CN111484533B - 手性螺环膦-氮-膦三齿配体及其铱催化剂的制备方法和应用 - Google Patents
手性螺环膦-氮-膦三齿配体及其铱催化剂的制备方法和应用 Download PDFInfo
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- CN111484533B CN111484533B CN202010012689.5A CN202010012689A CN111484533B CN 111484533 B CN111484533 B CN 111484533B CN 202010012689 A CN202010012689 A CN 202010012689A CN 111484533 B CN111484533 B CN 111484533B
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- phosphine
- chiral
- nitrogen
- tridentate ligand
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- 239000003446 ligand Substances 0.000 title claims abstract description 68
- 239000003054 catalyst Substances 0.000 title claims abstract description 45
- 125000003003 spiro group Chemical group 0.000 title claims abstract description 36
- 229910052741 iridium Inorganic materials 0.000 title claims abstract description 33
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 title claims abstract description 33
- AKRNGHFZKLRTJN-UHFFFAOYSA-N P.P.[N] Chemical compound P.P.[N] AKRNGHFZKLRTJN-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 24
- 150000002576 ketones Chemical class 0.000 claims abstract description 17
- 150000001728 carbonyl compounds Chemical class 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 125000001424 substituent group Chemical group 0.000 claims abstract description 11
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims description 67
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 38
- 239000007787 solid Substances 0.000 claims description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 24
- -1 OTf anion Chemical class 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 238000003786 synthesis reaction Methods 0.000 claims description 21
- 230000015572 biosynthetic process Effects 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 229910052723 transition metal Inorganic materials 0.000 claims description 11
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 9
- 238000005984 hydrogenation reaction Methods 0.000 claims description 9
- 239000000758 substrate Substances 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000012298 atmosphere Substances 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- PARWUHTVGZSQPD-UHFFFAOYSA-N phenylsilane Chemical compound [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 claims description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-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
- 239000002585 base Substances 0.000 claims description 4
- 239000012018 catalyst precursor Substances 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 4
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 claims description 4
- 239000005052 trichlorosilane Substances 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- ORBBTCHHNMWMCP-UHFFFAOYSA-K cycloocta-1,5-diene trichloroiridium Chemical group [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1 ORBBTCHHNMWMCP-UHFFFAOYSA-K 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- 238000006268 reductive amination reaction Methods 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 238000004807 desolvation Methods 0.000 claims 2
- RRKODOZNUZCUBN-CCAGOZQPSA-N (1z,3z)-cycloocta-1,3-diene Chemical compound C1CC\C=C/C=C\C1 RRKODOZNUZCUBN-CCAGOZQPSA-N 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 230000000536 complexating effect Effects 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 abstract description 4
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 abstract description 4
- 230000003287 optical effect Effects 0.000 abstract description 4
- 125000000217 alkyl group Chemical group 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
- 238000005481 NMR spectroscopy Methods 0.000 description 50
- 239000012074 organic phase Substances 0.000 description 29
- 238000001035 drying Methods 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- 238000004896 high resolution mass spectrometry Methods 0.000 description 17
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- 238000002844 melting Methods 0.000 description 16
- 230000008018 melting Effects 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 15
- 239000002274 desiccant Substances 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
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- 230000000171 quenching effect Effects 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 229910052786 argon Inorganic materials 0.000 description 8
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- 239000012362 glacial acetic acid Substances 0.000 description 7
- 125000001072 heteroaryl group Chemical group 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
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- 230000003197 catalytic effect Effects 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
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- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 3
