CN108558751B - 3-硝基喹啉衍生物的合成工艺 - Google Patents
3-硝基喹啉衍生物的合成工艺 Download PDFInfo
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- MJZNIHATXONCTG-UHFFFAOYSA-N 7-fluoro-3-nitro-2-phenylquinoline Chemical compound C1=CC=C(C=C1)C2=C(C=C3C=CC(=CC3=N2)F)[N+](=O)[O-] MJZNIHATXONCTG-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明涉及一种3‑硝基喹啉衍生物的合成方法，在铜盐催化剂的作用下，硝基烯烃与邻位醛基取代的芳基叠氮在溶剂存在条件下发生[3+2]环加成反应，其中硝基烯烃为烷基、取代烷基、芳基或取代芳基取代的硝基烯烃，邻位醛基取代的芳基叠氮中芳基为芳基或取代芳基。本发明采用廉价易得的邻位醛基取代的芳基叠氮为原料，同硝基烯烃在铜盐的催化下发生[3+2]环加成得到3‑硝基喹啉类化合物，反应收率高且催化剂低廉，反应副产物只有氮气和水，后处理简单，是一种环境友好的合成方法。
Description
技术领域
本发明涉及一种3-硝基喹啉衍生物的合成方法，属于有机及药物合成技术领域。
技术背景
喹啉在有机合成中是一类重要的含氮杂环化合物。其中，3号位氮原子取代的喹啉在天然产物中广泛存在，如白叶藤碱类喹啉碱，具有良好的抗疟疾和抗癌的活性，此外，一些含有这种骨架的化合物也具有抗癌，抗疟，抗哮喘，抗糖尿病，抗菌，抗肿瘤等特性。3-硝基喹啉类化合物作为这类化合物的前体，具有性质稳定，易于衍生化的特点，在有机合成中备受关注，在药物合成上具有相当大的潜质。
然而到目前为止，3-硝基喹啉类化合物合成的方法非常少，主要有以下三种：(1)直接对喹啉环进行硝化，存在选择性不高，生成几种位置的异构体，并且会氧化喹啉环，形成喹啉的氮氧化物，因此直接硝化的方式很少用于合成3-硝基喹啉类化合物。(2)采用2-氨基苯甲醛和α-硝基酮类化合物在醇类溶剂中缩合得到3-硝基喹啉，但是这种酮类化合物在制备上较为繁琐，底物有很强的局限性。(3)2004年，姚清发课题组报道邻氨基苯甲醛和硝基烯烃在DABCO作为有机碱的条件下，使用苯作为溶剂回流，可以得到3-硝基-1，2-二氢喹啉，随后在DDQ或硅胶条件下氧化得到3-硝基喹啉。这种方法被广泛采用，但是存在三方面问题，一是第一步环加成过程中需要使用毒性较大的苯作为溶剂，二是由于邻氨基苯甲醛非常容易聚合，价格十分昂贵，而且实际中会导致收率变低，三是反应需要分两步进行，且使用了多个当量的碱和氧化剂，后处理复杂。
发明内容
为解决现有技术的不足，本发明采用廉价易得的邻位醛基取代的芳基叠氮为原料，同硝基烯烃在铜盐的催化下得到3-硝基喹啉类化合物。反应副产物只有氮气和水，后处理简单，是一种环境友好的合成方法。
为达到上述目的，本发明是通过以下的技术方案来实现的：3-硝基喹啉衍生物的合成工艺，其特征在于：在铜盐催化剂的作用下，硝基烯烃与邻位醛基取代的芳基叠氮在溶剂存在条件下发生[3+2]环加成反应，其中硝基烯烃为烷基、取代烷基、芳基或取代芳基取代的硝基烯烃，邻位醛基取代的芳基叠氮中芳基为芳基或取代芳基。
其具体反应式如式Ⅰ所示：
式Ⅰ中R1为芳基或者取代芳基，烷基或者取代烷基，R为卤素、甲基、甲氧基、氢或芳基。
按上述方案，所述的铜盐催化剂选自CuI,CuCl,CuBr,Cu2O或Cu(OTf)2。
按上述方案，所述的铜盐催化剂为CuI。
按上述方案，所述的铜盐催化剂用量按物质的量计为硝基烯烃用量的0.01-0.2倍。
按上述方案，所述的铜盐催化剂用量按物质的量计为硝基烯烃用量的0.01倍。
按上述方案，所用溶剂为DMSO，DMF，DMA，乙醇，甲苯和乙腈当中的任意一种或它们的混合。
按上述方案，所用溶剂为DMF。
按上述方案，反应在80-130℃的温度范围内进行。
按上述方案，反应在110℃条件下进行。
按上述方案，反应时间为8-15小时。
以CuI作为催化剂，在110℃反应条件下，其具体反应式为：
具体的反应步骤为：将硝基烯烃，邻位醛基取代的芳基叠氮，CuI和溶剂，在加热条件下经磁力搅拌反应8-15个小时，反应完成后，用乙酸乙酯溶解后，有机层经饱和食盐水洗涤，无水硫酸钠干燥后，减压蒸去溶剂即得粗产品，再经过柱层析分离提纯即得产物3-硝基喹啉化合物。
本发明的有益效果是：本发明采用廉价易得的邻位醛基取代的芳基叠氮为原料，同硝基烯烃在铜盐的催化下发生[3+2]环加成得到3-硝基喹啉类化合物，反应收率高且催化剂低廉，反应副产物只有氮气和水，后处理简单，是一种环境友好的合成方法。
附图说明
为了更清楚地说明本发明实施案例的技术方案，下面对实施例的附图作简单的介绍。
图1是本发明实施例1合成的2-苯基-3-硝基喹啉化合物的1H NMR表征图谱；
图2是本发明实施例1合成的2-苯基-3-硝基喹啉化合物的13C NMR表征图谱；
图3是本发明实施例2合成的2-(2-溴苯基)-3-硝基喹啉化合物的1H NMR表征图谱；
图4是本发明实施例2合成的2-(2-溴苯基)-3-硝基喹啉化合物的13C NMR表征图谱；
图5是本发明实施例3合成的2-苯基-3-硝基-7-氟喹啉化合物的1H NMR表征图谱；
图6是本发明实施例3合成的2-苯基-3-硝基-7-氟喹啉化合物的13C NMR表征图谱；
图7是本发明实施例4合成的2-(2-呋喃基)-3-硝基喹啉化合物的1H NMR表征图谱；
图8是本发明实施例4合成的2-(2-呋喃基)-3-硝基喹啉化合物的13C NMR表征图谱；
图9是本发明实施例5合成的2-苯基-3-硝基-6，7-二甲氧基喹啉化合物的1H NMR表征图谱；
图10是本发明实施例5合成的2-苯基-3-硝基-6，7-二甲氧基喹啉化合物的13C NMR表征图谱。
具体实施方式
为了更好地理解本发明，下面结合实施例进一步阐明本发明的内容，但本发明的内容不仅仅局限于下面的实施例。
实施例1：
具体步骤为：向圆底烧瓶(50mL)中加入硝基苯乙烯(1mmol)、2-叠氮苯甲醛(1.5mmol)、CuI(0.01mmol)，DMF(2mL)，在110℃下磁力搅拌反应8小时后，用乙酸乙酯溶解后，有机层经饱和食盐水洗涤，无水硫酸钠干燥后，减压蒸去溶剂即得粗产品，粗产品用乙酸乙酯/石油醚＝1:10(V/V)为淋洗液进行柱分离提纯即得所需产品2-苯基-3-硝基喹啉，为黄色固体，收率为85％。
如图1和图2，所得产品的核磁氢谱图结果为：1H NMR(600MHz,DMSO-d6):δ8.60(s,1H),8.20(d,J＝8.4Hz,1H),7.90(d,J＝8.4Hz,1H),7.86(t,J＝7.8Hz,1H),7.63(t,J＝7.2Hz,1H),7.58(d,J＝7.8Hz,2H),7.30(d,J＝7.8Hz,2H),2.42(s,3H).13C NMR(100MHz,CDCl3,ppm)δ152.1,148.3,143.9,137.0,132.8,132.6,129.8,129.6,128.7,128.6,128.4,128.1,125.5.
实施例2：
具体步骤为：向圆底烧瓶(50mL)中加入硝基邻溴苯乙烯(1mmol)、2-叠氮苯甲醛(1.5mmol)、CuI(0.01mmol)，甲苯(2mL)，在110℃下磁力搅拌反应12小时后，用乙酸乙酯溶解后，有机层经饱和食盐水洗涤，无水硫酸钠干燥后，减压蒸去溶剂即得粗产品，，粗产品用乙酸乙酯/石油醚＝1:10(V/V)为淋洗液进行柱分离提纯即得所需产品2-(2-溴苯基)-3-硝基喹啉，为黄色固体，收率为78％。
如图3和图4，所得产品的核磁氢谱图结果为：1H NMR(600MHz,CDCl3,ppm)δ8.98(s,1H),8.25(d,J＝8.4Hz,1H),8.06(d,J＝7.8Hz,1H),7.95(t,J＝7.2Hz,1H),7.74(t,J＝7.2Hz,1H),7.65(d,J＝7.8Hz,1H),7.59-7.45(m,2H),7.34(t,J＝7.2Hz,1H).13C NMR(100MHz,CDCl3,ppm)δ152.2,148.5,143.0,139.4,133.4,133.3,132.4,130.3,130.1,129.8,129.0,128.9,127.7,126.0,121.8.
实施例3：
具体步骤为：向圆底烧瓶(50mL)中加入硝基苯乙烯(1mmol)、2-叠氮-4-氟苯甲醛(1.5mmol)、Cu2O(0.01mmol)，DMSO(2mL)，在100℃下磁力搅拌反应15小时后，用乙酸乙酯溶解后，有机层经饱和食盐水洗涤，无水硫酸钠干燥后，减压蒸去溶剂即得粗产品，，粗产品用乙酸乙酯/石油醚＝1:15(V/V)为淋洗液进行柱分离提纯即得所需产品2-苯基-3-硝基-7-氟喹啉，产品为黄色固体，收率为72％。
如图5和图6，所得产品的核磁氢谱图结果为：1H NMR(600MHz,CDCl3,ppm)δ8.70(s,1H),8.03-7.97(m,1H),7.86(d,J＝9.6Hz,1H),7.65(s,2H),7.48-7.51(m,4H).13C NMR(150MHz,CDCl3,ppm)δ166.0,164.3,153.3,149.6(d,J＝13.4Hz),143.5,136.7,132.7,130.8(d,J＝10.4Hz),129.8,128.8,122.5,119.3(d,J＝25.9Hz),113.8(d,J＝21.0Hz).
实施例4：
具体步骤为：向圆底烧瓶(50mL)中加入2-呋喃硝基苯乙烯(1mmol)、2-叠氮苯甲醛(1.5mmol)、CuCl(0.01mmol)，DMA(2mL)，在100℃下磁力搅拌反应12小时后，用乙酸乙酯溶解后，有机层经饱和食盐水洗涤，无水硫酸钠干燥后，减压蒸去溶剂即得粗产品，，粗产品用乙酸乙酯/石油醚＝1:15(V/V)为淋洗液进行柱分离提纯即得所需产品2-(2-呋喃基)-3-硝基喹啉，产品为黄色固体，收率为69％。
如图7和图8，所得产品的核磁氢谱图结果为：1H NMR(400MHz,CDCl3,ppm)δ8.45(s,1H),8.16(d,J＝8.4Hz,1H),7.83-7.89(m,2H),7.65-7.60(m,2H),7.23(d,J＝3.6Hz,1H),6.59-6.60(m,1H).13C NMR(100MHz,CDCl3,ppm)δ149.7,148.1,145.2,142.3,140.6,132.6,131.7,129.6,128.4,128.4,125.3,113.1,112.3.
