CN109608395A - 过渡金属催化的c-h活化/环合反应高效合成异喹啉衍生物的绿色合成新方法 - Google Patents
过渡金属催化的c-h活化/环合反应高效合成异喹啉衍生物的绿色合成新方法 Download PDFInfo
- Publication number
- CN109608395A CN109608395A CN201811586801.5A CN201811586801A CN109608395A CN 109608395 A CN109608395 A CN 109608395A CN 201811586801 A CN201811586801 A CN 201811586801A CN 109608395 A CN109608395 A CN 109608395A
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- China
- Prior art keywords
- silver
- dimer
- palladium
- chloride
- rhodium
- Prior art date
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- Granted
Links
- 238000007363 ring formation reaction Methods 0.000 title claims abstract description 11
- 230000007704 transition Effects 0.000 title claims abstract description 7
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 title claims 2
- 238000010499 C–H functionalization reaction Methods 0.000 title abstract description 6
- 238000003786 synthesis reaction Methods 0.000 title description 6
- 230000015572 biosynthetic process Effects 0.000 title description 5
- 238000001308 synthesis method Methods 0.000 title 1
- 239000002904 solvent Substances 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- -1 pyrrole radicals Chemical class 0.000 claims description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- WQIQNKQYEUMPBM-UHFFFAOYSA-N pentamethylcyclopentadiene Chemical compound CC1C(C)=C(C)C(C)=C1C WQIQNKQYEUMPBM-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 10
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- PZSJYEAHAINDJI-UHFFFAOYSA-N rhodium(3+) Chemical class [Rh+3] PZSJYEAHAINDJI-UHFFFAOYSA-N 0.000 claims description 8
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 8
- 229940071536 silver acetate Drugs 0.000 claims description 8
- 239000000654 additive Substances 0.000 claims description 7
- 238000010898 silica gel chromatography Methods 0.000 claims description 7
- 230000000996 additive effect Effects 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N aminomethyl benzene Natural products NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000005864 Sulphur Substances 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 5
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- 239000000539 dimer Substances 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- MBAKFIZHTUAVJN-UHFFFAOYSA-I hexafluoroantimony(1-);hydron Chemical compound F.F[Sb](F)(F)(F)F MBAKFIZHTUAVJN-UHFFFAOYSA-I 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- RWRDJVNMSZYMDV-UHFFFAOYSA-L radium chloride Chemical class [Cl-].[Cl-].[Ra+2] RWRDJVNMSZYMDV-UHFFFAOYSA-L 0.000 claims description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 235000013495 cobalt Nutrition 0.000 claims description 3
- JAWGVVJVYSANRY-UHFFFAOYSA-N cobalt(3+) Chemical compound [Co+3] JAWGVVJVYSANRY-UHFFFAOYSA-N 0.000 claims description 3
- 229910052741 iridium Inorganic materials 0.000 claims description 3
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 3
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Natural products CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 claims description 3
- 229910052709 silver Inorganic materials 0.000 claims description 3
- 239000004332 silver Substances 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 2
- RRKODOZNUZCUBN-CCAGOZQPSA-N (1z,3z)-cycloocta-1,3-diene Chemical compound C1CC\C=C/C=C\C1 RRKODOZNUZCUBN-CCAGOZQPSA-N 0.000 claims description 2
- ZXMGHDIOOHOAAE-UHFFFAOYSA-N 1,1,1-trifluoro-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical class FC(F)(F)S(=O)(=O)NS(=O)(=O)C(F)(F)F ZXMGHDIOOHOAAE-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 claims description 2
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims description 2
- YESGVEQXKRJBBJ-UHFFFAOYSA-N 1-(dichloromethyl)-2,3,4,5-tetramethylcyclopenta-1,3-diene Chemical compound ClC(C1=C(C(=C(C1C)C)C)C)Cl YESGVEQXKRJBBJ-UHFFFAOYSA-N 0.000 claims description 2
- RYKLZUPYJFFNRR-UHFFFAOYSA-N 3-hydroxypiperidin-2-one Chemical compound OC1CCCNC1=O RYKLZUPYJFFNRR-UHFFFAOYSA-N 0.000 claims description 2
- BRYKBDMLJJLFAB-UHFFFAOYSA-N 4-methylbenzenesulfonic acid;silver Chemical compound [Ag].CC1=CC=C(S(O)(=O)=O)C=C1 BRYKBDMLJJLFAB-UHFFFAOYSA-N 0.000 claims description 2
- QSNFOTSEFALLLC-UHFFFAOYSA-L C(=O)=[Co](I)I Chemical compound C(=O)=[Co](I)I QSNFOTSEFALLLC-UHFFFAOYSA-L 0.000 claims description 2
- LJANIJWBPMOASO-UHFFFAOYSA-N C(CC(=O)C)(=O)[Co] Chemical compound C(CC(=O)C)(=O)[Co] LJANIJWBPMOASO-UHFFFAOYSA-N 0.000 claims description 2
- OVEMSLBFEHSYSF-UHFFFAOYSA-N ClC(CBBB)Cl Chemical compound ClC(CBBB)Cl OVEMSLBFEHSYSF-UHFFFAOYSA-N 0.000 claims description 2
- NWBUFJZQWAXFGH-UHFFFAOYSA-K [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1.C1=CCCC=CCC1 Chemical class [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1.C1=CCCC=CCC1 NWBUFJZQWAXFGH-UHFFFAOYSA-K 0.000 claims description 2
- UVNZNIGDKACWAA-UHFFFAOYSA-N [Ru].C1CC=CCCC=C1 Chemical compound [Ru].C1CC=CCCC=C1 UVNZNIGDKACWAA-UHFFFAOYSA-N 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000002503 iridium Chemical class 0.000 claims description 2
- MILUBEOXRNEUHS-UHFFFAOYSA-N iridium(3+) Chemical class [Ir+3] MILUBEOXRNEUHS-UHFFFAOYSA-N 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- RPNNPZHFJPXFQS-UHFFFAOYSA-N methane;rhodium Chemical compound C.[Rh] RPNNPZHFJPXFQS-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- 229910001630 radium chloride Inorganic materials 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- 239000010948 rhodium Substances 0.000 claims description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical compound [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 claims description 2
- SONJTKJMTWTJCT-UHFFFAOYSA-K rhodium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Rh+3] SONJTKJMTWTJCT-UHFFFAOYSA-K 0.000 claims description 2
