Multilevel screening of dual-role ionic liquids as solvent and phase transfer catalyst for efficient aromatic O,S-glycosidations

Dual-role ILs act as solvent and PTC for efficient aromatic O,S-glycosidations. • Multilevel screening and experimental validation identify the optimal IL. • Screened optimal IL achieves superior performance with various acceptors. • Mechanism analysis reveals the intensification mechanism.Provide a general strategy for screening ILs in aromatic O,S-glycosidations. Aromatic O,S-glycosidations between (thio)phenols and glycosyl halides are valuable for synthesizing aromatic O,S-glycosides but often limited by immiscible reactants. This work presents a reaction intensification strategy for efficient O,S-glycosidations by using dual-role ionic liquids (ILs) that act as solvent and phase transfer catalyst (PTC). Taking the reaction between 4-nitrophenol and 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide to form p-nitrophenyl-2,3,4,6-tetra-O-acetyl-beta-D-galactopyranoside as an example, multilevel computational screening, experimental validation, and comprehensive mechanistic analysis are performed to identify the optimal dual-role IL and understand the explicit intensification mechanism. Specifically, 11,890 IL candidates are first screened as solvents via solubility indicators and physical properties. The easiness of formation and hydrophobicity of ion pairs transferring the liquid–liquid interface are considered to screen ILs as PTCs. After these, 36 potential ILs are filtered out. Considering the availability, 1-octyl-3-methyl-imidazolium tetrafluoroborate is eventually tested via experiment and achieves the best performance. Compared with the basecase IL reported previously, the yield is improved from 34.2 % to 53 %. Meanwhile, this IL exhibits far more superior catalytic efficiency with different acceptors. The acceptors involved are common phenols (i.e., 4-nitrophenol, phenol and p-Cresol) and thiophenols (i.e., 4-methylbenzenethiol, 4-nitrobenzenethiol), which corresponds to O- and S-bridge products, respectively. Mechanism analyses reveal that the reaction is mainly intensified through the extraction effect of ion pair led by the IL, which promotes ion pair transfer from aqueous phase to IL phase and thus leads to better contacts of reactants and catalytic efficiency. Clearly, this work offers useful guidance to screen dual-role ILs as solvent and PTC for efficient aromatic O,S-glycosidations.