Copper‐mediated nitrogenation of aryl halides with sodium azide can result in either aryl azides or aniline derivatives. The selectivity of the transformation is highly dependent on reaction time and temperature, which led to contradictory literature results with respect to product selectivity and the conditions applied. The advantages of a strictly controlled flow reactor environment were exploited in order to facilitate selective haloarene transformations. Reaction conditions were carefully investigated to understand their role on product selectivity. Aryl azides and aryl amines were successfully prepared from the same starting materials using the same auxiliaries by means of precise control over residence time and reaction temperature, thereby ensuring time‐, cost‐ and atom‐efficient syntheses.magnified image

SummaryThe preparation of novel multi-substituted 1,2,3-triazole-modified β-aminocyclohexanecarboxylic acid derivatives in a simple and efficient continuous-flow procedure is reported. The 1,3-dipolar cycloaddition reactions were performed with copper powder as a readily accessible Cu(I) source. Initially, high reaction rates were achieved under high-pressure/high-temperature conditions. Subsequently, the reaction temperature was lowered to room temperature by the joint use of both basic and acidic additives to improve the safety of the synthesis, as azides were to be handled as unstable reactants. Scale-up experiments were also performed, which led to the achievement of gram-scale production in a safe and straightforward way. The obtained 1,2,3-triazole-substituted β-aminocyclohexanecarboxylates can be regarded as interesting precursors for drugs with possible biological effects.

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.

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