CN103772297B - 手性六元氮杂环卡宾前体化合物及其制备方法和应用 - Google Patents
手性六元氮杂环卡宾前体化合物及其制备方法和应用 Download PDFInfo
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- CN103772297B CN103772297B CN201410037647.1A CN201410037647A CN103772297B CN 103772297 B CN103772297 B CN 103772297B CN 201410037647 A CN201410037647 A CN 201410037647A CN 103772297 B CN103772297 B CN 103772297B
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- phenyl
- chirality
- carbon
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 220
- 238000002360 preparation method Methods 0.000 title claims abstract description 119
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 239000002243 precursor Substances 0.000 title claims abstract description 41
- 125000004070 6 membered heterocyclic group Chemical group 0.000 title claims abstract description 35
- 238000006243 chemical reaction Methods 0.000 claims abstract description 91
- -1 boric acid compound Chemical class 0.000 claims abstract description 52
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 16
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000002148 esters Chemical class 0.000 claims abstract description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 48
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 46
- 229910052799 carbon Inorganic materials 0.000 claims description 40
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 39
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- 239000002585 base Substances 0.000 claims description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 25
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- 239000003513 alkali Substances 0.000 claims description 24
- 239000000010 aprotic solvent Substances 0.000 claims description 24
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 230000000694 effects Effects 0.000 claims description 18
- 239000012188 paraffin wax Substances 0.000 claims description 18
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 17
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 17
- 230000035484 reaction time Effects 0.000 claims description 17
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 15
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 239000001119 stannous chloride Substances 0.000 claims description 15
- 235000011150 stannous chloride Nutrition 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 229910052763 palladium Inorganic materials 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 claims description 12
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 11
- 101001053401 Arabidopsis thaliana Acid beta-fructofuranosidase 3, vacuolar Proteins 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 10
- 239000002253 acid Chemical group 0.000 claims description 9
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 9
- 239000003638 chemical reducing agent Substances 0.000 claims description 9
- 230000009467 reduction Effects 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims description 7
- 150000004820 halides Chemical class 0.000 claims description 7
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 7
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 7
- 239000002798 polar solvent Substances 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 239000002841 Lewis acid Substances 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 150000007517 lewis acids Chemical class 0.000 claims description 6
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 6
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 6
- KYLUAQBYONVMCP-UHFFFAOYSA-N (2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P KYLUAQBYONVMCP-UHFFFAOYSA-N 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- ORPNDFMZTDVBGA-UHFFFAOYSA-N (2-methoxyphenyl)phosphane Chemical compound COC1=CC=CC=C1P ORPNDFMZTDVBGA-UHFFFAOYSA-N 0.000 claims description 3
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 101001053395 Arabidopsis thaliana Acid beta-fructofuranosidase 4, vacuolar Proteins 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 3
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 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 claims description 3
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 3
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 claims description 3
- 229940072033 potash Drugs 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 3
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 241000370738 Chlorion Species 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 2
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 150000004985 diamines Chemical class 0.000 claims description 2
- VDCSGNNYCFPWFK-UHFFFAOYSA-N diphenylsilane Chemical group C=1C=CC=CC=1[SiH2]C1=CC=CC=C1 VDCSGNNYCFPWFK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 1
- RLAHWVDQYNDAGG-UHFFFAOYSA-N Methanetriol Chemical compound OC(O)O RLAHWVDQYNDAGG-UHFFFAOYSA-N 0.000 claims 1
- 150000001336 alkenes Chemical class 0.000 claims 1
- 229910052802 copper Inorganic materials 0.000 claims 1
- 239000010949 copper Substances 0.000 claims 1
- 229940124530 sulfonamide Drugs 0.000 claims 1
- 150000003456 sulfonamides Chemical class 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 abstract description 9
- 238000006722 reduction reaction Methods 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000004327 boric acid Substances 0.000 abstract description 4
- 238000007259 addition reaction Methods 0.000 abstract description 3
- 150000001299 aldehydes Chemical class 0.000 abstract description 2
- 238000006482 condensation reaction Methods 0.000 abstract description 2
- 235000003642 hunger Nutrition 0.000 abstract description 2
- 150000002466 imines Chemical class 0.000 abstract 1
- 150000002576 ketones Chemical class 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 178
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 66
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 61
- 238000005160 1H NMR spectroscopy Methods 0.000 description 61
- 239000007787 solid Substances 0.000 description 50
- 239000000047 product Substances 0.000 description 21
- 0 CCC(C1)*1[C@](C=CC)NCC Chemical compound CCC(C1)*1[C@](C=CC)NCC 0.000 description 14
- 238000000967 suction filtration Methods 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 13
