Synthesis and antidepressant-like activity of selenophenes obtained via iron(iii)-PhSeSePh-mediated cyclization of Z-selenoenynes

Article abstract of DOI:10.1039/c1ob06548c

We present here the synthesis and antidepressant-like action of a series of 2,5-disubstituted-3-(organoseleno)-selenophenes prepared by a novel synthetic route, the FeCl₃-diorganyl dichalcogenide-mediated intramolecular cyclization of (Z)-chalc

Full text of DOI:10.1039/c1ob06548c

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Organic &
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PAPER
Synthesis and antidepressant-like activity of selenophenes obtained via
iron(III)–PhSeSePh-mediated cyclization of Z-selenoenynes†
Bibiana M. Gai, Andre´ L. Stein, Juliano A. Roehrs, Filipe N. Bilheri, Cristina W. Nogueira and Gilson Zeni*
Received 8th September 2011, Accepted 10th October 2011
DOI: 10.1039/c1ob06548c
We present here the synthesis and antidepressant-like action of a series of
2,5-disubstituted-3-(organoseleno)-selenophenes prepared by a novel synthetic route, the
FeCl3–diorganyl dichalcogenide-mediated intramolecular cyclization of (Z)-chalcogenoenynes. The
cyclized products were obtained in good yields. The results showed that 2c, 2d, 2e and 2o, evaluated in
the mouse forced-swimming test, elicited an antidepressant-like activity. The studies clearly show that
the phenyl group at the 2-position and an organoselenium group at the 3-position of the selenophene
ring are essential for the antidepressant-like activity of selenophenes. A close inspection of the results
also revealed that the fluorophenyl portion in the organoselenium group is fundamental for the
antidepressant-like action of this class of organochalcogens.
synthesis. In fact, chalcogenophene oligomers are compounds of
current interest because many of them show biological, optical and
Introduction
electrochemical activities.12 A great number of 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.13 Regarding the synthesis of the heterocycles, the
transition-metal catalyzed cyclization reaction of simple acyclic
precursors is one of the most attractive ways to directly construct
complicated molecules under mild conditions.14 In this way,
palladium is one of the most common transition metals used,15
although it sometimes displays intolerance to some functionalities
or proceeds with a lack of regioselectivity. Recently, we presented
our contribution to this field by developing a general and
mild protocol for seleno- and tellurophene synthesis via the
reaction of enynes with diorganoyl dichalcogenides, catalyzed by
CuI; however, the use of alkyl enyne substrates was a limiting
factor of this methodology.13a,16 During the past years, there has
been an impressive increasing attention to the development of
environmentally benign protocols and the great challenge for
chemists is to apply cost-effective, green, mild and alternative
methodologies.17 In this sense, iron salts have appeared as a
versatile alternative, due to their low price, low toxicity and
environmentally benign properties. Considering these aspects,
many findings concerning iron-mediated organic transformations
have been reported. For example, iron trichloride was applied
in the cross-coupling of Grignard reagents with several organic
electrophiles,18 iron-catalyzed C–N,19 C–O,20 and C–S21 bond
formation. Among these transformations iron salts have also
emerged as alternative and promising catalysts or promoters for
the cyclization process.22
Depression is a common, debilitating, life-threatening illness with
a significant incidence in the population. Numerous antidepres-
sant drugs are now available, presumably acting via different
mechanisms. The most widely used treatment for depression is
based on drugs affecting serotonin (5-HT) neurotransmission,
such as those inhibiting 5-HT reuptake at nerve terminals
(e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, parox-
etine and sertraline).1 Selective serotonin reuptake inhibitors
(SSRIs) show antidepressant action in both clinical and ex-
perimental studies.2 However, the heterogeneity of the clinical
responses to antidepressants and susceptibility to adverse effects
are the major clinical problems. In this sense, new directions
for antidepressant treatment have been developed. Recently, we
reported that 3-(4-fluorophenylselenyl)-2,5-diphenylselenophene
produces an antidepressant-like action in experimental models
predictive of depression and this effect is mediated through an
interaction with the serotonergic system.3 In this way, interest in
the chemistry of selenophenes has increased remarkably due to
their chemical properties,4 biological activity and pharmaceutical
potential.3,5 Some selenophene compounds are known as effective
anti-bacterial,6 anti-apoptotic7 and anti-tumoral8 agents. Previous
reports from our research group have shown the hepatoprotective,9
anticonvulsant, antioxidant,10 antinociceptive and anti-allodynic11
properties of 3-alkynyl selenophene. Chalcogenophene heterocy-
cles and their derivatives have also numerous uses in the fields
of physical organic chemistry, materials chemistry and organic
Laborato´rio de S´ıntese, Reatividade, Avaliac¸a˜o Farmacolo´gica e Toxi-
colo´gica de Organocalcogeˆnios, CCNE, UFSM, Santa Maria - Rio Grande
do Sul, Brasil, 97105-900. E-mail: gzeni@pq.cnpq.br
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob06548c
In continuation of our studies on the preparation of novel
heterocyclic systems containing selenium, and based on the fact
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that selenophenes have antidepressant-like activity, we synthesized
new 2,5-disubstituted-3-(organoseleno)-selenophenes to investi-
gate the structure–antidepressant activity relationship. Thus,
our findings on FeCl3/RSeSeR,23 as an alternative system to
IPy2BF4,24 halogen25 NXS,26 trichloroisocyanuric acid (TCCA),27
I(coll)2PF6/BF3·3OEt2,28 organoselenium29 and organotellurium
electrophiles30 to promote cyclization of functionalized alkynes,
associated with the fact that currently there are no reports
concerning the cyclization ofenynes using aFeCl3/RSeSeR system
to prepare selenophene derivatives, encouraged us to examine if
3-organoseleno chalcogenophenes 2 would be generated from (Z)-
chalcogenoenynes 1 via intramolecular cyclization reactions using
FeCl3/RSeSeR as the cyclizing agent (Scheme 1).