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 2
- VIHDTGHDWPVSMM-UHFFFAOYSA-N ruthenium;triphenylphosphane Chemical compound [Ru].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 VIHDTGHDWPVSMM-UHFFFAOYSA-N 0.000 claims description 2
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 2
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 2
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 2
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 claims description 2
- 229910000367 silver sulfate Inorganic materials 0.000 claims description 2
- 229910001494 silver tetrafluoroborate Inorganic materials 0.000 claims description 2
- WCGIGOVLOFXAMG-UHFFFAOYSA-N silver;trifluoromethanesulfonic acid Chemical compound [Ag].OS(=O)(=O)C(F)(F)F WCGIGOVLOFXAMG-UHFFFAOYSA-N 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 claims 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims 2
- 125000003118 aryl group Chemical group 0.000 claims 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims 1
- BEOKBUHJDGJDKO-UHFFFAOYSA-N [Cl].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 Chemical compound [Cl].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 BEOKBUHJDGJDKO-UHFFFAOYSA-N 0.000 claims 1
- OTVPWGHMBHYUAX-UHFFFAOYSA-N [Fe].[CH]1C=CC=C1 Chemical compound [Fe].[CH]1C=CC=C1 OTVPWGHMBHYUAX-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229910017052 cobalt Inorganic materials 0.000 claims 1
- 239000010941 cobalt Substances 0.000 claims 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims 1
- 238000006471 dimerization reaction Methods 0.000 claims 1
- QEQGAEHEPGMNCC-UHFFFAOYSA-N fluoromethanesulfonic acid;silver Chemical compound [Ag].OS(=O)(=O)CF QEQGAEHEPGMNCC-UHFFFAOYSA-N 0.000 claims 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims 1
- 150000003303 ruthenium Chemical class 0.000 claims 1
- 229910052707 ruthenium Inorganic materials 0.000 claims 1
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 abstract description 7
- 239000011593 sulfur Substances 0.000 abstract description 6
- 229910052717 sulfur Inorganic materials 0.000 abstract description 6
- 239000003960 organic solvent Substances 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000000746 purification Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- BNJMRELGMDUDDB-UHFFFAOYSA-N $l^{1}-sulfanylbenzene Chemical compound [S]C1=CC=CC=C1 BNJMRELGMDUDDB-UHFFFAOYSA-N 0.000 description 1
- LVMPWFJVYMXSNY-UHFFFAOYSA-N (2,3-dimethoxyphenyl)methanamine Chemical compound COC1=CC=CC(CN)=C1OC LVMPWFJVYMXSNY-UHFFFAOYSA-N 0.000 description 1
- 239000001211 (E)-4-phenylbut-3-en-2-one Substances 0.000 description 1
- KLIDCXVFHGNTTM-UHFFFAOYSA-N 2,6-dimethoxyphenol Chemical group COC1=CC=CC(OC)=C1O KLIDCXVFHGNTTM-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- 238000006407 Bischler-Napieralski reaction Methods 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000007445 Chromatographic isolation Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 238000006929 Pictet-Spengler synthesis reaction Methods 0.000 description 1
