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C-H Activation

Strong, aliphatic C–H bonds succumb to direct arylation

Dual-catalyst approach allows chemists to construct connections between a vast array of aliphatic and aromatic molecules

by Bethany Halford
August 1, 2018 | A version of this story appeared in Volume 96, Issue 32


A coupling reaction uses decatungstate and a nickel catalyst to forge a bond between an aliphatic and an aryl bromide to make epibatidine.
A new dual-catalysis reaction can make a protected version of the potent alkaloid epibatidine.

While many chemistries have been developed to incite C–H bonds to react, certain types of aliphatics stubbornly resist such transformations. Now, chemists at Princeton University and Merck & Co. have come up with a dual-catalyst reaction that activates aliphatics with recalcitrant C–H bonds, provoking them to react with aryl bromides.

The finding opens new avenues for medicinal chemists, who are always on the lookout for reactions that give them the ability to add complexity to existing drug candidates quickly and easily, says Princeton’s David W. C. MacMillan, who led the research. The reaction will allow medicinal chemists to tweak a compound to improve its properties or to prepare a series of similar compounds to compare how structural modifications alter their activity.

The reaction combines light-driven, polyoxometalate-facilitated hydrogen atom transfer and nickel catalysis (Nature 2018, DOI: 10.1038/s41586-018-0366-x). A decatungstate catalyst generates carbon-centered radicals from strong, neutral C–H bonds. These radicals then act as nucleophiles in nickel-mediated cross-coupling with aryl bromides, forging C(sp3)–C(sp2) bonds between the aliphatic and aryl groups.

“You go into this thinking it’s going to be an unholy mess, but it turns out it’s exquisitely selective,” MacMillan says, adding that the group can predict with 95% accuracy which C–H bond will react. The C–H bond that reacts must yield a stable radical and that radical must be able to attach to the nickel and participate in reductive elimination with the metal.

“The direct cross-coupling of unactivated, aliphatic C–H bonds is one of those transformations that synthetic chemists dream about,” comments Erik Alexanian, an organic chemist who studies aliphatic C–H functionalization at the University of North Carolina, Chapel Hill. The new reaction, he says “is sure to find broad application. It’s a wonderful example of how innovative applications of dual catalysis can unlock solutions to challenging problems in synthesis.”


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