Et3N·3HF Complex Fluorination for Preparing Alkyl Fluorides
Fluorinated organic compounds, both analogues of natural products and synthetic materials, gain enormous interest by organic and medicinal chemists, biochemists, material scientists, and others because of its unique chemical properties and biological activity. Consequently, there is a continuously growing demand of methods to synthesize such compounds. Although plenty of methods to introduce fluorine and fluorinated groups into organic compounds do exist, not all used reagents can be handled easily and safely in ordinary organic chemistry laboratories. A frequently used fluorination reagent is the triethylamine trihydrofluoride complex, Et3N·3HF [triethylamine tris(hydrogenfluoride)] as a source of nucleophilic fluoride [1, 2, 3, 4].
Originally, Et3N·3HF was formed in situ for ring opening of epoxides . In 1980, Franz prepared the neat reagent by addition of an ethereal solution of anhydrous HF to a slight excess of Et3N at 0 °C, followed by distillation of the separated crude product . This reagent has important advantages over anhydrous liquid HF itself and most of the other HF-based fluoride sources: (i) it is less corrosive and can be used in ordinary borosilicate glassware up to temperatures of approximately 150 °C, (ii) it is soluble in less polar and polar aprotic solvents such as methylene chloride, diethyl ether, or acetonitrile and also in substrates of different kind, and (iii) it is useful for a series of different types of fluorination reactions as shown in this chapter. Et3N·3HF is a colorless liquid at room temperature with a melting point of −27 °C, a boiling point of 78 °C at 1.5 mbar, has a density of 0.996 g/L at 25 °C, and has a pH close to neutral .
In the solid state, the N-H···F hydrogen bond (bond distance 2.687 Å) is donated to the central fluoride of a H2F3─ or [F(HF)2]─ ion and binds this and the cation in a discrete ion pair . Although the reagent is less corrosive than anhydrous HF or the pyridine/HF complex (Olah’s reagent), the liquid has to be handled with care and any skin contact must be avoided.
Nucleophilic Substitution at sp3 Carbon Atoms
Using a modified diisopropylethylamine·3HF reagent led to higher yields and, moreover, was useful for the preparation of 1,1,1,3,3,3-hexafluoroisopropyl fluoromethyl ether (Sevoflurane), an important inhaled anesthetic, and a couple of analogs .
This reaction did also work for 1-bromoadamantane, 1-bromo-1-phenylethane, 1-bromo-1,1-diphenyl ethane, and exo-2-bromo-1-bromomethyl-7,7-dimethylbicyclo[2.2.1]heptane but did not work for ordinary bromoalkanes such as 1,5-dibromopentane, bromocycloheptane, and 4-bromooct-1-ene .
Analogously, a variety of benzylic fluorides including substituted benzyl, naphthyl, and pyridyl systems were synthesized via Rhodium-catalyzed nucleophilic fluorination of benzylic trichloroacetimidates. The reaction proceeds by partial racemization suggesting the Rh-catalyzed formation of a benzylic cation as a likely intermediate .
Electrochemical Fluorinations (Transformation of C-H to C-F Bond)
Strong electron withdrawing groups in the aromatic ring do accelerate the reaction and generally better yields were obtained particularly in case of ordinary alkyl aryl sulfides .
Recently, 18F-radiofluorination of methyl phenylthio acetate was described using [18F]Et4NF∙4HF as fluorinating agent and Bu4NClO4 as additional electrolyte . Radiolabeling using 18F-modified Et3N∙3HF was used so far only for 18F-labeling of aromatic positions, e.g., of N-trifluoroacetyl phenylalanine methyl ester .
Ring Opening of Epoxides
An overview on ring opening of epoxides with different fluoride donors was given by Böhm covering the literature until 1990 . Another review by Miethchen and Peters covers the literature until 1996  and Haufe reviewed syntheses of vicinal fluorohydrins, among others by epoxide ring opening, until 2003  or 2005 .
The same protocol was used for the preparation of 2,3,4-trideoxy-2,3,4-trifluoro hexose analogues of d-glucose and d-altrose  (not shown in a Scheme).
Transformations of terminal epoxides under similar conditions tolerate different functional groups such as acetates and ethers. The corresponding 1,2-difluoroalkyl derivatives were isolated in 67–78% yield. These conversions proceed as two step processes consisting of acid-catalyzed epoxide ring opening to form vicinal fluorohydrins followed by nucleophilic deoxygenation/fluoridation .
Electrophilic Additions Across Double Bonds
In addition to application of Et3N·3HF in substitution reactions, this reagent has also been applied to provide the source of nucleophilic fluoride as reaction partner in electrophilic addition reactions across double bonds such as hydrofluorinations, halofluorinations (formal additions of interhalogens), and other combinations of electrophiles with fluoride sources such as sulfenyl- or selenenylfluorinations. These reactions allow the introduction of a fluoride under much milder conditions and usually more selective than direct hydrofluorination. Moreover, the target β-halo-, β-thio-, or β-seleno substituents are very useful functionalities for elimination or substitution reactions [1, 2, 3, 4, 75].
Analogously, bromofluorination of bis(metallyl)polyoxyethylene glycol ethers was found to be highly regioselective providing the corresponding tertiary fluorides in 67–86% yields and surprisingly high diastereoselectivity of 85:15. In case of the nor-methyl derivatives, the reactions are not selective leading to complex mixtures of regio- and diastereomers .
The reaction is quite sensitive to the conditions. Particularly, the used fluoride equivalent is crucial. An amine:HF ratio of 1:4.5 (combination of Et3N·3HF with Olah’s reagent) was shown to be optimal. In case of application of Et3N·3HF alone, the conversion was <5%, while application of Olah’s reagent alone gave rise to a variety of side reactions and the target product was isolated in only 19% yield. Also the concentration of the reactants is important and should amount 0.1–0.2 mmol/mL. Dichloroethane can be replaced by dichloromethane without any effect on the reaction yield. Mechanistic investigations showed that from p-iodotoluene the hypervalent difluoroiodo species is formed as the actual electrophilic species forming a iodonium ion, which is replaced by fluoride in the final step (see above). Using a C2-symmetric chiral cocatalyst, 10% enantiomeric excess was found in the product of o-nitrophenyl derivative [93, 95]. In a back-to-back publication, Jacobsen et al. reported a very similar reaction. These authors used the same catalyst, but m-CPBA as an oxidizer and Olah’s reagent exclusively as fluoride source .
Sulfenyl- and Selenenylfluorinations
Amino- and Amidofluorination
Conclusion and Future Directions
In summary, this chapter showed that Et3N∙3HF is an extraordinary and highly versatile fluorinating agent suitable for many different synthetic applications, particularly for the preparation of plenty of alkyl fluorides. Moreover, a broad variety of vinyl fluorides were synthesized from acetylenes using Et3N∙3HF and many fluorinating substitutions at sp2 hybridized carbon atoms were described in the literature. Furthermore, the reagent has been used in organometallic chemistry for the preparation metal-fluorine bonds of catalytic metal complexes. Last but not least, the reagent has been applied for deprotection of silylethers. All these reactions are out of the scope of this chapter. In the future, many more examples will demonstrate the versatility of Franz’s reagent.
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