^‡ These authors contributed equally. In recent years, significant conceptual advances have taken place in the field of amide bond cross-coupling. Mild and selective functionalization of amides by transition-metal catalysis has an enormous potential for widespread applications in both industry and academia due to the unparalleled prevalence of amide-containing molecules. However, direct metal insertion into the N–C(O) amide bond is extremely difficult as a consequence of amidic resonance. In this account, we summarize our work on the development of new cross-coupling reactions of amides by N–C bond activation, and briefly discuss other modern developments in this area. 1 Introduction 2 Amide Bond Ground-State Distortion 3 Acyl Amide N–C Cross-Coupling 3.1 Suzuki Cross-Coupling 3.2 Negishi Cross-Coupling 3.3 Esterification and Amidation via N–C Cross-Coupling 4 Decarbonylative Amide N–C Cross-Coupling 4.1 Heck Cross-Coupling 4.2 Suzuki Cross-Coupling 4.3 C–H Activation 4.4 Decarbonylative Borylation 5 Transition-Metal-Free Activation of Amide Bonds 6 Mechanistic Studies 7 Conclusions and Outlook

Amides are of fundamental interest in many fields of chemistry involving organic synthesis, chemical biology and biochemistry. Here, we report the first catalytic Buchwald–Hartwig coupling of both common esters and amides by highly selective C(acyl)–X (X = O, N) cleavage to rapidly access aryl amide functionality via a cross-coupling strategy. Reactions are promoted by versatile, easily prepared, well-defined Pd–PEPPSI type precatalysts, and proceed in good to excellent yields and with excellent chemoselectivity for the acyl bond cleavage. The method is user friendly because it employs commercially-available, moisture- and air-stable precatalysts. Notably, for the first time we demonstrate selective C(acyl)–N and C(acyl)–O cleavage/Buchwald–Hartwig amination under the same reaction conditions, which allows for streamlining amide synthesis by avoiding restriction to a particular acyl metal precursor. Of broad interest, this study opens the door to using a family of well-defined Pd(II)–NHC precatalysts bearing pyridine “throw-away” ligands for the selective C(acyl)-amination of bench-stable carboxylic acid derivatives.