CN108794420B - 基于四甲基螺二氢茚骨架的双噁唑啉配体化合物及其中间体和制备方法与用途 - Google Patents
基于四甲基螺二氢茚骨架的双噁唑啉配体化合物及其中间体和制备方法与用途 Download PDFInfo
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- CN108794420B CN108794420B CN201711405090.2A CN201711405090A CN108794420B CN 108794420 B CN108794420 B CN 108794420B CN 201711405090 A CN201711405090 A CN 201711405090A CN 108794420 B CN108794420 B CN 108794420B
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- tetramethyl
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- 239000003446 ligand Substances 0.000 title claims abstract description 44
- 150000001875 compounds Chemical class 0.000 title claims abstract description 40
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- -1 aminoethanol compound Chemical class 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000000958 aryl methylene group Chemical group 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- XIWMTQIUUWJNRP-UHFFFAOYSA-N amidol Chemical compound NC1=CC=C(O)C(N)=C1 XIWMTQIUUWJNRP-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 70
- XKZQKPRCPNGNFR-UHFFFAOYSA-N 2-(3-hydroxyphenyl)phenol Chemical compound OC1=CC=CC(C=2C(=CC=CC=2)O)=C1 XKZQKPRCPNGNFR-UHFFFAOYSA-N 0.000 abstract description 5
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 abstract description 5
- 238000006053 organic reaction Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 67
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 125000001072 heteroaryl group Chemical group 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
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- 125000004104 aryloxy group Chemical group 0.000 description 13
- 238000001035 drying Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 125000003107 substituted aryl group Chemical group 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
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- IISBACLAFKSPIT-UHFFFAOYSA-N bisphenol A Chemical class C=1C=C(O)C=CC=1C(C)(C)C1=CC=C(O)C=C1 IISBACLAFKSPIT-UHFFFAOYSA-N 0.000 description 8
- 125000005553 heteroaryloxy group Chemical group 0.000 description 8
- 239000007832 Na2SO4 Substances 0.000 description 7
- 229920001774 Perfluoroether Polymers 0.000 description 7
- 238000006555 catalytic reaction Methods 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- VPMMJSPGZSFEAH-UHFFFAOYSA-N 2,4-diaminophenol;hydrochloride Chemical compound [Cl-].NC1=CC=C(O)C([NH3+])=C1 VPMMJSPGZSFEAH-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 230000000171 quenching effect Effects 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- WMPDAIZRQDCGFH-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 4
- 238000006713 insertion reaction Methods 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
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- 239000000741 silica gel Substances 0.000 description 4
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 125000003003 spiro group Chemical group 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical class [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000004312 hexamethylene tetramine Substances 0.000 description 3
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 125000001424 substituent group Chemical group 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
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 229930185605 Bisphenol Natural products 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical class [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- NWYYWIJOWOLJNR-RXMQYKEDSA-N l-valinol Chemical compound CC(C)[C@H](N)CO NWYYWIJOWOLJNR-RXMQYKEDSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000012074 organic phase Substances 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
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- NPZQHIGJQZDIRT-VXGBXAGGSA-N (1R,5S)-1-(2-chlorophenyl)-5-methyl-3-oxabicyclo[3.1.0]hexan-2-one Chemical compound C[C@]12C[C@]1(C(=O)OC2)c1ccccc1Cl NPZQHIGJQZDIRT-VXGBXAGGSA-N 0.000 description 1
- LMIRXBIPZDDRMA-VXGBXAGGSA-N (1S,5S)-1-(3-chlorophenyl)-5-methyl-3-oxabicyclo[3.1.0]hexan-2-one Chemical compound ClC=1C=C(C=CC=1)[C@@]12C(OC[C@]2(C1)C)=O LMIRXBIPZDDRMA-VXGBXAGGSA-N 0.000 description 1
- HFZMDGITULWQGC-VXGBXAGGSA-N (1S,5S)-1-(4-chlorophenyl)-5-methyl-3-oxabicyclo[3.1.0]hexan-2-one Chemical compound ClC1=CC=C(C=C1)[C@@]12C(OC[C@]2(C1)C)=O HFZMDGITULWQGC-VXGBXAGGSA-N 0.000 description 1
- OWEYKIWAZBBXJK-UHFFFAOYSA-N 1,1-Dichloro-2,2-bis(4-hydroxyphenyl)ethylene Chemical compound C1=CC(O)=CC=C1C(=C(Cl)Cl)C1=CC=C(O)C=C1 OWEYKIWAZBBXJK-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- ZXTHWIZHGLNEPG-UHFFFAOYSA-N 2-phenyl-4,5-dihydro-1,3-oxazole Chemical compound O1CCN=C1C1=CC=CC=C1 ZXTHWIZHGLNEPG-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical class [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 238000006364 Duff aldehyde synthesis reaction Methods 0.000 description 1
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 description 1
- 229910021577 Iron(II) chloride Inorganic materials 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical class [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical class [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 238000004639 Schlenk technique Methods 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical class [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
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- 238000007171 acid catalysis Methods 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
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- 244000309464 bull Species 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910017052 cobalt Chemical class 0.000 description 1
- 239000010941 cobalt Chemical class 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical class [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Chemical class 0.000 description 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000004367 cycloalkylaryl group Chemical group 0.000 description 1
- 238000005888 cyclopropanation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
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- 238000000605 extraction Methods 0.000 description 1
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- 239000012362 glacial acetic acid Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical class [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 1
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- 239000011777 magnesium Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
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- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 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
- 229920000642 polymer Polymers 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Chemical class 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical class [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Chemical class 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000006209 tert-butylation Effects 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- KPZYAGQLBFUTMA-UHFFFAOYSA-K tripotassium;phosphate;trihydrate Chemical compound O.O.O.[K+].[K+].[K+].[O-]P([O-])([O-])=O KPZYAGQLBFUTMA-UHFFFAOYSA-K 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Chemical class 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
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Abstract
本发明公开了一种基于四甲基螺二氢茚骨架的双噁唑啉配体化合物及其中间体和制备方法与用途。所述的双噁唑啉配体化合物是具有通式I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。该双噁唑啉配体以廉价易得的四甲基螺二氢茚二酚为起始原料，经过一系列反应步骤制备获得,关键中间体是具有通式II所示结构的化合物。本发明开发了新型的噁唑啉配体，可用于催化有机反应，特别是可作为手性的噁唑啉配体广泛用于金属催化的不对称反应中，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四甲基螺二氢茚骨架的双噁唑啉配体化合物及其中间体和制备方法和应用。该类配体可用于偶联反应或不对称催化反应。
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,该技术是获得手性化合物最直接的、最有效的化学方法。它具有手性增殖、高对映选择性、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是合成化学领域中一项挑战性的课题，其核心科学问题之一是发展和发现新型高效的手性配体及其催化剂。尽管手性配体的设计合成已经取得快速发展，有如下众多的优秀手性双噁唑啉配体被合成出来，并有相当一些配体已经应用于工业化生产，但仍然存在包括配体的适用范围有限，对反应底物依赖度高等问题，还没有任何一种手性配体是通用的。因而寻求新型骨架的手性配体一直是催化不对称合成反应中的永恒主题。
手性配体的设计合成(如何提高催化活性和对映选择性)主要考虑电性和结构因素(如二面角、位阻和骨架刚性等)。当前普遍认为，二面角对于不对称催化的对映选择性有极大影响(比如文献Acc.Chem.Res.2007,40,1385–1393；Tetrahedron:Asymmetry 15(2004)2185–2188；J.Org.Chem.1999,65,6223)。
1999年，Birman等人从间甲氧基苯甲醛出发，经过6步反应合成得到了外消旋的螺二氢茚二酚SPINOL(1,1'-螺二氢茚-7,7'-二醇)，又通过化学拆分获得了相应的光学对映体(Tetrahedron:Asymmetry 1999,10,12)；不过按照此路线或者其他公开方法都是无法获得相应的3,3,3',3'-四甲基-1,1'-螺二氢茚-7,7'-二醇。在2003年，周其林等以这种光学活性的螺二氢茚二酚SPINOL为原料，经过5步反应合成了基于螺二氢茚骨架的双噁唑啉配体SpiroBOX(Tetrahedron:Asymmetry17(2006)634，CN101565434，CN100432083)，已经分别成功应用于催化不对称反应。不过，从工业可用的原料间甲氧基苯甲醛出发，至少经过11步合成反应和1步手性拆分才能得到相应的SpiroBOX，反应步骤冗长，制备成本较高，影响实用性。
四甲基螺二氢茚二酚(3,3,3',3'-四甲基-1,1'-螺二氢茚-6,6'-二醇，MSPINOL)可从工业化的双酚系列产品通过酸催化直接高产率得到，并已有规模化制备方法和手性拆分方法(反应式如下，J.Chem.Soc.,1962,415-418；Org.Lett.,2004,6,2341-2343；US2006/0020150；US4879421；Bull.Chem..Soc.Japan,1977,44,496-505；中国发明专利。申请号CN 201711330428.2)。
四甲基螺二氢茚二酚MSPINOL及其衍生物主要报道用于制备高聚物。相应的原料双酚非常廉价，可从丙酮和苯酚或其衍生物进行缩合反应获得；工业上有很多双酚系列产品(双酚A，双酚C等等)大规模销售，比如双酚A在全球年产销量高达三百多万吨，每吨价格不到1万元。本发明拟利用廉价易得的四甲基螺二氢茚二酚，设计制备相应的基于四甲基螺二氢茚骨架的噁唑啉配体；该类配体相比基于螺二氢茚骨架的噁唑啉配体来说，螺环骨架上无活泼的芳亚甲基，四甲基螺二氢茚骨架更稳定并且刚性更强，原料廉价丰富，合成路线更短，制备成本低廉，实用性强，有独特的二面角预示着不同的催化效果或用途。基于本发明公开的方法，制备基于四甲基螺二氢茚骨架的双噁唑啉配体，从工业化大吨位原料双酚出发，一般只要7步合成反应路线即可,大部分反应后处理简单易规模化(如下反应式为例)，并从中间体四甲基螺环二酸出发经2步反应可制备基于四甲基螺二氢茚骨架的不同结构的双噁唑啉配体MSpiroBOX。
发明内容
本发明的目的是提供一种基于四甲基螺二氢茚骨架的双噁唑啉配体化合物及其制备方法和应用。
一种基于四甲基螺二氢茚骨架的双噁唑啉配体，是具有如下通式I的化合物或所述化合物的对映体、消旋体或非对映异构体：
各式中：R1和R6分别独立选自氢、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、杂芳基或取代的杂芳基；R2、R3、R4、R5分别独立选自氢、卤素、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、芳基或取代的芳基、杂芳基或取代的杂芳基；R7选自氢、C1～C10的烷基或全氟烷基、C3～C6的环烷基、金刚烷基、二茂铁基、C6～C14芳基、芳基亚甲基、杂芳基亚甲基、芳基乙基、取代的芳基、C5～C14杂芳基、取代的杂芳基、羟甲基、烷基苯甲酸基亚甲基、芳基苯甲酸基亚甲基、CH(Me)OH、CH(Me)OCOPh、CMe2OSiMe3、CMe2OBn、CH2OSiMe2 tBu、CH2SMe、CH2SPh、CH2CH2SMe、CMe2SMe、CMe2Ph、CMePh2、CPh3、CH(Ph)OH、CH(Ph)OMe、CH(Ph)OBn、CH(Ph)OCOMe、CH(Ph)OCOPh、烷氧基亚甲基、芳氧基亚甲基；R8和R9分别独立选自氢、C1～C10的烷基或全氟烷基、C3～C6的环烷基、C6～C14芳基、取代的芳基、C5～C14杂芳基、取代的杂芳基、烷氧基亚甲基、芳氧基亚甲基、CH2OCHPh2、CH2OCPh3、CH2OCH2Ph；R7和R8可以构成环状结构或苯并环状结构；其中所述取代的芳氧基、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、羟基、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、C6～C14芳基、芳氧基、杂芳基；所述的杂芳基是C5～C14的杂芳基；
一种制备上述的基于四甲基螺二氢茚骨架的双噁唑啉配体的中间体化合物，是具有如下通式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：
式中：R1和R6分别独立选自氢、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、杂芳基或取代的杂芳基；R2、R3、R4、R5分别独立选自氢、卤素、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、芳基或取代的芳基、杂芳基或取代的杂芳基；其中所述取代的芳氧基、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、羟基、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；R2和R5同时为氢时，R6和R1可选自羟基。
所述如式I所示的基于四甲基螺二氢茚骨架的双噁唑啉配体优选是如下任一化合物：
所述如式II所示的基于四甲基螺二氢茚骨架的双噁唑啉配体的中间体化合物,优选是如下任一化合物：
所述的如式II所示的中间体化合物的制备方法，包含如下步骤：以四甲基螺二氢茚二酚(式1)为起始原料，经达夫(Duff)反应制备化合物2(当R2和R5不等于氢)，或经叔丁基化后再进行达夫(Duff)反应和脱叔丁基反应制备化合物2(当R2和R5至少一个等于氢)；化合物2可经醚化反应制备式II化合物，或化合物2与三氟甲磺酸酐成酯得到化合物3后再进行钯催化偶联反应制备式II化合物，或酯3经钯催化还原反应制备酯式II化合物：
其中，式1、2、3、4、5中R1～R6的含义如如式II中所述,R选自C1～C10的烷基或全氟烷基、C3～C6的环烷基、芳基或取代的芳基、杂芳基或取代的杂芳基；其中所述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，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；HMTA是六亚甲基四胺，TFA是三氟乙酸。
所述的如式I所示化合物的制备方法，包含如下步骤：以式II化合物为起始原料，经高锰酸钾氧化反应制备式III的化合物，再经酰氯化反应后与氨基乙醇类化合物缩合成酰胺醇，最后环化得到式I化合物：
其中，R1～R9的含义如式I中所述。
本发明的双噁唑啉配体的应用：所述的双噁唑啉配体与铁、金、银、铜、锌、镁、铑、钌、镍、钼、钯或钴等的金属盐络合，制备催化剂。
所述的双噁唑啉配体可应用于金属催化的偶联反应、插入反应、不对称反应，优选用于金属催化的不对称傅克烷基化反应和不对称N-H、O-H、S-H、Si-H或C-H等的插入反应。
本发明的双噁唑啉配体以廉价易得的四甲基螺二氢茚二酚为起始原料，合成反应路线简单，易规模化应用。该新型的双噁唑啉配体可用于催化有机反应，特别是可作为手性的噁唑啉配体广泛用于金属催化的不对称反应中，具有经济实用性和工业应用前景。
应理解，在本发明范围中，本发明的上述各种技术特征和在下文实施例中具体描述的各种技术特征之间都可以互相组合，从而构成新的或优先的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1是本发明实施例中产物(Ra,S,S)-I-Ph的X射线晶体衍射图。
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和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
3,3,5,3',3',5'-六甲基-1,1'-螺二氢茚-7,7'-二甲醛(II-b)和3,3,5,3',3',5'-六甲基-1,1'-螺二氢茚-7,7'-二甲酸(III-b)的合成
第一步：在500mL三口烧瓶中，加入3,3,5,3',3',5'-六甲基-1,1'-螺二氢茚-6,6'-二醇(HMSPINOL,10mmol,3.4g)，六次甲基四胺(HMTA,80mmol,11.2g)，N2保护。接着加入120mL三氟乙酸，回流反应过夜。第二天加入120mL冰醋酸，继续回流反应3天。然后降温至95℃，加入120mL盐酸(4mol/L)，搅拌5小时，停止反应，降至室温。把反应液倒入水中，析出大量沉淀，抽滤得到黄色固体产物II-b1(3.2g，收率：82％)。m.p.283.7-285.6℃；1H NMR(400MHz,CDCl3)δ12.01(s,2H),9.57(s,2H),7.20(s,2H),2.57(d,J＝13.5Hz,2H),2.38(d,J＝13.5Hz,2H),2.26(s,6H),1.37(s,6H),1.35(s,6H).
