Nickel nanoparticles assisted regioselective synthesis of pyrazoloquinolinone and triazoloquinazolinone derivatives

Article abstract of DOI:10.1039/c4nj02372b

Biologically important pyrazoloquinolinone and triazoloquinazolinone derivatives were synthesized by the condensation reaction of 3-amino-1H-1,2,4-triazole/3-amino-5-methyl-1H-pyrazole, dimedone and aryl aldehydes using catalytic amount of magnetically re

Full text of DOI:10.1039/c4nj02372b

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Nickel nanoparticles assisted regioselective
synthesis of pyrazoloquinolinone and
Cite this:DOI: 10.1039/c4nj02372b
triazoloquinazolinone derivatives†
Nongthombam Geetmani Singh,a Rammamorthy Nagarajaprakash,b
Jims World Star Rani,a Chingrishon Kathing,a Ridaphun Nongruma and
Rishanlang Nongkhlaw*a
Biologically important pyrazoloquinolinone and triazoloquinazolinone derivatives were synthesized by
the condensation reaction of 3-amino-1H-1,2,4-triazole/3-amino-5-methyl-1H-pyrazole, dimedone and aryl
aldehydes using catalytic amount of magnetically retrievable nickel nanoparticles under reflux condition. This
protocol eliminates the usage of toxic reagents, complex work-up conditions, etc., with the added benefit of
reusability of the catalyst without compromising the yield or purity of the product.
Received (in Montpellier, France)
22nd December 2014,
Accepted 24th February 2015
DOI: 10.1039/c4nj02372b
www.rsc.org/njc
the unnecessary wastage of chemicals, resources and time. Synthesis
of N-heterocycles by MCR methods has been the prime target of
Introduction
Metal nanocatalysis has emerged as a novel strategy for the synthetic chemists, since nitrogen containing moieties form an
syntheses of diverse organic molecules, and its application in integral part of many biologically active molecules and natural
various organic transformations1 as a heterogeneous catalyst is products. Triazoloquinazolinone in particular, has established itself
remarkable. The synthetic utility of nanocatalysts derived from as an important therapeutic agent11 and has found multiple applica-
Ag, Au, Ni, Fe, Pd, Cu, Fe2O3, NiO, etc. has become an intriguing tions as an anti-HIV,12 analgesic,13 antihypertensive,14 anti-
topic of discussion within the research fraternity.
histaminic,15 antitumour16 and anticancer17 agent, etc. Many
Synthetic studies on heterocycles have been evolving since time research groups have reported its synthesis using different conven-
immemorial and in this present decade of nanotechnology, tional and non-conventional18 methods. They used either silica gel,19
researchers are trying to harvest the potential possessed by nano- molecular iodine,20 H6P2W18O62Á18H2O21 or hydrotalcites,22 etc.
particles to various extents. Amongst nanocatalysts, nickel nano-
Another class of nitrogen heterocycle, i.e. pyrazolo[3,4-b]quino-
particles have emerged as potent eco-friendly catalysts owing to lines, has emerged as an important pharmaceutical entity due to
their unique recyclability properties which allow them to be their parasiticidal,23 bactericidal,24 antiviral25 and antimalarial26
retrieved with ease by using a simple magnet after completion of properties. They have also found application as vasodilators27 and
a reaction and then reused multiple times without compromising has been extensively studied for their enzyme inhibiting activity.28
the yield of the desired products. This has been exploited for the
All the reported syntheses of triazoloquinazolinone and
chemo-selective oxidative coupling of thiols,2 the hydrothermal pyrazoloquinolinone derivatives encountered certain drawbacks,
Heck reaction,3 a-alkylation of methyl ketones,4 reduction of alde- such as the use of expensive catalysts, long reaction time, toxic
hydes and ketones,5a–c the transfer hydrogenation reaction,6 simple reaction conditions, purification complications, low yield, etc.
olefin hydrogenation,7 Wittig-type olefination for the synthesis of According to our survey no literature has been reported on the
stilbenes from alcohol8 and as supports for hydrogen adsorption.9 synthesis of triazoloquinazolinones and pyrazoloquinolinones
Nanocatalysis of multicomponent reactions (MCRs) has also using nanoparticles. Moreover, the necessity to develop a catalyst
become considerably important these days due to its strategic which can be reused after recycling by simple methods led us to the
advantages over conventional synthetic methods.10 MCR minimizes development of a novel protocol involving the use of magnetically
retrievable nickel nanoparticles (Fig. 1).
a Centre for Advanced Studies in Chemistry, North Eastern Hill University,
Shillong-793022, India. E-mail: rlnongkhlaw@nehu.ac.in; Fax: +91-364-2550076;
Tel: +91-364-2722628
b Department of Chemistry, Pondicherry University, Puducherry 605014, India
Results and discussion
† Electronic supplementary information (ESI) available. CCDC 1024256 and
Our present work deals with the synthesis of triazoloquinazo-
linones/pyrazoloquinolinones through a simple method in
1024257. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c4nj02372b
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Fig. 1 Some biologically important triazoloquinazolinones and pyrazolo-
Fig. 3 SEM image of Ni NPs: (A) before use (B) after 6 runs.
quinolinones.
Similarly, when other organic solvents such as ethanol, methanol,
dichloromethane, etc. were employed, a negligible yield or no
yield was obtained. The nickel nanoparticles were characterized
by scanning electron microscopy (SEM), transmission electron
microscopy (TEM), energy-dispersive X-ray (EDAX) and powder
XRD (Fig. 3).
As we can see from the images, the size of the nanoparticles
varied from 2–12 nm before being implemented as a catalyst.
A histogram diagram of the synthesized nickel nanoparticles
is shown in Fig. 4. However, after the sixth cycle, the nano-
particles seem to have aggregated to give particles of size 50 nm
and above.
Further, in order to dispense any doubts regarding the
oxidation of the nickel nanoparticles by air to nickel oxides,
we performed EDAX and powder XRD analysis on the synthe-
sized nanoparticles. The EDAX spectrum (Fig. 5) show no traces
of oxygen moieties and the nanoparticles appear to be com-
prised of nickel only.
Fig. 2 TEM image of Ni NPs: (a) before use (b) after 6 runs.
which the reactants, 3-amino-1H-1,2,4-triazole/3-amino-5-methyl-
1H-pyrazole (1 mmol), aldehyde (1 mmol) and dimedone (1 mmol)
were refluxed in acetonitrile. Instead of using a base or an acid
catalyst, we decided on using nickel nanoparticles as catalyst and
study the multi-component reaction (Scheme 1).
Catalyst preparation and characterization
The nickel nanoparticles were prepared as reported29 by
chemical reduction of nickel chloride hexahydrate with hydra-
zine hydrate at room temperature without using any protective
agent or inert gas protection.
Ni2+ + N2H4 + ÀOH - Ni + N2 + 2H2O
The nickel nanoparticles were retrieved magnetically and
reused several times. The time taken for completion of reaction
was 10 minutes, and the product was recovered in pure form as
crystals on cooling. When the reaction was carried out under
solvent-free conditions, the desired product was not obtained.
Fig. 4 Histogram diagram of Ni NPs.
Scheme 1 Proposed scheme for the synthesis of various triazoloquinazo-
linone and pyrazoloquinolinone derivatives.
Fig. 5 EDAX of prepared nickel nanoparticle.
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Fig. 6 Powder XRD pattern of Ni(0) nanoparticles.
Fig. 8 Proposed mechanism for the synthesis of 6a.
Moreover, the strong magnetic attraction exhibited by our
nanoparticles confirmed that it is not antiferromagnetic and so
dispelled any uncertainty of it being NiO.
The powder XRD pattern of the nickel nanoparticles (Fig. 6)
displayed characteristic dihedral angles at 44.871, 51.791 and
76.811, corresponding to nickel(0) nanoparticles.
derivatives are similar but regioselectivity plays a role in the
formation of pyrazoloquinolinones and hence, cyclisation
occurs through carbon and not through nitrogen. All the
derivatives which were synthesized are shown in Table 1.
The formation of the desired product was confirmed from
1
The above characterized nanoparticles were then employed
for the synthesis of 5a–h and 6a–j. Due to the presence of three
non-equivalent nucleophilic centers i.e. N2, C4 and NH2, etc., in
the aminopyrazole building block unit, reactions of 3-amino-
pyrazoles with cyclic 1,3-diketones and aromatic aldehydes may
lead to different tricyclic products. Thus, such kind of reactions
can generate mixtures of pyrazoloquinolinones (Hantzsch-type
product) and pyrazoloquinazolinones (Biginelli-type product).
However, regioselective catalysis30 can be employed to enhance
the selectivity of a particular product. Normally, the, Hantzsch-
type is favoured over the Biginelli-type product due to the
higher electrophilic character of C4 as compared to N2. In
our case, we found that nickel nanoparticles were an ideal
catalyst for the regioselective synthesis of pyrazoloquinolinones
(Hantzsch-type product) from substituted aminopyrazole.
Proposed mechanisms for the synthesis of 5c and 6a are shown
in Fig. 7 and 8 respectively. Basically the mechanisms of
formation of triazoloquinazolinone and pyrazoloquinolinone
the melting point data, infra-red, mass spectra and H-NMR &
13C-NMR spectra. The IR spectrum of 5c showed absorption
peaks at 3436 cmÀ1 which corresponds to –NH stretching. The
carbonyl absorption peak appeared at 1649 cmÀ1 which was
much lower than expected but can be attributed to the deloca-
lization of CQO. Another absorption peak at 618 cmÀ1 was
observed, which corresponds to C–Cl stretching.
The 1H-NMR spectrum of 5c displayed two singlets at
0.705 ppm and 0.788 ppm which are due to the six methyl
protons on the third ring. A singlet at 10.94 ppm was also
observed, which can be correlated to the bridging –NH proton.
In the 13C spectrum of 5c we observed a peak at 192.98 ppm
which can be correlated to the presence of carbonyl carbon.
Another important peak was observed at 57.34 ppm which
corresponds to the methine carbon of the desired product i.e.
5c. The mass spectrum of 5c exhibited a molecular ion peak at
m/z 328 (M+) which further corroborated the formation of 5c.
The XRD analysis of a single crystal of 5c gave final confirma-
tion of the formation of the desired product.
The IR spectrum of 6a showed absorption peaks at
3237 cmÀ1 which corresponds to –NH stretching. The carbonyl
absorption peak appeared at 1590 cmÀ1, which was much lower
than expected, but can be attributed to the delocalization of
CQO. The 1H NMR spectrum of 6a displayed two singlets at
0.696 ppm and 0.757 ppm which are due to the six methyl
protons on the third ring. A singlet at 11.484 ppm was also
observed which can be correlated to the bridging –NH proton.
The 13C-NMR spectrum of 6a displayed a peak at 192.78 ppm
which clearly indicated the presence of a carbonyl carbon.
Another peak at 35.08 ppm validated the presence of the
methine carbon. The mass spectrum of 6a exhibited the mole-
cular ion peak at m/z 307 (M+) which suggested the formation
of 6a. Finally, from the XRD analysis of a single crystal of 6a,
we were able to confirm affirmatively that the desired product
was synthesized.
Fig. 7 Proposed mechanism for the synthesis of 5c.
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Table 1 Synthesis of compounds 5a–h and 6a–j
Compound
Aldehyde
Product
Time/min
10
Yield (%)
90
Appearance
Mp (found)/1C
5a
Light yellow crystal
249–251
5b
5c
5d
10
10
10
93
92
90
Pale yellow crystal
Pale yellow crystal
Colourless crystal
301–302
297–298
303–305
5e
5f
10
10
10
88
85
91
Colourless crystal
Pale yellow solid
Yellow crystal
230–232
290–292
282–285
5g
5h
6a
10
10
89
96
Pale yellow solid
Colourless crystal
303–304
230–232
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Table 1 (continued)
Compound
Aldehyde
Product
Time/min
10
Yield (%)
95
Appearance
Mp (found)/1C
6b
Yellowish solid
295–297
6c
6d
6e
10
10
10
98
94
93
Pale yellow crystal
Pale yellowish crystal
Yellow crystal
300–302
310–312
298–300
6f
10
95
Light pinkish solid
272–275
6g
6h
10
10
97
96
Colourless crystal
Colourless crystal
305–307
338–340
6i
6j
10
10
96
91
Colourless crystal
315–317
262–265
Yellow solid
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Fig. 9 Optimization of catalyst loading with respect to yield of 6c.
Fig. 11 ORTEP image of 5c (CCDC 1024257).
Fig. 10 Reusability plot of nickel nanoparticles.
Catalyst optimization
A series of tests were performed to standardize the optimum
quantity of nickel nanoparticle required for the chemical con-
densation concerned (Scheme 1), and 10 mole percent was
found to be the ideal amount. Another set of tests were
performed to optimize the time of reaction, and 10 minutes
was concluded to be the ideal time. The optimization plot for
catalyst loading and reaction time is shown in Fig. 9.
Fig. 12 ORTEP image of 6a (CCDC 1024256).
In order to study the reusability of the catalyst, several re-
runs were performed for the synthesis of 6c using recycled
nickel nanoparticles and it was found that the yield of the
desired product (i.e. 6c) was not significantly affected till the
sixth cycle (as shown in Fig. 10). A slight decrease can be
observed, however, which can be attributed to the aggregation
of the nanoparticles, as is evident from the TEM images (Fig. 2).
The process of recycling the nanoparticles was carried out in a
very simple and easy manner. It involves recovery of the
nanoparticles from the reaction mixture on completion of the
synthesis process using an ordinary magnet. They were then
thoroughly washed with acetone and Millipore water and
allowed to dry. After drying, they were reused again as a
catalyst.
PRO (Agilent, 2011), data reduction CrysAlis PRO and cell
refinement CrysAlis PRO. The structures were solved by direct
methods and refined by Olex2.refine. ORTEP images of 5c and
6a are shown in Fig. 11 and 12.
Conclusion
The utility of nickel nanoparticles in the catalysis of Hantzsch
and Biginelli type reactions have been successfully demonstrated
under short reaction time conditions. Through our approach we
have opened up a wider scope for nickel nanoparticles in
regioselective catalysis and the formation of C–N bonds.
Experimental
X-Ray crystallography
The single crystal X-ray diffraction (XRD) data were collected at All the chemicals involved in the synthesis were purchased
293 K with Mo Ka radiation (l = 0.71073 Å) using an Agilent from Alfa Aesar, Sigma Aldrich & Merck and were used without
Xcalibur (Eos, Gemini) diffractometer equipped with a graphite further purification. The purity of the products were confirmed
1
monochromator. The software used for data collection CrysAlis by infrared (IR), H-NMR, 13C-NMR and mass spectra besides
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X-ray diffraction (XRD) and melting point data. Melting points Notes and references
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1
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Acknowledgements
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