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NK and DOH acknowledge support from the University of St Andrews, Engineering and Physical Sciences Research Council (EPSRC, Grant No.: EP/L017911/1), and the EPSRC UK National Mass Spectrometry Facility at Swansea University. This work was also supported by the Natural Sciences and Engineering Research Council of Canada (NSERC), the FRQNT Centre in Green Chemistry and Catalysis (CGCC), and the Université Laval. 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. Publisher PDF

The synthesis of 3-(2,2,2-trifluoroethyl)-2,3-dihydrobenzofurans, 3-(2,2,2-trifluoroethyl)indolines, 3-[(pentafluorosulfanyl)methyl]-2,3-dihydrobenzofurans, and 3-[(pentafluorosulfanyl)methyl]indolines using an intramolecular reductive radical cyclization from readily available acyclic precursors is reported. The CF3- and SF5-containing heterocycles are obtained in moderate to excellent yields. Notably, this transformation represents the first example of an aryl radical addition to a SF5-containing alkene. Finally, the possibility of oxidation of some of the products generated to benzofurans and indoles is shown.

We report that the addition of a catalytic amount of trifluoroacetic acid (TFA) shortens the induction period associated with the 1,1,1,3,3,3-hexafluoroisopropoanol (HFIP)-promoted Friedel-Crafts reaction of benzylic fluorides. This faster initiation is due to TFA’s strong hydrogen-bond donation capability, not its Bronsted acidity. The improved reaction conditions were applied to a set of substrates, demonstrating how they could improve yields and reliability of this transformation.

Two methods for the introduction of the (E)-3-(pentafluorosulfanyl)allyl chain unto various nucleophiles were investigated: a palladium-catalyzed Tsuji–Trost reaction of (E)-ethyl [3-(pentafluorosulfanyl)allyl]carbonate and a nucleophilic substitution reaction on (E)-[3-(pentafluorosulfanyl)allyl] 4-methylbenzenesulfonate. Various nucleophiles were examined including phenols, aliphatic and aromatic amines, aliphatic and aromatic thiols and malonates. Overall, the two approaches were found to be complementary as the Tsuji–Trost reaction worked better with phenols while the SN2 reaction generally provided better results with the amines. In addition, the sulfur-based product could only be obtained using the SN2 reaction while the malonates only worked under the Tsuji–Trost conditions.

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.

A systematic study of the reactivity of ( E )-4,4,4-trifluorobut-2-en-1-yl 4-methylbenzenesulfonate towards different classes of nucleophiles (alcohols, amines, thiols and malonates) was performed. A single set of reaction conditions (with small variations) allowed the isolation of the substitution product in moderate to good yields for all the nucleophiles tested with the exception of benzyl alcohol and indole.

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.

The Friedel-Crafts benzylation of arenes using benzyl alcohols activated in situ with XtalFluor-E is described. A wide range of 1,1-diarylmethanes and 1,1,1-triarylmethanes were prepared under experimentally simple and mild conditions, without the need for a transition metal or a strong Lewis acid. Notably, the reactivity observed demonstrates the potential of XtalFluor-E to induce C-OH bond ionization and SN1 reactivity of benzylic alcohols.

The formation of amides through the in situ activation of carboxylic acids with [Et2NSF2]BF4 is presented. A wide range of carboxylic acids and amines were used to produce the corresponding amides in up to 99 % yield. The reaction of hindered amines was also possible in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) under slightly modified conditions. An enantiopure carboxylic acid and amine were both shown to react without racemization.

International audience; From 4 antiplasmodial hit-molecules identified in 2-trichloromethylquinazoline series, we conducted a global Structure-Activity relationship (SAR) study involving 26 compounds and covering 5 molecular regions (I – V), aiming at defining the corresponding pharmacophore and identifying new bioactive derivatives. Thus, after studying the aniline moiety in detail, thienopyrimidine, quinoline and quinoxaline bio-isosters were synthesized and tested on the K1 multi-resistant P. falciparum strain, along with a cytotoxicity evaluation on the human HepG2 cell line, to define selectivity indecies. SARs first showed that thienopyrimidines and quinolines were globally more cytotoxic, while quinoxaline analogs appeared as active asandless cytotoxic than their quinazoline counterparts. Such pharmacomodulation in quinoxaline series not only provided a new antiplasmodial reference hit-molecule (IC50 = 0.4 μM, selectivity index = 100), but also highlighted an active (IC50 = 0.4 μM) and quite selective (SI = 265) synthesis intermediate.

We report that the addition of a catalytic amount of trifluoroacetic acid (TFA) shortens the induction period associated with the 1,1,1,3,3,3-hexafluoroisopropoanol (HFIP)-promoted Friedel-Crafts reaction of benzylic fluorides. This faster initiation is due to TFA’s strong hydrogen-bond donation capability, not its Bronsted acidity. The improved reaction conditions were applied to a set of substrates, demonstrating how they could improve yields and reliability of this transformation.

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 SF

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.

An effective process for the regioselective Tsuji—Trost reaction of 4,4,4-trifluorobut-2-ene derived carbonate (I) and (VI), or acetate (VII) with aromatic alcohols, secondary amines, and malonate type C-nucleophiles is developed.

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 CF bond through hydrogen bonding is proposed. This mode of activation enables the selective reaction of benzylic CF bonds in the presence of other benzylic leaving groups.

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.

The presented method proceeds for a wide range of carboxylic acids and amines and without racemization [viz.

The procedure provides an efficient method to prepare a number of primary chlorides, bromides, and iodides.