CN112047879B - 一种铜催化选择性合成卤代芳胺的方法 - Google Patents
一种铜催化选择性合成卤代芳胺的方法 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及一种铜催化选择性合成卤代芳胺类化合物的新方法,属于有机合成领域。
背景技术
卤代芳胺类化合物作为一类重要的有机小分子,具有广泛的生物活性,常被用于药物及其中间体、功能材料等的合成,也可以作为合成含芳香环类化合物进一步转化的原料。典型的药物包括血管内皮生长因子受体(VEGFR)拮抗剂或口服酪氨酸激酶抑制剂凡德他尼(Vandetanib)、表皮生长因子受体(EGFR)拮抗剂吉非替尼(Gefitinib)、香草酸受体(TRPV-1)拮抗剂、香草酸受体I型(VR1)活性抑制剂。该类化合物在抗肿瘤药、抗炎药、局麻药和杀虫剂等医药和农药领域中都得到了广泛的应用。因此,快速高效地获得卤代芳胺类化合物一直是人们的研究热点。
经典的芳胺亲电卤代反应存在卤化试剂毒性大、反应条件苛刻、选择性较差等问题。从原子经济性和环境的角度来说,金属催化芳胺惰性C-H键转化为C-X(X=halogen)的方法更加简单、环保。最初,此类方法通常需要昂贵的金属催化剂或卤源,而且他们仅适用于单一位置的Csp2-H卤代反应,其官能团耐受性较差(路线1)。之后,廉价金属铜被用于苯胺衍生物Csp2-H卤代反应(路线2)。而1-萘胺衍生物和苯胺衍生物卤代反应鲜有报道。
发明内容
本发明的目的在于提供一种以吡啶为导向基团,铜催化的萘基吡啶酰胺类化合物和苯基吡啶酰胺类化合物的Csp2-H卤代芳胺类化合物的合成方法,本发明以过渡金属铜催化首次实现1-萘胺衍生物C2和C4位双卤代和苯胺C4位单卤代,并且,该方法原料简单易得,反应条件温和,副产物少,是一种快速高效的合成方法。
本发明的技术方案如下:
一种铜催化选择性合成卤代芳胺类化合物的方法,所述方法为:
反应底物与卤化试剂(III)于有机溶剂中,在催化剂、氧化剂的作用下,于0~80℃(优选60℃)下反应0.5~6h(优选3h),反应结束后(TLC检测),反应液经后处理,得到产物卤代芳胺类化合物;
所述反应底物与卤化试剂(III)、催化剂、氧化剂的物质的量之比为1:0.5~3:0.05~0.2:0.1~3,优选为1:2:0.1:2;
所述催化剂为氯化铜、醋酸铜、三氟甲磺酸铜、溴化铜、醋酸钯、溴化铁中的一种或两种以上任意比例的混合物,优选溴化铜;
所述氧化剂为过氧化二叔丁基、醋酸碘苯、特戊酸碘苯、三氟乙酸碘苯、过硫酸钾中的一种或两种以上任意比例的混合物,优选醋酸碘苯;
所述有机溶剂为1,2-二氯乙烷、四氢呋喃、N,N-二甲基甲酰胺、乙腈和二甲基亚砜中的一种或两种以上任意比例的混合溶剂,优选N,N-二甲基甲酰胺;所述有机溶剂的体积用量以反应底物的物质的量计为0.5~30mL/mmol,优选5mL/mmol;
所述后处理的方法为:反应结束后,将反应液冷却至室温(20~30℃),过滤,滤液减压浓缩后进行硅胶柱层析,以石油醚:乙酸乙酯体积比80:1的混合液为展开剂,收集含目标化合物的洗脱液,蒸除溶剂并干燥,即得产物;
所述反应底物如式(I-a)或式(I-b)所示,相应的产物如式(II-a)或式(II-b)所示;
式(I-a)、(II-a)、(I-b)、(II-b)或(III)中:
R1为H、C1-C4烷基、C1-C4烷氧基、杂环基或卤素,优选R1为H、甲基、Br或Cl;
R2为H、C1-C4烷基、C1-C4烷氧基、杂环基或卤素,优选R2为H、甲基、Br或Cl;
R3为H、C1-C4烷基、C1-C4烷氧基、杂环基或卤素,并且R3不位于4位,优选R3为H、甲基、F、Br或Cl;
X为F、Cl、Br或I;
Y为C或N。
本发明产物卤代芳胺类化合物的结构经1H NMR、13C NMR、MS、HRMS等方法表征并得以确认。
与现有技术相比,本发明的有益效果:本发明首次实现了卤代芳胺类化合物的直接合成,避免了传统方法中金属催化剂价格昂贵,卤化试剂毒性大,副产物多等问题。同时,产物通过简单的水解即可脱去吡啶导向基,也可发生进一步官能团化合成芳杂环类化合物。本发明操作简便,反应条件温和,选择性高,产物收率高,底物适用性广,是一种高效的有机合成手段。
具体实施方式
下面通过具体实施例对本发明作进一步的说明,但本发明的保护范围不限于此。
实施例1
在25mL的单口瓶中加入N-(萘基)吡啶酰胺(49.62毫克,0.2mmol),氯代琥珀酰亚胺(77.99毫克,0.6mmol),氯化铜(5.31毫克,20mol%),醋酸碘苯(128.79毫克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物39.19毫克,收率62%。
1H NMR(400MHz,CDCl3)δ9.96(s,1H),8.71(d,J=4.4Hz,1H),8.33(d,J=7.6Hz,1H),8.28(d,J=8.7Hz,1H),7.95(t,J=7.8Hz,2H),7.70(s,1H),7.62(dd,J=13.8,6.7Hz,2H),7.56(dd,J=7.3,4.9Hz,1H).13C NMR(101MHz,CDCl3)δ163.37,149.23,148.49,137.83,132.09,131.87,130.18,129.42,128.94,128.23,127.58,127.02,126.93,125.10,124.28,123.00.HRMS(ESI+):Calculated for C16H10Cl2N2OH:[M+H]+317.0243,Found:317.0229.
实施例2
在25mL的单口瓶中加入N-(萘基)吡啶酰胺(49.62毫克,0.2mmol),溴代琥珀酰亚胺(83.49毫克,0.48mmol),溴化铜(8.83毫克,20mol%),醋酸碘苯(128.79克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物61.40毫克,收率76%。
1H NMR(400MHz,CDCl3)δ9.94(s,1H),8.71(d,J=4.7Hz,1H),8.33(d,J=7.8Hz,1H),8.24(d,J=8.4Hz,1H),8.05(d,J=1.6Hz,1H),7.95(dd,J=7.6,5.8Hz,2H),7.63(t,J=7.6Hz,1H),7.60–7.52(m,2H).13C NMR(101MHz,CDCl3)δ163.24,149.21,148.50,137.82,132.83,132.10,132.01,131.78,128.22,128.00,127.87,127.04,124.57,122.99,122.77,119.51.HRMS(ESI+):Calculated for C16H10Br2N2OH:[M+H]+404.9233,Found:404.9228.
实施例3
在25mL的单口瓶中加入3-甲基-N-(萘基)吡啶酰胺(52.42毫克,0.2mmol),氯代琥珀酰亚胺(77.99毫克,0.6mmol),氯化铜(5.31毫克,20mol%),醋酸碘苯(128.79毫克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物49.50毫克,收率75%。
1H NMR(400MHz,CDCl3)δ10.03(s,1H),8.23(d,J=8.3Hz,1H),8.13(d,J=7.0Hz,1H),8.05(s,1H),7.95(d,J=8.2Hz,1H),7.82(t,J=7.1Hz,1H),7.60(dt,J=14.8,7.1Hz,2H),7.40(d,J=7.3Hz,1H),2.68(s,3H).13C NMR(101MHz,CDCl3)δ164.70,146.23,145.79,141.28,136.59,131.97,131.68,130.06,129.83,128.83,128.12,127.42,126.84,126.45,124.97,124.34,20.82.HRMS(ESI+):Calculated for C17H12Cl2N2OH:[M+H]+331.0399,Found:331.0392.
实施例4
在25mL的单口瓶中加入3-甲基-N-(萘基)吡啶酰胺(52.42毫克,0.2mmol),溴代琥珀酰亚胺(83.49毫克,0.48mmol),溴化铜(8.83毫克,20mol%),醋酸碘苯(128.79克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物21.50毫克,收率24%。
1H NMR(400MHz,CDCl3)δ10.15(s,1H),8.54(d,J=4.1Hz,1H),8.27(dd,J=6.7,2.8Hz,1H),8.00(dd,J=6.6,2.8Hz,1H),7.69(d,J=8.0Hz,2H),7.65–7.57(m,2H),7.43(dd,J=7.8,4.6Hz,1H),2.79(s,3H).13C NMR(101MHz,CDCl3)δ164.80,146.32 145.83,141.31,136.65,132.06,131.75,130.15,129.95,128.92,128.17,127.49,126.92,126.50,125.04,124.36,20.79.HRMS(ESI+):Calculated for C17H12Br2N2OH:[M+H]+418.9389,Found:418.9352.
实施例5
在25mL的单口瓶中加入3-溴-N-(萘基)吡啶酰胺(65.20毫克,0.2mmol),氯代琥珀酰亚胺(77.99毫克,0.6mmol),氯化铜(5.31毫克,20mol%),醋酸碘苯(128.79毫克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物18.91毫克,收率24%。
1H NMR(400MHz,CDCl3)δ9.83(s,1H),8.66(dd,J=4.5,1.4Hz,1H),8.29–8.25(m,1H),8.14(dd,J=8.1,1.4Hz,1H),8.02–7.97(m,1H),7.70(s,1H),7.64–7.59(m,2H),7.39(dd,J=8.1,4.5Hz,1H).13C NMR(101MHz,CDCl3)δ162.38,146.90,146.37,144.37,132.12,131.91,130.18,129.42,128.98,128.35,127.59,127.21,126.89,125.10,124.28,120.26.HRMS(ESI+):Calculated for C16H9BrCl2N2OH:[M+H]+394.9348,Found:394.9333.
实施例6
在25mL的单口瓶中加入3-溴-N-(萘基)吡啶酰胺(65.20毫克,0.2mmol),溴代琥珀酰亚胺(83.49毫克,0.48mmol),溴化铜(8.83毫克,20mol%),醋酸碘苯(128.79克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物58.35克,收率57%。
1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),8.79(d,J=5.3Hz,1H),8.24(s,1H),8.19(d,J=8.4Hz,1H),8.15(d,J=2.0Hz,1H),7.95(d,J=8.4Hz,1H),7.89(dd,J=5.3,2.0Hz,1H),7.80–7.74(m,1H),7.71–7.64(m,1H).13C NMR(101MHz,CDCl3)δ162.25,146.90,146.22,144.38,132.77,132.09,131.95,131.73,128.36,128.01,127.84,127.25,124.54,122.77,120.25,119.54.HRMS(ESI+):Calculated for C16H9Br3N2OH:[M+H]+482.8338,Found:482.8322.
实施例7
在25mL的单口瓶中加入N-(萘基)吡嗪酰胺(49.82毫克,0.2mmol),氯代琥珀酰亚胺(77.99毫克,0.6mmol),氯化铜(5.31毫克,20mol%),醋酸碘苯(128.79毫克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物44.38毫克,收率70%。
1H NMR(400MHz,CDCl3)δ9.63(s,1H),9.54(d,J=0.8Hz,1H),8.88(d,J=2.4Hz,1H),8.68(dd,J=2.2,1.6Hz,1H),8.28(dd,J=7.5,1.9Hz,1H),7.91(dd,J=7.4,1.9Hz,1H),7.70(s,1H),7.67–7.57(m,2H).13C NMR(101MHz,CDCl3)δ162.09,148.10,145.03,143.88,142.88,132.53,131.69,130.17,129.04,128.65,128.40,127.70,126.86,125.20,123.97.HRMS(ESI+):Calculated for C15H9Cl2N3OH:[M+H]+318.0195,Found:318.0191.
实施例8
在25mL的单口瓶中加入N-(萘基)吡嗪酰胺(49.82毫克,0.2mmol),溴代琥珀酰亚胺(83.49毫克,0.48mmol),溴化铜(8.83毫克,20mol%),醋酸碘苯(128.79克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物66.98毫克,收率77%。
1H NMR(400MHz,CDCl3)δ9.62(s,1H),9.53(d,J=1.2Hz,1H),8.87(d,J=2.4Hz,1H),8.68(dd,J=2.3,1.6Hz,1H),8.24(d,J=8.4Hz,1H),8.04(s,1H),7.90(d,J=8.2Hz,1H),7.61(dddd,J=25.6,8.1,6.9,1.2Hz,2H).13C NMR(101MHz,CDCl3)δ161.96,148.10,145.01,143.84,142.88,132.74,131.89,131.72,131.21,128.37,128.10,127.94,124.24,123.19,119.58.HRMS(ESI+):Calculated for C15H9Br2N3OH:[M+H]+405.9185,Found:405.9166.
实施例9
在25mL的单口瓶中加入4-氯-N-(萘基)吡啶酰胺(56.41毫克,0.2mmol),氯代琥珀酰亚胺(77.99毫克,0.6mmol),氯化铜(5.31毫克,20mol%),醋酸碘苯(128.79毫克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物21.70毫克,收率31%。
1H NMR(400MHz,CDCl3)δ9.84(s,1H),8.60(d,J=5.2Hz,1H),8.33(d,J=1.3Hz,1H),8.28(d,J=7.8Hz,1H),7.92(d,J=7.8Hz,1H),7.70(s,1H),7.62(td,J=13.6,6.6Hz,2H),7.56(dd,J=5.1,1.7Hz,1H).13C NMR(101MHz,CDCl3)δ162.22,150.66,149.39,146.40,132.34,131.71,130.18,128.98,128.32,127.66,127.17,126.91,125.17,124.09,123.62.HRMS(ESI+):Calculated for C16H9Cl3N2OH:[M+H]+350.9853,Found:350.9854.
实施例10
在25mL的单口瓶中加入4-氯-N-(萘基)吡啶酰胺(56.41毫克,0.2mmol),溴代琥珀酰亚胺(83.49毫克,0.48mmol),溴化铜(8.83毫克,20mol%),醋酸碘苯(128.79克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物58.96毫克,收率63%。
1H NMR(400MHz,DMSO)δ10.99(s,1H),8.79(d,J=5.3Hz,1H),8.24(s,1H),8.19(d,J=8.4Hz,1H),8.15(d,J=2.0Hz,1H),7.95(d,J=8.4Hz,1H),7.89(dd,J=5.3,2.0Hz,1H),7.80–7.74(m,1H),7.71–7.64(m,1H).13C NMR(101MHz,DMSO)δ162.49,151.12,150.42,144.86,133.38,132.45,132.42,130.76,128.52,127.15,126.91,124.65,122.67,121.65,120.52.HRMS(ESI+):Calculated for C16H9ClBr2N2OH:[M+H]+438.8843,Found:438.8827.
实施例11
在25mL的单口瓶中加入6-甲基-N-(萘基)吡啶酰胺(52.42毫克,0.2mmol),氯代琥珀酰亚胺(77.99毫克,0.6mmol),氯化铜(5.31毫克,20mol%),醋酸碘苯(128.79毫克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物31.02毫克,收率47%。
1H NMR(400MHz,CDCl3)δ10.81(s,1H),8.34(dd,J=9.0,6.2Hz,2H),8.15(d,J=7.7Hz,1H),8.11–8.05(m,1H),7.82(t,J=7.7Hz,1H),7.67–7.63(m,2H),7.38(d,J=7.7Hz,1H),2.71(s,3H).13C NMR(101MHz,CDCl3)δ162.60,157.44,149.24,138.11,131.96,131.30,128.22,127.74,127.18,127.12,126.57,126.41,125.56,121.05,119.79,118.79,24.60.HRMS(ESI+):Calculated for C17H12Cl2N2OH:[M+H]+331.0399,Found:331.0389.
实施例12
在25mL的单口瓶中加入6-甲基-N-(萘基)吡啶酰胺(52.42毫克,0.2mmol),溴代琥珀酰亚胺(83.49毫克,0.48mmol),溴化铜(8.83毫克,20mol%),醋酸碘苯(128.79克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物26.88毫克,收率30%。
1H NMR(400MHz,CDCl3)δ10.03(s,1H),8.25(d,J=8.4Hz,1H),8.14(d,J=7.7Hz,1H),8.06(s,1H),7.96(d,J=8.3Hz,1H),7.82(t,J=7.7Hz,1H),7.61(dt,J=15.1,7.1Hz,2H),7.41(d,J=7.7Hz,1H),2.69(s,3H).13C NMR(101MHz,CDCl3)δ163.44,157.72,148.56,137.94,132.88,132.27,132.21,131.83,128.19,127.99,127.88,126.80,124.70,122.66,120.08,119.53,24.53.HRMS(ESI+):Calculated for C17H12Br2N2OH:[M+H]+418.9389,Found:418.9382.
实施例13
在25mL的单口瓶中加入N-(苯基)吡啶酰胺(39.62毫克,0.2mmol),氯代琥珀酰亚胺(77.99毫克,0.6mmol),氯化铜(5.31毫克,20mol%),醋酸碘苯(128.79毫克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物24.60毫克,收率53%。
1H NMR(400MHz,CDCl3)δ10.03(s,1H),8.60(ddd,J=4.7,1.4,0.9Hz,1H),8.28(d,J=7.8Hz,1H),7.90(td,J=7.7,1.7Hz,1H),7.78–7.68(m,2H),7.48(ddd,J=7.6,4.8,1.2Hz,1H),7.38–7.30(m,2H).13C NMR(101MHz,CDCl3)δ162.11,149.61,148.10,137.85,136.48,129.33,129.20,126.71,122.54,120.98.HRMS(ESI+):Calculated forC12H9ClN2OH:[M+H]+233.0476,Found:233.0468.
实施例14
在25mL的单口瓶中加入N-(苯基)吡啶酰胺(39.62毫克,0.2mmol),溴代琥珀酰亚胺(83.49毫克,0.48mmol),溴化铜(8.83毫克,20mol%),醋酸碘苯(128.79克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物29.81毫克,收率54%。
1H NMR(400MHz,CDCl3)δ10.04(s,1H),8.60(d,J=4.6Hz,1H),8.27(d,J=7.8Hz,1H),7.90(td,J=7.7,1.7Hz,1H),7.75–7.63(m,2H),7.56–7.41(m,3H).13C NMR(101MHz,CDCl3)δ162.09,149.53,148.09,137.85,136.93,132.12,126.74,122.52,121.28,116.92.HRMS(ESI+):Calculated for C12H9BrN2OH:[M+H]+276.9971,Found:276.9965.
实施例15
在25mL的单口瓶中加入N-(苯基)吡啶酰胺(39.81毫克,0.2mmol),氯代琥珀酰亚胺(77.99毫克,0.6mmol),氯化铜(5.31毫克,20mol%),醋酸碘苯(128.79毫克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物34.45毫克,收率70%。
1H NMR(400MHz,CDCl3)δ9.67(s,1H),9.50(d,J=0.9Hz,1H),8.81(d,J=2.4Hz,1H),8.63–8.52(m,1H),7.76–7.64(m,2H),7.39–7.30(m,2H).13C NMR(101MHz,CDCl3)δ160.77,147.81,144.81,144.22,142.49,135.93,129.96,129.33,121.14.HRMS(ESI+):Calculated for C11H8ClN3OH:[M+H]+234.0429,Found:234.0422.
