P-TSA catalyzed facile and efficient synthesis of polyhydroquinoline derivatives through Hantzsch multi-component condensation

Article abstract of DOI:10.1248/cpb.56.1002

A facile and efficient synthetic route to polyhydroquinolines has been developed via four-component condensation reactions of aldehydes, dimedone, ethyl acetoacetate and ammonium acetate in the presence of p-toluene-sulfonic acid (p-TSA) catalyst in ethan

Full text of DOI:10.1248/cpb.56.1002

1
002
Notes
Chem. Pharm. Bull. 56(7) 1002—1004 (2008)
Vol. 56, No. 7
P-TSA Catalyzed Facile and Efficient Synthesis of Polyhydroquinoline
Derivatives through Hantzsch Multi-Component Condensation
Sanjeeva Reddy CHERKUPALLY* and Raghu MEKALA
Department of Chemistry, Kakatiya University; Warangal-506 009, India.
Received January 25, 2008; accepted April 2, 2008; published online April 9, 2008
A facile and efficient synthetic route to polyhydroquinolines has been developed via four-component conden-
sation reactions of aldehydes, dimedone, ethyl acetoacetate and ammonium acetate in the presence of p-toluene-
sulfonic acid (p-TSA) catalyst in ethanol at ambient temperature through Hantzsch reaction. Simple work-up
procedure, environmentally friendly, inexpensive and non-toxic catalyst, shorter reaction times along with excel-
lent product yields are the significant features of this practical method.
Key words p-toluenesulfonic acid; polyhydroquinoline; one-pot conversion; multi-component condensation
Compounds containing the 4-substituted 1,4-dihydropyri- in the presence of p-TSA catalyst to form the corresponding
dine (DHP) nucleus comprise a large family of medicinally polyhydroquinolines 5. Excellent yields of polyhydroquino-
important compounds. They can cure the disordered heart lines were obtained by carrying out the reaction in ethanol
ratio as a chain-cutting agent of factor IV channel, possess solvent at room temperature for 2—3 h (Chart 1).
the calcium channel agonist-antagonist modulation activi-
The scope and generality of this four-component coupling
1—3)
ties
and also behave as neuroprotectants, cerebral antiis- one-pot synthesis of polyhydroquinoline derivatives through
4,5)
chaemic agents and chemosensitizers. A recent computa- Hantzsch reaction is illustrated with different aldehydes
tional analysis of the comprehensive medicinal chemistry (Table 1). This method has the ability to tolerate a variety of
database found that the DHP framework to be among the functional groups such as hydroxyl, methoxy, methyl, nitro,
most prolific chemotypes found. Thus, the synthesis of 4- halides, olefins etc., under the reaction conditions. Both, the
substituted 1,4-dihydro-pyridines (1,4-DHPs) is of continu- electron-rich and electron-deficient aldehydes as well as het-
ing interest.
erocyclic aldehyde (furfural) worked well, leading to high
Recently, several methods have been reported comprising yields of product. The structures of all the products were es-
6
)
7)
the use of microwave, iodotrimethylsilane (TMSI), ionic tablished from their spectral data.
8,9)
10)
11)
12)
liquids,
metal triflates,
organocatalysts and polymers
HY-zeolite,
HClO –SiO ,
Under solvent free conditions, the reaction proceeded
4
2
13)
14,15)
for the synthesis of 1,4- quickly but the obtained yellow solid contained many other
DHPs. However, the use of high temperatures, expensive by products. We then studied the reaction using different sol-
metal precursors, catalysts that are harmful to environment, vents. In each case, the reactants were mixed together with
and longer reaction times limit the use of these methods. 10 mol% p-TSA, stirred with 5 ml solvent. The polar sol-
Therefore, there is a scope to find potential alternate proce- vents such as ethanol and acetonitrile were found much bet-
dures for the synthesis of 1,4-DHPs especially that are in
high demand and having advantages such as low cost, non-
toxic and environmentally benign.
