CN116947854A - Preparation method of imidazo [2,1-a ] isoquinoline compound - Google Patents
Preparation method of imidazo [2,1-a ] isoquinoline compound Download PDFInfo
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- CN116947854A CN116947854A CN202310923421.0A CN202310923421A CN116947854A CN 116947854 A CN116947854 A CN 116947854A CN 202310923421 A CN202310923421 A CN 202310923421A CN 116947854 A CN116947854 A CN 116947854A
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- Prior art keywords
- hydrochloride
- ethyl acetate
- imidazo
- isoquinolinium
- reaction
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- -1 imidazo [2,1-a ] isoquinoline compound Chemical class 0.000 title claims abstract description 103
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000003054 catalyst Substances 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000003495 polar organic solvent Substances 0.000 claims abstract description 11
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 11
- 238000005286 illumination Methods 0.000 claims abstract description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 102
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 54
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 24
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 229910052707 ruthenium Inorganic materials 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- LZCZIHQBSCVGRD-UHFFFAOYSA-N benzenecarboximidamide;hydron;chloride Chemical compound [Cl-].NC(=[NH2+])C1=CC=CC=C1 LZCZIHQBSCVGRD-UHFFFAOYSA-N 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 10
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000003446 ligand 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 8
- 239000002585 base Substances 0.000 claims description 7
- SEACYXSIPDVVMV-UHFFFAOYSA-L eosin Y Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C([O-])=C(Br)C=C21 SEACYXSIPDVVMV-UHFFFAOYSA-L 0.000 claims description 7
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 7
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 6
- 150000004696 coordination complex Chemical class 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 5
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 5
- 235000011009 potassium phosphates Nutrition 0.000 claims description 5
- RXAOGVQDNBYURA-UHFFFAOYSA-N (4-chlorobenzenecarboximidoyl)azanium;chloride Chemical compound Cl.NC(=N)C1=CC=C(Cl)C=C1 RXAOGVQDNBYURA-UHFFFAOYSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- KVMVAFKWEWLDPU-UHFFFAOYSA-N 2-chlorobenzenecarboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=CC=CC=C1Cl KVMVAFKWEWLDPU-UHFFFAOYSA-N 0.000 claims description 4
- VCDJPGDATCBGMF-UHFFFAOYSA-N 2-fluorobenzenecarboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=CC=CC=C1F VCDJPGDATCBGMF-UHFFFAOYSA-N 0.000 claims description 4
- XIZFRYIWRFNILW-UHFFFAOYSA-N 3-bromobenzenecarboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=CC=CC(Br)=C1 XIZFRYIWRFNILW-UHFFFAOYSA-N 0.000 claims description 4
- YDBIEYOHXLUHLK-UHFFFAOYSA-N 3-methoxybenzenecarboximidamide;hydrochloride Chemical compound Cl.COC1=CC=CC(C(N)=N)=C1 YDBIEYOHXLUHLK-UHFFFAOYSA-N 0.000 claims description 4
- DKIFMADLURULQV-UHFFFAOYSA-N 4-(trifluoromethyl)benzenecarboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=CC=C(C(F)(F)F)C=C1 DKIFMADLURULQV-UHFFFAOYSA-N 0.000 claims description 4
- IMTHEBSPHHMJOJ-UHFFFAOYSA-N 4-bromobenzenecarboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=CC=C(Br)C=C1 IMTHEBSPHHMJOJ-UHFFFAOYSA-N 0.000 claims description 4
- JQDATBKJKUWNGA-UHFFFAOYSA-N 4-fluorobenzenecarboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=CC=C(F)C=C1 JQDATBKJKUWNGA-UHFFFAOYSA-N 0.000 claims description 4
- AJOSDIDPIBJFAI-UHFFFAOYSA-N 4-methoxybenzenecarboximidamide;hydrochloride Chemical compound Cl.COC1=CC=C(C(N)=N)C=C1 AJOSDIDPIBJFAI-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 4
- QEAXZIMXYPAZAX-UHFFFAOYSA-N [amino-(3-methylphenyl)methylidene]azanium;chloride Chemical compound [Cl-].CC1=CC=CC(C(N)=[NH2+])=C1 QEAXZIMXYPAZAX-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- SIIJRCRHAIMFNT-UHFFFAOYSA-N cyclopropanamine;hydrochloride Chemical compound Cl.NC1CC1 SIIJRCRHAIMFNT-UHFFFAOYSA-N 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- WCQOBLXWLRDEQA-UHFFFAOYSA-N ethanimidamide;hydrochloride Chemical compound Cl.CC(N)=N WCQOBLXWLRDEQA-UHFFFAOYSA-N 0.000 claims description 4
- MTDUPZAXNYELOU-UHFFFAOYSA-N hydron;4-methylbenzenecarboximidamide;chloride Chemical compound Cl.CC1=CC=C(C(N)=N)C=C1 MTDUPZAXNYELOU-UHFFFAOYSA-N 0.000 claims description 4
- 229910052741 iridium Inorganic materials 0.000 claims description 4
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 claims description 4
- 229940043267 rhodamine b Drugs 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- USHZYUPZIKQYMI-UHFFFAOYSA-N 2-methylbenzenecarboximidamide;hydrochloride Chemical compound Cl.CC1=CC=CC=C1C(N)=N USHZYUPZIKQYMI-UHFFFAOYSA-N 0.000 claims description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical class N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 3
- 229930187593 rose bengal Natural products 0.000 claims description 3
- AZJPTIGZZTZIDR-UHFFFAOYSA-L rose bengal Chemical compound [K+].[K+].[O-]C(=O)C1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1C1=C2C=C(I)C(=O)C(I)=C2OC2=C(I)C([O-])=C(I)C=C21 AZJPTIGZZTZIDR-UHFFFAOYSA-L 0.000 claims description 3
- 229940081623 rose bengal Drugs 0.000 claims description 3
- STRXNPAVPKGJQR-UHFFFAOYSA-N rose bengal A Natural products O1C(=O)C(C(=CC=C2Cl)Cl)=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C(I)C(O)=C(I)C=C21 STRXNPAVPKGJQR-UHFFFAOYSA-N 0.000 claims description 3
- MKJPBOVLAZADQJ-UHFFFAOYSA-N [amino(pyridin-3-yl)methylidene]azanium;chloride Chemical compound Cl.NC(=N)C1=CC=CN=C1 MKJPBOVLAZADQJ-UHFFFAOYSA-N 0.000 claims description 2
- IONKMFGAXKCLMI-UHFFFAOYSA-N [amino(pyridin-4-yl)methylidene]azanium;chloride Chemical compound [Cl-].NC(=[NH2+])C1=CC=NC=C1 IONKMFGAXKCLMI-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 70
- 239000007800 oxidant agent Substances 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000001590 oxidative effect Effects 0.000 abstract description 5
- 238000005580 one pot reaction Methods 0.000 abstract description 4
- 125000000524 functional group Chemical group 0.000 abstract description 3
- 125000001424 substituent group Chemical group 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 77
- 238000004440 column chromatography Methods 0.000 description 55
- BYLPZVAKOZYZPH-UHFFFAOYSA-N imidazo[2,1-a]isoquinoline Chemical compound C1=CC=C2C3=NC=CN3C=CC2=C1 BYLPZVAKOZYZPH-UHFFFAOYSA-N 0.000 description 37
- 239000003208 petroleum Substances 0.000 description 30
- 239000003480 eluent Substances 0.000 description 28
- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 27
- 238000005481 NMR spectroscopy Methods 0.000 description 27
- 238000012512 characterization method Methods 0.000 description 27
- 239000011941 photocatalyst Substances 0.000 description 23
- 238000003756 stirring Methods 0.000 description 23
- 239000000203 mixture Substances 0.000 description 9
- 150000002537 isoquinolines Chemical class 0.000 description 8
- 238000000746 purification Methods 0.000 description 7
- 238000000926 separation method Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- NMVVJCLUYUWBSZ-UHFFFAOYSA-N aminomethylideneazanium;chloride Chemical compound Cl.NC=N NMVVJCLUYUWBSZ-UHFFFAOYSA-N 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000003222 pyridines Chemical class 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical class NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 2
- GQSHFYGCUBUDCI-UHFFFAOYSA-N 3h-imidazo[4,5-h]isoquinoline Chemical class C1=CN=CC2=C(NC=N3)C3=CC=C21 GQSHFYGCUBUDCI-UHFFFAOYSA-N 0.000 description 2
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- KVKBSQGRHHMWRC-UHFFFAOYSA-N 1-(1h-imidazol-2-yl)isoquinoline Chemical class C1=CNC(C=2C3=CC=CC=C3C=CN=2)=N1 KVKBSQGRHHMWRC-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- RGHQKFQZGLKBCF-UHFFFAOYSA-N 2-bromoethyl acetate Chemical group CC(=O)OCCBr RGHQKFQZGLKBCF-UHFFFAOYSA-N 0.000 description 1
