Polyhydroquinolines: 1-sulfopyridinium chloride catalyzed an efficient one-pot multicomponent synthesis via Hantzsch condensation under solvent-free conditions

Article abstract of DOI:10.1007/s11164-016-2559-y

Abstract: A simple and highly efficient method has been developed for the construction of polyhydroquinoline derivatives via one-pot, four-component Hantzsch condensation of various aldehydes, dimedone, ethyl acetoacetate, and ammonium acetate in the pres

Full text of DOI:10.1007/s11164-016-2559-y

Res Chem Intermed
DOI 10.1007/s11164-016-2559-y
Polyhydroquinolines: 1-sulfopyridinium chloride
catalyzed an efficient one-pot multicomponent synthesis
via Hantzsch condensation under solvent-free
conditions
1
1
1
•
B. Sakram
S. Rambabu
•
B. Sonyanaik
•
K. Ashok
1
Received: 9 February 2016 / Accepted: 22 April 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract A simple and highly efficient method has been developed for the construction
of polyhydroquinoline derivatives via one-pot, four-component Hantzsch condensation
of various aldehydes, dimedone, ethyl acetoacetate, and ammonium acetate in the
presence of an ionic liquid, 1-sulpopyridinium chloride, as a catalyst under solvent-free
conditions. This methodology has an advantage of high yields, short reaction times, a
clean reaction profile, and reusability of the catalyst.
Graphical Abstract
Keywords Hantzsch condensation Á Polyhydroquinolines Á Multicomponent
reaction Á Solvent-free conditions Á 1-Sulfopyridiniumchloride
Electronic supplementary material The online version of this article (doi:10.1007/s11164-016-2559-y)
contains supplementary material, which is available to authorized users.
&
B. Sakram
bschemou@gmail.com
1
Department of Chemistry, Osmania University, Hyderabad, Telangana State 500007, India
123

B. Sakram et al.
Introduction
Multicomponent reactions (MCRs) are efficient synthetic tools for the construction
of chemically and biological active compounds. They have unique advantages such
as the generation of highly diverse and complex products from readily available
substrates in a single synthetic operation without isolation of intermediates, and
with maximum selectivity in minimal time, high atom economy, and high purity
with excellent yields [1–3]. Nowadays, ionic liquid catalyzed reactions have gained
considerable attention because of their interesting properties like high thermal
stability, non-flammability, an ability to dissolve a wide range of materials, eco-
friendly nature, and reusability, all contributing to carrying out reactions more
effectively [4, 5]. Moreover, reactions under solvent-free conditions are also
increasingly attractive to researchers due to the fact that without solvent, reactions
usually need shorter reaction times, simpler reactors, and require simple and
efficient workup procedures [6, 7].
1
,4-Dihydropyridine (1,4-DHP) derivatives are well known as calcium channel
modulators and have emerged as one of the most important classes of drugs for the
treatment of cardiovascular diseases (e.g. amlodipine, nifedipine, nimodipine,
nicardipine, and efonidipine, etc.; Fig. 1) [8–11]. Thus, in recent years an increasing
interest has been focused on their syntheses. 1,4-DHPs were also found to possess
antiviral [12], antioxidant [13], antitumour [14], anti-inflammatory [15], antimalar-
ial [16], antibacterial [17], and antitubercular [18] activities. They also act as NADH
coenzymes for the reduction of carbonyl compounds and their derivatives [19], as
neuroprotectants, with platelet anti-aggregatory activity and cerebral anti-ischemic
activity in the treatment of Alzheimer’s disease, and as chemosensitizers in tumor
therapy [20].
In view of their pharmacological activities, numerous methods have been
reported for the synthesis of structurally related polyhydroquinoline derivatives. The
classical method involves the condensation of an aldehyde with ethyl acetoacetate
Fig. 1 Examples of dihydropyridine calcium channel blocker
1
23

Polyhydroquinolines: 1-sulfopyridinium chloride catalyzed…
and ammonia in acetic acid or in refluxing alcohol [21–23]. However, these methods
suffer from several drawbacks such as long reaction times, use of large quantities of
volatile organic solvents, low yields, and harsh reaction conditions. Thus, chemists
have developed more competent methods including conventional heating [24],
microwave irradiation [25], ultrasound irradiation [26], and also using various
catalytic systems such as ionic liquids [27], L-proline [28], magnetic Fe O
3
4
nanoparticles [29], molecular iodine [30], Sc(OTf) [31], HClO –SiO [32], PPA–
3
4
2
SiO2 [33], PTSA [34], FeF3 [35], CAN [36], P(4-VPH)HSO4 [37], cellulose
sulphuric acid [38], cross-linked poly(AMPS-co-AA) [39] and 1,3-bromo/chloro-
5
,5-dimethylhydantoin [40]. However, most of these methods have one or several
draw backs such as low yields, long reaction times, tedious workup procedures, and
the use of expensive and large quantities of reagents. Thus, to overcome these
limitations and in continuation of our previous studies on the development of eco-
friendly methodologies [41], we herein report the synthesis of polyhydroquinoline
derivatives utilizing an efficient, eco-friendly, and reusable ionic liquid, 1-sulfopy-
ridinium chloride [pyridine–SO H]Cl, as a catalyst under solvent-free conditions.
3
Experimental
Materials and methods
All the solvents and chemicals were purchased from Aldrich/Merck/Fisher and used
without further purification. The melting points were determined on a Buchi melting
point apparatus and are uncorrected. The progress of the reaction as well as the
purity of the compounds were checked using F254 silica-gel pre-coated TLC plates
with hexane and ethyl acetate as eluent. IR spectra were recorded on a Perkin Elmer
1
FT-IR spectrophotometer using KBr pellets. H NMR spectra were recorded on a
Bruker 400 MHz spectrometer and mass spectra were obtained using a Jeol JMSD-
400 spectrometer. Elemental analyses were performed on a Carlo-Erba model
EA1108 analytical unit.
General procedure for the synthesis of Hantzsch polyhydroquinolines
(
5a–m)
Ionic liquid, [pyridine–SO H]Cl (10 mol%, 0.1 mmol, 19.56 mg) was added to a
3
mixture of dimedone (1 mmol, 140.18 mg), aldehyde (1 mmol), ethyl acetoacetate
(
1 mmol, 127.46 lL), and ammonium acetate (3 mmol, 231.25 mg), and heated at
10 °C under neat conditions for an appropriate time, as described in Table 1. After
1
completion of the reaction shown by TLC, the mixture was diluted with water and
the product was extracted with ethyl acetate (3 9 10 mL). The combined organic
layer was dried over Na SO and concentrated under reduced pressure, and then
2
4
purified by recrystallization from ethanol to obtain the pure polyhydroquinoline
derivatives. The recovered catalyst was washed with ethyl acetate, dried under
vacuum at 90 °C for about 2.5 h, and reused for consecutive reactions.
123

B. Sakram et al.
Table 1 Optimizing the
reaction conditions
a
Entry
Amount of
IL (mol%)
Temp. (°C)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
–
RT
60
180
120
120
120
60
–
–
Trace
32
35
36
68
82
82
93
91
–
110
140
RT
60
–
5
Reaction conditions Dimedone
5
60
(
(
(
1 mmol), benzaldehyde
1 mmol), ethyl acetoacetate
1 mmol), and ammonium
5
110
140
110
110
30
5
30
acetate (3 mmol) under solvent-
free conditions
10
15
25
1
0
25
a
Isolated yields
Spectral data of representative compounds
Ethyl 4-(4-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-
-
1
carboxylate (5b) White solid; IR (KBr, tmax, cm ): 3285, 2962, 1701, 1606,
1
1
510, 1382, 1231, 1023, 765; H NMR (400 MHz, CDCl ); d (ppm) 0.94 (s, 3H),
3
1
.07 (s, 3H), 1.24 (t, 3H, J = 7.2 Hz), 2.21–2.24 (m, 3H), 2.35–2.41 (m, 4H), 4.09
q, 2H, J = 7.2 Hz), 5.07 (s, 1H), 5.92 (s, 1H), 7.30 (d, 2H, J = 8.0 Hz), 7.39 (d,
(
?
2
H, J = 8.0 Hz); Mass (ESI) m/z: 417 (M ); Anal. Calcd. for C H BrNO : C,
21 24 3
6
0.29; H, 5.78; N, 3.35. Found: C, 60.36; H, 5.71; N, 3.42.
Ethyl 4-(5-chloro-2-hydroxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydro-
-
1
quinoline-3-carboxylate (5f) Pale yellow solid; (KBr, tmax, cm ): 3317, 3253,
1
096, 2961, 1654, 1608, 1591, 1490, 1368, 1230, 1122, 819, 643; H NMR (400 MHz,
3
DMSO-d ): d 0.84 (s, 3H), 1.01–1.05 (m, 6H), 2.06 (d, J = 16.0 Hz, 1H), 2.21–2.45
6
(
m, 6H), 3.88–3.95 (m, 2H), 4.91 (s, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.85 (d,
J = 8.4 Hz, 1H), 6.96–6.98 (m, 1H), 9.30 (s, 1H), 9.58 (s, 1H); Mass (ESI) m/z: 390
?
(
H, 6.32; N, 3.76.
M?H) ; Anal. Calcd. for C H ClNO4: C, 64.69; H, 6.20; N, 3.59. Found: C, 64.58;
21 24
Ethyl 2,7,7-trimethyl-5-oxo-4-styryl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate
-
1
1
(
5i)
White solid; IR (KBr, tmax, cm ): 3312, 2962, 1674, 1601, 1482; H
NMR (400 MHz, CDCl ): d (ppm) 1.08 (s, 3H), 1.12 (s, 3H), 1.24–1.32 (m, 3H),
3
2
J = 7.0 Hz), 5.74 (s, 1H), 6.22 (d, 2H, J = 7.1 Hz), 7.22–7.31 (m, 5H). Mass (ESI)
.27 (t, 3H, J = 7.3 Hz), 2.32–2.36 (m, 4H), 4.11–4.20 (m, 2H), 4.71 (d, 1H,
?
m/z: 366 (M?H) ; Anal. Calcd. For C H NO : C, 75.59; H, 7.45; N, 3.83. Found:
C, 75.72; H, 7.33; N, 3.91.
2
3
27
3
Ethyl 2,7,7-trimethyl-5-oxo-4-propyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate
1
-
(
5j) White solid; IR (KBr, tmax, cm ): 3283, 3206, 3082, 2963, 1703, 1606,
1
1494, 1379, 1279, 1213, 843; H NMR (400 MHz, CDCl ): d (ppm) 0.83 (t, 3H,
J = 6.9 Hz), 1.09 (s, 6H), 1.18–1.22 (m, 2H), 1.29 (t, 3H, J = 6.9 Hz), 1.33–1.40
3
(
m, 2H), 2.22 (d, J = 17.2 Hz, 2H), 2.30 (s, 3H), 2.37 (d, J = 17.2 Hz, 2H), 4.02 (t,
1
23

Polyhydroquinolines: 1-sulfopyridinium chloride catalyzed…
?
H, J = 5.5 Hz), 4.10–4.22 (m, 2H), 6.32 (s, 1H); Mass (ESI) m/z: 306 (M?H) ;
1
Anal. Calcd. For C H NO : C, 70.79; H, 8.91; N, 4.59. Found: C, 70.92; H, 8.70;
N, 4.66.
1
8
27
3
4
-(5-Chloro-pyridin-2-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydro-quinoline-3-
-
1
carboxylic acid ethyl ester (5l) Pale yellow solid; IR (KBr, tmax, cm ): 3321,
3
1
250, 3090, 1595, 1242, 1070; H NMR (400 MHz, CDCl ): d (ppm) 0.86 (s, 3H),
3
1
.01–1.06 (m, 6H), 2.06 (d, 1H, J = 16.4 Hz), 2.25 (d, 1H, J = 16.3 Hz), 2.29–2.46
m, 5H), 3.89–3.99 (m, 2H), 5.06 (s, 1H), 5.92 (s, 1H), 7.14 (d, 2H, J = 8.7 Hz),
(
?
7
6
.29 (s, 1H); Mass (ESI) m/z: 375 (M?H) ; Anal. Calcd. For C H ClN O : C,
20 23 2 3
4.08; H, 6.18; N, 7.47. Found: C, 64.18; H, 6.01; N, 7.56.
Results and discussion
Polyhydroquinoline derivatives (5a–m) were synthesized via Hantzsch multicom-
ponent condensation of various aryl/alkyl/heteryl aldehydes (2a–m) with dimedone
(
1), ethyl acetoacetate (3), and ammonium acetate (4) under neat conditions at
1
catalyst with excellent yields. The schematic representation is shown in Scheme 1.
10 °C in the presence of an eco-friendly ionic liquid, [pyridine–SO H]Cl, as a
3
The ionic liquid [pyridine–SO H]Cl was prepared according to the published
3
procedure [42] from readily available starting materials, as shown in Scheme 2.
We initially investigated the reaction of benzaldehyde (2a) with dimedone (1),
ethyl acetoacetate (3), and ammonium acetate (4) as a model reaction in the absence
as well as in the presence of an ionic liquid (5, 10 and 15 mol%) at different
temperatures ranging from room temperature to 140 °C under solvent-free
conditions. The observations are as follows: Without catalyst at room temperature
the formation of product (5a) was not observed; as the temperature increases to
1
40 °C, only 35 % of the product was observed (Table 1, entries 1–4). In the
presence of 5 mol% of catalyst, at room temperature only 36 % of the product was
formed; as the temperature increased to 110 °C the yield of the product dramatically
increased to 82 %, however, further increments of temperature up to 140 °C did not
Scheme 1 1-Sulfopyridinium chloride catalyzed Hantzsch polyhydroquinoline synthesis
123

B. Sakram et al.
Scheme 2 Synthesis of ionic liquid, 1-sulfopyridinium chloride
show any affect on product yield and reaction time (Table 1, entries 5–8). To
achieve better yields, the above reaction was conducted with 10 and 15 mol % of
the catalyst, and observed the maximum yield (93 %) in shorter reaction times
(
25 min) with 10 mol % of the catalyst. We also observed that as the amount of the
catalyst increased to 15 mol % the yield slightly decreased due to the formation of
unidentified impurities. Thus, the optimum condition is 10 mol% of the catalyst at
1
10 °C under solvent-free conditions.
With the optimized conditions in hand, we proceeded to examine the scope of the
reaction using a variety of different aromatic, aliphatic, and hetero aromatic
aldehydes (Scheme 1), and obtained the desired polyhydroqunoline derivatives
(5a–m) with excellent yields and in shorter reaction times (Table 2). After
completion of the reaction, the catalyst was recovered by evaporating the aqueous
layer, washed with warm ethyl acetate, dried under vacuum and at 90 °C for about
2
.5 h, and reused for subsequent reactions for additional four cycles. In this process,
Table 2 1-Sulfopyridinium chloride catalyzed synthesis of polyhydroquinolines (5a–m) under solvent-
free conditions
Analog
Aldehyde
Time
min)
Yield
a
(%)
Melting points (°C)
(
Found
Reported
References]
[
5
5
5
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
Benzaldehyde
25
30
35
25
35
30
35
35
30
35
30
25
25
93
89
91
90
91
92
92
90
92
91
90
84
91
202–204
254–256
178–180
244–246
198–200
208–209
225–227
278–280
206–207
150–151
248–250
238–240
169–170
203–204 [29]
252–254 [33]
177–178 [29]
244–246 [33]
196–198 [29]
208–210 [37]
226–228 [37]
277–279 [37]
206–207 [31]
150–152 [31]
248–249 [31]
–
4-Bromo benzaldehyde
3–Nitro benzaldehyde
4-Nitro benzaldehyde
3-Ethoxy-4-hydroxybenzaldehyde
5-Chloro-2-hydroxybenzaldehyde
5-Bromo-2-hydroxybenzaldehyde
3,5-Dibromo-2-hydroxybenzaldehyde
Cinnamaldehyde
g
h
i
j
Butyraldehyde
k
l
Furan-2-carbaldehyde
5-Chloropicolinaldehyde
1H-Indole-3-carbaldehyde
m
–
Reaction conditions Dimedone (1 mmol), aldehyde (1 mmol), ethyl acetoacetate (1 mmol), ammonium
acetate (3 mmol), and [pyridine–SO
3
H]Cl (10 mol%), neat conditions, 110 °C
a
Isolated yields after purification
1
23

Polyhydroquinolines: 1-sulfopyridinium chloride catalyzed…
Scheme 3 Plausible mechanism for the formation of polyhydroquinolines catalyzed by ionic liquid,
3
[pyridine–SO H]Cl
we observed a slight decrease in its activity in terms of product yield. For example,
the reaction of dimedone (1), benzaldehyde (2a) ethyl acetoacetate (3), and
ammonium acetate (4) gave the desired product (5a) in 91, 89, 86, and 83 % yields
over an additional four cycles. All the synthesized compounds were characterized
1
by IR, H NMR and mass spectral data, as well as via elemental analyses studies,
and the melting points of the known compounds were also compared with the
literature values, where both were found to be in good agreement.
A plausible mechanism for the formation of polyhydroquinolines catalyzed by an
ionic liquid, [pyridine–SO H]Cl is described in Scheme 3. The carbonyl oxygen of
3
aldehyde is activated in the presence of [pyridine–SO H]Cl and readily reacts with
3
the enolic form of dimedone, affording the corresponding chalcone type compound
A. Intermediate A undergoes cyclization with ethyl-3-aminobut-2-enoate B, which
is formed in situ by the reaction of ethyl acetoacetate with ammonium acetate
followed by dehydration;this results in the corresponding polyhydroquinoline in
excellent yields.
Conclusion
In conclusion, we have developed a simple, efficient, and eco-friendly protocol for
the synthesis of polyhydroquinolines via Hantzsch multicomponent condensation of
dimedone, aryl/alkyl/heteryl aldehydes, ethyl acetoacetate, and ammonium acetate
utilizing 1-sulfopyridinium chloride as a catalyst. This method offers several
advantages including high yields, short reaction times, a simple workup procedure,
reusability of the catalyst, and the ability to avoid use of hazardous organic solvents.
123

B. Sakram et al.
Acknowledgments We gratefully acknowledge the head of the Department of Chemistry, Osmania
University, for providing research facilities. One of the authors (B. Sonyanaik) thanks the University
Grant Commission (UGC) New Delhi, India, for providing research fellowships.
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23