Turning an Intrinsically Inefficient Reaction Efficient: Homogeneously Catalyzed Continuous-Flow Amination of Alcohols with Ammonia

Abstract

Primary amines are key intermediates in pharmaceuticals, agrochemicals, and polymers, and their efficient synthesis from readily available alcohols and ammonia is highly desirable, particularly as water is formed as the sole by-product. However, reduced reaction rates caused by low concentrations of reactive intermediates and the undesired formation of secondary and tertiary amines often impede selective access to the desired product. Herein, we demonstrate that a transformation commonly regarded as intrinsically inefficient and typically requiring high catalyst loadings, can be rendered highly effective through alternative process design. By transferring the reaction to a continuous capillary flow reactor, performance was drastically improved at 280 °C and 70 bar using a homogeneous Ru catalyst at only 1.2 mol%. The optimization and substrate scope focused on pharmaceutically interesting structural motifs, achieving conversions exceeding 99 % and selectivities up to 98 % within 23.3 min. Stable continuous operation over 30 h confirmed robustness of the approach, including successful substrate switching without interrupting production, demonstrating operational flexibility. Furthermore, reliable crystallization enabled facile product isolation with high to excellent purities exceeding 95%, and catalyst recyclability was demonstrated, providing a basis for further process intensification.