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Abstract Amides are among the most important and ubiquitous functional groups in organic chemistry and process development. In this Practical Synthetic Procedure, a protocol for the Suzuki–Miyaura cross-coupling of amides by selective N–C(O) bond activation catalyzed by commercially available, air- and moisture-stable palladium/N-heterocyclic carbene (NHC) complexes is described. The procedure described involves [Pd(IPr)(cin)Cl] [IPr = 2,6-(diisopropylphenyl)imidazol-2-ylidene, cin = cinnamyl] at 0.10 mol% at room temperature and is performed on decagram scale. Furthermore, a procedure for the synthesis of amide starting materials is accomplished via selective N-tert-butoxycarbonylation, which is the preferred method over N-acylation. The present protocol carries advantages of operational simplicity, commercial availability of catalysts, and excellent conversions at low catalyst loadings. The method is generally useful for activation of N–C(O) amide bonds in a broad spectrum of amide precursors. The protocol should facilitate the implementation of amide cross-coupling reactions. 

The cross-coupling of aryl esters has emerged as a powerful platform for the functionalization of otherwise inert acyl C–O bonds in chemical synthesis and catalysis. Herein, we report a combined experimental and computational study on the acyl Suzuki–Miyaura cross-coupling of aryl esters mediated by well-defined, air- and moisture-stable Pd( ii )–NHC precatalysts [Pd(NHC)(μ-Cl)Cl] 2 . We present a comprehensive evaluation of [Pd(NHC)(μ-Cl)Cl] 2 precatalysts and compare them with the present state-of-the-art [(Pd(NHC)allyl] precatalysts bearing allyl-type throw-away ligands. Most importantly, the study reveals [Pd(NHC)(μ-Cl)Cl] 2 as the most reactive precatalysts discovered to date in this reactivity manifold. The unique synthetic utility of this unconventional O–C(O) cross-coupling is highlighted in the late-stage functionalization of pharmaceuticals and sequential chemoselective cross-coupling, providing access to valuable ketone products by a catalytic mechanism involving Pd insertion into the aryl ester bond. Furthermore, we present a comprehensive study of the catalytic cycle by DFT methods. Considering the clear advantages of [Pd(NHC)(μ-Cl)Cl] 2 precatalysts on several levels, including facile one-pot synthesis, superior atom-economic profile to all other Pd( ii )–NHC catalysts, and versatile reactivity, these should be considered as the ‘first-choice’ catalysts for all routine applications in ester O–C(O) bond activation. 

The Pd–NHC-catalyzed acyl-type Buchwald–Hartwig cross-coupling of amides by N–C(O) cleavage (transamidation) provides a valuable alternative to the classical methods for amide synthesis. Herein, we report a combined experimental and computational study of the Buchwald–Hartwig cross-coupling of amides using well-defined, air- and moisture-stable [Pd(NHC)(allyl)Cl] precatalysts. Most crucially, we present a comprehensive evaluation of a series of distinct Pd( ii )–NHC precatalysts featuring different NHC scaffolds and throw-away ligands for the synthesis of functionalized amides that are not compatible with stoichiometric transition-metal-free transamidation methods. Furthermore, we present evaluation of the catalytic cycle by DFT methods for a series of different Pd( ii )–NHC precatalysts. The viability of accessing NHC-supported acyl-palladium( ii ) amido complexes will have implications for the design and development of cross-coupling methods involving stable amide electrophiles.