39,64.71,49.55,
46.17,44.25,38.70,34.31,30.77,29.57,26.84,26.00,22.47,14.41.ppm.
HRMS(EI)for C15H22F2):Calcd:384.1901；Found:384.1900
The application of the difluoromethyl of the bromo-derivative of the vitamin E skeleton of the palladium chtalyst of embodiment 6
Vitamin E can promote reproduction.It can promote sex hormone to secrete, and make man's sperm motility and quantity increase；Make woman
Female hormone concentration increases, and improves fecundity, prevention of miscarriage.Orchiatrophy and epithelial cell occur during vitamin E deficiency
Denaturation, breeds exception.Clinically commonly use vitamin E treatment threatened abortion and habitual abortion.In addition to preventing and treating male sterility
Disease also has certain help.Other function aspects also have, protection T lymphocytes, protection red blood cell, Green Tea Extract oxidation, suppression blood
Platelet aggregation is so as to reduce myocardial infarction and the danger of cerebral infarction.It is also comprehensive to burn, frostbite, capillary hemorrhage, climacteric
There is good curative effect in terms of conjunction disease, beauty.It has also been found that vitamin E can suppress the lipid peroxidation reaction in ocular lens body, make
Peripheral vasodilation, improves blood circulation etc..In view of the biological isoelectronic species property of difluoromethyl and hydroxyl, we attempt to adopt
Difluoromethyl is incorporated into such molecular skeleton by the method invented with us, and concrete operations are as follows：Under argon gas atmosphere, by bromo
Substrate (225mg, 0.5mmol), double (bis- Ya Benzyl benzylacetones) palladium (21mg, 0.035mmol), the cyclopentadienyls of 1,1'- double (diphenylphosphine) two
Iron (38mg, 0.07mmol), SIPrAgCl (53.5mg, 0.1mmol), sodium tert-butoxide (96.1mg, 1.0mmol) are dissolved in 5.0ml
Toluene in, into system add 150uL trimethyl difluoro silicon.Room temperature is cooled to after being reacted 48 hours at 80 DEG C, is added
Reaction is quenched in 10ml distilled water, and filtrate is extracted (25ml × 3) with dichloromethane after diatomite filtering, merges organic phase, anhydrous
Sodium sulphate is dried, concentration, post separation, and obtaining the product of corresponding difluoromethyl, (59%) 123mg, separation yield is.
1H NMR(400MHz,CDCl3) δ 7.11 (s, 1H), 7.07 (s, 1H), 6.53 (t, J=57.2Hz, 1H), 2.79
(t, J=7.1Hz, 2H), 2.21 (s, 3H), 1.90~1.72 (m, 2H), 1.63~1.1 (m, 24H), 0.90~0.86 (m,
12H)；
19F NMR(376MHz,CDCl3)δ-107.26(d,J1=57.2Hz)；
13C NMR(101MHz,CDCl3) δ 154.27 (t, J=1.9Hz), 126.95,125.63 (t, J=5.8Hz),
124.91 (t, J=22.3Hz), 124.59 (t, J=6.2Hz), 120.70,115.54 (t, J=236.9Hz), 76.87,
40.30,39.55,37.61,37.57,37.46,32.96,32.84,31.12,24.97,24.61,24.40,22.88,
22.79,22.42,21.10,19.91,19.81,16.24..ppm.
The application of the difluoromethyl of the bromo-derivative of the Etamivan skeleton of the palladium chtalyst of embodiment 7
Etamivan is that a kind of central is breathed and circulatory failure, arcotic, the poisoning first-aid medication of other central depressants,
In view of the biological isoelectronic species property of difluoromethyl and hydroxyl, we attempt to draw difluoromethyl using the method that we invent
Enter into such molecular skeleton, concrete operations are as follows：Under argon gas atmosphere, by bromo substrate (152.1mg, 0.5mmol), double (two
Ya Benzyl benzylacetones) palladium (41mg, 0.07mmol), 1,1'- double (diphenylphosphine) ferrocene (76mg, 0.14mmol), SIPrAgCl
(113mg, 0.2mmol), sodium tert-butoxide (96.1mg, 1.0mmol) is dissolved in 5.0ml toluene, adds 150uL's into system
Trimethyl difluoro silicon.Room temperature is cooled to after being reacted 6 hours at 80 DEG C, reaction, diatomite mistake is quenched in the distilled water for adding 10ml
Filtrate is extracted (25ml × 3) with dichloromethane after filter, merges organic phase, and anhydrous sodium sulfate drying, concentration, post separation obtains phase
(65%) 83mg, separation yield is to the product for the difluoromethyl answered.
1H NMR(400MHz,CDCl3) δ 7.58 (d, J=7.6Hz, 1H), 7.00 (d, J=7.6Hz, 1H), 6.95 (s,
1H), 6.94 (t, J=55.6Hz, 1H), 3.89 (s, 3H), 3.55 (br, 2H), 3.24 (br, 2H), 1.25~1.13 (m, 6H)
；19F NMR(376MHz,CDCl3)δ-115.88(d,J1=55.6Hz)；13C NMR(101MHz,CDCl3)δ170.28,
157.47 (t, J=5.8Hz), 141.06 (t, J=2.0Hz), 126.45 (t, J=5.8Hz), 123.37 (t, J=22.4Hz),
111.25 (t, J=236.5Hz), 109.27,55.86,43.33,39.40,14.36,12.95ppm
Application in gram level scale of the difluoromethyl of the bromo-derivative of the palladium chtalyst of embodiment 7
In order to further investigate we invention difluoromethyl method practicality, we have been attempted in a gram level scale
On synthesis, specific experiment operation it is as follows：Under argon gas atmosphere, by bromo substrate (2.51g, 10mmol), double (bis- Ya Benzyl bases third
Ketone) palladium (402mg, 0.7mmol), double (diphenylphosphine) ferrocene (776mg, 1.4mmol) of 1,1'-, SIPrAgCl (1.08g,
2mmol), sodium tert-butoxide (1.92g, 20mmol) is dissolved in 100ml toluene, and 3.0mL trimethyl difluoro is added into system
Silicon.Room temperature is cooled to after being reacted 6 hours at 80 DEG C, reaction is quenched in the distilled water for adding 200ml, and filtrate is used after diatomite filtering
Dichloromethane extracts (250ml × 3), merges organic phase, and anhydrous sodium sulfate drying, concentration, post separation obtains corresponding difluoro first
(80%) 1.88g, separation yield is to the product of base.
Claims (16)
1. a kind of compound R CF containing difluoromethyl2H preparation method, it is characterised in that comprise the following steps：Inert gas is protected
Under shield, have additive or without any additive in the case of, in organic solvent, the condition that palladium catalyst, part and alkali are present
Under, compound R X and trimethyl difluoromethyl silicon are subjected to coupling reaction, the compound R CF containing difluoromethyl is obtained2H；
RX+TMSCF2H→RCF2H
Wherein, X is bromine or iodine, and R is C5~C30Aryl, C5~C30Heteroaryl,OrN is 2,3 or 4, R10And R11Various regions be independently methyl, ethyl,
Propyl group or isopropyl；Described " C5~C30Aryl " or described " C5~C30Heteroaryl " in hydrogen atom can be following
One or more of substituent is replaced：Halogen, C1~C12Alkyl, C5~C10Aryl, halogen substitution C5~C10's
Aryl,C4~C15Heteroaryl,C3~
C12Heterocyclylalkyl；R1For C1~C6Alkyl, R2For C1~C20Alkyl, C5~C10Aryl, " C5~C10Aryl substitution
C1~C20Alkyl " or " C3~C10Cycloalkyl substitution C1~C20Alkyl ", R3、R4、R5、R6、R7And R8It is each independent
For C1~C12Alkyl or C5~C10Aryl；R9For C3~C12Heterocyclylalkyl；M is 1,2,3,4,5,6,7,8,9 or 10；
When the X is I, described palladium catalyst is (dibenzalacetone) palladium, three (dibenzalacetone) two palladium, four (three
Phenylphosphine) palladium, palladium bichloride, palladium bromide, palladium iodide, palladium, palladium trifluoroacetate, four acetonitriles close trifluoromethanesulfonic acid palladium, four acetonitriles
P-methyl benzenesulfonic acid palladium, diacetonitrile close palladium bichloride, tetramino and close palladium bichloride, two (triphenylphosphine) palladium bichlorides, palladium nitrate, 1,1'- couple
One or more in (diphenylphosphine) ferrocene palladium chloride and diacetyl acetone palladium；The part is the double (diphenyl of 1,1'-
Phosphine) ferrocene, double diphenylphosphine methane, 1,2 pairs of (diphenylphosphine) ethane, double (diphenylphosphine) propane of 1,3-, 1,1'- dinaphthalenes-
The double diphenyl phosphines of 2,2'-, triphenylphosphine, tricyclohexyl phosphine, the double diphenylphosphine -9,9- dimethyl xanthenes of 4,5-, double (2- diphenyl
Phosphorus phenyl) ether, the phenyl -1'- of 1,2,3,4,5- penta (di-t-butyl phosphorus base) ferrocene, (R) -1- [(S) -2- (dicyclohexylphosphontetrafluoroborates
Base) ferrocenyl] ethyl dicyclohexylphosphontetrafluoroborate, Isosorbide-5-Nitrae-bis- (diphenylphosphine) butane, 1,10 Féraud beautiful jades, 2,2- bipyridyls and tetramethyl
One or more in ethylenediamine；
When the X is Br, described palladium catalyst is (dibenzalacetone) palladium, three (dibenzalacetone) two palladium, four (three
Phenylphosphine) palladium, palladium bichloride, palladium bromide, palladium iodide, palladium, palladium trifluoroacetate, diacetonitrile close palladium bichloride, tetramino close chlorination
In palladium, two (triphenylphosphine) palladium bichlorides, palladium nitrate, 1,1'- double (diphenylphosphine) ferrocene palladium chlorides and diacetyl acetone palladium
One or more；Described part is 1,1'- double (diphenylphosphine) ferrocene, double diphenylphosphine methane, 1,2 pairs of (diphenyl
Phosphine) ethane, double (diphenylphosphine) propane of 1,3-, the double diphenyl phosphines of 1,1'- dinaphthalenes -2,2'-, triphenylphosphine, the double diphenylphosphines of 4,5- -
9,9- dimethyl xanthene, double (2- diphenylphosphines phenyl) ethers, (R) -1- [(S) -2- (dicyclohexyl phosphino-) ferrocenyl] second
One kind in base dicyclohexylphosphontetrafluoroborate, Isosorbide-5-Nitrae-bis- (diphenylphosphines) butane, 1,10 Féraud beautiful jades, 2,2- bipyridyls and tetramethylethylenediamine
Or it is a variety of；
Described alkali is inorganic base, and described alkali is sodium tert-butoxide (NaOtBu), potassium tert-butoxide (KOtBu), Methanaminium, N,N,N-trimethyl-, fluoride
(Me4NF), tetrabutyl ammonium fluoride (TBAF), potassium fluoride (KF), sodium fluoride (NaF), rubidium fluoride RbF (RuF), cesium fluoride (CsF), first
One or more in sodium alkoxide (NaOMe) and potassium methoxide (KOMe)；It is described have additive in the case of, when X be I when, it is described to add
Plus agent is double (2,6- diisopropyl phenyl) -4, the 5- glyoxalidine silver chlorates of 1,3-, double (2,4, the 6- trimethylphenyls) -4 of 1,3-,
5- glyoxalidine silver chlorate, 1,3- double (2,4,6- trimethylphenyls)-imidazoles silver chlorate, 1,3- dicyclohexyls-imidazoles silver chlorate, spies
Valeric acid silver, silver nitrate, silver trifluoromethanesulfonate, silver hexafluoroantimonate, silver tetrafluoroborate, silver acetate, silver carbonate, silver oxide, silver fluoride,
One kind in stannous chloride, cuprous bromide, cuprous iodide, copper sulphate, copper nitrate, iron chloride, frerrous chloride and ferrous sulfate or
It is a variety of；When X is Br, the additive is double (2,6- diisopropyl phenyl) -4, the 5- glyoxalidine silver chlorates of 1,3-, 1,3-
Double (2,4,6- trimethylphenyls) -4,5- glyoxalidine silver chlorates, 1,3- double (2,4,6- trimethylphenyls)-imidazoles silver chlorate, 1,3-
Dicyclohexyl-imidazoles silver chlorate, pivalic acid silver, silver nitrate, silver trifluoromethanesulfonate, silver tetrafluoroborate, silver acetate, silver carbonate, oxygen
Change the one or more in silver, silver fluoride, stannous chloride, cuprous bromide, cuprous iodide, copper sulphate and frerrous chloride.
2. the compound R CF as claimed in claim 1 containing difluoromethyl2H preparation method, it is characterised in that：
When described R is C5~C30Aryl when, described " C5~C30Aryl " be C5~C10Aryl；
When described R is C5~C30Heteroaryl when, described " C5~C30Heteroaryl " be that hetero atom is that oxygen, sulphur or nitrogen are former
Son, hetero atom number are the C of 1~35~C10Heteroaryl.
3. the compound R CF as claimed in claim 2 containing difluoromethyl2H preparation method, it is characterised in that：As described R
For C5~C10Aryl when, described " C5~C10Aryl " be phenyl or naphthyl；
When described R is the C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1~35~C10Heteroaryl when, it is described
" the C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1~35~C10Heteroaryl " be pyridine radicals.
4. the compound R CF as claimed in claim 1 containing difluoromethyl2H preparation method, it is characterised in that：When described
“C5~C30Aryl " or described " C5~C30Heteroaryl " in hydrogen atom when being optionally substituted by halogen, described " halogen " is
Fluorine, chlorine, bromine or iodine；
As described " C5~C30Aryl " or described " C5~C30Heteroaryl " in hydrogen atom by C1~C12Alkyl take
Dai Shi, described " C1~C12Alkyl " be C1~C6Alkyl；
As described " C5~C30Aryl " or described " C5~C30Heteroaryl " in hydrogen atom by C5~C10Aryl take
Dai Shi, described " C5~C10Aryl " be phenyl；
As described " C5~C30Aryl " or described " C5~C30Heteroaryl " in hydrogen atom by the " C that halogen replaces5~
C10Aryl " substitution when, the described " C of halogen substitution5~C10Aryl " described in " C5~C10Aryl " be phenyl, institute
" the C of halogen substitution stated5~C10Aryl " described in " halogen " be fluorine, chlorine, bromine or iodine；
As described " C5~C30Aryl " or described " C5~C30Heteroaryl " in hydrogen atom by C4~C15Heteroaryl
During substitution, described " C4~C15Heteroaryl " be that hetero atom is the C that oxygen, sulphur or nitrogen-atoms, hetero atom number are 1~24~C12's
Heteroaryl；
As described " C5~C30Aryl " or described " C5~C30Heteroaryl " in hydrogen atom by C3~C12Heterocycle alkane
When base replaces, described " C3~C12Heterocyclylalkyl " be that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is the C of 1~33
~C5Heterocyclylalkyl；
As described " C5~C30Aryl " or described " C5~C30Heteroaryl " in hydrogen atom by " C1~C12Alkyl take
The C in generation3~C12Heterocyclylalkyl " substitution when, described " C1~C12Alkyl-substituted C3~C12Heterocyclylalkyl " described in
" C1~C12Alkyl " be C1~C6Alkyl；
As described R1For C1~C6Alkyl when, described " C1~C6Alkyl " be methyl, ethyl, propyl group, isopropyl, positive fourth
Base, isobutyl group, the tert-butyl group, 1- amyl groups, 2- amyl groups, 3- amyl groups, 1- hexyls, 2- hexyls or 3- hexyls；
As described R2For C1~C20Alkyl when, described " C1~C20Alkyl " be C1~C10Alkyl；
As described R2For C5~C10Aryl when, described " C5~C10Aryl " be phenyl；
As described R2For " C5~C10Aryl substitution C1~C20Alkyl " when, described " C5~C10Aryl substitution C1
~C20Alkyl " described in " C5~C10Aryl " be phenyl；
As described R2For " C3~C10Cycloalkyl substitution C1~C20Alkyl " when, described " C3~C10Cycloalkyl substitution
C1~C20Alkyl " described in " C1~C20Alkyl " be C1~C10Alkyl；
As described R3、R4、R5、R6、R7And R8It is independently each C1~C12Alkyl when, described " C1~C12Alkyl " be
C1~C6Alkyl；
As described R3、R4、R5、R6、R7And R8It is independently each C5~C10Aryl when, described " C5~C10Aryl " be
Phenyl；
As described R9For C3~C12Heterocyclylalkyl when, described " C3~C12Heterocyclylalkyl " be that hetero atom is oxygen, sulphur or nitrogen
Atom, hetero atom number is the C of 1~33~C5Heterocyclylalkyl.
5. the compound R CF as claimed in claim 4 containing difluoromethyl2H preparation method, it is characterised in that：
As described " C5~C30Aryl " or described " C5~C30Heteroaryl " in hydrogen atom by C1~C6Alkyl substitution
When, described " C1~C6Alkyl " be methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, 1- amyl groups, 2-
Amyl group, 3- amyl groups, 1- hexyls, 2- hexyls or 3- hexyls；
As described " C5~C30Aryl " or described " C5~C30Heteroaryl " in hydrogen atom by the " benzene that halogen replaces
When base " replaces, described " phenyl " is 3- phenyl or 4- phenyl；
As described " C5~C30Aryl " or described " C5~C30Heteroaryl " in hydrogen atom by hetero atom be oxygen, sulphur or
Nitrogen-atoms, hetero atom number are 1~2 C4~C12Heteroaryl substitution when, it is described that " hetero atom is oxygen, sulphur or nitrogen-atoms, miscellaneous original
Subnumber is 1~2 C4~C12Heteroaryl " be pyrrole radicals or benzothiazolyl；
As described " C5~C30Aryl " or described " C5~C30Heteroaryl " in hydrogen atom by hetero atom be oxygen, sulphur or
Nitrogen-atoms, hetero atom number is the C of 1~33~C5Heterocyclylalkyl substitution when, it is described " hetero atom is oxygen, sulphur or nitrogen-atoms,
Hetero atom number is the C of 1~33~C5Heterocyclylalkyl " be
As described " C5~C30Aryl " or described " C5~C30Heteroaryl " in hydrogen atom by " C1~C6Alkyl take
The C in generation3~C12Heterocyclylalkyl " substitution when, described " C1~C6Alkyl-substituted C3~C12Heterocyclylalkyl " described in
“C3~C12Heterocyclylalkyl " be that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is the C of 1~33~C5Heterocyclylalkyl；
As described R2For C1~C10Alkyl when, described " C1~C10Alkyl " for methyl, ethyl, propyl group, isopropyl, just
Butyl, isobutyl group, the tert-butyl group, 1- amyl groups, 1- hexyls, 1- heptyl, 1- octyl groups, 1- nonyls or 1- decyls；
As described R2The C replaced for phenyl1~C20Alkyl when, the described " C of phenyl substitution1~C20Alkyl " described in
" C1~C20Alkyl " be C1~C10Alkyl；
As described R2For C3~C10Cycloalkyl substitution C1~C10Alkyl when, described " C3~C10Cycloalkyl substitution
C1~C10Alkyl " described in " C3~C10Cycloalkyl " be C3~C6Cycloalkyl；
As described R3、R4、R5、R6、R7And R8It is independently each C1~C6Alkyl when, described " C1~C6Alkyl " be first
Base, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, 1- amyl groups, 2- amyl groups, 3- amyl groups, 1- hexyls, 2- hexyls or
3- hexyls；
As described R9It is oxygen, sulphur or nitrogen-atoms for hetero atom, hetero atom number is the C of 1~33~C5Heterocyclylalkyl when, institute
State " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is the C of 1~33~C5Heterocyclylalkyl " be morpholinyl.
6. the compound R CF as claimed in claim 5 containing difluoromethyl2H preparation method, it is characterised in that：
As described " C5~C30Aryl " or described " C5~C30Heteroaryl " in hydrogen atom by " the 4- benzene that halogen replaces
When base " replaces, described " the 4- phenyl of halogen substitution " is the bromo- phenyl of 4-；
As described " C5~C30Aryl " or described " C5~C30Heteroaryl " in hydrogen atom when being replaced by pyrrole radicals, institute
" pyrrole radicals " stated is 1- pyrrole radicals；
As described " C5~C30Aryl " or described " C5~C30Heteroaryl " in hydrogen atom replaced by benzothiazolyl
When, described " benzothiazolyl " is
As described " C5~C30Aryl " or described " C5~C30Heteroaryl " in hydrogen atom by " C1~C6Alkyl take
The hetero atom in generation is oxygen, sulphur or nitrogen-atoms, and hetero atom number is the C of 1~33~C5Heterocyclylalkyl " when replacing, it is described
“C1~C6Alkyl-substituted hetero atom be oxygen, sulphur or nitrogen-atoms, hetero atom number is the C of 1~33~C5Heterocyclylalkyl " in
Described " C1~C6Alkyl " be methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, 1- amyl groups, 2- penta
Base, 3- amyl groups, 1- hexyls, 2- hexyls or 3- hexyls；
As described R2For " the C of phenyl substitution1~C10Alkyl " when, the described " C of phenyl substitution1~C10Alkyl " in institute
" the C stated1~C10Alkyl " for methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, 1- amyl groups, 1- hexyls,
1- heptyl, 1- octyl groups, 1- nonyls or 1- decyls；
As described R2For " C3~C6Cycloalkyl substitution C1~C10Alkyl " when, described " C3~C6Cycloalkyl substitution
C1~C10Alkyl " described in " C3~C6Cycloalkyl " be cyclopropyl；
As described R9During for morpholinyl, described " morpholinyl " is
7. the compound R CF as claimed in claim 6 containing difluoromethyl2H preparation method, it is characterised in that：
As described " C5~C30Aryl " or described " C5~C30Heteroaryl " in hydrogen atom by " methyl substituted miscellaneous original
Son is oxygen, sulphur or nitrogen-atoms, and hetero atom number is the C of 1~33~C5Heterocyclylalkyl " when replacing, it is described that " methyl replaces
Hetero atom be oxygen, sulphur or nitrogen-atoms, hetero atom number is the C of 1~33~C5Heterocyclylalkyl " be
As described R2The C replaced for cyclopropyl1~C10Alkyl when, described " C1~C10Alkyl " be methyl, ethyl, third
Base, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, 1- amyl groups, 1- hexyls, 1- heptyl, 1- octyl groups, 1- nonyls or 1- decyls.
