CN105085129A - Compound containing difluromethylation and preparation method therefor - Google Patents
Compound containing difluromethylation and preparation method therefor Download PDFInfo
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- CN105085129A CN105085129A CN201410192590.2A CN201410192590A CN105085129A CN 105085129 A CN105085129 A CN 105085129A CN 201410192590 A CN201410192590 A CN 201410192590A CN 105085129 A CN105085129 A CN 105085129A
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Abstract
The invention discloses a compound containing difluromethylation and a preparation method therefor. The invention provides a preparation method of a compound RCF2H containing the difluromethylation. The preparation method comprises the following steps of: under the protection of inert gas, performing a coupling reaction on a compound RX and trimethyl difluromethylation silicon in an organic solvent under the existing conditions of a palladium catalyst, a ligand and alkali so as to obtain the compound RCF2H containing the difluromethylation. Through the adoption of the difluromethylation reaction of the compound disclosed by the invention, the difluromethylation of the compound with various aryl halogen compounds such as aryl iodide, aryl bromide and natural products (such as estrone or vitamin E) can be realized, the conditions of the type of reactions are mild, raw materials are cheap and easy to obtain, the conversion rate of the reaction is high, the compatibility of base groups is good, and the compound has a good market application prospect. RX+TMSCF2H -> RCF2H
Description
Technical field
The present invention relates to the compound and preparation method thereof containing difluoromethyl.
Background technology
By introducing fluorine atom and fluoroalkyl can well strengthen the fat-soluble of its and metabolic stability in drug molecule, in molecule, introduce fluorine atom and fluoroalkyl in the last few years becomes developing direction in the compounding design of drug molecule.In numerous fluoroalkyls, difluoromethyl can be simulated hydroxyl or sulfydryl due to it and be become the fluoroalkyl group that in SARS drug design, a class is important on physiologically active.Therefore in molecule, introduce difluoromethyl become an important topic in pharmaceutical chemistry and organic fluorine chemistry.But the direct difluoromethyl Measures compare that the transition metal of known report participates in is few, and (background document 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 steps of report is loaded down with trivial details, substrate narrow application range, reaction conversion ratio are low, production cost is high, be not suitable for suitability for industrialized production.Such as, report in U.S. chemical abstract (J.Am.Chem.Soc.2012,134,5524-5527) and adopt the cuprous halide of 1-3 equivalent under cesium fluoride existent condition, 120 DEG C, 4-butyl iodobenzene and TMSCF
2h carries out reacting the compound of preparation containing difluoromethyl.But the consumption of this reaction cuprous halide is large, and temperature of reaction is high, long reaction time, and applicable substrate spectrum is narrow, is not suitable for suitability for industrialized production.Therefore, finding that a kind of suitable substrates scope is wide, reaction method is simple, reaction conditions is gentle, transformation efficiency is high, cheaper starting materials is easy to get, be suitable for the method for the introducing difluoromethyl of suitability for industrialized production is current urgent problem.
Summary of the invention
Technical problem to be solved by this invention is that compou nd synthesis method steps with difluoromethyl in prior art is loaded down with trivial details in order to overcome, route length, low conversion rate, cost of material is expensive, production cost is high, be not suitable for the defects such as suitability for industrialized production, and provides a kind of compound containing difluoromethyl and preparation method thereof.The difluoromethylization reaction of the present invention's report can realize realizing difluoromethyl with the multiple aryl halides such as aryl iodide, aryl bromide and natural product (such as oestrone or vitamin-E), such reaction conditions is gentle, cheaper starting materials is easy to get, reaction conversion ratio is high, group is compatible good, has good market application foreground.
The invention provides a kind of compound R CF containing difluoromethyl
2the preparation method of H, it comprises the following steps: under protection of inert gas, in organic solvent, under palladium catalyst, part and alkali existent condition, compound R X and trimethylammonium difluoromethyl silicon is carried out linked reaction, obtains the compound R CF containing difluoromethyl
2h;
RX+TMSCF
2H→RCF
2H
Wherein, X is bromine or iodine, and R is C
5~ C
30aryl (preferred C
5~ C
10aryl, described " C
5~ C
10aryl " preferred phenyl or naphthyl, described phenyl is preferred further
described " naphthyl " is preferred
), C
5~ C
30the heteroaryl (C that preferred heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1 ~ 3
5~ C
10heteroaryl, the described " C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1 ~ 3
5~ C
10heteroaryl " preferred pyridyl, described pyridyl is preferred
),
or
n is 2,3 or 4, R
10and R
11various places are independently methyl, ethyl, propyl group or sec.-propyl, described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom can be replaced by one or more in substituents: halogen (such as fluorine, chlorine, bromine or iodine), C
1~ C
12alkyl (described " C
1~ C
12alkyl " preferred C
1~ C
6alkyl, described " C
1~ C
6alkyl " such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, 1-amyl group, 2-amyl group, 3-amyl group, 1-hexyl, 2-hexyl or 3-hexyl), C
5~ C
10aryl (described " C
5~ C
10aryl " preferred phenyl), the C of halogen substiuted
5~ C
10aryl (described " the C of halogen substiuted
5~ C
10aryl " described in " C
5~ C
10aryl " preferred phenyl, described " phenyl " be 3-phenyl or 4-phenyl preferably, the described " C of halogen substiuted
5~ C
10aryl " described in " halogen " such as fluorine, chlorine, bromine or iodine, preferred fluorine, chlorine or bromine, the number of described " halogen " preferably 1 ~ 2, the described " C of halogen substiuted
5~ C
10aryl " the preferred bromo-phenyl of 4-),
c
4~ C
15heteroaryl (preferred heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is the C of 1 ~ 2
4~ C
12heteroaryl, it is described that " heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is the C of 1 ~ 2
4~ C
12heteroaryl " preferably pyrryl, benzothiazolyl or 9-azepine tablet held before the breast by officials base, described " pyrryl " be 1-pyrryl preferably, and described " benzothiazolyl " is preferred
described " 9-azepine tablet held before the breast by officials base " is preferred
),
c
3~ C
12heterocyclylalkyl (preferred heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the C of 1 ~ 3
3~ C
5heterocyclylalkyl, it is described that " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the C of 1 ~ 3
3~ C
5heterocyclylalkyl " preferably
) or " C
1~ C
12alkyl replace C
3~ C
12heterocyclylalkyl " (described " C
1~ C
12alkyl replace C
3~ C
12heterocyclylalkyl " described in " C
1~ C
12alkyl " preferred C
1~ C
6alkyl, described " C
1~ C
6alkyl " such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, 1-amyl group, 2-amyl group, 3-amyl group, 1-hexyl, 2-hexyl or 3-hexyl; Described " C
1~ C
12alkyl replace C
3~ C
12heterocyclylalkyl " described in " C
3~ C
12heterocyclylalkyl " preferably heteroatoms be oxygen, sulphur or nitrogen-atoms, heteroatoms number is the C of 1 ~ 3
3~ C
5heterocyclylalkyl, it is described that " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the C of 1 ~ 3
3~ C
5heterocyclylalkyl " preferably
described " by C
1~ C
12the C that replaces of alkyl
3~ C
12heterocyclylalkyl " preferred further
).R
1for C
1~ C
6alkyl (described " C
1~ C
6alkyl " such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, 1-amyl group, 2-amyl group, 3-amyl group, 1-hexyl, 2-hexyl or 3-hexyl).R
2for C
1~ C
20alkyl (described " C
1~ C
20alkyl " preferred C
1~ C
10alkyl, described " C
1~ C
10alkyl " such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, 1-amyl group, 1-hexyl, 1-heptyl, 1-octyl group, 1-nonyl or 1-decyl), C
5~ C
10aryl (described " C
5~ C
10aryl " preferred phenyl), " C
5~ C
10aryl replace C
1~ C
20alkyl " (described " C
5~ C
10aryl replace C
1~ C
20alkyl " described in " C
5~ C
10aryl " preferred phenyl; Described " C
5~ C
10aryl replace C
1~ C
20alkyl " described in " C
1~ C
20alkyl " preferred C
1~ C
10alkyl, described " C
1~ C
10alkyl " such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, 1-amyl group, 1-hexyl, 1-heptyl, 1-octyl group, 1-nonyl or 1-decyl; Described " C
5~ C
10aryl replace C
1~ C
20alkyl " preferred benzyloxy) or " C
3~ C
10the C of cycloalkyl substituted
1~ C
20alkyl " (described " C
3~ C
10the C of cycloalkyl substituted
1~ C
20alkyl " described in " C
1~ C
20alkyl " preferred C
1~ C
10alkyl, described " C
1~ C
10alkyl " such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, 1-amyl group, 1-hexyl, 1-heptyl, 1-octyl group, 1-nonyl or 1-decyl; Described " C
3~ C
10the C of cycloalkyl substituted
1~ C
20alkyl " described in " C
3~ C
10cycloalkyl " preferred C
3~ C
6cycloalkyl, described " C
3~ C
6cycloalkyl " preferred cyclopropyl; Described " C
3~ C
10the C of cycloalkyl substituted
1~ C
20alkyl " preferably
).R
3, R
4, R
5, R
6, R
7and R
8be independently C separately
1~ C
12alkyl (described " C
1~ C
12alkyl " preferred C
1~ C
6alkyl, described " C
1~ C
6alkyl " such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, 1-amyl group, 2-amyl group, 3-amyl group, 1-hexyl, 2-hexyl or 3-hexyl) or C
5~ C
10aryl (described " C
5~ C
10aryl " preferred phenyl).R
9for C
3~ C
12heterocyclylalkyl (described " C
3~ C
12heterocyclylalkyl " preferably heteroatoms be oxygen, sulphur or nitrogen-atoms, heteroatoms number is the C of 1 ~ 3
3~ C
5heterocyclylalkyl, it is described that " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the C of 1 ~ 3
3~ C
5heterocyclylalkyl " preferred morpholinyl, described " morpholinyl " is preferred
).M is 1,2,3,4,5,6,7,8,9 or 10.
In the present invention, described R is preferably as follows arbitrary substituting group further:
In the present invention, described RCF
2h is preferably as follows arbitrary compound further,
In the present invention, " rare gas element " described in described " protection of inert gas " can be the GPF (General Protection False gas of this generic operation in this area, one or more in the present invention in preferred helium, neon, argon gas and nitrogen.
In the present invention, described organic solvent can be the conventional organic solvent of such linked reaction in this area, one or more in the present invention particularly preferably in ether solvent, halogenated hydrocarbon solvent, amide solvent, nitrile solvents and aromatic hydrocarbon solvent.One or more in the preferred dioxane of described ether solvent, tetrahydrofuran (THF), glycol dimethyl ether and diethylene glycol dimethyl ether; The preferred methylene dichloride of described chlorinated hydrocarbon solvent and/or 1,2 ,-ethylene dichloride; The preferred DMF of described amide solvent and/or N,N-dimethylacetamide; The preferred acetonitrile of described nitrile solvents; The preferred toluene of described aromatic hydrocarbon solvent.
In the present invention, described organic solvent is preferably the organic solvent except deoxidation.Organic solvent can according to the routine operation of organic solvent deoxygenation in this area except the operation of deoxidation, such as bubbling deoxygenation.
In the present invention, the Molar of described organic solvent and described RX is than preferred 1mL/mmol ~ 100mL/mmol.
In the present invention, described TMSCF
2the molar ratio of H and described RX preferably 5 ~ 1.
In the present invention, described palladium catalyst is palladium catalyst conventional in linked reaction in this area, preferred (dibenzalacetone) palladium (Pd (dba) in the present invention
2), three (dibenzalacetone) two palladium (Pd
2(dba)
3), tetrakis triphenylphosphine palladium (Pd (PPh
3)
4), Palladous chloride (PdCl
2), palladium bromide (PdBr
2), palladium iodide (PdI
2), palladium (Pd (OAc)
2), palladium trifluoroacetate (Pd (TFA)
2), a hydration trifluoromethanesulfonic acid palladium (Pd (OTf)
2(H
2o)), four acetonitriles close trifluoromethanesulfonic acid palladium (Pd (OTf)
2(MeCN)
4), four acetonitrile tosic acid palladium (Pd (OTs)
2(MeCN)
4), diacetonitrile closes Palladous chloride (PdCl
2(MeCN)
2), two cyanophenyls close Palladous chloride (PdCl
2(PhCN)
2), tetramino closes Palladous chloride (PdCl
2(NH
3)
4), two (triphenylphosphine) Palladous chloride (PdCl
2(PPh
3)
2), four acetonitriles close fluoroboric acid palladium (Pd (BF
4)
2(MeCN)
4), Palladous nitrate (Pd (NO
3)
2), 1,1'-two (diphenylphosphine) ferrocene palladium chloride ((dppf) PdCl
2) and diacetyl acetone palladium (Pd (acac)
2) in one or more.
In the present invention, the molar ratio of described palladium catalyst and described RX preferably 0.0001 ~ 0.1.
In the present invention, the conventional alkali matched with palladium catalyst when described alkali is linked reaction in this area, preferred mineral alkali in the present invention, described mineral alkali preferred tertiary sodium butylate (NaO
tbu), potassium tert.-butoxide (KO
tbu), Methanaminium, N,N,N-trimethyl-, fluoride (Me
4nF), tetrabutyl ammonium fluoride (TBAF), Potassium monofluoride (KF), Sodium Fluoride (NaF), rubidium fluoride (RuF), cesium fluoride (CsF), trimethyl carbinol lithium (LiO
tbu) one or more, in sodium methylate (NaOMe), lithium methoxide (LiOMe) and potassium methylate (KOMe).
