CN1842533A - 次亚膦酸酯-咪唑啉及其金属络合物 - Google Patents
次亚膦酸酯-咪唑啉及其金属络合物 Download PDFInfo
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- CN1842533A CN1842533A CNA2004800245408A CN200480024540A CN1842533A CN 1842533 A CN1842533 A CN 1842533A CN A2004800245408 A CNA2004800245408 A CN A2004800245408A CN 200480024540 A CN200480024540 A CN 200480024540A CN 1842533 A CN1842533 A CN 1842533A
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- Prior art keywords
- alkyl
- compound
- formula
- cod
- phenyl
- Prior art date
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- 229910052751 metal Inorganic materials 0.000 title claims abstract description 23
- 239000002184 metal Substances 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 103
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 26
- 239000001257 hydrogen Substances 0.000 claims abstract description 25
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 24
- 150000002894 organic compounds Chemical class 0.000 claims abstract description 23
- 125000004429 atom Chemical group 0.000 claims abstract description 12
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 12
- 239000003446 ligand Substances 0.000 claims abstract description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract 5
- -1 trimethylene, tetramethylene Chemical group 0.000 claims description 132
- 238000000034 method Methods 0.000 claims description 88
- 238000006243 chemical reaction Methods 0.000 claims description 73
- 238000002360 preparation method Methods 0.000 claims description 68
- 229910052799 carbon Inorganic materials 0.000 claims description 63
- 125000000217 alkyl group Chemical group 0.000 claims description 60
- 239000002585 base Substances 0.000 claims description 48
- 150000004696 coordination complex Chemical class 0.000 claims description 39
- 150000001721 carbon Chemical group 0.000 claims description 32
- 229910052741 iridium Inorganic materials 0.000 claims description 31
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 29
- 229910052801 chlorine Inorganic materials 0.000 claims description 23
- 229910052731 fluorine Inorganic materials 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 20
- 229910052794 bromium Inorganic materials 0.000 claims description 18
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 13
- 150000002500 ions Chemical class 0.000 claims description 12
- 229910052703 rhodium Inorganic materials 0.000 claims description 12
- 239000010948 rhodium Substances 0.000 claims description 12
- 125000000746 allylic group Chemical group 0.000 claims description 11
- 150000001412 amines Chemical class 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 229910052740 iodine Inorganic materials 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 230000003197 catalytic effect Effects 0.000 claims description 10
- 229910052698 phosphorus Inorganic materials 0.000 claims description 10
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 10
- 150000003512 tertiary amines Chemical class 0.000 claims description 10
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 9
- 229910000085 borane Inorganic materials 0.000 claims description 9
- 229910000077 silane Inorganic materials 0.000 claims description 9
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 9
- 150000001336 alkenes Chemical class 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 239000012434 nucleophilic reagent Substances 0.000 claims description 8
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 8
- 229910052707 ruthenium Inorganic materials 0.000 claims description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 229910052763 palladium Inorganic materials 0.000 claims description 7
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 7
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 6
- 238000007259 addition reaction Methods 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 230000002140 halogenating effect Effects 0.000 claims description 6
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 229910052728 basic metal Inorganic materials 0.000 claims description 5
- 150000003818 basic metals Chemical class 0.000 claims description 5
- 150000001993 dienes Chemical class 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 125000004437 phosphorous atom Chemical group 0.000 claims description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
- 229910017008 AsF 6 Inorganic materials 0.000 claims description 4
- 229910018286 SbF 6 Inorganic materials 0.000 claims description 4
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 4
- 229910052697 platinum Inorganic materials 0.000 claims description 4
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 3
- 229910020366 ClO 4 Inorganic materials 0.000 claims description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 3
- 150000001450 anions Chemical class 0.000 claims description 3
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 3
- 239000002815 homogeneous catalyst Substances 0.000 claims description 3
- 150000003141 primary amines Chemical group 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- 150000004645 aluminates Chemical class 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 229910052737 gold Inorganic materials 0.000 claims description 2
- 238000001465 metallisation Methods 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 229910052709 silver Inorganic materials 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims 1
- 229910017052 cobalt Inorganic materials 0.000 claims 1
- 239000010941 cobalt Substances 0.000 claims 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims 1
- 239000010949 copper Substances 0.000 claims 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims 1
- 239000010931 gold Substances 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 150000002902 organometallic compounds Chemical class 0.000 claims 1
- 239000004332 silver Substances 0.000 claims 1
- 150000002430 hydrocarbons Chemical class 0.000 abstract description 17
- 239000004215 Carbon black (E152) Substances 0.000 abstract description 7
- 229930195733 hydrocarbon Natural products 0.000 abstract description 7
- 239000003054 catalyst Substances 0.000 abstract description 5
- 238000007792 addition Methods 0.000 abstract description 4
- 125000005842 heteroatom Chemical group 0.000 abstract description 4
- 230000007704 transition Effects 0.000 abstract description 2
- 125000006702 (C1-C18) alkyl group Chemical group 0.000 abstract 1
- 150000002739 metals Chemical class 0.000 abstract 1
- FVZVCSNXTFCBQU-UHFFFAOYSA-N phosphanyl Chemical group [PH2] FVZVCSNXTFCBQU-UHFFFAOYSA-N 0.000 abstract 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 93
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 80
- 238000005160 1H NMR spectroscopy Methods 0.000 description 62
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 55
- 239000000243 solution Substances 0.000 description 40
- 239000000460 chlorine Substances 0.000 description 36
- 238000004679 31P NMR spectroscopy Methods 0.000 description 31
- 239000003921 oil Substances 0.000 description 30
- 235000019198 oils Nutrition 0.000 description 30
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 29
- 238000004440 column chromatography Methods 0.000 description 28
- 239000003480 eluent Substances 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- 238000005984 hydrogenation reaction Methods 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- 239000012043 crude product Substances 0.000 description 13
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 12
- 229910052786 argon Inorganic materials 0.000 description 12
- JSYGRUBHOCKMGQ-UHFFFAOYSA-N dichloramine Chemical compound ClNCl JSYGRUBHOCKMGQ-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 150000002431 hydrogen Chemical class 0.000 description 11
- JYNCGMPITYHLBX-UHFFFAOYSA-N C(C)N(CC)CC[Mg] Chemical compound C(C)N(CC)CC[Mg] JYNCGMPITYHLBX-UHFFFAOYSA-N 0.000 description 10
- 150000001408 amides Chemical class 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000000376 reactant Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- 230000009466 transformation Effects 0.000 description 8
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 8
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 7
- 101150065749 Churc1 gene Proteins 0.000 description 7
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 7
- 102100038239 Protein Churchill Human genes 0.000 description 7
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 229910014033 C-OH Inorganic materials 0.000 description 6
- 229910014570 C—OH Inorganic materials 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000012442 inert solvent Substances 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- RYIOLWQRQXDECZ-UHFFFAOYSA-N phosphinous acid Chemical compound PO RYIOLWQRQXDECZ-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 125000001931 aliphatic group Chemical group 0.000 description 5
- 150000003851 azoles Chemical class 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 150000001733 carboxylic acid esters Chemical class 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 239000011574 phosphorus Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 5
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 4
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 150000005826 halohydrocarbons Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 235000006408 oxalic acid Nutrition 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 4
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 3
- 238000004293 19F NMR spectroscopy Methods 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 238000005576 amination reaction Methods 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000011914 asymmetric synthesis Methods 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 230000026030 halogenation Effects 0.000 description 3
- 238000005658 halogenation reaction Methods 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 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 3
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 3
- 238000006459 hydrosilylation reaction Methods 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 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 3
- SJYNFBVQFBRSIB-UHFFFAOYSA-N norbornadiene Chemical compound C1=CC2C=CC1C2 SJYNFBVQFBRSIB-UHFFFAOYSA-N 0.000 description 3
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 3
- RRKODOZNUZCUBN-CCAGOZQPSA-N (1z,3z)-cycloocta-1,3-diene Chemical compound C1CC\C=C/C=C\C1 RRKODOZNUZCUBN-CCAGOZQPSA-N 0.000 description 2
- KYLUAQBYONVMCP-UHFFFAOYSA-N (2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P KYLUAQBYONVMCP-UHFFFAOYSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- PRBHEGAFLDMLAL-UHFFFAOYSA-N 1,5-Hexadiene Natural products CC=CCC=C PRBHEGAFLDMLAL-UHFFFAOYSA-N 0.000 description 2
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 2
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- WNRGWPVJGDABME-UHFFFAOYSA-N 3,5-Dimethoxyaniline Chemical compound COC1=CC(N)=CC(OC)=C1 WNRGWPVJGDABME-UHFFFAOYSA-N 0.000 description 2
- NTPLXRHDUXRPNE-UHFFFAOYSA-N 4-methoxyacetophenone Chemical compound COC1=CC=C(C(C)=O)C=C1 NTPLXRHDUXRPNE-UHFFFAOYSA-N 0.000 description 2
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
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- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 description 1
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
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- 125000006229 isopropoxyethyl group Chemical group [H]C([H])([H])C([H])(OC([H])([H])C([H])([H])*)C([H])([H])[H] 0.000 description 1
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- 230000003287 optical effect Effects 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- PMJHHCWVYXUKFD-UHFFFAOYSA-N piperylene Natural products CC=CC=C PMJHHCWVYXUKFD-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
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- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
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- 235000013599 spices Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 description 1
- 239000005052 trichlorosilane Substances 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- IPSRAFUHLHIWAR-UHFFFAOYSA-N zinc;ethane Chemical group [Zn+2].[CH2-]C.[CH2-]C IPSRAFUHLHIWAR-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
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- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
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Abstract
式I和Ia化合物,其中X1为仲膦基;R3为具有1-20个碳原子的烃基、具有2-20个原子和至少一个选自O、S、NH和NR或-SO2-R基团的杂原子的杂烃基;R为C1-C18-烷基、苯基或苄基;R4基团各自或两个R4基团一起具有为具有1-20个原子的烃基;R01为具有1-20个碳原子的烃基;且R02和R’02各自为氢原子或独立地具有R01的含义,或R01和R02与其连接的碳原子一起形成3-8元烃环或杂烃环。该化合物为过渡金属I和VIII族的络合物的手性配体,其作为不对称加成(例如将氢不对称加成至前手性不饱和有机化合物上)的催化剂。
Description
本发明涉及手性含磷咪唑啉;其制备方法;在该制备中使用的中间体;包含选自元素周期表过渡I和VIII族的元素(d-10和d-8金属,在下文中称为TM8金属)和作为配体的含磷咪唑啉的金属络合物;将氢、硼烷或硅烷加成至前手性有机化合物中的碳-碳或碳-杂原子多重键上,或将C-亲核试剂或胺加成至烯丙型化合物上的不对称合成方法,特别是在催化量的金属络合物的存在下使用氢进行碳-碳或碳-杂原子多重键的不对称氢化;和金属络合物作为将氢、硼烷或硅烷加成至前手性有机化合物中碳-碳或碳-杂原子多重键上,或将C-亲核试剂或胺加成至烯丙型化合物上的不对称合成的催化剂的用途,特别是使用氢进行的碳-碳或碳-杂原子多重键的不对称氢化。
最近对基于被配位基团取代的唑啉和咪唑啉的手性配体产生兴趣。包含这些配体的金属络合物为与具有双键的有机化合物加成反应的手性合成用的优良催化剂。在所述文献中描述了以下结构(A)至(D):
A)G.Helmchen和A.Pfaltz,Accounts of Chemical Research,第33卷,第6期,336至345页(2000);
B)WO 01/18012,F.Menges等,Organic Letters(2002),第4卷,第26期,4713至4716页;C.A.Busacca等,Organic Letters(2003),第5卷,第4期,595至598页,和
C)EP-A2-1 191 030,A.Pfaltz等,Adv.Synth.Catal.2003,345,第1+2期,33至43页。
M.Casey等描述了下式的咪唑啉的仲醇(Synlett 2003,第1期,102至106页),该化合物为二乙基锌与醛类对映异构体选择性反应形成仲醇的直接催化剂。
已发现次亚膦酸酯-唑啉、膦-唑啉和膦-咪唑啉凭其优良的催化活性,为手性金属络合催化剂的有用配体,催化活性取决于反应物,同时可达到优异的对映异构体选择性。研究已表明可获得的选择性很大程度上取决于反应物,因此使用已知的配体并不能达到所有的目标。因而需要其他的配体来增加反应物的有效对映异构体选择性反应的机会。
已惊奇地发现可用简单的方法制备这样的P,N-配体,所述配体基于咪唑啉,其磷-O-甲基基团连接在咪唑啉环中的两个氮原子的α位非手性碳原子上并且咪唑啉环中包含至少一个手性碳原子。这些取代的咪唑啉使用TM8金属形成手性络合物,对于在前手性有机化合物中将氢、硼烷或硅烷对映异构选择加成至碳-碳或碳-杂原子多重键上,或将C-亲核试剂或胺对映异构选择加成至烯丙型化合物上,或将芳基三氟甲磺酸酯或烯基三氟甲磺酸酯对映异构选择偶合至烯烃上(Heck反应),该手性络合物为优异的催化剂。该催化剂的催化活性令人惊奇地高并可与前述配体相匹敌或较之更好。氮原子的取代可强烈地影响立体选择性和催化活性并与前手性反应物相匹配。就对映异构体选择性而言,已发现含磷咪唑啉是优秀的,特别在烯烃(甚至具有两个前手性中心)的前手性顺式异构体的氢化中具有可接受的高非对应选择性。
所述配体可由重要中间体与伯芳胺反应的简单、新型的方法制备。该方法对于随后含磷基团的引入具有高的模块性(modularity),因此就催化活性和立体选择性而言所述配体的空间和电子性质可很好地与待反应物相匹配。
本发明提供了式I和Ia化合物,
其中
X1为仲膦基;
R3为具有1-20个碳原子的烃基、通过碳原子连接并具有2-20个原子和至少一个选自O、S、NH和NR或-SO2-R基团的杂原子的杂烃基;
R为C1-C18-烷基、苯基或苄基;
R4基团各自独立地为氢或具有1-20个碳原子的烃基,或两个R4基团与其连接的碳原子一起形成3-8元烃环;
R01为具有1-20个碳原子的烃基;和
R02和R’02各自为氢原子或独立地具有R01的含义,或
R01和R02与其连接的碳原子一起形成3-8元烃环或杂烃环。
就本发明的目的而言,术语仲膦基包括下式的结构:
其中所述碳原子被氢或1-3个烃基取代,所述氧原子被一个烃基取代,所述氮原子被两个烃基取代,或两个烃基与其连接的原子一起形成4-8元环,且所述氮原子含有其他烃基。所述氮原子也可被烃基-磺酰基取代。通过将氧原子、N-烃基或N-烃基-磺酰基插入在P-C键之间的开链或环状烃基中以下表示的用于第一式的烃基也可应用在其他式中。
作为膦基P(C)C的X1可包含两个相同的或两个不同的烃基,或两个烃基与磷原子一起可形成3-8元环。优选膦基包含两个相同的烃基。所述烃基可为未取代或取代的并可包含1-22个碳原子,优选1-12个碳原子。在式I和Ia化合物中,特别优选其中膦基包含两个相同或不同的选自直链或支链的C1-C12-烷基;未取代或C1-C6-烷基或C1-C6-烷氧基取代的C5-C12-环烷基或C5-C12-环烷基-CH2-;苯基或苄基;以及被卤原子(例如氟、氯和溴)、C1-C6-烷基、C1-C6-卤代烷基(例如三氟甲基)、C1-C6-烷氧基、C1-C6-卤代烷氧基(例如三氟甲氧基)、(C6H5)3Si、(C1-C12-烷基)3Si、仲氨基或-CO2-C1-C6-烷基(例如-CO2CH3)取代的苯基或苄基的基团。
膦基中的两个基团也可一起形成未取代或卤原子-、C1-C6-烷基或C1-C6-烷氧基-取代的1,2-亚甲基、1,3-亚丙基、1,4-亚丁基或1,5-亚戊基。优选取代基连接在磷原子的两个邻位。
所述膦基可为下式的基团:
或
其中o和p各自独立地为2-10的整数且o+p的和为4-12,优选5-8,并且苯环为未取代或被C1-C4-烷基和/或C1-C4-烷氧基取代。实例有下式的[3.3.1]phobyl和[4.2.1]phobyl:
其中两个烃基与磷原子一起形成3-8元环的仲膦基的实例特别为下式的基团:
其可在磷原子的一个或两个邻位和如需要在间位被C1-C4-烷基或C1-C4-烷氧基取代。
磷上的烷基取代基(优选包含1-6个碳原子)的实例为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基以及戊基和己基的异构体。磷上的未取代或烷基取代的环烷基取代基的实例有环戊基、环己基、甲基环己基、乙基环己基和二甲基环己基。磷上的烷基-、烷氧基-、卤代烷基-和/或卤代烷氧基-取代的苯基和苄基取代基的实例有甲苯基、二甲苯基、三甲苯基、乙基苯基、甲苄基、甲氧基苯基、二甲氧基苯基、三氟甲基苯基、双三氟甲基苯基、三(三氟甲基)(tristrifluoromethyl)苯基、三氟甲氧基苯基和双三氟甲氧基苯基。
当X1为含氧原子的仲膦基时,磷上的取代基可为例如直链或支链的C1-C12-烷氧基;未取代或C1-C6-烷基或C1-C6-烷氧基取代的C5-C12-环烷氧基或C5-C12-环烷基甲氧基;苯氧基或苄氧基,其中所述环状基团被卤素(例如氟、氯和溴)、C1-C6-烷基、C1-C6-卤代烷基(例如三氟甲基)、C1-C6-烷氧基、C1-C6-卤代烷氧基(例如三氟甲氧基)、(C6H5)3Si、(C1-C12-烷基)3Si、仲氨基或-CO2-C1-C6-烷基(例如-CO2CH3)取代。一些实例有甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、环己氧基、苯氧基和苄氧基。
当X1为含氮原子的仲膦基时,磷上的取代基可为例如开链或环状仲氨基或二磺酰基氨基。一些实例有二甲基氨基、二乙基氨基、二正和异丙基氨基、二正丁基氨基、甲基丙基氨基、苯基甲基氨基、吡咯烷-N-基、哌啶-N-基、吗啉-N-基、二(甲基-磺酰基)氨基、二(乙基磺酰基)氨基、二(丙基磺酰基)氨基、二(丁基磺酰基)氨基、二(甲基磺酰基)氨基、二(对甲苯磺酰基)氨基、二(三氟甲基磺酰基)氨基。
成环的二价基团的实例有-(C1-C4-烷基)N-C(R’)2-[C(R”)2]1-4-N(C1-C4-烷基)-、-O-C(R’)2-[C(R”)2]1-4-N(C1-C4-烷基)-、-O-C(R’)2-[C(R”)2]1-4-O-、-CH2-CH2-CH2-O-和-CH2-CH2-CH2-N(C1-C4-烷基)-,其中R’和R”各自独立地为氢或C1-C4-烷基。α位连接有氧原子的环状膦基的其他实例有下式的基团:
和
优选膦基X1包含相同或不同(优选相同)的选自以下的基团:C1-C6-烷基;未取代的环戊基或环己基和被1-3个C1-C4-烷基或C1-C4-烷氧基取代的环戊基或环己基;未取代或被1-3个C1-C4-烷基、C1-C4-烷氧基、F、Cl、C1-C4-氟代烷基或C1-C4-氟代烷氧基取代的苄基和特别是苯基。
在式I化合物中,X1优选为基团-PR1R2,其中R1和R2各自独立地为具有1-20个碳原子的烃基,所述烃基未取代或被卤原子、C1-C6-烷基、C1-C6-卤代烷基、C1-C6-烷氧基、C1-C6-卤代烷氧基、(C6H5)3Si、(C1-C12-烷基)3Si或-CO2-C1-C6-烷基取代;或R1和R2一起形成未取代或被C1-C4-烷基或C1-C4-烷氧基-取代的1,2-亚甲基、1,3-亚丙基、1,4-亚丁基或1,5-亚戊基。
优选R1和R2为相同或不同(特别是相同)的选自以下的基团:支链的C3-C6-烷基;未取代的环戊基或环己基和被1-3个C1-C4-烷基或C1-C4-烷氧基取代的环戊基或环己基;未取代的苄基和被1-3个C1-C4-烷基或C1-C4-烷氧基取代的苄基;以及特别是未取代的苯基和被1-3个C1-C4-烷基、C1-C4-烷氧基、-NH2、OH、F、Cl、C1-C4-氟代烷基或C1-C4-氟代烷氧基取代的苯基。
特别优选R1和R2为相同或不同(特别是相同)的选自以下的基团:未取代的苯基和被1-3个C1-C4-烷基、C1-C4-烷氧基或C1-C4-氟代烷基取代的苯基。
基团R3和R4可为未取代或取代的,例如被C1-C6-烷基、C1-C6-烷氧基、环己基、C6-C10-芳基、C7-C12-芳烷基、C1-C4-烷基-C6-C10-芳基、C1-C4-烷氧基-C6-C10-芳基、C1-C4-烷基-C7-C12-芳烷基、C1-C4-烷氧基-C7-C12-芳烷基、-CO-OR5、卤素(优选F或Cl)、-CO-NR6R7或-NR6R7取代,其中R5为氢、碱金属、C1-C6-烷基、环己基、苯基或苄基,且R6和R7各自独立地为氢、C1-C6-烷基、环己基、苯基或苄基,或R6和R7一起形成1,4-亚丁基、1,5-亚戊基或3-氧杂-1,5-亚戊基(3-oxapentylene)。
烃基R3优选包含1-16个且特别优选1-12个碳原子。烃基R3可为C1-C18-烷基,优选Cl-C12-烷基并特别优选C1-C8-烷基;C3-C12-环烷基,优选C4-C8-环烷基并特别优选C5-C6-环烷基;或C6-C16-芳基并优选C6-C12-芳基。
当R3为烷基时,优选为C1-C8-烷基。烷基的实例有甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基以及二十烷基。支链烷基的实例有异丙基、异丁基、叔丁基、异戊基、异己基以及1,1,2,2-四甲基乙基。
当R3为环烷基时,例如可为环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基或环十二烷基。
芳烃基R3优选包含6-18个且特别优选6-14个碳原子。杂芳烃基R3优选包含3-14个且特别优选3-11个碳原子。烃基R3可为C6-C14-芳基且优选C6-C10-芳基,或C3-C11-芳基且优选C4-C10-杂芳基。
一些芳基的实例有苯基、萘基、蒽基、菲基以及联苯基(biphenyl)。
杂烃基R3优选包含总共2-16个原子,特别优选总共2-12个原子,且包含1-3个选自O、S和NR的杂原子。杂烃基R3可为C2-C18-杂烷基,优选C2-C12-杂烷基且特别优选C2-C8-杂烷基;C3-C12-杂环烷基,优选C4-C8-杂环烷基且特别优选C4-C5-杂环烷基;或C3-C16-杂芳基且优选C4-C11-杂芳基。
当R3为杂芳基时,优选为C2-C8-烷基。杂烷基的实例有甲氧基甲基、甲氧基乙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、异丙氧基甲基、异丙氧基乙基、异丁氧基乙基、叔丁氧基乙基、甲基硫基乙基、二甲基氨基乙基。
当R3为杂环烷基时,例如可为氧杂环丁基、四氢呋喃基、氧杂环己基、二烷基、吡咯烷基或N-甲基氮杂环己基。
当R3为杂芳基时,例如可为呋喃基、噻吩基、吡咯基、咪唑啉(imidizolinyl)、唑啉基、噻唑基、吡唑啉基、苯并呋喃基、吡啶基、嘧啶基、哒嗪基、吡嗪基、喹唑啉基、喹喔啉基、吲哚基、苯并咪唑基、喹啉基、异喹啉基或吖啶基。
R3上优选的取代基有C1-C4-烷基、C1-C4-烷氧基、环己基、C6-C10-芳基、C7-C12-芳烷基、C1-C4-烷基-C6-C10-芳基、C1-C4-烷氧基-C6-C10-芳基、C1-C4-烷基-C7-C12-芳烷基、C1-C4-烷氧基-C7-C12-芳烷基、-CO-OR5、卤素(优选F或Cl)、-CO-NR6R7或-NR6R7,其中R5为C1-C6-烷基、环己基、苯基或苄基,且R6和R7各自独立地为氢、C1-C6-烷基、环己基、苯基或苄基,或R6和R7一起形成1,4-亚丁基、1,5-亚戊基或3-氧杂-1,5-亚戊基。
在优选的亚族中,R3为选自C1-C12-烷基、C5-C6-环烷基和C6-C12-芳基的烃基,其中环状基团为未取代或被卤素(F、Cl、Br)、C1-C4-烷基、C1-C4-全氟代烷基或C1-C4-烷氧基取代。
烃基R4优选包含1-16个,特别优选1-12个且非常特别优选1-8个碳原子。烃基R4可为C1-C18-烷基,优选C1-C12-烷基且特别优选C1-C8-烷基;C3-C12-环烷基,优选C4-C8-环烷基且特别优选C5-C6-环烷基;C6-C16-芳基且优选C6-C12-芳基;或C7-C16-芳烷基且优选C7-C12-芳烷基。
当两个R4基团一起形成烃基时,所述烃基为优选包含3-7个且特别优选4-6个碳原子的亚烷基。实例有1,3-亚丙基;1,3-或1,4-亚丁基;1,3-、1,4-或1,5-亚戊基;以及1,3-、1,4-、1,5-、2,5-、2,6-或1,6-亚己基。
当R4为烷基时,优选为直链或支链的C1-C8-烷基。烷基的实例有甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基以及二十烷基。支链烷基的实例有异丙基、异丁基、叔丁基、异戊基、异己基以及1,1,2,2-四甲基乙基。
当R4为环烷基时,例如可为环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基或环十二烷基。
当R4为芳基时,例如可为苯基、萘基、蒽基、菲基或联苯基。
当R4为芳烷基时,可为苄基或萘基甲基。
R4上优选的取代基有卤素(F、Cl、Br)、C1-C4-烷基或C1-C4-烷氧基。
在优选的亚族中,R4为选自C1-C6-烷基、C5-C6-环烷基和苄基的烃基,其中所述环状基团为未取代或被卤素(F、Cl、Br)、C1-C4-烷基、C1-C4-卤代烷基(例如三氟甲基)或C1-C4-烷氧基取代。
烃基R01优选包含1-16个,特别优选1-12个且非常特别优选1-8个碳原子。烃基R01可为C1-C18-烷基,优选C1-C12-烷基且特别优选C1-C8-烷基;C3-C12-环烷基,优选C4-C8-环烷基且特别优选C5-C6-环烷基;C6-C16-芳基且优选C6-C12-芳基;或C7-C16-芳烷基且优选C7-C12-芳烷基。R01、R02和R’02各自独立地采用R4的实施方案和优选。在特别优选的实施方案中,R01为具有至少3个碳原子的α-支化的烷基,例如α-支链的C3-C12-烷基且更优选C3-C8-烷基。α-支化的烷基的实例有异丙基;丁-2-基;叔丁基;戊-2-或-3-基;己-2-或-3-基;庚-2-、-3-或-4-基以及异辛基(1,1,3,3,3-五甲基-丙-1-基)。
当R01和R02与其连接的碳原子一起形成3-8元烃环或杂烃环时,该环为优选具有3-8个且特别优选5或6个环原子的脂族、烯属不饱和或芳族稠环体系。稠合脂族烃环的实例有环丙烷-1,2-二基、环丁烷-1,2-二基、环戊烷-1,2-二基、环己烷-1,2-二基、环庚烷-1,2-二基以及环辛烷-1,2-二基。稠合杂脂族烃环的实例有氧杂环丁烷-1,2-二基、四氢呋喃-1,2-二基、氧杂环己烷-1,2-二基、二烷-1,2-二基、吡咯烷-1,2-二基以及N-甲基氮杂环己烷-1,2-二基。稠合芳烃环的实例有1,2-亚苯基和1,2-亚萘基。稠合杂芳烃环的实例有呋喃-1,2-二基、噻吩-1,2-二基、吡咯-1,2-二基、咪唑啉-1,2-二基、唑啉-1,2-二基、噻唑-1,2-二基、吡唑啉-1,2-二基、苯并呋喃-1,2-二基、吡啶-1,2-二基、嘧啶-1,2-二基、哒嗪-1,2-二基、吡嗪-1,2-二基、喹唑啉-1,2-二基、喹喔啉-1,2-二基、吲哚-1,2-二基、苯并咪唑-1,2-二基、喹啉-1,2-二基、异喹啉-1,2-二基以及吖啶-1,2-二基。
当R02和R’02为不同的基团或R01和R02一起成环时,式I和Ia化合物包含其他手性碳原子。本发明包括这些化合物的外消旋物或非对映异构体。在本发明的催化加成反应中非对映异构体的相对构型可对对映异构体选择性有积极的影响。优选R02和R’02为氢。在其他优选的基团中,R02和R’02各自为氢且R01为α-支链的C3-C8-烷基。
优选的本发明化合物的亚族由式Ib和Ic化合物构成,
其中
X1为-PR1R2,
R1和R2为相同或不同的且特别为相同的选自以下的基团:α-支链的C3-C6-烷基;未取代的C5-C7-环烷基和被1-3个C1-C4-烷基或C1-C4-烷氧基取代的C5-C7-环烷基;未取代的苯基和被1-3个C1-C4-烷基、C1-C4-烷氧基或C1-C4-氟代烷基取代的苯基;以及未取代或被C1-C4-烷基或C1-C4-烷氧基取代的1,2-亚甲基、1,3-亚丙基、1,4-亚丁基和1,6-亚己基;
R3为苄基或C6-C12-芳基,且所述芳基和苄基为未取代或被卤素、C1-C4-烷基、C1-C4-卤代烷基或C1-C4-烷氧基取代;
R4为C1-C6-烷基或苄基,和
R01为α-支链的C3-C8-烷基。
式I和Ia化合物可采用已知的方法在金属有机化合物(例如烷基锂)的存在下通过咪唑啉甲醇与卤代仲膦反应制备。M.Casey等在Synlett 2003,No.1,102-106页中描述了咪唑啉甲醇的制备。
可以采用新方法(卤代亚胺酯作为重要中间体)多步制备式I和Ia化合物。新方法可得到取代基的不同组合。
本发明还提供了一种制备式I和Ia化合物的方法,
S型,其特征在于;
a)在叔胺存在下将式II化合物
其中R8为C1-C8-烷基,Hal为Cl、Br或I,
与至少等当量的式III化合物反应,
其中R01和R02如上定义,形成式IV化合物,
b)将式IV化合物与至少等当量的卤化剂反应,形成式V化合物,
c)在叔胺的存在下用式R3-NH2(X)的伯胺将式V化合物环化,形成式VI化合物,
d)将式VI化合物与至少两倍当量的式VII或至少一倍当量的式VIIa的金属有机化合物反应,形成式VIII化合物,
R4-X2 (VII), R4-(X2)2 (VIIa),
其中R4如上定义,X2为碱金属或-Me1X3,Me1为Mg或Zn,且X3为Cl、Br或I,
和
e)将式VIII化合物的羟基金属化并随后与式IX的卤代膦反应,得到式Ia或Ib化合物,
X1-Y1 (IX),
其中X1如上定义,Y1为Cl、Br或I。
Hal优选Cl或Br且特别优选Cl。R8优选为C1-C4-烷基且特别优选异丙基。
本发明还提供了式V化合物,其中R01、R02、R’02、R8以及Hal如上定义,包括优选。
方法步骤a
草酸单酯为已知而且有些可市售购得,或者可通过酯化草酸单酰卤的简单方法制备。该反应最好在-20至20℃下进行。该反应最好无溶剂。
式III的化合物同样为已知并可市售购得或可通过已知的方法或类似这些已知方法的方法制备。
该反应最好在低温(例如-20至20℃)下、惰性溶剂中进行,所述惰性溶剂如链烷醇(甲醇、乙醇、乙二醇、乙二醇单甲醚)、醚(乙醚、丁醚、四氢呋喃和二烷)或卤代烃(二氯甲烷、氯仿、四氯乙烷和氯苯)。
叔胺用于结合形成的卤化氢并且最好加入至少等摩尔量。合适的叔胺的实例有三烷基胺(三甲基胺、三乙基胺、三丙基胺、三丁基胺、甲基二乙基胺或二甲基乙基胺)和氮原子被C1-C4-烷基取代的环或多环胺(N-甲基哌啶和N-甲基吗啉)。
高收率地得到的式IV化合物。可采用已知的方法将其分离和纯化。
方法步骤b)
式IV化合物通过卤化形成式V的卤代亚胺的重排最好在较高的温度(例如50-150℃)下进行。如果卤化剂为液体,不必使用溶剂。并且在固体卤化剂的情况下,该反应可在惰性溶剂如卤代烃(二氯甲烷、氯仿、四氯乙烷和氯苯)存在下进行。为加快该反应,可使用卤化催化剂,例如叔胺、N,N-二烷基酰胺或N-烷基内酰胺(三甲基胺、三乙基胺、三丁基胺、二氮杂二环十一烷、二甲基甲酰胺、二甲基乙酰胺、N-甲基吡咯烷酮)。其量例如占式IV化合物的O.1-5%摩尔。同时也可将卤化催化剂用作溶剂。例如合适的卤化剂有SOCl2、SOBr2、PCl3、PCl5以及OPCl3。最好使用过量的卤化剂。得到高收率的式V的卤代亚胺。
方法步骤c)
最好在较高的温度(例如70-150℃)和惰性溶剂存在下进行卤代亚胺的环化,形成式IV化合物。合适的溶剂例如有芳烃(苯、甲苯、二甲苯)或卤代烃(二氯甲烷、氯仿、四氯乙烷和氯苯)。叔胺用于结合形成的卤化氢并且最好加入至少等量。合适的叔胺的实例有三烷基胺(三甲基胺、三乙基胺、三丙基胺、三丁基胺、甲基二乙基胺或二甲基乙基胺)和氮原子被C1-C4-烷基取代的环或多环胺(N-甲基哌啶和N-甲基吗啉)。加入等摩尔或稍过量的式X的胺。
方法步骤d)
羧酸酯与金属-烃化合物或金属卤代烃化合物的反应为已知。当X2为碱金属时,可为Na、K且特别是Li。在基团Me1X3中,Me1例如可为Mg或Zn。该反应最好在低温(例如-30至-80℃)下进行,通过往式VI的化合物的溶液中加入式VII或VIIa的化合物,随后让该混合物升温(例如至室温)。然后在该温度或较高温度(高达使用溶剂的沸点)下可完成该反应。合适的溶剂特别为醚如乙醚、丁醚、四氢呋喃和二烷。
方法步骤e)
通过碱金属烷基化物且特别是烷基锂(例如甲基锂、乙基锂、丙基锂或丁基锂)或Grignard试剂(如甲基卤化镁、乙基卤化镁、丙基卤化镁、丁基卤化镁或苄基卤化镁)可有效将式VIII化合物金属化形成金属醇盐。最好使用等量的或稍过量的碱金属烷基化物或Grignard试剂。该加成反应最好在较低温度(例如-20至-80℃)下进行。最好存在叔胺(如三甲基胺、三乙基胺、三丁基胺或四甲基乙二胺)。随后该反应可在室温下完成,加入式IX的卤代膦并且在该温度下可完成反应。该反应优选在惰性溶剂,例如醚或烃(戊烷、己烷、环己烷、甲基环己烷、苯、甲苯或二甲苯)存在下进行。
得到高总收率的式Ia和Ib化合物。选择原料化合物使得本发明的化合物以模块方式构建,就R3和R4而言,简单的起始化合物可得到各种取代基。
式I和Ia的新型化合物为选自TM8金属(特别是选自Ru、Rh和Ir)的金属络合物的配体,其为不对称合成(例如前手性不饱和有机化合物的不对称氢化)的优异的催化剂或催化剂前体。如果使用前手性不饱和有机化合物,在有机化合物合成中可诱导产生过量很多的光学异构体并且在短反应时间内可得到高的化学转化率。就所选反应物而言与已知的配体比较,对映异构体选择性非常高。
本发明还提供了选自TM8金属与作为配体的式I和Ia化合物的络合物。
可能的金属例如有Cu、Ag、Au、Ni、Co、Rh、Pd、Ir、Ru和Pt。优选的金属为铑、铱、钌、铂和钯。
特别优选的金属为钌、铑和铱。
取决于金属原子的氧化数和配位数,金属络合物可包含其他配体和/或阴离子。其也可为阳离子金属络合物。在文献中广泛描述了这些类似金属络合物及其制备方法。
例如所述金属络合物可具有通式XI和XII,
A1MeLn (XI), (A1MeLn)(z+)(E-)z (XII),
其中
A1为式I或Ia化合物,
L表示相同或不同的单齿、阴离子或非离子配体,或两个L一起表示相同或不同的二齿、阴离子或非离子配体;
当L为单齿配体时,n为2、3或4,或当L为二齿配体时,n为1或2;
z为1、2或3;
Me为选自铑和铱的金属,所述金属的氧化态为0、1、2、3或4;
E-为含氧酸或络酸的阴离子;并且
所述阴离子配体平衡所述氧化态为1、2、3或4的金属的电荷。
以上描述的优选和实施方案应用于式XI和XII化合物。
单齿非离子配体例如可选自烯烃(例如乙烯、丙烯)、烯丙基类(烯丙基、2-甲代烯丙基)、溶剂化溶剂(腈、线形或环状醚、未烷基化或N-烷基化酰胺和内酰胺、胺、膦、醇、羧酸酯、磺酸酯)、一氧化二氮以及一氧化碳。
单齿阴离子配体例如可选自卤素(F、Cl、Br、I)、拟卤化物(氰化物、氰酸盐、异氰酸盐)和羧酸、磺酸以及膦酸的阴离子(碳酸盐、甲酸盐、乙酸盐、丙酸盐、甲基磺酸盐、三氟甲基磺酸盐、苯基磺酸盐、甲苯磺酸盐)。
二齿非离子配体例如可选自线形或环状二烯烃(例如己二烯、环辛二烯、降冰片二烯)、二腈(丙二腈)、未烷基化或N-烷基化羧酸的二酰胺、二胺、二膦、二醇、乙酰丙酮化物、二羧酸二酯以及二磺酸二酯。
二齿阴离子的配体例如可选自二羧酸、二磺酸和二膦酸的阴离子(例如乙二酸、丙二酸、丁二酸、马来酸、亚甲基二磺酸以及亚甲基二膦酸)。
优选的金属络合物还包括其中E为-Cl-、-Br-、-I-、ClO4 -、CF3SO3 -、CH3SO3 -、HSO4 -、BF4 -、B(苯基)4 -、B(C6F5)4 -、B(3,5-二(三氟甲基)苯基)4 -(BARF)、四(C1-C5-全氟代烷基)铝酸根(如(CF5CF2O)4Al-)、PF6 -、SbCl6 -、AsF6 -或SbF6 -的络合物。
特别优选特别适合氢化的金属络合物具有式XIII和XIV,
[A1Me1YZ] (XIII), [A1Me1Y]+E1 - (XIV),
其中
A1为式I或Ia化合物;
Me1为铑或铱;
Y表示两种烯烃或二烯;
Z为Cl、Br或I;和
E1 -为含氧酸或络酸的阴离子。
以上描述的实施方案和优选应用于式I和Ia化合物。
当Y为烯烃时,可为C2-C12-,优选C2-C6-且特别优选C2-C4-烯烃。实例有丙烯、1-丁烯且特别是乙烯。所述二烯可包含5-12个且优选5-8个碳原子并可为开链、环状或多环二烯。所述二烯的两个烯基优选通过一个或两个CH2基团连接。实例有1,3-戊二烯、环戊二烯、1,5-己二烯、1,4-环己二烯、1,4-或1,5-庚二烯、1,4-或1,5-环庚二烯、1,4-或1,5-辛二烯、1,4-或1,5-环辛二烯和降冰片二烯。Y优选表示两个乙烯或1,5-己二烯、1,5-环辛二烯或降冰片二烯。
在式XIII中Z优选为Cl或Br。E1的实例有ClO4 -、CF3SO3 -、CH3SO3 -、HSO4 -、BF4 -、B(苯基)4 -、BARF、PF6 -、SbCl6 -、AsF6 -或SbF6 -。
本发明的钌络合物例如可具有式XV
[RuaHbZc(A1)dLe]f(Ek)g(S)h (XV),
其中Z为Cl、Br或I;A1为式I或Ia化合物;L表示相同或不同的配体;E-为含氧酸、无机酸或络酸的阴离子;S为能作为配体配位的溶剂;且a为1-3,b为0-4,c为0-6,d为1-3,e为0-4,f为1-3,g为1-4,h为0-6和k为1-4,所述络合物的总电荷为0。
以上描述的Z、A1、L以及E-的优选应用于式XV化合物。配体L还可为芳烃或杂芳烃(例如苯、萘、甲苯、二甲苯、枯烯、1,3,5-、吡啶、联苯、吡咯、苯并咪唑或环戊二烯基)和作为Lewis酸的金属盐(例如ZnCl2、AlCl3、TiCl4和SnCl4)。溶剂配体例如可为醇、胺、酰胺、内酰胺以及砜。
在以下文献及其引用的文献中描述了该类型的络合物:
D.J.Ager,S.A.Laneman,Tetrahedron:Asymmetry,8,1997,3327-3355;
T.Ohkuma,R.Noyori,Comprehensive Asymmetric Catalysis(E.N.Jacobsen,A.Pfaltz,H.Yamamoto,Eds.),Springer,Berlin,1999,199-246;
J.M.Brown,Comprehensive Asymmetric Catalysis(E.N.Jacobsen,A.Pfaltz,H.Yama-moto,Eds.),Springer,Berlin,1999,122-182;
T.Ohkuma,M.Kitamura,R.Noyori,Catalytic AsymmetricSynthesis,第2版(I.Ojima,Ed.),Wiley-VCH New York,2000,1-110;
N.Zanetti等,Organometallics 15,1996,860。
本发明的金属络合物由文献(参见US-A-5,371,256、US-A-5,446,844、US-A-5,583,241以及E.Jacobsen,A.Pfaltz,H.Yamamoto(编辑),Comprehensive Asymmetric Catalysis I-III,Springer Verlag,Berlin,1999以及文中引用的文献)已知方法制备。
本发明的金属络合物作为均相催化剂或催化剂前体,其可在反应条件下活化并可用于前手性不饱和有机化合物的不对称加成反应。
例如所述金属络合物在氢供体(如甲醇、乙醇、异丙醇或甲酸)存在下,可用于具有碳-碳或碳-杂原子双键的前手性化合物的不对称氢化(氢加成)或转移氢化。例如在Pure and Appl.Chem.,第68卷,第1期,131-138页(1996)中描述了这种使用可溶的均相金属络合物的氢化。优选的待氢化的不饱和化合物包含基团C=C、C=N和/或C=O。根据本发明,所述氢化优选使用钌、铑和铱的金属络合物进行。
本发明的金属络合物也可用作具有碳-碳双键的前手性有机化合物不对称硼氢化(硼烷加成)的催化剂。例如Tamio Hayashi在E.Jacobsen、A.Pfaltz、H.Yamamoto编辑的Comprehensive AsymmetricCatalysis I-III,Springer Verlag,Berlin,1999,351-364页描述了这种硼氢化。合适的硼烷例如有儿茶酚硼烷(catecholborane)。所述手性硼化合物可用于合成和/或可采用已知的方法转化为制备手性中间体或活性物质有用的结构单元的其他手性有机化合物。该反应的实例有3-羟基四氢呋喃的制备(如DE 19,807,330中描述)。
本发明的金属络合物也可用作具有碳-碳或碳-杂原子双键的前手性有机化合物不对称硅氢化(硅烷加成)的催化剂。例如G.Pioda和A.Togni在Tetrahedron:AsymMetry,1998,9,3093或S.Uemura等在Chem.Commun.1996,847中描述了这种硅氢化。合适的硅烷例如有三氯硅烷或二苯基硅烷。例如C=O和C=N基团的硅氢化优选使用铑和铱的金属络合物进行。例如C=C基团的硅氢化优选使用钯的金属络合物进行。手性的甲硅烷基化合物可用于合成和/或可采用已知的方法转化为制备手性中间体或活性物质有用的结构单元的其他手性有机化合物。该反应的实例有形成醇的水解反应。
本发明的金属络合物也可用作不对称烯丙类化合物的取代反应(将C-亲核试剂加成至烯丙基化合物上)的催化剂。例如A.Pfaltz和M.Lautens在E.Jacobsen、A.Pfaltz、H.Yamamoto编辑的Comprehensive Asymmetric Catalysis I-III,Springer Verlag,Berlin,1999,833-884页中描述了这种烯丙基化。烯丙基化合物的合适前体例如有1,3-二苯基-3-乙酰氧基-1-丙烯或3-乙酰氧基-1-环己烯。优选该反应使用钯的金属络合物进行。所述手性烯丙基化合物可用于制备手性中间体或活性物质的合成。
本发明的金属络合物也可用作不对称的氨基化(将胺加成至烯丙基化合物上)或醚化(将醇或酚加成至烯丙基化合物上)的催化剂。例如A.Pfaltz和M.Lautens在E.Jacobsen,A.Pfaltz,H.Yamamoto编辑的Comprehensive Asymmetric Catalysis I-III,Springer Verlag,Berlin,1999,833-884页中描述了这种氨基化和醚化。合适的胺包括氨、伯胺和仲胺。合适的醇为酚和脂族醇。烯丙基化合物的氨基化或醚化优选使用钯的金属络合物进行。手性胺和醚可用于制备手性中间体或活性物质的合成。
本发明的金属络合物也可用作不对称异构化的催化剂(参见M.Beller等在用于有机合成的过渡金属(Transition Metals for OrganicSynthesis),第1卷,Wiley-VCH,Weinheim 1998,147-156页)。
本发明还提供了本发明的金属络合物作为通过将氢、硼烷或硅烷不对称加成至前手性有机化合物中碳-碳或碳-杂原子多重键上,或将C-亲核试剂或胺不对称加成至烯丙基化合物上制备手性有机化合物的均相催化剂的用途。
本发明的另一方面为一种制备手性有机化合物的方法,在催化剂存在下通过将氢、硼烷或硅烷不对称加成至前手性有机化合物中碳-碳或碳-杂原子多重键上,或将C-亲核试剂、醇或胺不对称加成至烯丙基化合物上,其特征在于所述加成反应在催化量的至少一种本发明的金属络合物存在下进行。
在开链或环状有机化合物中优选的待氢化的前手性不饱和化合物可包含一个或多个相同或不同的基团C=C、C=N和/或C=O,同时基团C=C、C=N和/或C=O可为环系或环外基团的一部分。前手性不饱和化合物可为链烯、环烯、杂环烯、稠合的杂芳族或开链或环状酮、酮亚胺以及腙酮。例如其可为式XVI,
R15R16C=D (XVI),
其中选择R15和R16使得该化合物为前手性并各自独立地为包含选自O、S和N的杂原子的各自包含1-30个且优选1-20个碳原子的开链或环状烃基或杂烃基;
D为O或式CR17R18或NR19的基团;
R17和R18各自独立地具有R15和R16相同的含义,
R19为氢、C1-C12-烷基、C1-C12-烷氧基、C3-C12-环烷基、C3-C12-环烷基-C1-C6-烷基、C3-C11-杂环烷基、C3-C11-杂环烷基-C1-C6-烷基、C6-C14-芳基、C5-C13-杂芳基、C7-C16-芳烷基或C6-C14-杂芳烷基,
R15和R16与其连接的碳原子一起形成具有3-12个环原子的烃环或杂烃环;
R15和R17与其连接的C=C基团一起形成具有3-12个环原子的烃环或杂烃环;
R15和R19与其连接的C=N基团一起形成具有3-12个环原子的烃环或杂烃环;
杂环中的杂原子选自O、S和N;
且R15、R16、R17、R18和R19为未取代或被C1-C6-烷基、C1-C6-烷氧基、环己基、C6-C10-芳基、C7-C12-芳烷基、C1-C4-烷基-C6-C10-芳基、C1-C4-烷氧基-C6-C10-芳基、C1-C4-烷基-C7-C12-芳烷基、C1-C4烷氧基-C7-C12-芳烷基、-OH、=O、-NR21R22、-CO-OR20或-CO-NR21R22取代,其中R20为H、碱金属、C1-C6-烷基、环己基、苯基或苄基,且R21和R22各自独立地为氢、C1-C6-烷基、环己基、苯基或苄基,或R21和R22一起形成1,4-亚丁基、1,5-亚戊基或3-氧杂-1,5-亚戊基(oxtapentylene)。
上述已提及取代基的实例和优选。
例如R15和R16各自可为C1-C20-烷基且优选C1-C12-烷基;包含选自O、S和N的杂原子的C1-C20-杂烷基且优选C1-C12-杂烷基;C3-C12-环烷基且优选C4-C8-环烷基;包含选自O、S和N杂原子的碳连接的C3-C11-杂环烷基且优选C4-C8-杂环烷基;C3-C12-环烷基-C1-C6-烷基且优选C4-C8-环烷基-C1-C6-烷基;包含选自O、S和N杂原子的C3-C11-杂环烷基-C1-C6-烷基且优选C4-C8-杂环烷基-C1-C6-烷基;C6-C14-芳基且优选C6-C10-芳基;包含选自O、S和N杂原子的C5-C13-杂芳基且优选C5-C9-杂芳基;C7-C15-芳烷基且优选C7-C11-芳烷基;包含选自O、S和N杂原子的C6-C12-杂芳烷基且优选C6-C10-杂芳烷基。
当R15和R16、R15和R17、或R15和R19在各种情况下与其连接的基团一起形成烃环或杂烃环时,该环优选包含4-8个环原子。例如所述杂烃环可包含1-3个且优选一个或两个杂原子。
R19优选为氢、C1-C6-烷基、C1-C6-烷氧基、C4-C8-环烷基、C4-C8-环烷基-C1-C4-烷基、C4-C10-杂环烷基、C4-C10-杂环烷基-C1-C4-烷基、C6-C10-芳基、C5-C9-杂芳基、C7-C12-芳烷基以及C5-C13-杂芳烷基。
不饱和有机化合物的一些实例有苯乙酮、4-甲氧基苯乙酮、4-三氟甲基苯乙酮、4-硝基苯乙酮、2-氯-苯乙酮、未取代或取代的苯并环己酮或苯并环戊酮的亚胺,来自未取代或取代的四氢喹啉、四氢吡啶以及二氢吡咯的亚胺,前手性烯烃(如甲基均二苯乙烯、甲氧基苯基丁烯、不饱和羧酸酯和酰胺及其盐,例如α-和如果合适的β-位取代的丙烯酸、丁烯酸或肉桂酸)的顺反异构体以及烯属不饱和醇或醚。优选的羧酸酯为下式的羧酸酯和所述酸的盐和酰胺:
R23-CH=C(R24)-C(O)OR25
其中R23为C1-C6-烷基;未取代的C3-C8-环烷基或被1-4个C1-C6-烷基、C1-C6-烷氧基、C1-C6-烷氧基-C1-C4-烷氧基取代的C3-C8-环烷基;或未取代的C6-C10-芳基(优选苯基)或被1-4个C1-C6-烷基、C1-C6-烷氧基、C1-C6-烷氧基-C1-C4-烷氧基取代的C6-C10-芳基(优选苯基)。R24为直链或支链的C1-C6-烷基(例如异丙基)、环戊基、环己基或苯基,其各自可未取代或如上定义取代的基团,或被保护的氨基(例如乙酰氨基),且R25为C1-C4-烷基。适合氢化的反应物例如还有前手性烯丙基醇类和β-enamide类。
使用钌络合物氢化的适合反应物例如有前手性α-和β-酮羧酸盐、酯和酰胺;前手性1,3-二酮;前手性酮;α-和β-烷氧基酮;α-和β-羟基酮;α-和β-卤代酮以及α-和β-氨基酮。
本发明的方法可在低温或升温下(例如-40至150℃,优选-20至100℃且特别优选0至80℃)进行。温度的选择可影响最佳收率,在较高的温度下获得较高的最佳收率。
本发明的方法可在常压或加压下进行。例如压力可为105至2×107Pa(帕斯卡)。优选在常压或加压下进行氢化。
优选使用的催化剂量为0.00001-10%摩尔,特别优选0.0001-5%摩尔且特别是0.01-5%摩尔,基于待氢化的化合物计算。
所述配体和催化剂的制备以及该加成反应可无溶剂或惰性溶剂(为一种可用的溶剂或溶剂混合物)的存在下进行。例如合适的溶剂有脂族的、环脂族的和芳族的烃(戊烷、己烷、石油醚、环己烷、甲基环己烷、苯、甲苯、二甲苯)、脂族的卤代烃(二氯甲烷、氯仿、二氯乙烷以及四氯乙烷)、腈(乙腈、丙腈、苄腈)、醚(乙醚、丁醚、叔丁基甲基醚、乙二醇二甲醚、乙二醇二乙醚、二乙二醇二甲醚、四氢呋喃、二烷、二乙二醇单甲或单乙醚)、酮(丙酮、甲基异丁基酮)、羧酸酯和内酯(乙酸乙酯或乙酸甲酯、戊内酯)、N-取代的内酰胺(N-甲基吡咯烷酮)、羧酰胺(二甲基乙酰胺、二甲基甲酰胺)、无环脲(二甲基咪唑啉)、亚砜和砜(二甲基亚砜、二甲基砜、环丁亚砜、环丁砜)、醇(甲醇、乙醇、丙醇、丁醇、乙二醇单甲醚、乙二醇单乙醚、二乙二醇单甲醚)以及水。可使用一种溶剂或至少两种溶剂的混合物。
可在助催化剂(例如季铵卤化物(碘化四丁基铵))和/或质子络酸(例如HBArF(参见例如US-A-5,371,256、US-A-5,446,844、US-A-5,583,241以及EP-A-0 691 949))的存在下进行所述反应。所述助催化剂特别用于氢化。
用作催化剂的金属络合物可以单独制备和分离的化合物形式加入,或可在反应之前原位形成,随后与待氢化的反应物混合。最好使用分离的金属络合物时在反应中补充加入配体或在原位制备中使用过量的配体。过量例如可为1-10且优选1-5mol,基于用于制备的金属化合物计算。
本发明使用的催化剂可在反应之前原位制备。为此,本发明的金属化合物和配体可以分别装在不同的容器中的套装形式(在适当的情况下以溶液形式)作为商品销售,这点为本发明的另一个主题。
本发明的方法通常将催化剂置于反应容器中,随后加入反应物,如果需要加入反应辅助剂,随后加入待加入的化合物,随后开始反应。待加入的气体化合物(例如氢或氨)优选在压力下通入。在不同类型的反应器中所述方法可连续或间歇进行。
可根据本发明制备的手性有机化合物为用于制备特别是用于药物、香料和农用化学品生产领域的活性物质或中间体。
以下实施例阐述了本发明。
A)前体和中间体的制备
实施例A1:制备
a)将草酰氯(40ml,0.47mol)置于三颈烧瓶中并经冰浴冷却至0℃。由滴液漏斗缓慢加入异丙醇(18ml,0.24mol)。在升至室温后,在132℃下常压分馏,馏出产物(26.0g,36%,无色油形式的)。
1H-NMR(400.1MHz,CDCl3,300K):δ=1.39(d,J=6.4Hz,6H,CH(CH3)2),5.18(sep,J=6.4Hz,1H,CH(CH3)2)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=21.7(2×CH3),74.4(CH),155.6(Cl-C=O),161.7(O-C=O)ppm.
