The Formal Cross-Coupling of Amines and Carboxylic Acids to Form sp3–sp3 Carbon–Carbon Bonds
Zirong Zhang
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 930 N University Ave, Ann Arbor, MI, 48109 USA
Search for more papers by this authorCorresponding Author
Prof. Tim Cernak
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 930 N University Ave, Ann Arbor, MI, 48109 USA
Search for more papers by this authorZirong Zhang
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 930 N University Ave, Ann Arbor, MI, 48109 USA
Search for more papers by this authorCorresponding Author
Prof. Tim Cernak
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 930 N University Ave, Ann Arbor, MI, 48109 USA
Search for more papers by this authorGraphical Abstract
An amine–carboxylic acid C−C coupling would be a valuable addition to the synthetic toolbox of carbon–carbon bond-forming reactions. Using miniaturized high-throughput experimentation, we have developed the first amine–acid cross-coupling to form C(sp3)−C(sp3) bonds based on preactivation of the building blocks and nickel catalysis.
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.
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