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 sec-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.