A one-pot multi-component synthesis of N-cyclohexyl-3-arylquinoxaline-2- amines using ZnO nanoparticles as a heterogeneous reusable catalyst

Article abstract of DOI:10.2174/157017813805077262

A general synthetic route to synthesis of N-cyclohexyl-3-aryl-quinoxaline- 2-amines has been developed using ZnO nanoparticles under mild conditions. The multi-component reactions of aldehydes, o-phenylenediamine and cyclohexyl isocyanide were carried out to afford some N-cyclohexyl-3-aryl-quinoxaline-2- amines derivatives. The present approach offers several advantages such as high yields, environmentally benign, easy purification, recovery and reusability of the catalyst.

Full text of DOI:10.2174/157017813805077262

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Letters in Organic Chemistry, 2013, 10, 47-52
47
A One-Pot Multi-Component Synthesis of N-cyclohexyl-3-aryl-
quinoxaline-2-amines Using ZnO Nanoparticles as a Heterogeneous
Reusable Catalyst
Abolfazl Ziarati, Javad Safaei-Ghomi* and Sahar Rohani
Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, 51167 Kashan, IR Iran
Received August 01, 2012: Revised September 12, 2012: Accepted October 15, 2012
Abstract: A general synthetic route to synthesis of N-cyclohexyl-3-aryl-quinoxaline-2-amines has been developed using
ZnO nanoparticles under mild conditions. The multi-component reactions of aldehydes, o-phenylenediamine and cyclo-
hexyl isocyanide were carried out to afford some N-cyclohexyl-3-aryl-quinoxaline-2-amines derivatives. The present ap-
proach offers several advantages such as high yields, environmentally benign, easy purification, recovery and reusability
of the catalyst.
Keywords: N-cyclohexyl-3-aryl-quinoxaline-2-amines, ZnO nanoparticles, heterogeneous catalyst, multi-component.
INTRODUCTION
Lately, it was reported that ZnO nanoparticles as an effi-
cient heterogeneous catalyst, offer huge opportunities for a
wide range of applications in chemical synthesis and chemi-
cal manufacturing procedures [16, 17].
Multicomponent reactions (MCRs) are highly important
transformations due to their capacity to combine three or
more substrates into a single target in one operation [1-4]. A
substantial increase in molecular complexity has typically
been attained by MCRs to offer a chance for diversity ori-
ented synthesis. MCRs have proven to be useful in drug dis-
covery, as well as in the total synthesis of natural compounds
[5-8].
In continuation to progress of the synthetic approach for
the production of various medicinally compounds using re-
usable nano catalysts [18-20], utilization of ZnO nanoparti-
cles catalyzed multicomponent synthesis of N-cyclohexyl-3-
aryl-quinoxaline-2-amines in mild conditions has been per-
formed by present study for the first time (Scheme 1).
Isocyanide-based multicomponent reactions (IMCRs) are
particularly interesting as they are more versatile than other
MCRs [9]. The high potential of isocyanides has often been
observed in developing of the MCRs on the diversity of
available bond forming procedures, functional group toler-
ance, and the high levels of stereo-, chemo-, and regioselec-
tivity. Therefore MCRs including isocyanides have appeared
as suitable tools for the synthesis of varied chemical struc-
tures [10, 11].
RESULTS AND DISCUSSION
Herein we wish to report a convenient and environmen-
tally benign method for the synthesis of N-cyclohexyl-3-
aryl-quinoxaline-2-amines by condensation of aldehydes
with o-phenylenediamine and cyclohexyl isocyanide in etha-
nol at reflux in the presence of ZnO NPs as catalyst. ZnO
NPs are a cheap heterogeneous reagent, which can easily be
prepared. Safety and ease in handling, rate enhancement,
easy work up and high yields procedures for reuse are the
properties which encouraged us to use this interesting rea-
gent as a catalyst. To the best of our knowledge there are no
reports on the applicability of ZnO NPs for the synthesis of
N-cyclohexyl-3-aryl-quinoxaline-2-amines in the literature.
On the other hand, the quinoxaline groups are important
substructures which have been found in many medicinal
compounds. Various considered structures in pharmaceutical
and biological properties have motivated the proposed re-
search to develop the convenient and efficient synthetic
strategies for the synthesis of substituted N-cyclohexyl-3-
aryl-quinoxaline-2-amines scaffolds [12].
In the initial experiments the catalytic behaviors of
same types of catalyst were compared in the reaction of
4-chlorobenzaldehyde, o-phenylenediamine and cyclohexyl
isocyanide at reflux (Table 1). In absence of catalyst, the
reaction did not progress at all but in presence of ZnO the
reaction processed in high yield.
The chemical synthesis productivity can be enhanced by
nano sized catalysts because of their low size and high sur-
face to volume ratios. Moreover, this productivity was im-
proved by using heterogonous catalysts due to their simplic-
ity of separation [13-15].
Expectedly, the catalytic system should be influenced by
various reaction factors, such as solvent system and amount
of the employed catalyst. To establish the optimal reaction
conditions, a set of experiments varying the amount of ZnO
NPs, and effect of solvent were taken into account.
*Address correspondence to this author at the Department of Organic
Chemistry, Faculty of Chemistry, University of Kashan, 51167 Kashan, IR
Iran; Tel: (+98) 361 5912385, Fax: (+98) 361 5552935;
E-mail: safaei@kashanu.ac.ir
1875-6255/13 $58.00+.00
© 2013 Bentham Science Publishers

48 Letters in Organic Chemistry, 2013, Vol. 10, No. 1
Ziarati et al.
R
R
NH2
N
N
ZnO NPs
+
+
EtOH, reflux
NH2
NH
NC
CHO
1
2a-i
3
4a-i
Scheme 1. Synthesis of N-cyclohexyl-3-aryl-quinoxaline-2-amines using ZnO nanoparticles under mild conditions.
Table 1. Optimization of the Model Reaction Using Various
Catalysts.
Time
(min)
Yielda
%
Entry
Catalyst (mol%)
1
2
3
4
5
6
7
8
none
200
110
100
100
130
70
0
ZnO (10)
32
46
31
23
89
96
96
ZnO (15)
MgO (15)
CuO (15)
ZnO NPs (3)
ZnO NPs (4)
ZnO NPs (5)
55
Fig. (1). SEM image of ZnO nanoparticles.
55
aYields refer to the pure isolated products.
to pure Hexagonal phase of ZnO with P63mc group (JCDPS
No. 36-1451). The crystallite size diameter (D) of the ZnO
nanoparticles has been calculated by Debye–Scherrer equa-
tion (D = Kꢀ/ꢁcosꢂ), where ꢁ FWHM (full-width at half-
maximum or half-width) is in radian and ꢂ is the position of
the maximum diffraction peak, K is the so-called shape fac-
tor, which usually has a value of about 0.9, and k is the X-
ray wavelength (1.5406 Å for Cu Kꢃ). Crystallite size of zinc
oxide has been found to be 24 nm.
We have screened the effect of different solvents with
varying polarity and protic nature. It was observed that etha-
nol proved to be the best choice for this reaction over any
organic solvents such as acetonitrile and toluene. It was also
observed that the good results were not obtained in solvent
free conditions. The results have been presented in (Table 2).
Table 2. Optimization of the Model Reaction Using Various
Solvents.
Entry
Solvent
Time
Yielda, %
1
2
3
4
5
CH3CN
Toluene
H2O
120
100
110
55
51
39
68
96
82
11
EtOH
EtOH/H2O
Solvent-free
80
6
210
Fig. (2). The XRD pattern of zinc oxide nanoparticles.
a Isolated yield.
The chemical purity of the samples as well as their
stoichiometry was tested by EDAX studies. The EDAX
spectra given in Fig. (4) have shown the presence of zinc and
oxygen as the only elementary components.
In order to investigate the particle size and morphology
of zinc oxide nanoparticles, SEM image of ZnO NPs was
presented in Fig. (1). These results show that ZnO NPs were
obtained with an average diameter of 10-30 nm.
In addition the specific surface area was measured by ni-
trogen physisorption (the BET method), the specific surface
area was found to be approximately 86 m2/g.
The XRD pattern of ZnO nanoparticles was shown in
Fig. (3). All reflection peaks in Fig. (3) can easily be indexed

Synthesis of N-cyclohexyl-3-aryl-quinoxaline-2-amines Catalyzed By ZnO Nanoparticles
Letters in Organic Chemistry, 2013, Vol. 10, No. 1
49
The study was then extended to synthesis of various N-
cyclohexyl-3-aryl-quinoxaline-2-amines using ZnO NPs in
high yields. Reactions were carried out in ethanol at reflux
conditions in presence of ZnO NPs 4 % mol. The results are
listed in Table 3.
A proposed mechanism for this multi-component reac-
tion has been outlined in Scheme 2.
In first step of this reaction, the o-phenylenediamine 1
with aromatic aldehyde 2 is followed by attack of cyclohexyl
isocyanide 3 on the resulting intermediate in presence of
Fig. (3). EDX spectrum of ZnO nanoparticles.
Table 3. Synthesis of N-cyclohexyl-3-aryl-quinoxaline-2-amines catalyzed by ZnO NPs.
R
N
N
NH
4a-i
Mp(°C)Ref
Found
Producta
Aldehyde
Time(min)
Yield(%)b
Reported
CHO
4a
4b
60
55
93
96
183-184
188-189
185-18621
CHO
190-19121
174-17521
Cl
CHO
4c
65
90
173-174
HO
CHO
CHO
4d
4e
65
70
93
94
198-199
175-176
199-20021
177-17821
Me
MeO
CHO
4f
60
55
92
95
206-207
185-186
207-20821
O2N
CHO
CHO
4g
-
F
4h
70
87
192-193
-
Me
CHO
4i
65
89
190-191
192-19321
NO2
aAll products were characterized from their melting points and spectroscopic (1H NMR and 13C NMR) data and then compared with authentic samples.
bIsolated yield

50 Letters in Organic Chemistry, 2013, Vol. 10, No. 1
Ziarati et al.
H
N
R
NH2
C
H
ZnO NPs
R
+
NH2
NH2
CHO
2
1
C
N
R
H
N
R
H
N
N
H
N
N
NH2
3
H
N
R
R
N
N
dehydrogenation
N
NH
NH
4
Scheme 2. Proposed mechanism for the formation of N-cyclohexyl-3-aryl-quinoxaline-2-amines.
ZnO nanoparticles. Following cyclization and dehydrogena-
tion, the product 4 is obtained [12].
CONCLUSION
Summarizingly, we have reported that ZnO nanoparticles
are a highly efficient catalyst for the synthesis of N-
cyclohexyl-3-aryl-quinoxaline-2-amines through a multi-
component condensation of aldehydes, o-phenylenediamine
and cyclohexyl isocyanide in one pot. This method is appli-
cable to a wide range of substrates, including aromatic alde-
hydes, and provides the corresponding N-cyclohexyl-3-aryl-
quinoxaline-2-amines in good to excellent yields. The pre-
sent methodology offers advantages such as reduced reaction
times, high yields, operational simplicity, reduced toxicity of
ZnO NPs, along with catalyst recoverability and recyclabil-
ity.
The same reaction was carried out five times conse-
quently to check the reusability of catalyst and it was found
that, all the five times, products showed tolerable decrease in
activity (Fig. 4).
EXPERIMENTAL SECTION
All the chemical reagents used in our experiments were
of analytical grade and were used without further
purification. A multiwave ultrasonic generator (Sonicator
3000; Bandeline, MS 73, Germany), equipped with a con-
verter/transducer and titanium oscillator (horn), 12.5mm in
diameter, operating at 20 kHz with a maximum power output
of 60W, was used for the ultrasonic irradiation. The ultra-
Fig. (4). Recoverability of ZnO nanoparticles.
1
sonic generator automatically adjusted the power level. H
The characterization of the nano ZnO before and after re-
using five times showed the same particle size by TEM (Fig.
5). Interestingly, the shape and size of the nanoparticles did
not highlight any change before and after the reaction. We
believe that, this is also the possible reason for the extreme
stability of the ZnO nanoparticles presented herein.
NMR and 13C NMR spectra were recorded on Bruker
Avance-400 MHz spectrometers in the presence of
tetramethylsilane as internal standard. The IR spectra were
recorded on FT-IR Magna 550 apparatus using with KBr
plates. Melting points were determined on Electro thermal

Synthesis of N-cyclohexyl-3-aryl-quinoxaline-2-amines Catalyzed By ZnO Nanoparticles
Letters in Organic Chemistry, 2013, Vol. 10, No. 1
51
Fig. (5). TEM images of ZnO nanoparticles before use (a) and after five times reuse (b).
9200, and were not corrected. The elemental analyses of (C,
H, N) were performed on a Carlo ERBA Model EA 1108
analyzer. Microscopic morphology of products was visual-
ized by SEM (LEO 1455VP). Powder X-ray diffraction
(XRD) was carried out on a Philips diffractometer of X’pert
Company with mono chromatized Cu Kꢀ radiation (ꢀ =
1.5406 Å). The N2 adsorption/desorption analysis (BET) was
performed at -196 °C using an automated gas adsorption ana-
lyzer (Tristar 3000, Micromeritics). The mass spectra were
recorded on a Joel D-30 instrument at an ionization potential
of 70 eV. The compositional analysis was done by energy
dispersive analysis of X-ray (EDAX, Kevex, Delta Class I).
Transmission electron microscopy (TEM) images were ob-
tained on a Philips EM208 transmission electron microscope
with an accelerating voltage of 100 kV.
26.15, 33.71, 52.18, 127.32, 128.82, 128.55, 129.73, 130.15,
131.19, 132.67, 133.39, 134.51, 138.57, 141.22, 142.67,
148.87, 150.99; IR (KBr) v: 3155, 1629, 1620 cm-1. Anal.
Calcd. for C21H23N3: C, 74.73; H, 6.23; N, 13.12%; Found:
C, 74.63; H, 6.17; N, 13.21.
N-Cyclohexyl-3-(3-methylphenyl)-quinoxaline-2-
°
1
amine (4h): Mp C: 192-194. H NMR (400 MHz, DMSO-
d6): ꢁ: 1.18–2.37 (m, 10H), 2.66 (s, 3H), 3.38 (m, 1H), 4.41
(s, 1H, NH), 7.25–8.31 (m, 8H, Ar). 13C NMR (100 MHz,
DMSO-d6); ꢁ: 24.13, 25.57, 30.17, 39.84, 52.51, 126.67,
128.51, 128.47, 129.97, 130.74, 131.27, 134.17, 138.56,
141.97, 141.09, 142.97, 150.93. IR (KBr) v: 3160, 1641,
1623 cm-1. Anal. Calcd. for C21H23N3: C, 79.51; H, 7.25; N,
13.24%; Found: C, 79.47; H, 7.12; N, 13.44.
CATALYST RECOVERY
General Procedure for the Preparation of Zinc Oxide
The recovered catalyst from the experiment was washed
by acetone (3ꢂ5 mL). Then, it was dried and used in the syn-
thesis of N-cyclohexyl-3-aryl-quinoxaline-2-amines.
The catalyst was prepared by ultrasonic irradiation ap-
proach. Anhydrous ZnCl2 was used as the Zn source. Firstly
the substrate was dipped slowly into Deionized water and
then NaOH was added to the mixture to maintain a pH of 12.
Afterward the suspension was ultrasonically irradiated in
30min with a high density ultrasonic probe immersed di-
rectly in to the solution. The precipitate was dried at 120 °C
for 24 h and finally the cake was calcined at 600 °C for 12 h
to obtain a fine white powder [21].
CONFLICT OF INTEREST
The author(s) confirm that this article content has no con-
flicts of interest.
ACKNOWLEDGEMENTS
General Procedure for the Preparation of N-cyclohexyl-
3-aryl-quinoxaline-2-amines Derivatives (4a-4i)
The authors are grateful to University of Kashan for sup-
porting this work by Grant NO: 159196/IX.
A solution of o-phenylenediamine (2 mmol), aldehyde (2
mmol), cyclohexyl isocyanide (2 mmol) and ZnO NPs (4
mol %), in ethanol (3 mL) was stirred under reflux for ap-
propriate times. During the procedure the reaction was moni-
tored by TLC. After completion, the reaction mixture was
filtered until heterogeneous catalyst was recovered. The fil-
trate solution was evaporated and washed with cold chloro-
form to obtain pure N-cyclohexyl-3-aryl-quinoxaline-2-
amines.
REFERENCES
[1]
Blackwell, H.E. Hitting the SPOT: small-molecule macroarrays
advance combinatorial synthesis. Curr. Opin. Chem. Biol., 2006,
10, 203-212.
[2]
[3]
Toure, B.B.; Hall, D.G. Natural product synthesis using multicom-
ponent reaction strategies. Chem. Rev., 2009, 109, 4439-4486.
Domling, A. Recent developments in isocyanide based multicom-
ponent reactions in applied chemistry. Chem. Rev., 2006, 106, 17-
89.
[4]
[5]
Brauer, S.; Almstetter, M.; Antuch, W.; Behnke, D.; Taube, R.;
Furer, P.; Hess, S. Evolutionary chemistry approach toward finding
novel inhibitors of the type 2 diabetes target glucose-6-phosphate
translocase. J. Comb. Chem., 2005, 7, 218-226.
Ugi, I.; Werner, B.; Domling, A. The chemistry of isocyanides,
their multicomponent reactions and their libraries. Molecules, 2003,
8, 53-66.
Spectral Data of New Compounds are Given Below:
N-Cyclohexyl-3-(4-fluorophenyl)-quinoxaline-2-amine
(4g): Mp C: 185-186. H NMR (400 MHz, DMSO-d6): ꢁ:
1.15–2.18 (m, 10H), 3.51 (m, 1H), 4.47 (s, 1H, NH), 7.40–
8.42 (m, 8H, Ar). 13C NMR (100 MHz, DMSO-d6); ꢁ: 23.34,
°
1

52 Letters in Organic Chemistry, 2013, Vol. 10, No. 1
Ziarati et al.
[6]
[7]
[8]
Roh, E.J.; Keller, J.M.; Olah, Z.; Iadarola, M.J.; Jacobson, K.A.
Structure–activity relationships of 1,4-dihydropyridines that act as
enhancers of the vanilloid receptor 1 (TRPV1). Bioorg. Med.
Chem., 2008, 16, 9349-9358.
Shobha,D.; Chari, M.A.; Mukkanti, K.; Kim, S.Y. Synthesis and
anti-neuroinflammatory activity studies of substituted 3,4-
dihydroquinoxalin-2-amine derivatives. Tetrahedron Lett., 2012,
53, 2675-2679.
Kumar, A.; Maurya, R.A. Synthesis of polyhydroquinoline deriva-
tives through unsymmetric Hantzsch reaction using organo-
catalysts. Tetrahedron, 2007, 63, 1946-1952.
Domling, A.; Ugi, I. Multicomponent reactions with isocyanides.
Angew. Chem., Int. Ed., 2000, 39, 3168-3210.
Shaabani, A.; Maleki, A.; Rezayan, A.H.; Sarvary, A. Recent pro-
gress of isocyanide-based multicomponent reactions in Iran. Mol.
Divers., 2011, 15, 41-68.
Sadjadi, S.; Heravi, M.M. Recent application of isocyanides in
synthesis of heterocycles. Tetrahedron, 2011, 67, 2707-2752.
Heravi, M.M.; Baghernejad, B.; Oskooie, H.A. A novel three-
component reaction for the synthesis of N-cyclohexyl-3-aryl-
quinoxaline-2-amines. Tetrahedron Lett., 2009, 50, 767-769.
Koukabi, N.; Kolvari, E.; Khazaei, A.; Zolfigol, M.A.; Shirmardi-
Shaghasemi, B.; Khavasi, H.R. Hantzsch reaction on free nano-
Fe2O3 catalyst: excellent reactivity combined with facile catalyst
recovery and recyclability Chem. Commun., 2011, 47, 9230-9232.
Shylesh, S.; Schunemann, V.; Thiel. W.R. Magnetically separable
nanocatalysts: bridges between homogeneous and heterogeneous
catalysis. Angew. Chem. Int. Ed., 2010, 49, 3428-3459.
[15]
[16]
Astruc, D.; Lu, F.; Aranzaes. J.R. Nanoparticles as recyclable cata-
lysts: the frontier between homogeneous and heterogeneous cataly-
sis. Angew. Chem. Int. Ed., 2005, 44, 7852-7872.
Ghosh, P.P.; Das, A.R. Nano crystalline ZnO: a competent and
reusable catalyst for one pot synthesis of novel benzylamino
coumarin derivatives in aqueous media. Tetrahedron Lett., 2012,
53, 3140-3143.
Indulkar, U.U.; Kale, S.R.; Gawande, M.B.; Jayaram R.V.
Ecofriendly and facile nano ZnO catalyzed solvent-free enamina-
tion of 1,3-dicarbonyls. Tetrahedron Lett., 2012, 53, 3857-3860.
Safaei-Ghomi J.; Ziarati, A.; Teymuri, R. CuI Nanoparticles as
new, efficient and reusable catalyst for the one-pot synthesis of 1,4-
dihydropyridines. Bull. Korean Chem. Soc., 2012, 33, 2679-2682.
Safaei-Ghomi J.; Ziarati, A.; Zahedi, S. Ferric chloride supported
on nano silica as a reusable heterogeneous catalyst for the one-pot
synthesis of 1, 4-dihydropyridines under mild conditions. J. Chem.
Sci., 2012, 124, 933-939.
Safaei-Ghomi J.; Ziarati, A. An efficient FeCl3/SiO2 NPs as a reus-
able heterogeneous catalyzed five-component reactions of
tetrahydropyridines under mild conditions. J. Iran. Chem. Sci., DOI
10.1007/s13738-012-0134-z.
[17]
[18]
[19]
[9]
[10]
[11]
[12]
[20]
[21]
[13]
[14]
Rao, G.B.D.; Kaushik, M. P.; Halve, A.K. An efficient synthesis of
naphtha[1,2-e]oxazinone and 14-substituted-14H-dibenzo[a,j]xan-
thene derivatives promoted by zinc oxide nanoparticle under ther-
mal and solvent-free conditions. Tetrahedron Lett., 2012, 53, 2741-
2744.