CN113896647B - 一种叔酰胺的合成方法 - Google Patents

一种叔酰胺的合成方法 Download PDF

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CN113896647B
CN113896647B CN202010648789.7A CN202010648789A CN113896647B CN 113896647 B CN113896647 B CN 113896647B CN 202010648789 A CN202010648789 A CN 202010648789A CN 113896647 B CN113896647 B CN 113896647B
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王少华
梁欢
余兰
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Abstract

本发明属于有机合成技术领域，具体涉及一种叔酰胺类化合物的合成方法，其反应通式如下：

Description

一种叔酰胺的合成方法
技术领域
本发明属于有机合成技术领域，具体涉及一种叔酰胺类化合物的合成方法。
背景技术
酰胺类化合物广泛应用于医疗药物、工业材料、生活用品等方面,深入地影响人们的生活。作为一种存在于各类化合物中的重要结构单元，酰胺基团的合成方法自然得到了广泛关注和大力发展。以活化甲酰胺的C(sp2)-H构筑C-C键为手段的氢氨甲酰化法引入酰胺基团至有机分子的策略，由于其独特的反应模式，在近些年来也受到了化学家们的关注。但是，传统的以甲酰胺为底物的氢氨甲酰化反应通常会遇到选择性差，底物适用性低，反应催化体系复杂等问题(Adv.Synth.Catal.,2008,350,2209；Organomet.Chem.,1987,331,379；Org.Lett., 2003,5,2687；J.Am.Chem.Soc.,2009,131,5070.)。本发明创造性地将由甲酰胺转化得到的N, N-二取代氨基丙二腈作为合成子，借助其亲核属性来实现对不饱和键的加成，而后将加成产物和催化剂，依次加入到有机溶剂中，加热条件下得到叔酰胺类化合物。该合成方法原料易得，操作简单，反应条件温和，底物适用性广，改进了现有制备方法的诸多不足。因此本发明有良好的实用价值和社会经济效率，对同类产品及下游产品的工艺开发具有很好的借鉴意义。
Figure SMS_1
发明内容
本发明的目的在于克服现有制备技术的缺陷，提供一种反应条件简单，底物适用性广，操作方便的叔酰胺类化合物的合成方法。
本发明的技术方案为：含季碳中心的α-氨基丙二腈、催化剂，依次加入到有机溶剂中，加热条件下得到叔酰胺，反应式如下：
Figure SMS_2
其中：
(1)R1、R2不在同一个环系上时，R1选自甲基、正丁基、苄基，R2选自甲基、取代苯基、取代苄基；
(2)R1、R2在同一环系上时，R1、R2连同N原子选自哌啶基、吗啉基、二氢吲哚基、1,2,3,4- 四氢异喹啉基、1,2,3,4-四氢喹啉基；
(3)R选自甲基，正丙基，正戊基，苯基，取代苯基，呋喃基，乙氧羰基；
(4)所用催化剂选自氟化铜、醋酸铜、二甲醇铜、溴化铜、氯化铜、硫酸铜、磷酸铜三氟甲烷磺酸铜、三氟甲烷磺酸银、三氟甲烷磺酸锌、三氟甲磺酸铝；
(5)所用的溶剂选自二甲基亚砜、乙腈、二氯甲烷、四氢呋喃、乙醚、甲醇、1,4-二氧六环、丙酮、氯仿、1,2-二氯乙烷、甲苯、正庚烷、N,N-二甲基甲酰胺的一种或几种；
(6)所用加热的温度选自40℃-200℃，维持时间2-48小时，优选100℃，维持10小时；
(7)反应中各物质的摩尔量比选自：含季碳中心的α-氨基丙二腈：催化剂＝1:0.01-1，优选季碳中心的α-氨基丙二腈：催化剂＝1:0.05。
具体实施方式
以下通过具体实施例对本发明做进一步的说明，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.以(E)-6,6-二氰基-6-(二甲氨基)-5-苯基己-2-烯酸酯为原料(反应式1)
Figure SMS_3
氩气保护下，在10mL的密封管中将(E)-6,6-二氰基-6-(二甲氨基)-5-苯基己-2-烯酸酯(125 mg，0.4mmol)，氟化铜(2mg，0.02mmol)，依次加入到搅拌的DMSO(1.5mL)中，在100℃下反应10小时完成反应，反应结束后，加水淬灭反应，用乙酸乙酯萃取水相三次，合并所有机相，以饱和食盐水洗涤，并使用无水Na2SO4干燥。有机相经浓缩后柱层析得黄色液体(74 mg，67％yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ7.34–7.21(m,5H),6.86(dt,J＝15.6,7.2Hz,1H),5.79(dt, J＝15.6,1.4Hz,1H),4.14(q,J＝7.1Hz,2H),3.81(dd,J＝8.0,6.5Hz,1H),3.07–2.96(m,1H), 2.91(d,J＝21.4Hz,6H),2.59–2.48(m,1H),1.25(t,J＝7.1Hz,3H).13CNMR(100MHz, Chloroform-d)δ171.72,166.52,146.68,138.95,129.05,127.82,127.34,122.96,60.24,48.43,37.78,37.14,36.06,14.32.HRMS(ESI)calcd for C16H21NO3[M+H]+:276.1594,found 276.1589.
2.以(E)-6,6-二氰基-6-(甲基(苯基)氨基)-5-苯基己-2-烯酸酯为原料(反应式2)
Figure SMS_4
氩气保护下，在一个10mL的密封管中将(E)-6,6-二氰基-6-(甲基(苯基)氨基)-5-苯基己-2-烯酸酯(74mg，0.2mmol)，氟化铜(1mg，0.01mmol)，依次加入到搅拌的DMSO(1.5mL)中，在60℃下反应34小时完成反应，反应结束后，加水淬灭反应，用乙酸乙酯萃取水相三次，合并所有机相，以饱和食盐水洗涤，并使用无水Na2SO4干燥。有机相经浓缩后经柱层析得黄色液体(41mg，60％yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ7.40–7.29(m,3H),7.23–7.16(m,3H),7.05–6.98(m, 2H),6.94(s,2H),6.76(dt,J＝14.9,7.2Hz,1H),5.77(d,J＝15.6Hz,1H),4.15(q,J＝7.1Hz,2H), 3.57(dd,J＝8.6,6.4Hz,1H),3.22(s,3H),3.04–2.92(m,1H),2.54–2.42(m,1H),1.25(t,J＝ 7.1Hz,3H).13C NMR(100MHz,Chloroform-d)δ171.85,166.29,145.95,143.26,139.02,129.55, 128.43,127.99,127.90,127.83,127.05,122.95,60.10,48.11,37.66,37.47,14.18.HRMS(ESI) calcd for C21H23NO3[M+H]+:338.1751,found 338.1745.
3.以(E)-6,6-二氰基-6-(甲基(对甲苯基)氨基)-5-苯基己-2-烯酸酯为原料(反应式3)
Figure SMS_5
氩气保护下，在一个50mL的反应瓶将(E)-6,6-二氰基-6-(甲基(对甲苯基)氨基)-5-苯基己-2-烯酸酯(1000mg，2.58mmol)，三氟甲烷磺酸铜(374mg，1.03mmol)，依次加入到搅拌的DMSO(10mL)中，在140℃下反应10小时完成反应，反应结束后，加水淬灭反应，用乙酸乙酯萃取水相三次，合并所有机相，以饱和食盐水洗涤，并使用无水Na2SO4干燥。有机相经浓缩后经柱层析得黄色液体(517mg，57％yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ7.25–7.18(m,3H),7.18–7.12(m,2H),7.07–7.01(m, 2H),6.91–6.69(m,3H),5.77(dd,J＝15.6,1.3Hz,1H),4.15(q,J＝7.1Hz,2H),3.59(dd,J＝8.6, 6.4Hz,1H),3.20(s,3H),3.03–2.92(m,1H),2.53–2.44(m,1H),2.39(s,3H),1.26(t,J＝7.1Hz, 3H).13C NMR(100MHz,Chloroform-d)δ172.05,166.35,146.05,140.73,139.15,137.97,130.17, 128.44,127.93,127.63,127.05,122.93,60.13,47.93,37.73,37.51,21.08,14.23.HRMS(ESI) calcd for C22H25NO3[M+H]+:352.1907,found 352.1906.
4.以(E)-6-(丁基(苯基)氨基)-6,6-二氰基-5-苯基己-2-烯酸乙酯为原料(反应式4)
Figure SMS_6
氩气保护下，在10mL的密封管中将(E)-6-(丁基(苯基)氨基)-6,6-二氰基-5-苯基己-2-烯酸乙酯(208mg，0.5mmol)，三氟甲烷磺酸铜(182mg，0.5mmol)，依次加入到搅拌的乙醚(1.5mL)中，在100℃下反应3小时完成反应，在旋转蒸发仪上抽干溶剂，经柱层析得黄色液体(114 mg，60％yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ7.40–7.27(m,3H),7.26–6.82(m,7H),6.77(dt,J＝15.5, 7.2Hz,1H),5.78(dt,J＝15.5,1.3Hz,1H),4.16(q,J＝7.0Hz,2H),3.71(dt,J＝13.3,7.6Hz,1H), 3.58(dt,J＝13.3,7.5Hz,1H),3.49(dd,J＝8.8,6.1Hz,1H),3.03–2.91(m,1H),2.50–2.39(m, 1H),1.43(p,J＝7.3Hz,2H),1.29–1.23(m,5H),0.86(t,J＝7.3Hz,3H).13C NMR(100MHz, Chloroform-d)δ171.39,166.35,146.07,141.85,139.20,129.42,128.92,128.43,128.03,127.86,127.02,122.94,60.12,49.36,48.45,37.60,29.64,19.91,14.22,13.73.HRMS(ESI)calcd for C24H29NO3[M+H]+:380.2220,found 380.2214.
5.以(E)-6-(苄基(甲基)氨基)-6,6-二氰基-5-苯基己-2-烯酸酯为原料(反应式5)
Figure SMS_7
氩气保护下，在一个10mL的反应管将(E)-6-(苄基(甲基)氨基)-6,6-二氰基-5-苯基己-2-烯酸酯(39mg，0.1mmol)，硫酸铜(1.6mg，0.1mmol)，依次加入到搅拌的甲醇(1mL)中，在80℃下反应4小时完成反应，在旋转蒸发仪上抽干溶剂，经柱层析得黄色液体(25mg，72％yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ7.36–6.96(m,10H),6.96–6.76(m,1H),5.87–5.71(m, 1H),4.67–4.21(m,2H),4.20–4.10(m,2H),3.91–3.74(m,1H),3.14–2.99(m,1H),2.85(d,J ＝51.4Hz,3H),2.64–2.47(m,1H),1.26(t,J＝7.1Hz,3H).13C NMR(100MHz,Chloroform-d)δ172.10,171.77,166.37,166.29,146.44,146.21,138.98,138.62,137.15,136.32,129.03,128.95, 128.86,128.49,127.81,127.78,127.67,127.56,127.34,127.23,126.20,123.12,122.96,60.14,52.82,51.22,48.46,48.35,37.84,37.67,34.66,34.31,14.23.HRMS(ESI)calcd for C22H25NO3[M+H]+:352.1907,found 352.1902.
6.以(E)-6,6-二氰基-6-((4-甲氧基苄基)(甲基)氨基)-5-苯基己-2-烯酸酯为原料(反应式6)
Figure SMS_8
氩气保护下，在一个10mL的反应管中将(E)-6,6-二氰基-6-((4-甲氧基苄基)(甲基)氨基)-5-苯基己-2-烯酸酯(418mg，1mmol)，氟化铜(102mg，1mmol)依次加入到搅拌的二甲基亚砜(2 mL)中，在200℃下反应2小时完成反应，反应结束后，加水淬灭反应，用乙酸乙酯萃取水相三次，合并所有机相，以饱和食盐水洗涤，并使用无水Na2SO4干燥。有机相经浓缩后经柱层析得黄色液体(352mg，92％yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ7.34–7.22(m,5H),7.07(d,J＝8.6Hz,1H),6.98–6.87(m, 1H),6.87–6.72(m,3H),5.89–5.71(m,1H),4.62–4.20(m,2H),4.16(q,J＝7.2Hz,2H),3.85(td,J＝8.5,6.5Hz,1H),3.77(d,J＝7.7Hz,3H),3.13–3.00(m,1H),2.92–2.73(m,3H),2.63– 2.50(m,1H),1.27(t,J＝7.1Hz,3H).13C NMR(100MHz,Chloroform-d)δ171.89,171.58, 166.29,166.23,158.97,158.77,146.43,146.24,139.02,138.60,129.18,129.10,128.96,128.86,128.07,127.71,127.62,127.49,127.30,127.23,123.01,122.85,114.16,113.80,60.06,55.16, 55.10,52.19,50.51,48.37,48.25,37.78,37.61,34.37,33.95,14.16.HRMS(ESI)calcd for C23H27NO4[M+H]+:382.2013,found 382.2007.
