CN116283868A - Synthesis method of spiro [ benzofuran-cyclohexene ] compound - Google Patents
Synthesis method of spiro [ benzofuran-cyclohexene ] compound Download PDFInfo
- Publication number
- CN116283868A CN116283868A CN202310054770.3A CN202310054770A CN116283868A CN 116283868 A CN116283868 A CN 116283868A CN 202310054770 A CN202310054770 A CN 202310054770A CN 116283868 A CN116283868 A CN 116283868A
- Authority
- CN
- China
- Prior art keywords
- reaction
- benzofuran
- spiro
- cyclohexene
- equiv
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 23
- 125000003003 spiro group Chemical group 0.000 title claims abstract description 20
- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 83
- 239000003054 catalyst Substances 0.000 claims abstract description 33
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims abstract description 25
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 14
- JKJWYKGYGWOAHT-UHFFFAOYSA-N bis(prop-2-enyl) carbonate Chemical compound C=CCOC(=O)OCC=C JKJWYKGYGWOAHT-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 72
- -1 5-fluorophenyl Chemical group 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 25
- 239000007810 chemical reaction solvent Substances 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 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
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 claims 1
- 230000009471 action Effects 0.000 abstract description 3
- 239000002253 acid Substances 0.000 abstract description 2
- 239000003513 alkali Substances 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- 230000009467 reduction Effects 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 229910052723 transition metal Inorganic materials 0.000 abstract description 2
- 150000003624 transition metals Chemical class 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- 238000004440 column chromatography Methods 0.000 description 23
- 239000003480 eluent Substances 0.000 description 21
- 239000003208 petroleum Substances 0.000 description 21
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 2
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 2
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 2
- 150000001555 benzenes Chemical group 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 2
- 229960002867 griseofulvin Drugs 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- VCQONKRSTAUGEP-UHFFFAOYSA-N 1-benzofuran-4-carbonitrile Chemical compound N#CC1=CC=CC2=C1C=CO2 VCQONKRSTAUGEP-UHFFFAOYSA-N 0.000 description 1
- RNEOFIVNTNLSEH-UHFFFAOYSA-N 2-bromo-1-benzofuran Chemical compound C1=CC=C2OC(Br)=CC2=C1 RNEOFIVNTNLSEH-UHFFFAOYSA-N 0.000 description 1
- GDRNNORFRGCNGA-UHFFFAOYSA-N 2-chloro-1-benzofuran Chemical compound C1=CC=C2OC(Cl)=CC2=C1 GDRNNORFRGCNGA-UHFFFAOYSA-N 0.000 description 1
- LODIRNHHOYPTKA-UHFFFAOYSA-N 2-fluoro-1-benzofuran Chemical compound C1=CC=C2OC(F)=CC2=C1 LODIRNHHOYPTKA-UHFFFAOYSA-N 0.000 description 1
- DNWQESYPNMYPBK-UHFFFAOYSA-N 2-methoxy-1-benzofuran Chemical compound C1=CC=C2OC(OC)=CC2=C1 DNWQESYPNMYPBK-UHFFFAOYSA-N 0.000 description 1
- JGYWACJSZBPNJH-UHFFFAOYSA-N 3-fluoro-1-benzofuran Chemical compound C1=CC=C2C(F)=COC2=C1 JGYWACJSZBPNJH-UHFFFAOYSA-N 0.000 description 1
- ZRXHLJNBNWVNIM-UHFFFAOYSA-N 3-methyl-1-benzofuran Chemical compound C1=CC=C2C(C)=COC2=C1 ZRXHLJNBNWVNIM-UHFFFAOYSA-N 0.000 description 1
- VLACSJKCZFFVQE-UHFFFAOYSA-N 4-(trifluoromethyl)-1-benzofuran Chemical compound FC(F)(F)C1=CC=CC2=C1C=CO2 VLACSJKCZFFVQE-UHFFFAOYSA-N 0.000 description 1
- YFKGZOJEQUDHAD-UHFFFAOYSA-N 4-bromo-1-benzofuran Chemical compound BrC1=CC=CC2=C1C=CO2 YFKGZOJEQUDHAD-UHFFFAOYSA-N 0.000 description 1
- UNIRGDBCGVDPQU-UHFFFAOYSA-N 4-chloro-1-benzofuran Chemical compound ClC1=CC=CC2=C1C=CO2 UNIRGDBCGVDPQU-UHFFFAOYSA-N 0.000 description 1
- NZUXZSQNFHYMCH-UHFFFAOYSA-N 4-fluoro-1-benzofuran Chemical compound FC1=CC=CC2=C1C=CO2 NZUXZSQNFHYMCH-UHFFFAOYSA-N 0.000 description 1
- NWCMFNIMUUMBGZ-UHFFFAOYSA-N 4-methoxy-1-benzofuran Chemical compound COC1=CC=CC2=C1C=CO2 NWCMFNIMUUMBGZ-UHFFFAOYSA-N 0.000 description 1
- WLHCBQAPPJAULW-UHFFFAOYSA-N 4-methylbenzenethiol Chemical compound CC1=CC=C(S)C=C1 WLHCBQAPPJAULW-UHFFFAOYSA-N 0.000 description 1
- HOPJVUYLPKTWEF-UHFFFAOYSA-N 4-nitro-1-benzofuran Chemical compound [O-][N+](=O)C1=CC=CC2=C1C=CO2 HOPJVUYLPKTWEF-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000007163 Dermatomycoses Diseases 0.000 description 1
- DATNQPSGIFVQCG-UHFFFAOYSA-N Filifolinol Natural products CC1CCC(O)C(C)(C)C12Cc3cc(ccc3O2)C(=O)C DATNQPSGIFVQCG-UHFFFAOYSA-N 0.000 description 1
- 241000788461 Heliotropium filifolium Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000228143 Penicillium Species 0.000 description 1
- 240000007164 Salvia officinalis Species 0.000 description 1
- 235000002912 Salvia officinalis Nutrition 0.000 description 1
- 208000002474 Tinea Diseases 0.000 description 1
- 241000893966 Trichophyton verrucosum Species 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- BGEVVKDFAMDZGO-BKGUAONASA-N methyl (2r,3'r,6's)-3'-hydroxy-2',2',6'-trimethylspiro[3h-1-benzofuran-2,1'-cyclohexane]-5-carboxylate Chemical compound C1C2=CC(C(=O)OC)=CC=C2O[C@]21[C@@H](C)CC[C@@H](O)C2(C)C BGEVVKDFAMDZGO-BKGUAONASA-N 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000002020 sage Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a synthesis method of spiro [ benzofuran-cyclohexene ] compounds, which takes benzofuran azadiene and allyl carbonate as reaction raw materials, and the spiro [ benzofuran-cyclohexene ] compounds are obtained through reaction under the action of an organic phosphine catalyst. The invention has the advantages that: the reaction is efficient, the yield is high, the organic phosphine catalyst is cheap and easy to obtain and stable, and no pungent smell exists; strong acid or strong alkali and an additional oxidation or reduction agent are not needed to be added in the reaction, so that the conditions are mild; the transition metal is not required to be used as a catalyst in the reaction, so that the method is economical, practical and environment-friendly; the reaction substrate is easy to prepare; the reaction efficiency is high after the reaction is amplified, and the method has practical value.
