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Z-alkenyl halides made easy

Tough-to-prepare motif succumbs to metathesis

by Bethany Halford
March 25, 2016 | A version of this story appeared in Volume 94, Issue 13

Hoveyda’s group used cross-metathesis to make the Z-alkenyl fluoride in this derivative of the antidepressant perphenazine.
Structure of a perphenazine analog that contains a Z-alkenyl fluoride.
Hoveyda’s group used cross-metathesis to make the Z-alkenyl fluoride in this derivative of the antidepressant perphenazine.

One of organic chemists’ dirty little secrets, says Boston College’s Amir Hoveyda, is how hard it is to make alkenyl halides, a motif that features a halide attached to a double bond. “We use them all the time for cross-coupling,” he says, “but we never talk about how we make them.” The truth, Hoveyda says, is that making alkenyl bromides and chlorides is difficult, and making alkenyl fluorides is almost unheard of—until now.

Hoveyda, along with Boston College chemists Ming Joo Koh, Thach T. Nguyen, and Hanmo Zhang and MIT’s Richard R. Schrock, has now used cross-metathesis chemistry to prepare Z-alkenyl bromides, chlorides, and fluorides (Nature 2016, DOI: 10.1038/nature17396). Cross-metathesis reactions are those that use a metal catalyst to get the carbons in two carbon-carbon double bonds to swap their bonding partners and form two new carbon-carbon double bonds. This reaction exchanges the substituents attached to the carbon atoms.

A molybdenum catalyst developed by Hoveyda’s group makes this cross-metathesis reaction work well with Z-dihaloalkenes, which came as a surprise to Hoveyda, he says, after structural analysis suggested the reaction wouldn’t work. “Our only hope was that the reaction intermediates, although they are not very stable, would stick around long enough to do the chemistry, and lo and behold they did,” he says. The reaction works efficiently to give Z-alkenyl halides—also known as cis-alkenyl halides—in high yield. It also tolerates a variety of functional groups, suggesting the transformation could be used in the late stages of a synthetic scheme.

“Hoveyda and colleagues’ transformation offers a powerful strategy for preparing cis-alkenyl halides, especially given that alkenes are abundant motifs in fine chemicals such as pharmaceuticals and agrochemicals,” writes David Sarlah, a chemistry professor at the University of Illinois, Urbana-Champaign, in a commentary on the new work.

Hoveyda tells C&EN that an air-stable paraffin capsule containing the catalyst will be commercially available from Aspira Scientific in the near future.



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