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.

10.2. Synthesis of Other -Amino Acid Derivatives 3676 10.2.1. Synthesis of -Amino Ketones 3676 10.2.2. Synthesis of -Amino Nitriles 3679 10.2.3. Synthesis of -Amino Phosphinates 3680 10.2.4. Synthesis of -Amino Sulfonates 3681 11. Synthesis of 1,2-Amino Alcohols 3681 11.1. 1,2-Addition to R-Alkoxy Imines 3681 11.2. 1,2-Addition of R-Substituted Organometallic Reagents to N-tert-Butanesulfinyl Imines 3687 * E-mail: jellman@berkeley.edu. † These authors contributed equally to this work. Chem. Rev. 2010, 110, 3600–3740 3600

Synthesis and Applications of tert-Butanesulfinamide

Good Partnership between Sulfur and Fluorine: Sulfur-Based Fluorination and Fluoroalkylation Reagents for Organic Synthesis

Oxidative Coupling between Two Hydrocarbons: An Update of Recent C–H Functionalizations

Fluoroalkylation reaction, featuring the transfer of a fluoroalkyl group to a substrate, is a straightforward and efficient method for the synthesis of organofluorine compounds. In fluoroalkylation reactions, fluorine substitution can dramatically influence the chemical outcome. On the one hand, the chemistry of alkylation with non-fluorinated reagents may not be applicable to fluoroalkylations, so it is necessary to tackle the fluorine effects to achieve efficient fluoroalkylation reactions. On the other hand, fluorine substitution may bring about new reactivities and transformations that cannot be realized in alkylation with non-fluorinated reagents; thus, fluorine substitution can be used to explore new synthetic methods. This tutorial review provides a brief overview of the unique fluorine effects in recently developed nucleophilic, electrophilic, radical, and transition metal-mediated fluoroalkylation reactions by comparing with either their non-fluorinated counterparts or fluorinated counterparts with different numbers of fluorine substituents.

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The unique fluorine effects in organic reactions: recent facts and insights into fluoroalkylations

The radical fluoroalkylation of isocyanides with fluorinated sulfones is enabled by visible-light photoredox catalysis. A wide range of readily available mono-, di-, and trifluoromethyl heteroaryl sulfones can thus be used as efficient radical fluoroalkylation reagents under mild conditions. This method not only describes a new synthetic application of fluorinated sulfones, but also provides a new route to fluoroalkyl radicals.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.201510533

Radical Fluoroalkylation of Isocyanides with Fluorinated Sulfones by Visible-Light Photoredox Catalysis.

Two-in-one: Me3 SiCF2 Br is an efficient difluorocarbene source and is compatible with both neutral and aqueous basic conditions. Bromide-ion-initiated [2+1] cycloaddition with alkenes/alkynes and hydroxide ion promoted α-addition with (thio)phenols, (thio)alcohols, sulfinates, heterocyclic amines, and H-phosphine oxides give the corresponding gem-difluorinated compounds with broad functional-group tolerance.

Synthesis of gem-Difluorocyclopropa(e)nes and O-, S-, N-, and P-Difluoromethylated Compounds with TMSCF2Br†

Difluorocarbene is a versatile, reactive intermediate for use in organic synthesis. Over the past decade, significant progress has been made in difluorocarbene chemistry owing to the increasing demand for various fluorinated molecules. Not only the substrate scope for some classical difluorocarbene reagents has been largely expanded, but also new and environmentally friendly difluorocarbene reagents for difluoromethylation and gem-difluorocyclization have been developed. This review summarizes the difluoromethylation, gem-difluorocyclopropanation, gem-difluorocyclopropenation, gem-difluoroolefination, and trifluoromethylation achieved in the last decade using both the classical and the new difluorocarbene sources. 1	Introduction 2	Difluorocarbene Sources 3	Difluoromethylation 3.1	O-Difluoromethylation 3.2	S-Difluoromethylation 3.3	N-Difluoromethylation 3.4	Difluoromethylation of Ambident N,O- and N,S-Nucleophiles 3.5	Se- and P-Difluoromethylation 3.6	C-Difluoromethylation 3.7	Sn-Difluoromethylation 4	gem-Difluorocyclization 4.1	gem-Difluorocyclopropanation 4.2	gem-Difluorocyclopropenation 5	gem-Difluoroolefination and Related Reactions 6	Trifluoromethylation 7	Miscellaneous 8	Conclusions

Chuanfa Ni

Papers

Good Partnership between Sulfur and Fluorine: Sulfur-Based Fluorination and Fluoroalkylation Reagents for Organic Synthesis

The unique fluorine effects in organic reactions: recent facts and insights into fluoroalkylations

Radical Fluoroalkylation of Isocyanides with Fluorinated Sulfones by Visible-Light Photoredox Catalysis.

Synthesis of gem-Difluorocyclopropa(e)nes and O-, S-, N-, and P-Difluoromethylated Compounds with TMSCF2Br†

Recent Advances in the Synthetic Application of Difluorocarbene