Practical Electrochemical Anodic Oxidation of Polycyclic Lactams for Late Stage Functionalization

• Published in: Angewandte Chemie International Edition 2015-09, Vol.54 (36), p.10555-10558
• Main Authors: Frankowski, Kevin J., Liu, Ruzhang, Milligan, Gregory L., Moeller, Kevin D., Aubé, Jeffrey
• Format: Article
• Language: English
• Subjects: Amides; anodic oxidation; Anodizing; Complement; Derivatives; Dichloromethane; diversity-oriented synthesis; Electrochemical Techniques - methods; Electrochemistry; Electrodes; heterocycles; Intermediates; lactams; Lactams - chemistry; Lewis acid; N-acyliminium ions; Nuclear electric power generation; Oxidation; Oxidation-Reduction; Regeneration; Strategy; Synthesis
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201504775

Electrochemistry provides a powerful tool for the late‐stage functionalization of complex lactams. A two‐stage protocol for converting lactams, many of which can be prepared through the intramolecular Schmidt reaction of keto azides, is presented. In the first step, anodic oxidation in MeOH using a repurposed power source provides a convenient route to lactams bearing a methoxy group adjacent to nitrogen. Treatment of these intermediates with a Lewis acid in dichloromethane permits the regeneration of a reactive acyliminium ion that is then reacted with a range of nucleophilic species. An improvised electrochemical apparatus was constructed and utilized for the anodic oxidation of complex lactam substrates. Combining synthetic electrochemistry with the azido‐Schmidt/lactam disconnection has enabled the synthesis of novel lactam derivatives by N‐acyliminium ion diversification. This mild, late‐stage functionalization strategy complements the methods for heterocycle synthesis.