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Alcohols From Aliphatics

Organic Synthesis: Reaction transforms primary C–H bonds with help from oxygen atom, catalyst

by Bethany Halford
March 5, 2012 | A version of this story appeared in Volume 90, Issue 10

A reaction scheme showing silyl ether stretching across three carbons to form a five-membered ring.
Silyl ether stretches across three carbons to functionalize a C–H bond.

Mundane primary C–H bonds can be turned into useful C–OH moieties with the help of an oxygen atom in the same molecule and an iridium catalyst (Nature, DOI: 10.1038/nature10785). The new reaction, developed by University of California, Berkeley, chemists John F. Hartwig and Eric M. Simmons, creates 1,3-diols—a molecular motif found in polymers, pharmaceuticals, and natural products.

Selectively functionalizing a single, unactivated C–H bond in a molecule that’s full of them presents a considerable challenge for synthetic chemists, since the difference in reactivity between such groups is subtle. Hartwig and Simmons realized they could make an unreactive primary alkyl group into a reactive site if they used a nearby oxygen atom as a guide.

They used diethylsilane to transform an alcohol or ketone precisely three carbons away from the primary C–H bond into a silyl ether. In the presence of an iridium-phenanthroline catalyst, the silicon atom in this group reaches across the three carbons and displaces hydrogen to form a five-membered ring in a C–H silylation reaction. Subsequent oxidation turns the molecule into a 1,3-diol.

“The key challenge was to identify a catalyst system that was reactive enough to activate aliphatic C–H bonds yet would selectively functionalize only a single C–H bond,” Simmons tells C&EN. It was only by combining diethylsilane and a phenanthroline ligand that they were able to achieve this goal, Simmons says.

The reaction selectively functionalizes only the primary C–H bond three carbon atoms away from the oxygen guide, even when there are more reactive C–H bonds in the molecule. The transformation proceeds in good yield and tolerates a range of functional groups.

“This method should be suitable for the total synthesis of complex molecules containing a variety of functional groups, as well as in the top-down derivatization of isolated natural products, active pharmaceutical ingredients, and medicinal chemistry intermediates,” Hartwig points out. He adds that there are several directions the researchers can go next with the new reaction. For example, he’d like to apply the approach to secondary C–H bonds.

“In many ways, this method is a game-changer for those interested in using guided C–H functionalization logic in synthesis,” comments Phil S. Baran, an organic synthesis expert at Scripps Research Institute. “It is one of the few options out there for achieving selective hydroxylation of unactivated aliphatic C–H bonds that are not the most inherently reactive ones—and that has stood as the primary challenge in this area for decades.”



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