CN110283179B - A kind of method for directly constructing indolo ring compound - Google Patents
A kind of method for directly constructing indolo ring compound Download PDFInfo
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- CN110283179B CN110283179B CN201910678742.2A CN201910678742A CN110283179B CN 110283179 B CN110283179 B CN 110283179B CN 201910678742 A CN201910678742 A CN 201910678742A CN 110283179 B CN110283179 B CN 110283179B
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- Prior art keywords
- benzonitrile
- oxo
- iodobenzyl
- indole
- bromo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 title claims abstract description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 30
- 125000006481 2-iodobenzyl group Chemical group [H]C1=C([H])C(I)=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 239000003208 petroleum Substances 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 239000003480 eluent Substances 0.000 claims abstract description 7
- 150000001879 copper Chemical class 0.000 claims abstract description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000741 silica gel Substances 0.000 claims abstract description 4
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 4
- 239000000758 substrate Substances 0.000 claims abstract description 4
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 83
- -1 2,5-dibromobenzyl Chemical group 0.000 claims description 55
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 24
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 14
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 14
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 13
- 150000008359 benzonitriles Chemical class 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 4
- KXNFZFHHBPSTMF-UHFFFAOYSA-N 2-[(2-iodophenyl)methyl-methylamino]benzonitrile Chemical compound IC1=C(CN(C2=C(C#N)C=CC=C2)C)C=CC=C1 KXNFZFHHBPSTMF-UHFFFAOYSA-N 0.000 claims description 3
- VLOSQQHGWZSZIW-UHFFFAOYSA-N 2-[(2-iodophenyl)methylsulfanyl]benzonitrile Chemical compound IC1=C(CSC2=C(C#N)C=CC=C2)C=CC=C1 VLOSQQHGWZSZIW-UHFFFAOYSA-N 0.000 claims description 3
- 125000006280 2-bromobenzyl group Chemical group [H]C1=C([H])C(Br)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- WYCAWWICLUSQPF-UHFFFAOYSA-N 2-[(2,5-dibromophenyl)methylsulfanyl]benzonitrile Chemical compound C1=CC=C(C(=C1)C#N)SCC2=C(C=CC(=C2)Br)Br WYCAWWICLUSQPF-UHFFFAOYSA-N 0.000 claims description 2
- MRBKGXCYDNNUPE-UHFFFAOYSA-N 2-[(2-bromophenyl)methyl-methylamino]benzonitrile Chemical compound C=1C=CC=C(C#N)C=1N(C)CC1=CC=CC=C1Br MRBKGXCYDNNUPE-UHFFFAOYSA-N 0.000 claims description 2
- ZMWPUXQAOSLKJW-UHFFFAOYSA-N 2-[(2-bromophenyl)methylsulfanyl]benzonitrile Chemical compound C1=CC=C(C(=C1)CSC2=CC=CC=C2C#N)Br ZMWPUXQAOSLKJW-UHFFFAOYSA-N 0.000 claims description 2
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 1
- YVHPHQBRUPLYOS-UHFFFAOYSA-N dichloromethane;methane Chemical compound C.ClCCl YVHPHQBRUPLYOS-UHFFFAOYSA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 42
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 39
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 32
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 22
- 238000005481 NMR spectroscopy Methods 0.000 description 22
- 239000007787 solid Substances 0.000 description 22
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 11
- 229910052786 argon Inorganic materials 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 238000013467 fragmentation Methods 0.000 description 11
- 238000006062 fragmentation reaction Methods 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 11
- 229910052739 hydrogen Inorganic materials 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 238000000926 separation method Methods 0.000 description 10
- ZYZIFFMSPJVFOX-UHFFFAOYSA-N 10h-[1]benzofuro[3,2-b]indole Chemical compound C12=CC=CC=C2OC2=C1NC1=CC=CC=C21 ZYZIFFMSPJVFOX-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 9
- 239000004810 polytetrafluoroethylene Substances 0.000 description 9
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 8
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 8
- 230000002194 synthesizing effect Effects 0.000 description 6
- FPQLXWGSGNEDCF-UHFFFAOYSA-N 10H-[1]benzothiolo[3,2-b]indole Chemical compound C12=CC=CC=C2SC2=C1NC1=CC=CC=C21 FPQLXWGSGNEDCF-UHFFFAOYSA-N 0.000 description 3
- HATARQVDJCYJAE-UHFFFAOYSA-N 3-bromo-10H-[1]benzofuro[3,2-b]indole Chemical compound BrC(C=C1)=CC2=C1NC1=C2OC2=C1C=CC=C2 HATARQVDJCYJAE-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 238000007146 photocatalysis Methods 0.000 description 3
- 230000001699 photocatalysis Effects 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 239000004809 Teflon Substances 0.000 description 2
- 229920006362 Teflon® Polymers 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- NVLARRGLDXCISW-UHFFFAOYSA-N [O-][N+](=O)C1=CC(C=O)=CC=C1C1=CC2=CC=CC=C2S1 Chemical compound [O-][N+](=O)C1=CC(C=O)=CC=C1C1=CC2=CC=CC=C2S1 NVLARRGLDXCISW-UHFFFAOYSA-N 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 229960003280 cupric chloride Drugs 0.000 description 1
- 229960004643 cupric oxide Drugs 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 1
- 229940112669 cuprous oxide Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明公开了一种直接构建吲哚并环化合物的方法，特征是以2‑[(2‑碘苯甲基)氧代]苯甲腈衍生物作为底物，将催化剂铜盐和碱、2‑[(2‑碘苯甲基)氧代]苯甲腈衍生物按摩尔比0.02～0.2:2～4:1，在溶剂中于90℃反应8‑20h，以石油醚/二氯甲烷/乙酸乙酯按体积比20～5:2:1混合作为洗脱剂，过硅胶柱分离，得到目标产物。本发明方法操作简单，条件温和，产率较高，是一种绿色新颖的合成方法。The invention discloses a method for directly constructing an indolo ring compound, which is characterized by using a 2-[(2-iodobenzyl)oxo]benzonitrile derivative as a substrate, a catalyst copper salt and a base, 2 ‑[(2‑iodobenzyl)oxo]benzonitrile derivative in a molar ratio of 0.02～0.2:2～4:1, reacted in a solvent at 90° C. for 8-20h, using petroleum ether/dichloromethane/ Ethyl acetate was mixed as an eluent in a volume ratio of 20-5:2:1, and separated through a silica gel column to obtain the target product. The method of the invention has the advantages of simple operation, mild conditions and high yield, and is a green and novel synthesis method.
Description
Technical Field
The invention belongs to the technical field of methods for directly constructing an indole-fused ring compound, and particularly relates to a method for directly synthesizing an indole-fused ring compound by activating an aryl side chain C-H bond.
Background
Indole tetra-fused ring structural units are widely present in organic intermediates, pharmaceutical compounds and organisms, so that the reaction for directly constructing the indole fused ring compounds is widely applied to the fields of material chemistry and pharmaceutical chemistry. However, the methods for synthesizing the indolo ring compounds that exist at present basically require the use of a transition metal as a catalyst. The high cost of transition metal complex oxidants and metal residues limits their large-scale application in the industrial and pharmaceutical industries. In addition, most methods for synthesizing indole-fused ring compounds are to synthesize indole-fused ring compounds using indole and derivatives thereof as raw materials, for example (Chunyan Du, Jianming Chen, Yunlong Guo, Kun Lu, Shanghui Ye, Jiann Zheng, Yunqi Liu, Zhuigan Shuai, Gui Yu.J.org.Chem.2009,74,7322 and 7327), etc., it is necessary to construct a part of rings of the indole-fused ring compound and then synthesize the rest of rings.
