Flipping the Metalation of 4-Dimethylaminopyridine: Steric Repulsion versus London Dispersion Attraction.

ABSTRACT: Non-covalent interactions, including the coordination of an organolithium reagent by a directing group and the steric hindrance from substituents, play a crucial role in determining the selectivity of metalation reactions. Here, we demonstrate the effective utilization of steric interactions for flipping the lithiation of 4-dimethylaminopyridine (DMAP). Introduction of a Me₃Si substituent to the position 1 of DMAP or simple complexation with t-BuLi allows selective C3-lithiation, due to the steric hindrance of a C2-H bond by the bulky moiety at the pyridine nitrogen. This simple approach creates a convenient way to achieve the selective C3-functionalization of DMAP. In contrast, the utilization of an even bulkier i-Pr₃Si substituent leads to exclusive C2-functionaliza

SUBMITTER: Verkhov VA 

PROVIDER: S-EPMC11771546 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature