CN108314642B - 一种2-甲基吡啶类化合物的合成方法 - Google Patents

一种2-甲基吡啶类化合物的合成方法 Download PDF

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CN108314642B
CN108314642B CN201810090848.6A CN201810090848A CN108314642B CN 108314642 B CN108314642 B CN 108314642B CN 201810090848 A CN201810090848 A CN 201810090848A CN 108314642 B CN108314642 B CN 108314642B
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高庆贺
原焕
刘兆敏
吴曼曼
孙佳佳
周晨阳
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Xinxiang Medical University
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Abstract

本发明公开了一种2‑甲基吡啶类化合物的合成方法，属于有机合成技术领域。本发明的技术方案要点为：一种2‑甲基吡啶类化合物的合成方法，具体步骤为：将三乙胺和醋酸肟酯类化合物溶于溶剂中，然后加入催化剂，在氧气氛围中于120‑160℃反应制得2‑甲基吡啶类化合物。本发明合成过程简单高效，通过无过渡金属催化的一锅串联反应一步直接制得2‑甲基吡啶类化合物，避免了由于多步反应中多种试剂的使用以及对各步反应中间体的纯化处理等引起的资源浪费和环境污染，反应条件温和，底物适用范围广，同时以三乙胺为原料极大地降低了生产成本。

Description

一种2-甲基吡啶类化合物的合成方法
技术领域
本发明属于有机合成技术领域，具体涉及一种2-甲基吡啶类化合物的合成方法。
背景技术
研究表明，2-甲基吡啶是一种重要的有机中间体，主要用于生产长效磺胺、抗过敏药扑尔敏、丁苯吡胶乳、兽药、氮肥增效剂、染料中间体和除草剂百革枯及杀草快除草剂等。据不完全统计，2-甲基吡啶的用量国内每年大约以25％的速度增加，因此2-甲基吡啶国内市场潜力很大。而目前合成2-甲基吡啶的方法主要包括乙醛法、乙炔法、乙烯法和丙烯腈法，但是以上四种合成方法需要高温高压的反应环境并且收率低、副反应多，从而极大地提高了在实际生产中的成本。因此，研究并开发以廉价且安全的试剂为原料、经由简便的操作步骤来合成2-甲基吡啶类化合物，不仅具有一定的理论意义，而且具有重要的应用价值和市场潜力。
发明内容
本发明解决的技术问题是提供了一种2-甲基吡啶类化合物的合成方法，该方法从三乙胺及醋酸肟酯类化合物等简单易制备的原料出发，通过一锅串联反应一步制得2-甲基吡啶类化合物，合成过程操作方便，反应条件温和，底物适用范围广，适合于工业化生产。
本发明为解决上述技术问题采用如下技术方案，一种2-甲基吡啶类化合物的合成方法，其特征在于具体步骤为：将三乙胺和醋酸肟酯类化合物1溶于溶剂中，然后加入催化剂，在氧气氛围中于120-160℃反应制得2-甲基吡啶类化合物2，该合成方法中的反应方程式为：
Figure BDA0001563646880000011
其中R为苯基、取代苯基、2-萘基或噻吩基，该取代苯基为3,4-亚甲二氧基苯基、3,4-二氯基苯基或一元取代苯基，一元取代苯基苯环上的取代基为甲基、乙基、叔丁基、甲氧基、乙氧基、硝基、三氟甲基、氟、氯或溴，溶剂为甲苯、乙腈或1,4-二氧六环，催化剂为碘单质、N-碘代丁二酰亚胺或碘化铵。
进一步优选，所述三乙胺、醋酸肟酯类化合物1与催化剂的投料摩尔比为2:1:1.5，醋酸肟酯类化合物1与溶剂的投料配比为1mmol:4mL。
进一步优选，所述2-甲基吡啶类化合物2为下列化合物之一：
Figure BDA0001563646880000021
本发明与现有技术相比具有以下优点：1、合成过程为无过渡金属催化的一锅串联反应，过程简单、高效，同时避免了由于多步反应中多种试剂的使用以及对各步反应中间体的纯化处理等引起的资源浪费和环境污染；2、以三乙胺为原料极大地降低了生产成本；3、反应条件温和，操作简便；4、底物的适用范围广。因此，本发明为2-甲基吡啶类化合物的合成提供了一种经济实用且绿色环保的新方法。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例1
Figure BDA0001563646880000031
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1a(0.5mmol,95.5mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到粉色固体产物2-甲基-4,6-二对甲基苯基吡啶2a(49.1mg,72％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ(ppm)7.92(d,J＝8.0Hz,2H),7.68(s,1H),7.57(d,J＝7.6Hz,2H),7.33–7.24(m,5H),2.67(s,3H),2.41(s,3H),2.40(s,3H)；13C NMR(100MHz,CDCl3)δ(ppm)158.6,157.5,149.3,138.8,138.6,137.1,135.9,129.7,129.4,127.0,126.9,119.3,115.6,24.8,21.3,21.2；HRMS(ESI):m/z[M+Na]+calcd for C20H19NNa:296.1410；found:296.1410。
实施例2
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1a(0.5mmol,95.5mg)、碘化铵(0.75mmol,168.7mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2a(43mg,63％)。
实施例3
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1a(0.5mmol,95.5mg)、N-碘代丁二酰亚胺(0.75mmol,108.7mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2a(45.7mg,67％)。
实施例4
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1a(0.5mmol,95.5mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于120℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2a(41.6mg,61％)。
实施例5
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1a(0.5mmol,95.5mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于160℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2a(37.5mg,55％)。
实施例6
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1a(0.5mmol,95.5mg)、碘单质(0.75mmol,190.5mg)和1,4-二氧六环(2mL)，然后在O2氛围下置于120℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2a(28.7mg,42％)。
实施例7
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1a(0.5mmol,95.5mg)、碘单质(0.75mmol,190.5mg)和乙腈(2mL)，然后在O2氛围下置于120℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2a(34.8mg,51％)。
实施例8
Figure BDA0001563646880000041
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1b(0.5mmol,95.5mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2b(46.4mg,68％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ(ppm)7.86(s,1H),7.79(d,J＝7.6Hz,1H),7.69(s,1H),7.47(d,J＝7.6Hz,2H),7.40–7.33(m,2H),7.30(s,1H),7.24(t,J＝8.8Hz,2H),2.69(s,3H),2.45(s,6H)；13C NMR(100MHz,CDCl3)δ(ppm)158.6,157.8,149.6,139.8,138.8,138.7,138.3,129.6,129.5,128.9,128.6,127.8(4),127.7(9),124.2(4),124.1(8),119.7,116.2,24.8,21.5(4),21.4(9)；HRMS(ESI):m/z[M+H]+calcd for C20H20N:274.1590；found:274.1590。
实施例9
Figure BDA0001563646880000051
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1c(0.5mmol,95.5mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2c(38.9mg,57％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ(ppm)7.45–7.41(m,1H),7.32–7.24(m,7H),7.17(s,1H),7.09(s,1H),2.67(s,3H),2.40(s,3H),2.33(s,3H)；13C NMR(100MHz,CDCl3)δ(ppm)159.2,157.7,150.1,140.6,139.5,135.7,135.0,130.7,130.6,129.6,129.3,128.2,128.1,126.0,125.9,121.7(0),121.6(5),24.7,20.3(7),20.3(5)；HRMS(ESI):m/z[M+H]+calcd for C20H20N:274.1590；found:274.1590。
实施例10
Figure BDA0001563646880000052
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1d(0.5mmol,102.6mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2d(54.9mg,73％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ(ppm)7.94(d,J＝8.4Hz,2H),7.69(s,1H),7.60(d,J＝8.0Hz,2H),7.34–7.27(m,5H),2.76–2.69(m,4H),2.67(s,3H),1.32–1.24(m,6H)；13C NMR(100MHz,CDCl3)δ(ppm)158.6,157.6,149.3,145.2,145.0,137.4,136.2,128.5,128.2,127.1,127.0,119.3,115.7,28.7,28.6,24.8,15.6,15.5；HRMS(ESI):m/z[M+Na]+calcd for C22H23NNa:324.1723；found:324.1724。
实施例11
Figure BDA0001563646880000061
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1e(0.5mmol,116.6mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2e(61.6mg,69％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ(ppm)7.94(d,J＝8.4Hz,2H),7.70(s,1H),7.62(d,J＝8.0Hz,2H),7.54–7.47(m,4H),7.29(s,1H),2.68(s,3H),1.38(s,9H),1.36(s,9H)；13C NMR(100MHz,CDCl3)δ(ppm)158.6,157.6,152.1,151.9,149.2,137.1,135.9,126.9,126.7,126.0,125.6,119.4,115.8,34.6(9),34.6(5),31.3(0),31.2(9),24.8；HRMS(ESI):m/z[M+H]+calcd for C26H32N:358.2529；found:358.2527。
实施例12
Figure BDA0001563646880000062
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1f(0.5mmol,88.6mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2f(51.4mg,84％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ(ppm)8.03(d,J＝7.2Hz,2H),7.72(s,1H),7.71–7.65(m,2H),7.54–7.39(m,6H),7.33(s,1H),2.70(s,3H)；13C NMR(100MHz,D CDCl3)δ(ppm)158.8,157.7,149.5,139.8,138.8,129.0,128.9,128.8,128.7,127.1(4),127.0(9),119.8,116.2,24.8；HRMS(ESI):m/z[M+H]+calcd for C18H16N:246.1277；found:246.1277。
实施例13
Figure BDA0001563646880000071
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1g(0.5mmol,103.6mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2g(52.6mg,69％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ(ppm)7.98(d,J＝8.8Hz,2H),7.64–7.58(m,3H),7.21(s,1H),6.99(d,J＝8.8Hz,4H),3.84(s,6H),2.64(s,3H)；13C NMR(100MHz,CDCl3)δ(ppm)160.2(3),160.2(1),158.5,157.1,148.8,132.5,131.1,128.3,128.1,118.6,114.8,114.3,114.0,55.2(9),55.2(6),24.7；HRMS(ESI):m/z[M+H]+calcd for C20H20NO2:306.1489；found:306.1492。
实施例14
Figure BDA0001563646880000072
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1h(0.5mmol,110.6mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2h(51.6mg,62％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ(ppm)7.97(d,J＝8.8Hz,2H),7.61(d,J＝8.8Hz,3H),7.22(s,1H),7.02–6.96(m,4H),4.08(q,J＝6.8Hz,4H),2.65(s,3H),1.48–1.40(m,6H)；13C NMR(100MHz,CDCl3)δ(ppm)159.6(8),159.6(5),158.4,157.2,148.9,132.3,130.9,128.3,128.1,118.5,114.9,114.8,114.6,63.6,63.5,24.7,14.7(9),14.7(7)；HRMS(ESI):m/z[M+H]+calcd for C22H24NO2:334.1802；found:334.1806。
实施例15
Figure BDA0001563646880000081
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1i(0.5mmol,110.6mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2i(58.3mg,70％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ(ppm)7.56–7.50(m,3H),7.21–7.12(m,3H),6.93–6.87(m,2H),6.02(s,2H),6.00(s,2H),2.64(s,3H)；13C NMR(100MHz,CDCl3)δ(ppm)158.6,157.0,149.0,148.4,148.3(0),148.2(6),148.1,134.3,132.9,121.0,120.9,119.0,115.1,108.7,108.4,107.6,107.3,101.4,101.2,24.74；HRMS(ESI):m/z[M+H]+calcd for C20H16NO4:334.1074；found:334.1073。
实施例16
Figure BDA0001563646880000082
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1j(0.5mmol,97.6mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2j(40.7mg,58％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ(ppm)8.06–7.96(m,2H),7.68–7.59(m,3H),7.26(s,1H),7.17(q,J＝8.8Hz,4H),2.67(s,3H)；13C NMR(100MHz,CDCl3)δ(ppm)164.7,164.6,162.2,162.1,159.0,156.6,148.6,135.8,134.8,128.9,128.8(4),128.7(6)119.6,116.1,115.9,115.7,115.6,115.5,24.8；HRMS(ESI):m/z[M+H]+calcd for C18H14F2N:282.1089；found:282.1088。
实施例17
Figure BDA0001563646880000091
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1k(0.5mmol,105.8mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2k(47.7mg,61％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ(ppm)7.97(d,J＝8.4Hz,2H),7.63(s,1H),7.59(d,J＝8.4Hz,2H),7.45(t,J＝8.4Hz,4H),7.28(s,1H),2.68(s,3H)；13C NMR(100MHz,CDCl3)δ(ppm)159.2,156.5,148.4,138.0,137.1,135.2,135.0,129.3,128.9,128.4,128.3,119.8,115.6,24.8；HRMS(ESI):m/z[M+H]+calcd for C18H14Cl2N:314.0498；found:314.0495。
实施例18
Figure BDA0001563646880000092
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1l(0.5mmol,128mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2l(53.4mg,53％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):7.91(d,J＝8.4Hz,2H),7.62(d,J＝8.8Hz,4H),7.59(s,1H),7.53(d,J＝8.4Hz,2H),7.28(s,1H),2.68(s,3H)；13C NMR(100MHz,CDCl3)δ(ppm)159.2,156.5,148.5,138.4,137.5,132.2,131.8,128.7,128.6,123.4,119.8,115.5,24.8；HRMS(ESI):m/z[M+H]+calcd forC18H14Br2N:401.9488；found:401.9486。
实施例19
Figure BDA0001563646880000101
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1m(0.5mmol,123mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2m(47.9mg,50％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ(ppm)8.16(d,J＝1.6Hz,1H),7.88(dd,J＝8.4,2.0Hz,1H),7.75(d,J＝2.0Hz,1H),7.61(s,1H),7.60–7.52(m,2H),7.49(dd,J＝8.4,2.0Hz,1H),7.29(s,1H),2.72(s,3H)；13C NMR(100MHz,CDCl3)δ(ppm)159.5,155.2,147.5,139.0,138.3,133.5,133.4,133.3,133.0(5),131.0(9),130.7,129.0,128.9,126.3,126.2,120.2,115.5,24.7；HRMS(ESI):m/z[M+H]+calcd for C18H12Cl4N:381.9718；found:381.9718。
实施例20
Figure BDA0001563646880000102
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1n(0.5mmol,122.6mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2n(52.4mg,55％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ(ppm)8.16(d,J＝8.0Hz,2H),7.77(s,4H),7.74(d,J＝6.8Hz,3H),7.37(s,1H),2.73(s,3H)；13C NMR(100MHz,CDCl3)δ(ppm)159.6,156.3,148.4,142.7,142.1,131.2,131.0,130.9,130.7,127.5,127.4,126.1(3),126.0(9),126.0(5),126.0,125.8,125.7(1),125.6(8),125.6,125.5,125.3,122.8,122.6,120.7,116.4,24.8；HRMS(ESI):m/z[M+H]+calcdfor C20H14F6N:382.1025；found:382.1029。
实施例21
Figure BDA0001563646880000111
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1o(0.5mmol,111.1mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2o(38.5mg,46％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ(ppm)8.94(s,1H),8.55(s,1H),8.44(d,J＝7.6Hz,1H),8.37–8.28(m,2H),8.04(d,J＝8.0Hz,1H),7.82(s,1H),7.78–7.66(m,2H),7.45(s,1H),2.76(s,3H)；13C NMR(100MHz,CDCl3)δ(ppm)160.1,155.3,148.9,148.8,147.6,140.9,140.1,133.0,132.9,130.3,129.8,123.8(4),123.7(8),122.1(0),122.0(5),120.9,115.9,24.8；HRMS(ESI):m/z[M+Na]+calcd for C18H13N3NaO4:358.0798；found:358.0796。
实施例22
Figure BDA0001563646880000112
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1p(0.5mmol,113.6mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2p(40.5mg,47％)。该化合物的表征数据如下：1H NMR(600MHz,DMSO-d6):δ(ppm)8.42(s,1H),8.31(d,J＝7.2Hz,2H),8.26(s,1H),8.23–8.17(m,1H),8.05(d,J＝9.0Hz,1H),8.00(s,1H),7.78–7.72(m,1H),7.58(t,J＝7.2Hz,2H),7.55–7.51(m,1H)；13CNMR(150MHz,DMSO-d6)δ(ppm)168.2,160.9,159.3,155.5,145.4,141.7,138.0,132.7,132.4,129.9,128.9,127.3,124.2,124.1,120.3,120.1,117.7,109.1,109.0；HRMS(ESI):m/z[M+H]+calcd for C16H12FN2O:267.0928；found:267.0927。
实施例23
Figure BDA0001563646880000121
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1q(0.5mmol,91.6mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2q(52.7mg,82％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ(ppm)7.68–7.60(m,2H),7.52(dd,J＝4.0,1.2Hz,1H),7.44–7.36(m,2H),7.21(s,1H),7.17–7.08(m,2H),2.60(s,3H)；13C NMR(100MHz,CDCl3)δ(ppm)159.0,152.6,144.8,142.3,141.5,128.3,127.9,127.4,126.9,125.2,124.6,117.9,112.5,24.5；HRMS(ESI):m/z[M+H]+calcd for C14H12NS2:258.0406；found:258.0408。
实施例24
Figure BDA0001563646880000122
在35mL的Schlenk管中加入三乙胺(1.0mmol,101mg)、1r(0.5mmol,91.6mg)、碘单质(0.75mmol,190.5mg)和甲苯(2mL)，然后在O2氛围下置于140℃油浴中搅拌反应12h。加入50mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，之后有机相用质量浓度为10％的Na2S2O3溶液和饱和食盐水依次洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝100/1)得到目标产物2r(42.4mg,66％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ(ppm)7.95(d,J＝2.0Hz,1H),7.71–7.65(m,2H),7.60(s,1H),7.49–7.43(m,2H),7.40(dd,J＝4.8,2.8Hz,1H),7.25(s,1H),2.64(s,3H)；13C NMR(100MHz,CDCl3)δ(ppm)158.9,153.6,143.8,142.3,140.0,126.9,126.4,126.2,125.9,123.7,122.8,118.7,115.0,24.7；HRMS(ESI):m/z[M+H]+calcd for C14H12NS2:258.0406；found:258.0407。
以上实施例描述了本发明的基本原理、主要特征及优点，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，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。

Claims (3)

1.一种2-甲基吡啶类化合物的合成方法，其特征在于具体步骤为：将三乙胺和醋酸肟酯类化合物1溶于溶剂中，然后加入催化剂，在氧气氛围中于120-160℃反应制得2-甲基吡啶类化合物2，该合成方法中的反应方程式为：
Figure FDA0002693514130000011
其中R为苯基、取代苯基、2-萘基或噻吩基，该取代苯基为3,4-亚甲二氧基苯基、3,4-二氯基苯基或一元取代苯基，一元取代苯基苯环上的取代基为甲基、乙基、叔丁基、甲氧基、乙氧基、硝基、三氟甲基、氟、氯或溴，溶剂为甲苯、乙腈或1,4-二氧六环，催化剂为碘单质、N-碘代丁二酰亚胺或碘化铵。
2.根据权利要求1所述的2-甲基吡啶类化合物的合成方法，其特征在于：所述三乙胺、醋酸肟酯类化合物1与催化剂的投料摩尔比为2:1:1.5，醋酸肟酯类化合物1与溶剂的投料配比为1mmol:4mL。
3.根据权利要求1所述的2-甲基吡啶类化合物的合成方法，其特征在于所述2-甲基吡啶类化合物2为下列化合物之一：
Figure FDA0002693514130000021
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