mentioned above, compound 3 was transformed to 4 with
Py•BrF3 in very good yield.
oxidation of the sulfur atom may serve as a precursor for
various ArCF3 compounds.15 Indeed, the HOF•CH3CN
complex16 turns the above sulfides into a good leaving
sulfone group in a fast and usually quantitative reaction
(Scheme 2).17 This can be demonstrated by using 4-nitro-
benzoyl chloride (26) which, with Lawesson’s reagent,
produced the dithioester 27.18 When this interme-
diate was reacted with BrF3 it resulted in 1-nitro-
4-(trifluoromethyl)benzene (28) which is a dead end as
far as a labeling process with regards to 18F is concerned.
When, however, 27 was reacted with the more tamed
Py•BrF3 complex, a mixture of the corresponding sulfide,
sulfoxide, and traces of sulfone 29 was formed. This
mixture was treated with HOF•CH3CN, rapidly transfer-
ring all sulfur-containing compounds to the sulfone 29
(n = 2), which contains the desired leaving sulfonyl
group. This compound was subjectedto KFand kryptofix,
conditions that mimic the 18F labeling, and the desirable
1-nitro-4-(trifluoromethyl)benzene (28) was obtained in
70% yield. The reduction of the nitro to the amine group
proceeded quickly, and 30, which could be made now with
18F, was formed in good yield and may be tagged to a
variety of biological active compounds (Scheme 2).
The trend of radical pathways governing pure aliphatic
derivatives when using Py•BrF3 could be further demon-
strated by comparison with other reactions of BrF3 utiliz-
ing such routes. When reacting BrF3 with 1,3-dithiane-
2-carboxylic acids such as 22, a two-step mechanism governs
the reaction, with one step being of a radical nature and
responsible for the formation of 23 in 60% yield.12 It is
reasonable to assume that this is the reason for retaining
some of the selectivity when 22 was reacted with the Py•BrF3
complex forming 23 although this time in 35% yield only.
Similarly, when the halogenated backbone of 24, which
partially prevents radical side reactions, was reacted with
Py•BrF3, 2513 was formed in 35% yield. This is lower than
the yield obtained with BrF3 alone (Table 3), meaning that
while radical reactions were kept low, they nevertheless exist
with Py•BrF3 especially when it lacks good anchors.
Table 3. Comparing Aliphatic Reactions with BrF3 and
Py•BrF3
Scheme 2
An interesting benefit of the reactions with the Py•BrF3
complex emerged when considering the field of Positron
Emission Tomography (PET). This is a noninvasive tech-
nique using isotopes such as 18F for the diagnostic of
cancer, myocardial problems, brain diseases, and much
more.14 This powerful tool has spread rapidly, and today,
almost every major hospital has PET facilities, for either
pure medicinal or research uses, or both. The best mimic
for the naturally found hydrogens is the 18F radionuclide
making it very popular in this field.
The importance of the CF3 group in medicinal chemistry
is well-known, and quite a few important drugs contain
this group. However, very few examples in the literature
describe a CF3 group labeled with 18F, and all of those
suffer from verylow chemical and especially radiochemical
yields. We used the less reactive Py•BrF3 complex to create
ArCF2SR (or ArOCF2SR) intermediates, which after the
In conclusion, this work demonstrates the unique fea-
tures of the Py•BrF3 complex especially in the field of
aromatic fluorinations. Its main advantage is reducing the
parallel electrophilic bromination process, which fre-
quently accompanies reactions with reagents based on
fluorine and bromine. It also opens new possibilities for
(15) Rozen, S.; Mishani, E. J. Chem. Soc., Chem. Commun. 1994,
2081.
(16) (a) Rozen, S.; Carmeli, M. J. Am. Chem. Soc. 2003, 125, 8118. (b)
Dayan, S.; Kol, M.; Rozen, S. Synthesis 1999, 1427.
(17) (a) Rozen, S.; Bareket, Y. J. Org. Chem. 1997, 62, 1457. (b) Amir,
E.; Rozen, S. Angew. Chem., Int. Ed. 2005, 44, 7374. (c) Harel, T.; Amir,
E.; Rozen, S. Org. Lett. 2006, 8, 1213.
(18) (a) Yousif, N. M.; Pedersen, U.; Yde, B.; Lawesson, S. O.
Tetrahedron 1984, 40, 2663. (b) Rozen, S.; Mishani, E. J. Chem. Soc.,
Chem. Commun. 1993, 1761.
(12) Sasson, R.; Rozen, S. Tetrahedron 2005, 61, 1083.
(13) Hagooly, Y.; Rozen, S. J. Org. Chem. 2008, 73, 6780.
(14) Welch, M. J.; Redvanly, C. S. RadiopharmaceuticalsÀ
Radiochemistry and Applications; New York: Wiley, 2005.
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Org. Lett., Vol. 14, No. 4, 2012