Synthesis of phenylthiomethyl compounds from trichloromethyl derivatives

Article abstract of DOI:10.1055/s-1999-3376

A new method for the conversion of trichloromethyl compounds into the corresponding phenylthiomethyl derivatives by reaction with sodium thiophenolate in the presence of thiophenol is described. This transformation proceeds at room temperature in high yield and has been applied to a variety of trichloromethyl compounds.

Full text of DOI:10.1055/s-1999-3376

SHORT PAPER
225
Synthesis of Phenylthiomethyl Compounds from Trichloromethyl Derivatives
MoisŽs Romero-Ortega,*a AydeŽ Fuentes,a Carlos Gonz‡lez,a David Morales,a Raymundo Cruzb
a
Departamento de Qu’mica Org‡nica, Facultad de Qu’mica, Universidad Aut—noma del Estado de MŽxico,
Paseo Col—n/Paseo Tollocan s/n Toluca, Estado de MŽxico, C.P. 50000, MŽxico
b Instituto de Qu’mica, Universidad Nacional Aut—noma de MŽxico, Ciudad Universitaria, MŽxico, D.F.
Fax +1(72)173890; E-mail: cgr@coatepec.uaemex.mx
Received 19 March 1998; revised 27 July 1998
lective as illustrated by the results with ethyl trichloro-
Abstract: A new method for the conversion of trichloromethyl
acetate (Entry a), trichloroacetonitrile (Entry b) and 1-(2-
compounds into the corresponding phenylthiomethyl derivatives by
chloroethyl)-2-trichloroacetylpyrrole (Entry d). In each
reaction with sodium thiophenolate in the presence of thiophenol is
case, the phenylthiomethyl derivative was the major or
exclusive product, with no significant ester cleavage,
phenylthioimidate formation, or side chain chloride dis-
placement, respectively, being observed.
Except for our own recently disclosed study,1 the process
described herein has not previously been reported. The re-
action of trichloromethyl compounds with thiolates has
been described,6Ð8 but the products were thio ortho esters
or 1,1-bis(alkylthio)methyl compounds, the latter being
analogous to our result with 2-trichloromethylimidazole
(1e).
described. This transformation proceeds at room temperature in
high yield and has been applied to a variety of trichloromethyl com-
pounds.
Key words: trichloromethyl compounds, thiophenol, sodium
thiophenolate, phenylthiomethyl derivatives, nucleophilic substitu-
tion
We recently reported1 that 2-trichloromethylpyrimidines
substituted with one or two alkoxycarbonyl groups were
rapidly and quantitatively converted into the correspond-
ing 2-phenylthiomethylpyrimidines by sodium thio-
phenolate in the presence of thiophenol at room
temperature.2 This reaction was demonstrated to be an
ionic process proceeding via an intermediate 1,1-bis(phe-
nyl-thio)methyl compound which was the major product
in the absence of thiophenol. The synthetic importance of
phenylthiomethyl compounds and the derived sulfoxides
and sulfones,3Ð5 especially in carbonÐcarbon bond form-
ing reactions, prompted us to examine the possibility of
effecting this conversion with other trichloromethyl com-
pounds, many of which are readily available.
In conclusion, trichloromethyl compounds bearing a sub-
stituent which is highly carbanion stabilizing, are effi-
ciently converted into phenylthiomethyl derivatives with
3 equivalents of an equimolar thiophenol/sodium thio-
phenolate mixture at room temperature. This process is
expected to be particularly useful in those instances where
the halomethyl compounds, the usual precursors of
phenylthiomethyl compounds, are not readily available,
or unavailable by other routes.9Ð10
We have now found that the reaction of a variety of
trichloromethyl compounds 1 with a 1:1 sodium thiophe-
nolate/thiophenol mixture (3 equiv) produced the expect-
ed phenylthiomethyl derivatives 2, usually in excellent
yields (Scheme, Table 1).
The trichloromethyl compounds 1aÐc and 1jÐl are commercially
available, whereas 1eÐg and 1i were easily synthesized in good
yields by literature methods.11,12 Compound 1h was prepared by a
new method developed by us, which will be published elsewhere.
Melting points are uncorrected and were measured on a mel-temp II
apparatus. 1H NMR spectra were recorded on a Varian Gemini 200
(200 MHz) spectrometer using CDCl3 as solvent and are reported in
d from internal TMS. IR spectra were recorded on a Nicolet FT-SX
spectrophotometer and mass spectra on a Jeol JMS-Ax 505 HA
mass spectrometer. Analytical TLC plates and silica gel 60 (230Ð
400 mesh) were purchased from Merck. THF was distilled from so-
dium benzophenone ketyl prior to use. The reactions were conduct-
ed under N2 atmosphere.
Scheme
Several aspects of the data given in the Table deserve
comment. Firstly, the reaction is successful in those cases
where the substituent attached to the trichloromethyl Phenylthiomethyl 2 Derivatives from Trichloromethyl Com-
pounds 1; General Procedure
Thiophenol (6.6 equiv) was added to a suspension of NaH (3.3
equiv, washed free of mineral oil with anhyd hexane from a 50%
suspension of NaH in mineral oil) in anhyd THF (1Ð3 mL/mmol of
group is strongly carbanion stabilizing (e.g., Entries aÐd,
fÐi), but fails when such a group is absent (Entry k) or
when it is only moderately carbanion stabilizing (Entries
j, l) even under more vigorous conditions. This is expect-
the trichloromethyl compound 1) under a nitrogen atmosphere. Af-
ed provided that the reaction proceeds via at least two carb-
anionic intermediates.1 In this regard it is informative to
note that the reaction of 2-trichloromethylimidazole (1e)
is very slow and stops at the 1,1-bis(phenylthio)methyl
stage (Entry e). Lastly, the reactions are highly chemose-
ter 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
the Table. The mixture was then quenched with sat. aq NH4Cl solu-
tion and extracted with EtOAc (3 × 50 mL). The organic phase was
washed with H2O, dried (Na2SO4) and the solvent was evaporated
Synthesis 1999, No. 2, 225Ð227 ISSN 0039-7881 © Thieme Stuttgart á New York

226
M. Romero-Ortega et al.
SHORT PAPER
Table 1 Reduction of Trichloromethyl Compounds with Sodium Thiophenolate/Thiophenol
Entry
Substrate (1)
Product (2)
Reaction
Time (min)
Ratio of hexane/
EtOAc for column
chromatography
Yield
(%)
a
CCl3CO2Et
CCl3CN
PhSCH2CO2Et
PhSCH2CN
10
5
80:20
75:25
98
75
b
c
d
e
f
5
80:20
80:20
80:20
90:10
90:10
95:5
~100
~100
40
5
720
5
71
g
h
10
5
98
80
i
60
80:20
91
a
j
PhCCl3
CHCl3
–
a
k
l
–
a
CF3CCl3
–
a No reaction.
Table 2 Physical Properties and Spectral Data of Reduction Derivatives 2 of Trichloromethyl Compounds 1
Prod-
ucta
mp
(°C)
IR (CHCl3)
1H NMR (CDCl3/TMS)
d, J (Hz)
MS (70 eV)
m/z (%)
n (cm–1)
2a
2b
2c
oil
1736, 1286, 1030
1.22 (t, J = 7.2, 3 H), 3.61 (s, 2 H), 4.17 (q, J = 7.2, 9 H), 7.21– 196 (M+, 90), 123 (100)
7.45 (m, 5 H)
oil
2245, 1581, 1479, 3.57 (s, 2 H), 7.31–7.40 (m, 3 H), 7.52–7.59 (m, 2 H)
1438
149 (M+, 48), 109 (100)
79–80
3222, 1646, 1390, 4.08 (s, 2 H), 6.25–6.30 (m, 1 H), 6.88–6.93 (m, 1 H), 7.01– 217 (M+, 58), 94 (100)
1102
7.06 (m, 1 H), 7.19–7.32 (m, 3 H), 7.38–7.43 (m, 2 H), 9.55
(br, 1 H)
2d
oil
1642, 1467, 1409
3432, 1445, 1104
3.75 (t, J = 5.6, 2 H), 4.12 (s, 2 H), 4.57 (t, J = 5.6, 2 H), 6.16– 279 (M+), (40), 281 (M+ + 2)
6.19 (m, 1 H), 6.97–7.04 (m, 2 H), 7.20–7.43 (m, 5 H)
(15), 156 (100), 158 (36)
2e
2f
oil
5.73 (s, 1 H), 6.95 (s, 2 H), 7.24–7.36 (m, 10H), 9.12 (br, 1 H) 298 (M+, 20), 297 (100)
138–139
3399, 3054, 1434, 4.40 (s, 2 H), 7.15–7.33 (m, 9 H), 7.76–7.59 (br, 3 H)
1274
240 (M+, 65), 131 (100)
Synthesis 1999, No. 2, 225–227 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of Phenylthiomethyl Compounds from Trichloromethyl Derivatives
227
Table 2 (continued)
Prod-
ucta
mp
(°C)
IR (CHCl3)
1H NMR (CDCl3/TMS)
d, J (Hz)
MS (70 eV)
m/z (%)
n (cm–1)
2g
2h
2i
58–59
1728, 1586, 1555, 1.41 (t, J = 7, 3 H), 4.42 (q, J = 7, 2 H), 4.42 (s, 2 H), 7.19– 274 (M+, 100)
1295 7.33 (m, 3 H), 7.37–7.41 (m, 2 H), 9.20 (s, 2 H)
203
oil
3419, 3058, 1643, 4.04 (s, 2 H), 7.25–7.46 (m, 8 H), 7.61–7.70 (m, 2 H, 7.99 (s, 294 (M+, 100)
1510, 1490
1 H), 12.33 (br, 1 H)
1588, 1507, 1408
3.11 (s, 3 H), 3.16 (s, 3 H), 7.11–7.32 (m, 3 H), 7.40–7.49 (m, 246 (M+, 100)
2 H), 8.49 (s, 1 H)
a Satisfactory microanalyses were obtained: C ± 0.37, H ± 0.18, N ± 0.32, S ± 0.28.
in vacuo. The product was obtained from the residue by column
chromatography on silica gel using hexane/EtOAc mixtures as the
eluent (Tables 1 and 2).
(3) Field, L. Synthesis 1978, 713.
(4) Trost, B. M. Chem. Rev. 1988, 78, 363.
(5) Simpkins, N. S. Sulphones in Organic Synthesis, Pergamon:
Oxford, 1993.
(6) Holan, G.; Samuel, E. L.; Ennis, B. C. J. Chem. Soc. (C) 1967,
30.
Acknowledgement
(7) Dainter, R. S.; Jackson, T.; Omar, A. H.; Suschitzsky, H.;
Wakefield, B.J. J. Chem. Soc., Perkin Trans. 1 1989, 283.
(8) Dainter, R. S.; Suschitzsky, H.; Wakefield, B. J. Tetrahedron
Lett. 1984, 25, 5693.
(9) Croce, P. D.; La Rosa, C.; Ritieni, A. Synthesis 1989, 783.
(10) Cohen, S.; Dinar, N. J. J. Am. Chem. Soc. 1962, 27, 3545.
(11) Gonzalez, J.; Perez, A, A.; Muchowski, J. M. Can. J. Chem.
1997, 75, 1409.
Financial support for this research from ÒCoordinacion de Investi-
gacion de la Universidad Aut—noma del Estado de MŽxico (clave
1249/97)Ó is gratefully acknowledged. The authors wish to thank
Professor Joseph M. Muchowski from Roche Bioscience for help-
ful discussions and his interest in our work.
References
(12) Holan, G.; Samuel, E. L.; Ennis, B. C. ; Hinde; R. W. J. Chem.
(1) Guzman, A.; Romero, M.; Talam‡s, F. X.; Villena, R.; Green-
house, R.; Muchowski, J. M. J. Org. Chem. 1996, 61, 2470.
(2) An analogous reaction occurred with sodium ethanethiolate in
the presence of ethanethiol.1
Soc. (C) 1967,20.
Synthesis 1999, No. 2, 225Ð227 ISSN 0039-7881 © Thieme Stuttgart á New York