Easily accessible 2^A-O-Ts-β-cyclodextrin via efficient aqueous conditions

A simple and efficient method for the synthesis of 2^A-O-Ts-β-cyclodextrin (2^A-O-Ts-β-CD), an important intermediate in cyclodextrin chemistry, is reported. The method employs 1-tosyl-1H-1,2,4-triazole (Ts-1H-Trz) as a mild tosylating reagent under aqueous conditions, using NaHCO₃ as a weak base. The methodology avoids strictly anhydrous conditions, eliminates the use of hazardous reagents such as NaH, and allows commercially available hydrated β-cyclodextrin to be used directly without prior dehydration. Reaction parameters, including co-solvent composition, temperature, base, and the nature and stoichiometry of the tosylating reagent, were evaluated to identify efficient conditions. A 1 : 1.6 (v/v) water/1,4-dioxane mixture at 50 °C provided the best balance between β-cyclodextrin solubility and suppression of side reactions. Among the tosylating reagents examined, namely tosyl chloride (Ts-Cl), 1-tosyl-1H-imidazole (Ts-Im), and Ts-1H-Trz, the latter exhibited the highest efficiency, affording 2^A-O-Ts-β-CD in 43% isolated yield with a decrease in the relative ESI-MS signal of the corresponding by-product ions. NMR investigations were carried out to probe the effect of host-guest interactions between β-cyclodextrin and Ts-1H-Trz on the reaction outcome. The developed protocol provides a safer, more sustainable, and operationally straightforward approach for the preparation of 2-monotosylated β-cyclodextrin. The isolated yield obtained in aqueous medium exceeds those reported for previous aqueous methods and is comparable to that achieved by the most efficient conventional non-aqueous procedures.