CN117362141A - 一种钯催化的不对称氢解合成轴手性联芳基化合物的方法 - Google Patents
一种钯催化的不对称氢解合成轴手性联芳基化合物的方法 Download PDFInfo
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- -1 biaryl compound Chemical class 0.000 title claims abstract description 92
- 238000000034 method Methods 0.000 title claims abstract description 35
- 238000007327 hydrogenolysis reaction Methods 0.000 title claims abstract description 25
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 97
- 239000003446 ligand Substances 0.000 claims abstract description 39
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 238000006579 Tsuji-Trost allylation reaction Methods 0.000 claims abstract description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 34
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 239000012696 Pd precursors Substances 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 13
- 229910052751 metal Inorganic materials 0.000 claims description 12
- 239000002184 metal Substances 0.000 claims description 12
- 239000000758 substrate Substances 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- ZNORAFJUESSLTM-UHFFFAOYSA-N [4-[5-bis(3,5-ditert-butyl-4-methoxyphenyl)phosphanyl-1,3-benzodioxol-4-yl]-1,3-benzodioxol-5-yl]-bis(3,5-ditert-butyl-4-methoxyphenyl)phosphane Chemical compound C1=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=C1P(C=1C(=C2OCOC2=CC=1)C=1C(=CC=C2OCOC2=1)P(C=1C=C(C(OC)=C(C=1)C(C)(C)C)C(C)(C)C)C=1C=C(C(OC)=C(C=1)C(C)(C)C)C(C)(C)C)C1=CC(C(C)(C)C)=C(OC)C(C(C)(C)C)=C1 ZNORAFJUESSLTM-UHFFFAOYSA-N 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000012354 sodium borodeuteride Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 239000012448 Lithium borohydride Substances 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- RZZDRSHFIVOQAF-UHFFFAOYSA-N [4-(5-diphenylphosphanyl-1,3-benzodioxol-4-yl)-1,3-benzodioxol-5-yl]-diphenylphosphane Chemical compound C=12OCOC2=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1C1=C2OCOC2=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RZZDRSHFIVOQAF-UHFFFAOYSA-N 0.000 claims description 2
- XJJVPYMFHXMROQ-UHFFFAOYSA-N [4-[5-bis(3,5-dimethylphenyl)phosphanyl-1,3-benzodioxol-4-yl]-1,3-benzodioxol-5-yl]-bis(3,5-dimethylphenyl)phosphane Chemical compound CC1=CC(C)=CC(P(C=2C=C(C)C=C(C)C=2)C=2C(=C3OCOC3=CC=2)C=2C(=CC=C3OCOC3=2)P(C=2C=C(C)C=C(C)C=2)C=2C=C(C)C=C(C)C=2)=C1 XJJVPYMFHXMROQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 165
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 128
- 150000001875 compounds Chemical class 0.000 description 50
- 238000005481 NMR spectroscopy Methods 0.000 description 48
- 239000007787 solid Substances 0.000 description 26
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 22
- 238000004128 high performance liquid chromatography Methods 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 230000014759 maintenance of location Effects 0.000 description 21
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- 230000015572 biosynthetic process Effects 0.000 description 19
- 239000000047 product Substances 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- 239000012299 nitrogen atmosphere Substances 0.000 description 12
- 101001110286 Homo sapiens Ras-related C3 botulinum toxin substrate 1 Proteins 0.000 description 11
- 102100022122 Ras-related C3 botulinum toxin substrate 1 Human genes 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
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- 238000003818 flash chromatography Methods 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000000376 reactant Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
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- 239000008346 aqueous phase Substances 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 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 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 description 5
- 239000005052 trichlorosilane Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 239000002480 mineral oil Substances 0.000 description 4
- 235000010446 mineral oil Nutrition 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- UOMIMNVOKYMECJ-UHFFFAOYSA-N 1-bromo-n,n-dimethylnaphthalen-2-amine Chemical compound C1=CC=CC2=C(Br)C(N(C)C)=CC=C21 UOMIMNVOKYMECJ-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 101150003085 Pdcl gene Proteins 0.000 description 3
- 150000001394 ortho substituted aryl bromides Chemical class 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 2
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- HTJWUNNIRKDDIV-UHFFFAOYSA-N bis(1-adamantyl)-butylphosphane Chemical compound C1C(C2)CC(C3)CC2CC13P(CCCC)C1(C2)CC(C3)CC2CC3C1 HTJWUNNIRKDDIV-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- AEDZKIACDBYJLQ-UHFFFAOYSA-N ethane-1,2-diol;hydrate Chemical compound O.OCCO AEDZKIACDBYJLQ-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000004712 monophosphates Chemical class 0.000 description 2
- 238000005457 optimization Methods 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
- 239000012071 phase Substances 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- YDMRDHQUQIVWBE-UHFFFAOYSA-N (2-hydroxyphenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1O YDMRDHQUQIVWBE-UHFFFAOYSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- TWDQSJDFXUMAOI-UHFFFAOYSA-N (5-fluoro-2-hydroxyphenyl)boronic acid Chemical compound OB(O)C1=CC(F)=CC=C1O TWDQSJDFXUMAOI-UHFFFAOYSA-N 0.000 description 1
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- WENXBAFANCRIGK-UHFFFAOYSA-N 1-bromonaphthalen-2-amine Chemical compound C1=CC=CC2=C(Br)C(N)=CC=C21 WENXBAFANCRIGK-UHFFFAOYSA-N 0.000 description 1
- KMZLFHHLCFEZMT-UHFFFAOYSA-N 2-bromo-1-methyl-3-phenylmethoxybenzene Chemical compound CC1=CC=CC(OCC=2C=CC=CC=2)=C1Br KMZLFHHLCFEZMT-UHFFFAOYSA-N 0.000 description 1
- HUGNLEZLTOVJLD-UHFFFAOYSA-N 2-bromo-3-methylphenol Chemical compound CC1=CC=CC(O)=C1Br HUGNLEZLTOVJLD-UHFFFAOYSA-N 0.000 description 1
- BHZOYEUHMVUPJQ-UHFFFAOYSA-N 2-bromo-4-propan-2-ylphenol Chemical compound CC(C)C1=CC=C(O)C(Br)=C1 BHZOYEUHMVUPJQ-UHFFFAOYSA-N 0.000 description 1
- TZGKWDUHXIFYHI-UHFFFAOYSA-N 2-methoxy-1-phenylnaphthalene Chemical compound COC1=CC=C2C=CC=CC2=C1C1=CC=CC=C1 TZGKWDUHXIFYHI-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 150000005347 biaryls Chemical group 0.000 description 1
- FWKICRREDMVWRF-UHFFFAOYSA-N bis(4-methoxyphenyl)phosphane Chemical compound C1=CC(OC)=CC=C1PC1=CC=C(OC)C=C1 FWKICRREDMVWRF-UHFFFAOYSA-N 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000010596 desymmetrization reaction Methods 0.000 description 1
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
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- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 description 1
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- 239000000463 material Substances 0.000 description 1
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- LULXBAGMGMJJRW-UHFFFAOYSA-N n,2-bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)CC(=O)N[Si](C)(C)C LULXBAGMGMJJRW-UHFFFAOYSA-N 0.000 description 1
- UTBXTYQECNLQPU-UHFFFAOYSA-N naphthalen-2-amine Chemical compound C1=C[CH]C2=CC(N)=C=CC2=C1 UTBXTYQECNLQPU-UHFFFAOYSA-N 0.000 description 1
- PJDLZCFUBVEWHO-UHFFFAOYSA-N naphthalen-2-ylphosphane Chemical compound C1=CC=CC2=CC(P)=CC=C21 PJDLZCFUBVEWHO-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- PENAXHPKEVTBLF-UHFFFAOYSA-L palladium(2+);prop-1-ene;dichloride Chemical compound [Pd+]Cl.[Pd+]Cl.[CH2-]C=C.[CH2-]C=C PENAXHPKEVTBLF-UHFFFAOYSA-L 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种钯催化的不对称氢解合成轴手性联芳基化合物的方法,是通过动力学拆分实现芳基三氟甲磺酸酯的钯催化不对称氢解,从而可以轻松构建一系列具有优异选择性因子(s值最高达70)的轴向手性联芳基化合物。另外,由这些轴向手性联芳基化合物为原料制备了一些手性单膦配体,并将其应用于钯催化的不对称烯丙基烷基化反应,获得了具有优异的对映选择性和区域选择性的烯丙基烷基化的产物,证明了该方法的潜在用途。本发明操作简单实用,催化剂商业可得,反应条件温和,能耗低,环境友好。
Description
技术领域
本发明属于不对称催化合成领域,涉及一种钯催化芳基三氟甲磺酸酯的不对称氢解,经过动力学拆分合成了一系列轴手性联芳基化合物的方法。
技术背景
氢解是一种有吸引力的合成方法,广泛应用于有机合成和工业流程(参考文献一:a)J.Newham,Chem.Rev.1963,63,123;b)A.R.Pinder,Synthesis 1980,425;c)T.Turek,D.L.Trimm,A.W.Cant,Catal.Rev.1994,36,645;d)C.Bianchini,A.Meli,Acc.Chem.Res.1998,31,109;e)A.Wilsily,Y.Nguyen,E.Fillion,J.Am.Chem.Soc.2009,131,15606;f)A.Martin,U.Armbruster,I.Gandarias,P.L.Arias,Eur.J.LipidSci.Technol.2013,115,9;g)R.R.Chianelli,Catal.Rev.1984,26,361;b)M.L.Poutsma,Energy Fuels 1990,4,113;h)A.N.Startsev,Russ.Chem.Rev.1992,61,175;i)K.Ichimura,Y.Inoue,I.Yasumori,Catal.Rev.1992,34,301;j)A.M.Ruppert,K.Weinberg,R.Palkovits,Angew.Chem.Int.Ed.2012,51,2564;k)Y.Wang,J.Zhou,X.Guo,RSCAdv.2015,5,74611;l)K.Tomishige,Y.Nakagawa,M.Tamura,Green Chem.2017,19,2876.)。然而,氢解主要集中在外消旋或非手性化合物的合成上,不对称形式的研究相对较少。主要原因如下:1)严重的副反应;2)底物与手性催化剂的配位困难;3)较差的化学和立体选择性控制。近年来,在碳氧键的不对称氢解方面取得了一些例子。1991年,Chan报道了以手性铑络合物为催化剂,顺式环氧琥珀酸钠的均相不对称氢解反应,得到中等的对映选择性(参考文献二:(a)A.S.C.Chan,J.P.Coleman,J.Chem.Soc.,Chem.Commun.1991,535.)。后来,Bakos还使用含有水溶性磺化配体的相同铑催化剂体系对该化合物进行了不对称氢解(参考文献三:(a)J.Bakos,á.Orosz,S.Cserépi,I.Tóth,D.Sinou,J.Mol.Catal.A 1997,116,85.)。2016年,张等人通过动力学拆分开发了钯催化的α-酰氧基酮与邻位取代的芳基C-O键的对映选择性氢解(参考文献三:(a)J.Chen,Z.Zhang,D.Liu,W.Zhang,Angew.Chem.Int.Ed.2016,55,8444.)。同时,还研究了内消旋二卤化物的去对称化或外消旋叔醇化合物的形式不对称氢解。(参考文献四:a)E.P.Kündig,P.D.Chaudhuri,D.House,G.Bernardinelli,Angew.Chem.Int.Ed.2006,45,1092;b)A.Mercier,W.C.Yeo,J.Chou,P.D.Chaudhuri,G.Bernardinelli,E.P.Kündig,Chem.Commun.2009,5227;c)A.Mercier,X.Urbaneja,W.C.Yeo,P.D.Chaudhuri,G.R.Cumming,D.House,G.Bernardinelli,E.P.Kündig,Chem.Eur.J.2010,16,6285;d)A.Mercier,W.C.Yeo,X.Urbaneja,E.P.Kündig,Chimia2010,64,177;e)M.Hirai,S.Terada,H.Yoshida,K.Ebine,T.Hirata,O.Kitagawa,Org.Lett.2016,18,5700;f)M.-W.Chen,Q.-A.Chen,Y.Duan,Z.-S.Ye,Y.-G.Zhou,Chem.Commun.2012,48,1698;g)J.-Q.Zhou,W.-J.Sheng,J.-H.Jia,Q.Ye,J.-R.Gao,Y.-X.Jia,Tetrahedron Lett.2013,54,3082;h)Q.Yin,S.-G.Wang,S.-L.You,Org.Lett.2013,15,2688;i)C.-B.Yu,Y.-G.Zhou,Angew.Chem.Int.Ed.2013,52,13365;j)B.Song,C.-B.Yu,W.-X.Huang,M.-W.Chen,Y.-G.Zhou,Org.Lett.2015,17,190;k)J.Zheng,J.Jongcharoenkamol,B.B.C.Peters,J.Guhl,S.Ponra,M.S.G.Ahlquist,P.G.Andersson,Nat.Catal.2019,2,1093.)。尽管在该领域已经付出了相当大的努力,但由于底物在氢解条件下的不兼容性不利于构建手性版本。因此,新型催化剂体系的开发和底物范围的扩大将进一步推动不对称氢解在有机合成中的应用。
轴手性联芳基结构是一类重要的骨架,广泛存在于天然产物、药物和配体中。(参考文献五:a)G.Bringmann,D.Menche,Acc.Chem.Res.2001,34,615;b)P. M./>Chem.Rev.2003,103,3213;c)J.Clayden,W.J.Moran,P.J.Edwards,S.R.LaPlante,Angew.Chem.Int.Ed.2009,48,6398;d)M.C.Kozlowski,B.J.Morgan,E.C.Linton,Chem.Soc.Rev.2009,38,3193.)。通过动力学或动态动力学拆分的策略合成轴手性联芳基化合物是非常有重要的方法之一。因此,发展一种通过动力学拆分的方法构建具有轴手性联芳基化合物非常有意义的。基于此,本发明提供一种钯催化芳基三氟甲磺酸酯的不对称氢解经过动力学拆分合成轴手性联芳基化合物,并成功将其应用于单膦配体的合成及应用中。
发明内容
本发明的目的是提供一种钯催化的不对称氢解合成轴手性联芳基化合物的方法,本发明操作简便实用,原料易得,较高的选择性因子,且能够快速合成手性单膦配体。
本发明的技术方案如下:
一种通过动力学拆分的策略,实现钯催化的不对称氢解合成轴手性联芳基化合物的方法,所述方法以钯的手性双膦配合物为催化剂,芳基三氟甲磺酸酯为底物,还原试剂作为氢源,经过不对称氢解合成了一系列具有轴手性的联芳基化合物。所述方法的反应式如下:
式中:
R为甲氧基、苄氧基、异丙氧基、环戊胺基或二甲氨基;
Ar为苯环、萘环或含有取代基的芳环,所述的取代基为氟、甲基、甲氧基、乙基、异丙基、叔丁基、苯基中的一种;
所述催化剂为金属钯前体和手性双膦配体的配合物。
基于以上技术方案,优选的,反应溶剂为有机溶剂,所述有机溶剂为N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、四氢呋喃(THF)、甲醇(MeOH)的一种。
基于以上技术方案,优选的,反应温度:-50℃-30℃,优选为-20℃或-40℃;反应时间:0.5-36小时,优选为3小时。
基于以上技术方案,优选的氢源为还原试剂,所述还原试剂为硼氢化钠(NaBH4)、硼氘化钠(NaBD4)、硼氢化锂(LiBH4)、硼氘化锂(LiBD4)、硼氢化钾(KBH4)、硼氘化钾(KBD4)其中的一种,优选为硼氢化钠或硼氘化钠。
基于以上技术方案,优选的,金属钯前体与手性双膦配体摩尔比为1:1-1:3。
基于以上技术方案,优选的,反应中芳基三氟甲磺酸酯、金属钯前体与手性双膦配体的摩尔比为1:0.005:0.0006-1:0.05:0.100,优选为1:0.05:0.075。
基于以上技术方案,优选的,所述金属钯前体为三氟乙酸钯(Pd(TFA)2)、醋酸钯(Pd(OAc)2)中的一种。
基于以上技术方案,优选的,所述手性双膦配体为(R)-SegPhos,(S)-SegPhos,(R)-DM-SegPhos,(S)-DM-SegPhos,(R)-DTBM-SegPhos,(S)-DTBM-SegPhos,(R)-DifluorPhos,(S)-DifluorPhos,(R)-3,5-t-Bu-4-MeO-MeOBIPHEP,(S)-3,5-t-Bu-4-MeO-MeOBIPHEP中的一种。
基于以上技术方案,优选的,所述催化剂的制备方法为:氮气保护下,将金属钯前体和手性双膦配体在反应溶剂中30℃油浴下搅拌10-60分钟得到。
基于以上技术方案,优选的,所述方法的具体反应步骤为:
氮气氛围下,将金属钯前体和手性双膦配体在反应溶剂中30℃油浴下搅拌10分钟-60分钟后,然后加入芳基三氟甲磺酸酯,加毕将反应体系置于-50-30℃搅拌20分钟后,加入氢源,加毕封口维持该温度反应一定时间,TLC监测跟踪,反应结束,加水淬灭反应,然后纯化得到产物。
基于以上技术方案,优选的,所述纯化的步骤为:加水淬灭后,用乙酸乙酯萃取三次,合并有机相,然后用无水硫酸钠干燥,过滤,减压旋除溶剂,柱层析分离得到产物。
基于以上技术方案,优选的,所述芳基三氟甲磺酸酯与溶剂的比例为0.35mmol:3.5mL。
基于以上技术方案,优选的,在氮气氛围中,将金属钯前体和手性双膦配体加入到Schlenk管中,然后加入溶剂室温搅拌十分钟后、加入芳基三氟甲磺酸酯,加毕置于零下20℃或零下40℃搅拌20分钟后,加入氢源,加毕封口,反应一定时间,加水淬灭反应,用乙酸乙酯萃取三次,然后用无水硫酸钠干燥,过滤,减压旋除溶剂,柱层析分离得到产物。产物的选择性因子和对映体过量分别通过核磁共振仪及高效液相色谱仪测定。
本发明还涉及保护上述方法合成的轴手性联芳基化合物在合成手性单膦配体中的应用,将此方法成功用于手性单膦配体的合成。
本发明还涉及保护上述手性单膦配体在钯催化不对称烯丙基烷基化反应中的应用,将这些合成的手性单膦配体应用到钯催化不对称烯丙基烷基化反应中,获得了优异的结果,从而证明了手性单膦配体和本发明的不对称氢解方法的实用性。
通过本发明通过动力学拆分方法可以实现芳基三氟甲磺酸酯的钯催化不对称氢解反应,以较高的选择性因子得到一系列具有光学纯度的轴手性联芳基化合物(s值最高可达70)。本发明具有较高的选择性因子,操作简便实用,原料易得,催化剂商业可得,反应条件温和,能耗低,环境友好。另外,由这些轴向手性联芳基化合物为原料制备了一些手性单膦配体,并将其应用于钯催化的不对称烯丙基烷基化反应,获得了具有优异的对映选择性和区域选择性的烯丙基烷基化的产物,证明了该方法的潜在用途。
有益效果
(1)原料简单易得,催化剂制备方便,反应操作简便实用。
(2)反应活性高,能获得高纯度的产物。
(3)能够快速构建轴手性联芳基化合物,进一步能够合成非常有用的手性单膦配体。
具体实施方式
下面通过实施例详述本发明,但本发明并不限于下述的实施例。
下述实施例中合成原料邻位取代芳基溴化物S1-S3的参考文献如下:(a)D.Schaarschmidt,M.Grumbt,A.Hildebrandt,H.Lang,Eur.J.Org.Chem.2014,6676-6685.(b)K.Yang,Y.Mao,J.Xu,H.Wang,Y.He,W.Li,Q.Song,J.Am.Chem.Soc.2021,143,10048-10053.
