Synthesis of α-Trifluoromethyl Esters

Synthesis of α-Trifluoromethyl Esters


Organic compounds with fluorine substituents can be very useful, e.g., in pharmaceutical chemistry. One commonly used fluorinated group is CF3. Reactions that allow the connection of this group to sp3-hybridized carbon atoms are rare, and especially the α-trifluoromethylation of carbonyl derivatives is still challenging.

Thomas Poisson, Normandy University, Rouen, France, and Institut Universitaire de France, Paris, Tatiana Besset, Normandy University, and colleagues have developed a synthesis that provides easy access to α-trifluoromethyl esters (pictured) and starts from readily available α-chloro aldehydes. The team used an N-Heterocyclic carbene (NHC) organocatalyst, Togni’s reagent (3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole) as a CF3+ source, and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) as a base in a mixture of methanol and dichloromethane at 0 °C.

The desired α-trifluoromethyl esters were obtained in moderate to good yields. The proposed reaction mechanism involves an addition of the NHC catalyst to the carbonyl group of the α-chloro aldehyde, an abstraction of HCl by the base to form an enolate, an electrophilic attack of the CF3+ source at the α-position, and the formation of the ester regeneration of the catalyst via a nucleophilic attack by methanol.


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