CN116283899A - 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound and synthesis method thereof - Google Patents
3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound and synthesis method thereof Download PDFInfo
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- -1 cyclopentenone compound Chemical class 0.000 title claims abstract description 38
- FCEHBMOGCRZNNI-UHFFFAOYSA-N thianaphthalene Natural products C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000001308 synthesis method Methods 0.000 title abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 27
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 84
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical group FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 29
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 23
- 230000002194 synthesizing effect Effects 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 16
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical group COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003172 aldehyde group Chemical group 0.000 claims description 2
- 125000005336 allyloxy group Chemical group 0.000 claims description 2
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical group O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 claims description 2
- 239000000758 substrate Substances 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- 238000005481 NMR spectroscopy Methods 0.000 description 63
- 239000000047 product Substances 0.000 description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical class O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 description 20
- 239000012043 crude product Substances 0.000 description 20
- 239000003480 eluent Substances 0.000 description 20
- 239000003208 petroleum Substances 0.000 description 20
- 238000010898 silica gel chromatography Methods 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- 238000004809 thin layer chromatography Methods 0.000 description 20
- 238000012512 characterization method Methods 0.000 description 18
- 238000002390 rotary evaporation Methods 0.000 description 18
- 239000012298 atmosphere Substances 0.000 description 16
- XKSQZCFVTJKNNU-UHFFFAOYSA-N [2-(trifluoromethyl)-1h-indol-3-yl]methanol Chemical compound C1=CC=C2C(CO)=C(C(F)(F)F)NC2=C1 XKSQZCFVTJKNNU-UHFFFAOYSA-N 0.000 description 12
- ABOQNJDBQHUXNW-UHFFFAOYSA-N 3-(trifluoromethyl)-1-benzothiophene Chemical compound C1=CC=C2C(C(F)(F)F)=CSC2=C1 ABOQNJDBQHUXNW-UHFFFAOYSA-N 0.000 description 11
- 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 11
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 11
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003377 acid catalyst Substances 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- DORMTBIPKNPJPY-UHFFFAOYSA-N acetic acid;iodobenzene Chemical compound CC(O)=O.IC1=CC=CC=C1 DORMTBIPKNPJPY-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- OJLPWVOWEHJINA-UHFFFAOYSA-N 2,2,2-trifluoro-1-(1h-indol-3-yl)ethanol Chemical compound C1=CC=C2C(C(O)C(F)(F)F)=CNC2=C1 OJLPWVOWEHJINA-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000006229 Nazarov cyclization reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000005693 optoelectronics Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000004065 semiconductor Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/78—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
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Abstract
The invention discloses a 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound and a synthesis method thereof, wherein the 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound is obtained by taking perfluoroalkyl 3-indolyl methanol compound as a raw material and reacting in a solvent under the catalysis of a catalyst. The method has the advantages of easily available raw materials, mild conditions, high yield, wide substrate range, atom economy and the like.
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis, and in particular relates to a 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound and a synthesis method thereof.
Background
Among the sulfur heterocyclic compounds, benzothiophene polycyclic compounds are a unique class, which are widely present in many bioactive molecules; benzothiophenes having unique electron-rich properties are also important organic synthetic intermediates, which can be used in a wide variety of organic optoelectronic materials and organic semiconductors after electrophilic substitution-coupling. Cyclopentene is not only an important backbone of many important bioactive molecules, but cyclopentenones are also key intermediates for the synthesis of many natural products and pharmaceutical molecules such as prostaglandins. However, the synthesis methods of benzothiophene ring-fused cyclopentenones are rare at present. At present, the benzothiophene cyclopentenones derivatives are usually realized through a cyclization reaction catalyzed by transition metal or a functionalization reaction of benzothiophene, but the reaction often needs a noble metal catalyst and a multi-step reaction, and has high cost and complex operation.
Fluorine-containing compounds have very important applications in the fields of chemistry, medicine, pesticides, functional materials, etc., for example: about 20% of the pharmaceutical and 30% of the pesticide molecules contain at least one F atom. The introduction of fluorine atoms or fluorine-containing groups into drug molecules, which can improve the molecular properties of drugs, such as metabolic stability, lipophilicity, permeability, and interactions with biological targets, has become a popular method for drug screening. The perfluoroalkyl has strong electron withdrawing property, larger steric hindrance, good lipophilicity and stability, and is also an important synthon. Therefore, developing a simple and efficient synthesis method to realize the efficient synthesis of perfluoroalkyl benzothiophene [ b ] cyclopentenone compounds has extremely important significance.
Disclosure of Invention
This section is intended to outline some aspects of embodiments of the invention and to briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section as well as in the description summary and in the title of the application, to avoid obscuring the purpose of this section, the description summary and the title of the invention, which should not be used to limit the scope of the invention.
The present invention has been made in view of the above-mentioned or technical blank problems occurring in the prior art.
One of the objects of the present invention is to provide a 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound which contains functional groups such as perfluoroalkyl, carbonyl and amine groups, and can be converted into various fluorine-containing and non-fluorine-containing compounds through further structural chemical conversion and modification.
In order to solve the technical problems, the invention provides the following technical scheme: a3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound has a structural formula shown in formula (I):
wherein R is 1 One of hydrogen, halogen, ester group, sulfonyl oxygen group, nitro group, cyano group, methoxy group, methyl group, aldehyde group, allyloxy group, benzoyloxy group, methyl acrylate group and phenyl group;
p is selected from one of P-toluenesulfonyl, P-bromobenzenesulfonyl, benzoyl and acetyl;
n is selected from 1,2, 3, 4, 6 or 7.
It is another object of the present invention to provide a method for synthesizing 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compounds as described above, which does not require a metal catalyst, and only uses inexpensive paratoluenesulfonic acid hydrate as a catalyst, thereby successfully realizing efficient synthesis of 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compounds. The method has the advantages of simple and easily obtained raw materials, mild conditions, high yield, wide substrate range, atom economy and the like.
The specific technical scheme is as follows: taking a compound shown in a formula (II) as a raw material, and reacting in a solvent under the catalysis of a catalyst to obtain the compound shown in the formula (I);
wherein R in formula (II) 1 P, n and R in formula (I) 1 The correspondence between P, n is consistent.
As a preferred embodiment of the method for synthesizing a 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound of the present invention, wherein: the catalyst is selected from one of paratoluenesulfonic acid hydrate, trifluoromethanesulfonic acid and trifluoroacetic acid.
As a preferred embodiment of the method for synthesizing a 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound of the present invention, wherein: the molar ratio of the catalyst to the compound shown in the formula (II) is 0.1-0.5:1.
As a preferred embodiment of the method for synthesizing a 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound of the present invention, wherein: the molar ratio of the catalyst to the compound shown in the formula (II) is 0.3:1.
As a preferred embodiment of the method for synthesizing a 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound of the present invention, wherein: the solvent is hexafluoroisopropanol or a mixed solvent of hexafluoroisopropanol and dichloroethane.
As a preferred embodiment of the method for synthesizing a 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound of the present invention, wherein: the volume ratio of the hexafluoroisopropanol to the dichloroethane is 1:0.5-4.
As a preferred embodiment of the method for synthesizing a 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound of the present invention, wherein: the volume ratio of hexafluoroisopropanol to dichloroethane is 1:1.
As a preferred embodiment of the method for synthesizing a 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound of the present invention, wherein: the concentration of the compound shown in the formula (II) in the solvent is 0.05-0.2 mol/L.
As a preferred embodiment of the method for synthesizing a 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound of the present invention, wherein: compared with the prior art, the method has the following beneficial effects that the reaction temperature is 5-60 ℃ and the reaction time is 5-48 hours:
the method of the invention does not need to use a metal catalyst, only takes the low-cost paratoluenesulfonic acid hydrate as the catalyst, and successfully realizes the novel efficient synthesis of the 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound. The method has the advantages of simple and easily obtained raw materials, mild conditions, high yield, wide substrate range, atom economy and the like.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the description of the embodiments will be briefly described below, it being obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art. Wherein:
FIG. 1 is a chart showing the hydrogen nuclear magnetic resonance spectrum of the target product 1a prepared in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the target product 1a prepared in example 1 of the present invention;
FIG. 3 is a nuclear magnetic resonance fluorine spectrum of the target product 1a prepared in example 1 of the present invention;
FIG. 4 is a single crystal diffractogram of the target product 1a prepared in example 1 of the present invention;
FIG. 5 is a schematic diagram showing the reaction mechanism represented by the raw material 2a in example 1 of the present invention.
Detailed Description
In order that the above-recited objects, features and advantages of the present invention will become more apparent, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways other than those described herein, and persons skilled in the art will readily appreciate that the present invention is not limited to the specific embodiments disclosed below.
Further, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic can be included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.
The starting materials used in the examples were p-toluenesulfonyl protected perfluoroalkyl 3-indolemethanol compounds prepared by the methods reported in the literature (Tetrahedron, 2017,73 (16), 2283-2289;Journal of the American Chemical Society,2002,124 (44): 13179-13184.).
Example 1
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indolemethanol 2a (0.2 mmol) protected by tosyl and paratoluenesulfonic acid hydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (1 mL) and dichloroethane (1 mL) are added under the atmosphere for reaction for 11h under normal temperature, TLC monitors the reaction, solvent is removed by rotary evaporation after the reaction is finished, and crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/80-1/10, V/V) to obtain target product 1a (93.2 mg, white solid, yield 93%).
The reaction equation is:
the target product 1a is characterized, the nuclear magnetic resonance hydrogen spectrum is shown in fig. 1, the nuclear magnetic resonance carbon spectrum is shown in fig. 2, and the nuclear magnetic resonance fluorine spectrum is shown in fig. 3:
1 H NMR(600MHz,CDCl 3 )δ8.21–8.15(m,1H),7.90–7.85(m,1H),7.77(s,1H),7.64(d,J＝8.0Hz,2H),7.51–7.46(m,2H),7.38(d,J＝7.8Hz,1H),7.29–7.18(m,5H),7.13(d,J＝7.7Hz,1H),4.57(qd,J＝7.6,3.8Hz,1H),4.39(d,J＝3.1Hz,1H),2.38(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ194.5,164.3(q,J＝1.4Hz),145.1,143.8,139.7,137.4,135.1,131.8,130.5,129.8,128.9,128.3,127.5,126.9,126.8,126.5,124.8(q,J＝279.7Hz),123.5,123.2,54.9,48.4(q,J＝30.5Hz),21.4；
19 F NMR(565MHz,CDCl 3 )δ-70.35(d,J＝8.0Hz,3F).
the structure and relative configuration of compound 1a was confirmed by single crystal diffraction, as shown in fig. 4.
The reaction mechanism of the present invention represented by raw material 2a is shown in FIG. 5: firstly, hydroxyl in 2a is activated by acid, then dehydrated to generate carbonium ion B, then intramolecular Nazarov cyclizes to generate intermediate C, then active intermediate D generated by protonation is attacked by water to generate intermediate E, and then ring opening and proton transfer are carried out to obtain a final product 1a, and meanwhile, the acid catalyst is released.
Example 2
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indolemethanol 2b (0.2 mmol) protected by tosyl and paratoluenesulfonic acid hydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (1 mL) and dichloroethane (1 mL) are added under the atmosphere for reaction for 11h under normal temperature, TLC monitors the reaction, solvent is removed by rotary evaporation after the reaction is finished, and crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/50-1/7,V/V) to obtain target product 1b (102.4 mg, white solid, yield 99%).
The reaction equation is:
characterization of the above target product 1 b:
1 H NMR(600MHz,CDCl 3 )δ8.19(d,J＝7.0Hz,1H),7.92–7.86(m,1H),7.62(s,2H),7.50–7.43(m,2H),7.22–7.13(m,3H),7.01(s,1H),6.82(s,1H),4.86(s,1H),4.67–4.25(m,1H),2.37(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ160.7,144.9,144.1,140.4,136.2,130.7,129.7,129.6,129.6,127.9,127.3,126.6,126.3,126.0,124.2,123.5,123.2,115.2(q,J＝13.9Hz),60.4,49.6(q,J＝31.6Hz),21.5；
19 F NMR(565MHz,CDCl 3 )δ-70.53(d,J＝6.7Hz,3F),-111.33(s,1F).
example 3
Taking a 10mL eggplant-shaped bottle, sequentially adding trifluoromethyl 3-indolemethanol 2c (0.2 mmol) protected by tosyl and p-toluenesulfonic acid hydrate (0.06 mmol), adding hexafluoroisopropanol (1 mL) and dichloroethane (1 mL) under the atmosphere, reacting for 12h at 60 ℃, monitoring the reaction by TLC, cooling to room temperature after the reaction is finished, removing the solvent by rotary evaporation, and separating the crude product by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/20-1/4, V/V) to obtain a target product 1c (100.76 mg, light yellow solid, yield 75%).
The reaction equation is:
characterization of the above target product 1 c:
1 H NMR(600MHz,CDCl 3 )δ8.12(dd,J＝5.5,3.0Hz,1H),7.90(s,1H),7.87(dd,J＝5.7,3.0Hz,1H),7.60(d,J＝7.5Hz,4H),7.48(dd,J＝5.8,3.0Hz,2H),7.34(d,J＝8.7Hz,1H),7.21(t,J＝6.9Hz,4H),6.91(dd,J＝8.7,1.9Hz,1H),6.65(s,1H),4.32–4.19(m,2H),2.38(s,3H),2.34(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ193.4,164.2,147.9,145.8,145.0,144.1,139.3,137.0,134.1,132.9,131.6,130.3,129.8,129.7,129.2,128.4,127.0,126.7,126.6,123.5,123.3,122.8,121.3,54.3,47.9(q,J＝30.7Hz),21.5,21.4；
19 F NMR(565MHz,CDCl 3 )δ-70.49(d,J＝7.0Hz,3F).
example 4
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indolemethanol 2d (0.2 mmol) protected by tosyl and paratoluenesulfonic acid hydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (1 mL) and dichloroethane (1 mL) are added under the atmosphere to react for 19h at 60 ℃, TLC monitors the reaction, cooling is carried out to room temperature after the reaction is finished, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/20-1/5, V/V) to obtain the target product 1d (76.2 mg, yellow solid, yield 70%).
The reaction equation is:
characterization of the above target product 1 d:
1 H NMR(600MHz,CDCl 3 )δ8.73(s,1H),8.16–8.10(m,2H),8.00(d,J＝2.3Hz,1H),7.91–7.87(m,1H),7.76–7.71(m,3H),7.53–7.47(m,2H),7.27(d,J＝8.2Hz,2H),4.64(qd,J＝7.4,3.1Hz,1H),4.45(d,J＝3.2Hz,1H),2.39(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ193.4,164.7(q,J＝1.8Hz),145.2,145.0,144.6,142.0,139.0,136.8,130.2,130.1,129.7,127.3,126.8,126.7,125.8,124.4(q,J＝280.2Hz),124.3,123.5,123.4,122.0,53.9,47.7(q,J＝31.2Hz),21.5；
19 F NMR(565MHz,CDCl 3 )δ-70.47(d,J＝7.6Hz,3F).
example 5
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indolemethanol 2e (0.2 mmol) protected by tosyl and paratoluenesulfonic acid hydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (1 mL) and dichloroethane (1 mL) are added under the atmosphere to react for 48h at 60 ℃, TLC monitors the reaction, cooling is carried out to room temperature after the reaction is finished, solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/50-1/5, V/V) to obtain the target product 1e (91.0 mg, yellow solid, yield 87%).
The reaction equation is:
characterization of the above target product 1 e:
1 H NMR(600MHz,CDCl 3 )δ8.49(s,1H),8.14(dd,J＝5.8,3.2Hz,1H),7.88(dd,J＝6.0,3.1Hz,1H),7.69(d,J＝8.1Hz,2H),7.64(d,J＝8.4Hz,1H),7.54(d,J＝8.4Hz,1H),7.51–7.48(m,2H),7.40(s,1H),7.25(d,J＝7.3Hz,3H),4.53(qd,J＝7.5,2.8Hz,1H),4.38(d,J＝3.0Hz,1H),2.39(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ193.4,164.6,145.1,144.5,140.1,139.2,136.8,132.7,130.7,130.6,130.2,130.1,127.2,126.7,126.7,126.6,125.4,123.5,123.4,117.8,110.1,53.9,47.8(q,J＝31.6Hz),21.5；
19 F NMR(565MHz,CDCl 3 )δ-70.45(d,J＝7.7Hz,3F).
example 6
Taking a 10mL eggplant-shaped bottle, sequentially adding trifluoromethyl 3-indolemethanol 2f (0.2 mmol) protected by tosyl and p-toluenesulfonic acid hydrate (0.06 mmol), adding hexafluoroisopropanol (1 mL) and dichloroethane (1 mL) under the atmosphere, reacting for 12h at 60 ℃, monitoring the reaction by TLC, cooling to room temperature after the reaction is finished, rotationally evaporating to remove the solvent, and separating the crude product by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/20-1/5, V/V) to obtain a target product 1f (104.8 mg, yellow solid, yield 99%).
