CN112679290A - 一种镍催化的烯烃不对称氢炔基化方法及在制备amg837中的应用 - Google Patents
一种镍催化的烯烃不对称氢炔基化方法及在制备amg837中的应用 Download PDFInfo
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- CN112679290A CN112679290A CN202110002513.6A CN202110002513A CN112679290A CN 112679290 A CN112679290 A CN 112679290A CN 202110002513 A CN202110002513 A CN 202110002513A CN 112679290 A CN112679290 A CN 112679290A
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- nickel
- reaction
- bromide
- iodide
- nmr
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- 150000001336 alkenes Chemical class 0.000 title claims abstract description 53
- 238000000034 method Methods 0.000 title claims abstract description 33
- 239000001257 hydrogen Substances 0.000 title claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 title claims abstract description 16
- ZOPNBMMVVZRSGH-NRFANRHFSA-N (3s)-3-[4-[[3-[4-(trifluoromethyl)phenyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound C1=CC([C@H](CC(O)=O)C#CC)=CC=C1OCC1=CC=CC(C=2C=CC(=CC=2)C(F)(F)F)=C1 ZOPNBMMVVZRSGH-NRFANRHFSA-N 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 title claims description 8
- 238000005905 alkynylation reaction Methods 0.000 title abstract description 5
- 239000003446 ligand Substances 0.000 claims abstract description 53
- -1 alkynyl bromide compound Chemical class 0.000 claims abstract description 52
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 46
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000000654 additive Substances 0.000 claims abstract description 12
- 230000000996 additive effect Effects 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 239000003513 alkali Substances 0.000 claims abstract description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052751 metal Inorganic materials 0.000 claims abstract description 9
- 239000002184 metal Substances 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 229910052759 nickel Inorganic materials 0.000 claims abstract description 6
- 150000002815 nickel Chemical class 0.000 claims abstract description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 97
- 238000006243 chemical reaction Methods 0.000 claims description 90
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 66
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 56
- YUYCVXFAYWRXLS-UHFFFAOYSA-N trimethoxysilane Chemical compound CO[SiH](OC)OC YUYCVXFAYWRXLS-UHFFFAOYSA-N 0.000 claims description 33
- 235000009518 sodium iodide Nutrition 0.000 claims description 32
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 30
- IBSOYFJDSVROOT-UHFFFAOYSA-L diiodonickel;hexahydrate Chemical compound O.O.O.O.O.O.I[Ni]I IBSOYFJDSVROOT-UHFFFAOYSA-L 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 14
- 229910052710 silicon Inorganic materials 0.000 claims description 14
- 239000010703 silicon Substances 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- RRSIMIHTHWYRRA-UHFFFAOYSA-L dibromonickel;1-methoxy-2-(2-methoxyethoxy)ethane Chemical compound Br[Ni]Br.COCCOCCOC RRSIMIHTHWYRRA-UHFFFAOYSA-L 0.000 claims description 6
- 125000004185 ester group Chemical group 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000001347 alkyl bromides Chemical class 0.000 claims description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 4
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 4
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- AOPCKOPZYFFEDA-UHFFFAOYSA-N nickel(2+);dinitrate;hexahydrate Chemical compound O.O.O.O.O.O.[Ni+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O AOPCKOPZYFFEDA-UHFFFAOYSA-N 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- QQQSFSZALRVCSZ-UHFFFAOYSA-N triethoxysilane Chemical compound CCO[SiH](OCC)OCC QQQSFSZALRVCSZ-UHFFFAOYSA-N 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- JRTIUDXYIUKIIE-KZUMESAESA-N (1z,5z)-cycloocta-1,5-diene;nickel Chemical compound [Ni].C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 JRTIUDXYIUKIIE-KZUMESAESA-N 0.000 claims description 2
- VHSVJTYBTJCDFL-UHFFFAOYSA-L 1,2-dimethoxyethane;nickel(2+);dibromide Chemical compound Br[Ni]Br.COCCOC VHSVJTYBTJCDFL-UHFFFAOYSA-L 0.000 claims description 2
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 claims description 2
- LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical compound CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 125000003172 aldehyde group Chemical group 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 2
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- OCMNCWNTDDVHFK-UHFFFAOYSA-L dichloronickel;1,2-dimethoxyethane Chemical compound Cl[Ni]Cl.COCCOC OCMNCWNTDDVHFK-UHFFFAOYSA-L 0.000 claims description 2
- NBBQQQJUOYRZCA-UHFFFAOYSA-N diethoxymethylsilane Chemical compound CCOC([SiH3])OCC NBBQQQJUOYRZCA-UHFFFAOYSA-N 0.000 claims description 2
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 claims description 2
- XYYQWMDBQFSCPB-UHFFFAOYSA-N dimethoxymethylsilane Chemical compound COC([SiH3])OC XYYQWMDBQFSCPB-UHFFFAOYSA-N 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- BLQJIBCZHWBKSL-UHFFFAOYSA-L magnesium iodide Chemical compound [Mg+2].[I-].[I-] BLQJIBCZHWBKSL-UHFFFAOYSA-L 0.000 claims description 2
- 229910001641 magnesium iodide Inorganic materials 0.000 claims description 2
- VWQUXHVMSWBXML-UHFFFAOYSA-L magnesium;dibromide;hydrate Chemical compound O.Br[Mg]Br VWQUXHVMSWBXML-UHFFFAOYSA-L 0.000 claims description 2
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 claims description 2
- UQPSGBZICXWIAG-UHFFFAOYSA-L nickel(2+);dibromide;trihydrate Chemical compound O.O.O.Br[Ni]Br UQPSGBZICXWIAG-UHFFFAOYSA-L 0.000 claims description 2
- WHGYCGOFTBFDLW-UHFFFAOYSA-L nickel(2+);diperchlorate;hexahydrate Chemical compound O.O.O.O.O.O.[Ni+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O WHGYCGOFTBFDLW-UHFFFAOYSA-L 0.000 claims description 2
- BFSQJYRFLQUZKX-UHFFFAOYSA-L nickel(ii) iodide Chemical compound I[Ni]I BFSQJYRFLQUZKX-UHFFFAOYSA-L 0.000 claims description 2
- PARWUHTVGZSQPD-UHFFFAOYSA-N phenylsilane Chemical compound [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 claims description 2
- 229920001843 polymethylhydrosiloxane Polymers 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- AKQNYQDSIDKVJZ-UHFFFAOYSA-N triphenylsilane Chemical compound C1=CC=CC=C1[SiH](C=1C=CC=CC=1)C1=CC=CC=C1 AKQNYQDSIDKVJZ-UHFFFAOYSA-N 0.000 claims description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical group OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 125000000524 functional group Chemical group 0.000 abstract description 3
- 150000002431 hydrogen Chemical class 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 229910052723 transition metal Inorganic materials 0.000 abstract description 2
- 150000003624 transition metals Chemical class 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 152
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 73
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 63
- 239000000047 product Substances 0.000 description 46
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 35
- 238000005160 1H NMR spectroscopy Methods 0.000 description 35
- 238000004440 column chromatography Methods 0.000 description 31
- 238000004128 high performance liquid chromatography Methods 0.000 description 31
- 229910052757 nitrogen Inorganic materials 0.000 description 31
- 238000003756 stirring Methods 0.000 description 31
- 239000007810 chemical reaction solvent Substances 0.000 description 30
- 239000012230 colorless oil Substances 0.000 description 30
- RMNIZOOYFMNEJJ-UHFFFAOYSA-K tripotassium;phosphate;hydrate Chemical compound O.[K+].[K+].[K+].[O-]P([O-])([O-])=O RMNIZOOYFMNEJJ-UHFFFAOYSA-K 0.000 description 30
- 239000011734 sodium Substances 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- 238000001228 spectrum Methods 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000004293 19F NMR spectroscopy Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 229910004161 SiNa Inorganic materials 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- FSWNRRSWFBXQCL-UHFFFAOYSA-N (3-bromophenyl)methanol Chemical compound OCC1=CC=CC(Br)=C1 FSWNRRSWFBXQCL-UHFFFAOYSA-N 0.000 description 2
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- HTFXWAOSQODIBI-UHFFFAOYSA-N 2-benzyl-1,3-dihydropyrrolo[3,4-c]pyridine Chemical compound C1C2=CC=NC=C2CN1CC1=CC=CC=C1 HTFXWAOSQODIBI-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- OLJUNPNLXGLDHB-UHFFFAOYSA-N COC(=O)C(=C)C1=CC=C(O)C=C1 Chemical compound COC(=O)C(=C)C1=CC=C(O)C=C1 OLJUNPNLXGLDHB-UHFFFAOYSA-N 0.000 description 1
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 1
- 102100026148 Free fatty acid receptor 1 Human genes 0.000 description 1
- 101000912510 Homo sapiens Free fatty acid receptor 1 Proteins 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 229910021588 Nickel(II) iodide Inorganic materials 0.000 description 1
- 102000000536 PPAR gamma Human genes 0.000 description 1
- 108010016731 PPAR gamma Proteins 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000798 anti-retroviral effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 150000001642 boronic acid derivatives Chemical group 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 1
- 229960003804 efavirenz Drugs 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- NTNUDYROPUKXNA-UHFFFAOYSA-N methyl 2-(triphenyl-$l^{5}-phosphanylidene)acetate Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OC)C1=CC=CC=C1 NTNUDYROPUKXNA-UHFFFAOYSA-N 0.000 description 1
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- 150000002894 organic compounds Chemical class 0.000 description 1
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- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- 238000002604 ultrasonography Methods 0.000 description 1
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- 229910009112 xH2O Inorganic materials 0.000 description 1
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Abstract
本发明公开了一种镍催化的烯烃不对称氢炔基化的方法及在制备AMG837中的应用,属于有机化学和药物化学领域。本发明在金属镍盐、手性配体、碱、氢源、添加剂等作用下,使烯烃与炔基溴化合物在有机溶剂中进行反应,以优秀的区域选择性和对映选择性得到苄位炔基取代的化合物。本发明方法使用廉价的过渡金属镍作为催化剂,使用商业可得的烯烃和炔基溴化物为原料,条件温和,官能团兼容性好,操作简便。
Description
技术领域
本发明方法属于有机化学和药物化学领域,涉及非活化烯烃的不对称氢炔基化制备手性苄位炔基取代化合物的方法。
背景技术
在过去的二十年里,金属氢化学如FeH、CoH和CuH开始受到合成化学家们的关注。相较钯、铑等过渡-金属,镍廉价易得,储藏丰富。NiH化学是一个尚待开发的新领域,在金属催化领域中具有潜在的应用价值。
炔烃化合物是多种功能性分子的重要合成前体,同时也是生物活性分子和药物分子的重要组成单元,如:抗肿瘤药物(–)-Chamaecynone,艾滋病的抗逆转录病毒药物Efavirenz等药物中都含有此类基团。因此,炔烃化合物在制药、材料和有机合成领域有着广泛的应用。
合成AMG837:
方法一:
方法二:
方法三:
方法四:
方法五:
我们发展的方法合成AMG837
烯烃是一类容易制备、化学性质相对稳定的有机化合物,被广泛地用于各种有机合成中。近几年来,从烯烃出发,利用金属氢催化的烯烃氢官能团化策略能快速地向分子中引入一系列的官能团。因此,通过简单易得的烯烃,在镍催化下一步高效制备手性苄位炔基化合物的方法具有重要的研究价值,我们发展的合成AMG837的方法具有步骤简单,反应条件温和,原料简单易得,同时利用金属镍氢催化的策略高产率、高对映选择性的实现了烯烃与炔烃的偶联,为AMG837的合成提供了一中简单高效的方法。
发明内容
本发明的目的是提供一种手性苄位炔基化合物的合成方法,该方法原料廉价易得,操作简便,底物范围广且官能团兼容性好,具有优秀的区域选择性和对映选择性。
本发明实现上述目的之一采用以下技术方案:一种镍催化烯烃的不对称氢炔基化方法,包括以下步骤:在惰性气体中,将金属镍类催化剂、手性配体L*、碱、氢源、添加剂溶于干燥的有机溶剂中,然后加入烯烃和炔基溴化合物得到反应混合物,反应完全后,再经柱层析分离纯化反应得到目标产物
其中,R1为烯烃的末端取代基,为氢原子、烷基、芳基、烷基溴、酯基、硅醚、烷氧基中的任一种;
其中,Ar为取代芳基或杂芳基。
优选的,所述Ar中芳基上的取代基为氢原子、氟原子、氯原子、溴原子、烷氧基、含氟烷基、氰基、磺酰基、醛基、酮、酯基、硼酸酯基的任一种;杂芳基为吡啶、嘧啶、噻吩、吲哚中的任一种。3、根据权利要求1所述的镍催化烯烃的不对称氢炔基化方法,其特征在于:所述金属镍类催化剂是金属镍盐、手性配体L*是PyrOx配体、Box配体或Biox配体,碱是无机碱、添加剂是含碘的无机盐。
优选的,金属镍类催化剂:手性配体:碱:氢源:添加剂:芳基烯烃:炔基溴化合物:有机溶剂的用量摩尔比为0.01-0.02:0.012-0.04:0.4-0.6:0.4-1.0:0.02-1.0:0.2-0.3:0.2-0.3;反应温度为-10℃~25℃;
优选的,金属镍类催化剂:手性配体:碱:氢源:添加剂:芳基烯烃:炔基溴化合物:有机溶剂的用量比为摩尔:摩尔:摩尔:摩尔:摩尔:摩尔:体积mL=0.01:0.012:0.5:0.5:0.4:0.2:0.3:1.0;反应温度为0℃。
