Protic pyridinium ionic liquid as a green and highly efficient catalyst for the synthesis of polyhydroquinoline derivatives via Hantzsch condensation in water

Article abstract of DOI:10.1016/j.molliq.2012.09.017

The four-component Hantzsch condensation reaction of dimedone, ethyl acetoacetate, ammonium acetate and various aromatic and aliphatic aldehydes in the presence of 2-methylpyridinium trifluoromethanesulfonate ([2-MPyH]OTf) as a green and highly efficient

Full text of DOI:10.1016/j.molliq.2012.09.017

Journal of Molecular Liquids 177 (2013) 44–48
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Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Protic pyridinium ionic liquid as a green and highly efficient catalyst for the synthesis
of polyhydroquinoline derivatives via Hantzsch condensation in water
Mahmood Tajbakhsh , Heshmatollah Alinezhad , Mohammad Norouzi a,b,⁎,
a
a
c
b
Saeed Baghery , Maryam Akbari
Department of Chemistry, Mazandaran University, Babolsar, Iran
Department of Chemistry, Payame Noor University, P.O. Box 19395-3697, Tehran, Iran
Young Researchers Club, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran
a
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 May 2012
Received in revised form 17 August 2012
Accepted 25 September 2012
Available online 4 October 2012
The four-component Hantzsch condensation reaction of dimedone, ethyl acetoacetate, ammonium acetate and
various aromatic and aliphatic aldehydes in the presence of 2-methylpyridinium trifluoromethanesulfonate
([2-MPyH]OTf) as a green and highly efficient catalyst in water affords polyhydroquinoline derivatives in good
to excellent yields. This reaction has been carried out in the presence of 1 mol% of [2-MPyH]OTf at room temper-
ature. The described novel synthesis method proposes several advantages of short reaction times, high yields,
mild condition, high melting point, simplicity and easy workup compared to the traditional method of synthesis.
Keywords:
©
2012 Elsevier B.V. All rights reserved.
2-Methylpyridinium
trifluoromethanesulfonate
Green synthesis
Hantzsch condensation
Polyhydroquinoline
Water solvent
1
. Introduction
-Substituted 1,4-dihydropyridine (1,4-DHP) nucleus is a fertile
methods such as conventional heating [10,11], L-proline [12], various
catalysts such as ammonium nitrate (CAN) [13], silica perchloric acid
4
(HClO
FeF [17], K
[21], SBA-Pr-SO
[24].
4
–SiO
2
) [14], trimethylsilyl chloride [15], nickel nanoparticle [16],
[PW11CoO40] [18], p-TSA [19], solar heat [20], hafnium (IV)
H [22], Bakers' yeast [23], iron (III) trifluoroacetate
source of biologically important molecules possessing various important
pharmacological properties such as antihypertensive, anti-therosclerotic,
hepto-protective, anti-mutagenic, vasodilator, bronchodilator, anti-
tumor, geroprotective and anti-diabetic agents. Thus, these compounds
are analogues of NADH coenzymes, which have been investigated for
their calcium channel activity and the heterocyclic rings are found in
variety of bioactive compounds [1–6]. In 1882, Arthur Hantzsch reported
first synthesis of symmetrically substituted 1,4-dihydropyridines by the
one-pot, four component condensation of two molecules of ethylaceto-
acetate, aromatic aldehyde and ammonia [7]. The standard Hantzsch pro-
cedure does not need the intervention of any additive or reagent and the
reaction was originally conducted either in acetic acid or at reflux in alco-
hol for rather long periods, resulting in low or modest yields of condensa-
tion products. Replacement of ammonia by ammonium acetate allowed
the efficient synthesis of Hantzsch compounds in aqueous medium as
well as under solvent free conditions [8,9].
3
7
3
Ionic liquids are salts consisting of ions, which exist in the liquid
state at ambient temperatures [25]. They show reasonably high ionic
conductivities. Although the first ionic liquid, ethylammonium nitrate
(m.p 12 °C) was reported as early as 1914 [26], ionic liquids have
found great interest only recently. Ionic liquids are usually character-
ized by a wide electrochemical window of stability, a reasonable ionic
conductivity (similar to most non-aqueous electrolytes). ILs typically
consist of organic nitrogen-containing heterocyclic cations and inorgan-
ic anions [25]. Nevertheless, in the last few years they have become
more attractive in other fields such as catalysis [27], formation of
metal nanostructures [28], analytical chemistry [29] including sensors
[30] and for electrochemical biosensors [31]. Due to their high polari-
ties, the ionic liquids are expected to be very suitable solvents for the re-
actions between organo-soluble and water soluble reagents. Utility of
the ionic liquids as solvents for various organic reactions [32,33] and
polymerization reactions [34–36] has been studied. Generally, ILs are
defined as those fused salts with a melting point less than 100 °C,
with salts with higher melting points referred to as molten salts. The
Realizing the importance of polyhydroquinoline derivatives in the
synthesis of various drug sources, we reported many characteristic
⁎
Corresponding author. Tel.: +98 191 3257681; fax: +98 191 3257680.
E-mail addresses: mnorouzi346@yahoo.com, mnorouzi346@pnu.ac.ir (M. Norouzi).
0167-7322/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molliq.2012.09.017

M. Tajbakhsh et al. / Journal of Molecular Liquids 177 (2013) 44–48
45
Brønsted acidic AILs have been incorporated within the organic synthe-
sis section, since that is the principal application of that compounds
37].
However, some of reported methods in the synthesis of polyhydro-
quinoline derivatives have one or more disadvantages such as moisture
sensitive, or highly toxic in environment and unpleasant experimental
procedure and reagents which are expensive. A mild and efficient cata-
lyst for the synthesis of polyhydroquinoline is very desirable. Performing
organic reactions in aqueous media has attracted much attention
because of wonderful water properties. It would be significantly safe,
cheap, non-toxic and environmentally friendly compared to organic
solvents [38].
Multi-component reactions (MCRs) have emerged as an efficient and
powerful tool in modern synthetic organic chemistry allowing the facile
creation of several new bonds in a one-pot reaction [39]. We would like
to report a highly efficient and green four-component Hantzsch conden-
sation in the presence of 2-methylpyridinium trifluoromethanesulfonate
Table 1
Hantzsch condensation synthesis of polyhydroquinoline derivatives in the presence of
2-MPyH]OTf as a catalyst.
[
[
Entry
Aldehyde
M.p (°C)
Time
Yield (%)
[Ref.]
(min)
1
2
3
4
5
6
7
8
9
Benzaldehyde
203–205
207–209
233–235
241–243
201–203
184–186
216–218
228–230
201–203
257–259
202–204
212–214
193–195
262–264
246–248
182–184
233–235
188–190
204–206
172–174
242–244
143–145
203–205
245–247
223–225
142–144
147–149
161–163
8
6
5
5
7
5
8
6
7
6
6
7
6
7
6
7
4
2
2
3
1
2
95 [41]
96 [15]
97 [42]
97 [23]
96 [43]
97 [13]
94 [16]
95 [41]
96 [15]
96 [41]
96 [44]
96 [45]
97 [10]
96 [41]
96 [46]
96 [46]
97 [14]
98 [17]
97 [10]
97 [10]
98 [10]
98 [17]
93 [18]
95 [44]
95 [15]
92 [41]
92 [41]
94 [41]
2-Chlorobenzaldehyde
4-Chlorobenzaldehyde
2,4-Dichlorobenzaldehyde
3,4-Dichlorobenzaldehyde
4-Fluorobenzaldehyde
3-Hydroxybenzaldehyde
4-Hydroxybenzaldehyde
3-Methoxybenzaldehyde
4-Methoxybenzaldehyde
3,4-Dimethoxybenzaldehyde
4-Hydroxy-3-methoxybenzaldehyde
3,4,5-Trimethoxybenzaldehyde
4-Methylbenzaldehyde
2,5-Dimethylbenzaldehyde
4-Isopropylbenzaldehyde
4-Dimethylaminobenzaldehyde
4-Trifluoromethylbenzaldehyde
2-Nitrobenzaldehyde
1
1
12
0
1
1
1
1
1
17
18
1
2
2
2
2
3
4
5
6
([2-MPyH]OTf) [40] as an ionic liquid catalyst in water using various
aromatic and aliphatic aldehyde, dimedone, ethyl acetoacetate and am-
monium acetate to produce the polyhydroquinoline derivatives in good
to excellent yields.
