The most significant advances in ligand-driven Pd-catalyzed organic synthesis over the past two years are presented. Processes involving C─H activation of substrates, avoiding their prefunctionalization are illustrated. Both the activity and selectivity of the catalyst depend on the design of the ligands (pyridones, pyridines, amino acids, phosphines, thioacids) and their interaction with the metal and the substrates.

Abstract

The activation of C─H bonds mediated by transition metals has become an essential tool for synthetic chemists, enabling more efficient, selective, and sustainable processes. This progress has been driven by the elimination of precursor prefunctionalization, shortening and reducing the cost of syntheses. However, challenges remain in this methodology, both in terms of activity and selectivity. The introduction of DG to achieve maximum selectivity represents the core of this issue, as it fails to overcome the problem of prefunctionalization, and reaction control remains dependent on substrate design. Recently, we have witnessed a revolution in this field, as activity and selectivity of new processes are no longer controlled by the substrate but by the catalyst. It is the design of the catalyst itself—particularly the ligands—that determines whether the reaction occurs, its rate, and selectivity. This review analyzes the crucial role of ligands in Pd-catalyzed C─H functionalizations in the period from 2022 to the present, focusing on five types of ligands:(i) mono-N-protected amino acids (MPAAs); (ii) pyridones; (iii) pyridines, related N-heterocycles; (iv) thioacids; (v) phosphines and NHCs. For each category, its role, how the reaction is accelerated, and the origin of its selectivity is analyzed.