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‐functionalization due to the dispersion interactions with organometallic bases. For the first time, it is demonstrated that the i‐Pr3Si moiety can serve as a directing group, providing a new type of direct ortho‐metalation effect.