Justine Desroches

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.

Halogenation of Primary Alcohols Using a Tetraethylammonium Halide/[Et2NSF2]BF4 Combination

The halogenation of primary alcohols is presented. The use of a combination of tetraethylammonium halide and [Et(2)NSF(2)]BF(4) (XtalFluor-E) allows for chlorination and bromination reactions to proceed efficiently (up to 92% yield) with a wide range of alcohols. Iodination reactions are also possible albeit in lower yields.

Introduction of the 4,4,4-trifluorobut-2-ene chain exploiting a regioselective Tsuji-Trost reaction catalyzed by palladium nanoparticles.

A palladium-nanoparticle-catalyzed Tsuji-Trost reaction of 4,4,4-trifluorobut-2-en-1-yl acetate and ethyl(4,4,4-trifluorobut-2-en-1-yl)carbonate was accomplished with various nucleophiles including phenols, amines, and malonates. In the case of the phenols, isomerization of the double bond in the product (up to 20%) was observed as a side reaction. Further synthetic transformations including hydrogenation, the Diels-Alder reaction, and asymmetric dihydroxylation of a product were also examined.

Racemic and enantioselective metal-catalyzed synthesis of SF5-containing diarylmethanols

The racemic and enantioselective metal-catalyzed addition of arylboronic acids to 4- and 3-(pentafluorosulfur)benzaldehydes is reported. The racemic synthesis was accomplished using a Pd-based system and a wide range of arylboronic acids could be used, resulting in yields of 42 to 98% of the corresponding SF5-containing diarylmethanols. A ruthenium-based system, along with (R,R)-Me-BIPAM as the chiral ligand, was investigated and optimized for the enantioselective version. In this case, while the chiral SF5-containing diarylmethanols were generally obtained in good yields (up to 94%) and enantioselectivities (up to 98% ee), limitations were also observed. For instance, 4-(pentafluorosulfur)benzaldehyde generally provided slightly better yields than 3-(pentafluorosulfur)benzaldehyde. In addition, lower yields and enantioselectivities were observed when using either 4- and 3-substituted arylboronic acids bearing electron-withdrawing (e.g., CO2Et, NO2, CF3) or 2-substituted arylboronic acids (regardless of the nature of the substituent). Overall, the SF5-containing diarylmethanols described herein represent novel and potentially useful fluorinated building blocks for the synthesis of biologically active compounds.

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.