In recent years, p-toluenesulfonic acid (p-TSA) has been
1
6—22)
used for many synthetic organic transformations
includ-
ing the synthesis of ZDO947, in which it has been used as a
23)
dehydrating reagent. The most characteristic feature of p-
TSA is that its catalytic amount is only enough to complete
reactions in many cases. Additionally, many advantages such
as low cost, eco-friendly nature, ease of handling, non-toxic-
ity and high reactivity make p-TSA a potent catalyst in the
synthetic transformations. These facts inspired us to use p-
TSA catalyst for the synthesis of polyhydroquinolines. More-
over, no report has been made so far about the use of p-TSA
as a catalyst in the Hantzsch condensation. Herein, we report
the studies of a facile Hantzsch condensation for the synthe-
sis of polyhydroquinoline derivatives by one-pot four-compo-
nent condensation of aldehydes, dimedone, ethyl acetoacetate
and ammonium acetate using a catalytic amount of p-TSA at
ambient temperature. This method not only preserves the
simplicity, but also consistently gives the corresponding
products in good to excellent yields.
Chart 1
Thus, we have treated a variety of substituted aldehydes 1,
dimedone 2, ethyl acetoacetate 3, and ammonium acetate 4,
Chart 2
∗
To whom correspondence should be addressed. e-mail: chsrkuc@yahoo.co.in
© 2008 Pharmaceutical Society of Japan

July 2008
1003
Table 1. p-TSA Catalyzed Synthesis of Polyhydroquinoline Derivatives
Time
h)
Yield
(%)
Entry
Aldehyde
Product
Product characterization data
a)
(
1
4)
ꢀ1
mp 202—204 °C (lit. 203—204 °C ). IR (KBr) cm : 3287, 3077, 2964,
1
1
696, 1610. H-NMR (CDCl ) d: 0.93 (3H, s), 1.06 (3H, s), 1.20 (3H, t,
Jꢁ7.1 Hz), 2.12—2.28 (4H, m), 2.34 (3H, s), 4.05 (2H, q, Jꢁ7.1 Hz),
3
5
5
5
5
a
b
c
2.0
2.0
2.5
2.0
93
85
91
90
5
7
.06 (1H, s), 6.63 (1H, s), 7.07—7.12 (1H, m), 7.17—7.22 (2H, m),
.27—7.32 (2H, m).
14)
ꢀ1
mp 178—180 °C (lit. 178—179 °C ). IR (KBr) cm : 3285, 3210, 3080,
1
2
960, 1705, 1605, 1530. H-NMR (CDCl ) d: 0.93 (3H, s), 1.08 (3H, s),
3
1.21 (3H, t, Jꢁ7.1 Hz), 2.12—2.41 (7H, m), 3.68 (2H, q, Jꢁ7.1 Hz), 5.15
(
1H, s), 6.86 (1H, s), 7.35 (1H, t, Jꢁ7.9 Hz), 7.72 (1H, d, Jꢁ7.9 Hz), 7.96
(1H, m), 7.98 (1H, m).
14)
ꢀ1
mp 184—186 °C (lit. 185—186 °C ). IR (KBr) cm : 3290, 2960, 1695,
1
1
610, 1490, 1380, 1220, 1025, 764. H-NMR (CDCl ) d: 0.93 (3H, s),
3
1.08 (3H, s), 1.19 (3H, t, Jꢁ7.3 Hz), 2.12—2.26 (4H, m), 2.37 (3H, s),
4
7
.06 (2H, q, Jꢁ7.3 Hz), 5.02 (1H, s), 5.81 (1H, s), 6.86—6.90 (2H, m),
.22—7.28 (2H, m).
14)
ꢀ1
mp 244—246 °C (lit. 245—246 °C ). IR (KBr) cm : 3275, 3200, 3075,
1
2
965, 1705, 1650, 1605. H-NMR (CDCl ) d: 0.94 (3H, s), 1.08 (3H, s),
3
d
1.19 (3H, t, Jꢁ7.1 Hz), 2.12—2.35 (4H, m), 2.36 (3H, s), 4.05 (2H, q,
Jꢁ7.1 Hz), 5.03 (1H, s), 6.46 (1H, s), 7.15—7.20 (2H, m), 7.25—7.27
(
2H, m).
1
4)
ꢀ1
mp 206—208 °C (lit. 207—208 °C ). IR (KBr) cm : 3062, 2955, 1720,
1
1
640, 1610, 1468, 1385, 1228, 1020, 745. H-NMR (CDCl ) d: 0.94 (3H,
3
5
e
f
2.5
2.0
89
92
s), 1.06 (3H, s), 1.20 (3H, t, Jꢁ7.2 Hz), 2.02—2.20 (4H, m), 2.39 (3H, s),
.05 (2H, q, Jꢁ7.2 Hz), 4.61 (1H, s), 7.11—7.30 (4H, m), 7.61 (1H, s).
4
14)
ꢀ1
mp 260—262 °C (lit. 261—262 °C ). IR (KBr) cm : 3275, 3080, 2960,
1
1
700, 1650. H-NMR (CDCl ) d: 0.95 (3H, s), 1.08 (3H, s), 1.21 (3H, t,
3
5
Jꢁ7.1 Hz), 2.12—2.27 (7H, m), 2.33 (3H, s), 4.05 (2H, q, Jꢁ7.1 Hz),
.02 (1H, s), 6.65 (1H, s), 7.00 (2H, d, Jꢁ7.9 Hz), 7.18
2H, d, Jꢁ7.9 Hz).
mp 255—257 °C (lit. 256—257 °C ). IR (KBr) cm : 3275, 2957, 1705,
5
(
12)
ꢀ1
1
1
647, 1605, 1497, 1382, 1217, 1032, 766. H-NMR (CDCl ꢂDMSO-d )
3 6
5
5
5
g
h
i
2.0
3.0
2.0
93
87
89
d: 0.93 (3H, s), 1.08 (3H, s), 1.22 (3H, t, Jꢁ7.2 Hz), 2.02—2.11 (4H, m),
.31 (3H, s), 3.73 (3H, s), 4.01 (2H, q, Jꢁ7.2 Hz), 4.81 (1H, s), 6.64 (2H,
d, Jꢁ7.3 Hz), 7.11 (2H, d, Jꢁ7.3 Hz), 8.64 (1H, s).
2
12)
ꢀ1
mp 232—234 °C (lit. 233—234 °C ). IR (KBr) cm : 3390, 2955, 1700,
1
1
645, 1590, 1480, 1385, 1220, 782. H-NMR (CDCl ) d: 0.93 (3H, s),
3
1.07 (3H, s), 1.19 (3H, t, Jꢁ7.2 Hz), 2.09—2.19 (3H, m), 2.20—2.34
4H, m), 4.06 (2H, q, Jꢁ7.6 Hz), 4.98 (1H, s), 5.61, (1H, s), 6.65 (2H, d,
Jꢁ8.9 Hz), 7.17 (2H, d, Jꢁ8.4 Hz).
(
1
4)
ꢀ1
mp 211—212 °C (lit. 211—212 °C ). IR (KBr) cm : 3390, 2955, 1700,
1
1
645, 1590, 1480, 1385, 1220, 1030, 782. H-NMR (CDCl ) d: 0.95 (3H,
3
s), 1.09 (3H, s), 1.24 (3H, t, Jꢁ7.2 Hz), 2.02—2.20 (4H, m), 2.30 (3H, s),
.81 (3H, s), 4.06 (2H, q, Jꢁ7.2 Hz), 4.81 (1H, s), 6.61 (2H, s), 6.83 (1H,
s), 7.69 (1H, s), 8.50 (1H, s).
mp 197—199 °C (lit. 198—199 °C ). IR (KBr) cm : 3240, 2955, 1694,
3
14)
ꢀ1
1
1
645, 1610, 1490, 1380, 1217, 1027, 753. H-NMR (CDCl ) d: 0.95 (3H,
3
s), 1.08 (3H, s), 1.21 ( 3H, t, Jꢁ7.3 Hz), 2.19—2.35 (4H, m), 2.38 (3H, s),
.82 (3H, s), 3.84 (3H, s), 4.07 (2H, q, Jꢁ7.3 Hz), 5.03 (1H, s), 5.92 (1H,
5
5
5
j
2.0
2.0
3.0
88
86
90
3
s), 6.69 (1H, d, Jꢁ8.30 Hz), 6.77 (1H, dd, Jꢁ1.96, 8.30 Hz), 6.93 (1H, d,
Jꢁ1.96 Hz).
1
5)
ꢀ1
mp 214—216 °C (lit. 213—215 °C ). IR (KBr) cm : 3282, 3080, 2960,
1
1
710, 1650, 1600, 1490. H-NMR (CDCl ) d: 0.83 (3H, s), 1.08 (3H, s),
.22 (3H, t, Jꢁ7.1 Hz), 2.13—2.39 (7H, m), 4.04 (2H, q, Jꢁ7.1 Hz), 5.03
3
k
l
1
(
1H, s), 6.42 (1H, s), 7.18 (1H, m), 7.18 (1H, m), 7.35 (1H, d, Jꢁ2.0 Hz).
1
2)
ꢀ1
mp 204—206 °C (lit. 204—206 °C ). IR (KBr) cm : 3300, 2965, 1675,
1
1
602, 1483. H-NMR (CDCl ) d: 1.09 (3H, s), 1.11 (3H, s), 1.24—1.31
(3H, m), 2.28 (3H, t, Jꢁ7.3 Hz), 2.33—2.37 (4H, m), 4.11—4.20 (2H,
m), 4.70 (1H, d, Jꢁ7.0 Hz), 5.75 (1H, s), 6.21 (2H, d, Jꢁ7.1 Hz), 7.22—
3
7
.30 (5H, m).
15)
ꢀ1
mp 199—201 °C (lit. 198—200 °C ). IR (KBr) cm : 3302, 2963, 1674,
1
1
603, 1484. H-NMR (CDCl ) d: 1.09 (3H, s), 1.13 (3H, s), 1.26 (3H, t,
3
Jꢁ7.1 Hz), 2.18—2.33 (4H, m), 2.38 (3H, s), 3.77 (3H, s), 4.13—4.27
2H, m), 4.72 (1H, d, Jꢁ6.1 Hz), 6.17 (1H, dd, Jꢁ6.1, 16.2 Hz), 6.46 (1H,
s), 6.59 (1H, d, Jꢁ16.2 Hz), 6.79—6.89 (2H, m), 7.11—7.17 (1H, m),
.38 (1H, d, Jꢁ1.3 Hz).
5m
2.5
91
(
7

1
004
Table 1. (Continued)
Entry Aldehyde
Vol. 56, No. 7
Time
h)
Yield
(%)
Product
Product characterization data
a)
(
1
4)
ꢀ1
mp 245—247 °C (lit. 246—248 °C ). IR (KBr) cm : 3288, 3078, 2969,
1
1
687, 1602, 1493, 1034, 941, 877, 826. H-NMR (CDCl ) d: 1.03 (3H, s),
3
5n
2.0
91
1.12 (3H, s), 1.26 (3H, t, Jꢁ6.9 Hz), 2.21—2.27 (3H, m), 2.35—2.38
4H, m), 4.10—4.18 (2H, m), 5.25 (1H, s), 5.80 (1H, s), 6.02 (1H, s),
.20 (1H, s), 7.17 (1H, s).
(
6
a) The yields refer to isolated products.
acetoacetate (1 mmol) and p-TSA (10 mol%) in ethanol (5 ml), aldehyde
1 mmol) and ammonium acetate (1 mmol) were added at ambient tempera-
ture. The reaction mixture was stirred at room temperature until the reaction
completed (monitored by TLC). The resulting yellow solid product was fil-
tered, treated with water followed by brine solution and extracted with ethyl
ter solvents than the non-polar solvents like toluene,
dichloromethane, cyclohexane etc. Obviously, the results
could be interpreted with the much better solubility of the
catalyst and the reagents in the polar solvents. Among
(
ethanol and acetonitrile, ethanol stands out as the solvent of acetate. The organic layer was dried over anhydrous sodium sulfate and
evaporated to dryness to afford the crude product. The crude product was
subjected to column chromatography over silica gel using 30% EtOAc in
hexane as eluent to obtain pure polyhydroquinolines.
choice, with its fast conversion, high yield and low toxicity.
We also carried out the reactions without any catalyst, but
the polyhydroquinoline derivatives were isolated in poor
yields (15—20%), and the major product isolated was a
Acknowledgement The authors thank the Director, Indian Institute of
dimedone aldehyde adduct. The use of just 10 mol% of p- Chemical Technology, Hyderabad, India for providing the spectral data.
TSA in stirring ethanol is sufficient to push the reaction for-
ward. Higher amounts of p-TSA did not lead to significant
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ian Gemini-200 MHz NMR spectrometer in CDCl or a CDCl ꢂDMSO-d
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