Lukas Pfeifer

cis‐Specific Hydrofluorination of Alkenylarenes under Palladium Catalysis through an Ionic Pathway

This paper describes the hydrofluorination of alkenes through sequential H(-) and F(+) addition under palladium catalysis. The reaction is cis specific, thus providing access to benzylic fluorides. The mechanism of this reaction involves an ionic pathway and is distinct from known hydrofluorinations involving radical intermediates. The first catalytic enantioselective hydrofluorination is also disclosed.

18F‐Labeling of Aryl‐SCF3, ‐OCF3 and ‐OCHF2 with [18F]Fluoride

We report that halogenophilic silver(I) triflate permits halogen exchange (halex) nucleophilic (18)F-fluorination of aryl-OCHFCl, -OCF2Br and -SCF2Br precursors under mild conditions. This Ag(I)-mediated process allows for the first time access to a range of (18)F-labeled aryl-OCHF2, -OCF3 and -SCF3 derivatives, inclusive of [(18)F]riluzole. The (18)F-labeling of these medicinally important motifs expands the radiochemical space available for PET applications.

Coordination diversity in hydrogen-bonded homoleptic fluoride–alcohol complexes modulates reactivity

The nucleophilic reactivity of fluoride ion is altered in the presence of hydrogen-bond donors, including alcohols. Relatively little is known about the coordination involved; to rectify this, the X-ray structures of fourteen novel fluoride–alcohol complexes with tetrabutylammonium as the counterion have been determined. The coordination number varies from two to four depending on the steric bulk of the alcohol and is closely linked to trends in reactivity. This diversity in coordination stoichiometry is unprecedented but significant, as it implies differences in the ability of the fluoride–alcohol complexes to dissociate in solution with release of a more active and/or selective fluoride source.

Cross-Coupling of [2-Aryl-1,1,2,2-tetrafluoroethyl](trimethyl)silanes with Aryl Halides.

The synthesis of arylCF2CF2SiMe3 and their reactivity in cross-coupling reactions with aryl iodides and aryl bromides to afford a range of 1,1,2,2-tetrafluoro-1,2-arylethanes is reported. The use of pyridine as an alternative to phenanthroline, and the ability to carry out the reaction at 60 °C or room temperature are the key features of this Cu-Ag mediated cross-coupling methodology. The chemistry is compatible with (hetero)aryl halides, offering a platform to develop products of interest in material and medicinal chemistry.

Asymmetric nucleophilic fluorination under hydrogen bonding phase-transfer catalysis

H-bond to deliver fluoride Simple fluoride salts are theoretically convenient reagents for carbon-fluorine bond formation. In practice, they are often insoluble in the solvents that dissolve their reaction partners. Pupo et al. developed urea-based catalysts that make fluoride soluble through hydrogen bonding. Moreover, their chiral substituents bias the reaction toward one of two mirror image products of C–F bond formation. This strategy should be applicable to the asymmetric addition of other salts, too. Science, this issue p. 638 A hydrogen bonding catalyst renders fluoride soluble and then guides it to form a C–F bond enantioselectively. Common anionic nucleophiles such as those derived from inorganic salts have not been used for enantioselective catalysis because of their insolubility. Here, we report that merging hydrogen bonding and phase-transfer catalysis provides an effective mode of activation for nucleophiles that are insoluble in organic solvents. This catalytic manifold relies on hydrogen bonding complexation to render nucleophiles soluble and reactive, while simultaneously inducing asymmetry in the ensuing transformation. We demonstrate the concept using a chiral bis-urea catalyst to form a tridentate hydrogen bonding complex with fluoride from its cesium salt, thereby enabling highly efficient enantioselective ring opening of episulfonium ion. This fluorination method is synthetically valuable considering the scarcity of alternative protocols and points the way to wider application of the catalytic approach with diverse anionic nucleophiles.

Synthesis and Reactivity of 18F-Labeled α,α-Difluoro-α-(aryloxy)acetic Acids

In this work, we describe the 18F-labeling of α,α-difluoro-α-(aryloxy)acetic acid derivatives and demonstrate that these building blocks are amenable to post-18F-fluorination functionalization. Protodecarboxylation offers a new entry to 18F-difluoromethoxyarene, and the value of this approach is further demonstrated with coupling processes leading to representative 18F-labeled TRPV1 inhibitors and TRPV1 antagonists.

Controlled Single and Double Iodofluorination of Alkynes with DIH- and HF-Based Reagents

A novel protocol for the regio- and stereoselective iodofluorination of internal and terminal alkynes using 1,3-diiodo-5,5,-dimethylhydantoin and HF-based reagents is disclosed. This approach is used to prepare a fluorinated tamoxifen derivative in two steps from commercially available starting materials. A facile method enabling controlled regioselective double iodofluorination of terminal alkynes is also presented.