Unleashing the Power of Potassium 2-Ethylhexanoate as a Mild and Soluble Base for Pd-catalyzed C-N Cross-Coupling

The formation of C-N bonds by Pd-catalyzed cross-coupling is one of the most widely practiced reactions in chemical synthesis. Typical reaction conditions involve either a strong base, which limits the scope of substrates, or an insoluble, inorganic base, which complicates running reactions on large scale. Reaction conditions are needed that can facilitate C-N couplings using a base that is both mild and soluble. We report the discovery of a combination of a phosphorinane ligand and a soluble carboxylate base, potassium 2-ethylhexanoate (K-2-EH) that, together, facilitate the coupling of base-sensitive reactants. To explore the enhanced substrate scope of reaction with this base and catalyst, we performed a scope evaluation using representative reactants selected from the chemical literature using chemical descriptors and clustering to ensure their chemical diversity. These results show that this phosphorinane ligand and K-2-EH couple primary aliphatic amines, amides, sulfonamides, and heteroaromatic nucleophiles, as well as acidic secondary nitrogen nucleophiles, such as secondary arylamines, heteroarylamines, and amides, with a range of electrophiles. The stabilities of several coupling products in the presence of a range of previously reported bases show that other soluble bases de-compose those products under standard reaction conditions, while K-2-EH did not. Finally, quantitative structure-reactivity relationship models, trained on ligand screening data, were developed to understand the structural features that engender reactivity.