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It’s hard to improve on a classic. But Richard Y. Liu was eager to take on that challenge.
Cross-coupling reactions, including Suzuki-Miyaura coupling and Buchwald-Hartwig amination, are some of the most-used transformations in organic synthesis. Chemists have used them for decades to construct molecular scaffolds. The reactions have “had so many years to be optimized to work with almost everything,” says Liu, an assistant professor of chemistry and chemical biology at Harvard University. The list of molecular pieces that these reactions can stitch together is constantly growing, adding to the chemical space of complex molecules that chemists can create with the techniques.
Liu doesn’t want to just add to chemical space, though. He wants to multiply it by developing reactions that use existing starting materials in new ways.
Now he and his group have unveiled a three-component reaction that takes Suzuki coupling partners—an aryl halide and an arylboronic acid—and inserts a nitrogen between them to make an amine product (Science 2024, DOI: 10.1126/science.adl5359).
“I love this theme of getting alternative products without buying any new starting material,” Liu says. This remixed cross coupling effectively makes Buchwald products from Suzuki starting materials, a strategy Liu says could be useful for medicinal chemists looking to quickly screen their libraries of cross-coupling fragments for combinations with pharmaceutical potential.
He and his team took inspiration from carbonylative cross-coupling reactions that put carbon monoxide between the organic fragments to make a ketone. But instead of CO, they used an electrophilic nitrogen source.
It was a bit tricky to get all three pieces to come together correctly, Liu says. “Every time you add more components, more things can go wrong.” The researchers had to deliberately slow down the Suzuki reaction’s catalytic cycle using a bulky phosphine ligand so that the nitrogen would have time to jump in.
The researchers ensured the reaction worked with a wide variety of medicinally relevant aryl halide and boronic acid coupling partners, even using it to modify entire drug molecules. And by adding carbon monoxide, they found that it’s possible to do a four-component reaction to make an amide.
The work is “a great example of inventing new catalytic cycles based on fundamental knowledge,” says Jin-Quan Yu of Scripps Research in California in an email. He says that the Buchwald reaction still has many advantages for synthesis but that this new reaction is a nice complement.
Liu says he and his group are working to identify new tricks to coax out of old reactions. And they want others to be inspired to do the same. “We’re hoping that academics could look at this strategy and think, ‘What else can we insert in there?’ ”.
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