Tuning Wittig Stereoselectivity in Thienostilbene Synthesis via Optimized Reaction Conditions in Batch and Flow Systems

This study investigates the influence of reaction conditions on the stereoselective Wittig synthesis of a thienostilbene analogue of trans-resveratrol. Reaction conditions were systematically varied across batch experiments and analysed using Spearman correlation, principal component analysis (PCA), and response surface methodology (RSM) to identify key factors (base type and amount, solvent type and volume, system configuration, and reaction time) affecting conversion and the trans/cis ratio. The base type, solvent type, and system configuration had the strongest impact on stereoselectivity, while solvent volume proved effective in enhancing the trans-isomer. PCA revealed that cyclic ether solvents combined with medium-strong bases provide the best balance between conversion and selectivity. RSM predicted optimal conditions in a two-phase NaOH system via phase transfer catalysis (PTC) with increased organic solvent volume, which experimentally increased conversion from 35% to over 92% and raised the trans/cis ratio to 1.81. Transferring the optimized process to continuous flow dramatically reduced reaction time, achieving 67.5% conversion in 15 min while maintaining stereoselectivity. These results demonstrate how statistical optimization combined with flow processing can significantly accelerate the development of stereoselective Wittig reactions.