The Formal Cross‐Coupling of Amines and Carboxylic Acids to Form sp<sup>3</sup>–sp<sup>3</sup> Carbon–Carbon Bonds
Zirong Zhang, Tim Cernak
Abstract
) bonds from activated amines and carboxylic acids. Amines and carboxylic acids are ubiquitous building blocks, available in broad chemical diversity and at lower cost than typical C-C coupling partners. To leverage amines and acids for C-C coupling, we developed a reductive nickel-catalyzed cross-coupling utilizing building block activation as pyridinium salts and redox-active esters, respectively. Miniaturized high-throughput experimentation studies were critical to our reaction optimization, with subtle experimental changes such as order of reagent addition, composition of a binary solvent system, and ligand identity having a significant impact on reaction performance. The developed protocol is used in the late-stage diversification of pharmaceuticals while more than one thousand systematically captured and machine-readable reaction datapoints are reposited.