Copper-catalyzed Si−H, B−H, P−H, S−H, and N−H insertion reactions of 2,2,2-trifluoro-1-diazoethane and 1-aryl 2,2,2-trifluorodiazoethanes generated a large number of new fluorine-containing chemical entities for medicinal chemists. With selected Si−H and B−H insertion reactions, we demonstrate successful extension to asymmetric catalysis.

Copper-catalyzed Si−H, B−H, P−H, S−H, and N−H insertion reactions of 2,2,2-trifluoro-1-diazoethane and 1-aryl 2,2,2-trifluorodiazoethanes generated a large number of new fluorine-containing chemical entities for medicinal chemists. With selected Si−H and B−H insertion reactions, we demonstrate successful extension to asymmetric catalysis.

The first organomediated asymmetric ¹⁸F fluorination has been accomplished using a chiral imidazolidinone and [¹⁸F]N-fluorobenzenesulfonimide. The method provides access to enantioenriched ¹⁸F-labeled α-fluoroaldehydes (>90 % ee), which are versatile chiral ¹⁸F synthons for the synthesis of radiotracers. The utility of this process is demonstrated with the synthesis of the PET (positron emission tomography) tracer (2S,4S)-4-[¹⁸F]fluoroglutamic acid.

We report that halogenophilic silver(I) triflate permits halogen exchange (halex) nucleophilic ¹⁸F-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 ¹⁸F-labeled aryl-OCHF₂, -OCF₃ and -SCF₃ derivatives, inclusive of [¹⁸F]riluzole. The ¹⁸F-labeling of these medicinally important motifs expands the radiochemical space available for PET applications.

The first organomediated asymmetric ¹⁸F fluorination has been accomplished using a chiral imidazolidinone and [¹⁸F]N-fluorobenzenesulfonimide. The method provides access to enantioenriched ¹⁸F-labeled α-fluoroaldehydes (>90 % ee), which are versatile chiral ¹⁸F synthons for the synthesis of radiotracers. The utility of this process is demonstrated with the synthesis of the PET (positron emission tomography) tracer (2S,4S)-4-[¹⁸F]fluoroglutamic acid.

We report that halogenophilic silver(I) triflate permits halogen exchange (halex) nucleophilic ¹⁸F-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 ¹⁸F-labeled aryl-OCHF₂, -OCF₃ and -SCF₃ derivatives, inclusive of [¹⁸F]riluzole. The ¹⁸F-labeling of these medicinally important motifs expands the radiochemical space available for PET applications.

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.

Molecules labeled with fluorine-18 are used as radiotracers for positron emission tomography. An important challenge is the labeling of arenes not amenable to aromatic nucleophilic substitution (S_NAr) with [¹⁸F]F⁻. In the ideal case, the ¹⁸F fluorination of these substrates would be performed through reaction of [¹⁸F]KF with shelf-stable readily available precursors using a broadly applicable method suitable for automation. Herein, we describe the realization of these requirements with the production of ¹⁸F arenes from pinacol-derived aryl boronic esters (arylBPin) upon treatment with [¹⁸F]KF/K₂₂₂ and [Cu(OTf)₂(py)₄] (OTf=trifluoromethanesulfonate, py=pyridine). This method tolerates electron-poor and electron-rich arenes and various functional groups, and allows access to 6-[¹⁸F]fluoro-L-DOPA, 6-[¹⁸F]fluoro-m-tyrosine, and the translocator protein (TSPO) PET ligand [¹⁸F]DAA1106.

Molecules labeled with fluorine-18 are used as radiotracers for positron emission tomography. An important challenge is the labeling of arenes not amenable to aromatic nucleophilic substitution (S_NAr) with [¹⁸F]F⁻. In the ideal case, the ¹⁸F fluorination of these substrates would be performed through reaction of [¹⁸F]KF with shelf-stable readily available precursors using a broadly applicable method suitable for automation. Herein, we describe the realization of these requirements with the production of ¹⁸F arenes from pinacol-derived aryl boronic esters (arylBPin) upon treatment with [¹⁸F]KF/K₂₂₂ and [Cu(OTf)₂(py)₄] (OTf=trifluoromethanesulfonate, py=pyridine). This method tolerates electron-poor and electron-rich arenes and various functional groups, and allows access to 6-[¹⁸F]fluoro-L-DOPA, 6-[¹⁸F]fluoro-m-tyrosine, and the translocator protein (TSPO) PET ligand [¹⁸F]DAA1106.

