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Althou
gh protic solvents are
generally not preferred for nucleophilic displacement reactions because oftheir partial positive char
ge and hydro
gen-bondin
g capacity that solvate the nucleophile and reduce itsreactivity, we recently reported a remarkably beneficial effect of usin
g tertiary alcohols as a reactionmedia for nucleophilic fluorination with alkali metal fluorides, as well as fluorine-18 radiolabelin
g with[
18F]fluoride ion for the preparation of PET radiopharmaceuticals. In this work, we investi
gate furtherthe influence of the
tert-alcohol reaction medium for nucleophilic fluorination with alkali metal fluoridesby studyin
g various interactions amon
g tert-alcohols, the alkali metal fluoride (CsF), and the sulfonyloxysubstrate. Factors such as hydro
gen bondin
g between CsF and the
tert-alcohol solvent, the formation ofa
tert-alcohol solvated fluoride, and hydro
gen bondin
g between the sulfonate leavin
g group and the
tert-alcohol appear to contribute to the dramatic increase in the rate of the nucleophilic fluorination reactionin the absence of any kind of catalyst. We found that fluorination of 1-(2-mesyloxyethyl)naphthalene (
5)and
N-5-bromopentanoyl-3,4-d
imethoxyaniline (
8) with Bu
4N
+F
- in a
tert-alcohol afforded the correspondin
g fluoro products in much hi
gher yield than obtained by the conventional methods usin
g dipolaraprotic solvents. The protic medium also suppresses formation of byproducts, such as alkenes, ethers,and cyclic adducts.