CN112745350B - Synthesis method of 4-alkyl phosphonate substituted indole compound - Google Patents
Synthesis method of 4-alkyl phosphonate substituted indole compound Download PDFInfo
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- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 53
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims abstract description 44
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims abstract description 44
- -1 indole compound Chemical class 0.000 title claims abstract description 35
- 238000001308 synthesis method Methods 0.000 title claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- 238000000034 method Methods 0.000 claims abstract description 26
- 150000002475 indoles Chemical group 0.000 claims abstract description 21
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 18
- 125000001041 indolyl group Chemical group 0.000 claims abstract description 15
- 239000003446 ligand Substances 0.000 claims abstract description 11
- 239000007800 oxidant agent Substances 0.000 claims abstract description 10
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 9
- 230000001590 oxidative effect Effects 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract 2
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract 2
- 150000003904 phospholipids Chemical group 0.000 claims abstract 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 19
- 230000008569 process Effects 0.000 claims description 16
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 14
- FJOLTQXXWSRAIX-UHFFFAOYSA-K silver phosphate Chemical compound [Ag+].[Ag+].[Ag+].[O-]P([O-])([O-])=O FJOLTQXXWSRAIX-UHFFFAOYSA-K 0.000 claims description 13
- 229910000161 silver phosphate Inorganic materials 0.000 claims description 13
- 229940019931 silver phosphate Drugs 0.000 claims description 13
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- PAGZTSLSNQZYEV-UHFFFAOYSA-L 2,2-dimethylpropanoate;palladium(2+) Chemical compound [Pd+2].CC(C)(C)C([O-])=O.CC(C)(C)C([O-])=O PAGZTSLSNQZYEV-UHFFFAOYSA-L 0.000 claims description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims description 4
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- XEFCWBLINXJUIV-UHFFFAOYSA-N acetic acid;iodobenzene Chemical compound CC(O)=O.CC(O)=O.IC1=CC=CC=C1 XEFCWBLINXJUIV-UHFFFAOYSA-N 0.000 claims description 2
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims description 2
- 229960002163 hydrogen peroxide Drugs 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 2
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 2
- 229940096017 silver fluoride Drugs 0.000 claims description 2
- REYHXKZHIMGNSE-UHFFFAOYSA-M silver monofluoride Chemical compound [F-].[Ag+] REYHXKZHIMGNSE-UHFFFAOYSA-M 0.000 claims description 2
- 229910001923 silver oxide Inorganic materials 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 229910052723 transition metal Inorganic materials 0.000 abstract description 8
- 150000003624 transition metals Chemical class 0.000 abstract description 8
- 230000004913 activation Effects 0.000 abstract description 4
- 150000002894 organic compounds Chemical class 0.000 abstract description 2
- 125000005600 alkyl phosphonate group Chemical group 0.000 abstract 1
- 125000004429 atom Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 22
- 239000002904 solvent Substances 0.000 description 16
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 239000011261 inert gas Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 239000003208 petroleum Substances 0.000 description 11
- 238000001035 drying Methods 0.000 description 10
- 239000012295 chemical reaction liquid Substances 0.000 description 9
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 description 8
- 230000002194 synthesizing effect Effects 0.000 description 8
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 230000000996 additive effect Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- CZHYKKAKFWLGJO-UHFFFAOYSA-N dimethyl phosphite Chemical compound COP([O-])OC CZHYKKAKFWLGJO-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- SEOVTRFCIGRIMH-UHFFFAOYSA-N indole-3-acetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CNC2=C1 SEOVTRFCIGRIMH-UHFFFAOYSA-N 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- 229940124602 FDA-approved drug Drugs 0.000 description 1
- 238000006641 Fischer synthesis reaction Methods 0.000 description 1
- 102000018997 Growth Hormone Human genes 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 239000002841 Lewis acid Chemical group 0.000 description 1