- 238000006796 Pomeranz-Fritsch reaction Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- AXNBHOOQHIIQFA-UHFFFAOYSA-N [S].C(F)(F)F Chemical compound [S].C(F)(F)F AXNBHOOQHIIQFA-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229930008407 benzylideneacetone Natural products 0.000 description 1
- 229960004895 bretylium tosylate Drugs 0.000 description 1
- KVWNWTZZBKCOPM-UHFFFAOYSA-M bretylium tosylate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.CC[N+](C)(C)CC1=CC=CC=C1Br KVWNWTZZBKCOPM-UHFFFAOYSA-M 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- GCUVBACNBHGZRS-UHFFFAOYSA-N cyclopenta-1,3-diene cyclopenta-2,4-dien-1-yl(diphenyl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.c1cc[c-](c1)P(c1ccccc1)c1ccccc1 GCUVBACNBHGZRS-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical class [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- NWJUMMHVDMNYMJ-UHFFFAOYSA-N n-benzyl-1,1,1-trifluoromethanamine Chemical compound FC(F)(F)NCC1=CC=CC=C1 NWJUMMHVDMNYMJ-UHFFFAOYSA-N 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- BWHOZHOGCMHOBV-BQYQJAHWSA-N trans-benzylideneacetone Chemical compound CC(=O)\C=C\C1=CC=CC=C1 BWHOZHOGCMHOBV-BQYQJAHWSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
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Abstract
本发明涉及一种以水作为溶剂、硫叶立德为卡宾供体、过渡金属催化的C‑H活化/环合反应高效在芳（杂）环上形成C‑C键，并环合成异喹啉衍生物的绿色合成新方法。与传统方法相比，本方法原料易得，步骤简单，避免了毒性有机溶剂的使用，是一种温和、快速、简便、有效、环境友好的制备异喹啉母环的方法，具有广阔的应用前景。
Description
技术领域
本发明涉及一种以水作为溶剂、硫叶立德为卡宾供体、过渡金属催化的C-H活化/环合反应高效在芳（杂）环上形成C-C键并环合成异喹啉衍生物的绿色合成新方法。
背景技术
异喹啉及其衍生物是一种常见的有机化合物母环结构，广泛存在于多种药物、天然化合物1-5和有机材料6, 7。合成异喹啉及其衍生物的传统方法包括Pomeranz-Fritsch反应8、Bischler-Napieralski反应9和Pictet-Spengler反应10，这些反应一般存在如下缺点：步骤繁琐、条件苛刻、收率低、官能团适用性差等。近年来，C-H活化在有机合成领域取得了快速的发展，多种含N原子的导向基团的化合物，分别与炔类或者重氮类等化合物，通过过渡金属催化，可快速构建含有异喹啉母环结构的各种化合物11-17。然而已有的这些方法依然有一定局限性，如原料难合成、不稳定、难保存，甚至具有潜在危险性，反应条件不够绿色环保，需要添加多种添加剂，并使用毒性有机溶剂等。因此，开发经济、高效、安全、绿色的C-H活化方法来合成异喹啉及其衍生物是一项具有重大意义的研究。硫叶立德是一种卡宾前体化合物，与重氮化合物相比，具有安全性，稳定性和易合成等优点，最近成为C-H活化研究的热点18-23。本发明提供一种以苄胺类化合物为起始原料，硫叶立德作为卡宾供体，以水作为溶剂，通过过渡金属催化，简捷高效地在芳杂环上形成C-C键并环合成异喹啉衍生物的绿色合成新方法。
发明内容
本发明实现了以水作为溶剂、硫叶立德作为卡宾供体，通过过渡金属催化的C-H活化一步偶联并环合构建异喹啉及其衍生物的合成新方法，解决了传统合成方法步骤冗长、反应条件苛刻、低原子利用率、使用有毒有机溶剂造成环境污染、成本较高等问题。本发明原料易得，步骤简单，是一种温和、快速、简便、有效、环境友好的制备异喹啉母环的方法，具有广阔的应用前景。
本发明的化学反应式如下所示：
A环为苯基、萘基、噻吩基、呋喃基、吡啶基、吡咯基、吲哚基中的一种；
R1为氢、卤素、烷基、苯基、烷氧基、羰基、醛基、羧基、氰基、硝基、烷酰氧基、酰胺基中的一种或一种以上；
R2为氢、烷基、杂芳基中的一种；
R3为苯基、噻吩基、呋喃基、吡啶基、萘基、吡咯基、吲哚基、烷基、烯基、炔基的一种或一种以上。
制备步骤如下：
（1）在洁净的反应器中依次加入苄胺类化合物、硫叶立德化合物、催化剂、添加剂和水，放入100℃油浴锅里搅拌24h；
（2）反应结束后，加入二氯甲烷萃取，收集二氯甲烷层，减压除去溶剂，残留物采用硅胶柱层析分离纯化即得产品。
