Regioselective synthesis of functionalized 2-(phenylthio)benzoates by '[3+3] cyclization/homo-Michael' reactions of 1-methoxy-1-trimethylsilyloxy-3-phenylthio-1,3-butadienes with 1,1-diacylcyclopropanes

Article abstract of DOI:10.1016/j.tetlet.2008.02.025

2-(Phenylthio)benzoates containing a remote halide function are regioselectively prepared by '[3+3] cyclization/homo-Michael' reactions of 1-methoxy-1-trimethylsilyloxy-3-phenylthio-1,3-butadienes with 1,1-diacylcyclopropanes.

Full text of DOI:10.1016/j.tetlet.2008.02.025

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2466–2468
Regioselective synthesis of functionalized 2-(phenylthio)benzoates
by ‘[3+3] cyclization/homo-Michael’ reactions of
1-methoxy-1-trimethylsilyloxy-3-phenylthio-1,3-butadienes
with 1,1-diacylcyclopropanes
Muhammad A. Rashid a, Inam Iqbal a, Nasir Rasool a, Muhammad Imran a, Peter Langer a,b,
*
a Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 12 January 2008; revised 2 February 2008; accepted 5 February 2008
Available online 9 February 2008
Abstract
2-(Phenylthio)benzoates containing a remote halide function are regioselectively prepared by ‘[3+3] cyclization/homo-Michael’
reactions of 1-methoxy-1-trimethylsilyloxy-3-phenylthio-1,3-butadienes with 1,1-diacylcyclopropanes.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Cyclizations; Cyclopropanes; Diaryl sulfides; Regioselectivity; Silyl enol ethers
Functionalized diaryl sulfides (diaryl thioethers) are
present in a number of pharmacologically relevant natural
and non-natural products.1 For example, it has been
reported that fluorinated diaryl sulfides act as serotonin
transporter ligands.2 The scope of classic methods3 for
the synthesis of diaryl sulfides is often limited by their
low regioselectivity and by the formation of polysulfides,
due to the harsh reaction conditions. Relatively mild tran-
sition metal-catalyzed4 and metal-free5 syntheses of diaryl
sulfides have been reported. These reactions are limited
by the fact that the synthesis of highly substituted and
sterically encumbered products is often difficult or not pos-
sible at all. In addition, the synthesis of substituted arenes,
which are required as starting materials, can be a difficult
task. All reactions outlined above rely on the formation
of a carbon–sulfur bond. An alternative approach is based
on a building block strategy which relies on the assembly of
the arene moiety by the formation of two carbon–carbon
bonds. Only a few examples of this type of reaction have
been reported to date. For example, diaryl sulfides were
prepared by cobalt(I)-catalyzed [4+2] cycloaddition of
alkynyl sulfides with 1,3-butadienes.6 Chan and co-workers
reported a convenient synthesis of diaryl sulfides by [3+3]
cyclizations of 1-methoxy-3-phenylthio-1-trimethylsilyl-
oxy-1,3-butadiene.7a In addition, Michael reactions of this
reagent have been reported.7b Diaryl sulfides were prepared
also by [4+2] cycloadditions of 1-methoxy-3-phenylthio-1-
trimethylsilyloxy-1,3-butadiene.8 Recently, we reported the
synthesis of salicylates by the cyclization of 1,3-bis(trimethyl-
silyloxy)-1,3-butadienes with 1,1-diacylcyclopropanes.9
Herein, we report our preliminary results related to what
are, to the best of our knowledge, the first ‘cyclization/
homo-Michael’ reactions of 3-arylthio-1-trimethylsilyloxy-
1,3-butadienes with 1,1-diacylcyclopropanes. These reac-
tions provide a new and convenient approach to function-
alized 2-(arylthio)benzoates, which are not readily
available by other methods.
The P2O5-mediated reaction7a of methyl acetoacetate (1)
with various thiophenols afforded 3-(phenylthio)crotonates
2a–d which were transformed, by deprotonation (LDA)
*
Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.025

M. A. Rashid et al. / Tetrahedron Letters 49 (2008) 2466–2468
2467
SAr
ArSH
P2O5
OSiMe3
OMe
O
O
O
O
SAr
SAr O
TiX4
3a-d
O
OMe
OMe
OMe
(2 equiv.)
CH2Cl2
20 °C, 18 h
ref. 7a
1
2a-d
R2
R1
+
CH2Cl2
R1
R2
X
_
78
20 °C
1) LDA, THF
_78 °C, 1 h
2) Me3SiCl
_78 20 °C
5a-o
4a-e
OSiMe3
SAr
Scheme 3. Synthesis of 5a–o.
OMe
3a-d
Table 2
Products and yields
Scheme 1. Synthesis of 3a–d.
3
4
5
Ar
R1
R2
X
% (5)a
and subsequent silylation, into 1-methoxy-1-trimethylsilyl-
oxy-3-arylthio-1,3-butadienes 3a–d (Scheme 1, Table 1).
The synthesis of 3a has been previously reported.7a
a
a
a
a
a
a
a
b
b
b
c
a
b
c
a
b
c
d
e
f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
4-ClC6H4
4-FC6H4
Me
Et
Ph
Me
Ph
Ph
Me
Ph
Me
Me
Ph
Cl
Cl
Cl
Cl
Br
Br
Br
Cl
Cl
Br
Cl
Cl
Br
Cl
Cl
48
47
43
40
58
30
40
40
41
45
43
47
41
35
33
The TiCl4-mediated cyclization of 3a with 1,1-diacetyl-
cyclopropane (4a) afforded 2-(phenylthio)benzoate 5a
(Scheme 2). During optimization, the stoichiometry
(1.5 equiv of TiCl4 and of 4a) and the concentration
(30 mL/mmol of 3a) played an important role.10 The yields
dropped when only 1.0 equiv of TiCl4 and of 4a were
employed. The yield also decreased when an excess of 3a
was used. A complex mixture was obtained when the reac-
tion was carried out in a highly concentrated solution (as
reported7a for the reaction of 3a with 4-(trimethylsilyl-
oxy)pent-3-en-2-one). The formation of 5a can be
explained by TiCl4-mediated attack of the terminal carbon
atom of 3a onto 4a to give intermediate A, cyclization via
the central carbon atom (intermediate B), TiCl4-assisted
d
a
e
b
a
b
b
a
b
a
a
b
g
h
i
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
3-(MeO)C6H4
3-(MeO)C6H4
j
k
l
c
c
m
n
o
d
d
a
Yields of isolated products.
cleavage of the spirocyclopropane moiety and aromatiza-
tion. The process can be regarded as a domino ‘[3+3] cycli-
zation/homo-Michael’ reaction. Reactions of acceptor-
substituted cyclopropanes have been classified by Dani-
shefsky in terms of ‘strictly nucleophilic ring openings’,
‘electrophilically assisted ring openings’, and ‘spiro-activa-
tions’.11 In the domino ‘[3+3]-cyclization/homo-Michael’
reaction reported herein a ‘spiro-activation’ and an activa-
tion by an electrophile are operating.12
Table 1
Products and yields
2,3
Ar
% (2)a
% (3)a
a7a
b
Ph
85
84
86
71
90
91
88
88
4-MeC6H4
4-ClC6H4
3-(MeO)C6H4
c
d
The cyclization of 1-trimethylsilyloxy-3-arylthio-1,3-
butadienes 3a–d with 1,1-diacylcyclopropanes 4a–e, in the
presence of TiCl4 or TiBr4, afforded 5-haloethyl-2-(aryl-
thio)benzoates 5a–o (Scheme 3, Table 2). Products 5b–
d,g,i,j,l,o, derived from the unsymmetrical cyclopropanes
4b–d, were formed with very good regioselectivity. This
can be explained by the regioselective attack of the terminal
carbon atom of 3a–d onto the acetyl rather than the less
reactive aroyl group of 4b–d.
In conclusion, we reported the first ‘[3+3] cyclization/
homo-Michael’ reaction of 1-trimethylsilyloxy-3-arylthio-
1,3-butadienes with 1,1-diacylcyclopropanes. This reaction
provides a convenient approach to 2-(phenylthio)benzoates
containing a remote halide function. The products are not
readily available by other methods.
a
Yields of isolated products.
OSiMe
SPh
3
SPh O
TiCl4
OMe
3a
(2 equiv.)
OMe
O
O
Me
Me
CH2Cl2
+
Me
Me
Cl
_
78
20 °C
5a (48%)
4a
TiCl4
Me3SiCl
_
_
(Cl3Ti)2O
+
TiCl3
SPh O
O
SPh
OMe
OMe
TiCl4
Cl3TiO
Me
Cl3TiO
Me
O
_
Me
H2O
Acknowledgment
Cl_
Me
B
A
Financial support by the State of Pakistan (scholarships
for M.A.R., N.R., and I.I.) is gratefully acknowledged.
Scheme 2. Possible mechanism of the formation of 5a.

