CN109232316B - 一类α-三级腈结构β-二羰基化合物的合成方法 - Google Patents

一类α-三级腈结构β-二羰基化合物的合成方法 Download PDF

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CN109232316B
CN109232316B CN201811345616.7A CN201811345616A CN109232316B CN 109232316 B CN109232316 B CN 109232316B CN 201811345616 A CN201811345616 A CN 201811345616A CN 109232316 B CN109232316 B CN 109232316B
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梁德强
杨锐蓉
王宝玲
李维莉
马银海
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Abstract

本发明提供一类α‑三级腈结构β‑二羰基化合物的合成方法，以偶氮二异丁腈（AIBN）与β‑酮酯的碳‑碳偶联反应，在廉价水合硝酸铜的催化下生成由其它方法无法合成的含α‑三级腈结构的β‑二羰基化合物，并一步构建连续的三级和四级碳原子中心。本发明方法官能团耐受性好，并避免了过量强碱的使用和氰烷基化试剂的预先溴化，同时反应条件温和、操作简单，适合工业化推广。

Description

一类α-三级腈结构β-二羰基化合物的合成方法
技术领域
本发明属于有机合成技术领域，具体涉及一类α-三级腈结构β-二羰基化合物的合成方法。
背景技术
腈是分子中带有氰基(-CN)的化合物。氰基结构中氮原子和碳原子是通过碳氮三键连接，可以通过化学反应转换成其他的官能团化合物，比如腈经过加氢还原得到酰胺类化合物，进一步还原可以得到伯胺类化合物。腈也可以通过水解得到羧酸类化合物，再经过还原得到醛类化合物或醇类化合物。由于氰基结构的特殊性能，使得腈类化合物广泛地应用于材料科学、制药工业、农用化学品等领域。在腈类化合物中，带有α-氰烷基结构的1,3-二羰基化合物是一类多功能合成子，同时还被广泛应用于配位化学和主客体超分子自组装，具有广泛的应用前景。传统合成α-氰烷基-β-二羰基化合物的方法是通过1,3-二羰基化合物与2-溴乙腈进行亲核取代反应制备得到；其反应路线如下：
Figure BDA0001863666850000011
该方法需要过量的强碱并使用成本高昂的预先溴代乙腈作为氰烷基化试剂。2016年，Kim和Wu报道了一种通过β-二羰基化合物和乙腈交叉脱氢偶联反应制得α-氰烷基-β-二羰基化合物的方法；其反应路线如下：
Figure BDA0001863666850000012
该方法需要较高的反应温度和较长的反应时间，以及使用过量的危险品(过氧化物)作为自由基引发剂。由于化合物结构的特殊性，以上方法都仅限于合成一级腈类化合物，无法合成含有α-二级或三级腈结构的β-二羰基化合物。
发明内容
为了解决现有技术中的问题，本发明的目的在于提供一类α-三级腈结构β-二羰基化合物的合成方法，该方法反应条件温和、操作简单、官能团耐受性好，并避免了过量强碱的使用和氰烷基化试剂的预先溴化。
本发明的目的是这样实现的：
一类α-三级腈结构β-二羰基化合物(式II化合物)的合成方法，由式I化合物与式III化合物在催化剂作用下反应制得，其特征在于，反应路线如下：
Figure BDA0001863666850000021
其中：
R1是噻吩、吡啶或苯基，所述苯基被R1a、R1b和R1c取代；
R2是C1-6烷基、-OH、-O-C1-6烷基；
R3是C1-6烷基；
R1a、R1b和R1c独立的选自：氢、卤素、羟基、C1-6烷基、-O-C1-6烷基。
本文所用的术语“卤素”是指氟、氯、溴或碘，优选为氟、氯或溴。
本文所用的术语“C1-6烷基”是指具有1-6个碳原子的饱和的直链或支链烃基，例如甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基等，优选甲基、乙基、丙基、异丙基、叔丁基或异丁基。
本发明的一个实施方案包括其中R1是苯基的化合物(如下式IV)，所述苯基是未取代的或被一个或多个下列基团取代：甲基、卤素、-OCH3或-OH。
Figure BDA0001863666850000022
本发明的一个实施方案包括其中R2和/或R3各自独立地为C1-6烷基，例如甲基、乙基、丙基、异丙基、叔丁基或叔丁基。
本发明的一个实施方案包括其中R2各自独立地为-O-C1-6烷基，例如甲氧基、乙氧基。
本发明的一个实施方案包括其中反应所使用的催化剂为选自CuI、CuBr、CuCl、Cu(OAc)2或Cu(NO3)2·3H2O；优选Cu(NO3)2·3H2O。
本发明的一个实施方案包括其中所使用的溶剂选自1,2-二氯乙烷(DCE)、甲苯、四氢呋喃、二甲亚砜(DMSO)、乙腈、硝基甲烷、乙醇；优选1,2-二氯乙烷(DCE)。
本发明的一个实施方案包括其中反应温度为50-110℃；优选80℃。
本发明式II化合物选自2a-2k化合物，具体如下表1。
表1 2a-2k化合物
Figure BDA0001863666850000031
Figure BDA0001863666850000041
Figure BDA0001863666850000051
有益效果
本发明提供一类α-三级腈结构β-二羰基化合物的合成方法，以偶氮二异丁腈(AIBN)与β-酮酯的碳-碳偶联反应，在廉价水合硝酸铜的催化下生成由其它方法无法合成的含α-三级腈结构的β-二羰基化合物，并一步构建连续的三级和四级碳原子中心。本发明方法官能团耐受性好，并避免了过量强碱的使用和氰烷基化试剂的预先溴化，同时反应条件温和、操作简单，适合工业化推广。
具体实施方式
为了使本发明的目的和技术方案更加清楚，下面对本发明的优选实施例进行详细的描述。要说明的是：以下实施例只用于对本发明进行进一步的说明，而不能理解为对本发明保护范围的限制。本领域的技术人员根据本发明的上述内容做出的一些非本质的改进和调整均属于本发明的保护范围。本发明所用原料与试剂均为市售产品。
实施例1
β-酮酯氰异丙基化反应合成α-三级腈-β-二羰基化合物(以2a的合成为例)，反应路线如下：
Figure BDA0001863666850000061
操作步骤：装有磁力搅拌子的35mL耐压管中加入苯甲酰乙酸乙酯1a(38mg，0.2mol)，AIBN(99mg，0.6mmol)和Cu(NO3)2·3H2O(4.8mg，0.02mmol)，最后加入DCE(2.0mL)。该混合物在80℃反应12h后，用饱和Na2S2O3水溶液(1.0mL)和水(10.0mL)淬灭反应，然后用二氯甲烷(10mL×3)萃取三次。蒸干有机溶剂得到的残留物用硅胶进行柱层析(石油醚/乙酸乙酯＝8:1，v/v)，得到浅黄色油状物2a(27mg，52％产率)。
参照上述实施例1，考察催化剂、溶剂、温度等条件对反应的影响，具体情况见下表2。
表2反应条件考察a
Figure BDA0001863666850000062
Figure BDA0001863666850000071
a反应条件：1a(0.2mmol)，溶剂(2.0mL)，封管进行，12h。
bAIBN均分为2份，间隔6小时分2次加入。
反应条件一开始在80℃的1,2-二氯乙烷(DCE)溶剂中使用苯甲酰乙酸乙酯1a作为模型底物与3当量的AIBN反应(表2)。实验结果表明，在10mol％的某些铜盐的催化下，目标碳-碳偶联反应可以进行，目标三级腈产物2a的产率为16-52％。这些有效的铜盐包括CuI(序号1)，CuBr(序号2)，CuCl(序号3)，Cu(OAc)2(序号4)和Cu(NO3)2·3H2O(序号6)。Cu(NO3)2·3H2O的催化效果最好，而CuSO4·5H2O不能催化该反应进行(序号5)。当Fe(NO3)3·9H2O(序号7)或AgNO3(序号8)被用作催化剂时，反应进行地非常缓慢。对照实验表明，不加入铜催化剂时，没有反应发生(序号9)。对溶剂进行了考察，该反应在甲苯(序号10)、四氢呋喃(THF，序号13)或二甲亚砜(DMSO，序号14)中进行时也变得非常迟缓，而乙腈(序号11)、硝基甲烷(序号12)和乙醇(序号15)中的反应产率较低。升温(序号16)或降温(序号17)，或降低AIBN(序号19)或铜催化剂(序号21)的用量，都会导致产率降低。而增加AIBN用量(一次性加入或分批加入，序号18)或铜催化剂用量(序号20)也都不能获得有益效果。
参照上述实施例1，考察底物对本发明反应的影响，具体情况见下表3。
表3底物对本发明反应的影响
Figure BDA0001863666850000081
反应条件：1(0.2mmol)，偶氮化合物(0.6mmol)，Cu(NO3)2·3H2O(0.02mmol)，DCE(2.0mL)，封管进行，80℃，12h。
研究该氰烷基化反应的底物适用范围，发明人使用该反应从活泼亚甲基化合物1和偶氮试剂出发合成了大量三级腈(表3)。芳酰基苯环对位或间位带有供电子或吸电子取代基的芳酰基乙酸乙酯都顺利地和AIBN反应生成对应α-氰异丙基-β-酮酯2b,c，产率36-65％。该氰异丙基化反应对位阻敏感，因为使用芳基邻位有取代基的底物时，三级腈产物2d1-3的产率较低。2,4,5-三氟苯甲酰基和2,3,4,5-四氟苯甲酰基底物的反应中，也观察到了类似的位阻效应。值得注意的是，β-杂芳酰基三级腈2g,h也可以通过本反应分别由对应的2-噻吩酰基乙酸乙酯和皮考啉酰基乙酸乙酯合成得到。苯甲酰甲酯、异丙酯和叔丁酯也都能参与本反应，并以31-55％的产率生成对应三级腈2i,j。酰基和酯基的组合至关重要。N-甲基苯甲酰乙酰苯胺和AIBN的反应得到复杂的混合物，我们无法从其中分离到任何纯净产物。偶氮二异戊腈(AMBN)和偶氮二异庚腈(AMVN)也是可用的氰烷基化试剂，它们与苯甲酰乙酸乙酯1a的反应以中等产率生成对应三级腈2k1,2k2。
目标产物的核磁数据
2a,2-苯甲酰-3-氰基-3-甲基丁酸乙酯，淡黄色油状物.1H NMR(400MHz,CDCl3)δ＝1.17(t,J＝7.1Hz,3H),1.55(s,3H),1.58(s,3H),4.13-4.25(m,2H),4.35(s,1H),7.50(dd,J＝7.6,7.9Hz,2H),7.62(dd,J＝7.4,7.4Hz,1H),7.98-8.00(m,2H)；13C NMR(100MHz,CDCl3)δ＝191.37,166.38,136.18,134.09,128.94,128.53,123.09,62.32,60.37,32.87,26.05,26.03,13.86；HRMS(ESI-TOF)Calcd for C15H18NO3 +([M+H]+)260.1281.Found260.1286.
2b1,3-氰基-3-甲基-2-(4-甲基苯甲酰)丁酸乙酯,淡黄色油状物.1H NMR(400MHz,CDCl3)δ＝1.18(t,J＝7.1Hz,3H),1.54(s,3H),1.57(s,3H),2.43(s,3H),4.13-4.25(m,2H),4.32(s,1H),7.29(d,J＝8.0Hz,2H),7.90(d,J＝8.3Hz,2H)；13C NMR(100MHz,CDCl3)δ＝190.91,166.53,145.25,133.68,129.64,128.72,123.20,62.26,60.19,32.86,26.11,26.00,21.75,13.91；HRMS(ESI-TOF)Calcd for C16H20NO3 +([M+H]+)274.1438.Found274.1450.
2b2,3-氰基-2-(4-甲氧基苯甲酰)-3-甲基丁酸乙酯,白色固体:mp 86-87℃.1HNMR(400MHz,CDCl3)δ＝1.19(t,J＝7.1Hz,3H),1.53(s,3H),1.57(s,3H),3.89(s,3H),4.13-4.26(m,2H),4.30(s,1H),6.96(ddd,J＝2.9,2.0,9.0Hz,2H),7.99(ddd,J＝2.9,2.0,9.0Hz,2H)；13C NMR(100MHz,CDCl3)δ＝189.69,166.63,164.33,131.04,129.12,123.27,114.13,62.18,60.00,55.62,32.87,26.15,25.99,13.92；HRMS(ESI-TOF)Calcd forC16H20NO4 +([M+H]+)290.1387.Found 290.1385.
2b3,2-(4-溴苯甲酰)-3-氰基-3-甲基丁酸乙酯,淡黄色油状物.1H NMR(400MHz,CDCl3)δ＝1.19(t,J＝7.1Hz,3H),1.54(s,3H),1.58(s,3H),4.13-4.26(m,2H),4.27(s,1H),7.65(ddd,J＝2.3,1.9,8.7Hz,2H),7.86(ddd,J＝2.3,1.9,8.7Hz,2H)；13C NMR(100MHz,CDCl3)δ＝190.41,166.13,134.79,132.32,129.99,129.60,122.94,62.51,60.43,32.82,26.06,25.94,13.91；HRMS(ESI-TOF)Calcd for C15H17BrNO3 +([M+H]+)338.0386.Found338.0376.
2b4,2-(4-氯苯甲酰)-3-氰基-3-甲基丁酸乙酯,淡黄色油状物.1H NMR(400MHz,CDCl3)δ＝1.19(t,J＝7.1Hz,3H),1.55(s,3H),1.58(s,3H),4.13-4.26(m,2H),4.28(s,1H),7.48(ddd,J＝2.4,2.0,8.7Hz,2H),7.94(ddd,J＝2.4,2.0,8.7Hz,2H)；13C NMR(100MHz,CDCl3)δ＝190.18,166.16,140.80,134.38,129.94,129.32,122.96,62.50,60.46,32.83,26.07,25.94,13.91；HRMS(ESI-TOF)Calcd for C15H17ClNO3 +([M+H]+)294.0891.Found294.0894.
2b5,3-氰基-2-(4-氟苯甲酰)-3-甲基丁酸乙酯,白色固体:mp 145-146℃.1H NMR(400MHz,CDCl3)δ＝1.19(t,J＝7.1Hz,3H),1.55(s,3H),1.58(s,3H),4.14-4.26(m,2H),4.28(s,1H),7.18(dddd,J＝1.9,1.9,8.6,8.5Hz,2H),8.01-8.06(m,2H)；13C NMR(100MHz,CDCl3)δ＝189.73,166.30(d,1J(C–F)＝255.5Hz),166.25,132.52(d,4J(C–F)＝3.0Hz),131.34(d,3J(C–F)＝9.5Hz),123.00,116.20(d,2J(C–F)＝21.9Hz),62.45,60.47,32.84,26.08,25.97,13.90；19F NMR(376MHz,CDCl3)δ＝-102.90to-102.97(m,1F)；HRMS(ESI-TOF)Calcdfor C15H17FNO3 +([M+H]+)278.1187.Found 278.1201.
2c1,3-氰基-3-甲基-2-(3-甲基苯甲酰)丁酸乙酯,淡黄色油状物.1H NMR(400MHz,CDCl3)δ＝1.18(t,J＝7.1Hz,3H),1.54(s,3H),1.57(s,3H),2.42(s,3H),4.13-4.26(m,2H),4.35(s,1H),7.38(dd,J＝7.6,7.5Hz,1H),7.43(d,J＝7.5Hz,1H),7.78(d,J＝7.6Hz,1H),7.80(s,1H)；13C NMR(100MHz,CDCl3)δ＝191.58,166.44,138.87,136.24,134.89,129.04,128.78,125.76,123.13,62.24,60.26,32.89,26.07,25.98,21.36,13.88；HRMS(ESI-TOF)Calcd for C16H20NO3 +([M+H]+)274.1438.Found 274.1440.
2c2,2-(3-溴苯甲酰)-3-氰基-3-甲基丁酸乙酯,淡黄色油状物.1H NMR(400MHz,CDCl3)δ＝1.20(t,J＝7.1Hz,3H),1.55(s,3H),1.58(s,3H),4.14-4.26(m,2H),4.28(s,1H),7.39(dd,J＝7.9,7.9Hz,1H),7.73-7.76(m,1H),7.89-7.92(m,1H),8.12(dd,J＝1.8,1.8Hz,1H)；13C NMR(100MHz,CDCl3)δ＝190.14,165.99,137.82,136.94,131.53,130.50,126.99,123.31,122.86,62.52,60.44,32.88,26.02,25.88,13.89；HRMS(ESI-TOF)Calcdfor C15H17BrNO3 +([M+H]+)338.0386.Found 338.0390.
2c3,2-(3-氯苯甲酰)-3-氰基-3-甲基丁酸乙酯,淡黄色油状物.1H NMR(400MHz,CDCl3)δ＝1.20(t,J＝7.1Hz,3H),1.55(s,3H),1.58(s,3H),4.14-4.28(m,2H),4.29(s,1H),7.45(dd,J＝7.9,7.9Hz,1H),7.58-7.61(m,1H),7.85-7.87(m,1H),7.97(dd,J＝1.8,1.8Hz,1H)；13C NMR(100MHz,CDCl3)δ＝190.25,166.00,137.64,135.39,134.02,130.28,128.58,126.55,122.86,62.51,60.48,32.88,26.02,25.88,13.88；HRMS(ESI-TOF)Calcdfor C15H17ClNO3 +([M+H]+)294.0891.Found 294.0887.
2d1,3-氰基-3-甲基-2-(2-甲基苯甲酰)丁酸乙酯,淡黄色油状物.1H NMR(400MHz,CDCl3)δ＝1.14(t,J＝7.1Hz,3H),1.57(s,6H),2.53(s,3H),4.09-4.21(m,2H),4.27(s,1H),7.26-7.30(m,2H),7.42(ddd,J＝1.3,7.6,7.5Hz,1H),7.63-7.66(m,1H)；13CNMR(100MHz,CDCl3)δ＝194.68,166.38,139.38,136.73,132.32,132.26,128.37,125.78,123.12,62.40,62.13,32.88,26.15,25.81,21.12,13.83；HRMS(ESI-TOF)Calcd forC16H20NO3 +([M+H]+)274.1438.Found 274.1434.
2d2,3-氰基-2-(2-羟基苯甲酰)-3-甲基丁酸乙酯,淡黄色油状物.1H NMR(400MHz,CDCl3)δ＝1.23(t,J＝7.1Hz,3H),1.55(s,3H),1.60(s,3H),4.17-4.31(m,2H),4.34(s,1H),6.94(ddd,J＝1.1,7.3,7.3Hz,1H),7.04(dd,J＝1.0,8.4Hz,1H),7.54(ddd,J＝1.5,7.3,7.3Hz,1H),7.76(dd,J＝1.5,8.2Hz,1H),11.82(s,1H)；13C NMR(100MHz,CDCl3)δ＝196.88,165.93,163.28,137.62,129.69,122.91,119.44,119.19,119.08,62.68,59.99,32.84,26.28,26.17,13.93；HRMS(ESI-TOF)Calcd for C15H18NO4 +([M+H]+)276.1230.Found 276.1231.
2d3,2-(2-氯苯甲酰)-3-氰基-3-甲基丁酸乙酯,淡黄色油状物.1H NMR(400MHz,CDCl3)δ＝1.17(t,J＝7.1Hz,3H),1.58(s,3H),1.62(s,3H),4.10-4.22(m,2H),4.44(s,1H),7.33-7.37(m,1H),7.43-7.44(m,2H),7.49(ddd,J＝1.1,1.0,7.5Hz,1H)；13C NMR(100MHz,CDCl3)δ＝194.22,165.75,137.88,132.56,131.03,130.74,129.72,127.11,122.86,63.62,62.30,32.93,25.86,25.69,13.86；HRMS(ESI-TOF)Calcd for C15H17ClNO3 +([M+H]+)294.0891.Found 294.0891.
2e,3-氰基-3-甲基-2-(2,4,5-三氟苯甲酰)丁酸乙酯,淡黄色油状物.1H NMR(400MHz,CDCl3)δ＝1.21(t,J＝7.1Hz,3H),1.59(s,3H),1.60(s,3H),4.21(q,J＝7.1Hz,2H),4.31(s,1H),7.02-7.08(m,1H),7.76-7.82(m,1H)；13C NMR(100MHz,CDCl3)δ＝187.74(d,3J(C–F)＝4.5Hz),165.64,157.15(ddd,J(C–F)＝251.7,10.0,2.5Hz),153.86(ddd,J(C–F)＝260.3,14.8,13.0Hz),147.37(ddd,J(C–F)＝247.7,12.7,3.2Hz),123.01,121.47(ddd,J(C–F)＝14.4,4.0,4.0Hz),119.24(ddd,J(C–F)＝20.4,3.8,2.5Hz),106.91(dd,J(C–F)＝30.18,21.2Hz),63.42(d,4J(C–F)＝7.9Hz),62.40,33.08,26.26,25.48,13.92；19F NMR(376MHz,CDCl3)δ＝-110.03to-110.14(m,1F),-122.53to-122.66(m,1F),-139.52to-139.66(m,1F)；HRMS(ESI-TOF)Calcd for C15H15F3NO3 +([M+H]+)314.0999.Found 314.1005.
2f,3-氰基-3-甲基-2-(2,3,4,5-四氟苯甲酰)丁酸乙酯,淡黄色油状物.1H NMR(400MHz,CDCl3)δ＝1.23(t,J＝7.1Hz,3H),1.60(s,3H),1.61(s,3H),4.20-4.27(m,2H),4.28(s,1H),7.57-7.64(m,1H)；13C NMR(100MHz,CDCl3)δ＝186.95-186.89(m),165.35,148.72-148.52(m),146.25-145.98(m),144.18(dddd,J(C–F)＝262.4,12.5,12.3,3.8Hz),140.93(dddd,J(C–F)＝255.3,18.0,12.5,3.2Hz),122.80,120.67-120.88(m),112.13(ddd,J(C–F)＝20.5,2.9,2.6Hz),63.60(d,4J(C–F)＝7.1Hz),62.61,33.11,26.27,25.36,13.92；19FNMR(376MHz,CDCl3)δ＝-135.40to-135.53(m,1F),-135.68to-135.81(m,1F),-144.94to-145.09(m,1F),-152.61(dd,J＝21.0,19.8,1F)；HRMS(ESI-TOF)Calcd for C15H14F4NO3 +([M+H]+)332.0904.Found 332.0915.
2g,3-氰基-3-甲基-2-(噻吩-2-羰基)丁酸乙酯,白色半固体.1H NMR(400MHz,CDCl3)δ＝1.23(t,J＝7.1Hz,3H),1.56(s,3H),1.58(s,3H),4.17-4.29(m,3H),7.18(dd,J＝4.9,3.9Hz,1H),7.76(dd,J＝1.0,4.9Hz,1H),7.81(dd,J＝1.0,3.9Hz,1H)；13C NMR(100MHz,CDCl3)δ＝183.88,166.16,143.43,135.87,133.32,128.54,122.94,62.42,61.26,32.93,26.12,25.73,13.93；HRMS(ESI-TOF)Calcd for C13H16NO3S+([M+H]+)266.0845.Found 266.0842.
2h,3-氰基-3-甲基-2-甲基吡啶酰丁酸乙酯,淡黄色油状物.1H NMR(400MHz,CDCl3)δ＝1.15(t,J＝7.1Hz,3H),1.57(s,3H),1.61(s,3H),4.11-4.23(m,2H),5.04(s,1H),7.53(ddd,J＝1.2,4.8,7.6Hz,1H),7.90(ddd,J＝1.7,7.8,7.8Hz,1H),8.13(ddd,J＝1.0,0.9,4.7Hz,1H),8.67(ddd,J＝0.9,1.6,4.7Hz,1H)；13C NMR(100MHz,CDCl3)δ＝193.28,166.79,152.06,148.88,137.31,127.87,123.42,122.58,61.80,58.04,32.47,26.12,25.65,13.90；HRMS(ESI-TOF)Calcd for C14H17N2O3 +([M+H]+)261.1234.Found261.1223.
2i1,2-苯甲酰-3-氰基-3-甲基丁酸甲酯,白色半固体.1H NMR(400MHz,CDCl3)δ＝1.54(s,3H),1.58(s,3H),3.73(s,3H),4.41(s,1H),7.49-7.53(m,2H),7.64(dddd,J＝1.2,1.2,6.9,6.8Hz,1H),7.98-8.01(m,2H)；13C NMR(100MHz,CDCl3)δ＝191.43,166.90,136.08,134.23,129.03,128.59,123.07,59.85,53.09,32.97,26.10,25.92；HRMS(ESI-TOF)Calcd for C14H16NO3 +([M+H]+)246.1125.Found 246.1129.
2i2,3-氰基-2-(4-氟苯甲酰)-3-甲基丁酸甲酯,白色固体:mp 133-134℃.1H NMR(400MHz,CDCl3)δ＝1.54(s,3H),1.58(s,3H),3.74(s,3H),4.34(s,1H),7.15-7.21(m,2H),8.01-8.06(m,2H)；13C NMR(100MHz,CDCl3)δ＝189.73,166.75,166.37(d,1J(C–F)＝255.8Hz),132.50(d,4J(C–F)＝3.0Hz),131.38(d,3J(C–F)＝9.6Hz),122.94,116.27(d,2J(C–F)＝22.0Hz),60.02,53.16,32.96,25.98；19F NMR(376MHz,CDCl3)δ＝-102.73to-102.81(m,1F)；HRMS(ESI-TOF)Calcd for C14H15FNO3 +([M+H]+)264.1030.Found 264.1040.
