Trialkylamines are widely found in naturally-occurring alkaloids, synthetic agrochemicals, biological
probes, and especially pharmaceuticals agents and pre-clinical candidates. Despite the recent
breakthrough of catalytic alkylation of dialkylamines, the selective a-C(sp3
)–H bond functionalization of
widely available trialkylamine scaffolds holds promise to streamline complex trialkylamine synthesis,
accelerate drug discovery and execute late-stage pharmaceutical modification with complementary
reactivity. However, the canonical methods always result in functionalization at the less-crowded site.
Herein, we describe a solution to switch the reaction site through fundamentally overcoming the steric
control that dominates such processes. By rapidly establishing an equilibrium between a-amino C(sp3
)-H
bonds and a highly electrophilic thiol radical via reversible hydrogen atom transfer, we leverage a slower
radical-trapping step with electron-deficient olefins to selectively forge a C(sp3
)-C(sp3
) bond with the
more-crowded a-amino radical, with the overall selectivity guided by Curtin-Hammett principle. This subtle
reaction profile has unlocked a new strategic concept in direct C-H functionalization arena for forging C–
C bonds from a diverse set of trialkylamines with high levels of site-selectivity and preparative utility.
Simple correlation of site-selectivity and 13C NMR shift serves as a qualitative predictive guide. The broad
consequences of this dynamic system, together with the ability to forge N-substituted quaternary carbon
centers and implement late-stage functionalization techniques, holds tremendous potential to streamline
complex trialkylamine synthesis and accelerate drug discovery
RhI/RhIII catalyst-controlled divergent aryl/heteroaryl C–H bond functionalization of picolinamides with alkynes