步骤（1）中，催化剂为钯碳、四（三苯基膦）钯、醋酸钯、氯化钯、二（乙腈）二氯化钯、二（苯腈）二氯化钯，1，1’-二（二苯基膦基）二茂铁二氯化钯、二（三苯基膦）二氯化钯、双（二亚苄基丙酮）钯、三（二亚苄基丙酮）二钯、氯化烯丙基钯（II）二聚物、（1,5-环辛二烯）二氯化钯（II）、铑碳、三氯化铑、醋酸铑、乙酰丙酮三苯基膦羰基铑、双环辛烯氯化铑二聚体、二氯（五甲基环戊二烯基）合铑（III）二聚体、(二(六氟锑酸)三乙腈(五甲基环戊二烯基)铑(III))、三苯基膦氯化铑、三氯化钌、三苯基膦氯化钌、二氯二羰基双三苯基膦钌、双（2-甲基烯丙基）（1,5-环辛二烯）钌（II）、对伞花烃二氯化钌二聚体、氯化钴、乙酰乙酰钴、八羰基二钴、二氯（五甲基环戊二烯基）合钴（III）二聚体、五甲基环戊二烯基羰基二碘化钴、(二(六氟锑酸)三乙腈(五甲基环戊二烯基)钴(III))、三氯化铱、二氯(五甲基环戊二烯)合铱(III)二聚体、双（1,5-环辛二烯）氯化铱（Ⅰ）二聚体、甲氧基（环辛二烯）合铱二聚体中的一种或一种以上。
步骤（1）中的添加剂为硝酸银、乙酸银、碳酸银、硫酸银、甲烷磺酸银、三氟甲烷磺酸银、对甲苯磺酸银、双三氟甲烷磺酰亚胺银，三氟甲烷磺酸银，六氟锑酸银、四氟硼酸银、六氟磷酸银中的一种或一种以上。
步骤（1）中苄胺类化合物：硫叶立德化合物：催化剂：添加剂的摩尔比为1:（1.2~3.0）：（0.02~0.05）：（0.08~0.2）。
用核磁共振氢谱（1H NMR）、碳谱（13C NMR）以及高分辨质谱证实了在芳杂环上形成C-C键以及环合成异喹啉衍生物的结构，如附图1、附图2。其中核磁共振图采用VarianINOVA-400 型核磁共振仪测定，以四甲基硅烷（TMS）为内标（δ 0 ppm），氘代氯仿为溶剂；高分辨质谱用 Agilent 1946B 质谱仪测定。
附图说明
图1 为本发明化合物1的核磁氢谱图。
图2 为本发明化合物1的核磁碳谱图。
具体实施方法
下面结合具体实施方式对本发明作进一步描述,有助于对本发明的理解。但并不能以此来限制本发明的权利范围,而本发明的权利范围应以权利要求书阐述的为准。
实施实例1：化合物1的合成
（1）在洁净的反应器中依次加入苄胺（21.4 mg,0.2 mmol）、2,6-二甲氧基苯基硫叶立德（102.5 mg,0.4 mmol）、二氯（五甲基环戊二烯基）合铑（III）二聚体（6.18 mg,0.01mmol）、醋酸银（6.67 mg,0.04 mmol）和水(2 mL)，放入100℃油浴锅里搅拌24 h。
（2）反应结束后，加入二氯甲烷萃取，收集二氯甲烷层，减压除去溶剂，残留物采用硅胶柱层析分离纯化即得白色固体，收率75 %。1H NMR (400 MHz, CDCL3) δ 9.39 (s,1H), 8.00 (d, J = 8.1 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.71 (s, 1H), 7.67(t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 6.69(d, J = 8.4 Hz, 2H), 3.73 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 157.25(s,2C),150.79, 146.38, 135.22, 129.02, 128.57, 126.49, 126.36, 125.85, 125.67,121.36, 117.92, 103.12(2C), 54.95(s,2C). HRMS (ESI): m/z计算值C17H15NO2H+:266.1176, 实测值: 266.1177。
实施实例2：化合物2的合成
（1）在洁净的反应器中依次加入对溴苄胺（37.2 mg,0.2 mmol）、2,6-二甲氧基苯基硫叶立德（102.5 mg,0.4 mmol）、二氯（五甲基环戊二烯基）合铑（III）二聚体（6.18 mg,0.01mmol）、醋酸银（6.67 mg,0.04 mmol）和水(2 mL)，放入100℃油浴锅里搅拌24 h。
（2）反应结束后，加入二氯甲烷萃取，收集二氯甲烷层，减压除去溶剂，残留物采用硅胶柱层析分离纯化即得白色固体，收率71.1 %。1H NMR (400 MHz, CDCl3) δ 9.34 (s,1H), 7.99 (d, J = 1.6 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.65 (dd, J = 8.8,1.6 Hz, 1H), 7.61 (s, 1H), 7.35 (t, J = 8.4 Hz, 1H), 6.68 (d, J = 8.4 Hz,2H), 3.73 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 158.22 (s,2C), 151.72 (s),148.65 (s), 137.30 (s), 130.50 (s), 129.89 (s), 129.19 (s), 128.92 (s),125.73 (s), 124.86 (s), 121.45 (s), 118.51 (s), 104.17 (s,2C), 55.99 (s,2C).HRMS (ESI): m/z计算值C17H14BrNO2H+: 344.0281, 实测值: 344.0282。
实施实例3：化合物3的合成
（1）在洁净的反应器中依次加入对甲基苄胺（24.2 mg,0.2 mmol）、2,6-二甲氧基苯基硫叶立德（102.5 mg,0.4 mmol）、二氯（五甲基环戊二烯基）合铑（III）二聚体（6.18 mg,0.01 mmol）、醋酸银（6.67 mg,0.04 mmol）和水(2 mL)，放入100℃油浴锅里搅拌24 h。
（2）反应结束后，加入二氯甲烷萃取，收集二氯甲烷层，减压除去溶剂，残留物采用硅胶柱层析分离纯化即得浅黄色固体，收率56.4 %。1H NMR (400 MHz, CDCl3) δ 9.31 (s,1H), 7.89 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 9.7 Hz, 2H), 7.42 (dd, J = 8.4,1.2 Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 2H), 3.73 (s,6H), 2.54 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 157.26 (s,2C), 150.32 (s),146.29 (s), 139.35 (s), 135.55 (s), 128.50 (s), 128.17 (s), 126.32 (s),124.56 (s), 120.92 (s), 118.02 (s), 103.12 (s,2C), 54.94 (s,2C), 21.06 (s).HRMS (ESI): m/z计算值C18H17NO2H+: 280.1332, 实测值: 280.1331.
