Design, synthesis, and application of 1H-imidazol-3-ium trinitromethanide {[HIMI]C(NO2)3} as a recyclable nanostructured ionic liquid (NIL) catalyst for the synthesis of imidazo[1,2-a]pyrimidine-3-carbonitriles

Article abstract of DOI:10.1007/s13738-018-1415-y

In this study, 1H-imidazol-3-ium trinitromethanide (1) {[HIMI]C(NO₂)₃} as a green and recyclable catalyst based on nanostructure ionic liquid (NIL) was designed, synthesized, fully characterized by various analysis techniques, and ap

Full text of DOI:10.1007/s13738-018-1415-y

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-018-1415-y
ORIGINAL PAPER
Design, synthesis, and application of 1H-imidazol-3-ium
trinitromethanide {[HIMI]C(NO2)3} as a recyclable nanostructured ionic
liquid (NIL) catalyst for the synthesis of imidazo[1,2-a]pyrimidine-3-
carbonitriles
Meysam Yarie1 · Mohammad Ali Zolfigol1 · Saeed Baghery1 · Abbas Khoshnood2 · Diego A. Alonso2 · Mehdi Kalhor3 ·
Yadollah Bayat4 · Asiye Asgari4
Received: 10 August 2017 / Accepted: 25 May 2018
© Iranian Chemical Society 2018
Abstract
In this study, 1H-imidazol-3-ium trinitromethanide (1) {[HIMI]C(NO2)3} as a green and recyclable catalyst based on nano-
structure ionic liquid (NIL) was designed, synthesized, fully characterized by various analysis techniques, and applied as
catalyst for the synthesis of 4-amino-1,2-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carbonitrile derivatives via one-pot
three-component condensation reaction. The reaction tolerates a wide range of electron-donating and electron-withdrawing
substituents on aldehydes with malononitrile and 2-aminobenzimidazole at 50 °C under neat conditions. The described
reaction is compatible with the green chemistry disciplines and their main advantages are short reaction time, high yields,
simplicity of product isolation, and clean reaction profile. Additionally, the NIL catalyst (1) {[HIMI]C(NO2)3} can be readily
recovered in the reaction vessel using a mixture of EtOAc/H2O (1:1) and reused for four consecutive runs without a signifi-
cant loss in catalytic activity. The present study can open up a new and promising insight in the course of rational design,
synthesis and applications of nanostructured task-specific ionic liquids (NTSILs) for numerous green purposes.
Keywords Multicomponent reactions (MCRs) · Knoevenagel condensation · Nanostructured ionic liquid (NIL) · Solvent-
free · 1H-Imidazol-3-ium trinitromethanide {[HIMI]C(NO2)3}
Electronic supplementary material The online version of this
Introduction
article (https://doi.org/10.1007/s13738-018-1415-y) contains
supplementary material, which is available to authorized users.
Fused salts are liquids including unique ions, ionic liquids
(ILs). Through careful election of substrates it is feasible
to synthesize ionic liquids that are liquid or solid at and
below or high room temperature. The development of air
and moisture stable ILs has provided improved ionic liquid
chemistry, and the emerging use of these ILs will be investi-
gated first [1]. Because of the unique chemical and physical
properties of ionic liquids, such as their low vapor pres-
sure, non-volatility, thermal stability, non-flammability, and
controlled miscibility, nowadays they have become a very
interesting tool for chemists in numerous fields, especially
in green chemistry. The re-evaluation of classical organic
synthesis in these novel medium has led to a superb series
of examples where chemical yields, regio-, chemo- and ste-
reoselective, as well as the recycling of catalysts have been
deeply improved [1–7]. While ionic liquids were firstly pre-
sented as alternative green reaction media, at the moment
* Meysam Yarie
myari.5266@gmail.com
* Mohammad Ali Zolfigol
zolfi@basu.ac.ir; mzolfigol@yahoo.com
* Abbas Khoshnood
abbas.khoshnood@ua.es
* Diego A. Alonso
diego.alonso@ua.es
1
Department of Organic Chemistry, Faculty of Chemistry,
Bu-Ali Sina University, Hamadan 6517838683, Iran
2
Organic Synthesis Institute, and Organic Chemistry
Department, Alicante University, Apdo. 99, 03080 Alicante,
Spain
3
Department of Chemistry, Payame Noor University,
Tehran 19395-4697, Iran
4
Faculty of Chemistry and Chemical Engineering, Malek
Ashtar University of Technology, Tehran, Iran
Vol.:(0123456789)
1 3

Journal of the Iranian Chemical Society
they have improved far outside this boundary, displaying
their noteworthy role in controlling reactions as solvent or
catalysts. Another feature of ILs is their ability to be reused
many times [8].
One-pot multicomponent reactions (MCRs) have been
explained as a process where more than three reactants are
combined in a single reaction to produce a product that con-
tains portions of all the components [9–24]. More specifi-
cally, the use of multicomponent reactions (MCRs) benefits
from various valuable features such as conventional reaction
design and atom economy. Therefore, among all current syn-
thetic tools in organic chemistry, MCRs have particularly
appeared as an efficient, inexpensive, and attractive meth-
odology for both academic and industrial purposes. On the
other hand, purification of products resulting from MCRs
is very simple, since all the organic reagents employed are
expended and are combined into the target compound. Mul-
ticomponent reactions, leading to interesting heterocyclic
scaffolds, are mainly useful for the production of chemical
libraries of ‘drug-like’ molecules.
Scheme 1 Synthesis of 1H-imidazol-3-ium trinitromethanide catalyst
(1) {[HIMI]C(NO2)3}
Experimental
General
Chemicals and materials were achieved from Merck, Fluka,
and Sigma-Aldrich and were applied without any additional
purification. All reactions were identified through thin layer
chromatography (TLC) on gel F254 plates. 1H NMR (400
and 300 MHz) spectra were recorded on Bruker Avance 400
and Bruker Avance 300 NMR spectrometers, respectively,
in proton-coupled mode. 13C NMR (100, 75.5 MHz) spectra
were recorded on Bruker Avance 400 and Bruker Avance
300 NMR spectrometers, respectively, in proton-decoupled
mode at 20 °C in DMSO-d6; chemical shifts are given in δ
(parts per million) and the coupling constants (J) in Hertz.
Low-resolution mass spectra (EI) were obtained at 70 eV
on a Agilent mass spectrometer, model Network 5973 cou-
pled with 6890N Network GC system. High-resolution mass
spectra (HRMS) analyses (EI) were also carried out at 70 eV
on an Agilent 7200-QTOF Network spectrometer. Catalyst
1 was characterized by FT-IR, 1H NMR, 13C NMR, TGA,
DTG, DTA, XRD, SEM, and HRTEM analysis. X-ray dif-
fraction (XRD) patterns of catalyst 1 was attained on a APD
2000, Ital structure with Cu Kα radiation (λ=0.1542 nm)
operating at 50 kV and 20 mA in a 2 h range of 10°–70° with
step size 0.01° and time step 1.0 s to assess the crystallinity
of the catalyst. Fourier transform infrared spectra of the sam-
ples were recorded on a Perkin–Elmer FT-IR spectrometer
17259 using KBr disks. Thermo gravimetric analyses via
a Perkin–Elmer TGA were synthesized on catalysts. The
SEM analyses were prepared with a TESCAN/MIRA with
a maximum acceleration voltage of the primary electrons of
26 kV. High-resolution transmission electron microscope,
(HRTEM) measurements were carried out on a JEOL JEM-
2010 microscope operating at an accelerating voltage of
200 kv with a LaB6 filament. Sample was prepared by drop
casting the dispersed particles onto a 300-mesh copper grid
coated with a holey carbon film. It is equipped with a camera
from Gatan, model Orius 831 and it reaches a resolution
between layers of 0.14 nm and between points 0.25 nm.
Numerous imidazo[1,2-a]pyrimidine derivatives are
significant as pharmaceuticals since they have been found
to have several biological activities [25–29], being remark-
able clinical examples the anti-ulcerative omeprazole, the
antihistaminic astemizole, and the fungicide rabenzazole
[35]. Due to the significance of this type of compounds,
a number of synthetic procedures and catalysts have been
reported for the synthesis of 4-amino-1,2-dihydrobenzo[4,5]
imidazo[1,2-a]pyrimidine-3-carbonitrile derivatives such
as EtOH/NH4OAc [31], melamine trisulfonic acid (MTSA)
[32], p-TSA [33], piperidine [35], silica sulfuric acid (SSA)
[36], alum [37], Me3N [38–40, 42], and water mediated syn-
thesis [34, 41, 43].
We have previously investigated on the design, synthe-
sis, applications, and development of green, nanostructured,
ionic liquids, molten salts, and organocatalysts for organic
functional group transformations as well as for eco-friendly
multicomponent synthesis of biologically important het-
erocyclic compounds [44–54]. Due to the above mentioned
advantages of multicomponent reactions and ionic liquids,
an eco-compatible imidazo[1,2-a]pyrimidine derivatives
synthesis involving both methodologies would be highly
desirable [55]. Herein, we report the synthesis of a green,
mild, efficient, and reusable nanostructured ionic liquid cata-
lyst, namely 1H-imidazol-3-ium trinitromethanide {[HIMI]
C(NO2)3} (1) (Scheme 1) [56] and its application to the
one-pot three-component synthesis of 4-amino-1,2-dihyd-
robenzo[4,5]imidazo[1,2-a]pyrimidine-3-carbonitrile deriv-
atives at 50 °C under neat conditions (Scheme 2).
1 3