实施例16
在25mL的单口瓶中加入N-(苯基)吡嗪酰胺(39.81毫克,0.2mmol),溴代琥珀酰亚胺(83.49毫克,0.48mmol),溴化铜(8.83毫克,20mol%),醋酸碘苯(128.79克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物27.26毫克,收率47%。
1H NMR(400MHz,CDCl3)δ9.67(s,1H),9.50(d,J=0.8Hz,1H),8.82(d,J=2.3Hz,1H),8.63–8.54(m,1H),7.67(d,J=8.8Hz,2H),7.51(d,J=8.8Hz,2H).13C NMR(101MHz,CDCl3)δ160.79,147.85,144.84,144.23,142.51,136.44,132.31,121.47,117.63.HRMS(ESI+):Calculated for C11H8BrN3OH:[M+H]+277.9924,Found:277.9915.
实施例17
在25mL的单口瓶中加入N-(3-甲基苯基)吡嗪酰胺(42.42毫克,0.2mmol),氯代琥珀酰亚胺(77.99毫克,0.6mmol),氯化铜(5.31毫克,20mol%),醋酸碘苯(128.79毫克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物22.15毫克,收率45%。
1H NMR(400MHz,CDCl3)δ9.98(s,1H),8.59(d,J=4.6Hz,1H),8.27(d,J=7.8Hz,1H),7.89(t,J=7.7Hz,1H),7.69(s,1H),7.55(dd,J=8.6,1.7Hz,1H),7.47(dd,J=6.9,5.4Hz,1H),7.31(d,J=8.6Hz,1H),2.38(s,3H).13C NMR(101MHz,CDCl3)δ162.05,149.71,148.07,137.81,136.84,136.37,129.54,126.63,122.49,122.05,118.50,20.33.HRMS(ESI+):Calculated for C13H11ClN2OH:[M+H]+247.0633,Found:247.0626.
实施例18
在25mL的单口瓶中加入N-(3-甲基苯基)吡啶酰胺(42.42毫克,0.2mmol),溴代琥珀酰亚胺(83.49毫克,0.48mmol),溴化铜(8.83毫克,20mol%),醋酸碘苯(128.79克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物34.80毫克,收率60%。
1H NMR(400MHz,CDCl3)δ9.99(s,1H),8.61(d,J=4.6Hz,1H),8.28(d,J=7.8Hz,1H),7.91(t,J=7.7Hz,1H),7.72(s,1H),7.54–7.46(m,3H),2.42(s,3H).13C NMR(101MHz,CDCl3)δ162.09,149.70,148.10,138.74,137.86,137.06,132.83,126.69,122.53,121.93,119.56,118.75,23.21.HRMS(ESI+):Calculated for C13H11BrN2OH:[M+H]+291.0128,Found:291.0118.
实施例19
在25mL的单口瓶中加入N-(3-氟苯基)吡啶酰胺(43.21毫克,0.2mmol),氯代琥珀酰亚胺(77.99毫克,0.6mmol),氯化铜(5.31毫克,20mol%),醋酸碘苯(128.79毫克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物25.50毫克,收率51%。
1H NMR(400MHz,CDCl3)δ10.09(s,1H),8.60(d,J=4.6Hz,1H),8.27(d,J=7.8Hz,1H),7.90(dd,J=17.4,9.4Hz,2H),7.50(dd,J=7.5,4.8Hz,1H),7.35(d,J=4.1Hz,2H).13CNMR(101MHz,CDCl3)δ162.21,158.25(d,1JC-F=246Hz),149.25,148.15,137.93,130.67,126.93,122.61,115.89(d,3JC-F=7Hz),115.88,108.33(d,2JC-F=26Hz).19F NMR(376MHz,CDCl3)δ-113.22.HRMS(ESI+):Calculated for C12H8FClN2OH:[M+H]+251.0382,Found:251.0372.
实施例20
在25mL的单口瓶中加入N-(3-氟苯基)吡啶酰胺(43.21毫克,0.2mmol),溴代琥珀酰亚胺(83.49毫克,0.48mmol),溴化铜(8.83毫克,20mol%),醋酸碘苯(128.79克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物40.57毫克,收率69%。
1H NMR(400MHz,CDCl3)δ10.06(s,1H),8.60(d,J=4.5Hz,1H),8.27(d,J=7.8Hz,1H),8.03(s,1H),7.92(t,J=7.7Hz,1H),7.59(dd,J=8.7,2.3Hz,1H),7.54–7.46(m,1H),7.42(d,J=8.7Hz,1H).13C NMR(101MHz,CDCl3)δ162.21,1659.29(d,1JC-F=245Hz),149.24,148.15,138.63(d,3JC-F=10.0Hz),137.93,133.50,133.49,126.93,122.61,116.32(d,4J=3Hz),108.20(d,2J=27Hz),103.25(d,2J=21Hz).19F NMR(376MHz,CDCl3)δ-105.22.HRMS(ESI+):Calculated for C12H8FBrN2OH:[M+H]+294.9877,Found:294.9850.
实施例21
在25mL的单口瓶中加入N-(3-氯苯基)吡啶酰胺(46.41毫克,0.2mmol),氯代琥珀酰亚胺(77.99毫克,0.6mmol),氯化铜(5.31毫克,20mol%),醋酸碘苯(128.79毫克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物25.00毫克,收率47%。
1H NMR(400MHz,CDCl3)δ10.04(s,1H),8.57(d,J=4.6Hz,1H),8.24(d,J=7.8Hz,1H),8.02(d,J=2.3Hz,1H),7.89(td,J=7.8,1.5Hz,1H),7.54(s,1H),7.52–7.45(m,2H).13C NMR(101MHz,CDCl3)δ162.13,149.13,148.10,138.01,137.86,134.88,133.85,126.88,122.53,121.20,119.12,116.72.HRMS(ESI+):Calculated for C12H8Cl2N2OH:[M+H]+267.0086,Found:267.0060.
实施例22
在25mL的单口瓶中加入N-(3-氯苯基)吡啶酰胺(46.41毫克,0.2mmol),溴代琥珀酰亚胺(83.49毫克,0.48mmol),溴化铜(8.83毫克,20mol%),醋酸碘苯(128.79克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物53.31毫克,收率86%。
1H NMR(400MHz,CDCl3)δ10.06(s,1H),8.60(d,J=4.5Hz,1H),8.27(d,J=7.2Hz,1H),8.03(s,1H),7.92(t,J=7.7Hz,1H),7.59(dd,J=8.7,2.3Hz,1H),7.54–7.46(m,1H),7.42(d,J=8.7Hz,1H).13C NMR(101MHz,CDCl3)δ162.19,149.25,148.15,137.94,137.37,133.00,130.70,127.51,126.93,122.61,121.40,118.99.HRMS(ESI+):Calculated forC12H8ClBrN2OH:[M+H]+310.9581,Found:310.9580.
实施例23
在25mL的单口瓶中加入N-(3-溴苯基)吡啶酰胺(55.20毫克,0.2mmol),氯代琥珀酰亚胺(77.99毫克,0.6mmol),氯化铜(5.31毫克,20mol%),醋酸碘苯(128.79毫克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物33.47毫克,收率54%。
1H NMR(400MHz,CDCl3)δ10.04(s,1H),8.59(d,J=4.0Hz,1H),8.26(d,J=7.8Hz,1H),8.16(s,1H),7.91(t,J=7.7Hz,1H),7.66(d,J=8.7Hz,1H),7.49(dd,J=6.7,5.6Hz,1H),7.41(d,J=8.0Hz,1H).13C NMR(101MHz,CDCl3)δ162.17,149.25,148.15,137.93,137.36,130.52,129.47,126.92,124.51,122.76,122.60,119.68.HRMS(ESI+):Calculatedfor C12H8BrClN2OH:[M+H]+310.9581,Found:310.9575.
实施例24
在25mL的单口瓶中加入N-(3-溴苯基)吡啶酰胺(55.20毫克,0.2mmol),溴代琥珀酰亚胺(83.49毫克,0.48mmol),溴化铜(8.83毫克,20mol%),醋酸碘苯(128.79克,2.0eq),N,N-二甲基甲酰胺(4毫升)。在空气气氛下60℃搅拌3.0h。然后混合物冷却至室温,冷却过滤后减压浓缩。经硅胶柱层析(展开剂:石油醚:乙酸乙酯=80:1)纯化得白色固体目标产物48.13毫克,收率68%。
1H NMR(400MHz,CDCl3)δ10.03(s,1H),8.57(s,1H),8.24(d,J=7.6Hz,1H),8.15(s,1H),7.90(d,J=7.7Hz,1H),7.67–7.52(m,2H),7.52–7.43(m,1H).13C NMR(101MHz,CDCl3)δ162.14,149.16,148.12,137.94,137.89,133.78,126.90,125.08,124.41,122.55,119.77,119.12.HRMS(ESI+):Calculated for C12H8Br2N2OH:[M+H]+354.9076,Found:354.9072.
Claims (7)
1.一种铜催化选择性合成卤代芳胺类化合物的方法,其特征在于,所述方法为:
反应底物与卤化试剂(III)于有机溶剂中,在催化剂、氧化剂的作用下,于0~80℃下反应0.5~6h,反应结束后,反应液经后处理,得到产物卤代芳胺类化合物;
所述反应底物与卤化试剂(III)、催化剂、氧化剂的物质的量之比为1:0.5~3:0.05~0.2:0.1~3;
所述催化剂为氯化铜、醋酸铜、三氟甲磺酸铜、溴化铜、醋酸钯、溴化铁中的一种或两种以上任意比例的混合物;
所述氧化剂为过氧化二叔丁基、醋酸碘苯、特戊酸碘苯、三氟乙酸碘苯、过硫酸钾中的一种或两种以上任意比例的混合物;
所述反应底物如式(I-a)或式(I-b)所示,相应的产物如式(II-a)或式(II-b)所示;
式(I-a)、(II-a)、(I-b)、(II-b)或(III)中:
R1为H、C1-C4烷基、C1-C4烷氧基、杂环基或卤素;
R2为H、C1-C4烷基、C1-C4烷氧基、杂环基或卤素;
R3为H、C1-C4烷基、C1-C4烷氧基、杂环基或卤素,并且R3不位于4位;
X为Cl或Br;
Y为C或N。
2.如权利要求1所述铜催化选择性合成卤代芳胺类化合物的方法,其特征在于,反应温度为60℃,反应时间为3h。
3.如权利要求1所述铜催化选择性合成卤代芳胺类化合物的方法,其特征在于,所述催化剂为溴化铜。
4.如权利要求1所述铜催化选择性合成卤代芳胺类化合物的方法,其特征在于,所述氧化剂为醋酸碘苯。
5.如权利要求1所述铜催化选择性合成卤代芳胺类化合物的方法,其特征在于,所述有机溶剂为1,2-二氯乙烷、四氢呋喃、N,N-二甲基甲酰胺、乙腈和二甲基亚砜中的一种或两种以上任意比例的混合溶剂。
6.如权利要求1所述铜催化选择性合成卤代芳胺类化合物的方法,其特征在于,所述有机溶剂的体积用量以反应底物的物质的量计为0.5~30mL/mmol。
7.如权利要求1所述铜催化选择性合成卤代芳胺类化合物的方法,其特征在于,所述后处理的方法为:反应结束后,将反应液冷却至室温,过滤,滤液减压浓缩后进行硅胶柱层析,以石油醚:乙酸乙酯体积比80:1的混合液为展开剂,收集含目标化合物的洗脱液,蒸除溶剂并干燥,即得产物。
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