Regioselective synthesis of diaryl sulfides by [3+3] cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-dienes

Article abstract of DOI:10.1016/j.tetlet.2007.01.150

Functionalized and sterically encumbered diaryl sulfides were prepared based on [3+3] cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-dienes.

Full text of DOI:10.1016/j.tetlet.2007.01.150

Tetrahedron Letters 48 (2007) 2321–2323
Regioselective synthesis of diaryl sulfides by [3+3] cyclizations
of 1,3-bis(trimethylsilyloxy)-1,3-dienes
Muhammad A. Rashid,a Helmut Reinkea and Peter Langera,b,
*
aInstitut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
bLeibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 21 December 2006; revised 23 January 2007; accepted 26 January 2007
Available online 1 February 2007
Abstract—Functionalized and sterically encumbered diaryl sulfides were prepared based on [3+3] cyclizations of 1,3-bis(trimethyl-
silyloxy)-1,3-dienes.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Diaryl sulfides are of considerable pharmacological rel-
evance and occur in a number of natural products.
These include various dibenzothiophenes,1 highly cyto-
toxic lissoclinotoxins (varacins),2 lissoclibadins (isolated
from Lissoclinum cf. badium),3 cyclo(penta-1,4-phenyl-
ene sulfide), cyclotetra(p-phenylene sulfide),4 and a
number of natural products isolated from Streptomyces
griseus.5 Diaryl sulfides have been prepared by thermal
reaction of arenes with sulfur.6 However, these reactions
often suffer from low regioselectivity, harsh reaction
conditions and formation of polysulfides. Diaryl sulfides
are available also by condensation of Grignard or
organolithium compounds with chlorophenyl sulfide7
and by base-mediated reaction of chloroarenes with
thiophenols.8 Some years ago, Chan and co-workers
reported9 the synthesis of salicylates by formal [3+3]
cyclization of 1,3-bis(trimethylsilyloxy)-1,3-dienes10
with 3-siloxy-2-en-1-ones. In recent years, we have
reported the application of this method to the synthesis
of a variety of functionalized arenes.11 Chan and Prasad
reported the synthesis of 2-(thiophenoxy)benzoates
based on [3+3] cyclizations of 1-trimethylsilyloxy-1-
methoxy-3-thiophenoxy-1,3-butadiene.12 Herein, we
report what is, to the best of our knowledge, the first
synthesis of diaryl sulfides by [3+3] cyclizations of 1,3-
encumbered and functionalized diaryl sulfides which
are not readily available by other methods. In contrast to
the coupling reactions outlined above, our method
relies on the assembly of one of the two arene
moieties.
The reaction of 3-chloropentane-2,4-dione (2) with thio-
phenols 1a–e afforded, following a known procedure,13
3-(thiophenoxy)pentane-2,4-diones 3a–e. Silylation of
the latter gave the novel 2-thiophenoxy-3-silyloxy-2-en-
1-ones 4a–e (Scheme 1, Table 1). The TiCl4 mediated
[3+3] cyclization of 4a–e with 1,3-bis(trimethylsilyl-
oxy)-1,3-dienes 5a–d—readily available from methyl
acetoacetate, ethyl 3-oxopentanoate, ethyl 3-oxohexano-
ate, and ethyl acetoacetate9—afforded diaryl sulfides 6a–
j (Scheme 1, Table 1).14 During the optimization of the
cyclization reaction, the (high) concentration, the tem-
perature, and the choice of Lewis acid proved to be
important parameters. In fact, we have earlier found
for related reactions that the use of SnCl4 or BF3ÆOEt2
resulted in a decrease of yield. No conversion was
observed when Me3SiOTf was employed. All structures
were established by spectroscopic methods. The struc-
ture of 6a was independently confirmed by X-ray crystal
structure analysis (Fig. 1).15
bis(silyl enol ethers). These reactions provide
a
convenient and regioselective approach to sterically
The triethylamine mediated reaction of ethyl 4-chloro-
acetoacetate with thiophenol (1a) afforded ethyl 4-(thio-
phenoxy)acetoacetate (7a),16 which was transformed in
two steps into novel thiophenoxy-substituted 1,3-
bis(trimethylsilyloxy)-1,3-diene 9a (Scheme 2, Table 2).
Likewise, 9b was prepared from ethyl 4-chloroacetoace-
tate and 4-methoxythiophenol (1b). The TiCl4 mediated
Keywords: Arenes; Cyclizations; Diaryl sulfides; Silyl enol ethers.
*
Corresponding author. Tel.: +49 381 4986410; fax: +49 381
4986412; e-mail: peter.langer@uni-rostock.de
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.150

2322
M. A. Rashid et al. / Tetrahedron Letters 48 (2007) 2321–2323
O
O
O
O
SH
Me
Me
R1
Me
Me
S
Cl
i
2
R1
R2
R2
1a-e
3a-e
ii
OH O
R3
Me
Me3SiO OSiMe3
R4
Me
Me3SiO
Me
O
R3
R4
Me
5a-d
S
S
iii
Figure 1. ORTEP plot of 6a.
R1
R1
R2
R2
For substituents R1 - R4,
see Tables 1 and 2
6a-j
4a-e
Scheme 1. Synthesis of 6a–j: Reagents and conditions: (i): C5H5N/
C5H11N, CH2Cl2, MeOH, 0!20 ꢁC, 6 h; (ii): Me3SiCl, NEt3, C6H6,
20 ꢁC, 72 h; (iii): TiCl4, CH2Cl2, ꢀ78!20 ꢁC, 20 h.
O
O
O
O
Cl
OEt
SH
S
i
OEt
+
R
7a,b
R
[3+3] cyclization of 9a and 9b with 1,1,3,3-tetrameth-
oxypropane afforded diaryl sulfides 10a and 10b,
respectively.
1a,b
ii
The [3+3] cyclization of 1,3-bis(trimethylsilyloxy)-1,3-
dienes 9a and 9b with 3-silyloxy-2-en-1-ones 11a
and 11b—prepared from pentane-2,4-dione and hep-
tane-3,4-dione—afforded diaryl sulfides 12a and 12b,
respectively (Scheme 3, Table 3). Bis(diaryl sulfides)
12c and 12d were prepared by cyclization of 9a and
9b with 2-thiophenoxy-3-silyloxy-2-en-1-one 4a,
respectively.
Me3SiO
S
O
Me3SiO OSiMe3
iii
OEt
S
OEt
R
9a,b
8a,b
R
iv
OMe OMe
OMe
OH
O
MeO
S
OEt
In conclusion, we have reported the synthesis of func-
tionalized and sterically encumbered diaryl sulfides by
[3+3] cyclizations of 4-thiophenoxy-1,3-bis(trimethyl-
silyloxy)-1,3-dienes with 3-siloxy-2-en-1-ones and 1,1,
3,3-tetramethoxypropane and by [3+3] cyclization of
1,3-bis(trimethylsilyloxy)-1,3-dienes with 2-thiophen-
oxy-3-siloxy-2-en-1-ones.
R
10a,b
Scheme 2. Synthesis of 10a,b: Reagents and conditions: (i): NEt3,
CH2Cl2, 30 min, 0 ꢁC; (ii): Me3SiCl, NEt3, C6H6, 20 ꢁC, 72 h; (iii): (1)
LDA, THF, ꢀ78 ꢁC, 1 h, (2) Me3SiCl, ꢀ78!20 ꢁC; (iv): TiCl4,
CH2Cl2, ꢀ78!20 ꢁC, 20 h.
Table 1. Synthesis of 6a–j
3,4
5
6
R1
R2
R3
R4
% (3)a
% (4)a
% (6)a
a
a
a
b
b
b
c
a
b
c
a
b
c
d
e
f
H
H
H
H
H
H
H
H
H
H
H
OMe
OMe
OMe
Br
Me
H
H
Me
Et
H
Me
Et
H
Me
H
OMe
OEt
OEt
OEt
OEt
OEt
OMe
OEt
OMe
OEt
72
81
48
40
40
43
35
38
36
33
32
30
d
b
c
33
90
a
b
a
b
g
h
i
28
81
73
79
92
81
d
e
OMe
OMe
e
j
H
Me
a Yields of isolated products.

M. A. Rashid et al. / Tetrahedron Letters 48 (2007) 2321–2323
2323
Table 2. Synthesis of 10a,b
7. See for example: Chua, M.; Hoyer, H. Z. Naturforsch. B
1965, 20, 416.
7–10
R
% (7)a
% (8)a
% (9)a
% (10)a
8. (a) Campbell, J. R. J. Org. Chem. 1964, 29, 1830; (b)
Baxter, I.; Ben-Haida, A.; Colquhoun, H. M.; Hodge, P.;
Kohnke, F. H.; Williams, D. J. Chem. Eur. J. 2000, 6,
4285.
a
b
H
OMe
80
81
84
78
89
85
31
30
a Yields of isolated products.
9. (a) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980,
102, 3534; (b) Brownbridge, P.; Chan, T.-H.; Brook,
M. A.; Kang, G. J. Can. J. Chem. 1983, 61, 688.
10. For a review of 1,3-bis(silyl enol ethers), see: Langer,
P. Synthesis 2002, 441.
11. (a) Dede, R.; Langer, P. Tetrahedron Lett. 2004, 45, 9177;
(b) Nguyen, V. T.; Appel, B.; Langer, P. Tetrahedron 2006,
62, 7674; (c) Ahmed, Z.; Fischer, C.; Spannenberg, A.;
Langer, P. Tetrahedron 2006, 62, 4800; (d) Nguyen, V. T.
H.; Bellur, E.; Appel, B.; Langer, P. Synthesis 2006, 1103;
(e) Mroß, G.; Langer, P. Tetrahedron Lett. 2006, 47, 8519;
(f) Ahmed, Z.; Langer, P. Synlett 2006, 3361; (g) Mamat,
C.; Pundt, T.; Schmidt, A.; Langer, P. Tetrahedron Lett.
2006, 47, 2183.
Me3SiO OSiMe3
S
OH
O
OEt
S
9a,b
OEt
R1
i
Me3SiO
O
R1
R2
R2
R2
R2
+
R3
R3
12a-d
4a,11a,b
Scheme 3. Synthesis of 12a–d: Reagents and conditions: (i): TiCl4,
CH2Cl2, ꢀ78!20 ꢁC, 20 h.
12. Chan, T. H.; Prasad, C. V. C. J. Org. Chem. 1986, 51,
3012.
13. Yoshida, Z.; Ogoshi, H.; Tokumitsu, T. Tetrahedron 1970,
26, 2987.
Table 3. Synthesis of 12a–d
4a,11
9
12
R1
R2
R3
% (12)a
14. General procedure for the synthesis of diaryl sulfides 6a–j,
10a,b, and 12a–d: To a dichloromethane solution (2 mL/
mmol) of 4, 11, or 1,1,3,3-tetramethoxypropane (1.0
mmol) and of 5 or 9 (1.0 mmol) was added TiCl4
(1.0 mmol) at ꢀ78 ꢁC. The solution was allowed to warm
to ambient temperature within 20 h. To the solution was
added a saturated solution of NaHCO3 (15 mL). The
organic and the aqueous layer were separated and
the latter was extracted with diethyl ether (3 · 20 mL).
The filtrate was concentrated in vacuo and the residue was
purified by chromatography (silica gel, EtOAc/n-hep-
tane = 1:4). Synthesis of methyl 4,6-dimethyl-5-(thiophen-
oxy) salicylate (6a): Starting with 3-(silyloxy)alk-2-en-1-
one 4a (200 mg, 0.71 mmol), 1,3-bis(silyl enol ether) 5a
(185 mg, 0.71 mmol), and TiCl4 (0.08 mL, 0.71 mmol), 6a
was isolated as a colorless solid (99 mg, 48%), mp 77 ꢁC;
1H NMR (250 MHz, CDCl3): d 2.40 (s, 3H, CH3), 2.72 (s,
3H, CH3), 3.95 (s, 3H, OCH3), 6.89 (d, 2H, J = 8.2 Hz,
ArH), 6.76 (s, 1H, ArH), 6.91 (s, 1H, ArH), 7.05 (br t, 1H,
J = 7.2 Hz, ArH), 7.18 (br t, 1H, J = 7.4 Hz, ArH), 11.17
(s, 1H, OH); 13C NMR (75 MHz, CDCl3): d 21.4, 2.7,
52.3, (CH3), 112.4 (C), 117.7 (CH), 122.7 (C), 124.6 (CH),
125.2 (2C, CH), 128.9 (2C, CH), 138.2, 147.1, 151.4, 162.5,
171.8 (C); IR (KBr): ~m ¼ 3061 (m), 2954 (m), 1663 (s), 1478
(s), 1360 (s), 1233 (s), 1187 (m), 1024 (m), 947 (w), 740 (s),
690 (m), 629 (w) cmꢀ1; GC–MS (EI, 70 eV): m/z (%): 288.1
(M+, 57), 256.1 (100), 185.1 (7), 91 (6). Elemental Anal.
Calcd (%) for C16H16O3S (288.08): C, 66.64; H, 5.59.
Found: C, 66.81; H, 5.68.
15. CCDC 632304 contains all crystallographic details of this
publication which are available free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge Crystal-
lographic Data Centre, 12 Union Road, GB-Cambridge
CB21EZ; Fax: (+44)1223 336 033; or deposit@
ccdc.cam.ac.uk.
16. (a) Sircar, I.; Gregor, E. K.; Anderson, K. R.; Haleen,
S. J.; Shih, Y.-H.; Weishaar, R. E.; Steffen, R. P.;
Pugsley, T. A.; Taylor, M. D. J. Med. Chem. 1991, 34,
2248; (b) Shimada, K.; Kaburagi, Y.; Fukuyama, T.
J. Am. Chem. Soc. 2003, 125, 4048.
11a
11b
4a
a
b
a
b
a
b
c
H
OMe
H
Me
Et
Me
Me
H
H
PhS
PhS
48
35
34
34
4a
d
OMe
a Yields of isolated products.
Acknowledgment
Financial support by the state of Pakistan (HEC schol-
arship for M.A.R.) is gratefully acknowledged.
References and notes
1. See for example: Mori, Y.; Taneda, S.; Hayashi, H.;
Sakushima, A.; Kamata, K.; Suzuki, A. K.; Yoshino, S.;
Sakata, M.; Sagai, M.; Seki, K.-i. Biol. Pharm. Bull. 2002,
25, 145.
2. (a) Davidson, B. S.; Molinski, T. F.; Barrows, L. R.;
Ireland, C. M. J. Am. Chem. Soc. 1991, 113, 4709; (b)
Behar, V.; Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115,
7017; (c) Toste, F. D.; Still, I. W. J. J. Am. Chem. Soc.
1995, 117, 7261.
3. (a) Davis, R. A.; Sandoval, I. T.; Concepcion, G. P.;
Moreira da Rocha, R.; Ireland, C. M. Tetrahedron 2003,
59, 2855; (b) 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.
4. Kaplan, M. L.; Reents, W. D. Tetrahedron Lett. 1982, 23,
373.
5. Hosoya, Y.; Adachi, H.; Nakamura, H.; Nishimura, Y.;
Naganawa, H. Tetrahedron Lett. 1996, 37, 9227.
6. 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 trifluorome-
thanesulfonic acid catalyzed sulfurization of cycloalkanes,
see: (c) Olah, G. A.; Wang, Q.; Prakash, G. K. S. J. Am.
Chem. Soc. 1990, 112, 3697.