Enhanced utilization of ester enolates in slow-kinetic α-functionalization of esters: Insights into enolate consumption and preservation strategies

Ester enolates, generated by lithium diisopropylamide (LDA)-mediated deprotonation of the α-hydrogen of esters, serve as highly reactive intermediates for C-C bond formation. However, they readily undergo self-condensation and decomposition, substantially reducing product yields, particularly in reactions with electrophiles that exhibit intrinsically slow kinetics. However, the key factors governing these side reactions, especially across esters with diverse structural features, remain insufficiently understood, limiting the rational design of effective suppression strategies. Here, we systematically studied the consumption behavior of enolates derived from esters with diverse structural features and developed tailored strategies to maintain high enolate concentrations over extended reaction times, several of which leveraged microreactor-based enolate generation. Using ethyl acetate (EA)-derived enolates, the most susceptible to side reactions, as a model, key factors governing enolate depletion in batch operation were identified, including insufficient mixing, excessive LDA consumption, and localized alkaline environments. Guided by these insights, a hybrid strategy operable under cryogenic conditions that coupled continuous-flow enolate generation with batch reaction time extension for EA-derived enolates were developed. Rapid mixing in continuous flow efficiently engaged most of the LDA in EA-derived enolate formation, thereby suppressing both self-condensation and decomposition. This hybrid approach sustained elevated EA-derived enolate concentrations for more than 60 min, outperforming conventional batch protocols. Subsequently, ester-specific enolate generation and preservation strategies for structurally diverse esters based on their distinct consumption pathways were established. Finally, using EA as a representative case, this tailored strategy significantly improved the yield of slow-kinetic Claisen condensation to the corresponding β-keto ester within 60 min.