Chemistry
The starting (Z)-chalcogenoenynes 1 were readily available by
using the process of hydrochalcogenation of alkynes.31 Our initial
studies on the cyclization focused on the development of an
optimum set of reaction conditions. We investigated the procedure
with respect to five key variables: (1) solvents, (2) diorganyl
diselenide loading, (3) iron trichloride loading, (4) temperature
and (5) atmosphere. In this way, the optimization process was per-
formed using selenoenyne 1a and diphenyl diselenide as standard
substrates. Thus, a mixture of diphenyl diselenide (0.25 mmol) and
FeCl3 (0.25 mmol), using CH3CN as solvent, was reacted with 1a
(0.25 mmol) under reflux for 4 h. As shown in Table 1, using
these reaction conditions, the desired product 2a was obtained
in 77% yield (Table 1, entry 1).◦Regarding the temperature, the
use of a lower temperature (25 C) proved to be worse than the
use of reflux (Table 1, entry 2). To identify the solvent potentially
suitable for the cyclization, we initially chose CH3CN, MeOH,
DMSO and THF. All solvents tested gave the desired product 2a
in acceptable yields (Table 1, entries 1–12). However, we chose
CH2Cl2 as solvent because it gave the product not only in a
similar yield but also in a shorter reaction time (Table 1, entry
11). Next, the amount of FeCl3 was investigated by varying from a
catalytic ratio (0.1 equiv) to 1.5 equiv, with the best result obtained
Scheme 1 General scheme.
Table 1 Influence of reaction conditions in the FeCl3/PhSeSePh cyclization of (Z)-selenoenyne 1aa
Entry
[Fe] (equiv)
Solvent
PhSeSePh (equiv)
Atmosphere
Time (h)
Yield (%)
1
FeCl3 (1)
FeCl3 (1)
FeCl3 (1)
FeCl3 (1)
FeCl3 (0.1)
FeCl3 (1)
FeCl3 (1)
FeCl3 (1.5)
FeCl3 (1)
FeCl3 (1)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
MeOH
MeOH
MeOH
DMSO
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMSO
DMSO
DMSO
DMSO
DMSO
CH3CN
CH3NO2
DMF
1.0
1.0
2.0
—
1.0
1.0
0.55
0.55
1.0
argon
argon
argon
argon
argon
argon
argon
argon
argon
argon
argon
argon
argon
argon
argon
argon
4
6
3
77
67
68
2b
3
c
4
5
6
7
8
9
12
24
24
24
24
36
24
2
—
26
80
68
70
54
69
74
74
68
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
1.0
1.0
FeCl3 (1)
FeCl3 (1)
0.55
0.55
0.55
0.55
0.55
1.0
3
FeCl3·6H2O (1)
Fe(acac)3 (1)
FeCl2·4H2O (1)
K3Fe(CN)6 (1)
FeCl3 (0.1)
FeCl3 (0.1)
FeCl3 (0.1)
FeCl3 (0.1)
FeCl3 (0.1)
FeCl3 (0.1)
FeCl3 (0.1)
FeCl3 (0.1)
FeCl3 (0.1)
FeCl3 (0.1)
FeCl3 (0.1)
FeCl3 (0.2)
24
24
24
24
24
24
24
24
24
36
24
24
24
24
24
12
c
—
Trace
—
c
argon
20
55
50
50
43
23
20
15
25
20
32
67
1.0
2.0
air atmosphere
air atmosphere
air atmosphere
oxygen atmosphere
air atmosphere
air atmosphere
air atmosphere
air atmosphere
air atmosphere
air atmosphere
air atmosphere
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
Dioxane
CH2Cl2
Toluene
DMSO
a Reaction performed at 0.25 mmol scale in solvent (3 mL) and yields of 2 are given for isolated products. b Reaction carried out at room temperature.
c (Z)-selenoenyne 1a was recovered.