In the present invention, the molar ratio of described alkali and compound R X preferably 5 ~ 1.
In the present invention, described part is the conventional ligands carrying out with palladium metal in this area coordinating, in the present invention preferably 1,1'-two (diphenylphosphine) ferrocene (dppf), two diphenylphosphine methane (dppm), 1,2 pairs of (diphenylphosphine) ethane (dppe), 1, two (diphenylphosphine) propane (dppp) of 3-, 1,1'-dinaphthalene-2,2'-two diphenyl phosphine (Binap), triphenylphosphine (PPh
3), tri-butyl phosphine (P
tbu
3), tricyclohexyl phosphine (PCy
3), 4, the two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (Xantphos), two (2-diphenylphosphine phenyl) ether (DPEPhos), (2-dicyclohexyl phosphino--3, 6-dimethoxy-2', 4', 6'-tri-tert-1, 1'-biphenyl) [2-(2-amino-ethyl phenyl)] palladium (II) (BrettPhos), 1, 2, 3, 4, 5-penta phenyl-1'-(di-t-butyl phosphorus base) ferrocene (Q-Phos), (R)-1-[(S)-2-(dicyclohexyl phosphino-) ferrocenyl] ethyl dicyclohexylphosphontetrafluoroborate (Josiphos), 1, two (diphenylphosphine) butane (dppb) of 4-, 1, 10 Féraud beautiful jades (1, 10-phen), 2, one or more in 2-dipyridyl (Bypyridine) and Tetramethyl Ethylene Diamine (TMEDA).
In the present invention, described part and the molar ratio of palladium catalyst preferably 3 ~ 0.5.
In the present invention, described linked reaction temperature preferably 25 DEG C ~ 150 DEG C.
In the present invention, described linked reaction process can adopt the traditional test methods in this area (such as TLC, HPLC or NMR) to monitor, for reaction end when generally disappearing with compound R X, and preferably 1 hour ~ 48 hours reaction times.
In the present invention, described linked reaction can be carried out under additive existent condition, described additive be carry out with palladium catalyst in this area with the use of conventional additives, in the present invention preferably 1, 3-two (2, 6-diisopropyl phenyl)-4, 5-glyoxalidine silver chloride (SIPrAgCl), 1, 3-two (2, 6-diisopropyl phenyl)-imidazoles silver chloride (IPrAgCl), 1, 3-two (2, 4, 6-trimethylphenyl)-4, 5-glyoxalidine silver chloride (SIMesAgCl), 1, 3-two (2, 4, 6-trimethylphenyl)-imidazoles silver chloride (ImesAgCl), 1, 3-dicyclohexyl-imidazoles silver chloride (ICyAgCl), trimethylacetic acid silver (AgOPiv), Silver Nitrate (AgNO
3), silver trifluoromethanesulfonate (AgOTf), phosphofluoric acid silver (AgPF
6), silver hexafluoroantimonate (AgSbF
6), silver tetrafluoroborate (AgBF
4), Silver monoacetate (AgOAc), silver carbonate (Ag
2cO
3), silver suboxide (Ag
2o), silver fluoride (AgF), cuprous chloride (CuCl), cuprous bromide (CuBr), cuprous iodide (CuI), copper sulfate (CuSO
4), cupric nitrate (Cu (NO
3)
2), iron(ic) chloride (FeCl
3), iron protochloride (FeCl
2) and ferrous sulfate (FeSO
4) in one or more.
In the present invention, when described linked reaction is carried out under additive existent condition, the molar ratio of described additive and described RX preferably 0.001 ~ 1.
In the present invention, when X is iodine, preferably adopt following reaction conditions:
In the present invention, " rare gas element " described in described " protection of inert gas " can be the GPF (General Protection False gas of this generic operation in this area, one or more in the present invention in preferred helium, neon, argon gas and nitrogen.
In the present invention, described organic solvent can be the conventional organic solvent of such linked reaction in this area, one or more in the present invention particularly preferably in ether solvent, halogenated hydrocarbon solvent, amide solvent, nitrile solvents and aromatic hydrocarbon solvent.One or more in the preferred dioxane of described ether solvent, tetrahydrofuran (THF), glycol dimethyl ether and diethylene glycol dimethyl ether, further preferably dioxane and/or tetrahydrofuran (THF).The preferred chlorinated hydrocarbon solvent of described halogenated hydrocarbon solvent; The preferred methylene dichloride of described chlorinated hydrocarbon solvent and/or 1,2 ,-ethylene dichloride; The preferred DMF of described amide solvent and/or N,N-dimethylacetamide; The preferred acetonitrile of described nitrile solvents; The preferred toluene of described aromatic hydrocarbon solvent.Described organic solvent is preferred dioxane, tetrahydrofuran (THF), N further, dinethylformamide, N,N-dimethylacetamide, toluene, dioxane and the mixed solvent of tetrahydrofuran (THF), dioxane and the mixed solvent of acetonitrile or the mixed solvent of dioxane and glycol dimethyl ether.When adopt dioxane and the mixed solvent of tetrahydrofuran (THF) time, the volume ratio of described dioxane and described tetrahydrofuran (THF) preferably 1 ~ 5, further preferably 1 ~ 3.When adopt dioxane and the mixed solvent of acetonitrile time, the volume ratio of described dioxane and described acetonitrile preferably 1 ~ 5, further preferably 1 ~ 3.When adopt dioxane and the mixed solvent of glycol dimethyl ether time, the volume ratio of described dioxane and described glycol dimethyl ether preferably 1 ~ 5, further preferably 1 ~ 3.
In the present invention, the Molar of described organic solvent and described RX than preferred 1mL/mmol ~ 100mL/mmol, preferred 1mL/mmol ~ 10mL/mmol further.
In the present invention, described TMSCF
2the molar ratio of H and described RX preferably 5 ~ 1, further preferably 5 ~ 2, more further preferably 2.4 ~ 2.
In the present invention, described palladium catalyst is palladium catalyst conventional in linked reaction in this area, preferred (dibenzalacetone) palladium (Pd (dba) in the present invention
2), three (dibenzalacetone) two palladium (Pd
2(dba)
3), tetrakis triphenylphosphine palladium (Pd (PPh
3)
4), Palladous chloride (PdCl
2), palladium bromide (PdBr
2), palladium iodide (PdI
2), palladium (Pd (OAc)
2), palladium trifluoroacetate (Pd (TFA)
2), a hydration trifluoromethanesulfonic acid palladium (Pd (OTf)
2(H
2o)), four acetonitriles close trifluoromethanesulfonic acid palladium (Pd (OTf)
2(MeCN)
4), four acetonitrile tosic acid palladium (Pd (OTs)
2(MeCN)
4), diacetonitrile closes Palladous chloride (PdCl
2(MeCN)
2), two cyanophenyls close Palladous chloride (PdCl
2(PhCN)
2), tetramino closes Palladous chloride (PdCl
2(NH
3)
4), two (triphenylphosphine) Palladous chloride (PdCl
2(PPh
3)
2), four acetonitriles close fluoroboric acid palladium (Pd (BF
4)
2(MeCN)
4), Palladous nitrate (Pd (NO
3)
2), 1,1'-two (diphenylphosphine) ferrocene palladium chloride ((dppf) PdCl
2) and diacetyl acetone palladium (Pd (acac)
2) in one or more.Preferred (dibenzalacetone) palladium (Pd (dba) further
2), three (dibenzalacetone) two palladium (Pd
2(dba)
3), tetrakis triphenylphosphine palladium (Pd (PPh
3)
4), Palladous chloride (PdCl
2) and two (diphenylphosphine) ferrocene palladium chloride ((dppf) PdCl of 1,1'-
2) in one or more, more further preferably (dibenzalacetone) palladium (Pd (dba)
2) and/or three (dibenzalacetone) two palladium (Pd
2(dba)
3).
In the present invention, the molar ratio of described palladium catalyst and described RX preferably 0.0001 ~ 0.1, further preferably 0.01 ~ 0.1, more further preferably 0.02 ~ 0.1.
In the present invention, the conventional alkali matched with palladium catalyst when described alkali is linked reaction in this area, preferred mineral alkali in the present invention, described mineral alkali preferred tertiary sodium butylate (NaO
tbu), potassium tert.-butoxide (KO
tbu), Methanaminium, N,N,N-trimethyl-, fluoride (Me
4nF), tetrabutyl ammonium fluoride (TBAF), Potassium monofluoride (KF), Sodium Fluoride (NaF), rubidium fluoride (RuF), cesium fluoride (CsF), trimethyl carbinol lithium (LiO
tbu) one or more, in sodium methylate (NaOMe), lithium methoxide (LiOMe) and potassium methylate (KOMe), further preferred tertiary sodium butylate (NaO
tbu), Methanaminium, N,N,N-trimethyl-, fluoride (Me
4nF) one or more and in cesium fluoride (CsF), then preferred tertiary sodium butylate (NaO further
tbu).
In the present invention, the molar ratio of described alkali and compound R X preferably 5 ~ 1, further preferably 3 ~ 1.
In the present invention, described part is the conventional ligands carrying out with palladium metal in this area coordinating, in the present invention preferably 1,1'-two (diphenylphosphine) ferrocene (dppf), two diphenylphosphine methane (dppm), 1,2 pairs of (diphenylphosphine) ethane (dppe), 1, two (diphenylphosphine) propane (dppp) of 3-, 1,1'-dinaphthalene-2,2'-two diphenyl phosphine (Binap), triphenylphosphine (PPh
3), tri-butyl phosphine (P
tbu
3), tricyclohexyl phosphine (PCy
3), 4, the two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (Xantphos), two (2-diphenylphosphine phenyl) ether (DPEPhos), (2-dicyclohexyl phosphino--3, 6-dimethoxy-2', 4', 6'-tri-tert-1, 1'-biphenyl) [2-(2-amino-ethyl phenyl)] palladium (II) (BrettPhos), 1, 2, 3, 4, 5-penta phenyl-1'-(di-t-butyl phosphorus base) ferrocene (Q-Phos), (R)-1-[(S)-2-(dicyclohexyl phosphino-) ferrocenyl] ethyl dicyclohexylphosphontetrafluoroborate (Josiphos), 1, two (diphenylphosphine) butane (dppb) of 4-, 1, 10 Féraud beautiful jades (1, 10-phen), 2, one or more in 2-dipyridyl (Bypyridine) and Tetramethyl Ethylene Diamine (TMEDA).Further preferably 1, two (diphenylphosphine) ferrocene (dppf) of 1'-, two diphenylphosphine methane (dppm), 1, 2 pairs of (diphenylphosphine) ethane (dppe), 1, two (diphenylphosphine) propane (dppp) of 3-, 1, 1'-dinaphthalene-2, the two diphenyl phosphine (Binap) of 2'-, 4, the two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (Xantphos), two (2-diphenylphosphine phenyl) ether (DPEPhos) and 1, one or more in two (diphenylphosphine) butane (dppb) of 4-, again further preferably 1, two (diphenylphosphine) ferrocene (dppf) of 1'-, 4, the two diphenylphosphine-9 of 5-, one or more in 9-dimethyl xanthene (Xantphos) and two (2-diphenylphosphine phenyl) ether (DPEPhos), optimum is 1, two (diphenylphosphine) ferrocene (dppf) of 1'-.
In the present invention, the molar ratio of described part and compound R X preferably 0.01 ~ 1, further preferably 0.025 ~ 0.5, more further preferably 0.05 ~ 0.3, optimum is 0.1 ~ 0.15.
In the present invention, the temperature of described linked reaction preferably 25 DEG C ~ 150 DEG C, preferably 60 DEG C ~ 100 DEG C further, more preferably 70 DEG C ~ 100 DEG C further, optimum is 80 DEG C ~ 90 DEG C.
In the present invention, the process of described linked reaction can adopt the traditional test methods in this area (such as TLC, HPLC or NMR) to monitor, for reaction end when generally disappearing with compound R X, preferably 1 hour ~ 48 hours reaction times, preferably 2 hours ~ 30 hours further, more preferably 3 hours ~ 4 hours further.
In the present invention, described linked reaction can be carried out under additive existent condition, described additive be carry out with palladium catalyst in this area with the use of conventional additives, in the present invention preferably 1, 3-two (2, 6-diisopropyl phenyl)-4, 5-glyoxalidine silver chloride (SIPrAgCl), 1, 3-two (2, 6-diisopropyl phenyl)-imidazoles silver chloride (IPrAgCl), 1, 3-two (2, 4, 6-trimethylphenyl)-4, 5-glyoxalidine silver chloride (SIMesAgCl), 1, 3-two (2, 4, 6-trimethylphenyl)-imidazoles silver chloride (ImesAgCl), 1, 3-dicyclohexyl-imidazoles silver chloride (ICyAgCl), trimethylacetic acid silver (AgOPiv), Silver Nitrate (AgNO
3), silver trifluoromethanesulfonate (AgOTf), phosphofluoric acid silver (AgPF
6), silver hexafluoroantimonate (AgSbF
6), silver tetrafluoroborate (AgBF
4), Silver monoacetate (AgOAc), silver carbonate (Ag
2cO
3), silver suboxide (Ag
2o), silver fluoride (AgF), cuprous chloride (CuCl), cuprous bromide (CuBr), cuprous iodide (CuI), copper sulfate (CuSO
4), cupric nitrate (Cu (NO
3)
2), iron(ic) chloride (FeCl
3), iron protochloride (FeCl
2) and ferrous sulfate (FeSO
4) in one or more.Further preferably 1,3-two (2,6-diisopropyl phenyl)-4,5-glyoxalidine silver chlorides (SIPrAgCl), 1,3-two (2,4,6-trimethylphenyl)-4,5-glyoxalidine silver chlorides (SIMesAgCl), 1,3-two (2,4,6-trimethylphenyl)-imidazoles silver chloride (ImesAgCl), trimethylacetic acid silver (AgOPiv), Silver Nitrate (AgNO
3), silver trifluoromethanesulfonate (AgOTf), silver hexafluoroantimonate (AgSbF
6), silver tetrafluoroborate (AgBF
4), one or more in cuprous chloride (CuCl) and cuprous iodide (CuI), again further preferably 1,3-two (2,6-diisopropyl phenyl)-4,5-glyoxalidine silver chloride (SIPrAgCl), 1,3-two (2,4,6-trimethylphenyl)-4,5-glyoxalidine silver chlorides (SIMesAgCl), Silver Nitrate (AgNO
3) and silver hexafluoroantimonate (AgSbF
6) in one or more, the best is 1,3-two (2,6-diisopropyl phenyl)-4,5-glyoxalidine silver chloride (SIPrAgCl).
In the present invention, when described linked reaction is carried out under additive existent condition, the molar ratio of described additive and described RX preferably 0.025 ~ 1, further preferably 0.08 ~ 1, more further preferably 0.1 ~ 1.
In the present invention, when X is bromine, preferably adopt following reaction conditions:
In the present invention, " rare gas element " described in described " protection of inert gas " can be the conventional inert gas of this generic operation in this area, one or more in the present invention in preferred helium, neon, argon gas and nitrogen.
In the present invention, described organic solvent can be the conventional organic solvent of such linked reaction in this area, one or more in the present invention particularly preferably in ether solvent, halogenated hydrocarbon solvent, amide solvent, nitrile solvents and aromatic hydrocarbon solvent.One or more in the preferred dioxane of described ether solvent, tetrahydrofuran (THF), glycol dimethyl ether and diethylene glycol dimethyl ether, further preferably dioxane and/or tetrahydrofuran (THF).The preferred chlorinated hydrocarbon solvent of described halogenated hydrocarbon solvent; The preferred methylene dichloride of described chlorinated hydrocarbon solvent and/or 1,2 ,-ethylene dichloride; The preferred DMF of described amide solvent and/or N,N-dimethylacetamide; The preferred acetonitrile of described nitrile solvents; The preferred toluene of described aromatic hydrocarbon solvent.Described organic solvent is the mixed solvent of the mixed solvent of dioxane, tetrahydrofuran (THF), methylene dichloride, toluene, toluene and tetrahydrofuran (THF), dioxane and toluene, toluene and the mixed solvent of acetonitrile or the mixed solvent of toluene and glycol dimethyl ether further preferably.When adopting the mixed solvent of toluene and tetrahydrofuran (THF), the volume ratio of described toluene and described tetrahydrofuran (THF) preferably 1 ~ 5, further preferably 1 ~ 3.When adopting the mixed solvent of dioxane and toluene, the volume ratio of described dioxane and described toluene preferably 1 ~ 5, further preferably 1 ~ 3.When adopt toluene and the mixed solvent of acetonitrile time, the volume ratio of described dioxane and described glycol dimethyl ether preferably 1 ~ 5, further preferably 1 ~ 3.When adopt toluene and the mixed solvent of glycol dimethyl ether time, the volume ratio of described toluene and described glycol dimethyl ether preferably 1 ~ 5, further preferably 1 ~ 3.
In the present invention, the Molar of described organic solvent and described RX than preferred 1mL/mmol ~ 100mL/mmol, preferred 1mL/mmol ~ 10mL/mmol further.
In the present invention, described TMSCF
2the molar ratio of H and described RX preferably 5 ~ 1, further preferably 5 ~ 2, more further preferably 3 ~ 2, optimum is 2.4.
In the present invention, described palladium catalyst is palladium catalyst conventional in linked reaction in this area, preferred (dibenzalacetone) palladium (Pd (dba) in the present invention
2), three (dibenzalacetone) two palladium (Pd
2(dba)
3), tetrakis triphenylphosphine palladium (Pd (PPh
3)
4), Palladous chloride (PdCl
2), palladium bromide (PdBr
2), palladium iodide (PdI
2), palladium (Pd (OAc)
2), palladium trifluoroacetate (Pd (TFA)
2), a hydration trifluoromethanesulfonic acid palladium (Pd (OTf)
2(H
2o)), four acetonitriles close trifluoromethanesulfonic acid palladium (Pd (OTf)
2(MeCN)
4), four acetonitrile tosic acid palladium (Pd (OTs)
2(MeCN)
4), diacetonitrile closes Palladous chloride (PdCl
2(MeCN)
2), two cyanophenyls close Palladous chloride (PdCl
2(PhCN)
2), tetramino closes Palladous chloride (PdCl
2(NH
3)
4), two (triphenylphosphine) Palladous chloride (PdCl
2(PPh
3)
2), four acetonitriles close fluoroboric acid palladium (Pd (BF
4)
2(MeCN)
4), Palladous nitrate (Pd (NO
3)
2), 1,1'-two (diphenylphosphine) ferrocene palladium chloride ((dppf) PdCl
2) and diacetyl acetone palladium (Pd (acac)
2) in one or more.Preferred (dibenzalacetone) palladium (Pd (dba) further
2), three (dibenzalacetone) two palladium (Pd
2(dba)
3), tetrakis triphenylphosphine palladium (Pd (PPh
3)
4) and two (diphenylphosphine) ferrocene palladium chloride ((dppf) PdCl of 1,1'-
2) in one or more, more further preferably (dibenzalacetone) palladium (Pd (dba)
2) and/or three (dibenzalacetone) two palladium (Pd
2(dba)
3).
In the present invention, the molar ratio of described palladium catalyst and described RX preferably 0.0001 ~ 0.1, further preferably 0.01 ~ 0.1, more further preferably 0.05 ~ 0.1.
In the present invention, the conventional alkali matched with palladium catalyst when described alkali is linked reaction in this area, preferred mineral alkali in the present invention, described mineral alkali preferred tertiary sodium butylate (NaO
tbu), potassium tert.-butoxide (KO
tbu), Methanaminium, N,N,N-trimethyl-, fluoride (Me
4nF), tetrabutyl ammonium fluoride (TBAF), Potassium monofluoride (KF), Sodium Fluoride (NaF), rubidium fluoride (RuF), cesium fluoride (CsF), trimethyl carbinol lithium (LiO
tbu) one or more, in sodium methylate (NaOMe), lithium methoxide (LiOMe) and potassium methylate (KOMe), further preferred tertiary sodium butylate (NaO
tbu), Methanaminium, N,N,N-trimethyl-, fluoride (Me
4nF) one or more and in cesium fluoride (CsF), then preferred tertiary sodium butylate (NaO further
tbu).
In the present invention, the molar ratio of described alkali and compound R X preferably 5 ~ 1, further preferably 3 ~ 1.
In the present invention, described part is the conventional ligands carrying out with palladium metal in this area coordinating, in the present invention preferably 1,1'-two (diphenylphosphine) ferrocene (dppf), two diphenylphosphine methane (dppm), 1,2 pairs of (diphenylphosphine) ethane (dppe), 1, two (diphenylphosphine) propane (dppp) of 3-, 1,1'-dinaphthalene-2,2'-two diphenyl phosphine (Binap), triphenylphosphine (PPh
3), tri-butyl phosphine (P
tbu
3), tricyclohexyl phosphine (PCy
3), 4, the two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (Xantphos), two (2-diphenylphosphine phenyl) ether (DPEPhos), (2-dicyclohexyl phosphino--3, 6-dimethoxy-2', 4', 6'-tri-tert-1, 1'-biphenyl) [2-(2-amino-ethyl phenyl)] palladium (II) (BrettPhos), 1, 2, 3, 4, 5-penta phenyl-1'-(di-t-butyl phosphorus base) ferrocene (Q-Phos), (R)-1-[(S)-2-(dicyclohexyl phosphino-) ferrocenyl] ethyl dicyclohexylphosphontetrafluoroborate (Josiphos), 1, two (diphenylphosphine) butane (dppb) of 4-, 1, 10 Féraud beautiful jades (1, 10-phen), 2, one or more in 2-dipyridyl (Bypyridine) and Tetramethyl Ethylene Diamine (TMEDA).Further preferably 1, two (diphenylphosphine) ferrocene (dppf) of 1'-, two diphenylphosphine methane (dppm), 1, 2 pairs of (diphenylphosphine) ethane (dppe), 1, 1'-dinaphthalene-2, the two diphenyl phosphine (Binap) of 2'-, 4, the two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (Xantphos), two (2-diphenylphosphine phenyl) ether (DPEPhos) and 1, one or more in two (diphenylphosphine) butane (dppb) of 4-, again further preferably 1, two (diphenylphosphine) ferrocene (dppf) of 1'-, 4, the two diphenylphosphine-9 of 5-, one or more in 9-dimethyl xanthene (Xantphos) and two (2-diphenylphosphine phenyl) ether (DPEPhos), optimum is 1, two (diphenylphosphine) ferrocene (dppf) of 1'-.
In the present invention, the molar ratio of described part and compound R X preferably 0.01 ~ 1, further preferably 0.025 ~ 0.5, more further preferably 0.1 ~ 0.3.
In the present invention, described linked reaction temperature preferably 25 DEG C ~ 150 DEG C, preferably 60 DEG C ~ 100 DEG C further, more preferably 70 DEG C ~ 100 DEG C further, optimum is 80 DEG C ~ 90 DEG C.
In the present invention, described linked reaction process can adopt the traditional test methods in this area (such as TLC, HPLC or NMR) to monitor, for reaction end when generally disappearing with compound R X, preferably 1 hour ~ 48 hours reaction times, preferably 2 hours ~ 30 hours further, further preferably 3 hours ~ 16 hours again, optimum was 4 hours ~ 12 hours.
In the present invention, described linked reaction can be carried out under additive existent condition, described additive be carry out with palladium catalyst in this area with the use of conventional additives, in the present invention preferably 1, 3-two (2, 6-diisopropyl phenyl)-4, 5-glyoxalidine silver chloride (SIPrAgCl), 1, 3-two (2, 6-diisopropyl phenyl)-imidazoles silver chloride (IPrAgCl), 1, 3-two (2, 4, 6-trimethylphenyl)-4, 5-glyoxalidine silver chloride (SIMesAgCl), 1, 3-two (2, 4, 6-trimethylphenyl)-imidazoles silver chloride (ImesAgCl), 1, 3-dicyclohexyl-imidazoles silver chloride (ICyAgCl), trimethylacetic acid silver (AgOPiv), Silver Nitrate (AgNO
3), silver trifluoromethanesulfonate (AgOTf), phosphofluoric acid silver (AgPF
6), silver hexafluoroantimonate (AgSbF
6), silver tetrafluoroborate (AgBF
4), Silver monoacetate (AgOAc), silver carbonate (Ag
2cO
3), silver suboxide (Ag
2o), silver fluoride (AgF), cuprous chloride (CuCl), cuprous bromide (CuBr), cuprous iodide (CuI), copper sulfate (CuSO
4), cupric nitrate (Cu (NO
3)
2), iron(ic) chloride (FeCl
3), iron protochloride (FeCl
2) and ferrous sulfate (FeSO
4) in one or more.Further preferably 1,3-two (2,6-diisopropyl phenyl)-4,5-glyoxalidine silver chlorides (SIPrAgCl), 1,3-two (2,4,6-trimethylphenyl)-4,5-glyoxalidine silver chlorides (SIMesAgCl), 1,3-two (2,4,6-trimethylphenyl)-imidazoles silver chloride (ImesAgCl), trimethylacetic acid silver (AgOPiv), Silver Nitrate (AgNO
3), silver trifluoromethanesulfonate (AgOTf), silver carbonate (Ag
2cO
3) and cuprous chloride (CuCl) in one or more, again further preferably 1,3-two (2,6-diisopropyl phenyl)-4,5-glyoxalidine silver chloride (SIPrAgCl), 1,3-two (2,4,6-trimethylphenyl)-4,5-glyoxalidine silver chloride (SIMesAgCl) and Silver Nitrate (AgNO
3) in one or more, optimum is 1,3-two (2,6-diisopropyl phenyl)-4,5-glyoxalidine silver chloride (SIPrAgCl).
In the present invention, when described linked reaction is carried out under additive existent condition, the molar ratio of described additive and described RX preferably 0.001 ~ 1, further preferably 0.01 ~ 1, more further preferably 0.1 ~ 0.2.
Present invention also offers compound R CF
2h, wherein, the definition of R is same as above.
Present invention also offers described compound R CF
2the application of H in the pharmaceutical intermediate preparing drug molecule or fluorine-containing difluoromethyl, described medicine comprises medicine and agricultural chemicals.The compound of fluorine-containing difluoromethyl prepare the application examples in drug molecule or medicine intermediate as with Publication about Document situation about being reported: a) Kirsch, P.ModernFluoroorganicChemistry:Synthesis, Reactivity, Applications; Wiley – VCH:Weinheim, 2004.b) Hiyama, T.OrganofluorineCompounds:ChemistryandProperties; Springer-Verlag:Berlin, 2000.c) Uneyama, K.OrganofluorineChemistry; 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 having specially appointed, described " alkyl " is comprise the representative examples of saturated aliphatic alkyl having and specify carbonatoms object side chain or straight chain; As at " C
1~ C
20alkyl " in be defined as the group being included in and there is in straight chain or branched structure 1,2,3,4,5,6,7,8,9,11,11,12,13,14,15,16,17,18,19 or 20 carbon atom.Such as, " C
1~ C
10alkyl " specifically comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, heptyl, octyl group, nonyl and decyl etc.
In the present invention, when not having specially appointed, described " cycloalkyl " refers to full carbon monocycle or polycyclic moiety, and wherein each ring can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.The cycloalkyl of 1 ~ 3 ring that such as 3 ~ 20 carbon is formed, the cycloalkyl of 1 ring that 3 ~ 12 carbon is formed such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, cyclodecane and cyclo-dodecyl.
In the present invention, when not having specially appointed, described " aryl " refer to any stable can up to the monocycle of 7 atoms or bicyclic carbocyclic in each ring, wherein at least one ring is aromatic nucleus; The example of above-mentioned aryl unit comprises phenyl, naphthyl, tetralyl, 2,3-indanyls, xenyl, phenanthryl, anthryl or acenaphthenyl (acenaphthyl).Be appreciated that at aryl substituent be two ring substituents, and one of them ring is in the situation of non-aromatic ring, connection is undertaken by aromatic ring.
In the present invention, when not having specially appointed, described " heteroaryl " represents can up to the stable monocycle of 7 atoms or two rings in each ring, and wherein at least one ring is aromatic nucleus and is selected from the heteroatoms of O, N and S containing 1-4; Heteroaryl in this range of definition includes but not limited to: acridyl, carbazyl, cinnolines base, quinoxalinyl, pyrazolyl, indyl, benzotriazole base, furyl, thienyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrahydroquinoline." heteroaryl " it should also be understood that to be the N-oxide derivative comprising any nitrogen-containing hetero aryl.Heteroaryl substituent is two ring substituents and ring is non-aromatic ring or under not comprising heteroatomic situation wherein, is appreciated that to connect and carries out respectively by aromatic ring or by the heteroatoms comprising ring.
In the present invention, when not having specially appointed, described " Heterocyclylalkyl " is at this separately or when using as the part of another group, refer to 4 ~ 12 yuan of monocycles or the polycyclic moiety that comprise 1 ~ 4 heteroatoms (as one or more in nitrogen, oxygen and sulphur), wherein each ring can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.In addition, any heterocycloalkyl ring can condense on cycloalkyl, aryl, heteroaryl or heterocycloalkyl ring.Heterocyclylalkyl in this range of definition includes but not limited to: oxazoline, oxygen cyclobutyl, pyranyl, THP trtrahydropyranyl, azetidinyl, 1, 4-alkyl dioxin, six hydrogen azatropylidene bases, piperazinyl, piperidyl, pyrrolidyl, morpholinyl, thio-morpholinyl, dihydrofuran base, glyoxalidine base, indolinyl, dihydro-isoxazole base, dihydro isothiazolyl, Er Qing oxadiazolyl, dihydro-oxazole base, dihydro pyrazinyl, pyrazoline base, dihydropyridine base, dihydro-pyrimidin base, pyrrolin base, dihydro tetrazyl, thiodiazoline base, dihydro-thiazolyl, dihydro-thiophene base, dihydro triazolyl, dihydro azetidinyl, tetrahydrofuran base and tetrahydro-thienyl and N-oxide compound thereof.Heterocyclylalkyl can be connected with other groups through carbon atom wherein or heteroatoms.
In the present invention, when not having specially appointed, described " halogen " represents fluorine, chlorine, bromine, iodine or astatine.
In the present invention, the described " C determining carbon number range
x1~ C
y1" substituting group (x1 and y1 is integer), as " C
x1~ C
y1" alkyl, " C
x1~ C
y1" alkoxyl group, " C
x1~ C
y1" aryl, " C
x1~ C
y1" heteroaryl or " C
x1~ C
y1" alkoxy carbonyl, all represent and do not comprise substituent carbon number, such as C
1~ C
20alkyl represents and does not comprise substituent C
1~ C
20alkyl.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are all commercially.
In the present invention, described room temperature refers to envrionment temperature, is 10 DEG C ~ 35 DEG C.
Positive progressive effect of the present invention is: difluoromethylization of the present invention reaction can realize realizing difluoromethyl with the multiple aryl halides such as aryl iodide, aryl bromide and natural product (such as oestrone or vitamin-E), such reaction conditions is gentle, cheaper starting materials is easy to get, reaction conversion ratio is high, group is compatible good, has good market application foreground.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
The difluoromethyl repercussion study of the iodo aromatic hydrocarbon (RI) that embodiment 1 palladium participates in
Under the condition of argon gas, by 4-phenyl iodobenzene (0.1mmol), trimethylammonium difluoromethyl silicon, palladium catalyst, additive, part and alkali are dissolved in dry deoxygenation solvent with ratio corresponding in form, be heated to the temperature listed in form, after being reacted to the time listed by form, the phenylfluoroform adding equal proportion, as interior mark, determines yield by fluorine spectrum.For the screening of palladium catalyst in table 1, for the screening of additive in table 2, for the screening of alkali in table 3, for the screening of solvent in table 4, for the screening of part in table 5, for the screening of temperature of reaction in table 6, for the screening in reaction times in table 7, for the screening of palladium catalyst dosage in table 8, for the screening of additive dosage in table 9, for the screening of part dosage in table 10, for TMSCF
2with the screening of alkali dosage in table 11.
Under the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl iodobenzene and 2.4 equivalents (2.4eq) carries out linked reaction, with 2.0 equivalent sodium tert-butoxides for alkali, take dioxane as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl iodobenzene), adding mol ratio is the palladium catalyst of 5%, mol ratio is the part dppf of 10%, mol ratio is the additive SIPrAgCl of 20%, 80 DEG C, react 4 hours, the concrete data of palladium catalyst screening are in table 1.
The screening table of table 1 palladium catalyst
| Numbering | The kind of palladium catalyst | Fluorine spectrum ( 19FNMR) yield (%) |
| 1 | Pd(dba) 2 | 90 |
| 2 | Pd 2(dba) 3 | 85 |
| 3 | Pd(PPh 3) 4 | 56 |
| 4 | PdCl 2 | 43 |
| 5 | PdBr 2 | 10 |
| 6 | PdI 2 | 7 |
| 7 | Pd(OAc) 2 | 12 |
| 8 | Pd(TFA) 2 | 16 |
| 9 | Pd(OTf) 2(H 2O) | ＜5 |
| 10 | Pd(OTf) 2(MeCN) 4 | 15 |
| 11 | Pd(OTs) 2(MeCN) 4 | 11 |
| 12 | PdCl 2(MeCN) 2 | 9 |
| 13 | PdCl 2(PhCN) 2 | ＜5 |
| 14 | PdCl 2(NH 3) 4 | 7 |
| 15 | PdCl 2(PPh 3) 2 | 11 |
| 16 | Pd(BF 4) 2(MeCN) 4 | ＜5 |
| 17 | Pd(NO 3) 2 | 23 |
| 18 | (dppf)PdCl 2 | 45 |
| 19 | Pd(acac) 2 | 6 |
Under the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl iodobenzene and 2.4eq carries out linked reaction, with 2 equivalent sodium tert-butoxides for alkali, take dioxane as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl iodobenzene), and interpolation mol ratio is the palladium catalyst Pd (dba) of 5%
2, mol ratio is the part dppf of 10%, and mol ratio is the additive of 20%, 80 DEG C, and react 4 hours, the concrete data of selection of additives are in table 2.
The screening table of table 2 additive
| Numbering | The kind 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 | AgPF 6 | ＜5 |
| 9 | AgSbF 6 | 55 |
| 10 | AgBF 4 | 36 |
| 11 | AgOAc | 18 |
| 12 | Ag 2CO 3 | 22 |
| 13 | Ag 2O | 7 |
| 14 | AgF | 21 |
| 15 | CuCl | 35 |
| 16 | CuBr | 33 |
| 17 | CuI | 42 |
| 18 | CuSO 4 | 6 |
| 19 | Cu(NO 3) 2 | 8 |
| 20 | FeCl 3 | 6 |
| 21 | FeCl 2 | 7 |
| 22 | FeSO 4 | 12 |
| 23 | Nothing | 34 |
Under the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl iodobenzene and 2.4eq carries out linked reaction, the alkali of 2 equivalents, take dioxane as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl iodobenzene), and interpolation mol ratio is 5% palladium catalyst Pd (dba)
2, mol ratio is the part dppf of 10%, and mol ratio is additive 20%SIPrAgCl, 80 DEG C, reacts 4 hours, and the concrete data of alkali screening are in table 3.
The screening table of table 3 alkali
| Numbering | The kind 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 monofluoride | 6 |
| 6 | Sodium Fluoride | 5 |
| 7 | Rubidium fluoride | 7 |
| 8 | Cesium fluoride | 36 |
| 9 | Trimethyl carbinol lithium | ＜5 |
| 10 | Sodium methylate | 5 |
| 11 | Lithium methoxide | 4 |
| 12 | Potassium methylate | 8 |
Under the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl iodobenzene and 2.4eq carries out linked reaction, with the sodium tert-butoxide of 2 equivalents for alkali, adds 5%Pd (dba)
2mol ratio is the part dppf of 10%, mol ratio is the additive SIPrAgCl of 20%, 80 DEG C, react 4 hours, the Molar added of solvent than the concrete data for 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl iodobenzene) solvent screening in table 4.
The screening table of table 4 solvent
Under the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl iodobenzene and 2.4eq carries out linked reaction, with the sodium tert-butoxide of 2 equivalents for alkali, take dioxane as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl iodobenzene), and interpolation mol ratio is the palladium catalyst Pd (dba) of 5%
2, mol ratio is the part of 10%, and mol ratio is the additive SIPrAgCl of 20%, 80 DEG C, and react 4 hours, the concrete data of ligand screening are in table 5.
The screening table of table 5 part
| Numbering | The kind of part | Fluorine spectrum ( 19FNMR) yield (%) |
| 1 | dppf | 90 |
| 2 | dppm | 35 |
| 3 | dppe | 46 |
| 4 | dppp | 37 |
| 5 | Binap | 42 |
| 6 | PPh 3 | 9 |
| 7 | P tBu 3 | ＜5 |
| 8 | PCy 3 | 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 the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl iodobenzene and 2.4eq carries out linked reaction, with the sodium tert-butoxide of 2 equivalents for alkali, take dioxane as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl iodobenzene), and interpolation mol ratio is the palladium catalyst Pd (dba) of 5%
2, mol ratio is the part of 10%, and mol ratio is the additive SIPrAgCl of 20%, reacts 4 hours, and the concrete data of temperature of reaction screening are in table 6.
The screening table of table 6 temperature of reaction
| Numbering | Temperature of reaction (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 the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl iodobenzene and 2.4eq carries out linked reaction, with the sodium tert-butoxide of 2 equivalents for alkali, take dioxane as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl iodobenzene), and interpolation mol ratio is the palladium catalyst Pd (dba) of 5%
2, mol ratio is the part dppf of 10%, and mol ratio is the additive SIPrAgCl of 20%, and temperature is 80 DEG C, and the concrete data of reaction times screening are in table 7.
The screening table in table 7 reaction times
| Numbering | Reaction times (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 the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl iodobenzene and 2.4eq carries out linked reaction, with the sodium tert-butoxide of 2 equivalents for alkali, take dioxane as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl iodobenzene), interpolation palladium catalyst Pd (dba)
2, mol ratio is the part dppf of 10%, and mol ratio is the additive SIPrAgCl of 20%, 80 DEG C, reacts for 4 times, and the concrete data of palladium catalyst dosage screening are in table 8.
The screening table of table 8 palladium catalyst dosage
| Numbering | Palladium catalyst Pd (dba) 2With the molar ratio of compound R X | 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 the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl iodobenzene and 2.4eq carries out linked reaction, with the sodium tert-butoxide of 2 equivalents for alkali, take dioxane as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl iodobenzene), and interpolation mol ratio is the palladium catalyst Pd (dba) of 7%
2, mol ratio is the part dppf of 10%, SIPrAgCl is additive, 80 DEG C, reacts 4 hours, and the concrete data of the dosage screening of additive are in table 9.
The screening table of table 9 additive dosage
| Numbering | The molar ratio of additive SIPrAgCl and compound R X | 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 the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl iodobenzene and 2.4eq carries out linked reaction, with the sodium tert-butoxide of 2 equivalents for alkali, take dioxane as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl iodobenzene), adding mol ratio is the palladium catalyst of 5%, part is dppf, mol ratio is the additive SIPrAgCl of 20%, 80 DEG C, react 4 hours, the concrete data of part dppf dosage screening are in table 10.
The screening table of table 10 part dppf dosage
| Numbering | The molar ratio of part dppf and compound R X | 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 the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl iodobenzene and 2.4eq carries out linked reaction, with the sodium tert-butoxide of 2 equivalents for alkali, take dioxane as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl iodobenzene), and interpolation mol ratio is the palladium catalyst Pd (dba) of 5%
2, mol ratio is the part dppf of 10%, and mol ratio is the additive SIPrAgCl of 20%, 80 DEG C, reacts 4 hours, alkali and TMSCF
2the concrete data of the dosage screening of H are in table 11.
