CuI/glycerol mediated stereoselective synthesis of 1,2-bis-chalcogen alkenes from terminal alkynes: Synthesis of new antioxidants

Article abstract of DOI:10.1016/j.tetlet.2014.07.109

(E)-1,2-Bis-chalcogen alkenes were stereoselectively prepared in good yields by the addition of diorganyl dichalcogenides to terminal alkynes using CuI/Zn/glycerol as a recyclable catalytic system. The antioxidant activity in vitro of four (E)-1,2-bis-cha

Full text of DOI:10.1016/j.tetlet.2014.07.109

Tetrahedron Letters 55 (2014) 5275–5279
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
CuI/glycerol mediated stereoselective synthesis of 1,2-bis-chalcogen
alkenes from terminal alkynes: synthesis of new antioxidants
a
a,b
a
a
a
Lóren C. C. Gonçalves , Francine N. Victória , David B. Lima , Pedro M. Y. Borba , Gelson Perin ,
b
a,
⇑
Lucielli Savegnago , Eder J. Lenardão
a
LASOL, CCQFA, Universidade Federal de Pelotas—UFPel, PO Box 354, 96010-900 Pelotas, RS, Brazil
Grupo de Pesquisa em Neurobiotecnologia—GPN, CDTec, Universidade Federal de Pelotas, UFPel, Pelotas, RS, Brazil
b
a r t i c l e i n f o
a b s t r a c t
Article history:
(E)-1,2-Bis-chalcogen alkenes were stereoselectively prepared in good yields by the addition of diorganyl
Received 1 July 2014
Revised 23 July 2014
Accepted 25 July 2014
Available online 2 August 2014
dichalcogenides to terminal alkynes using CuI/Zn/glycerol as
antioxidant activity in vitro of four (E)-1,2-bis-chalcogen alkenes synthesized was evaluated and
E)-1,2-bis-(4-methoxyphenylselanyl)styrene 3b presented excellent activity. The catalytic system used
in the synthesis was recovered and used directly up to 5 cycles without loss of activity.
Ó 2014 Elsevier Ltd. All rights reserved.
a recyclable catalytic system. The
(
Keywords:
Catalysis
Bis-chalcogen alkenes
Glycerol
CuI/Zn
Antioxidant
New strategies for the preparation of bis-chalcogen alkenes have
been the object of intense research, due to the continued interest in
synthetic applications and, more recently, new pharmacological
properties of vinyl chalcogenides, as can be observed in several arti-
Volatile organic solvents (VOCs) are responsible for most of
waste and pollution generated by chemical processes8 and the
search for green, reusable solvents is still a great challenge in
9
organic synthesis. Possessing a unique combination of physical
1
,2
cles.
Classical methods for the synthesis of 1,2-bis-chalcogen
and chemical properties and some advantages of water, such as
highly polar, biodegradable, immiscible with hydrocarbons and
ethers, and aptitude to dissolve inorganic compounds, glycerol is
alkenes described over the years involve mainly three different
3
approaches: reaction of vinyl dichlorides with thiolate anions,
reaction of alkynes with radical chalcogen species,4 and reactions
ideal for use as a sustainable solvent in organic synthesis.
10,11
5
of alkynes with dichalcogenides mediated by transition metals,
Recently, our group described environmental friendly proce-
6
amidst others. However, most of these protocols described for
dures for the selective preparation of vinyl chalcogenides starting
from terminal alkynes and diorganyl dichalcogenides.1
2–14
We
the preparation of bis-chalcogen alkenes require the use of heavy
metals, high temperature, and present other limitations, including
toxicity and hazard associated with the use of volatile organic
solvents. Besides, in a general way, these protocols afford selec-
tively (Z)-1,2-bis-chalcogen alkenes or, in some cases, a mixture
of Z and E isomers and other side products.6
4 4
observed that NaBH /[bmim]BF is a convenient recyclable system
to prepare (Z)-vinyl chalcogenides starting from propargyl and
derivative alcohols. When phenyl acetylene was used, (E)-1,2-bis-
phenylchalcogen styrenes were obtained in good yields.12 Addi-
tionally, (E)-bis-chalcogen styrenes were obtained in good yields
On the other hand, pyrazoles are an important class of hetero-
cyclic compounds, and molecules containing the pyrazole nucleus
stand out due their application as catalysts,7a liquid crystal, and
4
and high selectivity using alumina/NaBH under solvent-free
1
3
conditions, while the Z isomer was preferably obtained when
7b
14
PEG-400 was used as solvent.
also their pharmacological activities, such as anti-inflammatory,
Herein, we report the direct copper-catalyzed addition of diaryl
dichalcogenides to terminal alkynes, using CuI/Zn/glycerol as the
antipyretic, and analgesic.7
c,d
Nevertheless, the synthesis of
15
1
,2-bis-chalcogen alkenes containing the pyrazole unit has not
catalytic system (Scheme 1). This approach provides straightfor-
been explored.
ward, efficient, and stereoselective access to
E)-1,2-bis-chalcogen alkenes, some of them are potent antioxi-
dants, in a stereoselective fashion.
a variety of
(
⇑
Corresponding author. Tel./fax: +55 53 32757533.
E-mail address: lenardao@ufpel.edu.br (E.J. Lenardão).
http://dx.doi.org/10.1016/j.tetlet.2014.07.109
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
0

5
276
L. C. C. Gonçalves et al. / Tetrahedron Letters 55 (2014) 5275–5279
diphenyl diselenide 2a in 95% yield (entry 1), (E)-1,2-bis-(p-meth-
CuI (5 mol%), Zn
glycerol
R
Y
Ar
R
YAr
ylphenyl)seleno alkene 3b was obtained exclusively in 92% yield
after only 3 h (Table 2, entry 2). Similarly, 3c and 3d were prepared,
respectively, from 2c and 2d in 82% and 80% yields after 3 h of stir-
ring at 110 °C (entries 3 and 4). In contrast, diaryl diselenides 2e
+
Ar
Y
1
10 oC, N
2
1a-c
2a-h
Scheme 1. General scheme of the reaction.
ArY
3
-i
(
R = p-Cl) and 2f (R = m-CF
groups, were less reactive, affording the respective products 3e
56%, E:Z ratio = 100:0) and 3f (60% yield, E:Z ratio = 75:25) only
3
), containing electron-withdrawing
(
in moderated yields (Table 2, entries 5 and 6). A similar electronic
effect was not observed in the alkyne component of the reaction,
once lower yields were obtained both with 1-methyl-4-ethynil-
benzene 1b and 1-chloro-4-ethynylbenzene 1c, which afforded
the respective (E)-bis-chalcogen alkenes 3g (73% yield, entry 7)
and 3h (55% yield, entry 8) in similar yields and selectivity. When
diphenyl disulfide 2g was used, a higher reaction time was needed
to prepare (E)- and (Z)-1,2-bis-(phenylthio)styrene 3i in 60% yield
and a E:Z ratio of 68:32. In contrast, when diphenyl ditelluride 2h
was used, no product 3j could be isolated and only traces were
detected by GC/MS.
Phenyl acetylene 1a and diphenyl diselenide 2a were used as
model substrates to determine the best reaction conditions
Table 1). Thus, a mixture of 1a (0.6 mmol) and 2a (0.6 mmol)
was stirred at 110 °C (oil bath), in the presence of CuI as catalyst
5 mol %), Zn dust (0.6 mmol) and glycerol (1.0 mL) under N atmo-
sphere. After 5 h, (E)-1,2-bis-(phenylselanyl)styrene 3a was
obtained in 95% yield with a E:Z ratio of 90:10 (Table 1, entry 1).
Aiming to improve the yield and selectivity of the reaction, the
mixture was stirred for 24 h, giving 3a in a similar yield and selec-
tivity (Table 1, entry 2). When we used a lower amount of catalyst
(
(
2
(
3 mol %) the desired product 3a was obtained in 72% yield, even
Due to the importance of the pyrazole unit in biologically active
heterocyclic compounds, we decided to extend the methodology
using N-propynyl pyrazoles 4a–c as alkyne partners, aiming to pre-
pare (E)-bis-chalcogen alkene pyrazoles. Differently to the
observed for the aryl alkynes 1a–c, propynyl pyrazoles 4a–c affor-
ded a mixture of bis- and mono-chalcogen alkenes (Table 3). Thus,
when 1-(prop-2-yn-1-yl)-1H-pyrazole 4a reacted with diphenyl
diselenide 2a under our conditions for 2 h, a mixture of (E)-5a,
after 24 h of reaction (Table 1, entry 3). Similarly, when the amount
of zinc was diminished to 0.3 mmol, yield of 3a was only 64% after
2
4 h (Table 1, entry 4). Remarkably, poor yields of 3a were
obtained in the absence of CuI or Zn (Table 1, entries 5 and 6)
and only traces were formed when both of them were not present
(Table 1, entry 7). We tested also the reaction at a milder temper-
ature (60 °C) and a mixture of (E)- and (Z)-1,2-bis-(phenylsela-
nyl)styrene 3a in 39% yield was isolated after 24 h (Table 1, entry
(Z)-6a, and gem-7a was obtained in a 50:13:37 ratio and in an
8
). It was observed also that nitrogen atmosphere is critical to
overall yield of 90% (Table 2, entry 1). A higher selectivity for the
bis-chalcogen alkene was observed for 3,5-dimethyl-1-(prop-
the formation of 3a in good yield, once decrease in yield and selec-
tivity was observed in the reaction performed in an open flask
2
-yn-1-yl)-1H-pyrazole 4b, which afforded exclusively a mixture
(Table 1, entry 9).
