CN106187656A - 镁辅助镍催化多氟芳烃单芳基化的方法 - Google Patents
镁辅助镍催化多氟芳烃单芳基化的方法 Download PDFInfo
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- CN106187656A CN106187656A CN201610512110.5A CN201610512110A CN106187656A CN 106187656 A CN106187656 A CN 106187656A CN 201610512110 A CN201610512110 A CN 201610512110A CN 106187656 A CN106187656 A CN 106187656A
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- Prior art keywords
- nickel
- magnesium
- phenyl
- aromatic hydrocarbons
- arylation
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- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 229910052759 nickel Inorganic materials 0.000 title claims abstract description 32
- 150000004945 aromatic hydrocarbons Chemical class 0.000 title claims abstract description 29
- 238000006254 arylation reaction Methods 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 20
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 239000011777 magnesium Substances 0.000 title claims abstract description 17
- 238000006555 catalytic reaction Methods 0.000 title claims abstract description 16
- 229910052749 magnesium Inorganic materials 0.000 title claims abstract description 15
- -1 alkyl Grignard reagent Chemical class 0.000 claims abstract description 35
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003446 ligand Substances 0.000 claims abstract description 16
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 11
- 239000004215 Carbon black (E152) Substances 0.000 claims abstract description 9
- 125000003118 aryl group Chemical group 0.000 claims abstract description 9
- 229930195733 hydrocarbon Natural products 0.000 claims abstract description 9
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 41
- 238000006243 chemical reaction Methods 0.000 claims description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 14
- 229940091250 magnesium supplement Drugs 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 239000000376 reactant Substances 0.000 claims description 8
- 239000000377 silicon dioxide Substances 0.000 claims description 7
- HJDKCHUESYFUMG-UHFFFAOYSA-N cycloocta-1,5-diene;nickel Chemical compound [Ni].C1CC=CCCC=C1 HJDKCHUESYFUMG-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 5
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- MQRWBMAEBQOWAF-UHFFFAOYSA-N acetic acid;nickel Chemical compound [Ni].CC(O)=O.CC(O)=O MQRWBMAEBQOWAF-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 claims description 3
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 3
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical group [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 3
- UGVPKMAWLOMPRS-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].CC[CH2-] UGVPKMAWLOMPRS-UHFFFAOYSA-M 0.000 claims description 3
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 claims description 3