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.

Various 3-fluoropyrrolidines and 4-fluoropyrrolidin-2-ones were prepared by 5-exo-trig iodocyclisation from allylic fluorides bearing a pending nitrogen nucleophile. These bench-stable precursors were made accessible upon electrophilic fluorination of the corresponding allylsilanes. The presence of the allylic fluorine substituent induces syn-stereocontrol upon iodocyclisation with diastereomeric ratios ranging from 10:1 to > 20:1 for all N-tosyl-3-fluoropent-4-en-1-amines and amides. The sense and level of stereocontrol is strikingly similar to the corresponding iodocyclisation of structurally related allylic fluorides bearing pending oxygen nucleophiles. These results suggest that the syn selectivity observed upon ring closure involves I₂–π complexes with the fluorine positioned inside.

A series of 3-fluoropyrrolidines have been studied to investigate the influence of the stereoelectronic fluorine gauche effect on ring conformations in the solid state by single-crystal X-ray analysis and in solution phase by NMR spectroscopy. As part of these studies 1D ¹⁹F–¹H heteronuclear NOE (HOESY) experiments have been optimised for applications to small molecules and are described in detail. These have been employed to estimate ¹⁹F–¹H internuclear distances and were combined with vicinal ³J(F,H) and ³J(H,H) scalar coupling constants to analyse the ring conformations. Where possible the derived solution-phase structural data have been compared with those of the crystalline state. The results demonstrate the influence of the gauche effect in stabilising C^γ-exo conformations of the fluorinated pyrrolidines. It was further shown that when steric interactions were also present, this conformational bias was diminished and the contribution of the alternative C^γ-endo conformation was seen to increase in solution at lower sample temperatures.

Molecular imaging has witnessed an upsurge in growth, with positron emission tomography leading the way. This trend has encouraged numerous synthetic chemists to enter the field of ¹⁸F-radiochemistry and provide generic solutions to address the well-recognized challenges of late-stage fluorination. This Minireview focuses on recent developments in the ¹⁸F-labeling of aromatic substrates.

A range of racemic 4-deoxy-4,4-difluorinated carbohydrates were prepared by using a diversity-oriented de novo synthesis starting with three commercially available two-carbon building blocks. A common gem-difluorinated glycal was prepared in 35 % yield in seven steps, from which five different 4-deoxy-4,4-difluoro- and 4-deoxy-2,4,4-trifluorohexopyranosides were accessed using well-established functional group manipulations.

When reacted in the presence of external oxidants, gold complexes are capable of catalyzing oxidative homo- and cross-coupling reactions involving the formation of new CC bonds. Over the last few years, several cascade processes have been reported in which coupling is preceded by a gold-mediated aryl CH functionalization or nucleophilic addition. These reactions combine the unique reactivity of gold with oxidative coupling, enabling the construction of CC bonds between coupling partners that are not easily accessed using alternative catalysts. In this Concept paper, the development of gold-catalyzed oxidative coupling reactions is discussed focusing on CC bond-forming reactions of broad synthetic appeal.

Performing gold-catalyzed organic transformations in the presence of fluorinating reagents can lead to both fluorinated and non-fluorinated products. Gold(I) complexes can activate alkynes towards nucleophilic attack by fluoride leading to fluoroalkenes under mild conditions. Fluorinated products can also be prepared upon performing gold-catalyzed transformations in the presence of electrophilic sources of fluorine. In most cases, however, the combination of gold and electrophilic fluorinating reagents does not lead to fluorination but delivers products of oxidative homo- or cross-coupling. In these processes the “F⁺” source is likely acting as a sacrificial two-electron external oxidant performing the key oxidation of gold(I) to gold(III) in the redox cycle. Oxidative coupling is an emerging field of gold catalysis which, when combined with the well-established reactivity of gold as a soft π-acid, holds promise as a mild and efficient method for the construction of complex organic molecules.