Synthesis of trifluoromethyl ketones by nucleophilic trifluoromethylation of esters under a fluoroform/KHMDS/triglyme system

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.

Repurposing of F-gases: challenges and opportunities in fluorine chemistry

“…[162][163][164] They also reported the use of potassium bases in the presence of a polyether solvent such as triglyme for the trifluoromethylation of a range of carbonyl compounds using HCF 3 . 165,166 For enantioenriched substrates a stereodivergent trifluoromethylation was reported, depending on the base used. 163,164 A more recent strategy utilised borazine as a Lewis acid to form highly reactive CF 3 À adducts from a reaction of CF 3 H with an alkali metal hydride.…”

Ex-situ generation and synthetic utilization of bare trifluoromethyl anion in flow via rapid biphasic mixing

“…1a ). To avoid these issues on directly using CF 3 H gas with vulnerable decomposition of CF 3 − intermediate even at cryogenic temperatures, the researchers have chosen indirect methods by using the stabilizing additives of CF 3 anion 13 – 19 such as Ruppert-Prakash reagent 20 , or by generating the hemiaminolate adduct [Me 2 NCH(O)CF 3 ]K 9 or coordinate metal cation 21 , 22 in DMF or glyme solvent. However, the stabilization method cannot guarantee the use of unstable CF 3 − intermediate, because (1) the stabilized CF 3 - narrowed down their reaction scope due to the less reactivity; (2) its lifetime is still too short to secure the availability.…”

KHMDS/Triglyme Cryptate as an Alternative to Phosphazene Base in Stereodivergent Pentafluoroethylation of N-Sulfinylimines Using HFC-125

“…Although excellent stereodivergent diastereoselectivities can be achieved by this protocol, P 4 - t Bu is expensive, hindering the extension of this methodology. In the continuation of our efforts in using HFCs for organic chemical transformations, ,,, we now disclose a new protocol for the stereodivergent pentafluoroethylation of N -sulfinylimines using HFC-125 that affords highly stereochemically enriched pentafluoroethylated amines (Scheme e). We investigated classic batch conditions but also micro-flow pentafluoroethylation.…”

“…However, due to the negative influence of HFC-125 on climate change and global warming, the use of HFC-125 is being phased out . Thus, alternative uses of HFC-125, such as its chemical transformation to high-value chiral fluoro-organics, are essential. , Even though several pentafluoroethylations using HFC-125 have been reported, stereoselective pentafluoroethylation of imines using HFC-125 has not been described to date. Recently, we reported the stereodivergent trifluoromethylation of imines using the greenhouse gas HFC-23 (fluoroform, HCF 3 ) .…”