A facile synthesis of 1-chloro-2,2,2-trifluoroethyl sulfides

Article abstract of DOI:10.1055/s-0029-1219232

A facile synthesis of structurally diverse 1-chloro-2,2,2-trifluoroethyl sulfides from readily available 1-bromo-1-chloro-2,2,2-trifluoroethane (Halothane) and various aliphatic and aromatic thiols in the presence of sodium dithionite/sodium bicarbonate is described. The synthetic utility of the prepared sulfides is illustrated by the synthesis of biologically potent heterocycles and by their electrophilic reactions with thiophene.

Full text of DOI:10.1055/s-0029-1219232

PAPER
1159
A Facile Synthesis of 1-Chloro-2,2,2-trifluoroethyl Sulfides
S
ynthesisof 1-Chl
u
oro-2,2,2-tr
i
r
fluoroeth
i
yl Sulf
y
ide
s
Pustovit,*a Anatoliy Alexeenko,a Sergii Trofymchuk,a Oleg Lukin,*b,c Andrey A. Tolmachevb,c
a
b
c
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmans’ka St. 5, 02094 Kiev, Ukraine
National Taras Shevchenko University, ChemBioCenter, Volodymyrska St. 62, 01033 Kiev, Ukraine
Enamine Ltd., A. Matrosova St. 23, 01103 Kiev, Ukraine
Fax +380(44)5373253; E-mail: oleg.lukin@mail.univ.kiev.ua
Received 25 September 2009; revised 10 December 2009
preparation of diversely functionalized 1-chloro-2,2,2-tri-
fluoroethyl sulfides.
Abstract: A facile synthesis of structurally diverse 1-chloro-2,2,2-
trifluoroethyl sulfides from readily available 1-bromo-1-chloro-
2,2,2-trifluoroethane (Halothane®) and various aliphatic and aro-
matic thiols in the presence of sodium dithionite/sodium bicarbon-
ate is described. The synthetic utility of the prepared sulfides is
illustrated by the synthesis of biologically potent heterocycles and
by their electrophilic reactions with thiophene.
The reaction of Halothane® (1) with thiols 2 giving rise to
the corresponding sulfides 3 is outlined in Scheme 1. De-
spite the apparent simplicity of the reaction, the proper se-
lection of conditions tolerating a variety of functional
groups on the thiol component turned out to be problem-
atic. In the course of our research it was found that a com-
bination of sodium dithionite and sodium bicarbonate in
N,N-dimethylformamide or dimethyl sulfoxide promotes
the alkylation of thiols under very mild conditions. The re-
action proceeds at 40–45 °C, yielding 1-chloro-2,2,2-tri-
fluoroethyl sulfides with hydroxy, amino, amide, and
ester functional groups in 32–80% yield. Notably, similar
conditions were used for a different purpose in the so-
called sulfinatodehalogenation10 reactions.
Key words: thiols, radical reactions, alkylations, fluorinated com-
pounds, sulfides
Compounds bearing fluoroalkyl groups exhibit a broad
spectrum of biological activity.1 In this context the devel-
opment of reliable methods for the preparation of the
fluoroalkyl derivatives is of great importance in drug dis-
covery and agrochemistry. Trifluoroethylation is one of
the most useful reactions leading to such biologically ac-
tive species. Monochlorinated fluoroethyl sulfides are es-
pecially useful building blocks for fluoroalkylation2 and
the preparation of fluorinated olefins3 and heterocycles.
Monochlorinated trifluoroethyl sulfides are usually pre-
pared by chlorination of the corresponding trifluoroethy-
lated precursors with chlorine,4 sulfuryl chloride,5 and
phosphorus pentachloride.6 The 1-chlorotrifluoroethyl
group can also be introduced directly by the reaction of ar-
omatic thiols with 1-bromo-1-chloro-2,2,2-trifluoroeth-
ane (Halothane®) in the presence of sodium hydride.7
However, the use of these aggressive reagents limits the
available methods for the preparation of 1-chloro-2,2,2-
trifluoroethyl sulfides to the preparation of nonfunctional-
ized compounds only, whereas for biomedical purposes
methods for preparing diversely functionalized analogues
of organofluorine compounds are highly desirable. There
are reports on a mild perfluoroalkylation of aliphatic dis-
ulfides and aliphatic thiols in the presence of sodium hy-
droxymethanesulfinate resulting in the formation of the
corresponding perfluoroalkyl sulfides in low yield.8,9
However, no sulfides with functional groups were ob-
tained by this method. In this connection the use of alter-
native reagents and the development of new synthetic
routes to trifluoroethyl sulfides are necessary. In this con-
tribution we report an easy and efficient method for the
Cl
Cl
NaHCO3, Na2S2O4
DMF or DMSO
+
RSH
F3C
SR
F3C
Br
3
1
2
Scheme 1 The synthetic route developed for the preparation of
functionalized 1-chloro-2,2,2-trifluoroethyl sulfides
Although SN2 nucleophilic substitution of the bromide
with a thiolate cannot be fully excluded in our case, most
probably the reaction proceeds by a radical mechanism
initiated by the sulfoxylate radical anion generated from
the dithionite anion. The detection of byproducts includ-
ing 1,1,1-trifluo-2-chlororoethane, sulfinate salt, and di-
sulfides and a substantial reduction of the fluoroalkylation
product yields, e.g., from 63% to about 3% for 2-(1-chlo-
ro-2,2,2-trifluoroethyl)ethanol in the presence of p-dini-
trobenzene as a radical trap are supportive of the radical
mechanism.
Although the mechanism of the transformation is not fully
proven, the method provides the desired sulfides 3 in good
to high yields with usually no need for chromatographic
purification of the products. As can be discerned from
Table 1, the major limitation of the method is its sensitiv-
ity to the steric load around the sulfur atom of the thiol,
which can lead to a decreased or no yield of the sulfide,
resulting in the formation of the corresponding disulfides.
For example, aliphatic thiols with comparable steric loads
around their sulfur atoms produce the corresponding
sulfides under identical conditions in similar yields (42–
65%) (entries 1–6). The only exception is the reaction
SYNTHESIS 2010, No. 7, pp 1159–1165
x
x
.
x
x
.2
0
1
0
Advanced online publication: 20.01.2010
DOI: 10.1055/s-0029-1219232; Art ID: T18809SS
© Georg Thieme Verlag Stuttgart · New York

1160
Y. Pustovit et al.
PAPER
with 2-furylmethanethiol yielding only 34% of the desired reduced yields (44% and 38%, respectively; entries 10
sulfide, due to the partial polymerization of the reagent and 11, respectively) compared with that of thiophenol
under the reaction conditions (entry 7). Reaction with tert- (51%) (entry 8). In the case of the heteroaromatic thiols
butyl thiol gave rise to the disulfide as the only product (entries 12–21), the steric load at the sulfur atom is rela-
(entry 22). No traces of the desired sulfide were detected tively low, and the differences in the yields of the sulfides
by 19F NMR in the latter case. Reactions of the aromatic appear to result from electronic factors. Generally, the
thiols revealed a similar trend (entries 8–11); methyl-2- heteroaromatic units that can be easily oxidized resulted
sulfanylbenzoate and 2-aminobenzenethiol resulted in in lower yields (entries 12–14, 17, 18).
Table 1 Synthesis of Functionalized 1-Chloro-2,2,2-trifluoroethyl Sulfides 3
Entry
Product
3
Solvent
Yield (%)
63
Bp (°C)/pressure (Torr)
105–108/20
Cl
1
3a
DMF
F
OH
S
S
F
F
F
F
O
2
3
3b
3c
DMSO
DMSO
63
63
80/15
F
OMe
Cl
F
F
S
OMe
98–100/15
F
Cl
O
OMe
4
3da
DMF
65
103/0.8
F
S
O
F
F
OMe
F
F
Cl
S
O
Cl
H
N
5
6
3eb
3f
DMSO
DMF
42
62
–
OEt
F
O
Cl
F
F
103–104/12
S
F
F
F
7
8
9
3g
3h
3ic
DMSO
DMF
34
51
65
98–100/25
87–89/12
97–100/12
F
S
O
Cl
F
F
S
F
Cl
S
F
F
DMF
F
Cl
O
OMe
S
F
F
10
3jd
DMF
44
(55–57)g
F
Cl
F
NH2
F
S
11
12
3k
3l
DMF
DMF
38
32
76/0.3
F
Cl
Cl
N
N
(98–100)g
F
S
F
F
Synthesis 2010, No. 7, 1159–1165 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-Chloro-2,2,2-trifluoroethyl Sulfides
1161
Table 1 Synthesis of Functionalized 1-Chloro-2,2,2-trifluoroethyl Sulfides 3 (continued)
Entry
13
Product
3
Solvent
DMF
Yield (%)
41
Bp (°C)/pressure (Torr)
88/1
Cl
Cl
N
F
3m
S
S
F
N
F
F
Me
N
N
170/18 (108–110)g
98/14
F
14
15
3n
3o
DMF
DMF
33
67
F
N
Cl
N
F
S
F
S
F
Cl
F
16
17
18
19
3p
3q
3r
3s
DMF
47
35
76
74
70–71/12
101/1 (42–44)g
123/0.7
S
S
F
F
Cl
F
F
N
DMF
F
F
S
F
O
Cl
S
N
S
DMSO
DMSO
F
F
F
F
S
103–107/23
N
F
Cl
F
F
20
3t
DMF
81
89/13
F
S
F
F
N
Cl
N
N
F
F
3ue
3vf
DMF
DMF
45
0
–
–
S
21
22
F
Cl
Cl
F
F
S
F
a Mixture of two diastereomers (51:49).
b The compound was purified by chromatography (EtOAc–hexane, 1:5).
c An alternative route to the compound is reported in ref. 7.
d The compound was purified by chromatography (EtOAc–hexane, 1:4).
e The isolated liquid product was of high purity; no distillation needed.
f The only product was di(tert-butyl) disulfide, isolated in 85% yield.
g Mp (°C).
To illustrate the synthetic utility of the obtained sulfides, membered oxathianone. On the other hand, methyl 2-[(1-
compounds 3d, 3c, 3j, and 6 were employed in a series of chloro-2,2,2-trifluoroethyl)sulfanyl]benzoate (3j) gave
Lewis acid mediated reactions. As shown in Scheme 2, rise to a benzoxathianone 5 (Scheme 3).
heating of 3d (mixture of two diastereomers) with zinc(II)
Cl
chloride gave rise to the corresponding five-membered
O
OMe
*
1,3-oxathiolanone 4. It is noteworthy that the reaction pro-
ceeds regiospecifically, because no six-membered ring
byproducts were detected. An attempt to carry out the in-
tramolecular cyclization of methyl 3-[(1-chloro-2,2,2-tri-
fluoroethyl)sulfanyl]propanoate (3c) under similar
conditions gave only a tar, instead of the expected six-
O
O
S
CF3
ZnCl2
65%
*
*
O
*
F3C
OMe
S
MeO
O
3d dr = 49:51
4 dr = 1:4
Scheme 2
Synthesis 2010, No. 7, 1159–1165 © Thieme Stuttgart · New York

1162
Y. Pustovit et al.
PAPER
under reduced pressure and the residue was distilled under reduced
pressure or chromatographed (silica gel) (see Table 1).
O
S
O
OMe
CF3
O
ZnCl2
91%
2-[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]ethanol (3a)
1H NMR (500 MHz, CDCl3): d = 2.23 (s, 1 H), 3.04 (m, 1 H), 3.09
(m, 1 H), 3.94 (m, 2 H), 5.41 (q, 3JHF = 6.5 Hz, 1 H).
S
CF3
5
Cl
13C NMR (125 MHz, CDCl3): d = 34.0, 61.5, 62.2 (q, 2JCF = 36 Hz),
3j
123.0 (q, 1JCF = 279 Hz).
Scheme 3
19F NMR (188 MHz, CDCl3): d = –72.95 (d, 3JFH = 6.5 Hz).
Anal. Calcd for C4H6ClF3OS: C, 24.69; H, 3.11; Cl, 18.22; F, 29.29;
S, 16.48. Found: C, 24.83; H, 3.19; Cl, 18.00; F, 29.07; S, 16.14.
Only a few reports on the synthesis of fluorinated oxa-
thiolanones with potential applications as enzyme
inhibitors11,12 and plant growth regulators13,14 have ap- Methyl [(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]acetate (3b)
1H NMR (500 MHz, CDCl3): d = 3.55 (d, 2JHH = 15.7 Hz, 1 H), 3.63
peared so far.
(d, 2JHH = 15.7 Hz, 1 H), 3.79 (s, 3 H), 5.50 (q, 3JHF = 6.5 Hz, 1 H).
The 2,2,2-trifluoro-1-sulfanylethyl cation intermediates
formed in the presence of zinc(II) chloride can also be ap-
plied in intermolecular electrophilic reactions, e.g., with
electron-rich aromatic compounds. Scheme 4 shows that
the zinc(II) chloride mediated reaction of 6 with thiophene
yields a mixture of two regioisomers.
13C NMR (125 MHz, CDCl3): d = 32.1, 52.9, 61.2 (q, 2JCF = 36 Hz),
122.9 (q, 1JCF = 279 Hz), 169.0.
19F NMR (188 MHz, CDCl3): d = –72.77 (d, 3JFH = 6.5 Hz).
Anal. Calcd for C5H6ClF3O2S: C, 26.98; H, 2.72; Cl, 15.93; F,
25.60; S, 14.40. Found: C, 27.23; H, 2.88; Cl, 15.77; F, 25.29; S,
14.25.
CF3
O
Methyl 3-[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]propanoate
O
*
ZnCl2
46%
F3C
S
(3c)
S
O
+
1H NMR (500 MHz, CDCl3): d = 2.73 (t, 3JHH = 7.0 Hz, 2 H), 3.12
S
S
O
(m, 2 H), 3.73 (s, 3 H), 5.28 (q, 3JHF = 6.5 Hz, 1 H).
Cl
6
7
13C NMR (125 MHz, CDCl3): d = 26.1, 34.1, 52.0, 62.1 (q,
2JCF = 36 Hz), 123.0 (q, 1JCF = 279 Hz), 171.6.
Scheme 4
19F NMR (188 MHz, CDCl3): d = –72.76 (d, 3JFH = 6.5 Hz).
To summarize, the method for the preparation of 1-chlo-
ro-2,2,2-trifluoroethyl sulfides described in this work tol-
erates a wide variety of functional groups on the thiol
fragment, and is thus far the most straightforward proce-
dure for the synthesis of these compounds, with potential
use in the parallel synthesis of combinatorial libraries of
these biologically potent compounds. The sulfides thus
obtained can also be used as versatile synthetic building
Anal. Calcd for C6H8ClF3O2S: C, 30.45; H, 3.41; Cl, 14.98; F,
24.09; S, 13.55. Found: C, 30.74; H, 3.53; Cl, 15.17; F, 23.76; S,
13.32.
Dimethyl 2-[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]succinate
(3d)
Minor Diastereomer (49%)
2
1H NMR (500 MHz, CDCl3): d = 2.81 (dd, JHH = 32.7 Hz,
3JHH = 5.2 Hz, 1 H), 3.09 (dd, 2JHH = 32.7 Hz, 3JHH = 9.5 Hz, 1 H),
blocks. The latter was demonstrated in this work by the 3.73 (s, 3 H), 4.02 (m, 1 H), 5.61 (q, 3JHF = 6.6 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 35.6, 41.4, 52.3, 53.16, 60.6 (q,
syntheses of heterocyclic compounds and thiophene de-
rivatives.
2JCF = 37 Hz), 122.6 (q, 1JCF = 279 Hz), 170.17, 170.55.
19F NMR (188 MHz, CDCl3): d = –72.85 (d, 3JFH = 6.6 Hz).
