Copper oxide nanoparticle catalysed synthesis of imidazo[1,2-a]pyrimidine derivatives, their optical properties and selective fluorescent sensor towards zinc ion

Article abstract of DOI:10.1016/j.tetlet.2018.05.005

Synthesis of biologically active fused imidazo[1,2-a]pyrimidines were achieved via A³ coupling involving 2-aminobenzimidazole, aldehyde and terminal alkyne, followed by 6-endo-dig cyclization using copper oxide nanoparticles under solvent free

Full text of DOI:10.1016/j.tetlet.2018.05.005

Accepted Manuscript
Copper oxide nanoparticle catalysed synthesis of imidazo[1,2-a]pyrimidine de-
rivatives, their optical properties and selective fluorescent sensor towards zinc
ion
Manish Rawat, Diwan S. Rawat
PII:
S0040-4039(18)30586-0
https://doi.org/10.1016/j.tetlet.2018.05.005
TETL 49952
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 March 2018
30 April 2018
2 May 2018
Please cite this article as: Rawat, M., Rawat, D.S., Copper oxide nanoparticle catalysed synthesis of imidazo[1,2-
a]pyrimidine derivatives, their optical properties and selective fluorescent sensor towards zinc ion, Tetrahedron
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Copper oxide nanoparticle catalyzed synthesis of
imidazo[1,2-a]pyrimidine derivatives, their optical
properties and selective fluorescent sensor towards zinc ions
Manish Rawat and Diwan S. Rawat*
CuO
CuO
N
H2N
CuO
CuO
CuO
R3
CHO
HN
CuO
R3
R2
N
N
N
E
Factor= 0.11
Atom Economy= 94.4
%
R2
20 examples
Yield 70-90%
Zinc
ion

1
Tetrahedron Letters
journal homepage: www.els evier.com
Copper oxide nanoparticle catalysed synthesis of imidazo[1,2-a]pyrimidine
derivatives, their optical properties and selective fluorescent sensor towards zinc ion
Manish Rawat and Diwan S. Rawat ∗
Department of Chemistry, University of Delhi, Delhi-110007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Synthesis of biologically active fused imidazo[1,2-a] pyrimidines were achieved via A3 coupling
involving 2-aminobenzimidazole, aldehyde and terminal alkyne, followed by 6-endo-dig
cyclization using copper oxide nanoparticles under solvent free condition. Further optical
properties of imidazo[1,2-a]pyrimidines were studied which showed the effect of electron-
donating and electron-withdrawing substitution on the fluorescence intensities of these
compounds. Out of 20 compounds, 2,4-bis(4-methoxyphenyl)benzo[4,5]imidazo[1,2-a]
pyrimidine can act as a fluorescent sensor for zinc ion with detection limit 4.74 µM, which is
much lower than the maximum allowable zinc concentration in drinking water by WHO.
Received in revised form
Accepted
Available online
Keywords:
Decarboxylative strategies
A3 & KA2 coupling reactions
Green & sustainable chemistry
Magnetically recoverable
Propargyl amines
2009 Elsevier Ltd. All rights reserved.
1. Introduction
quinoline19,20 and coumarin21,22 have been designed but
complicated and multistep synthesis, makes these chemosensors
Imidazo-fused heterocyclic scaffolds are one of the important
core moieties which is found in many natural products and
biologically active molecules which shows antibacterial,1
anticancer,2 antimicrobial3 and antifungal4 activities. These are
one of the structural motifs of various marketed drugs5-8 such as
divaplon9 and fasiplon10 (figure 1). Apart from biological
importance, these moieties possess interesting optical properties
and behave as organic fluorophores.11 Various methods have been
reported for the synthesis of fused imidazo[1,2-a]pyrimidines
but most of these methods suffers from a drawback of longer
reaction time, multistep synthetic protocol, use of
expensive/harmful chemicals, non-recyclable catalytic system
and generation of unwanted side products.12
less enthralling. To avoid these complications, imidazo[1,2-
a]pyrimidines can be used as fluorescent chemosensors
specifically for the detection of zinc ion in biological system.
In order to make the synthetic protocol sustainable and
environment friendly, green synthetic methods have gained
importance in recent times. So, in order to meet the green
chemistry requirements efforts are being made to develop a
catalytic system that is robust and environment friendly for the
synthesis of biologically active heterocycles such as imidazo[1,2-
a]pyrimidines. Literature survey revealed that only two methods
are reported for the synthesis of this class of compounds using
homogeneous catalyst13 and heterogeneous nano catalyst14 and
this gives a scope to develop an alternative methodology for the
synthesis of imidazo[1,2-a] pyrimidines so as to overcome some
of the problems associated with known methods. Detection of
zinc ion in the biological system is essential to avoid various
neurological disorders like Alzheimer’s disease and Parkinson’s
disease associated with accumulation of zinc ions in the body. 15-
Figure 1: Biologically active molecules and organic fluorophores
With this background in mind and in continuation of our
interest towards nanocatalysis,23-29 we propose an alternative eco-
friendly synthetic methodology for the synthesis of imidazo[1,2-
a]pyrimidines using copper oxide (CuO) nanoparticles29,30 under
neat condition via A3 coupling followed by 6-endo-dig
cyclization. The structural and spectroscopic properties of
imidazo[1,2-a]pyrimidines can be helpful in the optoelectronic
application of these compounds and it can be used for the
detection of zinc ion.
18
In recent years various fluorescent chemosensors containing
———
∗ Corresponding author. Tel.: +91-11-27662683; fax: +91-11-27667501; e-mail: dsrawat@chemistry.du.ac.in

2
product whereas the alkyne containing cyclic substituent like
2. Results and discussion
cyclohexylacetylene afforded the moderate yield of the product
(Table 2, 4p).
Table 1: Optimization of CuO NPs catalysed synthesis of Fused
Imidazo[1,2-a]pyrimidinesa
Table 2: CuO NPs catalyzed synthesis of imidazopyrimidine
derivatives.a
N
N
N
N
CuO NP
R3
N
R3CHO
2a-o
NH2
Neat, 100 º C
R2
R2
H
3a-f
4a-t
1
Entry
Catalyst (mg)
Solvent
Temp.
(ºC)
Time
(h)
Yieldb
(%)
1.
2.
HS-CuO* (10mg)
HS-CuO (10mg)
HS-CuO (10mg)
HS-CuO (10mg)
HS-CuO (10mg)
HS-CuO (10mg)
HS-CuO (10mg)
HS-CuO (10mg)
HS-CuO (10mg)
HS-CuO (10mg)
HS-CuO (10mg)
No Catalyst
Toluene
ACN
DMF
EG
80
80
6
6
65
63
30
63
35
52
72
74
90
52
3.
80
12
12
12
12
3
4.
80
5.
PEG
EtOH
water
Neat
Neat
Neat
Neat
Neat
Neat
Neat
80
6.
80
7.
80
8.
80
4
9.
100
120
60
1
10.
11.
12.
13.
14.
24
24
24
4
Trace
amount
-
100
100
100
HS-CuO (5 mg)
HS-CuO (20 mg)
53
76
2
aReaction conditions: 2-aminobenzimidazole
1 (0.5 mmol), para-chloro
benzaldehyde 2 (0.5 mmol), phenylacetylene 3 (0.5 mmol) CuO NPs (5-20
mg) solvent (2ml) were stirred at mentioned temperatures. bIsolated Yield.
*
Hierarchically porous sphere like copper oxide (HS-CuO)
Optimization of synthesis of fused imidazo[1,2-a]pyrimidines was
started from 2-aminobenzimidazole (1), para-chloro benzaldehyde
(2) and phenylacetylene (3) with CuO NPs in the presence of various
solvents as mentioned in Table 1. Initially reaction was performed in
non-polar and polar solvents like toluene (Table 1, entry 1),
acetonitrile (Table 1, entry 2), DMF (Table 1, entry 3) and product
was isolated in poor to moderate yields (Table 1, entry 1-3). When
reaction was carried out in green solvents such as ethylene glycol,
PEG, ethanol and water the desired product was isolated in poor to
moderate yields (Table 1, entry 4-7), with maximum yield in water.
Under neat condition the desired product was isolated in 90% yield
in 1h at 100 (Table 1, entry 9). Increasing temperature to 120 or
lowering the reaction temperature to 60 has negative affect in the
isolated yield of the product (Table 1, entry 10, 11). Similarly
increase or decrease of catalyst amount led to lower the yield of the
product (Table 1, entry 13, 14) and no product formation was
observed in the absence of the catalyst (Table 1, entry 12).
Therefore, 10 mg of CuO NPs at 100 under neat condition was the
optimum condition for the synthesis of fused imidazo[1,2-
a]pyrimidine (Table 1, entry 9). Next, heterocyclic aldehydes were
screened and corresponding products were obtained in excellent
yield (Table 2, entry 4j, 4l) whereas the aliphatic aldehyde like
butyraldehyde afford the moderate yield of the product (Table 2,
entry 4o). Unfortunately, cyclic aldehydes and aromatic
aReaction condition: 2-amino-benzimidazole (1, 0.5 mmol), aldehydes (2, 0.5
mmol), alkynes (3, 0.5 mmol) and CuO NPs (10 mg) were stirred at 100℃ for
1-2 hours
Next, we examined the recyclability of CuO NPs catalyst for the
synthesis of product 4b under optimized conditions. Reaction
mixture was centrifuged, washed with ethanol and catalyst was dried
in the oven after completion of reaction. The catalyst was further
used to carry out five cycles of reaction, there was no significantly
loss of catalytic activity of catalyst as shown in figure 2.
nitrogen-containing
carboxaldehyde,
aldehydes
pyrrole-2-carboxaldehyde
such
as
pyridine-2-
and
cyclohexanecarboxaldehyde were failed to afford the
corresponding desired products. Aromatic alkynes bearing
electron donating and withdrawing groups provided the desired
product in good and moderate yield (Table 2, entry 4d, 4f, 4s).
Aliphatic alkyne like pentyne failed to provide the desired
Figure 2: Recyclability of CuO NPs catalysed synthesis of 4a.
The green chemistry metrics was calculated for compound 4b under
optimized condition as shown in table 3. It is evident from the table

3
that the green chemistry metrices are close to ideal values (detailed
calculations can be seen in supporting documents).
4r in absorption and emission maxima due to aliphatic chain
attached to the moiety. Fluorescence studies revealed that
electron-donating groups attached to imidazo[1,2-a]pyrimidines
increases the fluorescence properties of the molecules as
compared to electron-withdrawing groups and aliphatic groups
attached to the moiety.
Table 3: Measurement of Green chemistry metrices for 4b
S.No.
GC metrices
Ideal
value
0
Calulated
4b
0.11
1.
2.
E factor
Process mass intensity (PMI)
1
1.11
Figure 5: Absorption and fluorescence spectra of imidazo[1,2-a]
pyrimidines measured in DCM.
3.
4.
Reaction mass efficiency (RME)
Atom economy (AE)
100%
100%
90%
94.4%
Absorption spectra of Fluorescence spectra of
imidazo[1,2-a]pyrimidines imidazo[1,2a]pyrimidin
5
Carbon efficiency (CE)
100%
96%
measured in DCM.
es measured in DCM.
The plausible mechanism for the synthesis of imidazo[1,2-
a]pyrimidine is shown in figure 3. The first step is formation of
CuO complex as shown in figure 3.
N
O
NH2
R3
N
H
H
R2
H2O
R3
N
N
N
H
CuO
R2
A
R2
CuO
R3
N
CuO
NH
N
B
H
CuO
R2
R2
R3
R3
N
N
6-endo-dig
cyclization
Effect of metal ions on photophysical studies of 4s.
Absorption Spectra
N
N
N
NH
Demetallation
4
Figure 3: Plausible mechanism for CuO NPs catalyzed synthesis of Fused
Imidazo[1,2-a] pyrimidines.
Then the attack of copper acetylide to in situ generated imine
(A), resulting in the formation of CuO NPs complex intermediate
(B). CuO NPs activates the triple bond which favors the
intramolecular 6-endo-dig cyclization leading to the formation of
desired product (4).
(a)
Figure 4: X-ray Crystallography Structure of Compound 4b (CCDC
1828497)
Next, we studied the photophysical properties of these
compounds. The spectroscopic data of some of the derivatives
are presented in figure 5. In Set A where R3 group is varied and
set B where R2 group is varied, the electronic spectra of
imidazo[1,2-a]pyrimidines exhibit two intense bands within 256
– 382 nm regions whereas in the fluorescence spectra one band
was observed. In case of absorption spectra, there is
bathochromic shift due to the electron-donating group like
methyl group (4i), hypsochromic shift due to electron-
withdrawing group like nitro, pyridine etc (4c, 4l and 4q)
whereas in case of aliphatic substitution Absmax further decreases
(4o).
(b)
Figure 6: UV-vis spectra of 4s (a) upon addition of different metal ions Na+1
Cu+2, Fe+2, Fe+3, Hg+2, Ni+2, Pb+2, Sn+2and Zn+2 (b) upon varying amount of
zinc ions from 0 to 1 equivalent.
,
The photophysical properties (UV-vis and fluorescence) of
compound 4s (4.9 ×10-4 M, MeOH: H2O (4:1, v/v) was explored
by the addition of different metal ions such as sodium, iron, lead,
mercury, copper, nickel, tin and zinc in water (10-1 M buffered
with HEPES solution at pH = 7.2).
In set A, a hypsochromic shift is observed (4b, 4i, 4o and 4l) in
comparison to compounds 4c and 4q due to the electron
withdrawing groups attached. In set B where R2 group is varied,
there is bathochromic shift of 4g, 4d, 4b and 4f in comparison to

4
The UV-vis absorption spectra of compound 4s showed two
peaks at 297.32 and 352.33 nm. After addition of one equivalent
of Na+1, Cu+2, Fe+2, Fe+3, Hg+2, Ni+2, Pb+2, Sn+2 slight change in
absorbance value was observed in all cases but addition of Zn+2
exhibited significant change in absorbance value of compound 4s
(Fig 6(a)). The absorption spectrum of 4s was further analyzed
by changing the concentration of zinc ions. The absorbance value
at 352.33 nm increases as the concentration of zinc ion increases
(Fig 6(b)).
Determination of binding constant and detection limit
The stoichiometry of complex formed was determined by the
Job’s plot which clearly indicated that there is 1:1 binding mode
between zinc ion and compound 4s. The binding constant
between 4s and Zn+2 can be determined from Benesi Hildebrand
plot32(Fig 9).
Fluorescence spectra
Figure 8: Job’s plot for determination of stoichiometry of complex formed
between 4s and zinc ion
(a)
Figure 9: Benesi Hildebrand plot for the determination of binding constant
between 4s and Zn+2
.
(b)
Figure 7: Fluorescence spectrum of 4s (4.9 ×10-4 M, MeOH: H2O (4:1, v/v)
containing HEPES, pH=7.2) a) upon addition of different metal ions Na+1
,
Cu+2, Fe+2, Fe+3, Hg+2, Ni+2, Pb+2, Sn+2and Zn+2 (b) upon varying amount of
zinc ions from zero to one equivalent.
The fluorescence spectrum of 4s was investigated in the presence
of metal ions like Na+1, Cu+2, Fe+2, Fe+3, Hg+2, Ni+2, Pb+2, Sn+2
and Zn+2. The investigation revealed that there is prominent
change in fluorescence intensity of 4s compound in the presence
of zinc ion whereas no significant change in fluorescence
intensity was observed in case of other metal ions. From this
observation, it can be concluded that there is strong binding
between 4s and zinc metal ion in comparison to other
compounds. Generally, transition and post transition cations
having open shell d-orbitals quenches the fluorescence due to the
rapid electron transfer between cation and ligands which led to
non-radiative decay of the excited states whereas these electron-
transfer processes are not possible in case of transitions cations
having close shell d-orbitals (like zinc).31 The fluorescence
spectrum of 4s was investigated by varying the concentration of
zinc ions. The fluorescence intensity of 4s was increased initially
with increasing the concentration of zinc ion and after a point it
remained constant.
Figure 10: Plot between (I
determination of the detection limit for 4s.
- ] for
Imin)/(Imax -Imin) and log [Zn+2
The binding constant of the 1:1 complex of compound 4s and
zinc ion can be obtained from the ratio of intercept/slope which
comes out to be log Ka = 3.698 (Ka = 0.05 × 105) which is in
good agreement with the value of binding constant of some
reported zinc-binding chemosensors (0.3-7.09).33-35 The detection

5
limit can be obtained from the reported methods36-37 by plotting a
normalized graph between (I - Imin)/ (Imax -Imin) and log [Zn+2]
at 490 nm (Fig. 10). The detection limit of compound 4s was
found to be 4.79µM which is lower than the WHO guidelines for
the tolerance limit of zinc in drinking water (76 µM).38
13 Kumar, A.; Kumara, M.; Mauryaa, S.; Khannab, R. S. J. Org.
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In conclusion, we have developed a green method for one-pot
synthesis of imidazo[1,2-a]pyrimidines from easily available
starting materials via 6-endo-dig cyclization using recyclable
CuO nanoparticles without using bases and additives under
solvent free condition. From sustainability point of view, green
chemistry metrices like atom economy (94.4%) and E factor
(0.11) are in the good agreement with the ideal values.
Photophysical studies showed that these compounds possess
good fluorescence quantum yield and one of the compound
showed good affinity for zinc ion with stoichiometry ratio of 1:1,
good binding constant and lower detection limit for detecting
micromolar concentration of zinc ion.
20 Lee, H. G.; Lee, J. H.; Jang, S. P.; Hwang, I. H.; Kim, S. J.; Kim, Y.;
Kim, C.; Harrison, R. G. Inorg. Chim. Acta. 2013, 394, 542-551.
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22 Kang, J.; Kang, H. K.; Kim, H.; Lee, J.; Song, E. J.; Jeong, K.D.;
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23 Rajesh, U. C.; Pavan, S. V.; Rawat, D. S. RSC Adv. 2016, 6, 2935-
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24 Rajesh, U. C.; Manohar, S.; Rawat, D. S. Adv. Synth. Catal. 2013,
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DSR thanks Department of Science and Technology, New Delhi,
India (DST/INT/JSPS/P-214/2016) for financial support. M.R.
acknowledges CSIR for the award of Shyama Prasad Mukherjee
Fellowship (File No: SPM-09/045(0249)/2016-EMR-I). We
thank USIC-CIF, University of Delhi, for assistance in acquiring
analytical data.
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Highlights:

6
•
•
Solvent free synthesis of fused imidazo[1,2-
a]pyrimidines via A3 coupling.
Use of copper oxide nanoparticles as
recyclable catalyst.
a
•
•
Short reaction time and good yield.
Imidazo[1,2-a]pyrimidines act as a sensor for
zinc ion.