CN100577650C - 用于不对称催化反应的催化剂及其中的手性配体 - Google Patents
用于不对称催化反应的催化剂及其中的手性配体 Download PDFInfo
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- CN100577650C CN100577650C CN200580014717A CN200580014717A CN100577650C CN 100577650 C CN100577650 C CN 100577650C CN 200580014717 A CN200580014717 A CN 200580014717A CN 200580014717 A CN200580014717 A CN 200580014717A CN 100577650 C CN100577650 C CN 100577650C
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- enantiomer
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- enantiomeric mixture
- alkyl
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- 238000006243 chemical reaction Methods 0.000 title claims abstract description 24
- 239000003446 ligand Substances 0.000 title abstract description 12
- 239000003054 catalyst Substances 0.000 title abstract description 6
- 238000006555 catalytic reaction Methods 0.000 title description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 50
- 239000000203 mixture Substances 0.000 claims abstract description 46
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 28
- 150000003624 transition metals Chemical class 0.000 claims abstract description 24
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 19
- 125000003118 aryl group Chemical group 0.000 claims abstract description 18
- 125000000746 allylic group Chemical group 0.000 claims abstract description 14
- 238000006467 substitution reaction Methods 0.000 claims abstract description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 11
- 150000001721 carbon Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000010948 rhodium Substances 0.000 claims description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 5
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 5
- 239000000758 substrate Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 4
- 229910052703 rhodium Inorganic materials 0.000 claims description 4
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 229910052707 ruthenium Inorganic materials 0.000 claims description 3
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical group Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 claims description 3
- 239000005052 trichlorosilane Substances 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 2
- 229910052741 iridium Inorganic materials 0.000 claims description 2
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical class PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 abstract description 12
- 125000000547 substituted alkyl group Chemical group 0.000 abstract description 11
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 9
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- -1 pyrimidyl diphosphine compounds Chemical class 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000004679 31P NMR spectroscopy Methods 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 238000006579 Tsuji-Trost allylation reaction Methods 0.000 description 3
- JZOSBBLJKXSBBN-UHFFFAOYSA-N [3-(4-diphenylphosphanyl-2,6-dimethoxypyridin-3-yl)-2,6-dimethoxypyridin-4-yl]-diphenylphosphane Chemical compound COC=1N=C(OC)C=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1C=1C(OC)=NC(OC)=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 JZOSBBLJKXSBBN-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 230000002152 alkylating effect Effects 0.000 description 2
- 238000007105 allylic amination reaction Methods 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- LWFWUJCJKPUZLV-UHFFFAOYSA-N n-trimethylsilylacetamide Chemical class CC(=O)N[Si](C)(C)C LWFWUJCJKPUZLV-UHFFFAOYSA-N 0.000 description 2
- 239000012434 nucleophilic reagent Substances 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000004904 shortening Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical class O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- IBTGEEMBZJBBSH-UHFFFAOYSA-N 2,6-dimethoxypyridine Chemical compound COC1=CC=CC(OC)=N1 IBTGEEMBZJBBSH-UHFFFAOYSA-N 0.000 description 1
- MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 description 1
- IRLDCGSNDXFFQH-UHFFFAOYSA-N 5-bromo-2,4-dimethoxypyridine Chemical compound COC1=CC(OC)=C(Br)C=N1 IRLDCGSNDXFFQH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- BWHOZHOGCMHOBV-UHFFFAOYSA-N Benzalacetone Natural products CC(=O)C=CC1=CC=CC=C1 BWHOZHOGCMHOBV-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- 239000012327 Ruthenium complex Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000006887 Ullmann reaction Methods 0.000 description 1
- 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 description 1
- GDMCOFXEPNHXJT-UHFFFAOYSA-N [5-(6-diphenylphosphanyl-2,3-dihydro-1,4-benzodioxin-5-yl)-2,3-dihydro-1,4-benzodioxin-6-yl]-diphenylphosphane Chemical compound O1CCOC(C=2C=3C=4OCCOC=4C=CC=3P(C=3C=CC=CC=3)C=3C=CC=CC=3)=C1C=CC=2P(C=1C=CC=CC=1)C1=CC=CC=C1 GDMCOFXEPNHXJT-UHFFFAOYSA-N 0.000 description 1
- 230000004308 accommodation Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- TWKVUTXHANJYGH-UHFFFAOYSA-L allyl palladium chloride Chemical compound Cl[Pd]CC=C.Cl[Pd]CC=C TWKVUTXHANJYGH-UHFFFAOYSA-L 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000006459 hydrosilylation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 238000000711 polarimetry Methods 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- ZNCPFRVNHGOPAG-UHFFFAOYSA-L sodium oxalate Chemical compound [Na+].[Na+].[O-]C(=O)C([O-])=O ZNCPFRVNHGOPAG-UHFFFAOYSA-L 0.000 description 1
