CN111606849A - 一种2-(2-氨基苯基)喹啉类化合物的合成方法 - Google Patents

一种2-(2-氨基苯基)喹啉类化合物的合成方法 Download PDF

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CN111606849A
CN111606849A CN202010643761.4A CN202010643761A CN111606849A CN 111606849 A CN111606849 A CN 111606849A CN 202010643761 A CN202010643761 A CN 202010643761A CN 111606849 A CN111606849 A CN 111606849A
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aminophenyl
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CN111606849B (zh
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范学森
杨玉洁
贾瑞雪
张新迎
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    • 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
    • C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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Abstract

一种2‑(2‑氨基苯基)喹啉类化合物的合成方法，属于有机合成技术领域。该合成方法采用如下操作：将2‑炔基苯胺类化合物1、催化剂、添加剂和六氟异丙醇混合，在含氧气体氛围或惰性气体氛围下加热反应，分别得到2‑(2‑氨基苯基)喹啉类化合物2或2‑(2‑氨基苯基)喹啉类化合物3。该合成方法通过两分子2‑炔基苯胺之间的串联反应，通过改变反应的气氛，可以选择性地一步合成出不同种类的2‑(2‑氨基苯基)喹啉类化合物。该方法具有原料简单易得、操作简便、条件温和、底物适用范围广等优点，具有潜在的工业应用前景。

Description

一种2-(2-氨基苯基)喹啉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-(2-氨基苯基)喹啉类化合物的合成方法。
背景技术
喹啉是一类重要的含氮杂环，许多含喹啉骨架的化合物表现出良好的抗疟疾、抗炎和抗精神***等药理活性。喹啉衍生物还可与金属形成配合物，显示出良好的电化学性能。基于以上特征，官能团化喹啉衍生物在医药和精细化学品等诸多领域得到了广泛应用。
目前，人们已经为2-(2-氨基苯基)喹啉类化合物的合成发展了一些可靠的方法，但这些方法仍然存在原料不易得到、反应条件苛刻、合成步骤繁琐和原子经济性低等问题。
因此，研究并开发从简单易得的原料出发，经由简便的操作步骤来合成2-(2-氨基苯基)喹啉类化合物的绿色高效新方法，具有十分重要的理论意义和实用前景。
发明内容
本发明解决的技术问题是提供了一种2-(2-氨基苯基)喹啉类化合物的合成方法，该合成方法通过两分子2-炔基苯胺之间的串联反应，一步合成2-(2-氨基苯基)喹啉类化合物。该方法具有原料简单易得、操作简便、条件温和、底物适用范围广等优点，具有潜在的工业应用前景。
本发明为解决上述技术问题采用如下技术方案，一种2-(2-氨基苯基)喹啉类化合物的合成方法，包括如下操作：将2-炔基苯胺类化合物1、催化剂、添加剂和六氟异丙醇(HFIP)混合，在含氧气体氛围或惰性气体氛围下加热反应，分别得到2-(2-氨基苯基)喹啉类化合物2或2-(2-氨基苯基)喹啉类化合物3，反应方程式为：
Figure BDA0002572269950000021
其中：R1为氢、卤素、三氟甲基、C1-4烷基或C1-4烷氧基，R2为环丙基、噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为卤素、三氟甲基、C1-4烷基或C1-4烷氧基。
进一步地，在上述技术方案中，所述催化剂为硫酸铜、三氟甲磺酸酮{Cu(OTf)2}、三氟甲磺酸铋{Bi(OTf)3}、三氟甲磺酸锂(LiOTf)或乙酸铋{Bi(OAc)3}。
进一步地，在上述技术方案中，所述添加剂为三氟乙酸(TFA)、2,4,6-三甲基苯甲酸(MesCOOH)或1-金刚烷甲酸(1-AdCOOH)。
进一步地，在上述技术方案中，反应氛围为含氧气体氛围或惰性气体氛围，含氧气体氛围(例如氧气、空气中)有利于2-(2-氨基苯基)喹啉类化合物2的生成，惰性气体氛围(例如氮气、氩气中)有利于2-(2-氨基苯基)喹啉类化合物3的生成。
进一步地，在上述技术方案中，所述2-炔基苯胺类化合物1、添加剂和催化剂投料摩尔比为1:0.25-2:0.05-0.15。
进一步地，在上述技术方案中，所述加热反应温度为60-120℃。
发明有益效果：
本发明与现有技术相比具有以下优点：1)合成过程简单、高效，从2-炔基苯胺类化合物出发，通过两分子间的串联反应一步得到2-(2-氨基苯基)喹啉类化合物；2)通过改变反应的气氛，可以选择性地合成出不同种类的2-(2-氨基苯基)喹啉类化合物；3)原料价廉易得、反应条件温和、操作简便、底物的适用范围广、原子经济性高，符合绿色化学的要求。因此，本发明为2-(2-氨基苯基)喹啉类化合物的合成提供了一种高效实用的新方法。
附图说明
图1为实施例3中化合物2d的单晶X-射线衍射图(椭球率30％)。
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 BDA0002572269950000031
向15mL反应管中依次加入1a(57.9mg,0.3mmol)、催化剂、添加剂和六氟异丙醇(2mL)，盖上塞子密封，然后置于油浴中，升温搅拌反应。待反应结束后，冷却至室温，抽滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝10/1)得目标产物2a和3a。
改变反应的催化剂、添加剂、温度、反应气氛及底物的当量比等反应条件，得到一系列反应结果，见表1。
表1各种条件下2a和3a的合成a
Figure BDA0002572269950000041
实施例2
向15mL反应管中依次加入1a(57.9mg,0.3mmol)、三氟甲磺酸铋(19.7mg,0.03mmol)、2,4,6-三甲基苯甲酸(49.3mg,0.3mmol)和六氟异丙醇(2mL)，盖上塞子密封，将其置于80℃油浴中搅拌反应20h。待反应结束后，冷却至室温，抽滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝10/1)得黄色固体产物2a(43.2mg,72％)。该化合物的表征数据为：Yellowsolid(43.2mg,72％).1H NMR(400MHz,CDCl3):δ4.61(br s,2H),6.43(t,J＝7.6Hz,1H),6.74(d,J＝8.0Hz,2H),6.98-7.02(m,6H),7.26(t,J＝8.0Hz,2H),7.43(t,J＝7.6Hz,1H),7.52(t,J＝8.0Hz,1H),7.59(d,J＝7.6Hz,2H),7.66(d,J＝8.4Hz,1H),7.77(t,J＝7.6Hz,1H),8.21(d,J＝8.4Hz,1H).13C NMR(150MHz,CDCl3):δ116.7,117.8,123.9,124.4,125.2,127.4,127.65,127.74,127.8,128.5,129.2,129.49,129.51,130.1,131.7,131.9,133.8,136.60,136.64,145.4,146.2,146.7,158.4,197.2.HRMS calcd for C28H21N2O:401.1648[M+H]+,found:401.1647.
向15mL反应管中依次加入1a(57.9mg,0.3mmol)、三氟甲磺酸铋(19.7mg,0.03mmol)、2,4,6-三甲基苯甲酸(49.3mg,0.3mmol)和六氟异丙醇(2mL)，在氮气气氛下将反应管密封，然后将混合物置于80℃油浴中搅拌反应20h。待反应结束后，冷却至室温，抽滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝10/1)得淡黄色固体产物3a(37.1mg,64％)。该化合物的表征数据为：Light yellow solid(37.1mg,64％).1H NMR(400MHz,CDCl3):δ4.36(br s,2H),4.40(s,2H),6.40-6.44(m,1H),6.68(d,J＝8.0Hz,1H),6.72(dd,J1＝8.0Hz,J2＝1.6Hz,1H),6.93-6.97(m,1H),7.00(d,J＝6.8Hz,2H),7.07-7.10(m,2H),7.14-7.17(m,4H),7.20-7.23(m,2H),7.47-7.50(m,1H),7.67-7.71(m,1H),7.93(d,J＝8.4Hz,1H),8.16(d,J＝8.0Hz,1H).13C NMR(100MHz,CDCl3):δ35.6,116.3,117.6,125.3,126.1,126.8,126.9,127.2,127.8,128.2,128.6,128.7,129.2,129.9,130.1,131.2,136.1,138.3,140.1,144.5,144.9,147.1,158.7.HRMS calcd for C28H23N2:387.1856[M+H]+,found:387.1857.
上述反应采用方程式简单表示如下：
Figure BDA0002572269950000061
实施例3
依照实施例2的方法和步骤，通过改变反应物1，可以合成出各种2-(2-氨基苯基)喹啉类化合物2，具体结果见表2。
表2各种2-(2-氨基苯基)喹啉类化合物2的合成a,b
Figure BDA0002572269950000062
Figure BDA0002572269950000071
a反应条件：1(0.3mmol),Bi(OTf)3(0.03mmol),MesCO2H(0.3mmol),HFIP(2mL),80℃,air,20h；b分离收率。
代表性产物表征数据如下：
(2-(2-Amino-5-methylphenyl)-6-methyl-3-phenylquinolin-4-yl)(pheny l)methanone(2b)
Yellow solid(39.8mg,62％).1H NMR(400MHz,CDCl3):δ1.92(s,3H),2.45(s,3H),4.38(br s,2H),6.56(s,1H),6.62(d,J＝8.0Hz,1H),6.80(d,J＝8.0Hz,1H),6.99-7.00(m,4H),7.23-7.27(m,3H),7.41-7.44(m,2H),7.58(d,J＝7.6Hz,3H),8.10(d,J＝8.8Hz,1H).13C NMR(150MHz,CDCl3):δ20.1,21.8,116.6,123.8,123.9,124.6,126.9,127.3,127.58,127.62,128.4,129.2,129.5,129.7,131.7,132.2,132.4,133.7,136.7,136.8,137.8,142.7,145.2,145.4,157.5,197.5.HRMS calcd for C30H25N2O:429.1961[M+H]+,found:429.1962.
(2-(2-Amino-5-ethylphenyl)-6-ethyl-3-phenylquinolin-4-yl)(phenyl)methanone(2c)Yellow solid(50.0mg,73％).1H NMR(400MHz,CDCl3):δ0.76(t,J＝7.6Hz,3H),1.23(t,J＝7.6Hz,3H),2.19(q,J＝7.6Hz,2H),2.74(q,J＝7.6Hz,2H),4.54(br s,2H),6.54(s,1H),6.66(d,J＝8.0Hz,1H),6.80(d,J＝8.0Hz,1H),6.98(br s,4H),7.23-7.27(m,3H),7.42(t,J＝7.2Hz,2H),7.59(d,J＝8.0Hz,2H),7.63(d,J＝8.8Hz,1H),8.12(d,J＝8.8Hz,1H).13C NMR(150MHz,CDCl3):δ15.5,15.8,27.7,29.1,116.7,122.8,123.8,124.3,127.2,127.7,128.4,128.6,129.4,129.5,131.2,131.3,131.8,133.6,133.7,136.8,137.0,143.1,144.0,145.49,145.52,157.6,197.6.HRMS calcd for C32H29N2O:457.2274[M+H]+,found:457.2279.
(2-(2-Amino-5-bromophenyl)-6-bromo-3-phenylquinolin-4-yl)(phenyl)methanone(2d)
Yellow solid(49.2mg,59％).1H NMR(400MHz,CDCl3):δ4.55(br s,2H),6.60(d,J＝8.4Hz,1H),6.87(s,1H),7.06-7.10(m,5H),7.26-7.30(m,3H),7.45(t,J＝7.6Hz,1H),7.56(d,J＝8.0Hz,2H),7.82(s,1H),7.85(d,J＝9.2Hz,1H),8.07(d,J＝8.8Hz,1H).13C NMR(150MHz,CDCl3):δ109.3,118.2,122.2,125.1,125.5,127.4,128.0,128.6,129.5,131.1,132.1,132.6,133.9,134.1,134.2,135.6,136.3,144.4,145.28,145.31,157.3,196.3.HRMS calcd for C28H19Br2N2O:556.9859[M+H]+,found:556.9852.
2-(2-Aminophenyl)-3-(4-(tert-butyl)phenyl)quinolin-4-yl)(4-(tert-butyl)phenyl)methanone(2h)
Yellow solid(41.5mg,54％).1H NMR(400MHz,CDCl3):δ1.11(s,9H),1.22(s,9H),4.66(br s,2H),6.42(t,J＝7.6Hz,1H),6.75(t,J＝8.4Hz,2H),6.98-7.02(m,5H),7.21(d,J＝8.4Hz,2H),7.45(d,J＝8.4Hz,2H),7.51(t,J＝8.0Hz,1H),7.70(d,J＝8.4Hz,1H),7.75(t,J＝7.6Hz,1H),8.19(d,J＝8.4Hz,1H).13C NMR(150MHz,CDCl3):δ30.9,31.1,34.3,35.1,116.6,117.7,124.0,124.48,124.50,125.2,125.3,127.5,129.1,129.37,129.41,129.9,130.3,131.9,132.0,133.7,134.4,145.4,146.4,146.6,150.2,157.3,158.5,197.1.HRMS calcd for C36H37N2O:513.2900[M+H]+,found:513.2890.
(2-(2-Aminophenyl)-3-(4-methoxyphenyl)quinolin-4-yl)(4-methoxyphenyl)methanone(2i)
Yellow solid(33.1mg,48％).1H NMR(400MHz,CDCl3):δ3.66(s,3H),3.79(s,3H),4.61(br s,2H),6.47(t,J＝7.6Hz,1H),6.57(br s,2H),6.73-6.76(m,4H),6.99-7.03(m,3H),7.48(t,J＝7.6Hz,1H),7.59-7.64(m,3H),7.73(t,J＝7.6Hz,1H),8.18(d,J＝8.4Hz,1H).13C NMR(150MHz,CDCl3):δ55.0,55.5,113.3,113.8,116.7,117.9,124.1,124.8,125.3,127.4,129.0,129.07,129.10,129.42,129.45,129.8,131.4,131.66,131.74,132.0,145.3,146.4,146.5,158.7,164.1,195.7.HRMS calcd for C30H25N2O3:461.1860[M+H]+,found:461.1849.
(2-(2-Aminophenyl)-3-(4-(trifluoromethyl)phenyl)quinolin-4-yl)(4-(trifluoromethyl)phenyl)methanone(2m)
Yellow solid(57.1mg,71％).1H NMR(400MHz,CDCl3):δ4.59(br s,2H),6.44(t,J＝7.6Hz,1H),6.66(d,J＝7.6Hz,1H),6.75(d,J＝8.0Hz,1H),7.03(t,J＝7.6Hz,1H),7.26(br s,4H),7.54(d,J＝8.4Hz,2H),7.58(d,J＝7.2Hz,1H),7.62-7.67(m,3H),7.83(t,J＝7.6Hz,1H),8.25(d,J＝8.4Hz,1H).13C NMR(150MHz,CDCl3):δ116.8,118.0,123.2(q,1JC-F＝271.2Hz),123.4,123.6,123.7(q,1JC-F＝271.2Hz),124.87,124.95,125.7(q,3JC-F＝4.5Hz),128.2,129.6,129.7,129.756(q,2JC-F＝31.8Hz),129.759,130.6,130.8,130.9,131.5,135.2(q,2JC-F＝32.9Hz),139.1,140.3,145.4,145.5,147.0,158.0,195.9.19F NMR(565MHz,CDCl3)δ:-62.9(s),-63.4(s).HRMS calcd for C30H19F6N2O:537.1396[M+H]+,found:537.1397.
(2-(2-Aminophenyl)-3-(thiophen-2-yl)quinolin-4-yl)(thiophen-2-yl)methanone(2p)
Yellow solid(23.5mg,38％).1H NMR(400MHz,CDCl3):δ4.51(br s,2H),6.57(t,J＝7.6Hz,1H),6.76-6.78(m,2H),6.92-6.96(m,3H),7.08-7.13(m,2H),7.18(d,J＝4.0Hz,1H),7.55(t,J＝8.0Hz,1H),7.64(d,J＝4.8Hz,1H),7.77(t,J＝8.4Hz,2H),8.19(d,J＝8.4Hz,1H).13CNMR(150MHz,CDCl3):δ116.7,118.0,123.6,124.3,124.8,125.3,126.7,127.9,128.3,129.5,129.6,130.5,130.6,131.1,135.7,135.8,137.2,143.7,145.4,146.6,146.9,158.6,188.6.HRMS calcd forC24H17N2OS2:413.0777[M+H]+,found:413.0771.
(2-(2-Aminophenyl)-3-cyclopropylquinolin-4-yl)(cyclopropyl)methanone(2q)
Yellow solid(12.8mg,26％).1H NMR(400MHz,CDCl3):δ0.39-0.43(m,2H),0.70-0.75(m,2H),1.22-1.25(m,2H),1.56-1.59(m,2H),2.09-2.16(m,1H),2.44-2.50(m,1H),4.26(br s,2H),6.82-6.86(m,2H),7.19-7.23(m,1H),7.29(dd,J1＝8.0Hz,J2＝2.0Hz,1H),7.53-7.57(m,1H),7.68-7.72(m,1H),7.75(d,J＝8.4Hz,1H),8.10(d,J＝8.4Hz,1H).13CNMR(150MHz,CDCl3):δ8.6,13.6,13.9,24.4,116.7,118.0,122.6,124.4,125.7,127.2,129.3,129.5,130.3,130.5,144.5,146.4,150.4,161.3,207.6.HRMS calcd for C22H21N2O:329.1648[M+H]+,found:329.1648.
(2-(2-Amino-5-methylphenyl)-3-(4-chlorophenyl)-6-methylquinolin-4-yl)(4-chlorophenyl)methanone(2r)
Yellow solid(44.7mg,60％).1H NMR(400MHz,CDCl3):δ1.96(s,3H),2.46(s,3H),4.36(br s,2H),6.52(s,1H),6.64(d,J＝8.0Hz,1H),6.83(d,J＝8.0Hz,1H),6.99(br s,3H),7.25-7.27(m,3H),7.34(s,1H),7.52(d,J＝8.4Hz,2H),7.61(d,J＝8.4Hz,1H),8.10(d,J＝8.8Hz,1H).13CNMR(150MHz,CDCl3):δ20.2,21.8,116.8,123.6,123.7,124.3,127.2,128.0,129.1,129.3,130.0,130.4,130.8,131.9,132.7,133.7,134.8,135.2,138.1,140.7,142.7,144.8,145.5,157.3,196.0.HRMS calcd forC30H23Cl2N2O:497.1182[M+H]+,found:497.1168.
