1,3-Disulfonic acid imidazolium hydrogen sulfate: A reusable and efficient ionic liquid for the one-pot multi-component synthesis of pyrimido[4,5-b]quinoline derivatives

Article abstract of DOI:10.1039/c5ra02198g

A green, simple and convenient method for the synthesis of pyrimido[4,5-b]quinoline derivatives has been developed through a three-component one-pot condensation of 6-amino-1,3-dimethyluracil, aldehydes, and cyclic 1,3-diketones in the presence of 1,3-dis

Full text of DOI:10.1039/c5ra02198g

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1,3-Disulfonic acid imidazolium hydrogen sulfate: a
reusable and efficient ionic liquid for the one-pot
multi-component synthesis of pyrimido[4,5-b]-
quinoline derivatives†
Cite this: RSC Adv., 2015, 5, 23586
Received 4th February 2015
Accepted 26th February 2015
a
a
b
*
*
Kamal Mohammadi, Farhad Shirini and Asieh Yahyazadeh
DOI: 10.1039/c5ra02198g
www.rsc.org/advances
A green, simple and convenient method for the synthesis of pyrimido- heterocycles made by this procedure, pyrimidoquinoline
[4,5-b]quinoline derivatives has been developed through a three- derivatives extensively investigated due to their diverse medic-
component one-pot condensation of 6-amino-1,3-dimethyluracil, inal properties.4 Many of these compounds display wide range
aldehydes, and cyclic 1,3-diketones in the presence of 1,3-disulfonic of pharmaceutical and biological activities such as antima-
acid imidazolium hydrogen sulfate [dsim]HSO4 as an efficient catalyst. larial,5 anticancer,6 antimicrobial,7 and anti-inammatory,8
The present methodology offers several advantages such as excellent activities. Further, the utility of quinoline derivatives in the
yields, simple procedure, short reaction times, high yields of the preparation of some dyes and pigments,9 avoring agents,10 and
products and easy work-up procedures. Also, the catalyst was readily in luminescence chemistry,11 has been reported.
recovered and could be reused several times without a noticeably
In view of the pharmacological and biological importance of
these heterocycles as drug molecules, many synthetic
approaches including multi-component strategies have been
developed for the synthesis of quinoline derivatives.12–15
However, most of the previously reported methods suffer from
some disadvantages such as high temperature, harsh reaction
conditions, expensive catalysts/reagents, poor yields of the
products, volatile and toxic organic solvents and long reaction
times. Therefore, to overcome these problems development of
more simple, efficient and eco-compatible procedures is still
demanding.
Because of the increasing concern of the harmful effects of
organic solvents on the environment and human body, the
investigation of greener alternatives to conventional organic
solvents has aroused the attention of organic and medicinal
chemists. In recent years, ionic liquids (ILs) have gained much
importance as environmentally and green solvents, catalysts
and reagents for a variety of chemical applications.16 Ionic
liquids are dened as salts that are in a liquid form at or below
100 ꢀC.17 They have several unique properties like high chemical
and thermal stability, negligible vapor pressure, non-volatility,
environmental compatibility, reusability, greater selectivity
and ease of isolation.18,19 ILs have been successfully employed as
dual solvent–catalyst for several organic transformations such
as esterication,20 Diels–Alder,21 and Wittig,22 synthesis.
Among them, ILs based on imidazolium ion have designed
to use instead of solid acids and traditional mineral liquid acids
like sulfuric acid and hydrochloric acid in chemical
synthesis.23,24 Also, the modication of the structures of ILs can
result in unique solvent properties that dramatically inuence
decrease in its activity.
