Friedel–Crafts Benzylation of Activated and Deactivated Arenes

Abstract

NO going back makes possible facile Friedel–Crafts benzylations with moderate reaction temperatures, simple reaction workups, and improved substrate scope for the formation of synthetically important diarylmethanes (see scheme). Upon complexation with BF3⋅OEt2, hydroxamates serve as reversible leaving groups that stabilize highly reactive carbocations. Even deactivated arenes and electron‐deficient benzylhydroxamates react cleanly under these conditions.

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

“…Ar emarkable procedure is described by Bode and Schäfer,i nw hich benzyl hydroxamates and as toichiometric amount of BF 3 OEt 2 are employed to generate diarylmethanes. [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. [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.…”

Indium(III)‐Catalyzed Reductive Monoalkylation of Electron‐Rich Benzenes with Aliphatic Carboxylic Acids Leading to Arylalkane Derivatives

“…Most Friedel-Crafts benzylations have been achieved by either Lewis or Brønsted acids such as FeBr 3 , [2] Ca(OTf) 2 , [3] BF 3 /OEt 2 , [4] InCl 3 , [5] and TfOH. [6] As another approach to the alkylation of a benzene ring, reductive benzylation of benzenes with aromatic aldehydes in the presence of a Lewis acid and an appropriate reducing reagent has been reported [Equation (2) in Scheme 1].…”

Catalytic Friedel–Crafts Reactions of Highly Electronically Deactivated Benzylic Alcohols

“…[1,2] Thec lassical version requires stoichiometric quantities of Lewis acid and uses alkyl halides as starting materials,w hich are often generated in as eparate step from alcohol precursors.V ariants developed recently by Bode and Stephan have expanded the scope of the Friedel-Crafts reaction to include electronically deactivated benzylic electrophiles through the use of benzylic N-methylhydroxamic acids and fluorides,respectively (Figure 1a). [3] However, like the classical version, these reactions require additional steps for substrate preactivation and use stoichiometric activating agents.T he need to improve the step-and atomeconomy of the Friedel-Crafts reaction prompted the ACS Green Chemistry Pharmaceutical Roundtable to designate the development of catalytic versions starting directly from alcohols,w hich produce water as the only stoichiometric byproduct, as at op priority for green chemistry. [4] Accordingly, the past years have witnessed numerous reports of Lewis or Brønsted acid catalyzed Friedel-Crafts reactions of electronically activated benzylic alcohols, [5][6][7] but the inability of the reaction to accommodate electronically deactivated alcohols remains as triking limitation.…”