Bis(2-pyridyl)diselenoethers as versatile ligands for copper-catalyzed C-S bond formation in glycerol

Article abstract of DOI:10.1016/j.tetlet.2015.07.060

In this Letter, we describe a simple and efficient general methodology for CuI/bis(2-pyridyl)diselenoether-catalyzed C-S coupling reactions of aryl halides with thiols using glycerol as an environmentally friendly solvent. The products were obtained in moderate to excellent yields. The performance of CuI/L3-catalyzed C-S coupling reactions in glycerol is comparable to the related cross-coupling reactions in common organic solvents using transition-metal salts as catalyst. The use of the system CuI/L3/glycerol related in this work offers the possibility of performing the reaction in the absence of toxic organic solvents, expensive metals and using ultrasound as an alternative energy source.

Full text of DOI:10.1016/j.tetlet.2015.07.060

Accepted Manuscript
Bis(2-pyridyl)diselenoethers as versatile ligands for copper-catalyzed C-S bond
formation in glycerol
Roberta Cargnelutti, Ernesto S. Lang, Ricardo F. Schumacher
PII:
S0040-4039(15)01213-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.07.060
TETL 46549
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
5 June 2015
15 July 2015
18 July 2015
Please cite this article as: Cargnelutti, R., Lang, E.S., Schumacher, R.F., Bis(2-pyridyl)diselenoethers as versatile
ligands for copper-catalyzed C-S bond formation in glycerol, Tetrahedron Letters (2015), doi: http://dx.doi.org/
1
0.1016/j.tetlet.2015.07.060
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Bis(2-pyridyl)diselenoethers as versatile ligands for
copper-catalyzed C-S bond formation in glycerol
Roberta Cargnelutti, Ernesto S. Lang and Ricardo F. Schumacher
Leave this area blank for abstract info.

1
Tetrahedron Letters
Bis(2-pyridyl)diselenoethers as versatile ligands for copper-catalyzed C-S bond
formation in glycerol
a
a
b
Roberta Cargnelutti , Ernesto S. Lang and Ricardo F. Schumacher 
a
Departamento de Química, Laboratório de Materiais Inorgânicos, Universidade Federal de Santa Maria, 97105-900, Santa Maria, RS, Brazil.
LASOL - CCQFA - Universidade Federal de Pelotas - UFPel - P.O. Box 354 - 96010-900, Pelotas, RS, Brazil.
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
In this work, we described a simple and efficient general methodology for CuI/
bis(2-pyridyl)diselenoether-catalyzed C–S coupling reactions of aryl halides with
thiols using glycerol as an environmentally friendly solvent. The products were
obtained in moderate to excellent yields. The performance of CuI/L3-catalyzed C–S
coupling reactions in glycerol is comparable to the related cross-coupling reactions in
common organic solvents using transition-metal salts as catalyst. The use of the
system CuI/L3/glycerol related in this work offers the possibility of performing the
reaction in the absence of toxic organic solvents, expensive metals and using
ultrasound as an alternative energy source.
Available online
Keywords:
C-S cross coupling
Copper iodide
Bis(2-pyridyl)diselenoether
Glycerol
2015 Elsevier Ltd. All rights reserved.
Sulfide
1
. Introduction
In view of these previous results, selenium-containing
nitrogen ligands appear as an alternative to previous described
The C–S cross-coupling reaction is a powerful means for the
copper/ligand system for synthetic organic chemistry. In this
field, recent reports have described its use as chiral ligands for
asymmetric catalysis on the construction of stereoselective new
preparation of numerous compounds that are biological,
chemical, material or pharmaceutical interest. Several drugs
currently used for the treatment in therapeutic areas such as
cancer, inflammation and HIV contain aryl sulfides as the
functional group. In organic chemistry, the use of transition-
metal-catalyzed C-S bond formation is a very important way to
prepare these compounds and catalysts such as Co, Pd, Fe, In and
Cu are the most employed for this purpose. Among them, Cu is
predominantly attractive due to its special redox properties,
1
11
C-C bonds. Still, the use of organoselenium compounds have
been shown as catalyst in organic transformations, such as the
selective a1d2dition of thiols to α,β-unsaturated carbonyl
compounds.