The reaction equation is:
characterization of the above target product 1 f:
1 H NMR(600MHz,CDCl 3 )δ9.88(s,1H),8.68(s,1H),8.19–8.12(m,1H),7.92–7.86(m,1H),7.76(s,2H),7.73(d,J＝8.2Hz,2H),7.64(s,1H),7.53–7.47(m,2H),7.26(d,J＝7.9Hz,2H),4.65(qt,J＝7.7,3.7Hz,1H),4.41(d,J＝3.0Hz,1H),2.39(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ194.1,190.6,145.2,144.4,141.5,139.1,137.2,133.7,131.6,130.3,130.0,129.7,127.2,126.7,126.7,126.4,126.0,123.6,123.4,54.0,47.7(q,J＝31.0Hz),21.5；
19 F NMR(565MHz,CDCl 3 )δ-70.50(d,J＝7.7Hz,3F).
example 7
10mL eggplant-shaped bottle is taken, 2g (0.2 mmol) of trifluoromethyl 3-indolyl methanol protected by tosyl and 0.06 mmol) of p-toluenesulfonic acid hydrate are sequentially added, hexafluoroisopropanol (1 mL) and dichloroethane (1 mL) are added under the atmosphere for reaction for 7h at normal temperature, TLC monitors the reaction, the solvent is removed by rotary evaporation after the reaction is finished, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/24-1/6, V/V) to obtain 1g (109.4 mg, white solid, yield 88%).
The reaction equation is:
characterization of the above target product 1 g:
1 H NMR(600MHz,CDCl 3 )δ8.24–8.17(m,1H),8.16–8.06(m,2H),7.88(d,J＝7.4Hz,1H),7.75(s,1H),7.67(d,J＝8.2Hz,2H),7.63(t,J＝7.5Hz,1H),7.54–7.46(m,5H),7.24(d,J＝8.1Hz,2H),7.18(dd,J＝8.7,2.5Hz,1H),7.01(d,J＝2.4Hz,1H),4.51(qd,J＝7.6,3.2Hz,1H),4.37(d,J＝3.2Hz,1H),2.40(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ193.8,164.7,164.3,149.8,145.1,144.0,139.7,137.4,133.9,133.2,132.7,130.5,130.1,129.9,129.7,128.9,128.6,127.0,126.8,126.6,124.7(q,J＝281.1Hz),123.7,123.3,122.2,120.6,54.7,48.1(q,J＝30.2Hz),21.5；
19 F NMR(565MHz,CDCl 3 )δ-70.38(d,J＝7.8Hz,3F).
example 8
Taking a 10mL eggplant-shaped bottle, sequentially adding trifluoromethyl 3-indolemethanol protected by tosyl (0.2 mmol) and paratoluenesulfonic acid hydrate (0.06 mmol), adding hexafluoroisopropanol (1 mL) and dichloroethane (1 mL) under the atmosphere, reacting for 10h at 60 ℃, monitoring the reaction by TLC, cooling to room temperature after the reaction is finished, rotationally evaporating to remove the solvent, and separating the crude product by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/20-1/5, V/V) to obtain a target product 1h (113.6 mg, light yellow solid, yield 97%).
The reaction equation is:
characterization of the above target product 1 h:
1 H NMR(600MHz,CDCl 3 )δ8.18–8.14(m,1H),7.99(s,1H),7.89–7.84(m,1H),7.66(d,J＝8.3Hz,2H),7.54(d,J＝16.0Hz,1H),7.51–7.46(m,2H),7.45(d,J＝8.6Hz,1H),7.41(dd,J＝8.4,1.6Hz,1H),7.23(d,J＝8.1Hz,2H),7.21(d,J＝1.3Hz,1H),6.34(d,J＝16.0Hz,1H),4.56(qd,J＝7.7,3.2Hz,1H),4.35(d,J＝3.3Hz,1H),3.76(s,3H),2.38(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ194.1,167.0,164.4(q,J＝2.1Hz),145.1,144.1,143.0,139.6,137.3,137.0,133.2,131.6,130.4,129.9,128.2,127.9,127.3,127.0,126.8,126.6,123.6,123.3,118.8,54.7,51.8,48.2(q,J＝31.8Hz),21.5；
19 F NMR(565MHz,CDCl 3 )δ-70.40(d,J＝7.8Hz,3F).
example 9
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indolemethanol 2i (0.2 mmol) protected by tosyl and paratoluenesulfonic acid hydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (1 mL) and dichloroethane (1 mL) are added under the atmosphere for reaction for 24h at normal temperature, TLC monitors the reaction, solvent is removed by rotary evaporation after the reaction is finished, and crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/20-1/5, V/V) to obtain target product 1i (86.4 mg, yellow solid, yield 77%).
The reaction equation is:
characterization of the above target product 1 i:
1 H NMR(600MHz,CDCl 3 )δ8.21–8.16(m,1H),8.05(s,1H),7.91–7.86(m,2H),7.76(s,1H),7.66(d,J＝8.2Hz,2H),7.53–7.49(m,2H),7.24(d,J＝8.1Hz,2H),7.21(d,J＝8.2Hz,1H),4.58(qd,J＝7.6,3.3Hz,1H),4.41(d,J＝3.3Hz,1H),3.89(s,3H),2.39(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ193.6,165.7,145.1,144.1,139.7,137.3,135.6,131.1,130.5,129.9,129.2,128.4,127.6(q,J＝1.8Hz),127.1,126.9,126.7,123.6,123.3,52.4,48.2(q,J＝30.1Hz),21.9,21.5；
19 F NMR(565MHz,CDCl 3 )δ-70.39(d,J＝6.3Hz,3F).
example 10
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indolemethanol 2j (0.2 mmol) protected by tosyl and paratoluenesulfonic acid hydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (1 mL) and dichloroethane (1 mL) are added under the atmosphere to react for 17h under normal temperature, TLC monitors the reaction, solvent is removed by rotary evaporation after the reaction is finished, and crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/20-1/6, V/V) to obtain target product 1j (102.7 mg, light yellow solid, yield 90%).
The reaction equation is:
characterization of the above target product 1 j:
1 H NMR(600MHz,CDCl 3 )δ8.16–8.07(m,1H),7.91–7.84(m,2H),7.63(d,J＝8.2Hz,2H),7.50(s,1H),7.50–7.45(m,2H),7.23(d,J＝8.1Hz,2H),7.20(s,1H),4.48(qd,J＝7.7,3.3Hz,1H),4.27(d,J＝3.3Hz,1H),2.39(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ193.4,164.3,145.1,144.4,139.5,136.8,134.6,132.8,131.6,131.5,130.3,130.0,129.8,129.0(q,J＝1.1Hz),127.1,126.8,126.6,124.6(q,J＝280.3Hz),123.5,123.3,54.2,48.2(q,J＝31.1Hz),21.5；
19 F NMR(565MHz,CDCl 3 )δ-70.47(d,J＝7.8Hz,3F).
example 11
Taking a 10mL eggplant-shaped bottle, sequentially adding p-toluenesulfonyl-protected heptafluoropropyl 3-indolemethanol 2k (0.2 mmol) and p-toluenesulfonic acid hydrate (0.06 mmol), adding hexafluoroisopropanol (1 mL) and dichloroethane (1 mL) under the atmosphere, reacting for 23h at normal temperature, monitoring the reaction by TLC, removing the solvent by rotary evaporation after the reaction is finished, and separating the crude product by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/25-1/6, V/V) to obtain a target product 1k (108.3 mg, white solid, yield 90%).
The reaction equation is:
characterization of the above target product 1 k:
1 H NMR(600MHz,CDCl 3 )δ8.22–8.18(m,1H),7.98(s,1H),7.90–7.86(m,1H),7.72(d,J＝8.2Hz,2H),7.51–7.47(m,2H),7.45(d,J＝7.7Hz,1H),7.26–7.21(m,3H),7.18(t,J＝7.5Hz,1H),7.13(d,J＝7.7Hz,1H),4.86–4.78(m,1H),4.62(d,J＝2.4Hz,1H),2.37(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ194.7,164.2(t,J＝2.9Hz),145.3,143.7,139.7,137.8,135.5,130.3,129.7,128.9,127.0,127.0,126.9,126.9,126.5,123.5,123.1,54.5–54.4(m),46.2(t,J＝22.6Hz),21.3,carbon signals corresponding to the C 3 F 7 group cannot be identified due to C-F coupling；
19 F NMR(565MHz,CDCl 3 )δ 19 F NMR(565MHz,CDCl 3 )δ-80.34(t,J＝10.5Hz,3F),-111.93(ddd,J＝278.2,20.4,10.0Hz,1F),-117.94–-118.66(m,1F),-123.72(ddd,J＝291.2,14.8,3.0Hz,1F),-124.62–-125.43(m,1F).
example 12
A10 mL eggplant-shaped bottle is taken, 2L (0.2 mmol) of nine-fluorobutyl 3-indolyl methanol protected by tosyl and p-toluenesulfonic acid hydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (1 mL) and dichloroethane (1 mL) are added under the atmosphere for reaction for 16h under normal temperature, TLC monitors the reaction, after the reaction is finished, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/25-1/6, V/V) to obtain 1L (117.3 mg, light yellow solid, yield 90%).
The reaction equation is:
characterization of the above target product 1 l:
1 H NMR(600MHz,CDCl 3 )δ8.24–8.17(m,1H),8.09–7.81(m,2H),7.72(d,J＝8.1Hz,2H),7.53–7.46(m,2H),7.40(d,J＝7.3Hz,1H),7.25–7.20(m,3H),7.18(t,J＝7.5Hz,1H),7.13(d,J＝7.7Hz,1H),4.90–4.80(m,1H),4.64(d,J＝2.1Hz,1H),2.37(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ194.7,164.2(t,J＝3.3Hz),145.3,143.8,139.8,137.7,135.4,130.3,129.7,128.9,127.0,126.5,123.5,123.1,117.2(q,J＝287.3Hz),54.7–54.5(m),46.7(t,J＝22.0Hz),21.3,carbon signals corresponding to the C 4 F 9 group cannot be identified due to C-F coupling；
19 F NMR(565MHz,CDCl 3 )δ-80.80(t,J＝9.1Hz,3F),-111.03–-111.90(m,1F),-116.38–-117.41(m,1F),-119.94–-120.61(m,1F),-121.29–-121.98(m,1F),-125.16–-125.83(m,1F),-125.84–-126.53(m,1F).
example 13
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indolemethanol 2m (0.2 mmol) protected by benzoyl and paratoluenesulfonic acid hydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (1 mL) and dichloroethane (1 mL) are added under the atmosphere, the reaction is carried out for 23h under normal temperature conditions, TLC monitors the reaction, solvent is removed by rotary evaporation after the reaction is finished, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/100-1/7,V/V) to obtain a target product 1m (50.0 mg, white solid, yield 88%).
The reaction equation is:
characterization of the above target product 1 m:
1 H NMR(600MHz,CDCl 3 )δ8.77(s,1H),8.18(d,J＝7.8Hz,1H),7.77(d,J＝8.0Hz,1H),7.71–7.65(m,2H),7.48(t,J＝7.4Hz,1H),7.46–7.40(m,2H),7.34(t,J＝7.4Hz,1H),7.30(d,J＝4.1Hz,2H),7.23–7.13(m,2H),4.65(qd,J＝8.0,2.8Hz,1H),4.58(s,1H)；
13 C NMR(150MHz,CDCl 3 )δ195.4,166.1,164.8(q,J＝2.2Hz),145.1,140.1,135.8,132.97,131.7,130.5,129.1,128.6(q,J＝0.6Hz),128.3,127.2,126.8,127.0,126.3,125.1(q,J＝279.6Hz),123.4,123.2,56.4–56.2(m),48.9(q,J＝31.3Hz)；
19 F NMR(565MHz,CDCl 3 )δ-70.11(d,J＝8.0Hz,3F).
example 14
Taking a 10mL eggplant-shaped bottle, sequentially adding acetyl-protected trifluoromethyl 3-indolyl methanol 2n (0.2 mmol) and p-toluenesulfonic acid hydrate (0.06 mmol), adding hexafluoroisopropanol (1 mL) and dichloroethane (1 mL) under the atmosphere, reacting for 11h under normal temperature, monitoring the reaction by TLC, removing the solvent by rotary evaporation after the reaction is finished, and separating the crude product by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/25-1/3, V/V) to obtain a target product 1n (60.0 mg, yellow solid, yield 77%).
The reaction equation is:
characterization of the above target product 1 n:
1 H NMR(600MHz,CDCl 3 )δ8.21–8.16(m,1H),8.06(s,1H),7.93–7.87(m,1H),7.51–7.44(m,3H),7.33(t,J＝7.5Hz,1H),7.24(t,J＝7.5Hz,1H),7.20(d,J＝7.5Hz,1H),4.62–4.50(m,2H),1.82(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ195.3,169.6,164.8(q,J＝2.0Hz),145.1,140.3,135.6,131.8(q,J＝3.3Hz),130.4,129.0,128.6,128.5(q,J＝2.6Hz),127.2,126.9,126.5,125.0(q,J＝279.9Hz),123.4,123.3,55.9,49.4(q,J＝30.7Hz),23.1；
19 F NMR(565MHz,CDCl 3 )δ-70.21(d,J＝7.5Hz,3F).
example 15
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indolemethanol 2o (0.2 mmol) protected by p-nitrobenzoyl and p-toluenesulfonic acid hydrate (0.06 mmol) are sequentially added, hexafluoroisopropanol (1 mL) and dichloroethane (1 mL) are added under the atmosphere for reaction at normal temperature for 23h, TLC monitors the reaction, solvent is removed by rotary evaporation after the reaction is finished, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/50-1/6, V/V) to obtain the target product 1o (113.2 mg, light yellow solid, yield 95%).
The reaction equation is:
characterization of the above target product 1 o:
1 H NMR(600MHz,CDCl 3 )δ8.16–8.11(m,1H),8.02(s,1H),7.89–7.85(m,1H),7.63(d,J＝8.6Hz,2H),7.54(d,J＝8.6Hz,2H),7.49–7.46(m,2H),7.02(d,J＝8.7Hz,1H),6.90(d,J＝2.4Hz,1H),6.76(dd,J＝8.7,2.7Hz,1H),4.54(qd,J＝7.8,3.3Hz,1H),4.27(d,J＝3.3Hz,1H),3.72(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ195.0,164.4,159.7,145.0,139.7,139.3,135.7,132.4,130.5,128.3,128.2,128.0,126.9,126.5,124.8(q,J＝279.7Hz),123.5,123.4,123.3,113.6,113.4,55.4,54.3,48.5(q,J＝30.2Hz)；
19 F NMR(565MHz,CDCl 3 )δ-70.42(d,J＝8.0Hz,3F).
example 16
In order to verify the potential industrial scale-up application of the present invention, gram scale-up experiments were also performed with the following specific steps.
A100 mL round bottom flask is taken, trifluoromethyl 3-indolemethanol 2a (2 mmol, 1.003g) protected by p-toluenesulfonyl and p-toluenesulfonic acid hydrate (0.6 mmol) are sequentially added, hexafluoroisopropanol (10 mL) and dichloroethane (10 mL) are added under the atmosphere to react for 11h under normal temperature, TLC monitors the reaction, after the reaction is finished, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/80-1/10, V/V) to obtain a target product 1a (803.4 g, white solid, yield 80%).
The reaction equation is:
it can be seen that when the raw material p-toluenesulfonyl-protected trifluoromethyl 3-indolemethanol 2a is amplified to 2mmol (1.003 g), the expected product can be obtained in 80% yield when the p-toluenesulfonic acid hydrate catalyst loading is 30mol%, and the invention is fully shown to be applicable to industrial application.
Example 17
The 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compounds prepared in examples 1-16 can be used as intermediates for further structural modification and chemical conversion into various compounds. The present example performs the following experiments:
a10 mL round bottom flask was taken and the 3-trifluoromethyl benzothiophene [ b ] was allowed to stand under atmospheric conditions]Cyclopentenone Compound 1a (0.15 mmol) was dissolved in a dry mixed solvent of THF (1.5 mL) and MeOH (1.5 mL), followed by addition of NaBH at 0deg.C 4 (0.45 mmol) and B (OH) 3 (0.45 mmol) and stirring at normal temperature to react for 1h (thin layer chromatography tracking reaction until reaction is complete), extracting with ethyl acetate twice after reaction, mixing organic phases, washing with saturated sodium chloride aqueous solution, drying with anhydrous magnesium sulfate, filtering, concentrating by rotary evaporation to remove solvent, separating crude product by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/50-1/7,V/V), to obtain reduction product 3 (74.7 mg, white solid, yield 99%).
Characterization of the above target product 3:
1 H NMR(600MHz,CDCl 3 )δ7.89(d,J＝7.4Hz,1H),7.83(d,J＝7.6Hz,1H),7.80(s,1H),7.63(d,J＝8.1Hz,2H),7.37(dq,J＝13.6,6.9Hz,2H),7.26–7.20(m,3H),7.19–7.13(m,2H),7.07(d,J＝7.9Hz,1H),5.33(t,J＝4.4Hz,1H),4.30–4.27(m，1H)，4.15–4.07(m，2H)，2.40(s，3H)；
13 C NMR(150MHz,CDCl 3 )δ145.5,144.1,143.1,137.5,137.2,136.0,133.7,133.4,129.8,128.0,127.9,127.2,127.2,126.6,125.3(q,J＝279.6Hz),125.1,125.0,123.4,122.4,80.0,53.9,51.9(q,J＝30.5Hz),21.5；
19 F NMR(565MHz,CDCl 3 )δ-70.75(d,J＝8.0Hz,3F).
it can be seen that, taking 3-trifluoromethyl benzothiophene [ b ] cyclopentenone compound 1a prepared in example 16 as an example, alcohol product 3 can be obtained by reducing carbonyl group with sodium borohydride, and the reaction equation is as follows:
example 18
Examples 1-16 the 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compounds obtained can be used as intermediates for further structural modification and chemical conversion to various compounds. The present example performs the following experiments:
a10 mL round bottom flask was taken, 3-trifluoromethyl benzothiophene [ b ] cyclopentenone compound 1a (0.15 mmol) was dissolved in a mixed solvent of DCM (1.2 mL) and HFIP (0.3 mL) under atmospheric conditions, NBS (0.45 mmol) was added, the reaction was carried out at room temperature for 2h (thin layer chromatography was followed until the reaction was complete), the reaction was completed, dichloromethane was extracted twice, the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by rotary evaporation, and the crude product was separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/50 to 1/10, V/V) to give product 4 (77.1 mg, brown solid, yield 78%).
Characterization of the above target product 4:
1 H NMR(600MHz,CDCl 3 )δ8.30–8.23(m,1H),7.91–7.85(m,1H),7.71(d,J＝8.2Hz,2H),7.58(s,1H),7.54–7.45(m,2H),7.22(d,J＝8.8Hz,3H),6.75(d,J＝30.4Hz,1H),5.45(s,1H),4.44–4.24(m,1H),2.38(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ192.8,163.3–163.2(m),145.0,144.3,140.8,140.2,135.9,135.3,133.5,131.2–131.1(m),130.5,129.5,128.0,126.8,126.4,125.9–125.8(m),124.8(q,J＝279.2Hz),123.6,123.2,122.4,55.1,51.0(q,J＝30.0Hz),21.5；
19 F NMR(565MHz,CDCl 3 )δ-69.98(d,J＝6.8Hz,3F).
it can be seen that, taking 3-trifluoromethylbenzothiophene [ b ] cyclopentenone compound 1a prepared in example 16 as an example, 3-trifluoromethylbenzothiophene [ b ] cyclopentenone compound 1a can also be aniline bis-brominated product 4 under the action of N-bromosuccinimide (NBS), the reaction equation is as follows:
example 19
Examples 1-16 the 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compounds obtained can be used as intermediates for further structural modification and chemical conversion to various compounds. The present example performs the following experiments:
a10 mL round bottom flask was taken, 3-trifluoromethylbenzothiophene [ b ] cyclopentenone 1a (0.15 mmol) was added, THF (1.5 mL) was added under argon atmosphere, then n-BuLi (0.45 mmol) was gradually added dropwise at-78deg.C to react for 8h (thin layer chromatography was followed by completion of the reaction), after completion of the reaction, 2mL saturated ammonium chloride solution was added at-78deg.C to quench and stir to room temperature, ethyl acetate was extracted twice, the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by rotary evaporation, and the crude product was separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/50-1/7,V/V) to give product 5 (39.5 mg, pale yellow solid, yield 52%).
Characterization of the above target product 5:
1 H NMR(600MHz,CDCl 3 )δ8.83(s,1H),7.86(d,J＝7.2Hz,1H),7.81(d,J＝6.8Hz,1H),7.73(d,J＝8.0Hz,1H),7.60(d,J＝7.8Hz,2H),7.42–7.36(m,2H),7.34–7.29(m,1H),7.25(d,J＝9.3Hz,2H),7.15(d,J＝3.3Hz,2H),3.92(d,J＝7.1Hz,1H),3.89–3.79(m,1H),2.83(s,1H),2.41(s,3H),2.24–2.14(m,1H),2.09–2.01(m,1H),1.40–1.30(m,3H),1.24–1.15(m,1H),0.86(t,J＝6.8Hz,3H)；
13 C NMR(150MHz,CDCl 3 )δ145.6,144.0,143.7,138.5,137.6,137.0,133.8,132.7,129.9,129.3,128.7,126.4,126.0(q,J＝279.7Hz),125.4,124.9,123.9,123.8,121.4,84.7,58.6,49.8(q,J＝28.7Hz),39.4,26.9,22.8,21.4,13.8；
19 F NMR(565MHz,CDCl 3 )δ-70.48(d,J＝7.7Hz,3F).
it can be seen that, taking 3-trifluoromethyl benzothiophene [ b ] cyclopentenone compound 1a prepared in example 16 as an example, 3-trifluoromethyl benzothiophene [ b ] cyclopentenone compound 1a can also undergo nucleophilic addition reaction with n-butyllithium in tetrahydrofuran solution at-78 ℃ to obtain tertiary alcohol 5, and the reaction equation is as follows:
example 20
Examples 1-16 the 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compounds obtained can be used as intermediates for further structural modification and chemical conversion to various compounds. The present example performs the following experiments:
a10 mL round bottom flask was charged with 3-trifluoromethylbenzothiophene [ b ] cyclopentenone compound 1a (0.15 mmol), iodobenzene acetate (0.3 mmol) and cesium carbonate (0.18 mmol), followed by sequentially adding chloroform (3 mL) and tetrabutylammonium iodide (0.24 mmol) under atmospheric conditions and reacting for 12 hours at 0℃until the reaction was completed (after the completion of the reaction by thin layer chromatography, 2mL of saturated aqueous sodium thiosulfate solution was added at 0℃for quenching and stirring to room temperature, the organic phase was extracted twice with methylene chloride, and washed with saturated aqueous sodium chloride solution. The organic phases were combined, dried over anhydrous magnesium sulfate, concentrated by rotary evaporation, and the crude product was separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/25 to 1/5, V/V) to give product 6 (33.3 mg, pale yellow solid, yield 43%).
Characterization of the above target product 6:
1 H NMR(600MHz,CDCl 3 )δ8.28–8.23(m,1H),7.95–7.90(m,1H),7.79(d,J＝7.8Hz,2H),7.65(d,J＝7.7Hz,1H),7.54–7.50(m,2H),7.45(d,J＝8.4Hz,1H),7.36–7.31(m,1H),7.23(d,J＝8.0Hz,2H),7.14(t,J＝7.5Hz,1H),3.64(s,1H),2.38(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ189.1,160.3,145.7,145.0,142.0,140.7,136.7,131.9,130.0,129.9,127.7,127.1,126.5,125.6,124.9,124.7,124.0,123.2,115.0,93.5,21.6；
19 F NMR(565MHz,CDCl 3 )δ-66.01(s,3F).
it can be seen that, taking the 3-trifluoromethyl benzothiophene [ b ] cyclopentenone compound 1a prepared in example 16 as an example, the 3-trifluoromethyl benzothiophene [ b ] cyclopentenone compound 1a can be oxidized and cyclized under the action of iodobenzene acetate, tetrabutylammonium iodide and alkali to obtain a product 6, and the reaction equation is as follows:
example 21
On the basis of example 1, the reaction conditions such as acid catalyst, solvent and reaction time were optimized, and the specific optimization results are shown in the following table 1:
TABLE 1
As can be seen from the data in Table 1, tsOH.H was first used at normal temperature in a mixed solvent of Hexafluoroisopropanol (HFIP) and 1, 2-dichloroethane (1:1) or in a solvent using hexafluoroisopropanol alone 2 O (10 mol%) as catalyst enables to obtain the desired product 1a in an isolated yield of more than 70%. In the case of using 1, 2-dichloroethane, tetrahydrofuran and toluene as solvents alone, respectively, no reaction occurs. By changing the ratio of hexafluoroisopropanol to dichloroethane, it was found that the yield was better at a ratio of 1:1. When the amount of p-toluenesulfonic acid monohydrate as a catalyst was increased, tsOH.H was found 2 O (30 mol%) works best as a catalyst and gives the desired product 1a in 90% isolated yield. While other common acid catalysts, such as the reaction decomposition when stronger trifluoromethanesulfonic acid is used; and when trifluoroacetic acid is used as a catalyst, the reaction cannot be performed. The blank control test shows thatNo reaction takes place without catalyst.
The method of the invention does not need to use a metal catalyst, and only takes the low-cost paratoluenesulfonic acid hydrate as the catalyst, thereby successfully realizing the high-efficiency synthesis of the 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound. The method has the advantages of simple and easily obtained raw materials, mild conditions, high yield, wide substrate range, atom economy and the like.
It should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered in the scope of the claims of the present invention.
Claims (10)
1. A 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound characterized by: the structural formula is shown as formula (I):
wherein R is 1 One of hydrogen, halogen, ester group, sulfonyl oxygen group, nitro group, cyano group, methoxy group, methyl group, aldehyde group, allyloxy group, benzoyloxy group, methyl acrylate group and phenyl group;
p is selected from one of P-toluenesulfonyl, P-bromobenzenesulfonyl, benzoyl and acetyl;
n is selected from 1,2, 3, 4, 6 or 7.
2. The method for synthesizing a 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound according to claim 1, wherein: taking a compound shown in a formula (II) as a raw material, and reacting in a solvent under the catalysis of a catalyst to obtain the compound shown in the formula (I);
wherein R in formula (II) 1 P, n and R in formula (I) 1 The correspondence between P, n is consistent.
3. The method for synthesizing a 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound according to claim 2, wherein: the catalyst is selected from one of paratoluenesulfonic acid hydrate, trifluoromethanesulfonic acid and trifluoroacetic acid.
4. A method for synthesizing a 3-perfluoroalkyl benzo [ b ] cyclopentane [ d ] thiophenone compound according to claim 2 or 3, wherein: the molar ratio of the catalyst to the compound shown in the formula (II) is 0.1-0.5:1.
5. The method for synthesizing a 3-perfluoroalkyl benzo [ b ] cyclopentane [ d ] thiophenone compound according to claim 4, wherein: the molar ratio of the catalyst to the compound shown in the formula (II) is 0.3:1.
6. The method for synthesizing a 3-perfluoroalkyl benzo [ b ] cyclopentane [ d ] thiophenone compound according to any one of claims 2, 3 and 5, wherein: the solvent is hexafluoroisopropanol or a mixed solvent of hexafluoroisopropanol and dichloroethane.
7. The method for synthesizing a 3-perfluoroalkyl benzo [ b ] cyclopentane [ d ] thiophenone compound according to claim 6, wherein: the volume ratio of the hexafluoroisopropanol to the dichloroethane is 1:0.5-4.
8. The method for synthesizing a 3-perfluoroalkyl benzo [ b ] cyclopentane [ d ] thiophenone compound according to claim 7, wherein: the volume ratio of hexafluoroisopropanol to dichloroethane is 1:1.
9. The method for synthesizing a 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound according to any one of claims 2, 3, 5, 7, 8, wherein: the concentration of the compound shown in the formula (II) in the solvent is 0.05-0.2 mol/L.
10. The method for synthesizing a 3-perfluoroalkyl benzothiophene [ b ] cyclopentenone compound according to any one of claims 2, 3, 5, 7, 8, wherein: the reaction temperature is 5-60 ℃ and the reaction time is 5-48 hours.
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