A New Strategy for the Synthesis of Tertiary Amides via a Copper-Catalyzed Decyanation Reaction of N,N-Disubstituted 2-Aminomalononitriles

doi:10.6023/A20070296

Acta Chimica Sinica ›› 2020, Vol. 78 ›› Issue (10): 1064-1068.DOI: 10.6023/A20070296 Previous Articles Next Articles

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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

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

投稿日期:2020-07-07 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（Nos.21472077，21772071）和广东省教育厅项目（Nos.2017KTSCX185，2017KSYS010，2016KCXTD005，2019KZDXM035）资助项目.中国发明专利申请号（No.202010648789.7）.

A New Strategy for the Synthesis of Tertiary Amides via a Copper-Catalyzed Decyanation Reaction of N,N-Disubstituted 2-Aminomalononitriles

Liang Huan^a, Gou Along^a, Gao Zhupeng^a, Lei Linsheng^a, Wang Bowen^a, Yu Lan^a, Xu Xuetao^b, Wang Shaohua^a

a School of Pharmacy, Lanzhou University, Lanzhou 730000, China;
b School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China

Received:2020-07-07 Published:2020-09-09
Supported by:
Project supported by the National Natural Science Foundation of China (Nos. 21472077, 21772071) and Department of Education of Guangdong Province (Nos. 2017KTSCX185, 2017KSYS010, 2016KCXTD005, 2019KZDXM035). Chinese patent pending (No. 202010648789.7).

1. A20070296.pdf(9199KB)

Abstract

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

Cite this article

Liang Huan, Gou Along, Gao Zhupeng, Lei Linsheng, Wang Bowen, Yu Lan, Xu Xuetao, Wang Shaohua. A New Strategy for the Synthesis of Tertiary Amides via a Copper-Catalyzed Decyanation Reaction of N,N-Disubstituted 2-Aminomalononitriles[J]. Acta Chimica Sinica, 2020, 78(10): 1064-1068.

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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

A New Strategy for the Synthesis of Tertiary Amides via a Copper-Catalyzed Decyanation Reaction of N,N-Disubstituted 2-Aminomalononitriles

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