Angewandte
Chemie
phenylvinyl)-benzoic acid (5h) (entry 8), the more electron-
rich terminal phenyl group underwent the phenyl migration,
rather than the aromatic backbone, and the fluorinated
isobenzofuranone 6h was isolated in 86% yield. Substitution
at the 4-position of the terminal aromatic ring was tolerated
well with halides (entries 10 and 11), thus giving high yields
(69–76%), but a slightly lower yield was obtained with the
methyl substituent (entry 9). In entry 12, however, the
aromatic backbone underwent the phenyl migration, thus
resulting in a d-lactone fused to an aromatic ring (6l). The low
32% yield was due to elimination problems and formation of
the alkene in conjugation with the aromatic ring, thus giving
3-methyl-1H-isochromen-1-one (8l) in 12% yield (see the
Supporting Information). The novel products generated with
4 are different to those reported from the fluorolactonizations
of 5a and 5h with electrophilic fluorinating reagents; these
reactions afforded g-lactones containing a primary alkyl
fluoride (Figure 3).[4a,d]
hydroxy group occurs at the more-substituted carbon atom
because it is better able to stabilize the partial positive charge
and is therefore more electrophilic. The p donation of the
aromatic ring results in the phenonium ion intermediate 14
with the iodoaryl group acting as an excellent leaving group.
Finally, 14 is ring opened by fluoride, thus resulting in 6a with
fluorination at the quaternary center. A similar aryl migration
has also been reported in the difluorination of styrenes using
4, and in the intramolecular lactonization of 5a with
(diacetoxyiodo)benzene.[13a,17] The same mechanism can be
used to rationalize all of the results in Table 2. In compounds
5h–k the more-electron-rich terminal aromatic ring under-
went the aryl migration, whereas in 5l the aromatic backbone
underwent the aryl migration to form the d-lactone 6l.
Since 4 is easily prepared from simple anionic fluoride
salts, it is an attractive reagent for preparing 18F-labelled
radiotracers for PET imaging. To explore its potential
application for synthesizing 18F-labelled lactones, we further
investigated the fluorocyclization of 5a using molecular sieves
as the only additive (see Table S1 in the Supporting Informa-
tion). This protocol would ensure that the fluoride could only
be provided by 4 and was not coming from the tetrafluoro-
borate anion of the silver catalyst, as reported by Szabó and
co-workers in the difluorination of styrenes.[13a] Without any
metal catalyst we obtained a 63% yield of 6a (Scheme 1). A
short reaction time is essential in view of the short half-life of
18F (110 min) and on reducing the reaction time from 18 to
The proposed mechanism for the fluorolactonizations is
shown in Figure 4. In the first step the metal catalyst activates
the fluoroiodane to form 11 which undergoes an electrophilic
addition to the alkene in 5a to give the cyclic iodonium
intermediate 12. An intramolecular nucleophilic attack of the
Scheme 1. Fluorocyclization with fluoroiodane 4 and molecular sieves.
1 hours, the yield of 6a fell from 63 to 46% yield (see
Table S1). After further optimization (see Table S1), 6a was
produced in a good 58% yield within just 1 hour at 408C in
acetonitrile by using 1.5 equivalents of 4.
Figure 3. Fluorocyclizations with fluoraza reagents.[4a,d]
This new fluorination protocol was applied to a small
series of unsaturated carboxylic acids (Table 3). These
promising results suggest that 4 holds great potential for
preparing novel 18F-labelled heterocycles and developing new
PET tracers, which are currently inaccessible with conven-
tional nucleophilic fluorination chemistry.
In conclusion, we have developed a new and mild method
for the synthesis of fluorinated lactones using the air- and
moisture-stable 4 in combination with AgBF4. This unusual
reaction combines an intramolecular fluorocyclization with
an aryl migration to deliver novel lactones, which contain
a tertiary alkyl fluoride. In contrast, the same reactions with
fluoraza reagents provide lactones containing a primary alkyl
fluoride. Furthermore, the fluorination can also proceed
without a metal catalyst in 1 hour, thus demonstrating clearly
that 4 is suitable for the production of new 18F-labelled
radiotracers for PET imaging.
Figure 4. Proposed mechanism for the intramolecular fluorocycliza-
tions.
Angew. Chem. Int. Ed. 2015, 54, 14911 –14914
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim