1H-imidazol-3-ium tricyanomethanide {[HIM]C(CN)3} as a nanostructured molten salt catalyst: application to the synthesis of pyrano[4,3‐b]pyrans

Article abstract of DOI:10.1007/s11164-016-2826-y

In this work, we have synthesized a novel nanostructured molten salt, ¹H-imidazol-3-ium tricyanomethanide {[HIMI]C(CN)₃} (1), as an efficient and green protocol-compatible catalyst. This new molten salt has been fully characterized b

Full text of DOI:10.1007/s11164-016-2826-y

Res Chem Intermed
DOI 10.1007/s11164-016-2826-y
1H-imidazol-3-ium tricyanomethanide {[HIM]C(CN)3}
as a nanostructured molten salt catalyst: application
to the synthesis of pyrano[4,3-b]pyrans
Mohammad Ali Zolfigol1 Meysam Yarie1
•
•
Saeed Baghery1 Abbas Khoshnood2
•
•
Diego A. Alonso2
Received: 21 October 2016 / Accepted: 30 November 2016
Ó Springer Science+Business Media Dordrecht 2017
Abstract In this work, we have synthesized a novel nanostructured molten salt, 1H-
imidazol-3-ium tricyanomethanide {[HIMI]C(CN)3} (1), as an efficient and green
protocol-compatible catalyst. This new molten salt has been fully characterized by
1
different analytical techniques, such as FT-IR, HNMR, 13CNMR, thermal gravi-
metric analysis, derivative thermal gravimetric analysis, differential thermal anal-
ysis, X-ray diffraction, scanning electron microscopy, and high-resolution
transmission electron microscopy. Additionally, the catalytic activity of
{[HIMI]C(CN)3} (1, 2 mol%) has been tested in a three-component domino Kno-
evenagel condensation reaction. A range of structurally diverse aromatic aldehydes
(2a–p), malononitrile (3), and 4-hydroxy-6-methyl-2H-pyran-2-one (4) are tolerated
for the synthesis of 2-amino-7-methyl-5-oxo-4-aryl-4,5-dihydropyrano[4,3-b]pyran-
3-carbonitrile derivatives (5a–p) under neat conditions at 50 °C. The obtained
results have demonstrated that catalyst 1 shows interesting catalytic properties, such
Electronic supplementary material The online version of this article (doi:10.1007/s11164-016-2826-y)
contains supplementary material, which is available to authorized users.
&
&
&
&
1
Mohammad Ali Zolfigol
zolfi@basu.ac.ir; mzolfigol@yahoo.com
Meysam Yarie
myari.5266@gmail.com
Abbas Khoshnood
abbas.khoshnood@ua.es
Diego A. Alonso
diego.alonso@ua.es
Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University,
Hamedan 6517838683, Iran
2
´
Departamento de Quımica Organica, and Instituto de Sıntesis Organica, Universidad de
Alicante, Apdo. 99, 03080 Alicante, Spain
´
´
´
123

M. A. Zolfigol et al.
as clean reaction profile, cost-effectiveness, and green conditions. Importantly, the
aforementioned catalyst is thermally stable with a 171 °C melting point not showing
any significant loss in catalytic activity after 7 reaction cycles.
Keywords Multicomponent reactions Á Knoevenagel condensation Á
Nanostructured molten salt Á Neat conditions Á Green chemistry
Introduction
Nowadays, multicomponent reactions (MCRs) have been successfully applied to
create highly functionalized and complex molecules via a single procedure [1–11].
This type of reaction have opened up new approaches towards the preparation of
combinatorial libraries of varied pharmacologically significant organic molecules
and have provided efficient and leading scaffolds towards novel drug discovery.
Furthermore, multicomponent reactions involve the one-shot activation of different
molecules and bonds providing advantages, such as structural diversity, high
selectivity, high atom economy, and green conditions.
The pyrano[4,3-b]pyran scaffold, as a non-peptide human immunodeficiency
virus inhibitor, shows a noteworthy structural subunit for the discovery of novel
drug candidates, such as fused pyran-2-ones. Additionally, the pyrano[4,3-b]pyran
skeleton has been found in various natural and biologically active products such as
davallialactone, arisugacins, pyripyropenes, philigridrins, clavilactone, and ter-
ritrems [12–14]. The synthesis of pyrano[4,3-b]pyranes is usually performed in a
three-component reaction of aldehydes, malononitrile and 4-hydroxy-6-methyl-2H-
pyran-2-one catalyzed by different systems, such as KF-Al2O [3, 15] alum [16], b-
alanine/CaSO [4, 17] eggshell (ES)-supported Cu(OH)2 nanoribbons [18], thiourea
dioxide [19], nano-CaO based on eggshell waste [20], electro-catalysis [21], ZnO
nanoparticles [22], 4-(succinimido)-1-butane sulfonic acid (SBSA) [23], piperidine
[24], heteropolyacid (H6P2W18O62.18H2O) [25] and [BBMIm](HSO4)2 [26].
Ionic liquids (ILs) and molten salts (MSs) are liquid or solid materials at room
temperature fully composed by ions [27–30]. The attention on these compounds as
high-tech and green media of the future has rapidly increased due to their high
thermal stability, near-zero vapor pressure, tenable properties as regards hydropho-
bicity, polarity, and solvent miscibility behavior by suitable modification of the
cation and the anion. Generally, on account of their uncommon miscibility behavior,
ionic liquids present an increased potential to revolutionize reaction technology.
The difference between MSs (very corrosive medium, high-melting and highly
viscous) and ILs (relatively low viscosity and liquid below 100 °C) is determined by
their melting point pattern [31].
We have previously investigated the design, synthesis, applications, and develop-
ment of green nanostructured ILs, MSs, and organocatalysts for organic functional
group transformations as well as for eco-friendly multicomponent synthesis of
biologically heterocyclic compounds [32–47]. As a continuation of these studies, here
we report the synthesis of a green mild, efficient, and reusable nanostructured MS
catalyst, namely 1H-imidazol-3-ium tricyanomethanide {[HIMI]C(CN)3} (1,
123

1H-imidazol-3-ium tricyanomethanide {[HIM]C(CN)3} as a…
Scheme 1) and its catalytic application in a three-component domino Knoevenagel
condensation between several structurally diverse aromatic aldehydes, malononitrile,
and 4-hydroxy-6-methyl-2H-pyran-2-one to prepare 2-amino-7-methyl-5-oxo-4-aryl-
4,5-dihydropyrano[4,3-b]pyran-3 carbonitrile derivatives (5) under neat conditions at
50 °C (Scheme 2).
Experimental
Materials and methods
All the materials were purchased from Merck, Fluka, Sigma-Aldrich and Across
Organic and were used without any additional purification. All reactions were
detected by thin layer chromatography (TLC) on gel F254 plates. Proton-coupled
mode NMR (400 or 300 MHz) spectra were recorded on Bruker Avance 400 or
Bruker Avance 300 NMR spectrometers, respectively, at 20 °C in DMSO-d6.
Proton-decoupled 13CNMR (100 or 75.5 MHz) spectra were recorded on Bruker
Avance 400 and Bruker Avance 300 NMR spectrometers, respectively, at 20 °C in
DMSO-d6; chemical shifts are given in d (parts per million) and the coupling
constants (J) in Hertz. An X-ray diffraction (XRD) pattern of catalyst 1 was attained
on a APD 2000, Ital, structure with Cu K_radiation (k = 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 nfrared (FT-IR) spectra
of the samples were recorded on a Perkin–Elmer FT-IR spectrometer 17259 using
KBr disks. Thermo-gravimetric analyses were carried out using a Perkin–Elmer
TGA apparatus. The scanning electron microscopy (SEM) analyses were prepared
with a TESCAN/MIRA with a maximum acceleration voltage of the primary
electrons between 10 and 15 kV. The high-resolution transmission electron
microscopy (HRTEM) used a HRTEM-200 microscope from JEOL, model JEM-
Scheme 1 Synthesis of 1H-imidazol-3-ium tricyanomethanide {[HIMI]C(CN)3} (1) as a green, mild,
and efficient nanostructured molten salt catalyst
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M. A. Zolfigol et al.
Scheme 2 One-pot three-component synthesis of 2-amino-7-methyl-5-oxo-4-aryl-4,5-dihydropyrano
[4,3-b]pyran-3-carbonitriles via domino Knoevenagel condensation using {[HIMI]C(CN)3} (1) as a new
nanostructured molten salt catalyst
2010, working at 200 kV with a LaB6 filament was used for the corresponding
studies, with a resolution between layers of 0.14 nm and between points of 0.25 nm.
It was equipped with a camera from Gatan, model Orius 831.
General procedure for the synthesis of 1H-imidazol-3-ium
tricyanomethanide {[HIMI]C(CN)3} (1)
To an aqueous solution of tricyanomethane (5.0 mmol, 455.0 mg) in deionized
water (10 mL) imidazole (5.0 mmol, 340.0 mg) was added and the resulting
mixture was stirred at room temperature for 120 min. The solvent was then removed
under reduced pressure and the obtained white residue was dried under vacuum at
100 °C during 120 min in a standard glassware oven. The white solid formed was
suspended in Et2O and, after filtration with generous washings with Et2O, it was
dried in vacuo. Then, catalyst 1 was characterized by various techniques, including:
1
FT-IR, HNMR, 13CNMR, thermal gravimetric analysis (TGA), derivative thermal
gravimetric (DTG) analysis, differential thermal analysis (DTA), X-ray diffraction
(XRD), SEM, HRTEM, and melting-point determination.
