Cobalt-Catalyzed Cross-Coupling Reactions of Bench-Stable Zinc Reagents

Jan 13, 2017

Transition-metal-catalyzed cross-coupling reactions are indispensable tools for the construction of carbon-carbon bonds, which is of great importance for the synthesis of pharmaceuticals and agrochemicals. Boron organometallics have been extensively used for such reactions in medicinal chemistry, due to their broad availability and air- and moisture-stability, however many boronic esters have genotoxic properties which make their manipulations on an industrial scale especially difficult. In comparison, organozinc reagents display an excellent functional group compatibility and a better reactivity in coupling reactions. One of the most prominent applications for organozinc reagents is their use for the so-called Negishi cross-coupling, which earned its discoverer a share of the Nobel Prize for Chemistry in 2010. Most of these reactions are catalyzed by palladium or nickel; however, these metals have the disadvantage of toxicity and/or high costs. In contrast, cobalt salts are an inexpensive and less toxic alternative for carbon-carbon bond forming reactions.

Solid and bench-stable organozinc reagents (Picture: Peter Dowling)

LMU chemists, including the graduate student Jeffrey Hammann and the master student Ferdinand Lutter, led by Professor Paul Knochel have now developed a robust and broadly applicable cobalt-catalyzed cross-coupling of solid and bench-stable organozinc reagents. “Cobalt-catalyzed couplings are of special interest since cobalt salts are much less toxic than palladium salts and additionally are ca. 800 times cheaper,” notes Professor Knochel. “These coupling reactions can also be performed in technical (undistilled) THF with similar efficiency.”

Cross-couplings between heterocyclic moieties are also a synthetic challenge in industrial research. When palladium or nickel catalysts are used, catalyst deactivation is often observed owing to chelation of the reagents with the catalyst. “This method can also easily link heterocyclic moieties. The spectrum of coupling partners undergoing these couplings is very broad,” says Professor Knochel. “Basically, these coupling reactions can be performed with almost all types of unsaturated organic halides bearing various sensitive functional groups." These results appeared in the leading journal Angewandte Chemie International, and open the way to the use for a whole series of applications relevant to the pharmaceutical and agrochemical industry replacing palladium- or nickel-catalysts by inexpensive and less toxic cobalt-catalysts.

Publication: Angewandte Chemie