CN113582999A - 一种制备咪唑并[1,5-a]吲哚化合物的方法 - Google Patents
一种制备咪唑并[1,5-a]吲哚化合物的方法 Download PDFInfo
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- CN113582999A CN113582999A CN202110777792.3A CN202110777792A CN113582999A CN 113582999 A CN113582999 A CN 113582999A CN 202110777792 A CN202110777792 A CN 202110777792A CN 113582999 A CN113582999 A CN 113582999A
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- imidazo
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- acetate
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- -1 imidazo [1,5-a ] indole compound Chemical class 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 title claims description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims abstract description 46
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims abstract description 24
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims abstract description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 22
- 150000001336 alkenes Chemical class 0.000 claims abstract description 14
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical group [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 13
- 239000000654 additive Substances 0.000 claims abstract description 13
- 230000000996 additive effect Effects 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 238000006352 cycloaddition reaction Methods 0.000 claims abstract description 8
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 3
- 239000010948 rhodium Substances 0.000 claims abstract description 3
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 3
- 235000017281 sodium acetate Nutrition 0.000 claims abstract 2
- 239000001632 sodium acetate Substances 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 77
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000000468 ketone group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 23
- 125000000524 functional group Chemical group 0.000 abstract description 6
- 230000007935 neutral effect Effects 0.000 abstract description 5
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 294
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 192
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 50
- 238000003818 flash chromatography Methods 0.000 description 50
- 239000011541 reaction mixture Substances 0.000 description 50
- 239000000741 silica gel Substances 0.000 description 50
- 229910002027 silica gel Inorganic materials 0.000 description 50
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 49
- 238000005160 1H NMR spectroscopy Methods 0.000 description 49
- 239000003208 petroleum Substances 0.000 description 34
- 239000007787 solid Substances 0.000 description 32
- 239000000047 product Substances 0.000 description 13
- BSZGFXNZRDBQDL-UHFFFAOYSA-N 1h-imidazo[1,5-a]indole Chemical compound C1=CC=C2N3CN=CC3=CC2=C1 BSZGFXNZRDBQDL-UHFFFAOYSA-N 0.000 description 10
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 5
- 229960003987 melatonin Drugs 0.000 description 5
- 229930014626 natural product Natural products 0.000 description 5
- 238000007363 ring formation reaction Methods 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000010499 C–H functionalization reaction Methods 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- LIPRDGLTSNKRER-QXMHVHEDSA-N C(C1=CC=CC=C1)NC(\C=C/OC1=CC=CC=C1)=O Chemical compound C(C1=CC=CC=C1)NC(\C=C/OC1=CC=CC=C1)=O LIPRDGLTSNKRER-QXMHVHEDSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- HOWGUJZVBDQJKV-UHFFFAOYSA-N docosane Chemical compound CCCCCCCCCCCCCCCCCCCCCC HOWGUJZVBDQJKV-UHFFFAOYSA-N 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- MAJDOTZACCBSBK-UHFFFAOYSA-N (2-methoxyphenyl) 2-(2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound CON1C(N2C(=CC=3C=CC=CC2=3)C1CC(=O)OC1=C(C=CC=C1)OC)=O MAJDOTZACCBSBK-UHFFFAOYSA-N 0.000 description 1
- AUQBEDQCNPWKAP-UHFFFAOYSA-N (3-chlorophenyl) 2-(2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound CON1C(N2C(=CC=3C=CC=CC2=3)C1CC(=O)OC1=CC(=CC=C1)Cl)=O AUQBEDQCNPWKAP-UHFFFAOYSA-N 0.000 description 1
- IOWHYGLDZNRBFX-UHFFFAOYSA-N (3-methylphenyl) 2-(2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound CON1C(N2C(=CC=3C=CC=CC2=3)C1CC(=O)OC=1C=C(C=CC=1)C)=O IOWHYGLDZNRBFX-UHFFFAOYSA-N 0.000 description 1
- ULDLMPKZMRLVRK-UHFFFAOYSA-N (4-bromophenyl) 2-(2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound CON1C(N2C(=CC=3C=CC=CC2=3)C1CC(=O)OC1=CC=C(C=C1)Br)=O ULDLMPKZMRLVRK-UHFFFAOYSA-N 0.000 description 1
- CFJGEEJKFHQJPV-UHFFFAOYSA-N (4-chlorophenyl) 2-(2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound CON1C(N2C(=CC=3C=CC=CC2=3)C1CC(=O)OC1=CC=C(C=C1)Cl)=O CFJGEEJKFHQJPV-UHFFFAOYSA-N 0.000 description 1
- GIKLVPNJXJGUOU-UHFFFAOYSA-N (4-fluorophenyl) 2-(2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound CON1C(N2C(=CC=3C=CC=CC2=3)C1CC(=O)OC1=CC=C(C=C1)F)=O GIKLVPNJXJGUOU-UHFFFAOYSA-N 0.000 description 1
- MQWPMTLSYOTGNY-UHFFFAOYSA-N (4-iodophenyl) 2-(2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound CON1C(N2C(=CC=3C=CC=CC2=3)C1CC(=O)OC1=CC=C(C=C1)I)=O MQWPMTLSYOTGNY-UHFFFAOYSA-N 0.000 description 1
- WGDYDNYCKYXZLT-UHFFFAOYSA-N (4-methoxyphenyl) 2-(2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound CON1C(N2C(=CC=3C=CC=CC2=3)C1CC(=O)OC1=CC=C(C=C1)OC)=O WGDYDNYCKYXZLT-UHFFFAOYSA-N 0.000 description 1
- ZVGFQLLANUEVEQ-UHFFFAOYSA-N (4-methylphenyl) 2-(2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound CON1C(N2C(=CC=3C=CC=CC2=3)C1CC(=O)OC1=CC=C(C=C1)C)=O ZVGFQLLANUEVEQ-UHFFFAOYSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- KXEJFZUVGWNSAG-UHFFFAOYSA-N 2-(2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)-N-methyl-N-phenylacetamide Chemical compound CON1C(N2C(=CC=3C=CC=CC2=3)C1CC(=O)N(C1=CC=CC=C1)C)=O KXEJFZUVGWNSAG-UHFFFAOYSA-N 0.000 description 1
- UHMBTJVBCBULTK-UHFFFAOYSA-N 2-(2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)-N-phenylacetamide Chemical compound CON1C(N2C(=CC=3C=CC=CC2=3)C1CC(=O)NC1=CC=CC=C1)=O UHMBTJVBCBULTK-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- ZYEYYSFKSLYLHA-UHFFFAOYSA-N 2-methoxy-3-phenacyl-3H-imidazo[1,5-a]indol-1-one Chemical compound CON1C(N2C(=CC=3C=CC=CC2=3)C1CC(C1=CC=CC=C1)=O)=O ZYEYYSFKSLYLHA-UHFFFAOYSA-N 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
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- YYYKVJIYKXKGAD-UHFFFAOYSA-N CON(C(CC(C1=CC=CC=C1)=C=O)C1=CC(C=CC=C2)=C2N11)C1=O Chemical compound CON(C(CC(C1=CC=CC=C1)=C=O)C1=CC(C=CC=C2)=C2N11)C1=O YYYKVJIYKXKGAD-UHFFFAOYSA-N 0.000 description 1