British Green chemistry (Green chem.,2017,19, 4798-4803) describes a method for producing indole tetracyclic rings by activating C-H bonds using photocatalysis by dissolving 1.0 equivalent of diaryl azide in tetrahydrofuran and pumping the reaction mixture into a 16mL FEP-coiled reactor irradiated with a 254nm light source for 10 minutes to convert to the corresponding indole tetracyclic product. Although the method adopts photocatalysis and does not use transition metal catalysis, the requirement on reaction equipment is higher.
U.S. journal of organic chemistry (J.org.chem.2009,74, 7322-7327) discloses a method for the synthesis of indolyltetrafused rings by activation of the C-H bond using 1.0 equivalent of 4- (benzo [ b ] thiophen-2-yl) -3-nitrobenzaldehyde and 3.0 equivalents of triphenylphosphine in a solution of o-dichlorobenzene under heating and refluxing to give 8-formyl-6H-indolo [3,2-b ] benzo [ b ] thiophene. This approach requires the construction of a portion of the rings of the indolo ring compound prior to the synthesis of the remaining rings.
It can be seen that the prior art mostly uses metal catalysts, so that it is difficult to avoid metal residues in the synthesized drug. The adoption of photocatalysis has the problems of high requirements on equipment and difficult control of reaction selectivity.
Disclosure of Invention
The invention aims to provide a method for directly constructing an indole-fused ring compound, which adopts anhydrous copper sulfate as a catalyst and nitrile as a nitrogen source to catalyze the activation of a C-H bond of an aryl side chain to directly synthesize the indole-fused ring compound.
The invention relates to a method for directly constructing an indole-fused ring compound, which is characterized by comprising the following steps: taking a 2- [ (2-iodobenzyl) oxo ] benzonitrile derivative as a substrate, reacting a catalyst copper salt and an alkali with the 2- [ (2-iodobenzyl) oxo ] benzonitrile derivative according to a molar ratio of 0.02-0.2: 2-4: 1 in a solvent at 90 ℃ for 8-20h, mixing petroleum ether/dichloromethane/ethyl acetate according to a volume ratio of 20-5: 2:1 to obtain an eluent, and separating by using a silica gel column to obtain a target product.
The 2- [ (2-iodobenzyl) oxo ] benzonitrile derivative may be 2- [ (2-iodobenzyl) oxo ] benzonitrile, 2- [ (2-bromophenyl) oxo ] benzonitrile, 2- [ (5-bromo-2-iodobenzyl) oxo ] benzonitrile, 2- [ (2, 5-dibromobenzyl) oxo ] benzonitrile, 2- [ (5-chloro-2-iodobenzyl) oxo ] benzonitrile, 2- [ (5-chloro-2-bromobenzyl) oxo ] benzonitrile, 2- [ (5-chloro-2-bromophenyl) oxo ] benzonitrile, 2- [ (2-iodo-5-methylbenzyl) oxo ] benzonitrile, 2- [ (2-bromo-5-methylbenzyl) oxo ] benzonitrile, 4-bromo-2- [ (2-iodobenzyl) oxo ] benzonitrile, or mixtures thereof, 4-bromo-2- [ (2-bromobenzyl) oxo ] benzonitrile, 2- [ (1-iodonaphthalen-2-yl) methoxy ] benzonitrile, 2- [ (1-bromonaphthalen-2-yl) methoxy ] benzonitrile, 2- [ (2-iodobenzyl) sulfanyl ] benzonitrile, 2- [ (2-bromophenylmethyl) sulfanyl ] benzonitrile, 2- [ (5-chloro-2-iodobenzyl) sulfanyl ] benzonitrile, 2- [ (5-chloro-2-bromophenylmethyl) sulfanyl ] benzonitrile, 2- [ (5-chloro-2-bromobenzyl) sulfanyl ] benzonitrile, 2- [ (5-bromo-2-iodobenzyl) sulfanyl ] benzonitrile, 2- [ (2, 5-dibromobenzyl) sulfanyl ] benzonitrile, 2- [ (2-iodobenzyl) (methyl) amino ] benzonitrile or 2- [ (2- Bromobenzyl) (methyl) amino ] benzonitrile.