- 239000002879 Lewis base Substances 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- DMULVCHRPCFFGV-UHFFFAOYSA-N N,N-dimethyltryptamine Chemical compound C1=CC=C2C(CCN(C)C)=CNC2=C1 DMULVCHRPCFFGV-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- VAZSKTXWXKYQJF-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)OOS([O-])=O VAZSKTXWXKYQJF-UHFFFAOYSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical group BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 239000000380 hallucinogen Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003617 indole-3-acetic acid Substances 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 150000002497 iodine compounds Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical group 0.000 description 1
- 150000007527 lewis bases Chemical class 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 229960005343 ondansetron Drugs 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 150000004714 phosphonium salts Chemical group 0.000 description 1
- 230000008635 plant growth Effects 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
- 229960003708 sumatriptan Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
- C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Indole Compounds (AREA)
Abstract
The invention belongs to the technical field of organic compound synthesis, and provides a synthesis method for preparing a 4-position alkyl phosphonate substituted indole compound. The method adopts an indole compound with a di-tert-butyl phosphono guiding group on a nitrogen atom as a raw material, and constructs a series of indole compounds substituted by indole 4-position carbon-hydrogen bond phospholipid groups in the presence of a palladium catalyst, a ligand, an oxidant and an organic solvent. The method adopts the transition metal to catalyze the remote activation of the C-H bond of the indole, greatly shortens the reaction steps for preparing the 4-substituted indole compound, and has the advantages of high atom utilization rate, cheap and easily obtained raw materials, simple and safe operation.
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis, and relates to a synthesis method of a 4-alkyl phosphonate substituted indole compound.
Background
The indole skeleton is widely present in nature and has unique biological activity. The essential amino acids tryptophan, serotonin 5-hydroxytryptamine and the plant growth hormone indole-3-acetic acid in human body all have indole skeleton. Also, indole backbones are widely present in marketed drugs such as sumatriptan (for migraine treatment), indomethacin (for anti-inflammatory) and ondansetron (for nausea treatment). The bioactive hallucinogen dimethyltryptamine is also an indole backbone compound. Since 2014 FDA approved drug molecules, 24 of the marketed drugs were found to all contain indole backbones, which makes the indole ring the 4 th most common heterocycle of the marketed drugs, indicating the unique biological activity of the indole backbone in the drug molecule.
Because of the important biological activity of indole ring, the synthesis of polysubstituted indole has been a hot research focus in organic chemistry. Currently, there are 3 main methods for synthesizing indole: 1. synthesis of the indole skeleton by cyclization, e.g., fischer synthesis; 2. pretreating indole to obtain a halogenated indole compound, and then carrying out coupling reaction to obtain a polysubstituted indole compound; 3. transition metals catalyze the functionalization of indole C-H bonds. Obviously, the utilization rate of atoms directly activating the C-H bond is high, and the steps are simple. However, no transition metal-catalyzed indole C-H bond activation has been reported for C-P bond formation. Therefore, the development of a novel method for synthesizing the 4-alkyl phosphonate substituted indole compound is of great significance.
Disclosure of Invention
The invention adopts transition metal to catalyze the selective activation of indole C-H bond, and the formation of C-P bond is constructed for the first time, thereby providing a novel method for synthesizing 4-alkyl phosphonate substituted indole compound
In order to achieve the purpose, the method utilizes a di-tert-butyl phosphono guiding group to enable transition metal palladium to be inserted into the 7-position of indole so as to activate the para-position of the indole, so that a dialkyl phosphate radical selectively attacks the 4-position of the indole, and the 4-alkyl phosphonate substituted indole compound is synthesized.
As a preferred mode of the present invention, the reaction equation for synthesizing the 4-alkyl phosphonate substituted indole compound is as follows:
in the formulae (2) and (3), R 1 ，R 2 Is an optional substituent;
the synthesis process of the compound shown in the formula (1) comprises the following steps: dissolving a compound shown in a formula (2) in a solvent in the presence of a catalyst, a ligand and an oxidant, and reacting with a compound shown in a formula (3) to generate a compound shown in a formula (1);
the solvent is an organic solvent without hydroxyl, and does not contain tetrahydrofuran;
in the reaction system, the molar ratio of the compound shown in the formula (2), the compound shown in the formula (3) and the oxidant is 1 (2-10) to (2-10);
the reaction temperature is 80-100 ℃, and the reaction time is 8-24h.
Further preferably, in the formulae (2) and (3), R 1 ，R 2 Selected from aryl, alkyl, alkenyl, alkynyl, cyano, halogen, alkoxy, phenoxy, H, NO 2 Any of the groups.
Further preferably, the palladium catalyst is selected from any one of palladium tetrakistriphenylphosphine, palladium chloride, palladium acetate and palladium pivalate.
Further preferably, the ligand is selected from any one of monodentate phosphine ligand, bidentate phosphine ligand, pyridine ligand and bipyridine ligand.
Further preferably, the reaction system contains an additive, and the reaction equation is as follows:
the additive is any one of alkali, lewis base, quaternary ammonium salt, quaternary phosphonium salt and Lewis acid reagent;
the molar ratio of the compound shown in the formula (2) to the additive is 1: 2-5.
Further preferably, the solvent is any one of 1,2-dichloroethane, dichloromethane, acetonitrile, 1,4-dioxane, benzene, toluene, xylene.
Further preferably, the oxidizing agent is selected from any one of silver salt, copper salt, peroxide, persulfate and high iodine compound.
Further preferably, the oxidizing agent is selected from any one of silver carbonate, silver oxide, silver phosphate, silver fluoride, hydrogen peroxide, tert-butyl hydroperoxide, iodobenzene diacetic acid, ammonium persulfate, and potassium persulfate.
The invention synthesizes the 4-alkyl phosphonate substituted indole compound for the first time, and has the following advantages:
(1) The invention remotely activates the indole 4-position C-H bond by using transition metal, and the C-P bond is constructed at the 4-position for the first time, thereby providing a method for synthesizing the 4-alkyl phosphonate substituted indole compound;
(2) The raw materials adopted by the invention have wide sources and low price, the reaction reagents are common and are commercially available, the operation is simple, and the industrial production is facilitated;
(3) The synthetic method has wide applicability of the substrate, can be compatible with various functional groups, and can quickly prepare the 4-alkyl phosphonate substituted indole compounds with various structures.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
Examples 1-6 are provided to illustrate the substrate applicability of the process of the present invention, and examples 7-12 are provided to illustrate that the process of the present invention can still obtain the corresponding alkyl 4-phosphonate substituted indole compound under the conditions of changing the oxidant, additive, solvent, reaction temperature, gas protection, etc.
Example 1: in this example, N-di-tert-butylphosphonoindole was reacted with diethyl phosphite to synthesize 4-phosphonic acid diethyl ester substituted indole (1 aa):
the reaction equation is:
the synthesis steps and the process are as follows: to a 10mL reaction tube equipped with a magnetic stirrer were added 2a (0.1mmol, 27.7mg), diethyl phosphite (0.3mmol, 41.4mg), palladium acetate (10 mol%,2.3 mg), 2-chloropyridine (20 mol%,2.3 mg), silver phosphate (0.15mmol, 62.8mg), potassium persulfate (0.2mmol, 54.1mg), and then 2.0mL of acetonitrile; fixing the reaction tube on a magnetic stirrer under the protection of inert gas, reacting for 24 hours at 60 ℃, adding a proper amount of water into the reaction liquid, extracting with ethyl acetate, drying with anhydrous sodium sulfate, finally removing the solvent by using a rotary evaporator, and separating and purifying the crude product by column chromatography (petroleum ether: ethyl acetate = 20.
The nuclear magnetic data for compound (1 aa) is:
1 H NMR(600MHz,CDCl 3 )δ8.73(d,J＝8.5Hz,1H),7.66(dd,J H-P ＝14.5Hz,J＝7.2Hz,1H),7.33(dd,J＝3.5Hz,J H-P ＝1.4Hz,1H),7.26(m,1H),7.10(dd,J＝3.5Hz,J H-P ＝2.4Hz,1H),4.19–4.01(m,4H),1.31(d,J H-P ＝14.9Hz,18H),1.28(t,J＝7.0Hz,6H).
13 C NMR(151MHz,CDCl 3 )δ141.53(d,J C-P ＝16.8Hz),130.23(dd,J C-P ＝12.2,5.0Hz),127.80(d,J C-P ＝4.6Hz),127.09(d,J C-P ＝9.0Hz),122.67(d,J C-P ＝15.8Hz),120.69(d,J C-P ＝3.3Hz),118.33(d,J C-P ＝189.1Hz),107.43(dd,J C-P ＝4.6,2.6Hz),61.90(d,J C-P ＝5.2Hz),38.58(d,J C-P ＝68.6Hz),26.56,16.28(d,J C-P ＝6.5Hz).
31 P NMR(243MHz,CDCl 3 )δ63.96,19.16。
example 2: in this example, N-di-tert-butylphosphonoindole was reacted with dimethyl phosphite to synthesize 4-dimethyl phosphonate-substituted indole (1 ab):
the reaction equation is:
the synthesis steps and the process are as follows: to a 10mL reaction tube equipped with a magnetic stirrer were added 2a (0.1mmol, 27.7mg), dimethyl phosphite (0.3mmol, 33.0mg), palladium acetate (10 mol%,2.3 mg), 2-chloropyridine (20 mol%,2.3 mg), silver phosphate (0.15mmol, 62.8mg), potassium persulfate (0.2mmol, 54.1mg), and then 2.0mL of acetonitrile; the reaction tube was fixed to a magnetic stirrer under inert gas protection and reacted at 80 ℃ for 16 hours, an appropriate amount of water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and finally the solvent was removed using a rotary evaporator, and the crude product was isolated and purified by column chromatography (petroleum ether: ethyl acetate =50: 1) to give the objective product (1 ab) with a yield of 71%.
The nuclear magnetic data for compound (1 ab) is:
1 H NMR(600MHz,CDCl 3 )δ8.78(dd,J＝8.5Hz,J H-P ＝0.7Hz,1H),7.68(dd,J H-P ＝14.5Hz,J＝7.2Hz,1H),7.35(dd,J＝3.4Hz,J H-P ＝1.3Hz,1H),7.29(td,J＝7.9Hz,J H-P ＝4.2Hz,1H),7.09(dd,J＝3.5Hz,J H-P ＝1.7Hz,1H),3.78(d,J H-P ＝11.2Hz,6H),1.33(d,J H-P ＝14.9Hz,18H).
13 C NMR(151MHz,CDCl 3 )δ141.62(d,J C-P ＝16.9Hz),130.23,128.05(d,J C-P ＝4.6Hz),127.38(d,J C-P ＝9.1Hz),122.79(d,J C-P ＝15.9Hz),121.02(d,J C-P ＝3.3Hz),116.95(d,J C-P ＝190.1Hz),107.32,52.60(d,J C-P ＝5.2Hz),38.64(d,J C-P ＝68.5Hz),26.61.
31 P NMR(243MHz,CDCl 3 )δ64.12,22.17。
example 3: in this example, 4-phosphonic acid diethyl ester-5-carboxylic acid ethyl ester indole (1 bb) was synthesized by reacting N-di-tert-butylphosphonyl-5-carboxylic acid ethyl ester indole with diethyl phosphite:
the reaction equation is:
The nuclear magnetic data for compound (1 bb) is:
1 H NMR(600MHz,CDCl 3 )δ8.79(dd,J＝8.7Hz,J H-P ＝1.1Hz,1H),7.41–7.39(m,2H),7.37–7.34(m,1H),4.39(q,J＝7.2Hz,2H),4.25–4.05(m,4H),1.39(t,J＝7.2Hz,3H),1.33(d,J H-P ＝15.0Hz,18H),1.32(t,J＝7.8Hz,6H).
13 C NMR(151MHz,CDCl 3 )δ169.97(d,J C-P ＝5.7Hz),142.27(d,J C-P ＝16.1Hz),132.66(d,J C-P ＝7.9Hz),131.41,128.87(d,J C-P ＝4.3Hz),123.09(d,J C-P ＝13.2Hz),120.13(d,J C-P ＝2.6Hz),116.80(d,J C-P ＝187.0Hz),108.80,62.26(d,J C-P ＝4.9Hz),61.73,38.69(d,J C-P ＝68.0Hz),26.57,16.28(d,J C-P ＝6.7Hz),14.04.
31 P NMR(243MHz,CDCl 3 )δ64.60,16.52。
example 4: in this example, 4-phosphonic acid diethyl ester tryptophan (1 cb) was synthesized using the reaction of tryptophan with diethyl phosphite:
the reaction equation is:
The nuclear magnetic data for compound (1 cb) is:
1 H NMR(600MHz,CDCl 3 )δ8.83(d,J＝8.5Hz,1H),7.78–7.65(m,1H),7.33(s,1H),7.26–7.22(m,1H),5.90(d,J＝8.6Hz,1H),4.61–4.57(m,1H),4.17(m,4H),3.74(d,J H-P ＝2.1Hz,3H),3.70–3.47(m,2H),1.34(s,9H),1.32–1.27(m,24H).
13 C NMR(151MHz,CDCl 3 )δ173.17,155.70,142.74(d,J C-P ＝17.4Hz),129.48–128.50(m),128.13(d,J C-P ＝8.1Hz),126.90,122.26(d,J C-P ＝15.4Hz),121.18(d,J C-P ＝3.0Hz),118.50,116.34,79.32,62.45(dd,J C-P ＝52.8Hz,J C-P ＝5.9Hz),60.34,54.84,52.27,38.62(dd,J C-P ＝68.4Hz,J C-P ＝12.9Hz),28.17,28.08,26.62(d,J C-P ＝11.4Hz).
31 P NMR(243MHz,CDCl 3 )δ64.38,19.92。
example 5: in this example, N-di-tert-butylphosphonyl-6-methoxyindole was reacted with diethyl phosphite to synthesize 4-phosphonic acid diethyl ester-6-methoxyindole (1 db), and the reaction equation is:
the synthesis steps and the process are as follows: to a 10mL reaction tube equipped with a magnetic stirrer, 2d (0.1mmol, 30.7mg), diethyl phosphite (0.3mmol, 41.4mg), palladium acetate (10 mol%,2.3 mg), 2,6-lutidine (20 mol%,2.1 mg), silver phosphate (0.15mmol, 62.8mg), potassium persulfate (0.2mmol, 54.1mg), and 1.0mL of acetonitrile were added; fixing the reaction tube on a magnetic stirrer under the protection of inert gas, reacting for 16 hours at 80 ℃, adding a proper amount of water into the reaction liquid, extracting with ethyl acetate, drying with anhydrous sodium sulfate, finally removing the solvent by using a rotary evaporator, and separating and purifying the crude product by column chromatography (petroleum ether: ethyl acetate = 20.
The nuclear magnetic data for compound (1 db) is:
1 H NMR(600MHz,CDCl 3 )δ8.37(s,1H),7.33(d,J H-P ＝16.0Hz,1H),7.23–7.19(m,1H),7.03–7.01(m,1H),4.21–4.03(m,4H),3.86(s,3H),1.34(d,J H-P ＝14.9Hz,18H),1.30(t,J＝7.0Hz,6H).
13 C NMR(151MHz,CDCl 3 )δ156.15(d,J C-P ＝19.9Hz),142.86(d,J C-P ＝19.6Hz),126.48(d,J C-P ＝4.5Hz),124.19,118.82(d,J C-P ＝189.4Hz),116.95(d,J C-P ＝10.0Hz),107.30,103.82(d,J C-P ＝2.9Hz),62.07(d,J C-P ＝5.1Hz),55.76,38.68(d,J C-P ＝68.7Hz),26.62,16.31(d,J C-P ＝6.5Hz).
31 P NMR(243MHz,CDCl 3 )δ64.20,18.47。
example 6: in this example, N-di-tert-butylphosphonyl-6-trifluoromethylindole was reacted with diethyl phosphite to synthesize 4-phosphonic acid diethyl ester-6-trifluoromethylindole (1 eb), and the reaction equation was:
Nuclear magnetic data for compound (1 eb) were:
1 H NMR(600MHz,CDCl 3 )δ9.11(s,1H),7.92(d,J H-P ＝15.0Hz,1H),7.56–7.45(m,1H),7.23–7.14(m,1H),4.25–4.06(m,4H),1.34(d,J H-P ＝15.0Hz,18H),1.33(t,J＝7.8Hz,6H).
13 C NMR(151MHz,CDCl 3 )δ140.87(d,J C-P ＝16.5Hz),133.28–131.62(m),130.41(d,J C-P ＝4.0Hz),125.52–124.98(m),123.80–123.70(m),123.64–123.42(m),119.88(d,J C-P ＝191.5Hz),118.06,107.62,62.37(d,J C-P ＝5.4Hz),38.73(d,J C-P ＝67.6Hz),26.55,16.36(d,J C-P ＝6.4Hz).
31 P NMR(243MHz,CDCl 3 )δ65.56,16.96.
19 F NMR(565MHz,CDCl 3 )δ-60.77。
example 7: in this example, N-di-tert-butylphosphonoindole was reacted with diethyl phosphite to synthesize 4-phosphonic acid diethyl ester substituted indole (1 aa), and the reaction equation is:
the synthesis steps and processes are as follows: to a 10mL reaction tube equipped with a magnetic stirrer were added 2a (0.1mmol, 27.7mg), diethyl phosphite (0.5mmol, 69.0mg), palladium acetate (10 mol%,2.3 mg), 2-chloropyridine (20 mol%,2.3 mg), silver phosphate (0.15mmol, 62.8mg), potassium persulfate (0.2mmol, 54.1mg), and then 2.0mL of acetonitrile; fixing the reaction tube on a magnetic stirrer under the protection of inert gas, reacting for 24 hours at 60 ℃, adding a proper amount of water into the reaction liquid, extracting with ethyl acetate, drying with anhydrous sodium sulfate, finally removing the solvent by using a rotary evaporator, and separating and purifying the crude product by column chromatography (petroleum ether: ethyl acetate =20: 1) to obtain the target product (1 aa) with the yield of 72%.
Example 8: synthesizing 4-diethyl phosphonate substituted indole (1 aa) by reacting N-di-tert-butylphosphonoindole with diethyl phosphite, wherein the reaction equation is as follows:
the synthesis steps and the process are as follows: to a 10mL reaction tube equipped with a magnetic stirrer, 2a (0.1mmol, 27.7mg), diethyl phosphite (0.3mmol, 41.4mg), palladium pivalate (10 mol%,2.3 mg), 2-chloropyridine (20 mol%,2.3 mg), potassium persulfate (0.2mmol, 54.1mg) and then 2.0mL of acetonitrile were added; fixing the reaction tube on a magnetic stirrer under the protection of inert gas, reacting for 24 hours at 60 ℃, adding a proper amount of water into the reaction liquid, extracting with ethyl acetate, drying with anhydrous sodium sulfate, finally removing the solvent by using a rotary evaporator, and separating and purifying the crude product by column chromatography (petroleum ether: ethyl acetate = 20.
Example 9: in this example, N-di-tert-butylphosphonoindole was reacted with diethyl phosphite to synthesize 4-phosphonic acid diethyl ester substituted indole (1 aa), and the reaction equation is:
the synthesis steps and the process are as follows: to a 10mL reaction tube equipped with a magnetic stirrer were added 2a (0.1mmol, 27.7mg), diethyl phosphite (0.3mmol, 41.4mg), palladium acetate (10 mol%,2.3 mg), 2-chloropyridine (20 mol%,2.3 mg), silver phosphate (0.15mmol, 62.8mg), potassium persulfate (0.2mmol, 54.1mg), and then 2.0mL dioxane; fixing the reaction tube on a magnetic stirrer under the protection of inert gas, reacting for 24 hours at 60 ℃, adding a proper amount of water into the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, and finally removing the solvent by using a rotary evaporator, wherein the yield of crude nuclear magnetism (the internal standard is dibromomethane) is 10%.
Example 10: in this example, N-di-tert-butylphosphonoindole was reacted with diethyl phosphite to synthesize 4-phosphonic acid diethyl ester substituted indole (1 aa), and the reaction equation is:
the synthesis steps and the process are as follows: to a 10mL reaction tube equipped with a magnetic stirrer, 2a (0.1mmol, 27.7mg), diethyl phosphite (0.3mmol, 41.4mg), palladium acetate (10 mol%,2.3 mg), 2-chloropyridine (20 mol%,2.3 mg), silver phosphate (0.15mmol, 62.8mg), potassium persulfate (0.2mmol, 54.1mg), and further 2.0mL of acetonitrile were added; fixing the reaction tube on a magnetic stirrer under the protection of inert gas, reacting for 24 hours at 100 ℃, adding a proper amount of water into the reaction liquid, extracting with ethyl acetate, drying with anhydrous sodium sulfate, finally removing the solvent by using a rotary evaporator, and separating and purifying the crude product by column chromatography (petroleum ether: ethyl acetate =20: 1) to obtain the target product (1 aa) with the yield of 75%.
Example 11: in this example, N-di-tert-butylphosphonoindole was reacted with diethyl phosphite to synthesize 4-phosphonic acid diethyl ester substituted indole (1 aa), and the reaction equation is:
the synthesis steps and the process are as follows: to a 10mL reaction tube equipped with a magnetic stirrer, 2a (0.1mmol, 27.7mg), diethyl phosphite (0.3mmol, 41.4mg), palladium pivalate (10 mol%,2.1 mg), 2-chloropyridine (20 mol%,2.3 mg), silver phosphate (0.15mmol, 62.8mg), potassium persulfate (0.2mmol, 54.1mg), and further 2.0mL of acetonitrile were added; fixing the reaction tube on a magnetic stirrer under the protection of inert gas, reacting for 24 hours at 100 ℃, adding a proper amount of water into the reaction liquid, extracting with ethyl acetate, drying with anhydrous sodium sulfate, finally removing the solvent by using a rotary evaporator, and separating and purifying the crude product by column chromatography (petroleum ether: ethyl acetate = 20.
Example 12: in this example, N-di-tert-butylphosphonoindole was reacted with diethyl phosphite to synthesize 4-phosphonic acid diethyl ester substituted indole (1 aa), and the reaction equation is:
the synthesis steps and the process are as follows: to a 10mL reaction tube equipped with a magnetic stirrer, 2a (0.1mmol, 27.7mg), diethyl phosphite (0.3mmol, 41.4mg), palladium pivalate (10 mol%,2.1 mg), 2-chloropyridine (20 mol%,2.3 mg), silver phosphate (0.15mmol, 62.8mg), potassium persulfate (0.2mmol, 54.1mg), and further 2.0mL of acetonitrile were added; fixing the reaction tube on a magnetic stirrer under the protection of inert gas, reacting for 6 hours at 100 ℃, adding a proper amount of water into the reaction liquid, extracting with ethyl acetate, drying with anhydrous sodium sulfate, finally removing the solvent by using a rotary evaporator, and separating and purifying the crude product by column chromatography (petroleum ether: ethyl acetate =20: 1) to obtain the target product (1 aa) with the yield of 48%.
The invention adopts the transition metal to catalyze the selective activation of indole C-H bond, and the formation of C-P bond is constructed for the first time, thus providing a novel method for synthesizing 4-alkyl phosphonate substituted indole compound. The method utilizes a di-tert-butyl phosphono guiding group to enable transition metal palladium to be inserted into the 7-position of indole so as to activate the para-position of the indole, and enables dialkyl phosphate free radicals to selectively attack the 4-position of the indole, so that the 4-alkyl phosphonate substituted indole compound is synthesized. The invention synthesizes the 4-alkyl phosphonate substituted indole compound for the first time, and has the following advantages:
(1) The invention remotely activates the indole 4-position C-H bond by using transition metal, and the C-P bond is constructed at the 4-position for the first time, thereby providing a method for synthesizing the 4-alkyl phosphonate substituted indole compound;
(2) The raw materials adopted by the invention have wide sources and low price, the reaction reagents are common and are commercially available, the operation is simple, and the industrial production is facilitated;
(3) The synthetic method has wide applicability of substrates, can be compatible with various functional groups, and can quickly prepare the 4-alkyl phosphonate substituted indole compounds with various structures.
Claims (1)
1. A synthesis method of palladium-catalyzed 4-alkyl phosphonate substituted indole is characterized in that an indole compound with a di-tert-butyl phosphono guiding group on a nitrogen atom is used as a raw material, and a series of indole compounds substituted by indole 4-carbon hydrogen bond phospholipid groups are constructed in the presence of a palladium catalyst, a ligand, an oxidant and an organic solvent, wherein the reaction formula is as follows:
in the formula (2), R 1 Is alkyl and aryl substituted at any position of an indole ring;
in the formula (3), R 2 Is alkyl or aryl;
the synthesis process of the compound shown in the formula (1) comprises the following steps: dissolving a compound shown in a formula (2) in an organic solvent in the presence of a palladium catalyst, a ligand and an oxidant, and reacting with a compound shown in a formula (3) to generate a compound shown in a formula (1);
the palladium catalyst is any one of palladium tetratriphenylphosphine, palladium chloride, palladium acetate and palladium pivalate;
the ligand is selected from any one of pyridine ligands;
the oxidant is selected from any one of silver carbonate, silver oxide, silver phosphate, silver fluoride, hydrogen peroxide, tert-butyl hydroperoxide, iodobenzene diacetic acid, ammonium persulfate and potassium persulfate, and the molar ratio of the compound shown in the formula (2), the compound shown in the formula (3) and the oxidant is 1 (2-10) to (2-10);
the organic solvent is any one of 1,2-dichloroethane, dichloromethane, acetonitrile, 1,4-dioxane, benzene, toluene and xylene;
the reaction temperature is 80-100 ℃, and the reaction time is 8-24h.
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| CN111187298A (en) * | 2020-02-27 | 2020-05-22 | 成都大学 | C2-phosphono methylene indole compound and preparation method and application thereof |
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| Electronic Nature of Ketone Directing Group as a Key To Control C‑2 vs C‑4 Alkenylation of Indoles;Veeranjaneyulu Lanke，et al.;《Org. Lett.》;20161013(第18期);5496-5499 * |
| α-芳基烯基膦酸酯的合成研究进展;施波超，等;《有机化学》;20161231;第36卷;673-686 * |
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