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 150000004696 coordination complex Chemical class 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 229910001868 water Inorganic materials 0.000 description 7
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000010189 synthetic method Methods 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 4
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229910000765 intermetallic Inorganic materials 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 150000002790 naphthalenes Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HUCQPHINKBNKRU-UHFFFAOYSA-N (4-methylphenyl)phosphane Chemical compound CC1=CC=C(P)C=C1 HUCQPHINKBNKRU-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 2
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 2
- GWJSQKNYHPYZRN-UHFFFAOYSA-N 2-methylpropane-2-sulfonamide Chemical compound CC(C)(C)S(N)(=O)=O GWJSQKNYHPYZRN-UHFFFAOYSA-N 0.000 description 2
- ADLVDYMTBOSDFE-UHFFFAOYSA-N 5-chloro-6-nitroisoindole-1,3-dione Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC2=C1C(=O)NC2=O ADLVDYMTBOSDFE-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 2
- TVJJMJNPQDVCRT-UHFFFAOYSA-N CC1=C(C=CC=C1)C1=CC=CC=C1.[P] Chemical group CC1=C(C=CC=C1)C1=CC=CC=C1.[P] TVJJMJNPQDVCRT-UHFFFAOYSA-N 0.000 description 2
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- JIUCMDZTNNHGKO-RUZDIDTESA-N Clc(cc1)cc([C@@H](c2ccccc2)Nc2ccccc2)c1Nc1ccccc1 Chemical compound Clc(cc1)cc([C@@H](c2ccccc2)Nc2ccccc2)c1Nc1ccccc1 JIUCMDZTNNHGKO-RUZDIDTESA-N 0.000 description 1
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- GQYVYOJMLFOQAE-CYBMUJFWSA-N N[C@H](c(cccc1)c1F)c1cc(Cl)ccc1N Chemical compound N[C@H](c(cccc1)c1F)c1cc(Cl)ccc1N GQYVYOJMLFOQAE-CYBMUJFWSA-N 0.000 description 1
- TXTPIGYQTSOFKF-CYBMUJFWSA-N N[C@H](c1ccccc1)c(cc(cc1)Cl)c1N Chemical compound N[C@H](c1ccccc1)c(cc(cc1)Cl)c1N TXTPIGYQTSOFKF-CYBMUJFWSA-N 0.000 description 1
- 239000012327 Ruthenium complex Substances 0.000 description 1
- 238000007296 Stetter synthesis reaction Methods 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 238000005865 alkene metathesis reaction Methods 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000091 aluminium hydride Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 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
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229960002163 hydrogen peroxide Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
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- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
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- 150000002736 metal compounds Chemical class 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
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- 238000006053 organic reaction Methods 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000006049 ring expansion reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- QAZLUNIWYYOJPC-UHFFFAOYSA-M sulfenamide Chemical compound [Cl-].COC1=C(C)C=[N+]2C3=NC4=CC=C(OC)C=C4N3SCC2=C1C QAZLUNIWYYOJPC-UHFFFAOYSA-M 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
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- B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
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- C07C29/44—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by addition reactions, i.e. reactions involving at least one carbon-to-carbon double or triple bond
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Abstract
本发明涉及有机合成领域,具体为手性六元氮杂环卡宾前体化合物的制备方法和应用。该化合物具有如式(V)所示结构,上述手性六元氮杂环卡宾前体化合物可催化多种手性反应,如不饱和酯、α,β-不饱亚胺与二硼烷频哪醇硼酸酯的加成反应,或者醛与硼酸类化合物的缩合反应,或者酮的还原反应,有较好的催化效率和对映选择性。
Description
技术领域
本发明涉及有机合成领域,具体为手性六元氮杂环卡宾前体化合物的制备方法和应用。
背景技术
1991年,Arduengo等首次分离并表征了N-杂环卡宾(NHCs)单体,之后N-杂环卡宾(NHCs)化学的发展出现了一个飞跃。由于N-杂环卡宾催化的反应具有无金属参与、价格低廉且反应对环境要求较为宽松等优点,因而受到越来越多的关注,其独特的催化性能也为人们寻找新型的性能良好的催化剂开辟了崭新的视野。此外,由于N-杂环卡宾是强δ-电子供体,能与几乎所有的过渡金属络合得到N-杂环卡宾金属络合物,这些有机络合物能催化许多有机反应,如烯烃复分解反应、偶联反应、stetter反应、醛酮的还原反应等。在许多催化反应中,其催化效果,已经达到或超过了传统膦配体,N-杂环卡宾配体及其金属络合物在有机催化领域中正发挥着越来越重要的作用。
目前已合成的N-杂环卡宾类型较多,其主要类型如下所示。首个分离出的游离N-杂环卡宾为五元环咪唑型卡宾,在咪唑环的1,3位连有取代基。这种类型是最典型的也是应用最多的一种N-杂环卡宾,目前研究的范围最广。除此之外,五元环卡宾还包括咪唑啉型(4,5-二氢咪唑)、苯并咪唑型、1,2,4-三唑型、(苯并)噻唑型等,还包括六元环四氢嘧啶型,四元环和七元环等非典型的N-杂环卡宾。
尽管N-杂环卡宾配体及其金属络合物在非手性有机催化领域已取得了很多成就,但是在不对称催化方面,它们的应用才刚刚起步。近年来,国内外一些课题组陆续开展了手性氮杂环卡宾及其金属化合物在催化不对称合成反应中的应用研究。
2002年,波士顿大学的Hoveyda课题组[6-7]在JACS(JournaloftheAmericanChemicalSociety)上报道了一种结构新颖的手性氮杂环卡宾钌配合物,它可以有效的促进催化不对称开环或关环反应,反应式如下。
LutzH.Gade课题组分别于2002年和2006年在Organometallics报道了,通过噁唑啉咪唑的溴盐和氧化银在二氯甲烷作为溶剂,室温下反应3h得到其相应的银配体,简单过滤后,控制加入Pd(COD)Cl2作为钯源,合成得到一种简单的噁唑啉的氮杂环卡宾钯配合物,该化合物对Suzuki反应具有良好的催化效果,反应式如下。
2003年,新奥尔良大学的Nolan课题组在JACS上,报道了以一种轴手性的氮杂环卡宾钯环配合物,对Suzuki反应具有良好的催化效果,反应式如下。2006年,该课题组以这种钯化合物对Buchwald-Hartwig反应进行催化研究,研究发现这种钯的配合物对Buchwald-Hartwig偶联反应具有很好的催化活性,而且反应条件温和,反应产率高,其成果发表在JACS和JOC上。
同济大学的叶松课题组于2008年在JOC上报道了一例以手性NHC配体作为催化剂,以Cs2CO3作为碱,可以有效催化[2+2]环加成反应。同年,该课题组在OrganicLetters上也报道了相应的深入研究。
上面的研究主要集中在易于合成、性质稳定的手性五元环氮杂卡宾及其金属化合物,而手性六元环氮杂卡宾及其金属络合物的研究还比较少。近年来关于NHCs的研究开始扩展到六元、七元等扩环杂环体系。研究者将杂环原子数大于五的NHCs称为扩环-氮杂环卡宾(ringexpandedNHCs,RE-NHCs)。与传统的五元-NHCs相比,扩环-氮杂环卡宾除表现出更强的碱性之外,由于N-Ccarbene-N之间的夹角增大,致使N原子上取代基的改变对配体电子效应和空间效应的影响更显著;同时,环的构型也不再局限于五元环的平面构型,导致其形成金属化合物的反应活性及生成的金属化合物的稳定性、催化反应的活性和选择性均发生改变,因而扩环-氮杂环卡宾在现代有机化学中发挥着越来越重要的作用。2010年McQuade课题组[17]合成了一类手性六元氮杂卡宾前体及其氯化亚铜的络合物,并将其应用于α,β-不饱和酯的不对称硼酸酯加成反应,取得了较好的对映选择性,反应式如下,而其他课题组报道的扩环-氮杂环卡宾大都是非手性的。
纵观手性六元环氮杂卡宾及其金属络合物的构建方法,在不久的将来,该类化合物在催化不对称有机合成反应及药物合成反应中将会有越来越多的应用。因此,开发新型手性六元环氮杂卡宾及其金属络合物显得尤为重要,对该领域的研究不但能推动该类化合物商业化或产业化,而且能大大降低有些不对称药物合成反应的生产成本。
发明内容
本发明的目的是通过一种简便的合成路线,开发一类新型手性六元氮杂环卡宾前体化合物及其金属配合物的合成方法,以扩大手性六元氮杂卡宾在有机不对称合成反应和药物合成反应中的应用范围。
本发明所述的手性六元氮杂环卡宾前体化合物,为具有式(V)所示结构的化合物:
其中,R1和R2为氢原子、卤原子、1-6个碳的直链烷烃基、含1-6个碳的支链烷烃基、含2-6个碳的烯烃基、甲氧基、硝基;优选为氢原子、卤原子。更优选的,R1和R2分别为氢、氟、氯或溴。
R3、R4选自1-12个碳的直链烷烃基或3-12个碳环烷烃基、含3-12个碳的支链烷烃基、含2-6个碳的烯烃基、含2-6个碳的炔烃、芳环基、芳杂环基、萘环基、取代的含1-12个碳的直链烷烃基或取代的含3-12个碳的环烷烃基、取代的含1-12个碳的支链烷烃基、取代的含2-6个碳的烯烃基、取代的含2-6个碳的炔烃、取代的芳环基、取代的芳杂环基或取代的萘环基;优选为芳环基、芳杂环基、萘环基、取代的芳环基、取代的芳杂环基或取代的萘环基。更优选的,R3和R4为相同的取代基,选自苯基、取代苯基或芳环取代基。更为优选的,R3和R4为甲基、乙基、丙基、异丙基、丁基、苯基、连苯基、对甲苯基、间苯甲基、间二苯甲基、对氟苯基、间对氟苯基、对甲氧基苯基、间甲氧基苯基、对硝基苯基、间硝基苯基、间三苯甲基、对氰苯基、间氰苯基、对三氟甲基苯基或萘基。
R5为氯离子、四氟硼酸根离子、硫酸根离子、甲酸根离子、乙酸根离子;优选为氯离子、四氟硼酸根离子。
或者,所述手性六元氮杂环卡宾前体化合物选自以下化合物之一:
上述的手性六元氮杂环卡宾前体化合物的合成路线如下:
(i)(R-)-叔丁基亚磺酰胺,路易斯酸(如钛酸四异丙酯);(ii)还原剂(如二异丙基氢化铝锂),非质子溶剂如四氢呋喃;(iii)酸(iv)催化剂、有机膦配体;(v)原甲酸三甲酯或原甲酸三乙酯
制备方法,包括如下步骤:
(i)在路易斯酸催化作用下,将如通式(I’)所示的邻胺基酮类化合物和(R-)-叔丁基亚磺酰胺,在非质子溶剂中进行反应,然后从反应产物中收集式(Ⅰ)化合物;路易斯酸为氯化锌、氯化锡、氯化铜、四氯化钛、钛酸四异丙酯,优选钛酸四异丙酯;非质子溶剂为苯、甲苯、乙醚、四氢呋喃,优选四氢呋喃。式(I’)化合物、(R-)-叔丁基亚磺酰胺、路易斯酸的摩尔比为1:1~2:0.5~1;反应温度为0~110℃,优选70~100℃;反应时间为1~24小时,优选6~12小时;
收率在80%~95%,反应通式如下:
(ii)在非质子溶剂中,将如通式(I)所示的邻胺基叔丁基亚磺酰亚胺类化合物和还原剂进行反应,然后从反应产物中收集式(II)化合物;非质子溶剂为苯、甲苯、乙醚、四氢呋喃,优选四氢呋喃;所用的还原剂为氢化钠、硼氢化钠、氢化铝锂和二异丙基氢化铝锂,优选二异丙基氢化铝锂(DIBAL);反应温度为-80~60℃,优选为-78~0℃;反应时间为1~6小时,优选为1~3小时;式(I)化合物、还原剂的摩尔比为1:1~3;反应通式如下:
(iii)在极性溶剂中,将如通式(II)所示的邻胺基叔丁基亚磺酰胺类化合物和酸进行反应,然后从反应产物中收集式(III)化合物;极性溶剂为甲醇、乙醇、异丙醇、乙腈、1,4-二氧六环中的一种或者混合物,优选1,4-二氧六环或甲醇与1,4-二氧六环的混合物;所用的酸为甲酸、乙酸、硫酸、盐酸,优选盐酸;反应温度为0~50℃,优选15~30℃;时间为1~4小时,优选1~2小时;所述的式(II)化合物、酸的摩尔比为1:1~5;反应通式如下:
(iv)在非质子溶剂中,将如通式(III)所示的1,3-二胺类化合物和卤代物,在碱和催化剂的加热进行反应或在碱和催化剂作用下用微波加热进行反应,然后从反应产物中收集式(IV)化合物;反应温度为90~130℃,优选90~120℃;反应时间为0.5~24小时,优选1~6小时;卤代物的结构式为X-R3或X-R4,其中X为卤原子;式(III)化合物、卤代物、催化剂、碱的摩尔比为1:1~1.2:0.01~0.1:1~3;非质子溶剂为苯、甲苯、乙醚、四氢呋喃,所用的催化剂为钯催化剂和膦配体,选自四(三苯基膦)钯,、[1,1'-双(二苯基膦)二茂铁]二氯化钯、氯化钯、醋酸钯、双(三环己基膦)二氯化钯、双(三苯基膦)二氯化钯(II)、二(二亚苄基丙酮)钯(0)、三(二亚苄基丙酮)二钯、(1,5-环辛二烯)二氯化钯、二(乙酰丙酮)钯(II),所用配体为三环己基膦、三苯基膦、2-二环己基磷-2'-甲基联苯、2-(二-叔丁基膦)联苯、三(邻甲苯基)膦、三(间甲苯基)膦、三(对甲苯基)膦、三(2-甲氧基苯基)膦或1,1'-联萘-2,2'-双二苯膦;反应通式如下:
(v)在极性溶剂中,将如通式(IV)所示的二胺取代类化合物、原甲酸三甲酯或原甲酸三乙酯、路易斯酸作用下进行反应,然后从反应产物中收集式(V)化合物;反应温度为10~100℃,优选10~60℃;反应时间为0.5~24小时,优选2~12小时;式(IV)化合物、原甲酸三甲酯或原甲酸三乙酯、路易斯酸的摩尔比为1:1~3:0.1~0.3;反应通式如下:
所得到的手性六元氮杂环卡宾前体化合物可用作催化剂,催化以下反应之一:
反应(I):
其中R1’、R2’分别选自氢、卤原子、含1-6个碳的直链烷烃基、含1-6个碳的支链烷烃基、含2-6个碳的烯烃基、苯基、取代苯基、甲氧基或硝基;优选的,R1’为苯基,R2’为甲氧基。
在非质子溶剂中,将如通式(VI-1)所示的化合物、二硼烷频哪醇硼酸酯、氯化亚铜、手性六元氮杂环卡宾前体化合物在碱作用下进行反应,然后从反应产物中收集式(VII-1)化合物,(VII-1)化合物经过进一步氧化水解得手性醇化合物VII-1-1;反应条件为,反应温度为-78~60℃,反应时间为1~48小时,其中(VI-1)化合物、二硼烷频哪醇硼酸酯、氯化亚铜、手性六元氮杂环卡宾前体化合物、碱的摩尔比为1:1~3:0.1~0.3:0.01~0.3:0.01~0.3;
反应(II):
其中,R1’、R2’分别选自氢、卤原子、含1-6个碳的直链烷烃基、含1-6个碳的支链烷烃基、含2-6个碳的烯烃基、苯基、取代苯基、甲氧基或硝基;优选的,R1’为C1~C4烷基、苯基或取代苯基,R2’为对甲基苯磺酰基。
在非质子溶剂中,将如通式(VI-2)所示的化合物、二硼烷频哪醇硼酸酯、氯化亚铜、手性六元氮杂环卡宾前体化合物在碱的作用下进行反应,然后从反应产物中收集式(VII-2)化合物;反应条件为,反应温度为-78~60℃,反应时间为1~48小时;式(VI-2)化合物、二硼烷频哪醇硼酸酯、氯化亚铜、手性六元氮杂环卡宾前体化合物和碱的摩尔比为1:1~3:0.1~0.3:0.01~0.3:0.01~0.3。
反应(III):
R1’、R2’分别选自氢、卤原子、含1-6个碳的直链烷烃基、含1-6个碳的支链烷烃基、含2-6个碳的烯烃基、苯基、取代苯基、甲氧基或硝基;优选的,R1’和R2’分别为C1~C4烷基或苯基。
在非质子溶剂中,将如通式(VI-3)所示的化合物、通式(VI-3’)所示的化合物、氯化亚铜、手性六元氮杂环卡宾前体化合物在碱的作用下进行反应,然后从反应产物中收集式(VII-3)化合物;反应条件为,反应温度为-78~60℃,反应时间为1~48小时,式(VI-3)化合物、式(VI-3’)化合物、氯化亚铜、手性六元氮杂环卡宾前体化合物和碱的摩尔比为1:1~3:0.1~0.3:0.01~0.3:0.01~0.3。
反应(IV):
R1’、R2’分别选自氢、卤原子、含1-6个碳的直链烷烃基、含1-6个碳的支链烷烃基、含2-6个碳的烯烃基、苯基、取代苯基、甲氧基或硝基。优选的,R1’为为C1~C4烷基、苯基或取代苯基。
在非质子溶剂中,将如通式(VI-3)所示的化合物、通式(VI-3’)所示的化合物、氯化亚铜、手性六元氮杂环卡宾前体化合物在碱的作用下进行反应,然后从反应产物中收集式(VII-4)化合物;反应条件为,反应温度为-78~60℃,反应时间为1~48小时,式(VI-4)化合物、还原剂、氯化亚铜、手性六元氮杂环卡宾前体化合物和碱的摩尔比为1:1~3:0.1~0.3:0.01~0.3:0.01~0.3。
上述反应中,非质子溶剂为苯、甲苯、乙醚、二氯甲烷、1,2-二氯乙烷、四氢呋喃,所用的碱为三乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯DBU、N,N-二异丙基乙胺DIPEA、碳酸铯、碳酸钾、碳酸钠、叔丁醇钠、叔丁醇钾、氢化钠、氢化钾。
上述手性六元氮杂环卡宾前体化合物可催化手性反应,如不饱和酯、α,β-不饱亚胺与二硼烷频哪醇硼酸酯的加成反应,或者醛与硼酸类化合物的缩合反应,或者酮的还原反应,有较好的催化效率和对映选择性。
具体实施方式
化合物I的代表性合成方法(通法1):
将2mmol化合物I’(0.1eq.)、2.2mmol叔丁基亚磺酰胺(1.1eq.)、溶剂无水THF(20ml),2mmol钛酸四异丙酯加入反应瓶中,在86℃搅拌;用TLC监测反应进程,反应结束后,将反应液倒入NaHCO3(60ml)溶液,有大量黄色固体析出,抽滤,溶液用乙酸乙酯(100ml)萃取三次,有机相用无水Na2SO4干燥,抽滤,旋干,柱层析分离(石油醚:乙酸乙酯=10:1~3:1)得到产物。
无水THF可用苯、甲苯或乙醚代替;钛酸四异丙酯可用氯化锌、氯化锡、氯化铜或四氯化钛代替。
化合物II的代表性合成方法(通法2):
将1mmol化合物I溶于20mlTHF中,抽真空,氮气保护,控制温度-78℃,缓慢滴加1.5M的DIBAL的甲苯溶液1ml,用TLC监测反应进程,反应结束后,加饱和NaCl溶液淬灭,用乙酸乙酯萃取,有机相用无水Na2SO4干燥,抽滤,旋干,柱层析分离(石油醚:乙酸乙酯=6:1~3:1)得到产物。
THF可用苯、甲苯或乙醚代替;DIBAL可用氢化钠、硼氢化钠或氢化铝锂代替。
化合物III的代表性合成方法(通法3):
将1mmol化合物II溶于5ml无水甲醇和5ml无水1,4-二氧六环的混合溶剂中,得一黄色溶液,滴加2ml浓度为2.2M的HCl的二氧六环溶液,用TLC监测反应进程,反应结束后,旋干溶剂,加20ml水,用30ml乙酸乙酯萃取,有机相弃去,水相用NH3.H2O调至PH=8,之后用乙酸乙酯萃取至无产品为止。有机相用饱和NaCl溶液洗一次,无水NaSO4干燥,旋干,得到产物。
盐酸可用甲酸、乙酸、硫酸代替,无水甲醇和、无水1,4-二氧六环的混合溶剂可用甲醇、乙醇、异丙醇、乙腈或1,4-二氧六环的任一种或者其中两种的混合物代替。
化合物IV的代表性合成方法(通法4):
将1mmol化合物III和2mmol2-溴萘,0.01mmol的Pd2(dba)3即三(二亚苄基丙酮)二钯,0.011mmol的BINAP(1,1'-联萘-2,2'-双二苯膦),2.5mmol的叔丁醇钠溶于10ml甲苯中,温度110℃,反应2~8h。取一抽滤漏斗垫入硅藻土,抽滤,用乙酸乙酯洗,将溶液旋干,柱层析分离(石油醚:乙酸乙酯=50:1)得到产物。
甲苯可用苯、甲苯、乙醚或四氢呋喃代替,三(二亚苄基丙酮)二钯可用四(三苯基膦)钯,、[1,1'-双(二苯基膦)二茂铁]二氯化钯、氯化钯、醋酸钯、双(三环己基膦)二氯化钯、双(三苯基膦)二氯化钯(II)、二(二亚苄基丙酮)钯(0)、(1,5-环辛二烯)二氯化钯、二(乙酰丙酮)钯(II)代替,膦配体1,1'-联萘-2,2'-双二苯膦可替换为三环己基膦、三苯基膦、2-二环己基磷-2'-甲基联苯、2-(二-叔丁基膦)联苯、三(邻甲苯基)膦、三(间甲苯基)膦、三(对甲苯基)膦、三(2-甲氧基苯基)膦,叔丁醇钠可用碳酸铯、碳酸钾、碳酸钠、叔丁醇钾代替。
化合物IV的代表性合成方法(通法5):
将1mmol化合物IV溶于5ml原甲酸三甲酯或原甲酸三乙酯,室温下加入0.1ml的甲酸和0.1ml的浓盐酸,反应3h后,旋干溶剂,柱层析分离(二氯甲烷:甲醇=15:1)得到产物。甲酸可替换为氯化铵、硫酸铵、四氟硼酸胺、甲酸胺、乙酸、盐酸。
实施例1
化合物I-1的制备与表征:
将4.0g(20.3mmol)化合物I’与3.84g的叔丁基亚磺酰胺溶于100mlTHF中,40mmol钛酸四异丙酯加入,用TLC监测反应进程,采用通法1进行反应,在86℃搅拌12hr,反应结束后,将反应液倒入NaHCO3(200ml)溶液,有大量黄色固体析出,抽滤,溶液用乙酸乙酯(300ml)萃取三次,有机相用无水Na2SO4干燥,抽滤,旋干,柱层析分离(石油醚:乙酸乙酯=10:1)得到化合物I-1为5.4g,产率为89%,熔点140~142℃;1HNMR(400MHz,CDCl3,ppm)δ:7.49(s,3H),7.24-7.26(m,2H),7.29-7.13(m,3H),6.73-6.91(m,4H),6.51(s,4H),1.28(s,9H);13CNMR(100MHz,DMSO-d6,δ):156.3,141.5,128.5,128.1,128.0,127.1,126.2,111.5,57.4,55.8,22.8;MS(ESI-TOF)m/z:301.2[M+H]+。
实施例2
化合物I-2的制备与表征:
制备条件同实施例1,产率为88%,熔点138~140℃;1HNMR(400MHz,CDCl3,ppm)δ:7.50(s,3H),7.26(s,1H),7.16(d,J=7.6Hz,1H),6.84(s,1H),6.71(d,J=8.8Hz,1H),1.27(s,9H);13CNMR(100MHz,CDCl3,δ):154.3,141.8,128.5,128.1,128.0,127.1,126.2,111.3,57.5,55.8,22.7;MS(ESI-TOF)m/z:335.2[M+H]+。
实施例3
化合物I-3的制备与表征:
制备条件同实施例1,产率为86%,熔点136~138℃;1HNMR(400MHz,CDCl3,ppm)δ:7.51-7.53(m,1H),7.15-7.30(m,3H),6.71(d,J=8.8Hz,1H),1.27(s,9H);13CNMR(100MHz,CDCl3,δ):152.1,141.9,128.6,128.3,128.1,127.5,126.4,111.6,57.5,55.8,22.8;MS(ESI-TOF)m/z:353.1[M+H]+。
实施例4
化合物II-1的制备与表征:
取一个250ml的三颈瓶烘干,采用通法2进行反应,将4.0g(13.3mmol)化合物I-1溶于100mlTHF中,抽真空,氮气保护,控制温度-78℃,缓慢滴加1.5M的DIBAL的甲苯溶液10ml,可见有气泡产生,溶液颜色变浅,液氮控温-78℃下反应3h。加饱和NaCl溶液淬灭,升至室温,用乙酸乙酯萃取,静置,有大量胶体析出,抽滤,旋干,柱层析分离(石油醚:乙酸乙酯=6:1~3:1)得到淡黄色固体产物II-1为3.2g,产率为80%,熔点154~156℃;1HNMR(400MHz,CDCl3,ppm)δ:7.39-7.43(m,4H),7.33-7.36(m,1H),7.10-7.15(m,1H),6.62-6.75(m,3H),5.70(d,J=2.4Hz,1H),4.38(s,2H),3.74(d,J=1.6Hz,1H),1.29(s,9H);13CNMR(100MHz,CDCl3,δ)144.3,140.5,129.1,129.0,128.5,128.3,127.6,126.1,111.9,116.7,57.4,55.8,22.7;MS(ESI-TOF)m/z:303.1[M+H]+。
实施例5
化合物II-2的制备与表征:
制备条件同实施例4,产率为80%,熔点151~153℃;1HNMR(400MHz,CDCl3,ppm)δ:7.36-7.43(m,5H),7.07(dd,J1=2.4Hz,J2=8.4Hz,1H),6.65-6.69(m,2H),5.63(d,J=2.4Hz,1H),4.39(brs,2H),3.69(d,J=2.0Hz,1H),1.29(s,9H);13CNMR(100MHz,CDCl3,δ)142.9,139.7,129.1,128.9,128.6,128.1,127.9,127.5,122.6,117.8,57.1,55.8,22.6;MS(ESI-TOF)m/z:337.2[M+H]+。
实施例6
化合物II-3的制备与表征:
制备条件同实施例4,产率为81%,熔点144~146℃;1HNMR(400MHz,CDCl3,ppm)δ:7.63(dd,J1=1.2Hz,J2=7.6Hz,1H),7.34-7.39(m,1H),7.12-7.26(m,1H),7.07(t,J=2.4Hz,2H),6.67(d,J=8.8Hz,2H),5.88(d,J=2.8Hz,1H),4.49(brs,2H),3.61(brs,1H),1.28(s,9H);13CNMR(100MHz,CDCl3,δ)161.7,159.2,143.1,129.7,129.3,127.8,127.3,125.8,124.2,122.5,117.9,115.9,115.7,55.9,22.6;MS(ESI-TOF)m/z:337.2[M+H]+。
实施例7
化合物III-1的制备与表征:
将5mmol化合物II-1抽真空,氮气保护,采用通法3进行反应,溶于24ml无水甲醇和24ml无水1,4-二氧六环的混合溶剂中,得一黄色溶液,滴加10ml,2.2M的HCl的二氧六环溶液,反应2h,反应溶液为深黄色。反应完成后,旋干溶剂,得一深黄色油状液体,加100ml水,用50ml乙酸乙酯萃取,水相为黄色,有机相弃去,水相用NH3.H2O调至PH=8,此时反应液由黄色变为白色再到浅白色,之后用乙酸乙酯萃取至无产品为止。有机相用饱和NaCl溶液洗一次,无水NaSO4干燥,旋干,得一淡黄色油状液体III-1为623mg,产率96%。1HNMR(400MHz,CDCl3,ppm)δ:7.38-7.43(m,4H),7.31-7.33(m,1H),7.12(td,J1=1.2Hz,J2=7.6Hz,2H),7.02(d,J=3.6Hz,1H),6.68-6.76(m,2H),5.25(s,1H),4.46(brs,2H),1.83(brs,2H);13CNMR(100MHz,CDCl3,δ)145.6,144.0,128.7,128.6,128.4,128.2,127.1,127.0,118.0,116.6,57.8;MS(ESI-TOF)m/z:199.1[M+H]+。
实施例8
化合物III-2的制备与表征:
制备条件同实施例7,淡黄色油状液体,产率97%。1HNMR(400MHz,CDCl3,ppm)δ:7.37-7.42(m,4H),7.30-7.33(m,1H),7.03-7.07(m,2H),6.58(d,J=8.0Hz,1H),5.17(s,1H),4.39(brs,2H),1.91(brs,2H);13CNMR(100MHz,CDCl3,δ)144.1,143.2,130.2,128.7,128.1,127.8,127.4,126.9,122.6,117.6,57.5;MS(ESI-TOF)m/z:233.2[M+H]+。
实施例9
化合物III-3的制备与表征:
制备条件同实施例7,淡黄色油状液体,产率96%。1HNMR(400MHz,CDCl3,ppm)δ:7.41(t,J=1.6Hz,1H),7.29-7.38(m,1H),7.19(dd,J1=0.8Hz,J2=7.6Hz,1H),7.00-7.16(m,3H),6.60(d,J=8.4Hz,1H),5.45(s,1H),4.53(brs,2H),1.82(brs,2H);13CNMR(100MHz,CDCl3,δ)161.8,159.4,144.3,130.2,130.1,129.2,129.1,128.4,128.3,128.0,127.8,124.5,122.6,117.5,115.8,115.6,51.4;MS(ESI-TOF)m/z:251.2[M+H]+。
实施例10
化合物VI-1的制备与表征:
将0.5mmol化合物III-1和1.0mmol溴苯,0.005mmol的Pd2(dba)30.006mmol的BINAP,1.2mmol的叔丁醇钠溶于10ml甲苯中,采用通法4进行反应,温度110℃,反应6h,或者用微波,反应30min,取一抽滤漏斗垫入硅藻土,抽滤,用乙酸乙酯洗,将溶液旋干,柱层析分离(石油醚:乙酸乙酯=50:1)得到浅黄色固体化合物IV-1为160mg,产率为94%。1HNMR(400MHz,CDCl3,ppm)δ:7.36-7.42(m,6H),7.25-7.28(m,2H),7.11-7.19(m,3H),6.93-6.96(m,4H),6.81(t,J=3.6Hz,1H),6.69(d,J=8.0Hz,2H),6.23(s,1H),5.83(1H,s),4.35(s,1H);13CNMR(100MHz,CDCl3,δ):146.9,143.6,141.8,140.8,132.1,129.4,129.1,128.9,127.9,127.7,121.7,120.7,119.2,118.4,117.8,114.0,58.9;MS(ESI-TOF)m/z:338.2[M+H]+。
实施例11
化合物IV-2的制备与表征:
IV-2的制备条件同实施例10,浅黄色固体化合物,产率为93%。1HNMR(400MHz,CDCl3,ppm)δ:7.58(d,J=8.0Hz,2H),7.48-7.54(m,4H),7.38-7.46(m,10H),7.26-7.36(m,5H),7.16(d,J=6.8Hz,1H),6.96-7.03(m,3H),6.72(d,J=8.4Hz,2H),6.20(s,1H),5.83(d,J=5.6Hz,1H),4.38(d,J=6.0Hz,1H);13CNMR(100MHz,CDCl3,δ):146.2,143.0,141.4,141.0,140.9,133.5,132.3,131.3,129.0,128.9,128.7,128.4,128.0,127.9,127.8,127.7,126.5,126.3,126.2,122.1,119.7,117.7,114.2,58.9;MS(ESI-TOF)m/z:503.1[M+H]+。
实施例12
化合物IV-3的制备与表征:
IV-3的制备条件同实施例10,浅黄色固体化合物,产率为94%。1HNMR(400MHz,CDCl3,ppm)δ:7.39(d,J=4.4Hz,4H),7.34(d,J=3.2Hz,2H),7.21-7.23(m,2H),7.19(d,J=1.2Hz,2H),7.04(d,J=7.6Hz,1H),6.98(d,J=8.4Hz,2H),6.90(d,J=2.0Hz,2H),6.88(d,J=2.0Hz,3H),6.59(d,J=8.4Hz,2H),6.28(s,1H),5.75(s,1H),2.26(s,3H);13CNMR(100MHz,CDCl3,δ):144.6,142.6,140.9,140.7,131.1,130.5,129.8,129.0,128.8,128.2,127.9,127.5,120.8,118.8,117.8,114.1,59.2,20.7,20.4;MS(ESI-TOF)m/z:379.2[M+H]+。
实施例13
化合物IV-4的制备与表征:
IV-4的制备条件同实施例10,浅黄色固体化合物,产率为91%。1HNMR(400MHz,CDCl3,ppm)δ:7.34-7.40(m,4H),7.21-7.28(m,1H),7.07(dd,J1=1.2Hz,J2=7.6Hz,1H),6.92-6.98(m,3H),6.91-6.95(m,1H),6.58(s,3H),6.41(s,1H),6.28(s,2H),6.04(s,1H),5.76(d,J=4.4Hz,1H),4.18(brs,1H),2.27(s,6H),2.20(s,6H);13CNMR(100MHz,CDCl3,δ):147.0,143.7,141.8,141.1,139.1,138.9,132.7,128.9,128.8,128.2,127.8,127.5,122.4,121.6,120.3,119.7,115.4,111.8,58.6,21.5,21.4;MS(ESI-TOF)m/z:407.1[M+H]+。
实施例14
化合物IV-5的制备与表征:
IV-5的制备条件同实施例10,浅黄色固体化合物,产率为95%。1HNMR(400MHz,CDCl3,ppm)δ:7.63-7.74(m,4H),7.49(t,J=4.8Hz,2H),7.40-7.43(m,5H),7.28-7.33(m,4H),7.21(ddd,J1=2.0,J2=8.0,J3=8.8Hz,2H),6.80(d,J=2.0Hz,1H),6.68-6.76(m,2H),6.29(s,1H),5.96(s,1H),4.50(brs,2H);13CNMR(100MHz,CDCl3,δ):144.3,141.4,132.7,129.2,129.1,129.0,128.9,128.5,127.9,127.7,127.6,126.5,126.4,126.3,126.2,123.3,122.4,120.3,119.9,117.9,111.2,106.7,58.7;MS(ESI-TOF)m/z:451.1[M+H]+。
实施例15
化合物IV-6的制备与表征:
IV-6的制备条件同实施例10,浅黄色固体化合物,产率为88%。1HNMR(400MHz,CDCl3,ppm)δ:7.34-7.40(m,4H),7.22-7.24(m,2H),7.07(d,J=7.2Hz,1H),6.92-6.98(m,2H),6.85-6.91(m,4H),6.57-6.60(m,2H),6.22(s,1H),5.69(s,1H),4.23(brs,1H);13CNMR(100MHz,CDCl3,δ):159.0,157.5,156.7,155.1,143.1,143.0,142.5,140.4,139.3,130.8,129.1,128.9,128.5,127.8,127.7,121.1,120.3,120.2,117.7,116.1,115.9,115.8,115.6,114.9,59.6;MS(ESI-TOF)m/z:387.1[M+H]+。
实施例16
化合物IV-7的制备与表征:
IV-7的制备条件同实施例10,浅黄色固体化合物,产率为78%。1HNMR(400MHz,CDCl3,ppm)δ:7.30-7.38(m,4H),7.21-7.24(m,2H),7.01(d,J=6.8Hz,1H),6.92-6.98(m,2H),6.83-6.91(m,4H),6.56-6.60(m,2H),6.21(s,1H),5.66(s,1H),4.21(brs,1H),3.76(s,6H),;13CNMR(100MHz,CDCl3,δ):150.2,149.3,142.5,142.1,140.4,139.3,130.8,129.1,128.9,127.8,127.7,121.1,120.3,120.2,117.8,116.2,115.9,115.6,115.1,114.9,55.3;MS(ESI-TOF)m/z:411.2[M+H]+。
实施例17
化合物IV-8的制备与表征:
IV-8的制备条件同实施例10,浅黄色固体化合物,产率为88%。1HNMR(400MHz,CDCl3,ppm)δ:7.73-7.97(m,4H),7.22-7.24(m,2H),6.92-6.98(m,3H),6.76-6.91(m,4H),6.51-6.62(m,2H),6.23(s,1H),5.69(s,1H),4.08(brs,1H);13CNMR(100MHz,CDCl3,δ):153.7,145.6,140.8,140.6,131.7,130.3,129.7,129.3,128.8,128.4,127.5,127.1,120.8,118.6,117.6,114.5,53.4;MS(ESI-TOF)m/z:441.2[M+H]+。
实施例18
化合物IV-1’的制备与表征:
将0.5mmol化合物III-2和1.0mmol溴苯,0.005mmol的Pd2(dba)30.006mmol的BINAP,1.2mmol的叔丁醇钠溶于10ml甲苯中,采用通法4进行反应,温度110℃,反应6h,或者用微波,反应30min,取一抽滤漏斗垫入硅藻土,抽滤,用乙酸乙酯洗,将溶液旋干,柱层析分离(石油醚:乙酸乙酯=50:1)得到浅黄色固体化合物IV-1’为176mg,产率为91%。1HNMR(400MHz,CDCl3,ppm)δ:7.35-7.43(m,5H),7.20-7.31(m,2H),7.15-7.19(m,4H),6.91-6.96(m,3H),6.78(t,J=7.6Hz,1H),6.63(d,J=7.6Hz,2H),6.03(s,1H),5.70(d,J=6.4Hz,1H),4.22(d,J=6.4Hz,1H);13CNMR(100MHz,CDCl3,δ):146.5,143.1,140.3,140.0,133.8,129.4,129.3,129.1,128.7,128.2,127.8,126.7,121.1,120.4,118.6,117.9,113.9,58.90;MS(ESI-TOF)m/z:385.2[M+H]+。
实施例19
化合物IV-2’的制备与表征:
IV-2’的制备条件同实施例18,浅黄色固体化合物,产率为92%。1HNMR(400MHz,CDCl3,ppm)δ:7.50-7.61(m,6H),7.38-7.46(m,12H),7.30-7.33(m,3H),6.98(d,J=8.0Hz,2H),6.71(d,J=8.4Hz,2H),6.08(s,1H),5.76(d,J=5.6Hz,1H),4.32(d,J=6.0Hz,1H);13CNMR(100MHz,CDCl3,δ):145.9,142.6,140.9,140.7,140.0,139.9,134.1,133.9,129.2,128.7,128.6,128.4,128.2,128.1,128.0,127.8,126.7,126.5,126.4,126.3,120.9,117.9,114.2,58.9;MS(ESI-TOF)m/z:538.1[M+H]+。
实施例20
化合物IV-3’的制备与表征:
IV-3’的制备条件同实施例18,浅黄色固体化合物,产率为89%。1HNMR(400MHz,CDCl3,ppm)δ:7.41(d,J=4.4Hz,4H),7.32(d,J=3.2Hz,2H),7.21-7.23(m,2H),7.19(d,J=1.2Hz,2H),7.04(d,J=7.6Hz,1H),6.90(d,J=2.0Hz,2H),6.88(d,J=2.0Hz,2H),5.76(s,1H),2.26(s,3H),2.23(s,3H);13CNMR(100MHz,CDCl3,δ):154.6,148.6,145.9,143.7,131.5,130.4,129.8,129.1,128.8,128.2,127.9,127.5,120.8,118.8,117.8,114.1,59.3,20.7,20.4;MS(ESI-TOF)m/z:413.1[M+H]+。
实施例21
化合物IV-4’的制备与表征:
IV-4’的制备条件同实施例18,浅黄色固体化合物,产率为90%。1HNMR(400MHz,CDCl3,ppm)δ:7.30-7.43(m,6H),7.15-7.21(m,4H),6.61(s,1H),6.55(s,2H),6.45(s,1H),6.28(s,2H),5.90(s,1H),5.70(d,J=2.8Hz,1H),4.13(brs,1H),2.29(s,6H),2.23(s,6H);13CNMR(100MHz,CDCl3,δ):146.8,143.3,140.4,140.3,139.2,138.9,134.4,129.0,128.6,128.2,127.8,126.7,122.8,121.1,121.0,120.5,115.6,111.8,58.6,21.5;MS(ESI-TOF)m/z:442.2[M+H]+。
实施例22
化合物IV-5’的制备与表征:
IV-5’的制备条件同实施例18,浅黄色固体化合物,产率为95%。1HNMR(400MHz,CDCl3,ppm)δ:7.62-7.73(m,6H),7.41-7.52(m,6H),7.31-7.37(m,5H),7.25-7.27(m,3H),7.15-7.23(m,4H),7.02(dd,J1=2.4Hz,J2=8.8Hz,1H),6.88(s,1H),6.61(s,1H),6.22(d,J=6.8Hz,1H),4.45(d,J=7.2Hz,1H);13CNMR(100MHz,CDCl3,δ):144.1,141.2,141.0,134.7,134.6,132.7,129.8,129.7,129.3,129.2,128.8,128.7,128.3,128.2,127.8,127.6,126.9,126.6,126.5,126.4,126.3,124.7,123.6,122.8,120.8,120.0,117.8,116.2,116.0,112.0,111.6,107.3,52.8;MS(ESI-TOF)m/z:486.2[M+H]+。
实施例23
化合物IV-6’的制备与表征:
IV-6’的制备条件同实施例10,浅黄色固体化合物,产率为86%。1HNMR(400MHz,CDCl3,ppm)δ:7.36-7.43(m,4H),7.25-7.27(m,2H),7.12(d,J=6.8Hz,1H),6.91-6.98(m,2H),6.84-6.90(m,2H),6.57-6.60(m,2H),6.26(s,1H),5.67(s,1H),4.27(brs,1H);13CNMR(100MHz,CDCl3,δ):159.1,157.3,156.1,155.4,143.7,143.3,142.6,140.4,139.4,130.4,129.5,128.9,128.7,127.6,121.1,120.3,117.8,
116.2,115.9,115.4,114.1,59.4;MS(ESI-TOF)m/z:421.2[M+H]+。
实施例24
化合物IV-7’的制备与表征:
IV-7’的制备条件同实施例18,浅黄色固体化合物,产率为76%。1HNMR(400MHz,CDCl3,ppm)δ:7.36-7.44(m,4H),7.25-7.29(m,2H),7.06(d,J=6.8Hz,1H),6.93-6.99(m,2H),6.83-6.91(m,4H),6.23(s,1H),5.68(s,1H),3.76(s,6H);13CNMR(100MHz,CDCl3,δ):158.2,149.6,142.3,142.2,140.5,139.3,130.7,129.4,128.7,127.6,127.1,121.1,120.3,120.2,117.8,116.8,115.9,115.6,115.1,114.2,55.4;MS(ESI-TOF)m/z:445.1[M+H]+。
实施例25
化合物IV-8’的制备与表征:
IV-8’的制备条件同实施例18,浅黄色固体化合物,产率为86%。1HNMR(400MHz,CDCl3,ppm)δ:7.74-7.98(m,4H),7.23-7.26(m,2H),6.94-6.99(m,3H),6.76-6.92(m,4H),6.52-6.63(m,2H),6.26(s,1H),5.71(s,1H),4.13(brs,1H);13CNMR(100MHz,CDCl3,δ):158.7,149.6,140.8,140.1,131.7,130.3,129.7,129.4,128.8,128.3,127.6,127.1,120.8,118.9,117.6,114.5,53.7;MS(ESI-TOF)m/z:475.1[M+H]+。
实施例26
化合物IV-1’’的制备与表征:
将0.5mmol化合物III-3和1.0mmol溴苯,0.005mmol的Pd2(dba)30.006mmol的BINAP,1.2mmol的叔丁醇钠溶于10ml甲苯中,采用通法4进行反应,温度110℃,反应6h,或者用微波,反应30min,取一抽滤漏斗垫入硅藻土,抽滤,用乙酸乙酯洗,将溶液旋干,柱层析分离(石油醚:乙酸乙酯=50:1)得到浅黄色固体化合物IV-1’为180mg,产率为89%。1HNMR(400MHz,CDCl3,ppm)δ:7.29-7.36(m,4H),7.14-7.25(m,5H),6.98-6.99(m,2H),6.84(t,J=7.2Hz,1H),6.73(d,J=7.6Hz,2H),6.54(s,1H),6.08(d,J=7.6Hz,1H),4.27(d,J=7.6Hz,1H);13CNMR(100MHz,CDCl3,δ):162.1,159.7,146.2,143.1,140.8,132.1,129.8,129.7,129.5,129.1,129.0,128.6,128.3,126.3,124.8,124.7,121.3,119.8,119.2,118.2,116.2,115.9,114.3,52.9;MS(ESI-TOF)m/z:403.2[M+H]+。
实施例27
化合物IV-2’’的制备与表征:
IV-2’’的制备条件同实施例26,浅黄色固体化合物,产率为91%。1HNMR(400MHz,CDCl3,ppm)δ:7.62(d,J=8.0Hz,2H),7.50-7.57(m,4H),7.39-7.49(m,8H),7.12-7.46(m,5H),7.06(d,J=2.0Hz,3H),6.77(d,J=7.6Hz,2H),6.53(s,1H),6.09(d,J=6.8Hz,1H),4.32(d,J=7.6Hz,1H);13CNMR(100MHz,CDCl3,δ):145.5,142.5,140.9,140.8,140.5,134.0,132.4,132.1,129.8,129.7,129.0,128.8,128.7,128.3,128.1,126.8,126.7,126.6,126.5,126.4,124.8,120.4,118.2,116.2,115.9,114.5,52.9;MS(ESI-TOF)m/z:555.2[M+H]+。
实施例28
化合物IV-3’’的制备与表征:
IV-3’’的制备条件同实施例26,浅黄色固体化合物,产率为89%。1HNMR(400MHz,CDCl3,ppm)δ:7.43(d,J=6.4Hz,4H),7.36(d,J=7.6Hz,2H),7.22-7.26(m,2H),7.21(d,J=1.2Hz,2H),7.06(d,J=8.0Hz,1H),6.92(d,J=4.0Hz,2H),6.88(d,J=2.0Hz,2H),5.75(s,1H),2.26(s,3H),2.23(s,3H);13CNMR(100MHz,CDCl3,δ):158.9,148.7,145.6,143.5,131.8,130.6,129.7,129.1,128.6,128.2,127.3,127.1,120.6,118.5,117.3,114.1,59.6,20.8,20.6;MS(ESI-TOF)m/z:431.1[M+H]+。
实施例29
化合物IV-4’’的制备与表征:
IV-4’’的制备条件同实施例26,浅黄色固体化合物,产率为88%。1HNMR(400MHz,CDCl3,ppm)δ:7.31-7.39(m,3H),7.10-7.20(m,3H),6.94(d,J=2.0Hz,1H),6.61(s,3H),6.45(s,1H),6.38(s,1H),6.31(s,1H),5.99(d,J=8.0Hz,1H),4.10(d,J=8.0Hz,1H),2.28(s,6H),2.21(s,6H);13CNMR(100MHz,CDCl3,δ):146.3,143.0,140.9,139.2,139.0,132.4,129.6,129.5,128.4,128.1,127.1,126.9,125.9,124.6,122.9,121.1,120.2,116.1,115.9,115.8,112.2,52.8,21.4;MS(ESI-TOF)m/z:459.2[M+H]+。
实施例30
化合物IV-5’’的制备与表征:
IV-5’’的制备条件同实施例26,浅黄色固体化合物,产率为93%。1HNMR(400MHz,CDCl3,ppm)δ:7.63-7.82(m,5H),7.54(d,J=5.2Hz,1H),7.40-7.50(m,3H),7.19-7.38(m,6H),7.11-7.18(m,4H),7.03(dd,J1=2.4Hz,J2=8.8Hz,1H),6.89(d,J=2.0Hz,1H),6.62(s,1H),6.24(d,J=7.6Hz,1H),4.45(d,J=7.6Hz,1H);13CNMR(100MHz,CDCl3,δ):162.1,159.7,143.7,140.9,140.6,134.8,134.6,132.8,129.8,129.7,129.3,128.9,128.7,128.3,127.7,127.6,127.0,126.6,126.5,126.4,124.8,123.6,122.9,120.9,117.9,116.2,116.0,112.0,107.3,52.8;MS(ESI-TOF)m/z:504.1[M+H]+。
实施例31
化合物IV-6’’的制备与表征:
IV-6’’的制备条件同实施例26,浅黄色固体化合物,产率为83%。1HNMR(400MHz,CDCl3,ppm)δ:7.37-7.44(m,4H),7.21-7.26(m,2H),7.13(d,J=7.6Hz,1H),6.91-6.96(m,2H),6.84-6.88(m,2H),6.56-6.61(m,2H),6.26(s,1H),5.68(s,1H),4.26(brs,1H);13CNMR(100MHz,CDCl3,δ):159.6,157.8,156.2,155.3,143.8,143.1,142.7,140.2,139.5,130.6,129.2,128.6,128.2,127.6,121.5,120.4,117.8,116.7,115.9,115.3,114.2,59.3;MS(ESI-TOF)m/z:439.2[M+H]+。
实施例32
化合物IV-7’’的制备与表征:
IV-7’’的制备条件同实施例26,浅黄色固体化合物,产率为77%。1HNMR(400MHz,CDCl3,ppm)δ:7.34-7.43(m,4H),7.21-7.26(m,2H),7.04(d,J=8.0Hz,1H),6.92-6.98(m,2H),6.81-6.89(m,4H),6.22(s,1H),5.67(s,1H),3.77(s,6H);13CNMR(100MHz,CDCl3,δ):158.1,149.5,142.4,142.1,140.5,139.8,130.9,129.4,128.7,127.6,127.6,121.1,120.3,120.2,117.3,116.8,115.9,115.2,115.4,114.1,
55.8;MS(ESI-TOF)m/z:463.1[M+H]+。
实施例33
化合物IV-8’’的制备与表征:
IV-8’’的制备条件同实施例26,浅黄色固体化合物,产率为82%。1HNMR(400MHz,CDCl3,ppm)δ:7.78-7.96(m,4H),7.22-7.26(m,2H),6.91-6.97(m,3H),6.73-6.91(m,4H),6.56-6.63(m,2H),6.27(s,1H),5.72(s,1H),4.11(brs,1H);13CNMR(100MHz,CDCl3,δ):161.2,149.8,140.7,140.5,131.7,130.6,129.7,129.4,128.8,128.2,127.8,127.1,120.8,118.9,117.8,114.6,53.8;MS(ESI-TOF)m/z:493.1[M+H]+。
实施例34
化合物V-1的制备与表征:
将0.5mmol化合物IV-1溶于5ml原甲酸三甲酯,采用通法5进行反应,室温下加入0.1ml的甲酸和0.1ml的浓盐酸,反应3h后,旋干溶剂,柱层析分离(二氯甲烷:甲醇=15:1)得到浅黄色固体化合物V-1为170mg,产率为86%。1HNMR(400MHz,CDCl3,ppm)δ:8.75(s,1H),7.95(d,J=5.2Hz,2H),7.34(d,J=6.8Hz,3H),7.48-7.58(m,3H),7.43(d,J=6.8Hz,2H),7.28-7.32(m,5H),7.19-7.27(m,2H),7.04(d,J=2.4Hz,1H),6.86(s,1H),6.65(d,J=2.0Hz,1H);13CNMR(100MHz,CDCl3,δ):151.3,143.8,142.5,139.4,139.2,139.0,138.6,135.4,132.1,129.5,129.4,129.1,129.0,128.9,128.8,128.5,128.3,128.2,127.1,125.9,122.9,117.2,65.5;MS(ESI-TOF)m/z:361.2[M]+;HRMS(ESI-TOF)m/z:calcdforC26H21N2 +[M]+361.1699,Found361.1692.
实施例35
化合物V-2的制备与表征:
V2的制备条件同实施例34,V-2为浅黄色固体化合物,产率为92%。1HNMR(400MHz,CDCl3,ppm)δ:8.91(s,1H),7.91(d,J=8.4Hz,2H),7.63(d,J=1.2Hz,2H),7.33-7.54(m,16H),7.22-7.31(m,2H),7.10(d,J=1.6Hz,1H),6.92(s,1H),6.79(d,J=7.6Hz,1H);13CNMR(100MHz,CDCl3,δ):151.3,143.8,142.5,139.4,139.2,138.9,138.5,135.4,132.1,129.5,129.4,129.2,129.1,128.8,128.7,128.5,128.3,128.2,128.0,127.3,127.1,125.8,122.9,117.2,65.5;MS(ESI-TOF)m/z:513.2[M]+;HRMS(ESI-TOF)m/z:calcdforC38H29N2 +[M]+513.2325,Found513.2328.
