Scalable Electrochemical Hofmann Rearrangement as Platform for Orthogonally Protected Aminoketone Synthons

Abstract

The Hofmann rearrangement is among the most reliable methods for the conversion of primary carboxamides into amines and carbamates, yet access to free α-aminoketone building blocks through this transformation remains elusive. Under the oxidative and basic conditions required, non-protected enolizable ketones are incompatible with oxidative halo species and basic environment necessary for this transformation, whereas the resulting α-amido compounds are chemically and configurationally labile. Here, we show that masking β-ketoamides as cyclic acetals enables electrochemical Hofmann rearrangement in flow with an orthogonal deprotection pathway to the carbamate generated during the transformation. Under galvanostatic conditions, using sodium bromide as both mediator and supporting electrolyte, acetal-protected β-ketoamides are converted into the corresponding methyl carbamates in good to excellent yields. The process established avoids stoichiometric chemical oxidizers and has been demonstrated on gram to hectogram scale (100 g) without loss of efficiency, allowing recovery and reuse of the bromide as mediator. The resulting orthogonally protected carbamates serve as versatile divergent intermediates: chemoselective cleavage of either protecting group, grants access to ketones and amines, whereas sequential deprotection furnishes free 2-aminocycloalkanones and fused azaheterocycles by telescoped, purification-free sequences. The integration of electrochemistry and flow processes thus provides a scalable and sustainable platform for accessing orthogonally protected aminoketone synthons as versatile carbonyl-containing nitrogen building blocks.