CN112778067B - 一种铜催化1,2,3-硫二唑化合物与胺合成硫代酰胺化合物的方法 - Google Patents
一种铜催化1,2,3-硫二唑化合物与胺合成硫代酰胺化合物的方法 Download PDFInfo
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- CN112778067B CN112778067B CN202110126333.9A CN202110126333A CN112778067B CN 112778067 B CN112778067 B CN 112778067B CN 202110126333 A CN202110126333 A CN 202110126333A CN 112778067 B CN112778067 B CN 112778067B
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- copper
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- phenyl
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- thiodiazole
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- -1 thioamide compound Chemical class 0.000 title claims abstract description 70
- 238000000034 method Methods 0.000 title claims abstract description 25
- 150000001412 amines Chemical class 0.000 title claims abstract description 19
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 10
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 239000010949 copper Substances 0.000 title claims abstract description 9
- 229910052802 copper Inorganic materials 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 186
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- 239000003446 ligand Substances 0.000 claims abstract description 22
- 150000001879 copper Chemical class 0.000 claims abstract description 18
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 16
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 230000009471 action Effects 0.000 claims abstract description 7
- 239000012298 atmosphere Substances 0.000 claims abstract description 5
- 230000001681 protective effect Effects 0.000 claims abstract description 5
- 239000012429 reaction media Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 258
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 92
- 238000004440 column chromatography Methods 0.000 claims description 86
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 84
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 60
- 239000012074 organic phase Substances 0.000 claims description 51
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 50
- 239000002904 solvent Substances 0.000 claims description 49
- 239000003208 petroleum Substances 0.000 claims description 45
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical group [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 43
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 43
- 238000001035 drying Methods 0.000 claims description 43
- 239000003480 eluent Substances 0.000 claims description 43
- 238000001914 filtration Methods 0.000 claims description 43
- 239000012046 mixed solvent Substances 0.000 claims description 43
- 229910052757 nitrogen Inorganic materials 0.000 claims description 43
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 21
- 150000003556 thioamides Chemical class 0.000 claims description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- 238000003786 synthesis reaction Methods 0.000 claims description 14
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 8
- 229940024606 amino acid Drugs 0.000 claims description 7
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000004129 indan-1-yl group Chemical group [H]C1=C([H])C([H])=C2C(=C1[H])C([H])([H])C([H])([H])C2([H])* 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 4
- 150000003973 alkyl amines Chemical class 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 239000002274 desiccant Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Chemical group 0.000 claims description 4
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 4
- 230000000171 quenching effect Effects 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 3
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Chemical group C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- QPNJHVDIRZNKOX-LURJTMIESA-N ethyl (2s)-pyrrolidine-2-carboxylate Chemical compound CCOC(=O)[C@@H]1CCCN1 QPNJHVDIRZNKOX-LURJTMIESA-N 0.000 claims description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 3
- MWZPENIJLUWBSY-SECBINFHSA-N methyl (2r)-2-amino-3-(4-hydroxyphenyl)propanoate Chemical compound COC(=O)[C@H](N)CC1=CC=C(O)C=C1 MWZPENIJLUWBSY-SECBINFHSA-N 0.000 claims description 3
- KCUNTYMNJVXYKZ-JTQLQIEISA-N methyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate Chemical compound C1=CC=C2C(C[C@H](N)C(=O)OC)=CNC2=C1 KCUNTYMNJVXYKZ-JTQLQIEISA-N 0.000 claims description 3
- CEMZBWPSKYISTN-YFKPBYRVSA-N methyl (2s)-2-amino-3-methylbutanoate Chemical compound COC(=O)[C@@H](N)C(C)C CEMZBWPSKYISTN-YFKPBYRVSA-N 0.000 claims description 3
- VSDUZFOSJDMAFZ-VIFPVBQESA-N methyl L-phenylalaninate Chemical compound COC(=O)[C@@H](N)CC1=CC=CC=C1 VSDUZFOSJDMAFZ-VIFPVBQESA-N 0.000 claims description 3
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical group COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 claims description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- XIMBESZRBTVIOD-UHFFFAOYSA-N piperidine-2-carboxamide Chemical compound NC(=O)C1CCCCN1 XIMBESZRBTVIOD-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 2
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical class C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 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
- 125000000984 3-chloro-4-fluorobenzyl group Chemical group [H]C1=C(F)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 2
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 claims description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 claims description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000000173 4-trifluoromethoxy benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC(F)(F)F)C([H])([H])* 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 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
- HDULBKVLSJEMGN-UHFFFAOYSA-N dicyclohexylphosphane Chemical compound C1CCCCC1PC1CCCCC1 HDULBKVLSJEMGN-UHFFFAOYSA-N 0.000 claims description 2
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 2
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- 239000011261 inert gas Substances 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
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 3
- 238000004821 distillation Methods 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 11
- 239000002994 raw material Substances 0.000 abstract description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 174
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 41
- 238000005160 1H NMR spectroscopy Methods 0.000 description 41
- 238000012512 characterization method Methods 0.000 description 41
- 238000010438 heat treatment Methods 0.000 description 41
- 238000003756 stirring Methods 0.000 description 41
- 238000005406 washing Methods 0.000 description 41
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 26
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- 238000001228 spectrum Methods 0.000 description 19
- 239000000203 mixture Substances 0.000 description 10
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- 238000004293 19F NMR spectroscopy Methods 0.000 description 5
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- 150000001408 amides Chemical class 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 4
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- 239000005864 Sulphur Substances 0.000 description 3
- XOCUXOWLYLLJLV-UHFFFAOYSA-N [O].[S] Chemical compound [O].[S] XOCUXOWLYLLJLV-UHFFFAOYSA-N 0.000 description 3
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- 230000000694 effects Effects 0.000 description 3
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- 125000001391 thioamide group Chemical group 0.000 description 3
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- ZKXWKVVCCTZOLD-UHFFFAOYSA-N copper;4-hydroxypent-3-en-2-one Chemical compound [Cu].CC(O)=CC(C)=O.CC(O)=CC(C)=O ZKXWKVVCCTZOLD-UHFFFAOYSA-N 0.000 description 2
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
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- 239000000376 reactant Substances 0.000 description 2
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- 150000004763 sulfides Chemical class 0.000 description 2
- WQYSXVGEZYESBR-UHFFFAOYSA-N thiophosphoryl chloride Chemical compound ClP(Cl)(Cl)=S WQYSXVGEZYESBR-UHFFFAOYSA-N 0.000 description 2
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- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
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- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 1
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- WIHHVKUARKTSBU-UHFFFAOYSA-N 4-bromobenzene-1,2-diamine Chemical compound NC1=CC=C(Br)C=C1N WIHHVKUARKTSBU-UHFFFAOYSA-N 0.000 description 1
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- 238000006237 Beckmann rearrangement reaction Methods 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
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Abstract
本发明属于有机化学的技术领域,公开了一种铜催化1,2,3‑硫二唑化合物与胺合成硫代酰胺化合物的方法。方法为在保护性氛围下,以有机溶剂为反应介质,将1,2,3‑硫二唑化合物与胺类化合物在铜盐催化剂或铜催化剂和膦配体的作用下反应,后续处理,获得硫代酰胺化合物。本发明的方法以铜盐为催化剂,并采用膦配体,产率较高、底物适用性广。此外,该反应以1,2,3‑硫二唑化合物和胺类化合物为原料,具有原料廉价易制备、操作简便、原子经济性高的优点。
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种铜催化1,2,3-硫二唑化合物与胺合成硫代酰胺化合物的方法。
背景技术
硫不仅是自然界第五常见的元素,而且是所有生命形式必不可少的元素。它以有机硫化合物的形式存在于生物体内,如三种氨基酸(半胱氨酸,胱氨酸和甲硫氨酸)、两种维生素(维生素H和维生素B1)等。因此,对有机硫化物的研究一直是生物化学与有机合成化学的研究热点之一。另外,有机硫化物凭借其特殊的结构赋予的独特性能,在有机超导体、有机光电分子及其器件领域占据重要的位置。
作为一种重要的有机硫化物,硫代酰胺仅是将酰胺类化合物中的氧原子替换成了硫原子。然而一个原子的微小结构变化导致了显著的物理与化学性质的改变,包括红外光谱、紫外光谱、核磁共振的吸收峰存在明显的位移差,C=X键键长的变化(X=O或S),-NH-亲质子性的增强等等(Effect of Thioxopeptide Bonds onα-Helix Structure andStability.J.Am.Chem.Soc.,2008,130,8079-8084;Hydrogen Bonding Abilities ofThioamide.J.Phys.Chem.A.,2002,106,7010-7017.)。正是由于一系列物理性质的改变,硫代酰胺化合物才显示出与普通酰胺类化合物明显不同的化学反应活性。
硫代酰胺骨架作为一种类肽键结构,其合成及应用在精细化工、生物医药等领域受到了高度重视,例如,制备多种杂环化合物,包括硫代内酰胺、硫代吡喃、噻唑等;或者硫代酰胺的取代肽键用来研究多肽和蛋白质的二级结构和生物学活性等。作为一种重要的生物、化学骨架,目前已经有多种合成硫代酰胺的方法被开发出来。
迄今为止,有三种较为实用的合成硫代酰胺的反应策略:(1)使用醛(酮)与胺类、酰胺等作为前体或原料,利用六甲基二硅硫烷(Conversion of amides and lactams tothioamides and thiolactams using hexamethyldisilathiane.J.Org.Chem.,1994,59,348-354;)、硫单质(Preparation of Thioamide Building Blocks via Microwave-Promoted Three-Component Kindler Reactions.J.Comb.Chem.,2003,5,145-148)、硫化氢(Thiolysis and hydrolysis of imino and iminium triflates:Synthesis ofsecondary and tertiary thioamides and 18O-labeled amides.Tetrahedron Lett.,1998,39,245-248;)、PSCl3(Expeditious Microwave-Assisted Thionation with theSystem PSCl3/H2O/Et3N under Solvent-Free Condition.J.Org.Chem.,2008,73,2890-2893)、硫化膦(P4S10/dimethicone tandem:efficient reagent for thionation ofvarious aromatic amides and esters.Tetrahedron,2010,66,5583-5588)、硫代酸盐(AFacile Conversion of Amides and Lactams to Thioamides and Thiolactams usingTetrathiomolybdate.Tetrahedron Lett.,1995,36,8311-8314)、Lawesson试剂及其类似物(Applications of Lawesson’s Reagent in Organic and OrganometallicSyntheses.Synthesis.2003,13,1929-1958.)等作为氧硫交换剂或反应物合成硫代酰胺的反应;(2)由肟或肟酯通过氧硫交换剂介导后,与胺发生Beckmann重排合成硫代酰胺的反应(Facile Synthesis of Thioamides via P2S5-Mediated Beckmann Rearrangement ofOximes.Chin.J.Chem.,2012,30,1687-1689);(3)在胺的催化下,硫化氢和腈发生加成反应合成硫代酰胺化合物。在这些工作中,氧硫交换反应模式被最广泛地研究,但其底物仅限于富电子底物。除了少数特殊底物以外,大多数缺电子的底物的反应往往受限,常常需要更改反应条件以得到较高的产率。同时,受到电子效应的影响,底物官能团兼容性方面表现一般。另外,前两种反应方法原子利用率低,而第三种反应方法仅能合成游离胺的硫代酰胺化合物,底物丰富度受限。因此,发展一种原子经济性高、底物适用范围广的合成方法显得尤为紧迫与重要。
发明内容
针对现有技术存在的问题和不足之处,本发明的目的在于提供一种温和条件下铜催化的1,2,3-硫二唑化合物与胺合成硫代酰胺化合物的方法。本发明的方法使用易得的1,2,3-硫二唑化合物和种类丰富且廉价的胺类化合物为原料,铜盐作为催化剂,膦化合物作为配体,在常见溶剂和适当温度的作用下以较高收率得到硫代酰胺化合物。本发明的方法具有价格低廉,操作安全简单,底物适用性广泛,原子经济性高,环境友好等优点,解决了现有方法中使用溶剂量的烷基胺,不能兼容芳基胺的技术问题。
本发明的目的通过以下技术方案实现:
一种铜催化的1,2,3-硫二唑化合物与胺合成硫代酰胺化合物的方法,包括如下步骤:在保护性氛围下,以有机溶剂为反应介质,将1,2,3-硫二唑化合物与胺类化合物在铜盐催化剂或铜催化剂和膦配体的作用下反应,后续处理,获得硫代酰胺化合物;
所述R1为取代或未取代的芳基、烷基、环烷基、-COOR(R为烷基)、苯并呋喃基;
所述取代的苯基优选为烷基取代的苯基、烷氧基取代的苯基、卤素取代的苯基;其中烷基为C1~5烷基,烷氧基为C1~5烷氧基。
所述R1优选为苯基、4-甲基苯基、4-甲氧基苯基、3-氟苯基、4-氯苯基、4-溴苯基、4-氰基苯基、环己基、叔丁基、乙酯基(-COOCH2CH3)、4-(1,2-亚甲基二氧基)苯基、2-苯并呋喃基。
当R2为氢时,R3为苄基、苯环上取代的苄基、苯基、取代的苯基、萘基甲基、2-丙炔基、1-茚满基、2-(3-吲哚基)乙基、1-苯基乙基;苯环上取代的苄基中取代基为烷氧基、氟取代的烷氧基、氰基、卤素,取代的苯基中取代基为烷氧基、乙酰基、卤素、乙炔基、氟取代的烷基;
所述R3优选为苄基、4-甲氧基苄基、4-三氟甲氧基苄基、4-氰基苄基、4-溴苄基、3-氯-4-氟苄基、萘-1-基甲基、2-丙炔基、1-茚满基、2-(3-吲哚基)乙基、苯基、2-甲氧基苯基、4-乙酰基苯基、2-氟苯基、4-三氟甲基苯基、3-乙炔基苯基、1-苯基乙基(Ph(CH3)CH-,);
R3优选为甲基、乙基、异丙基、苄基。
或者胺类化合物为氨基酸烷基酯、环胺化合物;所述氨基酸烷基酯优选为甘氨酸甲酯、L-缬氨酸甲酯、L-苯丙氨酸甲酯、L-脯氨酸乙酯、D-酪氨酸甲酯、L-色氨酸甲酯;所述环胺化合物优选为吗啉、吲哚、哌啶-2-甲酰胺。
所述铜盐为乙酸铜、[1,3-双(二苯基膦基)丙烷]乙酸铜、[1,4-双(二苯基膦基)丁烷]乙酸铜、[1,1’-双(二苯基膦基)二茂铁]乙酸铜中的一种以上。
所述膦配体为4,5-双二苯基膦-9,9-二甲基氧杂蒽、1,3-双(二苯基膦)丙烷、2,2'-双二苯膦基-1,1'-联萘、1,4-双(二苯基膦基)丁烷、1,1'-双(二苯基膦)二茂铁、2-(二环己基膦)-3,6-二甲氧基-2'-4'-6'-三-I-丙基-11'-联苯、三苯基膦、三环己基膦中的一种以上,优选为4,5-双二苯基膦-9,9-二甲基氧杂蒽。
所述反应的温度为50~95℃,反应的时间为4~26小时。
所述胺类化合物与1,2,3-硫二唑化合物的反应摩尔比为(0.5~3):1。所述铜盐与1,2,3-硫二唑化合物的摩尔比为(0.05~0.2):1。所述膦配体与1,2,3-硫二唑化合物的摩尔比为(0.05~0.2):1。
所述有机溶剂为乙腈、N,N-二甲基甲酰胺、四氢呋喃、1,4-二氧六环中一种以上。所述保护性氛围为氮气或惰性气体。
所述后续处理是指淬灭反应,乙酸乙酯萃取,去除有机相中溶剂,柱层析分离。所述去除有机相中溶剂是指去除有机相中水,去除有机溶剂。
所述淬灭反应是指向反应体系中加入饱和氯化钠溶液;所述去除有机相中水是指采用干燥剂进行干燥,干燥剂为无水硫酸镁,然后过滤;所述去除有机相中有机溶剂是指减压蒸馏去除有机溶剂。
所述柱层析的洗脱液为石油醚和乙酸乙酯的混合溶剂,石油醚和乙酸乙酯的体积比20:1-5:1。
本发明的合成方法的化学反应方程式:
本发明的合成方法具有如下优点及有益效果:
(1)本发明的方法以铜盐为催化剂,膦化合物为配体,具有产率高、底物适用性广等特点;而且本发明以1,2,3-硫二唑化合物和胺类化合物为原料,具有原料廉价易制备、操作简便、原子经济性高的优势。
(2)本发明合成方法底物适应性广、催化剂廉价、条件温和,因而有望实际应用于规模生产。
附图说明
图1是实施例1所得目标产物的氢谱图;
图2是实施例14所得目标产物的氢谱图;
图3是实施例19所得目标产物的氢谱图;
图4是实施例31所得目标产物的氢谱图;
图5是实施例35所得目标产物的氢谱图;
图6是实施例37所得目标产物的氢谱图;
图7是实施例38所得目标产物的氢谱图;
图8是实施例39所得目标产物的氢谱图;
图9是实施例40所得目标产物的氢谱图;
图10是实施例41所得目标产物的氢谱图。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述,但本发明的实施方式不限于此。
实施例1
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔苯胺和3毫升N,N-二甲基甲酰胺,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率90%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=8.57(s,1H),7.54(d,J=7.9Hz,2H),7.46–7.38(m,2H),7.34(dd,J=13.0,6.4Hz,5H),7.22(t,J=7.4Hz,1H),4.25(s,2H).氢谱图如图1所示。
13C NMR(126MHz,CDCl3)δ=201.33,138.52,135.01,129.61,129.45,128.90,128.11,127.06,123.71,54.91.MS(EI):227,225,224,91,65.
根据以上数据推断所得产物的结构:
实施例2
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔2-甲氧基苯胺和3毫升N,N-二甲基甲酰胺,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率85%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=9.16(s,1H),9.03(d,J=8.1Hz,1H),7.46–7.39(m,2H),7.36(t,J=6.9Hz,3H),7.12(t,J=7.8Hz,1H),6.95(t,J=7.8Hz,1H),6.81(d,J=8.2Hz,1H),4.27(s,2H),3.64(s,3H).
13C NMR(126MHz,CDCl3)δ=198.89,149.68,134.93,129.91,129.24,128.25,127.93,126.48,121.35,120.34,110.35,56.01,55.82.MS(EI):257,226,166,151,91.
根据以上数据推断所得产物的结构:
实施例3
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔3-乙炔基苯胺和3毫升N,N-二甲基甲酰胺,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率92%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=8.65(s,1H),7.59(d,J=10.4Hz,2H),7.39(t,J=7.0Hz,2H),7.33(t,J=8.0Hz,4H),7.25(t,J=7.7Hz,1H),4.20(s,2H),3.07(s,1H).
13C NMR(126MHz,CDCl3)δ=201.85,138.51,134.96,130.62,129.54,129.46,128.92,128.14,127.15,124.42,122.86,82.70,78.36,54.81.MS(EI):251,160,134,117,91.
根据以上数据推断所得产物的结构:
实施例4
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔2-氟苯胺和3毫升N,N-二甲基甲酰胺,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率71%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=8.57(s,1H),8.46(t,J=7.8Hz,1H),7.48–7.39(m,2H),7.36(d,J=6.7Hz,3H),7.15(dt,J=15.2,7.0Hz,2H),7.10–7.02(m,1H),4.28(s,2H).
19F NMR(471MHz,CDCl3)δ=-126.72(d,J=12.9Hz,1F).
13C NMR(126MHz,CDCl3)δ=201.83,154.50(d,J=247.5Hz),134.68,129.63,129.49,128.20,127.68(d,J=8.1Hz),126.84(d,J=10.2Hz),124.83,124.04(d,J=3.7Hz),115.41(d,J=19.3Hz),55.18.MS(EI):245,226,154,134,91.
根据以上数据推断所得产物的结构:
实施例5
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔4-氨基苯乙酮和3毫升N,N-二甲基甲酰胺,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率58%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=8.83(s,1H),7.93(d,J=8.5Hz,2H),7.78(d,J=8.5Hz,2H),7.42(d,J=6.9Hz,2H),7.37(d,J=7.3Hz,3H),4.27(s,2H),2.56(s,3H).
13C NMR(126MHz,CDCl3)δ=201.75,197.01,142.59,134.88,134.82,129.52,129.51,129.26,128.23,122.57,55.49,26.61.MS(EI):269,178,134,91,65.
根据以上数据推断所得产物的结构:
实施例6
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔4-三氟甲基苯胺和3毫升N,N-二甲基甲酰胺,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率65%。
所得产物的结构表征数据如下:
1H NMR(400MHz,CDCl3)δ=8.68(s,1H),7.77(d,J=8.3Hz,2H),7.61(d,J=8.3Hz,2H),7.54–7.44(m,2H),7.40(t,J=9.0Hz,3H),4.30(s,2H).
19F NMR(376MHz,CDCl3)δ=-62.41(s,1F).
13C NMR(101MHz,CDCl3)δ=202.07,141.38,134.73,129.55,128.68,128.35,128.30,126.05(dd,J=7.4,3.7Hz),123.76(q,J=271.8Hz).123.33,55.24.MS(EI):295,262,204,134,91.
根据以上数据推断所得产物的结构:其中“Bn”表示苄基;
实施例7
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔苯甲胺和3毫升四氢呋喃,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为20:1的石油醚:乙酸乙酯混合溶剂,产率91%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.34(m,3H),7.31–7.22(m,6H),7.15(d,J=6.6Hz,2H),4.80(d,J=5.4Hz,2H),4.14(s,2H).
13C NMR(126MHz,CDCl3)δ=202.30,136.03,134.94,129.49,129.25,128.89,127.99,127.89,127.81,53.10,50.15.MS(EI):241,150,91,65.
根据以上数据推断所得产物的结构:
实施例8
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔1-萘甲胺和3毫升四氢呋喃,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为12:1的石油醚:乙酸乙酯混合溶剂,产率92%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.71(d,J=7.8Hz,1H),7.65(dd,J=17.3,8.0Hz,2H),7.42–7.31(m,2H),7.25(t,J=7.5Hz,2H),7.20(d,J=6.9Hz,1H),7.11(dt,J=17.1,7.0Hz,5H),5.04(d,J=4.9Hz,2H),3.96(s,2H).
13C NMR(126MHz,CDCl3)δ=201.83,135.17,133.85,131.46,131.38,129.28,129.17,129.08,128.88,127.70,127.26,126.88,126.23,125.36,123.32,53.01,48.86.MS(EI):291,258,141,115,91.
根据以上数据推断所得产物的结构:
实施例9
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔4-甲氧基苯甲胺和3毫升四氢呋喃,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为20:1的石油醚:乙酸乙酯混合溶剂,产率92%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.25(t,J=7.2Hz,2H),7.20(d,J=7.2Hz,2H),7.16(d,J=7.3Hz,2H),7.02(d,J=8.5Hz,2H),6.73(d,J=8.6Hz,2H),4.64(d,J=5.2Hz,2H),4.04(s,2H),3.67(s,3H).
13C NMR(126MHz,CDCl3)δ=201.90,159.35,134.99,129.44,129.28,129.21,128.02,127.82,114.25,55.30,53.08,49.76.MS(EI):271,134,121,91,65.
根据以上数据推断所得产物的结构:
实施例10
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔4-三氟甲氧基苯甲胺和3毫升四氢呋喃,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为12:1的石油醚:乙酸乙酯混合溶剂,产率89%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.41(s,1H),7.35(t,J=7.2Hz,2H),7.30(t,J=7.2Hz,1H),7.26(d,J=7.3Hz,2H),7.19(d,J=8.5Hz,2H),7.13(d,J=8.3Hz,2H),4.82(s,2H),4.15(s,2H).
19F NMR(471MHz,CDCl3)δ=-57.87(s,3F).
13C NMR(126MHz,CDCl3)δ202.77,148.77,134.84,129.46,129.30,129.18,127.95,121.27,120.41(q,J=259.35Hz),53.09,48.99.MS(EI):325,251,175,117,91.
根据以上数据推断所得产物的结构:
实施例11
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔3-氯-4-氟苯甲胺和3毫升四氢呋喃,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为12:1的石油醚:乙酸乙酯混合溶剂,产率87%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.43(s,1H),7.27(t,J=7.3Hz,2H),7.22(d,J=7.0Hz,1H),7.17(d,J=7.5Hz,2H),7.11(d,J=6.8Hz,1H),6.99–6.89(m,2H),4.67(d,J=5.3Hz,2H),4.03(s,2H).
19F NMR(376MHz,CDCl3)δ=-116.34(d,J=6.5Hz,1F).
13C NMR(126MHz,CDCl3)δ202.96,157.59(d,J=249.2Hz,1C),134.89,133.26(d,J=3.8Hz,1C),129.93,129.39,129.30,127.97,127.60(d,J=7.3Hz,1C),121.21(d,J=18.1Hz,1C),116.85(d,J=21.3Hz,1C),53.04,48.45.MS(EI):293,260,143,117,91.
根据以上数据推断所得产物的结构:
实施例12
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔4-溴苯甲胺和3毫升四氢呋喃,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为12:1的石油醚:乙酸乙酯混合溶剂,产率94%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.39(d,J=8.2Hz,3H),7.34(t,J=7.3Hz,2H),7.30(d,J=6.9Hz,2H),7.24(d,J=7.6Hz,2H),7.10(s,1H),7.02(d,J=8.2Hz,2H),4.75(s,2H),4.13(s,2H).
13C NMR(126MHz,CDCl3)δ202.65,135.11,134.83,131.92,129.47,129.46,129.30,127.96,121.83,53.07,49.18.MS(EI):321,319,169,91,89.
根据以上数据推断所得产物的结构:
实施例13
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔4-氰基苯甲胺和3毫升四氢呋喃,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率85%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.60(s,1H),7.54(d,J=8.1Hz,2H),7.37(t,J=7.2Hz,2H),7.33(d,J=6.9Hz,1H),7.27(dd,J=12.4,7.8Hz,4H),4.90(s,2H),4.17(s,2H).
13C NMR(126MHz,CDCl3)δ=203.49,141.73,134.85,132.49,129.45,129.33,128.16,128.02,118.57,111.46,53.05,48.91.MS(EI):266,134,116,91,65.
根据以上数据推断所得产物的结构:
实施例14
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔色胺和3毫升1,4-二氧六环,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率69%。
所得产物的结构表征数据如下:
1H NMR(400MHz,CDCl3)δ=7.99(s,1H),7.57(d,J=7.9Hz,1H),7.39(d,J=8.1Hz,1H),7.32–7.21(m,4H),7.15(t,J=7.4Hz,1H),7.08(d,J=4.6Hz,3H),6.68(s,1H),4.08(s,2H),3.96(q,J=6.1Hz,2H),3.03(t,J=6.5Hz,2H).氢谱图如图2所示。
13C NMR(126MHz,CDCl3)δ201.63,136.39,134.65,129.60,129.12,127.70,126.98,122.39,122.12,119.69,118.63,111.90,111.33,53.12,45.96,23.29.MS(EI):294,257,207,128,100.
根据以上数据推断所得产物的结构:
实施例15
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔1-(2-氨基乙基)茚满和3毫升1,4-二氧六环,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为5:1的石油醚:乙酸乙酯混合溶剂,产率36%。
所得产物的结构表征数据如下:
1H NMR(400MHz,CDCl3)δ=7.44–7.35(m,2H),7.35–7.23(m,6H),7.19(dt,J=12.0,5.5Hz,2H),6.12(q,J=7.8Hz,1H),4.20(q,J=16.4Hz,2H),3.09–2.84(m,2H),2.76(ddd,J=19.7,7.5,4.2Hz,1H),1.91–1.61(m,1H).
13C NMR(101MHz,CDCl3)δ=202.10,143.68,141.56,134.94,129.44,129.27,128.41,127.89,126.92,125.05,123.70,60.87,53.27,32.70,30.28.MS(EI):267,152,116,115,91.
根据以上数据推断所得产物的结构:
实施例16
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔1-苯基乙-1-胺和3毫升1,4-二氧六环,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率85%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.36(ddd,J=23.6,18.1,12.8Hz,3H),7.31–7.25(m,3H),7.24(dt,J=11.7,4.0Hz,3H),7.18–7.12(m,2H),5.80–5.65(m,1H),4.08(s,2H),1.46(d,J=6.9Hz,3H).
13C NMR(126MHz,CDCl3)δ=200.89,141.24,135.08,129.41,129.23,128.79,127.85,127.73,126.25,54.54,53.22,20.29.MS(EI):255,222,163,131,105.
根据以上数据推断所得产物的结构:
实施例17
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.5毫摩尔4-(苯并呋喃-2-基)-1,2,3-硫二唑、0.5毫摩尔N-甲基苯胺和3毫升乙腈,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率69%。
所得产物的结构表征数据如下:
1H NMR(400MHz,CDCl3)δ=7.50(dd,J=9.8,2.8Hz,1H),7.42(ddd,J=8.8,6.1,3.9Hz,4H),7.31–7.12(m,4H),6.50(s,1H),4.13(s,2H),3.80(s,3H).
13C NMR(101MHz,CDCl3)δ=198.59,154.68,153.57,145.34,130.01,128.81,128.57,125.64,123.67,122.62,120.71,110.99,104.70,46.25,43.97.MS(EI):281,248,207,131,109.
根据以上数据推断所得产物的结构:
实施例18
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔吗啉和3毫升1,4-二氧六环,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率73%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.34–7.29(m,4H),7.24(ddd,J=6.5,5.0,3.2Hz,1H),4.39–4.28(m,4H),3.78–3.68(m,2H),3.67–3.55(m,2H),3.48–3.29(m,2H).
13C NMR(126MHz,CDCl3)δ=199.91,135.78,128.97,127.76,127.14,66.31,66.10,50.82,50.57,50.17.MS(EI):221,188,134,130,91.
根据以上数据推断所得产物的结构:
实施例19
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔哌啶-2-甲酰胺和3毫升1,4-二氧六环,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为5:1的石油醚:乙酸乙酯混合溶剂,产率66%。
所得产物的结构表征数据如下:
1H NMR(400MHz,CDCl3)δ=7.50–7.07(m,5H),6.46(d,J=1.9Hz,1H),6.33(s,1H),6.14(d,J=28.6Hz,1H),4.46(d,J=15.2Hz,1H),4.34(d,J=15.2Hz,1H),4.13(d,J=13.4Hz,1H),3.10(td,J=13.4,2.6Hz,1H),2.27(d,J=14.1Hz,1H),1.91–1.43(m,4H),1.14–0.91(m,1H).氢谱图如图3所示。
13C NMR(101MHz,CDCl3)δ=201.68,171.66,135.76,128.96,127.81,127.16,59.97,50.68,48.73,25.56,25.15,19.69.
根据以上数据推断所得产物的结构:
实施例20
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔N-甲基苯胺和3毫升乙腈,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率96%。各反应物加入量放大20倍,产率为77%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.44–7.31(m,3H),7.24–7.13(m,3H),6.99(dt,J=5.4,4.2Hz,4H),4.02(s,2H),3.72(s,3H).
13C NMR(126MHz,CDCl3)δ=202.82,145.43,136.74,129.68,128.67,128.49,128.14,126.65,125.95,50.75,46.31.MS(EI):241,150,132,91,77.
根据以上数据推断所得产物的结构:
实施例21
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔N-甲基苯并[d]噻唑-6-胺和3毫升乙腈,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率43%。
所得产物的结构表征数据如下:
1H NMR(400MHz,CDCl3)δ=9.11(s,1H),7.93(d,J=8.5Hz,1H),7.81(s,1H),7.15(d,J=6.4Hz,3H),7.08(d,J=8.5Hz,1H),6.97(d,J=6.0Hz,2H),4.08(s,2H),3.81(s,3H).
13C NMR(101MHz,CDCl3)δ=203.32,156.33,153.77,143.80,136.58,133.79,128.58,128.21,126.78,123.48,122.87,121.09,50.93,46.63.MS(EI):298,250,207,192,132.
根据以上数据推断所得产物的结构:
实施例22
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.5毫摩尔4-(对甲苯基)-1,2,3-硫二唑、0.5毫摩尔N-甲基苯胺和3毫升乙腈,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率86%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.34(s,3H),7.10–6.93(m,4H),6.89(d,J=7.6Hz,2H),3.95(s,2H),3.70(s,3H),2.26(s,3H).
13C NMR(126MHz,CDCl3)δ=203.10,145.43,136.16,133.75,129.74,128.87,128.63,128.54,125.98,50.25,46.31,21.13.MS(EI):255,207,150,105,77.
根据以上数据推断所得产物的结构:
实施例23
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.5毫摩尔4-(4-甲氧基苯基)-1,2,3-硫二唑、0.5毫摩尔N-甲基苯胺和3毫升乙腈,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率84%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.36(d,J=4.8Hz,3H),7.00(d,J=6.9Hz,2H),6.91(d,J=8.0Hz,2H),6.70(d,J=7.9Hz,2H),3.94(s,2H),3.74(s,3H),3.70(s,3H).
13C NMR(126MHz,CDCl3)δ=203.25,158.37,145.40,129.74,129.71,128.78,128.52,125.97,113.53,55.21,49.81,46.31.MS(EI):271,198,150,121,109.
根据以上数据推断所得产物的结构:
实施例24
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.5毫摩尔4-(苯并[d][1,3]二氧杂环-5-基)-1,2,3-硫二唑、0.5毫摩尔N-甲基苯胺和3毫升乙腈,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率56%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.31(d,J=5.6Hz,3H),6.95(d,J=7.1Hz,2H),6.55(s,1H),6.52(d,J=7.9Hz,1H),6.25(d,J=7.9Hz,1H),5.82(s,2H),3.84(s,2H),3.64(s,3H).
13C NMR(126MHz,CDCl3)δ=202.89,147.35,146.29,145.38,130.35,129.72,128.57,125.95,121.90,109.20,107.85,100.87,50.19,46.33.MS(EI):285,178,150,109,77.
根据以上数据推断所得产物的结构:
实施例25
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.5毫摩尔4-(3-氟苯基)-1,2,3-硫二唑、0.5毫摩尔N-甲基苯胺和3毫升乙腈,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率81%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.36(d,J=1.5Hz,3H),7.11(dd,J=14.5,7.1Hz,1H),7.00(s,2H),6.85(t,J=8.4Hz,1H),6.75(d,J=7.5Hz,2H),4.00(s,2H),3.72(s,3H).
19F NMR(471MHz,CDCl3)δ=-113.42(s,1F).
13C NMR(126MHz,CDCl3)δ=201.74,162.54(d,J=245.4Hz),145.24,139.10(d,J=7.5Hz),129.80,129.51(d,J=8.3Hz),128.70,125.86,124.40(d,J=2.7Hz),115.59(d,J=22.0Hz),113.59(d,J=21.0Hz),50.33(d,J=1.3Hz),46.28.MS(EI):259,211,150,109,77.
根据以上数据推断所得产物的结构:
实施例26
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.5毫摩尔4-(4-氯苯基)-1,2,3-硫二唑、0.5毫摩尔N-甲基苯胺和3毫升乙腈,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率89%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.48(d,J=4.6Hz,1H),7.38(t,J=7.4Hz,2H),7.24(d,J=19.1Hz,1H),7.10(d,J=8.2Hz,2H),6.80(d,J=8.2Hz,2H),6.42(s,1H),5.12(q,J=7.8Hz,2H),3.72(s,3H).
13C NMR(126MHz,CDCl3)δ=205.31,143.71,138.92,133.96,129.86,129.07,128.71,128.36,126.80,73.44,46.91.
MS(EI):275,241,150,109,77.
根据以上数据推断所得产物的结构:
实施例27
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.5毫摩尔4-(4-溴苯基)-1,2,3-硫二唑、0.5毫摩尔N-甲基苯胺和3毫升乙腈,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率75%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.38(d,J=4.5Hz,3H),7.28(d,J=7.9Hz,2H),7.12–6.95(m,2H),6.88(d,J=7.9Hz,2H),3.94(s,2H),3.71(s,3H).
13C NMR(126MHz,CDCl3)δ=201.94,145.25,135.72,131.20,130.49,129.86,128.71,125.90,120.67,49.99,46.31.
MS(EI):321,319,210,169,171.
根据以上数据推断所得产物的结构:
实施例28
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.5毫摩尔4-(1,2,3-硫二唑-4-基)苯甲腈、0.5毫摩尔N-甲基苯胺和3毫升乙腈,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为12:1的石油醚:乙酸乙酯混合溶剂,产率67%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.60(s,1H),7.54(d,J=8.1Hz,2H),7.37(t,J=7.2Hz,2H),7.33(d,J=6.9Hz,1H),7.27(dd,J=12.4,7.8Hz,4H),4.90(s,2H),4.17(s,2H).
13C NMR(126MHz,CDCl3)δ=203.49,141.73,134.85,132.49,129.45,129.33,128.16,128.02,118.57,111.46,53.05,48.91.
MS(EI):266,134,116,91,65.
根据以上数据推断所得产物的结构:
实施例29
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.5毫摩尔4-环己基-1,2,3-硫二唑、0.5毫摩尔N-甲基苯胺和3毫升乙腈,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率73%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.39(dt,J=27.6,7.4Hz,3H),7.10(d,J=7.6Hz,2H),3.70(s,3H),2.35(d,J=7.0Hz,2H),2.12–1.92(m,1H),1.59(dd,J=31.5,11.0Hz,5H),1.16(d,J=12.7Hz,2H),1.08–0.87(m,1H),0.65(d,J=12.2Hz,2H).
13C NMR(126MHz,CDCl3)δ=205.26,145.70,129.85,128.37,125.95,50.65,45.95,39.49,32.72,26.19,26.13.
MS(EI):247,214,165,132,91.
根据以上数据推断所得产物的结构:
实施例30
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.5毫摩尔4-(叔丁基)-1,2,3-硫二唑、0.5毫摩尔N-甲基苯胺和3毫升乙腈,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率71%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.41(dd,J=24.4,6.7Hz,3H),7.17(d,J=7.0Hz,2H),3.75(s,3H),2.73(s,2H),0.94(s,9H).
13C NMR(126MHz,CDCl3)δ=205.26,145.70,129.85,128.37,125.95,50.65,45.95,39.49,32.72,26.19,26.13.
MS(EI):221,164,150,112,56.
根据以上数据推断所得产物的结构:
实施例31
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.5毫摩尔4-(1,2,3-硫二唑)-甲酸乙酯、0.5毫摩尔N-甲基苯胺和3毫升乙腈,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率74%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.43(dq,J=14.5,7.2Hz,3H),7.25(d,J=7.0Hz,2H),4.09(q,J=7.1Hz,2H),3.75(s,3H),3.67(s,2H),1.20(t,J=7.1Hz,3H).氢谱图如图4所示。
13C NMR(126MHz,CDCl3)δ=195.52,167.96,145.30,130.04,128.89,125.62,61.29,50.36,45.82,14.04.
MS(EI):237,208,192,128,100.
根据以上数据推断所得产物的结构:
实施例32
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔N-乙基苯胺和3毫升乙腈,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为5:1的石油醚:乙酸乙酯混合溶剂,产率63%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.37(d,J=4.9Hz,3H),7.18(s,3H),7.02(s,2H),6.98–6.87(m,2H),4.34(q,J=7.1Hz,2H),3.99(s,2H),1.26(t,J=7.1Hz,3H).
13C NMR(126MHz,CDCl3)δ=201.95,143.48,136.82,129.60,128.62,128.57,128.15,126.96,126.64,52.32,51.28,11.22.
MS(EI):255,146,118,91,77.
根据以上数据推断所得产物的结构:
实施例33
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔异丙基苯胺和3毫升乙腈,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率70%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.36(dt,J=23.0,7.3Hz,3H),7.17(d,J=1.8Hz,3H),7.01(s,2H),6.83(d,J=7.5Hz,2H),6.02(dt,J=13.4,6.7Hz,1H),3.94(s,2H),1.11(d,J=6.8Hz,6H).
13C NMR(126MHz,CDCl3)δ=201.98,139.12,136.90,128.97,128.76,128.54,128.12,126.58,53.64,51.88,20.16.
MS(EI):269,194,160,136,118.
根据以上数据推断所得产物的结构:
实施例34
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔N-苄基苯胺和3毫升乙腈,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率76%。
所得产物的结构表征数据如下:
1H NMR(500MHz,CDCl3)δ=7.37–7.25(m,8H),7.21(dd,J=9.3,5.6Hz,3H),7.06(dd,J=6.5,2.9Hz,2H),6.85–6.57(m,2H),5.62(s,2H),4.08(s,2H).
13C NMR(126MHz,CDCl3)δ=203.58,143.25,136.70,135.62,129.32,128.90,128.71,128.54,128.41,128.17,127.79,127.19,126.72,60.39,51.24.
MS(EI):317,284,208,167,123.
根据以上数据推断所得产物的结构:
实施例35
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.5毫摩尔1,3-二(1,2,3-硫二唑-4-基)苯、1毫摩尔N-甲基苯胺和6毫升乙腈,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为5:1的石油醚:乙酸乙酯混合溶剂,产率54%。
所得产物的结构表征数据如下:
1H NMR(400MHz,CDCl3)δ=7.36(s,6H),7.02(d,J=18.4Hz,5H),6.82(d,J=7.4Hz,2H),6.71(s,1H),3.92(s,4H),3.74(s,6H).氢谱图如图5所示。
13C NMR(101MHz,CDCl3)δ=202.72,145.37,136.78,129.74,128.81,128.50,127.91,127.04,125.97,50.41,46.27.
MS(EI):221,164,150,112,91.
根据以上数据推断所得产物的结构:
实施例36
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔甘氨酸甲酯和3毫升四氢呋喃,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率53%。
所得产物的结构表征数据如下:
1H NMR(400MHz,CDCl3)δ=7.64(s,1H),7.52–6.99(m,5H),4.37(d,J=4.6Hz,2H),4.18(s,2H),3.76(s,3H).
13C NMR(101MHz,CDCl3)δ=202.89,169.15,134.72,129.50,129.24,127.92,52.74,52.66,47.24.
MS(EI):223,134,91,72,51.
根据以上数据推断所得产物的结构:
实施例37
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔L-缬氨酸甲酯和3毫升四氢呋喃,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率57%。
所得产物的结构表征数据如下:
1H NMR(400MHz,CDCl3)δ=7.55(s,1H),7.40(t,J=7.3Hz,2H),7.32(dd,J=16.9,6.9Hz,3H),5.10(dd,J=8.2,4.7Hz,1H),4.16(q,J=16.3Hz,2H),3.72(s,3H),2.27(dq,J=13.7,6.8Hz,1H),0.98–0.70(m,6H).氢谱图如图6所示。
13C NMR(101MHz,CDCl3)δ=202.86,171.12,134.88,129.43,129.23,127.91,62.61,53.21,52.29,30.84,18.40,18.28.
MS(EI):265,232,206,134,115.
根据以上数据推断所得产物的结构:
实施例38
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔L-苯丙氨酸甲酯和3毫升四氢呋喃,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率52%。
所得产物的结构表征数据如下:
1H NMR(400MHz,CDCl3)δ=7.44(s,1H),7.35(dd,J=5.9,5.4Hz,3H),7.21(dd,J=10.3,4.9Hz,5H),6.96–6.55(m,2H),5.40(dt,J=7.3,5.4Hz,1H),4.13(dd,J=38.0,16.2Hz,2H),3.74(s,3H),3.34(dd,J=14.0,5.6Hz,1H),3.11(dd,J=14.0,5.1Hz,1H).氢谱图如图7所示。
13C NMR(101MHz,CDCl3)δ=202.04,170.92,135.08,134.49,129.49,129.20,129.07,128.62,127.87,127.18,58.33,53.17,52.50,36.03.
MS(EI):313,280,254,180,162.
根据以上数据推断所得产物的结构:
实施例39
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔L-脯氨酸乙酯和3毫升1,4-二氧六环,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率68%。
所得产物的结构表征数据如下:
1H NMR(400MHz,CDCl3)δ=7.67–6.83(m,5H),5.00(dd,J=9.0,2.8Hz,1H),4.42–4.02(m,4H),3.81–3.45(m,2H),2.49–2.13(m,1H),2.13–1.84(m,3H),1.26(t,J=7.1Hz,3H).氢谱图如图8所示。
13C NMR(101MHz,CDCl3)δ=199.18,170.35,135.36,128.69,128.36,126.89,65.77,61.29,51.46,51.09,29.40,25.07,14.16.MS(EI):277,244,204,144,91.
根据以上数据推断所得产物的结构:
实施例40
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔D-酪氨酸甲酯和3毫升四氢呋喃,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为10:1的石油醚:乙酸乙酯混合溶剂,产率82%。
所得产物的结构表征数据如下:
1H NMR(400MHz,CDCl3)δ=7.48(d,J=6.2Hz,1H),7.43–7.28(m,3H),7.20(d,J=7.5Hz,2H),6.72–6.50(m,4H),5.91(s,1H),5.35(dd,J=12.7,5.4Hz,1H),4.11(dd,J=41.7,16.2Hz,2H),3.75(d,J=7.1Hz,3H),3.23(dd,J=14.2,5.5Hz,1H),3.03(dd,J=14.2,5.2Hz,1H).氢谱图如图9所示。
13C NMR(101MHz,CDCl3)δ=202.30,171.26,155.06,134.43,130.21,129.51,129.23,127.90,126.66,115.65,58.57,53.04,52.63,35.30.
根据以上数据推断所得产物的结构:
实施例41
在氮气保护下,向反应容器中依次加入0.05毫摩尔乙酸铜、0.05毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、0.5毫摩尔4-苯基-1,2,3-硫二唑、0.5毫摩尔L-色氨酸甲酯和3毫升四氢呋喃,于90℃下搅拌反应24h,停止加热和搅拌,冷却至室温。将反应液用饱和食盐水水洗、乙酸乙酯萃取,合并有机相,使用无水硫酸镁干燥,过滤,减压蒸馏蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为5:1的石油醚:乙酸乙酯混合溶剂,产率63%。
所得产物的结构表征数据如下:
1H NMR(400MHz,CDCl3)δ=8.18(s,1H),7.54(d,J=6.4Hz,1H),7.48(d,J=7.9Hz,1H),7.36(d,J=8.1Hz,1H),7.31–7.18(m,4H),7.14(t,J=7.4Hz,1H),7.10–6.92(m,2H),6.58(d,J=1.8Hz,1H),5.44(dd,J=12.4,5.2Hz,1H),4.07(s,2H),3.69(d,J=6.4Hz,3H),3.64–3.48(m,1H),3.34(dd,J=14.9,4.8Hz,1H).氢谱图如图10所示。
13C NMR(101MHz,CDCl3)δ=202.12,171.35,136.06,134.60,129.48,129.04,127.68,127.50,122.77,122.33,119.82,118.48,111.34,109.13,58.29,53.08,52.61,25.92.
根据以上数据推断所得产物的结构:
本发明中当胺类化合物为N-烷基苯胺类化合物或N-苄基苯胺类化合物(即R2、R3都不为氢且R3为烷基或苄基)时,制备方法中选用铜盐催化剂,无需配体,此时有机溶剂优选为乙腈;当胺类化合物中R2为氢或胺类化合物为氨基酸烷基酯、环胺化合物时,制备方法中选用铜盐催化剂和膦配体。
当胺类化合物中R2为氢,R3为苄基、苯环上取代的苄基、苯基、取代的苯基、萘基甲基、2-丙炔基、1-茚满基、2-(3-吲哚基)乙基、1-苯基乙基时,制备方法中,有机溶剂优选为DMF。
当胺类化合物为烷基胺时,选用醋酸铜与膦配体以及四氢呋喃或者1,4-二氧六环类醚溶剂,产物收率高。
本发明的方法中醋酸铜类是最优催化剂,其余铜催化剂如氯化铜,氯化亚铜,硫酸铜,乙酰丙酮铜等常见铜催化剂均无法催化反应得到目标产物。但是向体系中加入乙酸钠提供醋酸阴离子,则部分上述铜盐也可催化该反应,但是效果不佳。这说明铜盐与醋酸根离子对于该反应是至关重要的。当然,除了催化剂之外,配体对该反应也具有至关重要的作用,但是对于N-烷基苯胺类化合物,即使不加配体,反应也可顺利的发生,这可能跟物质本身性质有关。以苯胺与4-苯基-1,2,3-硫二唑为例,反应的条件为:0.1mmol苯胺,0.1mmol的4-苯基-1,2,3-硫二唑,0.01mmol的醋酸铜,0.01mmol的膦配体(4,5-双二苯基膦-9,9-二甲基氧杂蒽),0.5mL的溶剂DMF,温度为90℃,反应时间为8h。考察反应温度:反应温度过低如:室温下,该反应不发生;反应温度为60℃时,GC测得的产率为55%;90℃时,产率为95%。考察催化剂:采用乙酰丙酮铜和醋酸钠替代醋酸铜,产率为28%;无醋酸铜,产率为0。考察配体:不用配体,反应不发生;选用三苯基膦替代膦配体,产率为47%。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其它的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (8)
1.一种铜催化的1,2,3-硫二唑化合物与胺合成硫代酰胺化合物的方法,其特征在于:包括如下步骤:在保护性氛围下,以有机溶剂为反应介质,将1,2,3-硫二唑化合物与胺类化合物在铜盐催化剂或铜盐催化剂和膦配体的作用下反应,后续处理,获得硫代酰胺化合物;
所述R1为取代或未取代的芳基、烷基、环烷基、-COOR,R为烷基、苯并呋喃基;
当R2为氢时,R3为苄基、苯环上取代的苄基、苯基、取代的苯基、萘基甲基、2-丙炔基、1-茚满基、2-(3-吲哚基)乙基、1-苯基乙基、烷基;苯环上取代的苄基中取代基为烷氧基、氟取代的烷氧基、氰基、卤素,取代的苯基中取代基为烷氧基、乙酰基、卤素、乙炔基、氟取代的烷基;
当R2为苯基、4-氯苯基、5-苯并[d]噻唑基时,R3为烷基或苄基;
或者胺类化合物为氨基酸烷基酯、环胺化合物或烷基胺;
所述铜盐为乙酸铜、[1,3-双(二苯基膦基)丙烷]乙酸铜、[1,4-双(二苯基膦基)丁烷]乙酸铜、[1,1’-双(二苯基膦基)二茂铁]乙酸铜中的一种以上;
所述膦配体为4,5-双二苯基膦-9,9-二甲基氧杂蒽、1,3-双(二苯基膦)丙烷、2,2'-双二苯膦基-1,1'-联萘、1,4-双(二苯基膦基)丁烷、1,1'-双(二苯基膦)二茂铁、2-(二环己基膦)-3,6-二甲氧基-2'-4'-6'-三-I-丙基-11'-联苯、三苯基膦、三环己基膦中的一种以上;
当胺类化合物中R2为苯基、4-氯苯基、5-苯并[d]噻唑基,R3为烷基或苄基时,所述反应在铜盐催化剂的作用下进行;
当胺类化合物中R2为氢,R3为苄基、苯环上取代的苄基、苯基、取代的苯基、萘基甲基、2-丙炔基、1-茚满基、2-(3-吲哚基)乙基、1-苯基乙基、烷基;苯环上取代的苄基中取代基为烷氧基、氟取代的烷氧基、氰基、卤素,取代的苯基中取代基为烷氧基、乙酰基、卤素、乙炔基、氟取代的烷基时,所述反应在铜盐催化剂和膦配体的作用下进行;
胺类化合物为氨基酸烷基酯、环胺化合物或烷基胺时,所述反应在铜盐催化剂和膦配体的作用下进行;
所述反应的温度为50~95℃。
所述取代的苯基为烷基取代的苯基、烷氧基取代的苯基、卤素取代的苯基;
当R2为氢时,R3为苄基、4-甲氧基苄基、4-三氟甲氧基苄基、4-氰基苄基、4-溴苄基、3-氯-4-氟苄基、萘-1-基甲基、2-丙炔基、1-茚满基、2-(3-吲哚基)乙基、苯基、2-甲氧基苯基、4-乙酰基苯基、2-氟苯基、4-三氟甲基苯基、3-乙炔基苯基、1-苯基乙基;
当R2为苯基、4-氯苯基、5-苯并[d]噻唑基时,R3为烷基或苄基;其中烷基为C1~5烷基;
所述氨基酸烷基酯为甘氨酸甲酯、L-缬氨酸甲酯、L-苯丙氨酸甲酯、L-脯氨酸乙酯、D-酪氨酸甲酯、L-色氨酸甲酯;所述环胺化合物为吗啉、吲哚、哌啶-2-甲酰胺。
3.根据权利要求2所述铜催化的1,2,3-硫二唑化合物与胺合成硫代酰胺化合物的方法,其特征在于:
所述R1为苯基、4-甲基苯基、4-甲氧基苯基、3-氟苯基、4-氯苯基、4-溴苯基、4-氰基苯基、环己基、叔丁基、乙酯基、4-(1,2-亚甲基二氧基)苯基、2-苯并呋喃基;
当R2为苯基、4-氯苯基、5-苯并[d]噻唑基时,R3为甲基、乙基、异丙基、苄基。
4.根据权利要求1所述铜催化的1,2,3-硫二唑化合物与胺合成硫代酰胺化合物的方法,其特征在于:所述膦配体为4,5-双二苯基膦-9,9-二甲基氧杂蒽。
5.根据权利要求1所述铜催化的1,2,3-硫二唑化合物与胺合成硫代酰胺化合物的方法,其特征在于:反应的时间为4~26小时;
所述有机溶剂为乙腈、N,N-二甲基甲酰胺、四氢呋喃、1,4-二氧六环中一种以上。
6.根据权利要求1所述铜催化的1,2,3-硫二唑化合物与胺合成硫代酰胺化合物的方法,其特征在于:所述胺类化合物与1,2,3-硫二唑化合物的反应摩尔比为(0.5~3):1;所述铜盐与1,2,3-硫二唑化合物的摩尔比为(0.05~0.2):1;所述膦配体与1,2,3-硫二唑化合物的摩尔比为(0.05~0.2):1。
7.根据权利要求1所述铜催化的1,2,3-硫二唑化合物与胺合成硫代酰胺化合物的方法,其特征在于:所述保护性氛围为氮气或惰性气体;
所述后续处理是指淬灭反应,乙酸乙酯萃取,去除有机相中溶剂,柱层析分离;所述去除有机相中溶剂是指去除有机相中水,去除有机溶剂。
8.根据权利要求7所述铜催化的1,2,3-硫二唑化合物与胺合成硫代酰胺化合物的方法,其特征在于:所述淬灭反应是指向反应体系中加入饱和氯化钠溶液;所述去除有机相中水是指采用干燥剂进行干燥,干燥剂为无水硫酸镁,然后过滤;所述去除有机相中有机溶剂是指减压蒸馏去除有机溶剂;
所述柱层析的洗脱液为石油醚和乙酸乙酯的混合溶剂,石油醚和乙酸乙酯的体积比20:1-5:1。
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