8. the compound R CF containing difluoromethyl as described in any one of claim 1~72H preparation method, it is characterised in that：
Described R is selected from following any substituent：
9. the compound R CF as claimed in claim 1 containing difluoromethyl2H preparation method, it is characterised in that：Described is " lazy
Property gas shield " described in " inert gas " be helium, neon, argon gas and nitrogen in one or more；
And/or,
Described organic solvent is in ether solvent, halogenated hydrocarbon solvent, amide solvent, nitrile solvents and aromatic hydrocarbon solvent
It is one or more；
And/or,
Described organic solvent and described RX Molar ratio are 1mL/mmol~100mL/mmol；
And/or,
Described TMSCF2H and described RX molar ratio is 5~1；
And/or,
Described palladium catalyst and described RX molar ratio are 0.0001~0.1；
And/or,
Described alkali and compound R X molar ratio are 5~1；
And/or,
Described part and the molar ratio of palladium catalyst are 3~0.5；
And/or,
Described coupling reaction temperature is 25 DEG C~150 DEG C；
And/or,
The time of described coupling reaction is 1 hour~48 hours.
10. the compound R CF as claimed in claim 9 containing difluoromethyl2H preparation method, it is characterised in that：
Described additive and described RX molar ratio are 0.001~1.
11. the compound R CF containing difluoromethyl as described in claim 9 or 102H preparation method, it is characterised in that：When X is
During iodine, using following reaction condition：
Described ether solvent be dioxane, tetrahydrofuran, glycol dimethyl ether and diethylene glycol dimethyl ether in one kind or
It is a variety of；
And/or,
Described halogenated hydrocarbon solvent is chlorinated hydrocarbon solvent, described amide solvent for DMF and/or
DMAC N,N' dimethyl acetamide；
And/or,
Described nitrile solvents are acetonitrile；
And/or,
Described aromatic hydrocarbon solvent is toluene；
And/or,
Described organic solvent and described RX Molar ratio are 1mL/mmol~10mL/mmol；
And/or,
Described TMSCF2H and described RX mol ratio is 5~2；
And/or,
Described palladium catalyst is (dibenzalacetone) palladium, three (dibenzalacetone) two palladium, tetrakis triphenylphosphine palladium, chlorination
One or more in palladium and double (diphenylphosphine) the ferrocene palladium chlorides of 1,1'-；
And/or,
Described palladium catalyst and described RX mol ratio are 0.01~0.1；
And/or,
Described inorganic base is the one or more in sodium tert-butoxide, Methanaminium, N,N,N-trimethyl-, fluoride and cesium fluoride；
And/or,
Described alkali and compound R X molar ratio are 3~1；
And/or,
Described part is 1,1'- double (diphenylphosphine) ferrocene, double diphenylphosphine methane, 1,2 pairs of (diphenylphosphine) ethane, 1,
It is the double diphenyl phosphines of double (diphenylphosphine) propane of 3-, 1,1'- dinaphthalenes -2,2'-, the double diphenylphosphine -9,9- dimethyl xanthenes of 4,5-, double
One or more in (2- diphenylphosphines phenyl) ether and double (diphenylphosphine) butane of 1,4-；
And/or,
Described part and compound R X molar ratio are 0.025~0.5；
And/or,
Described coupling reaction temperature is 60 DEG C~100 DEG C；
And/or,
The time of described coupling is 2 hours~30 hours；
And/or,
Described additive is double (2,6- diisopropyl phenyl) -4, the 5- glyoxalidine silver chlorates of 1,3-, 1,3- double (2,4,6- tri-
Tolyl) -4,5- glyoxalidine silver chlorate, double (2,4,6- the trimethylphenyls)-imidazoles silver chlorates of 1,3-, pivalic acid silver, silver nitrate,
One or more in silver trifluoromethanesulfonate, silver hexafluoroantimonate, silver tetrafluoroborate, stannous chloride and cuprous iodide；
And/or,
Described additive and described RX molar ratio are 0.08~1.
12. the compound R CF as claimed in claim 11 containing difluoromethyl2H preparation method, it is characterised in that：Described has
Machine solvent is dioxane, tetrahydrofuran, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, toluene, dioxane and four
The mixed solvent or dioxane and the mixed solvent of glycol dimethyl ether of the mixed solvent of hydrogen furans, dioxane and acetonitrile；
And/or,
Described TMSCF2H and described RX mol ratio is 2.4~2；
And/or,
Described palladium catalyst is (dibenzalacetone) palladium and/or three (dibenzalacetone) two palladium；
And/or,
Described palladium catalyst and described RX mol ratio are 0.02~0.1；
And/or,
Described inorganic base is sodium tert-butoxide；
And/or,
Described part is double (diphenylphosphine) ferrocene of 1,1'-, double diphenylphosphine -9,9- dimethyl xanthenes of 4,5- and double
One or more in (2- diphenylphosphines phenyl) ether；
And/or,
Described part and compound R X molar ratio are 0.05~0.3；
And/or,
Described coupling reaction temperature is 70 DEG C~100 DEG C；
And/or,
The time of described coupling is 3 hours~4 hours；
And/or,
Described additive is double (2,6- diisopropyl phenyl) -4, the 5- glyoxalidine silver chlorates of 1,3-, 1,3- double (2,4,6- tri-
Tolyl) one or more in -4,5- glyoxalidine silver chlorate, silver nitrate and silver hexafluoroantimonate；
And/or,
Described additive and described RX molar ratio are 0.1~1.
13. the compound R CF as claimed in claim 12 containing difluoromethyl2H preparation method, it is characterised in that：
When the mixed solvent using dioxane and tetrahydrofuran, the volume of described dioxane and described tetrahydrofuran
Ratio is 1~5；When the mixed solvent using dioxane and acetonitrile, the volume of described dioxane and described acetonitrile
Ratio is 1~5；When the mixed solvent using dioxane and glycol dimethyl ether, described dioxane and described second
The volume ratio of glycol dimethyl ether is 1~5；
And/or,
Described part is double (diphenylphosphine) ferrocene of 1,1'-；
And/or,
Described part and compound R X molar ratio are 0.1~0.15；
And/or,
Described coupling reaction temperature is 80 DEG C~90 DEG C；
And/or,
Described additive is double (2,6- diisopropyl phenyl) -4,5- glyoxalidine silver chlorates of 1,3-.
14. the compound R CF containing difluoromethyl as described in claim 9 or 102H preparation method, it is characterised in that：When X is
During bromine, using following reaction condition：
Described ether solvent be dioxane, tetrahydrofuran, glycol dimethyl ether and diethylene glycol dimethyl ether in one kind or
It is a variety of；
And/or,
Described halogenated hydrocarbon solvent is chlorinated hydrocarbon solvent；
And/or,
Described amide solvent is N,N-dimethylformamide and/or DMAC N,N' dimethyl acetamide；
And/or,
Described nitrile solvents are acetonitrile；
And/or,
Described aromatic hydrocarbon solvent is toluene；
And/or,
Described organic solvent and described RX Molar ratio are 1mL/mmol~10mL/mmol；
And/or,
Described TMSCF2H and described RX molar ratio is 5~2；
And/or,
Described palladium catalyst be (dibenzalacetone) palladium, three (dibenzalacetone) two palladium, tetrakis triphenylphosphine palladium and 1,
One or more in double (diphenylphosphine) the ferrocene palladium chlorides of 1'-；
And/or,
Described palladium catalyst and described RX molar ratio are 0.01~0.1；
And/or,
Described inorganic base is the one or more in sodium tert-butoxide, Methanaminium, N,N,N-trimethyl-, fluoride and cesium fluoride；
And/or,
Described alkali and compound R X molar ratio are 3~1；
And/or,
Described part is 1,1'- double (diphenylphosphine) ferrocene, double diphenylphosphine methane, 1,2 pairs of (diphenylphosphine) ethane, 1,
The double diphenyl phosphines of 1'- dinaphthalenes -2,2'-, the double diphenylphosphine -9,9- dimethyl xanthenes of 4,5-, double (2- diphenylphosphines phenyl) ethers and
One or more in double (diphenylphosphine) butane of 1,4-；
And/or,
Described part and compound R X molar ratio are 0.025~0.5；
And/or,
The temperature of described coupling reaction is 60 DEG C~100 DEG C；
And/or,
The time of described coupling reaction is 2 hours~30 hours；
And/or,
Described additive is double (2,6- diisopropyl phenyl) -4, the 5- glyoxalidine silver chlorates of 1,3-, 1,3- double (2,4,6- tri-
Tolyl) -4,5- glyoxalidine silver chlorate, double (2,4,6- the trimethylphenyls)-imidazoles silver chlorates of 1,3-, pivalic acid silver, silver nitrate,
One or more in silver trifluoromethanesulfonate, silver carbonate and stannous chloride；
And/or,
Described additive and described RX molar ratio are 0.01~1.
15. the compound R CF as claimed in claim 14 containing difluoromethyl2H preparation method, it is characterised in that：
Described organic solvent be dioxane, tetrahydrofuran, dichloromethane, toluene, the mixed solvent of toluene and tetrahydrofuran,
The mixed solvent or toluene and the mixed solvent of glycol dimethyl ether of the mixed solvent of dioxane and toluene, toluene and acetonitrile；
And/or,
Described TMSCF2H and described RX molar ratio is 3~2；
And/or,
Described palladium catalyst is (dibenzalacetone) palladium and/or three (dibenzalacetone) two palladium；
And/or,
Described palladium catalyst and described RX molar ratio are 0.05~0.1；
And/or,
Described inorganic base is sodium tert-butoxide；
And/or,
Described part is double (diphenylphosphine) ferrocene of 1,1'-, double diphenylphosphine -9,9- dimethyl xanthenes of 4,5- and double
One or more in (2- diphenylphosphines phenyl) ether；
And/or,
Described part and compound R X molar ratio are 0.1~0.3；
And/or,
Described coupling reaction temperature is 70 DEG C~100 DEG C；
And/or,
The time of described coupling reaction is 3 hours~16 hours；
And/or,
Described additive is double (2,6- diisopropyl phenyl) -4, the 5- glyoxalidine silver chlorates of 1,3-, 1,3- double (2,4,6- tri-
Tolyl) one or more in -4,5- glyoxalidine silver chlorate and silver nitrate；
And/or,
Described additive and described RX molar ratio are 0.1~0.2.
16. the compound R CF as claimed in claim 15 containing difluoromethyl2H preparation method, it is characterised in that：When using first
During the mixed solvent of benzene and tetrahydrofuran, described toluene and the volume ratio of described tetrahydrofuran are 1~5；When using two
During the mixed solvent of the ring of oxygen six and toluene, described dioxane and the volume ratio of described toluene are 1~5；When using first
During the mixed solvent of benzene and acetonitrile, described toluene and the volume ratio of described acetonitrile are 1~5；When using toluene and second
During the mixed solvent of glycol dimethyl ether, described toluene and the volume ratio of described glycol dimethyl ether are 1~5；
And/or,
Described TMSCF2H and described RX molar ratio is 2.4；
And/or,
Described part is double (diphenylphosphine) ferrocene of 1,1'-；
And/or,
Described coupling reaction temperature is 80 DEG C~90 DEG C；
And/or,
The time of described coupling reaction is 4 hours~12 hours；
And/or,
Described additive is double (2,6- diisopropyl phenyl) -4,5- glyoxalidine silver chlorates of 1,3-.
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|---|---|---|---|---|
| CN104650120A (en) * | 2013-11-19 | 2015-05-27 | 中国科学院上海有机化学研究所 | Difluoromethyl silver compound, single crystal, synthetic method and application |
Non-Patent Citations (3)
| Title |
|---|
| Copper-Mediated Difluoromethylation of (Hetero)aryl Iodides and b-Styryl Halides with Tributyl(difluoromethyl)stannane;G.K.Surya Prakash et al.;《Angew. Chem. Int. Ed.》;20121025;第51卷;12090-12094 * |
| Copper-Mediated Difluoromethylation of Aryl and Vinyl Iodides;Patrick S. Fier et al.;《Journal of the American Chemical Society》;20120307;第134卷;5524-5527 * |
| rn：1366392-22-4，1307239-07-1，915799-67-6，140135-76-8，139219-68-4，114467-73-1，53731-26-3;STN Columbus;《REGISTRY》;20120411;rn：1366392-22-4，1307239-07-1，915799-67-6，140135-76-8，139219-68-4，114467-73-1，53731-26-3 * |
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