Table 11 alkali and TMSCF
2the dosage screening table of H
Conclusion: by the condition optimizing of form 1 ~ 11, we determine the fluorine-based silicon of trimethylammonium two with 2.4 equivalents, mol ratio is two (bis-Ya Benzyl benzylacetones of 5%) palladium, mol ratio is 10% 1, two (diphenylphosphine) ferrocene of 1'-, mol ratio is the SIPrAgCl of 20%, the sodium tert-butoxide of 2 equivalents is alkali, dioxane is as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl iodobenzene), and reacting under the condition of 80 DEG C 4 hours is optimum reaction condition.
The experiment of the difluoromethyl of the iodo aromatic hydrocarbon (RI) of embodiment 2 palladium chtalyst
Under argon gas atmosphere, by iodo aromatic hydrocarbon (0.5mmol), two (bis-Ya Benzyl benzylacetone) palladium (14.5mg, 0.025mmol), 1, two (diphenylphosphine) ferrocene (28mg of 1'-, 0.05mmol), additive SIPrAgCl (53.5mg, 0.1mmol), sodium tert-butoxide (96.1mg, 1.0mmol) be dissolved in the dioxane of 5mL, in system, add the trimethylammonium difluoro silicon of 150uL.React at 80 DEG C after 4 hours and be cooled to room temperature, add the distilled water cancellation reaction of 10mL, after diatomite filtration, filtrate is with dichloromethane extraction (25ml × 3), merge organic phase, anhydrous sodium sulfate drying, concentrated, post is separated, obtain the product 1a ~ 1l of corresponding difluoromethyl, concrete yield is in table 12.
The difluoromethyl substrate applicability research of table 12 iodine band aromatic hydrocarbons
The Structural Identification data of compound 1a ~ 1l are as follows:
Compound 1a
HNMR(400MHz,CDCl
3)δ7.70(d,J＝8.4Hz,2H),7.62(m,4H),7.49(m,2H),7.42(m,1H),6.72(t,J＝56.4Hz,1H)；
19FNMR(376MHz,CDCl
3)δ-110.33(d,J＝56.4Hz)；
13CNMR(126MHz,CDCl
3)δ114.89(t,J＝239.4Hz),126.15(t,J＝5.0Hz),127.37,127.55,128.03,129.04,133.34(t,J＝22.7Hz),140.30,143.82(t,J＝2.5Hz)ppm.GC-MS(EI,m/z):204.0(M+),183.0,152.0
Compound 1b
1HNMR(400MHz,CDCl
3)δ8.05(d,J＝8.4Hz,2H),7.52(d,J＝8.4Hz,2H),6.66(t,J＝56.0Hz,1H),1.58(s,9H)；
19FNMR(376MHz,CDCl
3)δ-112.03(d,J＝56.0Hz)；
13CNMR(126MHz,CDCl
3)δ28.29,81.77,114.26(t,J＝240.1Hz),125.58(t,J＝5.9Hz),129.91,134.35,138.10(t,J＝25.0Hz),165.00ppm.HRMS(EI)forC
12H
14O2F
2):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℃.
Compound 1c
1HNMR(400MHz,CDCl
3)δ7.45～7.35(m,7H),7.03(d,J＝8.4Hz,2H),6.60(t,J＝56.8Hz,1H),5.10(s,2H)；
19FNMR(376MHz,CDCl
3)δ-108.30(d,J＝56.8Hz)；
13CNMR(126MHz,CDCl
3)δ70.20,114.89,114.99(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
1HNMR(300MHz,CDCl
3)δ7.48～7.42(m,4H),6.64(t,J＝57.0Hz,1H),1.35(s,9H)；
19FNMR(282MHz,CDCl
3)δ-110.27(d,J＝57.0Hz)；
13CNMR(101MHz,CDCl
3)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
1HNMR(400MHz,CDCl
3)δ7.56(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)；
19FNMR(376MHz,CDCl
3)δ-110.13(d,J＝56.8Hz)；
13CNMR(126MHz,CDCl
3)δ111.29,114.48(t,J＝239.0Hz),119.30,120.35,127.22(t,J＝6.1Hz),131.55(t,J＝22.8Hz),142.61ppm.HRMS(EI)forC
10H
6OF
2S):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℃.
Compound 1f
1HNMR(400MHz,CDCl
3)δ7.51(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)；
19FNMR(376MHz,CDCl
3)δ-111.33(d,J＝56.4Hz)；
13CNMR(126MHz,CDCl
3)δ12.82,14.15,39.29,43.23,114.83(t,J＝239.7Hz),125.73(t,J＝6.2Hz),126.60,134.92(t,J＝22.6Hz),139.19,170.19ppm.HRMS(ESI)forC
12H
16NOF
2):Calcd:228.1194；Found:228.1196.IR:＝2977,2937,2242,1628,1578,1474,1460,1433,1382,1349,1289,1221,1161,1098,1072,1033,911,877,834,733,647cm
-1.
Compound 1g
1HNMR(400MHz,CDCl
3)δ7.47～7.42(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)；
19FNMR(376MHz,CDCl
3)δ-109.92(d,J＝56.4Hz)；
13CNMR(126MHz,CDCl
3)δ11.92,46.99,57.42,115.00(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
1HNMR(400MHz,CDCl
3)δ6.71(s,2H),6.56(t,J＝56.8Hz,1H),3.87(s,6H),3.85(s,3H)；
19FNMR(376MHz,CDCl
3)δ-109.40(d,J＝56.8Hz,1H)；
13CNMR(101MHz,CDCl
3)δ56.25,60.90,102.70(t,J＝6.3Hz),114.72(t,J＝239.5Hz),129.77(t,J＝22.6Hz),139.85,153.60ppm.HRMS(EI)forC
10H
12O
3F
2):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
1HNMR(400MHz,CDCl
3)δ7.48～7.37(m,6H),7.20～7.09(m,3H),6.63(t,J＝56.4Hz,1H),5.11(s,2H)；
19FNMR(376MHz,CDCl
3)δ-110.65(d,J
1＝56.4Hz)；
13CNMR(101MHz,CDCl
3)δ159.10,136.61,135.89(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)forC
14H
12OF
2):Calcd:234.0856；Found:234.0853.IR:ν/cm
-1＝3250,2972,2932,1604,1497,1456,1385,1258,1180,1057,1019,861,795,750,831,697.M.P.:51～52℃.
Compound 1j
1HNMR(400MHz,CDCl
3)δ7.42(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)；
19FNMR(376MHz,CDCl
3)δ-108.23(d,J＝56.8Hz)；
13CNMR(101MHz,CDCl
3)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)forC
11H
12OF
2):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
1HNMR(400MHz,CDCl
3)δ7.63～7.56(m,6H),7.45～7.43(m,2H),6.68(t,J＝56.4Hz,1H)；
19FNMR(376MHz,CDCl
3)δ-110.57(d,J＝56.4Hz)；
13CNMR(126MHz,CDCl
3)δ114.73(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)forC
13H
9BrF
2):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℃.
Compound 1l
1HNMR(400MHz,CDCl
3)δ7.40(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)；
19FNMR(376MHz,CDCl
3)δ-108.11(d,J＝56.8Hz)；
13CNMR(101MHz,CDCl
3)δ26.39,53.80,55.45,66.26,67.03,114.57,114.96(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)forC
14H
19NO
2F
2):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 of the aryl bromide (RBr) that embodiment 3 palladium participates in
Under the condition of argon gas, by 4-phenyl bromobenzene (0.1mmol), trimethylammonium difluoromethyl silicon, palladium catalyst, additive, part and alkali are dissolved in dry deoxygenation solvent with ratio corresponding in form, be heated to the temperature listed in form, after being reacted to the time listed by form, the phenylfluoroform adding equal proportion, as interior mark, determines yield by fluorine spectrum.For the screening of palladium catalyst in table 13, for the screening of additive in table 14, for the screening of alkali in table 15, for the screening of solvent in table 16, for the screening of part in table 17, for the screening of temperature of reaction in table 18, for the screening in reaction times in table 19, for the screening of palladium catalyst dosage in table 20, for the screening of additive dosage in table 21, for the screening of part dosage in table 22, for TMSCF
2with the screening of alkali dosage in table 23.
Under the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl bromobenzene and 2.4eq carries out linked reaction, with 2 equivalent sodium tert-butoxides for alkali, take dioxane as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl bromobenzene), adding mol ratio is the palladium catalyst of 5%, mol ratio is the part dppf of 10%, mol ratio is the additive SIPrAgCl of 20%, 80 DEG C, react 4 hours, the concrete data of palladium catalyst screening are in table 13.
The screening table of table 13 palladium catalyst
| Numbering | The kind of palladium catalyst | Fluorine spectrum ( 19FNMR) yield (%) |
| 1 | Pd(dba) 2 | 80 |
| 2 | Pd 2(dba) 3 | 75 |
| 3 | Pd(PPh 3) 4 | 46 |
| 4 | PdCl 2 | 23 |
| 5 | PdBr 2 | 8 |
| 6 | PdI 2 | 6 |
| 7 | Pd(OAc) 2 | 11 |
| 8 | Pd(TFA) 2 | 14 |
| 9 | Pd(OTf) 2(H 2O) | ＜5 |
| 10 | Pd(OTf) 2(MeCN) 4 | ＜5 |
| 11 | Pd(OTs) 2(MeCN) 4 | ＜4 |
| 12 | PdCl 2(MeCN) 2 | 8 |
| 13 | PdCl 2(PhCN) 2 | ＜5 |
| 14 | PdCl 2(NH 3) 4 | 6 |
| 15 | PdCl 2(PPh 3) 2 | 10 |
| 16 | Pd(BF 4) 2(MeCN) 4 | ＜5 |
| 17 | Pd(NO 3) 2 | 13 |
| 18 | (dppf)PdCl 2 | 55 |
| 19 | Pd(acac) 2 | 9 |
Under the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl bromobenzene and 2.4eq carries out linked reaction, with 2 equivalent sodium tert-butoxides for alkali, take dioxane as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl bromobenzene), and interpolation mol ratio is the palladium catalyst Pd (dba) of 5%
2, mol ratio is the part dppf of 10%, and mol ratio is the additive of 20%, 80 DEG C, and react 4 hours, the concrete data of selection of additives are in table 14.
The screening table of table 14 additive
| Numbering | The kind 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 | AgPF 6 | ＜5 |
| 9 | AgSbF 6 | ＜5 |
| 10 | AgBF 4 | 6 |
| 11 | AgOAc | 14 |
| 12 | Ag 2CO 3 | 25 |
| 13 | Ag 2O | 17 |
| 14 | AgF | 23 |
| 15 | CuCl | 25 |
| 16 | CuBr | 13 |
| 17 | CuI | 12 |
| 18 | CuSO 4 | 16 |
| 19 | Cu(NO 3) 2 | ＜5 |
| 20 | FeCl 3 | ＜5 |
| 21 | FeCl 2 | 7 |
| 22 | FeSO 4 | ＜5 |
| 23 | Nothing | 24 |
Under the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl bromobenzene and 2.4eq carries out linked reaction, the alkali of 2 equivalents, take dioxane as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl bromobenzene), and interpolation mol ratio is 5% palladium catalyst Pd (dba)
2, mol ratio is the part dppf of 10%, and mol ratio is additive 20%SIPrAgCl, 80 DEG C, reacts 4 hours, and the concrete data of alkali screening are in table 15.
The screening table of table 15 alkali
| Numbering | The kind 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 monofluoride | 6 |
| 6 | Sodium Fluoride | 5 |
| 7 | Rubidium fluoride | 7 |
| 8 | Cesium fluoride | 23 |
| 9 | Trimethyl carbinol lithium | ＜5 |
| 10 | Sodium methylate | 5 |
| 11 | Lithium methoxide | ＜5 |
| 12 | Potassium methylate | 7 |
Under the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl bromobenzene and 2.4eq carries out linked reaction, with the sodium tert-butoxide of 2 equivalents for alkali, adds 5%Pd (dba)
2mol ratio is the part dppf of 10%, mol ratio is the additive SIPrAgCl of 20%, 80 DEG C, react 4 hours, Molar that solvent adds is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl bromobenzene), and the concrete data of solvent screening are in table 16.
The screening table of table 16 solvent
Under the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl bromobenzene and 2.4eq carries out linked reaction, take sodium tert-butoxide as alkali, take dioxane as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl bromobenzene), and interpolation mol ratio is the palladium catalyst Pd (dba) of 5%
2, mol ratio is the part of 10%, and mol ratio is the additive SIPrAgCl of 20%, 80 DEG C, and react 4 hours, the concrete data of ligand screening are in table 17.
The screening table of table 17 part
| Numbering | The kind of part | Fluorine spectrum ( 19FNMR) yield (%) |
| 1 | dppf | 86 |
| 2 | dppm | 23 |
| 3 | dppe | 27 |
| 4 | dppp | 15 |
| 5 | Binap | 33 |
| 6 | PPh 3 | 8 |
| 7 | P tBu 3 | ＜5 |
| 8 | PCy 3 | ＜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 the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl bromobenzene and 2.4eq carries out linked reaction, with the sodium tert-butoxide of 2 equivalents for alkali, take toluene as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl bromobenzene), and interpolation mol ratio is the palladium catalyst Pd (dba) of 5%
2, mol ratio is the part of 10%, and mol ratio is the additive SIPrAgCl of 20%, reacts 4 hours, and the concrete data of temperature of reaction screening are in table 18.
