CN104788370B - A kind of method that configuration controllably synthesizes 2 (4 nitro) bytyry N-oxide compounds - Google Patents
A kind of method that configuration controllably synthesizes 2 (4 nitro) bytyry N-oxide compounds Download PDFInfo
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- CN104788370B CN104788370B CN201510220751.9A CN201510220751A CN104788370B CN 104788370 B CN104788370 B CN 104788370B CN 201510220751 A CN201510220751 A CN 201510220751A CN 104788370 B CN104788370 B CN 104788370B
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- nitrogen
- chiral
- oxygen
- solvent
- scandium
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- -1 N-oxide compounds Chemical class 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 24
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 50
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims abstract description 23
- 150000004699 copper complex Chemical class 0.000 claims abstract description 12
- 229910052706 scandium Inorganic materials 0.000 claims abstract description 12
- SIXSYDAISGFNSX-UHFFFAOYSA-N scandium atom Chemical compound [Sc] SIXSYDAISGFNSX-UHFFFAOYSA-N 0.000 claims abstract description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
- 239000003446 ligand Substances 0.000 claims description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 19
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 239000003480 eluent Substances 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 4
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 4
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 4
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 4
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 4
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 125000003944 tolyl group Chemical group 0.000 claims description 4
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 5
- VBYPTHUTHBYWTG-UHFFFAOYSA-N N1=CC=CC=C1.[O].[N] Chemical compound N1=CC=CC=C1.[O].[N] VBYPTHUTHBYWTG-UHFFFAOYSA-N 0.000 claims 5
- 239000003513 alkali Substances 0.000 claims 5
- 238000004587 chromatography analysis Methods 0.000 claims 3
- MFYLRNKOXORIPK-UHFFFAOYSA-N (3-nitrophenyl)-phenylmethanone Chemical class [O-][N+](=O)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 MFYLRNKOXORIPK-UHFFFAOYSA-N 0.000 claims 2
- ZYMCBJWUWHHVRX-UHFFFAOYSA-N (4-nitrophenyl)-phenylmethanone Chemical class C1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=CC=C1 ZYMCBJWUWHHVRX-UHFFFAOYSA-N 0.000 claims 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
- 229910052802 copper Inorganic materials 0.000 claims 2
- 239000010949 copper Substances 0.000 claims 2
- MPHAMPBWVIOFMQ-UHFFFAOYSA-L CS(=O)(=O)[O-].[Cu+2].[F].CS(=O)(=O)[O-] Chemical compound CS(=O)(=O)[O-].[Cu+2].[F].CS(=O)(=O)[O-] MPHAMPBWVIOFMQ-UHFFFAOYSA-L 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical class O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims 1
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims 1
- QUJLPICXDXFRSN-UHFFFAOYSA-N scandium;trifluoromethanesulfonic acid Chemical compound [Sc].OS(=O)(=O)C(F)(F)F QUJLPICXDXFRSN-UHFFFAOYSA-N 0.000 claims 1
- 238000010025 steaming Methods 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 abstract description 16
- OLBVUFHMDRJKTK-UHFFFAOYSA-N [N].[O] Chemical class [N].[O] OLBVUFHMDRJKTK-UHFFFAOYSA-N 0.000 abstract description 15
- 230000002194 synthesizing effect Effects 0.000 abstract description 5
- DOTMOQHOJINYBL-UHFFFAOYSA-N molecular nitrogen;molecular oxygen Chemical compound N#N.O=O DOTMOQHOJINYBL-UHFFFAOYSA-N 0.000 description 44
- 239000000047 product Substances 0.000 description 25
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000003756 stirring Methods 0.000 description 11
- XLHDKOPRDYEEQY-UHFFFAOYSA-N 1-pyridin-2-ylprop-2-en-1-one Chemical compound C=CC(=O)C1=CC=CC=N1 XLHDKOPRDYEEQY-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical group [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 8
- 238000006845 Michael addition reaction Methods 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 4
- 150000008041 alkali metal carbonates Chemical class 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 150000001879 copper Chemical class 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- RRONHWAVOYADJL-HNNXBMFYSA-N (2s)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 RRONHWAVOYADJL-HNNXBMFYSA-N 0.000 description 2
- WHQUHTXULUACFD-KRWDZBQOSA-N (3s)-4-[[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]methoxy-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1COP(O)(=O)C[C@@H](O)CC(O)=O WHQUHTXULUACFD-KRWDZBQOSA-N 0.000 description 2
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 2
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 2
- ZUNOXMJBNMKYOM-UHFFFAOYSA-N 2-hydroxy-3-(trifluoromethyl)benzaldehyde Chemical compound OC1=C(C=O)C=CC=C1C(F)(F)F ZUNOXMJBNMKYOM-UHFFFAOYSA-N 0.000 description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 2
- 229940126650 Compound 3f Drugs 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- HGDWHTASNMRJMP-UHFFFAOYSA-N [1-(hydroxyamino)-1-oxo-5-(3-phenoxyphenyl)pentan-2-yl]phosphonic acid Chemical compound ONC(=O)C(P(O)(O)=O)CCCC1=CC=CC(OC=2C=CC=CC=2)=C1 HGDWHTASNMRJMP-UHFFFAOYSA-N 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- FTKASJMIPSSXBP-UHFFFAOYSA-N ethyl 2-nitroacetate Chemical compound CCOC(=O)C[N+]([O-])=O FTKASJMIPSSXBP-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 2
- MUTCAPXLKRYEPR-ITWZMISCSA-N methyl (e,3r,5s)-7-[4-bromo-2,3-bis(4-fluorophenyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)\C=C\N1C(C(C)C)=C(Br)C(C=2C=CC(F)=CC=2)=C1C1=CC=C(F)C=C1 MUTCAPXLKRYEPR-ITWZMISCSA-N 0.000 description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical class C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- PXTJYUCVGRMOBC-QFIPXVFZSA-N OC([C@H]1N(Cc(cccc2C(F)(F)F)c2O)CCC1)(c1ccccc1)c1ccccc1 Chemical compound OC([C@H]1N(Cc(cccc2C(F)(F)F)c2O)CCC1)(c1ccccc1)c1ccccc1 PXTJYUCVGRMOBC-QFIPXVFZSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- LYGJENNIWJXYER-BJUDXGSMSA-N nitromethane Chemical class [11CH3][N+]([O-])=O LYGJENNIWJXYER-BJUDXGSMSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 150000002927 oxygen compounds Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003325 scandium Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
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Abstract
本发明涉及一种构型可控地合成2‑(4‑硝基)丁酰基吡啶氮‑氧化合物的方法，包括以下步骤：1)将2‑烯酰基吡啶氮‑氧类化合物和硝基甲烷或其类似物分别加入到手性铜配合物催化体系或手性钪配合物催化体系中，在室温下反应；2)将反应完成后的溶液分离提纯获得构型相反的2‑(4‑硝基)丁酰基吡啶氮‑氧化合物。The invention relates to a method for synthesizing 2-(4-nitro)butyrylpyridine nitrogen-oxygen compounds with controllable configuration, comprising the following steps: 1) combining 2-enoylpyridine nitrogen-oxygen compounds and nitromethane or its analogues were added to the chiral copper complex catalytic system or chiral scandium complex catalytic system, and reacted at room temperature; 2) the solution after the reaction was separated and purified to obtain 2-(4-nitro ) butyrylpyridine nitrogen-oxygen compound.
Description
技术领域technical field
本发明属于有机合成方法学领域，特别是指一种构型可控地合成2-(4-硝基)丁酰基吡啶氮-氧化合物的方法。The invention belongs to the field of organic synthesis methodology, in particular to a method for synthesizing 2-(4-nitro)butyrylpyridine nitrogen-oxygen compound with controllable configuration.
背景技术Background technique
不对称合成研究是手性物质创造的关键方法和手段，是化学研究最为活跃的领域之一，它与人类健康的手性医药、农药、香料、香精、食品添加剂以及多种功能材料等相关领域密切相关，具有重要的理论意义和应用前景。Asymmetric synthesis research is a key method and means for the creation of chiral substances, and it is one of the most active fields of chemical research. They are closely related and have important theoretical significance and application prospects.
