Efficient synthesis of 2,4-diaryl hexahydroquinoline-5-one derivatives in the presence of triethylamine

Article abstract of DOI:10.1007/s11164-014-1773-8

Abstract A convenient and efficient protocol for the synthesis of 2,4-diaryl hexahydroquinoline-5-one derivatives has been accomplished by a three-component reaction of 1,3-diaryl-2-propen-1-ones, dimedone and ammonium acetate catalyzed by triethylamine under solvent-free conditions. The simple experimental procedure, use of an inexpensive catalyst, short reaction times, and excellent yields make this procedure facile, practical, and sustainable.

Full text of DOI:10.1007/s11164-014-1773-8

Res Chem Intermed
DOI 10.1007/s11164-014-1773-8
Efficient synthesis of 2,4-diaryl hexahydroquinoline-5-
one derivatives in the presence of triethylamine
•
Zahed Karimi-Jaberi Maryam Azadi
Received: 2 June 2014 / Accepted: 23 July 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract A convenient and efficient protocol for the synthesis of 2,4-diaryl
hexahydroquinoline-5-one derivatives has been accomplished by a three-component
reaction of 1,3-diaryl-2-propen-1-ones, dimedone and ammonium acetate catalyzed
by triethylamine under solvent-free conditions. The simple experimental procedure,
use of an inexpensive catalyst, short reaction times, and excellent yields make this
procedure facile, practical, and sustainable.
Keywords 2,4-Diaryl hexahydroquinoline-5-one ꢀ Dimedone ꢀ Chalcone ꢀ
Ammonium acetate ꢀ Et3N
Introduction
Chalcones (1,3-diaryl-2-propen-1-ones) have been found to be versatile and
convenient intermediates in the synthesis of a wide variety of heterocyclic
compounds [1, 2]. Chalcones constitute an important group of natural products with
widespread distribution in spices, tea, beer, fruits and vegetables, and belong to the
flavonoid family, which possess a number of interesting biological and pharma-
cological activities [3–6]. Some of quinolines derivatives exhibit anti-bacterial, anti-
asthmatic, anti-malarial, anti-hypertensive, and anti-platelet properties and are used
as tyrosine kinase inhibitors [7, 8]. However, polyhydroquinoline derivatives show a
broad range of biological activities such as calcium antagonistic activity [9] and as
anticancer agents [10].
In addition, 1,4-dihydropyridines (DHPs) play a predominant role in medicinal
chemistry owing to their significant biological activity [11]. DHPs are commercially
Z. Karimi-Jaberi (&) ꢀ M. Azadi
Department of Chemistry, Firoozabad Branch, Islamic Azad University,
P.O. Box 74715-117, Firoozabad, Fars, Iran
e-mail: zahed.karimi@yahoo.com; z.karimi@iauf.ac.ir
123

Z. Karimi-Jaberi, M. Azadi
used as calcium channel blockers for treatment of cardiovascular diseases, including
hypertension [12].
Due to a wide range of applicability in medicine, bioorganics, industry, and
synthetic organic chemistry, various approaches toward the synthesis of this class of
compounds have been explored [10, 13–16]. 2,4-Diarylpolyhydroquinoline-5-ones
have been synthesized through the reaction of 5,5-dimethyl-1,3-cyclohexane-
dione(dimedone), 1,3-diphenyl-2-propen-1-ones (chalcones) and ammonium ace-
tate. For this synthesis, a number of methods have been reported such as DMF [17],
microwave irradiation [18] infrared irradiation [19], ionic liquid [20] and HClO4–
SiO2 [21]. However, there have always been the need to develop more efficient and
greener procedures for the synthesis of polyhydroquinolines, as well as, of course,
other kinds of organic compounds.
As a continuation of our interest in the area of development of practical and
environmentally friendly procedures for synthesis of biologically active molecules
by multicomponent reactions [22–24], here an efficient approach for the synthesis of
2,4-diaryl hexahydroquinoline-5-one derivatives has been described by three-
component reaction of 1,3-diaryl-2-propen-1-ones, dimedone and ammonium
acetate using triethylamine as a catalyst.
Experimental
1,3-diaryl-2-propen-1-ones (chalcones) have been synthesized through the cross-
aldol condensation of arylaldehydes and acetophenones according to a modified
reported method [25].
General procedure for the synthesis of 2,4-diaryl hexahydroquinoline-5-one
derivatives
A mixture of dimedone (1 mmol), 1,3-diphenyl-2-propen-1-one derivatives
(1 mmol), ammonium acetate (4 mmol) and triethylamine (0.1 ml) was stirred at
80 °C for the appropriate time, as shown in Table 1. After reaction completion, as
monitored by TLC, the reaction mixture was cooled to ambient temperature,
quenched with 1 N HCl, and extracted with chloroform. The combined organic
layer was dried over anhydrous NaSO4, filtered, and evaporated to give the crude
product. The solid was recrystalized from ethanol to afford the pure product.
Spectral data
7,7-Dimethyl-2,4-diphenyl-1,4,5,6,7,8-hexahydroquinoline-5-one (4a): IR (KBr,
1
cm-1): 3,290, 3,022, 2,981, 1,668, 1,626, 1,594, 1,488, 1,444, 778, 765, 690; H
NMR (500 MHz, DMSO-d6) d: 0.92 (s, 3H, CH3), 1.04 (s, 3H, CH3), 2.24–2.35 (m,
4H, 2 9 CH2), 5.25 (d, J = 6.6 Hz, 1H), 5.94 (d, J = 6.6 Hz, 1H), 6.57 (s, 1H,
NH), 7.42 (d, J = 8.0 Hz, 2H, ArH), 7.32–7.46 (m, 3H, ArH), 7.56–7.78 (m, 5H)
ppm; 13C NMR (125 MHz, DMSO-d6) d: 14.0, 18.0, 38.4, 59.9, 101.9, 105.7, 123.8,
126.4, 127.4, 128.4, 128.7, 129.8, 134.5, 140.6, 143.9, 147.4, 170.9 ppm;
123

