CN107445912A - 一种制备异噁唑化合物的方法 - Google Patents
一种制备异噁唑化合物的方法 Download PDFInfo
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- CN107445912A CN107445912A CN201710668260.XA CN201710668260A CN107445912A CN 107445912 A CN107445912 A CN 107445912A CN 201710668260 A CN201710668260 A CN 201710668260A CN 107445912 A CN107445912 A CN 107445912A
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- -1 isoxazole compound Chemical class 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 63
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims abstract description 51
- 239000002253 acid Substances 0.000 claims abstract description 16
- 239000005749 Copper compound Substances 0.000 claims abstract description 14
- 150000001880 copper compounds Chemical class 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 239000002841 Lewis acid Substances 0.000 claims abstract description 8
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 239000000758 substrate Substances 0.000 claims abstract description 7
- 238000010490 three component reaction Methods 0.000 claims abstract description 6
- 239000000654 additive Substances 0.000 claims abstract description 3
- 230000000996 additive effect Effects 0.000 claims abstract description 3
- 239000010949 copper Substances 0.000 claims description 56
- 239000011777 magnesium Substances 0.000 claims description 42
- 150000004718 beta keto acids Chemical class 0.000 claims description 18
- 229910052802 copper Inorganic materials 0.000 claims description 16
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 10
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 10
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 7
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 claims description 6
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 6
- 238000006555 catalytic reaction Methods 0.000 claims description 5
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- UMRSVAKGZBVPKD-UHFFFAOYSA-N acetic acid;copper Chemical compound [Cu].CC(O)=O UMRSVAKGZBVPKD-UHFFFAOYSA-N 0.000 claims 3
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims 2
- 239000002585 base Substances 0.000 claims 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 1
- 101000713585 Homo sapiens Tubulin beta-4A chain Proteins 0.000 claims 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
- 102100036788 Tubulin beta-4A chain Human genes 0.000 claims 1
- 239000012954 diazonium Substances 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- 239000000052 vinegar Substances 0.000 claims 1
- 235000021419 vinegar Nutrition 0.000 claims 1
- 239000012973 diazabicyclooctane Substances 0.000 abstract description 43
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 2
- 230000009257 reactivity Effects 0.000 abstract description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 abstract 1
- 150000007513 acids Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 114
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 112
- 238000004458 analytical method Methods 0.000 description 82
- 238000004440 column chromatography Methods 0.000 description 42
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 41
- 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 34
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- 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 23
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- JJKQRSNEGCOSOC-VOTSOKGWSA-N 1-[(e)-3-(4-hydroxy-3,5-dimethoxyphenyl)prop-2-enoyl]-2,3-dihydropyridin-6-one Chemical compound COC1=C(O)C(OC)=CC(\C=C\C(=O)N2C(C=CCC2)=O)=C1 JJKQRSNEGCOSOC-VOTSOKGWSA-N 0.000 description 4
