3,6-Dioxaoctamethylenediamminium trifluoromethanesulfonate [3,6-DOMDA]OTf as a novel ionic liquid catalyst for the synthesis of functionalized 1,4-dihydropyridines

Article abstract of DOI:10.1016/j.molliq.2017.02.073

In this research [3,6-DOMDA]OTf as a novel ionic liquid was synthesized and fully characterized by Fourier transform infrared (FT-IR), nuclear magnetic resonance (¹H NMR, ¹³C NMR, ¹⁹F NMR), Mass spectrometry, Thermal gravi

Full text of DOI:10.1016/j.molliq.2017.02.073

Accepted Manuscript
3,6-Dioxaoctamethylenediamminium trifluoromethanesulfonate
[3,6-DOMDA]OTf as a novel ionic liquid catalyst for the
synthesis of functionalized 1,4-dihydropyridines
Saeed Baghery, Mohammad Ali Zolfigol
PII:
DOI:
Reference:
S0167-7322(16)33775-8
doi: 10.1016/j.molliq.2017.02.073
MOLLIQ 6986
To appear in:
Journal of Molecular Liquids
Received date:
Revised date:
Accepted date:
25 November 2016
12 February 2017
18 February 2017
Please cite this article as: Saeed Baghery, Mohammad Ali Zolfigol
,
3,6-Dioxaoctamethylenediamminium trifluoromethanesulfonate [3,6-DOMDA]OTf as a
novel ionic liquid catalyst for the synthesis of functionalized 1,4-dihydropyridines. The
address for the corresponding author was captured as affiliation for all authors. Please
check if appropriate. Molliq(2017), doi: 10.1016/j.molliq.2017.02.073
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ACCEPTED MANUSCRIPT
3,6-Dioxaoctamethylenediamminium
trifluoromethanesulfonate
[3,6-
DOMDA]OTf as a novel ionic liquid catalyst for the synthesis of
functionalized 1,4-dihydropyridines
Saeed Baghery and Mohammad Ali Zolfigol*
Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan 6517838683, Iran
*Corresponding Author: Fax: +98 8138380709; Tel: +98 8138282807.
E-mail: zolfi@basu.ac.ir and mzolfigol@yahoo.com (M.A. Zolfigol).
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Abstract: In this research [3,6-DOMDA]OTf as a novel ionic liquid was synthesized and fully
13
characterized by Fourier transform infrared (FT-IR), nuclear magnetic resonance (1H NMR, C
NMR, 19F NMR), Mass spectrometry, Thermal gravimetric (TG), Derivative thermal gravimetric
(DTG) and Differential thermal analysis (DTA). Described [3,6-DOMDA]OTf was used as a
novel ionic liquid catalyst for the domino one-pot four-component synthesis of functionalized
1,4-dihydropyridine derivatives by a combination of various aldehydes, malononitrile,
o
acetylenedicarboxylates and anilines under solvent-free condition at 50 C. [3,6-DOMDA]OTf
catalyst with etheric bonds can be recovered and reused up to six times without significant loss
of activity. The mentioned compounds were synthesized in high to excellent yields, short
reaction time and their products could be easily separated.
Keywords: 3,6-Dioxaoctamethylenediamminium trifluoromethanesulfonate [3,6-DOMDA]OTf;
Functionalized 1,4-dihydropyridines; Catalysis; Ionic liquid; Solvent-free condition.
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1.
Introduction
Nowadays, multicomponent reactions (MCRs) are known as a significant tool for the
production of densely functionalized buildings from commercially available starting materials
[1]. Among the reaction conditions, the nature of catalyst is more effective in determining yield,
selectivity, temperature, solvents and etc. Thus, the improvement in mildness, recyclability, cost
efficiency, surface area of catalysts for MCRs will remain a task and a matter of more research
groups’ interest [2].
In a Huisgen 1,4-dipolar addition, the intermediate is prepared in situ via the addition of
nitrogen heterocycles to electron-deficient alkynes and reacted with various dipolarophilic
reagents leading to a wide range of heterocyclic compounds [3,4]. Numerous reports prove the
synthesis of highly functionalized structures using zwitterions produced from nitrogen
heterocycles and activated alkynes [5]. As an example, substituted 1,4-dihydropyridine
derivatives (1,4-DHP) are considered as ‘distinguished scaffold’ because their bio-activity,
various pharmaceutical abilities are known in pharmacology as calcium channel blockers and
have been used as cardiovascular agents for the treatment of hypertension [6]. Moreover, 1,4-
DHPs are also found valuable for other biological activities such as antiviral [7], antioxidant [8],
anti-tumor [9] and anticancer activities [10]. Several processes and catalysts were reported for
the synthesis of 1,4-DHPs such as Sm/ZrO2 [11], NEt3 [12], PEG-400 [13], KF/Al2O3 [14],
NaOH [15], piperidine [16], SDS [17], L-proline [18], sulfated boric acid-functionalized MNPs
[19] and etc. Since, 1,4-DHPs are good candidates for drug components, their synthesis and
applications has been extensively reviewed [20]. One of the most important feature of 1,4-DHPs
is the application of a Hantzsch ester as NAD(P)H analogue for the catalytic hydrogenation of
inactivated aldehydes [21,22], and 1,2,4-triazolinediones [23] as a reducing agent (Fig. 1). Thus,
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knowledge based design and syntheses of target molecules with dihydropyridine moieties for the
development of biomimetic reactions and their mechanisms are our main research interest [24].
Fig. 1. NADH and some typical synthesized 1,4-DHPs analogues.
Room temperature ionic liquids (RTILs) have been studied as potential green alternatives
to conventional volatile organic solvents. Ionic liquids (ILs) are defined as salt with melting
point below the boiling point of water. Ionic liquids are identified by several different names like
designer solvents, neoteric solvents, ionic fluids and molten salts. Most of the ionic liquids are
composed of organic cation and inorganic anions [25]. Ionic liquids have great potential for
developing catalytic technologies. Catalytic reactions in ionic liquids have been studied; for
example, the first report of the use of an IL as a catalyst in Friedel Crafts acylation was reported
in 1986 [26]. A number of reviews cover the area of ILs in general, for example [27].
As a part of our continual study on the synthesis of 1,4-DHPs [28], herein, we wish to
report a convenient method for the synthesis of functionalized 1,4-dihydropyridine derivatives
via a domino one-pot four-component reaction by using 3,6-dioxaoctamethylenediamminium
trifluoromethanesulfonate [3,6-DOMDA]OTf as a novel ionic liquid catalyst. A good range of
1,4-DHPs were prepared via condensation of various aldehydes, malononitrile,
acetylenedicarboxylates and anilines under solvent-free condition at 50 oC (Scheme 1).
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O
NH2
S
F3C
+
O
O
Solvent-free
0-5 oC to r.t., 30 min
OH
O
H2N
O
S
H2
N
O
H
F3C
O
H
CF3
O
O
S
O
O
O
N
H2
3,6-Dioxaoctamethylenediamminium trifluoromethanesulfonate
[3,6-DOMDA]OTf
1
N
R''O2C
R''O2C
O
2
[3,6-DOMDA]OTf (1 mol%)
Solvent-free, 50 o
N
+
R
R
H
4
C
R''O2C
N
H2N
N
3
NH2
CO2R''
5
R'
R'
R'' = Me or Et
R' = H, Me, Cl, Br
Scheme 1. A domino one-pot four-component synthesis of functionalized 1,4-dihydropyridine derivatives using 3,6-
dioxaoctamethylenediamminium trifluoromethanesulfonate [3,6-DOMDA]OTf as a novel ionic liquid catalyst.
2.
2.1. General information.
All chemicals and solvents were purchased from Merck, Fluka and Sigma-Aldrich. All
Experimental
reagents were used without any further purification. TLC was performed on UV-active
aluminium-backed silica gel plates F254. Melting points were measured with a thermo scientific
apparatus and are uncorrected. FT-IR spectra were recorded with a Bruker spectrophotometer in
1
13
19
KBr pellets. H NMR, C NMR and F NMR spectra were achieved by a Bruker DRX-400
spectrometer at 400, 100 and 376 MHz, respectively via TMS as an internal standard in DMSO-
d6. The mass spectra were recorded on MS Model: 5975C VL MSD with Tripe-Axis Detector.
TGA was carried out with a Perkin–Elmer TGA at a heating rate of 10 °C min-1 from room
temperature to 600 °C.
2.2. General procedure for the synthesis of 3,6-dioxaoctamethylenediamminium
trifluoromethanesulfonate [3,6-DOMDA]OTf as a novel ionic liquid catalyst.
3,6-Dioxaoctamethylenediamine (3 mmol; 0.445 g; 0.438 mL) was charged in a round
bottom flask, which was equipped with a magnetic stirring and condenser. Then
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trifluoromethanesulfonic acid (6 mmol; 0.901 g; 0.530 mL) was added slowly over a period of 5
o
minutes while stirring and cooling to maintain the temperature at 0-5 C. In the next step, the
reaction mixture was stirred for an additional period of 25 minutes at room temperature. The
attained yellow viscous liquid was washed and decanted repeatedly with diethyl ether to remove
o
any unreacted starting materials and achieve high purity, and then dried under vacuum at 50 C
1
13
for 60 minutes. [3,6-DOMDA]OTf was known via FT-IR, H NMR, C NMR, 19F NMR, mass,
TG, DTG and DTA (Scheme 1).
3,6-Dioxaoctamethylenediamminium trifluoromethanesulfonate [3,6-DOMDA]OTf:
Yellow viscous liquid; Yield: 98% (1.318 g); IR (KBr): υ 3554, 3260, 3202, 3166, 3010, 2917,
1762, 1628, 1509, 1298, 1185, 1148, 1039, 767, 648, 524 cm-1; 1H NMR (400 MHz, DMSO-d6):
δppm 7.67 (s, 3H, ―NH), 6.19 (s, 2H, ―CH2), 3.57 (t, J = 12.0 Hz, 2H, ―CH2), 2.98 (m, 2H,
13
19
―CH2); C NMR (100 MHz, DMSO-d6): δppm 66.9, 69.8, 84.9, 116.1, 119.3, 122.5, 125.7; F
NMR (376 MHz, DMSO-d6): δppm -79.77; MS: m/z = 448.35 [M]+.
2.3. General procedure for the domino one-pot four-component synthesis of functionalized
1,4-dihydropyridines using [3,6-DOMDA]OTf.
3,6-Dioxaoctamethylenediamminium trifluoromethanesulfonate [3,6-DOMDA]OTf as a
novel IL catalyst (1 mol%; 0.0045 g) was added to a mixture of numerous aldehydes (1 mmol),
malononitrile (1 mmol; 0.066 g), acetylenedicarboxylates (1 mmol) and anilines (1 mmol) under
o
solvent-free condition at 50 C for an appropriate time. After completion of the reaction which
was checked by TLC (n-hexane/ethyl acetate: 5/2), the resulting mixture was washed with water
(10 mL) and filtered to separate catalyst from other materials (the reaction mixture was insoluble
in water and catalyst was soluble in water). The water was removed and the crude product was
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purified by recrystallization from ethanol/water (5:1) to yield pure products (the spectral data
analyses for compounds refer to supplementary data).
3.
Results and discussion
The aims of this research are design, synthesis and application of novel ionic liquids
(ILs) based on cationic core with etherical bonds. The synthesized novel IL is fully
1
characterized by using advanced spectroscopic instruments such as, FT-IR, H NMR, 13C
19
NMR, F NMR, Mass spectrometry, TG, DTG and DTA. The described IL is eco-friendly
and a benign solvent and catalyst because metal free reagents and catalysis have played a
major role in preventing pollution in our environment. It is obvious that the recyclability and
reusability should be considered in the course of design and synthesis of target IL. Finally
the full characterized IL was applied in the synthesis of 1,4-dihydropyridine derivatives.
