Green and efficient utilization of ethyl acetate-derived ester enolates for aldol condensation in continuous flow: from ultralow temperature to room temperature

Lithium diisopropylamide (LDA)-mediated aldol condensation between esters and electrophiles ( e.g. , aldehydes, ketones) represents a versatile route to β-hydroxy esters. However, ester enolates, particularly those derived from ethyl acetate (EA), are highly reactive and prone to self-condensation and decomposition. These intrinsic limitations necessitate cryogenic conditions, thereby increasing energy consumption and limiting scalability. Herein, we reported a continuous-flow strategy that enabled LDA-mediated aldol condensation of EA at room temperature, affording good to excellent yields within 1.5 s at an equimolar ester-to-electrophile ratio. Using 3-pyridine aldehyde as a model electrophile, batch studies revealed that minimizing the residence time of the enolate was critical for improving yield. Nevertheless, even under optimized batch conditions, yields remained limited at room temperature (10% with 1.2 equivalents (eq.) of LDA and 38% with 2.0 eq.). In contrast, the continuous-flow approach, enabled by rapid micromixing and precise residence time control, facilitated near-quantitative enolate formation and afforded the corresponding β-hydroxy ester in near-quantitative yield using only 1.2 eq. of LDA. The characteristic micromixing time required for EA deprotonation, and the optimal residence time range for efficient enolate formation were identified. This strategy exhibited broad substrate scope, accommodating electrophiles both with and without acidic α-protons, and was further extended to the aldol condensation of carboxylic acids. Furthermore, downstream functionalizations of EA-derived β-hydroxy esters can be efficiently performed directly on the crude product following solvent removal by vacuum distillation, obviating the need for intermediate purification. Overall, this work established a robust, operationally simple, and energy-efficient platform for LDA-mediated aldol condensation of EA.