Hideki Amii

C−F Bond Activation in Organic Synthesis

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

A New Method for Aromatic Difluoromethylation: Copper-Catalyzed Cross-Coupling and Decarboxylation Sequence from Aryl Iodides

A new methodology for aromatic difluoromethylation is described. Aryl iodides reacted with α-silyldifluoroacetates upon treatment with copper catalyst in DMSO or DME to give the corresponding aryldifluoroacetates in moderate to good yields. The subsequent hydrolysis of aryldifluoroacetates and KF-promoted decarboxylation afforded a variety of difluoromethyl aromatics.

α-Trifluoromethylated Carbanion Synthons

Trifluomethylated organic compounds often have properties that make them suitable for diverse applications, including materials science, agrochemistry, and pharmaceutical industry. But of all the therapeutic drugs currently available, about 10% of them have a partially fluorinated moiety. Thus, a great deal of attention is being paid to the development of reliable methodologies for trifluoromethylation. Introduction of a trifluoromethyl group into the target molecules mostly relies on either trifluoromethylating reagents or trifluoromethylated synthetic blocks. The chemistry of trifluoromethyl carbanions, nucleophilic trifluoromethylating agents such as the Ruppert-Prakash reagent, and organometallic species has been intensively developed for their important synthetic applications. But the chemistry of beta,beta,beta-trifluoroethyl carbanions (alpha-trifluoromethyl carbanions) and organometallic species has remained undeveloped despite their potential usefulness in organic synthesis. The issue needs to be addressed. This Account outlines successful alkylations and useful synthetic applications of alpha-trifluoromethyl carbanions, such as alpha-substituted beta,beta,beta-trifluoroethyl, alpha-trifluoromethylethenyl, trifluoroacetimidoyl, alpha-trifluoromethyloxiranyl, and related alpha-trifluoromethylated carbanions. The strong electron-withdrawing effect of the alpha-trifluoromethyl group may stabilize the carbanion species electronically. But alpha-trifluoromethyl carbanions and their corresponding organometallic species mostly release fluoride spontaneously to produce difluoroalkenes. This notorious decomposition of alpha-trifluoromethylated carbanions and anionoids has hindered the development of these species for organic synthesis. A well-designed device for the generation, stabilization, and acceleration for alkylation of the alpha-trifluoromethylated carbanions is needed for their synthetic application, as well as stabilization by the electron-withdrawing alpha-substituent. The reported alpha-substituted alpha-trifluoromethyl carbanions can be roughly categorized into three classes based on their structures. The first category, A, is pi-conjugation-stabilized carbanions, which are stabilized by ester, nitro, sulfone, carbonyl, or phenyl groups. alpha-Substituents of these carbanions can delocalize the negative charges on their pi-system with large sigma R electron-withdrawing effects; this prevents accumulation of negative charge on the fluorine atoms. The second category, B, consists of carbanions with sp(3) orbitals either of highly halogenated carbanionsexamples include pentafluoroethyl(trimethyl)fluorosilicate, pentafluoroethyllithium, and alpha,alpha-dichloro-beta,beta,beta-trifluoroethylzinc speciesor of cyclic structures such as oxiranyl- and aziridinyllithiums. Both of these carbanions are also stabilized since they reduce molecular orbital (MO) overlapping of the carbanion orbital to C-F bond orbitals. The third category, C, has carbanions with their anion center at the sp(2) orbital, such as alpha-trifluoromethylated alkenyl carbanions and imidoyl carbanions. These sp(2) orbitals of the carbanion center usually have a small overlap with the C-F bonds of trifluoromethyl groups. The small overlap is able to suppress the E2-type eliminations. alpha-Trifluoromethylated carbanions are, in general, unstable. Their stability is largely affected by factors like hybridization of the orbital that accommodates lone pair electrons, the electronic nature of the alpha-substituents, the degree of covalency in a bond between the carbon and metal, the class of countercation, stabilization by chelation of a metal cation, and so on. The stability, therefore, can be sometimes controlled by tuning these factors adequately so that they can be used for organic synthesis. The chemistry of alpha-trifluoromethylated carbanions for organic synthesis has been progressing steadily. However, the simplest trifluoroethyl and trifluoroacetyl carbanions have never been successfully produced and employed for organic synthesis. Elegant generation and synthetic application of these metal species are one of the most attractive and challenging subjects for active investigation in the future.