1H-imidazol-3-ium tricyanomethanide {[HIMI]C(CN)3} (1)
M.p: 171–173 °C; Yield: (95%, 756.0 mg). FT-IR (KBr): t 3125, 3023, 2914, 1662,
1549, 1448, 1327, 1100 cm-1. 1HNMR (400 MHz): d 11.94 (br.s, 2H), 7.62 (s, 1H),
7.00 (s, 2H). 13CNMR (100 MHz): d 166.4, 135.6, 122.3, 69.6.
General procedure for the synthesis of 2-amino-7-methyl-5-oxo-4-aryl-4,5-
dihydropyrano[4,3-b]pyran-3-carbonitrile derivatives 5
To a previously prepared mixture in a round-bottom flask of the corresponding
aromatic aldehyde (1.0 mmol), 4-hydroxy-6-methyl-2H-pyran-2-one (1.0 mmol,
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1H-imidazol-3-ium tricyanomethanide {[HIM]C(CN)3} as a…
126.0 mg), and malononitrile (1.0 mmol, 66 mg), catalyst 1 (2.0 mol%, 3.2 mg)
was added, and the consequent mixture was magnetically stirred under neat
conditions at 50 °C. After completion of the reaction, as detected by TLC (n-
hexane/ethyl acetate: 5/2), 10 mL of ethyl acetate were added to the mixture, stirred
and refluxed for 10 min. The obtained mixture was then washed with water (10 mL)
and decanted to separate the NMS catalyst from the reaction mixture. Noticeable,
the reaction mixture was soluble in hot ethyl acetate and the NMS catalyst was
soluble in water. Then, the organic phases were dried over MgSO4, followed by
evaporation under reduced pressure to remove the solvent, and the crude product
was purified via recrystallization from a mixture of ethanol/water: 10/1.
Spectral data for analyzed compounds
Compounds 5b,6 5e,6 5g,6 5h,5 5i,5 5k,5 5l,5 5m,13 5o,13 and 5p13 are known, and
they were characterized by comparison of their physical and spectroscopic data with
those described in the literature. Data for the new compounds or those not fully
characterized in the literature follow:
2-Amino-7-methyl-5-oxo-4-phenyl-4H,5H-pyrano[4,3-b]pyran-3-carbonitrile (5a)
White solid; M.p: 250–252 °C; Yield: (92%, 258 mg). IR (KBr): t 3400, 3324,
3207, 3084, 2199, 1711, 1674, 1614, 1385, 1261, 1138 cm-1. 1HNMR (400 MHz) d
7.33 (t, J = 7.4 Hz, 2H), 7.25 (t, J = 9.6 Hz, 1H), 7.21 (d, J = 7.2 Hz, 2H), 7.18
(s, 1H), 6.28 (s, 2H), 4.28 (s, 1H), 2.26 (s, 3H). 13CNMR (100 MHz) d 162.9, 161.3,
158.1, 158.03, 157.99, 157.95, 143.6, 128.4, 127.5, 127.0, 119.3, 100.7, 97.9, 57.8,
36.2, 19.3.
2-Amino-4-(4-methoxyphenyl)-7-methyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-3-carbonitrile
(5c)
White solid; M.p: 212–214 °C; Yield: (90%, 279 mg). IR (KBr): t 3454, 3313,
3227, 3009, 2185, 1731, 1676, 1646, 1606, 1510, 1380, 1257 cm-1 1HNMR
.
(400 MHz) d 7.27 (br.s, 1H), 7.20 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H),
6.36 (s, 2H), 4.31 (s, 1H), 3.82 (s, 3H), 2.31 (s, 3H). 13CNMR (100 MHz) d 162.7,
161.3, 158.2, 157.94, 157.90, 157.8, 135.6, 128.6, 119.4, 113.7, 101.0, 97.9, 58.1,
55.0, 35.4, 19.3.
2-Amino-4-(3-methoxyphenyl)-7-methyl-5-oxo-4,5-dihydropyrano[4,3-b]pyran-3-
carbonitrile (5d)
White solid; M.p: 233–235 °C; Yield: (90%, 279 mg). IR (KBr): t 3411, 3322,
3296, 3185, 3095, 2960, 2208, 1704, 1675, 1644, 1615, 1587, 1383, 1269,
.
1047 cm-1 1HNMR (300 MHz) d 7.26–7.20 (m, 3H), 6.85–6.78 (m, 1H),
6.76–6.72 (m, 2H), 6.28 (d, J = 0.7 Hz, 1H), 4.26 (s, 1H), 3.73 (s, 3H), 2.23 (s,
3H). 13CNMR (75 MHz) d 163.4, 161.8, 159.6, 158.6, 145.6, 130.0, 120.0, 119.7,
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M. A. Zolfigol et al.
114.2, 112.3, 101.1, 98.4, 58.3, 55.4, 36.6, 31.1, 19.8. MS (EI, 70 eV): m/z = 282
(M?–CO, 2%), 184 (100), 156 (25), 141 (20), 127 (30), 114 (34).
2-Amino-4-(4-cyanophenyl)-7-methyl-5-oxo-4,5-dihydropyrano[4,3-b]pyran-3-
carbonitrile (5f)
White solid; M.p: 230–232 °C; Yield: (92%, 281 mg). IR (KBr): t 3443, 3339,
3230, 3184, 3113, 2226, 2193, 1697, 1669, 1633, 1603, 1584, 1382, 1263,
1
1139 cm-1. HNMR (300 MHz) d 7.84–7.80 (m, 1H), 7.80–7.75 (m, 1H), 7.43 (d,
J = 1.8 Hz, 1H), 7.42–7.39 (m, 1H), 7.34 (s, 2H), 6.31 (d, J = 0.9 Hz, 1H), 4.43 (s,
1H), 2.23 (s, 3H). 13CNMR (75 MHz) d 163.9, 161.8, 159.1, 158.6, 149.5, 132.9,
129.2, 119.5, 119.2, 110.3, 100.1, 98.5, 57.3, 36.8, 19.8; MS: m/z = 279 (M?–CN),
179 (100), 152 (80), 128 (30).
2-Amino-4-(4-chlorophenyl)-7-methyl-5-oxo-4H,5H-pyrano[4,3-b]pyran-3-carbonitrile
(5j)
White solid; M.p: 220–222 °C; Yield: 94%, 295 mg). IR (KBr): t 3383, 3328, 3195,
3098, 2202, 1710, 1674, 1613, 1383, 1261, 1141 cm-1. 1HNMR (400 MHz) d 7.47
(d, J = 8.4 Hz, 2H), 7.35 (s, 1H), 7.33 (d, J = 8.4 Hz, 2H), 6.38 (s, 2H), 4.41 (s,
1H), 2.32 (s, 3H). 13CNMR (100 MHz) d 163.1, 161.3, 160.1, 158.2, 142.6, 132.1,
131.5, 129.7, 129.5, 128.3, 119.2, 100.2, 97.9, 57.3, 35.7, 19.3.
2-Amino-4-(2-fluorophenyl)-7-methyl-5-oxo-4,5-dihydropyrano[4,3-b]pyran-3-
carbonitrile (5n)
White solid; M.p: 238–240 °C; Yield: (92%, 274 mg). IR (KBr): t 3414, 3328,
3305, 3222, 3092, 2198, 1707, 1674, 1644, 1613, 1384, 1260, 1138 cm-1. 1HNMR
(300 MHz) d 7.40–6.96 (m, 6H), 6.30 (d, J = 0.9 Hz, 1H), 4.54 (s, 1H), 2.23 (s,
3H). 13CNMR (75 MHz) d 163.6, 162.6 (d, J = 187 Hz), 162.4, 159.1, 158.8,
130.53 (d, J = 16 Hz), 130.51 (d, J = 12 Hz), 129.6 (d, J = 11 Hz), 125.0 (d,
J = 4 Hz), 119.6, 116.0 (d, J = 28 Hz), 99.9, 98.4, 56.9, 31.3, 19.8. MS (EI,
70 eV): m/z = 253 (M?–45, 2%), 172 (100), 145 (90), 121(30).
Results and discussion
Synthesis and characterization of 1H-imidazol-3-ium tricyanomethanide
{[HIMI]C(CN)3} (1)
Initially, 1H-imidazol-3-ium tricyanomethanide {[HIMI]C(CN)3} (1) was synthe-
sized by the reaction between imidazole and methanetricarbonitrile through a proton
transfer mechanism in water for 120 min. The structure of the catalyst (1) was fully
characterized by FT-IR, 1H NMR, 13C NMR, mass spectrometry, TGA, DTG, DTA,
XRD, SEM, and HRTEM analyses.
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1H-imidazol-3-ium tricyanomethanide {[HIM]C(CN)3} as a…
The FT-IR spectrum of {[HIMI]C(CN)3} (1) (Fig. 1) exhibited a broad peak at
3450 cm-1 which can be related to the N–H stretching absorption of the
imidazolium moiety. Furthermore, the absorption band at 2079 cm-1 is related to
the C:N stretching on the tricyanomethanide counter ion. By comparing the IR
absorptions of catalyst 1 and imidazole (Fig. 1), it is clear that not only has the
intensity of the band related to the stretching absorption of CN groups decreased but
its wavelength has also very slightly shifted to lower values, which could be related
to mesomeric effects.
