WO2022188082A1 - 一种低催化量下进行靛红化合物和环丙烯酮化合物反应的方法 - Google Patents
一种低催化量下进行靛红化合物和环丙烯酮化合物反应的方法 Download PDFInfo
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- WO2022188082A1 WO2022188082A1 PCT/CN2021/080091 CN2021080091W WO2022188082A1 WO 2022188082 A1 WO2022188082 A1 WO 2022188082A1 CN 2021080091 W CN2021080091 W CN 2021080091W WO 2022188082 A1 WO2022188082 A1 WO 2022188082A1
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- Prior art keywords
- compound
- cyclopropenone
- isatin
- rare earth
- reaction
- Prior art date
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- -1 isatin compound Chemical class 0.000 title claims abstract description 97
- 238000006243 chemical reaction Methods 0.000 title claims abstract description 50
- JXDYKVIHCLTXOP-UHFFFAOYSA-N Pseudoisatin Natural products C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 20
- 230000003197 catalytic effect Effects 0.000 title claims abstract description 5
- GGRQLKPIJPFWEZ-UHFFFAOYSA-N cycloprop-2-en-1-one Chemical compound O=C1C=C1 GGRQLKPIJPFWEZ-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229910052761 rare earth metal Inorganic materials 0.000 claims abstract description 21
- 239000003054 catalyst Substances 0.000 claims abstract description 20
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 229910052710 silicon Inorganic materials 0.000 claims abstract description 10
- 239000010703 silicon Substances 0.000 claims abstract description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 96
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical group CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- GRPKBUFLDGGEPH-UHFFFAOYSA-N 9H-pyrano[2,3-b]indol-2-one Chemical class C1=CC=C2C(C=CC(O3)=O)=C3NC2=C1 GRPKBUFLDGGEPH-UHFFFAOYSA-N 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 5
- 229910000510 noble metal Inorganic materials 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- 239000000047 product Substances 0.000 description 25
- 239000002904 solvent Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 229910006400 μ-Cl Inorganic materials 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- HCIBTBXNLVOFER-UHFFFAOYSA-N diphenylcyclopropenone Chemical compound O=C1C(C=2C=CC=CC=2)=C1C1=CC=CC=C1 HCIBTBXNLVOFER-UHFFFAOYSA-N 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- ORYSFKVWQQMDAX-UHFFFAOYSA-N 1-ethylindole-2,3-dione Chemical compound C1=CC=C2N(CC)C(=O)C(=O)C2=C1 ORYSFKVWQQMDAX-UHFFFAOYSA-N 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 238000003818 flash chromatography Methods 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 8
- 229940126214 compound 3 Drugs 0.000 description 8
- 229940125782 compound 2 Drugs 0.000 description 7
- 239000012265 solid product Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 230000018044 dehydration Effects 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- 238000006392 deoxygenation reaction Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052746 lanthanum Inorganic materials 0.000 description 3
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 description 3
- 238000005580 one pot reaction Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- FVHNEDLBZCSUSN-UHFFFAOYSA-N pyrano[2,3-c]pyrazole Chemical compound O1C=CC=C2C=NN=C21 FVHNEDLBZCSUSN-UHFFFAOYSA-N 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- QNWMFJDRMZWZNN-UHFFFAOYSA-N 2,6-dimethylaniline;hydron;chloride Chemical compound Cl.CC1=CC=CC(C)=C1N QNWMFJDRMZWZNN-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- 229910052691 Erbium Inorganic materials 0.000 description 1
- 235000000177 Indigofera tinctoria Nutrition 0.000 description 1
- 229910052779 Neodymium Inorganic materials 0.000 description 1
- 229910052772 Samarium Inorganic materials 0.000 description 1
- XYQRXRFVKUPBQN-UHFFFAOYSA-L Sodium carbonate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]C([O-])=O XYQRXRFVKUPBQN-UHFFFAOYSA-L 0.000 description 1
- 229910052769 Ytterbium Inorganic materials 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- UYAHIZSMUZPPFV-UHFFFAOYSA-N erbium Chemical compound [Er] UYAHIZSMUZPPFV-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229940097275 indigo Drugs 0.000 description 1
- COHYTHOBJLSHDF-UHFFFAOYSA-N indigo powder Natural products N1C2=CC=CC=C2C(=O)C1=C1C(=O)C2=CC=CC=C2N1 COHYTHOBJLSHDF-UHFFFAOYSA-N 0.000 description 1
- 150000005625 indol-2-ones Chemical class 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 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
- 150000002739 metals Chemical class 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- QEFYFXOXNSNQGX-UHFFFAOYSA-N neodymium atom Chemical compound [Nd] QEFYFXOXNSNQGX-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229940018038 sodium carbonate decahydrate Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- NAWDYIZEMPQZHO-UHFFFAOYSA-N ytterbium Chemical compound [Yb] NAWDYIZEMPQZHO-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/48—Ring-opening reactions
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0202—Polynuclearity
- B01J2531/0205—Bi- or polynuclear complexes, i.e. comprising two or more metal coordination centres, without metal-metal bonds, e.g. Cp(Lx)Zr-imidazole-Zr(Lx)Cp
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
- B01J2531/11—Lithium
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/30—Complexes comprising metals of Group III (IIIA or IIIB) as the central metal
- B01J2531/37—Lanthanum
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/30—Complexes comprising metals of Group III (IIIA or IIIB) as the central metal
- B01J2531/38—Lanthanides other than lanthanum
Definitions
- the invention belongs to the technical field of preparation of fused heterocycles, and in particular relates to a method for reacting an isatin compound and a cyclopropenone compound under a low catalytic amount.
