The potential antioxidant activity of 2,3-dihydroselenophene, a prototype drug of 4-aryl-2,3-dihydroselenophenes

Article abstract of DOI:10.1016/j.bmc.2011.01.005

Here we present our results in palladium cross-coupling reaction of aryl boronic acids with 4-iodo-2,3-dihydroselenophene derivatives. The cross-coupled products were obtained in satisfactory yields. A dehydrogenation of4,5-diphenyl-2,3-dihydroselenophene

Full text of DOI:10.1016/j.bmc.2011.01.005

Bioorganic & Medicinal Chemistry 19 (2011) 1418–1425
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
The potential antioxidant activity of 2,3-dihydroselenophene, a prototype
drug of 4-aryl-2,3-dihydroselenophenes
Ricardo F. Schumacher, Alisson R. Rosário, Ana C. G. Souza, Carmine I. Acker, Cristina W. Nogueira,
⇑
Gilson Zeni
Laboratório de Síntese, Reatividade, Avaliação Farmacológica e Toxicológica de Organocalcogênios, CCNE, UFSM, Santa Maria, Rio Grande do Sul, CEP 97105-900, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Here we present our results in palladium cross-coupling reaction of aryl boronic acids with 4-iodo-2,
3-dihydroselenophene derivatives. The cross-coupled products were obtained in satisfactory yields. A
dehydrogenation of4,5-diphenyl-2,3-dihydroselenophene was activated by DDQ and the 2,3-diarylselen-
ophene was obtained in good yield. Regarding the antioxidant activity, the selenophene derivative 3a was
effective in counteracting lipid and protein oxidation as well as scavenging ABTS radical. The findings of
the present study indicate that 3a is a prototype for future drug development programs to treat disorders
mediated by reactive oxygen species.
Received 17 November 2010
Revised 4 January 2011
Accepted 5 January 2011
Available online 11 January 2011
Keywords:
Radical
Oxidative stress
Antioxidant activity
Selenophenes
Ó 2011 Elsevier Ltd. All rights reserved.
Reactive oxygen species
1. Biochemistry
tool for selective construction of carbon–carbon bonds.7 The palla-
dium-catalyzed Suzuki–Miyaura cross-coupling reaction of aryl
Oxidative stress is characterized by an increased concentration
of intracellular oxidizing species, such as reactive oxygen species
(ROS) and is often accompanied by the loss of antioxidant defense
capacity.1 It is well known that excess ROS attack many organs,
and induce oxidative damage directly to critical biological mole-
cules, such as lipoproteins, proteins and nucleotides, causing lipid
peroxidation, and protein oxidation. Metabolic oxidative stress has
been implicated, directly or indirectly, in the development of dis-
eases and degenerative processes, including inflammation, cancer,
dementia and physiological aging.2 Moreover, oxidative stress also
plays a central role in liver pathologies.3 Antioxidant pharmaco-
therapy in various forms has emerged as a mean to minimize the
biomolecular damage caused by attack of ROS on vital constituents
of living organisms.4 Therefore, there is a great interest in looking
for new organoselenides, such as functionalized selenophene
rings,5 which could represent a good pharmacological alternative
to counteract oxidative stress.6
halides with boronic acids and esters has become a common and
convenient synthetic method in organic chemistry for biaryl com-
pounds.8 Many examples of Suzuki coupling reactions, between
heterocyclic halides and phenyl boronic acids, have appeared in
the literature over the past two decades,9 being the key stage in
the synthesis of many currently interesting heterocycle-incorpo-
rated compounds.10 More recently, significant advances have been
made in the use of organoboron reagents as coupling partners in a
number of palladium-mediated carbon–carbon bond formation.
Among them, the use of potassium organotrifluoroborates, as the
organoboron coupling partner, has some advantages in comparison
to boronic acids and boronic esters, such as be more nucleophilic,
stable in the air, crystalline as solids, and easily prepared.11
Chalcogenophene heterocycles (S, Se, and Te) and their deriva-
tives have numerous uses in the fields of biochemistry, physical or-
ganic chemistry, materials chemistry, and organic synthesis. For
example, selenophene oligomers are compounds of current inter-
est because many of them show photoenhanced biological activi-
ties12 and crystalline polymerizations.13
2. Chemistry
Thus, a wide variety of oligomers and related chalcogen com-
pounds, including mixed thiophene-pyrrole oligomers, have been
synthesized mainly with the expectation of obtaining excellent
precursor compounds for molecular devices and electroconductive
polymers.14 In addition, chalcogenophenes are widely studied
agents with a diverse array of biological effects, these include anti-
oxidant,15 antinociceptive,16 and antiinflammatory properties17 as
The palladium-catalyzed cross-coupling reactions of aryl
halides or triflates with boronic acids, commonly referred to
Suzuki–Miyaura reactions, are a powerful, versatile, and popular
⇑
Corresponding author. Tel.: +55 55 3220 8140; fax: +55 55 3220 8998.
E-mail address: gzeni@pq.cnpq.br (G. Zeni).
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.01.005

R. F. Schumacher et al. / Bioorg. Med. Chem. 19 (2011) 1418–1425
1419
well as efficacy as maturation inducing agents.18 A great number of
I
I2 (1.1 equiv)
CH2Cl2
R
these heterocycles have been synthesized and their chemistry has
attracted a good deal of interest and activity from a variety of
standpoints, such as structures, stereochemistry, reactivities, and
applications to organic synthesis.19 The electrophilic cyclization
of alkynes bearing, an organochalcogen moiety, is a powerful ap-
proach to the preparation of several functionalized chalcogenoph-
enes with high regioselectivity,20 particularly, when one considers
that there are many ways to transform selectively the resulting
halogen, sulfur, selenium, and tellurium functionalities into a great
number of interesting substituted heterocycles.
SeBu
R
Se
1a-h
(67 - 93%)
R=C6H5, 4-MeC6H4, 4-ClC6H4, 4-MeOC6H4,
Sen-Bu, SCH3, CH(OH)C5H11, H
Scheme 2.
Table 1
Optimization conditionsa
During the course of our research program aiming at structure–
activity relationship studies in order to evaluate the pharmacology
activity of heterocycles,5,15–17 we required the synthesis of 2,
3-dihydroselenophenes having a substituted aromatic ring at the
4-position. Since the Suzuki reaction has proven to be successful
for the selective arylation of heterocyles,21 it was of interest to ex-
plore this reaction to obtain 4-aryl-2,3-dihydroselenophene deriv-
atives. To our knowledge this methodology has not been explored
and we now wish to report the application of 4-iodo-2,3-dihyd-
roselenophenes 1a–h as substrates on the cross-coupling reaction
with boronic acids 2a–j in the presence of a palladium salt to ob-
tain 4-aryl-2,3-dihydroselenophenes 3a–r (Scheme 1).
Entry
[Pd]
Base
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
PdCl2
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
KOH
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Dioxane
Toluene
CH3CN
THF
DMF
DMF
DMF
DMF
DMF
25
30
10
78
46
57
10
60
72
77
74
50
25b
63c
40d
70e
55f
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
3. Results and discussion
The starting 4-iodo-2,3-dihydroselenophenes 1a–h were read-
ily available by using the electrophilic cyclization protocol of homo
propargyl selenides. The treatment of these selenides with iodine
(1.1 equiv) in CH2Cl2 at room temperature lead to the formation
of the 4-iodo-2,3-dihydroselenophenes 1a–h. By this methodology
a wide range of substituents at 5-position could be used and the
starting materials were obtained in isolated yields of 67–93%
(Scheme 2).22
a
The reaction was performed using 1a (0.25 mmol), 2a (1.5 equiv), [Pd]
(2 mol %), base (2 equiv), H2O (0.4 mL) and solvent (2 mL).
b
Using 1 mol % of Pd(PPh3)4.
Using 5 mol % of Pd(PPh3)4.
Reaction at 70 °C.
Reaction at 110 °C.
c
d
e
f
Reaction performed using 2 equiv of 2a.
Our initial studies have focused on the development of an opti-
mum set of reaction conditions. In this way, 4-iodo-5-phenyl-2,3-
dihydroselenophene 1a and phenyl boronic acid 2a were used as
standard substrates. Thus, a mixture of 4-iodo-2,3-dihydroselen-
ophene 1a (0.25 mmol), phenyl boronic acid 2a (0.375 mmol) were
reacted with different palladium catalysts, bases and solvents, the
results are shown in Table 1.
As shown in Table 1, both Pd(0) and Pd(II) catalysts with differ-
ent ligands were tested, the best result was obtained using
Pd(PPh3)4 2 mol % which gave the desired product 3a in 78% yield
(Table 1, entry 4). It is important to note that when the amount of
catalyst was changed from 2 to 5 mol % and using less than 2 mol %
of Pd(PPh3)4, a decrease in the yields of the coupling products were
observed (Table 1, entries 13 and 14). The presence of base was
crucial for a clean, high-yielding reaction. For this reason, in our
experiments we investigated the influence of other bases. As listed
in Table 1, when the reaction was carried out using Na2CO3,
Cs2CO3, KOH, and K3PO4 the target product was obtained in poor
to moderated yields (Table 1, entries 5–8). The best result was ob-
tained using K2CO3, which gave the desired product 3a in 78% yield
(Table 1, entry 4). Regarding the influence of the solvents, all sol-
vents tested (dioxane, toluene, CH3CN, and THF) gave the product
in good yields (Table 1, entries 9–12), however, the highest yield
was achieved using a mixture of DMF/H2O, which furnished the
desired product 3a in 78% yield (Table 1, entry 4). It is also impor-
tant to mention that when the temperature of the Suzuki reaction
was changed from 100 to 70 °C or 110 °C the yields of the coupling
products were not improved (Table 1, entries 15 and 16).
Thus, careful analysisof theoptimized reactionsrevealed that the
optimum conditions for this coupling reaction were found to be the
use of 4-iodo-5-phenyl-2,3-dihydroselenophene 1a (0.25 mmol)
and phenyl boronic acid 2a (1.5 equiv), Pd(PPh3)4 (2 mol %), in
DMF/H2O, at 100 °C. In this condition we are able to prepare 4,5-di-
phenyl-2,3-dihydroselenophene 3a in 78% (Scheme 3).
In order to demonstrate the efficiency of this protocol, we ex-
plored the generality of our method extending the conditions to
other 4-iodo-2,3-dihydroselenophene compounds 1a–h with dif-
ferent arylboronic acids 2a–j and the results are summarized in
Table 2. First, to determine the real influence of the substituent
at aromatic ring of boronic acids, we kept the substrate 1a invari-
able. The results revealed that the reaction is not sensitive to the
electronic effect of the aromatic ring attached in the boron atom.
For example, arylboronic acid bearing an electron-donating
group methoxyl at the para position gave a very similar yield than
the arylboronic acid bearing an electron-withdrawing group CF3
(Table 2, entry 3 vs 8). Differentiation in the reactivity between
Pd(PPh3)4 (2 mol%)
I
Ar
R1
I
Ph
[Pd], Base
K2CO3 (2 equiv)
Ar B(OH)2
Ph B(OH)2
Solvent,100 °C
R1
DMF / H2O, 100°C
Ph
Ph
3a (78 %)
Se
1a-h
Se
Se
1a
Se
3a-r
2a-j
2a
Scheme 1.
Scheme 3.

1420
R. F. Schumacher et al. / Bioorg. Med. Chem. 19 (2011) 1418–1425
Table 2
Products of cross-coupling reactiona
Entry
3-Iodo-dihydroselenophene 1
Boronic acid 2
Product 3
Yieldb (%)
I
B(OH)2
2a
Se
1
77
Ph
Se
3a
1a
B(OH)2
2b
2
3
1a
74
50
Ph
Se
3b
OMe
MeO
B(OH)2
2c
1a
Ph
Se
3c
B(OH)2
4
5
1a
1a
75
70
2d
Ph
Se
3d
B(OH)2
2e
Ph
Se
3e
Cl
Br
Cl
Br
B(OH)2
2f
6
7
1a
1a
67
60
Ph
Se
3f
B(OH)2
2g
Ph
Se
Se
Se
Se
3g
B(OH)2
CF3
F3C
8
9
1a
1a
1a
50
77
66
2h
2i
Ph
3h
B(OH)2
NO2
O2N
Ph
3i
O
B(OH)2
Me
Me(O)C
10
2j
Ph
3j

R. F. Schumacher et al. / Bioorg. Med. Chem. 19 (2011) 1418–1425
1421
Table 2 (continued)
Entry
3-Iodo-dihydroselenophene 1
Boronic acid 2
Product 3
Yieldb (%)
I
I
I
Se
Se
Se
11
12
13
2b
80
67
64
1b
Se
3k
OMe
2b
1c
Se
Se
OMe
3l
Cl
2b
1d
Cl
3m
I
SeBu
Se
Se
Se
14
15
2b
2b
71
62
1e
SeBu
Se
Se
Se
3n
I
SMe
1f
SMe
3o
I
C5H11
OH
1g
16
17
2b
70
C5H11
OH
3p
I
H
Se
1h
2b
2e
42
60
H
Se
Se
3q
Cl
18
1h
H
3r
a
The reaction was performed using 1 (0.25 mmol), 2 (1.5 equiv), Pd(PPh3)4 (2 mol %), K2CO3 (2 equiv) in DMF/H20 (5:1) at 100 °C.