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using 1.0 equiv (Table 1, entry 11). To better understand if the
activity of the iron system is due to the different ligand partner
type in the iron complex or to the effect of dry iron salt, some
experiments were also carried out using FeCl3·6H2O, Fe(acac)3,
FeCl3·4H2O and K3Fe(CN)6 and a very sluggish reactivity was
observed (Table 1, entries 13–16). We observed that the amount
of PhSeSePh affected the reaction result. Fortunately, decreasing
the amount of PhSeSePh from 1.0 to 0.55 equiv did not modify
the reaction behavior and the product was obtained in a similar
yield (Table 1, entry 12). This result is significant because it
suggests that the two portions of diphenyl diselenide (PhSe) were
incorporated in the final product and indicates an atom economy,
which is an important concept of green chemistry philosophy.
Considering that the absence of air in the system could hamper the
catalyst reactivity of iron reoxidation, we next hypothesized that
the cyclization could be achieved under catalytic conditions, if one
changes the inert reaction to an open atmosphere. A comparison
of reaction run using rigorously dried systems (Table 1, entry
5) versus those run in an open atmosphere (Table 1, entry 18)
showed that the yield was higher in the latter case. However, no
significant improvement in the yield was found when an oxygen
atmosphere was adopted (Table 1, entry 21). On the basis of this
encouraging result, a range of other solvents was screened to find
the best conditions that might be applied to the cyclization reaction
using a catalytic system (Table 1, entries 19–29). We were pleased
to observe that FeCl3 (20 mol%) in DMSO efficiently catalyzed
the cyclization of 1a in an excellent isolated yield (Table 1, entry
28). This result is significant in order to make our methodology
more attractive from an economic standpoint and eco-friendly.
The above results suggest that while FeCl3 (1 equiv), PhSeSePh
(0.55 equiv) in CH2Cl2 at 40 ◦C were the best conditions to carry
out the reaction under argon atmosphere, the use of PhSeSePh
(0.55 equiv) in DMSO at 110 ◦C were the best conditions for the
catalytic system (FeCl3 20 mol%) in an open atmosphere. After
obtaining two sets of conditions (catalytic and non-catalytic) for
the cyclization of 1a, we next investigated the cyclization of several
enynes with different diorganyl dichalcogenides (Table 2).
With the optimized conditions defined, we started the inves-
tigation of the scope of the cyclization process. Initially, we
kept the enyne structures constant and studied the influence of
different diorganyl dichalcogenides. No significant differences in
yields were found with neutral, electron rich and electron poor
diorganyl dichalcogenides (Table 2, entries 1–5). However, the
cyclization using diorganyl dichalcogenides bearing a sterically
hindered functionality gave only moderated yields (63 and 59%)
under identical conditions (Table 2, entries 6 and 7). These results
revealed that the reaction does not significantly depend on the
electronic effects of the substituents in the aromatic ring of the
diorganyl dichalcogenides but that it seems to be sensitive to the
steric effects. Under the same conditions, diaryl ditellurides reacted
similarly and products 2h–i were obtained in moderate yields
(Table 2, entries 8 and 9). Interestingly, the cyclization reaction
of 1a also proceeded smoothly with dialkyl diselenides and
ditellurides but noticeably lower yields were obtained compared
to the use of aryl derivatives. The yields obtained in the cyclization
reaction using diselenides are consistently higher than those ob-
tained with tellurides, partly because selenides are less susceptible
to selenoxide elimination than the corresponding tellurides.32
Other enynes having functionalities such as sterically hindered
1e, electron poor aromatic rings 1f and unsymmetrical system 1g
reacted without difficulty and gave excellent yields (Table 2, entries
12–15). Encouraged by the success of the cyclization reactions of
aryl enynes with diorganyl dichalcogenides, we then turned our
interests to the reactions of alkyl enynes. In accordance with
previous observations made by us, selenoenyne cyclization via
copper salts with (Z)-alkyl selenoenynes was markedly met with
failure.13a Thankfully, the results summarized in Table 2 show that
the optimized conditions described above proved to be general
for the cyclization of alkyl selenoenynes with a large variety
of functionalized diorganyl dichalcogenides. We were pleased
to find out that all reactions afforded the desired selenophene
products in good yields and substituents having either electron-
donating or electron-withdrawing groups on the aromatic ring
of diorganyl dichalcogenides have almost no significant effect
on these reactions (Table 2, entries 16–24). Furthermore, both
aryl and alkyl telluroenynes were successfully used as substrates
affording the desired tellurophenes; even though, as expected, the
yields of the cyclizations of alkyl telluroenynes were lower than
those of aryl telluroenynes (Table 2, entries 25–28). The efficiency
of this system was further extended to the cyclization reactions of
various selenoenynes using the catalytic conditions determined in
Table 1, entry 28. The obtained yields were good but considerably
lower compared to the non-catalytic conditions (Table 2, entries
1–11; yields in parentheses).