优选的,所述的金属镍盐是碘化镍、碘化镍水合物、氯化镍、氯化镍六水合物、氯化镍乙二醇二甲醚复合物、溴化镍、溴化镍三水合物、溴化镍二乙二醇二甲醚复合物、溴化镍乙二醇二甲醚复合物、双-(1,5-环辛二烯)镍复合物、硝酸镍六水合物、高氯酸镍六水合物、四氟硼酸镍六水合物中的任一种;
所述的手性配体L*为以下的任一种:
所述的碱,其阳离子为Li+、Na+、K+、Mg2+和Cs+中的任一种,阴离子为[CO3]2-、[HCO3]-、[PO4]3-、[HPO4]2-、[H2PO4]-、F-、[OH]-、[CH3COO]-、[OMe]-和[OtBu]-中的任一种;
所述的氢源为聚甲基氢硅氧烷、三甲氧基硅烷、三乙氧基硅烷、二乙氧基甲基硅烷、二甲氧基甲基硅烷、苯基硅烷、三苯基硅烷、三乙基硅烷、硼烷二甲硫醚、频哪醇硼烷中的任一种;所述的添加剂为氯化锂、氯化钠、溴化锂、溴化钾、溴化镁、溴化镁水合物、碘化锂、碘化钠、碘化钾、碘化锌、碘化镁、四丁基氯化铵、四丁基溴化铵、四丁基碘化铵、乙酸钠、乙酸钾、甲醇、异丙醇、苄醇、乙腈中的一种或多种;所述的溶剂为四氢呋喃、甲苯、1,2-二氯乙烷、氯仿、乙腈、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、N,N-二甲基丙烯基脲、N-甲基吡咯烷酮、三氟甲苯、甲醇、乙醇、水、乙二醇二甲醚、二乙二醇二乙醚和二甲基亚砜中的一种或多种。
本发明的另一技术方案:所述的镍催化烯烃的不对称氢炔基化方法的应用,在制备AMG837中的应用,具体制备方法反应式如下:
本发明的另一技术方案:以上任一方法制备的手性苄位炔基化合物,结构式如下:
其中,R1为烯烃的末端取代基,为氢原子、烷基、芳基、烷基溴、酯基、硅醚、烷氧基中的任一种;
其中,Ar为取代芳基或杂芳基。
本发明的有益效果是:
1、所述的反应温度为0℃,在该温度下,反应效果最佳,能以有优异的产率和对映选择性得到产物。
2、所述的镍催化烯烃的不对称氢炔基化方法的应用,在制备AMG837中的应用,上述方法合成步骤简便,使用了廉价易得的金属镍催化剂,以良好的产率和对映选择性得到AMG837前体。
3、所述的手性配体L*的作用:与金属镍配位,在反应的过程中控制手性。
4、通过实施例1和实施例2可以看出不同的配体反应效果有较大的差异,L*47PyrOx配体在该反应中是优势配体,在反应过程中与金属催化剂结合,能够很好的控制产物的手性,提供高收率高对映选择性的产物。
5、通过实施例26和实施例27同样可以看出不同的配体反应效果不同,L*47PyrOx配体在该反应中反应效果最佳,同时从实施例26可以看出该反应还能兼容不同的金属镍催化剂和溶剂,当添加剂的量改变时,反应也能取得优异的效果。
附图说明
下面结合附图对本发明的作进一步说明。
图1是合成3aa的H谱;
图2是合成3aa的C谱;
图3是合成3ia的H谱;
图4是合成3ia的C谱;
图5是合成3oa的H谱;
图6是合成3oa的C谱;
图7是合成3wa的H谱;
图8是合成3wa的C谱;
图9是合成3xa的H谱;
图10是合成3xa的C谱;
图11是合成3xa的F谱;
具体实施方式
通过以下详细说明可以进一步理解本发明的特点和优点。所提供的实施例仅是对本发明方法的说明,而不以任何方式限制本发明揭示的其余内容。
实施例1
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,8.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS硅基保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率82%),将目标产物测ee值(94%)。1H NMR(500MHz,CDCl3)δ7.34–7.29(m,2H),6.91–6.80(m,2H),3.81(s,3H),3.63(dd,J=8.2,5.5Hz,1H),1.84–1.75(m,1H),1.78–1.67(m,1H),1.15–1.07(m,21H),1.03(t,J=7.3Hz,3H);13C NMR(126MHz,CDCl3)δ158.3,134.2,128.5,113.7,110.3,83.1,55.3,39.7,32.2,18.8,11.7,11.4;HRMS(ESI)calcd.for C21H35OSi[M+H]+m/z 331.2452,found 331.2458;IR(neat,cm-1)2940,2864,2167,1510,1245,670;[α]D 18=–16.6(c=1.05,CHCl3);HPLC analysis:CHIRALCEL twoconnected OD-H columns,hexanes/isopropanol=100/0,flow 0.5mL/min,220nm UVdetector,tR(major)=22.7min,tR(minor)=26.5min.
实施例2
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,8.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS硅基保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率32%),将目标产物测ee值(50%)。1H NMR(500MHz,CDCl3)δ7.34–7.29(m,2H),6.91–6.80(m,2H),3.81(s,3H),3.63(dd,J=8.2,5.5Hz,1H),1.84–1.75(m,1H),1.78–1.67(m,1H),1.15–1.07(m,21H),1.03(t,J=7.3Hz,3H);13C NMR(126MHz,CDCl3)δ158.3,134.2,128.5,113.7,110.3,83.1,55.3,39.7,32.2,18.8,11.7,11.4;HRMS(ESI)calcd.for C21H35OSi[M+H]+m/z 331.2452,found 331.2458;IR(neat,cm-1)2940,2864,2167,1510,1245,670;[α]D 18=–16.6(c=1.05,CHCl3);HPLC analysis:CHIRALCEL twoconnected OD-H columns,hexanes/isopropanol=100/0,flow 0.5mL/min,220nm UVdetector,tR(major)=22.7min,tR(minor)=26.5min.
实施例3
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,8.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS硅基保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率73%),将目标产物测ee值(94%)。1H NMR(500MHz,CDCl3)δ7.39–7.31(m,4H),7.29–7.21(m,4H),7.20–7.15(m,2H),4.00(dd,J=8.5,6.1Hz,1H),3.16–2.93(m,2H),1.13–0.85(m,21H);13C NMR(126MHz,CDCl3)δ141.5,138.9,129.6,128.4,128.0,127.8,126.8,126.4,109.2,84.5,45.5,41.3,18.7,11.4;HRMS(ESI)calcd.for C25H34SiNa[M+Na]+m/z 385.2322,found 385.2325;IR(neat,cm-1)2941,2863,2170,1453,882,696;[α]D 18=–20.7(c=1.16,CHCl3);HPLC analysis:CHIRALCEL two connected OD-Hcolumns,hexanes/isopropanol=100/0,flow 0.8mL/min,220nm UV detector,tR(minor)=16.7min,tR(major)=19.6min.
实施例4
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,8.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS硅基保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率66%),将目标产物测ee值(84%)。1H NMR(500MHz,CDCl3)δ7.45–7.37(m,2H),7.36–7.28(m,2H),7.27–7.22(m,1H),4.24(dd,J=8.9,6.5Hz,1H),3.67(s,3H),2.80(dd,J=15.1,8.9Hz,1H),2.73(dd,J=15.1,6.5Hz,1H),1.26–0.64(m,21H);13CNMR(126MHz,CDCl3)δ171.4,140.4,128.7,127.5,127.2,108.1,84.1,51.9,44.0,35.4,18.7,11.3;HRMS(ESI)calcd.for C21H33O2Si[M+H]+m/z345.2244,found 345.2247;IR(neat,cm-1)2942,2864,2174,1742,882,664;[α]D 18=–12.0(c=0.93,CHCl3);HPLCanalysis:CHIRALCEL OD-H column,hexanes/isopropanol=99/1,flow 0.5mL/min,220nmUV detector,tR(minor)=8.1min,tR(major)=20.9min.
实施例5
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,8.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TBDPS硅基保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率42%),将目标产物测ee值(96%)。1H NMR(500MHz,CDCl3)δ7.85–7.80(m,4H),7.42–7.34(m,8H),6.93–6.82(m,2H),3.82(s,3H),3.76(dd,J=7.7,6.1Hz,1H),1.92–1.78(m,2H),1.12–0.99(m,12H);13C NMR(126MHz,CDCl3)δ158.4,135.7,134.0,133.9,133.7,129.4,128.6,127.7,113.9,113.1,82.3,55.4,39.9,32.1,27.2,18.7,11.9;HRMS(ESI)calcd.for C28H32OSiNa[M+Na]+m/z 435.2115,found 435.2115;IR(neat,cm-1)2929,2856,2169,1510,1246,698;[α]D 18=–12.9(c=0.65CHCl3);HPLC analysis:CHIRALCEL OD-H column,hexanes/isopropanol=100/0,flow 0.8mL/min,220nm UVdetector,tR(minor)=26.9min,tR(major)=28.6min.
实施例6
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,8.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS硅基保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率70%),将目标产物测ee值(90%)。1H NMR(500MHz,CDCl3)δ7.44–7.39(m,2H),7.35–7.30(m,2H),7.25–7.21(m,1H),3.92(dd,J=9.4,5.4Hz,1H),3.90–3.84(m,1H),3.76–3.70(m,1H),2.04–1.88(m,2H),1.19–1.06(m,21H),0.93(s,9H),0.09(s,3H),0.08(s,3H);13C NMR(126MHz,CDCl3)δ142.1,128.5,127.6,126.6,109.7,83.4,60.8,42.2,35.2,26.1,18.9,18.8,18.4,11.4,–5.1,–5.2;HRMS(ESI)calcd.for C26H47OSi2[M+H]+m/z 431.3160,found 431.3154;IR(neat,cm-1)2942,2864,2172,1741,1247,665;[α]D 18=–24.4(c=1.24,CHCl3);HPLC analysis:CHIRALCEL two connected OD-H columns,hexanes/isopropanol=100/0,flow 0.5mL/min,220nm UV detector,tR(minor)=14.3min,tR(major)=15.0min.
