CN116082353A - Preparation method of dihydrobenzofuran spiro-pyrrolidone - Google Patents
Preparation method of dihydrobenzofuran spiro-pyrrolidone Download PDFInfo
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- CN116082353A CN116082353A CN202211735860.0A CN202211735860A CN116082353A CN 116082353 A CN116082353 A CN 116082353A CN 202211735860 A CN202211735860 A CN 202211735860A CN 116082353 A CN116082353 A CN 116082353A
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- dihydrobenzofuran
- spiro
- reaction
- ethyl acetate
- pyrrolidone
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- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- YMZTUCZCQMQFMK-UHFFFAOYSA-N 3-methyl-1-benzofuran-2-carboxylic acid Chemical class C1=CC=C2C(C)=C(C(O)=O)OC2=C1 YMZTUCZCQMQFMK-UHFFFAOYSA-N 0.000 claims abstract description 26
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 239000003446 ligand Substances 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 238000000926 separation method Methods 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 162
- 238000004440 column chromatography Methods 0.000 claims description 24
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- 239000000047 product Substances 0.000 claims description 22
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- 239000003208 petroleum Substances 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- 238000002390 rotary evaporation Methods 0.000 claims description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 17
- 239000000706 filtrate Substances 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 12
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- -1 3-methylbenzofuran-2-carboxylic acid derivative compound Chemical class 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 8
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000001632 sodium acetate Substances 0.000 claims description 6
- 235000017281 sodium acetate Nutrition 0.000 claims description 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 4
- 239000001488 sodium phosphate Substances 0.000 claims description 4
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 4
- CXQRZKIIGJLWPJ-UHFFFAOYSA-N diphenylphosphane;1-naphthalen-1-ylnaphthalene Chemical group C=1C=CC=CC=1PC1=CC=CC=C1.C1=CC=C2C(C=3C4=CC=CC=C4C=CC=3)=CC=CC2=C1 CXQRZKIIGJLWPJ-UHFFFAOYSA-N 0.000 claims description 3
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 3
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 239000008346 aqueous phase Substances 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000003003 spiro group Chemical group 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 238000003780 insertion Methods 0.000 abstract description 4
- 230000037431 insertion Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 238000003379 elimination reaction Methods 0.000 abstract description 3
- 238000013508 migration Methods 0.000 abstract description 3
- 230000005012 migration Effects 0.000 abstract description 3
- 125000002029 aromatic hydrocarbon group Chemical class 0.000 abstract description 2
- 238000010276 construction Methods 0.000 abstract description 2
- 230000008030 elimination Effects 0.000 abstract description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 abstract description 2
- 238000006464 oxidative addition reaction Methods 0.000 abstract description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 150000002940 palladium Chemical class 0.000 abstract 1
- 239000012044 organic layer Substances 0.000 description 45
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 18
- 238000006467 substitution reaction Methods 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 16
- 239000012267 brine Substances 0.000 description 15
- 239000010410 layer Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- 239000011734 sodium Substances 0.000 description 6
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000007341 Heck reaction Methods 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 150000001491 aromatic compounds Chemical class 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001907 coumarones Chemical class 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000010496 migratory insertion reaction Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000004040 pyrrolidinones Chemical class 0.000 description 1
- 150000003239 pyrrolones Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—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 three hetero rings
- C07D491/20—Spiro-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
- C07D491/22—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 four or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a preparation method of dihydrobenzofuran spiro-pyrrolidone, and belongs to the field of organic synthesis. According to the method, 3-methylbenzofuran-2-formic acid derivatives are used as raw materials, palladium salt is used as a catalyst, and the corresponding compound is generated by reacting in an organic solvent at the temperature of 100-140 ℃ for 18-36 hours under the combined action of alkali and ligand. According to the invention, the 3-methylbenzofuran-2-formic acid derivative which is easy to prepare is taken as a raw material, through the oxidative addition of a palladium catalyst and a halogenated aromatic hydrocarbon structure in the raw material, then the series migration insertion of an olefin double bond and a furan ring double bond is carried out, and finally, two rings can be constructed by one-step elimination of beta-H, so that the rapid construction of dihydrobenzofuran spiro pyrrolidone is realized. The method has the advantages of mild reaction conditions, simple and convenient operation, easily available reaction raw materials, wide substrate applicability, excellent yield, excellent diastereoselectivity, easy separation of target products and the like.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of palladium-catalyzed dihydrobenzofuran spiro-pyrrolidone.
Background
Dihydrobenzofuran compounds often have biological activities such as antiviral, antifungal and antitubercular activities and are widely found in natural products and drug molecules (Eur. J. Med. Chem.2015,97, 356-376). The N-alkyl substituted pyrrolidone derivative has good biological activity and can be used as immunosuppressant, anti-inflammatory and antibacterial agent. In addition, due to the high rigidity and three-dimensional characteristics of the spiro structure, chemists often introduce the spiro structure into a parent structure for drug development to improve the activity of the drug. In view of the importance of dihydrobenzofuran and N-alkyl substituted pyrrolones, combining these two dominant structures via spiro fashion is likely to construct more biologically active drug molecules, which is of great research value. Compound a (Synthesis 2019,51,3847-3858) and compound B (CN 111892608A) shown below:
based on this, finding a simple synthetic method for such compounds is a primary problem to be solved. Palladium-catalyzed dearomatization based on a migratory insertion strategy has been a highly efficient reaction strategy for derivatization of aromatic compounds for over a decade. The Konchel team in 2007 reported the dearomatization Heck reaction of the first pyrrole (chem. Asianj.2007,2, 416-433), and as the study progressed, such methods gradually extended to other aromatic compounds including benzofurans. The method can be used for preparing the dihydrobenzofuran compound containing the spiro structure by using easily available benzofuran raw materials through a dearomatization Heck reaction in molecules and a one-step reaction. The prior literature mainly relies on coordination insertion of aryl palladium intermediate to furan double bond to realize dearomatization, and reaction research on the dearomatization of benzofuran by alkyl palladium intermediate has not been reported, but the synthesis method is still limited (a.J. am. Chem. Soc.2018,140,13945-13951; b.Angew.chem. Int. Ed.2019,58,17068-17073; c.J. org. Chem.2020,85, 7817-7839).
Disclosure of Invention
In view of the above problems in the prior art, the present invention aims to provide a method for preparing dihydrobenzofuran spiro-pyrrolidone, which utilizes easily prepared reaction raw materials, and synthesizes dihydrobenzofuran spiro-pyrrolidone in one step with high efficiency through a series migration insertion and beta-H elimination process after palladium catalytic oxidation addition.
In order to achieve the above purpose, the following technical scheme is provided:
the preparation method of the dihydrobenzofuran spiro-pyrrolidone is characterized in that 3-methylbenzofuran-2-formic acid derivatives shown in a formula (1) are used as raw materials, under the catalysis of a palladium catalyst, the raw materials react in an organic solvent at a temperature of 100-140 ℃ for 18-36 hours under the combined action of alkali and ligand, and after the reaction is finished, the dihydrobenzofuran spiro-pyrrolidone shown in the formula (2) is obtained through post-treatment, wherein the reaction general formula is as follows:
wherein: r is R 1 Any one selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy and halogen; r is R 2 Any one selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl and halogen; r is R 3 Is a hydrogen atom or a C1-C4 alkyl group; x is a bromine atom or an iodine atom.
Preferably, R 1 Any one selected from methyl, methoxy and chlorine atoms; r is R 2 Any one selected from methyl, methoxy, trifluoromethyl, fluorine atom and chlorine atom; r is R 3 Is a hydrogen atom or a methyl group.
Preferably, the palladium catalyst is selected from any one of palladium acetate and palladium chloride.
Preferably, the organic solvent is selected from any one of N, N-dimethylformamide, toluene, tetrahydrofuran and dimethyl sulfoxide, the volume ratio of the organic solvent to the 3-methylbenzofuran-2-formic acid derivative is 5-20:1, preferably 10:1, the volume unit is milliliter, and the volume unit is millimole.
Preferably, the ligand is selected from any one of triphenylphosphine, tri-tert-butylphosphine tetrafluoroborate, 1, 2-bis (diphenylphosphine) ethane, 2 '-bis (diphenylphosphine) -1,1' -binaphthyl, (rac) -MonoPhos.
Preferably, the base is selected from any one of potassium carbonate, sodium carbonate, lithium carbonate, sodium acetate, sodium phosphate.
Preferably, the molar ratio of the 3-methylbenzofuran-2-formic acid derivative, the palladium catalyst, the ligand and the base is 1:0.03-0.08:0.1-0.15:2-4, preferably 1:0.05:0.12:3.
Preferably, the reaction temperature is 110 to 130 ℃, the reaction time is 20 to 28 hours, preferably 120 ℃ for 24 hours.
The post-treatment steps after the reaction are finished are as follows: after the reaction is finished, diluting a reaction system with water and ethyl acetate, extracting an aqueous phase by using ethyl acetate, treating the combined organic phases by using saline, separating liquid to obtain an organic phase, drying by using anhydrous sodium sulfate, filtering, removing a solvent from filtrate by rotary evaporation, and separating by column chromatography to obtain a target product, wherein a mobile phase of the column chromatography is a petroleum ether and ethyl acetate mixture with the volume ratio of 30-10:1; or after the reaction is finished, the system directly and rotationally evaporates to remove the solvent, and then the target product is obtained through column chromatography separation, wherein the mobile phase of the column chromatography is a petroleum ether and ethyl acetate mixture with the volume ratio of 30-10:1.
By adopting the technology, compared with the prior art, the invention has the following beneficial effects:
according to the invention, the 3-methylbenzofuran-2-formic acid derivative which is easy to prepare is taken as a raw material, through the oxidative addition of a palladium catalyst and a halogenated aromatic hydrocarbon structure in the raw material, then the series migration insertion of an olefin double bond and a furan ring double bond is carried out, and finally, two rings can be constructed by one-step elimination of beta-H, so that the rapid construction of dihydrobenzofuran spiro pyrrolidone is realized. The method has the advantages of mild reaction conditions, simple and convenient operation, easily available reaction raw materials, wide substrate applicability, excellent yield, excellent diastereoselectivity, easy separation of target products and the like.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto;
example 1:
3-methylbenzofuran-2-carboxylic acid derivative 1a (0.2 mmol), palladium acetate (0.01 mmol), triphenylphosphine (0.024 mmol) and sodium carbonate (0.6 mmol) were successively added to the reaction tube. After three nitrogen substitutions, 2mL of N, N-dimethylformamide was added by syringe and allowed to react at 120℃for 24 hours. After the reaction, the reaction mixture was diluted with water and ethyl acetate, then the aqueous layer was extracted three times with ethyl acetate, then the combined organic layers were washed with brine, and the organic layers were separated to obtain an organic layer, which was dried over anhydrous sodium sulfate, filtered, and the filtrate was taken and subjected to rotary evaporation to remove the solvent, and then separated by column chromatography (petroleum ether: ethyl acetate=30:1, v/v) to obtain the objective product 2a in 79% yield.
