CN112778261B - Method for synthesizing isocoumarin derivatives under catalysis of silver and application of isocoumarin derivatives - Google Patents
Method for synthesizing isocoumarin derivatives under catalysis of silver and application of isocoumarin derivatives Download PDFInfo
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- CN112778261B CN112778261B CN202110126945.8A CN202110126945A CN112778261B CN 112778261 B CN112778261 B CN 112778261B CN 202110126945 A CN202110126945 A CN 202110126945A CN 112778261 B CN112778261 B CN 112778261B
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- isocoumarin
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- phenylethynyl
- benzaldehyde
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- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000006555 catalytic reaction Methods 0.000 title claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 12
- 125000003151 isocoumarinyl group Chemical class C1(=O)OC(=CC2=CC=CC=C12)* 0.000 title claims abstract description 10
- 229910052709 silver Inorganic materials 0.000 title claims abstract description 9
- 239000004332 silver Substances 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- 239000000758 substrate Substances 0.000 claims abstract description 19
- SDSQNHMKRHPAIM-UHFFFAOYSA-N 2-(2-phenylethynyl)benzaldehyde Chemical compound O=CC1=CC=CC=C1C#CC1=CC=CC=C1 SDSQNHMKRHPAIM-UHFFFAOYSA-N 0.000 claims abstract description 15
- 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 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 27
- -1 silver tetrafluoroborate Chemical group 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 17
- 239000012074 organic phase Substances 0.000 claims description 14
- 238000000605 extraction Methods 0.000 claims description 13
- 239000003208 petroleum Substances 0.000 claims description 12
- 238000010898 silica gel chromatography Methods 0.000 claims description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 10
- 239000003480 eluent Substances 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- 229910001494 silver tetrafluoroborate Inorganic materials 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 2
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 150000002512 isocoumarins Chemical class 0.000 description 21
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 230000008034 disappearance Effects 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 8
- 125000003107 substituted aryl group Chemical group 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical compound ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 0.000 description 3
- 241001092080 Hydrangea Species 0.000 description 3
- 235000014486 Hydrangea macrophylla Nutrition 0.000 description 3
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- IQZZFVDIZRWADY-UHFFFAOYSA-N isocoumarin Chemical compound C1=CC=C2C(=O)OC=CC2=C1 IQZZFVDIZRWADY-UHFFFAOYSA-N 0.000 description 3
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- 101710134784 Agnoprotein Proteins 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 150000004982 aromatic amines Chemical class 0.000 description 2
- 150000008378 aryl ethers Chemical class 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 229910001961 silver nitrate Inorganic materials 0.000 description 2
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 1
- 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 description 1
- IJPBPBZPJIUTFD-UHFFFAOYSA-N 2-(2-phenylethynyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C#CC1=CC=CC=C1 IJPBPBZPJIUTFD-UHFFFAOYSA-N 0.000 description 1
- WBXZJUGIVVHLBD-UHFFFAOYSA-N 2-[2-(4-methylphenyl)ethynyl]benzaldehyde Chemical compound C1=CC(C)=CC=C1C#CC1=CC=CC=C1C=O WBXZJUGIVVHLBD-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- CVVZKIZTBMTKLW-UHFFFAOYSA-N 5-fluoro-2-(2-phenylethynyl)benzaldehyde Chemical compound O=CC1=CC(F)=CC=C1C#CC1=CC=CC=C1 CVVZKIZTBMTKLW-UHFFFAOYSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- PNLPQMXCGDQQAK-UHFFFAOYSA-N CC(C=C1)=CC(C=O)=C1C#CC1=CC=CC=C1 Chemical compound CC(C=C1)=CC(C=O)=C1C#CC1=CC=CC=C1 PNLPQMXCGDQQAK-UHFFFAOYSA-N 0.000 description 1
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
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- 230000000767 anti-ulcer Effects 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
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- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- CQXDYNJSSOSLAH-UHFFFAOYSA-N pyrano[4,3-b]quinolin-1-one Chemical compound C1=CC=C2C=C3C(=O)OC=CC3=NC2=C1 CQXDYNJSSOSLAH-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a method for synthesizing isocoumarin derivatives under the catalysis of silver and application of the method. The method comprises the following steps: 2- (phenylethynyl) benzaldehyde is used as a model substrate, monovalent silver salt is used as a catalyst, and the reaction is carried out at the temperature of not less than 30 ℃ to generate the isocoumarin derivative. The isocoumarin derivative is prepared by the one-step method under the catalysis of monovalent silver salt by taking 2- (phenylethynyl) benzaldehyde as a model substrate for the first time in the field. The method is simple, convenient and efficient, the used raw materials are simple and easy to obtain, and the method is nontoxic, has few steps, mild conditions and low cost, and is suitable for large-scale industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a method for synthesizing isocoumarin derivatives under the catalysis of silver and application of the method.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Derivatives of isocoumarin are valuable synthetic intermediates in organic synthesis, and are characteristic of many natural products and drugs. In 2012, study of yili et al found that isocoumarin has a certain therapeutic effect on mice with senile dementia; the study of the royal bin and the like in 2012 finds that two isocoumarin compounds, namely, hydrangea and hydrangea-4' -O-beta-D-glucoside, are extracted from hydrangea, and reports that the two isocoumarin compounds have the functions of reducing blood sugar and protecting liver; the Japanese scholars Joji in 1994 find that isocoumarin compounds in hydrangea have biological activities such as antiulcer and antiallergic activities. Generally, the active ingredients of bioactive isocoumarin derivatives extracted from natural products are often low, and in order to enhance the bioactivity of the obtained compounds, the structure of the compounds needs to be optimized and modified, and various synthetic methods are established mainly by means of transition metal catalysis to obtain the heterocyclic compounds. Pi-electrophilic transition metal catalyst mediated intramolecular cyclization of alkynyl-substituted carboxylic acids or esters is one of the common strategies for the construction of isocoumarin derivatives, and in general such schemes rely on the activation of a propargyl C ≡ C bond-electrophilic transition metal catalyst by coordination of pi, which can initiate 6-endoheterocyclic reactions and generate structurally diverse six-membered heterocyclic compounds. Another approach to isocoumarin scaffolds is to spontaneously form carbon-metal bonds and heterocyclic backbones through metal salt-mediated cyclization, and generate organometallic intermediates via appropriate synthetic reactions (e.g., cross-coupling and α -arylation) to yield the target heterocycles. These strategies allow various five-and six-membered heterocycles to be obtained directly from relatively simple organic substrates.
The o-alkynylbenzaldehyde forms a multifaceted and easily available building block and is suitable for building compounds of various heterocyclic compounds, and the synthesis of the heterocyclic o-alkynylbenzaldehyde provides a convenient way for synthesizing the substituted isocoumarin; however, to date, only a few relevant synthetic schemes have been disclosed. Notably, Youn and colleagues reported the pioneering work of NHC catalyzed oxidation of the intramolecular heterocycles of ortho-alkynyl benzaldehydes to generate five and six membered heterocyclic scaffolds. Unfortunately, this scheme provides the corresponding product with low selectivity, which is highly dependent on the nature of the substituents in the starting ortho-alkynylbenzaldehyde. Subsequently, the Singh and Ghorai project groups expand the substrate range of the o-alkynyl pyridine aldehyde heterocyclic ring, and realize the selective formation of pyrano [4, 3-b ] quinolinone. With respect to the structure-related ortho-alkynylbenzaldehydes, only one example of the heterocyclic ring thereof has been realized so far.
During the research process, the inventor finds that the following problems exist in the methods for synthesizing the isocoumarin derivatives: 1. the catalyst is expensive and the synthesis cost is high; 2. no ready-made substrate exists, further synthesis is needed, and the steps are complicated; 3. the regioselectivity is poor; 4. the reaction yield is not high, and a large amount of byproducts exist, so that the purification is influenced.
Disclosure of Invention
In order to solve the defects of the prior art, the invention provides a method for synthesizing isocoumarin derivatives under the catalysis of silver and application thereof.
In order to achieve the above objects, the first aspect of the present invention provides a method for synthesizing isocoumarin derivatives under the catalysis of silver, wherein 2- (phenylethynyl) benzaldehyde is used as a model substrate, monovalent silver salt is used as a catalyst, and the reaction is carried out at a temperature of not lower than 30 ℃ to generate the isocoumarin derivatives, which have the structural formula:
wherein the chemical formula of the 2- (phenylethynyl) benzaldehyde is
Wherein R is selected from the group consisting of hydrogen, aryl, electron donating or electron withdrawing substituted aryl, electron donating or electron withdrawing heteroaryl, C 4 -C 8 Straight-chain or branched alkyl, R 1 Is selected from C 1 -C 5 Linear alkyl or alkoxy, aryl, substituted aryl, heterocyclic radical, substituted heterocyclic radical, aromatic heterocyclic radical, substituted aromatic heterocyclic radical, aromatic amine, aliphatic amine and aromatic ether;
the reaction formula is as follows:
the monovalent silver salt is AgBF 4 、AgNO 3 、Ag 2 CO 3 And AgOTf. The solvent is CH 3 CN, DMF, toluene, DCE and DMA.
The second aspect of the invention provides the application of the method in the preparation of a medical health-care medicament.
One or more embodiments of the present invention have at least the following advantageous effects:
the invention provides a method for synthesizing isocoumarin derivatives under the catalysis of silver, which takes 2- (phenylethynyl) benzaldehyde as a model substrate for the first time and prepares the isocoumarin derivatives in one step under the catalysis of monovalent silver salt. The method is simple, convenient and efficient, the used raw materials are simple, easy to obtain, non-toxic, few in steps, mild in conditions and low in cost, and the method is suitable for large-scale industrial production.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
FIG. 1 is a drawing of Compound 2a prepared in example 2 of the present invention 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 2 is a photograph of Compound 2a prepared in example 2 of the present invention 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 3 is a drawing of Compound 2b, prepared according to example 5 of the invention 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 4 is a drawing of Compound 2b, prepared according to example 5 of the invention 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 5 is a photograph of Compound 2c, prepared according to example 6 of the present invention 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 6 is a drawing of Compound 2c, prepared according to example 6 of the invention 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 7 is a drawing of Compound 2d, prepared according to example 7 of the invention 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 8 is a photograph of Compound 2d, prepared according to example 7 of the present invention 13 Nuclear magnetic resonance spectrum of C-NMR.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
As introduced by the background art, the method for synthesizing isocoumarin derivatives in the prior art has the problems of difficult acquisition of substrates, harsh reaction conditions, toxic byproducts, high synthesis cost and the like, and in order to solve the technical problems, the invention provides a method for synthesizing isocoumarin derivatives under the catalysis of silver in a first aspect, 2- (phenylethynyl) benzaldehyde is used as a model substrate, monovalent silver salt is used as a catalyst, and the reaction is carried out at a temperature of not lower than 30 ℃ to generate the isocoumarin derivatives, wherein the structural formula of the method is as follows:
wherein the chemical formula of the 2- (phenylethynyl) benzaldehyde is
R is selected from hydrogen, aryl, substituted aryl for electron donating or electron withdrawing, heteroaryl for electron donating or electron withdrawing, C 4 -C 8 Straight or branched alkyl, R 1 Is selected from C 1 -C 5 Linear alkyl or alkoxy, aryl, substituted aryl, heterocyclic radical, substituted heterocyclic radical, aromatic heterocyclic radical, substituted aromatic heterocyclic radical, aromatic amine, aliphatic amine and aromatic ether;
the reaction formula is as follows:
in one or more embodiments of the invention, the monovalent silver salt is AgBF 4 、AgNO 3 、Ag 2 CO 3 Or AgOTf;
preferably, the monovalent silver salt is silver tetrafluoroborate or silver nitrate;
further preferably, the monovalent silver salt is silver tetrafluoroborate.
The catalyst can improve the conversion rate of raw materials and the yield of products, and can further improve the yield of isocoumarin derivatives when the monovalent silver salt is silver tetrafluoroborate.
In one or more embodiments of the present invention, R is selected from hydrogen, 4-fluorophenyl, or 4-methylphenyl;
R 1 is selected from C 1 -C 5 Linear alkyl or alkoxy, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, preferably aryl or substituted aryl.
In one or more embodiments of the invention, the aryl is phenyl and the electron donating or electron withdrawing substituted aryl is substituted with halogen, C 1 -C 6 Straight-chain alkyl, C 1 -C 6 Branched alkyl, C 1 -C 2 Straight-chain alkoxy or C 1 -C 2 Phenyl substituted with a branched alkoxy group, said heteroaryl group containing one or more heteroatoms selected from N, O, S.
In one or more embodiments of the present invention, the electron donating or electron withdrawing substituted aryl group is phenyl substituted with F, Cl, Br, methyl, ethyl, n-propyl, t-butyl, n-pentyl, methoxy, ethoxy, and the like;
in one or more embodiments of the invention, the reaction temperature is 30-60 ℃, and the temperature can improve the conversion rate of the raw materials and the yield of the product.
Preferably, the reaction temperature is 40 ± 8 ℃, which can further improve the conversion rate of the raw material and the yield of the product.
In one or more embodiments of the present invention, the raw material is added to a solvent to be dissolved, and then a catalyst is added thereto and heated to perform a reaction. The solvent can improve the conversion rate of raw materials and simultaneously improve the yield of products.
The solvent is selected from CH 3 CN, DMF, toluene, DCE, DMA.
Preferably, the solvent is N, N-Dimethylformamide (DMF) or toluene.
Further preferably, the solvent is toluene.
In one or more embodiments of the invention, the molar ratio of 2- (phenylethynyl) benzaldehyde to monovalent silver salt is 10: 1.
In one or more embodiments of the present invention, the reaction time is 0 to 10 hours, and the reaction time is not 0.
Preferably, the reaction time is 6. + -. 0.5 h.
In one or more embodiments of the present invention, the reacted solution is added to an extraction solvent to extract to obtain an organic phase, the solvent in the organic phase is removed, and silica gel column chromatography is performed to obtain the isocoumarin derivative.
The extraction solvent adopted by the extraction is one or more of 1, 2-dichloroethane, toluene, nitromethane, ethyl acetate, diethyl ether, n-hexane, cyclohexane, petroleum ether or dichloromethane;
the extraction solvent adopted by the extraction is dichloromethane;
the extraction is carried out for 1-3 times, and 5-20 mL of extraction solvent is used each time;
the organic phase obtained is dried over anhydrous magnesium sulfate and the organic solvent is removed.
The eluent of the silica gel column chromatography is petroleum ether and ethyl acetate;
the volume ratio of the petroleum ether to the ethyl acetate is 1-50: 1-3, and preferably 20: 1.
The second aspect of the invention provides the application of the method in preparing a medical health-care medicament.
In order to make the technical solutions of the present invention more clearly understood by those skilled in the art, the technical solutions of the present invention will be described in detail below with reference to specific embodiments.
Example 1
Compound 1a, i.e., 2- (phenylethynyl) benzaldehyde (0.0560mg,0.5mmol), was added to 2mL of DMF, dissolved at 40 ℃ and silver tetrafluoroborate (0.0097g, 0.05mmol) was added to the system and the mixture was stirred with heating for 6 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL of water, extracting with dichloromethane (3X 10mL), combining organic phases, drying over anhydrous magnesium sulfate, filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and passing through silica gelColumn chromatography (eluent is V) Petroleum ether :V Acetic acid ethyl ester 100:5) gave compound 2a in 75% yield.
Example 2
Compound 1a, i.e., 2- (phenylethynyl) benzaldehyde (0.0560mg,0.5mmol), was added to 2mL of toluene, dissolved at 40 ℃ and then silver tetrafluoroborate (0.0097g, 0.05mmol) was added to the system and the mixture was stirred with heating for 6 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL of water, extracting with dichloromethane (3X 10mL), mixing organic phases, drying with anhydrous magnesium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Acetic acid ethyl ester 100:5) gave compound 2a in 88% yield.
Example 3
Compound 1a, i.e., 2- (phenylethynyl) benzaldehyde (0.0560mg,0.5mmol), was added to 2mL of toluene, dissolved at 40 deg.C, followed by addition of silver nitrate (0.0085g, 0.05mmol) to the system and stirring with heating continued for 6 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL water, extracting with dichloromethane (3X 10mL), mixing organic phases, drying with anhydrous magnesium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and subjecting to silica gel column chromatography (eluent V) Petroleum ether :V Ethyl acetate 100:5) gave compound 2a in 60% yield.
Example 4
Compound 1a, i.e., 2- (phenylethynyl) benzaldehyde (0.0560mg,0.5mmol) was added to 2mL of toluene, and dissolved at 40 ℃ followed by addition of silver carbonate (0.0140g, 0.05mmol) to the system and further stirring with heating for 6 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL of water, extracting with dichloromethane (3X 10mL), mixing organic phases, drying with anhydrous magnesium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Ethyl acetate 100:5) gave compound 2a in 78% yield.
The reactions of examples 1 to 4 are shown below:
compound 1 a:
1 H NMR(400MHz,CDCl 3 ) As shown in fig. 1,. delta.6.97 (s,1H, CH), 7.43-7.53 (m,5H, ArH), 7.71-7.75 (m,1H, ArH), 7.88-7.91 (m,2H, ArH),8.32(d, J ═ 8.0Hz,1H, ArH), 13 C-NMR(CDCl 3 100MHz), as shown in fig. 2, δ 76.7,101.8,120.6,125.3,126.0,128.2,128.9,129.7,130.0,132.0,134.9,137.5,153.7,162.4; HRMS (ESI) m/z calculated for C 15 H 11 O 2 [M+H] + :223.0754,found 223.0760.
Example 5
Compound 1b, 5-fluoro-2- (phenylethynyl) benzaldehyde (0.0540mg,0.5mmol), was added to 2mL of toluene, dissolved at 40 deg.C, and then silver tetrafluoroborate (0.0097g, 0.05mmol) was added to the system, and the mixture was stirred with heating for 6 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL of water, extracting with dichloromethane (3X 10mL), mixing organic phases, drying with anhydrous magnesium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Acetic acid ethyl ester 100:5) gave compound 2b in 71% yield.
1 H NMR(400MHz,CDCl 3 ) δ 6.91(s,1H, CH), 7.13-7.21 (m,2H, ArH), 7.45-7.50 (m,3H, ArH), 7.87-7.89 (m,2H, ArH),8.33(dd, J ═ 8.8Hz, J ═ 5.6Hz,1H, ArH) as shown in fig. 3; 13 C-NMR(100MHz,CDCl 3 ) Delta 94.3(d, J) as shown in FIG. 4 F-C ＝4.8Hz),120.2(d,J F-C ＝19.8Hz),121.9(d,J F-C ＝4.0Hz),125.3,125.4,126.7(d,J F-C ＝16.7Hz),128.4(d,J F-C ＝7.6Hz),128.9,130.3,131.7,154.3；HRMS(ESI)m/z calculated for C 15 H 10 FO 2 [M+H] + :241.0659,found 241.0663.
Example 6
Compound 1c, 5-methyl-2- (phenylethynyl) benzaldehyde (0.0550mg,0.5mmol), was added to 2mL of toluene, dissolved at 40 deg.C, and silver tetrafluoroborate (0.0097g, 0.05mmol) was added to the system and the mixture was stirred with heating for 6 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL of water, extracting with dichloromethane (3X 10mL), mixing organic phases, drying with anhydrous magnesium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Ethyl acetate 100:5) gave compound 2c in 78% yield.