- NDOPHXWIAZIXPR-UHFFFAOYSA-N 2-bromobenzaldehyde Chemical compound BrC1=CC=CC=C1C=O NDOPHXWIAZIXPR-UHFFFAOYSA-N 0.000 description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
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- 125000002541 furyl group Chemical group 0.000 description 3
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- 125000004076 pyridyl group Chemical group 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
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- 229910052757 nitrogen Inorganic materials 0.000 description 2
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- 125000004437 phosphorous atom Chemical group 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
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- 229910052717 sulfur Inorganic materials 0.000 description 2
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- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- DRCPJRZHAJMWOU-UHFFFAOYSA-N 2-diphenylphosphinobenzaldehyde Chemical compound O=CC1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 DRCPJRZHAJMWOU-UHFFFAOYSA-N 0.000 description 1
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- KRRMXFPHVAZCST-UHFFFAOYSA-N CCP(CC)(Cl)Cl Chemical compound CCP(CC)(Cl)Cl KRRMXFPHVAZCST-UHFFFAOYSA-N 0.000 description 1
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- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 150000002431 hydrogen Chemical class 0.000 description 1
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- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
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- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
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Abstract
本发明涉及一种手性螺环膦‑氮‑膦三齿配体SpiroPNP及其铱催化剂Ir‑SpiroPNP制备方法和应用。该手性螺环膦‑氮‑膦三齿配体是具有式I所示的化合物,或其消旋体或旋光异构体,或其催化可接受的盐,主要结构特征是具有手性螺二氢茚骨架和具有大位阻取代基的膦配体。该手性螺环膦‑氮‑膦三齿配体可以由具有螺环骨架的7‑二芳/烷基膦基‑7′‑氨基‑1,1′‑螺二氢茚类化合物为手性起始原料合成。该手性螺环膦‑氮‑膦三齿配体的铱催化剂是具有式II所示的化合物,或其消旋体或旋光异构体,或其催化可接受的盐,可用于催化羰基化合物的不对称催化氢化反应,特别是在简单双烷基酮的不对称氢化反应中表现出很高的收率(>99%)和对映选择性(高达99.8%ee),具有实用价值。
Description
技术领域
本发明属于有机合成技术领域,涉及一类手性螺环膦-氮-膦三齿配体及其铱催化剂的制备方法和应用,具体涉及一类具有螺环骨架的手性膦-氮-膦三齿配体及其铱催化剂的制备方法和在简单双烷基酮不对称催化氢化中的应用。
背景技术
过渡金属不对称催化氢化具有原子经济性高,反应条件温和,催化活性高,对映选择性好等优点,其已经成为获得手性分子最为简单方便和高效的方法之一,并且已经在手性药物分子和手性农药的工业生产中得到了广泛的应用,例如L-多巴,碳青霉素,金朵儿等。正是由于在手性控制领域做出了杰出的贡献,2001年诺贝尔化学奖授予了Konwles,Noyori和Sharpless三位教授,彰显了不对称催化合成领域本身的重要科学意义以及可能对相关领域如医药、农药、化工、材料等产生的深远影响。
在几类不饱和分子中,酮是最容易获得了一类不饱和分子,其不对称催化氢化也受到了科学家们的广泛关注。经过40多年的发展,科学家们发展出多种多样的催化体系实现了官能团化酮和芳基烷基酮的不对称催化氢化,获得了很高的催化效率和对映选择性。其关键就在于催化剂对这两类底物羰基平面的精准识别。在上述羰基底物不对称催化氢化取得巨大成就的同时,对于另一类代表性的羰基底物,即电性和位阻差异均很小的双烷基酮的高对映选择性不对称催化氢化一直是科学家的追求和梦想,但是没有得到很好的实现。如何实现像酶一样对手性的精准控制,高对映选择性不对称催化氢化双烷基酮,例如甲基乙基酮仍然是一个巨大但富有意义的挑战。针对其氢化产物在手性药物和手性农药合成中有着非常重要的用途,设计和发展新型高效的手性配体及催化剂仍然是不对称催化研究领域的难点和挑战,具有非常重要的意义。
最近,我们研究小组基于优势的手性螺环骨架,设计合成了三类结构新颖的三齿配体。第一类是手性螺环吡啶胺基膦三齿配体SpiroPAP(Xie,J.-H.;Liu,X.-Y.;Xie,J.-B.;Wang,L.-X.;Zhou,Q.-L.Angew.Chem.Int.Ed.2011,50,7329-9332),其铱络合物Ir-SpiroPAP在羰基化合物的不对称催化氢化反应中有非常突出的表现,对映选择性高达99%ee,TON可高达450万。该手性螺环吡啶胺基膦三齿配体的铱催化剂Ir-SpiroPAP对β-芳基-β-酮酸酯的不对称催化氢化也非常有效,能给出高达99%ee的映选择性,TON可以高达123万(Xie,J.-H.;Liu,X.-Y.;Yang,X.-H.;Xie,J.-B.;Wang,L.-X.;Zhou,Q.-L.Angew.Chem.Int.Ed.2012,51,201-203)。第二类是手性螺环膦-氮-硫三齿配体SpiroSAP,其铱络合物Ir-SpiroSAP在β-烷基-β-酮酸酯等羰基化合物不对称催化氢化中可以获得优秀的对映选择性(高达99.9%ee)和高达35万的转化数(Bao,D.-H.;Wu,H.-L.;Liu,C.-L.;Xie,J.-H.;Zhou,O.-L.Angew.Chem.Int.Ed.2015,54,8791-8794)。第三类是手性螺环膦-氨基-噁唑林三齿配体SpiroOAP,其铱络合物Ir-SpiroOAP在α-酮酰胺等羰基化合物不对称催化氢化中可以获得优秀的对映选择性(高达98%ee)和高达1万的转化数(Zhang,F.-H.;Wang,C.;Xie,J.-H.;Zhou,Q.-L.Adv.Synth.Catal.2019,361,2832-2835)。
简单双烷基酮,如甲基乙基酮高对映选择性不对称催化氢化的难点在于催化剂对底物羰基平面的手性识别非常困难。实现催化剂对羰基两端结构非常相似的甲基和乙基的精准识别关键在于设计出具有巨大空间位阻的手性催化剂。
发明内容
本发明的目的在于提供一类手性螺环膦-氮-膦三齿配体及其铱催化剂的制备方法和在简单双烷基酮不对称催化氢化中的应用。这类手性螺环三齿配体是基于手性螺环吡啶胺基膦三齿配体的铱催化剂Ir-SpiroPAP,手性螺环膦-氮-硫三齿配体铱催化剂Ir-SpiroSAP和手性螺环膦-氨基-噁唑啉三齿配体的铱催化剂Ir-SpiroOAP在羰基化合物不对称催化氢化中结构与催化活性和对映选择性的关系设计的。在手性螺环胺基膦配体SpiroAP(Xie,J.-B.;Xie,J.-H.;Liu,X.-Y.;Kong,W.-L.;Li,S.;Zhou,Q.-L.J.Am.Chem.Soc.2010,132,4538-4539.周其林,谢建华,谢剑波,王立新CNCN101671365A)上引入新的磷原子使之成为新型膦-氮-膦三齿配体,通过在磷原子引入不同大小的取代基可以非常方便地调节金属中心周围的空间位阻大小,从而显著地提高了催化剂对底物的手性控制,并在简单双烷基酮等羰基化合物不对称催化氢化中获得了优秀的对映选择性(高达99.8%ee)和高达4300的转化数(TON),从而为催化羰基化合物不对称氢化的手性配体及其催化剂提供了一类新产品。
本发明提供的手性螺环膦-氮-膦三齿配体SpiroPNP,是具有式I的化合物或所述化合物的对映体、消旋体,或其催化可接受的盐。
本发明提供的手性螺环膦-氮-膦三齿配体的铱催化剂Ir-SpiroPNP,是具有式II的化合物或所述化合物的对映体、消旋体,或其催化可接受的盐。
其中,R1选自C1~C10的烃基、苯基、取代苯基、1-萘基、2-萘基、杂芳基或苄基,所述的苯基上的取代基为C1~C10的烃基、烷氧基,取代基数量为1~5,杂芳基为呋喃基、噻吩基或吡啶基;
R2、R3、R4、R5分别独立选自H、C1~C10烷基、苯基、取代苯基、1-萘基、2-萘基、杂芳基或苄基,所述的苯基上的取代基为C1~C10的烃基、烷氧基,取代基数量为1~5,杂芳基为呋喃基、噻吩基或吡啶基;或C1~C10烷氧基;或R2~R3、R4~R5并为C3~C7脂肪环、芳香环;R2、R3、R4、R5可以相同也可以不同;
R6、R7分别独立选自H、C1~C10烷基、C1~C10烷氧基、C1~C10脂肪胺基,n=0~3;或当n≥2时,两个相邻的R6、R7可并为C3~C7脂肪环或芳香环,R6、R7可以相同也可以不同;
R8、R9分别独立选自C1~C10烷基、C1~C10烷氧基,苯基、取代苯基、1-萘基、2-萘基、杂芳基或苄基,所述的苯基上的取代基为C1~C10的烃基、烷氧基,取代基数量为1~5,杂芳基为呋喃基、噻吩基或吡啶基;或R8和R9可通过C2~C4的碳链,含氮、氧、硫的碳链、芳香环、或杂芳香环连接成环;R8、R9可以相同也可以不同。
X可以是Cl,Br,OMe,BF4,OTf等常见的阴离子。
本发明提供的手性螺环膦-氮-膦三齿配体SpiroPNP及其铱催化剂Ir-SpiroPNP的制备方法,其特征是以具有手性螺二氢茚骨架的式4所示的消旋或光学活性的7-二芳/烷基膦基-7′-氨基-1,1′-螺二氢茚类化合物为起始原料经过下述反应式制备:
其中,式1、2、3、4、5、I、II中R1~R9的含义与上述一致。具有手性螺二氢茚骨架的式4所示的化合物是按文献方法制备(J.-B.Xie,J.-H.Xie,X.-Y.Liu,W.-L.Kong,S.Li,Q.-L.Zhou,J.Am.Chem.Soc.2010,132,4538;周其林,谢建华,谢剑波,王立新,CN101671365A)。
手性螺环膦-氮-膦三齿配体SpiroPNP及其铱催化剂Ir-SpiroPNP的制备方法描述如下:在有机溶剂,碱和钯催化剂存在的条件下,具有式1所示的化合物先与式2所示的化合物在反应器中反应12~24小时制备得到式3所示的化合物;在有机溶剂和还原剂存在的条件下,式3所示的化合物与式4所示的化合物经还原胺化得到式5所示的化合物;在有机溶剂和还原剂存在的条件下,式5所示的化合物发生还原反应得到式I所示的化合物;式I所示的化合物与各种铱催化剂前体在有机溶剂中络合得到式II所示的化合物。
在上述合成方法中,所述的有机溶剂可为甲醇、乙醇、丙醇、异丙醇、丁醇、四氢呋喃、甲苯、二甲苯、甲基叔丁基醚、乙醚、二氧六环、N,N-二甲基甲酰胺、二甲亚砜、二氯甲烷、氯仿、1,2-二氯乙烷中的一种或其中几种的混合溶剂;所述的还原试剂可为氢化铝锂、硼氢化钠、三乙酰氧基硼氢化钠、腈基硼氢化钠、三氯硅烷,苯硅烷等;所述的碱包括有机碱和无机碱,其中有机碱可为吡啶、三乙胺、三丁胺、N-甲基吗啡啉、N,N-二乙基异丙基胺;无机碱可为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾;钯催化剂可为醋酸钯、钯碳;铱催化剂可为1,5-环辛二烯氯化铱二聚体、二(1,5-环辛二烯)二-M-甲氧基二铱。
本发明所述的手性螺环膦-氮-膦三齿配体及其铱催化剂的应用,是用于催化简单双烷基酮等羰基化合物的不对称催化氢化反应。
作为优先方案,首先使所述的手性螺环膦-氮-膦三齿配体与过渡金属盐形成配合物,然后用于催化简单双烷基酮等羰基化合物的不对称催化氢化反应。
作为优先方案,在惰性气体氛围下,将所述的手性螺环膦-氮-膦三齿配体与过渡金属盐加入有机溶剂中,在70-100℃和0.1-20atm的氢气氛围中搅拌反应10~24小时制备得到手性螺环膦-氮-膦三齿配体与过渡金属盐形成的配合物。
作为更进一步的优先方案,所述的手性螺环膦-氮-膦三齿配体与过渡金属盐的摩尔比为1∶1~2∶1,以1.2∶1~1.8∶1为最佳。
作为更优先方案,所述过渡金属盐为铱的金属盐。所述的铱金属盐为[Ir(COD)Cl]2(COD=环辛二烯)、[Ir(COD)2]BF4、[Ir(COD)2]PF6、[Ir(COD)2]SbF6或[Ir(COD)2]OTf。
作为更进一步优先方案,所述有机溶剂为甲醇、乙醇、丙醇、异丙醇、丁醇、四氢呋喃、甲苯、甲基叔丁基醚、1,4-二氧六环、N,N-二甲基甲酰胺、二甲亚砜中的一种或其中几种的混合溶剂。
作为进一步优先方案,向制备所得到的配合物溶液中加入羰基化合物和碱,在0.1-100atm的氢气氛围和0-80℃条件下进行氢化反应;所述的羰基化合物与所述配合物的摩尔比为100∶1~500000∶1。底物浓度为0.001~10.0M,碱浓度为0.005M~1.0M;所述的碱为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、乙醇钠、乙醇钾、叔丁醇钠、叔丁醇钾、叔丁醇锂、三乙胺、三丁胺或N-甲基吗啉。
作为进一步优化方案,所述的手性螺环膦-氮-膦三齿配体选自如下化合物或所述化合物的对映体、消旋体或其催化可接受的盐:
作为进一步优化方案,所述的手性螺环膦-氮-膦三齿配体铱催化剂选自如下化合物或所述化合物的对映体、消旋体或其催化可接受的盐:
本发明提供的手性螺环膦-氮-膦三齿配体,主要结构特征是具有手性螺二氢茚骨架和具有大位阻取代基的膦配体,可作为手性配体用于铱催化简单双烷基酮等羰基化合物的不对称催化氢化反应中,即其铱催化剂在催化简单双烷基酮的不对称氢化反应中取得了很高的收率(>99%)和对映选择性(高达99.8%ee)。与现有技术相比,本发明具有如下显著的效果:
1)本发明提供的手性螺环膦-氮-膦三齿配体与过渡金属盐形成配合物后用于简单双烷基酮等羰基化合物的不对称氢化反应具有优异的对映选择性和较高催化活性。
2)本发明提供的手性螺环膦-氮-膦三齿配体及其铱催化剂的制备方法简单,特别适用于羰基化合物的不对称催化氢化,反应条件温和,效率高、适于规模化生产,具有实用价值。
3)本发明提供了多种具有重要生物活性的手性双烷基醇,这些手性双烷基醇广泛用于药物分子的工业合成中,具有重大的实用价值。
具体实施方式
下面结合实施例对本发明作进一步详细、完整的说明,列出的实施将有助于理解本发明,但不能限制本发明的内容。
实施例1:
配体Ia的合成路线:
在氩气氛围中,称取(R)-7′-二-(3,5-二叔丁基苯基)膦基-7′-氨基-1,1′-螺二氢茚4a(300mg,0.46mmol)于100mL干燥的Schlenk管中,注射器打入12mL无水甲醇,搅拌溶解。加入2-二苯基膦苯甲醛(176mg,0.61mmol)和冰醋酸(42μL)。室温搅拌反应3小时。打开反口塞,一次性倒入NaBH3CN(87mg,1.38mmol),反应在40度下反应15小时。反应结束后冷却至室温,体系旋干,加入二氯甲烷溶解,饱和碳酸氢钠溶液淬灭。二氯甲烷萃取,合并有机相,有机相用无水硫酸镁干燥,抽滤除去干燥剂,滤液用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚∶乙酸乙酯=30∶1)得到白色固体Ia 342mg,收率为80%。
Ia的数据:
1H
NMR(400MHz,CDCl3)
δ7.37-7.25(m,6H),7.25-7.22(m,3H),7.22-7.14(m,5H),7.11(dd,J=7.0,4.1Hz,1H),7.08-6.98(m,3H),6.94-6.82(m,3H),6.82-6.73(m,3H),6.63(d,J=7.3Hz,1H),6.06(d,J=7.9Hz,1H),4.32-4.15(m,1H),3.80(dd,J=15.8,5.4Hz,1H),3.66(t,J=5.3Hz,1H),3.14-2.78(m,3H),2.69(dd,J=15.6,9.1Hz,1H),2.38(dd,J=21.2,11.7Hz,1H),2.18-1.85(m,3H),1.16(s,18H),1.10(s,18H).
13C
NMR(101MHz,CDCl3)
δ152.28(d,J=24.3Hz),149.82(dd,J=6.3,1.7Hz),144.15(t,J=3.1Hz),143.97(d,J=7.1Hz),143.67(d,J=22.6Hz),137.76(d,J=11.6Hz),136.50(dd,J=11.1,3.0Hz),136.24(d,J=13.2Hz),135.27(d,J=23.7Hz),134.60(d,J=15.3Hz),133.81(dd,J=19.8,9.4Hz),133.41(d,J=1.8Hz),133.20(s),131.88(d,J=3.3Hz),129.02(s),128.70(s),128.63-128.36(m),128.28(d,J=10.2Hz),128.13(s),127.93(s),126.74(d,J=23.6Hz),126.35(d,J=5.2Hz),125.69(s),121.74(d,J=41.3Hz),113.60(s),108.52(s),61.57(d,J=3.3Hz),45.28(d,J=27.1Hz),38.31(d,J=3.3Hz),36.20(s),34.69(s),31.33(d,J=4.7Hz).
31P
NMR(162MHz,CDCl3)
δ-16.84(s),-17.93(s).
HR-MS(MALDI)
Calcd for C64H73NP2[M+H]+:918.5291;Found:918.5295.
实施例2:
配体Ib的合成路线:
中间体3a的合成:
在25mL Schlenk管中称取Pd(OAc)2(56mg),dppp(103mg),2a(310mg),置换成氩气,打入脱气后的DMSO(4.0mL),搅拌均匀,打入邻溴苯甲醛(118μL)和二异丙基乙胺(248μL),油浴加热反应至100度反应20小时。反应结束后冷却至室温,加入10mL乙酸乙酯和10mL水,乙酸乙酯萃取,合并有机相,有机相用无水硫酸镁干燥,抽滤除去干燥剂,滤液用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚∶乙酸乙酯=5∶1)得到白色固体3a 242mg,收率为66%。
中间体3a的数据:
白色固体,熔点202-204℃.
1H
NMR(400MHz,CDCl3)
δ10.74(s,1H),8.15(dd,J=7.3,3.1Hz,1H),7.67(t,J=7.5Hz,1H),7.55(ddd,J=7.5,5.9,1.7Hz,1H),7.32-7.16(m,7H),2.33(s,12H).
13C
NMR(101MHz,CDCl3)
δ191.49(d,J=5.8Hz),139.45(d,J=6.5Hz),138.49(d,J=13.1Hz),135.73(d,J=94.8Hz),134.07(d,J=2.8Hz),133.63(d,J=11.1Hz),132.85-132.40(m),132.10(d,J=2.3Hz),131.56(s),129.38(d,J=9.9Hz),128.69(d,J=8.8Hz),21.28(s).
31P
NMR(162MHz,CDCl3)
δ31.46.
HR-MS(MALDI)
Calcd for C23H23O2P[M+H]+:363.1508;Found:363.1512.
中间体5a的合成:
在氩气氛围中,称取(R)-7′-二-(3,5-二叔丁基苯基)膦基-7′-氨基-1,1′-螺二氢茚4a(273mg,0.42mmol)于100mL干燥的Schlenk管中,注射器打入12mL无水甲醇,搅拌溶解。加入3a(200mg,0.55mmol)和冰醋酸(32μL,0.55mmol)。室温搅拌反应3小时。打开反口塞,一次性倒入NaBH3CN(160mg,2.52mmol),反应在40度下反应15小时。反应结束后冷却至室温,体系旋干,加入二氯甲烷溶解,饱和碳酸氢钠溶液淬灭。二氯甲烷萃取,合并有机相,有机相用无水硫酸镁干燥,抽滤除去干燥剂,滤液用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚∶乙酸乙酯=3∶1)得到白色固体5a 398mg,收率为95%。
中间体5a的数据:
1H
NMR(400MHz,CDCl3)
δ7.38-7.23(m,8H),7.21-7.06(m,7H),7.02(t,J=7.7Hz,1H),6.96(dd,J=8.0,1.8Hz,2H),6.86(dd,J=7.3,1.7Hz,2H),6.61(d,J=7.4Hz,1H),5.87(d,J=7.9Hz,1H),4.67(dd,J=17.0,5.9Hz,1H),4.12(dd,J=17.5,5.8Hz,1H),3.74(t,J=5.6Hz,1H),3.16-2.88(m,2H),2.87-2.73(m,1H),2.52(dd,J=15.6,9.3Hz,1H),2.41-2.24(m,13H),2.03(dd,J=12.8,7.2Hz,1H),1.94(dd,J=13.1,8.5Hz,1H),1.71(dd,J=22.6,9.9Hz,1H),1.24(s,18H),1.12(s,18H).