1 H NMR(600MHz,CDCl 3 )δ7.44(d,J＝7.8Hz,1H),7.23-7.35(m,5H),6.97(t,J＝7.2Hz,1H),6.87(d,J＝7.8Hz,1H),5.68(s,1H),5.34(s,1H),5.16(d,J＝15.0Hz,1H),4.37(d,J＝15.6Hz,1H),3.00(d,J＝13.8Hz,1H),2.88(d,J＝13.8Hz,1H),1.66(s,3H). 13 C NMR(101MHz,CDCl3)δ174.1,161.5,148.8,147.4,137.6,131.0,128.1,127.8,124.7,122.9,121.4,121.2,120.8,110.6,102.6,93.0,67.9,48.4,47.9,29.8.HRMS m/z(ESI+):Calculated for C 20 H 18 NO 2 + ([M+H] + ):304.1332,found 304.1340.
Example 2:
3-methylbenzofuran-2-carboxylic acid derivative 1b (0.2 mmol), palladium acetate (0.01 mmol), triphenylphosphine (0.024 mmol) and sodium carbonate (0.6 mmol) were successively added to the reaction tube. After three nitrogen substitutions, 2mL of toluene was added by syringe and allowed to react at 120℃for 28 hours. After the reaction, the reaction mixture was diluted with water and ethyl acetate, then the aqueous layer was extracted three times with ethyl acetate, then the combined organic layers were washed with brine, and the organic layers were separated to obtain an organic layer, which was dried over anhydrous sodium sulfate, filtered, and the filtrate was taken and subjected to rotary evaporation to remove the solvent, and then separated by column chromatography (petroleum ether: ethyl acetate=30:1, v/v) to obtain the objective product 2b in 42% yield.
1 H NMR(400MHz,CDCl 3 )7.58(d,J＝7.6Hz,0.8H),7.34-7.29(m,3.5H),7.25-7.18(m,1.5H),7.20-7.08(m,0.2H),6.99-6.05(m,0.8H),6.90-6.88(m,0.2H),6.85(d,J＝8.4Hz,0.8H),6.67(d,J＝8.0Hz,0.2H),6.17(q,J＝7.2Hz,0.2H),5.90(q,J＝7.2Hz,0.8H),5.19-5.13(m,1H),4.42-4.34(m,1H),3.09(d,J＝14.8Hz,0.8H),2.94(d,J＝14.0Hz,0.8H),2.86-2.82(m,1H),2.13(d,J＝7.2Hz,2.4H),2.00(d,J＝7.2Hz,0.6H),1.63(s,2.4H),1.60(s,0.6H). 13 C NMR(100MHz,CDCl 3 )δ176.2,174.7,161.7,159.8,147.6,146.7,140.8,139.0,138.7,137.6,129.8,129.4,128.0,127.9,127.7,127.6,126.1,124.9,124.6,123.1,122.9,121.2,121.1,120.8,120.5,119.8,117.7,115.4,110.3,110.2,93.3,91.6,69.0,67.9,49.8,48.4,48.3,46.1,29.7,29.1,14.30.HRMS m/z(ESI+):Calculated for C 21 H 20 NO 2 + ([M+H] + ):318.1489,found 318.1497.
Example 3:
3-methylbenzofuran-2-carboxylic acid derivative 1c (0.2 mmol), palladium acetate (0.01 mmol), triphenylphosphine (0.024 mmol) and sodium carbonate (0.6 mmol) were successively added to the reaction tube. After three nitrogen substitutions, 2mL of tetrahydrofuran was added by syringe and allowed to react at 120℃for 30 hours. After the reaction, the system is directly distilled to remove the solvent, and then a column chromatography separation method (petroleum ether: ethyl acetate=10:1, v/v) is adopted to separate and obtain the target product 2c, and the yield is 45%.
1 H NMR(400MHz,CDCl 3 )δ7.34-7.30(m,3H),7.26-7.24(m,1H),6.95(d,J＝2.4Hz,1H),6.85-6.82(m,1H),6.78-6.76(m,1H),5.63(s,1H),5.33(s,1H),5.14(d,J＝15.2Hz,1H),4.36(d,J＝15.1Hz,1H),3.80(s,3H),2.98(d,J＝14.0Hz,1H),2.87(d,J＝14.0Hz,1H),1.65(s,3H). 13 C NMR(100MHz,CDCl 3 )δ174.3,156.0,154.9,149.2,147.5,137.6,128.1,127.8,125.1,122.9,120.8,117.9,110.9,105.6,102.6,93.4,67.9,56.1,48.4,47.9,29.8.HRMS m/z(ESI+):Calculated for C 21 H 20 NO 3 + ([M+H] + ):334.1438,found 334.1442.
Example 4:
3-methylbenzofuran-2-carboxylic acid derivative 1d (0.2 mmol), palladium chloride (0.01 mmol), triphenylphosphine (0.024 mmol) and sodium carbonate (0.6 mmol) were successively added to the reaction tube. After three nitrogen substitutions, 2mL of dimethyl sulfoxide was added by syringe and allowed to react at 120℃for 18 hours. After the reaction, the reaction mixture was diluted with water and ethyl acetate, then the aqueous layer was extracted three times with ethyl acetate, then the combined organic layers were washed with brine, and the organic layers were separated to obtain an organic layer, which was dried over anhydrous sodium sulfate, filtered, and the filtrate was taken and subjected to rotary evaporation to remove the solvent, and then separated by column chromatography (petroleum ether: ethyl acetate=30:1, v/v) to obtain the objective product 2d in 67% yield.
1 H NMR(400MHz,CDCl 3 )δ7.31-7.21(m,6H),6.77-6.72(d,J＝8.0Hz,1H),6.64(s,1H),5.55(s,1H),5.23(s,1H),5.11(d,J＝15.2Hz,1H),4.32(d,J＝15.2Hz,1H),2.94(d,J＝14.0Hz,1H),2.83(d,J＝14.0Hz,1H),2.30(s,3H),1.62(s,3H). 13 C NMR(125MHz,CDCl 3 )δ174.2,161.8,148.7,147.5,141.8,137.6,128.0,127.7,122.9,122.4,122.1,120.8,120.7,111.0,101.3,93.2,67.9,48.3,47.9,29.8,21.8.HRMS m/z(ESI+):Calculated for C 21 H 20 NO 2 + ([M+H] + ):318.1489,found 318.1499.
Example 5:
3-methylbenzofuran-2-carboxylic acid derivative 1e (0.2 mmol), palladium acetate (0.01 mmol), tri-tert-butylphosphine tetrafluoroborate (0.024 mmol), and sodium carbonate (0.6 mmol) were successively added to the reaction tube. After three nitrogen substitutions, 2mLN, N-dimethylformamide was added by syringe and allowed to react at 120℃for 20 hours. After the reaction, the reaction mixture was diluted with water and ethyl acetate, then the aqueous layer was extracted three times with ethyl acetate, then the combined organic layers were washed with brine, and the organic layers were separated to obtain an organic layer, which was dried over anhydrous sodium sulfate, filtered, and the filtrate was taken and subjected to rotary evaporation to remove the solvent, and then separated by column chromatography (petroleum ether: ethyl acetate=10:1, v/v) to obtain the objective product 2e in 71% yield.
1 H NMR(400MHz,CDCl 3 )7.33-7.25(m,5H),6.54(dd,J＝8.4,2.0Hz,1H),6.42(d,J＝2.4Hz,1H),5.48(s,1H),5.18(s,1H),5.14(d,J＝15.1Hz,1H),4.36(d,J＝15.1Hz,1H),3.78(s,3H),2.98(d,J＝14.0Hz,1H),2.88(d,J＝14.0Hz,1H),1.65(s,3H). 13 C NMR(125MHz,CDCl 3 )δ174.2,163.1,162.8,148.2,147.5,137.6,128.1,127.8,122.9,121.7,120.7,117.5,108.6,99.7,95.9,93.9,67.9,55.6,48.4,47.9,29.8.HRMS m/z(ESI+):Calculated for C 21 H 20 NO 3 + ([M+H] + ):334.1438,found 334.1438.
Example 6:
3-methylbenzofuran-2-carboxylic acid derivative 1f (0.2 mmol), palladium acetate (0.01 mmol), 1, 2-bis (diphenylphosphine) ethane (0.024 mmol) and sodium carbonate (0.6 mmol) were successively added to the reaction tube. After three nitrogen substitutions, 2mLN, N-dimethylformamide was added by syringe and allowed to react at 100℃for 28 hours. After the reaction, the reaction mixture was diluted with water and ethyl acetate, then the aqueous layer was extracted three times with ethyl acetate, then the combined organic layers were washed with brine, and the organic layers were separated to obtain an organic layer, which was dried over anhydrous sodium sulfate, filtered, and the filtrate was taken and subjected to rotary evaporation to remove the solvent, and then separated by column chromatography (petroleum ether: ethyl acetate=30:1, v/v) to obtain the objective product 2f in a yield of 68%.
1 H NMR(400MHz,CDCl 3 )δ7.31-7.22(m,5H),6.91(dd,J＝8.0,1.6Hz,1H),6.82(d,J＝1.6Hz,1H),5.62(d,J＝1.2Hz,1H),5.32(d,J＝1.2Hz,1H),5.10(d,J＝14.8Hz,1H),4.34(d,J＝14.8Hz,1H),2.96(d,J＝14.0Hz,1H),2.84(d,J＝14.0Hz,1H),1.62(s,3H). 13 C NMR(125MHz,CDCl 3 )δ174.1,161.4,149.3,148.6,136.1,133.9,131.1,128.0,124.5,124.2,121.5,121.3,121.2,110.5,102.6,92.7,67.8,48.0,47.7,29.7.HRMS m/z(ESI+):Calculated for C 20 H 17 ClNO 2 + ([M+H] + ):338.0942,found 338.0952.
Example 7:
1g (0.2 mmol) of 3-methylbenzofuran-2-carboxylic acid derivative, palladium chloride (0.01 mmol), 2 '-bis (diphenylphosphine) -1,1' -binaphthyl (0.024 mmol) and sodium carbonate (0.6 mmol) were successively introduced into the reaction tube. After three nitrogen substitutions, 2mL of dimethyl sulfoxide was added by syringe and allowed to react at 140℃for 18 hours. After the reaction, the reaction mixture was diluted with water and ethyl acetate, then the aqueous layer was extracted three times with ethyl acetate, then the combined organic layers were washed with brine, and the organic layers were separated to obtain an organic layer, which was dried over anhydrous sodium sulfate, filtered, and the filtrate was taken and subjected to rotary evaporation to remove the solvent, and then separated by column chromatography (petroleum ether: ethyl acetate=30:1, v/v) to obtain 2g of the objective product in a yield of 64%.
1 H NMR(400MHz,CDCl 3 )7.40(d,J＝7.6Hz,1H),7.23-7.19(m,1H),7.15-7.13(m,1H),7.09-7.07(m,1H),7.03(s,1H),6.93(t,J＝7.6Hz,1H),6.83(d,J＝8.0Hz,1H),5.64(s,1H),5.30(s,1H),5.07(d,J＝14.8Hz,1H),4.30(d,J＝14.8Hz,1H),2.95(d,J＝14.0Hz,1H),2.82(d,J＝14.0Hz,1H),2.36(s,3H),1.61(s,3H). 13 C NMR(100MHz,CDCl 3 )δ174.1,161.5,148.8,147.6,137.9,134.6,131.0,128.6,124.7,122.6,121.4,121.4,121.2,110.6,102.7,93.1,67.9,48.2,47.9,29.9,21.5.HRMS m/z(ESI+):Calculated for C 21 H 19 NO 2 + ([M+H] + ):318.1489,found 318.1495.
Example 8:
3-methylbenzofuran-2-carboxylic acid derivative (0.2 mmol), palladium acetate (0.01 mmol), (rac) -MonoPhos (0.024 mmol) and sodium carbonate (0.6 mmol) were added sequentially to the reaction tube. After three nitrogen substitutions, 2mL of N, N-dimethylformamide was added by syringe and allowed to react at 130℃for 18 hours. After the reaction, the reaction mixture was diluted with water and ethyl acetate, then the aqueous layer was extracted three times with ethyl acetate, then the combined organic layers were washed with brine, and the organic layers were separated to obtain an organic layer, which was dried over anhydrous sodium sulfate, filtered, and the filtrate was separated by column chromatography separation (petroleum ether: ethyl acetate=30:1, v/v) to obtain the objective product in 71% yield after removing the solvent by rotary evaporation.
1 H NMR(400MHz,CDCl 3 )δ7.40(d,J＝7.2Hz,1H),7.25-7.19(m,2H),6.99-6.91(m,3H),6.83(d,J＝8.4Hz,1H),5.63(d,J＝1.2Hz,1H),5.27(d,J＝1.2Hz,1H),5.07(d,J＝14.8Hz,1H),4.29(d,J＝14.8Hz,1H),2.93(d,J＝14.0Hz,1H),2.81(d,J＝14.0Hz,1H),1.62(s,3H). 13 C NMR(125MHz,CDCl 3 )δ174.1,163.77,162.8(J＝245.0Hz),149.5(J＝7.5Hz),148.6,133.0(J＝2.5Hz),131.1,124.6,124.3(J＝8.8Hz),121.5,121.2,114.9(J＝22.5Hz),110.5,108.3(J＝22.5Hz),102.6,92.7,67.9,47.9,47.7,29.6. 19 F NMR(375MHz,CDCl 3 )δ-113.7.HRMS m/z(ESI+):Calculated for C 20 H 17 FNO 2 + ([M+H] + ):322.1244,found 322.1238.
Example 9:
3-methylbenzofuran-2-carboxylic acid derivative 1i (0.2 mmol), palladium acetate (0.01 mmol), triphenylphosphine (0.024 mmol) and potassium carbonate (0.6 mmol) were successively added to the reaction tube. After three nitrogen substitutions, 2mL of dimethyl sulfoxide was added by syringe and allowed to react at 120℃for 26 hours. After the reaction, the reaction mixture was diluted with water and ethyl acetate, then the aqueous layer was extracted three times with ethyl acetate, then the combined organic layers were washed with brine, and the organic layers were separated to obtain an organic layer, which was dried over anhydrous sodium sulfate, filtered, and the filtrate was taken and subjected to rotary evaporation to remove the solvent, and then separated by column chromatography (petroleum ether: ethyl acetate=30:1, v/v) to obtain the objective product 2i in 52% yield.
1 H NMR(400MHz,CDCl 3 )δ7.32(d,J＝7.6,Hz,1H),7.18-7.10(m,4H),6.85(t,J＝7.6Hz,1H),6.75(d,J＝8.0Hz,1H),5.55(s,1H),5.19(s,1H),5.00(d,J＝15.2Hz,1H),4.20(d,J＝15.2Hz,1H),2.86(d,J＝14.0Hz,1H),2.73(d,J＝14.0Hz,1H),1.53(s,3H). 13 C NMR(125MHz,CDCl 3 )δ173.6,161.9,147.4,147.2,137.4,136.4,128.1,127.8,123.6,123.0,121.8,121.7,120.7,111.2,103.2,93.9,67.9,48.4,47.7,29.8.HRMS m/z(ESI+):Calculated for C 20 H 17 ClNO 2 + ([M+H] + ):338.0942found 338.0952.
Example 10:
3-methylbenzofuran-2-carboxylic acid derivative 1j (0.2 mmol), palladium chloride (0.01 mmol), triphenylphosphine (0.024 mmol) and lithium carbonate (0.6 mmol) were successively added to the reaction tube. After three nitrogen substitutions, 2mL of N, N-dimethylformamide was added by syringe and allowed to react at 120℃for 24 hours. After the reaction, the reaction mixture was diluted with water and ethyl acetate, then the aqueous layer was extracted three times with ethyl acetate, then the combined organic layers were washed with brine, and the organic layers were separated to obtain an organic layer, which was dried over anhydrous sodium sulfate, filtered, and the filtrate was taken and subjected to rotary evaporation to remove the solvent, and then separated by column chromatography (petroleum ether: ethyl acetate=10:1, v/v) to obtain the objective product 2j in 48% yield.
1 H NMR(400MHz,CDCl 3 )δ7.41(d,J＝7.2Hz,1H),7.24-7.19(m,1H),7.12(d,J＝8.4Hz,1H),6.94(t,J＝7.6Hz,1H),6.85-6.80(m,3H),5.64(s,1H),5.30(s,1H),5.08(d,J＝15.2Hz,1H),4.31(d,J＝15.2Hz,1H),3.80(s,3H),2.92(d,J＝14.0Hz,1H),2.81(d,J＝14.0Hz,1H),1.61(s,3H). 13 C NMR(100MHz,CDCl 3 )δ174.1,161.4,159.6,148.7,139.7,139.2,131.0,124.6,121.5,121.4,121.2,114.1,110.6,108.1,102.7,93.2,67.6,55.6,48.5,48.1,30.0.HRMS m/z(ESI+):Calculated for C 21 H 19 NO 3 Na + ([M+Na] + ):356.1257,found 256.1266.
Example 11:
to the reaction tube was successively added 1k (0.2 mmol) of the 3-methylbenzofuran-2-carboxylic acid derivative, palladium acetate (0.01 mmol), triphenylphosphine (0.024 mmol) and sodium acetate (0.6 mmol). After three nitrogen substitutions, 2mL of N, N-dimethylformamide was added by syringe and allowed to react at 120℃for 28 hours. After the reaction, the reaction mixture was diluted with water and ethyl acetate, then the aqueous layer was extracted three times with ethyl acetate, then the combined organic layers were washed with brine, and the organic layers were separated to obtain an organic layer, which was dried over anhydrous sodium sulfate, filtered, and the filtrate was taken and subjected to rotary evaporation to remove the solvent, and then separated by column chromatography (petroleum ether: ethyl acetate=30:1, v/v) to obtain the objective product 2k in 67% yield.
1 H NMR(400MHz,CDCl 3 )δ7.32(d,J＝7.6Hz,1H),7.19-7.06(m,4H),6.85(t,J＝7.6Hz,1H),6.75(d,J＝8.0Hz,1H),5.55(s,1H),5.20(s,1H),5.00(d,J＝15.2Hz,1H),4.21(d,J＝15.2Hz,1H),2.83(d,J＝14.0Hz,1H),2.74(d,J＝14.0Hz,1H),1.52(s,3H). 13 C NMR(100MHz,CDCl 3 )δ174.1,161.4,148.5,146.0,139.6,133.7,131.1,128.4,124.5,123.3,122.0,121.6,121.2,110.6,102.8,92.8,67.6,48.1,47.8,29.8.HRMS m/z(ESI+):Calculated for C 20 H 17 NO 2 + ([M+H] + ):338.0942,found 338.0949.
Example 12:
1l (0.2 mmol) of 3-methylbenzofuran-2-carboxylic acid derivative, palladium acetate (0.01 mmol), triphenylphosphine (0.024 mmol) and sodium phosphate (0.6 mmol) were successively added to the reaction tube. After three nitrogen substitutions, 2mL of N, N-dimethylformamide was added by syringe and allowed to react at 110℃for 28 hours. After the reaction, the reaction mixture was diluted with water and ethyl acetate, then the aqueous layer was extracted three times with ethyl acetate, then the combined organic layers were washed with brine, and the organic layers were separated to obtain an organic layer, which was dried over anhydrous sodium sulfate, filtered, and the filtrate was taken and subjected to rotary evaporation to remove the solvent, and then separated by column chromatography (petroleum ether: ethyl acetate=20:1, v/v) to obtain 2l of the objective product in 75% yield.
1 H NMR(400MHz,CDCl 3 )δ7.59(d,J＝8.0Hz,2H),7.55(s,1H),7.41(d,J＝7.6Hz,1H),7.36(d,J＝7.6Hz,1H),7.24-7.20(m,1H),6.95(t,J＝7.6Hz,1H),6.83(d,J＝8.0Hz,1H),5.66(s,1H),5.30(s,1H),5.18(d,J＝15.6Hz,1H),4.38(d,J＝15.6Hz,1H),2.97(d,J＝14.0Hz,1H),2.88(d,J＝14.0Hz,1H),1.65(s,3H). 13 CNMR(125MHz,CDCl 3 )δ174.2,161.3,151.2,148.5,138.7,131.2,130.4(q,J＝32.0Hz),125.6(q,J＝4.0Hz),124.5,124.0(q,J＝271.0Hz),121.6,121.4,121.2,120.2(q,J＝4.0Hz),110.6,102.8,92.6,77.4,76.8,67.8,48.2,47.6,29.6. 19 F NMR(375MHz,CDCl 3 )δ-62.1.HRMS m/z(ESI+):Calculated for C 21 H 17 F 3 NO 2 + ([M+H] + ):322.1238,found 322.1244.
Example 13:
to the reaction tube was successively added 1m (0.2 mmol) of the 3-methylbenzofuran-2-carboxylic acid derivative, palladium acetate (0.01 mmol), triphenylphosphine (0.024 mmol) and sodium phosphate (0.6 mmol). After three nitrogen substitutions, 2mL of dimethyl sulfoxide was added by syringe and allowed to react at 130℃for 24 hours. After the reaction, the reaction mixture was diluted with water and ethyl acetate, then the aqueous layer was extracted three times with ethyl acetate, then the combined organic layers were washed with brine, and the organic layers were separated to obtain an organic layer, which was dried over anhydrous sodium sulfate, filtered, and the filtrate was taken and subjected to rotary evaporation to remove the solvent, and then separated by column chromatography (petroleum ether: ethyl acetate=10:1, v/v) to obtain the objective product 2m in 60% yield.