- 229940039790 sodium oxalate Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004454 trace mineral analysis Methods 0.000 description 1
- BWHOZHOGCMHOBV-BQYQJAHWSA-N trans-benzylideneacetone Chemical compound CC(=O)\C=C\C1=CC=CC=C1 BWHOZHOGCMHOBV-BQYQJAHWSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
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- B—PERFORMING OPERATIONS; TRANSPORTING
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Abstract
本发明提供了式(I)的二嘧啶基二膦基化合物或其对映异构体或其对映异构体混合物,其中R是任选被取代的烷基、环烷基、芳基或杂芳基;R’和R”独立地是任选被取代的烷基、环烷基、芳基或杂芳基。式(I)化合物是手性旋转对映异构的二嘧啶基二膦化合物,因此可以用作产生手性过渡金属催化剂的配体,所述催化剂可用于多种不对称反应,例如钯催化不对称烯丙位取代反应。根据本文公开的方法,本发明的化合物易于以高的对映结构体纯度获得。
Description
手性膦配体的设计和合成在有效的不对称过渡金属催化反应中起着重要作用。因此,已经合成和评估了大量有效的手性二膦配体。手性旋转对映异构的二膦,例如BINAP(美国专利第4,739,084号;J.Am.Chem.Soc.1980,102,7932)、BIPHEP(Helv.Chim.Acta.1988,71,897)、MeO-BIPHEP(Helv Chim.Acta.1991,74,370)、BICHEP(美国专利第5,021,593号;Chem.Lett.1989,1849)、SEGPHOS(美国专利第5,872,273号;Adv.Synth.Catal.2001,343,264)、SYNPHOS(Tetrahedron Lett.2002,43,2789;Tetrahedron Lett.2003,44,823)、TunaPhos(J.Org.Chem.2000,65,6223)、四甲基-BITANP(美国专利第5,907,045号;J.Chem.Soc.,Chem.Commun.1995,685)、四甲基-BTIOP(J.Org.Chem.2000,65,2043)和P-Phos(美国专利第5,886,182号;J.Am.Chem.Soc.2000,122,11513),显示了良好的对映选择性,尤其在铑(Rh)、钌(Ru)和钯(Pd)催化的不对称反应中如此。在这些配体中,P-Phos家族包括含氮的二杂环结构,如下图1所示。已经发现与P-Phos配体形成的铑和钌络合物以良好的对映选择性催化宽范围底物的不对称加氢作用。
图1.
尽管在该领域有广泛的研究,仍存在使用这些配体仅获得适度的对映选择性的许多反应。例如,在钯催化烯丙位取代反应(其是控制碳-碳键和碳-杂原子键形成引入的最有力工具)中,仅发现一些手性二膦配体有应用(Chem.Rev.,1996,96,395)。因此,对研发如下的新型手性二膦配体保持高度期望:其具有特殊性质,在多种不对称催化反应(例如不对称烯丙位取代反应)中具有选择性且有效,并且易于以高光学纯度合成获得。
因此,本发明提供了具有下式的二嘧啶基二膦化合物或其对映异构体或其对映异构体混合物,
其中
R是任选被取代的烷基、环烷基、芳基或杂芳基;
R’和R”独立地是任选被取代的烷基、环烷基、芳基或杂芳基。
式(I)化合物是手性旋转对映异构的二嘧啶基二膦化合物,因此可以用作产生手性过渡金属催化剂的配体,所述催化剂可用于多种不对称反应,例如钯催化不对称烯丙位取代反应。根据本文公开的方法,本发明的化合物易于以高的对映结构体纯度获得。
从下列的说明和所附权利要求书出发,本发明的其它目的、特征、优点和方面对本领域技术人员而言将变得显而易见。然而应当理解,当表明为本发明的优选实施方案时,下列的说明、所附的权利要求书和具体实施例仅作为说明的形式给出。通过阅读下文,在所公开发明的宗旨和范围内作各种变化和变通将对本领域技术人员而言变得易于明白。
下面列出的是用于描述本发明化合物的各种术语的定义。当术语在说明书各处使用时,这些定义适用于它们,除非它们在单独的或作为较大基团一部分时限于具体的实例。
术语“任选被取代的烷基”指具有1-20个碳原子、优选1-7个碳原子的未取代或取代的直链或支链烃基。示例性的未取代烷基包括甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、戊基、新戊基、己基、异己基、庚基、辛基等。被取代的烷基包括但不限于被一个或多个下列基团取代的烷基:羟基、烷氨基、二烷基氨基、环烷基、链烯基或烷氧基。
术语“低级烷基”指具有1-6个碳原子的如上所述任选被取代的烷基。
术语“链烯基”指具有至少两个碳原子并且附着点进一步包含碳碳双键的任一上述烷基。优选具有2至4个碳原子的基团。
术语“卤素”、“卤离子”和“卤代”指氟、氯、溴和碘。
术语“烷氧基”指烷基-O-。
术语“环烷基”指3-6个碳原子的任选被取代的单环脂肪族烃基,其可以被一个或多个取代基如烷基或烷氧基取代。
示例性的单环烃基包括但不限于环丙基、环丁基、环戊基、环己基等。
术语“芳基”指在环部分具有6-12个碳原子的单环或双环芳香烃基,例如苯基、联苯基、萘基和四氢萘基,其各自可任选被1-4个取代基取代,例如任选被取代的烷基、环烷基或烷氧基。
术语“单环芳基”指如芳基中所述任选被取代的苯基。
术语“杂芳基”指芳香杂环,例如单环或双环芳基,例如吡咯基、吡唑基、咪唑基、三唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吲哚基、苯并噻唑基、苯并噁唑基、苯并噻吩基、喹啉基、异喹啉基、苯并咪唑基、苯并呋喃基等,任选被例如低级烷基或低级烷氧基取代。
如上文所述,本发明涉及式(I)化合物,涉及它们的制备方法,以及涉及这些化合物在不对称催化中的用途。当在钯催化不对称烯丙位取代反应中用作手性配体时,本发明的化合物尤其有用。
需要时,可以引入保护基团,以防止现有官能团在用于进行本发明的特定化学转化的条件下与反应组分发生不期望的反应。对特定反应的保护基团的需要和选择对本领域技术人员而言是已知的,它取决于待保护官能团(氨基、羟基等)的性质、取代基为其一部分的分子的结构和稳定性,以及反应条件。
符合这些条件的公知的保护基以及它们的引入和去除描述于例如McOmie的“有机化学中的保护基团”(“Protective Groups in OrganicChemistry”,Plenum Press,伦敦,NY(1973)和Greene及Wuts的“有机合成中的保护基团”(“Protective Groups in Organic Synthesis”,JohnWiley and Sons,Inc.,NY(1999))中。
优选如下定义的式(I)化合物或其对映异构体或其对映异构体混合物,其中:R是单环芳基;R’和R”独立地是低级烷基。
进一步优选如下定义的式(I)化合物或其对映异构体或其对映异构体混合物,其中:R是苯基;R’和R”是甲基。
本发明的具体实施方案是:
(R)-5,5′-双(二取代膦基)-1,1′,3,3′-四烷基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮,还称作(R)-PM-Phos;和
(S)-5,5′-双(二取代膦基)-1,1′,3,3′-四烷基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮,还称作(S)-PM-Phos。
优选本发明的化合物具有至少85%对映异构体过量(ee)、更优选至少95%ee、最优选至少98%ee的旋光纯度。
本发明的化合物可用于产生手性过渡金属催化剂,该催化剂包含与式(I)化合物或其对映异构体或其对映异构体混合物结合的适宜的过渡金属:
其中
R是任选被取代的烷基、环烷基、芳基或杂芳基;
R’和R”独立地是任选被取代的烷基、环烷基、芳基或杂芳基。
特别有用的是如下定义的本发明的催化剂,其中过渡金属结合于式(I)化合物或其对映异构体或其对映异构体混合物,其中R是单环芳基;R’和R”独立地是低级烷基。
尤其有用的是如下定义的本发明的催化剂,其中过渡金属结合于式(I)化合物或其对映异构体或其对映异构体混合物,其中R是苯基;R’和R”是甲基。
尤其有用的还是如下定义的本发明的催化剂,其中过渡金属结合于式(I)化合物,该化合物选自:(R)-5,5′-双(二取代膦基)-1,1′,3,3′-四烷基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮和(S)-5,5′-双(二取代膦基)-1,1′,3,3′-四烷基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮。
适于本发明催化系统的过渡金属包括但不限于铜(Cu)、铱(Ir)、镍(Ni)、钯(Pd)、铂(Pt)、铑(Rh)和钌(Ru)。优选过渡金属是钯。
特别有用的是如下定义的本发明的催化剂,其中过渡金属是钯,并且过渡金属结合于式(I)化合物或其对映异构体或其对映异构体混合物,其中R是单环芳基;R’和R”独立地是低级烷基。
尤其有用的是如下定义的本发明的催化剂,其中过渡金属是钯,并且过渡金属结合于式(I)化合物或其对映异构体或其对映异构体混合物,其中R是苯基;R’和R”是甲基。
尤其有用的还是如下定义的本发明的催化剂,其中过渡金属是钯,并且过渡金属结合于式(I)化合物,所述式(I)化合物选自:
(R)-5,5′-双(二取代膦基)-1,1′,3,3′-四烷基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮;和
(S)-5,5′-双(二取代膦基)-1,1′,3,3′-四烷基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮。
本发明的化合物可如下制备:在溶剂如四氢呋喃(THF)中用碱如二异丙基氨基锂(LDA)或双(三甲基硅烷基)氨基锂使式(II)化合物去质子化:
其中R’和R”如上文定义,且X代表卤素,例如碘、溴或氯,
优选温度为约-78℃。然后将所得阴离子,其中X已经自发迁移到6-位,用式(III)化合物处理:
Cl-PR2 (III)
其中R如上文定义,
得到式(IV)化合物:
其中,R、R’、R”和X如上文定义。
式(II)和式(III)化合物是已知的,或者如果它们是新的,则可以根据本领域公知的方法制备。
然后将所得式(IV)化合物用氧化剂如过氧化氢在惰性溶剂(例如丙酮)中处理,得到式(V)化合物:
其中R、R’、R”和X如上文定义。优选氧化在约-10℃至0℃温度下进行。
所得式(V)化合物可以在Ullmann偶联条件下转化为式(VI)化合物,例如,式(V)化合物可以在惰性溶剂(例如N,N-二甲基甲酰胺(DMF)或二甲基亚砜(DMSO))中用铜粉处理,得到式(VI)化合物:
其中,R、R’、R”和X如上文定义。优选Ullmann偶联反应在无机盐(例如碳酸钠、碳酸钾或草酸钠或它们的混合物)的存在下(以促进偶联反应)、在约100℃至约160℃、优选约140℃的温度下进行。令人感兴趣的是,偶联反应伴有R’和R”基团从氧原子到氮原子的自发迁移。
然后通过已知方法将所得外消旋式(VI)化合物拆分成旋光对映体,即对映异构体,例如通过分离它们的非对映异构的盐来拆分,例如通过使它们的(+)-或(-)二苯甲酰酒石酸盐例如从乙酸乙酯和氯仿的1∶1混合物中分步结晶来拆分。然后可释放出下式旋光活性化合物:
其中R、R’和R”如上文定义,
例如通过用碱如氢氧化钠(NaOH)水溶液处理而被释放,
得到式R-(VI)或S-(VI)的游离化合物或其对映异构体混合物。
也可以通过手性色谱法如使用手性吸附剂的高压液相色谱(HPLC)来拆分外消旋式(VI)化合物。
