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.

4-Acylresorcinol esthers of the formula ##STR1## in which R 1 is lower alkyl, R 2 is fluorinated lower alkyl, R 3 is hydrogen, lower alkoxy, trifluoromethyl or halogen, alk is an alkylene or hydroxyalkylene radical which is uninterrupted or interrupted by oxygen, one of the radicals R 4 , R 5 and R 7 is a group of the formula --NH--C(═O)--R 8 , a radical R 4 or R 5 which differs from this is a radical R 9 and a radical R 7 which differs from this is a radical R 10 , R 6 is hydrogen, lower alkyl, trifluoromethyl, halogen, carboxyl which is free, esterified or amidated, cyano or lower alkanoyl, R 8 is carboxyl which is free, esterified or amidated or 5-tetrazolyl, R 9 is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl and R 10 is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, cyano or carboxyl which is free, esterified or amidated, and their salts have antiallergic and antiinflammatory properties. They are prepared, for example, by reacting compounds of the formulae ##STR2## in which one of the radicals X 5 and X 6 is hydroxyl which is free or in salt form and the other is an alkoxy radical substituted by reactive esterified hydroxy or epoxy. The invention also relates to intermediates of the formula ##STR3## in which R 2 is fluorinated lower alkyl, R 3 is hydrogen, lower alkoxy, trifluoromethyl or halogen and R 11 is hydrogen or a group of the formula R 1 --C(--O)--, in which R 1 is lower alkyl, and their salts.

Oxaloamino substituted fluorinated resorcinol ethers and anti-allergic and anti-inflammatory use thereof

There is described a process for producing fungicidally active 4-phenylpyrrole derivatives of the formula I (I) 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 (II) 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.

3-cyano-4-phen-il pyrrole derivatives

Die Umsetzung von Brom- bzw. Chlordifluoressigsaureallylestern mit Monochlorsilanen in Gegenwart von Zink unter Erwarmen ergibt Silylester von α,α-Difluor-γ,δ-pentensauren. The reaction of bromine or Chlordifluoressigsaureallylestern with monochlorosilanes in the presence of zinc under heating yields silyl ester of α, α-difluoro-γ, δ-pentenoic acids. Durch Hydrolyse erhalt man die freien Sauren, aus denen nach ublichen Methoden Saurederi vate herstellbar sind. By hydrolysis to give the free acids from which derivatives can be prepared by customary methods Saurederi. Die Pentensauren und Pentensaurederivate eignen sich zur Herstellung von Polymeren und Copolymeren, aus denen metallorganische Polymere und Copolymere mit katalytischen Eigen schaften erhaltlich sind. The pentenoic acids and pentenoic suitable for the production of polymers and copolymers from which organometallic polymers and copolymers with catalytic properties own text.

Process for the preparation of 2,2-difluoropent-4-ene-carboxylic acids and derivatives

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.

Verbindungen der Formel I Compounds of formula I worin R 1 , R 2 , R 3 und R 4 fur H, Alkyl oder Aryl stehen, m und n 0 oder 1 bedeuten, und A einen zweiwertigen organischen Rest darstellt, der mit der (CR 1 R 2 ) m NF-SO 2 (CR 3 R 4 ) n Gruppen einen 5- bis 8- gliedrigen Ring bildet, eignen sich hervorragend als C-Fluorierungsmittel, insbesondere als stereoselektive Fluorierungsmittel, wenn die Verbindungen ein chirales C-Atom enthalten, und in einer optisch aktiven Form vorliegen. wherein R 1, R 2, R 3 and R 4 is H, alkyl or aryl, m and n are 0 or 1, and A represents a divalent organic radical which with the (CR 1 R 2) m NF-SO 2 (CR 3 R 4) n group forming a 5- to 8-membered ring, are outstandingly suitable as C-fluorinating agent, especially as a stereoselective fluorination when the compounds contain a chiral carbon atom, and in an optically active form present ,

Robert W. Lang

Papers

Oxaloamino substituted fluorinated resorcinol ethers and anti-allergic and anti-inflammatory use thereof

3-cyano-4-phen-il pyrrole derivatives

Process for the preparation of 2,2-difluoropent-4-ene-carboxylic acids and derivatives

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

N-fluorinated sulfon amides, process for their preparation and their use