Telescoped continuous synthesis of aromatic amines via copper catalyzed azidation and Staudinger reduction

This dissertation presents a telescoped continuous flow methodology for synthesizing aromatic amines, key intermediates in the pharmaceutical and fine chemical industries. Their production requires highly chemoselective methods for carbon-nitrogen bond formation. A copper coil capillary reactor functions as both the containment vessel and the catalyst source, promoting copper catalyzed cross coupling through dynamic surface leaching. Within this catalytic environment, sodium azide is employed as the nitrogen nucleophile. Unlike traditional amines, the azide anion selectively couples with the aryl halide, preventing unwanted over arylation. This specific pathway forms an aryl azide intermediate, whose subsequent conversion continuously generates stoichiometric nitrogen gas. The reactor is engineered to overcome the limitations of traditional batch methods, for which managing the gas expansion and keeping isothermal conditions can be difficult. While parametric optimization of the direct thermal amination maximized substrate conversion, it ultimately revealed a severe apparent molar deficit caused by unselective nitrene degradation.Therefore, a Staudinger reduction was integrated into the continuous architecture, utilizing triphenylphosphine to intercept the transient aryl azide and avoid the thermal degradation pathway. Ultimately, the optimized telescoped sequence achieved a 91.8% amine yield for the p-bromotoluene and demonstrated viability for several substituted aryl bromides. However, the Staudinger bypass significantly reduces the overall atom economy due to the stoichiometric generation of triphenylphosphine oxide waste, and the exhibited poorer reaction performance when processing sterically hindered or strongly coordinating functional groups.