- XNWUACWXMASTKK-UHFFFAOYSA-N CON(C(CC(NC1=CC=CC=C1)=O)C1=CC(C=CC=C2)=C2N11)C1=C=O Chemical compound CON(C(CC(NC1=CC=CC=C1)=O)C1=CC(C=CC=C2)=C2N11)C1=C=O XNWUACWXMASTKK-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- VLVLYFHVOUVCHR-UHFFFAOYSA-N N-benzyl-2-(2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetamide Chemical compound C(C1=CC=CC=C1)NC(CC1N(C(N2C1=CC=1C=CC=CC2=1)=O)OC)=O VLVLYFHVOUVCHR-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- TYALFHCQNODWCW-UHFFFAOYSA-N benzyl 2-(2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound CON1C(N2C(=CC=3C=CC=CC2=3)C1CC(=O)OCC1=CC=CC=C1)=O TYALFHCQNODWCW-UHFFFAOYSA-N 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
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- 229940126214 compound 3 Drugs 0.000 description 1
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- 150000008049 diazo compounds Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- HIOKFUBVEMXINZ-UHFFFAOYSA-N ethyl 2-(2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound CON1C(N2C(=CC=3C=CC=CC2=3)C1CC(=O)OCC)=O HIOKFUBVEMXINZ-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002527 isonitriles Chemical class 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000002974 melatonin derivative Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- CQJOLJIEPJFHNO-UHFFFAOYSA-N methyl 2-(2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound CON1C(N2C(=CC=3C=CC=CC2=3)C1CC(=O)OC)=O CQJOLJIEPJFHNO-UHFFFAOYSA-N 0.000 description 1
- RVWHKQVTBWSDCN-UHFFFAOYSA-N methyl 2-methoxy-1-oxo-3-(2-oxo-2-phenoxyethyl)-3H-imidazo[1,5-a]indole-6-carboxylate Chemical compound CON1C(N2C(=CC=3C=C(C=CC2=3)C(=O)OC)C1CC(OC1=CC=CC=C1)=O)=O RVWHKQVTBWSDCN-UHFFFAOYSA-N 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- HTNWDOOJEXIBLS-UHFFFAOYSA-N phenyl 2-(1-oxo-2-phenylmethoxy-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound C(C1=CC=CC=C1)ON1C(N2C(=CC=3C=CC=CC2=3)C1CC(=O)OC1=CC=CC=C1)=O HTNWDOOJEXIBLS-UHFFFAOYSA-N 0.000 description 1
- HGSZBSONCSJQJT-UHFFFAOYSA-N phenyl 2-(1-oxo-2-propan-2-yloxy-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound C(C)(C)ON1C(N2C(=CC=3C=CC=CC2=3)C1CC(=O)OC1=CC=CC=C1)=O HGSZBSONCSJQJT-UHFFFAOYSA-N 0.000 description 1
- KPCLGTKEYSADIT-UHFFFAOYSA-N phenyl 2-(2,5-dimethoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound CON1C(N2C(=CC=3C(=CC=CC2=3)OC)C1CC(=O)OC1=CC=CC=C1)=O KPCLGTKEYSADIT-UHFFFAOYSA-N 0.000 description 1
- ZGMXLZWJRVXQTF-UHFFFAOYSA-N phenyl 2-(2,6-dimethoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound CON1C(N2C(=CC=3C=C(C=CC2=3)OC)C1CC(=O)OC1=CC=CC=C1)=O ZGMXLZWJRVXQTF-UHFFFAOYSA-N 0.000 description 1
- HHHYGXZUWZVLLU-UHFFFAOYSA-N phenyl 2-(2,7-dimethoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound CON1C(N2C(=CC=3C=CC(=CC2=3)OC)C1CC(=O)OC1=CC=CC=C1)=O HHHYGXZUWZVLLU-UHFFFAOYSA-N 0.000 description 1
- MFGPGTSXGXJAGQ-UHFFFAOYSA-N phenyl 2-(2-ethoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound C(C)ON1C(N2C(=CC=3C=CC=CC2=3)C1CC(=O)OC1=CC=CC=C1)=O MFGPGTSXGXJAGQ-UHFFFAOYSA-N 0.000 description 1
- GRLFRVUIIYVGDI-UHFFFAOYSA-N phenyl 2-(2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound CON1C(N2C(=CC=3C=CC=CC2=3)C1CC(=O)OC1=CC=CC=C1)=O GRLFRVUIIYVGDI-UHFFFAOYSA-N 0.000 description 1
- QNUWRUWSMZSCPT-UHFFFAOYSA-N phenyl 2-(2-methoxy-1-oxo-6-thiophen-2-yl-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound CON1C(N2C(=CC=3C=C(C=CC2=3)C=2SC=CC=2)C1CC(=O)OC1=CC=CC=C1)=O QNUWRUWSMZSCPT-UHFFFAOYSA-N 0.000 description 1
- CBXVWUJNTNVMLC-UHFFFAOYSA-N phenyl 2-(2-methoxy-4-methyl-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound CON1C(N2C(=C(C=3C=CC=CC2=3)C)C1CC(=O)OC1=CC=CC=C1)=O CBXVWUJNTNVMLC-UHFFFAOYSA-N 0.000 description 1
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- WLKPAJCMJBLXSO-UHFFFAOYSA-N phenyl 2-(2-methoxy-5-methyl-3-oxo-1H-pyrrolo[1,2-c]imidazol-1-yl)acetate Chemical compound CON1C(N2C(C1CC(=O)OC1=CC=CC=C1)=CC=C2C)=O WLKPAJCMJBLXSO-UHFFFAOYSA-N 0.000 description 1
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- PMCNDAFNBIDUBJ-UHFFFAOYSA-N phenyl 2-(5-fluoro-2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound FC=1C=2C=C3N(C=2C=CC=1)C(N(C3CC(=O)OC1=CC=CC=C1)OC)=O PMCNDAFNBIDUBJ-UHFFFAOYSA-N 0.000 description 1
- XORHYEYALKTYLC-UHFFFAOYSA-N phenyl 2-(6-bromo-2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound BrC1=CC=2C=C3N(C=2C=C1)C(N(C3CC(=O)OC1=CC=CC=C1)OC)=O XORHYEYALKTYLC-UHFFFAOYSA-N 0.000 description 1
- QPXHLJPOKUAJBA-UHFFFAOYSA-N phenyl 2-(6-chloro-2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound ClC1=CC=2C=C3N(C=2C=C1)C(N(C3CC(=O)OC1=CC=CC=C1)OC)=O QPXHLJPOKUAJBA-UHFFFAOYSA-N 0.000 description 1
- JFODIHMEAZLAHA-UHFFFAOYSA-N phenyl 2-(6-cyano-2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound C(#N)C1=CC=2C=C3N(C=2C=C1)C(N(C3CC(=O)OC1=CC=CC=C1)OC)=O JFODIHMEAZLAHA-UHFFFAOYSA-N 0.000 description 1
- XFSZTKHGBTWZIC-UHFFFAOYSA-N phenyl 2-(6-ethoxy-2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound C(C)OC1=CC=2C=C3N(C=2C=C1)C(N(C3CC(=O)OC1=CC=CC=C1)OC)=O XFSZTKHGBTWZIC-UHFFFAOYSA-N 0.000 description 1
- KCMMIQLGZNHQJL-UHFFFAOYSA-N phenyl 2-(6-ethyl-2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound C(C)C1=CC=2C=C3N(C=2C=C1)C(N(C3CC(=O)OC1=CC=CC=C1)OC)=O KCMMIQLGZNHQJL-UHFFFAOYSA-N 0.000 description 1
- DLGMHHOEHNGARF-UHFFFAOYSA-N phenyl 2-(6-fluoro-2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound FC1=CC=2C=C3N(C=2C=C1)C(N(C3CC(=O)OC1=CC=CC=C1)OC)=O DLGMHHOEHNGARF-UHFFFAOYSA-N 0.000 description 1
- WVOUYHMTUXJPSJ-UHFFFAOYSA-N phenyl 2-(6-iodo-2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound IC1=CC=2C=C3N(C=2C=C1)C(N(C3CC(=O)OC1=CC=CC=C1)OC)=O WVOUYHMTUXJPSJ-UHFFFAOYSA-N 0.000 description 1
- IOTKHOJLZTVLAR-UHFFFAOYSA-N phenyl 2-(7-bromo-2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound BrC=1C=CC=2C=C3N(C=2C=1)C(N(C3CC(=O)OC1=CC=CC=C1)OC)=O IOTKHOJLZTVLAR-UHFFFAOYSA-N 0.000 description 1
- OJLKWNTYNJGCGV-UHFFFAOYSA-N phenyl 2-(7-chloro-2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound ClC=1C=CC=2C=C3N(C=2C=1)C(N(C3CC(=O)OC1=CC=CC=C1)OC)=O OJLKWNTYNJGCGV-UHFFFAOYSA-N 0.000 description 1
- YXTZHFIFLCCFAW-UHFFFAOYSA-N phenyl 2-(7-fluoro-2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound FC=1C=CC=2C=C3N(C=2C=1)C(N(C3CC(=O)OC1=CC=CC=C1)OC)=O YXTZHFIFLCCFAW-UHFFFAOYSA-N 0.000 description 1
- NIIPGDFIRSGMNJ-UHFFFAOYSA-N phenyl 2-[4-(2-acetamidoethyl)-2,6-dimethoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl]acetate Chemical compound C(C)(=O)NCCC1=C2N(C=3C=CC(=CC1=3)OC)C(N(C2CC(=O)OC1=CC=CC=C1)OC)=O NIIPGDFIRSGMNJ-UHFFFAOYSA-N 0.000 description 1
