A convenient and efficient synthesis of trifluoromethyl vinyl sulfoxide and its reactivity in addition reactions

Article abstract of DOI:10.1055/s-0030-1258515

We report a novel high-yielding approach to trifluoromethyl vinyl sulfoxide from 2-mercaptoethanol and trifluoromethyl iodide. Additionally, the principal ability of this compound to react with N-, O-, and S-nucleophiles is demonstrated.

Full text of DOI:10.1055/s-0030-1258515

LETTER
2075
A Convenient and Efficient Synthesis of Trifluoromethyl Vinyl Sulfoxide and
Its Reactivity in Addition Reactions
Synthesis of
T
ri
i
fluorom
u
ethyl
V
inyl
b
S
ulfoxide ov V. Sokolenko,* Irina I. Maletina, Lev M. Yagupolskii,† Yurii L. Yagupolskii
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanskaya Str. 5, 02094 Kiev, Ukraine
Fax +38(044)5732643; E-mail: sokolenko_liubov@mail.ru
Received 26 May 2010
anol and perfluorohexyl iodide or ethyl bromodifluoroac-
Abstract: We report a novel high-yielding approach to trifluoro-
methyl vinyl sulfoxide from 2-mercaptoethanol and trifluoromethyl
iodide. Additionally, the principal ability of this compound to react
with N-, O-, and S-nucleophiles is demonstrated.
etate.3 It should be mentioned here that only aza-Michael
reaction of compounds 2 and 3 with primary,4 secondary,4
and macrocyclic5 amines was investigated.
Key words: trifluoromethylation, oxidation, nucleophilic addition, In this letter we wish to describe the practical high-yield-
bromination, vinyl sulfoxides
ing preparation of trifluoromethyl vinyl sulfoxide (1) us-
ing readily available starting materials on each stage.
Additionally, we have shown the principal ability of al-
kene 1 to undergo addition reactions with various nucleo-
philic and electrophilic agents.
Perfluoroalkyl vinyl sulfoxides are promising precursors
for the preparation of more complex molecules containing
CF3SO group. Double bond of such a building block is ac-
tivated by fluorinated sulfoxy moiety being the strong
electron acceptor.1 It opens various ways to modification
of unsaturated part of such sulfoxides. To the best of our
knowledge, there are only three fluoroalkyl vinyl sulfox-
ides containing trifluoromethyl (1),2 tridecafluorohexyl
(2),3a and ethyl difluoroacetyl (3)3b groups described in
the literature (Figure 1). The compound of significant in-
terest is the simplest representative of the family – trifluo-
romethyl vinyl sulfoxide (1).
The initial route towards compound 1 was chosen by anal-
ogy with Wakselman’s work3 and started from 2-mercap-
toethanol (4) and CF3I (Scheme 2). Nevertheless, the
present method differs from previously described meth-
odology; our strategy involves cheaper reactants (Oxone®
instead of trifluoroperacetic acid and triethylamine in-
stead of DBU) and leads to the more convenient isolation
of intermediates and higher overall yield of the desired
product.
The reaction between 2-mercaptoethanol and CF3I occurs
in the presence of sodium formate/sodium sulfite mixture
in DMF–water solution.6 However, 2-mercaptoethanol
does not react with CF3Br under these conditions. Alcohol
5 was converted into chloride 6 in nearly quantitative
yield by the action of sulfinyl chloride under reflux.7
Oxidation of compound 6 proceeds under the action of
MCPBA (method A), freshly prepared trifluoroperacetic
acid (method B), or Oxone® (method C, Table 1).
O
S
CF3
1
O
S
O
S
C6F13
CF2COOEt
2
3
It is noteworthy to mention that the best results were
achieved with Oxone®,8 in this case yield of sulfoxide is
nearly quantitative, and product separation is easy and
convenient. Trifluoromethyl vinyl sulfoxide (1) was pre-
pared by elimination of HCl from the compound 7 accord-
ing to the procedure described earlier,2 but we have found
that increasing of the reaction time from 20 hours to 120
hours led to significant enlargement of the desired product
yield.
Figure 1 Three fluoroalkyl vinyl sulfoxides described in the litera-
ture
This molecule was first synthesized in our laboratory in
19672 as shown in Scheme 1. However, this method in-
cludes the use of the toxic trifluoromethanesulfenyl chlo-
ride and gives only 32% overall yield of compound 1.
Fluoroalkyl vinyl sulfoxides 2 and 3 were obtained by
Wakselman and co-workers starting from 2-mercaptoeth-
CH2=CH2
autoclave,
80–100 °C
H2O2, AcOH
20 °C, 48 h and
then 90 °C, 3 h
O
S
Et3N, Et2O
20 °C, 20 h
O
S
SCF3
CF3SCl
Cl
Cl
CF3
CF3
80%
67%
60%
1
Scheme 1 Synthesis of trifluoromethyl vinyl sulfoxide described earlier
SYNLETT 2010, No. 14, pp 2075–2078
x
x
.x
x
.2
0
1
0
Advanced online publication: 22.07.2010
DOI: 10.1055/s-0030-1258515; Art ID: G13710ST
© Georg Thieme Verlag Stuttgart · New York

2076
L. V. Sokolenko et al.
LETTER
CF3I, Na2SO3, HCO2Na⋅2H2O
SOCl2
SH
HO
SCF3
SCF3
HO
Cl
Cl
79 °C, 2 h
96%
DMF–H2O, 25 °C, 24 h
68%
4
5
6
method
A or B or C
O
S
O
DBU
Et3N, Et2O
MCPBA, CH2Cl2
S
diglyme
S
CF3
CF3
CF3
25 °C, 120 h
82%
–20 to 25 °C, 24 h
25 °C, 24 h
56%
16%
7
8
1
Scheme 2
Table 1 Oxidation of Sulfide 6 to Sulfoxide 7
Method
Oxidant (equiv)
MCPBA (1)
Solvent
Time (h)
24
Temp (°C)
0–25
Yield (%)
A
B
C
CH2Cl2
70
76
96
CF3CO3H (1)
Oxone® (1.5)
CF3CO2H
CH2Cl2–H2O
24
–20 to 25
25
120
DBU was also used for elimination of HCl from 7, but in acetic acid under severe conditions (without solvent at
this case reaction was accompanied by substantial resini- heating).
fication and yield of compound 1 was only 60%. Addi-
We supposed that these reactions proceed as electrophilic
tionally, attempt to obtain trifluoromethyl vinyl sulfoxide
addition initiated by protonation of the double bond of
(1) by another way was undertaken. Compound 6 was
alkene 1. Substantial polymerization is observed in these
converted to trifluoromethyl vinyl sulfide (8)9 under the
cases, and yields of products 11 and 12 are moderate.
action of equivalent amount of DBU. Oxidation of sulfide
Aliphatic alcohols and mercaptanes as well as phenols and
thiophenols (entries 5–8) were shown to react with alkene
8 by MCPBA (1 equiv) leads to sulfoxide 1.
Nevertheless, yields of compounds 8 and 1 in this strategy
1 under the basic catalysis. Sodium hydride was found to
are low due to the low boiling point (26–27 °C)9 of prod-
be the most suitable base in these reactions. Amount of
base depends on the nature of nucleophile, and it is evi-
uct 8 and its high volatility.
Trifluoromethyl vinyl sulfoxide (1) is the typical Michael dent that the weaker nucleophile needs the greater quanti-
acceptor in which double bond is activated by the strong ty of NaH.
electron-withdrawing substituent – the trifluoromethyl-
We have found that bromine addition to the compound 1
proceeds in ether solution at reflux (Scheme 4). The prod-
uct of this interaction 17 was obtained as mixture of dia-
sulfonyl group (sp = 0.691). Therefore, the reactivity of
this compound is of interest.
In our study we also explored ability of alkene 1 to react stereomers in a ratio of 3:1.
with different N-, O-, and S-nucleophiles. These interac-
tions could be described by general equation shown in
Scheme 3. The results are summarized in Table 2.
O
O
S
Br2 (1.1 equiv)
Et2O
S
Br
CF3
CF3
reflux, 2–3 h
85%
Br
O
S
O
S
17
1
NuH
Nu
CF3
CF3
Scheme 4
34–96%
1
9–16
Scheme 3 Reactions of trifluoromethyl vinyl sulfoxide (1) with
nucleophiles
Elimination of HBr from 17 occurs easily in the presence
of triethylamine and leads to the alkene 18 in good yield
(Scheme 5). The structure of compound 18 was confirmed
by APT spectrum.
Remarkably, trifluoromethyl vinyl sulfoxide (1) reacts
with cyclic and aliphatic amines (entries 1 and 2) readily
with excellent yields. Michael adducts 9 and 10 could be
isolated in a pure form after the removal of the solvent
without further purification. It should be noted that in the
case of (R)-(+)-phenylethylamine product 10 (entry 2)
was obtained as a 1:1 mixture of diastereomers.
O
S
O
S
Et3N, Et2O
CF3
CF3
Br
r.t., 24 h
70%
Br
Br
17
18
Scheme 5
Aromatic amines (aniline and 4-fluoroaniline, entries 3
and 4) react with 1 in the presence of catalytic amounts of
Synlett 2010, No. 14, 2075–2078 © Thieme Stuttgart · New York

LETTER
Synthesis of Trifluoromethyl Vinyl Sulfoxide
2077
Table 2 Reactions of Trifluoromethyl Vinyl Sulfoxide 1 with Nucleophiles
Entry Nucleophile
(equiv)
Cat.
(mol%)
Solvent Time Temp (°C) Product
(h)
Mp
(°C)
Bp
(°C) (bar)
Yield
(%)
O
S
1
–
Et2O
24
r.t.
CF3
23–24
75–78 (6.7·10–5) 97 (91)a
O
NH
N
O
(1)
9
O
Ph
S
2
3
–
Et2O
24
3
r.t.
oil
–
–
96
48
CF3
N
Ph
NH2
H
(1)
10
H
O
N
S
NH2
AcOH (10)
–
120–140
126–127
CF3
(1)
11
H
N
O
S
F
NH2
4
AcOH (10)
–
3
110
110–111
–
34
CF3
F
(1)
12
O
S
n-BuOH
5
6
7
8
NaH (2.5)
NaH (5)
–
0.5 r.t.
–
96 (1.3·10–2)
50
55
76
70
n-Bu
O
CF3
(1)
13
MeO
O
S
MeO
OH
–
3
100–110
61–62
–
–
CF3
O
(1)
14
15
O
S
i-PrSH
NaH (0.5)
NaH (0.5)
–
0.5 r.t.
70 (1.3·10–2)
S
CF3
(1)
S
O
S
F
SH
Et2O
24
r.t.
oil
–
F3C
F
(1)
16
a Yield of 9 after distillation.
(4) Magnier-Bouvier, C.; Blazejewski, J.-C.; Larpent, C.;
Magnier, E. Tetrahedron Lett. 2006, 47, 9121.
(5) de Castries, A.; Magnier, E.; Monmotton, S.; Fensterbank,
H.; Larpent, C. Eur. J. Org. Chem. 2006, 4685.
In summary, we have reported a convenient and efficient
synthesis of trifluoromethyl vinyl sulfoxide (1) in four
steps (51% overall yield) from commercial starting mate-
rials. Furthermore, the conditions for interaction of this
alkene with different nucleophiles and electrophiles were
found. A series of compounds containing the (trifluorom-
ethylsulfinyl)ethyl moiety was synthesized. Further stud-
ies on the reactivity of trifluoromethyl vinyl sulfoxide are
currently in progress.
(6) 2-[(Trifluoromethyl)thio]ethanol (5)
Reaction was carried out in the three-neck flask equipped by
condenser (–80 °C), mechanical stirrer, and bubbler. To the
stirred suspension of sodium sulfite (113.5 g, 0.9 mol) and
sodium formate (93.6 g, 0.9 mol) in DMF–H2O (600 mL:180
mL) mixture mercaptoethanol (70 g, 0.9 mol) in DMF (100
mL) was added in a single portion at 0 °C under argon. CF3I
(216 g, 1.1 mol) was bubbled into the reaction mixture for 2–
3 h at r.t. After stirring at r.t. for 24 h the solution was poured
into H2O (300 mL). Product was extracted by Et2O (5 × 300
mL), organic layer was washed by diluted HCl (3 × 50 mL),
H2O (5 × 200 mL) and dried (MgSO4). Solvent was removed
by distillation at atmospheric pressure, and product was
purified by distillation. Yield 90 g, 68%; bp 124–126 °C. 1H
NMR (299.5 MHz, DMSO-d6): d = 3.06 (t, 3J = 6.2 Hz, 2 H,
CH2), 3.64 (t, 3J = 6.2 Hz, 2 H, CH2), 5.01–5.35 (br s, 1 H,
OH). 19F NMR (282.2 MHz, DMSO-d6): d = –39.96 (s,
References and Notes
(1) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
(2) Knunyants, I. N.; Rozhkov, I. N.; Alexandrov, A. M.;
Yagupolskii, L. M. J. Gen. Chem. USSR (Engl. Transl.)
1967, 37, 1210.
(3) (a) Magnier, E.; Tordeux, M.; Goumont, R.; Magder, K.;
Wakselman, C. J. Fluorine Chem. 2003, 124, 55.
(b) Moïse, J.; Goumont, R.; Magnier, E.; Wakselman, C.
Synthesis 2004, 2297.
Synlett 2010, No. 14, 2075–2078 © Thieme Stuttgart · New York

2078
L. V. Sokolenko et al.
LETTER
(8) Oxidation of Sulfide 6 to Sulfoxide 7 Using Oxone®
SCF3). Anal. Calcd for C3H5F3OS: C, 24.66; H, 3.45; S,
21.94. Found: C, 24.87; H, 3.40; S, 22.03.
To the stirred mixture (mechanical stirrer) of SiO2 (340 g)
and H2O (135 mL) Oxone® (125 g, 0.41 mol of KHSO5) and
a solution of sulfide 6 (45 g, 0.27 mol) in CH2Cl2 (700 mL)
were added in a single portion. The reaction mixture was
stirred at r.t. for 120 h (monitoring by 19F NMR). Silica gel
was filtered off and washed with CH2Cl2 (ca 300 mL). The
organic layer was washed with a FeSO4 solution, dried
(MgSO4), and filtered. Solvent was removed at atmospheric
pressure, and product was purified by distillation. Yield 47
g, 96%; bp 64 °C (9.3·10–3 bar). 1H NMR (299.5 MHz,
CDCl3): d = 3.17–3.27 (m, 1 H, CH2), 3.44–3.51 (m, 1 H,
CH2), 3.88–4.06 (m, 2 H, CH2). 19F NMR (282.2 MHz,
CDCl3): d = –74.15 (s, SOCF3). 13C NMR (125.8 MHz,
CDCl3): d = 35.5 (s, b-CH2), 51.4 (q, 3JCF = 2.5 Hz, a-CH2),
125.4 (q, 1JCF = 333.3 Hz, CF3).
(7) 2-Chloroethyl Trifluoromethyl Sulfide (6)
SOCl2 (25 mL, 0.33 mol) was added dropwise to the alcohol
5 (45 g, 0.31 mol) at 0 °C over 30 min. The reaction mixture
was stirred under reflux for 2 h. After cooling to r.t. H2O (0.3
mL), followed by K2CO3 (2 g), was added, and the resulting
mixture was allowed to stand overnight. Product 6 was
purified by vacuum distillation (6.7·10–5 bar) over K2CO3
into cooled trap and following distillation at atmospheric
pressure. Yield 49 g, 96%; bp 94–96 °C. 1H NMR (299.5
MHz, CDCl3): d = 3.21 (t, 3J = 7.5 Hz, 2 H, CH2), 3.72 (t,
3J = 7.5 Hz, 2 H, CH2). 19F NMR (282.2 MHz, DMSO-d6):
d = –41.38 (s, SCF3). 13C NMR (125.8 MHz, CDCl3):
d = 31.8 (q, 3JCF = 2.5 Hz, a-CH2), 42.2 (s, b-CH2), 130.7 (q,
1JCF = 306.9 Hz, CF3).
(9) Harris, J. F. Jr. J. Org. Chem. 1967, 32, 2063.
Synlett 2010, No. 14, 2075–2078 © Thieme Stuttgart · New York