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

Recent advances in catalysis have made the incorporation of fluorine into complex organic molecules easier than ever before, but selective, general and practical fluorination reactions remain sought after. Fluorination of molecules often imparts desirable properties, such as metabolic and thermal stability, and fluorinated molecules are therefore frequently used as pharmaceuticals or materials. But the formation of carbon-fluorine bonds in complex molecules is a significant challenge. Here we discuss reactions to make organofluorides that have emerged within the past few years and which exemplify how to overcome some of the intricate challenges associated with fluorination.

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Catalysis for fluorination and trifluoromethylation

The 3,3′-disubstituted oxindole structural motif is a prominent feature in many alkaloid natural products, which include all kinds of tetrasubstituted carbon stereocenters, spirocyclic or not, all-carbon or heteroatom-containing. The catalytic asymmetric synthesis of the tetrasubstituted carbon stereocenter at the C-3 position of the oxindole framework integrates new synthetic methods and chiral catalysts, reflects the latest achievements in asymmetric catalysis, and facilitates the synthesis of sufficient quantities of related compounds as potential medicinal agents and biological probes. This review summarizes the recent progress in this area, and applications in the total synthesis of related bioactive compounds.

Catalytic Asymmetric Synthesis of Oxindoles Bearing a Tetrasubstituted Stereocenter at the C‐3 Position

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.

Fluorination in Medicinal Chemistry: Methods, Strategies, and Recent Developments

Cinchona Alkaloid Catalyzed Enantioselective Fluorination of Allyl Silanes, Silyl Enol Ethers, and Oxindoles

https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.200501041

Highly Enantioselective Catalytic Fluorination and Chlorination Reactions of Carbonyl Compounds Capable of Two‐Point Binding

The first catalytic enantioselective hydroxylation reaction of both 3-aryl and 3-alkyl-2-oxindoles using the DBFOX−Zn(II) complex, leading to pharmaceutically important chiral 3-hydroxy-2-oxindoles was described. The structure of oxidant was found to play an important role to increase the enantioselectivity. The methodology has successfully applied to the highly enantioselective hydroxylation of β-keto esters using the DBFOX−Ni(II) complex.

Lewis Acid-Catalyzed Enantioselective Hydroxylation Reactions of Oxindoles and β-Keto Esters Using DBFOX Ligand

New approaches to enantioselective fluorination: Cinchona alkaloids combinations and chiral ligands/metal complexes

The first examples of an elective sense of enantioselectivity in enantioselective fluorination reaction using (S,S)-bis(oxazoline)-Ph complexed with Cu(II) or Ni(II) are described.

Takehisa Ishimaru

Papers

Cinchona Alkaloid Catalyzed Enantioselective Fluorination of Allyl Silanes, Silyl Enol Ethers, and Oxindoles

Highly Enantioselective Catalytic Fluorination and Chlorination Reactions of Carbonyl Compounds Capable of Two‐Point Binding

Lewis Acid-Catalyzed Enantioselective Hydroxylation Reactions of Oxindoles and β-Keto Esters Using DBFOX Ligand

New approaches to enantioselective fluorination: Cinchona alkaloids combinations and chiral ligands/metal complexes

First Enantio-Flexible Fluorination Reaction Using Metal-Bis(oxazoline) Complexes