Friedel–Crafts Reaction of Benzyl Fluorides: Selective Activation of CF Bonds as Enabled by Hydrogen Bonding

Abstract

A Friedel-Crafts benzylation of arenes with benzyl fluorides has been developed. The reaction produces 1,1-diaryl alkanes in good yield under mild conditions without the need for a transition metal or a strong Lewis acid. A mechanism involving activation of the C-F bond through hydrogen bonding is proposed. This mode of activation enables the selective reaction of benzylic C-F bonds in the presence of other benzylic leaving groups.

Vessel Effect in C–F Bond Activation Prompts Revised Mechanism and Reveals an Autocatalytic Glycosylation

“…[25][26][27]31,[42][43][44][45][46] The effect of adding drying agents to this particular glycosylation seems highly important as Toshima has reported an increase in yield from 32 % to 99 % of the desired glycoside when 100 wt.-% 5Å molecular sieves were added. [15] As this reaction is reported to be catalyzed by HF formed in situ, [15,16] it was likely to be influenced by the vessel material as well. [15] As this reaction is reported to be catalyzed by HF formed in situ, [15,16] it was likely to be influenced by the vessel material as well.…”

“…[11,12] Several other applications of C(sp 3 )-F bond activation have been developed, and significant highlights in this vast field of research have recently been reviewed in detail by Hamel and Paquin. Paquin and co-workers have developed methods for chemoselective benzylic-, [13][14][15][16][17] allylic- [13] and propargylic [18] C-F bond activation mediated through hydrogen bonding, reporting that the hydrogen fluoride developed during the reaction would function as an active catalyst, resulting in an autocatalytic kinetic profile. Paquin and co-workers have developed methods for chemoselective benzylic-, [13][14][15][16][17] allylic- [13] and propargylic [18] C-F bond activation mediated through hydrogen bonding, reporting that the hydrogen fluoride developed during the reaction would function as an active catalyst, resulting in an autocatalytic kinetic profile.…”

C−C Coupling of Benzyl Fluorides Catalyzed by an Electrophilic Phosphonium Cation

“…[11] While transitionmetal-based methods have been developed to achieve such targets, [12] several metal-free methods have been described, [13] the majority involving Lewis acid-mediated Friedel-Crafts chemistry (see Scheme 1). [16] While this approach is interesting, it does exploit HFIP to initiate the reaction, generating HF as the catalyst, which limits scale-up because of the toxicity of this chemical. [14] Hall et al [15] described direct Friedel-Crafts coupling with deactivated benzylic alcohol using ferroceniumboronic acids.A lthough halogens are well known as good leaving groups,b enzyl fluorides are very stable and generally unreactive.I n2 014, Paquin et al described ac lever method for acid activation of fluorides and subsequent functionalization.…”

C−C Coupling of Benzyl Fluorides Catalyzed by an Electrophilic Phosphonium Cation

“…In 2014, Paquin et al described a clever method for acid activation of fluorides and subsequent functionalization. [16] While this approach is interesting, it does exploit HFIP to initiate the reaction, generating HF as the catalyst, which limits scale-up because of the toxicity of this chemical.…”