b)将(S)-缬氨醇(Valinol)(3.00g,29mmol)溶解在50ml的异丙醇中,并与三乙胺(4.10ml,29mmol)混合。在冰中冷却的同时缓慢加入草酸单异丙酯酰氯(3.73ml,29mmol)。搅拌4小时后,将该溶液减压蒸发,随后溶解于110ml的乙酸乙酯/水(12∶1)中。使用15ml乙酸乙酯萃取水相一次,随后用每次5ml的2N HCl水溶液洗涤该合并的有机萃取液三次。随后用MgSO4干燥该溶液并用旋转蒸发器蒸发。得到无色固体5.92g(27.26mmol,94%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.93(d,J=6.8Hz,3H,CH(CH3)2),0.96(d,J=6.8Hz,3H,CH(CH3)2),1.36(d,J=6.4Hz,6H,OCH(CH3)2),1.94(sep,J=6.8Hz,1H,CH(CH3)2),2.31(br s,1H,OH),3.72(m,3H,CH2和CH),5.12(sep,J=6.4Hz,1H,OCH(CH3)2),7.28(br s,1H,NH)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=18.8(CH(CH3)2),19.5(CH(CH3)2),21.6(OCH(CH3)2),28.9(CH(CH3)2),57.8(CH(CH2),63.1(CH2),71.7(OCH),157.5(N-C=O),160.4(O-C=O)ppm.
实施例A2:制备(A2)
用4.00g(34mmol)的(S)-叔-亮氨醇(leucinol)重复实施例A1b的方法,得到5.37g(23.12mmol,68%)酰胺A2。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.96(s,9H,C(CH3)3),1.35(d,J=7Hz,6H,CH(CH3)2,2.24(br s,1H,OH),3.61(t,J=7.6Hz,1H,CHC(CH3)3),3.85(m,2H,CH2),5.12(m,1H,OCH),7.27(br s,1H,NH)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=21.6(CH(CH3)2),26.9(C(CH3)3),33.8(C(CH3)3),60.5(CH2),62.4(NCH),71.8(CH(CH3)2),157.8(N-C=O),160.5(O-C=O)ppm.
实施例A3:制备(A3)
i-Pr=异丙基
将酰胺A1(0.50g,2.2mmol)溶解于SOCl2(3.0ml)中,加入二甲基甲酰胺(DMF)(4μl,2.5%摩尔)并在85℃下将该混合物回流16小时。在高真空下除去SOCl2,以定量的产率得到无色油状的氯代亚胺A3。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.91(d,J=6.8Hz,3H,CH(CH3)2),0.95(d,J=6.8Hz,3H,CH(CH3)2),2.05(sep,J=6.8Hz,1H,CH(CH3)2),3.67(m,2H,CH2),3.93(m,1H,CH(CH2)),5.16(sep,J=6.0,1H,OCH(CH3)2)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=18.3(CH(CH3)2),19.3(CH(CH3)2),21.6(OCH(CH3)2),31.4(CH(CH3)2),45.3(CH2),71.0(CH(CH2)),72.0(OCH(CH3)2),136.5(COCCl),158.6(CO)ppm.
实施例A4:制备(A4)
将酰胺A2(5.00g,21.6mmol)溶解于SOCl2(12.0ml)中,加入二甲基甲酰胺(DMF)(40μl,2.5%摩尔)并在85℃下将该混合物回流16小时。在高真空下除去SOCl2后,经球形冷凝管蒸馏(bulb tube distillation)纯化粗产物(炉温:100℃/0.15mbar)。得到无色油形式的产物(5.21g/19.4mmol/90%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.96(s,9H,C(CH3)3),1.35(d,J=12Hz,6H,CH(CH3)2),3.67(t,J=10.6Hz,1H,CH2),3.87(m,2H,CH2和CH),5.16(sep,J=8.4Hz,1H,OCH(CH3)2)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=21.6(CH(CH3)2),26.6(C(CH3)3),35.6(C(CH3)3),44.8(CH2),71.8(CH(CH2)),74.6(OCH(CH3)2),136.6(COCCl),158.7(O-C=O)ppm.
实施例A5(对照):制备(A5)
Cy=环己基
将氯代亚胺A3(560mg,2.2mmol)溶解于无水甲苯(5ml)中并与三乙胺(2ml)混合。在往该混合物中滴加环己胺(290μl,2.5mmol)在3ml甲苯中的溶液后,在110℃下将该混合物加热12小时。将该溶液冷却至室温进行后处理。每次用3ml的1N KOH水溶液洗涤该混合物两次,振摇并每次用10ml甲苯萃取水相两次。经MgSO4干燥和过滤后,将溶液移至旋转蒸发器。得到黄色油形式的,经柱色谱纯化,洗脱剂为戊烷/乙醚/三乙基胺(8∶1∶1)。得到360mg纯的咪唑啉A5(1.28mmol,56%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.84(d,J=6.8Hz,3H,CH(CH3)2),0.95(d,J=7.2Hz,3H,CH(CH3)2),1.27-1.25(m,5H,Cy),1.32(d,J=6.0Hz,6H,O-CH(CH3)2)1.55-1.90(m,6H;5H Cy,1H CH(CH3)2)),3.08(t,J=9.6Hz,1H,CH2),3.36(t,J=9.6Hz,1H,CH2),3.57(t,J=9.6Hz,1H,CH,Im),3.81(q,J=4.8Hz,1H,CH,Cy),5.18(sep,J=6.0Hz,1H,OCH(CH3)2)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=17.9(CH(CH3)2),19.2(CH(CH3)2),21.7(OCH(CH3)2),25.5(CH2,Cy),25.6(CH2,Cy),25.8(CH2,Cy),30.8(CH2,Cy),31.6(CH2,Cy),33.0(CH(CH3)2),46.7(CH2,Im),54.8(CH,Cy),69.9(CH,Im),70.5(OCH(CH3)2),156.6(C=N),161.5(C=O)ppm.
实施例A6:制备(A6)
Ph=苯基
用氯代亚胺A3(406mg,1.6mmol)和苯胺(290μl,3.2mmol)重复实施例A5的方法,经柱色谱纯化,洗脱剂为戊烷/乙醚/三乙胺(8∶1∶1),得到黄色油形式的咪唑啉A6(275mg,1.00mmol,63%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.93(d,J=6.8Hz,3H,CH(CH3)2),1.03(d,J=6.8Hz,3H,CH(CH3)2),1.15(d,J=6.4Hz,3H,OCH(CH3)2),1.18(d,J=6.4Hz,3H,OCH(CH3)2),1.91(sep,J=6.4Hz,1H,CH(CH3)2),3.59(t,J=9.2Hz,1H,CH2),3.92(t,J=9.2Hz,1H,CH2),4.10(m,1H,CH,Im),5.10(sep,J=6.4Hz,1H,OCH(CH3)2),6.95(d,J=8.0Hz,2H,Ar-H),7.09(t,J=7.6Hz,1H,Ar-H),7.28t,J=7.6Hz,2H,Ar-H)ppm,
13C-NMR(100.6MHz,CDCl3;300K):δ=18.1(CH(CH3)2),19.1(CH(CH3)2),21.4(OCH(CH3)2),32.9(CH(CH3)2),54.9(CH2),70.4(CH),71.6(OCH(CH3)2),121.1(CH,Ar),124.5(CH,Ar-C),129.2(CH,Ar-C),141.5(C-N,Ar-C),154.3(N-C=N),161.0(C=O)ppm.
实施例A7(对照):制备(A7)
用氯代亚胺A4(400mg,1.49mmol)和环己胺(256μl,2.24mmol)重复实施例A5的方法,经柱色谱纯化,洗脱剂为戊烷/乙醚(Et2O)/三乙胺(7∶2∶1),得到无色油形式的咪唑啉A7(294mg,1.00mmol,67%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.87(s,9H,C(CH3)3),1.01-1.85(m,10H,Cy-H),1.32(d,J=6.3Hz,6H,OCH(CH3)2),3.16(m,1H,Im-H),3.31(m,1H,Im-H),3.48(m,1H,Cy-H),3.76(m,1H,Im-H),5.19(sep,J=6.3Hz,1H,OCH(CH3)2)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=22.3(OCH(CH3)2),25.8(CH2,Cy),25.9(CH2,Cy),26.1(CH2,Cy),26.3(C(CH3)),30.8(OH2,Cy),31.6(CH2,Cy),34.7(C(CH3)3),45.6(CH2,Im),55.1(CH,Cy),70.2(CH,Im),74.4(OCH(CH3)2),157.0(C=N),162.0(C=O)ppm.
实施例A8:制备(A8)
Bn=苄基;tBu=叔丁基
用参见实施例A13的氯代亚胺A4(590mg,2.2mmol)和苄胺(280μl,2.6mmol)重复实施例A5的方法,经柱色谱纯化,洗脱剂为戊烷/Et2O/三乙胺(8∶1∶1),得到280mg的黄色油形式的产物(0.93mmol,43%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.86(s,9H,C(CH3)3);1.32(dd,J=6.4,3.5Hz,6H,CH(CH3)2),3.06(t,J=9.6Hz,1H,CH2,Im),3.26(t,J=9.6Hz,1H,CH,Im),3.83(t,J=9.6Hz,1H,CH2,Im),4.43(s br,2H,CH2Ph),5.20(sep,J=6.4Hz,1H,CH(CH3)2),7.25-7.45(m,5H,Ph-H)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=21.7(CH(CH3)2),26.0(C(CH3)3),34.2(C(CH3)3),51.0(CH2,Bn-H),51.4(CH2),70.4(CH(CH3)2),74.5(CH),127.6(CH,Ar-C),127.8(CH,Ar-C),128.7(CH,Ar-C),137.3(C,ipso,Ar-C),156.5(N-C=N),161.0(C=O)ppm.
实施例A9:制备(A9)
用氯代亚胺A4(1.15g,4.3mmol)和苯胺(475μl,5.2mmol)重复实施例A2的方法,经柱色谱纯化,洗脱剂为戊烷/Et2O/三乙胺(4∶5∶1),得到橙色油形式的咪唑啉A9(900mg,3.12mmol,72%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.96(s,9H,C(CH3)3),1.11(d,J=6.0Hz,3H,CH(CH3)2),1.16(d,J=6Hz,3H,CH(CH3)2),3.65(t,J=9.4Hz,1H,CH2),3.87(t,J=9.2Hz,1H,CHC(CH3)3),4.00(t,J=9.2Hz,1H,CH2),5.09(sep,J=6.4Hz,1H,OCH(CH3)2),6.94(dd,J=8.8,1.0Hz,2H,Ar-H),7.08(t,J=7.2Hz,1H,对-Ar-H),7.27(t,J=7.6Hz,2H,Ar-H)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=21.3和21.4(OCH(CH3)2),26.0(C(CH3)),34.2(C(CH3)3),53.5(CH2),70.3(OCH(CH3)2),75.1(CHC(CH3)3),121.0(CH,Ar),124.4(CH,对,Ar),129,2(CH,Ar),141.5(C,Ar),154.3(C=N),161.0(C=O)ppm.
实施例10:制备A(10)
Me=甲基
用氯代亚胺A4(1.15g,4.3mmol)和p-甲氧基苯胺(1.07g,8.6mmol)重复实施例A5的方法,经柱色谱纯化,洗脱剂为戊烷/Et2O/三乙胺(8∶1∶1),得到黄色粘稠的油形式的咪唑啉A10(420mg,1.32mmol,31%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.96(s,9H,C(CH3)3),1.07(d,J=6.0Hz,3H,CH(CH3)2),1.13(d,J=6.0Hz,3H,CH(CH3)2),3.54(t,J=9.2Hz,1H,CH2),3.77(s,3H,OCH3),3.81(t,J=9.2Hz,1H,CH),3.97(t,J=9.2Hz,1H,CH2),5.02(sep,J=6.4Hz,1H,OCH(CH3)2),6.81(d,J=8.8Hz,2H,Ar-H),6.94(d,J=9.0Hz,2H,Ar-H)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=214和21.5(CH(CH3)2),26.0(C(CH3)3),34.2(C(CH3)3),54.7(CH2),55.6(OCH3),70.0(OCH(CH3)2),75.3(CH),114.5(CH,Ar-C),124.1(CH,Ar-C),135.2(N-C,Ar-C),155.2(C-O,Ar-C),157.3(N-C=N),160.9(C=O)ppm.
实施例A11:制备A(11)
用氯代亚胺A4(1.15g,4.3mmol)和4-氨基三氟甲苯(1.07ml,8.6mmol)重复实施例A5的方法,经柱色谱纯化,洗脱剂为戊烷/三乙胺(9∶l),得到红色油形式的咪唑啉A11(1.10g,3.07mmol,71%。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.96(s,9H,C(CH3)3),1.23(d,J=6.4Hz,3H,CH(CH3)2),1.25(d,J=6.4Hz,3H,CH(CH3)2),3.72(t,J=8.8Hz,1H,CH2),3.90(t,J=9.2Hz,1H,CHC(CH3)3),4.03(t,J=8.8Hz,1H,CH2),5.17(sep,J=6.4Hz,1H,OCH(CH3)2),6.96(d,J=8.8Hz,2H,Ar-H),7.52(d,J=8.8Hz,2H,Ar-H)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=21.4(CH(CH3)2),25.9(C(CH3)3),34.2(C(CH3)3),52.6(CH2),65.9(OCH),75.1(CH,Im),119.2(CH,Ar),126.4(CH,Ar),143.9(C-N,Ar),152.8(N-C=N),160.8(C=O)ppm.
19F-NMR(376.4MHz,CDCl3,300K):δ=-63.2ppm.
实施例A12:制备A(12)
MeO=甲氧基
用氯代亚胺A4(400mg,1.49mmol)和3,5-二甲氧基苯胺(342mg,2.24mmol)重复实施例A5的方法,经柱色谱纯化,洗脱剂为戊烷/三乙胺(9∶1),得到无色油形式的咪唑啉A12(117mg,0.336mmol,23%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.96(s,9H,C(CH3)3),1.19(d,J=6.6Hz,3H,CH(CH3)2),1.22(d,J=7.01Hz,3H,CH(CH3)2),3.64(t,J=8.8Hz,1H,CH2),3.85(dd,J=10.9Hz,9.2Hz,1H,CHC(CH3)3),3.74(s,6H,MeO),3.99(dd,J=11.1Hz,8.8Hz,1H,CH2),5.13(sep,J=6.3Hz),6.11(d,J=2.3Hz,2H,Ar-H),6.20(t,J=2.0Hz,1H,Ar-H)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=21.8(CH(CH3)2),26.9(C(CH3)3),34.5(C(CH3)3),53.6(CH2),55.7(CH3O),70.8(OCH),75.3(CH,Im),96.5(CH,Ar),99.7(CH,Ar),143.9(C-N,Ar),154.5(N-C=N),161.6(C=O和C-O,Ar)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=18.1(Ar-CH3),21.4和21.6(je CH(CH3)2),26.5(C(CH3)3),34.6(C(CH3)3),54.8(CH2),70.1(OCH),76.0(CH,Im),126.4(C,Ar),127.3(CH,Ar),127.8(C,Ar),131.4(CH,Ar),136.4(C),157.1(C)ppm.
实施例A13:制备A(13)
用氯代亚胺A4(0.50g,1.86mmol)和邻氨基甲苯(0.30ml,2.80mmol)重复实施例A5的方法,经柱色谱纯化,洗脱剂为戊烷/三乙胺(9∶1),得到无色油形式的咪唑啉Al(160mg,0.652mmol,35%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.92(d,J=6.0Hz,3H,CH(CH3)2),1.00(br,12H,C(CH3)3和CH(CH3)2),2.32(s,3H,Ar-CH3),3.45(br,1H,CH2),3.72(br,1H,CHC(CH3)3),4.06(dd,J=11.4Hz,9.6Hz,1H,CH2),4.91(sep,J=6.3Hz),6.96(m br,1H,Ar-H),7.11-7.24(m,3H,Ar-H)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=18.1(Ar-CH3),21.4和21.6(各CH(CH3)2),26.5(C(CH3)3),34.6(C(CH3)3),54.8(CH2),70.1(OCH),76.0(CH,Im),126.4(C,Ar),127.3(CH,Ar),127.8(C,Ar),131.4(CH,Ar),136.4(C),157.1(C)ppm.
