C3‐Cyanation of Pyridines: Constraints on Electrophiles and Determinants of Regioselectivity. (9th January 2023)

• Record Type: Journal Article
• Authors: Zhang, Ming; Zhou, Qingyang; Luo, Heng; Tang, Zi‐Lu; Xu, Xiufang; Wang, Xiao‐Chen
• Is Part Of: Angewandte Chemie. Volume 135:Number 6(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-01-09
• Subjects: Boron -- C−H Functionalization -- Cyanation -- Heterocycles -- Pyridine; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.202216894
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: Methods for C−H cyanation of pyridines are rare. Here, we report a method for C3‐selective cyanation of pyridines by a tandem process with the reaction of an in situ generated dihydropyridine with a cyano electrophile as the key step. The method is suitable for late‐stage functionalization of pyridine drugs. The low reduction potential of the electrophile and effective transfer of the nitrile group were found to be essential for the success of this method. We studied the reaction mechanism in detail by means of control experiments and theoretical calculations and found that a combination of electronic and steric factors determined the regioselectivity of reactions involving C2‐substituted pyridines. Abstract : C3‐selective cyanation of pyridines was accomplished by a tandem process of borane‐catalyzed pyridine hydroboration, substitution of the resulting dihydropyridine with a cyano electrophile, and finally oxidative aromatization. This method was suitable for use in late‐stage cyanation of pyridine drugs.