CN116589388A - Preparation method of beta-ketosulfone compound - Google Patents
Preparation method of beta-ketosulfone compound Download PDFInfo
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- CN116589388A CN116589388A CN202310556852.8A CN202310556852A CN116589388A CN 116589388 A CN116589388 A CN 116589388A CN 202310556852 A CN202310556852 A CN 202310556852A CN 116589388 A CN116589388 A CN 116589388A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 56
- 238000006243 chemical reaction Methods 0.000 claims abstract description 136
- -1 alkenyl azide compound Chemical class 0.000 claims abstract description 92
- 239000002904 solvent Substances 0.000 claims abstract description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 claims abstract description 8
- 239000007800 oxidant agent Substances 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 230000001590 oxidative effect Effects 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims abstract description 6
- 239000012298 atmosphere Substances 0.000 claims abstract description 3
- 239000011261 inert gas Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 165
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 62
- 239000012074 organic phase Substances 0.000 claims description 53
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 52
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 50
- 239000007788 liquid Substances 0.000 claims description 35
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 31
- 238000004440 column chromatography Methods 0.000 claims description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 26
- 239000003208 petroleum Substances 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 7
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 6
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- 229940045803 cuprous chloride Drugs 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- DORMTBIPKNPJPY-UHFFFAOYSA-N acetic acid;iodobenzene Chemical compound CC(O)=O.IC1=CC=CC=C1 DORMTBIPKNPJPY-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 125000004799 bromophenyl group Chemical group 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 2
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- 229940076286 cupric acetate Drugs 0.000 claims description 2
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 2
- 229940112669 cuprous oxide Drugs 0.000 claims description 2
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 2
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000006501 nitrophenyl group Chemical group 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 2
- HDMGAZBPFLDBCX-UHFFFAOYSA-M potassium;sulfooxy sulfate Chemical compound [K+].OS(=O)(=O)OOS([O-])(=O)=O HDMGAZBPFLDBCX-UHFFFAOYSA-M 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 3
- HWUPLUNLNUHIQZ-UHFFFAOYSA-N copper;trifluoromethanesulfonic acid Chemical compound [Cu].OS(=O)(=O)C(F)(F)F.OS(=O)(=O)C(F)(F)F HWUPLUNLNUHIQZ-UHFFFAOYSA-N 0.000 claims 1
- 150000003254 radicals Chemical class 0.000 abstract description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 4
- 230000007062 hydrolysis Effects 0.000 abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 4
- 238000011065 in-situ storage Methods 0.000 abstract description 3
- 238000007342 radical addition reaction Methods 0.000 abstract description 3
- 239000003513 alkali Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000007142 ring opening reaction Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 67
- 239000000243 solution Substances 0.000 description 53
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 48
- 238000012512 characterization method Methods 0.000 description 24
- 239000012299 nitrogen atmosphere Substances 0.000 description 24
- 230000035484 reaction time Effects 0.000 description 24
- 229920006395 saturated elastomer Polymers 0.000 description 24
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 24
- 235000017557 sodium bicarbonate Nutrition 0.000 description 24
- 239000007858 starting material Substances 0.000 description 24
- 239000010949 copper Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 238000010523 cascade reaction Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 3
- 229940001584 sodium metabisulfite Drugs 0.000 description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 239000000370 acceptor Substances 0.000 description 2
- UEQYFPCXXRUPKQ-UHFFFAOYSA-N azidoethene Chemical class C=CN=[N+]=[N-] UEQYFPCXXRUPKQ-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 150000002978 peroxides Chemical class 0.000 description 2
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical compound N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 description 2
- ISNKSXRJJVWFIL-UHFFFAOYSA-N (sulfonylamino)amine Chemical compound NN=S(=O)=O ISNKSXRJJVWFIL-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 238000010499 C–H functionalization reaction Methods 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000012803 optimization experiment Methods 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 238000012113 quantitative test Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
-
- 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
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/34—Sulfur atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a beta-ketone sulfone compound, which comprises the steps of adding an alkenyl azide compound, a metabisulfite and oxime ester compound, a catalyst, an oxidant and water into a solvent, placing the solvent in an inert gas atmosphere, stirring and reacting, and obtaining the beta-ketone sulfone compound after complete post-treatment of the reaction. Specifically, an alkyl free radical is formed through oxime ester ring opening, then a cyanoalkyl sulfonyl free radical is formed in situ by serially connecting metabisulfite, and the cyanoalkyl sulfonyl free radical is further subjected to free radical addition, hydrogen atom capture and hydrolysis with an alkenyl azide derivative to form the beta-ketosulfone compound. The invention realizes the preparation of the product in one step, has simple operation, no need of adding alkali in the reaction process, mild reaction conditions and high reaction yield, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a beta-ketosulfone compound.
Background
The beta-ketosulfone is composed of three basic functional groups of sulfonyl, carbonyl and active methylene (alpha-acidic proton), is a general component in organic synthesis, and can be further converted into carbocycle and heterocyclic compounds with potential value. These compounds have attracted considerable attention for their unique biological activities, including anti-hepatitis, anti-bacterial, anti-fungal, etc. Conventionally, β -ketosulfones have been mainly produced by various methods such as sulfonation of carbonyl or silylether compounds, acylation of diazonium compounds with aldehydes or alkyl sulfones, etc., but these methods generally have problems of troublesome raw material production, complicated synthesis steps or after-treatment.
Alkenyl azide as the combination of azide and alkenyl exhibits high reactivity, becomes a highly versatile synthon in organic synthesis, can react with reagents such as electrophiles, nucleophiles, dipoles and radical acceptors, and performs C-H functionalization, hydrolysis, cycloaddition and tandem reactions. Among them, the three-component radical tandem process of vinyl azide compounds is attracting attention due to its high degree of adjustment and chemical selectivity, and rapid and selective obtaining of different products under mild conditions. And the vinyl azide can be used as a free radical acceptor to easily form beta-ketone sulfone, beta-carboline and beta-ketone phosphine, which is a novel structure for constructing beta-C (sp 3 ) The framework of the H molecule provides a new route.
In recent years, alkenyl azide is taken as a synthon to construct a beta-ketone sulfone compound, for example, CN105777593A discloses a preparation method of a beta-aryl ketone substituted sulfone compound, wherein the beta-aryl ketone substituted sulfone compound is prepared by reacting alkenyl azide derivatives with sulfonyl hydrazides under the catalysis of KI and the participation of tert-butyl peroxide. Both the alkenyl azide and the sulfur source of such reactions are limited, in that the alkenyl azide is only linked to an aryl or alkyl group to participate in the reaction and the sulfonyl source is limited to arylsulfonyl hydrazide compounds. The source range of the raw materials is narrow, and the popularization and the application are not facilitated. Moreover, the sulfonyl hydrazine is exposed to open fire, high heat or contact with an oxidant, so that the danger of combustion and explosion is caused, toxic gas is emitted, tert-butyl peroxide is used as the oxidant, the peroxide is expensive, the peroxide is easy to explode, and the danger is easy to occur.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention aims to provide a preparation method of beta-ketosulfone compounds, which solves the technical problems that the existing preparation method is complex in preparation steps and limited in raw material sources, and is not beneficial to popularization and application.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
the preparation method of the beta-ketone sulfone compound comprises the steps of adding an alkenyl azide compound shown in a formula 1, a metabisulfite shown in a formula 2, an oxime ester compound shown in a formula 3, a catalyst, an oxidant and water into a solvent, stirring and reacting in an inert gas atmosphere, and obtaining the beta-ketone sulfone compound shown in a formula I after complete post-treatment, wherein the reaction formula is as follows:
wherein in formula 1, R 1 Selected from phenyl, tolyl, n-butylphenyl, t-butylphenyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, cyanophenyl, nitrophenyl, naphthyl, biphenyl, thienyl, n-hexyl, n-decyl, phenethyl or phenoxymethyl; in the formula 2, A is Na or K; in formula 3, Y is CH 2 Or O; r is R 2 Selected from phenyl or benzyloxy.
Further, the catalyst is selected from one or more of cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, cupric acetate and copper trifluoromethane sulfonate. The catalyst is preferably cuprous chloride.
Further, the oxidant is selected from one or more of potassium hydrogen peroxymonosulfate, potassium persulfate, iodobenzene acetate, tert-butyl hydroperoxide and di-tert-butyl peroxide. The oxidizing agent is preferably a potassium hydrogen peroxymonosulfate complex salt.
Further, the solvent is selected from one or more of tetrahydrofuran, acetonitrile, ethyl acetate and ethanol. The solvent is preferably tetrahydrofuran.
Further, the temperature of the stirring reaction is 80-100 ℃. The temperature of the stirring reaction is preferably 90 ℃.
Further, the molar ratio of the alkenyl azide compound, metabisulfite, oxime ester compound, and water is 1:2:2.
Further, the molar ratio of the alkenyl azide to water is 1:5-40. The molar ratio of alkenyl azide to water is preferably 1:20.
And further, the post-treatment is to extract and separate the reaction liquid after the reaction is completed by using ethyl acetate, wash an organic phase by using saturated sodium bicarbonate aqueous solution, then re-separate the organic phase, dry the obtained organic phase by using anhydrous sodium sulfate, decompress concentrate to remove the solvent, separate the residue by column chromatography, and obtain the beta-ketone sulfone compound I by using ethyl acetate/petroleum ether as an eluent.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention forms alkyl free radical through oxime ester ring opening, then forms cyanoalkyl sulfonyl free radical in situ by serial connection of metabisulfite, and forms beta-ketone sulfone compound by free radical addition, hydrogen atom capture and hydrolysis with alkenyl azide derivative. The preparation method realizes three-component radical tandem reaction of alkenyl azide, oxime ester and metabisulfite through the tandem process of radical relay, radical addition, hydrogen atom capture and hydrolysis, and constructs 4 new chemical bonds comprising 1 C.ident.N bond, 2C-S bonds and 1 C=O bond in one step. The preparation method is simple to operate and easy to implement; no alkali is needed in the reaction process, the reaction condition is mild, the reaction yield is high, and the method is suitable for industrial production.
2. The invention has wide sources of raw materials, low price, low cost and high safety, and is suitable for popularization and application.
Detailed Description
The following describes the embodiments of the present invention in further detail with reference to specific examples.
Numerical ranges in this disclosure are understood to also specifically disclose each intermediate value between the upper and lower limits of the ranges. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control. As used herein, the terms "comprising," "including," "having," "containing," and the like are intended to be inclusive and mean an inclusion, but not limited to.
The experimental methods used in the present invention are conventional methods unless otherwise specified.
The materials, reagents and the like used in the present invention can be synthesized by a method of purchase or known method unless otherwise specified.
In the quantitative test of the invention, three repeated experiments are set, and the results are averaged.
Examples 1-19 are reaction condition optimization experiments.
Note that: in the present invention, "equiv" means equivalent and is based on the molar amount of alkenyl azide compound, such as: if the addition amount of the alkenylazide compound is 0.2mmol and the addition amount of sodium metabisulfite is 2.0equiv, the addition amount of sodium metabisulfite is 0.4mmol, and so on.
Example 1
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (35.8 mg,0.2 mmol) represented by formula 1a, a sulfur dioxide source (sodium metabisulfite) represented by formula 2a (76.0 mg,0.4mmol,2.0 equiv), oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), potassium hydrogen peroxydisulfate complex salt (Oxone) (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv), tetrahydrofuran (THF) (1.0 mL) was added, the reaction vessel was stirred at 90℃under nitrogen atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was separated by extraction with ethyl acetate, the organic phase was separated by washing with saturated aqueous sodium hydrogencarbonate solution and then separated by column chromatography, the solvent was removed under reduced pressure after drying the obtained organic phase with anhydrous sodium sulfate, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-1 (89% yield). The product structure characterization data are: 1 HNMR(400MHz,CDCl 3 )δ:7.92(d,J＝8.4Hz,2H),7.48(d,J＝8.4Hz,2H),4.61(s,2H),3.42(t,J＝7.2Hz,2H),2.62(t,J＝7.2Hz,2H),2.30-2.23(m,2H)； 13 C NMR(101MHz,CDCl 3 )δ:187.9,141.6,133.7,130.6,129.4,118.1,59.9,51.8,18.2,16.2.
example 2
The preparation method of the beta-ketosulfone compound mainly has the same steps as in the example 1, and the difference is that: the target product I-1 was obtained in a yield of 76% by substituting CuBr for CuCl.
Example 3
The preparation method of the beta-ketosulfone compound mainly has the same steps as in the example 1, and the difference is that: the CuI is used for replacing CuCl, and the yield of the target product I-1 is 80%.
Example 4
The preparation method of the beta-ketosulfone compound mainly has the same steps as in the example 1, and the difference is that: with Cu 2 O replaces CuCl, and the yield of the target product I-1 is 52%.
Example 5
The preparation method of the beta-ketosulfone compound is mainly the same as in example 1, but is notThe method is characterized in that: by Cu (OAc) 2 The yield of the target product I-1 was 63% instead of CuCl.
Example 6
The preparation method of the beta-ketosulfone compound mainly has the same steps as in the example 1, and the difference is that: by Cu (OTf) 2 The yield of the target product I-1 was 65% instead of CuCl.
Example 7
The preparation method of the beta-ketosulfone compound mainly has the same steps as in the example 1, and the difference is that: by K 2 S 2 O 8 The yield of the target product I-1 was 70% instead of Oxone.
Example 8
The preparation method of the beta-ketosulfone compound mainly has the same steps as in the example 1, and the difference is that: by PhI (OAc) 2 The yield of the target product I-1 was 83% instead of Oxone.
Example 9
The preparation method of the beta-ketosulfone compound mainly has the same steps as in the example 1, and the difference is that: replacement of Oxone with t-butylhydroperoxide (TBHP) gives a yield of 68% of the desired product I-1.
Example 10
The preparation method of the beta-ketosulfone compound mainly has the same steps as in the example 1, and the difference is that: the target product I-1 was obtained in 58% yield by substituting di-tert-butyl peroxide (DTBP) for Oxone.
Example 11
The preparation method of the beta-ketosulfone compound mainly has the same steps as in the example 1, and the difference is that: the THF was replaced with acetonitrile to give the desired product I-1 in 80% yield.
Example 12
The preparation method of the beta-ketosulfone compound mainly has the same steps as in the example 1, and the difference is that: the ethyl acetate was used in place of THF to give the desired product I-1 in 40% yield.
Example 13
The preparation method of the beta-ketosulfone compound mainly has the same steps as in the example 1, and the difference is that: the THF was replaced with ethanol to give the desired product I-1 in 71% yield.
Example 14
The preparation method of the beta-ketosulfone compound mainly has the same steps as in the example 1, and the difference is that: the water content was 5.0equiv, giving a yield of the desired product I-1 of 60%.
Example 15
The preparation method of the beta-ketosulfone compound mainly has the same steps as in the example 1, and the difference is that: the water content was 10.0equiv, giving 83% yield of the desired product I-1.
Example 16
The preparation method of the beta-ketosulfone compound mainly has the same steps as in the example 1, and the difference is that: the water content was 40.0equiv, giving a yield of the desired product I-1 of 45%.
Example 17
The preparation method of the beta-ketosulfone compound mainly has the same steps as in the example 1, and the difference is that: the reaction temperature was 80℃to give a yield of the desired product I-1 of 74%.
Example 18
The preparation method of the beta-ketosulfone compound mainly has the same steps as in the example 1, and the difference is that: the reaction temperature was 100deg.C, and the yield of the target product I-1 was 82%.
Example 19
The preparation method of the beta-ketosulfone compound mainly has the same steps as in the example 1, and the difference is that: by K 2 S 2 O 5 Instead of Na 2 S 2 O 5 The yield of the target product I-1 was 69%.
