Reverse polarity of amide nitrogen enables expedient access to N-cyano amides

Heng Yang, Xiangke Zhang, Fei-Yang Cao, Yu-Heng Zhang, Yan Pan, Ye-Cheng Wang, Mingji Dai () and Jian-Jun Dai ()
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Heng Yang: Hefei University of Technology
Xiangke Zhang: Berkeley
Fei-Yang Cao: Hefei University of Technology
Yu-Heng Zhang: Hefei University of Technology
Yan Pan: Hefei University of Technology
Ye-Cheng Wang: Berkeley
Mingji Dai: Emory University
Jian-Jun Dai: Hefei University of Technology

Nature Communications, 2025, vol. 16, issue 1, 1-9

Abstract: Abstract N-Cyano amides are pivotal in agrochemicals, biologically active compounds, and nitrogen-containing heterocycles synthesis. Here, we present an umpolung cyanation strategy for the synthesis of N-cyano amides. By applying the readily accessible O-tosyl hydroxamates as nitrogen electrophiles, direct nucleophilic cyanation can be achieved with trimethylsilyl cyanide (TMSCN) under mild and transition metal-free conditions. This protocol features excellent functional group tolerance, easy scalability, and broad substrate scope (over 70 examples). Moreover, preliminary experimental studies and density functional theory (DFT) calculations support an SN2-type mechanism of this reaction. Our work not only provides efficient, robust, and practical approaches to a variety of useful and complex N-cyano amide molecules but also expands the concept and scope of SN2-type reaction at the non-anomeric amide electrophilic nitrogen center.

Date: 2025
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DOI: 10.1038/s41467-025-63052-7

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