Selectfluor‐Mediated Chlorination and Fluorination of Arenes: Late‐Stage Functionalization of APIs and Its Biological Effects

• Published in: ChemMedChem Vol. 18; no. 15; pp. e202300144 - n/a
• Main Authors: Gradl, Susanne, Zantop, Viviane, Gmeiner, Peter, Hübner, Harald, Heinrich, Markus R.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01-08-2023
• Subjects: active pharmaceutical ingredients; Aromatic compounds; Biological effects; Chloride ions; Chlorides; Chlorination; Chlorine; Dopamine receptors; Fluorination; Fluorine; Halogenation; Molecular Structure; Opioid receptors; Reagents; screening; Selectfluor; fluorination; screening; chlorination; active pharmaceutical ingredients; Selectfluor
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202300144

By using active pharmaceutical ingredients (APIs) previously recovered from expired drugs, it is shown that Selectfluor can act as a reagent for operationally simple late‐stage fluorination and chlorination of electron‐rich arenes under mild reaction conditions. As shown in mechanistic experiments, aromatic fluorination thereby competes with chlorine‐for‐fluorine exchange on Selectfluor and subsequent aromatic chlorination, whereat the chloride ions may either be provided by the hydrochloride salt of the respective API or by triethylammonium chloride. Biological testing of the fluorinated or chlorinated APIs at adrenergic, dopaminergic, muscarinergic, opioid or serotoninergic receptors demonstrated that improved binding affinities can be achieved via this straightforward strategy.
Late‐stage chlorination and fluorination of active pharmaceutical ingredients (APIs), which were previously recovered from expired drugs, was carried out under mild conditions using Selectfluor in the presence of the API hydrochloride salt or triethylammonium chloride. Biological testing revealed that improved binding affinities can be achieved via this straightforward strategy.