CN110372747B - 一种含三氟甲基的C3*-TunePhos配体及其合成方法 - Google Patents
一种含三氟甲基的C3*-TunePhos配体及其合成方法 Download PDFInfo
- Publication number
- CN110372747B CN110372747B CN201810326420.7A CN201810326420A CN110372747B CN 110372747 B CN110372747 B CN 110372747B CN 201810326420 A CN201810326420 A CN 201810326420A CN 110372747 B CN110372747 B CN 110372747B
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- organic solvent
- drying
- ice bath
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000001308 synthesis method Methods 0.000 title description 3
- 239000003446 ligand Substances 0.000 claims abstract description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 38
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 24
- 230000002950 deficient Effects 0.000 claims abstract description 18
- 230000008878 coupling Effects 0.000 claims abstract description 13
- 238000010168 coupling process Methods 0.000 claims abstract description 13
- 238000005859 coupling reaction Methods 0.000 claims abstract description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 13
- 150000002009 diols Chemical class 0.000 claims abstract description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 9
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 8
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 230000009471 action Effects 0.000 claims abstract description 6
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 82
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- -1 3, 5-dimethylphenyl Chemical group 0.000 claims description 40
- 239000003960 organic solvent Substances 0.000 claims description 40
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- 238000001035 drying Methods 0.000 claims description 29
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 claims description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 238000004440 column chromatography Methods 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 16
- 239000012074 organic phase Substances 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 14
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 13
- 239000011630 iodine Substances 0.000 claims description 13
- 229910052740 iodine Inorganic materials 0.000 claims description 13
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 238000010791 quenching Methods 0.000 claims description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical class [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000002994 raw material Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- XYXNTHIYBIDHGM-UHFFFAOYSA-N ammonium thiosulfate Chemical class [NH4+].[NH4+].[O-]S([O-])(=O)=S XYXNTHIYBIDHGM-UHFFFAOYSA-N 0.000 claims description 3
- 238000006192 iodination reaction Methods 0.000 claims description 3
- 238000006366 phosphorylation reaction Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 238000006722 reduction reaction Methods 0.000 claims description 3
- 230000002829 reductive effect Effects 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical group Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 claims description 3
- 239000005052 trichlorosilane Substances 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000008346 aqueous phase Substances 0.000 claims description 2
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims description 2
- MDDUHVRJJAFRAU-YZNNVMRBSA-N tert-butyl-[(1r,3s,5z)-3-[tert-butyl(dimethyl)silyl]oxy-5-(2-diphenylphosphorylethylidene)-4-methylidenecyclohexyl]oxy-dimethylsilane Chemical compound C1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C(=C)\C1=C/CP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 MDDUHVRJJAFRAU-YZNNVMRBSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- XGRJZXREYAXTGV-UHFFFAOYSA-N chlorodiphenylphosphine Chemical compound C=1C=CC=CC=1P(Cl)C1=CC=CC=C1 XGRJZXREYAXTGV-UHFFFAOYSA-N 0.000 abstract description 3
- OEPBVXQEVBURGC-UHFFFAOYSA-N 4-bromo-2-fluoro-1-(trifluoromethyl)benzene Chemical compound FC1=CC(Br)=CC=C1C(F)(F)F OEPBVXQEVBURGC-UHFFFAOYSA-N 0.000 abstract description 2
- KYOIPUDHYRWSFO-UHFFFAOYSA-N [Br].[Li] Chemical group [Br].[Li] KYOIPUDHYRWSFO-UHFFFAOYSA-N 0.000 abstract description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 abstract description 2
- 125000002346 iodo group Chemical group I* 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 41
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 15
- 239000003921 oil Substances 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000004679 31P NMR spectroscopy Methods 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000004293 19F NMR spectroscopy Methods 0.000 description 4
- 125000006575 electron-withdrawing group Chemical group 0.000 description 4
- 150000003248 quinolines Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 2
- FFRYUAVNPBUEIC-UHFFFAOYSA-N quinoxalin-2-ol Chemical class C1=CC=CC2=NC(O)=CN=C21 FFRYUAVNPBUEIC-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 230000003335 steric effect Effects 0.000 description 2
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- GTCCGKPBSJZVRZ-RFZPGFLSSA-N (2r,4r)-pentane-2,4-diol Chemical compound C[C@@H](O)C[C@@H](C)O GTCCGKPBSJZVRZ-RFZPGFLSSA-N 0.000 description 1
- LJWZSXDLNMOUIP-UHFFFAOYSA-N N1C=CN=C2N=CC=C21 Chemical class N1C=CN=C2N=CC=C21 LJWZSXDLNMOUIP-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 238000006887 Ullmann reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 150000001543 aryl boronic acids Chemical class 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical class C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 238000006894 reductive elimination reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
- B01J31/2447—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring
- B01J31/2452—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring with more than one complexing phosphine-P atom
- B01J31/2457—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring with more than one complexing phosphine-P atom comprising aliphatic or saturated rings, e.g. Xantphos
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65525—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a seven-(or more) membered ring
- C07F9/65527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a seven-(or more) membered ring condensed with carbocyclic rings or carbocyclic ring systems
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
- B01J2231/646—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of aromatic or heteroaromatic rings
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/827—Iridium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
Abstract
本发明公开一类含三氟甲基的C3*‑TunePhos配体,从手性的二醇出发,然后与2‑氟‑4‑溴三氟甲苯发生芳基亲核取代反应得到醚,随后在锂试剂的作用下发生锂溴交换,与二苯基氯化磷反应,随后用双氧水进行氧化。之后在锂试剂的作用下与碘作用发生碘代,然后乌尔曼偶联,最后经过还原得到了在其对称轴上引入三氟甲基的缺电子配体。
Description
技术领域
本发明涉及一种含三氟甲基的C3*-TunePhos的合成方法。
背景技术
在过渡金属催化的不对称反应中,手性双膦配体占据着十分重要的地位。在反应过程中,手性双膦配体的空间立体效应和电子效应是控制反应效率和立体选择性的关键,因此,设计合成不同立体效应和电子效应的手性双膦配体一直是有机化学家们研究的重要课题。(文献1:Genet,J.P.;Ayad,T.;Ratovelomanana-Vidal,V.Chem.Rev.2014,114,2824.)
相比于富电子双膦配体的广泛发展,缺电子双膦配体却研究较少,但它也有其自身的优点,如:它是很好的π电子受体,可以有效调节催化剂的电性;它还可以促进还原消除等基元反应的进行。因此缺电子双膦配体的合成有着重要的意义。(文献2:(a)You,S.-L.;Hou,X.-L.;Dai,L.-X.;Yu, Y.-H.;Xia,W.J.Org.Chem.2002,67,4684;(b)Wawrzyniak,P.;Slawin,A. M.Z.;Woollins,J.D.;Kilian,P.Dalton Trans.2010,39,85.)
自从1991年Achiwa小组开创性地报道合成了C2对称的氟代的双膦配体以来,一些新的缺电子手性双膦配体被相继合成并被成功应用于各种各样的不对称催化反应中(文献3:Murata,M.;Morimoto,T.;Achiwa,K. Synlett.1991,11,827)。其中比较经典的如DifluroPhos缺电子双膦配体,并将其应用于钌催化的不对称氢化反应中,与其他的富电子双膦配体相比,该缺电子配体表现出更好的催化效果(文献4:Jeulin,S.;Duprat dePaule,S.; Ratovelomanana-Vidal,V.;J.-P.;Champion,N.;Dellis,P.Angew.Chem.Int.Ed.2004,43,320)。
中科院大连化学物理研究所周永贵研究员课题组通过对BiPhep型配体进行修饰,引入拉电子基团,2011年和2012年,分别报道合成了一系列的缺电子轴手性双膦配体,其中CF3O-BiPhep和TfO-BiPhep并且被成功应用于铱催化的喹啉类化合物的不对称氢化反应中,并且S/C分别可以高达 50000和20000(文献5:(a)Zhang,D.-Y.;Wang,D.-S.;Wang,M.-C.;Yu, C.-B.;Gao,K.;Zhou,Y.-G.Synthesis 2011,2796;(b)Zhang,D.-Y.;Yu, C.-B.;Wang,M.-C.;Gao,K.;Zhou,Y.-G.Tetrahedron Lett.2012,53,2556)。在2016年,报道合成了F12-C3*-TunePhos,该缺电子配体与金属钌配位后,成功实现了芳基硼酸对α,β-不饱和酮的1,4-加成反应,结果取得了高达99%的对映选择性。值得一提的是,用未引入拉电子氟原子的C3*-TunePhos作为配体时,该反应是不能发生的(文献6:Hu,S.-B.;Chen,Z.-P.;Zhou,J.; Zhou,Y.-G.Tetrahedron Lett.2016,57,1925)。大部分文献报道的都是在膦上所连的二芳基上引入拉电子基团,而关于在其对称轴上引入拉电子基的配体还是鲜有报道。
发明内容
本发明的目的是提供了一种含三氟甲基的C3*-TunePhos配体及其合成方法,并进一步将其应用于亚胺磷酸酯的不对称氢化反应中。本发明从手性的二醇出发,经过芳基亲核取代、磷酰化、碘代、乌尔曼偶联、还原五步实现该含三氟甲基的C3*-TunePhos配体的合成。本发明操作简便,易于纯化,合成的双膦配体有特殊的缺电子效应。
为实现上述目的,本发明的技术方案如下:
一类含三氟甲基的C3*-TunePhos配体,具有下述结构:
式中:R1为C1-C4烷基或芳基;
R2,R3,R4其中一个为缺电子的三氟甲基,其余为H;
Ar为苯基,或3,5-二甲基苯基,或3,5-二叔丁基4-甲氧基苯基或者缺电子的苯基。
优选所述缺电子的苯基为4-三氟甲基苯基。
本发明还提供上述一类含三氟甲基的C3*-TunePhos配体的合成方法,包括下述反应过程:
(1)手性二醇在碱的作用下与芳基氟代物发生芳基亲核取代,得化合物3;
(2)所述化合物3经磷酰化反应,得化合物4;
(3)所述化合物4经碘代反应,得化合物5;
(4)所述化合物5经乌尔曼偶联,得化合物6;
(5)所述化合物6经还原反应,得化合物7;
作为优选的技术方案,所述方法包括以下步骤:
a)在氮气保护冰浴下取碱于反应瓶中,加入有机溶剂A,缓慢加入手性二醇,待反应不再有气泡冒出后,滴加氟代芳基化合物,之后缓慢升温至100℃,当原料二醇消失后,停止反应,冷至室温,在冰浴下加入饱和氯化铵溶液淬灭反应,减压除去有机溶剂A,萃取,合并有机相,干燥,旋干,柱层析得到醚类化合物;
b)在氮气保护下,将醚类化合物用有机溶剂B溶解,-78℃下,滴加正丁基锂,两小时后,滴加二芳基氯化膦,一小时后升至室温反应,之后在冰浴下缓慢滴加饱和氯化铵溶液淬灭反应,之后在冰浴条件下缓慢滴加双氧水,待反应完全后,在冰浴下缓慢滴加饱和硫代硫酸钠溶液除去未反应的双氧水,萃取,合并有机相,无水硫酸钠干燥,旋干柱层析得膦氧化合物;
c)在氮气保护下,取制得的膦氧化合物用有机溶剂C溶解后,在-78℃下滴加锂试剂,反应两个小时,用有机溶剂C将碘溶解后,滴加入反应体系中,搅拌半小时后,自然升至室温反应八个小时;之后在冰浴下缓慢加入饱和氯化铵溶液淬灭反应,用饱和硫代硫酸铵溶液除去未反应的碘;萃取,合并有机相,无水硫酸钠干燥,旋干,柱层析得到碘代的芳基化合物;
d)氮气保护下,取碘代的芳基化合物于反应瓶中,加入有机溶剂D和活化的铜粉,放入油浴中加热,待原料消失后,加入饱和氯化铵溶液淬灭反应,抽滤;萃取,合并有机相,干燥,旋干,柱层析得到偶联产物;
e)在氮气保护下,取偶联产物于反应瓶中,加入有机溶剂E,在冰浴下加入二异丙基乙基胺,滴加还原剂,移至110℃油浴中反应,待反应完全;停止反应,在氮气下冷至室温,移至冰浴下,滴加脱气的的氢氧化钠溶液,在40℃条件下搅拌一个小时,分液,萃取水相后,合并有机相,用脱气水洗,无水硫酸钠干燥,旋干,柱层析得缺电子双膦配体。
作为优选的技术方案,
所述步骤a)中,碱为氢化钠或叔丁醇钾;有机溶剂A为N,N’-二甲基甲酰胺、N-甲基吡咯烷酮、甲苯、N,N’-二甲基丙烯基脲中至少一种;物料摩尔比为,手性二醇:碱:氟代芳基化合物=1:(2.1~3.0):(2.1~3.0);
所述步骤b)中,有机溶剂B为四氢呋喃或乙醚;物料摩尔比为,醚类化合物:正丁基锂:二芳基氯化磷:双氧水=1:(2.1~3.0):(2.1~3.0):(2.1~3.0);
所述步骤c)中,有机溶剂C为四氢呋喃或乙醚;物料摩尔比为,膦氧化合物:锂试剂:碘=1:(2.1~3.0):(2.1~4.0);
所述步骤d)中,有机溶剂D为N,N’-二甲基甲酰胺、四氢呋喃、乙醚中至少一种;物料摩尔比为,碘代的的芳基化合物:铜粉=1:(8.0~10.0)油浴的加热温度为140~160℃;
所述步骤e)中,有机溶剂E为甲苯,还原剂为三氯硅烷,物料摩尔比为偶联产物:二异丙基乙基胺:还原剂:氢氧化=1:(10.0~20.0):(10.0~20.0):(9.0~19.0)。
优选地,步骤a)萃取用的有机溶剂为二氯甲烷、乙酸乙酯,乙醚中至少一种;步骤b)萃取用的有机溶剂为二氯甲烷或乙酸乙酯;步骤c)萃取用的有机溶剂为二氯甲烷或乙酸乙酯;步骤d)萃取用的有机溶剂为二氯甲烷、乙酸乙酯、氯仿中至少一种;步骤e)萃取用的有机溶剂为二氯甲烷、乙酸乙酯、氯仿中至少一种。
优选地,步骤d)所用的偶联试剂为活化的铜粉,活化具体操作如下:
取20g铜粉至于250mL反应瓶中,搅拌下加入100mL含碘10%的丙酮溶液,室温下剧烈搅拌30分钟,砂芯过滤,将固体转移到瓶中,加入丙酮:浓盐酸(v:v=1:1)100mL,剧烈搅拌5分钟,过滤,用无水丙酮,无水乙醚依次洗涤,用油泵抽干。
本发明还提供上述一类含三氟甲基的C3*-TunePhos配体在不对称催化反应中的应用。
优选地,所述不对称催化反应包括不对称氢化反应。
优选地,所述不对称氢化反应包括钯催化的亚胺膦酸酯的不对称氢化反应、铱催化的喹啉类化合物以及喹啉盐的不对称氢化反应、铱催化的芳香杂并环化合物的不对称氢化、铱催化的喹喔啉酮类化合物的不对称氢化反应。
优选地,所述芳香杂并环化合物为吡咯并吡嗪类化合物。本发明从手性的二醇出发,然后与2-氟-4-溴三氟甲苯发生芳基亲核取代反应得到醚,随后在锂试剂的作用下发生锂溴交换,与二苯基氯化磷反应,随后用双氧水进行氧化。之后在锂试剂的作用下与碘作用发生碘代,然后乌尔曼偶联,最后经过还原得到了在其对称轴上引入三氟甲基的缺电子配体,具有以下优点
1.原料便宜易得。
2.反应易于操作并且产物易于纯化。
3.合成的双膦配体具有特殊的缺电子效应。
1)可以被成功应用于钯催化的亚胺膦酸酯的不对称氢化反应中,可以取得优秀的反应活性及对映选择性。
2)可以应用于铱催化的喹啉类化合物以及喹啉盐的不对称氢化反应中,反应可以完全转化,并能取得良好的对映选择性。
手套箱中,[Ir(COD)Cl]2(1.7mg,2.5umol)和配体(5.25umol),1mL甲苯于反应瓶中搅拌10分钟,之后加入碘(6.4mg,25umol),将其倒入底物的反应瓶中,用1.5mL甲苯冲洗反应瓶,放入反应釜中,移出手套箱,充入20atm氢气,在室温下反应24小时后停止反应。
用L1作为配体时,conversion:75%,84%ee,HPLC(OJ-H,
Hexane/i-PrOH=95/5,flow rate=0.8mL/min,30℃,254nm):t1=13.9min, t2=15.2min(maj).
