CN109053558B - 一种n-杂环酰胺衍生物的合成方法 - Google Patents

一种n-杂环酰胺衍生物的合成方法 Download PDF

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CN109053558B
CN109053558B CN201811093557.9A CN201811093557A CN109053558B CN 109053558 B CN109053558 B CN 109053558B CN 201811093557 A CN201811093557 A CN 201811093557A CN 109053558 B CN109053558 B CN 109053558B
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吴剑
王艳艳
徐方舟
寻曦炜
黎泽莲
罗德霞
陈顺红
薛伟
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Abstract

本发明公开了一种N‑杂环酰胺衍生物的合成方法，反应通式如下。即：以咪唑并杂环胺类化合物I为原料，在催化剂的作用下，在碱性条件下于有机溶剂中和80～200℃的条件下与空气或氧气发生反应开环，同时插入氧原子，生成如反应通式所示的N‑杂环酰胺衍生物II。本方法具有操作简单、收率高、底物普适性广等特点。

Description

一种N-杂环酰胺衍生物的合成方法
技术领域
本发明属于金属催化有机合成领域，具体来说涉及通过金属催化氧化、将咪唑并杂环胺类化合物开环，插入氧原子，环制备N-杂环酰胺衍生物的合成方法。
背景技术
酰胺是一类具有广泛生物活性的化合物，是众多药物分子结构中的重要片段，同时也是一种重要的药物中间体。对酰合成方法的研究是人们比较感兴趣的方向，关于酰胺类化合物的合成，已经有大量的文献进行了报道，Montalbetti及Williams等人分别在其综述文章中详细和系统的总结了酰胺类化合物的合成方法(Montalbetti，et,al.Tetrahedron,2005,61,10827-10852，Williams,J.M.J.et al.Chem.Soc.Rev.,2011,40,3405–3415)。其中，包含了传统经典的制备方法(包括酰氯与胺缩合、酸与胺直接在DDC等催化剂的作用下缩合)，特别是在金属催化作用下，将醛、醇、肟、氯代物等小分子与胺反应，直接构建“C-N键”形成酰胺键(Chem.Soc.Rev.,2011,40,3405–3415)。2015年，Wang等以TBHP(叔丁基过氧化氢)为氧化剂，选择性的将吡唑并吡啶类化合物中的C-C及C-N断开，形成了系列N-吡啶酰胺衍生物，其中酰胺上的氧原子源于TBHP(Wang H.et al.RSCAdv.,2015,5,100102)。
迄今为止，尚未见到采用金属催化剂，通过空气或氧气作为酰胺中O原子的来源，使咪唑并芳杂环胺类化合物开环，制备得到N-杂环酰胺衍生物的方法。
发明内容
本发明的目的在于提供的一种新颖的制备N-杂环酰胺衍生物的方法。本发明的目的可以通过如下技术方案来实现：
本发明的目的可以通过如下技术方案来实现：
含有咪唑并杂环胺类衍生物I为原料，催化剂和碱性存在的条件下，加热到80～200℃，在于有机溶剂中与空气或氧气发生反应开环，同时插入氧原子，生成如反应通式所示的N-杂环酰胺衍生物II；
Figure GDA0003254180390000021
反应通式中，反应原料I中，
Figure GDA0003254180390000022
可以选自
Figure GDA0003254180390000023
Figure GDA0003254180390000024
Figure GDA0003254180390000025
其中，R为C1-C10的烃基或芳杂环基团；R1为C1-C10的烃基、取代苯基或杂环基团；R3为H、-CH3、F、Cl、Br、I、-NO2、-CF3或-OCF3，且可在环上任意位置取代。
进一步地，反应原料I中，
Figure GDA0003254180390000026
可选自
Figure GDA0003254180390000027
Figure GDA0003254180390000028
其中，R为C2-C6的烷基或取代苯基；R1为C2-C5的烷基、取代苯基或杂环基团；R3为H、-CH3、Cl或Br，且可在环上任意位置取代。
作为本发明的进一步优化，反应原料I中，
Figure GDA0003254180390000029
可选自
Figure GDA00032541803900000210
Figure GDA00032541803900000211
其中，R为叔丁基、环己基或对甲氧基苯基；R1为C3-C4的烷基、取代苯基或杂环基团；R3为H或-CH3，且可在环上任意位置取代。
作为进一步地改进，本发明所述的具体包含如下步骤：
1)、在通式I所述的原料加入到反应管中，随后加入催化剂和有机溶剂，并通入或氧气将反应体系暴露在空气中。在80～200℃条件下反应6-12小时；
2)、待步骤1)反应完全后，分出有机相，直接用柱层析分离即得到产物II。
作为进一步地改进，所述的N-杂环酰胺衍生物的合成方法，其特征在于，所述的有机溶剂为1,2-二氯乙烷、二氯甲烷、甲苯、二甲苯、乙酸乙酯。优选为邻二甲苯、对二甲苯或间二甲苯。
作为本发明的进一步地改进，本发明所选择的催化剂为RuCl3、CuI、NiCl2、Cu(OTf)2、CuCl、Cu(OAc)2、CuBr、NiCl2、Cu(OAc)2、CuOAc、CuBr2或CuCl2；所述碱为DBU，NaOH，NaCO3，叔丁醇钠，叔丁醇钾或三乙胺。更进一步地优选的催化剂为Cu(OTf)2或Cu(OAc)2；优选的碱为叔丁醇钠或叔丁醇钾。
作为进一步地改进，本发明所述的α-羰基酰胺衍生物的制备方法中，所优选的温度为80～150℃，优选的反应时间为8-10小时。
本发明中采用的原料I——咪唑胺并杂环胺类化合物可以可参照我们之前的报道(Heterocycles,2016,92(9):1629-1642；Synfacts,2016,12(10):1024)进行制备。
有益效果
本发明提供的制备N-吡啶酰胺衍生物的合成方法，具有选择性好、收率高、并且有较好的普适性。此外，其原料的制备也比较方便，空气可直接作为N-吡啶酰胺衍生物结构中O原子的直接来源(试剂反应过程中不需要专门通入氧气)，与传统的方法相比，可避免使用氯化亚砜、酰氯、三氯氧磷等危险化合物的使用。
具体实施方式
实施例1：2-甲基-N-(吡啶-2-基)苯甲酰胺的制备
Figure GDA0003254180390000031
将1mmol N-环己基-2-(o-甲苯基)咪唑[1,2-a]吡啶-3-胺、0.1mmol醋酸铜、3mmol叔丁醇钾加入到带有搅拌子的10mL的反应管中，将反应体系直接与空气相通(或通过气球加入氧气)，加入3mL邻二甲苯，加热到150℃搅拌，TLC跟踪反应至反应8小时后完毕，停止反应，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率81％,黄褐色固体；m.p.80-81℃；1H NMR(400MHz,CDCl3)δ8.76(s,1H),8.33(d,J＝8.4Hz,1H),8.29–8.26(m,1H),7.80–7.71(m,2H),7.69(dd,J＝3.8,0.6Hz,1H),7.58(dd,J＝5.0,1.0Hz,1H),7.13(dd,J＝5.0,3.8Hz,1H),7.06(ddd,J＝7.3,4.9,0.9Hz,1H).13C NMR(101MHz,CDCl3)δ160.05,151.34,147.75,138.94,138.59,131.58,128.99,127.97,119.93,114.36.
实施例2：3-氯-N-(吡啶-2-基)苯甲酰胺的制备
Figure GDA0003254180390000041
将1mmol 2-(3-氯苯基)-N-环己基咪唑[1,2-a]吡啶-3-胺、0.1mmol醋酸铜、3mmol叔丁醇钾加入到带有搅拌子的10mL的反应管中，加入3mL邻二甲苯，将反应体系直接暴露在空气中(或通过气球加入氧气)，加热140℃并搅拌，TLC跟踪反应至反应完毕(9小时)，停止反应，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率96％，浅黄色固体；m.p.96-97℃；1H NMR(400MHz,CDCl3)δ8.89(s,1H),8.38(d,J＝8.4Hz,1H),8.25(d,J＝4.7Hz,1H),7.93(d,J＝1.8Hz,1H),7.81–7.75(m,2H),7.54(d,J＝8.1Hz,1H),7.43(t,J＝7.9Hz,1H),7.09(dd,J＝7.3,5.0Hz,1H).13C NMR(101MHz,CDCl3)δ164.37,151.28,147.78,138.71,136.04,135.16,132.30,130.14,127.74,125.19,120.21,114.32.
实施例3：N-(吡啶-2-基)苯甲酰胺的制备
Figure GDA0003254180390000042
将1mmol N-环己基-2-苯基咪唑[1,2-a]吡啶-3-胺、0.1mmol醋酸铜、3mmol叔丁醇钾加入到带有搅拌子的10mL的反应管中，加入3mL对二甲苯，将反应体系直接与空气相通(或通过气球加入氧气)，加热到110℃搅拌，TLC跟踪反应，10小时后反应完毕，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率99％，浅黄色固体；m.p.111-112℃；1HNMR(400MHz,CDCl3)δ9.01(s,1H),8.41(d,J＝8.4Hz,1H),8.19(s,1H),7.93(d,J＝7.4Hz,2H),7.76(t,J＝7.9Hz,1H),7.57(t,J＝7.3Hz,1H),7.49(t,J＝7.5Hz,2H),7.08–7.01(m,1H).13C NMR(101MHz,CDCl3)δ165.93,151.67,147.83,138.56,134.34,132.25,128.83,127.31,119.93,114.31.
实施例4：5-甲基-N-(吡啶-2-基)呋喃-2-甲酰胺的制备
Figure GDA0003254180390000051
将1mmol N-环己基-2-(5-甲基呋喃-2-基)咪唑[1,2-a]吡啶-3-胺、0.1mmol醋酸铜、3mmol叔丁醇钾加入到带有搅拌子的10mL的反应管中，加入3mL间二甲苯，将反应体系直接与空气相通(或通过气球通入氧气)，加热80℃搅拌，TLC跟踪反应，10小时后反应完毕，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率76％，浅黄色固体；m.p.93-94℃；1H NMR(400MHz,CDCl3)δ8.77(s,1H),8.35–8.29(m,2H),7.73(t,J＝8.8Hz,1H),7.18(d,J＝3.4Hz,1H),7.05(dd,J＝6.9,5.4Hz,1H),6.17(d,J＝3.3Hz,1H),2.38(s,3H).13C NMR(101MHz,CDCl3)δ156.23,155.60,151.21,147.79,145.71,138.49,119.72,117.24,114.10,109.16,13.84.
实施例5：5-溴-N-(吡啶-2-基)烟酰胺的制备
Figure GDA0003254180390000052
将1mmol 2-(5-溴吡啶-3-基)-N-环己基咪唑[1,2-a]吡啶-3-胺、0.1mmol三氟磺酸铜、3mmol叔丁醇钾加入到带有搅拌子的10mL的反应管中，加入3mL间二甲苯，将反应体系直接与空气中相通(或通过气球通入氧气)，加热140℃并搅拌，TLC跟踪反应，10小时后反应，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率55％，浅黄色固体；m.p.181-182℃；1H NMR(400MHz,CDCl3)δ9.15(s,1H),9.07(s,1H),8.86(s,1H),8.40(s,1H),8.35(d,J＝8.4Hz,1H),8.24(d,J＝4.0Hz,1H),7.80(t,J＝7.2Hz,1H),7.12(dd,J＝6.7,5.4Hz,1H).13C NMR(101MHz,CDCl3)δ162.61,154.04,150.93,147.73,146.25,138.96,137.98,131.37,121.12,120.65,114.65.
实施例6：N-(吡啶-2-基)噻吩-2-甲酰胺的制备
Figure GDA0003254180390000053
将1mmol N-环己基-2-(噻吩-2-基)咪唑并[1,2-a]吡啶-3-胺、0.1mmol醋酸铜、3mmol叔丁醇钾加入到带有搅拌子的10mL的反应管中，加入3mL间二甲苯，，将反应体系直接与空气中相通(或通过气球通入氧气)，加热130℃并搅拌，TLC跟踪反应，8小时后反应，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率77％，浅黄色固体；m.p.110-111℃；1H NMR(400MHz,CDCl3)δ8.76(s,1H),8.33(d,J＝8.4Hz,1H),8.29–8.26(m,1H),7.80–7.71(m,1H),7.69(dd,J＝3.8,0.6Hz,1H),7.58(dd,J＝5.0,1.0Hz,1H),7.13(dd,J＝5.0,3.8Hz,1H),7.06(ddd,J＝7.3,4.9,0.9Hz,1H).13C NMR(101MHz,CDCl3)δ160.05,151.34,147.75,138.94,138.59,131.58,128.99,127.97,119.93,114.36.
实施例7：N-(吡啶-2-基)噻吩-3-甲酰胺的制备
Figure GDA0003254180390000061
将1mmol N-环己基-2-(噻吩-3-基)咪唑并[1,2-a]吡啶-3-胺、0.1mmol三氟磺酸铜、3mmol叔丁醇钾加入到带有搅拌子的10mL的反应管中，加入3mL间二甲苯，将反应体系直接与空气中相通(或通过气球通入氧气)，加热110℃，TLC跟踪反应，10小时后反应完毕，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率78％，浅黄色固体；m.p.90-91℃；1H NMR(400MHz,CDCl3)δ8.79(s,1H),8.37(d,J＝8.4Hz,1H),8.26(d,J＝4.9Hz,1H),8.11–8.04(m,1H),7.80–7.71(m,1H),7.56(dd,J＝5.0,1.2Hz,1H),7.40(dd,J＝5.1,3.0Hz,1H),7.07(dd,J＝6.9,5.4Hz,1H).13C NMR(101MHz,CDCl3)δ161.10,151.48,147.58,138.73,137.28,129.57,127.00,126.31,119.89,114.39.
实施例8：2-氯-N-(吡啶-2-基)苯甲酰胺的制备
Figure GDA0003254180390000062
将1mmol 2-(2-氯苯基)-N-环己基咪唑[1,2-a]吡啶-3-胺、0.1mmol醋酸铜、3mmol叔丁醇钾加入到带有搅拌子的10mL的反应管中，加入3mL邻二甲苯，将反应体系直接与空气中相通(或通过气球通入氧气)，加热100℃，TLC跟踪反应，10小时后反应完毕，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率75％，白色固体；m.p.121-122℃；1H NMR(400MHz,CDCl3)δ9.44(s,1H),8.40(d,J＝8.4Hz,1H),7.96(dd,J＝4.9,1.0Hz,1H),7.80–7.72(m,1H),7.70(dd,J＝7.5,1.0Hz,1H),7.47–7.39(m,2H),7.36(ddd,J＝7.4,6.6,2.2Hz,1H),7.01(ddd,J＝7.3,5.0,0.9Hz,1H).13C NMR(101MHz,CDCl3)δ165.18,151.32,147.47,138.73,135.17,131.80,131.05,130.48,129.88,127.21,120.12,114.55.
实施例9：3-甲氧基-N-(吡啶-2-基)苯甲酰胺的制备
Figure GDA0003254180390000071
将1mmol N-环己基-2-(3-甲氧基苯基)咪唑[1,2-a]吡啶-3-胺、0.1mmol醋酸铜、3mmol叔丁醇钾加入到带有搅拌子的10mL的反应管中，加入3mL邻二甲苯，将反应体系直接与空气中相通(或通过气球通入氧气)，加热至90℃，TLC跟踪反应，10小时后反应完毕，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率71％，浅黄色固体；m.p.146-147℃；1H NMR(400MHz,CDCl3)δ8.80(s,1H),8.40(d,J＝8.4Hz,1H),8.27(dd,J＝4.9,0.9Hz,1H),7.81–7.73(m,1H),7.51–7.44(m,2H),7.39(t,J＝7.9Hz,1H),7.14–7.04(m,2H),3.87(s,3H).13C NMR(101MHz,CDCl3)δ165.63,160.03,151.55,147.80,138.60,135.70,129.85,119.97,119.05,118.69,114.25,112.39,55.51.
实施例10：4-甲基-N-(吡啶-2-基)苯甲酰胺的制备
Figure GDA0003254180390000072
将1mmol N-环己基-2-(对甲苯基)咪唑[1,2-a]吡啶-3-胺、0.1mmol醋酸铜(或三氟磺酸铜)、3mmol叔丁醇钾加入到带有搅拌子的10mL的反应管中，加入3mL邻二甲苯，将反应体系直接与空气中相通(或通过气球通入氧气)，加热至145℃，TLC跟踪反应，9小时后反应完毕，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率60％(醋酸铜为催化剂)，58％(三氟磺酸铜为催化剂)白色固体；m.p.139-140℃；1H NMR(400MHz,CDCl3)δ8.73(s,1H),8.39(dt,J＝8.4,0.9Hz,1H),8.26(d,J＝4.8Hz,1H),7.87–7.80(m,2H),7.78–7.70(m,1H),7.29(d,J＝7.9Hz,2H),7.05(ddd,J＝7.3,4.9,0.8Hz,1H),2.42(s,3H).13C NMR(101MHz,CDCl3)δ165.68,151.70,147.82,142.88,138.49,131.43,129.51,127.26,119.80,114.19,21.52.
实施例11：3-硝基-N-(吡啶-2-基)苯甲酰胺的制备
Figure GDA0003254180390000081
将1mmol N-环己基-2-(3-硝基苯基)咪唑[1,2-a]吡啶-3-胺、0.1mmol醋酸铜(或三氟磺酸铜)、3mmol叔丁醇钾加入到带有搅拌子的10mL的反应管中，加入3mL邻二甲苯，将反应体系直接与空气中相通(或通过气球通入氧气)，加热至120℃，TLC跟踪反应，9小时后反应完毕，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率56％(醋酸铜为催化剂)，59％(三氟磺酸铜为催化剂)；浅黄色固体；m.p.85-87℃；1H NMR(400MHz,CDCl3)δ9.28(s,1H),8.79(t,J＝1.8Hz,1H),8.47–8.33(m,2H),8.31–8.26(m,1H),8.22(dd,J＝4.8,0.9Hz,1H),7.80(td,J＝8.5,1.8Hz,1H),7.70(t,J＝8.0Hz,1H),7.10(ddd,J＝7.3,5.0,0.8Hz,1H).13C NMR(101MHz,CDCl3)δ163.52,151.18,148.38,147.83,138.83,136.00,133.23,130.10,126.71,122.46,120.54,114.66.
实施例12：3-溴-N-(吡啶-2-基)苯甲酰胺的制备
Figure GDA0003254180390000082
将1mmol 2-(3-溴苯基)-N-环己基咪唑[1,2-a]吡啶-3-胺、0.1mmol醋酸铜、3mmol叔丁醇钾加入到带有搅拌子的10mL的反应管中，加入3mL邻二甲苯，，将反应体系直接与空气中相通(或通过气球通入氧气)，加热120℃并搅拌，TLC跟踪反应，8小时后反应结束，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率62％，浅黄色固体；m.p.96-97℃；1H NMR(400MHz,CDCl3)δ9.21(s,1H),8.41(d,J＝8.4Hz,1H),8.26(d,J＝4.0Hz,1H),8.14(t,J＝1.7Hz,1H),7.88(d,J＝7.8Hz,1H),7.84–7.76(m,1H),7.73–7.64(m,1H),7.38(t,J＝7.9Hz,1H),7.11(dd,J＝6.6,5.1Hz,1H).13C NMR(101MHz,CDCl3)δ164.48,151.39,147.41,138.98,136.15,135.23,130.74,130.33,125.93,123.02,120.20,114.64.
实施例13：N-(6-甲基吡啶-2-基)苯甲酰胺的制备
Figure GDA0003254180390000091
将1mmol N-叔丁基-2-苯基-5-甲基-咪唑[1,2-a]吡啶-3-胺、0.1mmol醋酸铜、3mmol叔丁醇钾加入到带有搅拌子的10mL的反应管中，加入3mL对二甲苯，将反应体系直接与空气中相通(或通过气球通入氧气)，加热至100℃，搅拌，TLC跟踪反应，10小时后反应完毕，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率79％，浅黄色固体；m.p.79-80℃；1H NMR(400MHz,CDCl3)δ9.05(s,1H),8.43(d,J＝8.4Hz,1H),8.13(s,1H),7.96(d,J＝7.4Hz,2H),7.73(t,J＝7.9Hz,1H),7.54(t,J＝7.3Hz,1H),7.50(t,J＝7.5Hz,2H),7.06–7.04(m,1H).2.48(s,3H).
实施例14：N-(吡啶-2-基)苯甲酰胺的制备
Figure GDA0003254180390000092
将1mmol N-叔丁基-2-苯基咪唑[1,2-a]吡啶-3-胺、0.1mmol醋酸铜、3mmol叔丁醇钠加入到带有搅拌子的10mL的反应管中，搅拌，加入3mL对二甲苯，将反应体系直接与空气中相通(或通过气球通入氧气)，加热至90℃，搅拌，TLC跟踪反应，10小时后反应完毕，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率90％，浅黄色固体；m.p.111-112℃核磁数据与实施例3相同.
实施例15：N-(吡啶-2-基)苯甲酰胺的制备
Figure GDA0003254180390000093
将1mmol N-对甲氧基苯基-2-苯基咪唑[1,2-a]吡啶-3-胺、0.1mmol醋酸铜、3mmol叔丁醇钠加入到带有搅拌子的10mL的反应管中，加入3mL对二甲苯，将反应体系直接与空气中相通(或通过气球通入氧气)，加热至100℃，搅拌，TLC跟踪反应，10小时后反应完毕，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率82％，浅黄色固体；m.p.111-112℃核磁数据与实施例3相同.
实施例16：N-(嘧啶-2-基)苯甲酰胺的制备
Figure GDA0003254180390000101
将1mmol N-环己基-2-苯基-5-甲基-咪唑[1,2-a]吡啶-3-胺、0.1mmol醋酸铜、3mmol叔丁醇钠加入到带有搅拌子的10mL的反应管中，加入3mL对二甲苯，将反应体系直接与空气中相通(或通过气球通入氧气)，加热至100℃，搅拌，TLC跟踪反应，10小时后反应完毕，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率79％，浅黄色固体；m.p.142℃℃；1H NMR(400MHz,CDCl3)δ9.12(s,1H),8.42(d,J＝8.4Hz,1H)7.96(d,J＝7.4Hz,2H),7.73(t,J＝7.9Hz,1H),7.54(t,J＝7.3Hz,1H),7.50(t,J＝7.5Hz,2H),7.06–7.04(m,1H).
