The Formal Cross-Coupling of Amines and Carboxylic Acids to Form sp3 -sp3 Carbon-Carbon Bonds

Abstract

We have developed a deaminative-decarboxylative protocol to form new carbon(sp³ )-carbon(sp³ ) 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.

Keywords: C−C coupling; amines; carboxylic acids; high-throughput screening; nickel.