Guiding Ligand Selection in Copper-Catalyzed Cross Couplings via Principal Component Analysis

Copper-catalyzed Ullmann-type couplings are a promising alternative to Pd-catalyzed C-O and C-N bond formations. Recent discoveries of numerous second-generation ligands for Cu-mediated Ullmann-type cross-coupling reactions have broadened the scope to include less reactive aryl halides and nucleophiles and have also enabled lower copper and ligand loadings in these processes. However, in contrast to Pd chemistry, in-silico workflows for guiding systematic ligand selection from early-stage screening through optimization remain significantly less developed for Cu-catalyzed C-O and C-N bond coupling reactions. This report describes the application of Principal Component Analysis (PCA) for streamlining ligand selection in Cu-catalyzed Ullmann-type coupling reactions. It provides a “map” of more than 80 ligands used in Ullmann couplings and is designed to reveal reactivity trends and highlight areas of high and low yields, thereby facilitating prioritization of high-value experiments in both medicinal and process chemistry settings. Validation for C-N and C-O couplings is provided using literature datasets, along with the development and application of a PCA-guided screening set for Ullmann couplings.