Csp3-tellurium copper cross-coupling: synthesis of alkynyl tellurides a novel class of antidepressive-like compounds

Article abstract of DOI:10.1016/j.tetlet.2008.12.024

We present here the results on the synthesis of functionalized alkynyl tellurides using the reaction of vinyl, alkynyl, and aryl tellurides with several alkynyl iodides catalyzed by copper iodide. The reaction proceeded cleanly under mild reaction conditi

Full text of DOI:10.1016/j.tetlet.2008.12.024

Tetrahedron Letters 50 (2009) 909–915
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Csp3-tellurium copper cross-coupling: synthesis of alkynyl tellurides
a novel class of antidepressive-like compounds
Afamefuna Elvis Okoronkwo b, Benhur Godoi a, Ricardo Frederico Schumacher a,
José Sebastião Santos Neto a, Cristiane Luchese a, Marina Prigol a, Cristina Wayne Nogueira a, Gilson Zeni a,
*
a Laboratório de Síntese, Reatividade, Avaliação Farmacológica e Toxicológica de Organocalcogênios, Departamento de Química, CCNE, UFSM, Santa Maria, RS, Brazil
b Department of Chemistry, Federal University of Technology, P.M.B. 704 Akure, Ondo State, Nigeria
a r t i c l e i n f o
a b s t r a c t
Article history:
We present here the results on the synthesis of functionalized alkynyl tellurides using the reaction of
vinyl, alkynyl, and aryl tellurides with several alkynyl iodides catalyzed by copper iodide. The reaction
proceeded cleanly under mild reaction conditions, at room temperature, in the absence of base and ligand
giving alkynyl tellurides in acceptable yields. The obtained compounds 3a–c and 3m–o were screened for
antidepressive-like activity using the tail suspension test (TST) in mice. Compounds 3a–c and 3m–o
administered at 10 mg/kg by oral route produced a significant antidepressant-like effect on the TST in
mice.
Received 24 October 2008
Revised 1 December 2008
Accepted 5 December 2008
Available online 13 December 2008
Keywords:
Copper cross-coupling
Tellurides
Ó 2008 Elsevier Ltd. All rights reserved.
Pharmacological activity
1. Pharmacology
eral ligands, such as aliphatic diamines, 1,10-phenanthroline,
amino acids and their derivatives, and others. These important
Depression is a common disorder with high lifetime rates. It is
a major cause of disability, and causes death both by suicide and
due to raised rates of physical disorders.1 Because the mechanism
of depression is quite complex, many currently available antide-
pressants have low rates of response and remission and even se-
vere adverse-effects.2,3 For that reason, it is necessary to research
and develop more effective antidepressant drugs. Organotellurium
compounds have demonstrated pharmacological properties, such
as antioxidant4–7 and chemoprotective,8–10 and display low acute
toxicity in animals.6,7,11 Therefore, organotellurium compounds
may be an important source of new antidepressant drugs. Follow-
ing our longstanding interest in pharmacological properties of
organochalcogens, the present study was undertaken to investi-
gate whether alkynyl vinyl tellurides 3a–c and 3m–o present anti-
depressant-like effect, employing tail suspension test (TST) in
mice.
findings allow the use of common organic solvents (dichloro-
methane, chloroform, toluene, benzene, DMF, and DMSO) and
weaker bases (K2CO3, Cs2CO3, and K3PO4), and they also allow
the use of not only aryl iodide, but also aryl bromides and chlo-
rides. After that, these reactions became more attractive and
nowadays they can be carried out at lower temperatures, under
milder conditions, and using a catalytic amount of the copper
salts.
Chalcogenide compounds have found such wide utility because
of their effects on an extraordinary number of very different reac-
tions, including many carbon–carbon bond formations,13 under
relatively mild reaction conditions. In addition, they have become
attractive synthetic targets because of their chemo-, regio-, and
stereoselective reactions,14 used in a wide variety of functional
groups, thus avoiding protection group chemistry and useful bio-
logical activities.15 Among chalcogenides, vinylic tellurides are
useful intermediates in organic synthesis.14d,16 Of the two isomers,
the Z-vinylic tellurides have been employed more frequently as
intermediates because of easy availability of these species.17 Late-
ly, we have employed vinylic tellurides in the synthesis of natural
products by using this cross-coupling reaction.18 To the best of our
knowledge, the application of carbon-tellurium single bond in the
copper cross-coupling has not been reported so far. In view of the
lack of synthetic protocols using tellurides in this cross-coupling,
there is a need for the development of a clear and mild procedure
that is to be carried out at room temperature in the absence of a
2. Chemistry
Great progress has been made in carbon-heteroatom bond for-
mation via the cross-coupling reaction of heteroatom compounds
using a copper-catalyzed system.12 These improvements are cer-
tainly a consequence of the studies regarding the effects of sev-
* Corresponding author. Tel.: +55 55 3220 9462; fax: +55 55 220 8031.
E-mail addresses: gzeni@quimica.ufsm.br, gzeni@pq.cnpq.br (G. Zeni).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.024

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A. E. Okoronkwo et al. / Tetrahedron Letters 50 (2009) 909–915
nanoparticles also showed certain activity (Table 1, entry 6). With
R2
Te
R1
BuTe
[Cu]
Cu(I) sources the yields varied from 55 to 96% (Table 1, entries 7–
10). Since, using CuI (10 mol %) as catalyst the product was ob-
tained in 96% yield, we considered CuI as the the best copper
source for this catalytic system.
I
R3
Solvent
R2
R1
R3
1
2
3
Scheme 1.
A series of approaches have shown that the use of ligands (such
as aliphatic diamines, 1,10-phenanthroline, amino acids and their
derivatives, and others) for copper catalysts resulted in numerous
advantages.22 For this reason, in our experiment we also investi-
gated the influence of some inexpensive ligands, such as 1,10-phe-
nanthroline, EDTA, DMEDA, TMEDA, and bipyridine. As listed in
Table 1, when the reaction was carried out using EDTA, DMEDA,
and bipyridine the target product was not obtained (Table 1, entry
20) or was obtained in moderate yields (Table 1, entries 17 and 18),
even though a long reaction time was used. The best ligands were
1,10-phenanthroline and TMEDA (Table 1, entries 16 and 19):
however, the reaction was not improved compared to reaction car-
ried out in the absence of ligand (Table 1, entry 9). Regarding the
influence of the solvent in this cross-coupling reaction, optimal re-
sults were achieved using DMF (Table 1, entry 9). By using DMSO,
EtOH, MeCN, THF, and hexane moderate yields were obtained (Ta-
ble 1, entries 11–15). It is relevant to note that when the amount of
catalyst is reduced from 10 to 1 mol %, a notable decrease in the
yields was observed (Table 1, entries 21–23). In addition, no reac-
tion occurred in the absence of copper catalyst even after 72 h.
Thus, the careful analysis of the optimized reactions revealed
that the optimum conditions for this cross-coupling reaction pro-
cedure were the addition of telluride 1a (1 mmol) and the appro-
base and a ligand. Thus, our continuing interest in the organochal-
cogen chemistry as well as copper-catalyzed cross-coupling reac-
tions prompted us to examine the cross-coupling reaction of
vinyl, aryl, and alkynyl tellurides 1 with alkynyl iodides 2 to obtain
a new class of tellurium compounds 3 (Scheme 1).
3. Results and discussion
The starting vinylic tellurides 1a–h, 1j, and 1k were readily
available by using the process of hydrotelluration of alkynes.19
The treatment of phenyllithium with elemental tellurium gave
in situ the lithium tellurolate anion that was treated with 1-bro-
mobutane to yield the telluride 1i.20 Finally, alkynyl tellurides 1l
and 1m were obtained from reaction of alkynyl lithium deriva-
tives with elemental tellurium followed by reaction with 1-
bromobutane.21
With the starting materials in hand, our initial studies have fo-
cused on the development of an optimum set of reaction condi-
tions. Hence, the coupling reaction of telluride 1a (1 mmol) with
alkynyl iodine 2a (1.2 mmol) was treated with different copper
catalysts under room temperature, in different solvents and in
the presence and absence of additives, in order to optimize the
reaction conditions.
priate alkynyl iodine 2a (1.2 equiv) to
a solution of CuI
(10 mol %) in DMF (3 mL) at room temperature.23
As shown in Table 1, of the Cu(II) sources investigated,
Cu(OAc)2, CuCl2, Cu(acac)2, and Cu(OTf)2 provided similar results
giving the products in moderate yields: however, the use of CuBr2
greatly increased the product yield (Table 1, entries 1–5). Cu2O
Using this condition, we were able to prepare alkynyl tellurides
3a in 96% yield. To demonstrate the efficiency of this reaction, we
explored the method by extending these conditions to other
organotellurium compounds 1a–k with different alkynyl iodines
2a–e, and the results are summarized in Table 2.
Table 1
First we explored the coupling of different vinyl tellurides;
functionalized (1a–g, 1j, and 1k), nonfunctionalized (1h), and aryl
tellurides (1i) gave the desired products in moderate to good iso-
lated yields. Most importantly, the cross-coupling turned out to
be general with respect to a diverse array of functionality in the
electrophile sources. Satisfactorily, our experiments also showed
that the reaction with electrophile sources having aryl, alkyl, and
propargyl (2a–e) groups gave the product in acceptable yields. Fi-
nally, it is worth mentioning that through our methodology, it was
possible to prepare highly functionalized organophosphorated
alkynyl tellurides 3e0–f0 and 3g0.
In view of the fact of occurrence of diyne systems in many com-
pounds with biological interest, we attempt to broaden the scope
of our methodology performing the reaction using the alkynyl tel-
lurides 1l and 1m and iodo alkynes to give symmetrical and
unsymmetrical alkynyl tellurides 4. It was found that the reaction
worked well affording the desired coupling products in satisfactory
yields. The results are summarized in Table 3.
Our working mechanism for the copper-catalyzed preparation
of alkynyl tellurides is based on the following experimental data
obtained: (1) in all cases we detected BuI as a side product; (2)
the reaction works in the complete absence of reoxidant to change
Cu(I)–Cu(0)–Cu(I); (3) no product was obtained when a sp2-carbon
was bound to the tellurium atom in place of Bu group and; (4) no
product was obtained using terminal alkynes in place of alkynyl io-
dide, then it could involve: (a) BuTe complexation with CuI; (b)
insertion of CuI into the alkyne followed by nucleophilic attack of
the tellurium atom on the copper to give the cationic organo-
Cu(III) complex a;24 (c) nucleophilic attack of iodide anion on the
butyl group bound to the tellurium atom to give the Cu(III) inter-
Optimization of reaction conditions for the formation of 3aa
SMe
Te
Ph
[Cu] / [Ligand]
Solvent
OH
I
Ph
SMe
BuTe
2a
3a
1a
OH
Entry
Catalyst (mol %)
Solvent
Ligand
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Cu(OAc)2(10)
CuBr2(10)
CuCl2(10)
Cu(acac)2(10)
Cu(OTf)2(10)
Cu2Onano(10)
CuCl(10)
CuBr(10)
CuI(10)
CuCN(10)
CuI(10)
CuI(10)
CuI(10)
CuI(10)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
EtOH
MeCN
THF
None
—
—
—
—
—
—
—
—
—
—
—
—
42
72
55
43
42
42
69
55
96
61
52
36
45
34
40
86
42
32
75
—
—
CuI(10)
CuI(10)
CuI(10)
CuI(10)
CuI(10)
CuI(10)
CuI(1)
CuI(3)
Hexane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
—
1,10-Phen
EDTA
DMEDA
TMEDA
BiPy
—
—
—
50
65
65
CuI(5)
a
Reactions were performed in the presence of 1a (1 mmol), 2a (1.2 mmol) at
room temperature for 6 h.
b
The yield was determined by GC.

A. E. Okoronkwo et al. / Tetrahedron Letters 50 (2009) 909–915
911
Table 2
Copper-catalyzed formation of alkynyl tellurides 3a
Entry
Telluride 1
Iodine 2
Product 3b
SMe
Ph
OH
Ph
HO
Ph
I
1
Ph Te
BuTe
SMe
2a
1a
3a-62%
SMe
I
2
1a
2b
Ph
Te
3b-40%
SMe
C5H11
I
3
4
1a
1a
Ph Te
3c-72%
C5H11
2c
SMe
I
Ph
Te
HO
3d-52%
HO
HO
2a
2d
SMe
I
OH
OH
5
6
1a
Ph
Te
2e
3f-40%
SPh
Ph
Ph Te
3g-44%
BuTe
SPh
1b
SPh
Ph Te
7
8
1b
1b
2b
2c
Ph
3h-48%
SPh
Ph Te
C5H11
3i-43%
SPh
9
1b
2d
2a
Ph
Ph
Te
HO
3j-40%
SBn
Ph
OH
10
Te
BuTe
SBn
1c
3k-47%
SBn
11
12
13
14
1c
2b
2c
2a
2b
Ph
Ph Te
3l-54%
SBn
1c
Ph Te
C5H11
3m-60%
SMe
C4H9
OH
C4H9 Te
BuTe
SMe
1d
3n-30%
SMe
1d
C4H9
Te
Ph
3o-46%
(continued on next page)

912
A. E. Okoronkwo et al. / Tetrahedron Letters 50 (2009) 909–915
Table 2 (continued)
Entry
Telluride 1
Iodine 2
Product 3b
SMe
15
16
17
1d
2c
C4H9 Te
3p-50%
C5H11
OH
SMe
C6H13
2a
C6H13
Te
BuTe
SMe
1e
3q-35%
SMe
1e
2b
2c
C6H13 Te
3r-43%
Ph
SMe
18
19
1e
C5H11
OH
C6H13
Te
3s-49%
SPh
C4H9
2a
C4H9 Te
3t-55%
BuTe
SPh
1f
SPh
20
1f
2b
2c
Ph
C4H9
Te
3u-58%
SPh
21
22
1f
C5H11
OH
C4H9 Te
3v-60%
SPh
C6H13
2a
C6H13
Te
BuTe
SPh
1g
3w-51%
SPh
23
1g
1g
2b
2c
C6H13 Te
Ph
3x-47%
SPh
24
25
26
27
C6H13 Te
C5H11
3y-70%
Ph
Te
OH
BuTe
Ph
2a
2b
2c
1h
3z-47%
Ph
1h
1h
Ph
Te
3a’-54%
Ph
Te
C5H11
3b’-60%
OH
TeBu
Te
28
2a
1i
3c’-48%

A. E. Okoronkwo et al. / Tetrahedron Letters 50 (2009) 909–915
913
Table 2 (continued)
Entry
Telluride 1
Iodine 2
Product 3b
Te
Ph
29
30
31
1i
2b
3d’-43%
Te
C5H11
1i
2c
2a
3e’-47%
P(O)(OEt)2
Ph
OH
Ph
Te
BuTe
P(O)(OEt)2
1j
3f’-34%
P(O)(OEt)2
32
1j
2b
2b
Te
3g’-48%
Ph
Ph
C6H13
BuTe
P(O)(OEt)2
33
Te
Ph
C6H13
P(O)(OEt)2
1k
3h’-44%
a
Reactions were performed in the presence of 1 (0.5 mmol), 2 (0.6 mmol), CuI (10 mol %), using DMF at room temperature.
Yields are given for isolated products.
b
Table 3
Copper-catalyzed formation of symmetrical and unsymmetrical alkynyl tellurides 4a
Entry
1
Telluride 1
Product 4
Yieldb (%)
25
OH
Ph
TeBu
Ph
Te
4a
1l
Ph
Ph
Te
4b
Ph
2
3
4
5
1l
39
30
40
36
35
Te
C5H11
1l
4c
OH
C5H11
TeBu
C5H11
C5H11
Te
1m
4d
Te
Ph
1m
1m
4e
C5H11
Te
4f
C5H11
6
a
Reactions were performed in the presence of 1 (0.5 mmol), 2 (0.6 mmol), CuI (10 mol %), using DMF at room temperature.
b
Yields are given for isolated products.
mediated b; (d) the reductive elimination to give the product and
regenerate Cu(I) (Scheme 2).
for antidepressant-like activity using the TST in mice.25 The results
of antidepressant-like effect of compounds 3a–c and 3m–o on TST
are presented in Figure 1. Alkynyl vinyl tellurides 3a–c and 3m–o,
giving per oral route, produced an antidepressant-like effect on the
mouse TST. Alkynyl vinyl tellurides 3a–c and 3m–o produced a sig-
nificant antidepressant-like effect on the TST at doses equal and
higher than 10 mg/kg (data not shown) (p < 0.05 by Duncan’s test).
At the dose of 1 mg/kg compounds 3c, 3m, 3n, and 3o presented
antidepressant-like effect on the TST, while compounds 3a and
4. Pharmacology
Based on the previous screening for pharmacological activity of
alkynyl vinyl tellurides, compounds 3a–c and 3m–o were chosen
for evaluating antidepressant-like effect of this class of organoch-
alcogens. The obtained compounds 3a–c and 3m–o were screened

914
A. E. Okoronkwo et al. / Tetrahedron Letters 50 (2009) 909–915
5. Conclusions
250
200
150
100
50
In summary, we showed by the procedure described herein that
organotellurium compounds having a carbon–tellurium single
bond are suitable substrates to copper cross-coupling reactions,
providing an interesting protocol for the synthesis of alkynyl tellu-
rides. The synthesized compounds have promising antidepressive-
like activity and should be pharmacologically interesting. We ex-
pect that these findings would be useful in choosing a method
for the synthesis of highly functionalized tellurium alkynes. This
reaction associated with electrophilic cyclizations of alkynes29 or
palladium cross-coupling of tellurides13 can contribute to an inter-
esting alternative route to the preparation of pharmacologically ac-
tive compounds. The moderate yields obtained for these
compounds were consequence of the remarkable instability of
these products in front of the purification methods. The application
of tellurides 4 in the synthesis of unsymmetrical 1,3-diyne systems
using copper and palladium catalysts is currently underway.
0
Control
3a
3b
3c
3m
3n
3o
250
200
150
100
50
Acknowledgments
We are grateful to FAPERGS, CAPES (SAUX / 2007) and CNPq for
the financial support. CNPq and CAPES are also acknowledged for
the fellowships.
References and notes
0
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3b did not present the effect at this dose (Fig. 1a). Alkynyl vinyl tel-
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pound 3o is comparable with the effect of paroxetine in the TST
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Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett. 2002, 4, 2803; (d)
Ranu, B. C.; Saha, A.; Jana, R. Adv. Synth. Catal. 2007, 349, 2690; (e) Carril, M.;
SanMartin, R.; Dominguez, E.; Tellitu, I. Chem. Eur. J. 2007, 13, 5100; (f) Verma,
A. K.; Singh, J.; Chaudhary, R. Tetrahedron Lett. 2007, 48, 7199.
23. General procedure for cross-coupling reaction: A 10 mL Schlenk tube, equipped
I
R2
BuI
I-
I-
III
R1
Bu
Te Cu
R2
a
I
Scheme 2.
with a magnetic stir bar, rubber septum, and argon, containing the CuI

A. E. Okoronkwo et al. / Tetrahedron Letters 50 (2009) 909–915
915
(0.0095 g, 0.05 mmol) in DMF (3 mL), was charged sequentially with the
desired telluride (0.5 mmol) in DMF (1 mL) and the appropriate alkynyl iodine
(0.6 mmol) in DMF (1 mL) drop-by-drop. The mixture was stirred at room
temperature, and the reaction time was determined monitoring the reaction by
TLC. The reaction mixture was then quenched with aqueous NH4Cl (10 mL),
washed with ethyl acetate (3 ꢀ 15 mL), dried with MgSO4, and the solvent was
removed under vacuum. The products were purified by column
chromatography. Selected spectral and analytical data for 3–a0. Yield: 0.179 g
(54%). 1H NMR (CDCl3, 400 MHz), d (ppm): 7.48 (d, J = 10.27 Hz, 1H), 7.44–7.21
(m, 8H), 7.16 (d, J = 10.02 Hz, 1H), 7.09–7.06 (m, 2H). 13C NMR (CDCl3,
100 MHz), d (ppm): 138.59, 137.79, 131.78, 128.72, 128.47, 128.16, 127.87,
126.76, 123.20, 111.35, 107.35, 47.92. MS (relative intensity) m/z: 330 ([M-2]
9) 201 (100), 100 (74), 76 (21), 50 (14). Anal. Calcd for C16H12Te: C, 57.91; H,
3.64. Found: C, 57.98; H, 3.81.
and exploratory activities and to avoid some false positive results in the TST,
mice were evaluated in an open-field test. Open-field test: The open-field was
made of polywood and surrounded by walls 30 cm in height. The floor of the
open-field, 45 cm in length and 45 cm in width, was divided by masking tape
markers into 09 squares (3 rows of 3). Each animal was placed individually at
the center of the apparatus and observed for 6 min to record the locomotor
(number of segments crossed with the four paws) and exploratory activities
(expressed by the number of time rearing on the hind limbs).34 Statistical
analysis: Data were analyzed by using a one-way analysis of variance (ANOVA),
followed by Duncan’s Multiple Range Test when appropriate. Results were
considered significantly different at values of p < 0.05.
26. Willner, P. Trends Pharmacol. Sci. 1991, 12, 131.
27. Zomkowski, A. D. E.; Hammes, L.; Lin, J.; Calixto, J. B.; Santos, A. R. S.; Rodrigues,
A. L. S. NeuroReport 2002, 13, 387.
24. Vicente, J.; Herrero, P. G.; Sánchez, Y. G.; Jones, P. G.; Bautista, D. Eur. J. Inorg.
Chem. 2006, 115.
28. Rosa, A. O.; Kaster, M. P.; Binfare, R. W.; Morales, S.; Martin-Aparicio, E.;
Navarro-Rico, M. L.; Martinez, A.; Medina, M.; García, A. G.; Lopez, M. G.;
Rodrigues, A. L. S. Prog. Neuro-Psychoph. 2008, 32, 1549.
29. Alves, D.; Luchese, C.; Nogueira, C. W.; Zeni, G. J. Org. Chem. 2007, 72, 6726.
30. Steru, L.; Chermat, R.; Thierry, B.; Simon, P. Psychopharmacology 1985, 85,
367.
31. Rodrigues, A. L. S.; Da Silva, G. L.; Mateussi, A. S.; Fernandes, E. S.; Miguel, O. G.;
Yunes, R. A.; Calixto, J. B.; Santos, A. R. S. Life Sci. 2002, 70, 1347.
32. Mantovani, M.; Pertile, R.; Calixto, J. B.; Santos, A. R. S.; Rodrigues, A. L. S.
Neurosci. Lett. 2003, 34, 1.
33. Ripoll, N.; David, D. J. P.; Dailly, E.; Hascoet, M.; Bourin, M. Behav. Brain Res.
2003, 143, 193.
25. Bioassay: Antidepressant-like activity: The total duration of immobility
induced by tail suspension was measured according to the method described
by Steru et al.30 Mice were suspended on the edge of a table 50 cm above the
floor by the adhesive tape placed approximately 1 cm from the tip of the tail.
Immobility time defined as the absence of escape-oriented behaviors was
scored during 6 min, as described previously.31,32 Mice were treated with
alkynyl vinyl tellurides 3a–c and 3m–o (1, 10, 50, and 100 mg/kg, per oral (p.o.)
or with canola oil (10 ml/kg, p.o.) 30 min before challenge test. Paroxetine, an
antidepressant-drug, was used as a positive control and administered (16 mg/
kg, intraperitoneal, i.p.) 30 min before the challenge test.33 To assess the
possible effects of alkynyl vinyl tellurides 3a–c and 3m–o on the locomotor
34. Walsh, R. N.; Cummins, R. A. Psychol. Bull. 1976, 83, 482.