- Pyrano[2,3- b ]indol-2-one skeleton containing pyran and indole is one of the most important structural units in medicinal chemistry, such as the following pyrano[2 ,3- b ]indol-2-one skeleton compound: .
- the amount of the catalyst needs to be as small as possible, which is beneficial to the reaction cost, reaction stability and product purification.
- the invention discloses the reaction of isatin compound and cyclopropenone compound catalyzed by a relatively small amount of silylamino rare earth compound, and the reaction of isatin compound, phosphite and cyclopropenone catalyzed by the silylamino rare earth compound to realize a simple source of raw materials,
- the method for synthesizing pyrano[2,3- b ]indol-2-one compounds is simple with simple steps, mild reaction conditions, high activity and good generality.
- the technical scheme adopted in the present invention is: a method for carrying out the reaction of an isatin compound and a cyclopropenone compound under a low catalytic amount, comprising the following steps: in the presence of an amine compound and a phosphite, using a silicon amino group The rare earth compound is used as a catalyst, and the isatin compound and cyclopropenone are reacted in an organic solvent.
- the isatin compound of the present invention reacts with cyclopropenone under anhydrous and oxygen-free conditions, and the product of the reaction of the isatin compound and cyclopropenone is a pyrano[2,3- b ]-indol-2-one compound.
- the chemical structural formula of the amine compound is as follows: .
- the chemical structural formula of the silicon amino rare earth compound is as follows: .
- Ln is a positive trivalent rare earth metal ion; the general formula of the chemical structure of the isatin compound is as follows: .
- R 1 is selected from one of allyl, benzyl, ethyl, methyl, and acetyl groups
- R 2 is selected from chlorine, fluorine, bromine, methyl, methoxy, nitro, trifluoro One of methyl and trifluoromethoxy
- Ar is selected from one of phenyl, 4-methylphenyl, 4-fluorophenyl, and 4-chlorophenyl.
- the chemical formula of the catalyst of the present invention is: [(Me 3 Si) 2 N] 3 Ln( ⁇ -Cl)Li(THF) 3 , in which (Me 3 Si) 2 N represents trimethylsilylamino, and Ln represents positive trivalent Rare earth metal ions, selected from one of lanthanum, neodymium, samarium, erbium or ytterbium, preferably lanthanum (La), under the same conditions, relative to the other four metals, the reaction catalyzed by pyrano[2, 3- b ]-indol-2-one compound was produced in high yield; ⁇ - represented bridge; THF represented tetrahydrofuran.
- the phosphite is diethyl phosphite; the anhydrous and oxygen-free conditions are preferably in an inert atmosphere.
- the reaction is carried out in an organic solvent, and the organic solvent is 1,4-dioxane, ethylene glycol dimethyl ether, tetrahydrofuran, 1,2-dichloroethane, chlorobenzene, toluene, n-hexane.
- the organic solvent is 1,4-dioxane, ethylene glycol dimethyl ether, tetrahydrofuran, 1,2-dichloroethane, chlorobenzene, toluene, n-hexane.
- a kind of; preferably toluene Under the same conditions, the yield in toluene is significantly higher than that of other solvents, and a remarkable technical effect has been achieved.
- the reaction temperature is 100-120°C, preferably 110°C; the reaction time is 2-3 hours, preferably 2.5 hours.
- the dosage of the catalyst is 10% of the mole number of cyclopropenone; the mole dosage ratio of the catalyst and the amine compound is 1:(1-3), preferably 1:1.
- the catalyst of the invention is low in consumption, and the reaction can be carried out efficiently while avoiding the increase of the reaction cost and simplifying the post-treatment of the reaction system.
- the dosage of the diethyl phosphite is 1 to 1.5 times the mole number of cyclopropenone; the preferred dosage of the phosphite is 1.2 times the mole amount of the cyclopropenone; diethyl phosphite of the present invention
- the amount of ester is beneficial to the completion of the reaction, avoids waste caused by the inability of the diethyl phosphite to react completely, and is also conducive to post-processing.
- the consumption of the isatin compound is 1 to 1.5 times the mole number of cyclopropenone; preferably the consumption of the isatin compound is 1.2 times the mole weight of the cyclopropenone; the consumption of the isatin compound of the present invention is beneficial to The improvement of the reaction yield avoids waste and is also conducive to post-processing.
- the reaction process includes mixing silicon amino rare earth compounds and amine compounds in a solvent under anhydrous and oxygen-free conditions; then adding phosphite, isatin compound and solvent, and then adding cyclopropenone and solvent after mixing , and then one-pot reaction, then terminate the reaction, carry out extraction, dry the extract with desiccant, filter, remove the solvent under reduced pressure, and finally obtain pyrano[2,3- b ]indol-2-one by flash column chromatography compound.
- water is used to terminate the reaction
- the extraction agent is ethyl acetate
- the drying agent is anhydrous sodium sulfate
- the eluent is an ethyl acetate/petroleum ether system (volume ratio is 1:10).
- the present invention uses silicon amino rare earth compounds [(Me 3 Si) 2 N] 3 Ln( ⁇ -Cl for the first time in the presence of amine compounds ) Li(THF) 3 is used as a catalyst to catalyze the reaction of isatin compound, phosphite and cyclopropenone in a molar amount of 10% to prepare pyrano[2,3- b ]indol-2-one compound, and the raw materials are simple and easy
- the yield of the target product is high, up to 91%.
- the synthetic route disclosed in the present invention adopts a one-pot reaction method, and the catalyst, amine compound, isatin compound, phosphite and cyclopropenone are added to the solvent for one-pot reaction, the catalyst dosage is few, the reaction time is short, and the product yields.
- the yield is high, and the defects of complicated reaction steps and low yield in the prior art are overcome.
- the method disclosed in the present invention does not use noble metal catalysts, the catalyst dosage is small, the reaction cost is low, and it is also conducive to protecting the environment; meanwhile, the catalyst synthesis method used in the present invention is simple, the yield is high, and the whole preparation of pyrano[2, The process of 3- b ]indol-2-one compounds is controllable.
- the present invention takes isatin compound, phosphite and cyclopropenone as reactants, takes silicon amino rare earth compound as catalyst, and in the presence of amine compound, reacts in organic solvent to prepare pyrano[2 under anhydrous and oxygen-free conditions
- the ,3- b ]indol-2-one compound does not need other reagents and other reaction steps.
- the product of the present invention is obtained by the reaction, and the purified product is obtained through conventional purification, and the steps are simple.
- Synthesis Example 1 Synthesis of catalyst [(Me 3 Si) 2 N] 3 La( ⁇ -Cl)Li(THF) 3 : at -10°C, the n -BuLi Hexane solution (60 mmol, 2.52 M) was added dropwise to a 100 mL Schlenk reaction flask containing (Me 3 Si) 2 NH (60 mmol) and reacted at room temperature for 30 minutes.
- Example 1 For other catalysts, refer to Example 1 for the preparation method.
- Synthesis Example 2 Synthesis of Amine Compound L 1 and Amine Compound L 2 : .
- This yellow solid was mixed with 2,6-dimethylaniline hydrochloride (1.77 g, 11.2 mmol) in 50 mL of ethanol and refluxed for 48 hours. Cool and filter. The filtrate was concentrated, ethanol and water were added, neutralized with aqueous sodium hydroxide and extracted with ether. The obtained organic phase was dried with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and a yellow solid was obtained by silica gel column separation, which was the desired L 1 , and the yield was 10%.
- the main NMR test data are as follows: 1 H NMR (400 MHz, CDCl 3 ) ⁇ : 12.25 (s, 1H), 7.09 ⁇ 6.97 (m, 6H), 4.93 (s, 1H), 2.21 (s, 12H), 1.74 ( s, 6H).
- LaCl 3 (0.024 mmol, 10 mol%), L 1 (0.024 mmol), and toluene (0.1 mL) were weighed into the reaction flask under the protection of argon in the reaction flask after dehydration and deoxygenation.
- diethyl phosphite compound 2, 37 ⁇ L, 0.29 mmol
- isatin compound N -ethylisatin, 0.29 mmol
- toluene 0.3 mL
- Toluene 0.6 mL
- 2,3-diphenylcyclopropenone compound 3, 50 mg, 0.24 mmol
- Pyrano[2,3- b ]indol-2-one skeleton is a kind of very important structural unit, which widely exists in natural products and drug molecules, and has certain biological activities. Therefore, it is of great theoretical and practical significance to study the efficient synthesis technology of pyrano[2,3- b ]indol-2-one skeletons.
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Abstract
一种低催化量下进行靛红化合物和环丙烯酮化合物反应的方法；在胺化合物、亚磷酸酯存在下，以硅氨基稀土化合物为催化剂，在有机溶剂中将靛红化合物和环丙烯酮进行反应，合成吡喃并[2,3-b]吲哚-2-酮化合物。上述反应中催化剂用量少，而且无需贵金属催化，是一种高效、简易制备吡喃并[2,3-b]吲哚-2-酮骨架化合物的方法。
Description
本发明属于稠杂环制备技术领域，具体涉及一种低催化量下进行靛红化合物和环丙烯酮化合物反应的方法。
吡喃并[2,3-
b]吲哚-2-酮骨架含吡喃和吲哚，是药物化学中最重要的结构单元之一，比如已经证实具有实际药用的如下吡喃并[2,3-
b]吲哚-2-酮骨架化合物：
。
现有技术存在不同制备吡喃并[2,3-
b]吲哚-2-酮骨架的方法，比如：
。
现有方法可以合成吡喃并[2,3-
b]吲哚-2-酮化合物，但是均存在一些缺陷，例如：产率低、合成步骤繁琐、底物结构复杂、需使用贵金属催化剂，等等。
另外，对于催化合成方案，催化剂的用量需要尽可能的少，对反应成本、反应稳定性以及产物提纯有利。
本发明公开了较少量硅氨基稀土化合物催化靛红化合物和环丙烯酮化合物反应，通过硅氨基稀土化合物催化的靛红化合物、亚磷酸酯和环丙烯酮的反应，实现一种原料来源简单、步骤简洁、反应条件温和、高活性、普适性好的合成吡喃并[2,3-
b]吲哚-2-酮化合物的方法。
为达到上述发明目的，本发明采用的技术方案是：一种低催化量下进行靛红化合物和环丙烯酮化合物反应的方法，包括以下步骤：在胺化合物、亚磷酸酯存在下，以硅氨基稀土化合物为催化剂，在有机溶剂中将靛红化合物和环丙烯酮进行反应。
胺化合物与硅氨基稀土化合物在靛红化合物和环丙烯酮化合物反应中的应用。
本发明靛红化合物和环丙烯酮在无水无氧条件下进行反应，靛红化合物和环丙烯酮进行反应的产物为吡喃并[2,3-
b]-吲哚-2-酮化合物。
本发明中，所述胺化合物的化学结构式如下所示：
。
所述硅氨基稀土化合物的化学结构式如下所示：
。
其中，Ln为正三价的稀土金属离子；所述靛红化合物的化学结构通式如下：
。
所述环丙烯酮通式结构如下：
。
所述吡喃并[2,3-
b]-吲哚-2-酮化合物的化学结构式如下所示：
。
上述结构式中，R
1选自烯丙基、苄基、乙基、甲基、乙酰基中的一种；R
2选自氯、氟、溴、甲基、甲氧基、硝基、三氟甲基、三氟甲氧基中的一种；Ar选自苯基、4-甲基苯基、4-氟苯基、4-氯苯基中的一种。
本发明催化剂的化学式：[(Me
3Si)
2N]
3Ln(μ-Cl)Li(THF)
3，式中，(Me
3Si)
2N表示三甲基硅氨基，Ln表示正三价的稀土金属离子，选自镧、钕、钐、铒或镱中的一种，优选为镧（La），在同样条件下，相对于其他四种金属，其催化的反应对于吡喃并[2,3-
b]-吲哚-2-酮化合物生成产率较高；μ-代表桥键；THF代表四氢呋喃。
本发明中，亚磷酸酯为亚磷酸二乙酯；所述在无水无氧条件下优选为在惰性气氛中。
上述技术方案中，反应在有机溶剂中进行，有机溶剂为1,4-二氧六环、乙二醇二甲醚、四氢呋喃、1,2-二氯乙烷、氯苯、甲苯、正己烷中的一种；优选为甲苯。同一条件下，在甲苯中产率明显高于其他溶剂，取得了显著进步的技术效果。
上述技术方案中，所述反应温度为100～120℃，优选110℃；所述反应时间为2～3小时，优选2.5小时。