13C
NMR(101MHz,CDCl3)
δ151.70(d,J=24.0Hz),149.96(d,J=7.0Hz),149.70(d,J=5.3Hz),144.59(d,J=4.2Hz),144.19(d,J=1.7Hz),143.82(d,J=6.7Hz),138.10(dd,J=12.4,10.8Hz),137.18-136.64(m),135.38(d,J=24.1Hz),133.64(dd,J=4.9,2.6Hz),133.37(d,J=12.1Hz),133.02(d,J=12.4Hz),132.54(s),132.00(d,J=11.9Hz),131.11(d,J=2.5Hz),129.91(s),129.39(dd,J=15.2,9.8Hz),129.12(s),128.90(s),127.93(d,J=34.0Hz),127.68-127.26(m),126.85(s),125.70(s),125.60(s),121.78(d,J=53.7Hz),113.39(s),108.13(s),61.53(d,J=2.8Hz),45.82(d,J=4.6Hz),37.47(s),36.53(s),34.67(d,J=7.4Hz),31.29(d,J=3.6Hz),30.78(d,J=40.6Hz),21.29(d,J=2.8Hz).
31P
NMR(162MHz,CDCl3)
δ32.16,-15.24.
HR-MS(MALDI)
Calcd for C68H81NOP2[M+H]+:990.5866;Found:990.5869.
配体Ib的合成:
将5a(348mg,0.35mmol)称入100mL封管中,置换成氩气,打入甲苯(15mL)和二异丙基乙胺(581μL,3.5mmol),在0度下将三氯硅烷(354μL)缓慢滴加至反应体系中,滴毕将反应放入120度油浴中反应24小时。反应结束后,在0度下用12N氢氧化钠溶液淬灭反应,乙酸乙酯萃取,合并有机相,有机相用无水硫酸镁干燥,抽滤除去干燥剂,滤液用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚∶乙酸乙酯=30∶1)得到白色固体Ib 130mg,收率为37%。
Ib的数据:
1H
NMR(400MHz,CDCl3)
δ7.25-7.22(m,3H),7.18(t,J=7.4Hz,1H),7.13-7.06(m,1H),7.03(t,J=7.7Hz,3H),6.94(s,3H),6.87(d,J=7.7Hz,2H),6.80(t,J=6.1Hz,7H),6.62(d,J=7.4Hz,1H),6.06(d,J=7.9Hz,1H),4.20(d,J=15.7Hz,1H),3.88(dd,J=16.0,5.4Hz,1H),3.71(t,J=5.2Hz,1H),2.95(ddt,J=32.3,17.4,12.8Hz,3H),2.68(dd,J=15.6,9.2Hz,1H),2.49-2.33(m,1H),2.24(s,12H),2.17-2.03(m,2H),1.96(dd,J=22.2,10.0Hz,1H),1.17(s,18H),1.11(s,18H).
13C
NMR(101MHz,CDCl3)
δ152.25(d,J=24.3Hz),149.82(t,J=5.8Hz),144.23(d,J=3.6Hz),144.14(d,J=2.5Hz),143.94(d,J=7.0Hz),143.65(d,J=22.4Hz),137.92-137.53(m),136.45(s),136.31(s),136.21(d,J=2.3Hz),136.12(s),135.40(s),135.11(d,J=10.6Hz),134.91(s),133.37(s),133.27(s),131.74(d,J=3.3Hz),131.62(d,J=4.8Hz),131.42(d,J=4.9Hz),130.45(d,J=14.4Hz),128.60(d,J=36.4Hz),128.21(s),127.95(d,J=20.8Hz),126.67(d,J=36.3Hz),126.17(d,J=5.2Hz),125.66(s),121.71(d,J=27.1Hz),113.45(s),108.52(s),61.61(d,J=3.3Hz),45.35(d,J=26.8Hz),38.29(s),36.21(s),34.69(d,J=2.2Hz),31.33(d,J=3.2Hz),30.90(d,J=38.2Hz),21.30(s).
31P
NMR(162MHz,CDCl3)
δ-16.76,-17.76.
HR-MS(MALDI)
Calcd for C68H81NP2[M+H]+:974.5917;Found:974.5922.
实施例3:
配体Ic的合成路线:
中间体3b的合成:
在25mL Schlenk管中称取Pd(OAc)2(112mg),dppp(206mg),2b(1026mg),置换成氩气,打入脱气后的DMSO(8.0mL),搅拌均匀,打入邻溴苯甲醛(234μL)和二异丙基乙胺(496μL),油浴加热反应至100度反应20小时。反应结束后冷却至室温,加入20mL乙酸乙酯和20mL水,乙酸乙酯萃取,合并有机相,有机相用无水硫酸镁干燥,抽滤除去干燥剂,滤液用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚∶乙酸乙酯=5∶1)得到白色固体3b 752mg,收率为71%。
中间体3b的数据:
白色固体,熔点58-60℃.
1H
NMR(400MHz,CDCl3)
δ10.79(s,1H),8.15(dd,J=7.5,3.2Hz,1H),7.66(t,J=7.6Hz,1H),7.61(s,2H),7.55(t,J=7.4Hz,1H),7.45(d,J=13.0Hz,4H),7.29-7.20(m,1H),1.26(s,36H).
13C
NMR(101MHz,CDCl3)
δ191.52(d,J=5.5Hz),151.22(d,J=12.0Hz),139.45(d,J=6.4Hz),136.32(d,J=94.0Hz),133.41(d,J=10.7Hz),132.44(d,J=11.7Hz),131.92(d,J=3.2Hz),130.90(s),128.41(d,J=8.8Hz),126.15(d,J=2.6Hz),126.02(d,J=10.7Hz),34.93(s),31.15(s).
31P
NMR(162MHz,CDCl3)
δ32.83.
HR-MS(MALDI)
Calcd for C35H47O2P[M+H]+:531.3386;Found:531.3390.
中间体5b的合成:
在氩气氛围中,称取(R)-7′-二-(3,5-二叔丁基苯基)膦基-7′-氨基-1,1′-螺二氢茚4a(550mg,0.86mmol)于100mL干燥的Schlenk管中,注射器打入12mL无水甲醇,搅拌溶解。加入3b(601mg,1.13mmol)和冰醋酸(64μL,1.13mmol)。室温搅拌反应3小时。打开反口塞,一次性倒入NaBH3CN(323mg,5.16mmol),反应在40度下反应15小时。反应结束后冷却至室温,体系旋干,加入二氯甲烷溶解,饱和碳酸氢钠溶液淬灭。二氯甲烷萃取,合并有机相,有机相用无水硫酸镁干燥,抽滤除去干燥剂,滤液用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚∶乙酸乙酯=3∶1)得到白色固体5b 980mg,收率为99%。
中间体5b的数据:
1H
NMR(400MHz,CDCl3)
δ7.57(s,2H),7.40(t,J=12.0Hz,5H),7.31(s,1H),7.26-6.98(m,7H),6.93(t,J=9.2Hz,3H),6.81(d,J=6.8Hz,2H),6.54(d,J=7.1Hz,1H),5.83(d,J=7.7Hz,1H),4.86(d,J=13.2Hz,1H),4.20(d,J=16.6Hz,1H),3.78(s,1H),2.94(p,J=16.1Hz,2H),2.80-2.57(m,1H),2.33(dt,J=21.1,10.0Hz,2H),1.96(d,J=17.4Hz,1H),1.83(t,J=10.5Hz,1H),1.55(q,J=10.3Hz,1H),1.25(s,36H),1.20(s,18H),1.08(s,18H)
13C
NMR(101MHz,CDCl3)
δ151.34(d,J=23.7Hz),150.87(dd,J=18.0,11.9Hz),149.98(d,J=7.5Hz),149.69(d,J=5.2Hz),144.96(d,J=3.9Hz),144.78(d,J=7.6Hz),144.23(s),143.84(d,J=6.4Hz),137.12(d,J=14.2Hz),136.71(d,J=11.2Hz),135.41(d,J=24.1Hz),133.39(d,J=11.9Hz),132.52(s),132.47(s),132.14(s),131.47(d,J=5.3Hz),130.77(d,J=2.4Hz),130.05(s),129.31(d,J=22.2Hz),129.06(s),128.04(s),127.66(d,J=18.8Hz),127.37(dd,J=9.5,5.7Hz),126.83(s),126.25(d,J=10.5Hz),125.93(s),125.83(s),125.75(s),125.52(s),125.37(d,J=12.5Hz),122.17(s),121.34(s),113.30(s),107.93(s),61.50(d,J=2.8Hz),45.99(d,J=4.6Hz),37.01(s),36.67(s),34.95(s),34.68(d,J=6.2Hz),31.30(d,J=1.2Hz),30.76(d,J=38.9Hz).
