CN109776546A - A method of preparing indoles and pyrroles's ketone compound - Google Patents
A method of preparing indoles and pyrroles's ketone compound Download PDFInfo
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- CN109776546A CN109776546A CN201910187778.0A CN201910187778A CN109776546A CN 109776546 A CN109776546 A CN 109776546A CN 201910187778 A CN201910187778 A CN 201910187778A CN 109776546 A CN109776546 A CN 109776546A
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- chloride
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- -1 ketone compound Chemical class 0.000 title claims abstract description 69
- 238000000034 method Methods 0.000 title claims abstract description 24
- 150000002475 indoles Chemical class 0.000 title abstract 5
- 150000003233 pyrroles Chemical class 0.000 title abstract 4
- 150000001345 alkine derivatives Chemical class 0.000 claims abstract description 19
- 239000002841 Lewis acid Substances 0.000 claims abstract description 18
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 18
- 230000004913 activation Effects 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 52
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 45
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 37
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 37
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 239000003153 chemical reaction reagent Substances 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 19
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 125000004104 aryloxy group Chemical group 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 229910052725 zinc Inorganic materials 0.000 claims description 17
- 239000011701 zinc Substances 0.000 claims description 17
- 125000005103 alkyl silyl group Chemical group 0.000 claims description 15
- 125000005104 aryl silyl group Chemical group 0.000 claims description 15
- 239000011592 zinc chloride Substances 0.000 claims description 15
- 235000005074 zinc chloride Nutrition 0.000 claims description 15
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 14
- AXAZMDOAUQTMOW-UHFFFAOYSA-N dimethylzinc Chemical group C[Zn]C AXAZMDOAUQTMOW-UHFFFAOYSA-N 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- 238000010504 bond cleavage reaction Methods 0.000 claims description 12
- 229910052702 rhenium Inorganic materials 0.000 claims description 12
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical group [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 8
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 7
- 229910052805 deuterium Inorganic materials 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 6
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 6
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 6
- BHHYHSUAOQUXJK-UHFFFAOYSA-L zinc fluoride Chemical compound F[Zn]F BHHYHSUAOQUXJK-UHFFFAOYSA-L 0.000 claims description 6
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 claims description 6
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 3
- 229910021575 Iron(II) bromide Inorganic materials 0.000 claims description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 3
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 3
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 3
- 229960003280 cupric chloride Drugs 0.000 claims description 3
- 229940045803 cuprous chloride Drugs 0.000 claims description 3
- 229940046149 ferrous bromide Drugs 0.000 claims description 3
- 229960002089 ferrous chloride Drugs 0.000 claims description 3
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- GYCHYNMREWYSKH-UHFFFAOYSA-L iron(ii) bromide Chemical compound [Fe+2].[Br-].[Br-] GYCHYNMREWYSKH-UHFFFAOYSA-L 0.000 claims description 3
- 239000003446 ligand Substances 0.000 claims description 3
- FEONEKOZSGPOFN-UHFFFAOYSA-K tribromoiron Chemical compound Br[Fe](Br)Br FEONEKOZSGPOFN-UHFFFAOYSA-K 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 239000004246 zinc acetate Substances 0.000 claims description 3
- 229940102001 zinc bromide Drugs 0.000 claims description 3
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 claims description 3
- ZMLPZCGHASSGEA-UHFFFAOYSA-M zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F ZMLPZCGHASSGEA-UHFFFAOYSA-M 0.000 claims description 3
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Substances [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 claims description 3
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- OWQUYBAASOSGNO-CDNKMLFNSA-N 2-[[(Z)-N-(2-hydroxy-5-sulfoanilino)-C-phenylcarbonimidoyl]diazenyl]benzoic acid Chemical compound C1=CC=C(C=C1)/C(=N/NC2=C(C=CC(=C2)S(=O)(=O)O)O)/N=NC3=CC=CC=C3C(=O)O OWQUYBAASOSGNO-CDNKMLFNSA-N 0.000 abstract 2
- 229940043798 zincon Drugs 0.000 abstract 2
- 238000003776 cleavage reaction Methods 0.000 abstract 1
- 125000004432 carbon atom Chemical group C* 0.000 description 77
- 238000006243 chemical reaction Methods 0.000 description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 50
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 239000000047 product Substances 0.000 description 22
- 238000002360 preparation method Methods 0.000 description 19
- 238000004440 column chromatography Methods 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 239000003480 eluent Substances 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- JRXXLCKWQFKACW-UHFFFAOYSA-N biphenylacetylene Chemical group C1=CC=CC=C1C#CC1=CC=CC=C1 JRXXLCKWQFKACW-UHFFFAOYSA-N 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- VGSGLWXSLAJHFS-UHFFFAOYSA-N 2,3-bis(4-methoxyphenyl)pyrrolo[1,2-a]indol-1-one Chemical compound COC1=CC=C(C=C1)C1=C(C(N2C1=CC=1C=CC=CC2=1)=O)C1=CC=C(C=C1)OC VGSGLWXSLAJHFS-UHFFFAOYSA-N 0.000 description 2
- YOODRTPALSMYCL-UHFFFAOYSA-N 2,3-diphenylpyrrolo[1,2-a]indol-1-one Chemical compound C12=CC3=CC=CC=C3N2C(=O)C(C=2C=CC=CC=2)=C1C1=CC=CC=C1 YOODRTPALSMYCL-UHFFFAOYSA-N 0.000 description 2
- IAQSGKOQWLECTR-UHFFFAOYSA-N 3,4-dihydro-1H-pyrrolo[3,2-b]indol-2-one Chemical class N1C(CC2=C1C=1C=CC=CC=1N2)=O IAQSGKOQWLECTR-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 2
- 229910017052 cobalt Inorganic materials 0.000 description 2
- 239000010941 cobalt Substances 0.000 description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical class C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WSXUXTVJTIPBAF-UHFFFAOYSA-N 1-bromo-3-[2-(3-bromophenyl)ethynyl]benzene Chemical group BrC1=CC=CC(C#CC=2C=C(Br)C=CC=2)=C1 WSXUXTVJTIPBAF-UHFFFAOYSA-N 0.000 description 1
- QFRLNLXZHMUYHO-UHFFFAOYSA-N 1-chloro-4-[2-(4-chlorophenyl)ethynyl]benzene Chemical group C1=CC(Cl)=CC=C1C#CC1=CC=C(Cl)C=C1 QFRLNLXZHMUYHO-UHFFFAOYSA-N 0.000 description 1
- YKUOFMNGWLZXHA-UHFFFAOYSA-N 1-methoxy-4-[2-(4-methoxyphenyl)ethynyl]benzene Chemical group C1=CC(OC)=CC=C1C#CC1=CC=C(OC)C=C1 YKUOFMNGWLZXHA-UHFFFAOYSA-N 0.000 description 1
- FASNPPWZLHQZAJ-UHFFFAOYSA-N 3,3-dimethylbut-1-ynylbenzene Chemical compound CC(C)(C)C#CC1=CC=CC=C1 FASNPPWZLHQZAJ-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- LWDFRYZPWBLPLS-UHFFFAOYSA-N C1=CC=C(C=C1)C(=O)N(C(=O)C2=CC=CC=C2)C(=O)Cl Chemical compound C1=CC=C(C=C1)C(=O)N(C(=O)C2=CC=CC=C2)C(=O)Cl LWDFRYZPWBLPLS-UHFFFAOYSA-N 0.000 description 1
- GPNFGPZJFCVELY-UHFFFAOYSA-N N1C(C=C2C1=C1C=CC=CC1=N2)=O Chemical class N1C(C=C2C1=C1C=CC=CC1=N2)=O GPNFGPZJFCVELY-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 150000001503 aryl iodides Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 125000005059 halophenyl group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- GZTNBKQTTZSQNS-UHFFFAOYSA-N oct-4-yne Chemical compound CCCC#CCCC GZTNBKQTTZSQNS-UHFFFAOYSA-N 0.000 description 1
- VQLUKRCNHUTCAP-UHFFFAOYSA-N pyrrolo[3,2-b]indole Chemical class C1=CC=C2C3=NC=CC3=NC2=C1 VQLUKRCNHUTCAP-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- FWSPXZXVNVQHIF-UHFFFAOYSA-N triethyl(ethynyl)silane Chemical compound CC[Si](CC)(CC)C#C FWSPXZXVNVQHIF-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Indole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention relates to organic chemical synthesis technical fields, more particularly to a kind of method for preparing indoles and pyrroles's ketone compound, under the conditions of including the following steps: existing for catalyst, lewis acid and the zincon, alkynes shown in benzazolyl compounds shown in Formula II and formula III is by c h bond activation/C-N cleavage reaction to get indoles shown in Formulas I and pyrroles's ketone compound.The present invention using indoles and alkynes existing for catalyst, lewis acid and the zincon under the conditions of, reacted in a solvent, realize the synthesis of indoles and pyrroles's ketone compound.
Description
Technical Field
The invention relates to the field of organic chemical synthesis, in particular to a method for preparing an indolopyrrolidone compound.
Background
Indolopyrrolidone compounds are important nitrogen-containing heterocyclic compounds and widely exist in nature. It has various biological activities and special chemical properties, can be used as active structural units of a plurality of natural products and medicines, and has important research value and application prospect in the fields of organic synthesis, medicines and chemical industry.
The preparation method of indolopyrrolidone compounds in the prior art mainly comprises the following steps: the following methods are disclosed in J.org.chem.2017,82, 5263-: (as shown in FIG. 1); the method uses a ruthenium catalyst to catalyze the reaction of indole and alkyne to produce the indolopyrrole compound, but uses a substrate, namely, the R 'substituent in alkyne is mainly methyl, although R' is an example of aryl, the corresponding yield is not high (< 79%); the following methods are disclosed in j.am.chem.soc.2014,136, 5424-5431: (as shown in FIG. 2) which uses a cobalt catalyst to catalyze the reaction of indole with alkyne to produce indolopyrrole compounds, but uses as substrate alkyne groups methyl for the R 'substituent, although there are also examples where R' is aryl, the corresponding yields are not high (< 72%); the following methods are disclosed in chem.lett.2015,44, 1104-1106: it is mainly focused on the reaction of sulfamide with alkyne (as shown in fig. 3), only one involving indole (as shown in fig. 4), and the yield is low (39%).
Therefore, the development of new methods for preparing indolopyrrolones is of great significance.
Disclosure of Invention
The invention aims to provide a method for preparing an indolopyrrolidone compound.
The structural formula of the indolopyrrolidone compound is shown in a formula I:
R1independently represent mono-, di-, tri-, tetra-or unsubstituted;
R1each independently selected from: hydrogen, deuterium, halogen, alkyl (specifically, alkyl having 1 to 20 carbon atoms), cycloalkyl (specifically, cycloalkyl having 3 to 20 ring carbon atoms), heteroalkyl (heteroatom-containing alkyl substituent, such as-CH)2CH2N(CH3)2) (in particular heteroalkyl having from 1 to 20 carbon atoms), aralkyl (alkyl substituents bearing an aryl group, such as, in the simplest case, benzyl, PhCH2-, that is, an aralkyl group having 7 carbon atoms) (specifically, an aralkyl group having 7 to 30 carbon atoms), an alkoxy group (specifically, an alkoxy group having 1 to 20 carbon atoms), an aryloxy group (specifically, an aryloxy group having 6 to 30 carbon atoms), an aryl group (specifically, an aryl group having 6 to 30 carbon atoms), an alkylsilyl group (specifically, an alkylsilyl group having 3 to 20 carbon atoms), an arylsilyl group (specifically, an arylsilyl group having 6 to 20 carbon atoms), and combinations thereof;
Raand RbEach independently selected from: an alkyl group (specifically, an alkyl group having 1 to 20 carbon atoms), a cycloalkyl group (specifically, a cycloalkyl group having 3 to 20 ring carbon atoms), a heteroalkyl group (specifically, a heteroalkyl group having 1 to 20 carbon atoms), an aralkyl group (specifically, an aralkyl group having 7 to 30 carbon atoms), an alkoxy group (specifically, an aralkyl group having 1 to 20 carbon atoms), a heterocyclic group, and a heterocyclic groupAlkoxy), aryloxy (specifically, aryloxy having 6 to 30 carbon atoms), aryl (specifically, aryl having 6 to 30 carbon atoms, halogen-substituted aryl, alkoxy-substituted aryl, alkyl-substituted aryl), alkylsilyl (specifically, alkylsilyl having 3 to 20 carbon atoms), arylsilyl (specifically, arylsilyl having 6 to 20 carbon atoms), and combinations thereof.
The method for preparing the indolopyrrolidone compound provided by the invention comprises the following steps:
in the presence of a catalyst, Lewis acid and a zinc reagent, leading the indole compound shown in the formula II and alkyne shown in the formula III to undergo C-H bond activation/C-N bond cleavage reaction to obtain the indolopyrrolidone compound shown in the formula I:
in the formula II, R1Independently represent mono-, di-, tri-, tetra-or unsubstituted;
R1each independently selected from: hydrogen, deuterium, halogen, an alkyl group (specifically, an alkyl group having 1 to 20 carbon atoms), a cycloalkyl group (specifically, a cycloalkyl group having 3 to 20 ring carbon atoms), a heteroalkyl group (specifically, a heteroalkyl group having 1 to 20 carbon atoms), an aralkyl group (specifically, an aralkyl group having 7 to 30 carbon atoms), an alkoxy group (specifically, an alkoxy group having 1 to 20 carbon atoms), an aryloxy group (specifically, an aryloxy group having 6 to 30 carbon atoms), an aryl group (specifically, an aryl group having 6 to 30 carbon atoms), an alkylsilyl group (specifically, an alkylsilyl group having 3 to 20 carbon atoms), an arylsilyl group (specifically, an arylsilyl group having 6 to 20 carbon atoms), and combinations thereof; specifically, R1Selected from: hydrogen, deuterium, halogen, methyl, methoxy, benzyl, benzyloxy;
R2and R3Each independently selected from: an alkyl group (specifically, an alkyl group having 1 to 20 carbon atoms), a cycloalkyl group (specifically, an alkyl group having 1 to 20 carbon atoms)A cycloalkyl group having 3 to 20 ring carbon atoms), a heteroalkyl group (specifically, a heteroalkyl group having 1 to 20 carbon atoms), an aralkyl group (specifically, an aralkyl group having 7 to 30 carbon atoms), an alkoxy group (specifically, an alkoxy group having 1 to 20 carbon atoms), an aryloxy group (specifically, an aryloxy group having 6 to 30 carbon atoms), an aryl group (specifically, an aryl group having 6 to 30 carbon atoms), an alkylsilyl group (specifically, an alkylsilyl group having 3 to 20 carbon atoms), an arylsilyl group (specifically, an arylsilyl group having 6 to 20 carbon atoms), and combinations thereof;
specifically, R2,R3Is a phenyl group, and the phenyl group,
in the formula III, RaAnd RbEach independently selected from: an alkyl group (specifically, an alkyl group having 1 to 20 carbon atoms), a cycloalkyl group (specifically, a cycloalkyl group having 3 to 20 ring carbon atoms), a heteroalkyl group (specifically, a heteroalkyl group having 1 to 20 carbon atoms), an aralkyl group (specifically, an aralkyl group having 7 to 30 carbon atoms), an alkoxy group (specifically, an alkoxy group having 1 to 20 carbon atoms), an aryloxy group (specifically, an aryloxy group having 6 to 30 carbon atoms), an aryl group (specifically, an aryl group having 6 to 30 carbon atoms, a halogen-substituted aryl group, an alkoxy-substituted aryl group, an alkyl-substituted aryl group), an alkylsilyl group (specifically, an alkylsilyl group having 3 to 20 carbon atoms), an arylsilyl group (specifically, an arylsilyl group having 6 to 20 carbon atoms), and combinations thereof; raAnd RbEach independently selected from the group consisting of halogen, propyl, isopropyl, cyclopropyl, n-butyl, phenyl, halophenyl, methylphenyl, trifluoromethylphenyl, methoxyphenyl, trifluoromethoxyphenyl, and naphthyl;
in the above process, the catalyst may be a rhenium complex,
the rhenium complex contains at least one CO ligand;
specifically, the rhenium complex may specifically be rhenium decacarbonyl.
The rhenium complex is used in an amount of 1 to 30 mol%, specifically 5 mol%, based on the molar amount of the indole compound represented by formula II.
The lewis acid may be: at least one of zinc chloride, zinc bromide, zinc fluoride, zinc iodide, zinc trifluoromethanesulfonate, zinc acetate, zinc cyanide, aluminum chloride, ferric chloride, cupric chloride, silver trifluoromethanesulfonate, cupric bromide, ferric bromide, cupric iodide, cuprous chloride, cuprous bromide, cuprous iodide, ferrous chloride, and ferrous bromide,
the dosage of the Lewis acid is 1 to 100 percent of the molar weight of the indole compound shown in the formula II;
preferably, the lewis acid is zinc chloride, and the amount of the lewis acid is 10 to 100 percent of the molar amount of the indole compound shown in formula II; more preferably, the lewis acid is used in an amount of 20% to 40% or 30% of the molar amount of the indole compound of formula II.
The zinc reagent may be: the organic zinc reagent can be dimethyl zinc or diethyl zinc.
The dosage of the zinc reagent is 1 to 100 percent of the indole compound shown in the formula II; preferably, the zinc reagent is used in an amount of 10% to 50% of the indole compound of formula II; more preferably, the zinc reagent is used in an amount of 30% of the indole compound of formula II.
The molar ratio of the indole compound shown in the formula II to the alkyne shown in the formula III can be 1:1 to 1: 10; specifically, the mol ratio of the indole compound shown in the formula II to the alkyne shown in the formula III is 1: 2.5.
The C-H bond activation/C-N bond cleavage reaction is carried out in a solvent which can be: at least one of benzene, toluene and xylene, and specifically toluene.
In the system of C-H bond activation/C-N bond cleavage reaction, the molar concentration of the indole compound shown in the formula II can be 0.01-2 mol/L, and specifically, the molar concentration of the indole compound shown in the formula II is 0.2 mol/L.
The temperature range of the C-H bond activation/C-N bond cleavage reaction is 50-150 ℃, and the time range is 10-100H.
The synthesis method has higher reaction yield, and substrates containing different substituents can better participate in the reaction, such as alkyl, aryl, alkoxy, halogen and the like, and have wider substituent compatibility.
Drawings
FIG. 1 is a reaction equation for the production of an indolopyrrole compound by the reaction of indole with alkyne using a ruthenium catalyst in the prior art.
FIG. 2 is a reaction equation for producing an indolopyrrole compound by the reaction of indole and alkyne catalyzed by a cobalt catalyst in the prior art.
FIG. 3 is a prior art reaction equation for a thioamide with an alkyne.
FIG. 4 is a reaction equation of indole and alkyne disclosed in the prior art.
FIG. 5 is a reaction equation for preparing 1, 2-diphenyl-3H-pyrrolo [1,2-a ] indol-3-one in example 1 of the invention.
FIG. 6 is a reaction equation for preparing 7-methyl-1, 2-diphenyl-3H-pyrrolo [1,2-a ] indol-3-one in example 2 of the present invention.
FIG. 7 is a reaction equation for preparing 7-methoxy-1, 2-diphenyl-3H-pyrrolo [1,2-a ] indol-3-one in example 3 of the invention.
FIG. 8 is a reaction equation for preparing 7-chloro-1, 2-diphenyl-3H-pyrrolo [1,2-a ] indol-3-one in example 4 of the invention.
FIG. 9 is a reaction equation for preparing 1, 2-di-p-methylphenyl-3H-pyrrolo [1,2-a ] indol-3-one in example 5 of the invention.
FIG. 10 is a reaction equation for the preparation of 1, 2-bis (4-methoxyphenyl) -3H-pyrrolo [1,2-a ] indol-3-one in example 6 of the invention.
FIG. 11 is a reaction equation for the preparation of 1, 2-bis (4-chlorophenyl) -3H-pyrrolo [1,2-a ] indol-3-one in example 7 of the present invention.
FIG. 12 is a reaction scheme for the preparation of 1, 2-bis (3-bromophenyl) -3H-pyrrolo [1,2-a ] indol-3-one in example 8 of the present invention.
FIG. 13 is a reaction equation for the preparation of 1-tert-butyl-2-phenyl-3H-pyrrolo [1,2-a ] indol-3-one in example 9 of the present invention.
FIG. 14 is a reaction equation for the preparation of 1, 2-dipropyl-3H-pyrrolo [1,2-a ] indol-3-one in example 10 of the invention.
Detailed Description
The present invention will be described below with reference to specific examples, but the present invention is not limited thereto.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials and the like used in the following examples are commercially available unless otherwise specified.
According to one embodiment of the present invention, there is disclosed a method for preparing an indolopyrrolidone compound, the method comprising the steps of:
under the condition of the existence of a catalyst, Lewis acid and a zinc reagent, the indole compound shown in the formula II and alkyne shown in the formula III are subjected to C-H bond activation/C-N bond cleavage reaction to obtain the indolopyrrolidone compound shown in the formula I;
wherein,
R1independently represent mono-, di-, tri-, tetra-or unsubstituted;
R1each independently selected from the group consisting of: hydrogen, deuterium, halogen, alkyl groups having 1 to 20 carbon atoms, cycloalkyl groups having 3 to 20 ring carbon atoms, heteroalkyl groups having 1 to 20 carbon atoms, aralkyl groups having 7 to 30 carbon atoms, alkoxy groups having 1 to 20 carbon atoms, aryloxy groups having 6 to 30 carbon atoms, aryl groups having 6 to 30 carbon atoms, alkylsilyl groups having 3 to 20 carbon atoms, arylsilyl groups having 6 to 20 carbon atoms, and combinations thereof;
R2,R3,Raand RbEach independently selected from the group consisting of: an alkyl group having 1 to 20 carbon atoms, a cycloalkyl group having 3 to 20 ring carbon atoms, a heteroalkyl group having 1 to 20 carbon atoms, an aralkyl group having 7 to 30 carbon atoms, an alkoxy group having 1 to 20 carbon atoms, an aryloxy group having 6 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, an alkylsilyl group having 3 to 20 carbon atoms, an arylsilyl group having 6 to 20 carbon atoms, and combinations thereof.
According to one embodiment of the invention, wherein R is1Selected from the group consisting of hydrogen, deuterium, halogen, alkyl groups having 1 to 20 carbon atoms, cycloalkyl groups having 3 to 20 ring carbon atoms, aralkyl groups having 7 to 30 carbon atoms, alkoxy groups having 1 to 20 carbon atoms, aryloxy groups having 6 to 30 carbon atoms and aryl groups having 6 to 30 carbon atoms; preferably, R1Selected from hydrogen, deuterium, halogen, methyl, methoxy, benzyl and benzyloxy.
According to one embodiment of the invention, wherein R is2,R3,RaAnd RbEach independently selected from the group consisting of halogen, alkyl having 1 to 20 carbon atoms, cycloalkyl having 3 to 20 ring carbon atoms, aralkyl having 7 to 30 carbon atoms, alkoxy having 1 to 20 carbon atoms, aryloxy having 6 to 30 carbon atoms, aryl having 6 to 30 carbon atoms; preferably, R2,R3Is phenyl, RaAnd RbEach independently selected from halogen, propyl, isopropyl, cyclopropyl, n-butyl and phenylHalophenyl, methylphenyl, trifluoromethylphenyl, methoxyphenyl, trifluoromethoxyphenyl, and naphthyl.
According to one embodiment of the invention, wherein the catalyst is a rhenium complex, the rhenium complex contains at least one CO ligand; preferably, the rhenium complex is rhenium decacarbonyl.