As can be seen from the above examples 1 to 19, the optimal reaction conditions are those of example 1, i.e., the reaction was stirred at 90℃under nitrogen atmosphere. Based on obtaining the optimal reaction conditions, the inventor further selects alkenyl azide compounds and oxime ester compounds with different substituents as raw materials under the optimal reaction conditions to develop a copper-catalyzed three-component radical tandem reaction method.
Example 20
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (35.8 mg,0.2 mmol) represented by formula 1a, a sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (133.2 mg,0.4mmol,2.0 equiv) represented by formula 3b, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv), then THF (1.0 mL) was added, then the reaction vessel was stirred at 90℃under nitrogen atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate to give a liquid, the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and then separated into a liquid, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-2 (81% yieldd). The product structure characterization data are: 1 HNMR(400MHz,CDCl 3 )δ:7.80(d,J＝8.4Hz,2H),7.45(d,J＝8.4Hz,2H),7.38-7.30(m,5H),4.44(d,J＝15.2Hz,1H),4.07(d,J＝15.2Hz,1H),3.93-3.88(m,1H),3.80-3.73(m,1H),3.68-3.62(m,1H),2.92(d,J＝6.4Hz,2H)； 13 C NMR(101MHz,CDCl 3 )δ:187.7,141.5,138.2,133.7,130.3,129.4,129.3,128.7,127.4,117.1,60.3,57.2,36.4,24.4；HRMS m/z(ESI)calcd for C 18 H 17 ClNO 3 S([M+H] + )362.0612found362.0617.
example 21
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (35.8 mg,0.2 mmol) represented by formula 1a, a sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (145.2 mg,0.4mmol,2.0 equiv) represented by formula 3c, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv) and thenTHF (1.0 mL), then the reactor was stirred at 90 ℃ under nitrogen atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate, the organic phase was separated by washing with saturated aqueous sodium bicarbonate solution and then separated by water, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-3 (76% yield). The product structure characterization data are: 1 HNMR(400MHz,CDCl 3 )δ:7.74(d,J＝8.4Hz,2H),7.43(d,J＝8.4Hz,2H),7.34-7.31(m,5H),4.75(d,J＝10.8Hz,1H),4.64(d,J＝10.8Hz,1H),4.58(s,2H),4.43-4.37(m,1H),3.95-3.89(m,1H),3.44-3.39(m,1H),2.86-2.80(m,1H),2.78-2.72(m,1H)； 13 C NMR(101MHz,CDCl 3 )δ:187.7,141.3,135.8,133.7,130.2,129.3,128.7,128.6,128.3,115.9,73.0,70.4,61.3,56.7,22.7；HRMS m/z(ESI)calcd for C 19 H 19 ClNO 4 S([M+H] + )392.0718,found 392.0716.
example 22
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (35.8 mg,0.2 mmol) represented by formula 1a, a sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (103.6 mg,0.4mmol,2.0 equiv) represented by formula 3d, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv), THF (1.0 mL) was added, the reaction vessel was stirred at 90℃under nitrogen atmosphere until the starting material disappeared (reaction time: 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate to give a solution, the organic phase was washed with a saturated aqueous sodium hydrogencarbonate solution and then again with a solution, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the target product I-4 (79% yield). The product structure characterization data are: 1 HNMR(400MHz,CDCl 3 )δ:7.91(d,J＝8.4Hz,2H),7.51(d,J＝8.0Hz,2H),4.83(s,2H),4.70(s,2H),4.66(s,2H)； 13 C NMR(101MHz,CDCl 3 )δ:187.3,141.7,133.7,130.4,129.5,114.3,82.3,57.4,56.6；HRMS m/z(ESI)calcd for C 11 H 11 ClNO 4 S([M+H] + )288.0092,found 288.0098.
example 23
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (35.8 mg,0.2 mmol) represented by formula 1b, a sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv), then THF (1.0 mL) was added, then the reaction vessel was stirred at 90℃under nitrogen atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate to give a liquid, the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and then separated into a liquid, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-5 (82% yieldd). The product structure characterization data are: 1 H NMR(400MHz,CDCl 3 )δ:7.94(s,1H),7.85(d,J＝8.0Hz 1H),7.61(d,J＝8.0Hz 1H),7.46(t,J＝8.0Hz,1H),4.63(s,2H),3.43(t,J＝7.6Hz,2H),2.62(t,J＝7.2Hz,2H),2.30-2.23(m,2H)； 13 C NMR(101MHz,CDCl 3 )δ:188.0,136.9,135.3,134.6,130.3,128.9,127.4,118.2,59.9,51.8,18.1,16.2.
example 24
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (35.8 mg,0.2 mmol) represented by formula 1c, a sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv), then THF (1.0 mL) was added, then the reaction vessel was stirred at 90℃under nitrogen atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate to give a liquid, the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and then separated into a liquid, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-6 (79% yield). The product structure characterization data are: 1 HNMR(500MHz,CDCl 3 )δ:7.67-7.65(m,1H),7.52-7.46(m,2H),7.41(t,J＝7.5Hz 1H),4.70(s,2H),3.48(t,J＝7.5Hz,2H),2.65(t,J＝7.5Hz,2H),2.32-2.26(m,2H)； 13 C NMR(126MHz,CDCl 3 )δ:191.1,136.9,133.6,131.6,130.8,130.5,127.4,118.1,63.1,52.2,18.2,16.2.