The solvent is chlorobenzene, DMF or DMSO.
The copper salt of the catalyst is anhydrous copper sulfate, cuprous iodide, copper iodide, cuprous chloride, cupric chloride, cuprous oxide or cupric oxide.
The alkali is potassium tert-butoxide, potassium hydroxide, sodium tert-butoxide, lithium tert-butoxide, sodium hydride, calcium hydride, cesium carbonate, cesium fluoride or lithium bistrimethylsilyl amide.
The invention discloses a method for synthesizing an indole-fused ring compound in a molecule by using nitrile as a nitrogen source for the first time, which overcomes the defect of complicated steps in the existing method for synthesizing the indole-fused ring compound. The method has the advantages of simple operation, mild conditions and high yield, and is a green and novel synthesis method.
Detailed Description
Example 1:
synthesis of 10H-benzofuro [3,2-b ] indole
0.5mmol of 2- [ (2-iodobenzyl) oxo ] benzonitrile, 0.05 equivalent of anhydrous copper sulfate and 2.2 equivalents of potassium tert-butoxide were added to a 100mL Schlenk reaction tube, vacuum dried for 15 minutes, 10mL of chlorobenzene was added under argon (or nitrogen) atmosphere, a polytetrafluoroethylene stopper was added to the reaction tube, and the mixture was put into an oil bath and reacted at 90 ℃ for 12 hours. After the reaction is finished, filtering, concentrating and removing the solvent, and carrying out column chromatography separation, wherein an eluent is petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:2:1), and the obtained white solid is 10H-benzofuro [3,2-b ] indole; the yield thereof was found to be 98%.
The white solid was analyzed by chemical shift and fragmentation by hydrogen nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) as 10H-benzofuro [3,2-b ] indole.
1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.83(d,J＝7.6Hz,1H),7.66-7.61(m,2H),7.45(d,J＝8.0Hz,1H),7.34-7.21(m,4H).13C NMR(100MHz,CDCl3)δ159.2,143.7,139.7,125.2,123.9,122.9,122.7,120.4,118.7,117.9,117.2,114.3,112.8,112.6.
Example 2:
synthesis of 10H-benzofuro [3,2-b ] indole
0.5mmol of 2- [ (2-bromophenylmethyl) oxo ] benzonitrile, 0.05 equivalent of anhydrous copper sulfate, and 2.2 equivalents of potassium tert-butoxide were added to a 100mL Schlenk reaction tube, vacuum-dried for 15 minutes, 10mL of chlorobenzene was added under an argon (or nitrogen) atmosphere, a polytetrafluoroethylene stopper was added to the reaction tube, and the mixture was put into an oil bath and reacted at 90 ℃ for 12 hours. After the reaction is finished, filtering, concentrating and removing the solvent, and carrying out column chromatography separation, wherein an eluent is petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:2:1), and the obtained white solid is 10H-benzofuro [3,2-b ] indole; the yield thereof was found to be 77%.
The white solid was analyzed by chemical shift and fragmentation by hydrogen nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) as 10H-benzofuro [3,2-b ] indole.
1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.83(d,J＝7.6Hz,1H),7.66-7.61(m,2H),7.45(d,J＝8.0Hz,1H),7.34-7.21(m,4H).13C NMR(100MHz,CDCl3)δ159.2,143.7,139.7,125.2,123.9,122.9,122.7,120.4,118.7,117.9,117.2,114.3,112.8,112.6.