1 Introduction
Multi-component reactions (MCRs) have recently emerged as
highly valuable synthetic tools for the rapid generation of
structurally diverse and complex heterocyclic compounds.1
These types of reactions offer signicant advantages over
conventional multi-step syntheses including high degree of
atom economy, ease of execution, bond forming efficiency,
reduction in the number of work-up steps, excellent yields,
extraction and purication processes and hence minimize
waste generation.2 Therefore, most of the scientic endeavors
have been focused on the application of the MCRs in the
synthesis of various biologically active substrates and natural
products.3
One of the most important MCRs is the electrophilic reaction
of an aldehyde with two different nucleophiles for constructing
the bioactive compounds. Among the different manufactured
aDepartment of Chemistry, College of Science, University of Guilan, PO Box
41335-1914, Rasht, Iran. E-mail: shirini@guilan.ac.ir; fshirini@gmail.com; Fax: +98
1313233262; Tel: +98 1313233262
bDepartment of Chemistry, College of Science, University of Guilan, PO Box 41335-
1914, Rasht, Iran. E-mail: yahyazadehphd@yahoo.com; Fax: +98 1313233262; Tel:
+98 1313233262
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5ra02198g
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Table 1 Effect of the catalyst concentration for the synthesis of model
the outcome of various reactions. For example, the introduction
of Brønsted-acidic functional groups into cations or anions of
the ILs, especially the SO3H-functional group, obviously
increased their acidities and water solubilities.25,26 Therefore,
these ILs can be used as highly effective acid catalysts and have
been attracted immense concern as green alternative for H2SO4,
HF and AlCl3 catalysts in organic synthesis.27
reactiona
Catalyst concentration
(mmol)
Time
(min)
Yieldb
(%)
Entry
1
2
3
4
—
200
40
15
5
68
91
91
0.15
0.25
0.35
15
a
2 Results and discussions
Reaction condition: 4-chlorobenzaldehyde (1 mmol), dimedone
(1 mmol), 6-amino-1,3-dimethyluracil (1 mmol) and different amounts
of [dsim]HSO4 at 70 ꢀC in ethanol. b Isolated yield.
Very recently we have reported the preparation of 1,3-disulfonic
acid imidazolium hydrogen sulfate [dsim]HSO4 and its applica-
tion in the promotion of the synthesis of quinoline and xanthene
derivatives.28–31 Herein and in continuation of these studies, we
wish to report the applicability of this reagent in the acceleration
of the synthesis of pyrimidoquinolines via a one-pot, three-
component reaction of aldehydes, 6-amino-1,3-dimethyluracil
and cyclic 1,3-dicarbonyl compounds using [dsim]HSO4 as
recyclable catalyst in ethanol at 70 ꢀC (Scheme 1).
Initially, the reaction of 4-chlorobenzaldehyde, 6-amino-1,3-
dimethyluracil and dimedone was selected as a model and the
effect of the catalyst concentration was examined using
different quantities of [dsim]HSO4. As can be seen from Table 1,
0.25 mmol of the catalyst gave an excellent yield in 15 min
(Table 1, entry 3). Using lower amounts of the catalyst resulted
in lower yields, while higher amounts of [dsim]HSO4 did not
improve the yield and the reaction time and in the absence of
the catalyst, the yield of the product was found to be poor aer
long reaction times.
Table
reactiona
2 Temperature optimization for the synthesis of model
Entry
Temperature (ꢀC)
Time (min)
Yieldb (%)
1
2
3
4
25
50
70
Reux
180
55
15
28
65
91
92
15
a
Reaction condition: 4-chlorobenzaldehyde (1 mmol), dimedone
(1 mmol), 6-amino-1,3-dimethyluracil (1 mmol) and [dsim]HSO4
(0.25 mmol) at different temperature in ethanol. b Isolated yield.
Table 3 Influence of the solvents on the synthesis of model reactiona
Entry
Solvent
Temperature (ꢀC)
Yieldb (%)
Next, we attempted to optimize the temperature on the
model reaction using 0.25 mmol [dsim]HSO4 in different
temperature conditions. As shown in Table 2, the shorter times
and excellent yields were obtained when the reaction was
carried out at 70 ꢀC (Table 2, entry 3). The results are also
indicated that at room temperature the reaction is not pro-
ceeded considerably even aer long times (Table 2, entry 1).
It is well known that the reaction medium plays an impor-
tant role in the catalytic reaction. In order to evaluate the effect
of solvent, we investigated different solvents in the above reac-
tion using 0.25 mmol of the catalyst at 70 ꢀC. The best reaction
activity was achieved in the system using ethanol as a solvent in
comparison with the other solvents under similar reaction
conditions (Table 3, entry 3). The results show that the catalytic
performance is strongly affected by the type of solvent.
1
2
3
4
5
6
None
90
Reux
70
85
Reux
Reux
35
80
91
60
55
10
Methanol
Ethanol
Water
Acetonitrile
n-Hexane
a
Reaction condition: 4-chlorobenzaldehyde (1 mmol), dimedone
(1 mmol), 6-amino-1,3-dimethyluracil (1 mmol) and [dsim]HSO4
(0.25 mmol) for 15 min. b Isolated yield.
ꢀ
was performed at 70 C in ethanol, while the relative ratio of
the substrate/6-amino-1,3-dimethyluracil/dimedone/[dsim]HSO4
was 1.0 mmol/1.0 mmol/1.0 mmol/0.25 mmol, respectively.
Aer optimization of the reaction conditions and in order
Consequently, optimization of the reaction conditions
showed that the best results were obtained when the reaction to study the generality of this procedure, we investigated the
reaction of 6-amino-1,3-dimethyluracil and dimedone with
various substituted benzaldehydes to give functionalized
pyrimido[4,5-b]quinolines. The results are shown in Table 4. As
expected, aromatic aldehydes containing electron-donating and/
or electron-withdrawing groups were utilized in the present case
to form the corresponding pyrimido[4,5-b]quinoline derivatives
in good to excellent yields. It was noteworthy to mention that the
transformations were carried out without any signicant
amounts of undesirable side products.
Scheme
1 The synthesis of substituted pyrimido[4,5-b]quinoline
derivatives in the presence of [dsim]HSO4.
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In order to expand the scope of the present method, the synthesis of 5-(4-chlorophenyl)-1,3,8,8-tetramethyl-7,8,9,10-tetra-
replacement of dimedone with 1,3-cyclohexanedione was also hydropyrimido[4,5-b]quinoline-2,4,6-trione. Table 5 clearly shows
examined under similar reaction conditions. It was found that that [dsim]HSO4 can act as an effective and benet catalyst
using this substrate the corresponding products could also be compared with the other reported reagents in the literature.
obtained in high yields (Table 4, entries 11–17). All the products
were characterized by NMR, IR and melting points and also by
comparison with the authentic samples reported in the
literature.
3 Experimental
3.1 General
A probable mechanism for the formation of pyrimido[4,5-b]-
quinolines is proposed in Scheme 2. On the basis of this
mechanism and at the rst step, the adduct (I) is created
through the [dsim]HSO4-catalyzed Knoevenagel condensation
between the aldehyde and cyclic 1,3-diketone. Then, the
6-amino-1,3-dimethyluracil attacks to the adduct (I) via a
Michael addition to produce an open chain intermediate (II).
Subsequently, intermediate (II) undergoes intramolecular
cyclization by the reaction of nucleophilic amino function to
carbonyl group followed by dehydration to generate pyrimido-
[4,5-b]quinolines (III).
In addition to the benets from the economic point of view,
recovery and reuse of the catalyst is very important in order to
avoid wastes. Therefore, we decided to investigate the catalytic
performance of the recycled IL in the model reaction. For this
purpose, all the water added for ltering and washing the
product, was collected and washed with CH2Cl2 (2 ꢁ 10 mL) to
remove the organic impurities. Then, water was evaporated and
the extracted catalyst was dried. As shown in Fig. 1, the recov-
Chemicals were purchased from Fluka and Merck Chemical
Companies and used without further purication. All yields
refer to isolated products and progress of the reactions was
monitored by TLC using silica gel polygrams SIL G/UV 254
plates. The products were characterized by comparison of their
spectral (IR, 1H NMR and 13C NMR) and physical data with
authentic samples.
3.2 Instrumentation
Melting points were recorded on an electrothermal digital
melting point apparatus model IA9100 in open capillary tubes.
IR spectra were recorded on a Perkin-Elmer model Spectrum
One FT-IR Spectrometer. The 1H NMR spectra were obtained on
a Bruker DRX-400 Avance spectrometer and 13C NMRs were
recorded on a Bruker DRX-100 Avance spectrometer (d in ppm).
3.3 General procedure for the synthesis of quinoline
derivatives in the presence of [dsim]HSO4
ered catalyst could be reused three times without signicant 0.25 mmol of [dsim]HSO4 was added to a mixture of aldehyde
decrease in the catalytic activity.
(1 mmol), 6-amino-1,3-dimethyluracil (1 mmol) and cyclic
To demonstrate the advantage of the present method in 1,3-diketone (1 mmol) in ethanoꢀl (1 mL). The reaction mixture
comparison with previously reported procedures, we compared was heated in an oil bath at 70 C with stirring for the appro-
the performance of [dsim]HSO4 (time, yield and reaction condi- priate time as mentioned in Table 4. Aer completion of the
tions) with the efficiency of some of the other catalysts used in the reaction (monitored by TLC), the reaction mixture was allowed
Table 4 Synthesis of pyrimido[4,5-b]quinoline derivatives using [dsim]HSO4 as the catalysta
M.P. (ꢀC)
Entry
R1
R2
Product
Time (min)
Yieldb (%)
Found
Reported [Ref.]
1
2
3
4
5
6
7
8
4-OMeC6H4
4-O2NC6H4
4-ClC6H4
2-O2NC6H4
3-O2NC6H4
3-BrC6H4
2-ClC6H4
2-Cl-6-FC6H3
4-FC6H4
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
1a
2a
3a
4a
5a
6a
7a
8a
25
15
15
35
30
30
35
20
20
20
30
18
15
15
18
30
35
85
92
91
87
90
89
88
90
90
90
89
88
90
92
90
88
86
>300
>300, [12]
—, [13]
292–294, [12]
—, [13]
This work
280–282 [14]
>300, [12]
This work
234–236 [14]
—, [13]
303–305
291–293
287–290
287–290
281–283
>300
302–304
230–232
227–230
250–252
>300
9
9a
1a
10
11
12
13
14
15
16
17
4-BrC6H4
3-O2NC6H4
4-FC6H4
11b
12b
13b
14b
15b
16b
17b
—, [13]
311–313, [15]
310–313, [15]
301–303, [15]
This work
This work
284–285 [12]
4-ClC6H4
>300
4-O2NC6H4
2-Cl-6-FC6H3
4-(CH3)2NC6H4
4-MeC6H4
300–302
298–300
278–280
281–284
a
Reaction conditions: 4-chlorobenzaldehyde (1 mmol), dimedone (1 mmol), 6-amino-1,3-dimethyluracil (1 mmol) and [dsim]HSO4 (0.25 mmol) at
70 ꢀC in ethanol. b Isolated yield.
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Scheme 2 Suggested mechanism for the synthesis of pyrimido[4,5-b]quinoline derivatives in the presence of [dsim]HSO4.
d6): d 3.16 (m, 16H), 5.69 (s, 1H), 7.49–7.53 (t, J ¼ 8 Hz, 1H, ArH),
7.59–7.61 (d, J ¼ 8.0 Hz, 1H, ArH), 7.88 (s, 1H, ArH), 7.91–7.93 (d,
J ¼ 8.0 Hz, 1H, ArH), 10.15 (s, NH) ppm; 13C NMR (100 MHz,
DMSO-d6): d 25.81, 27.72, 30.11, 30.53, 37.55, 41.90, 50.41,
89.12, 113.53, 117.21, 122.71, 127.92, 133.74, 141.60, 146.00,
147.27, 148.25, 150.12, 160.93, 195.74 ppm.
5-(2-Chloro-6-uorophenyl)-1,3,8,8-tetramethyl-7,8,9,10-tetra-
hydropyrimido[4,5-b]quinoline-2,4,6(1H,3H,5H)-trione (Table
4, entry 8). Light yellow solid, m.p. 302–304 C; IR (KBr): nmax
ꢀ
Fig. 1 Results of the reusability of [dsim]HSO4 in the synthesis of 5-(4-
chlorophenyl)-1,3,8,8-tetramethyl-7,8,9,10-tetrahydropyrimido[4,5-b]-
quinoline-2,4,6-trione at 70 ꢀC in ethanol (Table 4, entry 3).
3290, 3232, 3075, 2943, 2873, 1701, 1660, 1642, 1607, 1495,
1453, 1378, 1359, 1210, 886, 788, 730, 687 cmꢂ1 1H NMR
.
(400 MHz, DMSO-d6): d 0.91 (s, 3H), 1.04–108 (m, 3H), 1.96–2.0
(d, J ¼ 16 Hz, 2H), 2.18–2.23 (d, J ¼ 16.4 Hz, 2H), 3.05 (s, 3H),
3.45 (s, 3H), 5.42 (s, 1H), 7.01–7.051 (t, 1H, ArH), 7.122–7.154
(m, 2H, ArH), 9.06 (s, NH) ppm; 13C NMR (100 MHz, DMSO-d6):
d 21.53, 26.32, 28.15, 29.94, 30.20, 43.16, 50.52, 88.14, 113.46,
115.02, 122.27, 126.53, 127.94, 135.00, 146.16, 147.22, 150.01,
160.16, 161.42, 195.90 ppm.
to cool to room temperature. The solid obtained was ltered
and washed with water, because [dsim]HSO4 is soluble in water.