Derivatives in the presence of triethylamine
Table 1 The effect of solvent on the model reaction
Entry
Solvent
Time (min)
Yield (%)
1
2
3
4
5
EtOH
180
180
150
150
45
82
78
60
80
97
MeOH
H2O
CH3CN
Solvent-free
Reaction conditions: dimedone (1 mmol), 1,3-diphenyl-2-propen-1-one (1 mmol) and ammonium acetate
(4 mmol) in the presence of Et3N (0.1 ml) at 80 °C
7,7-Dimethyl-2-phenyl-4-(4-chlorophenyl)-1,4,5,6,7,8-hexahydroquinoline-5-one
(4b): IR (KBr, cm-1): 3,244, 3,032, 2,986, 1,666, 1,606, 1,584, 1,500, 1,456, 834,
1
776; H NMR (500 MHz, DMSO-d6) d: 0.96 (s, 3H, CH3), 1.04 (s, 3H, CH3),
2.30–2.42 (m, 4H, 2 9 CH2), 5.62 (d, J = 6.8 Hz, 1H), 6.32 (d, J = 6.8 Hz, 1H),
7.25 (s, 1H, NH), 7.33 (d, J = 8.0 Hz, 2H, ArH), 7.53 (d, J = 8.0 Hz, 2H, ArH),
7.55–7.77 (m, 5H, ArH) ppm;
7,7-Dimethyl-4-(2,4-dichlorophenyl)-2-phenyl-1,4,5,6,7,8-hexahydroquinoline-
5-one (4c): IR(KBr, cm-1): 3,224, 3,062, 2,960, 1,662, 1,580, 1,488, 820, 770, 694;
1H NMR (500 MHz, DMSO-d6) d: 1.04 (s, 3H, CH3), 1.14 (s, 3H, CH3), 2.04–2.10
(m, 4H, 2 9 CH2), 2.42 (s, J = 16 Hz, 2H, CH2), 5.12 (d, J = 5.2 Hz, CH), 5.36
(d, J = 5.2 Hz, CH), 6.58 (s, 1H, NH), 7.16–7.38 (m, 3H, ArH), 7.38 (m, 5H, ArH)
ppm;
7,7-Dimethyl-2-phenyl-4-(4-nitrophenyl)-1,4,5,6,7,8-hexahydroquinoline-5-one
(4d): IR (KBr, cm-1): 3,344, 3,040, 2,952, 2,862, 1,654, 1,588, 1,478, 832, 752,
1
696; H NMR (500 MHz, DMSO-d6) d: 0.98 (s, 3H, CH3), 1.06 (s, 3H, CH3),
2.33–2.42 (m, 4H, 2 9 CH2), 6.04 (d, J = 6.4 Hz, 1H), 6.54 (d, J = 6.4 Hz, 1H),
6.88 (s, 1H, NH), 7.36 (d, J = 8.0 Hz, 2H, ArH), 7.60 (d, J = 8.0 Hz, 2H, ArH),
7.50–7.62 (m, 5H, ArH) ppm;
7,7-Dimethyl-2-phenyl-4-(4-methoxyphenyl)-1,4,5,6,7,8-hexahydroquinoline-5-
one (4e): IR (KBr, cm-1): 3,222, 3,034, 2,952, 2,860, 2,828, 1,660, 1,584, 1,444,
1
840, 759, 696; H NMR (500 MHz, DMSO-d6) d: 0.94 (s, 3H, CH3), 1.04 (s, 3H,
CH3), 2.19–2.31 (m, 4H, 2 9 CH2), 3.78 (s, 3H, OCH3), 5.80 (d, J = 7.0 Hz, 1H),
6.64 (d, J = 7.0 Hz, 1H), 7.15 (s, 1H, NH), 7.36 (d, J = 8.4 Hz, 2H, ArH), 7.64 (d,
J = 8.4 Hz, 2H, ArH), 7.46–7.72 (m, 5H, ArH) ppm;
7,7-Dimethyl-2-phenyl-4-(4-methylphenyl)-1,4,5,6,7,8-hexahydroquinoline-5-
one (4f): IR (KBr, cm-1): 3,228, 3,044, 2,948, 2,872, 1,662, 1,582, 1,490, 812, 762,
1
694; H NMR (500 MHz, DMSO-d6) d: 0.92 (s, 3H, CH3), 1.04 (s, 3H, CH3),
2.31–2.45 (m, 4H, 2 9 CH2), 2.24 (s, 3H, CH3), 5.61 (d, J = 7.0 Hz, 1H), 5.84 (d,
J = 7.0 Hz, 1H), 6.22 (s, 1H, NH), 7.40 (d, J = 8.4 Hz, 2H, ArH), 7.54 (d,
J = 8.4 Hz, 2H, ArH), 7.41–7.63 (m, 5H, ArH) ppm;
7,7-Dimethyl-2-(4-chlorophenyl)-4-(3-nitrophenyl)-1,4,5,6,7,8-hexahydroquino-
line-5-one (4g): IR (KBr, cm-1): 3,228, 3,074, 2,966, 1,668, 1,588, 1,534, 1,492,
1,344, 826; 1H NMR (500 MHz, DMSO-d6) d: 0.94 (s, 3H, CH3), 1.04 (s, 3H, CH3),
2.23–2.33 (m, 4H, 2 9 CH2), 5.74 (d, J = 6.6 Hz, 1H), 6.62 (d, J = 6.6 Hz, 1H),
123

Z. Karimi-Jaberi, M. Azadi
7.12 (s, 1H, NH), 7.34 (d, J = 8.4 Hz, 2H, ArH), 7.54 (d, J = 8.4 Hz, 2H, ArH),
7.44–7.60 (m, 4H, ArH) ppm;
7,7-Dimethyl-2-(4-nitrophenyl)-4-(4-chlorophenyl)-1,4,5,6,7,8-hexahydroquino-
line-5-one (4h): IR (KBr, cm-1): 3,226, 3,076, 2,964, 1,664, 1,584, 1,534, 1,496,
1,348, 828; 1H NMR (500 MHz, DMSO-d6) d: 0.82 (s, 3H, CH3), 1.00 (s, 3H, CH3),
2.18–2.29 (m, 4H, 2 9 CH2), 5.64 (d, J = 6.5 Hz, 1H), 5.81 (d, J = 6.5 Hz, 1H),
6.20 (s, 1H, NH), 7.48 (d, J = 8.0 Hz, 2H, ArH), 7.60 (d, J = 8.0 Hz, 2H, ArH),
7.38–7.46 (m, 4H, ArH) ppm;
7,7-Dimethyl-2-(4-chlorophenyl)-4-(4-methylphenyl)-1,4,5,6,7,8-hexahydroquin-
oline-5-one (4i): IR (KBr, cm-1): 3,318, 3,040, 2,956, 2,878, 1,666, 1,584, 1,496,
1
816, 774; H NMR (500 MHz, DMSO-d6) d: 0.96 (s, 3H, CH3), 1.08 (s, 3H, CH3),
2.27–2.39 (m, 4H, 2 9 CH2), 2.22 (s, 3H, CH3), 6.37 (d, J = 7.0 Hz, 1H), 6.98 (d,
J = 7.0 Hz, 1H), 7.21 (s, 1H, NH), 7.42 (d, J = 8.0 Hz, 2H, ArH), 7.78 (d,
J = 8.0 Hz, 2H, ArH), 7.57–7.71 (m, 4H, ArH) ppm;
7,7-Dimethyl-2-(4-nitrophenyl)-4-phenyl-1,4,5,6,7,8-hexahydroquinoline-5-one
(4j): IR (KBr, cm-1): 3,278, 3,076, 2,972, 2,888, 1,655, 1,590, 1,556, 1,494, 1,398,
1,344, 843, 759, 695; 1H NMR (500 MHz, DMSO-d6) d: 0.96 (s, 3H, CH3), 1.08 (s,
3H, CH3), 2.22–2.36 (m, 4H, 2 9 CH2), 5.73 (d, J = 6.8 Hz, 1H), 6.69 (d,
J = 6.8 Hz, 1H), 6.79 (s, 1H, NH), 7.42 (d, J = 8.4 Hz, 2H, ArH), 7.78 (d,
J = 8.4 Hz, 2H, ArH), 7.28–7.36 (m, 5H, ArH) ppm;
7,7-Dimethyl-2-(4-chlorophenyl)-4-phenyl-1,4,5,6,7,8-hexahydroquinoline-5-one
1
(4k): IR (KBr, cm-1): 3,244, 3,028, 2,984, 1,628, 1,588, 1,500, 834, 766, 696; H
NMR (500 MHz, DMSO-d6) d: 0.98 (s, 3H, CH3), 1.09 (s, 3H, CH3), 2.31–2.44 (m,
4H, 2 9 CH2), 5.70 (d, J = 6.6 Hz, 1H), 6.64 (d, J = 6.6 Hz, 1H), 6.89 (s, 1H,
NH), 7.38 (d, J = 8.4 Hz, 2H, ArH), 7.66 (d, J = 8.4 Hz, 2H, ArH), 7.52–7.66 (m,
5H, ArH) ppm;
7,7-Dimethyl-2-(4-bromophenyl)-4-phenyl-1,4,5,6,7,8-hexahydroquinoline-5-one
(4l): IR (KBr, cm-1): 3,242, 3,038, 2,974, 1,666, 1,602, 1,506, 1,496, 832, 778, 692;
1H NMR (500 MHz, DMSO-d6) d: 0.92 (s, 3H, CH3), 1.04 (s, 3H, CH3), 2.24–2.32
(m, 4H, 2 9 CH2), 6.76 (d, J = 6.4 Hz, 1H), 7.10 (d, J = 6.4 Hz, 1H), 7.29 (s, 1H,
NH), 7.44 (d, J = 8.4 Hz, 2H, ArH), 7.70 (d, J = 8.4 Hz, 2H, ArH), 7.48–7.62 (m,
5H, ArH) ppm;
7,7-Dimethyl-2-(4-methylphenyl)-4-phenyl-1,4,5,6,7,8-hexahydroquinoline-5-
one (4m): IR (KBr, cm-1): 3,248, 3,030, 2,996, 2,980, 1,640, 1,624, 1,592, 1,490,
1
8,31, 770, 696; H NMR (500 MHz, DMSO-d6) d: 0.92 (s, 3H, CH3), 1.02 (s, 3H,
CH3), 2.27–2.31 (m, 4H, 2 9 CH2), 2.26 (s, 3H, CH3), 5.42 (d, J = 6.4 Hz, 1H),
6.23 (d, J = 6.4 Hz, 1H), 6.65 (s, 1H, NH), 7.32 (d, J = 8.4 Hz, 2H, ArH), 7.58 (d,
J = 8.4 Hz, 2H, ArH), 7.44–7.56 (m, 5H, ArH) ppm;
Results and discussion
First, 1,3-diaryl-2-propen-1-ones (chalcones) have been synthesized through the
cross-aldol condensation of arylaldehydes and acetophenones according to a
modified reported method (Scheme 1) [25].
123

Derivatives in the presence of triethylamine
O
O
O
NaOH
H
R
R
'
R
R'
R
O
O
O
Et3N
CH3COONH4
N
H
R'
O
R
R'
1
2
3
4
Scheme 1 Synthesis of 2,4-diaryl hexahydroquinoline-5-one derivatives
Table 2 Optimization of temperature
Entry
Temperature
Time (min)
Yield (%)
1
2
3
3
4
5
6
r.t.
50
60
70
80
90
100
180
100
100
60
50
76
82
88
96
89
87
45
45
45
Reaction conditions: dimedone (1 mmol), 1,3-diphenyl-2-propen-1-one (1 mmol) and ammonium acetate
(4 mmol) in the presence of Et3N (0.1 ml)
In the initial experiment, various conditions have been investigated in the model
three-component reaction of 1,3-diphenyl-2-propen-1-one 1, dimedone 2 and
ammonium acetate 3 in the presence of Et3N.
The reactions were scrutinized using different conditions. In this context, various
solvents, such as EtOH, CH3CN, H2O, MeOH and solvent-free conditions, were
investigated. Under solvent-free conditions, the best level for the synthesis of diaryl
hexahydroquinoline was determined (Table 1). The effect of temperature was also
evaluated for the model reaction. However, at room temperature, it was found that
reaction time increases with a decrease in yield of the product. The best results have
been obtained at 80 °C. So, 80 °C was chosen as the reaction temperature for all
subsequent reactions (Table 2).
Therefore, the results show that the reaction proceeds cleanly at 80 °C in 45 min
affording the product 4a in 97 % yield using 0.1 ml of triethylamine under solvent-
free conditions.
As represented in Table 3, all chalcones reacted well to give the expected
products at high yields, either bearing electron-withdrawing groups or electron-
donating groups. The structures of 4a–m were determined on the basis of their NMR
and IR spectral data [17–21].
123

Z. Karimi-Jaberi, M. Azadi
Table 3 Reaction of dimedone, 1,3-diaryl-2-propen-1-one derivatives and ammonium acetate
R
O
O
O
Et3N
CH3COONH4
N
H
R'
O
R
R'
4
1
2
3
Entry
R
H
R0
Product
Time (min)
Yield (%)
m.p. (°C) [17–21]
1
H
4a
4b
4c
4d
4e
4f
45
25
20
35
40
55
30
35
50
25
30
45
55
97
93
91
93
86
84
93
93
85
87
91
89
88
204–206
222–224
205–207
210–213
192–194
185–187
235–237
241–143
234–236
220–223
249–251
231–233
211–213
2
4-Cl
H
3
2,4-Cl2C6H3
4-NO2
4-OCH3
4-CH3
3-NO2
4-Cl
H
4
H
5
H
6
H
7
4-Cl
4-NO2
4-Cl
4-NO2
4-Cl
4-Br
4-CH3
4g
4h
4i
8
9
4-CH3
H
10
11
12
13
4j
H
4k
4l
H
H
4m
Under the optimal reaction conditions, a range of 1,3-diaryl-2-propen-1-ones
were treated with dimedone and ammonium acetate in order to examine the scope of
the three-component reaction. It was found that most of the reactions proceeded
smoothly to afford the corresponding 2,4-diaryl hexahydroquinoline-5-one 4a-m in
good to excellent yields (84–97 %), and several representative examples are
summarized in Table 3.
Conclusion
In conclusion, a convenient and novel alternative method has been described for the
synthesis of 2,4-diaryl hexahydroquinoline-5-one derivatives by a three-component
reaction of 1,3-diaryl-2-propen-1-ones, dimedone and ammonium acetate catalyzed
by triethylamine at 80 °C under solvent-free conditions. This method has the
advantages of short reaction times with excellent yields, mild reaction conditions,
simple workup, and using an inexpensive catalyst.
Acknowledgment We gratefully acknowledge the funding support from Islamic Azad University,
Firoozabad Branch.
123

Derivatives in the presence of triethylamine
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