Alkyl fluorides synthesis nucleophilic substitution

For example, perfluoro-4-/ 6>-propylpyridine was found to be an excellent building block for macrocycle synthesis.Nucleophilic substitution reaction with di-oxyanions, prepared in situ from bis-trimethylsilyl derivatives of appropriate alkyl and aryl diols and catalytic quantities of fluoride ion, firstly give bridged systems, in... 

Nucleophilic substitution reactions of halide anions in aprotic solvents are often accompanied by elimination reactions. For instance, reactions of secondary alkyl halides with potassium fluoride solubilized in acetonitrile with the aid of 18-crown-6 [3] give olefins as the main reaction product (Liotta and Harris, 1974). Similarly, the dicyclohexyl-18-crown-6 complex of potassium iodide acted exclusively as a base in its reaction with 2-bromo-octane in DMF (Sam and Simmons, 1974). The strongly basic character of weakly solvated fluoride has been exploited in peptide synthesis (Klausner and Chorev, 1977 Chorev and Klausner, 1976). It was shown that potassium fluoride solubilized... 

Cyclizations of o-(a -haloalk oxy)phenols have been widely studied and were used to afford an expedient synthesis of 5-alkyl-2,3-dihydro-l,4-benzodioxins <2004SC2487>. This approach via a nucleophilic substitution was used for the synthesis of 8-substituted-2-hydroxymethyl-l,4-benzodioxane derivatives 164 in an enantiopure form. Use of CsF instead of more basic conditions allowed higher yields and enantiomeric excess (Equation 28) <2001ASC95>. Dry tetrabutylammonium fluoride (TBAF) in THF was required and was basic enough to initiate an intramolecular Sn substitution from the protected phenol 165 to the fluoro-l,4-benzodioxane 166 <1996T6187>. 

The fact that fluoride is a poor leaving group in aliphatic nucleophilic substitutions and the high volatility of fluoroaliphatic compounds are the keys to the Finkelstein synthesis of alkyl fluorides. An alkyl iodide, bromide, or tosylate is heated in a polar solvent vith an alkali fluoride and the volatile alkyl fluoride is removed by distillation during the reaction [30] (Scheme 2.11). For safe handling of primary alkyl fluorides it must be kept in mind that the even-membered compounds of this series are toxic, because they can be oxidatively metabolized to the poisonous fluoroacetate [31]. 

RCO , an indifferent nucleophile in prohc solvents, enjoys a large rate enhancement, permitting rapid alkylation with haloalkanes in hexamethylphosphoric triamide [301, 302], When the Williamson ether synthesis is carried out in dimethyl sulfoxide [303], the yields are raised and the reaction time shortened. Displacements on unreactive haloarenes become possible [304] (conversion of bromobenzene to tert-butoxybenzene with tert-C UgO in dimethyl sulfoxide in 86% yield at room temperature). The fluoride ion, a notoriously poor nucleophile or base in protic solvents, reveals its hidden capabilities in dipolar non-HBD solvents and is a powerful nucleophile in substitution reactions on carbon [305],... 

The final method uses an entirely different approach. Treatment of an 0-alkyl hydrogen methylphosphonothioic acid (24) with picryl fluoride in the presence of a tertiary base in acetone at room temperature results in the formation of the corresponding phosphonofluoridate (23) The method is useful for the synthesis of 0-r r -butyl-substituted phosphonofluoridates that cannot be prepared by nucleophilic displacement methods using r r -butanol. It has also been employed for the synthesis of optically active phosphonofluoridates using resolved thio acid precursors (see below). ... 

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