Cross-coupling of amides by N-C bond activation

The amide bond is one the most important functional motifs in chemistry and biology. However, despite the central role of amides as ubiquitous pharmacophores in medicinal chemistry, but also as bench-stable intermediates in organic synthesis, transition-metal- catalyzed transformations of amides by N-C bond activation have been unexplored. The major reason is that high activation energy is required for the N-C(O) bond scission due to nN→*πC=O conjugation (amide bond resonance of 15-20 kcal/mol in planar amides, ca. 40% double bond character). In 2015, we introduced a new generic mode of activation of amide bonds by geometric distortion, whereby metal insertion into an inert amide bond can proceed only if the classic Pauling's amide bond resonance has been disrupted. With this new concept put forward, we successfully developed several new types of twisted amides and metal-catalyzed transformations during my Ph.D. research. The focus of this thesis is on three parts: (1) the use of amides as acyl electrophiles in metal-catalyzed Suzuki cross-coupling reactions; (2) the use of amides as aryl electrophiles in metal-catalyzed cross-coupling reactions, including palladium-catalyzed Heck reaction and rhodium-catalyzed C-H bond functionalization; (3) the development of new type of amides as acyl electrophiles with the use of new Pd-NHC catalyst systems. These studies have demonstrated the potential of amides as acyl- and aryl-electrophiles in catalytic cross-coupling chemistry by activation of the typically inert amide N-C(O) bond.Ph.D.Includes bibliographical reference