Communication
Some direct aromatic trifluoromethylthiolations have already
been described.[6,7,9] However, they suffer in general from vari-
ous drawbacks including regioselectivity issues, limitations of
reactivity, the use of excess metal, basic conditions, necessity
of directing groups, the use of unstable reagents, bis-function-
alization, etc. Faced with such shortcomings, cross-coupling re-
actions with boronic acids often appear as an efficient alterna-
tive. Some trifluoromethylthiolations of boronic acids have also
been discussed in the literature.[10] Nucleophilic approaches
have been performed by using CF3SNMe4, but the CF3SÀ anion
is known to be unstable and, consequently, difficult to prepare
Abstract: The most reactive 2nd generation of trifluoro-
methanesulfenamides undergoes copper-catalyzed
a
cross-coupling reaction with boronic acids to afford CF3S-
molecules. Contrary to the previous methods in the litera-
ture, no base addition, no heating, and no large excess of
reagents are required to obtain good results. Furthermore,
a crucial role of a small amount of water to favor this reac-
tion has been demonstrated. This constitutes the mildest
described conditions for such a reaction.
and store.[10d] To circumvent this instability, in situ generation
From the fluorine characterization by Moissan[1] to today, fluori-
nated compounds have always fascinated chemists because of
their specific, and often unusual, properties.[2] Such interests
have largely contributed to the continuously growing develop-
ment of new methods to synthesize fluorinated molecules.[3] In
recent years, more elaborate fluorinated substituents have
emerged. In particular, the CF3S group has seen a great deal of
interest. Such moiety is one of the most lipophilic fluoroalkyl
groups (Hansch parameter pR =1.44).[4] This physicochemical
property is of great interest in life sciences, because this con-
tributes to the transmembrane permeation of the molecule
and, thus, to improve their biodisponibility.[5]
[10b]
of this anion has been explored, by using CF3SiMe3/S8
or
[10g]
CF3CO2Na/S8
systems. However, a large excess of CF3SiMe3
or CF3CO2Na should be used and a stoichiometric amount of
metal is required. Furthermore, with trifluoroacetate, high tem-
peratures are required. Strategies using electrophilic trifluoro-
methylthiolating reagents have been also developed.[10a,c,e,f]
However, in these methods the trifluoromethylthiolating re-
agents A and B (see Figure 1) are used; they were prepared
starting from the non-commercially available reagent CF3SAg.
Furthermore, in these reactions the use of carbonate as basic
system is always required, and in most of them 2 equiv are
necessary.[10a,c,e] Although carbonate is a moderately strong
base, such basic conditions could eventually constitute an
issue with very sensitive compounds even if the Suzuki cross-
coupling reaction is well-recognized for its compatibility with
functional groups. Consequently, it could be judicious to devel-
op a non-basic new method, based on the use of a stable,
easy to obtain reagent.
The synthesis of CF3S molecules has been largely reported in
the literature, but these methods are mainly based on indirect
strategies involving the trifluoromethylation of sulfur com-
pounds. However, the preliminary preparation of these sulfur
compounds can constitute a difficult step, in particular in the
case of more elaborate molecules.[6] To circumvent this draw-
back, more elegant direct trifluoromethylthiolation methods
have been recently described, often based on the use of shelf-
stable reagents (Figure 1).[6a,b,7]
In recent years, we have developed a new family of very
stable reagents, namely the trifluoromethanesulfenamides (1
and 2), which have demonstrated their high efficiency in vari-
ous electrophilic trifluoromethylthiolations.[9a,b,11] Consequently,
their use in cross-coupling reactions with boronic acids has
been considered (Table 1).
Aromatic compounds constitute an important class of or-
ganic substrates in various fields of applications and, in partic-
ular, in life sciences.[8] Consequently, trifluoromethylthiolation
of aromatic compounds represents a challenging reaction.
Table 1. Trifluoromethylthiolation of biphenylboronic acid (3a).
Figure 1. Electrophilic trifluoromethylthiolating reagent.
Entry
CF3S
reagent
K2CO3
[equiv]
T
[8C]
4a
[%][a]
[a] Q. Glenadel, S. Alazet, A. Tlili, Dr. T. Billard
Institute of Chemistry and Biochemistry (ICBMS—UMR CNRS 5246)
UniversitØ de Lyon, UniversitØ Lyon 1, CNRS
1
2
3
4
5
6
7[b]
1
2
2
2
2
2
2
2
2
0.2
0
2
40
40
40
40
RT
RT
RT
0
66
50
35
95
10
32
43 Bd du 11 novembre 1918, 69622 Villeurbanne (France)
[b] Dr. T. Billard
CERMEP - in vivo imaging
Groupement Hospitalier Est
59 Bd Pinel, 69003 Lyon (France)
0
0
[a] Yield of products, as determined by 19F NMR spectroscopy using
PhOCF3 as an internal standard. [b] No precautions, no inert atmosphere.
Supporting information for this article is available on the WWW under
Chem. Eur. J. 2015, 21, 14694 – 14698
14695
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