CN108069918A - The method that one kettle way prepares 3- difluoromethyl isoxazole compounds - Google Patents
The method that one kettle way prepares 3- difluoromethyl isoxazole compounds Download PDFInfo
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- CN108069918A CN108069918A CN201810049236.2A CN201810049236A CN108069918A CN 108069918 A CN108069918 A CN 108069918A CN 201810049236 A CN201810049236 A CN 201810049236A CN 108069918 A CN108069918 A CN 108069918A
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- 238000000034 method Methods 0.000 title claims abstract description 27
- DQQVDPZSGLYBAI-UHFFFAOYSA-N 3-(difluoromethyl)-1,2-oxazole Chemical class FC(F)C=1C=CON=1 DQQVDPZSGLYBAI-UHFFFAOYSA-N 0.000 title description 6
- -1 alkynes compound Chemical class 0.000 claims abstract description 25
- 150000002545 isoxazoles Chemical class 0.000 claims abstract description 19
- 238000006467 substitution reaction Methods 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- OVRWUZYZECPJOB-UHFFFAOYSA-N 2,2-difluoroethanamine Chemical compound NCC(F)F OVRWUZYZECPJOB-UHFFFAOYSA-N 0.000 claims abstract description 10
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract 2
- 229910052802 copper Inorganic materials 0.000 claims abstract 2
- 239000010949 copper Substances 0.000 claims abstract 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- 150000001345 alkine derivatives Chemical class 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 7
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 7
- OWQUYBAASOSGNO-CDNKMLFNSA-N 2-[[(Z)-N-(2-hydroxy-5-sulfoanilino)-C-phenylcarbonimidoyl]diazenyl]benzoic acid Chemical compound C1=CC=C(C=C1)/C(=N/NC2=C(C=CC(=C2)S(=O)(=O)O)O)/N=NC3=CC=CC=C3C(=O)O OWQUYBAASOSGNO-CDNKMLFNSA-N 0.000 claims description 6
- 230000031709 bromination Effects 0.000 claims description 6
- 238000005893 bromination reaction Methods 0.000 claims description 6
- 229940043798 zincon Drugs 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 5
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 229940102001 zinc bromide Drugs 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical class CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 4
- DYDNPESBYVVLBO-UHFFFAOYSA-N formanilide Chemical compound O=CNC1=CC=CC=C1 DYDNPESBYVVLBO-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- MFYLRNKOXORIPK-UHFFFAOYSA-N (3-nitrophenyl)-phenylmethanone Chemical class [O-][N+](=O)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 MFYLRNKOXORIPK-UHFFFAOYSA-N 0.000 claims description 2
- ZYMCBJWUWHHVRX-UHFFFAOYSA-N (4-nitrophenyl)-phenylmethanone Chemical group C1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=CC=C1 ZYMCBJWUWHHVRX-UHFFFAOYSA-N 0.000 claims description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000002240 furans Chemical class 0.000 claims description 2
- 150000002790 naphthalenes Chemical class 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 5
- 239000011261 inert gas Substances 0.000 claims 3
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims 2
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 claims 2
- KYARBIJYVGJZLB-UHFFFAOYSA-N 7-amino-4-hydroxy-2-naphthalenesulfonic acid Chemical compound OC1=CC(S(O)(=O)=O)=CC2=CC(N)=CC=C21 KYARBIJYVGJZLB-UHFFFAOYSA-N 0.000 claims 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 claims 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 claims 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 claims 1
- 239000011701 zinc Substances 0.000 claims 1
- 229910052725 zinc Inorganic materials 0.000 claims 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 abstract description 9
- 239000006227 byproduct Substances 0.000 abstract description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 abstract 1
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 238000005859 coupling reaction Methods 0.000 abstract 1
- PHTUOMUGZYONMG-UHFFFAOYSA-N diazo(fluoro)methane Chemical compound FC=[N+]=[N-] PHTUOMUGZYONMG-UHFFFAOYSA-N 0.000 abstract 1
- 125000000524 functional group Chemical group 0.000 abstract 1
- 229910052740 iodine Inorganic materials 0.000 abstract 1
- 239000011630 iodine Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 312
- 239000000047 product Substances 0.000 description 90
- 239000000758 substrate Substances 0.000 description 45
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 41
- 238000004293 19F NMR spectroscopy Methods 0.000 description 41
- 238000005160 1H NMR spectroscopy Methods 0.000 description 41
- 238000012512 characterization method Methods 0.000 description 41
- 238000004984 proton decoupled 19F NMR spectroscopy Methods 0.000 description 36
- 239000007787 solid Substances 0.000 description 31
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 16
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 10
- 239000012230 colorless oil Substances 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 0 *c1n[o]c(*)c1 Chemical compound *c1n[o]c(*)c1 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000007877 drug screening Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- DKNMRIXYSHIIGC-UHFFFAOYSA-N 2,2-difluoroacetaldehyde Chemical compound FC(F)C=O DKNMRIXYSHIIGC-UHFFFAOYSA-N 0.000 description 1
- CUMCMYMKECWGHO-UHFFFAOYSA-N 3-methyl-1,2-oxazole Chemical compound CC=1C=CON=1 CUMCMYMKECWGHO-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- PONSNPKRGOGSIO-UHFFFAOYSA-N FC#CC1=CC(=CC=C1)OC Chemical class FC#CC1=CC(=CC=C1)OC PONSNPKRGOGSIO-UHFFFAOYSA-N 0.000 description 1
- OHVTVCXFFBSXJC-UHFFFAOYSA-N FC(c1n[o]c(-c2ccccc2)c1)F Chemical compound FC(c1n[o]c(-c2ccccc2)c1)F OHVTVCXFFBSXJC-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UMRSVAKGZBVPKD-UHFFFAOYSA-N acetic acid;copper Chemical compound [Cu].CC(O)=O UMRSVAKGZBVPKD-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- UXOLDCOJRAMLTQ-UTCJRWHESA-N ethyl (2z)-2-chloro-2-hydroxyiminoacetate Chemical compound CCOC(=O)C(\Cl)=N\O UXOLDCOJRAMLTQ-UTCJRWHESA-N 0.000 description 1
- FMVJYQGSRWVMQV-UHFFFAOYSA-N ethyl propiolate Chemical compound CCOC(=O)C#C FMVJYQGSRWVMQV-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- ZBJWWKFMHOAPNS-UHFFFAOYSA-N loretin Chemical compound C1=CN=C2C(O)=C(I)C=C(S(O)(=O)=O)C2=C1 ZBJWWKFMHOAPNS-UHFFFAOYSA-N 0.000 description 1
- 229950010248 loretin Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000003863 metallic catalyst Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members 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
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of methods that new one kettle way prepares 3 difluoromethyls substitution isoxazole compounds, this method is to be prepared into fluoro diazomethane using the difluoroethylamine being commercially available in market, then coupling reaction occurs under cheap copper catalysis with alkynes compound and obtains；This method is easy to operate, reaction condition is mild, at low cost, by-product is few, high income, functional group tolerance's height, and can be with iodine.Done simultaneously deeper into mechanism study, and propose in the reaction mechanism that can pass through difluoromethyl oxime compound intermediate.
Description
Technical field
The present invention relates to a kind of new one kettle way prepare 3- difluoromethyls substitution isoxazole compounds method, especially
It is related to the method that 3- difluoromethyls substitution isoxazole compounds are prepared using difluoroethylamine and terminal alkyne as raw material, belongs to green
Chemistry and pharmaceutical intermediate synthesis technical field.
Background technology
Isoxazole heterocycle skeleton is not only distributed widely in many active drug molecules, and is weight in Synthetic Organic Chemistry
The intermediate wanted.And No. 3 positions attempt to introduce difluoromethyls in isoxazole skeletons, can by influence compound it is fat-soluble,
The performances such as stability and permeability change its bioactivity, this is more useful in performance by the active medicine for causing script
The features such as amount is less, toxicity is low, drug effect is high, metabolic capability is strong.Thus for a long time, multifarious 3- difluoros how to be efficiently synthesized
Methyl-isoxazole is always the hot issue that chemists study.Common synthetic method includes：
(1) 1989 year, the acetylenic ketone and hydroxylamine hydrochloride that Linderman is substituted using difluoromethyl took the lead in having synthesized 3- bis- as raw material
Methyl fluoride isoxazole, but the alkynyl ketone synthesis condition of itself is just very harsh, yield is also very low.In addition the most key is last
One step ring closure reaction poor selectivity (can be nitrogen-atoms to Carbonyl addition or oxygen atom is to Carbonyl addition), and substrate
Limitation is very big.(R.J.Linderman et al,Tetrahedron Letters 1989,30,2049-2052)
(2) 2015 years, E.Schmitt and F.R.Leroux were made using fluoroalkylamine reagent (N, N- dimethyl tetrafluoro ethamine)
For difluoromethyl source, and fluorine amine salt is translated under boron trifluoride ether effect.It is tried afterwards using silyl enol ether as nucleophilic
Agent is prepared into the ketone ammonium salt compound of difluoromethyl substitution, and difluoromethyl isoxazole is then condensed to yield with hydroxylamine hydrochloride.The party
Method starting material is not cheap, and silyl enol ether also needs previously prepared, and step is tediously long, unfriendly to environment and economy.(F.R.Leroux
et al,Org.Lett.2015,17,4510-4513)
(3) 2017 years, P.K.Mykhailiuk used ethyl difluoro as difluoromethyl source, in lithium aluminium hydride reduction
Property under the conditions of be reduced into difluoro acetaldehyde, and original flavor is condensed to yield the oxime of difluoromethyl substitution with hydroxylamine hydrochloride.Afterwards, exist
Oxime is changed into chloro oxime, and original flavor generation difluoromethyl itrile oxides in alkaline conditions under NCS oxidizing conditions.It is last in situ
The itrile oxides of generation occurs [3+2] cycloaddition reaction with alkynes and obtains difluoromethyl isoxazole.Equally, which exists
Condition is harsh, the defects such as step is tediously long, uneconomical, and combined coefficient is low.(P.K.Mykhailiuk et al,
Eur.J.Org.Chem.2017,3935-3940)
3- difluoromethyl isoxazoles are synthesized in spite of so a plurality of synthetic route, but reaction step is generally tediously long, directly
Connecing causes combined coefficient low.Up to the present, there are no document report is a kind of efficiently, efficiently synthetic method.
The content of the invention
For some existing problems used in the building-up process of existing 3- difluoromethyls isoxazole, as reaction step is superfluous
The shortcomings of length, raw material availability are low, severe reaction conditions, be easy to get the purpose of the invention is to provide a kind of efficient, raw material,
The synthetic method for the 3- difluoromethyl isoxazole heterocyclic compounds that reaction condition is mild, product yield high, by-product are few, the party
3- difluoromethyl isoxazole of the method design synthesis with brand new, raw material sources are provided for drug screening and new drug synthesis.
The present invention uses following technical scheme：
A kind of method that one kettle way prepares 3- difluoromethyls substitution isoxazole compounds, by the terminal alkyne class of Formulas I
It closes object to be dissolved in chloroform, adds 2,2- difluoroethylamines and nitrite tert-butyl and acetic acid, add in cuprous iodide and zinc bromide examination
Agent, and under nitrogen protection at room temperature stirring 24 it is small when.Directly solvent is removed by vacuum distillation after to the reaction time
It goes, is the isoxazole compound that can obtain the substitution of 3- difluoromethyls using flash column column chromatography.
Wherein, the preparation method of the 3- difluoromethyls substitution isoxazole compounds of gram quantity grade is by the terminal alkyne of Formulas I
Class compound is dissolved in chloroform, adds 2,2- difluoroethylamines, acetic acid, adds in cuprous iodide and bromination zincon, and in nitrogen
Prior to stirring fully dissolving in 15 minutes under ice-water bath under protection.It is slowly added to nitrite tert-butyl with this condition again, at this time
It can be seen that zinc bromide is dissolved and solution becomes bright green, then system is transferred to and is stirred at room temperature.React 24 it is small when
Suction filtered through kieselguhr is used afterwards, and washs filter residue with dichloromethane, and filtrate is washed with hypo solution, and liquid separation obtains organic
Phase, organic phase are dried with anhydrous magnesium sulfate, and then directly solvent is removed by being evaporated under reduced pressure, utilizes flash column column chromatography
Obtain gram quantity grade 3- difluoromethyls substitution isoxazole compounds.
In Formulas I and Formula II, R is independently selected from aryl or alkyl.
In preferred scheme, Formulas I and Formula II R bases be independent free phenyl, xenyl, 4- tolyls, 4- amyls phenyl,
4- methoxyphenyls, 4- chlorphenyls, 4- bromophenyls, 4- fluorophenyls, 4- trifluoromethyls, 4- cyano-phenyls, 4- nitrobenzophenones,
4- methyl formates base, 4- acetophenones base, 4- methylbenzenes thioether group, 4- methylsulfinylphenyls, 4- methylsulfonyl phenyls, 2-
Methoxyphenyl, 2- chlorphenyls, 2- propylene carbamate bases phenyl, 3- nitrobenzophenones, 3- fluorophenyls, 3- hydroxy phenyls, 3- (uncles
Butyl diphenyl silylation) phenyl, 3- benzyq carbamate bases phenyl, 3- t-butyl carbamate bases phenyl, 3- amino
Acetylphenyl, 3- amino benzoyls phenyl, 3- amino-(2,2- benzyloxies) base phenyl, the fluoro- 3- methoxyphenyls of 2-, 2-
Methoxyl group -3- fluorophenyls, β naphthalenes, thiophene, furans, pyridine, 1H- indoles -1- group-4 ethyl formates, styryl, ethyl, ethyl
4- methoxy benzoic acids ester group, 4- ethyl nitrobenzoates, group-4 ethyl formate, N- phenyl formamide bases.
The molar ratio of preferred scheme, Formulas I terminal alkyne class compound and difluoroethylamine is 1:1~10；End shown in Formulas I
The molar ratio of Terminal Acetylenes hydrocarbon compound and nitrite tert-butyl is 1:1~10；Mole of Formulas I terminal alkyne class compound and acetic acid
Than for 1:0.2~5；Formulas I terminal alkyne class compound and the molar ratio of cuprous iodide are 1:0.05~1；Formulas I terminal alkyne class
The molar ratio for closing object and zinc bromide is 1:1~10；When reaction time is 12-48 small；Reaction condition is room temperature.
Compared with the prior art, technical scheme brings following technical advantage：
(1) present invention prepares 3- difluoromethyls substitution isoxazole compounds process is easy to operate, mild condition, entire reaction
Process can carry out under room temperature and air conditions.
(2) present invention prepares commercialized raw material difluoroethylamine that 3- difluoromethyls substitution isoxazole compounds use with
Terminal alkyne may be employed existing maturation process and simply synthesize, and safe, avoid the preparation process of complicated raw material.
(3) the 3- difluoromethyls of the invention that prepare substitute metallic catalyst of the isoxazole compounds in the process without costliness,
Production cost is reduced, is good for the environment.
(4) method that the present invention prepares 3- difluoromethyls substitution isoxazole compounds has the characteristics of side reaction is few, high income,
Yield reaches 58~93%.
(5) method of the invention for preparing 3- difluoromethyls substitution isoxazole compounds is limited to from substrate, to establish fragrance
Class 3- difluoromethyls substitution isoxazoles storehouse provides raw material sources for drug screening and new drug synthesis.
Description of the drawings
Fig. 1 is the mono-crystalline structures figure of 9 product of embodiment.
Specific embodiment
The following example is intended to further illustrate present invention rather than limits the protection model of the claims in the present invention
It encloses.
According to following synthetic method：
Terminal alkyne class compounds substrate (0.25mmol, 1equiv) is dissolved in chloroform, adds 2,2- difluoroethylamines
(0.75mmol, 3equiv) and nitrite tert-butyl (0.75mmol, 3equiv) and acetic acid (0.1mmol, 0.4equiv), add in
Cuprous iodide (0.025mmol, 0.1equiv) and bromination zincon (0.5mmol, 2equiv), and under nitrogen protection in room temperature
It is lower stirring 24 it is small when.Directly solvent by being evaporated under reduced pressure is removed after to the reaction time, utilizes flash column column chromatography
Obtain product 3- difluoromethyls substitution isoxazole compounds.
Examples 1 to 41 need to only change the species of terminal alkyne class compounds substrate, it is possible to prepare according to above method
The isoxazole compound of 3- difluoromethyls substitution as shown in following formula 1~41：
Embodiment 1：
Substrate：4- phenyl ethynyl phenyls
Product：
Characterization of The Products data：Pale yellow solid (58.8mg, 87%yield)；mp:124.5–124.8；1H NMR
(400MHz,CDCl3) δ 7.86 (d, J=8.0Hz, 2H), 7.71 (d, J=8.0Hz, 2H), 7.64 (d, J=8.0Hz, 2H),
7.49 (t, J=8.0Hz, 2H), 7.42 (t, J=8.0Hz, 1H), 6.84 (t, J=54.0Hz, 1H), 6.75 (s, 1H)；13C
NMR(100MHz,CDCl3) δ 171.7,159.7 (t, J=30.0Hz), 143.9,140.0,129.3,128.4,128.0,
(127.4,126.7,125.6,109.4 t, J=237.0Hz), 96.4；19F NMR(376MHz,CDCl3) δ -115.15 (d, J=
54.0Hz,2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.15(s,2F)；HRMS(ESI)m/z calcd for
C16H12ONF2 +[M+H]+272.0882,found 272.0880.
Embodiment 2：
Substrate：Phenylacetylene
Product：
Characterization of The Products data：Colorless oil (44.4mg, 91%yield)；1H NMR(400MHz,CDCl3)δ7.81–
7.78 (m, 2H), 7.49-7.47 (m, 3H), 6.81 (t, J=54.0Hz, 1H), 6.72 (s, 1H)；13C NMR(100MHz,
CDCl3) δ 171.9,159.7 (t, J=30.0Hz), 131.2,129.5,126.8,126.3,109.4 (t, J=237.0Hz),
96.4；19F NMR(376MHz,CDCl3) δ -115.27 (d, J=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-
115.27(s,2F)；HRMS(ESI):m/z calcd for C10H8ONF2 +[M+H]+196.0569,found 196.0572.
Embodiment 3：
Substrate：4- methyl phenylacetylenes
Product：
Characterization of The Products data：Foamy solid (44.5mg, 85%yield)；1H NMR(400MHz,CDCl3)δ7.68(d,J
=8.0Hz, 2H), 7.29 (d, J=8.0Hz, 2H), 6.79 (t, J=54.0Hz, 1H), 6.67 (s, 1H), 2.41 (s, 3H)；13C
NMR(100MHz,CDCl3) δ 172.2,159.7 (t, J=30Hz), 141.7,130.2,126.2,124.2,109.5 (t, J=
237.0Hz),95.8,21.9；19F NMR(376MHz,CDCl3) δ -115.26 (d, J=54.0Hz, 2F)；19F{1H}NMR
(376MHz,CDCl3)δ-115.26(s,2F)；HRMS(ESI):m/z calcd for C11H10ONF2 +[M+H]+210.0725,
found 210.0723.
Embodiment 4：
Substrate：4- n-amylbenzene acetylene
Product：
Characterization of The Products data：Colorless oil (53.2mg, 80%yield)；1H NMR(400MHz,CDCl3)δ7.71(d,
J=8.0Hz, 2H), 7.30 (d, J=8.0Hz, 2H), 6.80 (t, J=54.0Hz, 1H), 6.67 (s, 1H), 2.66 (t, J=
8.0Hz, 2H), 1.68-1.61 (m, 2H), 1.38-1.31 (m, 4H), 0.90 (t, J=7.0Hz, 3H)；13C NMR(100MHz,
CDCl3) δ 172.2,159.7 (t, J=30Hz), 146.7,129.5,126.3,124.4,109.5 (t, J=237Hz), 95.8,
36.2,31.8,31.2,22.8,14.3；19F NMR(376MHz,CDCl3) δ -115.25 (d, J=54.0Hz, 2F)；19F{1H}
NMR(376MHz,CDCl3)δ-115.25(s,2F)；HRMS(ESI)m/z calcd for C15H18ONF2 +[M+H]+
266.1351,found 266.1346.
Embodiment 5：
Substrate：4- Methoxy-phenylacetylenes
Product：
Characterization of The Products data：Pale yellow solid (46.7mg, 83%yield)；mp:72.3–73.1；1H NMR
(400MHz,CDCl3) δ 7.73 (d, J=8.0Hz, 2H), 6.99 (d, J=8.0Hz, 2H), 6.78 (t, J=54.0Hz, 1H),
6.59(s,1H),3.87(s,3H)；13C NMR(100MHz,CDCl3) δ 172.0,162.0,159.7 (t, J=30Hz),
(128.0,119.7,114.9,109.5 t, J=235.0Hz), 95.0,55.8；19F NMR(376MHz,CDCl3)δ-115.28
(d, J=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.28(s,2F)；HRMS(ESI):m/z calcd
for C11H10O2NF2 +[M+H]+226.0674,found 226.0672.
Embodiment 6：
Substrate：4- chlorobenzene acetylene
Product：
Characterization of The Products data：White solid (54.6mg, 95%yield)；mp:82.9–84.3；1H NMR(400MHz,
CDCl3) δ 7.73 (d, J=8.0Hz, 2H), 7.46 (d, J=8.0Hz, 2H), 7.80 (t, J=54.0Hz, 1H), 6.72 (s,
1H)；13C NMR(100MHz,CDCl3) δ 170.8,159.8 (t, J=38.0Hz), 137.4,129.8,127.6,125.3,
109.3 (t, J=237Hz), 96.8；19F NMR(376MHz,CDCl3) δ -115.29 (d, J=54.0Hz, 2F)；19F{1H}NMR
(376MHz,CDCl3)δ-115.29(s,2F)；HRMS(ESI):m/z calcd for C10H7ONClF2 +[M+H]+
230.0179,found 230.0174.
Embodiment 7：
Substrate：4- bromobenzene acetylene
Product：
Characterization of The Products data：White solid (58.8mg, 86%yield)；mp:103.7–104.5；1H NMR(400MHz,
CDCl3) δ 7.68-7.62 (m, 4H), 6.80 (t, J=54.0Hz, 1H), 6.73 (s, 1H)；13C NMR(100MHz,CDCl3)δ
170.9,159.9 (t, J=30.0Hz), 132.9,127.8,125.8,109.3 (t, J=235.0Hz), 96.9；19F NMR
(376MHz,CDCl3) δ -115.29 (d, J=54.0Hz, 2F)19F{1H}NMR(376MHz,CDCl3)δ-115.29(s,2F)；
HRMS(ESI):m/z calcd for C10H7ONF3Br+[M+H]+273.9674,found 273.9677.
Embodiment 8：
Substrate：4- fluorobenzene acetylene
Product：
Characterization of The Products data：Pale yellow foamy solid (48.9mg, 92%yield)；1H NMR(400MHz,
CDCl3) δ 7.82-7.78 (m, 2H), 7.21-7.17 (m, 2H), 6.80 (t, J=54.0Hz, 1H), 6.68 (s, 1H)；13C NMR
(100MHz,CDCl3) δ 171.0,164.5 (d, J=252.0Hz), 159.8 (t, J=30Hz), 128.5 (d, J=9.0Hz),
123.3 (d, J=3.0Hz), 116.8 (d, J=23.0Hz), 109.4 (t, J=236Hz), 96.3；19F NMR(376MHz,
CDCl3) δ-108.11-- 108.18 (m, 1F) ,-115.30 (d, J=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-
108.14(s,1F),-115.30(s,2F)；HRMS(ESI):m/z calcd for C10H7ONF3 +[M+H]+214.0474,
found 214.0471.
Embodiment 9：
Substrate：4- trifluoromethyl phenylacetylenes
Product：
Characterization of The Products data：White crystalline solid (50.9mg, 77%yield)；mp:84.7–86.2；1H
NMR(400MHz,CDCl3) δ 7.93 (d, J=8.0Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 6.84 (s, 1H), 6.83 (t, J
=54.0Hz, 1H)；13C NMR(100MHz,CDCl3) δ 170.3,159.9 (t, J=30Hz), 132.8,128.3 (q, J=
330Hz), 126.7,126.6 (q, J=4.0Hz), 122.6,109.2 (t, J=237.0Hz), 98.0；19F NMR(376MHz,
CDCl3) δ -63.07 (s, 1F), -115.31 (d, J=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-63.07(s,
1F),-115.31(s,2F)；HRMS(ESI):m/z calcd for C11H7ONF5 +[M+H]+264.0442,found
264.0440.
Embodiment 10：
Substrate：4- cyano phenylacetylenes
Product：
Characterization of The Products data：White solid (41.2mg, 75%yield)；mp:112.7–114.2；1H NMR(400MHz,
CDCl3) δ 7.92 (d, J=8.0Hz, 2H), 7.80 (d, J=8.0Hz, 2H), 6.87 (s, 1H), 6.82 (t, J=52.0Hz,
1H)；13C NMR(100MHz,CDCl3) δ 169.7,160.0 (t, J=30Hz), 133.3,130.5,126.8,118.2,
(114.8,109.1 t, J=236Hz), 98.7；19F NMR(376MHz,CDCl3) δ -115.34 (d, J=52.0Hz, 2F)；19F
{1H}NMR(376MHz,CDCl3)δ-115.34(s,2F)；HRMS(ESI):m/z calcd for C11H7ON2F2 +[M+H]+
221.0521,found 221.0518.
Embodiment 11：
Substrate：4- nitrobenzene acetylenes
Product：
Characterization of The Products data：Yellow solid (44.5mg, 74%yield)；mp:163.6–165.3；1H NMR(400MHz,
CDCl3) δ 8.38 (d, J=8.0Hz, 2H), 8.00 (d, J=8.0Hz, 2H), 6.93 (s, 1H), 6.84 (t, J=54.0Hz,
1H)；13C NMR(100MHz,CDCl3) δ 169.4,160.1 (t, J=30Hz), 149.3,132.1,127.2,124.9,109.1
(t, J=237.0Hz), 99.2；19F NMR(376MHz,CDCl3) δ -115.28 (d, J=54.0Hz, 2F)；19F{1H}NMR
(376MHz,CDCl3)δ-115.28(s,2F)；HRMS(ESI):m/z calcd for C10H7O3N2F2 +[M+H]+241.0419,
found 241.0415.
Embodiment 12：
Substrate：4- methyl formate base phenylacetylenes
Product：
Characterization of The Products data：White solid (55.1mg, 87%yield)；mp:123.4–124.4；1H NMR(400MHz,
CDCl3) δ 8.15 (d, J=8.0Hz, 2H), 7.86 (d, J=8.0Hz, 2H), 6.83 (s, 1H), 6.81 (t, J=54.0Hz,
1H),3.95(s,3H)；13C NMR(100MHz,CDCl3) δ 170.8,166.4,159.9 (t, J=30.0Hz), 132.4,
(130.7,130.5,126.2,109.3 t, J=237Hz), 98.0,52.8；19F NMR(376MHz,CDCl3)δ-115.31(d,
J=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.31(s,2F)；HRMS(ESI)m/z calcd for
C12H10O3NF2 +[M+H]+254.0623,found 254.0619.
Embodiment 13：
Substrate：4- acetylenylbenzene ethyl ketones
Product：
Characterization of The Products data：White solid (45.6mg, 77%yield)；mp:125.0–126.2；1H NMR(400MHz,
CDCl3) δ 8.07 (d, J=8.0Hz, 2H), 7.90 (d, J=8.0Hz, 2H), 6.85 (s, 1H), 6.82 (t, J=54.0Hz,
1H),2.65(s,3H)；13C NMR(100MHz,CDCl3) δ 197.4,170.6,159.9 (t, J=30.0Hz), 138.8,
(130.5,129.4,126.5,109.2 t, J=237.0Hz), 98.1,27.1；19F NMR(376MHz,CDCl3)δ-115.27
(d, J=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.27(s,2F)；HRMS(ESI)m/z calcd for
C12H12O2NF2 +[M+H]+240.0831,found 240.0824.
Embodiment 14：
Substrate：4- Dimethyl sulfide phenylacetylenes
Product：
Characterization of The Products data：White solid (48.8mg, 81%yield)；mp:87.8-88.3；1H NMR(400MHz,
CDCl3) δ 7.70 (d, J=8.0Hz, 2H), 7.32 (d, J=8.0Hz, 2H), 6.79 (t, J=54.0Hz, 1H), 6.67 (s,
1H),2.53(s,3H)；13C NMR(100MHz,CDCl3) δ 171.6,159.7 (t, J=30.0Hz), 143.2,126.6,
(126.4,123.2,109.4 t, J=237.0Hz), 95.9,15.4；19F NMR(376MHz,CDCl3) δ -115.25 (d, J=
54.0Hz,2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.25(s,2F)；HRMS(ESI):m/z calcd for
C11H10ONF2S+[M+H]+242.0446,found 242.0440.
Embodiment 15：
Substrate：4- methylsulfinyl phenylacetylenes
Product：
Characterization of The Products data：White solid (49.2mg, 77%yield)；mp:111.7–113.3；1H NMR(400MHz,
CDCl3) δ 7.92 (d, J=8.0Hz, 2H), 7.74 (d, J=8.0Hz, 2H), 6.82 (s, 1H), 6.79 (t, J=54.0Hz,
1H),2.74(s,3H)；13C NMR(100MHz,CDCl3) δ 170.3,159.7 (t, J=30.0Hz), 148.8,129.0,
(127.0,124.7,109.1 t, J=237Hz), 97.7,44.1；19F NMR(376MHz,CDCl3) δ -115.35 (d, J=
54.0Hz,2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.35(s,2F)；HRMS(ESI)m/z calcd for
C11H10O2NF2S+[M+H]+258.0395,found 258.0392.
Embodiment 16：
Substrate：4- methyl sulphonyl phenylacetylenes
Product：
Characterization of The Products data：Yellow solid (49.2mg, 72%yield)；mp:159.0–160.9；1H NMR(400MHz,
CDCl3) δ 8.09 (d, J=8.0Hz, 2H), 8.01 (d, J=8.0Hz, 2H), 6.91 (s, 1H), 6.84 (t, J=54.0Hz,
1H),3.11(s,3H)；13C NMR(100MHz,CDCl3) δ 169.7,160.0 (t, J=30.0Hz), 142.7,131.5,
(128.8,127.2,109.1 t, J=237Hz), 98.8,44.8；19F NMR(376MHz,CDCl3) δ -115.28 (d, J=
54.0Hz,2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.28(s,2F)；HRMS(ESI):m/z calcd for
C11H10O3NF2S+[M+H]+274.0344,found 274.0339.
