A copper(II)-thioamide combination as a robust heterogeneous catalytic system for green synthesis of 1,4-disubstituted-1,2,3-triazoles under click conditions

Article abstract of DOI:10.1039/c5ra16581d

An efficient and practical synthesis of 1,4-disubstituted-1,2,3-triazoles under click conditions using a copper(ii)-thioamide combination as an efficient heterogeneous catalyst is disclosed. Mild reaction conditions and high yields make this method an attractive option for the preparation of triazole derivatives. The key to this procedure was the generation of Cu(I) required for the azide-alkyne cycloaddition, which was achieved by in situ reduction of Cu(II) using thiobenzanilide as reduction agent and ligand.

Full text of DOI:10.1039/c5ra16581d

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A copper (II)-thioamide combination as a robust heterogeneous catalytic system for green synthesis
of 1,4-disubstituted 1,2,3-triazoles under click conditions
a*
b
b
b
Zohreh Mirjafary , Leila Ahmadi , Masomeh Moradi and Hamid Saeidian
a
Department of Chemistry, Tehran Science and Research Branch, Islamic Azad University, Tehran, Iran
b
Department of Science, Payame Noor University (PNU), PO Box: 19395ꢀ4697, Tehran, Iran
Eꢀmail: zmirjafary@srbiau.ac.ir
Abstract: An efficient and practical synthesis of 1,4ꢀdisubstituted 1,2,3ꢀtriazoles under click conditions
using a copper (II)ꢀthioamide combination as an efficient heterogeneous catalyst is disclosed. Mild
reaction conditions and high yields make this method as an attractive option for the preparation of triazole
derivatives. The key to this procedure was the generation of Cu (I) required for the azideꢀalkyne
cycloaddition, which was achieved by in situ reduction of Cu (II) using thiobenzanilide as reduction agent
and ligand.
Keywords: Heterogeneous catalyst, 1,2,3ꢀtriazoles, click chemistry, thiobenzanilide, Huisgen
cycloaddition
Introduction
The aromatic heterocyclic compounds with a fiveꢀmembered ring containing two carbon atoms and three
nitrogen atoms was named 1,2,3ꢀtriazoles. These compounds constitute a major class of naturally
occurring compounds and privileged medicinal scaffolds that exhibit a broad range of biological and
1
ꢀ6
pharmaceutical properties, such as antiꢀHIV, antibacterial, anticancer, antifungal, and antiviral agents.
7
ꢀ11
Figure 1 shows representative bioactive 1,2,3ꢀtriazoleꢀcontaining drugs.
N
N
N
N
N
N
N
PhS
OEt
P
O
OH
OEt
as antiꢀinflammatory agent
R
O
as anticancer agent
Ph
N
H
N
N
N
N
N
O
N
S
N
N
F
N
Me
ArHN
O
N
2
CO Na
HN
12 25
C H
O
NH
2
as hypocholesterolemic agent
as antiviral agent
as antibiotic agent
Fig. 1. Representative bioactive 1,2,3ꢀtriazoles.
1