用L2作为配体时,conversion:33%,80%ee,HPLC(OJ-H,
Hexane/i-PrOH=95/5,flow rate=0.8mL/min,30℃,254nm):t1=14.0min, t2=15.4min(maj).
3)可以应用于铱催化的芳香杂并环化合物的不对称氢化中,如吡咯并吡嗪类化合物,反应也可以完全转化,也能取得中等的对映选择性。
手套箱中,[Ir(COD)Cl]2(2.0mg,3umol)和配体(6.6umol),1mL四氢呋喃于反应瓶中搅拌5分钟,将其倒入装有底物(73mg,0.2mmol)和 Cs2CO3(39mg,0.12mmol)的反应瓶中,用2mL四氢呋喃冲洗反应瓶,放入反应釜中,移出手套箱,充入400psi氢气,在室温下反应24小时后停止反应。用NaHCO3溶液搅30分钟,二氯甲烷萃取,干燥。
用L1作为配体时,conversion:95%,72%ee,HPLC(OD-H, Hexane/i-PrOH=95/5,flow rate=0.6mL/min,30℃,230nm):t1=11.2min (maj),t2=14.3min.用L2作为配体时,conversion:62%,46%ee,HPLC (OD-H,Hexane/i-PrOH=95/5,flow rate=0.6mL/min,30℃,230nm):t1= 10.8min(maj),t2=13.7min.
4)可以应用于铱催化的喹喔啉酮类化合物的不对称氢化反应中,也能取得很好的反应活性以及中等的对映选择性。
手套箱中,[Ir(COD)Cl]2(0.9mg,1.25umol)和配体(2.0mg,2.75umol),碘(1.6mg,6.25umol),1mL四氢呋喃于反应瓶中搅拌5分钟,将其倒入底物(59.1mg,0.25umol)的反应瓶中,用0.5mL四氢呋喃冲洗反应瓶,放入反应釜中,移出手套箱,充入700psi氢气,在室温下反应24小时后停止反应。conversion:95%,48%ee,HPLC(AD-H,Hexane/i-PrOH=80/20,flow rate=0.8mL/min,30℃,254nm):t1=13.8min,t2=17.5min(maj).
值得一提的是,我们用没有三氟甲基的配体对对照试验,发现当配体引入拉电子基后,能明显提高反应的选择性。
具体实施方式
下面通过实施例详述本发明;但本发明并不限于下述的实施例。
实施例1 4,10-(CF3)2-C3*-TunePhos配体的合成
在氮气保护冰浴下取氢化钠(2.100g,60%in mineral oil,52.5mmol)于反应瓶中,加入无水DMF,缓慢加入(2R,4R)-2,4-戊二醇1a(2.605g,25.0
mmol),待反应不再有气泡冒出后,滴加氟代芳基化合物2a(13.36g,55.0 mmol),之后缓慢升温至100℃,当原料二醇消失后,停止反应,冷至室温,在冰浴下加入饱和氯化铵溶液淬灭反应,减压除去DMF,加入有机溶剂萃取,合并有机相,干燥,旋干,柱层析得到醚类化合物。收率为92%。 mp:56-57℃.1H NMR(400MHz,CDCl3)δ7.37(d,J=8.3Hz,2H),7.03(dd, J=8.3,0.8Hz,2H),6.90(s,2H),4.76-4.63(m,2H),2.11-1.95(m,2H),1.35 (d,J=6.1Hz,6H).13C NMR(100MHz,CDCl3)δ158.3(q,JF-C=1.0Hz), 130.3(q,JF-C=5.0Hz),129.1(q,JF-C=1.0Hz),125.4(q,JF-C=271.0Hz), 125.0,119.0,120.6(q,JF-C=30.0Hz),73.3,46.5,21.6.19F NMR(376MHz, CDCl3)δ-62.3.HRMS Calculated For C19H16Br2F6O2[M+Na]+570.9319, found:570.9324.[α]20 D=+21.74.(c=0.46,CHCl3).
b)取上述制得的醚类化合物3a(5.50g,10.0mmol)在氮气保护下用无水THF溶解,-78℃下,滴加正丁基锂(15.0mL,1.6M in Hexanes,24.0 mmol),两小时后,滴加二苯基氯化膦(2.750g,5.0mmol),一小时后升至室温反应,之后加入在冰浴下缓慢滴加饱和氯化铵溶液淬灭反应,之后在冰浴条件下缓慢滴加双氧水(30%in water,6.0mmol),待反应完全后,在冰浴下缓慢滴加饱和硫代硫酸钠溶液除去未反应的双氧水,萃取,合并有机相,无水硫酸钠干燥,旋干柱层析得膦氧化合物。收率为62%。mp:57-58 ℃.1H NMR(400MHz,CDCl3)δ7.68-7.58(m,9H),7.58-7.50(m,5H), 7.49-7.40(m,8H),7.27-7.19(m,2H),7.15(d,J=13.0Hz,2H),4.61(m,2H), 2.04-1.94(m,2H),1.19(d,J=6.0Hz,6H).13C NMR(100MHz,CDCl3)δ 155.4(d,JP-C=15.0Hz),138.6(d,JP-C=100.0Hz),132.3,132.1,132.0,131.1,127.3(q,JF-C=5.0Hz),123.2(d,JP-C=10.0Hz),122.2(q,JF-C=30.0Hz), 116.7(d,JP-C=2.0Hz),70.8,44.1,19.2.31P NMR(162MHz,CDCl3)δ28.8. 19F NMR(376MHz,CDCl3)δ-62.7.HRMS Calculated For C43H36F6O4P2 [M+H]+793.2066,found:793.2044.[α]20 D=-19.50.(c=0.20,CHCl3).
c)在氮气保护下,取制得的膦氧化合物(0.506g,5.0mmol)用有机溶剂溶解后,在-78℃下滴加二异丙基胺基锂(12mmol),反应两个小时,用有机溶剂将碘(2.024g,20.0mmol)溶解后,滴加入反应体系中,搅拌半小时后,自然升至室温反应八个小时。之后在冰浴下缓慢加入饱和氯化铵溶液淬灭反应,用饱和硫代硫酸铵溶液除去未反应的碘。萃取,合并有机相,无水硫酸钠干燥,旋干,柱层析得到碘代的芳基化合物。收率为83%。 mp:100-102℃.1HNMR(400MHz,CDCl3)δ7.75-7.63(m,8H),7.61-7.43 (m,14H),6.86-6.98(m,2H),5.20-5.37(m,2H),2.28(t,J=6.1Hz,2H),1.19 (d,J=6.3Hz,6H).13C NMR(100MHz,CDCl3)δ156.5(d,JP-C=15.0Hz), 142.8(d,JP-C=101.0Hz),132.2,132.1,131.6(d,JP-C=13.0Hz),130.4(d,JP-C=13.0Hz),128.8(d,JP-C=12.0Hz),128.0(q,JF-C=30.0Hz),126.7(q, JF-C=5.0Hz)124.7(q,JF-C=273.0Hz)101.0(d,JP-C=7.0Hz),77.3(q,JF-C= 32.0Hz),44.4,19.7.19FNMR(376MHz,CDCl3)δ-60.52.31P NMR(162 MHz,CDCl3)δ33.5.HRMS Calculated ForC43H34F6O4P2I2[M+Na]+ 1066.9818,found:1066.9812.[α]20 D=+3.67.(c=0.30,CHCl3).
d)氮气保护下,取碘代的芳基化合物(0.522g,0.5mmol)于反应瓶中,加入有机溶剂和活化的铜粉(0.320g,5.0mmol),放入油浴中加热至160℃反应,待原料消失后,加入饱和氯化铵溶液淬灭反应,抽滤。萃取,合并有机相,干燥,旋干。柱层析得到偶联产物。收率为40%。mp:122-123℃. 1H NMR(400MHz,CDCl3)δ7.93-7.70(m,4H),7.68-7.33(m,18H),6.98-6.93(m 2H),4.02-3.90(m,2H),1.57-1.45(m,2H),0.61(d,J=5.9Hz, 6H).13C NMRδ154.8(d,JP-C=13.0Hz),140.0(d,JP-C=97.0Hz),133.7(d, JP-C=107.0Hz),132.4(d,JP-C=10.0Hz),132.1(d,JP-C=9.0Hz),131.6(d, JP-C=2.0Hz),131.3,130.6,128.4(q,JF-C=12.0Hz),126.6(q,JF-C=5.0Hz) 126.5(q,JF-C=5.0Hz),124.0(q,JF-C=2.0Hz),71.8,46.8,22.3 19F NMR (376MHz,CDCl3)δ-62.6.31P NMR(162MHz,CDCl3)δ28.1.HRMSCalculated For C43H35F6O4P2.[M+H]+791.1909,found:791.1913.[α]20 D= +25.66.(c=0.3,CHCl3).并且尝试用二氯甲烷和正己烷作为溶剂,成功培养出了该化合物的单晶,结构如下:
通过以上单晶结构,得出所合成的配体的构型是正确的。所合成的配体的构型为(Sax,R,R)-C3TunePhos.
在氮气保护下,取偶联产物(0.158g,0.2mmol)于反应瓶中,加入有机溶剂5mL,在冰浴下加入二异丙基乙基胺(0.541g,4.0mmol),滴加三氯硅烷(0.517g,4.0mmol),移至110℃油浴中反应,待反应完全。停止反应,在氮气下冷至室温,移至冰浴下,滴加脱气的2M的氢氧化钠溶液20mL,在40℃条件下搅拌一个小时,分液,水相用有机溶剂萃取,合并有机相,用脱气水洗,无水硫酸钠干燥,旋干,柱层析得缺电子双膦配体,收率为 83%。mp:93-95℃.1HNMR(400MHz,CDCl3)δ7.43(d,J=8.0Hz,2H), 7.33-7.10(m,20H),6.80(d,J=7.9Hz,2H),4.20-4.00(m,2H),1.48-1.38(m, 2H),0.61(d,J=5.9Hz,6H).13C NMRδ155.3,147.9,137.2,135.4,133.7, 132.3,131.8(q,JF-C=24.0Hz),129.5,128.7,128.3,126.7(q,JF-C=5.0Hz), 126.3,124.8,122.0,121.7,71.2,47.3,22.9.19F NMR(376MHz,CDCl3)δ -62.3.31PNMR(162MHz,CDCl3)δ-11.7.HRMS Calculated For C43H34F6O2P2[M+H]+759.2011,found:759.2007.[α]20 D=-2.67.(c=0.3, CHCl3).
应用例1:链状亚胺膦酸酯的不对称氢化
称取链状亚胺膦酸酯(84.6mg,0.2mmol),三氟醋酸钯与配体的配合物 (4.4mg,4.0umol),在手套箱中加入2,2,2-三氟乙醇:二氯甲烷(V:V=2:1) 的混合溶剂3.0mL,装釜,出手套箱,充入600psi氢气,放入40℃油浴中进行反应,24小时后停止反应,旋蒸除去溶剂,柱层析得白色固体(81.0 mg,95%yield,95%ee);1H NMR(400MHz,CDCl3)δ7.43(d,J=8.3Hz, 2H),7.24-7.14(m,2H),7.15-7.10(m,3H),6.91(d,J=8.0Hz,2H),4.95 -4.80(m,1H),4.82-4.65(m,1H),4.44-4.28(m,1H),2.24(s,3H),1.43-1.35 (m,6H),1.21(d,J=6.2Hz,3H),0.77(d,J=6.2Hz,3H).13C NMR(100 MHz,CDCl3)δ142.5,138.0,133.9,128.8,128.5(d,JPC=6.0Hz),127.9(d, JPC=2.0Hz),127.5(d,JPC=3.0Hz),127.1,72.8(d,JPC=8.0Hz),72.5(d, JPC=8.0Hz),56.6(d,JPC=157.0Hz),24.3(d,JPC=3.0Hz),24.2(d,JPC=3.0Hz),23.8(d,JPC=5.0Hz)22.8(d,JPC=6.0Hz)21.3.31P NMR(162MHz, CDCl3)δ18.0.HPLC(IA,Hexane/i-PrOH=65/35,flow rate=0.7mL/min), 30℃,254nm:t1=12.1min,t2=21.5min(maj).[α]20 D=-3.37.(c=1.60, CHCl3).
应用例2:环状亚胺膦酸酯的不对称氢化
称取六元环状亚胺膦酸酯(69.5mg,0.2mmol),三氟醋酸钯与配体的配合物(4.4mg,4.0umol),在手套箱中加入2,2,2-三氟乙醇:二氯甲烷(V:V=2:1)的混合溶剂3.0mL,装釜,出手套箱,充入600psi氢气,放入40℃油浴中进行反应,24小时后停止反应,旋蒸除去溶剂,柱层析得白色固体 (65.7mg,94%yield,91%ee);1H NMR(400MHz,CDCl3)δ7.89-7.78(m, 1H),7.38-7.30(m,1H),7.24-7.17(m,1H),7.03(d,J=8.2Hz,1H),5.69-5.79 (m,1H),5.06(dd,J=7.7Hz,JPH=20.4Hz,1H),4.88-4.76(m,1H),4.72-4.58 (m,1H),1.46-1.34(m,6H),1.31(d,J=6.1Hz,3H),1.10(d,J=6.1Hz,3H). 13C NMR(100MHz,CDCl3)δ151.6(d,JPC=9.0Hz),129.8,127.8(d,JPC= 5.0Hz),125.4,119.1,116.4(d,JPC=4.0Hz),73.7(d,JPC=8.0Hz),73.3(d, JPC=7.0Hz),54.3(d,JPC=153.0Hz),24.1(d,JPC=3.0Hz),24.0(d,JPC= 4.0Hz),23.8(d,JPC=5.0Hz),23.4(d,JPC=5.0Hz).31P NMR(162MHz,CDCl3)δ14.4.HPLC(AD-H,Hexane/i-PrOH=80/20,flow rate=0.8 mL/min),30℃,220nm:t1=7.3min(maj),t2=8.1min.
