Exploring New Parameter Spaces for the Oxidative Homocoupling of Aniline Derivatives: Sustainable Synthesis of Azobenzenes in a Flow System

Aromatic azo compounds have countless applications, not merely in the chemical industry, but also in medicinal chemistry, biotechnology, and the field of renewable resources. However, in the synthetic batch routine, the synthesis of azobenzenes often constitutes a significant challenge, mainly because of the ease of overreaction leading to nonoptimal selectivity, and also because of reactivity issues necessitating long reaction times and special reaction conditions. We therefore exploited the benefits of continuous-flow processing for the copper-mediated oxidative homocoupling of arylamines to facilitate the time-, cost-, and atom-effective synthesis of azobenzenes. The novel process window of increased temperature and pressure ranges in combination with the application of overheated solvents afforded a remarkable chemical intensification. Precise control of the residence time restricted the possibility of undesired reaction pathways, such as overreaction to azoxy products, but at the same time ensured sufficient reactivity to furnish valuable aromatic azo compounds, even in the cases of deactivated halogen-substituted anilines and multisubstituted derivatives. As compared with earlier batchwise syntheses, the designed process displays significant advances in terms of sustainability and productivity