CN111138345B - 铁盐催化下基于肟酯和不饱和酮合成多取代吡啶衍生物的方法 - Google Patents

铁盐催化下基于肟酯和不饱和酮合成多取代吡啶衍生物的方法 Download PDF

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CN111138345B
CN111138345B CN202010041784.8A CN202010041784A CN111138345B CN 111138345 B CN111138345 B CN 111138345B CN 202010041784 A CN202010041784 A CN 202010041784A CN 111138345 B CN111138345 B CN 111138345B
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缪春宝
关弘蓉
杨海涛
姜艳
孟启
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Abstract

本发明属于有机合成技术领域，具体涉及一种铁盐催化下基于肟酯和不饱和酮合成多取代吡啶衍生物的方法。首次报道以α,β‑不饱和酮为底物，其和酮肟酯直接在铁盐的催化作用下，无溶剂加热一步反应得到多取代吡啶衍生物。和文献中方法比，本发明中的原料不饱和酮合成便捷，催化剂简单易得，使用无溶剂反应条件且反应副产物仅为醋酸和水，具有环境友好的优点。合成的多取代吡啶，不同的底物反应产率良好。该方法在合成多取代吡啶衍生物方法上具有潜在的应用价值。

Description

铁盐催化下基于肟酯和不饱和酮合成多取代吡啶衍生物的 方法
技术领域
本发明属于有机合成技术领域，特别涉及铁盐催化下基于肟酯与不饱和酮合成多取代吡啶衍生物的方法。
背景技术
吡啶类化合物是一类非常重要的六元含氮杂环化合物，其独特的结构使其在化学合成、药物合成、生物化学等领域是一类重要的中间体。因此，吡啶类化合物的合成方法一直引起了国内外专家的广泛兴趣，目前常见的合成多取代吡啶类化合物的现有方法如下：
方法一、采用环丙醇和乙烯基叠氮化物为原料，在金属锰的催化作用下，甲醇作为溶剂，氮气氛围下室温搅拌后再加入乙酸继续反应，最终得到1，2，3，5-四取代吡啶化合物[J.Am.Chem.Soc.2009,131(35):12570-12572]。
Figure BDA0002368024920000011
该反应除了可以用于合成吡啶环外，还可以用于合成其它杂环化合物，比如δ-内酰胺和氮杂双环化合物等。缺点是使用了剂量的金属锰，环境不友好。
方法二、用苯乙醛和叠氮基三甲基硅烷在铜盐的催化作用下，NHPI为氧化剂，水和DMF作为混合溶剂，氧气氛围下80℃反应24小时，最终得到2-苯乙酰基吡啶类化合物[Org.Lett.2015,17(3):584-587]。
Figure BDA0002368024920000012
该反应的特点是可以在吡啶的2-位上引入一个苯甲酰基，且适用范围较广，缺点是只能在吡啶环的3-和5-位上引入相同的芳基。
方法三、以肟酯与醛为起始原料，溴化亚铜为催化剂，亚硫酸氢钠作为碱，在DMSO溶液中120℃反应，经过[2+2+2]环加成反应合成多取代的吡啶环类化合物[Org.Lett.2011,13,19,5394-5397]。
Figure BDA0002368024920000021
该反应的特点是可以合成对称取代的吡啶类化合物，选用肟酯作为原料具有良好的官能团兼容性，不同的芳香醛甚至多聚甲醛都可以适用于该反应。但是1-，6-位和3-，5-位必须是相同的取代基，且当吡啶的2-或5-位连接不同的取代基时，其产率很低。
方法四、以查尔酮肟酯和丁炔二酸二甲酯为原料，醋酸铜为催化剂，亚硫酸氢钠作为碱，在DMSO溶液中90℃反应，经过[4+2]环加成反应最终得到多取代吡啶环类化合物[安徽工程大学学报，2018，33(4):24-28]。
Figure BDA0002368024920000022
该反应的特点是具有高度的区域选择性，且查尔酮肟酯作为原料合成简单，但是只能在吡啶环的2-和3-位上引入酯基团，具有一定的局限性。
方法五、以肟酯和α,β-不饱和醛为原料，碘化亚铜为催化剂，铵盐作为碱，在DMSO溶液中60℃反应得到多取代的吡啶环类化合物。[J.Am.Chem.Soc.2013,135(10),3756–3759.]
Figure BDA0002368024920000031
该反应的特点是可以合成不对称多取代吡啶类化合物，且具有良好的官能团兼容性。但是，该反应只适用于α,β-不饱和醛，不适合α,β-不饱和酮，这样制得的吡啶环上，有一个α位只能是氢原子。
方法六、2017年，有人报道以肟酯和α,β-不饱和苯磺酰胺为原料，铜盐为催化剂，亚硫酸氢钠作为碱，在DMSO溶液中60℃反应，制备多取代的吡啶类化合物(Angew.Chem.Int.Ed.2017,129(28),8352–8356.)。
Figure BDA0002368024920000032
该反应的特点是能够在吡啶环上的不同位点上引入取代基团，且官能团兼容性良好。但是，原料亚胺需要从α,β-不饱和酮和对甲苯磺酰胺提前制备，而且所用的铜催化剂比较复杂。
但是这些方法仍然存在许多问题和缺陷：1)合成高选择性吡啶环的底物通常需要提前修饰且不易制得；2)大多需要贵金属催化或者反应条件苛刻；3)采用简便易得的底物只能合成多取代对称吡啶类化合物。因此，目前仍然需要找出一种可以利用简单的底物，在较为温和的条件下合成高选择性不对称多取代的吡啶类化合物的方法。
发明内容
针对背景技术中存在的问题和不足之处，本发明首次提出了直接用α,β-不饱和酮与肟酯在铁盐催化下无溶剂一步合成多取代吡啶衍生物的方法。本发明中的原料不饱和酮合成路线简单，且不同的取代基反应产率良好，催化剂廉价易得，无溶剂反应且反应副产物为醋酸和水，对环境友好。
合成方法为：以肟乙酸酯1和α,β-不饱和酮2为原料，在铁盐的催化作用下，无溶剂高温发生反应，得到多取代吡啶衍生物3：
Figure BDA0002368024920000041
R1选自取代或非取代的芳基；取代或未取代的杂环基团；其中，芳基或者杂环基团的取代基选自硝基、甲基、甲氧基、氰基、卤素取代的苯基或者吡啶基团；
R2选自氢原子；烷基如甲基、乙基等；
R3、R5选自甲基；取代的芳基；其中，芳基的取代基选自硝基、甲基、甲氧基、氰基、卤素基取代的苯基或者呋喃、吡啶等杂环基团；
R4选自甲基；酯基。
该反应中所用的不同铁盐为：无水三氯化铁、七水合硫酸亚铁、硬脂酸铁、氯化亚铁、三溴化铁或者三乙酰丙酮铁，催化剂用量0.05-1.0equiv。反应条件为：无溶剂下加热至80-160℃，反应1-10小时，原料α,β-不饱和酮：肟乙酸酯的摩尔比1:1-2.0。
原料α,β-不饱和酮：酮肟乙酸酯：催化剂的摩尔比优选为1：2.0：0.05，反应温度优选为140℃，催化剂优选为无水三氯化铁。
肟酯类化合物选自酮肟酯，其结构通式如式I所示：
Figure BDA0002368024920000042
其中，R1选自取代或非取代的芳基；取代或未取代的杂环基团；其中，芳基或者杂环基团的取代基选自硝基、甲基、甲氧基、氰基、卤素取代的苯基或者吡啶基团；
R2选自氢原子；烷基如甲基、乙基等。
上述酮肟酯为苯乙酮肟酯，1-四氢萘酮肟乙酸酯，苯丙酮肟酯，2-乙酰基吡啶O-酰基肟。
α,β-不饱和酮类化合物，其结构通式如式II所示：
Figure BDA0002368024920000051
其中，R3、R5选自甲基；取代的芳基；其中，芳基的取代基选自硝基、甲基、甲氧基、氰基、卤素基取代的苯基或者呋喃、吡啶等杂环基团；
R4选自甲基；酯基。
上述方法合成的多取代吡啶衍生物的结构式为：
Figure BDA0002368024920000052
其中，R1、R2、R3、R4、R5，均选自氢原子、卤素原子、烷基、芳基、取代芳基、硝基、烷氧基、氰基、氨基、酰基中的任意一种。
本发明的有益效果：迈克尔加成反应是碳碳键形成非常有效的一种方法，本发明选用的原料之一：α,β-不饱和酮是一种良好的迈克尔加成反应的受体，廉价易得，本发明首次在铁盐的催化作用下，将α,β-不饱和酮与肟酯发生[3+3]环加成反应，制备多取代吡啶衍生物。该反应是在无溶剂下进行的，环境友好，通过改变烯酮和肟酯的结构能够选择性的控制吡啶环上的取代基，制备出丰富的多取代吡啶化合物。
具体实施方式
以下通过具体实施方式对本发明的技术方案进行进一步的说明和描述。
实施例1
以苯乙酮肟酯1a和α,β-不饱和酮2a为原料，按照2a：1a：无水氯化铁摩尔比＝1:2:0.05，查尔酮0.5mmol，无溶剂空气中加热反应至140℃，反应3小时后，冷却至室温。然后，向反应体系中加入乙酸乙酯(10mL)使大部分固体溶解，加入稀氨水(10mL，浓度为：1mol/L)洗涤一次，再用水(10mL)洗涤2次，分离出有机层，经无水Na2SO4干燥，旋干得粗产品，柱层析得到目标产物3aa，产率为77％。
Figure BDA0002368024920000061
对所得产物进行测试，测试所用的仪器为：AVANCE 300MHz型核磁共振仪(Bruker公司，TMS为内标)；SGW X-4显微熔点仪(温度计未经校正)。以下实施例测试方法与本实施例相同。
3aa：白色固体，核磁表征如下:1H-NMR(300MHz,d6-CDCl3)δ8.21(d,J＝7.08Hz,4H),7.9(s,2H),7.76(d,J＝6.7Hz,2H),7.51(m,9H)；13C-NMR(75MHz,d6-CDCl3),δ157.6,150.3,139.7,139.2,130.9,129.24,129.17,129.1,128.8,127.31,127.26,117.3,77.6,77.2,76.7.
实施例2
以苯乙酮肟酯1a和α,β-不饱和酮2b为原料，按照2b：1a：无水氯化铁摩尔比＝1:2:0.05，无溶剂空气中加热反应至140℃，反应3小时后，冷却至室温。然后，向反应体系中加入乙酸乙酯(10mL)使大部分固体溶解，加入稀氨水(10mL，浓度为：1mol/L)洗涤一次，再用水(10mL)洗涤2次，分离出有机层，经无水Na2SO4干燥，旋干得粗产品，经柱层析得到目标产物3ab，产率为75％。
Figure BDA0002368024920000071
3ab：白色固体，核磁表征如下：1H-NMR(300MHz,d6-CDCl3),δ8.20(m,4H),7.89(s,2H),7.66(d,J＝8.0Hz,2H),7.52(t,J＝7.5Hz,4H),7.44(tt,1J＝7.5Hz,2J＝1.3Hz,2H),7.33(d,J＝8.0Hz,2H),2.44(d,3H)；13C-NMR(75MHz,d6-CDCl3),δ157.5,150.1,139.8,139.2,136.2,129.9,129.1,128.8,127.2,127.1,117.0,77.5,77.2,76.8,21.4.
实施例3
以苯乙酮肟酯1a和α,β-不饱和酮2c为原料，按照2c：1a：无水氯化铁摩尔比＝1:2:0.05，无溶剂空气中加热反应至140℃，反应3小时后，冷却至室温。然后，向反应体系中加入乙酸乙酯(10mL)使大部分固体溶解，加入稀氨水(10mL，浓度为：1mol/L)洗涤一次，再用水(10mL)洗涤2次，分离出有机层，经无水Na2SO4干燥，旋干得粗产品，柱层析得到目标产物3ac，产率为74％。
Figure BDA0002368024920000081
3ac：白色固体，核磁表征如下：1H-NMR(300MHz,d6-CDCl3),δ8.21(d,J＝7.1Hz,2H),8.12(d,J＝8.1Hz,2H),7.86(s,2H),7.73(d,J＝7.0Hz,2H),7.49(m,6H),7.31(d,J＝8.0Hz,2H),2.43(s,3H)；13C-NMR(75MHz,d6-CDCl3),δ157.6,157.5,150.2,139.8,139.3,139.2,136.9,129.6,129.2,129.1,129.1,128.8,127.3,127.3,127.1,117.0,116.9,77.5,77.2,76.8,21.5.
实施例4
以苯乙酮肟酯1a和α,β-不饱和酮2d为原料，按照2d：1a：无水氯化铁摩尔比＝1:2:0.05，无溶剂空气中加热反应至140℃，反应3小时后，冷却至室温。然后，向反应体系中加入乙酸乙酯(10mL)使大部分固体溶解，加入稀氨水(10mL，浓度为：1mol/L)洗涤一次，再用水(10mL)洗涤2次，分离出有机层，经无水Na2SO4干燥，旋干得粗产品，柱层析得到目标产物3ad，产率为71％。
Figure BDA0002368024920000082
3ad：白色固体，核磁表征如下：1H-NMR(300MHz,d6-CDCl3)δ8.20(d,J＝7.2Hz,4H),7.87(s,2H),7.72(d,J＝8.7Hz,2H),7.52(t,J＝7.2Hz,4H),7.45(t,J＝7.2Hz,2H),7.06(d,J＝8.8Hz,2H),3.90(s,3H)；13C-NMR(75MHz,d6-CDCl3)δ157.8,149.1,139.5,137.6,135.3,129.5,129.3,128.9,128.6,127.3,116.9,77.6,77.2,76.7.
实施例5
以苯乙酮肟酯1a和α,β-不饱和酮2e为原料，按照2e：1a：无水氯化铁摩尔比＝1:2:0.05，无溶剂空气中加热反应至140℃，反应3小时后，冷却至室温。然后，向反应体系中加入乙酸乙酯(10mL)使大部分固体溶解，加入稀氨水(10mL，浓度为：1mol/L)洗涤一次，再用水(10mL)洗涤2次，分离出有机层，经无水Na2SO4干燥，旋干得粗产品，柱层析得到目标产物3ae，产率为68％。
Figure BDA0002368024920000091
3ae：白色固体，核磁表征如下：1H-NMR(300MHz,d6-CDCl3)δ8.19(m,4H),7.85(s,2H),7.74(m,2H),7.50(m,6H),7.45(m,2H),7.06(d,J＝8.8Hz,2H),3.90(s,3H)；13C-NMR(75MHz,d6-CDCl3)δ160.6,157.5,157.4,157.1,150.1,139.7,139.2,132.2,131.3,129.1,129.0,128.9,128.7,128.43,128.36,127.2,127.1,116.6,116.5,116.4,114.6,114.1,55.4.
实施例6
以苯乙酮肟酯1a和α,β-不饱和酮2f为原料，按照2f：1a：无水氯化铁摩尔比＝1:2:0.05，无溶剂空气中加热反应至140℃，反应3小时后，冷却至室温。然后，向反应体系中加入乙酸乙酯(10mL)使大部分固体溶解，加入稀氨水(10mL，浓度为：1mol/L)洗涤一次，再用水(10mL)洗涤2次，分离出有机层，经无水Na2SO4干燥，柱层析得到目标产物3af，产率为72％。
Figure BDA0002368024920000101
3af：白色固体，核磁表征如下：1H-NMR(300MHz,d6-CDCl3)δ8.21(m,2H),8.18(m,2H),7.84(s,2H),7.69(m,6H),7.50(m,9H)；13C-NMR(75MHz,d6-CDCl3)δ157.8,149.1,139.5,137.6,135.3,129.5,129.3,128.9,128.6,127.3,116.9,77.6,77.2,76.7.
实施例7
以苯乙酮肟酯1a和α,β-不饱和酮2g为原料，按照2g：1a：无水氯化铁摩尔比＝1:2:0.05，无溶剂空气中加热反应至140℃，反应3小时后，冷却至室温。然后，向反应体系中加入乙酸乙酯(10mL)使大部分固体溶解，加入稀氨水(10mL，浓度为：1mol/L)洗涤一次，再用水(10mL)洗涤2次，分离出有机层，经无水Na2SO4干燥，柱层析得到目标产物3ag，产率为67％。
Figure BDA0002368024920000102
3ag：白色固体，核磁表征如下：1H-NMR(300MHz,d6-CDCl3)δ8.18(m,4H),7.90(d,J＝1.3Hz,1H),7.85(d,J＝1.3Hz,1H),7.73(m,2H),7.50(m,8H)；13C-NMR(75MHz,d6-CDCl3)δ157.7,156.4,150.5,139.5,139.0,138.1,135.3,129.3,129.2,129.0,128.9,128.5,127.3,127.2,117.5,117.0,77.6,77.2,76.7.
实施例8
以苯乙酮肟酯1a和α,β-不饱和酮2h为原料，按照2h：1a：无水氯化铁摩尔比＝1:2:0.05，无溶剂空气中加热反应至140℃，反应3小时后，冷却至室温。然后，向反应体系中加入乙酸乙酯(10mL)使大部分固体溶解，加入稀氨水(10mL，浓度为：1mol/L)洗涤一次，再用水(10mL)洗涤2次，分离出有机层，经无水Na2SO4干燥，柱层析得到目标产物3ah，产率为71％。
Figure BDA0002368024920000111
3ah：白色固体，核磁表征如下：1H-NMR(300MHz,d6-CDCl3)δ8.40(t,J＝2.2Hz,1H),8.38(t,J＝2.2Hz,1H),8.20(m,4H),7.90(m,4H),7.50(m,8H)；13C-NMR(75MHz,d6-CDCl3)δ158.0,148.2,147.9,145.5,139.1,129.6,129.0,128.3,127.2,124.5,117.0,77.6,77.2,76.7.
实施例9
以苯乙酮肟酯1a和α,β-不饱和酮2i为原料，按照2i：1a：无水氯化铁摩尔比＝1:2:0.05，无溶剂空气中加热反应至140℃，反应3小时后，冷却至室温。然后，向反应体系中加入乙酸乙酯(10mL)使大部分固体溶解，加入稀氨水(10mL，浓度为：1mol/L)洗涤一次，再用水(10mL)洗涤2次，分离出有机层，经无水Na2SO4干燥，柱层析得到目标产物3ai，产率为71％。
Figure BDA0002368024920000112
3ai：白色固体，核磁表征如下：1H-NMR(300MHz,d6-CDCl3)δ8.38(m,4H),8.19(m,2H),7.99(d,J＝1.3Hz,1H),7.95(d,J＝1.3Hz,1H),7.76(m,2H),7.54(m,6H)；13C-NMR(75MHz,d6-CDCl3)δ158.2,155.0,148.3,145.6,139.1,138.6,129.6,129.5,129.4,129.0,128.0,127.3,127.3,124.1,118.6,117.9.
实施例10
以苯乙酮肟酯1a和α,β-不饱和酮2j为原料，按照2j：1a：无水氯化铁摩尔比＝1:2:0.05，无溶剂空气中加热反应至140℃，反应3小时后，冷却至室温。然后，向反应体系中加入乙酸乙酯(10mL)使大部分固体溶解，加入稀氨水(10mL，浓度为：1mol/L)洗涤一次，再用水(10mL)洗涤2次，分离出有机层，经无水Na2SO4干燥，柱层析得到目标产物3aj，产率为80％。
Figure BDA0002368024920000121
3aj：白色固体，核磁表征如下：1H-NMR(300MHz,d6-CDCl3)；δ8.21(m,4H),7.86(s,2H),7.84(d,J＝0.8Hz),7.51(m,6H),13C-NMR(75MHz,d6-CDCl3)δ158.0,148.3,143.6,139.2,133.0,129.5,128.9,128.0,127.2,118.6,117.0,112.8.
实施例11
以苯乙酮肟酯1a和3-苯甲酰基丙烯酸乙酯2k为原料，按照2k：1a：无水氯化铁摩尔比＝1:2:0.05，无溶剂空气中加热反应至140℃，反应3小时后，冷却至室温。然后，向反应体系中加入乙酸乙酯(10mL)使大部分固体溶解，加入稀氨水(10mL，浓度为：1mol/L)洗涤一次，再用水(10mL)洗涤2次，分离出有机层，经无水Na2SO4干燥，柱层析得到目标产物3ak，产率为85％。
Figure BDA0002368024920000131
3ak：淡黄色液体，核磁表征如下：1H-NMR(300MHz,d6-CDCl3)；δ8.26(s,2H),8.20(m,4H),7.51(m,6H),4.03(s,3H)；13C-NMR(75MHz,d6-CDCl3)δ166.1,157.9,139.2,138.7,129.6,128.9,127.2,117.9,52.9.
实施例12
以1-四氢萘酮肟乙酸酯1b和α,β-不饱和酮2a为原料，按照2a：1b：无水氯化铁摩尔比＝1:2:0.05，无溶剂空气中加热反应至140℃，反应3小时后，冷却至室温。然后，向反应体系中加入乙酸乙酯(10mL)使大部分固体溶解，加入稀氨水(10mL，浓度为：1mol/L)洗涤一次，再用水(10mL)洗涤2次，分离出有机层，经无水Na2SO4干燥，柱层析得到目标产物3ba，产率为87％。
Figure BDA0002368024920000132
3ba：白色固体，核磁表征如下：1H-NMR(300MHz,d6-CDCl3)；δ8.57(dd,1J＝7.7Hz,2J＝1.3Hz,1H),7.18(m,2H),7.60(s,1H),7.46(m,9H),7.34(td,1J＝7.4Hz,2J＝1.6Hz),7.23(dd,1J＝7.3Hz,2J＝0.9Hz),2.91(m,4H)；13C-NMR(75MHz,d6-CDCl3)δ154.4,152.6,149.3,139.6,139.4,138.2,135.2,129.1,128.9,128.8,128.7,128.5,128.05,127.95,127.5,127.1,126.8,125.8,120.0,28.2,25.3.
实施例13
以苯丙酮肟酯1c和α,β-不饱和酮2a为原料，按照2a：1c：无水氯化铁摩尔比＝1:2:0.05，无溶剂空气中加热反应至140℃，反应3小时后，冷却至室温。然后，向反应体系中加入乙酸乙酯(10mL)使大部分固体溶解，加入稀氨水(10mL，浓度为：1mol/L)洗涤一次，再用水(10mL)洗涤2次，分离出有机层，经无水Na2SO4干燥，柱层析得到目标产物3ca，产率为77％。
Figure BDA0002368024920000141
3ca：白色固体，核磁表征如下：1H-NMR(300MHz,d6-CDCl3)；δ8.07(d,1J＝7.1Hz,2H),7.67(d,1J＝7.0Hz,2H),7.60(s,1H),7.44(m,11H),2.25(s,3H)；13C-NMR(75MHz,d6-CDCl3)δ159.6,154.2,151.7,141.5,140.4,139.5,129.6,128.9,128.7,128.6,128.2,128.0,127.1,127.0,120.1,18.1.
实施例14
以2-乙酰基吡啶O-酰基肟1d和α,β-不饱和酮2a为原料，按照2a：1d：无水氯化铁摩尔比＝1:2:0.05，无溶剂空气中加热反应至140℃，反应3小时后，冷却至室温。然后，向反应体系中加入乙酸乙酯(10mL)使大部分固体溶解，加入稀氨水(10mL，浓度为：1mol/L)洗涤一次，再用水(10mL)洗涤2次，分离出有机层，经无水Na2SO4干燥，柱层析得到目标产物3da，产率为57％。
Figure BDA0002368024920000142
3da：白色固体，核磁表征如下：1H-NMR(300MHz,d6-CDCl3)；δ8.70(m,2H),8.65(d,1J＝1.6Hz,1H),8.21(d,1J＝7.0Hz,2H),7.99(d,1J＝1.6Hz 1H),7.88(dd,1J＝7.8Hz,2J＝1.8Hz,1H),7.83(d,1J＝7.9Hz,2H),7.99(m,6H),7.35(dd,1J＝7.4Hz,2J＝1.2Hz,1H)；13C-NMR(75MHz,d6-CDCl3)δ157.2,156.4,156.3,150.3,149.1,139.5,138.8,136.9,129.1,129.1,128.8,127.3,127.1,123.9,121.6,118.5,117.6.
实施例15
以苯乙酮肟酯1a、α,β-不饱和酮2a为原料，按照2a：1a：无水氯化铁摩尔比＝1:2:0.05，无溶剂空气中加热反应至80℃，TLC检测，得到目标产物3aa，产率为45％。
实施例16
以苯乙酮肟酯1a、α,β-不饱和酮2a为原料，按照2a：1a：无水氯化铁摩尔比＝1:2:0.05，无溶剂空气中加热反应至120℃，TLC检测，得到目标产物3aa，产率为69％。
实施例17
以苯乙酮肟酯1a、α,β-不饱和酮2a为原料，按照2a：1a：无水氯化铁摩尔比＝1:1:0.05，无溶剂空气中加热反应至140℃，TLC检测，得到目标产物3aa，产率为55％。
实施例18
以苯乙酮肟酯1a、α,β-不饱和酮2a为原料，按照2a：1a：无水氯化铁摩尔比＝1:1.5:0.05，无溶剂空气中加热反应至140℃，TLC检测，得到目标产物3aa，产率为67％。
实施例19
以苯乙酮肟酯1a、α,β-不饱和酮2a为原料，按照2a：1a：七水合硫酸亚铁摩尔比＝1:2:0.05，无溶剂空气中加热反应至140℃，反应3小时后，冷却至室温。然后，向反应体系中加入乙酸乙酯(10mL)使大部分固体溶解，加入稀氨水(10mL，浓度为：1mol/L)洗涤一次，再用水(10mL)洗涤2次，分离出有机层，经无水Na2SO4干燥，柱层析得到目标产物3aa，产率为57％。
实施例20
以苯乙酮肟酯1a、α,β-不饱和酮2a为原料，按照2a：1a：硬脂酸铁摩尔比＝1:2:0.05，无溶剂空气中加热反应至140℃，反应3小时后，冷却至室温。然后，向反应体系中加入乙酸乙酯(10mL)使大部分固体溶解，加入稀氨水(10mL，浓度为：1mol/L)洗涤一次，再用水(10mL)洗涤2次，分离出有机层，经无水Na2SO4干燥，柱层析得到目标产物3aa，产率为51％。
对比实施例1
以苯乙酮肟酯1a、α,β-不饱和酮2a为原料，按照2a：1a：无水氯化铁摩尔比＝1:2:0.05，无溶剂空气中加热反应至60℃，TLC检测，得到目标产物3aa，产率为30％。
对比实施例2
以苯乙酮肟酯1a、α,β-不饱和酮2a为原料，按照2a：1a：无水氯化铜摩尔比＝1:2:0.05，无溶剂空气中加热反应至140℃，TLC检测，得不到目标产物3aa。
对比实施例3
以苯乙酮肟酯1a、α,β-不饱和酮2a为原料，按照2a：1a：无水氯化锌摩尔比＝1:2:0.05，无溶剂空气中加热反应至140℃，TLC检测，得不到目标产物3aa。
对比实施例4
以苯乙酮肟酯1a、α,β-不饱和酮2a为原料，按照2a：1a：无水氯化铁摩尔比＝1:2:0.05，溶剂甲苯用量为4mL，空气中加热反应至140℃，TLC检测，得到目标产物3aa，产率为43％。

Claims (1)

1.一种多取代吡啶衍生物的合成方法，其特征在于：所述合成方法步骤如下：
以α,β-不饱和酮和酮肟乙酸酯为原料，在铁盐的催化作用下，在空气条件下，无溶剂加热反应得到多取代吡啶化合物；
所述的酮肟乙酸酯为苯乙酮肟酯，1-四氢萘酮肟乙酸酯，苯丙酮肟酯，2-乙酰基吡啶O-酰基肟；
所述的α，β-不饱和酮类化合物，其结构通式如式II所示：
Figure FDA0002959092990000011
其中，R3、R5选自取代的C6芳基；其中，芳基的取代基选自硝基、甲基、甲氧基、氰基、卤素；
R4选自甲基；
所述的铁盐催化剂选自无水三氯化铁、七水合硫酸亚铁、硬脂酸铁中的一种；
所述原料α,β-不饱和酮：酮肟乙酸酯：催化剂的摩尔比＝1：1-2.0：0.05-1.0，反应温度为80-160℃。
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108178745A (zh) * 2018-03-29 2018-06-19 河南师范大学 含氟烷基吡啶衍生物的合成方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Michael addition of ethyl acetoacetate to a,b-unsaturated oximes in the presence of FeCl3: a novel synthetic route to substituted nicotinic acid derivatives;Andrey M. Chibiryaev et al.,;《Tetrahedron Letters》;20001231;第41卷;第8012页 *
Synthesis of Highly Substituted Pyridines through Copper-Catalyzed Condensation of Oximes and a,b-Unsaturated Imines;Wei Wen Tan et al.,;《Angew. Chem. Int. Ed.》;20170609;第56卷;第8241-8242页 *
Synthesis of Multisubstituted Pyridines;Zhi He et al.,;《Org. Lett.》;20121228;第15卷(第2期);第336-337页 *

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