2j1,2-苯甲酰-3-氰基-3-甲基丁酸异丙酯,淡黄色油状物.1H NMR(400MHz,CDCl3)δ＝1.09(d,J＝6.2Hz,3H),1.20(d,J＝6.3Hz,3H),1.56(s,3H),1.58(s,3H),4.28(s,1H),4.99-5.08(m,1H),7.47-7.52(m,2H),7.62(dddd,J＝1.2,1.2,7.4,6.8Hz,1H),7.97-8.00(m,2H)；13C NMR(100MHz,CDCl3)δ＝191.33,165.89,136.17,134.01,128.88,128.46,123.13,70.33,60.82,32.74,26.15,25.99,21.38,21.32；HRMS(ESI-TOF)Calcd forC16H20NO3 +([M+H]+)274.1438.Found 274.1439.
2j2,2-苯甲酰-3-氰基-3-甲基丁酸叔丁酯,淡黄色油状物.1H NMR(400MHz,CDCl3)δ＝1.35(s,9H),1.55(s,3H),1.58(s,3H),4.17(s,1H),7.47-7.52(m,2H),7.61(dddd,J＝1.2,1.2,6.8,6.8Hz,1H),7.98-8.00(m,2H)；13C NMR(100MHz,CDCl3)δ＝191.52,165.45,136.30,133.86,128.82,128.42,123.26,83.77,62.03,32.64,27.58,26.17,26.07；HRMS(ESI-TOF)Calcd for C17H22NO3 +([M+H]+)288.1594.Found 288.1597.
2k1,2-苯甲酰-3-氰基-3-甲基戊酸乙酯,20:21非对映异构体的混合物,淡黄色油状物.1H NMR(400MHz,CDCl3)δ＝1.10-1.19(m,6H major and 6H minor),1.52(s,3Hminor),1.55(s,3H major),1.62-1.72(m,1H major and 1H minor),1.89-2.00(m,1Hmajor and 1H minor),4.14-4.22(m,2H major and 2H minor),4.45(s,1H major),4.47(s,1H minor),7.48-7.52(m,2H major and 2H minor),7.60-7.65(m,1H major and 1Hminor),7.98-8.00(m,2H major and 2H minor)；13C NMR(100MHz,CDCl3)δ＝191.57(minor),191.50(major),166.46(minor),166.33(major),136.36(minor),136.21(major),134.07(minor),134.05(major),128.95(minor),128.92(major),128.48(minor),128.47(major),122.15(minor),122.09(major),62.25(minor),62.23(major),58.98(major and minor),37.99(minor),37.75(major),31.17(major and minor),22.18(major),21.85(minor),13.85(major and minor),9.03(major),8.92(minor)；HRMS(ESI-TOF)Calcd for C16H20NO3 +([M+H]+)274.1438.Found 274.1439.
2k2,2-苯甲酰-3-氰基-3,5-二甲基己酸乙酯,2:5非对映异构体的混合物,淡黄色油状物.1H NMR(400MHz,CDCl3)δ＝0.99-1.21(m,9H major and 9H minor),1.49-1.55(m,1H major and 1H minor),1.58(s,3H minor),1.59(s,3H major),1.81-1.99(m,2H majorand 2H minor),4.12-4.24(m,2H major and 2H minor),4.43(s,1H major),4.45(s,1Hminor),7.50(dd,J＝7.7,7.8Hz,2H major and 2H minor),7.62(dd,J＝7.5,7.3Hz,1Hmajor and 1H minor),7.97-8.00(m,2H major and 2H minor)；13C NMR(100MHz,CDCl3)δ＝191.58(minor),191.45(major),166.45(minor),166.34(major),136.42(minor),136.25(major),134.06(major and minor),128.96(minor),128.94(major),128.51(major),128.47(minor),122.71(minor),122.65(major),62.31(minor),62.28(major),59.90(major),59.56(minor),46.18(major),45.96(minor),36.72(minor),36.30(major),25.30(major),25.26(minor),24.43(minor),24.42(major),23.79(minor),23.71(major),23.38(major),23.07(minor),13.91(minor),13.88(major)；HRMS(ESI-TOF)Calcd for C18H24NO3 +([M+H]+)302.1751.Found 302.1752.

Claims (12)

1.一类α-三级腈结构β-二羰基化合物的合成方法，由式I化合物与式III化合物在催化剂作用下反应制得式II化合物，其特征在于，反应路线如下：
Figure FDA0002812352790000011
其中：
R1是噻吩、吡啶或苯基，所述苯基被R1a、R1b和R1c取代；
R2是C1-6烷基、-OH、-O-C1-6烷基；
R3是C1-6烷基；
R1a、R1b和R1c独立的选自：氢、卤素、羟基、C1-6烷基、或-O-C1-6烷基；所述催化剂为Cu(NO3)2·3H2O。
2.如权利要求1所述的方法，其特征在于：所述“C1-6烷基”选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基或异己基。
3.如权利要求1所述的方法，其特征在于：所述“C1-6烷基”选自甲基、乙基、丙基、异丙基、丁基或异丁基。
4.如权利要求1-3任一项所述的方法，其特征在于：所述“卤素”是指氟、氯、溴或碘。
5.如权利要求1-3任一项所述的方法，其特征在于：所述R1是苯基的化合物的苯基是未取代的或被一个或多个下列基团取代：甲基、卤素、-OCH3或-OH。
6.如权利要求1所述的方法，其特征在于：其中R2和/或R3各自独立地为C1-6烷基。
7.如权利要求1所述的方法，其特征在于：其中R2和/或R3各自独立地为甲基、乙基、丙基、异丙基、丁基或叔丁基。
8.如权利要求1-3任一项所述的方法，其特征在于：其中R2各自独立地为-O-C1-6烷基。
9.如权利要求1-3任一项所述的方法，其特征在于：其中R2各自独立地为甲氧基或乙氧基。
10.如权利要求1所述的方法，其特征在于：反应所使用的溶剂选自1,2-二氯乙烷(DCE)、甲苯、四氢呋喃、二甲亚砜(DMSO)、乙腈、硝基甲烷、乙醇。
11.如权利要求1所述的方法，其特征在于：反应温度为50-110℃。
12.如权利要求1所述的方法，其特征在于，所述式II化合物选自：
2-苯甲酰-3-氰基-3-甲基丁酸乙酯；
3-氰基-3-甲基-2-(4-甲基苯甲酰)丁酸乙酯；
3-氰基-2-(4-甲氧基苯甲酰)-3-甲基丁酸乙酯；
2-(4-溴苯甲酰)-3-氰基-3-甲基丁酸乙酯；
2-(4-氯苯甲酰)-3-氰基-3-甲基丁酸乙酯；
3-氰基-2-(4-氟苯甲酰)-3-甲基丁酸乙酯；
3-氰基-3-甲基-2-(3-甲基苯甲酰)丁酸乙酯；
2-(3-溴苯甲酰)-3-氰基-3-甲基丁酸乙酯；
2-(3-氯苯甲酰)-3-氰基-3-甲基丁酸乙酯；
3-氰基-3-甲基-2-(2-甲基苯甲酰)丁酸乙酯；
3-氰基-2-(2-羟基苯甲酰)-3-甲基丁酸乙酯；
2-(2-氯苯甲酰)-3-氰基-3-甲基丁酸乙酯；
3-氰基-3-甲基-2-(2,4,5-三氟苯甲酰)丁酸乙酯；
3-氰基-3-甲基-2-(2,3,4,5-四氟苯甲酰)丁酸乙酯；
3-氰基-3-甲基-2-(噻吩-2-羰基)丁酸乙酯；
3-氰基-3-甲基-2-甲基吡啶酰丁酸乙酯；
2-苯甲酰-3-氰基-3-甲基丁酸甲酯；
3-氰基-2-(4-氟苯甲酰)-3-甲基丁酸甲酯；
2-苯甲酰-3-氰基-3-甲基丁酸异丙酯；
2-苯甲酰-3-氰基-3-甲基丁酸叔丁酯；
2-苯甲酰-3-氰基-3-甲基戊酸乙酯；
2-苯甲酰-3-氰基-3,5-二甲基己酸乙酯。
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Metal Bridging for Directing and Accelerating Electron Transfer as Exemplified by Harnessing the Reactivity of AIBN;Yinjun Xie等;《Angew.Chem.Int.Ed.》;20151231(第54期);第5900-5904页 *

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