A novel catalytic one-pot three-component reaction of aldehydes, o-phenylenediamine derivatives and isocyanides for synthesis of 3,4-dihydroquinoxalin-2-amine derivatives in the presence of zirconium tetrachloride

Article abstract of DOI:10.1007/s13738-018-1301-7

Abstract: A simple and efficient one-pot procedure for the synthesis of biologically interesting 3,4-dihydroquinoxalin-2-amine derivatives through a three-component condensation reaction of o-phenylenediamines, carbonyl compounds and isocyanides in ethano

Full text of DOI:10.1007/s13738-018-1301-7

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-018-1301-7
ORIGINAL PAPER
A novel catalytic one‑pot three‑component reaction of aldehydes,
o‑phenylenediamine derivatives and isocyanides for synthesis
of 3,4‑dihydroquinoxalin‑2‑amine derivatives in the presence
of zirconium tetrachloride
Seyed Ali Jehbez1 · Hamid Reza Safaei1
Received: 22 July 2017 / Accepted: 11 January 2018
© Iranian Chemical Society 2018
Abstract
A simple and efcient one-pot procedure for the synthesis of biologically interesting 3,4-dihydroquinoxalin-2-amine deriva-
tives through a three-component condensation reaction of o-phenylenediamines, carbonyl compounds and isocyanides in
ethanol at room temperature is described. In this work, unlike the other methods, aldehydes reacted as well as ketones in
the presence of 10 mol% of zirconium tetrachloride as catalyst to aford good to excellent yields of products. This method-
ology is of great value because of its environmentally benign character, high yields, ease of handling and reliable for both
aldehydes and ketones. The newly synthesized compounds were systematically characterized by IR, 1H NMR, 13C NMR
and elemental analysis.
Graphical Abstract
A novel catalytic one-pot three-component reaction of aldehydes, o-phenylenediamine derivatives and isocyanides for syn-
thesis of 3,4-dihydroquinoxalin-2-amine derivatives in the presence of zirconium tetrachloride
.
Keywords Zirconium tetrachloride · Aromatic aldehydes · Multicomponent reaction · Isocyanides · 3,4-Dihydroquinoxalin-
2-amines
Introduction
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-018-1301-7) contains
Since 2008 that Shaabani frst reported isocyanide-based
synthesis of 3,4 dihydroquinoxalin derivatives through
a simple three-component condensation reaction of
o-phenylenediamine derivatives, carbonyl compounds
and isocyanides in the presence of catalytic amount of
p-toluenesulfonic acid (p-TSA) [1], the development of an
supplementary material, which is available to authorized users.
* Hamid Reza Safaei
safaei@iaushiraz.ac.ir; hrsafaei@yahoo.com
1
Department of Applied Chemistry, Faculty of Science,
Shiraz Branch, Islamic Azad University, P.O. Box 719935,
Shiraz, Iran
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
efective method for the synthesis of these compounds is
still an important challenge. A number of research groups
have modifed synthesis of amino-substituted 3,4 dihyd-
roquinoxalines and a variety of catalysts including ceric
ammonium nitrate (NH4)2Ce(NO3)6 [2], ethylenediamine-
tetraacetic acid (EDTA) [3], Amberlyst-15 [4], Cellulose-
SO3H [5], silica gel-supported sulfuric acid [6], AIKIT-5
[7] and guanidinium-based sulfonic acid [8] have been
employed for the improvement of this reaction. Among the
quinoxaline derivatives, dihydroquinoxalines are attractive
due to their interesting biological activity such as inhibit-
ing of cholesteryl ester transfer proteins [9, 10] and anti-
neuroinfammatory efect [6].
3,4-dihydroquinoxalin-2-amine derivatives in ethanol at
room temperature (Scheme 2).
Quinoxaline derivatives are one of the oldest well-known
heterocyclic compounds. They have attracted much attention
due to a wide variety of biological activities and extensive
application in electronic industries [20, 21]. Quinoxalines
are also a common occurrence in many pharmacological
active substances of natural or synthetic origin [22, 23].
They play an important role as the basic skeleton for a num-
ber of biologically active compounds such as antibacterial,
antidiabetic, antiviral, anticancer and anthelmintic [24–26].
Furthermore, quinoxaline derivatives show very interesting
photoelectron properties. They serve as dyes, semiconduc-
tors, electron luminescent materials and chemical switches
[27–30]. Among the diverse derivatives of quinoxalines,
dihydroquinoxalines have gained more attention due to its
pharmacological activities. Some reports showed that they
have antiviral efects against retroviruses such as HIV [31,
32]. Dihydroquinoxalines are also useful as growth promoter
in meat-producing animals and as coccidiostats in poultry
[33–35]. Some derivatives of these compounds displayed
inhibitory efects on serine proteases such as factor Xa,
thrombin and/or factor VIIa [36].
Despite remarkable efforts in exploring many cata-
lysts, unfortunately, none of them consider the synthesis of
3,4-dihydroquinoxalin derivatives from aldehyde derivatives
as a goal. Besides, most of these methods sufer from some
drawbacks such as lack of generality, application of toxic
reagents, efortful preparation of catalyst, tedious work-up,
generation of undesired products and low yields for the alde-
hyde derivatives, so that some attempts to use aldehydes
instead of ketones for gaining 3,4-dihydroquinoxalin deriva-
tives of aldehyde were not successful. It can be related to
oxidation capability of the title compound in the presence
of applied catalyst [11, 12] (Scheme 1).
Among the vast range of methodologies for synthesis of
quinoxalines, multicomponent reactions (MCRs) have been
receiving much attention due to the convergent nature, supe-
rior atom economy, straightforward experimental procedures
and wide range of industrial applications [37, 38]. In the past
decades, multicomponent reactions isocyanide-based MCRs
(IMCRs) are particularly valuable [39–41]. They were used
So, based on above facts and as a part of our research
program to develop facile and efcient methods in organic
synthesis [13–19], we report here the application of
zirconium(IV) chloride, as a mild and efcient Lewis acid
catalyst for the synthesis of aldehyde building blocks of
Scheme 1 Aldehyde’s hydrogen involves in reaction path way [11, 12] and quinoxaline derivative is formed
Scheme 2 Synthesis of
3,4-dihydroquinoxalin-2-amine
derivatives 4
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Journal of the Iranian Chemical Society
Table 1 The one-pot condensation reaction between o-phenylenedi-
amine (1 mmol), p-nitrobenzaldehyde (1 mmol) and cyclohexyl iso-
cyanide (1 mmol) at room temperature and under various reaction
conditions
in many cycloaddition reactions and proved themselves that
it is impossible to remove them from building blocks of
modern multicomponent chemistry because they are able to
react with both nucleophiles and electrophiles at the same
carbon [42, 43].
Entry Catalyst Mol (%) Solvent (3 mL) Time (h) Yield (%)a
It is well known that acid catalysts are essential for vari-
ous chemical reactions in industrial heterocycle chemistry.
The principles of “green chemistry” emphasize the usage
of environmentally benign catalysts and chemicals to have
minimal malignant efects on the environment. One of the
most suitable strategies to design environmentally benign
reaction systems is to perform the reaction in the presence
of Lewis acid catalysts with strong acidic sites.
1
2
3
4
5
6
7
8
CaClb2
CaCl2
CaCl2
CaCl2
CaCl2
CaCl2
CaCl2
NiCl2
5
EtOH
EtOH
EtOH
EtOH
MeCN
H2O
24
15
13
20
15
15
73
81
85
83
64
73
57
10
15
20
15
15
15
10
EtOH/H2O (2:1) 15
EtOH
0.5
Unde-
siredc
Moreover, in very recent years, because of the easy
availability in earth crust [44] and low toxicity [45] Zr (ΙV)
compounds, especially ZrCl4 have received considerable
attention in various organic reactions [46–48]. A strong
9
Bu4NOH
Bu4NOH 10
5
EtOH
EtOH
EtOH
EtOH
EtOH
MeCN
H2O
EtOH/H2O (2:1)
H2O
THF
n-hexane
EtOH
MeCN
EtOH/H2O (2:1)
EtOH
20
20
4
1.5
5
5
5
5
1
1
1
1
1
1
24
77
75
81
94
90
10
11
12
13
14
15
16
17
18
19
20
21
22
23
ZrCl4
ZrCl4
ZrCl4
ZrCl4
ZrCl4
ZrCl4
Zr(DS)4 2.5
Zr(DS)4 2.5
Zr(DS)4 2.5
Zr(DS)4 2.5
Zr(DS)4 2.5
Zr(DS)4 2.5
5
coordination of Zr(IV) (charge to size ratio = 22.22 e2 m−10
)
10
15
10
10
10
[49], with the negatively charged parts of organic com-
pounds in combination with the other advantages of ZrCl4
such as stability and commercially available, low cost and
low toxicity, makes it very useful and applicable reagent or
catalyst in Lewis acid-catalyzed chemical reactions.
Recently, we reported the non-toxic and inexpensive zir-
conium tetrakis (dodecyl sulfate) [Zr (DS)4] as a Lewis acid
surfactant combined for synthesis of quinazoline derivatives
[50]. Herein we report a direct ZrCl4-catalyzed multicom-
ponent isocyanide-based reaction for the synthesis of title
compounds.
71
23d
32
24
Trace
Trace
21
Trace
21
–
–
< 15
aIsolated yield
bOn the bases of our previous work [56]
Results and discussion
cThe color of the reaction mixture was turn to dark green, and it can
be due to complex formation between o-phenylenediamine and Ni
Initially to optimize the reaction conditions, the one-pot
condensation reaction of o-phenylenediamine (1 mmol),
p-nitrobenzaldehyde (1 mmol) and cyclohexyl isocyanide
(1 mmol) was selected as a pilot experiment. The reaction
yield and time were monitored at room temperature under
various conditions. The results are summarized in Table 1.