- BPOHHIFTIFSTNA-UHFFFAOYSA-N 4-(4-aminophenyl)-3-methylaniline;hydrochloride Chemical compound Cl.CC1=CC(N)=CC=C1C1=CC=C(N)C=C1 BPOHHIFTIFSTNA-UHFFFAOYSA-N 0.000 description 1
- 241001477352 Bengalia Species 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- 102000015617 Janus Kinases Human genes 0.000 description 1
- 108010024121 Janus Kinases Proteins 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- 150000001345 alkine derivatives Chemical group 0.000 description 1
- 238000010719 annulation reaction Methods 0.000 description 1
- NHYXMAKLBXBVEO-UHFFFAOYSA-N bromomethyl acetate Chemical compound CC(=O)OCBr NHYXMAKLBXBVEO-UHFFFAOYSA-N 0.000 description 1
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 125000004857 imidazopyridinyl group Chemical class N1C(=NC2=C1C=CC=N2)* 0.000 description 1
- OSILBMSORKFRTB-UHFFFAOYSA-N isoquinolin-1-amine Chemical compound C1=CC=C2C(N)=NC=CC2=C1 OSILBMSORKFRTB-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- INYDZJIFKXAPNM-UHFFFAOYSA-N pyridin-3-ylmethanamine;hydrochloride Chemical compound Cl.NCC1=CC=CN=C1 INYDZJIFKXAPNM-UHFFFAOYSA-N 0.000 description 1
- OOSYLIFOSMQOJA-UHFFFAOYSA-N pyridin-4-ylmethanamine;hydrochloride Chemical compound Cl.NCC1=CC=NC=C1 OOSYLIFOSMQOJA-UHFFFAOYSA-N 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an imidazo [2,1-a ] isoquinoline compound. The invention mixes amidine hydrochloride, isoquinoline onium salt, catalyst, alkali and polar organic solvent, and carries out cyclization reaction under illumination condition to obtain the imidazo [2,1-a ] isoquinoline compound. The preparation method has the advantages of mild and easily controlled conditions, high reaction efficiency, economical steps, no oxidant, good tolerance of functional groups (substrates substituted by different substituents such as halogen, trifluoromethyl, nitro or cyano groups can be tolerated in the reaction process and corresponding products are generated), and the prepared target product has higher purity of 98.5-99.9 percent and has higher market popularization value. Compared with the multi-step synthetic reaction, the method can obtain the target product through one-step reaction, and has the advantage of step economy.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an imidazo [2,1-a ] isoquinoline compound.
Background
Imidazo [2,1-a ] isoquinoline is an important compound and has wide application value. Imidazo [2,1-a ] isoquinoline is one of the most important frameworks in medicines, and has various biological activities such as reducing progesterone concentration, inhibiting cytochrome P1A1 activity, resisting colon cancer activity, inhibiting Janus kinase and the like. The construction of imidazo [2,1-a ] isoquinoline backbones has attracted great attention in recent years due to its good biological activity and synthetic applications.
At present, the method for synthesizing imidazo [2,1-a ] isoquinoline mainly comprises the following steps: (a) Huang et al (Huang, et al, "One-Pot Synthesis of Imidazolyl Isoquinolines under a PalladiumCatalyzed C-H activity/Annulation (CHAA) reaction," Synthesis: international Journal of Methods in Synthetic Organic Chemistry (2017)) synthesized imidazoisoquinolines by palladium-catalyzed imidazole/benzimidazole and terminal alkyne One-pot methods with the aid of microwaves;
(a)Huang，et al.Synthesis,2016，49(06)：1335-1341.
(b) Xu et al (Liu Y, lu L, zhou H, et al, chemodingent synthosis of N- (pyridin-2-yl) amides and 3-bromooimidazo [1,2-a ] pyridines from alpha-bromo ketones and-amipyridines [ J ]. RSC adv.2019,9 (59): 34671-34676.DOI:10.1039/C9RA 06724H) starting with alpha-bromoketone and 1-aminoisoquinoline in toluene with I2 and TBHP as catalyst and oxidant, respectively, synthesizing N- (pyridin-2-yl) amide and 3-bromoimidazo [2,1-a ] pyridine compounds;
(b)Xu，et al.，RSC Advances，2019，9(59)：34671-34676.
(c) Lee et al (Um, kyusik, lee, et al Synthesis of Imidazopyridines via Copper-Catalyzed, formAza- [3+2]Cycloaddition Reaction of Pyridine Derivatives with alpha-Diazo Oxime Ethers [ J ] Journal of Organic Chemistry, 2017) synthesized imidazoisoquinolines by the Aza- [3+2] cycloaddition reaction of isoquinolines and alpha-diazoxime ether in trifluoroethanol under the catalysis of copper;
(c)Lee，et al.The Journal of Organic Chemistry，2017，82(19)：10209-10218.
however, the above-mentioned methods have limitations such as severe reaction conditions, use of an oxidizing agent, difficulty in obtaining raw materials, cumbersome synthesis steps, and limited substrate range.
Disclosure of Invention
The invention aims to provide a preparation method of imidazo [2,1-a ] isoquinoline compounds, which has the advantages of mild reaction conditions, easiness in control, high reaction efficiency, economical steps, no use of an oxidant and good tolerance of functional groups.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of imidazo [2,1-a ] isoquinoline compounds, which comprises the following steps:
mixing amidine hydrochloride, isoquinoline onium salt, a catalyst, alkali and a polar organic solvent, and performing cyclization reaction under the illumination condition to obtain the imidazo [2,1-a ] isoquinoline compound;
the amidine hydrochloride has a structure shown in a formula I:
the R is 1 Phenyl, alkyl, cycloalkyl, alkyl-substituted phenyl, alkoxy-substituted phenyl, halogen-substituted phenylA trifluoromethyl substituted phenyl or an azacyclyl;
the isoquinolinium salt has a structure shown in formula II:
the imidazo [2,1-a ] isoquinoline compound has a structure shown in a formula III:
in the formula II and the formula III, R 2 Is nitro, halogen, alkyl or alkoxy; the R is 3 Is an ester group or a cyano group.
Preferably, the amidine hydrochloride comprises benzamidine hydrochloride, 4-fluoro-benzamidine hydrochloride, 4-chloro-benzamidine hydrochloride, 4-bromo-benzamidine hydrochloride, 4-trifluoromethyl-benzamidine hydrochloride, 4-methyl-benzamidine hydrochloride, 4-methoxy-benzamidine hydrochloride, 3-bromo-benzamidine hydrochloride, 3-methyl-benzamidine hydrochloride, 3-methoxy-benzamidine hydrochloride, 2-fluoro-benzamidine hydrochloride, 2-chloro-benzamidine hydrochloride, 2-methyl-benzamidine hydrochloride, 3-pyridylcarbamidine hydrochloride, 4-pyridylcarbamidine hydrochloride, formamidine hydrochloride, acetamidine hydrochloride or cyclopropylamide hydrochloride;
the isoquinolinium salt includes isoquinolinium ethyl acetate bromide, 5-nitroisoquinolinium ethyl acetate bromide, 5-methoxyisoquinolinium ethyl acetate bromide, 6-bromoisoquinolinium ethyl acetate bromide, 6-methylisoquinolinium ethyl acetate bromide, 6-methoxyisoquinolinium ethyl acetate bromide, 7-methoxyisoquinolinium ethyl acetate bromide, 4-bromoisoquinolinium ethyl acetate bromide, isoquinolinium methyl acetate bromide, or isoquinolinium acetonitrile bromide.
Preferably, the catalyst comprises a metal complex or an organic dye;
the metal complex comprises a ruthenium ligand compound or an iridium ligand compound; the organic dye comprises eosin Y, rose bengal or rhodamine B.
Preferably, the base comprises an inorganic base and/or an organic base;
the inorganic base comprises potassium carbonate, potassium phosphate, potassium hydroxide or cesium carbonate;
the organic base comprises potassium tert-butoxide, 1, 8-diazabicyclo [5.4.0] undec-7-ene or triethylene diamine.
Preferably, the polar organic solvent comprises one or more of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, toluene, ethyl acetate, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran and dichloromethane.
Preferably, the molar ratio of the amidine hydrochloride to the isoquinolinium salt is 1.5-3: 1, a step of;
the molar ratio of the isoquinolinium salt to the catalyst is 1:0.001 to 0.003;
the molar ratio of the isoquinolinium salt to the base is 1:1 to 6;
the dosage ratio of the polar organic solvent to the quinolinium salt is 1L:0.1 to 0.2mol.