实施例5：
具体步骤为：向圆底烧瓶(50mL)中加入硝基苯乙烯(1mmol)、2-叠氮-4,5-二甲氧基苯甲醛(1.5mmol)、CuBr(0.01mmol)，DMF(2mL)，在130℃下磁力搅拌反应11小时后，用乙酸乙酯溶解后，有机层经饱和食盐水洗涤，无水硫酸钠干燥后，减压蒸去溶剂即得粗产品，，粗产品用乙酸乙酯/石油醚＝1:2.5(V/V)为淋洗液进行柱分离提纯即得所需产品2-苯基-3-硝基-6，7-二甲氧基喹啉，产品为黄色固体，收率为78％。
如图9和图10，所得产品的核磁氢谱图结果为：1H NMR(600MHz,CDCl3,ppm)δ8.55(s,1H),7.60(d,J＝4.8Hz,2H),7.52-7.44(m,4H),7.15(s,1H),4.05(s,3H),4.04(s,3H).13C NMR(100MHz,CDCl3,ppm)δ155.3,151.4,150.3,146.1,142.5,137.6,130.9,129.1,128.6,128.0,121.4,108.1,105.2,56.5,56.3.
本发明采用价廉易得的CuI作为催化剂，对硝基烯烃和2-叠氮苯甲醛的反应进行催化，合成了3-硝基取代的喹啉化合物，与已有方法相比，本发明所述的反应原料廉价易得，操作简便，反应收率高且催化剂低廉，副产物仅为氮气和水，原子经济性好，是一种具有潜在应用价值的方法。
上述施例不以任何形式限制本发明，凡采用等同替换或等小变换的方式所获得的技术方案，均落在本发明的保护范围内。
Claims (10)
1.3-硝基喹啉衍生物的合成工艺，其特征在于：在铜盐催化剂的作用下，硝基烯烃1与邻位醛基取代的芳基叠氮2在溶剂存在条件下发生[3+2]环加成反应，其具体反应方程式如式Ⅰ所示，
式Ⅰ中R1为芳基或者取代芳基，烷基或者取代烷基，R为卤素、甲基、甲氧基、氢或芳基。
2.根据权利要求1所述的合成工艺，其特征在于：所述的铜盐催化剂选自CuI，CuCl，CuBr或Cu(OTf)2。
3.根据权利要求2所述的合成工艺，其特征在于：所述的铜盐催化剂为CuI。
4.根据权利要求1至3任意之一所述合成工艺，其特征在于：所述的铜盐催化剂用量按物质的量计为硝基烯烃用量的0.01-0.2倍。
5.根据权利要求4所述的合成工艺，其特征在于：所述的铜盐催化剂用量按物质的量计为硝基烯烃用量的0.01倍。
6.根据权利要求1至3任意之一所述的合成工艺，其特征在于所用溶剂为DMSO，DMF，DMA，乙醇，甲苯和乙腈当中的任意一种或它们的混合。
7.根据权利要求6所述的合成工艺，其特征在于所用溶剂为DMF。
8.根据权利要求6所述的合成工艺，其特征在于：反应在80-130℃的温度范围内进行。
9.根据权利要求8所述的合成工艺，其特征在于：反应在110℃条件下进行。
10.根据权利要求6所述的合成工艺，其特征在于：反应时间为8-15小时。
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| An Investigation of the Reaction of 2-Aminobenzaldehyde Derivatives with Conjugated Nitro-olefins: An Easy and Efficient Synthesis of 3-Nitro-1,2-dihydroquinolines and 3-Nitroquinolines;Ming-Chung Yan，et al.;《J.Org.Chem.》;20040212;第69卷(第5期);1565-1570 * |
| Bifunctional acid-base ionic liquid for the one-pot synthesis of fine chemicals:Thioethers, 2H-chromenes and 2H-quinoline derivatives;Marial J. Climent，et al.;《Applied Catalyst A: General》;20140514;第481卷;27-38 * |
| ISOLATION, BIOLOGICAL ACTIVITIES AND SYNTHESIS OF INDOLOQUINOLINE ALKALOIDS: CRYPTOLEPINE, ISOCRYPTOLEPINE AND NEOCRYPTOLEPINE;Prakash T. Parvatkar，et al.;《Curr. Org. Chem》;20111231;第15卷(第7期);1036-1057 * |
| Synthesis of 3-Amino- and 3-Nitro-2-arylquinolines;HENRY E.BAUMGARTEN,et al.;《Journal of the American Chemical Society》;19570320;第79卷;1502-1505 * |
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