7.以(E)-6,6-二氰基-6-吗啉基-5-苯基己-2-烯酸酯为原料(反应式7)
Figure SMS_9
氩气保护下，在一个25mL的密封管将(E)-6,6-二氰基-6-吗啉基-5-苯基己-2-烯酸酯(1060mg，3mmol)，溴化铜(34mg，0.15mmol)，依次加入到搅拌的丙酮(5mL)中，在120℃下反应 14小时完成反应，在旋转蒸发仪上抽干溶剂，经柱层析得黄色液体(850mg，89％yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ7.37–7.30(m,2H),7.29–7.25(m,1H),7.25–7.21(m, 2H),6.93–6.83(m,1H),5.81(d,J＝15.6Hz,1H),4.16(q,J＝7.1Hz,2H),3.86–3.74(m,2H), 3.70–3.61(m,1H),3.53–3.36(m,4H),3.34–3.25(m,1H),3.10–2.99(m,2H),2.63–2.52(m, 1H),1.26(t,J＝7.1Hz,3H).13C NMR(100MHz,Chloroform-d)δ170.17,166.33,146.27,138.76, 129.11,127.51,127.41,123.01,66.65,66.15,60.17,48.18,45.94,42.44,37.40,14.20.HRMS(ESI)calcd for C18H23NO4[M+H]+:318.1700,found 318.1695.
8.以(E)-6,6-二氰基-5-苯基-6-(哌啶-1-基)己-2-烯酸酯为原料(反应式8)
Figure SMS_10
氩气保护下，在一个50mL的反应瓶中将(E)-6,6-二氰基-5-苯基-6-(哌啶-1-基)己-2-烯酸酯(3.5 g，10mmol)，氯化铜(403mg，3mmol)，依次加入到搅拌的乙腈(30mL)中，在90℃下回流反应30小时完成反应，在旋转蒸发仪上抽干溶剂，经柱层析得黄色液体(2.1g，66％ yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ7.33–7.27(m,2H),7.25–7.20(m,3H),6.88(dt,J＝15.5, 7.1Hz,1H),5.79(dt,J＝15.6,1.3Hz,1H),4.14(q,J＝7.2Hz,2H),3.86–3.79(m,1H),3.78– 3.69(m,1H),3.40–3.23(m,3H),3.07–2.97(m,1H),2.59–2.49(m,1H),1.58–1.47(m,3H), 1.47–1.26(m,3H),1.25(t,J＝7.1Hz,3H).13C NMR(100MHz,Chloroform-d)δ169.71, 166.42,146.77,139.36,128.91,127.63,127.10,122.77,60.10,48.15,46.55,43.24,37.62,25.82,25.43,24.40,14.21.HRMS(ESI)calcd for C19H25NO3[M+H]+:316.1907,found 316.1901
9.以(E)-6,6-二氰基-6-(4-甲基哌啶-1-基)-5-苯基己-2-烯酸酯为原料(反应式9)
Figure SMS_11
氩气保护下，在一个10mL的反应管将(E)-6,6-二氰基-6-(4-甲基哌啶-1-基)-5-苯基己-2-烯酸酯(110mg，0.3mmol)，三氟甲烷磺酸银(4mg，0.015mmol)依次加入到搅拌的1,4-二氧六环(1.5 mL)中，在90℃下反应38小时完成反应，反应结束后，加水淬灭反应，用乙酸乙酯萃取水相三次，合并所有机相，以饱和食盐水洗涤，并使用无水Na2SO4干燥。有机相经浓缩后经柱层析得黄色固体(62mg，63％yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ7.34–7.27(m,2H),7.25–7.19(m,3H),6.87(dt,J＝15.5, 7.2Hz,1H),5.78(dd,J＝15.7,8.9Hz,1H),4.67–4.49(m,1H),4.13(qd,J＝7.2,1.9Hz,2H), 3.87–3.75(m,2H),3.09–2.96(m,1H),2.95–2.61(m,1H),2.60–2.46(m,2H),1.69–1.28(m, 3H),1.24(t,J＝7.1Hz,3H),1.16–0.78(m,3H),0.75–0.01(m,2H).13C NMR(100MHz, Chloroform-d)δ169.93,169.58,166.43,166.35,146.84,146.65,139.44,139.12,128.90,128.86,127.60,127.10,122.79,122.71,60.08,48.34,47.86,45.79,42.61,42.48,37.62,37.56,34.47,33.80, 33.58,33.47,30.90,21.54,14.19.HRMS(ESI)calcd for C20H27NO3[M+H]+:330.2064,found 330.2060,熔程：43.4–45.6℃
10.以(E)-6,6-二氰基-6-(吲哚-1-基)-5-苯基己-2-烯酸酯为原料(反应式10)
Figure SMS_12
氩气保护下，在一个100mL的反应瓶将(E)-6,6-二氰基-6-(吲哚-1-基)-5-苯基己-2-烯酸酯(9.630g，25mmol)，三氟甲烷磺酸锌(3.635g，10mmol)依次加入到搅拌的二氯甲烷(50mL)中，在60℃下反应12小时完成反应，在旋转蒸发仪上抽干溶剂，经柱层析得白色固体(6.653 g，76％yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ8.30(d,J＝8.1Hz,1H),7.32(d,J＝4.4Hz,4H),7.28–7.22(m,1H),7.18(t,J＝7.7Hz,1H),7.11(d,J＝7.3Hz,1H),7.03–6.84(m,2H),5.83(dd,J＝15.6, 1.3Hz,1H),4.17–4.06(m,3H),3.83–3.69(m,2H),3.19–3.05(m,2H),2.97(ddd,J＝16.3, 10.5,6.3Hz,1H),2.66–2.54(m,1H),1.24(t,J＝7.1Hz,3H).13C NMR(100MHz,Chloroform-d)δ169.80,166.28,146.07,143.05,138.01,131.03,129.06,127.89,127.49,127.43,124.44,123.82, 123.16,117.20,60.15,51.17,47.53,37.32,27.88,14.17.HRMS(ESI)calcd for C22H23NO3[M+H]+:350.1751,found 350.1747,熔程：80.2–83.2℃。
11.以(E)-6,6-二氰基-6-(3,4-二氢异喹啉-2(1H)-基)-5-苯基己-2-烯酸酯为原料(反应式11)
Figure SMS_13
氩气保护下，在一个25mL的密封管将(E)-6,6-二氰基-6-(3,4-二氢异喹啉-2(1H)-基)-5-苯基己 -2-烯酸酯(1198.482mg，3mmol)，磷酸铜(190mg，0.5mmol)，依次加入到搅拌的四氢呋喃(5mL)的混合溶剂中，在85℃下反应18小时完成反应，在旋转蒸发仪上抽干溶剂，经柱层析得淡黄色液体(896mg，82％yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ7.34–7.09(m,8H),7.03–6.84(m,2H),5.86–5.75(m, 1H),4.89–4.29(m,2H),4.18–4.10(m,2H),3.97–3.54(m,3H),3.13–3.00(m,1H),2.90–2.24(m,3H),1.24(t,J＝7.1Hz,3H).13C NMR(100MHz,Chloroform-d)δ170.60,170.48,166.32,146.43,138.89,138.59,134.88,133.88,133.17,132.24,129.01,128.58,128.18,127.64,127.59,127.27,126.72,126.54,126.39,126.35,126.15,125.81,122.97,60.09,48.77,48.71,47.06, 44.57,42.94,40.24,37.57,28.93,28.38,14.16.HRMS(ESI)calcdfor C23H25NO3[M+H]+: 364.1907,found 364.1900.
12.以(E)-6,6-二氰基-5-(4-(二甲基氨基)苯基)-6-吗啉代己烯-2-烯酸酯为原料(反应式12)
Figure SMS_14
氩气保护下，在一个10mL的密封管将(E)-6,6-二氰基-5-(4-(二甲基氨基)苯基)-6-吗啉代己烯 -2-烯酸酯(396mg，1mmol)，醋酸铜(91mg，0.5mmol)，依次加入到搅拌的四氢呋喃：二氯甲烷：1,4-二氧六环＝1:1:1(3mL)的混合溶剂中，在140℃下反应12小时完成反应，在旋转蒸发仪上抽干溶剂，经柱层析得黄色固体(282mg，78％yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ7.07–7.01(m,2H),6.87(dt,J＝15.5,7.2Hz,1H),6.68– 6.61(m,2H),5.86–5.72(m,1H),4.13(q,J＝7.2Hz,2H),3.81–3.71(m,1H),3.70–3.57(m, 2H),3.52–3.28(m,5H),3.13–3.03(m,1H),3.01–2.93(m,1H),2.91(s,6H),2.56–2.46(m, 1H),1.24(t,J＝7.1Hz,3H).13C NMR(100MHz,Chloroform-d)δ170.86,166.45,149.66, 146.93,128.21,126.20,122.69,112.86,66.71,66.29,60.09,47.24,45.97,42.41,40.43,37.56,14.21.HRMS(ESI)calcd for C20H28N2O4[M+H]+:361.2122,found 361.2117,熔程：54.3℃–57.2℃。
13.以(E)-6,6-二氰基-5-(呋喃-2-基)-6-吗啉己基-2-烯酸酯为原料(反应式13)
Figure SMS_15
氩气保护下，在一个10mL的反应管将(E)-6,6-二氰基-5-(呋喃-2-基)-6-吗啉己基-2-烯酸酯(34 mg，0.1mmol)，氟化铜(1mg，0.01mmol)依次加入到搅拌的甲醇：二氯甲烷＝1:2(1mL)的混合溶剂中，在60℃下反应34小时完成反应，在旋转蒸发仪上抽干溶剂，经柱层析得黄色液体(26mg，85％yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ7.32(dd,J＝1.9,0.8Hz,1H),6.86(dt,J＝15.6,7.1Hz,1H), 6.31(dd,J＝3.3,1.9Hz,1H),6.15(d,J＝3.3Hz,1H),5.84(dt,J＝15.6,1.5Hz,1H),4.15(q,J＝ 7.1Hz,2H),3.99(t,J＝7.3Hz,1H),3.81–3.73(m,1H),3.70–3.52(m,3H),3.51–3.45(m,3H), 3.40–3.32(m,1H),3.00–2.90(m,1H),2.78–2.68(m,1H),1.25(t,J＝7.1Hz,3H).13C NMR(100MHz,Chloroform-d)δ168.19,166.20,151.76,145.35,141.89,123.35,110.63,106.80,66.71, 66.43,60.22,46.17,42.63,41.13,34.16,14.18.HRMS(ESI)calcd for C16H21NO5[M+H]+: 308.1492,found 308.1491.
14.以(E)-6,6-二氰基-5-甲基-6-吗啉代己酸酯-2-烯酸酯为原料(反应式14)
Figure SMS_16
氩气保护下，在一个100mL的反应瓶将(E)-6,6-二氰基-5-甲基-6-吗啉代己酸酯-2-烯酸酯(5.823g，20mmol)，二甲醇铜(628mg，5mmol)，依次加入到搅拌的四氢呋喃：丙酮＝2:1(50 mL)的混合溶剂中，在100℃下反应25小时完成反应，在旋转蒸发仪上抽干溶剂，经柱层析得淡黄色液体(4.099g，80％yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ6.91–6.80(m,1H),5.87–5.80(m,1H),4.16(qd,J＝7.1, 1.5Hz,2H),3.70–3.47(m,8H),2.77(q,J＝6.9Hz,1H),2.65–2.53(m,1H),2.33–2.22(m,1H), 1.29–1.23(m,3H),1.14(dd,J＝6.9,1.3Hz,3H).13C NMR(100MHz,Chloroform-d)δ173.61, 166.27,146.01,123.17,66.93,66.68,60.23,46.00,42.12,36.24,34.55,17.56,14.20.HRMS(ESI) calcd for C13H21NO4[M+H]+:256.1543,found256.1543.
