Mild and Scalable C4-Alkylation of Pyridine Derivatives: Enhanced Regioselectivity via Silane-Assisted Electroreduction

Pyridine derivatives are valuable components of biologically active compounds, materials, and ligands; however, traditional methods for site-selective direct functionalization are often hindered by multistep procedures and harsh conditions. Herein, we report a streamlined approach for the selective C4-alkylation of pyridine derivatives under electroreductive conditions using alkyl bromides. The addition of chlorotrimethylsilane significantly enhanced the yield and regioselectivity, and mechanistic studies revealed that the reaction involves a temporary dearomatization step, yielding a 1,4-difunctionalized intermediate, which then re-aromatizes upon air exposure. This method is scalable, mild, and highly selective, and demonstrates a broad substrate scope and good functional-group tolerance. In addition, C4-alkylated pyridines can undergo a subsequent electroreductive ortho-alkylation under standard conditions. This stepwise strategy allows the sequential incorporation of distinct alkyl groups through the selective use of different alkyl bromides at each stage, providing a versatile strategy for accessing structurally diverse di- and trifunctionalized pyridines.