Scalable Electrochemical Hofmann Rearrangement as Platform for Orthogonally Protected Aminoketone Synthons

The Hofmann rearrangement is among the most reliable
methods for the conversion of primary carboxamides into amines and carba-
mates, yet access to free α-aminoketone building blocks through this transfor-
mation remains elusive. Under the oxidative and basic conditions required,
non-protected enolizable ketones are incompatible with oxidative halo spe-
cies 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 electro-
chemical Hofmann rearrangement in flow with an orthogonal deprotection
pathway to the carbamate generated during the transformation. Under galva-
nostatic 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
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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 pro-
vides a scalable and sustainable platform for accessing orthogonally protected aminoketone synthons as versatile carbonyl-containing
nitrogen building blocks.