Facile synthesis of α-functionalized vinyl sulfides bearing β-trifluoromethyl group: a highly potential CF3-containing building blocks

Article abstract of DOI:10.1016/j.tetlet.2007.03.105

The β-(trifluoromethyl)vinylsulfides on treatment with n-BuLi/TMEDA were readily lithiated at α-position of the sulfanyl group, and the generated α-lithiovinylsulfides were trapped with a variety of electrophiles to give the corresponding β-trifluoromethy

Full text of DOI:10.1016/j.tetlet.2007.03.105

Tetrahedron Letters 48 (2007) 3727–3730
Facile synthesis of a-functionalized vinyl sulfides bearing
b-trifluoromethyl group: a highly potential CF3-containing
building blocks
Takeshi Hanamoto,* Ryoko Anno, Kenji Yamada and Kousuke Ryu
Department of Chemistry and Applied Chemistry, Saga University, Honjyo-machi 1, Saga 840-8502, Japan
Received 31 January 2007; revised 13 March 2007; accepted 19 March 2007
Available online 23 March 2007
Abstract—The b-(trifluoromethyl)vinylsulfides on treatment with n-BuLi/TMEDA were readily lithiated at a-position of the
sulfanyl group, and the generated a-lithiovinylsulfides were trapped with a variety of electrophiles to give the corresponding
b-trifluoromethyl-a-functionalized vinylsulfides in good to high yields.
Ó 2007 Elsevier Ltd. All rights reserved.
Organic fluorine compounds play an important role in
various fields such as agrochemicals, pharmaceuticals,
polymers and dyes presumably due to their intrinsic
properties.1 In association with these situations, the
growing demand for selectively fluorinated organic com-
pounds has requested the development of a new meth-
odology for the selective introduction of fluorine to
readily available organic compounds. Among them,
the preparation of trifluoromethylated molecules has
been of significant subject to chemists from a wide vari-
ety of fields.2 In the course of our study on versatile fluo-
rinated building blocks,3 we have paid attention to novel
trifluoromethylated olefins containing more than one
functional group. For instance, two different functional
groups could allow to manipulate more complex organic
molecules by use of each characteristic feature. One of
the straightforward ways to prepare such olefins seemed
to be the introduction of additional functional group to
trifluoromethylated olefins bearing another functional
group in advance. In view of this strategy we sought
an appropriate candidate as the starting trifluoromethy-
lated olefin.4 By literature survey we concluded that
b-(trifluoromethyl)vinylsulfide would be the best precursor
to our purpose for the reason of both its easy availability
and its promising reactivity.5 In connection of this sul-
fide, however, some reactions of the corresponding sulf-
oxide and sulfone have already been reported.6 The
associated report concerning the preparation of a-sulfa-
nylvinyl carbanion and its synthetic application also
encouraged us to examine the sulfide.7 In this Letter,
we will report the first convenient synthesis of vari-
ous a-functionalized-b-(trifluoromethyl)vinylsulfides as
highly potential synthetic intermediates.
We initially planned the preparation of three kinds of
aryl b-(trifluoromethyl)vinylsulfide. According to the
reported procedure for b-(trifluoromethyl)vinylphenyl
sulfide,5 we conducted the reaction of three thiophenols
(2) and 3,3,3-trifluoro-2-bromopropene (1) under the
basic conditions. These reactions proceeded smoothly
to afford the corresponding aryl vinyl sulfides (3) as a
mixture of stereoisomers in good to high yields
(Scheme 1).8 The obtained E/Z-mixtures could be easily
separated to each other by column chromatography on
silica gel.
F3C
Br
F3C
KOH
+
ArSH
EtOH
SAr
1
2
3
a: 84%
b: 83%
c: 59%
a: Ar = p-Tol
Keywords: Trifluoromethyl group; Vinylsulfide; Functional group;
Building block.
b: Ar = Ph
c: Ar = 2-Py
*
Corresponding author. Tel.: +81 952 28 8704; fax: +81 952 28
8548; e-mail: hanamoto@cc.saga-u.ac.jp
Scheme 1. Preparation of aryl b-(trifluoromethyl)vinylsulfide (3).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.105

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T. Hanamoto et al. / Tetrahedron Letters 48 (2007) 3727–3730
Table 1. Synthesis of (E)-aryl b-(trifluoromethyl)-(a-trimethylsilyl)-
vinyl sulfide (4)a
F3C
TMS
F3C
H
i) TBAF, AcOH
rt, THF
S-p-Tol
S-p-Tol
i) n-BuLi/TMEDA
F3C
ii) TMSCl
F3C
TMS
SAr
4aa
Scheme 2. Desilylation of 4aa by means of TBAF.
3a'
-78 °C, THF
SAr
3
4
Entry
Vinyl sulfide
Additive
Productb (yield, %)
substantially decreased the yield (entry 1). On the con-
trary to our expectation, the reaction using the corre-
sponding 2-pyridyl sulfide (3c) gave no desired product
(entry 4). This finding suggested that an electron-with-
drawing group attached to sulfur atom did not necessar-
ily stabilize the adjacent vinyl carbanion.
1
2
3
4
3a
3a
3b
3c
None
4aa (45)
4aa (82)
4ba (90)
4ca (0)
TMEDA
TMEDA
TMEDA
a All reactions were conducted in THF at ꢀ78 °C.
b Isolated yield.
Although it is well accepted that alkenyl anions have a
tendency toward their configuration with retention to
a high degree,11 we determined the configuration of
the product as follows. We conducted the desilylation
of the product (4aa) by means of TBAF in the presence
of a small amount of acetic acid (Scheme 2). The GC–
MS analysis of the crude reaction mixture gave a single
peak. The structural assignment of this desilylated sul-
fide was performed on the basis of the comparison
of both the 1H NMR spectrum and the GC–MS analysis.
The spectrum and retention time of the desilylated sul-
fide (3a0) were identical with those of the parent sulfide
(E-3a). We therefore confirmed the E configuration of
the product (4aa).
We continued to examine the substitution reaction of
the corresponding E-sulfides (3) using chlorotrimethyl-
silane (TMSCl) as an electrophile in the next step.9
Thus, the (E)-b-(trifluromethyl)-a-(p-tolylsulfanyl)vinyl
anion was generated by the successive addition
of N,N,N0,N0-tetramethylethylenediamine (TMEDA,
1.2 equiv) and n-BuLi (1.2 equiv) to the p-tolyl sulfide
(3a) in THF at ꢀ78 °C for 15 min, and was treated with
TMSCl (1.1 equiv) at this temperature for another
15 min to give the desired product in 82% yield (Table 1,
entry 2).10 However, the same reaction was conducted
by means of the Z-sulfide instead of the E-sulfide to
afford the corresponding E/Z-mixtures in poor yields
along with a considerable amount of the starting Z-sul-
fide. The reason is not clear at this time. It is noteworthy
that the combined use of n-BuLi and TMEDA is essen-
tial to the successful reaction.7 The use of n-BuLi alone
Under the similar conditions, a variety of electrophiles
were employed for this substitution reaction to evaluate
the scope of the functionalization of E-3a. These results
are summarized in Table 2. As seen in Table 2, most
Table 2. Synthesis of (E)-b-(trifluoromethyl)-a-functionalized vinyl p-tolyl sulfide (4a)a
i) n-BuLi/TMEDA
ii) Electrophile (E+)
F3C
F3C
E
-78 °C, THF
15 min
S-p-Tol
E-3a
S-p-Tol
4a
Entry
1
Electrophile
MeI
Product
Yieldb (%)
83
F3C
F3C
F3C
F3C
F3C
Me
4ab
S-p-Tol
TMS
2c
TMSCH2I
Bu3SnCl
4ac
4ad
4ae
4af
91
81
95
54
S-p-Tol
SnBu3
3
S-p-Tol
SPh
4
PhSS(O)2Ph
PhNCO
S-p-Tol
CONHPh
5
S-p-Tol

T. Hanamoto et al. / Tetrahedron Letters 48 (2007) 3727–3730
3729
Table 2 (continued)
Entry
Electrophile
I2
Product
Yieldb (%)
91
F3C
I
6
7
4ag
4ah
S-p-Tol
HO
HO
F3C
98
CHO
S-p-Tol
S-p-Tol
F3C
OMe
8
9
4ai
—
86
MeO
CHO
O
—
NR
79
Me
O
O
F3C
Me
10
4aj
Me
Cl
S-p-Tol
O
O
O
F3C
F3C
O
11
12
4ak
4al
60
76
O
CN
Et
S-p-Tol
O
O
Et
O
Cl
S-p-Tol
a All reactions were conducted using E-3a (1 equiv) with electrophiles (1.1 equiv) at ꢀ78 °C for 15 min.
b Isolated yield.
Me
reactions proceeded well to give the corresponding prod-
Me
ucts in good to high yields except for acetophenone
(entry 9). These results have indicated that the b-(triflu-
oromethyl)-a-sulfanylvinyl anion should provide impor-
tant b-(trifluoromethyl)vinyl intermediates in organic
synthesis. It is noteworthy that the sulfanyl group
should play an important role of these substitution reac-
tions in comparison with the corresponding sulfonyl
group.4
NH2NH2•H2O
EtOH, reflux
F3C
O
N
F3C
N
H
S-p-Tol
4aj
Scheme 3. Synthesis of pyrazole (5j).
5j, 88%
Finally, utilization of the product was preliminarily
investigated. The reaction of a,b-unsaturated ketone
(4aj) with hydrazine monohydrate was conducted in
ethanol under reflux conditions. On the contrary to
our expectation, the corresponding 3-p-tolyl-5-(trifluo-
romethyl)-1H-pyrazole was obtained as a desulfuriza-
tion product (5j) in 88% yield (Scheme 3).12 Although
the detailed reaction mechanism is not clear at present,
the plausible mechanism of the formation of 5j was
depicted in Scheme 4.
In summary, we have demonstrated the convenient syn-
thesis of 4aa–4al as highly promising trifluoromethy-
lated building blocks. Since most of these products
have a variety of functional groups, they should be ap-
plied to cyclization, cross-coupling reaction, reduction,
for example, to lead to more complex trifluoromethyl-
ated compounds that were not easily accessible. Further
studies on their synthetic utility are under progress in
our laboratory.
Ar
Ar
p-Tol-S
p-Tol-S
Ar
Ar
p-Tol-S
F3C
NNH2
4aj
5j
=
NH
N
NNH2
CF3
F3C
F3C
N
H
N
H
S-p-Tol
Scheme 4. Plausible mechanism for the formation of 5j.

3730
T. Hanamoto et al. / Tetrahedron Letters 48 (2007) 3727–3730
mixture was gradually warmed to ambient temperature
Acknowledgement
overnight. The reaction was quenched with saturated
aqueous ammonium chloride, and the organic layer was
separated from the mixture. The resulting aqueous layer
was extracted with hexane three times. The combined
organic layer was dried over sodium sulfate, and concen-
trated in vacuo. The resulting oily residue was purified by
silica gel chromatography (hexane as eluant) to give E-3a
as colorless oil (1.69 g, 74%) and Z-3a as a white solid
(0.22 g, 10%). Compound E-3a: Rf = 0.68 (hexane); mmax
(neat)/cmꢀ1 1619, 1300, 1279, 1119, 938, 832, 810; dH
(CDCl3) 2.38 (3H, s), 5.32 (1H, dq, J 15.2, 6.4), 7.11 (1H,
dq, J 15.2, 2.0), 7.20–7.40 (4H, m); dF (CDCl3) ꢀ63.4 (1F,
dd, J 6.6, 2.7); GC–MS m/z 218 (84, M+), 217 (18), 134
(80), 123 (37), 91 (100), 77 (51), 69 (47), 65 (79); Anal.
Calcd for C10H9F3S: C, 55.03; H, 4.16. Found: C, 55.12;
H, 4.16. Compound Z-3a: Rf = 0.50 (hexane); dH (CDCl3)
2.36 (3H, s), 5.60 (1H, dq, J 11.0, 8.6), 6.82 (1H, dq, J 11.0,
0.9), 7.10–7.40 (4H, m); dF (CDCl3) ꢀ61.1 (1F, d, J 7.4).
9. The compound (4ba) was synthesized with the aid of
another method. Yamazaki, T.; Ishikawa, N. Bull. Soc.
Chim. Fr. 1986, 937; Yamazaki, T.; Takita, K.; Ishikawa,
N. J. Fluorine Chem. 1985, 30, 357.
We greatly thank F-Tech Co., Ltd for a gift of 3,3,3-tri-
fluoro-2-bromopropene.
References and notes
1. Uneyama, K. In Organofluorine Chemistry; Blackwell:
Oxford, 2006; Chambers, R. D. In Fluorine in Organic
Chemistry; Blackwell: Oxford, 2004; Organofluorine Com-
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Hudlicky A. E. Pavlath, In Chemistry of Organic Fluorine
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1995.
2. Pang, W.; Zhu, S.; Jiang, H.; Zhu, S. Tetrahedron 2006,
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Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432;
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3. Hanamoto, T.; Egashira, M.; Ishizuka, K.; Furuno, H.;
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Chem. 2003, 4279.
10. Preparation of 4aa: To
a solution E-3a (84.0 mg,
0.385 mmol) in THF (2 mL) under argon was added
TMEDA (74 lL, 0.46 mmol) at room temperature, and
the whole mixture was cooled to ꢀ78 °C. After being
stirred for 10 min at this temperature, to this mixture was
added n-BuLi (2.71 M in hexane solution, 170 lL,
0.46 mmol) dropwise via syringe. After being stirred for
10 min, TMSCl (54 lL, 0.42 mmol) was added to the
solution, and the whole mixture was stirred for 15 min.
The reaction was quenched with water at this temperature
and extracted with hexane/ether = 3/1. After the usual
work-up, the residue was purified by Florisil chromato-
graphy (hexane as eluant) to give 91.7 mg of 4aa as pale
yellow oil in 82% yield: mmax (neat)/cmꢀ1 1585, 1276, 1135,
1109, 847, 817; dH (CDCl3) 0.35 (9H, s), 2.43 (3H, s), 5.25
(1H, q, J 9.0), 7.25–7.40 (4H, m); dF (CDCl3) ꢀ56.9 (3F, d,
J 10.0); GC–MS m/z 290 (0.5, M+), 141 (48), 107 (47), 91
(21), 77 (55), 73 (100), 65 (17); Anal. Calcd for
C13H17F3SSi C, 53.76; H, 5.90. Found: C, 53.87; H, 5.78.
11. Walborsky, H. M.; Turner, L. M. J. Am. Chem. Soc. 1972,
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4. The only one example was reported in respect of the
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T.; Furukawa, H.; Fujiwara, T. Chem. Lett. 1982, 593.
8. Preparation of 3a: A 100 mL round-bottomed flask
equipped with a magnetic stir bar was charged with
20 mL of ethanol and potassium hydroxide (0.64 g,
11.4 mmol). To the stirred solution was successively added
4-methylbenzenethiol (1.30 g, 10.5 mmol) and 3,3,3-triflu-
oro-2-bromopropene (1.3 mL, 12.5 mmol) at 0 °C. The
12. Yamanaka, H.; Takekawa, T.; Morita, K.; Ishihara, T.;
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