example 25
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (31.8 mg,0.2 mmol) represented by formula 1d, a sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv.) and THF (1.0 mL) were added, and the reactor was stirred at 90deg.C under nitrogen to reactTLC monitors the progress of the reaction until the starting material disappeared (reaction time: 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate, the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and then separated into a liquid, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-7 (78% yield). The product structure characterization data are: 1 HNMR(400MHz,CDCl 3 )δ:7.88(d,J＝8.0Hz,2H),7.31(d,J＝8.0Hz,2H),4.59(s,2H),3.42(t,J＝7.6Hz,2H),2.61(t,J＝7.2Hz,2H),2.43(s,3H),2.30-2.23(m,2H)； 13 C NMR(101MHz,CDCl 3 )δ:188.4,146.2,133.0,129.7,129.3,118.1,59.9,51.7,21.8,18.2,16.2.
example 26
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (40.2 mg,0.2 mmol) represented by formula 1e, a sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv), then THF (1.0 mL) was added, then the reaction vessel was stirred at 90℃under nitrogen atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate to give a liquid, the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and then separated into a liquid, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-8 (73% yield). The product structure characterization data are: 1 HNMR(400MHz,CDCl 3 )δ:7.73(d,J＝8.0Hz,2H),7.33(d,J＝8.0Hz,2H),4.40(s,2H),3.24(t,J＝7.2Hz,2H),2.42(t,J＝7.2Hz,2H),2.12-2.05(m,2H),1.14(s,9H)； 13 C NMR(101MHz,CDCl 3 )δ:188.4,159.0,132.9,129.3,126.1,118.1,59.9,51.7,35.3,30.9,18.3,16.3.HRMS m/z(ESI)calcd for C 16 H 22 NO 3 S([M+H] + )308.1315,found 308.1220.
example 27
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (40.2 mg,0.2 mmol) represented by formula 1f, sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv), then THF (1.0 mL) was added, then the reaction vessel was stirred at 90℃under nitrogen atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate to give a liquid, the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and then separated into a liquid, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-9 (72% yield). The product structure characterization data are: 1 HNMR(500MHz,CDCl 3 )δ:7.91(d,J＝8.5Hz,2H),7.33(d,J＝8.0Hz,2H)，4.59(s,2H),3.44(t,J＝7.5Hz,2H),2.69(t,J＝8.0Hz,2H),2.63(t,J＝7.5Hz,2H),2.32-2.26(m,2H),1.65-1.59(m,2H),1.38-1.34(m,2H),0.93(t,J＝7.5Hz,3H)； 13 C NMR(126MHz,CDCl 3 )δ:188.4,151.1,133.2,129.4,129.1,118.1,60.0,51.7,35.8,33.0,22.3,18.3,16.3,13.8；HRMS m/z(ESI)calcd for C 16 H 22 NO 3 S([M+H] + )308.1315,found 308.1320.
example 28
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (44.2 mg,0.2 mmol) represented by formula 1g, sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv), then THF (1.0 mL) was added, then the reaction vessel was stirred at 90℃under nitrogen atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate to give a liquid, the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and then separated into a liquid, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-10 (63% yield). The product structure characterization data are: 1 H NMR(400MHz,CDCl 3 )δ:8.07(d,J＝8.4Hz,2H),7.75(d,J＝8.4Hz,2H),7.63(d,J＝7.2Hz,2H),7.51-7.41(m,3H),4.65(s,2H),3.46(t,J＝7.2Hz,2H),2.65(t,J＝7.2Hz,2H),2.35-2.28(m,2H)； 13 C NMR(101MHz,CDCl 3 )δ:188.4,147.6,139.2,134.1,129.9,129.1,128.7,127.6,127.3,118.0,60.1,51.7,18.3,16.3；HRMS m/z(ESI)calcd for C 18 H 17 NO 3 SNa([M+Na] + )350.0821,found 350.0950.
example 29
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (29.0 mg,0.2 mmol) represented by formula 1H, sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O(72μL,4mmol,20.0 equiv), THF (1.0 mL) was added, then the reactor was stirred at 90 ℃ under nitrogen atmosphere and monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate, the organic phase was separated by washing with saturated aqueous sodium bicarbonate solution and then separated by distillation, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the target product I-11 (82% yield). The product structure characterization data are: 1 H NMR(500MHz,CDCl 3 )δ:8.00(d,J＝7.0Hz,2H),7.67(t,J＝7.5Hz,1H),7.54(t,J＝8.0Hz,2H),4.63(s,2H),3.45(t,J＝7.5Hz,2H),2.63(t,J＝7.0Hz,2H),2.32-2.26(m,2H)； 13 C NMR(126MHz,CDCl 3 )δ:189.0,135.4,134.8,129.2,129.0,118.1,59.9,51.8,18.2,16.2.
example 30
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (32.6 mg,0.2 mmol) represented by formula 1i, sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv), then THF (1.0 mL) was added, then the reaction vessel was stirred at 90℃under nitrogen atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate to give a liquid, the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and then separated into a liquid, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-12 (81% yield). The product structure characterization data are: 1 HNMR(500MHz,CDCl 3 )δ:8.06-8.03(m,2H),7.21(t,J＝8.5Hz,2H),4.60(s,2H),3.44(t,J＝7.5Hz,2H),2.64(t,J＝7.5Hz,2H),2.32-2.26(m,2H)； 13 C NMR(126MHz,CDCl 3 )δ:187.4,166.7(d,J C-F ＝259.2Hz),132.2(d,J C-F ＝9.8Hz),132.0(d,J C-F ＝2.9Hz),118.0,116.4(d,J C-F ＝22.3Hz),60.1,51.7,18.3,16.3； 19 FNMR(471MHz,CDCl 3 )δ:-101.3；HRMS m/z(ESI)calcd for C 12 H 13 FNO 3 S([M+H] + )270.0595,found 270.0591.
example 31
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (44.6 mg,0.2 mmol) represented by formula 1j, sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv), then THF (1.0 mL) was added, then the reaction vessel was stirred at 90℃under nitrogen atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate to give a liquid, the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and then separated into a liquid, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-13 (83% yield). The product structure characterization data are: 1 H NMR(400MHz,CDCl 3 )δ:7.86(d,J＝8.4Hz,2H),7.68(d,J＝8.4Hz,2H),4.60(s,2H),3.43(t,J＝7.6Hz,2H),2.64(t,J＝7.2Hz,2H),2.33-2.25(m,2H)； 13 C NMR(101MHz,CDCl 3 )δ:188.1,134.1,132.4,130.6(2),118.0,60.0,51.7,18.2,16.3.
example 32
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (42.6 mg,0.2 mmol) represented by formula 1k, sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv), then THF (1.0 mL) was added, then the reaction vessel was stirred at 90℃under nitrogen atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate to give a liquid, the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and then separated into a liquid, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-14 (84% yield). The product structure characterization data are: 1 H NMR(400MHz,CDCl 3 )δ:8.11(d,J＝8.0Hz,2H),7.78(d,J＝8.0Hz,2H),4.68(s,2H),3.44(t,J＝7.2Hz,2H),2.64(t,J＝7.2Hz,2H),2.32-2.25(m,2H)； 13 C NMR(101MHz,CDCl 3 )δ:188.4,138.0,135.8(m,J C-F ＝33.1Hz),129.6,126.1(m,J C-F ＝3.6Hz),123.2(m,J C-F ＝274.0Hz),118.1,60.1,51.8,18.1,16.2； 19 FNMR(376MHz,CDCl 3 )δ:-63.3.
example 33
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (34.0 mg,0.2 mmol) represented by formula 1l, sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O(72μL,4mmol20.0 equiv), THF (1.0 mL) was added, then the reactor was stirred at 90 ℃ under nitrogen atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate, the organic phase was separated by washing with saturated aqueous sodium bicarbonate solution and then separated into a solution, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the target product I-15 (80% yield). The product structure characterization data are: 1 H NMR(400MHz,CDCl 3 )δ:8.11(d,J＝8.0Hz,2H),7.84(d,J＝8.0Hz,2H),4.64(s,2H),3.43(t,J＝7.2Hz,2H),2.65(t,J＝7.2Hz,2H),2.33-2.26(m,2H)； 13 C NMR(101MHz,CDCl 3 )δ:188.0,138.2,132.8,129.7,127.8,118.0,117.4,60.3,51.8,18.2,16.3.
example 34
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (40.6 mg,0.2 mmol) represented by formula 1m, sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv), then THF (1.0 mL) was added, then the reaction vessel was stirred at 90℃under nitrogen atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate to give a liquid, the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and then separated into a liquid, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-16 (86% yield). The product structure characterization data are: 1 H NMR(400MHz,CDCl 3 )δ:8.13(d,J＝6.4Hz,2H),8.02(t,J＝7.2Hz,2H),4.68(s,2H),3.94(s,3H),3.44(t,J＝7.6Hz,2H),2.63(t,J＝6.8Hz,2H),2.30-2.23(m,2H)； 13 C NMR(101MHz,CDCl 3 )δ:188.7,165.7,138.3,135.2,130.0,129.1,118.1,60.0,52.6,51.7,18.1,16.2.
example 35
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (38.0 mg,0.2 mmol) represented by formula 1n, a sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv), then THF (1.0 mL) was added, then the reaction vessel was stirred at 90℃under nitrogen atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate to give a liquid, the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and then separated into a liquid, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-17 (79% yield). The product structure characterization data are: 1 HNMR(400MHz,DMSO-d6)δ:8.39(d,J＝8.8Hz,2H),8.28(d,J＝8.8Hz,2H),5.31(s,2H),3.44(t,J＝8.0Hz,2H),2.71(t,J＝7.2Hz,2H),2.51-2.50(m,2H),2.12-2.05(m,2H)； 13 C NMR(101MHz,DMSO-d6)δ:189.3,150.5,140.3,130.5,123.9,119.7,59.8,52.1,17.8,15.3.
example 36
A preparation method of a beta-ketosulfone compound comprises the following steps:
alkenyl azide of formula 1o was added to Schlenk flaskCompound (31.8 mg,0.2 mmol), sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv), then THF (1.0 mL) was added, then the reaction vessel was stirred at 90℃under nitrogen atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate to give a liquid, the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and then separated into a liquid, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-18 (73% yield). The product structure characterization data are: 1 HNMR(400MHz,CDCl 3 )δ:7.79(s,1H),7.77-7.72(m,1H),7.50-7.46(m,1H),7.42(t,J＝7.6Hz,1H),4.61(s,2H),3.45(t,J＝7.2Hz,2H),2.64(t,J＝7.2Hz,2H),2.44(s,3H),2.33-2.26(m,2H)； 13 C NMR(101MHz,CDCl 3 )δ:189.1,139.1,135.7,135.5,129.6,128.9,126.5,118.0,60.0,51.8,21.3,18.3,16.3.HRMS m/z(ESI)calcd for C 13 H 15 NO 3 SNa([M+Na] + )288.0665,found 288.0668.
example 37
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (39.0 mg,0.2 mmol) represented by formula 1p, sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv), THF (1.0 mL) was added, the reactor was stirred at 90℃under nitrogen atmosphere to react, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time: 12 hours), after completion of the reaction, the reaction mixture after completion of the reaction was extracted with ethyl acetate to separate the reaction mixture,the organic phase was washed with saturated aqueous sodium bicarbonate solution and then separated, the resulting organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-19 (72% yield). The product structure characterization data are: 1 H NMR(400MHz,CDCl 3 )δ:8.75(d,J＝8.4Hz,1H),8.10-8.05(m,2H),7.91(d,J＝8.0Hz,1H),7.66(t,J＝7.2Hz,1H),7.58-7.55(m,2H),4.72(s,2H),3.51(t,J＝7.6Hz,2H),2.63(t,J＝7.2Hz,2H),2.33-2.25(m,2H)； 13 CNMR(101MHz,CDCl 3 )δ:191.2,142.1,135.3,133.9,132.9,131.1,129.1,128.7,127.0,125.3,124.3,118.1,62.6,51.9,18.3,16.3.
example 38
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (30.2 mg,0.2 mmol) represented by formula 1q, sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv), then THF (1.0 mL) was added, then the reaction vessel was stirred at 90℃under nitrogen atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate to give a liquid, the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and then separated into a liquid, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-20 (74% yieldd). The product structure characterization data are: 1 H NMR(400MHz,CDCl 3 )δ:7.85(t,J＝4.0Hz,2H),7.23(t,J＝4.4Hz,1H),4.53(s,2H),3.45(t,J＝7.6Hz,2H),2.65(t,J＝7.2Hz,2H),2.34-2.27(m,2H)； 13 C NMR(101MHz,CDCl 3 )δ:180.9,142.7,137.5,135.6,129.0,118.0,61.0,51.6,18.3,16.3；HRMS m/z(ESI)calcd for C 10 H 12 NNaO 3 S 2 ([M+Na] + )280.0073,found280.0076.
example 39
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (30.6 mg,0.2 mmol) represented by formula 1r, sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv), then THF (1.0 mL) was added, then the reaction vessel was stirred at 90℃under nitrogen atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate to give a liquid, the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and then separated into a liquid, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-21 (76% yieldd). The product structure characterization data are: 1 HNMR(400MHz,CDCl 3 )δ:4.03(s,2H),3.32(t,J＝7.6Hz,2H),2.69(t,J＝7.2Hz,2H),2.62(t,J＝7.2Hz,2H),2.29-2.22(m,2H),1.62-1.57(m,4H),1.33-1.27(m,4H),0.88(t,J＝6.4Hz,3H)； 13 C NMR(101MHz,CDCl 3 )δ:199.5,117.9,63.2,51.5,45.1,31.4,28.4,22.9,22.4,18.2,16.3,14.0；HRMS m/z(ESI)calcd for C 12 H 22 NO 3 S([M+H] + )260.1315,found 260.1311.
example 40
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (41.8 mg,0.2 mmol) represented by formula 1s, a sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv), then THF (1.0 mL) was added, then the reaction vessel was stirred at 90℃under nitrogen atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate to give a liquid, the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and then separated into a liquid, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-22 (74% yieldd). The product structure characterization data are: 1 HNMR(400MHz,CDCl 3 )δ:3.98(s,2H),3.25(t,J＝7.2Hz,2H),2.62(t,J＝7.2Hz,2H),2.56(t,J＝7.2Hz,2H),2.21-2.14(m,2H),1.54(t,J＝6.4Hz,2H),1.26-1.18(m,14H),0.81(t,J＝6.4Hz,3H)； 13 C NMR(101MHz,CDCl 3 )δ:199.5,118.0,63.1,51.5,45.0,31.8,29.5,29.3,29.2(2),28.7,22.9,22.6,18.2,16.2,14.1；HRMS m/z(ESI)calcd for C 16 H 30 NO 3 S([M+H] + )316.1941,found 316.1947.
example 41
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (34.6 mg,0.2 mmol) represented by formula 1t, sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv.) and THF (1.0 mL) were added, the reactor was stirred at 90deg.C under nitrogen atmosphere and monitored by TLC for the disappearance of starting material (reverse)The reaction time was 12 hours), after the completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate, the organic phase was washed with a saturated aqueous sodium hydrogencarbonate solution and then separated into a liquid, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent was: petroleum ether/ethyl acetate=2:1) to give the target product I-23 (66% yield). The product structure characterization data are: 1 H NMR(400MHz,CDCl 3 )δ:7.23(t,J＝6.8Hz,2H),7.18-7.13(m,3H),3.96(s,2H),3.16(t,J＝7.6Hz,2H),3.00(t,J＝7.2Hz,2H),2.89(t,J＝7.2Hz,2H),2.52(t,J＝7.2Hz,2H),2.17-2.10(m,2H)； 13 C NMR(101MHz,CDCl 3 )δ:198.5,139.7,128.6,128.4,126.4,118.0,63.6,51.4,46.2,29.0,18.1,16.2；HRMS m/z(ESI)calcd for C 14 H 17 NNaO 3 S([M+Na] + )302.0821,found 302.0821.
example 42
A preparation method of a beta-ketosulfone compound comprises the following steps:
into a Schlenk flask were charged alkenyl azide (35.0 mg,0.2 mmol) represented by formula 1u, sulfur dioxide source (76.0 mg,0.4mmol,2.0 equiv) represented by formula 2a, oxime ester (102.8 mg,0.4mmol,2.0 equiv) represented by formula 3a, cuCl (4.02 mg,20 mol%), oxone (147.5 mg,0.24mmol,1.2 equiv), H 2 O (72. Mu.L, 4mmol,20.0 equiv), then THF (1.0 mL) was added, then the reaction vessel was stirred at 90℃under nitrogen atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 12 hours), after completion of the reaction, the reaction solution after completion of the reaction was extracted with ethyl acetate to give a liquid, the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and then separated into a liquid, the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate=2:1) to give the objective product I-24 (56% yieldd). The product structure characterization data are: 1 H NMR(400MHz,CDCl 3 )δ:7.31(t,J＝7.6Hz,2H),7.03(t,J＝7.2Hz,1H),6.90(d,J＝8.0Hz,2H),4.75(s,2H),4.30(s,2H),3.35(t,J＝7.6Hz,2H),2.60(t,J＝7.2Hz,2H),2.50-2.18(m,2H)； 13 C NMR(101MHz,CDCl 3 )δ:196.4,156.9,129.8,122.3,118.1,114.5,72.8,59.7,51.9,18.0,16.1；HRMS m/z(ESI)calcd for C 13 H 16 NO 4 S([M+H] + )282.0795,found 282.0797.
the possible reaction mechanism of the present invention can be deduced as follows:
first, oxime ester 3a is cleaved by single electron transfer reduction under the action of a copper catalyst to produce γ -cyanoalkyl radical a. At the same time, free radical A captures in situ generated SO 2 Providing a more reactive free radical B. Then, azido vinyl group 1a is easily attacked by radical B, resulting in the formation of carbon-centered radical C, followed by N removal 2 The free radical D is obtained. Subsequently, D takes up hydrogen atoms from solvent THF to produce imine intermediate E and relatively stable free radical F. At the same time, free radical F can reduce Cu (n+1) To regenerate Cu (n) Thereby completing the catalytic cycle. Finally, intermediate E is rapidly hydrolyzed to give the desired end product I-1.
Finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the technical solution, and those skilled in the art should understand that modifications and equivalents may be made to the technical solution of the present invention without departing from the spirit and scope of the present invention, and all such modifications and equivalents are included in the scope of the claims.
Claims (10)
1. The preparation method of the beta-ketone sulfone compound is characterized in that an alkenyl azide compound shown in a formula 1, a metabisulfite shown in a formula 2, an oxime ester compound shown in a formula 3, a catalyst, an oxidant and water are added into a solvent, and the mixture is stirred and reacted in an inert gas atmosphere, and the reaction is completely post-treated to obtain the beta-ketone sulfone compound shown in a formula I, wherein the reaction formula is as follows:
wherein in formula 1, R 1 Selected from phenyl, tolyl, n-butylphenyl, t-butylphenyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, cyanophenyl, nitrophenyl, naphthyl, biphenyl, thienyl, n-hexyl, n-decyl, phenethyl or phenoxymethyl; in the formula 2, A is Na or K; in formula 3, Y is CH 2 Or O; r is R 2 Selected from phenyl or benzyloxy.
2. The preparation method of the beta-ketosulfone compound according to claim 1, wherein the catalyst is one or a mixture of more of cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, cupric acetate and cupric trifluoromethane sulfonate.
3. The method for preparing the beta-ketosulfone compound according to claim 1, wherein the oxidant is one or more selected from potassium hydrogen peroxydisulfate complex salt, potassium persulfate, iodobenzene acetate, tert-butyl hydroperoxide and di-tert-butyl peroxide.
4. The method for preparing the beta-ketosulfone compound according to claim 1, wherein the solvent is one or a mixture of several selected from tetrahydrofuran, acetonitrile, ethyl acetate and ethanol.
5. The method for producing a β -ketosulfone compound according to claim 1, wherein the temperature of the stirring reaction is 80 to 100 ℃.
6. The method for producing β -ketosulfone compound according to claim 1, wherein the molar ratio of alkenyl azide compound, metabisulfite, oxime ester compound and water is 1:2:2.
7. The method for producing β -ketosulfone compound according to claim 1, wherein the molar ratio of alkenyl azide to water is 1:5-40.
8. The method for preparing the beta-ketosulfone compound according to claim 1, wherein the post-treatment is that after the reaction liquid after the reaction is completed is extracted and separated by ethyl acetate, an organic phase is washed by saturated sodium bicarbonate aqueous solution and then is separated by liquid, the obtained organic phase is dried by anhydrous sodium sulfate and is concentrated under reduced pressure to remove a solvent, the residue is separated by column chromatography, and ethyl acetate/petroleum ether is used as an eluent to obtain the beta-ketosulfone compound I.
9. The method for producing a β -ketosulfone compound according to claim 5, wherein the temperature of the stirring reaction is 90 ℃.
10. The method for producing β -ketosulfone compound according to claim 7, wherein the molar ratio of alkenyl azide to water is 1:20.
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