As it is shown in Table 1, the best result was obtained in
the presence of 10 mol% of ZrCl4 (entry 12). Furthermore,
increasing the amount of catalyst decreases the yield of reac-
tion (entry 13).
dA gummy solid was obtained which makes the separation of prod-
ucts very hard
23). This result establishes the crucial role of ZrCl4 as an
efcient catalyst for progress of the reaction. It is notewor-
thy to mention that performing the reaction in the presence
of Zr(DS)4 that was reported before by our group [50] as a
good catalyst for the synthesis of quinazoline derivatives in
this reaction produced quinoxaline instead of 3,4-dihydro-
quinoxalin derivatives (entry 17). Moreover, the capability
of Zr(DS)4 as catalyst for formation of 3,4-dihydroquinoxa-
lin derivative was investigated in various solvents such as
EtOH, THF, CH3CN and n-hexane, and only trace amounts
of products were detected (entries 18–22). It can be related
to the formation of micelles in water related to other organic
solvents. Furthermore, Zr(DS)4 has more steric hinders than
ZrCl4 for interaction with other raw materials in the path of
reactions.
In addition, according to the results that are listed in
Table 1, among the applied solvents the best results were
obtained in ethanol (entries 3, 9 and 12). Only a trace
amount of the product was detected in H2O and mixture
of EtOH/H2O (entries 15 and 16). It may be attributed to
hydrolysis of ZrCl4 to hydrated hydroxyl chloride cluster.
This conversion is rapid and virtually irreversible [51].
Moreover, the pilot reaction was proceeded in the absence
of ZrCl4 in EtOH at room temperature and the reaction was
not performed even after elongation time up to 24 h (entry
In the next step, to establish the generality and ef-
ciency of the presented method, we explored the reaction
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Journal of the Iranian Chemical Society
Table 3 Condensation reaction of model reaction in the presence of
various hard and soft metallic salts
with various aromatic diamines, isocyanides, aliphatic,
alicyclic and aromatic ketones and aldehydes under opti-
mized conditions and obtained results are summarized in
Table 2.
Entry
Metallic Cat.
Hard(H) or
t(h)
Yields (%)a
soft(S) acid
Except for 4n and 4o, all reactions were completed
within 1.5–4 h and desired products were obtained in
good to excellent yields (72–94%). As shown in Table 2,
unlike the other methods, the high yields of products were
obtained in case of aldehydes as well as ketones. Here it
should be mentioned that, to the best of our knowledge
this is the frst time that the products of combining of alde-
hydes with o-aryl-diamines and isocyanides are reported
(entries 4e, 4f and 4h–4j). Furthermore, products of
entries 4b, 4d, 4l and 4m–p are also new. In the view of
the mechanism, the reaction is sterically controlled. In the
other words, the reaction outcome of our method seems to
be independent of the nature of the R2 groups, while it was
deeply infuenced by the nature of the used isocyanides
(R4), showing to sufer from steric hindrance.
1
2
3
4
5
CuCl
AgCl
ZnCl2
FeCl3
AlCl3
S
S
1.5
1.5
1.5
2.5
2.5
69
58
62
Trace
trace
Moderate
H
H
The one-pot condensation reaction between o-phenylenediamine
(1 mmol), p-nitrobenzaldehyde (1 mmol) and cyclohexyl isocyanide
(1 mmol) at room temperature and under various reaction conditions
aIsolated yield were determined just for 3,4-dihydroquinoxalin deriva-
tives
valence metals of Lewis acids such as ferric chloride and
aluminum chloride are much less active. The results have
indicated that the catalytic activity of metallic salts is
not ascribed to its function of the so-called hard and soft
Lewis acid. So, interaction of isocyanides and catalyst in
term of acid base interaction may not the main factor in
the mechanism of the reaction. This complies with other’s
reports [52–54].
