CN103664769B - 一种联吡啶衍生物或类似物的合成方法 - Google Patents

一种联吡啶衍生物或类似物的合成方法 Download PDF

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CN103664769B
CN103664769B CN201310717930.4A CN201310717930A CN103664769B CN 103664769 B CN103664769 B CN 103664769B CN 201310717930 A CN201310717930 A CN 201310717930A CN 103664769 B CN103664769 B CN 103664769B
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段新方
廖连燕
孔兴蕊
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Beijing Normal University
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Abstract

本发明涉及一种无需外加配体的联吡啶衍生物或类似物的合成方法，该方法为2-卤代吡啶及衍生物或类似物，镍盐，锌粉或锰粉，与卤化盐，在溶剂中混合加热而获得偶联产物。本发明的优点在于：无需外加催化剂配体，特别是无需外加高毒性有机膦配体，催化剂镍盐价格低且用量小，操作简便，条件温和，易于放大，特别适合工业化生产，适用范围广泛，收率高，成本低和环境友好。

Description

一种联吡啶衍生物或类似物的合成方法
技术领域
本发明涉及有机化合物制备以及催化合成领域，具体涉及一种联吡啶衍生物及类似物的方法。
背景技术
联吡啶及类似物是一类非常重要的含氮型双齿配体，在配位化学、分析化学、超分子化学、纳米化学等中有着极其广泛的应用[Hapke,M.；Brandt,L.；Lützen,A.Chem.Soc.Rev.2008,37,2782]；在有机化学中，联吡啶化合物常常是过渡金属催化反应催化剂的优良配体，不少光学活性联吡啶又在不对称催化反应中占有重要的地位[Fletcher,N.C.J.Chem.Soc.,Perkin Trans.12002,1831]。同时，不少的联吡啶化合物在天然产物化学中也占有非常重要的地位。例如Caerulomycins与Collismycins系列联吡啶天然产物，显示出良好生物活性[Duan,X.F.；Ma,Z.Q.；Zhang,F.；Zhang,Z.B.J.Org.Chem.2009,74,939.]。
基于联吡啶及类似物的广泛应用和重要的生物活性，已有不少文献报道了此类化合物的合成方法，其中比较典型和通用的方法有下图所示两类：过渡金属催化的偶联反应和还原型偶联反应[Newkome,G.R.；Patri,A.K.；Holder,E.；Schubert,U.S.Eur.J.Org.Chem.2004,235]：
上述方法中方法(1)的优点是既可用于对称型产物的合成，也可用于非对称型产物的合成。但一个明显的局限是金属试剂(M＝Zn,SnR3等)的制备对此类底物而言非常困难，这些化合物的合成本身即是有机化学中一大难题之一。方法(2)虽然克服了上述金属试剂制备的困难，但由于人们一直认为生成的联吡啶或类似物可以络合催化金属(如Ni等)，从而使催化剂中毒而失去活性，因此此类反应通常要加入大量的催化金属Ni及配体，甚至使用等当量镍盐和四当量的三苯基膦才能使反应完成[Janiak,C.；Deblon,S.；Uehlin,S.Synthesis1999,959]。这显然为此类化合物的制备带来了极大的困难，并造成试剂的浪费和环境污染。此外，现行的方法(2)绝大多数仅适用于对称型产物的制备。上述的两种方法，由于使用了难以制备的金属试剂或使用了大量的催化金属及配体，使得这些方法一般停留于实验室应用，难以乃至无法用于工业生产。
发明内容
本发明的目的在于克服现有技术中，制备联吡啶及其类似物时的三大缺陷：(1)需使用难以制备的金属试剂；(2)需要添加大量金属催化剂/配体；(3)还原偶联大多数仅适用于对称型偶联；从而提供了一种通用的无需外加配体的自催化型联吡啶衍生物及类似物的合成方法。
本发明涉及一种无需外加配体的自催化型合成联吡啶衍生物或类似物的方法，所述方法包括：
2-卤代吡啶及衍生物或类似物，镍盐，锌粉或锰粉，与卤化盐，在溶剂中混合加热而获得偶联产物。
本发明所述的方法的反应如下式所示：
优选的，所述方法中的2-卤代吡啶衍生物包括一取代、二取代或多取代的2-卤代吡啶，取代基为烷基、烷氧基、苯基、酮基、酯基、氰基、酰胺基或苄醇基中的一种或多种。
优选的，所述的2-卤代吡啶类似物包括2-卤代哒嗪、2-卤代喹啉、2-卤代异喹啉、2-卤代喹喔啉以及一取代、二取代或多取代的2-卤代哒嗪、2-卤代喹啉、2-卤代异喹啉、2-卤代喹喔啉，取代基为烷基、烷氧基、苯基、酮基、酯基、氰基、酰胺基或苄醇基中的一种或多种。
所述2-卤代吡啶或其衍生物或其类似物包括两种不同的底物时，比如RX、R’X时，会同时发生三种偶联反应，即两底物自身的偶联反应和两底物间的偶联反应，为克服此问题，一般可控制其中一种底物的量过量，进而使得反应具有较好的选择性。即使当选择等当量的两种底物进行反应时，并期待获得底物间偶联的产物，虽然实际反应会产生不需要的两种底物自身偶联的产物，但是体系中也会有相应的底物间偶联产物产生，而这些产物则可以通过后续处理得到分离，虽然相对于同种底物偶联的选择性以及产率降低了，但是其为制备传统方法难以制备的产物提供了一种新的方法。
优选的，所述所述2-卤代吡啶或其衍生物或其类似物包括两种不同的底物，且一种底物相对于另一种底物过量50％。通过其中一种底物的过量添加，进而可以实现对偶联反应选择性的控制。
优选的，2-卤代吡啶及衍生物或类似物中卤原子为氯、溴和碘。
优选的，所述镍盐包括六水和氯化镍，无水氯化镍，醋酸镍、溴化镍、乙酰丙酮镍的任一种或多种。
优选的，所述溶剂为二甲基甲酰胺、二甲基乙酰胺、甲基吡咯烷酮或乙腈。
优选的，加热温度为40～90℃。
本发明中自催化型制备联吡啶衍生物及类似物，通过对反应机制的突破、对催化体系、催化剂用量和反应条件的根本改变，从而得到了一种实施性强的生产工艺路线。人们普遍认为联吡啶及类似物可以与催化金属络合，从而毒化催化剂，现行的措施是加大催化剂的用量，使用强络合型的配体如有机膦配体，以抵销联吡啶及类似物与催化金属的络合，而本发明经过精心设计、不断的总结和反复的探索，提出了新的机制和措施，即利用这一络合进行催化反应，从而突破了现行方法的限制，完全取消了使用外加配体，很大程度上降低催化剂的用量，使得人们普遍认为困难的合成变得温和、选择性高、通用型强，从而建立了一种高效，实用和较环保的制备方法。
对于目前现行的技术，2-卤吡啶衍生物的还原型偶联反应绝大多数情况下只适合对称型偶联反应，本发明通过经过不断总结和反复探索，特别是反复调整调料比，投料方式，使得本发明所提供的技术完全可以使用于两种不同卤代吡啶或类似物的交叉偶联，建立了一种新的操作简便、催化剂投料小、无需外加配体的制备非对称型联吡啶及类似物的合成方法。申请人已经成功将该法应用于天然产物CaerulomycinF的一步法合成。
本发明提供的联吡啶及类似物的新合成方法，是以常见且廉价的镍盐为催化金属，2-卤代吡啶及类似物在价格低廉的无机卤化盐与金属锌粉或锰粉作用下，一步合成出目标产物，其具有如下的优点：
1)不需要加入外加配体，如价格高、毒性大有机膦等配体。
2)催化金属的用量可低至2mol％。
3)操作简单，且条件温和，易于放大，特别适合工业化生产。
4)适用范围广泛，收率高，成本低。
具体实施方式
以下结合实施例对本发明进行进一步详细的描述，但需要指出的是本发明不仅仅局限于以下实施例。
实施例1、2,2'-联吡啶-5,5'-二甲酸甲酯的合成
六水氯化镍(0.12g,0.5mmol)加入20mL N,N-二甲基甲酰胺中，依次加入2-溴代吡啶-5-甲酸甲酯(2.16g,10mmol)、无水氯化锂(0.43g,10mmol)和锌粉(0.78g,12mmol)。体系加热40℃，加一粒碘引发反应，随后保温在55―60℃反应至反应完全。反应混合物中加入浓氨水中和至碱性，所得混合液用二氯甲烷萃取，有机层经无水碳酸钠干燥，回收溶剂，所得粗品经柱色谱纯化得目标产物2,2'-联吡啶-5,5'-二甲酸甲酯，收率：77％。
产物呈白色固体，mp：260.6-261.9℃.νmax(KBr)/cm-11727.1H NMR(400MHz,CDCl3):δ9.23(s,2H),8.52(s,2H),8.39(s,2H),3.93(s,6H)；13C NMR(100MHz,CDCl3):δ165.6,158.3,150.6,138.1,122.5,121.3,52.5.
实施例2、2,2'-喹喔啉的合成
六水氯化镍(0.12g,0.5mmol)加入20mL N,N-二甲基甲酰胺中，依次加入2-氯喹喔啉(1.65g,10mmol)、无水氯化锂(0.43g,10mmol)和锰粉(0.61g,12mmol)。体系加热40℃，加一粒碘引发反应，随后保温在55―60℃反应至反应完全。反应混合物中加入浓氨水中和至碱性，所得混合液用二氯甲烷萃取，有机层经无水碳酸钠干燥，回收溶剂，所得粗品经柱色谱纯化得目标产物2,2'-喹喔啉，收率：72％。
产物呈白色固体，mp193-195℃.1H NMR(400MHz,CDCl3):δ8.81(d,J＝8.6Hz,2H),8.28(d,J＝8.6Hz,2H),8.20(d,J＝8.3Hz,2H),7.83(d,J＝8.1Hz,2H),7.70(t,J＝7.2Hz,2H),7.52(t,J＝7.4Hz,2H)；13C NMR(100MHz,CDCl3):δ150.0,146.5,136.8,130.2,127.7,127.1,126.8,122.4,121.6.
实施例3、2,2'-联吡啶-6,6'-二甲腈的合成
六水氯化镍(0.05g,0.2mmol)加入20mL N,N-二甲基甲酰胺中，依次加入2-氯-6-氰基吡啶(1.39g,10mmol)、无水氯化锂(0.65g,15mmol)和锌粉(0.56g,11mmol)。体系加热40℃，加一粒碘引发反应，随后保温在55―60℃反应至反应完全。反应混合物中加入浓氨水中和至碱性，所得混合液用二氯甲烷萃取，有机层经无水碳酸钠干燥，回收溶剂，所得粗品经柱色谱纯化得目标产物2,2'-联吡啶-6,6'-二甲腈，收率：83％。
产物呈白色固体，mp264.5―265.9℃.νmax(KBr)/cm-12236.1H NMR(400MHz,CDCl3):δ8.73(d,J＝8.1Hz,2H),8.02(t,J＝7.8Hz,2H),7.78(d,J＝7.6Hz,2H)；13CNMR(100MHz,CDCl3):δ155.6,138.4,133.4,129.0,124.6,117.0.
实施例4、6-甲氧基-2,2’-联吡啶的合成
六水氯化镍(0.12g,0.5mmol)加入20mL N,N-二甲基甲酰胺中，依次加入2-溴吡啶(3.9g,25mmol)、2-溴-6-甲氧基吡啶(1.9g,10mmol)无水氯化锂(0.43g,10mmol)和锌粉(0.78g,12mmol)。体系加热40℃，加一粒碘引发反应，随后保温在55―60℃反应至反应完全。反应混合物中加入浓氨水中和至碱性，所得混合液用二氯甲烷萃取，有机层经无水碳酸钠干燥，回收溶剂，所得粗品经柱色谱纯化得目标产物6-甲氧基-2,2’-联吡啶，收率：85％。
产物呈无色液体；1H NMR(400MHz,CDCl3):δ8.64(s,1H),8.3(d,J＝8.0Hz,1H),8.02(d,J＝7.4Hz,1H),7.77(m,1H),7.68(t,J＝8.0Hz,1H),7.25(m,1H),6.77(d,J＝8.1Hz,1H),4.03(s,3H)；13C NMR(100MHz,CDCl3):δ163.5,156.0,153.3,149.0,139.4,136.9,123.5,121.1,113.8,111.1,53.2.
实施例5、2,2'-联吡啶-5-甲胺的合成
六水氯化镍(0.12g,0.5mmol)、无水氯化锂(0.43g,10mmol)和锌粉(0.78g,12mmol)加入20mL N,N-二甲基甲酰胺中。将2-氯吡啶(1.7g,15mmol)、2-氯-5-吡啶甲胺(1.43g,10mmol)与20mL N,N-二甲基甲酰胺配制成溶液。体系加热50℃时，滴加上述溶液，约滴加5mL左右时，加一粒碘引发反应，随后保温在55―60℃，缓慢滴加上述溶液，滴加约需3小时，滴加完毕后，于60―70℃保温反应至反应完全。反应混合物中加入浓氨水中和至碱性，所得混合液用二氯甲烷萃取，有机层经无水碳酸钠干燥，回收溶剂，所得粗品经柱色谱纯化得目标产物2,2'-联吡啶-5-甲胺，收率：71％。
产物呈浅黄色固体；mp68―69℃.1H NMR(400MHz,CDCl3):δ8.63(s,1H),8.54(s,1H),8.27(dd,J＝2.0Hz,J＝8.0Hz,2H),7.78(m,2H),7.30(m,1H),4.70(s,2H),3.53(s,2H)；13C NMR(100MHz,CDCl3):δ155.9,155.1,149.1,147.9,137.1,136.7,135.8,123.8,121.3,121.1,62.3.
实施例6、天然产物Caerulomycin F的合成
六水氯化镍(0.12g,0.5mmol)、无水氯化锂(0.43g,10mmol)和锌粉(0.78g,12mmol)加入20mL N,N-二甲基甲酰胺中。将2-溴吡啶(3.2g,20mmol)、6-溴-4-甲氧基-2-吡啶甲醇(2.2g,10mmol)与20mL N,N-二甲基甲酰胺配制成溶液。体系加热50℃时，滴加上述溶液，约滴加5mL左右时，加一粒碘引发反应，随后保温在55―60℃，缓慢滴加上述溶液，滴加约需3小时，滴加完毕后，于60―70℃保温反应至反应完全。反应混合物中加入浓氨水中和至碱性，所得混合液用二氯甲烷萃取，有机层经无水碳酸钠干燥，回收溶剂，所得粗品经柱色谱纯化得目标产物Caerulomycin F，收率：72％。
产物呈浅黄色固体；mp＝63―64℃；1H NMR(400MHz,CDCl3):δ8.67(d,J＝4.6Hz,1H),8.39(d,J＝8.0Hz,1H),7.89(s,1H),7.88―7.79(m,1H),7.33―7.30(m,1H),6.77(d,J＝2.0Hz,1H),4.77(s,2H),4.14(br s,1H),3.94(s,3H)；13C NMR(100MHz,CDCl3):δ167.3,160.9,156.5,155.5,148.9,136.9,123.9,121.3,106.6,105.3,64.3,55.3.

Claims (3)

1.一种联吡啶衍生物或类似物的合成方法，包括：
2-卤代吡啶及衍生物或类似物，镍盐，锌粉或锰粉，与卤化盐，在溶剂中混合加热而获得偶联产物；
所述2-卤代吡啶的衍生物包括2-卤代吡啶以及一取代、二取代或多取代的2-卤代吡啶，取代基为烷基、烷氧基、苯基、酮基、酯基、氰基、酰胺基或苄醇基中的一种或多种；
所述的2-卤代吡啶类似物包括2-卤代哒嗪、2-卤代喹啉、2-卤代异喹啉、2-卤代喹喔啉以及一取代、二取代或多取代的2-卤代哒嗪、2-卤代喹啉、2-卤代异喹啉、2-卤代喹喔啉，取代基为烷基、烷氧基、苯基、酮基、酯基、氰基、酰胺基或苄醇基中的一种或多种；
所述2-卤代吡啶及衍生物或类似物中卤原子为氯、溴和碘；
所述镍盐包括六水合氯化镍，无水氯化镍，醋酸镍、溴化镍、乙酰丙酮镍的任一种或多种；
所述卤化盐包括氯化锂、溴化锂、氯化钠、溴化钠、氯化镁或溴化镁的任一种或多种；
所述溶剂为二甲基甲酰胺、二甲基乙酰胺、甲基吡咯烷酮或乙腈；
所述加热温度为40～90℃。
2.根据权利要求1所述的方法，其特征在于，所述2-卤代吡啶及衍生物或类似物、镍盐、锌粉或锰粉与卤化盐的摩尔比为1：0.02：1.1：1.0～1：0.08：1.2：1.5。
3.根据权利要求1所述的方法，其特征在于，所述2-卤代吡啶及衍生物或类似物包括两种不同的底物，且一种底物相对于另外一种物质过量50％。
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