1
Additionally, we have also studied the structure of {[HIMI]C(CN)3} (1) by H
and 13CNMR spectroscopy (Figs. 2, 3). The experiments were carried out in
DMSO-d6 as solvent and they can be compared with the spectra of the starting
materials imidazole and methanetricarbonitrile (see SI, Figs. S1–S4). Regarding the
1HNMR spectrum (Fig. 2), catalyst 1 showed two singlets (7.62 and 7.00 ppm),
corresponding to the aromatic protons of the imidazolium ring, and a broad singlet
at 11.94 ppm from the most acidic NH protons of the nanostructured molten salt
(NMS) catalyst (Fig. 2).
On the other hand, the 13CNMR (100 MHz, DMSO-d6) spectrum of 1 (Fig. 3)
showed two absorption resonances at 166.4 and 69.6 ppm corresponding to the
C(CN)3 group. As expected, the absorption resonance peak of the deprotonated
carbon had been shifted upfield from the reference value (77.9 ppm) of the starting
methanetricarbonitrile (see SI, S2). Finally, two absorption resonances at 135.6 and
122.3 ppm were detected corresponding to the aromatic carbons of the imidazolium
ring.
To determine the morphology and size of the nanostructured {[HIMI]C(CN)3}
(1) catalyst, SEM and HRTEM were studied. This image of the nanostructured
{[HIMI]C(CN)3} (1) catalyst shows that the average size of these particles is about
63 nm (Fig. 4). HRTEM analysis was completed via selected area electron
diffraction (SAED) patterns (Fig. 4b) to study the material’s crystalline nature.
Fig. 1 IR spectrum of tricyanomethane (a), imidazole (b) and {[HIMI]C(CN)3} (1) (c)
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M. A. Zolfigol et al.
Fig. 2 1H NMR spectrum (400 MHz, DMSO-d6) of {[HIMI]C(CN)3} (1)
The most distinguished SAED ring pattern was confirmed by the XRD results and
confirmed the nano-crystalline scale nature of the synthesized NMS catalyst.
Application of {[HIMI]C(CN)3} (1) as a NMS catalyst in the one-pot three-
component synthesis of 2-amino-7-methyl-5-oxo-4-aryl-4,5-
dihydropyrano[4,3-b]pyran-3-carbonitriles (5)
To start the study, the condensation of benzaldehyde 2a with malononitrile 3 and 4-
hydroxy-6-methyl-2H-pyran-2-one 4 using {[HIMI]C(CN)3} 1 as a NMS catalyst
was examined as the reaction model for the optimization (Table 1). First, as
depicted in entry 1, we demonstrated that, under neat and catalyst-free conditions,
the product was produced in trace amounts at room temperature after 6 h.
Interestingly, when increasing the temperature to 50 °C, the reaction preceded
smoothly affording (5a) in a 43% yield after 6 h. Then, the reaction was performed
using 2 mol% of 1 as the catalyst (entry 3), conditions that gratifyingly afforded 5a
in a 92% yield after only 10 min. No improvements were identified in the yield of
the reaction by using lower catalyst loadings (entry 5) or different temperatures
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1H-imidazol-3-ium tricyanomethanide {[HIM]C(CN)3} as a…
Fig. 3 13C NMR spectrum (100 MHz, DMSO-d6) of {[HIMI]C(CN)3} (1)
(entries 6 and 7). The reaction was also studied in the presence of different solvents
in order to compare the effect of this parameter on the process. Thus, the reaction of
benzaldehyde, 4-hydroxy-6-methyl-2H-pyran-2-one, and malononitrile in the pres-
ence of 2 mol% of NMS and different solvents (H2O, EtOH, MeCN, EtOAc, and n-
hexane) was investigated at 50 °C. The obtained results, which are summarized in
Table 1, pointed to the neat conditions as the best choice in this process.
After identifying the optimized reaction conditions [1 (2 mol%), neat conditions
at 50 °C], we investigated the scope of the process by performing the reaction of
several aldehydes, (2b–p), with malononitrile and 4-hydroxy-6-methyl-2H-pyran-2-
one (Table 2). Structurally different aromatic aldehydes with various electron-
donating and electron-withdrawing substituents efficiently reacted with 4-hydroxy-
6-methyl-2H-pyran-2-one and malononitrile under the optimized conditions. As
shown in Table 2, a series of aromatic aldehydes underwent electrophilic
substitution with malononitrile and 4-hydroxy-6-methyl-2H-pyran-2-one to give a
wide range of 2-amino-7-methyl-5-oxo-4-aryl-4,5-dihydropyrano[4,3-b]pyran-3-
carbonitriles 5 in good to excellent yields. As shown, the nature and electronic
properties of the substituents on the aromatic ring of the aldehydes did not affect the
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M. A. Zolfigol et al.
Fig. 4 Scanning electron microscopy (SEM) (a), electron diffraction (SAED) patterns (b) and
transmission electron microscopy (HRTEM) (c, d) of 1
reaction yield, although electron-poor aromatic aldehydes reacted faster than
electron-rich electrophiles.
A suggested mechanism for the synthesis of the 2-amino-7-methyl-5-oxo-4-aryl-
4,5-dihydropyrano[4,3-b]pyran-3-carbonitriles via one-pot three-component domino
Knoevenagel condensation/6p-electron is shown in Scheme 3 [15–26]. Initially,
{[HIMI]C(CN)3} 1, as a NMS catalyst, activates the carbonyl group of the aromatic
aldehyde 2 to give intermediate 6 and tautomerizes malononitrile. The Knoevenagel
condensation between intermediates 6 and 7 forms the arylidene malononitrile 8.
Next, 4-hydroxy-6-methyl-2H-pyran-2-one 4 performs a conjugate addition over 8
providing adduct 9, which is further tautomerized by 1 to produce intermediate 10.
Intramolecular cyclization of this compound affords 11, which suffers a tautomer-
ization process promoted by 1 to provide the corresponding fully aromatized
2-amino-7-methyl-5-oxo-4-aryl-4,5-dihydropyrano[4,3-b]pyran-3-carbonitrile 5.
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1H-imidazol-3-ium tricyanomethanide {[HIM]C(CN)3} as a…
Table 1 Optimization of reaction conditions
Entry Solvent
Catalyst loading
(mol%)
Temperature
(°C)
Time
(min)
Isolated yield of 5a (%)
1
–
–
r.t.
50
50
50
50
r.t.
70
50
50
50
50
50
360
360
10
Trace
43
2
–
–
3
–
2
92
4
–
1
20
87
5
–
0.5
2
60
83
6
–
60
Trace
92
7
–
2
10
8
H2O
EtOH
MeCN
EtOAc
n-
2
20
91
9
2
20
87
10
11
12
2
30
87
2
60
81
2
120
63
Hexane
Reaction conditions: benzaldehyde (2a, 1.0 mmol, 106 mg), malononitrile (3, 1.0 mmol, 66 mg), 4-
hydroxy-6-methyl-2H-pyran-2-one (4, 1.0 mmol, 126 mg). The optimum reaction conditions (entry 3) are
shown in bold
Reusability of {[HIMI]C(CN)3} 1 as a NMS catalyst was confirmed in the
condensation of 4-chlorobenzaldehyde 2j, malononitrile 3, and 4-hydroxy-6-
methyl-2H-pyran-2-one 4. Thus, once the reaction was finished, ethyl acetate was
added to the reaction 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 catalyst remained in the aqueous phase.
The recovered catalyst could be reused, within the limits of the experimental errors,
for seven continuous runs (Fig. 5). Furthermore, the reaction could be scaled up to
10.0 mmol of 4-chlorobenzaldehyde 2j, malononitrile 3 and 4-hydroxy-6-methyl-
2H-pyran-2-one 4, and in the presence of 20 mol% of {[HIMI]C(CN)3} 1 catalyst at
50 °C to afford compound 5j in a 94% yield after 10 min.
Conclusions
In summary, an efficient, green, and recyclable nanostructured molten salt catalyst,
namely 1H-imidazol-3-ium tricyanomethanide {[HIMI]C(CN)3} 1, was designed,
synthesized, and characterized, and its catalytic application was investigated in the
one-pot three-component synthesis of 2-amino-7-methyl-5-oxo-4-aryl-4,5-dihy-
dropyrano[4,3-b]pyran 3-carbonitriles via domino Knoevenagel condensation under
neat conditions at 50 °C. Compound 1, as a NMS catalyst, was fully characterized
and analyzed by FT-IR, 1H NMR, 13C NMR, mass spectrometry, TGA, DTG, DTA,
XRD, SEM, and HRTEM analyses. The proposed mechanism showed that the
buffer ability of {[HIMI]C(CN)3} possibly plays an important and dual catalytic
role in the defined reaction. Finally, the main advantages of the offered procedure
123

M. A. Zolfigol et al.
Table 2 Scope of domino Knoevenagel condensation
5b
5c
16 min., 90%
White solid
M.p: 212-214, [202-
205]6
20 min., 87%
5a
5d
White solid
10 min., 92%
15 min., 90%
White solid
M.p: 233-235
M.p: 207-209 [224-
White solid
225]6
M.p: 250-252, [234-236]6
5g
12 min., 90%
Cream solid
M.p: 217-219, [215-
218]6
5h
5f
5e
12 min., 93%
10 min., 92%
White solid
M.p: 230-232
25 min., 80%
White solid
Yellow solid
M.p: 232-234 [238-240]5
M.p: 144-146 [202-204]6
5k
5j
5l
5i
14 min., 91%
White solid
M.p: 262-264 [270-
271]5
10 min, 94%
White solid
M.p: 220-222, [231-
232]5
11 min., 94%
White solid
M.p: 212-215 [223-
225]5
12 min., 90%
White solid
M.p: 229-231, [234-235]5
123

1H-imidazol-3-ium tricyanomethanide {[HIM]C(CN)3} as a…
Table 2 continued
5o
5n
5m
5p
11 min., 91%
White solid
12 min., 92%
White solid
238-240
15 min., 92%
20 min., 91%
White solid
Cream solid
M.p: 231-233 [221-
223]13
M.p: 258-260 [217-219]13
M.p: >300 [256-258]13
Reaction conditions: ArCHO (1.0 mmol), malononitrile (1.0 mmol, 66 mg), 4-hydroxy-6-methyl-2H-
pyran-2-one (1.0 mmol, 126 mg), 1 (2 mol%, 3.2 mg). Isolated yield. M.p reported in SI unit (°C)
Fig. 5 Reusability study of 1 in the reaction of 4-chlorobenzaldehyde 2j, malononitrile 3, and 4-
hydroxy-6-methyl-2H-pyran-2-one 4
and/or study are the reasonably low cost, high yield, short reaction time, simple
work-up, recoverability, and reusability of the catalyst, and a cleaner reaction
profile, being in consequence in close agreement with green chemistry disciplines.