实施例A14:制备A(14)
用氯代亚胺A4(0.50g,1.86mmol)和1-萘胺(0.347g,2.42mmol)和碘化四丁基铵(0.343g,0.93mmol)重复实施例A5的方法,经柱色谱纯化,洗脱剂为戊烷/乙醚/三乙胺(8∶1∶1),得到无色固体形式的咪唑啉A14(0.445g,1.31mmol,71%)。
1H-NMR(250.1MHz,CDCl3,300K):δ=0.55-0.92(m br,6H,CH(CH3)2),1.08(s,9H,C(CH3)3),3.35-4.27(br,3H,CH2和CHC(CH3)3),4.82(sep,J=6.4Hz,1H,OCH(CH3)2),7.21(br,1H,Ar-H),7.43(pt,1H,Ar-H),7.56(m,2H,Ar-H),7.78(d,J=13.1Hz,1H,Ar-H),7.90(m,1H,Ar-H),8.09(br,1H,Ar-H)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=21.3和22.0(OCH(CH3)2),26.6(C(CH3)),35.6(C(CH3)3),56.5(CH2),69.9(OCH(CH3)2),76.4(CHC(CH3)3),123.7,126.0,126.8,127.0,127.8,128.6,131.4,134.8(各Ar-C),157.4(C=N),160.4(C=O)ppm.
实施例A15:制备A(15)
用氯代亚胺A3(584mg,2.30mmol)和3,5-二甲氧基苯胺(458mg,2.99mmol)重复实施例A5的方法,经柱色谱纯化,洗脱剂为戊烷/三乙胺(9∶1),得到无色油形式的咪唑啉A15(339mg,1.01mmol,44%)。
1H-NMR(400,1MHz,CDCl3,300K):δ=0.91(d,J=6.8Hz,3H,CHCH(CH3)2),1.02(d,J=6.8Hz,3H,CHCH(CH3)2),1.20(d,J=6.3Hz,3H,OCH(CH3)2),1.22(d,J=6.3Hz,3H,OCH(CH3)2),1.89(sept,J=6.8Hz,1H,CHCH(CH3)2)3.56(pt,1H,CH2),3.73(s,6H,OCH3),3.88(dd,J=10.6Hz,9.1Hz,1H,CHCH(CH3)2),4.00(m,1H,CH2),5.12(sept,J=6.3Hz),6.10(d,J=2.0Hz,2H,Ar-H),6.19(t,J=2.3Hz,1H,Ar-H)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=18.4(CH(CH3)2),19.5(CH(CH3)2),21.8(2C,OCH(CH3)2),33.2(CH(CH3)2),55.8(CH2,Im),55.7(2C,CH3O),70.8(OCH),75.3(CH,Im),96.6(CH,Ar),99.7(CH,Ar),143.4(C-N1Ar),154.5(N-C=N),161.5,161.6(C=O and C-O,Ar)ppm.
B)咪唑啉甲醇的制备
实施例B1:制备B1
将咪唑啉A5(200mg,0.71mmol)置于烘干的Schlenk烧瓶中并溶于无水乙醚(8ml)中。随后在剧烈搅拌的同时,在-78℃下缓慢滴加溴化甲基镁溶液(3M的乙醚溶液,0.72ml,2.14mmol)。让该反应溶液缓慢升至室温并再搅拌14小时。随后进行后处理,加入8ml冷NH4Cl水溶液。在相分离后,用Et2O(10ml)萃取水相两次。经MgSO4干燥该合并的有机萃取物。使用未进一步纯化的粗产物制备次亚膦酸酯。
1H-NMR(250MHz,CDCl3,300K,粗产物谱图):δ=0.85(d,J=6.5Hz,3H,CH(CH3)2),0.95(d,J=6.5Hz,3H,CH(CH3)2),1.00-1.50(m,5H,CH2,Cy),1.50(s,6H,HOC(CH3)2),1.50-2.0(m,6H,CH2(Cy),CH(CH3)2),3.30(t,J=9.5Hz,1H,Im),3.40(m,2H,Im),3.80(m,1H,CH,Cy)ppm.
实施例B2:制备B2
按照实施例B1的方法,将咪唑啉A6(200mg,0.73mmol)与溴化甲基镁溶液(0.73ml,2.19mmol)反应形成醇B2。得到非常纯的粗产物(165mg,0.67mmol,92%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.93(d,J=6.8Hz,3H,CH(CH3)2),1.00(d,J=6.8Hz,3H,CH(CH3)2),1.15(s,3H,CH3),1.20(s,3H,CH3),1.81(sep,J=6.8Hz,1H,CH(CH3)2),3.59(t,J=7.2Hz,1H,CH2),3.84(m,2H,CH2和CH,Im),4.77(s br,1H,OH),7.23(d,J=4.0Hz,2H,Ar-H),7.30(t,J=6.8Hz,1H,Ar-H),7.37(t,J=7.2Hz,2H,Ar-H)ppm.
13C-NMR(100.1MHz,CDCl3,300K):δ=18.1(CH(CH3)2),18.7(CH(CH3)2),28.8(HO-C(CH3)2),29-3(HO-C(CH3)2),61.4(CH2),68.0(CH,Im),69.5(HO-C(CH3)2),127.6(CH,Ar-C),129.1和129.5(CH,Ar-C),142.8(C,ipso,Ar),170.5(C=N)ppm.
实施例B3:制备B3
按照实施例B1的方法,将咪唑啉A7(260mg,0.88mmol)与溴化甲基镁溶液(0.88ml,2.65mmol)反应形成醇B3。得到非常纯的粗产物(180mg,0.67mmol,77%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.84(s,9H,C(CH3)3),1.09(m,1H,Cy),1.26(m,2H,Cy),1.42(s,3H,CH3),1.44(s,3H,CH3),1.46-1.84(br m,7H,Cy),3.31-3.42(m,2H,Cy and Im),3.47(m,1H,CH2),3.58(m,1H,Im)ppm.
13C-NMR(100.1MHz,CDCl3,300K):δ=25.7(Cy),25.9(C(CH3)2),26.2(Cy),26.3(Cy),28.2(HO-C(CH3)2),29.0(HO-C(CH3)2),34.9(C(CH3)3),47.7(C(CH3)2),68.0(Im),70.2(Im),170.5(C=N)ppm.
实施例B4:制备B4
如实施例B1中描述将咪唑啉A10(250mg,0.83mmol)与溴化苄基镁(1M的乙醚溶液,2.5ml,2.5mmol)反应。经柱色谱纯化,洗脱剂为戊烷/乙醚/三乙胺(8∶1∶1),得到黄色油形式的250mg(0.566mmol,68%)产物。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.86(s br,9H,C(CH3)3),2.16(s br,1H,OH),2.77(m,2H,CH2,Bn-H),3.00(m,1H,CH2,CH2Ph),3.45(t,J=9.0Hz,1H,Im),3.67(m,2H,Im),3.81(s,3H,OCH3),4.40(s br,1H,CH2,Bn-H),6.90(m,2H,Ar-H),7.10-7.40(m,12H,Ar-H)ppm.
实施例B5:制备B5
按照实施例B1的方法,将咪唑啉A9(200mg,0.73mmol)与溴化甲基镁溶液(0.73ml,2.19mmol)反应形成醇B4。得到非常纯的粗产物(165mg,0.67mmol,92%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.93(d,J=6.8Hz,3H,CH(CH3)2),1.00(d,J=6.8Hz,3H,CH(CH3)2),1.15(s,3H,CH3),1.20(s,3H,CH3),1.81(sep,J=6.8Hz,1H,CH(CH3)2),3.59(t,J=7.2Hz,1H,CH2),3.84(m,2H,CH2和CH,Im),4.77(s br,1H,OH),7.23(d,J=4.0Hz,2H,Ar-H),7.30(t,J=6.8Hz,1H,Ar-H),7.37(t,J=7.2Hz,2H,Ar-H)ppm.
13C-NMR(100.1MHz,CDCl3,300K):δ=18.1(CH(CH3)2),18.7(CH(CH3)2),28.8(HO-C(CH3)2),29.3(HO-C(CH3)2),61.4(CH2),68.0(CH,Im),69.5(HO-C(CH3)2),127.8(CH,Ar-C),129.1和129.5(CH,Ar-C),142.8(C,ipso,Ar),170.5(C=N)ppm.
实施例B6:制备B6
按照实施例B1的方法,将咪唑啉A10(400mg,1.26mmol)与溴化甲基镁溶液(1.26ml,3.78mmol,乙醚溶液)反应。得到黄色油形式的产物(130mg,36%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.95(s,9H,C(CH3)3),1.16(s,3H,CH3),1.20(s,3H,CH3),3.64(t,J=8.8Hz,1H,CH2),3.78(m,2H,CH和CH2,咪唑时),3.81(s,3H,OCH3),5.23(br s,1H,OH),6.87(d,J=8.8Hz,2H,Ar-H),7.13(d,J=8.8Hz,2H,Ar-H)ppm,
13C-NMR(100.6MHz,CDCl3,300K):δ=25.7(C(CH3)3),28.5(CH3),29.3(CH3),34.4(C(CH3)3),55.6(OCH3),60.1(CH2),69.4(C-OH),114.7(CH,Ar-C),130.3(CH,Ar-C),159.1(N-C=N)ppm.
实施例B7:制备B7
按照实施例B1的方法,将咪唑啉B7(200mg,0.56mmol)与溴化甲基镁溶液(3M的乙醚溶液,0.56ml,1.68mmol)反应。得到的醇(165mg,90%)以粗产物用于进一步反应。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.95(s,9H,C(CH3)3),1.19(s,3H,CH3),1.23(s,3H,CH3),3.67(t,J=8.4Hz,1H,CH2),3.83(m,2H,CH2 and CH,Im),4.73(s br,1H,OH),7.34(d,J=8.8Hz,2H,Ar-H),7.63(d,J=8.0Hz,2H,Ar-H)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=25.8(C(CH3)3),28.9(CH3),29.6(CH3),34.3(C(CH3)3),59.7(CH2),69.6(C-OH),71.7(CH,Im),122.5(CCF3),125.2(CCF3),126.7(CH,Ar-C),129.0(CH,Ar-C),146.3(C-N,Ar),169.6(C=N)ppm.
19F-NMR(376.4MHz,CDCl3,300K):δ=-63.6ppm.
实施例B8:制备B8
按照实施例B1的方法,将咪唑啉A12(98mg,0.28mmol)与溴化甲基镁溶液(3M的乙醚溶液,0.34ml,1.03mmol)反应。得到的醇(83mg,92%)以粗产物用于进一步反应。
1H-NMR(500.1MHz,CDCl3,295K):δ=0.94(s,9H,C(CH3)3),1.23(s,3H,CH3),1.27(s,3H,CH3),3.64(dd,J=9.0Hz,8.0Hz,1H,CH2),3.77(m,7H,CHC(CH3)3和CH3O),3.85(dd,J=10.8Hz,9.0Hz,1H,CH2),5.10(br,1H,OH),6.36-6.41(m,3H,Ar-H)ppm.
13C-NMR(125.8MHz,CDCl3,295K):δ=25.7(C(CH3)3),28.7和29.5(各OCH3),34.2(C(CH3)3),55.5(CH2和OCH3),59.6(CCH3)2),69.5(OCH),71.1(CH,Im),99.4(CH,Ar),107.1(CH,Ar),144.4(C-N,Ar),161.2(N-C=N),170.2(C-OMe,Ar)ppm.
实施例B9:制备B9
按照实施例B1的方法,将咪唑啉A8(111mg,0.367mmol)与溴化甲基镁溶液(3M的乙醚溶液,0.37ml,1.10mmol)反应。得到的醇(80mg,0.292mmol,80%)以粗产物用于进一步反应。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.85(s,9H,C(CH3)3),1.53(s,6H,CH3),3.09(m,1H,CH2),3.29(m,1H,CH2),3.64(dd,J=11.1Hz,8.3Hz,1H,CH2),4.37(d,J=15.2Hz,CH2Ph),4.48(d,J=15.4Hz,CH2Ph),7.24-7.38(m,5H,Ar-H)ppm.
13C-NMR(125.8MHz,CDCl3,295K):δ=26.1(C(CH3)3),28.5和29.2(各CH3),34.2(C(CH3)3),52.4(CH2Ph),54.0(C(CH3)2),69.0(OCH),71.4(CH,Im),127.4,128.0,129.2,137.7(和Ar-C),170.9(N-C=N)ppm.
实施例B10:制备B10
按照实施例B1的方法,将咪唑啉A13(149mg,0.493mmol)与溴化甲基镁溶液(3M的乙醚溶液,0.49ml,1.48mmol)反应。得到的醇(94mg,0.343mmol,70%)以粗产物用于进一步反应。由于两个非对映异构体的形成,在NMR图谱中观察到一些双组信号。不能分离该混合物。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.94(s,9H,C(CH3)3),1.08(s,3H,CH3),1.23(s,3H,CH3),2.28(s,3H,PhCH3),3.38,3.53,3.75-3.90(各m,3H、CH和CH2的总和),5.12(br s,1H,OH),7.08-7.29(m,4H,Ar-H)ppm.
13C-NMR(125.8MHz,CDCl3,295K):δ=18.1和18.5(PhCH3),26.1和26.2(C(CH3)3),27.1,28.0,29.0,30.6(CH3),34.6和34.7(C(CH3)3),58.1和58.3(C(CH3)2),69.6和69.7(OCH),72.0和72.1(CH,Im),127.2,128.6,130.2,130.5,131.6,137.6,138.0,140.9,141.1(各Ar-C),170.6和171.0(N-C=N)ppm.
实施例B11:制备B11
按照实施例B1的方法,将咪唑啉A14(80mg,0.236mmol)与溴化甲基镁溶液(3M的乙醚溶液,0.29ml,0.863mmol)反应。得到的醇(73mg,0.235mmol,99%)以粗产物用于进一步反应。非对映体的形成导致NMR图谱中的双组信号。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.96和0.97(s,9H,C(CH3)3),1.20和1.22(s,3H,CH3),1.27和1.29(s,3H,CH3),3.61,3.74,4.00,4.12(各m,3H、CH和CH2的总和),5.20(br s,1H,OH),7.34,7.43-7.59,7.84-7.93,8.00(m,的总和7H,Ar-H)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=25.7和25.9(C(CH3)3),26.7,27.7,28.5,30.1(CH3),34.3,34.4(s,C(CH3)3),59.3(CH2),65.9和69.5(C-OH),71.4和71.6(CH),123.2,125.5,125.6,126.6,126.7,127.0,127.1,127.2,127.6,128.6,128.7,128.8,131.7,134.6(Ar-C)ppm(C-N,Ar和C=N未检测到).
实施例B12:制备B12
按照实施例B1的方法,将咪唑啉A14(140mg,0.40mmol)与氯化乙基镁溶液(3M的乙醚溶液,0.40ml,1.20mmol)反应。后处理后,经柱色谱纯化,洗脱剂为戊烷/乙醚/三乙胺(8∶1∶1)。得到无色油形式的所需产物(60mg,0.177mmol,44%)。非对映体的形成导致NMR图谱中的双组信号。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.83-1.39(m,19H,Et和C(CH3)3),3.56,3.72,3.98-4.10(各m3,H、CH和CH2的总和),5.04(br s,1H,OH),7.37,7.41-7.56,7.83-7.95,8.06(m,7H,Ar-H的总和)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=8.7和8.8(各CH3),26.5和26.6(C(CH3)3),31.9,32.1,32.7,32.7(CH2),34.2,34.6(s,C(CH3)3),59.7和60.3(C-OH),72.5(br,CH2),75.4和75.5(CH),123.4,123.5,125.9,126.0,126.3,126.9,127.0,127.1,127.2,128.9,128.9,129.0,132.0,132.3,134.9,135.0(Ar-C)168.1(C=N)ppm.
实施例B13:制备B13
按照实施例B1的方法,将咪唑啉A14(150mg,0.44mmol)与氯化正丁基镁溶液(1M的乙醚溶液,1.53ml,1.33mmol)反应。后处理后,经柱色谱纯化,洗脱剂为戊烷/乙醚/三乙胺(8∶1∶1)。得到无色油形式的所需产物(15mg,0.038mmol,9%)。非对映体的形成导致NMR图谱中的双组信号。
1H-NMR(500.1MHz,CDCl3,295K):δ=0.68-1.64(m,27H,n-Bu和C(CH3)3),3.57,3.74,3.96-4.17(各br m,3H、CH和CH2的总和),5.07(br s,1H,OH),7.34,7.39,7.44,7.82-7.95,8.07(m,7H,Ar-H的总和)ppm.
13C-NMR(125.8MHz,CDCl3,295K):δ=14.0和14.2(各CH3),22.5,22.8,25.6,25.8,25.9,26.1,26.5,26.9(CH3和CH2),33.9和34.2(s,C(CH3)3),59.3和59.8(C-OH),72.1(br,CH2),74.5和76.7(CH),122.9,125.4,125.5,126.0,126.6,126.9,128.5,128.6,134.6,138.7(Ar-C)165.7(C=N)ppm.
实施例B14:制备B14
按照实施例B1的方法,将咪唑啉A15(147mg,0.44mmol)与溴化甲基镁溶液(0.44ml,1.32mmol,3M的乙醚溶液)反应。得到黄色油形式的产物(120mg,89%)。
1H-NMR(500.1MHz,CDCl3,295K):δ=0.96(d,J=6.8Hz,3H,CHCH(CH3)2),1.23(d,J=6.8Hz,3H,CHCH(CH3)2),1.28(s,3H,CH3),1.31(s,3H,CH3),1.88(sept,J=6.5Hz,1H,CHCH(CH3)2),3.63(m,1H,CH2),3.78(s,6H,OCH3),3.91(m,1H,CH,Im),3.96(m,1H,CH2,Im)5.21(br s,1H,OH),6.38(d,J=2.2Hz,2H,Ar-H),6.43(t,J=2,1Hz,1H,Ar-H)ppm.
