Visible‐Light‐Mediated Synthesis of β‐Chloro Ketones from Aryl Cyclopropanes

• Published in: Angewandte Chemie International Edition 2019-06, Vol.58 (25), p.8577-8580
• Main Authors: Petzold, Daniel, Singh, Pardeep, Almqvist, Fredrik, König, Burkhard
• Format: Article
• Language: English
• Subjects: Aromatic compounds; aryl cyclopropane; Bioactive compounds; Chlorine; Cyclopropane; Hydrochloric acid; Ketones; Labeling; late-stage modification; Nitric acid; Organic compounds; photochemistry; radical chain reaction; radical chain reactions; Reagents; Synthesis; β chloro ketone; β-chloro ketones
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.201902473

We report the visible‐light‐mediated synthesis of β‐chloro ketones from aryl cyclopropanes, oxygen, hydrochloric acid, and nitric acid. The operationally simple and catalyst‐free method uses cheap standard laboratory reagents and displays broad functional‐group tolerance. Moreover, scale up of the reaction and late‐stage functionalization of bioactive compounds is possible, providing the opportunity to utilize the cyclopropane ring as a masked β‐chloro ketone in a reaction sequence. We propose a light‐driven radical chain reaction initiated by the reaction of diluted hydrochloric and nitric acid to produce small quantities of molecular chlorine. The mechanistic hypothesis is supported by 18O labelling and UV/Vis experiments, cyclovoltammetry, and several control reactions. With a light touch: In situ generation of Cl2 from highly diluted HCl and HNO3 and its light‐mediated cleavage leads to efficient oxochlorination of aryl cyclopropanes. This method tolerates a wide range of functional groups and can be scaled up easily. The products are valuable synthetic intermediates that are difficult to obtain otherwise, and which might also find application in biochemistry, for example, as precursors to antibody–drug conjugates.