CuO nanoparticles: synthesis and application as an efficient reusable catalyst for the preparation of xanthene substituted 1,2,3-triazoles via click chemistry

Article abstract of DOI:10.1016/j.tetlet.2015.07.016

Abstract Copper(II) oxide (CuO) nanoparticles have been found to be an efficient catalyst for 1,3-dipolar cycloaddition (CuAAC) of aromatic azides and acetylenic xanthenes furnishing the corresponding xanthene substituted triazoles in excellent yields. Cu

Full text of DOI:10.1016/j.tetlet.2015.07.016

Accepted Manuscript
CuO Nanoparticles: Synthesis and application as an efficient Reusable Catalyst
for the preparation of xanthene substituted 1,2,3-triazoles via click chemistry
P. Iniyavan, G.L. Balaji, S. Sarveswari, V. Vijayakumar
PII:
S0040-4039(15)01146-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.07.016
TETL 46505
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 April 2015
18 June 2015
4 July 2015
Please cite this article as: Iniyavan, P., Balaji, G.L., Sarveswari, S., Vijayakumar, V., CuO Nanoparticles: Synthesis
and application as an efficient Reusable Catalyst for the preparation of xanthene substituted 1,2,3-triazoles via click
chemistry, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.07.016
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1
Tetrahedron Letters
jour nal homepage: w ww.elsevier. com
CuO Nanoparticles: Synthesis and application as an efficient Reusable Catalyst for
the preparation of xanthene substituted 1,2,3-triazoles via click chemistry
P. Iniyavan, G.L. Balaji, S. Sarveswari, V. Vijayakumar∗
Centre for Organic and Medicinal Chemistry, School of Advanced Sciences, VIT University, Vellore -632 014, Tamil Nadu, India.
ARTICLE INFO
ABSTRACT
Copper (II) oxide (CuO) nanoparticles have been found to be an efficient catalyst for 1,3-dipolar
cycloaddition (CuAAC) of aromatic azides and acetylenic xanthenes furnishing the
corresponding xanthene substituted triazoles in excellent yields. CuO nanoparticles have been
synthesized from copper acetate by simple co-precipitation method and characterized by
scanning electron microscope, energy dispersive X-ray analysis, transmission electron
microscope and X-ray diffraction analysis. The salient features of the present protocol are mild
reaction conditions, shorter reaction time, reusability of the catalyst, and applicable with a wide
range of substrates.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Click chemistry
xanthenes
2009 Elsevier Ltd. All rights reserved.
triazoles
CuO nanoparticles
Xanthenes are common natural products and an important
motif in a variety of biologically active and useful compounds1.
Compounds carrying the xanthene moiety exhibit promising
biological activities such as anticancer2, analgesic3, anti-
inflammatory4 and antibacterial5. Some of the xanthene based
compounds have found applications as antagonists for paralyzing
the action of zoxalamine and in photodynamic therapy6. In
addition, their derivatives can be used as pH sensitive fluorescent
materials for the visualization of biomolecular assemblies7, as
bactericides in agriculture8 and in laser technologies9. The
combination of two heterocyclic skeletons having different
biological functions to produce a new hybrid compound that is
more medically effective than its parent molecules10. Several
hybrid molecules having xanthene as one scaffold have been
synthesized and applied in optical and medicinal studies11. In
particular, xanthene-triazole based hybrid molecule has been
reported as a new fluorophore with emission wavelengths from
blue to yellow regions12.
catalytic systems for this pioneering work. However, the
reusability of copper catalyst for these protocols is infrequently
studied due to their homogeneous nature, which creating problem
during separation of catalyst/product(s).
In order to overcome these drawbacks, recent research in this
work has concentrated on heterogeneous catalytic systems, which
have several advantages, such as good dispersion of active sites,
easier and safer handling, easier separation from the reaction
mixture and reusability. A large number of protocols have been
developed for the azide-alkyne cycloaddition with the use of
heterogeneous catalysts such as polymeric imidazole-Cu(II)27,
silica supported copper catalyst28, hydroxyapatite supported
copper (II)29 and copper(I)-modified zeolites30. The
susceptibility results obtained with these different techniques are,
in general, excellent. But, since the discovery of nanostructured
copper oxide has shown a general beneficial effect in the
cycloaddition of alkynes and azides which has been used by
many research groups31.
On the other hand, 1,2,3-triazoles possess a number of
desirable features in the context of medicinal chemistry such as
anti-bacterial13, anti-viral14, antibiotic15, magnetic resonance
imaging16, anti-allergic17 and trypanocidal activities18. Recently,
1,2,3-triazoles are synthesized by a process known as Cu-
mediated ‘click chemistry’19 which has been explored in
molecular hybridization system to synthesize the new analogs of
quinolines20, chalcones21, peptides22 and several other hybrid
molecules23.
Various groups have demonstrated the usefulness of nano-
crystalline metal oxides as catalysts for organic transformations32.
According to the factors mentioned and our continuous interest in
synthesis of organic compounds33, we report herein the first
successful synthesis of xanthene substituted triazoles catalyzed
by copper oxide nanoparticles.
Synthesis of Catalyst.
A 300 mL aliquot of 0.02 M copper acetate aqueous
solution was mixed with 1 ml of glacial acetic acid in a round-
bottomed flask equipped with refluxing device. Acetic acid was
Thus far, CuSO4/sodium ascorbate24, CuI/PEG-40025 and
Cu (OAc) 3H2O/H2O26 are the most generalized and widely used
——— 2
∗ Corresponding author. Tel.: 09443916746; e-mail: kvpsvijayakumar@gmail.com

2
added to avoid hydrolyzation of Cu2+ ions. The solution was
heated to 100 ⁰C with vigorous stirring. Subsequently, 0.8 g of
sodium hydroxide as reducing agent was added rapidly into the
above boiling solution and stirred for 10 min until the value of
the mixture reached the pH 6-7, where a large amount of black
precipitate was formed instantly. After being cooled to room
temperature, the resultant suspension was irradiated with
ultrasonic horn (by using E-Chrom ultrasonic horn, 22 kHz
frequency, 800 W) in ambient air for 1 h. Finally the precipitate
was centrifuged, washed once with distilled water and three times
with absolute ethanol, respectively, and dried in air at room
temperature. The obtained dry black powder sample was used for
further analysis.
DMF at room temperature. On the other hand, aromatic azides
were synthesized from their corresponding aromatic amines by
diazo-phenyl formation with sodium nitrite in acidic conditions
followed by displacement with sodium azide
Fig. 3 TEM images of CuO nanoparticles
Fig. 1 SEM images of CuO nanoparticles
Fig. 4 EDS image of CuO nanoparticles
O
OH
R1
R2
R1
O
R2
O
OH
Br
O
5
O
O
R1
R2
BF3.OEt2
Ethanol
+
K2CO3
2h
O
O
O
O
1-4
1 = R1, R2 -H
2 = R1, R2 - OCH3,
10 = R1, R3 -H 95%
11 = R1, R3 - OCH3, 92%
13 = R1-OC2H5 R3 - H 76%
6, 7, 9
6 = R1, R2 -H 92%
7 = R1, R2 - OCH3 93%
9 = R1-OC2H5 R2 - H 90%
4 = R1-OC2H5 R2 - H
O
O
OH
Br
O
Fig. 2 XRD pattern of CuO nanoparticles
O
OH
O
O
O
BF3.OEt2
Ethanol
O
O
+
K2CO3
2h
XRD patterns (Fig. 2) of the products obtained are identical
to the single-phase CuO with a monoclinic structure and the
diffraction data were in good agreement with JCPDS card of
CuO (JCPDS 80-1268). The peak broadening clearly indicates
the small size of the products. The average size of the CuO
nanoparticles is estimated to be 4-7 nm according to the Scherrer
equation34. The EDX spectrum (Fig. 4) of CuO nanoparticles
indicates the presence of Copper and Oxygen. SEM and TEM
observations were carried out and shown in Figs. 1 and 3. From
the SEM analysis, the shape of formed CuO nanoparticles was
found to be spherical. From the TEM image it can be seen that
the particles are nearly spherical with relatively uniform
diameters and the particle size is found to be 3-6 nm which is in
good agreement with the size which estimated by Scherrer’s
equation from the XRD pattern.
O
O
O
3
O
5
8
93%
12 86%
Scheme 1 Synthesis of acetylenic xanthenes (10-13)
NH2
N3
14 H
87%
18 2-OCH3 86%
91%
90%
NaNO2 /HCl
15 3-NO2 95%
16 2-NO2 93%
17 4-CH3 74%
19 2-F
20 4-Cl
NaN3
0 °C
R3
R3
Scheme 2 Synthesis of aromatic azides (14-20)
N
R3
N
N
O
O
N3
10 mol% nano CuO
20 mol% NaOAs
O
O
O
O
The outline for the preparation of various xanthene
substituted triazoles is shown in Scheme 1, 2 and 3. For our
present study, the key starting material, hydroxy substituted 9-
aryl-1,8-dioxo-octahydroxanthenes (6-9) were synthesized
through condensation reaction of dimedone (4) and hydroxy
R3
t
BuOH-H2O
O
O
RT
10-13
18-31
Scheme 3 Synthesis of xanthene substituted triazoles (21-46)
benzaldehydes (1-3) using ethanol as solvent in the presence of
We
have
chosen
3,3,6,6-tetramethyl-9-(4-(prop-2-
35
catalytic amount of BF3:OEt2
. Subsequently, substituted
ynyloxy)phenyl)-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-
dione (10) and phenyl azide (14) as the model substrates to find
out the optimized reaction conditions for the synthesis of
3,3,6,6-tetramethyl-9-(4-(prop-2-ynyloxy)phenyl)-3,4,5,6,7,9-
hexahydro-1H-xanthene- 1,8(2H)-dione (10-13) was synthesized
by O-alkylation of 6-9 with propargyl bromide using K2CO3 and

3
xanthene substituted 1,2,3-triazole derivatives (21-46). First, the
model reaction was performed in the presence of various copper
salt catalysts (Table 1) along with either of D-glucose and
sodium ascorbate (NaOAs) as reductant. Though all of the
investigated copper sources were capable of catalyzing the
synthesis to the desired product, yield was found be less and
consuming more time. While we used CuO nanoparticles (Table
1) along with sodium ascorbate, the yield improved remarkably
in reasonable time. Several solvents were examined to set up a
standard reaction condition, and results showed that the reaction
proceeded with excellent yields when tertiary butanol-water (1:1)
mixture was utilized. The next parameter catalyst loading was
optimized and it was observed that 10 mol% CuO nanoparticles
is sufficient to catalyze the reaction effectively. With these
optimal conditions from the pilot study in-hand, we embarked on
an investigation for the scope of the reaction with various
xanthenes and azides. The reaction went along well with both
electron-withdrawing and electron-donating substituted aromatic
azides. The results are summarized in Table 2.
Table 1 Synthesis of derivative 21 in different conditions.
Entry
Catalyst (mol %)
CuO NPs (10)
CuO NPs (5)
Reductant
NaOAs
NaOAs
NaOAs
D-Glucose
-
Solvent
Time (min)
Yield (%)a
1
tBuOH-H2O
tBuOH -H2O
tBuOH -H2O
tBuOH -H2O
tBuOH -H2O
Ethanol
60
60
60
60
60
60
60
30
90
60
60
60
60
87
64
83
43
12
65
76
42
87
74
34
51
32
2
3
CuO NPs (15)
4
CuO NPs (10)
5
CuO NPs (10)
6
CuO NPs (10)
NaOAs
NaOAs
NaOAs
NaOAs
NaOAs
D-Glucose
NaOAs
D-Glucose
7
CuO NPs (10)
tBuOH
8
CuO NPs (10)
tBuOH -H2O
tBuOH -H2O
tBuOH -H2O
tBuOH -H2O
tBuOH -H2O
tBuOH -H2O
9
CuO NPs (10)
10
11
12
13
CuSO4.5H2O (10)
CuSO4.5H2O (10)
Cu(OAc)2.2H2O (10)
Cu(OAc)2.2H2O (10)
xanthene 10 (1 mmol), azide 14 (1.2 mmol) in room temperature under the above conditions.
Table 2 Synthesis of xanthenes substituted triazoles (21-46).
Entry
xanthenes
azides
Product
N
Yield (%)
N
N
O
O
O
N3
O
1
87
85
91
O
O
O
O
21
14
10
N
N
N
N
3
O
O
NO
2
NO
2
O
O
15
2
22
N
N
N
O
O
N
3
O2N
NO
2
O
O
3
4
16
23
N
N
N
N
3
O
O
78
O
17
24
O

4
N
N
N
O
N3
O
O
5
85
O
O
25
O
18
N
N
N
N3
O
O
6
F
87
74
F
O
26
O
19
N
N
N
Cl
O
N
3
O
Cl
27
7
8
O
O
20
N
N
N
O
O
O
O
N3
O
O
85
O
O
O
O
O
O
14
28
11
N
N
N
O
O
N
3
O
O
NO
2
82
9
O
O
NO
2
29
15
N
N
N
O
O
O
O2N
N
3
O
10
86
75
O
O
NO
2
30
16
N
N
N
O
O
O
O
N
3
11
12
O
O
31
17
N
N
N
O
82
84
O
O
O
O
N3
O
O
O
32
18
N
N
N
O
O
O
F
N
3
O
13
14
O
O
F
33
19
N
N
N
O
Cl
N
3
O
O
78
Cl
O
O
O
20
34

5
O
O
O
O
N
3
N
O
N
O
O
O
15
N
81
79
O
O
14
35
12
O
O
O
N
3
N
N
16
O
O
O
O
N
NO
2
36
15
NO
2
O
O
O
O
O
N
3
N
N
O
O
O
N
NO
2
17
18
85
86
NO
2
16
37
O
O
N
3
N
N
O
N
18
38
O
O
N3
N
O
N
84
O
N
19
F
39
19
F
O
O
O
N
3
N
N
O
O
N
Cl
20
85
20
40
Cl
N
N
O
O
N
N
3
O
O
O
O
O
O
NO
2
NO
2
21
15
13
O
76
79
O
41
N
N
N
O
N
3
O
O
O2N
22
NO
2
16
O
O
42
N
N
N
O
N
3
O
O
23
72
17
O
43
O
N
N
N
N3
O
O
O
O
O
24
18
O
O
44
74

6
N
N
N
O
79
68
O
O
F
N
3
25
F
O
45
O
19
N
N
N
O
Cl
N
3
O
O
26
Cl
O
O
46
20
a – isolated yields
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Reusability
The reusability of CuO NPs was also examined. After the
reaction, the catalyst was separated by centrifugation, washed three
times with 5 mL of methanol, dried at 100 °C overnight and
subjected to the subsequent run. The catalyst can be used for four
times without dramatic yield loss. The comparison of efficiency of
catalyst on repeated use is reported in Fig. 4.
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Conclusion
In conclusion, we have developed a simple and efficient protocol
for the synthesis of xanthene substituted 1,2,3-triazoles through 1,3-
dipolar cycloaddition of aromatic azides with acetylenic xanthenes
using Copper oxide nanoparticles as an efficient and recyclable
catalyst. The above protocol has been performed efficiently to
provide the desired products in good yields. Simple operation, short
reaction times, easy separation and inexpensive and recyclable
catalyst are the salient features of this method. The photo-physical
studies of the synthesized compounds are under the progress in
our group.
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Acknowledgements
18. (a) Papadopoulou, M. V.; Bloomer, W. D.; Rosenzweig, H. S.;
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Authors are thankful to the administration, VIT University,
Vellore, India for providing facilities to carry research work and also
thankful to SIF-Chemistry, VIT University for providing NMR and
XRD facilities. Authors are thankful to Nano Facilities, IIT Madras
for providing TEM facility. Author P. Iniyavan is thankful to the VIT
University for providing Research Associateship.
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7
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Tetrahedron 2014, 70, 6120-6126; (b) Ishikawa, S.; Hudson, R.;
Masnadi, M.; Bateman, M.; Castonguay, A.; Braidy, N.; Moores,
A.; Li, C. J. Tetrahedron 2014, 70, 8952-8958; (c) Amadine, O.;
Maati, H.; Abdelouhadi, K.; Fihri, A.; El Kazzouli, S.; Len, C.; El
Bouari, A.; Solhy, A. Journal of Molecular Catalysis A: Chemical
2014, 395, 409-419; (d) Woo, H.; Kang, H.; Kim, A.; Jang, S.;
Park, J. C.; Park, S.; Kim, B. S.; Song, H.; Park, K. H.
Molecules 2012, 17, 13235-13252; (e) Decan, M. R.; Impellizzeri,
S.; Marin, M. L.; Scaiano, J. C., Nat. Commun. 2014, 5, 4612.
32. (a) Nasir Baig, R. B.; Varma, R. S. ACS Sustainable Chem. Eng.
2013, 1, 805-809; (b) Calo, V.; Nacci, A.; Monopoli, A.; Laera,
S.; Cioffi, N. J. Org. Chem. 2003, 68, 2929-2933.
39. General synthetic procedure for the xanthene substituted
triazole derivatives (21-46)
azides (1.2 mmol), acetylenic xanthenes (1 mmol) and sodium
ascorbate (20 mol%) were added over 10 mol % of the CuO
nanoparticles suspension in TBA-H2O solvent mixture and it was
kept for stirring at room temperature. After completion of the
reaction as indicated by thin-layer chromatography (TLC), the
reaction mixture was centrifuged to separate the catalyst. The
filtrate was quenched with water and the product was extracted
with ethyl acetate. The combined organic phases were dried over
anhydrous Na2SO4 and concentrate under reduced pressure, and
then the residue was purified by column chromatography on silica
gel (hexane/ ethyl acetate, 70/30) to afford the pure products.
33. (a) Rajesh, K.; Palakshi Reddy, B.; Vijayakumar, V. Can. J.
Chem. 2011, 89, 1236-1244; (b) Rajesh, K.; Palakshi Reddy, B.;
Vijayakumar, V. Ultrason. Sonochem. 2012, 19, 522-531; (c)
Balaji, G. L.; Rajesh, K.; Venkatesh, M.; Sarveswari, S.;
Vijayakumar, V. RSC Advances 2014, 4, 39-46.
40. 3,3,6,6-tetramethyl-9-(4-((1-phenyl-1H-1,2,3-triazol-4-
yl)methoxy)phenyl)-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-
dione (21): white solid; mp. 190-192 ⁰C; 1H NMR (400 MHz,
CDCl3): δ 0.98, 1.09 (s, 12H, CH3), 2.21 (m, 4H, CH2), 2.45 (s,
4H, CH2), 4.70 (s, 1H, CH), 5.22 (s, 2H, CH2), 6.88 (d, J = 7.6 Hz,
2H, ArH), 7.23 (d, J = 8.4 Hz, 2H, ArH), 7.46 (t, J = 7.6 Hz, 1H,
ArH), 7.54 (t, J = 7.6 Hz, 2H, ArH), 7.73 (d, J = 7.6 Hz, 2H,
ArH), 8.01 (s, 1H, ArH) ppm; 13C NMR (100 MHz, CDCl3):
27.38, 29.25, 31.01, 32.22, 40.87, 50.78, 62.03, 76.73, 77.05,
77.25, 77.36, 114.38, 115.72, 120.67, 120.94, 128.90, 129.50,
129.78, 136.97, 137.33, 145.34, 156.64, 162.20, 196.57. DEPT-
135 (100 MHz, CDCl3): δ 27.39 (CH3, C-11, 11'), 29.27 (CH3, C-
11, 11'), 31.01 (CH, C-3), 40.88 (CH2, C-7, 7'), 50.79 (CH2, C-8,
8'), 62.06 (CH2, C-16), 114.37 (CH, C-15, 15'), 120.68 (CH, C-20,
20'), 128.87 (CH, C-18), 129.50 (CH, C-21, 21'), 129.77 (CH, C-
13, 13') ppm; ESI-MS (m/z): calcd 523.6 Found: 524.3 (M+1).
Anal. calcd. for C32H33N3O4 C, 73.40; H, 6.35; N, 8.02. Found C,
72.10; H, 6.42; N, 7.89.
34. Gopiraman, M.; Ganesh Babu, S.; Khatri, Z.; Kai, W.; Kim, Y.
A.; Endo, M.; Karvembu, R.; Kim, I. S. Carbon 2013, 62, 135-
148.
35. Sethukumar, A.; Vithya, V.; Udhaya Kumar, C.; Arul Prakasam,
B. J. Mol. Struct. 2012, 1008, 8-16.
36. General procedure for the synthesis of xanthenes (5, 6 and 7).
A
mixture of hydroxy benzaldehydes (1 mmol) and 5,5-
Dimethylcylcohexane-1,3-dione (2 mmol) was refluxed in ethanol
with BF3:OEt2 as catalyst for 3-4 hrs. After the completion of the
reaction (monitored by TLC), the resulting precipitate was
filtered, washed with water and a small amount of ice cold
ethanol. The crude product was recrystallized from absolute
ethanol and it was found to be pure and no further purification
was necessary.
37. General procedure for the synthesis of alkyne substituted
xanthenes (10-13)

8
Graphical Abstract
CuO Nanoparticles: Synthesis and
Leave this area blank for abstract info.
application as an efficient Reusable Catalyst
for the preparation of xanthene substituted
1,2,3-triazoles via click chemistry
P. Iniyavan, G.L. Balaji, S. Sarveswari, V. Vijayakumar∗
N
R
N
N
O
O
N3
10 mol% nano CuO
O
O
O
O
20 mol% NaOAs
tBuOH-H2O
RT
R
O
O