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铜催化的α-氨基丙二腈的脱氰氧代反应:一种合成叔酰胺的新方法

梁欢a, 苟阿龙a, 高珠鹏a, 雷林生a, 王博文a, 余兰a, 徐学涛b, 王少华a   

  1. a 兰州大学药学院 兰州 730000;
    b 五邑大学生物科技与大健康学院 江门 529020
  • 发布日期:2020-09-09
  • 通讯作者: 余兰, 王少华 E-mail:yul@lzu.edu.cn;wangshh@lzu.edu.cn
  • 基金资助:
    国家自然科学基金(No.21472077,21772071),广东省教育厅项目(No.2017KTSCX185,2017KSYS010,2016KCXTD005,2019KZDXM035)资助项目.中国发明专利申请号(202010648789.7)

A Direct Synthesis of Tertiary Amides via a Copper-Catalyzed Decyanation Reaction of N,N-Disubstituted 2-Aminomalononitriles

Liang Huana, Gou A-Longa, Gao Zhu-Penga, Lei Lin-Shenga, Wang Bo-Wena, Yu Lana, Xu Xue-Taob, Wang Shao-Huaa   

  1. a School of Pharmacy, Lanzhou University, Lanzhou 730000;
    b School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020
  • Published:2020-09-09
  • Supported by:
    Project supported by the Natural Science Foundation of China (No. 21472077, 21772071) and Department of Education of Guangdong Province (No. 2017KTSCX185, 2017KSYS010, 2016KCXTD005). Chinese patent pending (No. 202010648789.7)

新反应、新试剂的发展是有机合成化学的重要研究内容,基于前期在涉及α-氨基丙二腈合成方法学方面的工作基础,我们发展了一例铜催化的α-氨基丙二腈的脱氰氧代反应,为叔酰胺化合物的合成提供了新方法.此外,该工作首次完成了形式上的甲酰胺碳原子的极性反转,实现了将α-氨基丙二腈作为氨基甲酰负离子替代物的反应新模式,进一步丰富了有机合成化学多功能合成中间体的内容.本策略通过将甲酰胺转化为α-氨基丙二腈后,借助其亲核属性来合成α-氨基丙二腈底物,而后将底物重新转化为酰胺,从而实现形式上的氨基甲酰负离子的亲核加成(取代)反应,为酰胺化合物的合成提供了新的思路.该策略具有反应条件简单,底物适用性广及适合克级规模制备等特点.

关键词: α-氨基丙二腈, 甲酰胺, 氨基甲酰负离子, 铜催化

The development of new synthetic methodology and reagent is always a hot topic in organic synthesis community. Among the strategies used, chemical property investigation of synthetic intermediates with multifunctional groups represents a direct and efficient way. In this paper, as a systematic continuation of α-aminomalononitrile based synthetic application studies, α-aminomalononitrile has been developed for the first time as a surrogate for carbamoyl anions and applied to the synthesis of tertiary amides via a copper-catalyzed decyanation reaction. This strategy features simple reaction conditions, scalability, and wide substrate scope. This work not only further enriches the reaction model of aminonitrile compounds, but also provides an alternative synthetic strategy for the synthesis of substituted amides from simple formamides. In this process, the substrates could be readily synthesized through the nucleophilic addition or substitution reaction of α-aminomalononitriles, and they would be converted to corresponding tertiary amide in the presence of CuF2 in DMSO. As an example, the formal hydrocarbamoylation reaction of unsaturated bonds could be achieved. A general procedure for the strategy is as follows:α-aminomalononitrile derived from formamide is used to undergo nucleophilic addition or substitution reaction with electrophilic reagents. Next, the two cyano groups of the synthesized substrates could be removed under the catalysis of CuF2 to form a C=O double bond in situ, thereby achieving the synthesis of corresponding tertiary amide. During the reaction, the α-aminomalononitrile substrate (0.4 mmol), CuF2 (5 mol%), DMSO (3 mL) were placed in a sealed reaction tube at 100℃ at an argon atmosphere for about 32 hours. Then, the reaction system was washed out with ethyl acetate, and the organic phase was washed with water to remove DMSO. Next, the aqueous phase was extracted with ethyl acetate. Finally all organic phases were combined, washed once with saturated brine. After drying the organic phase over anhydrous sodium sulfate, it was concentrated by a vacuum pump. Finally, the residue was purified by flash column chromatography to give amide product.

Key words: α-Aminomalononitriles, Formamides, Carbamoyl anion, Copper catalysis