Design, synthesis, and biological evaluation of (E)- and (Z)-styryl-2-acetoxyphenyl sulfides and sulfones as cyclooxygenase-2 inhibitors

Article abstract of DOI:10.1016/j.bmc.2004.12.005

A new series of styryl acetoxyphenyl sulfides and sulfones possessing (E)- and (Z)-configurations were designed and prepared by stereospecific syntheses. All these compounds were evaluated for their ability to inhibit COX-2 enzyme in vitro. Structure-acti

Full text of DOI:10.1016/j.bmc.2004.12.005

Bioorganic & Medicinal Chemistry 13 (2005) 1715–1723
Design, synthesis, and biological evaluation of (E)-
and (Z)-styryl-2-acetoxyphenyl sulfides and sulfones
as cyclooxygenase-2 inhibitors
M. V. Ramana Reddy, Muralidhar Reddy Mallireddigari, Venkat R. Pallela,
Padmavathi Venkatapuram, Rengasamy Boominathan, Stanley C. Bell and
E. Premkumar Reddy*
Fels Institute for Cancer Research, Temple University School of Medicine, 3307 North Broad Street, Philadelphia,
PA 19140-5101, USA
Received 29September 2004; revised 2 December 2004; accepted 2 December 2004
Available online 25 December 2004
Abstract—A new series of styryl acetoxyphenyl sulfides and sulfones possessing (E)- and (Z)-configurations were designed and pre-
pared by stereospecific syntheses. All these compounds were evaluated for their ability to inhibit COX-2 enzyme in vitro. Structure–
activity relationship studies on these compounds revealed that only sulfides with (Z)-configuration have potential COX-2 inhibitory
activity. This inactivation of the enzyme is believed to be due to the selective covalent modification of COX-2 by the inhibitors.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
by aspirin reduces the production of PGE2 and PGI2,
which has an adverse ulcerogenic effect.5
Cyclooxygenases (COXs) are key enzymes in the synthe-
sis of prostaglandin H2, which is a precursor for the bio-
synthesis of prostaglandins, thromboxanes, and
prostacyclins.1 COX enzymes exist in two isoforms,
cyclooxygenase-1 (COX-1) and cyclooxygenase-2
(COX-2).2 COX-1 enzyme is constitutively expressed
and is critical for protection of gastric mucosa, platelet
aggregation and renal blood flow whereas COX-2 en-
zyme is inducible and expressed during inflammation,
pain, and oncogenesis.3 Since COX-2 is involved in
inflammation and pain, molecules that inhibit itꢀs enzy-
matic activity would be of therapeutic value. Many non-
steroidal anti-inflammatory drugs (NSAIDs) were found
to interact with these enzymes and inhibit their enzy-
matic activity.4 These molecules include aspirin and
indomethacin which are nonselective and inhibit both
COX-1 and COX-2 enzymes. Aspirin inhibits COX-1
more strongly than COX-24 and inhibition of COX-1
Recently several new inhibitors were developed, which
selectively inhibit COX-2 enzyme without interfering
with COX-1 enzymatic activity. These molecules include
celecoxib,6 rofecoxib,7 and valdecoxib,8 which inhibit
COX-2 enzyme without the side effects observed with
traditional NSAIDs. These selective inhibitors take
advantage of the larger enzymatic pocket in COX-2 ac-
tive site where valine at 523 has a smaller side chain that
accommodates the sulfur containing side chains of the
inhibitors, where the isoleucine at 523 in COX-1 has a
bigger side chain preventing the docking of the inhibitor
at the active site.9 This preferential binding of selective
inhibitors to COX-2 enzyme over COX-1 enzyme pre-
vents the side effects as seen in nonselective inhibitors.10
Aspirin is a unique NSAID that interacts with both
cyclooxygenases but inhibits COX-1 10- to 100-fold
more effectively than the COX-2 enzyme.11 Aspirinꢀs
inhibitory activity is due to its ability to acetylate serine
residues positioned at Ser530 in COX-1 and Ser516 in
COX-2.12,13 Acetylation of these residues prevents the
positioning of arachidonic acid to its binding site there-
by blocking the substrate to the active site of oxygena-
tion. Because of its dual inhibitory activity, some of
Keywords: Styryl sulfides; Sulfones; COX-2; Structure–activity
relationship.
*
Corresponding author. Tel.: +1 215 707 4307; fax: +1 215 707
1454; e-mail: reddy@temple.edu
0968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.12.005

1716
M. V. R. Reddy et al. / Bioorg. Med. Chem. 13 (2005) 1715–1723
aspirinꢀs therapeutic advantages can be attributed to its
ability to reduce inflammation by acetylating COX-2
and prevent platelet aggregation and anti-thrombosis
by acetylating COX-1.14 Recent studies15 on selective
COX-2 inhibitors revealed that patients with heart dis-
ease are more prone to myocardial infarction and this
may be due to TxA2/PGI2 imbalance created by selective
COX-2 inhibitors.16 These observations can be exploited
in designing a novel aspirin like molecule, which can
have all the benefits of COX-2 irreversible inhibition
and retaining anti-thrombotic activity by selective acet-
ylation of COX-1 enzyme. Recently, Kalgutkar and
co-workers17,18 have synthesized novel aspirin like ana-
logs with variations at acyl group, alkyl group, aryl sub-
stitution pattern and heteroatom substitution and
discovered a lead molecule that selectively acetylated,
and irreversibly inactivated, COX-2.
X
S
OH
i
ii
X
X
1
2
6
X
X
O2S
S
iii
iv
O
O
O
O
8
7
In this paper, we wish to report the synthesis of novel
(E)- and (Z)-styryl-2-acetoxyphenyl sulfides, sulfones,
and their selective inhibition of COX-2 enzyme. We be-
lieve that these compounds may be inhibiting COX-2
enzyme by modifying the serine residue located in the
catalytic domain of the enzyme. The significance of this
paper lies in the design and synthesis of new COX-2
inhibitors that may possess both anti-thrombotic activ-
ity of aspirin and anti-inflammatory activity of celecoxib
and rofecoxib.
Scheme 2. Reagents and conditions: (i) Br2, CCl4, 4 ꢁC, KOH, EtOH,
reflux 12 h; (ii) 2-hydroxythiophenol, AcOH, (Ac2)3MnÆ2H2O; (iii)
Ac2O, pyridine/CH2Cl2, 6 h; (iv) 30% H2O2, AcOH, 16 h.
OH
S
OH
OH
SH
i
ii
OH
OH
S
O2
O
O
9
10
X
X
2. Chemistry
iii
iv
The title compounds were synthesized using the reaction
sequence illustrated in Schemes 1–3. Accordingly, bro-
mination and dehydrobromination of styrenes (1) in
alcoholic potassium hydroxide solution yielded phenyl-
acetylenes (2).19 Nucleophilic addition of the thiol to
phenylacetylenes in the presence of a base yielded a
(Z)-styryl hydroxyphenyl sulfides (3) by trans addi-
tion.20 Acetylation of (Z)-styryl hydroxyphenyl sulfides
with acetic anhydride and pyridine gave (Z)-styryl acet-
O2S
S
O2
O
OH
O
8
11
Scheme 3. Reagents and conditions: (i) mercaptoacetic acid, NaOH,
MeOH, reflux 5 h; (ii) 30%H2O2, AcOH, 16 h; (iii) aromatic aldehyde,
benzoic acid, piperidine, toluene, reflux 4 h; (iv) Ac2O, pyridine/
CH2Cl2, 6 h.
X
oxyphenyl sulfides (4). Oxidation of these sulfides
with hydrogen peroxide21 in acetic acid resulted in the
formation of (Z)-styryl acetoxyphenyl sulfones (5)
(Scheme 1).
S
OH
i
ii
The corresponding (E)-isomers of styryl hydroxyphenyl
sulfides (6) were synthesized by free radical addition of
2-hydroxy thiophenol to phenylacetylene.22 Acetylation
of the resulting sulfide (7) followed by the oxidation
yielded (E)-styryl acetoxyphenyl sulfones (8) (Scheme
2). Alternately, (E)-styryl acetoxyphenyl sulfones were
also synthesized by Knoevenagel type condensation23
of 2-hydroxyphenylsulfonyl acetic acid (10) with various
aromatic aldehydes followed by acetylation of the styryl
sulfone (11) (Scheme 3). The (E)- and (Z)-configurations
to these isomers were assigned by NMR. All (Z)-isomers
have shown coupling constants between 10 and 11 Hz
for their vinylic protons whereas the coupling constants
for the vinylic protons in the (E)-isomers were found be-
tween 15 and 16 Hz.24
X
X
1
2
3
X
X
iii
iv
S
O2S
O
O
O
O
4
5
Scheme 1. Reagents and conditions: (i) Br2, CCl4, 4 ꢁC, KOH, EtOH,
reflux 12 h; (ii) 2-hydroxythiophenol, NaOH, MeOH, reflux 24 h; (iii)
Ac2O, pyridine/CH2Cl2, 6 h; (iv) 30% H2O2, AcOH, 16 h.

M. V. R. Reddy et al. / Bioorg. Med. Chem. 13 (2005) 1715–1723
1717
Table 2. In vitro enzyme inhibition by (E)-styryl acetoxyphenylsulfides
and sulfones
3. Results and discussion
We have synthesized a series of (E)- and (Z)-isomers of
styryl acetoxyphenylsulfides (4, 7) and sulfones (5, 8)
and evaluated their ability to inhibit COX-2 and
COX-1 enzymes in vitro by using recombinant COX-1
and COX-2 enzymes. IC50 values for inhibition of ovine
COX-1 and COX-2 by these compounds were deter-
mined by Enzyme Immuno Assay (Tables 1 and 2).25
X
n(O)S
O
O
Inhibition of COX-2 enzyme by aspirin is due to its ini-
tial binding to an arginine residue (Arg499) by its O-car-
boxylate group followed by the transfer of an acetyl
moiety to the weakly nucleophilic hydroxyl group of
the serine residue (Ser530 in COX-1 and Ser516
in COX-2).26 Based on this, we have decided to synthesize
a molecule capable of transferring an acetyl group to the
serine residue to prevent the interaction of arachidonic
acid with the COX-2 enzyme. Unlike aspirin, which
inhibits COX-1 preferentially over COX-2, most of the
(Z)-styryl acetoxyphenyl sulfides (4) inhibited COX-2
enzyme at lower concentrations as compared to COX-
1 showing their specificity toward COX-2 enzyme (Table
1). It has been shown that the fatty acid binding site in
COX-2 enzyme is larger than COX-127 and therefore
designing a molecule that fits in COX-2 pocket and
not in the COX-1 would result in specific inhibition of
the COX-2 enzyme. Selectivity of (Z)-styryl acetoxyphe-
nyl sulfides (4) for the COX-2 enzyme inhibition may be
due to the presence of the bulkier (Z)-styryl thio group
ortho to the acetate, which may fit well in the COX-2 en-
zyme pocket while not fitting into the COX-1 active site.
Compound
n
X
IC50 (lM)
COX-2
COX-1
7a
7b
7c
8a
8b
8c
8d
0
0
0
2
2
2
2
H
4-Cl
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
4-Br
H
4-Cl
4-Br
2,4,6-(OCH3)3
To study the structure–activity relationship of these
molecules (4), we have made (Z)-styryl acetoxyphenyl
sulfones (5), (E)-styryl acetoxyphenyl sulfide (7), and
(E)-styryl acetoxyphenyl sulfones (8) by different meth-
ods (Schemes 1–3). Analysis of COX-2 enzyme inhibi-
tion data clearly shows that either oxidation of the
thio group or the change in the configuration of the mol-
ecule from (Z) to (E) results in the loss of activity (Table
2). The oxidation of (Z)-styryl acetoxyphenyl sulfides (4)
to sulfones (5) could make the aromatic ring more elec-
tron deficient and consequently may hinder the transfer
of the acetyl group to the serine residue or the molecule
may not fit in the fatty acid binding site because of the
bulkier sulfone group. Another interesting aspect of
the structure–activity relationship of the sulfides (4) is
their geometrical configuration. Because of the presence
of a double bond in the molecule, styryl acetoxyphenyl
sulfides exist as trans (E) or cis (Z) isomers. Spatial
arrangement of atoms in a molecule are critical for drug
ligand interactions, which always determines the ability
of a molecule to bind to its receptor. Some of the drugs,
which are potent inhibitors of various targets, exist as
chiral molecules.28 Drugs such as desloratadine (Clar-
inexꢂ), fexofenadine (Allegraꢂ), esomeprazole (Nex-
iumꢂ), etc. are more active as an (R)- or (S)-isomer as
compared to the corresponding racemates. This suggests
that geometrical and stereoisomers differ in their drug
property and the spatial distribution of atoms in a mol-
ecule is critical for the biological activity of the drug.
Table 1. In vitro COX-1 and COX-2 inhibition by (Z)-styryl acetoxy-
phenylsulfides and sulfones
X
n(O)S
O
O
Compound
n
X
IC50 (lM)
COX-2
1.7
93
COX-1
Celecoxib
––
––
0
––
––
>100
15.5
>100
Aspirin
4a
4b
4c
H
4-F
10.8
18.9>100
10.6
0
0
2-F
4-Cl
>100
4d
4e
0
27.9>100
39.8
27.8
Our study shows that (Z)-styryl acetoxyphenyl sulfides
are more potent inhibitors of COX-2 enzymatic activity
than the corresponding (E)-isomers, which are inactive.
Styryl acetoxyphenyl sulfides in (Z)-configuration may
be a perfect fit for the fatty acid binding pocket of
COX-2, whereas molecules with (E)-configuration that
are more spatially distributed than (Z)-isomers may
not fit into the active site.
0
4-Br
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
4f
0
4-CH3
4-CH2CH3
4-(CH2)4CH3
3-OCOCH3
4-OCH3
2,4-F2
4-CF3
H
4g
4h
4i
0
46.4
73.7
0
0
2.8
53.8
4j
0
4k
4l
0
27.4
92.5
0
5a
5b
5c
2
>100
>100
>100
2
4-Cl
4-Br
Studies involving selective covalent modification of
serine (Ser516) in COX-2 and interaction of (Z)-styryl
2

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M. V. R. Reddy et al. / Bioorg. Med. Chem. 13 (2005) 1715–1723
acetoxyphenyl sulfide (4a) with other residues in the cat-
alytic domain are in progress.
were obtained by Quantitative Technologies Inc. (White
House, New Jersey) and the results were within 0.4% of
the calculated values unless otherwise mentioned.
4. Conclusions
5.2.2. Materials and methods. Reagents and solvents
were purchased from common suppliers and were used
without further purification. Reactions were monitored
by thin-layer chromatography (TLC) on silica gel plates
In this report, we have synthesized a series of novel (Z)-
and (E)-styryl acetoxyphenyl sulfides and sulfones and
examined their activity against COX-1 and COX-2 en-
zymes. Our results show that only the (Z)-styryl acet-
oxyphenyl sulfides selectively inhibit COX-2. Unlike
celecoxib, rofecoxib, and valdecoxib, these molecules
are likely to inhibit COX-2 enzyme by covalently modi-
fying the serine residue (Ser516) at the active site.
The structure–activity relationship of styryl acetoxyphe-
nyl sulfides and sulfones demonstrates that (Z)-configu-
ration and the unoxidized thio group are critical for the
COX-2 inhibitory activity. This work led to the discov-
ery of a series of compounds that are mechanistically
similar to aspirin but possessing higher degree of selec-
tivity towards COX-2 enzyme inhibition unlike aspirin.
˚
(60 A; Aldrich), visualized under 254 nm ultraviolet
light or iodine spray. Column chromatography separa-
tions were performed using silica gel (70–230 mesh) ob-
tained from the Aldrich Company. The solvents used for
elution varied depending on the compound and included
either one or a combination of the following: petroleum
ether, ethylacetate, chloroform, and methanol. All reac-
tions were conducted under a nitrogen atmosphere
unless otherwise noted. Yields were of purified product
and were not optimized. Celecoxib was prepared accord-
ing to the literature procedure.6 Ethynylbenzenes were
either purchased or prepared according to the procedure
in the literature.19
5.2.3. General procedure for the synthesis of (Z)-styryl-2-
hydroxyphenyl sulfides (3). To a stirred solution of so-
dium hydroxide (2 mmol) in absolute methanol
(20 mL) was added dropwise 2-hydroxythiophenol
(1 mmol) over a period of 0.75 h. On completion of
the addition and when the reaction was no longer exo-
thermic, phenylacetylene (1 mmol) was added, and the
reaction mixture was refluxed for 24 h. The reaction
mixture was then poured into ice-cold hydrochloric acid
(10 mL) solution and was stirred for 10 min. The solu-
tion was extracted with ethyl acetate (2 · 50 mL). The
combined organic layer was collected, washed with
water (2 · 30 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo, to afford the respective (Z)-styryl
hydroxyphenyl sulfides. Products 3 were used without
further purification for the preparation of compounds 4.
5. Experimental
5.1. COX-inhibition-EIA assay
Cyclooxygenase activity of ovine COX-1 and COX-2
was assayed using COX inhibitory screening assay kit
(Cayman Chemicals, MI). This assay directly measures
PGF2a, that was produced by stannous chloride reduc-
tion of COX derived PGH2 by enzyme immunoassay
(EIA). This assay is more accurate and reliable than
the peroxidase inhibition assay as shown by Gierse
et al.25 All assays were conducted in duplicate and
IC50 values are the average of duplicate determinations
for each compound. In brief, for the inhibition assay,
hematin reconstituted purified COX-1 and COX-2
enzymes (six units) in a reaction buffer containing
Tris–HCl (0.1 M, pH 8.0), 5 mM EDTA, 2 mM phenol,
were pre-incubated at room temperature for 1 h with
inhibitor concentrations ranging from 0.001 to 100 lM
in DMSO followed by the addition of arachidonic acid
(100 lM) for 2 min at 37 ꢁC. Reactions were terminated
by adding 50 lL of 1 M HCl followed by the addition of
100 lL of saturated stannous chloride. The final product
PGF2a formed was measured by EIA and IC50 values
were determined following the instructions given in the
kit manual.
5.2.3.1. (Z)-Styryl-2-hydroxyphenyl sulfide (3a). This
compound was obtained as light yellow solid (78%) by
reaction of 2-hydroxythiophenol with phenylacetylene.
Mp 71–73 ꢁC; 1H NMR (CDCl3):
d
6.03 (d,
J = 10.6 Hz, 1H), 6.15 (br s, OH), 6.52 (d, J = 10.6 Hz,
1H), 6.86–7.51 (m, 9H). Anal. Calcd for C14H12OS: C,
73.65; H, 5.30. Found: C, 73.95; H, 5.29.
5.2.3.2. (Z)-4-Fluorostyryl-2-hydroxyphenyl sulfide
(3b). This compound was obtained as light yellow solid
(81%) by reaction of 2-hydroxythiophenol with 4-fluoro-
phenylacetylene. Mp 55–57 ꢁC; 1H NMR (CDCl3): d
6.08 (d, J = 10.5 Hz, 1H), 6.18 (br s, OH), 6.57 (d,
J = 10.5 Hz, 1H), 6.91–7.58 (m, 8H). Anal. Calcd for
C14H11FOS: C, 68.27; H, 4.50. Found: C, 68.05; H, 4.53.
5.2. Chemistry
5.2.1. General information. Melting points were deter-
mined in open capillary tubes using a Mel-Tempꢂ elec-
tro thermal apparatus and are uncorrected. Proton
NMR (1H NMR) and carbon NMR (13C NMR) spectra
were determined in CDCl3 or DMSO-d6 solution on a
Bruker Avance 400 spectrometer. Proton chemical shifts
(d) are expressed in parts per million (ppm) relative to
tetramethylsilane as an internal standard. Spin multi-
plicities are given as s (singlet), d (doublet), br s (broad
singlet), m (multiplet), and q (quartet). Coupling con-
stants (J) are given in hertz (Hz). Elemental analyses
5.2.3.3. (Z)-2-Fluorostyryl-2-hydroxyphenyl sulfide
(3c). This product was obtained as a colorless liquid
(72% yield) by reaction of 2-hydroxythiophenol with
1
2-fluorophenylacetylene. H NMR (CDCl3): d 6.12 (d,
J = 10.7 Hz, 1H), 6.23 (br s, OH), 6.68 (d, J = 10.6 Hz,
1H), 7.01–7.90 (m, 8H). Anal. Calcd for C14H11FOS:
C, 68.27; H, 4.50. Found: C, 68.29; H, 4.52.

M. V. R. Reddy et al. / Bioorg. Med. Chem. 13 (2005) 1715–1723
1719
5.2.3.4. (Z)-4-Chlorostyryl-2-hydroxyphenyl sulfide
(3d). This product was obtained as a light yellow crystal-
line solid (78% yield) by reaction of 2-hydroxythiophe-
nol with 4-chlorophenylacetylene. Mp 51–53 ꢁC; 1H
NMR (CDCl3): d 6.06 (d, J = 10.7 Hz, 1H), 6.16 (br s,
OH), 6.46 (d, J = 10.7 Hz, 1H), 6.87–7.47 (m, 8H). Anal.
Calcd for C14H11ClOS: C, 63.99; H, 4.22. Found: C,
64.20; H, 4.21.
5.2.3.11. (Z)-2,4-Difluorostyryl-2-acetoxyphenyl sul-
fide (3k). This product was obtained as a colorless liquid
(69% yield) by reaction of 2-hydroxythiophenol with
1
2,4-difluorophenylacetylene; H NMR (CDCl3: d 6.26
(br s, OH), 6.35 (d, J = 10.5 Hz, 1H), 6.60 (d,
J = 10.6 Hz, 1H), 6.80–7.79(m, 7H). Anal. Calcd for
C14H10F2OS: C, 63.62; H, 3.81. Found: C, 63.41; H,
3.82.
5.2.3.5. (Z)-4-Bromostyryl-2-hydroxyphenyl sulfide
(3e). This product was obtained as a light yellow crystal-
line solid (85% yield) by reaction of 2-hydroxythiophe-
nol with 4-bromophenylacetylene. Mp 54–57 ꢁC; 1H
NMR (CDCl3): d 6.07 (d, J = 10.5 Hz, 1H), 6.21 (br s,
OH), 6.52 (d, J = 10.6 Hz, 1H), 6.99–7.60 (m, 8H). Anal.
Calcd for C14H11BrOS: C, 54.73; H, 3.61. Found: C,
54.58; H, 3.63.
5.2.3.12. (Z)-4-Trifluoromethylstyryl-2-acetoxyphenyl
sulfide (3l). This product was obtained as a colorless
semisolid (75% yield) by reaction of 2-hydroxythiophe-
1
nol with 4-trifluorophenylacetylene. H NMR (CDCl3):
d 6.16 (br s, OH), 6.28 (d, J = 10.6 Hz,1H), 6.52 (d,
J = 10.6 Hz, 1H), 7.14–7.78 (m, 8H). Anal. Calcd for
C15H11F3OS: C, 60.80; H, 3.74. Found: C, 60.58; H,
3.72.
5.2.3.6. (Z)-4-Methylstyryl-2-hydroxyphenyl sulfide
(3f). This product was obtained as a colorless liquid
(77% yield) by reaction of 2-hydroxythiophenol with
5.2.4. General procedure for the synthesis of (Z)-styryl-2-
acetoxyphenyl sulfides (4). A reaction mixture containing
(Z)-styryl hydroxyphenyl sulfide (3 mmol), dry pyridine
(3.2 mmol), and acetic anhydride (3.2 mmol) in 5 mL
dry methylene chloride was stirred at room temperature
for 6 h. Water was added to the reaction mixture, and
the aqueous solution was extracted with methylene chlo-
ride (2 · 10 mL). The combined organic phase was
washed with water, dried (Na2SO4), and filtered, and
the solvent was concentrated in vacuo. Chromatography
on silica gel (EtOAc/hexanes, 4:96) gave the desired
product 4.
1
4-methylphenylacetylene. H NMR (CDCl3): d 2.30 (s,
3H), 5.98 (d, J = 10.6 Hz, 1H), 6.21 (br s, OH), 6.52
(d, J = 10.6 Hz, 1H), 6.97–7.50 (m, 8H). Anal. Calcd
for C15H14OS: C, 74.34; H, 5.82. Found: C, 74.56; H,
5.85.
5.2.3.7. (Z)-4-Ethylstyryl-2-hydroxyphenyl sulfides
(3g). This product was obtained as a colorless liquid
(69% yield) by reaction of 2-hydroxythiophenol with
4-ethylphenylacetylene. 1H NMR (CDCl3): d 1.24 (t,
3H), 2.62 (q, 2H), 6.02 (d, J = 10.5 Hz, 1H), 6.18 (br s,
OH), 6.50 (d, J = 10.6 Hz, 1H), 7.02–7.57 (m, 8H). Anal.
Calcd for C16H16OS: C, 74.96; H, 6.29. Found: C, 74.79;
H, 6.31.
5.2.4.1. (Z)-Styryl-2-acetoxyphenyl sulfide (4a). This
product was obtained as a light yellow crystalline solid
(59% yield) by reaction of acetylation with 3a. Mp 54–
1
56 ꢁC; H NMR (CDCl3): d 2.31 (s, 3H, COCH3), 6.34
(d, J = 10.5 Hz,1H), 6.62 (d, J = 10.5 Hz, 1H), 7.12–
7.57 (m, 9H); 13C NMR (CDCl3): d 21.24 (CH3),
122.37 (CH@CH), 128.58 (CH@CH), 123.27–150.31
(Ar–C), 169.62 (OCOCH3). Anal. Calcd for
C16H14O2S: C, 71.08; H, 5.22. Found: C, 71.30; H, 5.23.
5.2.3.8. (Z)-4-Pentylstyryl-2-hydroxyphenyl sulfide
(3h). This product was obtained as a colorless liquid
(64% yield) by reaction of 2-hydroxythiophenol with
1
4-pentylphenylacetylene. H NMR (CDCl3): d 0.86 (t,
3H), 1.28 (m, 4H), 1.45 (m, 2H), 2.55 (t, 2H), 5.97 (d,
J = 10.6 Hz, 1H), 6.23 (br s, OH), 6.59(d, J = 10.6 Hz,
1H), 6.86–7.48 (m, 8H). Anal. Calcd for C19H22OS: C,
76.47; H, 7.43. Found: C, 76.62; H, 7.39.
5.2.4.2. (Z)-4-Fluorostyryl-2-acetoxyphenyl sulfide
(4b). This product was obtained as a yellow crystalline
solid (65% yield) by reaction of acetylation with 3b.
Mp 42–44 ꢁC; 1H NMR (CDCl3): d 2.26 (s, 3H,
COCH3), 6.28 (d, J = 10.5 Hz, 1H), 6.58 (d, J =
10.5 Hz, 1H), 7.10–7.59(m, 8H); 13C NMR (CDCl3): d
21.20 (COCH3),123.40 (CH@CH), 128.36 (CH@CH),
115.64–150.27 (Ar–C), 169.55 (OCOCH3). Anal. Calcd
for C16H13FO2S: C, 66.65; H, 4.54. Found: C, 66.87;
H, 4.53.
5.2.3.9. (Z)-3-Hydroxystyryl-2-hydroxyphenyl sulfide
(3i). This product was obtained as a colorless liquid
(66% yield) by reaction of 2-hydroxythiophenol with
3-hydroxyphenylacetylene. 1H NMR (CDCl3): d 6.24
(br s, OH), 7.08–7.59(m, 10H), 8.0 (br s, OH). Anal.
Calcd for C14H12O2S: C, 68.83; H, 4.95. Found: C,
68.51; H, 4.96.
5.2.4.3. (Z)-2-Fluorostyryl-2-acetoxyphenyl sulfide
(4c). This product was obtained as a colorless liquid
(62% yield) by reaction of acetylation with 3c. 1H
NMR (CDCl3): d 2.30 (s, 3H, COCH3), 6.46 (d,
J = 12.0 Hz, 1H), 6.78 (d, J = 10.0 Hz, 1H), 7.06–7.90
(m, 8H); 13C NMR (CDCl3): d 21.18 (COCH3), 123.59
(CH@CH), 128.95 (CH@CH), 115.63–150.37 (Ar–C),
169.57 (OCOCH3). Anal. Calcd for C16H13FO2S: C,
66.65; H, 4.54. Found: C, 66.68; H, 4.55.
5.2.3.10. (Z)-4-Methoxystyryl-2-acetoxyphenyl sulfide
(3j). This product was obtained as a colorless liquid
(74% yield) by reaction of 2-hydroxythiophenol with
4-methoxyphenylacetylene. 1H NMR (CDCl3): d 3.82
(s, 3H, OCH3), 6.11 (d, J = 10.5 Hz, 1H), 6.21 (br s,
OH), 6.58 (d, J = 10.5 Hz, 1H), 6.91–7.55 (m, 8H). Anal.
Calcd for C15H14O2S: C, 69.74; H, 5.46. Found: C,
69.87; H, 5.48.

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5.2.4.4. (Z)-4-Chlorostyryl-2-acetoxyphenyl sulfide
(Ar–C), 169.32 (COCH3), 173.52 (COCH3); Anal. Calcd
for C17H16O4S: C, 64.54; H, 5.10. Found: C, 64.69; H,
5.07.
(4d). This product was obtained as a light yellow crystal-
line solid (68% yield) by reaction of acetylation with 3d.
Mp 36–38 ꢁC; 1H NMR (CDCl3): d 2.31 (s, 3H,
COCH3), 6.36 (d, J = 10.5 Hz, 1H), 6.55 (d,
J = 10.5 Hz, 1H), 7.12–7.56 (m, 8H); 13C NMR
(CDCl3): d 21.22 (CH3), 123.57 (CH@CH), 128.96
(CH@CH), 126.17–150.32 (Ar–C), 169.55 (OCOCH3).
Anal. Calcd for C16H13ClO2S: C, 63.05; H, 4.30. Found:
C, 62.91; H, 4.32.
5.2.4.10. (Z)-4-Methoxystyryl-2-acetoxyphenyl sulfide
(4j). This product was obtained as a colorless liquid
(64% yield) by reaction of acetylation with 3j. 1H
NMR (CDCl3): d 2.31 (s, 3H, COCH3), 3.82 (s, 3H,
OCH3), 6.21 (d, J = 10.5 Hz, 1H), 6.58 (d, J = 10.5 Hz,
1H), 6.84–7.55 (m, 8H); 13C NMR (CDCl3): d 21.22
(CH3), 55.45 (OCH3), 123.45 (CH@CH), 128.67
(CH@CH), 122.42–155.23 (Ar–C), 169.60 (OCOCH3).
Anal. Calcd for C17H15O3S: C, 68.20; H, 5.05. Found:
C, 67.93; H, 5.06.
5.2.4.5. (Z)-4-Bromostyryl-2-acetoxyphenyl sulfide
(4e). This product was obtained as a light yellow crystal-
line solid (65% yield) by reaction of acetylation with 3e.
Mp 40–42 ꢁC; 1H NMR (CDCl3): d 2.31 (s, 3H,
COCH3), 6.37 (d, J = 10.5 Hz, 1H), 6.52 (d,
J = 10.0 Hz, 1H), 7.09–7.60 (m, 8H); 13C NMR
(CDCl3): d 22.74 (COCH3), 125.08 (CH@CH), 128.89
(CH@CH), 123.00–151.83 (Ar–C), 171.06 (OCOCH3).
Anal. Calcd for C16H13BrO2S: C, 55.03; H, 3.75. Found:
C, 54.83; H, 3.76.
5.2.4.11. (Z)-2,4-Difluorostyryl-2-acetoxyphenyl sul-
fide (4k). This product was obtained as a colorless liquid
(65% yield) by reaction of acetylation with 3l. 1H NMR
(CDCl3): d 2.34 (s, 3H, COCH3), 6.45 (d, J = 10.5 Hz,
1H), 6.70 (d, J = 10.5 Hz, 1H), 6.80–7.79(m, 7H); 13C
NMR (CDCl3): d 21.18 (COCH3), 123.22 (CH@CH),
128.67 (CH@CH), 120.76–150.30 (Ar–C), 169.53
(COCH3). Anal. Calcd for C16H12F2O2S: C, 62.73; H,
3.95. Found: C, 62.74; H, 3.95.
5.2.4.6. (Z)-4-Methylstyryl-2-acetoxyphenyl sulfide
(4f). This product was obtained as a colorless liquid
(67% yield) by reaction of acetylation with 3f. 1H
NMR (CDCl3): d 2.30 (s, 3H, COCH3), 2.33 (s, 3H),
6.18 (d, J = 10.5 Hz, 1H), 6.56 (d, J = 10.5 Hz, 1H),
7.07–7.59(m, 8H). Anal. Calcd for C 17H15O2S: C,
72.06; H, 5.34. Found: C, 71.79; H, 5.37.
5.2.4.12. (Z)-4-Trifluoromethylstyryl-2-acetoxyphenyl
sulfide (4l). This product was obtained as a colorless
semisolid (55% yield) by reaction of acetylation with
1
3m. H NMR (CDCl3): d 2.32 (s, 3H, COCH3), 6.48
(d, J = 10.5 Hz,1H), 6.60 (d, J = 10.5 Hz, 1H), 7.14–
7.78 (m, 8H); 13C NMR (CDCl3): d 21.14 (COCH3),
123.65 (CH@CH), 128.88 (CH@CH), 120.55–150.44
(Ar–C), 169.58 (OCOCH3). Anal. Calcd for
C17H12F3O2S: C, 60.53; H, 3.58. Found: C, 60.69; H,
3.59.
5.2.4.7. (Z)-4-Ethylstyryl-2-acetoxyphenyl sulfide (4g).
This product was obtained as a colorless liquid (59%
yield) by reaction of acetylation with 3g. 1H
NMR (CDCl3): d 1.27 (t, 3H), 2.31 (s, 3H, COCH3),
2.66 (q, 2H), 6.15 (d, J = 10.5 Hz, 1H), 6.53 (d,
J = 10.6 Hz, 1H), 7.02–7.67 (m, 8H). Anal. Calcd for
C18H17O2S: C, 72.70; H, 5.76. Found: C, 73.01; H, 5.77.
5.2.5. General procedure for the synthesis of (Z)-styryl-2-
acetoxyphenyl sulfone (5). To a solution containing (Z)-
styryl-2-acetoxyphenyl sulfides (15 mmol) in 20 mL of
glacial acetic acid was added 30% hydrogen peroxide
(8 mL) dropwise at room temperature. After the addi-
tion was complete, the reaction mixture was allowed
to stirr at room temperature for 16 h. The mixture was
then poured into ice-cold water and stirred for 10 min.
The separated solid filtered, and dried to give required
compound 5.
5.2.4.8. (Z)-4-Pentylstyryl-2-acetoxyphenyl sulfide
(4h). This product was obtained as a colorless liquid
(54% yield) by reaction of acetylation with 3h. 1H
NMR (CDCl3): d 0.93 (t, 3H), 1.34 (m, 4H), 1.76 (m,
2H), 2.29(s, 3H,COCH 3), 2.69(t, 2H), 6.12 (d,
J = 10.5 Hz, 1H), 6.59(d, J = 10.6 Hz, 1H), 7.11–7.61
(m, 8H). Anal. Calcd for C21H24O2S: C, 74.08; H,
7.10. Found: C, 74.30; H, 7.13.
5.2.5.1. (Z)-Styryl-2-acetoxyphenyl sulfone (5a). This
product was obtained as a white solid (88% yield) by
5.2.4.9. (Z)-3-Acetoxystyryl-2-acetoxyphenyl sulfide
(4i). A reaction mixture containing 3-hydroxystyryl-2-
hydroxyphenyl sulfide (3 mmol), dry pyridine
(6.4 mmol), and acetic anhydride (6.4 mmol) in 5 mL
dry methylene chloride was stirred at room temperature
for 6 h. Water was added to the reaction mixture, and
the aqueous solution was extracted with methylene chlo-
ride (2 · 10 mL). The combined organic phase was
washed with water, dried (Na2SO4), and filtered, and
the solvent was concentrated in vacuo. Chromatography
on silica gel (EtOAc/hexanes, 4:96) gave as a colorless
1
oxidation of 4a. Mp 98–100 ꢁC; H NMR (CDCl3): d
2.09(s, 3H, COCH ), 6.40 (d, J = 10.6 Hz, 1H), 6.94
3
(d, J = 10.6 Hz, 1H), 6.96–7.70 (m, 9H). Anal. Calcd
for C16H14O4S: C, 63.56; H, 4.67. Found: C, 63.59; H,
4.64.
5.2.5.2. (Z)-4-Chlorostyryl-2-acetoxyphenyl sulfone
(5b). This product was obtained as a white solid (81%
yield) by oxidation of 4d. Mp 84–86 ꢁC; 1H NMR
(CDCl3): d 2.21 (s, 3H, COCH3), 6.42 (d, J = 10.5 Hz,
1H), 6.58 (d, J = 10.5 Hz, 1H), 7.09–7.92 (m, 8H). Anal.
Calcd for C16H13ClO4S: C, 57.06; H, 3.89. Found: C,
57.19; H, 3.87.
1
liquid (63% yield). H NMR (CDCl3): d 2.28 (s, 3H,
COCH3), 2.41 (s, 3H, COCH3), 7.08–7.59(m, 10H);
13C NMR (CDCl3): d 21.14 (CH3), 30.55 (CH3),
123.69(CH @CH), 128.46 (CH@CH), 121.77–151.68

M. V. R. Reddy et al. / Bioorg. Med. Chem. 13 (2005) 1715–1723
1721
5.2.5.3. (Z)-4-Bromostyryl-2-acetoxyphenyl sulfone
(5c). This product was obtained as a white solid (86%
yield) by oxidation of 4e. Mp 88–90 ꢁC; 1H NMR
(CDCl3): d 2.22 (s, 3H, COCH3), 6.46 (d, J = 10.5 Hz,
1H), 6.62 (d, J = 10.5 Hz, 1H), 7.01–7.98 (m, 8H). Anal.
Calcd for C16H13BrO4S: C, 50.41; H, 3.44. Found: C,
50.53; H, 3.45.
5.2.7.1. (E)-Styryl-2-acetoxyphenyl sulfide (7a). This
product was obtained as a solid (78% yield) by reaction
of acetylation with 6a. Mp 77–79 ꢁC; 1H NMR (CDCl3):
d 2.29(s, 3H, COCH ), 6.79(d, J = 15.3 Hz, 1H), 7.49
3
(d, J = 15.3 Hz, 1H), 6.69–7.87 (m, 9H). Anal. Calcd
for C16H14O2S: C, 71.08; H, 5.22. Found: C, 70.92; H,
5.20.
5.2.7.2. (E)-4-Chlorostyryl-2-acetoxyphenyl sulfide
(7b). This product was obtained as a white solid
(82% yield) by reaction of acetylation with 6b. Mp 86–
88 ꢁC; H NMR (CDCl3): d 2.35 (s, 3H, COCH3), 6.93
(d, J = 15.3 Hz, 1H), 7.62 (d, J = 15.3 Hz, 1H), 7.03–
8.01 (m, 8H). Anal. Calcd for C16H13ClO2S: C, 63.05;
H, 4.30. Found: C, 63.09; H, 4.28.
5.2.6. General procedure for the synthesis of (E)-styryl-2-
hydroxyphenyl sulfides (6). To a solution containing phen-
ylacetylene (15 mmol) in 20 mL of glacial acetic acid
was added manganese(III) acetate dihydrate (7.5 mmol)
at room temperature. The mixture was stirred and
heated in an oil bath, and then 2-hydroxy thiophenol
(22.5 mmol) was added just before refluxing. The dark
brown color of manganese(III) acetate dihydrate disap-
peared within 2 min. The solvent was removed in vacuo
and the residue was triturated with water followed by
extraction with chloroform. The extract was dried over
anhydrous Na2SO4, filtered, and concentrated to dry-
ness. The products were separated by silica gel column
chromatography using chloroform as the eluting sol-
vent, resulted the desired product (6).
1
5.2.7.3. (E)-4-Bromostyryl-2-acetoxyphenyl sulfide
(7c). This product was obtained as a white solid
(81% yield) by reaction of acetylation with 6c. Mp 9 2–
1
94 ꢁC; H NMR (CDCl3): d 2.39(s, 3H, COCH ), 6.94
3
(d, J = 15.4 Hz, 1H), 7.60 (d, J = 15.0 Hz, 1H), 7.13–
8.00 (m, 8H). Anal. Calcd for C16H13BrO2S: C, 55.03;
H, 3.75. Found: C, 55.26; H, 3.74.
5.2.8. General procedure for the synthesis of (E)-styryl-2-
acetoxyphenyl sulfones (8). To a solution containing (E)-
styryl-2-acetoxyphenyl sulfides (15 mmol) in 20 mL of
glacial acetic acid was added 30% hydrogen peroxide
(8 mL) dropwise at room temperature. After the addi-
tion was complete, the reaction mixture was allowed
to stir at room temperature for 16 h. The mixture was
then poured into ice-cold water and stirred for 10 min.
The separated solid filtered, and dried to give required
compound 8.
5.2.6.1. (E)-Styryl-2-hydroxyphenyl sulfide (6a). This
product was obtained as a solid (88% yield) by reaction
of 2-hydroxythio phenol with phenylacetylene. Mp 92–
94 ꢁC; H NMR (CDCl3): d 6.71 (d, J = 15.3 Hz, 1H),
7.42 (d, J = 15.3 Hz, 1H), 6.61–7.82 (m, 9H), 8.16 (br
s, OH). Anal. Calcd for C14H12OS: C, 73.65; H, 5.30.
Found: C, 73.79; H, 5.31.
1
5.2.6.2. (E)-4-Chlorostyryl-2-hydroxyphenyl sulfide
(6b). This product was obtained as a white solid (82%
yield) by reaction of 2-hydroxythio phenol with 4-chloro-
5.2.8.1. (E)-Styryl-2-acetoxyphenyl sulfone (8a). This
product was obtained as a solid (81% yield) by oxidation
of 7a. Mp 114–116 ꢁC; 1H NMR (CDCl3): d 1.97 (s, 3H,
COCH3), 6.83 (d, J = 15.4 Hz, 1H), 7.59(d, J = 15.4 Hz,
1H), 6.79–7.97 (m, 9H). Anal. Calcd for C16H14O4S: C,
63.56; H, 4.67. Found: C, 63.82; H, 4.66.
1
phenyl acetylene. Mp 96–98 ꢁC; H NMR (CDCl3): d
6.86 (d, J = 15.3 Hz, 1H), 7.52 (d, J = 15.3 Hz, 1H),
6.93–7.91 (m, 8H), 8.21 (br s, OH). Anal. Calcd for
C14H11ClOS: C, 63.99; H, 4.22. Found: C, 64.07; H,
4.23.
5.2.6.3. (E)-4-Bromostyryl-2-hydroxyphenyl sulfide
(6c). This product was obtained as a white solid (81%
yield) by reaction of acetylation with 6c. Mp 102–
104 ꢁC; 1H NMR (CDCl3): d 6.94 (d, J = 15.4 Hz,
1H), 7.60 (d, J = 15.0 Hz, 1H), 7.13–8.00 (m, 8H), 8.18
(br s, OH). Anal. Calcd for C14H11BrOS: C, 54.73; H,
3.61. Found: C, 54.69; H, 3.61.
5.2.8.2. (E)-4-Chlorostyryl-2-acetoxyphenyl sulfone
(8b). This product was obtained as a white solid (86%
yield) by oxidation of 7b. Mp 120–122 ꢁC; H NMR
(CDCl3): d 2.35 (s, 3H, COCH3), 6.93 (d, J = 15.4 Hz,
1H), 7.62 (d, J = 15.4 Hz, 1H), 7.03–8.06 (m, 8H). Anal.
Calcd for C16H13ClO4S: C, 57.06; H, 3.89. Found: C,
56.96; H, 3.90.
1
5.2.7. General procedure for the synthesis of (E)-styryl-2-
acetoxyphenyl sulfides (7). A reaction mixture containing
styryl hydroxyphenyl sulfide (3 mmol), dry pyridine
(3.2 mmol), and acetic anhydride (3.2 mmol) in 5 mL
dry methylene chloride was stirred at room temperature
for 6 h. Water was added to the reaction mixture, and
the aqueous solution was extracted with methylene chlo-
ride (2 · 10 mL). The combined organic phase was
washed with water, dried (Na2SO4), and filtered, and
the solvent was concentrated in vacuo. Chromatography
on silica gel (EtOAc/hexanes, 4:96) gave the desired ace-
tate 7.
5.2.8.3. (E)-4-Bromostyryl-2-acetoxyphenyl sulfone
(8c). This product was obtained as a white solid (85%
1
yield) by oxidation of 7c. Mp 138–140 ꢁC; H NMR
(CDCl3): d 2.39(s, 3H, COCH ), 6.97 (d, J = 15.5 Hz,
3
1H), 7.63 (d, J = 15.0 Hz, 1H), 7.23–8.07 (m, 8H). Anal.
Calcd for C16H13BrO4S: C, 50.41; H, 3.44. Found: C,
50.47; H, 3.43.
5.2.9. General procedure for the synthesis of 2-hydroxy
phenylthio acetic acid (9). To a stirred solution of sodium
hydroxide (12.8 g, 320 mmol) in absolute methanol
(200 mL) was added dropwise 2-hydroxythio phenol

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M. V. R. Reddy et al. / Bioorg. Med. Chem. 13 (2005) 1715–1723
(20 g, 160 mmol) over a period of 0.75 h. On completion
of the addition and when no longer the reaction was
exothermic, chloroacetic acid (18.14 g, 192 mmol) was
added portion wise, and the reaction mixture was re-
fluxed for 5 h. This mixture was then poured into ice-
cold hydrochloric acid solution (20 mL) and was stirred
for 10 min. The solution was extracted with ethyl acetate
(2 · 100 mL). The combined organic layer was collected,
washed with water (2 · 50 mL), dried over anhydrous
Na2SO4, and concentrated under vacuo, to afford as a
yield) by reaction of 10 with 4-bromobenzaldehyde.
6.82 (d,
J = 15.4 Hz, 1H), 6.95–7.61 (m, 8H), 7.52 (d,
Mp 145–147 ꢁC; 1H NMR (CDCl3):
d
J = 15.4 Hz, 1H), 8.86 (br s, OH).
5.2.11.4. (E)-2,4,6-Trimethoxystyryl-2-hydroxyphenyl
sulfone (11d). This product was obtained as a white solid
(63% yield) by reaction of 10 with 2,4-6-trimethoxybenz-
aldehyde. Mp 132–134 ꢁC; 1H NMR (CDCl3): d 3.89(s,
9H, OCH3), 6.02 (s, 2H, Ar–H), 6.82 (d, J = 15.4 Hz,
1H), 6.95–7.61 (m, 6H), 7.52 (d, J = 15.4 Hz,1H), 8.78
(br s, OH).
1
oil in 98.4% yield. H NMR (CDCl3): d 3.46 (s, 2H,
CH2), 6.79–7.46 (m, 4H), 8.41 (br s, OH). Anal. Calcd
for C8H8O3S: C, 52.16; H, 4.38. Found: C, 52.29; H,
4.36. Product 9 was used immediately without further
purification for the preparation of compound 10.
5.2.12. General procedure for the synthesis of (E)-styryl-
2-acetoxyphenyl sulfone (8). A reaction mixture contain-
ing (E)-styryl hydroxyphenyl sulfone (3 mmol), dry
pyridine (3.2 mmol), and acetic anhydride (3.2 mmol)
in 5 mL dry methylene chloride was stirred at room tem-
perature for 6 h. Water was added to the reaction mix-
ture, and the aqueous solution was extracted with
methylene chloride (2 · 10 mL). The combined organic
phase was washed with water, dried (Na2SO4), and fil-
tered, and the solvent was concentrated in vacuo. Chro-
matography on silica gel (EtOAc/hexanes, 4:96) gave the
desired acetate 8.
5.2.10. General procedure for the synthesis of 2-hydroxy-
phenyl sulfonyl acetic acid (10). To a solution containing
2-hydroxyphenylthio acetic acid (15 g, 82 mmol) in
75 mL of glacial acetic acid was added 30% hydrogen
peroxide (30 mL) dropwise at room temperature. After
the addition was complete, the reaction was stirred for
16 h at room temperature. The solution was concen-
trated in vacuo, and the residue was filtered, washed
with petroleum ether and dried to give a white powder.
1
Yield 65%; Mp 125–126 ꢁC; H NMR (CDCl3): d 3.86
(s, 2H, CH2), 6.89–7.56 (m, 4H), 8.52 (br s, OH). Anal.
Calcd for C8H8O5S: C, 44.44; H, 3.73. Found: C, 44.36;
H, 3.74. Product 10 was used without further purifica-
tion for the preparation of compound 11.
5.2.12.1. (E)-Styryl-2-acetoxyphenyl sulfone (8a). This
product was obtained as a solid (81% yield) by reaction
of acetylation with 11a. Mp 114–116 ꢁC; 1H NMR
(CDCl3): d 1.97 (s, 3H, COCH3), 6.83 (d, J = 15.4 Hz,
1H), 6.79–7.97 (m, 9H), 7.59 (d, J = 15.4 Hz, 1H).
5.2.11. General procedure for the synthesis of (E)-styryl-
2-hydroxyphenyl sulfone (11). A mixture of 2-hydroxy-
phenyl sulfonyl acetic acid (10) (4.6 mmol), aromatic
aldehydes (5.1 mmol), benzoic acid (0.7 mmol), and
piperidine (0.6 mmol) in toluene (20 mL) was refluxed
for 4 h with continuous removal of water using a
Dean–Stark water separator. The reaction mixture was
cooled to room temperature, diluted with ethyl acetate,
washed with saturated NaHCO3 solution (20 mL), water
(30 mL), and the organic phase was separated, and dried
(Na2SO4). The solvent was removed in vacuo. Chroma-
tography on silica gel (chloroform) gave the desired
product 11.
5.2.12.2. (E)-4-Chlorostyryl-2-acetoxyphenyl sulfone
(8b). This product was obtained as a white solid (86%
yield) by reaction of acetylation with 11b. Mp 120–
122 ꢁC; 1H NMR (CDCl3): d 2.35 (s, 3H, COCH3),
6.93 (d, J = 15.4 Hz, 1H), 7.03–8.06 (m, 8H), 7.62 (d,
J = 15.4 Hz, 1H).
5.2.12.3. (E)-4-Bromostyryl-2-acetoxyphenyl sulfone
(8c). This product was obtained as a white solid (85%
yield) by reaction of acetylation with 11c. Mp 138–
140 ꢁC; 1H NMR (CDCl3): d 2.39(s, 3H, COCH 3),
6.97 (d, J = 15.5 Hz, 1H), 7.23–8.07 (m, 8H), 7.63 (d,
J = 15.0 Hz, 1H).
5.2.11.1. (E)-Styryl-2-hydroxyphenyl sulfone (11a).
This product was obtained as a white solid (56% yield)
by reaction of 10 with benzaldehyde. Mp126–128 ꢁC;
1H NMR (CDCl3): d 6.78 (d, J = 15.2 Hz, 1H), 6.91–
7.77 (m, 8H), 7.52 (d, J = 15.4 Hz, 1H), 8.92 (br s,
OH).
5.2.12.4. (E)-2,4,6-Trimethoxystyryl-2-acetoxyphenyl
sulfone (8d). This product was obtained as a white solid
(83% yield) by reaction of acetylation with 11d. Mp
122–124 ꢁC; 1H NMR (CDCl3): d 2.34 (s, 3H, COCH3),
3.89(s, 9H, OCH 3), 6.02 (s, 2H, Ar–H), 6.82 (d, J =
15.4 Hz, 1H), 6.95–7.61 (m, 6H), 7.52 (d, J = 15.4 Hz,
1H).
5.2.11.2. (E)-4-Chlorostyryl-2-hydroxyphenyl sulfone
(11b). This product was obtained as a white solid (63%
yield) by reaction of 10 with 4-chlorobenzaldehyde.
Mp 132–134 ꢁC; 1H NMR (CDCl3): d 6.88 (d, J =
15.0 Hz,1H), 6.95–7.87 (m, 8H), 7.62 (d, J = 15.5 Hz,
1H), 8.97 (br s, OH).
Acknowledgements
This work was supported by grants from the Depart-
ment of Defense, US Army Breast Cancer Research Pro-
gram, DAMD 17-02-1-0579, Onconova Therapeutics,
Inc. New Jersey and Fels Foundation, Philadelphia.
5.2.11.3. (E)-4-Bromostyryl-2-hydroxyphenyl sulfone
(11c). This product was obtained as a white solid (59%

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