Michael加成在有机合成中作为一种构建C-C键的有效方法，具有原子经济性的特点。2-烯酰基吡啶氮-氧化合物，由于其氮-氧和羰基氧上孤对电子存在，可以作为一种二齿配位的底物与手性金属催化剂配位合成对映选择性的产物，近年来受到广泛关注(Chem.Rev.2014,114,6081.)。2-烯酰基吡啶氮-氧化合物作为底物用于不对称合成已有一些报道。例如，小组和Pedro小组将其用于不对称的Diels-Alder反应(J.Org.Chem.2007,72,240；Org.Lett.2007,9,1983.)，Singh小组将其用于不对称Friedel-Crafts反应(Org.Lett.2008,10,4121；Org.Lett.2010,12,80.)，Pedro小组将其用于1,3-偶极环加成，Singh和Faita等小组将其用于不对称的Michael加成(Org.Lett.2011,13,5812；Chem.Eur.J.2012,18,11662；J.Org.Chem.2012,77,8802；Adv.Synth.Catal.2013,355,383；Org.Biomol.Chem.2013,11,2412；Chem.Rev.2014,114,6081)。但是，2-烯酰基吡啶氮-氧化合物与硝基甲烷或其类似物的Michael加成迄今还没有报道。Michael addition is an effective method for constructing CC bonds in organic synthesis, which has the characteristics of atom economy. 2-enoylpyridine nitrogen-oxygen compounds, due to the presence of lone pairs of electrons on nitrogen-oxygen and carbonyl oxygen, can be used as a bidentate coordination substrate to coordinate with chiral metal catalysts to synthesize enantioselective products, It has received extensive attention in recent years (Chem. Rev. 2014, 114, 6081.). There have been some reports of 2-enoylpyridine nitrogen-oxygen compounds as substrates for asymmetric synthesis. E.g, Group and Pedro group used it for asymmetric Diels-Alder reaction (J.Org.Chem.2007,72,240; Org.Lett.2007,9,1983.), Singh group used it for asymmetric Friedel-Crafts reaction (Org.Lett.2008,10,4121; Org.Lett.2010,12,80.), Pedro group used it for 1,3-dipolar cycloaddition, Singh and Faita et al. used it for asymmetric Michael addition (Org.Lett.2011,13,5812; Chem.Eur.J.2012,18,11662; J.Org.Chem.2012,77,8802; Adv.Synth.Catal.2013,355,383; Org . Biomol. Chem. 2013, 11, 2412; Chem. Rev. 2014, 114, 6081). However, the Michael addition of 2-enoylpyridine nitrogen-oxygen compounds to nitromethane or its analogues has not been reported so far.
2-烯酰基吡啶氮-氧化合物与硝基甲烷或其类似物的Michael加成可以得到2-(4-硝基)丁酰基吡啶氮-氧化合物，它在NH4Cl/Zn存在下经过简单的还原环化可以得到有生物活性的二氢吡咯衍生物，它也是天然产物烟碱类化合物的类似物(Annu.Rep.Med.Chem.1995,30,41；Eur.J.Pharmacol.2007,563,18；Pharmacol.Res.2014,83,20)。Michael addition of 2-enoylpyridine nitrogen-oxygen compounds to nitromethane or its analogues affords 2-(4-nitro)butyrylpyridine nitrogen-oxygen compounds by simple reduction in the presence of NH4Cl/Zn Cyclization can obtain biologically active dihydropyrrole derivatives, which are also analogs of natural product nicotinic compounds (Annu.Rep.Med.Chem.1995,30,41; Eur.J.Pharmacol.2007,563, 18; Pharmacol. Res. 2014, 83, 20).
发明内容Contents of the invention
本发明发展了2种催化体系催化2-烯酰基吡啶氮-氧类化合物和硝基甲烷或其类似物的Michael加成，是高对映选择性地合成不同构型2-(4-硝基)丁酰基吡啶氮-氧的方法。The present invention has developed two kinds of catalytic systems to catalyze the Michael addition of 2-enoylpyridine nitrogen-oxygen compounds and nitromethane or its analogues, which is a high enantioselective synthesis of different configurations of 2-(4-nitro ) butyrylpyridine nitrogen-oxygen method.
具体地，本发明包括以下方面：Specifically, the present invention includes the following aspects:
本发明提供一种构型可控地合成2-(4-硝基)丁酰基吡啶氮-氧化合物的方法，所述方法包括以下步骤：The invention provides a method for synthesizing 2-(4-nitro)butyrylpyridine nitrogen-oxygen compound with controllable configuration, said method comprising the following steps:
1)将2-烯酰基吡啶氮-氧类化合物和硝基甲烷或其类似物分别加入手性铜配合物催化体系或手性钪配合物催化体系中，在室温下反应；1) adding 2-enoylpyridine nitrogen-oxygen compounds and nitromethane or its analogs to the chiral copper complex catalytic system or the chiral scandium complex catalytic system respectively, and reacting at room temperature;
2)将反应完成后的溶液分离提纯获得构型相反的2-(4-硝基)丁酰基吡啶氮-氧。2) Separating and purifying the solution after the reaction to obtain 2-(4-nitro)butyrylpyridine nitrogen-oxygen with the opposite configuration.
在一个优选的实施方案中，所述2-烯酰基吡啶氮-氧类化合物的结构式为(E)-C5H4NO-C(O)-CH2＝CH-R，其中R选自由以下各项组成的组：苯基，乙烯基苯基，1-萘基，2-噻吩基，2-呋喃基，2-氟苯基，2-氯苯基，2-溴苯基，2-萘基，3-甲基苯基，3-甲氧基苯基，3-硝基苯基，3-氟苯基，3-氯苯基，3-溴苯基，4-三氟甲基苯基，4-硝基苯基，4-氟苯基，4-氯苯基，4-溴苯基，正丙基，正丁基，正戊基，正己基，环戊基，环己基。In a preferred embodiment, the structural formula of the 2-enoylpyridine nitrogen-oxygen compound is (E)-C 5 H 4 NO-C(O)-CH 2 =CH-R, wherein R is selected from the following Groups consisting of: phenyl, vinylphenyl, 1-naphthyl, 2-thienyl, 2-furyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-naphthalene Base, 3-methylphenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-trifluoromethylphenyl , 4-nitrophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, n-propyl, n-butyl, n-pentyl, n-hexyl, cyclopentyl, cyclohexyl.
在一个优选的实施方案中，所述2-烯酰基吡啶氮-氧类化合物可以选自2-肉桂酰基吡啶氮-氧，(E)-2(3-间氯苯基)丙烯酰基吡啶氮-氧，(E)-2(3-对三氟甲基苯基)丙烯酰基吡啶氮-氧，(E)-2(3-对溴苯基)丙烯酰基吡啶氮-氧，(E)-2(3-间甲氧基苯基)丙烯酰基吡啶氮-氧。In a preferred embodiment, the 2-alkenoylpyridine nitrogen-oxygen compound can be selected from 2-cinnamoylpyridine nitrogen-oxygen, (E)-2(3-m-chlorophenyl)acryloylpyridine nitrogen- Oxygen, (E)-2(3-p-trifluoromethylphenyl)acryloylpyridine nitrogen-oxygen, (E)-2(3-p-bromophenyl)acryloylpyridine nitrogen-oxygen, (E)-2 (3-m-methoxyphenyl)acryloylpyridine nitrogen-oxygen.
在一个优选的实施方案中，所述硝基甲烷类似物选自硝基乙烷、硝基乙酸乙酯。In a preferred embodiment, the nitromethane analog is selected from nitroethane, ethyl nitroacetate.
在一个优选的实施方案中，所述手性铜配合物催化体系是由铜盐、碱金属碳酸盐和配体L1以物质的摩尔量比1:1:1在溶剂中在氮气保护下室温搅拌反应制备而成。In a preferred embodiment, the chiral copper complex catalytic system is composed of copper salt, alkali metal carbonate and ligand L1 in a solvent at room temperature under nitrogen protection with a molar ratio of substances of 1:1:1 Prepared by stirring the reaction.
在一个优选的实施方案中，所述铜盐选自三氟甲磺酸铜、溴化铜、醋酸铜，优选为三氟甲磺酸铜；所述碱金属碳酸盐选自碳酸钠、碳酸钾及碳酸铯，优选为碳酸铯；所述配体L1结构式为：In a preferred embodiment, the copper salt is selected from copper trifluoromethanesulfonate, copper bromide, copper acetate, preferably copper trifluoromethanesulfonate; the alkali metal carbonate is selected from sodium carbonate, carbonic acid Potassium and cesium carbonate, preferably cesium carbonate; The ligand L1 structural formula is:
所述溶剂选自甲苯、乙酸乙酯、氯仿、四氢呋喃、甲基叔丁基醚，优选为甲苯。The solvent is selected from toluene, ethyl acetate, chloroform, tetrahydrofuran, methyl tert-butyl ether, preferably toluene.
在一个优选的实施方案中，所述手性钪配合物催化体系是由三氟甲磺酸钪、碱金属碳酸盐和配体L2以物质的摩尔量比1:1:1在溶剂中氮气保护下室温搅拌反应制备而成。In a preferred embodiment, the chiral scandium complex catalytic system is composed of scandium trifluoromethanesulfonate, alkali metal carbonate and ligand L2 in a solvent with nitrogen in a molar ratio of 1:1:1 Prepared by stirring reaction at room temperature under protection.
在一个优选的实施方案中，所述碱金属碳酸盐选自碳酸钠、碳酸钾及碳酸铯，优选为碳酸铯；所述配体L2结构式为：In a preferred embodiment, the alkali metal carbonate is selected from sodium carbonate, potassium carbonate and cesium carbonate, preferably cesium carbonate; the ligand L2 structural formula is:
所述溶剂选自甲苯、乙酸乙酯、氯仿、四氢呋喃、甲基叔丁基醚，优选为四氢呋喃。The solvent is selected from toluene, ethyl acetate, chloroform, tetrahydrofuran, methyl tert-butyl ether, preferably tetrahydrofuran.
在一个优选的实施方案中，所述配体L2的合成路线如下：In a preferred embodiment, the synthetic route of the ligand L2 is as follows:
在一个优选的实施方案中，所述2-烯酰基吡啶氮-氧类化合物与手性铜配合物或手性钪配合物的物质的量比10:1-20:1；所述2-烯酰基吡啶氮-氧类化合物的起始浓度为0.2-0.3mol/L；所述硝基甲烷与催化体系中的溶剂体积比为1/3-1/5。In a preferred embodiment, the molar ratio of the 2-enoylpyridine nitrogen-oxygen compound to the chiral copper complex or chiral scandium complex is 10:1-20:1; the 2-ene The initial concentration of the acylpyridine nitrogen-oxygen compound is 0.2-0.3 mol/L; the volume ratio of the nitromethane to the solvent in the catalytic system is 1/3-1/5.
在一个优选的实施方案中，所述分离提纯方式包括柱层色谱、液相色谱、蒸馏、重结晶，优选柱层色谱。In a preferred embodiment, the separation and purification methods include column chromatography, liquid chromatography, distillation, recrystallization, preferably column chromatography.
在一个优选的实施方案中，所述柱层色谱分离的洗脱剂为乙酸乙酯/石油醚混合溶剂。In a preferred embodiment, the eluent for the column chromatography separation is ethyl acetate/petroleum ether mixed solvent.
本发明的有益效果是：The beneficial effects of the present invention are:
1.发展了2-烯酰基吡啶氮-氧类化合物与硝基甲烷的不对称Michael加成。1. The asymmetric Michael addition of 2-enoylpyridine nitrogen-oxygen compounds to nitromethane was developed.
2.发展了两个不同的催化体系催化该反应可以高对映选择性地得到两种不同构型的产物，从而能构型可控地合成2-(4-硝基)丁酰基吡啶氮-氧化合物。2. Two different catalytic systems have been developed to catalyze the reaction, and two products with different configurations can be obtained with high enantioselectivity, so that the configuration can be controlled to synthesize 2-(4-nitro)butyrylpyridine nitrogen- Oxygen compounds.
3.得到的产物2-(4-硝基)丁酰基吡啶氮-氧类化合物经过简单的还原可以得到具有生物活性的二氢吡咯化合物。3. The obtained product 2-(4-nitro)butyrylpyridine nitrogen-oxygen compound can be simply reduced to obtain a biologically active dihydropyrrole compound.
注：本申请书中缩写对照：Note: Comparison of abbreviations in this application:
-Cbz:苄氧羰基；NMM:N-甲基吗啉；HOBT:1-羟基苯并三唑；EDCI:1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐；DMF:N,N-二甲基甲酰胺；DCM:二氯甲烷。-Cbz: benzyloxycarbonyl; NMM: N-methylmorpholine; HOBT: 1-hydroxybenzotriazole; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride salt; DMF: N,N-dimethylformamide; DCM: dichloromethane.
附图说明Description of drawings
图1，配体L2的1H NMR；Figure 1, 1 H NMR of ligand L2;
图2，配体L2的13C NMR；Figure 2, 13 C NMR of ligand L2;
图3，实施例1和2所得产物的1H NMR；Fig. 3, the 1 H NMR of the product obtained in embodiment 1 and 2;
图4，实施例1和2所得产物的13C NMR；Fig. 4, the 13 C NMR of the product obtained in embodiment 1 and 2;
图5，实施例3和4所得产物的1H NMR；Fig. 5, the 1 H NMR of the product obtained in embodiment 3 and 4;
图6，实施例3和4所得产物的13C NMR；Fig. 6, the 13 C NMR of the product obtained in embodiment 3 and 4;
图7，实施例5和6所得产物的1H NMR；Fig. 7, the 1 H NMR of the product obtained in embodiment 5 and 6;
图8，实施例5和6所得产物的13C NMR；Fig. 8, the 13 C NMR of the product obtained in embodiment 5 and 6;
图9，实施例7和8所得产物的1H NMR；Fig. 9, the 1 H NMR of the product obtained in Examples 7 and 8;
图10，实施例7和8所得产物的13C NMR；Fig. 10, the 13 C NMR of the product obtained in embodiment 7 and 8;
图11，实施例9所得产物的1H NMR；Fig. 11, the 1 H NMR of the product obtained in Example 9;
图12，实施例9所得产物的13C NMR；Fig. 12, the 13 C NMR of the product obtained in Example 9;
图13，实施例9所得产物的X-射线衍射单晶结构图。Fig. 13 is an X-ray diffraction single crystal structure diagram of the product obtained in Example 9.
具体实施方式detailed description
下面详细描述本发明的实施例，所述实施例的核磁谱图及相应产物的X-射线衍射单晶结构在附图中示出。The examples of the present invention are described in detail below, and the NMR spectra of the examples and the X-ray diffraction single crystal structures of the corresponding products are shown in the accompanying drawings.
一种构型可控地合成2-(4-硝基)丁酰基吡啶氮-氧的方法，包括以下步骤：A method for synthesizing 2-(4-nitro)butyrylpyridine nitrogen-oxygen with controllable configuration, comprising the following steps:
1)制备手性铜配合物催化体系及手性钪配合物催化体系。1) Preparation of chiral copper complex catalytic system and chiral scandium complex catalytic system.
所述手性铜配合物催化体系是由三氟甲磺酸铜，碳酸铯和配体L1以物质的摩尔量比为1:1:1在甲苯中氮气保护下室温搅拌反应2h制备而成；催化剂与反应物2-烯酰基吡啶氮-氧的物质的摩尔量比为1/10；甲苯的量在使反应物2–烯酰基吡啶氮–氧化合物的初始浓度为0.25mol/L。The chiral copper complex catalytic system is prepared by stirring copper trifluoromethanesulfonate, cesium carbonate and ligand L1 at a molar ratio of 1:1:1 in toluene at room temperature for 2 h under the protection of nitrogen; The molar ratio of the catalyst to the reactant 2-alkenoylpyridine nitrogen-oxygen is 1/10; the amount of toluene is such that the initial concentration of the reactant 2-alkenoylpyridine nitrogen-oxygen compound is 0.25 mol/L.
所述手性钪配合物催化体系是由三氟甲磺酸钪，碳酸铯和配体L2以物质的量比为1:1:1在甲苯中氮气保护下室温搅拌反应2h制备而成；催化剂与反应物2-烯酰基吡啶氮-氧的物质的量比为1/10；甲苯的量在使反应物2-烯酰基吡啶氮-氧的初始浓度为0.25mol/L。The chiral scandium complex catalytic system is prepared by stirring scandium trifluoromethanesulfonate, cesium carbonate and ligand L2 at a material ratio of 1:1:1 under the protection of nitrogen in toluene at room temperature for 2 hours; the catalyst The ratio of the substance to the reactant 2-alkenoylpyridine nitrogen-oxygen is 1/10; the amount of toluene is such that the initial concentration of the reactant 2-alkenoylpyridine nitrogen-oxygen is 0.25mol/L.
所述配体L2是由N-苄氧羰基苯丙氨酸与1，3-二氨基丙烷反应得到化合物1，然后化合物1在Pd/C，H2作用下反应得到化合物2，然后化合物2和2-羟基-3-三氟甲基-苯甲醛反应得到配体L2。The ligand L2 is obtained by the reaction of N-benzyloxycarbonylphenylalanine and 1,3-diaminopropane to obtain compound 1, and then compound 1 is reacted under Pd/C, H to obtain compound 2 , and then compound 2 and Reaction of 2-hydroxy-3-trifluoromethyl-benzaldehyde affords ligand L2.
2)将2–烯酰基吡啶氮–氧类化合物和硝基甲烷或其类似物分别加入到两种催化剂中，在室温下反应。2) Add 2-alkenoylpyridine nitrogen-oxygen compounds and nitromethane or its analogs into two catalysts respectively, and react at room temperature.
所述2–烯酰基吡啶氮–氧类化合物的结构式为(E)-C5H4NO-C(O)-CH2＝CH-R，其中R选自由以下各项组成的组：苯基，乙烯基苯基，1-萘基，2-噻吩基，2-呋喃基，2-氟苯基，2-氯苯基，2-溴苯基，2-萘基，3-甲基苯基，3-甲氧基苯基，3-硝基苯基，3-氟苯基，3-氯苯基，3-溴苯基，4-三氟甲基苯基，4-硝基苯基，4-氟苯基，4-氯苯基，4-溴苯基，正丙基，正丁基，正戊基，正己基，环戊基，环己基。The structural formula of the 2-enoylpyridine nitrogen-oxygen compound is (E)-C 5 H 4 NO-C(O)-CH 2 =CH-R, wherein R is selected from the group consisting of: phenyl , vinylphenyl, 1-naphthyl, 2-thienyl, 2-furyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-naphthyl, 3-methylphenyl , 3-methoxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-trifluoromethylphenyl, 4-nitrophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, n-propyl, n-butyl, n-pentyl, n-hexyl, cyclopentyl, cyclohexyl.
所述硝基甲烷类似结构底物包括硝基乙烷，硝基乙酸乙酯。The nitromethane-like substrates include nitroethane and ethyl nitroacetate.
2–烯酰基吡啶氮–氧在溶液中的初始浓度为0.25mol/L，硝基甲烷或其类似结构底物与催化体系中溶剂的体积比为1/3。The initial concentration of 2-enoylpyridine nitrogen-oxygen in the solution is 0.25mol/L, and the volume ratio of nitromethane or its similar structure substrate to the solvent in the catalytic system is 1/3.
3)将反应完成后的溶液分离提纯获得构型相反的2-(4-硝基)丁酰基吡啶氮-氧。3) Separating and purifying the solution after the reaction to obtain 2-(4-nitro)butyrylpyridine nitrogen-oxygen with the opposite configuration.
将反应完成后的溶液在真空下旋干，残留物用硅胶过柱，用乙酸乙酯/石油醚体系作为洗脱剂从体积比1/1-3/1过柱；在本申请中选用的洗脱剂为乙酸乙酯/石油醚混合溶剂，这并不是说其它洗脱剂体系就不是本申请的要求，只要符合洗脱目的的试剂均可以使用。The solution after the completion of the reaction is spin-dried under vacuum, the residue is passed through the column with silica gel, and the ethyl acetate/petroleum ether system is used as the eluent to pass through the column at a volume ratio of 1/1-3/1; The eluent is a mixed solvent of ethyl acetate/petroleum ether, which does not mean that other eluent systems are not the requirements of this application, as long as the reagents that meet the purpose of elution can be used.
反应方程式为：The reaction equation is:
本申请首次实现了硝基甲烷或其类似物对2-烯酰基吡啶氮-氧化合物的不对称Michael加成，并且发现用手性铜配合物催化体系和手性钪配合物催化体系分别催化这个反应可以得到2种不同构型的产物。所用催化剂易于制备，此方法是高对映选择性地合成不同构型的2-(4-硝基)丁酰基吡啶氮-氧化合物的方法。This application is the first to realize the asymmetric Michael addition of nitromethane or its analogues to 2-enoylpyridine nitrogen-oxygen compounds, and finds that the catalytic system of chiral copper complexes and chiral scandium complexes are used to catalyze this respectively The reaction can give two products with different configurations. The catalyst used is easy to prepare, and the method is a method for synthesizing 2-(4-nitro)butyrylpyridine nitrogen-oxygen compounds with different configurations with high enantioselectivity.
以下是本申请的配体的具体合成步骤及合成2-(4-硝基)丁酰基吡啶氮-氧化合物的具体实施例，在实施例中所使用的所有试剂均为直接购买的分析纯试剂，除THF重蒸外，其它使用前未经其他处理。试剂来源：所有溶剂、碱金属盐及硝基甲烷均购于国药，三氟甲磺酸铜和三氟甲磺酸钪等购于韶远韶远化学科技(上海)有限公司。The following are specific synthetic steps of the ligand of the present application and specific examples of the synthesis of 2-(4-nitro)butyrylpyridine nitrogen-oxygen compounds. All reagents used in the examples are analytically pure reagents purchased directly , except THF re-distillation, no other treatment before use. Sources of reagents: All solvents, alkali metal salts and nitromethane were purchased from Sinopharm, copper trifluoromethanesulfonate and scandium trifluoromethanesulfonate were purchased from Shaoyuan Shaoyuan Chemical Technology (Shanghai) Co., Ltd.
配体L1的合成(参考文献:Chem.Eur.J.2011,17,1114.)Synthesis of Ligand L1 (Reference: Chem.Eur.J.2011,17,1114.)
配体L2的合成:Synthesis of Ligand L2:
在一个100mL的圆底烧瓶中加入N-苄氧羰基苯丙氨酸(7.5mmol，2.245g)，DMF(50mL)冷却到0℃，再向其中依次加入NMM(24.0mmol，2.7mL)，HOBT(8.3mmol，1.114g)，EDCI(8.3mmol，1.582g)。30min后，向其中加入1，3-二氨基丙烷(3mmol)在室温反应10h。将反应后的溶液倒入冰水中，有大量白色沉淀析出。抽滤得到白色固体沉淀，然后依次用1M HCl(50mL)，水(50mL)，1M NaOH(50mL)，水(50mL)，预冷的乙醇(5mL)洗涤得到化合物1。Add N-benzyloxycarbonylphenylalanine (7.5mmol, 2.245g) in a 100mL round bottom flask, DMF (50mL) is cooled to 0 ℃, then add NMM (24.0mmol, 2.7mL), HOBT (8.3mmol, 1.114g), EDCI (8.3mmol, 1.582g). After 30 min, 1,3-diaminopropane (3 mmol) was added thereto and reacted at room temperature for 10 h. The reacted solution was poured into ice water, and a large amount of white precipitates precipitated out. The white solid precipitate was obtained by suction filtration, and then washed successively with 1M HCl (50 mL), water (50 mL), 1M NaOH (50 mL), water (50 mL), and pre-cooled ethanol (5 mL) to obtain compound 1.
在100mL圆底烧瓶中，加入化合物1(2mmol)，10％Pd/C(0.2mmol)，甲醇(30mL)，在1atm的H2中反应24h，将反应后的混合物过滤，将滤液旋干，用硅胶进行柱层析分离得到化合物2。In a 100mL round-bottomed flask, add compound 1 (2mmol), 10%Pd/C (0.2mmol), methanol (30mL ) , react in 1atm of H 24h, filter the reacted mixture, spin the filtrate to dryness, Compound 2 was obtained by column chromatography on silica gel.
在50mL圆底烧瓶中，加入化合物2(2mmol)，2-羟基3-三氟甲基苯甲醛(4.4mmol)，硫酸镁(2g)，二氯甲烷(20mL)，反应24h后，过滤得滤液，旋干用硅胶进行柱层析分离得到配体L2(95％的产率)(图1和2)。1H NMR(400MHz,CDCl3)δ13.49(s,2H),7.96(s,2H),7.63-7.61(d,2H),7.30-7.12(m,12H),6.94-6.90(m,2H),6.76(d,2H),4.08-4.05(q,2H),3.44-3.39(m,2H),3.02-3.18(d,4H),3.08-3.03(q,2H),1.60-1.59(m,2H)；13C NMR(100MHz,CDCl3)δ170.7,166.7,159.1,136.7,135.6,130.3,130.2,130.2,129.6,128.5,126.9,124.8-122.1(q,J＝270.6Hz),119.1,118.1,117.9,75.3,40.7,35.7,29.3；IR(film,ν/cm-1):3894,3796,3667,3642,3061,2924,1859,1666,1535,1450,1331,1121,876,843,752；HRMS(ESI)m/z calcd for C37H34F6N4O4[M+H]+713.2562,found 713.2561.In a 50mL round bottom flask, add compound 2 (2mmol), 2-hydroxyl 3-trifluoromethylbenzaldehyde (4.4mmol), magnesium sulfate (2g), dichloromethane (20mL), react for 24h, and filter to obtain the filtrate , spin-dried and separated by column chromatography on silica gel to obtain ligand L2 (95% yield) (Figures 1 and 2). 1 H NMR (400MHz, CDCl 3 )δ13.49(s,2H),7.96(s,2H),7.63-7.61(d,2H),7.30-7.12(m,12H),6.94-6.90(m,2H ),6.76(d,2H),4.08-4.05(q,2H),3.44-3.39(m,2H),3.02-3.18(d,4H),3.08-3.03(q,2H),1.60-1.59(m ,2H); 13 C NMR (100MHz, CDCl 3 ) δ170.7, 166.7, 159.1, 136.7, 135.6, 130.3, 130.2, 130.2, 129.6, 128.5, 126.9, 124.8-122.1 (q, J＝270.6Hz), 119.1, 118.1 ,117.9,75.3,40.7,35.7,29.3; IR(film,ν/cm -1 ):3894,3796,3667,3642,3061,2924,1859,1666,1535,1450,1331,1121,876,843,752; HRMS( ESI) m/z calcd for C 37 H 34 F 6 N 4 O 4 [M+H] + 713.2562, found 713.2561.
实施例1：(S)-2-(3-苯基-4-硝基)丁酰基吡啶氮-氧化合物的合成Embodiment 1: Synthesis of (S)-2-(3-phenyl-4-nitro)butyrylpyridine nitrogen-oxygen compound
在一个10mL反应管中加入三氟甲磺酸铜(10.9mg，0.03mmol)，配体L1(12.8mg，0.03mmol)，碳酸铯(9.8mg，0.03mmol)和溶剂Tol(1.2mL)，在氮气保护下室温搅拌2h。然后向反应管中加入2-肉桂酰基吡啶氮-氧化合物1a(67.6mg，0.3mmol)和硝基甲烷(0.3mL)在室温下搅拌反应。反应完成后(TLC跟踪检测)，旋干得到的残留物用乙酸乙酯/石油醚体系作为洗脱剂过色谱柱得到黄色油状的产物(S)-2-(3-苯基-4-硝基)丁酰基吡啶氮-氧化合物3a(70.4mg，89％yield，95％ee)。(图3，图4)Add copper trifluoromethanesulfonate (10.9mg, 0.03mmol), ligand L1 (12.8mg, 0.03mmol), cesium carbonate (9.8mg, 0.03mmol) and solvent Tol (1.2mL) in a 10mL reaction tube, in Stir at room temperature for 2 h under nitrogen protection. Then 2-cinnamoylpyridine nitrogen-oxygen compound 1a (67.6 mg, 0.3 mmol) and nitromethane (0.3 mL) were added to the reaction tube and the reaction was stirred at room temperature. After the reaction was completed (TLC tracking detection), the residue obtained by spin-drying was passed through the chromatographic column with the ethyl acetate/petroleum ether system as the eluent to obtain the yellow oily product (S)-2-(3-phenyl-4-nitrate yl) butyrylpyridine nitrogen-oxygen compound 3a (70.4 mg, 89% yield, 95% ee). (Figure 3, Figure 4)
1H NMR(400MHz,CDCl3，ppm):δ8.17-8.16(d,J＝6.4Hz,1H),7.51-7.49(dd,J＝7.8Hz,1.8Hz,1H),7.37-7.21(m,7H),4.80-4.75(dd,J＝12.6Hz,6.6Hz,1H),4.70-4.65(dd,J＝12.6Hz,8.6Hz,1H),4.26-4.20(m,1H),3.72-3.70(m,2H)；13C NMR(100MHz,CDCl3，ppm):δ194.5,145.9,140.4,138.7,128.8,128.2,127.7,127.4,126.8,125.7,79.5,45.8,39.4；IR(film,ν/cm-1):3850,3813,3732,3626,3586,3360,3030,2922,2297,1940,1842,1682,1549,1429,1296,1179,1030,854,766,669；HRMS(ESI)m/z calcd for C15H14N2O4[M+Na]+309.0851,found 309.0851. 1 H NMR (400MHz, CDCl 3 , ppm): δ8.17-8.16(d, J=6.4Hz, 1H), 7.51-7.49(dd, J=7.8Hz, 1.8Hz, 1H), 7.37-7.21(m ,7H),4.80-4.75(dd,J=12.6Hz,6.6Hz,1H),4.70-4.65(dd,J=12.6Hz,8.6Hz,1H),4.26-4.20(m,1H),3.72-3.70 (m,2H); 13 C NMR (100MHz, CDCl 3 , ppm): δ194.5, 145.9, 140.4, 138.7, 128.8, 128.2, 127.7, 127.4, 126.8, 125.7, 79.5, 45.8, 39.4; IR (film, ν/ cm -1 ):3850,3813,3732,3626,3586,3360,3030,2922,2297,1940,1842,1682,1549,1429,1296,1179,1030,854,766,669; HRMS(ESI)m/z calcd for C 15 H 14 N 2 O 4 [M+Na] + 309.0851, found 309.0851.
实施例2：(R)-2-(3-苯基-4-硝基)丁酰基吡啶氮-氧化合物的合成在一个10mL反应管中加入三氟甲磺酸钪(14.8mg，0.03mmol)，配体L2(1.4mg，0.03mmol)，碳酸铯(9.8mg，0.03mmol)和溶剂THF(1.2mL)，在氮气保护下室温搅拌2h。然后向反应管中加入2-肉桂酰基吡啶氮-氧化合物1a(67.6mg，0.3mmol)和硝基甲烷(0.3mL)在室温下搅拌反应。反应完成后(TLC跟踪检测)，旋干得到的残留物用乙酸乙酯/石油醚体系作为洗脱剂过柱得到黄色油状的产物(R)-2-(3-苯基-4-硝基)丁酰基吡啶氮-氧化合物3a(76.4mg，89％yield，95％ee)。(图3，图4)Example 2: Synthesis of (R)-2-(3-phenyl-4-nitro)butanoylpyridine nitrogen-oxygen compound Add scandium trifluoromethanesulfonate (14.8mg, 0.03mmol) into a 10mL reaction tube , ligand L2 (1.4mg, 0.03mmol), cesium carbonate (9.8mg, 0.03mmol) and solvent THF (1.2mL), stirred at room temperature for 2h under nitrogen protection. Then 2-cinnamoylpyridine nitrogen-oxygen compound 1a (67.6 mg, 0.3 mmol) and nitromethane (0.3 mL) were added to the reaction tube and the reaction was stirred at room temperature. After the reaction was completed (TLC tracking detection), the residue obtained by spinning was passed through the column with ethyl acetate/petroleum ether system as the eluent to obtain the yellow oily product (R)-2-(3-phenyl-4-nitro ) butyrylpyridine nitrogen-oxygen compound 3a (76.4 mg, 89% yield, 95% ee). (Figure 3, Figure 4)
1H NMR(400MHz,CDCl3，ppm):δ8.17-8.16(d,J＝6.4Hz,1H),7.51-7.49(dd,J＝7.8Hz,1.8Hz,1H),7.37-7.21(m,7H),4.80-4.75(dd,J＝12.6Hz,6.6Hz,1H),4.70-4.65(dd,J＝12.6Hz,8.6Hz,1H),4.26-4.20(m,1H),3.72-3.70(m,2H)；13C NMR(100MHz,CDCl3，ppm):δ194.5,145.9,140.4,138.7,128.8,128.2,127.7,127.4,126.8,125.7,79.5,45.8,39.4；IR(film,ν/cm-1):3850,3813,3732,3626,3586,3360,3030,2922,2297,1940,1842,1682,1549,1429,1296,1179,1030,854,766,669；HRMS(ESI)m/z calcd for C15H14N2O4[M+Na]+309.0851,found 309.0851. 1 H NMR (400MHz, CDCl 3 , ppm): δ8.17-8.16(d, J=6.4Hz, 1H), 7.51-7.49(dd, J=7.8Hz, 1.8Hz, 1H), 7.37-7.21(m ,7H),4.80-4.75(dd,J=12.6Hz,6.6Hz,1H),4.70-4.65(dd,J=12.6Hz,8.6Hz,1H),4.26-4.20(m,1H),3.72-3.70 (m,2H); 13 C NMR (100MHz, CDCl 3 , ppm): δ194.5, 145.9, 140.4, 138.7, 128.8, 128.2, 127.7, 127.4, 126.8, 125.7, 79.5, 45.8, 39.4; IR (film, ν/ cm -1 ):3850,3813,3732,3626,3586,3360,3030,2922,2297,1940,1842,1682,1549,1429,1296,1179,1030,854,766,669; HRMS(ESI)m/z calcd for C 15 H 14 N 2 O 4 [M+Na] + 309.0851, found 309.0851.
实施例3：(S)-2-(3-间氯苯基-4-硝基)丁酰基吡啶氮-氧化合物的合成Example 3: Synthesis of (S)-2-(3-m-chlorophenyl-4-nitro)butyrylpyridine nitrogen-oxygen compound
在一个10mL反应管中加入三氟甲磺酸铜(10.9mg，0.03mmol)，配体L1(12.8mg，0.03mmol)，碳酸铯(9.8mg，0.03mmol)和溶剂Tol(1.2mL)，在氮气保护下室温搅拌2h。然后向反应管中加入(E)-2(3-间氯苯基)丙烯酰基吡啶氮-氧化合物1f(77.9mg，0.3mmol)和硝基甲烷(0.3mL)在室温下搅拌反应。反应完成后(TLC跟踪检测)，旋干得到的残留物用乙酸乙酯/石油醚体系作为洗脱剂快速柱层析得到黄色油状的产物(S)-2-(3-间氯苯基-4-硝基)丁酰基吡啶氮-氧化合物3f(60.6mg，63％yield，90％ee)。(图5，图6)Add copper trifluoromethanesulfonate (10.9mg, 0.03mmol), ligand L1 (12.8mg, 0.03mmol), cesium carbonate (9.8mg, 0.03mmol) and solvent Tol (1.2mL) in a 10mL reaction tube, in Stir at room temperature for 2 h under nitrogen protection. Then (E)-2(3-m-chlorophenyl)acryloylpyridine nitrogen-oxygen compound 1f (77.9mg, 0.3mmol) and nitromethane (0.3mL) were added to the reaction tube and the reaction was stirred at room temperature. After the reaction was completed (TLC tracking detection), the residue obtained by spin drying was used as an eluent flash column chromatography to obtain yellow oily product (S)-2-(3-m-chlorophenyl- 4-nitro)butyrylpyridine nitrogen-oxygen compound 3f (60.6 mg, 63% yield, 90% ee). (Figure 5, Figure 6)
1H NMR(400MHz,CDCl3，ppm):δ8.20-8.18(d,J＝6.4Hz,1H),7.60-7.58(dd,J＝7.8Hz,1.6Hz,1H),7.41-7.17(m,6H),4.80-4.75(dd,J＝12.8Hz,6.3Hz,1H),4.69-4.64(dd,J＝12.7Hz,8.7Hz,1H),4.25-4.18(m,1H),3.72-3.67(m,2H)；13C NMR(100MHz,CDCl3，ppm):δ194.0,145.8,140.9,140.6,134.7,130.2,128.4,128.0,127.8,127.1,125.8,125.8,79.2,45.8,39.1；IR(film,ν/cm-1):3792,3684,2920,1692,1599,1551,1431,1254；HRMS(ESI)m/z calcd for C15H13ClN2O4[M+Na]+343.0462,found 343.0467. 1 H NMR (400MHz, CDCl 3 , ppm): δ8.20-8.18(d, J=6.4Hz, 1H), 7.60-7.58(dd, J=7.8Hz, 1.6Hz, 1H), 7.41-7.17(m ,6H),4.80-4.75(dd,J=12.8Hz,6.3Hz,1H),4.69-4.64(dd,J=12.7Hz,8.7Hz,1H),4.25-4.18(m,1H),3.72-3.67 (m,2H); 13 C NMR (100MHz, CDCl 3 , ppm): δ194.0, 145.8, 140.9, 140.6, 134.7, 130.2, 128.4, 128.0, 127.8, 127.1, 125.8, 125.8, 79.2, 45.8, 39.1; IR( film,ν/cm -1 ):3792,3684,2920,1692,1599,1551,1431,1254; HRMS(ESI)m/z calcd for C 15 H 13 ClN 2 O 4 [M+Na] + 343.0462, found 343.0467.
实施例4：(R)-2-(3-间氯苯基-4-硝基)丁酰基吡啶氮-氧化合物的合成Embodiment 4: Synthesis of (R)-2-(3-m-chlorophenyl-4-nitro)butyrylpyridine nitrogen-oxygen compound
在一个10mL反应管中加入三氟甲磺酸钪(14.8mg，0.03mmol)，配体L2(21.4mg，0.03mmol)，碳酸铯(9.8mg，0.03mmol)和溶剂THF(1.2mL)，在氮气保护下室温搅拌2h。然后向反应管中加入(E)-2(3-间氯苯基)丙烯酰基吡啶氮-氧化合物1f(77.9mg，0.3mmol)和硝基甲烷(0.3mL)在室温下搅拌反应。反应完成后(TLC跟踪检测)，旋干得到的残留物用乙酸乙酯/石油醚体系作为洗脱剂快速柱层析得到黄色油状的产物(R)-2-(3-间氯苯基-4-硝基)丁酰基吡啶氮-氧化合物3f(69.3mg，72％yield，96％ee)。(图5，图6)Add scandium trifluoromethanesulfonate (14.8mg, 0.03mmol), ligand L2 (21.4mg, 0.03mmol), cesium carbonate (9.8mg, 0.03mmol) and solvent THF (1.2mL) in a 10mL reaction tube, in Stir at room temperature for 2 h under nitrogen protection. Then (E)-2(3-m-chlorophenyl)acryloylpyridine nitrogen-oxygen compound 1f (77.9mg, 0.3mmol) and nitromethane (0.3mL) were added to the reaction tube and the reaction was stirred at room temperature. After the reaction was completed (TLC tracking detection), the residue obtained by spinning was used as an eluent for quick column chromatography with ethyl acetate/petroleum ether system to obtain a yellow oily product (R)-2-(3-m-chlorophenyl- 4-nitro)butyrylpyridine nitrogen-oxygen compound 3f (69.3 mg, 72% yield, 96% ee). (Figure 5, Figure 6)
1H NMR(400MHz,CDCl3，ppm):δ8.20-8.18(d,J＝6.4Hz,1H),7.60-7.58(dd,J＝7.8Hz,1.6Hz,1H),7.41-7.17(m,6H),4.80-4.75(dd,J＝12.8Hz,6.3Hz,1H),4.69-4.64(dd,J＝12.7Hz,8.7Hz,1H),4.25-4.18(m,1H),3.72-3.67(m,2H)；13C NMR(100MHz,CDCl3，ppm):δ194.0,145.8,140.9,140.6,134.7,130.2,128.4,128.0,127.8,127.1,125.8,125.8,79.2,45.8,39.1；IR(film,ν/cm-1):3792,3684,2920,1692,1599,1551,1431,1254；HRMS(ESI)m/z calcd for C15H13ClN2O4[M+Na]+343.0462,found 343.0467. 1 H NMR (400MHz, CDCl 3 , ppm): δ8.20-8.18(d, J=6.4Hz, 1H), 7.60-7.58(dd, J=7.8Hz, 1.6Hz, 1H), 7.41-7.17(m ,6H),4.80-4.75(dd,J=12.8Hz,6.3Hz,1H),4.69-4.64(dd,J=12.7Hz,8.7Hz,1H),4.25-4.18(m,1H),3.72-3.67 (m,2H); 13 C NMR (100MHz, CDCl 3 , ppm): δ194.0, 145.8, 140.9, 140.6, 134.7, 130.2, 128.4, 128.0, 127.8, 127.1, 125.8, 125.8, 79.2, 45.8, 39.1; IR( film,ν/cm -1 ):3792,3684,2920,1692,1599,1551,1431,1254; HRMS(ESI)m/z calcd for C 15 H 13 ClN 2 O 4 [M+Na] + 343.0462, found 343.0467.
实施例5：(S)-2-(3-对三氟甲基苯基-4-硝基)丁酰基吡啶氮-氧化合物的合成Example 5: Synthesis of (S)-2-(3-p-trifluoromethylphenyl-4-nitro)butyrylpyridine nitrogen-oxygen compound
在一个10mL反应管中加入三氟甲磺酸铜(10.9mg，0.03mmol)，配体L1(12.8mg，0.03mmol)，碳酸铯(9.8mg，0.03mmol)和溶剂Tol(1.2mL)，在氮气保护下室温搅拌2h。然后向反应管中加入(E)-2(3-对三氟甲基苯基)丙烯酰基吡啶氮-氧化合物1h(88.0mg，0.3mmol)和硝基甲烷(0.3mL)在室温下搅拌反应。反应完成后(TLC跟踪检测)，旋干得到的残留物用乙酸乙酯/石油醚体系作为洗脱剂快速柱层析得到黄色油状的产物(S)-2-(3-对三氟甲基苯基-4-硝基)丁酰基吡啶氮-氧化合物3h(90.4mg，85％yield，93％ee)。(图7，图8)Add copper trifluoromethanesulfonate (10.9mg, 0.03mmol), ligand L1 (12.8mg, 0.03mmol), cesium carbonate (9.8mg, 0.03mmol) and solvent Tol (1.2mL) in a 10mL reaction tube, in Stir at room temperature for 2 h under nitrogen protection. Then (E)-2(3-p-trifluoromethylphenyl)acryloylpyridine nitrogen-oxygen compound 1h (88.0 mg, 0.3 mmol) and nitromethane (0.3 mL) were added to the reaction tube and the reaction was stirred at room temperature . After the reaction was completed (TLC tracking detection), the residue obtained by spin drying was used as an eluent flash column chromatography to obtain yellow oily product (S)-2-(3-p-trifluoromethyl Phenyl-4-nitro)butyrylpyridine nitrogen-oxygen compound 3h (90.4 mg, 85% yield, 93% ee). (Figure 7, Figure 8)
1H NMR(400MHz,CDCl3，ppm):δ8.21-8.19(d,J＝6.4Hz,1H),7.62-7.59(dd,J＝7.9Hz,2.1Hz,1H),7.57-7.55(d,2H),7.44-7.28(m,4H),4.84-4.79(dd,J＝12.9Hz,6.2Hz,1H),4.73-4.68(dd,J＝12.9Hz,8.8Hz,1H),4.34-4.28(m,1H),3.82-3.69(m,2H)；13C NMR(100MHz,CDCl3，ppm):δ193.8,145.7,143.0,140.6,130.2-129.9(q,J＝32.5Hz),128.5,128.1,127.2,125.9(d,J＝2.0Hz),125.9-125.8(d,J＝3.7Hz),125.2-122.5(q,J＝270.5Hz),79.1,45.8,39.2；IR(film,ν/cm-1):3850,3813,3732,3645,3564,3501,3053,2920,2515,1940,1798,1730,1682,1566,1557,1433,1327,1117,1069,843,768,610；HRMS(ESI)m/z calcd for C16H13F3N2O4[M+Na]+377.0725,found377.0715. 1 H NMR (400MHz, CDCl 3 , ppm): δ8.21-8.19(d, J=6.4Hz, 1H), 7.62-7.59(dd, J=7.9Hz, 2.1Hz, 1H), 7.57-7.55(d ,2H),7.44-7.28(m,4H),4.84-4.79(dd,J=12.9Hz,6.2Hz,1H),4.73-4.68(dd,J=12.9Hz,8.8Hz,1H),4.34-4.28 (m, 1H), 3.82-3.69 (m, 2H); 13 C NMR (100MHz, CDCl 3 , ppm): δ193.8, 145.7, 143.0, 140.6, 130.2-129.9 (q, J＝32.5Hz), 128.5, 128.1 ,127.2,125.9(d,J=2.0Hz),125.9-125.8(d,J=3.7Hz),125.2-122.5(q,J=270.5Hz),79.1,45.8,39.2; IR(film,ν/cm -1 ):3850,3813,3732,3645,3564,3501,3053,2920,2515,1940,1798,1730,1682,1566,1557,1433,1327,1117,1069,843,768,610; HRMS(ESI)m/ z calcd for C 16 H 13 F 3 N 2 O 4 [M+Na] + 377.0725,found 377.0715.
实施例6：(R)-2-(3-对三氟甲基苯基-4-硝基)丁酰基吡啶氮-氧化合物的合成在一个10mL反应管中加入三氟甲磺酸钪(14.8mg，0.03mmol)，配体L2(21.4mg，0.03mmol)，碳酸铯(9.8mg，0.03mmol)和溶剂THF(1.2mL)，在氮气保护下室温搅拌2h。然后向反应管中加入(E)-2(3-对三氟甲基苯基)丙烯酰基吡啶氮-氧化合物1h(88.0mg，0.3mmol)和硝基甲烷(0.3mL)在室温下搅拌反应。反应完成后(TLC跟踪检测)，旋干得到的残留物用乙酸乙酯/石油醚体系作为洗脱剂快速柱层析得到黄色油状的产物(R)-2-(3-对三氟甲基苯基-4-硝基)丁酰基吡啶氮-氧化合物3h(78.7mg，74％yield，92％ee)。(图7，图8)Example 6: Synthesis of (R)-2-(3-p-trifluoromethylphenyl-4-nitro)butyrylpyridine nitrogen-oxygen compound In a 10mL reaction tube, scandium trifluoromethanesulfonate (14.8 mg, 0.03mmol), ligand L2 (21.4mg, 0.03mmol), cesium carbonate (9.8mg, 0.03mmol) and solvent THF (1.2mL), stirred at room temperature for 2h under nitrogen protection. Then (E)-2(3-p-trifluoromethylphenyl)acryloylpyridine nitrogen-oxygen compound 1h (88.0 mg, 0.3 mmol) and nitromethane (0.3 mL) were added to the reaction tube and the reaction was stirred at room temperature . After the reaction was completed (TLC tracking detection), the residue obtained by spin-drying was used as eluent flash column chromatography to obtain yellow oily product (R)-2-(3-p-trifluoromethyl Phenyl-4-nitro)butyrylpyridine nitrogen-oxygen compound 3h (78.7 mg, 74% yield, 92% ee). (Figure 7, Figure 8)
1H NMR(400MHz,CDCl3，ppm):δ8.21-8.19(d,J＝6.4Hz,1H),7.62-7.59(dd,J＝7.9Hz,2.1Hz,1H),7.57-7.55(d,2H),7.44-7.28(m,4H),4.84-4.79(dd,J＝12.9Hz,6.2Hz,1H),4.73-4.68(dd,J＝12.9Hz,8.8Hz,1H),4.34-4.28(m,1H),3.82-3.69(m,2H)；13C NMR(100MHz,CDCl3，ppm):δ193.8,145.7,143.0,140.6,130.2-129.9(q,J＝32.5Hz),128.5,128.1,127.2,125.9(d,J＝2.0Hz),125.9-125.8(d,J＝3.7Hz),125.2-122.5(q,J＝270.5Hz),79.1,45.8,39.2；IR(film,ν/cm-1):3850,3813,3732,3645,3564,3501,3053,2920,2515,1940,1798,1730,1682,1566,1557,1433,1327,1117,1069,843,768,610；HRMS(ESI)m/z calcd for C16H13F3N2O4[M+Na]+377.0725,found377.0715. 1 H NMR (400MHz, CDCl 3 , ppm): δ8.21-8.19(d, J=6.4Hz, 1H), 7.62-7.59(dd, J=7.9Hz, 2.1Hz, 1H), 7.57-7.55(d ,2H),7.44-7.28(m,4H),4.84-4.79(dd,J=12.9Hz,6.2Hz,1H),4.73-4.68(dd,J=12.9Hz,8.8Hz,1H),4.34-4.28 (m, 1H), 3.82-3.69 (m, 2H); 13 C NMR (100MHz, CDCl 3 , ppm): δ193.8, 145.7, 143.0, 140.6, 130.2-129.9 (q, J＝32.5Hz), 128.5, 128.1 ,127.2,125.9(d,J=2.0Hz),125.9-125.8(d,J=3.7Hz),125.2-122.5(q,J=270.5Hz),79.1,45.8,39.2; IR(film,ν/cm -1 ):3850,3813,3732,3645,3564,3501,3053,2920,2515,1940,1798,1730,1682,1566,1557,1433,1327,1117,1069,843,768,610; HRMS(ESI)m/ z calcd for C 16 H 13 F 3 N 2 O 4 [M+Na] + 377.0725,found 377.0715.
实施例7：(S)-2-(3-对溴苯基-4-硝基)丁酰基吡啶氮-氧化合物的合成Example 7: Synthesis of (S)-2-(3-p-bromophenyl-4-nitro)butyrylpyridine nitrogen-oxygen compound
在一个10mL反应管中加入三氟甲磺酸铜(10.9mg，0.03mmol)，配体L1(12.8mg，0.03mmol)，碳酸铯(9.8mg，0.03mmol)和溶剂Tol(1.2mL)，在氮气保护下室温搅拌2h。然后向反应管中加入(E)-2(3-对溴苯基)丙烯酰基吡啶氮-氧化合物1j(91.2mg，0.3mmol)和硝基甲烷(0.3mL)在室温下搅拌反应。反应完成后(TLC跟踪检测)，旋干得到的残留物用乙酸乙酯/石油醚体系作为洗脱剂快速柱层析得到黄色油状的产物(S)-2-(3-对溴苯基-4-硝基)丁酰基吡啶氮-氧化合物3j(81.0mg，74％yield，91％ee)。(图9，图10)Add copper trifluoromethanesulfonate (10.9mg, 0.03mmol), ligand L1 (12.8mg, 0.03mmol), cesium carbonate (9.8mg, 0.03mmol) and solvent Tol (1.2mL) in a 10mL reaction tube, in Stir at room temperature for 2 h under nitrogen protection. Then (E)-2(3-p-bromophenyl)acryloylpyridine nitrogen-oxygen compound 1j (91.2 mg, 0.3 mmol) and nitromethane (0.3 mL) were added to the reaction tube and the reaction was stirred at room temperature. After the reaction was completed (TLC tracking detection), the residue obtained by spin-drying was used as an eluent flash column chromatography to obtain yellow oily product (S)-2-(3-p-bromophenyl- 4-nitro)butyrylpyridine nitrogen-oxygen compound 3j (81.0 mg, 74% yield, 91% ee). (Figure 9, Figure 10)
1H NMR(400MHz,CDCl3，ppm):δ8.18-8.16(d,J＝6.4Hz,1H),7.58-7.55(dd,J＝7.9Hz,2.0Hz,1H),7.43-7.15(m,6H),4.79-4.74(dd,J＝12.7Hz,6.3Hz,1H),4.68-4.62(dd,J＝12.7Hz,8.8Hz,1H),4.24-4.16(m,1H),3.76-3.64(m,2H)；13C NMR(100MHz,CDCl3，ppm):δ194.0,145.7,140.5,137.9,131.9,129.2,128.4,127.0,125.7,121.6,79.2,45.7,38.8；IR(film,ν/cm-1):3850,3813,3732,3645,3586,3499,3063,2920,1865,1730,1682,1634,1551,1429,1296,1011,827,768；HRMS(ESI)m/z calcd for C15H13BrN2O4[M+Na]+386.9956,found 386.9960. 1 H NMR (400MHz, CDCl 3 , ppm): δ8.18-8.16(d, J=6.4Hz, 1H), 7.58-7.55(dd, J=7.9Hz, 2.0Hz, 1H), 7.43-7.15(m ,6H),4.79-4.74(dd,J=12.7Hz,6.3Hz,1H),4.68-4.62(dd,J=12.7Hz,8.8Hz,1H),4.24-4.16(m,1H),3.76-3.64 (m,2H); 13 C NMR (100MHz, CDCl 3 , ppm): δ194.0, 145.7, 140.5, 137.9, 131.9, 129.2, 128.4, 127.0, 125.7, 121.6, 79.2, 45.7, 38.8; IR (film, ν/ cm -1 ):3850,3813,3732,3645,3586,3499,3063,2920,1865,1730,1682,1634,1551,1429,1296,1011,827,768; HRMS(ESI)m/z calcd for C 15 H 13 BrN 2 O 4 [M+Na] + 386.9956, found 386.9960.
