CN107573283B - 一种芳香腈化合物的制备方法 - Google Patents
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Abstract
本发明属于医药化工中间体及相关化学技术领域，提供了一种芳香腈化合物的制备方法。以二甲基丙二腈为原料，在金属催化剂和添加剂的作用下，于无水有机溶剂中与2‑苯基吡啶类化合物反应得到芳香腈化合物。本发明的有益效果是操作简便、条件温和、环境友好、有实现工业化的可能性，并且以较高收率得到芳香腈化合物；利用该方法所合成的芳香腈化合物可以进一步官能化得到各类化合物，应用于天然产物、功能材料及精细化学品的开发与研究。
Description
技术领域
本发明属于医药化工中间体及相关化学技术领域，涉及到一种芳香腈化合物的制备方法。
背景技术
芳香腈类化合物在有机化学中是一类极其重要的结构单元，其在医药、农药、染料、功能材料和香料等领域中都有着很重要的应用价值。此外，芳基腈类化合物中的氰基官能团很容易转化成胺、醛、酰胺、羧酸、含氮杂环等其他重要的化合物。因此，合成芳香腈类化合物具有重要的意义和应用价值。目前，合成芳香腈化合物的方法主要有：桑德迈尔反应(Sandmeyer Reaction)、罗森孟德反应(Rosemund-Vonbraun Reaction)、过渡金属催化卤代芳烃的交叉偶联反应和sp2碳–氢键直接官能化反应。
作为最传统的芳香腈类化合物的合成方法，桑德迈尔反应和罗森孟德反应已在工业上广泛使用。然而，这些方法都存在一些缺点，桑德迈尔反应方法的缺陷：需要化学计量的氰化亚铜(CuCN)作为氰基化试剂，后处理繁琐，过量的金属铜和氰化试剂容易造成环境污染和资源浪费。罗森孟德反应方法的缺陷：会造成重金属污染和苛刻的反应条件(150-250℃)。随着人们对生态环境保护的重视，传统的化学工业正在渐渐被摒弃[HodgsonH.H.Chem.Rev.1947,40, 251-277]。自上世纪七十年代以来，过渡金属催化的交叉偶联反应因其高效性逐渐受到人们的广泛关注，成为构建碳-碳键合成芳香腈化合物的重要方法。然而，该类方法不仅原子经济性较差，在环境友好方面也存在不足，例如需要使用金属氰化物作为氰基源[Anbarasan P.,Schareina T.,Beller M.Chem.Soc.Rev.,2011,40,5049-5067]。近年来，芳烃sp2碳–氢键活化反应合成芳香腈化合物作为一个原子经济性好、区域选择性高的新方法受到广泛的关注[Ping Y.Y.,Ding Q.P.,Peng Y.Y.ACSCatal.2016,6,5989-6005]，其中使用的氰基化试剂包括：无机氰化物和有机氰化物。其中，无机氰化试剂普遍毒性较大，使用时具有较大的安全隐患。其次，由于使用化学计量的无机氰基化试剂，容易造成金属浪费。而且，有些无机氰基化试剂在有机溶剂中相对较差的溶解性也限制了他们的应用范围。有机氰化物与无机氰化物相比，其最显著的优势有：无金属废物产生；不会像无机氰化物一样容易和催化剂配位，导致催化剂失活。而已使用的有机氰化物有偶氮二异丁腈，氰醇，溴化氰，氰乙酸乙酯等，这些氰基化试剂不易合成或不稳定，那么开发稳定易得的有机氰基化试剂就具有极其重要的意义。
发明内容
本发明提供了一种芳香腈化合物的新颖制备方法，该方法环境友好、条件温和、操作简便，并且收率较高。
本发明的技术方案：
一种芳香腈化合物的制备方法，以二甲基丙二腈为原料，在金属催化剂和添加剂的作用下，于无水有机溶剂中与2-苯基吡啶衍生物在80℃～160℃条件下，反应16～24小时，即得到芳香腈化合物，合成路线如下：
R1选自氢(H)、苯基(Ph)、烷基(alkyl)、甲氧基(OMe)；
R2选自氢(H)、烷基(alkyl)、卤素(halides)、三氟甲基(CF3)、甲氧甲酰基(CO2Me)、硝基(NO2)；
2-苯基吡啶衍生物与金属催化剂的摩尔比为1:0.05～1:0.1；
二甲基丙二腈与2-苯基吡啶衍生物的摩尔比为1:1～1:20；
2-苯基吡啶衍生物与添加剂的摩尔比为1:1～1:30；
2-苯基吡啶衍生物的摩尔浓度为0.01mmol/mL～2mmol/mL。
有机溶剂包括四氢呋喃、乙二醇二甲醚、三氯甲烷、二氯甲烷、乙醚、二甲基亚砜、六氟异丙醇、丙酮、甲苯、氯苯、1,4-二氧六环、N,N-二甲基甲酰胺、正己烷。
金属催化剂包括(1,5-环辛二烯)氯铑(I)二聚体、六氟锑酸(三乙腈基-五甲基环戊二烯基)铑(III)、二氯(五甲基环戊二烯基)合铑(III)二聚体。
添加剂包括过碳酸银、醋酸银、四氟硼酸银、氧化银、氧化铜、醋酸铜、氯化铜、溴化铜、氧化铁、醋酸锌。
分离方法包括重结晶、柱层析等。重结晶方法使用的溶剂包括苯、乙醇、石油醚、乙腈、四氢呋喃、氯仿、正己烷、丙酮、乙酸乙酯、二氯甲烷；用柱层析方法进行产物分离时，可以使用硅胶或氧化铝作为固定相，展开剂一般为极性与非极性的的混合溶剂，如乙酸乙酯-石油醚、乙酸乙酯-正己烷、二氯甲烷 -石油醚、甲醇-石油醚。
本发明的有益效果是操作简便、条件温和、环境友好、有实现工业化的可能性，并且以较高收率得到芳香腈化合物；利用该方法所合成的芳香腈化合物可以进一步官能化得到各类化合物，应用于天然产物、功能材料及精细化学品的开发与研究。
附图说明
图1是实施例1中2-(2-吡啶基)苯腈的1H核磁谱图。
图2是实施例1中2-(2-吡啶基)苯腈的13C核磁谱图。
图3是实施例2中2-(2-吡啶基)-5-苯基苯腈的1H核磁谱图。
图4是实施例2中2-(2-吡啶基)-5-苯基苯腈的13C核磁谱图。
图5是实施例3中2-(2-吡啶基)-4-甲基苯腈的1H核磁谱图。
图6是实施例3中2-(2-吡啶基)-4-甲基苯腈的13C核磁谱图。
图7是实施例4中2-(2-吡啶基)-4-甲氧基苯腈的1H核磁谱图。
图8是实施例4中2-(2-吡啶基)-4-甲氧基苯腈13C核磁谱图。
图9是实施例5中2-(2-吡啶基)-5-甲氧基苯腈的1H核磁谱图。
图10是实施例5中2-(2-吡啶基)-5-甲氧基苯腈的13C核磁谱图。
图11是实施例6中2-(2-(4-甲基)吡啶基)苯腈的1H核磁谱图。
图12是实施例6中2-(2-(4-甲基)吡啶基)苯腈的13C核磁谱图。
图13是实施例7中2-(2-(5-溴)吡啶基)苯腈的1H核磁谱图。
图14是实施例7中2-(2-(5-溴)吡啶基)苯腈的13C核磁谱图。
图15是实施例8中2-(2-(5-三氟甲基)吡啶基)苯腈的1H核磁谱图。
图16是实施例8中2-(2-(5-三氟甲基)吡啶基)苯腈的13C核磁谱图。
具体实施方式
本发明所述的芳香腈化合物的制备方法，具有原料价格低廉、反应步骤少、反应条件温和、环境友好、便于操作和反应收率高等优点。
下面结合具体实施例，进一步阐述本发明。这些实施例仅用于说明本发明而不用于限制本发明的范围。在本领域内的技术人员对本发明所做的简单替换或改进均属于本发明所保护的技术方案之内。
实施例1：2-(2-吡啶基)苯腈的合成
在25mL反应器中，加入(1,5-环辛二烯)氯铑(I)二聚体(0.0049g,0.01mmol)，醋酸铜(0.073g,0.4mmol)，二甲基丙二腈(0.038g,0.4mmol)，加入无水1,4- 二氧六环1mL，搅拌下加入2-苯基吡啶(0.031g,0.2mmol)，160℃下搅拌18h。柱层析分离(硅胶，200-300目；展开剂，石油醚)得到2-(2-吡啶基)苯腈0.029 g，产率80％。
淡黄色油状液体；1H NMR(CDCl3,400MHz)δ8.77(d,J＝4.0Hz,1H),7.86-7.77 (m,4H),7.71-7.67(m,1H),7.53-7.49(m,1H),7.38-7.34(m,1H)；13C NMR(CDCl3, 100MHz)δ155.3,150.0,143.5,137.0,134.2,132.9,130.1,128.9,123.5,123.4, 118.8,111.1.