Journal of the Iranian Chemical Society
Scheme 2 One-pot three-
component synthesis of
4-amino-1,2-dihydrobenzo[4,
5]imidazo[1,2-a]pyrimidine-
3-carbonitriles catalyzed by 1
Spectral data for analysis of the obtained compounds
General procedure for the synthesis
of 1H‑imidazol‑3‑ium trinitromethanide {[HIMI]
C(NO2)3} (1) as a green NIL catalyst
4-Amino-2-phenyl-1,2-dihydrobenzo[4,5]imidazo[1,2-
a]pyrimidine-3-carbonitrile (5a): white solid; M.p:
218–220 °C; yield: (270 mg, 94%); IR (KBr): υ 3443,
3320, 3214, 3058, 2192, 1683, 1640, 1602, 1470, 1442,
1402, 1352 cm−1; 1H NMR (300 MHz) δ 8.62 (s, 1H), 7.63
(d, J = 7.8, 1H), 7.39–7.22 (m, 6H), 7.12 (td, J = 7.7, 1.0,
1H), 7.00 (td, J=7.9, 1.3, 1H), 6.85 (s, 2H), 5.22 (s, 1H);
13C NMR (75 MHz) δ 152.3, 149.6, 144.1, 143.4, 129.8,
129.2, 128.3, 126.4, 123.8, 120.3, 119.7, 116.6, 112.9, 62.5,
53.7; GC-MS: m/z = 156 [M+-C7H6N3, 10%], 155 (100),
127 (69), 103 (49), 76 (11); HRMS calcd. for C17H13N5
([M-C3H2N2])+ 221.0953, found. 221.0930.
To a round-bottomed flask (50 mL) containing imidazole
(5.0 mmol, 340 mg) and CH3CN (5 mL), trinitromethane
(5.0 mmol, 755 mg) was added drop wise. The result-
ing mixture was stirred over a period of 120 min at room
temperature. Subsequently, the solvent was removed via
evaporation under reduced pressure and finally the obtained
product was dried under vacuum at 80 °C for 120 min. The
resulting yellow solid was washed with Et2O three times
and then it was dried under vacuum. Characterization by
FT-IR, 1H NMR, 13C NMR, TGA, DTG, DTA, XRD, SEM,
and HRTEM analysis as well as melting point determination
were performed.
4-Amino-2-(2-methoxyphenyl)-1,2-dihydrobenzo[4,5]
imidazo[1,2-a]pyrimidine-3-carbonitrile (5b): white solid;
M.p: 219–221 °C; yield: (282 mg, 89%); IR (KBr): υ 3362,
3303, 3135, 3006, 2940, 2182, 1677, 1606, 1493, 1474,
1454, 1407, 1258 cm−1; 1H NMR (300 MHz) δ 8.26 (br.s,
1H), 7.62 (d, J = 7.9, 1H), 7.31–7.19 (m, 2H), 7.14–7.05
(m, 2H), 7.00 (t, J=8.6, 2H), 6.87 (t, J=7.4, 1H), 6.72 (s,
2H), 5.38 (s, 1H), 3.69 (s, 3H); 13C NMR (75 MHz) δ 156.8,
152.8, 149.9, 144.1, 130.7, 129.8, 129.6, 126.9, 123.6,
120.8, 120.2, 119.5, 116.4, 112.7, 111.8, 61.7, 55.8, 49.4;
GC-MS: m/z=185 [M+–C7H6N3, 10%], 184 (100), 156 (40),
119 (75), 91 (34), 78 (17); HRMS calcd. for C18H15N5O ([M
–C3H3N2])+ 250.0980, found. 250.0991.
1H-imidazol-3-ium trinitromethanide (1) {[HIMI]
C(NO2)3}: M.p: 73–75 °C; yield: (1062 mg, 97%); spec-
tral data: FT-IR (KBr): υ 3433, 3153, 2985, 1751, 1634,
1586, 1384, 1049 cm−1; 1H NMR (400 MHz): δ 7.70 (d,
2H, J=1.2), 9.10 (t, 1H, J=2.4), 14.09 (brs, 2H); 13C NMR
(100 MHz): δ 119.8, 134.9, 160.2.
General procedure for the synthesis
of 4‑amino‑1,2‑dihydrobenzo[4,5]imidazo[1,2‑a]
pyrimidine‑3‑carbonitrile derivatives
4-Amino-2-(2,3-dichlorophenyl)-1,2-dihydrobenzo[4,5]
imidazo[1,2-a]pyrimidine-3-carbonitrile (5f): White solid;
M.p: 230–232 °C; Yield: (324 mg, 91%); IR (KBr): υ 3428,
3293, 3207, 3176, 2198, 1678, 1629, 1600, 1472, 1447,
1382 cm−1; 1H NMR (300 MHz) δ 8.57 (br.s, 1H), 7.68 (d,
J=7.9, 1H), 7.63 (dd, J=7.4, 2.0, 1H), 7.43–7.31 (m, 2H),
7.25 (d, J =7.5, 1H), 7.14 (t, J =7.3, 1H), 7.03 (t, J =8.1,
1H), 6.95 (br.s, 2H), 5.73 (s, 1H); 13C NMR (75 MHz) δ
206.9, 152.0, 150.1, 144.0, 142.4, 132.7, 130.6, 130.0,
129.7, 129.3, 127.5, 123.9, 120.5, 118.9, 116.6, 113.0,
60.7, 52.1, 31.1; GC-MS: m/z=227 (M++4-C7H6N3, 0.1%),
225 (M++2-C7H6N3, 0.6), 223 (M+-C7H6N3, 1), 226 (7),
224 (42), 222 (62), 187 (100), 152 (13), 124 (14); HRMS
calcd. for C17H11Cl2N5 ([M –C3H2N2])+ 289.0174, found.
289.0158.
In a round-bottom flask, catalyst 1 {[HIMI]C(NO2)3}
(1.0 mol%, 2.2 mg) was added to a mixture of the corre-
sponding aromatic aldehyde (1.0 mmol), 2-aminobenzimi-
dazole (1.0 mmol, 133 mg), and malononitrile (1.0 mmol,
66 mg). The obtained mixture was stirred magnetically at
50 °C under solvent-free conditions for the appropriate
time. After completion of the reaction, as identified by TLC
(n-hexane/EtOAc: 5/3), EtOAc (10 mL) was added, and the
mixture was stirred and refluxed for 10 min. Then, the result-
ing solution was washed with water (10 mL). Separation
of the phases led to the crude product in the EtOAc phase
while catalyst 1 was soluble in water. The organic phase
was dried (MgSO4) and the solvent evaporated to afford the
corresponding crude product which was purified via recrys-
tallization from ethanol/water (10:1).
1 3

Journal of the Iranian Chemical Society
4-Amino-2-(2-fluorophenyl)-1,2-dihydrobenzo[4,5]
imidazo[1,2-a]pyrimidine-3-carbonitrile (5i): Cream
solid; M.p: 219–221 °C; Yield: (278 mg, 91%); IR (KBr):
υ 3405, 3313, 3083, 2194, 2180, 1680, 1634, 1603, 1472,
1444, 1406, 1252 cm−1; 1H NMR (300 MHz) δ 8.52 (s, 1H),
7.65 (d, J = 7.9, 1H), 7.42–7.31 (m, 1H), 7.31–7.07 (m,
5H), 7.02 (td, J=7.9, 1.2, 1H), 6.86 (br.s, 2H), 5.47 (s, 1H);
13C NMR (75 MHz) δ 160.0 (d, J = 246.1), 152.2, 149.9,
144.0, 130.5 (d, J= 8.2), 129.9 (d, J = 13.5), 129.7, 128.4
(d, J = 3.8), 125.2 (d, J = 2.9), 123.8, 120.4, 119.1, 116.5,
116.3 (d, J = 21.3), 112.8, 61.2, 48.9; GC-MS: m/z = 173
(M+–C7H6N3, 12%), 172 (100), 145 (82), 121 (30); HRMS
calcd. for C17H12FN5 ([M –C3H2N2])+ 239.0859, found.
239.0851.
1349 cm−1; 1H NMR (300 MHz) δ 8.79 (s, 1H), 8.24–8.12
(m, 2H), 7.78 (dd, J= 6.6, 1.2, 1H), 7.70 (d, J= 7.8, 1H),
7.65 (d, J = 7.8, 1H), 7.26 (dd, J = 7.8, 0.8, 1H), 7.13 (td,
J=7.8, 1.0, 1H), 7.03 (dd, J=7.8, 1.2, 1H), 7.00 (br.s, 2H),
5.50 (s, 1H); 13C NMR (75 MHz) δ 151.9, 150.1, 148.3,
145.5, 144.0, 133.2, 130.9, 129.7, 123.9, 123.3, 121.3,
120.5, 119.5, 116.7, 113.0, 61.0, 52.8; GC-MS: m/z=201
(M+–C7H5N3, 12%), 136 (100), 128 (11), 90 (17); HRMS
calcd. for C17H11N6O2 ([M–H])+ 331.0943, found. 331.0929.
Results and discussion
4-Amino-2-(4-nitrophenyl)-1,2-dihydrobenzo[4,5]
imidazo[1,2-a]pyrimidine-3-carbonitrile (5j): Cream solid;
M.p: > 300 °C; Yield: (299 m, 90%,); IR (KBr): υ 3466,
3425, 3326, 3222, 3081, 2917, 2188, 1678, 1640, 1600,
1519, 1470, 1445, 1405, 1350 cm−1; 1H NMR (300 MHz)
δ 8.77 (s, 1H), 8.25 (d, J= 7.8, 2H), 7.64 (d, J= 7.8, 1H),
7.59–7.54 (m, 2H), 7.26 (dd, J = 7.8, 0.8, 1H), 7.13 (td,
J=7.7, 1.0, 1H), 7.02 (td, J=7.9, 1.2, 1H), 6.97 (s, 2H), 5.45
(s, 1H); 13C NMR (75 MHz) δ 151.9, 150.6, 149.9, 147.5,
144.0, 129.7, 127.7, 124.5, 123.9, 120.5, 119.4, 116.7,
113.0, 61.1, 53.0; GC-MS: m/z=201 (M+–C7H5N3, 25%),
136 (100), 106 (37), 89 (33), 78 (29); HRMS calcd. for
C17H12N6O2 ([M –C3H3N2])+ 265.0726, found. 265.0735.
4-Amino-2-(3-nitrophenyl)-1,2-dihydrobenzo[4,5]
imidazo[1,2-a]pyrimidine-3-carbonitrile (5k): Yellow solid;
M.p: 228–230 °C; Yield: (302 mg, 91%); IR (KBr): υ 3302,
3225, 3144, 3075, 2192, 1682, 1630, 1602, 1535, 1475,
Synthesis and characterization of 1H‑imidazol‑3‑ium
trinitromethanide (1) {[HIMI]C(NO2)3} as a green
benign NIL catalyst
To start the study, 1H-imidazol-3-ium trinitromethanide (1)
{[HIMI]C(NO2)3} was synthesized by reaction between imi-
dazole and trinitromethane through a proton transfer mecha-
nism in MeCN (1 M) for 120 min. Then, the structure of 1
was investigated and fully characterized by melting point:
1
73–75 °C, FT-IR, HNMR, 13CNMR, TGA, DTG, DTA,
XRD, SEM, and HRTEM analyses.
The FT-IR spectrum of catalyst 1 displayed a broad peak
at 3433 cm−1 which can be assigned to the N–H stretching
absorption on imidazolium ring. Additionally, the absorption
peaks at 1586 and 1384 cm−1 are related to the asymmetric
and symmetric –NO2 stretching absorption bands on trini-
tromethanide counter ion (Fig. 1).
Fig. 1 IR spectrum of trini-
tromethane (a), imidazole (b)
and catalyst 1 (c)
1 3

