Direct and Chemoselective Electrophilic Monofluoromethylation of Heteroatoms (O-, S-, N-, P-, Se-) with Fluoroiodomethane

Abstract

The commercially available fluoroiodomethane represents a valuable and effective electrophilic source for transferring the CH 2 F unit to a series of heteroatom-centered nucleophiles under mild basic conditions. The excellent manipulability offered by its liquid physical state (bp 53.4°C) enables practical and straightforward one-step nucleophilic substitutions to retain the chiral information embodied, thus allowing it to overcome de facto the requirement for fluoromethylating agents with no immediate access. The high-yielding methodology was successfully applied to a variety of nucleophiles including a series of drugs currently in the market.

Scalable Synthesis of S-Fluoromethyl Benzenesulfonothioate

“…Among many fluoroalkyl groups, fluoroalkylthio groups, including the trifluoromethylthio group (−SCF 3 ), difluoromethylthio group (−SCF 2 H), and monofluoromethylthio group (−SCH 2 F), have received special attention, mainly because of their ability to fine-tune the drug molecule’s pharmacokimetic and pharmacodynamic properties. While a variety of efficient methods for the introduction of the trifluoromethylthio and difluoromethylthio groups have been reported in the past 10 years, methods for the incorporation of the monofluoromethylthio group are limited. − Notably, the drugs fluticasone, which is a steroid to treat nasal symptoms, and fluticasone propionate, which is used for long-term management of asthma, contain a monofluoromethylthio group (Figure ). …”

Innovative Strategies for the Construction of Diverse 1′-Modified C-Nucleoside Derivatives

“…The monofluoromethyl group has been less explored due to the intrinsic instability of the monofluoromethyl carbanion, which has a fleeting existence and rapidly decomposes at −78 °C to a carbene through the elimination of lithium fluoride. Recently, Luisi and Pace reported the first conditions to generate fluoromethyllithium in situ in the presence of electrophiles from fluoroiodomethane. , Inspired by this new methodology for nucleophilic monofluoromethylation, we conducted a trial reaction with the Weinreb amide 29 . The dropwise addition of MeLi·LiBr to a solution of FCH 2 I and 29 in 1:1 THF/Et 2 O at −78 °C using the reported optimized stoichiometry of 1:2:1.5 FCH 2 I/MeLi·LiBr/ 29 furnished the bromomethylketone 32 (Scheme ; page S2 in the SI), indicating that competitive halogen scrambling was occurring.…”

29th Annual GP2A Medicinal Chemistry Conference

“…The direct/full chemoselective conversion of a ketone into the homologated all-carbon quaternary aldehyde (Figure 6a) [33] and the telescoped homologation of imine surrogates to quaternary aziridines (Figure 6b) [34] will illustrate these unprecedented concepts. Additionally, the one-step mono-fluoromethylation of carbon electrophiles with extremely labile fluoromethyllithium reagents will provide a novel entry to valuable fluorinated building-blocks without the need to use protecting elements for fluoro-containing carbanions (Figure 6c) [35][36][37]. Moreover, novel strategies for introducing the difluoromethyl group through the proper activation of commercially available TMSCHF 2 with an alkoxide will be discussed [38,39].…”