.
Angewandte
Communications
Carbenes
Difluorocarbene-Derived Trifluoromethylthiolation and
[18F]Trifluoromethylthiolation of Aliphatic Electrophiles
Jian Zheng, Lu Wang, Jin-Hong Lin, Ji-Chang Xiao,* and Steven H. Liang*
Abstract:
The
first
trifluoromethylthiolation
and
the [18F]CF3S moiety has never been realized and thus
represents a significant challenge in the field.
[18F]trifluoromethylthiolation of alkyl electrophiles with
in situ generated difluorocarbene in the presence of elemental
sulfur and external (radioactive) fluoride ion is described. This
transition-metal-free approach is high yielding, compatible
with a variety of functional groups, and operated under mild
reaction conditions. The conceptual advantage of this exoge-
nous-fluoride-mediated transformation enables unprecedented
syntheses of [18F]CF3S-labeled molecules from most com-
monly used [18F]fluoride ions. The rapid radiochemical
reaction time (ꢀ 1 min) and high functional-group tolerance
allow access to a variety of aliphatic [18F]CF3S compounds in
high yields.
Recently, outstanding accomplishments have been made
for the incorporation of the CF3S group by nonradioactive
methods.[7] Two general strategies have been well established,
including direct trifluoromethylthiolation by constructing
a C SCF3 bond[8] or squential construction of S CF3 and
À
À
[8c,9]
À
C SCF3 bonds
(Scheme 1a), and trifluoromethylation of
T
he most advanced technology currently available for
studying in vivo molecular interactions, in terms of distribu-
tion, pharmacokinetics, and pharmacodynamics, positron
emission tomography (PET), is a non-invasive quantitative
imaging technology that is capable of detecting specific
biological and pharmacological changes at the molecular level
in humans and animals.[1] Of the positron emitting isotopes,
fluorine-18 (18F) is the most commonly used radionuclide
because of its relatively long half-life of 109.7 minutes, high-
yielding production and high specific activity, importance as
fluorine substitution as isotopologue in drug discovery, and
the extensive clinical use of [18F]FDG (2-[18F]fluoro-2-deoxy-
d-glucose).[2] Therefore, significant efforts have been devoted
to the exploration of novel and efficient methodologies
for 18F incorporation into small or biological molecules.[3]
However, approaches in 18F radiochemistry have so
far been mostly limited to [18F]fluorination[4] and
[18F]trifluoromethylation.[5] Despite the fact that the trifluor-
omethylthio group (CF3S) is a valuable pharmacophore in
medicinal chemistry and drug discovery,[6] the formation of
Scheme 1. Bond-formation strategies for the trifluoromethylthio (CF3S)
group. Ts=4-toluenesulfonyl.
sulfur-containing compounds to form a RS CF3 bond[10]
À
(Scheme 1b). In both strategies, the CF3S scaffold is derived
from either CF3S- or CF3-containing reagents without the
involvement of external fluoride, thus making it not appli-
cable or difficult for translation into 18F radiolabeling. In
particular, [18F]trifluoromethylthiolation, which involves the
use of most readily available [18F]fluorides for the formation
of the [18F]CF3S group, is a promising strategy, but to date no
convenient trifluoromethylthiolation reaction employs exter-
nal fluoride to construct the CF3S moiety. It is an urgent and
unmet need to explore efficient methods for fast trifluor-
omethylthiolation in which exogenous fluoride is involved,
and thus make [18F]trifluoromethylthiolation possible.
[*] J. Zheng,[+] J.-H. Lin, Prof. Dr. J.-C. Xiao
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (China)
E-mail: jchxiao@sioc.ac.cn
L. Wang,[+] Prof. Dr. S. H. Liang
Division of Nuclear Medicine and Molecular Imaging
Massachusetts General Hospital & Department of Radiology
Harvard Medical School, 55 Fruit St., White 427
Boston, MA (USA)
Difluorocarbene has served as a powerful reaction
intermediate in organic synthesis.[11] On the basis of our
previous studies showing difluorocarbene can be readily
trapped by fluoride to generate the trifluoromethyl anion
E-mail: liang.steven@mgh.harvard.edu
[+] These authors contributed equally to this work.
À
(CF3 ),[12] and the recent studies that the trifluoromethyl
Supporting information for this article is available on the WWW
anion can react with elemental sulfur (S8) to produce the
13236
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 13236 –13240