Unified and green oxidation of amides and aldehydes for the Hofmann and Curtius rearrangements

The Hofmann and Curtius rearrangements have been widely used in organic synthesis and developed for the industrial production (5-100 kg) of pharmaceutically relevant amines/amides. However, the existing use of a stoichiometric organic oxidant [(diacetoxyiodo)benzene or trichloroisocyanuric acid for the Hofmann rearrangement] for amides or an activating reagent (diphenylphosphoryl azide for the Curtius rearrangement) for carboxylic acids is environmentally unfriendly and economically less attractive. Herein, we report the first green oxidation of amides and aldehydes with oxone and halide (and NaN3) to generate N-halo amides and acyl azides, respectively, both of which rearrange into the common isocyanate intermediates and subsequently produce stable carbamates or ureas (the Hofmann and Curtius rearrangements) when trapped with alcohols or amines. This unified green approach is highly efficient as demonstrated by more than 30 examples for each rearrangement. Importantly, this approach generates inorganic nontoxic K2SO4 as the only byproduct, which is advantageous over the existing methods that produced stoichiometric, toxic, and organic iodobenzene, and chloro-isocyanuric acid, or diphenylphosphoric acid. Notably, three urea-based drugs and eight chiral urea catalysts were efficiently synthesized from corresponding aldehydes by this green oxidative Curtius rearrangement. This green oxidative approach for the Hofmann and Curtius rearrangements is expected to find wide applications in organic synthesis and process chemistry. The oxone-halide green oxidation system is extended to the oxidation of primary amides and aromatic aldehydes (with sodium azide) to generate N-haloamide and acyl azides, respectively, for subsequent Hofmann and Curtius rearrangements.

Automated summary

The Hofmann and Curtius rearrangements have been achieved through a green oxidation method using oxone and halide (and NaN3) to generate N-halo amides and acyl azides from amides and aldehydes, respectively. These intermediates further rearrange into stable carbamates or ureas (the Hofmann and Curtius rearrangements) when trapped with alcohols or amines. The method is efficient, environmentally friendly, and produces only non-toxic K2SO4 as a byproduct.