A New and Efficient Method for the Synthesis of Trifluoromethylthio- and Selenoethers

Article abstract of DOI:10.1021/ol036303q

(Equation presented) A new atom-economic procedure for preparation of trifluoromethyl thio- and selenoethers is reported, wherein both halves of aryl and alkyl disulfides and diselenides are able to be utilized with high efficiency.

Full text of DOI:10.1021/ol036303q

ORGANIC
LETTERS
2004
Vol. 6, No. 2
301-303
A New and Efficient Method for the
Synthesis of Trifluoromethylthio- and
Selenoethers
,†
Chaya Pooput,† Maurice Medebielle,‡ and William R. Dolbier, Jr.*
Department of Chemistry, UniVersity of Florida, GainesVille, Florida 32611-7200, and
UniVersite´ Claude Bernard-Lyon 1, Laboratoire SERCOF (UMR CNRS 5622),
Batiment E. CheVreul, 43, Bd du 11 noVembre 1918, F-69622 Villeurbanne, France
wrd@chem.ufl.edu
Received November 25, 2003
ABSTRACT
A new atom-economic procedure for preparation of trifluoromethyl thio- and selenoethers is reported, wherein both halves of aryl and alkyl
disulfides and diselenides are able to be utilized with high efficiency.
Aryl trifluoromethyl thioethers continue to attract much
interest within pharmaceutical and agrochemical companies,
as witnessed by the significant number of process patent
applications recently submitted that are devoted to their
preparation.1 This interest derives from the recognized
potential of the SCF3 group to have a positive influence on
biological activity. Diverse methods have been reported for
the synthesis of aryl trifluoromethyl thioethers,2 but two seem
to have emerged as preferred methods. The first is the classic
with aryl and alkyl disulfides.9-15 Although good yields can
be obtained, as exemplified below, the method suffers from
the fact that half of the disulfide is wasted in the process.16-18
(1) For example: Okano, K.; He, L. (Mitsubishi Chemical Corp.). PCT
Int. Appl. 2002 066423. Forat, G.; Mas, J.-M.; Saint-Jalmes, L. (Rhone-
Poulenc Chimi). U.S. Patent Appl. Publ. 2002 042542.
(2) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555-
6666.
(3) Boiko, V. N.; Shchupak, G. M.; Yagupolskii, L. M. J. Org. Chem.,
USSR 1977, 13, 972-975.
SRN1 reaction of aryl thiolates with trifluoromethyl iodide
(4) Wakselman, C.; Tordeux, M. Chem. Commun. 1984, 793-794.
(5) Wakselman, C.; Tordeux, M. J. Org. Chem. 1985, 50, 4047-4051.
(6) Umemoto, T.; Ishihara, S. Tetrahedron Lett. 1990, 31, 3579-3582.
(7) Koshechko, V. G.; Kiprianova, L. A.; Fileleeva, L. I. Tetrahedron
Lett. 1992, 33, 6677-6678.
or bromide. This method, first reported by Yagupolskii using
CF3I and UV irradiation in 1977,3 by Wakselman and
Tordeux using CF3Br (at 2 atm) in 1984,4,5 along with later
variations,6,7 has proved to be generally useful when using
aryl thiolates but less efficient when using alkanethiolates.8
(8) Popov, V. I.; Boiko, V. N.; Yagupolskii, L. M. J. Fluorine Chem.
1982, 21, 365-369.
(9) Wakselman, C.; Tordeux, M.; Clavel, J. L.; Langlois, B. R. Chem.
Commun. 1991, 993-994.
(10) Billard, T.; Langlois, B. R. Tetrahedron Lett. 1996, 37, 6865-6868.
(11) Quiclet-Sire, B.; Saicic, R. N.; Zard, S. Z. Tetrahedron Lett. 1996,
37, 9057-9058.
Scheme 1. Thiolate Method
(12) Russell, J.; Roques, N. Tetrahedron 1998, 54, 13771-13782.
(13) Roques, N. J. Fluorine Chem. 2001, 107, 311-314.
(14) Blond, G.; Billard, T.; Langlois, B. R. Tetrahedron Lett. 2001, 42,
2473-2475.
(15) Inschauspe, D.; Sortais, J.-P.; Billard, T.; Langlois, B. R. SynLett
2003, 233-235.
(16) This disadvantageous atom-inefficiency has been somewhat over-
come by using aryl and alkyl thiocyanates or sulfenyl chlorides as the
substrates with CF3TMS, instead of the disulfides.17,18
(17) Billard, T.; Large, S.; Langlois, B. R. Tetrahedron Lett. 1997, 38,
65-68.
(18) Movchen, V. N.; Kolomeitsev, A. A.; Yagupolskii, L. M. J. Fluorine
Chem. 1995, 70, 255-257.
The other popular method involves the reaction of tri-
fluoromethyl anion (generated in situ by various methods)
† The University of Florida.
‡ Universite´ Claude Bernard-Lyon 1.
10.1021/ol036303q CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/24/2003

CF3I would be used productively in two different reactions,
both of which lead to the same desired product.
Scheme 2. Nucleophilic Trifluoromethylation Methods
Scheme 4. Tandem CF3I Process
Indeed, when a total of 5 equiv of CF3I are used, while
maintaining the quantity of TDAE at 2.2 equiv, yields of
trifluoromethylthioether reached as high as 200%, based on
the numberr of equivalents of disulfide!23
Entries 1-3 show that with 5 equiv of CF3I, yields of
almost 200% could be obtained with both diaryl and dialkyl
disulfide. Entries 4-7 indicate attempts to optimize the
procedure. Although 3.2 equiv of CF3I (entry 3) were not
sufficient, more than 4.2 equiv gave nearly quantitative
yields. Moreover, 2 h of stirring at room temperature appears
to be sufficient. The lack of reactivity of t-butyl disulfide
had been noted previously, when CF3TMS was used as the
trifluoromethyl anion source.10
Recently, we have developed a trifluoromethyl anion
reagent that is derived directly from trifluoromethyl iodide.
When reduced by the organic reducing agent tetrakis-
(dimethylamino)ethylene (TDAE), the CF3I forms a reagent
anion that has been found to be effective for additions of
-
CF3 to aldehydes, ketones, acyl chlorides, and cyclic
sulfates.19-22 As can seen by the data in Table 1, this reagent
Table 1. Trifluoromethylation of Disulfides
It might be argued that these results could derive simply
from reduction (by TDAE) of the disulfide to 2 equiv of
thiolate anion, which then could react with the CF3I, with
the reaction proceeding entirely via reaction of thiolate anions
with CF3I. However, if that were the case, the 2.2 equiv of
TDAE (along with 2.2 equiv of CF3I) should have been
sufficient to obtain the high yields observed in Table 2.
stirring time at rt
(h)
NMR yield
(%)
entry
R
1
2
3
4
5
phenyl
butyl
ethyl
butyl
butyl
12
12
12
4
80
>98
>98
>98
>98
2
also proves to be an excellent choice for the conversion of
aryl and alkyl disulfides into their trifluoromethyl thioethers.
The reaction is very fast, and only 2 h of stirring at room
temperature was sufficient to give a quantitative yield, as
shown in the entries 4 and 5.
Table 2. Trifluoromethylation of Disulfides Using Excess CF3I
stirring time
at rt
(h)
NMR yield
(%)
entry
R
equiv of CF3I
ref
1
2
3
4
5
6
7
8
9
phenyl
butyl
4-pyridyl
butyl
butyl
butyl
butyl
ethyl
2-pyridyl
t-butyl
5
5
5
5
4.2
3.2
4.2
4.2
4.2
4.2
12
12
12
4
4
4
2
2
2
12
186
170
∼200
170
175
130
170
180
180
0
5, 24
25
26
25
25
25
25
27
28
Scheme 3. CF3I/TDAE Method
10
However, it occurred to us that this same CF3I that we
are using to generate the trifluoromethyl anion could also
be a substrate for reaction, via the SRN1 mechanism, with
the thiolate coproduct, thus potentially enabling both halves
of the disulfide to be used in a one-pot reaction, where the
However, in those cases where 2.2 equiv of TDAE were
used (Table 1), yields never exceeded 100%. This probably
means that the CF3I is reduced faster than the disulfides.
Nevertheless, a control reaction was carried out to provide
more definitive evidence for the proposed dual-mechanism
synthetic process. CF3I ( 5 equiv) and TDAE (2.2 equiv)
were added together in DMF at -20 °C, at which temper-
ature a deep red solution was formed as the TDAE was fully
oxidized by reaction with CF3I. The solution was then
(19) A¨ıt-Mohand, S.; Takechi, N.; Me´debielle, M.; Dolbier, W. R., Jr.
Org. Lett. 2001, 3, 4271-4273.
(20) Takechi, N.; Ait-Mohand, S.; Medebielle, M.; Dolbier, W. R., Jr.
Tetrahedron Lett. 2002, 43, 4317-4319.
(21) Takechi, N.; Ait-Mohand, S.; Medebielle, M.; Dolbier, W. R., Jr.
Org. Lett. 2002, 4, 4671-4672.
(22) Petrov, V. A. Tetrahedron Lett. 2001, 42, 3267-3289.
302
Org. Lett., Vol. 6, No. 2, 2004

allowed to warm to -5 °C, at which time n-butyl disulfide
was introduced. At this point there should be little, if any
TDAE remaining to react with the disulfide. Despite this,
the observed yield from this reaction was 160%, which
compares well with the 170% observed when using the
normal procedure (Table 2, entry 5). One can therefore
conclude that the reaction likely proceeds via the two-stage
process described above.
Since diselenides have reactivities that are similar to
disulfides, this nucleophilic trifluorination procedure was
applied to diphenyl diselenide. Again, when only 2.2 equiv
each of TDAE and CF3I were used, the reaction proceeded
well to give ∼100% yield. However, when 5 equiv of CF3I
were used, the reaction efficiently converted the diselenide
to 2 equiv of the selenoether24 (198% yield).
Scheme 5. Synthesis of Phenyl Trifluoromethyl Selenide
In conclusion, a new, atom-economic procedure for
preparation of trifluoromethyl thio- and selenoethers is
reported, wherein both halves of aryl and alkyl disulfides
and diselenides are able to be used with high efficiency.
Future work will demonstrate the extension of this methology
to the use of other perfluoroalkyl iodides.
Acknowledgment. Support of this work in part by the
National Science Foundation is acknowledged with thanks.
(23) Typical Procedure. In a 25 mL flask equipped with a reflux
condenser and a N2 inlet was added 10 mL of anhydrous DMF and 0.8 g
(3.7 mmol) of diphenyl disulfide. After cooling to -5 °C, 2 mL (8.1 mmol)
of TDAE and then 3.6 g of CF3I (18.4 mmol) were added. As the CF3I was
added, the solution gradually became dark orange and a white solid started
forming after a few minutes. The reaction mixture was maintained at around
0 °C for 30 min, and then the solution was allowed to warm to room
temperature, after which it was stirred at rt for an additional 2 h. The orange
solution was filtered and the solid washed with Et2O, which was combined
with the DMF filtrate. Water (25 mL) was added to the DMF filtrate and
the mixture extracted three times with Et2O. The combined ether layers
were washed with brine and dried over MgSO4. The solvent was removed
and the crude product purified by silica gel chromatography (CH2Cl2/
hexanes, 1:9) to give 1.6 g of phenyl trifluoromethyl sulfide (178% yield,
based upon the number moles of disulfide).
OL036303Q
(24) Billard, T.; Roques, N.; Langlois, B. R. J. Org. Chem. 1999, 64,
3813-3820.
(25) Ignatev, N. V.; Boiko, V. N.; Yagupolskii, L. M. J. Org. Chem.,
USSR 1985, 21, 592-592.
(26) 1H NMR, AB system: δ 7.37 (dd, J ) 4.7, 1.75 Hz, 2H), 8.51 (dd,
J ) 4.8, 2.0 Hz, 2H). 19F NMR: δ -41.0.
(27) Tyrra, W.; Naumann, D.; Hoge, B.; Yagupolskii, L. M. J. Fluorine
Chem. 2003, 119, 101-107.
(28) Yagupolskii, L. M.; Kondratenko, N. V.; Sambur, V. P. Synthesis
1975, 721-723.
Org. Lett., Vol. 6, No. 2, 2004
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