Regiodivergent Alkylation of Pyridines: Alkyllithium Clusters Direct Chemical Reactivity

Regiodivergent C-C bond-forming reactions are a powerful tool for constructing diverse molecular architectures from common precursors. While transition metal catalysis has dominated regioselective transformations, achieving similar precision with transition-metal-free methods remains an unmet challenge, particularly when using identical starting materials. In this work, we report a transition-metal-free, regiodivergent direct alkylation of electronically unbiased pyridines using 1,1-diborylalkanes as the sole alkylating agent. The key to controlling regioselectivity lies in the choice of alkyllithium activator of 1,1-diborylalkanes: methyllithium directs alkylation predominantly to the C4 position, while <i>sec</i>-butyllithium promotes C2-alkylation. Mechanistic studies reveal that the structural dynamics of alkyllithium clusters dictate the regioselectivity, with tetrameric clusters favoring C4-alkylation and dimeric clusters preferring C2-alkylation. This method demonstrates broad substrate scope, enables late-stage functionalization of complex molecules, and allows for the sequential installation of two distinct alkyl groups onto a pyridine scaffold. Our approach provides a versatile tool for site-selective pyridine functionalization, offering new possibilities for synthesizing diverse alkylated pyridines in pharmaceutical and materials research.