CN110423215B - 一种查尔酮吡啶盐及其制备方法和应用 - Google Patents

一种查尔酮吡啶盐及其制备方法和应用 Download PDF

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CN110423215B
CN110423215B CN201910771585.XA CN201910771585A CN110423215B CN 110423215 B CN110423215 B CN 110423215B CN 201910771585 A CN201910771585 A CN 201910771585A CN 110423215 B CN110423215 B CN 110423215B
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王琪琳
王乐乐
苗红杰
卜站伟
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Abstract

本发明公开了一种查尔酮吡啶盐及其制备方法和应用，属于有机合成技术领域。本发明通过将溴代甲基查尔酮和3‑硝基吡啶加在乙腈溶剂中，在60℃的温度下发生亲核取代反应来制备查尔酮吡啶盐。本发明操作简单，反应完全后，通过过滤即可拿到纯品。此外，本发明还以查尔酮吡啶盐为起始原料，研究了其与烯胺酮参与的串联环化反应，进一步验证了该查尔酮吡啶盐的实用性，合成了一类结构复杂的氮杂桥环化合物。

Description

一种查尔酮吡啶盐及其制备方法和应用
技术领域
本发明属于有机合成领域，具体涉及一种结构新型的查尔酮吡啶盐的制备及其在构筑复杂含氮桥环中的应用。
背景技术
吡啶具有稳定的芳香结构，对其直接进行去芳构化反应有很大的挑战。因此，需要对其进行预活化，才能打破其芳香结构发生系列化学反应。常见的活化方式有(图1)：N-酰基化活化、N-氧化活化、N-路易斯酸活化和N-烷基化活化(Chem.Rev.1982,82,223；Chem.Rev.2011,111,7157；Chem.Rev.2012,112,2642；Org.Biomol.Chem.2014,12,4807；Org.Chem.Front.2018,5,453.)。本发明首次引入查尔酮骨架，开发了吡啶新的活化基团，设计并合成了结构新型的查尔酮吡啶盐。查尔酮骨架的引入，不但起到了活化吡啶的作用，同时还引入一个亲电位点(羰基β-位)，为串联反应设计提供了可能。将其与双亲核试剂烯胺酮反应，成功应用于复杂含氮桥环的构筑中。
发明内容
针对现有技术中存在的问题，本发明提供一种查尔酮吡啶盐的制备方法及应用，其操作简单、反应条件温和、且目标产物容易分离，将其与双亲核试剂烯胺酮反应，应用在含氮桥环化合物的构建当中。
为解决上述技术问题，本发明采用以下技术方案：
一种查尔酮吡啶盐，其结构式如下：
Figure BDA0002173710270000011
其中，R1为H、卤原子；R2为H、卤原子或烷基。
所述的查尔酮吡啶盐的制备方法，步骤如下：将溴代甲基查尔酮和3-硝基吡啶，在有机溶剂中，60-80℃反应16h，薄层色谱跟踪反应至完全，反应结束后，通过布氏漏斗过滤分离纯化，得到目标产物，其反应通式如下：
Figure BDA0002173710270000021
其中，R1为H、卤原子；R2为H、卤原子或烷基。
进一步，所述的有机溶剂为乙腈。
进一步，所述反应温度为60℃。
进一步，所述溴代甲基查尔酮和3-硝基吡啶的摩尔比为1:1-1.5:1，优选为1.1:1。
所述的查尔酮吡啶盐在构筑复杂含氮桥环中的应用如下：将查尔酮吡啶盐和烯胺酮，在乙腈中，80℃反应2h，薄层色谱跟踪反应至完全，反应结束后，通过柱色谱进行纯化，得到目标产物，其反应式如下：
Figure BDA0002173710270000022
其中查尔酮吡啶盐和烯胺酮的摩尔比为1.2:1。
本发明的有益效果：本发明通过将溴代甲基查尔酮和3-硝基吡啶，加在乙腈溶剂中，在60℃的温度下发生反应来制备新型的查尔酮吡啶盐。本发明引入查尔酮骨架，开发了吡啶新的活化基团，引入新的反应位点，为后续的串联反应提供了可能。目标产物容易分离；操作简单、反应条件温和，并且将本发明开发的查尔酮吡啶盐成功应用于含氮复杂桥环的高效非对映选择性合成中。
附图说明
图1为吡啶常见的活化模式以及本专利申请的查尔酮吡啶盐。
图2为实施例1化合物3a的1H NMR图；
图3为实施例1化合物3a的13C NMR图；
图4为实施例2化合物5a的X-射线单晶衍射图。
具体实施方式
下面结合具体实施例，对本发明做进一步说明。应理解，以下实施例仅用于说明本发明而非用于限制本发明的范围，该领域的技术熟练人员可以根据上述发明的内容作出一些非本质的改进和调整。
实施例1
查尔酮吡啶盐3a的制备：往25mL圆底烧瓶中，加入溴代甲基查尔酮1a(8.8mmol，2.62g)，3-硝基吡啶2a(8.0mmol，0.99g)，然后加入10mL乙腈，混合物在60℃搅拌16h。反应完全后，过滤，滤饼即为目标化合物3a(黄色固体，88％收率)。
所得化合物3a的核磁共振氢谱、碳谱、红外以及高分辨质谱数据如下:
1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),9.41(d,J＝8.0Hz,1H),9.37(d,J＝8.0Hz,1H),8.47(dd,J 1＝J2＝8.0Hz,1H),8.17-8.14(m,3H),8.08(d,J＝16.0Hz,1H),7.88(d,J＝16.0Hz,1H),7.70(t,J＝8.0Hz,1H),7.61-7.50(m,4H),7.22(d,J＝8.0Hz,1H),6.43(s,2H)；13C NMR(100MHz,DMSO-d6)δ189.5,150.2,147.0,143.4,141.1,139.5,137.6,134.5,133.9,133.4,131.3,130.2,129.7,129.6,129.4,129.1,128.7,126.4,61.9.IR(KBr)ν3421,3021,1655,1599,1348cm-1.HRMS(ESI)calcd.for C21H17N2O3[M-Br]+:345.1234,found:345.1232.
化合物3b-l的制备方法同化合物3a，投料比与化合物3a相同，可得到化合物3b-l，反应产率如下，但需要强调的是本发明的化合物并不局限于以下所示化合物。
含有不同取代基的查尔酮吡啶盐的制备结果如下所示：
Figure BDA0002173710270000041
化合物3b(黄色固体，67％收率，通过过滤分离纯化):1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.41(d,J＝8.0Hz,1H),9.37(d,J＝8.0Hz,1H),8.47(t,J＝8.0Hz,1H),8.20-8.18(m,2H),8.16(d,J＝4.0Hz,1H),8.09(d,J＝12.0Hz,1H),7.87(d,J＝16.0Hz,1H),7.66(d,J＝12.0Hz,2H),7.57(t,J＝8.0Hz,1H),7.52(t,J＝8.0Hz,1H),7.23(d,J＝8.0Hz,1H),6.43(s,2H)；13C NMR(100MHz,DMSO)δ188.4,150.1,147.1,143.3,141.1,140.0,138.9,136.3,134.4,133.5,131.4,131.1,130.2,129.7,129.6,129.5,128.7,126.1,61.9.IR(KBr)ν3442,3001,1649,1595,1334cm-1.HRMS(ESI)calcd.for C21H16ClN2O3[M-Br]+:379.0844,found:379.0840.
化合物3c(黄色固体，82％收率，通过过滤分离纯化):1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.41(d,J＝8.0Hz,1H),9.38(d,J＝8.0Hz,1H),8.47(t,J＝8.0Hz,1H),8.15(d,J＝8.0Hz,1H),8.11(d,J＝8.0Hz,1H),8.09(d,J＝12.0Hz,2H),7.86(d,J＝16.0Hz,1H),7.80(d,J＝12.0Hz,2H),7.57(t,J＝8.0Hz,1H),7.52(t,J＝8.0Hz,1H),7.24(d,J＝8.0Hz,1H),6.43(s,2H)；13C NMR(100MHz,DMSO-d6)δ188.7,150.2,147.0,143.3,141.1,140.0,136.6,134.4,133.6,132.4,131.4,131.2,130.2,129.7,129.6,128.7,128.1,126.1,61.9.IR(KBr)ν3433,2999,1650,1593,1349cm-1.HRMS(ESI)calcd.for C21H16BrN2O3[M-Br]+:423.0339,found:423.0334.
化合物3d(黄色固体，70％收率，通过过滤分离纯化):1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.43-9.37(m,2H),8.48(dd,J1＝8.0Hz,J2＝4.0Hz,1H),8.17(d,J＝8.0Hz,2H),8.14(d,J＝8.0Hz,1H),8.03(d,J＝16.0Hz,1H),7.87(d,J＝16.0Hz,1H),7.56(t,J＝8.0Hz,1H),7.50(t,J＝8.0Hz,1H),7.24(d,J＝8.0Hz,1H),7.10(d,J＝12.0Hz,2H),6.44(s,2H),3.87(s,3H)；13C NMR(100MHz,DMSO-d6)δ187.6,163.9,150.1,147.0,143.3,141.1,138.7,134.7,133.3,131.6,131.1,130.5,130.2,129.7,129.6,128.6,126.5,114.6,62.0,56.1.IR(KBr)ν3444,2922,1648,1598,1329cm-1.HRMS(ESI)calcd.for C22H19N2O4[M-Br]+:375.1339,found:375.1346.
化合物3e(黄色固体，80％收率，通过过滤分离纯化):1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.42(d,J＝12.0Hz,1H),9.38(d,J＝8.0Hz,1H),8.48(dd,J1＝J2＝4.0Hz,1H),8.20-8.18(m,2H),8.14-8.09(m,2H),7.90(d,J＝16.0Hz,1H),7.76(d,J＝8.0Hz,1H),7.62(t,J＝8.0Hz,1H),7.59-7.51(m,2H),7.25(d,J＝8.0Hz,1H),6.44(s,2H)；13C NMR(100MHz,DMSO-d6)δ188.3,150.1,147.1,143.3,141.1,140.3,139.5,134.4,134.3,133.6,133.5,131.5,131.4,130.2,129.7,129.7,128.8,128.7,127.8,126.0,61.9.IR(KBr)ν3440,3010,1653,1602,1319cm-1.HRMS(ESI)calcd.for C21H16ClN2O3[M-Br]+:379.0844,found:379.0843.
化合物3f(黄色固体，83％收率，通过过滤分离纯化):1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.41(d,J＝8.0Hz,1H),9.37(d,J＝8.0Hz,1H),8.47(dd,J1＝J2＝8.0Hz,1H),8.32(s,1H),8.18(t,J＝8.0Hz,2H),8.11(d,J＝12.0Hz,1H),7.90(d,J＝8.0Hz,2H),7.59-7.51(m,3H),7.24(d,J＝8.0Hz,1H),6.44(s,2H)；13C NMR(100MHz,DMSO-d6)δ188.2,150.1,147.0,143.3,141.1,140.3,139.6,136.5,134.3,133.5,131.6,131.6,131.5,130.2,129.7,129.6,128.8,128.1,125.9,122.8,61.9.IR(KBr)ν3445,3012,1653,1615,1320cm- 1.HRMS(ESI)calcd.for C21H16BrN2O3[M-Br]+:423.0339,found:423.0334.
化合物3g(黄色固体，50％收率，通过过滤分离纯化):1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),9.43-9.38(m,2H),8.48(dd,J1＝J2＝8.0Hz,1H),8.15(d,J＝8.0Hz,1H),8.07(d,J＝16.0Hz,1H),7.97(t,J＝8.0Hz,2H),7.87(d,J＝16.0Hz,1H),7.59-7.45(m,4H),7.24(d,J＝8.0Hz,1H),6.45(s,2H),2.42(s,3H)；13C NMR(100MHz,DMSO-d6)δ189.5,150.2,147.0,143.4,141.1,139.4,138.8,137.6,134.5,134.5,133.4,131.2,130.2,129.7,129.7,129.6,129.2,128.7,126.5,126.4,61.9,21.36.IR(KBr)ν3441,2922,1648,1547,1354cm-1.HRMS(ESI)calcd.for C22H19N2O3[M-Br]+:359.1390,found:359.1390.
化合物3h(黄色固体，57％收率，通过过滤分离纯化):1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.44(d,J＝12.0Hz,1H),9.32(d,J＝4.0Hz,1H),8.48(dd,J1＝J2＝8.0Hz,1H),7.99(d,J＝8.0Hz,1H),7.80(t,J＝16.0Hz,1H),7.75(t,J＝8.0Hz,1H),7.61-7.47(m,5H),7.25(d,J＝16.0Hz,1H),7.16(d,J＝8.0Hz,1H),6.34(s,2H)；13C NMR(100MHz,DMSO-d6)δ193.5,150.1,147.1,143.3,141.2,141.0,140.7,133.8,133.4,132.8,131.6,130.3,130.0,129.8,129.7,129.4,128.6,128.4,119.2,61.8.IR(KBr)ν3440,3010,1651,1545,1315cm-1.HRMS(ESI)calcd.for C21H16BrN2O3[M-Br]+:423.0339,found:423.0340.
化合物3i(黄色固体，59％收率，通过过滤分离纯化):1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),9.44-9.39(m,2H),8.49(dd,J1＝4.0Hz,J2＝8.0Hz,1H),8.25(dd,J1＝J2＝8.0Hz,1H),8.18(d,J＝12.0Hz,2H),8.03(d,J＝16.0Hz,1H),7.89(d,J＝8.0Hz,1H),7.70(t,J＝8.0Hz,1H),7.59(t,J＝8.0Hz,2H),7.46-7.41(m,1H),7.09(d,J＝12.0Hz,1H),6.34(s,2H)；13C NMR(100MHz,DMSO-d6)δ188.9,164.4,161.9,149.8,146.7,143.2,140.7,137.6(d,J＝88.0Hz,1C),135.7,133.5,130.7(d,J＝8.0Hz,1C),130.3(d,J＝8.0Hz,1C),129.3,128.9,128.6,125.7,116.1(d,J＝21.0Hz,1C),115.9(d,J＝23.0Hz,1C),60.9.IR(KBr)ν3441,3067,1653,1594,1355cm-1.HRMS(ESI)calcd.for C21H16FN2O3[M-Br]+:363.1139,found:363.1138.
化合物3j(黄色固体，47％收率，通过过滤分离纯化):1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),9.43-9.39(m,2H),8.48(dd,J1＝J2＝4.0Hz,1H),8.21-8.16(m,3H),8.03(d,J＝12.0Hz,1H),7.91(d,J＝16.0Hz,1H),7.70(t,J＝8.0Hz,1H),7.64((dd,J1＝J2＝4.0Hz,1H),.7.59(t,J＝8.0Hz,2H),7.37(d,J＝4.0Hz,1H),6.44(s,2H)；13C NMR(100MHz,DMSO-d6)δ189.4,150.2,147.1,143.7,141.2,138.4,137.5,135.8,135.3,134.0,133.4,130.5,130.2,129.7,129.4,129.2,126.9,61.3.IR(KBr)ν3448,2929,1648,1601,1353cm-1.HRMS(ESI)calcd.for C21H16ClN2O3[M-Br]+:379.0844,found:379.0848.
化合物3k(黄色固体，58％收率，通过过滤分离纯化):1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.37(d,J＝12.0Hz,1H),9.24(d,J＝4.0Hz,1H),8.40(dd,J1＝J2＝4.0Hz,1H),8.17-8.12(m,3H),8.05(d,J＝8.0Hz,1H),7.94(d,J＝16.0Hz,1H),7.73-7.67(m,2H),7.59(d,J＝8.0Hz,2H),7.49(t,J＝8.0Hz,1H),6.41(s,2H)；13C NMR(100MHz,DMSO-d6)δ188.9,161.6(d,J＝247.0Hz,1C),149.1,146.2,142.2,140.7,138.1(d,J＝3.0Hz,1C),137.8(d,J＝3.0Hz,1C),137.0,133.6,132.5(d,J＝10.0Hz,1C),129.1,128.9,128.7,127.9,124.5,118.9(d,J＝14.0Hz,1C),117.4(d,J＝22.0Hz,1C),55.3.HRMS(ESI)calcd.for C21H16FN2O3[M-Br]+:363.1139,found:363.1137.
化合物3l(黄色固体，71％收率，通过过滤分离纯化):1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),9.39(d,J＝8.0Hz,1H),9.35(t,J＝4.0Hz,1H),8.47-8.43(m,1H),8.18(d,J＝8.0Hz,2H),8.10(dd,J1＝J2＝4.0Hz,1H),8.02(d,J＝16.0Hz,1H),7.96(d,J＝16.0Hz,1H),7.70(t,J＝8.0Hz,1H),7.59(t,J＝8.0Hz,2H),7.48-7.38(m,2H),6.41(s,2H)；13C NMR(100MHz,DMSO-d6)δ188.9,162.7(d,J＝245.0Hz,1C),149.5,146.4,142.7,140.6,137.7,136.9,136.9,133.6,132.4(d,J＝9.0Hz,1C),129.2,129.0,128.9,128.7,127.2,117.5(d,J＝22.0Hz,1C),114.8(d,J＝23.0Hz,1C),60.8.IR(KBr)ν3442,2998,1655,1605,1351cm- 1.HRMS(ESI)calcd.for C21H16FN2O3[M-Br]+:363.1139,found:363.1137.
实施例2
含氮复杂桥环化合物5a的制备：往10mL硬质玻璃反应试管中，加入查尔酮吡啶盐3a(0.18mmol，76.6mg)，烯胺酮4a(0.15mmol，34.4mg)，1.0mL乙腈，然后加入51.9mg四甲基胍(0.45mmol)，混合物在60℃搅拌5min。反应完全后，旋干，柱色谱分离纯化。得到目标产物5a(黄色固体，65.6mg，收率76％，>20:1dr)。
所得化合物5a的核磁共振氢谱、碳谱以及高分辨质谱数据如下:
1H NMR(400MHz,CDCl3)δ7.96(d,J＝8.0Hz,2H),7.58(t,J＝8.0Hz,1H),7.46(t,J＝8.0Hz,2H),7.16(d,J＝8.0Hz,2H),7.12(d,J＝8.0Hz,1H),7.07(t,J＝8.0Hz,1H),6.96(d,J＝8.0Hz,2H),6.89(d,J＝8.0Hz,2H),6.16(d,J＝8.0Hz,1H),5.23(t,J＝8.0Hz,1H),5.06(s,1H),4.53(d,J＝4.0Hz,1H),4.44-4.31(m,3H),3.72-3.58(m,2H),2.36(s,3H),2.14(q,J＝8.0Hz,2H),1.91(d,J＝20.0Hz,1H),1.72(d,J＝20.0Hz,1H),0.87(s,3H),0.81(s,3H)；13C NMR(100MHz,CDCl3)δ196.2,192.4,156.4,139.2,138.0,137.5,136.3,135.1,133.7,133.5,129.9,128.7,128.1,128.0,127.6,127.4,125.8,108.0,107.1,88.9,74.0,58.5,49.3,40.7,38.5,35.3,32.7,29.3,28.5,27.5,21.1.HRMS(ESI)calcd.for C36H36N3O4[M+H]+:574.2700,found:574.2698.
以上显示和描述了本发明的基本原理和主要特征以及本发明的优点。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，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。

Claims (8)

1.一种查尔酮吡啶盐，其特征在于结构式如下：
Figure 196560DEST_PATH_IMAGE001
，其中，R1为H、卤原子；R2为H、卤原子或烷基。
2.根据权利要求1所述的查尔酮吡啶盐的制备方法，其特征在于步骤如下：将溴代甲基查尔酮和3-硝基吡啶，在有机溶剂中，60-80℃反应16 h，薄层色谱跟踪反应至完全，反应结束后，通过布氏漏斗过滤分离纯化，得到目标产物，其反应通式如下：
Figure 396598DEST_PATH_IMAGE002
，
其中，R1为H、卤原子；R2为H、卤原子或烷基。
3.根据权利要求2所述的查尔酮吡啶盐的制备方法，其特征在于：所述的有机溶剂为乙腈。
4.根据权利要求2所述的查尔酮吡啶盐的制备方法，其特征在于：所述反应温度为60℃。
5.根据权利要求2所述的查尔酮吡啶盐的制备方法，其特征在于：所述溴代甲基查尔酮和3-硝基吡啶的摩尔比为1:1-1.5:1。
6.根据权利要求5所述的查尔酮吡啶盐的制备方法，其特征在于：所述溴代甲基查尔酮和3-硝基吡啶的摩尔比为1.1:1。
7.根据权利要求1所述的查尔酮吡啶盐在构筑复杂含氮桥环中的应用，其特征在于：将查尔酮吡啶盐和烯胺酮，在乙腈中，四甲基胍（TMG）作为碱，80℃反应2 h，薄层色谱跟踪反应至完全，反应结束后，通过柱色谱进行纯化，得到目标产物，其反应式如下：
Figure 435967DEST_PATH_IMAGE004
。
8.根据权利要求7所述的应用，其特征在于：所述查尔酮吡啶盐和烯胺酮的摩尔比为1.2:1。
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An Unexpected FeCl3‑Catalyzed Cascade Reaction of Indoles and o‑Hydroxychalcones for the Assembly of Chromane-Bridged Polycyclic Indoles;Wenbo Wang et al.;《Org. Lett.》;20180531;第20卷;3451-3454 *
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