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Allylic C–H Oxidation Yields Cyclic Ethers

Palladium-catalyzed C–H activation route uses alcohol nucleophiles for the first time to make cyclic ether drug candidates

by Stu Borman
July 14, 2014 | A version of this story appeared in Volume 92, Issue 28

A palladium-catalyzed C–H bond-activation reaction starting with terminal olefins makes it possible to synthesize pharmaceutically important six-membered cyclic ethers with unprecedented generality (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja503322e). Cyclic ethers such as chromans and pyrans are common elements in bioactive small molecules. But reactions used to create cyclic ethers are highly varied, involving different types of starting materials, catalysts, and reaction conditions—potentially making it difficult to decide which synthetic route to take. Using alcohols as nucleophiles to functionalize C–H bonds has not been one of the available options for making cyclic ethers. M. Christina White and coworkers at the University of Illinois, Urbana-Champaign, have now devised a Pd(II)/sulfoxide-catalyzed allylic C–H oxidation reaction that for the first time uses alcohol nucleophiles for that purpose. The reaction has a novel proposed mechanism in which allylic C–H cleavage to form a π-allyl intermediate, alcohol deprotonation, and C–O bond formation all occur at the palladium metal center. White’s team believes the reaction will be useful to chemists seeking to access cyclic ether-based drug candidates.


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