实施例17：N-(4-甲基苯并[d]噁唑-2-基)苯甲酰胺的制备
Figure GDA0003254180390000102
将1mmol N-环己基-5-甲基-2-苯基苯并[d]咪唑[2,1-b]噁唑-3-胺(或者N-叔丁基-5-甲基-2-苯基苯并[d]咪唑[2,1-b]噁唑-3-胺)、0.1mmol醋酸铜、3mmol叔丁醇钠加入到带有搅拌子的10mL的反应管中，加入3mL对二甲苯，将反应体系直接与空气中相通(或通过气球通入氧气)，加热至100℃，搅拌，TLC跟踪反应，10小时后反应完毕，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，当用N-环己基-5-甲基-2-苯基苯并[d]咪唑[2,1-b]噁唑-3-胺为原料时产率79％，当用N-叔丁基-5-甲基-2-苯基苯并[d]咪唑[2,1-b]噁唑-3-胺为原料时产率58％，浅黄色固体；mp.141.6-142.2℃；1H NMR(CD3OD,400MHz)δ7.93(2H,m),7.55(1H,m),7.43-7.47(2H,m),7.24(1H,brd,J＝7.6Hz),7.10(1H,t,J＝7.6Hz),7.04(1H,brd,J＝7.6Hz),2.47(3H,s).
实施例18：N-(苯并[d]噁唑-2-基)苯甲酰胺的制备
Figure GDA0003254180390000111
将1mmol N-环己基-5-甲基-2-苯基苯并[d]咪唑[2,1-b]噁唑-3-胺或者N-叔丁基-5-甲基-2-苯基苯并[d]咪唑[2,1-b]噁唑-3-胺、0.1mmol醋酸铜、3mmol叔丁醇钠加入到带有搅拌子的10mL的反应管中，加入3mL对二甲苯，将反应体系直接与空气中相通(或通过气球通入氧气)，加热至90℃，搅拌，TLC跟踪反应，9小时后反应完毕，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率：N-环己基-5-甲基-2-苯基本并[d]咪唑[2,1-b]噁唑-3-胺为原料时为35％；N-叔丁基-5-甲基-2-苯基苯并[d]咪唑[2,1-b]噁唑-3-胺为原料时为53％，浅黄色固体m.p.190.3-192.1℃；1H NMR(Acetone-d6,400MHz)δ8.20(2H,d,J＝7.2Hz),7.51-7.63(5H,m),7.30-7.37(2H,m).
实施例19：N-(7-甲基本并[d]噁唑-2-基)苯甲酰胺的制备
Figure GDA0003254180390000112
将1mmol N-环己基-5-甲基-2-苯基苯并[d]咪唑[2,1-b]噻唑-3-胺(或者N-叔丁基-5-甲基-2-苯基苯并[d]咪唑[2,1-b]噻唑-3-胺)、0.1mmol醋酸铜、3mmol叔丁醇钠加入到带有搅拌子的10mL的反应管中，加入3mL对二甲苯，将反应体系直接与空气中相通(或通过气球通入氧气)，加热至100℃，搅拌，TLC跟踪反应，10小时后反应完毕，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率：N-环己基-5-甲基-2-苯基苯并[d]咪唑[2,1-b]噻唑-3-胺为原料时为45％；N-叔丁基-5-甲基-2-苯基苯并[d]咪唑[2,1-b]噻唑-3-胺为原料时为51％，浅黄色固体，126-129℃；1H NMR(400MHz,DMSO-d6):d＝7.00(t,J＝7.6Hz,1H,ArH),7.20(t,J＝7.6Hz,1H,ArH),7.33(d,J＝7.9Hz,1H,ArH),7.63(d,J＝7.9Hz,1H,ArH).
实施例20：N-(3-甲基吡啶-2-基)苯甲酰胺的制备
Figure GDA0003254180390000121
将1mmol N-叔丁基-2-苯基-8-甲基-咪唑[1,2-a]吡啶-3-胺(或N-对甲氧基苯基-2-苯基-8-甲基-咪唑[1,2-a]吡啶-3-胺)、0.1mmol醋酸铜、3mmol叔丁醇钾加入到带有搅拌子的10mL的反应管中，加入3mL对二甲苯，将反应体系直接与空气中相通(或通过气球通入氧气)，加热至100℃(N-对甲氧基苯基-2-苯基-8-甲基-咪唑[1,2-a]吡啶-3-胺为120℃)，搅拌，TLC跟踪反应，8小时后反应完毕，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率：N-叔丁基-2-苯基-8-甲基-咪唑[1,2-a]吡啶-3-胺为原料时79％；N-对甲氧基苯基-2-苯基-8-甲基-咪唑[1,2-a]吡啶-3-胺为63％。浅黄色固体；m.p.79-80℃；1H NMR(400MHz,CDCl3)δ9.02(s,1H),8.47(d,J＝8.4Hz,1H),8.13(s,1H),7.86(d,J＝7.4Hz,2H),7.83(t,J＝7.9Hz,1H),7.43(t,J＝7.3Hz,1H),7.55(t,J＝7.5Hz,2H),7.07–7.05(m,1H)，2.56(s,3H).
实施例21：N-(3-甲基吡啶-2-基)苯甲酰胺的制备
Figure GDA0003254180390000122
将1mmol N-叔丁基-2-苯基-8-甲基-咪唑[1,2-a]吡啶-3-胺(或N-对甲氧基苯基-2-苯基-8-甲基-咪唑[1,2-a]吡啶-3-胺)、0.1mmol醋酸铜、3mmol叔丁醇钾加入到带有搅拌子的10mL的反应管中，加入3mL对二甲苯，将反应体系直接与空气中相通(或通过气球通入氧气)，加热至100℃，搅拌，TLC跟踪反应，10小时后反应完毕，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率：N-叔丁基-2-苯基-8-甲基-咪唑[1,2-a]吡啶-3-胺为原料时79％；N-对甲氧基苯基-2-苯基-8-甲基-咪唑[1,2-a]吡啶-3-胺为63％。浅黄色固体；m.p.79-80℃；1H NMR(400MHz,CDCl3)δ9.02(s,1H),8.47(d,J＝8.4Hz,1H),8.13(s,1H),7.86(d,J＝7.4Hz,2H),7.83(t,J＝7.9Hz,1H),7.43(t,J＝7.3Hz,1H),7.55(t,J＝7.5Hz,2H),7.07–7.05(m,1H)，2.56(s,3H).
实施例22：N-吡啶-2-基异丙酰胺的制备
Figure GDA0003254180390000131
将1mmol N-叔丁基-2-异丙基-咪唑[1,2-a]吡啶-3-胺(或N-对甲氧基苯基-2-异丙基-咪唑[1,2-a]吡啶-3-胺，或N-环己基-2-异丙基-咪唑[1,2-a]吡啶-3-胺)、0.1mmol醋酸铜、3mmol叔丁醇钾加入到带有搅拌子的10mL的反应管中，加入3mL对二甲苯，将反应体系直接与空气中相通(或通过气球通入氧气)，加热至100℃，搅拌，TLC跟踪反应，8小时后反应完毕，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率：N-叔丁基-2-异丙基-8-甲基-咪唑[1,2-a]吡啶-3-胺时为54％；N-对甲氧基苯基-2-异丙基-8-甲基-咪唑[1,2-a]吡啶-3-胺62％；N-对环己基-2-异丙基-8-甲基-咪唑[1,2-a]吡啶-3-胺为原料时为59％。浅黄色固体；m.p.mp 51-53℃.1H NMR(400MHz,CDCl3)8.26(dd,1H,J＝4.8,1.2Hz),8.23(d,1H,J＝8.4Hz),8.06(bs,1H),7.69(ddd,1H,J＝8.4,7.2,1.2Hz),7.02(ddd,1H,J＝7.2,4.8,0.4Hz),2.55(sept,1H,J＝6.8Hz),1.26(d,6H,J＝6.8Hz).
实施例23：N-吡啶-2-基异丁酰胺的制备
Figure GDA0003254180390000132
将1mmol N-叔丁基-2-异丁基-咪唑[1,2-a]吡啶-3-胺(或N-环己基-2-异丁基-咪唑[1,2-a]吡啶-3-胺)、0.1mmol醋酸铜、3mmol叔丁醇钾加入到带有搅拌子的10mL的反应管中，搅拌，加入3mL对二甲苯，将反应体系直接与空气中相通(或通过气球通入氧气)，加热至90℃，搅拌，TLC跟踪反应，8小时后反应完毕，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率：N-叔丁基-2-异丙基-8-甲基-咪唑[1,2-a]吡啶-3-胺时为54％；N-对甲氧基苯基-2-异丁基-咪唑[1,2-a]吡啶-3-胺45％；N-对环己基-2-异丁基-咪唑[1,2-a]吡啶-3-胺为原料时为64％。浅黄色油状物。1H NMR(400MHz,CDCl3),8.24(ddd,1H,J＝4.8,2.0,0.4Hz),8.23(d,1H,J＝8.4Hz),8.06(bs,1H),7.70(ddd,1H,J＝8.4,7.2,2.0Hz),7.03(ddd,1H,J＝7.2,4.8,0.8Hz),2.26-2.18(m,3H),1.01(d,6H,J＝6.4Hz)
实施例24：N-吡啶-2-基叔丁酰胺的制备
Figure GDA0003254180390000141
将1mmol N-叔丁基-2-叔丁基-咪唑[1,2-a]吡啶-3-胺(或N-对甲氧基苯基-2-叔丁基-咪唑[1,2-a]吡啶-3-胺)、0.1mmol醋酸铜、3mmol叔丁醇钾加入到带有搅拌子的10mL的反应管中，加入3mL对二甲苯，将反应体系直接与空气中相通(或通过气球通入氧气)，加热至90℃，搅拌，TLC跟踪反应，10小时后反应完毕，柱层析(石油醚：乙酸乙酯＝10：1)，脱溶，得到目标化合物，产率：N-叔丁基-2-叔丁基-咪唑[1,2-a]吡啶-3-胺27％；用N-对甲氧基苯基-2-叔丁基-咪唑[1,2-a]吡啶-3-胺为原料时收率为32％。浅黄色油状物。1H NMR(400MHz,CDCl3),8.24(ddd,1H,J＝4.8,2.0,0.4Hz),8.23(d,1H,J＝8.4Hz),8.06(bs,1H),7.70(ddd,1H,J＝8.4,7.2,2.0Hz),7.03(ddd,1H,J＝7.2,4.8,0.8Hz),2.26-2.18(m,3H),1.01(d,6H,J＝6.4Hz).

Claims (8)

1.一种N-杂环酰胺衍生物的合成方法，其特征在于，如下通式所示的I为原料，在催化剂和碱性存在的条件下，加热到80～200℃，在有机溶剂中与空气或氧气发生反应开环，同时插入氧原子，生成如反应通式所示的N-杂环酰胺衍生物II；
Figure FDA0003333349370000011
反应通式中，反应原料I中，
Figure FDA0003333349370000012
选自如下任一结构，
Figure FDA0003333349370000013
Figure FDA0003333349370000014
其中，R为C1-C10的烃基或芳杂环基团；R1为C1-C10的烃基、苯基或杂环基团；R3为H、-CH3、F、Cl、Br、I、-NO2、-CF3或-OCF3，且在环上任意位置取代；所述的催化剂为RuCl3、CuI、NiCl2、Cu(OTf)2、CuCl、Cu(OAc)2、CuBr、NiCl2、Cu(OAc)2、CuOAc、CuBr2或CuCl2；所述碱为DBU、NaOH、Na2CO3、叔丁醇钠、叔丁醇钾或三乙胺。
2.如权利要求1所述的N-杂环酰胺衍生物的合成方法，其特征在于，反应原料I中，
Figure FDA0003333349370000015
选自如下任一结构，
Figure FDA0003333349370000021
Figure FDA0003333349370000022
其中，R为C2-C6的烷基或苯基；R1为C2-C5的烷基、苯基或杂环基团；R3为H、-CH3、Cl或Br，且在环上任意位置取代。
3.如权利要求1任一项所述的N-杂环酰胺衍生物的合成方法，其特征在于，反应原料I中，
Figure FDA0003333349370000023
选自如下任意结构，
Figure FDA0003333349370000024
其中，R为叔丁基、环己基或对甲氧基苯基；R1为C3-C4的烷基、苯基或杂环基团；R3为H或-CH3，且在环上任意位置取代。
4.一种如权利要求1-3之一所述的N-杂环酰胺衍生物的合成方法，其特征在于包含如下步骤：
1)、在通式I所述的原料加入到反应管中，随后加入催化剂、碱以及有机溶剂，并通入氧气或将反应体系直接与空气相通，在加热条件下反应；
2)、待步骤1)反应完全后，分出有机相，直接用柱层析分离即得到产物II。
5.根据权利要求4所述的N-杂环酰胺衍生物的合成方法，其特征在于，所述的有机溶剂选自1,2-二氯乙烷、二氯甲烷、甲苯、二甲苯、乙酸乙酯。
6.根据权利要求5所述的N-杂环酰胺衍生物的合成方法，其特征在于，所述的有机溶剂为邻二甲苯、对二甲苯或间二甲苯。
7.根据权利要求1所述的N-杂环酰胺衍生物的合成方法，其特征在于，所述的催化剂为Cu(OTf)2或Cu(OAc)2；所述的碱选自叔丁醇钠或叔丁醇钾。
8.根据权利要求4所述的N-杂环酰胺衍生物的合成方法，其特征在于，所述加热温度为80～150℃，所述的时间为8-10小时。
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