Mechanochemical Solvent-Free Suzuki-Miyaura Cross-Coupling of Amides via Highly Chemoselective N-C Cleavage.

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 remain 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 rection time and shows excellent chemoselectivity for s 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 solvent-less solid-state methods. The results further mechanochemical reaction environments to advance the chemical repertoire of N-C bond interconversions to solid-state environmentally-friendly mechanochemical methods.