13C-NMR(100.6MHz,CDCl3,300K):δ=17.7,18.4(各CH(CH3)2),28.7(CH3),29.1(CH3),33.0(CH(CH3)2),55.6(OCH3),60.8(CH2),66.3(CH ,Im),69.9(C-OH),99.9(CH,Ar-C),106.7(CH,Ar-C),114.7(CH,Ar-C),161.3(C-N,Ar-C),171.4(N-C=N)ppm.
C)次亚膦酸酯的制备
实施例C1:制备C1
将醇B1(60mg,0.24mmol)悬浮于15ml戊烷中。在-78℃滴加正丁基锂(1.6M的己烷溶液,0.20ml,0.31mmol),随后滴加四甲基乙二胺(TMEDA)(62μl)。在移出冷浴后,在室温将该溶液搅拌1小时。随后在0℃下加入氯代二苯基膦(Ph2PCl)(57μl,0.31mmol)。将该溶液搅拌过夜。随后进行后处理,首先将该悬浮液蒸发至约1ml。随后直接将该残留物用制备硅胶柱分离。经柱色谱纯化粗产物,洗脱剂为戊烷/三乙胺(9∶1)。分离得到无色油形式的次亚膦酸酯C1(32mg,30%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.83(d,J=6.4Hz,3H,CH(CH3)2),0.88(d,6.8Hz,3H,CH(CH3)2),1.20-1.37(m,11H,CH2Cy和CH(CH3)2),1.67(s,6H,OC(CH3)2),3.12(sbr,1H,Cy),3.34(s br,1H,Im),3.76(s br,2H,Im),7.30(m,6H,Ar-H),7.51(m,4H,Ar-H)ppm.
31P-NMR(161.9MHz,CDCl3,300K):δ=86.9(96%)和-23.9(次亚膦酸酯,4%)ppm.
实施例C2:制备C2
按照实施例C1的方法,将醇B2(135mg,0.49mmol)与Ph2PCl(120μl,0.64mmol)反应。经柱色谱纯化,洗脱剂为戊烷/Et2O/三乙胺(8∶1∶1),得到浅黄色液体形式的产物(80mg,0.19mmol,38%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.91(d,J=6.4Hz,3H,CH(CH3)2),0.95(d,J =6.8Hz,3H,CH(CH3)2),1.87(sep,J=6.8Hz,1H,CH(CH3)2),3.45(q,J=7.2Hz,1H,CH2),3.77(t,J=9.6Hz,1H,CH),3.88(m,1H,CH2),6.95-7.10(m,5H,Ar-H),7.26(m br,10H,Ar-H)ppm.
31P-NMR(161.9MHz,CDCl3,300K):δ=87.9ppm.
实施例C3:制备C3
按照实施例C1的方法,将醇B2(120mg,0.487mmol)与氯代二(邻甲苯基)膦(172mg,0.633mmol)反应。经柱色谱纯化,得到无色油形式的产物(71mg,0.155mmol,32%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.97(d,J=7.0Hz,3H,CH(CH3)2),1.01(d,7.0Hz,3H,CH(CH3)2),1.89(sep,J=7.0Hz,1H,CH(CH3)2),1.60(s,6H,OC(CH3)2),2.29(s,3H,CH3,Tol),2.34.(s,3H,CH3,Tol),3.50(dd,J=9.0Hz,7.4Hz,CH2,Im-H),3.82(dd,J=10.5Hz,9.0Hz,CH2,Im-H),3.94(m,1H,CH,Im-H),6.85-7.34(m,13H,Ar-H)ppm.
31P-NMR(161.9MHz,CDCl3,300K):δ=72.8和-35.3(次亚膦酸酯,5%)ppm.
实施例C4:制备C4
按照实施例C1的方法,将醇B3(70mg,0.26mmol)与氯代二苯基膦(63μl,0.34mmol)反应。经柱色谱纯化,得到无色油形式的产物(38mg,0.087mmol,33%)。
1H-NMR(250.1MHz,CDCl3,300K):δ=0.67(m,2H,Cy),0.90(s br,9H,C(CH3)3),1.27-1.77(m br,14H,CH2,Cy-H和C(CH3)2),1.65(s br,6H,OC(CH3)2),3.15-3.47(m br,2H,Cy-H和Im-H),3.55-3.75(s br,2H,Im-H),7.31-7.58(m,10H,Ar-H)ppm.
31P-NMR(101.2MHz,CDCl3,300K):δ=86.6ppm.
实施例C5:制备C5
按照实施例C1的方法,将醇B3(70mg,0.26mmol)与氯代二(邻甲苯基)膦(93mg,0.34mmol)反应。经柱色谱纯化,得到无色油形式的产物(29mg,0.062mmol,24%)。
1H-NMR(250.1MHz,CDCl3,300K):δ=0.88(s br,11H,C(CH3)3和Cy-H),1.20-1.64(m,8H,CH2,Cy-H),1.65(s br,6H,C(CH3)2),2.35(s,3H,CH3,o-Tol),2.42(s,3H,CH3,o-Tol),3.12-3.35(m br,2H,Cy-H和Im-H),3.57-3.76(s br,2H,Im-H),6.95-7.27(m,6H,Ar-H),7.45-7.56(m,2H,Ar-H)ppm.
31P-NMR(101.3MHz,CDCl3,300K):δ=71.8ppm.
实施例C6:制备C6
按照实施例C1的方法,将醇B5(150mg,0.58mmol,79%)与Ph2PCl(106μl,0.57mmol)反应。经柱色谱纯化,洗脱剂为戊烷/三乙胺(9∶1),得到浅黄色液体形式的产物(125mg,64%)。
1H-NMR(250.1MHz,CDCl3,300K):δ=0.96(s,9H,C(CH3)3),1.60(s,3H,CH3),1.63(s,3H,CH3),3.55(m,1H,Im),3.80(d,J=2.5Hz,2H,Im),7.05(d,J =2.3Hz,5H,Ar-H),7.29(m,10H,Ar-H)ppm.
13P-NMR(101.2MHz,CDCl3,300K):δ=87.5ppm.
实施例C7:制备C7
按照实施例C1的方法,将醇B6(175mg,0.60mmol)与Ph2PCl(0.78mmol)反应。经柱色谱纯化,洗脱剂为戊烷/Et2O/三乙胺(8∶1∶1),得到透明油形式的产物(162mg,0.34mmol,57%)。
1H-NMR(250.1MHz,CDCl3,300K):δ=0.93(s,9H,C(CH3)3),1.59(s,3H,CH3),1.62(s,3H,CH3),3.50(m,1H,CH2),3.73(s,3H,OCH3),3.76(m,2H,CH2和CH),6.52(d,J=9.0Hz,2H,p-MeOPh),6.97(d,J=9.0Hz,2H,p-MeOPh),7.29(br s,10H,Ar-H)ppm.
31P-NMR(101.2MHz,CDCl3,300K):δ=87.2.
实施例C8:制备C8
按照实施例C1的方法,将醇B6(90mg,0.31mmol)与(邻甲苯基)2PCl(100mg,0.40mmol)反应。经柱色谱纯化,洗脱剂为戊烷/三乙胺(9∶1),得到无色油形式的产物(40mg,26%)。
1H-NMR(400.1MHz,CDCl3;300K):δ=0.95(s,9H,C(CH3)3),1.55(s,6H,邻甲苯基),2.23(d,J=1.2Hz,3H,CH3),2.32(d,J=1.0Hz,3H,CH3),3.48(t,J=5.6Hz,1H,CH2),3.67(s,3H,OCH3),3.74(m,2H CH2和CH),6.37(d,J=9.2Hz,2H,ρ-MeOPh),6.85(d,J=8.8Hz,2H,ρ-M8OPh),7.04-7.26(各种m,8H,邻甲苯基)ppm.
31P-NMR(161.9MHz,CDCl3,300K):δ=72.5ppm.
实施例C9:制备C9
按照实施例C1的方法,将醇B4(150mg,0.34mmol)与Ph2PCl(0.442mmol)反应。得到无色油形式的次亚膦酸酯C9(200mg,29mmol,86%,粗产物)。
1H-NMR(250MHz,CDCl3,300K):δ=0.70(s,9H,C(CH3)3),2.30(s,6H,甲苯基-CH3),3.15-3.80(m br,10H,OCH3,CH2Ph和Im-H),6.60-7.80(m,22H,Ar-H)ppm.
31P-NMR(101.2MHz,CDCl3,300K):δ=87.4.
实施例C10:制备C10
按照实施例C1的方法,将醇B7(109mg,0.33mmol)与Ph2PCl(80μl,0.43mmol)反应。经柱色谱纯化,洗脱剂为戊烷/三乙胺(9∶1),分离得到淡黄色油形式的次亚膦酸酯C10(113mg,0.22mmol,66%)。
1H-NMR(250.1MHz,CDCl3,300K):δ=0.96(s,9H,C(CH3)3),1.65(s,3H,CH3),1.70(s,3H,CH3),3.57(m,1H,CH2),3.83(m,2H,CH和CH2),7.13(s,4H,Ar-H),7.30(d,J=2.5Hz,10H,Ar-H)ppm.
31P-NMR(101.2MHz,CDCl3,300K):δ=88.3ppm.
实施例C11:制备C11
按照实施例C1的方法,将醇B8(77mg,0.24mmol)与Ph2PCl(60μl,0.327mmol)反应。经柱色谱纯化,洗脱剂为戊烷/三乙胺(9∶1),分离得到淡黄色油形式的次亚膦酸酯C11(38mg,0.075mmol,31%)。
1H-NMR(250.1MHz,CDCl3,295K):δ=0.94(s,9H,C(CH3)3),1.74(s,6H,CH3),3.52-3.87(br m,9H,CH,CH2和CH3O),6.15(s,1H,Ar-H),6.37(s,2H,Ar-H),7.20-7.68(m,10H,Ar-H)ppm.
31P-NMR(101.2MHz,CDCl3,300K):δ=88.5ppm.
实施例C12:制备C12
按照实施例C1的方法,将醇B9(80mg,0.29mmol)与Ph2PCl(70μl,0.38mmol)反应。经柱色谱纯化,洗脱剂为戊烷/乙醚/三乙胺(8∶1∶1),分离得到淡黄色油形式的次亚膦酸酯C12(51mg,0.11mmol,38%)。
1H-NMR(250.1MHz,CDCl3,300K):δ=0.93(s,9H,C(CH3)3),1.78(s,6H,CH3),2.89-3.78(br m,3H,CH2),4.06(d,J =15.2Hz,CH2Ph),4.28(d,J=15.9Hz,CH2Ph),6.97-7.90(m,15H,Ar-H)ppm.
31P-NMR(101.2MHz,CDCl3,300K):δ=88.4ppm.
实施例C13:制备C13
按照实施例C1的方法,将醇B10(94mg,0.343mmol)与ph2PCl(83μl,0.45mmol)反应。经柱色谱纯化,洗脱剂为戊烷/乙醚/三乙胺(8∶1∶1),分离得到淡黄色油形式的次亚膦酸酯C13(61mg,0.132mmol,39%)。
1H-NMR(250.1MHz,CDCl3,300K):δ=0.96(s,9H,C(CH3)3),1.67(s,6H,CH3),2.15和2.18(各s,3H、PhCH3的总和),3.11-3.97(br m,3H、CH和CH2的总和),6.83-7.67(m,14H,Ar-H)ppm.
31P-NMR(101.2MHz,CDCl3,300K):δ=87.8ppm.
实施例C14:制备C14
按照实施例C1的方法,将醇B11(60mg,0.20mmol)与Ph2PCl(48μl,0.26mmol)反应。经柱色谱纯化,洗脱剂为戊烷/乙醚/三乙胺(8∶1∶1),分离得到淡黄色油形式的次亚膦酸酯C14(48mg,0.097mmol,48%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=1.00和1.03(s,9H,C(CH3)3),1.54,1.60和1.70(s,6H,CH3),3.40-4.16(br m,3H、CH和CH2的总和),6.96-8.10(17H,Ar-H的总和)ppm.
31P-NMR(101.2MHz,CDCl3,300K):δ=87.5ppm.
实施例C15:制备C15
按照实施例C1的方法,将醇B12(60mg,0.18mmol)与Ph2PCl(43μl,0.26mmol)反应。在除去溶剂后,将次亚膦酸酯C15原位转化为相应的铱络合物。
实施例C16:制备C16
按照实施例C1的方法,将醇B13(15mg,0.063mmol)与Ph2PCl(9.2μl,0.082mmol)反应。在除去溶剂后,将次亚膦酸酯C16原位原位为相应的铱络合物。
实施例C17:制备C17
按照实施例C1的方法,将醇B14(120mg,0.392mmol)与Ph2PCl(94μl,0.51mmol)反应。经柱色谱纯化,洗脱剂为戊烷/乙醚/三乙胺(9∶1),分离得到淡黄色油形式的次亚膦酸酯C17(20mg,0.041mmol,10%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.96(pt,6H,CH(CH3)2),1.73(br s,6H,CH3),1.96(br,1H,CH(CH3)2),3.52-3.97(br m,9H,CH,CH2和CH3O),6.13(t,J=2.0Hz,1H,Ar-H),6.37(d,J=2.3Hz,2H,Ar-H),7.20-7.68(m,10H,Ar-H)ppm.
31P-NMR(101.2MHz,CDCl3,300K):δ=89.2ppm.
D)金属络合物的制备
实施例D1:含有次亚膦酸酯C1的铱络合物D1(COD为环辛二烯)
将[Ir(COD)Cl]2(27mg,0.039mmol)与二氯甲烷(0.5ml)一起置于反应容器中。往该溶液中滴加次亚膦酸酯C1(32mg,0.071mmol,溶解在二氯甲烷中,4.0ml),随后将该混合物加热至45℃。2小时后,将该溶液与四(双三氟甲基)苯基)硼酸钠(NaBArF)(74mg,0.078mmol)和水混合。在相分离和用二氯甲烷(10ml)萃取水相后,用MgSO4干燥合并的有机萃取物,随后用旋转蒸发器除去二氯甲烷。形成的橙色泡沫经硅胶柱色谱纯化,洗脱剂为二氯甲烷。得到橙色固体状的络合物D1(105mg,91%)。
1H-NMR(500.1MHz,CDCl3,295K):δ=-0.04(d,J=6.5Hz,3H,CH(CH3)2),0.74(d,J=7.0Hz,3H,CH(CH3)2),1.05(m,1H,CH2),1.23(m,2H,CH2),1.40-1.70(m,5H,COD和Cy),1.70-1.80(m,5H,COD和Cy),1.80(m,1H,CH(CH3)2),1.90(d,J=2.0Hz,3H,CH3),1.94(m,1H,CH2),2.10(m,1H,CH2),2.34(m,1H,CH2),2.34(s,3H,CH3),2.41(m,1H,CH2),2.55(m,2H,CH2),3.23(m,1H,CH,COD),3.39(dd,J=11.0,5.0Hz,1H,CH2,Im),3.46(t,J=11.5Hz,1H,CH2,Im),3.64(m,1H,CH,Im),3.85(m,1H,CH,Cy),5.04(m,1H,CH,COD),5.20(m,1H,CH,COD),7.11(m,2H,Ar-H),7.41-7.47(m,6H,Ar-H),7.52(sbr,3H,BArF),7.54(m,1H,Ar-H),7.71(s,8H,BArF),7.83(2H,N-Ar-H)ppm.
31P-NMR(161.9MHz,CDCl3,300K):δ=94.7ppm.
实施例D2:含有次亚膦酸酯C2的铱络合物D2
用次亚膦酸酯C2(80mg,0.186mmol)、[Ir(COD)Cl]2(69mg,0.102mmol)和NaBArF(193mg,0.205mmol)重复实施例D1的方法,得到络合物D2(210mg,71%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.10(d,J =6.4Hz,3H,CH(CH3)2),0.77(d,J=7.2Hz,3H,CH(CH3)2),1.17(s,3H,CH3),1.60(m,1H,CH2,COD),1.80(m,1H,CH2,COD),1.91(m,1H,CH2,COD),1.99(m,1H,CH2,COD),2.16(m,1H,CH2,COD),2.38(m,2H,CH2,COD),2.42(s,3H,CH3),2.59(m,3H:CH(COD)和CH2,(COD)和CH(CH3)2),3.37(m,1H,CH,COD),3.72(d,J=8.8Hz,2H,Im),3.85(t,J=8.5Hz,1H,Im),5.08(m,1H,CH,COD),5.31(m,1H,CH,COD),7.09(m,4H,Ar-H),7.41(s,6H,Ar-H),7.52(s,7H,Ar-H和BArF),7.71(s,8H,BArF),7.86(m,2H,Ar-H)ppm.
31P-NMR(161.9MHz,CDCl3,300K):δ=93.8ppm.
实施例D3:含有次亚膦酸酯C3的铱络合物D3
用次亚膦酸酯C3(72mg,0.157mmol)、[Ir(COD)Cl]2(58mg,0.0864mmol)和NaBArF(161mg,0.173mmol)重复实施例D1的方法,得到络合物D3(198mg,78%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.30(d,J=6.6Hz,3H,CH(CH3)2),0.85(d,J=8.8Hz,3H,CH(CH3)2),1.26(s br,4H,CH3和CH(CH3)),1.72(m,1H,CH2,COD),1.80(m,1H,CH2,COD),2.05-2.50(m,15H,COD,C(CH3)2和甲苯基-CH3),3.12(m,3H,CH(COD),3.67-3.91(m,3H,Im-H),5.06(m,1H,CH,COD),5.30(m,1H,CH,COD),6.97(m,2H,Ar-H),7.19-7.52(m br,16H,Ar-H和BArF),7.71(s,8H,BArF),8.31(m,1H,Ar-H)ppm.
31P-NMR(161.9MHz,CDCl3,300K):δ=101.0ppm.
