Computational Study on γ-C-H Functionalization of α,β-Unsaturated Ester Catalyzed by N-Heterocyclic Carbene: Mechanisms, Origin of Stereoselectivity, and Role of Catalyst.

The N-heterocyclic carbene (NHC)-catalyzed γ-C-H deprotonation/functionalization of α,β-unsaturated esters with hydrazones leading to the δ-lactams has been theoretically investigated by using density functional theory. Three possible reaction mechanisms including Mechanism A, for which the NHC catalyst serves as a nucleophilic catalyst to attack on the carbonyl carbon atom to initiate the reaction, Mechanism B, in which NHC triggers the reaction through the hydrogen bond, and Mechanism C, which is the direct deprotonation/functionalization process without the presence of NHC, have been suggested and studied in detail. The most favorable Mechanism A was identified to proceed through the following processes: nucleophilic attack on the carbonyl carbon of the ester by NHC, γ-deprotonation, formal [4 + 2] cycloaddition of dienolate with hydrazone, and regeneration of NHC. Multiple possible deprotonation pathways were explored, and the additive base such as K2CO3 would significantly lower the energy barrier. The formal [4 + 2] cycloaddition step is the stereoselectivity-determining step, and R-configured rather than S-configured product was preferentially generated. In addition, the C-H···O, C-H···N, LP···π, and C-H···π interactions have been identified in the most energetically favorable transition state involved in the stereoselectivity-determining step. The additional analysis indicates that NHC strengthens the acidity and electrophilicity to promote the deprotonation, indicating this is not a simple NHC-catalyzed umpolung carbonyl reaction. The mechanistic insights and the significant role of NHC obtained in this study should provide valuable insights for understanding the organocatalytic γ-C(sp3)-H bond functionalization reaction.