Communications
Table 2: Electrophilic trifluoromethylation of thiols.
solution to which further MeCN
100 mL) was added. The solution was
(
EntrySubstrate
Product
Yield [%]
82
cooled to À178C, and Me SiCF3
3
[
a]
1
2
3
4
5
6
S1 R=m-Br
(9.16 mL, 61.97 mmol, 1.54 equiv) was
added, followed by dropwise addition of
a solution of tetrabutylammonium tri-
phenyldifluorosilicate (TBAT; 0.065 g,
0.120 mmol, 0.3 mol% based on 5) in
MeCN (2 mL). The reaction mixture
was stirred for 16 h at À178C, then
warmed to À128C, at which temperature
further Me SiCF (1.31 mL, 8.9 mmol,
[
a]
S2 R=p-NO2
88
82
72
80
91
[
a]
S3 R=o-NH2
[
a]
S4 R=m-NH2
[
a]
S5 R=p-NHAc
[
a]
[b]
S6 R=o-OH
[
[
c]
a]
7
8
9
S7
S8
S9
95
58
81
3
3
0.22 equiv) was added. The reaction
mixture was warmed to room temper-
ature over 3 h and then stirred at room
temperature for a further 3 h. After the
volatile components of the mixture had
been removed, the residue was dried in
vacuo. Dry pentane (150 mL) was added
to the remaining brown solid, and the
resulting mixture was filtered through a
pad of dry alox. The clear, colorless
solution obtained was evaporated to
dryness, and the residue was dried in
vacuo to yield 1 (11.823 g, 35.8 mmol,
[
a]
[
[
a]
1
1
0
1
S10
53
51
a,d]
S11
[
a]
a]
1
1
1
2
3
4
S12
S13
S14
90
82
99
89%) as a white solid.
Received: August 27, 2006
Revised: October 18, 2006
Published online: December 8, 2006
[
[
c]
Keywords: electrophilicsubstitution·
.
hypervalent compounds · iodine ·
trifluoromethylation · umpolung
1
[
a] The reaction was carried out in CH Cl . [b] Yield was determined by H NMR spectroscopy. [c] The
2 2
reaction was carried out in MeOH. [d] The disulfide by-product was isolated in 41% yield.
[
1] a) P. Kirsch, Modern Fluoroorganic
[
15]
Chemistry: Synthesis, Reactivity,
try. Trifluoromethylthio-substituted sugars are rare com-
pounds. We are aware of only very few pyranose derivatives
Applications, Wiley-VCH, Weinheim, 2004; b) K. Uneyama,
Organofluorine Chemistry, Blackwell, Oxford, 2006; c) M.
Schlosser, Angew. Chem. 2006, 118, 5558; Angew. Chem. Int.
Ed. 2006, 45, 5432.
[
16]
bearing a SCF moiety that are comparable to product S12.
Previous methods for the direct preparation of S-trifluoro-
methyl-l-cysteine derivatives required reaction conditions
3
À
[2] For CF H as an alternative to CF Br as a source of CF , see:
3
3
3
[
17]
[18]
involving tBuOOH or liquid ammonia. However, with
compound 1 the S trifluoromethylation of simple cysteine
esters in either the N-protected or the unprotected form can
be carried out in high yield under very mild conditions. We
anticipate that the trifluoromethylation of cysteine residues in
higher peptides should also be possible by this method.
In conclusion, we have shown the very promising potential
of the mild, relatively cheap, and readily accessible reagent 1
in the C and S trifluoromethylation of a variety of substrates.
Further studies with an emphasis on catalytic and enantiose-
lective reactions with reagents of type 1 are ongoing in our
laboratory and shall be reported in due course.
a) S. Large, N. Roques, B. R. Langlois, J. Org. Chem. 2000, 65,
848; b) B. R. Langlois, T. Billard, Synthesis 2003, 185.
3] a) G. K. S. Prakash, A. K. Yudin, Chem. Rev. 1997, 97, 757; b) I.
Ruppert, K. Schlich, W. Volbach, Tetrahedron Lett. 1984, 25,
8
[
2
195.
[
4] a) T. Umemoto, Chem. Rev. 1996, 96, 1757, and references
therein; b) J.-J. Yang, R. L. Kirchmeier, J. M. Shreeve, J. Org.
Chem. 1998, 63, 2656; c) E. Magnier, J.-C. Blazejewski, M.
Tordeux, C. Wakselman, Angew. Chem. 2006, 118, 1301; Angew.
Chem. Int. Ed. 2006, 45, 1279.
5] P. Eisenberger, S. Gischig, A. Togni, Chem. Eur. J. 2006, 12, 2579.
6] R. L. Amey, J. C. Martin, J. Org. Chem. 1979, 44, 1779.
7] G. A. Rabah, G. F. Koser, Tetrahedron Lett. 1996, 37, 6453.
8] CCDC 618737 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.
[
[
[
[
Experimental Section
[9] J.-A. Ma, D. Cahard, J. Org. Chem. 2003, 68, 8726.
[10] a) V. P. Kukhar, V. A. Soloshonok, Fluorine-Containing Amino
Acids: Synthesis and Properties, Wiley, New York, 1995; b) K.
Uneyama in Enantiocontrolled Synthesis of Fluoro-Organic
Compounds (Ed.: V. A. Soloshonok), Wiley, Chichester, 1999,
chap. 12.
[
4]
Improved synthesis of 1: All manipulations were conducted under
an inert atmosphere. Dry KOAc (6.66 g, 67.9 mmol, 1.68 equiv) and
[
6]
intermediate 5 (11.94 g, 40.3 mmol) were stirred in dry MeCN
100 mL) for 1 h at ambient temperature. Filtration and washing of
(
the remaining white solid with MeCN gave a clear, almost colorless
756
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Angew. Chem. Int. Ed. 2007, 46, 754 –757