of (E)-5b and (Z)-5b in 90% yield and a E:Z ratio of 90:10 (Table 2,
entry 2). The reaction tolerates also the presence of a bromine
atom in the pyrazole ring, as in 5-bromo-1-(prop-2-yn-1-yl)-1H-
pyrazole 4c; however, only mono-adducts (Z)-6c, (E)-6c, and 7c
were isolated in 85% yield after 3 h [(Z)-6c:(E)-6c:7c
ratio = 66:6:28; Table 2, entry 3]. Similarly, a mixture of mono
phenylthio alkenes was isolated after 6 h of reaction in 78% yield
using diphenyl disulfide 2g and 1-(prop-2-yn-1-yl)-1H-pyrazole
With the best conditions in hand, we extended the protocol to
1
6
other terminal alkynes and diaryl dichalcogenides (Table 2). As
it can be seen in Table 2, for most of studied cases, the desired
products were obtained in excellent yields and stereoselectivity.
It was observed that the best yields and higher stereoselectivities
were obtained using diaryl diselenides 2a–d, containing electron-
donating and neutral groups at the aromatic ring (Table 2, entries
–4). The presence of electron-donor groups in 2b–d increases the
electron density on the selenium atom, making it a more reactive
nucleophile. Thus, while 5 h were necessary to prepare 3a from
1
4
a (Table 3, entry 4). No reaction was observed when diphenyl
ditelluride 2h was used.
The use of this catalytic system showed good results in studies
regarding their recyclability. Initially a reuse study of the CuI/Zn/
glycerol system was carried out for the reaction of 1a with 2a to
obtain 3a. After stirring at 110 °C for 5 h, the reaction mixture
was diluted and extracted with a mixture of hexane/ethyl acetate
Table 1
Synthesis of (E)-1,2-bis-(phenylselanyl)styrene 3a under different conditionsa
9
5:5 (3 ꢀ 3.0 mL). The upper organic phase was removed, the sol-
CuI, Zn
vent evaporated and the product 3a was isolated. The remaining
inferior phase containing a mixture of CuI/Zn/glycerol was dried
under vacuum and directly reused for further reactions, simply
by adding more reagents 1a and 2a. As shown in Table 4, the sys-
tem CuI/Zn/glycerol presented a good level of efficiency even after
reusing five times, being the product 3a obtained in 95%, 94%, 91%,
Se
Se
2a
glycerol
Se
+
110 °C, N2
Se
Yieldb (%)
1a
3a
Entry
CuI (mol %)
Zinc (mmol)
Time (h)
Ratioe (E/Z)
1
2
3
4
5
6
7
8
9
5
5
3
5
—
5
—
5
5
0.6
0.6
0.6
0.3
0.6
—
—
0.6
0.6
5
24
24
24
24
24
24
24
24
95
93
72
64
26
45
90:10
88:12
85:15
82:18
80:20
80:20
nd
8
8%, 84%, and 76% yields after successive cycles.
A plausible mechanism for the formation of (E)-1,2-bis-chalco-
gen alkenes 3a–i is depicted in Scheme 2, involving the initial
reduction of Cu(I) to Cu(0) by metal zinc; following which, Cu(0)
undergoes oxidative addition with diaryl dichalcogenide 2 to form
Traces
c
39
57
82:18
74:26
2
the intermediate (ArY) Cu(II). Following which, zinc could reduce
d
this intermediate to ArYCu, which reacts with the terminal alkyne
1a to give the respective (E)-1,2-bis-chalcogen alkenes 3. We
believe the reuse of CuI/Zn/glycerol for additional reaction is
possible in view of glycerol could be acting both, as a solvent and
by reducing Zn(II) to Zn(0) (Scheme 2).
Among organoselenium compounds, the class of bis-selanyl
alkene has attracted some attention, due to their chemical
a
Reactions performed using phenyl acetylene 1a (0.6 mmol), diphenyl diselenide
2
a (0.6 mmol), and glycerol (1.0 mL) under N
2
atmosphere.
b
Yields are given for isolated products.
Reaction was performed at 60 °C.
c
1
7
d
Reaction was performed in open atmosphere.
Determined by GC/MS of the crude reaction mixture and confirmed after iso-
e
lation of the individual isomers.

L. C. C. Gonçalves et al. / Tetrahedron Letters 55 (2014) 5275–5279
5277
Table 2
a
Synthesis of 1,2-bis-chalcogen alkenes (3a–i)
CuI (5 mol%), Zn
R
Ar
glycerol
Y
R
YAr
ArY 3 i
+
Ar
Y
10 oC, N
1
2
1a-c
2a-h
-
Entry
1
Alkyne 1
ArYYAr 2
Product 3
Time (h)
5
Yieldb (%)
95
Ratioc (E:Z)
Se
Se
1a
Se
90:10
100:0
2
a
Se
3a
OCH
3
Se
Se
OCH
3
2
3
1a
1a
Se
2b
3
3
92
82
CH
3
O
CH
3
O
Se
3b
Se
Se
Se
90:10
88:12
2c
Se
3c
Se
Se
Se
d
4
1a
3
80
2
Se
3
d
Cl
Se
Se
Cl
5
6
1a
1a
Se
2e
2
3
56
60
100:0
75:25
Cl
Cl
Se
3e
CF
3
Se
CF
3
Se
Se
CF
3
2f
Se
CF
3
3f
1
b
7
2a
2a
Se
5
6
73
55
86:14
91:09
Se
3g
Cl
Cl
1
c
8
9
Se
Se
S
3h
S
S
S
1a
1a
8
60
68:32
—
2g
3i
Te
Te
1
0
Te
h
24
Traces
2
Te
3j
a
All reactions were carried out with alkyne 1 (0.6 mmol) and diaryl chalcogenides 2 (0.6 mmol) in the presence of CuI (5 mol %), and Zn (1 equiv) in 1.0 mL of glycerol at
1
6
1
10 °C under N
2
atmosphere.
b
Yield after purification by column chromatography.
Determined by GC/MS of the crude reaction mixture and confirmed after isolation of pure products.
c
properties and pharmaceutical potential.2d Moreover, bis-selanyl
In the DPPH test only compound (E)-3b presented radical scav-
enging activity at concentrations of 100 and 500 M (see Fig. 1A),
with a maximal inhibition (Imax) of 36.47 ± 5.22%. In the ABTS assay
compound (E)-3a showed significant effect at concentrations rang-
ing from 10 to 100 lM, with a maximal inhibition of 26.25 ± 2.33%
(Fig. 1B), while compounds (E)-3b and (E)-3e did not present any
effect in the ABTS scavenging assay (Data not shown). This observa-
tion is in agreement with the fact that ABTS and DPPH scavenging
2
b
alkenes are known as potential antioxidant compounds. Based
on these considerations, we evaluated the antioxidant potential
of synthesized compounds (E)-3a, (E)-3b, (E)-3e, and (E)-5a. In
order to evaluate their free radical scavenger ability, DPPH (diphe-
l
nyl-2,4,6-trinitrophenyl-imino azanium)18 and ABTS (2,2 -azin-
0
obis(3-ethyl benzothiazoline-6-sulfonic acid)1
used and results are presented in Figure 1.
9,20
assays were

5
278
L. C. C. Gonçalves et al. / Tetrahedron Letters 55 (2014) 5275–5279
Table 3
Synthesis of bis- and mono-chalcogen alkenes derived from N-propynyl pyrazolesa
6 5
YC H
6 5
YC H
CuI (5 mol%)
R
Y
Zn, glycerol
R
R
R
N
N
N
N
N
N
N
N
+
+
Y
+
10 oC, N2
YC
5a-c
6 5
H
YC H
6 5
1
4a-c
2a,g
6a-c
7a-c
Entry
1
N-Propynyl pyrazole
Y
Product
Time (h)
2
Yieldb (%)
90
Ratioc
N
N
Se
Se
(E)-5a + (Z)-6a + 7a
(E)-5b + (Z)-5b
50:13:37
4a
N
N
2
2
94
90:10
4b
Br
N
N
3
4
Se
S
(E)-5c + (Z)-6c + (E)-6c + 7c
(Z)-6d + (E)-6d + 7d
3
6
85
78
19:48:6:27
19:38:43
4c
4a
a
b
c
Reaction conditions are the same as described in footnote of Table 2.
Yield after purification by column chromatography.
Determined by 1H NMR of the pure products.
Table 4
A
B
Reuse of catalytic system CuI/Zn/glycerol
50
Imax = 36.47± 5.22 %
50
Imax = 26.25 ± 2.33 %
*
*
4
0
40
30
20
10
0
CuI (5 mol%), Zn
glycerol
**
30
Se
Se
Se
*
*
+
*
20
1
10 °C, N2
Se
1
a
2a
3a
10
Cycle
Time (h)
Yield of 3aa (%)
0
1
0
50
100
500
1
10
50
100
Concentration (µM)
Concentration (µM)
1
2
3
4
5
6
5
5
5
5
5
95
94
91
88
84
76
C
D
0.5
0.5
***
0
.4
.3
.2
.1
.0
0.4
0.3
0.2
0.1
0.0
**
10
0
a
Yields are given for isolated products.
0
***
**
0
**
0
1/2 Zn
C
10
50
100
500
C
10
50
100
500
1/2 ZnI
2
Concentration ( µM)
Concentration ( µM)
YAr
CuI
E
YAr
0.5
3
Cu(0)
0
.4
0.3
.2
0.1
.0
ArYYAr
2
*
0
ArY Cu YAr
1a
ArYCu(I)
CuI
0
C
10
50
100
Concentration ( µM)
1/2 Zn
1/2 Zn(YAr)
2
Figure 1. In vitro antioxidant effect of 1,2-bis-chalcogen alkenes (E)-3a, (E)-3b, (E)-
3e, and (E)-5a. (A) Effect of (E)-3b on the DPPH assay; (B) Effect of (E)-3a on the
ABTS assay; (C) Effect of compound (E)-3a, (D) (E)-3b, and (E) (E)-5a on the FRAP
assay. Data were presented as mean ± standard error (SEM) and analyzed by one-
way ANOVA followed by Tukey’s multiple comparison test one appropriate. The
Scheme 2. A plausible mechanism of the reaction.
activities involve different mechanisms: while DPPH neutralization
involves the proton and electron transfer, the ABTS scavenging
activity involves only electron transfer.
⁄
⁄⁄
⁄⁄⁄
asterisks represent significant effect ( p <0.05; p <0.01 and p <0.001) of the
respective controls (C).
To extend the studies about the antioxidant capacity of (E)-3a,
(
E)-3b, (E)-3d, and (E)-5a, we evaluated their ferric ion reducing
(E)-3b showed effect at concentrations ranging from 100 to
500 M and (E)-5a presented effect only at 100 M.
Another important characteristic of an antioxidant compound is
its effect in preventing or reducing the lipid peroxidation.22 1,2-
Bis-chalcogen alkenes (E)-3a, (E)-3b, (E)-3e, and (E)-5a were eval-
uated for their potential on linoleic acid oxidation assay. All tested
power (FRAP). This assay takes advantage of an electron transfer
reaction in which a ferric salt is used as an oxidant.21 In this test,
compounds (E)-3a, (E)-3b, and (E)-5a, presented significant effect
l
l
(Figs. 1C–E). Compound (E)-3a was more effective, presenting
effect at concentrations equal to and higher than 50 M, while
l

L. C. C. Gonçalves et al. / Tetrahedron Letters 55 (2014) 5275–5279
5279
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A
B
IC50 = 6.50 ± 0.70 µM
max = 98.13 ± 0.69 %
IC50 = 84.67 ± 8.97 µM
max = 77.01 ± 4.49 %
I
I
1
20
120
100
80
60
40
20
0
100
**
***
8
0
6
0
#
***
#
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***
2
0
***
***
*** ***
10 50 100 500
0
C
I
1
10 50 100 500
C
I
0.1
1
Concentration ( µM)
Concentration ( µM)
2.
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IC50 = 107.50 ± 45.70 µM
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(c) Jesse, C. R.; Wilhelm, E. A.; Bortolatto, C. F.; Nogueira, C. W. Neurosci. Lett.
IC50 = 67.66 ± 28.70 µM
C
Imax = 93.06 ± 1.98 %
Imax = 84.90 ± 6.32 %
1
20
120
100
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0
#
80
***
**
1
1, 1199.
6
0
60
40
#
***
**
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***
4
0
***
2
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20
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0
0
C
I
10
50 100 500
C
I
10
50 100 500
Concentration (µM)
Concentration ( µM)
Figure 2. Effect of bis-chalcogen alkenes (E)-3a (A), (E)-3b (B), (E)-3e (C), and (E)-5a
D) on the linoleic acid oxidation assay. Data were presented as mean ± standard
5. (a) Kuniyasu, H.; Ogawa, A.; Miyazaki, S. I.; Ryu, I.; Kambe, N.; Sonoda, N. J. Am.
Chem. Soc. 1991, 113, 9796; (b) Silveira, C. C.; Cella, R.; Vieira, A. S. J. Organomet.
Chem. 2006, 691, 5861; (c) Usigi, S.; Yorimitsu, H.; Shinokubo, H.; Oshima, K.
Organic Lett. 2004, 6, 601.
(
error (SEM) and analyzed by one-way ANOVA followed by Tukey’s multiple
comparison test one appropriate. The asterisks represent significant difference from
⁄
⁄⁄
⁄⁄⁄
6. Perin, G.; Lenardão, E. J.; Jacob, R. G.; Panatieri, R. B. Chem. Rev. 2009, 109, 1277.
the induced group (I) (linoleic acid + SNP) ( p <0.05; p <0.01 and
p <0.001), #
7.
(a) Li, K.; Darkwa, J.; Guzei, I. A.; Mapolie, S. F. J. Organomet. Chem. 2002, 660,
08; (b) Torralba, M. C.; Cano, M.; Campo, J. A.; Heras, J. V.; Pinilla, E.; Torres, M.
represent significant difference from the control group (C).
1
R. Inorg. Chem. Commun. 2002, 5, 887; (c) Bekhit, A. A.; Abdel-Aziem, T. Bioorg.
Med. Chem. 1936, 2004, 12; (d) Selvam, C.; Jachak, S. M.; Thilagavathi, R.;
Chakraborti, A. K. Bioorg. Med. Chem. Lett. 2005, 15, 1793; (e) Barra, C. V.; Rocha,
F. V.; Netto, A. V. G.; Shimura, B.; Frem, R. C. G.; Mauro, A. E.; Carlos, I. Z.;
Ananias, S. R.; Quilles, M. B. J. Therm. Anal. Calorim. 2011, 106, 483.
Constable, D. J. C.; Jimenez-Gonzalez, C.; Henderson, R. K. Org. Process Res. Dev.
2007, 11, 133.
compounds showed significant effect in reducing the linoleic acid
oxidation induced by SNP, as can be seen in Figure 2. Compound
(
E)-3b (containing OMe group) was more potent and efficient in
reducing the linoleic acid oxidation, with an IC50 (concentration
that inhibits 50% of the oxidation) of 6.50 ± 0.70 M and Imax of
8.13 ± 0.69%, followed by compound (E)-3e (IC50 = 67.66 ± 28.70
8
9
.
.
l
Jessop, P. G. Green Chem. 2011, 13, 1391.
0. (a) Díaz-Álvarez, A. E.; Francos, J.; Lastra-Barreira, B.; Crochet, P.; Cadierno, V.
9
1
lM and Imax = 93.06 ± 1.98%), (E)-3a (IC50 = 84.67 ± 8.97
lM and
Chem. Commun. 2011, 6208; (b) Gu, Y.; Jèrôme, F. Green Chem. 2010, 12, 1127.
I
max = 77.01 ± 4.49%), and (E)-5a (IC50 = 107.50 ± 45.70
l
M
and
11. Pagliaro, M.; Rossi, M. The Future of Glycerol: New Usages for a Versatile Raw
Material In Clark, J. H., Kraus, G. A., Eds.; RSC Green Chemistry Series:
Cambridge, 2008.
I
max = 84.9 ± 6.32%).
Results indicated that modifications in the chemical structures of
,2-bis-chalcogen alkenes changed the antioxidant potential of
1
2. Lenardão, E. J.; Gonçalves, L. C. C.; Mendes, S. R.; Saraiva, M. T.; Alves, D.; Jacob,
1
R. G.; Perin, G. J. Braz. Chem. Soc. 2010, 21, 2093.
compounds. Data showed that (E)-1,2-bis[(4-methoxyphenyl)
seleno]styrene 3b was the more effective antioxidant among the
tested compounds. This could be explained by the presence of an
electron-donating substituent attached to the aromatic ring.
In summary, (E)-bis-chalcogen alkenes were synthesized using
an efficient and recyclable catalytic system containing CuI/Zn and
glycerol. The copper-catalyzed addition of diaryl dichalcogenides
to terminal alkynes furnished stereoselectively (E)-bis-chalcogen
alkenes in good to excellent yields. The catalytic system was
re-used up to 5 times and the efficiency was maintained after each
step of the reuse. This protocol is an efficient method to produce
new bis-chalcogen alkenes with potent antioxidant activity.
13. Perin, G.; Jacob, R. G.; Dutra, L. G.; Azambuja, F.; Santos, G. F. F.; Lenardão, E. J.
Tetrahedron Lett. 2006, 47, 935.
1
1
4. (a) Perin, G.; Borges, E. L.; Alves, D. Tetrahedron Lett. 2012, 53, 2066; (b) Lara, R.
G.; Rosa, P. C.; Soares, L. K.; Silva, M. S.; Jacob, R. G.; Perin, G. Tetrahedron 2012,
68, 10414.
5. (a) Gonçalves, L. C.; Fiss, G. F.; Perin, G.; Alves, D.; Jacob, R. G.; Lenardão, E. J.
Tetrahedron Lett. 2010, 51, 6772; (b) Gonçalves, L. C.; Lima, D. B.; Borba, P. M. Y.;
Perin, G.; Alves, D.; Jacob, R. G.; Lenardão, E. J. Tetrahedron Lett. 2013, 54, 3475.
16. General procedure for the addition reaction: To a round-bottomed flask, under
nitrogen atmosphere, containing CuI (0.03 mmol; 5 mol %) and Zn dust
(
3
0.6 mmol) was added glycerol (1.0 mL). The reaction mixture was stirred for
0 min at 110 °C and cooled to room temperature. After that, diaryl
dichalcogenide (0.6 mmol) and appropriated terminal alkyne (0.6 mmol)
were added and the reaction mixture was allowed to stir at 110 °C for the
time indicated in Tables 2 and 3. After that time, the solution was cooled to
room temperature, diluted with ethyl acetate (20.0 mL), and washed with
saturated aqueous NH
4
Cl (3 ꢀ 20.0 mL). The organic phase was separated,
Acknowledgments
dried over MgSO , and concentrated under vacuum. The residue was purified
4
by flash chromatography on silica gel using ethyl acetate/hexane as eluent.
Detailed experimental procedure and spectral data of products prepared are
listed in the Supplementary data.
Authors are grateful to FAPERGS (PRONEM 11/2026-4) CNPq,
CAPES and FINEP for the financial support.
17. For examples of glycerol acting as a solvent and a reducing agent in organic
synthesis, see: (a) García, N.; García-García, P.; Fernández-Rodríguez, M. A.;
García, D.; Pedrosa, M. R.; Arnáiz, F. J.; Sanz, R. Green Chem. 2013, 15, 999; (b)
Diaz-Álvarez, A. E.; Cadierno, V. Appl. Sci. 2013, 3, 55; (c) Thurow, S.; Webber,
R.; Perin, G.; Lenardão, E. J.; Alves, D. Tetrahedron Lett. 2013, 52, 3215.
Supplementary data
1
8. Ancerewicz, J.; Migliavacca, E.; Carrrupt, P. A.; Testa, B.; Bree, F.; Zini, R.;
Tillement, J. P.; Labidelle, S.; Guyot, D.; Chauvet-Monges, A. M.; Crevat, A.; Le
Ridant, A. Free Radical Biol. Med. 1998, 25, 113.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.07.
1
2
9. Re, R.; Pellegrini, N.; Proteggente, A.; Pannala, A.; Yang, M.; Rice-Evans, C. Free
Radical Biol. Med. 1999, 26, 1231.
0. Gülçin, I. Life Sci. 2006, 78, 803.
1
09.
References and notes
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