In this work, we demonstrate that directing group flexibility plays a decisive role in overcoming reactivity barriers in PdII-catalyzed alkene functionalization. Kinetic, organometallic, and DFT studies reveal that employing the rigid 8-aminoquinoline (AQ) auxiliary in α,α-disubstituted substrates leads to high activation barriers for a rate-determining protonation transition state arising from geometric distortion. Guided by these insights, we show that judicious tuning of the directing group can minimize energetic penalties with the use of a flexible 2-pyridylmethylamine (PM) auxiliary. This mechanistically informed approach led to a 115-fold rate increase for the model α,α-dimethyl substrate and broadens the scope to sterically encumbered alkenes, including α-spiro(hetero)cyclic systems, with tolerance for diverse N-H and C-H nucleophiles. Furthermore, we demonstrate that the mechanistic framework developed for hydroamination extends to other difunctionalization reactions such as carboamination and cyclopropanation. This work expands access to structurally complex and lipophilic scaffolds from readily available alkenes.
Lisboa et al. (2026) studied this question.