Angewandte
Chemie
DOI: 10.1002/anie.201209817
Synthetic Methods
An Electrophilic Hypervalent Iodine Reagent for
Trifluoromethylthiolation**
Xinxin Shao, Xueqiang Wang, Tao Yang, Long Lu,* and Qilong Shen*
À
The trifluoromethylthio group (CF3S ) is one of the most
lipophilic substituents.[1] It is well known that incorporation of
trifluoromethylthio group into small molecules greatly enhan-
ces their ability to cross lipid membranes and their in vivo
absorption rate.[2] Moreover, the high electronegativity of the
trifluoromethylthio group significantly improves the stability
of small molecules in acidic environments.[3] Thus, the
trifluoromethylthio group has been of interest to the phar-
maceutical and agrochemical industries for its use in iso-
setere-based drug design.[4,5] For example, the trifluorome-
thylthio group has been utilized as a halogen isostere in
Losartan analogues that are used clinically for the treatment
of cardiovascular diseases.[6]
reagents such as Umemotoꢀs reagent or Togniꢀs reagent,[13–16]
electrophilic trifluoromethylthio reagents are far less stud-
ied.[5] The only known electrophilic trifluoromethylthio
reagents include CF3SCl and CF3NR1R2 (R1,R2 = alkyl or
aryl). CF3SCl has been used to react with some nucleophiles.[5]
However, it is gaseous and highly toxic. CF3SN(Me)Ph,
developed by Billard and co-workers, reacted with alkyl
Grignard reagents to give the trifluoromethylthiolated prod-
ucts in good yields, but with limited functional group
tolerance.[14] A general method for the introduction of
a trifluoromethylthio group into the a position of a carbonyl
group is highly desirable.
Toward this end, inspired by our own and Togniꢀs recent
study on electrophilic trifluoromethylated hypervalent iodine
reagents,[15,16] we have now developed an air and moisture
stable trifluoromethylthiolated hypervalent iodine reagent 1.
Herein, we report the preparation of this new reagent and its
reaction with a variety of enolate nucleophiles to form highly
Classic methods[5,7] for the introduction of the trifluor-
omethylthio group into small molecules typically involve
halogen–fluorine exchange reactions of polyhalogenomethyl
thioethers[8] or the trifluoromethylation of sulphur-containing
compounds such as disulfides, thiocyanates, and thiols by
a single-electron transfer (SET) mechanism.[9] However, both
of these methods suffer from harsh reaction conditions and/or
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selectively and efficiently Csp3 SCF3 bonds. Moreover, it was
discovered that the trifluoromethylthiolated hypervalent
limited substrate scope. A more straightforward strategy
iodine reagent reacted with aryl and vinyl boronic acids to
[10]
3
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À
À
would be the direct formation of a new C SCF3 bond. In
form Csp2 SCF3 or with alkynes to form Csp SCF bonds
under mild conditions.
recent years, several elegant methods employing transition-
metal catalysts[11] or metal-free conditions[12] have emerged
for the direct trifluoromethanesulfanylation of aryl halides,
boronic acids, or alkynes with a nucleophilc trifluorome-
thylthio reagent under mild conditions. Despite their great
advantages, these reactions typically involved the formation
À
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of Csp2 SCF3 or Csp SCF3 bonds, whereas processes that
À
facilitate the construction of Csp3 SCF3 bonds remain largely
unexplored.
À
One attractive strategy for the construction of Csp3 SCF3
bonds is to use an electrophilic trifluoromethylthio reagent. In
contrast to the well-developed electrophilic trifluoromethyl
In an attempt to prepare the electrophilic trifluorome-
thylthiolated hypervalent iodine reagent 1, we initially tried
the reaction of 1-chloro-1,3-dihydro-3,3-dimethyl-1,2-benzio-
doxole with AgSCF3 in different solvents. It turns out that the
reaction is quite challenging, as it is well known that the
sulfide can be easily converted into disulfide under oxidative
conditions. Indeed, CF3SSCF3 was observed as the major
product when hexane, NMP, CH3CN, or DMF was used as the
solvent. However, when THF was used as the solvent, the
desired trifluoromethylthiolated hypervalent iodine reagent
1 was formed in 50% yield, as determined by 19F NMR
spectroscopy. The reaction can be scaled up to a 6.0 g scale
and compound 1 was isolated by flash chromatography on
silica gel as a colorless liquid in 51% yield. Compound 1 was
[*] X. Shao, X.-Q. Wang, T. Yang, Prof. Dr. L. Lu, Prof. Dr. Q. Shen
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (China)
E-mail: lulong@sioc.ac.cn
[**] The authors gratefully acknowledge financial support from the
National Basic Research Program of China (2012CB821600,
2010CB126103), the Key Program of Natural Science Foundation of
China (21032006), the National Natural Science Foundation of
China (21172245/21172244/B020304), Agro-scientific Research in
the Public Interest (201103007), the National Key Technologies
R&D Program (2011BAE06B05), the Shanghai Scientific Research
Program (10XD1405200), and SIOC for financial support.
1
characterized by H, 13C, and 19F NMR spectroscopy and by
Supporting information for this article is available on the WWW
elemental analysis.
Angew. Chem. Int. Ed. 2013, 52, 3457 –3460
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3457