(2-(2-Amino-5-methylphenyl)-3-(3-chlorophenyl)-6-methylquinolin-4-yl)(3-chlorophenyl)methanone(2s)
Yellow solid(43.2mg,58％).1H NMR(400MHz,CDCl3):δ1.96(s,3H),2.48(s,3H),4.42(br s,2H),6.55(s,1H),6.64(d,J＝8.4Hz,1H),6.83(d,J＝8.4Hz,1H),7.00-7.01(m,4H),7.21(t,J＝8.0Hz,1H),7.38(s,1H),7.40-7.43(m,2H),7.60(s,1H),7.63(d,J＝8.4Hz,1H),8.11(d,J＝8.4Hz,1H).13C NMR(150MHz,CDCl3):δ20.2,21.9,116.8,123.5,123.7,124.0,127.1,127.66,127.69,128.9,129.0,129.4,129.9,130.0,130.3,131.8,132.9,133.9,135.0,138.1,138.2,138.5,142.7,144.6,145.6,157.1,196.0.HRMS calcdfor C30H23Cl2N2O:497.1182[M+H]+,found:497.1173.
实施例4
依照实施例2的方法和步骤，通过改变反应物1，合成出各种2-(2-氨基苯基)喹啉类化合物3，具体结果见表3。
表3各种2-(2-氨基苯基)喹啉类化合物3的合成a,b
Figure BDA0002572269950000121
a反应条件：1(0.3mmol),Bi(OTf)3(0.03mmol),MesCO2H(0.3mmol),HFIP(2mL),80℃,N2,20h；b分离收率。
代表性产物表征数据如下：
2-(4-Benzyl-6-methyl-3-phenylquinolin-2-yl)-4-methylaniline(3b)
Light yellow solid(40.4mg,65％).1H NMR(600MHz,CDCl3):δ1.93(s,3H),2.48(s,3H),4.37(br s,4H),6.54(s,1H),6.58(d,J＝7.8Hz,1H),6.75(dd,J1＝8.4Hz,J2＝1.8Hz,1H),7.00(d,J＝7.2Hz,2H),7.05-7.07(m,2H),7.14-7.18(m,4H),7.22(t,J＝7.8Hz,2H),7.53(dd,J1＝8.4Hz,J2＝1.8Hz,1H),7.71(s,1H),8.06(d,J＝8.4Hz,1H).13CNMR(150MHz,CDCl3):δ20.1,22.1,35.5,116.3,124.1,126.0,126.3,126.7,126.8,127.1,127.6,128.2,128.5,129.1,129.6,130.1,131.4,131.8,136.0,136.7,138.5,140.3,142.3,143.6,145.7,157.9.HRMS calcd for C30H27N2:415.2169[M+H]+,found:415.2169.
2-(4-Benzyl-6-chloro-3-phenylquinolin-2-yl)-4-chloroaniline(3d)
Light yellow solid(39.5mg,58％).1H NMR(400MHz,DMSO-d6):δ4.32(s,2H),5.14(br s,2H),6.57(d,J＝8.4Hz,1H),6.80(d,J＝2.4Hz,1H),6.88(dd,J1＝8.8Hz,J2＝2.8Hz,1H),7.06(d,J＝7.2Hz,2H),7.14(t,J＝7.6Hz,1H),7.20-7.23(m,7H),7.77(dd,J1＝8.8Hz,J2＝2.4Hz,1H),7.96(d,J＝2.0Hz,1H),8.09(d,J＝9.2Hz,1H).13C NMR(150MHz,DMSO-d6):δ35.0,116.7,118.6,124.7,126.6,126.8,127.6,127.9,128.2,128.4,128.5,129.0,130.0,130.1,130.2,131.8,132.3,137.1,137.9,140.0,143.9,145.5,145.9,158.2.HRMS calcd for C28H21Cl2N2:455.1076[M+H]+,found:455.1075.
2-(4-Benzyl-6-bromo-3-phenylquinolin-2-yl)-4-bromoaniline(3e)
Light yellow solid(51.2mg,63％).1H NMR(400MHz,CDCl3):δ4.34(br s,4H),6.55(d,J＝8.4Hz,1H),6.83(d,J＝1.6Hz,1H),6.96(d,J＝7.2Hz,2H),7.04-7.05(m,3H),7.18-7.24(m,6H),7.78(d,J＝7.6Hz,1H),8.01(d,J＝8.8Hz,1H),8.11(s,1H).13C NMR(150MHz,CDCl3):δ35.5,109.3,117.9,121.4,126.4,127.2,127.6,127.8,128.08,128.10,128.2,128.7,129.9,131.52,131.55,133.0,133.7,136.7,137.3,139.4,144.0,144.2,145.6,157.7.HRMS calcd for C28H21Br2N2:543.0066[M+H]+,found:543.0065.
2-(4-(4-Ethylbenzyl)-3-(4-ethylphenyl)quinolin-2-yl)aniline(3f)
Light yellow solid(34.5mg,52％).1H NMR(400MHz,CDCl3):δ1.15-1.22(m,6H),2.53-2.62(m,4H),4.37(s,4H),6.40-6.44(m,1H),6.69(d,J＝8.0Hz,1H),6.72(dd,J1＝7.6Hz,J2＝1.6Hz,1H),6.92-6.96(m,3H),6.97-7.01(m,4H),7.05(d,J＝8.0Hz,2H),7.45-7.49(m,1H),7.65-7.69(m,1H),7.93(d,J＝7.6Hz,1H),8.14(d,J＝8.0Hz,1H).13C NMR(150MHz,CDCl3):δ15.3,15.5,28.4,28.5,35.3,116.3,117.6,125.4,126.3,126.7,126.8,127.3,128.0,128.1,128.5,129.0,129.8,130.1,131.3,135.4,136.0,137.5,141.9,143.0,144.87,144.90,147.0,158.9.HRMS calcd for C32H31N2:443.2482[M+H]+,found:443.2477.
2-(4-(4-Fluorobenzyl)-3-(4-fluorophenyl)quinolin-2-yl)aniline(3g)
Light yellow solid(38.0mg,60％).1H NMR(400MHz,CDCl3):δ4.30(br s,2H),4.34(s,2H),6.43-6.47(m,1H),6.67-6.70(m,2H),6.86(t,J＝8.8Hz,2H),6.90-6.92(m,4H),6.96-7.02(m,3H),7.51-7.55(m,1H),7.71-7.75(m,1H),7.93(d,J＝8.0Hz,1H),8.17(d,J＝8.0Hz,1H).13CNMR(150MHz,CDCl3):δ34.7,114.9(d,2JC-F＝20.9Hz),115.4(d,2JC-F＝20.7Hz),116.4,117.8,125.0,125.8,126.6,127.1,128.8,129.5(d,3JC-F＝7.7Hz),130.0,131.0,131.6(d,3JC-F＝7.7Hz),134.1(d,4JC-F＝3.3Hz),135.0,135.4(d,4JC-F＝3.3Hz),144.6,144.8,147.2,158.8,161.4(d,1JC-F＝244.1Hz),162.0(d,1JC-F＝245.0Hz).19F NMR(376MHz,CDCl3)δ:-114.5–-114.6(m),-116.7–-116.8(m).HRMS calcd forC28H21F2N2:423.1667[M+H]+,found:423.1667.
2-(4-(4-(Trifluoromethyl)benzyl)-3-(4-(trifluoromethyl)phenyl)quinolin-2-yl)aniline(3j)
Light yellow solid(53.2mg,68％).1H NMR(400MHz,CDCl3):δ4.40(br s,4H),6.43(t,J＝7.6Hz,1H),6.64-6.66(m,1H),6.69(d,J＝8.0Hz,1H),6.96-7.00(m,1H),7.08(d,J＝8.4Hz,2H),7.18(d,J＝8.0Hz,2H),7.43(d,J＝8.0Hz,2H),7.48(d,J＝8.0Hz,2H),7.55(t,J＝8.0Hz,1H),7.76(t,J＝7.2Hz,1H),7.88(d,J＝8.4Hz,1H),8.20(d,J＝8.4Hz,1H).13C NMR(150MHz,CDCl3):δ35.4,116.5,117.9,124.0(q,1JC-F＝270.2Hz),124.1(q,1JC-F＝270.3Hz),124.85(q,3JC-F＝6.6Hz),124.90,125.3,125.7(q,4JC-F＝3.2Hz),126.3,127.5,128.3,128.8(q,2JC-F＝31.7Hz),129.1,129.6(q,2JC-F＝31.7Hz),129.9,130.1,130.4,130.9,134.9,142.0,143.5,143.6,144.9,147.3,158.4.19F NMR(376MHz,CDCl3)δ:-62.4(s),-62.6(s).HRMS calcd for C30H21F6N2:523.1603[M+H]+,found:523.1602.
2-(4-(3-Chlorobenzyl)-3-(3-chlorophenyl)quinolin-2-yl)aniline(3k)
Yellow solid(40.9mg,60％).1H NMR(400MHz,CDCl3):δ4.29-4.39(m,4H),6.46(td,J1＝7.6Hz,J2＝1.2Hz,1H),6.68-6.72(m,2H),6.81(d,J＝6.4Hz,1H),6.92(d,J＝7.6Hz,1H),6.96-7.00(m,2H),7.05-7.06(m,1H),7.09(t,J＝8.0Hz,1H),7.13-7.18(m,3H),7.52-7.57(m,1H),7.72-7.76(m,1H),7.93(d,J＝8.0Hz,1H),8.18(d,J＝8.0Hz,1H).13C NMR(100MHz,CDCl3):δ35.2,116.4,117.8,124.9,125.5,126.3,126.5,126.6,127.4,127.6,128.2,128.3,129.0,129.2,129.7,129.9,130.1,130.9,133.8,134.5,134.8,139.9,141.7,143.9,144.9,147.3,158.4.HRMS calcd for C28H21Cl2N2:455.1076[M+H]+,found:455.1072.
2-(4-(2-Chlorobenzyl)-3-(2-chlorophenyl)quinolin-2-yl)aniline(3l)
Light yellow solid(38.8mg,57％).1H NMR(400MHz,CDCl3):δ4.19(d,J＝16.8Hz,1H),4.43(br s,2H),4.60(d,J＝17.2Hz,1H),6.43(t,J＝7.6Hz,1H),6.65(d,J＝7.6Hz,1H),6.69(d,J＝8.0Hz,1H),6.85(d,J＝7.6Hz,1H),6.94-6.99(m,2H),7.02-7.10(m,3H),7.12-7.16(m,1H),7.31(t,J＝8.4Hz,2H),7.49(t,J＝8.0Hz,1H),7.72(t,J＝8.0Hz,1H),7.79(d,J＝8.4Hz,1H),8.18(d,J＝8.4Hz,1H).13C NMR(100MHz,CDCl3):δ32.8,116.5,117.4,125.0,125.2,126.3,126.4,126.8,127.1,127.5,129.0,129.1,129.2,129.4,129.65,129.67,130.0,130.3,131.9,133.5,133.8,134.3,136.9,137.0,145.0,145.1,147.3,158.4.HRMS calcd for C28H21Cl2N2:455.1076[M+H]+,found:455.1076.
实施例5
本发明所合成的产物2-(2-氨基苯基)喹啉类化合物2可以进行一系列反应，从而合成进一步的衍生物。例如：
Figure BDA0002572269950000171
在0℃(冰水浴)下，向圆底烧瓶中依次加入2a(60.0mg，0.15mmol)和HCl水溶液(2M，1.5mL)，在0℃下搅拌15min后，向混合物中加入亚硝酸钠(11.4mg，0.165mmol)，继续搅拌1h。然后将此混合物置于60℃油浴中搅拌3h。反应结束后，冷却至室温，用饱和NaHCO3水溶液处理，然后用DCM(10mL×3)萃取。合并有机相用盐水洗涤，并用无水硫酸钠干燥，过滤并减压蒸发，得到残余物。将残余物通过硅胶柱分离(石油醚/乙酸乙酯＝20/1)得到白色固体4(36.8mg,64％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ7.29-7.35(m,3H),7.50-7.57(m,3H),7.76-7.83(m,6H),8.34(d,J＝8.4Hz,1H),8.39(d,J＝8.8Hz,1H),8.51-8.53(m,1H),8.55(d,J＝8.0Hz,1H),9.59-9.61(m,1H).13C NMR(150MHz,CDCl3):δ120.7,122.6,123.7,124.2,125.2,126.7,127.1,127.2,128.1,128.2,128.4,128.9,129.1,129.7,130.0,130.1,131.1,131.3,132.1,134.4,136.8,141.9,146.9,147.8,200.1.HRMScalcd for C28H18NO:384.1383[M+H]+,found:384.1383.
在圆底烧瓶中依次加入4(57.5mg，0.15mmol)、LiAlH4(0.3mL，0.3mmol，1M的THF溶液)和无水THF(1mL)，在室温下搅拌。通过TLC监测反应完成后，加入水淬灭反应，然后用DCM(10mL×3)萃取。合并有机相，用无水硫酸钠干燥，过滤并减压蒸发，得到残余物。将残余物通过硅胶柱分离(石油醚/乙酸乙酯＝10/1)得到白色固体5(30.1mg,72％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ7.59(t,J＝7.6Hz,1H),7.63-7.68(m,2H),7.71-7.77(m,2H),7.79-7.82(m,1H),8.04(d,J＝8.4Hz,1H),8.32(d,J＝8.4Hz,1H),8.53-8.55(m,1H),8.57-8.59(m,1H),8.65-8.67(m,1H),9.26(s,1H),9.52-9.54(m,1H).13C NMR(150MHz,CDCl3):δ122.7,123.4,123.57,123.62,126.2,126.3,127.1,127.6,127.7,128.0,128.2,129.2,129.5,129.6,129.8,129.9,130.2,131.2,132.1,147.61,147.64.HRMS calcd forC21H14N:280.1121[M+H]+,found:280.1111.
Figure BDA0002572269950000181
在圆底烧瓶中加入2a(80.0mg，0.2mmol)和稀硫酸(1M，2.5mL)，将得到的混合物在室温搅拌3h，然后冷却至0℃(冰水浴)。随后逐滴加入亚硝酸钠(82.8mg，1.2mmol)的水溶液(1mL)并搅拌1h。在15min内向混合液中加入叠氮化钠(78.1mg，1.2mmol)的水溶液(1mL)并在0℃下搅拌1h。过滤出沉淀物，用水洗涤得到灰绿色固体。将该固体加到1,2,4-三氯苯(5mL)中，并在214℃(液态金属浴)加热3h。减压除去溶剂，残余物通过硅胶柱分离(石油醚/乙酸乙酯＝10/1)得到黄色固体6(54.9mg,69％)。该化合物的表征数据如下：1H NMR(600MHz,CDCl3):δ6.84(d,J＝8.4Hz,1H),6.97(t,J＝8.4Hz,1H),7.32(t,J＝8.4Hz,2H),7.37-7.41(m,5H),7.47-7.50(m,2H),7.55(t,J＝7.8Hz,1H),7.72-7.74(m,3H),7.83(t,J＝8.4Hz,1H),7.99(d,J＝8.4Hz,1H).9.11(d,J＝8.4Hz,1H).13C NMR(150MHz,CDCl3):δ116.9,117.6,117.8,121.3,121.5,122.9,126.6,126.8,128.0,128.6,128.7,128.9,129.6,129.8,130.0,130.6,131.6,133.2,133.8,134.4,137.8,149.7,197.0.HRMS calcdfor C28H19N2O:399.1492[M+H]+,found:399.1483.
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 (8)

1.一种2-(2-氨基苯基)喹啉类化合物的合成方法，其特征在于，包括如下操作：将2-炔基苯胺类化合物1、催化剂、添加剂和六氟异丙醇混合，在含氧气体氛围或惰性气体氛围下加热反应，分别得到2-(2-氨基苯基)喹啉类化合物2或2-(2-氨基苯基)喹啉类化合物3，反应方程式为：
Figure FDA0002572269940000011
其中：R1为氢、卤素、三氟甲基、C1-4烷基或C1-4烷氧基，R2为环丙基、噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为卤素、三氟甲基、C1-4烷基或C1-4烷氧基。
2.根据权利要求1所述2-(2-氨基苯基)喹啉类化合物的合成方法，其特征在于：所述催化剂为硫酸铜、三氟甲磺酸酮、三氟甲磺酸铋、三氟甲磺酸锂或乙酸铋。
3.根据权利要求1所述2-(2-氨基苯基)喹啉类化合物的合成方法，其特征在于：所述添加剂为三氟乙酸、2,4,6-三甲基苯甲酸或1-金刚烷甲酸。
4.根据权利要求1所述2-(2-氨基苯基)喹啉类化合物的合成方法，其特征在于：所述催化剂选自三氟甲磺酸铋或三氟甲磺酸酮，添加剂选自2,4,6-三甲基苯甲酸或1-金刚烷甲酸。
5.根据权利要求1所述2-(2-氨基苯基)喹啉类化合物的合成方法，其特征在于：含氧气体氛围选自氧气或空气条件下，惰性气体氛围为氮气或氩气条件下。
6.根据权利要求5所述2-(2-氨基苯基)喹啉类化合物的合成方法，其特征在于：含氧气体氛围有利于2-(2-氨基苯基)喹啉类化合物2的生成，惰性气体氛围有利于2-(2-氨基苯基)喹啉类化合物3的生成。
7.根据权利要求1所述所述2-(2-氨基苯基)喹啉类化合物的合成方法，其特征在于：所述2-炔基苯胺类化合物1、添加剂和催化剂投料摩尔比为1:0.25-2:0.05-0.15。
8.根据权利要求1-7任意一项所述2-(2-氨基苯基)喹啉类化合物的合成方法，其特征在于：所述加热反应温度为60-120℃。
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