实施实例4：化合物4的合成
（1）在洁净的反应器中依次加入对三氟甲基苄胺（35.0 mg,0.2 mmol）、2,6-二甲氧基苯基硫叶立德（102.5 mg ,0.4 mmol）、二氯（五甲基环戊二烯基）合铑（III）二聚体（6.18mg,0.01 mmol）、醋酸银（6.67 mg,0.04 mmol）和水(2 mL)，放入100℃油浴锅里搅拌24 h。
（2）反应结束后，加入二氯甲烷萃取，收集二氯甲烷层，减压除去溶剂，残留物采用硅胶柱层析分离纯化即得白色固体，收率89 %。1H NMR (400 MHz, CDCl3) δ 9.73 (s,1H), 8.00 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.78 (s, 1H), 7.68(t, J = 7.8 Hz, 1H), 7.37 (t, J = 8.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 2H), 3.74(s, 6H).13C NMR (101 MHz, CDCl3) δ 157.18 (s,2C), 147.59 (s), 147.34 (q, J =3.1 Hz), 135.83 (s), 130.56 (s), 129.59 (s), 128.97 (s), 127.31 (s), 125.57(q, J = 31.6 Hz), 124.33 (q, J = 6.1 Hz), 121.85 (s), 121.66 (s), 117.22 (s),103.14 (s, 2C),54.94 (s, 2C). HRMS (ESI): m/z计算值C18H14F3NO2H+: 334.1049, 实测值: 334.1048.
实施实例5：化合物5的合成
（1）在洁净的反应器中依次加入邻甲基苄胺（24.2 mg,0.2 mmol）、2,6-二甲氧基苯基硫叶立德（102.5 mg ,0.4 mmol）、二氯（五甲基环戊二烯基）合铑（III）二聚体（6.18 mg,0.01 mmol）、醋酸银（6.67 mg,0.04 mmol）和水(2 mL)，放入100℃油浴锅里搅拌24 h。
（2）反应结束后，加入二氯甲烷萃取，收集二氯甲烷层，减压除去溶剂，残留物采用硅胶柱层析分离纯化即得浅黄色固体，收率80.3%。1H NMR (400 MHz, CDCl3) δ 9.59 (s,1H), 7.69 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.35(m, 2H), 6.69 (d, J = 8.4 Hz, 2H), 3.73 (s, 6H), 2.81 (s, 3H). 13C NMR (151MHz, CDCl3) δ 158.34(s,2C), 148.75(s), 147.32(s), 136.59(s), 135.32(s),129.93(s), 129.58(s), 127.62(s), 126.41(s), 125.10(s), 122.75(s), 119.06(s),104.21(s,2C), 56.00(s,2C), 18.47(s). HRMS (ESI): m/z计算值C18H17NO2H+:280.1332, 实测值: 280.1332.
实施实例6：化合物6的合成
（1）在洁净的反应器中依次加入2,3-二甲氧基苄胺（33.4 mg,0.2 mmol）、3,4-二甲氧基苯基硫叶立德（102.5 mg ,0.4 mmol）、二氯（五甲基环戊二烯基）合铑（III）二聚体（6.18mg,0.01 mmol）、醋酸银（6.67 mg,0.04 mmol）和水(2 mL)，放入100℃油浴锅里搅拌24 h。
（2）反应结束后，加入二氯甲烷萃取，收集二氯甲烷层，减压除去溶剂，残留物采用硅胶柱层析分离纯化即得黄色固体，收率37 %。1H NMR (400 MHz, CDCl3) δ 9.60 (s,1H), 7.93 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.66 – 7.58 (m, 2H), 7.50 (d, J= 9.2 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 4.08 (s, 3H), 4.04 (s, 3H), 4.02 (s,3H), 3.95 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 149.47 (s), 149.28 (s), 149.07(s), 148.62 (s), 147.00 (s), 144.00 (s), 132.68 (s), 132.35 (s), 122.95 (s),122.88 (s), 120.51 (s), 119.10 (s), 115.21 (s), 111.25 (s), 109.95 (s), 61.75(s), 57.09 (s), 56.04 (s), 56.00 (s). HRMS (ESI): m/z计算值C19H19NO4H+:326.1387, 实测值: 326.1388.
