CN110683979B - 一种氢氧化钠催化的多取代吡咯合成新方法 - Google Patents
一种氢氧化钠催化的多取代吡咯合成新方法 Download PDFInfo
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- CN110683979B CN110683979B CN201810735987.XA CN201810735987A CN110683979B CN 110683979 B CN110683979 B CN 110683979B CN 201810735987 A CN201810735987 A CN 201810735987A CN 110683979 B CN110683979 B CN 110683979B
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- sodium hydroxide
- chloroform
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 title claims abstract description 66
- 150000003233 pyrroles Chemical class 0.000 title claims abstract description 16
- 238000001308 synthesis method Methods 0.000 title claims description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 94
- 238000000034 method Methods 0.000 claims abstract description 34
- -1 isocyanoacetic acid ester compounds Chemical class 0.000 claims abstract description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 47
- 239000003054 catalyst Substances 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 229930015036 aurone Natural products 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical group [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 4
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 3
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 3
- 229940112669 cuprous oxide Drugs 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229940071536 silver acetate Drugs 0.000 claims description 3
- 229910001923 silver oxide Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 239000007809 chemical reaction catalyst Substances 0.000 claims 1
- 150000001529 aurone derivatives Chemical class 0.000 abstract description 23
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 abstract description 16
- 150000001875 compounds Chemical class 0.000 abstract description 15
- 239000000758 substrate Substances 0.000 abstract description 6
- 238000006317 isomerization reaction Methods 0.000 abstract description 4
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract description 2
- 239000008204 material by function Substances 0.000 abstract description 2
- 229930014626 natural product Natural products 0.000 abstract description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract description 2
- 238000007142 ring opening reaction Methods 0.000 abstract description 2
- 238000007036 catalytic synthesis reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 238000005481 NMR spectroscopy Methods 0.000 description 41
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 38
- 238000002360 preparation method Methods 0.000 description 26
- 238000012544 monitoring process Methods 0.000 description 22
- 239000002994 raw material Substances 0.000 description 22
- 238000004809 thin layer chromatography Methods 0.000 description 22
- 238000004440 column chromatography Methods 0.000 description 20
- CRXFROMHHBMNAB-UHFFFAOYSA-N methyl 2-isocyanoacetate Chemical compound COC(=O)C[N+]#[C-] CRXFROMHHBMNAB-UHFFFAOYSA-N 0.000 description 20
- 239000011734 sodium Substances 0.000 description 20
- 239000003208 petroleum Substances 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- 238000002844 melting Methods 0.000 description 18
- 230000008018 melting Effects 0.000 description 18
- 238000003756 stirring Methods 0.000 description 17
- 150000001345 alkine derivatives Chemical class 0.000 description 11
- 239000010949 copper Substances 0.000 description 6
- 229910052802 copper Inorganic materials 0.000 description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 3
- OMUOMODZGKSORV-UVTDQMKNSA-N aurone Chemical compound O1C2=CC=CC=C2C(=O)\C1=C\C1=CC=CC=C1 OMUOMODZGKSORV-UVTDQMKNSA-N 0.000 description 3
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 description 3
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 2
- CFCNTIFLYGKEIO-UHFFFAOYSA-N 2-isocyanoacetic acid Chemical compound OC(=O)C[N+]#[C-] CFCNTIFLYGKEIO-UHFFFAOYSA-N 0.000 description 2
- JZIBVTUXIVIFGC-UHFFFAOYSA-N 2H-pyrrole Chemical class C1C=CC=N1 JZIBVTUXIVIFGC-UHFFFAOYSA-N 0.000 description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 238000006352 cycloaddition reaction Methods 0.000 description 2
- 125000006575 electron-withdrawing group Chemical group 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- 150000002527 isonitriles Chemical class 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- 239000004332 silver Substances 0.000 description 2
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 2
- 229910001958 silver carbonate Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 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 1
- QMGHHBHPDDAGGO-IIWOMYBWSA-N (2S,4R)-1-[(2S)-2-[[2-[3-[4-[3-[4-[[5-bromo-4-[3-[cyclobutanecarbonyl(methyl)amino]propylamino]pyrimidin-2-yl]amino]phenoxy]propoxy]butoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide Chemical compound CN(CCCNC1=NC(NC2=CC=C(OCCCOCCCCOCCCOCC(=O)N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)NCC3=CC=C(C=C3)C3=C(C)N=CS3)C(C)(C)C)C=C2)=NC=C1Br)C(=O)C1CCC1 QMGHHBHPDDAGGO-IIWOMYBWSA-N 0.000 description 1
- IZGDXVLRMHXOJV-SFHVURJKSA-N (3s)-4-[2-[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]ethyl-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1CCP(O)(=O)C[C@@H](O)CC(O)=O IZGDXVLRMHXOJV-SFHVURJKSA-N 0.000 description 1
- RTTUBUXMNUJHRR-DXRVJIQQSA-N (3s)-4-[[(e)-2-[1-(4-fluorophenyl)-3-propan-2-ylindol-2-yl]ethenyl]-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound C12=CC=CC=C2C(C(C)C)=C(\C=C\P(O)(=O)C[C@@H](O)CC(O)=O)N1C1=CC=C(F)C=C1 RTTUBUXMNUJHRR-DXRVJIQQSA-N 0.000 description 1
- 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 1
- 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 1
- IAYSDKUKIIYRRA-UHFFFAOYSA-N 1-(isocyanatomethylsulfonyl)-4-methylbenzene Chemical class CC1=CC=C(S(=O)(=O)CN=C=O)C=C1 IAYSDKUKIIYRRA-UHFFFAOYSA-N 0.000 description 1
- BOOYHBPHFVNWNH-OAHLLOKOSA-N 1-tert-butyl-6-[[(1R)-1-(4-chlorophenyl)ethyl]amino]-5-[(4-fluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C[C@H](C1=CC=C(C=C1)Cl)NC2=NC3=C(C=NN3C(C)(C)C)C(=O)N2CC4=CC=C(C=C4)F BOOYHBPHFVNWNH-OAHLLOKOSA-N 0.000 description 1
- PSWDQTMAUUQILQ-UHFFFAOYSA-N 2-[(6-methoxy-4-methylquinazolin-2-yl)amino]-5,6-dimethyl-1h-pyrimidin-4-one Chemical compound N1=C(C)C2=CC(OC)=CC=C2N=C1NC1=NC(=O)C(C)=C(C)N1 PSWDQTMAUUQILQ-UHFFFAOYSA-N 0.000 description 1
- JWHYSEDOYMYMNM-QGZVFWFLSA-N 2-[4-[(2r)-2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]sulfanyl-2-methylphenoxy]acetic acid Chemical compound C([C@@H](OCC)CSC=1C=C(C)C(OCC(O)=O)=CC=1)OC1=CC=C(C(F)(F)F)C=C1 JWHYSEDOYMYMNM-QGZVFWFLSA-N 0.000 description 1
- 229940126650 Compound 3f Drugs 0.000 description 1
- KGPGFQWBCSZGEL-ZDUSSCGKSA-N GSK690693 Chemical compound C=12N(CC)C(C=3C(=NON=3)N)=NC2=C(C#CC(C)(C)O)N=CC=1OC[C@H]1CCCNC1 KGPGFQWBCSZGEL-ZDUSSCGKSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical compound N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-N anhydrous cyanic acid Natural products OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000004777 chromones Chemical class 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940125796 compound 3d Drugs 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 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 1
- 238000013508 migration Methods 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 150000003236 pyrrolines Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 150000003378 silver Chemical class 0.000 description 1