对比例1
称取链状亚胺膦酸酯(42.3mg,0.1mmol),三氟醋酸钯与配体的配合物 (2.2mg,2.0umol),在手套箱中加入2,2,2-三氟乙醇:二氯甲烷(V:V=2:1) 的混合溶剂1.5mL,装釜,出手套箱,充入600psi氢气,放入40℃油浴中进行反应,24小时后停止反应,旋蒸除去溶剂,柱层析得白色固体(41.0mg, 96%yield,62%ee);HPLC(IA,Hexane/i-PrOH=65/35,flow rate=0.7 mL/min):t1=12.0min,t2=21.0min(maj),30℃,254nm.[α]20 D=-12.00.(c =0.60,CHCl3)。
Claims (4)
2.如权利要求1所述的合成方法,其特征在于:所述方法包括以下步骤:
a)在氮气保护冰浴下取碱于反应瓶中,加入有机溶剂A,缓慢加入手性二醇,待反应不再有气泡冒出后,滴加氟代芳基化合物,之后缓慢升温至100℃,当原料二醇消失后,停止反应,冷至室温,在冰浴下加入饱和氯化铵溶液淬灭反应,减压除去有机溶剂A,萃取,合并有机相,干燥,旋干,柱层析得到醚类化合物;
b)在氮气保护下,将醚类化合物用有机溶剂B溶解,-78℃下,滴加正丁基锂,两小时后,滴加二芳基氯化膦,一小时后升至室温反应,之后在冰浴下缓慢滴加饱和氯化铵溶液淬灭反应,之后在冰浴条件下缓慢滴加双氧水,待反应完全后,在冰浴下缓慢滴加饱和硫代硫酸钠溶液除去未反应的双氧水,萃取,合并有机相,无水硫酸钠干燥,旋干柱层析得膦氧化合物;
c)在氮气保护下,取制得的膦氧化合物用有机溶剂C溶解后,在-78℃下滴加锂试剂,反应两个小时,用有机溶剂C将碘溶解后,滴加入反应体系中,搅拌半小时后,自然升至室温反应八个小时;之后在冰浴下缓慢加入饱和氯化铵溶液淬灭反应,用饱和硫代硫酸铵溶液除去未反应的碘;萃取,合并有机相,无水硫酸钠干燥,旋干,柱层析得到碘代的芳基化合物;
d)氮气保护下,取碘代的芳基化合物于反应瓶中,加入有机溶剂D和活化的铜粉,放入油浴中加热,待原料消失后,加入饱和氯化铵溶液淬灭反应,抽滤;萃取,合并有机相,干燥,旋干,柱层析得到偶联产物;
e)在氮气保护下,取偶联产物于反应瓶中,加入有机溶剂E,在冰浴下加入二异丙基乙基胺,滴加还原剂,移至110℃油浴中反应,待反应完全;停止反应,在氮气下冷至室温,移至冰浴下,滴加脱气的氢氧化钠溶液,在40℃条件下搅拌一个小时,分液,萃取水相后,合并有机相,用脱气水洗,无水硫酸钠干燥,旋干,柱层析得缺电子双膦配体。
3.如权利要求2所述的合成方法,其特征在于:
所述步骤a)中,碱为氢化钠或叔丁醇钾;有机溶剂A为N,N’-二甲基甲酰胺、N-甲基吡咯烷酮、甲苯、N,N’-二甲基丙烯基脲中至少一种;物料摩尔比为,手性二醇:碱:氟代芳基化合物=1:(2.1~3.0):(2.1~3.0);
所述步骤b)中,有机溶剂B为四氢呋喃或乙醚;物料摩尔比为,醚类化合物:正丁基锂:二芳基氯化磷:双氧水=1:(2.1~3.0):(2.1~3.0):(2.1~3.0);
所述步骤c)中,有机溶剂C为四氢呋喃或乙醚;物料摩尔比为,膦氧化合物:锂试剂:碘=1:(2.1~3.0):(2.1~4.0);
所述步骤d)中,有机溶剂D为N,N’-二甲基甲酰胺、四氢呋喃、乙醚中至少一种;物料摩尔比为,碘代的芳基化合物:铜粉=1:(8.0~10.0)油浴的加热温度为140~160℃;
所述步骤e)中,有机溶剂E为甲苯,还原剂为三氯硅烷,物料摩尔比为偶联产物:二异丙基乙基胺:还原剂:氢氧化钠=1:(10.0~20.0):(10.0~20.0):(9.0~19.0)。
4.如权利要求2所述的合成方法,其特征在于:
步骤a)萃取用的有机溶剂为二氯甲烷、乙酸乙酯、乙醚中至少一种;步骤b)萃取用的有机溶剂为二氯甲烷或乙酸乙酯;步骤c)萃取用的有机溶剂为二氯甲烷或乙酸乙酯;步骤d)萃取用的有机溶剂为二氯甲烷、乙酸乙酯、氯仿中至少一种;步骤e)萃取用的有机溶剂为二氯甲烷、乙酸乙酯、氯仿中至少一种。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810326420.7A CN110372747B (zh) | 2018-04-12 | 2018-04-12 | 一种含三氟甲基的C3*-TunePhos配体及其合成方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810326420.7A CN110372747B (zh) | 2018-04-12 | 2018-04-12 | 一种含三氟甲基的C3*-TunePhos配体及其合成方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110372747A CN110372747A (zh) | 2019-10-25 |
CN110372747B true CN110372747B (zh) | 2020-10-23 |
Family
ID=68243449
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810326420.7A Active CN110372747B (zh) | 2018-04-12 | 2018-04-12 | 一种含三氟甲基的C3*-TunePhos配体及其合成方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110372747B (zh) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1610688A (zh) * | 2000-11-17 | 2005-04-27 | 宾夕法尼亚州研究基金会 | 邻位取代的手性膦和三价膦酸酯及其在不对称催化反应中的用途 |
