Direct electrophilic N-trifluoromethylthiolation of amines with trifluoromethanesulfenamide

Article abstract of DOI:10.3762/bjoc.9.270

The CF3SN moiety is a substituent with interesting properties. However, there is no easy synthetic access to molecules bearing this group. The trifluoromethanesulfenamide is a new reagent for the electrophilic trifluoromethylthiolation which reacts easily with amines to obtain trifluoromethylsulfanylamines with good yields.

Full text of DOI:10.3762/bjoc.9.270

Direct electrophilic N-trifluoromethylthiolation of
amines with trifluoromethanesulfenamide
Sébastien Alazet1,2, Kevin Ollivier1 and Thierry Billard*1,2
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2354–2357.
1Institute of Chemistry and Biochemistry (ICBMS – UMR CNRS
5246), Université de Lyon, Université Lyon 1, CNRS, 43 Bd du 11
novembre 1918 – 69622 Lyon, France and 2CERMEP - in vivo
imaging, Groupement Hospitalier Est, 59 Bd Pinel – 69003 Lyon,
France
doi:10.3762/bjoc.9.270
Received: 02 August 2013
Accepted: 10 October 2013
Published: 04 November 2013
Email:
This article is part of the Thematic Series "Organo-fluorine chemistry III".
Guest Editor: D. O'Hagan
Thierry Billard* - thierry.billard@univ-lyon1.fr
* Corresponding author
© 2013 Alazet et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
amine; fluorine; organo-fluorine; trifluoromethanesulfenamide;
trifluoromethylsulfanylamine; trifluoromethylthiolation
Abstract
The CF3SN moiety is a substituent with interesting properties. However, there is no easy synthetic access to molecules bearing this
group. The trifluoromethanesulfenamide is a new reagent for the electrophilic trifluoromethylthiolation which reacts easily with
amines to obtain trifluoromethylsulfanylamines with good yields.
Introduction
In past decades, fluorinated molecules have found more and moiety (CF3SN). However, this group has found applications in
more applications in a variety of fields, especially in the design agrochemical and medicinal chemistry [14-20]. From a physico-
of new compounds for medicinal chemistry or agrochemistry chemical point of view, the CF3SN group possesses a Hansch’s
[1-9]. More recently, new substituents have emerged which as- hydrophobicity parameter πR = 1.50 [21]. This value, slightly
sociate the trifluoromethyl group with heteroatoms such as superior to the Hansch’s hydrophobicity parameter of the CF3S
CF3O or CF3S. Because of its high hydrophobicity (Hansch group, could be of great interest in the development of bio-
parameter πR = 1.44), the CF3S moiety is of particular interest logical active compounds. Yet, the common synthetic route to
[10]. Compounds with this group constitute important targets these compounds use the highly toxic and gaseous CF3SCl
for applications in pharmaceuticals and agrochemicals [4,11- [16,22-35].
13].
Results and Discussion
The association of a CF3 group to more than one heteroatom is Several years ago, we have described an easy access to tri-
rarely described in literature. In particular, there are only a few fluoromethanesulfenamides [36], starting from DAST, Ruppert
investigations regarding the trifluoromethylsulfanylamine reagent, and primary amines [37]. However, even though this
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Beilstein J. Org. Chem. 2013, 9, 2354–2357.
strategy gave good results with primary amines, secondary
amines do not react under these conditions, thus limiting the
access to a large panel of trifluoromethylsulfanylamines. The
trifluoromethanesulfenamide 1a is an efficient reagent for the
electrophilic trifluoromethylthiolation of carbon nucleophiles
[38-44]. Therefore, this reagent should react with amines to
perform transamination reactions with secondary amines
leading to various trifluoromethylsulfanylamines 3. The reac-
tion has been optimized with phenylpiperazine (2a) (Table 1).
Table 1: Reaction of phenylpiperazine (2a) with 1a under basic condi-
tions.
After preliminary deprotonation of 2a with BuLi, the trifluoro-
methanesulfenamide 1a is added. The expected product 3a is
obtained in 15 min with good yield. To improve the kinetic of
the reaction, the deprotonation and the transamination should be
performed at 0 °C (Table 1, entries 1 and 2). Longer reaction
times do not increase the yield, the reaction seems to be finished
in 15 min (Table 1, entries 2 and 3). As previously observed in
other works, the use of other bases with sodium or cesium
cations is not efficient since only Li is a Lewis acid strong
enough to activate 1a [38,44]. These optimal conditions have
been extended to selected amines 2 (Figure 1).
Entry
Base
T (°C)
t
3a (%)a
1
2
3
4
5
BuLi
BuLi
−78
0
15 min
15 min
3 h
65
86
84
0
BuLi
0
NaH
0
15 min
2 h 30
Cs2CO3
80
0
aCrude yields determined by 19F NMR spectroscopy by using PhOCF3
as an internal standard.
can also react under these new conditions, as illustrated with the
aniline (3n).
The reaction gives, in general, good yields with various second-
ary amines (3a–k). Because of their high volatility, some com- Amino alcohols and bis-amines can also be trifluoromethylthio-
pounds (3h and 3i) have not been isolated. Imines can be also lated, with the most nucleophile atom as a target (Figure 2). In
trifluoromethylthiolated in good yields (3m). Even if our first this case, 2.1 equiv of BuLi are required and reaction times are
developed method is compatible with primary amines [37], they loner (20 h).
Figure 1: Transamination of 1a with amines. (Isolated yields, in parentheses crude yields determined by 19F NMR with PhOCF3 as an internal stan-
dard).
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Beilstein J. Org. Chem. 2013, 9, 2354–2357.
Acknowledgements
We thank the CNRS for their financial support. The French
Fluorine Network is also thanked for its support.
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