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

Fluorine has received great attention in all fields of science. “Small atom with a big ego” was the title of the Symposium at the ACS meeting in San Francisco in 2000, where a number of the current scientific and industrial aspects of fluorine chemistry made possible by the small size and high electronegativity of the atom were discussed. This small atom has provided mankind with significant benefits in special products such as poly(tetrafluroethylene) (PTFE), freon, fluoro-liquid crystals, optical fiber, pharmaceutical and agrochemical compounds, and so on, all of which have their own unique properties that are otherwise difficult to obtain.1 For instance, at present, up to 30% of agrochemicals and 10% of pharmaceuticals currently used contain fluorine atoms. Therefore, organic fluorine compounds have received a great deal of interest and attention from the scientists involved in diverse fields of science and technology. Now, not only C-F bond formation but also selective C-F bond activation have become current subjects of active investigation from the viewpoint of effective synthesis of fluoroorganic compounds. The former is highlighted by designing a sophisticated fluorinating reagent for regioand stereocontrolled fluorination and developing versatile multifunctional and easily prepared building blocks. C-F bond formation has been treated extensively in several reviews2 and books.3 The latter is a subject that has been less explored but would be promising for selective defluorination of aliphatic fluorides, cross-coupling with aryl fluorides, and * To whom correspondence should be addressed. Phone: 81-78-803-5799. Fax: 81-78-803-5799. E-mail: amii@kobe-u.ac.jp and uneyamak@cc.okayamau.ac.jp. † Kobe University. ‡ Okayama University. Chem. Rev. 2009, 109, 2119–2183 2119

C-F bond activation in organic synthesis.

Perfluoroalkylation with Organosilicon Reagents

Synthetic Methods for Compounds Having CF3–S Units on Carbon by Trifluoromethylation, Trifluoromethylthiolation, Triflylation, and Related Reactions

Trifluoromethyltrimethylsilane: nucleophilic trifluoromethylation and beyond.

The preparation of a variety of novel perfluoroalkyl-substituted compounds in high yields using easily prepared (perfluoroalkyl)trimethylsilanes (1a-c) is described. (Trifluoromethyl)-, (pentafluoroethyl)-, and (heptafluoropropyl)trimethylsilane, 1a-c, respectively, react readily with carbonyl compounds, such as aldehydes and ketones, by a fluoride-initiated catalytic process. Fluoride-initiated addition of 1 to a carbonyl group generates an oxyanionic species which then further catalyzes the reaction. Even enolizable carbonyl compounds react cleanly under the reaction conditions. A study of the scope of the reactivity of 1a toward other carbonyl groups in esters, lactones and an acid chloride was also carried out

Preparation of trifluoromethyl and other perfluoroalkyl compounds with (perfluoroalkyl)trimethylsilanes

A convenient preparation of sulfuryl chloride fluoride

Preparation of α,α-difluoroalkanesulfonic acids

One-Pot Preparation of Pentafluoroethanesulfonic (Pentflic) Acid by the Organolithium Pathway

1,3-Dithiolan-2-ylium tetrafluoroborate (2) has been prepared and is found to be a good C-alkylating agent for the β-1,3-dithiolaniation of carbonyl compounds through their enol trimethylsilyl ethers

Donald R. Bellew

Papers

Preparation of trifluoromethyl and other perfluoroalkyl compounds with (perfluoroalkyl)trimethylsilanes

A convenient preparation of sulfuryl chloride fluoride

Preparation of α,α-difluoroalkanesulfonic acids

One-Pot Preparation of Pentafluoroethanesulfonic (Pentflic) Acid by the Organolithium Pathway

Preparation of 1,3-dithiolan-2-ylium Tetrafluoroborate and Its Reaction with Enol Trimethylsilyl Ethers