Difluorocarbene-Derived Trifluoromethylthiolation and [18F]Trifluoromethylthiolation of Aliphatic Electrophiles

Article abstract of DOI:10.1002/anie.201505446

The first trifluoromethylthiolation and [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 exogenous-fluoride-mediated transformation enables unprecedented syntheses of [¹⁸F]CF₃S-labeled molecules from most commonly 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.

Full text of DOI:10.1002/anie.201505446

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Angewandte
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International Edition: DOI: 10.1002/anie.201505446
German Edition: DOI: 10.1002/ange.201505446
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
under http://dx.doi.org/10.1002/anie.201505446.
anion can react with elemental sulfur (S8) to produce the
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trifluoromethylthio anion (CF3SÀ),[8c] we speculated that the
reaction of difluorocarbene with fluoride in the presence of
elemental sulfur may give the trifluoromethylthio anion,
which is a key intermediate for a trifluoromethylthiolation
reaction. This trifluoromethylthiolation protocol would
À
À
À
sequentially construct F CF2, S CF3, and C SCF3 bonds,
and involve the use of external fluoride for the formation of
the CF3S functionality. Even with the time constraint of PET
radiochemistry, if the reaction occurs fast enough, this
trifluoromethylthiolation strategy may be applicable in 18F-
labeled trifluoromethylthiolation. Herein we describe the first
trifluoromethylthiolation and [18F]trifluoromethylthiolation
of alkyl electrophiles with in situ generated difluorocarbene
in the presence of elemental sulfur and an external fluoride
ion under transition-metal-free conditions (Scheme 1c).
We have previously shown that difluoromethylene phos-
phobetaine (Ph3P+CF2CO2À; PDFA) is an efficient difluor-
ocarbene reagent.[12b,13] It can produce difluorocarbene in situ
À [14]
after decarboxylation of the phosphonium ylide Ph3P+CF2
under neutral conditions without the addition of any other
additive or base. Given the operational simplicity and mild
reaction conditions for the generation of difluorocarbene,
PDFA was used to verify our trifluoromethylthiolation
strategy. After screening various reaction conditions for
trifluoromethylthiolation (see Table S1 in the Supporting
Information), we found that the reactions employing CsF as
the fluoride source occurred rapidly and quantitatively at
708C, and is very attractive for the transition into radio-
labeling with short-lived isotopes, such as fluorine-18. Notably
no transition metal is necessary for these transformations.
As shown in Scheme 2, the current method shows a wide
substrate scope and high level of functional-group tolerance.
An array of benzyl bromides were converted smoothly into
the desired products in moderate to excellent yields (43–99%
yields; 2a–p). Electron-donating or electron-withdrawing
substituents on the arene had no effect on reaction yields
(2a–o). In addition to primary benzyl bromides, a secondary
bromide was also found to be reactive under these reaction
conditions (2p). It is worthy of note that low yields of the
isolated 2o and 2p were mainly due to their high volatility.
The transformation is applicable to allylic (2q) and several
functionalized heterocycles (2r–t) with good to excellent
yields (49–86%). Benzyl chlorides (2aCl and 2dCl) were also
successfully converted into the desired SCF3 products, albeit
in lower yields (59% and 60%, respectively) compared to
those obtained with benzyl bromides, and it is partially
attributed to the inferior leaving-group ability. Moderate
yields (46–58%) were obtained for the transformation of
aliphatic bromides and tosylate (3a–d, 4aTsO) although these
substrates are less reactive than their benzyl counterparts. In
the cases of aliphatic iodides, the desired products were
obtained in 62–91% yields (4a–c). Trifluoromethylthiolation
of the steroid 5 proceeded smoothly to provide the corre-
sponding product 6 in 51% yield with no evidence of
epimerization.
Scheme 2. Trifluoromethylthiolation of benzyl and alkyl electrophiles.
Reaction conditions: 1 (0.2 mmol), PDFA (0.4 mmol), S8 (0.15 mmol),
CsF (1.0 mmol), DMF (1.5 mL), 708C, 5 min. Yields are those of the
isolated products. The yields within parentheses were determined by
19F NMR spectroscopy with the use of trifluoromethylbenzene as an
internal standard. [a] Reaction conditions: PhCH2CH2OTs (0.2 mmol),
PDFA (0.4 mmol), S8 (0.15 mmol), CsF (1.0 mmol), tBu4NI
(0.1 mmol), DMF (1.5 mL), 708C, 20 min. [b] Reaction conditions: 5
(0.025 mmol), PDFA (0.05 mmol), S8 (0.02 mmol), CsF (0.125 mmol),
DMF (1.0 mL), 708C, 5 min. DMF=N,N-dimethylformamide.
Based on the previous reports, it seems that this reaction
may proceed through the following process (Scheme 3).
Decarboxylation of PDFA releases triphenylphosphine and
generates difluorocarbene in situ.[13a] Difluorocarbene is read-
ily trapped by cesium fluoride to produce the trifluoromethyl
anion A, followed by the formation of the trifluoromethylthio
anion B in the presence of elemental sulfur. The nucleophilic
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conversion (entry 1). Further optimization of the stoichiome-
tries of the precursor, PDFA, and elemental sulfur increased
the incorporation yield to 72% (entries 2–4). The formation
of the aliphatic [18F]SCF3 was very rapid and was completed in
77% yield within 1 minute (entries 5–7), which is ideal for
short-lived fluorine-18. [18F]Tetraethylammonium fluoride
and [18F]CsF provided inferior yields of 29–53% compared
with that of [18F]KF/K222, and an increased amount of K2CO3/
K222 during 18F drying gave the expected product but in low
yield (32–65%; see Table S2). The addition of 1–5% water led
to a dramatic reduction in conversion yields (as low as 4%,
entries 8–10). After thorough optimization of the radioactive
reaction conditions, we identified that the combination of
substrate, PDFA, and S8 (molar ratio of 1:0.5:1.5) and
[18F]KF/K222 in DMF at 708C provided the optimal outcome
(entry 5).
Scheme 3. Proposed reaction mechanism.
substitution between B and an alkyl electrophile furnishes the
final product. The final step for the reaction between B and
the electrophile should proceed by direct nucleophilic sub-
stitution without the occurrence of quarternization of triphe-
nylphosphine, since the phosphonium 1a’ was unreactive
under the optimal reaction conditions (Scheme 4a). As a side
reaction, triphenylphosphine and elemental sulfur undergo
redox reaction to give triphenylphosphine sulfide in 83%
yield for the trifluoromethylthiolation of substrate 1a (Sche-
me 4b).
As illustrated in Scheme 5, this new protocol allowed
direct incorporation of [18F]CF3S into a broad range of
aliphatic moieties and the transformation was tolerated with
a variety of functional groups, including ester, cyano, aryl
halide, ether, and thioether moieties. Analogous to reaction
outcomes in nonradioactive conditions, electron-rich and
electron-deficient substituents on aromatic rings did not
influence the radiochemical yield (Scheme 5a). While ortho-
substituted arenes had little or no effect on the radiochemical
incorporations, secondary halides were found to be less
reactive than their primary counterparts (Scheme 5b). The
[18F]trifluoromethylthiolation was also suitable for the trans-
formation of aliphatic and allylic halides (Scheme 5c). For
Scheme 4. The attempts at trifluoromethylthiolation of benzyl phos-
phonium bromide. [a] Yield of isolated product based on PDFA.
The conceptual advantage of CF3S formation by exoge-
nous fluoride ion makes this methodology potentially useful
in the direct radiolabeling of [18F]trifluoromethylthio groups.
Our initial radiochemical studies commenced with the
replacement of CsF with azeotropically dried [18F]KF/K222
under optimal nonradioactive reaction conditions (Table 1
and see Table S2 in the Supporting Information). We utilized
4-phenylbenzyl bromide as a model substrate and found that
the desired product [18F]2a was formed in 55% radiochemical
Table 1: Optimization of the [18F] trifluoromethylthiolation reaction
conditions.
Entry
Reagents (equiv)
DMF (mL) t [min] RCC [%][a]
Subst. (mg) PDFA S8
1
2
3
4
5
6
7
8
9
10
2
2
2
2
2
2
2
2
2
2
2
0.75 0.4
5
5
5
5
1
3
10
1
1
55Æ3 (n=3)
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.0 0.4
1.25 0.4
1.5 0.4
1.5 0.4
1.5 0.4
1.5 0.4
1.5 0.4[b]
1.5 0.4[c]
1.5 0.4[d]
61Æ4 (n=3)
64Æ2 (n=3)
72Æ7 (n=3)
77Æ6 (n=3)
72Æ5 (n=3)
71Æ1 (n=3)
25Æ1 (n=3)
7Æ3 (n=3)
4Æ1 (n=3)
Scheme 5. Difluorocarbene-mediated [18F]trifluoromethylthiolation of
aliphatic halides. [a] Reaction conditions: Precursor (0.008 mmol),
PDFA (1.5 mg), S8 (3.0 mg), DMF (0.4 mL), 708C, 1 min. [b] Incorpo-
ration yield and product identity were determined by radioTLC and
radioHPLC, respectively. [c] Radiochemical yield of the isolated product
was reported as decay noncorrected with radiochemical purity of
>95%. The isolation was performed by solid-phase extraction.
1
[a] Incorporation yield and product identity were determined by radioTLC
and radioHPLC, respectively. [b] 1% water in reaction mixture. [c] 3%
water in reaction mixture. [d] 5% water in reaction mixture.
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À
which is comparable with the recently reported aryl
[18F]CF3 and aryl [ F]SCF3 labeling.
[5a]
18
[15]
À
In summary, we have successfully developed an efficient,
fast, and transition-metal-free trifluoromethylthiolation
method with a wide substrate scope and applicability. This
strategy has been successfully applied to [18F]trifluoromethyl-
thiolation of alkyl electrophiles, and is the first example of
[18F]CF3S labeling. Rapid reaction time (ꢀ 1 min), opera-
tional simplicity, and exogenous addition of [18F]fluoride for
the formation of [18F]CF3S make this method suitable for
a wide range of complex and heterocyclic functionalities with
high radiochemical yields, as well as useful for radiolabeling
of CF3S-bearing pharmaceuticals.
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Acknowledgements
This work was financially supported by the National Natural
Science Foundation (21032006, 21172240, 21421002,
21472222, 21502214), National Basic Research Program of
China (2015CB931900, 2012CBA01200), and the Chinese
Academy of Sciences (XDA02020105, XDA02020106). We
thank Professor Jinbo Hu for helpful discussion. S.H.L is
a recipient of an NIH career development award.
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Keywords: carbenes · fluorine · isotopic labeling ·
positron emission tomography · sulfur
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Angew. Chem. 2015, 127, 13434–13438
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Received: June 13, 2015
Revised: July 7, 2015
Published online: September 21, 2015
13240 www.angewandte.org
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