The feasibility of the model reaction was screened
in the presence of diferent metallic salts. The obtained
results are summarized in Table 3. The salts of lower coor-
dination of metals such as copper, silver and zinc were
shown higher yield (entries 1–3, Table 3), while high
Table 2 Synthesis of 3,4-dihydroquinoxalin derivatives through a simple three-component condensation reaction of o-phenylenediamines,
diverse carbonyl compounds and isocyanides in the presence of catalytic amount of ZrCl4 under optimized conditions
Product
R1
R2
R3
R4
Time (h)
Yield (%)a
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
H
H
PhCO
PhCO
H
CH3
CH3
CH3
CH3
H
H
H
H
H
H
CH3
CH3
CH3
H
H
H
CH3
CH3
CH3
CH3
4-NO2–C6H4
4-NO2–C6H4
4-NO2–C6H4
4-NO2––C6H4
4-F–C6H4
4-F–C6H4
C6H5
C6H5
C6H5
4-OMe–C6H4
4-OMe–C6H4
4-NO2–C6H4
4-NO2–C6H4
C6H11
(CH3)3C
C6H11
(CH3)3C
C6H11
(CH3)3C
C6H11
(CH3)3C
C6H11
C6H11
C6H11
(CH3)3C
C6H11
2
2.5
2
2.5
1.5
2.5
2
2.5
2.5
3
3
4
3.5
5
5.5
2
83
79
87
78
94
87
85
80
90
85
86
82
80
77
72
85
87
H
PhCO
PhCO
H
PhCO
H
H
PhCO
H
C6H11
H
H
PhCO
(CH3)3C
(CH3)3CCH2(CH3)2C
(CH3)3CCH2(CH3)2C
H
2
aIsolated yields
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Journal of the Iranian Chemical Society
With these fndings in hand, we can have a second look at
Table 2 that shows, moving from acetone (entries 4a–4d) to
4-nitrobenzaldehyde (entries 4e–4h) and 4-fuorobenzalde-
hyde (entries 4i, 4j), the reactions were completed at almost
the same time and the corresponding products were obtained
in comparable yields. In contrast, when the reactions were
occurred with same diamines and carbonyl compounds in
the presence of diferent isocyanides, with changing the
isocyanide from cyclohexyl to 1,1,3,3-tetramethylbutyl and
then tert-butyl the reactions needed more time and the corre-
sponding yields were decreased. Moreover, the longest reac-
tion times related to those reactions that aromatic ketones
were used as carbonyl compounds (4l, 4m). Contrary to what
one might expect, when the 4-nitro or 4-fuorobenzaldehyde
was applied as carbonyl compounds the reaction was com-
pleted in shorter time than acetophenone. It can be attributed
to steric hinders of carbonyl group that is coordinated to
zirconium atom (Scheme 3). On the other hand, we cannot
ignore the electronic factor in this reaction. When the reac-
tion was performed with 4-methoxy derivative of benzalde-
hyde, the reaction time was increased while the yield was
decreased (entries 4n and 4o). In fact, the data in Table 2
show that two factors play a crucial role in this reaction and
directly afect the yields and rate: One is the nature of alde-
hydes, and the other one steric hinders of carbonyl groups.
Recently, on the basis of enantioselective catalytic prop-
erty of ZrCl4 a new coordination mechanism has been pro-
posed by Fioravanti and Pellacani to explain the formation
of obtained enantiopure products [55]. The factors that
afect this reaction in terms of nature are very close to our
reaction. In our case, although we have not established the
mechanism of the reaction but, according to the obtained
data from Table 2 we were convinced that the same path-
way is occurred as well. So, a catalytic cycle to explain the
ZrCl4-catalyzed three-component reaction of phenylenedi-
amine derivatives, carbonyl functional groups and isocya-
nides pathway performed on 3,4-dihydroquinoxalin-2-amine
derivatives is proposed (Scheme 3). In this explanation, frst,
carbonyl compound and phenylenediamine were coordinated
to zirconium tetrachloride. This coordination increases the
electrophilicity of carbonyl group, and in the next step the
reaction was followed by nucleophilic attack of free NH2 of
Scheme 3 Proposed mechanism of the three-component reaction of phenylenediamine derivatives, carbonyl functional groups and isocyanides
to performed 3,4-dihydroquinoxalin-2-amine derivatives
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Journal of the Iranian Chemical Society
phenylenediamine to carbonyl group. In this step the rate of
imine formation can be afected by steric hinders of R2 and
R3 on carbonyl group. Furthermore, the nature of aldehyde-
containing electron-withdrawing or electron-releasing group
can change the electrophilicity of the carbonyl group.
On the other hand, the good results for nitro- and
fluorobenzaldehyde can be achieved due to the influence
of the nitro and fluorine on the imine reactivity in the
path of reaction. In fact, the resonance and inductive elec-
tron-withdrawing effects of NO2 and F groups seem to be
strong enough to increase carbon electrophilicity of imine
for nucleophilic attack of isocyanides. Furthermore, it
may be due to the increasing electrophilicity of carbonyl
group in imine formation step. Finally, a favored intramo-
lecular nucleophilic attack followed by proton exchange
leads to the formation of 3,4-dihydroquinoxalin-2-amine
derivatives 4.
in our research we could synthesis the selective product
(DHQ) without any oxidation with various aldehydes.
Moreover, the used catalyst is inexpensive, commercially
available and is not toxic Table 4.
Conclusion
In conclusion we have developed a more practical and
reliable one-pot procedure for the synthesis of a wide
range of 3,4-dihydroquinoxalin-2-amine derivatives in
the presence of catalytic amount of zirconium tetrachlo-
ride. As compared to previous methods, excellent yields
even for aldehydes, easy work-up, use of inexpensive and
commercially available catalyst and good atom economy
are the main advantages of the presented method. Fur-
thermore, this method represents a simple and efficient
procedure, uses mild reaction conditions and has general
applicability. Besides, it avoids toxic catalysts and gives
nearly quantitative yields without any by-products.
In this type of reaction with aldehydes, oxidation gen-
erally occurs and its major product is (Q). In the literature
the researchers have produced the product (DHQ) but
with toxic, expensive and hard making catalyst, whereas
Table 4 Comparison of efciency of various methods for the synthesis of 3,4-dihydroquinoxalin-2-amine (DHQ)
Entry
Catalyst, condition
Time
Yield (%)
Ref.
DHQ
Q
1
2
3
4
ZrCl4, EtOH/r.t
MCM‐48/H5PW10V2O40, EtOH/r.t
Guanidinium-based sulfonic acid, H2O/r.t
1.5–5.5 h
50–60 min
60–85 min
12–48 h
72–94
81–87
73–89
15–88
–
–
–
–
This Work
[61]
[8]
MnO2@cellulose–SO3H or MnO2@wool–SO3H,
[60]
EtOH/r.t
5
6
7
8
CeO2-NPs, H2O/80 °C
ZnO NPs, EtOH/refux
CSA, EtOH/r.t
Silica gel-supported sulfuric acid, EtOH/r.t
Amberlyst-15, EtOH/r.t
EDTA, H2O/80 °C or r.t
DBU or DABCO, toluene/80 °C
Fe(ClO4)3, CH3CN/refux
CAN, EtOH/r.t
2–12 h
55–70 min
3 h
3–4 h
2–3 h
3 h
4 h
2 h
3 h
18 h
–
–
0–91
87–96
–
[59]
[11]
[5]
[6]
[4]
80–87
Not Reporteda
9
Not Reporteda
10
11
12
13
14
20
–
–
–
[3]
45–91
91–93
[58]
[12]
[2]
Not Reporteda
–
HCl, MeOH/r.t/under Ar
33–54
[57]
aThe method does not performed for aldehydes
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Journal of the Iranian Chemical Society
Experimental
Acknowledgements The authors thank the Islamic Azad University
(Shiraz Branch) Research Council for partial support of this work. The
authors also thank Dr. Neda Firoozi for her helpful discussion during
preparation of revised manuscript.
Chemicals and apparatus
Reagents and solvents were purchased from Merck, Fluka or
Aldrich and were used without further purifcation. Melting
points were determined in capillary tubes in an Electrother-
mal 9100 apparatus and uncorrected. The progress of the
reaction and the purity of compounds were monitored by
TLC analytical silica gel plates (Merck 60 F250). IR Spec-
tra: PerkinElmer Spectrum RXI. FT-IR apparatus. The 1H
NMR (300 MHz) and 13C NMR (75 MHz) were run on a
Bruker Avance DPX-250, FT-NMR spectrometer. Chemical
shifts are given as δ values against tetramethylsilane as inter-
nal standard, and J values are given in Hz. Microanalysis was
performed on a PerkinElmer 240-B microanalyzer.
Compliance with ethical standards
Conflict of interest All authors declare that they have no confict of
interest.
References
1. A. Shaabani, A. Maleki, H. Mofakham, H.R. Khavasi, Novel iso-
cyanide-based three-component synthesis of 3,4-dihydroquinox-
alin-2-amine derivatives. J. Comb. Chem. 10(2), 323–326 (2008)
2. J. Li, Y. Liu, C. Li, X. Jia, CAN-catalyzed syntheses of 3,4-dihy-
droquinoxalin-2-amine derivatives based on isocyanides. Tetra-
hedron Lett. 50(47), 6502–6505 (2009)
3. S.R. Kolla, Y.R. Lee, EDTA-catalyzed synthesis of 3,4-dihydro-
quinoxalin-2-amine derivatives by a three-component coupling of
one-pot condensation reactions in an aqueous medium. Tetrahe-
dron 66(44), 8938–8944 (2010)
Typical procedure for synthesis of N‑cyclohexyl‑3‑(4‑
nitrophenyl)‑3,4‑dihydroquinoxalin‑2‑amine (4e)
4. M.A. Chari, Amberlyst-15: an efcient and reusable catalyst for
multi-component synthesis of 3,4-dihydroquinoxalin-2-amine
derivatives at room temperature. Tetrahedron Lett. 52(46), 6108–
6112 (2011)
To a solution of 1,2-phenylenediamine (0.2 mmol),
4-nitrobenzaldehyde (0.2 mmol) and cyclohexylisocyanide
(0.2 mmol) in 1 mL of ethanol was added zirconium tet-
rachloride (0.02 mmol). The resulting mixture was stirred
for 1.5 h at room temperature. The reaction progress was
monitored by TLC (EtOAC/n-hexane 5: 2). After completion
of the reaction, the product was precipitated by addition of
10 mL of water and stirring the mixture for 3 h at 4 °C. Then
after, the products 4e were collected by fltration, washed
with 5% sodium hydroxide solution and distill water, dried
at room temperature, and the residues were recrystallized
from ethanol to aford the pure products N-cyclohexyl-3-(4-
nitrophenyl)-3,4-dihydroquinoxalin-2-amine 4e in excellent
yield (0.065 g, 94%). Yellow crystals, mp 199–202 °C. IR
(KBr, cm−1): 3247, 2912, 2831, 1619, 1500, 1446, 1311.
1H NMR (300 MHz, CDCl3): δ = 1.11–1.74 (10H, m, 5CH2
of cyclohexyl), 3.17 (1H, s, CH of cyclohexyl), 3.52 (1H,
s, NH), 5.69 (1H, s, CH–Ar), 6.71 (1H, s, NH-cyclohexyl),
6.74–7.08 (4H, Harom), 7.65 (2H, Harom), 8.22 (2H, Harom).
13C NMR (75 MHz, CDCl3): δ = 25.80, 26.72, 32.50 (car-
bons of cyclohexyl), 51.50 (carbon of cyclohexyl), 57.19
(CH–Ar), 116.99, 122.68, 123.82, 125.75, 125.92, 128.16,
134.0, 139.96, 143.15, 143.52 (Carom), 147.17 (N = C–NH).
Anal. calcd for C20H22N4O2: C, 68.55; H, 6.33; N, 15.99%.
Found: C, 68.51; H, 6.37; N, 15.95%.
5. H. Mofakham, Z. Hezarkhani, A. Shaabani, Cellulose-SO3H as a
biodegradable solid acid catalyzed one-pot three-component Ugi
reaction: synthesis of α-amino amide, 3,4-dihydroquinoxalin-
2-amine, 4H-benzo[b][1,4]thiazin-2-amine and 1,6-dihydropyra-
zine-2,3-dicarbonitrile derivatives. J. Mol. Catal. A: Chem. 360,
26–34 (2012)
6. D. Shobha, M.A. Chari, K. Mukkanti, S.Y. Kim, Synthesis and
anti-neuroinfammatory activity studies of substituted 3,4-dihy-
droquinoxalin-2-amine derivatives. Tetrahedron Lett. 53(22),
2675–2679 (2012)
7. D. Shobha, M.A. Chari, L.-C. Sang, S.A. Salem, K. Mukkanti, A.
Vinu, Room-temperature multicomponent synthesis of 3,4-dihyd-
roquinoxalin-2-amine derivatives using highly ordered 3D nano-
porous aluminosilicate catalyst. Synlett 13, 1923–1929 (2011)
8. M. Seyyedhamzeh, S.Hamidzad Shaabani, M. Sangachin, A.
Shaabani, Guanidinium-based sulfonic acid as a new Brønsted
acid organocatalyst in organic synthesis in water. Res. Chem.
Intermed. 42(4), 2845–2855 (2016)
9. Z. Jones, R. Groneberg, M. Drew, C.T. Eary, U.S. Patent
20,050,282,812 (2005)
10. R. Anand, V.J. Colandrea, M. Reiter, P. Vachal, A. Zwicker, J.E.
Wilson, F. Zhang, K. Zhao, U.S. Patent 9,126,976 B2 (2015)
11. A. Ziarati, J. Safaei-Ghomi, S. Rohanib, A one-pot multi-compo-
nent synthesis of N-cyclohexyl-3-arylquinoxaline- 2-amines using
ZnO nanoparticles as a heterogeneous reusable catalyst. Lett. Org.
Chem. 10(1), 47–52 (2013)
12. M.M. Heravi, B. Baghernejad, H.A. Oskooie, A novel three-
component reaction for the synthesis of N-cyclohexyl-3-aryl-
quinoxaline-2-amines. Tetrahedron Lett. 50(7), 767–769 (2009)
13. H.R. Safaei, M. Shekouhy, S. Rahmanpur, A. Shirinfeshan, Glyc-
erol as a biodegradable and reusable promoting medium for the
catalyst-free one-pot three component synthesis of 4H-pyrans.
Green Chem. 14, 1696–1704 (2012)
Supporting information available
Full experimental detail, IR, 1H and 13C NMR spectra for
compounds 4a–q. This material can be found via the “Sup-
plementary Content” section of this article’s webpage
14. H.R. Safaei, M. Shekouhy, V. Shafee, M. Davoodi, Glycerol based
ionic liquid with a boron core: a new highly efcient and reusable
promoting medium for the synthesis of quinazolinones. J. Mol.
Liq. 180, 139–144 (2013)
1 3

Journal of the Iranian Chemical Society
33. K.G.R. Sundlin, J.P. Salanitro, S. Stackhose, U.S. Patent 4,803,209
(1989)
15. H.R. Safaei, M. Davoodi, M. Shekouhy, Highly efcient synthesis
of substituted benzenes in the presence of B(HSO4)3 as a new and
reusable catalyst under solvent-free conditions. Synth. Commun.
43(16), 2178–2190 (2013)
34. K.G.R. Sundlin, J.P. Salanitro, S. Stackhose, U.S. Patent 4,886,781
(1989)
35. K.G.R. Sundlin, J.P. Salanitro, S. Stackhose, U.S. Patent 4,992,440
(1991)
16. H.R. Safaei, N. Shioukhi, M. Shekouhy, Isocyanide-based one-pot
three-component synthesis of novel spiroiminolactone derivatives
in water. Monatsh. Chem. 144(12), 1855–1863 (2013)
17. J.A. Gladysz, H.R. Safaei, S. Nouri, An unexpected role of carbon
disulfde: a new and efcient method for the synthesis of 2-sub-
stituted benzimidazoles. Helv. Chim. Acta 97(11), 1539–1545
(2014)
36. D.A. Dudley, J.J. Edmunds, U.S. Patent 6,410,536 B1 (2002)
37. C.O. Kappe, 100 Years of the Biginelli dihydropyrimidine syn-
thesis. Tetrahedron 49, 6937–6963 (1993)
38. C.O. Kappe, in Multicomponent Reactions, ed. by J. Zhu, H. Bien-
ayme (Wiley-VCH, Weinheim, 2005), p. 95
39. A. Dömling, I. Ugi, Multicomponent reactions with isocyanides.
Angew. Chem. Int. Ed. 39(18), 3168–3210 (2000)
40. A. Dömling, Recent developments in isocyanide based multicom-
ponent reactions in applied chemistry. Chem. Rev. 106(1), 17–89
(2006)
18. H.R. Safaei, M. Safaei, M. Shekouhy, Sulfuric acid-modifed
poly(vinylpyrrolidone) ((PVP–SO3H)HSO4): a new highly ef-
cient, bio-degradable and reusable polymeric catalyst for the syn-
thesis of acridinedione derivatives. RSC Adv. 5(9), 6797–6806
(2015)
41. V. Nair, C. Rajesh, A.U. Vinod, S. Bindu, A.R. Sreekanth, J.S.
Mathen, L. Balagopal, Strategies for heterocyclic construction via
novel multicomponent reactions based on isocyanides and nucleo-
philic carbenes. Acc. Chem. Res. 36(12), 899–907 (2003)
42. J.R. Sundberg, The Chemistry of Indoles (Academic, New York,
1996)
19. H.R. Safaei, F. Dehbozorgi, Isocyanide-based three component
reaction for synthesis of highly cyano substituted furan deriva-
tives. RSC Adv. 6(32), 26783–26790 (2016)
20. K. Toshima, R. Takano, T. Ozawa, S. Matsumura, Molecular
design and evaluation of quinoxaline-carbohydrate hybrids as
novel and efcient photo-induced GG-selective DNA cleaving
agents. Chem. Commun. 3, 212–213 (2002)
43. M.J.F. Da-Silva, J.S. Garden, C.A. Pinto, The chemistry of Isatins:
a review from 1975 to 1999. J. Braz. Chem. Soc. 12, 273–324
(2001)
21. Y.B. Kim, Y.H. Kim, J.Y. Park, S.K. Kim, Synthesis and bio-
logical activity of new quinoxaline antibiotics of echinomycin
analogues. Bioorg. Med. Chem. Lett. 14(2), 541–544 (2004)
22. G. Arthur, K.B. Elor, G.S. Robert, Z.Z. Guo, J.P. Richard, D.
Stanley, R.K. John, T. Sean, Novel transient receptor potential
vanilloid 1 receptor antagonists for the treatment of pain: struc-
ture–activity relationships for ureas with quinoline, isoquinoline,
quinazoline, phthalazine, quinoxaline, and cinnoline moieties. J.
Med. Chem. 48(3), 744–752 (2005)
44. J.P. Riley, R. Chester, Introduction to Marine Chemistry (Aca-
demic, New York, 1971)
45. F. Farnworth, S.L. Jones, I. McAlpine, Speciality Inorganic Chem-
icals (Royal Society of Chemistry, London, 1980). (Special pub-
lication No. 40)
46. L. Parise, L. Pellacani, F. Sciubba, L. Trulli, S. Fioravanti, Ste-
reoselective ZrCl
4-catalyzed mannich-type reaction of β-keto
23. J. Andres, Z. Belen, A. Ignacio, M. Antonio, Synthesis of new
quinoxaline-2-carboxylate 1,4-dioxide derivatives as anti-myco-
bacterium tuberculosis agents. J. Med. Chem. 48(6), 2019–2025
(2005)
esters with chiral trifuoromethyl aldimines. J. Org. Chem. 80(16),
8300–8306 (2015)
47. F. Tinnis, H. Lundberg, T. Kivijärvi, H. Adolfsson, Zirconium
(IV) chloride catalyzed amide formation from carboxylic acid and
amine: (S) tert-butyl 2-(benzylcarbamoyl) pyrrolidine-1-carboxy-
late. Org. Synth. 92, 227–236 (2015)
24. D. Gupta, N.N. Ghosh, R. Chandra, Synthesis and pharmacologi-
cal evaluation of substituted 5-[4-[2-(6,7-dimethyl-1,2,3,4-tetrahy-
dro-2-oxo-4-quinoxalinyl) ethoxy]phenyl]methylene]thiazolidine-
2,4-dione derivatives as potent euglycemic and hypolipidemic
agents. Bioorg. Med. Chem. Lett. 15(4), 1019–1022 (2005)
25. G.W.H. Cheeseman, R.F. Cookson, in The Chemistry of Hetero-
cyclic Compounds, vol. 35, 2nd edn., ed. by A. Weissberger, E.C.
Taylor (Wiley, New York, 1979), p. 1
48. M. Liu, G. Yin, ZrCl4-catalysed synthesis of new 4-(2-hydroxy-
phenyl) pyrazolo[3,4-b] pyridine derivatives. J. Chem. Research
39, 263–266 (2015)
49. J.E. Huheey, Inorganic Chemistry Principles of Structure and
Reactivity, 3rd edn. (Harper & Row, Singapore, 1990)
50. H.R. Safaei, M. Shekouhy, S. Khademi, V. Rahmanian, M. Safaei,
Diversity-oriented synthesis of quinazoline derivatives using zir-
conium tetrakis(dodecylsulfate) [Zr(DS)4] as a reusable Lewis
acid-surfactant-combined catalyst in tap water. J. Ind. Eng. Chem.
