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Medicinal Chemistry

Bulking up reagents with palladium lets chemists couple complex components

Starting materials are stable, reliable, and reasonably priced on small scales

by Bethany Halford
January 27, 2019 | A version of this story appeared in Volume 97, Issue 4


Reaction scheme shows a couple reaction that joins a complex, palladium-containing molecule with morpholine.

Palladium is a power tool for assembling molecules. Reactions catalyzed by the noble metal are key to making materials, medicines, and chemical probes. But when chemists want to add groups to molecules that are already complex, like many drugs, palladium- catalyzed reactions can be finicky, requiring considerable tinkering and time. Now, chemists led by Massachusetts Institute of Technology’s Stephen L. Buchwald and the University of ­Michigan’s Tim Cernak (who did the ­research while working at Merck & Co.) have come up with an alternative to Pd-catalyzed reactions that constructs complex molecules quickly. The reaction still makes use of Pd’s coupling power, but instead of using catalytic amounts of the metal, the researchers designed complex reactants that each include a Pd atom (Science 2019, DOI: 10.1126/science.aac6153). These Pd-containing starting reagents remain reactive, even after sitting on a benchtop for months, and reactions with them (example shown) work under milder conditions and with higher success than analogous Pd-catalyzed processes. Although Pd is expensive, these reactions don’t require much of it, costing about $1 for a 25 mg-scale reaction, the authors note, which is typical for drug discovery.


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