CN108339571A - P-手性源性有机磷化合物 - Google Patents
P-手性源性有机磷化合物 Download PDFInfo
- Publication number
- CN108339571A CN108339571A CN201711458962.1A CN201711458962A CN108339571A CN 108339571 A CN108339571 A CN 108339571A CN 201711458962 A CN201711458962 A CN 201711458962A CN 108339571 A CN108339571 A CN 108339571A
- Authority
- CN
- China
- Prior art keywords
- carom
- harom
- nmr
- compound
- cdcl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000002903 organophosphorus compounds Chemical class 0.000 title abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 132
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 29
- 229910052751 metal Inorganic materials 0.000 claims abstract description 28
- 239000002184 metal Substances 0.000 claims abstract description 27
- 239000000126 substance Substances 0.000 claims abstract description 8
- 229910000085 borane Inorganic materials 0.000 claims description 159
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 152
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 138
- -1 naphthene amino Chemical group 0.000 claims description 81
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 76
- 125000003118 aryl group Chemical group 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 238000006467 substitution reaction Methods 0.000 claims description 28
- 229910052799 carbon Inorganic materials 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 125000003282 alkyl amino group Chemical group 0.000 claims description 14
- 125000004104 aryloxy group Chemical group 0.000 claims description 14
- 229910052794 bromium Inorganic materials 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 229910052740 iodine Inorganic materials 0.000 claims description 11
- ULNVTMFBEVVUMH-UHFFFAOYSA-N P.[Cl] Chemical compound P.[Cl] ULNVTMFBEVVUMH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical group [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000004696 coordination complex Chemical class 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 4
- 150000001491 aromatic compounds Chemical class 0.000 claims description 3
- 150000001924 cycloalkanes Chemical group 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 42
- 230000015572 biosynthetic process Effects 0.000 abstract description 41
- 239000003446 ligand Substances 0.000 abstract description 27
- 238000006555 catalytic reaction Methods 0.000 abstract description 25
- 229910052723 transition metal Inorganic materials 0.000 abstract description 16
- 150000003624 transition metals Chemical class 0.000 abstract description 13
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 abstract description 4
- 239000003905 agrochemical Substances 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 238000006717 asymmetric allylation reaction Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 398
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 242
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 209
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 184
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 155
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 113
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 107
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 93
- 239000000243 solution Substances 0.000 description 93
- 238000002474 experimental method Methods 0.000 description 87
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 80
- 238000005160 1H NMR spectroscopy Methods 0.000 description 79
- 238000004679 31P NMR spectroscopy Methods 0.000 description 78
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 73
- 239000011734 sodium Substances 0.000 description 68
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 66
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 64
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 62
- 239000003208 petroleum Substances 0.000 description 58
- 235000019439 ethyl acetate Nutrition 0.000 description 54
- 239000007787 solid Substances 0.000 description 51
- 239000002904 solvent Substances 0.000 description 50
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 43
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 42
- 239000002585 base Substances 0.000 description 36
- 239000007789 gas Substances 0.000 description 35
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical group [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 34
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 34
- 239000010948 rhodium Substances 0.000 description 34
- 229910052786 argon Inorganic materials 0.000 description 32
- 239000003480 eluent Substances 0.000 description 32
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 31
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 31
- 239000000203 mixture Substances 0.000 description 31
- 238000004440 column chromatography Methods 0.000 description 29
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 238000004128 high performance liquid chromatography Methods 0.000 description 27
- 229910052739 hydrogen Inorganic materials 0.000 description 26
- 238000010898 silica gel chromatography Methods 0.000 description 26
- 239000012074 organic phase Substances 0.000 description 25
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical compound [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 description 24
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 23
- 239000001257 hydrogen Substances 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 19
- 229910052703 rhodium Inorganic materials 0.000 description 19
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 19
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 229920002678 cellulose Polymers 0.000 description 16
- 229960004217 benzyl alcohol Drugs 0.000 description 15
- 235000010980 cellulose Nutrition 0.000 description 15
- 229910052717 sulfur Inorganic materials 0.000 description 15
- 238000007792 addition Methods 0.000 description 14
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 13
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 13
- 150000002431 hydrogen Chemical class 0.000 description 12
- 238000005859 coupling reaction Methods 0.000 description 11
- 150000001335 aliphatic alkanes Chemical class 0.000 description 10
- 229910052698 phosphorus Inorganic materials 0.000 description 10
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 235000019445 benzyl alcohol Nutrition 0.000 description 9
- 239000004305 biphenyl Substances 0.000 description 9
- 235000010290 biphenyl Nutrition 0.000 description 9
- 230000008878 coupling Effects 0.000 description 9
- 238000010168 coupling process Methods 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 9
- 239000007800 oxidant agent Substances 0.000 description 9
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 8
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 8
- 125000002524 organometallic group Chemical group 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 8
- 239000011574 phosphorus Substances 0.000 description 8
- 238000010791 quenching Methods 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- IQVGRXFIVHSDFL-UHFFFAOYSA-N (2-bromophenyl)phosphane Chemical compound PC1=CC=CC=C1Br IQVGRXFIVHSDFL-UHFFFAOYSA-N 0.000 description 7
- WQONPSCCEXUXTQ-UHFFFAOYSA-N 1,2-dibromobenzene Chemical compound BrC1=CC=CC=C1Br WQONPSCCEXUXTQ-UHFFFAOYSA-N 0.000 description 7
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 238000010828 elution Methods 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 6
- GJMJIOGYTAVWAV-UHFFFAOYSA-N [Rh].B(O)(O)O Chemical compound [Rh].B(O)(O)O GJMJIOGYTAVWAV-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- XQJHRCVXRAJIDY-UHFFFAOYSA-N aminophosphine Chemical compound PN XQJHRCVXRAJIDY-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 229910052796 boron Inorganic materials 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- 229910052742 iron Inorganic materials 0.000 description 6
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical group [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 6
- 230000001590 oxidative effect Effects 0.000 description 6
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 6
- 230000000171 quenching effect Effects 0.000 description 6
- 238000006884 silylation reaction Methods 0.000 description 6
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 5
- HCAJAVWKBZKSHA-UHFFFAOYSA-N (2-methoxyphenyl)methyl-phenylphosphane Chemical compound COC1=CC=CC=C1CPC1=CC=CC=C1 HCAJAVWKBZKSHA-UHFFFAOYSA-N 0.000 description 5
- DKFDVEXWZZOMGS-UHFFFAOYSA-N (2-phosphanylphenyl)phosphane Chemical compound PC1=CC=CC=C1P DKFDVEXWZZOMGS-UHFFFAOYSA-N 0.000 description 5
- 150000001450 anions Chemical class 0.000 description 5
- 239000012300 argon atmosphere Substances 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 5
- 230000000903 blocking effect Effects 0.000 description 5
- 239000001913 cellulose Substances 0.000 description 5
- 239000010949 copper Substances 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 150000002894 organic compounds Chemical class 0.000 description 5
- 238000005691 oxidative coupling reaction Methods 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 239000004575 stone Substances 0.000 description 5
- KWGRBVOPPLSCSI-PSASIEDQSA-N (1s,2r)-2-(methylamino)-1-phenylpropan-1-ol Chemical compound CN[C@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-PSASIEDQSA-N 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 4
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 238000005937 allylation reaction Methods 0.000 description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 230000005595 deprotonation Effects 0.000 description 4
- 238000010537 deprotonation reaction Methods 0.000 description 4
- IPZJQDSFZGZEOY-UHFFFAOYSA-N dimethylmethylene Chemical compound C[C]C IPZJQDSFZGZEOY-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000003760 magnetic stirring Methods 0.000 description 4
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 125000004437 phosphorous atom Chemical group 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000006340 racemization Effects 0.000 description 4
- 229910000144 sodium(I) superoxide Inorganic materials 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- WBNGYVVEMNWMQQ-UHFFFAOYSA-N (2-bromophenyl)-phenylphosphane Chemical compound BrC1=CC=CC=C1PC1=CC=CC=C1 WBNGYVVEMNWMQQ-UHFFFAOYSA-N 0.000 description 3
- BBOLNFYSRZVALD-UHFFFAOYSA-N 1,2-diiodobenzene Chemical class IC1=CC=CC=C1I BBOLNFYSRZVALD-UHFFFAOYSA-N 0.000 description 3
- 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 3
- MRWWWZLJWNIEEJ-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-propan-2-yloxy-1,3,2-dioxaborolane Chemical compound CC(C)OB1OC(C)(C)C(C)(C)O1 MRWWWZLJWNIEEJ-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- CLCPOOATTJATQV-UHFFFAOYSA-N PBBr Chemical compound PBBr CLCPOOATTJATQV-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 3
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 230000008676 import Effects 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000001979 organolithium group Chemical group 0.000 description 3
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N pentanal Chemical compound CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 3
- 150000003003 phosphines Chemical class 0.000 description 3
- RYIOLWQRQXDECZ-UHFFFAOYSA-N phosphinous acid Chemical compound PO RYIOLWQRQXDECZ-UHFFFAOYSA-N 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 150000004756 silanes Chemical class 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- KYLUAQBYONVMCP-UHFFFAOYSA-N (2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P KYLUAQBYONVMCP-UHFFFAOYSA-N 0.000 description 2
- AKXKKSAGNHWXPQ-UHFFFAOYSA-N 1,2-dibromo-3,4-dimethylbenzene Chemical class CC1=CC=C(Br)C(Br)=C1C AKXKKSAGNHWXPQ-UHFFFAOYSA-N 0.000 description 2
- RZRZMIXQRKPUNW-UHFFFAOYSA-N 1-(2-diphenylphosphanylphenyl)-2,2-dimethylpropan-1-one Chemical compound CC(C)(C)C(=O)C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RZRZMIXQRKPUNW-UHFFFAOYSA-N 0.000 description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- LAXBNTIAOJWAOP-UHFFFAOYSA-N 2-chlorobiphenyl Chemical group ClC1=CC=CC=C1C1=CC=CC=C1 LAXBNTIAOJWAOP-UHFFFAOYSA-N 0.000 description 2
- 125000006304 2-iodophenyl group Chemical group [H]C1=C([H])C(I)=C(*)C([H])=C1[H] 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KLYCPFXDDDMZNQ-UHFFFAOYSA-N Benzyne Chemical compound C1=CC#CC=C1 KLYCPFXDDDMZNQ-UHFFFAOYSA-N 0.000 description 2
- 229930008564 C01BA04 - Sparteine Natural products 0.000 description 2
- 125000006519 CCH3 Chemical group 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- NIQCNGHVCWTJSM-UHFFFAOYSA-N Dimethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(=O)OC NIQCNGHVCWTJSM-UHFFFAOYSA-N 0.000 description 2
- BALXUFOVQVENIU-GNAZCLTHSA-N Ephedrine hydrochloride Chemical compound Cl.CN[C@@H](C)[C@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-GNAZCLTHSA-N 0.000 description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- SLRCCWJSBJZJBV-UHFFFAOYSA-N alpha-isosparteine Natural products C1N2CCCCC2C2CN3CCCCC3C1C2 SLRCCWJSBJZJBV-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 150000003935 benzaldehydes Chemical class 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 2
- 239000012069 chiral reagent Substances 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 230000000536 complexating effect Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- 229960002534 ephedrine hydrochloride Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 238000007037 hydroformylation reaction Methods 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000006362 organocatalysis Methods 0.000 description 2
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 2
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 150000004714 phosphonium salts Chemical class 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000012264 purified product Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- SLRCCWJSBJZJBV-AJNGGQMLSA-N sparteine Chemical compound C1N2CCCC[C@H]2[C@@H]2CN3CCCC[C@H]3[C@H]1C2 SLRCCWJSBJZJBV-AJNGGQMLSA-N 0.000 description 2
- 229960001945 sparteine Drugs 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 229910052727 yttrium Inorganic materials 0.000 description 2
- QFPIIICNJHDAKC-UHFFFAOYSA-N (2-bromophenyl)-dicyclohexylphosphane Chemical compound BrC1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 QFPIIICNJHDAKC-UHFFFAOYSA-N 0.000 description 1
- PLBNWWUTEQWTAP-UHFFFAOYSA-N (2-methoxyphenyl)methylphosphinous acid Chemical compound COC1=CC=CC=C1CPO PLBNWWUTEQWTAP-UHFFFAOYSA-N 0.000 description 1
- CRPXGEPKDVOTIY-UHFFFAOYSA-N (2-methylphenyl)-phenylphosphane Chemical compound CC1=CC=CC=C1PC1=CC=CC=C1 CRPXGEPKDVOTIY-UHFFFAOYSA-N 0.000 description 1
- 0 *c(c(*)c1*=C)c(*)c(*)c1P(*)* Chemical compound *c(c(*)c1*=C)c(*)c(*)c1P(*)* 0.000 description 1
- NCWDBNBNYVVARF-UHFFFAOYSA-N 1,3,2-dioxaborolane Chemical class B1OCCO1 NCWDBNBNYVVARF-UHFFFAOYSA-N 0.000 description 1
- HTDQSWDEWGSAMN-UHFFFAOYSA-N 1-bromo-2-methoxybenzene Chemical class COC1=CC=CC=C1Br HTDQSWDEWGSAMN-UHFFFAOYSA-N 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 241001076960 Argon Species 0.000 description 1
- IKSGBQXPXOUDJB-UHFFFAOYSA-N COC(CCC1=CC=CC=C1)=O.C(C)(=O)NC1=C(C=CC=C1O)[As](O)(O)=O Chemical class COC(CCC1=CC=CC=C1)=O.C(C)(=O)NC1=C(C=CC=C1O)[As](O)(O)=O IKSGBQXPXOUDJB-UHFFFAOYSA-N 0.000 description 1
- 229910052684 Cerium Inorganic materials 0.000 description 1
- 241000254173 Coleoptera Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000002879 Lewis base Substances 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- YTKHATNFOMQGFZ-UHFFFAOYSA-N Obtusilic acid Natural products CC1C(CCC2(C)CCC3(COC(=O)C=C/c4ccc(O)cc4)C(=CCC5C6(C)CCC(O)C(C)(C)C6CCC35C)C12)C(=O)O YTKHATNFOMQGFZ-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical class C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 229910004161 SiNa Inorganic materials 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 238000001632 acidimetric titration Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000013876 argon Nutrition 0.000 description 1
- 210000003323 beak Anatomy 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 150000005347 biaryls Chemical group 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N binaphthyl group Chemical group C1(=CC=CC2=CC=CC=C12)C1=CC=CC2=CC=CC=C12 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 150000001638 boron Chemical class 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- BWJRMVLPCQPWGR-UHFFFAOYSA-N boron;phosphane Chemical compound [B].P BWJRMVLPCQPWGR-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 1
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 1
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- ZMIGMASIKSOYAM-UHFFFAOYSA-N cerium Chemical compound [Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce] ZMIGMASIKSOYAM-UHFFFAOYSA-N 0.000 description 1
- 210000000080 chela (arthropods) Anatomy 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- YYDZNOUMWKJXMG-UHFFFAOYSA-N chloro(phenyl)phosphane Chemical compound ClPC1=CC=CC=C1 YYDZNOUMWKJXMG-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- CCRCUPLGCSFEDV-UHFFFAOYSA-N cinnamic acid methyl ester Natural products COC(=O)C=CC1=CC=CC=C1 CCRCUPLGCSFEDV-UHFFFAOYSA-N 0.000 description 1
- KUIAJKPVKOXUQO-UHFFFAOYSA-N cyclohexyl(phenyl)phosphane Chemical compound C1CCCCC1PC1=CC=CC=C1 KUIAJKPVKOXUQO-UHFFFAOYSA-N 0.000 description 1
- BSGUKFWHMSPLDO-UHFFFAOYSA-N cyclopenta-1,3-diene cyclopenta-2,4-dien-1-yl(phenyl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.P(c1ccccc1)[c-]1cccc1 BSGUKFWHMSPLDO-UHFFFAOYSA-N 0.000 description 1
- MYCZBBOLTYBTCX-UHFFFAOYSA-N cyclopenta-2,4-dien-1-amine;cyclopenta-1,3-diene;iron(2+) Chemical compound [Fe+2].C=1C=C[CH-]C=1.NC1=CC=C[CH-]1 MYCZBBOLTYBTCX-UHFFFAOYSA-N 0.000 description 1
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- XNYOSXARXANYPB-UHFFFAOYSA-N dicyclohexylborane Chemical compound C1CCCCC1BC1CCCCC1 XNYOSXARXANYPB-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- ZWWQRMFIZFPUAA-UHFFFAOYSA-N dimethyl 2-methylidenebutanedioate Chemical compound COC(=O)CC(=C)C(=O)OC ZWWQRMFIZFPUAA-UHFFFAOYSA-N 0.000 description 1
- FBSAITBEAPNWJG-UHFFFAOYSA-N dimethyl phthalate Natural products CC(=O)OC1=CC=CC=C1OC(C)=O FBSAITBEAPNWJG-UHFFFAOYSA-N 0.000 description 1
- LIKFHECYJZWXFJ-UHFFFAOYSA-N dimethyldichlorosilane Chemical compound C[Si](C)(Cl)Cl LIKFHECYJZWXFJ-UHFFFAOYSA-N 0.000 description 1
- YOTZYFSGUCFUKA-UHFFFAOYSA-N dimethylphosphine Chemical compound CPC YOTZYFSGUCFUKA-UHFFFAOYSA-N 0.000 description 1
- 229960001826 dimethylphthalate Drugs 0.000 description 1
- QKZWXPLBVCKXNQ-ROJLCIKYSA-N dipamp Chemical compound COC1=CC=CC=C1[P@@](C=1C=CC=CC=1)CC[P@@](C=1C(=CC=CC=1)OC)C1=CC=CC=C1 QKZWXPLBVCKXNQ-ROJLCIKYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 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 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- PUNYGFAPYLHNLV-UHFFFAOYSA-N iodo(phenyl)phosphane Chemical group IPC1=CC=CC=C1 PUNYGFAPYLHNLV-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 description 1
- 229960004002 levetiracetam Drugs 0.000 description 1
- 150000007527 lewis bases Chemical class 0.000 description 1
- DBYQHFPBWKKZAT-UHFFFAOYSA-N lithium;benzene Chemical compound [Li+].C1=CC=[C-]C=C1 DBYQHFPBWKKZAT-UHFFFAOYSA-N 0.000 description 1
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 1
- SZAVVKVUMPLRRS-UHFFFAOYSA-N lithium;propane Chemical compound [Li+].C[CH-]C SZAVVKVUMPLRRS-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000001465 metallisation Methods 0.000 description 1
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
- SAWKFRBJGLMMES-UHFFFAOYSA-N methylphosphine Chemical compound PC SAWKFRBJGLMMES-UHFFFAOYSA-N 0.000 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N monoethyl amine Natural products CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- BVXCVHRMIDFOLY-UHFFFAOYSA-N phenylphosphinous acid Chemical compound OPC1=CC=CC=C1 BVXCVHRMIDFOLY-UHFFFAOYSA-N 0.000 description 1
- 125000005538 phosphinite group Chemical group 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 150000003376 silicon Chemical class 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 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
- 150000003613 toluenes Chemical class 0.000 description 1
- 229910001428 transition metal ion Inorganic materials 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
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- 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
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
-
- 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
- B01J31/2282—Unsaturated compounds used as ligands
- B01J31/2286—Alkynes, e.g. acetylides
-
- 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
- B01J31/2282—Unsaturated compounds used as ligands
- B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
- C07B37/04—Substitution
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- 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
- C07F15/0073—Rhodium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F17/00—Metallocenes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic System
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/5022—Aromatic phosphines (P-C aromatic linkage)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/5027—Polyphosphines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/5045—Complexes or chelates of phosphines with metallic compounds or metals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/505—Preparation; Separation; Purification; Stabilisation
- C07F9/5054—Preparation; Separation; Purification; Stabilisation by a process in which the phosphorus atom is not involved
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/505—Preparation; Separation; Purification; Stabilisation
- C07F9/5063—Preparation; Separation; Purification; Stabilisation from compounds having the structure P-H or P-Heteroatom, in which one or more of such bonds are converted into P-C bonds
- C07F9/5072—Preparation; Separation; Purification; Stabilisation from compounds having the structure P-H or P-Heteroatom, in which one or more of such bonds are converted into P-C bonds from starting materials having the structure P-H
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6596—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having atoms other than oxygen, sulfur, selenium, tellurium, nitrogen or phosphorus as ring hetero atoms
-
- 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
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/44—Allylic alkylation, amination, alkoxylation or analogues
-
- 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
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
- B01J2231/645—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of C=C or C-C triple bonds
-
- 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
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/822—Rhodium
-
- 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
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/824—Palladium
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及具有通式(I)的新颖P‑手性源性有机磷化合物。本发明也提供了一种合成所述的式(I)化合物的方法。本发明也涉及如下所示的合成化合物(I)所涉及的具有通式(II)、(III)以及(IV)的中间物。
Description
本申请是申请日为2012年7月10日、申请人为:国家科学研究中心、第戎大学、斯特拉斯堡大学、辛赛勒有限公司、发明名称为“P-手性源性有机磷化合物”的中国专利申请201280044141.2的分案申请。
技术领域
本发明涉及新颖的具有通式(I)的P-手性源性(P-chirogenic)有机磷化合物。本发明也提供了一种合成所述的式(I)化合物的方法。本发明也涉及如下所示的合成化合物(I)所涉及的具有通式(II)、(III)以及(IV)的中间产物。
具有通式(I)的化合物可用作农用化学物和治疗物质,或用作精细化学的试剂或中间物。
并且,本发明涉及包含化合物(I)作为配体的金属络合物。本发明的新颖化合物和络合物用于利用过渡金属络合物的不对称催化或有机催化,尤其用于不对称氢化或烯丙基化。
背景技术
在过去的十年间,不对称有机催化和有机金属催化取得了重大突破并成为在实验室以及工业规模上合成手性物质的首选方法。多种手性催化剂通过磷配体与过渡金属的络合形成。有时,有机磷化合物也可直接用作有机催化剂。在后一种情况中,有机磷衍生物可用作反离子,在不对称反应中在相转移条件下用作有机催化剂或用作路易斯碱。
因为不对称催化不存在“通用”配体,所以新颖手性配体的合成和研究依然是持久发展的领域。
在大多数情况中,不对称反应所用的有机磷化合物衍生自天然物质或可轻易得到的前体(例如联萘酚、酒石酸、氨基酸、烃…),其中碳骨架存在手性。在有机磷有机金属催化剂中,使碳骨架的手性通过磷取代基转移到金属的配位层。不对称反应所用的最常见的手性有机磷化合物(例如Quinap、Binap、XyliPhos或DuPhos)具有轴向手性或平面手性或因为环仍具有手性。
磷中心具有手性(P-手性源性)的有机磷化合物(例如Dipamp或MiniPhos)从工业和立体化学角度讲在有机金属催化中特别令人关注。实际上,他们可根据磷原子上存在的取代基的性质直接将空间和电子明确定义的结构引到金属中心附近。所得到的手性环境比通过从碳骨架转移手性得到的环境更有效。
P-手性源性有机磷化合物作为有机催化剂也受到关注。它们可作为鏻盐、酸碱衍生物或有助于得到低价手性络合物。
但是,P-手性源性有机磷化合物因为难以合成以及对光学活性化合物的解析的微妙步骤而并不常用于不对称催化。
有机磷配体的不对称合成在过去的十年来因为将硼烷作为磷原子的保护基团引入而取得显著进步。有机磷硼烷络合物稳定,通常是结晶化合物,使得在P-中心上或在磷取代基的α或β位置上发生完全的反应。可轻易地发生硼烷去络合反应以定量地得到相应的P(III)-化合物,其中磷中心上的构型被完全保留(Uziel J.,Darcel C.,Moulin D.,Bauduin C.and JugéS.,Tetrahedron:Asymmetry,2001,12,1441-1449)。
现在,P-手性源性有机磷化合物的对映选择性合成基本上通过利用膦硼烷作为亲电或亲核试剂的两种方法达成。
在亲电方法中,次亚膦酸酯硼烷1或氯膦硼烷(VII)可利用从麻黄碱开始的方法制备(JugéS.,Stephan M.,Laffitte J.A.和Genêt J.P.,Tetrahedron Lett.,1990,31,6357-6360;Bauduin C.,Moulin D.,Kaloun E.B.,Darcel C.和JugéS.,J.Org.Chem.,2003,68,4293-4301)。然后,将这些亲电试剂用于制备二茂铁基桥连二膦和甲硅烷基桥连二膦。
在亲核方法中,膦硼烷3的α-位的碳负离子可通过使甲基膦硼烷去质子化或通过在金雀花碱存在下对二甲基膦硼烷进行动态动力学解析得到(Muci A.R.,Campos K.R.和Evans D.A.,J.Am.Chem.Soc.,1995,117,9075-9076;Yamada Y.和Imamoto T.,J.Org.Chem.,1999,64,2988-2989)。这些碳负离子与多种亲电试剂反应得到亚乙基桥连二膦或亚甲基桥连二膦。
另一种亲核方法使用在金雀花碱存在下对外消旋仲膦硼烷的动态动力学解析。在这些条件下得到的磷化锂硼烷4(M=Li)可用于通过形成两个P-C键合成钳配体。金属磷化物硼烷4是合成新颖类型的P-手性源性配体的非常重要的构件。但是,截止到目前,以高立体选择性制备这些化合物局限具有空间位阻取代基(例如叔丁基或金刚烷基)的锂化的实例(Crépy K.V.L.,Imamoto T.,Top.Curr.Chem.,2003,229,1-40;Imamoto T.,J.Synth.Org.Chem.,Jpn.,2007,65,1060-1069)。
因此,仍需要开发合成光学活性膦配体的新颖方法。这些方法应足够灵活,以轻易地得到宽泛的光学活性膦配体库,可以测试这些光学活性膦配体的不对称合成应用。
最近,本申请人开发了一种从氯膦硼烷(VII)开始制备P-手性源性仲膦硼烷(V)的新颖方法。这个新方法基于低温下的卤素/金属交换反应,其以P-原子上的构型完整保留的方式进行(方案1)。中间物磷化物硼烷4的随后质子化得到具有通式(V)的仲膦硼烷并且对映体极度过量(ee>90%)。
方案1
由于对开发新颖的光学活性膦化合物所做的深入研究,申请人发现,从氯膦硼烷(VII)开始,可以得到新颖类型的具有通式(Ⅰ)的配体或有机催化剂,且对映体非常地高度过量(方案2)。得到化合物(Ⅰ)的合成方法通用性强,可得到多种产物并可轻易修饰它们的取代基。
方案2
申请人为制备化合物(Ⅰ)而开发的方法涉及合成邻位具有活化基团的具有通式(IV)的中间物膦硼烷(方案2)。
本发明方法尤其能实现合成富对映体的邻位官能化的膦,例如邻-硼酸酯(o-boronate)、邻-硅烷基膦以及邻-羟甲基。
邻-硼酸膦(O-boronates phosphines)为两亲试剂,也就是具有路易斯酸和碱,并在将其作为配体的合成以及催化领域受到特别关注。就申请人了解,迄今没有关于手性硼烷或硼氢化膦(boranate phosphine)的描述。
手性对映体纯的邻-羟甲基膦因为它们可用作不对称有机催化剂以及在有机金属催化中用作配体也受到特别关注。例如,Nakamura报道了具有羟甲基化螯合链的非-P-手性源性膦用于Ni-催化的偶合反应的用途(Yoshikai N.,Matsuda H.和Nakamura E.,J.Am.Chem.Soc.2009,131,9590-9599)。
Beak等报道了制备具有羟甲基化螯合链的P-手性源性膦的唯一实例(TollefsonM.,Li J.和Beak P.,J.Am Chem.Soc.,1996,118,9052-9061)。其涉及次亚膦酸酯(phosphinite)重排并且合成方法不通用。
邻-羟甲基膦也可用作邻-羟甲基鏻盐的前体,已知其以合成的方式用于Wittig反应(Marcoux D.和Charette A.,Adv.Synth.Catal.2008,350,2967-2974;McNulty J.和Keskar K.,Tetrahedron Letters,2008,49,7054-7057)。也可以想到将邻-羟甲基鏻盐用作新颖的令人关注的有机催化剂。
研究了P-手性源性有机磷化合物(I)作为配体在不对称催化中的应用。特别地讲,化合物(I)可用作过渡金属(例如铑或钯)的配体,所得的络合物可适于不对称催化的氢化、烯丙基化、加氢甲酰基化或羰基化反应。化合物(I)的鏻盐也可用于利用相转移条件的不对称反应(例如氟化或氰化)。
定义
在本发明中,以下术语具有以下意思:
“P-手性源性”指通过使磷中心的两个取代基互换得到原始分子的立体异构体的磷化合物;
“有机磷”:指含有碳-磷键的有机化合物;
“有机催化”,指一种催化形式,藉此化学反应速率通过由碳、氢、硫和有机化合物中所见的其它非金属元素组成的被称为“有机催化剂”的有机的催化剂提高;
“利用过渡金属络合物的催化”,指一种催化形式,藉此化学反应速率通过有机金属化合物提高,也就是通过含有具有大体上共价特征的金属-元素结合的化合物提高。
“亲电偶合”指键形成,例如,P-C,归因于亲电试剂,例如芳炔;
“亲电试剂”指接受来自某个分子的电子对的反应物,该反应物与该分子形成共价结合;
“氧化偶合”指氧化过程导致的键形成;
“氧化试剂”指在氧化还原化学反应中得到电子的反应物;
“烷基”指任何饱和直链或支链烃链,具有1至12个碳原子,优选1至6个碳原子,以及更优选甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基和叔丁基;
“环烷基”,指取代或未取代的环状烷基取代基,例如环丙基、环戊基、或环己基;
“芳基”,指具有一个或多个芳香环的5至20个、优选6至12个碳原子的单环或多环系统(当为两个环时,将其称为联芳基),其中可述及苯基、联苯基、1-萘基、2-萘基、四氢萘基、茚满基和联萘基。术语芳基也意指包含至少一个选自氧、氮或硫原子的杂原子的任意芳香环。芳基可被彼此独立地在羟基、含有1、2、3、4、5或6个碳原子的直链或支链烷基(尤其甲基、乙基、丙基、丁基)、烷氧基或卤素原子(尤其溴、氯和碘)中选择的1至3个取代基取代。
“烃氧基(alcoxy)”,指任意O-烷基或O-芳基;
“烷氧基”,指任意O-烷基;
“环烷氧基”,指任意O-环烷基;
“芳氧基”,指任意O-芳基;
“烷氨基”,指任意N-烷基;
“环烷氨基”,指任意N-环烷基;
“芳氨基”,指任意N-芳基;
“酰基氯”指具有通式RCOCl的有机化合物,其中R表示选自烷基或芳基的取代或未取代基团;
“醛”指具有结构R-CHO的含有甲酰基的有机化合物,其中R表示选自烷基或芳基的取代或未取代基团;
“酮”指具有结构RC(=O)R'的有机化合物,其中R和R’可相同或不同并各自表示选自烷基或芳基的取代或未取代基团;
“卤代硅烷”指任意的卤素取代的硅烷;
“卤代烷烃”指衍生自烷烃并含有一种或多种卤素的化合物;
“卤代膦”指任意的卤素取代的膦;
“金属茂基”指包含被夹在两个环戊二烯基之间的金属的基团,或包含结合到环戊二烯基或类似取代基的π-云的金属的基团;
“硼酸盐试剂”指衍生自硼的试剂,尤其硼烷、硼烷络合物、硼酸酯或卤代硼烷;
“膦硼烷”,指膦与硼烷(BH3)之间的络合物;
“邻位”在本发明中,指芳香环上与磷原子位置相邻的位置;
“过渡金属盐”指过渡金属离子例如铁、铜、钯或铑与氯、硫酸根、硝酸根、乙酰丙酮酸根(acetocetonate)、四氟硼酸根、六氟磷酸根、六氟锑酸根、三氟甲磺酸根抗衡阴离子缔合的盐;
“过渡金属络合物”指由过渡金属和与之配位(结合)的一种或多种配体(中性或阴离子性的非金属的物质)组成的一种物质;
“o-An”表示邻-茴香基,“o-Tol”表示邻-甲苯基,“cHex”表示环己基,“Fc”表示二茂铁基,“Ph”表示苯基以及“i-Pr”表示异丙基。
发明内容
本发明涉及一种合成具有通式(I)的P-手性源性有机磷化合物的选择性方法,方案3中有此总结。
方案3
因此,本发明涉及一种制备具有式(I)的化合物的方法:
其中
R1和R2可相同或不同并各自表示选自烷基、环烷基、芳基、烷氧基、环烷氧基、芳氧基、烷氨基、环烷氨基、芳氨基、金属茂基的取代或未取代基团;
R3、R4、R5、R6可相同或不同并各自表示氢原子或选自烷基、环烷基、芳基、烷氧基、环烷氧基、芳氧基、烷氨基、环烷氨基、芳氨基的取代或未取代基团;
E表示选自PR7R8、P(BH3)R7R8、-C6H4-PR7R8、-C6H4-P(BH3)R7R8、-BR9R10、-CR11R12OH、-COR11、-SiR11R12R13、-SiR11R12-C6H4-PR7R8的取代或未取代基团;
其中
R7、R8可相同或不同并各自表示氢、选自烷基、环烷基、芳基、烷氧基、环烷氧基、芳氧基、烷氨基、环烷氨基、芳氨基、金属茂基的取代或未取代基团,
R9和R10可相同或不同并各自表示卤素、羟基、选自烷氧基、芳氧基、环烷氧基、烷氨基、芳氨基、环烷氨基、烷基、环烷基或芳基的取代或未取代基团;优选地,R9和R10为[(CH3)2C-O-]2或环己基;在一个优选实施方案中,R9和R10相同;
R11、R12和R13可相同或不同并各自表示氢、选自烷基、环烷基、芳基、烷氧基、芳氧基、环烷氧基的取代或未取代基团;
包括:
i)使氯膦硼烷(VII)
其中R1和R2如上定义,
与试剂RM反应,其中M为金属,优选Li,R为烷基或芳基;
并使此卤素-金属交换的产物与具有通式(VI)的芳香族化合物进一步反应
其中X和Y可相同或不同并各自表示F、Cl、Br、I,并且R3、R4、R5和R6如上定义,
得到相应的具有式(IV)的P-手性源性膦硼烷
其中X、R1、R2、R3、R4、R5和R6如上定义;
以及
ii)使化合物(IV)进行两次化学转化,得到化合物(I),所述的化学转化为移除硼烷基团的步骤(ii-a)以及使亲电试剂在邻位偶合或与氧化试剂在邻位氧化偶合、视情况然后在邻位亲电偶合的步骤(ii-b);步骤(ii-a)和(ii-b)以任意顺序进行。
根据一个实施方案,在本发明的方法中,化合物(VII)、(IV)和(I)是这样的:当R1是Me或tBu时,则R2不分别是tBu或Me。
根据一个实施方案,亲电试剂选自包括硼酸盐试剂、醛、酮、酰基氯、卤代硅烷、卤代烷烃、卤代膦或次亚膦酸酯的组。
根据另一个实施方案,氧化试剂选自包括过渡金属盐、过渡金属络合物的组,其中金属选自包括铁、铜的组。
根据一个实施方案,化合物(VII)是手性的。
根据一个实施方案,化合物(IV)先在步骤(ii-a)的条件下反应,得到具有通式(II)的中间化合物,
其中R1、R2、R3、R4、R5、R6以及X如上定义。
根据一个实施方案,化合物(IV)先在步骤(ii-b)的条件下反应,得到具有通式(III)的中间化合物,
其中R1、R2、R3、R4、R5、R6和E如上定义。
根据另一个实施方案,化合物(IV)先在步骤(ii-a)的条件下反应,得到具有通式(II)的中间化合物,并且其中化合物(II)然后在氧化剂和过量化合物(II)存在下,在步骤(ii-b)的条件下反应,得到具有通式(I’)的自身偶合的化合物
其中R1、R2、R3、R4、R5和R6如上定义。
本发明也涉及具有通式(I)的化合物
其中
E表示选自PR7R8、P(BH3)R7R8、-C6H4-PR7R8、-C6H4-P(BH3)R7R8、-BR9R10、-CR11R12OH、-COR11、-SiR11R12R13、-SiR11R12-C6H4-PR7R8的取代或未取代基团;
其中
R7、R8可相同或不同并各自表示氢、选自烷基、环烷基、芳基、烷氧基、环烷氧基、芳氧基、烷氨基、环烷氨基、芳氨基、金属茂基的取代或未取代基团;
R9和R10可相同或不同并各自表示卤素、羟基、选自烷氧基、芳氧基、环烷氧基、烷氨基、芳氨基、环烷氨基、烷基、环烷基或芳基的取代或未取代基团;优选地,R9和R10是[(CH3)2C-O-]2或环己基;在一个优选的实施方案中,R9和R10相同;
R11、R12和R13可相同或不同并各自表示氢、选自烷基、环烷基、芳基、烷氧基、芳氧基、环烷氧基的取代或未取代基团;
R1和R2可相同或不同并各自表示选自烷基、环烷基、芳基、烷氧基、环烷氧基、芳氧基、烷氨基、环烷氨基、芳氨基、金属茂基的取代或未取代基团,优选地,R1和R2不同;
R3、R4、R5、R6可相同或不同并各自表示氢原子或选自烷基、环烷基、芳基、烷氧基、环烷氧基、芳氧基、烷氨基、环烷氨基、芳氨基的取代或未取代基团;
条件是如果E是PR7R8或P(BH3)R7R8,
当R1和R2分别是Ph和Me或Me和Ph以及R3、R4、R5和R6各自是氢时,R7和R8分别不是Ph和Me;
当R1和R2分别是Me和C2-C6烷基或C2-C6烷基和Me以及R3、R4、R5和R6各自是氢时,R7和R8不是Me和C2-C6烷基;
当R1和R2各自是tBu以及R3、R4、R5和R6各自是氢时,R7和R8都不是tBu。
在一个实施方案中,如果E是-C6H4-(PR7R8)邻并且R3、R4、R5和R6各自是氢,当{R1,R2}是{Ph,Ph}、{o-Tol,o-Tol}、{Fc,Ph}或{o-An,Ph}时,则{R7,R8}分别不是{Ph,Ph}、{o-Tol,o-Tol}、{Fc,Ph}或{o-An,Ph}。
在一个实施方案中,如果E是CR11R12OH并且R3、R4、R5、R6和R12各自是氢,则{R1,R2,R11}不是{Fc,Ph,tBu}、{o-An,Ph,t-Bu}、{Fc,Ph,Ph}、{o-An,Ph,Ph}、{Ph,Fc,Ph}、{Ph,Fc,tBu}、{Ph,o-An,Ph}、{Ph,o-An,tBu}。
在一个实施方案中,如果E是CR11R12OH并且R3、R4、R5和R6各自是氢,则{R1,R2,R11,R12}不是{Ph,Ph,H,H}、{Ph,Ph,Me,H}、{Ph,Ph,Me,Me}、{Ph,Ph,H,-CHMeNBn2}、{Ph,Ph,H,2-(1-苄基)吡咯烷基}。
在一个实施方案中,如果E是BR9R10并且R3、R4、R5和R6各自是氢,则{R1,R2,[R9,R10]}不是{Ph,Ph,[(CH3)2C-O-]2}、{Me,Me,[(CH3)2C-O-]2}、{Ph,Ph,[-O-CH2-C(CH3)2-CH2-O-]}、{Me,Me,[-O-CH2-C(CH3)2-CH2-O-]}、{Ph,Ph,[-O-CH2-CH2-O-]}、{Me,Me,[-O-CH2-CH2-O-]}。
在一个实施方案中,如果E是-SiR11R12R13并且R3、R4、R5和R6各自为是氢,则{R1,R2,R11,R12,R13}不是{Ph,Ph,Me,Me,Me}、{Me,Me,Me,Me,Me}。
根据一个实施方案,基团R1和R2不同。在此实施方案中,化合物(I)是P-手性源性的。
本发明也涉及具有通式(II)的中间化合物
其中
X表示F、Cl、Br、I;以及
R1、R2、R3、R4、R5和R6如上定义,
条件是当X是Br,R3、R4、R5和R6各自是氢,并且R1是Me或tBu时,R2不分别是tBu或Me。
在一个实施方案中,如果X是Br并且R3、R4、R5和R6各自是氢,则{R1,R2}不是{Ph,Ph}、{o-Tol,o-Tol}、{Fc,Ph}、{o-An,Ph}、或{Ph,o-An}。
根据一个实施方案,基团R1和R2不同。在此实施方案中,化合物(II)是P-手性源性的。
本发明也涉及具有通式(III)的中间化合物
其中R1、R2、R3、R4、R5、R6和E如上定义。
在一个实施方案中,如果E是CR11R12OH并且R3、R4、R5和R6各自是氢,则{R1,R2,R11,R12}不是{Ph,Ph,H,H}。
根据一个实施方案,基团R1和R2不同。在此实施方案中,化合物(III)是手性的。
本发明也涉及具有通式(IV)的中间化合物
其中
X表示F、Cl、Br、I;以及
R1、R2、R3、R4、R5和R6如上定义,
条件是当X是Br,R3、R4、R5和R6各自是氢并且R1是Me或tBu时,R2不分别是tBu或Me。
在一个实施方案中,如果X是Br;并且R3、R4、R5和R6各自是氢,则{R1,R2}不是{Ph,Ph}、{o-Tol,o-Tol}、{iPr,iPr}、{cHex,cHex}、{Me,Me}、{o-An,Ph}、{Fc,Ph}、{iPr,Ph}、{cHex,Ph}、{Ph,Fc}或{Ph,o-An}。
在一个实施方案中,如果X是I并且R3、R4、R5和R6是氢,则{R1,R2}不是{Ph,Ph}、{cHex,cHex}、{Fc,Ph}或{o-An,Ph}。
根据一个实施方案,基团R1和R2不同。在此实施方案中,化合物(IV)是P-手性源性的。
本发明也涉及包含至少一个具有通式(I)、(II)、(III)或(IV)的化合物的金属络合物。在一个实施方案中,本发明的金属络合物包含铑和一种作为配体的具有通式(I)、(II)、(III)或(IV)的化合物,条件是如果配体是下述的具有通式(I)的化合物,即其中R1是Fc,R2是Ph,R3、R4、R5和R6各自是氢并且E是–C6H4-(PR7R8)邻,{R7,R8}不是{Ph,Fc}或{Fc,Ph}。
在一个实施方案中,本发明的金属络合物包含钯和一种作为配体的具有通式(I)、(II)、(III)或(IV)的化合物。
具体实施方式
应注意在所提及的任意反应中,底物分子中任意反应基团均可根据传统化学实践加以保护。在所提及的任意反应中的适宜的保护基团为本领域中常使用的那些保护基团。这些保护基团的形成和移除方法为适合于受保护分子的那些传统方法。
步骤(i)-由氯膦硼烷(VII)合成化合物(IV)
化合物(IV)的合成涉及卤素金属交换,然后与具有通式(VI)的芳香族化合物反应:
其中R1、R2、R3、R4、R5、R6和X如上定义。
在一个实施方案中,具有通式(VII)的化合物是这样的:R1是苯基、环己基、甲基、异丙基、邻甲苯基、邻茴香基、金属茂基并且R2如上所述,在此实施方案的一个优选方面中,R2也是苯基、环己基、甲基、异丙基、邻甲苯基、邻茴香基、二茂铁基、并且R1和R2相同或不同。
根据一个优选实施方案,试剂RM是t-BuLi。
在另一个实施方案中,具有通式(VI)的化合物是这样的:X是Br、或I并且Y是Br或I。根据一个实施方案,化合物(VI)中基团X和Y相同。根据一个优选实施方案,X和Y都是溴原子。根据另一个实施方案,X和Y是碘原子。在这些实施方案中,R3、R4、R5和R6优选是H或甲基;更优选地,R4和/或R5是甲基而其它是H。根据一个具体实施方案,化合物(VI)是1,2-二溴苯。
在另一个实施方案中,具有通式(IV)的化合物是这样的:X是Br或I,优选Br,R1是苯基、环己基、甲基、异丙基、邻甲苯基、邻茴香基、二茂铁基并且R2各自表示选自烷基、环烷基、芳基、烷氧基、环烷氧基、芳氧基、烷氨基、环烷氨基、芳氨基、二茂铁基的取代或未取代基团,条件是当R1是Me时,R2不是tBu;优选地,R2是苯基、环己基、甲基、异丙基、邻甲苯基、邻茴香基、二茂铁基;R1和R2相同或不同;R3、R4、R5和R6优选是H或甲基;更优选地,R4和/或R5是甲基而其它是H。
根据一个实施方案,步骤(i)在冷却条件下、在-110℃至-10℃(优选-90℃至-60℃,甚至更优选-78℃)的温度下进行。
根据一个实施方案,卤素金属交换在试剂RM(其中M是金属,优选Li并且R是烷基或芳基)存在下进行。在一个优选实施方案中,RM试剂是tBuLi。
根据一个实施方案,RM试剂是在戊烷、庚烷或THF中的溶液形式。在另一个实施方案中,RM试剂浓度是1.0至2.0M,优选1.6M。
根据一个实施方案,卤素金属交换在2至6当量(优选2至3当量)RM试剂(甚至更优选2.4当量RM试剂)存在下进行。
根据一个实施方案,随后添加具有通式(VI)的芳香族试剂期间所使用的溶剂选自包括四氢呋喃、醚、二甲醚、二烷、苯、甲苯、二甲苯、二甲亚砜或这些溶剂的混合物的组。根据一个优选实施方案,所使用的溶剂是四氢呋喃。
根据一个实施方案,得到不存在外消旋作用的化合物(IV)。根据一个实施方案,得到对映体过量范围在0至100%、优选85至100%的化合物(IV)。
通过酸解氨基膦硼烷(VIII)合成氯膦硼烷(VII)
根据一个实施方案,化合物(VII)可通过酸解具有通式(VIII)的化合物得到
其中R1和R2如上定义。
在一个实施方案中,本发明方法包括酸解化合物(VIII)得到化合物(VII)的初级步骤。
根据一个实施方案,化合物(VIII)的酸解是在2至20当量(优选4至16当量,甚至更优选4.0当量)的酸试剂存在下进行。
根据一个实施方案,酸解所使用的溶剂选自包括四氢呋喃、醚、二甲醚、二烷、苯、甲苯、二甲苯、二甲亚砜或这些溶剂的混合物的组。根据一个优选实施方案,酸解步骤所使用的溶剂是甲苯。
根据一个实施方案,酸解所使用的酸是选自包括H2SO4/NaCl、HBr气体、HI、MsOH、TsOH、无水HCl溶液或其混合物的组的酸。
根据一个实施方案,无水HCl是在选自包括甲苯、二乙醚、二烷、环戊基甲醚、乙酸乙酯、甲醇、乙醇、2-丙醇、丁醇和乙酸的组的溶剂中的溶液形式。在一个优选实施方案中,无水HCl溶于甲苯中。
在一个实施方案中,酸解优选在20℃下进行。
在一个实施方案中,中间化合物(VII)在过滤反应混合物并在减压下移除一半溶剂后分离。
在一个实施方案中,得到不存在外消旋作用的化合物(VII)。根据一个实施方案,得到对映体过量范围在0至100%(优选85至100%)的化合物(VII)。
合成化合物(IV)的另一种途径
在一个实施方案中,步骤(i)还包括使卤素-金属交换产物质子化得到化合物(V)的第一个中间步骤(a)
其中R1和R2可相同或不同并各自表示选自烷基、环烷基、芳基、烷氧基、环烷氧基、芳氧基、烷氨基、环烷氨基、芳氨基、金属茂基的取代或未取代基团,条件是当R1是Me或tBu时,R2不分别是tBu或Me;
并且还包括使化合物(V)与试剂RM(其中M是金属(优选Li)或镁有机化合物MgZ(其中Z是卤化物),并且R是烷基或芳基)反应的第二个中间步骤(b),
然后再使此中间化合物与化合物(VI)反应。
此另一个步骤(i)在以下方案中展示:
这个另一个合成途径的一个意义是化合物(V)可被纯化。这点在化合物(VII)如上所述由化合物(VIII)得到的情况下特别有意义。
根据一个实施方案,本发明方法还包括中间步骤(a)和(b)并且化合物(VII)、(V)、(IV)和(I)是这样的:当R1是Me或tBu时,则R2不分别是tBu或Me。
不希望受理论限制,但提出化合物(VI)在有机金属试剂RM存在下原位形成苯炔中间物。认为苯炔中间物是通过化合物(VI)的基团X和Y与金属M之间的交换、然后消除MX和MY得到。同时,通过有机金属试剂RM使化合物(V)去质子化以形成相应的阴离子。正是该亲电试剂苯炔然后与去质子化化合物(V)反应形成相应的邻位-金属化的膦硼烷,该膦硼烷通过金属与基团X之间的另一次交换转化成(IV)。
在一个实施方案中,具有通式(V)的化合物是这样的:R1是苯基、环己基、甲基、异丙基、邻-甲苯基、邻-茴香基、金属茂基并且R2如上所述;在此实施方案的一个优选方面中,R2也是苯基、环己基、甲基、异丙基、邻-甲苯、邻-茴香基、二茂铁基,并且R1和R2相同或不同。
根据一个优选实施方案,试剂RM是nBuLi。
在另一个实施方案中,具有通式(VI)的化合物是这样的:X是Br,或I并且Y是Br或I。根据一个实施方案,化合物(VI)中基团X和Y相同。根据一个优选实施方案,X和Y都是溴原子。根据另一个实施方案,X和Y是碘原子。在这些实施方案中,R3、R4、R5和R6优选是H或甲基;更优选地,R4和/或R5是甲基并且其它是H。根据一个具体实施方案,化合物(VI)是1,2-二溴苯。
在另一个实施方案中,具有通式(IV)的化合物是这样的:X是Br或I,优选Br,R1是苯基、环己基、甲基、异丙基、邻-甲苯基、邻-茴香基、二茂铁基并且R2各自表示选自烷基、环烷基、芳基、烷氧基、环烷氧基、芳氧基、烷氨基、环烷氨基、芳氨基、二茂铁基的取代或未取代基团的化合物,条件是当R1是Me时,R2不是tBu;优选地,R2是苯基、环己基、甲基、异丙基、邻-甲苯基、邻-茴香基、二茂铁基;R1和R2相同或不同;R3、R4、R5和R6优选地是H或甲基;更优选地,R4和/或R5是甲基并且其它是H。
根据一个实施方案,步骤(i)通常在冷却条件下、在-90℃至50℃(优选-78℃至-60℃)的温度下进行。
根据一个实施方案,步骤(i)通常在0.5至3当量(优选1.1至1.2当量)RM试剂存在下进行。
根据一个实施方案,步骤(i)中所使用的溶剂选自包括四氢呋喃、醚、二甲醚、二烷、苯、甲苯、二甲苯、二甲亚砜或这些溶剂的混合物的组。根据一个优选实施方案,步骤(i)中所使用的溶剂是四氢呋喃。
根据一个实施方案,中间化合物(IV)通过采用层析技术或采用重结晶加以纯化。
根据一个实施方案,得到对映体过量范围在0至100%、优选85至100%的化合物(IV)。
根据一个实施方案,得到不存在外消旋作用的化合物(IV),优选地对映体过量超出85%,优选地超出90%。
步骤(ii)-由化合物(IV)合成化合物(I)
步骤(ii-a)-移除硼烷基团
利用步骤(ii-a)由中间化合物(III)合成化合物(I)以及由中间化合物(IV)合成中间化合物(II)涉及通过移除硼烷保护基团使磷原子去保护。
根据一个实施方案,利用步骤(ii-a)移除硼烷基团通过移除硼烷基团的传统方法进行。根据一个优选实施方案,通过步骤(ii-a)移除硼烷基团利用1,4-二氮杂双环[2.2.2]辛烷(DABCO)作为活性剂、根据Brisset H.,Gourdel Y.,Pellon P.和Le Corre M.,Tetrahedron Lett.,1993,34,4523-4526中所述的步骤进行。根据另一个实施方案,利用步骤(ii-a)移除硼烷基团通过在乙醇、胺或烯烃中使化合物(III)受热并使所得化合物(I)重结晶进行。
根据一个实施方案,通过步骤(ii-a)移除硼烷基团不存在外消旋作用。
在一个实施方案中,利用一锅式步骤,从化合物(VIII)开始得到化合物(II),也就是说,不需要分离中间化合物(VII)和(IV)。
步骤(ii-b)-亲电或氧化偶合
通过步骤(ii-b)由中间化合物(II)合成化合物(I)以及由中间化合物(IV)合成中间化合物(III)涉及亲电偶合或氧化偶合,然后视情况进行亲电偶合。
在一个实施方案中,步骤(ii-b)涉及有机金属试剂RM和亲电试剂。根据另一个实施方案,步骤(ii-b)涉及有机金属试剂RM和氧化剂。根据另一个实施方案,步骤(ii-b)涉及有机金属试剂RM、氧化剂和亲电试剂。
根据一个实施方案,有机金属试剂RM选自包括nBuLi、sBuli、tBuLi、PhLi、格氏试剂(例如i-PrMgCl)的组。根据一个优选实施方案,有机金属试剂RM是nBuLi。
根据一个实施方案,亲电试剂选自包括硼试剂、醛、酮、酰基氯、卤代硅烷、卤代烷烃、卤代膦、次亚膦酸酯、迈克尔受体(例如α,β-不饱和酯、α,β-不饱和酮、α,β-不饱和膦衍生物)的组。根据一个优选实施方案,亲电试剂选自包括ClB(c-Hex)2、PhCHO、tBuCHO、tBuCOCl、(Me)3SiCl、(Me)2SiCl2、MeI、ClP(Ph)2、ClP(c-Hex)2、ClP(i-Pr)2、ClP(o-Tol)2、ClP(p-Tol)2、ClP(p-CF3Ph)2、PhO-P(Ph)(o-Tol)、PhO-P(Ph)(o-An)的组。
根据一个实施方案,氧化剂选自包括过渡金属盐、过渡金属络合物的组,其中金属选自包括铁、铜、铈、钯的组。根据一个优选实施方案,氧化剂选自包括Fe(acac)3、FeCl3、Cu(AcO)2的组。
不希望受理论限制,但提出化合物(IV)或(II)的活性基团X与有机金属试剂RM的金属交换。所得的阴离子与亲电试剂反应,然后得到具有通式(I)或(III)的化合物。该阴离子也可与金属盐反应,得到金属转移加成物,以通过氧化偶合得到自身偶合产物(III)、(I)或(I'),或通过与亲电试剂的反应得到邻位取代的化合物(III)或(I)。当由化合物(IV)或(II)得到的阴离子先与氧化剂反应并且化合物(IV)或(II)过量时,可能会发生自身偶合反应,得到式(I’)的具有联苯桥的二膦衍生物。
根据一个实施方案,在本发明中没有发生自身偶合反应。
根据一个实施方案,步骤(ii-b)通常在-90℃至50℃(优选-78℃至20℃)的温度下进行。
根据一个实施方案,步骤(ii-b)中所使用的溶剂选自包括四氢呋喃、醚、二甲醚、二烷、苯、甲苯、二甲苯、二甲亚砜或这些溶剂的混合物的组。根据一个优选实施方案,步骤(ii-b)中所使用的溶剂是四氢呋喃。
化合物(I)在不对称催化中的用途
本发明的化合物(Ⅰ)用于利用过渡金属络合物的不对称催化或有机催化。尤其是,化合物(Ⅰ)可用于催化的不对称反应,例如氢化、烯丙基化、C-C键形成、加氢甲酰基化或羰基化反应。
根据一个实施方案,化合物(Ⅰ)用作过渡金属(例如铑或钯、钌、铱)的配体。根据本实施方案的过渡金属的络合物适于不对称催化反应,优选烯丙基化或氢化反应。
中间化合物(II)、(III)和(IV)也可用于利用过渡金属络合物的不对称催化、有机催化或立体选择性合成。
实施例
本发明通过以下实施例来进一步阐述,这些实施例仅以阐述的方式给出并且不应被视为限制本发明范围。
A.概括
材料和方法
所有反应在Ar氛围下在无水玻璃仪器中进行。溶剂在Ar氛围下除去水分并刚进行过蒸馏,对于THF、二乙醚、甲苯和苯,用钠/苯甲酮进行,对于CH2Cl2用CaH2进行。用于HPLC的己烷和异丙醇是色谱级,不需进一步纯化而加以使用。仲丁基锂(1.4M,在环己烷中)、叔丁基锂(1.6M,在戊烷中)、异丙基锂(0.7M,在戊烷中)、二茂铁、2-溴苯甲醚、碘甲烷、BH3.SMe2、1,4-二氮杂双环[2.2.2]辛烷(DABCO)、2-异丙氧基-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane)购自Aldrich、Acros或Alfa Aesar,并如接收时般使用。(+)-麻黄碱和(-)-麻黄碱购自Aldrich并利用旋转蒸发仪共沸移除甲苯而加以干燥。HCl的甲苯溶液(0.2-0.4M)通过将HCl气体在甲苯中鼓泡获得并在使用前通过酸量滴定法滴定。(2S,4R,5S)-(-)-3,4-二甲基-2,5-二苯基-1,3,2-唑磷定-2-硼烷(2S,4R,5S)-(-)-3,4-dimethyl-2,5-diphenyl-1,3,2-oxazaphospholidine-2-borane)以及其对映体(2R,4S,5R)-(+)由适宜的(+)-麻黄碱或(-)-麻黄碱制得,如前人所述(S.Jugé,¨Phosphorus,Sulfur and Silicon&Related Compounds,2008,183(2-3),233-248;Darcel C.,Uziel J.and JugéS.,Phosphorus Ligands in Asymetric Catalysisand Applications,A.(Ed.),208,Wiley-VCH;Chaux F.,Frynas S.,Laureano H.,Salomon C.,Morata G.,Auclair M-L.,Stephan M.,Merdès R.,Richard P.,Ondel M-J.,Henry J.C.,Bayardon J.,Darcel C.,JugéS.,C.R.Chimie,2010,13,1213-1226)。
手性HPLC分析在SHIMADZU 10-系列仪器上进行,利用手性柱(Chiralcel OD-H、Chiralcel AD、Chiralcel OJ、Lux 5μ-纤维素-2),并利用己烷/丙-2-醇混合物作为流动相(流速1mL.min-1;UV检测λ=254nm)。薄层层析(TLC)在0.25mm E.Merck预涂覆的硅胶板上进行并经UV曝光、高锰酸钾或碘处理。快速层析利用指示溶剂进行,并采用硅胶60A(35-70μm;Acros)或氧化铝90标准化(Merck)。所有NMR光谱数据通过BRUKER AM 250、300AVANCE、500AVANCE DRX和600AVANCE II分光计在室温下记录。以s=单峰、d=双重峰、t=三重峰、q=四重峰、m=多重峰、brs=宽单峰、brd=宽双峰、dhept=双组七重峰、偶合常数采用赫兹的方式记录数据。熔点利用Kofler bench熔点仪测量,未校正。旋光度值是在20℃下通过Perkin-Elmer 341偏光计记录,采用10cm石英容器。红外光谱是通过Bruker Vector 22仪器记录。质谱和HRMS光谱是通过Mass,Bruker ESI micro TOF-Q仪器、在UniversitédeBourgogne(Dijon)记录。主峰m/z用强度表示为方括号中的基峰的百分比。元素分析在Universités P.&M.Curie(Paris)和Bourgogne的Microanalysis Laboratories(EA1108CHNS-O FISONS Instrument)测量,精确度高于0.3%。X-射线分析在UniversitédeBourgogne进行,在115K下通过Bruker Nonius Apex II CCD系统利用石墨-单色化Mo-Kα辐射收集数据。结构通过直接法(SIR92)解析并利用基于F2的全矩阵最小二乘法借助于WINGX程序精进。所有非氢原子利用各向异性热参数精进。氢原子包括在计算位置中或参见傅立叶差异图(CH3和BH3)。
A.1.氨基膦硼烷的制备
有机锂试剂的制备
通过金属-卤素交换的芳基锂试剂:将1当量仲丁基锂加入配备了磁力搅拌器和氩气进口的双颈烧瓶中。使混合物冷却到0℃,在搅拌下,利用注射器缓慢添加1当量2-溴苯甲醚。形成白色沉淀后,使混合物在0℃下搅拌1小时。有机锂试剂在使用前先溶于最少量的无水THF中。
通过使二茂铁去质子化来制备二茂铁基锂
在氩气氛围下,将二茂铁(0.74g,4mmol)和THF(10mL)加入配备了磁力搅拌器的250mL三颈烧瓶中。在0℃下,逐滴添加t-BuLi(2.75mL,1.6M,在己烷中,4.4mmol),使用前,使反应混合物在0℃下搅拌1小时。
基本步骤
在配备了磁力搅拌器和氩气进口的100mL三颈烧瓶中,将5mmol唑磷烷硼烷络合物溶于5mL无水THF中。使混合物在-78℃下冷却并缓慢地添加2当量(10mmol)有机锂试剂。搅拌所得混合物并回温至0℃(或RT)直到初始物完全反应。利用TLC在硅胶上(CH2Cl2作为洗脱液)监测反应,最后,在0℃下,利用2mL水进行水解。减压下移除THF,并利用二氯甲烷将水层萃取多次。利用MgSO4干燥合并的有机相,并移除溶剂。利用短硅胶柱纯化残余物,利用甲苯/AcOEt 95:5的混合物作为洗脱液,得到氨基膦硼烷。利用己烷/异丙醇7:3混合物使氨基膦硼烷重结晶。
根据公开的步骤,由(-)-麻黄碱制备(Sp)-(+)-N-甲基-N-[(1R,2S)(1-羟基-2-甲基-1-苯基-2-丙基)]氨基-邻-茴香基苯基膦硼烷。
(Sp)-(+)-N-甲基-N-[(1R,2S)(1-羟基-1-苯基-丙-2-基)]氨基二茂铁基苯基膦硼烷
得率=80%;橙色结晶;[α]D 20=+113.9(c 1.0,CHCl3);Rf=0.62(甲苯/EtOAc(9:1));IR(KBr,νcm-1):3500(O-H),2372(B-H),1455,1437,1386,1367,1217,1163,1106,1063,1022,998,956,884,822,763,746,721,698,646,614;1H NMR(CDCl3,300.13MHz)δ0.20-2.00(m,3H),0.91(d,J=6.3Hz,3H),2.05(brs,1H),2.38(d,J=8.4Hz,3H),4.16-4.25(m,1H),4.23-4.27(m,1H),4.30(brs,5H),4.51(d,J=11.7Hz,2H),4.58-4.62(m,1H),4.87(d,J=5.7Hz,1H),7.28-7.46(m,10H);31P NMR(CDCl3,121.5MHz)δ+70.7(m);13C NMR(CDCl3,75.0MHz)δ13.7,31.3,40.3,58.4(d,J=10.6Hz),70.9,71.9,73.0,79.6,127.3,128.4,128.8,128.9,129.1,131.1,132.2(d,J=9.8Hz),143.3;C26H31BFeNOP(471.17)的分析计算值:C 66.28,H 6.63,N 2.97;实验值:C 66.33,H 6.83,N 3.02。
(Rp)-(-)-N-甲基-[(1R,2S)(2-羟基-1-苯基)乙基]-氨基环己基苯基-膦硼烷
得率=87%;白色晶体;m.p.98℃;[α]20 D=-28.5(c=0.7,CHCl3);Rf=0.26(甲苯).IR(KBr,νcm-1)3538(O-H),3029-2857(C-H),2369(B-H),1492,1452,1436,1368,1257,1221,1159,1109,1086,1000,961,887,758,742,695;1H NMR(CDCl3)δ(ppm)0.10-1.60(m,3H,BH3),1.15(d,3H,3JHH=6.9,C-CH3),1.20-1.90(m,10H,CH2),2.27-2.34(m,1H,CyH-P),2.63(d,3H,3JPH=7.2,N-CH3),4.02-4.20(m,1H,CHN),4.80(d,1H,3JHH=4.0,CHO),7.10-7.65(m,10H,H arom.);13C NMR(CDCl3)δ(ppm)12.2(d,JPC=3.8,C-CH3),25.9(CH2),26.6-27.0(CH2),29.3(d,JPC=3.3,N-CH3),32.6(d,1JPC=43.7,CyCH-P),58.3(d,2JPC=8.1,CHN),78.6(d,3JPC=2.3,CHO),126.0(C arom.),127.4(C arom.),128.2(C arom.),128.3(d,JPC=9.4,C arom.),130.5(d,JPC=2.1,C arom.),130.8(d,JPC=55.7,C arom.),131.2(d,JPC=9.1,C arom.),142.5(C arom.);31P NMR(CDCl3)δ(ppm)+73.7(m);MS(EI)m/z(相对强度)368(M+-H;100),356(M++H-BH3;25),312(10),262(15),248(15),209(10),193(25),166(10),148(20);C22H32BNOP[M+-H]的HRMS(DCI,CH4)计算值:368.2315;实验值:368.2319;C22H32BNOP(369.2883)的分析计算值:C 71.55,H 9.01,N 3.79;实验值:C 71.71,H 9.13,N3.67。
(Rp)-(+)-N-甲基-N-[(1R,2S)(1-羟基-1-苯基-丙-2-基]氨基苯基-异-丙基膦硼烷
得率=80%;无色油;[α]D 20=+31.7(c 0.6,CHCl3);Rf=0.25(CH2Cl2);IR(νcm-1):3510(O-H),2974-2874(C-H),2380(B-H),1453,1436,1386,1220,1173,1107,1071,1023,1005,955,914,884,742,727,698,645,619,582;1H NMR(CDCl3,300.13MHz)δ0.10-0.90(m,3H),0.96(dd,J=17.1和7.2Hz,3H),1.03(d,J=6.9Hz,3H),1.09(dd,J=15.3和7.2Hz,3H),2.50(d,J=7.2Hz,3H),2.47-2.61(m,1H),3.97-4.09(m,1H),4.68(d,J=4.8Hz,1H),7.07-7.19(m,3H),7.23-7.37(m,5H),7.46(m,2H);31P NMR(CDCl3,121.5MHz)δ+76.4;13CNMR(CDCl3,75.0MHz)δ12.9(d,J=3.8Hz),17.5(d,J=5.3Hz),22.8(d,J=44.5Hz),29.9(d,J=3.0Hz),59.1(d,J=7.6Hz),79.2(d,J=2.3Hz),126.7,128.1,128.9,129.0(d,J=2.3Hz),131,7(d,J=55.9Hz),131.8(d,J=9.1Hz),143.2;MS(EI)m/z(相对强度)352(M++Na;100),338(M+-BH3+Na;95);C19H29BNNaOP[M+Na]+的HRMS(ESI)计算值:352.1962;实验值:352.1976。
A.2.仲膦硼烷(V)的制备
基本步骤
将6mmol氨基膦硼烷加入配备了磁力搅拌器、氩气进口和橡胶垫片的250mL双颈烧瓶中。然后,在室温下,在搅拌下,添加HCl的甲苯溶液(36mmol,10(ex:i-Pr)-15(ex:Fc)当量),无需先溶解氨基膦硼烷。1至48小时后,利用TLC监测反应进程,通过Millipore 4μm过滤器过滤出盐酸麻黄碱沉淀,通过多次真空/氩气循环移除过量HCl。在-85℃下,在4分钟期间,将叔丁基锂(12mmol,2当量)逐滴加入强烈搅拌的氯化膦硼烷的甲苯溶液中。在-85℃下搅拌5分钟后,在1分钟期间逐滴添加THF(6mL),反应混合物变成深黄色。一次性快速添加乙酸(2.8mL)。反应混合物变成亮白色并快速水解(50mL水)。利用CH2Cl2萃取水相多次。通过MgSO4干燥合并的有机层,移除溶剂。使残余物在硅胶上层析来加以纯化以得到纯仲膦硼烷(V)。
A.2.1.(S)-(-)-邻-茴香基苯基膦硼烷(V-f)
得率=98%(ee=97%);白色固体;Rf=0.50(石油醚/甲苯1:1);[α]20 D=-92(c0.4,CHCl3);IR(νcm-1)3206,3001-2837(C-H),2379和2259(B-H),1588,1575,1477,1463,1454,1438,1433,1296,1278,1247,1186,1159,1134,1112,1084,1072,1061,1042,1023,974,953,912,899,858,797,767,739,728,696;1H NMR(CDCl3):δ(ppm)0.50-1.70(m,3H),3.83(s,3H),6.54(dq,J=396Hz,J=6.8Hz,1H),6.93(dd,J=8.3Hz,J=3.5Hz,1H),7.04-7.08(m,1H)7.36-7.54(m,4H),7.64-7.80(m,3H);13C NMR(CDCl3):δ(ppm)55.9,110.9(d,J=3.9Hz),114.6(d,J=55.6Hz),121.4(d,J=12.4Hz),126.9(d,J=58.3Hz),128.8(d,JPC=10.4Hz),131.2(d,J=2.3Hz),132.9(d,J=9.5Hz),134.0(d,J=2.2Hz),135.0(d,J=13.6Hz),160.7(d,J=1.1Hz);31P NMR(CDCl3):δ(ppm)-15.3;MS(EI)m/z(相对强度)229(M+-H),294(M+-BH3;100),226(15),217(50),186(55),170(10),121(20),56(10);C13H16BNaOP的HRMS(ESI)计算值:253.0924.实验值:253.0926。邻-茴香基苯基膦硼烷(V-f)的对映体过量在Chiralcel OD-H柱上通过HPLC分析确定,洗脱液:己烷/异丙醇98:2,1mL/min,λ=254nm:(R),tR=9.75min;(S)-对映体,tR=10.50min。
A.2.2.(S)-二茂铁基苯基膦硼烷(V-g)
得率=60%(94%ee);橙色油;Rf=0.5(石油醚/甲苯1:1);IR(νcm-1)3200-3000(C-H),2385和2346(BH3),2253,1665,1484,1437,1412,1387,1366,1313,1157,1133,1107,1061,1027,1001,913,886,824,741,696;1H NMR(CDCl3):δ(ppm)0.87-1.67(m,3H),4.29(s,5H),4.49-4.54(m,4H),6.23(qd,J=381Hz,J=6.7Hz,1H),7.42-7.54(m,3H),7.65-7.71(m,2H);13C NMR(CDCl3):δ(ppm)64.1(d,J=67Hz),69.8,72.1(td,J=22.3Hz,J=7.1Hz),73.0(d,J=15Hz),128.0(d,J=57.2Hz),128.7(d,J=10.1Hz),131.1(d,J=2.0Hz),132.1(d,J=9.2Hz);31P NMR(CDCl3):δ(ppm)-6.5。二茂铁基苯基膦硼烷(V-g)的对映体过量在Chiralpack AD柱上通过HPLC分析确定,洗脱液:己烷/异丙醇95:5,1mL/min,λ=254nm:(R),tR=8.64min;(S)-对映体,tR=13.06min。
A.2.3.(R)-(-)-苯基-异-丙基膦硼烷(V-h)
得率=41%(ee=95%);无色油;Rf=0.70(石油醚/乙酸乙酯3/1);[α]20 D=-5.0(c 0.4,CHCl3);IR(νcm-1)3218,2966-2873(C-H),2386-2348(B-H),1439,1117,1070,914,879,656;1H NMR(CDCl3):δ(ppm)0.10-0.90(m,3H),1.19(ddd,J=16.6Hz,J=13.8Hz,J=7.1Hz,6H),2.23-2.28(m,1H),5.26(ddq,J=365.3Hz,J=6.8Hz,J=4.1Hz,1H),7.46-7.56(m,3H),7.66-7.72(m,2H);13C NMR(CDCl3):δ(ppm)17.8(d,J=38.5Hz),23.8(d,J=35.5Hz),124.8(d,J=53.6Hz),128.9(d,J=9.8Hz),131.7(d,J=3.0Hz),133.4(d,J=8.3Hz);31P NMR(CDCl3)δ(ppm):+15.6;MS(EI)m/z(相对强度)191(M-BH3+O+Na+;100);C9H16BNaP的HRMS(ESI)计算值:189.0977;实验值:189.0940。苯基-异-丙基膦硼烷(V-h)的对映体过量在Lux 5u-纤维素2柱上通过HPLC分析确定,洗脱液:己烷/异丙醇99:1,0.5mL/min,λ=210nm:(R),tR=27.06min;(S)-对映体,tR=29.87min。
A.2.4.(R)-环己基苯基膦硼烷(V-i)
得率=91%(95%ee);无色油;Rf=0.75(甲苯);IR(νcm-1)3341,3056,2930-2854(C-H),2388-2251,1486,1450,1437,1346,1293,1272,1203,1179,1123,1059,1047,1028,1002,911,875,845,822,748,702,675,592,508,488,480,429,406;1H NMR(CDCl3):δ(ppm)0.40-1.0(m,3H),1.15-1.40(m,5H),1.68-1.73(m,1H),1.79-1.90(m,4H),1.93-2.02(m,1H),5.23(dqd,J=365Hz,J=6.8Hz,J=4.5Hz,1H),7.47-7.51(m,2H),7.53-7.57(m,1H)7.66-7.70(m,2H);13C NMR(CDCl3):δ(ppm)26.0,26.7-26.8(m),28.1,28.6,33.7(d,J=34.8Hz),125.2(d,J=53.1Hz),129.2(d,J=9.6Hz),131.9,133.8(d,J=7.8Hz);31P NMR(CDCl3)δ(ppm):+11.6;MS(MALDI)m/z(相对强度)229(M+Na+;100),215(M-BH3+Na+;5),193(M–BH3+H+,15);C12H17NaP的HRMS(ESI)计算值:215.0960;实验值:215.0953。环己基苯基膦硼烷(V-i)的对映体过量在Chiralcel OJ柱上通过HPLC分析确定,洗脱液:己烷/异丙醇99:1,1mL/min,λ=210nm:(R),tR=12.54min;(S)-对映体,tR=13.54min。
A.2.5.(S)-(-)-苯基-邻-甲苯基膦硼烷(V-j)
得率=83%,(94%ee);白色油;Rf=0.58(石油醚/甲苯1:1);IR(νcm-1)3444,3058-2854(C-H),2391-2345(B-H),2252,1635-1592,1474,1454,1438,1384,1285,1138,1112,1060,1028,907,806,751,714,698,587,549,510,472,440;1H NMR(CDCl3):δ(ppm)0.50-1.50(m,3H),2.29(s,3H),6.35(dq,J=379Hz,J=6.9Hz,1H),7.18-7.24(m,2H),7.34-7.37(m,3H),7.40-7.43(m,1H),7.50-7.54(m,2H),7.60(ddd,J=13.8Hz,J=7.6Hz,J=0.95Hz,1H);13C NMR(CDCl3):δ(ppm)21.4(d,J=5.4Hz),125.2(d,J=55.8Hz),126.3(d,J=56.1Hz),126.9(d,J=11.8Hz),129.4(d,J=10.2Hz),131.4(d,J=7.7Hz),131.8(d,J=2.8Hz),132.3(d,J=2.6Hz),133.1(d,J=9.3Hz),134.7(d,J=13.8Hz),142.1(d,J=5.3Hz);31P NMR(CDCl3):δ(ppm)-5.4;MS(EI)m/z(相对强度)237(M+Na+,100),223(M-BH3+Na+,40),206(9);C13H16BNaP的HRMS(ESI)计算值:237.09749;实验值:237.09772。苯基-邻-甲苯基膦硼烷(V-j)的对映体过量在Chiralcel OD-H柱上通过HPLC分析确定,洗脱液:己烷/异丙醇98:2,1mL/min,λ=254nm:(R),tR=8.29min;(S)-对映体,tR=8.71min。
B.以一锅式步骤合成(S)-(2-溴苯基)-(2-甲氧基苯基)-苯基膦(II-n)
合成(VII)。将11.0mL(3.30mmol)刚滴定好的无水HCl的甲苯溶液加入0.33g(0.83mmol)(Rp)-N-甲基-[(1R,2S)(2-羟基-1-苯基)乙基]-氨基-邻-茴香基苯基膦硼烷(VIII)中,并使反应系在室温下搅拌1小时。利用Millipore 4μm过滤器过滤出盐酸麻黄碱。
步骤(i)。收集所得的邻-茴香基氯苯基膦硼烷(VII)溶液,将其通过四次真空/氩气循环来脱气并冷却到-80℃。然后,在氩气下,逐滴添加1.20mL(2.00mmol)t-BuLi(1.6M,在戊烷中)并使反应混合物在-80℃下搅拌5分钟。缓慢添加2mL无水THF,然后添加0.14mL(1.16mmol)1,2-二溴苯(VI),并使所得溶液在-78℃下搅拌1小时。然后,添加5mL水并利用二氯甲烷(3x10mL)萃取水相。利用MgSO4干燥合并的有机相,将其过滤并蒸发溶剂,得到残余物(IV-i),在氩气氛围下,利用3mL无水甲苯稀释该残余物(IV-i)。
步骤(ii-a)。添加0.28g(2.49mmol)DABCO,并在室温下,将所得溶液搅拌2小时。真空下使溶剂蒸发,并通过硅胶过柱层析使粗产物(II-i)纯化,将石油醚/乙酸乙酯3:1用作洗脱液。通过在二氯甲烷/甲醇中重结晶得到分析型纯样品。无色固体;总得率51%(0,22g);对映体过量:99%,利用HPLC分析(chiralpak AD,0.2mL.min-1,己烷/2-丙醇99:1,tR(R)=30.8min,tR(S)=35.0min);Rf 0.41(石油醚/乙酸乙酯3:1);mp 128-130℃;[α]D +20.6(c 0.5,CHCl3);IR(纯)3063,2930,2833,1581,1571,1553,1458,1428,1298,1271,1239,1162,1128,1093,1069,1041,1017,864,793,752cm-1;1H NMR(300MHz,CDCl3)δ3.77(s,3H),6.78-6.82(m,1H),6.65-6.70(m,1H),6.87-6.96(m,2H),7.18-7.24(m,2H),7.28-7.43(m,6H),7.58-7.63(m,1H);13C NMR(75.5MHz,CDCl3)δ55.7,110.3(d,J=1.5Hz),121.2,124.5(d,J=12.4Hz),127.3,128.5(d,J=7.4Hz),129.0,130.0,130.1(d,J=32.0Hz),130.6,132.8(d,J=2.4Hz),133.9,134.1,134.4,135.4(d,J=10.5Hz),138.5(d,J=11.4Hz),161.3(d,J=15.8Hz);31P NMR(121MHz,CDCl3)δ-15.3(s);C19H16PBrONa[M+Na]+的HRMS计算值393.0014,实验值393.0006;C19H16PBrO的分析计算值:C,61.48;H,4.34;实验值:C,61.37;H,4.59。
C.从仲膦硼烷(V)开始合成邻-卤代苯基膦硼烷(IV)
表1.化合物(IV)(X=Y并且R4=R5)的合成
a解络作用后分离。b从(-)-麻黄碱开始制备。c从(+)-麻黄碱开始制备。
C.1.邻溴代芳基膦硼烷(IV)的合成:
基本步骤
在氩气中,在-78℃下,将n-BuLi(0.83mmol)逐滴加入仲膦硼烷(V)(0.83mmol)的无水THF(2mL)溶液中。在此温度下,将所得溶液搅拌1小时,然后依序逐滴添加1,2-二溴苯(VI-a)(1.16mmol)和n-BuLi(0.17mmol)。在-78℃下一小时后,反应混合物利用水(10mL)淬火,并利用二氯甲烷(3x10mL)萃取。利用MgSO4干燥有机相,对其进行过滤并蒸发溶剂,得到残余物,然后通过硅胶柱层析和/或通过重结晶来纯化该残余物。
C.1.1.(2-溴苯基)-二苯基膦硼烷(IV-a)
从仲膦硼烷(V-a)开始;纯化:柱层析(利用2:1石油醚/乙酸乙酯洗脱)和/或在己烷/二氯甲烷中重结晶。白色固体;得率:75%;Rf 0.62(石油醚/乙酸乙酯2:1);IR(纯)3052,2924,2854,2814,2379,2340,1558,1480,1436,1424,1128,1106,1058,1025,998,738,690cm-1;1H NMR(300MHz,CDCl3)δ7.20-7.31(m,3H,Harom),7.36-7.49(m,6H,Harom),7.57-7.64(m,5H,Harom);13C NMR(75.5MHz,CDCl3)δ127.3(d,J=9.1Hz,Carom),128.0(d,J=5.9Hz,Carom),128.1(d,J=58.7Hz,Carom),128.8(d,J=10.4Hz,Carom),130.1(d,J=57.3Hz,Carom),131.3(d,J=2.4Hz,Carom),132.7(d,J=2.1Hz,Carom),133.3(d,J=9.6Hz,Carom),135.1(d,5.9Hz,Carom),136.6(d,J=10.1Hz,Carom);31P NMR(121MHz,CDCl3)δ26.6;C18H17PBBrNa(M+Na)+的HRMS计算值379.0221,实验值379.0197;C18H17PBBr的分析计算值:C,60.90;H,4.83;实验值:C,61.06;H,5.13。
C.1.2.(2-溴苯基)-二环己基膦硼烷(IV-b)
从仲膦硼烷(V-b)开始;使用如上的相同步骤,但是在-78℃下添加n-BuLi后,将所得溶液在此温度下搅拌30分钟,然后在室温下搅拌30分钟。
纯化:柱层析(利用3:1石油醚/二氯甲烷洗脱)和/或在甲醇/二氯甲烷中重结晶。白色固体;得率:63%;Rf 0.24(石油醚/二氯甲烷3:1);IR(纯)2930,2851,2379,1446,1418,1274,1061,890,854,758,736cm-1;1H NMR(300MHz,CDCl3)δ1.16-1.37(m,1OH,cHex),1.55-1.70(m,6H,cHex),1.80-1.85(m,2H,cHex),1.93-1.97(m,2H,cHex),2.77-2.85(m,2H,cHex),7.27-7.40(m,2H,Harom),7.60(dt,J=1.8,7.7Hz,Harom),8.07(ddd,J=1.7,7.6,12.6Hz,Harom);13C NMR(75.5MHz,CDCl3)δ25.7(d,J=1.3Hz,CH2),26.8(d,J=9.5Hz,CH2),27.0(d,J=8.5Hz,CH2),27.8(CH2),28.8(CH2),32.9(d,J=32.3Hz,CH),127.1(d,J=3.1Hz,Carom),127.3(d,J=10.9Hz,Carom),128.0(d,J=46.3Hz,Carom),132.4(d,J=2.1Hz,Carom),134.0(d,J=4.4Hz,Carom),140.1(d,J=15.0Hz,Carom);31P NMR(121MHz,CDCl3)δ40.9;C18H29PBrBNa(M+Na)+的HRMS计算值389.1179,实验值389.1157;C18H29PBrB的分析计算值:C,58.89;H,7.96;实验值:C,58.68;H,8.29。
C.1.3.(2-溴苯基)-二甲基膦硼烷(IV-c)
利用上述的相同步骤,从仲膦硼烷(V-c)开始,但是在-78℃下添加n-BuLi后,使所得溶液在此温度下搅拌30分钟,然后在室温下搅拌30分钟。
纯化:柱层析(利用3:1石油醚/乙酸乙酯洗脱)。无色油;得率:42%;Rf0.49(石油醚/乙酸乙酯3:1);IR(纯)3077,2375,2360,2335,1580,1559,1453,1413,1302,1289,1273,1256,1144,1109,1071,1022,946,919,755cm-1;1H NMR(300MHz,丙酮d6)δ1.55(d,J=10.4Hz,6H,CH3),7.24-7.33(m,2H,Harom),7.52-7.59(m,1H,Harom),7.70-7.77(m,1H,Harom);13C NMR(75.5MHz,丙酮d6)δ12.0(d,J=40.1Hz,CH3),127.5(Carom),128.6(d,J=10.9Hz,Carom),131.8(d,J=50.6Hz,Carom),134.2(d,J=2.2Hz,Carom),135.4(d,J=4.7Hz,Carom),137.0(d,J=15.7Hz,Carom);31P NMR(121MHz,丙酮d6)δ11.1-12.5(m);C8H13PBrBNa(M+Na)+的HRMS计算值252.9925,实验值252.9923;C8H13PBrB的分析计算值:C,41.62;H,5.68;实验值:C,41.29;H,6.07。
C.1.4.(2-溴苯基)-二异丙基膦硼烷(IV-d)
利用上述的相同步骤,从仲膦硼烷(V-d)开始,但是在-78℃下添加n-BuLi后,将所得溶液在此温度下搅拌30分钟,然后在室温下搅拌30分钟。
纯化:柱层析(利用3:1石油醚/二氯甲烷洗脱)。白色固体;得率:55%;Rf 0.26(石油醚/二氯甲烷3:1);IR(纯)2974,2932,2871,2393,2373,2349,1574,1557,1453,1422,1389,1370,1261,1110,1071,1046,1021,931cm-1;1H NMR(300MHz,CDCl3)δ0.86(dd,J=7.1,15.9Hz,6H,CH3),1.27(dd,J=7.0,15.8Hz,6H,CH3),2.95-3.09(m,2H,CH),7.22-7.35(m,2H,Harom),7.55(tt,J=1.8,7.7Hz,1H,Harom),8.04(ddd,J=1.5,7.5,12.6Hz,1H,Harom);13C NMR(75.5MHz,CDCl3)δ18.5(d,J=2.8Hz,CH3),18.7(CH3),22.8(d,J=33.1Hz,CH)126.7(d,J=3.1Hz,Carom),127.3(d,J=10.9Hz,Carom),128.7(d,J=46.6Hz,Carom),132.6(d,J=2.2Hz,Carom),134.2(d,J=4.4Hz,Carom),139.8(d,J=14.8Hz,Carom);31PNMR(121MHz,CDCl3)δ48.4-49.9(m);C12H21PBrBNa(M+Na)+的HRMS计算值309.0552,实验值309.0545;C12H21PBrB的分析计算值:C,50.22;H,7.38;实验值:C,50.57;H,7.53。
C.1.5.(2-溴苯基)-二(邻-甲苯基)膦硼烷(IV-e)和游离膦(II-e)
在氩气中,在-78℃下,将n-BuLi(0.83mmol)逐滴加入二-(邻-甲苯基)膦硼烷37e(0.19g,0.83mmol)的无水THF(2mL)溶液中。在此温度下,将所得溶液搅拌1小时,随后依序逐滴添加1,2-二溴苯(VI-a)(0.15mL,1.16mmol)和n-BuLi(0.17mmol)。在-78℃下一小时后,反应混合物利用水(10mL)淬火并利用二氯甲烷(3x10mL)萃取。通过MgSO4干燥有机相,将其过滤并蒸发溶剂,得到残余物(IV-e),在氩气氛围下,利用无水甲苯(5mL)稀释该残余物(IV-e)。添加DABCO(0.28g,2.49mmol),并在室温下将所得溶液搅拌过夜。真空下蒸发溶剂,并通过硅胶柱层析纯化粗制的解络产物(II-e),将石油醚/乙酸乙酯3:1用作洗脱液。白色固体;得率40%;Rf0.59(石油醚/乙酸乙酯3:1);IR(纯)3055,3002,2973,1588,1554,1466,1445,1422,1377,1271,1250,1201,1161,1130,1099,1017,867,746,715cm-1;1H NMR(300MHz,CDCl3)δ2.46(2s,6H,CH3),6.76-6.78(m,3H,Harom),7.12-7.14(m,2H,Harom),7.22-7.24(m,2H,Harom),7.27-7.29(m,2H,Harom),7.32(td,J=1.3,7.4Hz,2H,Harom),7.64-7.66(m,1H,Harom);13C NMR(75.5MHz,CDCl3)δ21.1(CH3),21.3(CH3),126.3(Carom),127.6(Carom),129.0(Carom),130.1(Carom),130.2(d,J=4.6Hz,Carom),130.6(d,J=32.5Hz,Carom),133.1(d,J=2.9Hz,Carom),133.2(Carom),134.0(d,J=11.4Hz,Carom),134.7(Carom),137.7(d,J=10.8Hz,Carom),142.8(d,J=27.4Hz,Carom);31P NMR(121MHz,CDCl3)δ-19.7;C20H18PBrNa(M+Na)+的HRMS计算值391.0222,实验值391.0203;C20H18PBr的分析计算值:C,65.06;H,4.91;实验值:C,65.14;H,5.00。
C.1.6.(2-溴-4,5-二甲基苯基)-二苯基膦硼烷(IV-f)
在氩气中,在-78℃下,将n-BuLi(0.83mmol)逐滴加入二苯基膦硼烷(V-a)(0.17g,0.83mmol)的无水THF(2mL)溶液中。在此温度下,将所得溶液搅拌1小时,然后依序逐滴添加4,5-二溴-邻-二甲苯(VI-b)(0.31g,1.16mmol)和n-BuLi(0.17mmol)。在-78℃下一小时后,反应混合物利用水(10mL)淬火并利用二氯甲烷(3x10mL)萃取。通过MgSO4干燥有机相,将其过滤并蒸发溶剂,得到残余物,然后通过硅胶柱层析纯化该残余物,将石油醚/二氯甲烷3:1用作洗脱液。在二氯甲烷/己烷中重结晶后可得到分析纯样品。白色固体;得率56%;Rf0.45(石油醚/乙酸乙酯3:1);IR(纯)3050,2986,2946,2917,2417,2388,2357,1588,1481,1471,1436,1343,1136,1125,1102,1062,1028,999,923,877,749,734,701,692cm-1;1H NMR(300MHz,CDCl3)δ2.17(s,3H,CH3),2.29(s,3H,CH3),7.21(d,J=12.3Hz,Harom),7.43-7.56(m,7H,Harom),7.65-7.72(m,4H,Harom);13C NMR(75.5MHz,CDCl3)δ19.4(CH3),19.5(CH3),124.7(d,J=4.4Hz,Carom),131.1(d,J=2.5Hz,Carom),133.2(d,J=9.6Hz,Carom),135.9(d,J=6.1Hz,Carom),136.3(d,J=9.9Hz,Carom),137.8(d,J=11.8Hz,Carom),142.6(d,J=2.2Hz,Carom);31P NMR(121MHz,CDCl3)δ25.5;C20H21PBBrNa(M+Na)+的HRMS计算值405.0553,实验值405.0563;C20H21PBBr的分析计算值:C,62.71;H,5.53;实验值:C,62.86;H,5.58。
C.1.7.(R)-(2-溴苯基)-(2-甲氧基苯基)-苯基膦硼烷(IV-i)
从仲膦硼烷(S)-(V-f)开始;纯化:柱层析(利用3:1石油醚/乙酸乙酯洗脱)。白色固体;得率:53%;对映体过量:95%,通过HPLC分析(chiralpak AD,0.2mL.min-1,己烷-2-丙醇99:1,tR(R)=29.4min,tR(S)=32.2min;Rf 0.18(石油醚/乙酸乙酯3:1);[α]D=-1.3(c1.6,CHCl3);IR(纯)3054,2940,2838,2384,1589,1575,1559,1478,1454,1431,1277,1265,1252,1164,1134,1103,1059,1021,854,802,733cm-1;1H NMR(300MHz,CDCl3)δ3.56(s,3H,OCH3),6.94(dd,J=3.8,8.3Hz,1H,Harom),7.08(tdd,J=0.8,2.1,7.5Hz,1H,Harom),7.28-7.33(m,3H,Harom),7.44-7.54(m,4H,Harom),7.60-7.64(m,1H,Harom),7.80-7.87(m,3H,Harom);13C NMR(75.5MHz,CDCl3)δ55.4(OCH3),111.5(d,J=4.6Hz,Carom),116.5(d,J=57.8Hz,Carom),121.5(d,J=12.2Hz,Carom),126.7(d,J=6.4Hz,Carom),127.0(d,J=9.2Hz,Carom),128.3(d,J=59.9Hz,Carom),128.4(d,J=10.5Hz,Carom),131.0(d,J=61.4Hz,Carom),131.1,(d,J=2.4Hz,Carom),131.7(d,J=2.1Hz,Carom),133.8(d,J=1.9Hz,Carom),133.9(d,J=9.8Hz,Carom),134.5,(d,J=6.0Hz,Carom),135.0(d,J=9.8Hz,Carom),135.6(d,J=9.8Hz,Carom),161.2(Carom);31P NMR(121MHz,CDCl3)δ23.7;C19H19PBrBONa(M+Na)+的HRMS计算值407.0346,实验值407.0333;C19H19BBrOP的分析计算值:C,59.27;H,4.97;实验值:C,58.79;H,5.25。
C.1.8.(R)-二茂铁基-(2-溴苯基)-苯基膦硼烷(IV-k)
从仲膦硼烷(S)-(V-g)开始;纯化:在己烷/二氯甲烷中重结晶。橙色固体;得率:47%;对映体过量:99%,通过HPLC分析(chiralcel OD-H,0.5mL.min-1,己烷-2-丙醇98:2,tR(R)=19.6min,tR(S)=23.2min;Rf0.39(石油醚/乙酸乙酯3:1);[α]D=+162.9(c 0.5,CHCl3);IR(纯)3092,3074,3054,2408,2382,2350,1571,1555,1483,1450,1437,1417,1387,1334,1308,1271,1249,1169,1130,1105,1060,1053,1022,998,844,765,753,739,721cm-1;1H NMR(300MHz,CDCl3)δ4.09(sl,5H,Cp),4.14-4.16(m,1H,Cp),4.51-4.53(m,1H,Cp),4.61-4.62(m,1H,Cp),4.84-4.87(m,1H,Cp),7.22-7.31(m,3H,Harom),7.48-7.59(m,4H,Harom),7.73-7.80(m,2H,Harom);13C NMR(75.5MHz,CDCl3)δ69.2(d,J=70.1Hz,Cp),69.9(Cp),72.0(Cp),72.1(d,J=5.0Hz,Cp),72.2(d,J=6.7Hz,Cp),74.7(d,J=14.5Hz,Cp),126.9(d,J=8.6Hz,Carom),127.0(d,J=7.2Hz,Carom),128.5(d,J=10.5Hz,Carom),129.7(d,J=61.4Hz,Carom),131.1(d,J=2.4Hz,Carom),132.1(d,J=2.0Hz,Carom),132.6(d,J=9.8Hz,Carom),132.9(d,J=58.1Hz,Carom),134.7(d,J=5.7Hz,Carom),135.6(d,J=8.8Hz,Carom);31P NMR(121MHz,CDCl3)δ23.3;C22H21PBrBFeNa(M+Na)+的HRMS计算值484.9905,实验值484.9912;C22H21PBrBFe的分析计算值:C,57.08;H,4.57;实验值:C,56.78;H,4.61。
C.1.9.(S)-(2-溴苯基)-苯基异丙基膦硼烷(IV-m)
从仲膦硼烷(R)-(V-h)开始;纯化:柱层析(利用3:1石油醚/乙酸乙酯洗脱)。无色油;得率:48%;对映体过量:95%,通过HPLC分析(lux 5u-纤维素2,0.2mL.min-1,己烷-2-丙醇98:2,tR(S)=35.2min,tR(S)=37.7min;Rf 0.52(石油醚/乙酸乙酯3:1);[α]D=-45.0(c0.3,CHCl3);IR(纯)2971,2932,2872,2381,1576,1453,1436,1417,1271,1254,1108,1065,1039,1024,739,696cm-1;1H NMR(300MHz,CDCl3)δ1.02(dd,J=7.1,17.1Hz,3H,CH3),1.32(dd,J=7.0,16.4Hz,3H,CH3),3.31-3.45(m,1H,CH),7.23-7.40(m,5H,Harom),7.48(ddd,J=1.3,2.5,7.9Hz,1H,Harom),7.55-7.61(m,2H,Harom),8.08(ddd,J=1.6,7.7,12.5Hz,1H,Harom);13C NMR(75.5MHz,CDCl3)δ17.3(d,J=2.3Hz,CH3),18.0(d,J=2.1Hz,CH3),21.3(d,J=35.7Hz,CH),127.4(d,J=10.8Hz,Carom),127.7(Carom),128.3(d,J=55.2Hz,Carom),128.4(Carom),128.5(Carom),129.6(d,J=50.6Hz,Carom),130.6(d,J=2.3Hz,Carom),132.4(Carom),132.6(Carom),132.8(d,J=2.2Hz,Carom),134.6(d,J=4.8Hz,Carom),138.1(d,J=14.6Hz,Carom);31P NMR(121MHz,CDCl3)δ35.0-35.6(m);C15H19PBBrNa(M+Na)+的HRMS计算值343.0396,实验值343.0407;C15H19PBBr的分析计算值:C,56.12;H,5.97;实验值:C,56.50;H,6.16。
C.1.10.(S)-(2-溴苯基)-环己基苯基膦硼烷(IV-n)
从仲膦硼烷(R)-(V-i)开始;纯化:柱层析(利用4:1石油醚/乙酸乙酯洗脱)。白色固体;得率:47%;对映体过量:95%,通过HPLC分析(chiralcel OD-H,0.2mL.min-1,己烷-2-丙醇98:2,tR(S)=26.1min,tR(S)=28.1min;Rf 0.46(石油醚/乙酸乙酯4:1);[α]D=-21.6(c 0.2,CHCl3);IR(纯)2936,2853,2385,2348,1577,1559,1489,1453,1439,1421,1133,1110,1057,1021,1003,762,737cm-1;1H NMR(300MHz,CDCl3)δ1.29-1.50(m,5H,CH2),1.74-1.83(m,3H,CH2),1.90-1.92(m,1H,CH2),2.03-2.05(m,1H,CH2),3.18-3.24(m,1H,CH),7.35(t,J=7.5Hz,1H,Harom),7.41-7.48(m,4H,Harom),7.58(d,J=7.8Hz,1H,Harom),7.65-7.68(m,2H,Harom),8.17-8.20(m,1H,Harom);13C NMR(75.5MHz,CDCl3)δ25.8(d,J=1.5Hz,CH2),26.7(CH2),26.8(CH2),27.0(d,J=12.6Hz,CH2),28.1(CH2),31.3(d,J=34.7Hz,CH),127.4(d,J=11.0Hz,Carom),128.0(d,J=12.6Hz,Carom),128.4(d,J=67.3Hz,Carom),128.5(d,J=9.9Hz,Carom),129.1(d,J=51.1Hz,Carom),130.6(d,J=2.4Hz,Carom),132.4(d,J=8.7Hz,Carom),132.8(d,J=2.2Hz,Carom),134.5(d,J=4.7Hz,Carom),138.3(d,J=15.1Hz,Carom);31P NMR(121MHz,CDCl3)δ31.3-31.6(m);C18H23PBBrNa(M+Na)+的HRMS计算值383.0071,实验值383.0723;C18H23PBBr的分析计算值:C,59.88;H,6.42;实验值:C,66.10;H,6.16。
C.2.邻碘苯基膦硼烷(IV-g,h,j,l)的合成
基本步骤:
在氩气中,在-78℃下,将n-BuLi(0.83mmol)逐滴加入仲膦硼烷(V)(0.83mmol)的无水THF(2mL)溶液中。在此温度下,将所得溶液搅拌1小时,然后依序逐滴添加1,2-二碘苯(VI-c)(1.16mmol)和n-BuLi(0.17mmol)。在-78℃下一小时后,反应混合物利用水(10mL)淬火并利用二氯甲烷(3x10mL)萃取。通过MgSO4干燥有机相,将其过滤并蒸发溶剂,得到残余物,该残余物通过硅胶柱层析和/或通过重结晶进行纯化。
C.2.1.(2-碘苯基)-二苯基膦硼烷(IV-g)
从仲膦硼烷(V-a)开始;纯化:柱层析(利用1:1石油醚/二氯甲烷洗脱)和/或在乙酸乙酯中重结晶。白色固体;得率:50%;Rf 0.45(石油醚/二氯甲烷1:1);IR(纯)3051,2401,2342,2245,1570,1555,1480,1436,1420,1311,1255,1188,1165,1126,1101,1054,1028,999,972,737,688cm-1;1H NMR(300MHz,CDCl3)δ7.13-7.19(m,1H,Harom),7.20-7.27(m,1H,Harom),7.33-7.40(m,1H,Harom),7.46-7.60(m,6H,Harom),7.68-7.75(m,4H,Harom),8.03(ddd,J=1.1,3.2,7.8Hz,1H,Harom);13C NMR(75.5MHz,CDCl3)δ101.2(d,J=8.4Hz,Carom),127.9(d,J=9.0Hz,Carom),128.1(d,J=58.8Hz,Carom),128.9(d,J=10.2Hz,Carom),131.3(d,J=2.4Hz,Carom),132.3(d,J=2.2Hz,Carom),133.3(d,J=58.6Hz,Carom),133.6(d,J=9.5Hz,Carom),136.5(d,J=10.5Hz,Carom),142.7(d,J=7.1Hz,Carom);31P NMR(121MHz,CDCl3)δ30.5;C18H17PIBNa(M+Na)+的HRMS计算值425.0101,实验值425.0096;C18H17PIB的分析计算值:C,53.78;H,4.26;实验值:C,53.97;H,4.36。
C.2.2.(2-碘苯基)-二环己基膦硼烷(IV-h)
利用上述的相同步骤,从仲膦硼烷(V-b)开始,但是在-78℃下添加n-BuLi后,在此温度下,将所得溶液搅拌10分钟,然后在室温下搅拌20分钟。
纯化:柱层析(利用2:1石油醚/二氯甲烷洗脱)。白色固体;得率:56%;Rf 0.33(石油醚/二氯甲烷2:1);IR(纯)2919,2851,2397,2352,1573,1556,1447,1414,1345,1064,1040,1004,918,887,852,818,762,734,714,639cm-1;1H NMR(300MHz,CDCl3)δ1.00-1.17(m,10H,Hcy),1.44-1.56(m,6H,Hcy),1.63-1.67(m,2H,Hcy),1.76-1.80(m,2H,Hcy),2.73-2.85(m,2H,Hcy),6.92(tt,J=1.5,7.5Hz,1H,Harom),7.22(tt,J=1.3,7.5Hz,1H,Harom),7.77(dt,J=1.5,7.9Hz,1H,Harom),7.86(ddd,J=0.9,7.7,12.9Hz,1H,Harom);13C NMR(75.5MHz,CDCl3)δ25.7(d,J=1.2Hz,CH2),26.9(d,J=3.5Hz,CH2),27.1(d,J=2.7Hz,CH2),27.8(CH2),28.7(d,J=1.2Hz,CH2),32.5(d,J=31.8Hz,CH),99.8(d,J=2.3Hz,Carom),127.9(d,J=11.2Hz,Carom),131.2(d,J=47.2Hz,Carom),132.2(d,J=2.2Hz,Carom),140.8(d,J=16.0Hz,Carom),141.7(d,J=5.2Hz,Carom);31P NMR(121MHz,CDCl3)δ41.6;C18H29PIBNa(M+Na)+的HRMS计算值437.1040,实验值437.1012;C18H29PIB的分析计算值:C,52.21;H,7.06;实验值:C,52.19;H,6.98。
C.2.3.(R)-(2-碘苯基)-(2-甲氧基苯基)-苯基膦硼烷(IV-j)和游离膦(II-j)
在氩气中,在-78℃下,将n-BuLi(0.83mmol)逐滴加入仲膦硼烷(S)-(V-f)(0.19g,0.83mmol)的无水THF(2mL)溶液中。在此温度下,使所得溶液搅拌一小时,然后,依序逐滴添加1,2-二碘苯(VI-c)(0.15mL,1.16mmol)和n-BuLi(0.17mmol)。在-78℃下一小时后,反应混合物利用水(10mL)淬火并利用二氯甲烷(3x10mL)萃取。通过MgSO4干燥有机相,将其过滤并蒸发溶剂,得到粗产物(IV-j),在氩气氛围下,利用无水甲苯(5mL)稀释粗产物(IV-j)。添加DABCO(0.28g,2.49mmol),并在室温下,使所得溶液搅拌过夜。真空下使溶剂蒸发,并通过硅胶柱层析纯化粗产物(II-j),将石油醚/乙酸乙酯3:1作为洗脱液。白色固体;得率:42%;对映体过量:95%,通过相应的氧化膦的1H NMR和/或31P NMR,将(R)-3,5-二硝基-N-(1-苯基-乙基)-苯甲酰胺作为手性试剂;Rf 0.45(石油醚/乙酸乙酯3:1);[α]D-24.2(c 0.4,CHCl3);IR(纯)3050,2933,2835,1584,1573,1554,1472,1462,1431,1300,1274,1241,1183,1163,1130,1094,1071,1043,1024,796,753,698cm-1;1H NMR(300MHz,CDCl3)δ3.67(s,3H,OCH3),6.56(ddd,J=1.7,4.4,7.4Hz,1H,Harom),6.72(dt,J=1.9,7.7Hz,1H,Harom),6.77-6.86(m,2H,Harom),6.92(td,J=1.7,7.6Hz,1H,Harom),7.13-7.32(m,7H,Harom),7.81(ddd,J=1.1,3.1,7.8Hz,1H,Harom);13C NMR(75.5MHz,CDCl3)δ55.8(OCH3),107.2(d,J=41.4Hz,Carom),110.4(d,J=1.5Hz,Carom),121.2(Carom),125.0(d,J=12.7Hz,Carom),128.1(Carom),128.5(Carom),128.6(Carom),128.9(Carom),130.0(Carom),130.6(Carom),133.9(Carom),134.1(Carom),134.2(Carom),134.5(Carom),135.8(d,J=10.9Hz,Carom),139.6(d,J=3.8Hz,Carom),141.9(d,J=9.0Hz,Carom),161.2(d,J=15.6Hz,Carom);31P NMR(121MHz,CDCl3)δ1.8;C19H16PIONa(M+Na)+的HRMS计算值440.9876,实验值440.9891;C19H16PIO的分析计算值:C,54.57;H,3.86;实验值:C,54.55;H,3.90。
C.2.4.(R)-二茂铁基-(2-碘苯基)-苯基膦硼烷(IV-l)
从仲膦硼烷(S)-(V-g)开始;纯化:在己烷/二氯甲烷中重结晶。橙色固体;得率55%;对映体过量:99%,通过HPLC分析(chiralcel OD-H,0.5mL.min-1,己烷-2-丙醇98:2,tR(R)=19.2min,tR(S)=25.2min;Rf 0.54(石油醚/乙酸乙酯3:1);[α]D+207.1(c 0.6,CHCl3);IR(纯)3124,3086,3052,2407,2380,2350,1553,1483,1426,1387,1368,1335,1100,1059,1027,1010,821,739,716,693cm-1;1H NMR(300MHz,CDCl3)δ4.07-4.08(m,1H,Cp),4.09(sl,5H,Cp),4.51-4.52(m,1H,Cp),4.62-4.63(m,1H,Cp),7.07(tt,J=1.6,7.5Hz,Harom),7.14(ddd,J=1.7,7.8,11.0Hz,1H,Harom),7.28-7.33(m,2H,Harom),7.50-7.63(m,3H,Harom),7.77-7.83(m,2H,Harom),7.91(ddd,J=1.0,3.1,7.8Hz,1H,Harom);13CNMR(75.5MHz,CDCl3)δ69.8(d,J=70.0Hz,Cp),70.0(Cp),71.7(d,J=3.7Hz,Cp),72.1(d,J=8.4Hz,Cp),72.3(d,J=6.5Hz,Cp),74.9(d,J=14.9Hz,Cp),100.2(d,J=9.8Hz,Carom),127.6(d,J=8.3Hz,Carom),128.6(d,J=10.5Hz,Carom),129.2(d,J=60.8Hz,Carom),131.3(d,J=2.4Hz,Carom),131.7(d,J=2.1Hz,Carom),133.4(d,J=9.5Hz,Carom),135.4(d,J=9.0Hz,Carom),136.0(d,J=58.3Hz,Carom),142.2(d,J=7.1Hz,Carom);31P NMR(121MHz,CDCl3)δ27.5;C22H21PIBFeNa(M+Na)+的HRMS计算值532.9764,实验值532.9747;C22H21PIBFe的分析计算值:C,51.82;H,4.15;实验值:C,52.03;H,4.12。
C.3通过在邻位直接烷基化合成(S)-邻-茴香基苯基-邻-甲苯基膦硼烷:
在氩气中,在-78℃下,将n-BuLi(1.25mmol;2.5当量)逐滴加入仲膦硼烷(V)(0.5mmol)的无水THF(3mL)溶液中。在此温度下,使所得溶液搅拌5分钟,然后,逐滴添加1,2-二溴苯(0.75mmol;1.5当量)。在-78℃下10分钟后,反应混合物利用MeI(0,5mL)淬火并搅拌10分钟。水解(1mL)后,真空下移除溶剂,利用二氯甲烷(3x10mL)萃取残余物。通过MgSO4干燥有机相,将其过滤并蒸发溶剂,得到粗产物40,通过在硅胶上短时间过滤纯化粗产物40。
1H NMR(CDCl3):δ(ppm)0.80-2.0(3H,m),2.30(3H,s),3.57(3H,s),6.9-8.0(13H,m);31P NMR(121MHz,CDCl3)δ+18.6(JPB=56Hz)
但是,后处理后,得到游离膦41以及其硼烷络合物40的混合物。将其溶于乙醇中并搅拌过夜以使解络作用完全。得率=92%;
(S)-(-)-邻-茴香基苯基-邻-甲苯基膦41
白色晶体(EtOH);Rf=0.68(甲苯);1H NMR(CDCl3):δ(ppm)2.33(3H,s),3.68(3H,s),6.53-6.58(1H,m),6.66-6.70(1H,m),6.74-6.85(2H,m),6.95-7.05(1H,m),7.08-7.30(8H,m);13C NMR(CDCl3):δ(ppm)21.2(d,3JP-C=21.3),55.7,110.2(d,JP-C=1.7),121.1,124.7(d,JP-C=11.6,125.9,128.3-128.6,129.9(d,JP-C=4.6),130.3,132.8,133.7,134.0,134.3,135.3-136.0,142.3(d,JP-C=26.0),161.3(d,JP-C=15.7);31P NMR(CDCl3):δ(ppm)-23.1。
41的对映体纯度通过在(+)-二-μ-氯双{2-[1-(二甲氨基)乙基]苯基-C,N}二钯存在下,利用31P NMR,与外消旋样品比较后确定。
D.膦硼烷(IV)解络为膦(II)
表2游离邻-卤代芳基膦(II)的合成
a从相应的仲膦硼烷(V)开始的整体得率。b从(+)-麻黄碱开始制备
一般步骤
将DABCO(1.5mmol)加入邻-溴膦硼烷(IV)(0.5mmol)的甲苯(3mL)溶液中。在氩气中,在室温下,将所得溶液搅拌过夜,然后真空下移除溶剂。通过硅胶快速层析和/或通过重结晶来纯化粗产物(II)。
D.1.(R)-(2-溴苯基)-(2-甲氧基苯基)-苯基膦(II-i)
纯化:柱层析(利用3:1石油醚/乙酸乙酯洗脱)以及在二氯甲烷/甲醇中重结晶。白色固体;得率90%;对映体过量99%,通过HPLC分析(chiralpak AD,0.2mL.min-1,己烷/2-丙醇99:1,tR(R)30.8min,tR(S)35.0min);Rf 0.41(石油醚/乙酸乙酯3:1);[α]D-20.6(c 0.5,CHCl3);IR(纯)3063,2930,2833,1581,1571,1553,1458,1428,1298,1271,1239,1162,1128,1093,1069,1041,1017,864,793,752cm-1;1H NMR(300MHz,CDCl3)δ3.77(s,3H,OCH3),6.78-6.82(m,1H,Harom),6.65-6.70(m,1H,Harom),6.87-6.96(m,2H,Harom),7.18-7.24(m,2H,Harom),7.28-7.43(m,6H,Harom),7.58-7.63(m,1H,Harom);13C NMR(75.5MHz,CDCl3)δ55.7(OCH3),110.3(d,J=1.5Hz,Carom),121.2(Carom),124.5(d,J=12.4Hz,Carom),127.3(Carom),128.5(d,J=7.4Hz,Carom),129.0(Carom),130.0(Carom),130.1(d,J=32.0Hz,Carom),130.6(Carom),132.8(d,J=2.4Hz,Carom),133.9(Carom),134.1(Carom),134.4(Carom),135.4(d,J=10.5Hz,Carom),138.5(d,J=11.4Hz,Carom),161.3(d,J=15.8Hz,Carom);31P NMR(121MHz,CDCl3)δ-15.3(s);C19H16PBrONa[M+Na]+的HRMS计算值393.0014,实验值393.0006;C19H16PBrO的分析计算值:C,61.48;H,4.34;实验量:C,61.37;H,4.59。
D.2.(R)-(2-溴苯基)-二茂铁基-苯基膦(II-k)
纯化:柱层析(利用3:1石油醚/乙酸乙酯洗脱)。橙色固体;得率75%;对映体过量(与BH3络合后):99%,通过HPLC分析(chiralcel OD-H,0.5mL.min-1,己烷/2-丙醇98:2,tR(R)19.6min,tR(S)23.2min);Rf 0.50(石油醚/乙酸乙酯3:1);[α]D 20+207.1(c 0.6;CHCl3)IR(纯)3104,3045,2926,2855,1741,1552,1481,1446,1436,1420,1308,1270,1248,1192,1163,1108,1098,1016,1003,890,821,748,698cm-1;1H NMR(300MHz,CDCl3)δ3.60-3.61(m,1H,Hfer),3.98(br.s,5H,Hfer),4.21-4.23(m,1H,Hfer),4.29-4.31(m,1H,Hfer),4.36-4.39(m,1H,Hfer),6.84(dt,J=2.1,7.4Hz,1H,Harom),7.06-7.19(m,2H,Harom),7.28-7.32(m,3H,Harom),7.34-7.42(m,3H,Harom);13C NMR(75.5MHz,CDCl3)δ69.9(Cfer),71.7(Cfer),72.3(Cfer),72.4(d,J=7.1Hz,Cfer),75.3(d,J=31.8Hz,Cfer),76.5(d,J=7.6Hz,Cfer),128.1(Carom),129.0(d,J=8.0Hz,Carom),129.4(d,J=30.3Hz,Carom),129.9(Carom),130.9(Carom),133.6(d,J=1.7Hz,Carom),134.8(d,J=1.5Hz,Carom),135.2(d,J=20.6Hz,Carom),137.3(d,J=8.6Hz,Carom),142.6(d,J=14.8Hz,Carom);31PNMR(121MHz,CDCl3)δ-16.6(s);C22H18PBrFe[M]+的HRMS计算值447.9675,实验值447.9686;C22H18PBrFe的分析计算值:C,58.84;H,4.04;实验值:C,59.19;H,4.05。
D.3.(S)-(2-溴苯基)-异丙基-苯基膦(II-m)
纯化:柱层析(利用3:1石油醚/乙酸乙酯洗脱)。无色油;得率:82%;对映体过量(与BH3络合后):95%,通过HPLC分析(lux 5μ纤维素-2,0.2mL.min-1,己烷/2-丙醇98:2,tR(S)39.6min,tR(R)42.3min);Rf 0.59(石油醚/乙酸乙酯3:1);[α]D 20-52.9(c 0.4;CHCl3)IR(纯)3054,2952,2865,1556,1449,1421,1384,1365,1250,1228,1155,1124,1096,1018,878,746,697cm-1;1H NMR(300MHz,CDCl3)δ1.06(dd,J=6.8,15.5Hz,3H,CH3),1.20(dd,J=6.9,16.0Hz,3H,CH3),2.41-2.47(m,1H,CH),7.19-7.22(m,1H,Harom),7.32-7.35(m,3H,Harom),7.37(td,J=1.3,7.6Hz,1H,Harom),7.46-7.50(m,3H,Harom),7.59(ddd,J=1.2,3.4,8.0Hz,1H,Harom);13C NMR(75.5MHz,CDCl3)δ19.3(d,J=19.6Hz,CH3),19.8(d,J=19.6Hz,CH3),25.3(d,J=9.1Hz,CH),127.3(Carom),128.3(2s,Carom),128.9(Carom),130.0(Carom),131.4(d,J=30.2Hz,Carom),132.8(Carom),133.3(d,J=2.6Hz,Carom),133.7(Carom),133.8(Carom),136.6(d,J=13.0Hz,Carom),138.6(d,J=14.8Hz,Carom);31P NMR(121MHz,CDCl3)δ-1.4(s);C15H16PBrNa[M+Na]+的HRMS计算值329.0065,实验值329.0057。
E.邻-boronato膦衍生物(III-42)和(I-43)的合成
E.1.邻-boronato膦硼烷(III-42)的合成
表3.邻-硼酸合苯基膦硼烷(III-42)的合成
E.1.1.[1,3,2]-二氧杂环戊硼烷-2-基衍生物
基本步骤
在氩气中,在-78℃下,将n-BuLi(0.55mmol)逐滴加入邻-溴膦硼烷(IV)(0.50mmol)的无水THF(2mL)溶液中。在此温度下,将所得溶液搅拌一小时,然后,逐滴添加2-异丙氧基-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(0.80mmol)。在-78℃下30分钟并在室温下20小时后,反应混合物利用水(10mL)淬火并利用二氯甲烷(3x10mL)萃取。通过MgSO4干燥有机相,将其过滤并蒸发溶剂,得到残余物,然后通过硅胶柱层析和/或通过重结晶纯化该残余物。
E.1.1.1.二苯基-[2-(4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷-2-基)-苯基]膦硼烷42a
从邻-溴苯基膦硼烷(IV-a)开始;纯化:柱层析(利用1:1石油醚/二氯甲烷洗脱)。白色固体;得率:51%;Rf 0.28(石油醚/二氯甲烷1:1);IR(纯)2976,2415,2373,2349,1584,1481,1435,1356,1320,1262,1215,1144,1107,1059,964,861,733,697,667,650cm-1;1H NMR(300MHz,CDCl3)δ0.95(s,12H,CH3),7.15-7.22(m,2H,Harom),7.27-7.42(m,8H,Harom),7.55-7.62(m,4H,Harom),7.84(ddd,J=1.4,2.9,7.2Hz,1H,Harom);13C NMR(75.5MHz,CDCl3)δ24.7(CH3),83.9(C(CH3)2),128.3(d,J=10.3Hz,Carom),129.9(d,J=2.5Hz,Carom),130.1(d,J=10.0Hz,Carom),130.6(d,J=2.5Hz,Carom),130.7(d,J=57.7Hz,Carom),133.5(d,J=9.3Hz,Carom),134.4(d,J=10.5Hz,Carom),134.5(d,J=55.4Hz,Carom),136.7(d,J=11.4Hz,Carom);31P NMR(121MHz,CDCl3)δ25.0;C24H21PB2O2Na(M+Na)+的HRMS计算值425.1991,实验值425.1975;C24H21PB2O2的分析计算值:C,71.69;H,7.27;实验值:C,71.70;H,7.06。
E.1.1.2.二环己基-[2-(4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷-2-基)-苯基]膦硼烷42b
从邻-溴苯基膦硼烷(IV-b)开始;纯化:柱层析(利用1:1石油醚/二氯甲烷洗脱)和/或在甲醇/二氯甲烷中重结晶。白色固体;得率66%;Rf 0.45(石油醚/二氯甲烷1:1);IR(纯)2986,2922,2849,2371,2347,1446,1373,1339,1317,1266,1139,1107,1053,960,855,823,764,749,674cm-1;1H NMR(300MHz,CDCl3)δ0.94-0.99(m,10H,cHex),1.20(s,12H,CH3),1.36-1.42(m,6H,cHex),1.60-1.62(m,2H,cHex),1.72-1.76(m,2H,cHex),2.39-2.52(m,2H,cHex),7.21-7.25(m,2H,Harom),7.66-7.70(m,1H,Harom),7.88(ddd,J=1.7,6.9,13.3Hz,1H,Harom);13C NMR(75.5MHz,CDCl3)δ25.1(CH3),25.8(d,J=1.0HZ,CH2),27.0(d,J=8.3Hz,CH2),27.2(d,J=8.5Hz,CH2),27.6(CH2),28.6(CH2),33.8(d,J=32.9Hz,CH),84.4(C(CH3)2),129.6(d,J=2.4Hz,Harom),130.4(d,J=12.1Hz,Harom),133.1(d,J=47.7Hz,Harom),136.7(d,J=8.1Hz,Harom),137.4(d,J=16.9Hz,Harom);31P NMR(121MHz,CDCl3)δ34.0;C24H41PB2O2Na(M+Na)+的HRMS计算值437.2931,实验值437.2905;C24H41PB2O2的分析计算值:C,69.60;H,9.98;实验值:C,69.49;H,10.06。
E.1.1.3.(S)-二茂铁基-苯基-[2-(4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷-2-基)-苯基]膦硼烷42c
从邻-溴苯基膦硼烷(R)-(IV-k)开始;纯化:柱层析(利用2:1石油醚/二氯甲烷洗脱)。橙色固体;得率43%;对映体过量:99%,通过HPLC分析(chiralcel OD-H,0.2mL.min-1,己烷-2-丙醇98:2,tR(R)=27.2min,tR(S)=29.7min;Rf 0.32(石油醚/二氯甲烷2:1);[α]D+116.7(c 0.3,CHCl3);IR(纯)2979,2927,2855,2396,1480,1352,1320,1266,1171,1145,1109,1054,1028,860,824,740,697cm-1;1H NMR(300MHz,CDCl3)δ0.93-0.1.03(2s,12H,CH3),3.91-3.92(m,1H,Cp),4.06(sl,5H,Cp),4.38-4.39(m,1H,Cp),4.47-4.48(m,1H,Cp),4.69-4.70(m,1H,Cp),7.14-7.40(m,6H,Harom),7.57-7.63(m,2H,Harom),7.73-7.77(m,1H,Harom);13C NMR(75.5MHz,CDCl3)δ24.6-24.7(2s,CH3),69.8(Cp),71.2(d,J=68.6Hz,Cp),71.6(d,J=4.0Hz,Cp),71.8(d,J=5.7Hz,Cp),72.3(d,J=4.6Hz,Cp),74.4(d,J=13.6Hz,Cp),83.8(C(CH3)2),127.8(d,J=10.4Hz,Carom),129.4(d,J=2.4Hz,Carom),129.7(d,J=9.4Hz,Carom),130.2(d,J=2.4Hz,Carom),132.2(d,J=60.6Hz,Carom),133.0(d,J=9.6Hz,Carom),133.6(d,J=9.2Hz,Carom),136.4(d,J=11.3Hz,Carom),137.2(d,J=54.9Hz,Carom);31P NMR(121MHz,CDCl3)δ20.8;C28H33PB2O2FeNa(M+Na)+的HRMS计算值533.1656,实验值533.1654;C28H33PB2O2Fe的分析计算值:C,65.94;H,6.52;实验值:C,65.73;H,6.45。
E.1.2.二环己基硼烷基衍生物
基本步骤
在氩气中,在-78℃下,将n-BuLi(0.55mmol)逐滴加入邻-溴膦硼烷(IV)(0.50mmol)的无水THF(2mL)溶液中。在此温度下,将所得溶液搅拌一小时,然后逐滴添加氯二环己基硼烷56b(1M己烷溶液)(0.80mmol)。在-78℃下30分钟以及在室温下20小时后,反应混合物利用水(10mL)淬火并利用二氯甲烷(3x10mL)萃取。通过MgSO4干燥有机相,将其过滤并蒸发溶剂,得到残余物,通过硅胶柱层析纯化该残余物。
E.1.2.1.(2-二环己基硼烷基-苯基)-二苯基膦硼烷42d
从邻-溴苯基膦硼烷(IV-a)开始。纯化:柱层析(利用3:1石油醚/乙酸乙酯洗脱)。白色固体;得率:71%;Rf 0.57(石油醚/乙酸乙酯3:1);IR(纯)2914,2842,2779,2494,2449,2158,1437,1106,688cm-1;1H NMR(300MHz,CDCl3)δ0.78-0.95(m,2H,Hcy),1.05-1.09(m,10H,Hcy),1.50-1.69(m,10H,Hcy),7.14-7.26(m,2H,Harom),7.29-7.32(m,1H,Harom),7.43-7.57(m,11H,Harom);13C NMR(75.5MHz,CDCl3)δ27.4(CH2),28.4(CH2),28.7(CH2),31.0(CH2),31.9(CH2),33.5(CH),125.5(d,J=8.7Hz,Carom),127.8(Carom),128.4(d,J=62.8Hz,Carom),128.7(d,J=10.6Hz,Carom),130.3(d,J=2.9Hz,Carom),130.5(d,J=8.5Hz,Carom),131.3(d,J=2.6Hz,Carom),132.8(d,J=5.8Hz,Carom),133.3(d,J=9.6Hz,Carom);31P NMR(121MHz,CDCl3)δ13.6;C30H39PB2Na(M+Na)+的HRMS计算值475.2878,实验值475.2869;C30H39PB2的分析计算值:C,79.68;H,8.69;实验值:C,79.80;H,8.99。
E.1.2.2二环己基-(2-二环己基硼烷基-苯基)膦硼烷42e
从邻-溴苯基-二环己基膦硼烷(IV-b)开始。纯化:柱层析(利用3:1石油醚/二氯甲烷洗脱)。白色固体;得率55%;Rf 0.63(石油醚/二氯甲烷3:1);IR(纯)2918,2845,2455,2412,2148,1442,1272,1169,1128,1082,1004,889,852,755cm-1;1H NMR(300MHz,CDCl3)δ0.88-1.08(m,4H,Hcy),1.15-1.50(m,20H,Hcy),1.65-1.85(m,16H,Hcy),1.98-2.15(m,4H,Hcy),7.20-7.27(m,2H,Harom),7.31-7.41(m,2H,Harom);13C NMR(75.5MHz,CDCl3)δ25.8(CH2),26.7(CH2),26.9-27.0(m,CH2),27.5(m,CH2),28.8(d,J=25.3Hz,CH2),31.7(d,J=16.8Hz,CH2),33.0(d,J=36.0Hz,CH),34.0(CH),124.8(d,J=8.0Hz,Harom),126.5(d,J=60.8Hz,Harom),129.7(d,J=2.8Hz,Harom),130.4(d,J=4.8Hz,Harom),130.7(d,J=14.7Hz,Harom);31P NMR(121MHz,CDCl3)δ18.0;C30H51PB2Na(M+Na)+的HRMS计算值487.3817,实验值487.3789;C30H51PB2的分析计算值:C,77.60;H,11.07;实验值:C,77.41;H,11.20。
E.1.2.3.(S)-二茂铁基-(2-二环己基硼烷基-苯基)膦硼烷42f
从二茂铁基-(邻-溴苯基)-苯基膦硼烷(R)-(IV-k)开始。纯化:柱层析(利用3:1石油醚/乙酸乙酯洗脱)。橙色固体;得率60%;对映体过量:99%,通过HPLC分析(chiralpakAD,0.2mL.min-1,己烷-2-丙醇98:2,tR(R)=21.2min,tR(S)=24.7min;Rf 0.62(石油醚/乙酸乙酯3:1);[α]D-51.4(c 0.4,CHCl3);IR(纯)2915,2843,2468,2418,2200,1436,1179,1171,1108,1027,1000,967,838,751,742,691cm-1;1H NMR(300MHz,CDCl3)δ0.77-0.80(m,6H,Hcy),0.98-0.99(m,2H,Hcy),1.10-1.19(m,5H,Hcy),1.32-1.40(m,4H,Hcy),1.46-1.47(m,1H,Hcy),1.59-1.66(m,4H,Hcy),3.80-3.81(m,1H,Hfer),4.20(s,5H,Hfer),4.31-4.32(m,1H,Hfer),4.38-4.39(m,1H,Hfer),4.41-4.42(m,1H,Hfer),7.11-7.14(m,3H,Harom),7.27-7.32(m,1H,Harom),7.36-7.44(m,3H,Harom),7.66-7.72(m,2H,Harom);13C NMR(75.5MHz,CDCl3)δ27.3(d,J=27.8Hz,CH2),28.4(d,J=24.5Hz,CH2),28.8(d,J=19.5Hz,CH2),31.0(d,J=12.9Hz,CH2),31.8(d,J=15.3Hz,CH2),33.4(CH),69.7(Cfer),70.0(d,J=75.6Hz,Cfer),70.9(d,J=7.3Hz,Cfer),72.2(d,J=14.8Hz,Cfer),72.7(d,J=8.7Hz,Cfer),73.0(d,J=6.1Hz,Cfer),125.2(d,J=8.5Hz,Carom),128.2(d,J=64.4Hz,Carom),128.4(d,J=10.5Hz,Carom),129.9(d,J=2.7Hz,Carom),130.3(d,J=15.5Hz,Carom),130.6(d,J=68.9Hz,Carom),131.0(d,J=2.4Hz,Carom),132.1(d,J=5.5Hz,Carom),132.7(d,J=9.4Hz,Carom);31P NMR(121MHz,CDCl3)δ8.3;C34H43PB2FeNa(M+Na)+的HRMS计算值583.2542,实验值583.2550;C34H43PB2Fe的分析计算值:C,72.90;H,7.74;实验值:C,73.20;H,7.94。
E.2.邻-boronato游离膦(I-43)的合成
(S)-(2-甲氧基苯基)-苯基-[2-(4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷-2-基)-苯基]膦43i的合成
在氩气中,在-78℃下,将n-BuLi(0.45mmol)逐滴加入邻-溴苯基膦(R)-(II-i)(0.15g,0.41mmol)的无水THF(2mL)溶液中。在此温度下,将所得溶液搅拌30分钟,然后逐滴添加硼衍生物(2-异丙氧基-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷)(0.13mL,0.66mmol)。在-78℃下30分钟并在室温下20小时后,反应混合物利用水(10mL)淬火并利用二氯甲烷(3x10mL)萃取。通过MgSO4干燥有机相,将其过滤并蒸发溶剂,得到残余物,该残余物然后通过硅胶柱层析进行纯化,将石油醚/乙酸乙酯5:1用作洗脱液。白色固体;得率58%;对映体过量:99%,通过HPLC分析(chiralpak AD,0.2mL.min-1,己烷-2-丙醇99:1,tR(R)=26.4min,tR(S)=34.1min;Rf0.33(石油醚/乙酸乙酯5:1);[α]D=-21.2(c 0.3,CHCl3);IR(纯)3053,2978,2932,1583,1471,1430,1379,1347,1313,1271,1240,1143,1101,1047,1024,963,858,744,697cm-1;1H NMR(300MHz,CDCl3)δ1.01-1.02(2s,12H,CH3),3.68(s,3H,O CH3),6.60(ddd,J=1.7,4.3,7.4Hz,1H,Harom),6.71-6.82(m,3H,Harom),7.18-7.24(m,8H,Harom),7.72-7.76(m,1H,Harom);13C NMR(75.5MHz,CDCl3)δ24.5-24.6(2s,CH3),55.7(OCH3),83.8(C(CH3)2),110.0(d,J=1.5Hz,Carom),121.0(Carom),127.0(Carom),127.2(d,J=13.9Hz,Carom),128.3(d,J=7.3Hz,Carom),128.4(Carom),130.0(Carom),130.4(Carom),132.1(d,J=1.2Hz,Carom),134.0(Carom),134.4(Carom),134.7(Carom),135.5(d,J=9.0Hz,Carom),138.0(d,J=11.7Hz,Carom),143.5(d,J=19.0Hz,Carom),161.4(d,J=15.8Hz,Carom);31P NMR(121MHz,CDCl3)δ-15.4;C25H28PBO3Na(M+Na)+的HRMS计算值419.1946,实验值419.1932;C25H28PBO3的分析计算值:C,71.79;H,6.75;实验值:C,71.60;H,6.56。
F.邻-甲醇膦衍生物(III-44)以及(I-45)的合成
F.1.邻-甲醇膦硼烷(III-44)的合成
表4.羟基膦硼烷(III-44)的合成
基本步骤
在-78℃下,将正丁基锂(0.44mmol,1.1eq.)加入邻-溴膦硼烷(IV)(0.4mmol)的无水THF(2mL)溶液中。在-78℃下搅拌一小时后,逐滴添加醛(0.8mmol,2eq(苯甲醛57a)或1.6mmol,4eq(特戊醛57b))的无水THF(0.5mL)溶液。使反应混合物在1h30期间搅拌至室温,然后利用水(2mL)水解并利用二氯甲烷(3x5mL)萃取。通过MgSO4干燥合并的有机相并真空移除溶剂以得到非对映体混合物,该非对映体混合物然后通过硅胶层析柱纯化分离,将乙酸乙酯/石油醚用作洗脱液。
F.1.1.(Sp)-[2-(二茂铁基苯基膦基硼烷)-苯基]苯基甲醇44a/44a’
使用185mg(R)-二茂铁基-邻-溴苯基膦硼烷(IV-k)以及170mg苯甲醛,得到相应的羟基膦硼烷44b和44b’,总得率71%并且非对映体比率44a/44a’45:55。
(Sp,S)-[2-(二茂铁基苯基膦基硼烷)-苯基]苯基甲醇44a
橙色固体-Rf:0.65(乙酸乙酯/石油醚1:9)-mp=70-72℃.
对映体过量>99%*;[α]D=+31.0(c=0.2;CHCl3).
IR(cm-1):3499(OH),3057-2855(C-H),2429(BH),2053,1983,1950,1886,1670,1590,1570,1499,1471,1453,1438,1412,1381,1348,1314,1264,1226,1197,1185,1172,1130,1107,1065,1034,1019,1003,958,887,816,768,699.
1H NMR(300MHz,CDCl3):δ(ppm)=1.35-1.91(m,3H,BH3),4.10(s,5H,Fc),4.13(s,1H,Fc),4.20(s,1H,Fc),4.56(s,1H,Fc),6.14(s,1H,CHOH),6.76-6.79(m,2H,Harom),6.78-7.04(m,1H,Harom),7.09-7.15(m,3H,Harom),7.17-7.21(m,2H,Harom),7.33-7.38(m,1H,Harom)7.47-7.65(m,2H,Harom).
RMN13C NMR(75MHz,CDCl3):δ(ppm)=69.8(d,J=3.8Hz,Fc),69.9(Fc),70.7(d,J=7.5Hz,Fc),71.6d,J=2.3Hz,Fc),72.2(d,J=2.3Hz,Fc),72.3(d,J=17.3Hz,Fc),74.8(d,J=16.6Hz,CHOH),126.0(Carom),126.7(Carom),127.3(Carom),127.8(Carom),128.5(d,J=3.8Hz,Carom),129(d,J=8.3Hz,Carom),130.3(d,J=16.6Hz,Carom),130.7(d,J=8.3Hz,Carom),131.0(d,J=12.0Hz,Carom),131.5(d,J=2.3Hz,Carom),131.7(d,J=2.3Hz,Carom),132.4(d,J=6.0Hz,Carom),132.6(d,J=9.8Hz,Carom),133.1(d,J=9.8Hz,Carom).
31P NMR(121MHz,CDCl3):δ(ppm)=+13.7(sl).
C29H28BFeNaOP[M+Na]+的精确质量计算值:513.1218,tr.513.1214.
*对映体纯度是通过HPLC在手性柱上确定(Chiralcel OD-H,己烷/iPrOH 98:2,0.8mL.min-1,λ=254nm,20℃,tR(Rp,Rc)=21.7min,tR(Sp,Rc)=25.9min,tR(Sp,Sc)=34.9min,tR(Rp,Sc)=49min。
(Sp,R)-[2-(二茂铁基苯基膦基硼烷)-苯基]苯基甲醇44a'
橙色固体-Rf:0.65(乙酸乙酯/石油醚1:9)-mp=172-174℃.
对映体过量>99%*;[α]D=-85(c=0.2;CHCl3).
IR(cm-1):3509(OH),3088-2907(C-H),2394(BH),1705,1606,1568,1495,1472,1449,1437,1371,1318,1262,1232,1171,1126,1107,1068,1017,1003,935,919,897,839,817,768,749,735,700,654.
1H NMR(300MHz,CDCl3):δ(ppm)=1.23-1.30(m,3H,BH3),4.10(s,5H,Fc),4.12(s,1H,Fc),4.56(s,1H,Fc),4.66(s,1H,Fc),4.79(s,1H,Fc),6.14(s,1H,CHOH),6.76-6.79(m,2H,Harom),6.98-7.09(m,1H,Harom),7.12-7.18(m,3H,Harom),7.20-7.21(m,2H,Harom),7.33-7.38(m,1H,Harom)7.51-7.63(m,3H,Harom),7.86-7.93(m,2H,Harom).
13C NMR(75MHz,CDCl3):δ(ppm)=69.8(d,J=3.8Hz,Fc),69.9(Fc),70.7(d,J=7.5Hz,Fc),71.6(d,J=2.3Hz,Fc),72.1(d,J=2.3Hz,Fc),72.2(d,J=17.3Hz,Fc),74.8(d,J=16.5Hz,CHOH),126(Carom),126.7(Carom),127.3(Carom),127.8(Carom),128.5(d,J=3.8Hz,Carom),129.0(d,J=8.3Hz,Carom),130.3(d,J=16.6Hz,Carom),130.7(d,J=8.3Hz,Carom),131.1(d,J=12Hz,Carom),131.0(d,J=2.5Hz,Carom),131.8(d,J=2.2Hz,Carom),132.1(d,J=6.1Hz,Carom),132.6(d,J=9.7Hz,Carom),133.1(d,J=9.7Hz,Carom).
31P NMR(121MHz,CDCl3):δ(ppm)=+14.2(sl).
C29H28BFeNaOP[M+Na]+的精确质量计算值:513.1218,tr.513.1214.
*对映体纯度是通过HPLC在手性柱上确定(Chiralcel OD-H,己烷/iPrOH 98:2,0.8mL.min-1,λ=254nm,20℃,tR(Rp,Rc)=21.7min,tR(Sp,Rc)=25.9min,tR(Sp,Sc)=34.9min,tR(Rp,Sc)=49min。
F.1.2.(Rp)-[2-(二茂铁基苯基膦基硼烷)-苯基]苯基甲醇44b以及44b’
使用185mg(S)-二茂铁基-邻-溴苯基膦硼烷(IV-k)以及170mg苯甲醛,得到相应的羟基膦硼烷44b和44b’,总得率72%并且非对映体比率44b/44b’64:26。
(Rp,R)-[2-(二茂铁基苯基膦基硼烷)-苯基]苯基甲醇44b’
橙色固体-Rf:0.65(乙酸乙酯/石油醚1:9)-mp=172-174℃
对映体过量>99%*;[α]D=-30.1(c=0.2;CHCl3).
IR(cm-1):3572(OH),3057-2922(C-H),2391(BH),1590,1494,1436,1412,1367,1313,1171,1130,1108,1060,1025,823,763,744,730,698.
1H NMR(300MHz,CDCl3):δ(ppm)=1.23-1.70(m,3H,BH3),4.08(s,5H,Fc),4.17(s,1H,Fc),4.56(s,1H,Fc),4.66(s,1H,Fc),4.90(s,1H,Fc),6.33(d,J=2.7Hz,1H,CHOH),7.05-7.10(m,1H,Harom),7.17-7.24(m,1H,Harom),7.27-7.30(m,2H,Harom),7.31-7.32(m,2H,Harom),7.33-7.40(m,3H,Harom)7.57-7.64(m,3H,Harom),7.89-7.96(m,2H,Harom).
13C NMR(75MHz,CDCl3):δ(ppm)=69.4(d,J=70.2Hz,Fc),69.9(Fc),71.1(d,J=6.8Hz,Fc),71.4(d,J=3Hz,Fc),72.1(d,J=6.8Hz,Fc),72.4(d,J=8.3Hz,Fc),75(d,J=16.6Hz,CHOH),126.2(Carom),126.8(Carom),127.4(d,J=51Hz,Carom),127.6(d,J=13.6Hz,Carom),127.9(Carom),128.6(Carom),129.1(d,J=9.8Hz,Carom),130.8(d,J=8.3Hz,Carom),131.0(d,J=27.9Hz,Carom),131.6(Carom),131.9(d,J=2.3Hz,Carom),132.0(Carom),132.7(d,J=7.5Hz,Carom),132.9(d,J=2.3Hz,Carom).
31P NMR(121MHz,CDCl3):δ(ppm)=+16.19(sl).
C29H28BFeNaOP[M+Na]+的精确质量计算值:513.1218,tr.513.1221.
*对映体纯度是通过HPLC在手性柱上确定(Chiralcel OD-H,己烷/iPrOH 98:2,0.8mL.min-1,λ=254nm,20℃,tR(Rp,Rc)=21.7min,tR(Sp,Rc)=25.9min,tR(Sp,Sc)=34.9min,tR(Rp,Sc)=49min。
(Rp,S)-[2-(二茂铁基苯基膦基硼烷)-苯基]苯基甲醇44b
橙色固体-Rf:0.66(乙酸乙酯/石油醚1:9)-mp=92-94℃.
对映体过量>99%*-[α]D=+62(c=0.2;CHCl3).
IR(cm-1):3498(OH),3055(C-H),2424(BH),1588,1470,1436,1410,137,1312,1261,1182,1170,1105,1063,1031,1017,1001,828,766,738,697,657,639.
1H NMR(300MHz,CDCl3):δ(ppm)=0.86-1.34(m,3H,BH3),4.11(s,5H,Fc),4.14(s,1H,Fc),4.57(s,1H,Fc),4.66(s,1H,Fc),4.80(s,1H,Fc),6.15(d,J=3Hz,1H,CHOH),6.78-6.99(m,2H,Harom),7.01-7.20(m,1H,Harom),7.14-7.22(m,5H,Harom),7.33-7.42(m,1H,Harom),7.51-7.63(m,3H,Harom)7.87-7.94(m,2H,Harom).
13C NMR(75MHz,CDCl3):δ(ppm)=69.0(d,J=72.4Hz,Fc),69.9(Fc),70.7(d,J=7.5Hz,Fc),71.6d,J=2.3Hz,Fc),72.2(d,J=2.3Hz,Fc),72.3(d,J=17.3Hz,Fc),74.8(d,J=17.4Hz,CHOH),126.0(Carom),126.7(Carom),127.3(d,J=8.3Hz,Carom),127.7(Carom),128.8(d,J=10.6Hz,Carom),130.3(d,J=17.4Hz,Carom),130.7(d,J=8.3Hz,Carom),131.0(d,J=12.1Hz,Carom),131.5(d,J=2.3Hz,Carom),131.7(d,J=2.3Hz,Carom),132.4(d,J=6Hz,Carom),133.1(d,J=9.8Hz,Carom),141.0(d,J=11.3Hz,Carom),146.6(d,J=11.3Hz,Carom).
31P NMR(121MHz,CDCl3):δ(ppm)=+12.8(sl).
C29H28BFeNaOP[M+Na]+的精确质量计算值:513.1218,实验值:513.1233.
对映体纯度是通过HPLC在手性柱上确定(Chiralcel OD-H,己烷/iPrOH 98:2,0.8mL.min-1,λ=254nm,20℃,tR(Rp,Rc)=21.7min,tR(Sp,Rc)=25.9min,tR(Sp,Sc)=34.9min,tR(Rp,Sc)=49min.
F.1.3.(R)叔丁基-(2-二茂铁基苯基膦基硼烷)-苯基甲醇44c和44c’的合成:
使用185mg(S)-二茂铁基苯基-邻-溴苯基膦硼烷(IV-k)以及138mg特戊醛,得到相应的羟基膦硼烷44c和44c’,总得率66%并且非对映体比率44c/44c’60:40。
(Rp,Rc)叔丁基-(2-二茂铁基苯基膦基硼烷)-苯基甲醇44c’:
橙色固体-Rf:0.56(乙酸乙酯/石油醚1:9)-mp=170-172℃.
对映体过量>99%*-[α]D=-214(c=0.2;CHCl3).
IR(cm-1):3553(OH),2957-2900(CH),2396(BH),1568,1464,1438,1416,1395,1362,1311,1292,1235,1197,1171(OCH3),1108,1062,1027,1001,829,741,699.
1H NMR(300MHz,CDCl3):δ(ppm)=0.61(s,9H,CH3)1.44-1.72(m,3H,BH3),4.05(s,5H,Fc),4.23(s,1H,Fc),4.55(s,1H,Fc),4.61(s,1H,Fc),4.68(s,1H,Fc),4.86(d,J=3.9Hz,1H,CHOH),7.0-7.07(m,1H,Harom),7.14-7.20(m,1H,Harom),7.39-7.45(m,1H,Harom),7.55-7.57(m,3H,Harom)7.70-7.77(m,1H,Harom),7.89-7.94(m,2H,Harom).
13C NMR(75MHz,CDCl3):δ(ppm)=26.7(CH3),69.9(Fc),70.1(d,J=72.4Hz,Fc),71.7(d,J=2.3Hz,C(CH3)3),72.0(d,J=6Hz,Fc),72.2(d,J=9Hz,Fc),74.9(d,J=16.6Hz,CHOH),76(d,J=8.3Hz,Fc),127.0(d,J=8.3Hz,Carom),128.4(d,J=10.6Hz,Carom),128.7(d,J=8.3Hz,Carom),130.3(Carom),130.8(d,J=2.3Hz,Carom),130.9(Carom),131.5(d,J=2.3Hz,Carom),131.6(Carom),132.7(d,J=6.8Hz,Carom),133.4(d,J=9Hz,Carom).
31P NMR(121MHz,CDCl3):δ(ppm)=+13.3(m).
C27H32BFeOPNa[M+Na]+的精确质量计算值:493.1531,tr.493.1547.
*对映体纯度是通过HPLC在手性柱上确定(Chiralpack AD,己烷/iPrOH 99:1.1mL.min-1,λ=254nm,20℃,tR((Sp,Rc ou Sc)=13.4min,tR(Rp,Sc)=14.7min),tR((Sp,Rcou Sc)=34.9min,tR(Rp,Rc)=50.9min)。
(Rp,S)叔丁基-(2-二茂铁基苯基膦基硼烷)-苯基甲醇44c:
橙色固体-Rf:0.35(乙酸乙酯/石油醚1:9)-mp=160-162℃.
对映体过量>99%*-[α]D=-232(c=0.2;CHCl3).
IR(cm-1):3585(OH),2950(C-H),2420(BH),2364,2161,2069,1587,1479,1435,1261,1230,1205,1171,107,1070,1056,1026,1002,907,857,826,781,764,749,728,704,683.
1H NMR(300MHz,CDCl3):δ(ppm)=0.94(s,9H,CH3)1.33-1.74(m,3H,BH3),4.01(s,5H,Fc),4.04(s,1H,Fc),4.50(s,1H,Fc),4.62(s,1H,Fc),4.73(s,1H,Fc),4.88(d,J=3.9Hz,1H,CHOH),6.98-7.05(m,1H,Harom),7.16-7.21(m,1H,Harom),7.40-7.45(m,1H,Harom),7.53-7.63(m,4H,Harom),7.73-7.85(m,2H,Harom).
13C NMR(75MHz,CDCl3):δ(ppm)=26.7(CH3),69.9(Fc),70.8(d,J=70.2Hz,Fc),71.3(d,J=9.8Hz,Fc),72.1(d,J=6Hz,Fc),75.2(d,J=16.6Hz,CHOH),76.9(CH3)3),127.0(d,J=9Hz,Fc),128.5(d,J=7.5Hz,Carom),128.8(d,J=9.7Hz,Carom),131.0(d,J=78.5Hz,Carom),132.0(d,J=35.5Hz,Carom),132.6(d,J=9Hz,Carom),133.4(d,J=7.5Hz,Carom),146.4(d,J=7.6Hz,Carom).
RMN31P(121MHz,CDCl3):δ(ppm)=+17.1(m).
C27H32BFeNaOP[M+Na]+的精确质量计算值:493.1531,tr.493.1528.
*对映体纯度是通过HPLC在手性柱上确定(Chiralpack AD,己烷/iPrOH 98:2,0.5mL.min-1,λ=254nm,20℃,tR((Sp,Rc ou Sc)=13.4min,tR(Rp,Sc)=14.7min)tR((Sp,Rcou Sc)=34.9min,tR(Rp,Rc)=50.9min)。
F.2.邻-甲醇游离膦(I-45)的合成
表5.邻-茴香基羟基膦硼烷(I-45d,e)的合成
F.2.1.(R)-[2-(邻-茴香基苯基膦基)-苯基]苯基甲醇45d和45d’的合成
使用135mg(S)-邻-茴香基-邻-溴苯基苯基膦(II-i)以及170mg苯甲醛57a,得到相应的羟基膦45d和45d’,总得率45%并且非对映比率45d/45d’78:22。
(R)-[2-(邻-茴香基苯基膦基)-苯基]苯基甲醇45d:
白色固体-Rf:0.46(乙酸乙酯/石油醚1:9)-mp=68-70℃.
对映体过量>99%*-[α]D=+123(c=0.2;CHCl3).
IR(cm-1):3409(OH),3054-2834(C-H),2332,2157,2037,1882,1583,1573,1493,1461,1430,1296,1272,1240,1179,1160,1128,1069,1019,916,881,850,824,793,746,696.
1H NMR(300MHz,CDCl3):δ(ppm)=3.71(s,3H,OCH3),6.31(sl,1H,CHOH),6.59-6.64(m,1H,Harom),6.70(d,J=6.9Hz,1H,Harom),6.78-6.88(m,2H,Harom),6.96-7.0(m,1H,Harom),7.13-7.22(m,4H,Harom),7.32-7.38(m,5H,Harom),7.47-7.50(m,2H,Harom),7.51-7.60(m,1H,Harom),7.67-7.74(m,1H,Harom).
13C NMR(75MHz,CDCl3):δ(ppm)=55.7(OCH3),73.4(d,J=24.9Hz,CHOH),110.2(d,J=2.3Hz,Carom),111.8(d,J=6.8Hz,Carom),121.0(Carom),121.2(d,J=11.3Hz,Carom),124.8(d,J=9.8Hz,Carom),126.7(d,J=2.3Hz,Carom),126.8(d,J=6.8Hz,Carom),127.8(d,J=15.0Hz,Carom),127.9(Carom),128.5(d,J=18.8Hz,Carom),128.6(Carom),129.5(Carom),130.4(Carom),131.2(Carom),133.9(d,J=7.5Hz,Carom),134.2(d,J=8.3Hz,Carom),136.0(d,J=9.0Hz,Carom),141.8(Carom),143.5(Carom),148.7(d,J=24.1Hz,Carom).
31P NMR(121MHz,CDCl3):δ(ppm)=-28.1(s).
C24H27NaO2P[M+Na]+的精确质量计算值:421.1328,tr.421.1345.
*对映体纯度是通过HPLC在手性柱上确定(Lux 5u纤维素-2,己烷/iPrOH 90:10,1mL.min-1,λ=254nm,20℃,tR((Sp,Rc ou Sc)=8.7min,tR(Rp,Rc ou Sc)=10.9min,tR(Sp,Rc ou Sc)=15.7min,tR(Rp,Rc ou Sc)=21.3min).
(R)-[2-(邻-茴香基苯基膦基)-苯基]苯基甲醇45d’:
白色油-Rf:0.30(乙酸乙酯/石油醚1:9).
对映体过量>99%*-[α]D=-47(c=0.2;CHCl3).
IR(cm-1):3355(OH),3058-2836(C-H),1952,1899,1812,1584,1573,1494,1471,1453,1431,1296,1273,1240,1179,1162,1128,1107,1069,1019,915,881,852,821,794,742,695,649.
1H NMR(300MHz,CDCl3):δ(ppm)=3.66(s,3H,OCH3),5.52(d,J=8Hz,1H,CHOH),6.74-6.80(m,1H,Harom),6.81-7.08(m,2H,Harom),7.12-7.24(m,6H,Harom),7.27-7.42(m,5H,Harom),7.47-7.67(m,2H,Harom),7.72-7.78(m,2H,Harom).
13C NMR(75MHz,CDCl3):δ(ppm)=55.8(OCH3),73(d,J=24.9Hz,CHOH),110.4(d,J=2.4Hz,Carom),111.5(d,J=6.8Hz,Carom),121(Carom),121.2(d,J=11.2Hz,Carom),124.3(Carom),126.8(d,J=2.3Hz,Carom),126.9(d,J=6.7Hz,Carom),127.8(d,J=15Hz,Carom),128(Carom),128.5(d,J=18.8Hz,Carom),128.6(Carom),129.5(Carom),130.2(Carom),133.2(Carom),133.6(d,J=18.1Hz,Carom),134.1(d,J=9.8Hz,Carom),134.7(d,J=10.7Hz,Carom),141.8(Carom),142.8(Carom),149(d,J=23.8Hz,Carom).
31P NMR(121MHz,CDCl3):δ(ppm)=-26.8(s).
C24H27NaO2P[M+Na]+的精确质量计算值:421.1328,tr.421.1346.
*对映体纯度是通过HPLC在手性柱上确定(Lux 5u纤维素-2,己烷/iPrOH 90:10,1mL.min-1,λ=254nm,20℃,tR((Sp,Rc ou Sc)=8.7min,tR(Rp,Rc ou Sc)=10.9min,tR(Sp,Rc ou Sc)=15.7min,tR(Rp,Rc ou Sc)=21.3min).
F.2.2.(R)-叔丁基-(2-邻-茴香基苯基膦基)-苯基甲醇45e和45e’的合成:
使用135mg(S)-邻-茴香基-邻-溴苯基苯基膦(IV-i)以及138mg特戊醛57b,得到相应的羟基膦45e和45e’,总得率50%并且非对映体比率45e/45e’38:62。
(R)-叔丁基-(2-邻-茴香基苯基膦基)-苯基甲醇45e:
白色固体-Rf:0.46(乙酸乙酯/石油醚1:9)-mp=76-78℃.
对映体过量>99%*-[α]D=+189(c=0.2;CHCl3).
IR(cm-1):3594(OH),2952-2835(C-H),1573,1462,1430,1361,1273,1462,1430,1361,1273,1240,1161,1069,1002,745,696.
1H NMR(300MHz,CDCl3):δ(ppm)=1.04(s,9H,CH3)3.74(s,1H,OCH3),5.5(d,J=7.5Hz,1H,CHOH),6.69-6.88(m,1H,Harom),6.90-6.97(m,3H,Harom),7.14-7.21(m,3H,Harom),7.31-7.36(m,5H,Harom),7.61-7.63(m,1H,Harom).
13C NMR(75MHz,CDCl3):δ(ppm)=26.4(CH3),55.8(OCH3),78.1(d,J=25.6Hz,CHOH),110.4(d,J=1.5Hz,Carom),112.0(d,J=6.8Hz,Carom),121.1(Carom),121.3(d,J=11.3Hz,Carom),126.8(d,J=12.8Hz,Carom),127.4(Carom),128.3(d,J=6.0Hz,Carom),128.6(Carom),130.1(Carom),132.9(Carom),133.7(d,J=20.4Hz,Carom),134.7(d,J=2.3Hz,Carom),135.4(d,J=14.3Hz,Carom),136.2(d,J=11.3Hz,Carom),147.8(d,J=23.4Hz,Carom)160.7(d,J=15.8Hz,Carom).
31P NMR(121MHz,CDCl3):δ(ppm)=-24.6(s).
C24H27NaO2P[M+Na]+的精确质量计算值:401.1641,tr.401.1653.
*对映体纯度是通过HPLC在手性柱上确定(Lux 5u纤维素-2,己烷/iPrOH 98:2,1mL.min-1,λ=254nm,20℃,tR((Rp,Rcou Sc)=7.3min,tR((Sp,Rc ou Sc)=8.4min,tR(Sp,Rc ou Sc)=10.2min,tR(Rp,Rc ou Sc)=12.7min).
(R)-叔丁基-(2-邻-茴香基苯基膦基)-苯基甲醇45e’:
白色固体-Rf:0.34(乙酸乙酯/石油醚1:9)-mp=70-72℃.
对映体过量>99%*-[α]D=+108(c=0.2;CHCl3).
IR(cm-1):3576-3448(OH),3054-2834(C-H),2340,1725,1583,1573,1461,1430,1393,1361,1271,1240,1180,1161,1128,1089,1068,1041,1024,1001,935,903,879,850,824,794,746,732,697.
1H NMR(300MHz,CDCl3):δ(ppm)=1.01(s,9H,CH3)3.07(s,1H,OCH3),5.58(d,J=8.1Hz,1H,CHOH),6.61-6.65(m,1H,Harom),6.84-6.89(m,2H,Harom),6.96-7.19(m,1H,Harom),7.14-7.19(m,1H,Harom),7.32-7.40(m,7H,Harom),7.62-7.64(m,1H,Harom).
13C NMR(75MHz,CDCl3):δ(ppm)=27.0(CH3),52.4(C(CH3)3),54.4(OCH3),80.3(d,J=4.7Hz,CHOH),110.4(d,J=6.8Hz,Carom),110.7(d,J=6.0Hz,Carom),119.8(d,J=12.0Hz,Carom),125(d,J=13.6Hz,Carom),128.1(d,J=12.1Hz,Carom),128.2(d,J=12.8Hz,Carom),129.1(d,J=10.6Hz,Carom),129.6(d,J=8.3Hz,Carom),130.2(d,J=18.9Hz,Carom),130.9(d,J=3.0Hz,Carom),131.4(d,J=2.3Hz,Carom),132.0(d,J=9.8Hz,Carom),132.9(d,J=14.3Hz,Carom),133.7(d,J=16.6Hz,Carom)134.2(d,J=1.5Hz,Carom),134.4(d,J=8.3Hz,Carom).
31P NMR(121MHz,CDCl3):δ(ppm)=-26.8(s).
C24H27NaO2P[M+Na]+的精确质量计算值:401.1641,tr.401.1629.
*对映体纯度是通过HPLC在手性柱上确定(Lux 5纤维素-2,己烷/iPrOH 98:2,1mL.min-1,λ=254nm,20℃,tR((Rp,Rcou Sc)=7.3min,tR((Sp,Rc ou Sc)=8.4min,tR(Sp,Rc ou Sc)=10.2min,tR(Rp,Rc ou Sc)=12.7min).
G.邻-酰基芳基膦衍生物(I-46)的合成
[邻-(叔丁基羰基)苯基]二苯基膦(I-46)
在氩气中,在-78℃下,将n-BuLi(0.55mmol)逐滴加入(2-溴苯基)二苯基膦(II-a)(0.50mmol)的无水THF(2mL)溶液中。在此温度下,将所得溶液搅拌一小时,然后,逐滴添加特戊酰氯(0.80mmol)。在室温下搅拌过夜后,反应混合物利用水(10mL)淬火并利用二氯甲烷(3x10mL)萃取。通过MgSO4干燥有机相,将其过滤并蒸发溶剂,得到残余物,该残余物通过硅胶柱层析进行纯化,将石油醚/乙酸乙酯3:1用作洗脱液。白色固体;得率78%;Rf0.43(石油醚/乙酸乙酯3:1);IR(纯)3049,2967,2928,2867,1686,1585,1477,1458,1431,1389,1361,1283,1192,967,947,778,741,691cm-1;1H NMR(300MHz,CDCl3)δ1.35(s,9H,CH3),7.18-7.22(m,1H,Harom),7.25-7.40(m,13H,Harom);13C NMR(75.5MHz,CDCl3)δ27.7(d,J=3.3Hz,CH3),44.7(C(CH3)3),124.8(d,J=8.6Hz,Carom),128.3(Carom),128.5(d,J=4.9Hz,Carom),128.7(Carom),133.3(Carom),133.5(Carom),134.6(d,J=15.8Hz,Carom),134.8(d,J=2.2Hz,Carom),137.0(d,J=10.4Hz,Carom),148.0(d,J=35.8Hz,Carom);31PNMR(121MHz,CDCl3)δ-10.4;C23H23PONa[M+Na]+的HRMS计算值369.1379,实验值369.1382。
H.邻-硅烷基(o-silano)膦衍生物(I-47)的合成
表6邻-硅烷基膦(I-47)的制备
H.1.邻-硅烷基膦47a,d的合成
H.1.1.(R)-(2-甲氧基-苯基)-苯基-(2-三甲基甲硅烷基-苯基)膦47a
在氩气中,在-78℃下,将n-BuLi(0.55mmol)逐滴加入(R)-(2-溴苯基)-(2-甲氧基苯基)-苯基膦(II-i)(0.19g,0.50mmol)的无水THF(2mL)溶液中。在此温度下,将所得溶液搅拌一小时,然后,逐滴添加三甲基氯硅烷(0.10mL,0.80mmol)。搅拌20h,直至室温,反应混合物利用水(10mL)淬火并利用二氯甲烷(3x10mL)萃取。通过MgSO4干燥有机相,对其过滤并蒸发溶剂,得到残余物,该残余物通过硅胶柱层析进行纯化,将石油醚/乙酸乙酯2:1用作洗脱液。白色固体;得率49%;对映体过量>95%,通过相应的氧化膦的31P NMR,将(R)-3,5-二硝基-N-(1-苯基-乙基)-苯甲酰胺用作手性试剂;Rf 0.38(石油醚/二氯甲烷2:1);[α]D+1.6(c 0.9,CHCl3);IR(纯)3057,2960,2900,1583,1572,1472,1431,1272,1242,1182,1160,1125,1114,1021,834,753,743cm-1;1H NMR(300MHz,CDCl3)δ0.20(d,J=1.5Hz,SiCH3),3.53(s,3H,OCH3),6.48(ddd,J=1.8,4.2,7.5Hz,1H,Harom),6.65-6.71(m,2H,Harom),6.91-6.93(m,1H,Harom),7.00-7.06(m,4H,Harom),7.10-7.17(m,4H,Harom),7.44-7.45(m,1H,Harom),13C NMR(75.5MHz,CDCl3)δ-0.1(d,J=9.6Hz,SiCH3),54.3(OCH3),109.0(d,J=1.4Hz,Carom),119.6(Carom),125.9(d,J=13.3Hz,Carom),126.7(Carom),126.8(d,J=0.9Hz,Carom),126.9(Carom),127.0(Carom),127.7(Carom),128.7(Carom),132.1(Carom),132.4(Carom),133.3(d,J=16.2Hz,Carom),133.7(d,J=1.2Hz,Carom),136.3(d,J=11.4Hz,Carom),141.7(d,J=11.3Hz,Carom),146.3(d,J=47.2Hz,Carom),159.6(d,J=15.5Hz,Carom);31P NMR(121MHz,CDCl3)δ-20.6;C22H25POSiNa(M+Na)+的HRMS计算值387.1304,实验值387.1296;C22H25POSi的分析计算值:C,72.49;H,6.91;实验值:C,72.19;H,7.02。
H.1.2.二苯基-(2-三甲基甲硅烷基-苯基)膦47d
在氩气中,在-20℃下,将i-PrMgCl.LiCl(0.28mL,0.52mmol)逐滴加入邻-碘代膦硼烷(IV-g)(0.19g,0.47mmol)的无水THF(2mL)溶液中。在此温度下,使所得溶液搅拌一小时,然后,逐滴添加三甲基氯硅烷(0.09mL,0.71mmol)。在-20℃下30分钟并在室温下20小时后,反应混合物利用水(10mL)淬火并利用二氯甲烷(3x10mL)萃取。通过MgSO4干燥有机相,将其过滤并蒸发溶剂,得到残余物,该残余物通过硅胶柱层析进行纯化,将石油醚/乙酸乙酯(3/1)用作洗脱液,得到相应的硅烷基化膦。无色油;得率25%;1H NMR(300MHz,CDCl3)δ0.26(d,J=1.5Hz,9H,CH3Si),7.08-7.18(m,13H,Harom),7.50-7.54(m,1H,Harom);31H NMR(121MHz,CDCl3)δ-10.2(s)。
H.2.硅烷基作为桥的二膦47b,c的合成
基本步骤:
在氩气中,在-78℃下,将n-BuLi(0.55mmol)逐滴加入邻-溴膦(II)(0.50mmol)的无水THF(3mL)溶液中。在此温度下,将所得溶液搅拌一小时,然后,逐滴添加二氯二甲基硅烷(0.23mmol)。在室温下搅拌过夜后,反应混合物利用水(10mL)淬火并利用二氯甲烷(3x10mL)萃取。通过MgSO4干燥有机相,将其过滤并蒸发溶剂,得到残余物,该残余物通过硅胶柱层析和/或重结晶进行纯化。
H.2.1.二膦47b:
纯化:柱层析(利用3:1二氯甲烷/石油醚洗脱)以及在甲醇/二氯甲烷中重结晶。白色固体;得率:52%;Rf0.28(二氯甲烷/石油醚3:1);IR(纯)3045,2966,1583,1478,1431,1251,1108,831,809,737,694cm-1;1H NMR(300MHz,CDCl3)δ0.63(t,J=1.5Hz,6H,SiCH3),6.90-6.95(m,8H,Harom),7.06-7.21(m,18H,Harom),7.64-7.68(m,2H,Harom);13C NMR(75.5MHz,CDCl3)δ2.58(t,J=10.1Hz,SiCH3),127.9(Carom),128.1(d,J=6.1Hz,Carom),128.2(Carom),129.1(Carom),133.2(d,J=18.8Hz,Carom),135.2(Carom),136.3(dd,J=2.8,16.0Hz,Carom),138.4(d,J=13.3Hz,Carom),143.0(d,J=12.0Hz,Carom),148.0(dd,J=3.3,47.5Hz,Carom);31P NMR(121MHz,CDCl3)δ-11.2;C38H34P2SiNa[M+Na]+的HRMS计算值603.1797,实验值603.1778。
H.2.2.二膦47c:
纯化:柱层析(利用3:1二氯甲烷/石油醚洗脱)。白色固体;得率:61%;Rf 0.10(二氯甲烷/石油醚3:1);[α]D-34.0(c 0.3,CHCl3)(ee=99%);IR(纯)3049,2954,2833,1575,1467,1271,1239,1110,1023,814,741,695cm-1;1H NMR(300MHz,CDCl3)δ0.74-0.75(m,6H,SiCH3),3.66(s,6H,OCH3),6.66(ddd,J=1.7,4.1,7.3Hz,2H,Harom),6.82-6.86(m,4H,Harom),7.04-7.07(m,6H,Harom),7.17-7.32(m,12H,Harom),7.64-7.66(m,2H,Harom);13CNMR(75.5MHz,CDCl3)δ2.62(dd,J=8.7,12.6Hz,SiCH3),55.5(OCH3),110.3(Carom),120.8(Carom),127.3(d,J=14.2Hz,Carom),127.8(Carom),127.9(d,J=6.2Hz,Carom),128.7(Carom),129.7(Carom),133.5(Carom),133.6(Carom),133.9(Carom),134.9(Carom),136.4(dd,J=2.1,15.7Hz,Carom),137.5(d,J=11.9Hz,Carom),142.7(d,J=11.3Hz,Carom),147.1(dd,J=2.5,47.1Hz,Carom),160.8(d,J=17.7Hz,Carom);31P NMR(121MHz,CDCl3)δ-20.0。
I.1,2-二膦基苯(I-48)的合成
表7.1,2-二膦基苯(I-48)的合成
a)在手性柱上通过HPLC确定
I.1利用氯膦合成
基本步骤
在氩气中,在-78℃下,将n-BuLi(1.6M,在己烷中)(0.37mL,0.59mmol)加入邻-溴芳基膦(II)(0.54mmol)的THF(2mL)溶液中,并在此温度下,使所得溶液搅拌一小时。此时,在-78℃下,添加氯膦(0.65mmol),并在室温下,将溶液搅拌过夜。利用水淬火后,利用二氯甲烷(3x5mL)萃取混合物,并通过MgSO4干燥有机相。真空下蒸发溶剂,得到残余物,该残余物通过硅胶层析柱和/或重结晶进行纯化。
I.1.1.(Sp)-1-二苯基膦基-2-(邻-茴香基苯基膦基)苯48a
纯化:柱层析(利用3:1石油醚/二氯甲烷洗脱)。分析纯样品通过在二氯甲烷/甲醇中重结晶获得。白色固体;得率70%;对映体过量99%,通过HPLC分析(chiralpak AD,0.2mL.min-1,己烷/2-丙醇99:1,tR(S)44.5min,tR(R)61.9min);Rf0.18(石油醚/二氯甲烷3:1);[α]D+58.6(c 0.3,CHCl3);IR(纯)3048,1581,1571,1469,1431,1299,1272,1240,1180,1160,1129,1090,1069,1022,793,743,719cm-1;1H NMR(300MHz,CDCl3)δ3.57(s,3H,OCH3),6.56(ddd,J=1.7,4.4,7.4Hz,1H,Harom),6.67-6.75(m,2H,Harom),6.90-7.00(m,2H,Harom),7.04-7.22(m,18H,Harom);13C NMR(75.5MHz,CDCl3)δ55.6(OCH3),110.2(d,J=1.5Hz,Carom),120.8(Carom),125.9(dd,J=6.7,13.9Hz,Carom),128.1(Carom),128.2(Carom),128.3(Carom),129.0(Carom),130.0(Carom),133.6(Carom),133.7(Carom),133.8(Carom),133.9(Carom),134.0(Carom),134.1(Carom),134.2(Carom),134.3(Carom),136.5(dd,J=4.9,11.0Hz,Carom),137.4(dd,J=5.1,12.1Hz,Carom),143.3(dd,J=10.7,21.7Hz,Carom),143.6(dd,J=9.5,32.5Hz,Carom),161.0(d,J=15.3Hz,Carom);31P NMR(121MHz,CDCl3)δ-14.0(d,J=164.8Hz),-23.6(d,J=164.8Hz);C31H26OP2Na[M+Na]+的HRMS计算值499.1351,实验值499.1375。
I.1.2.(Sp)-1-二环己基膦基-2-(邻-茴香基苯基膦基)-苯48b
纯化:柱层析(利用3:1石油醚/乙酸乙酯洗脱)。白色固体;得率47%;对映体过量99%,通过HPLC分析(Lux 5u纤维素2,0.5mL.min-1,己烷/2-丙醇98:2,tR(S)7.6min,tR(R)10.7min);Rf 0.62(石油醚/乙酸乙酯3:1);[α]D+57.1(c 0.3,CHCl3);IR(纯)2922,2847,1582,1571,1471,1445,1430,1241,1041,836,752,695cm-1;1H NMR(300MHz,CDCl3)δ1.00-1.20(m,10H,Hcy),1.48-1.79(m,12H,Hcy),3.62(s,3H,OCH3),6.54(ddd,J=1.5,3.6,7.2Hz,1H,Harom),6.73-6.85(m,3H,Harom),7.09-7.7.27(m,9H,Harom),7.43-7.47(m,1H,Harom);13C NMR(75.5MHz,CDCl3)δ26.4(d,J=8.6Hz,CH2),27.0-27.5(m,CH2),28.8(d,J=7.8Hz,CH2),29.1(d,J=10.5Hz,CH2),34.0(dd,J=5.4,14.7Hz,CH),34.9(dd,J=4.3,15.4Hz,CH),55.6(OCH3),110.1(Carom),120.8(Carom),127.5(dd,J=9.1,17.7Hz,Carom),127.8(Carom),128.0-128.1(m,Carom),128.6(Carom),129.7(Carom),132.4(dd,J=2.2,6.2Hz,Carom),133.4(d,J=7.5Hz,Carom),134.2(Carom),134.3(Carom),134.6(Carom),137.3(dd,J=3.8,15.2Hz,Carom),141.7(dd,J=17.0,31.2Hz,Carom),146.2(dd,J=8.2,32.4Hz,Carom),160.8(d,J=15.8Hz,Carom);31P NMR(121MHz,CDCl3)δ-12.2(d,J=167.8Hz),-23.2(d,J=167.8Hz);C31H38OP2Na[M+Na]+的HRMS计算值511.2290,实验值511.2295。
I.1.3.(Sp)-1-二-异-丙基膦基-2-(邻-茴香基苯基膦基)苯48c
纯化:柱层析(利用3:1石油醚/乙酸乙酯洗脱)。无色黏稠状油;得率43%;对映体过量99%,通过HPLC分析(Lux 5u纤维素2,0.3mL.min-1,己烷/2-丙醇98:2,tR(S)12.8min,tR(R)14.7min);Rf0.63(石油醚/乙酸乙酯3:1);[α]D+85.0(c 0.5CHCl3);IR(纯)2948,2864,1572,1461,1429,1271,1240,1180,1104,1070,1025,879,746cm-1;1H NMR(300MHz,C6D6)δ0.90(dd,J=7.2,12.0Hz,3H,CH3),1.12(dd,J=7.2,10.8Hz,3H,CH3),1.24(dd,J=7.2,13.8Hz,3H,CH3),1.36(dd,J=7.2,14.4Hz,3H,CH3),2.12-2.18(m,2H,CH),3.30(s,3H,OCH3),6.61(dd,J=4.4,8.1Hz,1H,Harom),6.86(t,J=7.4Hz,1H,Harom),7.06-7.11(m,2H,Harom),7.18-7.24(m,5H,Harom),7.31-7.33(m,1H,Harom),7.46-7.48(m,1H,Harom),7.57-7.60(m,2H,Harom);13C NMR(75.5MHz,C6D6)δ19.2(d,J=9.3Hz,CH3),19.5(d,J=12.5Hz,CH3),20.1(d,J=18.7CH3),20.2(dd,J=1.9,18.6Hz,CH3),24.3(dd,J=5.6,15.7Hz,CH),25.0(dd,J=4.5,16.6Hz,CH),54.9(OCH3),110.1(Carom),121.0(Carom),128.1(Carom),128.2(Carom),128.3(Carom),128.8(Carom),129.7(Carom),132.2(d,J=2.3Hz,Carom),132.3(d,J=2.8Hz,Carom),133.4(d,J=7.8Hz,Carom),134.6(Carom),134.9(Carom),135.0(Carom),138.2(dd,J=4.9,14.7Hz,Carom),142.1(d,J=19.4Hz,Carom),142.3(d,J=18.8Hz,Carom),147.1(dd,J=11.2,32.7Hz,Carom),161.2(d,J=15.1Hz,Carom);31P NMR(121MHz,C6D6)δ-3.7(d,J=165.0Hz),-20.7(d,J=165.0Hz);C25H30OP2Na[M+Na]+的HRMS计算值431.1664,实验值431.1682。
I.1.4.(Sp)-1-二(邻-甲苯基)膦基-2-(邻-茴香基-苯基膦基)苯48d
纯化:柱层析(利用3:1甲苯/石油醚洗脱)并在二氯甲烷/甲醇中重结晶。白色固体;得率37%;对映体过量99%,通过HPLC分析(Lux 5u纤维素2,0.5mL.min-1,己烷/2-丙醇98:2,tR(S)8.2min,tR(R)9.6min);Rf0.39(甲苯/石油醚3:1);[α]D+73.0(c 0.2,CHCl3);IR(纯)3050,2929,2834,1573,1469,1429,1272,1241,1130,1108,1070,1025,745cm-1;1H NMR(300MHz,C6D6)δ2.38(s,3H,CH3),2.54(s,3H,CH3),3.23(s,3H,OCH3),6.56(dd,J=4.2,7.8Hz,1H,Harom),6.82-6.85(m,1H,Harom),7.01-7.26(m,14H,Harom),7.27-7.30(m,2H,Harom),7.38-7.39(m,1H,Harom),7.53-7.55(m,1H,Harom);13C NMR(75.5MHz,C6D6)δ21.1(d,J=21.1Hz,CH3),21.3(d,J=21.1Hz,CH3),54.9(OCH3),126.0(d,J=5.7Hz,Carom),126.9(dd,J=6.9,16.0Hz,Carom),128.1(Carom),128.2(Carom),128.3(d,J=3.1Hz,Carom),128.5(d,J=6.9Hz,Carom),129.1(d,4.6Hz,Carom),129.8(Carom),130.2(2d,J=5.1Hz;J=4.7Hz,2Carom),133.7(Carom),133.9(Carom),134.0(d,J=6.9Hz,Carom),134.1(d,J=7.0Hz,Carom),134.2(Carom),134.4(Carom),134.6(Carom),136.1-136.3(m,Carom),137.5(dd,J=4.7,13.6Hz,Carom),142.7(2dd,J=9.9,34.0Hz;J=15.2,26.7Hz,2Carom),155.7(dd,J=11.1,32.8Hz,Carom),162.2(d,J=15.3Hz,Carom);31P NMR(121MHz,C6D6)δ-22.0(d,J=172.5Hz),-26.3(d,J=172.5Hz);C33H31OP2[M+H]+的HRMS计算值505.1845,实验值505.1841。
I.1.5.(Sp)-1-二(对-甲苯基)膦基-2-(邻-茴香基-苯基膦基)苯48e
纯化:柱层析(利用2:1甲苯/石油醚洗脱)。白色固体;得率52%;对映体过量99%,通过HPLC分析(Lux 5u纤维素2,0.5mL.min-1,己烷/2-丙醇90:10,tR(S)8.0min,tR(R)10.9min);Rf 0.17(甲苯/石油醚2:1);[α]D+58.0(c 0.3,CHCl3);IR(纯)3046,2963,2919,1572,1496,1470,1429,1396,1260,1240,1184,1090,1020,803,750,696cm-1;1H NMR(300MHz,CDCl3)δ2.32-2.33(2s,6H,CH3),3.67(s,3H,OCH3),6.62(ddd,J=1.7,4.3,7.4Hz,1H,Harom),6.76-6.84(m,2H,Harom),6.99-7.31(m,18H,Harom);13C NMR(75.5MHz,CDCl3)δ20.2(CH3),20.3(CH3),54.5(OCH3),109.1(d,J=1.3Hz,Carom),119.7(Carom),125.0(dd,J=6.5,13.9Hz,Carom),127.0(Carom),127.1(Carom),127.6(Carom),127.8(Carom),127.9(d,J=3.0Hz,Carom),128.0(d,J=2.7Hz,Carom),128.8(Carom),132.6(d,J=7.6Hz,Carom),132.7-133.2(m,Carom),135.6(dd,J=4.8,11.5Hz,Carom),136.95Carom),137.0(Carom),142.2(dd,J=10.1,31.6Hz,Carom),143.2(dd,J=11.2,32.4Hz,Carom),160.0(d,J=15.4Hz,Carom);31P NMR(121MHz,CDCl3)δ-15.4(d,J=162.8Hz),-24.1(d,J=162.8Hz);C33H30OP2Na[M+Na]+的HRMS计算值527.1664,实验值527.1687。
I.1.6.(Sp)-1-二(对-三氟甲基苯基)膦基-2-(邻-茴香基苯基膦基)苯48f
纯化:柱层析(利用2:1甲苯/石油醚洗脱)。白色固体;得率58%;对映体过量99%,通过HPLC分析(Lux 5u纤维素2,0.3mL.min-1,己烷/2-丙醇90:10,tR(S)11.3min,tR(R)13.1min);Rf 0.56(甲苯/石油醚2:1);[α]D+52.9(c 0.3,CHCl3);IR(纯)3050,2933,1431,1397,1320,1242,1163,1120,1105,1059,1015,830,750,696cm-1;1H NMR(300MHz,CDCl3)δ3.57(s,3H,OCH3),6.48-6.52(m,1H,Harom),6.65-6.74(m,2H,Harom),6.90-7.01(m,2H,Harom),7.06-7.25(m,12H,Harom),7.35(d,J=7.8Hz,2H,Harom),7.41(d,J=7.8Hz,2H,Harom);13C NMR(75.5MHz,CDCl3)δ55.6(OCH3),120.9(Carom),124.0(2q,J=272.4Hz,2CF3),124.9-125.1(m,Carom),128.2(Carom),128.4(d,J=7.3Hz,Carom),128.7(Carom),129.1(Carom),129.3(Carom),129.6(Carom),130.4(Carom),130.5(q,J=32.4Hz,Carom),133.9-134.2(m,Carom),134.5(Carom),135.6(dd,J=4.5,10.1Hz,Carom),140.8(d,J=9.8Hz,Carom),141.3-141.8(m,Carom),144.2(dd,J=10.5,32.8Hz,Carom),161.0(d,J=15.4Hz,Carom);31P NMR(121MHz,CDCl3)δ-14.5(d,J=164.5Hz),-24.0(d,J=164.5Hz);19FNMR(282MHz,CDCl3)δ-62.8(2s,CF3);C33H24OF6P2Na[M+Na]+的HRMS计算值635.1099,实验值635.1103。
I.1.7.(Rp)-1-二苯基膦基-2-(二茂铁基苯基膦基)苯48g
在氩气中,在-78℃下,将n-BuLi(1.6M,在己烷中)(0.37mL,0.50mmol)加入(S)-二茂铁基-(2-溴苯基)-苯基膦(II-k)(0.20g,0.45mmol)的THF(2mL)溶液中,在此温度下,将所得溶液搅拌一小时。此时,在-78℃下,添加氯二苯基膦(0.09mL,0.54mmol)并在室温下将溶液搅拌过夜。利用水淬火后,利用二氯甲烷(3x5mL)萃取混合物,并通过MgSO4干燥有机相。真空下蒸发溶剂,得到残余物,该残余物通过硅胶层析柱(将甲苯/石油醚(1/1)用作洗脱液)以及在二氯甲烷/丙酮中重结晶进行纯化。
纯化:柱层析(利用1:1甲苯/石油醚洗脱)并在二氯甲烷/丙酮中重结晶。橙色固体;得率:56%;对映体过量99%,通过HPLC分析(Lux 5u纤维素2,1.0mL.min-1,己烷/2-丙醇98:2,tR(S)5.5min,tR(R)7.9min);Rf0.34(甲苯/石油醚1:1);[α]D-55.5(c 0.2,CHCl3);IR(纯)3048,1585,1567,1478,1433,1307,1193,1158,1106,1069,1025,1000,888cm-1;1H NMR(300MHz,C6D6)δ4.04(sl,1H,Cp),4.19(sl,5H,Cp),4.22(sl,1H,Cp),4.26(sl,Cp),4.37(sl,1H,Cp),7.04-7.18(m,11H,Harom),7.30-7.34(m,3H,Harom),7.54-7.56(m,5H,Harom);13C NMR(75.5MHz,C6D6)δ69.4(Cfer),70.6(Cfer),71.2(d,J=5.3Hz,Cfer),72.7(d,J=5.4Hz,Cfer),73.8(d,J=24.1Hz,Cfer),77.4(d,J=11.1Hz,Cfer),128.1(Carom),128.2(2s,2Carom),128.3(Carom),128.5(d,J=5.8Hz,Carom),128.8(d,J=6.3Hz,Carom),133.6(Carom),133.7(Carom),133.8(Carom),134.2(Carom),134.4(2s,2Carom),134.5(Carom),137.4(dd,J=4.0,12.5Hz,Carom),138.6(dd,J=7.9,14.0Hz,Carom),139.1(d,J=9.8Hz,Carom),142.9(dd,J=12.3,30.8Hz,Carom),146.9(dd,J=13.7,32.3Hz,Carom);31P NMR(121MHz,C6D6)δ-13.6(d,J=155.5Hz),-24.6(d,J=155.5Hz);C34H28FeP2Na[M+Na]+的HRMS计算值577.0908,实验值577.0935。
I.1.8.(Rp)-1-二苯基膦基-2-(异丙基苯基膦基)苯48h
在-78℃下,在氩气中,将n-BuLi(1.6M,在己烷中)(0.37mL,0.50mmol)加入(R)-(2-溴苯基)-异丙基苯基膦(II-m)(0.14g,0.45mmol)的THF(2mL)溶液中,并在此温度下,将所得溶液搅拌一小时。此时,在-78℃下,添加氯二苯基膦(0.09mL,0.54mmol)并在室温下,将溶液搅拌过夜。利用水淬火后,利用二氯甲烷(3x5mL)萃取混合物并通过MgSO4干燥有机相。真空下蒸发溶剂,得到残余物,该残余物通过硅胶层析柱进行纯化,将石油醚/甲苯(2/1)作为洗脱液。
白色固体;得率:54%;对映体过量:98%,在转化成相应的二硫代膦后通过HPLC分析(Lux 5u纤维素2,0.8mL.min-1,己烷/2-丙醇80:20,tR(R)=16.2min,tR(S)=18.2min;Rf0.39(石油醚/甲苯2:1);[α]D+61.7(c 0.3,CHCl3);IR(纯)3050,2962,2923,2864,1477,1433,1381,1363,1305,1270,1229,1181,1155,1091,1069,1025,999,745,695,648cm-1;1HNMR(300MHz,CDCl3)δ1.07(ddd,J=2.6,6.8,13.6Hz,3H,CH3),1.11(ddd,J=2.9,6.8,12.8Hz,3H,CH3),2.48-2.55(m,1H,CH),6.94-6.97(m,1H,Harom),7.07-7.35(m,16H,Harom),7.38(td,J=1.3,7.5Hz,1H,Harom),7.66-7.68(m,1H,Harom);13C NMR(75.5MHz,CDCl3)δ19.5(dd,J=3.4,18.4Hz,CH3),19.7(dd,J=3.4,16.2Hz,CH3),25.9(dd,J=4.6,7.1Hz,CH),127.9(Carom),128.0(Carom),128.1(Carom),128.2(2s,Carom),128.3(Carom),128.4(Carom),128.7(Carom),128.9(Carom),131.9(d,J=5.1Hz,Carom),133.3(d,J=3.4Hz,Carom),133.4(d,J=3.7Hz,Carom),133.9(d,J=6.1Hz,Carom),134.0(t,J=4.1Hz,Carom),134.2(t,J=4.4Hz,Carom),136.9(d,J=9.5Hz,Carom),137.7(d,J=11.8Hz,Carom),138.0(dd,J=5.3,10.2Hz,Carom),143.5(dd,J=6.5,22.8Hz,Carom),144.8(dd,J=3.9,25.0Hz,Carom);31P NMR(121MHz,CDCl3)δ-13.1(d,J=155.8Hz),-14.2(d,J=155.8Hz);C27H27P2[M+H]+的HRMS计算值413.1582,实验值413.1586。
I.2.利用苯基次亚膦酸酯合成
I.2.1.(Sp)-1-二苯基膦基-2-(邻-甲苯基苯基膦基)苯48i
在-78℃下,在氩气中,将n-BuLi(1.6M,在己烷中)(0.41mL,0.65mmol)加入邻-溴二苯基膦(II-a)(0.20g,0.59mmol)的THF(3mL)溶液中,并在此温度下,将所得溶液搅拌一小时。此时,在-78℃下,逐滴添加(R)-苯基-邻-甲苯基苯基次亚膦酸酯(0.17g,0.59mmol)的THF(2mL)溶液,并在室温下,将混合物搅拌过夜。利用水淬火后,利用二氯甲烷(3x5mL)萃取混合物并通过MgSO4干燥有机相。真空下蒸发溶剂,得到残余物,该残余物通过硅胶层析柱进行纯化,将甲苯/石油醚(1/1)作为洗脱液。
无色黏稠固体;得率:54%;对映体过量:99%,通过HPLC分析(Lux5u纤维素2,0.2mL.min-1,己烷/2-丙醇98:2,tR(S)=19.5min,tR(R)=20.8min;Rf 0.43(石油醚/甲苯1:1);[α]D+33.0(c 0.3CHCl3);IR(纯)3051,1584,1477,1433,1269,1068,998,739,693cm-1;1HNMR(300MHz,C6D6)δ2.45(d,J=0.8Hz,3H,CH3),7.00-7.07(m,3H,Harom),7.08-7.19(m,12H,Harom),7.30-7.32(m,1H,Harom),7.36-7.38(m,1H,Harom),7.43-7.48m,6H,Harom);13C NMR(75.5MHz,C6D6)δ21.2(d,J=22.6Hz,CH3),126.0(Carom),128.3(Carom),128.4(m,Carom),128.5(Carom),128.6(d,J=7.3Hz,Carom),129.2(d,J=6.2Hz,Carom),130.2(d,J=4.5Hz,Carom),133.7(Carom),133.8(Carom),134.0(Carom),134.1(Carom),134.2(d,J=18.7Hz,Carom),134.3(Carom),134.4(Carom),134.5(Carom),136.7(dd,J=5.6,13.3Hz,Carom),137.0(dd,J=5.6,13.3Hz,Carom),137.7(dd,J=6.1,12.8Hz,Carom),138.0(dd,J=6.1,12.8Hz,Carom),142.4(d,J=26.2Hz,Carom),143.8(dd,J=11.7,32.9Hz,Carom),144.4(dd,J=12.2,33.2Hz,Carom);31P NMR(121MHz,C6D6)δ-12.7(d,J=154.0Hz),-19.8(d,J=154.0Hz);C31H26P2Na[M+Na]+的HRMS计算值483.1402,实验值483.1423。
I.2.2.(S,S)-二[1,2-(邻-茴香基-苯基)膦基]苯48j
在-78℃下,在氩气中,将n-BuLi(1.6M,在己烷中)(0.41mL,0.65mmol)加入(S)-邻-茴香基-(邻-溴)苯基膦(II-i)(0.22g,0.59mmol)的THF(3mL)溶液中,并在此温度下,将所得溶液搅拌一小时。此时,在-78℃下,逐滴添加(R)-苯基-邻-茴香基苯基次亚膦酸酯(0.18g,0.59mmol)的THF(2mL)溶液,并在室温下,将混合物搅拌过夜。利用水淬火后,利用二氯甲烷(3x5mL)萃取混合物并通过MgSO4干燥有机相。真空下蒸发溶剂,得到残余物,该残余物通过硅胶层析柱(将二氯甲烷/石油醚(2/1)作为洗脱液)并在二氯甲烷/甲醇中重结晶进行纯化。
白色固体;得率:52%;对映体过量:99%,在(+)-二-μ-氯双{2[1-(二甲基氨基)乙基]苯基-C,N}二钯存在下,通过31P NMR;Rf 0.39(二氯甲烷/石油醚2:1);[α]D+116.2(c0.4,CHCl3);IR(纯)3055,2937,2832,1571,1469,1429,1295,1270,1239,1178,1157,1130,1093,1069,1039,1023,1012,792,745,730,690cm-1;1H NMR(300MHz,CDCl3)δ3.57(s,6H,OCH3),6.69-6.72(m,2H,Harom),6.80-6.84(m,4H,Harom),6.99-7.02(m,2H,Harom),7.24-7.32(m,14H,Harom);13C NMR(75.5MHz,CDCl3)δ55.5(OCH3),110.2(Carom),120.8(Carom),126.6(t,J=3.6Hz,Carom),128.1(3s,Carom),128.9(Carom),129.8(Carom),133.5(t,J=3.2Hz,Carom),133.9(Carom),134.0(Carom),134.1(Carom),134.2(Carom),136.9(t,J=3.9Hz,Carom),143.3(t,J=11.9Hz,Carom),161.0(d,J=6.9Hz,Carom);31P NMR(121MHz,CDCl3)δ-23.4(s);C32H38O2P2Na[M+Na]+的HRMS计算值507.1637,实验值507.1637。
I.2.3.(1R,2S)-(+)-1-(异-丙基苯基膦基)-2-(邻-茴香基苯基膦基)-苯48k
在-78℃下,在氩气中,将n-BuLi(1.6M,在己烷中)(0.41mL,0.65mmol)加入(R)-异丙基-(2-溴苯基)-苯基膦(II-m)(0.18g,0.59mmol)的THF(3mL)溶液中,并在此温度下,将所得溶液搅拌一小时。此时,在-78℃下,逐滴添加(R)-苯基-邻-茴香基苯基次亚膦酸酯(0.18g,0.59mmol)的THF(2mL)溶液,并在室温下将混合物搅拌过夜。利用水淬火后,利用二氯甲烷(3x5mL)萃取混合物并通过MgSO4干燥有机相。真空下蒸发溶剂,得到残余物,该残余物通过硅胶层析柱进行纯化,将二氯甲烷/石油醚(2/1)作为洗脱液。
白色黏稠固体;得率:56%;对映体过量:99%,通过HPLC分析(Chiralpak AD,0.2mL.min-1,己烷/2-丙醇98:2,tR(RS)=24.5min,tR(SS)=27.5min;Rf 0.44(石油醚/二氯甲烷1:2);[α]D+85.0(c 0.2CHCl3);IR(纯)2954,1575,1461,1429,1271,1239,1179,1129,1070,1023,745,695cm-1;1H NMR(300MHz,CDCl3)δ6.81(td,J=6.8,15.4Hz,6H,CH3),2.47-2.57(m,1H,CH),3.61(s,3H,OCH3),6.47(ddd,J=1.5,3.8,7.2Hz,1H,Harom),6.65(t,J=7.4Hz,1H,Harom),6.79(ddd,J=0.7,4.7,8.2Hz,1H,Harom),6.89-6.92(m,1H,Harom),7.14-7.24(m,5H,Harom),7.30-7.39(m,8H,Harom),7.61-7.64(m,1H,Harom);13C NMR(75.5MHz,CDCl3)δ19.5(CH3),19.7(CH3),25.6(dd,J=8.1,10.7Hz,CH),55.6(OCH3),110.1(d,J=1.4Hz,Carom),120.7(Carom),126.0(dd,J=5.2,13.7Hz,Carom),127.8(d,J=7.2Hz,Carom),128.0(Carom),128.2(2s,Carom),128.8(d,J=17.2Hz,Carom),129.8(Carom),131.7(d,J=6.4Hz,Carom),133.3(d,J=19.2Hz,Carom),134.0(Carom),134.0(d,J=7.2Hz,Carom),134.2(Carom),134.4(Carom),137.3(dd,J=7.3,13.8Hz,Carom),138.3(d,J=2.9Hz,Carom),143.8(dd,J=13.9,31.6Hz,Carom),144.9(d,J=10.1Hz,Carom),160.9(d,J=13.5Hz,Carom);31P NMR(121MHz,CDCl3)δ-13.5(d,J=163.2Hz),-24.6(d,J=163.2Hz);C28H29OP2[M+H]+的HRMS计算值443.1688,实验值443.1667。
J.具有联苯桥的二膦的合成(I-49)
表8.具有联苯桥的二膦的合成(I'-49)
a以二硼烷络合物形式分离
J.1.二-2,2'-(二苯基膦基)联苯49a
在-78℃下,在氩气中,将n-BuLi(1.6M,在己烷中)(0.75mL,1.20mmol)加入(2-溴苯基)-二苯基膦(II-a)(0.41g,1.20mmol)的THF(5mL)溶液中,并在此温度下,将所得溶液搅拌一小时。然后,添加Fe(acac)3(0.52g,1.44mmol)的THF(7mL)溶液,并在-78℃下,使搅拌维持一小时。溶液利用水(2mL)淬火并利用二氯甲烷(3x10mL)萃取。通过MgSO4干燥有机相并在真空下蒸发溶剂,得到残余物,该残余物通过硅胶层析柱进行纯化,将石油醚/二氯甲烷(2/1)作为洗脱液。标题化合物是以白色固体的形式获得。得率:46%;Rf 0.32(石油醚/CH2Cl2 2/1);1H NMR(300MHz,CDCl3)δ6.80-6.84(m,2H,Harom),6.98-7.01(m,2H,Harom),7.04-7.22(m,24H,H arom);31P NMR(121MHz,CDCl3)δ-14.4。值得注意的是,(II-a)的偶合也利用FeCl3或Cu(OAc)2并且二膦49a以令人满意的得率获得(30-45%)。
J.2.二-2,2'-(二-邻-甲苯基膦基)联苯49b
在-78℃下,在氩气中,将n-BuLi(1.6M,在己烷中)(0.82mL,1.32mmol)加入(2-溴苯基)-二(邻-甲苯基)膦(II-e)(0.44g,1.20mmol)的THF(5mL)溶液中,并在此温度下,将所得溶液搅拌一小时。然后,添加Fe(acac)3(0.52g,1.44mmol)的THF(7mL)溶液,并在-78℃下,使搅拌维持一小时。溶液利用水(2mL)淬火并利用二氯甲烷(3x10mL)萃取。通过MgSO4干燥有机相并在真空下蒸发溶剂,得到残余物,该残余物通过硅胶层析柱进行纯化,将石油醚/二氯甲烷(2/1)作为洗脱液。标题化合物是以白色固体的形式获得。得率:36%;Rf 0.41(石油醚/甲苯20/1);IR(纯)3050,3002,1450,1428,1380,1267,1201,1129,1034,951,877,801,751,717cm-1;1H NMR(300MHz,CDCl3)δ2.11(s,6H,CH3),2.44(sl,6H,CH3),6.77-6.78(m,2H,Harom),6.92-6.93(m,2H,Harom),6.97-7.01(m,4H,Harom),7.06-7.09(m,2H,Harom),7.12-7.15(m,4H,Harom),7.19(td,J=1.4,7.5Hz,2H,Harom),7.23-7.29(m,6H,Harom);13C NMR(75.5MHz,CDCl3)δ20.9(d,J=24.1Hz,CH3),21.5(t,J=12.1Hz,CH3),125.7(d,J=6.6Hz,Carom),127.2(Carom),127.4(Carom),128.2(Carom),128.6(Carom),129.6(t,J=3.0Hz,Carom),129.9(t,J=2.0Hz,Carom),131.2(dd,J=4.2,3.7Hz,Carom),132.6(Carom),133.1(Carom),135.2(Carom),135.6(d,J=14.4Hz,Carom),135.7(Carom),136.1(d,J=24.1Hz,Carom),143.0(d,J=25.7Hz,Carom),143.3(d,J=28.3Hz,Carom);31P NMR(121MHz,CDCl3)δ-28.5.C40H36P2Na(M+Na)+的HRMS计算值601.2185,实验值601.2164。
J.3.(S,S)-二-2,2'-(二茂铁基苯基膦基)联苯基二硼烷以及游离二膦49c的合成
在-78℃下,在氩气中,将n-BuLi(1.6M,在己烷中)(0.30mL,0.48mmol)加入(S)-二茂铁基-(2-溴苯基)-苯基膦(II-k)(0.20g,0.44mmol)的THF(4mL)溶液中,并在此温度下,将所得溶液搅拌一小时。然后,添加Fe(acac)3(0.19g,0.53mmol)的THF(5mL)溶液并在-78℃下,使搅拌维持一小时。溶液利用水(2mL)淬火并利用二氯甲烷(3x10mL)萃取。通过MgSO4干燥有机相并在真空下蒸发溶剂,得到残余物,该残余物通过硅胶层析柱进行纯化,将石油醚/乙酸乙酯(20/1)作为洗脱液。将得到的橙色粉末溶于THF中并添加BH3.DMS。搅拌过夜后,加水(1mL)并利用二氯甲烷(3x5mL)萃取溶液。通过MgSO4干燥有机相并蒸发溶剂,得到橙色固体,该橙色固体在己烷和二氯甲烷的混合物中重结晶。标题二硼烷化合物是以橙色晶体的形式获得。得率:35%;对映体过量:99%,通过HPLC分析(chiralcel OD-H,0.5mL.min-1,己烷-2-丙醇98:2,tR(S,S)=27.2min,tR(R,R)=30.9min;Rf0.42(石油醚/乙酸乙酯3:1);[α]D-58.3(c 0.3,CHCl3);IR(纯)3053,2435,2371,2338,1459,1435,1171,1106,1057,1026,1001,823,742,697cm-1;1H NMR(300MHz,CDCl3)δ3.89(s,10H,Cp),4.16(sl,2H,Cp),4.21(sl,2H,Cp),4.32-4.34(m,4H,Cp),6.67-6.68(m,2H,Harom),6.97-7.14(m,6H,Harom),7.52-7.57(m,6H,Harom),7.91-7.97(m,4H,Harom);13C NMR(75.5MHz,CDCl3)δ69.7(Cp),69.8(d,J=68.1Hz,Cp),70.9(d,J=5.3Hz,Cp),71.0(d,J=7.9Hz,Cp),72.7(d,J=1.6Hz,Cp),75.0(d,J=18.2Hz,Cp),127.2(d,J=9.0Hz,Carom),128.3(d,J=10.2Hz,Carom),129.2(d,J=2.1Hz,Carom),130.3(d,J=54.0Hz,Carom),131.0(d,J=2.2Hz,Carom),132.2(d,J=61.5Hz,Carom),132.6(d,J=7.7Hz,Carom),133.5(d,J=9.2Hz,Carom),134.0(d,J=8.3Hz,Carom),143.6(dd,J=3.2,9.7Hz,Carom);31P NMR(121MHz,CDCl3)δ17.2;C44H42P2B2Fe2Na(M+Na)+的HRMS计算值789.1539,实验值789.1549;C44H42P2B2Fe2的分析计算值:C,68.99;H,5.53;实验值:C,69.27;H,5.43。
(S,S)-二-2,2'-(二茂铁基苯基膦基)联苯49c
在室温下,将二膦二硼烷(0.06g,0.08mmol)和DABCO(0.05g,0.48mmol)在无水甲苯(4mL)中的溶液搅拌过夜。真空下蒸发溶剂后,使残余物通过硅胶层析柱进行纯化,将石油醚/乙酸乙酯(3/1)作为洗脱液,得到呈橙色固体形式的标题化合物。得率:90%;对映体过量:99%,通过HPLC分析(chiralcel OD-H,0.3mL.min-1,己烷-2-丙醇98:2,tR(R,R)=19.6min,tR(S,S)=22.3min;Rf0.21(石油醚/乙酸乙酯20:1);[α]D-129.3(c 0.2,CHCl3);IR(纯)3069,2925,1477,1454,1431,1411,1306,1260,1192,1158,1107,1019,1000,815,747,699cm-1;1H NMR(300MHz,CDCl3)δ3.82(sl,2H,Cp),4.20(s,10H,Cp),4.43-4.44(m,2H,Cp),4.55(sl,2H,Cp),4.82-4.83(m,2H,Cp),6.53-6.54(m,2H,Harom),7.05(td,J=1.3,7.4Hz,2H,Harom),7.20-7.22(m,2H,Harom),7.27(td,J=1.2,7.4Hz,2H,Harom),7.28-7.34(m,10H,Harom);13C NMR(75.5MHz,CDCl3)δ69.2(Cp),69.8(Cp),71.0(t,J=3.5Hz,Cp),71.5(Cp),74.5(t,J=17.1Hz,Cp),127.1(Carom),127.5(Carom),127.7(t,J=3.7Hz,Carom),128.3(Carom),130.2(t,J=3.8Hz,Carom),132.4(Carom),134.4(t,J=10.7Hz,Carom),137.9(dd,J=4.0,4.7Hz,Carom),138.9(t,J=4.7Hz,Carom),145.6(t,J=17.1Hz,Carom);31P NMR(121MHz,CDCl3)δ-23.6;C44H36P2Fe2Na(M+Na)+的HRMS计算值761.0883,实验值761.0846;C44H36P2Fe2的分析计算值:C,71.57;H,4.91;实验值:C,71.12;H,5.06。
J.4.(R,R)-二-2,2'-(环己基苯基膦基)联苯49d
利用针对49a所述的相同步骤,从(R)-(2-溴苯基)-环己基-苯基膦(II-o)开始。通过硅胶柱层析纯化产物,将混合物己烷/CH2Cl2作为洗脱液。
31P NMR(CDCl3):δ=-17.1
J.5.(S,S)-二-2,2'-(苯基-邻-甲苯基膦基)联苯49e
利用针对49a所述的相同步骤,从(S)-(2-溴苯基)-苯基-(邻-甲苯基)膦(II-o)开始。通过硅胶柱层析纯化产物,将混合物己烷/EtOAc 50:1作为洗脱液。
31P NMR(CDCl3):δ=-18.7和-23.0
K.通过手性铑络合物催化不对称氢化
将铑络合物形式的手性二膦(I-48)和(I'-49c)在催化的不对称氢化反应中测试。所用底物是α-乙酰氨基肉桂酸甲酯63、衣康酸二甲酯65、左乙拉西坦69的前体67以及脱氢酯70和72:
K.1.用1,2-二膦基苯配体(I-48)制备铑络合物
基本步骤
在氩气中,将二膦(0.1mmol)的二氯甲烷(3.5mL)溶液逐滴加入[Rh(COD)2]BF4(0.09mmol)的二氯甲烷(2.5mL)溶液中。在此温度下,将所得溶液搅拌一小时,然后添加二乙醚(10mL)。过滤出沉淀并利用二乙醚(3x5mL)冲洗,得到铑络合物。
(环辛-1,5-二烯)-(Sp)-[1-二苯基膦基-2-(邻-茴香基-苯基膦基)-苯48a]四氟硼酸铑
基本步骤;橙色固体;得率80%;1H NMR(300MHz,CDCl3)δ2.35-2.45(m,8H,CH2),3.66(s,3H,OCH3),4.83-5.21(m,4H,CH),6.99-7.00(m,2H,Harom),7.12-7.14(m,1H,Harom),7.45-7.60(m,20H,Harom);31P NMR(121MHz,CDCl3)δ49.9(dd,J=27.6,150.7Hz),57.0(dd,J=27.6,150.7Hz);C39H38OP2Rh[M-BF4]+的HRMS计算值687.1447,实验值687.1436。
(环辛-1,5-二烯)-(Sp)-[1-二环己基膦基-2-(邻-茴香基-苯基膦基)-苯48b]四氟硼酸铑
基本步骤;橙色固体;得率63%;1H NMR(300MHz,CDCl3)δ0.85-1.40(m,12,Hcy),1.66-1.76(m,6H,Hcy),1.93-1.97(m,1H,Hcy),2.17-2.51(m,11H,Hcy/CH2),3.55(s,3H,OCH3),4.66-4.73(m,2H,CH),5.57(sl,1H,CH),5.92(sl,1H,CH),6.93-7.02(m,3H,Harom),7.36-7.62(m,9H,Harom),7.71-7.75(m,1H,Harom);31P NMR(121MHz,CDCl3)δ53.2(dd,J=24.9,150.6Hz),62.5(dd,J=24.9,145.4Hz);C39H50OP2Rh[M-BF4]+的HRMS计算值699.2386,实验值699.2362。
(环辛-1,5-二烯)-(Sp)-[1-二异丙基膦基-2-(邻-茴香基-苯基膦基)-苯48c]四氟硼酸铑
基本步骤;橙色固体;得率53%;1H NMR(300MHz,CDCl3)δ0.89(dd,J=7.0,16.3Hz,3H,CH3),1.18(dd,J=7.2,16.4Hz,3H,CH3),1.25-1.29(m,6H,CH3),2.29-2.46(m,6H,CH2/CH),2.53-2.60(m,2H,CH2),2.66-2.82(m,2H,CH2),3.60(s,3H,OCH3),4.75-4.79(2sl,2H,CHCOD),5.67(sl,1H,CHCOD),6.05(sl,1H,CHCOD),6.98-7.07(m,3H,Harom),7.41-7.47(m,3H,Harom),7.51-7.69(m,3H,Harom),7.64-7.67(m,3H,Harom),7.78-7.80(m,1H,Harom);31P NMR(121MHz,CDCl3)δ52.5(dd,J=23.9,152.3Hz),69.5(dd,J=23.9,146.3Hz);C33H42OP2Rh[M-BF4]+的HRMS计算值619.1760,实验值619.1758。
(环辛-1,5-二烯)-(Sp)-[1-二(对-甲苯基)膦基-2-(邻-茴香基-苯基膦基)-苯48e]四氟硼酸铑
基本步骤;橙色固体;得率54%;1H NMR(300MHz,CDCl3)δ2.31-2.43(m,8H,CH2),2.42(s,3H,CH3),2.44(s,3H,CH3),3.66(s,3H,OCH3),4.83-5.21(m,4H,CH),6.97-7.02(m,2H,Harom),7.12-7.15(m,1H,Harom),7.25-7.26(m,2H,Harom),7.31-7.35(m,4H,Harom),7.42-7.54(m,5H,Harom),7.55-7.61(m,7H,Harom);31P NMR(121MHz,CDCl3)δ49.8(dd,J=26.7,148.2Hz),56.2(dd,J=26.7,150.7Hz);C41H42OP2Rh[M-BF4]+的HRMS计算值715.1760,实验值715.1733。
(环辛-1,5-二烯)-(Sp)-[1-二(对-三氟甲基苯基)膦基-2-(邻-茴香基-苯基膦基)-苯48f]四氟硼酸铑
基本步骤;黄色固体;得率66%;1H NMR(300MHz,CDCl3)δ2.38-2.50(m,8H,CH2),3.70(s,3H,OCH3),4.90-5.31(m,4H,CH),6.96-6.98(m,2H,Harom),7.12(dd,J=5.1,8.4Hz,1H,Harom),7.47-7.63(m,12H,Harom),7.69-7.72(m,4H,Harom),7.81-7.82(m,2H,Harom);31P NMR(121MHz,CDCl3)δ49.7(dd,J=29.2,148.2Hz),56.0(dd,J=29.2,153.0Hz);C41H36OF6P2Rh[M-BF4]+的HRMS计算值823.1195,实验值823.1192。
(环辛-1,5-二烯)-(Rp)-[1-二苯基膦基-2-(二茂铁基-苯基膦基)-苯48g]四氟硼酸铑
基本步骤;深橙色固体;得率73%;1H NMR(300MHz,CDCl3)δ1.91-2.00(m,2H,CH2),2.23-2.25(m,2H,CH2),2.51-2.64(m,4H,CH2),3.61(s,5H,Cp),4.42(sl,1H,Cp),4.51(sl,1H,Cp),4.62-4.65(m,4H,Cp/CH),5.22-5.23(m,1H,CH),5.61-5.62(m,1H,CH),7.35-7.42(m,4H,Harom),7.45-7.47(m,3H,Harom),7.52-7.55(m,3H,Harom),7.61-7.69(m,6H,Harom),7.74-7.76(m,1H,Harom),7.90-7.93(m,2H,Harom);31P NMR(121MHz,CDCl3)δ51.0(dd,J=29.1,148.2Hz),58.2(dd,J=29.1,153.0Hz);C42H40FeP2Rh[M-BF4]+的HRMS计算值765.1005,实验值765.0987。
(环辛-1,5-二烯)-(Rp)-[1-二苯基膦基-2-(异丙基-苯基膦基)-苯48h]四氟硼酸铑
基本步骤;橙色固体;得率60%;1H NMR(300MHz,CDCl3)δ1.22(dd,J=7.0,14.7Hz,3H,CH3),1.28(dd,J=7.0,19.5Hz,3H,CH3),2.13-2.16(m,2H,CH2),2.32-2.58(m,6H,CH2),3.29-3.33(m,1H,CH),4.84-4.85(m,1H,CH),4.92-4.93(m,1H,CH),5.04-5.05(m,1H,CH),5.69-5.70(m,1H,CH),7.49-7.71(m,19H,Harom);31P NMR(121MHz,CDCl3)δ57.8(dd,J=28.5,154.9Hz),67.8(dd,J=28.5,148.6Hz);C35H38P2Rh[M-BF4]+的HRMS计算值623.1498,实验值623.1500。
(环辛-1,5-二烯)-(1S,2S)-[1,2-(邻-茴香基-苯基膦基)-苯48j]四氟硼酸铑
在氩气中,将二膦48j(0.059mmol)的THF(1.7mL)溶液逐滴加入[Rh(COD)2]BF4(0.055mmol)的THF(1.2mL)悬浮液中。在此温度下,将所得溶液搅拌一小时并将溶剂蒸发到约1mL。添加二乙醚(5mL)并过滤出所得的沉淀,然后利用二乙醚(3x5mL)冲洗,得到相应的铑络合物。
橙色固体;得率64%;1H NMR(300MHz,CDCl3)δ2.33-2.51(m,8H,CH2),3.60(s,6H,OCH3),5.07(sl,4H,CH),6.89-6.93(m,4H,Harom),7.09-7.11(m,2H,Harom),7.42-7.58(m,12H,Harom),7.67-7.70(m,4H,Harom);31P NMR(121MHz,CDCl3)δ50.7(d,J=149.8Hz);C40H40O2P2Rh[M-BF4]+的HRMS计算值717.1553,实验值717.1522。
(环辛-1,5-二烯)-(1S,2R)-[2-(异丙基-苯基膦基)-1-(邻-茴香基-苯基膦基)-苯48k]四氟硼酸铑
在氩气中,将二膦48k(0.059mmol)的THF(1.7mL)溶液逐滴加入[Rh(COD)2]BF4(0.055mmol)的THF(1.2mL)悬浮液中。在此温度下,将所得溶液搅拌一小时并将溶剂蒸发到约1mL。添加二乙醚(5mL)并过滤出所得沉淀,然后利用二乙醚(3x5mL)冲洗,得到相应的铑络合物。
橙色固体;得率70%;1H NMR(300MHz,CDCl3)δ1.07(dd,J=6.8,15.0Hz,3H,CH3),1.17(dd,J=6.8,19.1Hz,3H,CH3),2.05-2.17(m,2H,CH2),2.28-2.30(m,2H,CH2),2.45-2.47(m,2H,CH2),2.56-2.58(m,2H,CH2),3.10-3.14(m,1H,CH),3.60(s,3H,OCH3),4.70(sl,2H,CH),5.00(sl,1H,CH),5.70(sl,1H,CH),7.04-7.13(m,3H,Harom),7.52-7.61(m,13H,Harom),7.76-7.79(m,2H,Harom);31P NMR(121MHz,CDCl3)δ50.4(dd,J=26.9,150.1Hz),64.0(dd,J=26.9,146.3Hz);C36H40OP2Rh[M-BF4]+的HRMS计算值653.1604,实验值653.1591。
K.2.用二膦配体(I'-49c)制备铑络合物
(环辛-1,5-二烯)-[(S,S)-2,2’-双(二茂铁基-苯基膦基)-1,1’-联苯49c]四氟硼酸铑
在氩气中,将二膦49c(0.074g,0.1mmol)的二氯甲烷(3.5mL)溶液逐滴加入[Rh(COD)2]BF4(0.036g,0.09mmol)的二氯甲烷(2.5mL)溶液中。在此温度下,将所得溶液搅拌一小时,然后添加二乙醚(10mL)。过滤出沉淀并利用二乙醚(3x5mL)冲洗,得到呈橙色粉末形式的铑络合物5。
得率65%;1H NMR(300MHz,CDCl3)δ2.00-2.02(m,2H,CH2),2.17-2.22(m,2H,CH2),2.47-2.51(m,2H,CH2),2.59-2.64(m,2H,CH2),3.08(sl,2H,Hfer),4.09(sl,10H,Hfer),4.30(br.s,2H,Hfer),4.64-4.72(m,8H,Hfer/CH),6.63(d,J=7.1Hz,2H,Harom),7.11(t,J=7.5Hz,2H,Harom),7.25-7.27(m,10H,Harom),7.37(t,J=7.3Hz,Harom),8.18(br.s,2H,Harom);31P NMR(121MHz,CDCl3)δ21.0(d,J=145.6Hz);C52H48Fe2P2Rh[M-BF4]+的HRMS计算值949.0982,实验值949.0999。
K.3.不对称的催化氢化反应
一般步骤
将[Rh(COD)L*]BF4(0.005mmol,1mol%)和底物(0.5mmol)在无水溶剂(7.5mL)中的溶液引入不锈钢高压釜中。关闭高压釜,利用氢气清洗,然后利用氢气加压。在室温下搅拌16h后,使压力释放到大气压,并将溶液转移到圆底烧瓶中。通过旋转蒸发仪来移除溶剂,得到残余物,该残余物通过硅胶柱层析进行纯化,得到氢化产物。对映体过量是在手性柱上通过HPLC确定。
利用配体(I-48)或(I-49)的铑络合物的不对称的催化氢化反应的结果显示在表9和10中。
表9.利用配体(I-48)的铑络合物的不对称的催化氢化反应
表10.利用配体(I'-49c)的铑络合物的不对称的催化氢化反应
2-乙酰氨基-3-苯基丙酸甲酯64
64的对映体过量在Chiralcel OD-H上通过HPLC确定,己烷/2-丙醇95:5,1mL.min-1,tR(R)21.4min,tR(S)34.7min.1H NMR(300MHz,CDCl3)δ1.97(s,3H,CH3),3.06-3.08(m,2H,CH2Ph),3.64(s,3H,CH3),4.86-4.88(m,1H,CH),6.11(br s,1H,NH),7.19-7.22(m,5H,Harom)。
3-甲基琥珀酸二甲酯66
66的对映体过量是在Chiralcel OD-H上通过HPLC确定,己烷/2-丙醇95:5,0.5mL.min-1,tR(R)13.0min,tR(S)21.8min.1H NMR(300MHz,CDCl3)δ1.14(d,J=7.1Hz,3H,CH3),2.31(dd,J=3.0,16.5Hz,1H,CH2),2.66(dd,J=8.1,16.5Hz,1H,CH2),2.84-2.86(m,1H,CH),3.60(s,3H,CH3),3.62(s,3H,CH3)。
L.利用手性钯络合物催化不对称烯丙基化
在手性钯络合物存在下,在将丙二酸二甲酯74至衍生物76的催化的不对称烯丙基化反应中测试手性二膦(I-48)。使反应在室温下进行并将18h反应后得到的结果显示在表11中。
表11.利用钯络合物和二膦(I-48)的不对称的催化烯丙基化
(a)1%[Pd(C3H5)Cl]2.(b)条件A:NaH和B:BSA/KOAc
1,3-二苯基丙烯基乙酸酯75与丙二酸二甲酯74的烯丙基烷基化的一般步骤
在Schlenk管中,在氩气氛围中,将配体(12μmol,1.2mol%)和[Pd(η3-C3H5)Cl]2(5μmol,0.5mol%)溶于二氯甲烷(2mL)中。使反应混合物在室温下搅拌一小时并将(E)-1,3-二苯基丙-2-烯-1-基乙酸酯75(0.25g,1mmol)的二氯甲烷(1mL)溶液转移到这个Schlenk管。20分钟后,将此溶液转移到另一个反应容器中,此容器装有N,O-双(三甲基甲硅烷基)乙酰胺(0.49mL,2mmol)、催化量的KOAc和丙二酸二甲酯74(0.23mL,2mmol)的CH2Cl2(4mL)溶液。使反应混合物在室温下搅拌18小时。然后,利用二乙醚稀释反应混合物,并利用饱和NH4Cl水溶液(2x5mL)冲洗有机层,然后通过MgSO4干燥。减压下蒸发得到残余物,该残余物通过硅胶层析进行纯化,将石油醚/乙酸乙酯(10/1)用作洗脱液,得到烷基化产物。
2-羧基甲氧基-3,5-二苯基戊-4-烯酸甲酯76
76的对映体过量在Chiralpak AD上通过HPLC确定,己烷/2-丙醇90:10,0.5mL.min-1,tR(R)15.8min,tR(S)22.7min.1H NMR(CDCl3)(ppm),3.56(s,3H,CH3),3.75(s,3H,CH3),4.02(d,J=10.9Hz,1H,CH),4.27(dd,J=8.8,J=10.8Hz,1H,CH),6.40(dd,J=8.6,15.7Hz,1H,CH=),6.54(d,J=15.7Hz,1H,CH=),7.10-7.40(10H,m,Harom)。
Claims (7)
1.一种制备式(I)的化合物的方法,
其中
R1和R2可相同或不同并各自表示选自烷基、环烷基、芳基、烷氧基、环烷氧基、芳氧基、烷氨基、环烷氨基、芳氨基和金属茂基的取代或未取代基团;
R3、R4、R5、R6可相同或不同并各自表示氢原子或选自烷基、环烷基、芳基、烷氧基、环烷氧基、芳氧基、烷氨基、环烷氨基和芳氨基的取代或未取代基团;
E表示-BR9R10;
其中
R9和R10可相同或不同并各自表示卤素、羟基或选自烷氧基、芳氧基、环烷氧基、烷氨基、芳氨基、环烷氨基、烷基、环烷基或芳基的取代或未取代基团,
其中,除非另有说明,否则烷基自身或作为另一取代基的一部分包含1至12个碳原子,芳基自身或作为另一取代基的一部分在其环中含有5至20个碳原子,环烷基自身或者作为另一取代基的一部分在其环中含有3、5或6个碳原子;
所述方法包括:
(i)使氯膦硼烷(VII)
其中R1和R2如上定义,
与试剂RM反应,其中M是金属并且R为烷基或芳基;并使此卤素-金属交换的产物与式(VI)的芳香族化合物反应
其中X和Y可相同或不同并各自表示F、Cl、Br或I,并且R3、R4、R5和R6如上定义,
得到相应的式(IV)的P-手性源性膦硼烷
其中X、R1、R2、R3、R4、R5和R6如上定义;
以及
(ii)使化合物(IV)进行两次化学转化,得到化合物(I):移除硼烷基团的步骤(ii-a)以及使亲电试剂在邻位偶合的步骤(ii-b);步骤(ii-a)和(ii-b)以任意顺序进行;
其中所述的亲电试剂是硼酸盐试剂。
2.根据权利要求1所述的方法,其中化合物(VII)是手性的。
3.根据权利要求1所述的方法,其中化合物(IV)先在步骤(ii-a)的条件下反应,得到式(II)的中间化合物,
其中R1、R2、R3、R4、R5、R6和X如权利要求1定义。
4.根据权利要求1所述的方法,其中化合物(IV)先在步骤(ii-b)的条件下反应,得到式(III)的中间化合物,
其中R1、R2、R3、R4、R5、R6和E如权利要求1定义。
5.一种式(I)的化合物
其中
E表示-BR9R10;
其中
R9和R10可相同或不同并各自表示卤素、羟基或选自烷氧基、芳氧基、环烷氧基、烷氨基、芳氨基、环烷氨基、烷基、环烷基或芳基的取代或未取代基团,
R1和R2可相同或不同并各自表示选自烷基、环烷基、芳基、烷氧基、环烷氧基、芳氧基、烷氨基、环烷氨基、芳氨基和金属茂基的取代或未取代基团;
R3、R4、R5、R6可相同或不同并各自表示氢原子或选自烷基、环烷基、芳基、烷氧基、环烷氧基、芳氧基、烷氨基、环烷氨基和芳氨基的取代或未取代基团;
其中,除非另有说明,否则烷基自身或作为另一取代基的一部分包含1至12个碳原子,芳基自身或作为另一取代基的一部分在其环中含有5至20个碳原子,环烷基自身或者作为另一取代基的一部分在其环中含有3、5或6个碳原子。
6.一种式(III)的化合物
其中R1、R2、R3、R4、R5、R6和E如权利要求5所定义。
7.一种金属络合物催化剂,其包括根据权利要求5所述的式(I)或根据权利要求6所述的式(III)的至少一种化合物。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161506291P | 2011-07-11 | 2011-07-11 | |
US61/506,291 | 2011-07-11 | ||
FR1156686A FR2978151B1 (fr) | 2011-07-22 | 2011-07-22 | Composes organophosphores p-chirogeniques |
FR1156686 | 2011-07-22 | ||
CN201280044141.2A CN103797020B (zh) | 2011-07-11 | 2012-07-10 | P‑手性源性有机磷化合物 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201280044141.2A Division CN103797020B (zh) | 2011-07-11 | 2012-07-10 | P‑手性源性有机磷化合物 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN108339571A true CN108339571A (zh) | 2018-07-31 |
Family
ID=45093932
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201711458962.1A Pending CN108339571A (zh) | 2011-07-11 | 2012-07-10 | P-手性源性有机磷化合物 |
CN201280044141.2A Expired - Fee Related CN103797020B (zh) | 2011-07-11 | 2012-07-10 | P‑手性源性有机磷化合物 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201280044141.2A Expired - Fee Related CN103797020B (zh) | 2011-07-11 | 2012-07-10 | P‑手性源性有机磷化合物 |
Country Status (7)
Country | Link |
---|---|
US (2) | US9186661B2 (zh) |
EP (2) | EP3150613A1 (zh) |
CN (2) | CN108339571A (zh) |
FR (1) | FR2978151B1 (zh) |
MA (1) | MA35262B1 (zh) |
RU (1) | RU2652807C2 (zh) |
WO (1) | WO2013007724A1 (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105481909B (zh) * | 2015-11-11 | 2018-04-20 | 武汉凯特立斯科技有限公司 | 手性双膦配体及其在不对称氢化及相关反应中的应用 |
EP3452488A1 (de) * | 2016-05-06 | 2019-03-13 | Basf Se | P-chirale phosphinliganden und deren verwendung zur asymmetrischen synthese |
CN107702520A (zh) * | 2017-09-15 | 2018-02-16 | 漳州片仔癀药业股份有限公司 | 一种天然麝香的冷凝干燥方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101148456A (zh) * | 2007-10-12 | 2008-03-26 | 北京大学 | 一种有机磷酸催化剂及其制备方法和应用 |
WO2008055963A1 (de) * | 2006-11-09 | 2008-05-15 | Rheinisch-Westfälische Technische Hochschule Aachen | Neues verfahren zur herstellung von organischen phosphorverbindungen, mit diesem verfahren hergestellte phosphorverbindungen, deren metallkomplexe und verwendung |
CN101314608A (zh) * | 2007-09-30 | 2008-12-03 | 赢创德固赛有限责任公司 | 二齿有机磷配体及其用途 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2922819A (en) * | 1958-03-14 | 1960-01-26 | Ici Ltd | O-phenylene-bis-(dialkylphosphines) |
US5481008A (en) * | 1993-09-13 | 1996-01-02 | Hoffmann-La Roche Inc. | Process for the preparation of optically active compounds |
JP3800194B2 (ja) * | 2002-07-22 | 2006-07-26 | Jsr株式会社 | 結晶性1,2−ポリブタジエンの製造方法 |
-
2011
- 2011-07-22 FR FR1156686A patent/FR2978151B1/fr active Active
-
2012
- 2012-07-10 WO PCT/EP2012/063489 patent/WO2013007724A1/en active Application Filing
- 2012-07-10 CN CN201711458962.1A patent/CN108339571A/zh active Pending
- 2012-07-10 EP EP16194819.5A patent/EP3150613A1/en not_active Withdrawn
- 2012-07-10 RU RU2014104685A patent/RU2652807C2/ru not_active IP Right Cessation
- 2012-07-10 US US14/232,435 patent/US9186661B2/en not_active Expired - Fee Related
- 2012-07-10 CN CN201280044141.2A patent/CN103797020B/zh not_active Expired - Fee Related
- 2012-07-10 EP EP12732846.6A patent/EP2731956B1/en not_active Not-in-force
-
2014
- 2014-01-08 MA MA36659A patent/MA35262B1/fr unknown
-
2015
- 2015-10-06 US US14/876,072 patent/US9707553B2/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008055963A1 (de) * | 2006-11-09 | 2008-05-15 | Rheinisch-Westfälische Technische Hochschule Aachen | Neues verfahren zur herstellung von organischen phosphorverbindungen, mit diesem verfahren hergestellte phosphorverbindungen, deren metallkomplexe und verwendung |
CN101314608A (zh) * | 2007-09-30 | 2008-12-03 | 赢创德固赛有限责任公司 | 二齿有机磷配体及其用途 |
CN101148456A (zh) * | 2007-10-12 | 2008-03-26 | 北京大学 | 一种有机磷酸催化剂及其制备方法和应用 |
Non-Patent Citations (1)
Title |
---|
KEN TAMURA ET AL.: "Enantiopure 1,2-Bis(tert-butylmethylphosphino)benzene as a Highly Efficient Ligand in Rhodium-Catalyzed Asymmetric Hydrogenation", 《ORGANIC LETTERS》 * |
Also Published As
Publication number | Publication date |
---|---|
FR2978151A1 (fr) | 2013-01-25 |
CN103797020A (zh) | 2014-05-14 |
US9186661B2 (en) | 2015-11-17 |
WO2013007724A1 (en) | 2013-01-17 |
EP2731956A1 (en) | 2014-05-21 |
US9707553B2 (en) | 2017-07-18 |
RU2014104685A (ru) | 2015-08-20 |
FR2978151B1 (fr) | 2013-08-30 |
US20160023199A1 (en) | 2016-01-28 |
RU2652807C2 (ru) | 2018-05-03 |
EP2731956B1 (en) | 2016-11-09 |
US20140142325A1 (en) | 2014-05-22 |
MA35262B1 (fr) | 2014-07-03 |
CN103797020B (zh) | 2018-01-30 |
EP3150613A1 (en) | 2017-04-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2975683B2 (ja) | キラールフォスフォラン遷移金属触媒 | |
Chapp et al. | Platinum-catalyzed asymmetric alkylation of bis (isitylphosphino) ethane: stereoselectivity reversal in successive formation of two P− C bonds | |
Hayashi et al. | New chiral chelating phosphine complexes containing tricarbonyl (η6-arene) chromium for highly enantioselective allylic alkylation | |
Pullarkat et al. | A novel approach toward asymmetric synthesis of alcohol functionalized C-chiral diphosphines via two-stage hydrophosphination of terminal alkynols | |
JPH0320290A (ja) | 2,2’―ビス〔ジー(m―トリル)ホスフィノ〕―1,1’―ビナフチル | |
Darcel et al. | Direct use of chiral or achiral organophosphorus boranes as pro-ligands for transition metal catalyzed reactions | |
Alayrac et al. | Recent advances in synthesis of P-BH 3 compounds | |
CN103797020B (zh) | P‑手性源性有机磷化合物 | |
JP2011503221A (ja) | 触媒的不斉付加反応に使用する二座キラル配位子 | |
TWI517899B (zh) | 雙芳基二膦配位子化合物及其中間物和製法以及金屬複合物 | |
Derrien et al. | Asymmetric hydrogenation reactions mediated by a new class of bicyclic bisphosphinites | |
US20050288523A1 (en) | Chiral diphosphorus compounds and transition metal complexes thereof | |
US20050107608A1 (en) | Ligands for use in catalytic processes | |
EP1633762A1 (en) | Ligands | |
US6583305B1 (en) | Ferrocene-based diphosphonites for asymmetrical catalysis | |
US5777087A (en) | Aryl diphosphines and catalysts containing the same | |
CA2287713A1 (en) | Optically active bisphosphinomethanes and their rhodium and copper complexes for catalytic asymmetric syntheses | |
JP2005523939A (ja) | フェロセニル配位子及び前記配位子の製造方法 | |
CN113735899A (zh) | 一种具有膦手性和轴手性化合物的合成方法 | |
JP2005325114A (ja) | キラルジホスフィノテルペン及びその遷移金属錯体 | |
US5929273A (en) | Process for preparing diphospines ligands and catalysts containing the same | |
CN111868065A (zh) | C-大位阻p-手性源性有机磷化合物 | |
CA2597883A1 (en) | Catalyst for asymmetric synthesis, ligand for use therein, and process for producing optically active compound through asymmetric synthesis reaction using them | |
EP1846350A2 (en) | Improved method for the preparation of enantiomerically enriched secondary alcohols by the addition of organoaluminium reagents to carbonyl compounds | |
JP6357691B2 (ja) | リン化合物及びその遷移金属錯体 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180731 |
|
WD01 | Invention patent application deemed withdrawn after publication |