First synthesis of 4-(arylsulfonyl)phenols by regioselective [3+3] cyclocondensations of 1,3-bis(silyloxy)-1,3-butadienes with 2-arylsulfonyl-3-ethoxy-2-en-1-ones

Article abstract of DOI:10.1016/j.tetlet.2008.10.097

The formal [3+3] cyclization of 1,3-bis(silyloxy)-1,3-butadienes with readily available 2-arylsulfonyl-3-ethoxy-2-en-1-ones resulted in regioselective formation of 4-(arylsulfonyl)phenols.

Full text of DOI:10.1016/j.tetlet.2008.10.097

Tetrahedron Letters 50 (2009) 115–117
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
First synthesis of 4-(arylsulfonyl)phenols by regioselective [3+3]
cyclocondensations of 1,3-bis(silyloxy)-1,3-butadienes with
2-arylsulfonyl-3-ethoxy-2-en-1-ones
Abdolmajid Riahi a,b, Mohanad Shkoor a, Olumide Fatunsin a, Mathias Lubbe a,
Helmut Reinke a, Peter Langer a,b,
*
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The formal [3+3] cyclization of 1,3-bis(silyloxy)-1,3-butadienes with readily available 2-arylsulfonyl-3-
ethoxy-2-en-1-ones resulted in regioselective formation of 4-(arylsulfonyl)phenols.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 20 August 2008
Revised 18 October 2008
Accepted 21 October 2008
Available online 1 November 2008
Keywords:
Arenes
Cyclizations
Sulfones
Regioselectivity
Silyl enol ethers
4-(Arylsulfonyl)phenols are of considerable pharmacological
relevance. This includes antibacterial activity,1 inhibition of
phospholipidase A2,2 inhibition of catechol O-methyltransferase,3
inhibition of dihydropteroate synthase of Escherichia coli,4 hypolip-
idemic activity,5 cytotoxicity against HeLa cells and the antipicor-
navirus,6 neuropeptide Y1 receptor binding activity,7 anti-HIV
activity,8 anticholesteremic activity,9 binding to human muscarinic
M1 and M2 receptors,10 histamine H3-receptor antagonistic activ-
ity,11 antiprotozoal activity,12 binding to neuroblastoma cells,13
binding to the human cannabinoid CB1 receptor,14 and inhibition
of the main protease of the recombinant SARS coronavirus.15
Diaryl sulfones are available by oxidation of diaryl sulfides.
For example, 4-(phenylsulfonyl)anisole has been prepared by
oxidation of 4-(phenylthio)anisole with hydrogen peroxide.16 An
alternative approach to this compound relies on the alumi-
num(III)chloride-mediated reaction of anisole with phenylsulfonic
acid chloride.17 However, this approach suffers from the formation
of a regioisomeric mixture, which is difficult to be separated. The
reaction of phenol with benzenesulfonic acid has been reported
to give 4-(phenylsulfonyl)phenol.18 However, no yield was given,
and the reaction required harsh conditions (240 °C). Recently, an
efficient approach to 4-(phenylsulfonyl)phenol, based on the
CuI/proline-mediated reaction of aryl iodides with sodium benz-
enesulfinate, has been reported.19 4-(Phenylsulfonyl)anisole has
been prepared by Suzuki reaction of 4-methoxybenzeneboronic
acid with phenylsulfonic acid chloride.20 Recently, its synthesis
by Cu(OAc)2-catalyzed reaction of 4-methoxybenzeneboronic acid
with sodium benzenesulfinate in the presence of 1,10-phenanthro-
line and oxygen has been reported.21 All of these reactions rely on
the coupling of two arene moieties. The application of these reac-
tions to the synthesis of sterically encumbered or functionalized
products can be difficult in some cases. In addition, the synthesis
of the required starting materials, functionalized arenes, can be a
tedious task.
Chan and coworkers were the first to report22 the TiCl4-medi-
ated [3+3] cyclization23 of 1,3-bis(trimethylsilyloxy)-1,3-butadi-
enes24 with 3-silyloxy-2-en-1-ones, which allows a convenient
synthesis of salicylates. In recent years, the application of this
methodology to the synthesis of various functionalized arenes
has been reported.23 Herein, we report, for the first time, the syn-
thesis of 4-(arylsulfonyl)phenols by [3+3] cyclocondensations of
1,3-bis(silyloxy)-1,3-butadienes with 2-arylsulfonyl-3-ethoxy-2-
en-1-ones. These reactions allow a convenient and regioselective
access to functionalized 4-(arylsulfonyl)phenols, which are not
readily available by other methods. In contrast to the C–S coupling
reactions that are outlined above, the method reported herein
* 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.2008.10.097

116
A. Riahi et al. / Tetrahedron Letters 50 (2009) 115–117
Table 1
Synthesis of 4a–n
involves the formation of one of the two arene moieties by forma-
tion of two C–C bonds.
a
1,3-Bis(silyloxy)-1,3-butadienes 3a–g were prepared from the
2
3
4
Ar
R1
R2
R3
%
corresponding b-ketoesters in two steps.22 2-Arylsulfonyl-3-
a
a
a
b
b
b
b
b
c
c
c
c
c
a
b
c
a
d
b
c
e
a
d
f
g
e
a
a
b
c
d
e
g
h
f
i
j
k
l
m
n
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4-(O2N)C6H4
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
80
76
75
57
65
65
60
59
47
48
47
50
52
45
ethoxy-2-en-1-ones 2a–d were prepared, following
a known
nBu
nHept
H
procedure,25 by reaction of b-ketosulfones 1a–d with triethyl
orthoformate and acetic anhydride (Scheme 1).
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeC6H4
Me
The TiCl4-mediated cyclization of 2a with 3a afforded the novel
4-(arylsulfonyl)phenol 4a in up to 80% yield (Scheme 2). The best
yield was obtained when the reaction was carried out, in a highly
concentrated solution.26 It is worth to be noted that the cyclization
proceeded with excellent regioselectivity. The formation of prod-
uct 4a might be explained by TiCl4-mediated attack of the terminal
carbon atom of 3a onto 2a to give intermediate A, cyclization via
the central carbon (intermediate B) and subsequent aromatization.
The formal [3+3] cyclization of 2-arylsulfonyl-3-ethoxy-2-en-1-
ones 2a–d with 1,3-bis(silyloxy)-1,3-butadienes 3a-g afforded the
4-(arylsulfonyl)phenols 4a–n in 45–80% yield (Scheme 3, Table 1).
The aryl groups located at the sulfonyl group of enones 2 have
nBu
nHept
nOct
H
Me
Et
nHex
nOct
H
Me
Me
Me
d
a
Yields of isolated products.
O
EtO
O
HC(OEt)3
R1
R1
SO2Ar
SO2Ar
i
1a-d
2a-d
Scheme 1. Synthesis of 2a–d. Reagents and conditions: (i) 1a–d (1.0 equiv),
HC(OEt)3 (1.2 equiv), Ac2O, reflux, 2 h.
Me3SiO OSiMe3
TiCl4
CH2Cl2
O
OH
OMe
3a
OMe
Me
EtO
O
_
78 to 20 ˚C
14 h
Figure 1. Ortep plot of 4d (30% probability level).
+
SO2Ph
Me
SO2Ph
4a
2a
some influence on the yields. The best yields were obtained for
products 4a–c derived from phenyl-substituted enone 2a. In con-
trast, the presence of a substituent located at carbon atom C-4 of
the 1,3-bis(silyloxy)-1,3-butadiene has no significant effect on
the yield. Products 4a–m, derived from enones 2a–c, contain a
methyl group located at carbon C-3 of the phenol moiety. Product
4n, containing an aryl group located at C-3, was prepared from
enone 2d. The yield was slightly lower than the yield of 4d (which
also contains, like 4n, a tosyl group located at C-4). All products
were formed with excellent regioselectivity.
_
H2O
Me3SiOEt
O
O
O
Me3SiO
OMe
TiCl4
OMe
OTiCl3
Me
O
_
Me3SiCl
Me
SO2Ph
SO2Ph
The structures of all products were confirmed by spectroscopic
methods. The structure of 4d was independently confirmed by
X-ray crystal structure analysis (Fig. 1).27
A
B
In conclusion, we have reported a convenient and regioselective
synthesis of 4-(arylsulfonyl)phenols by what are, to the best of our
knowledge, the first formal [3+3] cyclizations of 1,3-bis(silyloxy)-
1,3-butadienes with 2-arylsulfonyl-3-ethoxy-2-en-1-ones. The
reactions are easy to be carried out and the starting materials are
readily available. We currently study the preparative scope of the
methodology and applications to the synthesis of pharmacologi-
cally active products.
Scheme 2. Possible mechanism of the formation of 4a.
Me3SiO
OSiMe3
R3
O
OH
R2
TiCl4
R2
CH2Cl2
O
O
R3
3a-g
EtO
R1
SO2Ar
_
78 to 20 °C
14 h
O
+
R1
SO2Ar
2a-d
Acknowledgment
4a-n
Financial support by the State of Mecklenburg-Vorpom-
mern (Landesgraduierten-scholarship for M.S.) is gratefully
acknowledged.
Scheme 3. Synthesis of 4a–n.

A. Riahi et al. / Tetrahedron Letters 50 (2009) 115–117
117
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J.-R. J. Org. Chem. 2001, 66, 421; (c) Repichet, S.; Le Roux, C.; Dubac, J.
Tetrahedron Lett. 1999, 40, 9233; (d) Hajipour, A. R.; Zarei, A.; Khazdooz, L.;
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26. General procedure for the synthesis of 4-(arylsulfonyl)phenols 4a–n: To a CH2Cl2
solution (2 mL/1 mmol of 2a–d) of 2a–d were added 3a–g (1.1 mmol) and,
subsequently, TiCl4 (1.1 mmol) at 78 °C. The temperature of the solution was
allowed to warm to 20 °C during 14 h with stirring. To the solution was added
hydrochloric acid (10%, 20 mL) and the organic and the aqueous layer were
separated. The latter was extracted with CH2Cl2 (3 Â 20 mL). The combined
organic layers were dried (Na2SO4), filtered and the filtrate was concentrated in
vacuo. The residue was purifed by chromatography (silica gel, heptanes/EtOAc)
to give 4a–n.
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Methyl 6-hydroxy-2-methyl-3-tosylbenzoate (4d): Starting with 2a (0.402 g,
1.5 mmol) and 3a (0.429 g, 1.65 mmol), 4d was isolated (0.274 g, 57%) as a
yellowish solid (0.274 g, 57%), mp 109–110 °C. 1H NMR (250 MHz, CDCl3): d
2.28 (s, 3H, CH3Ar), 2.47 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 6.87 (d, 3J = 8.4 Hz, 1H,
Ar), 7.14–7.17 (m, 2H, Ar), 7.35–7.58 (m, 2H, Ar), 8.22 (d, 3J = 8.7 Hz, 1H, Ar),
11.03 (s, 1H, OH). 13C NMR (CDCl3, 75 MHz): d 19.0, 21.5 (2 Â CH3), 52.7
(OCH3), 115.1 (CCO2CH3), 115.6 (CHAr), 127.3 (2 Â CHTol), 129.6 (2 Â CHTol),
131.8 (CArSO2), 135.2 (CHAr), 138.9 (CArCH3), 142.6 (CTolSO2), 143.8 (CTolCH3),
1
165.2 (COH), 171.0 (CO). IR (KBr, cmÀ ):
m = 3072 (w), 3029 (w), 2953 (w),
2922 (w), 2852 (w), 1715 (w), 1673 (m), 1592 (m), 1574 (m), 1495 (w), 1435
(m), 1348 (m), 1300 (m), 1286 (m), 1218 (m), 1188 (m), 1155 (m), 1142 (s),
1109 (m), 1081 (m), 1040 (w), 1018 (w), 997 (m), 939 (m), 848 (w), 815 (m),
759 (w), 709 (m), 692 (m), 649 (m), 597 (w), 587 (m), 565 (m), 549 (m), 533 (s).
GC–MS (EI, 70 eV): m/z (%) = 320 ([M]+, 34), 289 (27), 288 (100), 271 (23), 269
(18), 256 (9), 255 (48), 224 (16), 223 (20), 222 (17), 181 (10), 152 (11), 149
(12), 121 (12), 105 (10), 91 (19), 77 (22), 65 (20), 51 (14). HRMS (EI): Calcd for
C16H16O5S ([M]+): 320.07130; found: 320.071076. All products gave correct
elemental analyses and/or HRMS data.
27. CCDC-699679 contains all crystallographic details of this publication and is
available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge Crystallographic Data Centre,
12 Union Road, GB-Cambridge CB21EZ; Fax: (+44)1223-336-033; or
deposit@ccdc.cam.ac.uk.