CN112961105B - 一种含氮杂环化合物的烷基化方法 - Google Patents

一种含氮杂环化合物的烷基化方法 Download PDF

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CN112961105B
CN112961105B CN202110119699.3A CN202110119699A CN112961105B CN 112961105 B CN112961105 B CN 112961105B CN 202110119699 A CN202110119699 A CN 202110119699A CN 112961105 B CN112961105 B CN 112961105B
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冯高峰
沈方旗
徐畅
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University of Shaoxing
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Abstract

本发明公开了一种含氮杂环化合物的烷基化方法，其特征在于，包括以下步骤：有机溶剂中，含氮杂环化合物、烷基试剂、酸、过氧化物，Selectfluor氟试剂，Cu催化剂混合后，加热至40~60℃下搅拌一定时间，所生成的产物经萃取、柱层析等得到高纯度的含氮杂环烷基化衍生物。本发明原料简单易得、反应条件绿色、温和、操作简单，使用廉价金属催化剂，且产品收率好，具有很好工业化应用价值。

Description

一种含氮杂环化合物的烷基化方法
技术领域
本发明属于医药技术领域，尤其涉及了一种含氮杂环化合物的烷基化方法。
技术背景
含氮杂环化合物是一类具有多样生物、生理活性的重要化合物。普遍存于药物、天然产物和配体支架中。在药物化学中，烷基对药物代谢和药代动力学特性具有神奇的作用。对将烷基直接引入杂芳烃的需求不断增长。Minisci反应的特征是将烷基直接加成到杂环芳烃上，在现代药物发展中引起了广泛关注，如何绿色高效、原子经济的合成一直是有机合成研究的重点之一。
近年来，化学工作者对含氮杂环化合物C-H进行了大量的烷基化工作，所得含氮杂环衍生物可用于合成各类药物中间体。该方面的工作不仅丰富了含氮杂环烷基化衍生物的种类，也拓展了含氮杂环在医药方面的应用。含氮杂环烷基化衍生物的合成具有非常重要的意义。然而，目前，对含氮杂环的C-H键的烷基化大多数是与卤代烃，烷基硼酸等进行反应，反应所需成本较高，底物限制较大。因此，需要发展一些脂肪烃的sp3 C-H键直接官能团化快速构建含氮杂环烷基化的方法。这些方法可以将轻质烷烃等化学原料转化为高价值产品，也可以在后期将更多功能引入天然产物或药物中。
基于此近年来许多新方法被化学工作者们发现并报道，其中比较常见方法是使用光催化和银催化使含氮杂环烷基化，这两种方法有一定的优点如底物普适性广等，但同时也存在一定的缺陷，光催化需要使用价格昂贵的Ir催化剂，同时反应放大比较困难，难以实现工业化的生产，而银催化的产率普遍较低。因此，发展一种催化成本低、而又高效率地构建含氮杂环烷基化的方法，具有十分重大的意义。
发明内容
本发明的目的是提供一种催化成本低、操作简单方便、产率高的含氮杂环化合物的烷基化方法。
本发明为实现上述目的，采取的技术方案如下：
一种含氮杂环化合物的烷基化方法，其特征在于，包括以下步骤：有机溶剂中，含氮杂环化合物、烷基试剂、酸、过氧化物，Selectfluor氟试剂，Cu催化剂混合后在加热40～60℃下搅拌一定时间，所生成的产物经萃取、柱层析等得到高纯度如式(3)所示的含氮杂环烷基化衍生物。
制备涉及的反应方程式如下所示。
Figure BDA0002921546500000021
作为上述方法的优先方案：
所述的有机溶剂为乙腈、丙酮、乙腈与二氯甲烷的混合溶剂中的一种。
所述的所述的含氮杂环化合物、烷基试剂、酸、Selectfluor氟试剂、过氧化物、五种物质的物质的量之比为1:10:1～2：2～4：1～2。
所述的含氮杂环化合物为取代的吡嗪、嘧啶、喹啉、异喹啉、吡啶、哒嗪中的任意一种，优选为：
Figure BDA0002921546500000022
。
所述的烷基试剂为环十二烷、环己烷、环己酮、四氢呋喃、二氧六环、三聚甲醛、四氢吡喃等中的任意一种。
所述的酸为三氯乙酸、三氟乙酸、三氟甲磺酸、98％浓硫酸中的任意一种。
所述过氧化物为过硫酸钠、过硫酸铵、过硫酸钾的任意一种。
所述的Cu催化剂为Cu粉、五水硫酸铜、三氟甲磺酸铜、碘化亚铜的任意一种，Cu催化剂的摩尔催化量为含氮杂环的5～10mol％。
所述的加热温度优选为40～60℃。
本发明的有益效果如下：
(1)、催化剂的选择：发明人通过对反应机理的分析，以及大量实验总结，最终确定以铜催化剂作为本发明的催化剂，与现有采用光催化反应(Ir络合物)和银催化的方法相比，本发明使用铜催化剂，具有成本低廉、容易获得等优点；
(2)、反应条件温和、操作更简单：本发明只需将原料混合后加热至40～60℃搅拌即可生成产物，且反应体系无需进行除水和无氧操作。
(3)、含氮杂环化合物、环己烷衍生物简单易得，容易通过改变原料得到结构多样的叔胺衍生物。
(4)、通过优化反应条件，可以有效提高反应收率，最高可达到97％.
(5)、烷基化试剂为饱和烷烃或者具有sp3 C-H键的试剂、原料简单易得，价格便宜。
以下结合具体实施方式对本发明做进一步说明。
具体实施方式
实施例1
在20mL反应管中依次加入磁子、4-甲基喹啉(0.5mmol)，环己烷(5mmol)，Selectfluor氟试剂(1mmol)，不同金属催化剂(5mol％),三氟乙酸(0.5mmol),乙腈5mL，在加热至40～60℃下反应16小时。反应液用乙酸乙酯萃取，旋蒸，柱层析分离，旋转蒸发除去溶剂，真空油泵抽干后得到产物3a。称重计算得到产物3a收率，如表1所示。
表1、不同金属催化剂对反应的影响和效果：
序号 催化剂 收率
实施例1-1 CuI 43％
实施例1-2 AgNO<sub>3</sub> 0％
实施例1-3 FeSO<sub>4</sub>·7H<sub>2</sub>O 0％
实施例1-4 CoC<sub>2</sub>O<sub>4</sub>·2H<sub>2</sub>O 0％
实施例1-5 Pd(OAc)<sub>2</sub> 39％
。
分析：如表1所示，不同的金属催化剂，催化效果不同，在其他条件相同的情下，使用CuI催化得到的产物产率最高，且成本更廉价。
产物3a经1H-NMR和13C-NMR确定，1H-NMR和13C-NMR数据和结构如下：
Figure BDA0002921546500000041
1H NMR(400MHz,CDCl3)δppm 8.05(d,J＝8.4Hz,1H),7.94(d,J＝8.4Hz,1H),7.68-7.64(m,1H),7.51-7.47(m,1H),7.17(s,1H),2.88(tt,J＝13.0,3.2Hz,1H),2.68(s,3H),2.07-1.99(m,2H),1.91-1.87(m,2H),1.81-1.76(m,1H),1.67-1.57(m,2H),1.52-1.41(m,2H),1.39-1.31(m,1H).
13C NMR(100MHz,CDCl3)δppm 166.5,147.6,144.2,129.5,128.9,127.0,125.4,123.6,120.2,47.6,32.8(*2),26.6(*2),26.1,18.8。
实施例2
在20mL反应管中依次加入磁子、4-甲基喹啉(0.5mmol)、环己烷(5mmol)，Selectfluor氟试剂(1mmol)、碘化亚铜(5mol％)、各种不同酸(0.5mmol)、乙腈5mL，在加热至40～60℃下反应16小时。反应液用乙酸乙酯萃取，旋蒸，柱层析分离，旋转蒸发除去溶剂，真空油泵抽干后得到产物3a。称重计算得到产物3a收率，如表2所示。
表2、不同酸对反应的影响和效果：
序号 酸 收率
实施例2-1 三氟乙酸(TFA) 43％
实施例2-2 盐酸(HCl) 0％
实施例2-3 硫酸(H<sub>2</sub>SO<sub>4</sub>) 39％
实施例2-4 三氟甲磺酸(TfOH) 36％
实施例2-5 三氯乙酸(TCA) 24％
。
分析：如表2所示，不同酸的选择，对于反应收率有较大影响，通过对比显示，在其他条件相同的情况下，使用三氟乙酸得到的产物产率最高。
实施例3
在20mL反应管中依次加入磁子、4-甲基喹啉(0.5mmol)、环己烷(5mmol)、Selectfluor氟试剂(1mmol)、碘化亚铜(5mol％)、三氟乙酸(0.5mmol)、有机溶剂5mL，在加热至40～60℃下反应16小时。反应液用乙酸乙酯萃取，旋蒸，柱层析分离，旋转蒸发除去溶剂，真空油泵抽干后得到产物3a。称重计算得到产物3a收率，如表3所示。
表3、不同溶剂对反应的影响和效果：
序号 有机溶剂 收率
实施例3-1 MeCN 43％
实施例3-2 acetone 19％
实施例3-3 THF 0％
实施例3-4 MeCN:H<sub>2</sub>O＝4:1 Trace
实施例3-5 CH<sub>2</sub>Cl<sub>2</sub> 0％
。
分析：如表3所示，不同溶剂对反应收率有较大影响，通过对比显示，在其他条件相同的情况下，使用乙腈作为有机溶剂时得到的产物产率最高。
实施例4
在20mL反应管中依次加入磁子、4-甲基喹啉(0.5mmol)，环己烷(5mmol)，Selectfluor氟试剂(x mmol),过硫酸钠(y mmol)，碘化亚铜(5mol％),三氟乙酸(0.5mmol),乙腈5mL，在加热至40～60℃下反应16小时。反应液用乙酸乙酯萃取，旋蒸，柱层析分离，旋转蒸发除去溶剂，真空油泵抽干后得到产物3a。称重计算得到产物3a收率，如表4所示。
表4、Selectfluor氟试剂和过硫酸钠的用量对反应的影响和效果
序号 Selectfluor氟试剂用量X 过硫酸钠用量y 收率
实施例4-1 1.0mmol 0mmol 43％
实施例4-2 1.0mmol 0.5mmol 63％
实施例4-3 2.0mmol 1.0mmol 92％
实施例4-4 2.0mmol 0mmol 69％
实施例4-5 0mmol 1.0mmol 0％
。
结合实施例1-4，和表1-4所示：
(1)、在不加入过硫酸钠的情况下，反应的收率普遍不高，最高不超过50％；
(2)、随着过硫酸钠用量的增加，反应的收率有显著提高，当选用1.0mmol的过硫酸钠和2.0mmol的选择性氟试剂时，得到的产物产率最高。
(3)、综合以上实施例1-4，最优工艺条件是：选用乙腈作为有机溶剂，5mol％的CuI作为催化剂，1当量的三氟乙酸，2当量的过硫酸钠，4当量的选择性氟试剂作为添加剂。
实施例5
在20mL反应管中依次加入磁子，4-甲基喹啉(0.5mmol)，四氢吡喃(5mmol)，Selectfluor氟试剂(2mmol),过硫酸钠(1mmol)，碘化亚铜(5mol％),三氟乙酸(0.5mmol),乙腈5mL，在加热至40～60℃下反应16小时。反应液用乙酸乙酯萃取，旋蒸，柱层析分离，旋转蒸发除去溶剂，真空油泵抽干后得到产物3h(产率75％)，产物结构经1H-NMR和13C-NMR确定，1H-NMR和13C-NMR数据和结构如下：
Figure BDA0002921546500000061
1H NMR(400MHz,CDCl3)δppm 8.05(d,J＝8.4,1H),7.93(d,J＝8.0,1H),7.67-7.63(m,1H),7.51-7.47(m,1H),7.45(s,1H),4.59(dd,J＝10.8,2.0,1H),4.20(dt,J＝12.0,1.6,1H),3.68(td,J＝12.0,2.8,1H),2.68(s,3H),2.10-2.11(m,1H),1.98-1.92(m,1H),1.77-1.71(m,2H),1.67-1.57(m,2H).
13C NMR(100MHz,CDCl3)δppm 162.1,147.2,145.0,129.6,129.1,116.8,127.5,125.8,123.7,118.8,81.6,68.9,32.8,25.9,23.7,18.9。
实施例6
在20mL反应管中依次加入磁子，4-溴异喹啉(0.5mmol)，环己烷(5mmol)，Selectfluor氟试剂(2mmol),过硫酸钠(1mmol)，碘化亚铜(5mol％),三氟乙酸(0.5mmol),乙腈5mL，在加热至40～60℃下反应16小时。反应液用乙酸乙酯萃取，旋蒸，柱层析分离，旋转蒸发除去溶剂，真空油泵抽干后得到产物3b(产率83％)，产物结构经1H-NMR和13C-NMR确定，1H-NMR和13C-NMR数据和结构如下：
Figure BDA0002921546500000062
1H NMR(400MHz,CDCl3)δppm 8.65(s,1H),8.21(d,J＝8.4Hz,1H),8.17(d,J＝8.0Hz,1H),7.75(t,J＝8.4Hz,1H),7.63(t,J＝8.0Hz,1H),3.51(tt,J＝11.6,3.2Hz,1H),1.98-1.90(m,4H),1.84-1.77(m,3H),1.58-1.42(m,2H),1.39-1.31(m,1H).
13C NMR(100MHz,CDCl3)δppm 165.4,143.6,134.9,130.8,127.7,127.6,125.1,117.5,41.5,32.5(*2),26.8(*2),26.2。
实施例7
在20mL反应管中依次加入磁子，2,3,5-三甲基吡嗪(0.5mmol)，环己烷(5mmol)，Selectfluor氟试剂(2mmol),过硫酸钠(1mmol)，碘化亚铜(5mol％),三氟乙酸(0.5mmol),乙腈5mL，在加热至40～60℃下反应16小时。反应液用乙酸乙酯萃取，旋蒸，柱层析分离，旋转蒸发除去溶剂，真空油泵抽干后得到产物3c(产率64％)，产物结构经1H-NMR和13C-NMR确定，1H-NMR和13C-NMR数据和结构如下：
Figure BDA0002921546500000071
1H NMR(400MHz,CDCl3)δppm 2.71(tt,J＝11.2,3.6Hz,1H),2.44(s,3H),2.39(s,3H),2.38(s,3H),1.81-1.78(m,3H),1.69-1.54(m,5H),1.38-1.20(m,3H).
13C NMR(100MHz,CDCl3)δppm 155.4,148.3,147.4,146.7,41.3,31.5(*2),26.6(*2),25.9,21.6,21.3,20.7。
实施例8
在20mL反应管中依次加入磁子，2-氯-3-氰基吡嗪(0.5mmol)，环己烷(5mmol)，Selectfluor氟试剂(2mmol),过硫酸钠(1mmol)，碘化亚铜(5mol％),三氟乙酸(0.5mmol),乙腈5mL，在加热至40～60℃下反应16小时。反应液用乙酸乙酯萃取，旋蒸，柱层析分离，旋转蒸发除去溶剂，真空油泵抽干后得到产物3d(产率48％)，产物结构经1H-NMR和13C-NMR确定，1H-NMR和13C-NMR数据和结构如下：
Figure BDA0002921546500000072
1H NMR(400MHz,CDCl3)δppm 8.47(s,1H),2.82(tt,J＝12.0,2.8Hz,1H),1.95-1.86(m,4H),1.79-1.75(m,1H),1.61-1.52(m,2H),1.44-1.32(m,2H),1.33-1.25(m,1H).
13C NMR(100MHz,CDCl3)δppm 165.6,150.8,141.8,127.2,114.1,44.1,31.9(*2),25.9(*2),25.5。
实施例9
在20mL反应管中依次加入磁子，4-氯喹啉(0.5mmol)，环己烷(5mmol)，Selectfluor氟试剂(2mmol),过硫酸钠(1mmol)，碘化亚铜(5mol％),三氟乙酸(0.5mmol),乙腈5mL，在加热至40～60℃下反应16小时。反应液用乙酸乙酯萃取，旋蒸，柱层析分离，旋转蒸发除去溶剂，真空油泵抽干后得到产物3e(产率93％)，产物结构经1H-NMR和13C-NMR确定，1H-NMR和13C-NMR数据和结构如下：
Figure BDA0002921546500000081
1H NMR(400MHz,CDCl3)δppm 8.14(d,J＝8.0Hz,1H),8.04(d,J＝8.0Hz,1H),7.71-7.67(m,1H),7.55-7.51(m,1H),7.40(s,1H),2.87(tt,J＝12.0,3.2Hz,1H),2.02-1.99(m,2H),1.90-1.85(m,2H),1.79-1.75(m,1H),1.64-1.53(m,2H),1.49-1.38(m,2H),1.34-1.30(m,1H).
13C NMR(100MHz,CDCl3)δppm 146.7,146.5,130.6(×2),129.7,129.4,129.2(×2),119.1,116.6,112.6(×2),112.5,62.5,49.3,36.0,23.1.
实施例10
在20mL反应管中依次加入磁子，2,3-二氮杂萘(0.5mmol)，环己烷(5mmol)，Selectfluor氟试剂(2mmol),过硫酸钠(1mmol)，碘化亚铜(5mol％),三氟乙酸(0.5mmol),乙腈5mL，在加热至40～60℃下反应16小时。反应液用乙酸乙酯萃取，旋蒸，柱层析分离，旋转蒸发除去溶剂，真空油泵抽干后得到产物3f(产率97％)，产物结构经1H-NMR和13C-NMR确定，1H-NMR和13C-NMR数据和结构如下：
Figure BDA0002921546500000091
1H NMR(400MHz,CDCl3)δppm 8.16-8.13(m,2H),7.83-7.81(m,2H),3.44(tt,J＝14.4,3.2Hz,2H),2.04-1.90(m,12H),1.81-1.78(m,2H),1.56-1.45(m,4H),1.41-1.33(m,2H).
13C NMR(100MHz,CDCl3)δppm 161.8(*2),131.1(*2),124.9(*2),124.2(*2),40.4(*2),32.3(*4),26.9(*4),26.3(*2)。
实施例11
在20mL反应管中依次加入磁子，2-甲基异烟酸甲酯(0.5mmol)，环己烷(5mmol)，Selectfluor氟试剂(2mmol),过硫酸钠(1mmol)，碘化亚铜(5mol％),三氟乙酸(0.5mmol),乙腈5mL，在加热至40～60℃下反应16小时。反应液用乙酸乙酯萃取，旋蒸，柱层析分离，旋转蒸发除去溶剂，真空油泵抽干后得到产物3g(产率48％)，产物结构经1H-NMR和13C-NMR确定，1H-NMR和13C-NMR数据和结构如下：
Figure BDA0002921546500000092
1H NMR(400MHz,CDCl3)δppm 7.49(s,2H),3.90(s,3H),2.72(tt,J＝11.2,3.6Hz,1H),2.57(s,3H),1.95-1.92(m,2H),1.84-1.81(m,2H),1.74-1.72(m,1H),1.52-1.29(m,4H),1.27-1.25(m,1H).
13C NMR(100MHz,CDCl3)δppm 167.3,166.3,158.6,137.9,119.8,116.8,52.5,46.7,33.0(*2),26.5(*2),26.0,24.6。

Claims (3)

1.一种含氮杂环化合物的烷基化方法，其特征在于，包括以下步骤：有机溶剂中，含氮杂环化合物、烷基试剂、酸、过氧化物，Selectfluor氟试剂、Cu催化剂混合后，加热至40～60℃下搅拌一定时间，所生成的产物经萃取、柱层析，得到含氮杂环烷基化衍生物；
Figure FDA0003750729910000011
所述的含氮杂环化合物、烷基试剂、酸、Selectfluor氟试剂、过氧化物五种物质的物质的量之比为1:10:1～2：2～4：1～2；所述过氧化物为过硫酸钠，所述的有机溶剂为乙腈、丙酮的一种，或者乙腈和二氯甲烷的混合溶剂；所述酸为三氯乙酸、三氟乙酸、三氟甲磺酸、98％浓硫酸的任意一种；所述的烷基试剂为环十二烷、环己烷、环己酮、四氢呋喃、二氧六环、三聚甲醛、四氢吡喃的任意一种；所述含氮杂环化合物结构如下：
Figure FDA0003750729910000012
。
2.根据权利要求1所述的一种含氮杂环化合物的烷基化方法，其特征在于：所述Cu催化剂为Cu粉、五水硫酸铜、三氟甲磺酸铜、碘化亚铜的任意一种。
3.根据权利要求1所述的一种含氮杂环化合物的烷基化方法，其特征在于：Cu催化剂的摩尔催化量为含氮杂环的5～10mol％。
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