31P
NMR(162MHz,CDCl3)
δ34.68,-13.84.
HR-MS(MALDI)
Calcd for C80H105NOP2[M+H]+:1158.7744;Found:1158.7748.
配体Ic的合成:
将5b(880mg,0.76mmol)称入100mL封管中,置换成氩气,打入甲苯(25mL)和二异丙基乙胺(1.3mL,7.6mmol),在0度下将三氯硅烷(775μL)缓慢滴加至反应体系中,滴毕将反应放入120度油浴中反应24小时。反应结束后,在0度下用12N氢氧化钠溶液淬灭反应,乙酸乙酯萃取,合并有机相,有机相用无水硫酸镁干燥,抽滤除去干燥剂,滤液用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚∶乙酸乙酯=30∶1)得到白色固体Ic 340mg,收率为39%。
Ic的数据:
1H
NMR(400MHz,CDCl3)
δ7.40(d,J=1.8Hz,2H),7.32-7.26(m,2H),7.23(t,J=7.5Hz,1H),7.15-7.03(m,10H),6.94(dd,J=7.8,1.7Hz,2H),6.86(dd,J=7.7,1.7Hz,2H),6.80(dd,J=6.6,4.0Hz,1H),6.66(d,J=7.3Hz,1H),6.08(d,J=7.9Hz,1H),4.20(dd,J=16.3,4.3Hz,1H),4.06(dd,J=16.3,5.3Hz,1·H),3.82(t,J=5.5Hz,1H),3.17-2.86(m,3H),2.75(dd,J=15.7,9.0Hz,1H),2.48(dd,J=21.2,11.3Hz,1H),2.16-2.00(m,3H),1.27(s,36H),1.22(s,18H),1.17(s,18H).
13C
NMR(101MHz,CDCl3)
δ152.23(d,J=24.3Hz),150.50-150.30(m),149.83(dd,J=6.2,4.2Hz),144.34(d,J=3.5Hz),144.13(d,J=2.5Hz),143.95(d,J=7.0Hz),143.56(d,J=22.2Hz),137.80(d,J=11.9Hz),136.36(d,J=13.1Hz),135.94(s),135.82(d,J=3.8Hz),135.61(d,J=6.3Hz),135.42(d,J=11.8Hz),135.13(s),133.37(s),133.16(s),131.81(d,J=3.2Hz),128.54(d,J=23.5Hz),128.21(s),127.94(dd,J=20.0,7.1Hz),126.88(s),126.29(s),125.96(d,J=5.3Hz),125.65(s),122.34(d,J=20.4Hz),121.70(d,J=31.3Hz),113.36(s),108.43(s),61.64(d,J=3.1Hz),45.51(d,J=26.4Hz),38.34(d,J=3.2Hz),36.23(s),34.77(d,J=9.9Hz),31.37(t,J=4.3Hz),30.93(d,J=36.6Hz).
31P
NMR(162MHz,CDCl3)
δ-14.66,-17.59.
HR-MS(MALDI)
Calcd for C80H105NP2[M+H]+:1142.7795;Found:1142.7798.
实施例4:
配体Id的合成路线:
中间体5c的合成:
在氩气氛围中,称取(R)-7′-(二苯基膦基)-2,2′,3,3′-四氢-1,1′-螺双[茚]-7-胺4b(182mg,0.43mmol)于100mL干燥的Schlenk管中,注射器打入20mL无水甲醇,搅拌溶解。加入3b(300mg,0.57mmol)和冰醋酸(33μL,0.57mmol)。40度搅拌反应3小时。打开反口塞,一次性倒入NaBH3CN(165mg,2.58mmol),反应在40度下反应12小时。反应结束后冷却至室温,体系旋干,加入二氯甲烷溶解,饱和碳酸氢钠溶液淬灭。二氯甲烷萃取,合并有机相,有机相用无水硫酸镁干燥,抽滤除去干燥剂,滤液用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚∶乙酸乙酯=3∶1)得到白色固体5c 399mg,收率为98%。
中间体5c的数据:
1H
NMR(400MHz,CDCl3)
δ7.65(s,1H),7.57(s,1H),7.41(d,J=12.9Hz,2H),7.33(d,J=12.8Hz,2H),7.26(s,1H),7.24(s,1H),7.21(d,J=6.5Hz,4H),7.13(t,J=7.5Hz,1H),7.05-6.95(m,8H),6.87(dt,J=14.8,7.5Hz,2H),6.73(t,J=7.7Hz,1H),6.56(d,J=7.3Hz,1H),5.40(d,J=7.9Hz,1H),4.33(dd,J=18.3,6.2Hz,1H),4.19(dd,J=18.3,4.4Hz,1H),3.51(t,J=5.4Hz,1H),3.15-2.76(m,4H),2.40(dd,J=22.0,10.8Hz,1H),2.29-2.08(m,3H),1.26(d,J=10.5Hz,36H).
13C
NMR(101MHz,CDCl3)
δ152.23(d,J=24.9Hz),150.82(dd,J=21.3,11.8Hz),144.76(d,J=7.5Hz),143.87(d,J=2.5Hz),143.72(d,J=7.4Hz),143.53(d,J=2.5Hz),138.33(d,J=13.8Hz),136.17(d,J=13.0Hz),134.02(d,J=22.4Hz),133.73(s),133.57(s),133.38(s),133.18(s),133.06(s),132.47(s),132.13(s),131.92(d,J=3.4Hz),131.81(s),131.28(d,J=33.7Hz),129.66(s),128.67(s),127.86(d,J=6.1Hz),127.78(s),127.72(s),127.33(s),126.80(d,J=9.6Hz),125.96(dd,J=10.4,4.6Hz),125.78(s),125.53(d,J=12.3Hz),125.27(d,J=12.5Hz),113.10(s),107.66(s),61.32(d,J=3.3Hz),45.49(d,J=4.3Hz),38.80(d,J=4.8Hz),36.29(s),34.79(d,J=5.9Hz),31.12(d,J=5.2Hz).
31P
NMR(162MHz,CDCl3)
δ35.57,-20.90.
HR-MS(MALDI)
Calcd for C64H73NOP2[M+H]+:934.5240;Found:934.5245.
配体Id的合成:
将5c(452mg,0.48mmol)称入100mL封管中,置换成氩气,打入甲苯(20mL)和苯硅烷(239μL,1.94mmol),室温将CF3SO2H(6.4μL)滴加至反应体系中,滴毕将反应放入120度油浴中反应24小时。反应结束后,用三乙胺淬灭反应,乙酸乙酯萃取,合并有机相,有机相用无水硫酸镁干燥,抽滤除去干燥剂,滤液用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚∶乙酸乙酯=30∶1)得到白色固体Id 228mg,收率为51%。
配体Id的数据:
1H
NMR(400MHz,CDCl3)
δ7.53(s,1H),7.48(s,1H),7.34(d,J=7.4Hz,1H),7.25(d,J=3.5Hz,2H),7.23-7.00(m,16H),7.00-6.88(m,2H),6.86-6.78(m,1H),6.71(d,J=7.3Hz,1H),5.77(d,J=8.0Hz,1H),3.97(dd,J=17.0,5.1Hz,1H),3.87(dd,J=16.9,4.2Hz,1H),3.54(t,J=5.4Hz,1H),3.23-3.01(m,4H),2.70-2.48(m,2H),2.39(td,J=11.6,5.7Hz,1H),2.26(dd,J=12.7,7.2Hz,1H),1.33(d,J=12.6Hz,36H)
13C
NMR(101MHz,CDCl3)
δ153.07(d,J=24.9Hz),150.68(d,J=6.8Hz),150.53(d,J=6.8Hz),144.12(s),144.09(s),144.02(s),143.58(d,J=2.2Hz),143.12(d,J=21.1Hz),139.33(d,J=13.7Hz),135.84(d,J=13.0Hz),135.35(s),135.26(s),135.10(d,J=2.2Hz),135.00(s),134.42-134.21(m),134.06(s),133.84(d,J=21.3Hz),133.11(d,J=19.0Hz),132.60(s),132.56(s),128.43(d,J=10.3Hz),128.26(s),128.16(d,J=1.8Hz),128.00(s),127.94(s),127.88(s),127.78(d,J=4.9Hz),127.52(d,J=14.8Hz),126.29(s),125.93(s),125.51(d,J=5.0Hz),122.47(d,J=9.6Hz),113.33(s),108.31(s),61.56(d,J=3.3Hz),45.23(d,J=27.3Hz),39.49(d,J=5.7Hz),36.31(s),34.84(d,J=4.7Hz),31.37(d,J=4.7Hz),30.91(s).
31P
NMR(162MHz,CDCl3)
δ-13.71,-22.22.
HR-MS(MALDI)
Calcd for C64H73NP2[M+H]+:918.5291;Found:918.5295.
实施例5:
配体Ie的合成路线:
中间体5d的合成:
在氩气氛围中,称取(R)-7-(双(3,5-二甲基苯基)膦基)-2,2”,3,3′-四氢-1,1′-螺双[茚]-7-胺4c(300mg,0.63mmol)于100mL干燥的Schlenk管中,注射器打入30mL无水甲醇,搅拌溶解。加入3b(435mg,0.82mmol)和冰醋酸(47μL,0.82mmol)。40度搅拌反应3小时。打开反口塞,一次性倒入NaBH3CN(239mg,3.78mmol),反应在40度下反应12小时。反应结束后冷却至室温,体系旋干,加入二氯甲烷溶解,饱和碳酸氢钠溶液淬灭。二氯甲烷萃取,合并有机相,有机相用无水硫酸镁干燥,抽滤除去干燥剂,滤液用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚∶乙酸乙酯=3∶1)得到白色固体5d 545mg,收率为87%。
中间体5d的数据:
1H
NMR(400MHz,CDCl3)
δ7.64(s,1H),7.56(s,1H),7.40(s,1H),7.37(s,1H),7.33(s,1H),7.30(s,1H),7.26(s,1H),7.24-7.11(m,3H),7.11-7.00(m,2H),6.87(ddd,J=21.4,14.7,7.6Hz,3H),6.69(d,J=7.5Hz,2H),6.59(t,J=6.3Hz,4H),5.55(d,J=7.9Hz,1H),4.34(dd,J=18.0,4.8Hz,1H),4.14(dd,J=17.8,5.7Hz,1H),3.47(t,J=5.4Hz,1H),3.07-2.74(m,4H),2.36(dd,J=22.0,10.5Hz,1H),2.19(s,6H),2.15-2.07(m,3H),2.05(s,6H),1.26(d,J=15.0Hz,36H).
13C
NMR(101MHz,CDCl3)
δ151.95(d,J=24.3Hz),150.83(dd,J=11.2,7.4Hz),144.76(d,J=7.1Hz),144.08(d,J=19.3Hz),143.66(d,J=7.0Hz),137.87(d,J=12.6Hz),137.09(d,J=6.8Hz),136.89(d,J=6.9Hz),135.76(d,J=12.2Hz),135.11(d,J=22.9Hz),133.35(d,J=12.2Hz),133.19(s),132.64(s),132.21(s),132.02(s),131.74(s),131.56(s),131.37(s),131.19(s),129.70(d,J=14.8Hz),129.51(s),128.52(s),127.63(s),127.19(s),127.06(d,J=9.6Hz),126.14(s),125.99(d,J=8.6Hz),125.82(d,J=3.8Hz),125.59(d,J=7.4Hz),125.27(d,J=12.3Hz),113.04(s),107.73(s),61.43(s),45.04(s),38.47(s),36.48(s),34.87(d,J=7.2Hz),31.19(d,J=6.1Hz),30.67(s),21.16(s).
31P
NMR(162MHz,CDCl3)
δ35.62,-20.12.
HR-MS(MALDI)
Calcd for C68H81NOP2[M+H]+:990.5866;Found:990.5868.
配体Ie的合成:
将5d(376mg,0.38mmol)称入100mL封管中,置换成氩气,打入甲苯(20mL)和苯硅烷(188μL,1.52mmol),室温将CF3SO2H(5.1μL)滴加至反应体系中,滴毕将反应放入120度油浴中反应24小时。反应结束后,用三乙胺淬灭反应,乙酸乙酯萃取,合并有机相,有机相用无水硫酸镁干燥,抽滤除去干燥剂,滤液用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚∶乙酸乙酯=30∶1)得到白色固体Id 145mg,收率为39%。
配体Ie的数据:
1H
NMR(400MHz,CDCl3)
δ7.40(s,1H),7.34(s,1H),7.17(t,J=7.4Hz,1H),7.13-6.85(m,10H),6.82(s,1H),6.68(dd,J=12.9,7.1Hz,2H),6.61(d,J=8.5Hz,5H),5.70(d,J=7.9Hz,1H),3.86-3.69(m,2H),3.36(t,J=5.3Hz,1H),3.11-2.90(m,4H),2.47(td,J=20.3,10.7Hz,2H),2.35-2.21(m,1H),2.20-2.09(m,7H),2.04(s,6H),1.24(s,18H),1.20(s,18H).
13C
NMR(101MHz,CDCl3)
δ152.87(d,J=24.8Hz),150.50(dd,J=10.2,6.6Hz),144.20(d,J=2.2Hz),143.89(d,J=7.7Hz),143.79(s),143.38(d,J=21.8Hz),139.12(d,J=13.0Hz),137.15(d,J=5.9Hz),136.99(d,J=8.0Hz),135.76(d,J=9.3Hz),135.34(d,J=3.4Hz),135.27(s),135.21(s),135.07(d,J=6.6Hz),134.95(s),134.11(s),132.90(s),132.80(d,J=3.0Hz),132.10(d,J=22.0Hz),130.83(d,J=19.2Hz),130.41(s),129.37(s),128.59(s),128.07(d,J=19.9Hz),127.81(d,J=5.3Hz),127.48(d,J=33.4Hz),126.24(s),125.71(s),125.51(d,J=4.8Hz),122.41(d,J=19.0Hz),113.30(s),108.37(s),61.65(d,J=2.8Hz),44.79(d,J=27.8Hz),39.41(d,J=5.4Hz),36.28(s),34.83(d,J=5.2Hz),31.37(d,J=5.7Hz),30.90(s),21.27(s).
31P
NMR(162MHz,CDCl3)
δ-14.57,-22.31.
HR-MS(MALDI)
Calcd for C68H81NP2[M+H]+:974.5917;Found:974.5922.
实施例6:
配体Ij的合成路线:
中间体6的合成:
将4-溴苯酚(6.9g,40.0mmol)和1-金刚烷醇(15.2g,100mmol)称入350mL封管中,打入冰醋酸(40mL)和浓硫酸(4.0mL)。反应在120度油浴中反应5小时。在反应过程中产物6析出。反应结束后,冷却至室温,用乙醇洗析出的固体,得到的固体用大过量的二氯甲烷溶解,柱层析得到白色固体63.0g,收率为10%。
中间体6的数据:
1H
NMR(400MHz,CDCl3)
δ1.81(m,12H),2.13(m,18H),5.35(s,1H),7.23(s,2H).