下述实施例中合成原料邻位取代芳基溴化物S4是可商购的原料。
下述实施例中合成原料邻位取代芳基溴化物S5和S6的参考文献如下:(a)B.Xu,M.-L.Li,X.-D.Zuo,S.-F.Zhu,Q.-L.Zhou,J.Am.Chem.Soc.2015,137,8700-8703.(b)M.Aki,T.Ogura,Y.Naruta,T.H.Le,T.Sato,T.Kitagawa,J.Phys.Chem.A 2002,106,3436-3444.S5和S6具体通过如下步骤制备:
将1-溴-2-萘胺(市售原料)(10mmol,2.221g)、1,4-二溴丁烷(10mmol,2.159g)、碘化钾(22mmol,3.652g)、碳酸钾(22mmol,3.041g)和乙腈(20mL)加入到反应瓶中,置于90℃下搅拌48小时。反应结束时,过滤反应液,然后滤液经减压浓缩得到粗产物。最后通过硅胶快速柱层析纯化,使用石油醚/乙酸乙酯(100/1)作为洗脱剂,得到所需的中间体S5。
将2-溴-3-甲基苯酚(市售原料)(10mmol,1.870g)、苄基溴(15mmol,1.8mL)、碳酸钾(20mmol,2.764g)和丙酮(15mL)加入到反应瓶中,置于90℃搅拌19小时。当TLC监测反应完成时,过滤反应液,然后滤液经减压浓缩得到粗产物。最后通过硅胶快速柱层析纯化,使用石油醚/乙酸乙酯(100/1)作为洗脱剂,得到所需的中间体S6。
下述实施例中芳基三氟甲磺酸酯rac-1a-rac-1m的合成参考文献如下:(a)M.Bartoszek,M.Beller,J.Deutsch,M.Klawonn,A.N.Nemati,A.Pews-Davtyan,Tetrahedron 2008,64,1316;(b)K.Mori,Y.Ichikawa,M.Kobayashi,Y.Shibata,M.Yamanaka,T.Akiyama,Chem.Sci.2013,4,4235;(c)D.-Y.Zhang,D.-S.Wang,M.-C.Wang,C.-B.Yu,K.Gao,Y.-G.Zhou,Synthesis 2011,17,2796;(d)D./>A./>B./>L.Rejc,A./>A./>Molecules 2016,21,267;(e)H.Yang,J.L.Petersen,K.K.Wang,Tetrahedron 2006,62,8133。其中:
合成芳基三氟甲磺酸酯(rac-1a、rac-1d、rac-1i和rac-1j)的合成路线如下:
合成芳基三氟甲磺酸酯(rac-1b)的详细步骤如下:
在氮气保护下,依次向反应瓶中加入1-溴-N,N-二甲基-2-萘胺(S1)(5mmol,1.250g)、2-羟基-5-氟苯基硼酸(6mmol,0.936g)、醋酸钯(0.15mmol,0.034g)、双(1-金刚烷基)丁基膦(0.22mmol,0.079g)、碳酸钾(20mmol,2.764g)和乙二醇二甲醚/水(32mL,3/1),加毕,在90℃搅拌4小时。TLC监测反应完全,停止反应冷却至室温。将两相分离,有机相用无水硫酸钠干燥,过滤和减压浓缩。使用石油醚/乙酸乙酯(50/1)为洗脱剂,用硅胶进行柱层析,得到纯净的中间体,直接用于下一步反应。
在氮气保护下,将上述中间体(4mmol,1.116g)溶解在四氢呋喃(30mL)中,置于0℃下搅拌。然后加入氢化钠(8mmol,0.320g,60%分散在矿物油中),反应持续1小时。随后,将N-苯基-双(三氟甲基磺酰亚胺)(8mmol,2.858g)加入到反应体系中,加毕,移至室温下进行过夜反应。反应结束时,在冰浴条件下向反应体系中缓慢加入水。分离有机相,水相用乙酸乙酯(10mL×3)萃取3次。合并有机相,用无水硫酸钠干燥,过滤并减压浓缩。粗产物通过硅胶快速柱色谱法纯化,使用石油醚/乙酸乙酯(100/1)作为洗脱剂,得到所需底物rac-1b。
使用上述合成rac-1b类似步骤,可以制备底物rac-1a、rac-1d、rac-1i和rac-1j。
合成芳基三氟甲磺酸酯(rac-1c、rac-1e-1h)的合成路线如下:
合成芳基三氟甲磺酸酯(rac-1f)的详细步骤如下:
在氮气保护下,将1-溴-N,N-二甲基-2-萘胺(50mmol,12.505g)溶解在四氢呋喃(200mL)中,置于-78℃冷浴中,缓慢加入正丁基锂(60mmol,24mL,2.5M的四氢呋喃溶液),并反应搅拌1小时。之后加入硼酸三甲酯(60mmol,6.7mL),加毕移至室温反应过夜。反应结束时,缓慢加入饱和氯化铵溶液,搅拌1小时。分离有机相,水相用乙酸乙酯萃取。合并有机相,用无水硫酸钠干燥,过滤并减压浓缩。通过重结晶纯化粗产物,得到纯的(2-(二甲基氨基)萘-1-基)硼酸(7.557g,70%收率,黄色固体)。
在氮气气氛下,将(2-(二甲氨基)萘-1-基)硼酸(5.2mmol,1.118g)、2-溴-4-异丙基苯酚(4mmol,0.804g)、醋酸钯(0.12mmol,0.027g)、双(1-金刚烷基)丁基膦(0.176mmol,0.063g)、碳酸钾(16mmol,2.211g)和1,2-二甲氧基乙烷/水(24mL,3/1)加入到反应瓶中,置于90℃油浴锅中回流4小时。当TLC监测反应完全,停止反应并冷却至室温。分离有机相,用无水硫酸钠干燥,过滤并减压浓缩。粗产物通过硅胶快速柱层析纯化,使用石油醚/乙酸乙酯(50/1)作为洗脱液,得到纯中间体,直接用于下一步反应。
在氮气保护下,将上述中间体(3.5mmol,1.060g)溶解在四氢呋喃(25mL)中,置于0℃下搅拌。然后加入氢化钠(7mmol,0.280g,60%分散在矿物油中),反应搅拌1小后加入N-苯基-双(三氟甲磺酰亚胺)(7mmol,2.501g),加毕,移至室温反应过夜。反应结束时,在冰浴条件下向反应体系中缓慢加入水。分离有机相,水相用乙酸乙酯(10mL×3)萃取。合并有机相,用无水硫酸钠干燥并减压浓缩。粗产物通过硅胶快速柱层析纯化,使用石油醚/乙酸乙酯(100/1)作为洗脱液,得到产物rac-1f。
使用上述合成rac-1f类似步骤,可以制备底物rac-1c、rac-1e、rac-1g和rac-1h。
合成芳基三氟甲磺酸酯(rac-1k-1m)的合成路线如下:
合成芳基三氟甲磺酸酯(rac-1k)的详细步骤如下:
在氮气保护下,将1-溴-2-异丙氧基萘(5mmol,1.326g)、2-羟基苯基硼酸(6mmol,0.828g)、四(三苯基膦)钯(1.5mmol,1.733g)、磷酸钾(20mmol,4.245g)和乙二醇二甲醚/水(55mL,8/3)加入到反应瓶中,置于100℃搅拌过夜。当TLC监测反应完成,停止反应并冷却至室温。分离有机相,然后用无水硫酸钠干燥,过滤并减压浓缩。粗产物通过硅胶快速柱层析纯化,使用石油醚/乙酸乙酯(50/1至20/1)作为洗脱剂,得到纯的中间体,其直接用于下一步反应。
在氮气保护下,将上述中间体(4.9mmol,1.372g)溶解在四氢呋喃(40mL)中,置于0℃下搅拌,然后加入氢化钠(9.8mmol,0.392g,60%分散于矿物油)。搅拌1小时后,将N-苯基-双-(三氟甲磺酰亚胺)(9.8mmol,3.501g)加入到上述反应体系中。然后,移至室温过夜反应。反应结束时,在冰浴条件下向混合物中缓慢加入水。分离有机相,水相用乙酸乙酯(10mL×3)萃取。合并有机相,用无水硫酸钠干燥,过滤并减压浓缩。粗产物通过硅胶快速柱层析纯化,使用石油醚/乙酸乙酯(100/1)作为洗脱剂,得到所需的底物rac-1k。
用上述合成rac-1k类似步骤,可以制备底物rac-1l和rac-1m。
下述实施例中已知物rac-1n的合成参考文献如下:C.Yao,P.Wu,Y.Huang,Y.Chen,L.Lia andY.-Mi.Li,Org.Biomol.Chem.2020,18,9712。
下述实施例中合成原料联芳基二酚S7的参考文献如下:K.Mori,Y.Ichikawa,M.Kobayashi,Y.Shibata,M.Yamanaka,T.Akiyama,Chem.Sci.2013,4,4235;
下述实施例中底物3制备的详细步骤如下:
在氮气气氛下,将上述化合物S7(0.6mmol,0.160g)溶解于四氢呋喃(10mL)中,然后加入氢化钠(2.4mmol,0.096g,60%分散在矿物油中),并将反应搅拌1小时。随后,加入N-苯基-双(三氟甲磺酰亚胺)(1.8mmol,0.643g),然后在室温下反应2小时。当TLC监测反应完成时,在冰浴条件下向反应体系中缓慢加入水以淬灭反应。分离有机相,水相用乙酸乙酯(8mL×3)萃取。合并有机相,用无水硫酸钠干燥,过滤并减压浓缩。粗产物通过硅胶快速柱层析纯化,使用石油醚/乙酸乙酯(40/1)作为洗脱剂,得到所需底物3。
