Carbon–Fluorine Bond Formation

We present a selection of carbon–fluorine bond formations that have been developed in the recent past. An overview of the most common fluorination reagents is followed by fluorination reactions organized by reactivity. We have distinguished between nucleophilic and electrophilic fluorinations as well as aliphatic and aromatic fluorinations. Each section is divided into more specific reaction classes and examples for syntheses of pharmaceuticals, $^{18}$F-radiolabeling, and mechanistic investigations are provided.Chemistry and Chemical Biolog

Self-control tames the coupling of reactive radicals

Highly reactive or unstable chemical reagents are challenging to prepare, store, and safely handle, so chemists frequently generate them in situ from convenient precursors. In an ideal case, the rate of release of the reagent would be matched to the rate of its “capture” in the desired chemical reaction, thereby preventing the reagent from accumulating and minimizing any opportunity for decomposition. However, this synchronization is rarely achieved or even attempted: The rate of release is usually dictated by the conditions of the reaction (1), rather than being regulated by capture of the reagent. In this issue, Tellis et al. (2) on page 433 and Zuo et al. (3) on page 437 independently report the use of iridium photocatalysis (4, 5) to supply highly reactive radical coupling partners (R⋅) to a nickel-catalyzed carbon-carbon bond-forming process (see the figure). Intriguingly, the two points of contact between the iridium and nickel cycles enforce autoregulated release of the radical, ensuring its efficient capture by nickel rather than its decomposition via other pathways

Palladium-Mediated Fluorination of Arylboronic Acids

Saving the best for last: Novel palladium complexes allow mild, two-step fluorination of aryl boronic acids (see scheme). The reaction is regiospecific, functional-group tolerant, has a broad substrate scope, and is ideally suited for the introduction of fluorine substituents at a late stage for aryl fluoride synthesis.Chemistry and Chemical Biolog

Sulfonium Salts as Leaving Groups for Aromatic Labelling of Drug-like Small Molecules with Fluorine-18.

Positron emission tomography (PET) is unique in that it allows quantification of biochemical processes in vivo, but difficulties with preparing suitably labelled radiotracers limit its scientific and diagnostic applications. Aromatic [(18)F]fluorination of drug-like small molecules is particularly challenging as their functional group compositions often impair the labelling efficiency. Herein, we report a new strategy for incorporation of (18)F into highly functionalized aromatic compounds using sulfonium salts as leaving groups. The method is compatible with pharmacologically relevant functional groups, including aliphatic amines and basic heterocycles. Activated substrates react with [(18)F]fluoride at room temperature, and with heating the reaction proceeds in the presence of hydrogen bond donors. Furthermore, the use of electron rich spectator ligands allows efficient and regioselective [(18)F]fluorination of non-activated aromatic moieties. The method provides a broadly applicable route for (18)F labelling of biologically active small molecules, and offers immediate practical benefits for drug discovery and imaging with PET

Palladium–mediated organofluorine chemistry

Producción CientíficaThe substitution of fluorine for hydrogen in a molecule may result in profound changes in its properties and behaviour. Fluorine does not introduce special steric constraints since the F atom has a small size. However, the changes in bond polarity and the possibility of forming hydrogen bonds with other hydrogen donor fragments in the same or other molecules, may change the solubility and physical properties of the fluorinated compound when compared to the non-fluorinated one. Fluorine forms strong bonds to other elements and this ensures a good chemical stability. Altogether, fluorinated compounds are very attractive in materials chemistry and in medicinal chemistry, where many biologically active molecules and pharmaceuticals do contain fluorine in their structure and this has been shown to be essential for their activityJunta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA302U13)Junta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA256U13

New methodology for the synthesis of fluorinated aromatics

This thesis is concerned with new methodology for the introduction of fluorine atoms, and trifluoromethyl groups into aromatic systems and the following approaches have been adopted: (i) The possibility of selective cleavage of the aryl-silicon bond of aryltrimethylsilanes by elemental fluorine to give the corresponding fluorinated aromatic compound was explored, and competing silicon and hydrogen substitution was observed. The affect of temperature and solvent upon this process was investigated. (ii) Attempts to modify the reactivity of dilute elemental fluorine (10% fluorine/nitrogen) towards aromatic systems at low reaction temperatures were made by the addition of pyridine and substituted pyridines. The effectiveness of this methodology was limited by the reactivity of the pyridine systems towards elemental fluorine.(Hi) The potential electrophilic fluorinating agents N-fluoro-2,3- bis(2H hexafluoropropyl) pyrrolidine and N-fluorosuccinimide have been synthesised by the direct fluorination of the corresponding N-trimethyl- silyl compounds.(iv) The cycloaddition reactions of hexafluorobut-2-yne with furan and 2-substituted furans have been employed to synthesise a series of benzenoid and heteroaromatic compounds containing two trifluoromethyl groups in high yield.(v) The synthesis of trifluoromethylpyridines by the cycloaddition of 3,3,3-trifluoropropene with oxazoles has also been investigated

New approaches to aromatic fluorinations

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Nucleophilicity index based on atomic natural orbitals

A simple method of evaluating a semilocal (regional) nucleophilicity is introduced. The concept involves use of the natural orbitals for atomic populations to identify the most “reactive population” of electrons on particular atom in molecule. The results of test calculations considering the regioselectivity problem in electrophilic aromatic substitution to the benzene derivatives are presented and briefly discussed

Synthetic applications of arene chromium tricarbonyl complexes

This thesis investigates the use of arene chromium complexes as phenyl cation synthons in the synthesis of homochiral N-phenylamino esters, and the dianion formation of a series of complexed aryl ethers. Chapter 1 reviews the properties of arene chromium tricarbonyl complexes and discusses in detail the ability of some of these complexes to undergo nucleophilic aromatic substitution. Chapter 2 outlines the biological importance of homochiral N-phenylamino esters. The N-phenylation of a series of amino alcohols are first investigated both by direct reaction of haloarene complexes with amino alcohols and also via a Smiles rearrangement of an aryl ether derivative. In addition, methodology is developed for the synthesis of a series of homochiral N-phenyl-α-amino esters and N-phenyl-β-amino esters. The synthetic strategy is then applied to the synthesis of some N-phenyl-β-lactams, in particular (+)SCH 48461. Chapter 3 reviews the directed metallation of complexed and uncomplexed arene compounds and discusses the mechanism involved. The generation of dianions in a series of complexed aryl ethers is investigated. Regioselective deprotonation is observed using different alkyllithium bases and the degree of dianion formation is confirmed by electrophilic quench of the dianionic intermediates with CD3OD and TMSC1

Metal-catalysed Halogen Exchange Reactions of Aryl Halides

Aryl halides are common synthetic targets themselves, and also highly versatile synthetic intermediates. Aryl chlorides are much more widely available and easier to synthesise than the other halide derivatives, so the development of effective methods for interconverting aryl halide derivatives would therefore be extremely useful. This article outlines which transformations are particularly desirable, and describes the progress that has been made on developing methods for carrying out those transformations using copper, nickel or palladium catalysts. The possible mechanisms of these reactions are discussed, with a view to identifying areas for future investigation