1H (500 MHz) and 13C (125 MHz) NMR spectra were recorded on
a Bruker Avance DRX 500 spectrometer; samples were prepared as
CDCl3 solns with TMS as an internal standard. 19F (188 MHz) NMR
spectra were recorded on a Varian Gemini 200 spectrometer; sam-
ples were prepared as CDCl3 solns (unless stated otherwise) with
CCl3F as an internal standard. Melting points were determined on a
Büchi melting point apparatus and are uncorrected. All chemicals
were purchased from commercial sources and were used without
further purification. Chromatographic purification of products was
performed on Merck silica gel 60 (0.040–0.063 mm).
Major Diastereomer (51%)
2
1H NMR (500 MHz, CDCl3): d = 2.84 (dd, JHH = 32.7 Hz,
2
3
JHH = 5.4 Hz, 1 H), 3.06 (dd, JHH = 32.7 Hz, JHH = 9.5 Hz, 1 H),
3.82 (s, 3 H), 4.02 (m, 1 H), 5.52 (q, 3JHF = 6.6 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 36.1, 42.4, 52.3, 53.20, 62.0 (q,
2JCF = 37 Hz), 122.8 (q, 1JCF = 279 Hz), 170.23, 170.64.
19F NMR (188 MHz, CDCl3): d = –73.65 (d, 3JFH = 6.6 Hz).
Anal. Calcd for C8H10ClF3O4S: C, 32.61; H, 3.42; Cl, 12.03; F,
19.34; S, 10.88. Found: C, 32.90; H, 3.48; Cl, 11.86; F, 19.09; S,
10.61.
1-Chloro-2,2,2-trifluoroethyl Sulfides 3; General Procedure
2-Bromo-2-chloro-1,1,1-trifluoroethane (1; 44.33 g, 0.225 mol)
was added dropwise to a stirred suspension of the appropriate thiol
2 (0.18 mol), 85% Na2S2O4 (38.69 g, 0.189 mol), and NaHCO3
(15.88 g, 0.189 mol) in the appropriate solvent (DMSO or DMF,
150 mL; see Table 1) at 35–40 °C. The reaction mixture was stirred
at 40–45 °C for 4 h, then poured into H2O (500 mL), and extracted
with Et2O (4 × 70 mL). The combined organic layers were washed
with H2O (3 × 50 mL) and dried (Na2SO4). The Et2O was removed
Ethyl N-{2-[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]ethyl}car-
bamate (3e)
1H NMR (500 MHz, CDCl3): d = 1.25 (t, 3JHH = 7.1 Hz, 3 H), 3.01
(m, 2 H), 3.46 (m, 2 H), 4.13 (q, 3JHH = 7.1 Hz, 2 H), 5.06 (br s, 1
H), 5.26 (q, 3JHF = 6.6 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.5, 31.6, 39.8, 61.2, 61.8 (q,
2JCF = 37 Hz), 123.0 (q, 1JCF = 279 Hz), 156.6.
Synthesis 2010, No. 7, 1159–1165 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-Chloro-2,2,2-trifluoroethyl Sulfides
1163
19F NMR (188 MHz, CDCl3): d = –72.73 (d, 3JFH = 6.6 Hz).
19F NMR (188 MHz, CDCl3): d = –73.25 (d, 3JFH = 6.6 Hz).
Anal. Calcd for C7H11ClF3NO2S: C, 31.65; H, 4.17; Cl, 13.34; F,
21.45; S, 12.07. Found: C, 31.77; H, 4.26; Cl, 13.06; F, 21.36; S,
12.01.
Anal. Calcd for C8H7ClF3NS: C, 39.76; H, 2.92; Cl, 14.67; F, 23.58;
S, 13.27. Found: C, 39.84; H, 2.99; Cl, 14.51; F, 23.39; S, 13.10.
2-[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]-1H-imidazole (3l)
1H NMR (500 MHz, CDCl3): d = 5.47 (q, 3JHF = 6.4 Hz, 1 H), 7.34
(s, 2 H), 11.51 (br s, 1 H).
{[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]methyl}benzene (3f)
1H NMR (500 MHz, CDCl3): d = 4.03 (s, 2 H), 4.96 (q, 3JHF = 6.4
Hz, 1 H), 7.34 (m, 5 H).
13C NMR (125 MHz, CDCl3): d = 62.9 (q, 2JCF = 36 Hz), 122.6 (q,
13C NMR (125 MHz, CDCl3): d = 35.4, 61.6 (q, JCF = 36 Hz),
1JCF = 277 Hz), 126.0, 132.3.
2
123.1 (q, 1JCF = 279 Hz), 128.1, 129.0, 129.2, 134.9.
19F NMR (188 MHz, CDCl3): d = –73.28 (d, 3JFH = 6.4 Hz).
19F NMR (188 MHz, CDCl3): d = –72.31 (d, 3JFH = 6.4 Hz).
Anal. Calcd for C5H4ClF3N2S: C, 27.72; H, 1.86; Cl, 16.37; F,
26.31; S, 14.80. Found: C, 27.98; H, 1.96; Cl, 16.43; F, 26.09; S,
14.61.
Anal. Calcd for C9H8ClF3S: C, 44.92; H, 3.35; Cl, 14.73; F, 23.68;
S, 13.32. Found: C, 45.21; H, 3.46; Cl, 14.96; F, 23.49; S, 13.01.
2-{[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]methyl}furan (3g)
1H NMR (500 MHz, CDCl3): d = 4.01 (d, 2JHH = 14.4 Hz, 1 H), 4.09
(d, 2JHH = 14.4 Hz, 1 H), 5.15 (q, 3JHF = 6.5 Hz, 1 H), 6.32 (s, 1 H),
6.35 (s, 1 H), 7.41 (s, 1 H).
2-[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]-1-methyl-1H-imida-
zole (3m)
1H NMR (500 MHz, CDCl3): d = 3.75 (s, 3 H), 5.66 (q, 3JHF = 6.4
Hz, 1 H), 7.07 (d, 3JHH = 1 Hz, 1 H), 7.21 (d, 3JHH = 1 Hz, 1 H).
2
2
13C NMR (125 MHz, CDCl3): d = 27.9, 61.7 (q, JCF = 36 Hz),
13C NMR (125 MHz, CDCl3): d = 33.8, 63.6 (q, JCF = 36 Hz),
109.3, 110.7, 123.1 (q, 1JCF = 279 Hz), 143.3, 148.4.
122.6 (q, 1JCF = 279 Hz), 124.3, 131.0, 135.0.
19F NMR (188 MHz, CDCl3): d = –72.38 (d, 3JFH = 6.5 Hz).
19F NMR (188 MHz, CDCl3): d = –73.52 (d, 3JFH = 6.4 Hz).
Anal. Calcd for C7H6ClF3OS: C, 36.45; H, 2.62; Cl, 15.37; F, 24.71;
S, 13.90. Found: C, 36.69; H, 2.73; Cl, 15.56; F, 24.67; S, 13.81.
Anal. Calcd for C6H6ClF3N2S: C, 31.25; H, 2.62; Cl, 15.37; F,
24.71; S, 13.90. Found: C, 31.37; H, 2.69; Cl, 15.19; F, 24.49; S,
13.75.
[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]benzene (3h)
1H NMR (500 MHz, CDCl3): d = 5.26 (q, 3JHF = 6.5 Hz, 1 H), 7.40
(m, 3 H), 7.62 (m, 2 H).
3-[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]-4H-1,2,4-triazole
(3n)
1H NMR (500 MHz, CDCl3): d = 6.18 (q, 3JHF = 6.6 Hz, 1 H), 8.35
13C NMR (125 MHz, benzene-d6): d = 65.5 (q, 2JCF = 35 Hz), 123.4
(s, 1 H), 9.08 (br s, 1 H).
(q, 1JCF = 279 Hz), 129.5, 129.6, 129.9, 135.0.
13C NMR (125 MHz, CDCl3): d = 61.6 (q, 2JCF = 37 Hz), 122.7 (q,
19F NMR (188 MHz, CDCl3): d = –72.58 (d, 3JFH = 6.5 Hz).
1JCF = 280 Hz), 145.4, 154.7.
Anal. Calcd for C8H6ClF3S: C, 42.39; H, 2.67; Cl, 15.64; F, 25.15;
S, 14.15. Found: C, 42.52; H, 2.72; Cl, 15.41; F, 24.91; S, 13.84.
19F NMR (188 MHz, CDCl3): d = –73.42 (d, 3JFH = 6.6 Hz).
Anal. Calcd for C4H3ClF3N3S: C, 22.08; H, 1.39; Cl, 16.29; F,
26.19; S, 14.74. Found: C, 22.30; H, 1.48; Cl, 16.48; F, 26.08; S,
14.61.
1-[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]-4-methylbenzene
(3i)
1H NMR (500 MHz, CDCl3): d = 2.38 (s, 3 H), 5.20 (q, 3JHF = 6.6
Hz, 1 H), 7.21 (d, 3JHH = 7.7 Hz, 2 H), 7.51 (d, 3JHH = 7.7 Hz, 2 H).
2-[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]-4-methyl-1,3-thiaz-
ole (3o)
2
13C NMR (125 MHz, CDCl3): d = 21.3, 65.8 (q, JCF = 35 Hz),
1H NMR (500 MHz, CDCl3): d = 2.46 (s, 3 H), 6.17 (q, 3JHF = 6.6
Hz, 1 H), 6.96 (s, 1 H).
122.9 (q, 1JCF = 279 Hz), 125.9, 130.3, 135.2, 140.6.
19F NMR (188 MHz, CDCl3): d = –73.25 (d, 3JFH = 6.6 Hz).
2
13C NMR (125 MHz, CDCl3): d = 17.1, 62.7 (q, JCF = 37 Hz),
117.0, 122.7 (q, 1JCF = 279 Hz), 154.3, 155.1.
Anal. Calcd for C9H8ClF3S: C, 44.92; H, 3.35; Cl, 14.73; F, 23.68;
S, 13.32. Found: C, 45.11; H, 3.44; Cl, 15.02; F, 23.41; S, 13.06.
19F NMR (188 MHz, CDCl3): d = –73.13 (d, 3JFH = 6.6 Hz).
Methyl 2-[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]benzoate (3j)
Anal. Calcd for C6H5ClF3NS2: C, 29.10; H, 2.03; Cl, 14.31; F,
23.01; S, 25.89. Found: C, 29.26; H, 2.11; Cl, 14.43; F, 22.73; S,
25.67.
1H NMR (500 MHz, CDCl3): d = 3.95 (s, 3 H), 5.64 (q, 3JHF = 6.3
3
Hz 1 H), 7.43 (t, JHH = 7.5 Hz, 1 H), 7.56 (t, 3JHH = 7.5 Hz, 1 H),
7.65 (d, 3JHH = 7.9 Hz, 1 H), 7.94 (d, 3JHH = 7.9 Hz, 1 H).
2-[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]thiophene (3p)
1H NMR (500 MHz): 5.10 (q, 3JHF = 6.4 Hz, 1 H), 7.08 (t, 3JHH = 4.4
Hz, 1 H), 7.38 (d, 3JHH = 3.6 Hz, 1 H), 7.56 (d, 3JHH = 5.4 Hz, 1 H).
2
13C NMR (125 MHz, CDCl3): d = 52.6, 64.1 (q, JCF = 35 Hz),
123.0 (q, 1JCF = 279 Hz), 128.3, 131.2, 131.9, 132.5, 132.6, 132.7,
166.9.
13C NMR (125 MHz, CDCl3): d = 65.4 (q, 2JCF = 35 Hz), 122.7 (q,
19F NMR (188 MHz, CDCl3): d = –72.15 (d, 3JFH = 6.3 Hz).
1JCF = 280 Hz), 125.9, 128.1, 133.3, 138.4.
Anal. Calcd for C10H8ClF3O2S: C, 42.19; H, 2.83; Cl, 12.45; F,
20.02; S, 11.26. Found: C, 42.44; H, 2.88; Cl, 12.60; F, 19.79; S,
11.02.
19F NMR (188 MHz, CDCl3): d = –72.40 (d, 3JFH = 6.4 Hz).
Anal. Calcd for C6H4ClF3S2: C, 30.97; H, 1.73; Cl, 15.24; F, 24.50;
S, 27.56. Found: C, 31.23; H, 1.76; Cl, 15.01; F, 24.12; S, 27. 34.
2-[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]aniline (3k)
1H NMR (500 MHz, CDCl3): d = 4.44 (br s, 2 H), 5.21 (q, 3JHF = 6.6
2-[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]-1,3-benzoxazole
(3q)
3
Hz, 1 H), 6.76 (m, 2 H), 7.25 (d, JHH = 7.8 Hz, 1 H), 7.47 (d,
3JHH = 7.8 Hz, 1 H).
1H NMR (500 MHz, CDCl3): d = 6.51 (q, 3JHF = 6.6 Hz, 1 H), 7.33
(m, 2 H), 7.49 (d, 3JHH = 7.5 Hz, 1 H), 7.66 (d, 3JHH = 7.5 Hz, 1 H).
2
13C NMR (125 MHz, CDCl3): d = 64.1 (q, JCF = 35 Hz), 111.9,
115.6, 118.9, 123.0 (q, 1JCF = 280Hz), 132.4, 137.8, 149.1.
Synthesis 2010, No. 7, 1159–1165 © Thieme Stuttgart · New York

1164
Y. Pustovit et al.
PAPER
2
13C NMR (125 MHz, CDCl3): d = 60.8 (q, JCF = 38 Hz), 110.4,
Minor Diastereomer (20%)
119.2, 122.4 (q, 1JCF = 279 Hz), 125.0, 125.1, 141.1, 152.4, 159.0.
19F NMR (188 MHz, CDCl3): d = –73.56 (d, 3JFH = 6.6 Hz).
1H NMR (500 MHz, CDCl3): d = 2.92 (dd, JHH = 17.6 Hz,
3JHH = 8.3 Hz, 1 H), 3.18 (dd, 2JHH = 17.6 Hz, 3JHH = 3.7 Hz, 1 H),
3.76 (s, 3 H), 4.35 (dd, 3JHH = 8.3 Hz, 3JHH = 3.7 Hz, 1 H), 5.61 (q,
3JHF = 5.2 Hz, 1 H).
2
Anal. Calcd for C9H5ClF3NOS: C, 40.39; H, 1.88; Cl, 13.25; F,
21.29; S, 11.98. Found: C, 40.52; H, 1.92; Cl, 13.21; F, 21.04; S,
11.81.
13C NMR (125 MHz, CDCl3): d = 37.2, 39.9, 52.5, 74.6 (q,
2JCF = 37 Hz), 122.6 (q, 1JCF = 280 Hz), 170.0, 172.3.
2-[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]-1,3-benzothiazole
(3r)
19F NMR (188 MHz, CDCl3): d = –79.61 (d, 3JFH = 5.2 Hz).
1H NMR (500 MHz, CDCl3): d = 6.74 (q, 3JHF = 6.9 Hz, 1 H), 7.37
Major Diastereomer (80%)
3
3
2
(t, JHH = 7.6 Hz, 1 H), 7.48 (t, JHH = 7.6 Hz, 1 H), 7.79 (d,
1H NMR (500 MHz, CDCl3): d = 2.87 (dd, JHH = 17.6 Hz,
3JHH = 8.2 Hz, 1 H), 7.95 (d, 3JHH = 8.2 Hz, 1 H).
3JHH = 11 Hz, 1 H), 3.26 (dd, 2JHH = 17.6 Hz, JHH = 3.2 Hz, 1 H),
3
3.76 (s, 3 H), 4.39 (dd, 3JHH = 11 Hz, 3JHH = 3.2 Hz, 1 H), 5.65 (q,
2
13C NMR (125 MHz, CDCl3): d = 60.8 (q, JCF = 37 Hz), 121.4,
3JHF = 5.4 Hz, 1 H).
122.5, 122.8 (q, 1JCF = 279 Hz), 125.5, 126.7, 135.8, 152.3, 159.5.
19F NMR (188 MHz, CDCl3): d = –73.09 (d, 3JFH = 6.9 Hz).
13C NMR (125 MHz, CDCl3): d = 38.9, 40.7, 52.6, 74.7 (q,
2JCF = 37 Hz), 122.6 (q, 1JCF = 280 Hz), 170.4, 172.1.
19F NMR (188 MHz, CDCl3): d = –79.90 (d, 3JFH = 5.4 Hz).
Anal. Calcd for C9H5ClF3NS2: C, 38.10; H, 1.78; Cl, 12.50; F,
20.09; S, 22.60. Found: C, 38.35; H, 1.98; Cl, 12.29; F, 19.81; S,
22.52.
Anal. Calcd for C7H7F3O4S: C, 34.43; H, 2.89; F, 23.34; S, 13.13.
Found: C, 34.06; H, 2.98; F, 22.96; S, 12.88.
2-[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]pyridine (3s)
1H NMR (500 MHz, CDCl3): d = 6.90 (q, 3JHF = 7.5 Hz, 1H), 7.15
2-(Trifluoromethyl)-4H-3,1-benzoxathian-4-one (5)
A mixture of anhyd ZnCl2 (1.9 g, 14 mmol) and 3j (2 g, 7 mmol)
was heated for 0.5 h at 110–115 °C. Upon cooling to r.t., the reac-
tion mixture was poured into H2O and extracted with CH2Cl2
(2 × 50 mL). The combined organic layers were washed with H2O
(3 × 25 mL) and dried (MgSO4). The solvent was removed under re-
duced pressure; this gave 5.
3
3
(t, JHH = 4.1 Hz, 1 H), 7.23 (d, JHH = 7.8 Hz, 1 H), 7.62 (t,
3JHH = 7.8 Hz, 1 H), 8.52 (d, 3JHH = 4.1 Hz, 1 H).
2
13C NMR (125 MHz, CDCl3): d = 59.3 (q, JCF = 37 Hz), 121.5,
122.5, 123.3 (q, 1JCF = 278 Hz), 137.2, 149.8, 152.3.
19F NMR (188 MHz, CDCl3): d = –72.71 (d, 3JFH = 7.5 Hz).
Yield: 1.5 g (91%); mp 60–62 °C.
2-[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]-5-(trifluorometh-
yl)pyridine (3t)
1H NMR (500 MHz, CDCl3): d = 5.88 (q, 3JHF = 5.2 Hz, 1 H), 7.39
3
3
1H NMR (500 MHz, CDCl3): d = 6.88 (q, 3JHF = 7.1 Hz, 1 H), 7.34
(t, JHH = 7.4 Hz, 2 H), 7.57 (t, JHH = 7.4 Hz, 1 H), 8.18 (d,
(d, 3JHH = 8.4 Hz, 1 H), 7.83 (d, 3JHH = 8.4 Hz, 1 H), 8.77 (s, 1 H).
3JHH = 8.0 Hz, 1 H).
2
13C NMR (125 MHz, CDCl3): d = 58.4 (q, JCF = 37 Hz), 122.0,
13C NMR (125 MHz, CDCl3): d = 77.7 (q, 2JCF = 37 Hz), 121.5 (q,
1JCF = 281 Hz), 123.3, 127.7, 127.9, 132.8, 134.1, 134.6, 160.5.
19F NMR (188 MHz, CDCl3): d = –75.76 (d, 3JFH = 5.2 Hz).
1
1
123.1 (q, JCF = 278 Hz), 123.3 (q, JCF = 272 Hz), 124.6 (q,
2JCF = 34 Hz), 134.1, 146.6, 157.2.
19F NMR (188 MHz, CDCl3): d = –62.87 (s, 3 F), –72.73 (d,
3JFH = 7.1 Hz, 3 F).
Anal. Calcd for C9H5F3O2S: C, 46.16; H, 2.15; F, 24.34; S, 13.69.
Found: C, 46.37; H, 2.33; F, 24.02; S, 13.50.
Anal. Calcd for C8H4ClF6NS: C, 32.50; H, 1.36; Cl, 11.99; F, 38.56;
S, 10.85. Found: C, 32.69; H, 1.44; Cl, 11.79; F, 38.42; S, 10.71.
Ethyl {[2,2,2-Trifluoro-1-(2-thienyl)ethyl]sulfanyl}acetate and
Ethyl {[2,2,2-Trifluoro-1-(3-thienyl)ethyl]sulfanyl}acetate (7)
Anhyd ZnCl2 (0.29 g, 2.1 mmol) was added to a soln of 614 (0.24 g,
1.0 mmol) and thiophene (0.15 g, 1.8 mmol) in MeNO2 (2 mL), and
the mixture was heated at reflux for 20 min. Upon cooling to r.t., the
reaction mixture was treated with aq K2CO3 and extracted with
CHCl3 (2 × 30 mL). The combined organic layers were dried
(MgSO4). After evaporation of the solvent under vacuum, the crude
product was purified by thick-layer chromatography (silica gel,
EtOAc–hexane, 1:9); this gave 7.
2-[(1-Chloro-2,2,2-trifluoroethyl)sulfanyl]pyrimidine (3u)
1H NMR (500 MHz, CDCl3): d = 6.70 (q, 3JHF = 7.2 Hz, 1 H), 7.15
(t, 3JHH = 4.9 Hz, 1 H), 8.63 (d, 3JHH = 4.9 Hz, 2 H).
2
13C NMR (125 MHz, CDCl3): d = 59.7 (q, JCF = 37 Hz), 118.2,
123.1 (q, 1JCF = 278 Hz), 158.0, 167.0.
19F NMR (188 MHz, CDCl3): d = –72.86 (d, 3JFH = 7.2 Hz).
Anal. Calcd for C6H4ClF3N2S: C, 31.52; H, 1.76; Cl, 15.51; F,
24.93; S, 14.02. Found: C, 31.64; H, 1.89; Cl, 15.70; F, 24.75; S,
13.90.
Yield: 0.13 g (46%); Rf = 0.5 (EtOAc–hexane, 1:9).
Ethyl {[2,2,2-Trifluoro-1-(2-thienyl)ethyl]sulfanyl}acetate
Major isomer (70%).
Methyl [5-Oxo-2-(trifluoromethyl)-1,3-oxathiolan-4-yl]acetate
(4)
1H NMR (500 MHz, CDCl3): d = 1.29 (t, 3JHH = 7.2 Hz, 3 H), 3.19
A mixture of anhyd ZnCl2 (0.91 g, 6.7 mmol) and 3d (0.99 g, 3.4
mmol) was heated for 2 h at 100 °C. After cooling to r.t., the reac-
tion mixture was poured into H2O and extracted with CH2Cl2
(2 × 40 mL). The combined organic layers were washed with H2O
(3 × 25 mL) and dried (MgSO4). After evaporation of the solvent
under vacuum, the crude product was purified by thick-layer chro-
matography (silica gel, EtOAc–hexane, 1:2); this gave 4.
2
2
(d, JHH = 15.9 Hz, 1 H), 3.45 (d, JHH = 15.9 Hz, 1 H), 4.2 (q,
3JHH = 7.2 Hz, 2 H), 5.04 (q, 3JHF = 8.1 Hz, 1 H), 7.00 (m, 1 H), 7.15
(m, 1 H), 7.35 (d, 3JHH = 5.1 Hz, 1 H).
19F NMR (188 MHz, CDCl3): d = –69.34 (d, 3JFH = 8.1 Hz).
Ethyl {[2,2,2-Trifluoro-1-(3-thienyl)ethyl]sulfanyl}acetate
Minor isomer (30%).
Yield: 0.54 g (65%); Rf = 0.7 (EtOAc–hexane, 1:2).
1H NMR (500 MHz, CDCl3): d = 1.29 (t, 3JHH = 7.2 Hz, 3 H), 3.14
2
2
(d, JHH = 15.6 Hz, 1 H), 3.42 (d, JHH = 15.6 Hz, 1 H), 4.2 (q,
Synthesis 2010, No. 7, 1159–1165 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-Chloro-2,2,2-trifluoroethyl Sulfides
1165
3JHH = 7.2 Hz, 2 H), 4.84 (q, 3JHF = 7.8 Hz, 1 H), 7.00 (m, 1 H), 7.15
(m, 1 H), 7.31 (d, 3JHH = 5.4 Hz, 1 H).
(3) Piettre, S.; De Cock, Ch.; Merenyi, R.; Viehe, H. G.
Tetrahedron 1987, 43, 4309.
(4) Fritz, H.; Sundermeyer, W. Chem. Ber. 1989, 122, 1757.
(5) Uneyama, K.; Momota, M. Tetrahedron Lett. 1989, 30,
2265.
(6) Tournier, L.; Zard, S. Z. Tetrahedron Lett. 2005, 46, 455.
(7) Kato, M.; Maeda, K.; Sato, K.; Omote, M.; Ando, A.;
Kumadaki, I. Chem. Pharm. Bull. 2000, 48, 683.
(8) Wakselman, C.; Tordeux, M.; Clavel, J. L.; Langlois, B.
J. Chem. Soc., Chem. Commun. 1991, 993.
19F NMR (188 MHz, CDCl3): d = –68.91 (d, 3JFH = 7.8 Hz).
Anal. Calcd for C10H11F3O2S2: C, 42.24; H, 3.90; F, 20.05; S, 22.56.
Found: C, 42.45; H, 3.95; F, 19.71; S, 22.29.
References
(1) (a) Biomedical Frontiers of Fluorine Chemistry, ACS
Symposium Series 639; Ojima, I.; McCarthy, J. R.; Welch,
J. T., Eds.; American Chemical Society: Washington DC,
1996. (b) Bégué, J.-P.; Bonnet-Delpon, D. Bioorganic and
Medicinal Chemistry of Fluorine; Wiley: Hoboken, 2008.
(c) Theodorides, G. Fluorine-Containing Agrochemicals, In
Advances in Fluorine Science, Vol. 2; Elsevier: Amsterdam,
2006, 121–175.
(9) Anselmi, E.; Blazejewski, J.-C.; Tordeux, M.; Wakselman,
C. J. Fluorine Chem. 2000, 105, 41.
(10) Huang, W.-Y. J. Fluorine Chem. 1992, 58, 1.
(11) Gouault, S.; Pommelet, L.-C.; Lequeux, T. Synlett 2002,
996.
(12) Seiichiro, H.; Satoru, N.; Akinori, K.; Tomoko, M.;
Kunitaka, M.; Toshio, F. J. Org. Chem. 1999, 64, 133.
(13) Krumkalns, E. V. US Patent Application 4282030, 1981;
Chem. Abstr. 1981, 95, 163901.
(2) Uneyama, K.; Momota, M.; Hayashida, K.; Itoh, T. J. Org.
Chem. 1990, 55, 5364.
(14) Pustovit, Yu.; Alekseenko, A.; Subota, A.; Tolmachev, A.
Khim. Geterotsikl. Soedin. 2006, 42, 278.
Synthesis 2010, No. 7, 1159–1165 © Thieme Stuttgart · New York