Nickel-Catalyzed Sonogashira Couplings: Extending the Reaction Scope to Aryl Bromides and Chlorides

Abstract

The alkyne motif is present in several naturally occurring molecules and specialty chemicals. The Sonogashira reaction is recognized as one of the most exploited methods for the synthesis of substituted alkynes. While palladium catalysts have been traditionally employed, recent efforts have been directed towards developing alternatives based on Earth-abundant metals such as nickel. However, nickel-catalyzed Sonogashira couplings still present important substrate limitations. While more reactive aryl iodides have been well documented, the coupling of more challenging yet cost-effective aryl bromides and chlorides lags significantly behind. Herein, we present a method for the nickel-catalyzed Sonogashira coupling of aryl bromides and chlorides, whose discovery was accelerated thanks to high-throughput experimentation. Fine-tuning of the bipyridine ligand was essential to activate chemoselectively C(sp2)−Br or C(sp2)−Cl bonds. A wide range of functionally diverse alkynes, including examples of active ingredients and their intermediates, were accessed in a single step and with yields up to 98%. The developed methodology is expected to be widely adopted by academia and industry, marking a step forward in the field of base metal catalysis.