123

M. A. Zolfigol et al.
H
N
CN
H
N
N
N
O
H
NC
N
H
CN
C(CN)3
N
O
H
H
C(CN)3
R
H
H
R
2
N
H
N
6
3
7
C
N
H
HN
H
N
N
N
Kn
con
oev
ena
gel
NC
NC
Michael
addition
N
den
sat
NC
NC
ion
CN
O
CN
R
N
H
H
N
H
O
O
H3C
O
R
N
N
9
H3C
O
O
8
4
R
O
CN
NC
O
R
N
N
R
CN
O
N
O
H
O
H
N
N
O
NMS cat.
H3C
NH2
Cyclization
O
5
H3C
O
NH
H3C
O
H
11
N
10
Scheme 3 Proposed mechanism for the synthesis of 2-amino-7-methyl-5-oxo-4-aryl-4,5-
dihydropyrano[4,3-b]pyran-3-carbonitriles 5 by {[HIMI]C(CN)3} 1 as a NMS catalyst
Acknowledgements We thank Bu-Ali Sina University, Iran National Science Foundation (INSF) (Grant
of Allameh Tabataba’i’s Award, Grant Number BN093), National Elites Foundation, University of
´
Alicante (VIGROB-173), and the Spanish Ministerio de Economıay Competitividad (CTQ2015-66624-P)
for financial support to our research groups.
References
1. A. Domling, Chem. Rev. 106, 17 (2006)
2. A. Domling, I. Ugi, Angew. Chem. Int. Ed. 39, 3168 (2000)
3. J. Zhu, H. Bienayme, Multicomponent Reactions (Wiley, Weinheim, 2005)
4. D.M. D’Souza, T.J.J. Mueller, Chem. Soc. Rev. 36, 3169 (2007)
5. D. Tejedor, F. Garcia-Tellado, Chem. Soc. Rev. 36, 484 (2007)
6. N.R. Candeias, F. Montalbano, P.M.S.D. Cal, P.M.P. Gois, Chem. Rev. 110, 6169 (2010)
7. K. Wang, D. Kim, A. Domling, J. Comb. Chem. 12, 111 (2010)
8. L.F. Tietze, Domino Reactions: Concepts for Efficient Organic Synthesis (Wiley, Weinheim, 2004)
¨
9. A. Domling, W. Wang, K. Wang, Chem. Rev. 112, 3083 (2012)
10. P. Slobbe, E. Ruijter, R.V.A. Orru, MedChemComm 3, 1189 (2012)
11. T.J.J. Muller, Science of Synthesis: Multicomponent Reactions (Georg Thieme, Stuttgart, 2014)
12. S. Wang, G.W.A. Milne, X. Yang, I.J. Posey, M.C. Nicklaus, L. Graham, W.G. Rice, J. Med. Chem.
39, 2047 (1996)
123

1H-imidazol-3-ium tricyanomethanide {[HIM]C(CN)3} as a…
13. A. Mazumder, S. Wang, N. Neamati, M. Niclaus, S. Sunder, J. Chen, G.W.A. Milne, W.G. Rice,
J.T.R. Burke, Y. Pommier, J. Med. Chem. 39, 2472 (1996)
14. L. Pochet, C. Doucet, M. Schynts, N. Thierry, N. Bogetto, B. Pirotte, K.Y. Jiang, B. Masereel, P.
Tullio, J. Delarge, M. Reboud-Ravaux, J. Med. Chem. 39, 2579 (1996)
15. X.S. Wang, J.X. Zhou, Z.S. Zeng, Y.L. Li, D.Q. Shi, S.J. Tu, ARKIVOC xi, 107 (2006)
16. D. Rajguru, B.S. Keshwal, S. Jain, V.W. Bhagwat, Monatsh. Chem. 144, 1411 (2013)
17. H. Leutbecher, L.A.D. Williams, H. Rosner, U. Beifuss, Bioorg. Med. Chem. Lett. 17, 978 (2007)
18. E. Mosaddegh, A. Hassankhani, H. Karimi-Maleh, Mater. Sci. Eng. C 46, 264 (2015)
19. M. Ghashang, S.S. Mansoor, K. Aswin, Chin. J. Catal. 35, 127 (2014)
20. E. Mosaddegh, A. Hassankhani, Chin. J. Catal. 35, 351 (2014)
21. M.N. Elinson, R.F. Nasybullin, G.I. Nikishin, Electrocatalysis 4, 56 (2013)
22. Z. Hossaini, F. Sheikholeslami-Farahani, S. Soltani, S.Z. Sayyed-Alangi, H. Sajjadi-Ghotabadi,
Chem. Heterocycl. Compd. 51, 26 (2015)
23. N.G. Khaligh, S.B.A. Hamid, Chin. J. Catal. 36, 728 (2015)
24. E.V. Stoyanova, I.C. Ivanova, D. Heber, Molecules 5, 19 (2000)
25. D. Rajguru, B.S. Keshwal, S. Jain, Chin. Chem. Lett. 24, 1033 (2013)
26. N.G. Khaligh, Monatsh. Chem. 145, 1643 (2014)
27. M. Deetlefs, K.R. Seddon, Chim. Oggi 24, 16 (2006)
28. M.J. Earle, J.M.S.S. Esperanca, M.A. Gilea, J.N. Canongia Lopes, L.P.N. Rebelo, J.W. Magee, K.R.
Seddon, J.A. Widegren, Nature 439, 831 (2006)
29. M. Kosmulski, J. Gustafsson, J.B. Rosenholm, Thermochim. Acta 412, 47 (2004)
30. P. Wasserscheid, T. Welton, Ionic Liquids in Synthesis (Wiley, Weinheim, 2003)
31. P. Wasserscheid, W. Keim, Angew. Chem. Int. Ed. 39, 3773 (2000)
32. M.A. Zolfigol, A. Khazaei, A.R. Moosavi-Zare, A. Zare, H.G. Kruger, Z. Asgari, V. Khakyzadeh, K.
Rostami, J. Org. Chem. 77, 3640 (2012)
33. M.A. Zolfigol, A. Khazaei, A.R. Moosavi-Zare, A. Zare, H.G. Kruger, Z. Asgari, V. Khakyzadeh, A.
Hasaninejad, J. Ind. Eng. Chem. 19, 721 (2013)
34. M.A. Zolfigol, H. Vahedi, S. Azimi, A.R. Moosavi-Zare, Synlett 24, 1113 (2013)
35. A.R. Moosavi-Zare, M.A. Zolfigol, O. Khaledian, V. Khakyzadeh, M.D. Farahani, H.G. Kruger, New
J. Chem. 38, 2342 (2014)
¨
36. A.R. Moosavi-Zare, M.A. Zolfigol, V. Khakyzadeh, C. Bottcher, M.H. Beyzavi, A. Zare, A. Hasa-
ninejad, R. Luque, J. Mater. Chem. A 2, 770 (2014)
37. M.A. Zolfigol, S. Baghery, A.R. Moosavi-Zare, S.M. Vahdat, RSC Adv. 5, 32933 (2015)
38. M.A. Zolfigol, S. Baghery, A.R. Moosavi-Zare, S.M. Vahdat, H. Alinezhad, M. Norouzi, RSC Adv.
5, 45027 (2015)
39. M.A. Zolfigol, S. Baghery, A.R. Moosavi-Zare, S.M. Vahdat, H. Alinezhad, M. Norouzi, RSC Adv.
4, 57662 (2014)
40. M.A. Zolfigol, F. Afsharnadery, S. Baghery, S. Salehzadeh, F. Maleki, RSC Adv. 5, 75555 (2015)
41. M.A. Zolfigol, S. Baghery, A.R. Moosavi-Zare, S.M. Vahdat, J. Mol. Catal. A Chem. 409, 216 (2015)
42. H. Sharghi, A. Khoshnood, M.M. Doroodmand, R. Khalifeh, J. Heterocycl. Chem. 53, 164 (2016)
43. M.A. Zolfigol, M. Yarie, RSC Adv. 5, 103617 (2015)
44. M.A. Zolfigol, M. Kiafar, M. Yarie, A.A. Taherpour, M. Saeidi-Rad, RSC Adv. 6, 50100 (2016)
45. M. Yarie, M.A. Zolfigol, Y. Bayat, A. Asgari, D.A. Alonso, A. Khoshnood, RSC Adv. 6, 82842
(2016)
46. M.A. Zolfigol, M. Yarie, S. Baghery, J. Mol. Liq. 222, 923 (2016)
47. M.A. Zolfigol, M. Yarie, S. Baghery, Synlett 27, 1418 (2016)
123