Electrophilic trifluoromethanesulfanylation of organometallic species with trifluoromethanesulfanamides

Article abstract of DOI:10.1002/anie.201205156

It's so easy. Direct trifluoromethanesulfanylation reactions remain difficult to perform because of the lack of reagents that are stable and easy to handle. Trifluoromethanesulfanamides are reagents which, in combination with readily available Grignard re

Full text of DOI:10.1002/anie.201205156

Angewandte
Chemie
DOI: 10.1002/anie.201205156
Organometallic Chemistry
Electrophilic Trifluoromethanesulfanylation of Organometallic Species
with Trifluoromethanesulfanamides**
FranÅois Baert, Julie Colomb, and Thierry Billard*
Dedicated to Dr. Bernard Langlois
More and more applications for fluorinated molecules are
being found in various fields, in particular in the fields of
medicinal chemistry and agrochemistry.[1] In recent years,
there has been growing interest in the association of the
trifluoromethyl group with heteroatoms such as CF3O or
CF3S. The CF3S moiety is of particular interest, because it has
a high hydrophobicity parameter (pR = 1.44).[2] Consequently,
compounds bearing this group are potentially important
targets for applications in pharmaceuticals and agrochemi-
cals.[1e,3]
Numerous methods for the introduction of this group onto
organic substrates are described in literature.[4] The main
strategies are indirect methods, wherein the CF3S moiety can
be constructed from a precursor already present in the
molecule by halogen–fluorine exchange reactions.[5] Another
way is through the trifluoromethylation of sulphur-containing
compounds. Examples include the nucleophilic[6] and radical
trifluoromethylation[7] of disulfides, thiocyanates, and thiols,
as well as the electrophilic trifluoromethylation of thiolates.[8]
Such strategies may be of interest, but require the preparation
of sulfur-precursors, must be fluorinated or trifluoromethy-
lated.
generating the CF3SCu reagent in situ from Ruppertꢀs
reagent, S8 and copper salts.[13] Nevertheless, these recent
direct trifluoromethanesulfanylations are essentially limited
to aromatic compounds. Furthermore, whereas researchers
have shown renewed interest in nucleophilic strategies,[11–13]
electrophilic methods remain underdeveloped.
We have, recently, described an easy synthesis of a family
of reagents that are stable and easy to handle, namely the
trifluoromethanesulfanamides.[14] These reagents have
already demonstrated their potential in the electrophilic
trifluoromethanesulfanylations of alkenes, alkynes,[15a] and
electron-rich aromatic compounds.[15b]
Herein, we will extend the application of these reagents to
organometallic nucleophiles. In previous papers, the use of
Lewis or protic acids has been required to activate the
trifluoromethanesulfanamides.[15] However, when the same
strategy (with BF3·Et2O as an activator) has been applied to
the reaction of 1a and phenylmagnesium chloride (2a), no
reaction was been observed. This was probably due to
reaction between the Grignard reagent and the Lewis acid.
Supposing that magnesium could play the role of a Lewis acid,
the same reaction was performed without additional activator
(Table 1).
With this change, the expected product 3a was obtained in
good yield, but with a long reaction time at 138C (entries 1
and 2). Increasing the temperature appears to be deleterious
for the reaction, probably owing to the thermal degradation
of a reaction intermediate. To increase the kinetic reaction,
the reacting medium was concentrated. Although temper-
A more elegant approach is the direct trifluoromethane-
sulfanylation of substrates. However, this method is still
limited. Some radical and electrophilic reactions have been
performed with CF3SCl.[9] However, this species is gaseous
and highly toxic. Some nucleophilic reactions have previously
been realized through the use of stabilized forms of the
unstable CF3S anion, but apart from CF3SCu the reactivity of
these species is relatively limited;[10] such reagents are
generally not stable enough to be stored for extended periods.
Most recently, metal-catalyzed coupling reactions with
Table 1: Conditions for trifluoromethanesulfanylation of 2a with 1a.
[12]
CF3SAg[11] or CF3SNMe4 have been described. However,
the reagents are not very stable and must be prepared before
use. Qing et al. have circumvented this main drawback by
Entry
[2a][a]
T [8C]
t [h]
3a [%][b]
[*] F. Baert, J. Colomb, Dr. T. Billard
Institute of Chemistry and Biochemistry (ICBMS—UMR CNRS
5246) Universitꢀ de Lyon, Universitꢀ Lyon 1, CNRS
43 Bd du 11 novembre, 69622 Lyon (France)
E-mail: thierry.billard@univ-lyon1.fr
1
2
3
4
5
6
7
8
0.4
0.4
0.4
0.4
2.0
2.0
2.0
2.0
13[c]
13[c]
21
60
21
3
31
8
4
8
3.5
6
3
50
77[e]
30[e]
6[e]
54[e]
73
J. Colomb, Dr. T. Billard
CERMEP—in vivo imaging, Groupement Hospitalier Est
59 Bd Pinel, 69003 Lyon (France)
0
0
83[e]
86[e]
0!20[d]
[**] We thank the CNRS and the Rꢀgion Rhꢁne-Alpes for their financial
support. The French Fluorine Network is also thanked for its
support.
[a] Final concentration [molLꢀ1]. [b] Crude yield, as determined by
19F NMR spectroscopy using PhOCF3 as an internal standard. [c] Ambi-
ent temperature in winter. [d] 08C for 10 min. then 208C. [e] No further
reaction progress.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205156.
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Communications
ature seems to be deleterious (entry 4), good yields are
obtained in a reasonable time at 08C (entries 6 and 7). It was
noticed that low temperature is crucial only at the time of 2a
addition, afterwards the reaction can be run at 208C to
achieve a good yield in a short time (entry 8). These
optimized conditions have been extended to other Grignard
reagents 2 as well (Figure 1).
Scheme 1. Reaction of 1a with Grignard reagents preformed in situ.
Yields shown are of isolated products; numbers in parentheses are
crude yields determined by 19F NMR spectroscopy using PhOCF3 as an
internal standard.
Table 2: Conditions for trifluoromethanesulfanylation of 5a with 1a.
Entry
T [8C]
Base
6a [%][a]
Figure 1. Synthesis of trifluoromethylthioethers from 1a and 2. Yields
shown are of isolated products; numbers in parentheses are crude
yields determined by 19F NMR spectroscopy using PhOCF3 as an
internal standard.
1
2
3
ꢀ78!RT[b]
ꢀ78
BuLi
BuLi
NaHMDS
49
73
58
ꢀ78
[a] Crude yield, as determined by 19F NMR spectroscopy using PhOCF3 as
an internal standard. [b] Deprotonation conducted at ꢀ788C; reaction
run at RT after the addition of 1a. NaHMDS=sodium hexamethyldi-
silazide.
In general, the reaction gives good yields for aromatic
compounds. In the case of 3 f and 3h, the reactions were
slower (an overnight reaction time was required for total
conversion). The difference in kinetics could be rationalized
by electronic effects. Indeed, in the ortho and para positions,
the methoxy group is an electron donor and so contributes to
diminishing the electronic density on Mg and, thus, its Lewis
acidity. For 3h, steric hindrance in the ortho position must
also play an important role. In the case of 3g, MeO is electron-
withdrawing in the meta position, and so enhances the Lewis
acidity of Mg. Good results were also obtained with aliphatic
reagents, even with a sterically hindered cyclohexyl group
(3e). In the case of a benzylic compound (3b), the low yield
observed could come from a decomposition of 3b under the
basic reaction conditions, by deprotonation of the acidic
benzylic protons in the position a to the SCF3 group.
yield was observed. This can be rationalized by the lower
Lewis acidity of Na, which, consequently, cannot activate 1a
as well as Li can.
In general this method furnishes satisfactory results with
aromatic or aliphatic substrates (Figure 2). The commercially
available organolithium reagents, which did not need to be
preformed, also react with 1a to give modest to satisfactory
yields (3k,l; volatile products), even with a hindered tert-butyl
derivative (3l; overnight reaction). Surprisingly, product 6b
seems to degrade in the basic medium, as previously observed
Starting from bromo derivatives 4 f,g, the corresponding
Grignard reagents were generated in situ using Turbo-
Grignard, as described by Knochel et al.[16] Then the trifluor-
omethanesulfanamide 1a was added to provide the expected
trifluoromethylthioethers 3 f,g in satisfactory yields
(Scheme 1). In the case of 3g, the modest yield of isolated
product comes from the difficulty of separating 3g from the
residual starting material, 4g.
The reaction between 1a and deprotonated terminal
alkynes has also been envisaged (Table 2). After deprotona-
tion with butyllithium, phenylacetylene reacted with 1a to
provide the expected product 6a in satisfactory yield. Because
of the thermal sensitivity of the alkynyl anion, better yield was
obtained by performing the reaction at ꢀ788C (entries 1 and
2). Phenylacetylene (5a) can also be deprotonated with
sodium hexamethyldisilazide (NaHMDS), however, a lower
Figure 2. Synthesis of trifluoromethylthioethers 6. Yields shown are of
isolated products; numbers in parentheses are crude yields deter-
mined by 19F NMR spectroscopy using PhOCF3 as an internal stan-
dard.
2
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Chemie
A. E. Pavlath), American Chemical Society, Washington, DC,
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with 3b. The formation of 6b has been tested with LiHMDS
as a base instead of BuLi, however, the results s were not
reproducible (yields varied between 11% and 40%). These
results suggest that 6b is very sensitive to basic conditions and
begins to decompose as soon as it is formed.
The reaction between 1a and the organozinc reagents
Et2Zn and EtO2C(CH2)2ZnBr has also been tested, but
without success. This could be explained by the lower
reactivity of organozinc reagents and the poor Lewis acidity
of zinc. Furthermore, the possibility of extending this reaction
to more fluorinated reagent has been verified. Grignard
reagent 2c reacts with pentafluoromethanesulfanamide 1b[14]
to give the corresponding pentafluoroethylthioether 9 in
satisfactory yield (Scheme 2). This result suggests that 1b and
1a are similarly reactive.
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Scheme 2. Synthesis of a pentafluoroethylthioether with 1b.
In conclusion, we have demonstrated that trifluorome-
thanesulfanamides (1) easily react with organometallic spe-
cies such as Grignard or organolithium reagents. These results
extend the applications of this new family of reagents, which
more and more appears to be a valuable alternative to CF3SCl
for trifluoromethanesulfanylation reactions. Furthermore,
their easy handling makes them accessible to the broad
community of synthetic chemists who are not organofluorine
specialists.
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Received: July 2, 2012
Revised: July 31, 2012
Published online: && &&, &&&&
Keywords: fluorine · grignard reaction ·
.
trifluoromethanesulfanamide · trifluoromethanesulfanylation ·
trifluoromethylthioether
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Chemie
Communications
Organometallic Chemistry
F. Baert, J. Colomb,
T. Billard*
&&&& — &&&&
It’s so easy! Direct trifluoromethane-
sulfanylation reactions remain difficult to
perform because of the lack of reagents
which are stable and easy to handle.
Trifluoromethanesulfanamides are
reagents which, in combination with
readily available Grignard reagents, can
be used by those without experience in
fluorine chemistry to easily synthesize
trifluoromethylthioethers.
Electrophilic
Trifluoromethanesulfanylation of
Organometallic Species with
Trifluoromethanesulfanamides
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!