下述实施例中rac-6的合成参考文献如下:E.C.K.Claverie,C.Bour,D.J.Cárdenas,A.M.Echavarren,Angew.Chem.Int.Ed.2008,47,7892;
下述实施例中rac-9的合成参考文献如下:A.J.Argüelles,S.Sun,B.G.Budaitis,P.Nagorny,Angew.Chem.Int.Ed.2018,57,5325;
下述实施例中NaCMe(CO2Me)2的合成参考文献如下:T.Hayashi,M.Kawatsura,Y.Uozumi,J.Am.Chem.Soc.1998,120,1681-1687.
实施例1-14
条件优化:改变有机溶剂的种类、钯前体、氢源的种类以及手性配体
在氮气氛围下,向反应管中加入醋酸钯(0.005mmol)和手性配体(0.0075mmol),N,N-二甲基甲酰胺(0.6mL),30℃搅拌10分钟后加入芳基三氟甲磺酸酯rac-1a(0.1mmol)和N,N-二甲基甲酰胺(0.4mL),然后置于-20℃冷浴中搅拌20分钟后加入硼氢化钠(0.15mmol),反应3小时。反应结束加水淬灭,用乙酸乙酯(2×15mL)萃取,合并有机相,用水洗一次,然后无水Na2SO4干燥,过滤以及减压旋除溶剂,柱层析分离得到纯的产物。
有机溶剂的种类、钯前体、氢源的种类以及手性配体,具体结果如表1;ee为对映选择性。
表1.芳基三氟甲磺酸酯1a的不对称氢解反应条件的优化
实施例15-29
芳基三氟甲磺酸酯rac-1的不对称氢解
在氮气氛围下,向反应管中加入醋酸钯(0.0175mmol)和手性配体L1(0.02625mmol),N,N-二甲基甲酰胺(2.1mL),30℃搅拌10分钟后加入芳基三氟甲磺酸酯rac-1(0.35mmol)和N,N-二甲基甲酰胺(1.4mL),然后置于-20℃或-40℃冷浴中搅拌20分钟后加入硼氢化钠(0.525mmol),反应一定时间。反应结束加水淬灭,用乙酸乙酯(2×15mL)萃取,合并有机相,用水洗一次,然后无水Na2SO4干燥,过滤以及减压旋除溶剂,柱层析分离得到纯的产物。
芳基三氟甲磺酸酯为rac-1,改变反应中rac-1的种类得到14个不同轴手性联芳基化合物(-)-1和化合物2实施例,改变的种类具体如下:
其中rac-1a-rac-1i的反应温度都为-20℃,rac-1j-rac-1n的反应温度都为-40℃。
其中(-)-1n的结构经与文献对照确定。(参考文献:L.Byrne,C.P.Norrby,R.H.Munday,A.R.Turner,P.D.Smith,Adv.Synth.Catal.2021,363,259-267.)。
实施例30-31
芳基三氟甲磺酸酯3的氢解去对称
在氮气氛围下,向反应管中加入醋酸钯(0.01mmol)、手性配体L1(0.015mmol)和N,N-二甲基甲酰胺(1.6mL),30℃搅拌10分钟后加入芳基三氟甲磺酸酯3(0.2mmol)和N,N-二甲基甲酰胺(0.4mL),然后置于-40℃冷浴中搅拌20分钟后加入硼氢化钠或硼氘化钠(0.3mmol),反应2小时。反应结束加水淬灭,用乙酸乙酯(2×15mL)萃取,合并有机相,用水洗一次,然后无水Na2SO4干燥,过滤以及减压旋除溶剂,柱层析分离得到纯的产物。
注:上述中氘代率大于99%
实施例32-35
轴手性单膦配体的合成
在氮气氛围下,向反应管中加入醋酸钯(33.7mg,0.15mmol)和手性配体L1(265.4mg,0.225mmol),N,N-二甲基甲酰胺(18mL),30℃搅拌10分钟后加入芳基三氟甲磺酸酯1l(1.375g,3mmol)和N,N-二甲基甲酰胺(12mL),然后置于-40℃冷浴中搅拌20分钟后加入硼氢化钠(170.2mg,4.5mmol),反应12小时。反应结束加水淬灭,用乙酸乙酯(2×15mL)萃取,合并有机相,用水洗一次,然后无水Na2SO4干燥,过滤以及减压旋除溶剂,柱层析分离得到纯的产物(-)-1l(0.350g,25%yield,>99%ee)。
在氮气氛围下,向反应管中加入(-)-1l(1.0当量,>99%ee)、芳基膦氧化合物Ar2P(O)H(1.2当量)、Ni(COD)2(1.0当量)、DPPF(1.0当量)、碳酸钠(1.0当量)和1,4-二氧六环(原料(-)-1l在二氧六环中的浓度为0.1M),加毕70℃反应10小时,反应结束,用硅藻土过滤以及减压旋除溶剂,柱层析分离得到纯的产物4。
具体地,当合成4a时,所使用各反应物量为(-)-1l(0.334g,0.73mmol),Ph2P(O)H(0.177g,0.87mmol),Ni(COD)2(0.201g,0.73mmol),DPPF(0.405g,0.73mmol),碳酸钠(0.077g,0.73mmol),1,4-二氧六环(7.3mL)。
当合成4b时,所使用各反应物量为(-)-1l(0.339g,0.74mmol),(4-MeOC6H4)2P(O)H(0.233g,0.89mmol),Ni(COD)2(0.204g,0.74mmol),DPPF(0.410g,0.74mmol),碳酸钠(0.078g,0.74mmol),1,4-二氧六环(7.4mL)。
当合成4c时,所使用各反应物量为(-)-1l(0.333g,0.73mmol),(4-MeC6H4)2P(O)H(0.200g,0.87mmol),Ni(COD)2(0.201g,0.73mmol),DPPF(0.405g,0.73mmol),碳酸钠(0.077g,0.73mmol),1,4-二氧六环(7.3mL)。
当合成4d时,所使用各反应物量为(-)-1l(0.320g,0.70mmol),(2-naphthyl)2P(O)H(0.253g,0.84mmol),Ni(COD)2(0.193g,0.70mmol),DPPF(0.388g,0.70mmol),碳酸钠(0.075g,0.70mmol),1,4-二氧六环(7.0mL)。
氮气氛围下,向反应管中加入上述化合物4(1.0当量)、三乙胺(5.0当量)和甲苯(10ml),冰浴条件下加入三氯硅烷(5.0当量),加毕100℃反应过夜,反应结束,冰浴下加水淬灭,然后柱层析分离得到纯的产物5。
具体地,当合成5a时,所使用各反应物量为4a(0.170g,0.33mmol),三乙胺(0.32mL,2.31mmol),甲苯(10mL),三氯硅烷(0.16mL,1.66mmol)。
当合成5b时,所使用各反应物量为4b(0.195g,0.34mmol),三乙胺(0.33mL,2.38mmol),甲苯(10mL),三氯硅烷(0.17mL,1.71mmol)。
当合成5c时,所使用各反应物量为4c(0.240g,0.45mmol),三乙胺(0.44mL,3.15mmol),甲苯(10mL),三氯硅烷(0.22mL,2.25mmol)。
当合成5d时,所使用各反应物量为4d(0.200g,0.33mmol),三乙胺(0.32mL,2.31mmol),甲苯(10mL),三氯硅烷(0.16mL,1.65mmol)。
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表2.轴手性单膦配体的合成
实施例36-40
轴手性单膦配体的应用
在氮气气氛下,向反应瓶中加入[PdCl(C3H5)]2(0.002mmol,0.7mg),手性单磷配体5(0.004mmol)和四氢呋喃(0.5mL),30℃下搅拌30min。然后,加入rac-6(0.2mmol,41.2mg)和四氢呋喃(0.5mL),再搅拌30分钟。然后冷却到-20℃或-40℃,加入NaCMe(CO2Me)2(0.4mmol,67.2mg)。反应持续了57个小时。将饱和氯化铵溶液加入到混合物中淬灭反应。混合物用乙酸乙酯稀释后转移到圆底烧瓶中。然后用无水硫酸钠干燥,过滤以及减压旋除溶剂。柱层析分离得到产物(7和8)。
在氮气气氛下,向反应瓶加入氯化烯丙基钯(II)二聚物([PdCl(C3H5)]2)(0.005mmol,1.8mg),手性单磷酸配体5a(0.022mmol,10.9mg)和甲苯(0.5mL),30℃下搅拌30min。然后,加入rac-9(0.25mmol,63.1mg)和甲苯(0.5mL),再搅拌30分钟。随后加入丙二酸二甲酯(0.75mmol,85.7μL)、N,O-双三甲硅基乙酰胺(0.75mmol,183.0μL)和醋酸锂(0.0075mmol,0.5mg)。反应在60℃下搅拌3小时。反应结束时,向混合物中加入饱和氯化铵溶液,使反应淬灭。混合物用乙酸乙酯稀释后转移到圆底烧瓶中,然后用无水硫酸钠干燥,过滤以及减压下浓缩,柱层析分离得到手性产物10。
实施例41
手性化合物(-)-1h的合成
氮气氛围下,向反应管中加入醋酸钯(33.7mg,0.15mmol)和手性配体L1(265.4mg,0.225mmol),N,N-二甲基甲酰胺(18mL),30℃搅拌10分钟后加入芳基三氟甲磺酸酯1h(1.414g,3mmol)和N,N-二甲基甲酰胺(12mL),然后置于-20℃冷浴中搅拌20分钟后加入硼氢化钠(170.2mg,4.5mmol),反应160分钟。反应结束加水淬灭,用乙酸乙酯(2×15mL)萃取,合并有机相,用水洗一次,然后无水Na2SO4干燥,过滤以及减压旋除溶剂,柱层析分离得到纯的产物(-)-1h(0.406g,29%yield,>99%ee)。
手性化合物11的合成
在氮气气氛下,向反应瓶中加入化合物(-)-1h(0.2mmol,94.3mg),[1,3-双二苯基磷丙烷]氯化钯(PdCl2(dppp))(0.012mmol,7.1mg),苯基溴化镁(1.2mmol,1.2mL,1.0M四氢呋喃溶液)和乙醚(1.5mL),加毕40℃下搅拌68小时,在反应结束时,慢慢地向混合物中加入水以使反应淬灭。将两相分离,水相用乙酸乙酯(10mL×2)萃取两次。
结合有机相,用无水硫酸钠干燥,过滤以及减压下浓缩。随后柱层析分离得到产物11。
1-(1-Bromonaphthalen-2-yl)pyrrolidine(S5):
1.653g,60%yield,yellow oil,new compound,Rf=0.62(hexanes/ethylacetate 50/1).1H NMR(40025.5.HRMS Calculated for C14H15BrN[M+H]+276.0382(79Br)and 278.0362(81Br),found:276.0383(79Br)and 278.0363(81Br).
1-(Benzyloxy)-2-bromo-3-methylbenzene(S6):
99%yield,colorless oil,new compound,Rf=0.81(hexanes/ethyl acetate20/1).1H NMR(400MHz,111.1,70.9,23.5.HRMS Calculated for C14H17BrNO+[M+NH4]+294.0488(79Br)and296.0468(81Br),found:294.0487(79Br)and 294.0468(81Br).
2-(2-(Dimethylamino)naphthalen-1-yl)phenyl trifluoromethanesulfonate(rac-1a):
1.585g,76%yield,yellow solid,mp=168-169℃,new compound,Rf=0.60(hexanes/ethyl acetateMHz,CDCl3)δ-74.97.HRMS Calculated for C19H17F3NO3S+[M+H]+396.0876,found:396.0878.
2-(2-(Dimethylamino)naphthalen-1-yl)-4-fluorophenyl trifluoromethanesulfonate(rac-1b):
1.534g,73%yield,white solid,mp=108-109℃,new compound,Rf=0.70(hexanes/ethyl acetate 20/1).(m,3H),7.40-7.35(m,2H),7.29-7.25(m,1H),7.24-7.16(m,1H),2.61(s,6H).13C NMR(100MHz,CDCl3)δ162.5,160.0,150.3,144.1(d,J=2.0Hz),135.1(d,J=8.0Hz),133.0,130.6,130.1,128.2,126.8,124.4(d,J=4.0Hz),123.6(d,J=9.0Hz),122.7,120.9(d,J=23.0Hz),119.5,118.3(q,J=318.0Hz),115.7(d,J=24.0Hz),44.1.19F NMR(376MHz,CDCl3)δ-74.84,-113.27.HRMSCalculated for C19H16F4NO3S+[M+H]+414.0782,found:414.0785.
2-(2-(Dimethylamino)naphthalen-1-yl)-4-methoxyphenyltrifluoromethanesulfonate(rac-1c):
0.898g,71%yield,yellow solid,mp=103-104℃,new compound,Rf=0.47(hexanes/ethyl acetate-74.96.HRMS Calculated for C20H19F3NO4S+[M+H]+426.0981,found:426.0984.
2-(2-(Dimethylamino)naphthalen-1-yl)-4-methylphenyltrifluoromethanesulfonate(rac-1d):
1.619g,80%yield,yellow solid,mp=98-99℃,new compound,Rf=0.75(hexanes/ethyl acetate 20/1).410.1032,found:410.1033.
2-(2-(Dimethylamino)naphthalen-1-yl)-4-ethylphenyltrifluoromethanesulfonate(rac-1e):
1.247g,73%yield,yellow solid,mp=96-97℃,new compound,Rf=0.77(hexanes/ethyl acetate 20/1).-75.00.HRMS Calculated for C21H21F3NO3S+[M+H]+424.1189,found:424.1191.
2-(2-(Dimethylamino)naphthalen-1-yl)-4-isopropylphenyltrifluoromethanesulfonate(rac-1f):
1.349g,67%yield,yellow solid,mp=92-93℃,new compound,Rf=0.87(hexanes/ethyl acetate 20/1).CDCl3)δ-75.01.HRMS Calculated for C22H23F3NO3S+[M+H]+438.1345,found:438.1348.
4-(tert-Butyl)-2-(2-(dimethylamino)naphthalen-1-yl)phenyltrifluoromethanesulfonate(rac-1g):
1.647g,90%yield,yellow solid,mp=103-104℃,new compound,Rf=0.76(hexanes/ethyl acetate128.1,126.5,125.8,124.8,124.2,124.1,121.3,119.5,118.4(q,J=318.0Hz),43.9,34.9,31.4.19F NMR(376MHz,CDCl3)δ-75.00.HRMS Calculated for C23H25F3NO3S+[M+H]+452.1502,found:452.1503.
3-(2-(Dimethylamino)naphthalen-1-yl)-[1,1'-biphenyl]-4-yltrifluoromethanesulfonate(rac-1h):
1.032g,52%yield,white solid,mp=142-143℃,new compound,Rf=0.67(hexanes/ethyl acetate 20/1).δ-74.86.HRMS Calculated for C25H21F3NO3S+[M+H]+472.1189,found:472.1193.
2-(2-(Pyrrolidin-1-yl)naphthalen-1-yl)phenyl trifluoromethanesulfonate(rac-1i):0.796g,77%yield,yellow solid,mp=111-112℃,new compound,Rf=0.72(hexanes/ethyl acetatefor C21H19F3NO3S+[M+H]+422.1032,found:422.1034.