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Claims (6)
1.一种基于过渡金属催化的C-H偶联/环合反应高效合成C-C键以及异喹啉衍生物的绿色合成新方法，其特征在于以（杂）芳基甲胺为起始原料，以硫叶立德化合物为卡宾供体，以水为溶剂，在芳（杂）环上形成C-C键，进一步环合成异喹啉类衍生物，其化学反应式为：
其中：
A环为苯基、萘基、噻吩基、呋喃基、吡啶基、吡咯基、吲哚基中的一种；
R1为氢、卤素、烷基、芳基、烷氧基、羰基、醛基、羧基、氰基、硝基、烷酰氧基、酰胺基中的一种或一种以上；
R2为氢、烷基、杂芳基中的一种；
R3为芳基、噻吩基、呋喃基、吡啶基、萘基、吡咯基、吲哚基、烷基、烯基、炔基的一种或一种以上。
2.一种制备合成权利要求1所述的衍生物的方法，其制备步骤如下：
应器中依次加入（杂）芳基甲胺类化合物、硫叶立德化合物、催化剂、添加剂和水，放入100℃油浴锅里搅拌24h；
反应结束后，加入二氯甲烷萃取，收集二氯甲烷层，减压除去溶剂，残留物采用硅胶柱层析分离纯化即得产品。
3.根据权利要求2所述的制备方法，其特征在于步骤（1）中的催化剂为钯碳、四（三苯基膦）钯、醋酸钯、氯化钯、二（乙腈）二氯化钯、二（苯腈）二氯化钯、1，1’-二（二苯基膦基）二茂铁二氯化钯、二（三苯基膦）二氯化钯、双（二亚苄基丙酮）钯、三（二亚苄基丙酮）二钯、氯化烯丙基钯（II）二聚物、（1,5-环辛二烯）二氯化钯（II）、铑碳、三氯化铑、醋酸铑、乙酰丙酮三苯基膦羰基铑、双环辛烯氯化铑二聚体、二氯（五甲基环戊二烯基）合铑（III）二聚体、(二(六氟锑酸)三乙腈(五甲基环戊二烯基)铑(III))、三苯基膦氯化铑、三氯化钌、三苯基膦氯化钌、二氯二羰基双三苯基膦钌、双（2-甲基烯丙基）（1,5-环辛二烯）钌（II）、对伞花烃二氯化钌二聚体、氯化钴、乙酰乙酰钴、八羰基二钴、二氯（五甲基环戊二烯基）合钴（III）二聚体、五甲基环戊二烯基羰基二碘化钴、(二(六氟锑酸)三乙腈(五甲基环戊二烯基)钴(III))、三氯化铱、二氯(五甲基环戊二烯)合铱(III)二聚体、双（1,5-环辛二烯）氯化铱（Ⅰ）二聚体、甲氧基（环辛二烯）合铱二聚体中的一种或一种以上。
4.根据权利要求2所述的制备方法，其特征在于步骤（1）中的添加剂为硝酸银、乙酸银、碳酸银、硫酸银、甲烷磺酸银、三氟甲烷磺酸银、对甲苯磺酸银、双三氟甲烷磺酰亚胺银、三氟甲烷磺酸银、六氟锑酸银、四氟硼酸银、六氟磷酸银中的一种或一种以上。
5.根据权利要求2所述的制备方法，其特征在于步骤（1）中的溶剂为水。
6.根据权利要求2所述的制备方法，步骤（1）中苄胺类化合物 : 硫叶立德化合物 : 催化剂 : 添加剂的摩尔比为1 :（1.2~3.0）:（0.02~0.05）:（0.08~0.2）。
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