Unlocking the Friedel-Crafts arylation of primary aliphatic alcohols and epoxides driven by hexafluoroisopropanol

Alcohols and epoxides are arguably ideal electrophiles for the Friedel-Crafts alkylation, since they are widely available, require no pre-activation, and produce no stoichiometric waste beyond water. However, neither primary aliphatic alcohols nor most classes of terminal epoxides are compatible with existing intermolecular Friedel-Crafts methodologies, and sequential Friedel-Crafts reactions starting from epoxides consequently remain underexplored. Here, we report that these limitations are easily overcome using Brønsted acid catalysis in hexafluoroisopropanol (HFIP) as a solvent. Electron-poor aromatic epoxides and aliphatic epoxides undergo stereospecific arylation to give an alcohol which, depending on the reaction conditions, can partake in a second nucleophilic substitution with a different arene in one pot. Phenyl ethanols react through a phenonium intermediate, whereas simple aliphatic alcohols participate in a rare intermolecular SN2 Friedel-Crafts process, delivering linear products exclusively. This work provides an alternative to metal-catalyzed cross-couplings for accessing important scaffolds, widening the range of applications of the Friedel-Crafts reaction. [Display omitted] •Access to a wide range of linear alcohols and arylated alkanes•Compatible with aliphatic and electronically deactivated epoxides•No pre-activation required for primary aliphatic alcohols•Hexafluoroisopropanol is key to the reactivity Substitution reactions are a common way to couple two molecular fragments at a sp3-hybridized carbon atom. The pre-activation of one or both coupling partners is typically required, which adds additional chemical steps and generates waste at each stage. Efforts to develop catalytic substitution reactions of arenes that bypass pre-activation, starting from common feedstocks, such as alcohols or epoxides, have been limited to specific structural subclasses. We report the discovery of catalytic conditions for the direct substitution of arenes with numerous classes of alcohols and epoxides that were not previously accessible, allowing for one-step access to branched alcohols and complex arylated products. Furthermore, since the products of epoxide substitution are alcohols, this discovery enables the direct bis-substitution of epoxides with two different arenes in one pot. We report catalytic conditions for the direct substitution of arenes with numerous classes of alcohols and epoxides that were not previously accessible—all without pre-activ