2-(2-Methoxynaphthalen-1-yl)phenyl trifluoromethanesulfonate(rac-1j):
1.418g,81%yield,yellow solid,mp=77-78℃,new compound,Rf=0.70(hexanes/ethyl acetate 10/1).HRMS Calculated for C18H14F3O4S+[M+H]+383.0559,found:383.0557.
2-(2-Isopropoxynaphthalen-1-yl)phenyl trifluoromethanesulfonate(rac-1k):
1.813g,89%yield,yellow oli,new compound,Rf=0.61(hexanes/ethylacetate 50/1).1H NMR(400J=318.3Hz),115.5,71.4,22.5,22.2.19F NMR(376MHz,CDCl3)δ-74.76.HRMS CalculatedforC20H18F3O4S+[M+H]+411.0872,found:411.0870.
2-(2-(Benzyloxy)naphthalen-1-yl)phenyl trifluoromethanesulfonate(rac-1l):
1.810g,80%yield,white solid,mp=93-94℃,new compound,Rf=0.51(hexanes/ethyl acetate 50/1).(q,J=318.0Hz),114.7,71.1.19F NMR(376MHz,CDCl3)δ-74.62.HRMS CalculatedforC24H18F3O4S+[M+H]+459.0872,found:459.0873.
2'-(Benzyloxy)-6'-methyl-[1,1'-biphenyl]-2-yltrifluoromethanesulfonate(rac-1m):
1.823g,76%yield,white solid,mp=64-65℃,new compound,Rf=0.60(hexanes/ethyl acetate 50/1).318.3Hz),109.9,70.2,20.1.19F NMR(376MHz,CDCl3)δ-74.62.HRMS Calculated forC21H18F3O4S+[M+H]+423.0872,found:423.0880.
2'-Methoxy-[1,1'-binaphthalen]-2-yl trifluoromethanesulfonate(rac-1n):
1.764g,41%yield,white solid,known compound,2e Rf=0.50(hexanes/ethylacetate 20/1).1H NMR127.00,126.96,124.9,123.8,119.7,118.4(q,J=318.0Hz),115.2,113.0,56.3.19F NMR(376MHz,CDCl3)δ-74.92.
(-)-2-(2-(Dimethylamino)naphthalen-1-yl)phenyltrifluoromethanesulfonate((-)-1a):
Conversion:53%,s 17.6,58.2mg,42%yield,83.8%ee,[α]20 D=-70.47(c0.84,CHCl3).HPLC:Chiralpak IA column,230nm,30℃,n-Hexane/i-PrOH=99.5/0.5,flow=0.5mL/min,retention time 8.5min(major)and 9.9min.
N,N-Dimethyl-1-phenylnaphthalen-2-amine(2a):
43.5mg,50%yield,white solid,known compound,3a Rf=0.68(hexanes/ethylacetate 20/1).1H NMR
(-)-2-(2-(Dimethylamino)naphthalen-1-yl)-4-fluorophenyltrifluoromethanesulfonate((-)-1b):
Conversion:50%,s 15.0,71.2mg,49%yield,74.4%ee,[α]20 D=-41.00(c0.60,CHCl3).HPLC:Chiralpak IA column,230nm,30℃,n-Hexane/i-PrOH=99.5/0.5,flow=0.5mL/min,retention time 8.2min(major)and 9.3min.
1-(3-Fluorophenyl)-N,N-dimethylnaphthalen-2-amine(2b):
45.7mg,49%yield,yellow oil,new compound,Rf=0.46(hexanes/dichloromethane 5/1).1H NMR(400
C18H17FN+[M+H]+266.1340,found:266.1341.
(-)-2-(2-(Dimethylamino)naphthalen-1-yl)-4-methoxyphenyltrifluoromethanesulfonate((-)-1c):
Conversion:41%,s 15.1,87.8mg,59%yield,55.2%ee,[α]20 D=-48.89(c1.54,CHCl3).HPLC:Chiralpak IA column,230nm,30℃,n-Hexane/i-PrOH=99.5/0.5,flow=0.5mL/min,retention time11.7min(major)and 13.0min.
1-(3-Methoxyphenyl)-N,N-dimethylnaphthalen-2-amine(2c):
35.1mg,36%yield,yellow oil,new compound,Rf=0.17(hexanes/dichloromethane 2/1).1H NMR(400
(-)-2-(2-(Dimethylamino)naphthalen-1-yl)-4-methylphenyltrifluoromethanesulfonate((-)-1d):
Conversion:52%,s 18.7,67.8mg,47%yield,82.5%ee,[α]20 D=-88.21(c0.84,CHCl3).HPLC:Chiralpak IA column,230nm,30℃,n-Hexane/i-PrOH=99.5/0.5,flow=0.5mL/min,retention time 8.5min(major)and 9.5min.
N,N-Dimethyl-1-(m-tolyl)naphthalen-2-amine(2d):
47.0mg,51%yield,yellow oil,new compound,Rf=0.24(hexanes/dichloromethane 5/1).1H NMR(400
(-)-2-(2-(Dimethylamino)naphthalen-1-yl)-4-ethylphenyltrifluoromethanesulfonate((-)-1e):
Conversion:51%,s 63.8,71.0mg,48%yield,93.4%ee,[α]20 D=-79.58(c0.96,CHCl3).HPLC:Chiralpak IA column,230nm,30℃,n-Hexane/i-PrOH=99.5/0.5,flow=0.5mL/min,retention time 8.0min(major)and 8.5min.
1-(3-Ethylphenyl)-N,N-dimethylnaphthalen-2-amine(2e):
48.1mg,50%yield,yellow oil,new compound,Rf=0.34(hexanes/dichloromethane 5/1).1H NMR(400
(-)-2-(2-(Dimethylamino)naphthalen-1-yl)-4-isopropylphenyltrifluoromethanesulfonate((-)-1f):
Conversion:52%,s 68.8,71.1mg,47%yield,96.4%ee,[α]20 D=-105.69(c1.00,CHCl3).HPLC:Chiralpak IB column,230nm,30℃,n-Hexane/i-PrOH=99.5/0.5,flow=0.5mL/min,retention time 7.8min(major)and 8.8min.
1-(3-Isopropylphenyl)-N,N-dimethylnaphthalen-2-amine(2f):
51.0mg,50%yield,colorless oil,new compound,Rf=0.25(hexanes/dichloromethane 5/1).1H NMR
(-)-4-(t-Butyl)-2-(2-(dimethylamino)naphthalen-1-yl)phenyltrifluoromethanesulfonate((-)-1g):
Conversion:49%,s 45.2,78.0mg,49%yield,85.2%ee,[α]20 D=-90.49(c1.20,CHCl3).HPLC:Chiralpak IB column,230nm,30℃,n-Hexane/i-PrOH=99.5/0.5,flow=0.5mL/min,retention time 7.4min(major)and 8.0min.
1-(3-(tert-Butyl)phenyl)-N,N-dimethylnaphthalen-2-amine(2g):
50.3mg,47%yield,yellow oil,new compound,Rf=0.36(hexanes/dichloromethane 5/1).1H NMR(400
(-)-3-(2-(Dimethylamino)naphthalen-1-yl)-[1,1'-biphenyl]-4-yltrifluoromethanesulfonat((-)-1h):
Conversion:53%,s 70.0,75.4mg,46%yield,98.4%ee,[α]20 D=-156.49(c0.80,CHCl3).HPLC:Chiralpak IA column,230nm,30℃,n-Hexane/i-PrOH=99.5/0.5,flow=0.5mL/min,retention time 9.8min(major)and 10.5min.
1-([1,1'-Biphenyl]-3-yl)-N,N-dimethylnaphthalen-2-amine(2h):
58.4mg,52%yield,yellow oil,new compound,Rf=0.29(hexanes/dichloromethane 5/1).1H NMR(400
(-)-2-(2-(Pyrrolidin-1-yl)naphthalen-1-yl)phenyltrifluoromethanesulfonate((-)-1i):
Conversion:65%,s 11.2,48.1mg,33%yield,95.9%ee,[α]20 D=-127.88(c0.71,CHCl3).HPLC:Chiralpak OD-3 column,230nm,30℃,n-Hexane/i-PrOH=99.0/1.0,flow=0.7mL/min,retention time8.0min and 10.1min(major).
1-(1-Phenylnaphthalen-2-yl)pyrrolidine(2i):
57.8mg,60%yield,yellow oil,new compound,Rf=0.81(hexanes/acetone 50/1).1H NMR(400MHz,
(-)-2-(2-Methoxynaphthalen-1-yl)phenyl trifluoromethanesulfonate((-)-1j):
Conversion:55%,s 13.0,57.6mg,43%yield,82.7%ee,[α]20 D=-82.96(c0.91,CHCl3).HPLC:Chiralpak IA column,230nm,30℃,n-Hexane/i-PrOH=98.0/2.0,flow=0.7mL/min,retention time 6.7min(major)and 7.8min.
