CN109666044A - 基于[2.2]对环芳烷骨架的有机磷化合物及其中间体和制备方法与用途 - Google Patents
基于[2.2]对环芳烷骨架的有机磷化合物及其中间体和制备方法与用途 Download PDFInfo
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- CN109666044A CN109666044A CN201810727287.6A CN201810727287A CN109666044A CN 109666044 A CN109666044 A CN 109666044A CN 201810727287 A CN201810727287 A CN 201810727287A CN 109666044 A CN109666044 A CN 109666044A
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- Prior art keywords
- substituted
- aryl
- compound
- methylene
- heteroaryl
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- 150000002903 organophosphorus compounds Chemical class 0.000 title claims abstract description 26
- OOLUVSIJOMLOCB-UHFFFAOYSA-N 1633-22-3 Chemical group C1CC(C=C2)=CC=C2CCC2=CC=C1C=C2 OOLUVSIJOMLOCB-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 62
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- 238000005859 coupling reaction Methods 0.000 claims abstract description 9
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 7
- 230000008878 coupling Effects 0.000 claims abstract description 5
- 238000010168 coupling process Methods 0.000 claims abstract description 5
- 238000007792 addition Methods 0.000 claims abstract description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 33
- 239000002585 base Substances 0.000 claims description 27
- -1 nitro, cyano, substituted silicon Chemical class 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 125000004104 aryloxy group Chemical group 0.000 claims description 24
- 125000003107 substituted aryl group Chemical group 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 16
- 239000000463 material Substances 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 229910001868 water Inorganic materials 0.000 claims description 16
- 229920001774 Perfluoroether Polymers 0.000 claims description 10
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 8
- 125000004166 substituted arylmethylene group Chemical group 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000005699 methyleneoxy group Chemical group [H]C([H])([*:1])O[*:2] 0.000 claims description 7
- 125000000958 aryl methylene group Chemical group 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 125000003609 aryl vinyl group Chemical group 0.000 claims description 5
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 5
- 239000005977 Ethylene Substances 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 239000000758 substrate Substances 0.000 claims description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 4
- 230000001335 demethylating effect Effects 0.000 claims description 3
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052737 gold Inorganic materials 0.000 claims description 3
- 239000010931 gold Substances 0.000 claims description 3
- 229910052740 iodine Chemical group 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 239000010948 rhodium Substances 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- 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 description 3