最后,式(VI)化合物或其对映异构体或其对映异构体混合物可以在有机碱(例如三乙胺或三正丁胺)和芳香烃溶剂(如甲苯或二甲苯)存在下用还原剂(例如三氯硅烷)处理,分别得到式(I)化合物或其对映异构体或其对映异构体混合物,其中R、R’和R”如上文定义。优选还原在高压釜中在甲苯中进行,温度约120℃。
然后,式(I)化合物可如下转化为本发明的手性过渡金属催化剂:使式(I)化合物或其对映异构体或其对映异构体混合物与适宜的过渡金属盐或其络合物反应,得到本发明的催化剂。适宜过渡金属盐或其络合物的选择是本领域技术人员公知的,其取决于所进行的不对称反应的性质。适用于本发明催化剂的制备的过渡金属盐或其络合物可选自例如本文解释性实例中描述的那些。这些过渡金属盐的其它实施例可例如从Seyden-Penne的“不对称合成中的手性辅剂和配体”(Chiral Auxiliariesand Ligands in Asymmetric Synthesis,John Wiley&Sons,Inc.,NY(1995))中找到。本发明的催化剂可以原位产生,或者可以在使用前分离出。
如本文所述可获得的本发明催化剂可用于在其它方面适于不对称诱导的反应条件下将外消旋或前手性的底物转化为手性产物。
这些不对称反应包括但不限于:催化氢化、氢化硅烷化、硼氢化、加氢甲醛基化、氢羧基化、加氢酰化、Heck反应和烯丙位取代反应。当用于烯丙位取代反应时,本发明的催化剂特别有效。例如,式(I)化合物可以与钯络合物(如烯丙基氯化钯或三(双苯亚甲基丙酮)钯的二聚体在适宜有机溶剂如二氯甲烷(DCM)中反应,获得本发明的催化剂。然后将所得催化剂原位用于适宜的钯催化反应,例如用于不对称烯丙位取代反应如烯丙位烷基化或烯丙位氨基化反应中。
如表1和表2所示,本发明的催化剂体系可以以良好的催化活性和对映异构选择性有效地用于不对称钯催化烯丙位烷基化和氨基化反应。
表1总结了在多种反应条件下采用丙二酸二甲酯的三甲基硅烷基烯醇化物作为亲核试剂和采用(R)-PM-Phos作为手性配体的钯催化烯丙位烷基化的结果。正如所期望的,在较低温度下以损害反应速率为代价,可获得较好的对映异构选择性。令人感兴趣的是,当使用醋酸钠(NaOAc)作为碱产生烯醇化物时,在各情况下均获得最佳的对映异构选择性。
表1:采用(R)-PM-Phos的钯催化烯丙位烷基化
a通过HPLC(Daicel Chiracel AD柱,1.0mL/分钟,己烷∶i-PrOH-95∶5 )测定对映异构体过量。
b通过1H NMR谱测定底物的转化。
cN,O-双(三甲基硅烷基)乙酰胺。
类似地,表2总结了采用苄胺作为亲核试剂和采用(R)-PM-Phos作为手性配体的钯催化烯丙位烷基化的结果。如在第1和2项中所举例的,采用本发明催化剂的不对称烯丙位氨基化提供了其催化活性和对映异构选择性显著高于在相同条件下采用众所周知的二膦配体BINAP所获得的催化活性和对映异构选择性的手性烯丙型胺。
表2:采用(R)-PM-Phos和(S)-BINAP的钯催化烯丙位氨基化
a通过HPLC(Daicel Chiracel OJ柱,0.6mL/分钟,己烷∶i-PrOH-95∶10)测定对映异构体过量。
b通过1H NMR谱测定底物的转化。
下述实施例旨在进一步阐述本发明,并不构成其限制。如果没有另外提及,所有蒸发在减压下进行,优选在约5-50mmHg下进行。终产物、中间体和原料的结构通过标准分析方法如微量分析、熔点和光谱学特征如MS、IR、NMR来确定。所用缩略语是本领域常规的缩略语。
实施例1
4-溴-5-(二苯基膦基)-2,6-二甲氧基嘧啶
于0℃向8.2mL(58.4mmol)二异丙胺在50mL无水THF中的磁力搅拌下的溶液中滴加34.2mL(54.7mmol)n-BuLi的己烷溶液(1.6M)。滴加后,所得溶液在室温下保持1小时,然后冷却至-78℃。向上述LDA溶液中在1小时内滴加5-溴-2,4-二甲氧基嘧啶(10g,45.6mmol)的50mLTHF溶液。温度允许略有升高,直到溶液颜色变为黑棕色,然后再次冷却至-78℃。向上述溶液中滴加ClPPh2(10mL,55.5mmol)在50mL THF中的溶液。最后允许温度自然升至室温。反应混合物于环境温度另外搅拌12小时。结束后,在剧烈搅拌下将反应混合物倾入300mL水中。用DCM(3×50mL)萃取产物。所合并的萃取液用水洗涤3次,经无水硫酸钠干燥。真空除去溶剂,得到粗品,其通过采用DCM作为洗脱剂的快速层析法、然后通过在甲醇和丙酮的1∶1混合物中重结晶而纯化,得到纯的白色粉末状4-溴-5-(二苯基膦基)-2,6-二甲氧基嘧啶:
1H NMR(500MHz)(CDCl3)δ3.55(s,3H,OCH3),4.02(s,3H,OCH3),7.31-7.38(m,10H,PhH);13C-NMR(126MHz)(CDCl3)δ54.4,55.8,110.9(d,J=24.0Hz),128.4(d,J=5.7Hz),128.6,132.6(d,J=20.1Hz),135.3(d,J=10.6Hz),162.6(d,J=41.5Hz),165.0,172.3(d,J=2.9Hz);31P-NMR(202MHz)(CDCl3)δ-9.0(s).
实施例2
4-溴-5-(二苯基氧膦基)-2,6-二甲氧基嘧啶
配有磁力搅拌器的圆底烧瓶装有来自实施例1的4-溴-5-(二苯基膦基)-2,6-二甲氧基嘧啶(13g)和150mL丙酮,将反应混合物剧烈搅拌并冷却至0℃。向该混合物中缓慢加入15mL约35%过氧化氢。TLC监测反应。待固体完全溶解后,反应完全。加入100mL水后,将产物用DCM(3×50mL)萃取。所合并的萃取液用水洗涤3次,经无水硫酸钠干燥。真空浓缩溶液,得到粗品,其通过在乙酸乙酯和己烷的1∶1混合物中重结晶而纯化,得到纯的无色结晶状4-溴-5-(二苯基氧膦基)-2,6-二甲氧基嘧啶:
1H NMR(500MHz)(CDCl3)δ3.49(s,3H),4.02(s,3H),7.43-7.46(m,4H),7.50-7.54(m,2H),7.67-7.72(m,4H);13C-NMR(126MHz)(CDCl3)δ54.7,56.1,128.6(d,J=12.6Hz),131.5(d,J=10.6Hz),132.0,133.1,134.0,158.8(d,J=6.8Hz),165.2,172.3(d,J=5.8Hz);31P-NMR(202MHz)(CDCl3)δ24.8(s).