1 H NMR(400MHz,CDCl 3 )δ7.40(dd,J＝7.6,1.2Hz,1H),7.23-7.19(m,1H),6.93(t,J＝7.6Hz,1H),6.83(d,J＝8.0Hz,1H),6.78(s,1H),6.73(s,1H),5.63(d,J＝1.2Hz,1H),5.29(d,J＝1.2Hz,1H),5.04(d,J＝14.8Hz,1H),4.28(d,J＝14.8Hz,1H),3.88(s,3H),3.87(s,3H),2.94(d,J＝14.0Hz,1H),2.79(d,J＝14.0Hz,1H),1.61(s,3H). 13 C NMR(125MHz,CDCl 3 )δ174.1,161.4,149.5,149.2,148.7,139.3,131.0,129.2,124.6,121.4,121.1,110.5,106.0,104.0,102.6,93.1,68.1,56.2,56.2,48.5,47.9,29.8.HRMS m/z(ESI+):Calculated for C 22 H 22 NO 4 + ([M+H] + ):364.1543,found 364.1551.
Example 14:
3-methylbenzofuran-2-carboxylic acid derivative 1n (0.2 mmol), palladium chloride (0.01 mmol), 1, 2-bis (diphenylphosphine) ethane (0.024 mmol) and sodium acetate (0.6 mmol) were successively added to the reaction tube. After three nitrogen substitutions, 2mL of dimethyl sulfoxide was added by syringe and allowed to react at 120℃for 26 hours. After the reaction, the reaction mixture was diluted with water and ethyl acetate, then the aqueous layer was extracted three times with ethyl acetate, then the combined organic layers were washed with brine, and the organic layers were separated to obtain an organic layer, which was dried over anhydrous sodium sulfate, filtered, and the filtrate was taken and subjected to rotary evaporation to remove the solvent, and then separated by column chromatography (petroleum ether: ethyl acetate=30:1, v/v) to obtain the objective product 2n in 77% yield.
1 H NMR(400MHz,CDCl 3 )δ7.41(d,J＝7.6Hz,1H),7.32-7.27(m,1H),7.24-7.20(m,1H),7.02(d,J＝7.6Hz,1H),6.99-6.92(m,2H),6.83(d,J＝8.0Hz,1H),5.65(s,1H),5.30(s,1H),5.24(d,J＝15.2Hz,1H),4.33(d,J＝15.2Hz,1H),2.96(d,J＝14.0Hz,1H),2.84(d,J＝14.0Hz,1H),1.64(s,3H). 13 C NMR(125MHz,CDCl 3 )δ174.2,161.4,157.6(d,J＝247.0Hz),150.7(d,J＝4.0Hz),148.5,131.1,130.6(d,J＝7.0Hz),124.5,124.1(d,J＝8.0Hz),121.6,121.2,116.5(d,J＝3.0Hz),114.6(d,J＝20.0Hz),110.6,102.7,92.7,68.3,47.7,45.6,29.7. 19 F NMR(375MHz,CDCl 3 )δ-116.8.HRMS m/z(ESI+):Calculated for C 20 H 16 FNO 2 Na + ([M+Na] + ):344.1057,found 344.1068.
Example 15:
to the reaction tube was successively added 1o (0.2 mmol) of the 3-methylbenzofuran-2-carboxylic acid derivative, palladium chloride (0.01 mmol), triphenylphosphine (0.024 mmol) and sodium acetate (0.6 mmol). After three nitrogen substitutions, 2mL of dimethyl sulfoxide was added by syringe and allowed to react at 120℃for 18 hours. After the reaction, the reaction mixture was diluted with water and ethyl acetate, then the aqueous layer was extracted three times with ethyl acetate, then the combined organic layers were washed with brine, and the organic layers were separated to obtain an organic layer, which was dried over anhydrous sodium sulfate, filtered, and the filtrate was taken and subjected to rotary evaporation to remove the solvent, and then separated by column chromatography (petroleum ether: ethyl acetate=20:1, v/v) to obtain the objective product 2o in 63% yield.
1 H NMR(400MHz,CDCl 3 )δ7.40(dd,J＝7.6,0.8Hz,1H),7.24-7.20(m,1H),6.94(td,J＝7.6,0.8Hz,1H),6.84(d,J＝8.4Hz,1H),6.70(s,1H),6.66(s,1H),5.98-5.97(m,2H),5.63(d,J＝0.8Hz,1H),5.27(d,J＝0.8Hz,1H),5.00(d,J＝14.8Hz,1H),4.24(d,J＝14.8Hz,1H),2.90(d,J＝14.0Hz,1H),2.77(d,J＝14.0Hz,1H),1.59(s,3H). 13 C NMR(125MHz,CDCl 3 )δ174.1,161.4,148.7,147.9,147.7,140.6,131.0,130.4,124.6,121.4,121.1,110.5,103.4,102.6,101.6,101.5,92.9,67.8,48.4,47.9,29.8.HRMS m/z(ESI+):Calculated for C 21 H 17 NO 4 Na + ([M+Na] + ):370.1050,found 370.1062.
Example 16:
3-methylbenzofuran-2-carboxylic acid derivative 1a' (0.2 mmol), palladium chloride (0.01 mmol), tri-tert-butylphosphine tetrafluoroborate (0.024 mmol) and sodium acetate (0.6 mmol) were successively added to the reaction tube. After three nitrogen substitutions, 2mL of dimethyl sulfoxide was added by syringe and allowed to react at 120℃for 26 hours. After the reaction, the reaction mixture was diluted with water and ethyl acetate, then the aqueous layer was extracted three times with ethyl acetate, then the combined organic layers were washed with brine, and the organic layers were separated to obtain an organic layer, which was dried over anhydrous sodium sulfate, filtered, and the filtrate was taken and subjected to rotary evaporation to remove the solvent, and then separated by column chromatography (petroleum ether: ethyl acetate=10:1, v/v) to obtain the objective product 2a in 50% yield.