Embodiment 17：
Substrate：2- Methoxy-phenylacetylenes
Product：
Characterization of The Products data：White solid (47.8mg, 85%yield)；mp:48.8–49.5；1H NMR(400MHz,
CDCl3) δ 7.98 (dd, J=1.6,8.0Hz, 1H), 7.47-7.42 (m, 1H), 7.08 (t, J=8.0Hz, 1H), 7.03 (d, J
=8.5Hz, 1H), 7.00 (s, 1H), 6.82 (t, J=54.0Hz, 1H), 3.97 (s, 3H)；13C NMR(100MHz,CDCl3)δ
168.0,159.7 (t, J=30.0Hz), 156.7,132.3,128.0,121.3,115.9,111.6,109.7 (t, J=
237.0Hz),100.4,55.9；19F NMR(376MHz,CDCl3) δ -115.28 (d, J=54.0Hz, 2F)；19F{1H}NMR
(376MHz,CDCl3)δ-115.28(s,2F)；HRMS(ESI):m/z calcd for C11H10O2NF2 +[M+H]+226.0674,
found 226.0671.
Embodiment 18：
Substrate：2- chlorobenzene acetylene
Product：
Characterization of The Products data：Colorless oil (47.1mg, 82%yield)；1H NMR(400MHz,CDCl3)δ7.98–
7.94 (m, 1H), 7.56-7.52 (m, 1H), 7.44-7.40 (m, 2H), 7.16 (s, 1H), 6.84 (t, J=54.0Hz, 1H)；13C
NMR(100MHz,CDCl3) δ 168.3,159.6 (t, J=30Hz), 132.4,131.9,131.4,129.8,127.7,125.7,
109.4 (t, J=237Hz), 101.4；19F NMR(376MHz,CDCl3) δ -115.33 (d, J=54.0Hz, 2F)；19F{1H}
NMR(376MHz,CDCl3)δ-115.33(s,2F)；HRMS(ESI):m/z calcd for C10H7ONClF2 +[M+H]+
230.0179,found 230.0176.
Embodiment 19：
Substrate：2- acetenyls-phenylpropiolic acid methyl esters
Product：
Characterization of The Products data：Colorless oil (53.7mg, 77%yield)；1H NMR(400MHz,CDCl3)δ7.95(d,
J=16.0Hz, 1H), 7.76-7.74 (m, 1H), 7.69-7.66 (m, 1H), 7.53-7.51 (m, 2H), 6.83 (t, J=
54.0Hz, 1H), 6.60 (s, 1H), 6.43 (d, J=16.0Hz, 1H), 3.82 (s, 3H)；13C NMR(100MHz,CDCl3)δ
170.4,166.9,159.5 (t, J=30Hz), 142.1,133.9,131.4,130.4,129.6,128.2,126.7,122.2,
109.3 (t, J=237.0Hz), 101.3,52.3；19F NMR(376MHz,CDCl3) δ -115.26 (d, J=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.26(s,2F)；HRMS(ESI)m/z calcd for C14H12O3NF2 +[M+H]+
280.0780,found 280.0774.
Embodiment 20：
Substrate：3- nitrobenzene acetylenes
Product：
Characterization of The Products data：Pale yellow solid (49.9mg, 83%yield)；mp:96.1–97.0；1H NMR
(400MHz,CDCl3) δ 8.64 (t, J=1.8Hz, 1H), 8.36-8.33 (m, 1H), 8.16-8.13 (m, 1H), 7.73 (t, J=
8.0Hz, 1H), 6.92 (s, 1H), 6.83 (t, J=54.0Hz, 1H)；13C NMR(100MHz,CDCl3)δ169.3,160.0(t,
), J=30.0Hz 149.0,131.8,130.9,128.3,125.6,121.3,109.1 (q, J=237.0Hz), 98.4；19F
NMR(376MHz,CDCl3) δ -115.34 (d, J=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.34(s,
2F)；HRMS(ESI):m/z calcd for C10H7O3N2F2 +[M+H]+241.0419,found 241.0414.
Embodiment 21：
Substrate：3- fluorobenzene acetylene
Product：
Characterization of The Products data：Pale yellow foamy solid (43.9mg, 82%yield)；1H NMR(400MHz,
CDCl3) δ 7.59-7.58 (m, 1H), 7.52-7.46 (m, 2H), 7.21-7.16 (m, 1H), 6.81 (t, J=54.0Hz, 1H),
6.75(s,1H)；13C NMR(100MHz,CDCl3) δ 170.6 (d, J=2.0Hz), 163.3 (d, J=247.0Hz), 159.8
(t, J=30.0Hz), 131.3 (d, J=9.0Hz), 128.7 (d, J=9.0Hz), 122.1 (d, J=3.0Hz), 118.2 (d, J
=21.0Hz), 113.4 (d, J=23.0Hz), 109.3 (t, J=237.0Hz), 97.3；19F NMR(376MHz,CDCl3)δ-
111.08-- 111.14 (m, 1F) ,-115.32 (d, J=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-111.11
(s,1F),-115.32(s,2F)；HRMS(ESI):m/z calcd for C10H7ONF3 +[M+H]+214.0474,found
214.0471.
Embodiment 22：
Substrate：3- hydroxyl phenylacetylenes
Product：
Characterization of The Products data：White solid (41.2mg, 78%yield)；mp:134.4–134.9；1H NMR(400MHz,
CD3OD) δ 7.32-7.30 (m, 2H), 7.27-7.25 (m, 1H), 6.95 (s, 1H), 6.95 (t, J=54.0Hz, 1H), 6.94-
6.91(m,1H)；13C NMR(100MHz,CD3OD) δ 173.1,161.0 (t, J=30.0Hz), 159.3,131.5,128.9,
(119.1,118.2,113.4,110.9 t, J=237.0Hz), 97.4；19F NMR(376MHz,CD3OD) δ -117.64 (d, J=
54.0Hz,2F)；19F{1H}NMR(376MHz,CD3OD)δ-117.64(s,2F)；HRMS(ESI)m/z calcd for
C10H8O2NF2 +[M+H]+212.0518,found 212.0513.
Embodiment 23：
Substrate：3- (tert-butyldiphenylsilanyl) oxygroup phenylacetylene
Product：
Characterization of The Products data：Colorless oil (96.0mg, 85%yield)；1H NMR(400MHz,CDCl3)δ7.77–
7.75 (m, 4H), 7.49-7.45 (m, 2H), 7.43-7.39 (m, 4H), 7.33-7.31 (m, 1H), 7.23 (t, J=2.0Hz,
1H), 7.19 (t, J=8.0Hz, 1H), 6.85 (dd, J=2.4,8.0Hz, 1H), 6.78 (t, J=54.0Hz, 1H), 6.5 (s,
1H),1.16(s,9H)；13C NMR(100MHz,CDCl3) δ 171.7,159.6 (t, J=30.0Hz), 156.5,135.9,
132.7,130.5,130.4,128.3,127.8,123.6,119.1,117.6,109.4 (t, J=237.0Hz), 96.5,
26.9,19.8；19F NMR(376MHz,CDCl3) δ -115.25 (d, J=54.0Hz, 2F)；19F{1H}NMR(376MHz,
CDCl3)δ-115.25(s,2F)；HRMS(ESI)m/z calcd for C26H26O2NF2Si+[M+H]+450.1695,found
450.1686.
Embodiment 24：
Substrate：3- benzyq carbamate base phenylacetylenes
Product：
Characterization of The Products data：Yellow solid (80.2mg, 93%yield)；mp:122.1–123.8；1H NMR(400MHz,
CDCl3) δ 7.92 (s, 1H), 7.54-7.47 (m, 2H), 7.43-7.36 (m, 6H), 7.16 (s, 1H), 6.76 (t, J=
54.0Hz,1H),6.72(s,1H),5.23(s,2H)；13C NMR(100MHz,CDCl3) δ 171.6,159.7 (t, J=
30.0Hz),153.6,139.2,136.1,130.3,129.0,128.8,128.7,127.6,121.2,121.2,116.1,
109.3 (t, J=237.0Hz), 97.0,67.7；19F NMR(376MHz,CDCl3) δ -115.27 (d, J=54.0Hz, 2F)；19F
{1H}NMR(376MHz,CDCl3)δ-115.27(s,2F)；HRMS(ESI)m/z calcd for C18H15O3N2F2 +[M+H]+
345.1045,found 345.1039.
Embodiment 25：
Substrate：3- t-butyl carbamate base phenylacetylenes
Product：
Characterization of The Products data：Pale brown solid (67.4mg, 87%yield)；mp:100.6–101.9；1H NMR
(400MHz,CDCl3) δ 7.94 (s, 1H), 7.47-7.44 (m, 1H), 7.43-7.36 (m, 2H), 6.80 (t, J=54.0Hz,
1H),6.77(s,1H),6.74(s,1H),1.53(s,9H)；13C NMR(100MHz,CDCl3) δ 171.8,159.7 (t, J=
30.0Hz), 152.9,139.7,130.1,127.6,121.0,120.8,116.0,109.4 (t, J=237.0Hz), 28.6；19F
NMR(376MHz,CDCl3) δ -115.29 (d, J=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.29(s,
2F)；HRMS(ESI)m/z calcd for C15H17O3N2F2 +[M+H]+311.1202,found 311.1196.
Embodiment 26：
Substrate：3- glycyl phenylacetylenes
Product：
Characterization of The Products data：Pale yellow solid (52.2mg, 83%yield)；mp:152.0–153.9；1H NMR
(400MHz,CD3OD) δ 8.15 (t, J=1.8Hz, 1H), 7.65 (d, J=8.0Hz, 1H), 7.59 (d, J=8.0Hz, 1H),
7.45 (t, J=8.0Hz, 1H), 7.02 (s, 1H), 6.97 (t, J=54.0Hz, 1H), 2.16 (s, 3H)；13C NMR(100MHz,
CD3OD) δ 172.8,171.9,161.1 (t, J=30.0Hz), 141.0,130.9,128.4,123.2,122.5,118.0,
110.9 (q, J=237.0Hz), 97.8,23.9；19F NMR(376MHz,CD3OD) δ -117.67 (d, J=54.0Hz, 2F)；19F
{1H}NMR(376MHz,CD3OD)δ-117.67(s,2F)；HRMS(ESI)m/z calcd for C12H11O2N2F2 +[M+H]+
253.0783,found 253.0779.
Embodiment 27：
Substrate：3- amino benzoyl phenylacetylenes
Product：
Characterization of The Products data：White solid (58.0mg, 74%yield)；mp:161.8–162.3；1H NMR(400MHz,
CDCl3)δ8.17(s,1H),8.09(br s,1H),7.90–7.88(m,2H),7.76–7.74(m,1H),7.59–7.56(m,
2H), 7.51-7.46 (m, 2H), 6.78 (t, J=54.0Hz, 1H), 6.75 (s, 1H)；13C NMR(100MHz,CDCl3)δ
171.5,166.3,159.8 (t, J=30.0Hz), 139.2,134.8,132.6,130.3,129.6,127.7,127.4,
(122.8,122.7,122.3,122.3,117.9,117.8,109.4 t, J=237.0Hz), 97.1；19F NMR(376MHz,
CDCl3) δ -115.31 (d, J=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.31(s,2F)；HRMS(ESI)
m/z calcd for C17H13O2N2F2 +[M+H]+315.0940,found 315.0937.
Embodiment 28：
Substrate：3- amino-(2,2- benzyloxies) base phenylacetylene
Product：
Characterization of The Products data：White solid (61.6mg, 63%yield)；mp:108.9–110.4；1H NMR(400MHz,
CDCl3) δ 7.28-7.25 (m, 4H), 7.21-7.15 (m, 8H), 7.09-7.08 (m, 1H), 7.02 (d, J=8.0Hz, 1H),
6.75 (dd, J=2.4,8.4Hz, 1H), 6.67 (t, J=54.0Hz, 1H), 6.48 (s, 1H), 4.63 (s, 4H)；13C NMR
(100MHz,CDCl3) δ 172.7,159.6 (t, J=30.0Hz), 149.9,138.2,130.4,129.2,127.6,126.9,
(115.3,114.9,109.7,109.5 t, J=237.0Hz), 96.3,54.6；19F NMR(376MHz,CDCl3)δ-115.22
(d, J=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.22(s,2F)；HRMS(ESI)m/z calcd for
C24H21ON2F2 +[M+H]+391.1617,found 391.1610.
Embodiment 29：
Substrate：The fluoro- 3- Methoxy-phenylacetylenes of 2-
Product：
Characterization of The Products data：Pale yellow solid (51.1mg, 84%yield)；mp:90.9–91.6；1H NMR
(400MHz,CDCl3) δ 7.53-7.47 (m, 2H), 7.04 (t, J=8.4Hz, 1H), 6.78 (t, J=54.0Hz, 1H), 6.60
(s,1H),3.94(s,3H)；13C NMR(100MHz,CDCl3) δ 170.7 (d, J=2.4Hz), 159.8 (t, J=30.0Hz),
152.7 (d, J=247.0Hz), 150.2 (d, J=10.5Hz), 122.8 (d, J=4.0Hz), 119.8 (d, J=7.4Hz),
114.1 (d, J=20.5Hz), 113.9 (d, J=2.4Hz), 109.4 (t, J=237.0Hz), 95.8,56.6；19F NMR
(376MHz,CDCl3) δ-115.39 (d, J=54.0Hz, 2F) ,-133.40-- 133.45 (m, 1F)；19F{1H}NMR
(376MHz,CDCl3)δ-115.39(s,2F),-133.43(s,1F)；HRMS(ESI)m/z calcd for C11H9O2NF3 +[M
+H]+244.0580,found 244.0576.
Embodiment 30：
Substrate：The fluorine-based phenylacetylenes of 2- methoxyl groups -3-
Product：
Characterization of The Products data：White solid (49.8mg, 82%yield)；mp:77.3–78.3；1H NMR(400MHz,
CDCl3) δ 7.39 (dd, J=2.0,8.0Hz, 1H), 7.33 (dq, J=2.0,8.0Hz, 1H), 7.17 (dd, J=8.0,
10.0Hz, 1H), 6.79 (t, J=54.0Hz, 1H), 6.68 (s, 1H), 3.96 (s, 3H)；13C NMR(100MHz,CDCl3)δ
171.1,159.8 (t, J=30.0Hz), 154.3 (d, J=253.0Hz), 148.7 (d, J=11.0Hz), 123.4 (d, J=
4.0Hz), 119.5 (d, J=7.8Hz), 117.2 (d, J=20.0Hz), 111.2 (d, J=2.6Hz), 111.3 (d, J=
19.0Hz), 109.3 (t, J=237.0Hz), 96.4,56.7；19F NMR(376MHz,CDCl3) δ -115.31 (d, J=
54.0Hz,2F),-130.09–-130.15(m,1F)；19F{1H}NMR(376MHz,CDCl3)δ-115.31(s,2F),-
130.12(s,1F)；HRMS(ESI)m/z calcd for C11H9O2NF3 +[M+H]+244.0580,found 244.0574.
Embodiment 31：
Substrate：β-naphthalene phenylacetylene
Product：
Characterization of The Products data：Pale yellow solid (45.5mg, 74%yield)；mp:75.3–75.9；1H NMR
(400MHz,CDCl3) δ 8.30 (s, 1H), 7.93-7.90 (m, 2H), 7.88-7.85 (m, 1H), 7.79 (dd, J=1.6,
8.6Hz, 1H), 7.59-7.54 (m, 2H), 6.85 (t, J=54.0Hz, 1H), 6.82 (s, 1H)；13C NMR(100MHz,
CDCl3) δ 172.0,159.8 (t, J=30.0Hz), 134.5,133.3,129.4,129.1,128.2,128.1,127.5,
(126.3,124.0,123.0,109.5 t, J=237.0Hz), 96.8；19F NMR(376MHz,CDCl3) δ -115.18 (d, J=
54.0Hz,2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.18(s,2F)；HRMS(ESI)m/z calcd for
C14H10ONF2 +[M+H]+246.0725,found 246.0720.
Embodiment 32：
Substrate：2- thiophene phenylacetylenes
Product：
Characterization of The Products data：Yellow oil (39.8mg, 79%yield)；1H NMR(400MHz,CDCl3)δ7.57(dd,J
=1.0,3.6Hz, 1H), 7.51 (dd, J=1.0,5.0Hz, 1H), 7.16 (dd, J=3.8,5.0Hz, 1H), 6.78 (t, J=
54.0Hz,1H),6.59(s,1H)；13C NMR(100MHz,CDCl3) δ 167.0,159.7 (t, J=30.0Hz), 129.3,
(128.6,128.5,128.2,109.3 t, J=237.0Hz), 96.1；19F NMR(376MHz,CDCl3) δ -115.37 (d, J=
54.0Hz,2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.37(s,2F)；HRMS(ESI)m/z calcd for
C8H6ONF2S+[M+H]+202.0133,found 202.0130.
Embodiment 33：
Substrate：2- furans phenylacetylenes
Product：
Characterization of The Products data：Colorless oil (32.9mg, 71%yield)；1H NMR(400MHz,CDCl3)δ7.58(d,
J=1.4Hz, 1H), 6.98 (d, J=3.4Hz, 1H), 6.79 (t, J=54.0Hz, 1H), 6.65 (s, 1H), 6.57 (dd, J=
1.8,3.5Hz,1H)；13C NMR(100MHz,CDCl3) δ 163.4,159.4 (t, J=30.0Hz), 145.1,142.7,
(112.4,111.9,109.2 t, J=237.0Hz), 96.1；19F NMR(376MHz,CDCl3) δ -115.41 (d, J=
54.0Hz,2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.41(s,2F)；HRMS(ESI)m/z calcd for
C8H6O2NF2 +[M+H]+186.0361,found 186.0358.
Embodiment 34：
Substrate：3- pyridine phenylacetylenes
Product：
Characterization of The Products data：Brown solid (28.5mg, 58%yield)；mp:51.2–52.1；1H NMR(400MHz,
CDCl3) δ 9.05 (s, 1H), 8.73 (d, J=4.0Hz, 1H), 8.11 (dt, J=2.0,8.0Hz, 1H), 7.46 (dd, J=
4.9,8.0Hz, 1H), 6.84 (s, 1H), 6.82 (t, J=54.0Hz, 1H)；13C NMR(100MHz,CDCl3)δ169.2,
159.9 (t, J=30.0Hz), 152.0,147.5,133.4,124.3,123.2,109.2 (t, J=237.0Hz), 97.6；19F
NMR(376MHz,CDCl3) δ -115.31 (d, J=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.31(s,
2F)；HRMS(ESI)m/z calcd for C9H7ON2F2 +[M+H]+197.0521,found 197.0516.
Embodiment 35：
Substrate：3- vinyl -1H- indoles -1- Ethyl formates
Product：
Characterization of The Products data：Pale yellow solid (54.5mg, 71%yield)；mp:104.1–105.1；1H NMR
(400MHz,CDCl3) δ 8.25 (d, J=8.0Hz, 1H), 8.13 (s, 1H), 7.91 (d, J=8.0Hz, 1H), 7.46-7.37
(m, 2H), 6.84 (t, J=54.0Hz, 1H), 6.74 (s, 1H), 4.55 (q, J=7.2Hz, 2H), 1.51 (t, J=7.2Hz,
3H)；13C NMR(100MHz,CDCl3) δ 166.9,159.5 (t, J=30.0Hz), 150.7,135.8,126.4,126.1,
(125.7,124.5,120.5,115.9,109.4 t, J=237.0Hz), 109.2,96.7,64.4,14.7；19F NMR
(376MHz,CDCl3) δ -115.21 (d, J=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.21(s,2F)；
HRMS(ESI)m/z calcd for C15H13O3N2F2 +[M+H]+307.0889,found 307.0883.
Embodiment 36：
Substrate：Styryl acetylene
Product：
Characterization of The Products data：Pale yellow solid (37.4mg, 68%yield)；mp:68.1–71.4；1H NMR
(400MHz,CDCl3) δ 7.55-7.52 (m, 2H), 7.43-7.41 (m, 2H), 7.39-7.37 (m, 2H), 6.98 (d, J=
16Hz, 1H), 6.78 (t, J=54.0Hz, 1H), 6.48 (s, 1H)；13C NMR(100MHz,CDCl3)δ170.5,159.5(t,J
=30.0Hz), 136.7,135.4,130.0,129.3,127.6,112.6,109.4 (t, J=237.0Hz), 98.1；19F NMR
(376MHz,CDCl3) δ -115.29 (d, J=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.29(s,2F)；
HRMS(ESI)m/z calcd for C12H10ONF2 +[M+H]+222.0725,found 222.0721.
Embodiment 37：
Substrate：N-pentyl -1- alkynes
Product：
Characterization of The Products data：Colorless oil (30.4mg, 60%yield)；1H NMR(400MHz,CDCl3)δ6.72(t,
J=54.0Hz, 1H), 6.20 (s, 1H), 2.79 (t, J=7.6Hz, 1H), 1.75-1.67 (m, 2H), 1.39-1.27 (m, 6H),
0.89 (t, J=7.0Hz, 3H)；13C NMR(100MHz,CDCl3) δ 176.0,159.1 (t, J=30.0Hz), 109.6 (t, J=
237.0Hz),97.9,31.7,29.0,27.7,27.1,22.8,14.3；19F NMR(376MHz,CDCl3)δ-115.17(d,J
=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.17(s,2F)；HRMS(ESI)m/z calcd for
C10H16ONF2 +[M+H]+204.1195,found 204.1199.
Embodiment 38：
Substrate：Butyl- 3- alkynes -1- base 4- methoxyl methyl benzoates
Product：
Characterization of The Products data：Pale yellow oil (49.7mg, 67%yield)；1H NMR(400MHz,CDCl3)δ7.97–
7.93 (m, 2H), 6.92-6.90 (m, 2H), 6.74 (t, J=54.0Hz, 1H), 6.37 (s, 1H), 4.60 (t, J=6.4Hz,
1H), 3.85 (s, 3H), 3.28 (t, J=6.4Hz, 2H)；13C NMR(100MHz,CDCl3)δ172.0,166.2,164.0,
159.2 (t, J=30.0Hz), 132.0,122.2,114.1,109.4 (t, J=237.0Hz), 99.3,61.4,55.8,27.1
；19F NMR(376MHz,CDCl3) δ -115.23 (d, J=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.23
(s,2F)；HRMS(ESI)m/z calcd for C14H14O4NF2 +[M+H]+298.0885,found 298.0881.
Embodiment 39：
Substrate：Butyl- 3- alkynes -1- base 4- nitrobenzene methyls
Product：
Characterization of The Products data：White solid (54.7mg, 70%yield)；mp:64.3–65.0；1H NMR(400MHz,
CDCl3) δ 8.29-8.27 (m, 2H), 8.18-8.15 (m, 2H), 6.74 (t, J=54.0Hz, 1H), 6.38 (s, 1H), 4.69
(t, J=6.3Hz, 1H), 3.34 (t, J=6.3Hz, 2H)；13C NMR(100MHz,CDCl3)δ171.3,164.7,159.3(t,
), J=30.0Hz 151.1,135.2,131.1,124.0,109.3 (t, J=237.0Hz), 99.5,62.6,27.0；19F NMR
(376MHz,CDCl3) δ -115.22 (d, J=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.22(s,2F)；
HRMS(ESI)m/z calcd for C13H14O5N3F2 +[M+NH4]+330.0896,found 330.0896.
Embodiment 40：
Substrate：Ethyl propiolate
Product：
Characterization of The Products data：Colorless oil (27.8mg, 58%yield)；1H NMR(400MHz,CDCl3)δ7.14(s,
1H), 6.82 (t, J=54.0Hz, 1H), 4.46 (q, J=7.1Hz, 1H), 1.42 (t, J=7.1Hz, 2H)；13C NMR
(100MHz,CDCl3) δ 162.3,159.6 (t, J=30.0Hz), 156.3,108.8 (t, J=237.0Hz), 106.5,63.1,
14.4；19F NMR(376MHz,CDCl3) δ -115.27 (d, J=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-
115.27(s,2F)；HRMS(ESI)m/z calcd for C7H8O3NF2 +[M+H]+192.0467,found 192.0459.
Embodiment 41：
Substrate：N- phenyl propyne amides
Product：
Characterization of The Products data：Pale yellow solid (38.0mg, 64%yield)；mp:127.9–128.7；1H NMR
(400MHz,CDCl3)δ8.29(br s,1H),7.66–7.64(m,2H),7.42–7.38(m,2H),7.25–7.20(m,2H),
6.83 (t, J=54.0Hz, 1H)；13C NMR(100MHz,CDCl3) δ 165.1,160.3 (t, J=30.0Hz), 152.9,
(136.5,129.7,126.2,120.7,108.7 t, J=237.0Hz), 105.2；19F NMR(376MHz,CDCl3)δ-
115.43 (d, J=54.0Hz, 2F)；19F{1H}NMR(376MHz,CDCl3)δ-115.43(s,2F)；HRMS(ESI)m/z
calcd for C11H9O2N2F2 +[M+H]+239.0627,found 239.0627.
In addition, we also attempt to have used other metal reagent system：
Comparative example 1：
Cuprous iodide in embodiment 1 is removed, when reaction 24 is small, directly solvent by being evaporated under reduced pressure is removed, can not be obtained
3- difluoromethyls substitute the target product of isoxazoles.
Comparative example 2：
Zinc bromide in embodiment 1 is removed, when reaction 24 is small, directly solvent by being evaporated under reduced pressure is removed, 3- can not be obtained
Difluoromethyl substitutes the target product of isoxazoles.
Comparative example 3：
It changes the bromination zincon in embodiment 1 into chlorination ferron (0.5mmol, 2equiv), when reaction 24 is small, can not obtain
3- difluoromethyls substitute the target product of isoxazoles.
Comparative example 4：
Change the bromination zincon in embodiment 1 into chlorination zincon (0.5mmol, 2equiv), it, directly will be molten when reaction 24 is small
Agent is removed by being evaporated under reduced pressure, and can obtain product Compound 1 using flash column column chromatography, (19mg, 0.07mmol, yield are
28%).
Comparative example 5：
Cuprous iodide in embodiment 1 is changed into acetic acid copper reagent (0.1mmol, 0.1equiv), when reaction 24 is small, directly by solvent
It is removed by being evaporated under reduced pressure, can obtain product Compound 1 using flash column column chromatography, (19mg, 0.07mmol, yield are
28%).
Claims (11)
1. the method that one kettle way prepares 3- difluoromethyls substitution isoxazole compounds, it is characterised in that：By end shown in formula I
Terminal Acetylenes hydrocarbon compound is dissolved in organic solvent, adds in 2,2- difluoroethylamines, nitrite tert-butyl and acetic acid, adds iodate Asia
Copper and bromination zincon, and a period of time is reacted under inert gas shielding, remove organic solvent afterwards and is purified to get to such as
3- difluoromethyls substitution isoxazole compounds shown in Formula II；
In Formulas I and Formula II, R is to be independently selected from aryl or alkyl.
2. the preparation method of the 3- difluoromethyls substitution isoxazole compounds of gram quantity grade, it is characterised in that：It will shown in formula I
Terminal alkyne class compound is dissolved in organic solvent, is added in 2,2- difluoroethylamines and acetic acid, is added cuprous iodide and zinc bromide
Reagent；It is that stirring to abundant dissolving, is then slowly added into the tertiary fourth of nitrous acid at 0 DEG C prior to temperature and under inert gas shielding
Ester reacts a period of time at room temperature；Organic solvent is removed afterwards and is purified different to get substituting to gram quantity grade 3- difluoromethyls
Oxazole compounds；
In Formulas I and Formula II, R is independently selected from aryl or alkyl.
3. method according to claim 1 or 2, it is characterised in that：R is independently selected from phenyl, xenyl, 4- tolyls, 4-
Amyl phenyl, 4- methoxyphenyls, 4- chlorphenyls, 4- bromophenyls, 4- fluorophenyls, 4- trifluoromethyls, 4- cyano-phenyls, 4-
Nitrobenzophenone, 4- methyl formate bases phenyl, 4- acetophenones base, 4- Dimethyl sulfides phenyl, 4- methylsulfinylphenyls, 4- methyl
Sulfonvlphenyl, 2- methoxyphenyls, 2- chlorphenyls, 2- propylene carbamate bases phenyl, 3- nitrobenzophenones, 3- fluorophenyls, 3-
Hydroxy phenyl, 3- (tert-butyldiphenylsilanyl) phenyl, 3- benzyq carbamate bases phenyl, 3- t-butyl carbamates
Base phenyl, 3- glycyls phenyl, 3- amino benzoyls phenyl, 3- amino-(2,2- benzyloxies) base phenyl, the fluoro- 3- of 2-
Methoxyphenyl, 2- methoxyl group -3- fluorophenyls, β naphthalenes, thiophene, furans, pyridine, 1H- indoles -1- group-4 ethyl formates, styrene
Base, ethyl, ethyl 4- methoxy benzoic acids ester group, 4- ethyl nitrobenzoates, group-4 ethyl formate, N- phenyl formamide bases.
4. method according to claim 1 or 2, it is characterised in that：Terminal alkyne class compound shown in formula I and 2,2-
The molar ratio of difluoroethylamine is 1:1~10.
5. method according to claim 1 or 2, it is characterised in that：Terminal alkyne class compound shown in formula I and nitrous
The molar ratio of tert-butyl acrylate is 1:1~10.
6. method according to claim 1 or 2, it is characterised in that：Terminal alkyne class compound shown in formula I and acetic acid
Molar ratio be 1:0.2~5.
7. method according to claim 1 or 2, it is characterised in that：Terminal alkyne class compound shown in formula I and iodate
Cuprous molar ratio is 1:0.05~1.
8. method according to claim 1 or 2, it is characterised in that：Terminal alkyne class compound and bromination shown in formula I
The molar ratio of zinc is 1:1~10.
9. method according to claim 1 or 2, it is characterised in that：When reaction time is 12~48 small.
10. according to the method described in claim 1, it is characterized in that：Reaction temperature is room temperature.
11. method according to claim 1 or 2, it is characterised in that：Organic solvent is chloroform；Inert gas is nitrogen.
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