CN115784826A - 一种镍催化非活化烯烃双碳官能团化反应的方法 - Google Patents
一种镍催化非活化烯烃双碳官能团化反应的方法 Download PDFInfo
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- CN115784826A CN115784826A CN202211465318.8A CN202211465318A CN115784826A CN 115784826 A CN115784826 A CN 115784826A CN 202211465318 A CN202211465318 A CN 202211465318A CN 115784826 A CN115784826 A CN 115784826A
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- 150000001336 alkenes Chemical class 0.000 title claims abstract description 51
- 238000000034 method Methods 0.000 title claims abstract description 38
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 229910052799 carbon Inorganic materials 0.000 title claims abstract description 16
- 238000007306 functionalization reaction Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 92
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims abstract description 56
- 229910052759 nickel Inorganic materials 0.000 claims abstract description 24
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims abstract description 9
- 150000004820 halides Chemical class 0.000 claims abstract description 9
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims abstract description 6
- 229910052751 metal Inorganic materials 0.000 claims abstract description 5
- 239000002184 metal Substances 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 90
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 75
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 30
- KVRSDIJOUNNFMZ-UHFFFAOYSA-L nickel(2+);trifluoromethanesulfonate Chemical compound [Ni+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F KVRSDIJOUNNFMZ-UHFFFAOYSA-L 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 17
- -1 nitro, hydroxyl Chemical group 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 8
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 229910052748 manganese Inorganic materials 0.000 claims description 5
- 239000011572 manganese Substances 0.000 claims description 5
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Chemical group 0.000 claims description 4
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
- UQPSGBZICXWIAG-UHFFFAOYSA-L nickel(2+);dibromide;trihydrate Chemical compound O.O.O.Br[Ni]Br UQPSGBZICXWIAG-UHFFFAOYSA-L 0.000 claims description 4
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 claims description 4
- AQIXEPGDORPWBJ-UHFFFAOYSA-N pentan-3-ol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 claims description 4
- IDYLMOYUCOPIRT-UHFFFAOYSA-L 4-methylbenzenesulfonate;nickel(2+) Chemical compound [Ni+2].CC1=CC=C(S([O-])(=O)=O)C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 IDYLMOYUCOPIRT-UHFFFAOYSA-L 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 3
- OCMNCWNTDDVHFK-UHFFFAOYSA-L dichloronickel;1,2-dimethoxyethane Chemical compound Cl[Ni]Cl.COCCOC OCMNCWNTDDVHFK-UHFFFAOYSA-L 0.000 claims description 3
- IZWRXCGNSVOSAT-UHFFFAOYSA-L dichloronickel;diphenyl(propyl)phosphane Chemical compound Cl[Ni]Cl.C=1C=CC=CC=1P(CCC)C1=CC=CC=C1 IZWRXCGNSVOSAT-UHFFFAOYSA-L 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- ZBRJXVVKPBZPAN-UHFFFAOYSA-L nickel(2+);triphenylphosphane;dichloride Chemical compound [Cl-].[Cl-].[Ni+2].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 ZBRJXVVKPBZPAN-UHFFFAOYSA-L 0.000 claims description 3
- 229910000008 nickel(II) carbonate Inorganic materials 0.000 claims description 3
- ZULUUIKRFGGGTL-UHFFFAOYSA-L nickel(ii) carbonate Chemical compound [Ni+2].[O-]C([O-])=O ZULUUIKRFGGGTL-UHFFFAOYSA-L 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 claims description 2
- 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
- SHWZFQPXYGHRKT-FDGPNNRMSA-N (z)-4-hydroxypent-3-en-2-one;nickel Chemical compound [Ni].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O SHWZFQPXYGHRKT-FDGPNNRMSA-N 0.000 claims description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-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
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 2
- 229940035437 1,3-propanediol Drugs 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- JSGVZVOGOQILFM-UHFFFAOYSA-N 3-methoxy-1-butanol Chemical compound COC(C)CCO JSGVZVOGOQILFM-UHFFFAOYSA-N 0.000 claims description 2
- WVYWICLMDOOCFB-UHFFFAOYSA-N 4-methyl-2-pentanol Chemical compound CC(C)CC(C)O WVYWICLMDOOCFB-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 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
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 claims description 2
- CYKXDHXBWOTQKY-UHFFFAOYSA-L dibromonickel;2-pyridin-2-ylpyridine Chemical compound Br[Ni]Br.N1=CC=CC=C1C1=CC=CC=N1 CYKXDHXBWOTQKY-UHFFFAOYSA-L 0.000 claims description 2
- XXECWTBMGGXMKP-UHFFFAOYSA-L dichloronickel;2-diphenylphosphanylethyl(diphenyl)phosphane Chemical compound Cl[Ni]Cl.C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 XXECWTBMGGXMKP-UHFFFAOYSA-L 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- ZLQBNKOPBDZKDP-UHFFFAOYSA-L nickel(2+);diperchlorate Chemical compound [Ni+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O ZLQBNKOPBDZKDP-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
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 229920000166 polytrimethylene carbonate Polymers 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- RRSIMIHTHWYRRA-UHFFFAOYSA-L dibromonickel;1-methoxy-2-(2-methoxyethoxy)ethane Chemical compound Br[Ni]Br.COCCOCCOC RRSIMIHTHWYRRA-UHFFFAOYSA-L 0.000 claims 1
- 150000008282 halocarbons Chemical group 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 abstract description 4
- 230000008878 coupling Effects 0.000 abstract description 3
- 238000010168 coupling process Methods 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 description 74
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 52
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 50
- 239000000047 product Substances 0.000 description 40
- 229910052757 nitrogen Inorganic materials 0.000 description 28
- 238000013375 chromatographic separation Methods 0.000 description 25
- 238000002156 mixing Methods 0.000 description 25
- 239000003208 petroleum Substances 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 25
- 238000003786 synthesis reaction Methods 0.000 description 23
- 230000015572 biosynthetic process Effects 0.000 description 22
- 230000000052 comparative effect Effects 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- WREVVZMUNPAPOV-UHFFFAOYSA-N 8-aminoquinoline Chemical class C1=CN=C2C(N)=CC=CC2=C1 WREVVZMUNPAPOV-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- GGQQNYXPYWCUHG-RMTFUQJTSA-N (3e,6e)-deca-3,6-diene Chemical class CCC\C=C\C\C=C\CC GGQQNYXPYWCUHG-RMTFUQJTSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 238000006254 arylation reaction Methods 0.000 description 2
- 238000006757 chemical reactions by type Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000006880 cross-coupling reaction Methods 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012847 fine chemical Substances 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- AJFDBNQQDYLMJN-UHFFFAOYSA-N n,n-diethylacetamide Chemical compound CCN(CC)C(C)=O AJFDBNQQDYLMJN-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
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Abstract
本发明公开了一种镍催化非活化烯烃双碳官能团化反应的方法,包括以下步骤:在溶剂中,以卤代物为亲电试剂,镍作为催化剂,金属单质作为还原剂,与非活化多取代烯烃反应构建碳碳双键。本发明在反应过程中使用带有导向基的烯烃,与镍催化剂进行配位,以较高的收率得到目标产物且非对映选择性均大于20:1。整个方法简单易行且安全,一步法直接得到非活化多取代烯烃与卤代物偶联的产物,在优化的反应条件之下,目标产品分离后产率可以高达95%,是一种通用、高效、经济和环境友好的构建碳碳键的方法。
Description
技术领域
本发明属于催化合成技术和精细化学品合成领域,涉及一种镍催化非活化烯烃双碳官能团化反应的方法。
背景技术
烯烃的双碳官能团化是构建复杂分子以及实现分子多样化的重要手段之一。因此实现烯烃的双碳官能团化是近年来有机化学家研究的热点,并且取得了非常卓越的科研成果,然而由于不可预测的区域选择性和β-氢消除,未活化烯烃的双碳官能团化仍然面临巨大挑战。尽管近些年来在未活化烯烃的双芳基化反应方面取得了重大进展,但大多数进展仅限于只能提供一个苄基立体中心的未活化末端烯烃,尤其是外消旋结构。而对于电子未激活的内烯双芳基化反应由于其反应活性低而面临着巨大的挑战。此外,对于两组分双碳官能团化反应已经有突破性的进展,通过巧妙地设计反应底物,利用烯烃的弱配位作用,控制反应的化学选择性和区域选择性,抑制β-氢消除对反应产生的不利影响。然而,这些两组分反应的优势恰恰是三组分反应所面临和亟待解决的关键科学难题。近些年来,虽然三组分(分子间)非活化烯烃的双碳官能团化反应取得了一定进展,但反应类型主要局限于亲核-亲电试剂对烯烃的双碳官能团化。综上,针对三组分双碳官能团化反应存在的诸多科学问题:缺少有效的催化体系、选择性难以控制、β-氢消除的竞争副反应以及烯烃底物的适用范围比较局限等。
发明内容
发明目的:针对现有技术存在的问题,本发明提供一种镍催化非活化内烯双碳官能团化反应的方法,解决现有三组分构建碳碳双键偶联通常只适用于末端烯烃的局限性。在此,本发明利用全新的反应体系,其中特定的烯烃与金属镍的配位作用以较高的收率且大于20:1的立体选择性得到目标产物,克服了反应过程存在的Mizoroki-Heck反应和直接交叉偶联反应。该方法发展了一种新颖、独特的非活化多取代烯烃双芳基化反应。
本发明的方法只需要一步反应直接构建新的碳碳双键同时具有原料易制备;催化剂、还原剂廉价易购;反应条件温和、无毒无害;反应选择性高、产率高;底物官能团相容性好且适用范围广,能够构建各种复杂分子。
技术方案:为了实现上述目的,本发明所述一种镍催化非活化烯烃双碳官能团化反应的方法,包括如下步骤:在溶剂中,以卤代物为亲电试剂,镍作为催化剂,廉价金属单质作为还原剂,与非活化烯烃反应构建碳碳双键。
反应通式表示如下:
式中:R1、R2、R3表示烯键上取代的基团;R4表示羰基α位的取代基团;R5X表示卤代烷烃;AQ八氨基喹啉。
其中,以R1、R2、R3表示烯键上的取代基,其烯烃上的取代基R1、R2、R3各自独立的任意选自氢、C1~C20的烷基、C1~C20卤取代烷基、C1~C20烷基羰基、硝基、羟基或者氰基。
其中,所述R4表示羰基α位上的取代基,其羰基α位上的取代基任意选自氢、C1~C20的烷基、C1~C20卤取代烷基、C1~C20烷基羰基、硝基、羟基或者氰基。
其中,所述X为氟、氯、溴或碘,所述R5表示卤代物上的取代基团,其卤代物上的取代基各自独立的任意选自芳基、取代芳基、氢、C1~C20的烷基、C1~C20卤取代烷基、C1~C20烷基羰基、硝基、羟基或者氰基。
其中,所述镍选自氯化镍,无水溴化镍,水合溴化镍,碘化镍,碳酸镍,双-(1,5-环辛二烯)镍,氯化镍乙二醇二甲基醚络合物,溴化镍乙二醇二甲基醚络合物,(2,2'-联吡啶)二溴化镍,二溴(1,10-菲咯啉)镍,氯代双三己基磷酸镍盐,双(三苯基膦)氯化镍,1,2-双(二苯基膦)乙烷氯化镍,(1,1'-双(二苯基膦)二茂铁)二氯化镍,溴化镍二乙二醇二甲醚复合物,乙酰丙酮镍,三氟甲磺酸镍,双(2,2,6,6,-四甲基-3,5-庚二酮酸)镍,双(六氟乙酰丙酮)合镍,高氯酸镍,对甲苯磺酸镍,1,3-双(二苯基膦丙烷)二氯化镍,四氟硼酸镍六水合物,双(三苯基膦)二溴化镍,二溴二(三丁基膦)镍中的任意一种。
其中,所述廉价金属单质选自锌、锰、镁金属还原剂中任意一种。
其中,所述有机溶剂选自甲醇、乙醇、乙二醇、正丙醇、异丙醇、1,3-丙二醇、甘油、正丁醇、异丁醇、叔丁醇、三氟乙醇、2-甲基-2-丁醇、3-甲氧基丁醇、仲丁醇、叔戊醇、4-甲基-2-戊醇、异戊醇、2-戊醇、3-戊醇、环戊醇、正戊醇、聚乙二醇200-10000、乙腈、苯腈、甲苯、丙酮、二氯甲烷、1,2-二氯乙烷、二甲亚砜、N,N二甲基甲酰胺、N,N-二乙基乙酰胺、N,N-二甲基丙烯基脲,N-甲基吡咯烷酮、乙酸乙酯、1,4-二氧六环或四氢呋喃中的一种或者多种。
其中,所述烯烃、卤代物、镍、锰的摩尔比为:1:(3~6):(0.1~0.2):(3~4)。
其中,所述反应的温度为30-60℃,时间为12-24小时。
作为优选,所述反应温度为50℃,时间为24小时。
本发明的方法中镍催化剂具有来源广泛和价格低廉的特点,反应过程中通过金属镍与烯烃的配位作用控制反应的区域选择性,以大于20:1的非对映选择性得到目标产物。此外,目前关于三组分非活化烯烃双芳基化反应的研究主要是局限于烷基、芳基金属化合物和卤代物作为反应试剂的交叉偶联反应。但本发明打破了传统的局限性,实现了三分子亲电试剂的交叉还原偶联,解决了反应受限于末端烯烃的现状,突破性地将烯烃底物拓展至挑战性的内烯和多取代烯烃,实现多个碳手性中心的高效构建。同时本发明将为非活化烯烃三组分双碳官能团化反应打开新的突破口、丰富其反应类型、拓展底物的适用范围并且解决反应过程中选择性的控制等科学难题;为构建结构复杂的手性分子提供简洁、高效、新颖的方法,在天然产物、药物以及手性材料等的开发与合成方面具有非常重要的科学意义和应用价值。
本发明中采用全新的反应体系和策略利用烯烃与镍催化剂的配位来控制反应过程中的区域选择性和立体选择性,使反应能够在非常温和的条件下与卤代物偶联以较高的区域选择性和立体选择性得到目标产物,特别是对复杂的底物也能取得理想的催化效果。
有益效果:与现有技术相比,本发明具有如下优点:
(1)本发明提供了一种廉价金属催化非活化烯烃双碳官能团化反应的研究,该方法在简单温和的条件下实现了非活化烯烃的碳碳键构建,突破性地将烯烃底物拓展至挑战性的内烯和多取代烯烃,实现多个碳手性中心的高效构建。
(2)本发明提供的廉价金属催化的烯烃亲电交叉还原偶联反应的模式,将为非活化烯烃三组分双碳官能团化反应打开新的突破口、丰富其反应类型、拓展底物的适用范围并且解决反应过程中区域选择性控制等科学难题。在优化的反应条件之下,目标产品分离后产率可以高达95%,是一种通用、高效、经济和环境友好的构建碳碳键的方法。
(3)本发明的方法之所以能够使用理想的镍作为催化剂进行三组分催化反应,关键是在于采用特定的反应体系,其通过镍催化剂与带有强8–氨基喹啉(AQ)导向基烯烃的配位作用并且结合特定的原料和反应条件,可以很好的控制反应的选择性,同时避免其他副反应的发生,对复杂的底物也能取得理想的催化效果。
(4)本发明的方法快速构建碳碳双键可以作为药物或生物活性分子的有机中间体,广泛应用于医药中间体和高附加值精细化学品的合成。
具体实施方式
根据下述实施例,可以更好地理解本发明。然而,本领域的技术人员容易理解,实施例所描述的内容仅用于说明本发明,而不应当也不会限制权利要求书中所详细描述的本发明。
实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和材料,如无特殊说明,均可从商业途径或通过下面方法简单制备获得。
其中部分初始底物通过如下方法合成或者商业购买,其余底物均为已报道或者可商业购买或者参考下述方法合成得到。
其中Ar与底物四,五,六,七上的芳香基相同。
方法:将芳香酚,碳酸铯依次加入圆底烧瓶,接着加入乙腈,原料溴代物。在80℃条件下回流直至原料反应完全。反应完全后,冷却至室温,加入水,用乙酸乙酯萃取得到目标产物,作为下一步的醇原料进行反应。
其中,R与最终底物产物上取代基相同。
第一步:在含有PCC(3.23g,15.0mmol,1.50equiv)和硅胶粉(0.9g,1.5equiv)的圆底烧瓶中加入无水二氯甲烷(20mL)。在搅拌的过程中慢慢加入醇(10.0mmol,1.0equiv),室温下反应三个小时后点板检测。反应完全后用短的砂芯漏斗过滤用二氯甲烷洗涤,滤液旋干得到目标产物醛。
第二步:在氮气条件下,将醛(6mmol,1.0equiv),丙二酸(0.94g,9.0mmol,1.5equiv),溶剂N,N-二甲基甲酰胺(10mL)依次加入耐高压封管中,继续加入乙酸(36.8μmL,0.6mol,0.1equiv),吡啶(48.5μmL,0.6mol,0.1equiv)将反应加热至100℃回流4小时。反应结束后加水淬灭,用乙酸乙酯萃取,真空旋干层析分离得到烯基酸。
第三步:在氮气条件下,将烯基酸和八氨基喹啉,无水二氯甲烷(15mL)依次加入干燥好的圆底烧瓶中,搅拌下加入4-二甲氨基吡啶,1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,反应2小时候用水淬灭,用乙酸乙酯萃取,真空旋干层析分离得到目标产物。
底物一:
1H NMR(400MHz,CDCl3):δ10.03(s,1H),8.90–8.60(m,2H),8.16(dd,J=8.3,1.7Hz,1H),7.59–7.49(m,2H),7.46(dd,J=8.3,4.2Hz,1H),7.16(dd,J=5.1,1.3Hz,1H),6.99–6.90(m,2H),6.06–5.96(m,1H),5.95–5.84(m,1H),3.70(d,J=6.4Hz,2H),3.34(d,J=5.9Hz,2H).13C NMR(100MHz,CDCl3):δ169.68,148.34,142.84,138.63,136.46,134.52,134.35,128.06,127.53,127.10,124.96,124.35,123.84,121.74,121.72,116.56,42.02,33.17.HRMS(ESI):Calcd for C18H17N2OS[M+H]+:309.0983;Found:309.1055.
底物二:
1H NMR(400MHz,CDCl3):δ10.02(s,1H),8.77(dt,J=5.3,1.6Hz,2H),8.15(ddd,J=8.3,5.1,1.7Hz,1H),7.61–7.48(m,2H),7.44(dt,J=8.3,4.2Hz,1H),6.01(d,J=3.0Hz,1H),5.93–5.83(m,3H),3.46(d,J=5.5Hz,2H),3.40–3.25(m,2H),2.25(s,3H).13C NMR(100MHz,CDCl3):δ169.72,151.98,150.91,148.32,138.60,136.43,134.52,132.00,128.04,127.51,124.78,121.71,121.69,116.51,106.41,106.20,106.19,42.13,31.72,13.68.HRMS(ESI):Calcd for C19H19N2O2[M+H]+:307.1441;Found:307.1449.
底物三:
1H NMR(400MHz,CDCl3):δ10.02(s,1H),8.83–8.66(m,2H),8.17–8.11(m,1H),7.88–7.80(m,2H),7.70(dt,J=5.4,3.3Hz,2H),7.57–7.47(m,2H),7.42(dd,J=8.2,4.2Hz,1H),6.02–5.61(m,2H),3.82–3.74(m,2H),3.31–3.20(m,2H),2.40–2.18(m,2H),2.09–1.78(m,2H).13C NMR(100MHz,CDCl3):δ169.91,168.57,148.34,138.64,136.39,135.53,134.52,134.06,132.25,128.03,127.50,123.53,123.34,121.71,121.63,116.45,42.15,37.75,30.14,28.26.HRMS(ESI):Calcd for C24H22N3O3[M+H]+:400.1656;Found:400.1655.
底物四:
1H NMR(400MHz,CDCl3):δ10.04(s,1H),8.94–8.67(m,2H),8.13(dd,J=8.2,1.7Hz,1H),7.71–7.33(m,4H),6.95–6.69(m,2H),6.11(d,J=1.4Hz,1H),5.97–5.71(m,2H),4.03(t,J=6.4Hz,2H),3.28(d,J=5.9Hz,2H),2.37(d,J=1.2Hz,3H),2.30–2.19(m,2H),1.91(dd,J=9.0,6.3Hz,2H),1.74–1.64(m,2H).13C NMR(100MHz,CDCl3):δ170.02,162.20,161.49,155.35,152.72,148.24,138.59,136.44,136.39,134.49,128.02,127.49,125.59,123.13,121.69,121.66,116.43,113.53,112.66,111.93,101.43,68.49,42.22,32.44,28.63,25.73,18.79.HRMS(ESI):Calcd for C27H27N2O4[M+H]+:443.1966;Found:443.1963.
底物五:
1H NMR(400MHz,CDCl3):δ10.09(s,1H),8.90–8.68(m,2H),8.14(dd,J=8.3,1.7Hz,1H),7.71–7.42(m,2H),7.38(dd,J=8.3,4.2Hz,1H),7.33–7.19(m,2H),7.04–6.72(m,3H),5.91–5.82(m,1H),5.82–5.74(m,1H),3.99(t,J=6.4Hz,2H),3.46–3.20(m,2H),2.47–2.16(m,2H),1.96–1.83(m,2H),1.78–1.64(m,2H).13C NMR(100MHz,CDCl3):δ170.11,159.15,148.32,138.63,136.82,136.40,134.54,129.55,129.52,128.04,127.50,122.93,121.69,121.64,120.65,116.46,114.58,67.76,42.27,32.59,29.02,25.99.HRMS(ESI):Calcd for C23H25N2O2[M+H]+:361.1911;Found:361.1914.
底物六:
1H NMR(400MHz,CDCl3):δ10.07(s,1H),8.77(dt,J=5.9,1.8Hz,2H),8.14(dd,J=8.2,1.7Hz,1H),7.62–7.45(m,2H),7.40(dd,J=8.3,4.2Hz,1H),6.69(d,J=8.5Hz,1H),6.48(d,J=2.5Hz,1H),6.30(dd,J=8.5,2.5Hz,1H),5.90(s,2H),5.86–5.69(m,2H),3.91(t,J=6.3Hz,2H),3.28(d,J=6.5Hz,2H),2.24(q,J=7.0Hz,2H),1.89–1.79(m,2H),1.73–1.61(m,2H).13C NMR(101MHz,CDCl3):δ170.11,154.72,148.34,141.58,138.66,136.80,136.42,134.56,128.05,127.52,122.95,121.71,121.64,116.45,108.06,105.70,101.21,98.13,68.82,42.28,32.57,29.02,25.93.HRMS(ESI):Calcd for C24H25N2O4[M+H]+:405.1809;Found:405.1808.
底物七:
1H NMR(400MHz,CDCl3):δ10.06(s,1H),8.85–8.73(m,2H),8.15(dd,J=8.2,1.7Hz,1H),7.60–7.47(m,2H),7.42(dd,J=8.2,4.2Hz,1H),7.15(d,J=8.6Hz,1H),6.70(dd,J=8.6,2.8Hz,1H),6.62(d,J=2.7Hz,1H),5.84(dt,J=14.9,6.5Hz,2H),4.01(t,J=6.4Hz,2H),3.29(d,J=6.5Hz,2H),2.87–2.77(m,2H),2.50(dd,J=18.9,8.6Hz,1H),2.35(q,J=7.0Hz,3H),2.18–1.91(m,6H),1.63–1.35(m,6H),1.32–1.22(m,1H),0.90(s,3H).13CNMR(100MHz,CDCl3):δ170.01,157.13,148.34,138.65,137.82,136.41,136.07,134.54,132.04,128.05,127.53,126.42,123.39,121.71,121.66,116.47,114.67,112.31,67.25,50.52,48.15,44.09,42.26,38.48,36.01,31.70,29.74,29.29,29.06,26.67,26.03,21.71,13.98.HRMS(ESI):Calcd for C34H39N2O3[M+H]+:523.2955;Found:523.2951.
底物八:
1H NMR(400MHz,CDCl3):δ10.05(s,1H),8.97–8.68(m,2H),8.15(dd,J=8.3,1.7Hz,1H),7.58–7.49(m,2H),7.44(dd,J=8.3,4.2Hz,1H),5.94–5.65(m,2H),4.12(q,J=7.1Hz,2H),3.28(d,J=5.3Hz,2H),2.40(t,J=7.6Hz,2H),2.31–2.15(m,2H),1.98–1.75(m,2H),1.24(t,J=7.1Hz,3H).13C NMR(100MHz,CDCl3):δ173.77,169.96,148.40,138.65,136.43,135.97,134.52,128.05,127.51,123.55,121.71,121.67,116.45,60.40,42.25,33.89,32.20,24.62,14.38.HRMS(ESI):Calcd for C19H23N2O3[M+H]+:327.1703;Found:327.1704.
实施例中全部的底物和产物的具体结构见表1。
实施例1
化合物1的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1a(0.3mmol),底物2a(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物1,其产率为84%。1H NMR(400MHz,CDCl3):δ9.70(s,1H),8.76(dd,J=4.2,1.7Hz,1H),8.69(dt,J=6.9,1.9Hz,1H),8.11(dd,J=8.3,1.7Hz,1H),7.51–7.34(m,3H),7.18(dt,J=15.0,7.4Hz,5H),7.10–7.01(m,5H),3.64(td,J=7.0,4.9Hz,1H),3.20(t,J=7.0Hz,1H),3.03(dd,J=15.0,6.1Hz,1H),2.88(dd,J=15.0,8.9Hz,1H),1.38(d,J=7.1Hz,3H).13C NMR(100MHz,CDCl3):δ170.45,148.03,144.00,141.69,138.26,136.30,134.42,128.81,128.47,127.90,127.86,127.36,126.38,126.20,121.56,121.40,116.45,48.47,44.75,41.51,19.03.HRMS(ESI):Calcd for C26H25N2O[M+H]+:381.1967,Found:381.1967.
实施例2
化合物2的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1b(0.3mmol),底物2a(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物2,其产率为74%。1H NMR(400MHz,CDCl3):δ9.77(s,1H),8.82–8.74(m,1H),8.74–8.68(m,1H),8.43–8.01(m,1H),7.57–7.40(m,3H),7.24–7.09(m,6H),7.06–6.99(m,2H),6.92(dt,J=7.8,3.9Hz,2H),3.71(td,J=6.4,2.8Hz,1H),3.11–2.94(m,1H),2.96–2.72(m,2H),2.02–1.84(m,1H),1.80–1.57(m,1H),0.90–0.59(t,3H).13C NMR(100MHz,CDCl3):δ170.59,148.12,141.52,141.46,138.37,136.39,134.51,129.60,129.16,127.96,127.79,127.78,127.46,126.42,126.26,121.65,121.48,116.54,52.53,47.16,42.21,26.21,12.52.HRMS(ESI):Calcd for C27H27N2O[M+H]+:395.2118;Found:395.2103.
实施例3
化合物3的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1c(0.3mmol),底物2a(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物3,其产率为69%。1H NMR(400MHz,CDCl3):δ9.37(s,1H),8.71(dd,J=4.3,1.7Hz,1H),8.55(dd,J=6.4,2.7Hz,1H),8.07(dd,J=8.3,1.7Hz,1H),7.44–7.35(m,5H),7.33–7.26(m,6H),7.22–7.11(m,2H),3.54(td,J=10.0,5.0Hz,1H),2.87–2.68(m,1H),2.67–2.51(m,2H),1.46(qd,J=7.1,2.7Hz,2H),0.59(t,J=7.3Hz,3H).13C NMR(100MHz,CDCl3):δ170.41,147.96,143.48,143.35,138.24,136.32,134.48,128.69,128.65,128.63,128.35,127.88,127.42,126.64,121.53,121.22,116.33,53.88,48.58,43.97,27.33,12.33.HRMS(ESI):Calcd for C27H27N2O[M+H]+:395.2118;Found:395.2105.
实施例4
化合物4的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1d(0.3mmol),底物2a(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=300∶1)得到产物4,其产率为69%。1H NMR(400MHz,CDCl3):δ9.69(s,1H),8.77(dd,J=4.3,1.7Hz,1H),8.70(dd,J=6.9,2.1Hz,1H),8.13(dd,J=8.3,1.7Hz,1H),7.56–7.36(m,3H),7.23–7.07(m,6H),7.03–6.96(m,2H),6.94–6.84(m,2H),3.68(dt,J=8.3,6.5Hz,1H),3.12–2.93(m,2H),2.82(dd,J=15.0,8.2Hz,1H),1.84(ddt,J=14.8,10.0,4.8Hz,1H),1.73–1.61(m,1H),1.44–1.03(m,4H),0.79(t,J=7.2Hz,3H).13C NMR(100MHz,CDCl3):δ170.61,148.14,141.87,141.45,138.42,136.42,134.56,129.58,129.21,128.00,127.81,127.79,127.51,126.43,126.25,121.67,121.48,116.59,50.69,47.41,42.23,33.09,30.09,22.90,14.14.HRMS(ESI):Calcd for C29H31N2O[M+H]+:423.2431;Found:423.2398.
实施例5
化合物5的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物2e(0.3mmol),底物2a(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物5,其产率为43%。1H NMR(400MHz,CDCl3):δ9.47(s,1H),8.70(dd,J=7.3,1.7Hz,1H),8.61(dd,J=4.3,1.7Hz,1H),8.08(dd,J=8.3,1.7Hz,1H),7.67–7.28(m,7H),7.28–7.20(m,1H),7.14(dd,J=5.0,2.0Hz,3H),6.98–6.85(m,2H),3.29–2.99(m,3H),2.87(d,J=14.0Hz,1H),1.54(s,3H).13C NMR(100MHz,CDCl3):δ169.94,147.90,145.86,138.38,137.84,136.21,134.59,130.88,128.60,127.88,127.70,127.43,126.79,126.38,126.30,121.54,121.37,116.40,50.35,49.87,41.99,23.85.HRMS(ESI):Calcd for C26H25N2O[M+H]+:381.1962;Found:381.1950.
实施例6
化合物6的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1f(0.3mmol),底物2a(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物6,其产率为73%。1H NMR(400MHz,CDCl3):δ9.73(s,1H),8.97–8.55(m,2H),8.30–7.97(m,1H),7.62–7.35(m,3H),7.24–7.08(m,6H),7.01(d,J=7.5Hz,2H),6.97–6.88(m,2H),3.71(d,J=7.1Hz,1H),3.18–2.90(m,2H),2.84(dd,J=14.9,8.2Hz,1H),1.85(tt,J=8.7,4.6Hz,1H),1.69(dd,J=9.5,4.6Hz,1H),1.37–1.10(m,16H),0.89(t,J=6.9Hz,3H).13C NMR(100MHz,CDCl3):δ170.60,148.11,141.87,141.46,138.39,136.39,134.54,129.55,129.19,127.97,127.80,127.77,127.48,126.41,126.23,121.64,121.46,116.56,50.71,47.40,42.23,33.34,32.01,29.83,29.72,29.67,29.59,29.43,27.85,22.80,14.25.HRMS(ESI):Calcd for C35H43N2O[M+H]+:507.3370;Found:507.3354.
实施例7
化合物7的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1g(0.3mmol),底物2a(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物7,其产率为88%。1H NMR(400MHz,CDCl3):δ9.75(s,1H),9.02–8.57(m,2H),8.11(dt,J=8.5,2.8Hz,1H),7.56–7.43(m,2H),7.40(dd,J=8.1,4.1Hz,1H),7.27–7.20(m,3H),7.17(dt,J=10.9,4.9Hz,5H),7.12–7.04(m,5H),7.02–6.90(m,2H),3.87(d,J=6.8Hz,1H),3.54–3.45(m,1H),3.26(dd,J=14.0,5.4Hz,1H),3.13(dd,J=15.0,6.7Hz,1H),3.06–2.97(m,1H),2.97–2.87(m,1H).13C NMR(100MHz,CDCl3):δ170.28,148.06,140.89,140.72,140.34,138.30,136.33,134.44,129.78,129.31,129.11,128.12,127.91,127.87,127.66,127.40,126.62,126.39,125.80,121.60,121.48,116.51,51.85,46.69,42.43,39.68.HRMS(ESI):Calcd for C32H29N2O[M+H]+:457.2274,Found:457.2259.
实施例8
化合物8的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1h(0.3mmol),底物2a(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物8,其产率为84%。1H NMR(400MHz,CDCl3):δ9.71(s,1H),8.82–8.65(m,2H),8.13(dd,J=8.3,1.7Hz,1H),7.54–7.40(m,3H),7.23–7.13(m,6H),7.05–6.87(m,5H),6.77(dd,J=5.1,3.4Hz,1H),6.67(dd,J=3.5,1.1Hz,1H),3.86(td,J=7.5,5.3Hz,1H),3.58–3.33(m,2H),3.15(ddd,J=14.8,9.2,1.0Hz,1H),3.06(dd,J=15.0,7.0Hz,1H),2.87(dd,J=15.0,8.0Hz,1H).13C NMR(100MHz,CDCl3):δ170.16,148.12,143.11,140.35,138.39,136.40,134.49,129.87,129.44,127.93,127.80,127.47,126.79,126.73,126.54,125.40,123.33,121.65,121.53,116.61,52.09,46.39,42.33,34.07.HRMS(ESI):Calcd forC30H27N2OS[M+H]+:463.1839;Found:463.1828.
实施例9
化合物9的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1i(0.3mmol),底物2a(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物9,其产率为75%。1H NMR(400MHz,CDCl3):δ9.69(s,1H),8.76(dd,J=4.3,1.7Hz,1H),8.71(dd,J=7.1,2.0Hz,1H),8.12(dd,J=8.2,1.7Hz,1H),7.59–7.36(m,3H),7.20–7.12(m,6H),7.09–6.96(m,2H),6.95–6.89(m,2H),5.71(s,2H),3.98–3.74(m,1H),3.52(ddd,J=8.4,6.7,5.4Hz,1H),3.08(ddd,J=22.3,15.2,6.8Hz,2H),2.95–2.69(m,2H),2.17(s,3H).13C NMR(100MHz,CDCl3):δ170.26,152.31,150.31,148.11,140.85,140.43,138.38,136.39,134.52,129.59,129.45,127.96,127.88,127.71,127.46,126.70,126.55,121.65,121.48,116.56,107.14,105.98,48.73,46.00,42.31,32.16,13.58.HRMS(ESI):Calcd for C31H29N2O2[M+H]+:461.2224;Found:461.2203.
实施例10
化合物10的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1j(0.3mmol),底物2a(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物10,其产率为83%。1H NMR(400MHz,CDCl3):δ9.68(s,1H),8.74(dd,J=4.3,1.8Hz,1H),8.68(dd,J=7.0,2.0Hz,1H),8.09(dt,J=8.3,2.0Hz,1H),7.76(dd,J=5.5,3.1Hz,2H),7.63(dd,J=5.6,2.9Hz,2H),7.51–7.32(m,3H),7.22–7.02(m,6H),7.04–6.94(m,2H),6.90(dd,J=7.5,2.0Hz,2H),3.64(dt,J=21.2,7.1Hz,3H),3.04(ddd,J=21.9,12.9,6.0Hz,2H),2.81(dd,J=15.1,8.0Hz,1H),1.89(ddd,J=15.4,10.4,5.1Hz,1H),1.82–1.68(m,1H),1.66–1.53(m,1H),1.53–1.41(m,1H);13C NMR(100MHz,CDCl3):δ170.30,168.38,148.06,141.13,140.99,138.28,136.32,134.42,133.84,132.10,129.38,129.05,127.90,127.88,127.81,127.40,126.46,126.45,123.15,121.59,121.43,116.52,50.19,47.20,41.97,37.89,30.37,26.96.HRMS(ESI):Calcd for C36H32N3O3[M+H]+:554.2438,Found:554.2425
实施例11
化合物11的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1k(0.3mmol),底物2a(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物11,其产率为83%。1H NMR(400MHz,CDCl3):δ9.71(s,1H),8.75(dd,J=4.3,1.7Hz,1H),8.70(dd,J=6.9,2.1Hz,1H),8.10(dd,J=8.3,1.7Hz,1H),7.52–7.34(m,4H),7.22–7.07(m,6H),7.02–6.96(m,2H),6.95–6.88(m,2H),6.74(dd,J=8.8,2.5Hz,1H),6.68(d,J=2.5Hz,1H),6.08(d,J=1.4Hz,1H),3.86(td,J=6.4,4.8Hz,2H),3.71(q,J=7.1Hz,1H),3.16–2.94(m,2H),2.83(dd,J=15.0,7.8Hz,1H),2.33(d,J=1.2Hz,3H),1.92(dq,J=15.1,5.2Hz,1H),1.74(dtd,J=15.5,10.2,9.1,6.3Hz,3H),1.48–1.32(m,2H).13C NMR(100MHz,CDCl3):δ170.40,162.11,161.43,155.24,152.66,148.09,141.27,141.20,138.27,136.34,134.40,129.46,129.12,127.90,127.84,127.80,127.36,126.48,126.40,125.46,121.62,121.49,116.49,113.38,112.59,111.78,101.35,68.30,50.40,47.21,42.02,32.92,28.96,24.17,18.68.HRMS(ESI):Calcd for C39H37N2O4[M+H]+:597.2748;Found:597.2769.
实施例12
化合物12的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1l(0.3mmol),底物2a(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物12,其产率为73%。1H NMR(400MHz,CDCl3):δ9.74(s,1H),8.90–8.37(m,2H),8.12(dd,J=8.3,1.7Hz,1H),7.54–7.39(m,3H),7.31–7.07(m,8H),7.05–6.98(m,2H),6.97–6.90(m,3H),6.88–6.79(m,2H),3.86(td,J=6.5,4.2Hz,2H),3.73(q,J=7.1Hz,1H),3.06(ddd,J=14.8,8.5,5.8Hz,2H),2.85(dd,J=15.0,7.9Hz,1H),1.94(ddd,J=15.4,9.8,5.4Hz,1H),1.76(dtd,J=13.6,7.2,4.2Hz,3H),1.44–1.26(m,2H).13C NMR(100MHz,CDCl3):δ170.45,159.05,148.10,141.44,141.28,138.34,136.36,134.48,129.52,129.44,129.16,127.94,127.84,127.81,127.43,126.47,126.36,121.63,121.47,120.50,116.53,114.53,67.63,50.51,47.25,42.09,33.03,29.32,24.33.HRMS(ESI):Calcd forC35H35N2O2[M+H]+:515.2693;Found:515.2692.
实施例13
化合物13的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1m(0.3mmol),底物2a(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物13,其产率为89%。1H NMR(400MHz,CDCl3):δ9.71(s,1H),8.77(dd,J=4.2,1.7Hz,1H),8.71(dd,J=6.9,2.1Hz,1H),8.12(ddd,J=8.3,2.9,1.7Hz,1H),7.60–7.38(m,3H),7.23–7.09(m,6H),7.05–6.96(m,2H),6.96–6.84(m,2H),6.66(dd,J=8.4,5.2Hz,1H),6.52–6.37(m,1H),6.23(dd,J=8.5,2.5Hz,1H),5.89(d,J=1.7Hz,2H),3.89–3.62(m,3H),3.11–2.99(m,2H),2.82(dd,J=15.0,7.9Hz,1H),1.99–1.84(m,1H),1.71(dd,J=13.1,9.1,6.8,3.5Hz,3H),1.39–1.25(m,2H).13C NMR(100MHz,CDCl3):δ170.51,154.63,148.24,148.15,141.49,141.44,141.29,138.39,136.42,134.50,129.56,129.19,127.99,127.87,127.85,127.49,126.50,126.39,121.68,121.52,116.58,107.99,105.69,101.14,98.14,68.72,50.53,47.28,42.12,33.05,29.36,24.32.HRMS(ESI):Calcd for C36H35N2O4[M+H]+:559.2592;Found:559.2588.
实施例14
化合物14的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1n(0.3mmol),底物2c(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物14,其产率为80%。1H NMR(400MHz,CDCl3):δ9.69(s,1H),8.77(dd,J=4.2,1.7Hz,1H),8.71(dd,J=6.9,2.2Hz,1H),8.13(dd,J=8.3,1.7Hz,1H),7.59–7.35(m,3H),7.15(d,J=8.6Hz,1H),6.92–6.87(m,2H),6.85–6.81(m,2H),6.78–6.70(m,4H),6.64(dd,J=8.6,2.7Hz,1H),6.57(d,J=2.7Hz,1H),3.84(t,J=4.1Hz,2H),3.79(s,3H),3.72(s,3H),3.69–3.56(m,1H),3.09–2.92(m,2H),2.85(dd,J=7.1,3.4Hz,2H),2.82–2.72(m,1H),2.50(dd,J=18.8,8.5Hz,1H),2.40–2.33(m,1H),2.29–1.91(m,6H),1.71–1.52(m,9H),0.90(s,3H).13C NMR(100MHz,CDCl3):δ170.64,158.17,157.13,148.13,138.41,137.75,136.42,134.54,132.99,132.96,131.89,130.59,130.26,128.00,127.49,126.36,121.68,121.50,116.58,114.59,113.25,113.20,112.27,67.83,55.28,55.21,50.51,49.36,48.15,46.56,44.09,42.50,38.48,36.01,31.69,30.13,29.76,27.64,26.68,26.04,21.71,13.98.HRMS(ESI):Calcd for C48H53N2O5[M+H]+:737.3949;Found:737.3940.
实施例15
化合物15的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1o(0.3mmol),底物2e(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物15,其产率为84%。1H NMR(400MHz,CDCl3):δ9.66(s,1H),8.77(dt,J=4.2,1.3Hz,1H),8.66(dd,J=5.9,3.1Hz,1H),8.13(dt,J=8.2,1.7Hz,1H),7.52–7.40(m,3H),7.20–7.13(m,2H),7.12(d,J=8.4Hz,2H),6.89(d,J=8.4Hz,2H),6.86–6.79(m,2H),4.06(q,J=7.1Hz,2H),3.62(dt,J=8.3,6.5Hz,1H),3.19–2.90(m,2H),2.75(dd,J=15.0,8.3Hz,1H),2.22(td,J=7.3,1.5Hz,2H),1.98–1.76(m,1H),1.64(dtd,J=13.3,10.5,5.0Hz,1H),1.53–1.37(m,2H),1.20(t,J=7.1Hz,3H).13C NMR(100MHz,CDCl3):δ173.44,169.78,148.23,139.47,139.42,138.30,136.47,134.27,132.42,132.34,130.59,130.30,128.26,128.20,127.99,127.43,121.75,121.73,116.62,60.39,49.73,46.75,42.10,34.16,32.83,23.09,14.32.HRMS(ESI):Calcd for C31H31Cl2N2O3[M+H]+:549.1706;Found:549.1685
实施例16
化合物16的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1a(0.3mmol),底物2b(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物16,其产率为88%。1H NMR(400MHz,CDCl3):δ9.72(s,1H),8.77(dd,J=4.3,1.7Hz,1H),8.72(dd,J=7.3,1.7Hz,1H),8.10(dd,J=8.3,1.7Hz,1H),7.65–7.36(m,3H),7.15–6.82(m,8H),3.64(dt,J=8.8,6.1Hz,1H),3.25–3.13(m,1H),2.99(dd,J=15.0,6.1Hz,1H),2.86(dd,J=15.0,8.8Hz,1H),2.31(s,3H),2.24(s,3H),1.35(d,J=7.1Hz,3H).13CNMR(100MHz,CDCl3):δ170.67,147.93,140.89,138.56,138.19,136.41,135.71,135.58,134.47,128.76,128.62,128.61,128.47,127.89,127.42,121.53,121.36,116.56,47.89,44.11,41.43,21.08,18.95.HRMS(ESI):Calcd for C28H29N2O[M+H]+:409.2274;Found:409.2256.
实施例17
化合物17的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1a(0.3mmol),底物2c(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物17,其产率为94%。1H NMR(400MHz,CDCl3):δ9.72(s,1H),8.96–8.58(m,2H),8.05(dd,J=8.3,1.7Hz,1H),7.54–7.26(m,3H),6.96(dd,J=14.7,8.4Hz,4H),6.74(dd,J=16.3,8.3Hz,4H),3.74(s,3H),3.67(s,3H),3.57(dt,J=9.0,6.2Hz,1H),3.15(q,J=6.9Hz,1H),2.99(dd,J=14.9,6.0Hz,1H),2.82(dd,J=14.9,8.9Hz,1H),1.32(d,J=10.8,7.9Hz,3H).13C NMR(100MHz,CDCl3):δ170.76,158.07,157.97,148.02,138.25,136.53,135.96,134.47,133.55,129.91,129.55,127.98,127.51,121.62,121.47,116.69,113.30,113.26,55.27,55.17,47.81,43.82,41.97,19.38.HRMS(ESI):Calcd for C28H29N2O3[M+H]+:441.2173;Found:441.2160.
实施例18
化合物18的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1a(0.3mmol),底物2d(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物18,其产率为88%。1H NMR(400MHz,CDCl3):δ9.69(s,1H),8.75(dd,J=4.2,1.7Hz,1H),8.68(dd,J=6.7,2.3Hz,1H),8.11(dd,J=8.3,1.7Hz,1H),7.51–7.32(m,3H),7.02–6.67(m,8H),3.56(dt,J=8.9,6.4Hz,1H),3.13(t,J=7.1Hz,1H),3.02(dd,J=14.9,6.0Hz,1H),2.81(dd,J=14.9,9.0Hz,1H),1.35(d,J=7.1Hz,3H).13C NMR(100MHz,CDCl3):δ170.14,162.71(d,J=11.6Hz),160.29(d,J=11.3Hz),148.17,139.53(d,J=3.2Hz),138.31,137.24,136.47,134.34,130.15(d,J=7.8Hz),129.73(d,J=7.7Hz),127.98,127.45,121.69(d,J=7.2Hz),116.57,114.94(d,J=9.0Hz),114.73(d,J=8.9Hz),48.07,44.16,42.12,19.66.19F NMR(376MHz,CDCl3)δ-116.47,-116.78.HRMS(ESI):Calcd forC26H23F2N2O[M+H]+:417.1773;Found:417.1796.
实施例19
化合物19的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1a(0.3mmol),底物2e(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物19,其产率为83%。1H NMR(400MHz,CDCl3):δ9.67(s,1H),8.76(dd,J=4.3,1.7Hz,1H),8.67(dd,J=6.4,2.6Hz,1H),8.11(dd,J=8.3,1.7Hz,1H),7.58–7.37(m,3H),7.22–7.11(m,4H),6.98–6.86(m,4H),3.56(dt,J=8.7,6.3Hz,1H),3.12(t,J=7.1Hz,1H),3.01(dd,J=14.9,6.0Hz,1H),2.79(dd,J=15.0,8.9Hz,1H),1.34(d,J=7.1Hz,3H).13C NMR(100MHz,CDCl3):δ169.85,148.16,142.24,139.97,138.24,136.42,134.26,132.26,132.03,130.05,129.68,128.24,128.19,127.93,127.38,121.69,121.66,116.55,47.93,44.09,41.83,19.48.HRMS(ESI):Calcd for C26H23Cl2N2O[M+H]+:449.1182;Found:449.1185.
实施例20
化合物20的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1a(0.3mmol),底物2f(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物20,其产率为95%。1H NMR(400MHz,CDCl3):δ9.65(s,1H),8.77(dd,J=4.2,1.7Hz,1H),8.65(dd,J=5.6,3.4Hz,1H),8.32–8.13(m,1H),7.54–7.40(m,3H),7.36–7.26(m,4H),6.93–6.65(m,4H),3.54(dt,J=8.6,6.3Hz,1H),3.12(t,J=7.1Hz,1H),3.00(dd,J=15.0,6.0Hz,1H),2.79(dd,J=14.9,8.8Hz,1H),1.34(d,J=7.1Hz,3H).13C NMR(100MHz,CDCl3):δ169.86,148.24,142.74,140.48,138.30,136.50,134.28,131.24,131.20,130.50,130.15,128.00,127.46,121.76,121.73,120.52,120.24,116.61,47.94,44.11,41.86,19.51.HRMS(ESI):Calcd for C26H23Br2N2O[M+H]+:537.0172;Found:537.0173.
实施例21
化合物21的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1a(0.3mmol),底物2g(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物21,其产率为88%。1H NMR(400MHz,CDCl3):δ9.80(s,1H),8.77(d,J=4.8Hz,2H),8.10(d,J=8.2Hz,1H),7.62(t,J=6.4Hz,2H),7.56–7.33(m,15H),7.20(dt,J=11.7,6.5Hz,4H),3.79(t,J=6.9Hz,1H),3.34(q,J=6.2Hz,1H),3.11(dt,J=15.1,5.1Hz,1H),3.02–2.84(m,1H),1.47(d,J=5.9Hz,3H).13C NMR(100MHz,CDCl3):δ170.45,148.08,143.01,140.97,140.89,140.76,139.13,139.05,138.29,136.36,134.46,129.32,129.02,128.78,128.72,127.92,127.42,127.12,127.08,127.02,126.96,126.64,121.60,121.49,116.54,48.06,44.26,41.41,18.98.HRMS(ESI):Calcd for C38H33N2O[M+H]+:533.2587;Found:533.2562.
实施例22
化合物22的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1a(0.3mmol),底物2h(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物22,其产率为83%。.1H NMR(400MHz,CDCl3):δ9.80(s,1H),8.97–8.48(m,2H),8.11(dd,J=8.3,1.7Hz,1H),7.60–7.20(m,3H),6.77–6.15(m,4H),3.92(dt,J=9.8,5.0Hz,1H),3.43(qd,J=7.0,4.6Hz,1H),2.99(dd,J=15.1,5.2Hz,1H),2.90–2.73(m,1H),2.43(d,J=1.1Hz,3H),2.38(d,J=1.1Hz,3H),1.39(d,J=7.1Hz,3H).13C NMR(100MHz,CDCl3):δ170.02,148.06,145.12,142.50,138.32,137.80,137.70,136.33,134.51,127.91,127.41,125.18,124.60,124.54,124.43,121.59,121.45,116.53,44.18,41.30,40.69,18.77,15.40,15.38.HRMS(ESI):Calcd for C24H25N2OS2[M+H]+:421.1403;Found:421.1393.
实施例23
化合物23的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1a(0.3mmol),底物2i(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物23,其产率为80%。1H NMR(400MHz,CDCl3):δ9.82(s,1H),8.90–8.60(m,2H),8.10(dd,J=8.3,1.7Hz,1H),7.60–7.32(m,3H),7.13(ddd,J=17.2,5.2,1.2Hz,2H),6.93(dd,J=5.1,3.4Hz,1H),6.88(dd,J=5.1,3.5Hz,1H),6.82(dd,J=7.4,3.5Hz,2H),4.04(dt,J=8.9,5.4Hz,1H),3.56(dd,J=7.2,5.2Hz,1H),3.06(dd,J=15.1,5.6Hz,1H),2.94(dd,J=15.1,9.0Hz,1H),1.46(d,J=7.1Hz,3H).13C NMR(100MHz,CDCl3):δ169.70,148.11,147.24,144.67,138.27,136.32,134.38,127.88,127.36,126.49,125.49,124.71,123.56,123.38,121.61,121.54,116.52,44.21,41.84,40.61,19.48.HRMS(ESI):Calcd forC22H21N2OS[M+H]+:393.1090;Found:393.1080.
实施例24
化合物24的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1a(0.3mmol),底物2j(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物24,其产率为85%。1H NMR(400MHz,CDCl3):δ9.75(s,1H),8.89–8.59(m,2H),8.12(dd,J=8.3,1.7Hz,1H),7.55–7.34(m,3H),7.19(ddd,J=10.3,5.0,2.9Hz,2H),6.88(ddd,J=7.4,3.0,1.3Hz,2H),6.82(ddd,J=11.7,5.0,1.3Hz,2H),3.78(ddd,J=8.5,6.3,5.0Hz,1H),3.34(qd,J=7.1,4.9Hz,1H),2.91(dd,J=14.9,6.4Hz,1H),2.82(dd,J=14.9,8.5Hz,1H),1.32(d,J=7.1Hz,3H).13C NMR(100MHz,CDCl3):δ170.45,148.15,144.49,142.18,138.34,136.39,134.44,128.14,128.01,127.95,127.43,124.74,124.70,121.75,121.65,121.54,121.22,116.56,43.58,41.61,39.60,18.94.HRMS(ESI):Calcd forC22H21N2OS[M+H]+:393.1090;Found:393.1079.
实施例25
化合物25的合成
在氮气条件下,10mL反应瓶中依次加入三氟甲磺酸镍(0.03mmol),底物1a(0.3mmol),底物2k(0.9mmol),N,N二甲基甲酰胺(0.6mL),锰粉(0.9mmol)。室温下混合均匀后,反应混合物在50℃下反应24h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=20∶1)得到产物25,其产率为89%。1H NMR(400MHz,CDCl3):δ9.66(s,1H),8.71(dd,J=4.2,1.6Hz,1H),8.64(dd,J=6.9,2.2Hz,1H),8.05(dt,J=8.3,1.5Hz,1H),7.81–7.59(m,2H),7.50–7.30(m,3H),7.02–6.72(m,4H),3.82(s,3H),3.77(s,3H),3.64(dt,J=8.7,6.3Hz,1H),3.17(t,J=7.1Hz,1H),2.99(dd,J=14.9,6.0Hz,1H),2.83(dd,J=15.0,8.8Hz,1H),2.49(s,3H),2.45(s,3H),1.33(d,J=7.0Hz,3H).13C NMR(100MHz,CDCl3):δ169.84,167.85,167.77,148.14,148.05,145.91,140.00,138.14,136.29,134.16,132.13,131.73,130.46,130.44,127.81,127.56,127.43,127.24,125.98,125.62,121.56,116.44,51.67,51.60,47.96,44.26,41.28,21.81,18.94.HRMS(ESI):Calcd for C32H33N2O5[M+H]+:525.2384;Found:525.2352.
实施例1~15的原料和产物结构式及对应的实验结果如下表1所示:
表1
对比例1
对比例1与实施例20的方法相同,不同之处在于:不加入镍催化剂,目标产物产率为0。
对比例2
对比例2与实施例20的方法相同,不同之处在于:不加入锰还原剂,目标产物产率为0。
对比例3
对比例3与实施例20的方法相同,不同之处在于:使用乙烯基乙酸作为烯烃底物,目标产物产率为0。
对比例4
实施例4与实施例20方法相同,不同之处在于:使用乙烯基乙酸乙酯作为烯烃底物,目标产物产率为0。
实施例26
实施例26与实施例20方法相同,不同之处在于:镍为氯化镍,还原剂为锌粉,有机溶剂为甲醇。烯烃、卤代物、镍、锌的摩尔比为:1:3:0.2:4。
实施例27
实施例27与实施例20方法相同,不同之处在于:镍为对甲苯磺酸镍,还原剂为镁粉,有机溶剂为乙醇。烯烃、卤代物、镍、镁的摩尔比为:1:6:0.1:3。
实施例28
实施例28与实施例20方法相同,不同之处在于:镍为碳酸镍,有机溶剂为二氯甲烷。
实施例29
实施例29与实施例20方法相同,不同之处在于:镍为双(三苯基膦)氯化镍,有机溶剂为二甲亚砜。
实施例30
实施例30与实施例20方法相同,不同之处在于:镍为氯化镍乙二醇二甲基醚络合物,有机溶剂为N,N-二乙基乙酰胺。
实施例31
实施例31与实施例20方法相同,不同之处在于:镍为四氟硼酸镍六水合物,,有机溶剂为N,N-二甲基丙烯基脲。
实施例32
实施例32与实施例20方法相同,不同之处在于:镍为1,3-双(二苯基膦丙烷)二氯化镍,有机溶剂为N-甲基吡咯烷酮。
以上所述,仅是本发明的较佳实施例而已,并非对本发明作任何形式上的限制,虽然本发明已以较佳实施例揭露如上,然而并非用以限定本发明,本发明中的各种镍催化剂理论上都能与带导向功能的烯烃配位形成活性的镍催化剂物种,从而有利于反应的顺利进行;取代基的修饰只是一定程度上影响反应,不对反应的发生起决定作用。任何熟悉本专业的技术人员不难理解,在不脱离本发明技术方案范围内,当可进行变动或修饰得到相应的实施例,例如对于所述的取代基可在本发明范围内进行替换、改变或修饰,均可以实现本发明方法。但凡是未脱离本发明技术方案的宗旨,依据本发明的对以上实施例所作的任何修改、修饰或等同与等效的变化,均仍属于本发明技术方案的范围内。
Claims (9)
2.根据权利要求1所述的镍催化非活化烯烃双碳官能团化反应的方法,其特征在于,以R1、R2、R3表示烯键上的取代基,其烯烃上的取代基R1、R2、R3各自独立的任意选自氢、C1~C20的烷基、C1~C20卤取代烷基、C1~C20烷基羰基、硝基、羟基或者氰基。
3.根据权利要求1所述的镍催化非活化烯烃双碳官能团化反应的方法,其特征在于,所述R4表示羰基α位上的取代基,其羰基α位上的取代基任意优选选自氢、C1~C20的烷基、C1~C20卤取代烷基、C1~C20烷基羰基、硝基、羟基或者氰基。
4.根据权利要求1所述的镍催化非活化烯烃双碳官能团化反应的方法,其特征在于,所述X为氟、氯、溴或碘,所述R5表示卤代物上的取代基团,其卤代物上的取代基各自独立的任意选自芳基、取代芳基、氢、C1~C20的烷基、C1~C20卤取代烷基、C1~C20烷基羰基、硝基、羟基或者氰基。
5.根据权利要求1所述的镍催化非活化烯烃双碳官能团化反应的方法,其特征在于,所述镍选自氯化镍,无水溴化镍,水合溴化镍,碘化镍,碳酸镍,双-(1,5-环辛二烯)镍,氯化镍乙二醇二甲基醚络合物,溴化镍乙二醇二甲基醚络合物,(2,2'-联吡啶)二溴化镍,二溴(1,10-菲咯啉)镍,氯代双三己基磷酸镍盐,双(三苯基膦)氯化镍,1,2-双(二苯基膦)乙烷氯化镍,(1,1'-双(二苯基膦)二茂铁)二氯化镍,溴化镍二乙二醇二甲醚复合物,乙酰丙酮镍,三氟甲磺酸镍,双(2,2,6,6,-四甲基-3,5-庚二酮酸)镍,双(六氟乙酰丙酮)合镍,高氯酸镍,对甲苯磺酸镍,1,3-双(二苯基膦丙烷)二氯化镍,四氟硼酸镍六水合物,双(三苯基膦)二溴化镍,二溴二(三丁基膦)镍中的任意一种。
6.根据权利要求1所述的镍催化非活化烯烃双碳官能团化反应的方法,其特征在于,所述廉价金属单质选自锌、锰、镁金属中的一种。
7.根据权利要求1所述的镍催化非活化烯烃双碳官能团化反应的方法,所述有机溶剂选自甲醇、乙醇、乙二醇、正丙醇、异丙醇、1,3-丙二醇、甘油、正丁醇、异丁醇、叔丁醇、三氟乙醇、2-甲基-2-丁醇、3-甲氧基丁醇、仲丁醇、叔戊醇、4-甲基-2-戊醇、异戊醇、2-戊醇、3-戊醇、环戊醇、正戊醇、聚乙二醇200-10000、乙腈、苯腈、甲苯、丙酮、二氯甲烷、1,2-二氯乙烷、二甲亚砜、N,N二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二甲基丙烯基脲,N-甲基吡咯烷酮、乙酸乙酯、1,4-二氧六环或四氢呋喃中的一种或者多种。
8.根据权利要求1所述的镍催化非活化烯烃双碳官能团化反应的方法,所述烯烃、卤代物、镍、锰的摩尔比为:1:(3~6):(0.1~0.2):(3~4)。
9.根据权利要求1所述的镍催化非活化烯烃双碳官能团化反应的方法,所述反应的温度为30-60℃,时间为12-24小时。
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