- HYNJDGXRZIOCHQ-UHFFFAOYSA-N phenyl 2-[4-(2-ethoxy-2-oxoethyl)-2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl]acetate Chemical compound CON1C(N2C(=C(C=3C=CC=CC2=3)CC(=O)OCC)C1CC(OC1=CC=CC=C1)=O)=O HYNJDGXRZIOCHQ-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- AFKKDLOOHGDCQB-UHFFFAOYSA-N tert-butyl 2-(2-methoxy-1-oxo-3H-imidazo[1,5-a]indol-3-yl)acetate Chemical compound CON1C(N2C(=CC=3C=CC=CC2=3)C1CC(=O)OC(C)(C)C)=O AFKKDLOOHGDCQB-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
Abstract
本发明提供了一种咪唑并[1,5‑a]吲哚化合物及其制备方法，属于有机合成技术领域。本发明提供的制备方法是采用铑催化吲哚与烯烃之间的[4+1]环加成反应来制备一系列咪唑并[1,5‑a]吲哚化合物，其中，催化剂为[Cp*RhCl2]2，添加剂为醋酸钠，溶剂为丙酮；所述吲哚和烯烃的摩尔比为1:1.2，所述催化剂的用量为吲哚摩尔量的5％，所述添加剂与吲哚的摩尔比为1:1。本发明提供的合成方法具有底物适用范围广、化学选择性和区域选择性高、产率良好、官能团耐受性好、反应步骤经济、温和的中性反应条件等优点。本发明所述咪唑并[1,5‑a]吲哚化合物的结构式为：
Description
技术领域
本发明属于有机合成技术领域，具体涉及一种制备咪唑并[1,5-a]吲哚化合物的方法。
背景技术
吲哚稠环类化合物广泛地存在于活性天然产物和药物分子中，鉴于它们的重要应用价值，构筑这类结构的方法引起了化学家的广泛关注。传统的构筑这类结构的方法往往涉及多步的官能团转化反应，而且需要多次分离纯化，具有步骤繁多、总产率较低等缺点。近年来，导向基团辅助和过渡金属催化的C–H活化反应得到了快速发展，与传统合成方法相比，过渡金属催化的C–H活化反应不需要对底物进行预官能团化，可以一步快速实现对惰性C–H键的直接官能团化，因而具有起始原料简单易得、合成步骤少、合成效率高等优点。在这一背景下，吲哚类底物和各种试剂之间的C–H环化反应成为了快速、高效地构建吲哚稠环类化合物的一个有力工具。
值得注意的是，在众多的吲哚稠环类化合物中，具有咪唑并[1,5-a]吲哚母核的化合物在药理活性分子中广泛体现，因此具有这些母核结构的化合物具有重要的潜在应用价值。具有咪唑并[1,5-a]吲哚母核的代表性活性化合物结构式如下：
然而，目前报道的吲哚类底物和各种试剂之间的C–H环化反应构建咪唑并[1,5-a]吲哚的方法或多或少存在一些明显的缺点，如需要使用危险的重氮化合物或恶臭的异腈为反应试剂、需要使用外源的金属或非金属氧化剂、底物适用范围较窄、产率较低、反应条件较苛刻等。因此，开发一种反应试剂友好且易得、不需要外源的氧化剂、底物适用范围广、产率优良、反应条件温和的合成咪唑并[1,5-a]吲哚类化合物的方法成为本发明亟待解决的技术问题。
发明内容
本发明的目的就是为了解决上述技术问题，从而提供一种制备咪唑并[1,5-a]吲哚化合物的方法并获得相应的咪唑并[1,5-a]吲哚母环化合物，在药理活性分子研究中具有潜在的应用价值。
本发明的目的之一是提供一种制备式(Ⅲ)所示咪唑并[1,5-a]吲哚化合物的方法，所述方法包括步骤S1：
S1：采用铑催化吲哚与烯烃之间的[4+1]环加成反应制备化合物Ⅲ，其中，催化剂为[Cp*RhCl2]2，添加剂为NaOAc，溶剂为丙酮；
步骤S1涉及的反应方程式如下：
其中，R1代表苯环上任意位置的取代基，其选自以下基团：氢、卤素、烷基、烷氧基、3-6元含一个N、O或S原子的杂环、氰基、酯基；
R2选自以下基团：氢、取代或未取代的烷基；
R3选自以下基团：取代或未取代的烷基；
R4选自以下基团：酯基、酰胺基、酮基；
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：甲基、苯基、酯基；所述的LG为芳氧基或对甲苯磺酰氧基。
本发明开发出了一类铑催化的吲哚和烯烃之间的[4+1]环加成反应，成功制备了一系列具有咪唑并[1,5-a]吲哚母核的化合物。该方法的最大特点是使用烯烃作为一碳合成子参与铑催化的[4+1]环加成反应。该反应具有底物适用范围广、化学选择性和区域选择性高、产率良好、官能团耐受性好、反应步骤经济、温和的中性反应条件等优点。该反应可以放大到克级规模，进一步证明这类反应的实用性。此外，本发明提供的上述合成方法还可以应用到对天然产物如褪黑素的结构修饰中，具有广阔的应用前景。
进一步的是，所述的卤素包括F、Cl、Br或I。
进一步的是，所述的烷基包括甲基或乙基，所述的烷氧基包括甲氧基或乙氧基；所述取代的烷基包括异丙基、叔丁基、苄基或CH2CO2Et。
进一步的是，所述的3-6元杂环包括以下基团：
进一步的是，所述步骤S1的反应温度为60℃，反应时间为24h。
进一步的是，所述化合物Ⅰ和化合物Ⅱ的摩尔比为1:1.2。
进一步的是，所述催化剂的量为化合物Ⅰ摩尔量的1％～10％，优选为5％(实施例中以剂用量为5％为例)。
进一步的是，所述添加剂与化合物Ⅰ的摩尔比为1:1。
本发明的目的之二是提供由上述方法制备得到的如式(Ⅲ)所示的咪唑并[1,5-a]吲哚化合物。并且本发明的实施例中提供了一系列已被成功合成的化合物Ⅲ，并对这一系列化合物进行了表征。
本发明的有益效果如下：
本发明开发出了一类铑催化的吲哚和烯烃之间的[4+1]环加成反应，成功制备了一系列具有咪唑并[1,5-a]吲哚母核的化合物。该方法具有底物适用范围广、化学选择性和区域选择性高、产率良好、官能团耐受性好、反应步骤经济、温和的中性反应条件等优点，且可以放大到克级规模，具有较好的实用性。此外，本发明提供的上述合成方法还可以应用到对天然产物如Melatonin(褪黑素)的结构修饰中，具有广阔的应用前景。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例对本发明进行具体描述，有必要指出的是，以下实施例仅仅用于对本发明进行解释和说明，并不用于限定本发明。本领域技术人员根据上述发明内容所做出的一些非本质的改进和调整，仍属于本发明的保护范围。
实施例1
反应条件的优化：按照表1涉及的反应式，选用吲哚1aa和(E)-苯基3-苯氧基丙烯酰酸酯2aa作为模板底物，按照表1所示步骤对反应条件进行优化。
首先，以NaOAc为添加剂，在一系列金属催化剂的催化下，1aa和2aa在DCE(1,2-二氯乙烷)中于60℃反应24h(序号1-6)，结果显示：当以[Cp*RhCl2]2为催化剂时(序号6)，[4+1]环化产物3aa收率为67％，且具有良好的区域选择性，C–H活化发生在吲哚C2位置并且C-C/C-N键在同一近端sp2杂化碳上形成。
然后，分别以[Cp*RhCl2]2和NaOAc为催化剂和添加剂，对各种溶剂进行筛选(序号7-15)，结果表明：除DMF(序号15)外，目标[4+1]环化反应在多种溶剂中均可耐受，以丙酮为最佳，在丙酮中产物3aa的收率为88％(序号10)。有趣的是，当以甲醇为溶剂时，得到的是3aa的酯交换产物即4aa作为最终产物(序号13)。
随后，在丙酮中研究了各种添加剂(序号16-22)，结果证明NaOAc是最有效的添加剂。
最后，进行了空白实验(序号23和24)。结果表明，[Cp*RhCl2]2和NaOAc均不可或缺，[Cp*RhCl2]2/NaOAc催化体系是成功实现[4+1]环化反应的关键。
值得注意的是，在优化反应条件过程中没有观察到[4+2]环化和C-H烯基化的背景反应产物，表明该转化具有良好的化学选择性。
表1.反应条件优化a
a反应条件：1aa(0.25mmol)，2aa(0.3mmol)，催化剂(5mol％)，添加剂(0.25mmol)，溶剂(4.0mL)，反应温度60℃，反应时间24h；b指分离产率；c指酯交换产物4aa的分离产率。
实施例2
按照下列反应式制备具有咪唑并[1,5-a]吲哚母核的化合物3。
其中反应条件如下：吲哚底物1(0.25mmol)，烯烃底物2aa(0.3mmol)，催化剂[Cp*RhCl2]2(5mol％)，添加剂NaOAc(0.25mmol)，溶剂丙酮(4.0mL)，反应温度60℃，反应时间24h。
在上述最佳反应条件下，对上述反应式中的R1、R2、R3基团进行不同取代，考查上述反应式对吲哚底物1的适用范围，考查结果如下表2：
表2.吲哚底物适用范围a,b
a反应条件：1(0.25mmol),2aa(0.3mmol),[Cp*RhCl2]2(5mol％),NaOAc(0.25mmol),acetone(4.0mL),60℃,24h.b指分离产率.ND代表相应产物未检出，即无法完成相应的反应.
上述结果表明，本发明提供的铑催化吲哚与烯烃之间的[4+1]环加成反应具有吲哚底物适用范围广、化学选择性和区域选择性高、产率良好、官能团耐受性好、反应步骤经济、温和的中性反应条件等优点，可以高效地合成一系列具有咪唑并[1,5-a]吲哚母核的化合物3。
实施例3
按照下列反应式制备具有咪唑并[1,5-a]吲哚母核的化合物4。
其中反应条件如下：吲哚底物1aa(0.25mmol)，烯烃底物2(0.3mmol)，催化剂[Cp*RhCl2]2(5mol％)，添加剂NaOAc(0.25mmol)，溶剂丙酮(4.0mL)，反应温度60℃，反应时间24h。
对上述反应式中的Ar基团和R4基团进行不同取代，考查上述反应式对烯烃底物2的适用范围，考查结果如下表3，表3中显示的产率均为分离产率，其中ND代表相应产物未检出，即无法完成相应的反应：
表3.烯烃底物适用范围a,b
a反应条件：1aa(0.25mmol),2(0.3mmol),[Cp*RhCl2]2(5mol％),NaOAc(0.25mmol),acetone(4.0mL),60℃,24h；b指分离产率；c使用(Z)-N-苯甲基-3-苯氧基丙烯酰基酰胺为反应底物.ND代表相应产物未检出，即无法完成相应的反应。
上述结果表明，本发明提供的铑催化吲哚与烯烃之间的[4+1]环加成反应具有烯烃底物适用范围广、化学选择性和区域选择性高、产率良好、官能团耐受性好、反应步骤经济、温和的中性反应条件等优点，可以高效地合成一系列具有咪唑并[1,5-a]吲哚母核的化合物4。
实施例4
将实施例3中的烯烃底物2的取代基团由ArO替换为TsO，在最佳反应条件下发生下列反应，计算所得产物4aa的产率为81％。
实施例5
克级放大反应实验：按照如下的反应条件进行克级放大反应，以1aa(6mmol)和2aa(7.2mmol)进行反应时，能以87％的产率得到目标产物3aa。放大反应实验结果证明：该反应可以放大到克级规模，进一步证明这类反应的实用性。此外，该反应还可以应用到对天然产物如melatonin(褪黑素)的结构修饰中，以74％的产率获得褪黑素衍生物4at。
Gram-scale experiments
Application in derivatization of natural products
实施例6
对上述实施例2、3、4和5中制备的系列化合物3和4的具体表征：
按照下述步骤，在25mL舒伦克试管中依次加入吲哚底物1(0.25mmol)、[Cp*RhCl2]2(5mol％)、NaOAc(0.25mmol)，然后向其中加入含有烯烃底物2(0.3mmol)的丙酮(4.0mL)溶液。然后用橡胶塞封住试管，将得到的反应混合物在60℃油浴中搅拌24小时。去除溶剂后，在硅胶上采用快速色谱法对得到的残留物进行分离纯化，得到所需的目标产物。按照上述方法成功制备出一系列具有咪唑并[1,5-a]吲哚母核的化合物3和4(化合物一至四十九)，并采用氢谱+碳谱+高分辨质谱对所得产物进行表征，所得化合物的表征结果如下：
化合物一(3aa)：
苯基2-(2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色无定形固体(74.2mg，产率88％)，熔点(mp)128-129℃。
1H NMR(600MHz,CDCl3)δ8.00(d,J＝8.1Hz,1H),7.59(d,J＝7.8Hz,1H),7.46-7.38(m,2H),7.37-7.31(m,1H),7.30-7.26(m,2H),7.16-7.08(m,2H),6.47(s,1H),5.38-5.30(m,1H),4.01(s,3H),3.31(dd,J＝16.5,6.2Hz,1H),3.08(dd,J＝16.5,7.2Hz,1H)；13C NMR(151MHz,CDCl3)δ168.51,152.46,150.37,134.79,132.80,130.96,129.69,126.35,124.17,123.50,121.46,121.42,113.02,100.20,65.09,55.29,37.86；HRMS(ESI)m/z:[M+H]+Calcd for C19H17N2O4337.1183；Found 337.1177.
化合物二(3ab)：
苯基2-(8-氟-2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(8-fluoro-2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到白色无定形固体(70.0mg，产率79％)，熔点(mp)122-123℃。
1H NMR(500MHz,CDCl3)δ7.77(d,J＝8.1Hz,1H),7.44-7.39(m,2H),7.30-7.26(m,2H),7.14-7.08(m,2H),6.96(ddd,J＝10.0,8.1,0.5Hz,1H),6.59(dd,J＝1.5,0.7Hz,1H),5.38-5.32(m,1H),4.01(s,3H),3.33(dd,J＝16.6,6.1Hz,1H),3.10(dd,J＝16.6,7.2Hz,1H)；13C NMR(126MHz,CDCl3)δ168.40,156.00(d,JC-F＝249.0Hz),152.09,150.39,134.81,133.04(d,JC-F＝9.9Hz),129.77,126.46,125.17(d,JC-F＝7.4Hz),121.61,121.44,109.16(d,JC-F＝3.9Hz),108.89(d,JC-F＝18.8Hz),96.23,65.20,55.18,37.74；HRMS(ESI)m/z:[M+H]+Calcd for C19H16FN2O4355.1089；Found 355.1083.
化合物三(3ac)：
苯基2-(8-氯-2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(8-chloro-2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到白色无定形固体(73.6mg，产率79％)，mp(熔点)78-79℃。
1H NMR(600MHz,CDCl3)δ7.88(d,J＝7.8Hz,1H),7.45-7.39(m,2H),7.30-7.24(m,3H),7.12(d,J＝7.7Hz,2H),6.61(s,1H),5.40-5.33(m,1H),4.01(s,3H),3.33(dd,J＝16.6,6.1Hz,1H),3.11(dd,J＝16.6,7.2Hz,1H)；13C NMR(151MHz,CDCl3)δ168.41,152.00,150.34,135.34,131.59,131.48,129.76,126.46,124.98,123.34,121.44,111.53,98.72,65.21,55.20,37.66；HRMS(ESI)m/z:[M+H]+Calcd for C19H16ClN2O4371.0793；Found371.0792.
化合物四(3ad)：
苯基2-(8-溴-2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(8-bromo-2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到淡黄色无定形固体(79.4mg，产率76％)，mp(熔点)97-98℃。
1H NMR(500MHz,CDCl3)δ7.93(d,J＝8.1Hz,1H),7.46-7.39(m,3H),7.30-7.26(m,1H),7.23-7.17(m,1H),7.15-7.10(m,2H),6.58(dd,J＝1.5,0.7Hz,1H),5.41-5.31(m,1H),4.01(s,3H),3.33(dd,J＝16.6,6.1Hz,1H),3.11(dd,J＝16.6,7.2Hz,1H)；13C NMR(126MHz,CDCl3)δ168.41,152.04,150.39,135.38,133.43,131.29,129.78,126.48,125.26,121.46,114.90,112.08,100.44,65.22,55.25,37.67；HRMS(ESI)m/z:[M+H]+Calcd forC19H16BrN2O4415.0288；Found415.0283.
化合物五(3ae)：
苯基2-(7-氟-2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(7-fluoro-2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到白色无定形固体(78.1mg，产率88％)，mp(熔点)119-120℃。
1H NMR(600MHz,CDCl3)δ7.91(dd,J＝8.8,4.5Hz,1H),7.46-7.37(m,2H),7.30-7.26(m,1H),7.24(dd,J＝9.0,2.2Hz,1H),7.11(d,J＝7.7Hz,2H),7.09-7.05(m,1H),6.45(s,1H),5.37-5.28(m,1H),4.00(s,3H),3.33(dd,J＝16.6,6.1Hz,1H),3.09(dd,J＝16.6,7.3Hz,1H)；13C NMR(151MHz,CDCl3)δ168.47,159.72(d,JC-F＝240.2Hz),152.22,150.35,136.53,133.69(d,JC-F＝10.3Hz),129.76,127.41,126.45,121.42,113.82(d,JC-F＝9.6Hz),112.35(d,JC-F＝25.9Hz),107.13(d,JC-F＝24.4Hz),100.19(d,JC-F＝4.2Hz),65.21,55.26,37.70；HRMS(ESI)m/z:[M+H]+Calcd for C19H16FN2O4355.1089；Found355.1088.
化合物六(3af)：
苯基2-(7-氯-2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(7-chloro-2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到淡黄色无定形固体(80.4mg，产率87％)，mp(熔点)87-88℃。
1H NMR(600MHz,CDCl3)δ7.89(d,J＝8.6Hz,1H),7.55(s,1H),7.45-7.38(m,2H),7.31-7.26(m,2H),7.10(d,J＝8.2Hz,2H),6.42(s,1H),5.36-5.30(m,1H),4.00(s,3H),3.33(dd,J＝16.6,6.0Hz,1H),3.09(dd,J＝16.6,7.3Hz,1H)；13CNMR(151MHz,CDCl3)δ168.44,152.04,150.34,136.18,133.91,129.77,129.31,129.18,126.47,124.54,121.41,121.16,113.90,99.76,65.22,55.20,37.66；HRMS(ESI)m/z:[M+H]+Calcd forC19H16ClN2O4371.0793；Found 371.0791.
化合物七(3ag)：
苯基2-(7-溴-2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(7-bromo-2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到白色无定形固体(83.4mg，产率80％)，mp(熔点)112-113℃。
1H NMR(600MHz,CDCl3)δ7.84(d,J＝8.6Hz,1H),7.72(d,J＝1.6Hz,1H),7.45-7.38(m,3H),7.30-7.26(m,1H),7.10(d,J＝7.7Hz,2H),6.42(s,1H),5.37-5.31(m,1H),4.00(s,3H),3.33(dd,J＝16.6,6.1Hz,1H),3.08(dd,J＝16.6,7.4Hz,1H)；13C NMR(151MHz,CDCl3)δ168.42,152.00,150.33,136.01,134.41,129.77,129.63,127.17,126.47,124.21,121.41,116.81,114.29,99.63,65.23,55.17,37.67；HRMS(ESI)m/z:[M+H]+Calcd forC19H16BrN2O4415.0288；Found415.0278.
化合物八(3ah)：
苯基2-(7-碘-2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(7-iodo-2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色粘稠油状物(99.2mg，产率86％)。
1H NMR(600MHz,CDCl3)δ7.93(d,J＝1.1Hz,1H),7.74(d,J＝8.5Hz,1H),7.60(dd,J＝8.5,1.4Hz,1H),7.45-7.38(m,2H),7.30-7.26(m,1H),7.10(d,J＝7.8Hz,2H),6.40(s,1H),5.37-5.31(m,1H),4.00(s,3H),3.33(dd,J＝16.6,6.1Hz,1H),3.08(dd,J＝16.6,7.3Hz,1H)；13C NMR(151MHz,CDCl3)δ168.42,152.00,150.33,135.62,134.97,132.74,130.39,130.13,129.77,126.47,121.41,114.71,99.33,87.47,65.22,55.12,37.69；HRMS(ESI)m/z:[M+H]+Calcd for C19H16IN2O4463.0149；Found 463.0141.
化合物九(3ai)：
苯基2-(6-氟-2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(6-fluoro-2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色无定形固体(75.9mg，产率86％)，mp(熔点)116-117℃。
1H NMR(600MHz,CDCl3)δ7.68(dd,J＝8.7,1.7Hz,1H),7.50(dd,J＝8.7,5.0Hz,1H),7.44-7.38(m,2H),7.30-7.26(m,1H),7.11(d,J＝7.9Hz,2H),7.05-7.00(m,1H),6.45(s,1H),5.36-5.29(m,1H),4.00(s,3H),3.33(dd,J＝16.5,6.1Hz,1H),3.08(dd,J＝16.5,7.3Hz,1H)；13C NMR(151MHz,CDCl3)δ168.49,160.59(d,JC-F＝242.1Hz),152.04,150.36,135.03(d,JC-F＝3.9Hz),130.92(d,JC-F＝13.1Hz),129.76,129.02,126.44,122.24(d,JC-F＝9.9Hz),121.43,112.04(d,JC-F＝24.3Hz),100.26(d,JC-F＝27.5Hz),100.10,65.19,55.23,37.81；HRMS(ESI)m/z:[M+H]+Calcd for C19H16FN2O4355.1089；Found 355.1085.
化合物十(3aj)：
苯基2-(6-氯-2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(6-chloro-2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到淡黄色无定形固体(77.5mg，产率84％)，mp 99-100℃。
1H NMR(600MHz,CDCl3)δ7.99(s,1H),7.48(d,J＝8.4Hz,1H),7.44-7.38(m,2H),7.30-7.26(m,1H),7.24(dd,J＝8.4,1.3Hz,1H),7.11(d,J＝8.2Hz,2H),6.45(s,1H),5.37-5.31(m,1H),4.01(s,3H),3.33(dd,J＝16.6,6.0Hz,1H),3.08(dd,J＝16.6,7.4Hz,1H)；13CNMR(151MHz,CDCl3)δ168.44,151.91,150.35,135.30,131.22,130.18,129.76,126.45,124.22,122.25,121.42,113.24,100.14,65.21,55.21,37.72；HRMS(ESI)m/z:[M+H]+Calcdfor C19H16ClN2O4371.0793；Found371.0785.
化合物十一(3ak)：
苯基2-(6-溴-2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(6-bromo-2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到淡黄色无定形固体(85.7mg，产率83％)，mp 115-116℃。
1H NMR(600MHz,CDCl3)δ8.15(s,1H),7.45-7.39(m,3H),7.37(dd,J＝8.4,1.7Hz,1H),7.29-7.26(m,1H),7.10(d,J＝7.6Hz,2H),6.45(d,J＝0.6Hz,1H),5.36-5.28(m,1H),4.00(s,3H),3.33(dd,J＝16.6,6.0Hz,1H),3.08(dd,J＝16.6,7.4Hz,1H)；13C NMR(151MHz,CDCl3)δ168.43,151.87,150.34,135.21,131.58,131.53,129.76,126.86,126.45,122.62,121.41,117.71,116.14,100.19,65.21,55.19,37.67；HRMS(ESI)m/z:[M+H]+Calcd forC19H16BrN2O4415.0288；Found415.0277.
化合物十二(3al)：
苯基2-(2-甲氧基-8-甲基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(2-methoxy-8-methyl-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到白色无定形固体(66.3mg，产率76％)，mp 77-78℃。
1H NMR(600MHz,CDCl3)δ7.83(d,J＝8.1Hz,1H),7.46-7.40(m,2H),7.30-7.27(m,1H),7.26-7.22(m,1H),7.13(d,J＝8.4Hz,2H),7.08(d,J＝7.3Hz,1H),6.51(s,1H),5.38-5.31(m,1H),4.01(s,3H),3.33(dd,J＝16.5,5.8Hz,1H),3.09(dd,J＝16.5,7.3Hz,1H),2.52(s,3H)；13C NMR(151MHz,CDCl3)δ168.67,152.64,150.41,134.25,132.54,131.03,130.73,129.75,126.41,124.31,123.93,121.46,110.57,98.84,65.15,55.37,37.97,18.80；HRMS(ESI)m/z:[M+H]+Calcd for C20H19N2O4351.1339；Found 351.1330.
化合物十三(3am)：
苯基2-(2,8-二甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(2,8-dimethoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到淡黄色无定形固体(75.4mg，产率82％)，mp 102-103℃。
1H NMR(600MHz,CDCl3)δ7.60(d,J＝8.1Hz,1H),7.45-7.38(m,2H),7.29-7.27(m,1H),7.27-7.25(m,1H),7.15-7.09(m,2H),6.71(d,J＝8.0Hz,1H),6.62-6.57(m,1H),5.37-5.32(m,1H),4.00(s,3H),3.94(s,3H),3.29(dd,J＝16.5,6.4Hz,1H),3.08(dd,J＝16.5,7.0Hz,1H)；13C NMR(151MHz,CDCl3)δ168.53,153.30,152.54,150.42,133.15,132.14,129.71,126.36,125.32,122.97,121.49,106.12,103.79,97.53,65.10,55.56,55.29,38.03；HRMS(ESI)m/z:[M+H]+Calcd for C20H19N2O5367.1288；Found 367.1279.
