Switchable Reactivity of Homopropargylic Alcohols Towards γ-Arylated Ketones and α-Arylated Tetrahydrofurans in HFIP

Abstract

A divergent synthetic strategy to access γ-arylated ketones and α-arylated tetrahydrofurans from readily available homopropargylic alcohols and arene nucleophiles is reported. This method expands the accessible chemical space of γ-arylated ketones via a unique triflic acid-catalyzed hydroalkoxylation/ring-opening arylation sequence proceeding through a 2,3-dihydrofuran intermediate, enabled by the properties of 1,1,1,3,3,3-hexafluoroisopropan-2-ol (HFIP) as solvent. This protocol provides a solution for preparing γ-arylated ketones incorporating sterically hindered arenes, while displaying compatibility with synthetically relevant functionalities to deliver linear and branched γ-arylated ketones, including both aliphatic and aromatic variants. Switching the reaction pathway by employing p-cymene as a hydride donor promotes a reductive hydroalkoxylation, affording α-arylated tetrahydrofurans with high efficiency. Mechanistic studies supported by DFT computations reveal a complex catalytic reaction network in which multiple pathways converge to the observed products.