α-Fluorinated Ethers as “Exotic” Entity in Medicinal Chemistry

Abstract

After nitrogen, fluorine occupies the position of second favorite heteroelement in life science-oriented research. In contrast, the trifluoromethoxy group is still perhaps the least well understood fluorine substituent, although its occurrence has significantly increased in the recent years. Today, significant application areas for trifluoromethoxy substituted pharmaceuticals are in the field of analgesics, anesthetics, cardiovascular drugs, respiratory drugs, psychopharmacologic drugs, neurological drugs, gastrointestinal drugs and anti-infective therapeutics. The present review will give an overlook of its use in medicinal chemistry.

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.…”

Umpolung of Fluoroform by CF Bond Activation: Direct Difluoromethylation of Lithium Enolates

“…[2] Generally, synthetic methods for the fluoromethylation reactions involve radical, electrophilic, or nucleophilic reactions.…”

“…A direct C sp 2 À F bond activation and CÀC bond formation sequence can be attained with lithium enolates, which take a central role in modern synthetic organic chemistry. [13] The difluoromethyl products are biologically and synthetically important, and therefore the introduction of the difluoromethyl group into organic compounds is of vital importance, [14] as shown for difluoromethyl ethers [2] or a-difluoromethyl a-amino acids. [15] The direct and simple a-difluoromethylation was found to proceed with lithium enolates using fluoroform as the difluoromethylating reagent (Scheme 2).…”

New trends in the chemistry of α-fluorinated ethers, thioethers, amines and phosphines

“…However, examples of trifluoromethyl ethers in pharmaceutical chemistry are still quite rare [16,17]. They were rapidly used as volatile, non-toxic, non-explosive and fast-acting inhalation anaesthetics and antiinflammatory agents.…”

“…N-Fluoro-, difluoro-and trifluoromethylated heterocycles will not be discussed in this review. A detailed description of the steric and electronic properties of these groups [16], their medicinal application [17] and reactivity [42] was recently reviewed in detail and will not be presented here.…”