上述技术方案中，所述催化剂的用量为环丙烯酮的摩尔数的10%；所述催化剂与胺化合物的摩尔用量比为1∶（1～3），优选1∶1。本发明催化剂的用量低，在使反应高效进行的同时避免增加反应成本并可简化反应体系的后处理。
上述技术方案中，所述亚磷酸二乙酯的用量为环丙烯酮的摩尔数的1～1.5倍；优选的亚磷酸酯的用量为1.2倍环丙烯酮的摩尔量；本发明亚磷酸二乙酯的用量有利于反应的完全，同时避免导致亚磷酸二乙酯无法反应完全而造成浪费，也利于后处理。
上述技术方案中，所述靛红化合物的用量为环丙烯酮的摩尔数的1～1.5倍；优选靛红化合物的用量为1.2倍环丙烯酮的摩尔量；本发明靛红化合物的用量有利于反应收率的提高，避免导致浪费，也利于后处理。
上述技术方案中，反应过程包括在无水无氧条件下，将硅氨基稀土化合物、胺化合物在溶剂中混合；然后加入亚磷酸酯、靛红化合物、溶剂，混合后再加入环丙烯酮、溶剂，然后一锅反应，再终止反应，进行萃取，用干燥剂干燥萃取液，过滤，减压除去溶剂，最后经快速柱层析得到吡喃并[2,3-
b]吲哚-2-酮化合物。优选的技术方案中终止反应采用水，萃取剂为乙酸乙酯，干燥剂为无水硫酸钠，洗脱剂为乙酸乙酯/石油醚体系（体积比为1∶10）。
上述技术方案可表示如下：
。
由于上述技术方案的运用，本发明与现有技术相比具有下列优点：1. 本发明首次在胺化合物存在下，使用硅氨基稀土化合物[(Me
3Si)
2N]
3Ln(μ-Cl)Li(THF)
3作为催化剂以10%的摩尔量催化靛红化合物、亚磷酸酯和环丙烯酮进行反应制备吡喃并[2,3-
b]吲哚-2-酮化合物，原料简单易得，目标产物的收率高，最高达到91%。
2. 本发明公开的合成路线采用一锅化反应方法，将催化剂、胺化合物、靛红化合物、亚磷酸酯和环丙烯酮加入溶剂中一锅反应，催化剂用量少，反应时间短，产物产率高，克服了现有技术反应步骤繁琐、产率偏低的缺陷。
3. 本发明公开的方法不使用贵金属催化剂，催化剂用量少，反应成本低，也有利于保护环境；同时本发明使用的催化剂合成方法简单，产率较高，整个制备吡喃并[2,3-
b]吲哚-2-酮化合物的过程可控。
本发明在无水无氧条件下，以靛红化合物、亚磷酸酯和环丙烯酮为反应物，以硅氨基稀土化合物为催化剂，在胺化合物存在下，有机溶剂中反应制备吡喃并[2,3-
b]吲哚-2-酮化合物，无需其他试剂与其他反应步骤，反应物料混合后，反应即得到本发明的产物，经过常规提纯，得到纯化产物，步骤简单。
本发明的原料都是现有产品，具体操作方法以及测试方法为本领域常规方法，如无特殊说明，都在常规条件下进行。下面结合实施例对本发明作进一步描述：合成例一：催化剂[(Me
3Si)
2N]
3La(μ-Cl)Li(THF)
3的合成：在-10℃下，将
n-BuLi的己烷溶液（60
mmol，2.52 M）滴加入到装有(Me
3Si)
2NH
（60 mmol）的100
mL Schlenk 反应瓶中，在室温下反应30分钟。将上述反应液加入到无水LaCl
3（20 mmol）的 THF（30 mL）悬浊液中，室温下搅拌过夜。减压除去溶剂，得到的固体粉末用热甲苯萃取以除去LiCl，浓缩，0℃下放置，析出大量晶体，即为所需的硅氨基镧化合物，收率85%。
其他催化剂可参考实施例一得制备方法。
合成例二：胺化合物L
1与胺化合物L
2的合成：
。
将苯胺（1.82 mL, 20 mmol）、1,3-二苯基-1,3-二酮（5.38 g, 24 mmol）混合于80 mL甲苯中，再加入对甲苯磺酸（0.35 g, 2 mmol）。混合物利用油水分离器回流除水24小时，冷却。减压除去溶剂，残余物用硅胶柱（洗脱剂: 乙酸乙酯:石油醚＝1:60）分离得黄色固体。将此黄色固体与2,6-二甲基苯胺的盐酸盐（1.77
g, 11.2 mmol）混合于50 mL乙醇中并回流48小时。冷却，过滤。滤液浓缩后加入乙醇和水，以氢氧化钠水溶液中和并以乙醚萃取。所得有机相用无水硫酸钠干燥，减压除溶剂，硅胶柱分离得黄色固体，即为所需
L
1
，收率10%。主要核磁测试数据如下：
1H NMR
(400 MHz, CDCl
3) δ: 12.90 (s, 1H),
7.45−7.43 (m, 2H), 7.31−7.16 (m, 8H), 7.07 (t,
J = 7.7 Hz, 2H), 6.92−6.80
(m, 4H), 6.70 (d,
J = 7.8 Hz, 2H), 5.42 (s, 1H), 2.10 (s, 6H)。
将2,6-二甲基苯胺（20 g, 0.17 mol），2,4-戊二酮（8.25 g, 0.08 mol）和对甲苯磺酸（14.2 g, 0.08 mol）混合于250
mL甲苯中，回流24小时。倾出甲苯，在固体剩余物中加入200
mL乙醚、150 mL水和36 g十水碳酸钠，搅拌25分钟。将分离出的醚层用硫酸镁干燥，减压除去溶剂。剩余物在100℃下真空干燥6小时，所得固体即为所需
L
2
，收率70%。主要核磁测试数据如下：
1H NMR
(400 MHz, CDCl
3) δ: 12.25 (s, 1H),
7.09−6.97 (m, 6H), 4.93 (s, 1H), 2.21 (s, 12H), 1.74 (s, 6H)。
实施例：[(Me
3Si)
2N]
3La(μ-Cl)Li(THF)
3催化
N-乙基靛红、亚磷酸二乙酯和2,3-二苯基环丙烯酮制备吡喃并[2,3-
b]吲哚-2-酮化合物：室温下，在经过脱水脱氧处理过的反应瓶中，在氩气保护下在反应瓶中称入[(Me
3Si)
2N]
3La(μ-Cl)Li(THF)
3（21.1
mg, 0.024 mmol, 10 mol%）、L
1（9.7 mg, 0.024 mmol）、甲苯（0.1
mL），常规混合10分钟，再加入亚磷酸二乙酯（化合物2, 37
μL, 0.29 mmol）、靛红化合物（
N-乙基靛红，0.29
mmol）、甲苯（0.3 mL），常规搅拌混合30分钟，再加入甲苯（0.6 mL）、2,3-二苯基环丙烯酮（化合物3, 50 mg，0.24
mmol），接着在110℃下搅拌2.5小时，加水终止反应，乙酸乙酯萃取三次，萃取液用无水硫酸钠干燥，过滤，减压除去溶剂，最后经硅胶柱快速柱层析（洗脱剂: 乙酸乙酯:石油醚＝1:10）得到黄色固体产物，收率88%；所制得产物的理论分子式以及主要核磁测试数据如下，通过分析可知，实际合成产物与理论分析一致。
1H NMR
(400 MHz, CDCl
3) δ: 7.36−7.31 (m,
4H), 7.25−7.21 (m, 3H), 7.19−7.10 (m, 5H), 7.00−6.96 (m, 1H), 6.78 (d, J = 8.0
Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H)。
更换靛红化合物（化合物1,0.29 mmol），其余不变，制备的产物吡喃并[2,3-
b]吲哚-2-酮化合物（化合物4）以及分离收率如下：
。
更换2,3-二苯基环丙烯酮（化合物3, 0.24 mmol），其余不变，制备的产物吡喃并[2,3-
b]吲哚-2-酮化合物（化合物4）以及分离收率如下：
。
上述反应过程如下：
。
部分所制得产物的理论分子式以及主要核磁测试数据如下：
。
1H NMR
(400 MHz, CDCl
3) δ: 7.33−7.30 (m,
4H), 7.24−7.20 (m, 3H), 7.19−7.12 (m, 5H), 7.02−6.98 (m, J = 8.0 Hz, 1H), 6.78
(d, J = 8.0 Hz, 1H), 3.82 (s, 3H)。
1H NMR
(400 MHz, CDCl
3) δ: 7.34−7.32 (m,
4H), 7.25−7.13 (m, 8H), 7.01−6.97 (m, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.05−5.96
(m, 1H), 5.30−5.20 (m, 2H), 4.91 (d, J = 5.2 Hz, 2H)。
1H NMR
(400 MHz, CDCl
3) δ: 7.35−7.24 (m,
11H), 7.21−7.12 (m, 6H), 7.00−6.96 (m, 1H), 6.78 (d, J = 8.0 Hz, 1H), 5.50 (s,
2H)。
1H NMR
(400 MHz, CDCl
3) δ: 7.35 (d, J =
8.4 Hz, 1H), 7.25−7.21 (m, 1H), 7.16−7.11 (m, 4H), 7.05−6.98 (m, 5H), 6.84 (d,
J = 8.0 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 2.37 (s, 3H), 2.26 (s, 3H), 1.50 (t,
J = 7.2 Hz, 3H)。
1H NMR
(400 MHz, CDCl
3) δ: 7.38 (d, J =
8.0 Hz, 1H), 7.28−7.19 (m, 3H), 7.12−7.01 (m, 5H), 6.92−6.87 (m, 2H), 6.82 (d,
J = 8.0 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.52 (t, J = 7.2 Hz, 3H)。
1H NMR
(400 MHz, CDCl
3) δ: 7.33−7.31 (m,
3H), 7.28−7.24 (m, 1H), 7.22−7.11(m, 7H), 6.97−6.92 (m, 1H), 6.45−6.42 (m, 1H),
4.33 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H)。
1H NMR
(400 MHz, CDCl
3) δ: 7.35−7.33 (m,
3H), 7.25−7.24 (m, 1H), 7.22−7.12 (m, 8H), 6.72 (d, J = 2.0 Hz, 1H), 4.33 (q, J
= 7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H)。
1H NMR
(400 MHz, CDCl
3) δ: 7.37−7.31 (m,
4H), 7.24−7.13 (m, 8H), 6.87 (d, J = 2.0 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H),
1.50 (t, J = 7.2 Hz, 3H)。
1H NMR
(400 MHz, CDCl
3) δ: 7.35−7.31 (m,
3H), 7.25−7.21 (m, 3H), 7.19−7.11 (m , 5H), 7.07−7.04 (m, 1H), 6.56−6.55 (m,
1H), 4.33 (q, J = 7.2 Hz, 2H), 2.23 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H)。
1H NMR
(400 MHz, CDCl
3) δ: 7.35−7.32 (m,
3H), 7.25−7.22 (m, 3H), 7.18−7.11 (m, 5H), 6.86−6.83 (m, 1H), 6.22 (d, J = 2.4
Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 3.53 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H)。