实施例7
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,8.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS硅基保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率87%),将目标产物测ee值(92%)。1H NMR(500MHz,CDCl3)δ7.38–7.31(m,2H),6.89–6.83(m,2H),3.84–3.74(m,4H),1.49(d,J=7.1Hz,3H),1.13–1.05(m,21H);13C NMR(126MHz,CDCl3)δ158.3,135.6,127.9,113.8,111.7,82.1,55.3,32.2,25.3,18.8,11.4;HRMS(ESI)calcd.for C20H33OSi[M+H]+m/z 317.2295,found 317.2294;IR(neat,cm-1)2940,2864,2164,1510,1243,665;[α]D 18=–4.0(c=1.15CHCl3);HPLCanalysis:CHIRALCEL two connected OD-H columns,hexanes/isopropanol=100/0,flow0.5mL/min,220nm UV detector,tR(major)=24.9min,tR(minor)=26.5min.
实施例8
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,8.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS硅基保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率62%),将目标产物测ee值(94%)。1H NMR(500MHz,CDCl3)δ7.40–7.36(m,2H),7.34–7.29(m,2H),7.25–7.20(m,1H),3.71(dd,J=8.2,6.1Hz,1H),3.39(t,J=6.8Hz,2H),1.89–1.80(m,2H),1.77–1.70(m,2H),1.54–1.40(m,4H),1.16–1.04(m,21H);13C NMR(126MHz,CDCl3)δ1142.1,128.4,127.5,126.6,109.8,83.5,38.9,38.8,33.9,32.8,27.9,26.5,18.8,11.4;HRMS(ESI)calcd.for C23H38BrSi[M+H]+m/z 421.1921,found421.1922;IR(neat,cm-1)2941,2864,2169,1735,1152,674;[α]D 18=–16.8(c=0.57,CHCl3);HPLC analysis:CHIRALCEL two connected OD-H columns,hexanes/isopropanol=100/0,flow 0.5mL/min,220nm UV detector,tR(major)=28.3min,tR(minor)=36.2min.
实施例9
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,8.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS硅基保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率67%),将目标产物测ee值(88%)。1H NMR(500MHz,CDCl3)δ7.42–7.37(m,2H),7.35–7.30(m,2H),7.26–7.20(m,1H),3.90–3.75(m,3H),2.61–2.53(m,1H),2.52–2.41(m,1H),2.17–2.08(m,1H),2.04–1.95(m,1H),1.95–1.85(m,1H),1.13–0.96(m,21H),0.93(s,3H),0.92(s,3H);13C NMR(126MHz,CDCl3)δ173.4,141.2,128.6,127.6,126.9,108.8,84.4,70.6,38.1,33.9,31.9,27.8,19.2,18.8,11.4;HRMS(ESI)calcd.forC25H41O2Si[M+H]+m/z 401.2870,found 401.2871;IR(neat,cm-1)2942,2864,2173,1742,1151,664;[α]D 18=–12.8(c=0.69,CHCl3);HPLC analysis:CHIRALPAK two connectedAD-H columns,hexanes/isopropanol=100/0,flow 0.5mL/min,220nm UV detector,tR(major)=33.5min,tR(minor)=39.3min.
实施例10
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率66%),将目标产物测ee值(86%)。1H NMR(500MHz,CDCl3)δ7.28–7.24(m,2H),6.88–6.82(m,2H),3.80(s,3H),3.55(t,J=7.0Hz,1H),1.84–1.77(m,2H),1.77–1.69(m,2H),1.68–1.57(m,5H),1.57–1.49(m,2H),1.46–1.39(m,1H),0.97(t,J=7.3Hz,3H),0.87(s,9H),0.13(s,3H),0.12(s,3H);13C NMR(126MHz,CDCl3)δ158.3,134.3,128.6,113.7,87.4,86.5,69.5,55.4,41.7,41.6,38.6,31.6,26.0,25.5,23.2,23.1,18.2,11.9,–2.6,–2.7;HRMS(ESI)calcd.for C24H39O2Si[M+H]+m/z 387.2714,found 387.2716;IR(neat,cm-1)2928,2854,1510,1249,836,776;[α]D 18=–7.6(c=0.34CHCl3);HPLC analysis:CHIRALCELtwo connected OD-H columns,hexanes/isopropanol=100/0,flow 0.5mL/min,220nm UVdetector,tR(major)=21.9min,tR(minor)=24.6min.
实施例11
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率50%),将目标产物测ee值(92%)。1H NMR(500MHz,CDCl3)δ7.41–7.37(m,2H),7.34–7.20(m,18H),3.78(dd,J=7.9,6.0Hz,1H),1.98–1.71(m,2H),1.03(t,J=7.4Hz,3H);13CNMR(126MHz,CDCl3)δ145.9,142.4,129.3,128.4,128.0,127.7,126.7,126.6,89.3,86.8,39.8,32.1,12.0;HRMS(ESI)calcd.for C30H27[M+H]+m/z 387.2107,found 387.2102;IR(neat,cm-1)3285,2921,1489,1446,753,697;[α]D 18=–3.3(c=1.02CHCl3);HPLCanalysis:CHIRALCEL two connected OD-H columns,hexanes/isopropanol=100/0,flow0.5mL/min,220nm UV detector,tR(minor)=45.5min,tR(major)=48.2min.
实施例12
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率81%),将目标产物测ee值(88%)。1H NMR(500MHz,CDCl3)δ7.44–7.40(m,2H),7.36–7.30(m,2H),7.26–7.22(m,1H),3.95(dd,J=9.1,6.0Hz,1H),3.76(t,J=6.2Hz,2H),3.74–3.69(m,1H),3.60–3.53(m,1H),3.48(t,J=6.2Hz,2H),2.09–1.90(m,2H),1.22–0.89(m,21H);13C NMR(126MHz,CDCl3)δ1141.6,128.5,127.6,126.8,109.4,83.6,70.9,68.6,38.9,35.4,30.5,18.8,11.4;HRMS(ESI)calcd.for C22H36BrOSi[M+H]+m/z 423.1713,found 423.1712;IR(neat,cm-1)2941,2863,2167,1113,882,665;[α]D 18=–20.7(c=1.47,CHCl3);HPLC analysis:CHIRALCEL OD-H column,hexanes/isopropanol=99/1,flow0.5mL/min,220nm UV detector,tR(minor)=7.1min,tR(major)=11.6min.
实施例13
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率71%),将目标产物测ee值(94%)。1H NMR(500MHz,CDCl3)δ7.94(s,1H),7.89–7.80(m,3H),7.61–7.44(m,3H),3.88(dd,J=8.0,5.6Hz,1H),2.01–1.93(m,1H),1.92–1.85(m,1H),1.23–1.16(m,21H),1.11(t,J=7.3Hz,3H);13C NMR(126MHz,CDCl3)δ139.5,133.5,132.5,128.0,127.8,127.7,126.2,126.1,126.0,125.6,109.9,83.7,40.6,31.9,18.8,11.8,11.5;HRMS(ESI)calcd.for C24H35Si[M+H]+m/z351.2503,found351.2504;IR(neat,cm-1)2940,2863,2167,1461,882,669;[α]D 18=–23.9(c=1.76,CHCl3);HPLC analysis:CHIRALCEL OD-H column,hexanes/isopropanol=100/0,flow 0.8mL/min,220nm UV detector,tR(minor)=7.5min,tR(major)=8.6min.
实施例14
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率66%),将目标产物测ee值(94%)。1H NMR(500MHz,CDCl3)δ.67–7.62(m,2H),7.62–7.58(m,2H),7.53–7.44(m,4H),7.41–7.30(m,1H),3.76(dd,J=8.3,5.4Hz,1H),1.97–1.75(m,2H),1.20–1.14(m,21H),1.11(t,J=7.4Hz,3H);13C NMR(126MHz,CDCl3)δ141.2,141.0,139.5,128.8,128.0,127.3,127.2,127.1,109.8,83.5,40.2,32.2,18.8,11.8,11.5;HRMS(APCI)calcd.for C26H36SiNa[M+Na]+m/z399.2478,found 399.2474;IR(neat,cm-1)2958,2863,2167,1486,761,695;[α]D 18=–11.9(c=1.46,CHCl3);HPLCanalysis:CHIRALCEL OD-H column,hexanes/isopropanol=100/0,flow 0.8mL/min,220nm UV detector,tR(minor)=10.4min,tR(major)=12.4min.
实施例15
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率91%),将目标产物测ee值(90%)。1H NMR(500MHz,CDCl3)δ7.38–7.33(m,1H),7.33–7.28(m,2H),7.26–7.22(m,1H),4.78–4.72(m,2H),3.68(dd,J=8.2,5.5Hz,1H),1.89–1.72(m,2H),1.17–1.09(m,21H),1.05(t,J=7.3Hz,3H),0.98(s,9H),0.13(s,3H),0.13(s,3H);13C NMR(126MHz,CDCl3)δ142.0,141.5,128.3,126.3,125.5,124.5,110.1,83.2,65.2,40.5,32.1,26.1,18.8,18.5,11.8,11.5,–5.0;HRMS(ESI)calcd.forC27H48OSi2Na[M+Na]+m/z 467.3136,found 467.3135;IR(neat,cm-1)2929,2863,2169,1077,835,670;[α]D 18=–15.2(c=1.33,CHCl3);HPLC analysis:CHIRALCEL two connected OD-H columns,hexanes/isopropanol=100/0,flow 0.5mL/min,220nm UV detector,tR(major)=14.3min,tR(minor)=14.8min.
实施例16
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率88%),将目标产物测ee值(90%)。1H NMR(500MHz,CDCl3)δ7.61(dd,J=7.5,1.8Hz,1H),7.23–7.18(m,1H),7.00–6.92(m,1H),6.84(dd,J=8.2,1.1Hz,1H),4.30(dd,J=10.0,4.2Hz,1H),3.93–3.86(m,1H),3.84–3.78(m,4H),2.06–1.94(m,1H),1.80–1.67(m,1H),1.15–1.05(m,21H),0.92(s,9H),0.08(s,3H),0.07(s,3H);13C NMR(126MHz,CDCl3)δ156.1,130.4,128.6,127.7,120.6,110.2,110.0,82.7,61.5,55.3,40.0,29.1,26.0,18.9,18.8,18.4,11.4,-5.0,-5.1;HRMS(ESI)calcd.for C27H48O2Si2Na[M+Na]+m/z483.3085,found 483.3087;IR(neat,cm-1)2940,2863,2166,1243,831,665;[α]D 18=–30.6(c=1.15,CHCl3);HPLC analysis:CHIRALCEL two connected OD-H columns,hexanes/isopropanol=100/0,flow 0.5mL/min,220nm UV detector,tR(minor)=15.0min,tR(major)=19.1min.
实施例17
在充满氮气的手套箱中,将溴化镍二乙二醇二甲醚复合物(3.5mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(90.0mg,2.0equiv),溶于干燥的DCE(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率66%),将目标产物测ee值(94%)。1H NMR(500MHz,CDCl3)δ7.58–7.55(m,1H),7.38–7.34(m,1H),7.32–7.28(m,1H),7.18(t,J=7.8Hz,1H),3.63(dd,J=8.2,5.4Hz,1H),1.85–1.77(m,1H),1.77–1.65(m,1H),1.13–1.03(m,21H),1.02(t,J=7.3Hz,3H);13C NMR(126MHz,CDCl3)δ144.4,130.9,129.9,129.7,126.3,122.5,108.9,84.3,40.1,31.9,18.8,11.7,11.4;HRMS(ESI)calcd.for C20H31BrSiNa[M+Na]+m/z401.1271,found 401.1272;IR(neat,cm-1)2940,2864,2169,1462,881,675;[α]D 18=–22.9(c=1.26,CHCl3);HPLC analysis:CHIRALPAK IE-3column,hexanes/isopropanol=100/0,flow 0.3mL/min,220nm UV detector,tR(minor)=13.3min,tR(major)=13.8min.
实施例18
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率52%),将目标产物测ee值(92%)。1H NMR(500MHz,CDCl3)δ10.01(s,1H),7.95–7.89(m,1H),7.77–7.73(m,1H),7.69–7.59(m,1H),7.49(t,J=7.6Hz,1H),3.75(dd,J=8.2,5.5Hz,1H),1.89–1.81(m,1H),1.81–1.71(m,1H),1.11–1.08(m,21H),1.03(t,J=7.4Hz,3H);13C NMR(126MHz,CDCl3)δ192.4,143.3,136.6,133.8,129.2,129.1,128.0,108.9,84.4,40.2,31.9,18.8,11.6,11.4;HRMS(ESI)calcd.for C21H32OSiNa[M+Na]+m/z351.2115,found 351.2113;IR(neat,cm-1)2940,2864,2169,1696,738,675;[α]D 18=–24.0(c=0.95,CHCl3);HPLC analysis:CHIRALCEL two connected OD-H columns,hexanes/isopropanol=100/0,flow 0.5mL/min,220nm UV detector,tR(major)=38.3min,tR(minor)=42.7min.
实施例19
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率65%),将目标产物测ee值(94%)。1H NMR(500MHz,CDCl3)δ7.70–7.67(m,1H),7.63–7.59(m,1H),7.55–7.51(m,1H),7.42(t,J=7.7Hz,1H),3.69(dd,J=8.2,5.5Hz,1H),1.86–1.67(m,2H),1.12–1.06(m,21H),1.02(t,J=7.3Hz,3H);13C NMR(126MHz,CDCl3)δ143.6,132.2,131.4,130.5,129.2,119.0,112.5,108.1,85.0,40.1,31.8,18.7,11.6,11.4;HRMS(ESI)calcd.for C21H32NSi[M+H]+m/z 326.2299found 326.2296;IR(neat,cm-1)2964,2864,2231,2169,882,664;[α]D 18=–21.4(c=0.29,CHCl3);HPLC analysis:CHIRALPAK AD-H column,hexanes/isopropanol=100/0,flow 0.8mL/min,220nm UVdetector,tR(minor)=13.5min,tR(major)=19.3min.
实施例20
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率83%),将目标产物测ee值(94%)。1H NMR(500MHz,CDCl3)δ8.13–8.06(m,1H),7.94–7.89(m,1H),7.62–7.53(m,1H),7.39(t,J=7.7Hz,1H),3.91(s,3H),3.72(dd,J=8.2,5.4Hz,1H),1.88–1.70(m,2H),1.12–1.08(m,21H),1.02(t,J=7.3Hz,3H);13C NMR(126MHz,CDCl3)δ167.2,142.4,132.2,130.3,128.9,128.4,128.0,109.2,84.2,52.1,40.3,32.0,18.8,11.7,11.4;HRMS(ESI)calcd.for C22H35O2Si[M+H]+m/z 359.2401,found359.2405;IR(neat,cm-1)2941,2864,2169,1726,1281,665;[α]D 18=–31.5(c=0.59,CHCl3);HPLC analysis:CHIRALCEL OD-H column,hexanes/isopropanol=100/0,flow0.5mL/min,220nm UV detector,tR(major)=20.5min,tR(minor)=22.2min.
实施例21
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率81%),将目标产物测ee值(92%)。1H NMR(500MHz,CDCl3)δ7.42–7.37(m,2H),7.35–7.29(m,2H),7.25–7.18(m,1H),3.72(dd,J=7.9,6.5Hz,1H),1.78–1.65(m,2H),1.58–1.41(m,2H),1.10(t,J=2.8Hz,21H),0.94(t,J=7.4Hz,3H);13C NMR(126MHz,CDCl3)δ142.4,128.4,127.6,126.5,110.2,83.1,41.3,38.8,20.6,18.8,13.9,11.4;HRMS(ESI)calcd.for C21H34SiNa[M+Na]+m/z 337.2322,found 337.2321;IR(neat,cm-1)2940,2864,2167,1462,882,670;[α]D 18=–18.2(c=1.44,CHCl3);HPLC analysis:CHIRALCEL twoconnected OD-H columns,hexanes/isopropanol=100/0,flow 0.3mL/min,220nm UVdetector,tR(major)=24.5min,tR(minor)=25.2min.
实施例22
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率90%),将目标产物测ee值(92%)。1H NMR(500MHz,CDCl3)δ7.43–7.38(m,2H),7.36–7.27(m,4H),7.27–7.16(m,4H),3.77(dd,J=7.8,5.7Hz,1H),2.73–2.56(m,2H),1.96–1.72(m,4H),1.15–1.10(m,21H);13C NMR(126MHz,CDCl3)δ142.3,142.1,128.6,128.5,128.4,127.5,126.6,125.8,109.9,83.5,38.8,38.6,35.6,29.1,18.9,18.8,11.4;HRMS(ESI)calcd.for C27H38SiNa[M+Na]+m/z 413.2635,found 413.2637;IR(neat,cm-1)2940,2863,2168,1453,882,696;[α]D 18=–25.3(c=1.37,CHCl3);HPLC analysis:CHIRALCEL two connected OD-H columns,hexanes/isopropanol=100/0,flow 0.8mL/min,220nm UV detector,tR(minor)=16.4min,tR(major)=18.0min.
实施例23
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率89%),将目标产物测ee值(94%)。1H NMR(500MHz,CDCl3)δ7.36–7.29(m,2H),7.19–7.13(m,2H),7.02–6.95(m,2H),6.93–6.85(m,2H),3.82(s,3H),3.70–3.64(m,1H),2.87–2.76(m,2H),2.05–1.96(m,2H),1.21–1.09(m,21H);13C NMR(126MHz,CDCl3)δ161.4(d,J=243.8Hz),158.4,137.5(d,J=3.1Hz),133.9,129.9(d,J=7.8Hz),128.4,115.2(d,J=20.9Hz),113.9,109.9,83.8,55.3,41.1,37.5,32.8,18.8,11.4;19F NMR(471MHz,CDCl3)δ–117.6;HRMS(ESI)calcd.for C27H37FOSiNa[M+Na]+m/z 447.2490,found447.2489;IR(neat,cm-1)2941,2863,2168,1508,1246,825;[α]D 18=–29.5(c=1.35,CHCl3);HPLC analysis:CHIRALCEL two connected OD-H columns,hexanes/isopropanol=100/0,flow 0.5mL/min,220nm UV detector,tR(major)=64.1min,tR(minor)=81.1min.
实施例24
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率88%),将目标产物测ee值(82%)。1H NMR(500MHz,CDCl3)δ7.29–7.25(m,1H),7.21–7.17(m,1H),7.07(dd,J=5.0,1.3Hz,1H),3.98(dd,J=9.6,5.1Hz,1H),3.90–3.83(m,1H),3.77–3.69(m,1H),2.07–1.97(m,1H),1.96–1.84(m,1H),1.15–1.03(m,21H),0.91(s,9H),0.08(s,3H),0.07(s,3H);13C NMR(126MHz,CDCl3)δ142.5,127.2,125.7,120.9,109.5,82.8,60.7,40.8,30.6,26.1,18.8,18.4,11.4,–5.1,–5.2;HRMS(ESI)calcd.for C24H44OSSi2Na[M+Na]+m/z 459.2544,found 459.2549;IR(neat,cm-1)2941,2863,2168,1103,831,775;[α]D 18=–22.0(c=1.10,CHCl3);HPLC analysis:CHIRALCELtwo connected OD-H columns,hexanes/isopropanol=100/0,flow 0.3mL/min,220nm UVdetector,tR(major)=24.5min,tR(minor)=25.4min.
实施例25
在充满氮气的手套箱中,将溴化镍二乙二醇二甲醚复合物(3.5mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(90.0mg,3.0equiv),溶于干燥的DCE(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率65%),将目标产物测ee值(96%)。1H NMR(500MHz,CDCl3)δ8.09–7.92(m,2H),7.48–7.41(m,2H),3.90(s,3H),3.70(dd,J=8.3,5.5Hz,1H),1.86–1.64(m,2H),1.17–0.98(m,21H),1.02(t,J=7.3Hz,3H);13C NMR(126MHz,CDCl3)δ167.1,147.4,129.8,128.6,127.7,108.9,84.1,52.1,40.5,31.9,18.7,11.6,11.4;HRMS(ESI)calcd.forC22H35O2Si[M+H]+m/z 359.2401,found 359.2405;IR(neat,cm-1)2941,2864,2168,1715,1276,663;[α]D 18=–15.6(c=1.45,CHCl3);HPLC analysis:CHIRALCEL two connectedOD-H columns,hexanes/isopropanol=100/0,flow 0.8mL/min,220nm UV detector,tR(major)=27.8min,tR(minor)=30.7min.
实施例26
在充满氮气的手套箱中,将溴化镍二乙二醇二甲醚复合物(3.5mg,5.0mol%),手性配体L*41(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(90.0mg,3.0equiv),溶于干燥的DCE(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率61%),将目标产物测ee值(74%)。1H NMR(500MHz,CDCl3)δ8.09–7.92(m,2H),7.48–7.41(m,2H),3.90(s,3H),3.70(dd,J=8.3,5.5Hz,1H),1.86–1.64(m,2H),1.17–0.98(m,21H),1.02(t,J=7.3Hz,3H);13C NMR(126MHz,CDCl3)δ167.1,147.4,129.8,128.6,127.7,108.9,84.1,52.1,40.5,31.9,18.7,11.6,11.4;HRMS(ESI)calcd.forC22H35O2Si[M+H]+m/z 359.2401,found 359.2405;IR(neat,cm-1)2941,2864,2168,1715,1276,663;[α]D 18=–15.6(c=1.45,CHCl3);HPLC analysis:CHIRALCEL two connectedOD-H columns,hexanes/isopropanol=100/0,flow 0.8mL/min,220nm UV detector,tR(major)=27.8min,tR(minor)=30.7min.
实施例27
在充满氮气的手套箱中,将溴化镍二乙二醇二甲醚复合物(3.5mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(90.0mg,3.0equiv),溶于干燥的Ph-CF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率61%),将目标产物测ee值(94%)。1H NMR(500MHz,CDCl3)δ8.09–7.92(m,2H),7.48–7.41(m,2H),3.90(s,3H),3.70(dd,J=8.3,5.5Hz,1H),1.86–1.64(m,2H),1.17–0.98(m,21H),1.02(t,J=7.3Hz,3H);13C NMR(126MHz,CDCl3)δ167.1,147.4,129.8,128.6,127.7,108.9,84.1,52.1,40.5,31.9,18.7,11.6,11.4;HRMS(ESI)calcd.for C22H35O2Si[M+H]+m/z 359.2401,found 359.2405;IR(neat,cm-1)2941,2864,2168,1715,1276,663;[α]D 18=–15.6(c=1.45,CHCl3);HPLC analysis:CHIRALCEL two connected OD-H columns,hexanes/isopropanol=100/0,flow 0.8mL/min,220nm UV detector,tR(major)=27.8min,tR(minor)=30.7min.
实施例28
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率74%,97:3dr)。1H NMR(500MHz,CDCl3)δ7.28–7.24(m,1H),7.22–7.18(m,2H),3.77(q,J=7.1Hz,1H),2.98–2.86(m,2H),2.51(dd,J=19.0,8.7Hz,1H),2.47–2.39(m,1H),2.34–2.26(m,1H),2.20–2.11(m,1H),2.10–2.00(m,2H),2.00–1.93(m,1H),1.67–1.58(m,2H),1.58–1.42(m,7H),1.18–1.06(m,21H),0.92(s,3H);13C NMR(126MHz,CDCl3)δ221.0,140.8,138.0,136.5,127.7,125.5,124.4,111.4,82.2,50.6,48.1,44.4,38.3,35.9,32.5,31.7,29.5,26.6,25.8,25.2,21.7,18.8,13.9,11.4;HRMS(ESI)calcd.forC31H46OSiNa[M+Na]+m/z 485.3210,found 485.3207;IR(neat,cm-1)2928,2863,2165,1738,735,675;[α]D 18=+93.4(c=0.91CHCl3);HPLC analysis:CHIRALCEL two connected OD-Hcolumns,hexanes/isopropanol=99.5/0.5,flow 0.5mL/min,220nm UV detector,tR(minor)=27.6min,tR(major)=29.1min.
实施例29
据文献报道的方法:K.M.Darwish,I.Salama,S.Mostafa,M.S.Gomaa,M.A.Helal,Design,synthesis,and biological evaluation of novel thiazolidinediones asPPARγ/FFAR1 dual agonists.Eur.J.Med.Chem.2016,109,157-172.
向装有磁子的250mL干燥圆底烧瓶中加入三苯基膦(14.4g,55mmol,1.1当量),用N2置换三次。将4-羟基苯甲醛(6.11g,50mmol,1.0当量)和3-溴苯甲醇(9.35g,50mmol,1.0当量)溶解于100mL四氢呋喃,通过注射器加入圆底烧瓶中。在冰水浴下向圆底烧瓶中滴加DIAD,并保持0℃反应一小时。恢复室温后反应12小时。反应完成后,真空蒸发除去溶剂,通过硅胶柱色谱(己烷:EtOAc=20:1~10:1)纯化,得到中间体S1(9.86g,67.8%收率),为白色固体。
1H NMR(500MHz,CDCl3)δ9.90(s,1H),7.89–7.81(m,2H),7.60(d,J=1.8Hz,1H),7.52–7.45(m,1H),7.37–7.33(m,1H),7.27(d,J=6.9Hz,1H),7.10–7.03(m,2H),5.12(s,2H);13C NMR(126MHz,CDCl3)δ190.9,163.4,138.3,132.1,131.5,130.6,130.5,130.4,125.9,122.9,115.2,69.4;HRMS(ESI)calcd.for C14H11O2BrNa[M+Na]+m/z 312.9835,found312.9834;IR(neat,cm-1)1682,1594,1264,1154,826,764;
向装有磁子的100mL圆底烧瓶中加入中间体S1(2.91g,10mmol,1.0当量)、4-三氟甲基苯硼酸(2.38g,12.5mmol,1.25当量)和四(三苯基膦)钯(0.28g,0.24mmol,2.4mol%),用N2置换三次。将碳酸钾(2.76g,20mmol,2.0当量)加入甲醇(10mL)和甲苯(40mL)的混合溶液中,在通入氮气流的情况下,用超声波处理30分钟后通过注射器加入圆底烧瓶中,在室温下反应12小时。反应结束后,将混合物于空气条件下搅拌30分钟,用硅藻土过滤,蒸发浓缩后通过硅胶柱色谱(己烷:EtOAc=15:1~10:1)纯化粗产物,得到中间体S2(2.50g,70%收率),为白色固体。1H NMR(500MHz,CDCl3)δ9.90(s,1H),7.88–7.84(m,2H),7.70(s,4H),7.68–7.66(m,1H),7.61–7.58(m,1H),7.52(t,J=7.6Hz,1H),7.50–7.46(m,1H),7.14–7.08(m,2H),5.23(s,2H);13C NMR(126MHz,CDCl3)δ190.9,163.7,144.3,140.4,136.9,132.1,130.3,129.7(q,J=32.9Hz),129.5,127.6,127.4,127.3,127.2(q,J=3.8Hz),126.4,125.9(q,J=3.9Hz),124.3(q,J=272.2Hz),115.2,70.2;19F NMR(471MHz,CDCl3)δ-62.4;HRMS(ESI)calcd.for C21H15F3O2Na[M+Na]+m/z 379.0916,found 379.0917;IR(neat,cm-1)2742,1684,1392,1117,843,782;
将中间体S2(2.50g,7mmol,1.0当量)和甲氧甲酰基亚甲基三苯基膦(2.81g,8.4mmol,1.2当量)加入装有磁子的圆底烧瓶中,置换N2三次,用注射器加入二氯甲烷(25mL),在室温下反应12小时。反应结束后,用硅藻土过滤,真空蒸发除去溶剂后,通过硅胶柱色谱(己烷:EtOAc=20:1~15:1)分离纯化,得到中间体S3(2.53g,87.6%收率)。1H NMR(500MHz,CDCl3)δ7.70(s,4H),7.69–7.63(m,2H),7.59–7.56(m,1H),7.53–7.43(m,4H),7.01(d,J=8.7Hz,2H),6.33(d,J=15.9Hz,1H),5.16(s,2H),3.80(s,3H);13C NMR(126MHz,CDCl3)δ167.8,160.5,144.5,144.4,140.3,137.4,129.9,129.4,127.5,127.3,127.2,126.4,125.8(q,J=3.8Hz),124.3(q,J=272.2Hz),115.6,115.3,70.0,51.7;19F NMR(471MHz,CDCl3)δ-62.4;HRMS(ESI)calcd.for C24H19F3O3Na[M+Na]+m/z 435.1179 found435.1181;IR(neat,cm-1)2948,1709,1615,1165,936,832;
向装有磁子的250mL干燥圆底烧瓶中加入三苯基膦(14.4g,55mmol,1.1当量),用N2置换三次。将4-羟基苯丙烯酸甲酯(8.91g,50mmol,1.0当量)和3-溴苯甲醇(9.35g,50mmol,1.0当量)溶解于100mL四氢呋喃,通过注射器加入圆底烧瓶中。在冰水浴下向圆底烧瓶中滴加DIAD,并保持0℃反应1小时。恢复室温后反应12小时。反应完成后,真空蒸发除去溶剂,通过硅胶柱色谱(己烷:EtOAc=20:1)纯化,得到中间体S1'(7.64g,44%收率),为白色固体。1H NMR(500MHz,CDCl3)δ7.65(d,J=16.0Hz,1H),7.61–7.57(m,1H),7.51–7.43(m,3H),7.35(d,J=7.6Hz,1H),7.28–7.22(m,1H),7.00–6.91(m,2H),6.32(d,J=16.0Hz,1H),5.06(s,2H),3.80(s,3H);13C NMR(126MHz,CDCl3)δ167.8,160.3,144.4,138.9,131.3,130.4,130.3,129.9,127.7,125.9,122.9,115.7,115.3,69.2,51.7;HRMS(ESI)calcd.forC17H15BrO3Na[M+Na]+m/z 369.0097 found 369.0098;IR(neat,cm-1)1720,1508,1437,1280,1167,775;
实施例30
在充满氮气的手套箱中,将碘化镍水合物(3.8mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(MeO)3SiH(64μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率68%),将目标产物测ee值(90%)。1H NMR(500MHz,CDCl3)δ7.71(s,4H),7.69–7.66(m,1H),7.59–7.55(m,1H),7.53–7.44(m,2H),7.36(d,J=8.4Hz,2H),6.98(d,J=8.6Hz,2H),5.13(s,2H),4.22(dd,J=8.5,6.8Hz,1H),3.68(s,3H),2.81(dd,J=15.1,8.6Hz,1H),2.72(dd,J=15.1,6.7Hz,1H),1.25–0.70(m,21H);13C NMR(126MHz,CDCl3)δ171.3,157.9,144.5,140.2,137.9,133.0,129.9(q,J=32.6Hz),129.3,128.6,127.5,127.3,127.0,126.4,125.8(q,J=3.9Hz),124.3(q,J=272.4Hz),115.0,108.5,83.9,69.9,51.8,44.0,34.7,18.7,11.3;19F NMR(471MHz,CDCl3)δ-62.3;HRMS(ESI)calcd.forC35H42F3O3Si[M+H]+m/z 595.2850,found 595.2844;IR(neat,cm-1)2942,2864,2173,1324,1070,665;[α]D 18=–2.3(c=1.20,CHCl3);HPLC analysis:CHIRALCEL two connected OD-H columns,hexanes/isopropanol=95/5,flow 0.5mL/min,220nm UV detector,tR(minor)=11.2min,tR(major)=17.3min.
实施例31
在充满氮气的手套箱中,将硝酸镍六水合物(2.9mg,5.0mol%),手性配体L*47(3.3mg,6.0mol%),磷酸钾一水合物(115.1mg,2.5equiv),碘化钠(60.0mg,2.0equiv),溶于干燥的PhCF3(1mL,0.20M)中,搅拌20分钟后加入(EtO)3SiH(92μL,0.5mmol,2.5equiv),接着搅拌5分钟,之后加入上述烯烃和TIPS保护的炔基溴化合物,将反应管密封并从手套箱中取出,在0℃下反应12小时。反应结束后,减压浓缩除去反应溶剂,柱层析分离纯化得到目标产物(无色油,产率76%),将目标产物测ee值(90%)。1H NMR(500MHz,CDCl3)δ7.71(s,4H),7.69–7.66(m,1H),7.59–7.55(m,1H),7.53–7.44(m,2H),7.36(d,J=8.4Hz,2H),6.98(d,J=8.6Hz,2H),5.13(s,2H),4.22(dd,J=8.5,6.8Hz,1H),3.68(s,3H),2.81(dd,J=15.1,8.6Hz,1H),2.72(dd,J=15.1,6.7Hz,1H),1.25–0.70(m,21H);13C NMR(126MHz,CDCl3)δ171.3,157.9,144.5,140.2,137.9,133.0,129.9(q,J=32.6Hz),129.3,128.6,127.5,127.3,127.0,126.4,125.8(q,J=3.9Hz),124.3(q,J=272.4Hz),115.0,108.5,83.9,69.9,51.8,44.0,34.7,18.7,11.3;19F NMR(471MHz,CDCl3)δ-62.3;HRMS(ESI)calcd.forC35H42F3O3Si[M+H]+m/z 595.2850,found 595.2844;IR(neat,cm-1)2942,2864,2173,1324,1070,665;[α]D 18=–2.3(c=1.20,CHCl3);HPLC analysis:CHIRALCEL two connected OD-H columns,hexanes/isopropanol=95/5,flow 0.5mL/min,220nm UV detector,tR(minor)=11.2min,tR(major)=17.3min.
实施例32
据文献报道的方法合成AMG 837(R.Yazaki,N.Kumagai,M.Shibasaki,Org.Lett.2011,13,5952-5955)
在10mL Schlenk管中装入上述原料(0.2mmol,1.0equiv)置换氮气,之后打入溶剂THF(0.10M)。将反应置于0℃冰浴中,用注射器向体系中缓慢加入四丁基氟化铵溶液(1.0mol/L的THF溶液;2.0mmol,10equiv)。4小时后,将反应用水淬灭。并将水层用乙醚萃取。合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。然后将混合物通过硅胶柱色谱法纯化(石油醚:乙酸乙酯=30:1),得到为无色油产物S4(78%收率,94%ee)。1H NMR(500MHz,CDCl3)δ7.70(s,4H),7.66(s,1H),7.59–7.55(m,1H),7.52–7.43(m,2H),7.35–7.29(m,2H),7.08–6.88(m,2H),5.12(s,2H),4.16–4.10(m,1H),3.67(s,3H),2.83(dd,J=15.5,8.3Hz,1H),2.72(dd,J=15.5,6.9Hz,1H),2.29(d,J=2.5Hz,1H);13C NMR(126MHz,CDCl3)δ171.3,158.0,144.5,140.3,137.9,132.4,129.4,128.6,127.6,127.3,127.0,126.4,125.9(q,J=3.6Hz),124.4(q,J=272.2Hz),115.1,84.7,71.4,70.0,51.9,43.0,33.2;19F NMR(471MHz,CDCl3)δ-62.3;HRMS(ESI)calcd.for C26H21F3O3Na[M+Na]+m/z461.1335,found 461.1336;IR(neat,cm-1)2942,2864,2173,1324,1070,665;[α]D 18=+4.7(c=1.37,CHCl3);HPLC analysis:CHIRALCEL OD-H column,hexanes/isopropanol=95/5,flow 0.7mL/min,254nm UV detector,tR(minor)=20.8min,tR(major)=28.7min.
Claims (8)
2.根据权利要求1所述的镍催化烯烃的不对称氢炔基化方法,其特征在于:所述Ar中芳基上的取代基为氢原子、氟原子、氯原子、溴原子、烷氧基、含氟烷基、氰基、磺酰基、醛基、酮、酯基、硼酸酯基的任一种;杂芳基为吡啶、嘧啶、噻吩、吲哚中的任一种。
3.根据权利要求1所述的镍催化烯烃的不对称氢炔基化方法,其特征在于:所述金属镍类催化剂是金属镍盐、手性配体L*是PyrOx配体、Box配体或Biox配体,碱是无机碱、添加剂是含碘的无机盐。
4.根据权利要求1所述的镍催化烯烃的不对称氢炔基化方法,其特征在于,金属镍类催化剂:手性配体:碱:氢源:添加剂:芳基烯烃:炔基溴化合物:有机溶剂的用量摩尔比为0.01-0.02:0.012-0.04:0.4-0.6:0.4-1.0:0.02-1.0:0.2-0.3:0.2-0.3;反应温度为-10℃~25℃。
5.根据权利要求1所述的镍催化烯烃的不对称氢炔基化方法,其特征在于,金属镍类催化剂:手性配体:碱:硅氢:添加剂:芳基烯烃:炔基溴化合物:有机溶剂的用量比为摩尔:摩尔:摩尔:摩尔:摩尔:摩尔:体积mL=0.01:0.012:0.5:0.5:0.4:0.2:0.3:1.0;反应温度为0℃。
6.根据权利要求1所述的镍催化烯烃的不对称氢炔基化方法,其特征在于,所述的金属镍盐是碘化镍、碘化镍水合物、氯化镍、氯化镍六水合物、氯化镍乙二醇二甲醚复合物、溴化镍、溴化镍三水合物、溴化镍二乙二醇二甲醚复合物、溴化镍乙二醇二甲醚复合物、双-(1,5-环辛二烯)镍复合物、硝酸镍六水合物、高氯酸镍六水合物、四氟硼酸镍六水合物中的任一种;
所述的手性配体L*为以下的任一种:
所述的碱,其阳离子为Li+、Na+、K+、Mg2+和Cs+中的任一种,阴离子为[CO3]2-、[HCO3]-、[PO4]3-、[HPO4]2-、[H2PO4]-、F-、[OH]-、[CH3COO]-、[OMe]-和[OtBu]-中的任一种;
所述的氢源为聚甲基氢硅氧烷、三甲氧基硅烷、三乙氧基硅烷、二乙氧基甲基硅烷、二甲氧基甲基硅烷、苯基硅烷、三苯基硅烷、三乙基硅烷、硼烷二甲硫醚、频哪醇硼烷中的任一种;
所述的添加剂为氯化锂、氯化钠、溴化锂、溴化钾、溴化镁、溴化镁水合物、碘化锂、碘化钠、碘化钾、碘化锌、碘化镁、四丁基氯化铵、四丁基溴化铵、四丁基碘化铵、乙酸钠、乙酸钾、甲醇、异丙醇、苄醇、乙腈中的一种或多种;
所述的溶剂为四氢呋喃、甲苯、1,2-二氯乙烷、氯仿、乙腈、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、N,N-二甲基丙烯基脲、N-甲基吡咯烷酮、三氟甲苯、甲醇、乙醇、水、乙二醇二甲醚、二乙二醇二乙醚和二甲基亚砜中的一种或多种。
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CN114716466A (zh) * | 2022-05-16 | 2022-07-08 | 南京大学 | 一种镍催化的不对称氢酰胺化制备手性α-氨基硼酸/硼酸酯的方法 |
CN114716466B (zh) * | 2022-05-16 | 2024-03-19 | 南京大学 | 一种镍催化的不对称氢酰胺化制备手性α-氨基硼酸/硼酸酯的方法 |
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