3.1. Characterization of 3,6-dioxaoctamethylenediamminium trifluoromethanesulfonate [3,6-
DOMDA]OTf as a novel ionic liquid catalyst.
In the FT-IR spectrum of [3,6-DOMDA]OTf as an IL catalyst the absorption bonds at
1298 cm-1 and 1185 cm-1 are linked to vibrational modes of O–SO2 bonds on triflate counter ion.
Furthermore, the known peak at 1039 cm−1 is related to S=O bond vibration on triflate counter
ion. Also, the identified peaks at 3554 cm−1, 3260 cm−1 and 3202 cm−1 are assigned to N–H
stretching of –NH3 groups on 3,6-dioxaoctamethylenediamminium cation. The changes in FT-IR
spectrum of [3,6-DOMDA]OTf in comparison with 3,6-dioxaoctamethylenediamine is a
confirmation of IL catalyst being produced (Fig. S67).
1
The H NMR spectrum of the [3,6-DOMDA]OTf as a IL catalyst displays two singlet at
7.67 ppm that can be assigned to –+NH3 groups on 3,6-dioxaoctamethylenediamminium cation
and at 6.19 ppm may be related to –OCH2CH2O– group on 3,6-dioxaoctamethylenediamminium
7

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cation (Fig. S68). Also, the triplet at 3.57 ppm can be linked to –OCH2 group on 3,6-
dioxaoctamethylenediamminium cation. Additionally, the multiplet at 2.98 ppm can be
connected to H3N–CH2 group on 3,6-dioxaoctamethylenediamminium cation.
13
Presence of four signals in the C NMR spectrum are in close agreement with the
structure of [3,6-DOMDA]OTf as an IL catalyst (Fig. S69). Furthermore a quartet at 125.7 to
13
19
116.1 ppm in the C NMR and a singlet at -79.77 ppm in the F NMR are linked to –CF3 on
triflate counter ion clearly confirm the protonation of 3,6-dioxaoctamethylenediamine via
trifluoromethanesulfonic acid. The substantial peaks of 13C NMR spectrum of IL catalyst at 84.0
ppm, 69.8 ppm and 66.9 ppm are linked to the –CH2 groups on 3,6-
dioxaoctamethylenediamminium cation.
The mass spectrum (EI, 70 eV) of [3,6-DOMDA]OTf as an IL catalyst is in close
accordance with the structure of the IL catalyst and presented the molecular ion peak (M+) at
448.35 m/z. Moreover, an important peak could be known at m/z 148.95, which relates to the
triflate counter ion. The 3,6-dioxaoctamethylenediamminium cation at m/z = 150.14 (Fig. S70)
could be identified too.
Figures S71 and S72 show the thermal behavior (TGA/DTG/DTA) of [3,6-DOMDA]OTf
as an IL catalyst. Thermal analysis of the [3,6-DOMDA]OTf displays two peaks (The DTA
analysis thermogram is downward therefore, decomposition of IL catalyst is endothermic)
between room temperature and 427 °C. The TGA, DTG and DTA thermal decomposition
process includes the following two steps. The first weight loss between 70 °C to nearly 110 °C is
attributed to the following dissociation. The weight loss is about 31 %. The largest weight loss
which was happened between 158 °C to nearly 427 °C is related to the second step of
dissociation of the ionic liquid. The weight loss is about 69 %. At a temperature above 427 °C,
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there is no weight loss. The weight loss is about 69 %. At a temperature above 427 °C, there is
no weight loss.
3.2. Application of [3,6-DOMDA]OTf as a novel ionic liquid catalyst in a domino one-pot
four-component synthesis of functionalized 1,4-dihydropyridines.
As mentioned above [3,6-DOMDA]OTf as a novel, efficient and reusable IL catalyst was
used for the preparation of functionalized 1,4-dihydropyridines by a domino one-pot four-
component condensation reaction of various aldehydes, malononitrile, acetylenedicarboxylates
o
and anilines under solvent-free condition at 50 C (Scheme 1). The present process not only
results in excellent yields of products but also avoids safety and financial issues of the catalyst.
In the first example, the catalytic effect of [3,6-DOMDA]OTf on the condensation
reaction of 4-chlorobenzaldehyde, malononitrile, diethyl acetylenedicarboxylate and 4-
bromoaniline under solvent-free condition was studied. After much research on the above
condensation, we found that when less than 1 mol % of IL catalyst was used, lower yields of the
corresponding product resulted (Table 1, entries 1-4), while using more than 1 mol % did not
increase the yield (Table 1, entries 8-12). In the absence of catalyst, this reaction could be
performed but the product was achieved in very low yield even after prolonged time (Table 1,
entry 1). Then, to optimize temperature, the reaction was carried out using 1 mol% of IL catalyst
under thermal solvent-free condition. As can be seen from Table 1 (entry 6), shorter reaction
time and excellent yield for the corresponding 1,4-DHP were attained at 50 oC.
Table 1. Optimizing the amount of catalyst and temperature in the reaction between 4-Chlorobenzaldehyde,
malononitrile, diethyl acetylenedicarboxylate and 4-bromoaniline in the presence of [3,6-DOMDA]OTf as an IL
catalyst under solvent-free condition.a
Entry
1
Catalyst loading (mol%)
Catalyst-free
Temperature (oC)
50
Time (min)
120
Yieldb (%)
15
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2
3
0.5
0.5
0.5
1
r.t.
50
30
20
20
20
10
10
20
10
10
10
10
31
54
54
78
96
96
78
96
96
93
91
4
100
r.t.
50
5
6
1
7
1
100
r.t.
50
8
2
9
2
10
11
12
2
100
50
5
10
50
Reaction condition: a4-Chlorobenzaldehyde (1 mmol; 0.140 g), malononitrile (1 mmol; 0.066 g), diethyl
acetylenedicarboxylate (1 mmol; 0.142 g; 0.123 mL), 4-bromoaniline (1 mmol; 0.172 g); bIsolated yield.
In order to optimize the reaction condition and evaluate the catalytic efficacy, a model
was chosen on condensation reaction between 4-chlorobenzaldehyde, malononitrile, diethyl
o
acetylenedicarboxylate and 4-bromoaniline using 1 mol% of IL catalyst at 50 C under solvent-
free condition (Table 2). Results showed that among the tested solvents such as H2O, C2H5OH,
CH3CN, CH2Cl2, CH3CO2Et, n-hexane, toluene and solvent-free system, the model reaction was
more facile and proceeded to afford highest yield under solvent-free condition (Table 2, entry 1).
Thus, solvent free condition is the best choice for running the reaction.
Table 2. Solvent effect in the reaction between 4-Chlorobenzaldehyde, malononitrile, diethyl
o
acetylenedicarboxylate and 4-bromoaniline at 50 C in the presence of 1 mol % of [3,6-DOMDA]OTf as an IL
catalyst.a
Entry
Solvent
Time (min)
Yieldb (%)
1
2
Solvent-free
H2O
10
10
96
91
10

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3
4
C2H5OH
CH3CN
10
10
20
20
30
30
93
90
83
79
57
65
5c
6
CH2Cl2
CH3CO2Et
n-Hexane
Toluene
7
8
Reaction condition: a4-Chlorobenzaldehyde (1 mmol; 0.140 g), malononitrile (1 mmol; 0.066 g), diethyl
acetylenedicarboxylate (1 mmol; 0.142 g; 0.123 mL), 4-bromoaniline (1 mmol; 0.172 g), [3,6-DOMDA]OTf (1
mol%; 0.0045 g); bIsolated yield; cReaction in CH2Cl2 as a solvent was investigated under reflux condition.
After optimization of the reaction condition, we studied the generality of this process.
Using this method, different types of aromatic aldehydes were treated with malononitrile,
acetylenedicarboxylates and anilines to produce the corresponding functionalized 1,4-
dihydropyridines in the presence of 1 mol% of [3,6-DOMDA]OTf as a novel IL catalyst under
o
solvent-free condition at 50 C (Table 3). Aromatic aldehydes with various functional groups
were subjected to the condensation reaction and the corresponding products were prepared in
good to high yields and short reaction time. As displayed in Table 3, electronic effects were
detected in these reactions. The substituted functional groups on the aryl aldehydes affected the
yield and reaction time. In comparison with electron with-drawing groups, we found that
electron-donating groups on the aryl aldehdes decreased both the reaction rate and yield of the
products. Also, dimethyl acetylenedicarboxylate took longer time than diethyl
acetylenedicarboxylate to react and afforded lower yield of corresponding products. Moreover,
4-bromoaniline took shorter time than 4-chloroaniline, 4-methyl aniline and aniline respectively
to react, and afforded higher yield of corresponding products.
Table 3. A domino one-pot four-component synthesis of functionalized 1,4-dihydropyridines using 1 mol% of [3,6-
DOMDA]OTf as a novel IL catalyst under solvent-free condition at 50 oC.a
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Entry
1
Product
M.p (oC) (color)
Time (min)
Yieldb (%)
174-176 (Red solid)
10
5
95
2
3
151-153 (Red solid)
203-205 (Red solid)
96
92
15
4
5
6
7
8
231-233 (Green solid)
178-180 (Red solid)
176-178 (Brown solid)
191-193 (Red solid)
193-195 (Red solid)
15
15
20
15
20
93
93
91
93
91
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9
237-239 (Red solid)
15
20
93
91
10
173-175 (Brown solid)
176-178 (Orange solid)
[17]
11
12
13
5
97
87
91
163-165 (Yellow solid)
[14]
30
20
185-187 (Yellow solid)
[14]
14
161-163 (Red solid) [17]
10
95
193-195 (Yellow solid)
[14]
15
16
17
20
30
10
91
87
95
143-145 (Yellow solid)
[14]
205-207 (Red solid) [17]
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215-217 (Yellow solid)
18
19
20
25
89
95
89
[13]
193-195 (Red solid)
10
25
163-165 (Yellow solid)
[15]
133-135 (Yellow solid)
[15]
21
15
93
176-178 (Yellow solid)
[17]
22
23
24
15
25
10
93
89
95
163-165 (Yellow solid)
[17]
178-180 (Yellow solid)
[17]
163-165 (Yellow solid)
[17]
25
15
93
a
Reaction condition: Aldehyde (1 mmol), malononitrile (1 mmol; 0.066 g), acetylenedicarboxylate (1 mmol),
anilines (1 mmol), [3,6-DOMDA]OTf (1 mol%; 0.0045 g); bIsolated yield.
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On the basis of our survey on the literature, a possible mechanism for the domino one-pot
four-component synthesis of functionalized 1,4-dihydropyridines using [3,6-DOMDA]OTf as an
IL catalyst has been suggested in Scheme 2 [11-18]. Firstly, aldehydes 1 undergo Knoevenagel
condensation with malononitrile 2 in the presence of IL catalyst to provide alkylidene
malononitrile 6. Anilines 4 was added to acetylenedicarboxylates 3 to give zwitterionic
intermediate 7 which undergoes Michael addition with 6 and the later via the migration of
hydrogen atom affords 8. The intramolecular addition of the amino group to the cyano triple
bond produces intermediate 9 which tautomerizes to provide 5.
Scheme 2. The probable mechanism for the domino one-pot four-component synthesis of functionalized 1,4-
dihydropyridines using [3,6-DOMDA]OTf as an IL catalyst.
In view of a greener chemistry, efficient recovery and reusability of the catalyst is very
desirable. Consequently the recyclability and reusability of [3,6-DOMDA]OTf as an IL catalyst
15

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was also studied. At the end of the reaction, the reaction mixture was cooled to room
temperature. Then, water (50 mL) was added to the mixture. The ionic liquid was dissolved in
water, and filtered for separation of the crude product. The separated product was washed twice
with water (2 × 3 mL). The water containing ionic liquid (IL is soluble in water) was evaporated
under reduced pressure and the residue liquid was recovered. The reusability of [3,6-
DOMDA]OTf was examined efficiently using 4-chlorobenzaldehyde, malononitrile, diethyl
acetylenedicarboxylate and 4-bromoaniline as model substrates in the above experimental
process. The recovered IL catalyst was reused directly for six times without any loss of its
activities (Fig. 2).
Fig. 2. Reusability investigations of the [3,6-DOMDA]OTf as an IL catalyst on the synthesis of diethyl 6-amino-1-
(4-bromophenyl)-4-(4-chlorophenyl)-5-cyano-1,4-dihydropyridine-2,3-dicarboxylate in 10 min.
To compare the efficacy of [3,6-DOMDA]OTf as an IL catalyst with other reported
catalysts for the synthesis of 1,4-dihydropyridines, we have organized the results of these
catalysts in Table 4. As Table 4 shows, [3,6-DOMDA]OTf has strangely improved the synthesis
16

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of 1,4-dihydropyridines in different terms (reaction condition, time and yield). The reaction time
was shorter and the yields were higher with our described catalyst.
Table 4. Comparison of the results in the synthesis of 1,4-dihydropyridines catalyzed by [3,6-DOMDA]OTf with
those other reported catalysts.
Entry
Reaction condition
Time (min)
Yield (%) [Ref.]
1
2
3
4
5
[3,6-DOMDA]OTf (1mol%), Solvent-free, 50 oC
PEG400 (4 mL), r.t.
30
600
600
600
5-20
87 [This work]
81 [13]
KF/Al2O3 (0.2 mmol), C2H5OH, r.t.
NaOH (10 mol%), C2H5OH, r.t.
No solvent, No catalyst, Grinding
80 [14]
78 [15]
92 [17]
6
7
[3,6-DOMDA]OTf (1mol%), Solvent-free, 50 oC
PEG400 (4 mL), r.t.
20
600
600
480
5-20
91 [This work]
80 [13]
8
KF/Al2O3 (0.2 mmol), C2H5OH, r.t.
NaOH (10 mol%), C2H5OH, r.t.
No solvent, No catalyst, Grinding
83 [14]
9
85 [15]
10
95 [17]
11
12
13
[3,6-DOMDA]OTf (1mol%), Solvent-free, 50 oC
KF/Al2O3 (0.2 mmol), C2H5OH, r.t.
NaOH (10 mol%), C2H5OH, r.t.
20
91 [This work]
86 [14]
480
480
92 [15]
17

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4.
Conclusion
In summary, we displayed that [3,6-DOMDA]OTf was a novel and efficient ionic liquid
catalyst for the domino one-pot four-component synthesis of functionalized 1,4-dihydropyridines
from commercially available substances. The structure of IL was fully characterized by
1
13
numerous techniques containing FT-IR, H NMR, C NMR, 19F NMR, mass, TGA, DTG and
DTA. The introduced process requires remarkably small amounts of green and ecofriendly IL
catalyst. Furthermore high yields, easy work-up, practicability, cost efficacy and environmentally
advantages are the benefits of this protocol. The presented [3,6-DOMDA]OTf was stable and
could be reused in six continuous runs with no substantial structural change and loss of activity.
Based on these views, it could be concluded that this cost-effective IL catalyst, with easy
experimental and work-up process, which avoids the use of large volumes of hazardous organic
solvents, makes it a valuable alternative to the previously reported procedures for the scale-up of
these three component reactions.
Acknowledgements
We thank Bu-Ali Sina University and Iran National Science Foundation (INSF) for
financial support (The Grant Number: 95831207) to our research groups.
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Graphical abstract
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Highlights
 [3,6-DOMDA]OTf as a novel ionic liquid was designed and synthesized.
 The functionalized 1,4-dihydropyridines was synthesized by [3,6-DOMDA]OTf.
 The prepared IL catalyst [3,6-DOMDA]OTf can be readily recovered.
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