Abstract
A straightforward method that enables the formation of biologically attractive trifluoromethyl ketones from readily available methyl esters using the potent greenhouse gas fluoroform (HCF3, HFC-23) was developed. The combination of fluoroform and KHMDS in triglyme at −40 °C was effective for this transformation, with good yields as high as 92%. Substrate scope of the trifluoromethylation procedure was explored for aromatic, aliphatic, and conjugated methyl esters. This study presents a straightforward trifluoromethylation process of various methyl esters that convert well to the corresponding trifluoromethyl ketones. The tolerance of various pharmacophores under the reaction conditions was also explored.
Highlights
In recent decades, organofluorine molecules have received widespread attention in the field of medicinal chemistry [1,2,3,4]
This study presents a straightforward trifluoromethylation process of various methyl esters that convert well to the corresponding trifluoromethyl ketones
The trifluoromethylation of methyl carboxylates to trifluoromethyl ketones is accomplished under basic conditions with fluoroform in triglyme at −40 °C
Summary
Organofluorine molecules have received widespread attention in the field of medicinal chemistry [1,2,3,4]. One of the problems facing the treatment of HCF3 for nucleophilic trifluoromethylation reactions is the low stability of the directly generated CF3 anion (CF3−) for decomposing to difluorocarbene (:CF2) and fluoride (F−) (Scheme 1a). Our group reported novel DMF-free systems for the nucleophilic trifluoromethylation reaction using HCF3, including the phosphazene base P4-t-Bu (P4-t-Bu), in 2013 (Scheme 1c) [45] and a potassium tert-butoxide (t-BuOK) or potassium hexamethyldisilazide (KHMDS)/glyme combination in 2018 (Scheme 1d) [46].
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