- 238000004293 19F NMR spectroscopy Methods 0.000 description 4
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 4
- 150000001345 alkine derivatives Chemical class 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- WUPPOLDDVHCHKK-UHFFFAOYSA-N 1,5-Dihydroxy-2,3-dimethoxy-10-methyl-9-acridone Chemical compound CN1C2=C(O)C=CC=C2C(=O)C2=C1C=C(OC)C(OC)=C2O WUPPOLDDVHCHKK-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- 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
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 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
- 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
- ZLMKEENUYIUKKC-UHFFFAOYSA-N 1-iodo-3,5-dimethylbenzene Chemical compound CC1=CC(C)=CC(I)=C1 ZLMKEENUYIUKKC-UHFFFAOYSA-N 0.000 description 1
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- FJVUVFPCFMLITB-UHFFFAOYSA-N 3-[3-acetyl-2-(2-fluorophenyl)-4-hydroxy-5-oxo-2h-pyrrol-1-yl]propanoic acid Chemical compound CC(=O)C1=C(O)C(=O)N(CCC(O)=O)C1C1=CC=CC=C1F FJVUVFPCFMLITB-UHFFFAOYSA-N 0.000 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-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
- 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
- MPHAMPBWVIOFMQ-UHFFFAOYSA-L CS(=O)(=O)[O-].[Cu+2].[F].CS(=O)(=O)[O-] Chemical compound CS(=O)(=O)[O-].[Cu+2].[F].CS(=O)(=O)[O-] MPHAMPBWVIOFMQ-UHFFFAOYSA-L 0.000 description 1
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- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- IEDBNTAKVGBZEP-VMPITWQZSA-N N-trans-sinapoyltyramine Chemical compound COC1=C(O)C(OC)=CC(\C=C\C(=O)NCCC=2C=CC(O)=CC=2)=C1 IEDBNTAKVGBZEP-VMPITWQZSA-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
- 238000010521 absorption reaction Methods 0.000 description 1
- XTCGYRFLVLFRGW-UHFFFAOYSA-N acronycidine Chemical compound COC1=C2C=COC2=NC2=C(OC)C(OC)=CC(OC)=C21 XTCGYRFLVLFRGW-UHFFFAOYSA-N 0.000 description 1
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- RXUUYDXKHLUSHV-UHFFFAOYSA-N magnesium;trifluoromethanesulfonic acid Chemical compound [Mg].OS(=O)(=O)C(F)(F)F RXUUYDXKHLUSHV-UHFFFAOYSA-N 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
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 1
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- 229910000510 noble metal Inorganic materials 0.000 description 1
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- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
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- 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
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Abstract
本发明公开了一种制备异噁唑化合物的方法,以β‑酮酸脂、α‑重氮酸脂与亚硝酸叔丁酯为反应底物,以铜化物为催化剂,路易斯酸为添加剂,三乙烯二胺(DABCO)为碱,通过三组分反应制备得到全取代的噁唑产物;本发明所使用的方法具有以下特点:催化剂的反应活性较高,反应条件温和,底物适用范围广,后处理方便,目标产物的收率较高,制备过程简单,所用原料来源广泛。
Description
技术领域
本发明涉及一种制备异噁唑化合物的方法。
背景技术
异噁唑是一类非常重要的五元杂环有机化合物,在生物、药物、农药、化工等方面都有相当广泛的应用。多种异噁唑化合物类衍生物表现出广泛的医药前景。例如:多种帕瑞考昔:COX-2抑制剂、磺胺甲基异恶唑:PABA拮抗剂、苯唑西林:β-内酰胺抗生素、异羟肟酸:4-羟基苯基丙酮酸双加氧酶抑制剂、来氟米特:抗风湿等多种含有异噁唑化合物骨架的化合物已经表现出了非常好的医药应用前景。因此,异噁唑化合物类化合物的合成一直是化学工作者的研究的热点。目前,制备异噁唑化合物的方法有着反应条件苛刻、原料制备繁琐、使用过度氧化剂等缺点。例如:
(1)Yoshimura等人报道了3,5-二甲基碘苯催化肟与炔烃的反应制备异噁唑化合物类化合物,但反应需要加入大量的氧化剂结合碘苯来氧化肟生成硝酮中间体,然后和炔烃发生[3+2]环加成反应构建异噁唑化合物骨架,且反应对溶剂的要求很高,三种混合溶剂的使用大大限制了其在工业生产中的应用(参见: Org. Lett.2013, 15,4010-4013; Org. Lett.2011, 13,2966-2969);
(2)Miyata等人报道了金催化的烯丙基肟脂的环化反应制备异噁唑化合物,但反应原料需要多步合成,且反应需要在贵金属金的催化下进行,从而使得制备过程的成本大大提高、不易于大规模工业化生产(参见: Org. Lett. 2010, 12, 2594-2597);
(3)最近Pal等人报道了α-硝基酮类化合物在不加催化剂条件下,以水和聚乙二醇400为溶剂和炔烃反应制备异噁唑化合物产物,该反应条件相当温和,但是原料硝基化合物的底物范围大大限制该反应的应用(参见:Adv. Synth. Catal.2014, 356, 160-164)。
因此,需要寻找一种原料来源简单,反应活性较高、成本低、安全、环保、操作简便的制备方法来有效合成异噁唑化合物化合物。
发明内容
本发明的目的是提供一种制备异噁唑化合物的方法,使反应更温和、更高效、更经济、更易操作。
为达到上述发明目的,本发明采用的技术方案是:
一种制备异噁唑化合物的方法,以β-酮酸脂、α-重氮酸脂与亚硝酸叔丁酯( t BuONO)为反应底物,以铜化物为催化剂,路易斯酸为添加剂,三乙烯二胺(DABCO)为碱,通过三组分反应制备得到异噁唑化合物;
其中,所述β-酮酸脂的化学结构式为以下化学结构式中的一种:
、、、
式中,R1选自氢、4-甲基、4-甲氧基、4-三氟甲基、4-氟、4-氯、4-溴、4-碘、3-甲基、3-甲氧基、3-氟、3-氯、3-溴、3-三氟甲基、2-甲基、2-甲氧基中的一种;
所述α-重氮酸脂的化学结构式为以下化学结构式中的一种:
、、
式中,R3选自乙基、异丙基、叔丁基、苄基、环己基、烯丙基中的一种;
所述铜化物选自:碘化亚铜(CuI)、醋酸铜(Cu(OAc)2)、一水醋酸铜(Cu(OAc)2.H2O)、三氟甲磺酸铜(Cu(OTf)2)、溴化亚铜(CuBr)、溴化铜(CuBr2)、中的一种。
上述技术方案中,所述三组分反应的反应温度为60~100℃,反应时间为6~24小时;优选反应温度为80℃,反应时间为12小时。
上述技术方案中,所述铜化物选自碘化亚铜、醋酸铜、一水醋酸铜、三氟甲磺酸铜、溴化亚铜、溴化铜中的一种;所述催化剂用量为β-酮酸脂的5~20mmol %,优选7.5 mol%。
上述技术方案中,所述路易斯酸为三氟甲磺酸镁;所述路易斯酸用量为β-酮酸脂的5~20mmol %,优选10 mol%。
上述技术方案中,所述碱的用量为β-酮酸脂的1~3当量;所述碱为三乙烯二胺。
上述技术方案中,所述β-酮酸脂、α-重氮酸脂与亚硝酸叔丁酯的摩尔比为1∶1.5∶1.5。
本发明还公开了根据上述制备异噁唑化合物的方法得到异噁唑化合物。
本发明还公开了铜化合物在制备异噁唑化合物中的应用;所述铜化物选自碘化亚铜、醋酸铜、一水醋酸铜、三氟甲磺酸铜、溴化亚铜、溴化铜中的一种。
本发明还公开了β-酮酸脂、α-重氮酸脂与亚硝酸叔丁酯作为三组分反应的反应底物在制备异噁唑化合物中的应用。
本发明还公开了铜化合物在催化β-酮酸脂、α-重氮酸脂与亚硝酸叔丁酯中的应用;所述铜化物选自碘化亚铜、醋酸铜、一水醋酸铜、三氟甲磺酸铜、溴化亚铜、溴化铜中的一种。
进一步的技术方案中,反应完成后用乙酸乙酯萃取,然后用旋转蒸发仪除去溶剂、硅胶吸附,最后用乙酸乙酯和石油醚的混合溶剂进行简单的柱层析。
上述技术方案中,所述部分β-酮酸脂、亚硝酸叔丁酯、催化剂、路易斯酸、碱皆为市场化商品,可直接购买,或者β-酮酸脂可以通过市场化的苯乙酮和市场化的溴乙酸乙酯经过亲核反应合成得到,α-重氮酸脂可以通过市场化的醇和市场化的溴乙酰溴反应,再和双Ts肼反应合成得到。
由于上述技术方案的运用,本发明与现有技术相比具有下列优点:
1.本发明首次使用铜作为催化剂催化β-酮酸脂、α-重氮酸脂和亚硝酸叔丁酯反应制备全取代的异噁唑化合物,与现有技术中的昂贵过渡金属等催化剂相比,使反应更安全、更绿色、更经济,反应时间较短,收率高,底物的适用范围广泛。
2.本发明公开的方法避免了使用氧化剂,而且反应条件温和,后处理更加简单,有利于产物的纯化和大规模工业化生产。
3.本发明使用的反应物、催化剂等原料廉价易得,符合当代绿色化学发展的要求和方向,适于工业化生产。
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CuI(0.15 mmol, 28 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2a(3 mmol, 342 mg), t BuONO(3mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3a,收率为63%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 8.02 – 7.87 (m, 2H), 7.58 – 7.45 (m, 3H),4.48 (q, J = 7.1 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H),1.32 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.4, 160.8, 159.7,156.2, 131.7, 128.6, 128.4, 125.6, 108.4, 62.6, 61.7, 13.9, 13.7; HRMS (ESI-TOF): Anal. Calcd. For C15H15NO5: 312.0842, Found: 312.0836 (M+Na+); IR (neat,cm-1): υ 2984, 1730, 1473, 1218, 1069, 726, 690。
实施例二
反应瓶中依次装入Cu(OAc)2(0.15 mmol, 27 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2a(3 mmol, 342 mg), t BuONO(3mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3a,收率为71%。所制得产物的主要测试数据如实施例一,通过分析可知,实际合成产物与理论分析一致。
实施例三
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3a,收率为80%。所制得产物的主要测试数据如实施例一,通过分析可知,实际合成产物与理论分析一致。
实施例四
反应瓶中依次装入Cu(OTf)2(0.15 mmol, 54 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2a(3 mmol, 342 mg), t BuONO(3mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3a,收率为67%。所制得产物的主要测试数据如实施例一,通过分析可知,实际合成产物与理论分析一致。
实施例五
反应瓶中依次装入CuBr(0.15 mmol, 21 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2a(3 mmol, 342 mg), t BuONO(3mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3a,收率为68%。所制得产物的主要测试数据如实施例一,通过分析可知,实际合成产物与理论分析一致。
实施例六
反应瓶中依次装入CuBr2(0.15 mmol, 33 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2a(3 mmol, 342 mg), t BuONO(3mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3a,收率为62%。所制得产物的主要测试数据如实施例一,通过分析可知,实际合成产物与理论分析一致。
实施例七
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中60℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3a,收率为66%。所制得产物的主要测试数据如实施例一,通过分析可知,实际合成产物与理论分析一致。
实施例八
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中100℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3a,收率为80%。所制得产物的主要测试数据如实施例一,通过分析可知,实际合成产物与理论分析一致。
实施例九
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约6小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3a,收率为64%。所制得产物的主要测试数据如实施例一,通过分析可知,实际合成产物与理论分析一致。
实施例十
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约24小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3a,收率为82%。所制得产物的主要测试数据如实施例一,通过分析可知,实际合成产物与理论分析一致。
实施例十一
反应瓶中依次装入Cu(OAc)2.H2O(0.1 mmol, 19 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3a,收率为62%。所制得产物的主要测试数据如实施例一,通过分析可知,实际合成产物与理论分析一致。
实施例十二
反应瓶中依次装入Cu(OAc)2.H2O(0.4 mmol, 76 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3a,收率为81%。所制得产物的主要测试数据如实施例一,通过分析可知,实际合成产物与理论分析一致。
实施例十三
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.1 mmol,32 mg),DABCO(5 mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3a,收率为60%。所制得产物的主要测试数据如实施例一,通过分析可知,实际合成产物与理论分析一致。
实施例十四
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.4 mmol,128 mg),DABCO(5 mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3a,收率为77%。所制得产物的主要测试数据如实施例一,通过分析可知,实际合成产物与理论分析一致。
实施例十五
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64 mg),DABCO(3 mmol, 336 mg),化合物1a(2 mmol, 384 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3a,收率为73%。所制得产物的主要测试数据如实施例一,通过分析可知,实际合成产物与理论分析一致。
实施例十六
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2mmol,64 mg),DABCO(6 mmol, 672 mg),化合物1a(2 mmol, 384 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3a,收率为78%。所制得产物的主要测试数据如实施例一,通过分析可知,实际合成产物与理论分析一致。
实施例十七
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1b(2 mmol, 412 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3b,收率为75%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 7.9Hz, 2H), 4.47 (q, J = 7.1 Hz, 2H), 4.34 (q, J = 7.1 Hz, 2H), 2.43 (s, 3H),1.43 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ171.8, 161.0, 159.9, 156.3, 142.4, 129.4, 128.4, 122.9, 107.8, 62.6, 61.7,21.5, 14.0, 13.8; HRMS (ESI-TOF): Anal. Calcd. For C16H17NO5: 326.0999, Found:326.0991 (M+Na+); IR (neat, cm-1): υ 2992, 1728, 1458, 1224, 1073, 827。
实施例十八
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1c(2 mmol, 444 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3c,收率为72%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.9 Hz, 2H), 7.00 (d, J = 8.9Hz, 2H), 4.47 (q, J = 7.1 Hz, 2H), 4.34 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H),1.43 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ171.6, 162.3, 161.0, 1600, 156.4, 130.3, 118.1, 114.0, 106.9, 62.6, 61.6,55.3, 13.9, 13.8; HRMS (ESI-TOF): Anal. Calcd. For C16H17NO6: 342.0948, Found:342.0940 (M+Na+); IR (neat, cm-1): υ 2983, 1727, 1470, 1220, 1178, 1070, 836。
实施例十九
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1d(2 mmol, 520 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3d,收率为67%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.3Hz, 2H), 4.50 (q, J = 7.1 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.9, 160.5,159.5, 156.4, 133.3 (q, J = 32.9 Hz), 128.94, 128.90, 125.7 (q, J = 3.7 Hz),123.4 (q, J = 273.7 Hz), 109.6, 62.8, 62.1, 13.9, 13.8; 19F NMR (376 MHz,CDCl3) δ -63.23; HRMS (ESI-TOF): Anal. Calcd. For C16H14F3NO5: 380.0716, Found:380.0709 (M+Na+); IR (neat, cm-1): υ 2987, 1731, 1321, 1224, 1125, 1063, 847。
实施例二十
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1e(2 mmol, 420 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3e,收率为69%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.3Hz, 2H), 4.50 (q, J = 7.1 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.9, 160.5,159.5, 156.4, 133.3 (q, J = 32.9 Hz), 128.94, 128.90, 125.7 (q, J = 3.7 Hz),123.4 (q, J = 273.7 Hz), 109.6, 62.8, 62.1, 13.9, 13.8; 19F NMR (376 MHz,CDCl3) δ -63.23; HRMS (ESI-TOF): Anal. Calcd. For C16H14F3NO5: 380.0716, Found:380.0709 (M+Na+); IR (neat, cm-1): υ 2987, 1731, 1321, 1224, 1125, 1063, 847。
实施例二十一
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1f(2 mmol, 452 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3f,收率为78%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.5Hz, 2H), 4.48 (q, J = 7.1 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.5, 160.6,159.6, 156.4, 138.1, 129.8, 129.0, 124.0, 108.5, 62.7, 61.9, 13.9, 13.8; HRMS(ESI-TOF): Anal. Calcd. For C15H14 35ClNO5: 346.0453, Found: 346.0445 (M+Na+);Anal. Calcd. For C15H14 37ClNO5: 348.0423, Found: 348.0435 (M+Na+); IR (neat, cm-1): υ 2992, 1728, 1458, 1222, 1071, 1009, 839。
实施例二十二
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1g(2 mmol, 538 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3g,收率为74%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.5Hz, 2H), 4.48 (q, J = 7.1 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.5, 160.6,159.6, 156.4, 132.0, 129.9, 126.6, 124.4, 108.6, 62.7, 61.90, 13.9, 13.8;HRMS (ESI-TOF): Anal. Calcd. For C15H14 79BrNO5: 389.9948, Found: 389.9948 (M+Na+); Anal. Calcd. For C15H14 81BrNO5: 391.9927, Found: 391.9943 (M+Na+); IR (neat,cm-1): υ 2981, 1726, 1464, 1219, 1066, 843, 725。
实施例二十三
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1h(2 mmol, 634 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3h,收率为81%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.5Hz, 2H), 4.48 (q, J = 7.1 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.6, 160.6,159.6, 156.4, 137.9, 129.8, 125.0, 108.6, 99.0, 62.7, 61.9, 13.95, 13.8; HRMS(ESI-TOF): Anal. Calcd. For C15H14INO5: 415.9989, Found: 415.9978 (M+H+); IR(neat, cm-1): υ 2983, 1728, 1470, 1220, 1073, 1006, 828。
实施例二十四
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1i(2 mmol, 412 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3i,收率为75%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 7.80 – 7.68 (m, 2H), 7.42 – 7.30 (m, 2H),4.48 (q, J = 7.1 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 1.43 (t, J= 7.2 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.5,160.8, 159.7, 156.1, 138.4, 132.4, 128.8, 128.5, 125.5, 108.2, 62.5, 61.7,21.2, 13.9, 13.7; HRMS (ESI-TOF): Anal. Calcd. For C16H17NO5: 326.0999, Found:326.0984 (M+Na+); IR (neat, cm-1): υ 2984, 1731, 1471, 1220, 1090, 1072, 847,781。
实施例二十五
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1j(2 mmol, 444 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3j,收率为83%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 7.60 – 7.48 (m, 2H), 7.47 – 7.35 (m, 1H),7.16 – 6.97 (m, 1H), 4.48 (q, J = 7.1 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 3.86(s, 3H), 1.43 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,CDCl3) δ 171.1, 160.8, 159.6, 159.5, 156.2, 129.7, 126.6, 120.6, 117.8,113.4, 108.6, 62.6, 61.8, 55.3, 13.9, 13.8; HRMS (ESI-TOF): Anal. Calcd. ForC16H17NO6: 342.0948, Found: 342.0942 (M+Na+); IR (neat, cm-1): υ 2984, 1730,1466, 1207, 1112, 1070, 848, 778。
实施例二十六
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1k(2 mmol, 420 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3k,收率为75%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 7.83 – 7.69 (m, 2H), 7.54 – 7.43 (m, 1H),7.30 – 7.21 (m, 1H), 4.48 (q, J = 7.1 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.44(t, J = 7.2 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ170.0 (d, J = 2.9 Hz), 162.4 (d, J = 247.5 Hz), 160.6, 159.6, 156.4, 130.5(d, J = 8.2 Hz), 127.4 (d, J = 8.7 Hz), 124.2 (d, J = 3.2 Hz), 118.8 (d, J =21.1 Hz), 115.6 (d, J = 24.5 Hz), 109.0, 62.8, 62.0, 14.0, 13.8; 19F NMR (376MHz, CDCl3) δ -111.21; HRMS (ESI-TOF): Anal. Calcd. For C15H14FNO5: 330.0748,Found: 330.0742 (M+Na+); IR (neat, cm-1): υ 2984, 1730, 1473, 1218, 1069,726, 690; IR (neat, cm-1): υ 2985, 1730, 1580, 1454, 1224, 1190, 1109, 860,784。
实施例二十七
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1l(2 mmol, 452 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3l,收率为70%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 8.02 – 7.95 (m, 1H), 7.91 – 7.82 (m, 1H),7.55 – 7.50 (m, 1H), 7.48 – 7.41 (m, 1H), 4.48 (q, J = 7.1 Hz, 2H), 4.37 (q,J = 7.1 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR(101 MHz, CDCl3) δ 169.8, 160.4, 159.5, 156.3, 134.7, 131.7, 130.0, 128.4,127.1, 126.5, 109.0, 62.7, 62.0, 13.9, 13.7; HRMS (ESI-TOF): Anal. Calcd. ForC15H14 35ClNO5: 346.0453, Found: 346.0441 (M+Na+); Anal. Calcd. For C15H14 37ClNO5:348.0423, Found: 348.0435 (M+Na+); IR (neat, cm-1): υ 2984, 1729, 1466, 1220,1070, 784。
实施例二十八
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1m(2 mmol, 538 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3m,收率为81%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 1.4 Hz, 1H), 7.91 (dd, J = 7.9,0.9 Hz, 1H), 7.68 (dd, J = 8.1, 0.9 Hz, 1H), 7.45 – 7.34 (m, 1H), 4.48 (q, J= 7.1 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H), 1.35 (t, J= 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.8, 160.4, 159.5, 156.4, 134.6,131.3, 130.2, 127.4, 127.0, 122.6, 109.0, 62.8, 62.0, 13.9, 13.8; HRMS (ESI-TOF): Anal. Calcd. For C15H14 79BrNO5: 389.9948, Found: 389.9956 (M+Na+); Anal.Calcd. For C15H14 81BrNO5: 391.9927, Found: 391.9936 (M+Na+); IR (neat, cm-1): υ2983, 1729, 1465, 1220, 1119, 1068, 783, 735。
实施例二十九
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1n(2 mmol, 520 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3n,收率为70%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 8.19 (d, J = 7.9 Hz, 1H), 7.82(d, J = 7.8 Hz, 1H), 7.74 – 7.62 (m, 1H), 4.50 (q, J = 7.1 Hz, 2H), 4.37 (q,J = 7.1 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR(101 MHz, CDCl3) δ 169.9, 160.4, 158.0 (d, J = 296.7 Hz), 131.7, 131.4,131.1, 129.4, 128.3 (q, J = 3.5 Hz), 126.4, 125.6 (q, J = 3.9 Hz), 123.5 (q,J = 273.7 Hz), 109.3, 62.8, 62.1, 13.9, 13.7; 19F NMR (376 MHz, CDCl3) δ -62.99; HRMS (ESI-TOF): Anal. Calcd. For C16H14F3NO5: 380.0716, Found: 380.0726(M+Na+); IR (neat, cm-1): υ 2987, 1730, 1306, 1227, 1119, 1070, 693。
实施例三十
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1o(2 mmol, 412 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3o,收率为65%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 7.49 – 7.39 (m, 2H), 7.35 – 7.25 (m, 2H),4.50 (q, J = 7.1 Hz, 2H), 4.22 (q, J = 7.1 Hz, 2H), 2.31 (s, 3H), 1.45 (t, J= 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.9,160.0, 159.8, 155.7, 137.8, 131.2, 130.5, 130.2, 125.5, 125.4, 110.1, 62.7,61.4, 19.8, 13.9, 13.7; HRMS (ESI-TOF): Anal. Calcd. For C16H17NO5: 326.0999,Found: 326.0989 (M+Na+); IR (neat, cm-1): υ 2984, 1730, 1446, 1219, 1070, 757。
实施例三十一
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1p(2 mmol, 444 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3p,收率为64%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 7.61 (dd, J = 7.6, 1.3 Hz, 1H), 7.54 – 7.45(m, 1H), 7.11 – 7.04 (m, 1H), 7.00 (d, J = 8.4 Hz, 1H), 4.47 (q, J = 7.1 Hz,2H), 4.27 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H), 1.24(t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.2, 161.0, 159.5, 156.6,155.1, 132.9, 130.1, 120.5, 115.0, 111.1, 111.0, 62.4, 61.2, 55.2, 13.9,13.8; HRMS (ESI-TOF): Anal. Calcd. For C16H17NO6: 342.0948, Found: 342.0947 (M+Na+); IR (neat, cm-1): υ 2983, 1732, 1466, 1213, 1047, 755。
实施例三十二
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1q(2 mmol, 484 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3q,收率为78%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.97 – 7.88 (m, 3H), 7.85 (d,J = 7.8 Hz, 1H), 7.60 – 7.58 (m, 2H), 4.49 (q, J = 7.1 Hz, 2H), 4.37 (q, J =7.1 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (101MHz, CDCl3) δ 171.5, 160.9, 159.8, 156.4, 134.4, 132.4, 129.4, 129.0, 128.4,128.1, 127.7, 126.9, 124.2, 122.8, 108.5, 62.6, 61.8, 13.9, 13.8; HRMS (ESI-TOF): Anal. Calcd. For C19H17NO5: 362.0999, Found: 362.0994 (M+Na+); IR (neat,cm-1): υ 2983, 1729, 1315, 1216, 1104, 1069, 750。
实施例三十三
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1r(2 mmol, 396 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3r,收率为68%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 8.17 (dd, J = 3.8, 0.7 Hz, 1H), 7.67 (dd, J= 5.0, 0.7 Hz, 1H), 7.20 (dd, J = 4.8, 4.1 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H),4.38 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.0, 160.4, 159.9, 156.5, 132.4, 132.0, 127.9,126.4, 105.8, 62.7, 61.6, 13.9, 13.9; HRMS (ESI-TOF): Anal. Calcd. ForC13H13NO5S: 318.0407, Found: 318.0410 (M+Na+); IR (neat, cm-1): υ 2983, 1720,1586, 1474, 1212, 1101, 1045, 853, 715。
实施例三十四
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1s(2 mmol, 408 mg),化合物2a(3 mmol, 342 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3s,收率为70%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 8.01 – 7.89 (m, 2H), 7.59 – 7.44 (m, 3H),5.99 – 5.89 (m, 1H), 5.32 (ddd, J = 13.8, 11.4, 1.1 Hz, 2H), 4.78 (d, J = 5.8Hz, 2H), 4.46 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,CDCl3) δ 171.8, 160.5, 159.7, 156.2, 131.8, 131.0, 128.7, 128.5, 125.6,119.2, 108.1, 66.4, 62.7, 13.9; HRMS (ESI-TOF): Anal. Calcd. For C16H15NO5:324.0842, Found: 324.0844 (M+Na+); IR (neat, cm-1): υ 2986, 1729, 1470, 1215,1114, 1068, 762, 689。
实施例三十五
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2b(3 mmol, 384 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3t,收率为79%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 8.01 – 7.89 (m, 2H), 7.59 – 7.44 (m, 3H),5.41 – 5.23 (m, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.43 (s, 3H), 1.42 (s, 3H),1.32 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.4, 160.9, 159.3,156.4, 131.6, 128.6, 128.4, 125.7, 108.4, 70.8, 61.8, 21.6, 13.8; HRMS (ESI-TOF): Anal. Calcd. For C16H17NO5: 326.0999, Found: 326.0994 (M+Na+); IR (neat,cm-1): υ 2984, 1730, 1470, 1224, 1104, 1069, 762, 690。
实施例三十六
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2c(3 mmol, 426 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3u,收率为77%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 7.95 – 7.92 (m, 2H), 7.72 – 7.31 (m, 3H),4.35 (q, J = 7.1 Hz, 2H), 1.64 (s, 9H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR (101MHz, CDCl3) δ 171.3, 161.0, 158.6, 157.0, 131.6, 128.6, 128.4, 125.8, 108.2,84.4, 61.7, 27.8, 13.9; HRMS (ESI-TOF): Anal. Calcd. For C17H19NO5: 340.1155,Found: 340.1153 (M+Na+); IR (neat, cm-1): υ 2981, 1729, 1273, 1154, 1070, 843,766, 690。
实施例三十七
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2d(3 mmol, 528 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3v,收率为64%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 7.99 – 7.90 (m, 2H), 7.55 – 7.43 (m, 5H),7.42 – 7.28 (m, 4H), 5.43 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 1.20 (t, J = 7.1Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.6, 160.7, 159.6, 156.0, 134.5, 131.7,128.6, 128.6, 128.5, 128.4, 125.6, 108.4, 68.1, 61.8, 13.7; HRMS (ESI-TOF):Anal. Calcd. For C20H17NO5: 374.0999, Found: 374.1001 (M+Na+); IR (neat, cm-1):υ 2983, 1730, 1470, 1207, 1116, 1068, 692。
实施例三十八
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2e(3 mmol, 504 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3w,收率为74%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 8.02 – 7.86 (m, 2H), 7.63 – 7.41 (m, 3H),5.23 – 5.01 (m, 1H), 4.34 (qd, J = 7.1, 1.3 Hz, 2H), 2.11 – 1.93 (m, 2H),1.87 – 1.74 (m, 2H), 1.68 – 1.53 (m, 3H), 1.50 – 1.37 (m, 2H), 1.37 – 1.22(m, 4H); 13C NMR (101 MHz, CDCl3) δ 171.4, 160.9, 159.2, 156.5, 131.6, 128.6,128.4, 125.7, 108.4, 75.6, 61.8, 31.3, 25.1, 23.5, 13.8; HRMS (ESI-TOF):Anal. Calcd. For C19H21NO5: 366.1312, Found: 366.1311 (M+Na+); IR (neat, cm-1):υ 2935, 1726, 1468, 1223, 1116, 1074, 755, 692。
实施例三十九
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2f(3 mmol, 378 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3x,收率为61%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 8.03 – 7.90 (m, 2H), 7.59 – 7.45 (m, 3H),6.13 – 5.94 (m, 1H), 5.46 (ddd, J = 17.2, 2.8, 1.4 Hz, 1H), 5.35 (ddd, J =10.4, 2.3, 1.1 Hz, 1H), 4.90 (dt, J = 5.9, 1.3 Hz, 2H), 4.34 (q, J = 7.1 Hz,2H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.6, 160.8, 159.4,156.0, 131.8, 130.8, 128.7, 128.4, 125.6, 119.7, 108.4, 67.0, 61.8, 13.8;HRMS (ESI-TOF): Anal. Calcd. For C16H15NO5: 324.0842, Found: 324.0849 (M+Na+);IR (neat, cm-1): υ 2986, 1730, 1471, 1315, 1208, 1116, 1068, 763, 689。
实施例四十
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2g(3 mmol, 420 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3y,收率为68%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 8.05 – 7.88 (m, 2H), 7.59 – 7.44 (m, 3H),6.00 – 5.85 (m, 1H), 5.77 – 5.64 (m, 1H), 4.83 (dd, J = 6.7, 0.7 Hz, 2H),4.34 (qd, J = 7.1, 0.5 Hz, 2H), 1.76 (d, J = 6.5 Hz, 3H), 1.32 (td, J = 7.1,0.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.5, 160.8, 159.5, 156.1, 133.0,131.7, 128.6, 128.4, 125.6, 123.8, 108.4, 67.2, 61.8, 17.7, 13.7; HRMS (ESI-TOF): Anal. Calcd. For C17H17NO5: 338.0999, Found: 338.1004 (M+Na+); IR (neat,cm-1): υ 2982, 1730, 1471, 1206, 1116, 1067, 965, 763, 689。
实施例四十一
反应瓶中依次装入Cu(OAc)2.H2O(0.15 mmol, 30 mg),Mg(OTf)2(0.2 mmol,64mg),DABCO(5 mmol, 560 mg),化合物1a(2 mmol, 384 mg),化合物2h(3 mmol, 392 mg), t BuONO(3 mmol,309 mg),环己烷(10.0 mL)。然后该体系在空气中80℃条件下加热约12小时后,用乙酸乙酯萃取(40 mL × 3),通过简单的柱层析即可得产物3z,收率为67%。所制得产物的主要测试数据如下,通过分析可知,实际合成产物与理论分析一致。
1H NMR (400 MHz, CDCl3) δ 8.02 – 7.87 (m, 2H), 7.56 – 7.41 (m, 3H),7.15 (dd, J = 4.9, 1.3 Hz, 1H), 6.97 – 6.86 (m, 2H), 4.60 (t, J = 6.9 Hz,2H), 4.28 (q, J = 7.1 Hz, 2H), 3.30 (t, J = 6.9 Hz, 2H), 1.26 (t, J = 7.1 Hz,3H); 13C NMR (101 MHz, CDCl3) δ 171.4, 160.5, 159.5, 155.9, 138.7, 131.6,128.5, 128.3, 126.8, 125.7, 125.4, 124.0, 108.3, 66.4, 61.7, 28.7, 13.6; HRMS(ESI-TOF): Anal. Calcd. For C19H17NO5S: 394.0720, Found: 394.0724 (M+Na+); IR(neat, cm-1): υ 2980, 2920, 1730, 1447, 1220, 1116, 1070, 763, 689。
Claims (10)
1.一种制备异噁唑化合物的方法,其特征在于,包括以下步骤:以β-酮酸脂、α-重氮酸脂与亚硝酸叔丁酯为反应底物,以铜化物为催化剂、路易斯酸为添加剂,在碱存在下,通过三组分反应制备得到异噁唑化合物;
其中,所述β-酮酸脂的化学结构式为以下化学结构式中的一种:
、、、
式中,R1选自氢、4-甲基、4-甲氧基、4-三氟甲基、4-氟、4-氯、4-溴、4-碘、3-甲基、3-甲氧基、3-氟、3-氯、3-溴、3-三氟甲基、2-甲基、2-甲氧基中的一种;
所述α-重氮酸脂的化学结构式为以下化学结构式中的一种:
、、
式中,R3选自乙基、异丙基、叔丁基、苄基、环己基、烯丙基中的一种。
2.根据权利要求1所述制备异噁唑化合物的方法,其特征在于:所述三组分反应的反应温度为60~100℃,反应时间为6~24小时。
3.根据权利要求1所述制备异噁唑化合物的方法,其特征在于:所述铜化物选自碘化亚铜、醋酸铜、一水醋酸铜、三氟甲磺酸铜、溴化亚铜、溴化铜中的一种;所述催化剂用量为β-酮酸脂的5~20mmol %。
4.根据权利要求1所述制备异噁唑化合物的方法,其特征在于:所述路易斯酸为三氟甲磺酸镁;所述路易斯酸用量为β-酮酸脂的5~20mmol %。
5.根据权利要求1所述制备异噁唑化合物的方法,其特征在于:所述碱的用量为β-酮酸脂的1~3当量;所述碱为三乙烯二胺。
6.根据权利要求1所述制备异噁唑化合物的方法,其特征在于:所述β-酮酸脂、α-重氮酸脂与亚硝酸叔丁酯的摩尔比为1∶1.5∶1.5。
7.根据权利要求1所述制备异噁唑化合物的方法得到异噁唑化合物。
8.铜化合物在制备异噁唑化合物中的应用;所述铜化物选自碘化亚铜、醋酸铜、一水醋酸铜、三氟甲磺酸铜、溴化亚铜、溴化铜中的一种。
9.β-酮酸脂、α-重氮酸脂与亚硝酸叔丁酯作为三组分反应的反应底物在制备异噁唑化合物中的应用。
10.铜化合物在催化β-酮酸脂、α-重氮酸脂与亚硝酸叔丁酯中的应用;所述铜化物选自碘化亚铜、醋酸铜、一水醋酸铜、三氟甲磺酸铜、溴化亚铜、溴化铜中的一种。
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CN107445912B (zh) | 2020-08-04 |
CN111747903A (zh) | 2020-10-09 |
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