20(5), 3019–3024 (2014)
26. A.E.A. Porter, in Comprehensive Heterocyclic Chemistry, vol. 3,
ed. by A.R. Katrizky, C.W. Rees (Pergamon, New York, 1984),
p. 157
27. S. Dailey, J.W. Feast, R.J. Peace, R.C. Saga, S. Till, E.L. Wood,
Synthesis and device characterization of side-chain polymer elec-
tron transport materials for organic semiconductor applications. J.
Mater. Chem. 11(9), 2238–2243 (2001)
51. S. Chandra, Comprehensive Inorganic Chemistry, vol. 2 (New Age
International, India, 2006), pp. 87–88
52. J. Liu, X. Fang, Q. Zhang, Q. Liu, X. Bi, Silver-catalyzed iso-
cyanide-alkyne cycloaddition: a general and practical method to
oligosubstituted pyrroles. Angew. Chem. 125(27), 7091–7095
(2013)
28. L.S. Jonathan, M. Hiromitsu, M. Toshihisa, M.L. Vincent, F.
Hiroyuki, Quinoxaline-oligopyrroles: improved pyrrole-based
anion receptors. Chem. Commun. 8, 862–863 (2002)
29. D.O. Brien, M.S. Weaver, D.G. Lidzey, D.D.C. Bradley, Use
of poly(phenyl quinoxaline) as an electron transport material in
polymer light-emitting diodes. Appl. Phys. Lett. 69(7), 881–883
(1996)
53. S. Kamijo, C.H. Kanazawa, Y. Yamamoto, Copper- or phosphine-
catalyzed reaction of alkynes with isocyanides. regioselective syn-
thesis of substituted pyrroles controlled by the catalyst. J. Am.
Chem. Soc. 127(25), 9260–9266 (2005)
30. O. Sascha, F. Rudiger, Quinoxalinodehydroannulenes: a novel
class of carbon-rich materials. Synlett 9, 1509–1512 (2004)
31. M. Rosner, U.-M. Billhardt-Troughton, R. Kirsch, J.-P. Kleim,
C.R.G. Meichsner, I. Winkler, Quinoxalines, a process for their
preparation and their use. U.S. Patent, 5723461A (1998)
32. U.-M. Billhardt, M. Rosner, G. Riess, I. Winkler, R. Bender, U.S.
Patent, 6,369,057 B1 (2002)
54. T. Saegusa, Y. Ito, S.H. Kobayashik, K. Hirota, H. Yoshioka, Syn-
thetic reactions by complex catalysts. XIV. Reaction of isocyanide
with amine catalyzed by group IB and IIB metal compounds. Bull.
Chem. Soc. Jpn. 42, 3310–3313 (1969)
55. S. Fioravanti, L. Pellacani, M.C. Vergari, Fluorinated β-nitro
amines by a selective ZrCl
4-catalyzed aza-Henry reaction of
1 3

Journal of the Iranian Chemical Society
novel quinoxalin-2-amine derivatives and 3,4-dihydroquinoxalin-
2-amines in water. RSC Adv. 4, 11459–11468 (2014)
(E)-trifluoromethyl aldimines. Org. Biomol. Chem. 10(41),
8207–8210 (2012)
60. A. Shaabani, Z. Hezarkhani, E. Badali, One-pot oxidative Ugi-
type three-component reaction of aromatic hydrocarbons of
petroleum naphtha: comparing catalytic efect of cellulose and
wool–SO3H supported with manganese dioxide nanostructures.
RSC Adv. 5, 91966–91973 (2015)
56. H.R. Safaei, M. Shekouhy, A. Shirinfeshan, S. Rahmanpur, CaCl2
as a bifunctional reusable catalyst: diversity-oriented synthesis of
4H-pyran library under ultrasonic irradiation. Mol. Divers. 16(4),
669–683 (2012)
57. M. Krasavin, V. Parchinsky, Expedient entry into 1,4-dihydroqui-
noxalines and quinoxalines via a novel variant of isocyanide-based
MCR. Synlett 5, 0645–0648 (2008)
61. E. Vessally, R. Hosseinzadeh-Khanmiri, E. Ghorbani-Kalhor, M.
Es’haghi, L. Ejlali, Eco-friendly synthesis of 3,4-dihydroquinox-
alin-2-amine, diazepine-tetrazole and benzodiazepine-2-carboxa-
mide derivatives with the aid of MCM-48/H5PW10V2O40. Appl.
Organometal. Chem. 31(10), 3729 (2017)
58. C. Neochoritis, J. Stephanidou-Stephanatou, C.A. Tsoleridis, Het-
erocyclizations via TosMIC-based multicomponent reactions: a
new approach to one-pot facile synthesis of substituted quinoxa-
line derivatives. Synlett 2, 0302–0305 (2009)
59. N. Edayadulla, Y.R. Lee, Cerium oxide nanoparticle-catalyzed
three-component protocol for the synthesis of highly substituted
1 3