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

Abstract

Trifluoroethoxy-substituted pyridines are among the core components of many biologically active scaffolds and 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 benzaldehydes, malononitrile, and trifluoroethanol (TFE), using a base. In this process, TFE serves a dual role as both the solvent and the source of the trifluoroethoxy group. Delightfully, diverse substituted benzaldehydes were efficiently transformed into the corresponding trifluoroethoxy-substituted pyridines in 54–95% yields. The reaction proceeds under mild conditions, avoids the need for pre-functionalized substrates, and exhibits broad functional group tolerance, providing a practical method for synthesizing diverse trifluoroethoxy-substituted pyridines.