The screening table of table 18 temperature of reaction
| Numbering | Temperature of reaction (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 the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl bromobenzene and 2.4eq carries out linked reaction, with the sodium tert-butoxide of 2 equivalents for alkali, take toluene as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl bromobenzene), and interpolation mol ratio is the palladium catalyst Pd (dba) of 5%
2, mol ratio is the part dppf of 10%, and mol ratio is the additive SIPrAgCl of 20%, and temperature is 80 DEG C, and the concrete data of reaction times screening are in table 19.
The screening table in table 19 reaction times
| Numbering | Reaction times (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 the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl bromobenzene and 2.4eq carries out linked reaction, with the sodium tert-butoxide of 2 equivalents for alkali, take toluene as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl bromobenzene), interpolation palladium catalyst Pd (dba)
2, mol ratio is the part dppf of 10%, and mol ratio is the additive SIPrAgCl of 20%, 80 DEG C, reacts for 6 times, and the concrete data of palladium catalyst dosage screening are in table 20.
The screening table of table 20 palladium catalyst dosage
| Numbering | Palladium catalyst Pd (dba) 2With the molar ratio of compound R X | 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 the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl bromobenzene and 2.4eq carries out linked reaction, with the sodium tert-butoxide of 2 equivalents for alkali, take toluene as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl bromobenzene), and interpolation mol ratio is the palladium catalyst Pd (dba) of 7%
2, mol ratio is the part dppf of 14%, SIPrAgCl is additive, 80 DEG C, reacts 6 hours, and the concrete data of the dosage screening of additive are in table 21.
The screening table of table 21 additive dosage
| Numbering | The molar ratio of additive SIPrAgCl and compound R X | 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 the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl bromobenzene and 2.4eq carries out linked reaction, with 2 equivalent sodium tert-butoxides for alkali, take dioxane as solvent, Molar adds than for 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl bromobenzene) palladium catalyst that mol ratio is 7%, part is dppf, mol ratio is the additive SIPrAgCl of 20%, 80 DEG C, react 6 hours, the concrete data of part dppf dosage screening are in table 22.
The screening table of table 22 part dppf dosage
| Numbering | The molar ratio of part dppf and compound R X | 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 the condition of argon gas, the trimethylammonium difluoromethyl silicon of 4-phenyl iodobenzene and 2.4eq carries out linked reaction, with the sodium tert-butoxide of 2 equivalents for alkali, take toluene as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl bromobenzene), and interpolation mol ratio is the palladium catalyst Pd (dba) of 7%
2, mol ratio is the part dppf of 14%, and mol ratio is the additive SIPrAgCl of 20%, 80 DEG C, reacts 6 hours, alkali and TMSCF
2the concrete data of the dosage screening of H are in table 23.
Table 23 alkali and TMSCF
2the dosage screening table of H
| Compile | TMSCF 2With rubbing of compound R X | Alkali sodium tert-butoxide and 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 determine the fluorine-based silicon of trimethylammonium two with 2.4 equivalents, mol ratio is the two (bis-Ya Benzyl benzylacetone of palladium catalyst of 7%) palladium, mol ratio is the ligand 1 of 14%, two (diphenylphosphine) ferrocene of 1'-, mol ratio is the additive SIPrAgCl of 20%, the sodium tert-butoxide of 2 equivalents, toluene is as solvent, Molar is than being 10L/mol (described Molar is than the ratio of molar weight referring to solvent volume and 4-phenyl bromobenzene), and reacting under the condition of 80 DEG C 6 hours is optimal conditions.
The experiment general rule of the difluoromethyl of the aryl bromide (RBr) of embodiment 4 palladium chtalyst
Under argon gas atmosphere, by aryl bromide (0.5mmol), two (bis-Ya Benzyl benzylacetone) palladium (20.1mg, 0.035mmol), 1, two (diphenylphosphine) ferrocene (38.8mg of 1'-, 0.07mmol), additive SIPrAgCl (53.5mg, 0.1mmol), sodium tert-butoxide (96.1mg, 1.0mmol) be dissolved in the toluene of 5mL, in system, add the trimethylammonium difluoro silicon of 150uL.React at 80 DEG C after 6 hours and be cooled to room temperature, add the distilled water cancellation reaction of 10mL, after diatomite filtration, filtrate is with dichloromethane extraction (25ml × 3), merge organic phase, anhydrous sodium sulfate drying, concentrated, post is separated, obtain product 1a, 1b, 1f, 2c of corresponding difluoromethyl ~ 2g and 2i ~ 2n, concrete yield is in table 24.
The difluoromethyl substrate applicability research of table 24 aryl bromide
The Structural Identification data of compound 2c ~ 2g and 2i ~ 2n are as follows:
Compound 2c
1HNMR(400MHz,CDCl
3)δ7.44(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)；
19FNMR(376MHz,CDCl
3)δ-109.67(d,J＝56.8Hz)；
13CNMR(101MHz,CDCl
3)δ14.24,22.83,29.41,29.43,29.61,31.52,32.05,35.98,115.11(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)forC
15H
22F
2):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
1HNMR(400MHz,CDCl
3)δ8.00(s,1H),7.96～7.90(m,3H),7.65～7.58(m,3H),6.84(t,J＝56.4Hz,1H)；
19FNMR(376MHz,CDCl
3)δ-109.66(d,J＝56.4Hz).
13CNMR(101MHz,CDCl
3)δ134.43(t,J＝1.4Hz),132.67,131.73(t,J＝22.3Hz),129.00,128.63,127.98,127.50,126.91,126.00(t,J＝7.6Hz),122.12(t,J＝4.8Hz),115.20(t,J＝238.5Hz).LRMS(EI,m/z):178(M
+),177,128,91.
Compound 2e
1HNMR(500MHz,CDCl
3)δ8.21(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)；
19FNMR(376MHz,CDCl
3)δ-110.83(d,J＝56.4Hz)；
13CNMR(126MHz,CDCl
3)δ115.57(t,J＝238.1Hz),123.68(t,J＝1.3Hz),124.78,124.92(t,J＝8.8Hz),126.49,127.29,128.90,129.67(t,J＝21.4Hz),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
1HNMR(400MHz,CDCl
3)δ7.70～7.65(m,2H),7.56～7.50(m,4H),7.16(m,2H),6.72(t,J＝56.4Hz,1H)；
19FNMR(376MHz,CDCl
3)δ-110.64(d,J＝56.4Hz,2F),114.84(m,1F)；
13CNMR(126MHz,CDCl
3)δ114.83(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)forC
13H
9F
3):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
1HNMR(400MHz,CDCl
3)δ7.40～7.36(m,3H),7.26～7.04(m,6H),6.60(t,J＝56.4Hz,1H)；
19FNMR(376MHz,CDCl
3)δ-110.80(d,J＝56.4Hz)；
13CNMR(101MHz,CDCl
3)δ111.83,114.21(t,J＝240.4Hz),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)forC
13H
10OF
2):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
1HNMR(400MHz,CDCl
3)δ7.45～7.35(m,7H),7.03(d,J＝8.4Hz,2H),6.60(t,J＝56.8Hz,1H),5.10(s,2H)；
19FNMR(376MHz,CDCl
3)δ-108.30(d,J＝56.8Hz)；
13CNMR(126MHz,CDCl
3)δ70.20,114.89,114.99(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
1HNMR(400MHz,CDCl
3)δ7.58(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)；
19FNMR(376MHz,CDCl
3)δ-110.45(d,J＝56.5Hz)；
13CNMR(126MHz,CDCl
3)δ146.33(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)forC
10H
9O
2F
2):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
1HNMR(400MHz,CDCl
3)δ7.36～7.29(m,6H),7.14～7.07(m,8H),6.60(t,J＝56.8Hz,1H)；
19FNMR(376MHz,CDCl
3)δ-108.62(d,J＝56.8Hz)；
13CNMR(126MHz,CDCl
3)δ115.05(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)forC
19H
15NF
2):Calcd:295.1173；Found:295.1176.IR:＝3062,3035,2962,1614,1593,1515,1486,1451,1430,1382,1334,1283,1269,1222,1191,1176,1125,1064,1016,948,903,839,758,734,698,633,623,528,506cm
-1.M.P.97～98℃.
Compound 2l
1HNMR(400MHz,CDCl
3)δ8.49(s,1H),8.35(s,1H),7.42～7.39(m,6H),6.68(t,J＝56.0Hz,1H),5.12(s,2H)；
19FNMR(376MHz,CDCl
3)δ-112.08(d,J＝56.0Hz)；
13CNMR(101MHz,CDCl
3)δ113.19(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)forC
13H
11NOF
2):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
1HNMR(400MHz,CDCl
3)δ8.23(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)；
19FNMR(376MHz,CDCl
3)δ-110.23(d,J＝56.4Hz)；
13CNMR(101MHz,CDCl
3)δ109.76,114.45(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)forC
19H
13NF
2):Calcd:293.1016；Found:293.1021.IR:＝3047,2975,1611,1520,1480,1453,1378,1365,1336,1319,1302,1230,1185,1168,1150,1123,1072,1022,916,839,750,725,625cm
-1.M.P.137～139℃.
Compound 2n
1HNMR(400MHz,CDCl
3)δ8.16(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)；
19FNMR(376MHz,CDCl
3)δ-111.59(d,J＝56.0Hz)；
13CNMR(101MHz,CDCl
3)δ114.29(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)forC
14H
9NSF
2):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℃.
The application of the difluoromethyl of the bromo-derivative of the oestrone skeleton of embodiment 5 palladium chtalyst
Oestrone is a kind of sexual hormoue and short sexual hormoue, be mainly used in treating uterine hypoplasia, menoxenia, climacterium the symptom such as obstacle, consider the biological isoelectronic species character of difluoromethyl and hydroxyl, it is as follows that difluoromethyl is incorporated into concrete operations in such molecular skeleton by the method that we attempt adopting us to invent: under argon gas atmosphere, by bromo substrate (164.5mg, 0.44mmol), two (bis-Ya Benzyl benzylacetone) palladium (36.1mg, 0.061mmol), 1, two (diphenylphosphine) ferrocene (66.9mg of 1'-, 0.12mmol), SIPrAgCl (93.3mg, 0.18mmol), sodium tert-butoxide (84.6mg, 0.88mmol) be dissolved in the toluene of 2.2ml, the trimethylammonium difluoro silicon of 132uL is added in system.React at 80 DEG C after 48 hours and be cooled to room temperature, add the distilled water cancellation reaction of 10mL, after diatomite filtration, filtrate is with dichloromethane extraction (25ml × 3), merge organic phase, anhydrous sodium sulfate drying, concentrated, post is separated, obtain the product (121mg, separation yield is 70%) of corresponding difluoromethyl.
1HNMR(400MHz,CDCl
3)δ7.38(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)；
19FNMR(376MHz,CDCl
3)δ-109.80(dd,J
1＝56.8Hz,J
2＝7.1Hz)；
13CNMR(101MHz,CDCl
3)δ143.40,137.49,131.73(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)forC
15H
22F
2):Calcd:384.1901；Found:384.1900
The application of the difluoromethyl of the bromo-derivative of the vitamin-E skeleton of embodiment 6 palladium chtalyst
Vitamin-E can promote reproduction.It can promote sex hormone secretion, and man's motility of sperm and quantity are increased; Woman's female hormone concentration is increased, improves Fertility, prevention of miscarriage.There will be testicular atrophy and epithelial cell sex change during vitamin E deficiency, breed exception.Conventional vitamin E treatment threatened abortion and habitual abortion clinically.Also certain help is had in addition to preventing and treating male infertility.Other function aspects also have, protection T lymphocyte, protection red corpuscle, Green Tea Extract oxidation, anticoagulant thus reduce the danger of myocardial infarction and cerebral infarction.Also there is good curative effect to aspects such as burn, frostbite, capillary hemorrhage, climacteric syndrome, beauty treatments.Also find that vitamin-E can suppress the lipid peroxidation in eye lens to react, and makes peripheral vasodilation, improves blood circulation etc.Consider the biological isoelectronic species character of difluoromethyl and hydroxyl, difluoromethyl is incorporated in such molecular skeleton by the method that we attempt adopting us to invent, concrete operations are as follows: under argon gas atmosphere, by bromo substrate (225mg, 0.5mmol), two (bis-Ya Benzyl benzylacetone) palladium (21mg, 0.035mmol), 1, two (diphenylphosphine) ferrocene (38mg of 1'-, 0.07mmol), SIPrAgCl (53.5mg, 0.1mmol), sodium tert-butoxide (96.1mg, 1.0mmol) be dissolved in the toluene of 5.0ml, the trimethylammonium difluoro silicon of 150uL is added in system.React at 80 DEG C after 48 hours and be cooled to room temperature, add the distilled water cancellation reaction of 10ml, after diatomite filtration, filtrate is with dichloromethane extraction (25ml × 3), merge organic phase, anhydrous sodium sulfate drying, concentrated, post is separated, obtain the product (123mg, separation yield is 59%) of corresponding difluoromethyl.