第二步：在100mL三口烧瓶中，加入II-b1(5mmol,1.97g)，N2保护。加入40mL二氯甲烷以及吡啶(40mmol,3.3mL)，冰浴冷至0℃以下，逐滴滴加三氟甲磺酸酐(20mmol,3.4mL)。加毕，自然升至室温并搅拌过夜，TLC监测反应完全。将反应液倒入分液漏斗中，依次用5％HCl溶液，饱和食盐水，饱和NaHCO3溶液，饱和食盐水洗涤，无水Na2SO4干燥。脱去溶剂后，适量二氯甲烷溶解，硅胶柱快速柱层析(乙酸乙酯/石油醚＝1/50)，得到白色固体产物II-b2(3.1g，收率95％)。m.p.155.4-157.2℃；1H NMR(400MHz,CDCl3)δ9.79(s,2H),7.35(s,2H),2.51(d,J＝12.8Hz,2H),2.45(s,6H),2.42(d,J＝12.8Hz,2H),1.50(s,6H),1.40(s,6H)。
第三步：在250mL三口烧瓶中，加入II-b2(3mmol,1.97g)，醋酸钯(0.6mmol,135mg)，1,3-双(二苯膦)丙烷(0.6mmol,248mg)，N2保护。加入150mL的N,N-二甲基甲酰胺(DMF)，得到澄清溶液，缓慢滴加三乙基硅烷(45mmol,7.2mL)。加毕，升至60℃，反应6小时，TLC监测反应完全。恢复室温，加入乙醚稀释反应液，依次用水，饱和NaHCO3溶液，饱和食盐水洗涤，无水Na2SO4干燥。脱去溶剂，快速柱层析(乙酸乙酯/石油醚＝1/15)，得黄色固体3,3,5,3',3',5'-六甲基-1,1'-螺二氢茚-7,7'-二甲醛(II-b)(950mg,收率88％)。m.p.173.6-175.9℃；1H NMR(400MHz,CDCl3)δ9.56(s,2H),7.53(s,2H),7.25(s,2H),2.56(d,J＝13.3Hz,2H),2.43(d,J＝17.1Hz,8H),1.45(s,6H),1.40(s,6H)。
第四步：将II-b(2.5mmol,900mg)加入到250mL圆底烧瓶中，加入80mL丙酮，溶解完全。向其中加入溶解有KMnO4(15mmol,2.37g)的水(20mL)和丙酮(80mL)的混合溶液。将反应升至45℃，反应过夜，TLC监测反应完全。恢复室温，向体系中加入4M NaOH溶液至反应液pH为10-11，抽滤，旋干丙酮，水相用石油醚洗涤三次，向水相中加入4M HCl溶液至pH＝2，析出大量白色固体。乙酸乙酯萃取三次，合并有机相，无水Na2SO4干燥，旋干，得白色固体产物3,3,5,3',3',5'-六甲基-1,1'-螺二氢茚-7,7'-二甲酸(III-b)(950mg，收率97％)。m.p.317.5-319.2℃；1H NMR(400MHz,DMSO)δ12.06(s,2H),7.26(s,2H),7.12(s,2H),2.74(d,J＝12.1Hz,2H),2.29(s,6H),2.18(d,J＝12.1Hz,2H),,1.37(s,6H),1.35(s,6H)。
实施例2
(S)-3,3,5,3',3',5'-六甲基-1,1'-螺二氢茚-7,7'-二甲醛((S)-II-b)和(S)-3,3,5,3',3',5'-六甲基-1,1'-螺二氢茚-7,7'-二甲酸((S)-III-b)的合成
按照实施例1的过程，用手性的(S)-3,3,5,3',3',5'-六甲基-1,1'-螺二氢茚-6,6'-二醇((S)-HMSPINOL)代替3,3,5,3',3',5'-六甲基-1,1'-螺二氢茚-6,6'-二醇(HMSPINOL)，即可制备得到相应的(S)-3,3,5,3',3',5'-六甲基-1,1'-螺二氢茚-7,7'-二甲醛((S)-II-b，总产率65％)和(S)-3,3,5,3',3',5'-六甲基-1,1'-螺二氢茚-7,7'-二甲酸((S)-III-b，总产率60％)。
实施例3
3,3,3',3'-四甲基-1,1'-螺二氢茚-6,6'-二羟基-7,7'-二甲醛(II-c)的合成
在反应瓶中加入5.2g化合物(BMSPINOL,12.4mmol)，10.8g六亚甲基四胺(HMTA，77mmol)，氮气保护，加入150mL三氟乙酸(TFA)，加热回流反应过夜，然后加150mL乙酸，继续回流反应72小时,加6摩尔/升盐酸200mL，搅拌回流水解28小时，再加100mL水，继续搅拌反应24小时，接着冷却反应液，抽滤并用水充分洗涤滤饼，滤饼干燥得4.6g黄色粉末状固体产物II-aa,产率80％。熔点为226-227℃.1H NMR(400MHz,CDCl3)δ12.55(s,2H),9.60(s,2H),7.30(s,2H),2.56(d,J＝13.5Hz,2H),2.39(d,J＝13.5Hz,2H),1.42(s,18H),1.37(s,6H),1.35(s,6H).
反应瓶中加入2g化合物II-aa(4.2mmol)，10g无水氯化铝(75mmol),氮气保护，加入30mL甲苯，冰浴下加入20mL硝基甲烷，室温搅拌反应过夜，TLC板监测反应进程，反应结束后在冰浴下慢慢加入3mol/L盐酸淬灭反应，搅拌反应过夜。加入乙酸乙酯萃取，用水和饱和氯化钠依次洗涤有机相，无水硫酸钠干燥，脱溶。残余物用二氯甲烷快速柱层析，可得1.2g浅黄色粉末状固体3,3,3',3'-四甲基-1,1'-螺二氢茚-6,6'-二羟基-7,7'-二甲醛(II-c),产率78％。熔点为219-220℃.1H NMR(400MHz,CDCl3)δ11.72(s,2H),9.58(s,2H),7.35(d,J＝8.6Hz,2H),6.94(d,J＝8.6Hz,2H),2.62(d,J＝13.5Hz,2H),2.43(d,J＝13.5Hz,2H),1.37(s,6H),1.35(s,6H).
实施例4
(R)-3,3,3',3'-四甲基-1,1'-螺二氢茚-6,6'-二羟基-7,7'-二甲醛((R)-II-c)的合成
按照实施例3的过程，用手性的(R)-BMSPINOL代替消旋体化合物BMSPINOL，即可制备得到相应的(R)-3,3,3',3'-四甲基-1,1'-螺二氢茚-6,6'-二羟基-7,7'-二甲醛((R)-II-c，总产率64％)。
实施例5
3,3,3',3'-四甲基-1,1'-螺二氢茚-7,7'-二甲醛(II-a)和3,3,3',3'-四甲基-1,1'-螺二氢茚-7,7'-二甲酸(III-a)的合成
按照实施例1的第二步到第四步的反应过程，第二步反应用3,3,3',3'-四甲基-1,1'-螺二氢茚-6,6'-二羟基-7,7'-二甲醛(II-c)代替3,3,5,3',3',5'-六甲基-1,1'-螺二氢茚-6,6'-二羟基-7,7'-二甲醛(II-b1)，第三步和第四步的反应中投料做相应的改变，即可制备得到相应的3,3,3',3'-四甲基-1,1'-螺二氢茚-7,7'-二甲醛(II-a，总收率85％)和3,3,3',3'-四甲基-1,1'-螺二氢茚-7,7'-二甲酸(III-a，总收率82％)。
按照上述一样的过程，改用手性的(R)-II-c作为原料，则得到了手性的(R)-II-a，(总收率86％)和(R)-III-a(总收率84％)。
实施例6
3,3,3',3'-四甲基-1,1'-螺二氢茚-6,6'-二甲氧基-7,7'-二甲醛(II-d)的合成
在反应瓶中加入3g的II-c和4g的碳酸钾，加入50mL丙酮，注入2mL的碘甲烷，搅拌回流反应12小时至TLC监控原料消失并完全成为一个产物点；加入浓氨水60mL,继续搅拌2小时。降至室温后，抽滤，热水洗涤3次，烘干得到白色粉末的II-d，收率95％。
实施例7
3,3,3',3'-四甲基-1,1'-螺二氢茚-6,6'-二苯基-7,7'-二甲醛(II-e)的合成
氮气保护，在反应瓶中加入II-cc(0.2g)，苯基硼酸0.38g，溴化钾0.1g，四(三苯基膦)钯(60mg)，再加入2mL乙二醇二甲醚(DME)和1mL水以及0.45g的三水合磷酸钾，90℃下搅拌反应24小时，TLC监控至反应结束。接着加水淬灭反应，用乙酸乙酯萃取，无水硫酸钠干燥，抽滤，滤液浓缩至干，硅胶柱快速柱层析得到粉末状固体II-e，收率：60％。1H NMR(400MHz,CDCl3)δ9.50(s,2H),7.45(d,J＝7.8Hz,2H),7.36–7.20(m,12H),2.74(d,J＝12.5Hz,2H),2.47(d,J＝12.5Hz,2H),1.58(s,6H),1.47(s,6H).
