Over the past decade, the most significant, conceptual advances in the field of fluorination were enabled most prominently by organo- and transition-metal catalysis. The most challenging transformation remains the formation of the parent C-F bond, primarily as a consequence of the high hydration energy of fluoride, strong metal-fluorine bonds, and highly polarized bonds to fluorine. Most fluorination reactions still lack generality, predictability, and cost-efficiency. Despite all current limitations, modern fluorination methods have made fluorinated molecules more readily available than ever before and have begun to have an impact on research areas that do not require large amounts of material, such as drug discovery and positron emission tomography. This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field.

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Introduction of Fluorine and Fluorine-Containing Functional Groups

Despite being largely absent from natural products and biological processes, fluorine plays a conspicuous and increasingly important role within pharmaceuticals and agrochemicals, as well as in materials science.1a−1c Indeed, as many as 35% of agrochemicals and 20% of pharmaceuticals on the market contain fluorine.1d Fluorine is the most electronegative element in the periodic table, and the introduction of one or more fluorine atoms into a molecule can result in greatly perturbed properties. Fluorine substituents can potentially impact a number of variables, such as the acidity or basicity of neighboring groups, dipole moment, and properties such as lipophilicity, metabolic stability, and bioavailability. The multitude of effects that can arise from the introduction of fluorine in small molecules in the context of medicinal chemistry has been extensively discussed elsewhere.2

For these reasons, methods to introduce fluorine into small organic molecules have been actively investigated for many years by specialists in the field of fluorine chemistry. However, particularly in the past decade, a combination of the increasing importance of fluorine-containing molecules and the successful development of bench stable, commercially available fluorine sources has brought the expansion of fluorine chemistry into the mainstream organic synthesis community. This has resulted in an acceleration in the development of new fluorination methods and consequently in methods for the asymmetric introduction of fluorine.3 Catalytic asymmetric fluorination methods have inevitably lagged somewhat behind their nonasymmetric counterparts as understanding of the modes of reactivity of new fluorinating reagents must generally be developed and understood before they can be extended to enantioselective catalysis.3b Indeed, the last special issue of Chemical Reviews dedicated to fluorine chemistry, in 1996, contained no articles addressing asymmetric fluorine chemistry, and the editor of the issue noted that “although fluorine chemistry is much less abstruse now than when I entered the field a generation ago, it remains a specialized topic and most chemists are unfamiliar, or at least uncomfortable, with the synthesis and behavior of organofluorine compounds.”4 The field has undoubtedly undergone great change within the last two decades.

As with the incorporation of the fluorine atom, the introduction of the trifluoromethyl (CF3) group into organic molecules can substantially alter their properties. As with fluorine, the prevalence of CF3 groups in pharmaceuticals and agrochemicals coupled with the development of new trifluoromethylating reagents also has led to a recent surge in the development of asymmetric trifluoromethylation and perfluoroalkylation. Although the fluorine and trifluoromethyl moieties are often found on the aromatic rings of many pharmaceutical and agrochemicals rather than in aliphatic regions, this may be a result of the lack of efficient methods for the asymmetric introduction of C–F and C–CF3 bonds into molecules; it could be the case that lack of chemical methods is restricting useful exploration of such molecules. However, there are still encouraging examples of drug candidates containing chiral fluorine and trifluoromethyl-bearing carbons (Figure ​(Figure11).



Figure 1

Molecules of medicinal interest bearing C–F and C–CF3 stereocenters.

Advances in catalytic enantioselective fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation reactions.

Monofluorination of Organic Compounds: 10 Years of Innovation.

Die wichtigsten konzeptionellen Fortschritt auf dem Gebiet der Fluorierungen der letzten zehn Jahre wurden durch die Organo- und Ubergangsmetallkatalyse ermoglicht. Die schwierigste Umwandlung ist weiterhin die Bildung der C-F-Stammbindung, was in erster Linie eine Folge der hohen Hydratationsenergie von Fluorid, starker Metall-Fluor-Bindungen und der hoch polarisierten Bindungen zu Fluor ist. Den meisten Fluorierungen fehlt es immer noch an Allgemeingultigkeit, Vorhersagbarkeit und Kosteneffizienz. Trotz der Einschrankungen sind fluorierte Verbindungen mit modernen Fluorierungsmethoden leichter zuganglich als je zuvor. Vor allem beginnen sich die modernen Methoden auf Forschungsgebiete auszuwirken, die keine grosen Materialmengen benotigen, z. B. die Wirkstoffentwicklung und die Positronenemissionstomographie. Diese Entwicklungen werden in diesem Aufsatz zusammengefasst und vor dem Hintergrund konventioneller Fluorierungsmethoden diskutiert.

Einführung von Fluor und fluorhaltigen funktionellen Gruppen

We report herein an operationally simple method for the direct conversion of benzylic C–H groups to C–F. We show that visible light can activate diarylketones to abstract a benzylic hydrogen atom selectively. Adding a fluorine radical donor yields the benzylic fluoride and regenerates the catalyst. The selective formation of mono- and difluorination products can be achieved by catalyst control. 9-Fluorenone catalyzes benzylic C–H monofluorination, while xanthone catalyzes benzylic C–H difluorination. The scope and efficiency of this new C–H fluorination method are significantly better than those of the existing methods. This is also the first report of selective C–H gem-difluorination.

Visible Light-Promoted Metal-Free C–H Activation: Diarylketone-Catalyzed Selective Benzylic Mono- and Difluorination

Efficient Synthesis of Phenanthridinone Derivatives via a Palladium-Catalyzed Coupling Process†

In the field of medicinal chemistry, it is widely recognized that the replacement of a hydrogen atom or a hydroxy group with a fluorine atom often improves the pharmacological activity of the parent compound. Although fluorine substitution on aromatic rings is a common tactic, several drug candidates with fluorine on a stereogenic carbon center have appeared in recent years. Consequently, the development of effective methods for the preparation of optically active fluorinated compounds is attracting considerable attention. We and others have already devised elegant systems for catalytic asymmetric fluorination reactions of carbonyl compounds, including b-keto esters, b-keto phosphonates, a-cyano phosphonates and a-cyano acetates, oxindoles, 7] acid derivatives, and aldehydes. As an extension of our acid–base catalytic system using late transition metal complexes, we recently reported the first example of catalytic diastereoand enantioselective conjugate addition of a-keto esters to nitroolefins. Focusing on a-keto esters as useful nucleophiles, we next became interested in asymmetric fluorination (Scheme 1). As the keto group in the product provides a good handle for further transformations, such reactions are expected to be useful for producing medicinally important chiral building blocks. Among them, b-fluoro-a-hydroxy and b-fluoro-a-amino acid derivatives are potentially useful as synthons for obtaining novel bioactive compounds and may contribute to pharmaceutical and chemical biology research. However, to date there is no example of an asymmetric reaction to access these compounds, because it has generally been believed that the monofluorinated products would tend to undergo facile enolization, resulting in the loss of optical purity. Difluorinated compounds might also be formed, albeit with difficulty. Based on our previous results, we envisaged that the use of mildly basic catalysts would permit the asymmetric fluorination of a-keto esters. Herein we report the first example of highly enantioselective mono-fluorination of a-keto esters catalyzed by Pd-m-hydroxo complexes 1. The resulting fluorinated products were successfully converted into chiral b-fluoro-a-hydroxy esters and b-fluoro-a-amino esters. As there are few generally applicable methods for the preparation of a substituted b-fluoro carboxylic acids, the present procedure is expected to be useful in medicinal chemistry research. Initially, we investigated the reaction of commercially available ethyl ester 2a with N-fluorobenzenesulfonimide (NFSI). Though our Pd-catalyzed fluorination reactions of 1,3-dicarbonyl compounds proceeded well in ethanol, no reaction was observed with a-keto ester 2a in this solvent (Table 1, entry 1). Careful solvent screening resulted in identification of methyl tert-butyl ether (MTBE) and cyclopentyl methyl ether (CPME) as the best solvents for the reaction. The yields and enantioselectivities obtained in the two solvents were comparable, but the fluorination reaction at 20 8C reached completion in 12 h in CPME, while it required 22 h in MTBE (Table 1, entries 8 and 9). Thus, CPME became our solvent of choice. As the corresponding fluorinated a-keto ester 3a was readily converted into the hydrate form during purification, the product was isolated after in situ reduction with diisobutylaluminium hydride (DIBAL-H). The low diastereoselectivity shown in Table 1 was later improved (see below). Furthermore, as the tert-butyl Scheme 1. Enantioselective mono-fluorination of a-keto esters. OTf = trifluoromethanesulfonate.

Catalytic asymmetric mono-fluorination of α-keto esters: synthesis of optically active β-fluoro-α-hydroxy and β-fluoro-α-amino acid derivatives.

Novel optically active axially chiral amino acid and amino alcohols have been synthesized efficiently via lactam ring-opening, with the aid of an optically active alcohol, amidoaza[5]helicene 5, which has been readily prepared by an additive-ligand-free Pd catalyzed domino coupling reaction in a single step. The stereostructures of these chiral molecules have also been clarified.

Synthesis of axially chiral amino acid and amino alcohols via additive-ligand-free Pd-catalyzed domino coupling reaction and subsequent transformations of the product amidoaza[5]helicene.

Synthesis of novel 1-aryl-substituted 8-methoxynaphthalenes and their tendency for atropisomerization

A palladium-mediated domino reaction was developed to conveniently synthesize phenanthridinone derivatives. Phosphine ligand 1 strongly promotes the domino process, which includes aryl-aryl coupling and C-N bond formations concomitant with a deamidation reaction. The versatility and applicability to a broad range of substrates make this reaction useful for the development of bioactive derivatives. [reaction: see text].

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Yuki Kitamura

Papers

Efficient Synthesis of Phenanthridinone Derivatives via a Palladium-Catalyzed Coupling Process†

Catalytic asymmetric mono-fluorination of α-keto esters: synthesis of optically active β-fluoro-α-hydroxy and β-fluoro-α-amino acid derivatives.

Synthesis of axially chiral amino acid and amino alcohols via additive-ligand-free Pd-catalyzed domino coupling reaction and subsequent transformations of the product amidoaza[5]helicene.

Synthesis of novel 1-aryl-substituted 8-methoxynaphthalenes and their tendency for atropisomerization

Efficient Synthesis of Phenanthridinone Derivatives via a Palladium-Catalyzed Coupling Process.