Alcohol

Catalysis

Electrophilic aromatic substitution

Friedel–Crafts reaction

Electrophile

Alkylation

SN2 reaction

Combinatorial chemistry

Physics

Organic chemistry

Astronomy

Nucleophile

Primary (astronomy)

Chemistry

Nucleophilic substitution

Chem

<h2>Summary</h2> 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 S<sub>N</sub>2 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.

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