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.

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

Asymmetric fluorination, trifluoromethylation, and perfluoroalkylation reactions.

Claisen rearrangement over the past nine decades.

A general synthesis of selectively 6-(trifluoromethyl)-substitued 2(1H)-pyridinones is described. Further transformation of one of these compounds leads to the new CF3-containing potassium-channel openers 2a and 2b.

Synthesis of selectively trifluoromethylated pyridine derivaties as potential antihypertensives

The invention relates to novel N-benzoyl-N,-4-(5-phenylpyrimid-2-yloxy)phenylureas of formula ##STR1## wherein X 1 is hydrogen, halogen, C 1 -C 3 alkoxy or C 1 -C 3 alkylthio, X 2 is halogen, methyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylthio, Y 1 , Y 2 , Y 3 and Y 4 are each independently hydrogen, halogen, methyl, trifluoromethyl or methoxy, Z is methyl, halomethyl containing 1 to 3 halogen atoms or pentafluoroethyl; and R 1 , R 2 and R 3 are each independently hydrogen, halogen, C 1 -C 3 alkyl, trifluoromethyl or C 1 -C 3 alkoxy, to the preparation thereof and to intermediates for the synthesis of these compounds, as well as to compositions containing them for use in pest control, especially for controlling representatives of the order Acarina that attack plants and animals and for controlling insects. The novel compounds exhibit especially pronounced activity against plant-destructive mites.

Substituted benzoylphenylureas compounds useful as pesticides

Fluorine-containing organozinc reagents. VI, The preparation of α-trifluoromethyl-α,β-unsaturated carboxylic acid esters

The title compound 1, which can be regarded as a synthetic equivalent of substituted 1,1,1-trifluoroacetone 2, is prepared by Zn-induced reductive addition of 1,1,1-trichloro-2,2,2-trifluoroethane (3) to formaldehyde (4). A brief survey of the scope of this CC-bond formation leading to a variety of new CF3-containing synthetic building blocks is also given.

Fluorine‐Containing Organozinc Reagents Part 1 A Simple Synthesis of 2,2‐Dichloro‐3,3,3‐trifluoropropanol

There is described a process for producing fungicidally active 4-phenylpyrrole derivatives of the formula I ##STR1## wherein R is halogen, C1 -C6 -alkyl or C1 -C6 -haloalkyl, and n is 0, 1 or 2, which process comprises reacting a 3-trifluoromethyl-4-phenylpyrrole of the formula II ##STR2## wherein Rn is as defined under the formula I, and R1 is hydrogen or an acyl group, at elevated temperature and elevated pressure, with ammonia. Important intermediates and the production thereof are also described.

Robert W. Lang

Papers

Synthesis of selectively trifluoromethylated pyridine derivaties as potential antihypertensives

Substituted benzoylphenylureas compounds useful as pesticides

Fluorine-containing organozinc reagents. VI, The preparation of α-trifluoromethyl-α,β-unsaturated carboxylic acid esters

Fluorine‐Containing Organozinc Reagents Part 1 A Simple Synthesis of 2,2‐Dichloro‐3,3,3‐trifluoropropanol

Production for producing 3-cyano-4-phenyl indoles and intermediates