Late‐Stage Conversion of Terminal Alkynes to Nitriles in Nucleoside Scaffolds: A Tool for Diversification

Abstract The small nucleoside molecule LJ‐4827 exhibited potent kinase inhibition and in vitro anticancer activity. Driven by bio‐isosteric principles, we synthesized LJ‐5157, which also demonstrated high kinase selectivity and anticancer efficacy. To further expand the structural diversity of bioactive nucleoside analogs, we developed a metal‐free, late‐stage strategy for converting terminal alkynes to nitriles using tert ‐butyl nitrite ( t BuONO). By substituting 2‐picoline N ‐oxide with N ‐methylmorpholine N ‐oxide (NMO) as the oxidant, we accomplished efficient nitrile formation in nucleoside scaffolds. This approach broadens the scope of alkyne cleavage chemistry and offers a practical route for analog diversification.