Mechanistic Studies on Stereoselective Organocatalytic Direct β-C–H Activation in an Aliphatic Chain by Chiral N-Heterocyclic Carbenes

The functionalization of aliphatic and aromatic C–H bonds has remained a priority in transition-metal catalysis for the last few decades. N-heterocyclic carbenes (NHCs) have very recently been proven as an effective organocatalytic alternative toward site-selective sp3 β-C–H bond functionalization in aliphatic esters and related compounds. We have employed modern density functional theory computations to provide the first mechanistic insights into this entirely new form of reactivity of NHCs, leading to β-C–H bond activation. NHC-catalyzed coupling between hydrazone and β-phenyl propionate leading to a γ-lactam bearing two chiral centers is reported. An interesting two-step mechanistic cascade that helps surmount the high bond dissociation energy of an otherwise inert β-C–H bond is identified. An initial addition–elimination at the ester group installs the chiral triazolium NHC to the substrate. The deprotonation of the α-C–H by the departing phenoxide first furnishes an α-enolate intermediate. A concerted protonation at the enolate oxygen by the phenol and a β-C–H deprotonation by the phenoxide leads to the vital nucleophilic β-carbanion intermediate. The origin of enantioselectivity in the C–C bond formation between the si prochiral face of the nucleophilic β-carbon and the re face of electrophilic hydrazone is traced to the differential in the C–H···π, C–H···O, and N–H···O interactions that exist in the transition states for the lower energy si,re and higher energy re,si modes in the Michael addition step. The computed enatio- and diastereoselectivities are in very good agreement with those in an earlier experimental report.