Graham Sandford

Catalytic decarboxylative fluorination for the synthesis of tri- and difluoromethyl arenes.

Treatment of readily available α,α-difluoro- and α-fluoroarylacetic acids with Selectfluor under Ag(I) catalysis led to decarboxylative fluorination. This operationally simple reaction gave access to tri- and difluoromethylarenes applying a late-stage fluorination strategy. Translation to [(18)F]labeling is demonstrated using [(18)F]Selectfluor bis(triflate), a reagent affording [(18)F]tri- and [(18)F]difluoromethylarenes not within reach with [(18)F]F2.

Radiosynthesis and Evaluation of [18F]Selectfluor bis(triflate)†

Positron (b) emission tomography (PET) is a noninvasive molecular imaging technique that allows for the in vivo investigation of physiological processes. As a radioisotope, fluorine-18 benefits from an advantageous half-life (109.7 min), a clean decay process (97% b emission), and a short b trajectory, which is a property that enables the acquisition of high-resolution images. The global use of the radiotracer [F]-2-fluoro-2-deoxy-d-glucose has generated a vast amount of invaluable clinical data and has stimulated a worldwide interest in PET and F radiochemistry. For applications other than radiolabeling, nucleophilic and electrophilic fluorination are complementary processes that are used indiscriminately; the method of choice depends on the reactivity profile of the precursor to be fluorinated. A similar degree of synthetic flexibility would facilitate significantly the production and evaluation of new F radiotracers but to date, this is far from the reality because the range of reactions suitable for F labeling remains limited in comparison with the number of transformations available to access nonlabeled fluorinated material. Electrophilic F-fluorination suffers from well-recognized drawbacks. The carrieradded method employed for the production of [F]F2 gas gives labeled products with low specific activity (SA). In addition, [F]F2, a reagent that requires specialist equipment for its handling, can react unselectively and lead to a mixture of products. This complication lowers the radiochemical yield (RCY) and may lead to problematic and time-consuming purification processes. Despite these limitations, clinical doses of the radiotracers [F]-2-fluoro-l-tyrosine and [F]-6-fluoro3,4-dihydroxy-l-phenylalanine are currently prepared relying on an electrophilic fluorodestannylation reaction using [F]F2. [4]

Asymmetric Electrophilic Fluorocyclization with Carbon Nucleophiles

Asymmetric Electrophilic Fluorocyclization with Carbon Nucleophiles Twist of ‘F’ate : Various helical-shaped fluorinated tetracyclic molecules were prepared by fluorocarbocyclization of prochiral alkenes. The development of a new class of chiral Selectfluor (1) proved instrumental in developing an asymmetric variant of this transformation. These novel chiral N-F reagents are readily accessible by fluorine transfer from shelf-stable N-fluoropyridinium salts. Angewandte Chemie

Palladium-Catalyzed C—F Activation of Polyfluoronitrobenzene Derivatives in Suzuki—Miyaura Coupling Reactions

Highly fluorinated nitrobenzene derivatives are suitable substrates for palladium-catalyzed C-F bond arylation using readily available palladium catalysts under both conventional heating and microwave conditions. Arylation occurs ortho to the nitro group offering a synthetic route to polyfluorinated 2-arylnitrobenzene systems. The regiochemistry of the arylation reactions suggests that there is a significant directing interaction between the nitro group and the incoming nucleophilic palladium catalyst which is facilitated by the presence of several fluorine atoms attached the ring. Investigations into the regioselectivity and reactivity of several tetrafluoro- and trifluoronitrobenzene derivatives provides further evidence for the highly nucleophilic character of the oxidative addition step in contrast to the concerted mechanism of more conventional Suzuki-Miyaura coupling reactions involving aryl iodides and bromides.

Polyhalogenated heterocyclic compounds. Macrocycles from perfluoro-4-isopropylpyridinePart 50. For part 49 see ref. 1.

Perfluoro-4-isopropylpyridine was used as a building block for the two-step synthesis of a variety of macrocyclic systems bearing pyridine sub-units which were characterised by X-ray crystallography. Electrospray mass spectrometry revealed that complexation of either cations and, unusually, anions is possible depending on the structure of the macrocycle.

ELEMENTAL FLUORINE IN ORGANIC CHEMISTRY

There is a gradual realisation that elemental fluorine, for a long time considered too reactive and uncontrollable, can be used in viable syntheses on both the laboratory and industrial scale. This review focuses on recent uses of fluorine for the preparation of perfluorinated and selectively fluorinated molecules as well as for the promotion of other organic transformations.

Organofluorine chemistry: applications, sources and sustainability

Fluorine is an essential element for life in the developed world that impacts hugely on the general public because many pharmaceuticals, agrochemicals, anaesthetics, materials and air conditioning materials owe their important properties to the presence of fluorine atoms within their structures. All fluorine atoms used in organic chemistry are ultimately sourced from a mined raw material, fluorspar (CaF2), but, given current usage and global reserve estimates, there is only sufficient fluorspar available for a further 100 years. New large scale raw material sources of fluorine are available but must be sufficiently developed for the benefits of fluorinated systems to continue in the long term.

Microreactors for oxidations using fluorine

Abstract Continuous flow gas–liquid thin film microreactors have been effectively used for the oxidation of alcohols and Baeyer–Villiger oxidation of ketones using elemental fluorine.

Ionic liquids as media for nucleophilic fluorination

The use of Room Temperature Ionic Liquids (RTILs) for a variety of halogen exchange (Halex) fluorination processes using alkali metal fluorides is assessed. Whilst fluorination of a range of halogenated substrates is possible in good yield, the utility of RTILs as reusable, inert media for such reactions is limited by the gradual decomposition of the RTIL in the presence of highly basic fluoride ion.

Elemental fluorine. Part 14.1 Electrophilic fluorination and nitrogen functionalisation of hydrocarbons

Selective fluorination of a range of hydrocarbons was achieved by reaction with either elemental fluorine or Selectfluor™, an electrophilic fluorinating reagent of the N–F class. An electrophilic mechanism is envisaged. On prolonged reaction, the strongly acidic reaction medium that is formed upon substitution of hydrogen by fluorine when Selectfluor™ is used as the fluorinating reagent, promotes loss of fluoride from the initial fluorinated product. Trapping of the subsequent carbocation by the acetonitrile solvent in a Ritter type process gives overall nitrogen functionalisation of hydrocarbons. Amidation of hydrocarbons could also be achieved in a one-stage process by reaction of the hydrocarbon with fluorine and a Lewis acid, such as boron trifluoride–diethyl ether, in acetonitrile.