Pier Alexandre Champagne

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

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.

Stereocontrolled approach to bromofluoroalkenes and their use for the synthesis of tri- and tetrasubstituted fluoroalkenes.

An addition/elimination reaction of organolithium reagents to silylated beta,beta-difluorostyrene derivatives followed by a bromination/desilicobromination reaction provides a simple and effective synthetic approach to a wide range of bromofluoroalkenes (up to >97/3). In addition, the bromofluoroalkenes can be used in Pd-catalyzed transformations giving access to both tri- and tetrasubstituted fluoroalkenes.

Enabling Nucleophilic Substitution Reactions of Activated Alkyl Fluorides through Hydrogen Bonding

It was discovered that the presence of water as a cosolvent enables the reaction of activated alkyl fluorides for bimolecular nucleophilic substitution reactions. DFT calculations show that activation proceeds through stabilization of the transition structure by a stronger F···H2O interaction and diminishing C-F bond elongation, and not simple transition state electrostatic stabilization. Overall, the findings put forward a distinct strategy for C-F bond activation through H-bonding.

Stereocontrolled Access to Unsymmetrical 1,1-Diaryl-2-fluoroethenes

A simple and effective method for stereocontrolled preparation of 1,1-diaryl-2-fluoroethenes is reported. First, 1-aryl-1-bromo-2-fluoroethenes are generated using an addition/elimination reaction of hydride to silylated beta,beta-difluorostyrene derivatives followed by a bromination/desilicobromination reaction. Subsequent Suzuki-Miyaura coupling with a variety of boronic acids gives access to the desired 1,1-diaryl-2-fluoroethenes.

Triol-promoted activation of C–F bonds: Amination of benzylic fluorides under highly concentrated conditions mediated by 1,1,1-tris(hydroxymethyl)propane

Summary Activation of the C–F bond of benzylic fluorides was achieved using 1,1,1-tris(hydroxymethyl)propane (2) as a hydrogen bond-donating agent. Investigations demonstrated that hydrogen bond-donating solvents are promoting the activation and hydrogen bond-accepting ones are hindering it. However, the reaction is best run under highly concentrated conditions, where solvents cannot interfere with the interaction between the organofluorine compound and the triol. Various benzylic fluorides react with secondary amines or anilines to form benzylic amines in good yields.

Stereochemical outcomes of C–F activation reactions of benzyl fluoride

In recent years, the highly polar C–F bond has been utilised in activation chemistry despite its low reactivity to traditional nucleophiles, when compared to other C–X halogen bonds. Paquin’s group has reported extensive studies on the C–F activation of benzylic fluorides for nucleophilic substitutions and Friedel–Crafts reactions, using a range of hydrogen bond donors such as water, triols or hexafluoroisopropanol (HFIP) as the activators. This study examines the stereointegrity of the C–F activation reaction through the use of an enantiopure isotopomer of benzyl fluoride to identify whether the reaction conditions favour a dissociative (SN1) or associative (SN2) pathway. [2H]-Isotopomer ratios in the reactions were assayed using the Courtieu 2H NMR method in a chiral liquid crystal (poly-γ-benzyl-L-glutamate) matrix and demonstrated that both associative and dissociative pathways operate to varying degrees, according to the nature of the nucleophile and the hydrogen bond donor.