15.以(E)-5-(二氰基(吗啉代)甲基)己二烯二酸二乙酯为原料(反应式15)
Figure SMS_17
氩气保护下，在一个15mL的密封管将(E)-5-(二氰基(吗啉代)甲基)己二烯二酸二乙酯(140 mg，0.4mmol)，三氟甲烷磺酸铝(24mg，0.05mmol)，依次加入到搅拌的二甲基亚砜(2mL)的溶剂中，在100℃下反应13小时完成反应，反应结束后，加水淬灭反应，用乙酸乙酯萃取水相三次，合并所有机相，以饱和食盐水洗涤，并使用无水Na2SO4干燥。有机相经浓缩后经柱层析得黄色液体(79mg，63％yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ6.85(dt,J＝15.6,7.2Hz,1H),5.87(dt,J＝15.6,1.5Hz, 1H),4.17(dq,J＝10.6,7.1Hz,4H),3.78–3.45(m,9H),2.82(td,J＝7.2,1.5Hz,2H),1.26(td,J ＝7.1,1.1Hz,6H).13C NMR(100MHz,Chloroform-d)δ168.64,166.05,165.89,144.44,123.70, 66.73,66.44,61.81,60.32,47.51,46.46,42.72,31.44,14.18,14.09.HRMS(ESI)calcd for C15H23NO6[M+H]+:314.1598,found 314.1594.
16.以(2E，4Z)-6,6-二氰基-6-吗啉代-5-苯基六-2-乙基二酸乙酯为原料(反应式16)
Figure SMS_18
氩气保护下，在一个15mL的密封管中将(2E，4Z)-6,6-二氰基-6-吗啉代-5-苯基六-2-乙基二酸乙酯(351mg，1mmol)，二甲醇铜(1mg，0.01mmol)，依次加入到搅拌的甲苯：1,2-二氯乙烷＝1:1(2mL)的溶剂中，在200℃下反应36小时完成反应，在旋转蒸发仪上抽干溶剂，经柱层析得黄色液体(274mg，87％yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ7.50(dd,J＝15.3,11.6Hz,1H),7.44–7.35(m,3H),7.35– 7.31(m,2H),6.50(d,J＝11.5Hz,1H),6.13–6.06(m,1H),4.16(q,J＝7.2Hz,2H),3.65(s,4H), 3.34(d,J＝28.2Hz,4H),1.24(t,J＝7.1Hz,3H).13C NMR(100MHz,Chloroform-d)δ168.91, 166.35,144.05,139.25,134.11,128.98,128.84,128.66,127.72,125.80,66.46,60.47,47.12,42.15, 14.12.HRMS(ESI)calcd for C18H21NO4[M+H]+:316.1543,found 316.1540.
17.以(2E，4Z)-6,6-二氰基-5-甲基-6-吗啉代己基-2,4-二烯酸乙酯为原料(反应式17)
Figure SMS_19
氩气保护下，在一个25mL的密封管将(2E，4Z)-6,6-二氰基-5-甲基-6-吗啉代己基-2,4-二烯酸乙酯(1.157g，4mmol)，三氟甲烷磺酸铜(0.362g，1mmol)，依次加入到搅拌的丙酮：甲醇＝1:2(6mL)的混合溶剂中，在100℃下反应12小时完成反应，在旋转蒸发仪上抽干溶剂，经柱层析得黄色固体(0.871g，86％yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ7.49(dd,J＝15.2,11.6Hz,1H),6.16(d,J＝11.4Hz,1H), 5.95(d,J＝15.2Hz,1H),4.20(q,J＝7.1Hz,2H),3.74–3.40(m,8H),2.06(d,J＝1.1Hz,3H), 1.28(t,J＝7.1Hz,3H).13C NMR(100MHz,Chloroform-d)δ170.81,166.51,139.98,137.92, 126.82,124.14,66.73,60.51,15.42,14.18.HRMS(ESI)calcd forC18H21NO4[M+H]+:254.1387, found 254.1384,熔程：40.1–42.9℃
18.以(2E，4Z)-6,6-二氰基-5-甲基-6-吗啉代己基-2,4-二烯酸乙酯为原料(反应式18)
Figure SMS_20
氩气保护下，在一个15mL的密封管将(2E，4Z)-6,6-二氰基-5-甲基-6-吗啉代己基-2,4-二烯酸乙酯(35mg，0.1mmol)，三氟甲烷磺酸铜(7mg，0.02mmol)，依次加入到搅拌的乙醚(1mL)中，在40℃下反应48小时完成反应，在旋转蒸发仪上抽干溶剂，经柱层析得黄色液体(23 mg，75％yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ7.52(dd,J＝15.2,11.6Hz,1H),6.10(d,J＝11.6Hz,1H), 5.96(d,J＝15.3Hz,1H),4.21(q,J＝7.0Hz,2H),3.65(s,8H),2.54–2.44(m,2H),1.47–1.38(m,2H),1.35–1.26(m,7H),0.87(t,J＝6.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ 170.49,166.58,144.87,137.93,126.36,124.25,66.80,60.54,31.64,29.63,28.17,22.33,14.21,13.91.HRMS(ESI)calcd for C17H27NO4[M+H]+:310.2013,found310.2008.
19.以2-苄基-2-吗啉代马来腈为原料(反应式19)
Figure SMS_21
氩气保护下，在一个15mL的密封管将2-苄基-2-吗啉代马来腈(97mg，0.4mmol)，氟化铜(2 mg，0.02mmol)，依次加入到搅拌的二甲基亚砜(1.5mL)中，在100℃下反应30小时完成反应，在反应结束后，加水淬灭反应，用乙酸乙酯萃取水相三次，合并所有机相，以饱和食盐水洗涤，并使用无水Na2SO4干燥。有机相经浓缩后，经柱层析得白色固体(79mg，96％yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ7.36–7.27(m,2H),7.25–7.18(m,3H),3.71(s,2H),3.61(s,4H),3.47–3.38(m,4H).13C NMR(100MHz,Chloroform-d)δ169.46,134.67,128.65,128.39, 126.75,66.62,66.29,46.36,41.99,40.67.HRMS(ESI)calcd forC12H15NO2[M+H]+:206.1176, found 206.1175.熔程：62.4–63.7℃。
20.以2-苄基-2-吗啉代马来腈为原料(反应式20)
Figure SMS_22
氩气保护下，在一个250mL的反应瓶中将2-苄基-2-吗啉代马来腈(12.065g，50mmol)，氟化铜(1.015g，10mmol)，依次加入到搅拌的二甲基亚砜(100mL)中，在150℃下回流反应 24小时完成反应，在反应结束后，加水淬灭反应，用乙酸乙酯萃取水相三次，合并所有机相，以饱和食盐水洗涤，并使用无水Na2SO4干燥。有机相经浓缩后，经柱层析得白色固体(1.887 g，92％yield)。
产物检测数据如下：
1H NMR(400MHz,Chloroform-d)δ7.36–7.27(m,2H),7.25–7.18(m,3H),3.71(s,2H),3.61(s,4H),3.47–3.38(m,4H).13C NMR(100MHz,Chloroform-d)δ169.46,134.67,128.65,128.39, 126.75,66.62,66.29,46.36,41.99,40.67.HRMS(ESI)calcd forC12H15NO2[M+H]+:206.1176, found 206.1175.熔程：62.4–63.7℃。

Claims (3)

1.一种叔酰胺类化合物的合成方法，其特征为含季碳中心的α-氨基丙二腈和催化剂，依次加入到有机溶剂中，加热条件下得到叔酰胺，反应式如下：
Figure FDA0004236658230000011
其中：
(1)R1、R2不在同一个环系上时，R1选自甲基、正丁基、苄基，R2选自甲基、取代苯基、取代苄基；
(2)R1、R2在同一环系上时，R1、R2连同N原子选自哌啶基、吗啉基、二氢吲哚基、1,2,3,4-四氢异喹啉基、1,2,3,4-四氢喹啉基；
(3)R选自甲基，正丙基，正戊基，苯基，取代苯基，呋喃基，乙氧羰基；
(4)所用催化剂选自氟化铜、醋酸铜、二甲醇铜、溴化铜、氯化铜、硫酸铜、磷酸铜、三氟甲烷磺酸铜、三氟甲烷磺酸银、三氟甲烷磺酸锌、三氟甲烷磺酸铝；
(5)所用的溶剂选自二甲基亚砜、乙腈、二氯甲烷、四氢呋喃、乙醚、甲醇、1,4-二氧六环、丙酮、氯仿、1,2-二氯乙烷、甲苯、正庚烷、N,N-二甲基甲酰胺的一种或几种；
(6)所用加热的温度选自40℃-200℃，维持时间2-48小时；
(7)反应中各物质的摩尔量比选自：含季碳中心的α-氨基丙二腈：催化剂＝1:0.01-1。
2.根据权利要求1所述的叔酰胺类化合物的合成方法，其特征在于，所述(6)中加热的温度为100℃，维持时间为10小时。
3.根据权利要求1所述的叔酰胺类化合物的合成方法，其特征在于，所述(7)中各物质的摩尔量比为季碳中心的α-氨基丙二腈：催化剂＝1:0.05。
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