Reagents for Selective Fluoromethylation: A Challenge in Organofluorine Chemistry

Abstract

The introduction of a monofluoromethyl moiety has undoubtedly become a very important area of research in recent years. Owing to the beneficial properties of organofluorine compounds, such as their metabolic stability, the incorporation of the CH2F group as a bioisosteric substitute for various functional groups is an attractive strategy for the discovery of new pharmaceuticals. Furthermore, the monofluoromethyl unit is also widely used in agrochemistry, in pharmaceutical chemistry, and in fine chemicals. The problems associated with climate change and the growing need for environmentally friendly industrial processes mean that alternatives to the frequently used CFC and HFBC fluoromethylating agents (CH2FCl and CH2FBr) are urgently needed and also required by the Montreal Protocol. This has recently prompted many researchers to develop alternative fluoromethylation agents. This Minireview summarizes both the classical and new generation of fluoromethylating agents. Reagents that act via electrophilic, nucleophilic, and radical pathways are discussed, in addition to their precursors.

Nickel-catalyzed oxidative fluoroalkylation of aryl halides via paired electrolysis

“…The CH 2 F group as the crucial motif contains in many biologically active molecules, such as a oqulone, uticasone propionate, and the anesthetic sevofurane. [42][43][44] The modi cation of functional molecules with the CH 2 F group is potentially useful to improve their bioactivities. Therefore, we sought to the CH 2 F group is potentially useful to improve their bioactivities.…”

Asymmetric Fluorination Reactions promoted by Chiral Hydrogen Bonding‐based Organocatalysts

“…Finally, a derivatization process took place to obtain a single crystal and the measurement of the absolute configuration of the products afforded the enantiomer R . To the best of our knowledge, this is the pioneering and only example of a fluoromethylation reaction promoted by non‐covalent organocatalysis [48] . Although the authors did not clarify completely the reaction mechanism, they successfully proved that hydrogen bonding is of utmost importance to enhance the selectivity of the process, obtaining the desired products 31 with good values of yield and enantioselectivity.…”

“…Finally, a derivatization process took place to obtain a single crystal and the measurement of the absolute configuration of the products afforded the enantiomer R. To the best of our knowledge, this is the pioneering and only example of a fluoromethylation reaction promoted by non-covalent organocatalysis. [48] Although the authors did not clarify completely the reaction mechanism, they successfully proved that hydrogen bonding is of utmost importance to enhance the selectivity of the process, obtaining the desired Focusing now on electrophilic monofluorination reactions, Hu and coworkers reported in 2012 the pioneering example of a cinchona-thiourea derivative capable of catalyzing the enantioselective fluorination of β-ketoesters (Scheme 14). [49] The reaction was conducted with indanone 33, tetralone 34 and cyclopentanone 35 carboxylate derivatives and with acyclic β-ketoesters 36 as the model substrates.…”

Synthesis of bis(aryloxy)fluoromethanes using a heterodihalocarbene strategy

“…Organofluorine molecules are widely used for medicinal, agrochemical and material purposes. Recently, a proliferation of methods has allowed easy access to a particularly desired class of these compounds: singly fluorinated compounds such as fluoromethyl ethers [1]. Still missing from the chemist's toolkit, however, are means to construct their more highly oxidized analogues, fluoromethylene acetals.…”