CN110642779B - 一种2,6-二芳基吡啶类物质及其制备方法 - Google Patents

一种2,6-二芳基吡啶类物质及其制备方法 Download PDF

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CN110642779B
CN110642779B CN201910961220.3A CN201910961220A CN110642779B CN 110642779 B CN110642779 B CN 110642779B CN 201910961220 A CN201910961220 A CN 201910961220A CN 110642779 B CN110642779 B CN 110642779B
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陈久喜
姚鑫容
戚林军
邵银林
李仁豪
赵志伟
刘继超
曾鸽
熊文章
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Abstract

本发明公开了一种2,6‑二芳基吡啶类物质及其制备方法，以5‑氧代‑5‑芳基戊腈和芳硼酸作为反应物进行反应制得；还加入了钯催化剂和酸性促进剂；钯催化剂为双(二亚苄基丙酮)钯或三(二亚苄基丙酮)二钯；酸性促进剂为三氟乙酸；反应温度为80‑100℃，反应时间为12‑24小时，整个反应在常压下进行，反应条件温和，容易达到，且安全。本发明方法可以直接合成目标产物，无需分离中间产物，反应过程简单产率最高可达到96％，大大简化了工艺工程，降低了能量消耗，具有高产率的优点；可以制备一系列的2,6‑二芳基吡啶类物质，该方法具有较强的底物普适性，从而为开发有关吡啶衍生物提供了较好的保证。

Description

一种2,6-二芳基吡啶类物质及其制备方法
技术领域
本发明涉及有机合成领域，更具体的说是涉及一种2,6-二芳基吡啶类物质及其制备方法。
背景技术
吡啶衍生物是一类重要的有机化合物，它既是金属有机催化反应中的重要溶剂，又是工业生产上常用的变性剂、助染剂；同时还是合成一系列产品(包括药品、消毒剂、染料等)的原料。因此，如何高效，快速，安全的合成吡啶衍生物一直是有机合成化学中的重要课题。
2,6-二芳基吡啶类物质就是常见的吡啶衍生物之一；在现有技术中，2,6-二芳基吡啶类物质主要通过以下方法制得：1、通过2,6-二氯吡啶、铬氏试剂和芳硼酸之间的反应来制备得到2,6-二芳基吡啶类物质(Chem.Eur.J.2012,18,446–450)；2、通过在Pd催化下，2,6-二氯吡啶和芳硼酸反应制备得到2,6-二芳基吡啶类物质(Org.Biomol.Chem.,2014,12,6944–6952)；但上述这些制备方法都存在一定的缺陷，例如方法1的原料不易保存，副反应较多，容易生成各种副产物，影响产率；方法2的催化剂需要自制，具有一定的局限性；由于这些缺陷的存在，使得这些方法的实用性和适用性都受到了一定的限制。
发明内容
针对现有技术存在的不足，本发明的目的在于提供一种2,6-二芳基吡啶类物质及其制备方法，该制备方法所用的原料易得，反应过程简单，产率高。
为实现上述目的，本发明提供了如下技术方案：一种2,6-二芳基吡啶类物质，其结构式为
Figure BDA0002228987170000011