中间体7的合成:
100mL干燥的三口烧瓶中加入NaH(66mg,2.75mmol)和无水DMSO(5mL),用冰水浴将体系降至0度,剧烈搅拌防止DMSO凝固。化合物6(500mg,1.13mmol)用40mL DMSO溶解,滴加到反应体系中,滴完在0度搅拌5分钟。碘甲烷(283μL,4.52mmol)滴加至体系中,继续搅拌反应15分钟。随后将反应升至室温搅拌2小时。反应结束后冰水淬灭反应,二氯甲烷萃取,有机相合并,无水硫酸镁干燥,抽滤除去干燥剂,滤液用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚)得到白色固体7446mg,收率为86%。
中间体7的数据:
白色固体,熔点为224-226℃.
1H
NMR(400MHz,CDCl3)
δ7.30(s,2H),3.65(s,3H),2.08(s,18H),1.76(s,12H).
13C
NMR(101MHz,CDCl3)
δ159.64,146.00,129.23,116.81,65.95,42.50,38.73,36.78,29.17.
HR-MS(EI)
Calcd for C27H35BrO[M]:454.1871;Found:454.1866.
中间体2c的合成:
在氩气氛围中,称取7(500mg,1.10mmol)于50mL干燥的Schlenk管中,注射器打入10mL无水四氢呋喃,搅拌溶解,丙酮液氮浴将体系降至-90度。滴加正丁基锂溶液(571μL,1.43mmol),滴加完后搅拌反应2小时。二乙基二氯膦(80μL,0.55mmol)滴加至反应体系中,滴完继续在-90度搅拌反应2小时,随后自然升至室温搅拌过夜。将反应体系降至-78度,滴加盐酸溶液(4.0mL,4.0M in dioxane),滴完升至室温搅拌反应4小时。反应结束后加入水淬灭反应。乙酸乙酯萃取,合并有机相,有机相用无水硫酸镁干燥,抽滤除去干燥剂,滤液用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚∶乙酸乙酯=3∶1)得到白色固体2c248mg,收率为56%。
中间体2c的数据:
白色固体,熔点>250℃.
1H
NMR(400MHz,CDCl3)
δ8.63(s,0.5H),7.55(s,2H),7.51(s,2H),7.45(s,0.5H),3.67(s,6H),2.10-2.02(m,36H),1.74(s,24H).
13C
NMR(101MHz,CDCl3)
δ164.14(d,J=3.1Hz),144.57(d,J=12.7Hz),129.06(d,J=13.1Hz),124.75(d,J=105.1Hz),66.02(s),61.67(s),44.88(s),42.50(s),38.73(s),36.70(s),29.06(s).
31P
NMR(162MHz,CDCl3)
δ22.71.
HR-MS(MALDI)
Calcd for C54H71O3P[M+H]+:799.5214;Found:799.5218.
中间体3c的合成:
在50mL Schlenk管中称取Pd(OAc)2(24mg),dppp(43mg),2c(395mg),置换成氩气,打入脱气后的DMSO(10.0mL),搅拌均匀,打入邻溴苯甲醛(48μL)和二异丙基乙胺(104μL),油浴加热反应至100度反应20小时。反应结束后冷却至室温,加入20mL乙酸乙酯和20mL水,乙酸乙酯萃取,合并有机相,有机相用无水硫酸镁干燥,抽滤除去干燥剂,滤液用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚∶乙酸乙酯=5∶1)得到白色固体3c 752mg,收率为62%。
中间体3c的数据:
白色固体,熔点198-200℃.
1H
NMR(400MHz,CDCl3)
δ10.81(s,1H),8.16(d,J=7.2Hz,1H),7.68(t,J=7.3Hz,1H),7.59(t,J=7.4Hz,1H),7.43(d,J=13.0Hz,4H),7.30-7.24(m,1H),3.69(s,6H),2.01(s,36H),1.71(s,24H).
13C NMR(101MHz,CDCl3)
δ190.44(d,J=5.5Hz),162.76(d,J=3.3Hz),143.23(d,J=12.4Hz),138.20(d,J=6.5Hz),134.95(d,J=94.4Hz),132.31(d,J=10.7Hz),131.35(d,J=11.7Hz),130.76(d,J=1.6Hz),128.99(d,J=11.9Hz),127.25(d,J=8.7Hz),124.42(d,J=109.3Hz),64.80(s),41.21(s),37.49(s),35.44(s),27.81(s).
31P
NMR(162MHz,CDCl3)
δ33.33.
HR-MS(MALDI)
Calcd for C61H75O4P[M+H]+:903.5476;Found:903.5478.
中间体5e的合成:
在氩气氛围中,称取(R)-7′-二-(3,5-二叔丁基苯基)膦基-7′-氨基-1,1′-螺二氢茚4a(199mg,0.31mmol)于100mL干燥的Schlenk管中,注射器打入15mL无水甲醇,搅拌溶解。加入3c(420mg,0.47mmol)和冰醋酸(70μL,1.24mmol)。80度搅拌反应5小时。打开反口塞,一次性倒入NaBH3CN(117mg,1.86mmol),反应在80度下反应13小时。反应结束后冷却至室温,体系旋干,加入二氯甲烷溶解,饱和碳酸氢钠溶液淬灭。二氯甲烷萃取,合并有机相,有机相用无水硫酸镁干燥,抽滤除去干燥剂,滤液用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚∶乙酸乙酯=3∶1)得到白色固体5e 465mg,收率为98%。
中间体5e的数据:
1H
NMR(400MHz,CDCl3)
δ7.44-7.38(m,5H),7.27-6.87(m,11H),6.78(d,J=6.9Hz,2H),6.54(d,J=7.3Hz,1H),5.79(d,J=7.9Hz,1H),4.89(dd,J=17.5,5.5Hz,1H),4.29(dd,J=17.3,4.5Hz,1H),3.85(t,J=5.3Hz,1H),3.67(d,J=9.5Hz,6H),3.04-2.84(m,2H),2.81-2.63(m,1H),2.35(dt,J=30.7,10.4Hz,2H),2.02-1.98(m,36H),1.93-1.76(m,3H),1.70(d,J=8.5Hz,24H),1.20(s,18H),1.08(s,18H).
13C
NMR(101MHz,CDCl3)
δ163.69(d,J=2.7Hz),163.57(d,J=2.9Hz),151.31(d,J=23.7Hz),150.09(d,J=7.5Hz),149.71(d,J=5.0Hz),145.13(d,J=4.0Hz),144.83(d,J=7.6Hz),144.26(s),144.10(d,J=8.3Hz),143.93(s),143.85(s),137.34(d,J=14.2Hz),136.55(d,J=11.2Hz),135.53(d,J=24.5Hz),133.44(d,J=11.9Hz),132.33(d,J=31.3Hz),130.75(s),130.55(d,J=11.6Hz),130.40(s),130.14(d,J=11.6Hz),129.50(d,J=22.2Hz),128.13(s),127.59(d,J=18.5Hz),127.29(dd,J=9.2,5.3Hz),127.06(d,J=9.7Hz),126.92(s),125.99(d,J=8.7Hz),125.61(s),125.49(d,J=12.7Hz),122.30(s),121.24(s),113.38(s),107.92(s),66.04(d,J=5.5Hz),61.60(d,J=2.4Hz),46.05(d,J=3.9Hz),42.61(d,J=3.5Hz),38.78(s),36.85(s),34.75(d,J=7.7Hz),31.38(s),29.21(s).
31P
NMR(162MHz,CDCl3)
δ34.46,-13.68.
HR-MS(MALDI)
Calcd for C106H133NO3P2[M+H]+:1530.9833;Found:1530.9835.
配体Ij的合成:
将5e(460mg,0.40mmol)称入25mL封管中,置换成氩气,打入苯硅烷(4.0mL),将反应放入140度油浴中反应24小时。反应结束后,体系用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚∶乙酸乙酯=30∶1)得到白色固体Ij 386mg,收率为85%。
配体Ij的数据:
1H
NMR(400MHz,CDCl3)
δ7.25(s,3H),7.17(t,J=7.4Hz,lH),7.05(t,J=8.9Hz,4H),7.01-6.94(m,5H),6.87(d,J=7.7Hz,2H),6.83(d,J=7.8Hz,2H),6.72-6.64(m,lH),6.60(d,J=7.4Hz,1H),5.99(d,J=7.9Hz,1H),4.20(dd,J=16.7,5.2Hz,1H),4.07(dd,J=16.3,5.2Hz,1H),3.80(t,J=5.4Hz,1H),3.66(s,6H),3.11-2.92(m,2H),2.92-2.77(m,1H),2.66(dd,J=15.6,9.3Hz,1H),2.43(dd,J=21.8,10.9Hz,1H),2.12-2.04(m,2H),1.99(s,36H),1.93-1.85(m,1H),1.70(s,24H),1.17(s,18H),1.13(s,18H).
13C
NMR(101MHz,CDCl3)
δ159.88(d,J=24.7Hz),151.03(d,J=24.3Hz),148.83(dd,J=11.0,6.4Hz),143.47(d,J=3.7Hz),143.14(d,J=2.2Hz),142.91(d,J=7.0Hz),142.51-142.31(m),142.17(s),136.42(d,J=11.8Hz),135.59(s),135.44(d,J=3.6Hz),135.26(s),134.34(d,J=23.7Hz),132.23(s),131.79(s),131.02(d,J=10.9Hz),130.82(d,J=10.6Hz),130.59(d,J=3.2Hz),129.15(d,J=8.3Hz),128.90(d,J=7.7Hz),127.54(d,J=7.6Hz),127.29(d,J=15.7Hz),126.86(d,J=20.3Hz),125.86(s),125.27(s),124.82(d,J=5.3Hz),124.59(s),120.69(d,J=5.2Hz),112.33(s),107.29(s),64.74(d,J=3.1Hz),60.62(d,J=3.3Hz),44.45(d,J=26.3Hz),41.66(s),37.59(s),35.91(s),33.71(d,J=2.4Hz),30.37(d,J=12.7Hz),28.24(s).
31P
NMR(162MHz,CDCl3)
δ-16.46,-17.32.
HR-MS(MALDI)
Calcd for C106H133NO2P2[M+H]+:1514.9884;Found:1514.9886.
实施例7:
催化剂IIf的合成路线:
在手套箱中,将催化剂前体[Ir(COD)Cl]2(31mg),配体Ij(150mg)称入25mLSchlenk管中,打入乙醇(5mL)和二氯甲烷(2mL)。将混合液转移至氢化釜中,充入12atm的氢气,油浴70度反应24小时。反应结束后冷却至室温,缓慢释放氢气,体系用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚∶乙酸乙酯=10∶1)得到白色固体IIf 142mg,收率为86%。
催化剂IIf的数据:
1H
NMR(600MHz,CDCl3)
δ7.49-7.31(m,8H),7.26-7.24(m,2H),7.22-7.00(m,7H),6.51(t,J=7.7Hz,1H),6.16(d,J=7.2Hz,1H),5.75(d,J=8.2Hz,1H),5.38(s,1H),4.87(d,J=10.2Hz,1H),4.27(d,J=12.1Hz,1H),3.64(s,3H),3.58(s,3H),3.18-2.96(m,1H),2.92(dd,J=16.1,8.1Hz,1H),2.55-2.39(m,1H),2.15(dd,J=12.0,6.8Hz,1H),2.09-1.58(m,64H),1.21(d,J=51.4Hz,36H),-22.22(ddd,J=17.0,13.5,8.3Hz,1H),-23.68-23.90(m,1H).
31P
NMR(162MHz,CDCl3)
δ24.28(dd,J=366.0,12.6Hz),12.40(dd,J=366.0,16.7Hz).
HR-MS(ESI)
Calcd for C106H135IrNO2P2[M-Cl]+:1708.9592;Found:1708.9582
单晶:
催化剂IIf的单晶数据:
实施例8:
手性螺环膦-氮-膦三齿配体铱络合物在羰基化合物不对称催化氢化反应中的应用。
在手套箱中称取催化剂(R)-II,叔丁醇钾放入氢化内管中,打入溶剂正丙醇和氢化底物,将氢化内管放入氢化釜中,用氢气快速置换反应釜中的气体三次,最后调节氢气压力为8~12atm,室温下搅拌反应至氢气压力不再降低为止。缓慢释放出反应釜中的氢气,旋转蒸发仪脱除溶剂后得粗产物。经短硅胶柱过滤除去催化剂后,用薄层层析或者核磁共振分析反应的转化率和收率,高效液相色谱分析产物的光学纯度,所得氢化实验结果见表1。
表1.羰基化合物的不对称催化氢化
Claims (12)
4.根据权利要求3所述的手性螺环膦-氮-膦三齿配体SpiroPNP及其铱催化剂Ir-SpiroPNP的合成方法,其特征包括如下步骤:
在有机溶剂,碱和钯催化剂存在的条件下,具有式1所示的化合物先与式2所示的化合物在反应器中反应12~24小时制备得到式3所示的化合物;在有机溶剂和还原剂存在的条件下,式3所示的化合物与式4所示的化合物经还原胺化得到式5所示的化合物;在有机溶剂和还原剂存在的条件下,式5所示的化合物发生还原反应得到式I所示的化合物;式I所示的化合物与铱催化剂前体在有机溶剂中络合得到式II所示的化合物;
在上述合成方法中,所述的有机溶剂为甲醇、乙醇、丙醇、异丙醇、丁醇、四氢呋喃、甲苯、二甲苯、甲基叔丁基醚、乙醚、二氧六环、N,N-二甲基甲酰胺、二甲亚砜、二氯甲烷、氯仿或1,2-二氯乙烷中的一种或其中几种的混合溶剂;所述的还原试剂为氢化铝锂、硼氢化钠、三乙酰氧基硼氢化钠、氰基硼氢化钠、三氯硅烷或苯硅烷;所述的碱包括有机碱和无机碱,其中有机碱为吡啶、三乙胺、三丁胺、N-甲基吗啡啉或N,N-二乙基异丙基胺;无机碱为氢氧化钠、氢氧化钾、碳酸钠或碳酸钾;钯催化剂为醋酸钯或钯碳;铱催化剂前体为1,5-环辛二烯氯化铱二聚体或二(1,5-环辛二烯)二-甲氧基二铱。
5.权利要求1或2中所述的手性螺环膦-氮-膦三齿配体或铱催化剂的应用,其特征是用于催化简单双烷基酮的不对称催化氢化反应。
6.根据权利要求5中所述的手性螺环膦-氮-膦三齿配体的应用,其特征是所述的手性螺环膦-氮-膦三齿配体首先与过渡金属盐制备配合物,然后再用于催化简单双烷基酮的不对称催化氢化反应。
9.根据权利要求6所述的应用,其特征在于所述配合物的制备包括如下步骤:将所述的手性螺环膦-氮-膦三齿配体与过渡金属盐加入有机溶剂中,在70-100℃和0.1~20atm的氢气氛围中搅拌反应10~24小时便可得到氢化反应所需的手性催化剂;所述的手性螺环膦-氮-膦三齿配体与过渡金属盐的摩尔比为1:1~2:1;所述的过渡金属盐为[Ir(COD)Cl]2、[Ir(COD)2]BF4、[Ir(COD)2]PF6、[Ir(COD)2]SbF6或[Ir(COD)2]OTf,COD为环辛二烯。
10.根据权利要求9所述的应用,其特征在于制备的配合物可直接不脱溶或脱溶后制备成存放的固体用于催化简单双烷基酮的不对称催化氢化反应。
11.根据权利要求5中所述的应用,其特征是在有机溶剂中,以权利要求9中所制备的配合物为手性催化剂,加入羰基化合物和碱,并在0.1~100atm的氢气氛围中搅拌反应0.1~80小时得到手性醇类化合物。
12.根据权利要求11所述的应用,其特征是羰基底物与催化剂的摩尔比为100:1~500000:1,;底物浓度为0.001~10.0M;碱为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、乙醇钠、乙醇钾、叔丁醇钠、叔丁醇钾、叔丁醇锂、三乙胺、三丁胺或N-甲基吗啉;碱浓度为0.005M~1.0M;反应温度为0~80℃。
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