- ZKUUVVYMPUDTGJ-UHFFFAOYSA-N methyl 5-hydroxy-4-methoxy-2-nitrobenzoate Chemical compound COC(=O)C1=CC(O)=C(OC)C=C1[N+]([O-])=O ZKUUVVYMPUDTGJ-UHFFFAOYSA-N 0.000 claims description 3
- 229940078494 nickel acetate Drugs 0.000 claims description 3
- PDXOPNHXAAQJJO-UHFFFAOYSA-N nickel;trifluoromethanesulfonic acid Chemical compound [Ni].OS(=O)(=O)C(F)(F)F PDXOPNHXAAQJJO-UHFFFAOYSA-N 0.000 claims description 3
- 239000012264 purified product Substances 0.000 claims description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004212 difluorophenyl group Chemical group 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 claims description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 claims 4
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims 1
- 229910001623 magnesium bromide Inorganic materials 0.000 claims 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 12
- 238000006880 cross-coupling reaction Methods 0.000 abstract description 8
- 229910052763 palladium Inorganic materials 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 5
- 239000000758 substrate Substances 0.000 abstract description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052802 copper Inorganic materials 0.000 abstract description 3
- 239000010949 copper Substances 0.000 abstract description 3
- 238000010168 coupling process Methods 0.000 abstract description 3
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 238000012805 post-processing Methods 0.000 abstract description 2
- 239000012190 activator Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- 238000012512 characterization method Methods 0.000 description 24
- 239000002131 composite material Substances 0.000 description 22
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 18
- NAZNQEXKAPLVKC-UHFFFAOYSA-N 2-iodo-5-methylthiophene Chemical compound CC1=CC=C(I)S1 NAZNQEXKAPLVKC-UHFFFAOYSA-N 0.000 description 15
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 9
- MDWRQYBWVTXIIJ-UHFFFAOYSA-N naphthalen-2-yl trifluoromethanesulfonate Chemical compound C1=CC=CC2=CC(OS(=O)(=O)C(F)(F)F)=CC=C21 MDWRQYBWVTXIIJ-UHFFFAOYSA-N 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 5
- KLECYOQFQXJYBC-UHFFFAOYSA-N 1-fluoro-2-phenylbenzene Chemical group FC1=CC=CC=C1C1=CC=CC=C1 KLECYOQFQXJYBC-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- MMARFGDTMJBIBK-UHFFFAOYSA-N 5-bromo-2-methoxy-1,3-dimethylbenzene Chemical compound COC1=C(C)C=C(Br)C=C1C MMARFGDTMJBIBK-UHFFFAOYSA-N 0.000 description 3
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- AJKNNUJQFALRIK-UHFFFAOYSA-N 1,2,3-trifluorobenzene Chemical compound FC1=CC=CC(F)=C1F AJKNNUJQFALRIK-UHFFFAOYSA-N 0.000 description 2
- XBBRRJVEANWDEF-UHFFFAOYSA-N 2-methyl-5-(2,3,5,6-tetrafluorophenyl)thiophene Chemical compound S1C(C)=CC=C1C1=C(F)C(F)=CC(F)=C1F XBBRRJVEANWDEF-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- SVFZEVQQPVQJCU-UHFFFAOYSA-N S(C)(=O)(=O)O.FC(S(=O)(=O)OC1=CC=CC=C1)(F)F Chemical class S(C)(=O)(=O)O.FC(S(=O)(=O)OC1=CC=CC=C1)(F)F SVFZEVQQPVQJCU-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- RBOGJRXPKONDGC-UHFFFAOYSA-N (2-methylphenyl) trifluoromethanesulfonate Chemical compound CC1=CC=CC=C1OS(=O)(=O)C(F)(F)F RBOGJRXPKONDGC-UHFFFAOYSA-N 0.000 description 1
- LJIHEZUTOPKWKJ-UHFFFAOYSA-N 1-(2,3,5,6-tetrafluorophenyl)naphthalene Chemical compound FC1=C(C(=C(C=C1F)F)F)C1=CC=CC2=CC=CC=C12 LJIHEZUTOPKWKJ-UHFFFAOYSA-N 0.000 description 1
- JXYFFTWOLRAWHG-UHFFFAOYSA-N 1-[4-(2,3,5,6-tetrafluorophenyl)phenyl]ethanone Chemical compound CC(=O)c1ccc(cc1)-c1c(F)c(F)cc(F)c1F JXYFFTWOLRAWHG-UHFFFAOYSA-N 0.000 description 1
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- ISZKSFRDANBEFN-UHFFFAOYSA-N 2-(2,3,4,6-tetrafluorophenyl)naphthalene Chemical compound FC1=C(C(=CC(=C1F)F)F)C1=CC2=CC=CC=C2C=C1 ISZKSFRDANBEFN-UHFFFAOYSA-N 0.000 description 1
- GSSMWQVIHFUKMR-UHFFFAOYSA-N 2-(2,3,5,6-tetrafluoro-4-methoxyphenyl)naphthalene Chemical compound FC1=C(C(=C(C(=C1F)OC)F)F)C1=CC2=CC=CC=C2C=C1 GSSMWQVIHFUKMR-UHFFFAOYSA-N 0.000 description 1
- RVFKZGFSCNMXGX-UHFFFAOYSA-N 2-(2,3,5,6-tetrafluorophenyl)naphthalene Chemical compound FC1=C(C(=C(C=C1F)F)F)C1=CC2=CC=CC=C2C=C1 RVFKZGFSCNMXGX-UHFFFAOYSA-N 0.000 description 1
- FOQANUVUIUWJDS-UHFFFAOYSA-N 2-(2,4,5-trifluorophenyl)naphthalene Chemical compound FC1=C(C=C(C(=C1)F)F)C1=CC2=CC=CC=C2C=C1 FOQANUVUIUWJDS-UHFFFAOYSA-N 0.000 description 1
- LHCVHUABXIJBOK-UHFFFAOYSA-N 2-(4-benzyl-2,3,5,6-tetrafluorophenyl)naphthalene Chemical compound C(C1=CC=CC=C1)C1=C(C(=C(C(=C1F)F)C1=CC2=CC=CC=C2C=C1)F)F LHCVHUABXIJBOK-UHFFFAOYSA-N 0.000 description 1
- RCGKCHWYLFSJOH-UHFFFAOYSA-N 2-[2,3,5,6-tetrafluoro-4-(3-phenylprop-2-enyl)phenyl]naphthalene Chemical compound C(C=CC1=CC=CC=C1)C1=C(C(=C(C(=C1F)F)C1=CC2=CC=CC=C2C=C1)F)F RCGKCHWYLFSJOH-UHFFFAOYSA-N 0.000 description 1
- APSMUYYLXZULMS-UHFFFAOYSA-N 2-bromonaphthalene Chemical compound C1=CC=CC2=CC(Br)=CC=C21 APSMUYYLXZULMS-UHFFFAOYSA-N 0.000 description 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- VNZSJCVNLKZQPE-UHFFFAOYSA-N 6-(2,3,5,6-tetrafluorophenyl)naphthalene-2-carbonitrile Chemical compound FC1=C(C(=C(C=C1F)F)F)C=1C=C2C=CC(=CC2=CC=1)C#N VNZSJCVNLKZQPE-UHFFFAOYSA-N 0.000 description 1
- 241001120493 Arene Species 0.000 description 1
- PYMKHSPKGRKCTP-UHFFFAOYSA-L C(C)(=O)[O-].[Ni+2].[F].C(C)(=O)[O-] Chemical compound C(C)(=O)[O-].[Ni+2].[F].C(C)(=O)[O-] PYMKHSPKGRKCTP-UHFFFAOYSA-L 0.000 description 1
- PRIXFRKHDNSQKA-UHFFFAOYSA-N Cc(c(F)c(c(-c1cc2ccccc2cc1)c1F)F)c1F Chemical compound Cc(c(F)c(c(-c1cc2ccccc2cc1)c1F)F)c1F PRIXFRKHDNSQKA-UHFFFAOYSA-N 0.000 description 1
- 208000035126 Facies Diseases 0.000 description 1
- RCGKCHWYLFSJOH-RMKNXTFCSA-N Fc(c(C/C=C/c1ccccc1)c(c(F)c1-c2cc3ccccc3cc2)F)c1F Chemical compound Fc(c(C/C=C/c1ccccc1)c(c(F)c1-c2cc3ccccc3cc2)F)c1F RCGKCHWYLFSJOH-RMKNXTFCSA-N 0.000 description 1
- 0 Fc1cc(F)c(-c2cc3ccccc3cc2)*(F)c1 Chemical compound Fc1cc(F)c(-c2cc3ccccc3cc2)*(F)c1 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000005577 Kumada cross-coupling reaction Methods 0.000 description 1
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 1
- OSRYLNKBCFIHFH-UHFFFAOYSA-N [S].COCC1=C(C=CC=C1)C(F)(F)F Chemical compound [S].COCC1=C(C=CC=C1)C(F)(F)F OSRYLNKBCFIHFH-UHFFFAOYSA-N 0.000 description 1
- UGAPHEBNTGUMBB-UHFFFAOYSA-N acetic acid;ethyl acetate Chemical compound CC(O)=O.CCOC(C)=O UGAPHEBNTGUMBB-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000005347 biaryls Chemical group 0.000 description 1
- 235000010338 boric acid Nutrition 0.000 description 1
- 125000005619 boric acid group Chemical class 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- NGPGYVQZGRJHFJ-UHFFFAOYSA-N chembl1604790 Chemical compound OC1=CC(O)=CC=C1N=NC1=CC=C([N+]([O-])=O)C=C1 NGPGYVQZGRJHFJ-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical group C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000004407 fluoroaryl group Chemical group 0.000 description 1
- 238000009432 framing Methods 0.000 description 1
- 229960002337 magnesium chloride Drugs 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- WQWUQDVFRYMMCY-UHFFFAOYSA-N naphthalen-1-yl trifluoromethanesulfonate Chemical compound C1=CC=C2C(OS(=O)(=O)C(F)(F)F)=CC=CC2=C1 WQWUQDVFRYMMCY-UHFFFAOYSA-N 0.000 description 1
- PJDLZCFUBVEWHO-UHFFFAOYSA-N naphthalen-2-ylphosphane Chemical compound C1=CC=CC2=CC(P)=CC=C21 PJDLZCFUBVEWHO-UHFFFAOYSA-N 0.000 description 1
- BMGNSKKZFQMGDH-FDGPNNRMSA-L nickel(2+);(z)-4-oxopent-2-en-2-olate Chemical compound [Ni+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O BMGNSKKZFQMGDH-FDGPNNRMSA-L 0.000 description 1
- LHJARSDQUNCSJG-UHFFFAOYSA-N nickel;propan-2-one Chemical compound [Ni].CC(C)=O LHJARSDQUNCSJG-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- QARVLSVVCXYDNA-UHFFFAOYSA-N phenyl bromide Natural products BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
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Abstract
本发明公开了一种镁辅助镍催化多氟芳烃单芳基化的方法,该方法以烷基格氏试剂为活化剂,采用镍源与双膦配体形成的复合物为催化剂,实现多氟芳烃与卤代芳烃或芳基磺酸酯之间的交叉偶联。该偶联方法高度可控,其单芳基化产物比例高达99%以上,且官能团耐受性好,底物适用性广,产率介于80%~96%之间。与以往的催化体系(钯体系、铜体系等)相比,本发明方法采用全新的镍催化体系,在温和条件下便可实现其交叉偶联,具有选择性优异、价格低廉、操作简单、后处理容易、污染小等优势,显示出较高的社会价值和工业推广前景。
Description
技术领域
本发明属于多氟芳烃芳基化技术领域,具体涉及一种多氟芳烃选择性单芳基化的方法。
背景技术
偶联反应是制备多氟联芳烃类化合物最有效的手段之一。自2005年TakashiSakai报道钯催化多氟苯硼酸和芳基卤代物交叉偶联制备多氟联芳烃(TakashiSakai.Org.Lett.2005,7,4915)以来,以钯催化为主的交叉偶联反应得到了迅速发展。尤其是以多氟芳烃为原料的直接交叉偶联更是得到了迅猛发展。(J.Am.Chem.Soc.2006,128,8574;Org.Lett.2009,11,3346;Org.Lett.2010,12,2116;J.Am.Chem.Soc.2010,132,16377;Org.Lett.2011,13,276;J.FluorineChem.2013,151,50;Appl.Organometal.Chem.2014,28,180;Tetrahedron.Lett.2015,56,123),相关化学反应方程式如下:
纵观这些报道文献,不难发现,现在的直接交叉偶联大都存在以下问题:
1、芳基化产率低,尤其是遇到四氟苯和三氟苯这类含有多个等价活性氢的底物时,除单芳基化产物外还会额外生成双芳基化甚至三芳基化产物。这些副产物的存在不仅直接导致了单芳基化主产物产率的降低(<75%),还给后续的分离纯化带来了极大困难。
2、现有的多氟苯直接偶联方法,大都需要高温(90~120℃)等苛刻条件,这进一步增加了反应工业化的困难。
3、现有的催化模式大都采用昂贵的钯催化体系,这使得反应成本大大提高。
2016年施章杰报道了镍、铜共催化的多氟苯芳基化反应(Org.Lett.DOI:10.1021/acs.orglett.6b00819),该反应使用廉价的镍为催化剂、以多氟苯为底物的直接交叉偶联反应,但也存在着如下缺陷:1)反应需要镍、铜两种金属共同催化完成;2)该反应在120℃高温的苛刻条件下完成,操作难度较大;3)含有多个酸性C-H键的多氟苯参与偶联反应选择性低(2.1:1)。不利于工业推广。相关化学反应方程式如下:
发明内容
本发明所要解决的技术问题在于克服现有芳基化方法难以实现多氟芳烃高效单芳基化且反应条件苛刻的难题,提供一种操作简单、成本低廉、反应条件温和、多氟芳烃单芳基化选择性和产率均高的方法。
解决上述技术问题所采用的技术方案由下述步骤组成:
1、在无水无氧条件下,以四氢呋喃为溶剂,将式I所示的多氟芳烃与烷基格氏试剂在20~50℃下搅拌12~18小时,然后加入1,4-二氧六环、乙二醇二甲醚、18-冠醚-6,常温搅拌30分钟。
2、在无水无氧条件下,将镍源、双膦配体加入四氢呋喃与1,4-二氧六环的混合液中,室温搅拌30分钟;其中所述的镍源为双(1,5-环辛二烯)镍、、醋酸镍、三氟醋酸镍、乙酰丙酮镍、三氟甲磺酸镍、氯化镍、溴化镍,及氯化镍或溴化镍乙二醇二甲醚复合物中的任意一种;所述的双膦配体的结构式如下所示:
其根据下述方法制备得到:以四氢呋喃为溶剂,将卤代芳烃与Mg粉按摩尔比为1.1:1回流反应至Mg粉完全消失,冷却至-78℃后,缓慢滴入双(2-二氯化膦)苯醚的四氢呋喃溶液,其中双(2-二氯化膦)苯醚与镁粉的摩尔比为1:8,滴加完毕后缓慢升至室温,继续搅拌8小时;将反应液冷却至-20℃,缓慢加入甲醇淬灭反应,分离纯化产物,得到双膦配体,具体合成路线如下所示:
式中Ar代表苯基、C1~C6烷基取代苯基、C1~C6烷氧基取代苯基、氟代苯基、三氟甲基苯基、萘基、呋喃基、硅氧基苯基中的任意一种,X1代表Cl、Br或I。
3、在无水无氧条件下,将步骤1和2所得反应液混合,并加入式II所示的卤代芳烃或芳基磺酸酯,0~40℃下搅拌至反应完全后,加入甲醇淬灭反应,分离纯化产物,得到式III所示的单芳基化多氟芳烃。
上述式I~III中,R1~R3各自独立的代表H、F、C1~C10烷基、C1~C6烷氧基、苯基、C1~C10烷基取代苯基、C1~C6烷氧基取代苯基、烯丙基、肉桂基、三氟甲基、苄基、硅基、硅氧基中的任意一种,且R1~R3中至少有一个为F;R代表H、C1~C10烷基、C1~C6烷氧基、苯基、C1~C10烷基取代苯基、C1~C6烷氧基取代苯基、甲酸C1~C6烷基酯基、F、Cl、CF3、CN中的任意一种,X代表Br、I或R′代表CF3、CH3或p-CH3-C6H4,Y代表C、O、N或S,且Y代表C时,Z=1,n=1、2或3;Y代表N时,Z=1或0,n=1或2;Y代表O、S时,Z=0,n=1或2
上述的R1~R3进一步优选各自独立的代表H、F、C1~C6烷基、C1~C4烷氧基、苯基、肉桂基、三氟甲基、苄基、C1~C4烷基取代硅基、中的任意一种,且R1~R3中至少有一个为F。
上述的R进一步优选H、C1~C10烷基、C1~C6烷氧基、苯基、甲酸C1~C6烷基酯基、F、Cl、CF3、CN中的任意一种。
上述的卤代芳烃或芳基磺酸酯与镍源、双膦配体、多氟芳烃、烷基格氏试剂、18-冠-6-醚的摩尔比为1:0.05~0.2:0.05~0.2:1.2~5.0:1.0~3.0:0~1.2,优选卤代芳烃或芳基磺酸酯与镍源、双膦配体、多氟芳烃、烷基格氏试剂、18-冠-6-醚的摩尔比为1:0.08:0.10:2.4:2.0:0.1,其中所述的烷基格氏试剂为甲基氯化镁、乙基氯化镁、正丙基氯化镁、异丙基氯化镁、甲基溴化镁、乙基溴化镁、正丙基溴化镁、异丙基溴化镁中的任意一种。
上述的镍源优选双(1,5-环辛二烯)镍,所述的Ar优选,5-二甲基-4-甲氧基苯基、苯基、3,4-二甲氧基苯基、萘基中的任意一种。
上述步骤1中,所述四氢呋喃与1,4-二氧六环、乙二醇二甲醚的体积比为1:0.25~4:0~0.3,优选四氢呋喃与1,4-二氧六环、乙二醇二甲醚的体积比为1:1.5:0.25。
本发明将多氟芳烃单芳基化反应拆为两步进行,第一步采用烷基格氏试剂活化多氟芳烃得到相应的多氟芳基镁试剂(即多氟芳基格氏试剂),第二步采用四氢呋喃和1,4-二氧六环为溶剂,以常见镍源和双膦配体间所形成的复合物为催化剂,催化多氟芳基格氏试剂与卤代芳烃(或芳基磺酸酯)之间交叉偶联(即Kumada交叉偶联反应),实现温和条件下多氟芳烃的高效单芳基化,两步一锅解决了多氟芳烃难以高效单芳基化的难题。
本发明在镁辅助下利用新型镍催化体系实现多氟芳烃单芳基化的方法,与现有技术相比,本发明的有益效果如下:
1、本发明首次解决了含有多个等价氢的多氟苯(四氟苯、三氟苯等)的偶联选择性问题,其单芳基化产物比例高达99%,且官能团耐受性好,底物适用性广,同时产率可达80%以上。
2、本发明催化剂为易得的镍复合物,相比昂贵的钯催化体系或双金属共催化体系,镍催化成本低,污染小,具有极高的经济价值和社会价值。
3、本发明反应条件温和,操作简便,反应基本都在室温下进行,后处理容易,相比现有钯催化技术需要高温的苛刻条件,本发明具有极高的工业生产前景。
具体实施方式
下面结合实施例对本发明进一步详细说明,但本发明的保护范围不仅限于这些实施例。
下面实施例中所用的双膦配体双(2-二(3,5-二甲基-4-甲氧基苯基)膦)苯醚按照下述方法制备得到:
将1.89g(8.8mmol)3,5-二甲基-4-甲氧基溴苯克与192mg(8mmol)镁粉置于40mL干燥四氢呋喃中,回流反应2小时,镁完全消失,然后在-78℃下,将其缓慢滴加到溶解有372mg(1.0mmol)双(2-二氯化膦)苯醚的20mL四氢呋喃溶液中,滴加完毕后缓慢升至室温,继续搅拌8小时;将反应液冷却至-20℃,缓慢加入甲醇淬灭反应,淬灭后缓慢升至室温,反应液用饱和氯化铵水溶液洗涤3次,并用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥后,过滤除去硫酸钠,滤液减压蒸干,经硅胶色谱柱层析分离,得到双(2-二(3,5-二甲基-4-甲氧基苯基)膦)苯醚,其产率为62%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.11(td,J=7.6,1.6Hz,4H),6.95-6.90(m,10H),6.83(ddd,J=7.6,4.2,1.6Hz,2H),6.52(dd,J=8.1,3.5Hz,2H),3.68(s,12H),2.19(s,24H)。
将上述的3,5-二甲基-4-甲氧基溴苯用等摩尔的2-溴萘替换,即可得到结构式如下的双膦配体双(2-二(2-萘基)膦)苯醚:
其产率为55%,结构表征数据为:1H NMR(600MHz,CDCl3):δ7.73(d,J=8.0Hz,4H),7.64(d,J=8.3Hz,4H),7.61(d,J=8.0Hz,4H),7.55(d,J=8.3Hz,4H),7.45(td,J=7.5,1.1Hz,4H),7.41(td,J=7.5,1.1Hz,4H),7.23(dt,J=7.8,1.4Hz,2H),7.15(t,J=7.0Hz,4H),6.92(t,J=7.2Hz,2H),6.87(dd,J=8.0,4.1Hz,2H),6.81(ddd,J=7.5,4.1,1.5Hz,2H)。
将上述的3,5-二甲基-4-甲氧基溴苯用等摩尔的3,4-二甲氧基溴苯替换,即可得到结构式如下的双膦配体双(2-二(3,4-二甲氧基苯基)膦)苯醚:
其产率为39%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.20(td,J=7.7,1.5Hz,2H),6.96(td,J=7.4,0.6Hz,2H),6.78-6.71(m,16H),3.86(s,12H),3.72(s,12H)。
实施例1
合成结构式如下的2-甲基-5-(2′,3′,5′,6′-四氟苯基)噻吩
1、在无水无氧条件下,将360mg(2.4mmol)1,2,4,5-四氟苯溶于1mL四氢呋喃中,然后加入1mL 2mol/L异丙基氯化镁的四氢呋喃溶液,常温搅拌反应12小时,向反应液中加入3mL1,4-二氧六环、0.6mL乙二醇二甲醚和26.4mg(0.10mmol)18-冠醚-6,常温继续搅拌30分钟。
2、在无水无氧条件下,在0.4mL四氢呋喃和0.6mL 1,4-二氧六环中加入20.6g(0.08mmol)双(1,5-环辛二烯)镍、77mg(0.1mmol)双(2-二(3,5-二甲基-4-甲氧基苯基)膦)苯醚,常温搅拌30分钟。
3、在无水无氧条件下,将步骤1和步骤2所得反应液混合,并加入224mg(1.0mmol)2-甲基-5-碘噻吩,常温搅拌6小时,TLC检测反应完全,加入0.5mL甲醇搅拌10分钟,待反应淬灭完全后,反应液用0.1mol/L盐酸洗涤,并用乙酸乙酯萃取,乙酸乙酯萃取液用无水硫酸钠干燥后,减压蒸干,然后经硅胶色谱柱层析分离,得到产物2-甲基-5-(2′,3′,5′,6′-四氟苯基)噻吩,其产率为91%,结构表征数据为:1H NMR(600MHz,CDCl3):δ7.42(d,J=3.6Hz,1H),6.99-6.93(m,1H),6.85(d,J=3.0Hz,1H),2.56(s,3H)。
实施例2
合成结构式如下的4-(2′,3′,5′,6′-四氟苯基)苯乙酮
在实施例1的步骤2中,将双(2-二(3,5-二甲基-4-甲氧基苯基)膦)苯醚用等摩尔的双(2-二(2-萘基)膦)苯醚替换,在步骤3中,将2-甲基-5-碘噻吩用等摩尔的对乙酰基苯基三氟甲磺酸酯替换,反应温度降至10℃,其他步骤与实施例1相同,得到4-(2′,3′,5′,6′-四氟苯基)苯乙酮,其产率为85%,结构表征数据为:1H NMR(400MHz,CDCl3):δ8.08(d,J=8.4Hz,2H),7.58(d,J=8.0Hz,2H),7.15-7.10(m,1H),2.66(s,3H)。
实施例3
合成结构式如下的2,3,5,6-四氟-1,1′-联苯
在实施例1的步骤3中,将2-甲基-5-碘噻吩用等摩尔的苯基三氟甲磺酸酯替换,反应温度升至40℃,其他步骤与实施例1相同,得到2,3,5,6-四氟-1,1′-联苯,其产率为91%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.54-7.44(m,5H),7.13-7.01(m,1H);
实施例4
合成结构式如下的2-甲基-2′,3′,5′,6′-四氟-1,1′-联苯
在实施例1的步骤3中,将2-甲基-5-碘噻吩用等摩尔的邻甲苯基三氟甲磺酸酯替换,反应温度升至40℃,其他步骤与实施例1相同,得到2-甲基-2′,3′,5′,6′-四氟-1,1′-联苯,其产率为77%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.42-7.22(m,4H),7.15-7.6(m,1H),2.22(s,1H)。
实施例5
合成结构式如下的2,3,5,6-四氟-3'-甲氧基-1,1'-联苯
在实施例1的步骤3中,将2-甲基-5-碘噻吩用等摩尔的苯基三氟甲磺酸酯替换,反应温度升至40℃,其他步骤与实施例1相同,得到2,3,5,6-四氟-3'-甲氧基-1,1'-联苯,其产率为86%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.41(t,J=8.0Hz,2H),7.09-6.99(m,4H),3.85(s,1H)。
实施例6
合成结构式如下的2,3,5,6-四氟-4'-甲氧基-1,1'-联苯
在实施例1的步骤3中,将2-甲基-5-碘噻吩用等摩尔的对甲氧基苯基三氟甲磺酸酯替换,反应温度升至40℃,其他步骤与实施例1相同,得到2,3,5,6-四氟-4'-甲氧基-1,1'-联苯,其产率为82%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.41(d,J=8.0Hz,2H),7.02(d,J=8.8Hz,2H),3.87(s,1H)。
实施例7
合成结构式如下的2-(2',3',5',6'-四氟苯基)萘
在实施例1的步骤3中,将2-甲基-5-碘噻吩用等摩尔的2-萘基三氟甲磺酸酯替换,反应温度升至40℃,其他步骤与实施实例1相同,得到2-(2',3',5',6'-四氟苯基)萘281mg,其产率为94%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.98-7.90(m,4H),7.60-7.57(m,3H),7.07-7.15(m,1H)。
实施例8
合成结构式如下的1-(2',3',5',6'-四氟苯基)萘
在实施例1的步骤3中,将2-甲基-5-碘噻吩用等摩尔的1-萘基三氟甲磺酸酯替换,反应温度升至40℃,其他步骤与实施例1相同,得到1-(2',3',5',6'-四氟苯基)萘,其产率为90%,结构表征数据为:1H NMR(400MHz,CDCl3):δ8.02(d,J=8.0Hz,1H),7.96(d,J=8.0Hz,1H),7.62-7.48(m,5H),7.25-7.16(m,1H)。
实施例9
合成结构式如下的2,3,5,6-四氟-1,1'-4',1”-三联苯
在实施例1的步骤3中,将2-甲基-5-碘噻吩用等摩尔的4-苯基苯基三氟甲磺酸酯替换,反应温度升至40℃,其他步骤与实施例1相同,得到2,3,5,6-四氟-1,1'-4',1”-三联苯,其产率为76%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.75(d,J=8.4Hz,2H),7.67(d,J=7.2Hz,2H),7.57(d,J=8.0Hz,2H),7.45(t,J=7.6Hz,2H),7.41(t,J=7.2Hz,1H),7.13-7.05(m,1H)。
实施例10
合成结构式如下的2,3,4',5,6-五氟-1,1'-联苯
在实施例1的步骤3中,将2-甲基-5-碘噻吩用等摩尔的对氟苯基三氟甲磺酸酯替换,反应温度升至40℃,其他步骤与实施例1相同,得到2,3,4',5,6-五氟-1,1'-联苯,其产率为87%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.47-7.44(m,2H),7.21-7.17(m,2H),7.12-7.03(m,1H)。
实施例11
合成结构式如下的2,3,5,6-四氟-4'-三氟甲基-1,1'-联苯
在实施例1的步骤3中,将2-甲基-5-碘噻吩用等摩尔的对三氟甲基苯基三氟甲磺酸酯替换,其他步骤与实施例1相同,得到2,3,5,6-四氟-4'-三氟甲基-1,1'-联苯,其产率为85%,结构表征数据为:1H NMR(400MHz,CDCl3):7.77(d,J=8.4Hz,2H),7.60(d,J=8.0Hz,2H),7.18-7.09(m,1H)。
实施例12
合成结构式如下的6-(2',3',5',6'-四氟苯基)-2-萘甲腈
在实施例1的步骤3中,将2-甲基-5-碘噻吩用等摩尔的6-氰基-2-萘基三氟甲磺酸酯替换,反应温度降至10℃,其他步骤与实施例1相同,得到6-(2',3',5',6'-四氟苯基)-2-萘甲腈,其产率为81%,结构表征数据为:1H NMR(400MHz,CDCl3):δ8.30(S,1H)8.04-7.98(m,3H),7.69(d,J=8.0Hz,2H),7.20-7.11(m,1H)。
实施例13
合成结构式如下的4-(2',3',5',6'-四氟苯基)-苯甲酸乙酯
在实施例1的步骤2中,将双(2-二(3,5-二甲基-4-甲氧基苯基)膦)苯醚用等摩尔的双(2-二(3,4-二甲氧基苯基)膦)苯醚替换;在步骤3中,将2-甲基-5-碘噻吩用等摩尔的对乙氧羰基苯基三氟甲磺酸酯替换,反应温度降至10℃,其他步骤与实施例1相同,得到4-(2',3',5',6'-四氟苯基)-苯甲酸乙酯,其产率为93%,结构表征数据为:1H NMR(400MHz,CDCl3):8.17(d,J=8.4Hz,2H),7.55(d,J=8.4Hz,2H),7.14-7.09(m,1H),4.19(q,J=7.2Hz,2H),1.42(t,J=7.2Hz,3H)。
实施例14
合成结构式如下的2-(2',3',4',6'-四氟苯基)萘
在实施例1的步骤1中,将1,2,4,5-四氟苯用等摩尔的1,2,3,5-四氟苯替换,在步骤3中,将2-甲基-5-碘噻吩用等摩尔的2-萘基三氟甲磺酸酯替换,反应温度升至40℃,其他步骤与实施例1相同,得到2-(2',3',4',6'-四氟苯基)萘,其产率为94%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.95-7.89(m,4H),7.57-7.50(m,3H),6.95-6.88(m,1H)。
实施例15
合成结构式如下的2-(4'-甲氧基-2',3',5',6'-四氟苯基)萘
在实施例1的步骤1中,将2.4mmol 1,2,4,5-四氟苯用等摩尔的3-甲氧基-1,2,4,5-四氟苯替换,在步骤3中,将2-甲基-5-碘噻吩用等摩尔的2-萘基三氟甲磺酸酯替换,反应温度升至40℃,其他步骤与实施例1相同,得到2-(4'-甲氧基-2',3',5',6'-四氟苯基)萘,其产率为87%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.96-7.89(m,4H),7.58-7.51(m,3H),4.15(s,3H)。
实施例16
合成结构式如下的2-(4'-甲基-2',3',5',6'-四氟苯基)萘
在实施例1的步骤1中,将2.4mmol 1,2,4,5-四氟苯用等摩尔的3-甲基-1,2,4,5-四氟苯替换;在步骤2中,将双(2-二(3,5-二甲基-4-甲氧基苯基)膦)苯醚用等摩尔的双(2-二(2-萘基)膦)苯醚替换;在步骤3中,将2-甲基-5-碘噻吩用等摩尔的2-萘基三氟甲磺酸酯替换,反应温度升至40℃,其他步骤与实施例1相同,得到2-(4'-甲基-2',3',5',6'-四氟苯基)萘,其产率为98.5%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.96-7.89(m,4H),7.56-7.53(m,3H),2.35(s,3H)。
实施例17
合成结构式如下的2-(4'-甲氧基甲基-2',3',5',6'-四氟苯基)萘
在实施例1的步骤1中,将1,2,4,5-四氟苯用等摩尔的对甲氧基甲基苯基三氟甲磺酸酯替换,在步骤3中,将2-甲基-5-碘噻吩用等摩尔的2-萘基三氟甲磺酸酯替换,反应温度升至40℃,其他步骤与实施例1相同,得到2-(4'-甲氧基甲基-2',3',5',6'-四氟苯基)萘其产率为87%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.97-7.89(m,4H),7.59-7.53(m,3H),4.66(s,2H),3.46(s,3H)。
实施例18
合成结构式如下的2-(4'-苄基-2',3',5',6'-四氟苯基)萘
在实施例1的步骤1中,将1,2,4,5-四氟苯用等摩尔的对苄基苯基三氟甲磺酸酯替换,在步骤3中,将2-甲基-5-碘噻吩用等摩尔的2-萘基三氟甲磺酸酯替换,反应温度升至40℃,其他步骤与实施例1相同,得到2-(4'-苄基-2',3',5',6'-四氟苯基)萘,其产率为83%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.95-7.88(m,4H),7.56-7.52(m,3H),7.35-7.26(m,5H),4.16(s,2H)。
实施例19
合成结构式如下的2-(2',4',5'-三氟苯基)萘
在实施例1的步骤1中,将2.4mmol的1,2,4,5-四氟苯用3.0mmol的1,3,5-四氟苯替换,2.0mmol的异丙基氯化镁用等摩尔的乙基氯化镁替换,反应温度升至50℃;在步骤2中,将双(2-二(3,5-二甲基-4-甲氧基苯基)膦)苯醚用等摩尔的双(2-苯基)膦)苯醚替换;在步骤3中,将2-甲基-5-碘噻吩用等摩尔的2-萘基三氟甲磺酸酯替换,反应温度升至40℃,其他步骤与实施例1相同,得到2-(2',4',5'-三氟苯基)萘,其产率为91%,结构表征数据为:1HNMR(400MHz,CDCl3):δ7.96-7.89(m,4H),7.56-7.52(m,3H),6.84-6.80(m,1H)。
实施例20
合成结构式如下的2-(4'-双甲基叔丁基硅基-2',3’,5',6’-四氟苯基)萘
在实施例1的步骤1中,将2.4mmol的1,2,4,5-四氟苯用等当量的4-双甲基叔丁基硅基-2,3,5,6-四氟苯替换;在步骤3中,将2-甲基-5-碘噻吩用等摩尔的2-萘基三氟甲磺酸酯替换,反应温度升至40℃,其他步骤与实施例1相同,得到2-(4'-双甲基叔丁基硅基-2',3’,5',6’-四氟苯基)萘,其产率为86%,结构表征数据为:1H NMR(400MHz,CDCl3):δ8.00-7.87(m,4H),7.58-7.50(m,3H),0.99(s,9H),0.44(s,6H)。
实施例21
合成结构式如下的2-(4'-肉桂基-2',3’,5',6’-四氟苯基)萘
在实施例1的步骤1中,将2.4mmol的1,2,4,5-四氟苯用等当量的4-肉桂基-2,3,5,6-四氟苯替换;在步骤3中,将2-甲基-5-碘噻吩用等摩尔的2-萘基三氟甲磺酸酯替换,反应温度升至40℃,其他步骤与实施例1相同,得到2-(4'-肉桂基-2',3’,5',6’-四氟苯基)萘,其产率为81%,结构表征数据为:1H NMR(600MHz,CDCl3):δ7.98-7.95(m,2H),7.93(d,J=8.3Hz,2H),7.56-7.55(m,3H),7.38(d,J=7.6Hz,2H),7.32(t,J=7.6Hz,2H),7.24(t,J=7.3Hz,1H),6.57(d,J=15.8Hz,1H),6.33(dt,J=15.8,6.7Hz,1H),3.71(d,J=6.7Hz,2H)。
上述实施例中的双(1,5-环辛二烯)镍也可用等摩尔的氯化镍、溴化镍、醋酸镍、三氟醋酸镍、乙酰丙酮镍或三氟甲磺酸镍替换,双膦配体双(2-二(3,5-二甲基-4-甲氧基苯基)膦)苯醚也可用等摩尔其他骨架结构相同或相似双膦配体替换,具体如:双(2-二(2-萘基)膦)苯醚、双(2-二(2-甲氧基苯基)膦)苯醚、双(2-二(3,4-二甲氧基苯基)膦)苯醚等,异丙基氯化镁也可用等摩尔的甲基氯化镁、乙基氯化镁、正丙基氯化镁、甲基溴化镁、乙基溴化镁、正丙基溴化镁或异丙基溴化镁替换,均可实现本发明的目的,得到与上述实施例相近的产物产率。
Claims (9)
1.一种镁辅助镍催化多氟芳烃单芳基化的方法,其特征在于它由下述步骤组成:
(1)在无水无氧条件下,以四氢呋喃为溶剂,将式I所示的多氟芳烃与烷基格氏试剂在0~50℃下搅拌2~18小时,然后加入1,4-二氧六环、乙二醇二甲醚、18-冠醚-6,常温搅拌30分钟;
(2)在无水无氧条件下,将镍源、双膦配体加入四氢呋喃与1,4-二氧六环的混合液中,室温搅拌30分钟;其中所述的镍源为双(1,5-环辛二烯)镍、、醋酸镍、三氟醋酸镍、乙酰丙酮镍、三氟甲磺酸镍、氯化镍、溴化镍,及氯化镍或溴化镍乙二醇二甲醚复合物中的任意一种;所述的双膦配体的结构式如下所示:
式中Ar代表苯基、C1~C6烷基取代苯基、C1~C6烷氧基取代苯基、氟代苯基、三氟甲基苯基、萘基、呋喃基、硅氧基苯基中的任意一种;
(3)在无水无氧条件下,将步骤(1)和(2)所得反应液混合,并加入式II所示的卤代芳烃或芳基磺酸酯,0~40℃下搅拌至反应完全后,加入甲醇淬灭反应,分离纯化产物,得到式III所示的单芳基化多氟芳烃;
上述式I~III中,R1~R3各自独立的代表H、F、C1~C10烷基、C1~C6烷氧基、苯基、C1~C10烷基取代苯基、C1~C6烷氧基取代苯基、烯丙基、肉桂基、三氟甲基、苄基、硅基、硅氧基中的任意一种,且R1~R3中至少有一个为F;R代表H、C1~C10烷基、C1~C6烷氧基、苯基、C1~C10烷基取代苯基、C1~C6烷氧基取代苯基、甲酸C1~C6烷基酯基、F、Cl、CF3、CN中的任意一种,X代表Br、I或R′代表CF3、CH3或p-CH3-C6H4,Y代表C、O、N或S,且Y代表C时,Z=1,n=1、2或3;Y代表N时,Z=1或0,n=1或2;Y代表O、S时,Z=0,n=1或2。
2.根据权利要求1所述的镁辅助镍催化多氟芳烃单芳基化的方法,其特征在于:所述的R1~R3各自独立的代表H、F、C1~C6烷基、C1~C4烷氧基、苯基、烯丙基、肉桂基、三氟甲基、苄基、C1~C4烷基取代硅基中的任意一种,且R1~R3中至少有一个为F。
3.根据权利要求1所述的镁辅助镍催化多氟芳烃单芳基化的方法,其特征在于:所述的R代表H、C1~C6烷基、C1~C6烷氧基、苯基、甲酸C1~C6烷基酯基、F、Cl、CF3、CN中的任意一种。
4.根据权利要求1~3任意一项所述的镁辅助镍催化多氟芳烃单芳基化的方法,其特征在于:所述的卤代芳烃或芳基磺酸酯与镍源、双膦配体、多氟芳烃、烷基格氏试剂、18-冠醚-6的摩尔比为1:0.05~0.2:0.05~0.2:1.2~5.0:1.0~3.0:0~1.2。
5.根据权利要求1~3任意一项所述的镁辅助镍催化多氟芳烃单芳基化的方法,其特征在于:所述的卤代芳烃或芳基磺酸酯与镍源、双膦配体、多氟芳烃、烷基格氏试剂、18-冠醚-6的摩尔比为1:0.08:0.10:2.4:2.0:0.1。
6.根据权利要求4所述的镁辅助镍催化多氟芳烃单芳基化的方法,其特征在于:所述的烷基格氏试剂为甲基氯化镁、乙基氯化镁、正丙基氯化镁、异丙基氯化镁、甲基溴化镁、乙基溴化镁、正丙基溴化镁、异丙基溴化镁中的任意一种。
7.根据权利要求4所述的镁辅助镍催化多氟芳烃单芳基化的方法,其特征在于:所述的镍源为双(1,5-环辛二烯)镍,所述的Ar代表,5-二甲基-4-甲氧基苯基、苯基、3,4-二甲氧基苯基、萘基中的任意一种。
8.根据权利要求1所述的镁辅助镍催化多氟芳烃单芳基化的方法,其特征在于:在步骤(1)中,所述四氢呋喃与1,4-二氧六环、乙二醇二甲醚的体积比为1:0.25~4:0~0.3。
9.根据权利要求1所述的镁辅助镍催化多氟芳烃单芳基化的方法,其特征在于:在步骤(1)中,所述四氢呋喃与1,4-二氧六环、乙二醇二甲醚的体积比为1:1.5:0.25。
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