Recyclable clay supported Cu (II) catalyzed tandem one-pot synthesis of 1-aryl-1,2,3-triazoles

Article abstract of DOI:10.1016/j.tet.2012.07.080

Montmorillonite KSF clay supported CuO nanoparticles efficiently catalyzes one-pot aromatic azidonation of aryl boronic acids followed by regioselective azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reaction producing corresponding 1-aryl-1,2,3-triazole derivatives at room temperature in excellent yields without use of any additives. Investigations on mechanism of CuAAC revealed that sodium azide, which is used as azidonating reagent in one-pot protocol reduces Cu(II) to click-active Cu(I). The catalytic efficiency of another Cu(II) source CuSO₄ in combination with NaN₃ for this one-pot CuAAC protocol, further supported our mechanism. This is the first report for use of Cu(II)/NaN₃ catalytic system for CuAAC protocol. The clay-Cu(II) catalyst being ligand-free, leaching-free, easy to synthesize from inexpensive commercially available precursors, recyclable, and environmentally friendly will be highly useful for economical synthesis of 1,4-disubstituted 1,2,3-triazoles.

Full text of DOI:10.1016/j.tet.2012.07.080

Tetrahedron 68 (2012) 8156e8162
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Recyclable clay supported Cu (II) catalyzed tandem one-pot synthesis
of 1-aryl-1,2,3-triazolesq
Shabber Mohammed a, Anil K. Padala a, Bashir A. Dar b, Baldev Singh b, B. Sreedhar c,
,
a,
*
Ram A. Vishwakarma a , Sandip B. Bharate
*
a Medicinal Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu 180001, India
b Natural Products Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu 180001, India
c Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology (CSIR), Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Montmorillonite KSF clay supported CuO nanoparticles efficiently catalyzes one-pot aromatic azidona-
tion of aryl boronic acids followed by regioselective azideealkyne 1,3-dipolar cycloaddition (CuAAC)
reaction producing corresponding 1-aryl-1,2,3-triazole derivatives at room temperature in excellent
yields without use of any additives. Investigations on mechanism of CuAAC revealed that sodium azide,
which is used as azidonating reagent in one-pot protocol reduces Cu(II) to click-active Cu(I). The catalytic
efficiency of another Cu(II) source CuSO4 in combination with NaN3 for this one-pot CuAAC protocol,
further supported our mechanism. This is the first report for use of Cu(II)/NaN3 catalytic system for
CuAAC protocol. The clayeCu(II) catalyst being ligand-free, leaching-free, easy to synthesize from in-
expensive commercially available precursors, recyclable, and environmentally friendly will be highly
useful for economical synthesis of 1,4-disubstituted 1,2,3-triazoles.
Received 12 April 2012
Received in revised form 20 July 2012
Accepted 24 July 2012
Available online 31 July 2012
Keywords:
Click chemistry
1,2,3-Triazoles
Heterogeneous catalyst
Montmorillonite KSF clay
Azide-alkyne 1,3-dipolar cycloaddition
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
The major limitations of existing CuAAC protocols realized in
terms of homogeneous nature of catalysts, thus creating problem
In recent years, the Cu(I)-catalyzed azideealkyne cycloaddition
(CuAAC) reaction1e3 has gained tremendous amount of attention as
it finds utility in drug discovery,4e8 biomolecular ligation,9 in vivo
tagging10 as well as in polymerization reactions.11 It is well known
that CuAAC reaction occurs only in presence of Cu(I) and does not
proceed in presence of Cu(II) or Cu(0); however, Cu (I) salts are
prone to redox processes so it is desirable to protect and stabilize
the active copper catalysts during CuAAC, which led to discovery of
several modified procedures, like using Cu(II)/Cu(0) salts with
various additives (e.g., reducing agents)/ligands.12 The most gen-
eralized and widely used version of this reaction involves use of
CuSO4/sodium ascorbate catalytic system in aqueous media. As
organic azides are explosive in nature, relatively unstable and
difficult to isolate, CuAAC strategy involving in situ generation of
organic azides from suitable precursors would be highly advanta-
geous and safe. As an efforts toward this aspect, Guo and co-
workers13 developed such protocol using NaN3/CuSO4/sodium
ascorbate catalytic system.
during separation of catalyst/product(s) and the requirement of
adding reducing agents and stabilizing ligands, which limited their
utilization in practical processes. Recent research in this area has
concentrated on heterogeneous catalytic systems,14e17 which have
several advantages, such as faster and simpler isolation of the re-
action products by filtration, as well as recovery and recycling of the
catalyst systems. Cu(I) species immobilized onto various supports,
such as silica,18 zeolites,19,20 activated charcoal,21 and amine-
functionalized polymers22 have been reported recently. However,
heterogeneous catalysts immobilized with Cu(I) species frequently
suffer from the general thermodynamic instability of Cu(I), which
results in its easy oxidation to Cu(II) and/or disproportionation to
Cu(0) and Cu(II), which limited their utilization in practical pro-
cesses. Recent studies indicated that immobilized Cu(II) species
could be reduced to Cu(I) species by alkyne during homocoupling
reaction. However, these protocols require organic solvents to
achieve high reactivity, need of inert atmosphere and higher re-
action times (48e72 h).23e26 Xia and co-workers26 developed ionic
liquid based heterogeneous catalysts for efficient synthesis of 1,2,3-
triazoles in aqueous medium. In recent studies, hydroxyapatite-
supported copper (II) (CuHAP)27 or Cu(II)ehydrotalcite28 cata-
lyzed azideealkyne cycloaddition reaction without use of any base
or reducing agents have been reported.
q
IIIM Publication number. IIIM/1466/2011.