2
3
On the other hand, the development of green methodologies
from renewable resources has grown because of the extensive use
of solvents in chemical industries and the impact of these on the
polarizability, easy handling, low cost and toxicity in comparison
to other metal catalysts.
4
13
environment, health and safety. Glycerol, an organic waste
generated by the biodiesel industry, has been recently proposed
Recently, several classes of ligands including phosphazene,
ethylene glycol, neocuproine, 1,2-diamino derivatives, between
others, rationalized such as bidentate ligands containing nitrogen
and/or oxygen as copper chelating atoms, have been found to
accelerate the C–S bond-forming reactions. The most accepted
explanation for this behavior is that the use of ligands may
14
by Gu and Jérôme as a valuable green solvent. The current
availability of glycerol on a large scale and low cost, combined
with its intrinsic properties, i.e. no toxicity, no flammability,
obtained from renewable sources and biodegradability, makes it
5
15
an ideal candidate to develop greener synthetic processes.
Recently, glycerol has proved to be an efficient solvent in many
organic reactions, including Suzuki-Miyaura cross-coupling
6
increase the solubility of copper salts in the solvents.
1
6
17
reactions, N-arylation of amines, metal and base-free synthesis
Still, recent advances in this field have described the use of
transition metal-catalyzed C-H activation for the construction of
C-S bonds, the use of Bunte-salts as thiol surrogate, synthesis of
18
of arylselanyl anilines and C-S bond forming reaction using
vinyl bromides and disulfides.
19
7
8
9
10
sulfide containing-fluorine and others.
In the light of these previous results and our recent interest on
2
0
the chemistry of bis(2-pyridyl)diselenide, we synthesized three
—
——
bis(2-pyridyl) diselenoethers containing one L1, three L2 and

Corresponding author. Tel.: +55-53-3275-7179; fax: +55-53-3275-7533; e-mail: rocargnelutti@yahoo.com.br (R. Cargnelutti);
ricardo.schumacher@ufpel.edu.br (R. F. Schumacher).

2
Tetrahedron
four L3 methylene groups between the selenium atoms and
solvent, to generate in situ two equivalents of the desired 2-
investigated its potential use as ligands in CuI-catalyzed C-S
cross-coupling reactions in the presence of glycerol as a
renewable solvent.
pyridylselenolate, followed by the addition of the corresponding
dibromoalkanes 2 (Scheme 1).
2
1b
2. Results and Discussion
For this purpose, initially we investigated a simple method to
synthesize the ligands (L1, L2 and L3) by reacting the bis(2-
2
1a
pyridyl)diselenide 1 with sodium borohydride using ethanol as
Scheme 1. General scheme for the synthesis of ligands L1, L2 and L3.
amount of CuI was reduced to 5 mol%, it was observed a better
result for the ligand L3 compared to ligand L1 (Table 1, compare
entries 7 and 6). These observations suggest the possibility to
form different catalytic species on the reaction media. One
Table 1. Optimization conditions for CuI/L-catalyzed C-S
cross coupling reaction.
a
22
possibility described in the literature is the formation of
polymeric complexes between CuI and nitrogen-based ligands,
which could have a catalytic activity increased if compared to the
monomeric species. Based on it, we believe that the L3, which
present the longer carbon chain between the selenium atoms,
showed the highest catalytic activity when coordinated to copper,
because of it better ability to form a polymeric complex. On the
other hand, at higher concentrations of the ligands, the possibility
to generate a stable monomer or dimer copper complex increase,
mainly for L1, which could reduce the reactivity of the metal. In
order to demonstrate the necessity for the use of ligands on this
cross-coupling reaction, a control experiment was conducted in
the absence of ligands and only 55% yield for the product 5a was
obtained (Table 1, entry 8). Still, no reaction was observed
suppressing the copper iodide or the catalytic system Cu/ligand
(Table 1, entry 9 and 10).