Preferably, the wavelength of the light source of the illumination is 200-1000 nm.
Preferably, the temperature of the cyclization reaction is 15-60 ℃ and the time is 6-24 h.
The invention provides an imidazo [2,1-a ]]The preparation method of the isoquinoline compound comprises the following steps: mixing amidine hydrochloride, isoquinoline onium salt, catalyst, alkali and polar organic solvent, and cyclizing under illumination to obtain imidazo [2,1-a ]]Isoquinoline compounds; the amidine hydrochloride has a structure shown in a formula I: the R is 1 Phenyl, alkyl, cycloalkyl, alkyl-substituted phenyl, alkoxy-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl or an azacyclyl; the isoquinolinium salt has a structure shown in formula II: the R is 2 Is nitro, halogen, alkyl or alkoxy; the R is 3 Is an ester group or a cyano group; the imidazo [2,1-a ]]The isoquinoline compound has a structure shown in a formula III.
The preparation method provided by the invention has the advantages of mild conditions (reaction can be performed at room temperature), easiness in control, high reaction efficiency, economical steps, no oxidant, good functional group tolerance (substrates substituted by different substituents such as halogen, trifluoromethyl, nitro or cyano can be tolerated in the reaction process, corresponding products are generated), and the like, and the prepared imidazo [2,1-a ] isoquinoline compound has higher purity, the purity is 98.5-99.9%, and the market popularization value is higher. Compared with the multi-step synthetic reaction, the method can obtain the target product through one-step reaction, and has the advantage of step economy. The preparation method provided by the invention provides the required energy for the cyclization reaction by utilizing illumination, and has the advantages of simple method, readily available raw materials and low cost.
Detailed Description
The invention provides a preparation method of imidazo [2,1-a ] isoquinoline compounds, which comprises the following steps:
mixing amidine hydrochloride, isoquinoline onium salt, a catalyst, alkali and a polar organic solvent, and performing cyclization reaction under the illumination condition to obtain the imidazo [2,1-a ] isoquinoline compound;
the amidine hydrochloride has a structure shown in a formula I:
the R is 1 Phenyl, alkyl, cycloalkyl, alkyl-substituted phenyl, alkoxy-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl or an azacyclyl;
the isoquinolinium salt has a structure shown in formula II:
the imidazo [2,1-a ] isoquinoline compound has a structure shown in a formula III:
in the formula II and the formula III, R 2 Is nitro, halogen, alkyl or alkoxy; the R is 3 Is an ester group or a cyano group.
In the present invention, all the preparation materials are commercially available products well known to those skilled in the art unless specified otherwise.
In the present invention, the amidine hydrochloride preferably includes benzamidine hydrochloride, 4-fluoro-benzamidine hydrochloride, 4-chloro-benzamidine hydrochloride, 4-bromo-benzamidine hydrochloride, 4-trifluoromethyl-benzamidine hydrochloride, 4-methyl-benzamidine hydrochloride, 4-methoxy-benzamidine hydrochloride, 3-bromo-benzamidine hydrochloride, 3-methyl-benzamidine hydrochloride, 3-methoxy-benzamidine hydrochloride, 2-fluoro-benzamidine hydrochloride, 2-chloro-benzamidine hydrochloride, 2-methyl-benzamidine hydrochloride, 3-pyridylformamidine hydrochloride, 4-pyridylformamidine hydrochloride, formamidine hydrochloride, acetamidine hydrochloride or cyclopropylamide hydrochloride.
In the present invention, the isoquinolinium salt preferably includes isoquinolinium ethyl acetate bromide, 5-nitroisoquinolinium ethyl acetate bromide, 5-methoxyisoquinolinium ethyl acetate bromide, 6-bromoisoquinolinium ethyl acetate bromide, 6-methylisoquinolinium ethyl acetate bromide, 6-methoxyisoquinolinium ethyl acetate bromide, 7-methoxyisoquinolinium ethyl acetate bromide, 4-bromoisoquinolinium ethyl acetate bromide, isoquinolinium methyl acetate bromide, or isoquinolinium acetonitrile bromide.
In the present invention, the isoquinolinium ethyl acetate bromide preferably has the structural formulaThe structural formula of the 5-nitroisoquinolinium ethyl acetate bromide is preferably +.>The structural formula of the 5-methoxyisoquinolinium ethyl acetate bromide is preferably +.>The structural formula of the 6-bromoisoquinolinium ethyl acetate bromide is preferably +.>The 6-methylisoquinolinium ethyl acetate bromideThe structural formula of the 6-methoxyisoquinolinium ethyl acetate bromide is preferablyThe structural formula of the 7-methoxyisoquinolinium ethyl acetate bromide is preferablyThe structural formula of the 4-bromoisoquinolinium ethyl acetate bromide is preferably +.>The structural formula of the isoquinolinium methyl acetate bromide is preferably +.>The isoquinolinium acetonitrile bromide is preferably of the formula +.>
In the present invention, the isoquinolinium salt is preferably prepared; the preparation method preferably comprises the following steps:
and mixing isoquinoline or isoquinoline derivatives, a brominating reagent and anhydrous diethyl ether, and carrying out bromination reaction to obtain the isoquinolinium salt.
In the present invention, the isoquinoline derivatives preferably include:
in the present invention, the brominating reagent preferably comprises ethyl bromoacetate, methyl bromoacetate or bromoacetonitrile. In the present invention, the molar ratio of isoquinoline or isoquinoline derivative to brominating agent is preferably 1:1, a step of; the ratio of the isoquinoline or isoquinoline derivative to the anhydrous diethyl ether is preferably 10mmol:2.5mL. In the present invention, the temperature of the bromination reaction is preferably room temperature, and the time is preferably 24 hours. After the bromination reaction, the present invention also preferably includes filtering the obtained product, washing with anhydrous diethyl ether and drying. The process of filtering, washing and drying is not particularly limited, and may be known to those skilled in the art.
In the present invention, the catalyst preferably includes a metal complex or an organic dye. In the present invention, the metal complex preferably includes a ruthenium ligand compound or an iridium ligand compound; the ruthenium ligand compound is preferably Ru (bpy) 3 Cl 2 The method comprises the steps of carrying out a first treatment on the surface of the The iridium ligand compound is preferably fac-Ir (ppy) 3 Or Ir [ dF (CF) 3 )ppy] 2 (dtbpy)PF 6 . In the present invention, the organic dye preferably includes eosin Y, rose bengal or rhodamine B.
In the present invention, the base preferably includes an inorganic base and/or an organic base; the inorganic base preferably comprises potassium carbonate, potassium phosphate, potassium hydroxide or cesium carbonate; the organic base preferably comprises potassium tert-butoxide, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or triethylenediamine (DBACO). The present invention utilizes a base to provide an alkaline environment.
In the present invention, the polar organic solvent preferably includes one or more of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, toluene, ethyl acetate, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran, and dichloromethane.
In the present invention, the molar ratio of the amidine hydrochloride to the isoquinolinium salt is preferably 1.5 to 3:1, more preferably 2.0 to 2.5:1. in the present invention, the molar ratio of the isoquinolinium salt to the catalyst is preferably 1:0.001 to 0.003, more preferably 1:0.002. in the present invention, the molar ratio of the isoquinolinium salt to the base is 1:1 to 6, more preferably 1:2 to 5, more preferably 1:3 to 4. In the present invention, the ratio of the polar organic solvent to the quinolinium salt used is preferably 1L:0.1 to 0.2mol.
In the present invention, the light source wavelength of the illumination is preferably 200 to 1000nm, more preferably 465 to 800nm. In the present invention, the temperature of the cyclization reaction is 15 to 60 ℃, more preferably 25 to 55 ℃, still more preferably 40 to 50 ℃; the time is preferably 6 to 24 hours, more preferably 12 to 20 hours. In the present invention, the cyclization reaction is preferably carried out under stirring. The stirring rate is not particularly limited in the present invention, and the reaction is ensured to proceed smoothly according to a process well known in the art.
In the invention, the required energy is provided for the cyclization reaction by adopting illumination, and the imidazo [2,1-a ] isoquinoline compound target product can be obtained by selecting the raw materials, so that the whole reaction does not need metal and oxidant, and the conditions are mild and easy to control. In addition, the preparation method of the imidazo [2,1-a ] isoquinoline compound provided by the invention has good adaptability to raw materials, and can be used for preparing imidazo [2,1-a ] isoquinoline compounds with different substituents.