实施例3
5,5′-二(二苯基氧膦基)-1,1′,3,3′-四甲基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮
将来自实施例2的4-溴-5-(二苯基氧膦基)-2,6-二甲氧基嘧啶(4.8g,11.5mmol)、铜粉(7.36g,115mmol)、碳酸钠(6.1g,58mmol)和10mL无水DMF的混合物在氮气中于140℃搅拌24小时。蒸发混合物至几乎干燥。残留物在50mL氯仿中沸腾数分钟,过滤除去不溶的固体,并用热氯仿(2×10mL)洗涤。用5N氨水(2×100mL)、水(2×100mL)和盐水(100mL)洗涤合并的滤液,然后用硫酸钠干燥。真空蒸发溶剂,残留物通过采用乙酸乙酯和氯仿的1∶1混合物作为洗脱剂的快速层析法纯化。真空浓缩洗脱液,产品通过在乙酸乙酯和DCM的溶液中重结晶而进一步纯化,得到纯的无色结晶状5,5′-二(二苯基氧膦基)-1,1′,3,3′-四甲基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮:
1H NMR(500MHz)(CDCl3)δ3.32(s,6H),3.41(s,6H),6.94-6.98(m,4H),7.15-7.18(m,2H),7.45-7.57(m,10H),8.03-8.07(m,4H);13C-NMR(126MHz)(CD2Cl2)δ28.4,34.0,104.7(d,J=113Hz),127.8(d,J=13.9Hz),128.2(d,J=12.6Hz),131.7(d,J=81.3Hz),131.8,131.8(d,J=12.3Hz),132.6(d,J=86.9Hz),132.4(d,J=2.5Hz),133.7(d,J=10.1Hz),153.9(d,J=12.6Hz),161.5(d,J=8.8Hz);31P-NMR(202MHz)(CDCl3)δ29.1(s).
实施例4
5,5′-二(二苯基氧膦基)-1,1′,3,3′-四甲基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮的旋光拆分
向来自实施例3的外消旋5,5′-二(二苯基氧膦基)-1,1′,3,3′-四甲基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮(1.4g,2.1mmol)和(-)-二苯甲酰基-L-酒石酸[(-)-DBTA](0.78g,2.1mmol)的混合物中加入15mL乙酸乙酯和15mL氯仿。加热溶解混合物并回流24小时。然后自然冷却至室温,并在环境温度下另外维持24小时。形成(R)-5,5′-二(二苯基氧膦基)-1,1′,3,3′-四甲基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮和(-)-DBTA的1∶1复合物的结晶。过滤收集复合物,用氯仿洗涤3次并干燥。(母液和洗涤液主要包含(S)对映异构体,其能够被(+)-DBTA拆分)。将复合物在20mL 5%氢氧化钠水溶液和20mL氯仿中搅拌直至完全溶解。分离有机层,用水(3×20mL)洗涤,用无水硫酸钠干燥并真空浓缩,得到(R)-5,5′-二(二苯基氧膦基)-1,1′,3,3′-四甲基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮粗品。该过程另外重复两次,得到(R)-5,5′-二(二苯基氧膦基)-1,1′,3,3′-四甲基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮纯品。
用(+)-DBTA经同样的方法可拆分(S)异构体。
实施例5
(R)-或(S)-5,5′-二(二苯基膦基)-1,1′,3,3′-四甲基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮;(R)-或(S)-PM-Phos
向装备磁力搅拌棒的50mL玻璃衬里的高压釜中加入400mg(0.60mmol)来自实施例4的(R)-或(S)-5,5′-二(二苯基氧膦基)-1,1′,3,3′-四甲基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮、1.2mL(12mmol)三氯硅烷、1.6mL(12mmol)三乙胺和5mL甲苯。密封高压釜,混合物在120℃至140℃油浴中加热搅拌1-3天。反应完全后,将混合物冷却至环境温度,搅拌下加入30mL氯仿,随后滴加3mL 50%氢氧化钠水溶液。通过短硅胶柱抽滤混合物,柱子用氯仿冲洗3次。真空浓缩所合并的滤液,得到粗品,将其在10mL氯仿中重结晶纯化,得到纯的无色结晶状(R)-或(S)-5,5′-二(二苯基膦基)-1,1′,3,3′-四甲基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮,(R)-PM-Phos:
1HNMR(500MHz)(CDCl3)δ3.17(s,6H),3.37(s,6H),6.99-7.10(m,10H),7.36-7.42(m,6H),7.74-7.77(m,4H);13C-NMR(126MHz)(CD2Cl2)δ28.7,34.3,127.6,127.8(d,J=3.8Hz),128.7(d,J=8.8Hz),130.2,131.1(d,J=2.5Hz),131.2(d,J=2.5Hz),134.3(d,J=8.8Hz),135.2(d,J=3.8Hz),135.8(d,J=23.9Hz),151.6,153.9(d,J=3.8Hz),154.3(d,J=5.0Hz),160.7;31P-NMR(202MHz)(CD2Cl2)δ-12.7(s).