实施例8
3,3,5,3',3',5'-六甲基-1,1'-螺二氢茚-7,7'-二噁唑啉的合成
将六甲基螺环二甲酸III-b(5mmol,1.97g)加入到反应瓶中，加入60mL氯化亚砜搅拌溶解，后逐滴加入三乙胺(20mmol,2.78mL)，滴加完毕，将反应升至60℃，搅拌反应3小时。减压旋蒸除去挥发物得酰氯。N2保护，加入50mL二氯甲烷溶解酰氯，冰浴冷却至0℃，依次加入三乙胺(20mmol,2.78mL)和L-缬氨醇(20mmol,2.07g)的二氯甲烷(10mL)溶液，加毕，升至室温，反应过夜，TLC监测反应完全。加水淬灭反应，二氯甲烷萃取，用Na2SO4干燥，脱溶至干，得产物酰胺醇IIIba用于下一步。
在反应瓶中加入酰胺醇IIIba(5mmol)和4-二甲氨基吡啶(DMAP,1mmol,122mg)，N2保护。加入75mL二氯甲烷搅拌溶解。冰水浴冷却至0℃，依次加入三乙胺(40mmol,5.7mL)和甲磺酰氯(MsCl,20mmol,1.6mL)，加完后使体系自然升温至室温，反应过夜，TLC监测反应完全。加水淬灭，二氯甲烷萃取，饱和食盐水洗涤，无水Na2SO4干燥。减压旋转脱溶，硅胶柱层析(乙酸乙酯/石油醚＝1/15-1/4)分离得到一对非对映异构体(Ra,S,S)-I-c(1.1g，收率84％)和(Sa,S,S)-I-cc(1.06g，收率81％)。
(Ra,S,S)-I-c：m.p.66.2-68.0℃；[α]D 20＝+93(c0.12,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.34(s,2H),7.03(d,J＝0.9Hz,2H),3.76(dd,J＝9.6,8.1Hz,2H),3.44(td,J＝9.4,7.2Hz,2H),2.95–2.88(m,2H),2.84(d,J＝12.2Hz,2H),2.32(s,6H),2.27(d,J＝12.2Hz,2H),1.45(dq,J＝13.6,6.8Hz,2H),1.36(s,12H),0.87(d,J＝6.7Hz,6H),0.66(d,J＝6.8Hz,6H)；
(Sa,S,S)-I-cc：[α]D 20＝-173(c0.15,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.51(s,2H),7.07(d,J＝0.8Hz,2H),3.67(dt,J＝9.7,5.7Hz,2H),3.60(dd,J＝7.9,6.2Hz,2H),2.89(dd,J＝9.6,8.1Hz,2H),2.67(d,J＝12.2Hz,2H),2.35(s,6H),2.29(d,J＝12.2Hz,2H),1.65(dq,J＝13.4,6.7Hz,2H),1.35(s,6H),1.37(s,6H),0.81(d,J＝6.8Hz,6H),0.73(d,J＝6.8Hz,6H)。
按照上述过程，可以获得以下双噁唑啉配体化合物及其表征：
[(Ra,S,S)-I-Ph]：
1.35g,91％yield(two steps)；white soild,m.p.171-172℃；[α]D 20＝-47(c0.12,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.48(d,J＝0.7Hz,2H),7.26(dd,J＝8.3,6.0Hz,4H),7.23–7.13(m,6H),7.01(d,J＝0.8Hz,2H),4.72(t,J＝10.2Hz,2H),4.21(dd,J＝10.0,8.2Hz,2H),3.06(dd,J＝10.3,8.2Hz,2H),2.99(d,J＝12.1Hz,2H),2.32(d,J＝12.1Hz,2H),2.21(s,6H),1.38(s,6H),1.32(s,6H)；
单晶数据(如图1)：Cell:a＝8.0415(4)b＝9.7317(5)c＝41.5986(18)；alpha＝90beta＝90gamma＝90；Temperature:130K；Volume 3255.4(3)Space group P 21 21 21；Hall groupP 2ac 2ab；
[(Sa,S,S)-I-Ph]：
1.29g,87％yield(two steps)；white soild,m.p.101-102℃；[α]D 20＝-94(c0.13,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.58(s,2H),7.16(dt,J＝14.3,7.8Hz,6H),7.02(d,J＝8.7Hz,6H),4.82(dd,J＝10.1,6.1Hz,2H),3.71(dd,J＝7.9,6.3Hz,2H),3.18(dd,J＝10.0,8.3Hz,2H),2.67(d,J＝12.3Hz,2H),2.32(s,6H),2.28(d,J＝12.3Hz,2H),1.35(s,6H),1.23(s,6H)；
[(Ra,S,S)-I-d]：
1.31 g,84％yield(two steps)；white soild,m.p.57-58℃；[α]D 20＝+51(c0.15,CH2Cl2)；1H NMR(400 MHz,CDCl3)δ7.50(s,2H),7.25(dd,J＝9.0,5.5 Hz,4H),7.18(t,J＝7.3 Hz,2H),7.08(dd,J＝10.7,4.0 Hz,6H),4.04(qd,J＝9.2,4.8 Hz,2H),3.76(t,J＝8.7Hz,2H),3.10(dd,J＝13.6,4.7 Hz,2H),2.79(dd,J＝14.2,5.5 Hz,4H),2.42(s,6H),2.28(dd,J＝14.3,11.1 Hz,4H),1.40(s,6H),1.32(s,6H)；
[(Sa,S,S)-I-d]：
1.26 g,81％yield(two steps)；white soild,m.p.43-44 ℃；[α]D20＝-24(c0.19,CH2Cl2)；1H NMR(400 MHz,CDCl3)δ.7.43(s,2H),7.29–7.22(m,6H),7.18(t,J＝7.3Hz,2H),7.09(d,J＝7.0 Hz,4H),7.03(d,J＝0.9 Hz,2H),4.28–3.96(m,2H),3.57(dd,J＝8.2,6.2 Hz,2H),3.02(t,J＝8.8 Hz,2H),2.91(dd,J＝13.8,4.0 Hz,2H),2.75(d,J＝12.2Hz,2H),2.33(s,6H),2.29(d,J＝12.2 Hz,2H),2.08(dd,J＝13.7,10.5 Hz,2H),1.38(s,6H),1.34(s,6H)；
[(Ra,4S,4’S,5S,5’S)-I-DPh]：
1.42 g,76％yield(two steps)；white soild,m.p.196-197℃；[α]D 20＝-97(c0.10,CH2Cl2)；1H NMR(400 MHz,CDCl3)δ7.69(s,2H),7.30(dd,J＝10.8,5.1 Hz,6H),7.24–7.08(m,14H),6.95(s,2H),4.64(d,J＝10.3Hz,2H),4.08(d,J＝10.3 Hz,2H),2.97(d,J＝12.0 Hz,2H),2.27(d,J＝12.0 Hz,2H),2.18(s,6H),1.30(s,6H),0.91(s,6H)；
[(Sa,4S,4’S,5S,5’S)-I-DPh]：
1.38g,74％yield(two steps)；white soild,m.p.52-53℃；[α]D 20＝+8(c0.12,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.51(d,J＝1.0Hz,2H),7.31–7.27(m,6H),7.25–7.19(m,6H),7.10–6.99(m,4H),6.94–6.87(m,4H),6.80(d,J＝1.1Hz,2H),4.90(d,J＝9.0Hz,2H),4.75(d,J＝9.0Hz,2H),2.64(d,J＝12.6Hz,2H),2.29(d,J＝12.5Hz,2H),2.15(s,6H),1.31(s,6H),1.17(s,6H)；(S,S)-I-1a：Rf＝0.7(石油醚:乙酸乙酯＝4:1)；
White soild,m.p.30.5-31.2℃；[α]D 20＝+28(c0.10,CH2Cl2)；1HNMR(400MHz,CDCl3)δ7.63(dd,J＝5.9,3.0Hz,2H),7.34–7.28(m,4H),7.26–7.13(m,6H),7.08(d,J＝7.0Hz,4H),4.08–3.89(m,2H),3.81–3.69(m,2H),3.03(dd,J＝13.7,5.0Hz,2H),2.86(dd,J＝13.6,4.9Hz,4H),2.33(d,J＝12.2Hz,2H),2.27(dd,J＝13.7,9.7Hz,2H),1.42(s,6H),1.35(s,6H)；
(S,S)-I-1b：Rf＝0.4(石油醚:乙酸乙酯)
White soild,m.p.49.2-50.2℃；[α]D 20＝-105(c0.11,CH2Cl2)；1HNMR(400MHz,CDCl3)δ7.60(dd,J＝7.2,1.6Hz,2H),7.26–7.13(m,10H),7.08(d,J＝7.0Hz,4H),4.26–4.01(m,2H),3.57(dd,J＝8.3,6.2Hz,2H),3.04(t,J＝8.8Hz,2H),2.86(dd,J＝13.8,4.1Hz,2H),2.79(d,J＝12.2Hz,2H),2.32(d,J＝12.2Hz,2H),2.16–1.98(m,2H),1.41(s,6H),1.37(s,6H)；
实施例9
用手性六甲基螺环二甲酸制备3,3,5,3',3',5'-六甲基-1,1'-螺二氢茚-7,7'-二噁唑啉
将(S)-3,3,5,3',3',5'-六甲基-1,1'-螺二氢茚-7,7'-二甲酸((S)-III-b)(5mmol,1.97g)加入到反应瓶中，加入60mL氯化亚砜搅拌溶解，后逐滴加入三乙胺(20mmol,2.78mL)，滴加完毕，将反应升至60℃，搅拌反应3小时。减压旋蒸除去挥发物得酰氯。N2保护，加入60mL二氯甲烷溶解酰氯，冰浴冷却至0℃，依次加入三乙胺(20mmol,2.78mL)和L-缬氨醇(20mmol,2.07g)的二氯甲烷(15mL)溶液，加毕，升至室温，反应过夜，TLC监测反应完全。加水淬灭反应，二氯甲烷萃取，用Na2SO4干燥，脱溶至干，得产物酰胺醇(S)-IIIba用于下一步。
在反应瓶中加入酰胺醇(S)-IIIba(5mmol)和4-二甲氨基吡啶(DMAP,1mmol,122mg)，N2保护。加入80mL二氯甲烷搅拌溶解。冰水浴冷却至0℃，依次加入三乙胺(40mmol,5.7mL)和甲磺酰氯(MsCl,20mmol,1.6mL)，加完后使体系自然升温至室温，反应过夜，TLC监测反应完全。加水淬灭，二氯甲烷萃取，饱和食盐水洗涤，无水Na2SO4干燥。减压旋转脱溶，硅胶柱层析(乙酸乙酯/石油醚＝1/6)纯化得到(Sa,S,S)-I-cc(收率91％)。
实施例10
不对称分子内环丙烷化反应的应用：
向Schlenk管中加入FeCl2·4H2O(2.0mg,0.01mmol)，配体(Ra,S,S)-I-Ph(7.1mg,0.012mmol)，添加剂NaBArF(10.6mg,0.012mmol)，N2保护，加入溶剂CHCl3(1.5mL)，室温下搅拌配位4小时，然后向反应液中加入α-重氮酯衍生物8(0.1mmol)的CHCl3溶液(0.5mL)，升温至60℃继续反应24小时，TLC监测反应完成，停止反应，降至室温，浓缩反应液，硅胶柱快速柱层析(乙酸乙酯/石油醚＝1/10)，得到产物手性的环丙烷化产物9。
反应结果如下：
(1S,5S)-1-(4-chlorophenyl)-5-methyl-3-oxabicyclo[3.1.0]hexan-2-one(9a)
21mg,93％yield；white solid；m.p.122-123℃；92％ee；HPLCanalysis:Chiralpak OJ-H(hexane/i-PrOH＝80/20,1.0mL/min,210nm),tR(major)18.115min,tR(minor)21.659min；[α]D 20＝+49(c0.04,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.39–7.32(m,2H),7.23–7.16(m,2H),4.36(d,J＝9.2Hz,1H),4.19(d,J＝9.2Hz,1H),1.58(d,J＝5.0Hz,1H),1.41(d,J＝5.0Hz,1H),1.17(s,3H)；
比较实施例：用文献已知的配体1,1'-螺二氢茚-7,7'-二(苯基噁唑啉)(Ra,S,S)-SpiroBOX–Ph代替上述同样的反应过程中的配体(Ra,S,S)-I-Ph，则所得产物9a的光学纯度小于80％ee。
(1S,5S)-1-(3-chlorophenyl)-5-methyl-3-oxabicyclo[3.1.0]hexan-2-one(9b)
21mg,93％yield；white solid；m.p.67-68℃；96％ee；HPLCanalysis:ChiralpakAS-H(hexane/i-PrOH＝80/20,1.0mL/min,210nm),tR(major)12.981min,tR(minor)19.715min；[α]D 20＝+75(c 0.07,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.24(dd,J＝3.9,1.3Hz,2H),7.19(dd,J＝3.3,1.8Hz,1H),7.13–7.03(m,1H),4.29(d,J＝9.2Hz,1H),4.12(d,J＝9.2Hz,1H),1.54(d,J＝5.0Hz,1H),1.35(d,J＝5.0Hz,1H),1.11(s,3H)；
(1R,5S)-1-(2-chlorophenyl)-5-methyl-3-oxabicyclo[3.1.0]hexan-2-one(9c)
22mg,96％yield；white solid；m.p.120-121℃；95％ee；HPLCanalysis:Chiralpak AS-H(hexane/i-PrOH＝80/20,1.0mL/min,210nm),tR(major)13.977min,tR(minor)16.589min；[α]D 20＝+3(c 0.05,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.42–7.31(m,1H),7.28–7.18(m,3H),4.31(dd,J＝27.4,9.0Hz,2H),1.45(d,J＝5.0Hz,1H),1.36(d,J＝5.0Hz,1H),1.08(s,3H).
实施例11
跟金属盐形成络合物的应用：
向Schlenk管中加入FeCl2·4H2O(2.0mg,0.01mmol)，配体(Ra,S,S)-I-Ph(0.01mmol)，N2保护，加入溶剂CHCl3(2mL)，室温下搅拌配位4小时，减压浓缩，真空抽干，即定量得到络合物[(Ra,S,S)-I-Ph]FeCl2；
向Schlenk管中加入Cu(OTf)2(0.01mmol)，配体(Ra,S,S)-I-Ph(0.01mmol)，N2保护，加入溶剂CHCl3(2mL)，室温下搅拌配位4小时，减压浓缩，真空抽干，即定量得到络合物[(Ra,S,S)-I-Ph]Cu(OTf)2。
实施例12
不对称分子间Si-H插入反应的应用：
向Schlenk管中加入Fe(OTf)2(1.77mg,0.005mmol)，配体(Ra,S,S)-I-Ph(3.6mg,0.006mmol)，添加剂NaBArF(5.3mg,0.006mmol)，N2保护，加入溶剂CH2Cl2(1.5mL)，室温下搅拌配位4小时，然后向反应液中加入重氮酯衍生物10(0.1mmol)的CH2Cl2溶液(0.5mL)，搅拌30min后，加入三乙基硅烷(64μL,0.4mmol)，升温至40℃继续反应48小时，TLC监测反应完成，停止反应，降至室温，浓缩反应液，硅胶柱快速柱层析(乙酸乙酯/石油醚＝1/100)，得到不对称分子间Si-H插入反应的产物11。
反应结果如下：
methyl 2-phenyl-2-(triethylsilyl)acetate(11a)
25mg,95％yield；colorless oi l；91％ee；HPLC analysi s:Chiralpak OD-H(hexane/i-PrOH＝99/1,0.8mL/min,225nm),t(major)2.014min,t(minor)10.637min；1HNMR(400MHz,CDCl3)δ7.36(dd,J＝6.9,5.5Hz,2H),7.31–7.25(m,2H),7.20–7.13(m,1H),3.67(s,3H),3.53(s,1H),0.90(dd,J＝9.5,6.3Hz,9H),0.59(ddd,J＝11.9,7.9,3.4Hz,6H).
methyl 2-(4-chlorophenyl)-2-(triethylsilyl)acetate(11b)
27mg,90％yield；colorless oil；93％ee；HPLC analysis:Chiralpak PA-2(hexane/i-PrOH＝98/2,0.8mL/min,214nm),t(minor)5.485min,t(major)6.553min；1HNMR(400MHz,CDCl3)δ7.31–7.22(m,4H),3.68(s,3H),3.51(s,1H),0.90(dd,J＝9.5,6.3Hz,9H),0.58(ddd,J＝12.0,7.9,3.6Hz,6H).
Claims (3)
1.一种基于四甲基螺二氢茚骨架的双噁唑啉配体，其特征在于，是具有如下通式I的化合物或所述化合物的对映体或非对映异构体：
各式中：R1和R6分别独立选自氢、C1～C10的烷基、芳基；R2、R3、R4、R5分别独立选自氢、C1～C10的烷基；R7选自氢、C1～C10的烷基、C6～C14芳基、芳基亚甲基；R8和R9分别独立选自氢、C1～C10的烷基、C6～C14芳基。
2.根据权利要求1所述的基于四甲基螺二氢茚骨架的双噁唑啉配体，其特征在于，如式I所示的化合物选自如下任一化合物：
3.如权利要求1所述的式I化合物的制备方法，其特征在于包含如下步骤：以式II化合物为起始原料，经高锰酸钾氧化反应制备式III的化合物，再经酰氯化反应后与氨基乙醇类化合物缩合成酰胺醇，最后环化得到式I化合物：
其中，R1～R9的含义如权利要求1所述。
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