CN111925325B - 一种二芳香醚类化合物的合成方法 - Google Patents
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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
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种二芳香醚类化合物的合成方法，包括如下步骤：将苯甲酰胺衍生物、醋酸镍、磷酸银、金刚烷甲酸钾加入到有机溶剂N,N‑二甲基乙酰胺中，氧气条件下加热进行反应，反应完全后，后处理得到所述的二芳香醚类化合物。该方法通过简单易得的原料一步合成二芳香醚类化合物，转化效率高，原子经济性好；同时合成方法操作简单，反应收率高，同时底物适应性广。
Description
技术领域
本发明属于有机合成领域，具体涉及一种二芳香醚类化合物的合成方法。
背景技术
二芳香醚类化合物是一类十分重要的结构骨架，其结构广泛存在于药物分子、天然产物以及功能性材料中。传统合成二芳香醚类的方法通常利要经典的偶联反应的方法如：Ullmann、buchwald-hartwig等人名反应。其广泛的工业化主要是在马大为以及Taillefer的工作的基础上实现的。但是纵观这些反应往往需要对底物进行预官能团化得到芳基氯代烃以及芳基硼酸在预苯酚类化合物发生偶联反应来实现目标产物的合成。因此较多的反应步骤和较为苛刻的反应条件使得这些传统的反应都会不可避免地产生大量的废碱，废酸以及金属废料。寻求发展新的不同方法是非常必要的。
过渡金属催化的C-H键活化的策略，经过几十年的发展提供了一种原子经济型、步骤经济型来构筑复杂化合物的合成方法。但是为了进一步解决反应中面临的反应活性以及化学选择性的问题，化学家们通过在反应底物中安装导向基团就能够有效的解决这一问题。过去几年中通过导向基团辅助的C-H键活化的方法来实现二芳香醚类化合物的合成已经有所报道。例如，Daugulis课题组报道了利用苯甲酰胺作为反应底物,在金属铜作为反应的催化剂和苯酚类化合物的偶联反应得到二芳香醚类化合物。与此同时，宋毛平课题组也同样报道了在Cu的催化体系下，苯甲酰胺的衍生物同样能够和苯酚发生偶联反应得到目标产物。进来，Punniyamurthy课题组报道了同样在Cu催化体系下，萘酰胺衍生物能够和芳基硼酸化合物发生偶联反应得到二芳香醚类化合物。然而，利用双碳氢键作为潜在的官能团来合成二芳香醚类化合物的目标还没有得以实现。受最近利用双碳氢键作为官能团来合成联苯化合物的启发，我们课题组首次发展了一种利用廉价广发易得的醋酸镍作为催化剂，苯甲酰胺作为反应底物，在以磷酸银作为反应的氧化剂，金刚烷甲酸钾作为添加剂在氧气的反应氛围下能够顺利合成二芳香醚类化合物，该方法条件温和，反应适应性广，同时作为导向基团的8-氨基喹啉基在反应结束之后，可以通过酸性条件或者碱性条件进行脱除(1、Da Liu等，European Journal of Organic Chemistry，2019年，第41期第6930-6934页，Nickel-Catalyzed Ortho C–H Methylation of Aromatic Amides with Di-tert-butylPeroxide as Methylation Reagent；2、 J.Org.Chem.2018,83,7860-7866，Palladium-Catalyzed H/D Exchange Reaction with 8-Aminoquinoline as the Directing Group:Access to ortho-Selective Deuterated Aromatic Acids andβ-Selective DeuteratedAliphatic Acids)，为合成对称以及不对称的二芳香醚类化合物提供了一种简单有效的方法。值得注意的是，该反应的化学选择性非常好，之前报道的联苯化合物中反应中是完全被抑制的。
发明内容
本发明提供了一种二芳香醚类化合物的合成方法，该合成方法底物适用性广，化学选择性好，反应活性高。
一种二芳香醚类化合物的合成方法，包括如下步骤：将苯甲酰胺衍生物、醋酸镍、磷酸银以及金刚烷甲酸钾加入到有机溶剂N,N-二甲基乙酰胺中，氧气条件下加热到140℃进行反应，反应完全后，后处理得到所述的二芳香醚类化合物；
所述的苯甲酰胺衍生物的结构如式(II)所示：
所述的二芳香醚类化合物的结构如式(I)所示：
式(I)～(II)中，R1选自H、烷基、甲氧基、苯基、三氟甲基、卤素以及酯基；
本发明中，不需要通过经典的偶联反应对底物进行预官能团化得到芳基卤代物、芳基硼酸和苯酚，可直接由碳氢键之间的直接偶联得到目标二芳香醚产物，目标产物中的氧原子来自于碱酸根中的氧原子。
作为优选，所述的有机溶剂为N,N-二甲基乙酰胺(DMAc)。
作为优选，反应温度为140℃，反应时间为24小时。
同现有技术相比，本发明的有益效果体现在：
(1)本发明通过简单易得的原料直接通过惰性的碳氢键一步合成二芳香醚类化合物，转化效率高，原子经济性好；
(2)本发明的合成方法操作简单，反应收率高，同时底物适应性广。
附图说明
图1为实施例1得到的化合物的氢谱和碳谱谱图；
图2为实施例2得到的化合物的氢谱和碳谱谱图；
图3为实施例3得到的化合物的氢谱和碳谱谱图；
图4为实施例4得到的化合物的氢谱和碳谱谱图；
图5为实施例5得到的化合物的氢谱和碳谱谱图；
图6为实施例6得到的化合物的氢谱和碳谱谱图；
图7为实施例7得到的化合物的氢谱和碳谱谱图；
图8为实施例8得到的化合物的氢谱和碳谱谱图；
图9为实施例9得到的化合物的氢谱和碳谱谱图；
图10为实施例10得到的化合物的氢谱和碳谱谱图；其中，氢谱在400 MHz核磁仪器上进行测试。碳谱在100MHz核磁仪器上进行测试。测试条件均为室温下使用四甲基硅烷作内标，样品用氘代氯仿溶解。
具体实施方式
下面结合具体实施例对本发明做进一步的描述，以下具体实施例都是本发明的最优实施方式。
实施例1～10
按照表1的原料配比在试管中加入苯甲酰胺(0.2mmol)、醋酸镍(0.04mmol)、磷酸银(0.4mmol)、金刚烷甲酸钾(0.4mmol)和有机溶剂 DMAc(2ml)，混合搅拌均匀，充氧气在氧气氛围下反应24h。按照表2 的反应条件反应完成后，冷却，用硅藻土抽滤，用饱和的氢氧化钠溶液 (1mol/L)进行洗涤，饱和食盐水洗，收集有机相用硫酸钠干燥，硅胶拌样，经过柱层析纯化得到相应的二芳香醚类化合物(Ⅰ)，反应过程如下式所示：
表1实施例1～10的原料配比
表2实施例1～10的反应条件和反应结果
表1和表2中，T为反应温度，t为反应时间，Me为甲基，CF3为三氟甲基，Ph为苯基，2-COOMe为2-甲酸甲酯基。
实施例1～10制备得到部分化合物的结构确认数据：
2,2'-oxybis(N-(quinolin-8-yl)benzamide)(I-1)
Yield:(33.2mg,65％)；White solid；mp:214.4-214.9℃.1H NMR(CDCl3, 400MHz)δ12.37(s,2H),8.96(dd,J1＝7.6Hz,J2＝1.2Hz,2H),8.52(dd,J1＝8.0Hz,J2＝1.6Hz,2H),8.16(dd,J1＝4.4Hz,J2＝1.6Hz,2H),7.92(d,J＝ 8.4Hz,2H),7.53-7.48(m,4H),7.40-7.37(m,4H),7.17-7.13(m,4H).13C NMR(CDCl3,100MHz)δ162.8,154.7,148.1,138.9,135.7,135.3,133.4, 132.4,127.8,127.2,126.1,124.8,121.7,121.5,119.8,116.9.HRMS (ESI-TOF)calcd for C32H22N4O3[M+H]+:511.1770,found:511.1770.
6,6'-oxybis(2-methyl-N-(quinolin-8-yl)benzamide)(I-2)
Yield:(38.8mg,72％)；White solid；mp:>230℃.1H NMR(CDCl3,400MHz) δ9.94(s,2H),8.74(d,J＝7.6Hz,2H),8.10(dd,J1＝4.0Hz,J2＝1.2Hz,2H), 7.79(dd,J1＝8.0Hz,J2＝1.2Hz,2H),7.35(t,J＝8.0Hz,2H),7.28-7.23(m, 4H),7.05(dd,J1＝8.4Hz,J2＝4.4Hz,2H),6.99(d,J＝7.6Hz,2H),6.93(d,J ＝8.0Hz,2H),2.40(s,6H).13C NMR(CDCl3,100MHz)δ165.4,153.8,147.7, 137.9,137.8,135.4,134.3,130.4,129.6,127.4,126.9,125.8,121.5,121.1, 116.5,116.4,19.5.HRMS(ESI-TOF)calcd for C34H26N4O3[M+H]+:539.2083, found:539.2083.
3,3”-oxybis(N-(quinolin-8-yl)-[1,1'-biphenyl]-2-carboxamide)(I-3)
Yield:(40.4mg,61％)；White solid；mp:>230℃.1H NMR(CDCl3,400MHz) δ9.81(s,2H),8.56(d,J＝7.2Hz,2H),8.11(s,2H),7.77(d,J＝8.0Hz,2H), 7.48-7.43(m,6H),7.24-7.12(m,14H),7.01(dd,J1＝7.6Hz,J2＝4.0Hz,2H). 13C NMR(CDCl3,100MHz)δ164.9,154.4,147.5,141.9,139.6,137.9,135.3, 134.3,130.6,129.2,128.5,128.3,127.5,127.3,126.9,125.7,121.3,120.9, 118.4,116.5.HRMS(ESI-TOF)calcd for C44H30N4O3[M+H]+:663.2396, found:663.2396.
6,6'-oxybis(2-fluoro-N-(quinolin-8-yl)benzamide)(I-4)
Yield:(30.6mg,56％)；White solid；mp:202.5-203.2℃.1H NMR(CDCl3, 400MHz)δ10.29(s,2H),8.76(dd,J1＝7.6Hz,J2＝1.2Hz,2H),8.26(dd,J1＝4.4Hz,J2＝1.6Hz,2H),7.91(dd,J1＝8.4Hz,J2＝1.6Hz,2H),7.44-7.35 (m,6H),7.13(dd,J1＝8.4Hz,J2＝4.4Hz,2H),6.98(d,J＝8.4Hz,2H),6.93 (d,J＝8.4Hz,2H).13C NMR(CDCl3,100MHz)δ160.1(d,JC-F＝251.0Hz), 159.5,154.4(d,JC-F＝6.3Hz),147.5,137.7,135.2,133.7,131.3(d,JC-F＝9.9 Hz),127.1,126.6,121.5,120.8,117.8(d,JC-F＝19.0Hz),116.5,114.7(d,JC-F＝3.6Hz),111.5(d,JC-F＝21.6Hz).HRMS(ESI-TOF)calcd for C32H20F2N4O3[M+H]+:547.1582,found:547.1578.
6,6'-oxybis(2-chloro-N-(quinolin-8-yl)benzamide)(I-5)
Yield:(26.0mg,45％)；White solid；mp:203.4-204.5℃.1H NMR(CDCl3, 400MHz)δ9.92(s,2H),8.72(dd,J1＝7.6Hz,J2＝1.2Hz,2H),8.19(dd,J1＝ 4.4Hz,J2＝1.6Hz,2H),7.84(dd,J1＝8.4Hz,J2＝1.6Hz,2H),7.36(d,J＝ 7.6Hz,2H),7.31(d,J＝8.4Hz,2H),7.27(dd,J1＝8.0Hz,J2＝1.2Hz,2H), 7.22(dd,J1＝8.4Hz,J2＝0.8Hz,2H),7.10(dd,J1＝8.0Hz,J2＝4.0Hz,2H), 7.04(dd,J1＝8.0Hz,J2＝0.8Hz,2H).13C NMR(CDCl3,100MHz)δ162.1,154.4,147.8,137.9,135.5,133.9,132.6,131.2,129.4,127.4,126.9,125.5, 121.9,121.2,117.6,116.8.HRMS(ESI-TOF)calcd for C32H20Cl2N4O3[M+H]+:579.0991,found:579.0988.
6,6'-oxybis(2-bromo-N-(quinolin-8-yl)benzamide)(I-6)
Yield:(28.0mg,42％)；White solid；mp:205.0-206.7℃.1H NMR(CDCl3, 400MHz)δ9.88(s,2H),8.71(dd,J1＝7.6Hz,J2＝1.2Hz,2H),8.19(dd,J1＝ 4.4Hz,J2＝1.6Hz,2H),7.83(dd,J1＝8.4Hz,J2＝1.6Hz,2H),7.39(dd,J1＝ 8.0Hz,J2＝0.8Hz,2H),7.34(t,J＝8.0Hz,2H),7.28-7.24(m,4H),7.11-7.08 (m,4H).13C NMR(CDCl3,100MHz)δ163.1,154.3,147.8,137.9,135.5, 133.9,131.5,128.6,127.4,126.9,121.9,121.2,120.9,118.2,116.8.HRMS (ESI-TOF)calcd for C32H20Br2N4O3[M+H]+:666.9980,found:666.9978.
6,6'-oxybis(N-(quinolin-8-yl)-2-(trifluoromethyl)benzamide)(I-7)
Yield:(29.1mg,45％)；White solid；mp:169.9-171.0℃.1H NMR(CDCl3, 400MHz)δ9.91(s,2H),8.69(dd,J1＝7.6Hz,J2＝1.2Hz,2H),8.11(dd,J1＝ 4.4Hz,J2＝1.6Hz,2H),7.83(dd,J1＝8.0Hz,J2＝1.6Hz,2H),7.54-7.51(m, 4H),7.36-7.32(m,4H),7.26(dd,J1＝8.4Hz,J2＝1.2Hz,2H),7.06(dd,J1＝ 8.0Hz,J2＝4.0Hz,2H).13C NMR(CDCl3,100MHz)δ162.2,154.2,147.7, 137.8,135.5,133.9,131.1,129.3(q,JC-F＝32.5Hz),128.3(q,JC-F＝2.7Hz), 127.3,126.9,122.9,122.8(q,JC-F＝330.4Hz),122.1(q,JC-F＝4.5Hz),122.0,121.2,116.8.HRMS(ESI-TOF)calcd for C34H20F6N4O3[M+H]+:647.1518, found:647.1516.
(2,2'-oxybis(4-methoxy-N-(quinolin-8-yl)benzamide)(I-8)
Yield:(28.0mg,49％)；White solid；mp:205.2-205.4℃.1H NMR(CDCl3, 400MHz)δ12.32(s,2H),8.96(dd,J1＝7.6Hz,J2＝0.8Hz,2H),8.48(d,J＝ 9.2Hz,2H),8.21(dd,J1＝4.4Hz,J2＝1.6Hz,2H),7.91(dd,J1＝8.4Hz,J2＝ 1.6Hz,2H),7.50(t,J＝8.0Hz,2H),7.36(dd,J1＝8.4Hz,J2＝1.2Hz,2H), 7.14(dd,J1＝8.0Hz,J2＝4.0Hz,2H),6.91(dd,J1＝8.8Hz,J2＝2.4Hz,2H), 6.61(d,J＝2.4Hz,2H),3.77(s,6H).13C NMR(CDCl3,100MHz)δ163.6,162.7,155.8,148.0,138.9,135.7,135.5,133.8,127.8,127.2,121.5,121.4, 118.7,116.7,110.7,105.3,55.8.HRMS(ESI-TOF)calcd for C34H26N4O5[M+H]+:571.1981,found:579.1980.
dimethyl 3,3'-oxybis(4-(quinolin-8-ylcarbamoyl)benzoate)(I-9)
Yield:(21.6mg,35％)；White solid；mp:208.9-209.8℃.1H NMR(CDCl3, 400MHz)δ12.31(s,2H),8.95(dd,J1＝7.6Hz,J2＝1.2Hz,2H),8.61(d,J＝ 8.4Hz,2H),8.14(dd,J1＝4.4Hz,J2＝1.6Hz,2H),8.08(dd,J1＝8.4Hz,J2＝ 1.2Hz,2H),7.95(dd,J1＝8.4Hz,J2＝1.6Hz,2H),7.76(d,J＝1.2Hz,2H), 7.52(t,J＝8.0Hz,2H),7.42(dd,J1＝8.0Hz,J2＝0.8Hz,2H),7.17(dd,J1＝ 8.4Hz,J2＝4.4Hz,2H),3.87(s,6H).13C NMR(CDCl3,100MHz)δ165.4, 161.6,154.2,148.2,138.8,135.9,134.9,134.8,132.9,129.9,127.8,127.2,125.9,122.2,121.6,120.7,117.1,52.6.HRMS(ESI-TOF)calcd for C36H26N4O7[M+H]+:617.1880,found:627.1883.
6,6'-oxybis(3-iodo-N-(quinolin-8-yl)benzamide)(I-10)
Yield:(26.7mg,35％)；White solid；mp:228.6-229.6℃.1H NMR(CDCl3, 400MHz)δ12.18(s,2H),8.91(dd,J1＝7.6Hz,J2＝1.2Hz,2H),8.80(d,J＝ 2.0Hz,2H),8.19(dd,J1＝4.0Hz,J2＝1.6Hz,2H),7.96(dd,J1＝8.4Hz,J2＝ 1.6Hz,2H),7.80(dd,J1＝8.8Hz,J2＝2.4Hz,2H),7.52(t,J＝8.0Hz,2H), 7.43(dd,J1＝8.4Hz,J2＝1.2Hz,2H),7.20(dd,J1＝8.4Hz,J2＝4.4Hz,2H), 6.88(d,J＝8.8Hz,2H).13C NMR(CDCl3,100MHz)δ160.9,154.1,148.2, 142.1,141.2,138.8,135.9,134.8,128.0,127.8,127.2,122.1,121.7,121.5,117.1,88.6.HRMS(ESI-TOF)calcd for C32H20I2N4O3[M+H]+:762.9703, found:762.9705。
Claims (3)
1.一种二芳香醚化合物的合成方法，其特征在于，包括如下步骤：将苯甲酰胺化合物、镍催化剂、氧化剂、添加剂加入到有机溶剂中，氧气条件下，将温度控制在140℃下反应24h，反应完全后，后处理得到所述的二芳香醚类化合物；
所述的苯甲酰胺衍生物的结构如式（II）所示：
所述的二芳香醚类化合物的结构如式（I）所示：
式（I）~（II）中，R1选自H、烷基、甲氧基、苯基、三氟甲基、卤素以及酯基；
所述的镍催化剂为醋酸镍；
所述的氧化剂为磷酸银；
所述的添加剂为金刚烷甲酸钾。
2.根据权利要求1所述的二芳香醚化合物的合成方法，其特征在于，所述的R1选自H、甲基、苯基、F、Cl、Br、I、三氟甲基或甲氧羰基。
3.根据权利要求1所述的二芳香醚类化合物的合成方法，其特征在于，所述的有机溶剂为N,N-二甲基乙酰胺。
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| CN1462735A (zh) * | 2003-06-20 | 2003-12-24 | 中国科学院上海有机化学研究所 | 以氨基酸为添加剂的二芳基醚合成方法 |
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