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

C-H bonds are ubiquitous in organic compounds. It would, therefore, appear that direct functionalization of substrates by activation of C-H bonds would eliminate the multiple steps and limitations associated with the preparation of functionalized starting materials. Regioselectivity is an important issue because organic molecules can contain a wide variety of C-H bonds. The use of a directing group can largely overcome the issue of regiocontrol by allowing the catalyst to come into proximity with the targeted C-H bonds. A wide variety of functional groups have been evaluated for use as directing groups in the transformation of C-H bonds. In 2005, Daugulis reported the arylation of unactivated C(sp(3))-H bonds by using 8-aminoquinoline and picolinamide as bidentate directing groups, with Pd(OAc)2 as the catalyst. Encouraged by these promising results, a number of transformations of C-H bonds have since been developed by using systems based on bidentate directing groups. In this Review, recent advances in this area are discussed.

Catalytic Functionalization of C(sp2) ? H and C(sp3) ? H Bonds by Using Bidentate Directing Groups

This Review summarizes the advancements in Pd-catalyzed C(sp3)–H activation via various redox manifolds, including Pd(0)/Pd(II), Pd(II)/Pd(IV), and Pd(II)/Pd(0). While few examples have been reported in the activation of alkane C–H bonds, many C(sp3)–H activation/C–C and C–heteroatom bond forming reactions have been developed by the use of directing group strategies to control regioselectivity and build structural patterns for synthetic chemistry. A number of mono- and bidentate ligands have also proven to be effective for accelerating C(sp3)–H activation directed by weakly coordinating auxiliaries, which provides great opportunities to control reactivity and selectivity (including enantioselectivity) in Pd-catalyzed C–H functionalization reactions.

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Palladium-Catalyzed Transformations of Alkyl C-H Bonds.

“All new is well-forgotten old”, the proverb goes. The current “fluorine boom” is news only to a novice in the field: the exceptional importance of fluorinated organic compounds in numerous areas has been known for a long time. The sharpest increase in the number of fluorine-containing pharmaceuticals and agrochemicals is dated back to 30 years ago. Also around that time (1979), the first monograph devoted to industrial applications of organofluorine compounds was published, covering not only fluorine-containing biologically active materials but also refrigerants, propellants, surfactants, textile chemicals, polymers, and dyes. The increasingly broad realization of the key role of organofluorine compounds in numerous areas has recently attracted many new scientists to the field. The development of new methods for the selective introduction of fluorine and fluorinecontaining groups into organic molecules for biologically active and other useful materials has become a hot area. Over 100 reviews, book chapters, and highlights on this subject have appeared in the literature in the past few years. As citing all of these publications in this review article is impossible, we provide references to only the most recent, general, and comprehensive ones. Molecules bearing a trifluoromethyl group constitute one of the most important classes of selectively fluorinated compounds. As early as 1928, Lehmann reported his observations of biological activity of some trifluoromethylated organic derivatives and already in 1959 Yale published a detailed review article entitled “The Trifluoromethyl Group in Medicinal Chemistry”. Since then, numerous books and reviews have appeared in the literature covering various aspects of trifluoromethylated organic and organometallic compounds. Within this family, derivatives bearing the CF3 group on aromatic rings are particularly numerous and important. Some examples of such compounds used as active ingredients of pharmaceuticals and agrochemicals are shown in Scheme 1. Trifluoromethylated building blocks and intermediates are clearly needed to make such molecules. The simplest trifluoromethylated aromatic compound, benzotrifluoride, was originally prepared by Swarts at the end of the 19th century. In his work, Swarts treated benzotrichloride with “two thirds of its weight of antimony fluoride” to obtain a mixture of PhCF2Cl and PhCF3, from which the two were separated and isolated pure by distillation. In the early 1930s, two industrial groups, one from Kinetic Chemicals, Inc. and one from I. G. Farbenindustrie AG patented their discoveries on the successful use of HF instead of SbF3 for the Swarts reaction. These inventions were the starting point for the modern large-scale manufacturing of trifluoromethylated aromatics. Other methods have been developed for conversion of various C1 units on the ring to CF3 with a variety of fluorinating agents. While representing an outstanding discovery and a classic of organic and organofluorine chemistry, the Swarts reaction is nonetheless neither atom-economical nor environmentally benign, as it deals with stoichiometric quantities of hazardous chemicals and generates large amounts of chlorine waste. To convert a CH3 group on the ring to CF3, the methyl is first exhaustively chlorinated to produce 3 equiv of HCl as a

Aromatic Trifluoromethylation with Metal Complexes

Iron Catalysis in Organic Synthesis

A combination of weakly coordinating auxiliaries and ligand acceleration allows for the development of both ortho- and meta-selective C–H olefination of phenol derivatives. These reactions demonstrate the feasibility of directing C–H functionalizations when functional groups are distal to target C–H bonds. The meta-C–H functionalization of electron-rich phenol derivatives is unprecedented and orthogonal to previous electrophilic substitution of phenols in terms of regioselectivity. These methods are also applied to functionalize α-phenoxyacetic acids, a fibrate class of drug scaffolds.

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Pd(II)-catalyzed ortho- or meta-C-H olefination of phenol derivatives.

A Pd(II)-catalyzed trifluoromethylation of ortho C–H bonds with an array of N-arylbenzamides derived from benzoic acids is reported. N-Methylformamide has been identified as a crucial promoter of C–CF3 bond formation from the Pd center. X-ray characterization of the C–H insertion intermediate has revealed a rare coordination mode of acidic amides as directing groups and the origin of their capacity in directing C–H activation.

Pd(II)-catalyzed ortho trifluoromethylation of arenes and insights into the coordination mode of acidic amide directing groups.

Pd(II) insertion into β-methylene C(sp3)–H bonds was enabled by a mutually repulsive and electron-rich quinoline ligand. Ligand tuning led to the development of a method that allows for installation of an aryl group on a range of acyclic and cyclic amides containing β-methylene C(sp3)–H bonds.

Ligand-Enabled Methylene C(sp3)–H Bond Activation with a Pd(II) Catalyst

The synthesis of internal benzyl alkynes and 1,2-diarylalkynes has been developed via palladium-catalyzed decarboxylative coupling reactions of alkynyl carboxylic acids with benzyl chlorides or aryl halides. In the presence of Pd(OAc)2 and Xphos (L3), alkynyl carboxylic acids smoothly underwent the reaction with various benzyl halides, providing the corresponding benzyl alkynes in moderate to good yields. It is noteworthy that the optimal conditions are compatible with a wide range of aryl halides including less active aryl chlorides.

Palladium-Catalyzed Decarboxylative Coupling of Alkynyl Carboxylic Acids with Benzyl Halides or Aryl Halides

An efficient synthesis of N-methyl-3-chalcogeno-indoles has been developed via iodine-mediated electrophilic annulation reactions of 2-alkynylaniline derivatives with disulfides or diselenides In the presence of iodine and iron, a variety of 2-alkynylanilines selectively underwent the electrophilic annulation with numerous disulfides or diselenides leading to the corresponding 3-sulfenylindoles and 3-selenenylindoles in moderate to excellent yields It is noteworthy that iron can promote the reaction

Xing-Guo Zhang

Papers

Pd(II)-catalyzed ortho- or meta-C-H olefination of phenol derivatives.

Pd(II)-catalyzed ortho trifluoromethylation of arenes and insights into the coordination mode of acidic amide directing groups.

Ligand-Enabled Methylene C(sp3)–H Bond Activation with a Pd(II) Catalyst

Palladium-Catalyzed Decarboxylative Coupling of Alkynyl Carboxylic Acids with Benzyl Halides or Aryl Halides

Iron-Facilitated Iodine-Mediated Electrophilic Annulation of N,N-Dimethyl-2-alkynylanilines with Disulfides or Diselenides