Silica-supported perchloric acid (HClO4-SiO2): A mild, reusable and highly efficient heterogeneous catalyst for multicomponent synthesis of 1,4-dihydropyridines via unsymmetrical Hantzsch reaction

Article abstract of DOI:10.1007/s11164-012-0968-0

Facile synthesis of some 1,4-dihydropyridine derivatives via Hantzsch reaction of 5,5-dimethyl-1,3-cyclohexanedione (dimedone), 1,3-diphenyl-2-propen- 1-one derivatives and ammonium acetate under solvent-free condition in the presence of silica-supported perchloric acid (HClO₄-SiO₂) is described. The catalyst is easily prepared, stable, reusable and efficient under the reaction conditions.

Full text of DOI:10.1007/s11164-012-0968-0

Res Chem Intermed
DOI 10.1007/s11164-012-0968-0
Silica-supported perchloric acid (HClO –SiO ): a mild,
4
2
reusable and highly efficient heterogeneous catalyst
for multicomponent synthesis of 1,4-dihydropyridines
via unsymmetrical Hantzsch reaction
Syed Sheik Mansoor
•
•
Krishnamoorthy Aswin
•
•
Kuppan Logaiya
Saleem Malik
Prasanna Nitiya Sudhan
Received: 4 October 2012 / Accepted: 6 December 2012
Ó Springer Science+Business Media Dordrecht 2012
Abstract Facile synthesis of some 1,4-dihydropyridine derivatives via Hantzsch
reaction of 5,5-dimethyl-1,3-cyclohexanedione (dimedone), 1,3-diphenyl-2-propen-
1
-one derivatives and ammonium acetate under solvent-free condition in the pres-
ence of silica-supported perchloric acid (HClO –SiO ) is described. The catalyst is
4
2
easily prepared, stable, reusable and efficient under the reaction conditions.
Keywords HClO –SiO Á 1,4-Dihydropyridine Á Hantzsch reaction Á
4
2
Multicomponent reaction
Introduction
In recent decades, multicomponent reactions (MCRs) have gained wide applica-
bility in the field of synthetic organic chemistry as they increase the efficiency of the
reaction and decrease the number of laboratory operations along with quantities of
solvent and chemicals used. These methods also considerably reduce the reaction
time and facilitate the yield of products compared with normal multiple-step
methods [1]. Therefore, the design of novel MCRs has attracted great attention from
research groups working in medicinal chemistry and drug discovery. Some of the
examples of MCRs include synthesis of 3,4-dihydropyrimidine derivatives [2] and
1
-carbamatoalkyl-2-naphthols [3]. Nevertheless, development and discovery of new
MCRs is still in demand.
,4-Dihydropyridines (DHPs) play a predominant role in medicinal chemistry
1
owing to their significant biological activity [4]. A number of dihydropyridine
calcium antagonists have been introduced as potential drugs for treatment of
S. S. Mansoor (&) Á K. Aswin Á K. Logaiya Á P. N. Sudhan Á S. Malik
Bioactive Organic Molecule Synthetic Unit, Research Department of Chemistry, C. Abdul Hakeem
College, Melvisharam 632 509, Tamil Nadu, India
e-mail: smansoors2000@yahoo.co.in
123

S. S. Mansoor et al.
congestive heart failure and angina pectoris [5–7]. The 1,4-DHPs may lead to other
beneficial effects such as regression of left-ventricular pressure and vascular
hypertrophy, renal protection and antiatherogenic activity [8–10]. Furthermore, the
dihydropyridine skeleton is common in anticoagulant, antibacterial and antimyco-
bacterial activities [4, 11]. They also function as neuro-protectants and as anti-
platelet treatment of aggregators and are important in Alzheimer’s disease as anti-
ischaemic agents [12–15]. They play an important role as antitubercular agents [16,
17]. DHPs are commercially used as calcium channel blockers for treatment of
cardiovascular diseases, including hypertension [18].
To model and understand these biological properties and to develop new
chemotherapeutic agents based upon the 1,4-DHP motif, considerable effort has been
devoted to establish efficient and rapid methods for their synthesis. 1,4-DHPs are
generally synthesized using the Hantzsch method [19], which involves cyclocon-
densation of an aldehyde, a b-ketoester and ammonia either in acetic acid or under
reflux in alcohols for long reaction times, typically leading to low yields [20, 21].
In recent years, several new efficient methods have been developed, including the
use of FeF [22], p-TSA [23], PPA–SiO [24], grinding [25], ceric ammonium
3
2
nitrate [26], PTSA–SDS [27], tris(pentafluorophenyl)borane [28], triphenylphos-
phine [29], cellulose sulphuric acid [30] and solid-state synthesis [31]. These
methods, however, suffer from drawbacks such as unsatisfactory yields, acidic or
basic catalysts, extended reaction times, elevated temperatures, tedious work-up,
anhydrous organic solvents and use of stoichiometric and/or relatively expensive
reagents. Moreover, the main disadvantage of almost all existing methods is that the
catalysts are destroyed in the work-up procedure and cannot be recovered or reused.
Therefore, the search continues for a better catalyst for synthesis of 1,4-DHPs and
polyhydroquinolines in terms of operational simplicity, reusability, economic
viability and greater selectivity.
During the course of our studies directed towards the development of practical
and environmentally friendly procedures for synthesis of biologically active
molecules, such as 3,4-dihydropyrimidin-2(1H)-ones/thiones/imines [32], b-amino
ketone compounds [33], amidoalkyl naphthols [34] and 2-amino-4,6-diphenylpyr-
idine-3-carbonitrile derivatives [35] by multicomponent reactions, we developed the
applicability of a novel recyclable heterogeneous solid-supported perchloric acid
(
HClO –SiO ) for efficient, convenient and facile synthesis of 1,4-DHP derivatives
4 2
via Hantzsch reaction of dimedone, 1,3-diphenyl-2-propen-1-one derivatives and
ammonium acetate under solvent-free condition at 80 °C (Scheme 1). In addition, to
the best of our knowledge, there are no reports on the use of solid-supported
perchloric acid as a heterogeneous catalyst for this conversion. This fact prompted
us to investigate HClO –SiO for synthesis of 1,4-DHP derivatives in a facile and
4
2
practical manner.
Solid-supported reagents are unique acid catalysts that have become popular over
the last two decades. The activity and selectivity of these reagents are dispersed on
the surface of a support, and because of this, the effective surface area of the reagent
is increased significantly, and hence they are expected to perform more effectively
than the individual reagents. Low toxicity, moisture resistance, air tolerance and low
1
23

4 2
Silica-supported perchloric acid (HClO –SiO )
R1
R1
O
O
HClO -SiO
4
2
(1 mol %)
+
NH OAc
4
+
3
Solvent free
o
O
80 C
O
N
H
R2
R2
1
2a - 2l
4a - 4l
Scheme 1 Multicomponent synthesis of various 1,4-dihydropyridine derivatives
prices are other common features that motivate use of solid-supported reagents as
attractive alternatives to conventional Lewis acids or metal triflates [36].
Recently, HClO –SiO has emerged as a powerful catalyst in various organic
4
2
transformations, including Hantzsch condensation [37] and electrophilic substitu-
tion of indole with various aldehydes and ketones [38]. It is also reported that
HClO –SiO can act as a catalyst for various syntheses, including synthesis of
4
2
amidoalkyl naphthols [39], xanthene derivatives [40], poly-substituted quinolines
41] and homoallylic amines [42].
[
Results and discussion
We have developed an efficient synthesis of 1,4-DHP derivatives from reaction of
dimedone, 1,3-diphenyl-2-propen-1-one derivatives and ammonium acetate pro-
moted by a catalytic amount of HClO –SiO under solvent-free conditions at 80 °C.
4
2
Herein, we report our results.
Effect of catalyst
In an initial endeavour, 1 mmol each of dimedone (1), 1,3-diphenyl-2-propen-1-one
2) and ammonium acetate were stirred at 80 °C under solvent-free condition
(
without catalyst. After 6 h, only 60 % of the expected product 4a was obtained after
work-up and recrystallization of the crude product from ethanol (Table 1, entry 1).
To improve the yield and optimize the reaction conditions, the same reaction was
carried out in the presence of a catalytic amount of 0.4 mol% of HClO –SiO under
4
2
similar conditions. Surprisingly, a significant improvement was observed and the
yield of 4a was dramatically increased to 70 % after stirring; the mixture was stirred
for only 5 h (entry 2). With this optimistic result in hand, we further investigated the
best reaction conditions using different amounts of HClO –SiO .
4
2
Increasing the quantity of the catalyst to 0.6, 0.8 and 1 mol% gave the
corresponding product in 80, 87 and 96 % yields in 4, 3 and 2.5 h, respectively. Use
123

S. S. Mansoor et al.
Table 1 The reaction of dimedone, 1,3-diphenyl-2-propen-1-one and ammonium acetate: effect of
catalysis
a
Entry
Catalyst
Amount of
catalyst (mol%)
Time (h)
Yield (%)
1
2
3
4
5
6
HClO
HClO
HClO
HClO
HClO
HClO
4
4
4
4
4
4
–SiO
–SiO
–SiO
–SiO
–SiO
–SiO
2
2
2
2
2
2
0.0
0.4
0.6
0.8
1.0
1.4
6.0
5.0
4.0
3.0
2.5
2.0
60
70
80
87
96
85
Reaction conditions: dimedone (1 mmol), 1,3-diphenyl-2-propen-1-one (1 mmol) and ammonium acetate
(
a
1 mmol) under solvent-free condition; 80 °C
Isolated yields
Table 2 The reaction of dimedone, 1,3-diphenyl-2-propen-1-one and ammonium acetate: effect of
solvent
a
Entry
Solvent
Amount of
catalyst (mol%)
Time (h)
Yield (%)
1
2
3
4
5
6
7
Ethanol
Methanol
t-BuOH
Acetonitrile
THF
1.0
1.0
1.0
1.0
1.0
1.0
1.0
4.0
4.0
8.0
8.0
6.0
8.0
2.5
82
78
25
20
25
66
96
1,4-Dioxane
None
Reaction conditions: dimedone (1 mmol), 1,3-diphenyl-2-propen-1-one (1 mmol) and ammonium acetate
(1 mmol) in the presence of HClO
4 2
–SiO (1 mol %); 80 °C
a
Isolated yields
of just 1 mol% was sufficient to drive the reaction forward; larger amounts of the
catalyst did not improve the results. Although the use of 1.4 mol% of HClO –SiO
4
2
permitted the reaction time to be decreased to 2 h, the yield unexpectedly decreased
to 85 % (entry 4). A possible explanation for the low product yield is that the
starting material or the product may have been destroyed during the reaction when
an excess amount (1.4 mol%) of HClO –SiO was used in the exothermic reaction
4
2
and that 1 mol% HClO –SiO was sufficient to catalyze the reaction effectively.
4
2
Effect of solvent
The solvent played an important role in the synthesis of 1,4-DHP derivatives.
Various reaction media were screened (ethanol, methanol, t-BuOH, acetonitrile,
THF and 1,4-dioxane) using the model reaction (Table 2, entries 1–6). It was found
that the best results were obtained with 1 mol% of HClO –SiO under solvent-free
4
2
1
23

4 2
Silica-supported perchloric acid (HClO –SiO )
Table 3 Optimization of temperature using HClO
condition
4
–SiO
2
(0.1 mol %) as catalyst under solvent-free
a
Entry
Temperature (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
50
60
4.0
3.5
3.0
2.5
2.5
2.5
76
82
88
96
88
84
70
80
90
100
Reaction conditions: dimedone (1 mmol), 1,3-diphenyl-2-propen-1-one (1 mmol) and ammonium acetate
(1 mmol) in the presence of HClO
4 2
–SiO (1 mol %) under solvent-free condition
a
Isolated yields
condition (Table 2, entry 7). The reaction was completed within 2.5 h, and the
expected product was obtained in 96 % yield.
Optimization of temperature
We also examined the effect of temperature. The reaction was studied at various
temperatures from 50 to 100 °C. When increasing the temperature, the product yield
increased up to 80 °C. After 80 °C, increasing temperature leads to decrease in
yields; For example the reaction of dimedone (1), 1,3-diphenyl-2-propen-1-one (2a)
and ammonium acetate at 100 °C under solvent-free condition gave the corre-
sponding product (Table 3, entry 6) in 84 % yield, while decreasing the temperature
to 80–85 °C led to the product in 96 % yield. At higher temperature the starting
material or the product may have been destroyed during the reaction. Therefore, our
optimized condition is 1 mol% of HClO –SiO under solvent-free condition at
4
2
8
0 °C.
Reusability of the catalyst
The reusability of the catalyst is one of the most important benefits and makes it
useful for commercial applications. Thus, the recovery and reusability of HClO4–
SiO was investigated. The reusability of the catalyst was checked by separating the
2
HClO –SiO from the reaction mixture by simple filtration, washing with CH Cl ,
4
2
2
2
and drying in a vacuum oven at 60 °C for 5 h prior to reuse in subsequent reactions.
The recovered catalyst could be reused at least three additional times in subsequent
reactions without significant loss in product yield (Fig. 1) (Table 4).
Synthesis of 7,7-dimethyl-5-oxo-2,4-diphenyl-1,4,5,6,7,8-hexahydroquinoline
derivatives
Under the optimized set of reaction conditions, we conducted the same reactions
using dimedone (1), a variety of different substituted 1,3-diphenyl-2-propen-1-ones
123

S. S. Mansoor et al.
100
Recyclability of HClO - SiO
9
9
9
9
9
8
8
8
8
8
8
6
4
2
0
8
6
4
2
0
4
2
96 %
94 %
93 %
9
0 %
1
2
3
4
Number of Runs
Fig. 1 Recyclability of HClO
4
–SiO
2
catalyst on the product 4a
4 2
Table 4 Effect of recyclability of HClO –SiO catalyst on the product 4a yield
a
Entry
Cycle
Time (h)
Yield (%)
1
2
3
4
0
1
2
3
2.5
2.5
2.5
2.5
96
94
93
90
Reaction conditions: dimedone (1 mmol), 1,3-diphenyl-2-propen-1-one (1 mmol) and ammonium acetate
(1 mmol) in the presence of HClO
4 2
–SiO (1 mol %) under solvent-free condition; 80 °C
a
Isolated yield
(
2a–l) and ammonium acetate 3 in the presence of 1 mol% of HClO –SiO under
4 2
similar conditions (Scheme 1). As expected, satisfactory results were observed, and
the results are summarized in Table 5. It is shown that in general a wide range of
chalcones could react with dimedone and ammonium acetate smoothly to give 4a–
l in good to excellent yields (Table 5, entries 1–12). It is also notable that the
electronic property of the aromatic ring of chalcones has some effects on the rate of
the condensation process. Generally speaking, shorter reaction time was needed for
substrates bearing electron-withdrawing groups on the aromatic rings (Table 5,
entries 2–4, 6 and 7). On the other hand, substrates bearing electron-donating
groups can afford the corresponding products with almost equally satisfactory
yields. A slightly longer reaction period was necessary to complete the reaction
(Table 5, entries 5, 8 and 9). A possible mechanism for the formation of title
compounds 4a–l is shown in Scheme 2.
1
23

4 2
Silica-supported perchloric acid (HClO –SiO )
a
Table 5 Reaction of dimedone, 1,3-diphenyl-2-propen-1-one derivatives and ammonium acetate
b
Entry
R1
R2
Product
Time (h)
Yield (%)
M.p. (°C)
Found
Reported
1
2
3
4
5
6
7
8
9
H
H
4a
4b
4c
4d
4e
4f
2.5
2.0
2.0
2.0
3.0
2.0
2.0
3.0
3.0
2.0
2.0
3.0
96
90
92
88
88
93
90
87
85
92
93
86
204–206
220–222
250–252
234–236
210–212
224–226
210–212
192–194
186–188
237–239
244–246
234–236
203–205 [31]
222–224 [31]
248–250 [31]
232–234 [31]
208–210 [31]
222–224 [31]
212–214 [31]
190–192 [31]
184–186 [31]
236–238 [31]
242–244 [31]
233–235 [31]
H
4-NO
4-Cl
4-Br
2
H
H
H
4-CH
3
4-Cl
4-NO
H
2
H
4g
4h
4i
4-OCH
3
H
4-CH
3
H
1
1
1
0
1
2
3-NO
2
4-Cl
4j
4-Cl
4-NO
4-Cl
2
4k
4l
4-CH
3
All reactions were carried out at 80 °C
a
Reaction conditions: dimedone (1 mmol), 1,3-diphenyl-2-propen-1-one (1 mmol) and ammonium
4 2
acetate (1 mmol) in the presence of HClO –SiO (1 mol %) under solvent-free condition
b
Isolated yield
Experimental
Apparatus and analysis
Chemicals were purchased from Merck, Fluka and Aldrich Chemical Companies.
1
All yields refer to isolated products unless otherwise stated. H nuclear magnetic
1
3
resonance (NMR) (500 MHz) and C NMR (125 MHz) spectra were obtained
using a Bruker DRX-500 Avance at ambient temperature with tetramethylsilane
(
TMS) as internal standard. Fourier-transform infrared (FT-IR) spectra were
obtained from KBr discs on a Shimadzu spectrometer. Mass spectra were
determined on a Varion-Saturn 2000 GC/MS instrument. Elemental analysis was
carried out by means of a PerkinElmer 2400 CHN elemental analyzer flowchart.
Preparation of silica-supported perchloric acid (HClO –SiO )
4
2
HClO (1.8 g, 12.5 mmol, as 70 % aq. solution) was added to a suspension of SiO2
4
(
230–400 mesh, 23.7 g) in Et O (70.0 mL). The mixture was concentrated, and the
2
residue was heated at 100 °C for 72 h under vacuum to furnish HClO –SiO
4
2
(
0.5 mmol/g) as a free-flowing powder (50 mg = 0.025 mmol of HClO ) [43].
4
123

S. S. Mansoor et al.
O
Ar
O
O
O
Ar
O
Michael
addition
+
Ar'
Ar'
O
O
O-H
O
Ar
O
O
Ar
Intramolecular
condensation
NH OAc
4
-
-
AcOH
H O
2
Ar'
N
H
Ar'
H N
OH
2
O
Ar
-
H O
2
N
H
Ar'
Scheme 2 Mechanism of the reaction
General procedure for the synthesis of 7,7-dimethyl-5-oxo-2,4-diphenyl-
,4,5,6,7,8-hexahydroquinoline derivatives
1
A mixture of dimedone (1 mmol), 1,3-diphenyl-2-propen-1-one derivatives
(
1 mmol), ammonium acetate (1 mmol) and HClO –SiO (1 mol%) was stirred at
4 2
8
0 °C for the appropriate time, as shown in Table 5. After completion of the
reaction [thin-layer chromatography (TLC) monitoring], the reaction mixture was
cooled to ambient temperature, CH Cl was added and the HClO –SiO was filtered
2
2
4
2
off. The filtrate was concentrated to dryness, and the crude solid product was
crystallized from EtOH to afford the pure ethyl 7,7-dimethyl-5-oxo-2,4-diphenyl-
1
,4,5,6,7,8-hexahydroquinoline derivatives (Table 5).
Spectral data for the synthesized compounds
,7-Dimethyl-5-oxo-2,4-diphenyl-1,4,5,6,7,8-hexahydroquinoline (4a)
7
-
IR (KBr, cm ): 3,290, 3,022, 2,981, 1,668, 1,626, 1,594, 1,488, 1,444, 778, 765,
1
1
6
90; H NMR (500 MHz, DMSO-d ) d: 0.92 (s, 3H, CH ), 1.04 (s, 3H, CH ),
6
3
3
1
23

4 2
Silica-supported perchloric acid (HClO –SiO )
2
.24–2.35 (m, 4H, 2 9 CH ), 5.25 (d, J = 6.6 Hz, 1H), 5.94 (d, J = 6.6 Hz, 1H),
2
6
.57 (s, 1H, NH), 7.42 (d, J = 8.0 Hz, 2H, ArH), 7.32–7.46 (m, 3H, ArH),
1
3
7
.56–7.78 (m, 5H) ppm; C NMR (125 MHz, DMSO-d ) d: 14.0, 18.0, 38.4, 59.9,
6
1
01.9, 105.7, 123.8, 126.4, 127.4, 128.4, 128.7, 129.8, 134.5, 140.6, 143.9, 147.4,
?
70.9 ppm; MS (ESI): m/z 330 (M?H) . Anal. Calcd. for C H NO (%): C, 83.89;
1
H, 6.99; N, 4.25. Found: C, 83.80; H, 6.91; N, 4.19.
2
3 23
7
8
,7-Dimethyl-5-oxo-2-(4-nitrophenyl)-4-phenyl-1,4,5,6,7,
-hexahydroquinoline (4b)
-
1
IR (KBr, cm ): 3,278, 3,076, 2,972, 2,888, 1,655, 1,590, 1,556, 1,494, 1,398,
1
1
,344, 843, 759, 695; H NMR (500 MHz, DMSO-d ) d: 0.96 (s, 3H, CH ), 1.08 (s,
6
3
3
J = 6.8 Hz, 1H), 6.79 (s, 1H, NH), 7.42 (d, J = 8.4 Hz, 2H, ArH), 7.78 (d,
H, CH ), 2.22–2.36 (m, 4H, 2 9 CH ), 5.73 (d, J = 6.8 Hz, 1H), 6.69 (d,
3
2
1
J = 8.4 Hz, 2H, ArH), 7.28–7.36 (m, 5H, ArH) ppm; C NMR (125 MHz, DMSO-
3
d ) d: 14.1, 18.4, 22.4, 35.6, 60.6, 104.0, 106.2, 120.7, 123.4, 126.9, 128.1, 130.2,
6
?
30.6, 134.8, 141.2, 143.7, 146.5, 170.1 ppm; MS (ESI): m/z 375 (M?H) . Anal.
1
Calcd. for C H N O (%): C, 73.79; H, 5.88; N, 7.48. Found: C, 73.75; H, 5.90; N,
2
3 22 2 3
7
.50.
7
8
,7-Dimethyl-5-oxo-2-(4-chlorophenyl)-4-phenyl-1,4,5,6,7,
-hexahydroquinoline (4c)
-
1
1
IR (KBr, cm ): 3,244, 3,028, 2,984, 1,628, 1,588, 1,500, 834, 766, 696; H NMR
(
500 MHz, DMSO-d ) d: 0.98 (s, 3H, CH ), 1.09 (s, 3H, CH ), 2.31–2.44 (m, 4H,
6
3
3
2
7
9 CH ), 5.70 (d, J = 6.6 Hz, 1H), 6.64 (d, J = 6.6 Hz, 1H), 6.89 (s, 1H, NH),
.38 (d, J = 8.4 Hz, 2H, ArH), 7.66 (d, J = 8.4 Hz, 2H, ArH), 7.52–7.66 (m, 5H,
2
1
3
ArH) ppm; C NMR (125 MHz, DMSO-d ) d: 14.2, 18.2, 35.5, 60.6, 104.3, 106.3,
6
1
MS (ESI): m/z 364.45 (M?H) . Anal. Calcd. for C H ClNO (%): C, 75.94; H,
20.6, 123.5, 127.4, 128.2, 129.7, 130.2, 134.90, 141.3, 143.4, 146.8, 169.6 ppm;
?
2
3 22
6
.05; N, 3.85. Found: C, 75.90; H, 6.04; N, 3.82.
7
8
,7-Dimethyl-5-oxo-2-(4-bromophenyl)-4-phenyl-1,4,5,6,7,
-hexahydroquinoline (4d)
-
IR (KBr, cm ): 3,242, 3,038, 2,974, 1,666, 1,602, 1,506, 1,496, 832, 778, 692; H
1
1
NMR (500 MHz, DMSO-d ) d: 0.92 (s, 3H, CH ), 1.04 (s, 3H, CH ), 2.24–2.32 (m,
6
3
3
4H, 2 9 CH ), 6.76 (d, J = 6.4 Hz, 1H), 7.10 (d, J = 6.4 Hz, 1H), 7.29 (s, 1H,
2
NH), 7.44 (d, J = 8.4 Hz, 2H, ArH), 7.70 (d, J = 8.4 Hz, 2H, ArH), 7.48–7.62 (m,
1
3
5
1
1
6
H, ArH) ppm; C NMR (125 MHz, DMSO-d ) d: 14.5, 19.1, 36.1, 62.4, 100.3,
6
06.9, 122.3, 124.4, 127.4, 130.2, 130.9, 132.2, 133.5, 140.4, 141.4, 143.4,
?
69.9 ppm; MS (ESI): m/z 408.9 (M?H) . Anal. Calcd. for C H BrNO (%): C,
7.66; H, 5.40; N, 3.43. Found: C, 67.66; H, 5.39; N, 3.40.
2
3 22
123

S. S. Mansoor et al.
7
8
,7-Dimethyl-5-oxo-2-(4-methylphenyl)-4-phenyl-1,4,5,6,7,
-hexahydroquinoline (4e)
-
IR (KBr, cm ): 3,248, 3,030, 2,996, 2,980, 1,640, 1,624, 1,592, 1,490, 831, 770,
1
1
6
96; H NMR (500 MHz, DMSO-d ) d: 0.92 (s, 3H, CH ), 1.02 (s, 3H, CH ),
6
3
3
2
J = 6.4 Hz, 1H), 6.65 (s, 1H, NH), 7.32 (d, J = 8.4 Hz, 2H, ArH), 7.58 (d,
.27–2.31 (m, 4H, 2 9 CH ), 2.26 (s, 3H, CH ), 5.42 (d, J = 6.4 Hz, 1H), 6.23 (d,
2
3
1
J = 8.4 Hz, 2H, ArH), 7.44–7.56 (m, 5H, ArH) ppm; C NMR (125 MHz, DMSO-
3
d ) d: 14.2, 18.0, 37.9, 61.2, 103.4, 105.8, 122.8, 124.7, 128.5, 130.3, 131.4, 141.4,
6
?
42.5, 143.9, 147.5, 148.1, 169.8 ppm; MS (ESI): m/z 344 (M?H) . Anal. Calcd.
1
for C H NO (%): C, 83.96; H, 7.29; N, 4.08. Found: C, 83.97; H, 7.22; N, 4.04.
2
4 25
7
8
,7-Dimethyl-5-oxo-2-phenyl-4-(4-chlorophenyl)-1,4,5,6,7,
-hexahydroquinoline (4f)
-
IR (KBr, cm ): 3,244, 3,032, 2,986, 1,666, 1,606, 1,584, 1,500, 1,456, 834, 776; H
1
1
NMR (500 MHz, DMSO-d ) d: 0.96 (s, 3H, CH ), 1.04 (s, 3H, CH ), 2.30–2.42 (m,
6
3
3
4
NH), 7.33 (d, J = 8.0 Hz, 2H, ArH), 7.53 (d, J = 8.0 Hz, 2H, ArH), 7.55–7.77 (m,
H, 2 9 CH ), 5.62 (d, J = 6.8 Hz, 1H), 6.32 (d, J = 6.8 Hz, 1H), 7.25 (s, 1H,
2
1
3
5
1
1
H, ArH) ppm; C NMR (125 MHz, DMSO-d ) d: 14.1, 20.4, 33.9, 61.3, 104.4,
6
05.8, 122.8, 123.4, 124.9, 127.7, 132.5, 133.3, 134.4, 136.2, 140.1, 141.5, 143.5,
?
49.6, 168.7 ppm; MS (ESI): m/z 364.45 (M?H) . Anal. Calcd. for C H ClNO
2
3 22
(
%): C, 75.94; H, 6.05; N, 3.85. Found: C, 75.90; H, 6.02; N, 3.82.
7
8
,7-Dimethyl-5-oxo-2-phenyl-4-(4-nitrophenyl)-1,4,5,6,7,
-hexahydroquinoline (4g)
-
IR (KBr, cm ): 3,344, 3,040, 2,952, 2,862, 1,654, 1,588, 1,478, 832, 752, 696; H
1
1
NMR (500 MHz, DMSO-d ) d: 0.98 (s, 3H, CH ), 1.06 (s, 3H, CH ), 2.33–2.42 (m,
6
3
3
4H, 2 9 CH ), 6.04 (d, J = 6.4 Hz, 1H), 6.54 (d, J = 6.4 Hz, 1H), 6.88 (s, 1H,
2
NH), 7.36 (d, J = 8.0 Hz, 2H, ArH), 7.60 (d, J = 8.0 Hz, 2H, ArH), 7.50–7.62 (m,
1
3
5
9
1
7
H, ArH) ppm; C NMR (125 MHz, DMSO-d ) d: 14.4, 17.9, 36.3, 55.6, 62.3,
6
8.5, 106.4, 113.6, 126.4, 127.2, 128.5, 130.4, 134.5, 139.6, 140.4, 141.7, 155.6,
?
69.8 ppm; MS (ESI): m/z 375 (M?H) . Anal. Calcd. for C H N O (%): C,
3.79; H, 5.88; N, 7.49. Found: C, 73.74; H, 5.85; N, 7.47.
2
3 22 2 3
7
8
,7-Dimethyl-5-oxo-2-phenyl-4-(4-methoxyphenyl)-1,4,5,6,7,
-hexahydroquinoline (4h)
-
IR (KBr, cm ): 3,222, 3,034, 2,952, 2,860, 2,828, 1,660, 1,584, 1,444, 840, 759,
1
1
6
96; H NMR (500 MHz, DMSO-d ) d: 0.94 (s, 3H, CH ), 1.04 (s, 3H, CH ),
6
3
3
2
J = 7.0 Hz, 1H), 7.15 (s, 1H, NH), 7.36 (d, J = 8.4 Hz, 2H, ArH), 7.64 (d,
.19–2.31 (m, 4H, 2 9 CH ), 3.78 (s, 3H, OCH ), 5.80 (d, J = 7.0 Hz, 1H), 6.64 (d,
2
3
1
J = 8.4 Hz, 2H, ArH), 7.46–7.72 (m, 5H, ArH) ppm; C NMR (125 MHz, DMSO-
3
d ) d: 14.1, 21.1, 32.4, 60.5, 100.3, 105.4, 119.4, 122.4, 126.4, 129.4, 130.6, 133.3,
6
?
35.6, 140.4, 143.7, 144.4, 145.8, 148.5, 169.5 ppm; MS (ESI): m/z 360 (M?H) .
1
1
23

4 2
Silica-supported perchloric acid (HClO –SiO )
Anal. Calcd. for C H NO (%): C, 80.22; H, 6.98; N, 3.90. Found: C, 80.20; H,
2
4
25
2
7
.00; N, 3.88.
7
8
,7-Dimethyl-5-oxo-2-phenyl-4-(4-methylphenyl)-1,4,5,6,7,
-hexahydroquinoline (4i)
-
1
1
IR (KBr, cm ): 3,228, 3,044, 2,948, 2,872, 1,662, 1,582, 1,490, 812, 762, 694; H
NMR (500 MHz, DMSO-d ) d: 0.92 (s, 3H, CH ), 1.04 (s, 3H, CH ), 2.31–2.45 (m,
6
3
3
4
H, 2 9 CH ), 2.24 (s, 3H, CH ), 5.61 (d, J = 7.0 Hz, 1H), 5.84 (d, J = 7.0 Hz,
2 3
1
H), 6.22 (s, 1H, NH), 7.40 (d, J = 8.4 Hz, 2H, ArH), 7.54 (d, J = 8.4 Hz, 2H,
1
3
ArH), 7.41–7.63 (m, 5H, ArH) ppm; C NMR (125 MHz, DMSO-d ) d: 14.4, 20.5,
6
3
3.8, 62.4, 104.5, 106.1, 124.7, 128.9, 130.8, 131.9, 132.7, 141.5, 141.9, 142.6,
?
47.2, 148.5, 168.3 ppm; MS (ESI): m/z 344 (M?H) . Anal. Calcd. for C H NO
%): C, 83.96; H, 7.29; N, 4.08. Found: C, 83.92; H, 7.26; N, 4.06.
1
2
4 25
(
7,7-Dimethyl-5-oxo-2-(4-chlorophenyl)-4-(3-nitrophenyl)-1,4,5,6,7,8-
hexahydroquinoline (4j)
-
IR (KBr, cm ): 3,228, 3,074, 2,966, 1,668, 1,588, 1,534, 1,492, 1,344, 826; H
1
1
NMR (500 MHz, DMSO-d ) d: 0.94 (s, 3H, CH ), 1.04 (s, 3H, CH ), 2.23–2.33 (m,
6
3
3
4H, 2 9 CH ), 5.74 (d, J = 6.6 Hz, 1H), 6.62 (d, J = 6.6 Hz, 1H), 7.12 (s, 1H,
2
NH), 7.34 (d, J = 8.4 Hz, 2H, ArH), 7.54 (d, J = 8.4 Hz, 2H, ArH), 7.44–7.60 (m,
1
3
4
1
1
6
H, ArH) ppm; C NMR (125 MHz, DMSO-d ) d: 14.1, 19.1, 33.3, 61.6, 103.7,
6
05.6, 124.8, 128.0, 128.8, 131.6, 132.6, 140.9, 141.2, 141.5, 146.3, 147.6,
?
68.1 ppm; MS (ESI): m/z 409.45 (M?H) . Anal. Calcd. for C H ClN O (%): C,
7.56; H, 5.16; N, 6.82. Found: C, 67.54; H, 5.12; N, 6.79.
2
3
21
2 3
7
8
,7-Dimethyl-5-oxo-2-(4-nitrophenyl)-4-(4-chlorophenyl)-1,4,5,6,7,
-hexahydroquinoline (4k)
-
1
1
IR (KBr, cm ): 3,226, 3,076, 2,964, 1,664, 1,584, 1,534, 1,496, 1,348, 828; H
NMR (500 MHz, DMSO-d ) d: 0.82 (s, 3H, CH ), 1.00 (s, 3H, CH ), 2.18–2.29 (m,
6
3
3
4
NH), 7.48 (d, J = 8.0 Hz, 2H, ArH), 7.60 (d, J = 8.0 Hz, 2H, ArH), 7.38–7.46 (m,
H, 2 9 CH ), 5.64 (d, J = 6.5 Hz, 1H), 5.81 (d, J = 6.5 Hz, 1H), 6.20 (s, 1H,
2
1
3
4
1
1
6
H, ArH) ppm; C NMR (125 MHz, DMSO-d ) d: 13.9, 21.6, 33.6, 63.4, 105.7,
6
06.6, 123.2, 126.9, 131.5, 131.6, 133.4, 141.5, 141.9, 143.8, 147.6, 148.7,
?
65.6 ppm; MS (ESI): m/z 409.45 (M?H) . Anal. Calcd. for C H ClN O (%):C,
7.56; H, 5.16; N, 6.82. Found: C, 67.55; H, 5.15; N, 6.83.
2
3
21
2 3
7
8
,7-Dimethyl-5-oxo-2-(4-chlorophenyl)-4-(4-methylphenyl)-1,4,5,6,7,
-hexahydroquinoline (4 l)
-
IR (KBr, cm ): 3,318, 3,040, 2,956, 2,878, 1,666, 1,584, 1,496, 816, 774; H NMR
1
1
(
500 MHz, DMSO-d ) d: 0.96 (s, 3H, CH ), 1.08 (s, 3H, CH ), 2.27–2.39 (m, 4H,
6
3
3
2
7
9 CH ), 2.22 (s, 3H, CH ), 6.37 (d, J = 7.0 Hz, 1H), 6.98 (d, J = 7.0 Hz, 1H),
2 3
.21 (s, 1H, NH), 7.42 (d, J = 8.0 Hz, 2H, ArH), 7.78 (d, J = 8.0 Hz, 2H, ArH),
123

S. S. Mansoor et al.
1
3
7
6
1
.57–7.71 (m, 4H, ArH) ppm; C NMR (125 MHz, DMSO-d ) d: 14.1, 18.4, 36.4,
6
3.3, 99.6, 107.6, 125.8, 127.9, 128.3, 129.3, 130.2, 132.7, 134.5, 139.6, 141.3,
?
42.0, 170.3 ppm; MS (ESI): m/z 378.45 (M?H) . Anal. Calcd. for C H ClNO
2
4 24
(
%): C, 76.30; H, 6.36; N, 3.71. Found: C, 76.28; H, 6.40; N, 3.71.
Conclusions
HClO –SiO is an efficient, non-toxic, reusable and solid-supported acid catalyst,
4
2
prepared and utilized for synthesis of 1,4-DHPs via three-component reaction of
dimedone with a wide range of 1,3-diphenyl-2-propen-1-one derivatives and
ammonium acetate in solvent-free condition. This modified methodology is superior
to existing methodologies for synthesis of 1,4-DHPs.
Acknowledgments The authors gratefully acknowledge the University Grants Commission, Govern-
ment of India, New Delhi for financial support (Major Research Project: F. No. 40-44/2011(SR)). The
authors also acknowledge C. Abdul Hakeem College Management, Dr. W. Abdul Hameed, Principal and
Dr. M. S. Dastageer, Head of the Research Department of Chemistry for the facilities and support.
References
1. A. Domling, I. Ugi, Angew. Chem. Int. Ed. 39, 3168 (2000)
2. P. Karthikeyan, S.S.Kumar, A.S. Arunrao, M.P. Narayan, P.R. Bhagat, Res Chem. Intermed. (2012).
doi:10.1007/s11164-012-0689-4
3
4
5
. Z. Song, X. Sun, L. Liu, Y. Cui, Res. Chem. Intermed. (2012). doi:10.1007/s11164-012-0744-1
. K. Sirisha, D. Bikshapathi, G. Achaiah, V.M. Reddy, Eur. J. Med. Chem. 46, 1564 (2011)
. C.E. Sunkel, M.F. Fau de Casa-Juana, L. Santos, A.G. Garcia, C.R. Artalijero, M. Villarroya, M.A.
Gonzalez-Morales, M.G. Lopez, J. Cillero, S. Alonso, J.P. Priego, J. Med. Chem. 35, 2407 (1992)
. D. Vo, W.C. Matowe, M. Ramesh, N. Iqbal, M.W. Wolowyk, S.E. Howlett, E.E. Knaus, J. Med.
Chem. 38, 2851 (1995)
6
7. S.F. Flaim, R. Zelis, Fed. Proc. 40, 2877 (1981)
8. T. Godfraind, S.J. Salomone, Cardiovasc. Pharmacol. 30, S1 (1997)
9. P.A. Van Zwieten, Blood Press. 1, 5 (1998)
1
1
1
1
1
1
1
0. W.G. Nayler, J. Clin. Basic Cardiol. 2, 155 (1999)
1. R.S. Kumar, A. Idhayadhulla, A.J.A. Nasser, J. Selvin, Eur. J. Med. Chem. 46, 804 (2011)
2. V. Klusa, Drugs Future 20, 135 (1995)
3. R.G. Bretzel, C.C. Bollen, E. Maeser, K.F. Federlin, Am. J. Kidney Dis. 21, 53 (1993)
4. R. Boer, V. Gekker, Drugs Future 20, 499 (1995)
5. R.G. Bretzel, C.C. Bollen, E. Maeser, K.F. Federlin, Am. J. Kidney Dis. 17, 465 (1992)
6. A.R. Trivedi, D.K. Dodiya, B.H. Dholariya, V.B. Kataria, V.R. Bhuva, V.H. Shah, Bioorg. Med.
Chem. Lett. 21, 5181 (2011)
17. M. Khoshneviszadeh, N. Edraki, K. Javidnia, A. Alborzi, B. Pourabbas, J. Mardaneh, R. Miri Bioorg,
Med. Chem. 17, 1579 (2009)
8. A.C. Gaudio, A. Korolkovas, Y. Takahata, J. Pharm. Sci. 83, 1110 (1994)
9. A. Hantzsch, Liebigs Ann. Chem. 215, 1 (1882)
0. R. Alajarin, J.J. Vaquero, J.L.N. Garcia, J. Alvarez-Builla, Synlett. 297 (1992)
1. A. Sausins, G. Duburs, Heterocycles 27, 269 (1988)
2. R. Surasani, D. Kalita, A.V.D. Rao, K. Yarbagi, K.B. Chandrasekhar, J. Fluor. Chem. 135, 91 (2012)
3. S. Ko, C.F. Yao, Tetrahedron 62, 7293 (2006)
4. A. Khojastehnezhad, F. Moeinpour, A. Davoodnia, Chin. Chem. Lett. 22, 807 (2011)
5. S. Kumar, P. Sharma, K.K. Kapoor, M.S. Hundal, Tetrahedron 64, 536 (2008)
6. S. Ko, C.F. Yao, Tetrahedron Lett. 62, 7293 (2006)
1
1
2
2
2
2
2
2
2
2
7. A. Kumar, R.A. Maurya, Synlett 6, 883 (2008)
1
23

4 2
Silica-supported perchloric acid (HClO –SiO )
2
8. S. Chandrasekhar, Y.S. Rao, L. Sreelakshmi, B. Mahipal, C.R. Reddy, Synthesis 11, 1737 (2008)
9. A. Debache, W. Ghalem, R. Boulcina, A. Belfaitah, S. Rhouati, B. Carboni, Tetrahedron Lett. 50,
248 (2009)
2
5
3
3
3
3
0. J. Safari, S.H. Banitaba, S.D. Khalili, J. Mol. Catal. A Chem. 335, 46 (2011)
1. T.-S. Jin, Y. Yin, L.-B. Liu, T.-S. Li, Arkivoc xiv, 28 (2006)
2. S.S. Mansoor, S.S. Shafi, S.Z. Ahmed, Arab. J. Chem. (2011). doi:10.1016/j.Arabjc.2011.09.018
3. S.S. Mansoor, K. Aswin, K. Logaiya, S.P.N. Sudhan, J. Saudi Chem. Soc. (2012). http://dx.doi.org/
1
0.1016/j.jscs.2012.04.008
4. S.S. Mansoor, K. Aswin, K. Logaiya, S.P.N. Sudhan, J. Saudi Chem. Soc. (2012). http://dx.doi.org/
0.1016/j.jscs.2012.06.003
5. S.S. Mansoor, K. Aswin, K. Logaiya, S.P.N. Sudhan, J. Saudi Chem. Soc. (2012). http://dx.doi.org/
0.1016/j.jscs.2012.07.011
3
3
1
1
3
3
3
6. S. Rostamizadeh, A.M. Amani, G.H. Mahdavinia, N. Shadjou, Chin. Chem. Lett. 20, 779 (2009)
7. M. Maheswara, V. Siddaiah, G.L.V. Damu, C.V. Rao, Arkivoc ii, 201 (2006)
8. T. Vinod Kamble, R. Kailash Kadam, S. Neeta Joshi, B. Dnyanoba Muley, Catal. Commun. 8, 498
(2007)
39. H.R. Shaterian, H. Yarahmadi, M. Ghashang, Tetrahedron 64, 1263 (2008)
40. M.A. Bigdeli, M.M. Heravi, G.H. Mahdavinia, J. Mol. Catal. A Chem. 275, 25 (2007)
41. M. Narasimhulu, T.S. Reddy, K.C. Mahesh, P. Prabhakar, C.B. Rao, Y. Venkateswarlu, J. Mol. Catal.
A Chem. 266, 114 (2007)
4
4
2. L. Nagarapu, V. Paparaju, G. Pathuri, S. Kantevari, R.R. Pakkiru, R. Kamalla, J. Mol. Catal. A Chem.
267, 53 (2007)
3. A. K. Chakraborthi, R. Gulhane, Chem. Commun. 22, 1896 (2003)
123