2468
M. A. Rashid et al. / Tetrahedron Letters 49 (2008) 2466–2468
6. (a) Hilt, G.; Luers, S. Synthesis 2003, 1784; (b) Hilt, G.; Luers, S.;
¨
¨
References and notes
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Bose, G.; Nguyen, V. T. H.; Ullah, E.; Lahiri, S.; Go¨rls, H.; Langer,
P. J. Org. Chem. 2004, 69, 9128.
10. General procedure for the synthesis of diaryl sulfides 5a–o: To a
dichloromethane solution (30 mL/mmol) of 1-trimethylsilyloxy-3-
arylthio-1,3-butadienes 3 (1.0 mmol) and 1,1-diacylcyclopropane 4
(1.5 mmol) was added TiX4 (1.5 mmol, X = Cl, Br) at ꢀ78 °C. The
solution was allowed to warm to ambient temperature within 14 h. To
the solution was added an aqueous solution of HCl (25 mL, 1 M). The
organic and the aqueous layers were separated and the latter was
extracted with dichloromethane (3 ꢁ 20 mL). The combined organic
layers were dried (Na2SO4), filtered and the filtrate was concentrated
in vacuo. The residue was purified by chromatography (silica gel,
EtOAc/n-heptane).
1. For dibenzothiophenes, see for example: (a) Mori, Y.; Taneda, S.;
Hayashi, H.; Sakushima, A.; Kamata, K.; Suzuki, A. K.; Yoshino, S.;
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lissoclinotoxins (varacins), see: (b) Davidson, B. S.; Molinski, T. F.;
Barrows, L. R.; Ireland, C. M. J. Am. Chem. Soc. 1991, 113,
4709; (c) Behar, V.; Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115,
7017; (d) Toste, F. D.; Still, I. W. J. J. Am. Chem. Soc. 1995, 117,
7261; For lissoclibadins, see: (e) Davis, R. A.; Sandoval, I. T.;
Concepcion, G. P.; Moreira da Rocha, R.; Ireland, C. M. Tetra-
hedron 2003, 59, 2855; (f) Liu, H.; Fujiwara, T.; Nishikawa, T.;
Mishima, Y.; Nagai, H.; Shida, T.; Tachibana, K.; Kobayashi, H.;
Mangindaan, R. E. P.; Namikoshi, M. Tetrahedron 2005, 61,
8611; For cyclo(penta-1,4-phenylene sulfide) and cyclotetra(p-pheny-
lene sulfide), see: (g) Kaplan, M. L.; Reents, W. D. Tetra-
hedron Lett. 1982, 23, 373; For natural products isolated from
Streptomyces griseus, see: (h) Hosoya, Y.; Adachi, H.; Naka-
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9227.
2. Huang, Y.; Bae, S. A.; Zhu, Z.; Guo, N.; Roth, B. L.; Laruelle, M. J
Med. Chem. 2005, 48, 2559.
3. For the thermal reaction of arenes with sulfur, see for example: (a)
Dougherty, G.; Hammond, P. D. J. Am. Chem. Soc. 1935, 57, 117; (b)
Glass, H. B.; Reid, E. E. J. Am. Chem. Soc. 1929, 51, 3428. For the
trifluoromethanesulfonic acid-catalyzed sulfurization of cycloalkanes,
see: (c) Olah, G. A.; Wang, Q.; Prakash, G. K. S. J. Am. Chem. Soc.
1990, 112, 3697. For condensations of organometallic compounds
with chlorophenyl sulfide, see for example: (d) Chua, M.; Hoyer, H.
Z. Naturforsch. B 1965, 20, 416. For base-mediated reactions of
chloroarenes with thiophenols, see: (e) Campbell, J. R. J. Org. Chem.
1964, 29, 1830; (f) Baxter, I.; Ben-Haida, A.; Colquhoun, H. M.;
Hodge, P.; Kohnke, F. H.; Williams, D. J. Chem. Eur. J. 2000, 6,
4285.
Methyl 5-(2-chloroethyl)-4,6-dimethyl-2-(phenylthio)-benzoate (5a):
Starting with 4a (378 mg, 3.0 mmol), 3a (562 mg, 2.0 mmol), TiCl4
(0.33 mL, 3.0 mmol) and CH2Cl2 (60 mL), 5a was isolated as highly
viscous oil (322 mg, 48%); 1H NMR (250 MHz, CDCl3): d = 2.19 (s,
3H, CH3), 2.21 (s, 3H, CH3), 3.09 (t, 2H, J = 7.5 Hz, CH2), 3.43 (t,
2H, J = 7.1 Hz, CH2), 3.76 (s, 3H, OCH3), 6.96 (s, 1H, ArH), 7.11–
7.21 (m, 5H, ArH); 13C NMR (62 MHz, CDCl3): d = 16.8, 20.1
(CH3), 33.0, 41.6 (CH2), 52.2 (CH3), 126.9.0 (CH), 129.04 (2C, CH),
130.3 (C), 130.5 (2C, CH),133.1 (CH), 134.1, 135.1, 136.0, 136.6, 138.9
(C), 169.3 (C@O); IR (ATR): ~m ¼ 2948 (w), 2871 (w), 1727 (s), 1579
(m), 1437 (m), 1268 (s), 1148 (s), 1039 (m), 1023 (m), 933 (w), 777 (w),
738 (s), 689 (s), 557 (w) cmꢀ1; GC–MS (EI, 70 eV): m/z (%): 336 (M+,
37Cl, 37), 334 (M+, 35Cl, 100), 301 (61), 285 (56), 267 (36) 253 (66), 210
(13), 115 (8), 77 (9); elemental Anal. Calcd for C18H19ClO2S (334.86):
C, 64.56; H, 5.72. Found: C, 64.59; H, 5.84.
´
´
4. (a) Fernandez-Rodrıguez, M. A.; Shen, Q.; Hartwig, J. F. J. Am.
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S. I.; Kuznetsova, T. S. Tetrahedron 1982, 38, 1693.
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´
4, 2803; (b) Rabai, J. Synthesis 1989, 523; (c) Gendre, F.; Yang, M.;
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