Introduction of an efficient DABCO-based bis-dicationic ionic salt catalyst for the synthesis of arylidenemalononitrile, pyran and polyhydroquinoline derivatives

Article abstract of DOI:10.1016/j.molstruc.2020.127730

—An affordable DABCO-based bis-dicationic ionic salt ([(DABCO)₂C₃H₅OH]·2Cl) was utilized for the synthesis of arylidenemalononitrile, tetrahydrobenzo[b]pyran, pyrano[2,3-d]-pyrimidinone (thione), dihydropyrano[3,2-c]chrome

Full text of DOI:10.1016/j.molstruc.2020.127730

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Introduction of an efficient DABCO-based bis-dicationic ionic salt catalyst for the
synthesis of arylidenemalononitrile, pyran and polyhydroquinoline derivatives
Mehdi Zabihzadeh, Atefeh Omidi, Farhad Shirini, Hassan Tajik, Mohaddeseh
Safarpoor Nikoo Langarudi
PII:
S0022-2860(20)30054-5
DOI:
https://doi.org/10.1016/j.molstruc.2020.127730
MOLSTR 127730
Reference:
To appear in:
Journal of Molecular Structure
Received Date:
Accepted Date:
12 October 2019
13 January 2020
Please cite this article as: Mehdi Zabihzadeh, Atefeh Omidi, Farhad Shirini, Hassan Tajik,
Mohaddeseh Safarpoor Nikoo Langarudi, Introduction of an efficient DABCO-based bis-dicationic
ionic salt catalyst for the synthesis of arylidenemalononitrile, pyran and polyhydroquinoline
derivatives, Journal of Molecular Structure (2020), https://doi.org/10.1016/j.molstruc.2020.127730
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Introduction of an efficient DABCO-based bis-dicationic
ionic liquid catalyst for the synthesis of
arylidenemalononitrile, pyran and polyhydroquinoline
derivatives
Mehdi Zabihzadeh, Atefeh Omidi, Farhad Shirini*, Hassan Tajik*, Mohaddeseh
Safarpoor Nikoo Langarudi
Department of Chemistry, College of Science, University of Guilan, Rasht, 41335-19141, Iran
E-mail: shirini@guilan.ac.ir (and also fshirini@gmail.com).

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Introduction of an efficient DABCO-based bis-dicationic ionic salt
catalyst for the synthesis of arylidenemalononitrile, pyran and
polyhydroquinoline derivatives
Mehdi Zabihzadeh, Atefeh Omidi, Farhad Shirini*, Hassan Tajik*, Mohaddeseh Safarpoor
Nikoo Langarudi
Department of Chemistry, College of Science, University of Guilan, Rasht, 41335-19141, Iran
E-mail: shirini@guilan.ac.ir (and also fshirini@gmail.com).
Abstract—An affordable DABCO-based bis-dicationic ionic salt ([(DABCO)2C3H5OH]·2Cl) was utilized for the synthesis of
arylidenemalononitrile,
tetrahydrobenzo[b]pyran,
pyrano[2,3-d]-pyrimidinone
(thione),
dihydropyrano[3,2-c]chromene,
and
polyhydroquinoline derivatives. The significant features of the presented method are ease of preparation and handling of the catalyst, high
catalytic activity, short reaction times, no column chromatographic separation and simple work-up procedure. Also, the catalyst can be
recovered easily and reused for several cycles in the studied reactions.
Keywords: DABCO, Dicationic ionic salt, Knoevenagel condensation, Multi-component reactions, pyran derivatives,
polyhydroquinolines.
1. Introduction
One of the most rapidly growing areas of chemistry research is the design and development of green and economical catalytic
systems. Nowadays, ionic liquids (ILs) are accepted as appropriate green catalysts/solvents in organic synthesis. This is due to their
distinctive properties such as negligible vapor pressure, thermal and chemical stability, ease of handling, environmental friendly
nature, and ability to dissolve many organic and inorganic substances [1, 2]. Dicationic ionic liquids (DILs) are attractive new
members of ILs. These compounds contain two cationic head groups, linked by a rigid or flexible alkyl chain(s) in different lengths.
Aside from the basic properties of traditional monocationic ILs, DILs have more active sites, higher selectivity, and higher thermal
stability. Because of their unique properties, these compounds have been used as electrolytes, lubricants, and stationary phase in gas
chromatography [3, 4].
1,4-Diazabicyclo[2.2.2]octane (DABCO) is a small cage-like tertiary amine that is used as an easily available, inexpensive and non-
toxic catalyst for miscellaneous organic reactions [5, 6]. In recent years, dicationic ionic liquids based on DABCO have been
synthesized and utilized as efficacious catalysts, potent antimicrobial and antibacterial agents [7-10].
The Knoevenagel condensation is one of the most important organic reactions for C=C bond formation. The reaction occurs through
nucleophilic attack of a compound containing active methylene group to an aldehyde followed by dehydration [11]. This method is
appropriate for the preparation of various substituted electrophilic alkenes which can be utilized as versatile intermediates for many
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other types of reactions. Moreover, Knoevenagel adducts themselves exhibit a range of significant biological properties including
anti-oxidant, anti-inflammatory, and anti-cancer activities [12].
4H-Pyrans and pyran-annulated heterocyclic scaffolds have been attracted the great attention due to their diverse useful biological
and pharmacological activities such as anti-cancer [13, 14], anti-HIV [15], anti-diabetic [16], antimicrobial [17], antiviral and
antileishmanial properties [18]. They are also used as cognition-enhancing drugs for the treatment of neurodegenerative disease,
including Parkinson's disease, Schizophrenia, Alzheimer's disease, Huntington's disease and Down's syndrome [19]. Apart from
their pharmaceutical importance, pyran derivatives like 2-amino-4H-pyrans exhibit significant photochemical activities [20]. They
also utilized in pigments and cosmetics applications [21]. Some of 2-amino-3-cyano-4H-pyran derivatives which display strong
pharmacological activities are shown in figure 1.
Polyhydroquinoline (PHQ) derivatives are another important class of heterocyclic compounds that possess a variety of remarkable
pharmacological and biological properties. The derivatives of these heterocycles are known to exhibit antitumor, antitubercular,
antibacterial, and antimalarial activities [22, 23]. Also, these compounds are well known as Ca2+ channel blockers for treatment of
cardiovascular diseases [24].
Regarding notable properties of pyran and polyhydroquinoline derivatives and importance of the Knoevenagel condensation, their
reactions have been investigated in the presence of different types of catalysts including, sodium carbonate [25], Fe3O4 MNPs–
guanidine [26], silica-L-proline [27], sulfonated carbon/silica composites [28], Fe3O4@SiO2@Ni-Zn-Fe LDH [12], 1,1,3,3-
tetramethylguanidium lactate [29], MP(DNP) [30], Fe3O4@SiO2@CuO–Fe2O3 [31], Na2S/Al2O3 [32], KF-Clinoptilolite [33],
[C4(MIm)2]·2HSO4 [34] HAP–Cs2CO3 [35], and Fe3O4–cysteamine hydrochloride [36] for the promotion of the Knoevenagel
condensation, ZnFe2O4 nanopowder [37], SO42-/MCM-41[38], Fe2O3@SiO2@VB1 [39], (S)-proline [40], Urea [41],
Fe3O4@SiO2/DABCO [42], NH4VO3 [21], Nano ZnO [43], diammonium hydrogen phosphate [40], 2,2,2-trifluoroethanol [44], p-
dodecylbenzenesulfonic acid [45], Nano-sawdust-OSO3H [46], N-methylimidazole [47], Urea:ChCl [48], DABCO [49], Al-HMS-
20 [50], CaHPO4 [51], [H2-pip][H2PO4]2 [52], Fe3O4@MCM‐41@Zr‐piperazine‐MNPs [53], Fe3O4@SiO2@(CH2)3-Urea-SO3H/HCl
[54], Nano-titania Sulfuric Acid and B(OH)3 [55] for the synthesis of pyran derivatives, ED/MIL‐101(Cr) [56], L-Proline [57],
P2O5/AL2O3 [58], NS-[C4(DABCO-SO3H)2]·4Cl [23], BiBr3 [59], ChCl/urea [60], [βCD/Im](OTs)2-Silica [61], ceric ammonium
nitrate (CAN) [62], tetraethylammonium 2-(carbamoyl) benzoate [63], La3+/4A [22], FSM-16-SO3H [64], and Glycine [65] for the
synthesis of polyhydroquinoline derivatives.
Despite undeniable advantages of these methods, most of them suffer from some disadvantages like long reaction times, need to
excess amounts of reagents or catalysts, generation of a waste containing metals and transition metals, difficulties in the preparation
of the catalyst, and tedious work-up procedure. Therefore, further efforts are needed to introduce more efficient and cleaner
procedures for the synthesis of the above mentioned important target molecules.
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2. Experimental
2.1. Materials
Chemicals were purchased form Merck (Munich) and Aldrich (Mumbai) Chemical Companies and utilized without any further
purification. Products were characterized by comparison of their physical constants such as melting point, FT-IR and/or NMR
spectra with those of the authentic samples or those reported in the literature. Yields refer to the isolated products. Thin layer
chromatography (TLC) was used for determination of the purity of substrates, products and reaction monitoring over silica-gel
polygram SILG/UV 254 plates.
2.2. Characterization techniques
Melting points were determined by electro-thermal IA9100 melting point apparatus in capillary tubes. The starting temperature of
the approximate melting range was input via the keyboard and the melting point range was observed visually. FT-IR spectra were
1
recorded on a Perkin-Elmer Spectrum BX series and KBr pellets were used for solid samples. The H NMR and 13C NMR spectra
were acquired by a Bruker Ultrashield 400 MHz instrument using deuterated solvents and TMS as an internal standard. Mass
spectra were obtained with an Agilent Technologies 5975C spectrometer via a mass selective detector (MSD) operating at an
ionization potential of 70 eV.
2.3. Preparation of 1,1'-(2-hydroxypropane-1,3-diyl)bis(1,4-diazabicyclo[2.2.2]octan-1-ium) chloride {[(DABCO)2C3H5OH]·2Cl}
1, 3-Dichloro-2-propanol (0.464 mL, 5.0 mmol) was added to a mixture of DABCO (1.121 g, 10.0 mmol) in dry CH3CN (50 mL)
and stirred for 24 h under reflux conditions. After completion of the reaction the solvent was removed under vacuum, and the
obtained solid was washed with diethyl ether. After drying, [(DABCO)2C3H5OH]·2Cl was obtained as a white solid in 98 % yield.
Spectral data for [(DABCO)2C3H5OH]·2Cl: 1H NMR (400 MHz, DMSO-d6): δ (ppm) 3.04 (t, J=7.6 Hz, 12 H), 3.40-3.43 (m, 4 H),
3.44-3.51 (m, 6 H), 3.56-3.63 (m, 6H), 5.03 (sep, 1H), 7.05 (d, J=8 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 44.6, 52.7,
54.0, 66.0. FT-IR (KBr, cm−1) υmax: 3419, 2962, 2895. MS: m/e=353(M+).
2.4. General procedure for the Knoevenagel condensation of aldehydes and malononitrile
In
a
15 mL round-bottomed flask,
a
mixture of aromatic aldehyde (1 mmol), malononitrile (1.1 mmol) and
o
[(DABCO)2C3H5OH]·2Cl (10 mg, 2.8 mol%) in water (3 mL) was stirred magnetically at 85 C while the reaction progress was
monitored by TLC (n-hexane-EtOAc (7:3)). After completion of the reaction, the mixture was cooled to room temperature and
filtered off. The solid product was recrystallized from ethanol to afford the pure product.
2.5. General procedure for the synthesis of pyran derivatives
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In a 15 mL round-bottomed flask, a mixture of aromatic aldehyde (1 mmol), molononitrile (1.1 mmol), the requested C–H activated
acidic compound (1 mmol), and [(DABCO)2C3H5OH]·2Cl (10 mg, 2.8 mol%) in water (3 mL) stirred magnetically under reflux
conditions. The progress of the reaction was monitored by TLC (n-hexane-EtOAc (8:2)). After completion of the reaction, the
mixture was diluted with water (3 mL) and the solid product was decanted. Recrystallization from ethanol afforded the pure product
in high yields.
2.6. General procedure for the synthesis of polyhydroquinoline derivatives
In a 10 mL round-bottomed flask a mixture of aromatic aldehyde (1 mmol), dimedone or 1,3-cyclohexanedione (1 mmol), ethyl
acetoacetate or methyl acetoacetate (1 mmol), ammonium acetate (2 mmol) and [(DABCO)2C3H5OH]·2Cl (30 mg, 8.5 mol%) was
stirred and heated in an oil-bath at 120 oC for an appropriate period of time. After completion of the reaction (Monitored by TLC),
water was added to separate the catalyst and the crude product was separated and recrystallized from EtOH to afford the requested
product.
2.7. Spectroscopic data of the selected previously introduced and new compounds
1
2-amino-4-(2-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (Table 3, entry 3, 2c): H NMR
(500 MHz, DMSO-d6): 훿 (ppm) 0.98 (s, 3H), 1.07 (s, 3H), 2.09 (d, J=8.0 Hz, 1H), 2.27 (d, J=8.0 Hz, 1H), 2.53(s, 2H), 4.70 (s, 1H),
7.03 (s, 2H), 7.16-7.22 (m, 2H), 7.26-7.29 (m, 1H), 7.36-7.38 (m, 1H); 13C NMR (125 MHz, DMSO-d6): 훿 (ppm) 196.0, 163.6,
159.1, 119.7, 112.2, 57.3, 50.4, 40.5, 39.4, 32.3, 28.8, 27.3, 142.0, 130.4, 129.9, 128.6. FT-IR (KBr, cm-1): 3469, 2962, 2196, 1600.
White solid, m.p.= 213-215 °C.
Ethyl 4-(4-chlorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Table 4, entry 2, 5b): 1H NMR (400
MHz, CDCl3): δ (ppm) 0.948 (s, 3H, CH3), 1.086 (s, 3H, CH3), 1.219 (t, J=7.2 Hz, 3H, CH3), 2.143-2.345 (m, 4H, CH2), 2.386 (s,
3H), 4.08 (q, J = 7.2 Hz, 2H), 5.047 (s, 1H, CH), 6.5 (br, 1H, NH), 7.18 (d, J= 8.3 Hz, 2H, ArH), 7.28 (d, J = 8.2 Hz, 2H, ArH). FT-
IR (KBr, cm-1): 3284, 3212, 3075, 2948, 1698, 1611, 1481, 1377, 1227, 1079, 828. White solid, m.p.= 236-238 °C.
1
Ethyl 4-(4-methoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Table 4, entry 6, 5f): H NMR
(400 MHz, CDCl3): δ (ppm) 0.952 (s, 3H, CH3), 1.073 (s, 3H, CH3), 1.236 (t, 3H, J=7.4 Hz, CH3), 2.178-2.269 (m, 4H), 2.362 (s,
3H), 3.744 (s, 3H), 4.085 (q, 2H, J=7.4 Hz, OCH2), 5.17 (s, 1H, CH), 6.742-6.764 (d, 2H, J=8.8 Hz, ArH), 7.23 (d, 2H, J=8.8 Hz,
ArH), 7.292 (s, 1H, NH). FT-IR (KBr, cm−1): 3278, 3201, 3077, 2959, 1702, 1604, 1498, 1379, 1272, 1223, 1108, 1071, 1030, 841,
760. Pale yellow solid, m.p = 255-257 °C.
1
Ethyl 2,7,7-trimethyl-4-(4-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Table 4, entry 11, 5k): H NMR (400
MHz, CDCl3): δ (ppm) 0.920 (s, 3H, CH3), 1.092 (s, 3H, CH3), 1.199 (t, 3H, J=7.3 Hz, CH3), 2.15 (dd, 2H, CH2), 2.26 (dd, 2H,
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CH2), 2.402 (s, 6H, CH3), 4.07 (q, 2H, J=7.4 Hz, OCH2), 5.178 (s, 1H, CH), 6.718 (s, 1H, NH), 7.51 (d, 2H, J=9.4 Hz, ArH), 8.09
(d, 2H, J=9.4 Hz, ArH). FT-IR (KBr, cm−1): 3293, 3215, 3082, 2958, 1699, 1619, 1528, 1487, 1379, 1221, 1068, 698. Pale yellow
solid, m.p = 228-232 °C.
Ethyl 2-methyl-5-oxo-4-(o-tolyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Table 4, entry 13, 5m, new compound): 1H NMR
(500 MHz, DMSO-d6): δ (ppm) 1.09 (t, J=7 Hz, 3H), 1.64-1.73 (m, 1H), 1.85-1.89 (m, 1 H), 2.10-2.23 (m, 2H), 2.31 (s, 3H), 2.43-
2.51 (m, 2H), 2.64 (s, 3H), 3.93-4.01 (m, 2H), 4.99 (s, 1H), 6.91-6.96 (m, 2H), 7.02 (t, J=7.5 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 9.07
(s, 1H). 13C NMR (125 MHz, DMSO-d6): δ (ppm) 13.5, 17.8, 18.8, 20.1, 25.7, 31.8, 36.2, 58.4, 104.6, 112.2, 124.9, 125.5, 128.1,
128.5, 134.3, 143.7, 147.4, 150.4, 166.5, 194.1. FT-IR (KBr, cm-1): 3307, 2983, 2958, 1695, 1607. Lemon solid, m.p: 234–236 °C.
3. Results and Discussion
In recent years, preparation, characterization and use of ionic liquid catalysts in organic reactions have been an important part of our
ongoing research program. In this regard, a number of mono- and dicationic ionic liquids based on DABCO have been synthesized
and their catalytic activities have been studied by our research group [10, 66, 67]. In continuation of these studies, we found that
[(DABCO)2C3H5OH]·2Cl is prepared and used as an intermediate for the preparation of a new catalyst which is formulated as
[(DABCO)2C3H5OH]·2BF4. Our further investigations clarified that [(DABCO)2C3H5OH]·2Cl is also able to act as an efficient
catalyst in organic transformations by itself, which was not attended by the previous research group [8]. So, in this article in
addition to full characterization of this reagent, we wish to report its efficiency in the promotion of some multi-component reactions
leading to the synthesis of some very important organic compounds.
3.1. Characterization of the catalyst
After preparation of the [(DABCO)2C3H5OH]·2Cl (Scheme 1), various techniques were used for the characterization of this
compound.
The amount of chloride in [(DABCO)2C3H5OH]·2Cl was determined by potentiometric titration method. For this purpose, 0.1 g of
the prepared ionic salt was solved in water and the obtained solution was titrated with 0.1 M AgNO3. As shown in Figure 2, the
change happened at 4.7 mL of consumed AgNO3. On the basis of this study it can be concluded that [(DABCO)2C3H5OH]·2Cl has
2 equivalents of chloride ion per one mol of this reagent.
The FT-IR spectra of DABCO, 1,3-dichloro-2-propanol and [(DABCO)2C3H5OH]·2Cl are presented in Figure 3. The IR spectrum
of DABCO exhibits a variety of stretching and bending vibrations which were eliminated or reduced in the spectrum of the prepared
ionic salt, probably due to the limitation of vibrations in the rings. In the case of [(DABCO)2C3H5OH]·2Cl, the broad absorption
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bond centered at 3419 cm-1 is related to the presence of the hydroxyl group. The absorption bands at 2962 and 2895 cm-1 can be
attributed to the asymmetric and symmetric stretching vibrations of C–H bonds.
In the mass spectrum of [(DABCO)2C3H5OH]·2Cl, as shown in Figure 4, the molecular ion peak (M+) appeared at m/e = 353 is
equal to the molecular weight of the catalyst. Also, other peaks related to the other fragmentations can be seen in this spectrum.
1H NMR and 13C NMR spectra of [(DABCO)2C3H5OH]·2Cl are presented in Figures 5 and 6. The 1H NMR spectrum of
[(DABCO)2C3H5OH]·2Cl as a symmetric dicationic ionic salt displayed a triplet peak at 3.04 ppm for Ha, a multiplet peak at 3.44–
3.51 ppm for Hb, a multiplet peak at 3.40–3.43 ppm for Hc, a septet peak at 5.03 ppm related to the proton attached to tertiary carbon
containing hydroxyl group (Hd), and a doblet peak for He (OH). Also the 13C NMR of [(DABCO)2C3H5OH]·2Cl properly showed
four types of carbons.
3.2. Catalytic activity
The catalytic study commenced with the optimization of the two‐component Knoevenagel condensation of 4-chlorobenzaldehyde (1
mmol) and malononitrile (1.1 mmol) as a model reaction (Table 1, entries 1-13). In this reaction, the presence of the catalyst is
necessary. Preliminary trials revealed that the reaction did not proceed under solvent-free conditions and only a trace amount of the
desired product was obtained. Then, we tried to find the best solvent for the reaction. For this purpose, the reaction was tested in
green solvents, such as water and EtOH. No significant product was observed when the mixture of the reaction was refluxed in
EtOH. In contrast, when the reaction was carried out in water, the yield improved drastically and the desired product was formed in
good yield. The best result was achieved when the reaction was performed in water using 2.8 mol% of [(DABCO)2C3H5OH]·2Cl at
85 oC (Table 1, entry 12) (Scheme 2). Any further increase in the catalyst amounts or temperature did not improve the reaction time
or yield. In order to study the generality of this catalytic system, a variety of aromatic aldehydes containing electron-donating or
electron-withdrawing groups in ortho, meta and para positions of the aromatic ring were used to obtain various
arylidenemalononitriles. The results are depicted in Table 2. According to this table, all reactions proceeded smoothly producing the
products in excellent yields (89−95 %) within 8−19 min of the reaction time and no significant difference for the substituent effect
was observed. Also, the isolated products were extremely pure and there was no need for further purification or even
recrystallization.
In the next step, the efficiency of [(DABCO)2C3H5OH]·2Cl in the promotion of the one pot three-component synthesis of pyran
derivatives via the tandem Knoevenagel-Michael reaction was investigated. For this purpose and to obtain the optimum reaction
conditions, we first conducted a series of trial reactions with 4-chlorobenzaldehyde (1 mmol), malononitrile (1.1 mmol), and
dimedone (5,5-dimethyl-1,3-cyclohexanedione) (1 mmol) under a variety of conditions (Table 1, entries 14-18). As shown in Table
1 (entry 17), the best result was obtained in refluxing water using 2.8 mol% of [(DABCO)2C3H5OH]·2Cl. Higher amounts of the
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catalyst gave no further improvement. To demonstrate the scope and generality of this protocol, different types of aromatic
aldehydes and other C−H activated acidic compounds such as 4-hydroxycoumarin and (thio) barbituric acids were reacted with
malononitrile using identical reaction conditions to obtain tetrahydrobenzo[b]pyran, pyrano[2,3-d]-pyrimidinone (thiones), and
dihydropyrano[3,2-c]chromene derivatives, respectively (Scheme 3, Table 3). As indicated in Table 3, all of them reacted smoothly
during acceptable reaction times. Furthermore, pyridine-4-carbaldehyde was used as a heterocyclic aldehyde under the same
conditions, and the related dihydropyrano[3,2-c]chromene derivative was successfully obtained in high yields (Table 3, entry 24).
Encouraged by these results, we decided to use this catalyst to promote the synthesis of polyhydroquinoline derivatives. These
compounds can be synthesized according to Hantzsch condensation using aromatic aldehydes, 1,3-cyclohexanedione derivatives, β-
ketoesters, and ammonium acetate via one-pot four-components reaction. Initially, in order to determine the optimized reaction
conditions, we checked the reaction of 4-chlorobenzaldehyde (1 mmol), dimedone (1 mmol), ethyl acetoacetate (1 mmol) and
various amount of ammonium acetate as a model system in the absence and/or presence of [(DABCO)2C3H5OH]·2Cl in green
solvents (H2O, EtOH) and also under solvent-free conditions at various temperatures. A summary of the obtained results is listed in
(Table 1, entries 19-28). The results showed when the reaction was carried out in the absence of the catalyst, only a trace amount of
the desired product was formed and the reaction progress is highly affected by catalyst loading and temperature. Also, when the
reaction was carried out in the absence of solvent, high yield during a short reaction time was achieved. Finally, the best result was
o
obtained using 2 mmol of ammonium acetate and 8.5 mol% of [(DABCO)2C3H5OH]·2Cl under solvent-free conditions at 120 C
(Table 1, entry 27). Subsequently, to reveal the generality of this method, different derivatives of polyhydroquinolines were
prepared and the results were summarized in Table 4.
The results of experiments on the synthesis of pyrans and polyhydroquinoline derivatives exhibits that [(DABCO)2C3H5OH]·2Cl
can be an efficient ionic salt catalyst for the multi-component reactions.
It should be mentioned that although the conversion yields in all of the above-mentioned reactions were 100 %, a small amounts of
the products wasted through the work‐up procedure and therefore the percentage yields are less than the conversion yields. Also,
using aliphatic aldehydes in these reactions led to a mixture of products, showing that this procedure is not suitable for these
substrates.
The possibility of the recycling of [(DABCO)2C3H5OH]·2Cl was also studied at modified conditions in the synthesis of 1b, 2b, 5b.
For this purpose, after completion of the reactions (Monitored by TLC), water was added into the reaction mixtures in order to
separate the catalyst ([(DABCO)2C3H5OH]·2Cl is soluble in water). Afterwards the reaction mixtures were filtered off and the
o
filtrates were evaporated under vacuum at 70 C. The obtained white precipitates were washed with diethyl ether and reused again
for the same reaction. The obtained results are demonstrated in Figure 7.
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Plausible mechanisms for the mentioned reactions are depicted in Scheme 5. As can be seen, [(DABCO)2C3H5OH]·2Cl as a bi-
functional donor–acceptor reagent, simultaneously can activate the carbonyl group of aldehyde and the methylene groups of
malononitrile or β-dicarbonyl. Then, the activated aldehyde is attacked by the activated malononitrile or β-dicarbonyl through a
Knoevenagel condensation reaction to generate arylidenemalononitriles (intermediate a) or the intermediate b. For the synthesis of
pyran derivatives, the Michael addition of the catalyst-activated enol c and the intermediate a generates the intermediate d. Finally,
intramolecular cyclization of the intermediate d affords the desired pyran derivatives. For the synthesis of polyhydroquinolines,
conjugate addition of the enamine (e) with the intermediate b leads to the formation of polyhydroquinolines followed by cyclization.
It was essential that the catalytic ability of [(DABCO)2C3H5OH]·2Cl compare with previous methods to clarify the merit of the
catalyst. Thus, the obtained results in the synthesis of 2-(4-chlorobenzylidene)malononitrile 1b, 2‐amino‐4‐(4-
chlorophenyl)‐7,7‐dimethyl‐5‐oxo‐5,6,7,8‐tetrahydro‐4Hchromene‐3‐carbonitrile
2b,
and
ethyl
2,7,7‐trimethyl‐4‐(4‐
cholorophenyl)‐5oxo‐1,4,5,6,7,8‐hexahydroquinoline‐3‐carboxylate 5b were compared to the various types of catalysts especially
some of the DABCO-based ionic liquids (Table 5). As shown in Table 5, [DABCO)2C3H5OH]·2Cl can be proposed as a useful
catalyst in terms of the amount of the catalyst, reaction times and yields.
4. Conclusion
In this study, [(DABCO)2C3H5OH]·2Cl was prepared as an efficient, affordable, and green ionic salt catalyst by a simple
nucleophilic reaction for the one-pot synthesis of a diverse set of arylidenemalononitrile, pyran and polyhydroquinoline derivatives.
The green conditions, easy catalyst preparation, use of a commercially available and inexpensive reagents, simple separation and
recovery of the catalyst from the reaction mixture, easy work-up procedure needing no special separation methods and absence of
organic solvents, short reaction times, high purity and high yields of the products are the considerable advantages of this protocol.
Acknowledgements
We are thankful to the Research Council of the University of Guilan for the partial support of this research.
References
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OMe
OMe
Br
MeO
O
CN
CN
O
NH2
H2N
O
NH2
NH2
anticancer activity
anti-tubercular
N
N
O
O
O
CN
CN
NH2
O
O
NH2
O
antimicrobial
antibacterial
Fig. 1. Some examples of 2-amino-3-cyano-4H-pyran derivatives with pharmacological activities.
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Fig. 2. Potentiometric titration curve of [(DABCO)2C3H5OH].2Cl.
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Fig. 3. FT-IR spectra of DABCO (a), 1, 3-dichloro-2-propanol (b) and [(DABCO)2C3H5OH]·2Cl (c).
14

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Fig. 4. The mass spectrum of [(DABCO)2C3H5OH]·2Cl.
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Fig. 5. The 1H NMR spectrum of [(DABCO)2C3H5OH]·2Cl.
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Fig. 6. The 13C NMR spectrum of [(DABCO)2C3H5OH]·2Cl.
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Fig. 7. Reusability of [(DABCO)2C3H5OH]·2Cl in the synthesis of 1b, 2b and 5b.
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Cl
Cl
dry CH3CN
Cl
N
Cl
N
N
2
+
N
OH
Reflux, 24 h
N
OH
N
Scheme 1. Preparation of [(DABCO )2C3H5OH]·2Cl.
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CN
[(DABCO)2C3H5OH]·2Cl (10 mg)
H2O (3 mL), 85 oC
Ar
ArCHO
NC
CN
CN
1 a-m
Scheme 2. Synthesis of arylidenemalononitriles by [(DABCO)2C3H5OH]·2Cl.
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O
O
O
Ar
CN
2 a-h
O
O
NH2
O
Ar
HN
CN
3 i-p
HN
X
N
O
[(DABCO)2C3H5OH]·2Cl (10 mg)
H2O (reflux)
X=O, S
H
ArCHO
NC
CN
X
N
H
O
NH2
OH
O
Ar
CN
O
O
O
4 q-x
O
NH2
Scheme 3. One-pot three-component reaction of different aldehydes, malononitrile and 1,3-dicarbonyl derivatives, catalyzed by
[(DABCO)2C3H5OH]·2Cl in water.
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ArCHO
O
O
Ar
O
O
[(DABCO)2C3H5OH]·2Cl (30 mg)
solvent-free, 120 oC
OR'
OR'
R
R
O
O
N
H
R
R
R: CH3, H
R': C2H5, CH3
NH4OAc
5 a-q
Scheme 4. [(DABCO)2C3H5OH]·2Cl catalyzed the synthesis of polyhydroquinoline derivatives.
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(IL)
O
Cl
Cl
NC
NC
H
H
H
H
R
R
N
N
N
O
H
N
O
O
IL
IL
d+
O
O
O
NC
R
R
H
Ar
OR'
H
NC
O
HO
O
NH4OAc
IL
IL
H2O
H2O
Ar
O
O
O
Ar
CN
CN
OR'
R
(a)
O
H2N
IL
OH
O
R
(b)
(e)
(c)
IL
Ar
Ar
O
O
O
Ar
H
CN
N
CN
NH
IL
OR'
C
R
O
O
OH
HN
R
(d)
IL
IL
H2O
O
O
Ar
O
Ar
O
CN
OR'
R
N
H
NH2
R
Scheme 5. The plausible mechanisms of the studied reactions in the presence of [(DABCO)2C3H5OH]·2Cl.