* Corresponding authors. Tel.: þ91 191 2569111; fax: þ91 191 2569333; e-mail
addresses: ram@iiim.ac.in (R.A. Vishwakarma), sbharate@iiim.ac.in (S.B. Bharate).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.080

S. Mohammed et al. / Tetrahedron 68 (2012) 8156e8162
8157
Herein, we report the use of recyclable heterogeneous clay
supported CuO nanoparticles for one-pot synthesis of 1-aryl-1,2,3-
triazoles (1) from aryl boronic acids (2) as depicted in Fig. 1. In the
present protocol, sodium azide apart from its role as an azidonation
reagent, also acts as a reducing agent producing in situ click-active
Cu(I). This one-pot CuAAC protocol also worked well in presence of
CuSO4/NaN3 catalytic system without need of additional reducing
agent, which is further support to our finding of sodium azide’s role
as a reducing agent in CuAAC.
clayeCu(II) in solvent for 30 min, followed by addition of azide 4a
and alkyne 5a produced desired triazole 1a.31 Similar to azidona-
tion reaction, water: ACN (1:1) solvent was found to be superior to
water alone in CuAAC reaction. Phenyl boronic acids, substituted
phenyl boronic acids as well as heteroaryl boronic acids partici-
pated well in both reactions as depicted in Table 1.
Having successfully developed clayeCu(II)/NaN3 catalyzed pro-
tocol for aromatic azidonation and CuAAC reaction under identical
reaction conditions, it looked obvious to convert these two steps
into one-pot protocol for synthesis of 1-aryl-1,2,3-triazoles 1 di-
rectly from aryl boronic acids 2. With known explosive and un-
stable nature of organic azides and its difficult isolation, this one-
pot CuAAC will be highly useful and safe. The model reaction be-
tween 4-hydroxy boronic acid 2a, sodium azide (3) and phenyl
acetylene (5a) was investigated (Table 2). Treatment of 2a with
sodium azide (3) in water: ACN (1:1) in presence of clayeCu(II)
catalyst (10 mol %) led to formation of corresponding aryl azide
(monitored by TLC). Further on addition of alkyne 5a produced
desired triazole 1a in 98% yield in total 8 h of reaction time (Table 2,
entry 1). Poor yields were obtained in organic solvents viz. i-PrOH,
THF, MeOH, DMF, DMSO, and acetone (entries 2e7). The ACN: H2O
(1:1) produced corresponding triazole in 98% yield in much lesser
time (time, 4 h; entry 8) compared with only water as a solvent
(time, 8 h; entry 1). The combination of water: butanol (1:1),
however was not able to show improvement over water. Increase in
the catalyst loading was able to reduce the reaction time. Loading of
20 mol % catalyst produced desired triazole in 6 h (entry 10). Re-
duction in catalyst loading, as low as 1 mol % also yielded excellent
yield of product 1a although it required 12 h of reaction time (entry
14). Thus, the 10 mol % of catalyst and water: ACN (1:1) as a reaction
medium were found to be optimum by considering reaction time
and yield. CuSO4 (10 mol %) also produced excellent yields of 1a in
both water as well as water: ACN (1:1) solvents (entries 15 and 17).
Further, the clayeCu(II) catalyst showed good catalytic efficiency
with the recovered catalyst indicating its recyclability over several
cycles without significant loss of catalytic activity.32
Ar B(OH)2
+
+
R
NaN3
Ar = aryl, heteroaryl
R = aryl, alkyl, alicyclic
Water: ACN (1:1)
Clay
Cu(II)
rt, 4-8 h
80-98%
N
N
N
R
Ar
Fig. 1. Clay-supported Cu(II)-catalyzed one-pot synthesis of 1-aryl-1,2,3-trizoles.
2. Results and discussion
The clay supported Cu(II) catalyst was prepared by treatment of
aqueous Cu oligomer with Montmorillonite KSF clay, followed by
solvent evaporation, drying in oven and finally calcination at 425 ꢀC
for
3 h. Initially, we checked the catalytic performance of
clayeCu(II) catalyst for azide formation from boronic acids in water
and ACN: water (1:1) medium at room temperature as depicted in
Table 1. Reaction worked in both solvents, however ACN: water
(1:1) medium produced higher yields of azides 4aef with lesser
reaction times. 4-Hydroxy phenyl boronic acid required minimal
time compared with other aryl boronic acids. Next, we examined
the catalytic performance of clayeCu(II)/NaN3 catalytic system in
click reaction for azides 4aef with alkyne 5a (Table 1). The se-
quence of addition of reactants was found to be very important.29 A
homocoupling of alkyne was observed when all reactants were
mixed together at same time.30 Thus, stirring sodium azide (3) and
With the optimal conditions in hand, scope of the clayeCu(II)
catalyzed one-pot CuAAC was investigated for variety of boronic
acids and alkynes. Various substituted aromatic, and hetero-
aromatic boronic acids, and different aromatic, alicyclic, and ali-
phatic alkynes were investigated (Table 3). It was noticed that the
triazole products were formed in excellent yields with varying re-
action times. The reaction time was dependent on the type of bo-
ronic acid but not on the type of alkyne used. 4-Hydroxy phenyl
Table 1
ClayeCu(II)/NaN3 catalyzed aromatic azidonationa and azideealkyne cycloadditionb
5a
+
Ph
N
N
N
Clay-Cu(II), 3
Clay-Cu(II)
Ph
+
Ar B(OH)2
NaN3
Ar N3
Ar
H2O: ACN (1:1)
H2O: ACN (1:1)
or H2O, rt
Azidonation
or H2O, rt
Cycloaddition
4a-f
1a-f
2a-f
3
Azidonation
% Yieldc (reaction time)d
Cycloaddition
% Yieldc (reaction time)d
Entry
Ar
Product
Water
ACN:water (1:1)
Product
Water
ACN:water (1:1)
1
2
3
4
5
6
ePh(4-OH)
ePh
ePh(3-CHO)
ePh(4-OMe)
-2-OMe pyridin-5-yl
ethiophen-3-yl
4a
4be
4c
4d
4e
4f
88 (8)
97 (3)
96 (6)
95 (5)
95 (8)
98 (3.5)
96 (3.5)
1a
94 (1.5)
88 (1.5)
90 (2)
90 (1.5)
92 (1.5)
92 (1.5)
98 (1)
97 (1)
97 (1)
98 (0.75)
98 (0.75)
98 (1)
84 (14)
80 (12)
78 (10)
82 (8)
1b16
1c
1d16
1e
1f
80 (8)
a
2aef (1 mmol), 3 (2 mmol) and clayeCu(II) (10 mol %).
b
c
4aef (1 mmol), 3 (0.6 mmol), 5a (1.1 mmol) and clayeCu(II) (10 mol %).
Isolated yields after silica gel column chromatography.
Reaction time in h.
d
e
3 mmol of 3 was used.

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S. Mohammed et al. / Tetrahedron 68 (2012) 8156e8162
Table 2
Catalyst optimization studies for one-pot CuAAC protocola
N
N
Clay-Cu(II)
N
+
+
NaN3
Ph
(HO)2B Ph(4-OH)
HO
H2O: ACN (1:1)
Ph
or H2O, rt
2a
3
5a
1a
Entry
Cu(II) catalyst
Mol % of catalyst
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
ClayeCuO
ClayeCuO
ClayeCuO
ClayeCuO
ClayeCuO
ClayeCuO
ClayeCuO
ClayeCuO
ClayeCuO
ClayeCuO
ClayeCuO
ClayeCuO
ClayeCuO
ClayeCuO
CuSO4
10
10
10
10
10
10
10
10
10
20
5
5
1
1
10
20
10
H2O
i-PrOH
THF
MeOH
DMF
DMSO
Acetone
H2O/ACN (1:1)
H2O/t-BuOH (1:1)
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O/ACN (1:1)
8
8
8
8
8
8
8
4
8
6
8
12
5
12
6
98
40
20
87
65
62
30
98
90
97
75
96
50
95
97
98
98
9
10
11
12
13
14
15
16
17
CuSO4
CuSO4
4
4
a
Reagents and reaction conditions: 2a (1 mmol), 3 (2 mmol), 5a (1.1 mmol) and Cu(II) catalyst.
Isolated yields after silica gel column chromatography.
b
Table 3
One-pot synthesis of 1-aryl-1,2,3-triazoles using clayeCu(II)/NaN3 or CuSO4/NaN3-catalyzed CuAAC reactiona,b
Clay-Cu(II)/NaN3 (3)
N
N
N
or
CuSO4/NaN3 (3)
Ar B(OH)2
+
R
Ar
R
ACN: H2O (1:1)
rt
2
5
1
Entry
Ar
R
Product
ClayeCu(II)/NaN3
CuSO4/NaN3
Time (h)
Time (h)
Yieldc (%)
Yieldc (%)
1
2
3
4
5
6
7
8
ePh(4-OH)
ePh
ePh
ePh
ePh
ePh
ePh
ePh
1a
4
6
8
6
4
5
6
6
3
3
6
8
8
6
8
98
96
85
97
96
95
92
94
97
98
96
80
80
94
85
2.5
3
5
4
2.5
4
3
3.5
2
2
3.5
5
98
97
88
98
97
96
96
95
98
98
97
83
85
96
90
1b16
1c
ePh(3-CHO)
ePh(4-OMe)
-2-methoxy pyridin-5-yl
ethiophen-3-yl
ePh(4-OMe)
ePh(4-OMe)
ePh(4-OH)
ePh(4-OH)
ePh
enaphth-2-yl
ePh(4-OPh)
ePh(4-OMe)
eindol-5-yl
1d16
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
e(CH2)5CH3
e(CH2)7CH3
e(CH2)7CH3
ecyclohexyl
eCH2dNHePh(4-F)
ecyclohexyl
ePh
9
10
11
12
13
14
15
5.5
5
6
ecyclohexyl
ecyclohexyl
a
2 (1 mmol), 3 (2 mmol), 5 (1.1 mmol) and clayeCu(II) catalyst (10 mol %) or CuSO4 (10 mol %) in water: ACN (1:1) at room temperature.
The one-pot CuAAC protocol using both catalytic systems also worked in water as reaction medium.
Isolated yields after silica gel column chromatography.
b
c
boronic acids gave respective triazoles faster (reaction time, 3e4 h)
In order to prove the role of sodium azide as reducing agent in
CuAAC reaction, a reaction between 4-hydroxy phenyl azide 4a and
phenyl acetylene 5a was performed using clayeCu(II) catalyst in
the absence of sodium azide. Corresponding triazole was not
formed, suggesting that sodium azide plays a crucial role in this
CuAAC protocol. Further to generalize our Cu(II)/NaN3 catalyzed
CuAAC protocol, another Cu(II) source viz. CuSO4 was explored.
Like, clayeCu(II) catalyst, CuSO4 also produced excellent yields of
triazoles as depicted in Table 3. All synthesized compounds were
stable and were fully characterized by NMR, IR, MS and melting
point analysis.
irrespective of type of alkyne used (entries 1, 9, 10). However, re-
action of phenyl boronic acid (non-substituted) required 6 h for
completion of the reaction (entries 2 and 11). Reaction of 2-
methoxy substituted pyridine-3-yl boronic acid proceeded
smoothly and was completed in 4 h (entry 5). Formyl substituted
phenyl boronic acid underwent slow reaction and complete con-
version was observed in 8 h with 85% isolated yield of desired tri-
azole (entry 3). 4-Methoxyphenyl as well as 4-phenoxyphenyl
boronic acids produced corresponding triazoles in 6e8 h (entries 4,
7, 8, 13 and 14). Indol-5-yl boronic acid also participated well in this
reaction producing corresponding triazole 1o in 85% yield
(entry 15).
The prepared catalyst was characterized for its physical na-
ture. It was found that the prepared clayeCu(II) catalyst exists in

S. Mohammed et al. / Tetrahedron 68 (2012) 8156e8162
8159
the form of highly dispersed CuO nanoparticles supported on
H
R
Montmorillonite KSF (MKSF), as indicated by temperature pro-
grammed reduction, X-ray diffraction and scanning electron mi-
croscopy (SEM) experiments. The H2 TPR curve of catalyst
showed three reduction peaks, a major peak at 225 ꢀC, small
shoulder at 370 ꢀC and a small broad peak at 540 ꢀC. The peak at
225 ꢀC belongs to the reduction of highly dispersed fine CuO
particles indicating that these particles are responsible for cata-
lytic activity in CuAAC reaction.33,34 XRD results were also in
agreement with TPR results, suggesting CuO supported on MKSF
in the form highly dispersed nanoparticles.35,36 Further, results of
SEM (EDAX) elemental analysis indicated 8.83% Cu content in the
prepared catalyst. XRD studies of the used catalyst indicated in-
tercalation of organic species into the clay during organic
transformation.37 Total specific area of Montmorillonite-KSF clay
and clay-supported CuO was found to be 37.3514 and
96.4551 m2/g, respectively.
(HO)2B Ar
2
N
N
NaN3
Ar
N
Clay Cu(II)
1
H
NaN3
Clay Cu(II)
3
Clay Cu(I)
Cu Clay
R
N
N3 Ar
4
N
Ar
N
R
Clay
Ar
Cu
N
Clay
Cu
N
N
Ar
N N
N
Clay
Cu
N
R
R
N
Ar
5
N
Fig. 2 shows the high resolution narrow X-ray photoelectron
spectra (XPS) for fresh clay supported Cu(II) catalyst, clayeCu(II)
catalyst treated with sodium azide; and CuSO4 treated with NaN3,
recorded to know the oxidation state of Cu after treating with so-
dium azide. As observed in Fig. 2a, binding energy peaks at 935.6 eV
and 955.3 eV can be attributed to 2p3/2 and 2p1/2 spin-orbit
splitddoublets, respectively, which are characteristic of Cu inþ2
oxidation state. On the other hand, when clayeCu(II) was treated
with sodium azide (Fig. 2b) and CuSO4 treated with NaN3 (Fig. 2c),
in addition to the binding energy peaks (935.9 eV, and 955.5 eV in
Fig. 2b, and 935.5 eV, and 955.7 eV in Fig. 2c), two additional sets of
binding energy peaks at 933.0 eV, and 952.7 eV (Fig. 2b), and
933.1 eV, and 942.2 eV (Fig. 2c) are also observed, which clearly
indicates that Cu is present in both þ1 and þ2 oxidation states.38,39
These results concluded that Cu(II) gets partially reduced to Cu(I)
state after treatment with NaN3, and thus is present as Cu(II)/Cu(I)
mixed valency dinuclear species.
Fig. 3. Plausible mechanism of one-pot CuAAC protocol using clayeCu(II)/NaN3
catalyst.
3. Conclusion
In summary, the developed one-pot protocol for synthesis of
1,4-disubstituted 1,2,3-triazoles is highly efficient, economical and
safe. The clayeCu(II) is ligand-free, leaching-free, easy to prepare,
easy to handle, environmentally friendly and can be recycled sev-
eral times without significant loss of catalytic activity; thus it will
be highly useful for economical synthesis of 1,4-disubstituted 1,2,3-
triazoles. Most importantly the protocol does not require additional
reducing agent when NaN3 is already present in the reaction me-
dium. The use of Cu(II)/NaN3 catalytic system in CuAAC reaction has
been reported for the first time.
As proved by experimental variation in the CuAAC protocol
(CuAAC in presence and in absence of NaN3) and by XPS anal-
ysis, it is evident that sodium azide reduces Cu 2þ to Cu 1þ
oxidation state. Thus, the plausible mechanism40 for one-pot
clayeCu(II)/NaN3 catalyzed CuAAC reaction is depicted in the
Fig. 3.
4. Experimental section
4.1. General
All chemicals were obtained from SigmaeAldrich Company and
used as received. NMR spectra were recorded on Brucker-Avance
DPX FT-NMR 400 MHz instrument. ESI-MS and HRMS spectra
were recorded on Agilent 1100 LC and HRMS-6540-UHD machines.
Melting points were recorded on digital melting point apparatus. IR
spectra were recorded on PerkineElmer IR spectrophotometer.
Reducible character of the catalyst was determined by Chembet-
3000 TPR/TPD/TPO instrument. XRD spectra and Scanning elec-
tron micrograph were obtained on XRD Mini-Flex Rigaku Model
and Jeol.JEM100C-XII electron microscope, respectively. XPS anal-
ysis was performed on a KRATOS-AXIS 165 instrument.
4.2. Preparation and characterization of clayeCu(II) catalyst
ClayeCu(II) catalyst was prepared by introducing of calculated
amount of aqueous copper oligomer to form a 10% copper de-
position on to Montmorillonite KSF and the system was stirred for
15 h followed by filtration and then washed with distilled water
several times to remove chlorides. The cake so formed was dried at
room temperature, kept overnight in air oven at 110 ꢀC and then
powdered and calcined at 425 ꢀC for 3 h. The calcined product is
referred to as clayeCu(II) catalyst and the catalyst so formed was
used in the experiments without further activation. Other catalysts
with 20 and 5% loading of Cu were also prepared in the same way.
Catalyst was characterized using temperature programmed re-
duction, XRD, and SEM analysis. The reducible character of catalyst
Fig. 2. High resolution narrow X-ray photoelectron spectra (XPS) for (a) fresh clay
supported Cu(II) catalyst; (b) clayeCu(II) catalyst treated with sodium azide; (c) CuSO4
treated with NaN3.

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S. Mohammed et al. / Tetrahedron 68 (2012) 8156e8162
acidity and specific surface area was determined by Chemisorption
analyzer, containing a quartz reactor (i.d.¼4 mm) and a T.C.D. de-
tector. Prior to TPD studies, samples were pretreated at 250 ꢀC for
2 h in flow of pure nitrogen (99.9%) then cooled to room temper-
ature. After the pre-treatment, samples were saturated with 10%
anhydrous ammonia gas until saturated adsorption. The tempera-
ture was increased to 80 ꢀC and kept there for 2 h to remove the
physisorbed ammonia. Finally the system was heated from 80 to
1200 ꢀC at the rate of 10 ꢀC/min and the desorbed gas was moni-
tored with a T.C.D. detector. All the flow rates were maintained at
normal temperature and pressure (NTP). Nitrogen adsorption and
desorption was determined at ꢁ196 ꢀC by means of an automated
adsorption apparatus. X-ray diffractograms were obtained with Cu
4.5. Generalprocedure forone-potsynthesisof 1,2,3-triazoles(1)
Aryl boronic acid (2, 1 mmol) and sodium azide (3, 2 mmol)
were stirred in water or water: ACN (1:1) for 10 min. Clay sup-
ported Cu catalyst (10 mol %) was then added and reaction mix-
ture was stirred for another 30 min. The in situ formation of aryl
azide was monitored by TLC. The alkyne (5, 1.1 mmol) was added
and reaction mixture was stirred at room temperature for speci-
fied time duration. The completion of reaction was monitored by
TLC. The reaction mixture was filtered through WhatmanÒ filter
paper and residue was washed with ethyl acetate. Remaining
solid (recovered catalyst) was washed with water, dried (at 100 ꢀC
for 3 h) and reused (in case of recyclability experiment). Filtrate
was extracted with EtOAc (3ꢃ50 mL) and dried over anhydrous
sodium sulfate. Combined organic layer was concentrated in
vacuo and crude reaction mixture was purified by silica gel
(#100e200) column chromatography using EtOAc: hexane as
eluting solvent to get corresponding 1-aryl-1,2,3-triazoles 1ae1o
in 80e98% yield.
ꢀ ꢀ
ꢀ
K-a radiation (1.5418 A) with scanning rate of 2 per min from 5 to
80ꢀ. The X-ray diffraction spectrum (XRD) of the prepared catalyst
is shown in Figure S2. To study the morphology, SEM of the sample
was carried out using electron microscope with ASID accelerating
voltage 15.0 kV. The SEM image of the clayeCu(II) catalyst is shown
in Figure S3.
XPS measurements were obtained on a KRATOS-AXIS 165 in-
strument equipped with dual aluminumemagnesium anodes using
4.5.1. 1-(4-Hydroxyphenyl)-4-phenyl-1H-1,2,3-triazole (1a). Yield:
98%; white solid; mp 206e208 ꢀC; Rf (40% EtOAc: n-hexane) 0.40;
Mg K radiation (h
n
¼253.6 eV) operated at 5 kV and 15 mA with pass
energy 80 eV and an increment of 0.1 eV. Samples were degassed
out for several hours in XPS chamber to minimize air contamina-
tion to sample surface. To overcome the charging problem, a charge
neutralizer of 2 eV was applied and the binding energy of C 1s core
level (BEꢂ284.6 eV) of adventitious hydrocarbon was used as
a standard. The XPS spectra were fitted using a non-linear square
method with the convolution of Lorentzian and Gaussian functions
after a polynomial background was subtracted from the raw
spectra.
1H NMR (CD3OD, 400 MHz):
d
8.75 (s, 1H), 7.91 (d, J¼7.2 Hz, 2H),
7.68 (d, J¼6.4 Hz, 2H), 7.46 (t, J¼7.6 Hz, 2H), 7.37 (t, J¼6.0 Hz, 1H),
6.96 (d, J¼9.2 Hz, 2H); 13C NMR (DMSO-d6, 100 MHz):
d 157.8, 146.9,
130.4, 128.9, 128.8, 128.1, 125.3, 121.9, 119.5, 116.0; IR (neat): nmax
3139, 1600, 1521, 1231, 1057 cmꢁ1; ESI-MS: m/z 238 [Mþ1]þ, 260
[MþNa]þ; HRMS (ESIþ): m/z 238.0800 calcd for C14H11N3OþHþ
(238.0794).
4.5.2. 1,4-Diphenyl-1H-1,2,3-triazole (1b).13 Yield: 96%; white solid;
mp 175e177 ꢀC; Rf (30% EtOAc: n-hexane) 0.64; 1H NMR (CDCl3,
400 MHz):
d
8.20 (s, 1H), 7.93 (d, J¼7.6 Hz, 2H), 7.81 (d, J¼8.0 Hz,
4.3. General procedure for aromatic azidonation
2H), 7.56 (t, J¼8.0 Hz, 2H), 7.47 (t, J¼7.6 Hz, 2H), 7.38 (t, J¼7.6 Hz,
1H), 7.26 (d, J¼1.6 Hz,1H); 13C NMR (CDCl3,100 MHz):
d 148.5,137.1,
Aryl boronic acids (2, 1 mmol) and sodium azide (3, 2 mmol)
were placed in round bottom flask and subsequently water or
water: ACN (1:1) added and stir for 10 min. Then clayeCu(II)
(10 mol %) was added and reaction mixture was stirred vigorously
at room temperature for 3e14 h. The completion of reaction was
monitored by TLC analysis. After completion of reaction, reaction
mixture was extracted with EtOAc (50 mLꢃ3) and dried over an-
hydrous sodium sulfate. Combined organic layer was concentrated
in vacuo and crude reaction mixture was purified by silica gel
(#100e200) column chromatography using EtOAc: hexane as
eluting solvent to get corresponding aryl azides 4aef in 80e98%
yield. All isolated azides were characterized by comparison of their
NMR and MS data with literature values.13,41e45
130.3, 129.8, 128.9, 128.8, 128.4, 125.9, 120.6, 117.6; IR (neat):nmax
3122, 2923, 2360, 1731, 1465, 1239, 1074 cmꢁ1; ESI-MS: m/z 222
[Mþ1]þ, 244 [MþNa]þ.
4.5.3. 1-(3-Formylphenyl)-4-phenyl-1H-1,2,3-triazole
85%; white solid; mp 162e165 ꢀC; Rf (30% EtOAc: n-hexane) 0.40;
1H NMR (CDCl3, 400 MHz):
(1c). Yield:
d
10.13 (s, 1H), 8.30 (d, J¼7.61 Hz, 2H),
8.19 (d, J¼7.2 Hz, 1H), 7.99 (d, J¼7.6 Hz, 1H), 7.94 (d, J¼7.2 Hz, 2H),
7.77 (t, J¼8.0 Hz,1H), 7.50 (t, J¼5.6 Hz, 2H), 7.41 (t, J¼4.0 Hz,1H); 13C
NMR (CDCl3, 100 MHz):
d 190.8, 148.9, 137.8, 137.7, 130.8, 130.6,
129.9, 129.0, 128.7, 125.9, 125.9, 120.1, 117.4; IR (neat):nmax 3140,
2819, 1700, 1593, 1236, 1015 cmꢁ1; ESI-MS: m/z 250 [Mþ1]þ, 272
[MþNa]þ; HRMS (ESIþ): m/z 250.0986 calcd for C15H11N3OþHþ
(250.0975).
4.4. General procedure for azideealkyne cycloaddition
4.5.4. 1-(4-Methoxyphenyl)-4-phenyl-1H-1,2,3-triazole (1d).13 Yield:
97%; white solid; mp 155e159 ꢀC; Rf (30% EtOAc: n-hexane) 0.53; 1H
Clay supported CuO catalyst (10 mol %) and sodium azide (3,
0.6 mmol) were mixed in water or water: ACN (1:1) in round bot-
tom flask and stirred for half an hour. Then organic azides (4,
1 mmol) and corresponding alkynes (5, 1.1 mmol) were added and
reaction mixture was stirred vigorously for specified period of time
(10e30 min). Completion of reaction was monitored by TLC. After
completion of reaction, reaction mixture was filtered through
WhatmanÒ filter paper, residue was washed with EtOAc
(50 mLꢃthree times). Organic layer was separated from filtrate and
was dried over anhydrous sodium sulfate. Combined organic layer
was concentrated in vacuo and crude reaction mixture was purified
by silica gel (#100e200) column chromatography using EtOAc:
hexane as eluting solvent to get corresponding 1-aryl-1,2,3-
triazoles 1ae1f in quantitative yield.
NMR (CDCl3, 400 MHz):
d
8.11 9s, 1H), 7.92 (d, J¼7.2 2H), 7.71 (d,
J¼7.4 Hz, 2H), 7.46 (t, J¼7.4 Hz, 2H), 7.35 (t, J¼7.2 Hz, 1H), 7.06 (d,
J¼7.2 Hz, 2H), 3.88 (s, 3H) Hz, 2H, 7.68 (d, J¼7.6 Hz, 2H), 7.46 (t,
J¼7.4 Hz, 2H), 7.37 (t, J¼7.2 Hz, 1H), 7.04 (d, J¼7.2 Hz, 2H), 3.89, (s,
3H); IR (neat):nmax 3130, 2958, 2360, 1726, 1520, 1232, 1044 cmꢁ1
ESI-MS: m/z 252 [Mþ1]þ.
;
4.5.5. 1-(2-Methoxy-pyridin-5-yl)-4-phenyl-1H-1,2,3-triazole
Yield: 96%; light yellow solid; mp 142e144 ꢀC; Rf (40% EtOAc: n-
hexane) 0.65; 1H NMR (CDCl3, 400 MHz):
8.56 (s, 1H), 8.12 (s, 1H),
(1e).
d
8.02 (d, J¼7.2 Hz,1H), 7.92 (d, J¼7.2 Hz, 2H), 7.49 (m, 2H), 7.40 (m,1H),
6.94 (d, J¼8.8 Hz,1H), 4.02 (s, 3H); 13C NMR (CDCl3,100 MHz):
d 164.1,
148.6, 139.1, 132.0,130.1, 129.2, 128.5,128.4, 125.9,117.9, 111.8, 54.1; IR
(neat):nmax 3138, 3045,1607, 1578, 1229,1032 cmꢁ1; ESI-MS: m/z 253

S. Mohammed et al. / Tetrahedron 68 (2012) 8156e8162
8161
[Mþ1]þ, 275 [MþNa]þ; HRMS (ESIþ): m/z 275.0908 calcd for
C14H12N4OþNaþ (275.0903).
7.92e7.87 (m, 3H), 7.81 (s, 1H), 7.58e7.51 (m, 2H), 2.92e2.90 (m,
1H), 2.16 (m, 2H), 1.88 (m, 2H), 1.79 (m, 1H), 1.55e1.39 (m, 4H),
1.36e1.22 (m, 1H); 13C NMR (CDCl3, 125 MHz):
d 154.5, 134.8, 133.3,
4.5.6. 1-Thiophen-3-yl-4-phenyl-1H-1,2,3-triazole (1f). Yield: 95%;
white solid; mp 164e166 ꢀC; Rf (20% EtOAc: n-hexane) 0.43; 1H NMR
132.7, 129.9, 128.2, 127.9, 127.3, 126.8, 119.0, 118.1, 117.7, 35.4, 33.0,
29.7, 26.2, 26.1; IR (neat):nmax 3130, 2925, 1569, 1499, 1240,
1040 cmꢁ1; ESI-MS: m/z 278 [M]þ; HRMS (ESIþ): m/z 300.1468
calcd for C18H19N3þNaþ (300.1471).
(CDCl3, 400 MHz):
7.62e7.61 (q, J¼1.2, 3.2 Hz,1H), 7.53e7.52 (m,1H), 7.50e7.48 (m,1H),
d
8.11 (s, 1H), 7.92 (d, J¼1.6 Hz, 1H), 7.90 (s, 1H),
7.68 (m, 1H), 7.44 (m, 1H), 7.38e7.32 (m, 1H); 13C NMR (CDCl3,
100 MHz):
d
148.0,135.9,130.2, 128.9,128.5, 127.3, 125.9,120.9, 118.0,
4.5.13. 1-(4-Phenoxy-phenyl)-4-phenyl-1H-1,2,3-triazole
114.1; IR (neat):nmax 3103, 1558, 1447, 1231, 1074 cmꢁ1; ESI-MS: m/z
228 [Mþ1]þ, 250 [MþNa]þ; HRMS (ESIþ): m/z 250.0415 calcd for
C12H9N3SþNaþ (250.0409).
(1m). Yield: 80%; white solid; mp 171e173 ꢀC; Rf (30% EtOAc: n-
hexane) 0.73; 1H NMR (CDCl3, 500 MHz):
d 8.15 (s, 1H), 7.92 (d,
J¼8.3 Hz, 2H), 7.74 (d, J¼8.9 Hz, 2H), 7.44 (t, J¼7.7 Hz, 2H), 7.34 (m,
3H), 7.16 (m, 3H), 7.08 (d, J¼8.5 Hz, 2H); 13C NMR (CDCl3, 100 MHz):
4.5.7. 1-(4-Methoxyphenyl)-4-hexyl-1H-1,2,3-triazole (1g). Yield:
92%; light yellow solid; mp 90e93 ꢀC; Rf (30% EtOAc: n-hexane)
d 158.0, 156.4, 148.4, 132.3, 130.0, 128.9, 128.4, 125.9, 124.2, 122.3,
119.5, 119.3, 117.8; IR (neat):nmax 3128, 2921, 2359, 1587, 1514, 1244,
1110 cmꢁ1; ESI-MS: m/z 314 [Mþ1]þ; HRMS (ESIþ): m/z 314.1261
calcd for C20H15N3OþHþ (314.1288).
0.35; 1H NMR (CDCl3, 400 MHz):
d
7.61 (d, J¼5.6 Hz, 2H), 7.60 (s,
1H), 6.99 (d, J¼6.8 Hz, 2H), 3.89 (s, 3H), 2.78 (t, J¼7.6 Hz, 2H), 1.73
(m, 2H), 1.43e1.30 (m, 6H), 0.91 (t, J¼6.0 Hz, 3H); 13C NMR (CDCl3,
100 MHz):
d
159.6, 149.0, 130.8, 122.1, 119.0, 114.7, 55.6, 31.6, 29.4,
4.5.14. 1-(4-Methoxyphenyl)-4-cyclohexyl-1H-1,2,3-triazole
29.0, 25.7, 22.6, 14.1; IR (neat):nmax 3130, 3080, 2926, 2359, 1520,
1254, 1038 cmꢁ1; ESI-MS: m/z 260 [Mþ1]þ, 280 [MþNa]þ; HRMS
(ESIþ): m/z 260.1738 calcd for C15H21N3OþHþ (260.1757).
(1n). Yield: 94%; white solid; mp 90e93 ꢀC; Rf (30% EtOAc: n-
hexane) 0.35; 1H NMR (CDCl3, 500 MHz):
d 7.62 (m, 3H), 6.98 (d,
J¼6.8 Hz, 2H), 3.82 (s, 3H), 2.82 (m, 1H), 2.18 (m, 2H), 1.90e1.80 (m,
3H), 1.40 (m, 4H), 1.30e1.26 (m, 1H); 13C NMR (CDCl3, 125 MHz):
4.5.8. 1-(4-Methoxyphenyl)-4-octyl-1H-1,2,3-triazole
94%; light yellow solid; mp 53e55 ꢀC; Rf (20% EtOAc: n-hexane) 0.36;
1H NMR (CDCl3, 400 MHz):
7.71e7.61 (m, 3H), 7.03 (d, J¼6.8 Hz,
(1h). Yield:
d 159.6, 154.2, 132.5, 121.8, 117.2, 114.7, 50.0, 38.8, 33.1, 29.4, 26.2; IR
(neat):nmax 3127, 2926, 2359, 1724, 1518, 1256, 1044 cmꢁ1; ESI-MS:
m/z 258 [Mþ1]þ; HRMS (ESIþ): m/z 258.1614 calcd for
C15H19N3OþHþ (258.1601).
d
2H), 3.89 (s, 3H), 2.82 (t, J¼7.6 Hz, 2H), 1.72 (m, 2H), 1.43e1.27 (m,
10H), 0.94 (t, J¼6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
d 159, 149.0,
132.5, 122.4, 119.0, 114.7, 55.6, 31.9, 30.4, 29.7, 29.5, 29.4, 25.7, 22.7,
4.5.15. 1-(Indol-5-yl)-4-cyclohexyl-1H-1,2,3-triazole
85%; light pink solid; mp 136e139 ꢀC; Rf (30% EtOAc: n-hexane)
0.31; 1H NMR (CDCl3, 400 MHz):
8.48 (s,1H), 7.91 (d, J¼1.6 Hz,1H),
(1o). Yield:
14.1; IR (neat):nmax 3125, 2921, 2359, 1727, 1520, 1254, 1046 cmꢁ1
;
ESI-MS: m/z 288 [Mþ1]þ, 310 [MþNa]þ; HRMS (ESIþ): m/z 288.2079
d
calcd for C17H25N3OþHþ(288.2070).
7.68 (s, 1H), 7.56e7.47 (m, 2H), 7.33 (t, J¼2.8 Hz, 1H), 6.63 (t,
J¼2.4 Hz, 1H); 13C NMR (CDCl3, 125 MHz):
d 154.0, 135.4, 130.9,
4.5.9. 1-(4-Hydroxyphenyl)-4-octyl-1H-1,2,3-triazole
97%; light pink solid; mp 98e100 ꢀC; Rf (30% EtOAc: n-hexane)
0.29; 1H NMR (CDCl3, 400 MHz):
(1i). Yield:
128.0, 126.2, 118.5, 113.2, 111.8, 103.3, 35.4, 33.1, 26.2, 26.1; IR
(neat):nmax 3350, 2925, 2359, 1447, 1221, 1044 cmꢁ1; ESI-MS: m/z
267 [Mþ1]þ; HRMS (ESIþ): m/z 267.1632 calcd for C16H18N4þHþ
(267.1604).
d
7.64 (s, 1H), 7.58 (d, J¼6.8 Hz,
2H), 7.06 (d, J¼7.2 Hz, 2H), 2.79 (t, J¼7.6 Hz, 2H), 1.76e1.72 (m, 2H),
1.39e1.26 (m, 10H), 0.88 (t, J¼6.8 Hz, 3H); 13C NMR (CDCl3,
100 MHz):
d 157.8, 148.8, 129.9, 122.3, 119.5, 116.7, 31.9, 29.4, 29.3,
Acknowledgements
29.2, 29.2, 25.5, 22.7, 14.1; IR (neat):nmax 3119, 2919, 1599, 1237,
1059 cmꢁ1; ESI-MS: m/z 274 [Mþ1]þ, 296 [MþNa]þ; HRMS (ESIþ):
m/z 296.1739 calcd for C16H23N3OþNaþ (296.1733).
M.S., A.K.P. and B.A.D. thank CSIR for award of Senior Research
Fellowship. Authors are thankful to analytical department, IIIM for
NMR and MS analysis of our compounds.
4.5.10. 1-(4-Hydroxyphenyl)-4-cyclohexyl-1H-1,2,3-triazole
(1j). Yield: 98%; white solid; mp 167e169 ꢀC; Rf (30% EtOAc: n-
Appendix A. Supplementary data
hexane) 0.31; 1H NMR (CDCl3, 400 MHz):
d 7.60e7.56 (m, 3H), 7.03
(d, J¼8.8 Hz, 2H), 6.25 (brs, OH), 2.86 (m, 1H), 2.14 (m, 2H), 1.85 (m,
Spectra of catalyst and all new compounds. Supplementary data
associated with this article can be found, in the online version at
www.sciencedirect.com. Supplementary data related to this article
can be found online at http://dx.doi.org/10.1016/j.tet.2012.07.080.
2H), 1.76 (m, 1H), 1.50e1.38 (m, 3H), 1.35e1.23 (m, 2H); 13C NMR
(CDCl3, 100 MHz): d 157.4, 154.0, 130.0, 122.2, 118.1, 116.6, 35.2, 33.0,
26.1, 26.0; IR (neat):nmax 3139, 2926, 2359, 1600, 1519, 1223,
1061 cmꢁ1; ESI-MS: m/z 244 [Mþ1]þ, 266 [MþNa]þ; HRMS (ESIþ):
m/z 244.1466 calcd for C14H17N3OþHþ (244.1444).
References and notes
4.5.11. 1-Phenyl-4-(4-fluoroanilinomethyl)-1H-1,2,3-triazole
(1k). Yield: 96%; white solid; mp 94e96 ꢀC; Rf (60% EtOAc: n-
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43. Piero, S.; Paolo, Z. J. Org. Chem. 1978, 43, 3539e3541.
29. Mixing together all reactants sodium azide (3), organic azide 4a, alkyne 5a and
clayeCu(II) catalyst in ACN: H2O (1:1) at one time and stirring for 1 h led to
formation of homo-coupling product of alkyne, however desired triazole 1a
was not formed. The homocoupling product of phenyl acetylene was isolated
and characterized using melting point, 1H NMR and MS data. 1,4-diphenylbuta-
44. Shao, C.-W.; Wang, X.-Y.; Zhang, Q.; Luo, S.; Zhao, J.-C.; Hu, Y.-F. J. Org. Chem.
2011, 76, 6832e6836.
45. Sutherland, H. S.; Blaser, A.; Kmentova, I.; Franzblau, S. G.; Wan, B.; Wang, Y.;
Ma, Z.; Palmer, B. D.; Denny, W. A.; Thompson, A. M. J. Med. Chem. 2010, 53,
855e866.
1,3-diyne: White solid; mp 87e89 ꢀC; 1H NMR (CDCl3, 400 MHz):
d
7.52 (d, J¼7.
8 Hz, 4H), 7.40e7.34 (m, 6H); GCeMS: m/z 202 (Mþ), 174.2, 150.2, 101.1, 87.9.