One-pot synthesis of α-(OCH₂CF₃)-substituted pyridines using TFE as a dual solvent–reagent

Abstract

Trifluoroethoxy-substituted pyridines are one of the core components of many biologically active scaffolds, which have a wide range of applications in fields such as materials science, agrochemicals, and pharmaceuticals. The strategic placement of fluorine-containing substituents, like the 2,2,2-trifluoroethoxy group in the target compound, is a crucial aspect of modern drug design. This group can act as a lipophilic hydrogen bond donor and participate in favourable interactions with biological targets. Here, we developed a novel and efficient method for synthesizing α-(OCH2CF3)-substituted pyridine-3,5-dicarbonitriles from readily available starting materials such as benzaldehyde, malononitrile, and trifluoroethanol (TFE), using a base. In this process, TFE serves a dual role as both solvent and source of the trifluoroethoxy group. Delightfully, diverse substituted-benzaldehydes were efficiently transformed into corresponding trifluoroethoxy-substituted pyridines in good to excellent yields. The reaction proceeds under mild conditions, avoids the need for pre-functionalized substrates, and exhibits broad functional group tolerance, providing a practical method to synthesize diverse trifluoroethoxy-substituted pyridines.