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Table 1. Optimization of the amounts of the catalyst, temperature and solvent for the synthesis of arylidenemalononitrile
(entries 1-13), tetrahydrobenzo[b]pyran (entries 14-18) and polyhydroquinoline (entries 19-28) derivative of 4-
chlorobenzaldehyde
Entry
Catalyst (mg)
Solvent
Temp. (°C)
Time (min)
Yield (%)
1
-
Solvent-free
Solvent-free
Solvent-free
Solvent-free
C2H5OH
C2H5OH
C2H5OH
H2O
100 oC
100 oC
100 oC
100 oC
r.t.
90
90
90
90
90
90
90
120
55
10
50
8
Trace
2
10
20
50
10
10
50
10
10
10
10
10
20
10
10
10
10
20
-
Trace
3
Trace
4
Trace
5
Trace
6
Reflux
Reflux
r.t.
Trace
7
Trace
8
Not completed
100(82)[a]
100(91)[a]
100(93)[a]
100(95)[a]
100(90)[a]
Trace
9
H2O
50 oC
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
H2O
Reflux
70 oC
H2O
H2O
85 oC
H2O
85 oC
11
60
60
30
10
15
120
90
90
120
120
120
50
55
10
60
Solvent-free
C2H5OH
H2O
100 oC
Reflux
50 oC
100(85)[a]
100(75)[a]
100(95)[a]
100(95)[a]
Trace
H2O
Reflux
Reflux
100 oC
Reflux
Reflux
Reflux
Reflux
Reflux
100 oC
100 oC
120 oC
120 oC
H2O
Solvent-free
C2H5OH
H2O
-
Trace
-
Trace
10
20
10
10
30
30
-
H2O
Not completed
Not completed
Not completed
100(84)[a]
100(87)[a]
100(95)[a]
Trace
H2O
C2H5OH
Solvent-free
Solvent-free
Solvent-free
Solvent-free
28
[a]Isolated yields
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Table 2. The Knoevenagel reaction of aromatic aldehydes and malononitrile in the presence of [(DABCO)2C3H5OH]·2Cl in
water medium
Entry
Aldehyde
Pro.
Time (min)
Yield (%)[a]
Mp (oC)
[Ref.]
1
C6H5-
1a
1b
1c
1d
1e
1f
8
91
95
91
94
93
91
91
90
91
90
89
89
92
82-84
[12]
[68]
[36]
[26]
[68]
[27]
[26]
[32]
[36]
[28]
[12]
[36]
[31]
2
4-ClC6H4-
8
161-163
94-96
3
2-ClC6H4-
11
10
11
15
13
11
13
13
17
19
17
4
4-BrC6H4-
162-164
187-189
133-135
113-115
138-140
100-102
161-163
102-104
140-142
268-270
5
4-OHC6H4-
4-OH-3-CH3OC6H3-
4-CH3OC6H4-
4-CH3C6H4-
2-CH3C6H4-
4-NO2C6H4-
3-NO2C6H4-
2-NO2C6H4-
Terephthalaldehyde
6
7
1g
1h
1i
8
9
10
11
12
13
1j
1k
1l
1m
[a]The yields are related to the isolated products
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Table 3. Synthesis of pyran derivatives (tetrahydrobenzo[b]pyran (2a-h), Pyrano[2,3-d]-pyrimidinone(thione) (3i-p), and
dihydropyrano[3,2-c]chromene (4q-x)) using 2.8 mol% of [(DABCO)2C3H5OH]·2Cl in refluxing water
Entry Ar
Pro.
Time (min)
Yield (%)[a]
Mp (oC)
[Ref]
1
C6H5-
2a
2b
2c
2d
2e
2f
30
10
15
15
15
15
30
25
30
15
10
15
20
30
30
35
20
60
30
60
60
20
30
90
95
93
89
87
90
87
85
86
93
87
83
85
88
80
80
95
98
95
95
93
95
96
225-228
208-210
213-215
176-179
202-205
213-217
200-204
210-214
224-225
237-240
260-264
236-237
266-268
266-270
>300
[53]
[68]
[69]
[70]
[53]
[70]
[70]
[8]
2
4-ClC6H4-
2-ClC6H4-
4-NO2C6H4-
3-NO2C6H4-
2-NO2C6H4-
4-CH3OC6H4-
4-HOC6H4-
C6H5-
3
4
5
6
7
2g
2h
3i
8
b9
[71]
[52]
[52]
[53]
[52]
[46]
[70]
[53]
[19]
[72]
[72]
[45]
[73]
[19]
[73]
b10
b11
b12
b13
b14
C15
C16
17
18
19
20
21
22
23
4-ClC6H4-
4-FC6H4-
3j
3k
3l
4-NO2C6H4-
3-NO2C6H4-
4-CH3OC6H4-
4-ClC6H4-
4-NO2C6H4-
C6H5-
3m
3n
3o
3p
4q
4r
234-235
252-254
259-261
240-242
257-258
250-252
219-220
242-244
4-ClC6H4-
3-ClC6H4-
4-NO2C6H4-
3-NO2C6H4-
4-CH3OC6H4-
3-CH3OC6H4-
4s
4t
4u
4v
4w
Pyridine-4-
carbaldehyde
24
4x
30
95
249-251
[73]
[a] The yields are related to the isolated products [b]X=O [c]X=S
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Table 4. Synthesis of various polyhydroquinolines in the presence of [(DABCO)2C3H5OH]·2Cl
Entry
Ar
R
R'
Product
Time (min)
Yield (%)a
Mp(oC)
Ref.
1
C6H5-
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
5a
5b
5c
5d
5e
5f
14
10
15
15
12
14
10
12
8
92
95
93
90
95
93
93
90
95
87
90
90
87
85
94
91
93
222-224
236-238
252-254
232-235
227-230
255-257
200-203
192-194
229-231
210-212
228-232
228-230
234-236
206-208
257-259
198-200
>300
[23]
[74]
[23]
[57]
[63]
[74]
[23]
[57]
[57]
[75]
[76]
[63]
New
[77]
[78]
[78]
[76]
2
4-ClC6H4-
3
4-BrC6H4-
4
4-OHC6H4-
5
4-OH-3-CH3OC6H3-
4-CH3OC6H4-
3-CH3OC6H4-
3,4,5-(CH3O)3C6H2-
4-(CH3)2NC6H4-
2-CH3C6H4-
6
7
5g
5h
5i
8
9
10
11
12
13
14
15
16
17
5j
21
37
11
21
35
14
17
12
4-NO2C6H4-
5k
5l
4-OH-3-CH3OC6H3-
2-CH3C6H4-
H
5m
5n
5o
5p
5q
3-NO2C6H4-
H
4-ClC6H4-
CH3
H
4-ClC6H4-
CH3
Terephthalaldehyde
CH3
C2H5
[a] The yields are related to the isolated products.
27

Journal Pre-proof
Table 5. Comparison of the activity of [(DABCO)2C3H5OH]•2Cl with previously reported catalysts in the synthesis of 2-(4-
Chlorobenzylidene)malononitrile
chlorophenyl)‐7,7‐dimethyl‐5‐oxo‐5,6,7,8‐tetrahydro‐4Hchromene‐3‐carbonitrile
1b
(entries
1-8),
(entries
2‐amino‐4‐(4-
and ethyl
2b
9-17),
2,7,7‐trimethyl‐4‐(4‐cholorophenyl)‐5oxo‐1,4,5,6,7,8‐hexahydroquinoline‐3‐carboxylate 5b (entries 18-26).
Time
Yield
(%)a
Entry Catalyst
Amount
Conditions
Ref.
(min.)
390
30
1
2
3
4
5
6
SiO2/NH4OAc
200 mg
CH2Cl2/60 oC
CH2Cl2/reflux
CH3CN/80 oC
PEG/H2O/r.t.
H2O/r.t.
90
90
95
96
88
95
[79]
[32]
[27]
[26]
[28]
[33]
Na2S/Al2O3
20 mol% on 500mg
100 mg
Silica-L-prolin
Fe3O4 MNPs–Guanidine
CSC-Star-Glu-IL2
KF-CP
540
150
180
5 mg
200 mg
160 mg
C2H5OH /40 oC/ultrasound 20
Fe3O4@SiO2@CuO–Fe2O3
MNPs
7
8
30 mg
H2O/reflux
H2O /85 oC
7
8
91
95
[31]
This
work
[(DABCO)2C3H5OH]·2Cl
10 mg (2.8 mol%)
9
SO4 2-/MCM-41
Urea
25 mg
C2H5OH /reflux
C2H5OH:H2O (1:1)/r.t.
H2O /80 oC
60
80
87
90
92
94
95
[38]
[41]
[42]
[48]
[49]
[70]
10
11
12
13
14
10 mol%
50 mg
180
25
Fe3O4@SiO2/DABCO
Urea:ChCl
2 mL
80 oC
60
DABCO
10 mol%
50 mg
H2O/reflux
120
15
[H2-DABCO][H2PO4]2
C2H5OH:H2O (2:1)/reflux
Fe3O4@MCM‐41@Zr‐piperazi
ne‐MNPs
15
30 mg
C2H5OH:H2O (7:3)/ 75 oC 10
90
[53]
16
17
2,2,2-trifluoroethanol
DABCO
2 mL
reflux
300
95
68
[44]
[8]
20 mol%
H2O/r.t.
150
10
This
work
18
[(DABCO)2C3H5OH]·2Cl
10 mg (2.8 mol%)
H2O/reflux
95
19
20
21
22
23
24
25
26
[C4(DABCO-SO3H)2] ·4Cl
ED/MIL‐101(Cr)
L-Proline
10 mg
Solvent-free/100 oC
C2H5OH/80 oC
18
92
90
87
93
88
96
97
92
[23]
[56]
[57]
[59]
[64]
[22]
[80]
[74]
500 mg
10 mol%
2 mol%
40 mg
120
360
150
20
C2H5OH /reflux
CH3CH2OH/r.t.
C2H5OH /reflux
C2H5OH /reflux
Solvent-free/100 oC
C2H5OH /reflux
BiBr3
FSM-16-SO3H
La3+/4A
100 mg
8 mg
240
35
SBA-15@AMPD-Co
MBM-450
50 mg
40
This
work
27
[(DABCO)2C3H5OH]·2Cl
30 mg (8.5 mol%)
Solvent-free/120 oC
10
95
28