b
Isolated yields.
halogen and boron atoms can be seen by coupling showed in the
reaction. Aryl boronic acid containing a methyl group at the ortho
position or naphthyl boronic acid, gave slightly difference in the
yield of product 3 compared to arylboronic acids no substituted
(Table 2, entry 1 vs 4 and 5). In an attempt to broaden the scope
of our methodology, the possibility of performing the reaction with
other 4-iodo-2,3-dihydroselenophene was also investigated. Then
the substrates 1b–d, which have aryl group in the 5-position of
experiments described in Table 2, entries 6 and 7, which provide
only the Suzuki product, without any homo-coupling product. To
the best of our knowledge, aryl halogen could react with boronic
acids in the presence of palladium catalysts to afford biaryl prod-
ucts.23 In our case, the halogen substituent was not affected. We
also found that steric effects had a little influence on the coupling

1422
R. F. Schumacher et al. / Bioorg. Med. Chem. 19 (2011) 1418–1425
the selenophene ring containing both electron-donating and elec-
tron-withdrawing groups, were also cross-coupled efficiently,
under the same reaction conditions (Table 2, entries 11–13).
Additionally, the substrates 1e and 1f, which have an additional
chalcogen atom in the 5-position, gave the Suzuki products in good
yields (Table 2, entries 14 and 15). These results are highly useful
in synthesis, particularly when one considers that there are many
ways to transform the resulting chalcogen functionalities into
other substituents.24 Finally, it is worth mentioning that, our reac-
tion system was also suitable for the cross-coupling of 4-iodo-2,3-
dihydroselenophene having either propargyl alcohol or with none
substituents in the 5 position, giving the desired products in good
yields (Table 2, entries 16–18).
compound 3a on protein and lipid oxidation induced by sodium
nitroprusside (SNP). SNP is a good chemical inducer of lipid perox-
idation,27 since it releases NOÅ in tissue preparations.28 This radical
easily produces peroxynitrite (ONOOÀ), together with superoxide
anion radical (O2ÁÀ), thus leading to lipid peroxidation and produc-
tion of additional free radicals.29 One product of lipid peroxidation
is malondialdehyde, which can be determined by measuring the
amount of thiobarbituric acid reactive species.30 As shown in
Fig. 1, compound 3a at concentrations equal or greater than
30 lM was effective in protecting against lipid peroxidation
induced by SNP in rat liver homogenate. The calculated IC50 value
Since selenophene derivatives exhibit a broad range of biologi-
cal activities and applications as intermediates in organic synthe-
sis, we wondered if it would be possible to prepare selenophenes
directly from 2,3-dihydroselenophenes. Recently, it was reported
that 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) is a useful pro-
moter for the oxidation of 2,3-dihydro-thiophene25 or -furan26 to
aromatic thiophene or furan. Gratifyingly, we found that the reac-
tion of 2,3-dihydroselenophene 3a (1 equiv) with DDQ (2 equiv) in
toluene at 90 °C gave the selenophene 4a in 86% yield (Scheme 4).
4. Pharmacology
Since the results from our research group and others have
demonstrated that the introduction of a substituent group into
unsaturated system of organochalcogen does not alter the pharma-
cological activity,6 compound 3a, a non substituted selenophene,
was chosen as a prototype drug to evaluate the antioxidant poten-
tial of 4-aryl-2,3-dihydroselenophenes.
Excessive production of ROS is known to affect lipid membrane
through lipid peroxidation and also oxidized proteins. Oxidative
stress can be accessed through the direct quantification of ROS,
antioxidants, and by the measurement of oxidative stress end
products. In this study, we investigated the antioxidant effects of
Figure 2. Effect of 3a on protein carbonyl content induced by SNP in rat liver
homogenate. Data are reported as mean SD of four independent experiments.
Results were reported as nmol carbonyl content/mg protein. (⁄) Denotes p <0.05 as
compared to the control tube (one-way ANOVA/Duncan). (#) Denotes p <0.05 as
compared to the induced tube (one-way ANOVA/Duncan). ‘I’ means the tube sample
containing SNP to induce protein carbonylation
Ph
Ph
Ph
DDQ (2 equiv)
Toluene, 90 oC
Ph
- 86%
Se
3a
Se
4a
Scheme 4.
Figure 3. Scavenging activity of compound 3a on ABTS radicals. Data are reported
as mean SD of four independent experiments. Results were reported as percent-
age of the control. (⁄) Denotes p <0.05 as compared to the control tube (one-way
ANOVA/Duncan).
R
Ph
Ph
Se
GSH
Figure 1. Effect of 3a on TBARS levels induced by SNP in rat liver homogenate. Data
are reported as mean SD of four independent experiments. Results were reported
as nmol MDA (malondialdehyde)/mg protein. (⁄) Denotes p <0.05 as compared to
the control tube (one-way ANOVA/Duncan). (#) Denotes p <0.05 as compared to the
induced tube (one-way ANOVA/Duncan). ‘I’ means the tube sample containing SNP
to induce lipid peroxidation.
Ph
R
1/2 GSSG + RH
Ph
Se
Scheme 5.

R. F. Schumacher et al. / Bioorg. Med. Chem. 19 (2011) 1418–1425
1423
was 80
l
M. Thus, compound 3a reduced lipid peroxidation show-
solution of K2CO3 (0.5 mmol, 0.069 g) in H2O (0.4 mL) was added.
The mixture was then heated at 100 °C. After the required time,
the reaction was cooled to rt, diluted with ethyl acetate (20 mL),
and washed with brine (2 Â 20 mL). The organic phase was sepa-
rated, dried over MgSO4, and concentrated under vacuum. The res-
idue was purified by flash chromatography on silica gel using
hexane and ethyl acetate as eluents.
ing a potential antioxidant activity.
A high level of ROS may result in protein oxidation, leading to
the production of carbonyl groups. Consequently, the determina-
tion of carbonyl content in proteins can be used as a biomarker
of oxidative protein damage.31 Oxidatively modified proteins in-
duced by SNP were significantly reduced by compound 3a at con-
centrations equal or greater than 10
lM (Fig. 2). The calculated IC50
value was 61 M. Taken together, these results indicate that
compound 3a was effective in counteracting lipid and protein
oxidation.
In addition, 3a was investigated as a compound able to quench
the ABTS radical. Stable radical ABTS has been widely used for the
determination of primary antioxidant activities of pure antioxidant
compounds, plant and fruit extracts, and foods materials.32 Com-
pound 3a showed a significant ABTS radical-scavenging activity
l
6.1.1. Selected spectral and analytical data for 4,5-diphenyl-2,3-
dihydroselenophene (3a)
Yield 0.055 g (78%). 1H NMR (400 MHz, CDCl3): d 7.23–7.05 (m,
10H), 3.49–3.44 (m, 2H), 3.38–3.34 (m, 2H). 13C NMR (100 MHz,
CDCl3): d 137.9, 136.8, 134.0, 133.4, 129.3, 127.1, 128.07, 128.0,
127.4, 126.3, 45.3, 23.3. MS (relative intensity) m/z: 283 (100),
202 (41), 176 (30), 167 (20), 126 (23), 100 (20). Anal. Calcd for
C16H14Se C, 67.37; H, 4.95. Found: C, 67.51; H, 5.01.
at concentrations equal or higher than 30 lM. Although the scav-
enging activity of 3a did not outperform ascorbic acid (Fig. 3),
the activity of 3a is better than diphenyl diselenide, a well known
antioxidant containing selenium.33
6.1.2. 5-Phenyl-4-o-tolyl-2,3-dihydroselenophene (3d)
Yield 0.056 g (75%). 1H NMR (400 MHz, CDCl3): d 7.14–7.07 (m,
9H), 3.42–3.38 (m, 2H), 3.32–3.38 (m, 2H), 2.07 (s, 3H). 13C NMR
(100 MHz, CDCl3): d 138.5, 136.5, 135.6, 135.1, 132.7, 130.2,
128.8, 128.3, 127.8, 127.1, 127.0, 125.8, 46.4, 23.8, 19.7. MS (rela-
tive intensity) m/z: 299 (100), 219 (20), 205 (65), 191 (47), 164
Since the selenium atom has a great ability to stabilize radical in
the alpha position34 and higher stability of a tertiary radical inter-
mediate if compared to the possibility of a radical formation in the
2 position, we proposed the mechanism depicted in Scheme 5 to
explain the antioxidant activity of compound 3a. The catalytic cy-
cle shows dangerous radical species adding to the double bond
from selenenophene ring and regeneration by thiol reduction of
the corresponding 2,3-dihydroselenophene radical.
(24), 128 (21), 91 (38). HRMS calcd for
323.0315. Found: 323.0321.
C
17H16Se [M+Na]+:
6.1.3. 4-(4-Bromophenyl)-5-phenyl-2,3-dihydroselenophene
(3g)
Yield 0.054 g (60%). 1H NMR (400 MHz, CDCl3): d 7.27–7.18 (m,
7H), 6.94–6.90 (m, 2H), 3.46–3.33 (m, 4H). 13C NMR (100 MHz,
CDCl3): d 136.8, 136.5, 134.8, 132.6, 131.1, 129.6, 129.2, 128.3,
127.7, 120.0, 45.0, 23.3. MS (relative intensity) m/z: 363 (15), 359
(100), 279 (13), 201 (47), 167 (27), 149 (21), 127 (22), 100 (32).
HRMS calcd for C16H13BrSe [M+Na]+: 386.9264. Found: 386.9272.
5. Conclusion
In summary, we have explored the Suzuki–Miyaura cross-cou-
pling reaction of 4-iodo-2,3-dihydroselenophene derivatives with
several aryl boronic acids in the presence of catalytic amount of
Pd(PPh3)4 and established a new route to obtain highly substituted
2,3-dihydroselenophene compounds in good to excellent yields.
The reaction of compound 2,3-dihydroselenophene 3a with DDQ
afforded the selenophene derivatives 4a in 86% yield. The findings
of the present study indicate that 3a is a prototype for future drug
development programs to treat disorders mediated by reactive
oxygen species.
6.1.4. 4,5-Di(p-tolyl)-2,3-dihydroselenophene (3k)
Yield 0.062 g (80%). 1H NMR (400 MHz, CDCl3): d 7.12–7.10 (m,
2H), 6.98–6.93 (m, 6H), 3.45–3.40 (m, 2H), 3.34–3.30 (m, 2H), 2.26
(s, 3H), 2.24 (s, 3H). 13C NMR (100 MHz, CDCl3): d 137.1, 135.8,
135.2, 134.0, 133.3, 132.5, 129.1, 128.8, 128.6, 127.9, 45.4, 23.0,
21.1, 21.0. MS (relative intensity) m/z: 314 (100), 233 (20), 218
(36), 202 (21), 182 (29), 141 (12), 115 (19). HRMS calcd for
C
18H18Se [M+Na]+: 337.0471. Found: 337.0483.
6. Experimental
6.1.5. 5-(4-Chlorophenyl)-4-p-tolyl-2,3-dihydroselenophene
(3m)
Proton nuclear magnetic resonance spectra (1H NMR) were ob-
tained at 200 MHz on a DPX-200 NMR spectrometer or at 400 MHz
on a DPX-400 NMR spectrometer. Spectra were recorded in CDCl3
Yield 0.053 g (64%). 1H NMR (200 MHz, CDCl3): d 7.24–7.12 (m,
4H), 7.01–6.92 (m, 4H), 3.50–3.31 (m, 4H), 2.27 (s, 3H). 13C NMR
(100 MHz, CDCl3): d 136.4, 135.5, 134.9, 134.7, 133.0, 131.0,
130.6, 128.8, 128.4, 127.9, 45.4, 23.4, 21.1. MS (relative intensity)
m/z: 333 (100), 280 (14), 218 (37), 202 (35), 189 (23), 131 (14).
HRMS calcd for C17H15ClSe [M+Na]+: 356.9925. Found: 356.9930.
solutions. Carbon-13 nuclear magnetic resonance spectra (13
C
NMR) were obtained either at 50 MHz on a DPX-200 NMR spec-
trometer or at 100 MHz on a DPX-400 NMR spectrometer. Spectra
were recorded in CDCl3 solutions. Column chromatography was
performed using Merck Silica Gel (230–400 mesh). Thin layer chro-
matography (TLC) was performed using Merck Silica Gel GF254
,
6.1.6. 5-(Butylselenyl)-4-p-tolyl-2,3-dihydroselenophene (3n)
Yield 0.063 g (71%). 1H NMR (200 MHz, CDCl3): d 7.25–7.11 (m,
4H), 3.37–3.25 (m, 4H), 2.81 (t, J = 7.2 Hz, 2H), 2.33 (s, 3H), 1.66
(qui, J = 7.3 Hz, 2H), 1.35 (sext, J = 7.3 Hz, 2H), 0.88 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3): d 139.5, 136.6, 135.3, 128.7,
127.7, 117.1, 44.5, 32.6, 28.9, 24.8, 22.7, 21.2, 13.5. MS (relative
intensity) m/z: 359 (100), 300 (31), 221 (98), 142 (90), 128 (71),
114 (83), 91 (18). HRMS calcd for C15H20Se2 [M+Na]+: 382.9793.
Found: 382.9803.
0.25 mm thickness. For visualization, TLC plates were either placed
under ultraviolet light, or stained with iodine vapor, or acidic van-
illin. Most reactions were monitored by TLC for disappearance of
starting material. MS spectra were determined using a Shimadzu
GC–MS-2010P. Elemental analyses were performed on a Vario EL
III elemental analysis instrument.
6.1. General procedure for the cross-coupling reaction
To a solution of appropriate 4-iodo-2,3-dihydroselenophene
(0.25 mol) in DMF (2 mL) was added Pd(PPh3)4 (0.0057 g,
2 mol %) and boronic acid (0.375 mmol) under argon. After a
6.1.7. 4-p-Tolyl-2,3-dihydroselenophene (3q)
Yield 0.023 g (42%). 1H NMR (400 MHz, CDCl3): d 7.26–7.24 (m,
2H), 7.11–7.09 (m, 2H), 6.93 (t, J = 1.7 Hz, 1H), 3.40 (t, J = 8.1 Hz,

1424
R. F. Schumacher et al. / Bioorg. Med. Chem. 19 (2011) 1418–1425
2H), 3.18 (t, J = 8.1 Hz, 2H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 139.9, 136.4, 129.1, 125.2, 116.5, 63.9, 38.7, 24.8, 21.1. MS (rela-
tive intensity) m/z: 223 (100), 208 (19), 143 (64), 128 (93), 115
(61), 91 (17). HRMS calcd for C11H12Se [M+Na]+: 247.0002. Found:
247.0014.
(c) The determination of the ABTS radical scavenging effect of
the compound 3a was performed according to the method
of Re,36 with some modifications. Initially, the ABTS radical
was generated by reacting 7 mM ABTS solution in water
with 140 mM potassium persulfate in the dark for 12–16 h.
In the day of the assay, the pre-formed ABTS radical solution
was diluted 1:88 in potassium phosphate buffer, pH 7.0.
Briefly, ABTS radical was added to a medium containing
6.2. General procedure for the aromatization with DDQ
To a solution of dihydroselenophene 3a (0.25 mmol) in toluene
(3 mL), DDQ (2 equiv) was added. The resulting solution was stir-
red at 90 °C for the desired time. The reaction was diluted with
ethyl acetate (30 mL) and washed with aqueous NH4Cl (3 Â
10 mL). After drying the organic phase over anhydrous MgSO4,
the solvent was removed under reduced pressure and the residue
purified by flash chromatography on silica gel using hexane as
eluent.
the compound 3a at different concentrations (1–100 lM).
The media were incubated for 30 min at 25 °C. The decrease
in absorbance was measured at 734 nm. Ascorbic acid was
used as a positive control. Results are expressed as percent-
age of the blank (without compound).
Acknowledgments
6.2.1. Selected spectral and analytical data for 2,3-diphenyl-
selenophene (4a)
We are grateful to FAPERGS (PRONEX-10/0005-1), CAPES
(SAUX) and CNPq (CNPq/INCT-catalise) for the financial support.
CNPq is also acknowledged for the fellowships.
Yield 0.06 g (86%). 1H NMR (200 MHz, CDCl3): d 7.95 (d,
J = 5.7 Hz, 1H), 7.43 (d, J = 5.7 Hz, 1H), 7.27–7.18 (m, 10H). 13C
NMR (100 MHz, CDCl3): d 144.8, 139.8, 137.5, 136.3, 133.7, 129.3,
129.2, 128.9, 128.3, 128.2, 127.1, 126.7. MS (relative intensity)
m/z: 283 (91), 268 (22), 202 (100), 189 (17), 176 (16), 101 (27).
HRMS calcd for C16H12Se [M+Na]+: 307.0002. Found: 307.0010.
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