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims description 2
- 125000005002 aryl methyl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 229910017052 cobalt Inorganic materials 0.000 claims description 2
- 239000010941 cobalt Substances 0.000 claims description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 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
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 229910052750 molybdenum Inorganic materials 0.000 claims description 2
- 239000011733 molybdenum Substances 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
- 229910052707 ruthenium Inorganic materials 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229910052709 silver Inorganic materials 0.000 claims description 2
- 239000004332 silver Substances 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 125000003709 fluoroalkyl group Chemical group 0.000 claims 1
- 238000013507 mapping Methods 0.000 claims 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 claims 1
- 239000000376 reactant Substances 0.000 claims 1
- 239000003446 ligand Substances 0.000 abstract description 24
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 abstract description 14
- 239000002994 raw material Substances 0.000 abstract description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 abstract description 7
- 239000000543 intermediate Substances 0.000 abstract description 5
- 238000006053 organic reaction Methods 0.000 abstract description 4
- 150000008300 phosphoramidites Chemical class 0.000 abstract description 4
- 150000008301 phosphite esters Chemical class 0.000 abstract description 2
- XRBCRPZXSCBRTK-UHFFFAOYSA-N phosphonous acid Chemical compound OPO XRBCRPZXSCBRTK-UHFFFAOYSA-N 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 93
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 230000006837 decompression Effects 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 235000011007 phosphoric acid Nutrition 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 238000004679 31P NMR spectroscopy Methods 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical group CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229910003771 Gold(I) chloride Inorganic materials 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 150000002466 imines Chemical class 0.000 description 3
- ZFJMTDFOGDGPTF-UHFFFAOYSA-N phosphanium;chloride;hydrochloride Chemical class P.Cl.Cl ZFJMTDFOGDGPTF-UHFFFAOYSA-N 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 3
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- DGWFDTKFTGTOAF-UHFFFAOYSA-N P.Cl.Cl.Cl Chemical compound P.Cl.Cl.Cl DGWFDTKFTGTOAF-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical compound [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-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
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
- NLLGFYPSWCMUIV-UHFFFAOYSA-N (3-methoxyphenyl)boronic acid Chemical compound COC1=CC=CC(B(O)O)=C1 NLLGFYPSWCMUIV-UHFFFAOYSA-N 0.000 description 1
- BIWQNIMLAISTBV-UHFFFAOYSA-N (4-methylphenyl)boronic acid Chemical compound CC1=CC=C(B(O)O)C=C1 BIWQNIMLAISTBV-UHFFFAOYSA-N 0.000 description 1
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 description 1
- QDMAXRJHDMKTQH-UHFFFAOYSA-N (r)-4,12-dibromo[2.2]paracyclophane Chemical compound C1CC(=CC=2)C(Br)=CC=2CCC2=CC=C1C=C2Br QDMAXRJHDMKTQH-UHFFFAOYSA-N 0.000 description 1
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 description 1
- SWWQQSDRUYSMAR-UHFFFAOYSA-N 1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol;hydrochloride Chemical group Cl.C1=CC(O)=CC=C1CC1C2=CC(O)=C(O)C=C2CCN1 SWWQQSDRUYSMAR-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- WCFQUEJTAKNNNQ-UHFFFAOYSA-N C(#N)CCOP(CCN(C(C)C)C(C)C)CCN(C(C)C)C(C)C Chemical compound C(#N)CCOP(CCN(C(C)C)C(C)C)CCN(C(C)C)C(C)C WCFQUEJTAKNNNQ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 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 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 235000010338 boric acid Nutrition 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 1
- WDVGNXKCFBOKDF-UHFFFAOYSA-N dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound COC1=CC=C(OC)C(C=2C(=CC(=CC=2C(C)C)C(C)C)C(C)C)=C1P(C1CCCCC1)C1CCCCC1 WDVGNXKCFBOKDF-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- QPUSANCBJDDXSA-UHFFFAOYSA-N ethanethiol;sodium Chemical compound [Na].CCS QPUSANCBJDDXSA-UHFFFAOYSA-N 0.000 description 1
- AFQSOHSPTULSFS-FGSKAQBVSA-N ethene;(z)-4-hydroxypent-3-en-2-one;rhodium Chemical compound [Rh].C=C.C=C.C\C(O)=C\C(C)=O AFQSOHSPTULSFS-FGSKAQBVSA-N 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- FDWREHZXQUYJFJ-UHFFFAOYSA-M gold monochloride Chemical compound [Cl-].[Au+] FDWREHZXQUYJFJ-UHFFFAOYSA-M 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000005217 methyl ethers Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000002815 nickel Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- OSCBARYHPZZEIS-UHFFFAOYSA-N phenoxyboronic acid Chemical class OB(O)OC1=CC=CC=C1 OSCBARYHPZZEIS-UHFFFAOYSA-N 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 229910001544 silver hexafluoroantimonate(V) Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000005338 substituted cycloalkoxy group Chemical group 0.000 description 1
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 230000017260 vegetative to reproductive phase transition of meristem Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
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Abstract
本发明公开了一种基于[2.2]对环芳烷骨架的有机磷化合物及其中间体和制备方法与用途。所述的有机磷化合物是具有通式I或II所示结构的化合物或所述化合物的对映体、消旋体或非对映异构体,包括亚膦酸酯配体、亚磷酸酯配体、亚磷酰胺酯配体和磷酸。该有机磷化合物以已知的4,12‑二卤[2.2]对环芳烷为原料,经由通式III作为关键中间体的制备路线获得。本发明开发了一类新型的有机磷化合物,可作为配体或有机催化剂应用于有机反应,特别是可用于加成、氢化、偶联和环化等许多催化反应中,具有经济实用性和工业应用前景。
Description
技术领域
本发明涉及有机化学技术领域,涉及一种新型的基于[2.2]对环芳烷骨架的有机磷化合物及其中间体和制备方法与用途。该类有机磷化合物可用于金属催化的偶联反应或不对称反应,或直接催化有机反应。
背景技术
不对称催化是当今合成化学中最为活跃的研究领域之一,该技术可以最直接的、最有效的方法获得光学活性分子,具有手性增殖、经济性,易于实现工业化的优点。实现高效高选择性的不对称催化反应关键科学问题之一是发现和发展新型高效的手性配体及其催化剂。当前手性配体的设计合成已经取得快速发展,有众多的优秀手性配体或催化剂被合成出来(如下各结构式所示),并有相当一些手性配体应用于工业化生产。不过,仍然存在包括配体的适用性有限,对反应底物高度依赖等很多问题,没有任何一种手性配体是通用的。因而寻求具有新型骨架的高效高选择性的手性配体及其催化剂一直是不对称催化研究中的长期的挑战性任务。
本发明拟利用廉价易得的4,12-二卤[2.2]对环芳烷的的对映体或消旋体为起始原料,设计制备相应的基于[2.2]对环芳烷骨架的有机磷化合物,包括亚膦酸酯配体、亚磷酸酯配体、亚磷酰胺酯配体和磷酸等;该类配体骨架稳定并且刚性强,原料廉价丰富,合成路线短,制备成本低,实用性强,易于修饰扩大配体/催化剂库,将大大丰富膦配体及催化剂的衍生物。另外基于该类骨架衍生的配体或催化剂,有跟已知配体不同的二面角预示着不同的催化效果或用途。
发明内容
本发明的目的是提供一种基于[2.2]对环芳烷骨架的有机磷化合物及其中间体和制备方法与用途。
一种基于[2.2]对环芳烷骨架的有机磷化合物,是具有如下通式I 或II的化合物或所述化合物的对映体、消旋体或非对映异构体:
式I和式II中:R1-R4分别独立选自氢、氟、氯、硝基、氰基、取代的硅基、C1-C10的烷基或全氟烷基、C3-C6的环烷基、C1-C4的烷氧基或全氟烷氧基、芳氧基或取代的芳氧基、杂芳氧基或取代的杂芳氧基、芳基亚甲基氧基或取代的芳基亚甲基氧基、杂芳基亚甲基氧基或取代的杂芳基亚甲基氧基、芳基或取代的芳基、稠芳基或取代的稠芳基、杂芳基或取代的杂芳基以及上述的任意可能的组合取代基;其中所述取代的芳氧基、取代的芳基、取代的稠芳基或取代的杂芳基是具有一个或多个取代基,所述取代基是独立选自卤素、N-二甲基胺基、C1-C4的烷基或全氟烷基、C3-C6的环烷基、C1-C4的烷氧基或全氟烷氧基、亚甲二氧基、芳基、芳氧基、杂芳基;所述的杂芳基是C5-C14的杂芳基;
式I中:X选自C1-C10的烷基或全氟烷基、C3-C6的环烷基、芳基亚甲基或取代的芳基亚甲基、芳基或取代的芳基、稠芳基或取代的稠芳基、杂芳基或取代的杂芳基、芳基乙烯基苯基或取代的芳基乙烯基苯基、C1-C10的烷氧基或全氟烷氧基、C1-C10的环烷氧基或取代的环烷氧基、芳氧基或取代的芳氧基、稠芳氧基或取代的稠芳氧基、杂芳氧基或取代的杂芳氧基、芳基亚甲基氧基或取代的芳基亚甲基氧基、杂芳基亚甲基氧基或取代的杂芳基亚甲基氧基、芳基乙烯基苯氧基或取代的芳基乙烯基苯氧基、取代的丙氧基、R6SO2NR5、NR5R6以及上述的任意可能的组合取代基,其中所述取代的芳氧基、取代的丙氧基、取代的芳基、取代的稠芳氧基或取代的杂芳基是具有一个或多个取代基,所述取代基是独立选自卤素、N-二甲基胺基、C1-C4的烷基或全氟烷基、 C3-C6的环烷基、C1-C4的烷氧基或全氟烷氧基、亚甲二氧基、芳基、芳氧基、杂芳基、取代脲基;所述的杂芳基是C5-C14的杂芳基;R5和R6分别独立选自氢、C1-C4的烷基、环烷基或取代的环烷基、芳基或取代的芳基、杂芳基或取代的杂芳基、芳基亚甲基或取代的芳基亚甲基、芳基甲基次亚甲基或取代的芳基甲基次亚甲基、取代的二芳基次亚甲基、芳基乙烯基次亚甲基或取代的芳基乙烯基次亚甲基;R5和R6可以组成2-亚甲基烷氧基吡咯烷基、2,5-二芳基吡咯烷基或2,5-二(取代的芳基)吡咯烷基、C3-C14环状体系或取代的苯并脂肪环状体系;其中所述取代的环烷基、取代的芳基或取代的杂芳基是具有一个或多个取代基,所述取代基是独立选自卤素、N-二甲基胺基、C1-C4的烷基或全氟烷基、C3-C6的环烷基、C1-C4的烷氧基或全氟烷氧基、亚甲二氧基、芳基、苄基、芳氧基、取代脲基。
所述的基于[2.2]对环芳烷骨架的有机磷化合物的中间体化合物,是具有如下通式III的化合物或所述化合物的对映体:
式中:R1-R4同式I化合物中所述。
如式III所示的基于[2.2]对环芳烷骨架的有机磷化合物的中间体化合物的制备方法,包含如下步骤:以如式III-1所示的4,12-二卤 [2.2]对环芳烷的的对映体或消旋体为起始原料,与有机硼试剂经偶联反应制备得到式III-2所示的化合物,再经脱甲基反应制备得到式III 化合物;
式中:R1-R4同式III化合物中所述;X选自氯、溴或碘原子;Y选自羟基、甲氧基、乙氧基、异丙氧基,或Y2选自四甲基乙二氧基、丙二氧基;
所述偶联反应的反应条件可参考各种如文献公开的Suzuki偶联反应,溶剂体系可用各种含水溶剂体系,包括甲苯/EtOH/H2O,或 CH3CN/H2O或二氧六环/H2O或乙二醇二甲醚/水或四氢呋喃/水或二甲亚砜/水,碱可以为碳酸钾、磷酸钾、碳酸钠、氟化铯、叔丁醇钾、碳酸铯或叔丁醇钠,催化剂为四苯基膦钯、dppfPdCl2、Pd/C、醋酸钯、氯化钯、pd(dba)2或各种镍盐以及各种BUCHWALD偶联催化剂,配体常用三苯基膦、三叔丁基膦、三环己基膦、BINAP、X-PHOS、xantphos、 Brettphos,反应温度为室温到120度,反应时间为0.5-48小时,碱的用量是式III-1化合物物质的量的1-6倍,有机硼试剂的用量是式 III-1化合物物质的量的2-6倍,催化剂用量是式III-1化合物物质的量的0.05-0.3倍,配体用量是催化剂物质的量的0-2倍;
所述脱甲基反应的反应条件可参考文献公开的各种甲基醚的脱甲基方法,常用脱甲基的试剂是三溴化硼、乙硫醇钠、浓氢溴酸,反应溶剂可以是四氢呋喃、二氯甲烷、N,N-二甲基甲酰胺和甲苯,反应温度为-10度到145度,反应时间1-24小时,脱甲基的试剂的用量是式III-2化合物物质的量的1-20倍。
所述的如式I所示化合物的制备方法,是以式III化合物为原料,在碱作用下与取代的双(二异丙基胺基)膦化物(i-Pr2N)2P-X经取代反应制备得到式I化合物,其反应式为:
式中:R1-R4和X同式I化合物中所述;
所述取代反应的反应条件中碱是选自1H‐四唑、三乙胺、4-二甲胺基吡啶,溶剂是四氢呋喃、二氯甲烷、乙腈、二氯乙烷、N,N-二甲基甲酰胺或甲苯,反应温度为20度到110度,反应时间1-24小时,化合物III、双(二异丙基胺基)膦化物和碱之间物质的量比1:1-2:1-10;
或者,是以式III化合物为原料,在碱作用下与取代的二氯化膦 Cl2P-X经取代反应制备得到式I化合物,其反应式为:
式中:R1-R4同式I化合物中所述;
该取代反应,可以用三乙胺、三丁胺、二异丙基乙基胺、氢化钠或丁基锂作碱(用量为式III化合物物质的量的2-10倍),二氯化膦 Cl2P-X用量为式II化合物物质的量的1-1.5倍,以四氢呋喃、二氯甲烷、二氯乙烷、甲苯、乙腈、二氧六环、N,N-二甲基甲酰胺作为反应溶剂,在室温搅拌反应1-12小时制备得到式I化合物;
或者,以式III化合物为原料,在碱作用下与三氯化膦经取代反应制备得到式I-1化合物,再跟HX和碱的作用物反应制备得到式I 化合物,其反应式为:
制备I-1的具体方法是,可以用三乙胺、三丁胺、或二异丙基乙基胺作碱(用量为式II化合物物质的量的2-4倍),三氯化膦PCl3用量为式III化合物物质的量的1倍,以四氢呋喃、二氯甲烷、二氯乙烷、甲苯、乙腈、乙醚或二氧六环作为反应溶剂,在-78度至室温搅拌反应0.5-2小时制备得到式I-1化合物或其溶液;制备I的具体方法是,以四氢呋喃、二氯甲烷、二氯乙烷、甲苯、乙腈、乙醚或二氧六环作为反应溶剂,HX和丁基锂或氢化钠(丁基锂或氢化钠用量为HX用量的物质的量的1-1.2倍)在-30度至室温反应0.5-1小时得到HX和碱的作用物后,然后和上述式I-1化合物或其溶液混合反应(HX用量是式I-1化合物物质的量的1-1.5倍),在-78度至室温搅拌反应6-12小时制备得到式I化合物。
所述的如式II所示化合物的制备方法,是以式III化合物为原料,在碱作用下与(i-Pr2N)2P-OCH2CH2CN经取代反应制备得到式II-1 化合物,再经氧化和水解反应制备得到式II所示化合物,其反应式为:
式中:R1-R4同式II化合物中所述;
制备式II-1化合物所述取代反应的反应条件中碱是1H-四唑、三乙胺、4-二甲胺基吡啶,溶剂是四氢呋喃、二氯甲烷、乙腈、二氯乙烷、N,N-二甲基甲酰胺和甲苯,反应温度为20度到110度,反应时间1-24小时,化合物III、(i-Pr2N)2P-OCH2CH2CN和碱之间物质的量比1:1-2:1-10;所述的如式II所示化合物的制备方法,氧化反应中氧化剂是叔丁基过氧化氢,溶剂是二氯甲烷、二氯乙烷或甲苯,反应温度为20度到60度,反应时间0.1-2小时,化合物II-1和叔丁基过氧化氢之间物质的量比1:2-5;水解反应中水解剂是1,8-二氮杂二环十一碳-7-烯(DBU),溶剂是二氯甲烷、二氯乙烷或甲苯,反应温度为20度到60度,反应时间0.1-2小时,化合物II-1和1,8-二氮杂二环十一碳-7-烯之间物质的量比1:2-4;
或者,以式III化合物为原料,与三氯氧膦经取代反应制备得到式II-2化合物,再进行水解反应制备得到式II化合物,其反应式为:
式中R1-R4如前文中对式II化合物中所述。
本发明所述的基于[2.2]对环芳烷骨架的有机磷化合物,所述如式 I所示的化合物可以是如下任一化合物及其对映体或消旋体:
本发明所述的基于[2.2]对环芳烷骨架的有机磷化合物,所述如式 II所示的化合物可以是如下任一化合物及其对映体或消旋体:
所述的基于[2.2]对环芳烷骨架的有机磷化合物的用途有:所述的如式I或II所示的有机磷化合物与金、银、铜、铑、钌、铱、镍、钼、铁、钯或钴的金属盐反应制备催化剂;或者所述的有机磷化合物用于金属催化的加成、氢化、偶联及其不对称反应;或者所述的有机磷化合物作为有机催化剂催化有机不对称反应。
本发明开发了一类新型的有机磷化合物,可作为配体用于金属催化的有机反应或直接催化有机反应,特别是可作为手性的膦配体或催化剂广泛用于包括不对称加成、不对称氢化、不对称偶联和不对称烯丙基烷基化等许多手性催化反应中,具有经济实用性和工业应用前景。
具体实施方式
以下实施例将有助于理解本发明,但不限于本发明的内容。
通用反应条件说明:当使用了对空气敏感的试剂的所有反应均控制在充满氮气的手套箱中进行或使用标准的Schlenk技术进行。反应溶剂用通用的标准过程干燥处理。
实施例1
(R)-8,8’-{9,9’-二(2-萘基)[2.2]对环芳烷}磷酸(II-5)的合成
反应式:
第一步,室温下,在氮气保护下把1毫摩尔的(R)‐4,12‐二溴[2.2]对环芳烷(1)、2.2毫摩尔3‐甲氧基‐4‐(2‐萘基)苯硼酸、0.1毫摩尔四(三苯基)膦钯和4毫摩尔碳酸钠混合在三口烧瓶中,加入二甲亚砜:水(10:1)的混合溶剂至澄清,之后再90℃下反应4小时。反应完毕,加入100毫升水和300毫升二氯甲烷,有机相用200毫升饱和食盐水洗涤后再用无水硫酸钠干燥,过滤,滤液减压浓缩至干,然后通过柱层析得到化合物2,该步收率80%。
第二步,在氮气保护下,把第一步得到的0.8毫摩尔化合物2加入到三口烧瓶中,加入 5毫升二氯甲烷至溶解澄清,然后在冰浴下加入5毫摩尔三溴化硼(1mol/L的二氯甲烷溶液)。室温下,反应2小时。反应完毕,用30毫升饱和的碳酸氢钠水溶液猝灭反应,加入 30毫升水和100毫升二氯甲烷,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩至干得到定量的化合物3。
第三步,在氮气保护下,把0.8毫摩尔化合物3、0.96毫摩尔双(二异丙基氨基)(2‐氰基乙氧基)膦和3.2毫摩尔1H‐四唑混合在一起,加入40毫升二氯甲烷至澄清,在室温下反应4小时后,加入20毫升饱和碳酸氢钠水溶液猝灭反应,用30毫升二氯甲烷萃取三次,合并有机相,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩至干,得到化合物4,该步产率52%。
第四步,把0.41毫摩尔化合物4用4毫升二氯甲烷溶解澄清,加入1.23毫摩尔叔丁基过氧化氢(70%的水溶液),搅拌反应30分钟后,加入5毫升饱和硫代硫酸钠溶液搅拌30分钟,然后加入5毫升水和20毫升二氯甲烷,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩至干,得到定量的中间体化合物,然后将其用3毫升二氯甲烷溶解澄清,加入0.82毫摩尔的1,8-二氮杂二环十一碳-7-烯(DBU),搅拌30分钟后,加入5毫升饱和碳酸氢钠溶液,继续搅拌30分钟,用40毫升二氯甲烷萃取,有机相用2mol/L稀盐酸洗涤两次,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩至干,然后通过柱层析得到面手性磷酸II-5,该步收率80%。
熔点191-192℃;[α]D 20=+156(c 0.46,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.94(s,2H),7.83 (s,2H),7.72(m,2H),7.65(m,2H),7.60–7.51(m,4H),7.43(m,2H),7.30(m,2H),7.28–7.21(m,4H),6.87(m,2H),6.76(s,2H),6.70(m,2H),5.37(s,1H),3.55(m, 2H),3.40–3.28(m,2H),3.15–3.01(m,2H),2.89(m,2H);13C NMR(101MHz,CHCl3) δ34.2,35.4,121.5,126.0,127.4,127.5,127.6,127.7,127.8,128.2,128.6,131.3,131.7, 131.8,132.5,133.2,133.9,134.0,135.1,137.4,139.2,139.5,148.3,148.4;31P NMR(162 MHz,CDCl3)δ-11.32;HRMS(ESI)Calcd for C48H34O4P[M-H]-:705.2195,found:705.2215.
实施例2
各种基于[2.2]对环芳烷骨架的面手性磷酸的制备,制备过程与实施例1同样,但是3‐甲氧基‐4‐(2‐萘基)苯硼酸分别用3‐甲氧基苯硼酸、3‐甲氧基‐4‐氟苯硼酸、3‐甲氧基‐4‐甲基苯硼酸、3‐甲氧基‐4‐[3,5‐二(三氟甲基)苯基]苯硼酸代替,制得相应的面手性磷酸的物性数据如下:
熔点189-190℃;[α]D 20=+203(c 0.13,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.64(s,2H),7.32 (m,2H),7.24(m,2H),7.15(m,2H),6.83(m,2H),6.73(s,2H),6.65(m,2H),3.50(s,1H),3.41– 3.22(m,4H),3.10–2.98(m,2H),2.76(m,2H).13C NMR(101MHz,CHCl3)δ34.0,35.6,119.3, 119.4,122.3,122.4,127.2,127.4,129.5,133.9,134.6,137.2,139.4,139.5,139.6,151.2, 151.3;31P NMR(162MHz,CDCl3)δ-11.98;HRMS(ESI)Calcd forC28H22O4P[M-H]-: 453.1256,found:453.1261.
熔点170-171℃;[α]D 20=+184(c 0.16,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.68(s,2H),7.21 (d,J=7.8Hz,2H),7.12(d,J=7.7Hz,2H),6.81(d,J=7.6Hz,2H),6.69–6.60(m,2H),3.43 (dt,J=14.1,9.3Hz,2H),3.33–3.16(m,2H),3.09–2.93(m,2H),2.82(dt,J=13.3,9.5Hz,2H), 2.41(s,6H).13C NMR(101MHz,CHCl3)δ15.0,32.9,34.2,119.6,126.3,126.8,126.9, 130.2,132.5,133.8,136.0,136.6,138.3,148.7,148.8;31P NMR(162MHz,CDCl3)δ-9.77; HRMS(ESI)Calcd for C30H26O4P[M-H]-:481.1569,found:481.1575.
熔点185-186℃;[α]D 20=+161(c 0.12,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.70(s,2H),7.17 –6.92(m,4H),6.79(d,J=7.6Hz,2H),6.61(d,J=8.0Hz,4H),4.44(s,1H),3.26(dt,J=23.2, 10.4Hz,4H),3.06–2.89(m,2H),2.83–2.64(m,2H).13C NMR(101MHz,CHCl3)δ33.8,35.3, 116.5,116.6,123.0,127.2,133.7,134.7,134.8,134.9,136.9,138.7,139.4,153.7;19F NMR(376MHz,CDCl3)δ-132.71(s).31P NMR(162MHz,CDCl3)δ-11.82(s).HRMS(ESI) Calcd for C28H20F2O4P[M-H]-:489.1067,found:489.1078.
熔点165-166℃;[α]D 20=+180(c 0.33,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.75(s,2H),7.46 (d,J=7.1Hz,4H),7.30(d,J=7.9Hz,2H),7.17(t,J=8.4Hz,6H),7.02(t,J=7.1Hz,2H), 6.77(d,J=7.7Hz,2H),6.67(s,2H),6.60(d,J=7.6Hz,2H),5.87(s,1H),3.50–3.33(m,2H), 3.29–3.15(m,2H),3.09–2.92(m,2H),2.78(dt,J=13.3,9.3Hz,2H).13CNMR(101MHz, CHCl3)δ34.0,35.4,121.4,127.5,127.6,127.7,128.4,129.5,131.1,133.9,137.3,148.3;31P NMR(162MHz,CDCl3)δ-11.59(s);HRMS(ESI)Calcd for C40H30O4P[M-H]-:605.1882, found:605.1899.
熔点106-107℃;[α]D 20=+110(c 0.20,CH2Cl2);1H NMR(400MHz,CDCl3)δ8.04(s,4H),7.73 (s,2H),7.65(s,2H),7.26m,2H),7.18(d,J=7.9Hz,2H),6.82(d,J=7.7Hz,2H),6.65(d,J= 7.5Hz,2H),6.52(s,2H),4.58(s,1H),3.44–3.31(m,2H),3.31–3.19(m,2H),2.95–2.74(m, 4H).13C NMR(101MHz,CHCl3)δ29.7,33.9,35.1,121.2,122.0,124.7,127.5,128.0, 128.4,128.5,129.7,130.7,131.0,131.3,131.7,132.0,134.1,135.1,137.3,138.4,139.3, 140.6,147.8;19F NMR(376MHz,CDCl3)δ-62.85(s).31P NMR(162MHz,CDCl3)δ-11.01(s); HRMS(ESI)Calcd for C44H26F12O4P[M-H]-:877.1377,found:877.1404.
实施例3
基于[2.2]对环芳烷骨架的面手性磷酸的用途‐不对称催化吲哚类化合物与磺酰亚胺衍生物的反应。
把1毫摩尔对甲苯磺酰亚胺衍生物1、1毫摩尔吲哚衍生物2、0.02毫摩尔平面手性磷酸(R)‐II‐6和300毫克分子筛混合在10毫升甲苯溶剂中,在‐20℃反应20小时,然后加入三乙胺中和结束反应,用乙酸乙酯萃取,然后用饱和食盐水洗涤后再用无水硫酸钠干燥,过滤,滤液减压浓缩至干,然后通过柱层析得到手性的3位烷基化吲哚衍生物3。产物光学纯度用手性HPLC测定。
典型产物表征如下:
产率99%,ee 97%,HPLC[AD‐H,正己烷/异丙醇=70/30,0.9毫升/分钟,λ=254nm,t (次要产物)=13.987分钟,t(主要产物)=22.637分钟]。1H NMR(400MHz,CDCl3)δ2.28(s, 3H),2.36(s,3H),5.13(d,J=7.2Hz,1H),5.78(d,J=6.8Hz,1H),6.67(d,J=2.0Hz,1H),6.95‐6.99 (m,3H),7.08(m,4H),7.14(m,1H),7.20‐7.28(m,2H),7.53(d,J=7.6Hz,2H),8.01(m,1H);13C NMR(100MHz,CDCl3)δ21.0,21.4,54.8,112.3,116.3,119.2,119.8,122.3,123.7,125.3,127.10, 127.12,128.9,129.2,136.5,137.0,137.3,137.4,142.9;
其他底物反应结果如下表:
实施例4
基于[2.2]对环芳烷骨架的面手性亚磷酸酯的合成
在氮气保护下,把0.8毫摩尔化合物3‐1、1毫摩尔双(二异丙基氨基)苯氧基膦和3毫摩尔1H‐四唑混合在一起,加入40毫升二氯甲烷至澄清,在室温下反应4小时后,加入 20毫升饱和碳酸氢钠水溶液猝灭反应,用30毫升二氯甲烷萃取,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩至干,柱层析纯化得到化合物4‐1,产率40%。
实施例5
基于[2.2]对环芳烷骨架的面手性亚磷酰胺的合成
在氮气保护下,把0.8毫摩尔化合物3‐11和NaH混合在10毫升四氢呋喃中,反应10分钟,然后加入1毫摩尔(二苄基基氨基)二氯化膦,室温搅拌反应3小时,加入30毫升饱和碳酸氢钠水溶液猝灭反应,用50毫升二氯甲烷萃取,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩至干,无水无氧柱层析纯化得到化合物4‐11,产率50%。
实施例6
基于[2.2]对环芳烷骨架的面手性亚磷酰胺的金络合物的合成
1毫摩尔的(SMe2)AuCl溶解在5毫升二氯甲烷中,冷却到0-5度,然后搅拌下滴加入含有1毫摩尔配体4-11的3毫升二氯甲烷,滴完后,自然升温到室温继续搅拌反应2小时,在通过TLC监控确认起始原料消失后,减压蒸出溶剂,真空干燥,得到定量的氯化亚金络合物4-12。
按照类似的反应过程,制备得到了以下结构的氯化亚金络合物4-13,产率均为定量:
实施例7
0.05毫摩尔AgSbF6和0.05毫摩尔的4-12混合在1毫升二氯甲烷中,室温搅拌五分钟,滤去不溶物,然后加入到含有1毫摩尔Au-A的5毫升二氯甲烷中,室温搅拌反应5小时,然后蒸出溶剂后进行柱层析纯化,得到65%产率的Au-B。产物核磁数据为1H NMR(400MHz,C6D6):δ1.39(s,3H),1.46(s,3H),1.91(s,3H),2.02(m,2H),2.39(d,J=20.3 Hz,1H),2.53(d,J=20.2Hz,1H),2.89(dd,J=11.2Hz,9.2Hz,1H),3.43(dd, J=9.2,11.2Hz,1H),3.66(dd,J=7.6,9.2Hz,1H),4.12(dd,J=6.0,9.2Hz, 1H),5.50(bs,2H),6.86(d,J=8.4Hz,2H),7.85(d,J=8.4Hz,2H)。
实施例8
氮气保护下,把Rh(acac)(C2H4)2(0.6mg,1.5μmol)和4-1(3μmol)溶解在甲苯(0.5mL)中,室温搅拌1小时,然后再依次加入亚胺9-1(0.05mmol)和苯基硼酸10-1(0.1mmol),氟化钾(0.2mmol)以及水(0.5mL),反应混合物在55℃搅拌反应20小时,结束反应后,柱层析纯化产物11-1,产率65%。m.p.118-120℃;1H NMR(400MHz,CDCl3)δ7.55 (d,J=8.3Hz,2H),7.22(m,2H),7.17(m,4H),7.09–7.02(m,4H),5.53(d,J=7.1Hz,1H), 5.18-5.15(m,1H),2.39(s,3H)。
实施例9
0.03毫摩尔的[Rh(COD)2BF4]和0.065毫摩尔的4‐11在10毫升二氯甲烷中络合30分钟后,注入含有5毫摩尔的A‐1的10毫升二氯甲烷,保持2个标准大气压的氢气压力下进行室温还原反应,24小时结束反应,纯化后可以得到100%的产物A‐2。
Claims (6)
1.一种基于[2.2]对环芳烷骨架的有机磷化合物,其特征在于,是具有如下通式I或II的化合物或所述化合物的对映体、消旋体或非对映异构体:
式I和式II中:R1-R4分别独立选自氢、氟、氯、硝基、氰基、取代的硅基、C1-C10的烷基或全氟烷基、C3-C6的环烷基、C1-C4的烷氧基或全氟烷氧基、芳氧基或取代的芳氧基、杂芳氧基或取代的杂芳氧基、芳基亚甲基氧基或取代的芳基亚甲基氧基、杂芳基亚甲基氧基或取代的杂芳基亚甲基氧基、芳基或取代的芳基、稠芳基或取代的稠芳基、杂芳基或取代的杂芳基以及上述的任意可能的组合取代基;其中所述取代的芳氧基、取代的芳基、取代的稠芳基或取代的杂芳基是具有一个或多个取代基,所述取代基是独立选自卤素、N-二甲基胺基、C1-C4的烷基或全氟烷基、C3-C6的环烷基、C1-C4的烷氧基或全氟烷氧基、亚甲二氧基、芳基、芳氧基、杂芳基;所述的杂芳基是C5-C14的杂芳基;
式I中:X选自C1-C10的烷基或全氟烷基、C3-C6的环烷基、芳基亚甲基或取代的芳基亚甲基、芳基或取代的芳基、稠芳基或取代的稠芳基、杂芳基或取代的杂芳基、芳基乙烯基苯基或取代的芳基乙烯基苯基、C1-C10的烷氧基或全氟烷氧基、C1-C10的环烷氧基或取代的环烷氧基、芳氧基或取代的芳氧基、稠芳氧基或取代的稠芳氧基、杂芳氧基或取代的杂芳氧基、芳基亚甲基氧基或取代的芳基亚甲基氧基、杂芳基亚甲基氧基或取代的杂芳基亚甲基氧基、芳基乙烯基苯氧基或取代的芳基乙烯基苯氧基、取代的丙氧基、R6SO2NR5、NR5R6以及上述的任意可能的组合取代基,其中所述取代的芳氧基、取代的丙氧基、取代的芳基、取代的稠芳氧基或取代的杂芳基是具有一个或多个取代基,所述取代基是独立选自卤素、N-二甲基胺基、C1-C4的烷基或全氟烷基、C3-C6的环烷基、C1-C4的烷氧基或全氟烷氧基、亚甲二氧基、芳基、芳氧基、杂芳基、取代脲基;所述的杂芳基是C5-C14的杂芳基;R5和R6分别独立选自氢、C1-C4的烷基、环烷基或取代的环烷基、芳基或取代的芳基、杂芳基或取代的杂芳基、芳基亚甲基或取代的芳基亚甲基、芳基甲基次亚甲基或取代的芳基甲基次亚甲基、取代的二芳基次亚甲基、芳基乙烯基次亚甲基或取代的芳基乙烯基次亚甲基;R5和R6可以组成2-亚甲基烷氧基吡咯烷基、2,5-二芳基吡咯烷基或2,5-二(取代的芳基)吡咯烷基、C3-C14环状体系或取代的苯并脂肪环状体系;其中所述取代的环烷基、取代的芳基或取代的杂芳基是具有一个或多个取代基,所述取代基是独立选自卤素、N-二甲基胺基、C1-C4的烷基或全氟烷基、C3-C6的环烷基、C1-C4的烷氧基或全氟烷氧基、亚甲二氧基、芳基、苄基、芳氧基、取代脲基。
2.一种制备权利要求1所述的基于[2.2]对环芳烷骨架的有机磷化合物的中间体化合物,其特征在于,是具有如下通式III的化合物或所述化合物的对映体:
式中:R1-R4如权利要求1中所述。
3.权利要求2所述的如式III所示的基于[2.2]对环芳烷骨架的有机磷化合物的中间体化合物的制备方法,包含如下步骤:以如式III-1所示的4,12-二卤[2.2]对环芳烷的的对映体或消旋体为起始原料,经偶联反应制备得到式III-2所示的化合物,再经脱甲基反应制备得到式III化合物;
式中:R1-R4如权利要求1中所述;X选自氯、溴或碘原子;Y选自羟基、甲氧基、乙氧基、异丙氧基,或Y2选自四甲基乙二氧基、丙二氧基。
4.权利要求1所述的如式I所示化合物的制备方法,其特征在于,以式III化合物为原料,在碱作用下与取代的双(二异丙基胺基)膦化物(i-Pr2N)2P-X经取代反应制备得到式I化合物,其反应式为:
式中:R1-R4和X如权利要求1中所述。
5.权利要求1所述的如式II所示化合物的制备方法,其特征在于,以式III化合物为原料,在碱作用下与(i-Pr2N)2P-OCH2CH2CN经取代反应制备得到式II-1化合物,再经氧化和水解反应制备得到式II所示化合物,其反应式为:
式中:R1-R4如权利要求1中所述。
6.一种如权利要求1所述的基于[2.2]对环芳烷骨架的有机磷化合物的用途,其特征在于,所述的如式I或II所示的有机磷化合物与金、银、铜、铑、钌、铱、镍、钼、铁、钯或钴的金属盐反应制备催化剂;或者所述的有机磷化合物用于金属催化的加成、氢化、偶联及其不对称反应;或者所述的有机磷化合物作为有机催化剂催化有机不对称反应。
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