实施例2：2-(2-吡啶基)-5-苯基苯腈的合成
操作同实施例1，由二甲基丙二腈与(4-苯基)-2-苯基吡啶反应得到2-(2- 吡啶基)-5-苯基苯腈0.038g，产率75％。
白色固体；1H NMR(CDCl3,400MHz)δ8.80(d,J＝4.0Hz,1H),8.01(s, 1H),7.94-7.83(m,4H),7.63-7.61(m,2H),7.52-7.35(m,4H)；13C NMR(CDCl3,100 MHz)δ155.0,150.1,142.1,142.0,138.4,137.0,132.7,131.5,130.6,129.3,128.7, 127.2,123.5,123.3,118.9,111.6.
实施例3：2-(2-吡啶基)-4-甲基苯腈的合成
操作同实施例1，由二甲基丙二腈与(3-甲基)-2-苯基吡啶反应得到2-(2- 吡啶基)-4-甲基苯腈0.033g，产率85％。
白色固体；1H NMR(CDCl3,400MHz)δ8.77(d,J＝4.0Hz,1H),7.85-7.78(m,2H),7.69-7.67(m,2H),7.36-7.30(m,2H),2.48(s,3H)；13C NMR(CDCl3,100MHz) δ155.4,150.0,143.9,143.4,136.86,134.1,130.8,129.6,123.4 123.3,119.1,108.1, 21.9.
实施例4：2-(2-吡啶基)-4-甲氧基苯腈的合成
操作同实施例1，由二甲基丙二腈与(3-甲氧基)-2-苯基吡啶反应得到2-(2-吡啶基)-4-甲氧基苯腈0.037g，产率88％。
白色固体；1H NMR(CDCl3,400MHz)δ8.77(d,J＝4.0Hz,1H),7.84-7.80(m,2H),7.71(d,J＝8.0Hz,1H),7.37-7.36(m,2H),7.02-6.99(m,1H),3.92(s,3H)；13C NMR (CDCl3,100MHz)δ163.0,155.3,150.0,145.7,137.0,135.8,123.6,123.5,119.2, 115.2,115.2,102.8,55.8.
实施例5：2-(2-吡啶基)-5-甲氧基苯腈的合成
在25mL反应器中，加入二氯(五甲基环戊二烯基)合铑(III)二聚体(0.0062g,0.01mmol)，氧化铜(0.064g,0.8mmol)，二甲基丙二腈(0.038g,0.4mmol)，加入无水甲苯1mL，搅拌下加入2-(4-甲氧基)苯基吡啶(0.037g,0.2mmol)，100℃下搅拌24h。柱层析分离(硅胶，200-300目；展开剂，石油醚)得到2-(2- 吡啶基)-4-甲氧基苯腈0.034g，产率81％。
白色固体；1H NMR(CDCl3,400MHz)δ8.75(d,J＝4.0Hz,1H),7.83-7.74(m,3H),7.33-7.20(m,3H),3.88(s,3H)；13C NMR(CDCl3,100MHz)δ159.7,155.1,149.9, 136.9,136.1,131.5,123.0,122.9,119.5,118.8,118.6,111.8,55.9.
实施例6：2-(2-(4-甲基)吡啶基)苯腈的合成
操作同实施例5，由二甲基丙二腈与2-苯基-4-甲基吡啶反应得到2-(2-(4-甲基)吡啶基)苯腈0.028g，产率70％。
白色固体；1H NMR(CDCl3,400MHz)δ8.61(d,J＝4.0Hz,1H),7.80(t,J＝8.0Hz,2H),7.67(t,J＝4.0Hz,1H),7.58(s,1H),7.49(t,J＝8.0Hz,1H),7.18(d,J＝8.0Hz, 1H),2.46(s,3H)；13C NMR(CDCl3,100MHz)δ155.3,149.7,148.2,143.7,134.2, 132.9,130.1,128.7,124.4,124.3,118.8,111.2,21.3.
实施例7：2-(2-(5-溴)吡啶基)苯腈的合成
在25mL反应器中，加入六氟锑酸(三乙腈基-五甲基环戊二烯基)铑(III)(0.0083g,0.01mmol)，氧化银(0.050g,0.4mmol)，二甲基丙二腈(0.038g,0.4 mmol)，加入六氟异丙醇1mL，搅拌下加入2-苯基-5-溴吡啶反应(0.047g,0.2 mmol)，130℃下搅拌22h。柱层析分离(硅胶，200-300目；展开剂，石油醚) 得到2-(2-(5-溴)吡啶基)苯腈0.031g，产率60％。
白色固体；1H NMR(CDCl3,400MHz)δ8.83(s,1H),7.98-7.96(m,1H),7.84-7.80 (m,2H),7.72-7.69(m,2H),7.55-7.51(m,1H)；13C NMR(CDCl3,100MHz)δ153.6, 151.1,142.3,139.5,134.3,133.0,129.8,129.1,124.3,121.0,118.5,110.9.
实施例8：2-(2-(5-三氟甲基)吡啶基)苯腈的合成
操作同实施例7，由二甲基丙二腈与2-苯基-5-三氟甲基吡啶反应得到 2-(2-(5-三氟甲基)吡啶基)苯腈0.039g，产率78％。
白色固体；1H NMR(CDCl3,400MHz)δ9.04(s,1H),7.93(d,J＝8.0Hz,1H),7.86 (dd,J＝20.0,8.0Hz,1H),7.74(t,J＝4.0Hz,1H),7.58(t,J＝8.0Hz,1H)；13C NMR (CDCl3,100MHz)δ158.58,146.95,146.92,142.01,134.47,134.34-134.24(q,JC-F＝10.0Hz),133.2,130.3,129.8,126.4,126.1,124.9,123.0,122.2,118.4,111.3。
Claims (2)
1.一种芳香腈化合物的制备方法，其特征在于，以二甲基丙二腈为原料，在金属催化剂和添加剂的作用下，于无水有机溶剂中与2-苯基吡啶衍生物在80℃～160℃条件下，反应16～24小时，即得到芳香腈化合物，合成路线如下：
R1选自氢、苯基、烷基、甲氧基；
R2选自氢、烷基、卤素、三氟甲基、甲氧甲酰基、硝基；
2-苯基吡啶衍生物与金属催化剂的摩尔比为1:0.05～1:0.1；
二甲基丙二腈与2-苯基吡啶衍生物的摩尔比为1:1～1:20；
2-苯基吡啶衍生物与添加剂的摩尔比为1:1～1:30；
2-苯基吡啶衍生物的摩尔浓度为0.01mmol/mL～2mmol/mL；
所述的金属催化剂为(1,5-环辛二烯)氯铑(I)二聚体、二(六氟锑酸)三乙腈(五甲基环戊二烯基)铑(III)、二氯(五甲基环戊二烯基)合铑(III)二聚体；
所述的添加剂为过碳酸银、醋酸银、四氟硼酸银、氧化银、氧化铜、醋酸铜、氯化铜、溴化铜、氧化铁或醋酸锌。
2.根据权利要求1所述的制备方法，其特征在于，所述的无水有机溶剂为四氢呋喃、乙二醇二甲醚、三氯甲烷、二氯甲烷、乙醚、二甲基亚砜、六氟异丙醇、丙酮、甲苯、氯苯、1,4-二氧六环、N,N-二甲基甲酰胺或正己烷。
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