Recrystallization in ethanol gives the requested product in high
yields.
1
The spectral (IR, H and 13C NMR) data of new compounds
are presented below:
5-(2-Chloro,
6-uorophenyl)-1,3-dimethyl-7,8,9,10-tetra-
5-(3-Nitrophenyl)-1,3,8,8-tetramethyl-7,8,9,10-tetrahydro-
pyrimido[4,5-b]quinolin-2,4,6(1H,3H,5H)-trione (Table 4, entry
5). Yellow solid, m.p. 287–290 ꢀC; IR (KBr): nmax 3391, 3068,
2953, 1702, 1668, 1653, 1607, 1594, 1525, 1500, 1380, 1350,
1212, 904, 873, 790, 734, 681 cmꢂ1. 1H NMR (400 MHz, DMSO-
hydropyrimido[4,5-b]quinoline-2,4,6(1H,3H,5H)-trione (Table 4,
entry 15). White solid, m.p. 298–300 ꢀC, IR (KBr): nmax 3555,
3405, 3173, 2955, 2872, 1697, 1660, 1607, 1606, 1506, 1467, 1356,
1205, 838, 793, 736, 693, 675 cmꢂ1. 1H NMR (400 MHz, DMSO-
Table 5 Comparison of catalytic activity of [dsim]HSO4 with other catalysts reported in literature for the synthesis of model reactiona
Entry
Catalyst
Time (min)
Yieldb (%)
Ref.
1
2
3
4
[dsim]HSO4 (0.25 mmol), ethanol/70 ꢀ
[bmim]Br (2 mL), solvent-free/95 ꢀC
p-TSA (20 mol%), H2O/90 ꢀC
C
15
210
150
60
91
90
89
91
This work
12
13
32
InCl3 (20 mol%), H2O/reux
a
All reactions were run with 4-chlorobenzaldehyde (1.0 mmol), dimedon (1.0 mmol), and malononitrile (1.0 mmol) at reux condition. b Isolated
yield.
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d6): d 1.78 (m, 1H), 1.94 (m, 1H), 2.17–2.34 (m, 2H), 2.66 (m, 2H),
3.05 (s, 3H), 3.46 (s, 3H), 5.44 (s, 1H), 7.016 (t, J ¼ 8.8 Hz, 1H,
ArH), 7.123 (d, J ¼ 8.0 Hz, 1H, ArH), 7.137 (d, J ¼ 8.0 Hz, 1H,
ArH), 9.11 (s, NH) ppm; 13C NMR (100 MHz, DMSO-d6): d 21.00,
21.23, 26.96, 27.99, 30.76, 37.14, 87.81, 114.52, 116.55, 126.01,
128.20, 128.40, 136.71, 145.05, 145.36, 150.00, 153.00, 160.00,
195.06 ppm.
5-(4-Dimethylaminophenyl)-1,3-dimethyl-7,8,9,10-tetrahydro-
pyrimido[4,5-b]quinoline-2,4,6(1H,3H,5H)-trione (Table 4, entry
16). Orange solid, m.p. 278–280 ꢀC, IR (KBr): nmax 3436, 3187,
3078, 2925, 2885, 1697, 1659, 1640, 1608, 1517, 1495, 1379, 1352,
1199, 825, 754, 702, 661 cmꢂ1. 1H NMR (400 MHz, DMSO-d6): d
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4 Conclusions
In conclusion, we have described a green and efficient one-pot
procedure for the three-component synthesis of pyrimido-
[4,5-b]quinolines in the presence of a catalytic amount of [dsim]-
HSO4 as a reusable and environmentally benign catalyst. The
notable advantages for the presented method are mild condi-
tions, ease of operation, efficiency, short reaction times, high
yields of the products, simple work-up procedure, non-
chromatographic purication of the products and simplicity
which makes this methodology a useful and attractive process
for the synthesis of pyrimidoquinoline derivatives as biologically
interesting compounds. Also, the catalyst is recyclable and could
be reused without signicant loss of activity. Further work to
explore this novel catalyst in other organic transformations is in
progress in our lab.
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Acknowledgements
The authors acknowledge nancial support for this work from
the Iran National Science Foundation (INSF) (Grant number
93014856) and partial support of this work by the Research
Council of the University of Guilan. F. Shirini and K. Moham-
madi also wish to thank the Sobhandarou Company for the
partial facilities.
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23590 | RSC Adv., 2015, 5, 23586–23590
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