Direct Amination of Unfunctionalized Aromatics

Arylamines are essential components of pharmaceuticals, agrochemicals, and organic materials. However, synthetic methods that incorporate arylamines within complex molecular systems generally require catalysts, forcing conditions, and pre-functionalized aromatics.

Daniele Leonori and colleagues, University of Manchester, UK, have developed a general method for direct amination of unfunctionalized aromatics. The researchers used a single-electron transfer (SET) process, mediated by a Ru(bpy)₃Cl₂ (bpy = 2,2'-bipyridine) catalyst, photoexcited with blue-light emitting (450 nm) diodes. This approach allowed them to generate aminium radicals from protonated O-aryl hydroxylamines. The highly electrophilic aminium radicals react with a range of unfunctionalized aromatics to produce arylamines (pictured) selectively, including complex molecules such as the alkaloid strychnine.

The team used the method to produce a complex drug hybrid that combines the therapeutic properties of two blockbuster drugs, donepezil for the palliative treatment of Alzheimer’s disease and the anti-inflammatory indometacin. The method provides a mild, rapid, and effective route to bioactive molecules from readily accessible starting materials.

• Synthesis of Arylamines via Aminium Radicals,
  Thomas D. Svejstrup, Alessandro Ruffoni, Fabio Juliá, Valentin M. Aubert, Daniele Leonori,
  Angew. Chem. Int. Ed. 2017.
  DOI: 10.1002/anie.201708693