Description
Technical Field
The invention belongs to the technical field of organic compound technology application, and in particular relates to a spiro [ benzofuran-cyclohexene ] compound and a high-efficiency convenient synthesis method thereof.
Background
The benzofuran spiro six-membered ring skeleton has a special structure, and the core skeleton of the benzofuran spiro six-membered ring skeleton is widely existing in compounds and medicines in the nature. For example, griseofulvin originally isolated from penicillium griseofulvin by oxford and his colleagues is an fda approved antifungal for the treatment of dermatophyte infections caused by different spore and ringworm bacteria. Filifolinol is a pharmacophore with this core backbone structure isolated from natural product Heliotropium filifolium, which has been demonstrated to have antiviral activity. Spirodesertol A is a compound extracted from the rhizome of Salvia officinalis, and cisplatin is used as positive control, which shows potent cytotoxicity to A-549, SMMC-7721 and MCF-7 cancer cell lines. In addition, various natural compounds containing benzofurans spiro six-membered ring skeletons have been found to have significant and novel biological activities.
Medicine and active molecule containing benzofuran spiro six-membered ring skeleton
The development of simple synthetic strategies for such frameworks has been a very interesting topic for the organic synthesis community, however few catalytic methods for synthesizing such frameworks have been reported, which are still highly challenging, and the aim of the present invention is to devise a simple and practical catalytic method for constructing such frameworks. Organophosphine catalysis is a very excellent catalyst in cyclization reactions and is often used as a high-efficiency catalyst for cyclization reactions. Therefore, the invention splits the parent nucleus structure into benzofuran azadiene and allyl carbonate, and constructs the parent nucleus structure through phosphine catalysis.
Disclosure of Invention
The invention innovatively realizes a method for efficiently constructing the benzofuran spiro six-membered ring skeleton. The inventor discovers that the benzofuranazadiene is a unique compound containing a benzofurane skeleton, and has the characteristics of stability, easiness in preparation and the like. In view of this, the present invention devised a reaction process for preparing spiro [ benzofuran-cyclohexene ] compounds by reacting a benzofuran azadiene with an allyl carbonate.
The synthesis method of the spiro [ benzofuran-cyclohexene ] compound provided by the invention takes benzofuran azadiene and allyl carbonate as reaction raw materials under the catalysis of an organic phosphine catalyst, and the corresponding conversion is effectively realized in a reaction solvent, so that the spiro [ benzofuran-cyclohexene ] compound shown in the formula (III) is prepared. Wherein the reaction process is represented by the following reaction formula (a):
in the above reaction formula, R 1 Is hydrogen or halogen atom substituted; r is R 2 Is benzene ring, naphthalene ring, substituted benzene ring; r is R 3 Is an alkyl or aryl-containing alkane.
Preferably, R 1 Is hydrogen, 5-fluorophenyl, 5-bromophenyl; r is R 2 Phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methoxyphenyl, 2-naphthyl, 3-fluorophenyl, 3-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-nitrophenyl; r is R 3 Is tert-butyl, isopropyl, cyclohexyl.
As shown in the reaction formula (a), the benzofuran azadiene shown in the formula (I) and allyl carbonate are used as reaction raw materials, and react in a reaction solvent under the action of an organic phosphine catalyst to obtain the spiro [ benzofuran-cyclohexene ] compound shown in the formula (III).
In the invention, the dosage ratio of the benzofuranazadiene shown in the formula (I) as the starting raw material to the allyl carbonate shown in the formula (II) is 1:1-1:2. Preferably, the dosage ratio of the two is 1:1.5.
In the invention, the solvent is any one or any combination of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetonitrile and toluene. Preferably, the solvent is acetonitrile.
The reaction temperature is 20-30 ℃;
the catalyst is PhEt 2 P、Ph 3 P、(4-FC 6 H 4 ) 3 P、(4-MeC 6 H 4 ) 3 P、Ph 2 CyP、Ph 2 MeP、Ph 2 EtP、PhMe 2 P、PhCy 2 P、Bu 3 P。
The synthesis reaction of the invention comprises the following steps:
the reaction of equation (a) comprises the steps of: adding benzofuran azadiene, allyl carbonate and acetonitrile into a reaction vessel, and stirring and reacting at 25 ℃ to obtain the spiro [ benzofuran-cyclohexene ] compound shown in the formula (III).
In one embodiment, as in equation (a), the synthesis of the present invention is carried out by adding benzofuran azadiene (X mmol), allyl carbonate (Y mmol), solvent (V mL) to reaction flask A and stirring the reaction system at 25deg.C for 12 hours. After the reaction is finished, the reaction system is cooled to room temperature, concentrated and separated by column chromatography to obtain the target product.
The invention also provides the spiro [ benzofuran-cyclohexene ] compound shown in the formula (III) prepared by the synthesis method,
wherein R is 1 Is hydrogen or halogen atom substituted; r is R 2 Is benzene ring, condensed ring, heterocycle, substituted benzene ring; r is R 3 Is an alkyl or aryl-containing alkane;
the invention also provides an application method of the spiro [ benzofuran-cyclohexene ] compound shown in the formula (III) in synthesizing potential medicaments containing benzofuran spiro six-membered ring frameworks.
The invention has the following advantages: a) The reaction is efficient, and the yield is high; b) The organic phosphine catalyst is cheap and easy to obtain, stable and has no pungent smell; c) Strong acid or strong alkali and an additional oxidation or reduction agent are not needed to be added in the reaction, so that the conditions are mild; d) The transition metal is not required to be used as a catalyst in the reaction, so that the method is economical, practical and environment-friendly; e) The reaction substrate is easy to prepare; f) The reaction efficiency is high after the reaction is amplified, and the method has practical value.
The invention takes benzofuran aza diene compound and allyl carbonate compound which are easy to prepare as reaction raw materials, and the spiro [ benzofuran-cyclohexene ] compound is obtained by reaction under the action of an organic phosphine catalyst. The reaction operation is simple, the reaction condition is mild, and the method is suitable for large-scale industrial production.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples, to which the present invention is not limited. Variations and advantages that would occur to one skilled in the art are included in the invention without departing from the spirit and scope of the inventive concept, and the scope of the invention is defined by the appended claims. The procedures, conditions, reagents, experimental methods, etc. for carrying out the present invention are common knowledge and common knowledge in the art, except for those specifically mentioned below, and the present invention is not particularly limited. The data presented in the examples below include specific operations and reaction conditions and products. The purity of the product was identified by nuclear magnetism.
The synthesis reaction of the aryl alkyl thioether compound comprises the following steps:
as shown in equation a: adding benzofuran azadiene, allyl carbonate and acetonitrile into a reaction vessel, and stirring at 25 ℃ for reaction to obtain the spiro [ benzofuran-cyclohexene ] compound shown in the formula (III). Concentrating, and separating by column chromatography to obtain the target product.
The spiro [ benzofuran-cyclohexene ] compounds shown in Table 1 are all synthesized by the method of the invention, and no publication has been made.
TABLE 1 novel spiro [ benzofuran-cyclohexene ] compounds of the invention
Example 1
After benzofuranazadiene (37.5 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, a reaction tube, was added tert-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) and then an organophosphine catalyst, phEt, were added 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give the product 1 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 81 percent,>20:1d.r.； 1 H NMR(400MHz,CDCl 3 )δ12.41(s,1H),8.39(d,J＝8.2Hz,1H),7.99(d,J＝8.4Hz,2H),7.43–7.37(m,3H),7.02(d,J＝4.4Hz,4H),6.99–6.90(m,2H),6.77(d,J＝8.4Hz,1H),6.08(s,1H),5.34(s,1H),4.28(s,1H),2.98–2.86(m,1H),2.70(d,J＝14.9Hz,1H),2.48(s,3H),1.01(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.9,171.7,170.1,163.3,143.5,138.9,138.7,138.4,134.3,130.5,129.5,128.8,127.4,126.9,126.6,121.9,119.2,117.5,112.5,101.4,90.7,82.1,50.4,38.3,29.7,27.5,21.6.HRMS(ESI)m/z:calcd.for C 32 H 31 NO 6 SNa + (M+Na) + 580.1764,found 580.1764.
example 2
After benzofuranazadiene (37.5 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, was added to the reaction tube, cyclohexylallyl carbonate (49) was added.0mg,0.15mmol,1.5 equiv.) followed by addition of the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give product 2 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 64%,9:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.38(s,1H),8.41(d,J＝8.1Hz,1H),7.98(d,J＝8.3Hz,2H),7.44–7.37(m,3H),7.03(d,J＝4.3Hz,4H),7.01–6.92(m,2H),6.78(d,J＝8.4Hz,1H),6.10(s,1H),5.36(s,1H),4.60–4.51(m,1H),4.33(s,1H),2.89(d,J＝14.8Hz,1H),2.74(d,J＝15.0Hz,1H),2.48(s,3H),1.25(s,4H),1.20(t,J＝8.6Hz,2H),1.05–0.96(m,4H). 13 C NMR(100MHz,CDCl 3 )δ181.7,171.5,170.0,163.6,143.5,138.8,138.2,134.1,130.5,129.5,128.7,127.5,126.9,126.7,122.0,119.7,112.5,100.5,90.4,73.2,49.9,37.9,31.1,30.1,29.7,25.0,23.1,22.8,21.6.HRMS(ESI)m/z:calcd.for C 34 H 34 NO 6 S + (M+H) + 584.2101,found 584.2096.
example 3
After benzofuranazadiene (37.5 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, a catalyst, was added to the reaction tube, isopropyl allyl carbonate (40.1 mg,0.15mmol,1.5 equiv.) was added, followed by the organophosphine catalyst, phEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and the product 3 (eluent polarity: petroleum ether/ethyl acetate 20:1) was obtained after separation by column chromatography. Yield: 72%,7:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.29(s,1H),8.41(d,J＝8.2Hz,1H),7.99(d,J＝8.0Hz,2H),7.43–7.37(m,3H),7.02(d,J＝4.3Hz,4H),6.98–6.91(m,2H),6.78(d,J＝8.5Hz,1H),6.10(s,1H),5.36(s,1H),4.78–4.71(m,1H),4.32(s,1H),2.90(d,J＝15.3Hz,1H),2.73(d,J＝15.0Hz,1H),2.48(s,3H),1.01(d,J＝6.2Hz,3H),0.42(d,J＝6.2Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ181.7,171.6,170.0,163.5,143.5,138.9,138.8,138.3,134.2,130.6,129.5,128.7,127.5,126.9,126.6,122.0,119.6,112.6,100.6,90.5,68.4,50.0,38.2,21.6,21.5,20.4.HRMS(ESI)m/z:calcd.for C 31 H 29 NO 6 SNa + (M+Na) + 566.1608,found 566.1590.
example 4
After adding 2-fluorobenzofuran azadiene (39.3 mg,0.1mmol,1.0 equiv.) and reaction solvent acetonitrile (1.0 mL) to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) was added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure and separated by column chromatography to give the product 4 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 82%,>20:1d.r.； 1 H NMR(400MHz,CDCl 3 )δ12.41(s,1H),8.47(d,J＝8.1Hz,1H),7.96(d,J＝8.4Hz,2H),7.49–7.43(m,1H),7.36(d,J＝7.8Hz,2H),7.19–7.15(m,1H),7.06–6.97(m,2H),6.93–6.83(m,3H),6.07(s,1H),5.34(s,1H),4.67(s,1H),2.89–2.82(m,1H),2.78(d,J＝15.1Hz,1H),2.47(s,3H),1.07(s,9H). 13 C NMR(100MHz,CDCl 3 )δ180.5,171.4,169.7,163.8,160.9(d,J＝247.7Hz),143.3,138.9,138.7,134.0,130.7,130.0,130.0,129.4,128.4(d,J＝8.3Hz),126.9,126.0(d,J＝14.0Hz),123.2(d,J＝3.4Hz),122.1,119.6,116.9,114.8(d,J＝22.9Hz),112.5,100.5,89.9,82.2,37.6,27.5,21.6.HRMS(ESI)m/z:calcd.for C 32 H 31 FNO 6 S + (M+H) + 576.1851,found 576.1841.
example 5
After adding 2-chlorobenzofuran azadiene (39.3 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, t-butyl allyl carbonate (45.0 m, etc.) was added to the reaction tubeg,0.15mmol,1.5 equiv.) then adding the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give the product 5 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 61%,>20:1d.r.； 1 H NMR(400MHz,CDCl 3 )δ12.48(s,1H),8.52(d,J＝8.1Hz,1H),7.90(d,J＝8.1Hz,2H),7.49(t,J＝7.8Hz,1H),7.33(d,J＝8.1Hz,2H),7.26–7.20(m,2H),7.12–7.01(m,3H),6.86(d,J＝8.4Hz,1H),6.05(s,1H),5.34(s,1H),4.87(s,1H),2.90(d,J＝15.2Hz,1H),2.77(d,J＝15.2Hz,1H),2.46(s,3H),1.11(s,9H). 13 C NMR(100MHz,CDCl 3 )δ180.3,171.5,169.7,164.2,143.2,138.9,138.7,137.1,135.5,133.9,130.7,129.9,129.3,129.1,128.1,126.8,126.0,122.2,119.9,116.7,112.7,100.8,89.4,82.4,43.5,36.8,27.6,21.6.HRMS(ESI)m/z:calcd.for C 32 H 30 ClNO 6 SNa + (M+Na) + 614.1375,found 614.1373.
example 6
After adding 2-bromobenzofuran azadiene (45.4 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) is added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give the product 6 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 72 percent,>20:1d.r.； 1 H NMR(400MHz,CDCl 3 )δ12.54(s,1H),8.54(d,J＝8.1Hz,1H),7.88(d,J＝8.2Hz,2H),7.52(t,J＝7.7Hz,1H),7.46(d,J＝7.9Hz,1H),7.32(d,J＝8.1Hz,2H),7.25–7.16(m,2H),7.09–6.99(m,2H),6.88(d,J＝8.4Hz,1H),6.04(s,1H),5.33(s,1H),4.82(s,1H),2.96(d,J＝15.3Hz,1H),2.71(d,J＝15.4Hz,1H),2.45(s,3H),1.14(s,9H). 13 C NMR(100MHz,CDCl 3 )δ180.3,171.6,169.9,164.5,143.2,138.9,138.9,138.6,133.9,132.6,130.7,130.0,129.2,128.4,126.8,126.7,122.3,120.2,116.6,112.9,101.4,100.8,89.2,82.5,45.7,36.3,27.8,21.6.HRMS(ESI)m/z:calcd.for C 32 H 31 BrNO 6 S + (M+H) + 636.1050,found 636.1049.
example 7
After adding 2-methoxybenzofuran azadiene (40.5 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) is added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure and separated by column chromatography to give the product 7 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 56 percent,>20:1d.r.； 1 H NMR(400MHz,CDCl 3 )δ12.33(s,1H),8.43(d,J＝8.1Hz,1H),7.94(d,J＝8.3Hz,2H),7.44–7.39(m,1H),7.35(d,J＝8.1Hz,2H),7.09(dd,J＝7.6,1.7Hz,1H),7.04–6.99(m,1H),6.96(t,J＝7.7Hz,1H),6.76–6.69(m,2H),6.58(d,J＝8.0Hz,1H),6.03(s,1H),5.32(s,1H),4.88(s,1H),3.61(s,3H),2.83(q,J＝15.1Hz,2H),2.46(s,3H),1.04(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.7,171.7,169.8,163.3,157.2,143.2,139.2,138.4,134.4,130.3,129.3,129.1,127.8,127.3,126.7,121.7,119.4,119.0,117.4,112.4,109.0,101.8,90.3,81.8,54.9,37.5,27.9,27.5,21.6.HRMS(ESI):calcd.for C 33 H 33 NO 7 SNa + (M+Na) + 610.1870,found 610.1884.
example 8
After adding 3-fluorobenzofuran azadiene (39.3 mg,0.1mmol,1.0 equiv.) and reaction solvent acetonitrile (1.0 mL) to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) is added followed byInto organic phosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure and separated by column chromatography to give the product 8 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 80%,10:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.47(s,1H),8.42(d,J＝8.1Hz,1H),7.99(d,J＝8.3Hz,2H),7.47–7.41(m,1H),7.40(d,J＝8.1Hz,2H),7.03–6.93(m,2H),6.84–6.74(m,3H),6.72–6.66(m,1H),6.09(s,1H),5.35(s,1H),4.28(s,1H),2.89(d,J＝15.0Hz,1H),2.69(d,J＝15.0Hz,1H),2.48(s,3H),1.05(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.4,171.5,169.9,163.7,162.2(d,J＝245.0Hz),143.6,141.2(d,J＝7.0Hz),139.0,134.0,130.6,130.0,129.5,128.8(d,J＝8.1Hz),127.0,124.7(d,J＝2.6Hz),122.1,119.6,115.5(d,J＝22.2Hz),113.5(d,J＝21.1Hz),112.5,100.7,90.4,82.3,50.0,38.3,27.6,21.6.HRMS(ESI)m/z:calcd.for C 32 H 31 FNO 6 S + (M+H) + 576.1851,found 576.1841.
example 9
After adding 3-methylbenzofuran azadiene (39.0 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) was added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give the product 9 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 61, 13:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.40(s,1H),8.39(d,J＝8.1Hz,1H),7.99(d,J＝8.3Hz,2H),7.44–7.37(m,3H),6.94–6.87(m,2H),6.85–6.75(m,4H),6.08(s,1H),5.33(s,1H),4.24(s,1H),2.90(d,J＝14.9Hz,1H),2.70(d,J＝15.0Hz,1H),2.48(s,3H),2.15(s,3H),1.02(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.9,171.7,170.1,163.1,143.5,138.9,138.7,138.2,136.8,134.3,130.5,129.5,129.5,127.3,127.1,126.9,125.9,121.8,119.1,112.4,101.4,90.7,82.0,50.3,38.1,27.9,27.5,21.6,21.1.HRMS(ESI)m/z:calcd.for C 33 H 33 NO 6 SNa + (M+Na) + 594.1921,found 594.1917.
example 10
After adding 4-nitrobenzofuran azadiene (42.0 mg,0.1mmol,1.0 equiv.) and reaction solvent acetonitrile (1.0 mL) to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) was added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give the product 10 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 62 percent,>20:1d.r.； 1 H NMR(400MHz,CDCl 3 )δ12.55(s,1H),8.40(d,J＝8.2Hz,1H),7.99(d,J＝8.4Hz,2H),7.92(d,J＝8.8Hz,2H),7.46–7.39(m,3H),7.24(d,J＝8.8Hz,2H),6.96(t,J＝7.7Hz,1H),6.77(d,J＝8.4Hz,1H),6.13(s,1H),5.39(s,1H),4.41(s,1H),2.92(d,J＝15.1Hz,1H),2.69(d,J＝15.0Hz,1H),2.49(s,3H),1.02(s,9H). 13 C NMR(100MHz,CDCl 3 )δ180.8,171.1,169.6,169.2,164.4,146.7,146.6,143.9,139.3,138.5,133.6,130.7,129.6,127.0,122.6,122.6,120.3,117.1,112.4,99.8,90.1,82.8,50.2,38.4,27.9,27.7,21.6.HRMS(ESI)m/z:calcd.for C 32 H 30 N 2 O 8 SNa + (M+Na) + 625.1615,found 625.1613.
example 11
After adding 4-cyanobenzofuran azadiene (40.0 mg,0.1mmol,1.0 equiv.) and reaction solvent acetonitrile (1.0 mL) to a reaction tube, t-butylallyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) was added followed by the organophosphine catalyst PhEt 2 P(3.3mg,20 mol%) and stirred at a reaction temperature of 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give the product 11 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 74 percent,>20:1d.r.； 1 H NMR(400MHz,CDCl 3 )δ12.54(s,1H),8.40(d,J＝8.2Hz,1H),7.99(d,J＝8.3Hz,2H),7.47–7.38(m,3H),7.34(d,J＝8.5Hz,2H),7.18(d,J＝8.4Hz,2H),7.00–6.94(m,1H),6.76(d,J＝8.4Hz,1H),6.12(s,1H),5.38(s,1H),4.35(s,1H),2.91(d,J＝15.2Hz,1H),2.67(d,J＝15.0Hz,1H),2.49(s,3H),1.02(s,9H). 13 C NMR(100MHz,CDCl 3 )δ180.9,171.2,169.7,164.3,144.5,143.8,139.3,138.5,133.7,131.2,130.6,129.6,129.5,127.0,122.5,120.1,118.7,117.2,112.4,110.4,99.8,90.2,82.7,50.6,38.4,27.7,27.6,21.6.HRMS(ESI)m/z:calcd.for C 32 H 31 ClNO 6 S + (M+H) + 583.1897,found 583.1896.
example 12
After adding 4-trifluoromethylbenzofuran azadiene (44.3 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, to a reaction tube, t-butylallyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) is added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give the product 12 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 74, 7:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.51(s,1H),8.40(d,J＝8.2Hz,1H),7.99(d,J＝8.3Hz,2H),7.45–7.38(m,3H),7.30(d,J＝8.1Hz,2H),7.17(d,J＝8.1Hz,2H),6.95(t,J＝7.7Hz,1H),6.76(d,J＝8.5Hz,1H),6.11(s,1H),5.37(s,1H),4.35(s,1H),2.92(d,J＝15.1Hz,1H),2.70(d,J＝15.0Hz,1H),2.49(s,3H),1.01(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.2,171.4,169.8,164.0,143.7,142.9,142.9,139.1,138.7,133.9,130.6,129.6,129.1,128.8,127.0,124.3(q,J＝3.8Hz),122.3,121.4(q,J＝270.2Hz)119.8,112.5,100.4,90.3,82.5,50.3,38.3,27.6,21.6.HRMS(ESI)m/z:calcd.for C 33 H 31 F 3 NO 6 S + (M+H) + 626.1819,found 626.1817.
example 13
After adding 4-fluorobenzofuran azadiene (44.3 mg,0.1mmol,1.0 equiv.) and reaction solvent acetonitrile (1.0 mL) to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) was added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and the product 13 (eluent polarity: petroleum ether/ethyl acetate 20:1) was obtained after separation by column chromatography. Yield: 81 percent,>20:1d.r.； 1 H NMR(400MHz,CDCl 3 )δ12.42(s,1H),8.41(d,J＝8.2Hz,1H),7.99(d,J＝8.3Hz,2H),7.46–7.37(m,3H),7.03–6.93(m,3H),6.81–6.70(m,3H),6.08(s,1H),5.34(s,1H),4.28(s,1H),2.90(d,J＝15.1Hz,1H),2.67(d,J＝15.0Hz,1H),2.48(s,3H),1.05(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.7,171.5,170.0,163.5,161.6(d,J＝245.0Hz),143.6,139.0,138.8,134.3(d,J＝3.2Hz),134.1,130.5,130.2(d,J＝7.9Hz),129.5,126.9,122.1,119.5,117.4,114.2(d,J＝21.2Hz),101.1,90.6,82.2,49.7,38.3,29.7,27.6,21.6.HRMS(ESI)m/z:calcd.for C 32 H 30 FNO 6 SNa + (M+Na) + 598.1670,found 598.1669.
example 14
After adding 4-chlorobenzofuran azadiene (41.0 mg,0.1mmol,1.0 equiv.) and reaction solvent acetonitrile (1.0 mL) to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) was added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. However, the method is thatThe reaction solution was then freed from the solvent under reduced pressure and separated by column chromatography to give the product 14 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 66%,10:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.45(s,1H),8.41(d,J＝8.1Hz,1H),7.98(d,J＝8.3Hz,2H),7.48–7.42(m,1H),7.39(d,J＝8.0Hz,2H),7.05–6.94(m,5H),6.79(d,J＝8.4Hz,1H),6.08(s,1H),5.34(s,1H),4.27(s,1H),2.88(d,J＝14.8Hz,1H),2.67(d,J＝15.0Hz,1H),2.48(s,3H),1.05(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.4,171.4,169.9,163.6,143.6,139.0,138.7,137.2,134.0,132.3,130.6,130.1,129.5,127.5,126.9,122.2,119.6,117.2,112.5,100.8,90.4,82.3,49.7,38.2,27.6,21.6.HRMS(ESI)m/z:calcd.for C 32 H 30 ClNO 6 SNa + (M+Na) + 614.1375,found 614.1374.
example 15
After adding 4-bromobenzofuran azadiene (45.4 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) is added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure and separated by column chromatography to give the product 15 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 72 percent,>20:1d.r.； 1 H NMR(400MHz,CDCl 3 )δ12.45(s,1H),8.41(d,J＝8.2Hz,1H),7.98(d,J＝8.3Hz,2H),7.49–7.42(m,1H),7.39(d,J＝8.1Hz,2H),7.18(d,J＝8.5Hz,2H),6.98(t,J＝7.7Hz,1H),6.92(d,J＝8.4Hz,2H),6.79(d,J＝8.4Hz,1H),6.08(s,1H),5.34(s,1H),4.25(s,1H),2.88(d,J＝15.0Hz,1H),2.68(d,J＝15.0Hz,1H),2.48(s,3H),1.05(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.4,171.4,169.9,163.7,143.6,139.1,138.7,137.8,134.0,130.6,130.5,130.5,129.5,126.9,122.3,120.4,119.6,117.2,112.5,100.7,90.4,82.4,49.8,38.3,27.6,21.6.HRMS(ESI)m/z:calcd.for C 32 H 31 BrNO 6 S + (M+H) + 636.1050,found 636.1036.
example 16
After adding 4-methoxybenzofuran azadiene (40.5 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) is added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure and separated by column chromatography to give the product 16 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 70 percent,>20:1d.r.； 1 H NMR(400MHz,CDCl 3 )δ12.36(s,1H),8.41(d,J＝8.0Hz,1H),7.98(d,J＝8.3Hz,2H),7.45–7.36(m,3H),6.98–6.92(m,3H),6.80(d,J＝8.4Hz,1H),6.61–6.56(m,2H),6.06(s,1H),5.32(s,1H),4.24(s,1H),3.65(s,3H),2.87(d,J＝14.9Hz,1H),2.69(d,J＝15.0Hz,1H),2.48(s,3H),1.05(s,9H). 13 C NMR(100MHz,CDCl 3 )δ182.0,171.7,170.1,163.1,158.3,143.5,138.9,138.8,134.3,130.7,130.5,129.8,129.5,126.9,122.0,119.1,117.4,112.9,112.6,101.6,90.8,82.0,55.2,49.4,38.1,27.6,21.6.HRMS(ESI)m/z:calcd.for C 33 H 33 NO 7 SNa + (M+Na) + 610.1870,found 610.1884.
example 17
After adding 1-naphthobenzofuran azadiene (42.6 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) is added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure and separated by column chromatography to give the product 17 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield is good：45％，>20:1d.r.； 1 H NMR(400MHz,CDCl 3 )δ12.40(s,1H),8.39(d,J＝8.1Hz,1H),7.99(d,J＝8.3Hz,2H),7.44–7.37(m,3H),6.94–6.87(m,2H),6.85–6.75(m,4H),6.08(s,1H),5.33(s,1H),4.24(s,1H),2.90(d,J＝14.9Hz,1H),2.70(d,J＝15.0Hz,1H),2.48(s,3H),2.15(s,3H),1.02(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.9,171.7,170.1,163.1,143.5,138.9,138.7,138.2,136.8,134.3,130.5,129.5,129.5,127.3,127.1,126.9,125.9,121.8,119.1,112.4,101.4,90.7,82.0,50.3,38.1,27.9,27.5,21.6,21.1.HRMS(ESI)m/z:calcd.for C 36 H 34 NO 6 S + (M+H) + 608.2101,found 608.2100.
Example 18
After adding 5' -fluorofuran azadiene (39.3 mg,0.1mmol,1.0 equiv.) and reaction solvent acetonitrile (1.0 mL) to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) was added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure and separated by column chromatography to give the product 18 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 90 percent,>20:1d.r.； 1 H NMR(400MHz,CDCl 3 )δ12.41(s,1H),8.10(d,J＝6.3Hz,1H),7.99(d,J＝8.3Hz,2H),7.40(d,J＝8.1Hz,2H),7.14(td,J＝8.9,2.8Hz,1H),7.05–6.98(m,5H),6.73(dd,J＝9.1,3.9Hz,1H),6.08(s,1H),5.34(s,1H),4.27(s,1H),2.95–2.85(m,1H),2.69(d,J＝15.0Hz,1H),2.49(s,3H),1.00(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.50(d,J＝3.2Hz),171.59,166.40,163.15,156.77(d,J＝241.8Hz),143.8,138.4,138.2,134.0,129.6,128.7,127.5,127.1,127.0,126.9,126.7,126.7,119.3,113.4(d,J＝8.2Hz),101.2,91.8,82.2,50.6,38.3,27.5,21.7.HRMS(ESI)m/z:calcd.for C 32 H 30 FNO 6 SK + (M+K + )614.1409,found 614.1406.
example 19
After adding 5' -bromofuran azadiene (45.4 mg,0.1mmol,1.0 equiv.) and reaction solvent acetonitrile (1.0 mL) to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) was added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure and separated by column chromatography to give the product 19 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 46%,>20:1d.r.； 1 H NMR(400MHz,CDCl 3 )δ12.41(s,1H),8.53(s,1H),7.99(d,J＝8.3Hz,2H),7.46(dd,J＝8.9,2.1Hz,1H),7.40(d,J＝8.1Hz,2H),7.06–6.97(m,5H),6.68(d,J＝8.9Hz,1H),6.08(s,1H),5.33(s,1H),4.27(s,1H),2.89(d,J＝14.8Hz,1H),2.68(d,J＝15.0Hz,1H),2.49(s,3H),1.00(s,9H). 13 C NMR(100MHz,CDCl 3 )δ180.2,171.6,168.8,163.1,143.8,141.4,138.31,138.2,133.9,132.4,129.6,128.7,127.6,127.0,126.8,126.8,119.4,114.2,114.1,101.2,91.6,82.2,50.5,38.3,27.5,21.7.HRMS(ESI)m/z:calcd.for C 32 H 30 BrNO 6 SNa + (M+Na) + 658.0869,found 658.0863.
example 20
Potassium carbonate (10.2 mg,0.037mmol,1.0 equiv.) and methyl iodide (4.6. Mu.L, 0.074mmol,2.0 equiv.) were added to the reaction tube, followed by the addition of reaction solvent DMF (1.0 mL), and then the addition of compound 1 (20.5 mg,0.037mmol,1.0 equiv.) and stirring at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give the product 20 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 78%,>20:1d.r.； 1 H NMR(400MHz,CDCl 3 )δ8.35(d,J＝8.1Hz,1H),8.00(d,J＝8.3Hz,2H),7.45–7.37(m,3H),7.10–7.05(m,2H),7.04–6.94(m,3H),6.93–6.87(m,1H),6.84(d,J＝8.4Hz,1H),5.69(s,1H),5.18(s,1H),4.38(s,1H),3.80(s,3H),2.97(d,J＝15.3Hz,1H),2.68(d,J＝15.4Hz,1H),2.49(s,3H),1.04(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.5,170.3,164.7,155.6,143.6,138.8,138.7,135.4,134.1,130.5,129.7,129.5,127.6,127.3,127.0,121.9,120.6,117.3,116.1,112.6,90.8,81.0,62.0,52.3,39.4,27.4,21.6.HRMS(ESI):m/z calcd for C 33 H 34 NO 6 S + (M+H) + 572.2101,found 572.2113.
example 21
4-Methylthiophenol (9.3 mg,0.075mmol,1.5 equiv.) and triethylamine (6.9. Mu.L, 0.05mmol,1.0 equiv.) are added to the reaction tube followed by the addition of the reaction solvent CHCl 3 (1.0 mL) and then compound 11 (29.1 mg,0.05mmol,1.0 equiv.) were added and stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give the product 20 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 65 percent,>20:1d.r.； 1 H NMR(400MHz,CDCl 3 )δ8.36(d,J＝8.2Hz,1H),7.93(d,J＝8.3Hz,2H),7.62–7.56(m,1H),7.43(d,J＝8.0Hz,2H),7.36(d,J＝8.5Hz,2H),7.21(t,J＝8.3Hz,4H),7.10(d,J＝7.9Hz,2H),7.06–6.99(m,2H),4.21(d,J＝13.5Hz,1H),3.85(d,J＝13.4Hz,1H),3.50(dd,J＝13.9,4.2Hz,1H),3.21–3.11(m,1H),2.76–2.60(m,2H),2.51(s,3H),2.34(s,3H),2.06(t,J＝13.9Hz,1H),1.16(s,9H). 13 C NMR(100MHz,CDCl 3 )δ202.9,179.3,169.7,166.1,144.2,139.6,139.4,138.0,137.2,131.8,131.1,130.5,129.9,129.8,129.7,129.6,127.0,123.1,118.2,112.2,111.9,110.2,90.7,82.5,58.9,53.2,45.6,40.0,33.5,27.6,21.7,21.1.HRMS(ESI):m/z calcd for C 39 H 40 NO 6 S 2 + (M+H) + 707.2244,found 707.2253.。
Claims (6)
1. a synthesis method of spiro [ benzofuran-cyclohexene ] compounds is characterized in that benzofuran azadiene and allyl carbonate are used as reaction raw materials, and react in a reaction solvent under the catalysis of an organic phosphine catalyst to obtain spiro [ benzofuran-cyclohexene ] compounds shown as a formula (III); the reaction process is shown in a reaction formula (a);
wherein R is 1 Is hydrogen or halogen atom substituted; r is R 2 Is benzene ring, naphthalene ring, substituted benzene ring; r is R 3 Is an alkyl or aryl-containing alkane.
2. The synthetic method according to claim 1, wherein the solvent is any one or any combination of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetonitrile, toluene.
3. The synthetic process according to claim 1, wherein the ratio of the starting benzofuranazadiene to allyl carbonate is 1:1 to 1:2.
4. The method of claim 1, wherein the reaction temperature is 20-30 ℃;
the catalyst is PhEt 2 P、Ph 3 P、(4-FC 6 H 4 ) 3 P、(4-MeC 6 H 4 ) 3 P、Ph 2 CyP、Ph 2 MeP、Ph 2 EtP、PhMe 2 P、PhCy 2 P、Bu 3 P.
5. A spiro [ benzofuran-cyclohexene ] compound prepared by the synthesis method according to any one of claims 1 to 4, which has the structure shown in formula (iii):
wherein R is 1 Is hydrogen or halogen atom substituted; r is R 2 Is benzene ring, naphthalene ring, substituted benzene ring; r is R 3 Is an alkyl or aryl-containing alkane.
6. The spiro [ benzofuran-cyclohexene ] compound according to claim 5, wherein the structure is represented by formula (III):
wherein R is 1 Any one selected from hydrogen, 5-fluorophenyl, 5-chlorophenyl and 5-bromophenyl;
R 2 any one selected from phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methoxyphenyl, 2-methylphenyl, 2-naphthyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-methoxyphenyl, 3-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-nitrophenyl, 4-methoxyphenyl;
R 3 selected from any one of methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclohexyl and benzyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310054770.3A CN116283868A (en) | 2023-02-03 | 2023-02-03 | Synthesis method of spiro [ benzofuran-cyclohexene ] compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310054770.3A CN116283868A (en) | 2023-02-03 | 2023-02-03 | Synthesis method of spiro [ benzofuran-cyclohexene ] compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116283868A true CN116283868A (en) | 2023-06-23 |
Family
ID=86817614
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310054770.3A Pending CN116283868A (en) | 2023-02-03 | 2023-02-03 | Synthesis method of spiro [ benzofuran-cyclohexene ] compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116283868A (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR090011A1 (en) * | 2012-03-28 | 2014-10-15 | Consejo Nac Invest Cient Tec | INHIBITING COMPOUNDS OF THE COMPLEMENT, ITS SALTS AND PHARMACEUTICALLY ACCEPTABLE DERIVATIVES, PROCEDURES FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT UNDERSTAND THEM |
| CN108484552A (en) * | 2018-06-15 | 2018-09-04 | 河南大学 | A kind of polysubstituted 3- benzofuranones spiral shell cyclohexene derivative and preparation method thereof |
| CN109651313A (en) * | 2019-01-28 | 2019-04-19 | 四川大学 | A kind of chirality 2,3- dihydro-benzofuran derivative and preparation method thereof |
| CN109761993A (en) * | 2019-01-31 | 2019-05-17 | 广西师范大学 | Spiral shell benzofuran -3,3 '-quinoline and its synthetic method and application |
| CN111961060A (en) * | 2020-08-27 | 2020-11-20 | 遵义医科大学 | Preparation method of spiroheterocyclic 2, 3-dihydrobenzofuran compound with optical activity |
| CN113354655A (en) * | 2021-05-27 | 2021-09-07 | 张家港威胜生物医药有限公司 | Bibenzo [5,6] spiroketal compound and preparation method thereof |
| CN113620918A (en) * | 2021-08-18 | 2021-11-09 | 山东大学 | Method for synthesizing spiro compound through Lewis acid catalyzed [3+2] cycloaddition reaction |
-
2023
- 2023-02-03 CN CN202310054770.3A patent/CN116283868A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR090011A1 (en) * | 2012-03-28 | 2014-10-15 | Consejo Nac Invest Cient Tec | INHIBITING COMPOUNDS OF THE COMPLEMENT, ITS SALTS AND PHARMACEUTICALLY ACCEPTABLE DERIVATIVES, PROCEDURES FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT UNDERSTAND THEM |
| CN108484552A (en) * | 2018-06-15 | 2018-09-04 | 河南大学 | A kind of polysubstituted 3- benzofuranones spiral shell cyclohexene derivative and preparation method thereof |
| CN109651313A (en) * | 2019-01-28 | 2019-04-19 | 四川大学 | A kind of chirality 2,3- dihydro-benzofuran derivative and preparation method thereof |
| CN109761993A (en) * | 2019-01-31 | 2019-05-17 | 广西师范大学 | Spiral shell benzofuran -3,3 '-quinoline and its synthetic method and application |
| CN111961060A (en) * | 2020-08-27 | 2020-11-20 | 遵义医科大学 | Preparation method of spiroheterocyclic 2, 3-dihydrobenzofuran compound with optical activity |
| CN113354655A (en) * | 2021-05-27 | 2021-09-07 | 张家港威胜生物医药有限公司 | Bibenzo [5,6] spiroketal compound and preparation method thereof |
| CN113620918A (en) * | 2021-08-18 | 2021-11-09 | 山东大学 | Method for synthesizing spiro compound through Lewis acid catalyzed [3+2] cycloaddition reaction |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108314658B (en) | A kind of preparation method of polysubstituted oxazole derivatives | |
| CN111233795B (en) | Preparation method and application of chiral gamma-butyrolactone compound and derivative thereof | |
| CN113912577B (en) | Rockwell intermediate, rockwell and its derivative, and preparation and application | |
| CN112940002B (en) | Method for synthesizing octatomic bridged ring compound through palladium-catalyzed asymmetric ring addition reaction | |
| Yan et al. | Synthesis of chiral tetronic acid derivatives via organocatalytic conjugate addition of ethyl 4-chloro-3-oxobutanoate to nitroalkenes | |
| CN109535120B (en) | Preparation method of 7-substituted-3, 4,4, 7-tetrahydrocyclobutane coumarin-5-ketone | |
| CN116283868A (en) | Synthesis method of spiro [ benzofuran-cyclohexene ] compound | |
| CN111662147B (en) | Process for preparing diynes and analogues thereof | |
| JP2016198736A (en) | Catalyst having amino-salicylaldimine ligand coordinated to metal and method for producing iodine cyclized product using the same | |
| CN113754604B (en) | Nitrogen-containing chiral ligand and application thereof in asymmetric oxidation reaction of thioether | |
| CN107868087A (en) | A kind of method for preparing pyrrolo-indole analog derivative | |
| CN109232282B (en) | Synthetic method of 2-aminobenzophenone compound | |
| Huang et al. | Asymmetric synthesis of highly functionalized furanones via direct Michael reactions mediated by a bulky primary amine | |
| CN111732552A (en) | Method for synthesizing 1, 3-oxazole-2-thioketone by palladium catalysis | |
| CN105272953A (en) | Method for synthesizing coumarone naphthoquinone derivative | |
| CN109384753B (en) | Synthetic method of 2-phenyl-3-methylbenzofuran compound | |
| CN112094234B (en) | Synthesis method of 6-phenyl-2, 3,4, 7-tetrahydro-1H-3-azepine derivative | |
| CN113754597B (en) | Benzhydryl piperazine compound containing linear olefin and preparation method thereof | |
| CN108947995A (en) | A kind of preparation method of polysubstituted dxadiazine derivatives | |
| CN114988976B (en) | Method for synthesizing chiral cyclopentenones by organically catalyzing Nazarov cyclization | |
| CN115572248B (en) | Method for preparing beta-amino sulfone compound | |
| CN113461700B (en) | Application of oxygen-promoted dearomatization reaction in construction of spiro-dienone skeleton | |
| CN111018869B (en) | Preparation method of chiral fused ring pyrano-dihydropyrrole compound | |
| CN110204456B (en) | Polysubstituted naphthalene derivative and synthesis method thereof | |
| RU2806043C1 (en) | Method for preparation of 1-methyl-n-aryl-3-oxo-8-phenyl-2-oxa-6-thiabicyclo[2.2.2]octane-5-carboxamides |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |