Facile Synthesis of Thiolacetates from Trichloromethyl Compounds

Article abstract of DOI:10.1055/s-2003-42463

A new method for the conversion of trichloromethyl compounds into the corresponding thiolacetates by treatment with sodium thiolacetate in the presence of thiolacetic acid is described. This transformation proceeds at room temperature in high yield when a strong electron-withdrawing substituent is attached to the trichloromethyl group.

Full text of DOI:10.1055/s-2003-42463

SHORT PAPER
2765
Facile Synthesis of Thiolacetates from Trichloromethyl Compounds
Synthesis of
T
hiolaceta
o
tes from
T
ri
i
c
hlorom
s
ethyl Co
é
mpounds s Romero-Ortega,*a Horacio Reyes,a Adrián Covarruvias-Zuñiga,b Raymundo Cruz,b
José Gustavo Avila-Zarragac
a
Departamento de Química Orgánica, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón/Paseo Tollocan,
Toluca Estado de México, México
Fax +52(722)2173890; E-mail: romero.ortega@usa.net
b
c
Instituto de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, México D.F., México
Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, México, D.F., México
Received 24 July 2003; revised 20 September 2003
etate derivatives 2, usually in excellent yields (Scheme 1,
Table 1).
Abstract: A new method for the conversion of trichloromethyl
compounds into the corresponding thiolacetates by treatment with
sodium thiolacetate in the presence of thiolacetic acid is described.
This transformation proceeds at room temperature in high yield
when a strong electron-withdrawing substituent is attached to the
trichloromethyl group.
Key words: trichloromethyl compounds, thiolacetic acid, sodium
thiolacetate, thiolacetate derivatives, nucleophilic substitution
Scheme 1
Several aspects of the data given in Table 1 deserve com-
ment. Firstly, the reaction is successful in those cases
where the substituent attached to the trichloromethyl
group is a carbonyl group (entries a–d) or an electron-
withdrawing heterocyclic system (e.g., entries e–h), but
fails when such groups are absent (entries j,k) even under
more vigorous conditions. Secondly, benzyl trichloroace-
tate (1i) is not converted into the S-acetyl derivative of
mercaptoactic acid benzyl ester, instead it was rapidly
transformed into benzyl thiolacetate 2i in high yield, by
SN2 displacement of trichloroacetate.9 Lastly, the reac-
tions are highly chemoselective as illustrated by the result
with the 1-(2-chloroethyl)-2-trichloroacetylpyrrole (1c)
(Entry c) to form the thiolacetate 2c as the exclusive prod-
uct, with no side chain chloride displacement being ob-
served.
Thiols are very important building blocks in organic
chemistry. In principle, many thiols can be prepared by
simple processes,1 but the subsequent transformation of
the initially formed thiols into sulfides or disulfides often
severely limits the utility of these synthetic processes.2
Thiolacetates are frequently used as versatile and relative-
ly stable intermediates for the preparation of thiols by
mild saponification or reduction.3 Several methods for the
conversion of alcohols into thiolacetates have been report-
ed. However, these methods generally require initial acti-
vation of the hydroxyl function by conversion into a
halide or a sulfonic acid ester and then treatment with thi-
olacetic acid under basic conditions.4 Thiolacetates can be
prepared from alcohols under Lewis acid catalysis5 and
stereoselectively using a modified Mitsunobu reaction.6
In a recent study, we reported that trichloromethyl com-
pounds bearing a carbanion stabilizing substituent are ef-
ficiently converted into phenylthiomethyl derivatives
using a thiophenol/sodium thiophenolate mixture at room
temperature.7 This reaction was demonstrated to be an
ionic process proceeding via an intermediate 1,1-bis(phe-
nylthio)methyl compound8 which was the major product
when the reaction was performed at –5 °C.
In summary, we have demonstrated that trichloromethyl
compounds bearing a substituent which is highly carban-
ion stabilizing, are efficiently converted into thiolacetate
derivatives with an excess of an equimolar thiolacetic
acid/sodium thiolacetate mixture at room temperature.
This process is expected to be particularly useful in those
instances where the halomethyl compounds or the corre-
sponding sulfonic acid esters, the usual precursors of thi-
olacetates derivatives are not readily available.
In connection with our studies on the reactivity of the
trichloromethyl group and the synthetic importance of
sulfur compounds in organic synthesis, we now wish to
report that the reaction of a variety of trichloromethyl
compounds 1 (many of which are readily available) with
1:1 thiolacetic acid/sodium thiolacetate mixture (10
equiv) in DMF at room temperature, produces the thiolac-
Thiolacetic acid, NaH, and the trichloromethyl compounds 1b and
1j were purchased from Aldrich and used as received. Compounds
1a,10 1d,11 1e,8 1f,8 and 1h8 were synthesized by literature methods.
Compound 1g was prepared by a new method developed by us,
which will be published elsewhere. Melting points are uncorrected
and were measured on an a Mel-Temp II apparatus. 1H NMR spec-
tra were recorded on a Varian Gemini 200 (200 MHz) spectrometer
using CDCl3 as solvent and are reported in ( ) ppm from internal
tetramethylsilane. 13C NMR spectra were also recorded in CDCl3
solution. The IR spectra were measured on a Nicolet FT-SX spec-
trophotometer in CHCl3 solution. Mass spectra were measured on a
SYNTHESIS 2003, No. 18, pp 2765–2767
x
x.
x
x
.
2
0
0
3
Advanced online publication: 04.11.2003
DOI: 10.1055/s-2003-42463; Art ID: M03303SS
© Georg Thieme Verlag Stuttgart · New York

2766
M. Romero-Ortega et al.
SHORT PAPER
Table 1 Reaction of Trichloromethyl Compounds 1 with Thiolacetic Acid/Sodium Thiolacetate
Entry
Substrate 1
Time
Product 2
Yielda
(%)
Ratio of Hexane–
EtOAc for Column
Chromatography
O
O
S
S
CH3
CH3
a
1.0 h
1.5 h
88
92
95:5
CCl3
O
O
CCl3
b
90:10
N
H
N
H
O
O
O
CCl3
N
S
CH3
c
d
e
2.0 h
2.0 h
2.0 h
92
90
89
90:10
60:40
80:20
N
O
O
Cl
Cl
O
O
S
CH3
CCl3
O
N
H
N
H
O
O
EtO
N
EtO
N
S
CH3
N
N
CCl3
O
OMe
N
O
OMe
N
O
O
O
f
2.5 h
92
90:10
MeO
MeO
S
CH3
N
N
CCl3
O
Ph
O
Ph
O
g
h
i
1.0 h
89
95
96
80:20
85:15
99:1
S
CH3
N
H
CCl3
N
H
O
N
N
O
N
N
O
1.5 h
H3C
H3C
S
CH3
N
N
O
CCl3
CCl3
N
N
S
CH3
CH3
O
15 min
CH3
CCl3
b
j
–
–
–
–
–
–
–
b
k
H–CCl3
–
a Yields refer to pure isolated products, properly characterized by spectral data.
b No reaction.
Jeol JMS-Ax 505 HA mass spectrometer. Analytical TLC plates
and silica gel 60 (230–400 mesh) were purchased from Merck. All
solvents were purified and dried prior to use.12
romethyl compound 1) under N2. After ca. 10 min, the appropriate
trichloromethyl derivative 1 (1 equiv) was added and the mixture
was stirred at r.t. for the time given in Table 1. The mixture was then
quenched with aq sat. NH4Cl solution, and extracted with EtOAc (3
× 50 mL). The organic phase was washed with H2O, dried (Na2SO4)
and the solvent was evaporated in vacuo. The product was isolated
from the residue by column chromatography on silica gel using hex-
ane–EtOAc mixtures as eluent (Table 1). The physical properties
and spectral data of thiolacetates 2 are given in Table 2.
Thiolacetates 2 from Trichloromethyl Compounds 1; General
Procedure
Thiolacetic acid (20 equiv) was added to a suspension of NaH (10
equiv of a 60% suspension in mineral oil, washed free of the carrier
with anhyd hexane) in anhyd DMF (1–3 mL/mmol of the trichlo-
Synthesis 2003, No. 18, 2765–2767 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of Thiolacetates from Trichloromethyl Compounds
2767
Table 2 Physical Properties and Spectral Data of Thiolacetate Derivatives 2
Product
2a
Mp (°C)
(Solvent)
IR (CHCl3)
(cm–1)
1H NMR (CDCl3/TMS)
, J (Hz)
MS (70 eV)
m/z (%)
b
43–44
(hexane–CH2Cl2)
2915, 1690, 1597,
1282, 1133
2.40 (s, 3 H), 4.40 (s, 2 H), 7.45–7.50 (m, 2 H), 7.57–7.62
(m, 1 H), 7.97–8.00 (m, 2 H)a
-
2b
64–65
(hexane–CH2Cl2)
3456, 1697, 1647, 1545,
1427, 1402, 1328, 1133
2.39 (s, 3 H), 4.19 (s, 2 H), 6.28–6.33 (m, 1 H), 7.04–7.09 183 (18, M+), 94
(m, 2 H), 9.55 (br, 2 H) (100)
2c
oil
1695, 1648, 1527, 1467,
1410, 1338, 1133
2.40 (s, 3 H), 3.79 (t, J = 5.8, 2 H), 4.23 (s, 2 H), 4.57 (t, 245 (15, M+), 156
J = 5.8, 2 H), 6.20 (dd, J = 4.1, 2.6, 1 H), 7.00–7.02 (m, (100)
1 H), 7.18 (dd, J = 4.1, 1.6, 1 H)
2d
2e
173–174
(hexane–CH2Cl2)
3255, 1682, 1638, 1509,
1425, 1130
2.39 (s, 3 H), 4.27 (s, 2 H), 7.19–7.28 (m, 2 H), 7.41–7.48 233 (25, M+), 144
(m, 1 H), 8.06 (d, J = 3.3, 1 H), 8.26–8.32 (m, 1 H), 11.33 (100)
(br, 1 H)c
oil
oil
1726, 1697, 1588, 1556,
1436, 1390, 1369, 1296,
1131
1.40 (t, J = 7.2, 3 H), 2.39 (s, 3 H), 4.42 (q, J = 7.2, 2 H), 240 (5, M+), 198
4.46 (s, 2 H), 9.20 (s, 2 H)
(100)
2f
2g
2h
2i
1737, 1698, 1571, 1550,
1427, 1303, 1275, 1133
2.40 (s, 3 H), 3.95 (s, 3 H), 4.01 (s, 3 H), 4.48 (s, 2 H),
9.22 (s, 1 H)
284 (10, M+), 242
(100)
198–199 (hexane– 3351, 1675, 1323, 1127
EtOAc)
2.43 (s, 3 H), 4.06 (s, 2 H), 7.32–7.48 (m, 3 H), 7.63–7.68 260 (35, M+), 218
(m, 2 H), 11.05 (br, 1 H)
(100)
33–34
(hexane–CH2Cl2)
1694, 1589, 1508, 1409,
1132
2.39 (s, 3 H), 3.18 (s, 3 H), 3.19 (s, 3 H), 4.10 (s, 2 H),
8.48 (s, 1 H)
212 (65, M+), 170
(100)
oil
1691, 1496, 1452, 1353,
1133
2.35 (s, 3 H), 4.12 (s, 2 H), 7.29 (m, 5 H)d
166 (35, M+), 91
(100)
a 13C NMR (CDCl3/TMS): = 30.15, 36.55, 128.45, 128.73, 133.65, 135.59, 193.16, 194.06.
b HRMS: m/z calcd for C10H10O2S: 194.0402; found: 194.0398.
c 13C NMR (CDCl3/TMs): = 29.83, 36.15, 111.66, 121.54, 122.02, 122.97, 125.32, 132.98, 136.51, 188.00, 194.38.
d 13C NMR (CDCl3/TMS): = 30.26, 33.37, 127.20, 128.56, 128.73, 137.52, 195.04.
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Acknowledgments
Financial support for this research was provided by the ‘Consejo
Nacional de Ciencia y Tecnología’ CONACyT (Clave 34084-E)
and is gratefully acknowledged. The authors wish to thank Profes-
sor Joseph M. Muchowski from the UNAM for helpful discussions
and his interest in our work.
(7) Romero-Ortega, M.; Fuentes, A.; González, C.; Morales, D.;
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Synthesis 2003, No. 18, 2765–2767 © Thieme Stuttgart · New York