CN107118171A - 一种异噁唑啉衍生物的制备方法 - Google Patents
一种异噁唑啉衍生物的制备方法 Download PDFInfo
- Publication number
- CN107118171A CN107118171A CN201710214896.7A CN201710214896A CN107118171A CN 107118171 A CN107118171 A CN 107118171A CN 201710214896 A CN201710214896 A CN 201710214896A CN 107118171 A CN107118171 A CN 107118171A
- Authority
- CN
- China
- Prior art keywords
- copper
- mmol
- compound
- butyl
- derivative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000002547 isoxazolines Chemical class 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 76
- 150000001344 alkene derivatives Chemical class 0.000 claims abstract description 19
- 239000000758 substrate Substances 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 239000005749 Copper compound Substances 0.000 claims abstract description 14
- 150000001880 copper compounds Chemical class 0.000 claims abstract description 14
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 150000008049 diazo compounds Chemical class 0.000 claims abstract description 7
- GOHOQHSBZVVKMA-UHFFFAOYSA-N C=1C=NOC=1.N1=CC=CC2=CC=CC=C21 Chemical compound C=1C=NOC=1.N1=CC=CC2=CC=CC=C21 GOHOQHSBZVVKMA-UHFFFAOYSA-N 0.000 claims abstract 2
- 241001597008 Nomeidae Species 0.000 claims abstract 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 126
- 239000010949 copper Substances 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- 239000002585 base Substances 0.000 claims description 15
- 239000000463 material Substances 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 11
- 150000001336 alkenes Chemical group 0.000 claims description 11
- -1 4- chlorphenyls Chemical group 0.000 claims description 10
- 229910052802 copper Inorganic materials 0.000 claims description 9
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 8
- 229910000366 copper(II) sulfate Inorganic materials 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- BXEFQPCKQSTMKA-UHFFFAOYSA-N OC(=O)C=[N+]=[N-] Chemical compound OC(=O)C=[N+]=[N-] BXEFQPCKQSTMKA-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 6
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 claims description 6
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical class [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- 229910021594 Copper(II) fluoride Inorganic materials 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- UMRSVAKGZBVPKD-UHFFFAOYSA-N acetic acid;copper Chemical compound [Cu].CC(O)=O UMRSVAKGZBVPKD-UHFFFAOYSA-N 0.000 claims description 4
- FGOSNANIQLJNSZ-UHFFFAOYSA-N acetonitrile copper Chemical compound [Cu].CC#N.CC#N.CC#N.CC#N FGOSNANIQLJNSZ-UHFFFAOYSA-N 0.000 claims description 4
- QUKGYYKBILRGFE-UHFFFAOYSA-N benzyl acetate Chemical compound CC(=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-UHFFFAOYSA-N 0.000 claims description 4
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 4
- GWFAVIIMQDUCRA-UHFFFAOYSA-L copper(ii) fluoride Chemical compound [F-].[F-].[Cu+2] GWFAVIIMQDUCRA-UHFFFAOYSA-L 0.000 claims description 4
- QNZRVYCYEMYQMD-UHFFFAOYSA-N copper;pentane-2,4-dione Chemical compound [Cu].CC(=O)CC(C)=O QNZRVYCYEMYQMD-UHFFFAOYSA-N 0.000 claims description 4
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 4
- 229940112669 cuprous oxide Drugs 0.000 claims description 4
- 239000012954 diazonium Substances 0.000 claims description 4
- 150000004702 methyl esters Chemical class 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical compound O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 claims description 4
- 229960004643 cupric oxide Drugs 0.000 claims description 3
- 150000001989 diazonium salts Chemical class 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 2
- JBVSBLLOZVDAAZ-UHFFFAOYSA-N 2-diazonio-1-[(2-methylpropan-2-yl)oxy]ethenolate Chemical compound CC(C)(C)OC([O-])=C[N+]#N JBVSBLLOZVDAAZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=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
- 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
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 2
- 229940007550 benzyl acetate Drugs 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- YVPJCJLMRRTDMQ-UHFFFAOYSA-N ethyl diazoacetate Chemical compound CCOC(=O)C=[N+]=[N-] YVPJCJLMRRTDMQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
- KOLLEYGVFGREID-UHFFFAOYSA-N oxo(phenyl)methanediazonium Chemical compound C(C1=CC=CC=C1)(=O)[N+]#N KOLLEYGVFGREID-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 1
- MGBJHYBIYAVEAX-UHFFFAOYSA-K [Cu+3].CS(=O)(=O)O.[F-].[F-].[F-] Chemical compound [Cu+3].CS(=O)(=O)O.[F-].[F-].[F-] MGBJHYBIYAVEAX-UHFFFAOYSA-K 0.000 claims 1
- 230000003647 oxidation Effects 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 claims 1
- 125000003011 styrenyl group Chemical class [H]\C(*)=C(/[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 238000007789 sealing Methods 0.000 abstract description 40
- 238000000034 method Methods 0.000 abstract description 5
- 239000007800 oxidant agent Substances 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 229910000510 noble metal Inorganic materials 0.000 abstract description 2
- 229910052751 metal Inorganic materials 0.000 abstract 2
- 239000002184 metal Substances 0.000 abstract 2
- 230000002194 synthesizing effect Effects 0.000 abstract 2
- 238000002474 experimental method Methods 0.000 abstract 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 abstract 1
- 238000012805 post-processing Methods 0.000 abstract 1
- 150000003254 radicals Chemical class 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 162
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
- 239000000047 product Substances 0.000 description 78
- 239000012973 diazabicyclooctane Substances 0.000 description 43
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 43
- 238000004440 column chromatography Methods 0.000 description 40
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 39
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 39
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 39
- 238000005406 washing Methods 0.000 description 39
- 238000005160 1H NMR spectroscopy Methods 0.000 description 37
- 239000012044 organic layer Substances 0.000 description 35
- 238000001035 drying Methods 0.000 description 33
- 238000010438 heat treatment Methods 0.000 description 33
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 32
- 150000001875 compounds Chemical class 0.000 description 18
- 229910002651 NO3 Inorganic materials 0.000 description 14
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 150000002923 oximes Chemical class 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000004293 19F NMR spectroscopy Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 3
- 150000002828 nitro derivatives Chemical class 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- AZYDOBGWKKQBJE-UHFFFAOYSA-N 1'-(2-chloroethyl)spiro[1,3-dioxolane-2,3'-indole]-2'-one Chemical compound C12=CC=CC=C2N(CCCl)C(=O)C21OCCO2 AZYDOBGWKKQBJE-UHFFFAOYSA-N 0.000 description 2
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- PRXLCSIMRQFQMX-UHFFFAOYSA-N [O].[I] Chemical compound [O].[I] PRXLCSIMRQFQMX-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006352 cycloaddition reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- YTJWOGDOCWTOTL-UHFFFAOYSA-N methyl 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylate Chemical compound O=C1CC(C(=O)OC)CN1C1=CC=C(F)C=C1 YTJWOGDOCWTOTL-UHFFFAOYSA-N 0.000 description 2
- 150000002918 oxazolines Chemical class 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 150000003613 toluenes Chemical class 0.000 description 2
- PLGXEPHZCXBYLP-UHFFFAOYSA-N (-)-munitagine Chemical compound C1C2=CC=C(OC)C(O)=C2C2CC(C=C(C(=C3)O)OC)=C3C1N2C PLGXEPHZCXBYLP-UHFFFAOYSA-N 0.000 description 1
- HJORMJIFDVBMOB-LBPRGKRZSA-N (-)-rolipram Chemical compound COC1=CC=C([C@H]2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-LBPRGKRZSA-N 0.000 description 1
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- VPMIAOSOTOODMY-KJAPKAAFSA-N (4r)-6-[(e)-2-[6-tert-butyl-4-(4-fluorophenyl)-2-propan-2-ylpyridin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1/C=C/C=1C(C(C)C)=NC(C(C)(C)C)=CC=1C1=CC=C(F)C=C1 VPMIAOSOTOODMY-KJAPKAAFSA-N 0.000 description 1
- GZTFUVZVLYUPRG-IZZDOVSWSA-N (e)-3-(4-tert-butylphenyl)-n-(2,3-dihydro-1,4-benzodioxin-6-yl)prop-2-enamide Chemical compound C1=CC(C(C)(C)C)=CC=C1\C=C\C(=O)NC1=CC=C(OCCO2)C2=C1 GZTFUVZVLYUPRG-IZZDOVSWSA-N 0.000 description 1
- QRDAPCMJAOQZSU-KQQUZDAGSA-N (e)-3-[4-[(e)-3-(3-fluorophenyl)-3-oxoprop-1-enyl]-1-methylpyrrol-2-yl]-n-hydroxyprop-2-enamide Chemical compound C1=C(\C=C\C(=O)NO)N(C)C=C1\C=C\C(=O)C1=CC=CC(F)=C1 QRDAPCMJAOQZSU-KQQUZDAGSA-N 0.000 description 1
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 1
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 1
- OMQWWRBNFWPIRR-ONEGZZNKSA-N 1-[(e)-2-(4-ethoxyphenyl)ethenyl]-4-nitrobenzene Chemical compound C1=CC(OCC)=CC=C1\C=C\C1=CC=C([N+]([O-])=O)C=C1 OMQWWRBNFWPIRR-ONEGZZNKSA-N 0.000 description 1
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- WOADNNTWYZOWNV-UHFFFAOYSA-N 3-cycloheptyl-9-(dimethylamino)pyrido[1,2]thieno[3,4-d]pyrimidin-4-one Chemical compound C1=2C(N(C)C)=CC=NC=2SC(C2=O)=C1N=CN2C1CCCCCC1 WOADNNTWYZOWNV-UHFFFAOYSA-N 0.000 description 1
- HZYLVYNCWLAIGF-UHFFFAOYSA-N 4-[[[2-(cyclohexylamino)-2-oxoethyl]-(4-propan-2-ylbenzoyl)amino]methyl]-N-hydroxybenzamide Chemical compound CC(C)c1ccc(cc1)C(=O)N(CC(=O)NC1CCCCC1)Cc1ccc(cc1)C(=O)NO HZYLVYNCWLAIGF-UHFFFAOYSA-N 0.000 description 1
- MWVKLRSIDOXBSE-UHFFFAOYSA-N 5-(1-piperidin-4-ylpyrazol-4-yl)-3-(6-pyrrolidin-1-yl-1,3-benzoxazol-2-yl)pyridin-2-amine Chemical compound NC1=NC=C(C2=CN(N=C2)C2CCNCC2)C=C1C(OC1=C2)=NC1=CC=C2N1CCCC1 MWVKLRSIDOXBSE-UHFFFAOYSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VCUKKMIXURRDKL-UHFFFAOYSA-N 9-(dimethylamino)-3-(4-ethylphenyl)pyrido[1,2]thieno[3,4-d]pyrimidin-4-one Chemical compound C1=CC(CC)=CC=C1N1C(=O)C(SC=2C3=C(N(C)C)C=CN=2)=C3N=C1 VCUKKMIXURRDKL-UHFFFAOYSA-N 0.000 description 1
- REDUQXCPUSNJOL-UHFFFAOYSA-N C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O Chemical compound C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O REDUQXCPUSNJOL-UHFFFAOYSA-N 0.000 description 1
- DGJMHKMYSDYOFP-MRXNPFEDSA-N C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O Chemical compound C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O DGJMHKMYSDYOFP-MRXNPFEDSA-N 0.000 description 1
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 1
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical compound ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- KSMITTDZTTZFML-LURJTMIESA-N Jasminine Chemical compound C[C@@H]1NC(=O)CC2=C1C=NC=C2C(=O)OC KSMITTDZTTZFML-LURJTMIESA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- BEXZJJQVPWJPOA-VOTSOKGWSA-N [(e)-hept-2-enyl] 6-methyl-4-(4-nitrophenyl)-2-oxo-3,4-dihydro-1h-pyrimidine-5-carboxylate Chemical compound CCCC\C=C\COC(=O)C1=C(C)NC(=O)NC1C1=CC=C([N+]([O-])=O)C=C1 BEXZJJQVPWJPOA-VOTSOKGWSA-N 0.000 description 1
- HGDWHTASNMRJMP-UHFFFAOYSA-N [1-(hydroxyamino)-1-oxo-5-(3-phenoxyphenyl)pentan-2-yl]phosphonic acid Chemical compound ONC(=O)C(P(O)(O)=O)CCCC1=CC=CC(OC=2C=CC=CC=2)=C1 HGDWHTASNMRJMP-UHFFFAOYSA-N 0.000 description 1
- HYWVELCSGZINQW-ZWKOTPCHSA-N ac1l4j9n Chemical compound CN([C@@H]1[C@H](O)C2=C(C3=C11)C=CC=C2OC)CCC1=CC1=C3OCO1 HYWVELCSGZINQW-ZWKOTPCHSA-N 0.000 description 1
- DORMTBIPKNPJPY-UHFFFAOYSA-N acetic acid;iodobenzene Chemical compound CC(O)=O.IC1=CC=CC=C1 DORMTBIPKNPJPY-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- YBFBENHWPRGUMU-UHFFFAOYSA-N chembl398496 Chemical compound OC(=O)C1=CC=CC=C1NC(=O)N1CCN(C=2N=C3C=CC(O)=CC3=NC=2)CC1 YBFBENHWPRGUMU-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000007342 radical addition reaction Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 150000003440 styrenes Chemical class 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 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
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