In order to complete our investigation and to further prove the
potential of 3-chalcogen selenophene derivatives as precursors for
increasing molecular complexity, we tested the reactivity of these
compounds toward halogenation and Li/Se exchange reactions.
In this way, the reaction of 2a with an excess of bromine in
refluxing CHCl3, afforded the resultant product 3a, in 86% isolated
yield (Scheme 2). This result is significant since these halogenated
selenophenes find applications in transition metal-catalyzed cross-
coupling reactions with various nucleophilic compounds for the
preparation of more complex molecules of selenophenes.33 In
addition, the reaction of selenophene 2j with n-butyllithium (1.0
equiv), THF (3 mL), at -78 ◦C gave the lithiated species. The
lithiated species was trapped by aldehydes (1.5 equiv) at -78 ◦C and
the reaction mixture was allowed to warm to room temperature,
affording the secondary alcohols 4a–c in good yields (Scheme 3).
Scheme 2 Synthesis of 3,4-dibromoselenophene 3a.
Scheme 3 Reactions of intermediate 3-lithio selenophene with aldehydes.
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Table 2 Synthesis of 3-organochalcogen chalcogenophene derivatives 2
Entry
1
(Z)-enyne
RYYR
Product
Yield A% (B%)a,b
74 (67)
2
3
1a
1a
81 (71)
78 (73)
4
5
6
1a
1a
1a
79 (55)
66 (57)
63 (50)
7
8
9
1a
1a
1a
(59)
36 (23)
43
10
11
1a
1a
n-BuSe)2
n-BuTe)2
60 (77)
40 (30)
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Table 2 (Contd.)
Entry
12
(Z)-enyne
RYYR
Product
Yield A% (B%)a,b
82
13
14
78
73
15
16
1g
66
67 (NR)
17
1h
58
18
19
20
1h
1h
1h
62
54
53
21
1h
44
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Table 2 (Contd.)
Entry
22
(Z)-enyne
RYYR
Product
Yield A% (B%)a,b
43
1h
23
24
1h
n-BuSe)2
64
45
25
46 (Trace)
26
27
28
1j
1j
43
51
37
a Reaction conditions A: enyne (0.25 mmol), diorganoyl dichalcogenide (0.55 equiv), FeCl3 (1 equiv) in CH2Cl2 (3 mL) under reflux for 2 h. Reaction
conditions B: enyne (0.25 mmol), diorganoyl dichalcogenide (0.55 equiv), FeCl3 (0.2 equiv) in DMSO (3 mL) at 110 ◦C under air atmosphere for 12 h.
b Yields of isolated products.
behavior that disengages the animal from active forms of coping
with stressful stimuli.35 This immobility, referred to as behavioral
Results and discussion
The structure–activity relationship studies were planned using
3-(4-fluorophenylselenyl)-2,5-diphenylselenophene as a prototype
molecule and a series of chemical alterations were performed. In
an attempt to investigate the potential antidepressant-like action
of a series of 3-chalcogen selenophenes prepared, the mouse
forced-swimming test (FST) was carried out. The FST is a well-
established screening paradigm for antidepressants.34 Immobility
is thought to reflect either a failure to persist in escape directed
behavior after persistent stress or the development of passive
despair in animals, is claimed to reproduce a condition similar to
human depression and is reduced by several agents therapeutically
effective in this disorder.36
As previously demonstrated by Gay et al.,3 selenophene 2c,
administered by i.g. route at the dose of 50 mg kg-1, reduced
significantly (by around 60%) the total immobility time of mice
in the FST (p <0.001). The positive control, paroxetine, at the
dose of 16 mg kg-1, given 45 min earlier by i.p. route, decreased
the immobility time in the FST by around 68% (p < 0.001)
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group of selenophene 2c and that chloro and trifluoromethyl
groups present higher steric parameters than fluorine, we suppose
that steric hindrance promoted by the presence of these groups
affects the antidepressant-like action of selenophenes 2d and
2e. The results also demonstrated that the antidepressant-like
action of selenophenes 2a–2e significantly depends on the elec-
tronic effects. The anti-immobility effects elicited by compounds
substituted with p-fluorine (2c), p-chloro (2d) and m-CF3 (2e)
indicate that the presence of electron withdrawing groups affects
the pharmacological properties of 3-chalcogen selenophenes.
Despite the fact that steric hindrance and electronic effects
can explain structure–activity relationship of the selenophenes
tested, we cannot discard the possibility of pharmacokinetic
influence on their in vivo effects. Chemical modifications per-
formed on selenophene structures could alter their pharmacoki-
netic properties and then modify their absorption, distribution,
metabolism and/or excretion. The absorption and distribution
of a drug molecule are controlled by its balance of lipophilicity
and hydrophilicity as well as ionization. In fact, the use of
fluorine in drug design is an example of a directed strategy to
increase lipophilicity, biological half-life and bioabsorption of
organic compounds, especially aromatic compounds, improving
their therapeutic effectiveness.37 The fluorophenyl group is slightly
more lipophilic than the benzoyl group, but chlorophenyl and
trifluoromethyphenyl groups are much more lipophilic.32 This ex-
ceedingly lipophilic property compromises the hydrogen-bonding
capability with water molecules and then it hinders the solubility
of a drug in intestinal fluid, impairing its absorption. Therefore,
the different absorptive properties of the selenophenes studied
could also explain the higher effectiveness of compound 2c than
2d and 2e. In addition, the strategic incorporation of fluorine
into organic molecules has been also widely used to prevent
deactivation of biologically active substances in vivo increasing
their biological half-life. According to Begue and Bonnet-Delpon
(2006)39 the replacement of a specific C–H bond with a C–F bond
can effectively block metabolic processes, which can also help us
to explain the more potent antidepressant-like action showed by
selenophene 2c in mice.
The logical next step in our investigation was to further clarify
whether substitutions at the 2 and 5-positions of the selenophene
ring could alter the antidepressant-like activity of the selenophene.
In order to answer this question compounds 2m, 2o and 2s were
challenged in the mouse FST (Fig. 2). Interestingly, selenophene
2m did not produce an anti-immobility effect in mice, suggesting
that the presence of the fluorophenyl group bonded to the
selenophene ring did not confer an antidepressant-like activity
(Fig. 2).
Compound 2s did not decrease the immobility time of mouse in
the FST (Fig. 2). Therefore, the lack of an anti-immobility effect
shown by compound 2s leads to the assumption that the phenyl
group at the 2-position of selenophene ring is necessary for the
antidepressant-like action of this class of compounds (Fig. 2). In
addition, selenophene 2o decreased significantly the immobility
time by around 52% (Fig. 2). This result suggests that the removal
of the phenyl group attached to the 5-position of selenophene ring
does not alter its antidepressant-like action. Thereby we postulate
that, in addition to the fluorophenyl portion directly bonded to
the selenium atom at the 3-position of selenophene, the presence
of a phenyl group bonded at the 2-position of the selenophene
Fig. 1 Effect of an acute administration of selenophenes 2a, 2b, 2c, 2d
and 2e on the immobility period in the mouse FST. Selenophenes were
intragastrically administered at 30 min before FST. Values represent means
of total immobility time for six mice in each group. Standard deviation
(SD) of all groups represents <10% of means. *** P <0.001 and * P <0.01
@
when compared to the control group. P <0.05 when compared to the
compound 2c-treated group. C means control, a group of mice treated with
canola oil. Prx means paroxetine, mice were administered with paroxetine
16 mg kg-1, i.p., 45 min before FST.
(Fig. 1). Compound 2c has a fluorophenyl portion and at the
same dose, route and pretreatment time has been reported to
interact with the serotonergic system, particularly by its inhibitory
effect on 5-HT uptake in synaptosomes of mouse brain.3 In
fact, the importance of fluorine in medicinal chemistry is well
recognized. Fluorine has played a particularly important and
historical role in the development of biologically active agents, as
antimicrobial, anticancer, anticoagulant, cardioprotective, anti-
inflammatory, hypoglycemic, antipsychotic and antidepressant
drugs.37 The presence of 4-fluorophenyl group appears to be
essential for optimum potency of neuroleptic agents, spiroperidol
and haloperidol.38 Further, the fluorophenyl group is also found in
the structure of other drugs that, like selenophene 2c, inhibit 5-HT
reuptake, such as paroxetine, citalopram and escitalopram. Thus,
the structural similarity between compound 2c and these SSRIs
raises the hypothesis that the antidepressant-like mechanism of
compound 2c could be related to the presence of the fluorophenyl
portion.
In order to confirm the importance of the fluorophenyl portion
to the antidepressant-like action of selenophenes, some examples
of selenophenes containing substituents at the phenyl group
bonded to the selenium atom were investigated in the mouse
FST. The antidepressant-like action of selenophenes 2a (without
a substituent), 2b (with a methyl substituent), 2d (with a p-chloro
substituent), and 2e (with a m-CF3 substituent) was investigated
(Fig. 1). Compounds 2a and 2b did not elicit antidepressant-
like action in the mouse FST. By contrast, compounds 2d and
2e showed a significant effect in reducing the total immobility
period (by around 17%), exerting an antidepressant-like action.
Moreover, selenophenes 2d and 2e were significantly less effective
as antidepressant-like agents than compound 2c (note the immo-
bility time elicited by 2c, 96 s, compared to 2d, 166 s, and 2e, 167
s) (Fig. 1).
Fluorine is the second smallest element with a size approxi-
mately 20% larger than the smallest element, hydrogen, and a
stepwise substitution of a hydrogen by fluorine, chloro or trifluo-
romethyl group gradually increases bulkiness.39 Based on the fact
that the fluorophenyl portion could represent the pharmacophoric
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corresponding secondary alcohols, and refluxing the selenophene
2a with an excess of bromine in a CHCl3 solution gave the
product bromide derivatives in good yields. Selenophenes 2c, 2d,
2e and 2o showed a significant antidepressant-like action when
investigated in the mouse FST. The structure–activity relationship
studies clearly show that the phenyl group at the 2-position and an
organoselenium group at the 3-position of the selenophene ring
are essential for the antidepressant-like activity of selenophenes. A
close inspection of the results also revealed that the fluorophenyl
portion in the organoselenium group is fundamental for the
antidepressant-like action of this class of organochalcogen. The
results of this study indicate that compounds 2c and 2o are promis-
ing novel selenophene compounds with potential for the treatment
of human depression. Our research group has been engaged in
targeting the exact mechanism by which these selenophenes play
their antidepressant-like action.
Fig. 2 Effect of an acute administration of selenophenes 2m, 2o and 2s as
compared to 2c on the immobility period in the mouse FST. Selenophenes
were intragastrically administered 30 min before FST. Values represent
means of total immobility time for six mice in each group. Standard
deviation (SD) of all groups represents <10% of means. *** P <0.001
when compared to the control group. C means control, a group of mice
treated with canola oil. Prx means paroxetine, mice were administered with
paroxetine 16 mg kg-1, i.p., 45 min before FST.
Experimental section
Proton nuclear magnetic resonance spectra (1H NMR) were
obtained at 200 MHz on a DPX-200 NMR spectrometer or
at 400 MHz on a DPX-400 NMR spectrometer. Spectra were
recorded in CDCl3 solutions. Chemical shifts are reported in ppm,
referenced to the solvent peak of CDCl3 or tetramethylsilane
(TMS) as the external reference. Data are reported as follows:
chemical shift (d), multiplicity, coupling constant (J) in Hertz
and integrated intensity. Carbon-13 nuclear magnetic resonance
spectra (13C NMR) were obtained either at 50 MHz on a
DPX-200 NMR spectrometer or at 100 MHz on a DPX-400
NMR spectrometer. Spectra were recorded in CDCl3 solutions.
All synthesized and tested compounds were obtained in purity
superior to 98% determined by combustion analysis, HPLC and
gas chromatography.
ring is essential for the antidepressant-like action of selenophene
in mice.
To further prove the real influence of the selenium group at
the 3-position of selenophene in the antidepressant-like activity,
we investigated the effect of two groups: a bromine (3a) and
a secondary alcohol group (4a, 4b and 4c) in the mouse FST.
Compounds 3a, 4a, 4b and 4c did not reduce the immobility
time in the mouse FST (Fig. 3). As a result, the lack of anti-
immobility effect of these compounds further proves that the
organoselenium group at the 3-position of selenophene is essential
for the antidepressant-like activity of selenophenes.
General procedure for iron-promoted cyclization of
Z-chalcogenoenynes and diorganoyl dichalcogenides (Condition A)
To a Schlenck tube, under argon, containing a mixture of FeCl3
(0.25 mmol) in dry CH2Cl2 (2 mL) was added the appropriate
diorganoyl dichalcogenide (0.55 equiv). The resulting solution
was stirred for 15 min at room temperature. After this, Z-
chalcogenoenyne (0.25 mmol) in CH2Cl2 (1 mL) was added
and resulting solution was stirred under reflux for 3 h. After
that the solution was cooled to room temperature, diluted with
dichloromethane (10 mL), and washed with saturated aq NH4Cl
(3 ¥ 10 mL). The organic phase was separated, dried over MgSO4,
and concentrated under vacuum. The residue was purified by flash
chromatography on silica gel using hexane as the eluent.
Fig. 3 Effect of an acute administration of selenophenes 3a, 4a, 4b
and 4c as compared to 2c on the immobility period in the mouse FST.
Selenophenes were intragastrically administered 30 min before FST. Values
represent means of total immobility time for six mice in each group.
Standard deviation (SD) of all groups represents <10% of means. *** P
<0.001 when compared to the control group. C means control, a group of
mice treated with canola oil. Prx means paroxetine, mice were administered
with paroxetine 16 mg kg-1, i.p., 45 min before FST.
General procedure for iron-catalyzed cyclization of
Z-chalcogenoenynes and diorganoyl dichalcogenides (Condition B)
To a solution of DMSO (2 mL), FeCl3 (20 mol%), under air
atmosphere, was added the appropriate diorganoyl dichalcogenide
(0.55 equiv). The resulting solution was stirred for 15 min at room
temperature. After thatZ-chalcogenoenyne (0.25mmol) in DMSO
(1 mL) was added and resulting solution was stirred under reflux
for 12 h. After that the solution was cooled to room temperature,
diluted with ethyl acetate (10 mL), and washed with saturated aq
NH4Cl (3 ¥ 10 mL). The organic phase was separated, dried over
Conclusion
In summary, we have demonstrated the FeCl3–diorganoyl
dichalcogenide-mediated cyclization of (Z)-enynes giving 3-
organochalcogen chalcogenophenes in good yields under mild
conditions. In addition, 3-chalcogen selenophenes were treated
under selenium/lithium exchange conditions with n-BuLi and
trapping of the lithium intermediates with aldehydes provided the
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MgSO4, and concentrated under vacuum. The residue was purified
by flash chromatography on silica gel using hexane as the eluent.
of the Federal University of Santa Maria, Brazil (# 124/2010).
The procedures in this study were performed in accordance with
the NIH Guide for the Care and Use of Laboratory Animals. All
efforts were made to minimize animals’ suffering and to reduce
the number of animals used in the experiments.
2,5-Diphenyl-3-(butylseleno)selenophene (2j)
Yield Condition A: 0.077 g (74%). Yield Condition B: 0.070 g
(67%). 1H NMR (CDCl3, 200 MHz): d 7.60–7.51 (m, 5 H), 7.44–
7.24 (m, 6H), 2.79 (t, J = 7.7 Hz, 2H), 1.59 (quint, J = 7.7 Hz,
2H), 1.30 (sex, J = 7.7 Hz, 2H), 0.83 (t, J = 7.7 Hz, 3H). 13C NMR
(CDCl3, 50 MHz):d 148.95, 146.99, 136.26, 135.71, 131.44, 129.34,
128.91, 128.22, 127.79, 127.77, 126.03, 122.63, 32.15, 28.56, 22.71,
13.46. MS (EI, 70 eV) m/z (relative intensity): 419 (58), 361 (19),
283 (100), 202 (81), 126 (6), 102 (7), 89 (8). Anal. (%) Calcd for
C20H20Se2: C 57.43; H 4.82. Found: C 57.62, H 4.89.
Drugs
For behavioral tests, selenophenes 2a, 2b, 2c, 2d, 2e, 2m, 2o, 2s,
3a, 4a, 4b and 4c were dissolved in canola oil and administered
intragastrically (i.g.). A single dose of 50 mg kg-1 was used for
all compounds for comparison purposes. Paroxetine, a positive
control, was dissolved in saline and administered intraperitoneally
(i.p.) at the dose of 16 mg kg-1. Mice received selenophenes and
paroxetine in a constant volume of 10 ml kg-1 of body weight.
Appropriate vehicle-treated groups were also simultaneously
assessed. The dose of 50 mg kg-1 and the pretreatment time of
30 min were chosen based on a previously published study that
established the time and the dose at which compound 2c reached
its maximum anti-immobility effect.11
2,5-Bis(4-fluorophenyl)-3-(phenylseleno)selenophene (2m)
Yield Condition A: 0.092 g (78%). 1H NMR (CDCl3, 200 MHz):
d 7.53–7.21 (m, 10H), 7.11–7.00 (m, 4H). 13C NMR (CDCl3,
50 MHz): d 162.66 (d, J = 248.09 Hz), 162.62 (d, J = 248.09 Hz),
148.27, 132.45, 132.36, 131,90 (d, J = 3.659 Hz), 131.78 (d, J =
3.659 Hz), 132.45, 132.43, 132.36, 131.07 (d, J = 8.05 Hz), 129.31,
127.75 (d, J = 8.05 Hz), 126.80, 122.58, 115.84 (d, J = 21.95 Hz),
115.36 (d, J = 21.95 Hz). MS (EI, 70 eV) m/z (relative intensity):
476 (67), 396 (68), 316 (26), 238 (100), 220 (14), 187 (11), 107 (15),
77 (6). HRMS calcd for C22H14F2Se2: 475,9394. Found: 475.9381.
Forced swimming test (FST)
The FST, as originally described by Porsolt (1977),34a,b is the most
widely used pharmacological assay for assessing antidepressant
activity. In this test, mice were individually forced to swim in
an open cylindrical container (diameter 10 cm, height 25 cm),
containing 19 cm of water at 25
1
◦C. The total duration of
2-Phenyl-3-(4-fluorophenylseleno)selenophene (2o)
immobility was recorded during the last 4 min of the 6-min period
after 30 min of selenophenes (50 mg kg-1, i.g.) or canola oil (10 ml
kg-1, i.g.) administration. Paroxetine, administered at the dose of
16 mg kg-1 (i.p.), 45 min before FST, was used as a positive control.
Each mouse was judged to be immobile when it ceased struggling
and remained floating motionless in the water, making only those
movements necessary to keep its head above water. A decrease in
the duration of immobility is indicative of an antidepressant-like
action.35
Yield Condition A: 0.066 g (66%). 1H NMR (CDCl3, 200 MHz):
d 7.89 (d, J = 5.73 Hz, 1H), 7.52–7.45 (m, 2H), 7.43–7.27 (m, 5H),
6.92 (t, J = 8.8 Hz, 2H). 13C NMR (CDCl3, 50 MHz): d 160.95 (d,
J = 246.18 Hz), 149.09, 136.31, 135, 86 (d, J = 8.08 Hz), 131.36,
130.11, 129.38, 128.32, 128.05, 126.55 (d, J = 3.65 Hz), 121.98,
116. 32 (d, J = 21.96 Hz). MS (EI, 70 eV) m/z (relative intensity):
382 (58), 302 (63), 287 (6), 221 (32), 206 (13), 150 (10), 126 (45),
115 (100), 89 (12), 77 (10), 51 (5). Anal. (%) Calcd for C16H11FSe2:
C 50.55; H 2.92. Found: C 50.71, H 2.98.
Statistical analysis
2,5-Dibutyl-3-(butylseleno)selenophene (2w)
The experimental results are presented as the mean S.E.M.
The non-paired t-test was considered appropriate to compare the
immobility times between control groups and selenophene-treated
groups. These analyses were performed using GraphPad Prism
version 5, and a significance level of 0.05 was chosen.
Yield Condition A: 0.060 g (64%). 1H NMR (CDCl3, 200 MHz):
d 6.81 (s, 1H), 2.92 (t, J = 7.7 Hz, 2H), 2.83–2.69 (m, 4H), 1.72–
1.53 (m, 6H), 0.97–0.85 (m, 9H). 13C NMR (CDCl3, 100 MHz):
d 150.71, 149.08, 131.87, 120.47, 35.14, 34.34, 33.06, 32.50, 29.92,
28.45, 22.80, 22.61, 22.13, 13.90, 13.79, 13.55. MS (EI, 70 eV) m/z
(relative intensity): 380 (92), 337 (53), 323 (66), 381 (100), 243 (92),
201 (57), 135 (33), 91 (81), 55 (41). HRMS calcd for C16H28Se2:
380.0521. Found: 380.0533.
Acknowledgements
The financial support by UFSM, CAPES, FAPERGS (PRONEX
research grant # 10/0005-1) and CNPq (INCT-catalise) is grate-
fully acknowledged. We thank CNPq for fellowships.
Animals
The behavioral experiments were conducted using male adult
Swiss mice (25–30 g) maintained at 22–25 ◦C with free access
to water and food, under a 12 : 12 h light/dark cycle, with lights
on at 7:00 a.m. All manipulations were carried out between 08:00
a.m. and 04:00 p.m and the experiments were performed according
to a randomized schedule. All tests were performed on separate
groups of animals and each animal was used only once in each
test. The animals were used according to the guidelines of the
Committee on Care and Use of Experimental Animal Resources
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