Selective Synthesis of Monofluorinated Compounds Applying Amine/HF Reagents

Abstract

For nucleophilic monofluorination, amine/HF reagents such as Et3N⋅3HF, Pyr⋅9HF (Olah's reagent) and similar combinations belong to the most frequently used fluoride sources, whereupon the selectivity of these reagents can be very different depending of its acidity, the nucleophilicity of the fluoride equivalent, and the structure of the particular substrate. These reagents can be used safely in ordinary chemistry laboratories for nucleophilic substitution reactions by fluoride at sp3‐hybridized carbon centers. For ring opening reactions of epoxides, the regio‐ and stereoselectivity is very much depending of the nature of the epoxide and the acidity of the HF reagent favoring either SN1 or SN2 type reactions. Similarly, the outcome of halofluorination and similar reactions with sulfur or seleno electrophiles can be controlled by the particular combination of the electrophile and the fluoride source. Examples for the application of these reaction types for the synthesis of fluorine‐containing analogues of natural products or biologically relevant compounds are in the focus of this personal account.

Nucleophilic fluorine substitution reaction of α-carbonyl benzyl bromide, phenylthiofluoroalkyl bromide, and 2-bromo-2-phenoxyacetonitrile

“… 15 Since that time, Et 3 N·3HF as a fluoride source for nucleophilic monofluorination in organic molecules has been used frequently. 16 In particular, Et 3 N·3HF has frequently been used in electrochemical fluorination of thioethers and O , S -acetal derivatives bearing α-electron-withdrawing groups in the last decades. 6,17 However, due to its weak nucleophilicity, the fluorination reactions of alkylhalides with Et 3 N·3HF usually require harsh reaction conditions, particularly high temperatures.…”