Mechanistically Guided Functionalization of α,α-Disubstituted Alkenyl Amides Enabled by a Conformationally Flexible Directing Auxiliary

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.