Entry
CuI ( mol%)
Ligand - (mol%)
L1 – 10
L2 – 10
L3 – 10
L1 – 5
L3 – 5
L1 – 10
L3 – 10
-
Yield (%)
94
1
2
3
4
5
6
7
8
9
10
10
10
10
10
5
89
95
83
85
49
5
85
10
-
55
Analysis of the results described in table 1 showed that the
optimal condition for the C–S cross-coupling reaction between 1-
iodo-2,6-dimethoxybenzene 3a and benzenethiol 4a in glycerol
as solvent is using 10 mol% of CuI and 10 mol% of L3 at 100 °C
(Table 1, entry 3).
L3 – 10
-
N.R.
N.R.
1
0
-
a
Reaction conditions: Aryliodide 3a (1.0 mmol), benzenethiol 4a (1.5 mmol),
CuI, ligand, KOH (3 equiv), glycerol (10 mL), Argon, 100 ºC, 24 h.
In order to demonstrate the efficiency of this C-S cross-
coupling reaction using glycerol as solvent, we explored the
generality of our method extending the coupling reaction to other
aryl halides 3 as well to other thiols 4 and the results are
summarized in table 2. As shown in table 2, groups attached to
the aryl halide such as electron rich, -neutral and –poor were
cross-coupled efficiently under these conditions and produced the
bis(aryl) sulfides 5 in moderate to excellent yields (Table 2,
entries 1-15). For example, reactions of aryl iodides containing
orto, meta or para-methoxy and -methyl substituents furnished
the desired products in 79 to 99% yield (Table 2, entries 1–6).
Comparing entries 1, 2, 3 and 6 in table 2, none steric influence
could be observed to this cross-coupling reaction based on the
presented results, aryl iodides 3a, 3b and 3c containing o- and p-
methoxy groups furnished the desired sulfides in comparable
yields with the non-substituted iodobenzene 3f. Besides, when
electron rich or electron poor groups were used directly attached
With these ligands in hands, 1-iodo-2,6-dimethoxybenzene 3a
and benzenethiol 4a were selected as model substrates to evaluate
the catalytic activity of the bis(2-pyridyl)diselenoethers
ligands/copper iodide system and the reactions are described in
table 1. The C-S cross coupling reaction was initially examined
employing 10 mol% of CuI and 10 mol% of the ligands L1, L2
and L3, using 3 equivalents of KOH as base in glycerol as
solvent at 100 ºC for 24 hours (Table 1, entries 1-3). These
preliminary results showed that the highest ligand efficiency can
be associated to the ligands containing one L1 and four L3
methylene groups between the selenium atoms that furnished the
desired (2,6-dimethoxyphenyl)(phenyl)sulfide 5a in 94 and 95%
yield, respectively. Based on these results, we reduced the
Cu/ligand catalytic system to 5 mol% to compare the efficiency
of L1 and L3, however, a lower isolated yield was observed in
both cases (Table 1, entries 4 and 5). When only the catalytic

3
to the arylthiol 4, good to excellent yields were obtained for the
sulfides and the reaction does not seems to be clearly influenced
to electronic effects (Table 2, entries 7-14). Thiol-containing
methoxy 4b or chloro 4c, 4d groups were satisfactorily used to
give the respective products 5g, 5l and 5m (Table 2, entries 7, 13
and 14). Still, it is important to mention that a good result was
obtained using the aryl bromide 3g, showing the versatility of
this reaction not only for iodides (Table 2, entry 11). The
methodology was also extended to the heteroaryl iodide 3h and
the 3-(4-methoxyphenylthio)pyridine 5k was obtained in 93%
isolated yield after 24 hours (Table 2, entry 12). Finally, when
the alkyl 1-dodecanothiol 4e was employed in the presence of 1-
iodo-2,6-dimethoxybenzene 3a in a catalytic system of CuI / L3
A plausible mechanism can be proposed for this CuI-
catalyzed C-S cross-coupling reaction of aryl halides and thiols
in the presence of bis(2-pyridyl)diselenoether ligand L3 (Scheme
2
3
1). Based on literature, the mechanism suggests that the
reaction occurs by an oxidative addition of the aryliodide 4 to the
active copper specie a to generate the intermediated b. The
reaction of intermediate b with the thiol 5 afford the intermediate
c, which can provide the C-S cross-coupling product by reductive
elimination. The role of the bis(2-pyridyl)diselenoether ligand L3
in the reaction can be either to promote the oxidative addition of
ArX to the Cu(I) specie or to stabilize the high-valent Cu(III)
2
3c
intermediate.
(10 mol% each), the (2,6-dimethoxyphenyl)(dodecyl)sulfide 5n
was readily synthesized in 62% (Table 2, entry 15).
a
Table 2. CuI/L3-catalyzed C–S cross-coupling reaction of aryl halides with thiols using glycerol as solvent.
Entry
1
Aryl halide 3
Thiol 4
Product 5
Yield (%)
95
4
a
3
3
a
5a
5b
2
3
87
79
4
4
a
a
b
3
c
5c
5d
5e
5f
4
5
6
7
99
87
78
83
3
d
4a
4ª
4ª
3
e
3
f
4
b
5g
5h
3
a
8
9
90
84
3
3
b
d
4b
4
4
b
b
5i
1
0
93
3
f
5b

4
Tetrahedron
1
1
1
2
7
9
7
3
3
3
g
4b
4b
5
j
h
5k
5l
1
1
1
3
4
5
88
99
62
4
c
3
3
3
a
a
a
4
d
5m
2 3
HS(CH )11CH
4
e
5n
a
Reaction conditions: Arylhalide 3 (1.0 mmol), thiol 4 (1.5 mmol), KOH (3.0 mmol), CuI (10 mol%), L3 (10 mol%), glycerol (10 mL), 100 °C, under Argon.
common organic solvents that combined with the use of CuI/L3,
related in this work, still offers the possibility of performing the
reaction in the absence of expensive metals and using the
ultrasound to accelerate this process.
Acknowledgments
This work was supported with funds from the Brazilian
agencies CAPES, CNPq and FAPERGS.
References and notes
Scheme 2. Proposed catalytic cycle.
Finally, exploring the possibility of perform the C-S cross-
coupling reaction employing a non-conventional energy source
and becoming the current methodology still greener, an
ultrasound probe was used. By the same reaction conditions
described before, the bis(aryl) sulfide 5a could be obtained in
1.
(a) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42,
5400. (b) Swapna, K.; Murthy, S. N.; Jyothi, M. T.; Nageswar, Y.
V. D. Org. Biomol. Chem. 2011, 9, 5989. (c) Vaddula, B. R.;
Varma, R. S.; Leazer, J. Eur. J. Org. Chem. 2012, 6852. (d) Rout,
L.; Saha, P.; Jammi, S.; Punniyamurthy, T. Eur. J. Org. Chem.
2
008, 640.
88% yield after only 1 hour and 30 minutes (Scheme 3).
2.
(a) Kalgutkar, A. S.; Kozak, K. R.; Crews, B. C.; Hochgesang Jr.,
G. P.; Marnett, L. J. J. Med. Chem. 1998, 41, 4800. (b) Llauger,
L.; He, L.; Kim, J.; Aguirre, J.; Rosen, N.; Peters, U.; Davies, P.;
Chiosis, G. J. Med. Chem. 2005, 48, 2892. (c) Martino, G. D.;
Edler, M. C.; Regina, G. L.; Cosuccia, A.; Barbera, M. C.;
Barrow, D.; Nicholson, R. I.; Chiosis, G.; Brancale, A.; Hamel, E.;
Artico M.; Silvestri, R. J. Med. Chem. 2006, 49, 947. (d) Tinsley,
H. N.; Gary, B. D.; Keeton, A. B.; Lu, W.; Li, Y.; Piazza, G. A.
Cancer Prev. Res. 2011, 4, 1275. (e) Reddy, M. V. R.;
Mallireddigari, M. R.; Pallela, V. R.; Venkatapuram, P.;
Boominathan, R; Bell, S. C.; Reddy, E. P. Bioorg. Med. Chem.
Scheme 3. The use of ultrasound to accelerate the C-S cross-
coupling reaction.
2
005, 13, 1715. (f) Kaldor, S. W.; Kalish, V. J.; Davies, J. F.;
3
. Conclusion
Shetty, B. V.; Fritz, J. E., Appelt, K.; Burgess, J. A.; Campanale,
K. M.; Chirgadze, N. Y.; Clawson, D. K.; Dressman, B. A.; Hatch,
S. D.; Khalil, D. A.; Kosa, M. B.; Lubbehusen, P. P.; Muesing, M.
A.; Patick, A. K.; Reich, S. H.; Su, K. S.; Tatlock, J. H. J. Med.
Chem. 1997, 40, 3979.
Beletskaya, I. P.; Ananikov, V. P. Chem. Rev. 2011, 111, 1596.
(a) Kamal, A.; Srinivasulu, V.; Murty, J. N. S. R. C; Shankaraiah,
N.; Nagesh, N.; Reddy, T. S.; Rao, A. V. S. Adv. Synth. Catal.
2013, 355, 2297. (b) Chen, C.-K.; Chen, Y.-W.; Lin, C.-H.; Lin,
H.-P.; Lee, C.-F. Chem. Commun. 2010, 46, 282. (c) Sperotto, E.;
van Klink, G. P. M.; de Vries, J. G.; van Koten, G. J. Org. Chem.
In conclusion, we have developed a simple and efficient
general methodology for CuI-catalyzed C–S cross-coupling
reaction of aryl halides with thiols using glycerol as solvent in
the presence of bis(2-pyridyl)diselenoether L3 as an ideal ligand.
The methodology allows the use of a broad scope of aryl iodides
and thiols, including aryl, heteroaryl and alkyl groups, and the
products are obtained in moderate to excellent yields. The results
showed that the performance of CuI/L3-catalyzed C–S cross-
coupling reactions in glycerol was comparable to the
performance of CuI in common toxic and non-environmentally
friend organic solvents. Glycerol is greener and safer than
3
4
.
.
2
008, 73, 5625. (d) Beletskaya, I. P.; Cheprakov, A. V. Coord.
Chem. Rev. 2004, 248, 2337.
(a) Qiu, Y.; Yao, Y.; Zhang, D.; Jiang, S. Synlett 2012, 23, 2853.
(b) Prasad, D. J. C.; Sekar, G. Synthesis 2010, 1, 79. (c) Palomo,
5
.

5
C.; Oiarbide, M.; Lopez, R.; Gomez-Bengoa, E. Tetrahedron Lett.
000, 41, 1283. (d) Enguehard-Gueiffier, C.; Thery, I.; Gueiffier,
Álvarez, A. E.; Francos, J.; Crochet, P.; Cadierno, V. Curr.
Green Chem. 2014, 1, 51.
2
A.; Buchwald, S. L. Tetrahedron 2006, 62, 6042. (e) Bates, C. G.;
Gujadhur, R. K.; Venkataraman, D. Org. Lett. 2002, 4, 2803. (f)
Herrero, M. T.; SanMartin, R.; Dominguez, E. Tetrahedron 2009,
16. Wolfson, A.; Dlugy, C. Chem. Pap. 2007, 61, 228.
17. Khatri, P. K.; Jain, S. L. Tetrahedron Lett. 2013, 54, 2740.
18. Thurow, S.; Penteado, F.; Perin, G.; Jacob, R. G.; Alves, D.;
Lenardão, E. J. Green Chem. 2014, 16, 3854.
6
5, 1500. (g) Deng, W.; Zou, Y.; Wang, Y. F.; Liu, L.; Guo, Q. X.
Synlett 2004, 1254. (h) Zhu, D., Xu, L.; Wu, F.; Wan, B.
Tetrahedron Lett. 2006, 47, 5781. (i) Chen, Y.-J.; Chen, H.-H.
Org. Lett. 2006, 8, 5609. (j) Verma, A. K.; Singh, J.; Chaudhary,
R. Tetrahedron Lett. 2007, 48, 7199. (k) Su, K.; Qiu, Y.; Yao, Y.;
Zhang, D.; Jiang S. Synlett 2012, 23, 2853.
19. Gonçalves, L. C. C.; Lima, D. B.; Borba, P. M. Y.; Perin, G.;
Alves, D.; Jacob, R. G.; Lenardão, E. J. Tetrahedron Lett. 2013,
54, 3475.
20. Cargnelutti, R.; Lang, E. S.; Piquini, P.; Abram, U. Inorg. Chem.
Commun. 2014, 45, 48.
6
7
8
.
.
.
Schwab, R. S.; Singh, D.; Alberto, E. E.; Piquini, P.; Rodrigues,
O. E. D.; Braga A. L. Catal. Sci. Technol. 2011, 1, 569.
Shen, C.; Zhang, P.; Sun, Q.; Bai, S.; Hor, T. S. A.; Liu, X. Chem.
Soc. Rev. 2015, 44, 291.
(a) Qiao, Z.; Gea, N.; Jiang, X. Chem. Comm. 2015, 51, 10295. (b)
Reeves, J. T.; Camara, K.; Han, Z. S.; Xu, Y.; Lee, H.; Busacca,
C. A.; Senanayake, C. H. Org. Lett. 2014, 16, 1196.
21. (a) Bhasin, K. K.; Singh, J. J. Organomet. Chem. 2002, 658, 71.
(b) Cargnelutti, R.; Lang, E. S.; de Oliveira, G. M.; Piquini, P. C.
Polyhedron 2012, 39, 106.
22. (a) Manifar, T.; Rohani, S.; Bender, T. P.; Goodbrand, H. B.;
Gaynor, R.; Saban, M. Ind. Eng. Chem. Res. 2005, 44, 789. (b)
Jones, G. O.; Liu, P.; Houk, K. N.; Buchwald, S. L. J. Am. Chem.
Soc. 2010, 132, 6205.
9
1
.
Xu, X.-H.; Matsuzaki, K.; Shibata, N. Chem. Rev. 2015, 115, 731.
23. (a) Rout, L.; Saha, P.; Jammi, S.; Punniyamurthy, T. Eur. J. Org.
Chem. 2008, 640. (b) Deng, W.; Zou, Y.; Wang, Y.; Liu, L.; Guo,
Q. Synlett 2004, 1254. (c) Hickman, A. J.; Sanford, M. S. Nature
2012, 484, 177.
0. (a) Abidi, N.; Schmink, J. R. J. Org. Chem. 2015, 80, 4123. (b)
Gelat, F.; Lohier, J.-F.; Gaumont, A.-C.; Perrio, S. Adv. Synth.
Catal. 2015, 357, 2011. (c) Yang, D.; Kelu Yan, K.; Wei, W.;
Zhao, J.; Zhang, M.; Sheng, X.; Li, G.; Lu, S.; Wang, H. J. Org.
Chem. 2015, 80, 6083.
Supplementary Material
1
1. (a) Godoi, M.; Paixão, M. W.; Braga, A. L. Dalton Trans. 2011,
4
0, 11347. (b) Vargas, F.; Sehnem, J. A.; Galetto, F. Z.; Braga, A.
L. Tetrahedron 2008, 64, 392.
Supplementary data (experimental procedures and spectral
data) associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tetlet.
1
1
2. Schneider, C. C.; Manarin, F.; Panatieri, R. B.; Barros, O. S. R.;
Zeni, G. J. Braz. Chem. Soc. 2010, 21, 2088.
3. Ricordi, V. G.; Freitas, C. S.; Perin, G.; Lenardão, E. J.; Jacob, R.
G.; Savegnago, L.; Alves, D. Green Chem. 2012, 14, 1030.
4. Gu, Y.; Jérôme, F. Green Chem. 2010, 12, 1127.
1
1
5. (a) Díaz-Álvarez, A. E.; Francos, J.; Lastra-Barreira, B.; Crochet,
P.; Cadierno, V. Chem. Commun. 2011, 47, 6208. (b) Díaz-