After the cyclization reaction, the obtained product system is preferably purified by column chromatography, and eluent used by the column chromatography is preferably a mixed solvent of petroleum ether and ethyl acetate; the volume ratio of petroleum ether to ethyl acetate in the mixed solvent is preferably 1-30: 1, more preferably 3 to 10:1, more preferably 5:1. the specific process of the column chromatography is not particularly limited in the present invention, and may be performed in a manner well known to those skilled in the art. According to the invention, petroleum ether and ethyl acetate are used as eluent for purification, so that the target compound with higher purity can be obtained.
In the present invention, the purity of the imidazo [2,1-a ] isoquinoline compound is preferably 98.5 to 99.9%.
In the present invention, the imidazo [2,1-a ] isoquinoline compounds preferably include:
in order to further illustrate the present invention, the following examples are provided to illustrate the preparation of imidazo [2,1-a ] isoquinoline compounds of the present invention in detail, but they are not to be construed as limiting the scope of the present invention.
In the following examples:
the catalyst is added in a molar percentage relative to the isoquinolinium salt;
the preparation method of the isoquinolinium salt comprises the following steps: isoquinoline or isoquinoline derivative (10 mmol) is dissolved in 2.5mL of anhydrous diethyl ether at room temperature, a brominating reagent (10 mmol) is added, and after 24 hours of reaction, filtration, washing with the anhydrous diethyl ether and drying are carried out to obtain isoquinoline onium salt; the brominating reagent is bromoethyl acetate, bromomethyl acetate or bromoacetonitrile.
Example 1
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
into the reaction tube were charged 0.3mmol benzamidine hydrochloride, 0.1mmol isoquinolinium ethyl acetate bromide, 1mol% Ru (bpy) 3 Cl 2 Photocatalyst, 0.2mmol cesium carbonate, 0.3mmol DBU and 1.0mL acetonitrile, under the irradiation of 465nm blue light source, stirring and reacting for 12h at 30 ℃, separating and purifying by column chromatography after the reaction is finished, wherein the volume ratio of petroleum ether to ethyl acetate in the column chromatography eluent is 5:1 to give imidazo [2,1-a ]]Isoquinoline compounds with yield of 78% and purity of 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.12(d,J＝7.5Hz,1H),8.77(dd,J＝6.1,3.2Hz,1H),7.82(dd,J＝7.9,1.6Hz,2H),7.73(dd,J＝5.9,3.3Hz,1H),7.65-7.61(m,2H),7.49-7.41(m,3H),7.20(d,J＝7.5Hz,1H),4.31(q,J＝7.1Hz,2H),1.23(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ161.2,151.8,145.0,134.7,130.4,130.3,129.5,128.5,128.2,127.6,126.7,124.4,124.3,123.0,114.2,113.7,60.6,14.0；MS(EI,70eV)m/z 316,287,271,244,231,216,189,140,128,116,101,89,77。
example 2
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
into the reaction tube were charged 0.3mmol of 4-fluorobenzamidine hydrochloride, 0.1mmol of isoquinolinium ethyl acetate bromide, 1mol% Ru (bpy) 3 Cl 2 The photocatalyst, 0.2mmol of potassium carbonate, 0.3mmol of DABCO and 1.0mL of acetonitrile are stirred for reaction for 12 hours at 15 ℃ under the irradiation of 465nm of blue light source, after the reaction is finished, the mixture is separated and purified by column chromatography, and the volume ratio of petroleum ether to ethyl acetate in column chromatography eluent is 5:1, obtaining a purified target product with the yield of 47% and the purity of 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.14(d,J＝7.5Hz,1H),8.76(dd,J＝6.0,3.4Hz,1H),7.84-7.76(m,3H),7.68-7.65(m,2H),7.26(d,J＝7.5Hz,1H),7.15(t,J＝8.8Hz,2H),4.33(q,J＝7.1Hz,2H),1.26(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ161.1,150.8,145.1,132.2,132.1,130.5,129.6,128.3,126.8,124.4,124.3,122.9,114.7,114.5,114.3,113.6,60.7,14.0；MS(EI,70eV)m/z 334,305,289,262,249,241,234,214,153,140,128,114,101,89；HRMS(ESI)m/z[M+H] + Calcd for C 20 H 16 N 2 O 2 F 335.1190,found 335.1202。
example 3
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
into a reaction tube were charged 0.2mmol of 4-chlorobenzamidine hydrochloride, 0.1mmol of isoquinolinium ethyl acetate bromide, 2mol% Ru (bpy) 3 Cl 2 The photocatalyst, 0.2mmol of potassium hydroxide, 0.3mmol of DBU and 1.0mL of dichloromethane are stirred for reaction for 12 hours at 25 ℃ under the irradiation of a 550nm green light source, and after the reaction is finished, the mixture is separated and purified by column chromatography, wherein the volume ratio of petroleum ether to ethyl acetate in a column chromatography eluent is 10:1, obtaining a purified target product, wherein the yield is 35%, and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.12(d,J＝7.5Hz,1H),8.76-8.74(m,1H),7.77(t,J＝5.5Hz,3H),7.66(dd,J＝5.7,3.6Hz,2H),7.43(d,J＝8.6Hz,2H),7.25(d,J＝7.5Hz,1H),4.34(q,J＝7.1Hz,2H),1.27(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ161.0,150.5,145.1,134.6,133.1,131.7,130.4,129.6,128.3,127.8,126.7,124.4,124.3,122.9,114.4,113.7,60.7,14.1；MS(EI,70eV)m/z 350,321,305,286,278,270,242,229,214,188,161,143,128,114,101,89；HRMS(ESI)m/z[M+H] + Calcd for C 20 H 16 N 2 O 2 Cl351.0895,found 351.0910。
example 4
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
to a reaction tube were added 0.2mmol of 4-bromobenzamidine hydrochloride, 0.1mmol of isoquinolinium ethyl acetate bromide, 1mol% of eosin Y photocatalyst, 0.2mmol of cesium hydroxide, 0.3mmol of DBU and 1.0mL of methylene chloride, and the mixture was stirred at 25℃for 12 hours under irradiation of a 520nm yellow light source, and after the reaction, the mixture was separated and purified by column chromatography, wherein the volume ratio of petroleum ether to ethyl acetate in the column chromatography eluent was 10:1, obtaining a purified target product, wherein the yield is 35%, and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.11(d,J＝7.5Hz,1H),8.78-8.73(m,1H),7.77-7.74(m,1H),7.73-7.70(m,2H),7.68-7.64(m,2H),7.59(d,J＝8.5Hz,2H),7.24(d,J＝7.5Hz,1H),4.34(q,J＝7.1Hz,2H),1.27(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ160.9,150.5,145.2,133.6,132.0,130.8,130.4,129.6,128.3,126.8,126.7,124.4,124.3,122.9,114.4,113.7,60.7,14.1；MS(EI,70eV)m/z 394,366,348,322,316,286,270,242,229,214,193,166,128；HRMS(ESI)m/z[M+H] + Calcd for C 20 H 16 N 2 O 2 Br 395.0390,found 395.0407。
example 5
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
0.3mmol of 4-trifluoromethyl benzamidine hydrochloride, 0.1mmol of isoquinolinium ethyl acetate bromide, 1mol% of rose-red light catalyst of Bengalia, 0.2mmol of potassium phosphate, 0.3mmol of DBU and 1.0mL of dichloromethane are added into a reaction tube, and under the irradiation of 465nm of blue light source, stirring is carried out at 25 ℃ for 12 hours, after the reaction is finished, separation and purification are carried out through column chromatography, and the volume ratio of petroleum ether to ethyl acetate in a column chromatography eluent is 20:1, obtaining a purified target product, wherein the yield is 40% and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.13(d,J＝7.5Hz,1H),8.77-8.74(m,1H),7.95(d,J＝8.1Hz,2H),7.77(dt,J＝7.2,3.8Hz,1H),7.72(d,J＝8.2Hz,2H),7.70-7.65(m,2H),7.26(d,J＝7.5Hz,1H),4.34(q,J＝7.1Hz,2H),1.24(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ160.8,150.1,145.2,138.3,130.7,130.4,129.7,128.4,126.8,124.5(q,J＝4.0Hz),124.3,124.2,122.9,114.6,114.1,60.8,14.0；MS(EI,70eV)m/z 384,365,355,339,312,291,270,242,214,168,128,114,101；HRMS(ESI)m/z[M+H] + Calcd for C 21 H 16 N 2 O 2 F 3 385.1158,found 385.1175。
example 6
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
into the reaction tube were charged 0.3mmol of 4-methylbenzamidine hydrochloride, 0.1mmol of isoquinolinium ethyl acetate bromide, 1mol% Ru (bpy) 3 Cl 2 Photocatalyst, 0.2mmol potassium phosphate, 0.3mmol DB U and 1.0mL tetrahydrofuran, under the irradiation of 465nm blue light source, stirring and reacting for 24 hours at 35 ℃, separating and purifying by column chromatography after the reaction is finished, wherein the volume ratio of petroleum ether and ethyl acetate in the column chromatography eluent is 5:1, obtaining a purified target product, wherein the yield is 36% and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.14(d,J＝7.5Hz,1H),8.80-8.77(m,1H),7.79-7.76(m,1H),7.74(d,J＝7.5Hz,2H),7.68-7.63(m,2H),7.27(d,J＝7.5Hz,2H),7.24(d,J＝7.5Hz,1H),4.34(q,J＝7.1Hz,2H),2.43(s,3H),1.27(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ161.3,151.9,145.1,138.4,131.7,130.4,130.2,129.4,128.4,128.2,126.7,124.43,124.38,123.0,114.0,113.5,60.6,21.4,14.1；MS(EI,70eV)m/z 330,301,285,270,258,242,230,214,202,150,128,101,89,77；HRMS(ESI)m/z[M+H] + Calcd for C 21 H 19 N 2 O 2 331.1441,found 331.1455。
example 7
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
0.3 mmole of 4-methoxybenzamidine hydrochloride, 0.1 mmole of isoquinolinium ethyl acetate bromide, 1 mole percent of rhodamine B photocatalyst, 0.2 mmole of cesium carbonate, 0.3 mmole of DBU and 1.0mL of acetonitrile are added into a reaction tube, and under the irradiation of 465nm of blue light source, stirring is carried out for 12 hours at 30 ℃, after the reaction is finished, separation and purification are carried out through column chromatography, and the volume ratio of petroleum ether to ethyl acetate in column chromatography eluent is 5:1, obtaining a purified target product, wherein the yield is 48%, and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.13(d,J＝7.5Hz,1H),8.78-8.76(m,1H),7.80(d,J＝7.5Hz,2H),7.77-7.74(m,1H),7.66-7.64(m,2H),7.22(d,J＝7.5Hz,1H),6.99(d,J＝8.8Hz,2H),4.34(q,J＝7.1Hz,2H),3.88(s,3H),1.28(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ161.3,160.0,151.7,145.0,131.7,130.4,129.4,128.2,127.11,127.05,126.7,124.4,123.0,114.0,113.3,113.1,60.5,55.4,14.1；MS(EI,70eV)m/z 346,317,301,274,259,230,219,176,159,128；HRMS(ESI)m/z[M+H] + Calcd for C 21 H 19 N 2 O 3 347.1390,found 347.1408。
example 8
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
0.3mmol of 3-bromobenzamidine hydrochloride, 0.1mmol of isoquinolinium ethyl acetate bromide, 1mol% of rose-red light catalyst of Bengali, 0.2mmol of cesium carbonate, 0.3mmol of DBU and 1.0mL of acetonitrile are added into a reaction tube, and under the irradiation of 465nm of blue light source, stirring is carried out at 30 ℃ for 12 hours, after the reaction is finished, separation and purification are carried out through column chromatography, and the volume ratio of petroleum ether to ethyl acetate in a column chromatography eluent is 5:1, obtaining a purified target product, wherein the yield is 35%, and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.14(d,J＝7.5Hz,1H),8.77-8.75(m,1H),7.99(s,1H),7.78(d,J＝7.5Hz,2H),7.69-7.66(m,2H),7.56(d,J＝7.9Hz,1H),7.32(d,J＝7.9Hz,1H),7.26(d,J＝7.5Hz,1H),4.34(q,J＝7.1Hz,2H),1.28(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ160.9,149.9,145.1,136.7,133.3,131.4,130.5,129.7,129.2,128.9,128.4,126.8,124.4,124.2,122.9,121.5,114.5,113.9,60.8,14.0；MS(EI,70eV)m/z 394,367,349,322,315,286,270,242,229,214,202,189,168,143,128,114,101,89；HRMS(ESI)m/z[M+H] + Calcd for C 20 H 16 N 2 O 2 Br 395.0390,found 395.0405。
example 9
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
into the reaction tube were charged 0.3mmol of 3-methylbenzamidine hydrochloride, 0.1mmol of isoquinolinium ethyl acetate bromide, 1mol% Ru (bpy) 3 Cl 2 Photocatalyst, 0.2mmol cesium carbonate, 0.3mmol DBU and 1.0mL 1, 2-dichloroethane, under irradiation of 465nm blue light source, stirring at 30deg.C for reaction for 12 hr, separating and purifying by column chromatography after reactionThe volume ratio of petroleum ether to ethyl acetate in the chromatographic eluent is 5:1, obtaining a purified target product, wherein the yield is 46%, and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.14(d,J＝7.5Hz,1H),8.79(t,J＝7.5Hz,1H),7.77-7.75(m,1H),7.66-7.64(m,3H),7.61(d,J＝7.7Hz,1H),7.34(t,J＝7.6Hz,1H),7.24-7.22(m,2H),4.32(q,J＝7.1Hz,2H),2.44(s,3H),1.24(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ161.3,151.9,145.0,137.1,134.5,130.8,130.4,129.5,129.3,128.2,127.5,126.7,124.4,124.3,123.0,114.2,113.6,60.5,21.5,14.0；MS(EI,70eV)m/z 330,301,285,271,258,242,230,214,202,151,140,128,121,101,89,77；HRMS(ESI)m/z[M+H] + Calcd for C 21 H 19 N 2 O 2 331.1441,found 331.1457。
example 10
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
into the reaction tube were charged 0.3mmol of 3-methoxybenzamidine hydrochloride, 0.1mmol of isoquinolinium ethyl acetate bromide, 1mol% Ru (bpy) 3 Cl 2 Photocatalyst, 0.2mmol cesium carbonate, 0.3mmol DBU and 1.0mL ethyl acetate, stirring and reacting for 12h at 30 ℃ under the irradiation of 465nm blue light source, separating and purifying by column chromatography after the reaction is finished, wherein the volume ratio of petroleum ether to ethyl acetate in the column chromatography eluent is 5:1, obtaining a purified target product, wherein the yield is 42% and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.14(d,J＝7.5Hz,1H),8.79(d,J＝7.5Hz,1H),7.81-7.73(m,1H),7.78-7.64(m,2H),7.41-7.34(m,3H),7.24(d,J＝7.5Hz,1H),7.00-6.97(m,1H),4.33(q,J＝7.1Hz,2H),3.88(s,3H),1.24(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ161.2,159.1,151.6,145.0,135.9,130.4,129.5,128.6,128.3,126.7,124.4,124.3,123.0,122.9,115.6,114.5,114.2,113.8,60.6,55.4,14.0；MS(EI,70eV)m/z 346,317,301,288,274,258,244,229,218,202,176,159,128,101,89,77；HRMS(ESI)m/z[M+H] + Calcd for C 21 H 19 N 2 O 3 347.1390,found 347.1407。
example 11
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
into the reaction tube were charged 0.3mmol of 2-fluorobenzamidine hydrochloride, 0.1mmol of isoquinolinium ethyl acetate bromide, 1mol% Ru (bpy) 3 Cl 2 Photocatalyst, 0.2mmol cesium carbonate, 0.3mmol DBU and 1.0mL dichloromethane, stirring and reacting for 24 hours at 30 ℃ under the irradiation of 465nm blue light source, separating and purifying by column chromatography after the reaction is finished, wherein the volume ratio of petroleum ether to ethyl acetate in the column chromatography eluent is 20:1, obtaining a purified target product, wherein the yield is 60% and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.13(d,J＝7.5Hz,1H),8.78-8.75(m,1H),7.79-7.76(m,1H),7.70-7.65(m,3H),7.45-7.40(m,1H),7.29-7.25(m,2H),7.15(t,J＝8.1Hz,1H),4.27(q,J＝7.1Hz,2H),1.14(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ161.0,145.2,131.7(d,J＝3.0Hz),130.4,130.34,130.30,129.5,128.3,126.8,124.3,124.0,123.84,123.80,123.0,115.3,115.1,114.5,60.6,13.7；MS(EI,70eV)m/z 334,305,289,286,262,249,229,214,140,128,114,89；HRMS(ESI)m/z[M+H H 2 O] + Calcd for C 20 H 18 N 2 O 3 F 353.1296,found 353.1281。
example 12
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
0.3mmol of 2-chlorobenzamidine hydrochloride, 0.1mmol of isoquinolinium ethyl acetate bromide, 1mol% of rose-red light catalyst of Bengali, 0.2mmol of cesium carbonate, 0.3mmol of DBU and 1.0mLN, N-dimethylacetamide are added into a reaction tube, and under the irradiation of 465nm blue light source, stirring is carried out at 30 ℃ for 24 hours, after the reaction is finished, separation and purification are carried out through column chromatography, and the volume ratio of petroleum ether to ethyl acetate in column chromatography eluent is 15:1, obtaining a purified target product with 61% of yield and 99.9% of purity;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.14(d,J＝7.4Hz,1H),8.78-8.74(m,1H),7.81-7.77(m,1H),7.69-7.64(m,2H),7.55-7.52(m,1H),7.50-7.46(m,1H),7.39-7.34(m,2H),7.29(d,J＝7.5Hz,1H),4.21(q,J＝7.1Hz,2H),1.05(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ160.9,148.6,145.0,134.7,134.2,131.5,130.4,129.61,129.55,129.1,128.4,126.8,126.4,124.3,124.0,123.0,115.3,114.6,60.5,13.6；MS(EI,70eV)m/z 350,315,305,187,278,270,242,229,214,114,101,89,77；HRMS(ESI)m/z[M+H] + Calcd for C 20 H 16 N 2 O 2 Cl 351.0895,found 351.0915。
example 13
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
0.2mmol of 2-methylbenzidine hydrochloride, 0.1mmol of isoquinolinium ethyl acetate bromide, 1mol% of rose-red light catalyst of Bengalte, 0.2mmol of cesium carbonate, 0.3mmol of DBU and 1.0mL of dimethyl sulfoxide are added into a reaction tube, and under the irradiation of 365nm ultraviolet light source, stirring is carried out at 30 ℃ for 24 hours, after the reaction is finished, separation and purification are carried out through column chromatography, wherein the volume ratio of petroleum ether to ethyl acetate in a column chromatography eluent is 5:1, obtaining a purified target product, wherein the yield is 78% and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.16(d,J＝7.5Hz,1H),8.80-8.75(m,1H),7.80-7.76(m,1H),7.68-7.64(m,2H),7.37(d,J＝7.5Hz,1H),7.34-7.23(m,4H),4.18(q,J＝7.1Hz,2H),2.26(s,3H),1.02(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ161.1,151.9,145.1,136.9,135.0,130.4,130.1,129.6,129.5,128.34,128.29,126.8,125.1,124.4,124.2,123.0,114.7,114.2,60.3,20.1,13.7；MS(EI,70eV)m/z 330,301,285,257,242,230,151,128,115,101,89,77；HRMS(ESI)m/z[M+H] + Calcd for C 21 H 19 N 2 O 2 331.1441,found 331.1461。
example 14
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
into the reaction tube were charged 0.3mmol of 3-pyridylmethylamide hydrochloride, 0.1mmol of isoquinolinium ethyl acetate bromide, 1mol% Ru (bpy) 3 Cl 2 Photocatalyst, 0.4mmol cesium carbonate, 0.3mmol DBU and 1.0 mM LN, N-dimethylformamide, stirring and reacting for 24 hours at 30 ℃ under the irradiation of 465nm blue light source, separating and purifying by column chromatography after the reaction is finished, wherein the volume ratio of petroleum ether and ethyl acetate in the column chromatography eluent is 5:1, obtaining a purified target product, wherein the yield is 25%, and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.14(d,J＝7.5Hz,1H),9.03(d,J＝1.4Hz,1H),8.76-8.72(m,1H),8.65(dd,J＝4.9,1.7Hz,1H),8.14(dt,J＝7.9,1.9Hz,1H),7.79-7.76(m,1H),7.69-7.65(m,2H),7.40(dd,J＝8.7,4.9Hz,1H),7.27(d,J＝7.6Hz,1H),4.32(q,J＝7.2Hz,2H),1.23(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ160.7,150.9,149.1,148.2,145.4,137.6,130.8,130.4,129.8,128.5,126.8,124.3,124.2,122.9,122.7,114.7,114.2,60.9,14.0；MS(EI,70eV)m/z 317,288,272,260,245,232,219,205,193,164,140,128,101,89,77；HRMS(ESI)m/z[M+H] + Calcd for C 19 H 16 N 3 O 2 318.1237,found 318.1255。
example 15
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
into the reaction tube were charged 0.3mmol of 4-pyridylmethylamide hydrochloride, 0.1mmol of isoquinolinium ethyl acetate bromide, 1mol% Ru (bpy) 3 Cl 2 Photocatalyst, 0.2mmol cesium carbonate, 0.6mmol DBU and 1.0mL toluene, stirring and reacting for 6 hours at 30 ℃ under the irradiation of 465nm blue light source, separating and purifying by column chromatography after the reaction is finished, wherein the volume ratio of petroleum ether to ethyl acetate in the column chromatography eluent is 5:1, obtaining a purified target product, wherein the yield is 24%, and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.12(d,J＝7.5Hz,1H),8.76-8.71(m,3H),7.79-7.75(m,3H),7.70-7.66(m,2H),7.28(d,J＝7.5Hz,1H),4.34(q,J＝7.1Hz,2H),1.26(t,J＝7.2Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ160.6,149.1,148.5,145.4,142.7,130.4,129.9,128.6,126.9,124.9,124.3,124.1,122.9,114.9,61.0,14.0；MS(EI,70eV)m/z 317,288,272,245,217,205,190,164,128,101,89,77；HRMS(ESI)m/z[M+H] + Calcd for C 19 H 16 N 3 O 2 318.1237,found 318.1256。
example 16
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
into the reaction tube were charged 0.3mmol of formamidine hydrochloride, 0.1mmol of isoquinolinium ethyl acetate bromide, 1mol% Ru (bpy) 3 Cl 2 Photocatalyst, 0.2mmol cesium carbonate, 0.3mmol DBU and 1.0mL acetonitrile, under the irradiation of 465nm blue light source, stirring and reacting for 24 hours at 30 ℃, separating and purifying by column chromatography after the reaction is finished, wherein the volume ratio of petroleum ether and ethyl acetate in the column chromatography eluent is 5:1, obtaining a purified target product, wherein the yield is 71% and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.04(d,J＝7.4Hz,1H),8.70-8.67(m,1H),8.25(s,1H),7.77(dd,J＝6.3,2.9Hz,1H),7.68-7.63(m,2H),7.25(d,J＝7.4Hz,1H),4.43(q,J＝7.1Hz,2H),1.43(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ160.8,146.3,139.5,130.2,129.5,128.4,126.9,124.1,123.7,123.2,117.8,114.5,60.6,14.5；MS(EI,70eV)m/z 240,225,212,195,183,168,155,140,128,116,101,89；HRMS(ESI)m/z[M+H] + Calcd for C 14 H 13 N 2 O 2 241.0972,found 241.0985。
example 17
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
into the reaction tube were charged 0.3mmol of acetamidine hydrochloride, 0.1mmol of isoquinolinium ethyl acetate bromide, 1mol% Ru (bpy) 3 Cl 2 Photocatalyst, 0.2mmol cesium carbonate, 0.3mmol DBU and 1.0mL acetonitrile, under the irradiation of 465nm blue light source, stirring and reacting for 12h at 30 ℃, separating and purifying by column chromatography after the reaction is finished, wherein the volume ratio of petroleum ether to ethyl acetate in the column chromatography eluent is 5:1, obtaining a purified target product, wherein the yield is 67% and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.06(d,J＝7.4Hz,1H),8.68-8.66(m,1H),7.76-7.73(m,1H),7.66-7.61(m,2H),7.18(d,J＝7.5Hz,1H),4.44(q,J＝7.1Hz,2H),2.77(s,3H),1.45(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ161.5,150.7,144.7,130.4,129.3,128.1,126.7,124.2,124.1,122.5,113.7,100.0,60.4,16.5,14.5；MS(EI,70eV)m/z 254,239,226,209,197,182,169,155,140,128,114,101,77；HRMS(ESI)m/z[M+H] + Calcd for C 15 H 15 N 2 O 2 255.1128,found 255.1139。
example 18
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
into the reaction tube were charged 0.3mmol of cyclopropylamide hydrochloride, 0.1mmol of isoquinolinium ethyl acetate bromide, 1mol% Ru (bpy) 3 Cl 2 Photocatalyst, 0.2mmol cesium carbonate, 0.3mmol DBU and 1.0mL acetonitrile, under the irradiation of 465nm blue light source, stirring and reacting for 6h at 30 ℃, separating and purifying by column chromatography after the reaction is finished, wherein the volume ratio of petroleum ether to ethyl acetate in the column chromatography eluent is 5:1, obtaining a purified target product, wherein the yield is 63% and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.04(d,J＝7.5Hz,1H),8.63-8.59(m,1H),7.71-7.68(m,1H),7.61-7.57(m,2H),7.12(d,J＝7.5Hz,1H),4.47(q,J＝7.1Hz,2H),2.86-2.80(m,1H),1.46(t,J＝7.1Hz,3H),1.30-1.26(m,2H),1.11-1.04(m,2H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ161.9,156.3,145.0,130.4,129.1,127.8,126.5,124.3,124.2,122.7,114.2,113.1,60.3,14.5,10.1,9.6；MS(EI,70eV)m/z 280,251,235,223,207,195,182,168,128,101；HRMS(ESI)m/z[M+H] + Calcd for C 17 H 17 N 2 O 2 281.1285,found 281.1299。
