Perfluoroalkyl groups, introduction

Perfluoroalkyl derivatives have important technical uses, e.g. sulphonic acids as surfactants introduction of perfluoroalkyl groups confers useful properties on many drugs. 

The development of synthetic methods for the selective introduction of short-chain perfluoroalkyl groups into organic molecules is of interest in drug development [464]. Fluoromodifications often confer unique properties on a molecule, for example in terms of increased metabolic stability and lipophilicity and, as a consequence, the pharmacokinetic profiles are often improved [465]. Burger and coworkers developed a domino process consisting of a SN reaction combined with a Claisen and a Cope rearrangement which allows the transformation of simple fluorinated compounds into more complex molecules with fluoro atoms [466]. Treatment of furan 2-917 with 2-hydroxymethyl thiophene (2-918) in the presence... 

Recent investigations focus on the introduction of fluorine atoms and perfluoroalkyl groups into molecules of known bioactive compounds to improve their properties. The modification of biological activity in this way can be connected with the following factors ... 

Syntheses of heterocyclic compounds with perfluorinated side chains are mainly performed by substitutional fluorinations of the available fragments or by the introduction of a perfluoroalkyl group in the heterocycle. The development of convenient approaches and direct perfluoro-alkylation methods is a current challenge. 

In the syntheses of heterocyclic compounds with perfluoroalkyl groups, the key methods are based on two types of chemical transformations. The first type involves the introduction of the perfluoroalkyl group on the heterocyclic system, namely, substitutional fluorination of fragments already available in the system or direct introduction of the perfluoroalkyl group onto the heterocycle. 

B. Strategies for the Introduction of Fluorine and Perfluoroalkyl Groups into Organic Molecules... 

IV. Introduction of Fluorine, Poiyfluoroaikyl, and Perfluoroalkyl Groups into Five>Membered Heterocycles via Cycloaddition Reactions... 

C. Introduction of Perfluoroalkyl Groups into Five-Membered Heterocycles via Diels-Alder/Retro Diels-Alder Reactions... 

Since perfluoroalkyl-substituted olefins and alkynes possess low-lying frontier orbitals, [4 + 2] cycloaddition reactions to oxazoles and thiazoles without strongly electron-donating substituents are unfavorable. On the other hand, five-membered heteroaromatic compounds possessing an electron-rich diene substructure, like furans, thiophenes, and pyrroles, should be able to add perfluoroalkyl-substituted olefins as well as alkynes in a normal Diels-Alder process. A reaction sequence consisting of a Diels-Alder reaction with perfluoroalkyl-substituted alkynes as dienophile, and a subsequent retro-Diels-Alder process of the cycloadduct initially formed, represents a preparatively valuable method for regioselective introduction of perfluoroalkyl groups into five-membered heteroaromatic systems. 

Electrocyclization reactions of perfluoroalkyl-substituted conjugated 1,3-dipoles (1,5-dipoles) and of heteropentadienyl anions and subsequent elimination with aromatization offer an elegant method for the selective introduction of perfluoroalkyl groups into five-membered heteroaromatic systems [79JCS(Pl)214j. 

Introduction of Perfluoroalkyl Groups into Organosilicon and Organogermanium... 

By reactionof a 1,1-difluoroethene with tributylphosphane in the presence of boron trifluoride-diethyl ether complex, the vinylphosphonium salt is obtained. On subsequent hydrolysis the selectivity of formation of the Z- and E-isomer is 100%, but it diminishes after the introduction into the alkene. together with the perfluoroalkyl group, of substituents such as phenyl and... 

Saturated, strained, small ring systems are uniquely stabilised by the introduction of perfluoroalkyl groups, as compared with the corresponding hydrocarbon derivatives, and this has allowed the study, for instance, of many long-lived valence-bond isomers... 

The introduction of electron-withdrawing perfluoroalkyl groups into unsaturated systems lowers frontier orbital energies [35], as deduced by theory [36] and photoelectron spectroscopy [37] for a series of fluorinated aUcenes, and manifestations of this effect are seen in much of the chemistry of such systems. 

By reaction of a 1,1-difluoroethene with tributylphosphane in the presence of boron trifluoride-diethyl ether complex, the vinylphosphonium salt is obtained. On subsequent hydrolysis the selectivity of formation of the Z- and F-isomer is 100%, but it diminishes after the introduction into the alkene. together with the perfluoroalkyl group, of substituents such as phenyl and 4-methoxyphcnyl. In accordance with this methodology, a method of substitution of fluorine by hydrogen at the fluoroolefinic double bond has been developed.194,206 The first stage of this reaction includes the formation of a fluoro-/5-phosphane from the fluoroalkene and tributylphosphane. The decomposition of this /l5-phosphane in the aqueous solvent leads to a fluoroalkene, e.g. formation of l.206... 

Of spedal importance for introduction of perfluoroalkyl groups into pharmaceuticals and for synthesis of perfluoroalkylated analogs of natural products is the reaction of FITS reagents with silyl enol ethers, leading to a-perfluoroalkyl carbonyl compounds [21] (Scheme 2.149). 

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