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

Complete Field Guide to Asymmetric BINOL-Phosphate Derived Brønsted Acid and Metal Catalysis: History and Classification by Mode of Activation; Brønsted Acidity, Hydrogen Bonding, Ion Pairing, and Metal Phosphates

Iron Catalysis in Organic Synthesis

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.

Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Green Chemistry Center, Peking University, 202 Chengfu Road, 098#, Beijing 100871, China State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 200060, China

Transition-Metal-Free Coupling Reactions

Title reaction proceeds with excellent regio- and stereoselectivities in the presence of a chiral N,N′-dioxide—Sb(III) catalyst.

Catalytic Asymmetric Bromoamination of Chalcones: Highly Efficient Synthesis of Chiral α-Bromo-β-Amino Ketone Derivatives

Highly efficient catalytic chloroamination reaction of α,β-unsaturated γ-keto esters and chalcones has been developed via a chloronium-based mechanism to deliver anti-regioselective vicinal chloroamines instead of the aziridinium intermediates delivered aminochlorides. The combination of TsNCl2 and TsNH2 as reagents made the transformation highly efficient, delivering the γ-carbonyl-β-chloro-α-amino acid derivatives and α-chloro-β-amino-ketone derivatives in nearly quantitative yields with up to 99% ee and 99:1 dr under 0.05−0.5 mol % catalyst loading. TsNHCl was demonstrated to act as the key reactive species to form a bridged chloronium ion intermediate in the presence of a chiral scandium complex. The method might provide useful information for further realization of other haloamination reactions.

Catalytic asymmetric chloroamination reaction of α,β-unsaturated γ-keto esters and chalcones.

Asymmetric expansion: A catalytic asymmetric ring-expansion reaction of the title compounds occurs in the presence of a Sc(OTf)(3) catalyst bearing an N,N'-dioxide-based ligand. Highly functionalized 2-quinolone derivatives containing a chiral C4-quaternary stereocenter were obtained in high yields and high levels of selectivity under mild reaction conditions (see scheme; Tf=trifluoromethanesulfonyl).

A Catalytic Asymmetric Ring‐Expansion Reaction of Isatins and α‐Alkyl‐α‐Diazoesters: Highly Efficient Synthesis of Functionalized 2‐Quinolone Derivatives

Enantioselective One-Pot Synthesis of 2-Amino-4-(indol-3-yl)-4H-Chromenes

A facile and efficient enantioselective Strecker reaction of ketimines catalyzed by a chiral alkali-metal salt has been developed. When 10 mol % BNPNa (BNP = 1,1'-binaphthyl-2,2'-diylphosphate) prepared in situ and 10 mol % para-tert-butyl-ortho-adamantylphenol (PBAP) were introduced into the reaction, up to 96% yield and up to 95% ee (ee = enantiomeric excess) were obtained. Both aliphatic and aromatic ketimines, especially sterically bulky cyclic ketimines derived from beta-acetonaphthone, alpha-indanone, and alpha-tetralone were found suitable for this reaction. On the basis of the experimental results and previous reports, trimethylsilyl cyanide (TMSCN) was indicated to be the real reactive nucleophile despite the existence of PBAP, and a possible working model was proposed to explain the origin of the asymmetric induction. The facile availability of 1,1'-binaphthyl-2,2'-diylphosphoric acid (BNPH) and the simplicity of the procedure are beneficial for practical applications.

Yunfei Cai

Papers

Catalytic Asymmetric Bromoamination of Chalcones: Highly Efficient Synthesis of Chiral α-Bromo-β-Amino Ketone Derivatives

Catalytic asymmetric chloroamination reaction of α,β-unsaturated γ-keto esters and chalcones.

A Catalytic Asymmetric Ring‐Expansion Reaction of Isatins and α‐Alkyl‐α‐Diazoesters: Highly Efficient Synthesis of Functionalized 2‐Quinolone Derivatives

Enantioselective One-Pot Synthesis of 2-Amino-4-(indol-3-yl)-4H-Chromenes

Facile and Efficient Enantioselective Strecker Reaction of Ketimines by Chiral Sodium Phosphate