化合物十四(3an)：
苯基2-(2-甲氧基-7-甲基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(2-methoxy-7-methyl-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色粘稠油状物(72.9mg，产率83％)。
1H NMR(600MHz,CDCl3)δ7.86(d,J＝8.3Hz,1H),7.44-7.39(m,2H),7.37(s,1H),7.30-7.26(m,1H),7.16(d,J＝8.3Hz,1H),7.11(d,J＝8.2Hz,2H),6.39(s,1H),5.35-5.29(m,1H),4.00(s,3H),3.31(dd,J＝16.4,6.3Hz,1H),3.07(dd,J＝16.4,7.2Hz,1H),2.45(s,3H)；13C NMR(151MHz,CDCl3)δ168.61,152.64,150.41,134.92,133.19,133.14,129.74,129.19,126.39,125.64,121.47,121.35,112.66,99.97,65.14,55.42,37.99,21.71；HRMS(ESI)m/z:[M+H]+Calcd for C20H19N2O4351.1339；Found 351.1331.
化合物十五(3ao)：
苯基2-(2,7-二甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(2,7-dimethoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色无定形固体(77.9mg，产率85％)，mp 117-118℃。
1H NMR(600MHz,CDCl3)δ7.86(d,J＝8.8Hz,1H),7.44-7.39(m,2H),7.29-7.26(m,1H),7.14-7.09(m,2H),7.04(d,J＝2.4Hz,1H),6.96(dd,J＝8.8,2.4Hz,1H),6.40(d,J＝0.8Hz,1H),5.34-5.27(m,1H),3.99(s,3H),3.85(s,3H),3.31(dd,J＝16.4,6.2Hz,1H),3.07(dd,J＝16.4,7.3Hz,1H)；13C NMR(151MHz,CDCl3)δ168.58,156.62,152.60,150.40,135.65,133.84,129.73,126.39,125.73,121.46,113.67,113.26,104.11,100.17,65.17,55.86,55.44,37.93；HRMS(ESI)m/z:[M+H]+Calcd for C20H19N2O5367.1288；Found367.1281.
化合物十六(3ap)：
苯基2-(7-乙基-2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(7-ethyl-2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色粘稠油状物(75.7mg，产率83％)。
1H NMR(600MHz,CDCl3)δ7.89(d,J＝8.3Hz,1H),7.44-7.38(m,3H),7.30-7.26(m,1H),7.19(d,J＝8.3Hz,1H),7.12(d,J＝7.9Hz,2H),6.42(d,J＝0.4Hz,1H),5.36-5.30(m,1H),4.00(s,3H),3.31(dd,J＝16.4,6.3Hz,1H),3.07(dd,J＝16.4,7.2Hz,1H),2.75(q,J＝7.6Hz,2H),1.28(t,J＝7.6Hz,3H)；13C NMR(151MHz,CDCl3)δ168.61,152.64,150.42,139.84,134.95,133.15,129.73,129.35,126.39,124.66,121.47,120.15,112.80,100.10,65.14,55.42,38.02,29.18,16.36；HRMS(ESI)m/z:[M+H]+Calcd for C21H21N2O4365.1496；Found 365.1488.
化合物十七(3aq)：
苯基2-(7-乙氧基-2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(7-ethoxy-2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色无定形固体(76.9mg，产率81％)，mp 131-132℃。
1H NMR(600MHz,CDCl3)δ7.85(d,J＝8.8Hz,1H),7.44-7.38(m,2H),7.28(d,J＝7.5Hz,1H),7.11(d,J＝8.1Hz,2H),7.03(d,J＝1.8Hz,1H),6.95(dd,J＝8.8,2.0Hz,1H),6.39(s,1H),5.34-5.26(m,1H),4.06(q,J＝7.0Hz,2H),3.99(s,3H),3.31(dd,J＝16.4,6.2Hz,1H),3.07(dd,J＝16.4,7.2Hz,1H),1.44(t,J＝7.0Hz,3H)；13C NMR(151MHz,CDCl3)δ168.60,155.94,152.63,150.40,135.58,133.84,129.73,126.39,125.69,121.46,113.80,113.65,104.99,100.18,65.16,64.14,55.45,37.94,15.05；HRMS(ESI)m/z:[M+H]+Calcdfor C21H21N2O5381.1445；Found381.1436.
化合物十八(3ar)：
苯基2-(2-甲氧基-6-甲基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(2-methoxy-6-methyl-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色粘稠油状物(68.7mg，产率78％)。
1H NMR(600MHz,CDCl3)δ7.81(s,1H),7.45(d,J＝8.1Hz,1H),7.44-7.39(m,2H),7.30-7.26(m,1H),7.14-7.08(m,3H),6.42(s,1H),5.36-5.30(m,1H),4.00(s,3H),3.30(dd,J＝16.4,6.3Hz,1H),3.07(dd,J＝16.4,7.2Hz,1H),2.49(s,3H)；13C NMR(151MHz,CDCl3)δ168.60,152.63,150.41,134.47,134.07,131.37,130.51,129.73,126.38,125.13,121.47,121.02,113.19,100.13,65.12,55.36,38.01,21.78；HRMS(ESI)m/z:[M+H]+Calcdfor C20H19N2O4351.1339；Found 351.1333.
化合物十九(3as)：
苯基2-(2,6-二甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(2,6-dimethoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色无定形固体(58.1mg，产率63％)，mp 107-108℃。
1H NMR(600MHz,CDCl3)δ7.49(d,J＝2.3Hz,1H),7.44(d,J＝8.7Hz,1H),7.43-7.39(m,2H),7.29-7.26(m,1H),7.13-7.09(m,2H),6.91(dd,J＝8.7,2.4Hz,1H),6.39(d,J＝1.4Hz,1H),5.35-5.29(m,1H),4.00(s,3H),3.88(s,3H),3.30(dd,J＝16.4,6.2Hz,1H),3.07(dd,J＝16.4,7.2Hz,1H)；13C NMR(151MHz,CDCl3)δ168.61,157.75,152.59,150.41,133.21,131.85,129.73,126.39,126.37,121.98,121.47,113.48,100.13,96.53,65.10,55.91,55.31,38.03；HRMS(ESI)m/z:[M+H]+Calcd for C20H19N2O5367.1288；Found367.1278.
化合物二十(3at)：
苯基2-(2-甲氧基-5-甲基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(2-methoxy-5-methyl-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到白色无定形固体(68.6mg，产率78％)，mp 87-88℃。
1H NMR(600MHz,CDCl3)δ7.44-7.40(m,2H),7.39(d,J＝7.8Hz,1H),7.30-7.27(m,1H),7.19-7.15(m,1H),7.14-7.09(m,3H),6.49(d,J＝1.5Hz,1H),5.34-5.27(m,1H),4.01(s,3H),3.30(dd,J＝16.3,6.3Hz,1H),3.08(dd,J＝16.4,7.0Hz,1H),2.91(s,3H)；13C NMR(151MHz,CDCl3)δ168.63,153.15,150.42,135.77,133.54,131.62,129.74,126.69,126.39,125.00,123.87,121.48,118.77,100.73,64.98,54.84,38.15,20.94；HRMS(ESI)m/z:[M+H]+Calcd for C20H19N2O4351.1339；Found351.1332.
化合物二十一(3au)：
苯基2-(7-(呋喃-2-基)-2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(7-(furan-2-yl)-2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色无定形固体(79.0mg，产率79％)，mp 120-121℃。
1H NMR(600MHz,CDCl3)δ7.97(d,J＝8.5Hz,1H),7.88(s,1H),7.66(dd,J＝8.5,1.5Hz,1H),7.48(d,J＝1.6Hz,1H),7.45-7.38(m,2H),7.30-7.26(m,1H),7.15-7.07(m,2H),6.65(d,J＝3.3Hz,1H),6.49(dd,J＝3.3,1.8Hz,1H),6.47(s,1H),5.36-5.29(m,1H),4.00(s,3H),3.32(dd,J＝16.5,6.2Hz,1H),3.09(dd,J＝16.5,7.2Hz,1H)；13C NMR(151MHz,CDCl3)δ168.49,154.37,152.23,150.36,141.94,135.48,133.16,130.14,129.71,126.77,126.38,121.42,120.68,116.66,113.18,111.80,104.60,100.47,65.12,55.28,37.78；HRMS(ESI)m/z:[M+H]+Calcd for C23H19N2O5403.1288；Found403.1286.
化合物二十二(3av)：
苯基2-(2-甲氧基-3-羰基-7-(噻吩-2-基)-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(2-methoxy-3-oxo-7-(thiophen-2-yl)-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色无定形固体(89.9mg，产率86％)，mp 132-133℃。
1H NMR(600MHz,CDCl3)δ7.97(d,J＝8.4Hz,1H),7.81(s,1H),7.61(dd,J＝8.4,1.5Hz,1H),7.46-7.38(m,2H),7.33-7.31(m,1H),7.30-7.26(m,2H),7.12(d,J＝7.7Hz,2H),7.09(dd,J＝5.0,3.7Hz,1H),6.49(s,1H),5.38-5.32(m,1H),4.01(s,3H),3.34(dd,J＝16.5,6.2Hz,1H),3.10(dd,J＝16.5,7.3Hz,1H)；13C NMR(151MHz,CDCl3)δ168.51,152.26,150.39,144.93,135.64,133.39,130.35,130.26,129.76,128.17,126.43,124.66,123.08,122.86,121.45,118.81,113.34,100.41,65.19,55.33,37.85；HRMS(ESI)m/z:[M+H]+Calcd for C23H19N2O4S 419.1060；Found419.1060.
化合物二十三(3aw)：
苯基2-(7-氰基-2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(7-cyano-2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:8/1→石油/乙酸乙酯:4/1)，得到白色无定形固体(23.4mg，产率26％)，mp 121-122℃。
1H NMR(600MHz,CDCl3)δ8.06(d,J＝8.4Hz,1H),7.93(s,1H),7.58(d,J＝8.4Hz,1H),7.45-7.39(m,2H),7.31-7.26(m,1H),7.10(d,J＝8.1Hz,2H),6.56(s,1H),5.42-5.35(m,1H),4.02(s,3H),3.38(dd,J＝16.8,5.8Hz,1H),3.12(dd,J＝16.8,7.5Hz,1H)；13C NMR(151MHz,CDCl3)δ168.25,151.28,150.25,136.90,132.65,132.59,129.79,127.30,126.55,126.54,121.35,119.62,113.83,106.96,100.23,65.27,54.97,37.37；HRMS(ESI)m/z:[M+H]+Calcd for C20H16N3O4362.1135；Found 362.1127.
化合物二十四(3ax)：
甲基2-甲氧基-3-羰基-1-(2-羰基-2-苯氧基乙基)-2,3-二氢-1H-咪唑并[1,5-a]吲哚-7-羧酸酯
methyl 2-methoxy-3-oxo-1-(2-oxo-2-phenoxyethyl)-2,3-dihydro-1H-imidazo[1,5-a]indole-7-carboxylate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:8/1→石油/乙酸乙酯:4/1)，得到淡黄色无定形固体(79.6mg，产率81％)，mp 126-127℃。
1H NMR(600MHz,CDCl3)δ8.33(s,1H),8.04(dd,J＝8.5,1.3Hz,1H),8.00(d,J＝8.5Hz,1H),7.45-7.38(m,2H),7.30-7.26(m,1H),7.10(d,J＝8.2Hz,2H),6.55(s,1H),5.40-5.33(m,1H),4.01(s,3H),3.94(s,3H),3.35(dd,J＝16.6,6.1Hz,1H),3.10(dd,J＝16.6,7.3Hz,1H)；13C NMR(151MHz,CDCl3)δ168.41,167.41,151.78,150.33,135.91,133.47,132.49,129.77,126.47,125.55,125.53,123.95,121.40,112.67,100.86,65.19,55.10,52.28,37.66；HRMS(ESI)m/z:[M+H]+Calcd for C21H19N2O6395.1238；Found395.1232.
化合物二十五(3ay)：
苯基2-(2-甲氧基-9-甲基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(2-methoxy-9-methyl-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到白色无定形固体(74.8mg，产率85％)，mp 122-123℃。
1H NMR(600MHz,CDCl3)δ7.96(d,J＝8.0Hz,1H),7.54(d,J＝7.8Hz,1H),7.42-7.37(m,2H),7.37-7.33(m,1H),7.32-7.28(m,1H),7.27-7.26(m,1H),7.10-7.05(m,2H),5.48-5.41(m,1H),3.97(s,3H),3.20-3.14(m,2H),2.31(s,3H)；13C NMR(151MHz,CDCl3)δ168.79,152.48,150.48,133.91,130.96,129.78,129.70,126.33,124.29,123.18,121.42,119.39,113.07,109.17,64.87,54.84,37.15,8.61；HRMS(ESI)m/z:[M+H]+Calcd forC20H19N2O4351.1339；Found 351.1333.
化合物二十六(3az)：
苯基2-(9-苯甲基-2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯phenyl 2-(9-benzyl-2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到白色无定形固体(42.4mg，产率40％)，mp 187-188℃。
1H NMR(600MHz,CDCl3)δ7.99(d,J＝8.1Hz,1H),7.49(d,J＝7.9Hz,1H),7.39-7.32(m,5H),7.30-7.26(m,4H),7.25-7.21(m,1H),6.96(d,J＝7.7Hz,2H),5.19(dd,J＝7.9,3.7Hz,1H),4.16(d,J＝16.5Hz,1H),4.10(d,J＝16.9Hz,1H),3.91(s,3H),2.75(dd,J＝16.6,7.9Hz,1H),2.68(dd,J＝16.5,3.8Hz,1H)；13C NMR(151MHz,CDCl3)δ168.57,152.25,150.45,139.09,133.14,131.05,130.67,129.63,129.06,128.83,126.96,126.22,124.43,123.34,121.40,119.79,113.15,112.75,64.83,54.78,36.96,30.39；HRMS(ESI)m/z:[M+H]+Calcd for C26H23N2O4427.1652；Found 427.1643.
化合物二十七(3ba)：
乙基2-(2-甲氧基-3-羰基-1-(2-羰基-2-苯氧基乙基)-2,3-二氢-1H-咪唑并[1,5-a]吲哚-9-基)乙酸酯
ethyl2-(2-methoxy-3-oxo-1-(2-oxo-2-phenoxyethyl)-2,3-dihydro-1H-imidazo[1,5-a]indol-9-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:8/1→石油/乙酸乙酯:4/1)，得到黄色粘稠油状物(41.7mg，产率39％)。
1H NMR(600MHz,CDCl3)δ7.98(d,J＝8.0Hz,1H),7.58(d,J＝7.8Hz,1H),7.40-7.34(m,3H),7.32-7.28(m,1H),7.26-7.21(m,1H),7.06(d,J＝7.9Hz,2H),5.55-5.47(m,1H),4.16(q,J＝7.1Hz,2H),3.98(s,3H),3.81-3.71(m,2H),3.34(dd,J＝16.7,4.8Hz,1H),3.20(dd,J＝16.7,7.1Hz,1H),1.25(t,J＝7.1Hz,3H)；13C NMR(151MHz,CDCl3)δ170.75,168.95,152.18,150.47,132.65,131.94,130.79,129.62,126.26,124.51,123.43,121.45,119.39,113.12,106.21,64.89,61.45,54.94,36.89,30.15,14.27；HRMS(ESI)m/z:[M+H]+Calcdfor C23H23N2O6423.1551；Found423.1541.
化合物二十八(3bb)：
苯基2-(2-乙氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(2-ethoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:12/1)，得到淡黄色无定形固体(76.7mg，产率88％)，mp 113-114℃。
1H NMR(600MHz,CDCl3)δ8.00(d,J＝8.1Hz,1H),7.59(d,J＝7.8Hz,1H),7.44-7.39(m,2H),7.36-7.32(m,1H),7.30-7.26(m,2H),7.15-7.10(m,2H),6.48(s,1H),5.39-5.29(m,1H),4.29-4.17(m,2H),3.34(dd,J＝16.6,6.1Hz,1H),3.05(dd,J＝16.6,7.4Hz,1H),1.38(t,J＝7.1Hz,3H)；13C NMR(151MHz,CDCl3)δ168.64,152.64,150.41,135.01,132.78,131.03,129.72,126.39,124.17,123.48,121.47,113.07,100.15,73.07,55.46,37.89,13.94；HRMS(ESI)m/z:[M+H]+Calcd for C20H19N2O4351.1339；Found 351.1330.
化合物二十九(3bc)：
苯基2-(2-异丙氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(2-isopropoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:12/1)，得到无色粘稠油状物(63.7mg，产率70％)。
1H NMR(600MHz,CDCl3)δ8.00(d,J＝8.1Hz,1H),7.59(d,J＝7.8Hz,1H),7.44-7.38(m,2H),7.36-7.32(m,1H),7.30-7.26(m,2H),7.12(d,J＝7.8Hz,2H),6.48(s,1H),5.37-5.29(m,1H),4.46-4.37(m,1H),3.39(dd,J＝16.9,5.9Hz,1H),3.00(dd,J＝16.9,7.7Hz,1H),1.39(d,J＝6.2Hz,3H),1.36(d,J＝6.2Hz,3H)；13C NMR(151MHz,CDCl3)δ168.71,153.00,150.41,135.29,132.76,131.03,129.71,126.36,124.12,123.43,121.48,121.44,113.06,100.12,79.12,55.81,37.74,21.15,21.11；HRMS(ESI)m/z:[M+H]+Calcd forC21H21N2O4365.1496；Found 365.1487.
化合物三十(3be)：
苯基2-(2-(苄氧基)-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl 2-(2-(benzyloxy)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:12/1)，得到白色无定形固体(85.3mg，产率83％)，mp 83-84℃。
1H NMR(600MHz,CDCl3)δ8.01(d,J＝8.1Hz,1H),7.58(d,J＝7.8Hz,1H),7.54-7.47(m,2H),7.44-7.39(m,3H),7.39-7.33(m,3H),7.30-7.27(m,1H),7.26-7.24(m,1H),7.00(d,J＝7.9Hz,2H),6.43(s,1H),5.20-5.14(m,2H),5.13-5.07(m,1H),3.08(dd,J＝16.7,5.7Hz,1H),2.84(dd,J＝16.7,7.7Hz,1H)；13C NMR(151MHz,CDCl3)δ168.56,152.83,150.31,135.14,135.11,132.83,130.98,130.05,129.64,129.28,128.81,126.30,124.19,123.53,121.49,113.08,100.21,79.45,55.75,37.43；HRMS(ESI)m/z:[M+H]+Calcd forC25H21N2O4413.1496；Found 413.1487.
化合物三十一(3bf)：
苯基2-(2-甲氧基-5-甲基-3-羰基-2,3-二氢-1H-吡咯并[1,2-c]咪唑-1-基)乙酸酯
phenyl 2-(2-methoxy-5-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:10/1)，得到无色粘稠油状物(55.8mg，产率74％)。
1H NMR(600MHz,CDCl3)δ7.43-7.36(m,2H),7.27-7.24(m,1H),7.11-7.06(m,2H),6.05-6.01(m,1H),5.98(dd,J＝3.1,1.4Hz,1H),5.18-5.13(m,1H),3.94(s,3H),3.18(dd,J＝16.2,6.4Hz,1H),2.97(dd,J＝16.3,6.8Hz,1H),2.46(s,3H)；13C NMR(151MHz,CDCl3)δ168.67,152.54,150.41,129.65,128.85,126.26,126.20,121.45,113.77,103.79,64.79,54.55,38.20,11.41；HRMS(ESI)m/z:[M+H]+Calcd for C16H17N2O4301.1183；Found301.1175.
化合物三十二(4aa)：
甲基2-(2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
methyl 2-(2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色粘稠油状物(59.0mg，产率86％)。
1H NMR(500MHz,CDCl3)δ7.99-7.92(m,1H),7.55(d,J＝7.8Hz,1H),7.34-7.28(m,1H),7.27-7.21(m,1H),6.39(d,J＝0.9Hz,1H),5.26-5.15(m,1H),3.95(s,3H),3.77(s,3H),3.08(dd,J＝16.3,5.8Hz,1H),2.80(dd,J＝16.3,7.7Hz,1H)；13C NMR(126MHz,CDCl3)δ170.29,152.50,135.11,132.80,130.90,124.03,123.40,121.37,112.95,99.97,64.99,55.35,52.21,37.39；HRMS(ESI)m/z:[M+H]+Calcd for C14H15N2O4275.1026；Found275.1020.