实施例8：(R)-2-(3-对溴苯基-4-硝基)丁酰基吡啶氮-氧化合物的合成Example 8: Synthesis of (R)-2-(3-p-bromophenyl-4-nitro)butyrylpyridine nitrogen-oxygen compound
在一个10mL反应管中加入三氟甲磺酸钪(14.8mg，0.03mmol)，配体L2(21.4mg，0.03mmol)，碳酸铯(9.8mg，0.03mmol)和溶剂THF(1.2mL)，在氮气保护下室温搅拌2h。然后向反应管中加入(E)-2(3-对溴苯基)丙烯酰基吡啶氮-氧化合物1j(91.2mg，0.3mmol)和硝基甲烷(0.3mL)在室温下搅拌反应。反应完成后(TLC跟踪检测)，旋干得到的残留物用乙酸乙酯/石油醚体系作为洗脱剂过柱得到黄色油状的产物(R)-2-(3-对溴苯基-4-硝基)丁酰基吡啶氮-氧化合物3j(75.6mg，69％yield，94％ee)。(图9，图10)Add scandium trifluoromethanesulfonate (14.8mg, 0.03mmol), ligand L2 (21.4mg, 0.03mmol), cesium carbonate (9.8mg, 0.03mmol) and solvent THF (1.2mL) in a 10mL reaction tube, in Stir at room temperature for 2 h under nitrogen protection. Then (E)-2(3-p-bromophenyl)acryloylpyridine nitrogen-oxygen compound 1j (91.2 mg, 0.3 mmol) and nitromethane (0.3 mL) were added to the reaction tube and the reaction was stirred at room temperature. After the reaction was completed (TLC tracking detection), the residue obtained by spin-drying was passed through the column with ethyl acetate/petroleum ether system as the eluent to obtain the product (R)-2-(3-p-bromophenyl-4- Nitro)butyrylpyridine nitrogen-oxygen compound 3j (75.6 mg, 69% yield, 94% ee). (Figure 9, Figure 10)
1H NMR(400MHz,CDCl3，ppm):δ8.18-8.16(d,J＝6.4Hz,1H),7.58-7.55(dd,J＝7.9Hz,2.0Hz,1H),7.43-7.15(m,6H),4.79-4.74(dd,J＝12.7Hz,6.3Hz,1H),4.68-4.62(dd,J＝12.7Hz,8.8Hz,1H),4.24-4.16(m,1H),3.76-3.64(m,2H)；13C NMR(100MHz,CDCl3，ppm):δ194.0,145.7,140.5,137.9,131.9,129.2,128.4,127.0,125.7,121.6,79.2,45.7,38.8；IR(film,ν/cm-1):3850,3813,3732,3645,3586,3499,3063,2920,1865,1730,1682,1634,1551,1429,1296,1011,827,768；HRMS(ESI)m/z calcd for C15H13BrN2O4[M+Na]+386.9956,found 386.9960. 1 H NMR (400MHz, CDCl 3 , ppm): δ8.18-8.16(d, J=6.4Hz, 1H), 7.58-7.55(dd, J=7.9Hz, 2.0Hz, 1H), 7.43-7.15(m ,6H),4.79-4.74(dd,J=12.7Hz,6.3Hz,1H),4.68-4.62(dd,J=12.7Hz,8.8Hz,1H),4.24-4.16(m,1H),3.76-3.64 (m,2H); 13 C NMR (100MHz, CDCl 3 , ppm): δ194.0, 145.7, 140.5, 137.9, 131.9, 129.2, 128.4, 127.0, 125.7, 121.6, 79.2, 45.7, 38.8; IR (film, ν/ cm -1 ):3850,3813,3732,3645,3586,3499,3063,2920,1865,1730,1682,1634,1551,1429,1296,1011,827,768; HRMS(ESI)m/z calcd for C 15 H 13 BrN 2 O 4 [M+Na] + 386.9956, found 386.9960.
实施例9：(R)-2-(3-间甲氧基苯基-4-硝基)丁酰基吡啶氮-氧化合物的合成Example 9: Synthesis of (R)-2-(3-m-methoxyphenyl-4-nitro)butyrylpyridine nitrogen-oxygen compound
在一个10mL反应管中加入三氟甲磺酸钪(14.8mg，0.03mmol)，配体L2(21.4mg，0.03mmol)，碳酸铯(9.8mg，0.03mmol)和溶剂THF(1.2mL)，在氮气保护下室温搅拌2h。然后向反应管中加入(E)-2(3-间甲氧基苯基)丙烯酰基吡啶氮-氧化合物1c(76.6mg，0.3mmol)和硝基甲烷(0.3mL)在室温下搅拌反应。反应完成后(TLC跟踪检测)，旋干得到的残留物用乙酸乙酯/石油醚体系作为洗脱剂快速柱层析得到黄色油状的产物(R)-2-(3-间甲氧基苯基-4-硝基)丁酰基吡啶氮-氧化合物3c(78.8mg，83％yield，92％ee)。(图11，图12，图13)Add scandium trifluoromethanesulfonate (14.8mg, 0.03mmol), ligand L2 (21.4mg, 0.03mmol), cesium carbonate (9.8mg, 0.03mmol) and solvent THF (1.2mL) in a 10mL reaction tube, in Stir at room temperature for 2 h under nitrogen protection. Then (E)-2(3-methoxyphenyl)acryloylpyridine nitrogen-oxygen compound 1c (76.6 mg, 0.3 mmol) and nitromethane (0.3 mL) were added to the reaction tube and the reaction was stirred at room temperature. After the reaction was completed (TLC tracking detection), the residue obtained by spin drying was used as an eluent flash column chromatography to obtain yellow oily product (R)-2-(3-m-methoxybenzene 4-nitro)butyrylpyridine nitrogen-oxygen compound 3c (78.8 mg, 83% yield, 92% ee). (Figure 11, Figure 12, Figure 13)
1H NMR(400MHz,CDCl3，ppm):δ8.19-8.18(d,J＝6.4Hz,1H),7.56-7.54(dd,J＝7.8Hz,1.6Hz,1H),7.38-7.19(m,3H),6.85-6.76(m,3H),4.78-4.73(dd,J＝12.6Hz,6.7Hz,1H),4.69-4.64(dd,J＝12.6Hz,8.4Hz,1H),4.22-4.19(m,1H),3.78(s,3H),3.73-3.70(m,2H)；13C NMR(100MHz,CDCl3，ppm):δ194.4,159.9,146.1,140.6,140.4,130.0,128.2,127.0,125.7,119.6,113.5,113.1,79.6,55.2,45.9,39.5；IR(film,ν/cm-1):3850,3813,3732,3645,3586,3501,3053,2922,1682,1549,1429,1258,1152,1042,853,768,565；HRMS(ESI)m/z calcd for C16H16N2O5[M+Na]+399.0957,found399.0956. 1 H NMR (400MHz, CDCl 3 , ppm): δ8.19-8.18(d, J=6.4Hz, 1H), 7.56-7.54(dd, J=7.8Hz, 1.6Hz, 1H), 7.38-7.19(m ,3H),6.85-6.76(m,3H),4.78-4.73(dd,J=12.6Hz,6.7Hz,1H),4.69-4.64(dd,J=12.6Hz,8.4Hz,1H),4.22-4.19 (m, 1H), 3.78 (s, 3H), 3.73-3.70 (m, 2H); 13 C NMR (100MHz, CDCl 3 , ppm): δ194.4, 159.9, 146.1, 140.6, 140.4, 130.0, 128.2, 127.0, 125.7, 119.6, 113.5, 113.1, 79.6, 55.2, 45.9, 39.5; IR (film, ν/cm -1 ): 3850, 3813, 3732, 3645, 3586, 3501, 3053, 2922, 1682, 1549, 1429, 1258 ,1152,1042,853,768,565; HRMS(ESI)m/z calcd for C 16 H 16 N 2 O 5 [M+Na] + 399.0957,found 399.0956.
在本申请的其它实施例中，2-烯酰基吡啶氮-氧化合物与手性铜配合物或手性钪配合物的物质的量比10:1-20:1，2-烯酰基吡啶氮-氧类化合物的起始浓度为0.1-0.5mol/L，硝基甲烷或其类似物与催化体系中溶剂的体积比为1/3-1/5。本申请无法穷尽所有实施例，仅能选择有代表性的有限实施例来做本申请的解释。In other embodiments of the present application, the mass ratio of 2-enoylpyridine nitrogen-oxygen compound to chiral copper complex or chiral scandium complex is 10:1-20:1,2-enoylpyridine nitrogen- The initial concentration of the oxygen compound is 0.1-0.5 mol/L, and the volume ratio of nitromethane or its analogues to the solvent in the catalytic system is 1/3-1/5. The present application cannot exhaust all the embodiments, and only representative limited embodiments can be selected for explanation of the present application.
尽管已经示出和描述了本发明的实施例，对于本领域的普通技术人员而言，可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换或变型，本发明的范围由所附权利要求及其等同物限定。Although the embodiments of the present invention have been shown and described, those skilled in the art can understand that various changes, modifications and substitutions can be made to these embodiments without departing from the principle and spirit of the present invention. or variants, the scope of the invention is defined by the appended claims and their equivalents.
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