Trifluoromethyl ethers – synthesis and properties of an unusual substituent

Abstract

After nitrogen, fluorine is probably the next most favorite hetero-atom for incorporation into small molecules in life scienceoriented research. This review focuses on a particular fluorinated substituent, the trifluoromethoxy group, which is finding increased utility as a substituent in bioactives, but it is still perhaps the least well understood fluorine substituent in currency. The present review will give an overview of the synthesis, properties and reactivity of this important substituent.

A New and Direct Trifluoromethoxylation of Aliphatic Substrates with 2,4‐Dinitro(trifluoromethoxy)benzene

“…[3,4] For example, in addition to trifluoromethoxy-substituted liquid crystals [5] and dyes, [6] several trifluoromethoxylated pesticides and pharmaceuticals are now present on the market (Figure 1). [5,7,8] This growing interest for trifluoromethyl ethers is related to the very peculiar characteristics of the CF 3 O group. On one hand, this substituent looks like chlorine [9] in the sense that it is electron-withdrawing by induction (c = 3.7, [10] s I = + + 0.51 to + 0.60 [11] ), but more than chlorine (s I = + + 0.47 [11a] ), and electron-donating by resonance (s R = À0.13 to À0.18 [11] ), but less than chlorine (s R = À0.25 [11a] ).…”

Electronic Fine‐Tuning of Oxygen Atom Transfer Reactivity of cis‐Dioxomolybdenum(VI) Complexes with Thiosemicarbazone Ligands

“…The rather unusual trifluoromethoxy group was included in the series because of its increasing use in the development of bioactive molecules. [32] For ligands adjacent in the series (i.e., with similar Hammett parameters), the properties discussed below are not always significantly different if experimental errors are taken into account. Therefore, discussions are based on observed trends rather than on quantitative differences between compounds that have similar Hammett constants.…”

Vipirinin, a Coumarin-based HIV-1 Vpr Inhibitor, Interacts with a Hydrophobic Region of VPR

“…It was unclear, however, why fluorination of the methyl group of the methoxy moiety resulted in a loss of activity. This fluorination yielded the more hydrophobic and lipophilic trifluoromethyl moiety, which has been shown to enhance drug effectiveness (29). Next, we checked the functionality of the amide and found it to be critical for activity.…”