Advertisement

If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.

ENJOY UNLIMITED ACCES TO C&EN

Fluorination

Asymmetric difluorination of alkenes achieved

Challenging reaction efficiently generates sought-after chiral difluoromethyl groups

by Stephen K. Ritter
July 1, 2016 | A version of this story appeared in Volume 94, Issue 27

Reaction scheme shows asymmetric difluorination of styrene derivatives to create chiral difluoromethyl groups.
This new difluorination method converts the C=C bond of styrene derivatives to a chiral difluoromethyl group.

The rapid advances made in synthetic organic fluorine chemistry over the past decade have led to the design of yet another sought-after reaction. Harvard University’s Eric N. Jacobsen and coworkers have created a direct catalytic method to convert alkenes to versatile chiral building blocks containing difluoromethyl groups (Science 2016, DOI: 10.1126/science.aaf8078).

The 1,1-difluoromethyl group, -CF2H, is a chemically inert lipophilic group that helps pharmaceuticals and agrochemicals reach their intended targets and helps prevent them from being metabolized too quickly. In particular, difluoromethyl has a slightly acidic C–H bond that enables it to serve as a surrogate for alcohols and thiols, which are key recognition elements for biologic targets such as enzymes and proteins. Chemists have several methods to generate difluoromethyl groups, but until now a general stereochemically controlled method has been elusive.

Jacobsen’s group discovered that the combination of hydrogen fluoride with an aryl iodide catalyst and an oxidizing agent can generate chiral difluoromethyl groups by reconfiguring the C=C bond of styrene derivatives bearing amide or ester groups. The new reaction builds on work reported earlier this year by the Jacobsen group (J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.6b02391) and Ryan Gilmour’s group at the University of Münster (J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.6b01183).

Working independently, the two teams discovered that an HF/aryl iodide system can facilitate the 1,2-difluorinaton of alkenes. Jacobsen’s group has now shown that steric control by choice of substituents on the double bond carbons can also direct the reaction, via an aryl migration process, to selectively form the chiral 1,1-difluoromethyl product.

The direct and efficient formation of strategically vital difluoromethylated stereocenters “is a beautiful solution to a timely problem,” Gilmour says.

“Over the past decade, chemists have successfully put fluorine in lots of different places,” adds Tobias Ritter of the Max Planck Institute for Kohlenforschung. “Difluoromethyl groups are really useful but often difficult to access, especially selectively. These now accessible molecules will almost certainly find immediate applications as useful building blocks.”

Advertisement

Article:

This article has been sent to the following recipient:

0 /1 FREE ARTICLES LEFT THIS MONTH Remaining
Chemistry matters. Join us to get the news you need.