Switchable Deep Eutectic Solvents for Sulfonamide Synthesis

Sulfonamides are pivotal structural motifs present in numerous pharmacologically active compounds. Since the turn of the century, scientists have been actively pursuing new, sustainable, yet simple methods for their synthesis under mild conditions, to eliminate the use of toxic chemicals and volatile organic compounds (VOCs), such as pyridine and dichloromethane, which are commonly employed. In some greener procedures, water is used as solvent. However stringent pH control is usually required to overcome the hydrolysis of sulfonyl chlorides and it is also reported how poor soluble starting materials lead to low reaction yields. In this communication, we report a new procedure where Deep Eutectic Solvents (DESs)4 are used as ecofriendly and highly effective reaction media for facilitating N–S bond-forming processes under heterogeneous and mild conditions, notably at room temperature and under air. By switching two choline chloride (ChCl)-based DESs, we have successfully synthesized various types of sulfonamides from primary and secondary aliphatic, as well as aromatic, amines and sulfonyl chlorides. A subtle interplay between the electronic effects and the solubility characteristics of the starting materials in the two different DESs seem to be responsible for driving the reaction successfully over the hydrolysis of sulfonyl chlorides. The reactions typically reach completion within two hours, affording the desired products in yields up to 97%. The procedure’s eco-friendliness is validated by quantitative metrics, such as E-factor and EcoScale, with products isolated by extraction or filtration after decantation.