Nucleophilic Substitution of Aliphatic Fluorides via Pseudohalide Intermediates.

A method for aliphatic fluoride functionalization with a variety of nucleophiles has been reported. Carbon-fluoride bond cleavage is thermodynamically driven by the use of silylated pseudohalides TMS-OMs or TMS-NTf2 , resulting in the formation of TMS-F and a trapped aliphatic pseudohalide intermediate. The rate of fluoride/pseudohalide exchange and the stability of this intermediate are such that little rearrangement is observed for terminal fluoride positions in linear aliphatic fluorides. The ability to convert organofluoride positions into pseudohalide groups allows facile nucleophilic attack by a wide range of nucleophiles. The late introduction of the nucleophiles also allows for a wide range of functional-group tolerance in the coupling partners. Selective alkyl fluoride mesylation is observed in the presence of other alkyl halides, allowing for orthogonal synthetic strategies.