example 19
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
into the reaction tube were charged 0.3mmol of benzamidine hydrochloride, 0.1mmol of 5-nitroisoquinolinium ethyl acetate bromide, 1mol% Ru (bpy) 3 Cl 2 Photocatalyst, 0.2mmol cesium carbonate, 0.3mmol DBU and 1.0mL acetonitrile, under the irradiation of 465nm blue light source, stirring and reacting for 10 hours at 30 ℃, separating and purifying by column chromatography after the reaction is finished, wherein the volume ratio of petroleum ether to ethyl acetate in the column chromatography eluent is 5:1, obtaining a purified target product, wherein the yield is 29%, and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.32(d,J＝8.0Hz,1H),9.14(d,J＝8.1Hz,1H),8.41(d,J＝7.9Hz,1H),8.07(d,J＝8.0Hz,1H),7.82(dd,J＝7.4,2.1Hz,2H),7.76(t,J＝8.0Hz,1H),7.50-7.45(m,3H),4.35(q,J＝7.1Hz,2H),1.25(t,J＝7.1,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ160.8,151.7,145.0,144.0,133.9,130.5,130.2,128.9,127.8,127.5,127.3,126.5,124.6,123.3,114.2,108.5,61.0,14.0；MS(EI,70eV)m/z 361,331,316,302,289,286,270,259,243,221,202,188,142,128,116,102,89；HRMS(ESI)m/z[M+H] + Calcd for C 20 H 16 N 3 O 4 362.1135,found 362.1152。
example 20
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
0.3mmol of benzamidine hydrochloride, 0.1mmol of 5-methoxyisoquinolinium ethyl acetate bromide, 1mol% of Ru (bpy) 3Cl2 photocatalyst, 0.2mmol of cesium carbonate, 0.3mmol of DBU and 1.0mL of acetonitrile are added into a reaction tube, and under the irradiation of a 465nm blue light source, stirring is carried out at 30 ℃ for 24 hours, after the reaction is finished, separation and purification are carried out through column chromatography, wherein the volume ratio of petroleum ether to ethyl acetate in a column chromatography eluent is 5:1, obtaining a purified target product, wherein the yield is 49% and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.12(d,J＝7.7Hz,1H),8.35(d,J＝8.2Hz,1H),7.81(dd,J＝7.9,1.6Hz,2H),7.66(d,J＝7.7Hz,1H),7.58(t,J＝8.1Hz,1H),7.48-7.40(m,3H),7.04(d,J＝7.9Hz,1H),4.32(q,J＝7.1Hz,2H),4.00(s,3H),1.23(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ161.2,154.9,151.9,144.8,134.7,130.3,128.8,128.5,127.6,124.0,123.5,121.6,116.3,113.6,108.59,108.55,60.6,55.8,14.0；MS(EI,70eV)m/z 346,317,301,286,274,258,242,231,204,176,159,129,101,89,77；HRMS(ESI)m/z[M+H] + Calcd for C 21 H 19 N 2 O 3 347.1390,found 347.1411。
example 21
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
into the reaction tube were charged 0.3mmol of benzamidine hydrochloride, 0.1mmol of 6-bromoisoquinolinium ethyl acetate bromide, 1mol% Ru (bpy) 3 Cl 2 Photocatalyst, 0.2mmol cesium carbonate, 0.3mmol DBU and 1.0mL acetonitrile, under the irradiation of 465nm blue light source, stirring and reacting for 24 hours at 30 ℃, separating and purifying by column chromatography after the reaction is finished, wherein the volume ratio of petroleum ether and ethyl acetate in the column chromatography eluent is 5:1, obtaining a purified target product, wherein the yield is 14% and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.15(d,J＝7.5Hz,1H),8.62(d,J＝8.7Hz,1H),7.92(d,J＝1.7Hz,1H),7.80(dd,J＝7.7,1.7Hz,2H),7.74(dd,J＝8.7,1.8Hz,1H),7.48-7.41(m,3H),7.13(d,J＝7.5Hz,1H),4.32(q,J＝7.1Hz,2H),1.23(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ161.1,152.0,144.6,134.4,131.7,131.5,130.2,129.1,128.7,127.7,126.1,125.5,123.9,121.6,113.9,113.0,60.7,14.0；MS(EI,70eV)m/z 394,367,349,322,315,309,287,270,242,214,205,188,139,127,89；HRMS(ESI)m/z[M+H] + Calcd for C 20 H 16 N 2 O 2 Br 395.0390,found 395.0414。
example 22
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
into the reaction tube were charged 0.3mmol of benzamidine hydrochloride, 0.1mmol of 6-methylisoquinolinium ethyl acetate bromide, 1mol% Ru (bpy) 3 Cl 2 Photocatalyst, 0.2mmol of potassium tert-butoxide, 0.3mmol of DBU and 1.0mL of acetonitrile, stirring and reacting for 24 hours at 30 ℃ under the irradiation of 465nm blue light source, separating and purifying by column chromatography after the reaction is finished, eluting by column chromatographyThe volume ratio of petroleum ether to ethyl acetate in the liquid is 5:1, obtaining a purified target product, wherein the yield is 45%, and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.11(d,J＝7.5Hz,1H),8.66(d,J＝8.3Hz,1H),7.81(dd,J＝7.9,1.6Hz,2H),7.55(s,1H),7.50-7.40(m,4H),7.17(d,J＝7.5Hz,1H),4.31(q,J＝7.1Hz,2H),2.54(s,3H),1.23(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ161.2,151.8,145.3,139.8,134.8,130.7,130.3,130.0,128.5,127.6,126.3,124.3,120.9,114.0,113.5,100.0,60.5,21.8,14.0；MS(EI,70eV)m/z 330,301,285,258,242,230,202,151,142,128,115,89,77；HRMS(ESI)m/z[M+H] + Calcd for C 21 H 19 N 2 O 2 331.1441,found 331.1455。
example 23
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
to the reaction tube were added 0.3mmol of benzamidine hydrochloride, 0.1mmol of 6-methoxyisoquinolinium ethyl acetate bromide, 1mol% of eosin Y photocatalyst, 0.2mmol of cesium carbonate, 0.3mmol of DBU and 1.0mL of acetonitrile, and the mixture was stirred at 30℃for 18 hours under irradiation of 465nm of blue light source, after the reaction, the mixture was separated and purified by column chromatography, wherein the volume ratio of petroleum ether and ethyl acetate in the column chromatography eluent was 5:1, obtaining a purified target product, wherein the yield is 35%, and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.12(d,J＝7.5Hz,1H),8.68(d,J＝8.9Hz,1H),7.80(dd,J＝7.9,1.6Hz,2H),7.47-7.42(m,3H),7.27(d,J＝7.5Hz,1H),7.17(d,J＝7.5Hz,1H),7.13(d,J＝7.4Hz,1H),4.31(q,J＝7.1Hz,2H),3.94(s,3H),1.22(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ161.3,160.7,152.0,145.4,134.7,132.3,130.3,128.5,127.6,126.2,124.9,118.5,117.2,113.8,113.1,107.3,60.5,55.5,14.0；MS(EI,70eV)m/z 346,317,301,274,259,232,214,176,158,115,89,77；HRMS(ESI)m/z[M+H] + Calcd for C 21 H 19 N 2 O 3 347.1390,found 347.1411。
example 24
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
to the reaction tube were added 0.15mmol of benzamidine hydrochloride, 0.1mmol of 7-methoxyisoquinolinium ethyl acetate bromide, 1mol% of eosin Y photocatalyst, 0.2mmol of cesium carbonate, 0.3mmol of DBU and 1.0mL of acetonitrile, and the mixture was stirred at 30℃for 18 hours under irradiation of 465nm of blue light source, after the reaction, the mixture was separated and purified by column chromatography, wherein the volume ratio of petroleum ether and ethyl acetate in the column chromatography eluent was 5:1, obtaining a purified target product, wherein the yield is 22%, and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.01(d,J＝7.4Hz,1H),8.08(s,1H),7.81(d,J＝6.5Hz,2H),7.64(d,J＝8.8Hz,1H),7.48-7.42(m,3H),7.24(dd,J＝8.8,2.5Hz,1H),7.15(d,J＝7.4Hz,1H),4.30(q,J＝7.1Hz,2H),3.96(s,3H),1.21(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ161.2,159.6,151.7,144.7,134.7,130.3,128.5,128.3,127.7,124.8,124.2,122.1,120.8,114.0,113.7,103.9,60.5,55.9,14.0；MS(EI,70eV)m/z 346,317,301,274,258,242,231,214,204,176,158,146,137,115,101,89；HRMS(ESI)m/z[M+H] + Calcd for C 21 H 19 N 2 O 3 347.1390,found 347.1410。