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
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Abstract
吡咯是一类重要的含氮五元杂环化合物，广泛存在于天然产物，药物以及功能材料中，同时也是重要的合成中间体。本发明涉及多取代吡咯衍生物的催化合成方法，是以异氰基乙酸酯类化合物与橙酮衍生物在氢氧化钠催化下进行1,3‑偶极环加成反应，然后通过开环异构得到对应产物。该反应能够快速、高效地构建多取代吡咯衍生物，具有很高的原子经济性。本发明所用底物易于制备、价格低廉，反应条件温和，操作简单，且底物适用范围广，不需要进行无水无氧操作，即可高收率得到目标化合物，具有广阔的应用前景。
Description
技术领域
本发明属于有机合成方法学领域，涉及一种氢氧化钠催化的多取代吡咯合成新方法。
背景技术
吡咯是一类重要的含氮五元杂环化合物，广泛存在于天然产物，药物以及功能材料中，同时也是重要的合成中间体。近几十年来，大量工作报道了具有吡咯骨架化合物的合成。到目前为止，虽然异氰类化合物参与的吡咯合成已经有了深入的研究，但相当一部分反应使用到了重金属诸如钌、铑、铜、银等过渡金属作催化剂，有的甚至需要一些复杂的配体参与，产物中重金属残留也阻碍了这一类方法在药物化学领域的应用。
异氰化合物和炔烃以及一些活化烯烃的反应是制备吡咯衍生物的重要方法之一，这一类反应具有原子经济、原料易得等诸多优点，受到了化学家们的广泛青睐。早在1979年，Sasaki(Chem.Pharm.Bull.,1979,27,2857-2861)等人就报道了第一例活化炔烃和对甲苯磺酰基甲基异氰在化学当量的DBU作用下通过1,3-偶极环加成反应生成吡咯的例子。反应过程首先是DBU拔掉异氰α位氢，形成1,3-偶极子，然后对丙炔酸酯的亲核加成、环化，形成2H-吡咯类似物，随后通过异构形成吡咯。虽然该方法只合成了两个产物，而且产率只有10％左右，但是异氰化合物合成吡咯的原子经济性优势明显体现出来，也为后续的研究做了重要铺垫。
2009年de Meijere(Chemistry,2009,15,227-236)小组进一步报道了铜催化下异氰化合物和缺电子炔烃的反应，在碱性条件(当量的KOtBu或者KHMDS)或者Cu催化剂作用下以中等到优异的收率得到了2,3,4-三取代吡咯衍生物。另外，作者发现在高温条件下，非活化的端炔和铜催化剂原位生成炔-铜物种后也能够和异氰化合物反应生成2,3-双取代吡咯衍生物。
2013年，毕锡和(Angew.Chem.Int.Ed.,2013,52,6953-6957)与雷爱文(Angew.Chem.Int.Ed.,2013,52,6958-6961)小组相继报道了银催化的非活化炔烃与异氰类化合物的反应生成多取代吡咯的例子，两个反应体系均使用了碳酸银做催化剂，只是改变了不同的溶剂。他们发现Ag2CO3能够有效活化炔烃以及异氰基，从而催化反应，而AgOAc,AgOTf,Ag2O,AgF等众多银盐几乎没有活性，主要生成了异氰化合物的二聚体，相反Ag2CO3作催化剂可以完全避免此类反应。该催化体系的发展为非活化炔烃和异氰化合物的反应开辟了方向。
2015年，Tiwari(Chem.Commun.,2015,51,13646-13649)等人发现，三氧化二铝负载的纳米铜做催化剂可以实现异氰化合物和非活化炔烃的环加成反应制备多取代吡咯。以K2CO3作碱，在加热条件下异氰基乙酸酯能够与多种芳基取代炔烃反应，并以良好的收率得到吡咯化合物。作者进一步尝试了烷基炔烃在相同反应条件下与异氰化合物的反应，却发现并不能得到对应的烷基取代吡咯，而是得到被氧化的α烷基酮取代吡咯，且反应产率较低，通过对反应条件作适当优化，使用tBuOK代替K2CO3后，能够以中等收率得到2,4-二取代吡咯化合物。2016年，该课题组(Angew.Chem.Int.Ed.,2013,52,6953-6957)利用四氧化三铁负载的纳米铜做催化剂也同样实现了异氰化合物和炔烃的反应，两分子的异氰基乙酸酯对炔烃进行加成后，形成吡咯啉化合物，然后脱除一分子氢氰酸，通过双键异构得到了一系列2,3,4-三取代吡咯衍生物。
2015年，Yang(Chem.Commun.,2016,52,4675-4678)小组发展了银催化的异氰化合物和碳碳双键的[3+2]环加成反应。以碳酸银做催化剂，K2CO3作碱，高温下色酮和异氰化合物反应，色酮C-O键断裂开环，生成2,4-二取代吡咯。同年，该课题组(Org.Lett.,2015,17,5590-5593)进一步报道了类似条件下α-碘取代色酮和异氰化合物的反应，与之前不同的是，在银催化下，色酮断开的C-O键再次重建，从而得到色酮并吡咯结构化合物。
2016年，George(Adv.Synth.Catal.,2016,358,3714-3718)等人发展了三苯基膦和醋酸铜共催化下异氰化合物和各类活化炔烃之间的Click环化反应。作者认为，反应首先生成的2,2,4-三取代的2H吡咯中间体会在键角张力引发下发生吸电子基的1,2-迁移，从而得到C3和C4位不同吸电子基的2,3,4-三取代吡咯衍生物。该方法条件相对温和，且官能团耐受度高，为多取代吡咯衍生物的合成提供了参考。
发明内容
本发明提供了一种多取代吡咯衍生物合成新方法。在催化剂作用下，橙酮与异氰基乙酸酯经1,3-偶极环加成反应，得到螺环吡咯啉衍生物，然后通过螺环开环异构得到对应的2,3,4-多取代吡咯衍生物。本发明条件温和，操作简单，经济环保，不需要进行无水无氧操作即可高收率得到目标化合物，且底物适用范围广，具有广阔的应用前景。
本发明提供的合成多取代吡咯衍生物的方法，其反应方程式如下：
式中R1为甲基，C1-10烷氧基，溴取代基等；Ar为苯基，甲基取代苯基，甲氧基取代苯基，卤原子取代苯基，萘基，二茂铁基，噻吩基，呋喃基，吲哚基，吡啶基等；EWG为甲酯，对甲苯磺酰基等。
所述的技术方案实施操作包括以下：将反应底物橙酮衍生物、催化剂置于反应瓶中，放入合适尺寸搅拌子，并将原料和催化剂溶于一定量溶剂中，然后加入适量的异氰化合物，在一定温度下搅拌反应，TLC跟踪监测。反应完成后，浓缩反应液，通过硅胶柱层析分离得到产物。
本发明所述的制备方法中，反应温度为0℃—40℃；优选25℃。
本发明所述的制备方法中，反应试剂组合物中催化剂为：氧化银，醋酸银，氧化亚铜，醋酸铜，三乙胺，碳酸钾，氢氧化钠；最优选为：氢氧化钠。
本发明所述的制备方法中，反应试剂组合物中催化剂与底物橙酮的摩尔百分比优选为:催化剂5mol％-30mol％，最优选为：20mol％。
本发明所述的制备方法中，反应试剂组合物中底物橙酮与异氰化合物的摩尔比优选为：橙酮衍生物：异氰化合物＝1:1-1:2，最优选为：1:1.2。
本发明所述的制备方法中，反应溶剂优选为：二氯甲烷，四氢呋喃，氯仿，甲苯，乙醚，甲醇，最优选为：甲醇。
本发明所述的制备方法中，橙酮底物浓度优选为：0.05-0.2mol/L，最优选为：0.1mol/L。
具体实施方式
本发明的任一实施方案中的监控方法是：薄层层析法。
结构确证技术手段均为本领域技术人员知晓的通用技术手段，核磁共振技术，高分辨质谱。
实施例1：
化合物3a的制备
步骤：
准确称取橙酮衍生物1a(22.2mg,0.1mmol)和氧化银(1.16mg,0.005mmol)置于装有搅拌子的10mL反应试管中，加入2mL二氯甲烷溶解，然后在0℃下加入异氰基乙酸甲酯2a(9.9mg,0.1mmol)，滴加完成后0℃搅拌反应。TLC监测直到原料1a反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3a 3.2mg，收率10％。
白色固体，熔点53-54℃，Rf＝0.2(石油醚:乙酸乙酯＝5:1)。1H NMR(400MHz,Chloroform-d)δ11.89(s,1H),9.70(br,1H),7.64(dd,J＝8.0,1.5Hz,1H),7.42–7.38(m,1H),7.35–7.26(m,6H),6.95(d,J＝8.4Hz,1H),6.78–6.74(m,1H),3.75(s,3H)；13C NMR(101MHz,Chloroform-d)δ195.54,162.52,161.23,135.78,132.80,132.69,132.08,130.20,127.57,127.49,126.28,124.46,120.41,118.49,117.98,51.76.HRMS(ESI):m/zcalcd.for[C19H15NNaO4,M+Na]+:344.0893；found:344.0894.
实施例2：
化合物3b的制备
步骤：
准确称取橙酮衍生物1a(22.2mg,0.1mmol)和醋酸银(1.67mg,0.01mmol)置于装有搅拌子的10mL反应试管中，加入1mL四氢呋喃溶解，然后在25℃下加入异氰基乙酸甲酯2b(23.43mg,0.12mmol)，滴加完成后25℃下搅拌反应。TLC监测直到原料1a反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3b 10.4mg，收率25％。
白色固体，熔点179-181℃，Rf＝0.1(石油醚:乙酸乙酯＝5:1)。1H NMR(400MHz,Chloroform-d)δ11.77(s,1H),10.21(br,1H),7.59(d,J＝8.0Hz,1H),7.39–7.35(m,2H),7.27(dt,J＝12.9,6.7Hz,5H),7.20(d,J＝7.8Hz,2H),7.08(d,J＝8.0Hz,2H),6.91(d,J＝8.4Hz,1H),6.72(t,J＝7.6Hz,1H),2.34(s,3H)；13C NMR(101MHz,Chloroform-d)δ194.91,162.47,144.50,137.72,135.96,132.70,131.00,130.48,130.31,129.46,128.02,127.76,127.69,127.21,125.48,124.82,120.03,118.56,117.97,21.54.HRMS(ESI):m/zcalcd.for[C24H19NNaO4S,M+Na]+:440.0927；found:440.0926.
实施例3：
化合物3c的制备
步骤：
准确称取橙酮衍生物1b(30.1mg,0.1mmol)和氧化亚铜(2.15mg,0.015mmol)置于装有搅拌子的10mL反应试管中，加入0.5mL氯仿溶解，然后在40℃下加入异氰基乙酸甲酯2a(14.85mg,0.15mmol)，滴加完成后40℃下搅拌反应。TLC监测直到原料1b反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3c 2.0mg，收率5％。
白色固体，熔点80-81℃，Rf＝0.2(石油醚:乙酸乙酯＝5:1)。1H NMR(400MHz,Chloroform-d)δ11.81(s,1H),9.62(br,1H),7.64(d,J＝7.6Hz,1H),7.43(d,J＝7.9Hz,3H),7.33(d,J＝2.5Hz,1H),7.21(d,J＝8.0Hz,2H),6.97(d,J＝8.3Hz,1H),6.78(t,J＝7.5Hz,1H),3.76(s,3H)；13C NMR(101MHz,Chloroform-d)δ195.19,162.56,161.05,135.97,132.52,131.86,131.82,130.83,130.75,126.55,124.16,121.79,120.58,120.36,118.63,118.15,51.86.HRMS(ESI):m/z calcd.for[C19H14BrNNaO4,M+Na]+:421.9998；found:421.9998.
实施例4：
化合物3d的制备
步骤：
准确称取橙酮衍生物1c(25.2mg,0.1mmol)和醋酸铜(2.15mg,0.02mmol)置于装有搅拌子的10mL反应试管中，加入1mL甲苯溶解，然后在25℃下加入异氰基乙酸甲酯2a(19.80mg,0.2mmol)，滴加完成后25℃下搅拌反应。TLC监测直到原料1c反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3d 3.5mg，收率10％。
白色固体，熔点65-67℃，Rf＝0.2(石油醚:乙酸乙酯＝5:1)。1H NMR(400MHz,Chloroform-d)δ11.93(s,1H),9.68(br,1H),7.64(dd,J＝7.9,1.3Hz,1H),7.40(t,J＝7.8Hz,1H),7.29(dd,J＝9.7,6.0Hz,3H),6.96(d,J＝8.3Hz,1H),6.84(d,J＝8.6Hz,2H),6.76(t,J＝7.6Hz,1H),3.79(s,3H),3.76(s,3H)；13C NMR(101MHz,Chloroform-d)δ195.79,162.53,161.30,158.97,135.78,132.77,132.00,131.43,126.54,124.95,124.22,120.47,120.23,118.55,117.97,113.11,55.13,51.73.HRMS(ESI):m/z calcd.for[C20H17NNaO5,M+Na]+:374.0999；found:374.0998.
实施例5：
化合物3e的制备
步骤：
准确称取橙酮衍生物1d(25.7mg,0.1mmol)和三乙胺(3.0mg,0.03mmol)置于装有搅拌子的10mL反应试管中，加入1mL乙醚溶解，然后在25℃下加入异氰基乙酸甲酯2a(11.88mg,0.12mmol)，滴加完成后25℃下搅拌反应。TLC监测直到原料1d反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3e 1.8mg，收率5％。
白色固体，熔点57-59℃(石油醚:乙酸乙酯＝5:1)。1H NMR(400MHz,Chloroform-d)δ11.80(s,1H),9.69(br,1H),7.64(d,J＝8.0Hz,1H),7.42(t,J＝7.8Hz,1H),7.36–7.33(m,2H),7.27–7.18(m,3H),6.96(d,J＝8.4Hz,1H),6.79(t,J＝7.6Hz,1H),3.76(s,3H)；13CNMR(101MHz,Chloroform-d)δ195.00,162.56,160.96,135.93,134.67,133.33,132.45,130.41,130.27,128.73,128.45,127.58,126.39,124.30,120.78,120.33,118.57,118.13,51.89.HRMS(ESI):m/z calcd.for[C19H14ClNNaO4,M+Na]+:378.0504；found:378.0500.
实施例6：
化合物3f的制备
步骤：
准确称取橙酮衍生物1e(25.2mg,0.1mmol)和碳酸钾(2.8mg,0.02mmol)置于装有搅拌子的10mL反应试管中，加入1mL甲醇溶解，然后在25℃下加入异氰基乙酸甲酯2a(11.88mg,0.12mmol)，滴加完成后25℃下搅拌反应。TLC监测直到原料1e反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3f 22.8mg，收率65％。
白色固体，熔点50-52℃，Rf＝0.2(石油醚:乙酸乙酯＝4:1)。1H NMR(400MHz,Chloroform-d)δ11.89(s,1H),9.77(br,1H),7.62(dd,J＝7.9,1.5Hz,1H),7.41–7.37(m,1H),7.30(d,J＝3.2Hz,1H),7.20(t,J＝7.9Hz,1H),6.95–6.89(m,3H),6.82–6.80(m,1H),6.74(t,J＝7.6Hz,1H),3.75(s,3H),3.74(s,3H)；13C NMR(101MHz,Chloroform-d)δ195.61,162.46,161.21,158.80,135.80,134.08,132.66,131.73,128.52,126.21,124.46,122.81,120.44,120.39,118.50,117.94,115.97,113.11,55.17,51.78.HRMS(ESI):m/z calcd.for[C20H17NNaO5,M+Na]+:374.0999；found:374.1001.
实施例7：
化合物3g的制备
步骤：
准确称取橙酮衍生物1f(25.7mg,0.1mmol)和氢氧化钠(0.8mg,0.02mmol)置于装有搅拌子的10mL反应试管中，加入1mL甲醇溶解，然后在25℃下加入异氰基乙酸甲酯2a(11.88mg,0.12mmol)，滴加完成后25℃下搅拌反应。TLC监测直到原料1f反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3g 34.9mg，收率98％。
白色固体，熔点163-165℃，Rf＝0.2(石油醚:乙酸乙酯＝5:1)。1H NMR(400MHz,Chloroform-d)δ11.67(s,1H),9.67(br,1H),7.72(d,J＝7.6Hz,1H),7.38(dd,J＝22.9,14.9Hz,4H),7.25(s,2H),6.95(d,J＝8.3Hz,1H),6.80(t,J＝7.4Hz,1H),3.72(s,3H)；13CNMR(101MHz,Chloroform-d)δ194.62,162.32,161.02,135.64,133.67,132.54,132.44,131.98,129.04,128.90,128.48,126.40,126.05,124.59,121.50,120.25,118.53,117.99,51.87.HRMS(ESI):m/zcalcd.for[C19H14ClNNaO4,M+Na]+:378.0504；found:378.0501.
实施例8：
化合物3h的制备
步骤：
准确称取橙酮衍生物1g(23.6mg,0.1mmol)和氢氧化钠(0.8mg,0.02mmol)置于装有搅拌子的10mL反应试管中，加入1mL甲醇溶解，然后在25℃下加入异氰基乙酸甲酯2a(11.88mg,0.12mmol)，滴加完成后25℃下搅拌反应。TLC监测直到原料1g反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3h 32.9mg，收率98％。
白色固体，熔点65-66℃，Rf＝0.2(石油醚:乙酸乙酯＝5:1)。1H NMR(400MHz,Chloroform-d)δ11.75(s,1H),9.61(br,1H),7.70(d,J＝7.5Hz,1H),7.40(dd,J＝15.7,8.0Hz,2H),7.17(d,J＝17.6Hz,4H),6.94(d,J＝8.1Hz,1H),6.81(t,J＝7.3Hz,1H),3.68(s,3H),2.13(s,3H)；13C NMR(101MHz,Chloroform-d)δ194.73,162.37,161.27,136.58,135.58,133.08,132.28,131.50,130.02,129.38,127.61,126.67,124.97,124.36,121.08,120.43,118.47,118.07,51.78,20.19.HRMS(ESI):m/z calcd.for[C20H17NNaO4,M+Na]+:358.1050；found:358.1051.
实施例9：
化合物3i的制备
步骤：
准确称取橙酮衍生物1h(27.2mg,0.1mmol)和氢氧化钠(0.8mg,0.02mmol)置于装有搅拌子的10mL反应试管中，加入1mL甲醇溶解，然后在25℃下加入异氰基乙酸甲酯2a(11.88mg,0.12mmol)，滴加完成后25℃下搅拌反应。TLC监测直到原料1h反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3i 36.4mg，收率98％。
白色固体，熔点57-59℃，Rf＝0.2(石油醚:乙酸乙酯＝5:1)。1H NMR(400MHz,Chloroform-d)δ11.62(s,1H),9.94(br,1H),7.82(t,J＝8.8Hz,2H),7.70(t,J＝8.7Hz,2H),7.44(dd,J＝16.1,6.6Hz,4H),7.33(dd,J＝21.2,12.7Hz,2H),6.87(d,J＝8.2Hz,1H),6.68(t,J＝7.5Hz,1H),3.51(s,3H)；13C NMR(101MHz,Chloroform-d)δ194.81,162.19,161.29,135.55,133.24,132.56,132.25,131.23,129.69,128.28,128.00,127.94,126.62,125.89,125.45,125.41,125.39,124.88,121.99,120.36,118.35,117.89,51.70.HRMS(ESI):m/z calcd.for[C23H17NNaO4,M+Na]+:394.1050；found:394.1047.
实施例10：
化合物3j的制备
步骤：
准确称取橙酮衍生物1i(27.2mg,0.1mmol)和氢氧化钠(0.8mg,0.02mmol)置于装有搅拌子的10mL反应试管中，加入1mL甲醇溶解，然后在25℃下加入异氰基乙酸甲酯2a(11.88mg,0.12mmol)，滴加完成后25℃下搅拌反应。TLC监测直到原料1i反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3j 36.4mg，收率98％。
白色固体，熔点63-64℃，Rf＝0.2(石油醚:乙酸乙酯＝5:1)。1H NMR(400MHz,Chloroform-d)δ11.85(s,1H),9.71(br,1H),7.79(dd,J＝13.7,4.6Hz,4H),7.71(dd,J＝7.9,1.1Hz,1H),7.48–7.43(m,3H),7.38(dd,J＝13.4,6.1Hz,2H),6.94(d,J＝8.3Hz,1H),6.76(t,J＝7.6Hz,1H),3.72(s,3H)；13C NMR(101MHz,Chloroform-d)δ195.41,162.55,161.27,135.80,132.94,132.63,132.60,132.03,130.36,129.17,128.40,128.10,127.65,126.95,126.48,125.96,125.88,124.51,120.76,120.47,118.52,118.05,51.79.HRMS(ESI):m/z calcd.for[C23H17NNaO4,M+Na]+:394.1050；found:394.1049.
实施例11：
化合物3k的制备
步骤：
准确称取橙酮衍生物1j(33.0mg,0.1mmol)和氢氧化钠(0.8mg,0.02mmol)置于装有搅拌子的10mL反应试管中，加入1mL甲醇溶解，然后在25℃下加入异氰基乙酸甲酯2a(11.88mg,0.12mmol)，滴加完成后25℃下搅拌反应。TLC监测直到原料1j反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3k 40.3mg，收率94％。
白色固体，熔点58-59℃，Rf＝0.5(石油醚:乙酸乙酯＝5:1)。M.P..1H NMR(400MHz,Chloroform-d)δ12.41(s,1H),9.49(br,1H),7.63(dd,J＝7.9,1.2Hz,1H),7.45(dd,J＝11.3,4.2Hz,1H),7.11(s,1H),7.02(d,J＝8.3Hz,1H),6.79(t,J＝7.6Hz,1H),4.74–4.73(m,2H),4.20–4.19(m,2H),3.94(s,5H),3.89(s,3H)；13C NMR(101MHz,Chloroform-d)δ197.06,162.97,160.75,136.18,133.16,129.73,125.17,125.03,120.68,120.46,118.66,118.19,71.76,69.33,68.07,51.72.HRMS(ESI):m/z calcd.for[C23H19FeNNaO4,M+Na]+:452.0556；found:452.0557.
实施例12：
化合物3l的制备
步骤：
准确称取橙酮衍生物1k(22.8mg,0.1mmol)和氢氧化钠(0.8mg,0.02mmol)置于装有搅拌子的10mL反应试管中，加入1mL甲醇溶解，然后在25℃下加入异氰基乙酸甲酯2a(11.88mg,0.12mmol)，滴加完成后25℃下搅拌反应。TLC监测直到原料1k反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3l 32.4mg，收率99％。
白色固体，熔点107-109℃，Rf＝0.2(石油醚:乙酸乙酯＝5:1)。1H NMR(400MHz,Chloroform-d)δ11.92(s,1H),9.65(br,1H),7.58(dd,J＝8.0,1.4Hz,1H),7.41–7.37(m,1H),7.31–7.27(m,2H),7.07(dd,J＝3.5,1.0Hz,1H),6.96–6.94(m,2H),6.76–6.72(m,1H),3.81(s,3H)；13C NMR(101MHz,Chloroform-d)δ195.65,162.53,160.87,135.91,132.86,132.61,129.06,126.57,126.49,125.67,125.26,123.55,120.97,120.41,118.54,117.96,51.87.HRMS(ESI):m/z calcd.for[C17H13NNaO4S,M+Na]+:350.0457；found:350.0458.
实施例13：
化合物3m的制备
步骤：
准确称取橙酮衍生物1l(21.2mg,0.1mmol)和氢氧化钠(0.8mg,0.02mmol)置于装有搅拌子的10mL反应试管中，加入1mL甲醇溶解，然后在25℃下加入异氰基乙酸甲酯2a(11.88mg,0.12mmol)，滴加完成后25℃下搅拌反应。TLC监测直到原料1l反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3m 30.8mg，收率99％。
白色固体，熔点48-50℃，Rf＝0.2(石油醚:乙酸乙酯＝5:1)。1H NMR(400MHz,Chloroform-d)δ12.04(s,1H),9.55(br,1H),7.50(dd,J＝8.0,1.5Hz,1H),7.42–7.38(m,1H),7.29(d,J＝3.2Hz,1H),7.25–7.24(m,1H),6.98(d,J＝8.4Hz,1H),6.85(d,J＝3.4Hz,1H),6.73–6.70(m,1H),6.39(dd,J＝3.3,1.8Hz,1H),3.89(s,3H)；13C NMR(101MHz,Chloroform-d)δ196.11,162.46,160.53,145.69,142.28,135.78,132.40,125.24,124.00,120.45,120.31,119.57,118.57,117.93,111.42,111.22,51.94.HRMS(ESI):m/zcalcd.for[C17H13NNaO5,M+Na]+:334.0686；found:334.0685.
实施例14：
化合物3n的制备
步骤：
准确称取橙酮衍生物1m(26.1mg,0.1mmol)和氢氧化钠(0.8mg,0.02mmol)置于装有搅拌子的10mL反应试管中，加入1mL甲醇溶解，然后在25℃下加入异氰基乙酸甲酯2a(11.88mg,0.12mmol)，滴加完成后25℃下搅拌反应。TLC监测直到原料1m反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3n 34.2mg，收率95％。
橙黄色固体，熔点232-233℃，Rf＝0.3(石油醚:乙酸乙酯＝2:1)。1H NMR(400MHz,DMSO-d6)δ12.45(br,1H),11.37(br,1H),11.04(s,1H),7.56(dd,J＝7.8,1.4Hz,1H),7.39(s,1H),7.37–7.36(m,2H),7.30(d,J＝8.1Hz,1H),7.11(d,J＝7.9Hz,1H),6.98(t,J＝7.5Hz,1H),6.82(t,J＝7.1Hz,2H),6.74(t,J＝7.5Hz,1H),3.60(s,3H)；13C NMR(101MHz,DMSO-d6)δ194.74,161.11,160.33,136.11,134.92,132.27,129.13,127.56,126.44,124.58,124.13,122.77,120.93,120.56,119.44,119.05,118.97,117.43,111.77,107.40,51.49.HRMS(ESI):m/z calcd.for[C21H16N2NaO4,M+Na]+:383.1002；found:383.1005.
实施例15：
化合物3o的制备
步骤：
准确称取橙酮衍生物1n(22.3mg,0.1mmol)和氢氧化钠(0.8mg,0.02mmol)置于装有搅拌子的10mL反应试管中，加入1mL甲醇溶解，然后在25℃下加入异氰基乙酸甲酯2a(11.88mg,0.12mmol)，滴加完成后25℃下搅拌反应。TLC监测直到原料1n反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3o 26.1mg，收率81％。
白色固体，熔点88-90℃，Rf＝0.1(石油醚:乙酸乙酯＝1:1)。1H NMR(400MHz,Chloroform-d)δ11.77(s,1H),10.56(br,1H),8.59(s,1H),8.53(d,J＝4.3Hz,1H),7.73(d,J＝7.8Hz,1H),7.67(d,J＝7.9Hz,1H),7.41(dd,J＝8.5,5.5Hz,2H),7.28(dd,J＝7.7,5.0Hz,1H),6.95(d,J＝8.3Hz,1H),6.79(t,J＝7.6Hz,1H),3.72(s,3H)；13C NMR(101MHz,Chloroform-d)δ194.77,162.59,160.90,150.34,147.88,138.06,135.97,132.38,129.46,127.96,126.99,124.18,122.55,121.36,120.26,118.66,118.21,51.87.HRMS(ESI):m/zcalcd.for[C18H14N2NaO4,M+Na]+:345.0846；found:345.0843.
实施例16：
化合物3p的制备
步骤：
准确称取橙酮衍生物1o(26.6mg,0.1mmol)和氢氧化钠(0.8mg,0.02mmol)置于装有搅拌子的10mL反应试管中，加入1mL甲醇溶解，然后在25℃下加入异氰基乙酸甲酯2a(11.88mg,0.12mmol)，滴加完成后25℃下搅拌反应。TLC监测直到原料1o反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3p 31.8mg，收率99％。
白色固体，熔点172-173℃，Rf＝0.2(石油醚:乙酸乙酯＝4:1)。1H NMR(400MHz,Chloroform-d)δ12.82(s,1H),9.60(br,1H),7.34–7.27(m,6H),6.95(s,1H),6.42(s,1H),5.90(s,2H),3.75(s,3H)；13C NMR(101MHz,Chloroform-d)δ193.88,162.39,161.23,154.05,140.01,132.87,131.63,130.21,127.59,127.42,125.12,124.61,120.07,112.90,109.52,101.76,98.48,51.71.HRMS(ESI):m/z calcd.for[C20H15NNaO6,M+Na]+:388.0792；found:388.0787.
实施例17：
化合物3q的制备
步骤：
准确称取橙酮衍生物1p(25.2mg,0.1mmol)和氢氧化钠(0.8mg,0.02mmol)置于装有搅拌子的10mL反应试管中，加入1mL甲醇溶解，然后在25℃下加入异氰基乙酸甲酯2a(11.88mg,0.12mmol)，滴加完成后25℃下搅拌反应。TLC监测直到原料1p反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3q 32.7mg，收率93％。
白色固体，熔点61-63℃，Rf＝0.3(石油醚:乙酸乙酯＝5:1)。1H NMR(400MHz,Chloroform-d)δ12.59(s,1H),9.84(br,1H),7.53(d,J＝8.9Hz,1H),7.35–7.24(m,6H),6.41(d,J＝2.3Hz,1H),6.28(dd,J＝8.9,2.4Hz,1H),3.80(s,3H),3.74(s,3H)；13C NMR(101MHz,Chloroform-d)δ194.27,165.81,165.58,161.33,134.50,132.94,131.79,130.23,127.56,127.42,125.62,124.55,120.10,114.37,107.06,100.78,55.5551.70.HRMS(ESI):m/z calcd.for[C20H17NNaO5,M+Na]+:374.0999；found:374.1000.
实施例18：
化合物3r的制备
步骤：
准确称取橙酮衍生物1q(30.1mg,0.1mmol)和氢氧化钠(0.8mg,0.02mmol)置于装有搅拌子的10mL反应试管中，加入1mL甲醇溶解，然后在25℃下加入异氰基乙酸甲酯2a(11.88mg,0.12mmol)，滴加完成后25℃下搅拌反应。TLC监测直到原料1q反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3r 39.2mg，收率98％。
白色固体，熔点64-66℃，Rf＝0.2(石油醚:乙酸乙酯＝5:1)。1H NMR(400MHz,Chloroform-d)δ12.00(s,1H),9.67(br,1H),7.44(d,J＝8.5Hz,1H),7.32–7.30(m,6H),7.12(d,J＝1.9Hz,1H),6.85(dd,J＝8.5,1.9Hz,1H),3.74(s,3H)；13C NMR(101MHz,Chloroform-d)δ194.95,162.95,161.12,133.57,132.57,131.88,130.18,130.14,127.64,127.62,126.11,124.29,121.95,121.16,120.51,119.17,51.81.HRMS(ESI):m/zcalcd.for[C19H14BrNNaO4,M+Na]+:421.9998；found:421.9996.
实施例18：
化合物3s的制备
步骤：
准确称取橙酮衍生物1r(23.6mg,0.1mmol)和氢氧化钠(0.8mg,0.02mmol)置于装有搅拌子的10mL反应试管中，加入1mL甲醇溶解，然后在25℃下加入异氰基乙酸甲酯2a(11.88mg,0.12mmol)，滴加完成后25℃下搅拌反应。TLC监测直到原料1r反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3s 30.2mg，收率90％。
白色固体，熔点62-63℃，Rf＝0.2(石油醚:乙酸乙酯＝2:1)。1H NMR(400MHz,Chloroform-d)δ9.71(br,1H),8.60(s,1H),7.30–7.20(m,6H),7.09(t,J＝7.9Hz,1H),6.70(d,J＝8.2Hz,1H),6.52(d,J＝7.5Hz,1H),3.70(s,3H),2.14(s,3H)；13C NMR(101MHz,Chloroform-d)δ194.86,161.25,157.45,137.66,132.54,132.29,131.42,130.00,127.56,127.47,127.38,127.28,124.99,122.59,120.77,114.51,51.71,21.79；HRMS(ESI):m/zcalcd.for[C20H17NNaO4,M+Na]+:358.1050；found:358.1053.
实施例19：
化合物3t的制备
步骤：
准确称取橙酮衍生物1s(50.8mg,0.1mmol)和氢氧化钠(0.8mg,0.02mmol)置于装有搅拌子的10mL反应试管中，加入1mL甲醇溶解，然后在25℃下加入异氰基乙酸甲酯2a(11.88mg,0.12mmol)，滴加完成后25℃下搅拌反应。TLC监测直到原料1s反应完全，直接将反应液浓缩，用柱层析法分离纯化，得到产物3t 30.2mg，收率90％。
无色油状物，Rf＝0.2(石油醚:乙酸乙酯＝5:1)。1H NMR(400MHz,Chloroform-d)δ12.56(s,1H),9.61(br,2H),7.52(d,J＝8.9Hz,1H),7.35–7.26(m,6H),6.38(d,J＝2.3Hz,1H),6.27(dd,J＝8.9,2.4Hz,1H),3.95(t,J＝6.5Hz,2H),3.74(s,3H),3.60(t,J＝6.6Hz,2H),1.78–1.72(m,2H),1.52–1.49(m,2H),1.42(dt,J＝14.2,7.2Hz,2H),1.34–1.26(m,10H),0.90(s,9H),0.05(s,6H)；13C NMR(101MHz,Chloroform-d)δ194.13,165.61,165.44,161.23,134.40,132.89,131.72,130.21,127.55,127.42,125.30,124.70,120.09,114.19,107.45,101.22,68.36,63.32,51.67,32.86,29.53,29.46,29.40,29.29,28.93,25.98,25.91,25.78,18.37,-5.26.HRMS(ESI):m/z calcd.for[C35H49NNaO6Si,M+Na]+:630.3221；found:630.3218.
在此说明的是，以上实施例仅用以说明本发明的技术方案而非限制，尽管通过参照本发明的优选实施例已经对本发明进行了描述，但本领域的普通技术人员应当理解，可以在形式上和细节上对其做出各种各样的改变，而不偏离本发明的精神和范围。
Claims (5)
1.一种氢氧化钠催化的多取代吡咯合成方法，如下式所示：
其特征在于，式中R1为甲基，C1-10烷氧基，溴取代基；Ar为苯基，甲基取代苯基，甲氧基取代苯基，卤原子取代苯基，萘基，二茂铁基，噻吩基，呋喃基，吲哚基，吡啶基；EWG为甲酯，对甲苯磺酰基；反应催化剂为氧化银，醋酸银，氧化亚铜，醋酸铜，三乙胺，碳酸钾，氢氧化钠；反应溶剂为二氯甲烷，四氢呋喃，氯仿，甲苯，乙醚，甲醇。
2.如权利要求1所述的合成方法，其特征在于，反应温度为0℃—40℃。
3.如权利要求1所述的合成方法，其特征在于，反应试剂组合物中催化剂与橙酮化合物的摩尔百分比为：5mol％—30mol％。
4.如权利要求1所述的合成方法，其特征在于，反应试剂组合物中橙酮化合物与异氰化合物的摩尔比为：橙酮化合物：异氰化合物＝1:1—1:2。
5.如权利要求1所述的合成方法，其特征在于，橙酮化合物浓度为：0.05mol/L—0.2mol/L。
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