实施例D4:含有次亚膦酸酯C4的铱络合物D4
用次亚膦酸酯C4(38mg,0.087mmol)、[Ir(COD)Cl]2(32mg,0.0479mmol)和NaBArF(89mg,0.0957mmol)重复实施例D1的方法,得到络合物D4(82mg,0.0508mmol,58%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.53(s,9H,C(CH3)),1.06(m,1H,CH2),1.29(m,2H,CH2),1.46-2.10(m,12H,CH2和CH3),2.36(m,6H,CH2和CH3),2.55(m,3H,CH和CH2(COD)),3.37-3.58(m,4H,CH,Im-H,Cy-H,COD),3.80(m,1H,CH),5.15(s br,2H,CH(COD)),7.18(m,2H,Ar-H),7.40(m,3H,Ar-H),7.51(s br,7H,Ar-H和BArF),7.71(s,8H,BArF),7.75(m,2H,Ar-H)ppm.
31P-NMR(161.9MHz,CDCl3,300K):δ=94.6ppm.
实施例D5:含有次亚膦酸酯C5的铱络合物D5
用次亚膦酸酯C5(29mg,0.0624mmol)、[Ir(COD)Cl]2(23mg,0.0343mmol)和NaBArF(64mg,0.0686mmol)重复实施例D1的方法,得到络合物D5(65mg,0.0396mmol,63%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.89(s,9H,C(CH3)),1.20(m,4H,CH2),1.45-2.05(m,19H),2.20-2.47(m,12H,CH2和CH3),3.12(m,1H,CH(COD)),3.45-3.62(m,4H,CH,Im-H,Cy-H),4.88(m,1H,CH(COD),5.34(s br,1H,CH(COD)),7.03-7.52(m,13H,Ar-H和BArF),7.71(s,BH,BArF),7.98(m,1H,Ar-H)ppm.
31P-NMR(161.9MHz,CDCl3,300K):δ=106.2ppm(纯度38.8ppm).
实施例D6:含有次亚膦酸酯C6的铱络合物D6
用次亚膦酸酯C6(125mg,0.28mmol)、[Ir(COD)Cl]2(103mg,0.154mmol)和NaBArF(264mg,0.28mmol)重复实施例D1的方法,得到络合物D6(260mg,58%)。
1H-NMR(500.1MHz,CDCl3,295K):δ=0.68(s,9H,C(CH3)3),1.26(s,3H,CH3),1.54(m,1H,CH2,COD),1.73(m,1H,CH2,COD),2.00(m,1H,CH2,COD),2.08(m,1H,CH2,COD),2.38(m,2H,CH2,COD),2.53(s,3H,CH3),2.62(m,3H,CH2和CH,COD),3.61(d,J=11.5Hz,1H,CH,Im),3.64(m,1H,CH,COD),3.80(t,J=11.5Hz,1H,CH2,Im),3.88(d,J=11.5Hz,1H,CH2,Im),5.02(m,1H,CH,COD),5.29(m,1H,CH,COD),7.14(m,4H,Ar-H),7.39-7.43(m,6H,Ar-H),7.54(s br,7H,BArF和Ar-H),7.71(s br,9H,BArF和Ar-H),7.76(m,1H,Ar-H)ppm.
31P-NMR(161.9MHz,CDCl3,300K):δ=91.1ppm.
实施例D7:含有次亚膦酸酯C7的铱络合物D7
用次亚膦酸酯C7(80mg,0.17mmol)、[Ir(COD)Cl]2(63mg,0.0935mmol)和NaBArF(159mg,0.17mmol)重复实施例D1的方法,得到络合物D7(175mg,63%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.67(s,9H,C(CH3)3),1.30(s,3H,CH3),1.53(m,1H,CH2,COD),1.70(m,1H,CH2,COD),2.0(m,2H,CH2,COD),2.37(m,2H,CH2,COD),2.51(s,3H,CH3),2.61(m,3H,CH2和CH,COD),3.60(m,2H,CH(COD),CH2(Im)),3.84(s,3H,OCH3),3.85(m,1H,CH,Im),3.87(d,J=7.6Hz,1H,CH2,Im),5.03(m,1H,CH,COD),5.28(m,1H,CH,COD),6.92(d,J =8.8Hz,2H,4-MeOPh),7.05(m,2H,Ar-H),7.15(dxd,J=11.0Hz,2H,4-MeOPh),7.39(s br,4H,BArF,Ar-H),7.52(s br,7H,BARF,Ar-H),7.71(s br,8H,BArF)ppm.
31P-NMR(161.9MHz,CDCl3,300K):δ=91.1ppm.
实施例D8:含有次亚膦酸酯C8的铱络合物D8
用次亚膦酸酯C8(40mg,0.082mmol)、[Ir(COD)Cl]2(30mg,0.045mmol)和NaBArF(77mg,0.082mmol)重复实施例D1的方法,得到络合物D8(50mg,0.030mmol,37%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.88(s br,9H,C(CH3)3),1.26(s,3H,邻甲苯基),1.52(s,3H,o-tolyl),1.66(m,1H,COD),1.90-2.20(m,6H,COD),2.29(m,1H,COD),2.31(s,3H,CH3),2.35(s,3H,CH3),2.55(m,2H,COD),3.72(m,1H,Im),3.78(s,3H,OCH3),3.82(m,2H,Im),4.91(m,1H,CH,COD),5.33(m,1H,CH,COD),6.89(d,J=8.8Hz,2H,间,4-MeOPh),7.00-7.30(m,9H,Ar-H),7.40(t,J=8.0Hz,1H,Ar-H),7.52(s,br,4H,BArF),7,72(s,br,8H,BArF)ppm.
31P-NMR(161.9MHz,CDCl3,300K):δ=101.8ppm.
实施例D9:含有次亚膦酸酯C9的铱络合物D9
用次亚膦酸酯C9(213mg,0.34mmol)、[Ir(COD)Cl]2(126mg,0.187mmol)和NaBArF(352mg,0.37mmol)重复实施例D1的方法,得到络合物D9(380mg,62%)。
1H-NMR(500.1MHz,CDCl3,295K):δ=0.78(s,9H,C(CH3)3),1.58(m,1H,CH2,COD),1.85(m,1H,CH2.COD),1.95(m,1H,CH2,COD),2.22(m,1H,CH2,COD),2.37(m,1H,CH2,COD),2.45(m,1H,CH2,COD),2.60(m,2H:1H CH2,COD;CH2的1H,Bn-H),2.65(m,1H,CH2,COD),2.75(m,1H,CH,COD),2.97(d,J=15.0Hz,1H,CH2,Bn-H),3.60(m,4H:CH的1H,COD;CH2的1H,Bn-H;1H of CH,Im;CH2的1H,Im),3.80(s,3H,OCH3),3.88(t,J=11.5Hz,1H,CH2,Im),4.80(dd,J=9.0,3.0Hz,1H,Ph-H)5.36(m,1H,CH,COD),5.37(d,J=12.0Hz,1H,CH2,Bn-H),5.51(m,1H,CH,COD),6.43(dd,J=9.0,3.0Hz,1H,Ar-H),6.61(dd,J=9.0,3.0Hz,1H,Ar-H),6.71(dd,J=9.0Hz,3.0Hz,1H,Ar-H),6.84(m,2H,Ar-H),7.16-7.31(m,9H,Ar-H),7.32(td,J=7.5,1.0Hz,1H,Ar-H),7.51(s br,4H,BArF),7.53-7.59(m,10H,Ar-H),7.72(s br,BH,BArF),7.92(m,2H,Ar-H)ppm.
31P-NMR(161.9MHz,CDCl3,300K):δ=89.6ppm.
实施例D10:含有次亚膦酸酯C10的铱络合物D10
用次亚膦酸酯C10(110mg,0.22mmol)、[Ir(COD)Cl]2(81mg,0.121mmol)和NaBArF(226mg,0.24mmol)重复实施例D1的方法,得到络合物D10(200mg,55%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.69(s,9H,C(CH3)3),1.28(s,3H,CH3),1.53(m,1H,CH2,COD),1.73(m,1H,CH2,COD),1.97(m,1H,CH2,COD),2.07(m,1H,CH2,COD),2.34(m,2H,CH2,COD),2.55(s,3H,CH3),2.55(m,3H,CH和CH2,COD),3.66(m,2H,1H(COD)和1H(Im)),3.80(t,J=11.0Hz,1H,Im),3.87(d,J=11.0Hz,1H,Im),5.00(m,1H,CH,COD),5.28(m,1H,CH,COD),7.14(t,J=9.5Hz,2H,间,Ar-H),7.29(d,J=7.6Hz,2H,Ar-H),7.40(m,3H,Ar-H),7.51(d,J=10.8Hz,7H,BArF和Ar-H),7.71(s br,8H,BArF),7.75(d,J=10.5Hz,4H,Ar-H)ppm.
31P-NMR(161.9MHz,CDCl3,300K):δ=91.7ppm.
19F-NMR(376.4MHz,CDCl3,300K):δ=-64.1(p-CF3-苯基),-63.5(CF3,BArF)ppm.
实施例D11:含有次亚膦酸酯C11的铱络合物D11
用次亚膦酸酯C11(38mg,0.075mmol)、[Ir(COD)Cl]2(28mg,0.0414mmol)和NaBArF(77mg,0.0825mmol)重复实施例D1的方法,得到络合物D11(98mg,0.058mmol,78%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.67(s,9H,C(CH3)3),1.42(d,J=2.0Hz,3H,CH3),1.56(m,1H,CH2,COD),1.72(m,1H,CH2,COD),1.91-2.13(m,2H,CH2,COD),2.37(m,2H,CH2,COD),2.56(s,3H,CH3),2.62(m,3H,CH2和CH,COD),3.59(m,2H,CH(COD),CH2(Im)),3.79-3.90(s,8H,CH,CH2(Im)和OCH3),5.01(m,1H,CH,COD),5.28(m,1H,CH,COD),6.23and 6.27(各s,2H,3,5-DiMeOPh),6.51(t,J=2.3Hz,1H,3,5-DiMeOPh)7.15(m,2H,Ar-H),7.40(m,3H,Ar-H),7.52(m,7H,BArF,Ar-H),7.70-7.81(br,10H,BArF)ppm.
31P-NMR(161.9MHz,CDCl3,300K):δ=91.1ppm.
实施例D12:含有次亚膦酸酯C12的铱络合物D12
用次亚膦酸酯C12(51mg,0.11mmol)、[Ir(COD)Cl]2(41mg,0.061mmol)和NaBArF(114mg,0.122mmol)重复实施例D1的方法,得到络合物C12(54mg,0.033mmol,30%)。
1H-NMR(500.1MHz,CDCl3,295K):δ=0.61(s,9H,C(CH3)3),1.62(m,1H,CH2,COD),1.80(m,1H,CH2,COD),2.01(d,J =2.3Hz,3H,CH3),2.16(m,1H,CH2,COD),2.36(m,1H,CH2,COD),2.40(m,2H,CH2,COD),2.51(s,3H,CH3),2.66(m,3H,CH2和CH,和COD),3.43(m,1H,COD),3.61(m,3H,CH2和CH,Im),4.52(d,J=16.4Hz,1H,PhCH2),4.97(d,J=16.4Hz,1H,PhCH2),5.11(m,1H,CH,COD),5.20(m,1H,CH,COD),5.33(m,1H,COD),7.18-7.47(m,10H,Ar-H),7.51(s br,7H,BArF和Ar-H),7.71(s br,8H,BArF和Ar-H),7.84(m,2H,Ar-H)ppm.
31P-NMR(161.9MHz,CDCl3,300K):δ=93.1ppm.
实施例D13:含有次亚膦酸酯C13的铱络合物D13
用次亚膦酸酯C13(61mg,0.132mmol)、[Ir(COD)Cl]2(49mg,0.073mmol)和NaBArF(135mg,0.145mmol)重复实施例D1的方法,得到络合物D13(153mg,0.093mmol,71%)。
1H-NMR(500.1MHz,CDCl3,295K):δ=0.73和0.74(s,9H,C(CH3)3),1.29(d,J=2.3Hz,3H,CH3),1.63(m,1H,CH2,COD),1.78(m,1H,CH2,COD),1.97-2.17(m,2H,CH2,COD),2.29-2.33(m,3H,CH2,COD),2.45(m,2H,COD),2.60(m,1H,CH2,COD),2.68(m,3H,CH和CH2,COD),3.45-3.97(m,3H,CH2和CH,Im),5.06(m,1H,CH,COD),5.33-5.40(m,3H,CH,COD),7.05(m,1H,Ar-H),7.22(2H,Ar-H),7.42(m,6H,Ar-H),7.51(s br,7H,8ArF和Ar-H),7.71(s br,8H,BArF和Ar-H),7.84(m,4H,Ar-H)ppm.
31P-NMR(161.9MHz,CDCl3,300K):δ=89.9ppm.
实施例D14:含有次亚膦酸酯C14的铱络合物D14
用次亚膦酸酯C14(48mg,0.097mmol)、[Ir(COD)Cl]2(36mg,0.053mmol)和NaBArF(100mg,0.107mmol)重复实施例D1的方法,得到络合物D14(98mg,0.059mmol,61%)。
1H-NMR(400.1MHz,CDCl3,295K):δ=0.75和0.80(s,9H,C(CH3)3),1.16(s,3H,CH3),1.58(m,1H,CH2,COD),1.76(m,1H,CH2,COD),2.00(m,1H,CH2,COD),2.11(m,1H,CH2,COD),2.40(m,2H,CH2,COD),2.50和2.60(各s,共计3H,CH3),2.65(m,3H,CH2和CH,COD),3.64-3.91(m,3H,CH Im和COD),4.12-4.24(m,1H,CH Im),5.06(m,1H,CH,COD),5.38(m,1H,CH,COD),7.16(m,2H,Ar-H),7.28(m,1H,Ar-H),7.39(m,3H,Ar-H),7.46-7.68(m,10H,Ar-H和BArF-H),7.72(s br,8H,BArF),7.78(m,1H,Ar-H),7.96(m,2H,Ar-H)ppm.
31P-NMR(161.9MHz,CDCl3,300K):δ=91.7ppm.
实施例D15:含有次亚膦酸酯C15的铱络合物D15
按照实施例D1的方法,原位将次亚膦酸酯C15与[Ir(COD)Cl]2(65mg,0.097mmol)和NaBArF(182mg,0.195mmol)反应,得到络合物D15(131mg,46%)。
1H-NMR(400.1MHz,CDCl3,295K)δ=0.75-0.89(m,12H,CH3和C(CH3)3),1.11(pt,2H,CH3),1.28(pt,1H,CH3),1.58(m,4H,CH2,COD和Et),1.76(m,1H,CH2,COD),2.00(m,1H,CH2,COD),2.11(m,1H,CH2,COD),2.40(m,2H,CH2,COD),2.65(m,3H,CH2,COD和Et),3.61-4.07(m,3H,CH Im和COD),4.45(m,1H,CH Im),4.98(m,1H,CH,COD),5.37(m,1H,CH,COD),7.06(m,1H,Ar-H),7.15(m,2H,Ar-H),7.39(m,3H,Ar-H),7.46-7.68(m,10H,Ar-H和BArF-H),7.72(s br,8H,BArF),7.78(m,1H,Ar-H),7.96(m,2H,Ar-H)ppm.
31P-NMR(181.9MHz,CDCl3,300K):δ=90.9ppm.
实施例D16:含有次亚膦酸酯C16的铱络合物D16
按照实施例D1的方法,原位将次亚膦酸酯C16与[Ir(COD)Cl]2(14mg,0.021mmol)和NaBArF(39mg,0.042mmol)反应,得到络合物D16(45mg,74%)。
1H-NMR(400.1MHz,CDCl3,295K):δ=0.28和0.55(pt,共计3H,CH3Bu)0.77-2.71(m,31H,CH2和CH3Bu,C(CH3)3,COD),3.61-4.07(m,3H,CH Im和COD),4.41(m,1H,CH Im),5.04(m,1H,CH,COD),5.38(m,1H,CH,COD),7.12(m,3H,Ar-H),7.39(m,3H,Ar-H),7.46-7.68(m,10H,Ar-H和BArF-H),7.72(s br,8H,BArF),7.78(m,1H,Ar-H),7.95(m,2H,Ar-H)ppm.
31P-NMR(161.9MHz,COCl3,300K):δ=92.1和92.8ppm.
实施例D17:含有次亚膦酸酯C17的铱络合物D17
用次亚膦酸酯C17(20mg,0.041mmol)、[Ir(COD)Cl]2(15mg,0.0224mmol)和NaBArF(42mg,0.045mmol)重复实施例D1的方法,得到络合物D17(36mg,0.022mmol,53%)。
1H-NMR(400.1MHz,CDCl3,300K):δ=0.07(d,J=6.6Hz,3H,CH(CH3)2),0.77(d,J=6.8Hz,3H,CH(CH3)2),1.34(d,J=1.8Hz,3H,CH3),1.55-2.67(br m,10H,CH(CH3)2),CH和CH2(COD)),2.44(s,3H,CH3),3.36(m,1H,CH,COD),3.71-3.82(m,9H,CH和CH2(Im),OCH3),5.06(m,1H,CH,COD),5.28(m,1H,CH,COD),6.12和6.24(各s,1H,Ar-H,3,5-DiMeOPh),6.48(t,J=2.3Hz,1H,3,5-DiMeOPh)7.10(m,2H,Ar-H),7.41(m,3H,Ar-H),7.52(m,7H,BArF,Ar-H),7.71(br,8H,BArF),7.85(m,2H,Ar-H)ppm.
31P-NMR(161.9MHz,CDCl3,300K):δ=93.8ppm.
E)应用实施例
实施例E1:反式-α-甲基均二苯乙烯的氢化
将19.4mg(0.1mmol)α-反式-甲基均二苯乙烯与1.6mg(0.002mmol)6h一起溶解于0.5ml二氯甲烷中,并将该溶液移至具有玻璃插件(insert)和磁力搅拌器的钢质高压釜中。随后在室温(RT)下使用50巴的H2将高压釜加压。2小时后,将高压釜减压,除去溶剂,将残留物溶解在庚烷中并经针筒式滤器(CHROMAFIL O-20/15MS 0.2μm,Macherey-Nagel)过滤。该溶液的GC/MS分析(100℃下2分钟,以7℃/分钟的速度升至250℃)表明完全转化。通过手性HPLC测定对映体过量(流速:在20℃下0.5ml/分钟;固定相:Daicel Chiralcel OJ,庚烷/异丙醇为99∶1)为85%(保留时间:13.4分钟(R),20.4分钟(S))。
结果显示在表1中。
表1:
催化剂 | 摩尔% | 时间[小时] | 转化率[%] | 对映体过量[%] |
D1 | 1 | 2 | 30 | 21 |
D2 | 1 | 2 | 72 | 79 |
D3 | 1 | 2 | >99 | 86 |
D4 | 1 | 2 | 38 | 4 |
D6 | 1 | 2 | 92 | 55 |
D7 | 1 | 2 | >99 | 61 |
D8 | 1 | 2 | 42 | 90 |
D10 | 1 | 2 | 97 | 71 |
D11 | 1 | 2 | 15 | 60 |
D12 | 1 | 2 | 8 | 35 |
D13 | 1 | 2 | 39 | 19 |
D14 | 1 | 2 | 31 | 7 |
D15 | 1 | 2 | 18 | 3 |
实施例E2:反式-2-(4-甲氧基苯基)-2-丁烯的氢化
方法类似于实施例E1。通过手性HPLC(Daicel Chiracel OD-H,100%庚烷)测定对映体过量(保留时间:13.8(S),15.5(R))。
结果显示在表2中。
表2:
催化剂 | 摩尔% | 时间[小时] | 转化率[%] | 对映体过量[%] |
D2 | 1 | 2 | >99 | 90 |
D3 | 1 | 2 | >99 | 91 |
D6 | 1 | 2 | 26 | 25 |
D7 | 1 | 2 | 85 | 50 |
D8 | 1 | 2 | >99 | 84 |
D9 | 1 | 2 | 5 | 45 |
D14 | 1 | 2 | >99 | 61 |
D15 | 1 | 2 | >99 | 32 |
D17 | 1 | 2 | >99 | 88 |
实施例E3:顺式-2-(4-甲氧基苯基)-2-丁烯的氢化
方法类似于实施例E1。通过手性HPLC(Daicel Chiracel OD-H,100%庚烷)测定对映体过量(保留时间:13.8(S),15.5(R))。
结果显示在表3a中。
表3a:
催化剂 | 摩尔% | 时间[小时] | 转化率[%] | 对映体过量[%] |
D2 | 1 | 2 | >99 | 94 |
D3 | 1 | 2 | >99 | 92 |
D4 | 1 | 2 | >99 | 4 |
D5 | 1 | 2 | >99 | 82 |
D6 | 1 | 2 | >99 | 55 |
D7 | 1 | 2 | >99 | 61 |
D8 | 1 | 2 | 97 | 76 |
D9 | 1 | 2 | 18 | 17 |
D10 | 1 | 2 | 97 | 71 |
D11 | 1 | 2 | 75 | 73 |
D12 | 1 | 2 | 48 | 40 |
D13 | 1 | 2 | >99 | 32 |
D14 | 1 | 2 | >99 | 45 |
D15 | 1 | 2 | >99 | 7 |
D17 | 1 | 2 | 99 | 89 |
比较实施例:
顺式-2-(4-甲氧基苯基)-2-丁烯的氢化使用类似的次亚膦酸酯-唑啉配体(结构(D)),(Pfaltz等,Adv.Synth.Catal.2003,345,1+2期,33-43页):
S:R’为异丙基,R”为苯基,
T:R’为异丙基,R”为邻甲苯基,
U:R’为叔丁基,R”为邻甲苯基。
结果显示在表3b中。
表3b:
催化剂 | 摩尔% | 时间[小时] | 转化率[%] | 对映体过量[%] |
S(比较) | 1 | 2 | >99 | 89 |
D2 | 1 | 2 | >99 | 94 |
T(比较) | 1 | 2 | >99 | 85 |
D3 | 1 | 2 | >99 | 92 |
U(比较) | 1 | 2 | >99 | 66 |
D8 | 1 | 2 | >99 | 76 |
对映体过量等于90%和高于90%有重要的经济意义,原因是采用仅一步或非常少的重结晶步骤可得到纯的非对映异构体。
实施例E4:2-(4-甲氧基苯基)-1-丁烯的氢化
采用类似于实施例E2的方法进行氢化。
结果显示在表4。
表4:
催化剂 | 摩尔% | 时间[小时] | 转化率[%] | 对映体过量[%] | 温度[℃] | 压力[帕] |
D2 | 1 | 2 | >99 | 44 | 25 | 50 |
D3 | 1 | 2 | >99 | 37 | 25 | 50 |
D6 | 1 | 2 | >99 | 36 | 25 | 50 |
D7 | 1 | 2 | >99 | 36 | 25 | 50 |
D5 | 1 | 2 | >99 | 2 | 25 | 50 |
D10 | 1 | 2 | >99 | 46 | 25 | 50 |
D14 | 1 | 2 | >99 | 22 | 25 | 50 |
D15 | 1 | 2 | >99 | 11 | 25 | 50 |
实施例E5:反式-β-甲基肉桂酸乙酯的氢化
所述方法与实施例E1类似。通过手性HPLC(Daicel ChiracelOB-H,100%庚烷/异丙醇99.5∶0.5)测定对映体过量(保留时间:24.3(S),29.4(R))。
结果显示在表5中。
表5:
催化剂 | 摩尔% | 时间[小时] | 转化率[%] | 对映体过量[%] |
D2 | 1 | 2 | >99 | 85 |
D3 | 1 | 2 | >99 | 91 |
D6 | 1 | 2 | 87 | 30 |
D7 | 1 | 2 | >99 | 31 |
D8 | 1 | 2 | 8 | 3 |
D9 | 1 | 2 | 61 | 48 |
D14 | 1 | 2 | >99 | 24 |
D15 | 1 | 2 | >99 | 23 |
实施例E6:顺式-2-甲基-3-苯基丙烯-2-醇的氢化
所述方法与实施例E1类似。通过手性HPLC(Daicel ChiracelOD-H,100%庚烷/异丙醇95∶5)测定对映体过量(保留时间:15.4(+),17.7(-))。
结果显示在表6中。
表6:
催化剂 | 摩尔% | 时间[小时] | 转化率[%] | 对映体过量[%] |
D2 | 2 | 2 | >99 | 95 |
D3 | 1 | 2 | >99 | 94 |
D6 | 2 | 2 | >99 | 78 |
D14 | 1 | 2 | >99 | 68 |
D15 | 1 | 2 | 65 | 29 |
实施例D7:6-甲氧基-1-甲基-3,4-二氢萘的氢化
所述方法与实施例E1类似。通过手性HPLC(Daicel ChiracelOD-H,100%庚烷)测定对映体过量(保留时间:24.8(R),29.7(S))。
结果显示在表7中。
表7:
催化剂 | 摩尔% | 时间[小时] | 转化率[%] | 对映体过量[%] |
D2 | 1 | 2 | >99 | 88 |
D4 | 1 | 2 | 20 | 70 |
D6 | 1 | 2 | >99 | 83 |
D9 | 1 | 2 | 54 | 14 |
D14 | 2 | 2 | 95 | 71 |
D15 | 2 | 2 | 76 | 25 |
Claims (23)
1.式I和Ia化合物,
其中
X1为仲膦基;
R3为具有1-20个碳原子的烃基、通过碳原子连接并具有2-20个原子和至少一个选自O、S、NH和NR或-SO2-R基团的杂原子的杂烃基;
R为C1-C18-烷基、苯基或苄基;
R4基团各自独立地为氢或具有1-20个碳原子的烃基,或两个R4基团与其连接的碳原子一起形成3-8元烃环;
R01为具有1-20个碳原子的烃基;和
R02和R’02各自为氢原子或独立地具有R01的含义,或
R01和R02与其连接的碳原子一起形成3-8元烃环或杂烃环。
2.权利要求1的化合物,其特征在于作为膦基的X1包含两个相同或两个不同的具有1-22个碳原子的烃基,或所述两个烃原子与所述磷原子一起形成3-8元环。
3.权利要求2的化合物,其特征在于X1为基团-PR1R2,其中R1和R2各自独立地为具有1-20个碳原子的烃基,所述烃基未取代或被卤素、C1-C6-烷基、C1-C6-卤代烷基、C1-C6-烷氧基、C1-C6-卤代烷氧基、(C6H5)3Si、(C1-C12-烷基)3Si或-CO2-C1-C6-烷基;或R1和R2一起形成未取代或C1-C4-烷基或C1-C4-烷氧基取代的1,2-亚甲基、1,3-亚丙基、1,4-亚丁基或1,5-亚戊基。
4.权利要求3的化合物,其特征在于R1和R2为相同或不同的选自以下的基团:支链的C3-C6-烷基、未取代的环戊基或环己基和被1-3个C1-C4-烷基或C1-C4-烷氧基取代的环戊基或环己基、未取代的苄基和被1-3个C1-C4-烷基或C1-C4-烷氧基取代的苄基以及未取代的苯基和被1-3个C1-C4-烷基、C1-C4-烷氧基、-NH2、OH、F、Cl、C1-C4-氟代烷基或C1-C4-氟代烷氧基取代的苯基。
5.权利要求3的化合物,其特征在于R1和R2为相同或不同的选自以下的基团:未取代的苯基和被1-3个C1-C4-烷基、C1-C4-烷氧基或C1-C4-氟代烷基取代的苯基。
6.权利要求1的化合物,其特征在于所述烃基R3为C1-C18-烷基、C3-C12-环烷基或C6-C16-芳基;所述杂烃基R3为C2-C18-杂烷基、包含1-3个选自O、S和NR的杂原子的C3-C12-杂环烷基或C3-C16-杂芳基,R为C1-C4-烷基。
7.权利要求6的化合物,其特征在于所述芳烃基R3为C6-C14-芳基。
8.权利要求7的化合物,其特征在于R3为未取代或被卤素、CF3、OCF3、C1-C4-烷基或C1-C4-烷氧基取代的C6-C10-芳基。
9.权利要求1的化合物,其特征在于R4为选自C1-C18-烷基、C3-C12-环烷基、C6-C16-芳基或C7-C16-芳烷基的烃基。
10.权利要求1的化合物,其特征在于R01为具有至少3个碳原子的α-支化的烷基,且R02和R’02各自为氢。
11.权利要求1的化合物,其特征在于所述化合物具有式Ib和Ic,
其中
X1为-PR1R2,
R1和R2为相同或不同的且特别为相同的选自以下的基团:α-支化的C3-C6-烷基;未取代的C5-C7-环烷基和被1-3个C1-C4-烷基或C1-C4-烷氧基取代的C5-C7-环烷基;未取代的苯基和被1-3个C1-C4-烷基、C1-C4-烷氧基或C1-C4-氟代烷基取代的苯基;以及未取代或被C1-C4-烷基或C1-C4-烷氧基取代的1,2-亚甲基、1,3-亚丙基、1,4-亚丁基和1,6-亚己基;
R3为苄基或C6-C12-芳基,且所述芳基和苄基为未取代或被卤素、C1-C4-烷基、C1-C4-卤代烷基或C1-C4-烷氧基取代;
R4为C1-C6-烷基或苄基,和
R01为α-支化的C3-C8-烷基。
12.一种制备式I和Ia化合物的方法,
其中R01、R02、R’02、R3、R4和X1如权利要求1所定义,且
表示R或S型,其特征在于:
a)在叔胺存在下将式II化合物
其中R8为C1-C8-烷基,Hal为Cl、Br或I,与至少等当量的式III化合物反应,
其中R01和R02如权利要求1所定义,形成式IV化合物,
b)将式IV化合物与至少等当量的卤化剂反应,形成式V化合物,
c)在叔胺的存在下用式R3-NH2(X)的伯胺将式V化合物环化,形成式VI化合物,
d)将式VI化合物与至少两倍当量的式VII或VIIa的有机金属化合物反应,形成式VIII化合物,
R4-X2 (VII), Rr-(X2)2 (VIIa),
其中R4如权利要求1所定义,X2为碱金属或-Me1X3,Me1为Mg或Zn,且X3为Cl、Br或I,
和
e)将式VIII化合物的羟基金属化并随后与式IX的卤代膦反应,得到式Ia或Ib化合物,
X1-Y1 (IX),
其中X1如权利要求1所定义,Y1为Cl、Br或I。
13.式V化合物,
其中R01、R02、R’02、R3和R4如权利要求1所定义,R8为C1-C8-烷基,Hal为Cl、Br或I。
14.权利要求13的化合物,其特征在于Hal为Cl。
15.选自TM8金属的金属络合物,所述络合物以式I和Ia化合物作为配体。
16.权利要求15的金属络合物,其特征在于所述TM金属为铜、银、金、镍、钴、铑、钌、钯、铱和铂。
17.权利要求16的金属络合物,其特征在于所述TM金属为铑、铱、钌、铂和钯。
18.权利要求15的金属络合物,其特征在于所述金属络合物具有式XI和XII,
A1MeLn (XI),(A1MeLn)(z+)(E-)z (XII),
其中
A1为式I或Ia化合物,
L表示相同或不同的单齿、阴离子或非离子配体,或两个L一起表示相同或不同的二齿、阴离子或非离子配体;
当L为单齿配体时,n为2、3或4,或当L为二齿配体时,n为1或2;
z为1、2或3;
Me为选自铑、铱和钌的金属,所述金属的氧化态为0、1、2、3或4;
E-为含氧酸或络酸的阴离子;并且
所述阴离子配体平衡所述氧化态为1、2、3或4的金属的电荷。
19.权利要求18的金属络合物,其特征在于E为-Cl-、-Br-、-I-、ClO4 -、CF3SO3 -、CH3SO3 -、HSO4 -、(CF3SO2)2N-、(CF3SO2)3C-、B(苯基)4 -、B[二(3,5-三氟甲基)苯基]4 -、B[二(3,5-二甲基)苯基]4 -、B(C6F5)4 -、B(4-甲基苯基)4 -、四-(C1-C5-全氟代烷基)铝酸根、BF4 -、PF6 -、SbCl6 -、AsF6 -或SbF6 -。
20.权利要求15的金属络合物,其特征在于具有式XIII和XIV,
[A1Me2YZ](XII), [A1Me2Y]+E1 - (XIV),
其中
A1为式I或Ia化合物;
Me1为铑或铱;
Y表示两种烯烃或二烯;
Z为Cl、Br或I;和
E1 -为含氧酸或络酸的阴离子。
21.权利要求20的金属络合物,其特征在于Y为C2-C12-烯烃、
包含5-12个碳原子的二烯,Z为Cl或Br,E1为BF4 -、ClO4 -、CF3SO3 -、CH3SO3 -、HSO4 -、B(苯基)4 -、B[二(3,5-三氟甲基)苯基]4 -、PF6 -、SbCl6 -、AsF6 -或SbF6 -。
22.一种制备手性有机化合物的方法,在催化剂存在下通过将氢、硼烷或硅烷不对称加成至前手性有机化合物中碳-碳或碳-杂原子多重键上,或将C-亲核试剂不对称加成至烯丙基化合物上,其特征在于所述加成反应在催化量的至少一种权利要求16的金属络合物存在下进行。
23.权利要求15的金属络合物作为通过将氢、硼烷或硅烷不对称加成至前手性有机化合物中碳-碳或碳-杂原子多重键上,或将C-亲核试剂或胺不对称加成至烯丙基化合物上制备手性有机化合物的均相催化剂的用途。
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CN102731572A (zh) * | 2011-04-08 | 2012-10-17 | 中国科学院上海有机化学研究所 | 含全氟烷基的膦配体、其制备方法、应用以及金属络合物 |
CN104072421A (zh) * | 2014-07-14 | 2014-10-01 | 郑州大学 | 一种手性咪唑啉硫配体及其合成方法 |
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GB2466629B (en) * | 2008-12-29 | 2011-08-17 | Schlumberger Holdings | Catalytic hydrogenation |
WO2016051309A1 (en) * | 2014-09-30 | 2016-04-07 | Semiconductor Energy Laboratory Co., Ltd. | Light-emitting element, display device, electronic device, and lighting device |
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DE4243030A1 (de) * | 1992-12-18 | 1994-06-23 | Basf Ag | Iminverbindungen |
WO2001018012A1 (en) * | 1999-09-08 | 2001-03-15 | Boehringer Ingelheim Pharmaceuticals, Inc. | Electronically tuned ligands |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102731572A (zh) * | 2011-04-08 | 2012-10-17 | 中国科学院上海有机化学研究所 | 含全氟烷基的膦配体、其制备方法、应用以及金属络合物 |
CN102731572B (zh) * | 2011-04-08 | 2015-08-05 | 中国科学院上海有机化学研究所 | 含全氟烷基的膦配体、其制备方法、应用以及金属络合物 |
CN104072421A (zh) * | 2014-07-14 | 2014-10-01 | 郑州大学 | 一种手性咪唑啉硫配体及其合成方法 |
CN104072421B (zh) * | 2014-07-14 | 2017-02-15 | 郑州大学 | 一种手性咪唑啉硫配体及其合成方法 |
Also Published As
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ATE390433T1 (de) | 2008-04-15 |
IL173713A0 (en) | 2006-07-05 |
WO2005021562A2 (en) | 2005-03-10 |
US20070010493A1 (en) | 2007-01-11 |
CN100439378C (zh) | 2008-12-03 |
IL173713A (en) | 2010-05-31 |
DE602004012755T2 (de) | 2009-04-09 |
CA2536869A1 (en) | 2005-03-10 |
WO2005021562A3 (en) | 2005-06-16 |
DE602004012755D1 (de) | 2008-05-08 |
EP1658298B1 (en) | 2008-03-26 |
ES2302026T3 (es) | 2008-07-01 |
EP1658298A2 (en) | 2006-05-24 |
IL193064A0 (en) | 2009-02-11 |
JP2007504115A (ja) | 2007-03-01 |
IL193064A (en) | 2010-06-16 |
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