The reaction is shown as follows:
compound 2 c:
1 H NMR(400MHz,CDCl 3 ) Δ 2.42(s,3H, CH) as shown in FIG. 5 3 ),6.87(s,1H,CH),7.35(d,J＝8.0Hz,1H,ArH),7.38–7.44(m,3H,ArH),7.48(dd,J＝8.0Hz,J’＝2.0Hz,1H,ArH),7.80–7.83(m,2H,ArH),8.06(s,1H,ArH)； 13 C-NMR(CDCl 3 100MHz), as shown in fig. 6, δ 21.4,101.8,120.4,125.1,125.9,128.8,129.4,129.8,132.1,135.1,136.2,138.5,152.8,162.5; HRMS (ESI) m/z calculated for C 16 H 13 O 2 [M+H] + :237.0910,found 237.0905
Example 7
Compound 1d, i.e., 2- (p-methylphenylethynyl) benzaldehyde (0.0590mL,0.5mmol), was added to 2mL of toluene, dissolved at 40 ℃ and silver tetrafluoroborate (0.0097g, 0.05mmol) was added to the system and the mixture was stirred with heating for 6 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction liquidThen, the mixture was poured into 30mL of water, extracted with dichloromethane (3X 10mL), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered under suction, and then the organic solvent was distilled off under reduced pressure to give a viscous liquid, which was subjected to silica gel column chromatography (eluent V) Petroleum ether :V Ethyl acetate 100:5) gave compound 2d in 81% yield.
The reaction is shown as follows:
1 H NMR(400MHz,CDCl 3 ) Delta.2.39 (s,3H, CH) as shown in FIG. 7 3 ),6.89(s,1H,CH),7.24–7.26(m,2H,ArH),7.44–7.48(m,2H,ArH),7.67–7.71(m,1H,ArH),7.75–7.77(m,2H,ArH),8.28(d,J＝8.0Hz,1H,ArH)； 13 C-NMR(100MHz,CDCl 3 ) As shown in fig. 8, δ 17.1,101.1,120.4,125.2,125.8,127.9,129.2,129.5,129.6,134.8,137.7,140.3,153.8,162.4; HRMS (ESI) M/z calculated for C16H13O2[ M + H [)]+:237.0910,found 237.0911.
Comparative example
Compound 1e, 2- (phenylethynyl) benzoic acid (0.0650mg,0.5mmol) was added to 2mL of toluene, dissolved at 40 deg.C, and silver tetrafluoroborate (0.0097g, 0.05mmol) was added to the system and the mixture was stirred with heating for 6 hours. TLC detects the disappearance of the substrate and the reaction is finished. Cooling the reaction solution, pouring into 30mL of water, extracting with dichloromethane (3X 10mL), mixing organic phases, drying with anhydrous magnesium sulfate, vacuum filtering, distilling under reduced pressure to remove organic solvent to obtain viscous liquid, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Ethyl acetate 100:5) gave compound 2e in 29% yield.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (4)
1. A method for synthesizing isocoumarin derivatives under the catalysis of silver is characterized by comprising the following steps: taking 2- (phenylethynyl) benzaldehyde as a model substrate, taking monovalent silver salt as a catalyst, firstly adding the model substrate into a solvent for dissolving, then adding the catalyst, and reacting at a temperature of not less than 30 ℃ to generate the isocoumarin derivative, wherein the structural formula of the isocoumarin derivative is as follows:
wherein the monovalent silver salt is silver tetrafluoroborate, and the solvent is toluene; the chemical formula of the 2- (phenylethynyl) benzaldehyde is,
r is H and R 1 Ph; r is F and R 1 Ph is obtained; r is CH 3 And R is 1 Ph is obtained; r is H and R 1 Is p-methylphenyl.
2. The method of claim 1, wherein: the temperature of the reaction was 40. + -. 8 ℃.
3. The method of claim 1, wherein: the molar ratio of 2- (phenylethynyl) benzaldehyde to monovalent silver salt is 10: 1; the reaction time is 6 +/-0.5 h.
4. The method of claim 1, wherein: adding an extraction solvent into the reacted solution for extraction to obtain an organic phase, removing the solvent in the organic phase, and performing silica gel column chromatography to obtain an isocoumarin derivative; the extraction solvent adopted by the extraction is dichloromethane, the extraction is carried out for 1-3 times, and 5-20 mL of the extraction solvent is used each time; drying the obtained organic phase by adopting anhydrous magnesium sulfate, and then removing the organic solvent; the eluent of the silica gel column chromatography is petroleum ether and ethyl acetate with the volume ratio of 20: 1.
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