DES as a green solvent to prepare 1,2-bis-organylseleno alkenes. Scope and limitations

Article abstract of DOI:10.1016/j.tetlet.2015.10.095

We describe here our results on the use of choline chloride/urea 1:2 as a deep eutectic solvent (DES) in the synthesis of vinyl selenides. A good selectivity for the (E)-1,2-bis-organylseleno alkenes was observed starting from terminal alkynes and diaryl

Full text of DOI:10.1016/j.tetlet.2015.10.095

Accepted Manuscript
DES as a Green Solvent to Prepare 1,2-bis-Organylseleno alkenes. Scope and
Limitations
Eric F. Lopes, Lóren C. Gonçalves, Julio C.G. Vinueza, Raquel G. Jacob, Gelson
Perin, Claudio Santi, Eder J. Lenardão
PII:
S0040-4039(15)30291-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.10.095
TETL 46924
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
9 October 2015
28 October 2015
Please cite this article as: Lopes, E.F., Gonçalves, L.C., Vinueza, J.C.G., Jacob, R.G., Perin, G., Santi, C.,
Lenardão, E.J., DES as a Green Solvent to Prepare 1,2-bis-Organylseleno alkenes. Scope and Limitations,
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.10.095
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Graphical Abstract
DES as a Green Solvent to Prepare 1,2-bis-
Organylseleno alkenes. Scope and Limitations
Leave this area blank for abstract info.
Eric F. Lopes, Lóren C. Gonçalves, Julio C. G. Vinueza,
Raquel G. Jacob, Gelson Perin, Claudio Santi and Eder J. Lenardão*

1
Tetrahedron Letters
DES as a Green Solvent to Prepare 1,2-bis-Organylseleno alkenes. Scope and
Limitations
Eric F. Lopes,a Lóren C. Gonçalves,a Julio C. G. Vinueza,a Raquel G. Jacob,a Gelson Perin,a Claudio
Santib and Eder J. Lenardãoa,*
a Laboratório de Síntese Orgânica Limpa - LASOL - CCQFA - Universidade Federal de Pelotas - UFPel - P.O. Box 354 - 96010-900, Pelotas, RS, Brazil,
b Dipartimento di Scienze Farmaceutiche, Group of Catalysis and Green Chemistry, Università degli Studi di Perugia, Perugia, Italy.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We describe here our results on the use of choline chloride/urea 1:2 as a deep eutectic solvent
(DES) in the synthesis of vinyl selenides. A good selectivity for the (E)-1,2-bis-organylseleno
alkenes was observed starting from terminal alkynes and diaryl or dibutyl diselenides in the
presence of NaBH4. The reaction of 1,3-butadiynes with diphenyl diselenide afforded
exclusively the respective mono-selenylated (Z)-alkenynes. Diphenyl ditelluride reacted with
phenylacetylene and 1,4-diphenyl-but-1-en-3-yne affording (Z)-phenyltelluro alkenes in good
yields.
Available online
Keywords:
Organoselenium Compounds
Green Chemistry
Bis-chalcogen Alkenes
Deep Eutectic Solvent
Alkynes
2015 Elsevier Ltd. All rights reserved.
1
The synthesis and reactivity of organoselenium compounds is
described in a number of books and reviews.1 Since the discover
that some selenium-containing small molecules possess GPx-
mimicking activity, acting as anti-oxidant,2,3 the search for new
bioactive Se-based molecules and selective methods to prepare
them have exponentially increased. More recently, 1,2-bis-
organylseleno alkenes have aroused the interest of chemists and
biochemists due to their pharmacological properties; more
specifically, some of them presented excellent antinociceptive
and antioxidant activities (Figure 1).4 The bis-selenylation of
alkynes is the most straightforward and atom-economic way to
prepare 1,2-bis-organylseleno alkenes.1e This reaction can be
performed using radical selenium species5 or diorganyl
diselenides in the presence of a transition metal,6 such as
palladium and furnishes selectively the Z-isomer. The use of
heavy metals and high temperature, besides the toxicity and
hazard associated with the use of volatile organic solvents
(VOCs) are some drawbacks of these protocols, which are
incompatible with the green requirements of the modern
chemical and pharmaceutical industry.7
protocols, some of them present limitations in the scope, e.g., are
restrict to internal alkynes and aromatic diselenides. Thus, the
search for new synthetic routes to these valuable chalcogen
derivatives in a green and selective way is deeply interesting.
Figure 1. (E)-1,2-Bis-arylseleno alkenes with antioxidant and
analgesic-like (antinociceptive) properties.4
Very recently, the use of deep eutectic solvents (DES) has
been explored in organic synthesis as a green alternative to VOCs
and fluorinated ionic liquids (ILs). DES are usually composed by
a quaternary ammonium salt and a hydrogen bond donor (HBD)
and are usually named as third generation or advanced ILs
(Figure 2).10 The possibility of using cheap, biodegradable
precursors, combined with several green features (negligible
volatility, high polarity, versatility), make DES a greener solvent
than the ‘classical’ ILs. The physical-chemical properties of DES
can be tuneable and are dependent of the stoichiometric ratio and
the identity of the ammonium salt and the HBD parts.10d One of
the most studied DES is the choline chloride (ChCl):urea 1:2
mixture, which has been successfully used as a solvent in cross-
Recently, improvements have been proposed by us4b,8 and
others4a,9 on the selective and clean synthesis of (E)-1,2-bis-
organylchalcogen alkenes. These new approaches include the use
of environmentally benign catalysts (FeCl3 or CuI/Zn4b), green
4a
solvents (glycerol,8a ionic liquid9) or even solvent-free conditions
under microwave irradiation.8b Despite the greenness of these
———
*Corresponding author. Tel./fax: +55 5332757533,
e-mail: lenardao@ufpel.edu.br

2
coupling,11 click (CuAAC) synthesis,12 hydrogenation13 and
dehydration reactions.14
solvents, including glycerol8a and the ionic liquid
[bmim][BF4]17 (Table 1, entries 9 and 10). Additional assays
were performed to verify the effect of time, temperature and
stoichiometric ratio of the reagents in the yield and selectivity of
the reaction. Thus, for example, it was observed a slight increase
in the selectivity to 3a when stoichiometric amounts of
phenylacetylene 1a and PhSe)2 2a were used, even if the yield
resulted to be slightly lower (Table 1, entry 11), indicating that
an excess of alkyne is necessary. It was observed also that
increasing the reaction time did not improve the final yield while
decreased the selectivity, with the formation also of the mono-
selenylated alkene 5a (Table 1, entry 12). The temperature and
the N2 atmosphere had also a crucial influence in the reaction,
and the yields were drastically diminished when the reaction was
performed at 60 °C or in an open flask (Table 1, entries 13 and
14). The presence of water in the reaction mixture (0.5 mL) had a
negative effect, reducing both, the selectivity and the yield of the
reaction (Table 1, entry 15), indicating that the removal of water
from the DES or their precursors is a critical point to be
considered. Finally, the effect of energy source was evaluated
and it was observed that both microwaves and ultrasound are not
suitable to this reaction, once only modest yields and low
selectivity were observed using them (Table 1, entries 16 and
17).
Figure 2. Deep Eutectic Solvents (DES) used in this study.
Thought the versatility and green features of DES combined
with the synthetic and biological attributes of 1,2-bis-
organylseleno alkenes and vinyl chalcogenides, we decided to
explore the use of a 1:2 mixture of choline chloride (ChCl) and
urea as a solvent in the synthesis of vinyl selenides and the
results are presented here (Scheme 1).
Scheme 1. General purpose.
Aiming to define the best protocol to the hydrochalcogenation
of terminal alkynes 1 with diorganyl dichalcogenides 2 using
DES as the reaction medium, different reducing systems were
tested to prepare the nucleophilic species of selenium in situ.
Initially, we chose phenylacetylene 1a (1.0 mmol) and diphenyl
diselenide 2a (0.5 mmol) as model substrates to define the best
reaction conditions (Table 1). We started by using thiourea
dioxide in the presence of 13% aq. NaOH (TUD/NaOH)15 as the
reducing agent to cleave the Se-Se bond in 2a and anhydrous
ChCl:urea 1:2 (DES A, 1.5 mL) as the reaction medium. Due to
the viscosity of the solvent, the reactions were performed at 90
°C, to facilitate the homogenization of the reaction mixture. By
using these conditions, the only product observed after 2 h under
N2 was (Z)-β-phenylselenostyrene 5a in 61% yield (Table 1,
entry 1). This result encouraged us to extend the reaction time
aiming to promote the insertion of a second moiety of PhSe, as in
the (E)-1,2-bis-phenylseleno styrene 3a. The reaction progress
was followed by TLC and after 22 h we observed the formation
of a mixture of the desired compound 3a, the (Z)-isomer 4a and
the mono-selenide 5a in 67% overall yield and a ratio 3a:4a:5a
of 18:76:6 (Table 1, entry 2).
Table 1. Optimization of the reaction conditions.a
Reducing
agentb
Yield
(%)c
61
67
85
65
43
85
98
94
75
85
82
88
39
60
38
ratio of
3a 4a 5a
0 100
18 76
42 14 44
89 11
79 12
Entry
Solvent
Time
1
2
3
TUD/NaOH
TUD/NaOH
TUD/NaOH
TUD/NaOH
TUD/NaOH
TUD/NaOH
aq. H3PO2
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
DES A
DES A
DES B
DES C
DES D
2 h
22 h
22 h
22 h
22 h
2 h
1 h
1 h
1 h
3 h
3 h
6 h
1 h
1 h
1 h
40 min
20 min
0
6
4
0
9
5
6d
7
Glycerol
DES A
60 10 30
34
91
3
9
63
0
8
9
DES A
Glycerol8a
[bmim][BF4]17
DES A
77 23
0
10
11e
12
13f
14g
15h
16i
26
96
0
4
74
0
DES A
DES A
DES A
DES A
DES A
DES A
76 10 14
26 28 46
NaBH4
NaBH4
NaBH4
NaBH4
57
58
91
7
8
7
36
34
2
Aiming to improve the selectivity for the (E)-1,2-
bis(phenylseleno)styrene 3a, different eutectic mixtures were
tested (Table 1, entries 3-5) and the best yield of 3a using
TUD/NaOH was obtained when ChCl/oxalic acid (DES C) was
used as the solvent (65% yield after 22 h, ratio 3a:4a = 89:11;
Table 1, entry 4). Because we are interested in new uses of
glycerol as a bio-based and renewable feedstock, the reaction was
also tested using this solvent, but the selectivity to the desired
(E)-1,2-bis-phenylseleno styrene 3a was inferior to that using
DES (Table 1, entry 6 vs. 4). ChCl:urea was then fixed as the
solvent and the reducing agent was changed to aqueous
hypophosphorous acid (0.5 mL, 50% w/w).16 In this case, the
diphenyl diselenide was totally consumed after 1 h to afford a
mixture of mono- and 1,2-bis-phenylseleno alkenes 5a, 3a and
4a, with large predominance of 5a (Table 1, entry 7).
79
49
17j
NaBH4
51 12 37
a
Reactions are performed using diphenyl diselenide 2a (0.15 mmol) and
reducing agent in 1.5 mL of solvent at 90 °C under N2 atmosphere. After the
generation the benzeneselenolate anion (30 min), phenylacetylene 1a (0.3
mmol) was added. b TUD/NaOH = a mixture of thiourea dioxide (0.3 mmol)
c
in 13% aq. NaOH (0.5 mL). Determined by GC/MS and 1H NMR of the
d
e
crude reaction mixture.
4.0 mL of glycerol was used as solvent.
f
Stoichiometric amounts of 1a and 2a (0.3 mmol) were used. The reaction
g
h
was performed at 60 °C. The reaction was performed in an open flask.
Water (0.5 mL) was added to the reaction mixture. i An ultrasound probe was
j
used instead an oil bath. The reaction was irradiated with microwaves
instead using an oil bath.
With the best conditions in hands,18 we selected different
alkynes and diselenides to speculate on the generality of the
reaction in the preparation of (E)-1,2-bis-organylseleno alkenes 3
(Table 2). As it can be seen in Table 2, starting from terminal
alkynes 1 the DES/NaBH4 system can be successfully used to
prepare selectively (E)-1,2-bis-organylseleno alkenes in most of
cases. For example, 4-ethynyl anisole 1b reacted with diphenyl
diselenide 2a to afford after 2 h a mixture of (E)-1,2-bis-
phenylseleno 4-methoxystyrene 3b and (Z)-2-phenylseleno-4-
methoxystyrene 5b in 77% overall yield and a 3b:5b ratio =
For our delight, when NaBH4 was used as reducing agent, the
desired (E)-1,2-bis-phenylseleno styrene 3a was obtained in
excellent yield and selectivity after 1 h at 90 °C under N2, among
a small amount of the (Z)-isomer 4a (94% yield, 3a:4a ratio=
91:9; Table 1, entry 8). This result is superior both in terms of
total yield and selectivity compared to the use of other green

3
83:17 (Table 2, entry 2). The mono and bis-selenylated alkenes
are easily separable by column chromatography. The presence of
two methoxyl groups in the aromatic ring of the arylalkyne, as in
3c, caused an increase in the amount of the respective (Z)-vinyl
selenide 5c and a mixture of (E)-1,2-bis-phenylseleno-3,5-
phenyltellurostyrene 5n being the only product after reaction
for 5 h (Table 2, entries 14 vs 1). When 1,4-diphenyl-but-1-en-3-
yne 1h was the starting material, the expected (Z)-1-
phenyltelluro-1,4-diphenyl-but-1-en-3-yne 5o was obtained in
42% yield after 15 h (Table 2, entry 15).
(dimethoxy)styrene
(dimethoxy)styrene 5c was obtained in 80% yield after 1 h, with
a 3c:5c ratio= 47:53 (Table 2, entry 3).
3c
and
(Z)-(2-phenylseleno)3,5-
To examine the involvement of a radical mechanism in the
reaction, phenylacetylene 1a and diphenyldiselenide 2a were
reacted in the presence of hydroquinone, a radical inhibitor. By
using 5 mol% of hydroquinone, a mixture of 3a, 4a and 5a was
obtained in 68% yield and a 3a:4a:5a ratio of 69:12:19 after 2 h
at 90 °C. When an equimolar amount of hydroquinone was used,
was used, after 3 h, the selenium derivatives were obtained in
76% yield and with a 3a:4a:5a ratio of 62:6:32. In both reactions,
unreacted diphenyl diselenide was recovered. These findings
indicate that the reaction occurs in part by a radical mechanism,22
once the yield of the 1,2-bis-phenylseleno alkene is reduced in
the presence of the radical scavenger, nevertheless ionic
intermediates could also be involved.23
When electron-withdrawing groups are present in the
arylalkyne, a longer time was necessary to complete the reaction.
Thus, 1-chloro-4-ethynylbenzene 1d reacted with PhSeSePh 2a
for 4 h to afford a mixture of the respective (E)-1,2-
bisphenylseleno alkene 3d and the (Z)-vinyl selenide 5d in 69%
yield and a 3d:5d ratio = 65:35. Surprising, the only product
from the reaction between 4-ethynyl benzonitrile 1e and 2a was
(Z)-(2-phenylseleno)4-(cyano)styrene 5d, isolated in 56% yield
after 5 h (Table 2, entry 5). 1-Dodecyne 1f and the conjugated
enyne 1-ethynylcyclohex-1-ene 1g reacted with diphenyl
diselenide 2a to afford exclusively the respective (E)-1,2-bis-
phenylseleno-alkenes 3f and 3g in 66 and 74% yields after 24
and 7 h respectively (Table 2, entries 6-7). These are very
interesting findings, once monoalkyl-substituted alkynes have a
low reactivity and poor selectivity in selenylation reactions in the
absence of a transition metal catalyst.1e The reaction was also
explored using diverse diaryl diselenides, containing electron-
donnor and electron-attractor groups in the aromatic ring (Table
2, entries 8-10). It was observed that electron-rich diselenides 2b
and 2c favored the formation of the respective (E)-1,2-bis-
arylseleno alkene, but with a decrease in selectivity and yields
compared to diphenyl diselenide 2a (Table 2, entries 8-9 vs entry
1). The presence of electron-withdrawing groups in the diaryl
diselenide 2d however, decreases the rate of the reaction and the
amount of the respective (E)-1,2-bis-arylseleno alkene 3j was
diminished compared to the monoselenylated alkene 5j (Table 2,
entry 10). Dibutyl diselenide 2e was also submitted to the
reaction with phenylacetylene 1a under our conditions and after 2
h it afforded selectively (E)-1,2-bis-butylseleno styrene 3k,
together with (Z)-2-butylselenostyrene 5k in 82% yield and a
3k:5k ratio = 82:18 (Table 2, entry 11). Aiming to prepare highly
functionalized vinyl chalcogenides, we decided to extend the
DES-based method to the 1,3-butadyines 1h and 1i. Despite the
low reactivity of internal alkynes to the reaction with selenolate,
the presence of a second, conjugated triple bond favors the
reaction. Thus, 1,4-diphenyl-but-1-en-3-yne 1h reacted with
diphenyl diselenide 2a to afford, after 12 h, the respective (Z)-1-
phenylseleno-1,4-diphenyl-but-1-en-3-yne 5l as the only product
in 89% yield (Table 2, entry 12). Similarly, the dimer of
propargyl alcohol 1i afforded after 5 h of reaction only (Z)-1,6-
dihydroxy-1-phenylseleno-hex-1-en-3-yne 5m in 73% yield
(Table 2, entry 13). The DES was also a good solvent to promote
the cleavage of the Te-Te bond of diphenyl ditelluride 2f with
NaBH4 and the subsequent hydroteluration of alkynes, affording
(Z)-vinyl tellurides in reasonable yields (Table 2, entries 14-15).
Vinyl tellurides are very useful precursors of alkenyl synthons in
organic synthesis. They can be easily converted to vinyl anions
by transmetalation with alkyl lithium19 or cyanocuprates,20 for
example, or directly coupled with terminal alkynes to afford
enediynes.21 In all these reactions, the configuration of the double
bond in the vinyl telluride is preserved, so the development of
methods to access this class of compounds is pertinent. It was
observed that diphenyl ditelluride 2f was less reactive under our
optimized conditions, affording the respective adducts in lower
yields compared to the selenium analog 2a. The difference in
reactivity reflected in the different products in the case of the
reaction with phenylacetylene 1a, with the (Z)-2-
Scheme 2. A plausible mechanism for the reaction.
A plausible explanation for the formation of bis- and mono-
chalcogen alkenes is depicted in Scheme 2 for the reaction
between phenylacetylene 1a and diorganyl diselenide 2. In the
formation of the (E)-1,2-bis-organylseleno-alkene 3 a transition
state like I could be involved, with concomitant addition of the
selenolate to the terminal carbon and the capture of a second
organylselanyl group by the incipient negative charge formed in
the internal carbon of the new double bond (path A). In the
formation of the (Z)-organylseleno alkene 5, a transition state like
II, involving the donation of a hydrogen from the solvent, could
be part in the reaction (path B).
In conclusion, the DES ChCl:urea (1:2) combined with NaBH4
was used for the first time in the selective synthesis of (E)-1,2-
bis-organylseleno alkenes starting from terminal alkynes and
diorganyl diselenides. This reaction system presents interesting
peculiarities, including the possibility to use alkyl and alkenyl
monosubstituted alkynes in a very efficient way, what is not
possible using other so-called green solvents.
Acknowledgments
We are grateful to CNPq and FAPERGS and Dipartimento di
Scienze Farmaceutiche- Università degli Studi di Perugia “Fondo
per il sostegno della Ricerca di Base 2015” for the financial
support. Eder J. Lenardão is Bolsista CAPES - Processo No.
BEX 6391/14-1. This research was undertaken as part of the
scientific activity of the international multidisciplinary “SeS
Redox and Catalysis” network.
References and notes

4
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5
Table 2. Synthesis of 1,2-bis-chalcogen alkenes (3 and 4) and vinyl chalcogenides 5.a
alkyne
R2SeSeR2
Time
(h)
Yield
Ratioc
3 : 4 : 5
Entry
1
Products
(%)b,[ref]
1
2
1
2
94 [8b]
93 : 7 : 0
2
3
77 [24]
83 : 0 : 17
2a
2a
1
80 [25]
47 : 0 : 53
4
5
4
5
69 [4b]
65 : 0 : 35
2a
2a
56
0 : 0 : 100
6
24
66 [9a]
100 : 0 : 0
2a
2a
7
8
7
2
74
100 : 0 : 0
74 [8b]
59 : 41 : 0
1a
1a
9
7
3
2
58 [4b]
86 : 14 : 0
67 : 0 : 33
82 : 0 : 18
10
11
79 [4b]
1a
1a
82 [5,26]
12
13
12
5
89 [27]
0 : 0 : 100
2a
2a
73 [27]
0 : 0 : 100

6
Tetrahedron Letters
14
5
68 [28]
0 : 0 : 100
1a
1h
15
15
42 [19]
0 : 0 : 100
2f
a All the reactions were carried out with alkyne 1 (0.6 mmol) and diarylchalcogenides 2 (0.6 mmol) 1.5 mL of DES at 90 ºC under N2 atmosphere. b Yield after
purification by column chromatography. c Determined by GC/MS of the crude reaction mixture and confirmed after isolation of pure products.