CN105820065B - 一种采用肼对氮杂环丙烷化合物开环的方法 - Google Patents
一种采用肼对氮杂环丙烷化合物开环的方法 Download PDFInfo
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- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 title claims abstract description 54
- -1 nitrogen heterocycle propane compound Chemical class 0.000 title claims abstract description 53
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N dimethylmethane Natural products CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 title claims abstract description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 229910052757 nitrogen Inorganic materials 0.000 title claims abstract description 29
- 239000001294 propane Substances 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title claims abstract description 21
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical group C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims abstract description 39
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 12
- 230000004913 activation Effects 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 229930195733 hydrocarbon Natural products 0.000 claims abstract description 5
- 230000000977 initiatory effect Effects 0.000 claims abstract description 4
- 239000000463 material Substances 0.000 claims abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- JSZOAYXJRCEYSX-UHFFFAOYSA-N 1-nitropropane Chemical compound CCC[N+]([O-])=O JSZOAYXJRCEYSX-UHFFFAOYSA-N 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims description 3
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 58
- 239000000047 product Substances 0.000 description 48
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 25
- 229940067157 phenylhydrazine Drugs 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 238000005481 NMR spectroscopy Methods 0.000 description 16
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 6
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
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- 238000005516 engineering process Methods 0.000 description 2
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- AVPDDAWOIXIWFB-UHFFFAOYSA-N CC(CC=CC(C)C=C1)C1NN Chemical compound CC(CC=CC(C)C=C1)C1NN AVPDDAWOIXIWFB-UHFFFAOYSA-N 0.000 description 1
- JFILLLZWNHOVHV-UHFFFAOYSA-N NNc1cc([N+]([O-])=O)ccc1 Chemical compound NNc1cc([N+]([O-])=O)ccc1 JFILLLZWNHOVHV-UHFFFAOYSA-N 0.000 description 1
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- 238000006352 cycloaddition reaction Methods 0.000 description 1
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 1
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
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Abstract
本发明公开了一种采用肼对氮杂环丙烷化合物开环的方法,以对甲苯磺酰基活化的氮杂环丙烷化合物为起始原料,以肼类化合物作亲核试剂,在无催化剂条件下,于硝基烷烃类溶剂中,使用肼类化合物对氮杂环丙烷化合物进行开环反应。本发明不使用任何催化剂,反应成本较低;硝基烷烃类溶剂环境友好,反应对水的耐受性强尤为可贵;本发明开环方法具有广泛的普适性,对不同结构的氮杂环丙烷和肼开环反应均可以获得较高的收率和优秀的区域选择性。
Description
技术领域
本发明涉及一种采用肼对氮杂环丙烷化合物开环的方法,属于有机合成技术领域。
背景技术
氮杂环丙烷化合物是有机合成中重要的合成砌块和中间体,存在于许多天然产物中,具有良好的抗病毒、抗肿瘤及其它生物活性。氮杂环丙烷可以发生一系列重要的有机反应,如开环反应、环加成反应、还原和消除反应等。
对于亲核试剂与氮杂环丙烷开环反应的报道已屡见不鲜,但是人们对氮杂环丙烷相关反应的研究热情依然不减,尤其是在无任何催化剂存在下发生的反应具有很大的研究价值。到目前为止,还未见关于肼类化合物与氮杂环丙烷直接开环反应的报道。因此,找到合适的条件使得设想的反应得以顺利发生有重要的理论意义和使用价值。
发明内容
本发明旨在提供一种采用肼对氮杂环丙烷化合物开环的方法。
本发明提供了一种采用肼对氮杂环丙烷化合物开环的方法,以对甲苯磺酰基活化的氮杂环丙烷化合物为起始原料,以肼类化合物作亲核试剂,在无催化剂条件下,于硝基烷烃类溶剂中,使用肼类化合物对氮杂环丙烷化合物进行开环反应。
上述方法中,所述对甲苯磺酰基活化的氮杂环丙烷化合物具有以下结构通式:
式中,R1代表H、C1~C20的烷基,或
其中,R2代表H、甲基或卤素。
或者,所述对甲苯磺酰基活化的氮杂环丙烷化合物具有以下结构通式:
其中,n为1~7。
优选地,所述n为3或4。
又或者,所述对甲苯磺酰基活化的氮杂环丙烷化合物具有以下结构通式:
式中,R3与R4均代表
其中,R5代表H、甲基或者卤素。
上述方法中,所述肼类化合物具有以下结构通式:
式中,R6代表H、甲基或硝基。
可能发生的反应如下:
上述方法中,所述硝基烷烃类溶剂为硝基甲烷、硝基乙烷或硝基丙烷中的一种,所述硝基烷烃类溶剂用量为3~10mL/mmol氮杂环丙烷化合物。
上述反应是在硝基烷烃类溶剂中进行的,由于硝基烷烃类溶剂具有一定的吸水性,暴露在空气中容易吸潮,而使体系带有微量的水分,因此,进一步研究反应对水的耐受性尤为重要。结果表明:反应在新蒸馏的硝基烷烃类溶剂中进行与在不经处理的分析纯硝基烷烃类溶剂中进行,两者反应速率和收率都没有明显差别,说明上述反应对于微量的水有很好的耐受性。
上述方法中,所述对甲苯磺酰基活化的氮杂环丙烷化合物与肼的摩尔比为3∶(1~12);优选的摩尔比为2∶(1~4)。
上述方法中,所述的开环反应在20~130℃下进行,反应时间为3~12h。进一步地,优选的反应温度为40~80℃。
本发明是以对甲苯磺酰基活化的氮杂环丙烷化合物做起始原料,甲苯磺酰基作为吸电子取代基,可以降低氮杂环上的电子云密度,使其容易被亲核试剂进攻;开环反应后产物上的对甲苯磺酰基采用常规方法即可去除,并不是本发明描述的重点,故本发明对其并未予以说明。
本发明提供了一种以肼为亲核试剂,在无催化剂条件下于硝基烷烃类溶剂体系中,采用肼对氮杂环丙烷化合物开环的方法,该方法除操作简单,反应条件温和外,还具有以下优点:
(1)该反应不使用任何催化剂,反应成本较低;
(2)硝基烷烃类溶剂环境友好,反应对水的耐受性强尤为可贵;
(3)本发明开环方法具有广泛的普适性,对不同结构的氮杂环丙烷和肼开环反应均可以获得较高的收率;
(4)反应所得开环产物具有优秀的区域选择性,特别是当氮杂环丙烷上取代基为脂肪链时,反应表现出非常高的区域选择性。
具体实施方式
下面通过实施例来进一步说明本发明,但不局限于以下实施例。
下面给出了对甲苯磺酰基活化的各种氮杂环丙烷化合物在不同的肼类化合物作用下进行开环反应的实施例。
实施例1:
在试管中加入结构式如1a所示的氮杂环丙烷0.2mmol,苯肼2a 0.32mmol,硝基甲烷0.8mL,加热至70℃下搅拌反应12h。粗产品经硅胶层析柱纯化得到单一构型的开环产物,结构式如表1中3a所示,采用核磁共振和高分辨质谱对产物进行表征证实了产物的结构。
表1 氮杂环丙烷1a与苯肼2a的反应
3a Yellowish white solid;mp 72–75℃;1H NMR(400MHz,CDCl3):δ7.77(d,J=8.3Hz,2H),7.30(d,J=8.1Hz,2H),7.24–7.18(m,5H),7.10–7.05(m,2H),6.83(t,J=7.6Hz,3H),5.08(dd,J=8.1,3.4Hz,1H),4.83(dd,J=9.9,4.4Hz,1H),3.84–3.77(m,1H),3.51–3.44(m,1H),3.19(s,2H),2.44(s,3H)ppm;13C NMR(100MHz,CDCl3):δ151.4,143.4,137.2,136.5,128.5,128.0,127.6,127.1,119.5,114.0,63.9,44.4,21.6ppm;HRMS(ESI):Calcd for C21H23N3O2S+H 403.1584,found 382.1596。
实施例2:
在试管中加入结构式如1a所示的氮杂环丙烷0.3mmol,肼2b 0.3mmol,硝基乙烷1.0mL,加热至50℃下搅拌反应10h。粗产品经硅胶层析柱纯化得到单一构型的开环产物,结构式如表2中3b所示,采用核磁共振对产物进行表征证实了产物的结构。
表2 氮杂环丙烷1a与肼2b的反应
3b Brown solid;mp 142–144℃;1H NMR(400MHz,CDCl3)δ7.27(d,J=8.3Hz,2H),7.31–7.24(m,7H),6.88(d,J=8.1Hz,2H),6.39(d,J=8.4Hz,2H),4.80–4.76(m,1H),4.71(t,J=6.3Hz,1H),4.41–4.36(m,1H),4.35–4.30(m,1H),3.36–3.30(m,1H),3.32–3.14(m,1H),2.18(s,3H),2.24(s,3H)ppm。
实施例3:
在试管中加入结构式如1a所示的氮杂环丙烷0.4mmol,肼2c 0.36mmol,硝基乙烷1.6mL,加热至40℃下搅拌反应4h。粗产品经硅胶层析柱纯化得到单一构型的开环产物,结构式如表3中3c所示,采用核磁共振和高分辨质谱对产物进行表征证实了产物的结构。
表3 氮杂环丙烷1a与肼2c的反应
3c Brown solid;1HNMR(400MHz,CDCl3)δ7.75(d,J=8.3Hz,2H),7.25(d,J=8.0Hz,2H),7.22–7.19(m,3H),7.09–7.03(m,3H),6.63–6.56(m,3H),5.35(dd,J=8.4,3.5Hz,1H),4.81(dd,J=10.0,4.4Hz,1H),3.81–3.74(m,1H),3.48–3.40(m,1H),3.22(s,2H),2.41(s,3H),2.25(s,3H)ppm;13C NMR(100MHz,CDCl3):δ151.5,143.4,138.9,137.2,136.6,129.8,129.0,128.5,127.9,127.6,127.1,120.5,114.8,111.2,63.8,44.3,21.8,21.7ppm;HRMS(ESI):Calcd forC22H25N3O2S+H 396.1746,found 396.1729。
实施例4:
在试管中加入结构式如1a所示的氮杂环丙烷0.2mmol,肼2d 0.35mmol,硝基甲烷2.0mL,加热至80℃下搅拌反应8h。粗产品经硅胶层析柱纯化得到单一构型的开环产物,结构式如表4中3d所示,采用核磁共振和高分辨质谱对产物进行表征证实了产物的结构。
表4 氮杂环丙烷1a与肼2d的反应
3d Yellowish solid;mp 133–134℃;1H NMR(400MHz,CDCl3)δ7.76(d,J=8.3Hz,2H),7.28(d,J=8.0Hz,2H),7.22–7.19(m,3H),7.07(dd,J=6.7,2.9Hz,2H),6.45(s,1H),6.43(s,2H),5.22(dd,J=8.4,3.3Hz,1H),4.80(dd,J=10.0,4.4Hz,1H),3.82–3.74(m,1H),3.48–3.42(m,1H),3.18(s,2H),2.43(s,3H),2.23(s,6H)ppm;13C NMR(100MHz,CDCl3):δ151.6,143.3,138.8,137.2,136.6,129.8,128.5,127.9,127.6,127.1,121.6,111.9,63.7,44.2,29.7,26.9,21.7,21.6ppm;HRMS(ESI):Calcd for C23H27N3O2S+H 410.1902,found 410.1897。
实施例5:
在试管中加入结构式如1a所示的氮杂环丙烷0.24mmol,肼2e 0.26mmol,硝基丙烷1.5mL,加热至60℃下搅拌反应7h。粗产品经硅胶层析柱纯化得到单一构型的开环产物,结构式如表5中3e所示,采用核磁共振对产物进行表征证实了产物的结构。
表5 氮杂环丙烷1a与肼2e的反应
3e Yellow solid;1H NMR(400MHz,CDCl3)δ7.73(d,J=8.3Hz,2H),7.63(t,J=2.3Hz,1H),7.60(dd,J=8.0,1.4Hz,1H),7.33–7.24(m,7H),3(d,J=2.3Hz,2H),7.15–7.10(m,2H),5.18(dd,J=7.7,4.8Hz,1H),4.92(dd,J=10,4.5Hz,1H),4.77(s,1H),3.85–3.79(m,1H),3.51–3.44(m,2H),2.41(s,3H)ppm。
实施例6:
在试管中加入表6结构式如1b所示的氮杂环丙烷0.4mmol,苯肼2a 0.5mmol,硝基乙烷2.0mL,加热至70℃下搅拌反应3h,粗产品经硅胶层析柱纯化得到开环产物,结构式如表6中4b所示,采用核磁共振和高分辨质谱对产物进行表征证实了产物的结构。
表6 氮杂环丙烷1b与苯肼2a的反应
4b Yellowish white solid;mp 139–140℃;1H NMR(400MHz,CDCl3):δ7.71(d,J=8.3Hz,2H),7.20(d,J=8.0Hz,2H),7.18–7.03(m,6H),6.74(t,J=7.3Hz,1H),6.71–6.66(m,2H),5.50(dd,J=8.0,4.6Hz,1H),4.90(dd,J=9.5,4.6Hz,1H),3.71–3.63(m,1H),3.47(s,12H),3.60–3.29(m,1H),2.38(s,3H),2.14(s,3H)ppm;13C NMR(100MHz,CDCl3):δ158.4,150.9,149.6,143.3,137.3,136.1,130.9,126.1,122.7,118.8,113.1,60.6,44.5,29.7,21.5,19.7ppm;HRMS(ESI):Calcd for HRMS(ESI):Calcd for C22H25N3O2S+H 396.1746,found 396.1725。
实施例7:
在试管中加入表7结构式如1c所示的氮杂环丙烷0.5mmol,苯肼2a 0.48mmol,硝基乙烷2.5mL,加热至80℃下搅拌反应4h,粗产品经硅胶层析柱纯化得到开环产物,结构式如表7中4c所示,采用核磁共振和高分辨质谱对产物进行表征证实了产物的结构。
表7 氮杂环丙烷1c与苯肼2a的反应
4c Yellowish white solid;mp 153–154℃;1H NMR(400MHz,CDCl3):δ7.76(d,J=8.1Hz,2H),7.28(d,J=8.0Hz,2H),7.20(t,J=7.9Hz,2H),7.10(t,J=7.5Hz,1H),7.03(d,J=7.5Hz,1H),6.91–6.84(m,2H),6.83–6.78(m,3H),5.16(dd,J=8.1,3.5Hz,1H),4.79(dd,J=9.9,4.4Hz,1H),3.84–3.68(m,1H),3.48–3.41(m,1H),3.23(s,2H),2.43(s,3H),2.25(s,3H)ppm;13C NMR(100MHz,CDCl3):δ151.5,143.4,137.2,129.8,128.4,127.1,124.7,119.5,114.0,63.9,44.4,21.6,18.4,13.7ppm;HRMS(ESI):Calcd for C22H25N3O2S+H396.1746,found 396.1725。
实施例8:
在圆底烧瓶中加入表8结构式如1d所示的氮杂环丙烷1.0mmol,苯肼2a 1.25mmol,硝基乙烷5.5mL,加热至50℃下搅拌反应10h,粗产品经硅胶层析柱纯化得到开环产物,结构式如表8中4d所示,采用核磁共振和高分辨质谱对产物进行表征证实了产物的结构。
表8 氮杂环丙烷1d与苯肼2a的反应
4d Yellowish brown solid;mp 68–70℃;1H NMR(400MHz,CDCl3)δ7.49(dd,J=6.6,1.6Hz,2H),7.22(s,1H),7.18–7.13(m,3H),7.01(dd,J=21.0,8.0Hz,4H),6.80–6.75(m,3H),5.42(dd,J=8.4,3.6Hz,1H),4.79(dd,J=10.1,4.4Hz,0H),3.79–3.71(m,1H),3.45–3.37(m,1H),3.24(s,2H),2.40(s,3H),2.25(s,3H)ppm;13C NMR(100MHz,CDCl3):δ151.5,143.3,137.7,137.2,133.5,129.2,127.5,127.1,119.3,114.0,63.6,44.5,21.6,21.1ppm;HRMS(ESI):Calcd for C22H25N3O2S+H 396.1746,found 396.1736。
实施例9:
在圆底烧瓶中加入表9结构式如1e所示的氮杂环丙烷0.6mmol,苯肼2a 0.7mmol,硝基甲烷3.5mL,加热至70℃下搅拌反应5h,粗产品经硅胶层析柱纯化得到开环产物,结构式如表9中4e所示,采用核磁共振和高分辨质谱对产物进行表征证实了产物的结构。
表9 氮杂环丙烷1e与苯肼2a的反应
4e Yellowish brown solid;mp 147–148℃;1H NMR(600MHz,CDCl3)δ7.70(d,J=8.2Hz,2H),7.29(ddd,J=13.4,7.5,1.6Hz,2H),7.19(d,J=8.1Hz,2H),7.17–7.10(m,4H),6.75(t,J=7.3Hz,1H),6.67(d,J=8.3Hz,2H),5.49(t,J=6.3Hz,1H),5.14(dd,J=9.2,4.1Hz,1H),3.76–3.69(m,2H),3.46–3.42(m,1H),2.39(s,3H)ppm;13C NMR(100MHz,CDCl3):δ150.2,143.2,137.2,136.9,133.1,129.7,128.8,127.0,118.6,112.3,59.7,44.7,29.7,21.5ppm;HRMS(ESI):Calcd for C21H22ClN3O2S+H 416.1200,found 416.1167。
实施例10:
在试管中加入表10结构式如1f所示的氮杂环丙烷0.3mmol,苯肼2a 0.4mmol,硝基甲烷1.5mL,加热至70℃下搅拌反应6h,粗产品经硅胶层析柱纯化得到开环产物,结构式如表10中4f所示,采用核磁共振和高分辨质谱对产物进行表征证实了产物的结构。
表10 氮杂环丙烷1f与苯肼2a的反应
4fYellowish brown solid;mp 147–148℃;1HNMR(400MHz,CDCl3)δ7.73(d,J=8.1Hz,2H),7.26–7.22(m,2H),7.21–7.10(m,3H),6.98(d,J=7.4Hz,2H),6.98(d,J=7.4Hz,1H),6.80(t,J=7.4Hz,1H),6.77(t,J=6.6Hz,2H),5.44(dd,J=8.1,4.0Hz,1H),4.77(dd,J=9.8,4.3Hz,1H),3.78–3.71(m,1H),3.43–3.36(m,1H),3.34(s,2H),2.41(s,3H)ppm;13C NMR(100MHz,CDCl3):δ151.0,143.5,139.3,134.4,129.2,127.6,126.0,119.5,113.6,63.3,44.7,29.7,21.7ppm;HRMS(ESI):Calcd for C21H22ClN3O2S+H 416.1200,found416.1189。
实施例11:
在试管中加入表11结构式如1g所示的氮杂环丙烷0.3mmol,苯肼2a 0.5mmol,硝基乙烷1.5mL,加热至60℃下搅拌反应4h,粗产品经硅胶层析柱纯化得到开环产物,结构式如表11中4g所示,采用核磁共振和高分辨质谱对产物进行表征证实了产物的结构。
表11 氮杂环丙烷1g与苯肼2a的反应
4g Yellowish solid;mp 114–115℃;1HNMR(600MHz,CDCl3)δ7.76–7.73(m,2H),7.28(dd,J=8.5,0.6Hz,2H),7.23–7.16(m,4H),7.06–6.99(m,2H),6.83(ddd,J=7.4,4.2,1.0Hz,2H),6.79(dd,J=8.8,1.0Hz,2H),5.20(dd,J=7.9,3.5Hz,1H),4.79(dd,J=9.7,4.3Hz,1H),3.82–3.72(m,1H),3.43–3.40(m,J=12.7,8.3,4.4Hz,1H),3.24(s,2H),2.44(s,3H)ppm;13C NMR(100MHz,CDCl3):δ151.5,143.4,137.7,137.2,133.4,129.2,127.6,127.1,119.4,114.1,64.7,44.4,29.8,21.7,21.1,18.7ppm;HRMS(ESI):Calcd forC21H22ClN3O2S+H 416.1200,found 416.1180。
实施例12:
在试管中加入表12结构式如1h所示的氮杂环丙烷0.3mmol,苯肼2a 0.4mmol,硝基甲烷1.5mL,加热至70℃下搅拌反应6h,粗产品经硅胶层析柱纯化得到成环产物,结构式如表12中4h所示,采用核磁共振和高分辨质谱对产物进行表征证实了产物的结构。
表12 氮杂环丙烷1h与苯肼2a的反应
4h Yellowish solid;mp 75℃ 1H NMR(400MHz,CDCl3)δ7.73(d,J=8.3Hz,2H),7.36–7.31(m,2H),7.27(d,J=8.8Hz,2H),7.24–7.15(m,2H),6.99–6.95(m,2H),6.82(t,J=7.3Hz,1H),6.78(d,J=7.9Hz,2H),5.29–5.26(m,1H),4.77(dd,J=9.7,4.3Hz,1H),3.79–3.71(m,1H),3.46–3.38(m,1H),3.26(s,2H),2.43(s,3H)ppm;13C NMR(100MHz,CDCl3):δ151.1,143.4,137.1,135.9,129.3,127.0,121.9,119.6,113.8,63.4,44.6,29.7,21.6ppm;HRMS(ESI):Calcd for C21H23BrN3O2S+H 460.0694,found 460.0674。
实施例13:
在试管中加入表13结构式如1i所示的氮杂环丙烷0.3mmol,苯肼2a 0.4mmol,硝基丙烷2.0mL,加热至70℃下搅拌反应6h,粗产品经硅胶层析柱纯化得到成环产物,结构式如表13中4h所示,采用核磁共振和高分辨质谱对产物进行表征证实了产物的结构。
表13 氮杂环丙烷1i与苯肼2a的反应
4i Yellowish solid;1H NMR(400MHz,CDCl3)δ7.90–7.80(m,2H),7.73–7.67(m,2H),7.48–7.43(m,2H),7.33–7.26(m,2H),7.14(dd,J=8.0Hz,2H),7.12–7.07(m,2H),6.73–6.67(m,3H),5.67(dd,J=7.8,4.9Hz,1H),5.53(dd,J=9.2,4.4Hz,1H),3.83–7.75(m,1H),3.67(s,2H),3.62–3.55(m,1H),2.35(s,3H)ppm;13C NMR(100MHz,CDCl3):δ150.5,143.3,129.1,138.4,126.6,125.2,122.6,118.7,112.8,60.3,45.0,21.5ppm;HRMS(ESI):Calcd for C25H25N3O2S+H 432.1746,found 432.1746。
实施例14:
在试管中加入表14结构式如1j所示的氮杂环丙烷0.5mmol,苯肼2a 0.5mmol,硝基甲烷3.5mL,加热至70℃下搅拌反应6h,粗产品经硅胶层析柱纯化得到成环产物,结构式如表14中4j所示,采用核磁共振和高分辨质谱对产物进行表征证实了产物的结构。
表14 氮杂环丙烷1j与苯肼2a的反应
4j Yellowish solid;mp 157–159℃;1H NMR(400MHz,CDCl3)δ7.77–7.74(m,3H),7.74–7.70(m,1H),7.67(d,J=8.5Hz,1H),7.56(s,1H),7.47–7.41(m,2H),7.26(d,J=8.0Hz,2H),7.23–7.15(m,3H),6.87–6.80(m,3H),5.27(dd,J=7.9,3.6Hz,1H),4.99(dd,J=9.7,4.4Hz,1H),3.93–3.86(m,1H),3.61–3.54(m,1H),3.31(s,2H),2.42(s,3H)ppm;13CNMR(100MHz,CDCl3):δ151.4,143.4,134.4,133.1,132.9,129.8,126.5,125.7,119.5,113.9,64.1,44.7,29.7,21.6ppm;HRMS(ESI):Calcd for C25H25N3O2S+H 432.1746,found432.1736。
实施例15:
在圆底烧瓶中加入表15结构式如1k所示的氮杂环丙烷1.1mmol,苯肼2a 1.3mmol,硝基甲烷8.5mL,加热至70℃下搅拌反应6h,粗产品经硅胶层析柱纯化得到成环产物,结构式如表15中4k所示,采用核磁共振和高分辨质谱对产物进行表征证实了产物的结构。
表15 氮杂环丙烷1k与苯肼2a的反应
4k Crimson oil;1H NMR(400MHz,CDCl3)δ7.59(d,J=8.2Hz,2H),7.49–7.46(m,2H),7.43–7.40(m,3H),7.00(d,J=8.1Hz,2H),4.78(d,J=6.9Hz,1H),4.06–3.95(m,1H),3.86–3.80(m,1H),2.46–2.39(m,1H),2.35–2.26(m,1H),2.24(s,3H),2.09–2.01(m,2H),1.89–1.81(m,2H),1.72–1.64(m,2H)ppm;13C NMR(100MHz,CDCl3):δ149.2,143.8,135.9,129.3,123.9,120.3,118.3,112.1,62.1,41.6,24.3,21.7,20.4,19.8ppm;HRMS(ESI):Calcd for C18H23N3O2S+H 346.1589,found 346.1581。
实施例16:
在试管中加入表16结构式如1l所示的氮杂环丙烷0.3mmol,苯肼2a 0.34mmol,硝基乙烷1.5mL,加热至80℃下搅拌反应7h,粗产品经硅胶层析柱纯化得到单一构型的开环产物,结构式如表17中4l所示,采用核磁共振和高分辨质谱对产物进行表征证实了产物的结构。
表16 氮杂环丙烷1l与苯肼2a的反应
4l White solid;1H NMR(400 MHz,CDCl3)δ7.78(d,J=8.3 Hz,2H),7.66–7.59(m,2H),7.51–7.43(m,3H),7.26(d,J=8.0 Hz,2H),5.29(d,J=9.1 Hz,1H),3.94–3.85(m,1H),3.65–3.59(m,1H),3.50–3.37(m,1H),2.41(s,3H),2.03–1.94(m,2H),1.82–1.64(m,1H),1.44–1.31(m,3H),0.73(t,J=7.4 Hz,3H),0.58(dt,J=20.6,7.4 Hz,1H)ppm。
Claims (6)
1.一种采用肼对氮杂环丙烷化合物开环的方法,以对甲苯磺酰基活化的氮杂环丙烷化合物为起始原料,其特征在于:以肼类化合物作亲核试剂,在无催化剂条件下,于硝基烷烃类溶剂中,使用肼类化合物对氮杂环丙烷化合物进行开环反应;
所述对甲苯磺酰基活化的氮杂环丙烷化合物具有以下结构通式:
式中,R1代表H、C1~C20的烷基、其中,R2代表H、甲基或卤素;
n为1~7;
R3与R4均代表其中,R5代表H、甲基或者卤素;
所述肼类化合物具有以下结构通式:
式中,R6代表H、甲基或硝基。
2.根据权利要求1所述的采用肼对氮杂环丙烷化合物开环的方法,其特征在于:所述n为3或4。
3.根据权利要求1所述的采用肼对氮杂环丙烷化合物开环的方法,其特征在于:所述硝基烷烃类溶剂为硝基甲烷、硝基乙烷或硝基丙烷中的一种,所述硝基烷烃类溶剂用量为3~10mL/mmol氮杂环丙烷化合物。
4.根据权利要求1所述的采用肼对氮杂环丙烷化合物开环的方法,其特征在于:所述对甲苯磺酰基活化的氮杂环丙烷化合物与肼的摩尔比为3:(1~12)。
5.根据权利要求4所述的采用肼对氮杂环丙烷化合物开环的方法,其特征在于:所述对甲苯磺酰基活化的氮杂环丙烷化合物与肼的摩尔比为2:(1~4)。
6.根据权利要求1所述的采用肼对氮杂环丙烷化合物开环的方法,其特征在于:所述的开环反应在20~130℃下进行,反应时间为3~12h。
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