Nickel-Catalyzed Cyanation of Unactivated Alkyl Sulfonates with Zn(CN)2
Aiyou Xia, Peizhuo Lv, Xin Xie and Yuanhong Liu*
*Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China,
Email: yhliu
sioc.ac.cn
A. Xia, P. Lv, X. Xie, Y. Liu, Org. Lett., 2020, 22, 7842-7847.
DOI: 10.1021/acs.orglett.0c02722
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Abstract
Nickel catalyzes a cyanation of unactivated primary and secondary alkyl mesylates with Zn(CN)2. The reaction provides an efficient route for the synthesis of alkyl nitriles with wide substrate scope, good functional group tolerance, and compatibility with heterocyclic compounds. A gradual in situ generation of alkyl iodide as the reactive intermediate is crucial for the success of the reaction.
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Details
The document discusses a study on the nickel-catalyzed cyanation of unactivated alkyl sulfonates using Zn(CN)2. This reaction provides an efficient method for synthesizing alkyl nitriles, which are valuable in organic and medicinal chemistry. The process demonstrates good functional group tolerance and compatibility with heterocyclic compounds. Mechanistic studies reveal that the in situ-generated alkyl iodide serves as the reactive intermediate, and its gradual release is crucial for the reaction's success. The study also highlights the challenges of using alkyl electrophiles in cross-coupling reactions due to their low tendency for oxidative addition and the potential for β-hydride elimination. The optimized reaction conditions involve using NiCl2·6H2O/Xantphos as the catalyst system, with zinc powder as a reductant and n-Bu4NI as an additive. The method avoids highly toxic reagents and achieves high yields for various substrates, including cyclic and acyclic alkyl mesylates. The research suggests that maintaining a low concentration of alkyl iodide is essential to minimize side reactions and improve yields. This new approach could have significant applications in pharmaceutical preparations and drug development. Further investigations into the detailed reaction mechanism and broader applications are ongoing.
Key Words
ID: J54-Y2020