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Developing more efficient methods for the construction of compounds containing triazoles is a topic of
immense importance. The synthesis of 1,2,3ꢀtriazoles strongly relies on copper (I)ꢀcatalyzed azideꢀalkyne
[
3 + 2] Huisgen cycloaddition reaction (CuAAC reaction) which is the best ‘click’ reaction to date, due to
12, 13
its wide range of applications in chemistry, biochemistry and polymer chemistry.
A major advance in
improving of this reaction was accomplished through the use of copper compounds as catalysts. 1,4ꢀ
disubstituted 1,2,3ꢀtriazoles were synthesized in the presence of copper (I) with high yields under very
mild conditions. Various CuAAC reactions involving different sources of copper (I) and solvents have
1
4ꢀ20
been developed, leading to 1,4ꢀdisubstituted 1,2,3ꢀtriazoles.
Copper (I) salts are less used because of
their general thermodynamic instability. One possible choice to protect the copper (I) center from
oxidation or dispropotionation and to enhance its catalytic activity in the CuAAC reactions is to use Cu
2
1ꢀ23
(I) salts supported by nitrogen, sulfur and polydentate or auxiliary ligands.
However, the preparation
of such supported copper (I) catalysts are tedious, expensive and not always easy. On the other hand,
recycling and reusability of them because of their generally homogeneous nature are difficult.
It should be noted that copper (II) salts did not work well in CuAAC reactions. Sharpless and coꢀworkers
established a very robust catalytic system for the CuAAC reactions, which made use of a less expensive
copper (II) precatalyst, along with substoichiometric amounts of sodium ascorbate for an in situ
14
reduction. Designing of new specific catalytic system for the CuAAC reactions has caused profound
effects in optimizing the efficiency of a wide range of 1,4ꢀdisubstituted 1,2,3ꢀtriazoles. Development of
such catalysts has resulted in more economical and environmentally friendly chemistry through replacing
expensive, unstable, or toxic catalysts.
In the context of our general interest in the synthesis of heterocycles and following our research on
24ꢀ29
thioamide chemistry,
herein, we propose a facile synthesis of 1,4ꢀdisubstituted 1,2,3ꢀtriazoles via the
CuAAC reaction in the presence of a copper (II)ꢀthioamide combination as an efficient and inexpensive
catalytic system (Scheme 1). Thioamides are a class of organosulfur compounds which recently become a
30ꢀ32
very important functional group in coordination chemistry.
The presence of nitrogen atom and the
larger and less electronegative sulfur atom as soft donor enables the thioamidesꢀNH to bind to a metal in
32
different ways, giving a variety of complexes. Moreover organosulfur compounds generally can reduce
31
copper (II) species. With these two promising properties of thioamides in hands, our attention were
focused on using thiobenzanilide in the CuAAC reaction as an reduction agent and ligand.
2

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N
N
R
N
CuCl /thiobenzanilide
2
+
NaN3 + RX
H O/EtOH, rt, 4 h
2
1
2
3
R = alkyl and benzyl
X = Cl, Br and I
9
5ꢀ60%
Scheme 1. Oneꢀpot synthesis of 1,4ꢀdisubstituted 1,2,3ꢀtriazoles 3 using copper (II)ꢀthioamide
combination.
Experimental
General information
All the chemicals required for the synthesis of 1,4ꢀdisubstituted 1,2,3ꢀtriazoles 3 were purchased from
SigmaꢀAldrich (St. Louis, MO, USA), Fluka (NeuꢀUlm, Germany) and Merck (Darmstadt, Germany)
companies and were used as received. The all synthesized compounds 3 gave satisfactory spectroscopic
1
13
data. A Bruker (DRX‑400 Avance) NMR was used to record the H NMR and C NMR spectra. All
NMR spectra were determined in CDCl at ambient temperature. Gas chromatographyꢀmass spectrometry
GCꢀMS) (Agilent HP 6890, electron ionization (EI), 70 eV, HPꢀ5 column (30 m × 0.25 mm × 0.2 ꢁm),
3
(
HP 5793 mass selective detector) was used to record the mass spectra. IR spectra were taken films KBr
pellets on a Nicolet spectrometer (Magna 550). Liquid chromatographyꢀmass spectrometry (LCꢀMS)
analysis was performed on an Agilent 1200 LC system (Agilent, Waldbronn, Germany) equipped with
Agilent 6410 triple quadrupole tandem mass spectrometer and managed by a Mass Hunter workstation
(Agilent Technologies, CA, USA). All the reactions are monitored by thin layer chromatography (TLC)
carried out on silica gel with UV light and iodine, as detecting agents.
General procedure for the synthesis of thiobenzanilide
Thiobenzanilide was prepared according to previously reported procedure via Willgerodt–Kindler
27
reaction (Scheme 2). benzaldehyde (4 mmol) was added to a mixture of aniline (6 mmol), elemental
◦
sulfur (5 mmol) and Na
2
S (10 mol%) in DMF (5 mL), then heated at 100 C for 8 h. After completion of
the reaction, monitored by TLC (nꢀhexane/EtOAc: 5/2), the obtained solid was removed by filtration. The
unreacted sulfur was removed by adding 5 mL EtOH, heating and then hot filtration. After cooling,
thiobenzanilide was crystallized and separated by simple filtration.
3

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O
S
NH2
H
N
Na S, DMF
2
H
+
S8
+
0
1
00 C, 8 h
thiobenzanilide
Scheme 2. Preparation of thiobenzanilide via Willgerodt–Kindler reaction.
General procedure for the synthesis of copper (I)-thioamide catalytic system
2
CuCl (2 mmol) was added into the solution of thiobenzanilide (2 mmol) in ethanol (1 mL) at room
temperature. After 40 min a dark red precipitate was observed which was filtrated, washed with ethanol
and dried at room temperature (Scheme 3). The obtained precipitate is stable in air and insoluble in
organic solvents, except DMSO and DMF.
S
N
EtOH
H
+
CuCl2
Cu (I)ꢀthioamide catalytic system
rt, 40 min
Scheme 3. General procedure for the synthesis of copper (I)ꢀthioamide catalytic system.
General procedure for the synthesis of 1,4-disubstituted 1,2,3-triazoles 3
2
To a suspension of copper (I)ꢀthioamide catalyst (10 mg) in H O/EtOH (5 mL, 1:1), was added sodium
azide (0.6 mmol) and alkyl halide (0.5 mmol), and the resulting mixture was stirred at room temperature
for 1 h. Phenylacetylene (0.5 mmol) was added to the reaction mixture and the mixture was stirred at an
ambient temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of the
reaction, the catalyst was recovered by centrifugation and filtration. The catalyst was reused in
subsequent reaction without losing any significant activity. Water (5 mL) was added to the reaction
mixture and extracted with EtOAc (3 × 10 mL) and dried over Na
4
2 4
SO . The crude was concentrated under

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vacuum and was purified by preparative TLC (eluent: petroleum ether/ethyl acetate 4:1) to afford the
desired products.
Results and discussion
2
In an initial attempt to synthesis of 1,4ꢀdisubstituted 1,2,3ꢀtriazoles 3 using a combination of CuCl and
thiobenzanilide as catalytic system, we focused on systematic evaluation of different conditions for the
model reaction (Table 1). The reaction of phenylacetylene, benzyl bromide and sodium azide was
checked without catalyst, and we get no desired product 3a (Table 1, entry 1), while good results were
obtained in the presence of copper (I)ꢀthioamide catalytic system after 4 h. We then continued to optimize
the model reaction by considering the efficiency of solvent. A mixture of H O/EtOH (1 : 1) was much
2
2
better than H O and no reaction was performed in EtOH (Table 1, entry 7). The effect of temperature was
also studied by carrying out the model reaction at room temperature, 50 °C, and 75 °C. It was observed
that the yield was not increased as the reaction temperature was raised to 75 °C. On using the optimized
amount of copper (I)ꢀthioamide catalytic system, we found that 10 mg could effectively catalyze the
reaction of phenylacetylene (0.5 mmol) and benzyl bromide (0.5 mmol) for the synthesis of the desired
product 3a. Using more than 10 mg of the catalyst had no significant effect on the yield. It is interesting
2
to note that replacement of CuCl with CuCl produced 3a in moderate yield (Table 1, entry 4). Trace
yield of 3a was observed in the absence of thiobenzanilide (Table 1, entry 2).
Table 1. Optimization of the copper (I)ꢀthioamide ꢀcatalyzed synthesis of 3a.
a
Entry
Catalyst
Solvent
T (°C) Yield (%)
1
2
3
4
5
6
7
8
9
No catalyst
H
H
2
2
O/EtOH
O/EtOH
rt
rt
0
trace
71
86
95
58
0
CuCl
2
CuCl
H O/EtOH
rt
2
CuCl/PhCSNHPh
H
2
O/EtOH
rt
CuCl
2
/PhCSNHPh H
2
O/EtOH
rt
rt
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
/PhCSNHPh
/PhCSNHPh
/PhCSNHPh
H O
2
2
2
2
2
2
2
EtOH
rt
H
2
O/EtOH
50
75
rt
65
69
/PhCSNHPh H O/EtOH
2
b
1
0
1
/PhCSNHPh
/PhCSNHPh
H
H
2
2
O/EtOH
O/EtOH
70
c
1
rt
91
a
Reaction conditions: Solvent (5 mL, 1 : 1), phenylacetylene (0.5 mmol) and benzyl bromide (0.5 mmol),
b
c
catalyst (10 mg) and reaction time: 4 h; catalyst (5 mg); catalyst (20 mg)
As mentioned above, Organoꢀthiols and thiones generally can reduce copper(II) and disulfide compounds
31
are formed according to equation (1):
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2
RSH
It is conceivable that thiobenzanilide can exhibit thioneꢀthiol tautomerism in the presence of Cu , so
formation of the corresponding disulfide is possible. Acceleration of the CuAAC reaction by using CuCl
thioamide combination supported that copper (II) is reduced to copper (I) (Table 1, entry 5 versus entry
). During the redox reaction, thiobenzanilide acting as reduction agent is oxidized to the corresponding
+
2 Cu2+
RSSR
+
2Cu+ + 2H+
(1)
2
+
2
ꢀ
2
disulfide according to equation (2).
S
Ph
N
Ph
H
tautomerism
SH
Ph
N
Ph
S
2
Cu2+
+
Ph
S
N
+
2
Cu+ + 2H+
(2)
N
Ph
Ph
Ph
LCꢀMass analysis of the alcoholic solution of catalyst system confirmed the formation of the
+
corresponding disulfide of thiobenzanilide (Fig. 1). The disulfide formed relative low intensity [M + H]
at m/z 425 under positive ion electrospray ionization (ESI) conditions. The most abundant ion in its ESIꢀ
MS is observed at m/z 180 as iminium fragment.
x10 2 +ESI Scan (23.02 min) Frag=60.0V 930903-Cu-Complex-01.d
1
.8
.6
.4
.2
0
180.0
N
Ph
Ph
0
0
0
0
+
H
Ph
N
Ph
S
S
N
Ph
Ph
4
24.9
100 200 300 400 500 600 700 800 900
Counts (%) vs. Mass-to-Charge (m/z)
Fig. 1. LCꢀMS spectrum of the corresponding disulfide of thiobenzanilide.
2
+
+
1
Reduction of Cu to Cu by thiobenzanilide is also consistent with the result obtained by HNMR
analysis of copper (I)ꢀthioamide catalytic system in DMSOꢀd (Fig. 2). NMR spectrum of complex
6
2
+
1
bearing Cu due to paramagnetism properties could not be obtained. The HNMR appearance of copperꢀ
thioamide catalyst revealed that a redox reaction take place in the combination of CuCl with
2
thiobenzanilide in ethanol. The univalence of the copper ions in catalytic system was also confirmed by
6

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the measured diamagnetism. It can be considered that probably the generated disulfide from
thiobenzanilide acts as a ligand. Therefore the disulfide was synthesized through oxidation of
3
3
thiobenzanilide by using DMSOꢀHCl system according to Scheme 4. The synthesized disulfide reacted
with CuCl and CuCl to give the corresponding complexes. The latter complex gave 3a in moderate yield
76%), while the former afforded 3a in very low yield.
2
(
S
Ph
N
Ph
Ph
DMSO/HCl
S
+
Me2S
N
Ph
S
N
H
Ph
Ph
Scheme 4. Synthesis of the corresponding disulfide of thiobenzanilide by using DMSOꢀHCl system.
1
1
Comparison the HNMR spectrum of copperꢀthioamide catalyst with HNMR spectrum of the disulfide
1
(
Fig. 2) shows that the thioamide acts as ligand not disulfide. The H NMR spectrum of copper (I)ꢀ
thioamide catalyst consisted of a broad line at δ = 11.82 ppm correlating with the NH and multiple lines
for the aromatic protons at δ = 7.83ꢀ6.90 ppm.
H
Cu
H
S
N
H
S
H
N
H
H
H
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H
H
H
N
S
H
S
H
H
N
1
Fig. 2. HNMR spectra of copper (I)ꢀthioamide catalyst (a) and the corresponding disulfide of
thiobenzanilide (b).
Unfortunately, all attempts to get single crystals of copper (I)ꢀthioamide catalytic system for Xꢀray
crystallography were failed due to its high insolubility. Assignments of selected characteristic IR bands
ꢀ1
(
4000ꢀ500 cm ) for thiobenzanilide and copper (I)ꢀthioamide catalyst are given in supporting information
Fig. 1S and 2S). The positions of bands provide significant hints regarding the bonding sites of the
(
thiobenzanilide when complexed with copper (I). Thiobenzanilide can show thioneꢀthiol tautomerism.
ꢀ1
The υ(SꢀH) band at 2550 cm is absent in IR spectrum of thiobenzanilide but the υ(NꢀH) band is
ꢀ1
observed at 3418 cm , indicating that thiobenzanilide exists in the thione rather than the thiol form in the
3
4
ꢀ1
ꢀ1
solid state. It shows that a adsorption band of the C=S bond is a region 1570ꢀ1395 cm (1526 cm for
35
ꢀ1
thiobenzanilide), which is shifted to 1516 cm after being reacted with copper (II), indicating that the
sulfur of the C=S participates as a coordinating site. This coordination is confirmed by the absence of the
ꢀ1
36
strong band at 1361 cm in IR spectrum of copper (I)ꢀthioamide catalyst.
Energyꢀdispersive Xꢀray spectroscopy (EDS) was used for the chemical characterization of copper (I)ꢀ
thioamide catalyst. EDS analysis exhibited the existence of chlorine atoms in catalytic system (Fig. 3).
CHN analysis exhibited 44.48 % C, 3.05 % H and 3.73 % N. These results indicate that copper (I)ꢀ
3
1
thioamide system has a polymeric or cluster structure which explain its stability and high insolubility. A
possible structure of one unit in the polymeric complex of copper (I)ꢀthioamide catalyst is shown in Fig.
4.
8

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1000
900
800
700
600
500
400
300
200
100
0
ClKα
S Kα
CuKα
CuLα
N Kα
C Kα
ClKβ
S Kβ
CuKβ
keV
10.00
0
Fig. 3. EDS analysis of copper (I)ꢀthioamide catalyst.
Ph
NH
Ph
S
Cl
Cu
H
S
N
Cu
Ph
Cl
Cl
Cl
Ph
Fig. 4. A possible structure of one unit in the polymeric complex of copper (I)ꢀthioamide catalyst.
Next we turned our attention to apply copper (I)ꢀthioamide catalyst for the reaction of phenylacetylene
with a series of alkyl/aryl halide to obtain the corresponding 1,4ꢀdisubstituted 1,2,3ꢀtriazoles 3. All the
substrates consistently furnished the desired triazoles in good to excellent yields (Table 2). Formation of
azides proceeds via a S 2 mechanism (Scheme 5). It is worth noting that direct displacement reactions
N
take place rapidly in benzylic systems. The π systems of the benzylic group provide extended
37
conjugation, which stabilizes the TS in the S
N
2 mechanism,
so benzyl halides afforded the
corresponding triazoles in excellent yield, as shown in Table 2. Various alkyl halides were subjected to
the same reaction conditions to obtain the corresponding 1,2,3ꢀtriazoles. The yields were good in general.
1
13
The structure of the products was confirmed by HꢀNMR, CꢀNMR, GCꢀMS and comparison with
20, 38
authentic samples prepared by reported methods (see supporting information).
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Table 2. Copper (I)ꢀthioamideꢀcatalyzed synthesis of 1,4ꢀdisubstituted 1,2,3ꢀtriazole derivatives 3.
Entry
1
Halide
Product
Yield (%)
95
N
N
N
Br
3
a
N
2
3
4
84
93
89
N
N
Cl
3
a
N
N
N
Br
Br
3
b
Br
F
N
F
N
N
F
F
Br
F
F
F
3c
F
F
F
N
5
66
CH3I
N
3
H C
N
3
d
10

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N
6
68
N
I
N
3e
N
7
8
9
N
61
59
58
Br
N
3
f
N
N
Br
N
3
g
N
Br
N
N
3
h
The reusability of the copper (I)ꢀthioamide catalyst was also studied for the model reaction. The catalyst
was recovered by simple filtration, washed with ethanol and reused with consistent activity even after
eight catalytic cycles (Fig. 5).
9
5
95
1
00
91
90
88
8
5
90
80
70
60
50
40
30
20
10
0
83
81
8
3
3
5
6
7
7
1
2
2
4
4
1
5
6
8
RUN
Fig. 5. Recyclability of copper (I)ꢀthioamide catalyst in oneꢀpot synthesis of 1,2,3ꢀtriazoles.
11

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A possible mechanism for this copper (I)ꢀthioamide catalyst multicomponent reaction was proposed in
+
Scheme 5. The reaction was initiated by the metalation of phenylacetylene in the presence of Cu ,
resulting copper acetylide followed by coordination of alkyl/benzyl azides to the copper of the acetylide
initiates an azideꢀalkyne 1,3ꢀdipolar cycloaddition to form the desired products 3.
in situ SN2
X
RX
H+
Ar
H
Ar
Cu
NaN3
copper acetylide
R
N3
Thioamide
in situ reduction
CuII
CuI
Ph
Cu
N
NH
R
N
N
N
H+
Ph
N
R
H
3
Scheme 5. Proposed mechanism for copper (I)ꢀthioamideꢀcatalyzed synthesis of 1,4ꢀdisubstituted 1,2,3ꢀ
triazole derivatives 3.
In summary, a very efficient protocol for the synthesis of 1,4ꢀdisubstituted 1,2,3ꢀtriazole derivatives was
reported via a multicomponent reaction in the presence of a cheap and easily recyclable heterogeneous
copper (I)ꢀthioamide catalyst. The catalyst was easily prepared with the reaction of CuCl and
2
thiobenzanilide. The catalyst was collected easily by filtration and the reusability of the catalyst was
successfully tested for eight runs only a very slight loss of catalytic activity. Further studies of
applicability of the heterogeneous copper (I)ꢀthioamide catalyst for synthesis of useful organic
compounds such as propargylamines are in progress.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at:
Acknowledgments
We are very grateful to Mr. Saleh Vahdati Khajeh for his valuable suggestions on this paper to reach
reasonable results.
12

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RSC Advances
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DOI: 10.1039/C5RA16581D
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RSC Advances
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DOI: 10.1039/C5RA16581D
A copper (II)-thioamide combination as a robust heterogeneous catalytic system for green
synthesis of 1,4-disubstituted 1,2,3-triazoles under click conditions
Zohreh Mirjafary, Leila Ahmadi, Masomeh Moradi and Hamid Saeidian
N
N
R
N
CuCl /thiobenzanilide
2
+
NaN3 + RX
H O/EtOH, rt, 4 h
2
1
2
3
R = alkyl and benzyl
X = Cl, Br and I
9
5-60%
One-pot synthesis of 1,4-disubstituted 1,2,3-triazoles 3 using copper (II)-thioamide combination was
reported.