Methyl fluorosulfonyldifluoroacetate (MFSDA): An Underutilised Reagent for Trifluoromethylation

Abstract

The introduction of fluorine groups to pharmaceutical compounds can have a dramatic effect on the lipophilicity and metabolic stability of the molecule in vivo. Around 20 % of drugs contain at least one fluorine atom. The trifluoromethyl group is known to have beneficial effects and can dramatically affect the biological activity when substituted for a methyl group, for example. In any case, the direct and late-stage introduction of a trifluoromethyl group is a powerful transformation in the tool box of the medicinal chemist. The use of methyl fluorosulfonyldifluoroacetate (MFSDA) as a relatively inexpensive reagent for trifluoromethylation was first reported in 1989; however, in our opinion it has been somewhat underutilised. Herein, a comprehensive review of trifluoromethylation using MFSDA is reported, which we hope will further expose readers to this useful reagent.

A Novel Non-Peptidic Agonist of the Ghrelin Receptor with Orexigenic Activity In vivo

“…Methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (MFSDA) was used as the reagent for the trifluoromethylation of pyridone 14 to give novel pyridone 8 3031. Before returning to in depth biological studies, the prepared pyridone 8 was deemed not toxic in the two cell lines tested: Hek293a-GHS-R1a and mHypoE-N38 using the resazurin toxicity assay (for details, see SI, Figure S1).…”

Quinolones Modulate Ghrelin Receptor Signaling: Potential for a Novel Small Molecule Scaffold in the Treatment of Cachexia

“…Other compounds such as the polyphenol naringin, the gamma-secretase inhibitor “semagacestat,” and biosynthetic intermediates of teaghrelins and emoghrelin have also shown a potential as GHS-R1a agonists [ 29 , 30 , 31 ]. Recently, we also demonstrated a novel, non-peptidic, 2-pyridone bears a crucial trifluoromethyl group [ 32 , 33 ] at the 3-position, which demonstrated a selective GHS-R1a agonist potential in vitro and promised modulation of food intake in vivo [ 22 ]. However, further studies are warranted to identify novel selective GHS-R1a-targeting small molecule agonists with increased potency and selectivity as well as improved pharmacokinetics and bioavailability.…”

The Synthesis and Evaluation of Fluoro‐, Trifluoromethyl‐, and Iodomuscimols as GABA Agonists

“…To explore this, we have carried out aD FT-based conformational Scheme3.Putative mechanism for the trifluoromethylationo f18. [17][18][19][20][21] Scheme4.Synthesis of iodomuscimol 5.a)33% HBrinAcOH,608C, 17 h, 19 %. bond approximately perpendicular to the aromatic ring, very similar to the X-ray structuref or 3 (see Computational Details in the Supporting Information).…”