First synthesis of 3,3-difluoroserine and cysteine derivatives via Mg(0)-promoted selective CF bond cleavage of trifluoromethylimines

Abstract 3,3-Difluoroserine and cysteine derivatives were synthesized via Mg(0)-promoted defluorination of trifluoromethylimines as a key step, followed by addition of alcohols and sulfenyl chloride, respectively.

A new sequential defluorination route to α-fluoro-α,β-unsaturated ketones from trifluoromethyl ketones

α-Fluoro-α,β-unsaturated ketones were prepared from trifluoromethyl ketones via a sequence involving Mg metal promoted successive double defluorination. Trifluoromethyl ketones were transformed to β,β-difluoroenol silyl ethers which were then coupled with aldehydes and ketones to β-hydroxy-α,α-difluoroketones. A second Mg-promoted defluorination of the hydroxyketones followed by acid-catalyzed hydrolysis of γ-hydroxy-β-fluoroenol silyl ethers provided α-fluoro-α,β-unsaturated ketones as a final product.

A review of Mg metal-promoted CF bond activation; a reliable synthetic approach to difluorinated organic compounds

Abstract The carbon–fluorine bond of a trifluoromethyl group attached to a π system can be activated by metallic magnesium in the system TMSCl–THF or DMF providing a variety of difluorinated compounds via a selective CF bond cleavage. Thus, trifluoromethyl ketones, α,β-unsaturated ketones, esters, imines, and aromatics can be transformed into the corresponding difluoroenol silyl ethers, enamines, and difluoro(trimethylsilyl)methyl aromatics in good to excellent yields, respectively. This protocol enabled us to synthesize β,β-difluoroamino acids, difluoroheterocycles, and functionalized difluoroacetates.

Novel axially chiral phosphine ligand with a fluoro alcohol moiety for Rh-catalyzed asymmetric arylation of aromatic aldehydes.

A new chiral phosphine ligand (R)-1 possessing a fluoroalcohol moiety was prepared. The (R)-1-coordinated Rh(I) complex showed an excellent catalytic activity for asymmetric 1,2-addition of arylboronic acids to aldehydes to afford highly enantioenriched diarylmethanols. The fluoroalcohol moiety in ligand (R)-1 plays a pivotal role for the high enantioselectivity of the present Rh(I)-catalyzed transformation.

A novel synthesis of β-trifluoromethyl-substituted isoserine via intramolecular rearrangement of imino ethers

The methodology for the construction of β-trifluoromethyl-substituted isoserine is reported. The fluorinated α-hydroxy-β-imino esters which are the precursors to amino acid derived isoserine were formed firstly via a base catalyzed intramolecular rearrangement of imino ethers, and the subsequent conversions of these compounds resultedin the formation of the designedisoerines and the related fluorinated compounds.

Boron-substituted difluorocyclopropanes: new building blocks of gem-difluorocyclopropanes.

Cycloaddition of difluorocarbene to alkenyl boronates 3 gave boron-substituted gem-difluorocyclopropanes 2 in stereospecific fashion. Upon treatment with lithium carbenoids, cyclopropyl boronates 2 underwent one-carbon homologation to afford a variety of gem-difluorocyclopropanes in good yields.

Flow microreactor synthesis in organo-fluorine chemistry

Summary Organo-fluorine compounds are the substances of considerable interest in various industrial fields due to their unique physical and chemical properties. Despite increased demand in wide fields of science, synthesis of fluoro-organic compounds is still often faced with problems such as the difficulties in handling of fluorinating reagents and in controlling of chemical reactions. Recently, flow microreactor synthesis has emerged as a new methodology for producing chemical substances with high efficiency. This review outlines the successful examples of synthesis and reactions of fluorine-containing molecules by the use of flow microreactor systems to overcome long-standing problems in fluorine chemistry.