Continuous Flow Conversion of Primary Amides to Amines: Dual Functionality of Trichloroacetonitrile in Sequential Dehydration and Selective Hydrogenation

Amines are widely used to synthesize pharmaceuticals, dyes, polymers, and other key molecules. To effortlessly synthesize amines from primary amides using the sequential flow process, identifying an optimal agent for the flow dehydration step is crucial. In this study, we developed a continuous flow method to convert primary amides to primary amines using sequential dehydration and hydrogenation reactions. We first optimized the dehydration step of primary amides using batch and flow conditions and then optimized the hydrogenation of nitriles under flow conditions using a pseudo solution. The dehydration step was efficiently catalyzed by cerium oxide in the presence of trichloroacetonitrile, which served as a water acceptor via a water-transfer reaction. Subsequently, selective hydrogenation was achieved using trichloroacetoamide, which is the hydrated form of trichloroacetonitrile, as the hydrogen chloride source. This integrated flow process enabled the synthesis of various primary amines with high selectivity and operational continuity, demonstrating promise for applications in the continuous flow synthesis of fine chemicals and pharmaceuticals