According to an embodiment of the present invention, wherein the lewis acid is at least one selected from the group consisting of zinc chloride, zinc bromide, zinc fluoride, zinc iodide, zinc trifluoromethanesulfonate, zinc acetate, zinc cyanide, aluminum chloride, ferric chloride, cupric chloride, silver trifluoromethanesulfonate, cupric bromide, ferric bromide, cupric iodide, cuprous chloride, cuprous bromide, cuprous iodide, ferrous chloride and ferrous bromide, and the amount of the lewis acid is 1 to 100% of the molar amount of the indole compound represented by formula II; preferably, the lewis acid is zinc chloride, and the amount of the lewis acid is 10 to 100 percent of the molar amount of the indole compound shown in formula II; more preferably, the amount of the lewis acid is 30% of the molar amount of the indole compound of formula II.
According to a preferred embodiment of the present invention, wherein the zinc reagent is a methyl zinc reagent, said zinc reagent is used in an amount of 1% to 100% of the indole compound represented by formula II; preferably, the zinc reagent is used in an amount of 10% to 50% of the indole compound of formula II; more preferably, the zinc reagent is used in an amount of 30% of the indole compound of formula II.
According to a preferred embodiment of the present invention, wherein the molar ratio of the indole compound of formula II to the alkyne of formula III is from 1:1 to 1: 10; preferably, the mol ratio of the indole compound shown in the formula II to the alkyne shown in the formula III is 1: 2.5.
According to a preferred embodiment of the present invention, the solvent in the system in which the C-H bond activation/C-N bond cleavage reaction is carried out may be selected from benzene, toluene, xylene, preferably toluene.
According to a preferred embodiment of the present invention, in the system of C-H bond activation/C-N bond cleavage reaction, the molar concentration of the indole compound represented by formula II is 0.01 to 2mol/L, and preferably, the molar concentration of the indole compound represented by formula II is 0.2 mol/L.
According to a preferred embodiment of the present invention, wherein said C-H bond activation/C-N bond cleavage formation reaction is carried out at a temperature in the range of 50 to 150 ℃ for a time in the range of 10-100H.
The preparation method of the compounds of formula-II and formula-III referred to in the following examples is:
a preparation method of the formula-II: under a nitrogen atmosphere, 1.2 equivalents of the sodium hydride solid were suspended in dry tetrahydrofuran at zero degrees centigrade, 1 equivalent of the corresponding indole compound was added, and stirring was continued for one hour at zero degrees centigrade. Then, 1.1 equivalents of N, N-dibenzoylcarbamoyl chloride was added to the system. After the addition was complete, the reaction was allowed to gradually warm to room temperature and the reaction was continued overnight. Quenching the reaction with saturated ammonium chloride aqueous solution, extracting with anhydrous ether, drying the organic phase with anhydrous magnesium sulfate, filtering, and removing the organic solvent to obtain a crude product. The pure product, namely the compound of the formula-II is obtained by column chromatography separation.
A preparation method of the formula-III: to a dry Schlenk flask, 6 mol% of bis (triphenylphosphine) palladium dichloride, 10 mol% of cuprous iodide, 1 equivalent of the corresponding aryl iodide reagent (or aryl bromide reagent) was added under nitrogen atmosphere at room temperature. With stirring, dry toluene, 1, 8-diazabicycloundecen-7-ene, 0.5 equivalents of triethylethynylsilane, and 40 mol% water were injected. The reaction system was placed in a dark environment and allowed to continue the reaction for 18 hours. After the reaction is finished, adding water into the system for quenching reaction, extracting with anhydrous ether, washing the organic phase with 10% hydrochloric acid for three times, drying the organic phase with anhydrous magnesium sulfate, filtering, and removing the organic solvent to obtain a crude product. And (4) obtaining a pure product, namely the compound of the formula-III by column chromatography separation.
Example 1
Preparation of 1, 2-Diphenyl-3H-pyrrolo [1,2-a ] indol-3-one (formula I-a) according to the reaction equation shown in FIG. 5
Into a 25mL Schlenk flask, at N2N, N-Diphenyl-1H-indole-1-carboxamide (0.5mmol, 156.2mg), 1, 2-diphenylacetylene (1.25mmol, 222.8mg), Re2(CO)10A mixture of (0.025mmol, 16.3mg), zinc chloride (0.15mmol, 20.4mg), dimethylzinc (0.15mmol, 1.2M, 0.125mL) and dry toluene (2.5mL) was heated to 150 deg.C for 24h and after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel, which was washed with EA. The filtrate was concentrated and then separated by column chromatography (eluent petroleum ether: dichloromethane 5/1, v/v) to give the objective product (formula I-a)141.2mg, 88% yield.
The target product was characterized as follows:1H NMR(400MHz,CDCl3):δ7.76(d,J=8.0Hz,1H),7.46-7.42(m,4H),7.40-7.35(m,4H),7.33–7.26(m,4H),7.09(t,J=7.6Hz,1H),6.49(s,1H);13C NMR(100MHz,CDCl3):164.45,141.64,141.32,134.54,133.73,131.94,131.42,130.47,129.68,129.53,128.80,128.47,128.39,128.29,127.29,123.33,122.57,112.54,108.16;HRMS(ESI):Calculated for C23H16NO([M+H]+) 322.12264, found 322.12231, with correct structure.
Example 2
Preparation of 7-methyl-1, 2-diphenyl-3H-pyrrolo [1,2-a ] indol-3-one (formula I-b) according to the reaction equation shown in FIG. 6
Into a 25mL Schlenk flask, at N2Under the protection of (1), 5-methyl-N, N-diphenyl-1H-indole-1-carboxamide (0.5mmol, 163.2mg), 1, 2-diphenylacetylene (1.25mmol, 222.8mg), Re2(CO)10(0.025mmol, 16.3mg), zinc chloride (0.15mmol, 20.4mg), dimethylzinc (0.15mmol, 1.2M, 0.125mL) and dry toluene (2.5mL) were heated to 150 ℃ for 24h and after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel, washed with EAWashing the silica gel thin layer. The filtrate was concentrated and then separated by column chromatography (eluent petroleum ether: dichloromethane 5/1, v/v) to give the objective product (formula I-a)164.2mg, yield 98%.
The target product was characterized as follows:1H NMR(500MHz,CDCl3):δ7.64(d,J=8.1Hz,1H),7.47–7.41(m,4H),7.41–7.34(m,3H),7.33–7.26(m,3H),7.19(s,1H),7.10(d,J=8.1Hz,1H),6.43(s,1H),2.37(s,3H)。13C NMR(126MHz,CDCl3):δ164.44(s),141.55(d,J=2.2Hz),134.04(s),132.85(d,J=16.3Hz),131.89(s),131.56(s),130.62(s),129.63(d,J=9.8Hz),128.85(s),128.41(dd,J=14.0,12.5Hz),122.82(s),112.20(s),108.16(s),77.31(s),77.06(s),76.80(s),21.38(s)。HRMS(APCI):calcd for C24H18NO([M+H]336.13829 as (+) and 336.13781 as found in the specification, and has correct structure.
Example 3
Preparation of 7-methoxy-1, 2-diphenyl-3H-pyrrolo [1,2-a ] indol-3-one (formula I-c) according to the reaction equation shown in FIG. 7
Into a 25mL Schlenk flask, at N2Under the protection of (3), 5-methoxy-N, N-diphenyl-1H-indole-1-carboxamide (0.5mmol, 171.2mg), 1, 2-diphenylacetylene (1.25mmol, 222.8mg), Re2(CO)10A mixture of (0.025mmol, 16.3mg), zinc chloride (0.15mmol, 20.4mg), dimethylzinc (0.15mmol, 1.2M, 0.125mL) and dry toluene (2.5mL) was heated to 150 deg.C for 24h and after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel, which was washed with EA. The filtrate was concentrated and then separated by column chromatography (eluent petroleum ether: dichloromethane 5/1, v/v) to give the desired product (formula I-a)156.2mg, 89% yield.
The target product was characterized as follows:1H NMR(500MHz,CDCl3):δ7.64(d,J=8.6Hz,1H),7.43(ddd,J=8.9,6.7,5.0Hz,4H),7.37(td,J=8.6,4.5Hz,3H),7.33–7.28(m,3H),6.93–6.85(m,2H),6.42(s,1H),3.81(s,3H).13C NMR(126MHz,CDCl3):δ164.36(s),156.45(s),142.36(s),141.56(s),134.80(s),132.02(s),131.59(s),130.67(s),129.81(s),129.63(t,J=22.2Hz),128.98(s),128.63(dd,J=38.2,26.6Hz),114.59(s),113.08(s),108.15(s),106.87(s),77.41(s),77.03(d,J=32.0Hz),55.89(s).HRMS(APCI):Calcd for C24H18NO2([M+H]352.13321 as (+) and 352.13293 as Found, with correct structure.
Example 4
Preparation of 7-chloro-1, 2-diphenyl-3H-pyrrolo [1,2-a ] indol-3-one (formula I-d) according to the reaction equation shown in FIG. 8
Into a 25mL Schlenk flask, at N2Under the protection of (3), 5-chloro-N, N-diphenyl-1H-indole-1-carboxamide (0.5mmol, 173.4mg), 1, 2-diphenylacetylene (1.25mmol, 222.8mg), Re2(CO)10A mixture of (0.025mmol, 16.3mg), zinc chloride (0.15mmol, 20.4mg), dimethylzinc (0.15mmol, 1.2M, 0.125mL) and dry toluene (2.5mL) was heated to 150 deg.C for 24h and after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel, which was washed with EA. The filtrate was concentrated and then separated by column chromatography (eluent petroleum ether: dichloromethane 5/1, v/v) to give the desired product (formula I-a)150.9mg, 85% yield.
The target product was characterized as follows:1H NMR(500MHz,CDCl3):δ7.65(d,J=8.5Hz,1H),7.45–7.34(m,8H),7.33–7.28(m,3H),7.23(dd,J=8.5,2.0Hz,1H),6.42(s,1H).13C NMR(126MHz,CDCl3):δ164.25(s),142.54(s),141.64(s),134.97(s),132.80(s),132.27(s),131.18(s),130.25(s),129.94(s),129.58(s),128.95(s),128.72(d,J=12.7Hz),128.46(d,J=10.8Hz),127.16(s),122.29(s),113.28(s),107.06(s),77.33(s),77.08(s),76.82(s).HRMS(APCI):Calcd for C23H15ClNO([M+H]356.08367 as (+) and 356.08304 as Found, with correct structure.
Example 5
Preparation of 1, 2-di-p-methylphenyl-3H-pyrrolo [1,2-a ] indol-3-one (formula I-e) according to the reaction equation shown in FIG. 9
Into a 25mL Schlenk flask, at N2Under the protection of (1), N-diphenyl-1H-indole-1-carboxamide (0.5mmol, 156.2mg), 1, 2-di-p-methylphenyl acetylene (1.25mmol, 257.9mg), Re2(CO)10A mixture of (0.025mmol, 16.3mg), zinc chloride (0.15mmol, 20.4mg), dimethylzinc (0.15mmol, 1.2M, 0.125mL) and dry toluene (2.5mL) was heated to 150 deg.C for 24h and after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel, which was washed with EA. The filtrate was concentrated and then separated by column chromatography (eluent petroleum ether: dichloromethane 5/1, v/v) to give the desired product (formula I-a)132.6mg, 76% yield.
The target product was characterized as follows:1H NMR(500MHz,CDCl3):δ7.75(dd,J=8.0,0.5Hz,1H),7.40–7.31(m,5H),7.29–7.25(m,1H),7.17(d,J=7.9Hz,2H),7.12(d,J=7.9Hz,2H),7.08(td,J=7.7,0.9Hz,1H),6.47(s,1H),2.38(s,3H),2.35(s,3H).13C NMR(126MHz,CDCl3):δ164.85(s),141.64(s),141.12(s),139.91(s),138.35(s),134.55(s),133.85(s),131.48(s),129.50(d,J=11.5Hz),129.09(s),128.73(s),128.45(s),127.81(s),127.15(s),123.26(s),122.52(s),112.54(s),107.80(s),77.32(s),77.07(s),76.81(s),21.49(d,J=9.2Hz).HRMS(APCI):Calcd for C25H20NO([M+H]350.15394 as (+) and 350.15375 as Found, with correct structure.
Example 6
Preparation of 1, 2-bis (4-methoxyphenyl) -3H-pyrrolo [1,2-a ] indol-3-one (formula I-f) according to the reaction equation shown in FIG. 10
Into a 25mL Schlenk flask, at N2N, N-Diphenyl-1H-indole-1-carboxamide (0.5mmol, 156.2mg), 1, 2-bis (4-methoxyphenyl) acetylene (1.25mmol, 297.9mg), Re2(CO)10(0.025mmol, 16.3mg), zinc chloride (0.15mmol, 20.4mg), dimethylzinc (0.15mmol, 1.2M, 0.125mL) and anhydrous formazanA mixture of benzene (2.5mL) was heated to 150 ℃ for 24h and after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel which was washed with EA. The filtrate was concentrated and then separated by column chromatography (eluent petroleum ether: dichloromethane 5/1, v/v) to give the objective product (formula I-a)181.0mg, yield 95%.
The target product was characterized as follows:1H NMR(500MHz,CDCl3):δ7.75(d,J=7.9Hz,1H),7.48–7.35(m,5H),7.30–7.22(m,1H),7.08(t,J=7.4Hz,1H),6.88(dd,J=16.6,8.8Hz,4H),3.84(s,3H),3.81(s,3H).13C NMR(126MHz,CDCl3):δ165.11(s),160.65(s),159.62(s),141.71(s),140.07(s),134.47(s),133.84(s),130.93(s),130.35(s),130.04(s),127.05(s),124.02(s),123.24(d,J=9.5Hz),122.44(s),114.27(s),113.89(s),112.48(s),107.49(s),77.31(s),77.06(s),76.80(s),55.31(d,J=11.2Hz).HRMS(APCI):Calcd for C25H20NO3([M+H]382.14377 as (+) and 382.14342 as Found, with correct structure.
Example 7
Preparation of 1, 2-bis (4-chlorophenyl) -3H-pyrrolo [1,2-a ] indol-3-one (formula I-g) according to the reaction equation shown in FIG. 11
Into a 25mL Schlenk flask, at N2Under the protection of (1), N-diphenyl-1H-indole-1-carboxamide (0.5mmol, 156.2mg), 1, 2-bis (4-chlorophenyl) acetylene (1.25mmol, 308.9mg), Re2(CO)10A mixture of (0.025mmol, 16.3mg), zinc chloride (0.15mmol, 20.4mg), dimethylzinc (0.15mmol, 1.2M, 0.125mL) and dry toluene (2.5mL) was heated to 150 deg.C for 24h and after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel, which was washed with EA. The filtrate was concentrated and then separated by column chromatography (eluent petroleum ether: dichloromethane 5/1, v/v) to give the objective product (formula I-a)175.1mg, 90% yield.
The target product was characterized as follows:1H NMR(500MHz,CDCl3):δ7.73(d,J=8.0Hz,1H),7.41–7.33(m,7H),7.32–7.26(m,3H),7.10(t,J=7.6Hz,1H),6.46(s,1H).13C NMR(126MHz,CDCl3):δ163.98(s),140.81(d,J=7.9Hz),136.12(s),134.74(d,J=15.9Hz),133.75(s),131.10(s),130.90(s),129.87(s),129.70(s),129.48(s),128.83(d,J=18.0Hz),127.78(s),123.74(s),122.91(s),112.76(s),108.70(s),77.41(s),77.16(s),76.91(s).HRMS(APCI):Calcd for C23H14Cl2NO([M+H]390.04470, Found 390.04438, with correct structure.
Example 8
Preparation of 1, 2-bis (3-bromophenyl) -3H-pyrrolo [1,2-a ] indol-3-one (formula I-H) according to the reaction equation shown in FIG. 12
Into a 25mL Schlenk flask, at N2Under the protection of (1), N-diphenyl-1H-indole-1-carboxamide (0.5mmol, 156.2mg), 1, 2-bis (3-bromophenyl) acetylene (1.25mmol, 420.0mg), Re2(CO)10A mixture of (0.025mmol, 16.3mg), zinc chloride (0.15mmol, 20.4mg), dimethylzinc (0.15mmol, 1.2M, 0.125mL) and dry toluene (2.5mL) was heated to 150 deg.C for 24h and after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel, which was washed with EA. The filtrate was concentrated and then separated by column chromatography (eluent petroleum ether: dichloromethane 5/1, v/v) to give 199.9mg of the objective product (formula I-a) in 84% yield.
The target product was characterized as follows:1H NMR(500MHz,CDCl3):δ7.75(d,J=7.9Hz,1H),7.63(dd,J=3.6,1.8Hz,2H),7.59–7.54(m,1H),7.45(ddd,J=8.0,1.8,1.0Hz,1H),7.42(d,J=7.8Hz,1H),7.35–7.28(m,3H),7.25(dd,J=8.4,7.3Hz,1H),7.18(t,J=7.9Hz,1H),7.12(td,J=7.7,0.8Hz,1H),6.52(s,1H).13C NMR(126MHz,CDCl3):δ163.57(s),140.86(s),140.48(s),134.65(s),133.64(s),133.03(d,J=5.9Hz),132.32(s),132.03(s),131.78(s),131.12(d,J=3.7Hz),130.56(s),129.94(s),128.06(s),127.87(s),127.16(s),123.76(s),123.01(d,J=14.9Hz),122.52(s),112.73(s),109.07(s).HRMS(APCI):Calcdfor C23H14Br2NO([M+H]477.94367, Found 477.94332(479.94124), knotThe structure is correct.
Example 9
According to the reaction equation shown in FIG. 13, 1-tert-butyl-2-phenyl-3H-pyrrolo [1,2-a ] indol-3-one (formula I-I)
Into a 25mL Schlenk flask, at N2Under the protection of (1), N-diphenyl-1H-indole-1-carboxamide (0.5mmol, 156.2mg), 3, 3-dimethylbutynylbenzene (1.25mmol, 197.8mg), Re2(CO)10A mixture of (0.025mmol, 16.3mg), zinc chloride (0.15mmol, 20.4mg), dimethylzinc (0.15mmol, 1.2M, 0.125mL) and dry toluene (2.5mL) was heated to 150 ℃ for reaction for 48h, after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel, which was washed with EA. The filtrate was concentrated and then separated by column chromatography (eluent petroleum ether: dichloromethane 5/1, v/v) to give the desired product (formula I-a)127.9mg, 85% yield.
The target product was characterized as follows:1H NMR(500MHz,CDCl3):δ7.69(d,J=7.9Hz,1H),7.41(dd,J=5.2,1.9Hz,3H),7.37–7.30(m,2H),7.27(d,J=7.7Hz,1H),7.25–7.19(m,1H),7.03(t,J=7.5Hz,1H),5.95(s,1H),1.24(s,9H).13C NMR(126MHz,CDCl3):δ165.13,143.69,142.88,141.17,134.62,133.90,133.76,128.69,128.47,128.10,126.72,123.13,122.39,112.39,105.95,34.53,30.39.HRMS(APCI):Calcd for C21H20ON([M+H]+) 302.15394, Found 302.15369, with correct structure.
Example 10
Preparation of 1, 2-dipropyl-3H-pyrrolo [1,2-a ] indol-3-one (formula I-j) according to the reaction equation shown in FIG. 14
Into a 25mL Schlenk flask, at N2N, N-Diphenyl-1H-indole-1-carboxamide (0.5mmol, 156.2mg), oct-4-yne (1.25mmol, 137.8mg), Re2(CO)10(0.025mmol,16.3mg), zinc chloride (0.15mmol, 20.4mg), a mixture of dimethylzinc (0.15mmol, 1.2M, 0.125mL) and dry toluene (2.5mL) was heated to 150 ℃ for reaction for 72h, after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel, which was washed with EA. The filtrate was concentrated and then separated by column chromatography (eluent petroleum ether: dichloromethane 5/1, v/v) to give the objective product (formula I-a)29.1mg, 23% yield.
The target product was characterized as follows:1H NMR(500MHz,CDCl3):δ7.64(dd,J=7.9,0.9Hz,1H),7.34(dt,J=7.8,0.9Hz,1H),7.21(td,J=7.7,1.2Hz,1H),7.03(td,J=7.6,1.1Hz,1H),6.28(s,1H),2.44(dd,J=8.4,6.9Hz,2H),2.32–2.24(m,2H),1.72–1.62(m,2H),1.62–1.51(m,2H),1.01(t,J=7.4Hz,3H),0.97(t,J=7.4Hz,3H).13C NMR(126MHz,CDCl3):δ166.01,144.40,142.52,135.55,134.27,133.97,126.50,122.71,122.19,112.03,104.73,28.04,25.73,22.33,22.30,14.09,14.00.HRMS(APCI):Calcd for C17H20ON([M+H]254.15394 as (+) and 254.15411 as Found, with correct structure.
In summary, the embodiments of the present invention provide a preparation method of polysubstituted isoindoline, which utilizes indole and alkyne to react in a solvent in the presence of a catalyst, lewis acid and a zinc reagent, so as to realize synthesis of polysubstituted isoindoline.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention.
Claims (10)
1. A process for preparing an indolopyrrolidone compound having the formula I:
in the formula I, R1Independently represent mono-, di-, tri-, tetra-or unsubstituted;
R1each independently selected from: hydrogen, deuterium, halogen, alkyl, cycloalkyl, heteroAlkyl, aralkyl, alkoxy, aryloxy, aryl, alkylsilyl, arylsilyl, and combinations thereof;
Raand RbEach independently selected from: alkyl, cycloalkyl, heteroalkyl, aralkyl, alkoxy, aryloxy, aryl, alkylsilyl, arylsilyl, and combinations thereof;
the method comprises the following steps:
in the presence of a catalyst, Lewis acid and a zinc reagent, leading the indole compound shown in the formula II and alkyne shown in the formula III to undergo C-H bond activation/C-N bond cleavage reaction to obtain the indolopyrrolidone compound shown in the formula I:
in the formula II R1In the same formula I as R1;
R2And R3Each independently selected from: alkyl, cycloalkyl, heteroalkyl, aralkyl, alkoxy, aryloxy, aryl, alkylsilyl, arylsilyl, and combinations thereof;
in the formula III, RaAnd RbIn the same formula I as RaAnd Rb。
2. The method of claim 1, wherein: the catalyst is a rhenium complex;
the rhenium complex is used in an amount of 1 to 30 mol% based on the molar amount of the indole compound of formula II.
3. The method of claim 2, wherein: the rhenium complex contains at least one CO ligand.
4. The method according to any one of claims 1-3, wherein: the Lewis acid is: at least one of zinc chloride, zinc bromide, zinc fluoride, zinc iodide, zinc trifluoromethanesulfonate, zinc acetate, zinc cyanide, aluminum chloride, ferric chloride, cupric chloride, silver trifluoromethanesulfonate, cupric bromide, ferric bromide, cupric iodide, cuprous chloride, cuprous bromide, cuprous iodide, ferrous chloride, and ferrous bromide,
the dosage of the Lewis acid is 1 to 100 percent of the molar weight of the indole compound shown in the formula II.
5. The method according to any one of claims 1-4, wherein: the zinc reagent is an organic zinc reagent;
the dosage of the zinc reagent is 1% -100% of the indole compound shown in the formula II.
6. The method of claim 5, wherein: the zinc reagent is dimethyl zinc and/or diethyl zinc.
7. The method according to any one of claims 1-6, wherein: the mol ratio of the indole compound shown in the formula II to the alkyne shown in the formula III is 1:1-1: 10.
8. The method according to any one of claims 1-7, wherein: the C-H bond activation/C-N bond cleavage reaction is carried out in a solvent,
the solvent is as follows: at least one of benzene, toluene and xylene.
9. The method according to any one of claims 1-8, wherein: in the system of C-H bond activation/C-N bond cleavage reaction, the molar concentration of the indole compound shown in the formula II is 0.01-2 mol/L.
10. The method according to any one of claims 1-9, wherein: the temperature of the C-H bond activation/C-N bond cleavage reaction is 50-150 ℃, and the time is 10-100H.
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