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

A green choice: Cyrene has been used as an eco-friendly alternative to environmentally harmful polar aprotic solvents in S_NAr reactions. This innovative protocol enabled the facile synthesis of a wide library of novel nicotinic esters, valuable precursors of bioactive compounds. This methodology could also be extended to scale-up processes, microwave-assisted synthesis, and one-pot telescoping reactions, thus enhancing its applicability in various eco-friendly synthetic contexts.

Abstract

The green solvent Cyrene^TM 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.

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