4-Organochalcogenoyl-1H-1,2,3-triazoles: Synthesis and functionalization by a nickel-catalyzed Negishi cross-coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2012.09.062

A general method for the synthesis of triazoles containing selenium and tellurium was accomplished via a CuCAAC reaction between organic azides and a terminal triple bond, generated by in situ deprotection of the silyl group. The reaction tolerates alkyl and arylazides, with alkyl and aryl substituents directly bonded to the chalcogen atom. The products were readily functionalized by a nickel-catalyzed Negishi cross-coupling reaction, furnishing the aryl-heteroaryl products at the 4-position in good yields.

Full text of DOI:10.1016/j.tetlet.2012.09.062

Tetrahedron Letters 53 (2012) 6495–6499
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
4-Organochalcogenoyl-1H-1,2,3-triazoles: synthesis and functionalization
by a nickel-catalyzed Negishi cross-coupling reaction
⇑
Hélio A. Stefani , Daiana M. Leal, Flávia Manarin
Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A general method for the synthesis of triazoles containing selenium and tellurium was accomplished via a
CuCAAC reaction between organic azides and a terminal triple bond, generated by in situ deprotection of
the silyl group. The reaction tolerates alkyl and arylazides, with alkyl and aryl substituents directly
bonded to the chalcogen atom. The products were readily functionalized by a nickel-catalyzed Negishi
cross-coupling reaction, furnishing the aryl-heteroaryl products at the 4-position in good yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 27 August 2012
Revised 13 September 2012
Accepted 14 September 2012
Available online 25 September 2012
Keywords:
Selenium
Tellurium
Triazoles
Nickel
Negishi
Introduction
many are employed for carbon–carbon bond formation under mild
conditions.
Although N-heterocycle compounds are broadly distributed in
nature, the 1,2,3-triazoles are not found as natural products.1,2
However, synthetic triazoles, due to their capacity for intermolec-
ular hydrogen bond formation, allow for interactions with biolog-
ical receptors3 and have numerous applications, as agrochemical
compounds,4 corrosion inhibitor, dyes,5 and as ionic liquids.6
The main synthesis route to 1,2,3-triazolic compounds is the
1,3-dipolar cycloaddition reaction,7 which was improved in 2003,
when the groups of Sharpless and co-workers8 and Meldal and
co-workers2 independently introduced the use of copper salts to
obtain better yields and good regioselectivity, among several
advantages.
These features include the copper catalyzed cycloaddition of
azides and alkynes to give triazoles, in the field of click chemis-
try.9,10 This kind of reaction can be performed under different
conditions, considered non-classical ones, including microwave
dielectric heating, ultrasound processing, ionic liquids as the reac-
tion media, and continuous flow processing.11
Interest in the reactions involving organochalcogen compounds
has increased because of their chemo-, regio-, and stereoselective
properties. Additionally, their compatibility with different func-
tional groups is notable, and they can be used with a wide variety
of functional groups, thus avoiding the use of protecting groups.16
Organochalcogen species can be introduced as either nucleo-
philes or electrophiles to other organic molecules, producing useful
intermediates for organic synthesis.17
The transition metal-catalyzed cross-coupling reaction of orga-
nometallics is a methodology widely used by many in the chemical
community to produce products prevalent in pharmaceuticals, li-
gands, and materials. Extensive research has focused on a variety
of ways to form C–C bonds using transition metal catalysts.18
The nickel-catalyzed Negishi cross-coupling reaction of aryl and
vinyl halides/triflates with organozinc reagents represents
a
powerful tool for the formation of carbon–carbon bonds in view
of the ready availability and high functional group compatibility
of organozinc compounds.19 Despite the described Negishi cross-
coupling reaction with various azoles (imidazole, oxazole, thiazole,
and pyrazole),20 to the best of our knowledge, no examples using
selenium- and tellurium-triazoles as electrophiles in this reaction
have been described in the literature.
In this context, we report herein a methodology to obtain
4-organochalcogenoyl-1,2,3-triazoles from copper-catalyzed 1,3-
dipolar cycloaddition of terminal organochalcogenoyl-alkynes to
azides. We also describe for the first time the catalytic system
based on nickel-phosphine to promote Negishi cross-coupling
Organochalcogenides have been found to be very important for
their biological effects and as intermediates and reagents in organ-
ic synthesis.12 The biological activity of these compounds includes
antioxidant,13 anti-inflammatory,14 neuroprotective activities as
well as cancer prevention,15 to mention a few. On the other hand,
the utility of these compounds is very broad in organic reactions;
⇑
Corresponding author. Tel.: +55 11 3091 3654.
E-mail address: hstefani@usp.br (H.A. Stefani).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.062

6496
H. A. Stefani et al. / Tetrahedron Letters 53 (2012) 6495–6499
R2
Table 2
RY
[Cu], base, TBAF
Solvent
Synthesis of 4-organochalcogenoyl-1H-1,2,3-triazoles
N
R2-ZnCl
N
R1 N3
N
RY
TMS
+
N
RY
[Ni], Phosphine
solvent
N
Cu(OAc)2 (10mol%)
Na ascorbate (0.5 eq.)
N
N
R1
R1
R1 N3
R = Bu, Ph
Y= Se, Te
R1 = Alkyl, aryl
R2= Aryl, heteroaryl
RY
TMS
+
N
N
TBAF (1.2 eq.), THF
50 oC, 2-3 hs
R1
2a-p
1a-d
YR= SePh (1a), SeBu (1b)
Figure 1. General scheme of the reactions.
1c 1d
TeBu ( ), TePh (
)
R1= Aryl, alkyl
Entry
1
Azide
Product
Yielda (%)
reaction with 4-organoselenium- and 4-organotellurium-1,2,3-tri-
azoles (Fig. 1).
PhSe
N
N3
2a
N
80
Results
N
Ph
PhSe
The terminal alkyne was obtained through the deprotection of
the silyl group. This synthesized compound is novel in the litera-
ture and represents an excellent building block because of the
presence of the chalcogen atom.
Initially, we focused our attention on the optimization of the
reaction conditions. In this way, we investigated some parameters
in the procedure, such as different copper loading salts, bases,
additives, and solvents (Table 1). For this purpose, we employed
trimethyl(phenylselanylethynyl)silane 1a as the source of a termi-
nal triple bond and benzylazide as a standard reagent. In the first
test, a mixture of 1a (0.5 mmol), benzylazide (0.6 mmol), and CuI
(1 equiv), using THF as the solvent, was reacted at room tempera-
ture for 3 h in the absence of a base.
N
N 2b
2
3
CH3(CH2)5-N3
77
76
N
(CH2)5CH3
PhSe
PhSe
N
N 2c
CH3(CH2)11-N3
N
(CH2)11CH3
N3
N
2d
2e
2f
N
N
N
N
4
5
65
60
As shown in Table 1, using these conditions, product 2a was ob-
tained in only 23% yield (entry 1). On the other hand, in the pres-
ence of a base (PMDTA), the desired product was isolated in 60%
PhSe
PhSe
N3
N
N
N3
N
N
Table 1
Effect of reaction conditions on CuAAC
PhSe
6
73
"Cu" source
N
OMe
N3
base/additive
N3
N
PhSe
TMS
+
TBAF, solvent
temperature
N
OMe
N
1a
2a
Ph
PhSe
Entry [Cu] (equiv)
Base or additive
(1.1 equiv)
Solvent
Yielda
(%)
2g
2h
N
N
7
8
42
53
1
2
3
4
5
6
CuI (1.0)
CuI (1.0)
CuI (0.1)
CuI (0.05)
CuCN (0.1)
CuSO4Á5H2O
(0.1)
—
THF
THF
THF
THF
THF
THF
23
60
72
Trace
24
NO2
PMDTA
PMDTA
PMDTA
PMDTA
PMDTA
NO2
N
PhSe
BuSe
N3
Trace
N
N
7
8
9
Cu(Oac)2 (0.1)
CuBr (0.1)
CuCl (0.1)
PMDTA
PMDTA
PMDTA
Na ascorbate
Et3N
Na ascorbate
Na ascorbate
Na ascorbate
Na ascorbate
Na ascorbate
Na ascorbate
Na ascorbate
Na ascorbate
Na ascorbate
Na ascorbate
THF
THF
THF
THF
75
70
64
78
35
36
74
62
45
Cl
Cl
10
11
12
13
14
15
16
17
18
19
20
21
Cu(OAc)2 (0.1)
Cu(OAc)2 (0.1)
Cu(OAc)2 (0.1)
Cu(OAc)2 (0.1)
Cu(OAc)2 (0.1)
Cu(OAc)2 (0.1)
Cu(OAc)2 (0.1)
Cu(OAc)2 (0.1)
Cu(OAc)2 (0.1)
Cu(OAc)2 (0.05)
Cu(OAc)2 (0.1)
Cu(OAc)2 (0.1)
THF
N3
N
N
MeCN
DMSO
MeOH
H2O
2i
9
75
68
N
Ph
BuSe
Dioxane 70
Dioxane 59e
N
83b
2j
N
10
CH3(CH2)11-N3
THF
THF
THF
THF
N
63b
(CH2)11CH3
80b,c
64b,d
BuSe
N3
N
a
b
c
2k
N
Yields are given for isolated products.
Reaction carried out at 50 °C.
Reactions were performed using 0.5 equiv of Na ascorbate.
Reaction performed using 0.1 equiv of Na ascorbate.
Reaction carried out at 80 °C.
N
11
55
d
e

H. A. Stefani et al. / Tetrahedron Letters 53 (2012) 6495–6499
6497
effective (Table 1, entries 4–6). Comparable results were obtained
using Cu(OAc)2, CuBr, and CuCl (entries 7–9).
Table 2 (continued)
Entry
Azide
Product
Yielda (%)
As described in the literature, sodium ascorbate is considered to
be a convenient additive for in situ reducing agents to generate cat-
alytically active Cu(I).21–23 This justifies the result found with the
combination of Cu(OAc)2 and sodium ascorbate (entry 10).
Additionally, we investigated the reaction behavior with differ-
ent solvents, including CH3CN, DMSO, MeOH, Dioxane, and H2O;
however THF gave the best results (Table 1, entries 10, 12–17).
In order to improve the results, we changed the temperature to
50 °C. This approach increased the yield of triazole 2a to 83% (entry
18) in a shorter reaction time.
N3
BuSe
N
N 2l
N
12
65
OMe
N3
OMe
N
BuSe
2m
N
N
With the optimized conditions in hand, Cu(OAc)2 (10 mol %), so-
dium ascorbate (0.5 equiv) at 50 °C in THF, we explored the gener-
ality of the protocol using different organic azides and acetylenes.
The results are summarized in Table 2.
Analysis of Table 2 shows that, in general, all of the reactions
proceeded under mild conditions, with a simple methodology, easy
isolation, and acceptable yields.
Aliphatic azide derivatives were employed as substrates; the
corresponding products were obtained in good yields (Table 2, en-
tries 1–4). However, we found a limitation in our methodology
when we attempted to react sodium azide as the dipole partner,
since no triazole product was obtained.
The reaction was sensitive to the electronic effects of the sub-
stituents on the aromatic ring of the azide. For example, an organic
azide containing an electron-donating group (OMe) gave a better
result than neutral and electron-withdrawing groups in the aro-
matic ring (Table 2, entries 5–8).
13
14
51
NO2
NO2
N
BuTe
PhTe
PhTe
N
N3
2n
50b
N
N
N
2o
2p
N3
58b
N
15
16
N
60b
N
CH3(CH2)11-N3
N
(CH2)11CH3
Additionally, we tried to broaden the scope of the methodology
by performing the reaction with other acetylene derivatives
containing YR = SeBu-n (1b), TeBu-n (1c), and TePh (1d). The sub-
strate containing the SeBu group furnished the corresponding
product in lower yields compared to SePh derivatives (Table 2, en-
tries 9–13).
a
Yields are given for isolated products. The reaction times vary between two and
three hours.
Conditions: acetylene (0.5 mmol), THF (4 mL), organic azide (0.55 mmol), CuI
(0.5 mmol), PMDTA (0.55 mmol, 0.11 mL), and TBAF (0.6 mmol).
b
Unfortunately, substrate 1c did not behave as the analogs 1a
and 1b under the conditions described, and the triazole was ob-
tained in only 20% yield. Thus, we attempted to find different con-
ditions compatible with the TeR substrate. In this way, we
submitted compounds 1c and 1d to different conditions (Table 1,
entry 2), furnishing the corresponding products in moderate yields
(Table 2, entries 14–16).
During the reaction of 1c, the formation of a black precipitate
was observed, probably composed of elemental tellurium. GC/MS
monitoring showed the formation of byproducts such as butyl io-
dide and the corresponding hydrogenated triazole from the detell-
uration reaction.
Table 3
Optimization of the nickel-catalyzed Negishi reaction
MeO
ZnCl
BuSe
N
"Ni" (mol%)
N
N
N
+
ligand (mol%)
THF, 60 oC
N
N
Ph
OMe
Ph
2j
3a
Entry
Catalyst (mol %)
Ligand (mol %)
Yield (%)
1
2
3
4
5
6
7
8
Ni(acac)2 (5)
DPE-Phos (10)
DPE-Phos (10)
—
DPE-Phos (10)
DPE-Phos (10)
DPE-Phos (10)
X-Phos (10)
S-Phos (10)
Ru-Phos (10)
PCy3 (10)
68
77
51
69
54
47
72
15
57
81
46
The synthesized products appeared as potential precursors to
explore the functionalization of triazole scaffolds. Since selenium
and tellurium functionalities have the ability to be converted into
other substituents,17 the possibility of employing these substrates
as useful intermediates in cross-coupling reactions was
investigated.24
Knochel and coworkers developed Pd-catalyzed cross-coupling
reactions with thiomethyl-substituted N-heterocycles with various
organozinc reagents, using Pd(OAc)2/S-Phos as the catalytic sys-
tem.25 Additionally, the same authors described an additional pro-
tocol by changing the catalytic system to Ni(acac)2/DPE-Phos.26
Following this, the ability of selenium and tellurium derivatives
was investigated under Ni-catalyzed cross-coupling reaction with
organozinc reagents.
NiCl2(PPh3)2 (5)
NiCl2(PPh3)2 (5)
NiBr2 (5)
NiCl2(dppf) (5)
NiCl2(dppe) (5)
NiCl2(PPh3)2 (5)
NiCl2(PPh3)2 (5)
NiCl2(PPh3)2 (5)
NiCl2(PPh3)2 (5)
NiCl2(PPh3)2 (2.5)
9
10
11
PCy3 (5)
yield (entry 2). As can be seen in the initial experiments, the base
plays an important role in the reaction.
Concerning the amount of the copper salt, the reaction was car-
ried out in a catalytic system, reducing the amount of CuI to
10 mol %; this change increased the yield of the product to 72% (en-
try 3). Other copper salts were tested, such as CuCN, CuSO4,
Cu(OAc)2, CuBr, and CuCl, however, some of them were less
Initially, we started by employing Ni(acac)2 and DPE-Phos as
the catalytic system, and used compound 2j as the electrophilic
partner. The arylated product was obtained in 68% yield (Table 3,
entry 1). The simple change of the catalyst to NiCl2(PPh3)2 provided
the product 3a in 77% yield (Table 3, entry 2). The reaction in the

6498
H. A. Stefani et al. / Tetrahedron Letters 53 (2012) 6495–6499
Table 4
Table 4 (continued)
Synthesis of 4-aryl-1H-1,2,3-triazoles by a nickel-catalyzed Negishi cross-coupling
Entry
9
Triazole
2k
Organozinc
Product
Yielda (%)
reaction
R2
R
ZnCl
N
NiCl2(PPh3)2 (5 mol%)
N
N
N
N
+
63
N
PCy3 (10 mol%)
THF, 60 oC
N
3i
R2
N
R1
N
R1
3a-k
(CH2)11CH3
1
MeO
2j
R = SeBu, R = Bn
R = SeBu, R1 = (CH2)11CH3 2k
R = SeBu, R1 = 4-OMe(C6H4) 2m
2o
R = TeBu, R1 = Bn
N
Yielda (%)
N
3j
Entry
Triazole
Organozinc
Product
10
2m
52
N
OMe
MeO
2j
2o
81
51
OMe
N
1
OMe
N
3a
N
Ph
N
N
3k
N
11
2m
73
2j
2o
73
43
N
2
3
N
3b
N
OMe
a
Ph
Yields are given for isolated products. The reaction times vary between two and
three hours.
b
The organozinc reagent was obtained from thiophene using the methodology
described previously.
N
N
2j
2o
71
42
3c
N
Ph
F
absence of the ligand DPE-Phos furnished the product in moderate
yield (Table 3, entry 3).
Since the preliminary tests were successful, a survey was per-
formed to find the optimal conditions, by changing the catalyst
and the ligand. Other nickel salts such as NiBr2, NiCl2(dppf), and
NiCl2(dppe) were less effective (Table 3, entries 4–6). Additionally,
N
4
5
2j
2j
54
60
F
N
3d
N
Ph
the influence of the phosphine ligand was investigated; thus, we
27
F3C
used Buchwald phosphine
in order to increase the yield of the
arylated product (Table 3, entries 7–9). However, the ligands tested
were less efficient compared to PCy3 (Table 3, entry 10).
A detailed analysis of Table 3 shows that the optimal conditions
for the coupling reaction were achieved using NiCl2(PPh3)2
(5 mol %) and PCy3 (10 mol %) in heated THF.
N
CF3
N
3e
N
Ph
We explored the generality of our method by applying these
conditions to different organozinc reagents, including selenium
and tellurium triazole derivatives. The results are summarized in
Table 4.
Inspection of Table 4 shows that the reaction worked well for
avariety of organozinc reagents, including aryl and heteroaryl
derivatives. However, poor yields were achieved for 4-organotellu-
rium-1H-1,2,3-triazoles.With alkylzinc reagent was not observed
coupling product.
N
6
7
8
2j
2j
2k
83
N 3f
N
Ph
N
S
62b
S
N 3g
N
Conclusions
Ph
MeO
In summary, using the click chemistry concept, we have devel-
oped an efficient route to synthesize different 4-organoselenium-
and 4-organotellurium-1H-1,2,3-triazoles via 1,3-dipolar cycload-
dition employing organochalcogen acetylenes in moderate to good
yields. For the first time, 4-organoselenium-1H-1,2,3-triazoles
were successfully subjected to a nickel-catalyzed Negishi cross-
coupling reaction, as the electrophile, obtaining different triazoles
70
N
N
OMe
3h
N
(CH2)11CH3

H. A. Stefani et al. / Tetrahedron Letters 53 (2012) 6495–6499
9. Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2003, 8, 1128.
6499
in moderate to good yields. All the obtained compounds are inter-
esting as a final product or as a building block for organic synthesis.
Further applications of this practical nickel-catalyzed Negishi
cross-coupling reaction with 4-organoselenium-1H-1,2,3-triazoles
and mechanistic investigations are underway in our laboratory.
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Acknowledgments
The authors would like to acknowledge Fundação de Amparo à
Pesquisa do Estado de São Paulo (FAPESP07/59404–2, 10/15677–8)
and Conselho Nacional de Desenvolvimento Científico e Tecnológ-
ico (CNPq) (300.613/2007–5 and 152208/2010-0 to HAS and DML,
respectively) for their financial support.
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