Photocatalytic construction of N-acyl-N,O-acetal-linked pyridines via aminocyclopropane ring opening

Abstract

Pyridine and quinoline linkers are privileged motifs in medicinal chemistry, yet their site-selective installation into complex scaffolds remains challenging. Here, we report that aminocyclopropanes serve as precursors to N-acyl-N,O-acetal linkers installed onto pyridines via visible-light-driven ring opening under oxidant-free conditions. The ring-opened radical is captured by N-aminopyridinium salts to forge C(sp³)–C(aryl) bonds at the C4-selective site of the pyridine core, while the concomitantly released N-centered radical oxidizes the reduced photocatalyst, enabling efficient turnover. Subsequent nucleophile trapping furnishes N-acyl-N,O-acetals bearing pyridine or quinoline units with a broad scope across both heteroarenes and aminocyclopropanes, including late-stage diversification of complex molecules. Substituting methanol with TMSN₃ provides azido-aminals, further expanding accessible architectures. The resulting N-acyl-N,O-acetal moieties function as versatile linchpins that engage diverse downstream manifolds, thereby enabling modular assembly and late-stage diversification of pyridine-containing targets.