N-trifluoromethylthiosaccharin: An easily accessible, shelf-stable, broadly applicable trifluoromethylthiolating reagent

Article abstract of DOI:10.1002/anie.201403983

A new, electrophilic trifluoromethylthiolating reagent, N-trifluoromethylthiosaccharin, was developed and can be synthesized in two steps from saccharin within 30minutes. N-trifluoromethylthiosaccharin is a powerful trifluoromethylthiolating reagent and allows the trifluoromethylthiolation of a variety of nucleophiles such as alcohols, amines, thiols, electron-rich arenes, aldehydes, ketones, acyclic β-ketoesters, and alkynes under mild reaction conditions. 'Sacch'ed out: A new, electrophilic trifluoromethylthiolating reagent, N-trifluoromethylthiosaccharin (1) can be synthesized in two steps from saccharin within 30minutes. The reagent 1 allows the trifluoromethylthiolation of a variety of nucleophiles such as alcohols, amines, thiols, electron-rich arenes, aldehydes, ketones, acyclic β-ketoesters, and alkynes under mild reaction conditions.

Full text of DOI:10.1002/anie.201403983

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DOI: 10.1002/anie.201403983
Synthetic Methods
N-Trifluoromethylthiosaccharin: An Easily Accessible, Shelf-Stable,
Broadly Applicable Trifluoromethylthiolating Reagent**
Chunfa Xu, Bingqing Ma, and Qilong Shen*
Abstract:
A new, electrophilic trifluoromethylthiolating
reagent, N-trifluoromethylthiosaccharin, was developed and
can be synthesized in two steps from saccharin within
30 minutes. N-trifluoromethylthiosaccharin is a powerful tri-
fluoromethylthiolating reagent and allows the trifluorome-
thylthiolation of a variety of nucleophiles such as alcohols,
amines, thiols, electron-rich arenes, aldehydes, ketones, acyclic
b-ketoesters, and alkynes under mild reaction conditions.
A
s one of the most lipophilic structural moieties, the
trifluoromethylthio group (CF3S) has attracted special inter-
ests from both academia and the pharmaceutical industry.[1]
Incorporation of the trifluoromethylthio group into leading
drug candidates has become an indispensible strategy for drug
discovery, thus resulting in a growing demand which chal-
lenges chemists to provide reliable methods for the introduc-
tion of this highly valued structural component.[2,3]
Figure 1. Electrophilic trifluoromethylthiolating reagents.
theless, its synthetic applications are rather limited. Since
2008, three different electrophilic trifluoromethylthiolating
reagents emerged as a potentially valuable replacement to
CF3SCl. Billard and co-workers reported the preparation of
the trifluoromethanesulfanylamides 2 from DAST, CF3SiMe3,
and primary amines. As one of the leading trifluoromethyl-
thiolating reagents, 2 is effective for trifluoromethylthiolation
of alkenes, alkynes, amines, indoles, and Grignard or lithium
reagents,[7] although a strong Lewis acid or Brønsted acid as
activator is generally required. In early 2013, Shen and Lu
reported the trifluoromethyl-substituted thioperoxide
reagent 3 which could trifluoromethylthiolate a variety of
substrates such as aryl and vinyl boronic acids, alkynes,
aldehydes, and b-ketoesters.[8] However, the preparation of
the reagent requires a multistep sequence. Shortly after,
Shibata and co-workers designed and synthesized a new
electrophilic trifluoromethylthiolating reagent (4), a trifluoro-
methanesulfonyl hypervalent iodonium ylide, which reacted
only with enamines, indoles, and two examples of b-ketoes-
ters, through an in situ reduction process.[9] Thus, develop-
ment of a readily accessible, easy-to-handle, electrophilic
trifluoromethylthiolating reagent, which is effective for
a broad substrate scope under relatively mild reaction
conditions, is highly desirable.
One general strategy for the formation of trifluorome-
thylthiolated compounds is the trifluoromethylation of thiols
and their derivatives, and significant progress has been
achieved previously.[2] An alternate attractive and straightfor-
ward route for the incorporation of the CF3S moiety is the
direct introduction of this functional group at the late stage of
a multistep synthetic sequence by employing an easily
available yet stable CF3S reagent.[2i] This strategy is partic-
ularly important for those nonspecialized laboratories since it
does not require specific skills and use of protective clothing
and/or equipment. However, until recently, the choice of
electrophilic trifluoromethylthiolating reagents was undeni-
ably limited and their access relatively difficult.
