but the trend is that the mildest conditions and lowest catalysts loadings can be achieved when expensive palladium catalysts are employed.Scheme 1-2 General mechanism for palladium-catalyzed cross-coupling reactions.These methods nowadays belong to the standard repertoire of organic synthesis and their importance can be hardly overrated, since the production of an enormous number of lifesaving drugs relies on cross-coupling chemistry. These monumental achievements were honored with the Nobel Prize, awarded in 2010 to Akira Suzuki, Ei-ichi Negishi and Richard F. Heck, [20] and the Wolf Prize 2019, awarded to Stephen L. Buchwald and John F. Hartwig. [21] Despite these advances, catalysis in general and coupling reactions in particular remain an attractive research area due to multiple challenges that are still associated with the atom-and step-economy of the envisioned transformations.
C−H ActivationThe prefunctionalization of substrates tworards the nucleophile/electrophile pair, that is needed for traditional cross-coupling, causes chemical waste during each synthetic step (Scheme 1-3, a). Moreover, many organometallic reagents call for special handling precautions due to their toxicity and/or hydrolytic sensitivity. An arguably more direct approach is reductive cross-coupling of two electrophiles (Scheme 1-3, b). [22] However, in addition to the innate challenge of overcoming undesired homocoupling, the waste balance is similarly problematic. In this context, C−H activation emerged as a powerful approach to unlock expedient reactivities of ubiquitously occurring C−H bonds while circumventing