Journal of the Iranian Chemical Society
1H- and 13CNMR spectra of catalyst 1 in DMSO-d6 are
first weight loss (~ 2%) from the catalyst (room tem-
perature to 110 °C) is due to the removal of physically
adsorbed water and organic solvents, which were used in
the synthesis of the NIL catalyst. The main weight loss
(90%) between 110 and 175 °C is associated mainly to
the thermal decomposition of NIL catalyst. Thus, catalyst
1 shows a one-step weight loss behavior decomposing
after 175 °C. The DTA analysis diagram is upward and
exothermic.
1
showed in Figures S29 and S30. Regarding the HNMR
spectrum, it can be clearly distinguished the resonance peak
corresponding to the acidic hydrogen (N–H) of the nano-
structured ionic liquid catalyst at 14.09 ppm. Also, it can be
seen a triplet at 9.10 ppm and a doublet at 7.70 ppm, reso-
nances linked to the aromatic protons of the imidazolium
ring (Figure S29).
Furthermore, the 13C NMR spectrum of 1 confirmed the
structure of the synthesized catalyst. Thus, presented peak
at 160.1 was related to the carbon of –C(NO2)3 group while
two peaks at 134.8 and 119.7 ppm were correlated to the
aromatic carbons in imidazolium ring (Figure S30).
The thermal gravimetric (TG), derivative thermal
gravimetric (DTG), and differential thermal (DTA) anal-
ysis of NIL catalyst 1 display the mass loss of organic
materials as they decompose upon heating (Fig. 2). The
The structure of catalyst 1 was further investigated
through X-ray diffraction (XRD) pattern (Fig. 3), scanning
electron microscopy (SEM) and high-resolution transmis-
sion electron microscopy (HRTEM) (Fig. 4). Peak width
(FWHM), size and inter planer distance linked to XRD
pattern of 1 were studied in the 16.30° to 52.00° degree
and the achieved results are summarized in Table 1. For
example, assignments for the highest diffraction line 23.50°
presented that an FWHM of 0.22, a crystalline size of the
NIL catalyst (1) {[HIMI]C(NO2)3} of ca. 36.89 nm via the
Scherrer equation [D = Kλ/(βcosθ)], where D is the mean
size of the arranged (crystalline) domains, which may be
smaller or equal to the grain size. K is a dimensionless shape
factor. The shape factor has a model value of about 0.9. λ is
the X-ray wavelength. β is the line width at half the maxi-
mum intensity (FWHM), after subtracting the instrumental
line width, in radians. θ is the Bragg diffraction angle in
degree and an inter planer distance of 0. 378115 nm (the
similar highest diffraction line at 23.50°) was investigated
by the Bragg equation: dhkl = λ/(2sinθ), λ: Cu radiation
(0.154178 nm) were attained. Achieving crystalline sizes
from several diffraction lines via the Scherrer equation were
found to be in the nanometer range (5.87–38.44 nm), which
is specially in a close accordance with the scanning elec-
tron microscopy (SEM) and high-resolution transmission
electron microscopy (HRTEM) (Fig. 4). To determine the
Fig. 2 The thermal gravimetric (TG), derivative thermal gravimetric
(DTG), and differential thermal (DTA) analysis of {[HIMI]C(NO2)3}
Fig. 3 XRD pattern of catalyst 1
1 3

Journal of the Iranian Chemical Society
Fig. 4 Scanning electron
microscopy (SEM) (a), high-
resolution transmission electron
microscopy (HRTEM) (b–e)
and particle size distribution (f)
of catalyst 1
morphology and the size of 1, SEM and HRTEM experi-
ments were also performed, showing a particle size for 1 of
about 5–53 nm (Fig. 4).
Application of catalyst (1) {[HIMI]C(NO2)3}
in the one‑pot three‑component synthesis
of 4‑amino‑1,2‑dihydrobenzo[4,5]imidazo[1,2‑a]
pyrimidine‑3‑carbonitrile
First, the condensation reaction of benzaldehyde (2a) with
malononitrile (3) and 2-aminobenzimidazole (4) was exam-
ined in the presence of a catalytic amount of catalyst 1 as
1 3

Journal of the Iranian Chemical Society
Table 1 XRD data for catalyst 1
afforded 5a in a 94% yield at 50 °C after only 10 min. Addi-
tionally, a temperature and catalyst loading study was also
carried out. As shown in Table 2, entries 5–8, no improve-
ment was detected in the yield of reaction by increasing the
temperature or the catalyst loading. Next, the influence in
the efficiency of the process of different solvents, such as,
EtOH, H2O, CH3CN, EtOAc, and n-hexane was investigated
in the presence of 1 mol% of NIL catalyst 1 at 50 °C. The
obtained results, which are summarized in Table 2, entries
9–13 clearly pointed to the solvent-free conditions as the
best choice in this model reaction.
Entry
2θ
Peak width
[FWHM]
(degree)
Size (nm)
Inter planer
distance (nm)
1
2
3
4
5
16.30
22.80
23.50
26.50
52.00
0.99
1.38
0.22
0.24
0.23
8.11
5.87
36.89
34.01
38.44
0.274346
0.389564
0.378115
0.335951
0.175650
With the optimized conditions in hand (Table 2, entry
4), we set out to investigate the scope of the reaction with
a range of aldehydes (2a-o), malononitrile (3), and 2-amin-
obenzimidazole (4) (Table 3). As exhibited in Table 3, the
scope of the reaction is broad and tolerates a series of aro-
matic aldehydes which react with 2-aminobenzimidazole
and malononitrile to provide the corresponding 4-amino-
1,2-dihydrobenzo[4,5] imidazo[1,2-a]pyrimidine-3-carboni-
triles 5a–o in high-to excellent-yields. In general, the nature
and electronic properties of the substituents on the aromatic
ring did not affect neither the reaction rate nor the yield of
the process. This synthetic protocol could be scaled up to
the standard model reaction for the optimization of con-
ditions (Table 2). As depicted in entry 1, under neat and
catalyst-free conditions, the reaction proceeded slowly at
50 °C affording 4-amino-2-phenyl-1,2-dihydrobenzo[4,5]
imidazo[1,2-a]pyrimidine-3-carbonitrile (5a) in a low yield
35% yield after 90 min. Importantly, when 0.5 mol% of 1
was employed, the reaction proceeded efficiently yielding 5a
in 90% isolated yield after only 20 min (Table 2, entry 2).
Subsequently, the reaction was performed using 1.0 mol%
of catalyst 1 at room temperature and at 50 °C (Table 2,
entries 3–4). Interestingly, the increased reaction efficiency
Table 2 Optimization of the reaction conditions
Entry
Solventc
Catalyst (1) (x mol%)
Temperature (°C)
Time (min)
Yield% (5a)a
1
2
3
4
5
6
7
8
9
10
11
12
13
–
–
–
–
–
–
–
–
50
50
r.t
90
20
60
10
10
10
10
10
25
14
30
40
30
35
90
50
94
94
93
94
94
89
91
77
65
70
0.5
1.0
1.0
1.0
1.0
1.5
2.0
1.0
1.0
1.0
1.0
1.0
50
70
90
50
50
50
50
50
50
50
–
EtOHb
H2Ob
CH3CNb
n-Hexaneb
EtOAcb
Reaction conditions: 2a (1.0 mmol, 106 mg), 3 (1.0 mmol, 66 mg), 4 (1.0 mmol, 133 mg)
aIsolated yield
b4 mL of solvent was used
1 3

Journal of the Iranian Chemical Society
Table 3 Scope of one-pot three-component synthesis of 4-amino-1,2-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carbonitriles
Entry
1
R
Time (min)
10
Product
Yield
(%)b
M.p. (°C) [Lit]ref
Color
White
H
5a, 94 (94)c
218–220
[208–209] 43
2
2-MeO
19
5b, 89
219–221
White
3
3-MeO
15
5c, 88
212–214
[216] 37
White
4
4-Cl
10
5d, 93
235–237
[238] 38
Yellow
1 3

Journal of the Iranian Chemical Society
Table 3 (continued)
Entry
R
Time (min)
10
Product
Yield
(%)b
M.p. (°C) [Lit]ref
Color
White
5
2-Cl
5e, 91
5f, 91
5 g, 94
5 h, 90
5i, 91
221–223
[236–238] 33
6
7
8
9
2,3-Cl2
3-Br
4-F
13
11
13
11
230–232
White
Cream
White
Cream
240–242
[238–240] 33
225–227
[266–268] 33
2-F
219–221
[224–226] 33
1 3

Journal of the Iranian Chemical Society
Table 3 (continued)
Entry
R
Time (min)
13
Product
Yield
(%)b
M.p. (°C) [Lit]ref
Color
10
4-NO2
5j, 90
>300
Cream
[239–241] 57
11
12
3-NO2
4-CN
14
12
5 k, 91
5 l, 89
228–230
Yellow
Yellow
[242–243] 43
226–228
[215] 31
aReaction conditions: catalyst 1 (1.0 mol%, 2.2 mg), ArCHO 2a-o (1.0 mmol), 3 (1.0 mmol, 66 mg), 4 (1.0 mmol, 133 mg)
bIsolated yield
cReaction performed at 10 mmol scale
10 mmol, as demonstrated for the reaction between ben-
zaldehyde (2a), malononitrile (3), and 2-aminobenzimida-
zole (4), which afforded 5a with a 94% yield at 50 °C under
solvent-free conditions using 10 mol% of catalyst 1.
Reusability of catalyst 1 was confirmed in the model con-
densation reaction between benzaldehyde, malononitrile,
and 2-aminobenzimidazole. Therefore, once the reaction
was completed, ethyl acetate was added and the resulting
mixture was heated. Extraction with water of the hot crude
mixture afforded the corresponding product and unreactive
starting materials in the organic phase, while the NIL cata-
lyst remained in the aqueous phase. After the evaporation
of water under vacuum at 80 °C for 120 min (see Experi-
mental section), the vessel was charged again with a new set
of reagents. As depicted in Fig. 5, the catalytic activity of
catalyst 1 was restored within the limits of the experimental
errors for the tested four continuous runs, being product 5a
obtained with a 90% yield after the 4th cycle.
Fig. 5 Reusability study of catalyst 1 in the 10 min reaction between
benzaldehyde, 2-aminobenzimidazole and malononitrile
Based on our previously knowledge [44–53], a probable
reaction mechanism for the synthesis of the 4-amino-1,2-di-
hydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carbonitrile
derivatives 5 is proposed in Scheme 3. Initially, {[HIMI]
C(NO2)3} activates the carbonyl group of the aromatic
aldehyde to afford intermediate 6, while malononitrile is
also tautomerized to 7. Then, the Knoevenagel condensation
of intermediate 6 and 7 occurs to form the arylidene malo-
nonitrile 8. Subsequently, 2-aminobenzimidazole (4) per-
forms a nucleophilic attack to 8 providing the corresponding
1 3

Journal of the Iranian Chemical Society
NO2
H
Scheme 3 Suggested mecha-
nism for the synthesis of
NO2
H
N
N
H
O2N
N
1
N
O2N
NO2
O
2
NO2
H
N
H
4-amino-1,2-dihydrobenzo[4,5]
imidazo[1,2-a]pyrimidine-
3-carbonitrile derivatives in the
presence of {[HIMI]C(NO2)3}
N
H
R
C(NO2)3
O
R
H
H
3
H
N
H
N
N
6
7
C
HN
R
H
5
N
Kno
cond
eve
ensa
nag
el
N
H
tion
N
N
N
NIL Cat.
H2O
H2N
N
H
C(NO2)3
N
Tautomerization
H
N
R
NH2
N
10
N
8
R
H
N
H
NH
H
4
N
N
HN
N
R
N
N
H
Michael
addition
C(NO2)3
N
H
N
N
C(NO2)3
NH
9
Cyclization
N
N
H
H
Michael adduct 9. Finally, cyclization of 9 produces interme-
diate 10, which then affords the final aromatized 4-amino-
1,2-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carbon-
itrile derivatives 5 after tautomerization.
Conclusions
In summary, we have designed, synthesized and character-
ized a green, efficient and recyclable nanostructured ionic
liquid catalyst 1, namely 1H-imidazol-3-ium trinitrometha-
nide {[HIMI]C(NO2)3}. Catalyst 1 was fully characterized
by FT-IR, 1H NMR, 13C NMR, thermal gravimetric (TG),
derivative thermal gravimetric (DTG), differential thermal
analysis (DTA), X-ray diffraction patterns (XRD), scanning
electron microscopy (SEM) and high-resolution transmis-
sion electron microscopy (HRTEM) analysis. Then, the
catalytic application of the aforementioned NIL catalyst
was studied in the one-pot three-component synthesis of
4-amino-1,2-dihydrobenzo[4,5] imidazo[1,2-a]pyrimidine-
3-carbonitrile derivatives at 50 °C under neat conditions.
The proposed mechanism exposed that the buffer ability of
1, possibly plays a significant and dual catalytic role in the
To compare the efficacy of {[HIMI]C(NO2)3} catalyst
with some reported catalysts for the synthesis of 4-amino-
1,2-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-car-
bonitrile derivatives, we have presented the results of those
reported catalysts to confirm the condensation of 4-chlo-
robenzaldehyde (2d), with malononitrile (3) and 2-amin-
obenzimidazole (4) in Table 4. As Table 4 shows, {[HIMI]
C(NO2)3} has improved the synthesis of this product.
Table 4 Comparison of the
results in the synthesis of 5d
catalyzed by {[HIMI]C(NO2)3}
and other those reported
Entry
1
Reaction condition
Time (min)
10
Yield (%)a
93
[Ref.]
{[HIMI]C(NO2)3} (1 mol%), Solvent-
free, 50 °C
Alum (10 mol%), EtOH, 70 °C
EtOH, Me2NH (2 mL 30%), reflux
H2O, MW, 80 °C
This work
catalysts in the literatures
2
3
4
5
210
5
5
86
37
91
93
[37]
[39]
[41]
[31]
EtOH, NH4OAc (10 mol%), reflux
20
aIsolated yield
1 3

Journal of the Iranian Chemical Society
29. E.I. Elnima, M. Uppal Zubair, A.A. Al-Badr, Antimicrob. Agents
Chemother. 19, 29 (1981)
defined reaction. Finally, main advantages of the presented
process are practically simple work up, low cost, short reac-
tion time, high yield, recyclability and reusability of the
catalyst and cleaner reaction profile which produces it in
close accordance with the green chemistry disciplines.
30. S. Ramalingan, S. Balasubramanian, Kabilan, Synth. Commun.
34, 1105 (2004)
31. L. Hu, Z. Zhan, M. Lei, L. Hu, J. Chem. Res. 36, 738 (2012)
32. X. Shang, M. Geng, L. Wu, Asian J. Chem. 24, 515 (2012)
33. M. Veeranarayana Reddy, J. Oh, Y. Tae Jeong, C. R. Chim. 17,
484 (2014)
Acknowledgements We thank Bu-Ali Sina University, Iran National
Science Foundation (INSF) (Grant number: 940124), National Elites
Foundation, University of Alicante (VIGROB-173), and the Spanish
Ministerio de Economíay Competitividad (CTQ2015-66624-P) for
financial support to our research groups.
34. A. Shaabani, A. Rahmati, M. Hossein Rezayan, Z. Darvishi, A.
Badri, Sarvari, QSAR Comb. Sci. 26, 973 (2007)
35. Z.M. Nofal, H.H. Fahmy, H.S. Mohamed, Arch. Pharm. Res. 25,
250 (2002)
36. L. Wu, F. Yan, C. Yang, Bull. Chem. Soc. Ethiop. 24, 417 (2010)
37. A.R. Karimi, F. Bayat, Lett. Org. Chem. 8, 631 (2011)
38. B. Insuasty, A. Salcedo, R. Abonia, J. Quiroga, M. Nogueras, A.
Sánchez, Heterocycl. Commun. 8, 287 (2002)
References
39. S.A. Komykhov, K.S. Ostras, A.R. Kostanyan, S.M. Desenko,
V.D. Orlov, H. Meier, J. Heterocycl. Chem. 42, 1111 (2005)
40. B. Insuasty, R. Salcedo, J. Abonia, A. Quiroga, Sanchez, Hetero-
cycl. Commun. 38, 287 (2002)
1. T. Welton, Chem. Rev. 99, 2071 (1999)
2. P. Wasserscheid, W. Keim, Angew. Chem. Int. Ed. 39, 3772 (2000)
3. J. Dupont, R.F. de Souza, P.A.Z. Suarez, Chem. Rev. 102, 3667
(2002)
41. G. Liu, Q. Shao, S. Tu, L. Cao, C. Li, D. Zhou, B. Han, J. Hetero-
cyclic Chem. 45, 1127 (2008)
4. H. Olivier-Bourbigou, L. Magna, J. Mol. Catal. A Chem. 182–
183, 419 (2002)
42. A. Nowicka, H. Liszkiewicz, W.P. Nawrocka, J. Wietrzyk, K.
Kempińska, A. Dryś, Cent. Eur. J. Chem. 12, 1047 (2014)
43. A. Dandia, R. Singh, A.K. Jain, D. Singh, Synth. Commun. 38,
3543 (2008)
5. P.J. Dyson, Transit. Met. Chem. 27, 353 (2002)
6. V.I. Pârvulescu, C. Hardacre, Chem. Rev. 107, 2615 (2007)
7. J. Durand, E. Teuma, M. Gómez, C. R. Chim. 10, 152 (2007)
8. P. Wasserscheid, T. Welton, Ionic Liquids in Synthesis, Wiley-
VCH Verlag: Stuttgart, (2002)
44. M.A. Zolfigol, A. Khazaei, A.R. Moosavi-Zare, A. Zare, H.G.
Kruger, Z. Asgari, V. Khakyzadeh, M. Kazem-Rostami, J. Org.
Chem. 77, 3640 (2012)
9. R. Hayes, G.G. Warr, R. Atkin, Chem. Rev. 115, 6357 (2015)
10. N. Isambert, M.M.S. Duque, J.C. Plaquevent, Y. Genisson, J. Rod-
riguez, T. Constantieux, Chem. Soc. Rev. 40, 1347 (2011)
11. K.L. Luska, P. Migowski, W. Leitner, Green Chem. 17, 3195
(2015)
45. M.A. Zolfigol, A. Khazaei, A.R. Moosavi-Zare, A. Zare, Z.
Asgari, V. Khakyzadeh, A. Hasaninejad, J. Ind. Eng. Chem. 19,
721 (2013)
46. M.A. Zolfigol, H. Vahedi, S. Azimi, A.R. Moosavi-Zare, Synlett.
24, 1113 (2013)
12. A. Domling, Chem. Rev. 16, 17 (2006)
47. A.R. Moosavi-Zare, M.A. Zolfigol, O. Khaledian, V. Khakyzadeh,
M.D. Farahaniand, H.G. Kruger, New J. Chem. 38, 2342 (2014)
48. A.R. Moosavi-Zare, M.A. Zolfigol, V. Khakyzadeh, C. Böttcher,
M.H. Beyzavi, A. Zare, A. Hasaninejad, R. Luque, J. Mater.
Chem. A. 2, 770 (2014)
13. A. Domling, I. Ugi, Angew. Chem. Int. Ed. 39, 3168 (2000)
14. J. Zhu, H. Bienayme, Reactions Multicomponent, (Wiley-VCH,
Weinheim, 2005)
15. D.M. D’Souza, T.J.J. Mueller, Chem. Soc. Rev. 36, 1095 (2007)
16. D. Tejedor, F. Garcia-Tellado, Chem. Soc. Rev. 36, 484 (2007)
17. N.R. Candeias, F. Montalbano, P.M.S.D. Cal, P.M.P. Gois, Chem.
Rev. 110, 6169 (2010)
49. M.A. Zolfigol, S. Baghery, A.R. Moosavi-Zare, S.M. Vahdat, RSC
Adv. 5, 32933 (2015)
50. M.A. Zolfigol, S. Baghery, A.R. Moosavi-Zare, S.M. Vahdat, H.
Alinezhad, M. Norouzi, RSC Adv. 5, 45027 (2015)
51. M.A. Zolfigol, S. Baghery, A.R. Moosavi-Zare, S.M. Vahdat, H.
Alinezhad, M. Norouzi, RSC Adv. 4, 57662 (2014)
52. M.A. Zolfigol, F. Afsharnadery, S. Baghery, S. Salehzadeh, F.
Maleki, RSC Adv. 5, 75555 (2015)
18. K. Wang, D. Kim, A.J. Domling, J. Comb. Chem. 12, 111 (2010)
19. L.F. Tietze, Domino Reactions: Concepts for Efficient Organic
Synthesis (Wiley-VCH, Weinheim, 2004)
20. A. Dömling, W. Wang, K. Wang, Chem. Rev. 112, 3083 (2012)
21. M. Shiri, Chem. Rev. 112, 3508 (2012)
22. R. Maleki, S. Rahimi, Maleki, J. Iran. Chem. Soc. 12, 191 (2015)
23. M. Maleki, R. Aghaei, Paydar, J. Iran. Chem. Soc. 14, 485 (2017)
24. T.J.J. Muller, Science of Synthesis: Multicomponent Reactions
(Georg Thieme, Stuttgart, 2014)
53. M.A. Zolfigol, S. Baghery, A.R. Moosavi-Zare, S.M. Vahdat, J.
Mol. Catal. A. Chem. 409, 216 (2015)
54. H. Sharghi, A. Khoshnood, M.M. Doroodmand, R. Khalifeh, J.
Heterocycl. Chem. 53, 164 (2016)
25. K. Kubo, Y. Inada, Y. Kohara, Y. Sugiura, M. Ojima, K. Itoh,
Y. Furukawa, K. Nishikawa, T. Nakat, J. Med. Chem. 36, 1772
(1993)
55. N. Isambert, M.M. Sanchez Duque, J.C. Plaquevent, Y. Génisson,
J. Rodriguez, T. Constantieux, Chem. Soc. Rev. 40, 1347 (2011)
56. Y. Huang, H. Gao, B. Twamley, J.M. Shreeve, Eur. J. Inorg. Chem.
2007, 2025 (2007)
26. M.S. Bartlett, T.D. Edlind, M.M. Durkin, M.M. Shaw, S.F.
Queener, J.W. Smith, Antimicrob. Agents Chemother. 36, 779
(1992)
57. M.A. Bodaghifard, Z. Faraki, A.R. Karimi, Curr. Org. Chem. 20,
1648 (2016)
27. R. Paramashivappa, P. Phani Kumar, P.V. Subba Rao, A. Srinivasa
Rao, Bioorg. Med. Chem. 13, 657 (2003)
28. A.N. Dhage, N.S. Jashi, S.G. Wadokar, A.V. Kasture, Indian
Drugs 23, 601 (1986)
1 3