实施例6
包含(R)-PM-Phos的钯催化剂的制备及其在催化不对称烯丙位烷基化反应中的应用
在氮气中,向[Pd(π-烯丙基)Cl]2(0.18mg,5.0×10-4mmol)在0.5mLDCM中的搅拌溶液中加入来自实施例5的(R)-PM-Phos(0.71mg,1.1×10-3mmol)。1小时后,加入外消旋乙酸1,3-二苯基烯丙酯(25mg,0.10mmol)在0.5mL DCM中的溶液,并将溶液搅拌0.5小时。加入N,O-二(三甲基硅烷基)乙酰胺(BSA,0.074mL,0.30mmol)、丙二酸二甲酯(0.035mL,0.30mmol)和NaOAc(0.4mg,0.005mmol),溶液于25℃搅拌。用TLC监测反应。2小时后,真空蒸发溶剂,残留物进行硅胶柱层析法(己烷∶EtOAc-8∶1),得到85.2%ee的(S)-构型产物(用HPLC测定对映异构体过量:Daicel Chiracel AD柱,1.0mL/分钟,己烷∶i-PrOH-95∶5)。
实施例7
包含(R)-PM-Phos的钯催化剂的制备及其在催化不对称烯丙位氨基化反应中的应用
在氮气中,向[Pd(π-烯丙基)Cl]2(0.37mg,1.0×10-3mmol)在0.5mLDCM中的搅拌溶液中加入来自实施例5的(R)-PM-Phos(1.4mg,2.2×10-3mmol)。1小时后,加入外消旋乙酸1,3-二苯基烯丙酯(25mg0.10mmol)的0.5mL DCM溶液,将溶液搅拌0.5小时。加入苄胺(0.026mL,0.24mmol),将溶液于25℃搅拌。用TLC监测反应。2小时后,真空蒸发溶剂,残留物进行硅胶柱层析法(己烷∶EtOAc-5∶1),得到81.1%ee的(R)-构型产物(用HPLC测定对映异构体过量:Daicel Chiracel OJ柱,0.6mL/分钟,己烷∶i-PrOH-90∶10)。
Claims (21)
2.根据权利要求1的化合物或其对映异构体或其对映异构体混合物,其中R是单环芳基;R’和R”独立地是C1-6烷基。
3.根据权利要求2的化合物或其对映异构体或其对映异构体混合物,其中R是苯基;R’和R”是甲基。
4.根据权利要求2的化合物,其选自:
(R)-5,5′-双(二取代膦基)-1,1′,3,3′-四烷基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮;和
(S)-5,5′-双(二取代膦基)-1,1′,3,3′-四烷基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮。
5.催化剂,包含过渡金属和式(I)化合物或其对映异构体或其对映异构体混合物,其中过渡金属与式(I)化合物或其对映异构体或其对映异构体混合物结合,
其中
R是芳基,其中术语芳基指在环部分具有6-12个碳原子的单环或双环芳香烃基;
R’和R”独立地是C1-20烷基。
6.根据权利要求5的催化剂,其中R是单环芳基;R’和R”独立地是C1-6烷基;或其对映异构体或其对映异构体混合物。
7.根据权利要求6的催化剂,其中R是苯基;R’和R”是甲基;或其对映异构体或其对映异构体混合物。
9.根据权利要求5的催化剂,其中过渡金属选自铜、铱、镍、钯、铂、铑和钌。
10.根据权利要求9的催化剂,其中过渡金属是钯。
11.根据权利要求10的催化剂,其中R是单环芳基;R’和R”独立地是C1-6烷基;或其对映异构体或其对映异构体混合物。
12.根据权利要求11的催化剂,其中R是苯基;R’和R”是甲基;或其对映异构体或其对映异构体混合物。
13根据权利要求11的催化剂,其中式(I)化合物选自:
(R)-5,5′-双(二取代膦基)-1,1′,3,3′-四烷基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮;和
(S)-5,5′-双(二取代膦基)-1,1′,3,3′-四烷基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮。
15.根据权利要求14的方法,其中过渡金属是钯。
16.根据权利要求15的方法,其中R是单环芳基;R’和R”独立地是C1-6烷基;或其对映异构体或其对映异构体混合物。
17.根据权利要求16的方法,其中R是苯基;R’和R”是甲基;或其对映异构体或其对映异构体混合物。
18.根据权利要求16的方法,其中式(I)化合物选自:
(R)-5,5′-双(二取代膦基)-1,1′,3,3′-四烷基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮;和
(S)-5,5′-双(二取代膦基)-1,1′,3,3′-四烷基-4,4′-联嘧啶-2,2′,6,6′-(1H,1′H,3H,3′H)-四酮。
19.制备式(I)化合物或其对映异构体或其对映异构体混合物的方法,
其中R是芳基,其中术语芳基指在环部分具有6-12个碳原子的单环或双环芳香烃基;R’和R”独立地是C1-20烷基;
该方法包括将下式化合物或其对映异构体或其对映异构体混合物
其中R是芳基,其中术语芳基指在环部分具有6-12个碳原子的单环或双环芳香烃基;R’和R”独立地是C1-20烷基;
用还原剂在有机碱和芳香烃溶剂中处理,得到式(I)化合物。
20.根据权利要求19的方法,其中还原剂是三氯硅烷,有机碱是三乙胺,芳香烃溶剂是甲苯,且还原反应在高压釜中进行。
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EP (1) | EP1747205B1 (zh) |
JP (1) | JP4926043B2 (zh) |
KR (1) | KR101189935B1 (zh) |
CN (1) | CN100577650C (zh) |
BR (1) | BRPI0510994A (zh) |
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PL (1) | PL1747205T3 (zh) |
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JP2009046469A (ja) * | 2007-07-26 | 2009-03-05 | Chiba Univ | 光学活性アリル化合物類の製造方法 |
ITMI20121489A1 (it) * | 2012-09-06 | 2014-03-07 | Univ Degli Studi Milano | Metodo per la riduzione di nitro derivati ad ammine |
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JPS62265293A (ja) | 1986-05-13 | 1987-11-18 | Takasago Corp | ルテニウム−ホスフイン錯体 |
JP3148136B2 (ja) | 1996-12-26 | 2001-03-19 | 高砂香料工業株式会社 | 新規なキラルジホスフィン化合物、その製造中間体、該ジホス フィン化合物を配位子とする遷移金属錯体並びに該錯体を含む 不斉水素化触媒 |
JP2000044544A (ja) | 1998-07-30 | 2000-02-15 | Daicel Chem Ind Ltd | ビピリミジン化合物及びその重合体とその利用法 |
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2005
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2008
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Non-Patent Citations (3)
Title |
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Reactivity of [(m-H)Os3(CO)8{Ph2PCH2P(Ph)C6H4}] withorganic heterothiols, X-ray structures of[H(m-H)Os3(CO)8(h2-pyS){Ph2PCH2P(Ph)C6H4}] and[Os3(CO)8(m-h2-pyS){Ph2PCH2P(Ph)C6H4}]. Shariff E. K. et al.Journal of Organometallic Chemistry,Vol.616 . 2000 * |
Reactivity of [(m-H)Os3(CO)8{Ph2PCH2P(Ph)C6H4}] withorganic heterothiols,X-ray structures of[H(m-H)Os3(CO)8(h2-pyS){Ph2PCH2P(Ph)C6H4}] and[Os3(CO)8(m-h2-pyS){Ph2PCH2P(Ph)C6H4}]. Shariff E.K.et al.Journal of Organometallic Chemistry,Vol.616. 2000 * |
Stereoselective addition reactions of diphenylphosphine topyridyl and pyrimidylalkynes: chiral1,2-diheteroaryl-1,2-bis(diphenylphosphino)ethanes and theirGroup 6 metal carbonyl complexes. Jonathan L. B. et al.Journal of Organometallic Chemistry,Vol.577 . 1999 * |
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PL1747205T3 (pl) | 2012-11-30 |
US20070225497A1 (en) | 2007-09-27 |
ES2390277T3 (es) | 2012-11-08 |
EP1747205A1 (en) | 2007-01-31 |
CN1950344A (zh) | 2007-04-18 |
WO2005108377A1 (en) | 2005-11-17 |
KR101189935B1 (ko) | 2012-10-12 |
EP1747205A4 (en) | 2008-02-13 |
US7674900B2 (en) | 2010-03-09 |
US20080255356A1 (en) | 2008-10-16 |
EP1747205B1 (en) | 2012-06-20 |
BRPI0510994A (pt) | 2007-12-04 |
KR20070008694A (ko) | 2007-01-17 |
JP4926043B2 (ja) | 2012-05-09 |
PT1747205E (pt) | 2012-09-20 |
JP2007537030A (ja) | 2007-12-20 |
US7713900B2 (en) | 2010-05-11 |
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