A Green Approach to Nucleophilic Aromatic Substitutions of Nicotinic Esters in Cyrene

Abstract

The green solvent CyreneTM has emerged as a valuable substitute for conventional polar aprotic organic solvents such as DMF, DMSO and NMP (renowned for their toxicity and environmental concerns). However, in the presence of bases, Cyrene is prone to polymerization, thus potentially incompatible with reactions where a base is needed to generate reactive nucleophiles. In this study, we developed an efficient synthetic strategy for nucleophilic aromatic substitutions of nicotinic esters in Cyrene. The success of this protocol relies on a very short reaction time (only 15 minutes) which prevents polymerization from occurring. Indeed, Cyrene not only outperformed typical solvents such as DMF and DMSO, but also, being highly soluble in water, allowed an easy purification of the desired products by simple precipitation upon the addition of ice-water.