example 25
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
0.3mmol of benzamidine hydrochloride, 0.1mmol of 4-bromoisoquinolinium ethyl acetate bromide, 1mol% of eosin Y photocatalyst, 0.2mmol of cesium carbonate, 0.3mmol of DBU and 1.0mL of toluene are added into a reaction tube, and under the irradiation of a white light source, stirring is carried out at 60 ℃ for 24 hours, after the reaction is finished, the mixture is separated and purified by column chromatography, and the volume ratio of petroleum ether to ethyl acetate in column chromatography eluent is 5:1, obtaining a purified target product, wherein the yield is 11%, and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.49(s,1H),8.79(d,J＝7.5Hz,1H),8.12(d,J＝7.8Hz,1H),7.82-7.78(m,2H),7.77-7.70(m,2H),7.49-7.41(m,3H),4.33(q,J＝7.1Hz,2H),1.25(t,J＝7.1Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ161.0,151.7,144.4,134.2,130.32,130.25,129.3,129.2,128.7,127.7,126.7,125.3,124.7,122.9,113.5,110.3,60.9,14.0；MS(EI,70eV)m/z 394,365,349,322,316,309,295,287,242,229,214,190,164,127,114,101,89；HRMS(ESI)m/z[M+H] + Calcd for C 20 H 16 N 2 O 2 Br 395.0390,found 395.0413。
example 26
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
into the reaction tube were charged 0.3mmol benzamidine hydrochloride, 0.1mmol isoquinolinium methyl acetate bromide, 1mol% Ru (bpy) 3 Cl 2 Photocatalyst, 0.2mmol cesium carbonate, 0.3mmol DBU and 1.0mL acetonitrile under 465nm blue light source irradiation, 30Stirring and reacting for 24 hours at the temperature, and separating and purifying by column chromatography after the reaction is finished, wherein the volume ratio of petroleum ether to ethyl acetate in the column chromatography eluent is 5:1, obtaining a purified target product, wherein the yield is 30% and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.11(d,J＝7.5Hz,1H),8.79-8.76(m,1H),7.82(dd,J＝8.1,1.6Hz,2H),7.76-7.74(m,1H),7.67-7.64(m,2H),7.50-7.42(m,3H),7.22(d,J＝7.4Hz,1H),3.83(s,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ161.6,151.9,145.2,134.6,130.4,130.2,129.5,128.6,128.3,127.8,126.7,124.1,124.3,123.0,114.2,113.4,51.4；MS(EI,70eV)m/z 302,287,276,271,257,244,233,214,189,151,140,128,115,101,89,77；HRMS(ESI)m/z[M+H] + Calcd for C 19 H 15 N 2 O 2 303.1128,found 303.1145。
example 27
The imidazo [2,1-a ] isoquinoline compounds obtained in this example have the following structure:
into the reaction tube were charged 0.3mmol benzamidine hydrochloride, 0.1mmol isoquinolinium acetonitrile bromide, 1mol% Ru (bpy) 3 Cl 2 Photocatalyst, 0.2mmol cesium carbonate, 0.3mmol DBU and 1.0mL acetonitrile, under the irradiation of 465nm blue light source, stirring and reacting for 24 hours at 30 ℃, separating and purifying by column chromatography after the reaction is finished, wherein the volume ratio of petroleum ether and ethyl acetate in the column chromatography eluent is 5:1, obtaining a purified target product, wherein the yield is 15%, and the purity is 99.9%;
the structure of the obtained product is characterized, and the structural characterization data are as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ8.74(dd,J＝8.1,1.2Hz,1H),8.26-8.24(m,2H),8.07(d,J＝7.2Hz,1H),7.80-7.77(m,1H),7.74-7.66(m,2H),7.55-7.51(m,2H),7.48-7.44(m,1H),7.29-7.27(m,1H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ,ppm)δ152.0,145.0,131.5,130.6,130.0,129.9,129.02,128.99,127.3,127.2,124.4,123.0,121.3,115.2,112.9,95.4；MS(EI,70eV)m/z 269,245,233,214,142,134,128,101,88；HRMS(ESI)m/z[M+H] + Calcd for C 18 H 12 N 3 270.1026,found270.1022。
although the foregoing embodiments have been described in some, but not all embodiments of the invention, other embodiments may be obtained according to the present embodiments without departing from the scope of the invention.
Claims (8)
1. The preparation method of the imidazo [2,1-a ] isoquinoline compound is characterized by comprising the following steps:
mixing amidine hydrochloride, isoquinoline onium salt, a catalyst, alkali and a polar organic solvent, and performing cyclization reaction under the illumination condition to obtain the imidazo [2,1-a ] isoquinoline compound;
the amidine hydrochloride has a structure shown in a formula I:
the R is 1 Phenyl, alkyl, cycloalkyl, alkyl-substituted phenyl, alkoxy-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl or an azacyclyl;
the isoquinolinium salt has a structure shown in formula II:
the imidazo [2,1-a ] isoquinoline compound has a structure shown in a formula III:
in the formula II and the formula III, R 2 Is nitro, halogen, alkyl or alkoxy; the R is 3 Is an ester group or a cyano group.
2. The production method according to claim 1, wherein the amidine hydrochloride comprises benzamidine hydrochloride, 4-fluoro-benzamidine hydrochloride, 4-chloro-benzamidine hydrochloride, 4-bromo-benzamidine hydrochloride, 4-trifluoromethyl-benzamidine hydrochloride, 4-methyl-benzamidine hydrochloride, 4-methoxy-benzamidine hydrochloride, 3-bromo-benzamidine hydrochloride, 3-methyl-benzamidine hydrochloride, 3-methoxy-benzamidine hydrochloride, 2-fluoro-benzamidine hydrochloride, 2-chloro-benzamidine hydrochloride, 2-methyl-benzamidine hydrochloride, 3-pyridyl-formamidine hydrochloride, 4-pyridyl-formamidine hydrochloride, acetamidine hydrochloride or cyclopropylamide hydrochloride;
the isoquinolinium salt includes isoquinolinium ethyl acetate bromide, 5-nitroisoquinolinium ethyl acetate bromide, 5-methoxyisoquinolinium ethyl acetate bromide, 6-bromoisoquinolinium ethyl acetate bromide, 6-methylisoquinolinium ethyl acetate bromide, 6-methoxyisoquinolinium ethyl acetate bromide, 7-methoxyisoquinolinium ethyl acetate bromide, 4-bromoisoquinolinium ethyl acetate bromide, isoquinolinium methyl acetate bromide, or isoquinolinium acetonitrile bromide.
3. The method of preparation according to claim 1, wherein the catalyst comprises a metal complex or an organic dye;
the metal complex comprises a ruthenium ligand compound or an iridium ligand compound;
the organic dye comprises eosin Y, rose bengal or rhodamine B.
4. The preparation method according to claim 1, wherein the base comprises an inorganic base and/or an organic base;
the inorganic base comprises potassium carbonate, potassium phosphate, potassium hydroxide or cesium carbonate;
the organic base comprises potassium tert-butoxide, 1, 8-diazabicyclo [5.4.0] undec-7-ene or triethylene diamine.
5. The method according to claim 1, wherein the polar organic solvent comprises one or more of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, toluene, ethyl acetate, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran, and dichloromethane.
6. The method according to claim 1, wherein the molar ratio of the amidine hydrochloride to the isoquinolinium salt is 1.5 to 3:1, a step of;
the molar ratio of the isoquinolinium salt to the catalyst is 1:0.001 to 0.003;
the molar ratio of the isoquinolinium salt to the base is 1:1 to 6;
the dosage ratio of the polar organic solvent to the quinolinium salt is 1L:0.1 to 0.2mol.
7. The method according to claim 1, wherein the light source wavelength of the illumination is 200-1000 nm.
8. The process according to claim 1, wherein the cyclization reaction is carried out at a temperature of 15 to 60 ℃ for a time of 6 to 24 hours.
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