化合物三十三(4ab)：
乙基2-(2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
ethyl 2-(2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色粘稠油状物(60.8mg，产率84％)。
1H NMR(600MHz,CDCl3)δ7.95(d,J＝8.1Hz,1H),7.56(d,J＝7.9Hz,1H),7.33-7.28(m,1H),7.26-7.23(m,1H),6.39(d,J＝0.9Hz,1H),5.24-5.16(m,1H),4.27-4.19(m,2H),3.95(s,3H),3.07(dd,J＝16.3,5.8Hz,1H),2.80(dd,J＝16.3,7.6Hz,1H),1.28(t,J＝7.2Hz,3H)；13C NMR(151MHz,CDCl3)δ169.82,152.52,135.20,132.80,130.89,124.00,123.38,121.36,112.95,99.94,65.01,61.29,55.38,37.67,14.25；HRMS(ESI)m/z:[M+H]+Calcd for C15H17N2O4289.1183；Found 289.1175.
化合物三十四(4ac)：
叔-丁基2-(2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
tert-butyl 2-(2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色粘稠油状物(61.3mg，产率78％)。
1H NMR(600MHz,CDCl3)δ7.96(d,J＝8.1Hz,1H),7.56(d,J＝7.8Hz,1H),7.33-7.28(m,1H),7.27-7.22(m,1H),6.38(d,J＝0.5Hz,1H),5.20-5.15(m,1H),3.95(s,3H),2.97(dd,J＝16.2,6.1Hz,1H),2.74(dd,J＝16.2,7.2Hz,1H),1.47(s,9H)；13C NMR(151MHz,CDCl3)δ169.05,152.53,135.44,132.82,130.89,123.92,123.34,121.33,112.94,99.70,81.93,65.01,55.56,38.87,28.09；HRMS(ESI)m/z:[M+H]+Calcd for C17H21N2O4317.1496；Found 317.1487.
化合物三十五(4ad)：
苯甲基2-(2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
benzyl 2-(2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色粘稠油状物(74.9mg，产率86％)。
1H NMR(600MHz,CDCl3)δ7.96(d,J＝8.1Hz,1H),7.54(d,J＝7.8Hz,1H),7.41-7.34(m,5H),7.34-7.30(m,1H),7.28-7.25(m,1H),6.30(s,1H),5.27-5.17(m,3H),3.89(s,3H),3.13(dd,J＝16.3,6.0Hz,1H),2.86(dd,J＝16.3,7.5Hz,1H)；13C NMR(151MHz,CDCl3)δ169.68,152.54,135.38,135.01,132.82,130.92,128.75,128.67,124.07,123.43,121.40,113.02,100.02,67.12,65.02,55.45,37.76；HRMS(ESI)m/z:[M+H]+Calcd forC20H19N2O4351.1339；Found 351.1330.
化合物三十六(4ae)：
2-甲氧苯基2-(2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
2-methoxyphenyl 2-(2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色粘稠油状物(64.2mg，产物70％)。
1H NMR(600MHz,CDCl3)δ7.99(d,J＝8.1Hz,1H),7.58(d,J＝7.8Hz,1H),7.36-7.31(m,1H),7.29-7.26(m,1H),7.26-7.23(m,1H),7.06(dd,J＝7.8,1.6Hz,1H),7.02-6.99(m,1H),6.99-6.96(m,1H),6.52(d,J＝0.8Hz,1H),5.36-5.29(m,1H),4.02(s,3H),3.84(s,3H),3.40(dd,J＝16.4,5.5Hz,1H),3.08(dd,J＝16.4,8.0Hz,1H)；13C NMR(151MHz,CDCl3)δ168.04,152.63,151.07,139.44,135.03,132.96,131.04,127.48,124.15,123.51,122.73,121.47,121.01,113.11,112.62,100.44,65.26,55.89,55.54,37.48；HRMS(ESI)m/z:[M+H]+Calcd for C20H19N2O5367.1288；Found 367.1279.
化合物三十七(4af)：
m-苯甲基2-(2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
m-tolyl 2-(2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色粘稠油状物(71.9mg，产率82％)。
1H NMR(600MHz,CDCl3)δ7.99(d,J＝8.1Hz,1H),7.59(d,J＝7.8Hz,1H),7.36-7.32(m,1H),7.31-7.26(m,2H),7.08(d,J＝7.5Hz,1H),6.95-6.87(m,2H),6.48(s,1H),5.38-5.30(m,1H),4.01(s,3H),3.31(dd,J＝16.4,6.2Hz,1H),3.07(dd,J＝16.4,7.3Hz,1H),2.37(s,3H)；13C NMR(151MHz,CDCl3)δ168.64,152.52,150.36,140.01,134.85,132.85,131.03,129.45,127.21,124.23,123.56,122.02,121.50,118.39,113.10,100.29,65.17,55.37,37.94,21.47；HRMS(ESI)m/z:[M+H]+Calcd for C20H19N2O4351.1339；Found351.1328.
化合物三十八(4ag)：
3-氯苯基2-(2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
3-chlorophenyl 2-(2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到淡黄色无定形固体(71.7mg，产率77％)，mp 121-122℃。
1H NMR(600MHz,CDCl3)δ7.99(d,J＝8.1Hz,1H),7.59(d,J＝7.9Hz,1H),7.37-7.31(m,2H),7.30-7.26(m,2H),7.17-7.13(m,1H),7.02(dd,J＝8.1,1.2Hz,1H),6.47(s,1H),5.37-5.30(m,1H),4.00(s,3H),3.30(dd,J＝16.5,6.3Hz,1H),3.09(dd,J＝16.5,7.1Hz,1H)；13C NMR(151MHz,CDCl3)δ168.19,152.47,150.81,135.03,134.62,132.80,131.03,130.48,126.72,124.32,123.63,122.19,121.53,119.87,113.11,100.29,65.15,55.21,37.86；HRMS(ESI)m/z:[M+H]+Calcd for C19H16ClN2O4371.0793；Found 371.0786.
化合物三十九(4ah)：
p-苯甲基2-(2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
p-tolyl 2-(2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色粘稠油状物(64.4mg，产率74％)。
1H NMR(600MHz,CDCl3)δ7.99(d,J＝8.0Hz,1H),7.59(d,J＝7.8Hz,1H),7.37-7.32(m,1H),7.30-7.26(m,1H),7.21(d,J＝8.2Hz,2H),7.03-6.97(m,2H),6.47(s,1H),5.39-5.30(m,1H),4.00(s,3H),3.31(dd,J＝16.4,6.3Hz,1H),3.07(dd,J＝16.5,7.3Hz,1H),2.36(s,3H)；13C NMR(151MHz,CDCl3)δ168.78,152.50,148.15,136.12,134.84,132.82,130.98,130.23,124.20,123.53,121.48,121.11,113.07,100.24,65.14,55.33,37.91,21.01；HRMS(ESI)m/z:[M+H]+Calcd for C20H19N2O4351.1339；Found 351.1332.
化合物四十(4ai)：
4-甲氧苯基2-(2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
4-methoxyphenyl 2-(2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色粘稠油状物(68.4mg，产率75％)。
1H NMR(600MHz,CDCl3)δ7.99(d,J＝8.1Hz,1H),7.58(d,J＝7.8Hz,1H),7.37-7.31(m,1H),7.29-7.26(m,1H),7.06-6.99(m,2H),6.93-6.90(m,2H),6.47(s,1H),5.38-5.29(m,1H),4.00(s,3H),3.81(s,3H),3.30(dd,J＝16.4,6.2Hz,1H),3.06(dd,J＝16.4,7.2Hz,1H)；13C NMR(151MHz,CDCl3)δ168.93,157.67,152.50,143.88,134.86,132.83,131.01,124.22,123.55,122.22,121.49,114.73,113.08,100.24,65.14,55.74,55.36,37.88；HRMS(ESI)m/z:[M+H]+Calcd for C20H19N2O5367.1288；Found 367.1277.
化合物四十一(4aj)：
4-氟苯基2-(2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
4-fluorophenyl 2-(2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到白色无定形固体(74.9mg，产率85％)，mp 86-87℃。
1H NMR(600MHz,CDCl3)δ7.99(d,J＝8.1Hz,1H),7.59(d,J＝7.9Hz,1H),7.37-7.31(m,1H),7.30-7.26(m,1H),7.14-7.02(m,4H),6.46(d,J＝0.7Hz,1H),5.37-5.29(m,1H),4.00(s,3H),3.30(dd,J＝16.5,6.3Hz,1H),3.08(dd,J＝16.5,7.1Hz,1H)；13C NMR(151MHz,CDCl3)δ168.60,160.55(d,JC-F＝245.2Hz),152.47,146.18(d,JC-F＝2.9Hz),134.69,132.79,131.00,124.29,123.60,122.89(d,JC-F＝8.5Hz),121.50,116.42(d,JC-F＝23.5Hz),113.09,100.24,65.13,55.24,37.82；HRMS(ESI)m/z:[M+H]+Calcd forC19H16FN2O4355.1089；Found 355.1083.
化合物四十二(4ak)：
4-氯苯基2-(2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
4-chlorophenyl 2-(2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到白色无定形固体(79.4mg，产率86％)，mp 93-94℃。
1H NMR(600MHz,CDCl3)δ7.99(d,J＝8.0Hz,1H),7.59(d,J＝7.9Hz,1H),7.40-7.32(m,3H),7.30-7.26(m,1H),7.10-7.02(m,2H),6.46(d,J＝0.7Hz,1H),5.37-5.29(m,1H),3.99(s,3H),3.30(dd,J＝16.5,6.3Hz,1H),3.08(dd,J＝16.5,7.1Hz,1H)；13C NMR(151MHz,CDCl3)δ168.35,152.46,148.83,134.65,132.79,131.84,131.02,129.81,124.31,123.62,122.84,121.51,113.11,100.26,65.14,55.22,37.86；HRMS(ESI)m/z:[M+H]+Calcd forC19H16ClN2O4371.0793；Found371.0791.
化合物四十三(4al)：
4-溴苯基2-(2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
4-bromophenyl 2-(2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色粘稠油状物(93.7mg，产率90％)。
1H NMR(600MHz,CDCl3)δ7.98(d,J＝8.1Hz,1H),7.58(d,J＝7.9Hz,1H),7.52(d,J＝8.7Hz,2H),7.37-7.31(m,1H),7.30-7.26(m,1H),7.00(d,J＝8.7Hz,2H),6.45(s,1H),5.36-5.28(m,1H),3.99(s,3H),3.29(dd,J＝16.5,6.3Hz,1H),3.08(dd,J＝16.5,7.0Hz,1H)；13C NMR(151MHz,CDCl3)δ168.24,152.43,149.36,134.62,132.77,130.98,124.29,123.59,123.24,121.49,119.51,113.07,100.24,65.11,55.19,37.83；HRMS(ESI)m/z:[M+H]+Calcd for C19H16BrN2O4415.0288；Found415.0284.
化合物四十四(4am)：
4-碘苯基2-(2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
4-iodophenyl 2-(2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色粘稠油状物(94.4mg，产率82％)。
1H NMR(600MHz,CDCl3)δ8.01-7.96(m,1H),7.74-7.68(m,2H),7.58(d,J＝7.9Hz,1H),7.37-7.32(m,1H),7.29-7.26(m,1H),6.91-6.85(m,2H),6.45(d,J＝0.8Hz,1H),5.36-5.29(m,1H),3.99(s,3H),3.29(dd,J＝16.5,6.3Hz,1H),3.08(dd,J＝16.5,7.0Hz,1H)；13CNMR(151MHz,CDCl3)δ168.22,152.45,150.21,138.80,134.63,132.78,131.00,124.31,123.62,121.51,113.09,100.26,90.49,65.13,55.20,37.87；HRMS(ESI)m/z:[M+H]+Calcdfor C19H16IN2O4463.0149；Found463.0143.
化合物四十五(4an)：
N-苯甲基-2-(2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酰胺
N-benzyl-2-(2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetamide
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:8/1→石油/乙酸乙酯:4/1)，得到白色无定形固体；((Z)-N-苯甲基-3-苯氧基丙烯酰基酰胺:39.4mg，产率45％；(E)-N-苯甲基-3-苯氧基丙烯酰基酰胺:38.4mg，产率44％)，mp 130-131℃。
1H NMR(600MHz,CDCl3)δ7.90(d,J＝8.0Hz,1H),7.52(d,J＝7.8Hz,1H),7.32-7.26(m,4H),7.26-7.22(m,3H),6.30(s,1H),6.16(s,1H),5.39-5.31(m,1H),4.47(d,J＝5.7Hz,2H),3.85(s,3H),2.94(dd,J＝14.9,6.2Hz,1H),2.60(dd,J＝14.9,7.3Hz,1H)；13C NMR(151MHz,CDCl3)δ168.56,152.25,137.90,135.29,132.80,130.87,128.87,127.98,127.80,124.01,123.42,121.43,112.92,100.03,64.70,55.33,43.88,39.63；HRMS(ESI)m/z:[M+H]+Calcd for C20H20N3O3 350.1499；Found 350.1490.
化合物四十六(4ao)：
2-(2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)-N-苯基乙酰胺
2-(2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)-N-phenylacetamide
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:8/1→石油/乙酸乙酯:4/1)，得到黄色无定形固体(61.2mg，产率73％)，mp 134-135℃。
1H NMR(600MHz,CDCl3)δ8.10(s,1H),7.86(d,J＝8.0Hz,1H),7.59(d,J＝7.8Hz,2H),7.49(d,J＝7.8Hz,1H),7.37-7.31(m,2H),7.26-7.22(m,1H),7.22-7.18(m,1H),7.16-7.11(m,1H),6.39(s,1H),5.46-5.40(m,1H),3.84(s,3H),3.07(dd,J＝15.0,6.4Hz,1H),2.72(dd,J＝15.0,7.5Hz,1H)；13C NMR(151MHz,CDCl3)δ167.24,152.42,137.73,135.21,132.82,130.78,129.21,124.80,124.06,123.50,121.51,120.18,112.75,100.32,64.69,55.21,40.48；HRMS(ESI)m/z:[M+H]+Calcd for C19H18N3O3336.1343；Found 336.1338.
化合物四十七(4ap)：
2-(2-甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)-N-甲基-N-苯基乙酰胺
2-(2-methoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)-N-methyl-N-phenylacetamide
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:8/1→石油/乙酸乙酯:4/1)，得到淡黄色无定形固体(49.3mg，产率56％)，mp 125-126℃。
1H NMR(600MHz,CDCl3)δ7.92(d,J＝7.8Hz,1H),7.56(d,J＝7.8Hz,1H),7.40-7.35(m,2H),7.33-7.31(m,1H),7.29-7.27(m,1H),7.25-7.22(m,1H),7.16-7.12(m,2H),6.42(d,J＝0.7Hz,1H),5.46-5.39(m,1H),3.87(s,3H),3.35(s,3H),2.84(dd,J＝16.2,6.0Hz,1H),2.44(dd,J＝16.2,7.7Hz,1H)；13C NMR(151MHz,CDCl3)δ169.01,152.05,143.24,136.07,132.81,130.90,130.20,128.40,127.32,123.81,123.26,121.32,112.92,99.94,64.55,55.32,37.79,37.47；HRMS(ESI)m/z:[M+H]+Calcd for C20H20N3O3350.1499；Found350.1492.
化合物四十八(4aq)：
2-甲氧基-1-(2-羰基-2-苯基乙基)-1H-咪唑并[1,5-a]吲哚-3(2H)-酮
2-methoxy-1-(2-oxo-2-phenylethyl)-1H-imidazo[1,5-a]indol-3(2H)-one
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:16/1→石油/乙酸乙酯:8/1)，得到黄色无定形固体(40.7mg，产率51％)，mp 128-129℃。
1H NMR(600MHz,CDCl3)δ8.02-7.94(m,3H),7.63-7.59(m,1H),7.54(d,J＝7.9Hz,1H),7.52-7.47(m,2H),7.33-7.29(m,1H),7.26-7.22(m,1H),6.39(s,1H),5.56-5.50(m,1H),3.95(s,3H),3.84(dd,J＝17.5,5.2Hz,1H),3.35(dd,J＝17.5,8.2Hz,1H)；13C NMR(151MHz,CDCl3)δ196.51,152.50,136.30,135.96,133.92,132.85,130.90,128.95,128.19,123.92,123.36,121.37,112.94,100.47,64.79,54.96,41.76；HRMS(ESI)m/z:[M+H]+Calcd for C19H17N2O3321.1234；Found 321.1226.
化合物四十九(4at)：
苯基2-(9-(2-乙酰氨基乙基)-2,7-二甲氧基-3-羰基-2,3-二氢-1H-咪唑并[1,5-a]吲哚-1-基)乙酸酯
phenyl2-(9-(2-acetamidoethyl)-2,7-dimethoxy-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-yl)acetate
将反应混合物直接在硅胶上进行快速色谱纯化(石油/乙酸乙酯:2/1→石油/乙酸乙酯:1/1)，得到淡黄色无定形固体(84.0mg，产率74％)，mp 111-112℃。
1H NMR(600MHz,DMSO-d6)δ8.01(t,J＝5.7Hz,1H),7.68(d,J＝8.8Hz,1H),7.44-7.36(m,2H),7.28-7.23(m,1H),7.22(d,J＝2.2Hz,1H),7.04(d,J＝7.9Hz,2H),6.94(dd,J＝8.8,2.3Hz,1H),5.49(dd,J＝6.6,3.9Hz,1H),3.87(s,3H),3.81(s,3H),3.48(dd,J＝16.6,3.8Hz,1H),3.34-3.26(m,2H),3.24(dd,J＝16.7,6.9Hz,1H),2.91-2.80(m,2H),1.80(s,3H)；13C NMR(151MHz,DMSO-d6)δ169.34,168.44,155.80,151.46,150.12,133.86,132.05,129.61,126.02,124.72,121.51,112.54,112.50,110.17,102.62,64.11,55.51,54.18,38.67,35.52,23.64,22.64；HRMS(ESI)m/z:[M+H]+Calcd for C24H26N3O6452.1816；Found452.1815。
Claims (10)
1.一种制备式(Ⅲ)所示咪唑并[1,5-a]吲哚化合物的方法，其特征在于，所述方法包括步骤S1：
S1：采用铑催化吲哚Ⅰ与烯烃Ⅱ之间的[4+1]环加成反应制备化合物Ⅲ，其中，催化剂为[Cp*RhCl2]2，添加剂为醋酸钠，溶剂为丙酮；
步骤S1涉及的反应方程式如下：
其中，R1代表苯环上任意位置的取代基，选自以下基团：氢、卤素、烷基、烷氧基、3-6元含一个N、O或S原子的杂环、氰基、酯基；
R2选自以下基团：氢、取代或未取代的烷基；
R3选自以下基团：取代或未取代的烷基；
R4选自以下基团：酯基、酰胺基、酮基；
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：甲基、苯基、酯基；所述的LG为芳氧基或对甲苯磺酰氧基。
2.根据权利要求1所述的方法，其特征在于，所述的卤素包括F、Cl、Br或I。
3.根据权利要求1所述的方法，其特征在于，所述的烷基包括甲基或乙基，所述的烷氧基包括甲氧基或乙氧基；所述取代的烷基包括异丙基、叔丁基、苄基或CH2CO2Et。
4.根据权利要求1所述的方法，其特征在于，所述的3-6元杂环包括以下基团：
5.根据权利要求1所述的方法，其特征在于，所述步骤S1的反应温度为60℃，反应时间为24h。
6.根据权利要求1所述的方法，其特征在于，所述化合物Ⅰ和化合物Ⅱ的摩尔比为1:1.2。
7.根据权利要求6所述的方法，其特征在于，所述催化剂的用量为化合物Ⅰ摩尔量的1％～10％，优选为5％。
8.根据权利要求1所述的方法，其特征在于，所述添加剂与化合物Ⅰ的摩尔比为1:1。
9.由权利要求1-8任一项所述方法制备得到的如式(Ⅲ)所示的咪唑并[1,5-a]吲哚化合物。
10.根据权利要求9所述的咪唑并[1,5-a]吲哚化合物，其特征在于，所述化合物Ⅲ包括具有以下任一结构的化合物：
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| US5637596A (en) * | 1994-05-24 | 1997-06-10 | Pharmacia S.P.A. | Azabicycloalkyl derivatives of imidazo[1,5-a]indol-3-one and process for their preparation |
| US5874457A (en) * | 1994-05-25 | 1999-02-23 | Pharmacia & Upjohn S.P.A. | Imidazolylalkyl derivatives of imidazo 1,5-a!indol-3-one |
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| US5637596A (en) * | 1994-05-24 | 1997-06-10 | Pharmacia S.P.A. | Azabicycloalkyl derivatives of imidazo[1,5-a]indol-3-one and process for their preparation |
| US5874457A (en) * | 1994-05-25 | 1999-02-23 | Pharmacia & Upjohn S.P.A. | Imidazolylalkyl derivatives of imidazo 1,5-a!indol-3-one |
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