9
0
1
2
3
3-Nitrobenzaldehyde
4-Nitrobenzaldehyde
2
. Experimental
4-Cyanobenzaldehyde
Cinnamaldehyde
Furan-2-carbaldehyde
Thiophene-2-carbaldehyde
Propionaldehyde
10
8
10
15
15
12
2
.1. General procedure for the synthesis of [2-MPyH]OTf as an ionic liquid
24
25
26
27
catalyst
Butyraldehyde
Isobutyraldehyde
The ionic liquid [2-MPyH]OTf as a catalyst was synthesized according
28
to literature [40]. A white solid was formed in high purity and then the
physical data (IR, NMR) of this known ionic liquid were found to be
identical. Spectral data: 1H NMR (400 MHz, CDCl
): δ 2.93 (s, 3H),
.26–7.67 (m, 2H), 8.29–8.36 (m, 1H), 8.84 (d, J=5.9 Hz, 1H), 17.21
―CH
2.27 (s, 3H, ―CH
(q, 2H, J=7.2 Hz, ―OCH
3H, Ar―H), 8.19 (brs, 1H, ―NH); C NMR (100 MHz, CDCl
13.9, 26.5, 27.2, 28.3, 33.4, 38.6, 47.5, 52.1, 58.1, 105.3, 107.3, 111.3,
14.9, 121.1, 135.3, 147.4, 147.9, 153.2, 155.1, 167.7, 195.1; IR (KBr,
cm ) 3396, 3280, 3067, 2959, 1687, 1550, 1475, 1263, 1223, 850.
Ethyl 2,7,7-trimethyl-5-oxo-4-p-tolyl-1,4,5,6,7,8-hexahydroquino-
line-3-carboxylate (Table 1—entry 14): Yield: 96%; M.p 262–264 °C
), 1.92–2.15 (dd, 2H, ―CH
), 3.57 (s, 3H, ―OCH
―), 4.71 (s, 1H, ―CH―), 6.45–6.73 (m,
―), 2.21–2.35 (dd, 2H, ―CH
3
3
2
2
―),
7
3
3
), 3.73 (s, 3H, ―OCH ), 4.03
3
1
3
(
brs, 1H); C NMR (100 MHz, CDCl
3
): δ 154.3, 146.8, 141.5, 128.1,
2
−
1
13
1
8
25.2, 120.9, 20.3; IR (KBr, cm ) 2983, 1631, 1365, 1223, 1070, 957,
87, 579.
3
): δ
1
−
1
2
.2. General procedure for the synthesis of polyhydroquinoline
derivatives
A mixture of aldehyde (1 mmol), dimedone (1 mmol), ethyl aceto-
acetate (1 mmol) and ammonium acetate (1 mmol) was added to
2-MPyH]OTf catalyst (1 mol%) in water (2 mL), and the reaction mixture
(Ref. [41] 260–261 °C); 1H NMR (400 MHz, CDCl
3
): δ 0.81 (s, 3H,
), 1.17 (t, 3H, J=7.2 Hz, ―CH ), 1.98 (s, 3H,
), 2.03 (dd, 2H, ―CH ―), 2.21 (dd, 2H, ―CH ―), 2.41 (s, 3H,
), 4.06 (q, 2H, J=7.1 Hz, ―OCH ―), 5.15 (s, 1H, ―CH―), 7.43
(d, 2H, J=9.2 Hz, Ar―H), 8.13 (d, 2H, J=9.2 Hz, Ar―H), 8.22 (brs,
1H, ―NH); 13C NMR (100 MHz, CDCl
): δ 14.3, 18.5, 23.1, 27.1, 27.8,
33.9, 37.6, 40.7, 51.3, 61.9, 77.5, 104.4, 111.9, 121.2, 127.1, 146.5,
―CH
―CH
―CH
3
), 1.07 (s, 3H, ―CH
3
3
[
3
2
2
was stirred at room temperature for an appropriate time. Completion of
the reactions was monitored by TLC (n-hexan/ethyl acetate 4:1). After
completion of the reaction, the resulting solid crude product was filtered
and then recrystallized from ethanol–water to obtain pure product. The
formation of products was related by comparing the melting points, IR
and NMR data with authentic samples and literature data.