2-Methoxy-1-phenylnaphthalene(2j):
43.2mg,53%yield,colorless oil,known compound,3b Rf=0.50(hexanes/ethyl acetate 50/1).1H NMR123.6,114.0,56.9.
(-)-2-(2-Isopropoxynaphthalen-1-yl)phenyl trifluoromethanesulfonate((-)-1k):
Conversion:53%,s 18.8,64.0mg,45%yield,84.9%ee,[α]20 D=-88.97(c0.88,CHCl3).HPLC:Chiralpak IA column,230nm,30℃,n-Hexane/i-PrOH=99.0/1.0,flow=0.6mL/min,retention time 7.1min(major)and 7.9min.
2-Isopropoxy-1-phenylnaphthalene(2k):
46.2mg,50%yield,colorless oil,new compound,Rf=0.68(hexanes/ethylacetate 50/1).1H NMR(400
(-)-2-(2-(Benzyloxy)naphthalen-1-yl)phenyl trifluoromethanesulfonate((-)-1l):
Conversion:44%,s 16.7,84.3mg,53%yield,62.6%ee,[α]20 D=-53.95(c1.24,CHCl3).HPLC:Chiralpak IA column,230nm,30℃,n-Hexane/i-PrOH=99.0/1.0,flow=0.6mL/min,retention time10.7min(major)and 15.4min.
2-(Benzyloxy)-1-phenylnaphthalene(2l):
44.8mg,41%yield,colorless oil,new compound,Rf=0.63(hexanes/ethylacetate 50/1).1H NMR(400C23H19O+[M+H]+311.1430,found:311.1430.
(-)-2'-(Benzyloxy)-6'-methyl-[1,1'-biphenyl]-2-yltrifluoromethanesulfonate((-)-1m):
Conversion:40%,s 5.3,84.1mg,57%yield,38.3%ee,[α]20 D=-25.00(c 1.28,CHCl3).HPLC:ChiralpakIA column,230nm,30℃,n-Hexane/i-PrOH=99.0/1.0,flow=0.6mL/min,retention time 7.5min(major)and 9.4min.
2-(Benzyloxy)-6-methyl-1,1'-biphenyl(2m):
36.4mg,38%yield,colorless oil,new compound,Rf=0.70(hexanes/ethylacetate 50/1).1H NMR(400for C20H22NO+[M+NH4]+292.1696,found:292.1703.
(R)-(-)-2'-Methoxy-[1,1'-binaphthalen]-2-yl trifluoromethanesulfonate((-)-1n):
Conversion:65%,s 3.7,49.1mg,33%yield,62.7%ee,[α]20 D=-74.15(c 0.53,CHCl3),[lit.3c:[α]20 D=-94.10(c 1.00,CHCl3)for>99%ee(R)].HPLC:Chiralpak IBcolumn,230nm,30℃,n-Hexane/i-PrOH=99.0/1.0,flow=0.7mL/min,retention time7.8min(minor)and 8.3min(major).
(R)-(-)-2-Methoxy-1,1'-binaphthalene(2n):
60.0mg,60%yield,white solid,known compound,Rf=0.58(hexanes/ethylacetate 20/1),34.8%ee,[α]20 D=-18.25(c 0.80,CHCl3),[lit.4a:[α]20 D=-42.20(c 1.23,CHCl3)for 97%ee(R)].1H NMR(400MHz,CDCl3)δ8.04-7.95(m,3H),7.89(d,J=8.1Hz,1H),7.68-7.61(m,1H),7.52-7.44(m,3H),7.39-7.29(m,3H),7.27-7.22(m,1H),7.18(d,J=8.5Hz,1H),3.78(s,3H).13C NMR(100MHz,CDCl3)δ154.7,134.7,134.4,133.8,133.1,129.6,129.1,128.6,128.4,127.92,127.86,126.5,126.3,126.0,125.8,125.7,125.6,123.7,123.3,113.9,56.8.HPLC:Chiralpak AD-H column,230nm,30℃,n-Hexane/i-PrOH=99.0/1.0,flow=0.6mL/min,retention time 10.0min(major)and 12.6min.
2-(2-Methoxynaphthalen-1-yl)-1,3-phenylene bis(trifluoromethanesulfonate)(3):
0.271g,85%yield,white solid,mp=95-96℃,new compound,Rf=0.67(hexanes/ethyl acetate 10/1). 19F NMR(376MHz,CDCl3)δ-74.54.HRMS Calculated for C19H13F6O7S2 +[M+H]+531.0001,found:531.0002.
(+)-(2-(2-(Benzyloxy)naphthalen-1-yl)phenyl)diphenylphosphine oxide(4a):
0.227g,61%yield,white solid,mp=144-145℃,new compound,Rf=0.19(hexanes/ethyl acetate 2/1),NMR(100MHz,CDCl3)δ153.3,141.2,141.1,137.7,134.5,134.4,134.0,133.8,133.7,133.2,133.0,132.9,132.7,132.2,132.0,131.92,131.86,131.8,131.5,131.4,131.03,131.00,130.72,130.70,129.9,128.6,128.4,127.8,127.7,127.5,127.4,127.3,127.1,126.7,126.0,125.7,123.82,123.78,123.4,114.0,70.3.31P NMR(162MHz,CDCl3)δ27.8.HRMS Calculated for C35H28O2P+[M+H]+511.1821,found:511.1819.HPLC:ChiralpakIA column,230nm,30℃,n-Hexane/i-PrOH=80/20,flow=1.0mL/min,retention time15.7min(major)and21.9min(minor).
(+)-(2-(2-(Benzyloxy)naphthalen-1-yl)phenyl)bis(4-methoxyphenyl)phosphine oxide(4b):
0.274g,65%yield,white solid,mp=135-136℃,new compound,Rf=0.14(hexanes/ethyl acetate 1/1), 13C NMR(100MHz,CDCl3)δ161.8,161.7,161.11,161.08,153.1,140.54,140.45,137.6,134.8,134.6,134.5,134.0,133.9,133.8,133.2,133.1,132.8,132.6,131.63,131.60,129.6,128.7,128.5,127.6,127.5,127.4,127.3,126.8,126.0,125.8,125.6,124.5,124.4,124.29,124.26,123.4,123.3,114.2,113.4,113.2,112.6,112.5,70.5,55.2,55.1.31P NMR(162MHz,CDCl3)δ28.4.HRMS Calculated for C37H32O4P+[M+H]+571.2033,found:571.2029.HPLC:Chiralpak IA column,230nm,30℃,n-Hexane/i-PrOH=60/40,flow=0.7mL/min,retention time 20.1min(major)and27.9min.
(+)-(2-(2-(Benzyloxy)naphthalen-1-yl)phenyl)di-p-tolylphosphine oxide(4c):
0.244g,62%yield,white solid,mp=69-70℃,new compound,Rf=0.31(hexanes/ethyl acetate 1/1),3H),7.14-7.04(m,3H),7.03-6.95(m,2H),6.80(dd,J=8.0,2.2Hz,2H),6.65(dd,J=8.0,2.3Hz,2H),5.06-4.96(m,2H),2.22(s,3H),2.15(s,3H).13C NMR(100MHz,CDCl3)δ153.3,141.22,141.19,140.9,140.78,140.75,137.8,134.6,134.5,134.4,133.8,133.5,132.9,132.8,132.0,131.9,131.7,131.6,131.5,131.4,130.7,129.8,129.7,129.4,128.7,128.6,128.5,128.4,127.9,127.8,127.5,127.4,127.3,127.2,126.7,125.9,125.8,124.1,124.0,123.3,114.1,70.5,21.54,21.45.31P NMR(162MHz,CDCl3)δ28.3.HRMSCalculated for C37H32O2P+[M+H]+539.2134,found:539.2139.HPLC:Chiralpak IAcolumn,230nm,30℃,n-Hexane/i-PrOH=60/40,flow=0.7mL/min,retention time 16.5min(major)and 28.2min.
(+)-(2-(2-(Benzyloxy)naphthalen-1-yl)phenyl)di(naphthalen-2-yl)phosphine oxide(4d):
0.261g,61%yield,white solid,mp=72-73℃,new compound,Rf=0.30(hexanes/ethyl acetate 1/1),4.95(s,2H).13C NMR(100MHz,CDCl3)δ153.2,141.1,141.0,137.7,134.7,134.6,134.40,134.37,134.2,134.1,134.0,133.9,133.7,133.4,133.3,133.2,133.0,132.9,132.3,132.2,132.0,131.9,131.8,131.1,130.3,130.0,129.8,129.3,129.0,128.5,128.3,127.8,127.67,127.65,127.63,127.58,127.5,127.2,127.1,127.0,126.8,126.74,126.66,126.62,126.56,126.4,126.1,126.0,125.4,123.7,123.6,123.4,113.8,70.5.31PNMR(162MHz,CDCl3)δ28.0.HRMS Calculated for C43H32O2P+[M+H]+611.2134,found:611.2137.HPLC:Chiralpak IA column,230nm,30℃,n-Hexane/i-PrOH=60/40,flow=0.7mL/min,retention time 19.3min(major)and27.1min(minor).
(-)-(2-(2-(Benzyloxy)naphthalen-1-yl)phenyl)diphenylphosphane(5a):
0.154g,94%yield,white solid,new compound,Rf=0.61(hexanes/ethylacetate 20/1),[α]20 D=-18.20(c128.0,127.9,127.8,127.7,127.3,126.5,126.1,125.52,125.48,125.4,123.5,114.7,70.3.31P NMR(162MHz,CDCl3)δ-13.7.HRMS Calculated for C35H28OP+[M+H]+495.1872,found:495.1869.
(-)-(2-(2-(Benzyloxy)naphthalen-1-yl)phenyl)bis(4-methoxyphenyl)phosphane(5b):
0.180g,95%yield,white solid,new compound,Rf=0.50(hexanes/ethylacetate 20/1),[α]20 D=-18.00(c133.6,131.41,131.35,129.4,128.9,128.8,128.6,128.53,128.47,128.4,128.3,127.7,127.6,127.3,126.4,126.0,125.6,125.5,125.4,123.5,114.7,113.9,113.82,113.79,113.7,70.4,55.20,55.16.31PNMR(162MHz,CDCl3)δ-16.5.HRMS Calculated for C37H32O3P+[M+H]+555.2084,found:555.2087.
(-)-(2-(2-(Benzyloxy)naphthalen-1-yl)phenyl)di-p-tolylphosphane(5c):
0.218g,93%yield,white solid,new compound,Rf=0.65(hexanes/ethylacetate 20/1),[α]20 D=-21.20(c0.50,CHCl3).1H NMR(400MHz,CDCl3)δ7.86-7.71(m,2H),7.50-7.43(m,1H),7.41-7.34(m,1H),7.34-7.05(m,11H),7.04-6.81(m,8H),4.88(dd,J=91.2,12.6Hz,2H),2.25(s,6H).13C NMR(100MHz,CDCl3)δ153.3,143.1,142.8,139.6,139.5,138.1,138.0,137.7,134.4,134.3,134.2,134.0,133.9,133.8,133.7,133.5,131.4,131.3,129.4,129.0,128.94,128.91,128.86,128.3,127.8,127.7,127.3,126.4,126.1,125.61,125.58,123.4,114.7,70.4,21.4.31P NMR(162MHz,CDCl3)δ-15.4.HRMS Calculatedfor C37H32OP+[M+H]+523.2185,found:523.2200.
(-)-(2-(2-(Benzyloxy)naphthalen-1-yl)phenyl)di(naphthalen-2-yl)phosphane(5d):
0.188g,96%yield,white solid,new compound,Rf=0.47(hexanes/ethylacetate 20/1),[α]20 D=-15.60(c130.4,130.3,130.2,129.6,129.3,128.9,128.4,128.2,128.1,127.9,127.73,127.72,127.69,127.65,127.6,127.5,127.39,127.37,126.50,126.46,126.3,126.1,126.03,126.00,125.5,125.4,123.5,114.7,70.4.31P NMR(162MHz,CDCl3)δ-12.4.HRMSCalculated for C43H32OP+[M+H]+595.2185,found:595.2185.
54.0mg,93%yield,known compounds,4e 7:8=16.7:1,92%ee,Rf=0.38(hexanes/ethyl acetate 20/1).HPLC:ChiralpakAD-H column,220nm,30℃,n-Hexane/i-PrOH=97/3,flow=0.7mL/min,retentiontime 10.1min(major)and 11.4min.
The 1H NMR data of the branched compound 7:1H NMR(400MHz,CDCl3)δ7.21-7.08(m,2H),6.88-6.74(m,2H),6.34-6.17(m,1H),5.20-5.00(m,2H),4.10(d,J=8.6Hz,1H),3.77(s,3H),3.70(s,3H),3.62(s,3H),1.42(s,3H).
The 1H NMR data ofthe linear compound 8:1H NMR(400MHz,CDCl3)δ7.21-7.08(m,2H),6.88-6.74(m,2H),6.42-6.35(m,1H),5.97-5.88(m,1H),3.79(s,3H),3.73(s,6H),2.74(d,J=7.0Hz,2H),1.44(s,3H).
(+)-dimethyl(R,E)-2-(1,3-diphenylallyl)malonate(10):
78.0mg,96%yield,known compound,Rf=0.27(hexanes/ethyl acetate 20/1),94%ee,[α]20 D=+21.00(c1.00,CHCl3),[lit.5b:[α]20 D=+6.1(c 1.00,CHCl3)for 50%ee(R)].1H NMR(400MHz,CDCl3)δ7.35-7.16(m,10H),6.48(d,J=15.8Hz,1H),6.33(dd,J=15.7,8.6Hz,1H),4.27(dd,J=10.8,8.7Hz,1H),3.96(d,J=10.9Hz,1H),3.70(s,3H),3.51(s,3H).HPLC:Chiralpak AD-H column,254nm,30℃,n-Hexane/i-PrOH=95/5,flow=1.0mL/min,retention time 15.9min(major)and 22.3min(minor).
(-)-1-([1,1':4',1″-Terphenyl]-2'-yl)-N,N-dimethylnaphthalen-2-amine(11):
54.3mg,68%yield,white solid,mp=65-66℃,new compound,Rf=0.56(hexanes/ethyl acetate 40/1),98%ee,[α]20 D=-41.60(c 1.00,CHCl3).1H NMR(400MHz,CDCl3)δ7.88-7.79(m,2H),7.78-7.68(m,5H),7.63(d,J=7.7Hz,1H),7.51-7.44(m,2H),7.44-7.32(m,3H),7.13-6.99(m,4H),6.97-6.90(m,2H),2.26(s,6H).13C NMR(100MHz,CDCl3)δ148.7,141.8,141.7,140.8,139.6,137.6,134.4,131.4,130.8,129.9,129.3,129.0,128.7,128.6,128.1,127.4,127.2,127.1,126.3,126.2,126.0,125.4,123.7,119.8,43.3.HRMS Calculated for C30H26N[M+H]+400.2060,found:400.2061.HPLC:Chiralpak IAcolumn,230nm,30℃,n-Hexane/i-PrOH=99.5/0.5,flow=0.6mL/min,retention time 7.4min and 7.9min(major).
Claims (10)
1.一种通过动力学拆分实现钯催化的不对称氢解合成轴手性联芳基化合物的方法,其特征在于,所述方法以钯的手性双膦配合物为催化剂,芳基三氟甲磺酸酯为底物,还原试剂作为氢源,经过不对称氢解合成具有轴手性的联芳基化合物。
反应式如下:
式中:
R为甲氧基、苄氧基、异丙氧基、环戊胺基或二甲氨基;
Ar为苯环、萘环或含有取代基的芳环,所述的取代基为氟、甲基、甲氧基、乙基、异丙基、叔丁基、苯基中的一种;
所述催化剂为金属钯前体和手性双膦配体的配合物。
2.根据权利要求1所述的方法,其特征在于,反应溶剂为有机溶剂,所述有机溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、甲醇的一种;反应温度:-50℃-30℃;反应时间:0.5-36小时。
3.根据权利要求1所述的方法,其特征在于:金属钯前体与手性双膦配体摩尔比为1:1-1:3。
4.根据权利要求1所述的方法,其特征在于:所述金属钯前体为三氟乙酸钯、醋酸钯中的一种;手性双膦配体为(R)-SegPhos,(S)-SegPhos,(R)-DM-SegPhos,(S)-DM-SegPhos,(R)-DTBM-SegPhos,(S)-DTBM-SegPhos,(R)-DifluorPhos,(S)-DifluorPhos,(R)-3,5-t-Bu-4-MeO-MeOBIPHEP,(S)-3,5-t-Bu-4-MeO-MeOBIPHEP中的一种。
5.根据权利要求1所述的方法,其特征在于:所述还原试剂为硼氢化钠、硼氘化钠、硼氢化锂、硼氘化锂、硼氢化钾、硼氘化钾中的一种。
6.根据权利要求1所述的方法,其特征在于:所述催化剂的制备方法为:氮气保护下,将金属钯前体和手性双膦配体在反应溶剂中30℃搅拌10分钟-60分钟得到。
7.根据权利要求1所述的方法,其特征在于,所述芳基三氟甲磺酸酯、金属钯前体与手性双膦配体的摩尔比为1:0.005:0.0006-1:0.05:0.100。
8.根据权利要求1所述的方法,其特征在于,所述方法的具体反应步骤为:
氮气保护下,将金属钯前体和手性双膦配体在反应溶剂中30℃搅拌10分钟-60分钟,然后加入芳基三氟甲磺酸酯,将反应体系置于-50-30℃下搅拌20分钟后,加入氢源,维持该温度进行反应,得到轴手性的联芳基化合物。
9.权利要求1-8中任意一项所述方法合成的轴手性联芳基化合物在合成手性单膦配体中的应用。
10.权利要求9中所述的手性单膦配体在钯催化不对称烯丙基烷基化反应中的应用。
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