Efficient, green and regioselective synthesis of 1,4,5-trisubstituted-1,2, 3-triazoles in ionic liquid [bmim]BF4 and in task-specific basic ionic liquid [bmim]OH

Article abstract of DOI:10.1007/s13738-013-0224-6

Convenient and environmentally benign procedures have been reported for the synthesis of 1,4,5-trisubstituted-1,2,3-triazoles by the reaction of aryl azides with active methylene compounds in ionic liquid [bmim]BF₄ in the presence of l-proline

Full text of DOI:10.1007/s13738-013-0224-6

J IRAN CHEM SOC
DOI 10.1007/s13738-013-0224-6
ORIGINAL PAPER
Efficient, green and regioselective synthesis of 1,4,5-trisubstituted-
1,2,3-triazoles in ionic liquid [bmim]BF4 and in task-specific basic
ionic liquid [bmim]OH
•
Harjinder Singh Jayant Sindhu
•
Jitender M. Khurana
Received: 4 October 2012 / Accepted: 17 January 2013
Ó Iranian Chemical Society 2013
Abstract Convenient and environmentally benign pro-
cedures have been reported for the synthesis of 1,4,5-tri-
substituted-1,2,3-triazoles by the reaction of aryl azides
with active methylene compounds in ionic liquid
[bmim]BF4 in the presence of L-proline as a catalyst and
also in task-specific basic ionic liquid [bmim]OH. The
methodologies defined herein avoid the severe conditions
as posed by earlier existing methods and proved to be
efficient in terms of good yields, operational simplicity,
easy workup and short reaction time.
(I)-catalyzed 1,3-dipolar cycloaddition of azides and alkynes
is often used to prepare 1,5-disubstituted 1,2,3-triazoles
[11–21]. However, the presence of the copper may induce
degradation of viruses or oligonucleotide strands in biologi-
cal systems [22, 23]. Copper ions are also potentially toxic
for living organisms. Base catalyzed reactions of aryl azides
with active methylene compounds also represent a powerful,
though less developed, approach to a variety of monocyclic
and bicyclic 1,2,3-triazole derivatives with different substi-
tution patterns in positions 4 and 5 of the ring. The reported
methods for 1,3-cycloaddition of aryl azides to active
methylene compounds involve long reaction time [24], use of
volatile catalysts [25] and toxic organic solvents such as
DMSO and 1,4-dioxane [24, 26].
Keywords 1,2,3-Triazoles Á [bmim]BF4 Á [bmim]OH Á
Ionic liquids Á Regioselective Á L-Proline
Room temperature ionic liquids have shown great
promise as attractive alternatives to conventional volatile
and toxic organic solvents [27, 28] owing to their negligible
vapour pressure, recyclability, solvophobic properties, and
ability to promote association of reactants in solvent cavity
during activation process. Therefore, room temperature
ionic liquids have received much attention as an alternative
reaction media for catalytic processes and also as task-
specific ionic liquids [29, 30]. In view of the emerging
importance of ionic liquids as novel reaction media and the
need for advent of novel methods that are devoid of listed
deficiencies, we wish to report the use of ionic liquids in the
synthesis of 1,4,5-trisubstituted-1,2,3-triazoles.
Introduction
1,2,3-Triazoles are an important class of compounds because
of their wide coverage of biological properties including
antiviral [1], antimicrobial [2], anti-HIV [3, 4], anticonvul-
sants [5] and anti-allergic [6]. In addition, compounds having
1,2,3-triazole group have found industrial applications as
dyes, corrosion inhibitors, sensors and photo-stabilizers [7].
The most popular method for the construction of 1,2,3-tria-
zole framework, is the 1,3-dipolar cycloaddition reaction of
azides with alkynes or enolizable compounds [8–10]. Copper
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-013-0224-6) contains supplementary
material, which is available to authorized users.
Experimental
H. Singh Á J. Sindhu Á J. M. Khurana (&)
Department of Chemistry, University of Delhi,
Delhi 110007, India
e-mail: jmkhurana1@yahoo.co.in;
jmkhurana@chemistry.du.ac.in
Structures of all of the compounds were identified by their
spectral data. Silica gel 60 F254 (precoated aluminium
plates) from Merck was used to monitor reaction progress.
Melting points were determined on a melting point
123

J IRAN CHEM SOC
apparatus and were uncorrected. IR (KBr) spectra were
recorded on Perkin Elmer FTIR spectrophotometer and the
values were expressed as mmax cm-1. Mass spectral data
were recorded on a Waters Micromass Spectrometer run-
ning under Mass Lynex version 4.0 software and equipped
with an ESI source. The NMR (1H and 13C) spectra were
recorded on Jeol JNM ECX-400P at 400 and 100 MHz,
respectively. The chemical shift values are recorded on d
scale and the coupling constants (J) are in Hertz. Different
aryl azides were prepared from corresponding aryl amines
by reported procedure [31].
v/v) as eluent, the reaction mixture was allowed to cool to
room temperature and was quenched with water (10 mL).
The precipitate formed was collected by filtration at pump,
washed with water and dried to yield pure 1,4,5-trisubsti-
tuted-1,2,3-triazoles (1a–1n).
Method B
A mixture of aryl azide (1.0 mmol), acetylacetone or ethyl
acetoacetate or methyl acetoacetate (1.0 mmol) was placed
in a 50 mL round-bottomed flask containing task-specific
basic ionic liquid [bmim]OH (10.0 mmol). The mixture
was stirred at 80 °C for appropriate time as mentioned in
Table 1. After completion of the reaction as monitored by
TLC using ethyl acetate:petroleum ether (60:40, v/v) as
eluent, the reaction mixture was allowed to cool to room
temperature and reaction was quenched with water
(10 mL). The precipitate formed was collected by filtration
at pump, washed with water and dried to yield pure 1,4,5-
trisubstituted-1,2,3-triazoles (1a–1n).
General procedure for the synthesis of 1,4,5-
trisubstituted-1,2,3-triazoles (1a–1n)
Method A
A mixture of aryl azide (1.0 mmol), acetylacetone or ethyl
acetoacetate or methyl acetoacetate (1.0 mmol) and L-
Proline (10 mol%) was placed in a 50 mL round-bottomed
flask containing 1.30 mL of ionic liquid, [bmim]BF4. The
mixture was stirred at 80 °C for appropriate time as men-
tioned in Table 1. After completion of reaction as moni-
tored by TLC using ethyl acetate:petroleum ether (60:40,
X-ray structure determination
X-ray intensity data for compound 1k was collected on
Oxford Diffraction Xcalibur CCD diffractometer with
Table 1 Synthesis of various 1,4,5-trisubstituted-1,2,3-triazoles
R1
N
O
N
Methods A & B
N
R1 N3
+
R3
R2
R2
R3
1a - 1n
Entry R1
R2
R3
Product Method A
Method B
Lit.Mp (°C)
Time (min) Yield (%) Time (min) Yield (%) Mp (°C)
1
4-NO2C6H4
CH3 COCH3
CH3 COCH3
CH3 COCH3
CH3 COCH3
CH3 COCH3
CH3 COCH3
CH3 COCH3
1a
1b
1c
1d
1e
1f
45
85
87
75
79
74
75
70
85
87
80
79
82
84
83
79
35
65
50
80
95
75
50
45
40
65
60
55
35
55
93
87
89
82
79
84
95
90
94
85
87
89
90
85
145–147 148 [32]
2
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
C6H5
116–118 119 [32]
120–122 120 [32]
118–120 120 [32]
120–121 120 [32]
108–110 108 [32]
3
60
4
125
140
120
65
5
6
7
4-FC6H4
1g
1h
80–82a
–
–
–
–
–
–
8
4-F,3-ClC6H3 CH3 COCH3
55
95–97
9
4-NO2C6H4
4-ClC6H4
4-BrC6H4
CH3 COOCH2CH3 1i
CH3 COOCH2CH3 1j
CH3 COOCH2CH3 1k
60
124–125
90–92a
164–165
55–57
10
11
12
13
14
a
95
75
4-F,3-ClC6H3 CH3 COOCH2CH3 1l
70
4-NO2C6H4
4-BrC6H4
CH3 COOCH3
CH3 COOCH3
1m
1n
50
155–156 154 [33]
204–206 200 [33]
70
Compound known but melting point reported for first time
123

J IRAN CHEM SOC
143.5, 137.4, 127.8, 125.2, 125.1, 117.7, 117.5, 27.8, 10.0;
HRMS (ESI): m/z = 254.4649 [M??1].
Ethyl 1-(4-nitrophenyl)-5-methyl–1H-1,2,3-triazole-4-
carboxylate 1i
IR (KBr, cm-1): mmax = 3,079, 1,720, 1,560, 1,532; 1H
NMR (400 MHz, CDCl3) dH: 8.44 (d, 2H, J = 8.76 Hz,
Ar–H), 7.71 (d, J = 8.8 Hz, 2H, Ar–H), 4.42–4.45 (q,
J = 7.32 Hz, 2H, OCH2), 2.66 (s, 3H, CH3), 1.40–1.44 (t,
J = 7.32 Hz, 3H, CH2 CH3); 13C NMR (100 MHz, CDCl3)
d 161.3, 148.1, 140.2, 138.8, 137.4, 125.8, 125.1, 61.3,
14.3, 10.1; HRMS (ESI): m/z = 277.4718 [M??1].
Fig. 1 ORTEP diagram showing X-ray structure of compound 1k
drawn with 50 % ellipsoid probability
Ethyl 1-(4-bromophenyl)-5-methyl-1H-1,2,3-triazole-4-
carboxylate 1k
˚
graphite monochromatic Mo Ka radiation (k = 0.71073 A)
IR (KBr, cm-1): mmax = 3,096, 1,718, 1,586, 1,563; 1H
NMR (400 MHz, DMSO) dH: 7.85 (d, 2H, J = 8.8 Hz,
Ar–H), 7.60 (d, J = 8.76 Hz, 2H, Ar–H), 4.31–4.36 (q,
J = 7.32 Hz, 2H, OCH2), 2.50 (s, 3H, CH3), 1.29–1.33 (t,
J = 7.36 Hz, 3H, CH2 CH3); 13C NMR (100 MHz,
DMSO) d 161.4, 142.1, 139.6, 134.3, 132.7, 127.5, 123.4,
60.5, 14.1, 9.7; HRMS (ESI): m/z = 310.3614 [M??1].
at temperature 298 K. Computations were carried out using
WinGX-32 graphical user interface. The structure was
solved by direct methods using SIR97. Data were refined and
extended using SHELX-97 software. Non-hydrogen atoms
were refined anisotropically. Carbon-bound hydrogen atoms
were included in idealized positions and refined using a
riding model. Crystallographic data (excluding structure
factors) for the structure have been deposited with the
Cambridge Crystallographic Data Center with CCDC No.
884194. These data can be obtained free of charge from the
CCDC via http://www.ccdc.cam.ac.uk/data_request/cif.
The single crystal image is given in Fig. 1.
Ethyl 1-(3-chloro-4-fluorophenyl)-5-methyl-1H-1,2,3-
triazole-4-carboxylate 1l
IR (KBr, cm-1): mmax = 3,073, 1,720, 1,570, 1,509; 1H
NMR (400 MHz, CDCl3) dH: 7.55 (d, 1H, J = 6.6 Hz,
Ar–H), 7.33 (d, 2H, J = 6.6 Hz Ar–H), 4.41–4.46 (q,
J = 7.32 Hz, 2H, OCH2), 2.57 (s, 3H, CH3), 1.40–1.43 (t,
J = 7.32 Hz, 3H, CH2 CH3); 13C NMR (100 MHz, CDCl3)
d 161.4, 157.5, 138.9, 136.8, 127.9, 125.3, 125.2, 117.7,
117.5, 61.2, 14.3, 9.9; HRMS (ESI): m/z = 284.4142
[M??1].
Crystallographic data
Chemical formula: C12 H12 Br N3 O2, crystal color: colorless,
crystal dimensions: 0.58 mm (max), 0.15 mm (mid),
0.07 mm (min), crystal system: monoclinic, space group: P 1
21/c 1, unit cell parameters: a = 13.7062(9), b = 7.7246(5),
c = 12.5297(9), number of formula units in the unit
cell (Z) = 4, absorption coefficient [l (mm-1)] = 3.165,
cell measurement theta = 3.0371 (min), 29.1657 (max),
goodness of fit (S) = 1.044, final R values: R (reflec-
tions) = 0.0429 (1,705), wR2 (reflections) = 0.1170
(2,285).
Results and discussion
We present herein an efficient and environmentally benign
protocol for the synthesis of 1,4,5-trisubstituted-1,2,3-tria-
zoles by the reaction of various aryl azides with active
methylene compounds in ionic liquid [bmim]BF4 in the
presence of L-proline as a catalyst and also in task-specific
basic ionic liquid [bmim]OH which acts as a reaction
medium as well as catalyst (Scheme 1).
Spectral data of new compounds
1-(1-(3-Chloro-4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-
4-yl)ethanone 1h
To achieve optimum reaction conditions, we investi-
gated the reaction of 4-nitrophenyl azide (1.0 mmol) and
acetylacetone (1.0 mmol) as model substrates in ionic
liquid [bmim]BF4 in the presence of basic catalysts such as
Et3NH, K2CO3, and L-proline. The best results were
obtained when the reaction was carried out in [bmim]BF4
IR (KBr, cm-1): mmax = 3,074, 1,685, 1,559; 1H NMR
(400 MHz, CDCl3) dH: 7.45 (d, 1H, J = 6.6 Hz, Ar–H),
7.24 (d, 2H, J = 6.6 Hz Ar–H), 2.62 (s, 3H, COCH3), 2.47
(s, 3H, CH3); 13C NMR (100 MHz, CDCl3) d 194.2, 160.3,
123

J IRAN CHEM SOC
R1
R2
Table 1). When this reaction was attempted at lower tem-
peratures, 40 and 60 °C, these required longer reaction
times for completion. Therefore, task-specific basic ionic
liquid [bmim]OH was chosen as optimum system at 80 °C
to extend this protocol. A number of other substituted aryl
azides also underwent 1,3-cycloaddition with acetylacetone
successfully under these conditions to afford corresponding
triazoles in excellent yields (1b–1h, ‘‘Method B’’).
N
O
N
Methods A & B
N
R1 N3
+
R3
R2
R3
1a - 1n
Method A: [bmim]BF4, L-proline (10 mol%) at 80 oC
Method B: [bmim]OH at 80 oC
Scheme 1 Synthesis of 1,4,5-trisubstituted-1,2,3-triazoles
Similarly, the reactions of aryl azides (1.0 mmol) with
ethyl acetoacetate (1.0 mmol) and methyl acetoacetate
(1.0 mmol) under these conditions yielded corresponding
ethyl 5-methyl-1-aryl-1H-1,2,3-triazole-4-carboxylates (1i–1l)
and methyl 5-methyl-1-aryl-1H-1,2,3-triazole-4-carboxylate
(1m–1n) in excellent yields. These results have been
compiled in Table 1 (method B). The results indicate that
reactions by both methods proceed fast and gave better
yields with aryl azides having electron withdrawing groups
compared to azides with electron donating groups. It can be
inferred from the above results that method B is slightly
superior as it requires shorter reaction times and the yields
are slightly better. Since addition of aryl azides to active
methylene compounds is catalyzed by base, therefore, ionic
liquid [bmim]BF4 acts as a reaction medium and L-proline
acts as a base in method A, whereas in method B task-
specific basic ionic liquid [bmim]OH functions both as the
reaction medium and the base.
as reaction medium in the presence of catalytic amounts of
L-proline (10 mol%) at 80 °C. The reaction underwent
completion in 45 min yielding 87 % of 1-(5-methyl-1-(4-
nitrophenyl)-1H-1,2,3-triazol-4-yl)ethanone (1a) after a
simple work up (entry 1, ‘‘Method A’’, Table 1). The
reaction in [bmim]BF4 at 80 °C in the absence of catalyst
resulted in incomplete reaction even after 12 h. The reac-
tions using catalytic amounts of Et3NH (10 mol%), K2CO3
(10 mol%) and L-proline (5 mol%) in [bmim]BF4 at 80 °C
required long reaction times and gave inferior yields.
Further, reaction in the presence of 15 mol% of L-proline
as a catalyst did not affect the reaction time and yield
significantly. Therefore, L-proline (10 mol%) in ionic
liquid [bmim]BF4 at 80 °C was chosen as optimum system
for this protocol. Subsequently, reactions of other substi-
tuted aromatic azides were carried out under these condi-
tions. The reactions proceeded smoothly for different aryl
azides to produce the corresponding 1,4,5-trisubstituted-
1,2,3-triazoles (1b–1h) in high yields.
The plausible mechanism of the reaction catalyzed by
basic ionic liquid [bmim]OH is outlined in Scheme 2. The
reaction proceeds via initial formation of enolate in the
presence of basic ionic liquid [bmim]OH, followed by
Huiseng [3?2] cycloaddition of aryl azide to form triazo-
line intermediate A, which subsequently undergoes elimi-
nation to yield 1,4,5-trisubstituted-1,2,3-triazoles.
The protocol was further extended by exploring the 1,3-
cycloaddition of aryl azides with other active methylene
compounds, e.g. ethyl acetoacetate and methyl acetoace-
tate. The reaction of 4-nitrophenyl azide (1.0 mmol) with
ethyl acetoacetate (1.0 mmol) in ionic liquid [bmim]BF4 in
the presence of 10 mol% of L-proline at 80 °C yielded
80 % of ethyl 5-methyl-1-(4-nitrophenyl)-1H-1,2,3-tria-
zole-4-carboxylate (1i). Similarly, other azides also gave
corresponding triazoles (1j–1l) in high yields. Also reac-
tions of 4-nitrophenyl azide (1.0 mmol) and 4-bromophe-
nyl azide (1.0 mmol) with methyl acetoacetate (1.0 mmol)
under similar reaction conditions yielded 83 and 79 % of
We have also investigated the recycling of basic ionic
liquid [bmim]OH. We observed that [bmim]OH could be
easily recovered after the completion of reaction and
reused in subsequent runs using the model reaction of
4-nitrophenyl azide with acetylacetone in [bmim]OH at
80 °C. After completion of the reaction, it was cooled and
water was added to the reaction mixture. The precipitate
formed was collected by filtration at pump. The filtrate was
concentrated under reduced pressure and dried to recover
the ionic liquid for subsequent use. No significant loss in
the yield of 1a was observed after three cycles as 1a was
obtained in 93, 90 and 85 % yield after first, second and
third cycle, respectively.
methyl
5-methyl-1-(4-nitrophenyl)-1H-1,2,3-triazole-4-
carboxylate (1m) and methyl 5-methyl-1-(4-bromophenyl)-
1H-1,2,3-triazole-4-carboxylate (1n), respectively. These
results have been summarized in Table 1 (‘‘Method A’’).
We further decided to explore this reaction using task-
specific basic ionic liquid [bmim]OH as a reaction medium
as well as the catalyst. Therefore, reaction of 4-nitrophenyl
azide (1.0 mmol) and acetylacetone (1.0 mmol) was
attempted in [bmim]OH without the aid of any catalyst at
80 °C. TLC analyses showed the reaction to be complete in
35 min yielding 93 % of 1-(5-methyl-1-(4-nitrophenyl)-
1H-1,2,3-triazol-4-yl)ethanone 1a (entry ‘‘Method B’’,
The cycloaddition of aryl azides to unsymmetrical
ketones leads to different regioisomers. The reaction of
various aryl azides by both methods (‘‘Method A’’ and
method B) is regioselective in nature and only one regio-
isomer was formed in case of unsymmetrical diketones as
supported by the structure of cycloadduct 1k which has
been identified by X-ray diffraction analysis Fig. 1. The
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J IRAN CHEM SOC
Scheme 2 Plausible
mechanistic pathway for
[bmim]OH catalysed synthesis
of 1,4,5-trisubstituted-1,2,3-
triazoles
R3
R2
N
O
O-
H
-O
R1-N3
[bmim]OH
-H2O
R3
R3
N
R2
R2
dipolar
cycloaddition
R1
N
H2O
R3
H
R1
R2
R2
N
N
-H2O
N
HO
N
N
R1
N
R3
A
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In conclusion, we have reported efficient and environ-
mentally benign methodologies for the synthesis of 1,4,5-
trisubstituted-1,2,3-triazoles in ionic liquid [bmim]BF4 in
the presence of catalytic amount of L-proline and also in
task-specific basic ionic liquid [bmim]OH. Corresponding
triazoles were obtained in good-to-excellent yields by both
methods. These methods offer advantages in terms of
operational simplicity, easy work up, short reaction times
and good yields as compared to previously reported
methods.
´
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