实施例36
化合物V-3的制备与表征:
V-3的制备条件同实施例34,V-3为浅黄色固体化合物,产率为90%。1HNMR(400MHz,CDCl3,ppm)δ:8.68(s,1H),7.72(d,J=8.4Hz,2H),7.49(d,J=8.0Hz,2H),7.42(t,J=6.4Hz,4H),7.30-7.38(m,4H),7.05-7.26(m,3H),6.71(s,1H),6.69(d,J=2.0Hz,1H),2.43(s,3H),2.23(s,3H);13CNMR(100MHz,CDCl3,δ):150.9,141.4,140.1,139.1,136.8,133.7,132.0,131.2,130.5,129.4,129.3,128.9,128.7,128.6,128.3,127.8,127.7,125.1,122.6,117.1,113.2,65.4,21.3,21.1;MS(ESI-TOF)m/z:389.2[M]+;HRMS(ESI-TOF)m/z:calcdforC28H25N2 +[M]+389.2012,Found389.2008.
实施例37
化合物V-4的制备与表征
V-4的制备条件同实施例34,V-4为浅黄色固体化合物,产率为90%。1HNMR(400MHz,CDCl3,ppm)δ:8.71(s,1H),7.52(s,2H),7.44(d,J=1.2Hz,2H),7.28-7.43(m,5H),7.20-7.25(m,3H),7.08(t,J=4.0Hz,1H),6.93(s,1H),6.87(s,1H),6.75-6.77(m,3H),2.43(s,6H),2.25(s,6H);13CNMR(100MHz,CDCl3,δ):150.7,140.8,139.9,139.2,136.2,132.5,132.1,131.4,129.3,129.2,128.7,128.6,128.4,125.3,122.8,117.2,65.3,21.2;MS(ESI-TOF)m/z:417.2[M]+;HRMS(ESI-TOF)m/z:calcdforC30H29N2 +[M]+417.2325,Found417.2327.
实施例38
化合物V-5的制备与表征:
V5的制备条件同实施例34,V-1为浅黄色固体化合物,产率为91%。1HNMR(400MHz,CDCl3,ppm)δ:9.03(s,1H),8.67(s,1H),8.45(s,1H),8.05(d,J=8.8Hz,2H),7.91(dd,J=13.2,8.4Hz,2H),7.70(t,J=8.8Hz,2H),7.52-7.54(m,5H),7.45-7.47(m,2H),7.14-7.34(m,6H),7.07(s,1H),6.74(d,J=8.8Hz,1H);13CNMR(100MHz,CDCl3,δ):139.0,136.8,133.7,133.6,133.0,132.1,130.6,130.0,127.9,129.4,129.3,128.9,128.8,128.7,128.5,128.1,127.9,127.8,127.6,127.5,127.2,125.2,124.4,123.0,121.9,65.4;MS(ESI-TOF)m/z:461.2[M]+;HRMS(ESI-TOF)m/z:calcdforC34H25N2 +[M]+461.2012,Found461.2001.
实施例39
化合物V-6的制备与表征:
V-6的制备条件同实施例34,V-6为浅黄色固体化合物,产率为87%。1HNMR(400MHz,CDCl3,ppm)δ:8.81(s,1H),8.02(s,2H),7.71-7.74(m,2H),7.23-7.43(m,9H),6.97(t,J=8.4Hz,3H),6.68(s,2H);13CNMR(100MHz,CDCl3,δ):162.3,151.8,129.5,128.9,128.6,122.5,120.3,117.8,117.7,117.5,116.9,116.7,115.9,115.7,115.6,115.3,65.9;MS(ESI-TOF)m/z:397.1[M]+;HRMS(ESI-TOF)m/z:calcdforC26H19F2N2 +[M]+397.1511,Found397.1512.
实施例40
化合物V-7的制备与表征:
V-7的制备条件同实施例34,V-7为浅黄色固体化合物,产率为86%。1HNMR(400MHz,CDCl3,ppm)δ:8.83(s,1H),8.01(s,2H),7.72-7.76(m,2H),7.21-7.45(m,8H),6.96(t,J=7.2Hz,3H),6.63(s,2H),3.72(s,6H);13CNMR(100MHz,CDCl3,δ):159.1,149.6,129.7,128.9,128.3,122.5,120.1,117.8,117.7,117.5,116.9,116.7,115.9,115.7,115.6,115.3,65.9;MS(ESI-TOF)m/z:421.2[M]+;HRMS(ESI-TOF)m/z:calcdforC28H25N2O2 +[M]+421.1911,Found421.1913.
实施例41
化合物V-8的制备与表征:
V-8的制备条件同实施例34,V-8为浅黄色固体化合物,产率为87%。1HNMR(400MHz,CDCl3,ppm)δ:8.87(s,1H),8.08(s,2H),7.73-7.78(m,2H),7.23-7.46(m,8H),6.98(t,J=6.8Hz,3H),6.73(s,2H);13CNMR(100MHz,CDCl3,δ):159.8,149.3,129.6,128.9,128.3,122.6,120.3,118.6,117.7,117.5,116.8,116.5,115.8,115.7,115.6,115.2,65.1;MS(ESI-TOF)m/z:451.1[M]+;HRMS(ESI-TOF)m/z:calcdforC26H19N4O4 +[M]+451.1401,Found451.1404.
实施例42
化合物V-1’的制备与表征:
V-1’的制备条件同实施例34,浅黄色固体化合物,产率为89%。1HNMR(400MHz,DMSO-d6,ppm)δ:9.30(s,1H),7.86(d,J=6.8Hz,2H),7.67-7.74(m,6H),7.33-7.49(m,7H),7.15(s,1H),6.69(d,J=9.2Hz,1H);13CNMR(100MHz,DMSO-d6,δ):153.0,140.0,139.9,136.8,132.7,131.1,131.0,129.8,129.6,128.4,128.3,125.6,124.8,119.0,62.8;MS(ESI-TOF)m/z:395.1[M]+;HRMS(ESI-TOF)m/z:calcdforC26H20ClN2 +[M]+395.1315,Found395.1308.
实施例43
化合物V-2’的制备与表征:
V-2’的制备条件同实施例34,V-2’为浅黄色固体化合物,产率为91%。1HNMR(400MHz,DMSO-d6,ppm)δ:9.30(s,1H),8.01(d,J=8.8Hz,2H),7.89(d,J=8.4Hz,2H),7.73-7.80(m,5H),7.64-7.67(m,4H),7.52-7.56(m,3H),7.36-7.48(m,10H),7.06(s,1H),6.82(d,J=8.8Hz,1H);13CNMR(100MHz,DMSO-d6,δ):152.7,142.8,141.3,139.9,139.0,138.9,138.7,135.8,132.9,130.8,129.9,129.7,129.5,129.4,129.1,129.0,128.8,128.7,128.6,128.2,128.1,128.0,127.2,127.0,126.9,125.8,125.5,125.1,119.1,62.9;MS(ESI-TOF)m/z:547.2[M]+;HRMS(ESI-TOF)m/z:calcdforC38H28ClN2 +[M]+547.1936,Found547.1935.
实施例44
化合物V-3’的制备与表征:
V-3’的制备条件同实施例34,浅黄色固体化合物,产率为89%。1HNMR(400MHz,DMSO-d6,ppm)δ:8.71(s,1H),7.73(d,J=6.8Hz,2H),7.46(d,J=8.0Hz,2H),7.40(t,J=6.4Hz,4H),7.30-7.36(m,4H),7.05-7.26(m,3H),6.70(s,1H),6.68(d,J=2.0Hz,1H),2.43(s,3H),2.22(s,3H);13CNMR(100MHz,DMSO-d6,δ):151.8,141.6,140.6,139.1,136.8,133.7,132.0,131.6,130.5,129.5,129.1,128.9,128.7,128.6,128.2,127.8,127.2,125.1,122.6,117.1,113.2,65.6,21.3,21.1;MS(ESI-TOF)m/z:423.1[M]+;HRMS(ESI-TOF)m/z:calcdforC28H24ClN2 +[M]+423.1623,Found423.1619.
实施例45
化合物V-4’的制备与表征:
V-4’的制备条件同实施例34,浅黄色固体化合物,产率为91%。1HNMR(400MHz,DMSO-d6,ppm)δ:9.17(s,1H),7.65(d,J=7.6Hz,2H),7.36-7.46(m,10H),7.15(s,1H),7.04(s,1H),6.73(d,J=8.8Hz,1H),2.41(s,6H),2.24(s,6H);13CNMR(100MHz,DMSO-d6,δ):152.6,140.5,140.1,139.7,139.5,136.6,132.6,132.3,131.0,130.9,129.8,129.6,128.2,127.9,125.6,125.5,121.9,119.1,62.4,21.2;MS(ESI-TOF)m/z:451.2[M]+;HRMS(ESI-TOF)m/z:calcdforC30H28ClN2 +[M]+451.1936,Found451.1916.
实施例46
化合物V-5’的制备与表征:
V-5’的制备条件同实施例34,浅黄色固体化合物,产率为93%。1HNMR(400MHz,DMSO-d6,ppm)δ:9.57(s,1H),8.49(d,J=1.2Hz,1H),8.31(t,J=8.8Hz,2H),8.17(d,J=1.6Hz,2H),8.14(d,J=6.4Hz,1H),8.07(d,J=8.8Hz,1H),7.97(t,J=5.6Hz,1H),7.91(d,J=5.6Hz,1H),7.81-7.88(m,4H),7.59-7.77(m,2H),7.19-7.46(m,9H),6.84(d,J=8.8Hz,1H);13CNMR(100MHz,DMSO-d6,δ):153.3,136.8,134.1,133.8,133.6,132.9,132.8,131.6,131.5,131.0,130.2,128.8,128.5,128.3,128.2,128.1,127.9,125.1,124.1,124.0,121.7,119.2,117.1,116.8,58.99;MS(ESI-TOF)m/z:495.1[M]+;HRMS(ESI-TOF)m/z:calcdforC34H24ClN2 +[M]+495.1623,Found495.1611.
实施例47
化合物V-6’的制备与表征:
V-6’的制备条件同实施例34,V-6’为浅黄色固体化合物,产率为85%。1HNMR(400MHz,DMSO-d6,ppm)δ:8.96(s,1H),8.08(s,2H),7.72-7.76(m,2H),7.26-7.43(m,8H),6.98(t,J=6.4Hz,3H),6.70(s,2H);13CNMR(100MHz,DMSO-d6,δ):162.6,150.8,129.5,128.9,128.3,122.5,120.1,117.8,117.5,117.2,116.9,116.7,115.9,115.8,115.6,115.1,65.8;MS(ESI-TOF)m/z:431.1[M]+;HRMS(ESI-TOF)m/z:calcdforC26H18ClF2N2 +[M]+431.1121,Found431.1117.
实施例48
化合物V-7’的制备与表征:
V-7’的制备条件同实施例34,浅黄色固体化合物,产率为84%。1HNMR(400MHz,DMSO-d6,ppm)δ:8.81(s,1H),8.02(s,2H),7.71-7.75(m,2H),7.21-7.43(m,8H),6.96(t,J=8.4Hz,3H),6.61(s,2H),3.73(s,6H);13CNMR(100MHz,DMSO-d6,δ):158.1,149.6,129.7,128.9,128.1,122.5,120.6,117.8,117.5,117.0,116.9,116.7,115.9,115.6,115.3,65.3;MS(ESI-TOF)m/z:361.2[M]+;HRMS(ESI-TOF)m/z:calcdforC28H24ClN2O2 +[M]+455.1521,Found455.1518.
实施例49
化合物V-8’的制备与表征:
V-8’的制备条件同实施例34,V-8为浅黄色固体化合物,产率为83%。1HNMR(400MHz,DMSO-d6,ppm)δ:9.16(s,1H),8.18(s,2H),7.75-7.79(m,2H),7.26-7.46(m,8H),6.97(t,J=8.8Hz,3H),6.76(s,2H);13CNMR(100MHz,DMSO-d6,δ):159.6,149.3,129.7,128.9,128.1,122.6,120.2,118.6,117.5,117.1,116.8,116.5,115.8,115.4,115.0,65.2;MS(ESI-TOF)m/z:485.1[M]+;HRMS(ESI-TOF)m/z:calcdforC26H18ClN4O4 +[M]+485.1011,Found485.1010.
实施例50
化合物V-1’’的制备与表征:
V-1’’的制备条件同实施例34,浅黄色固体化合物,产率为89%。1HNMR(400MHz,DMSO-d6,ppm)δ:9.21(s,1H),7.71(s,5H),7.55-7.57(m,2H),7.41-7.47(m,5H),7.16-7.27(m,5H),6.69(d,J=8.8Hz,1H);13CNMR(100MHz,DMSO-d6,δ):163.6,159.7,152.7,139.3,136.4,132.9,131.4,131.3,131.1,130.3,130.1,128.1,126.5,126.3,125.8,124.8,123.9,118.9,117.1,116.8,59.4;MS(ESI-TOF)m/z:413.1[M]+;HRMS(ESI-TOF)m/z:calcdforC26H19ClFN2 +[M]+413.1215,Found413.1210.
实施例51
化合物V-2’’的制备与表征:
V-2’’的制备条件同实施例34,浅黄色固体化合物,产率为91%。1HNMR(400MHz,DMSO-d6,ppm)δ:9.42(s,1H),8.05(d,J=8.8Hz,2H),7.89(d,J=8.4Hz,2H),7.81-7.84(m,6H),7.68-7.70(m,2H),7.54-7.58(m,3H),7.28-7.50(m,10H),6.85(d,J=9.2Hz,1H);13CNMR(100MHz,DMSO-d6,δ):163.4,159.7,152.9,142.9,142.6,139.1,138.8,135.9,132.9,131.5,131.3,130.2,129.7,129.5,129.4,129.2,128.8,128.2,127.5,125.9,125.2,124.1,119.1,117.1,116.9,58.9;MS(ESI-TOF)m/z:565.2[M]+;HRMS(ESI-TOF)m/z:calcdforC38H27ClFN2 +[M]+565.1841,Found565.1841.
实施例52
化合物V-3’’的制备与表征:
V-3’’的制备条件同实施例34,浅黄色固体化合物,产率为89%。1HNMR(400MHz,DMSO-d6,ppm)δ:9.12(s,1H),7.73(d,J=6.8Hz,2H),7.45(d,J=8.0Hz,2H),7.39(t,J=6.4Hz,4H),7.31-7.37(m,4H),7.03-7.26(m,2H),6.70(s,1H),6.68(d,J=2.0Hz,1H),2.43(s,3H),2.22(s,3H);13CNMR(100MHz,DMSO-d6,δ):153.7,141.8,140.6,139.6,136.8,133.7,132.1,131.6,130.5,129.5,129.3,128.9,128.7,128.6,128.2,127.8,127.6,125.1,122.6,117.6,113.2,65.1,21.5,21.2;MS(ESI-TOF)m/z:441.1[M]+;HRMS(ESI-TOF)m/z:calcdforC28H23ClFN2 +[M]+441.1528,Found441.1526.
实施例53
化合物V-4’’的制备与表征:
V-4’’的制备条件同实施例34,浅黄色固体化合物,产率为91%。1HNMR(400MHz,DMSO-d6,ppm)δ:9.18(s,1H),7.75(t,J=3.6Hz,1H),7.45(dd,J1=2.0Hz,J2=8.4Hz,2H),7.23-7.37(m,9H),7.05(s,1H),6.74(d,J=8.8Hz,1H),2.41(s,6H),2.24(s,6H);13CNMR(100MHz,DMSO-d6,δ):162.2,159.8,152.5,140.6,139.7,139.3,136.5,132.6,132.4,131.5,131.3,130.1,128.1,126.8,126.7,125.8,125.5,124.0,122.0,119.0,117.1,116.8,58.8,21.2,21.1;MS(ESI-TOF)m/z:469.2[M]+;HRMS(ESI-TOF)m/z:calcdforC30H27ClFN2 +[M]+469.1841,Found469.1843.
实施例54
化合物V-5’’的制备与表征:
V-5’’的制备条件同实施例34,浅黄色固体化合物,产率为93%。1HNMR(400MHz,DMSO-d6,ppm)δ:9.56(s,1H),8.46(d,J=1.6Hz,1H),8.31(d,J=8.8Hz,1H),8.25(d,J=2.0Hz,1H),8.15-8.17(m,2H),8.07(d,J=9.2Hz,1H),7.60-7.98(m,6H),7.20-7.59(m,9H);13CNMR(100MHz,DMSO-d6,δ):159.7,153.3,136.9,134.1,133.8,133.6,132.9,132.8,131.6,131.4,131.0,130.3,130.2,128.9,128.6,128.5,128.3,128.2,128.1,125.8,125.0,124.1,121.7,119.3,117.1,116.8,59.1;MS(ESI-TOF)m/z:513.1[M]+;HRMS(ESI-TOF)m/z:calcdforC34H23ClFN2 +[M]+513.1528,Found513.1520.
实施例55
化合物V-6’’的制备与表征:
V-6’’的制备条件同实施例34,浅黄色固体化合物,产率为85%。1HNMR(400MHz,DMSO-d6,ppm)δ:9.03(s,1H),8.09(s,2H),7.73-7.76(m,2H),7.21-7.43(m,8H),6.98(t,J=6.4Hz,3H),6.70(s,2H);13CNMR(100MHz,DMSO-d6,δ):162.2,150.6,129.5,128.9,128.3,122.6,120.3,117.8,117.4,117.2,116.9,116.1,115.9,115.8,115.4,115.1,65.8;MS(ESI-TOF)m/z:449.1[M]+;HRMS(ESI-TOF)m/z:calcdforC26H17ClF3N2 +[M]+449.1027,Found449.1023.
实施例56
化合物V-7’’的制备与表征:
V-7’’的制备条件同实施例34,浅黄色固体化合物,产率为84%。1HNMR(400MHz,DMSO-d6,ppm)δ:8.85(s,1H),8.01(s,2H),7.71-7.75(m,2H),7.22-7.43(m,8H),6.96(t,J=8.4Hz,3H),6.62(s,2H),3.71(s,6H);13CNMR(100MHz,DMSO-d6,δ):158.2,149.8,129.9,128.8,128.6,122.7,120.6,117.8,117.3,117.0,116.9,116.6,115.9,115.6,115.0,63.4;MS(ESI-TOF)m/z:473.1[M]+;HRMS(ESI-TOF)m/z:calcdforC28H23ClFN2O2 +[M]+473.1427,Found473.1424.
实施例57
化合物V-8’’的制备与表征:
V-8’’的制备条件同实施例34,浅黄色固体化合物,产率为83%。1HNMR(400MHz,DMSO-d6,ppm)δ:9.23(s,1H),8.19(s,2H),7.71-7.82(m,2H),7.26-7.46(m,8H),6.98(t,J=8.8Hz,3H),6.76(s,2H);13CNMR(100MHz,DMSO-d6,δ):157.8,149.6,129.7,128.9,128.1,122.6,120.5,118.4,117.8,117.1,116.8,116.5,115.8,115.4,115.0,61.1;MS(ESI-TOF)m/z:503.1[M]+;HRMS(ESI-TOF)m/z:calcdforC26H17ClFN4O4 +[M]+503.0913,Found503.0917.
实施例58~61为六元氮杂卡宾前体V1~V8、V1’~V8’的催化实验,催化效果及选择性(ee)如表1所示。
实施例58
化合物A-2的制备与表征:
将0.01mmol六元氮杂卡宾前体溶于3ml无水四氢呋喃,加入0.011mmol的氯化亚铜和0.01mmol的叔丁醇钠,搅拌2h,将1mmol化合物A-1,1.1mmol二硼烷二频哪醇酯加入反应液中,室温反应2~24h,TLC监测反应进程。反应完成后,取一抽滤漏斗垫入硅藻土,抽滤,用乙酸乙酯洗,有机相加入饱和食盐水洗1次,无水硫酸钠干燥,减压旋去溶剂,柱层析分离(石油醚:乙酸乙酯=20:1,石油醚:乙酸乙酯=4:1)得到产物,产率:99%,然后向产物A2加入1mol/L的氢氧化钠溶液5ml,再加入30%过氧化氢溶液1ml,反应1h后,用乙酸乙酯萃取,旋干有机相,对此产物用手性AD-H柱,流动相为正己烷:异丙醇=97:3(体积比),测得ee:40%.1HNMR(400MHz,CDCl3,ppm)δ:7.76(d,J=8.0Hz,1H),7.21(d,J=8.0Hz,2H),7.08-7.16(m,1H),3.70(s,3H),3.56(t,J=6.8Hz,1H),2.71-2.82(m,1.16(s,12H);13CNMR(100MHz,CDCl3,δ):173.6,140.7,128.7,127.8,126.9,125.9,124.6,83.2,51.8,29.4,27.3,21.4;MS(ESI-TOF)m/z:291.2[M+H]+。
实施例58的A-2产物,水解后脱去硼酸基团得到带手性的羟基基团。
实施例59
化合物B-2的制备与表征:
将0.01mmol六元氮杂卡宾前体溶于3ml无水四氢呋喃,加入0.011mmol的氯化亚铜和0.01mmol的叔丁醇钠,搅拌2h,将1mmol化合物B-1,1.1mmol二硼烷二频哪醇酯加入反应液中,室温反应24~48h,TLC监测反应进程。反应完成后,取一抽滤漏斗垫入硅藻土,抽滤,用乙酸乙酯洗,有机相加入饱和食盐水洗1次,无水硫酸钠干燥,减压旋去溶剂,柱层析分离(石油醚:乙酸乙酯=20:1,石油醚:乙酸乙酯=4:1)得到产物,产率:98%,然后经手性AD-H柱,流动相为正己烷:异丙醇=97:3(体积比),测得ee:43%.1HNMR(400MHz,CDCl3,ppm)δ:7.76(d,J=8.0Hz,1H),7.29(d,J=6.4Hz,2H),4.67(s,1H),2.92(s,1H),2.42(s,3H),1.30-1.38(m,4H),1.15(s,12H);13CNMR(100MHz,CDCl3,δ):142.9,137.6,129.5,127.3,84.5,33.9,25.0,24.7,24.5,21.5,19.5,13.9;MS(ESI-TOF)m/z:354.2[M+H]+。
实施例60
化合物C-2的制备与表征:
将0.01mmol六元氮杂卡宾前体溶于3ml无水四氢呋喃,加入0.011mmol的氯化亚铜和0.01mmol的叔丁醇钠,搅拌2h,将1mmol化合物C-1,1.1mmol苯硼酸加入反应液中,室温反应24~48h,TLC监测反应进程。反应完成后,取一抽滤漏斗垫入硅藻土,抽滤,用乙酸乙酯洗,有机相加入饱和食盐水洗1次,无水硫酸钠干燥,减压旋去溶剂,柱层析分离(石油醚:乙酸乙酯=10:1,石油醚:乙酸乙酯=3:1)得到产物,产率:91%,然后经手性AD-H柱,流动相为正己烷:异丙醇=97:3(体积比),测得ee:46%.1HNMR(400MHz,CDCl3,ppm)δ:7.24~7.31(m,10H),5.74(s,1H),2.5(brs,1H);13CNMR(100MHz,CDCl3,δ):141.6,128.5,127.3,126.4,76.1;MS(ESI-TOF)m/z:183.1[M-H]+。
实施例61
化合物D-2的制备与表征:
将0.01mmol六元氮杂卡宾前体溶于3ml无水四氢呋喃,加入0.011mmol的氯化亚铜和0.01mmol的叔丁醇钠,搅拌2h,将1mmol化合物D-1,1.1mmol二苯基硅烷加入反应液中,室温反应24~48h,TLC监测反应进程。反应完成后,取一抽滤漏斗垫入硅藻土,抽滤,用乙酸乙酯洗,有机相加入饱和食盐水洗1次,无水硫酸钠干燥,减压旋去溶剂,柱层析分离(石油醚:乙酸乙酯=10:1,石油醚:乙酸乙酯=3:1)得到产物,产率:94%,该产物再溶于4ml甲醇和水的混合溶液,再加入2eq的NH4F,室温搅拌3h,通过乙酸乙酯萃取并干燥后,经手性AD-H柱,流动相为正己烷:异丙醇=97:3(体积比),测得ee:51%.1HNMR(400MHz,CDCl3,ppm)δ:7.51-7.11(m,5H),4.87(q,J=6.3Hz,IH),2.12(s,IH),1.48(d,J=6.4Hz,3H).13CNMR(100MHz,CDCl3,δ):145.89,128.44,127.36,125.44,70.22,25.14;MS(ESI-TOF)m/z:121.2.[M-H]+。
六元氮杂卡宾前体V1~V8、V1’~V8’、V1’’~V8’’的催化效果如表1。
表1
Claims (10)
1.一类手性六元氮杂环卡宾前体化合物,其特征在于,结构式如式(V)所示:
其中,R1和R2分别为氢、卤原子、含1-6个碳的直链烷烃基、含1-6个碳的支链烷烃基、含2-6个碳的烯烃基、甲氧基或硝基;
R3、R4分别选自甲基、乙基、丙基、异丙基、丁基、苯基、联苯基、对甲苯基、间甲苯基、间二甲基苯基、对氟苯基、间氟苯基、对甲氧基苯基、间甲氧基苯基、对硝基苯基、间硝基苯基、间三甲基苯基、对氰苯基、间氰苯基、对三氟甲基苯基或萘基;
R5为氯离子、四氟硼酸根离子、硫酸根离子、甲酸根离子、乙酸根离子。
2.权利要求1所述的手性六元氮杂环卡宾前体化合物,其特征在于,所述的R1和R2分别为氢、氟、氯或溴。
3.权利要求1所述的手性六元氮杂环卡宾前体化合物,其特征在于,所述的R5为氯离子或四氟硼酸根离子。
4.权利要求1所述手性六元氮杂环卡宾前体化合物,其特征在于,选自以下化合物:
5.权利要求1~4中任一手性六元氮杂环卡宾前体化合物的制备方法,其特征在于,包括如下步骤:
(i)在路易斯酸催化作用下,将如通式(I’)所示的邻胺基酮类化合物和(R-)-叔丁基亚磺酰胺,在非质子溶剂中进行反应,然后从反应产物中收集式(Ⅰ)化合物;反应通式如下:
反应温度为0~110℃,反应时间为1~24小时;
所述的式(I’)化合物、(R-)-叔丁基亚磺酰胺、路易斯酸的摩尔比为1:1~2:0.5~1;
(ii)在非质子溶剂中,将如通式(I)所示的邻胺基叔丁基亚磺酰亚胺类化合物和还原剂进行反应,然后从反应产物中收集式(II)化合物;反应通式如下:
反应温度为-98~0℃,反应时间为1~6小时;所述的式(I)化合物、还原剂的摩尔比为1:1~3;
(iii)在极性溶剂中,将如通式(II)所示的邻胺基叔丁基亚磺酰胺类化合物和酸进行反应,然后从反应产物中收集式(III)化合物;反应通式如下:
反应温度为0~50℃,反应时间为1~4小时;所述的式(II)化合物、酸的摩尔比为1:1~5;
(iv)在非质子溶剂中,将如通式(III)所示的1,3-二胺类化合物和卤代物,在碱和催化剂作用下加热进行反应,然后从反应产物中收集式(IV)化合物;催化剂为钯催化剂和膦配体,反应通式如下:
反应温度为90~130℃,反应时间为0.5~24小时;卤代物的结构式为X-R3或X-R4,其中X为卤原子;
所述的式(III)化合物、卤代物、催化剂、碱的摩尔比为1:1~1.2:0.01~0.1:1~3;
(v)在极性溶剂中,将如通式(IV)所示的二胺取代类化合物、原甲酸三甲酯或原甲酸三乙酯、在路易斯酸作用下进行反应,然后从反应产物中收集式(V)化合物;反应通式如下:
反应温度为10~100℃,反应时间为0.5~24小时;所述的式(IV)化合物、原甲酸三甲酯或原甲酸三乙酯、路易斯酸的摩尔比为1:1~3:0.1~0.3。
6.权利要求5所述所述手性六元氮杂环卡宾前体化合物的制备方法,其特征在于,所述步骤(iv)中,在非质子溶剂中,将如通式(III)所示的1,3-二胺类化合物和卤代物,在碱和催化剂作用下用微波加热进行反应,然后从反应产物中收集式(IV)化合物。
7.权利要求5所述所述手性六元氮杂环卡宾前体化合物的制备方法,其特征在于,步骤(i)中路易斯酸为氯化锌、氯化锡、氯化铜、四氯化钛或钛酸四异丙酯,非质子溶剂为苯、甲苯、乙醚、四氢呋喃;
步骤(ii)中所述的非质子溶剂为苯、甲苯、乙醚或四氢呋喃,所述的还原剂为氢化钠、硼氢化钠、氢化铝锂或二异丙基氢化铝锂;
步骤(iii)所述的极性溶剂为甲醇、乙醇、异丙醇、乙腈或1,4-二氧六环中的一种或者混合物,所用的酸为甲酸、乙酸、硫酸、盐酸;
步骤(iv)所述的非质子溶剂为苯、甲苯、乙醚或四氢呋喃,所用的催化剂为四(三苯基膦)钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯、氯化钯、醋酸钯、双(三环己基膦)二氯化钯、双(三苯基膦)二氯化钯(II)、二(二亚苄基丙酮)钯(0)、三(二亚苄基丙酮)二钯、(1,5-环辛二烯)二氯化钯、二(乙酰丙酮)钯(II),所用膦配体为三环己基膦、三苯基膦、2-二环己基磷-2'-甲基联苯、2-(二-叔丁基膦)联苯、三(邻甲苯基)膦、三(间甲苯基)膦、三(对甲苯基)膦、三(2-甲氧基苯基)膦或1,1'-联萘-2,2'-双二苯膦;
步骤(v)所述的极性溶剂为甲醇、乙醇、异丙醇、乙腈、1,4-二氧六环,所用的路易斯酸为氯化铵、硫酸铵、四氟硼酸铵、甲酸铵、甲酸、乙酸、盐酸。
8.权利要求1~4任一项所述手性六元氮杂环卡宾前体化合物在催化以下任一种反应中的应用:
反应(I):
在非质子溶剂中,将如通式(VI-1)所示的化合物、二硼烷频哪醇硼酸酯、氯化亚铜、手性六元氮杂环卡宾前体化合物在碱作用下进行反应,反应温度为-78~60℃,反应时间为1~48小时,然后从反应产物中收集式(VII-1)化合物,(VII-1)化合物经过进一步氧化水解得手性醇化合物VII-1-1;
式(VI-1)化合物、二硼烷频哪醇硼酸酯、氯化亚铜、手性六元氮杂环卡宾前体化合物、碱的摩尔比为1:1~3:0.1~0.3:0.01~0.3:0.01~0.3;
其中,R1’选自氢、卤原子、含1-6个碳的直链烷烃基、含1-6个碳的支链烷烃基、苯基、取代苯基、甲氧基或硝基;
R2’选自氢、卤原子、含1-6个碳的直链烷烃基、含1-6个碳的支链烷烃基、苯基、取代苯基或甲氧基;
反应(II):
其中,R1’选自氢、卤原子、含1-6个碳的直链烷烃基、含1-6个碳的支链烷烃基、苯基、取代苯基或甲氧基;
R2’选自氢、含1-6个碳的直链烷烃基、含1-6个碳的支链烷烃基、苯基、取代苯基、对甲基苯磺酰基或甲氧基;
在非质子溶剂中,将如通式(VI-2)所示的化合物、二硼烷频哪醇硼酸酯、氯化亚铜、手性六元氮杂环卡宾前体化合物在碱的作用下进行反应,反应温度为-78~60℃,反应时间为1~48小时,然后从反应产物中收集式(VII-2)化合物;
式(VI-2)化合物、二硼烷频哪醇硼酸酯、氯化亚铜、手性六元氮杂环卡宾前体化合物和碱的摩尔比为1:1~3:0.1~0.3:0.01~0.3:0.01~0.3;
反应(III):
在非质子溶剂中,将如通式(VI-3)所示的化合物、通式(VI-3’)所示的化合物、氯化亚铜、手性六元氮杂环卡宾前体化合物在碱的作用下进行反应,反应温度为-78~60℃,反应时间为1~48小时;然后从反应产物中收集式(VII-3)化合物;
式(VI-3)化合物、式(VI-3’)化合物、氯化亚铜、手性六元氮杂环卡宾前体化合物和碱的摩尔比为1:1~3:0.1~0.3:0.01~0.3:0.01~0.3;
R1’选自氢、含1-6个碳的直链烷烃基、含1-6个碳的支链烷烃基、苯基或取代苯基;
R2’选自氢、含1-6个碳的直链烷烃基、含1-6个碳的支链烷烃基、苯基或取代苯基;
反应(IV):
在非质子溶剂中,将如通式(VI-4)所示的化合物、还原剂、氯化亚铜、手性六元氮杂环卡宾前体化合物在碱的作用下进行反应,反应温度为-78~60℃,反应时间为1~48小时;然后从反应产物中收集式(VII-4)化合物;
式(VI-4)化合物、还原剂、氯化亚铜、手性六元氮杂环卡宾前体化合物和碱的摩尔比为1:1~3:0.1~0.3:0.01~0.3:0.01~0.3;
还原剂为二苯基硅烷;
R1’选自氢、含1-6个碳的直链烷烃基、含1-6个碳的支链烷烃基、含2-6个碳的烯烃基、苯基或取代苯基;
R2’选自氢、卤原子、含1-6个碳的直链烷烃基、含1-6个碳的支链烷烃基、含2-6个碳的烯烃基、苯基、取代苯基、甲氧基或硝基。
9.权利要求8所述的应用,其特征在于,所述非质子溶剂为苯、甲苯、乙醚、二氯甲烷、1,2-二氯乙烷、四氢呋喃,所用的碱为三乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯、N,N-二异丙基乙胺、碳酸铯、碳酸钾、碳酸钠、叔丁醇钠、叔丁醇钾、氢化钠、氢化钾。
10.权利要求8所述的应用,其特征在于,反应(I)中的R1’为苯基,R2’为甲氧基;
反应(II)中的R1’为C1~C4烷基、苯基或取代苯基,R2’为对甲基苯磺酰基;
反应(III)中的R1’和R2’分别为C1~C4烷基或苯基;
反应(IV)中的R1’为C1~C4烷基、苯基或取代苯基。
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