Although cross-coupling reactions of amides by selective N-C cleavage are one of the most powerful and burgeoning areas in organic synthesis due to the ubiquity of amide bonds, the development of mechanochemical, solid-state methods remains a major challenge. Herein, we report the first mechanochemical strategy for highly chemoselective, solvent-free palladium-catalyzed cross-coupling of amides by N-C bond activation. The method is conducted in the absence of external heating, for short reaction time and shows excellent chemoselectivity for σ N-C bond activation. The reaction shows excellent functional group tolerance and can be applied to late-stage functionalization of complex APIs and sequential orthogonal cross-couplings exploiting double solventless solid-state methods. The results extend mechanochemical reaction environments to advance the chemical repertoire of N-C bond interconversions to solid-state environmentally friendly mechanochemical methods.
Keywords: Amide bonds; Mechanochemistry; N−C cleavage; Solvent-free; Suzuki-Miyaura cross-coupling.
© 2021 Wiley-VCH GmbH.