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The typical method for introducing fluorine at a specific aliphatic molecular site is the nucleophilic displacement of the corresponding sulfonate or halide by fluoride ion.[Angew. Chem., Int. Ed. Engl. 1981, 20, 647-667] Although alkali metal fluorides have traditionally been used for this purpose, fluorination with these reagents is known to proceed only under vigorous conditions due to their limited solubility in organic solvents and low nucleophilicity. As an alternative, a “naked” fluoride ion, which is not solvated tightly by bulky cations or solvent molecules, is usually used to improve these
reactions,[In Methoden der Organischen Chemie; Mueller, E., Ed.;Thieme-Verlag: Stuttgart, 1962; Vol. 5/3.] and over the past several decades, numerous kinds of phase-transfer type protocols, such as crown ether and quaternary ammonium fluoride derivatives, have been developed to enhance the nucleophilicity and solubility of fluoride ions in organic media and to accelerate this substitution reaction. [In Phase Transfer Catalysis, 3rd ed.; VCH: New York, 1993] Although the naked fluoride ion generated from phase transfer methods (e.g., tetrabutylammonium fluoride, TBAF, or KF-Kryptfix complex) is a good nucleophile, its synthetic utility can be limited by its strong basicity.[J. Am. Chem. Soc. 1995, 117, 5166-5167.]
Our laboratory has developed efficient and convenient preparation of 18-fluorine labeled compound and found that use of ionic liquid as a reaction media reduces a several radiopharmaceutical synthetic step [Nucl. Med. Biol. 2003, 30, 345-350] and protic solvent increases the rate of the nucleophilic fluorination and reducing formation of byproducts (such as alkenes, alcohols, or ethers) compared with conventional methods using dipolar aprotic solvents. [J. Am. Chem. Soc. 2006, 128, ASAP article].