1H NMR
(400 MHz, CDCl
3) δ：7.29−7.27 (m,
1H), 7.18−7.15 (m, 5H), 7.14−7.09 (m, 4H), 7.07−7.04 (m, 3H), 4.39 (q, J = 7.2
Hz, 2H), 1.51 (t, J = 7.2 Hz, 3H)。
1H NMR
(400 MHz, CDCl
3) δ：7.39−7.34 ( m,
4H), 7.26−7.17 ( m, 7H), 7.00−6.97 (m, 1H), 6.71 (d, J = 8.4 Hz, 1H), 4.36 (q,
J = 7.2 Hz, 2H), 1.55 (t, J = 7.2 Hz, 3H)。
1H NMR
(400 MHz, CDCl
3) δ: 7.34−7.32 ( m,
3H), 7.21−7.14 (m, 8H), 6.87−6.84 (m, 1H), 6.61 (d, J = 7.6 Hz, 1H), 4.76 (q, J
= 7.2 Hz, 2H), 1.55 (t, J = 7.2 Hz, 3H)。
扩展实施例一：室温下，在经过脱水脱氧处理过的反应瓶中，在氩气保护下在反应瓶中称入[(Me
3Si)
2N]
3La
(μ-Cl)Li(THF)
3（211 mg, 0.24 mmol, 10 mol%）、L
1（97 mg, 0.24 mmol）、甲苯（1 mL），常规混合10分钟，再加入亚磷酸二乙酯（2.9 mmol）、
N-乙基靛红（2.9
mmol）、甲苯（3 mL），常规搅拌混合30分钟，再加入甲苯（6 mL）、2,3-二苯基环丙烯酮（2.4 mmol），接着在110℃下搅拌2.5小时，加水终止反应，乙酸乙酯萃取三次，萃取液用无水硫酸钠干燥，过滤，减压除去溶剂，最后经硅胶柱快速柱层析（洗脱剂: 乙酸乙酯:石油醚＝1:10）得到黄色固体产物，收率68%；通过分析所制得产物的理论分子式以及主要核磁测试数据可知，实际合成产物与理论分析一致。
将上述反应时间2.5小时调整为5小时，其余不变，得到产物0.665g，收率76%；如下：
。
扩展实施例二：室温下，在经过脱水脱氧处理过的反应瓶中，在氩气保护下在反应瓶中称入[(Me
3Si)
2N]
3La(μ-Cl)Li(THF)
3（21.1
mg, 0.024 mmol, 10 mol%）、L
1（28.9 mg, 0.072 mmol）、甲苯（0.1
mL），常规混合10分钟，再加入亚磷酸二乙酯（化合物2, 37μL, 0.29 mmol）、靛红化合物（
N-乙基靛红，0.29 mmol）、甲苯（0.3 mL），常规搅拌混合30分钟，再加入甲苯（0.6 mL）、2,3-二苯基环丙烯酮（化合物3, 50 mg，0.24 mmol），接着在110℃下搅拌2.5小时，加水终止反应，乙酸乙酯萃取三次，萃取液用无水硫酸钠干燥，过滤，减压除去溶剂，最后经硅胶柱快速柱层析（洗脱剂: 乙酸乙酯:石油醚＝1:10）得到黄色固体产物，收率85%；通过分析所制得产物的理论分子式以及主要核磁测试数据可知，实际合成产物与理论分析一致。
对比例：
。
室温下，在经过脱水脱氧处理过的反应瓶中，在氩气保护下在反应瓶中称入[(Me
3Si)
2N]
3La(μ-Cl)Li(THF)
3（21.1
mg, 0.024 mmol, 10 mol%）、L
2（7.3 mg，0.024 mmol）、甲苯（0.1 mL），常规混合10分钟，再加入亚磷酸二乙酯（化合物2, 37 μL,
0.29 mmol）、靛红化合物（
N-乙基靛红，0.29 mmol）、甲苯（0.3 mL），常规搅拌混合30分钟，再加入甲苯（0.6 mL）、2,3-二苯基环丙烯酮（化合物3, 50 mg，0.24 mmol），接着在110℃下搅拌2.5小时，加水终止反应，乙酸乙酯萃取三次，萃取液用无水硫酸钠干燥，过滤，减压除去溶剂，最后经硅胶柱快速柱层析（洗脱剂: 乙酸乙酯:石油醚＝1:10）得到黄色固体产物，收率55%；通过分析所制得产物的理论分子式以及主要核磁测试数据可知，实际合成产物与理论分析一致。
室温下，在经过脱水脱氧处理过的反应瓶中，在氩气保护下在反应瓶中称入[(Me
3Si)
2N]
3La
(μ-Cl)Li(THF)
3（21.1 mg, 0.024 mmol,10mol%）、L
2（22.0 mg，0.072 mmol）、甲苯（0.1 mL），常规混合10分钟，再加入亚磷酸二乙酯（化合物2, 37 μL,
0.29 mmol）、靛红化合物（
N-乙基靛红，0.29 mmol）、甲苯（0.3 mL），常规搅拌混合30分钟，再加入甲苯（0.6 mL）、2,3-二苯基环丙烯酮（化合物3, 50 mg，0.24 mmol），接着在110℃下搅拌2.5小时，加水终止反应，乙酸乙酯萃取三次，萃取液用无水硫酸钠干燥，过滤，减压除去溶剂，最后经硅胶柱快速柱层析（洗脱剂: 乙酸乙酯:石油醚＝1:10）得到黄色固体产物，收率57%；通过分析所制得产物的理论分子式以及主要核磁测试数据可知，实际合成产物与理论分析一致。
室温下，在经过脱水脱氧处理过的反应瓶中，在氩气保护下在反应瓶中称入[(Me
3Si)
2N]
3La(μ-Cl)Li(THF)
3（21.1
mg, 0.024 mmol,10mol%）、甲苯（0.1 mL），常规混合10分钟，再加入亚磷酸二乙酯（化合物2, 37
μL, 0.29 mmol）、靛红化合物（
N-乙基靛红，0.29
mmol）、甲苯（0.3 mL），常规搅拌混合30分钟，再加入甲苯（0.6 mL）、2,3-二苯基环丙烯酮（化合物3, 50 mg，0.24
mmol），接着在110℃下搅拌2.5小时，加水终止反应，乙酸乙酯萃取三次，萃取液用无水硫酸钠干燥，过滤，减压除去溶剂，最后经硅胶柱快速柱层析（洗脱剂: 乙酸乙酯:石油醚＝1:10）得到黄色固体产物，收率48%；通过分析所制得产物的理论分子式以及主要核磁测试数据可知，实际合成产物与理论分析一致。