1HNMR(400MHz,CDCl
3)δ7.11(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)；
19FNMR(376MHz,CDCl
3)δ-107.26(d,J
1＝57.2Hz)；
13CNMR(101MHz,CDCl
3)δ154.27(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 embodiment 7 palladium chtalyst
Etamivan is that a kind of central is breathed and circulatory failure, narcotic, the poisoning first-aid medication of other central depressants, consider the biological isoelectronic species character of difluoromethyl and hydroxyl, difluoromethyl is incorporated in such molecular skeleton by the method that we attempt adopting us to invent, concrete operations are as follows: under argon gas atmosphere, by bromo substrate (152.1mg, 0.5mmol), two (bis-Ya Benzyl benzylacetone) palladium (41mg, 0.07mmol), 1, two (diphenylphosphine) ferrocene (76mg of 1'-, 0.14mmol), SIPrAgCl (113mg, 0.2mmol), sodium tert-butoxide (96.1mg, 1.0mmol) be dissolved in the toluene of 5.0ml, the trimethylammonium difluoro silicon of 150uL is added in system.React at 80 DEG C after 6 hours and be cooled to room temperature, add the distilled water cancellation reaction of 10ml, after diatomite filtration, filtrate is with dichloromethane extraction (25ml × 3), merge organic phase, anhydrous sodium sulfate drying, concentrated, post is separated, obtain the product (83mg, separation yield is 65%) of corresponding difluoromethyl.
1HNMR(400MHz,CDCl
3)δ7.58(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)；
19FNMR(376MHz,CDCl
3)δ-115.88(d,J
1＝55.6Hz)；
13CNMR(101MHz,CDCl
3)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 embodiment 7 palladium chtalyst
In order to investigate the practicality of the method for the difluoromethyl of our invention further, we have attempted the synthesis in gram level scale, specific experiment operation is as follows: under argon gas atmosphere, by bromo substrate (2.51g, 10mmol), two (bis-Ya Benzyl benzylacetone) palladium (402mg, 0.7mmol), 1, two (diphenylphosphine) ferrocene (776mg of 1'-, 1.4mmol), SIPrAgCl (1.08g, 2mmol), sodium tert-butoxide (1.92g, 20mmol) is dissolved in the toluene of 100ml, adds the trimethylammonium difluoro silicon of 3.0mL in system.React at 80 DEG C after 6 hours and be cooled to room temperature, add the distilled water cancellation reaction of 200ml, after diatomite filtration, filtrate is with dichloromethane extraction (250ml × 3), merge organic phase, anhydrous sodium sulfate drying, concentrated, post is separated, obtain the product (1.88g, separation yield is 80%) of corresponding difluoromethyl.
Claims (17)
1. the compound R CF containing difluoromethyl
2the preparation method of H; it is characterized in that comprising the following steps: under protection of inert gas, in organic solvent, under palladium catalyst, part and alkali existent condition; compound R X and trimethylammonium difluoromethyl silicon are carried out linked reaction, obtains the compound R CF containing difluoromethyl
2h;
RX+TMSCF
2H→RCF
2H
Wherein, X is bromine or iodine, and R is C
5~ C
30aryl, C
5~ C
30heteroaryl,
or
n is 2,3 or 4, R
10and R
11various places are independently methyl, ethyl, propyl group or sec.-propyl; Described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom can be replaced by one or more in substituents: halogen, C
1~ C
12alkyl, C
5~ C
10aryl, halogen substiuted C
5~ C
10aryl,
c
4~ C
15heteroaryl,
c
3~ C
12heterocyclylalkyl; R
1for C
1~ C
6alkyl, R
2for C
1~ C
20alkyl, C
5~ C
10aryl, " C
5~ C
10aryl replace C
1~ C
20alkyl " or " C
3~ C
10the C of cycloalkyl substituted
1~ C
20alkyl ", R
3, R
4, R
5, R
6, R
7and R
8be independently C separately
1~ C
12alkyl or C
5~ C
10aryl; R
9for C
3~ C
12heterocyclylalkyl; M is 1,2,3,4,5,6,7,8,9 or 10.
2. the compound R CF containing difluoromethyl as claimed in claim 1
2the preparation method of H, is characterized in that:
When described R is C
5~ C
30aryl time, described " C
5~ C
30aryl " be C
5~ C
10aryl;
When described R is C
5~ C
30heteroaryl time, described " C
5~ C
30heteroaryl " for heteroatoms be oxygen, sulphur or nitrogen-atoms, heteroatoms number is the C of 1 ~ 3
5~ C
10heteroaryl.
3. the compound R CF containing difluoromethyl as claimed in claim 2
2the preparation method of H, is characterized in that: when described R is C
5~ C
10aryl time, described " C
5~ C
10aryl " be phenyl or naphthyl;
Be oxygen, sulphur or nitrogen-atoms when described R is heteroatoms, heteroatoms number is the C of 1 ~ 3
5~ C
10heteroaryl time, the described " C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1 ~ 3
5~ C
10heteroaryl " be pyridyl.
4. the compound R CF containing difluoromethyl as claimed in claim 1
2the preparation method of H, is characterized in that: as described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom when being optionally substituted by halogen, described " halogen " is fluorine, chlorine, bromine or iodine;
As described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom by C
1~ C
12alkyl replace time, described " C
1~ C
12alkyl " be C
1~ C
6alkyl;
As described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom by C
5~ C
10aryl replace time, described " C
5~ C
10aryl " be phenyl;
As described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom by the " C of halogen substiuted
5~ C
10aryl " when replacing, the described " C of halogen substiuted
5~ C
10aryl " described in " C
5~ C
10aryl " be phenyl, the described " C of halogen substiuted
5~ C
10aryl " described in " halogen " be fluorine, chlorine, bromine or iodine;
As described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom by C
4~ C
15heteroaryl replace time, described " C
4~ C
15heteroaryl " for heteroatoms be oxygen, sulphur or nitrogen-atoms, heteroatoms number is the C of 1 ~ 2
4~ C
12heteroaryl;
As described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom by C
3~ C
12heterocyclylalkyl replace time, described " C
3~ C
12heterocyclylalkyl " for heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is the C of 1 ~ 3
3~ C
5heterocyclylalkyl;
As described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom by " C
1~ C
12alkyl replace C
3~ C
12heterocyclylalkyl " when replacing, described " C
1~ C
12alkyl replace C
3~ C
12heterocyclylalkyl " described in " C
1~ C
12alkyl " be C
1~ C
6alkyl;
As described R
1for C
1~ C
6alkyl time, described " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, 1-amyl group, 2-amyl group, 3-amyl group, 1-hexyl, 2-hexyl or 3-hexyl;
As described R
2for C
1~ C
20alkyl time, described " C
1~ C
20alkyl " be C
1~ C
10alkyl;
As described R
2for C
5~ C
10aryl time, described " C
5~ C
10aryl " be phenyl;
As described R
2for " C
5~ C
10aryl replace C
1~ C
20alkyl " time, described " C
5~ C
10aryl replace C
1~ C
20alkyl " described in " C
5~ C
10aryl " be phenyl;
As described R
2for " C
3~ C
10the C of cycloalkyl substituted
1~ C
20alkyl " time, described " C
3~ C
10the C of cycloalkyl substituted
1~ C
20alkyl " described in " C
1~ C
20alkyl " be C
1~ C
10alkyl;
As described R
3, R
4, R
5, R
6, R
7and R
8be independently C separately
1~ C
12alkyl time, described " C
1~ C
12alkyl " be C
1~ C
6alkyl;
As described R
3, R
4, R
5, R
6, R
7and R
8be independently C separately
5~ C
10aryl time, described " C
5~ C
10aryl " be phenyl;
As described R
9for C
3~ C
12heterocyclylalkyl time, described " C
3~ C
12heterocyclylalkyl " for heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is the C of 1 ~ 3
3~ C
5heterocyclylalkyl.
5. the compound R CF containing difluoromethyl as claimed in claim 4
2the preparation method of H, is characterized in that:
As described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom by C
1~ C
6alkyl replace time, described " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, 1-amyl group, 2-amyl group, 3-amyl group, 1-hexyl, 2-hexyl or 3-hexyl;
As described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom by " phenyl of halogen substiuted " replace time, described " phenyl " is 3-phenyl or 4-phenyl;
As described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom by heteroatoms be oxygen, sulphur or nitrogen-atoms, heteroatoms number is the C of 1 ~ 2
4~ C
12heteroaryl when replacing, it is described that " heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is the C of 1 ~ 2
4~ C
12heteroaryl " be pyrryl, benzothiazolyl or 9-azepine tablet held before the breast by officials base;
As described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom be oxygen, sulphur or nitrogen-atoms by heteroatoms, heteroatoms number is the C of 1 ~ 3
3~ C
5heterocyclylalkyl when replacing, it is described that " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the C of 1 ~ 3
3~ C
5heterocyclylalkyl " be
As described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom by " C
1~ C
6alkyl replace C
3~ C
12heterocyclylalkyl " when replacing, described " C
1~ C
6alkyl replace C
3~ C
12heterocyclylalkyl " described in " C
3~ C
12heterocyclylalkyl " for heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is the C of 1 ~ 3
3~ C
5heterocyclylalkyl;
As described R
2for C
1~ C
10alkyl time, described " C
1~ C
10alkyl " be methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, 1-amyl group, 1-hexyl, 1-heptyl, 1-octyl group, 1-nonyl or 1-decyl;
As described R
2for the C that phenyl replaces
1~ C
20alkyl time, the described " C that phenyl replaces
1~ C
20alkyl " described in " C
1~ C
20alkyl " be C
1~ C
10alkyl;
As described R
2for C
3~ C
10the C of cycloalkyl substituted
1~ C
10alkyl time, described " C
3~ C
10the C of cycloalkyl substituted
1~ C
20alkyl " described in " C
3~ C
10cycloalkyl " be C
3~ C
6cycloalkyl;
As described R
3, R
4, R
5, R
6, R
7and R
8be independently C separately
1~ C
6alkyl time, described " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, 1-amyl group, 2-amyl group, 3-amyl group, 1-hexyl, 2-hexyl or 3-hexyl;
As described R
9for heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is the C of 1 ~ 3
3~ C
5heterocyclylalkyl time, it is described that " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the C of 1 ~ 3
3~ C
5heterocyclylalkyl " be morpholinyl.
6. the compound R CF containing difluoromethyl as claimed in claim 5
2the preparation method of H, is characterized in that:
As described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom by " the 4-phenyl of halogen substiuted " replace time, described " the 4-phenyl of halogen substiuted " is the bromo-phenyl of 4-;
As described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom when being replaced by pyrryl, described " pyrryl " is 1-pyrryl;
As described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom when being replaced by benzothiazolyl, described " benzothiazolyl " is
As described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom when being replaced by 9-azepine tablet held before the breast by officials base, described " 9-azepine tablet held before the breast by officials base " is
As described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom by " C
1~ C
6alkyl replace heteroatoms be oxygen, sulphur or nitrogen-atoms, heteroatoms number is the C of 1 ~ 3
3~ C
5heterocyclylalkyl " when replacing, described " C
1~ C
6alkyl replace heteroatoms be oxygen, sulphur or nitrogen-atoms, heteroatoms number is the C of 1 ~ 3
3~ C
5heterocyclylalkyl " described in " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, 1-amyl group, 2-amyl group, 3-amyl group, 1-hexyl, 2-hexyl or 3-hexyl;
As described R
2for " the C that phenyl replaces
1~ C
10alkyl " time, the described " C that phenyl replaces
1~ C
10alkyl " described in " C
1~ C
10alkyl " be methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, 1-amyl group, 1-hexyl, 1-heptyl, 1-octyl group, 1-nonyl or 1-decyl;
As described R
2for " C
3~ C
6the C of cycloalkyl substituted
1~ C
10alkyl " time, described " C
3~ C
6the C of cycloalkyl substituted
1~ C
10alkyl " described in " C
3~ C
6cycloalkyl " be cyclopropyl;
As described R
9during for morpholinyl, described " morpholinyl " is
7. the compound R CF containing difluoromethyl as claimed in claim 6
2the preparation method of H, is characterized in that:
As described " C
5~ C
30aryl " or described " C
5~ C
30heteroaryl " in hydrogen atom by " methyl substituted heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the C of 1 ~ 3
3~ C
5heterocyclylalkyl " when replacing, it is described that " methyl substituted heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the C of 1 ~ 3
3~ C
5heterocyclylalkyl " be
As described R
2for the C that cyclopropyl replaces
1~ C
10alkyl time, described " C
1~ C
10alkyl " be methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, 1-amyl group, 1-hexyl, 1-heptyl, 1-octyl group, 1-nonyl or 1-decyl.
8. the compound R CF containing difluoromethyl as described in any one of claim 1 ~ 7
2the preparation method of H, is characterized in that: described R is preferably as follows arbitrary substituting group further:
9. the compound R CF containing difluoromethyl as claimed in claim 1
2the preparation method of H, is characterized in that: " rare gas element " described in described " protection of inert gas " is helium, one or more in neon, argon gas and nitrogen;
And/or,
Described organic solvent is one or more in ether solvent, halogenated hydrocarbon solvent, amide solvent, nitrile solvents and aromatic hydrocarbon solvent;
And/or,
Described organic solvent is 1mL/mmol ~ 100mL/mmol with the Molar ratio of described RX;
And/or,
Described TMSCF
2the molar ratio of H and described RX is 5 ~ 1;
And/or,
Described palladium catalyst is (dibenzalacetone) palladium, three (dibenzalacetone) two palladium, tetrakis triphenylphosphine palladium, Palladous chloride, palladium bromide, palladium iodide, palladium, palladium trifluoroacetate, one hydration trifluoromethanesulfonic acid palladium, four acetonitriles close trifluoromethanesulfonic acid palladium, four acetonitrile tosic acid palladiums, diacetonitrile closes Palladous chloride, two cyanophenyls close Palladous chloride, tetramino closes Palladous chloride, two (triphenylphosphine) Palladous chloride, four acetonitriles close fluoroboric acid palladium, Palladous nitrate, 1, one or more in two (diphenylphosphine) the ferrocene palladium chloride of 1'-and diacetyl acetone palladium,
And/or,
The molar ratio of described palladium catalyst and described RX is 0.0001 ~ 0.1;
And/or,
Described alkali is mineral alkali;
And/or,
The molar ratio of described alkali and compound R X is 5 ~ 1;
And/or,
Described part is 1, two (diphenylphosphine) ferrocene of 1'-, two diphenylphosphine methane, 1, 2 pairs of (diphenylphosphine) ethane, 1, two (diphenylphosphine) propane of 3-, 1, 1'-dinaphthalene-2, the two diphenyl phosphine of 2'-, triphenylphosphine, tri-butyl phosphine, tricyclohexyl phosphine, 4, the two diphenylphosphine-9 of 5-, 9-dimethyl xanthene, two (2-diphenylphosphine phenyl) ether, (2-dicyclohexyl phosphino--3, 6-dimethoxy-2', 4', 6'-tri-tert-1, 1'-biphenyl) [2-(2-amino-ethyl phenyl)] palladium (II), 1, 2, 3, 4, 5-penta phenyl-1'-(di-t-butyl phosphorus base) ferrocene, (R)-1-[(S)-2-(dicyclohexyl phosphino-) ferrocenyl] ethyl dicyclohexylphosphontetrafluoroborate, 1, two (diphenylphosphine) butane of 4-, 1, 10 Féraud beautiful jades, 2, one or more in 2-dipyridyl and Tetramethyl Ethylene Diamine,
And/or,
Described part and the molar ratio of palladium catalyst are 3 ~ 0.5;
And/or,
Described linked reaction temperature is 25 DEG C ~ 150 DEG C;
And/or,
The time of described linked reaction is 1 hour ~ 48 hours.
10. the compound R CF containing difluoromethyl as claimed in claim 9
2the preparation method of H, is characterized in that:
Described linked reaction is carried out under additive existent condition, described additive is 1, 3-two (2, 6-diisopropyl phenyl)-4, 5-glyoxalidine silver chloride, 1, 3-two (2, 6-diisopropyl phenyl)-imidazoles silver chloride, 1, 3-two (2, 4, 6-trimethylphenyl)-4, 5-glyoxalidine silver chloride, 1, 3-two (2, 4, 6-trimethylphenyl)-imidazoles silver chloride, 1, 3-dicyclohexyl-imidazoles silver chloride, trimethylacetic acid silver, Silver Nitrate, silver trifluoromethanesulfonate, phosphofluoric acid silver, silver hexafluoroantimonate, silver tetrafluoroborate, Silver monoacetate, silver carbonate, silver suboxide, silver fluoride, cuprous chloride, cuprous bromide, cuprous iodide, copper sulfate, cupric nitrate, iron(ic) chloride, one or more in iron protochloride and ferrous sulfate,
And/or,
The molar ratio of described additive and described RX is 0.001 ~ 1.
11. as described in claim 9 or 10 containing the compound R CF of difluoromethyl
2the preparation method of H, is characterized in that: when X is iodine, adopt following reaction conditions:
Described ether solvent is one or more in dioxane, tetrahydrofuran (THF), glycol dimethyl ether and diethylene glycol dimethyl ether;
And/or,
Described halogenated hydrocarbon solvent is chlorinated hydrocarbon solvent, and described amide solvent is DMF and/or N,N-dimethylacetamide;
And/or,
Described nitrile solvents is acetonitrile;
And/or,
Described aromatic hydrocarbon solvent is toluene;
And/or,
Described organic solvent is 1mL/mmol ~ 10mL/mmol with the Molar ratio of described RX;
And/or,
Described TMSCF
2the mol ratio of H and described RX is 5 ~ 2;
And/or,
Described palladium catalyst is one or more in two (diphenylphosphine) ferrocene palladium chloride of (dibenzalacetone) palladium, three (dibenzalacetone) two palladium, tetrakis triphenylphosphine palladium, Palladous chloride and 1,1'-;
And/or,
The mol ratio of described palladium catalyst and described RX is 0.01 ~ 0.1;
And/or,
Described mineral alkali is one or more in sodium tert-butoxide, Methanaminium, N,N,N-trimethyl-, fluoride and cesium fluoride;
And/or,
The molar ratio of described alkali and compound R X is 3 ~ 1;
And/or,
Described part is 1,1'-two (diphenylphosphine) ferrocene, two diphenylphosphine methane, 1,2 pairs of (diphenylphosphine) ethane, 1, two (diphenylphosphine) propane, 1 of 3-, the two diphenyl phosphine of 1'-dinaphthalene-2,2'-, 4,5-two diphenylphosphines-9, one or more in 9-dimethyl xanthene, two (2-diphenylphosphine phenyl) ether and Isosorbide-5-Nitrae-bis-(diphenylphosphine) butane;
And/or,
The molar ratio of described part and compound R X is 0.025 ~ 0.5;
And/or,
Described linked 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 1,3-two (2,6-diisopropyl phenyl)-4,5-glyoxalidine silver chlorides, 1,3-two (2,4,6-trimethylphenyl)-4,5-glyoxalidine silver chlorides, 1,3-two (2,4,6-trimethylphenyl) one or more in-imidazoles silver chloride, trimethylacetic acid silver, Silver Nitrate, silver trifluoromethanesulfonate, silver hexafluoroantimonate, silver tetrafluoroborate, cuprous chloride and cuprous iodide;
And/or,
The molar ratio of described additive and described RX is 0.08 ~ 1.
12. as claimed in claim 11 containing the compound R CF of difluoromethyl
2the preparation method of H, it is characterized in that: described organic solvent is dioxane, tetrahydrofuran (THF), N, dinethylformamide, N,N-dimethylacetamide, toluene, dioxane and the mixed solvent of tetrahydrofuran (THF), dioxane and the mixed solvent of acetonitrile or the mixed solvent of dioxane and glycol dimethyl ether;
And/or,
Described TMSCF
2the mol ratio of H and described RX is 2.4 ~ 2;
And/or,
Described palladium catalyst is (dibenzalacetone) palladium and/or three (dibenzalacetone) two palladium;
And/or,
The mol ratio of described palladium catalyst and described RX is 0.02 ~ 0.1;
And/or,
Described mineral alkali is sodium tert-butoxide;
And/or,
Described part is one or more in two (diphenylphosphine) ferrocene of 1,1'-, 4,5-two diphenylphosphine-9,9-dimethyl xanthenes and two (2-diphenylphosphine phenyl) ether;
And/or,
The molar ratio of described part and compound R X is 0.05 ~ 0.3;
And/or,
Described linked 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 one or more in 1,3-two (2,6-diisopropyl phenyl)-4,5-glyoxalidine silver chloride, 1,3-two (mesityl)-4,5-glyoxalidine silver chloride, Silver Nitrate and silver hexafluoroantimonate;
And/or,
The molar ratio of described additive and described RX is 0.1 ~ 1.
13. as claimed in claim 12 containing the compound R CF of difluoromethyl
2the preparation method of H, is characterized in that:
When adopt dioxane and the mixed solvent of tetrahydrofuran (THF) time, the volume ratio of described dioxane and described tetrahydrofuran (THF) is 1 ~ 5; When adopt dioxane and the mixed solvent of acetonitrile time, the volume ratio of described dioxane and described acetonitrile is 1 ~ 5; When adopt dioxane and the mixed solvent of glycol dimethyl ether time, the volume ratio of described dioxane and described glycol dimethyl ether is 1 ~ 5;
And/or,
Described part is two (diphenylphosphine) ferrocene of 1,1'-;
And/or,
The molar ratio of described part and compound R X is 0.1 ~ 0.15;
And/or,
Described linked reaction temperature is 80 DEG C ~ 90 DEG C;
And/or,
Described additive is 1,3-two (2,6-diisopropyl phenyl)-4,5-glyoxalidine silver chloride.
14. as described in claim 9 or 10 containing the compound R CF of difluoromethyl
2the preparation method of H, is characterized in that: when X is bromine, adopt following reaction conditions:
Described ether solvent is one or more in dioxane, tetrahydrofuran (THF), glycol dimethyl ether and diethylene glycol dimethyl ether;
And/or,
Described halogenated hydrocarbon solvent is chlorinated hydrocarbon solvent;
And/or,
Described amide solvent is DMF and/or N,N-dimethylacetamide;
And/or,
Described nitrile solvents is acetonitrile;
And/or,
Described aromatic hydrocarbon solvent is toluene;
And/or,
Described organic solvent is 1mL/mmol ~ 10mL/mmol with the Molar ratio of described RX;
And/or,
Described TMSCF
2the molar ratio of H and described RX is 5 ~ 2;
And/or,
Described palladium catalyst is one or more in two (diphenylphosphine) ferrocene palladium chloride of (dibenzalacetone) palladium, three (dibenzalacetone) two palladium, tetrakis triphenylphosphine palladium and 1,1'-;
And/or,
The molar ratio of described palladium catalyst and described RX is 0.01 ~ 0.1;
And/or,
Described mineral alkali is one or more in sodium tert-butoxide, Methanaminium, N,N,N-trimethyl-, fluoride and cesium fluoride;
And/or,
The molar ratio of described alkali and compound R X is 3 ~ 1;
And/or,
Described part is 1,1'-two (diphenylphosphine) ferrocene, two diphenylphosphine methane, 1,2 pairs of (diphenylphosphine) ethane, 1,1'-dinaphthalene-2, the two diphenyl phosphine, 4 of 2'-, one or more in 5-two diphenylphosphine-9,9-dimethyl xanthene, two (2-diphenylphosphine phenyl) ether and Isosorbide-5-Nitrae-bis-(diphenylphosphine) butane;
And/or,
The molar ratio of described part and compound R X is 0.025 ~ 0.5;
And/or,
The temperature of described linked reaction is 60 DEG C ~ 100 DEG C;
And/or,
The time of described linked reaction is 2 hours ~ 30 hours;
And/or,
Described additive is 1,3-two (2,6-diisopropyl phenyl)-4,5-glyoxalidine silver chlorides, 1,3-two (2,4,6-trimethylphenyl)-4,5-glyoxalidine silver chlorides, 1,3-two (2,4,6-trimethylphenyl) one or more in-imidazoles silver chloride, trimethylacetic acid silver, Silver Nitrate, silver trifluoromethanesulfonate, silver carbonate and cuprous chloride;
And/or,
The molar ratio of described additive and described RX is 0.01 ~ 1.
15. as claimed in claim 14 containing the compound R CF of difluoromethyl
2the preparation method of H, is characterized in that:
Described organic solvent is the mixed solvent of the mixed solvent of dioxane, tetrahydrofuran (THF), methylene dichloride, toluene, toluene and tetrahydrofuran (THF), dioxane and toluene, toluene and the mixed solvent of acetonitrile or the mixed solvent of toluene and glycol dimethyl ether;
And/or,
Described TMSCF
2the molar ratio of H and described RX is 3 ~ 2;
And/or,
Described palladium catalyst is (dibenzalacetone) palladium and/or three (dibenzalacetone) two palladium;
And/or,
The molar ratio of described palladium catalyst and described RX is 0.05 ~ 0.1;
And/or,
Described mineral alkali is sodium tert-butoxide;
And/or,
Described part is one or more in two (diphenylphosphine) ferrocene of 1,1'-, 4,5-two diphenylphosphine-9,9-dimethyl xanthenes and two (2-diphenylphosphine phenyl) ether;
And/or,
The molar ratio of described part and compound R X is 0.1 ~ 0.3;
And/or,
Described linked reaction temperature is 70 DEG C ~ 100 DEG C;
And/or,
The time of described linked reaction is 3 hours ~ 16 hours;
And/or,
Described additive is one or more in glyoxalidine silver chloride and Silver Nitrate of 1,3-two (2,6-diisopropyl phenyl)-4,5-glyoxalidine silver chloride, 1,3-two (mesityl)-4,5-;
And/or,
The molar ratio of described additive and described RX is 0.1 ~ 0.2.
16. as claimed in claim 15 containing the compound R CF of difluoromethyl
2the preparation method of H, is characterized in that: when adopting the mixed solvent of toluene and tetrahydrofuran (THF), the volume ratio of described toluene and described tetrahydrofuran (THF) is 1 ~ 5; When adopting the mixed solvent of dioxane and toluene, the volume ratio of described dioxane and described toluene is 1 ~ 5; When adopt toluene and the mixed solvent of acetonitrile time, the volume ratio of described dioxane and described glycol dimethyl ether is 1 ~ 5; When adopt toluene and the mixed solvent of glycol dimethyl ether time, the volume ratio of described toluene and described glycol dimethyl ether is 1 ~ 5;
And/or,
Described TMSCF
2the molar ratio of H and described RX is 2.4;
And/or,
Described part is two (diphenylphosphine) ferrocene of 1,1'-;
And/or,
Described linked reaction temperature is 80 DEG C ~ 90 DEG C;
And/or,
The time of described linked reaction is 4 hours ~ 12 hours;
And/or,
Described additive is 1,3-two (2,6-diisopropyl phenyl)-4,5-glyoxalidine silver chloride.
17. compound R CF
2h, wherein the definition of R is as described in any one of claim 1 ~ 8.
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| CN107235878B (en) * | 2016-03-28 | 2019-03-15 | 中国科学院上海有机化学研究所 | Difluoromethyl reagent, preparation method and application |
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| CN111004114B (en) * | 2019-12-27 | 2022-02-11 | 信阳师范学院 | Method for synthesizing remote fluoro aryl olefin |
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