Green-Solvent Selection for Acyl Buchwald–Hartwig Cross-Coupling of Amides (Transamidation)

The selection of solvents is essential as a suitable reaction milieu in chemical processes of industrial and academic impact. We present an evaluation of a range of green solvents for acyl Buchwald–Hartwig cross-coupling of amides to provide the first green-solvent selection guide for this powerful C–N to C–N′ cross-coupling interconversion engaging typically inert amide bonds, resulting in a net transamidation process of historically challenging amide bonds. Of the solvents considered, methyl tert-butyl ether (MTBE) and 2-methyltetrahydrofuran (2-MeTHF) were identified as the preferred alternative solvents for the acyl-Buchwald–Hartwig cross-coupling using well-defined and robust Pd(II)–NHC (NHC = N-heterocyclic carbene) precatalysts. MTBE and, in particular, 2-MeTHF are superior solvents in this cross-coupling manifold and recommended in terms of safety, health, biodegradability, and environmental score. The results indicate the replacement of hazardous solvents with green organic solvents in the biorelevant C–N to C–N′ cross-coupling manifold of amides to further the burgeoning chemical repertoire of amide-bond activation methods.