3
2
3
−
1
150.3, 154.3, 167.2, 193.5; IR (KBr, cm ) 3270, 3180, 3075, 2967,
1661, 1615, 1557, 1480, 1359, 1270, 1150, 875.
Ethyl 2,7,7-trimethyl-4-(4-trifluorophenyl)-5-oxo-1,4,5,6,7,8-hexa-
hydroquinoline-3-carboxylate (Table 1—entry 18): Yield: 98%; M.p
2
.3. Spectral data for the synthesis of polyhydroquinoline derivatives
1
88–190 °C (Ref. [17] 188–190 °C); 1H NMR (400 MHz, CDCl
3
): δ
3
), 1.27 (t, 3H, J=7.5 Hz,
Ethyl 4-(4-chlorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahy-
0.93 (s, 3H, ―CH
―CH ), 2.11 (dd, 2H, ―CH
―CH ), 4.12 (q, 2H, J=7.3 Hz, ―OCH
3
), 1.12 (s, 3H, ―CH
droquinoline-3-carboxylate (Table 1—ntry 3): Yield: 97%; M.p 233–
3
2
2
―), 2.17 (dd, 2H, ―CH ―), 2.39 (s, 3H,
2
3
35 °C (Ref. [43] 230–232 °C); 1H NMR (400 MHz, CDCl
H, ―CH ), 0.93 (s, 3H, ―CH ), 1.11 (t, 3H, J=7.3 Hz, ―CH
―), 2.12 (dd, 2H, ―CH ―), 2.26 (s, 3H, ―CH ), 3.95 (q,
H, J=7.2 Hz, ―OCH ―), 4.93 (s, 1H, ―CH―), 7.07 (d, 2H, J=9.1 Hz,
Ar―H), 7.15 (d, 2H, J=9.2 Hz, Ar―H), 7.91 (brs, 1H, ―NH); C NMR
100 MHz, CDCl ): δ 14.7, 18.8, 26.7, 29.3, 31.7, 35.3, 41.1, 50.4, 59.8,
5.9, 103.1, 110.8, 127.1, 128.6, 130.7, 144.3, 150.2, 164.9, 193.9; IR
3
): δ 0.81 (s,
), 2.04
3
2
―), 5.19 (s, 1H, ―CH―),
3
3
3
7.47 (d, 2H, J=9.3 Hz, Ar―H), 8.01 (d, 2H, J=9.4 Hz, Ar―H), 8.26
(
dd, 2H, ―CH
2
2
3
(brs, 1H, ―NH); 13C NMR (100 MHz, CDCl
3
): δ 14.9, 19.3, 27.6,
2
2
29.7, 32.9, 37.6, 54.7, 63.1, 105.4, 114.3, 123.9, 127.1, 129.6, 147.2,
13
−1
152.3, 155.2, 168.1, 196.1; IR (KBr, cm ) 3287, 3157, 3065, 2978,
(
7
3
1670, 1610, 1557, 1480, 1345, 1270, 1201, 875.
Ethyl 2,7,7-trimethyl-4-(4-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahy-
droquinoline-3-carboxylate (Table 1—entry 21): Yield: 98%; M.p
−
1
(
KBr, cm ) 3270, 3195, 3070, 2945, 1670, 1604, 1475, 1367, 1227,
1
105, 857.
242–244 °C (Ref. [10] 242–244 °C); 1H NMR (400 MHz, CDCl
3
): δ
3
), 1.15 (t, 3H, J=7.3 Hz,
Ethyl 4-(3,4-dimethoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-
0.86 (s, 3H, ―CH
―CH ), 2.09 (dd, 2H, ―CH
―CH ), 4.08 (q, 2H, J=7.4 Hz, ―OCH
3
), 1.06 (s, 3H, ―CH
hexahydroquinoline-3-carboxylate (Table 1—entry 11): Yield: 96%;
M.p 202–204 °C (Ref. [44] 198–199 °C); 1H NMR (400 MHz, CDCl
):
δ 0.93 (s, 3H, – CH ), 1.04 (s, 3H, ―CH ), 1.25 (t, 3H, J=7.3 Hz,
3
2
―), 2.18 (dd, 2H, ―CH
2
―), 2.37 (s, 3H,
―), 5.13 (s, 1H, ―CH―),
3
3
2
3
3
7.49 (d, 2H, J=9.4 Hz, Ar―H), 8.11 (d, 2H, J=9.4 Hz, Ar―H), 8.17

46
M. Tajbakhsh et al. / Journal of Molecular Liquids 177 (2013) 44–48
(
brs, 1H, ―NH); 13C NMR (100 MHz, CDCl
3
): δ 14.8, 20.1, 28.3, 29.8,
Table 2
Solvent effect in the synthesis of ethyl 4-(4-chlorophenyl)-2,7,7-trimethyl-5-oxo-1,4,
5,6,7,8-hexahydroquinoline-3-carboxylate (Table 1—entry 3).
3
1
1
4.1, 37.6, 43.7, 52.3, 61.3, 78.7, 105.7, 111.3, 124.5, 131.3, 147.2,
53.1, 157.1, 169.4, 196.1; IR (KBr, cm−1) 3275, 3169, 3070, 2958,
679, 1620, 1570, 1475, 1357, 1250, 1103, 987.
Solvent
2
H O
C
2
5
H OH
CH
3
CN
THF
Toluene
Ethyl 4-(furan-2-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydro-
Time (min)
Yield (%)
5
97
4
98
7
93
15
89
23
83
quinoline-3-carboxylate (Table 1—entry 24): Yield: 95%; M.p 245–
2
(
1
4
47 °C (Ref. [44] 246–248 °C); 1H NMR (400 MHz, CDCl
3
): δ 0.91
Reaction condition: a4-chlorobenzaldehyde (1 mmol), dimedone (1 mmol) ethyl
acetoacetate (1 mmol), ammonium acetate (1 mmol), [2-MPyH]OTf as a catalyst (1 mol%),
solvent (2 mL); isolated yield.
s, 3H, ―CH
.97 (dd, 2H, ―CH
3
), 1.04 (s, 3H, ―CH
3
), 1.27 (t, 3H, J=7.4 Hz, ―CH
3
),
),
b
2
―), 2.17 (dd, 2H, ―CH
2
―), 3.25 (s, 3H, ―CH
3
2
.27 (q, 2H, J=7.3 Hz, ―OCH ―), 5.17 (s, 1H, ―CH―), 6.18 (t, 1H,
J=9.1 Hz, Ar―H), 6.57 (d, 1H, J=9.3 Hz, Ar―H), 7.21 (d, 1H, J=
9
1
1
3
.3 Hz, Ar―H), 8.31 (brs, 1H, ―NH); 13C NMR (100 MHz, CDCl
3
): δ
Table 3
Optimization reaction conditions in the synthesis of ethyl 2,7,7-trimethyl-4-
(4-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Table 1—entry 21) .
4.3, 19.5, 27.1, 29.1, 33.2, 39.6, 51.3, 63.2, 103.2, 106.5, 109.7,
a
11.5, 143.1, 148.9, 151.7, 154.6, 166.5, 196.3; IR (KBr, cm−1) 3270,
Entry Amount of catalyst (mol%) Temperature (°C) Time (min) Yield (%)b
163, 3057, 2987, 1679, 1600, 1575, 1470, 1350, 1267, 957.
. Results and discussion
1
2
3
4
5
6
7
8
No catalyst
No catalyst
25
100
25
100
25
100
25
100
45
45
1
1
1
1
3
3
41
43
98
98
98
98
97
98
3
1
1
2
2
5
5
In a typical general experimental procedure, a solution of dimedone
(
1 mmol), aromatic aldehyde (1 mmol), ethyl acetoacetate (1 mmol)
and ammonium acetate (1 mmol) in water at room temperature in
the presence of a catalytic amount of 1 mol% [2-MPyH]OTf for a certain
period of time is required to complete the reaction. The resulting
polyhydroquinoline derivatives were filtered from the reaction mixture
a
Reaction condition: 4-nitrobenzaldehyde (1 mmol), dimedone (1 mmol) ethyl acetoacetate
(1 mmol), ammonium acetate (1 mmol), water solvent (2 mL); isolated yield.
b
2
and washed with H O and filtrate was recycled for reuse. The crude
product was purified by recrystallization from ethanol-water to afford
the pure product (Scheme 1).
To study the generality of this process, several examples illustrating
this method for the synthesis those polyhydroquinoline derivatives
were studied. To show the general applicability of this method, various al-
dehydes were efficiently reacted with dimedone, ethyl acetoacetate and
ammonium acetate in the same conditions. The results are summarized
in Table 1. The effect of electron and the nature of substituents on the
aromatic ring did show expected strong effects in terms of yields under
these reaction conditions. Aromatic aldehydes containing electron-
withdrawing groups (such as nitro groups) or electron-donating groups
water is obviously the best choice for these reactions. However, for this
reaction, considering the laboratory not industry, the best results were
achieved by carrying out the reaction at room temperature in ethanol
for 4 min using 1 mol% of [2-MPyH]OTf as a catalyst, but the result in
this paper is among the most useful and promising because water is
safe, benign, and cheap compared with organic solvents.
To optimize the temperature in the mentioned reaction, we have
carried out a model study with 4-nitrobenzaldehyde with dimedone,
ethyl acetoacetate and ammonium acetate using 1 mol%, 2 mol% or
5 mol% of catalyst at room temperatures or reflux (100 °C) in water sol-
vent. Table 3 clearly demonstrates that in the absence of the catalyst,
product was obtained in low yield after 45 min, while good results
were obtained in the presence of 1 mol% of ionic liquid catalyst and
25 °C was an effective temperature in terms of reaction time and yield
obtained (entry 3).
In order to show the merits of present method in comparisons with
other reported methods for the similar reactions, we have tabulated
some of the results in Table 4. As it is marked from the results, the present
method is found to be very efficient for the synthesis of polyhydro-
quinoline derivatives. In relation to Table 4, the required ratio for the
most catalysts is >1 mol% (Table 4, entries 3, 4, 5) and also the required
reaction times are much longer (Table 4, entries 2, 5, 6).
(such as hydroxy, alkoxyl groups) were employed and they were found
to react well to give the corresponding polyhydroquinoline in good to
excellent yields. Aromatic aldehydes having electron-withdrawing
groups on the aromatic ring (Table 1, entries 18–22) react faster than
electron-donating groups (Table 1, entries 8, 10, 12, and 14). Aliphatic
aldehydes (Table 1, entries 26–28) required longer reaction times,
which is most probably due to the electron-releasing and steric effects
of the methyl group.
We have also examined the effects of the solvent through some ex-
periments. As a model reaction, the reaction of 4-chlorobenzaldehyde
with dimedone, ethyl acetoacetate and ammonium acetate catalyzed
by 1 mol% ionic liquid in various solvents is summarized in Table 2.
The yields refer to the isolated yields. From Table 2 we can know that
O
O
R
Me
CO Et
O
R
O
2
2
CO Et
2
NH OAc, [2-MPyH]OTf (1mol%)
O
4
Me
Me
Me
Me
+
H O, r.t.
N
H
Me
O
H
2
1
3
4
H C
N
H
-O
O
3
+
F
S
catalyst: [2-MPyH]OTf
O
F
F
Scheme 1. Synthesis of polyhydroquinoline derivatives in the presence of [2-MPyH]OTf as an ionic liquid catalyst.

M. Tajbakhsh et al. / Journal of Molecular Liquids 177 (2013) 44–48
47
Table 4
Comparison synthesis of polyhydroquinoline in the presence of different catalysts .
-3-carboxylate without significant loss of activity. The results were sum-
marized in Table 5. Increasing of the catalyst to 2 mol%, 5 mol%, and
10 mol% resulted in decreasing the reaction yields to 98%, 97%, 95% re-
spectively. Use of just 1 mol% ionic liquid catalyst in water at room tem-
perature is sufficient to push the reaction forward. Higher amounts of
the catalyst did not improve the results to a greater extent. The yields
are, in general, very high regardless of the structural variations in aromatic
aldehyde.
a
Entry Catalyst/amount of Solvent/temperature
Time Yield (%)b
(min) [Ref.]
catalyst (mol%)
(°C)
1
2
3
4
5
6
7
[2-MPyH]OTf /1
H
2
O/r.t.
8
35
8
10
95 [This work]
K
7
[PW12CoO40]/1
[VEim]I/10
[HMIM]BF
L-proline/10
Hf(NPf /1
HClO -SiO /50 mgr Solvent free/90
CH CN/reflux
Solvent free/40
Solvent free/90
3
80 [18]
95 [47]
95 [48]
92 [12]
95 [21]
95 [14]
4
/12
C
2
5
H OH/Reflux
360
18)/60 180
8
2
)
4
Perfluorodecalin (C10F
4
2
Reaction condition: abenzaldehyde (1 mmol), dimedone (1 mmol) ethyl acetoacetate
(
4. Conclusion
1 mmol), ammonium acetate (1 mmol); bisolated yield.
In conclusion, 2-methylpyridinium trifluoromethanesulfonate was
used as a highly efficient and green catalyst for the synthesis of poly-
hydroquinoline derivatives which resulted to better yields. Ionic liquid
[2-MPyH]OTf effectively catalyzes the reaction of various aldehyde,
dimedone, ethyl acetoacetate and ammonium acetate in water to produce
polyhydroquinoline derivatives in good to excellent yields. The catalyst
offers several advantages including non-toxic, cleaner reactions, non-
corrosive, shorter reaction times, high yield of the products, high melting
point, mild reaction conditions, lower catalytic loading as well as simple
experimental and isolation procedures. Also, the catalysts were able to
be reused easily for six-time experiments with a small decrease in the
catalytic activity of the recovered catalyst.
In Scheme 2 we propose a possible mechanism for the synthesis of
polyhydroquinoline derivatives in the presence of [2-MPyH]OTf as a cat-
alyst. The polyhydroquinoline derivatives could be synthesized by two
methods. There is evidence in the paper that [2-MPyH]OTf catalyses
aldol related reactions such as Knoevenagel condensation type coupling
of aldehydes with active methylene compounds and then the Michael
type addition of intermediates jointly to provide the products [49].
The reusability of the catalysts is an important advantage and makes
them useful for commercial applications. The catalyst plays a crucial
role in the success of the reaction in terms of the rate and the yields
[50]. For example, 4-nitrobenzaldehyde reacted with dimedone, ethyl
acetoacetate and ammonium acetate in the presence of 1 mol% ionic
liquid catalyst to give the analogues product ethyl 2,7,7-trimethyl-
Table 5
Reusability studies of catalysts for the synthesis of ethyl 2,7,7-trimethyl-4-
4
-(4-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate
a
(4-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Table 1—entry 21) .
in yield 98% in water at room temperature after 1 min of reaction time.
After completion of the reaction (monitored by TLC), the product was
Number of experiments
Isolated yield (%)b
Fresh
98
1
2
3
4
5
extracted with CH
layer. Ionic liquid catalyst is more soluble in water than that in CH
vent. The catalyst could be reused six times for the synthesis of ethyl
2
Cl
2
and the catalyst was recovered from the aqueous
97
96
96
94
93
2
Cl sol-
2
Reaction condition: a4-nitrobenzaldehyde (1 mmol), dimedone (1 mmol) ethyl
acetoacetate (1 mmol), ammonium acetate (1 mmol), [2-MPyH]OTf as a catalyst
(1 mol%), water solvent (2 mL); isolated yield.
b
2,7,7-trimethyl-4-(4-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline
O
Method a.
O
R
Me
OEt
+
Me
O
Me
H N
Me
2
N+
N+
Me
H
CF SO -
-
CF SO
3
3
3
3
H
O
NH OAc
4
R
H
O
R
O
O
O
OEt
Me
Me
OEt
Me
Me
N
H
Me
O
Me
O
Me
NH OAc
4
N+
N+
H
Me
CF SO3-
-
CF SO
3
3
3
O
H
O
R
O
R
H
Method b.
Me
Me
+
OEt
Me
NH2
O
Scheme 2. The proposed mechanism of synthesis polyhydroquinoline derivatives in the presence of [2-MPyH]OTf.

48
M. Tajbakhsh et al. / Journal of Molecular Liquids 177 (2013) 44–48
[
[
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Acknowledgment
This research was supported by the make inquiries commission of
the University of Payame Noor, Sari, Iran.
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