1 H NMR(600MHz,CDCl 3 )δ7.44(d,J＝7.8Hz,1H),7.23-7.35(m,5H),6.97(t,J＝7.2Hz,1H),6.87(d,J＝7.8Hz,1H),5.68(s,1H),5.34(s,1H),5.16(d,J＝15.0Hz,1H),4.37(d,J＝15.6Hz,1H),3.00(d,J＝13.8Hz,1H),2.88(d,J＝13.8Hz,1H),1.66(s,3H). 13 C NMR(101MHz,CDCl3)δ174.1,161.5,148.8,147.4,137.6,131.0,128.1,127.8,124.7,122.9,121.4,121.2,120.8,110.6,102.6,93.0,67.9,48.4,47.9,29.8.HRMS m/z(ESI+):Calculated for C 20 H 18 NO 2 + ([M+H] + ):304.1332,found304.1340.
Examples 1-16 relate to the starting materials, target products and experimental results corresponding to the specific methods for synthesizing dihydrobenzofuran spiro pyrrolones as shown in Table 1:
TABLE 1 reaction results of palladium catalyzed Synthesis of Dihydrobenzofuran spiropyrrolidone [a]
[a] The reaction conditions are described in the examples; [b] the yield was isolated.
The foregoing description is only of a few specific embodiments of the invention, which are described in detail, but the scope of the invention is not limited thereto. Any changes or substitutions that would be easily recognized by those skilled in the art within the technical scope of the present disclosure are intended to be covered by the present invention. Accordingly, the scope of the invention should be assessed as that of the appended claims.
Claims (9)
1. The preparation method of the dihydrobenzofuran spiro-pyrrolidone is characterized in that 3-methylbenzofuran-2-formic acid derivative shown in a formula (1) is used as a raw material, under the catalysis of a palladium catalyst, the 3-methylbenzofuran-2-formic acid derivative reacts in an organic solvent for 18-36 hours at a temperature of 100-140 ℃ under the combined action of alkali and a ligand, and after the reaction is finished, the dihydrobenzofuran spiro-pyrrolidone shown in the formula (2) is obtained through post-treatment, wherein the reaction formula is as follows:
wherein: r is R 1 Any one selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy and halogen; r is R 2 Any one selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl and halogen; r is R 3 Is a hydrogen atom or a C1-C4 alkyl group; x is a bromine atom or an iodine atom.
2. A process for the preparation of dihydrobenzofuran spiro-pyrrolidone according to claim 1, wherein R is 1 Any one selected from methyl, methoxy and chlorine atoms; r is R 2 Any one selected from methyl, methoxy, trifluoromethyl, fluorine atom and chlorine atom; r is R 3 Is a hydrogen atom or a methyl group.
3. The preparation method of the dihydrobenzofuran spiro-pyrrolidone according to claim 1, wherein the palladium catalyst is selected from any one of palladium acetate and palladium chloride.
4. The preparation method of the dihydrobenzofuran spiro-pyrrolidone according to claim 1, wherein the organic solvent is selected from any one of N, N-dimethylformamide, toluene, tetrahydrofuran and dimethyl sulfoxide, the volume ratio of the organic solvent to the 3-methylbenzofuran-2-carboxylic acid derivative is 5-20:1, preferably 10:1, the volume unit is milliliter, and the volume unit is millimole.
5. A process for the preparation of dihydrobenzofuran spiro-pyrrolidone according to claim 1,it is characterized in that the ligand is selected from triphenylphosphine, tetra-fluoroboric acid tri-tert-butyl phosphine, 1, 2-bis (diphenyl phosphine) ethane, 2 '-bis (diphenyl phosphine) -1,1' -binaphthyl, and the likerac) -any one of MonoPhos.
6. The preparation method of the dihydrobenzofuran spiro-pyrrolidone according to claim 1, wherein the base is any one selected from potassium carbonate, sodium carbonate, lithium carbonate, sodium acetate and sodium phosphate.
7. The preparation method of the dihydrobenzofuran spiro-pyrrolidone according to claim 1, wherein the molar ratio of the 3-methylbenzofuran-2-carboxylic acid derivative, the palladium catalyst, the ligand and the base is 1:0.03-0.08:0.1-0.15:2-4, preferably 1:0.05:0.12:3.
8. The process for preparing a 3-methylbenzofuran-2-carboxylic acid derivative compound according to claim 1, wherein the reaction temperature is 110-130 ℃, preferably 120 ℃, and the reaction time is 20-28 hours, preferably 24 hours.
9. The method for preparing dihydrobenzofuran spiro-pyrrolidone according to claim 1, wherein the post-treatment step comprises: after the reaction is finished, diluting a reaction system with water and ethyl acetate, extracting an aqueous phase by using ethyl acetate, treating the combined organic phases by using saline, separating liquid to obtain an organic phase, drying by using anhydrous sodium sulfate, filtering, removing a solvent from filtrate by rotary evaporation, and separating by column chromatography to obtain a target product, wherein a mobile phase of the column chromatography is a petroleum ether and ethyl acetate mixture with the volume ratio of 30-10:1; or after the reaction is finished, the solvent is directly removed by rotary evaporation of the system, and then the target product is obtained by column chromatography separation, wherein the mobile phase of the column chromatography is a petroleum ether and ethyl acetate mixture with the volume ratio of 30-10:1.
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| ZHI ZHAO: "Ligand-Controlled Regiodivergent Asymmetric [5 + 2] and [3 + 2]Annulations of Vinyl Indoloxazolidones Catalyzed by Palladium", 《ORG. LETT.》, vol. 23, pages 4791 - 4795 * |
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