室温下，在经过脱水脱氧处理过的反应瓶中，在氩气保护下在反应瓶中称入LaCl
3（0.024 mmol, 10 mol%）、L
1（0.024 mmol）、甲苯（0.1
mL），常规混合10分钟，再加入亚磷酸二乙酯（化合物2, 37
μL, 0.29 mmol）、靛红化合物（
N-乙基靛红，0.29
mmol）、甲苯（0.3 mL），常规搅拌混合30分钟，再加入甲苯（0.6 mL）、2,3-二苯基环丙烯酮（化合物3, 50 mg，0.24
mmol），接着在110℃下搅拌2.5小时，加水终止反应，乙酸乙酯萃取三次，萃取液用无水硫酸钠干燥，过滤，减压除去溶剂，最后经硅胶柱快速柱层析（洗脱剂: 乙酸乙酯:石油醚＝1:10），没有得到产物，收率0。
扩展实施例三：室温下，在经过脱水脱氧处理过的反应瓶中，在氩气保护下在反应瓶中称入[(Me
3Si)
2N]
3Yb(μ-Cl)Li(THF)
3（0.024
mmol, 10 mol%）、L
1（9.7 mg, 0.024 mmol）、甲苯（0.1
mL），常规混合10分钟，再加入亚磷酸二乙酯（化合物2, 37
μL, 0.29 mmol）、靛红化合物（
N-乙基靛红，0.29
mmol）、甲苯（0.3 mL），常规搅拌混合30分钟，再加入甲苯（0.6 mL）、2,3-二苯基环丙烯酮（化合物3, 50 mg，0.24
mmol），接着在110℃下搅拌2.5小时，加水终止反应，乙酸乙酯萃取三次，萃取液用无水硫酸钠干燥，过滤，减压除去溶剂，最后经硅胶柱快速柱层析（洗脱剂: 乙酸乙酯:石油醚＝1:10）得到黄色固体产物，收率62%；通过分析所制得产物的理论分子式以及主要核磁测试数据可知，实际合成产物与理论分析一致。
吡喃并[2,3-
b]吲哚-2-酮骨架是一类很重要的结构单元，广泛存在于天然产物和药物分子中，具有一定的生物活性。因此，研究吡喃并[2,3-
b]吲哚-2-酮骨架的高效合成技术具有重要的理论和实际意义。
Claims (10)
- 一种低催化量下进行靛红化合物和环丙烯酮化合物反应的方法，其特征在于，包括以下步骤：在胺化合物、亚磷酸酯存在下，以硅氨基稀土化合物为催化剂，在有机溶剂中将靛红化合物和环丙烯酮进行反应；所述硅氨基稀土化合物的化学结构式如下所示：
其中，Ln为正三价的稀土金属离子；所述胺化合物的化学结构式如下所示：
所述靛红化合物的化学结构通式如下：
其中，R 1选自烯丙基、苄基、乙基、甲基、乙酰基中的一种；R 2选自氯、氟、溴、甲基、甲氧基、硝基、三氟甲基、三氟甲氧基中的一种；所述环丙烯酮的化学结构通式如下：
其中，Ar选自苯基、4-甲基苯基、4-氟苯基、4-氯苯基中的一种。 - 根据权利要求1所述的方法，其特征在于，所述催化剂与胺化合物的摩尔用量比为1∶（1～3）。
- 根据权利要求1所述的方法，其特征在于，所述有机溶剂为1,4-二氧六环、乙二醇二甲醚、四氢呋喃、1,2-二氯乙烷、氯苯、甲苯、正己烷中的一种；靛红化合物和环丙烯酮在无水无氧条件下进行反应；所述亚磷酸酯为亚磷酸二乙酯。
- 根据权利要求1所述的方法，其特征在于：按照摩尔比计，靛红化合物的用量为环丙烯酮的1～1.2倍；硅氨基稀土化合物的用量为环丙烯酮的10%。
- 根据权利要求1所述的方法，其特征在于：靛红化合物和环丙烯酮进行反应的产物为吡喃并[2,3- b]-吲哚-2-酮化合物。
- 根据权利要求1所述的方法，其特征在于：所述反应的温度为100～120℃；反应的时间为2～3小时。
- 根据权利要求1所述的方法，其特征在于：将硅氨基稀土化合物、胺化合物在有机溶剂中混合；然后加入亚磷酸酯、靛红化合物、有机溶剂，混合后再加入环丙烯酮、有机溶剂，然后进行反应。
- 胺化合物与硅氨基稀土化合物在靛红化合物和环丙烯酮化合物反应中的应用。
- 根据权利要求8所述的应用，其特征在于，所述胺化合物的化学结构式如下所示：
所述硅氨基稀土化合物的化学结构式如下所示：
其中，Ln为正三价的稀土金属离子。 - 根据权利要求8所述的应用，其特征在于，按照摩尔比计，硅氨基稀土化合物的用量为环丙烯酮的10%；所述硅氨基稀土化合物与胺化合物的摩尔用量比为1∶（1～3）。
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| WANG LU, ZHIGANG YAO, FAN XU, QI SHEN: "Lanthanide amides [(Me3Si)2N]3Ln(μ-Cl)Li(THF)3-catalyzed phospho-aldol-brook rearrangement reaction of dialkyl phosphites with isatins", HETEROATOM CHEMISTRY, vol. 23, no. 5, 10 August 2012 (2012-08-10), pages 449 - 456, XP055964892, DOI: 10.1002/hc.21036 * |
| XU JUNYU, CAO JING, FANG CHAO, LU TAO, DU DING: "Organocatalytic C–C bond activation of cyclopropenones for ring-opening formal [3 + 2] cycloaddition with isatins", ORGANIC CHEMISTRY FRONTIERS, vol. 4, no. 4, 20 November 2017 (2017-11-20), pages 560 - 564, XP055964893, DOI: 10.1039/C6QO00734A * |
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