CN115583958A - 二氢噻(噁)唑[3’,2’:1,5]二氢咪唑[4,5-b]哌啶衍生物的合成方法 - Google Patents
二氢噻(噁)唑[3’,2’:1,5]二氢咪唑[4,5-b]哌啶衍生物的合成方法 Download PDFInfo
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- 150000003053 piperidines Chemical class 0.000 title claims abstract description 17
- LWTIGYSPAXKMDG-UHFFFAOYSA-N 2,3-dihydro-1h-imidazole Chemical compound C1NC=CN1 LWTIGYSPAXKMDG-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 7
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 6
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 44
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims description 25
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 25
- 229910020366 ClO 4 Inorganic materials 0.000 claims description 20
- 239000012298 atmosphere Substances 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 6
- -1 saturated cyclic amine Chemical class 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- GCBNIIKPVIHBGR-UHFFFAOYSA-N 1,3-oxazole Chemical compound C1=COC=N1.C1=COC=N1 GCBNIIKPVIHBGR-UHFFFAOYSA-N 0.000 claims description 3
- 229940125904 compound 1 Drugs 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
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- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000003003 spiro group Chemical group 0.000 abstract description 4
- 230000008635 plant growth Effects 0.000 abstract description 3
- 230000001105 regulatory effect Effects 0.000 abstract description 3
- 239000003054 catalyst Substances 0.000 abstract description 2
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- 229910052751 metal Inorganic materials 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract description 2
- 239000005648 plant growth regulator Substances 0.000 abstract description 2
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
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- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 13
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229930014626 natural product Natural products 0.000 description 3
- 241000534944 Thia Species 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
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- 229910052755 nonmetal Inorganic materials 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- AIAJYBLPGVBVSS-UHFFFAOYSA-N 4,5,6,7-tetrahydro-1h-imidazo[4,5-b]pyridine Chemical class C1CCNC2=C1NC=N2 AIAJYBLPGVBVSS-UHFFFAOYSA-N 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
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- 239000012038 nucleophile Substances 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
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- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
- C07D513/20—Spiro-condensed systems
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/10—Spiro-condensed systems
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Abstract
本发明公开了一种二氢噻(噁)唑[3',2':1,5]二氢咪唑[4,5‑b]哌啶衍生物的合成方法，属于有机合成技术领域。本发明的技术方案要点为：
Description
技术领域
本发明属于有机合成技术领域，具体涉及一种二氢噻(噁)唑[3’,2’:1,5]二氢咪唑[4,5-b]哌啶衍生物的合成方法。
背景技术
二氢噻(噁)唑[3’,2’:1,5]二氢咪唑[4,5-b]哌啶衍生物作为一类结构复杂的螺环生物碱，其广泛存在于天然产物以及具有生物活性的化合物中，在抑制细菌生长、植物生长调节以及促进血管扩张等方面具有显著的生物活性。目前，该类化合物主要是通过从天然产物中提取的方式获得，存在的问题是分离过程复杂、产量相对较低且成本相对较高，这些不足之处也使得其进一步推广应用受到很大限制。有鉴于此，进一步研究并开发二氢噻(噁)唑[3’,2’:1,5]二氢咪唑[4,5-b]哌啶衍生物的简捷、绿色合成方法具有重要的理论意义和应用价值。
发明内容
本发明解决的技术问题是提供了一种二氢噻(噁)唑[3’,2’:1,5]二氢咪唑[4,5-b]哌啶衍生物的合成方法，该方法通过非金属氧铵盐促进N-芳基取代饱和环胺类化合物与氰酸盐/硫氰酸盐以及1,3-N,S-双亲核试剂/1,3-N,O-双亲核试剂的多组分串联反应合成二氢噻(噁)唑[3’,2’:1,5]二氢咪唑[4,5-b]哌啶衍生物，具有操作简便、无需过渡金属催化、反应条件绿色温和、底物适用范围广等优点，适合于工业化。
本发明为解决上述技术问题采用如下技术方案，二氢噻(噁)唑[3’,2’:1,5]二氢咪唑[4,5-b]哌啶衍生物的合成方法，其特征在于具体步骤为：将N-芳基取代饱和环胺类化合物1、氰酸盐/硫氰酸盐2以及双亲核试剂3溶于反应溶剂中，再加入氧铵盐T+Y-，在空气气氛下于0-50℃反应制得目标产物二氢噻(噁)唑[3’,2’:1,5]二氢咪唑[4,5-b]哌啶衍生物4，合成过程中的反应方程式为：
其中R1为苯基或取代苯基，该取代苯基苯环上的取代基为氟、氯、溴、碘、C1-4烷基、C1-4烷氧基、酯基、氰基、三氟甲基或硝基；R2为氢、酯基或苄基；Y-为BF4 -、ClO4 -、PF6 -或OTf-。
进一步优选，所述反应溶剂为乙醇。
进一步优选，所述N-芳基取代饱和环胺类化合物1、氰酸盐/硫氰酸盐2、双亲核试剂3与氧铵盐T+Y-的投料物质的量之比为1:1-3:1-3:2-4。
本发明与现有技术相比具有以下优点：(1)本发明通过非金属氧铵盐促进N-芳基取代饱和环胺类化合物与氰酸盐/硫氰酸盐以及双亲核试剂的多组分串联反应，直接合成二氢噻(噁)唑[3’,2’:1,5]二氢咪唑[4,5-b]哌啶衍生物，该反应直接构建出螺环结构单元，整个过程操作简单、效率较高；(2)本发明反应原料简单易得，合成过程无需使用任何金属催化剂，具有经济、绿色、对环境友好的特点，并且底物的适用范围广；(3)本发明制备的二氢噻(噁)唑[3’,2’:1,5]二氢咪唑[4,5-b]哌啶衍生物具有较好的植物生长调节作用，有望取代目前常规的天然螺环生物碱植物生长调节剂，故具有较好的产业化推广应用价值。因此，本发明为二氢噻(噁)唑[3’,2’:1,5]二氢咪唑[4,5-b]哌啶衍生物的合成提供了一种经济实用的新方法。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例1
在反应管中依次加入1a(0.2mmol,32mg)，乙醇(1mL)，T+ClO4 -(0.6mmol,153mg)，硫氰酸盐2a(0.3mmol,29mg)和双亲核试剂3a(0.3mmol,34mg)，在空气气氛下于25℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得黄色固体产物4a(45mg,77％)。该化合物的表征数据如下：mp 193-194℃.1H NMR(400MHz,CDCl3):δ7.30-7.26(m,2H),6.93-6.88(m,4H),5.87(s,1H),4.96-4.92(m,1H),3.37-3.31(m,1H),3.27-3.17(m,2H),3.10-2.97(m,2H),2.04-1.95(m,3H),1.88-1.83(m,1H).13C{1H}NMR(150MHz,CDCl3):δ186.8,148.2,129.7,120.8,116.4,78.8,77.9,48.5,38.7,32.1,31.3,19.3.MS:m/z 292[M+H]+。
实施例2
在反应管中依次加入1a(0.2mmol,32mg)，乙醇(1mL)，T+BF4 -(0.6mmol,146mg)，硫氰酸盐2a(0.3mmol,29mg)和双亲核试剂3a(0.3mmol,34mg)，在空气气氛下于25℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得黄色固体产物4a(34mg,58％)。
实施例3
在反应管中依次加入1a(0.2mmol,32mg)，乙醇(1mL)，T+PF6 -(0.6mmol,181mg)，硫氰酸盐2a(0.3mmol,29mg)和双亲核试剂3a(0.3mmol,34mg)，在空气气氛下于25℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得黄色固体产物4a(31mg,53％)。
实施例4
在反应管中依次加入1a(0.2mmol,32mg)，乙醇(1mL)，T+ClO4 -(0.6mmol,153mg)，硫氰酸盐2a(0.6mmol,58mg)和双亲核试剂3a(0.3mmol,34mg)，在空气气氛下于25℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得黄色固体产物4a(33mg,56％)。
实施例5
在反应管中依次加入1a(0.2mmol,32mg)，乙醇(1mL)，T+ClO4 -(0.6mmol,153mg)，硫氰酸盐2a(0.3mmol,29mg)和双亲核试剂3a(0.6mmol,68mg)，在空气气氛下于25℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得黄色固体产物4a(26mg,44％)。
实施例6
在反应管中依次加入1a(0.2mmol,32mg)，乙醇(1mL)，T+ClO4 -(0.4mmol,102mg)，硫氰酸盐2a(0.3mmol,29mg)和双亲核试剂3a(0.3mmol,34mg)，在空气气氛下于25℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得黄色固体产物4a(34mg,58％)。
实施例7
在反应管中依次加入1a(0.2mmol,32mg)，乙醇(1mL)，T+ClO4 -(0.8mmol,204mg)，硫氰酸盐2a(0.3mmol,29mg)和双亲核试剂3a(0.3mmol,34mg)，在空气气氛下于25℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得黄色固体产物4a(38mg,66％)。
实施例8
在反应管中依次加入1a(0.2mmol,32mg)，乙醇(1mL)，T+ClO4 -(0.6mmol,153mg)，硫氰酸盐2a(0.3mmol,29mg)和双亲核试剂3a(0.3mmol,34mg)，在空气气氛下于50℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得黄色固体产物4a(27mg,46％)。
实施例9
在反应管中依次加入1b(0.2mmol,39mg)，乙醇(1mL)，T+ClO4 -(0.6mmol,153mg)，硫氰酸盐2a(0.3mmol,29mg)和双亲核试剂3a(0.3mmol,34mg)，在空气气氛下于25℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得黄色固体产物4b(49mg,76％)。mp 119-120℃.1H NMR(400MHz,CDCl3):δ7.25-7.22(m,2H),6.84-6.80(m,2H),6.74(br s,1H),5.82(s,1H),4.97-4.92(m,1H),3.31-2.98(m,5H),2.05-1.85(m,4H).13C{1H}NMR(150MHz,CDCl3):δ186.9,146.8,129.5,125.8,117.6,78.7,77.8,48.5,38.9,32.1,31.3,19.1.MS:m/z 326[M+H]+。
实施例10
在反应管中依次加入1c(0.2mmol,57mg)，乙醇(1mL)，T+ClO4 -(0.6mmol,153mg)，硫氰酸盐2a(0.3mmol,29mg)和双亲核试剂3a(0.3mmol,34mg)，在空气气氛下于25℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得黄色固体产物4c(59mg,71％)。mp 178-179℃.1H NMR(400MHz,CDCl3):δ7.55(dd,J1＝7.2Hz,J2＝2.4Hz,2H),6.66(dd,J1＝6.8Hz,J2＝2.0Hz,2H),6.58(br s,1H),5.83(s,1H),4.98-4.93(m,1H),3.30-2.99(m,5H),2.05-1.88(m,4H).13C{1H}NMR(150MHz,CDCl3):δ186.9,147.9,138.4,118.1,82.7,78.7,77.3,48.5,38.8,32.2,31.3,19.1.MS:m/z 418[M+H]+。
实施例11
在反应管中依次加入1d(0.2mmol,37mg)，乙醇(1mL)，T+ClO4 -(0.6mmol,153mg)，硫氰酸盐2a(0.3mmol,29mg)和双亲核试剂3a(0.3mmol,34mg)，在空气气氛下于25℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得黄色固体产物4d(47mg,75％)。mp 224-225℃.1H NMR(400MHz,DMSO-d6):δ9.85(s,1H),7.64-7.60(m,2H),7.09(dd,J1＝7.6Hz,J2＝2.8Hz,2H),5.88(s,1H),4.75-4.70(m,1H),3.62-3.57(m,1H),3.32-3.25(m,1H),3.09-3.01(m,2H),2.89-2.82(m,1H),2.14-2.09(m,1H),2.01-1.96(m,1H),1.82-1.66(m,2H).13C{1H}NMR(150MHz,DMSO-d6):δ187.5,151.8,133.9,120.3,115.1,99.9,79.4,75.1,48.2,37.9,31.1,30.9,19.2.MS:m/z 317[M+H]+。
实施例12
在反应管中依次加入1e(0.2mmol,46mg)，乙醇(1mL)，T+ClO4 -(0.6mmol,153mg)，硫氰酸盐2a(0.3mmol,29mg)和双亲核试剂3a(0.3mmol,34mg)，在空气气氛下于25℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得黄色固体产物4e(32mg,45％)。mp 217-218℃.1H NMR(400MHz,CDCl3):δ7.52(d,J＝8.4Hz,2H),7.41(br s,1H),6.92(d,J＝8.4Hz,2H),5.95(s,1H),4.95-4.90(m,1H),3.46-3.41(m,1H),3.29-3.21(m,2H),3.10-2.98(m,2H),2.09-1.90(m,4H).13C{1H}NMR(150MHz,CDCl3):δ186.8,150.6,127.0(q,4JC-F＝3.3Hz),124.4(q,1JC-F＝269.1Hz),123.5(q,2JC-F＝32.9Hz),114.6,78.7,76.6,48.5,39.1,32.4,31.4,19.1.19F{1H}NMR(CDCl3,376MHz):δ-61.5.MS:m/z 360[M+H]+。
实施例13
在反应管中依次加入1f(0.2mmol,48mg)，乙醇(1mL)，T+ClO4 -(0.6mmol,153mg)，硫氰酸盐2a(0.3mmol,29mg)和双亲核试剂3a(0.3mmol,34mg)，在空气气氛下于25℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得黄色固体产物4f(55mg,74％)。mp 192-193℃.1H NMR(400MHz,DMSO-d6):δ9.78(s,1H),7.15(br s,2H),6.97(br s,2H),5.75(s,1H),4.76-4.71(m,1H),3.46-2.84(m,5H),2.10-1.65(m,4H).13C{1H}NMR(150MHz,DMSO-d6):δ187.4,150.3,131.4,123.1,122.1,118.4,114.9,79.3,76.2,48.2,38.1,31.2,30.9,19.4.MS:m/z 370[M+H]+。
实施例14
在反应管中依次加入1g(0.2mmol,48mg)，乙醇(1mL)，T+ClO4 -(0.6mmol,153mg)，硫氰酸盐2a(0.3mmol,29mg)和双亲核试剂3a(0.3mmol,34mg)，在空气气氛下于25℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得黄色液体产物4g(21mg,29％)。1H NMR(400MHz,CDCl3):δ7.59(dd,J1＝8.0Hz,J2＝1.2Hz,1H),7.31-7.27(m,1H),7.07(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.02-6.98(m,1H),6.48(br s,1H),5.59(s,1H),4.99-4.94(m,1H),3.43-3.35(m,1H),3.28-3.20(m,1H),3.10-2.97(m,3H),2.35-2.28(m,1H),2.07-1.98(m,2H),1.85-1.81(m,1H).13C{1H}NMR(150MHz,CDCl3):δ187.5,146.7,134.1,128.6,126.0,124.3,120.2,78.9,48.5,39.2,31.6,31.0,19.7.MS:m/z 370[M+H]+。
实施例15
在反应管中依次加入1h(0.2mmol,41mg)，乙醇(1mL)，T+ClO4 -(0.6mmol,153mg)，硫氰酸盐2a(0.3mmol,29mg)和双亲核试剂3a(0.3mmol,34mg)在空气气氛下于25℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得黄色液体产物4h(32mg,48％)。1H NMR(400MHz,CDCl3):δ7.97(dd,J1＝6.8Hz,J2＝2.0Hz,2H),7.70(br s,1H),6.63(dd,J1＝7.2Hz,J2＝2.0Hz,2H),5.80(s,1H),5.01-4.96(m,1H),3.89(s,3H),3.69-3.65(m,1H),3.42-3.38(m,1H),3.28-3.23(m,1H),3.05-3.01(m,2H),2.44-2.36(m,2H).13C{1H}NMR(150MHz,CDCl3):δ187.1,167.0,147.9,131.8,120.2,112.2,85.4,51.8,49.3,46.5,40.6,31.7.MS:m/z 358[M+Na]+。
实施例16
在反应管中依次加入1i(0.2mmol,39mg)，乙醇(1mL)，T+ClO4 -(0.6mmol,153mg)，硫氰酸盐2a(0.3mmol,29mg)和双亲核试剂3a(0.3mmol,34mg)，在空气气氛下于25℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得黄色液体产物4i(26mg,40％)。1H NMR(400MHz,CDCl3):δ7.02-6.98(m,2H),6.81-6.78(m,3H),5.81(s,1H),5.08-5.04(m,1H),3.63(d,J＝16.0Hz,1H),3.25-3.05(m,4H),2.16-2.13(m,2H),1.67-1.57(m,4H).13C{1H}NMR(150MHz,CDCl3):δ186.9,156.7(d,1JC-F＝237.3Hz),143.8,116.4(d,3JC-F＝7.7Hz),116.2(d,2JC-F＝23.0Hz),84.6,77.9,48.7,45.7,39.9,30.7,27.1,24.3.19F{1H}NMR(CDCl3,376MHz):δ-124.8.MS:m/z 324[M+H]+。
实施例17
在反应管中依次加入1j(0.2mmol,36mg)，乙醇(1mL)，T+ClO4 -(0.6mmol,153mg)，氰酸盐2b(0.3mmol,24mg)和双亲核试剂3a(0.3mmol,34mg)在空气气氛下于25℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得黄色液体产物4j(31mg,52％)。1H NMR(400MHz,CDCl3):δ7.02-6.95(m,2H),6.89-6.85(m,2H),5.58(s,1H),5.31(br s,1H),4.44-4.40(m,1H),3.31-3.16(m,2H),3.06-2.97(m,3H),2.05-1.87(m,4H).13C{1H}NMR(150MHz,CDCl3):δ162.2,157.6(d,1JC-F＝238.5Hz),145.2(d,4JC-F＝3.3Hz),119.0(d,3JC-F＝7.7Hz),116.1(d,2JC-F＝21.9Hz),77.9,75.2,46.7,38.5,32.3,31.8,19.6.19F{1H}NMR(CDCl3,376MHz):δ-122.9.MS:m/z 294[M+H]+。
实施例18
在反应管中依次加入1b(0.2mmol,39mg)，乙醇(1mL)，T+ClO4 -(0.6mmol,153mg)，硫氰酸盐2a(0.3mmol,29mg)和双亲核试剂3b(0.3mmol,23mg)在空气气氛下于25℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得白色固体产物4k(19mg,30％)。mp 181-182℃.1H NMR(400MHz,CDCl3):δ7.24-7.20(m,2H),6.82-6.79(m,2H),6.46(br s,1H),5.36(s,1H),4.61-4.57(m,1H),4.11-4.04(m,1H),3.92-3.88(m,1H),3.34-3.27(m,2H),3.15-3.09(m,1H),2.60-2.55(m,1H),2.05-1.97(m,2H),1.79-1.71(m,1H),1.63-1.55(m,2H).13C{1H}NMR(150MHz,CDCl3):δ182.2,146.7,129.4,125.4,117.0,91.1,76.2,61.2,40.7,39.2,25.2,22.8,17.3.MS:m/z 324[M+H]+。
实施例19
在反应管中依次加入1k(0.2mmol,47mg)，乙醇(1mL)，T+ClO4 -(0.6mmol,153mg)，硫氰酸盐2a(0.3mmol,29mg)和双亲核试剂3c(0.3mmol,47mg)在空气气氛下于25℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得黄色液体产物4l(36mg,44％,>20:1dr,98％ee)。1H NMR(400MHz,CDCl3):δ7.55-7.51(m,4H),7.43-7.39(m,2H),7.30(td,J1＝7.2Hz,J2＝1.2Hz,1H),7.01-6.94(m,3H),5.67(s,1H),5.20-5.16(m,1H),4.35(t,J＝8.8Hz,1H),4.25-4.21(m,1H),3.81(s,3H),3.45-3.40(m,1H),3.29-3.24(m,1H),2.09-2.06(m,1H),2.00-1.93(m,2H),1.82-1.76(m,1H).13C{1H}NMR(150MHz,CDCl3):δ189.8,171.0,147.3,140.5,133.5,128.8,128.3,126.8,126.6,116.1,101.8,76.6,68.2,60.3,52.9,39.7,25.7,17.7.HRMS(ESI)m/z:[M+H]+Calcd for C22H24N3O3S410.1533；Found 410.1534.HPLC(Daicel Chiralpak IA,hexane/iPrOH＝70/30,flowrate 1.0mL/min,λ＝254nm,retention times:(S)(major)16.1min,(R)(minor)11.4min)。
实施例20
在反应管中依次加入1a(0.2mmol,32mg)，乙醇(1mL)，T+ClO4 -(0.6mmol,153mg)，硫氰酸盐2a(0.3mmol,29mg)和双亲核试剂3d(0.3mmol,45mg)在空气气氛下于25℃搅拌反应6h，然后加入10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝5/1,v/v)得黄色液体产物4m(44mg,54％,>20:1dr,99％ee)。1H NMR(400MHz,CDCl3):δ7.40-7.24(m,7H),6.93-6.86(m,4H),5.61(s,1H),5.30(d,J＝12.4Hz,1H),5.23-5.17(m,2H),4.33(t,J＝8.8Hz,1H),4.23-4.20(m,1H),3.35-3.30(m,1H),3.22-3.17(m,1H),1.92-1.67(m,4H).13C{1H}NMR(150MHz,CDCl3):δ189.8,170.3,148.0,135.1,129.7,128.75,128.70,128.5,120.8,116.0,101.8,76.8,68.1,67.6,60.5,39.6,25.7,17.7.HRMS(ESI)m/z:[M+H]+Calcd for C22H24N3O3S410.1533；Found 410.1515.HPLC(Daicel Chiralpak IF,hexane/iPrOH＝80/20,flowrate 1.0mL/min,λ＝254nm,retention times:(S)(major)12.8min,(R)(minor)13.9min)。
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。
Claims (3)
1.二氢噻(噁)唑[3',2':1,5]二氢咪唑[4,5-b]哌啶衍生物的合成方法，其特征在于具体步骤为：将N-芳基取代饱和环胺类化合物1、氰酸盐/硫氰酸盐2以及双亲核试剂3溶于反应溶剂中，再加入氧铵盐T+Y-，在空气气氛下于0-50℃反应制得目标产物二氢噻(噁)唑[3',2':1,5]二氢咪唑[4,5-b]哌啶衍生物4，合成过程中的反应方程式为：
其中R1为苯基或取代苯基，该取代苯基苯环上的取代基为氟、氯、溴、碘、C1-4烷基、C1-4烷氧基、酯基、氰基、三氟甲基或硝基；R2为氢、酯基或苄基；Y-为BF4 -、ClO4 -、PF6 -或OTf-。
2.根据权利要求1所述的二氢噻(噁)唑[3',2':1,5]二氢咪唑[4,5-b]哌啶衍生物的合成方法，其特征在于：所述反应溶剂为乙醇。
3.根据权利要求1所述的二氢噻(噁)唑[3',2':1,5]二氢咪唑[4,5-b]哌啶衍生物的合成方法，其特征在于：所述N-芳基取代饱和环胺类化合物1、氰酸盐/硫氰酸盐2、双亲核试剂3与氧铵盐T+Y-的投料物质的量之比为1:1-3:1-3:2-4。
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| CN106220643A (zh) * | 2016-08-08 | 2016-12-14 | 中国科学院昆明植物研究所 | 灵芝内酯d及其药物组合物与其在制药和食品中的应用 |
| CN114302887A (zh) * | 2019-09-05 | 2022-04-08 | 伯尔尼大学 | 三环Janus激酶(JAK)抑制剂及其在治疗自身免疫性疾病中的用途 |
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