其中-R1是氢、甲基、叔丁基、卤素和三氟甲基中的任意一种；
-R2是氢、甲基、甲氧基、溴、三氟甲基、萘基、硝基、三氟甲基和苯氧基中的任意一种。
作为本发明的进一步改进，所述2,6-二芳基吡啶类物质是由5-氧代-5-芳基戊腈和芳硼酸反应而成；
所述5-氧代-5-芳基戊腈的结构式为
Figure BDA0002228987170000021
所述芳硼酸的结构式为
Figure BDA0002228987170000022
其反应式为
Figure BDA0002228987170000023
其中5-氧代-5-芳基戊腈与2,6-二芳基吡啶类物质中的-R1相同，均为氢、甲基、叔丁基、卤素和三氟甲基中的任意一种；
所述芳硼酸和2,6-二芳基吡啶类物质中的-R2相同，均为氢、甲基、甲氧基、溴、三氟甲基、萘基、硝基、三氟甲基和苯氧基中的任意一种。
作为本发明的进一步改进，所述5-氧代-5-芳基戊腈与芳硼酸的反应在溶剂中进行，所述溶剂为甲苯、二甲苯、甲醇、四氢呋喃和N,N-二甲基甲酰胺中的任意一种。
作为本发明的进一步改进，所述5-氧代-5-芳基戊腈与芳硼酸在溶剂中反应时，还向溶剂中加入了钯催化剂和酸性促进剂。
作为本发明的进一步改进，所述钯催化剂为双(二亚苄基丙酮)钯或三(二亚苄基丙酮)二钯。
作为本发明的进一步改进，所述酸性促进剂为三氟乙酸。
作为本发明的进一步改进，在空气氛围下，向反应容器中依次加入5-氧代-5-芳基戊腈、芳硼酸、钯催化剂、溶剂和酸性促进剂进行搅拌混合；混合均匀后，在温度为80-100℃的条件下反应12-24h，制得2,6-二芳基吡啶类物质。
作为本发明的进一步改进，向反应容器中加入的5-氧代-5-芳基戊腈和芳硼酸的物质的量之比为1：1.5-2.5。
作为本发明的进一步改进，向反应容器中加入的5-氧代-5-芳基戊腈和钯催化剂的物质的量之比为1：0.04-0.06。
本发明的有益效果：原料容易获得，来源较广，不需要自身制备，成本较低，同时毒性较低，不易对人体健康造成影响；可以直接合成目标产物，无需分离中间产物，且只需在常压下反应既可获得目标物，反应过程简单产率最高可达到96％，大大简化了工艺工程，降低了能量消耗，具有高产率的优点；且反应过程中废弃溶液较少，也未排放出其它污染气体和液体，因此本发明减少了废弃溶液的排放，具有保护环境和保障操作人员健康的优点；在本发明中所使用的的物质毒性较低，保证了操作人员的健康；此外，可以制备一系列的2,6-二芳基吡啶类物质，该方法具有较强的底物普适性，从而为开发有关吡啶衍生物提供了较好的保证。
附图说明
图1为本发明的反应机理图；
具体实施方式
实施例1
在空气氛围下，依次向25ml封管中加入原料5-氧代-5-苯基戊腈(0.4mmol)、苯硼酸(0.8mmol)、催化剂三(二亚苄基丙酮)二钯(5mol％)、溶剂甲醇(2mL)和三氟乙酸(4mmol)，然后于90℃反应12h，制得2,6-二苯基吡啶；最终产物收率为96％。
表征数据：1H NMR(400MHz,CDCl3)δ8.18(d,J＝7.6Hz,4H),7.85-7.81(m,1H),7.71(d,J＝7.8Hz,2H),7.54-7.50(m,4H),7.47-7.43(m,2H)；13C NMR(125MHz,CDCl3)δ156.9,139.5,137.5,129.0,128.7,127.0,118.6.
2,6-二苯基吡啶的结构式为
Figure BDA0002228987170000041
其反应式为
Figure BDA0002228987170000042
实施例2
在空气氛围下，依次向25ml封管中加入原料5-氧代-5-苯基戊腈(0.4mmol)、对甲酰基苯硼酸(0.8mmol)、催化剂三(二亚苄基丙酮)二钯(5mol％)、溶剂甲醇(2mL)和三氟乙酸(4mmol)，然后于90℃反应12h，制得2-苯基-6-(4-(甲酰基)苯基)吡啶；最终产物收率为86％。
表征数据：1H NMR(400MHz,CDCl3)δ10.10(s,1H),8.33(d,J＝8.0Hz,2H),8.15(d,J＝7.7Hz,2H),8.02(d,J＝7.9Hz,2H),7.90-7.87(m,1H),7.78(d,J＝7.7Hz,2H),7.54-7.51(m,2H),7.47(d,J＝7.1Hz,1H)；13C NMR(125MHz,CDCl3)δ192.1,157.3,155.3,145.0,139.0,137.8,136.5,130.2,129.3,128.8,127.6,127.0,119.8,119.4
2-苯基-6-(4-(甲酰基)苯基)吡啶的结构式为
Figure BDA0002228987170000051
其反应式为
Figure BDA0002228987170000052
实施例3
在空气氛围下，依次向25ml封管中加入原料5-氧代-5-苯基戊腈(0.4mmol)、对三氟甲基苯硼酸(0.8mmol)、催化剂三(二亚苄基丙酮)二钯(5mol％)、溶剂甲醇(2mL)和三氟乙酸(4mmol)，然后于90℃反应24h，制得2-苯基-6-(4-(三氟甲基)苯基)吡啶；最终产物收率为81％。
表征数据：1H NMR(400MHz,CDCl3)δ8.26(d,J＝8.0Hz,2H),8.15(d,J＝7.8Hz,2H),7.88-7.84(m,1H),7.77-7.72(m,4H),7.54-7.44(m,3H)；13C NMR(125MHz,CDCl3)δ157.2,155.3,142.8,139.2,137.7,130.8(d,JC-F＝32.4Hz),129.2,128.8,127.3,127.0,125.6(q,JC-F＝3.8Hz),124.3(d,JC-F＝272.2Hz),119.5,118.9.2-苯基-6-(4-(三氟甲基)苯基)吡啶的结构式如下：
Figure BDA0002228987170000053
其反应式为
Figure BDA0002228987170000054
实施例4
在空气氛围下，依次向25ml封管中加入原料5-氧代-5-苯基戊腈(0.4mmol)、对苯氧基苯硼酸(0.8mmol)、催化剂三(二亚苄基丙酮)二钯(5mol％)、溶剂甲醇(2mL)和三氟乙酸(4mmol)，然后于90℃反应20h，制得2-(4-苯氧基苯基)-6-苯基吡啶；最终产物的收率为93％。
表征数据：1H NMR(400MHz,CDCl3)δ8.14(d,J＝6.5Hz,4H),7.81(d,J＝7.6Hz,1H),7.69-7.65(m,2H),7.52-7.49(m,2H),7.44(d,J＝7.1Hz,1H),7.39-7.36(m,2H),7.16-7.12(m,3H),7.08(d,J＝7.9Hz,2H)；13C NMR(125MHz,CDCl3)δ158.6,157.3,156.9,156.8,156.2,138.0,129.9,129.7,129.3,128.8,128.7,127.3,123.6,123.2,119.3,118.9,118.8.
2-(4-苯氧基苯基)-6-苯基吡啶的结构式如下：
Figure BDA0002228987170000061
其反应式为
Figure BDA0002228987170000062
实施例5
在空气氛围下，依次向25ml封管中加入原料5-氧代-5-苯基戊腈(0.4mmol)、间甲氧基苯硼酸(0.8mmol)、催化剂三(二亚苄基丙酮)二钯(5mol％)、溶剂甲醇(2mL)和三氟乙酸(4mmol)，然后于90℃反应20h，制得2-(3-甲氧基苯基)-6-苯基吡啶；最终产物的收率为86％。
表征数据：1H NMR(400MHz,CDCl3)δ8.74(s,1H),8.43(d,J＝7.4Hz,1H),8.16-8.11(m,3H),7.88(d,J＝7.5Hz,1H),7.78-7.74(m,2H),7.61-7.58(m,1H),7.53-7.51(m,2H),7.47-7.44(m,1H),3.98(s,3H)；13C NMR(125MHz,CDCl3)δ167.1,157.0,155.8,139.4,138.9,138.0,131.8,130.7,130.2,129.3,128.9,128.8,128.1,127.2,119.4,119.1,52.3.
2-(3-甲氧基苯基)-6-苯基吡啶的结构式如下：
Figure BDA0002228987170000071
其反应式为
Figure BDA0002228987170000072
实施例6
在空气氛围下，依次向25ml封管中加入原料5-氧代-5-苯基戊腈(0.4mmol)、对碘苯硼酸(0.8mmol)、催化剂三(二亚苄基丙酮)二钯(5mol％)、溶剂甲醇(2mL)和三氟乙酸(4mmol)，然后于90℃反应20h，制得2-(4-碘苯基)-6-苯基吡啶；最终产物的收为78％。
表征数据：1H NMR(400MHz,CDCl3)δ8.15-8.13(m,2H),7.90(d,J＝8.5Hz,2H),7.84-7.80(m,3H),7.71(d,J＝7.7Hz,1H),7.66(d,J＝7.7Hz,1H),7.53-7.50(m,2H),7.45(d,J＝7.3Hz,1H)；13C NMR(125MHz,CDCl3)δ157.0,155.8,139.3,139.0,137.8,137.6,129.1,128.8,128.7,127.0,119.1,118.3,95.3.
2-(4-碘苯基)-6-苯基吡啶的结构式如下：
Figure BDA0002228987170000081
其反应式为
Figure BDA0002228987170000082
实施例7
在空气氛围下，依次向25ml封管中加入原料5-氧代-5-苯基戊腈(0.4mmol)、对溴苯硼酸(0.8mmol)、催化剂三(二亚苄基丙酮)二钯(5mol％)、溶剂甲醇(2mL)和三氟乙酸(4mmol)，然后于90℃反应20h，制得2-(4-溴苯基)-6-苯基吡啶；最终产物的收率为75％。
表征数据：1H NMR(400MHz,CDCl3)δ8.13(d,J＝7.1Hz,2H),8.04(d,J＝7.5Hz,2H),7.82(d,J＝7.2Hz,1H),7.72(d,J＝7.1Hz,1H),7.68-7.61(m,3H),7.53-7.49(m,2H),7.47-7.43(m,1H)；13C NMR(125MHz,CDCl3)δ157.0,155.7,139.2,138.3,137.7,131.8,129.2,128.8,128.6,127.0,123.5,119.0,118.4.
2-(4-溴苯基)-6-苯基吡啶的结构式如下：
Figure BDA0002228987170000083
其反应式为
Figure BDA0002228987170000084
实施例8
在空气氛围下，依次向25ml封管中加入原料5-氧代-5-(对甲苯基)戊腈(0.4mmol)、对三氟甲基苯硼酸(0.8mmol)、催化剂三(二亚苄基丙酮)二钯(5mol％)、溶剂甲醇(2mL)和三氟乙酸(4mmol)，然后于90℃反应20h，制得2-(对-甲苯基)-6-(4-(三氟甲基)苯基)吡啶；最终产物的收率为78％。
表征数据：1H NMR(400MHz,CDCl3)δ8.26(d,J＝8.1Hz,2H),8.05(d,J＝8.1Hz,2H),7.85-7.82(m,1H),7.76-7.69(m,4H),7.32(d,J＝7.9Hz,2H),2.44(s,3H)；13C NMR(125MHz,CDCl3)δ157.2,155.2,139.3,137.6,136.4,130.7(d,JC-F＝32.5Hz),129.5,127.3,126.9,125.6(q,JC-F＝3.8Hz),124.3(d,JC-F＝272.1Hz),119.2,118.6,100.0,21.3.
2-(4-溴苯基)-6-苯基吡啶的结构式如下：
Figure BDA0002228987170000091
其反应式为
Figure BDA0002228987170000092
实施例9
在空气氛围下，依次向25ml封管中加入原料5-氧代-5-(对甲苯基)戊腈(0.4mmol)、对甲氧基苯硼酸(0.8mmol)、催化剂三(二亚苄基丙酮)二钯(5mol％)、溶剂甲醇(2mL)和三氟乙酸(4mmol)，然后于90℃反应20h，制得2-(4-甲氧基苯基)-6-(对甲苯基)吡啶；最终产物的收率为88％。
表征数据：1H NMR(400MHz,CDCl3)δ8.11(d,J＝8.7Hz,2H),8.04(d,J＝8.1Hz,2H),7.79-7.76(m,1H),7.62-7.60(m,2H),7.30(d,J＝8.0Hz,2H),7.02(d,J＝8.7Hz,2H),3.88(s,3H),2.42(s,3H)；13C NMR(125MHz,CDCl3)δ160.6,156.6,156.3,139.1,137.6,129.4,128.4,127.0,117.9,114.1,55.4,21.3.
2-(4-甲氧基苯基)-6-(对甲苯基)吡啶的结构式如下：
Figure BDA0002228987170000101
其反应式为
Figure BDA0002228987170000102
实施例10
在空气氛围下，依次向25ml封管中加入原料5-氧代-5-(对甲苯基)戊腈(0.4mmol)、对氟苯硼酸(0.8mmol)、催化剂三(二亚苄基丙酮)二钯(5mol％)、溶剂甲醇(2mL)和三氟乙酸(4mmol)，然后于90℃反应20h，制得2-(4-氟苯基)-6-(对甲苯基)吡啶；最终产物的收率为80％。
表征数据：1H NMR(400MHz,CDCl3)δ8.16-8.13(m,2H),8.05(d,J＝8.0Hz,2H),7.80-7.77(m,1H),7.66(d,J＝7.8Hz,1H),7.61(d,J＝7.8Hz,1H),7.31(d,J＝7.9Hz,2H),7.20-7.17(m,2H),2.43(s,3H)；13C NMR(125MHz,CDCl3)δ163.6(q,JC-F＝248.1Hz),156.9,155.7,139.1,137.5,136.6,135.7(q,JC-F＝2.9Hz),129.5,128.8(q,JC-F＝8.3Hz),126.9,128.2(q,JC-F＝35.6Hz),115.6(q,JC-F＝21.5Hz),21.3.
2-(4-氟苯基)-6-(对甲苯基)吡啶的制备，结构式如下：
Figure BDA0002228987170000103
其反应式为
Figure BDA0002228987170000111
对比例1
将实施例1中加入的三氟乙酸用对甲基苯磺酸代替，其余条件不变；最终产物的收率为12％；
对比例2
将实施例1中加入的三氟乙酸用乙酸代替，其余条件不变；最终产物的收率为10％；
对比例3
将实施例1中加入的三氟乙酸用甲酸代替，其余条件不变；最终没有合成出2,6-二芳基吡啶。
对比例4
将实施例1中添加溶剂甲醇和三氟乙酸的顺序进行调换，即先加三氟乙酸，再加溶剂甲醇；其余条件不变；最终产物的收率仅为9％；
由实施例1与对比例4相比较可知，本发明中溶剂与酸性促进剂三氟乙酸的添加顺序对产物产率的影响很大，这是因为三氟乙酸的酸性太强，如果先加三氟乙酸，可能会使与三氟乙酸直接接触的钯催化剂、5-氧代-5-芳基戊腈和芳硼酸这些物质失活，从而造成产物的产率极低，甚至导致实验的失败，无法合成目标产物；因此本发明要先加溶剂，最后加入酸性促进剂三氟乙酸。
图1为本发明的反应机理图
由图1可知：Step1:首先钯催化剂与芳基1硼酸通过转移金属化形成芳基钯物种A，然后戊二腈中的一个氰基与钯配位并发生碳钯化形成亚胺-钯中间体C；然后中间体C水解生成5-氧代-5-芳基1戊腈I；
Step2:首先钯催化剂与芳基2硼酸通过转移金属化形成芳基钯物种D，然后5-氧代-5-芳基1戊腈I中氰基与钯配位并发生碳钯化形成亚胺-钯中间体F；在TFA存在下中间体F发生质子化生成中间体G，同时钯催化剂再生，然后G经历分子内环化脱水最后氧化生成目标产物III；
本发明的一种2,6-二芳基吡啶类物质及其制备方法，通过以5-氧代-5-芳基戊腈和芳硼酸作为反应物进行反应制得；其中5-氧代-5-芳基戊腈的结构式为
Figure BDA0002228987170000121
-R1是氢、甲基、叔丁基、卤素和三氟甲基中的任意一种；芳硼酸的结构式为
Figure BDA0002228987170000122
-R2是氢、甲基、甲氧基、溴、三氟甲基、萘基、硝基、三氟甲基和苯氧基中的任意一种；
反应物原料容易获得，来源较广，不需要自身制备，成本较低，同时毒性较低，不易对人体健康造成影响；本发明的反应在溶剂中进行，溶剂为甲苯、二甲苯、甲醇、四氢呋喃和N,N-二甲基甲酰胺中的任意一种，优选甲醇，因为反应物能够均匀得分散在甲醇中，从而使得反应更加充分，产率提高；此外，在反应时，还向溶剂中加入了钯催化剂和酸性促进剂；钯催化剂的添加量为原料5-氧代-5-芳基戊腈的4％-6％；本发明中所使用的的钯催化剂为双(二亚苄基丙酮)钯或三(二亚苄基丙酮)二钯，优选三(二亚苄基丙酮)二钯；在该催化剂的催化作用下，反应时间能够大大减少，从而降低了反应成本；本发明所使用的酸性促进剂为三氟乙酸；
本发明的反应温度为80-100℃，反应时间为12-24小时，整个反应在常压下进行，反应条件温和，容易达到，且安全。
本发明方法可以直接合成目标产物，无需分离中间产物，且只需在常压下反应既可获得目标物，反应过程简单产率最高可达到96％，大大简化了工艺工程，降低了能量消耗，具有高产率的优点；且反应过程中废弃溶液较少，也未排放出其它污染气体和液体，因此本发明减少了废弃溶液的排放，具有保护环境和保障操作人员健康的优点；在本发明中所使用的的物质毒性较低，保证了操作人员的健康；此外，可以制备一系列的2,6-二芳基吡啶类物质，该方法具有较强的底物普适性，从而为开发有关吡啶衍生物提供了较好的保证，适合大规模的推广与应用。
以上所述仅是本发明的优选实施方式，本发明的保护范围并不仅局限于上述实施例，凡属于本发明思路下的技术方案均属于本发明的保护范围。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理前提下的若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (3)

1.一种2，6-二芳基吡啶类物质的制备方法，其特征在于：在空气氛围下，向反应容器中依次加入5-氧代-5-芳基戊腈、芳硼酸、钯催化剂、溶剂和酸性促进剂进行搅拌混合；混合均匀后，在温度为80-100℃的条件下反应12-24h，制得2，6-二芳基吡啶类物质；
所述2，6-二芳基吡啶类物质的结构式为
Figure FDA0002974252450000011
其中-R1是氢、甲基、叔丁基、卤素和三氟甲基中的任意一种；
-R2是氢、甲基、甲氧基、溴、三氟甲基、萘基、硝基、三氟甲基和苯氧基中的任意一种。
所述5-氧代-5-芳基戊腈的结构式为
Figure FDA0002974252450000012
所述芳硼酸的结构式为
Figure FDA0002974252450000013
其反应式为
Figure FDA0002974252450000014
其中5-氧代-5-芳基戊腈与2，6-二芳基吡啶类物质中的-R1相同，均为氢、甲基、叔丁基、卤素和三氟甲基中的任意一种；
所述芳硼酸和2，6-二芳基吡啶类物质中的-R2相同，均为氢、甲基、甲氧基、溴、三氟甲基、萘基、硝基、三氟甲基和苯氧基中的任意一种；
所述溶剂为甲醇；
所述钯催化剂为双(二亚苄基丙酮)钯或三(二亚苄基丙酮)二钯；
所述酸性促进剂为三氟乙酸。
2.根据权利要求1所述的一种2，6-二芳基吡啶类物质的制备方法，其特征在于：向反应容器中加入的5-氧代-5-芳基戊腈和芳硼酸的物质的量之比为1∶1.5-2.5。
3.根据权利要求2所述的一种2，6-二芳基吡啶类物质的制备方法，其特征在于：向反应容器中加入的5-氧代-5-芳基戊腈和钯催化剂的物质的量之比为1∶0.04-0.06。
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