CN101230075A (zh) * | 2008-02-22 | 2008-07-30 | 武汉大学 | 中心手性诱导的轴手性双膦配体及其合成方法 |
CN101654463A (zh) * | 2009-09-02 | 2010-02-24 | 上海交通大学 | 5,5’位连接的1,1’-联苯类轴手性2,2’-双膦配体及其制备方法 |
CN103204877A (zh) * | 2012-01-11 | 2013-07-17 | 中国科学院大连化学物理研究所 | 一类具有轴手性的缺电子双膦配体及其制备方法 |
CN106866736A (zh) * | 2015-12-12 | 2017-06-20 | 中国科学院大连化学物理研究所 | 一种中心手性-轴手性缺电子双膦配体及其合成和应用 |
-
2018
- 2018-04-12 CN CN201810326420.7A patent/CN110372747B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1610688A (zh) * | 2000-11-17 | 2005-04-27 | 宾夕法尼亚州研究基金会 | 邻位取代的手性膦和三价膦酸酯及其在不对称催化反应中的用途 |
CN101230075A (zh) * | 2008-02-22 | 2008-07-30 | 武汉大学 | 中心手性诱导的轴手性双膦配体及其合成方法 |
CN101654463A (zh) * | 2009-09-02 | 2010-02-24 | 上海交通大学 | 5,5’位连接的1,1’-联苯类轴手性2,2’-双膦配体及其制备方法 |
CN103204877A (zh) * | 2012-01-11 | 2013-07-17 | 中国科学院大连化学物理研究所 | 一类具有轴手性的缺电子双膦配体及其制备方法 |
CN106866736A (zh) * | 2015-12-12 | 2017-06-20 | 中国科学院大连化学物理研究所 | 一种中心手性-轴手性缺电子双膦配体及其合成和应用 |
Also Published As
Publication number | Publication date |
---|---|
CN110372747A (zh) | 2019-10-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103087105B (zh) | 手性膦配体以及包含该配体的金属催化剂和它们的应用 | |
CN103059064B (zh) | 手性双膦配体与手性催化剂及制备、应用方法 | |
CN100482644C (zh) | 一种手性双烯配体、合成方法及其在不对称反应中的应用 | |
CN105859783A (zh) | 一种新型手性膦配体以及包含该配体的金属催化剂、其制备方法与应用 | |
CN108329194A (zh) | 一种香茅醛制备异胡薄荷醇的方法及其催化剂的回收方法 | |
CN113583042B (zh) | 一种磷酰氟类化合物的制备方法 | |
JP5454756B2 (ja) | ジホスフィン化合物、その遷移金属錯体およびその遷移金属錯体を含む触媒並びにホスフィンオキシド化合物及びジホスフィンオキシド化合物 | |
CN110494439B (zh) | 手性联苯二膦配体及其制备方法 | |
CN103204877A (zh) | 一类具有轴手性的缺电子双膦配体及其制备方法 | |
CN109503670B (zh) | 一类二茂铁骨架的手性单膦配体WJ-Phos及制备方法和应用 | |
CN110372747B (zh) | 一种含三氟甲基的C3*-TunePhos配体及其合成方法 | |
CN102391306A (zh) | 螺环苄胺-膦和制备方法及其应用 | |
CN101591360A (zh) | 离子液体型的单膦单咪唑盐镍(ⅱ)配合物及其制备和应用 | |
CN113402553B (zh) | 一种2-烷基-吲哚骨架的膦配体及其制备方法和应用 | |
CN107973820B (zh) | 一种离子型铁(ii)配合物的应用 | |
CN102746335B (zh) | 一种手性膦氧化物的制备方法 | |
CN114907404A (zh) | 5-(2-(二取代膦基)苯基)-1-烷基-1h-吡唑膦配体及其制备方法和应用 | |
CN101528757A (zh) | 2,2’,6,6’-四取代氮膦配体及其合成方法 | |
CN101712697B (zh) | 含咪唑盐基团的二茂铁膦亚胺配体、其制备以及在催化不对称烯丙基取代反应中的应用 | |
CN104163824B (zh) | 一种金‑{2‑(9‑蒽苯基)二环己基膦}‑乙腈的络合物的合成及应用 | |
CN111039767A (zh) | 一种三唑卡宾催化制备氘代醛的方法 | |
CN110317220B (zh) | 一种双手性中心环丙基硅烷化合物及其制备方法和应用 | |
CN115124569B (zh) | 手性胺基膦硼配合物的制备方法 | |
CN108383705A (zh) | 3,7-二乙基壬烷-4,6-二酮的一种制备方法 | |
WO2002062809A1 (fr) | Complexe de ruthenium et procede de production de compose alcool |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |