Ionic liquid containing copper(I): A new, green, homogeneous, and reusable catalyst for click cyclization

Article abstract of DOI:10.1080/00397911.2012.687424

An ionic liquid containing copper(I) is introduced as a new, green, homogeneous, and reusable catalyst for click synthesis of 1,4-disubstituted-1H- 1,2,3-triazoles from α-azido ketones and terminal alkynes in various solvents, especially in [bmim]BF₄

Full text of DOI:10.1080/00397911.2012.687424

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Ionic Liquid Containing Copper (I): A New, Green,
Homogeneous and Reusable Catalyst for Click
Cyclization
Amanollah Zarei Ahmady a , Fariba Heidarizadeh a & Mosadegh Keshavarz a
a Chemistry Department, Faculty of Sciences, ShahidChamran University, Ahvaz
61357-4-3169, Iran
Accepted author version posted online: 26 Jan 2013.
To cite this article: Amanollah Zarei Ahmady , Fariba Heidarizadeh & Mosadegh Keshavarz (2013): Ionic Liquid Containing
Copper (I): A New, Green, Homogeneous and Reusable Catalyst for Click Cyclization, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:10.1080/00397911.2012.687424
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Ionic liquid containing Copper (I): a new, green, homogeneous and reusable catalyst
for click cyclization
Amanollah Zarei Ahmady1, Fariba Heidarizadeh1,, Mosadegh Keshavarz1
1Chemistry Department, Faculty of Sciences, ShahidChamran University, Ahvaz 61357-
4-3169, Iran
Corresponding author: Fariba Heidarizadeh, Chemistry department, College of Science,
Shahid Chamran University, Ahvaz (6135743169), Iran, Tel.: +98-611 336 0018, Fax:
+98-611333 7009, E-mail address: heidarizadeh@scu.ac.ir
Abstract
Ionic liquid containing copper (I) is introduced as a new, green, homogeneous and
reusable catalyst for click synthesis of 1,4-disubstituted-1H-1,2,3-triazoles from α-azido
ketones and terminal alkynes in various solvents especially in [bmim]BF4. These
cyclization reactions were efficiently performed in the presence of introduced ionic liquid
catalyst with short reaction times and at high yields. This catalytic ionic liquid
exhibitsexcellent activity and can be simply recovered and reused for at least five runs
withoutany loss in its activity.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications® to view the free supplemental file.
O
O
25
°C, 10-15 min
N
N
N
N3
+
R2
5 runs
R2
R1
R1
[bmim]BF4,
[Cu(Im12)2]CuCl2
(82-90%)
KEYWORDS: Ionic liquid, Multicomponent, Click chemistry, Triazole, Organic azide.
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INTRODUCTION
Copper-catalyzed azide-alkyne cycloaddition (CuAAC) is a widely utilized, reliable, and
straightforward way for making covalent connections between building blocks containing
various functional groups. It has been applied in various ways in organic synthesis,
medicinal, surface, polymer and bioconjugation.[1–5]
Although many kinds of copper (I) have been introduced as catalyst for CuAAC
reactions, the main decencies of these copper (I) catalysts are their instability and high
tendency to oxidation which lead to catalytic inactivity. Almost all of them are applicable
and suitable for certain kind of solvents. In fact, there is no copper (I) catalyst which can
be employed for both organic and non-organic solvents due to their low solubility in all
of these solvents. For instance, the simple coordination complexes Cu(P(OMe)3)3Br [6]
and Cu(PPh3)3Br [7,8]are often used for reactions in organic solventswhere cuprous salts
have limited solubility. There is research which describes the bis(phosphine) complex,
Cu(PPh3)2OAc, as an excellent catalyst for the CuAAC reaction in toluene and
dichloromethane.[9]Several Cu(I) complexes with N-heterocyclic carbene ligands have
been described as CuAAC catalysts at elevated temperature in organic solvents or under
heterogeneous aqueous conditions.[10–12]In situ prepared Cu (I) from Cu (II) using sodium
ascorbate was introduced by Fokine and co-workers for click cyclization in water.[13]
Most of these catalysts have been less advised because of their thermodynamic
instability, the formation of undesired alkyne-alkyne coupling and other byproducts
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which are sometimes observed in their presence.[14,15] It is noticeable that whensuch
catalysts are soluble, cannot be recoverable and reusable. Although immobilizing of
copper (I) on various supportsturns it intoa recoverable catalyst, the immobilized
catalysts frequently suffer from leaching of the supported catalyst into the reaction
mixture which leads to product contamination and catalyst deficiency during the
recycling process.[16] These catalysts usually have low activity, low product yield, high
reaction temperature and require additive.
Thispaper aims to illustrate that [Cu(Im12)2]CuCl2 is a versatile homogeneous and
recyclable catalyst for the Huisgen preparation of 1,4-disubstituted 1,2,3-triazoles in
various organic and non-organic solvents especially in [bmim]BF4in accordance with the
principles of green chemistry.
RESULTS AND DISCUSSION
The user friendly and adjustable properties of ionic liquids have prompted numerous
applications, not only as environmentally benign reaction media, but also as catalysts,[17]
task-specific reagents,[18] and chirality transfer media.[19] From this perspective,
combining the synthetic potential of MCRs with the dual properties of RTILs as solvents
and promoters has resulted in the development of new and promising eco-compatible
organic transformations.[20] While some reports have been described the using of ionic
liquids as green solvent for CuAAC reaction, these methods require additive for effective
click cyclization and have long reaction times.[21,22] These reports do not represent the
catalytic activity of ionic liquids and used only as suitable medium to increase the
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solubility of the reactants. With these respects, we became interested in investigating the
effect of a new ionic liquid containing Cu (I), [Cu(Im12)2]CuCl2, as a new superior
catalyst for CuAAC reaction. To achieve this, at the first step, the new ionic liquid
containing Cu (I) catalyst was prepared according to the reported method (Scheme 1).[23]
To evaluate the efficiency of new introduced copper containing IL as catalyst for azide-
alkyne cycloaddition reaction in various solvents, we turned to run the click cyclization
between phenacylazide and phenyl acetylene in [bmim]BF4, H2O, [bmim]BF4/H2O,
THF/H2O, DMF/H2O, dioxane/H2O and CH2Cl2 as solvents. The results of using task-
specific ionic liquid, [Cu(Im12)2]CuCl2, as catalyst are reported in Table 1.
It can be seen that the introduced task specific ionic liquid, ([Cu(Im12)2]CuCl2), works
very well as a catalyst with various solvents even under neat conditions. This catalytic
ionic liquid is the first type of ionic liquids which can promote click cyclization. The
newly-introduced catalyst has removed the problems with the limited solubility of other
copper (I) catalysts which has been one of the main deficiencies associated with all other
kinds of copper (I) catalysts.Consequently, it can be employed in various types of organic
and non-organic solvents
Although this catalyst constitutes a homogenous phase with all of these solvents and
reduces the reaction times compared with the reported heterogeneous catalysts, it can be
readily recovered and reused. While the introduced catalyst givesdesirable results using
various solvents, [bmim]BF4 evidently stands out as the solvent of choicewith its fast
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reaction rate, high yield and environmental acceptability.
To exploit the generality and scope of the reaction in [bmim][BF4], the reaction was
extended to various structurally diverse terminal alkynes and α-azido ketones(Scheme 2).
The reaction progress was checked by TLC and the results are reported in table 2.
In all cases, click cyclization was completed in the course of a desirable and reasonable
time and 1,2,3-triazole derivatives were isolated in high yields. These observations
clearly indicate the generality and scope of the reaction with respect to various types of
terminal alkynes and organic azides (Table 2). For example the using of 1,3-
diethynylbenzene in click cyclizations led to the synthesis of interesting symmetrical bis-
triazoles (Table 2, entry 11 and Scheme 3).
Structural assignments of the products were confirmed by the appearance of a
singletwithinthe range of 7.8 to 8.5 ppm in 1H NMR spectra and indicated the
regioselective synthesis of 1,4-disubstituted triazoleregioisomers.[24]
An efficient catalyst should be easily recovered and reused. To investigate these
properties for our introduced catalyst, the reaction of phenacylazide with phenyl
acetylene was selected again as the model reaction. After completion of click cyclization,
the triazole product was easily extracted from the ionic liquids mixture using EtOAc. The
recovered ionic liquids mixture was reused in the next run. A roughly-consistent activity
was observed using [bmim]BF4 as solvent and [Cu(Im12)2]CuCl2 as catalyst over five
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runs (Figure 1). The yield difference between the first and fifth runs was only 3% which
indicates that the catalyst developed is maintaining its catalytic activity under reuse
circumstances.
Mechanistic pathway for click cyclization between organic azide and terminal alkyne
mediated by [Cu(Im12)2]CuCl2 is depicted in Figure 2.
The priority of this method to some of the previously reported ones is shown by the
comparison of the obtainedresults in Table 3.
CONCLOSION
We have introduced a new, homogeneous, green and reusable catalyst for regiospecific
synthesis of 1,4-disubstituted-1H-1,2,3-triazoles via Huisgen 1,3-dipolar
cycloadditionreaction between terminal alkynes and organic azides in various solvents.
The introduced ionic liquid containing copper (I), ([Cu(Im12)2]CuCl2), is the first ionic
liquid which can promote and catalyze click cyclization. The main advantages of this
catalyst over previously reported catalysts are its applicability for a wide range of
solvents, high ability to promote CuAAC reactions, simple recovery and reusability
procedure. Moreover, the mild reaction conditions, high yield of the products, ease of
work-up and the ecologically clean procedure will make the present catalyst a useful and
superior candidate for the synthesis of 1,4-disubstituted-1H-1,2,3-triazoles.
EXPERIMENTAL
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All of the triazole derivatives were prepared by our procedure. NMR spectra were
recorded in DMSO-d6 or CDCl3 on a Bruker Advanced DPX 500 and 400 MHz
instrument spectrometers using TMS as internal standard. IR spectra were recorded on a
BOMEMMB-Series 1998 FT-IR spectrometer. The spectroscopic and physical data of all
known compounds were compared with those of authentic samples.[24,25]
Preparation Of [Cu(Im12)2]Cucl2
To a Schlenk flask filled with CuCl (1.21 g, 12.22 mmol) a solution of 1-
dodecylimidazole (3.06 g, 12.95 mmol) in CH3CN (5 mL) was added. It was placed in an
ultrasonic bath at ambient temperature for about 30 min. The solvent was removed in
vacuo and the precipitate was washed with ether and dried under vacuum to give
[Cu(Im12)2]CuCl2 as a fine crystalline colorless solid.[23]
General Procedure For Synthesis Of 1,4-Disubstituted-1H-1,2,3-Triazoles Using
[Cu(Im12)2]Cucl2 As Catalyst
[Cu(Im12)2]CuCl2 (0.1mmol) was added to a round-bottomed flask containing [bmim]BF4
(4 mL), α-azido ketone (1 mmol), terminal alkyne (1 mmol). The reaction mixture was
stirred at room temperature for appropriate time (table 2).After completion of the reaction
(10-15 min) as monitored by TLC (EtOAc/n-hexan; 4:1 v/v),organic phase was extracted
with ethyl acetate (2×8 ml)and concentrated in vacuo. Ionic liquids mixture was kept for
the similar next runs. The solid residual was recrystallized froma mixture of
ethanol/water(3:1 v/v) to give pure product crystals. Isolated product was dried in
vacuum over night.
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Spectroscopic Data
•
1-phenyl-2-(4-phenyl-1H-1,2,3-triazole-1-yl)-1-ethanon(table 2, entry 1b): IR
max in cm-1, KBr): 1702(CO);1H NMR (400 MHz, DMSO-d6): δ = 6.28 (s, 2H,
(
COCH2), 7.34-7.38 (m, 1H), 7.47 (t, J= 7.7 Hz, 2H), 7.63 (t, J= 7.7 Hz, 2H), 7.78-7.74
(m, 1H), 7.88 (d, J= 8.15 Hz, 2H), 8.11 (d, J= 8.15 Hz, 2H), 8.53 (s, 1 H, CH
Triazole);13C NMR (100 MHz, DMSO-d6): δ = 56.5, 13.5, 125.6, 128.4, 128.7, 129.4,
129.5, 131.2, 134.6, 134.8, 146.8, 195.0 (CO).HRMS-FAB: m/z [M + H]+calcd for
C16H13N3O: 263.3; found: 263.3.Anal. Calcd for C16H13N3O: C, 72.92; H, 4.94; N, 15.95.
Found: C, 73.00; H, 4.86; N, 16.03.
•
Ethyl 2-(4-phenyl-1H-1,2,3-triazole-1-yl)acetate (table 2, entry 6b): IR ( max in
cm-1, KBr): 1198, 1215, 1755(CO); 1H NMR (500 MHz, CDCl3): δ = 1.34 (t, J= 7.12 Hz,
3H), 4.36 (q,J= 7.12 Hz, 2H), 5.23 (s, 2H), 7.38 (t, J= 7.38 Hz, 1H), 7.46 (t, J= 7.46 Hz,
2H), 7.89-7.87 (m, 2H), 7.96 (s, 1H);13C NMR (125 MHz, CDCl3): δ = 14.49, 51.38,
62.87, 121.42, 126.24, 128.69, 129.27, 130.82, 148.66, 166.72.HRMS-FAB: m/z [M +
H]+calcd for C12H13N3O2: 231.3; found: 231.3. Anal. Calcd for C12H13N3O2: C, 62.33; H,
5.67; N, 18.17. Found: C, 62.67; H, 5.30; N, 18.06.
•
1-(4-bromophenyl)-2-[(4-(1-hydroxyethyl)-1H-1,2,3-triazole-1-yl)]-1-
ethanone(table 2, entry 7b):IR ( max in cm-1, KBr): 1250, 1497, 1599, 1704 (CO), 3417
(OH); 1H NMR (400 MHz, DMSO-d6): 1.54 (d, J= 5.20 Hz, 3H), 4.19-4.16 (m, 1H), 4.95
(s, 1H), 5.96 (s, 2H), 7.79 (d, J= 8.60 Hz, 2H), 7.95 (d, 2H, J= 8.6 Hz), 8.37 (s, 1H, CH
Triazole);13C NMR (125 MHz, CDCl3): δ = 28.13, 45.97, 52.37, 121.47, 130.48, 130.86,
132.67, 148.81, 153.86, 189.82,. HRMS-FAB: m/z [M + H]+calcd for C12H12BrN3O2:
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310.2; found: 310.2. Anal. Calcd for C12H12BrN3O2: C, 46.47; H, 3.90; N, 13.55; Found:
C, 46.34; H, 3.91; N, 13.34.
•
2-[4-(1-hydroxyethyl)-1H-1,2,3-triazole-1-yl)]-1-(4-methoxyphenyl)-1-
ethanone(table 2, entry 8b): IR ( max in cm-1, KBr): 1170,1232, 1597, 1694 (CO), 3503
(OH); 1H NMR (500 MHz, CDCl3): 1.44 (d, J= 8.75 Hz, 3H),3.89 (s, 3H), 4.89-4.86 (m,
1H), 5.28 (s, 1H), 6.07 (s, 2H), 7.13 (d, J= 8.75 Hz, 2H), 7.87 (s, 1H, CH Triazole), 8.06
(d, J= 8.75 Hz, 2H);13C NMR (125 MHz, CDCl3): δ =28.13, 45.97, 52.37, 121.47,
130.48, 130.86, 132.67, 148.81, 153.86, 189.82. HRMS-FAB: m/z [M + H]+calcd for
C13H15N3O3: 261.3; found: 260.3. Anal. Calcd for C13H15N3O3: C, 59.76; H, 5.79; N,
16.08. Found: C, 60.11; H, 5.65; N, 16.25.
•
2-(4-{4-[1-(2-oxo-2-phenylethyl)-1H-1,2,3-triazol-4-yl)]phenyl}-1H-1,2,3-triazol-
1-yl)-1-phenyl-1-ethanone (table 2, entry 11b): IR ( max in cm-1, KBr): 686, 1226, 1696
(CO);1H NMR (500 MHz, DMSO-d6): δ = 6.30 (s, 4H, COCH2), 7.58 (t, J= 5.17 Hz, 1H),
7.64 (t, J= 5.17 Hz, 4H), 7.76 (t, J= 4.95 Hz, 2H), 7.87 (q, J= 2.33 Hz, 2H), 8.12-8.13 (m,
4H), 8.44 (s, 1H), 8.64 (s, 2H, CH triazole);13C NMR (125 MHz, DMSO-d6): δ = 56.91,
122.70, 125.51, 129.11, 129.90, 130.56, 132.29, 135.01, 135.17, 146.97, 193.06. Anal.
Calcd for C28H20N6O2: C, 69.63; H, 4.49; N, 18.74. Found: C, 69.22; H, 5.56; N, 18.81.
See the Supplementary Material, available online, for complete spectral details.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the Research Council of ShahidChamran University
for financial support.
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Table 1 Evaluation of copper containing ionic liquid catalyst efficiency for CuAAC
reaction in various solvents
O
O
N N
N
[Cu(Im12)2]CuCl2
Neat or Solvent
N3
+
Entry Solvent
Temperature(°C)
Time(min) Yield(℅)a
1
2
3
4
5
6
7
8
neat
60
25
25
25
25
25
25
50
25
10
20
20
15
20
20
25
75
90
75
78
80
79
75
80
[bmim]BF4
Dioxane/H2O (1:1 v/v)
THF/H2O (1:1 v/v)
[bmim]BF4/H2O (1:1 v/v)
CH2Cl2
H2O/DMF (1:1 v/v)
H2O
aYield refer to isolated and pure products
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Table 2 [Cu(Im12)2]CuCl2/[bmim]BF4mediumpromotes click cyclization between α-azido
ketones and terminal alkynes
Time
(min)
Melting
Yield
(%)c
Entery
α-azido ketone(a)
Product(b)
point(oC)
O
O
N
N
N
N3
1
10
10
146[24]
145[24]
90
86
O
O
N
N
N3
N
2
3
Br
Br
MeO
Cl
O
O
N
N
N3
N
10
142[24]
87
MeO
Cl
O
O
N
N
N3
N
4
5
6
7
10
10
10
15
152[25]
138[25]
112
84
84
88
83
O
O
N
N
N
O
O
N
N
H3C
EtO
N3
H3C
N
N3
EtO
O
O
N
N
N3
N
OH
108
CH3
Br
Br
O
O
N
N
N3
N
OH
CH3
8
9
15
10
10
118
85
82
85
MeO
MeO
O
O
N
N
N
NH2
N3
146[24]
163[24]
O
O
N
N
N3
N
NH2
10
MeO
MeO
O
N
N
N
N
N
O
O
N
N3
More than
300
11
15
85
cYields refer to isolated and pure products
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Table 3 Comparison of the results obtained by the present method with some of the
previous methods
No. Solvent
Catalyst
T (°C)
25
t (min)
10-15
960
Yield (℅)a
82-90 [This work]
95 [21]
1
2
[bmim]BF4
[Cu(Im12)2]CuCl2
[C8dabco][N(CN CuI/ i-
25
)2]
Pr2EtN(additive)
CuI/ i-
3
[bmim]BF4
25
25
960
68 [21]
Pr2EtN(additive)
Cu/ AlO(OH)
4
5
n-Hexan
180-1440
150-1440
82-97 [26]
82-99 [27]
t-BuOH (80%) PS[NEt3][OAc](CuI) 25
aYields refer to isolated and products
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Scheme 1 Preparation of [Cu(Im12)2]CuCl2
(H2C)11
N
CH3CN, 30 min
Cu
N
N
+
CuCl
N
N
(H2C)11
Cu Cl
N
Cl
(CH2)11
1 mmol
1.06 mmol
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Scheme 2 Click cyclization between various α-azido ketones and terminal alkynes using
ionic liquids as solvent and catalyst
O
N
N
N
[Cu(Im12)2]CuCl2
[bmim]BF4
O
N3
+
R2
R2
R1
R1
°C / 10-15 min
25
(1a-11a)
(1b-11b; 82-90%)
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Scheme 3 Synthesis of symmetrical bis-triazoles using task specific ionic liquids
O
O
N
O
N
N
N
N
N
[Cu(Im12)2]CuCl2
[bmim]BF4
N3
2eq
+
1eq
°
25
C/15 min
11a
(85%)
11b
ACCEPTED MANUSCRIPT

Figure 1. Reusability study of [Cu(Im12)2]CuCl2/[bmim]BF4 in azide-alkyne
cycloaddition
O
O
N
N
N
N3
25
°C, 10 min
+
5 runs
[bmim]BF4,
[Cu(Im12)2]CuCl2
91
100
90
80
70
60
50
40
30
20
10
0
89
89
88
88
Run 1
Run 2
Run3
Run4
Run 5

ACCEPTED MANUSCRIPT
Figure 2. Proposed mechanistic pathway for [Cu(Im12)2]CuCl2 catalyzed azide-alkyne
cycloaddition
R2
Cu Im12
O
O
R2
Cu Im12
N
H
R2
O
N
N
N
N
R1
R1
N
N
N
H+
N
R1
HIm12 CuCl
[
]
2
R2
Cu Im12
N
O
[Cu(Im12)2]CuCl2
N
R1
N
R2
H
Cu Im12
R2
O
N3
R1
ACCEPTED MANUSCRIPT