Example 3:
synthesis of 3-bromo-10H-benzofuro [3,2-b ] indole
0.5mmol of 2- [ (5-bromo-2-iodobenzyl) oxo ] benzonitrile, 0.05 equivalent of anhydrous copper sulfate, and 2.2 equivalents of potassium tert-butoxide were added to a 100mL Schlenk reaction tube, dried under vacuum for 15 minutes, 10mL of chlorobenzene was added under an argon (or nitrogen) atmosphere, a polytetrafluoroethylene stopper was added to the reaction tube, and the resulting mixture was put into an oil bath and reacted at 90 ℃ for 15 hours. After the reaction is finished, filtering, concentrating to remove the solvent, and carrying out column chromatography separation, wherein an eluant is petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:2:1), and the obtained white solid is 3-bromo-10H-benzofuro [3,2-b ] indole; the yield thereof was found to be 83%.
The white solid was analyzed by chemical shift and fragmentation by hydrogen nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) as 3-bromo-10H-benzofuro [3,2-b ] indole.
1H NMR(400MHz,CDCl3)δ8.09(s,1H),7.95(t,J＝0.4Hz,1H),7.67(d,J＝4.8Hz,1H),7.62(d,J＝5.6Hz,1H),7.35-7.31(m,4H).13C NMR(100MHz,CDCl3)δ159.4,142.4,138.1,126.3,125.6,124.5,122.9,119.7,118.3,118.1,115.6,113.8,113.4,112.9.
Example 4:
synthesis of 3-chloro-10H-benzofuro [3,2-b ] indole
0.5mmol of 2- [ (5-chloro-2-iodobenzyl) oxo ] benzonitrile, 0.05 equivalent of anhydrous copper sulfate, and 2.2 equivalents of potassium tert-butoxide were added to a 100mL Schlenk reaction tube, dried under vacuum for 15 minutes, 10mL of chlorobenzene was added under an argon (or nitrogen) atmosphere, a polytetrafluoroethylene stopper was added to the reaction tube, and the reaction tube was put into an oil bath and reacted at 90 ℃ for 14 hours. After the reaction is finished, filtering, concentrating to remove the solvent, and carrying out column chromatography separation, wherein an eluant is petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:2:1), and the obtained white solid is 3-chloro-10H-benzofuro [3,2-b ] indole; the yield thereof was found to be 86%.
The white solid was analyzed by chemical shift and fragmentation by hydrogen nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) as 3-chloro-10H-benzofuro [3,2-b ] indole.
1H NMR(400MHz,DMSO-d6)δ11.76(s,1H),7.84-7.81(m,2H),7.72-7.70(m,1H),7.59(d,J＝8.8Hz,1H),7.38-7.36(m,2H),7.22(dd,J＝8.8,2.0Hz,1H).13C NMR(100MHz,DMSO-d6)δ159.3,141.5,138.1,127.5,125.0,124.5,123.5,122.6,119.2,118.7,116.1,114.9,113.9,113.1.
Example 5:
synthesis of 3-methyl-10H-benzofuro [3,2-b ] indole
0.5mmol of 2- [ (2-iodo-5-methylbenzyl) oxo ] benzonitrile, 0.05 equivalent of anhydrous copper sulfate, and 2.2 equivalents of potassium tert-butoxide were added to a 100mL Schlenk reaction tube, dried under vacuum for 15 minutes, 10mL of chlorobenzene was added under an argon (or nitrogen) atmosphere, a polytetrafluoroethylene stopper was added to the reaction tube, and the reaction tube was put into an oil bath and reacted at 90 ℃ for 12 hours. After the reaction is finished, filtering, concentrating to remove the solvent, and carrying out column chromatography separation, wherein an eluant is petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:2:1), and the obtained white solid is 3-methyl-10H-benzofuro [3,2-b ] indole; the yield thereof was found to be 72%.
The white solid was analyzed by chemical shift and fragmentation by hydrogen nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) as 3-methyl-10H-benzofuro [3,2-b ] indole.
1H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.62-7.61(m,3H),7.35(d,J＝8.4Hz,1H),7.31-7.28(m,2H),7.09(dd,J＝8.4,1.6Hz,1H).13C NMR(100MHz,DMSO-d6)δ159.2,143.5,138.2,129.8,125.3,124.5,123.7,122.6,118.8,117.8,116.9,114.5,112.7,112.2.
Example 6:
synthesis of 7-bromo-10H-benzofuro [3,2-b ] indole
0.5mmol of 4-bromo-2- [ (2-iodobenzyl) oxo ] benzonitrile, 0.20 equivalent of anhydrous copper sulfate, and 2.2 equivalents of potassium tert-butoxide were added to a 100mL Schlenk reaction tube, dried under vacuum for 15 minutes, 10mL of chlorobenzene was added under an argon (or nitrogen) atmosphere, a polytetrafluoroethylene stopper was added to the reaction tube, and the resulting mixture was put into an oil bath and reacted at 90 ℃ for 14 hours. After the reaction is finished, filtering, concentrating to remove the solvent, and carrying out column chromatography separation, wherein an eluant is petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:2:1), and the obtained white solid is 7-bromo-10H-benzofuro [3,2-b ] indole; the yield thereof was found to be 68%.
The white solid was analyzed by chemical shift and fragmentation by hydrogen nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) as 7-bromo-10H-benzofuro [3,2-b ] indole.
1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),7.99(d,J＝1.6Hz,1H),7.77(d,J＝8.0Hz,1H),7.74(d,J＝8.4Hz,1H),7.58(d,J＝8.0Hz,1H),7.52(dd,J＝8.4,1.6Hz,1H),7.26(t,J＝7.2Hz,1H),7.16(t,J＝7.6Hz,1H).13C NMR(100MHz,DMSO-d6)δ159.2,143.2,140.0,126.5,125.1,123.2,120.2,120.0,118.3,117.0,116.4,116.2,113.7,113.0.
Example 7:
synthesis of 12H-benzo [ g ] benzofuro [3,2-b ] indole
0.5mmol of 2- [ (1-iodonaphthalen-2-yl) methoxy ] benzonitrile, 0.05 equivalent of anhydrous copper sulfate and 2.2 equivalents of potassium tert-butoxide were added to a 100mL Schlenk reaction tube, vacuum dried for 15 minutes, 10mL of chlorobenzene was added under argon (or nitrogen) atmosphere, a polytetrafluoroethylene stopper was added to the reaction tube, and the reaction tube was put into an oil bath and reacted at 90 ℃ for 13 hours. After completion of the reaction, the solvent was removed by filtration and concentration, and column chromatography was performed with petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:2:1) as eluent to give 12H-benzo [ g ] benzofuro [3,2-b ] indole as a white solid; the yield thereof was found to be 68%.
The white solid was analyzed by chemical shift and fragmentation by hydrogen nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) as 12H-benzo [ g ] benzofuro [3,2-b ] indole.
1H NMR(400MHz,DMSO-d6)δ12.52(s,1H),8.48(d,J＝8.0Hz,1H),8.00(d,J＝8.0Hz,1H),7.89(d,J＝8.8Hz,1H),7.85(d,J＝7.6Hz,1H),7.74(d,J＝7.6Hz,1H),7.67-7.61(m,2H),7.50(t,J＝7.2Hz,1H),7.42-7.35(m,2H).13C NMR(100MHz,DMSO-d6)δ159.1,143.9,134.1,130.5,129.2,126.5,124.9,124.2,124.1,123.5,123.1,121.1,120.9,119.2,118.4,117.1,113.1,108.4.
Example 8:
synthesis of 10H-benzo [4,5] thieno [3,2-b ] indole
0.5mmol of 2- [ (2-iodobenzyl) sulfanyl ] benzonitrile, 0.05 equivalent of anhydrous copper sulfate and 2.2 equivalents of potassium tert-butoxide are added to a 100mL Schlenk reaction tube, dried under vacuum for 15 minutes, 10mL of chlorobenzene is added under argon (or nitrogen) atmosphere, a polytetrafluoroethylene plug is added to the reaction tube, and the mixture is put into an oil bath and reacted at 90 ℃ for 12 hours. After the reaction is finished, filtering and concentrating to remove the solvent, and carrying out column chromatography separation, wherein an eluant is petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:2:1), and the obtained white solid is 10H-benzo [4,5] thieno [3,2-b ] indole; the yield thereof was found to be 98%.
The white solid was analyzed by chemical shift and fragmentation by hydrogen nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) as 10H-benzo [4,5] thieno [3,2-b ] indole.
1H NMR(400MHz,DMSO-d6)δ12.13(s,1H),8.07(d,J＝7.2Hz,1H),8.02(d,J＝8.4Hz,1H),7.78(d,J＝7.6Hz,1H),7.59(d,J＝8.0Hz,1H),7.49(t,J＝7.2Hz,1H),7.39(t,J＝6.8Hz,1H),7.28(t,J＝7.2Hz,1H),7.15(t,J＝7.2Hz,1H).13C NMR(100MHz,DMSO-d6)δ142.4,141.1,138.0,127.1,125.0,124.9,124.8,123.3,122.0,120.6,119.8,119.3,114.3,113.1.
Example 9:
synthesis of 3-chloro-10H-benzo [4,5] thieno [3,2-b ] indole
0.5mmol of 2- [ (5-chloro-2-iodobenzyl) sulfanyl ] benzonitrile, 0.05 equivalent of anhydrous copper sulfate, and 2.2 equivalents of potassium tert-butoxide were added to a 100mL Schlenk reaction tube, vacuum-dried for 15 minutes, 10mL of chlorobenzene was added under an argon (or nitrogen) atmosphere, a Teflon plug was added to the reaction tube, and the resulting mixture was put into an oil bath and reacted at 90 ℃ for 12 hours. After the reaction is finished, filtering and concentrating to remove the solvent, and carrying out column chromatography separation, wherein an eluant is petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:2:1), and the obtained white solid is 3-chloro-10H-benzo [4,5] thieno [3,2-b ] indole; the yield thereof was found to be 98%.
The white solid was analyzed by chemical shift and fragmentation by hydrogen nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) as 3-chloro-10H-benzo [4,5] thieno [3,2-b ] indole.
1H NMR(400MHz,DMSO-d6)δ12.35(s,1H),8.08(d,J＝7.6Hz,1H),8.04(d,J＝8.0Hz,1H),7.92(s,1H),7.61(d,J＝8.8Hz,1H),7.51(t,J＝7.2Hz,1H),7.42(t,J＝7.6Hz,1H),7.28(dd,J＝8.8,2.0Hz,1H).13C NMR(100MHz,DMSO-d6)δ142.9,139.5,139.4,126.8,125.3,125.1,125.0,124.3,123.1,123.0,120.9,118.7,114.5,113.8.
Example 10:
synthesis of 3-bromo-10H-benzo [4,5] thieno [3,2-b ] indole
0.5mmol of 2- [ (5-bromo-2-iodobenzyl) sulfanyl ] benzonitrile, 0.05 equivalent of anhydrous copper sulfate, and 2.2 equivalents of potassium tert-butoxide were added to a 100mL Schlenk reaction tube, vacuum-dried for 15 minutes, 10mL of chlorobenzene was added under argon (or nitrogen) atmosphere, a Teflon plug was added to the reaction tube, and the resulting mixture was put into an oil bath and reacted at 90 ℃ for 12 hours. After the reaction is finished, filtering, concentrating to remove the solvent, and carrying out column chromatography separation, wherein an eluant is petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:2:1), and the obtained white solid is 3-bromo-10H-benzo [4,5] thieno [3,2-b ] indole; the yield thereof was found to be 98%.
The white solid was analyzed by chemical shift and fragmentation by hydrogen nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) as 3-bromo-10H-benzo [4,5] thieno [3,2-b ] indole.
1H NMR(400MHz,DMSO-d6)δ12.37(s,1H),8.10-8.03(m,3H),7.58(d,J＝8.8Hz,1H),7.51(t,J＝7.2Hz,1H),7.43-7.38(m,2H).13C NMR(100MHz,DMSO-d6)δ142.9,139.7,139.2,126.8,125.7,125.3,125.1,124.9,123.7,121.7,120.9,115.0,113.7,112.1.
Example 11:
synthesis of 5-methyl-5, 10-indolino [3,2-b ] indole
0.5mmol of 2- [ (2-iodobenzyl) (methyl) amino ] benzonitrile, 0.05 equivalent of anhydrous copper sulfate and 2.2 equivalents of potassium tert-butoxide were added to a 100mL Schlenk reaction tube, dried under vacuum for 15 minutes, 10mL of chlorobenzene was added under an argon (or nitrogen) atmosphere, a polytetrafluoroethylene stopper was added to the reaction tube, and the mixture was put into an oil bath and reacted at 90 ℃ for 12 hours. After the reaction is finished, filtering, concentrating to remove the solvent, and carrying out column chromatography separation, wherein an eluant is petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:2:1), and the obtained white solid is 5-methyl-5, 10-indolino [3,2-b ] indole; the yield thereof was found to be 98%.
The white solid was analyzed by chemical shift and fragmentation by hydrogen nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) as 5-methyl-5, 10-indolino [3,2-b ] indole.
1H NMR(400MHz,DMSO-d6)δ11.20(s,1H),7.96(d,J＝7.6Hz,1H),7.76(d,J＝7.6Hz,1H),7.55(d,J＝8.0Hz,1H),7.50(d,J＝8.0Hz,1H),7.26-7.18(m,2H),7.12(d,J＝7.6Hz,1H),7.08(d,J＝7.2Hz,1H),4.10(s,3H).13C NMR(100MHz,DMSO-d6)δ141.3,140.7,127.3,124.6,122.0,121.9,118.5,118.4,118.1,117.8,115.0,114.7,112.7,110.4,31.9.
The above examples summarize that: the method for directly constructing the indole-fused ring compound comprises the steps of taking a 2- [ (2-iodobenzyl) oxo ] benzonitrile derivative as a substrate, enabling the molar ratio of a catalyst copper salt to the 2- [ (2-iodobenzyl) oxo ] benzonitrile derivative to be 0.02-0.2: 1, enabling the molar ratio of alkali to the 2- [ (2-iodobenzyl) oxo ] benzonitrile derivative to be 2-4: 1, reacting in a solvent at 90 ℃ for 8-20h, mixing petroleum ether/dichloromethane/ethyl acetate according to the volume ratio of 20-5: 10:1 to serve as an eluent, and separating through a silica gel column to obtain a target product. The invention relates to a method for synthesizing an indole-fused ring compound by directly constructing the indole-fused ring compound by catalyzing the activation of a C-H bond of an aryl side chain, and using nitrile as a nitrogen source for the first time.
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| 2-Aryl and 2-Heteroaryl Indoles from 1-Alkynes and o-Iodotrifluoroacetanilide through a Domino Copper-Catalyzed Coupling-Cyclization Process;Sandro Cacchi et al.;《Org. Lett.》;20030926;第3843-3846页 * |
| CuSO4-Catalyzed dual annulation to synthesize O,S or N-containing tetracyclic heteroacenes;Xiang-Huan Shan et al.;《Chem. Commun.》;20200304;第4063-4066页 * |
| Dicyanovinyl Heterotetracenes: Synthesis, Solid-State Structures, and Photophysical Properties;Chunyan Du et al.;《J. Org. Chem.》;20090827;第7322-7327页 * |
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