-
- 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
- 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
- C07D413/12—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 linked by a chain containing hetero atoms as chain links
-
- 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
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种异噁唑啉衍生物的制备方法,以烯烃衍生物、重氮衍生物以及亚硝酸叔丁酯为反应底物,以铜化物为催化剂,在碱的条件下,通过金属卡宾与自由基偶联,进一步串联环化反应制备得到异噁唑啉衍生物;本发明设计了一种温和的反应条件,选用原料廉价易得,选用便宜的金属铜化合物为催化剂,直接在封管体系中就可以很方便的合成异噁唑啉衍生物衍生物。避免了传统合成方法使用大量氧化剂,贵金属作为催化剂,无水无氧等苛刻的实验条件,使得反应简单易行,后处理简单,具有潜在的工业应用价值。
Description
技术领域
本发明涉及一种制备异噁唑啉衍生物的方法,属于有机合成技术领域。
背景技术
异噁唑啉是一类非常重要的杂环结构单元,广泛存在于有生理药物活性的天然产物、药物分子之中,同样也是一类可以转化为其他有价值骨架的重要的中间体,另外,在不对称催化反应中也经常扮演手型配体的角色。
目前,制备异噁唑啉衍生物的方法有着需要加入大量的氧化剂,贵金属作为催化剂,合成路线存在原料价格昂贵或多步合成,反应条件苛刻,反应时间较长等缺点。例如:
(1). Machetti等使用硝基化合物和1,2-偶极子在DABCO的催化作用下,通过碱的催化硝基化合物脱水,进而再进行环加成反应得到了异噁唑啉衍生物,但是硝基化合物由于其结构的局限性以及合成的复杂性,限制了该反应在合成中的应用。(参见:[a] Cecchi,L.; De Sarlo, F.; Machetti, F. Eur. J. Org. Chem. 2006, 4852. [b] Cecchi, L.;De Sarlo, F.; Machetti, F. Chem. – Eur. J. 2008, 14, 7903);
(2). Ciufolini等使用结构复杂的含有烯烃的肟为底物,醋酸碘苯为氧化剂,首先氧化剂将肟氧化为硝酮中间体,硝酮做为经典的偶极子和分子内的烯烃发成环加成反应构建异噁唑啉衍生物骨架。(参见:[a] Mendelsohn, B. A.; Lee, S.; Kim, S.; Teyssier,F.; Aulakh, V. S.; Ciufolini, M. A. Org. Lett. 2009, 11, 1539. [b] Jen, T.;Mendelsohn, B. A.; Ciufolini, M. A. J. Org. Chem. 2011, 76, 728.);
(3). Minakata等人在Ciufolini工作的基础上,以肟和烯烃为反应底物,通过加入叔丁氧碘,在叔丁氧碘的作用下,肟进行两次的1,3氢迁移,生成碘代肟的中间体,最后脱去碘化氢生成硝酮中间体,最后和烯烃进行环加成反应以较高的收率得到噁唑啉(参见:[a]Minakata, S.; Okumura, S.; Nagamachi, T.; Takeda, Y. Org. Lett. 2011, 13,2966. [b] Yoshimura, A.; Middleton, K. R.; Todora, A. D.; Kastern, B. J.;Koski, S. R.; Maskaev, A. V.; Zhdankin, V. V. Org. Lett. 2013, 15, 4010.);
(4). Li等人使用甲苯衍生物和烯烃在过渡金属钯的催化下制得噁唑啉类化合物。虽然该反应使用便宜易得的甲苯衍生物为底物,但是该反应需要加入贵金属钯为催化剂,并且需要加入4当量的硝酸银,这就大大限制了反应在合成中的应用。(参见:Li, C.; Deng,H.; Li, C.; Jia, X.; Li, J. Org. Lett. 2015, 17, 5718.);
(5). Xu bin等人发现芳基端炔和贫电子烯烃,加入当量级别的硝酸铜,可以中等到好的收率得到异噁唑啉衍生物类衍生物,但是当量的硝酸铜的引入也极大地限制该反应在工业生产中的应用。(参见:Gao, M.; Li, Y.; Gan, Y.; Xu, B. Angew. Chem., Int. Ed. 2015, 54, 8795);
(6). Kittakoop等人研究发现在水溶液条件下α-氯代肟和烯烃就可以以中等的收率得到异噁唑啉衍生物衍生物,但是该反应需要配得PH=4的缓冲溶液。(参见:Kesornpun,C.; Aree, T.; Mahidol, C.; Ruchirawat, S.; Kittakoop, P. Angew. Chem., Int. Ed. 2016, 55, 3997.);
(7). Han等人研究发现含有烯烃的肟为底物在TEMPO的作用下,肟结构中的羟基能生成氧自由基,进而分子内对烯烃的自由基加成反应,最后在不同的亲核试剂的捕获下制得异噁唑啉衍生物衍生物。但是其底物制备的复杂限制了其在工业生产中的应用。参见:([a]Han, B.; Yang, X.-L.; Fang, R.; Yu, W.; Wang, C.; Duan, X.-Y.; Liu, S. Angew. Chem., Int. Ed. 2012, 51, 8816. [b] Chen, F.; Yang, X.-L.; Wu, Z.-W.; Han, B.J. Org. Chem. 2016, 81, 3042. )。
发明内容
本发明的发明目的是提供一种异噁唑啉衍生物的制备方法,保证反应在温和的条件下反应的同时,降低昂贵的或者毒性高的催化剂的使用,原料廉价易得,使制备过程更绿色环保,更经济。
为达到上述发明目的,本发明采用的技术方案是:一种制备异噁唑啉衍生物的方法,以烯烃衍生物、重氮衍生物、亚硝酸叔丁酯为反应底物,以铜化物为催化剂,在碱存在下,反应制备得到异噁唑啉衍生物;
所述烯烃衍生物的化学结构式为:、、或;式中,R选自:苯基、4-叔丁基苯基、4-甲基苯基、4-甲氧基苯基、4-氯苯基、4-溴苯基、4-氟苯基、4-氰基苯基、4-甲酸甲酯基苯基、Bn基保护的4-羟基苯基、Ts基保护的4-羟基苯基、3-溴苯基、3-氟苯基、3-三氟甲基苯基、2-氯苯基、2-甲基苯基、2-甲氧基苯基、5氟取代苯基、1-萘基、4-吡啶基、正己基、正丁基、环己基、苄基、2-氯乙基、3-羟基丙基、1-羟基-1-二甲基、2-TBS保护的羟基乙基、1-苯氧基甲基、1-乙酸巯酯基甲基、甲酸甲酯基;
所述重氮选自:重氮乙酸乙酯、重氮乙酸异丙酯酯、重氮乙酸叔丁酯、苯甲酰重氮、重氮乙酸苄酯、重氮乙酸(2-呋喃)甲酯、重氮乙酸(4-甲基苯基)甲酯、重氮乙酸(4-氯苯基)甲酯;
所述铜化物选自:醋酸铜、碘化亚铜、氯化铜、乙酰丙酮铜、一水醋酸铜、三氟甲磺酸铜、硝酸铜、无水硫酸铜、五水硫酸铜、溴化亚铜、氟化铜、六氟磷酸四乙腈铜、氧化铜、氧化亚铜中的一种。
上述技术方案中,反应温度为60~100 ℃,优化温度为80 ℃;反应时间为6~24小时,优化反应时间为12小时。
上述技术方案中,催化剂的用量为反应底物烯烃衍生物的物质的量的5~20 %,优选用催化剂的用量为反应底物烯烃衍生物的物质的量的10 %。
上述技术方案中,重氮化合物的用量为反应底物烯烃衍生物的物质的量的1.5~3倍,优选用重氮化合物的用量为反应底物苯乙烯衍生物的物质的量的2倍。
上述技术方案中,亚硝酸叔丁酯的用量为反应底物烯烃衍生物的物质的量的1.5~3倍,优选用亚硝酸叔丁酯的用量为反应底物烯烃衍生物的物质的量的2倍。
上述技术方案中,反应在溶剂中进行;所用溶剂为:苯、N,N-二甲基甲酰胺、甲苯、乙腈、1,2-二氯乙烷、四氢呋喃、水,优选用甲苯作为溶剂。
上述技术方案中,碱为1,4-二氮杂二环[2.2.2]辛烷(DABCO),碳酸钾,碳酸钠,碳酸氢钠,碳酸铯,叔丁醇锂,DBU,TMEDA;碱的用量为1~3当量,优选用碱为DABCO,DABCO的用量为反应底物烯烃衍生物的物质的量的1倍。
结合上述技术方案,本发明反应的通式可以为:
进一步的技术方案中,反应完成后,用乙酸乙酯萃取,再用硅胶进行吸附真空旋干溶剂,然后用乙酸乙酯和石油醚的混合溶剂进行简单柱层析便可得最终产物。
上述技术方案中,所述催化剂、反应物皆为市场化商品,可直接购买得到。
本发明公开了烯烃衍生物、重氮衍生物、亚硝酸叔丁酯作为反应底物在制备异噁唑啉衍生物中的应用,以及铜化物作为催化剂在制备异噁唑啉衍生物中的应用或者铜化物在催化烯烃衍生物、重氮衍生物、亚硝酸叔丁酯反应体系中的应用;所述铜化物的用量为烯烃衍生物的物质的量的5~20 %;所述铜化物选自:醋酸铜、碘化亚铜、氯化铜、乙酰丙酮铜、一水醋酸铜、三氟甲磺酸铜、硝酸铜、无水硫酸铜、五水硫酸铜、溴化亚铜、氟化铜、六氟磷酸四乙腈铜、氧化铜、氧化亚铜中的一种。
由于上述技术方案运用,本发明与现有技术相比具有下列优点:
1). 本发明首次公开了烯烃衍生物、重氮衍生物、亚硝酸叔丁酯作为反应底物在便宜的催化剂催化下制备异噁唑啉衍生物,反应采用商业化的一水醋酸铜为催化剂,条件温和,无需无水无氧。
2). 本发明的反应体系避免了氧化剂的使用,减少了对环境的危害,同时减少了后处理麻烦的过程,更加适合工业化生产。
3). 本发明的反应通过多组份一锅法以中等偏高的产率构建异噁唑啉衍生物类化合物,更加适合工业化生产。
4). 本发明的体系发展了新的异噁唑啉衍生物类化合物的合成方法,对脂肪族烯烃以及芳环烯烃都适用。
具体实施方式
下面结合实施例对本发明作进一步描述:
实施例一:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO(3 mmol),甲苯15 mL,化合物1a(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4a,收率为88 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.44 – 7.37 (m, 2H),7.26 (d, J = 8.3 Hz, 2H), 5.76 (dd, J = 11.5, 9.0 Hz, 1H), 4.35 (q, J = 7.1Hz, 2H), 3.60 (dd, J = 17.8, 11.6 Hz, 1H), 3.22 (dd, J = 17.8, 9.0 Hz, 1H),1.37 (t, J = 7.1 Hz, 3H), 1.31 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 160.5,151.7, 151.1, 136.3, 125.7, 125.6, 84.8, 62.0, 41.1, 34.5, 31.2, 14.0; HRMS(ESI-TOF): Anal. Calcd. For C16H21NO3: 276.1594, Found: 276.1598 (M+H+); IR(neat, cm-1): υ 2962, 1717, 1588, 1244, 1109, 923, 831, 747。
实施例二:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1b(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4b,收率为75 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.23 – 7.15 (m, 2H),5.73 (dd, J = 11.5, 9.1 Hz, 1H), 4.35 (q, J = 7.1 Hz, 1H), 3.60 (dd, J =17.8, 11.5 Hz, 1H), 3.19 (dd, J = 17.8, 9.0 Hz, 1H), 2.34 (s, 2H), 1.37 (t, J= 7.1 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 160.5, 151.0, 138.4, 136.4, 129.4,125.8, 84.9, 62.0, 41.2, 21.0, 14.0; HRMS (ESI-TOF): Anal. Calcd. ForC13H15NO3: 234.1125, Found: 234.1135 (M+H+); IR (neat, cm-1): υ 2983, 1716,1588, 1244, 1117, 925, 816, 749。
实施例三:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1c(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4c,收率为87 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.29 – 7.21 (m, 2H),6.93 – 6.86 (m, 2H), 5.72 (dd, J = 11.5, 9.3 Hz, 1H), 4.35 (q, J = 7.1 Hz,2H), 3.79 (s, 3H), 3.58 (dd, J = 17.8, 11.5 Hz, 1H), 3.19 (dd, J = 17.8, 9.2Hz, 1H), 1.37 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.5, 159.8,151.1, 131.2, 127.4, 114.1, 84.8, 61.9, 55.2, 40.9, 14.0; HRMS (ESI-TOF):Anal. Calcd. For C13H15NO4: 250.1074, Found: 250.1082 (M+H+); IR (neat, cm-1): υ2936, 1716, 1514, 1245, 1118, 922, 861, 831。
实施例四:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1d(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4d,收率为94 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.37 – 7.31 (m, 2H),7.30 – 7.23 (m, 2H), 5.76 (dd, J= 11.6, 8.7 Hz, 1H), 4.35 (q, J = 7.1 Hz,2H), 3.64 (dd, J = 17.8, 11.6 Hz, 1H), 3.17 (dd, J = 17.8, 8.7 Hz, 1H), 1.37(t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.2, 151.0, 138.0, 134.4,128.9, 127.1, 84.0, 62.1, 41.4, 14.0; HRMS (ESI-TOF): Anal. Calcd. ForC12H12ClNO3: 254.0578, Found: 254.0578 (M+H+); IR (neat, cm-1): υ 2924, 1712,1593, 1251, 1113, 919, 819, 745。
实施例五:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1e(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4e,收率为74 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.53 – 7.47 (m, 2H),7.23 – 7.16 (m, 2H), 5.74 (dd, J = 11.6, 8.7 Hz, 1H), 4.35 (q, J = 7.1 Hz,2H), 3.65 (dd, J = 17.8, 11.6 Hz, 1H), 3.16 (dd, J = 17.8, 8.7 Hz, 1H), 1.37(t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.2, 151.0, 138.5, 131.9,127.4, 122.5, 84.0, 62.1, 41.4, 14.0; HRMS (ESI-TOF): Anal. Calcd. ForC12H12BrNO3: 298.0073, Found: 298.0083 (M+H+); IR (neat, cm-1): υ 2952, 1717,1592, 1244, 1119, 1010, 918, 822。
实施例六:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1f(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4f,收率为96 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.38 – 7.23 (m, 2H),7.15 – 6.93 (m, 2H), 5.76 (dd, J = 11.5, 8.9 Hz, 1H), 4.36 (q, J = 7.1 Hz,2H), 3.64 (dd, J = 17.8, 11.6 Hz, 1H), 3.18 (dd, J = 17.8, 8.9 Hz, 1H), 1.38(t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 162.6 (d, J = 247.4 Hz),160.3, 151.0, 135.2 (d, J = 3.2 Hz), 127.6 (d, J = 8.4 Hz), 115.6 (d, J =21.7 Hz), 84.1, 62.0, 41.3, 13.9; 19F NMR (376 MHz, CDCl3) δ -113.05; HRMS(ESI-TOF): Anal. Calcd. For C12H12FNO3: 238.0874, Found: 238.0883 (M+H+); IR(neat, cm-1): υ 2984, 1718, 1511, 1244, 1119, 920, 835, 750。
实施例七:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1g(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4g,收率为88 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.23 – 7.15 (m, 2H),5.73 (dd, J = 11.5, 9.1 Hz, 1H), 4.35 (q, J = 7.1 Hz, 1H), 3.60 (dd, J =17.8, 11.5 Hz, 1H), 3.19 (dd, J = 17.8, 9.0 Hz, 1H), 2.34 (s, 2H), 1.37 (t, J= 7.1 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 160.5, 151.0, 138.4, 136.4, 129.4,125.8, 84.9, 62.0, 41.2, 21.0, 14.0; HRMS (ESI-TOF): Anal. Calcd. ForC13H15NO3: 234.1125, Found: 234.1135 (M+H+); IR (neat, cm-1): υ 2983, 1716,1588, 1244, 1117, 925, 816, 749。
实施例八:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1h(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4h,收率为86 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.74 – 7.64 (m, 2H),7.50 – 7.40 (m, 2H), 5.84 (dd, J = 11.7, 8.3 Hz, 1H), 4.37 (q, J = 7.1 Hz,2H), 3.73 (dd, J = 17.8, 11.7 Hz, 1H), 3.18 (dd, J = 17.8, 8.2 Hz, 1H), 1.38(t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.0, 151.0, 144.7, 132.6,126.3, 118.2, 112.4, 83.4, 62.3, 41.6, 14.0; HRMS (ESI-TOF): Anal. Calcd. ForC13H12N2O3: 245.0921, Found: 245.0917 (M+H+); IR (neat, cm-1): υ 2922, 2224,1716, 1587, 1267, 1149, 1116, 909, 828, 745.
实施例九:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1i(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4i,收率为72 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.41 – 7.29 (m, 2H),7.18 – 7.01 (m, 2H), 5.78 (dd, J = 11.5, 8.7 Hz, 1H), 4.36 (q, J = 7.1 Hz,2H), 3.63 (dd, J = 17.8, 11.6 Hz, 1H), 3.20 (dd, J = 17.8, 8.7 Hz, 1H), 2.30(s, 3H), 1.38 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.3, 160.4,151.1, 150.7, 137.0, 127.0, 122.0, 84.2, 62.1, 41.4, 21.0, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C14H15NO5: 278.1023, Found: 278.1009 (M+H+); IR (neat,cm-1): υ 2922, 1746, 1710, 1512, 1222, 935, 915, 823。
实施例十:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1j(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4j,收率为72 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.44 – 7.27 (m, 5H),7.23 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 5.70 (dd, J = 11.3, 9.4Hz, 1H), 5.05 (s, 2H), 4.35 (q, J = 7.1 Hz, 2H), 3.56 (dd, J = 17.8, 11.5 Hz,1H), 3.18 (dd, J = 17.8, 9.2 Hz, 1H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (101MHz, CDCl3) δ 160.5, 159.0, 151.1, 136.6, 131.5, 128.5, 127.9, 127.4, 127.3,115.0, 84.8, 69.9, 62.0, 41.0, 14.0; HRMS (ESI-TOF): Anal. Calcd. ForC19H19NO4: 348.1206, Found: 348.1191 (M+Na+); IR (neat, cm-1): υ 2922, 1712,1512, 1237, 1113, 919, 822, 726。
实施例十一:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1k(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4k,收率为90 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.3 Hz,2H), 7.32 (d, J = 8.1 Hz, 2H), 7.28 – 7.19 (m, 2H), 7.03 – 6.96 (m, 2H), 5.75(dd, J = 11.6, 8.7 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.64 (dd, J = 17.8,11.6 Hz, 1H), 3.15 (dd, J = 17.8, 8.6 Hz, 1H), 2.45 (s, 3H), 1.37 (t, J = 7.1Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.2, 151.0, 149.5, 145.5, 138.4, 132.0,129.8, 128.3, 127.1, 122.7, 83.8, 62.1, 41.4, 21.6, 14.0; HRMS (ESI-TOF):Anal. Calcd. For C19H19NO6S: 390.1006, Found: 390.0997 (M+H+); IR (neat, cm-1):υ 2984, 1718, 1503, 1198, 1152, 863, 745。
实施例十二:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1l(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4l,收率为77 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.53 – 7.42 (m, 2H),7.31 – 7.19 (m, 2H), 5.75 (dd, J = 11.6, 8.5 Hz, 1H), 4.36 (q, J = 7.1 Hz,2H), 3.66 (dd, J = 17.8, 11.7 Hz, 1H), 3.19 (dd, J = 17.8, 8.5 Hz, 1H), 1.38(t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.2, 151.0, 141.8, 131.6,130.4, 128.7, 124.3, 122.8, 83.7, 62.2, 41.5, 14.0; HRMS (ESI-TOF): Anal.Calcd. For C12H12BrNO3: 319.9893, Found: 319.9904 (M+Na+); IR (neat, cm-1): υ2983, 1717, 1590, 1244, 1119, 918, 782, 746, 664.
实施例十三:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1m(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4m,收率为88 %。
对产物进行分析,结果如下:1 H NMR (400 MHz, CDCl3) δ 7.35 (td, J = 7.8,6.1 Hz, 1H), 7.14 – 6.97 (m, 3H), 5.78 (dd, J = 11.6, 8.5 Hz, 1H), 4.36 (q, J= 7.1 Hz, 2H), 3.66 (dd, J = 17.8, 11.6 Hz, 1H), 3.19 (dd, J = 17.8, 8.5 Hz,1H), 1.38 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ162.8 (d, J = 247.1Hz), 160.2, 151.0, 142.0 (d, J = 7.1 Hz), 130.4 (d, J = 8.3 Hz), 121.2 (d, J= 3.0 Hz), 115.3 (d, J = 21.2 Hz), 112.6 (d, J = 22.5 Hz), 83.8 (d, J = 1.7Hz), 62.0, 41.4, 13.9; 19F NMR (376 MHz, CDCl3) δ -111.86; HRMS (ESI-TOF):Anal. Calcd. For C12H12FNO3: 238.0874, Found: 238.0866 (M+H+); IR (neat, cm-1):υ 2985, 1718, 1590, 1245, 1119, 921, 786, 749。
实施例十四:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1n(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4n,收率为73 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 7.3,1.9 Hz, 1H), 7.38 (dd, J = 7.0, 2.0 Hz, 1H), 7.33 – 7.22 (m, 2H), 6.06 (dd, J= 11.7, 7.8 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.78 (dd, J = 17.9, 11.7 Hz,1H), 3.09 (dd, J = 17.9, 7.8 Hz, 1H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (101MHz, CDCl3) δ 160.1, 151.1, 140.6, 131.1 (q, J = 32.6 Hz), 129.4, 129.0,125.3 (q, J = 3.7 Hz), 123.7 (q, J = 270.7 Hz), 22.5 (q, J = 3.8 Hz), 83.8,62.1, 41.5, 13.9; HRMS (ESI-TOF): Anal. Calcd. For C13H12F3NO3: 310.0661,Found: 310.0657 (M+Na+); IR (neat, cm-1): υ 2987, 1719, 1593, 1326, 1118, 919,802, 658。
实施例十五:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1o(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4o,收率为91 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 7.3,1.9 Hz, 1H), 7.38 (dd, J = 7.0, 2.0 Hz, 1H), 7.33 – 7.22 (m, 2H), 6.06 (dd, J= 11.7, 7.8 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.78 (dd, J = 17.9, 11.7 Hz,1H), 3.09 (dd, J = 17.9, 7.8 Hz, 1H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (101MHz, CDCl3) δ 160.1, 151.1, 137.5, 130.9, 129.5, 129.3, 127.1, 126.2, 81.6,77.3, 77.0, 76.7, 62.0, 41.1, 13.9; HRMS (ESI-TOF): Anal. Calcd. ForC12H12ClNO3: 276.0398, Found: 276.0410 (M+Na+); IR (neat, cm-1): υ 2983, 1718,1592, 1244, 1118, 919, 748。
实施例十六:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1p(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4p,收率为81 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 6.08 (dd, J = 12.5,8.9 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.68 (dd, J = 17.9, 12.5 Hz, 1H), 3.39(dd, J = 17.9, 8.9 Hz, 1H), 1.40 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)δ 159.9, 150.7, 74.2, 62.3, 39.4, 13.9; 19F NMR (376 MHz, CDCl3) δ -140.78 – -143.34 (m, 2F), -150.18 – -153.80 (m, 2F), -159.14 – -163.14 (m, 2F); HRMS(ESI-TOF): Anal. Calcd. For C12H8F5NO3: 310.0497, Found: 310.0487 (M+H+); IR(neat, cm-1): υ 2988, 1720, 1504, 1257, 1123, 1017, 919, 968, 917。
实施例十七:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1q(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4q,收率为71 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.92 – 7.85 (m, 1H),7.81 (d, J = 8.2 Hz, 1H), 7.79 – 7.73 (m, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.57– 7.39 (m, 3H), 6.54 – 6.29 (m, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.81 (ddd, J =17.6, 11.7, 1.2 Hz, 1H), 3.22 (ddd, J = 17.6, 8.3, 0.6 Hz, 1H), 1.35 (t, J =7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.4, 151.4, 134.8, 133.8, 129.3,129.0, 128.8, 126.5, 125.8, 125.3, 122.6, 82.4, 62.1, 41.3, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C16H15NO3: 292.0944, Found: 292.0943 (M+Na+); IR (neat,cm-1): υ 2921, 1746, 1601, 1238, 1157, 926, 821, 745。
实施例十八:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1r(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4r,收率为73 %。
对产物进行分析,结果如下:1 H NMR (400 MHz, CDCl3) δ 8.64 (s, 2H), 7.27(d, J = 4.6 Hz, 2H), 5.80 (dd, J = 11.6, 8.1 Hz, 1H), 4.35 (qd, J = 7.1, 1.4Hz, 2H), 3.73 (dd, J = 17.7, 11.8 Hz, 1H), 3.19 (dd, J = 17.7, 8.0 Hz, 1H),1.37 (td, J = 7.1, 1.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 159.9, 150.9,150.2, 148.3, 120.1, 82.5, 62.2, 41.3, 13.9; HRMS (ESI-TOF): Anal. Calcd. ForC11H12N2O3: 221.0921, Found: 221.0926 (M+H+); IR (neat, cm-1): υ 2984, 1718,1592, 1248, 1120, 917, 822。
实施例十九:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1s(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4s,收率为74 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.41 – 7.34 (m, 4H),7.32 – 7.25 (m, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.35 (q, J = 17.5 Hz, 2H),1.77 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.6,150.9, 144.2, 128.5, 127.6, 124.4, 91.1, 61.9, 47.0, 28.1, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C13H15NO3: 256.0944, Found: 256.0947 (M+Na+); IR (neat,cm-1): υ 2981, 1717, 1587, 1249, 1125, 932, 766, 699。
实施例二十:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1t(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4t,收率为86 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 4.84 – 4.76 (m, 1H),4.34 (q, J = 7.1 Hz, 2H), 3.25 (dd, J = 17.5, 10.9 Hz, 1H), 2.84 (dd, J =17.5, 8.6 Hz, 1H), 1.83 – 1.70 (m, 1H), 1.66 – 1.53 (m, 1H), 1.43 – 1.26 (m,11H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.8, 151.2, 84.0,61.8, 38.2, 34.9, 31.5, 28.8, 24.9, 22.4, 14.0, 13.9; HRMS (ESI-TOF): Anal.Calcd. For C12H21NO3: 250.1414, Found: 250.1416 (M+Na+); IR (neat, cm-1): υ2929, 1717, 1250, 1122, 930, 747。
实施例二十一:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1u(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4u,收率为76 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 4.84 – 4.76 (m, 1H),4.34 (q, J = 7.1 Hz, 2H), 3.25 (dd, J = 17.5, 10.9 Hz, 1H), 2.84 (dd, J =17.5, 8.5 Hz, 1H), 1.85 – 1.72 (m, 1H), 1.66 – 1.55 (m, 1H), 1.44 – 1.31 (m,7H), 0.92 (t, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.8, 151.2, 84.0,61.8, 38.2, 34.6, 27.1, 22.3, 14.0, 13.8; HRMS (ESI-TOF): Anal. Calcd. ForC10H17NO3: 222.1101, Found: 222.1112 (M+Na+); IR (neat, cm-1): υ 2933, 1717,1254, 1122, 930, 748。
实施例二十二:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1v(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4v,收率为80 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 4.59 – 4.52 (m, 1H),4.34 (q, J = 7.1 Hz, 2H), 3.15 (dd, J = 17.6, 11.2 Hz, 1H), 2.93 (dd, J =17.6, 9.1 Hz, 1H), 1.91 – 1.53 (m, 6H), 1.37 (t, J = 7.1 Hz, 3H), 1.29 – 1.16(m, 3H), 1.10 – 0.94 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 160.8, 151.2, 88.2,61.8, 42.0, 35.7, 28.1, 27.9, 26.1, 25.6, 25.4, 14.0; HRMS (ESI-TOF): Anal.Calcd. For C12H19NO3: 248.1257, Found: 248.1268 (M+Na+); IR (neat, cm-1): υ2926, 2853, 1716, 1250, 1123, 931, 748。
实施例二十三:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1w(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4w,收率为73 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.35 – 7.27 (m, 2H),7.27 – 7.17 (m, 3H), 5.07 – 4.99 (m, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.17 (dd,J = 17.7, 10.9 Hz, 1H), 3.09 (dd, J = 14.0, 6.2 Hz, 1H), 2.93 (dd, J = 15.1,5.7 Hz, 1H), 2.87 (dd, J = 11.4, 4.2 Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H); 13CNMR (101 MHz, CDCl3) δ 160.6, 151.3, 135.8, 129.2, 128.5, 126.8, 84.2, 61.8,40.6, 37.7, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C13H15NO3: 256.0944, Found:256.0947 (M+Na+); IR (neat, cm-1): υ 2917, 1715, 1587, 1250, 1122, 927, 744,700。
实施例二十四:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1x(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管60 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4x,收率为77 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 5.12 – 4.94 (m, 1H),4.35 (q, J = 7.1 Hz, 2H), 3.75 – 3.57 (m, 2H), 3.36 (dd, J = 17.6, 11.0 Hz,1H), 2.91 (dd, J = 17.6, 7.7 Hz, 1H), 2.29 – 2.14 (m, 1H), 2.11 – 1.93 (m,1H), 1.37 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.5, 151.5, 80.5,62.1, 40.4, 38.6, 37.9, 14.1; HRMS (ESI-TOF): Anal. Calcd. For C8H12ClNO3:228.0398, Found: 228.0387 (M+Na+); IR (neat, cm-1): υ 2982, 1717, 1255, 1123,925, 767。
实施例二十五:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1y(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4y,收率为66 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 5.04 – 4.96 (m, 1H),4.35 (q, J = 7.1 Hz, 2H), 3.87 – 3.73 (m, 2H), 3.33 (dd, J = 17.6, 11.0 Hz,1H), 2.95 (dd, J = 17.6, 8.3 Hz, 1H), 2.52 (s, 1H), 2.04 – 1.96 (m, 1H), 1.94– 1.82 (m, 1H), 1.37 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.6,151.6, 81.6, 62.0, 58.8, 38.7, 37.5, 14.0; HRMS (ESI-TOF): Anal. Calcd. ForC8H13NO4: 210.0737, Found: 210.0739 (M+Na+); IR (neat, cm-1): υ 3419, 2940,1717, 1251, 1124, 928, 746。
实施例二十六:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1z(3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4z,收率为81 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 4.63 (dd, J = 11.3,9.4 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.28 – 3.07 (m, 2H), 2.33 (s, 1H),1.36 (t, J = 7.1 Hz, 3H), 1.32 (s, 3H), 1.18 (s, 3H); 13C NMR (101 MHz, CDCl3)δ 160.3, 152.0, 89.9, 70.9, 61.9, 34.1, 25.6, 24.4, 13.9; HRMS (ESI-TOF):Anal. Calcd. For C9H15NO4: 224.0893, Found: 224.0903 (M+Na+); IR (neat, cm-1):υ 3451, 2979, 1718, 1256, 1124, 930, 752。
实施例二十七:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1aa (3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4aa,收率为75 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 5.08 – 4.84 (m, 1H),4.37 – 4.32 (m, 2H), 3.91 – 3.60 (m, 2H), 3.28 (dd, J = 17.5, 11.0 Hz, 1H),2.96 (dd, J = 17.6, 8.3 Hz, 1H), 2.03 – 1.91 (m, 1H), 1.81 (td, J = 13.6, 5.8Hz, 1H), 1.37 (td, J = 7.1, 0.8 Hz, 3H), 0.89 (d, J = 0.7 Hz, 9H), 0.06 (d, J= 3.1 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 160.8, 151.6, 81.3, 61.9, 59.1,38.6, 37.8, 25.8, 18.2, 14.0, -5.5; HRMS (ESI-TOF): Anal. Calcd. ForC14H27NO4Si: 324.1602, Found: 324.1608 (M+Na+); IR (neat, cm-1): υ 2929, 1719,1250, 1096, 929, 832, 775。
实施例二十八:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1ab (3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4ab,收率为67 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.27 (dd, J = 9.7,6.3 Hz, 2H), 6.96 (t, J = 7.4 Hz, 1H), 6.89 (d, J = 8.0 Hz, 2H), 5.23 – 5.02(m, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.19 – 3.97 (m, 2H), 3.37 – 3.21 (m, 2H),1.36 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.3, 158.1, 151.4,129.4, 121.3, 114.5, 81.2, 67.9, 62.0, 35.7, 14.0; HRMS (ESI-TOF): Anal.Calcd. For C13H15NO4: 272.0893, Found: 272.0902 (M+Na+); IR (neat, cm-1): υ2927, 1720, 1256, 1231, 1120, 911, 746。
实施例二十九:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1ac (3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管100 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4ac,收率为71 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 5.00 – 4.92 (m, 1H),4.35 (q, J = 7.1 Hz, 2H), 3.29 (dd, J = 17.9, 11.0 Hz, 1H), 3.20 (qd, J =14.1, 5.9 Hz, 2H), 2.96 (dd, J = 17.9, 7.5 Hz, 1H), 2.63 (q, J = 7.5 Hz, 2H),1.37 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ198.9, 160.2, 151.3, 81.8, 62.0, 37.7, 37.3, 31.9, 14.0, 9.4; HRMS (ESI-TOF):Anal. Calcd. For C9H13NO4S: 246.0795, Found: 246.0785 (M+H+); IR (neat, cm-1):υ 2982, 1693, 1255, 1122, 921, 747。
实施例三十:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1ad (3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约6小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4ad,收率为75 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 5.22 (dd, J = 11.0,8.3 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 3.51 (dd, J = 9.7, 2.9Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.2, 159.5,150.9, 79.5, 62.1, 52.7, 37.4, 13.8; HRMS (ESI-TOF): Anal. Calcd. ForC8H11NO5: 202.0710, Found: 202.0718 (M+H+); IR (neat, cm-1): υ 2986, 1720,1252, 1216, 1122, 1016, 915, 748。
实施例三十一:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1ae (3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4ae,收率为73 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 4.57 (td, J = 10.7,3.0 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.30 (t, J = 10.0 Hz, 1H), 2.12 – 1.92(m, 2H), 1.80 – 1.58 (m, 6H), 1.52 – 1.44 (m, 1H), 1.40 – 1.23 (m, 6H); 13CNMR (101 MHz, CDCl3) δ 160.7, 156.1, 87.8, 61.6, 48.7, 29.5, 25.3, 25.2,24.9, 24.9, 24.4, 13.9; HRMS (ESI-TOF): Anal. Calcd. For C11H17NO3: 248.1257,Found: 248.1261 (M+Na+); IR (neat, cm-1): υ 2926, 2856, 1715, 1377, 1270,1105, 930。
实施例三十二:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1af (3 mmol),化合物2a (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物4af,收率为98 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 4.57 (td, J = 10.7,3.0 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.30 (t, J = 10.0 Hz, 1H), 2.12 – 1.92(m, 2H), 1.80 – 1.58 (m, 6H), 1.52 – 1.44 (m, 1H), 1.40 – 1.23 (m, 6H); 13CNMR (101 MHz, CDCl3) δ 160.7, 156.1, 87.8, 61.6, 48.7, 29.5, 25.3, 25.2,24.9, 24.9, 24.4, 13.9; HRMS (ESI-TOF): Anal. Calcd. For C11H17NO3: 248.1257,Found: 248.1261 (M+Na+); IR (neat, cm-1): υ 2926, 2856, 1715, 1377, 1270,1105, 930。
实施例三十三:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1a(3 mmol),化合物2b (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约24小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物5a,收率为87 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.44 – 7.36 (m, 2H),7.26 (d, J = 8.3 Hz, 2H), 5.74 (dd, J = 11.5, 9.0 Hz, 1H), 5.20 (hept, J =6.3 Hz, 1H), 3.59 (dd, J = 17.8, 11.5 Hz, 1H), 3.21 (dd, J = 17.8, 9.0 Hz,1H), 1.35 (dd, J = 6.3, 1.1 Hz, 6H), 1.31 (s, 9H); 13C NMR (101 MHz, CDCl3) δ160.0, 151.5, 151.3, 136.4, 125.6, 84.7, 69.8, 41.1, 34.4, 31.1, 21.6; HRMS(ESI-TOF): Anal. Calcd. For C17H23NO3: 290.1751, Found: 290.1740 (M+H+); IR(neat, cm-1): υ 2963, 1713, 1588, 1247, 1101, 923, 830.
实施例三十四:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1a(3 mmol),化合物2c (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物5b,收率为88 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.45 – 7.36 (m, 2H),7.27 (d, J = 8.3 Hz, 2H), 5.72 (dd, J = 11.5, 9.1 Hz, 1H), 3.56 (dd, J =17.7, 11.5 Hz, 1H), 3.18 (dd, J = 17.7, 9.1 Hz, 1H), 1.56 (s, 9H), 1.31 (s,9H); 13C NMR (101 MHz, CDCl3) δ 159.7, 152.2, 151.6, 136.6, 125.7, 125.6,84.6, 83.3, 41.4, 34.5, 31.2, 27.9; HRMS (ESI-TOF): Anal. Calcd. For C18H25NO3:326.1727, Found: 326.1731 (M+Na+); IR (neat, cm-1): υ 2968, 1731, 1596, 1251,1133, 914, 823。
实施例三十五:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1a(3 mmol),化合物2d (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物5c,收率为69 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.44 – 7.30 (m, 7H),7.27 – 7.20 (m, 2H), 5.72 (dd, J = 11.5, 9.1 Hz, 1H), 5.30 (s, 2H), 3.57 (dd,J = 17.8, 11.6 Hz, 1H), 3.20 (dd, J = 17.8, 9.1 Hz, 1H), 1.30 (s, 9H); 13C NMR(101 MHz, CDCl3) δ 160.3, 151.7, 150.9, 136.2, 134.8, 128.5, 128.5, 128.4,125.6, 84.9, 67.4, 41.0, 34.5, 31.1; HRMS (ESI-TOF): Anal. Calcd. ForC21H23NO3: 338.1751, Found: 338.1752 (M+H+); IR (neat, cm-1): υ 2962, 1708,1271, 1104, 919, 745, 692。
实施例三十六:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1a(3 mmol),化合物2e (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物5d,收率为71 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 8.38 – 8.29 (m, 2H),7.67 (t, J = 7.4 Hz, 1H), 7.59 – 7.46 (m, 4H), 7.39 (d, J = 8.3 Hz, 2H), 5.83(dd, J = 11.4, 8.9 Hz, 1H), 3.83 (dd, J = 17.7, 11.5 Hz, 1H), 3.48 (dd, J =17.7, 8.9 Hz, 1H), 1.41 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 186.2, 157.4,151.6, 136.5, 135.7, 133.5, 130.3, 128.3, 125.7, 84.1, 41.4, 34.5, 31.2; HRMS(ESI-TOF): Anal. Calcd. For C20H21NO2: 308.1645, Found: 308.1649 (M+H+); IR(neat, cm-1): υ 2962, 1650, 1361, 1250, 901, 702。
实施例三十七:
反应瓶中依次装入Cu(OAc)2.H2O (10 mol %),DABCO (3 mmol),甲苯15 mL,化合物1a(3 mmol),化合物2f (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物5e,收率为71 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.49 – 7.35 (m, 2H),7.30 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H),5.71 (dd, J = 11.5, 9.1 Hz, 1H), 5.27 (s, 2H), 3.56 (dd, J = 17.7, 11.6 Hz,1H), 3.19 (dd, J = 17.8, 9.1 Hz, 1H), 2.33 (s, 3H), 1.30 (s, 9H); 13C NMR (101MHz, CDCl3) δ 160.4, 151.6, 150.9, 138.4, 136.2, 131.8, 129.2, 128.6, 125.6,84.9, 67.4, 41.0, 34.5, 31.1, 21.1; HRMS (ESI-TOF): Anal. Calcd. For C22H25NO3:374.1727, Found: 374.1713 (M+Na+); IR (neat, cm-1): υ 2965, 1709, 1396, 1272,1102, 913, 806。
实施例三十八:
反应瓶中依次装入Cu(OAc)2.H2O (20 mol %),DABCO (3 mmol),甲苯15 mL,化合物1a(3 mmol),化合物2g(6 mmol),亚硝酸叔丁酯3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物5f,收率为73 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.42 – 7.37 (m, 2H),7.37 – 7.29 (m, 4H), 7.27 – 7.21 (m, 2H), 5.74 (dd, J = 11.5, 9.1 Hz, 1H),5.26 (s, 2H), 3.58 (dd, J = 17.7, 11.6 Hz, 1H), 3.21 (dd, J = 17.8, 9.1 Hz,1H), 1.30 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 160.2, 151.7, 150.7, 136.1,134.4, 133.3, 129.8, 128.7, 125.7, 125.6, 85.0, 66.5, 40.9, 34.5, 31.1; HRMS(ESI-TOF): Anal. Calcd. For C21H22ClNO3: 394.1180, Found: 394.1169 (M+Na+); IR(neat, cm-1): υ 2961, 1732, 1587, 1244, 1108, 922, 799。
实施例三十九:
反应瓶中依次装入Cu(OAc)2.H2O (5mol %),DABCO (3 mmol),甲苯15 mL,化合物1a(3 mmol),化合物2h (6 mmol),亚硝酸叔丁酯 3 (6 mmol),然后该体系在封管80 ℃条件下加热约12小时后,用乙酸乙酯萃取(20 mL × 3)、饱和食盐水洗涤三次,无水硫酸钠干燥有机层,通过简单的柱层析即可得产物5g,收率为65 %。
对产物进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.47 – 7.37 (m, 3H),7.24 (d, J = 8.3 Hz, 2H), 6.53 – 6.27 (m, 2H), 5.75 (dd, J = 11.5, 9.1 Hz,1H), 5.27 (s, 2H), 3.59 (dd, J = 17.8, 11.6 Hz, 1H), 3.22 (dd, J = 17.8, 9.1Hz, 1H), 1.31 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 160.2, 151.8, 150.8, 148.3,143.5, 136.2, 125.7, 125.7, 111.6, 110.6, 85.1, 59.1, 41.0, 34.6, 31.2; HRMS(ESI-TOF): Anal. Calcd. For C19H21NO4: 328.1543, Found: 328.1538 (M+H+); IR(neat, cm-1): υ 2961, 1720, 1587, 1241, 1107, 919, 743。
Claims (10)
1.一种异噁唑啉衍生物的制备方法,其特征在于,包括以下步骤:以烯烃衍生物、重氮衍生物、亚硝酸叔丁酯为反应底物,以铜化物为催化剂,在碱存在下,反应制备得到异噁唑啉衍生物;
所述烯烃衍生物的化学结构式为:、、或;式中,R选自:苯基、4-叔丁基苯基、4-甲基苯基、4-甲氧基苯基、4-氯苯基、4-溴苯基、4-氟苯基、4-氰基苯基、4-甲酸甲酯基苯基、Bn基保护的4-羟基苯基、Ts基保护的4-羟基苯基、3-溴苯基、3-氟苯基、3-三氟甲基苯基、2-氯苯基、2-甲基苯基、2-甲氧基苯基、5氟取代苯基、1-萘基、4-吡啶基、正己基、正丁基、环己基、苄基、2-氯乙基、3-羟基丙基、1-羟基-1-二甲基、2-TBS保护的羟基乙基、1-苯氧基甲基、1-乙酸巯酯基甲基、甲酸甲酯基;
所述重氮选自:重氮乙酸乙酯、重氮乙酸异丙酯酯、重氮乙酸叔丁酯、苯甲酰重氮、重氮乙酸苄酯、重氮乙酸(2-呋喃)甲酯、重氮乙酸(4-甲基苯基)甲酯、重氮乙酸(4-氯苯基)甲酯;
所述铜化物选自:醋酸铜、碘化亚铜、氯化铜、乙酰丙酮铜、一水醋酸铜、三氟甲磺酸铜、硝酸铜、无水硫酸铜、五水硫酸铜、溴化亚铜、氟化铜、六氟磷酸四乙腈铜、氧化铜、氧化亚铜中的一种。
2.根据权利要求1所述异噁唑啉衍生物的制备方法,其特征在于:反应温度为60~100℃;反应时间为6~24小时。
3.根据权利要求1所述异噁唑啉衍生物的制备方法,其特征在于:催化剂的用量为烯烃衍生物的物质的量的5~20 %。
4.根据权利要求1所述异噁唑啉衍生物的制备方法,其特征在于:重氮化合物的用量为烯烃衍生物的物质的量的1.5~3倍;亚硝酸叔丁酯的用量为烯烃衍生物的物质的量的1.5~3倍。
5.根据权利要求1所述异噁唑啉衍生物的制备方法,其特征在于:所述反应在溶剂中进行;所述溶剂为苯、N,N-二甲基甲酰胺、甲苯、乙腈、1,2-二氯乙烷、四氢呋喃或者水。
6.根据权利要求1所述异噁唑啉衍生物的制备方法,其特征在于:所述碱为1,4-二氮杂二环[2.2.2]辛烷、碳酸钾、碳酸钠、碳酸氢钠、碳酸铯、叔丁醇锂、1,8-二氮杂二环十一碳-7-烯或者四甲基乙二胺;所述碱的用量为苯乙烯衍生物的物质的量的1~3倍。
7.烯烃衍生物、重氮衍生物、亚硝酸叔丁酯作为反应底物在制备异噁唑啉衍生物中的应用。
8.根据权利要求1所述异噁唑啉衍生物的制备方法制备的异噁唑啉衍生物。
9.铜化物作为催化剂在制备异噁唑啉衍生物中的应用或者铜化物在催化烯烃衍生物、重氮衍生物、亚硝酸叔丁酯反应体系中的应用。
10.根据权利要求9所述应用,其特征在于:所述铜化物的用量为烯烃衍生物的物质的量的5~20 %;所述铜化物选自:醋酸铜、碘化亚铜、氯化铜、乙酰丙酮铜、一水醋酸铜、三氟甲磺酸铜、硝酸铜、无水硫酸铜、五水硫酸铜、溴化亚铜、氟化铜、六氟磷酸四乙腈铜、氧化铜、氧化亚铜中的一种。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710214896.7A CN107118171B (zh) | 2017-04-01 | 2017-04-01 | 一种异噁唑啉衍生物的制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710214896.7A CN107118171B (zh) | 2017-04-01 | 2017-04-01 | 一种异噁唑啉衍生物的制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107118171A true CN107118171A (zh) | 2017-09-01 |
CN107118171B CN107118171B (zh) | 2019-05-17 |
Family
ID=59724735
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710214896.7A Active CN107118171B (zh) | 2017-04-01 | 2017-04-01 | 一种异噁唑啉衍生物的制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN107118171B (zh) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108069918A (zh) * | 2018-01-18 | 2018-05-25 | 江西师范大学 | 一锅法制备3-二氟甲基异噁唑化合物的方法 |
WO2018191871A1 (zh) * | 2017-04-18 | 2018-10-25 | 苏州大学张家港工业技术研究院 | 一种异恶唑啉衍生物的制备方法 |
CN110483430A (zh) * | 2019-08-14 | 2019-11-22 | 上海应用技术大学 | 一种异噁唑衍生物的制备方法 |
CN112028848A (zh) * | 2020-09-09 | 2020-12-04 | 苏州大学 | 一种制备异噁唑啉的方法 |
CN113149924A (zh) * | 2021-03-29 | 2021-07-23 | 苏州大学 | 一种异噁唑啉的简单制备方法 |
-
2017
- 2017-04-01 CN CN201710214896.7A patent/CN107118171B/zh active Active
Non-Patent Citations (3)
Title |
---|
FEI CHEN ET AL.: "tert-Butyl nitrite-mediated vicinal sulfoximation of alkenes with sulfinic acids: a highly efficient approach toward α-sulfonyl ketoximes", 《ORG. CHEM. FRONT.》 * |
WEIGANG ZHANG ET AL.: "Trichloroisocyanuric Acid Promoted Cascade Cyclization/ Trifluoromethylation of Allylic Oximes: Synthesis of Trifluoromethylated Isoxazolines", 《ORG. LETT.》 * |
XIAO-WEI ZHANG ET AL.: "Transition-metal-free oxychlorination of alkenyl oximes: in situ generated radicals with tert-butyl nitrite", <ORG. BIOMOL. CHEM.》 * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018191871A1 (zh) * | 2017-04-18 | 2018-10-25 | 苏州大学张家港工业技术研究院 | 一种异恶唑啉衍生物的制备方法 |
CN108069918A (zh) * | 2018-01-18 | 2018-05-25 | 江西师范大学 | 一锅法制备3-二氟甲基异噁唑化合物的方法 |
CN108069918B (zh) * | 2018-01-18 | 2021-05-28 | 江西师范大学 | 一锅法制备3-二氟甲基异噁唑化合物的方法 |
CN110483430A (zh) * | 2019-08-14 | 2019-11-22 | 上海应用技术大学 | 一种异噁唑衍生物的制备方法 |
CN110483430B (zh) * | 2019-08-14 | 2023-02-10 | 上海应用技术大学 | 一种异噁唑衍生物的制备方法 |
CN112028848A (zh) * | 2020-09-09 | 2020-12-04 | 苏州大学 | 一种制备异噁唑啉的方法 |
CN113149924A (zh) * | 2021-03-29 | 2021-07-23 | 苏州大学 | 一种异噁唑啉的简单制备方法 |
WO2022206010A1 (zh) * | 2021-03-29 | 2022-10-06 | 苏州大学 | 一种异噁唑啉的简单制备方法 |
CN113149924B (zh) * | 2021-03-29 | 2023-11-03 | 苏州大学 | 一种异噁唑啉的简单制备方法 |
Also Published As
Publication number | Publication date |
---|---|
CN107118171B (zh) | 2019-05-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107118171A (zh) | 一种异噁唑啉衍生物的制备方法 | |
CN105801575A (zh) | 一种咪唑并[1,2-a]吡啶的合成方法 | |
CN103641722A (zh) | 一种邻硝基溴苄的生产方法 | |
CN111303020A (zh) | 一种5-氯-2-(吡啶-3-基)吡啶-3-胺的合成方法 | |
CN110483449B (zh) | 一种γ-内酯衍生物的制备方法 | |
CN107746392B (zh) | 一种含桥环结构的恶唑烷类化合物的制备方法 | |
CN102746077A (zh) | 一种制备酰胺化合物的方法 | |
CN103467225B (zh) | 一种制备1,4-二羰基衍生物的方法 | |
CN110317170B (zh) | 一种3-菲啶基甲酸丙酯类化合物的绿色合成方法 | |
CN115093372A (zh) | 一种咪唑衍生物的合成方法 | |
CN107513056A (zh) | 一种含四氢呋喃基团的喹啉类化合物的合成方法 | |
CN109535061B (zh) | 一种3-亚硝基吲哚衍生物及其制备方法 | |
CN109956948B (zh) | 天然产物(-)-newbouldine的合成方法 | |
CN107382892A (zh) | 一种3‑芳基‑4‑硝基异噁唑化合物的制备工艺 | |
CN109369678B (zh) | 一种天然产物异构体(-)-6-epi-Porantheridine的合成方法 | |
CN106928142A (zh) | 含芳硫基取代的1,3‑异喹啉二酮衍生物及其制备方法 | |
CN102731386B (zh) | 一种仲二酰亚胺衍生物的制备方法 | |
CN107043387B (zh) | 3a,6a-二氢吡咯并[3,4-d]异噁唑-4,6-二酮类化合物及其合成方法 | |
CN111747903B (zh) | 以铜化物为催化剂制备异噁唑化合物的方法 | |
CN104910090B (zh) | 二氢异噁唑类化合物及其合成方法 | |
CN111635372B (zh) | 一种恶唑酮衍生物及其合成方法 | |
CN110156716B (zh) | 一种苯并噻唑酯类衍生物的合成方法 | |
CN115745822B (zh) | 一种可见光催化的n-甲酰基酰胺化合物的制备方法 | |
WO2018191871A1 (zh) | 一种异恶唑啉衍生物的制备方法 | |
CN108947928B (zh) | 含氮、氧、氧三取代六元环内脂化合物及制备方法和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |