CN106187922B - 一种叔丁醇钠催化烯胺酮和磺酰叠氮环加成反应合成1,4-二取代-1,2,3-三氮唑的方法 - Google Patents
一种叔丁醇钠催化烯胺酮和磺酰叠氮环加成反应合成1,4-二取代-1,2,3-三氮唑的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 21
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 title claims abstract description 20
- -1 1, 4-disubstituted-1, 2, 3-triazole Chemical class 0.000 title claims abstract description 15
- HSVFKFNNMLUVEY-UHFFFAOYSA-N sulfuryl diazide Chemical compound [N-]=[N+]=NS(=O)(=O)N=[N+]=[N-] HSVFKFNNMLUVEY-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 238000006352 cycloaddition reaction Methods 0.000 title claims abstract description 9
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 9
- 238000006555 catalytic reaction Methods 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims abstract description 4
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 4
- 239000003054 catalyst Substances 0.000 claims abstract 2
- 238000011065 in-situ storage Methods 0.000 claims abstract 2
- 239000002994 raw material Substances 0.000 abstract description 4
- 229910021578 Iron(III) chloride Inorganic materials 0.000 abstract description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 150000001540 azides Chemical class 0.000 abstract 1
- 229910052751 metal Inorganic materials 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- 230000035484 reaction time Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 3
- 238000010504 bond cleavage reaction Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 150000000177 1,2,3-triazoles Chemical class 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
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Abstract
一种叔丁醇钠催化烯胺酮和叠氮环加成反应合成1,4‑二取代‑1,2,3‑三氮唑的方法。方法为采用N,N‑二甲基烯胺酮、伯胺和磺酰叠氮为原料，通过原位生成含NH结构的烯胺酮，随后在叔丁醇钠催化下，室温搅拌两小时即可高产率得到1,4‑二取代的1,2,3‑三氮唑类化合物，产物通过硅胶柱层析提纯。该方法的优点在于：1、反应条件温和，室温就可顺利实现；2、反应时间短，两步共四小时即可完成；3、原料绿色廉价，第一步操作使用的氯化铁为环境友好型催化剂，第二步反应无需金属，比大多数合成类似化合物的方法更加绿色；4、整体操作简单，适合放大生产。
Description
技术领域
本发明涉及一种叔丁醇钠催化烯胺酮和磺酰叠氮环加成反应合成1,4-二取代-1,2,3-三氮唑的方法。
背景技术
1,2,3-三氮唑类是常见的杂环化合物基本结构，这类杂环结构在生物医药、材料、化工中间体等许多领域具有重要的应用价值。在Sharpless等通过铜催化叠氮类化合物和炔直接进行环加成反应合成1,2,3-三氮唑并基于该反应提出“点击化学(clickchemistry)”的概念以来，这类化合物的合成和应用研究更是取得了前所未有的进展。目前合成1,2,3-三氮唑的方法除了铜催化的click环加成反应外，其它过渡金属如铑、钌、铱等也可用于催化这类环加成反应合成1,2,3-三氮唑类化合物。随着当前对可持续发展的日益重视，采用无过渡金属催化的方法合成1,2,3-三氮唑类化合物成为了广受关注的新课题，在过去的几年时间里，许多实用的无金属催化方法成功发展并报道出来。在众多已知的报道中，采用磺酰叠氮为氮源是一种使用较为广泛使用的有效方法，例如，文献曾报道烯胺酮和磺酰叠氮在碱促进条件下通过磺酰叠氮中的N-N键断裂和烯胺酮中的羰基和α-碳之间的碳-碳键断裂反应生成1,5-二取代1,2,3-三氮唑的方法(Angew.Chem.Int.Ed.2013,52,13265-13268)。有趣的是，通过烯胺酮和磺酰叠氮中的N-N键断裂反应合成1,4-二取代1,2,3-三氮唑的方法尚无报道。本方法通过叔丁醇钠促进的方法实现了磺酰叠氮N-N键断裂和烯胺酮反应生成1,4-二取代1,2,3-三氮唑的合成。反应条件温和、原料简单、产率优秀，在有机合成工业以及其它相关领域具有重要的应用前景。
发明内容
本发明目的在于提供烯胺酮和磺酰叠氮环加成反应合成1,4-二取代-1,2,3-三氮唑的方法。该反应方法条件温和，反应效率高，处理简单；所得产物在合成化学、化学生物学等领域具有较好的应用前景。
本发明是这样实现的，将N,N-二甲基取代的氨基烯胺酮1(0.3mmol),伯胺2(0.4mmol)和FeCl3(0.15mmol)置于25mL干燥的圆底烧瓶，加入2mL乙腈，室温搅拌2小时。随后加入磺酰叠氮3(0.4mmol)和叔丁醇钠(0.45mmol)，继续室温搅拌2小时。反应结束，烧瓶中加入5mL水，所得混合物以乙酸乙酯萃取(3×8mL)，合并有机相并以无水硫酸镁干燥，过滤，减压除去滤液中的溶剂，剩余物以硅胶柱色谱在乙酸乙酯：石油醚(6:1)混合物淋洗下提纯得到目标产物4。
本发明的技术效果是：1、原料廉价易得，合成条件温和；2、选择型生成1,4-二取代产物；3、对环境友好，所得产物在有机合成化学、化学生物学等领域有广泛应用前景，适用于大规模生产。
附图说明
图1为本发明中反应方程和产物结构等信息，
图2为本发明中产物4a的核磁共振氢谱，
图3为本发明中产物4a的核磁共振碳谱，
图4为本发明中产物4b的核磁共振氢谱，
图5为本发明中产物4b的核磁共振碳谱，
图6为本发明中产物4c的核磁共振氢谱，
图7为本发明中产物4c的核磁共振碳谱，
图8为本发明中产物4d的核磁共振氢谱，
图9为本发明中产物4d的核磁共振碳谱，
图10为本发明中产物4a的单晶结构图。
具体实施方式
本发明是这样实现的，将N,N-二甲基取代的氨基烯胺酮1(0.3mmol),伯胺2(0.4mmol)和FeCl3(0.15mmol)置于25mL干燥的圆底烧瓶，然后加入2mL乙腈，室温搅拌2小时。随后加入磺酰叠氮3(0.4mmol)和叔丁醇钠(0.45mmol)，继续室温搅拌2小时。反应结束，烧瓶中加入5mL水，所得混合物以乙酸乙酯萃取(3×8mL)，合并有机相并以无水硫酸镁干燥。过滤，减压出去滤液中的溶剂，剩余物以硅胶柱色谱在乙酸乙酯：石油醚(6:1)混合物淋洗下提纯得到目标产物4。所有产物结构和纯度经过核磁共振、高分辨质谱和单晶衍射等光谱分析方法确证无误。
如图2、图3、图4、图5、图6、图7、图8、图9、图10所示，各产物表征和数据分别为：
(4a)1H NMR(400MHz,CDCl3):δ8.73(s,1H),8.48(d,J＝7.6Hz,2H),7.81(d,J＝7.6Hz,2H),7.63(t,J＝7.6Hz,1H),7.59-7.47(m,5H)；13C NMR(100MHz,CDCl3):185.6,148.6,136.5,136.4,133.4,130.7,130.0,129.5,128.5,126.4,120.8.ESI-HRMS:Calcdfor C15H12N3O[M+H]+:250.0975；Found:250.0982.
(4b)1H NMR(400MHz,CDCl3):δ8.68(s,1H),8.48(d,J＝7.2Hz,2H),7.69-7.61(m,3H),7.54(t,J＝7.6Hz,2H),7.35(d,J＝8.0Hz,2H),2.43(s,3H)；13C NMR(100MHz,CDCl3):δ185.6,148.5,139.8,136.5,134.1,133.4,130.7,130.5,128.4,126.3,120.7,21.2.ESI-HRMS:Calcd for C16H14N3O[M+H]+:264.1131；Found:264.1132.
(4c)1H NMR(400MHz,CDCl3):δ8.63(s,1H),8.47(d,J＝6.8Hz,2H),7.70(d,J＝9.6Hz,2H),7.64(t,J＝7.6Hz,1H),7.53(t,J＝7.6Hz,2H),7.04(d,J＝8.8Hz,2H),3.87(s,3H)；13C NMR(100MHz,CDCl3):δ185.6,160.4,148.4,136.5,133.4,130.6,129.7,128.4,126.4,122.4,115.0,55.7.ESI-HRMS:Calcd for C16H14N3O2[M+H]+:280.1081；Found:280.1085.
(4d)1H NMR(400MHz,CDCl3):δ8.80(d,J＝3.6Hz,1H),8.67(s,1H),7.78(d,J＝4.4Hz,1H),7.68(d,J＝8.0Hz,2H),7.36(d,J＝7.6Hz,2H),7.27-7.23(m,1H),2.44(s,3H)；13C NMR(100MHz,CDCl3):δ177.2,148.0,142.3,139.8,136.4,135.2,134.1,130.5,128.5,125.6,120.6,21.1.ESI-HRMS:Calcd for C14H12N3OS[M+H]+:270.0696；Found:270.0707.
Claims (1)
1.一种叔丁醇钠催化烯胺酮和磺酰叠氮环加成反应合成1,4-二取代-1,2,3-三氮唑的方法，其特征是采用N,N-二甲基取代的烯胺酮1和伯胺2在50mol％当量的FeCl3催化剂、室温搅拌条件下原位生成含NH结构的烯胺酮I，随后加入磺酰叠氮和1.5摩尔当量的叔丁醇钠作为促进剂，在室温继续搅拌2小时，得到1,4-二取代-1,2,3-三氮唑，最后通过硅胶柱层析提纯目标产物4a-4d；
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