The first and simplest electrophilic trifluoromethylthio-
lating reagent was trifluoromethylsulfenyl chloride
(CF3SCl).[4] Although it reacts with a variety of nucleophiles,
the gaseous and toxic nature of the reagent restricts its further
utilization.[5] N-Trifluoromethylthiophthalimide (1; Fig-
ure 1),[6] which was originally prepared from phthalimide
and CF3SCl, now can be accessed by reactions of N-chloro- or
N-bromophthalimide with CuSCF3 or AgSCF3.[6d,e] Never-
Herein, we report the design and synthesis of the N-
trifluoromethylthiosaccharin (5), which can be efficiently
synthesized from commercially available N-chlorosaccharin
or through a two-step process from saccharin, a readily
available, low-cost commodity. The superior reactivity of 5
was further demonstrated by trifluoromethylthiolation a vari-
ety of nucleophiles such as alcohols, amines, thiols, and
electron-rich arenes, aldehydes, ketones, and acyclic b-
ketoesters under mild reaction conditions. The fast rates,
broad scope, and tolerance of functionality of these trifluoro-
methylthiolation reactions made 5 very attractive as a general
[*] C.-F. Xu, B.-Q. Ma, 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: shenql@sioc.ac.cn
[**] The authors gratefully acknowledge the financial support from
National Basic Research Program of China (2012CB821600), the
Key Program of Natural Science Foundation of China (21032006),
National Natural Science Foundation of China (21172245/
21172244/21372247) and SIOC for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403983.
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reagent which will allow rapid incorporation of CF3S into
small molecules.
N-trifluoromethylthiosaccharin (5) is easily synthesized
from the reaction of N-chlorosaccharin with AgSCF3 in
CH3CN for 10 minutes at room temperature, and is isolated in
84% yield. Alternatively, it could be prepared by a two-step
procedure, as shown in Equation (1). Treatment of saccharin
Figure 2. Results observed for reaction of 2-(naphthalen-2-yl)ethanol
with the reagents 1–5.
with tert-butyl hypochlorite in methanol at room temperature
for 5 minutes generates N-chlorosaccharin,[10] which was then
reacted with AgSCF3 in CH3CN for 10 minutes to form 5 in
86% yield, as determined by 19F NMR spectroscopy. The
reaction can be easily scaled up to 6.0 grams and 5 was
isolated as a white solid in 84% yield. The compound 5 was
characterized by 1H, 13C, and 19F NMR spectroscopy and
elemental analysis. The structure of 5 was unambiguously
confirmed by single-crystal X-ray analysis (see the Supporting
Information for details).[17]
The compound 5 is a highly stable, crystalline compound.
No detectable decomposition was observed after storage for
more than one month at ambient temperature. It is stable in
solvents such as CH2Cl2, ClCH2CH2Cl, toluene, and CH3CN
at room temperature for at least 12 hours as determined by
19F NMR spectroscopy, and is less stable in THF as roughly
60% of 5 was converted into CF3S-SCF3 after 48 hours at
room temperature. The compound 5 is not stable in more
polar solvents such as DMF and DMSO. It was completely
decomposed after 5 minutes in DMSO and after 10 hours in
DMF at room temperature as determined by 19F NMR
spectroscopy.
With this new reagent in hand, we then explored the
reactivity of 5 with a variety of nucleophiles. Reaction of 2-
(naphthalen-2-yl)ethanol with 5 in the presence of 2.3 equiv-
alents of triethylamine gave a quantitative yield of the CF3-
substituted thioperoxide[11] after 5 minutes at room temper-
ature (Figure 2). In contrast, when 1 was employed, only 12%
yield of product was detected and no improvement was
observed with elongated reaction time (12 h). Three other
reagents, 2–4, which have shown to be active for electrophilic
trifluoromethylthiolation for various substrates, each gave
less than 2% of the desired product. These results show that 5
displays remarkably increased reactivity compared to other
trifluoromethylthiolating reagents. The increased reactivity of
5 compared to that of its analogue 1, is likely due to the
stronger electron-withdrawing property of the sulfonyl group
as compared to that of a carbonyl group.
tolerated under standard reaction conditions (6b–c, 6 f, 6h–i,
6k–l, 6o). Notably, 6l, which was previously developed in our
group as a trifluoromethylthiolating reagent (reagent 3 in
Figure 1) in moderate yields by a multistep synthesis, can now
be obtained in 95% in one step within 5 minutes.[8a] The
structure of 3 was recently established as a trifluoromethyl-
substituted thioperoxide by Buchwald and co-workers
through a combination of spectroscopic techniques, derivati-
zation experiments, and the crystal sponge method.[8b]
Not only alcohols but also amines could be expediently
trifluoromethylthiolated under mild reaction conditions.[7a,j,12]
Reactions of various primary or secondary alkyl amines and
arylamines with 5 proceeded in high yields after 1 hour at
room temperature (Scheme 1). Billardꢀs reagents 7g and 7l
(reagents 2a and 2b in Figure 1), could also be accessed from
5 in excellent yields. Optically pure alkylamines including a-
aminoesters were readily converted into the trifluorome-
thylthiolated amines in excellent yields without erosion of the
enantioselectivity (7b–c, 7e). Even an imine could be
trifluoromethylthiolated in good yield under these reactions
conditions (7n). The compound 7n has been previously
synthesized from the trifluoromethanesulfenamide 2a under
the basic conditions.[7j] Reactions of hetarylamines, however,
were extremely slow. Billard has shown that Lewis acids such
as TiCl4, SnCl4, and ClSiMe3 could activate 2 for trifluor-
omethylthiolation of olefins.[7b] Inspired by these results, we
found that when Me3SiCl was used as an activator, the
reaction of hetarylamines with 5 occurred in acceptable yields
of the desired products after 8 hours at 608C (7i–j). Pre-
viously reported methods for the preparation of trifluorome-
thylthiolated amines required either the use of DAST,[7a]
CF3SCl, or the presence of 1.1 equivalents of nBuLi as the
base.[7j]
Encouraged by the superior performance of 5 compared
to that of other trifluoromethylthiolating reagents, we further
studied the reaction of thiols with 5. Reactions of 5 with
a variety of aryl and heteroaryl thiols occurred in excellent
yields. Common functional groups such as fluoride, chloride,
bromide, and nitro were tolerated under the optimized
reaction conditions (Scheme 1; 8c–f). Alkylthiol also reacted
with 5 to provide the desired product in good yield (8a). A
As shown in Scheme 1, 5 could trifluoromethylthiolate
a variety of alcohols. Primary, secondary, and tertiary alcohols
were readily converted into trifluoromethyl-substituted thio-
peroxides in excellent yields within 5 minutes. Functional
groups such as esters, ketones, halides, and alkenes were
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Scheme 2. Trifluoromethylthiolation of b-keto esters, aldehydes and
ketones with 5 under mild reaction conditions. Yields are those of the
isolated products. [a] Reaction conditions: b-keto ester (0.3 mmol),
NaH (0.33 mmol), 5 (0.39 mmol), THF (2.0 mL), 08C, 30 min.
[b] Reaction conditions: b-keto ester (0.3 mmol), 5 (0.66 mmol),
DMAP (1.26 mmol), toluene (6.0 mL), room temperature, 8 h. [c] Reac-
tion conditions: Aldehyde (0.3 mmol), 5 (0.36 mmol), morpholine
hydrochloride (30 mol%), CH2Cl2 (6.0 mL), 308C, 12 h. [d] Reaction
conditions: Ketone (0.3 mmol), 5 (0.45 mmol), morpholine hydrochlo-
ride (30 mol%), CH3CN (6.0 mL), 808C, 12 h. [e] Me3SiCl (0.45 mmol)
was added. [f] 608C, 12 h.
the presence of 4-dimethylaminopyridine (DMAP) as a base
results in a complex mixture.[8a] One example of mono-
trifluoromethylthiolation of acyclic b-keto esters was
reported recently by Shibata and co-workers. However, the
reaction occurred only in 48% yield.[9] It was found that
reactions of acyclic b-keto esters with 5 occurred to afford the
mono-trifluoromethylthiolated b-keto esters after 0.5 hours
at 08C when NaH was used as the base (Scheme 2; 9a–d).
Likewise, acyclic b-ketoamide also underwent mono-
trifluoromethylthiolation in good yield (9e). Interestingly,
a ditrifluoromethylthiolated b-keto ester was formed when
DMAP was used as the base (9 f). Reactions of a-substituted
acyclic b-keto esters or malonates with 5 occurred smoothly at
room temperature to give the trifluoromethylthiolated prod-
ucts in excellent yields (9l–o). Reactions of aldehydes and
ketones were much less effective when the reactions were
conducted using NaH as the base. Only 23% yield of the
corresponding trifluoromethylthiolated aldehyde was
observed for reaction of 2-phenylpropanal using DMAP as
the base. Interestingly, reactions of aldehydes and ketones
with 5 generated monotrifluoromethylthiolated products
when morpholine hydrochloride was use as the catalyst (9g–
k).
Scheme 1. Trifluoromethylthiolation of alcohols, amines, and thiols
with 5 under mild reaction conditions. Yields are those of the isolated
products. Reaction conditions for alcohols: alcohol (0.3 mmol), 5
(0.39 mmol), Et3N (100 mL, 2.3 equiv), CH2Cl2 (6.0 mL), room temper-
ature 5 min. Reaction conditions for amines: amine (0.30 mmol), 5
(0.30-0.39 mmol), CH2Cl2 (6 mL), room temperature, 0.5–1 h. Reaction
conditions for thiols: thiol (0.3 mmol), 5 (0.30–0.39 mmol), CH2Cl2
(6.0 mL), room temperature, 1 h. [a] Me3SiCl (1.3 equiv) was added as
additive, ClCH2CH2Cl was used as solvent, 608C for 8 h.
previously known method for the preparation of aryl
trifluoromethyldisulfide involved the use of highly toxic
CF3SCl or CF3SSCF3.[13] Thus, this method provided a straight-
forward route for the preparation of a family of potentially
useful trifluoromethyl-substituted disulfides.
The incorporation of a CF3S moiety through the mono-
trifluoromethylthiolation of acyclic b-keto esters using tri-
fluoromethylthiolating reagents other than CF3SCl is quite
challenging.[14] The reaction of acyclic b-keto esters with 3 in
Since 5 was effective for trifluoromethylthiolation of
different nucleophiles, we next evaluated the direct electro-
philic trifluoromethylthiolation of arenes.[7c,13c,15] As shown in
Scheme 3, a variety of electron-rich arenes reacted with 5 to
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Scheme 4. Copper-mediated trifluoromethylthiolation of alkynes. Reac-
tion conditions: alkyne (0.6 mmol), 5 (0.30 mmol), CuI (0.60 mmol),
pyridine (72 mL, 0.90 mmol), THF (2.0 mL), 608C, 4.5 h. Yields are
those of the isolated products.
Scheme 3. Trifluoromethylthiolation of electron-rich arenes with 5
[a] Reaction conditions: arene (0.3 mmol), 5 (0.36–0.45 mmol),
Me3SiCl (36 mL, 0.30 mmol), CH2Cl2 (6.0 mL), room temperature,
30 min. Yields are those of the isolated products. [b] CF3SO3H (24 mL,
0.30 mmol) was added as additive instead of Me3SiCl. [c] 608C for 8 h.
[d] Room temperature, 4 h. [e] 5 (0.45 mmol), Me3SiCl (54 mL,
0.45 mmol), CH3CN (6.0 mL), 608C, 18 h. [f] 808C, 18 h. [g] 808C,
36 h.
ity, ease of handling, and high activity makes 5 very attractive
as a general electrophilic reagent for the synthesis of a variety
of CF3S-containting molecules. Studies on the expansion of
the scope of this reagent are underway and will be reported
shortly.
give the corresponding trifluoromethylthiolated products in
good to excellent yields when either Me3SiCl or triflic acid
was used as an activator. For example, reactions of phenol and
N,N-dimethylaniline gave exclusively the para-trifluorome-
thylthiolated products in good yields (10d,e). Similarly,
reaction of 2-naphthanol produced 1-trifluoromethylthio-
lated-2-naphthanol in 67% yield. Notably, 3-chloro, 3-
bromo-, and 3-iodophenol were also converted effectively
into trifluoromethylthio-substituted arenes in reasonable
yields (10i–k). These compounds are of interest since many
transition metal catalyzed cross-coupling reactions have been
reported, thus allowing additional functional-group trans-
formations.[16]
To further extend the synthetic utility of 5, we studied the
trifluoromethylthiolation of alkynes. After a quick screening
of the reaction conditions, it was found that reaction of 1-
ethynyl-3-fluorobenzene with 5, conducted with a combina-
tion of 2.0 equivalents of CuI and 3.0 equivalents of pyridine
as the catalyst in THF, resulted in full conversion into the
trifluoromethylthiolated alkyne in 79% yield. Avariety of the
terminal alkynes with functional groups such as nitro, cyano,
fluoride, chloride, bromide, and amide can be transformed
into their corresponding alkynyl trifluoromethyl sulfides in
good yields (Scheme 4; 11a–d, 11 f, 11h). The reaction
conditions for the trifluoromethylthiolation of alkynes were
not as efficient as those previously reported.[3h,7f–h,8a] Never-
theless, these results demonstrated the broad reaction scope
of 5.
Received: April 3, 2014
Revised: May 26, 2014
Published online: && &&, &&&&
Keywords: electrophilic substitution · fluorine ·
.
NMR spectroscopy · sulfur · synthetic methods
[1] a) A. Leo, C. Hansch, D. Elkins, Chem. Rev. 1971, 71, 525; b) R.
Filler, Biomedical Aspests of Fluorine Chemsitry, Kodansha,
Tokyo, 1982; c) L. M. Yagupol’skii, A. Y. Ilchenko, N. V. Kon-
dratenko, Russ. Chem. Rev. 1974, 43, 32; d) C. Hansch, A. Leo,
R. W. Taft, Chem. Rev. 1991, 91, 165.
[2] a) F. Leroux, P. Jeschke, M. Schlosser, Chem. Rev. 2005, 105, 827;
b) B. Manteau, S. Pazenok, J.-P. Vors, F. R. Leroux, J. Fluorine
Chem. 2010, 131, 140; c) V. N. Boiko, Beilstein J. Org. Chem.
2010, 6, 880, and references therein; d) B. Manteau, S. Pazenok,
J.-P. Vor, F. R. Leroux, J. Fluorine Chem. 2010, 131, 140; e) G.
Landelle, A. Panossian, S. Pazenok, J.-P. Vors, F. R. Leroux,
Beilstein J. Org. Chem. 2013, 9, 2476; f) A. Tlili, T. Billard,
Angew. Chem. 2013, 125, 6952; Angew. Chem. Int. Ed. 2013, 52,
6818; g) T. Liang, C. N. Neumann, T. Ritter, Angew. Chem. 2013,
125, 8372; Angew. Chem. Int. Ed. 2013, 52, 8214; h) W.-M. He,
Z.-Q. Weng, Prog. Chem. 2013, 25, 1071; i) F. Toulgoat, S. Alazet,
T. Billard, Eur. J. Org. Chem. 2014, 2415; j) I. Kieltsch, P.
Eisenberger, A. Togni, Angew. Chem. 2007, 119, 768; Angew.
Chem. Int. Ed. 2007, 46, 754.
[3] Selected methods for the introduction of the trifluoromethylthio
group: a) Q.-Y. Chen, J.-X. Duan, Chem. Commun. 1993, 918;
b) D. J. Adams, J. H. Clark, J. Org. Chem. 2000, 65, 1456; c) D. J.
Adams, A. Goddard, J. H. Clark, D. J. Macquarrie, Chem.
Commun. 2000, 987; d) W. Tyrra, D. Naumann, B. Hoge, Y. L.
Yagupolskii, J. Fluorine Chem. 2003, 119, 101; e) I. Kieltsch, P.
Eisenberger, A. Togni, Angew. Chem. 2007, 119, 768; Angew.
Chem. Int. Ed. 2007, 46, 754; f) G. Teverovskiy, D. S. Surry, S. L.
Buchwald, Angew. Chem. 2011, 123, 7450; Angew. Chem. Int.
Ed. 2011, 50, 7312; g) C.-P. Zhang, D. A. Vicic, J. Am. Chem. Soc.
In summary, a new electrophilc N-trifluoromethylthiosac-
charin (5) for direct trifluoromethylthiolation has been
developed. The reagent 5 can be efficiently synthesized in
two steps and is effective for the direct transfer of the CF3S
group to various substrates such as alcohols, amines, thiols, b-
ketoesters, aldehydes, ketones, electron-rich arenes, and
alkynes under mild reaction conditions. The ready availabil-
4
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Chemie
2012, 134, 183; h) C. Chen, L.-L. Chu, F.-L. Qing, J. Am. Chem.
Soc. 2012, 134, 12454; i) C. Chen, Y. Xie, L.-L. Chu, R.-W. Wang,
X.-G. Zhang, F.-L. Qing, Angew. Chem. 2012, 124, 2542; Angew.
Chem. Int. Ed. 2012, 51, 2492; j) C.-P. Zhang, D. A. Vicic, Chem.
Asian J. 2012, 7, 1756; k) L. D. Tran, I. Popov, O. Daugulis, J. Am.
Chem. Soc. 2012, 134, 18237; l) Z. Weng, W. He, C. Chen, R. Lee,
D. Dan, Z. Lai, D. Kong, Y. Yuan, K.-W. Huang, Angew. Chem.
2013, 125, 1588; Angew. Chem. Int. Ed. 2013, 52, 1548; m) K.-P.
Wang, S. Y. Yun, P. Mamidipalli, D. Lee, Chem. Sci. 2013, 4,
3205; n) L. Zhai, Y. Li, J. Yin, K. Jin, R. Zhang, X. Fu, C. Duan,
Tetrahedron 2013, 69, 10262; o) M. Rueping, N. Tolstoluzhsky, P.
Nikolaienko, Chem. Eur. J. 2013, 19, 14043; p) G. Danoun, B.
Bayarmagnai, M. F. Grꢁnberg, L. J. Gooßen, Chem. Sci. 2014, 5,
1312.
125, 11014; Angew. Chem. Int. Ed. 2013, 52, 10814; h) Q. Xiao, J.
Sheng, Z. Chen, J. Wu, Chem. Commun. 2013, 49, 8647; i) J.
Sheng, S. Li, J. Wu, Chem. Commun. 2014, 50, 578; j) S. Alazet,
K. Ollivier, T. Billard, Beistein J. Org. Chem. 2013, 9, 2354.
[8] a) X.-X. Shao, X.-Q. Wang, T. Yang, L. Lu, Q. Shen, Angew.
Chem. 2013, 125, 3541; Angew. Chem. Int. Ed. 2013, 52, 3457;
b) E. V. Vinogradova, P. Mꢁller, S. L. Buchwald, Angew. Chem.
2014, 126, 3189; Angew. Chem. Int. Ed. 2014, 53, 3125; c) X.-Q.
Wang, T. Yang, X.-L. Cheng, Q. Shen, Angew. Chem. 2013, 125,
13098; Angew. Chem. Int. Ed. 2013, 52, 12860; d) Q.-H. Deng, C.
Rettenmeier, H. Wadepohl, L. H. Gade, Chem. Eur. J. 2014, 20,
93.
[9] Y.-D. Yang, A. Azuma, E. Tokunaga, M. Yamasaki, M. Shiro, N.
Shitaba, J. Am. Chem. Soc. 2013, 135, 8782.
[4] Selected examples for electrophilic trifluoromethylthiolation
using CF3SCl: a) L. M. Yagupolskii, N. V. Kondratenko, G. N.
Timofeeva, J. Org. Chem. USSR 1984, 20, 103; b) T. Umemoto, S.
Ishihara, Tetrahedron Lett. 1990, 31, 3579; c) S. Munavalli, D. K.
Rohrbaugh, F. R. Longo, H. D. Durst, Phosphorus Sulfur Silicon
Relat. Elem. 2002, 177, 1073; d) S. Munavalli, D. K. Rohrbaugh,
D. I. Rossman, W. G. Wagner, H. D. Durst, Phosphorus Sulfur
Silicon Relat. Elem. 2002, 177, 1021.
[10] G. S. Borovikova, E. S. Levchenko, E. I. Kaminskaya, Zh. Org.
Khim. 1986, 22, 100.
[11] a) S. Andreades, US3081350, 1963; b) D. Ceacareanu, M. R. C.
Gerstenberger, A. Haas, Chem. Ber. 1983, 116, 3325.
[12] A. Kolasa, M. Lieb, J. Fluorine Chem. 1995, 70, 45.
[13] a) S. Munavalli, J. Fluorine Chem. 1993, 60, 85; b) J. F. Harris, J.
Org. Chem. 1981, 46, 268; c) S. Andreades, J. F. Harris, W. A.
Sheppard, J. Org. Chem. 1964, 29, 898.
[5] CF3SCl was reported to have an L(ct)50 of between 440 and
[14] Monotrifluoromethylthiolation has previously been reported by
reaction of acyclic b-keto esters with CF3SCl: a) H. Bayreuther,
A. Haas, Chem. Ber. 1973, 106, 1418; b) V. I. Popov, A. Haas, M.
Lieb, J. Fluorine Chem. 1990, 47, 131.
[15] a) H. Richert, Belg. Patent 624397, 1963; b) H.-S. Lee, L. Geng,
T. Skotheim, WO Patent 96/29,753, 1996; c) T. S. Croft, Phos-
phorus Sulfur Relat. Elem. 1976, 2, 133; d) A. Haas, V. Hellwig, J.
Fluorine Chem. 1975, 6, 521.
[16] J. F. Hartwig, Organotransition Metal Chemistry: from Bonding
to Catalysis, University Science Books, Sausalito, 2010.
[17] CCDC 994834 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[18] During the reviewing of the manuscript, Billard and co-workers
reported a general method for mono-trifluoromethylthiolation
of carbonyl compounds using a new electrophilic trifluorome-
thylthiolating reagent: Chem. Eur. J. 2014, 20, DOI: 10.1002/
chem.201403409.
880 ppmminÀ1. Chem. Eng. News 1967, 45, 44.
[6] a) S. Munavalli, D. K. Rohrbaugh, D. I. Rossman, F. J. Berg,
G. W. Wagner, H. D. Durst, Synth. Commun. 2000, 30, 2847; b) T.
Bootwicha, X. Liu, R. Pluta, I. Atodiresei, M. Rueping, Angew.
Chem. 2013, 125, 13093; Angew. Chem. Int. Ed. 2013, 52, 12856;
c) M. Rueping, X. Liu, T. Bootwicha, R. Pluta, C. Merkens,
Chem. Commun. 2014, 50, 2508; d) R. Pluta, P. Nikolaienko, M.
Rueping, Angew. Chem. 2014, 126, 1676; Angew. Chem. Int. Ed.
2014, 53, 1650; e) K. Kang, C.-F. Xu, Q. Shen, Org. Chem. Front.
2014, 1, 294.
[7] a) A. L. Ferry, T. Billard, B. R. Langlois, E. Bacque, J. Org.
Chem. 2008, 73, 9362; b) A. Ferry, T. Billard, B. R. Langlois, E.
Bacque, Angew. Chem. 2009, 121, 8703; Angew. Chem. Int. Ed.
2009, 48, 8551; c) A. Ferry, T. Billard, E. Bacque, B. R. Langlois,
J. Fluorine Chem. 2012, 134, 160; d) Y. Yang, X.-L. Jang, F.-L.
Qing, J. Org. Chem. 2012, 77, 7538; e) J. Liu, L. L. Chu, F.-L.
Qing, Org. Lett. 2013, 15, 894; f) F. Baert, J. Colomb, T. Billard,
Angew. Chem. 2012, 124, 10528; Angew. Chem. Int. Ed. 2012, 51,
10382; g) S. Alazet, L. Zimmer, T. Billard, Angew. Chem. 2013,
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Synthetic Methods
’Sacch’ed out: A new, electrophilic tri-
fluoromethylthiolating reagent, N-tri-
fluoromethylthiosaccharin (1), was
developed and can be synthesized in two
steps from saccharin within 30 minutes.
The reagent 1 allows the trifluorome-
thylthiolation of a variety of nucleophiles
such as alcohols, amines, thiols, electron-
rich arenes, aldehydes, ketones, acyclic b-
ketoesters, and alkynes under mild reac-
tion conditions.
C.-F. Xu, B.-Q. Ma,
Q. Shen*
&&&& — &&&&
N-Trifluoromethylthiosaccharin: An
Easily Accessible, Shelf-Stable, Broadly
Applicable Trifluoromethylthiolating
Reagent
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!