(Invited) Electrochemical Hydrodefluorination of Trifluoromethyl Groups

Abstract

The difluoromethyl group (CF2H) has attracted significant recent attention in medicinal chemistry. This complements the well-documented importance of fluorine in small-molecule pharmaceuticals that impact bioavailability, potency and pharmacokinetics. This is exemplified by 28% of FDA-approved drugs containing one or more fluorine atom. The CF2H group is an H-bond donor that is also lipophilic, which is a unique combination, and is thus becoming an increasingly valuable tool within drug discovery. Current methods to prepare them are limited either by a limited scope or by the prohibitively expensive reagents that are required.We have developed methods to form these important difluoromethyl groups from readily installed trifluoromethyl groups using an electrochemical reductive approach. This reaction requires “deeply-reductive” potentials, which poses several problems, including functional group intolerance and low charge efficiencies. We have developed conditions that overcome these problems to produce a single-step process that can be applied to a wide scope of substrates, including those containing reductively sensitive functionality. Details of our studies into the electrochemical hydrodefluorination at highly reductive potentials will be presented.