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.
Highlights
The introduction of a monofluoromethyl moiety has undoubtedly become a very important area of research in recent years
A further method starts with a precursor compound that formally transfers a “CFR2” unit (R = SO2Ar or others) to the substrate in the initial step, and subsequently gives the desired CH2F group after work-up.[7a]. Fluoromethylation chemistry developed before 2009 has been nicely reviewed by Hu and co-workers.[7a]. In addition, Review articles focusing on fluorine-containing functional groups,[5b] difluoro- and fluoromethylation,[14] transition-metal-mediated di- and monofluoroalkylations,[15] sulfur-based fluorination and fluoroalkylation reagents,[16] and on shelf-stable reagents for fluorofunctionalization reactions[17] have been published
A very effective fluoromethylating reagent was developed in 2011 by Shibata and co-workers.[43]. It shows a pronounced preference for fluoroalkylation at oxygen atoms, which provides a synthetic approach for the preparation of monofluoromethyl ethers
Summary
Keywords : electrophiles · fluoromethylating agents · monofluoromethylation · nucleophiles · radical reactions. A fluoromethyl group can be generated by introducing fluorine in place of a suitable functional group[12] or by direct monofluorination,[13] the majority of synthetic procedures use a fluoromethylating agent instead, which can directly transfer a CH2F group.[14] A further method starts with a precursor compound that formally transfers a “CFR2” unit (R = SO2Ar or others) to the substrate in the initial step, and subsequently gives the desired CH2F group after work-up.[7a] Fluoromethylation chemistry developed before 2009 has been nicely reviewed by Hu and co-workers.[7a] In addition, Review articles focusing on fluorine-containing functional groups,[5b] difluoro- and fluoromethylation,[14] transition-metal-mediated di- and monofluoroalkylations,[15] sulfur-based fluorination and fluoroalkylation reagents,[16] and on shelf-stable reagents for fluorofunctionalization reactions[17] have been published. The introduction of CH2F moieties by transition-metal-mediated crosscoupling reactions is discussed in the Section covering the corresponding reagent
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