One-pot synthesis of 7-aryl-11,12-dihydrobenzo[h]pyrimido-[4,5-b]quinoline-8,10(7H,9H)-diones via three-component reaction in ionic liquid

Article abstract of DOI:10.1016/j.cclet.2010.07.017

A series of new 7-aryl-11,12-dihydrobenzo[h]pyrimido-[4,5-b]quinoline-8,10(7. H,9. H)-diones were synthesized via three-component reaction of aldehydes, 1-naphthylamine and barbituric acid in ionic liquid. The method provided several advantages such as easy work-up, high yields and environmentally benign procedure.

Full text of DOI:10.1016/j.cclet.2010.07.017

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 1435–1438
www.elsevier.com/locate/cclet
One-pot synthesis of 7-aryl-11,12-dihydrobenzo[h]pyrimido-
[4,5-b]quinoline-8,10(7H,9H)-diones via three-component
reaction in ionic liquid
*
Hong Yun Guo , Yi Yu
College of Chemical Engineering and Materials, Zhejiang University of Technology, Hangzhou 310014, China
Received 19 April 2010
Abstract
A series of new 7-aryl-11,12-dihydrobenzo[h]pyrimido-[4,5-b]quinoline-8,10(7H,9H)-diones were synthesized via three-
component reaction of aldehydes, 1-naphthylamine and barbituric acid in ionic liquid. The method provided several advantages
such as easy work-up, high yields and environmentally benign procedure.
# 2010 Hong Yun Guo. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Aldehyde; 1-Naphthylamine; Barbituric acid; Ionic liquid
7-Aryl-11,12-dihydrobenzo[h]pyrimido-[4,5-b]quinoline-8,10(7H,9H)-diones, a novel class of fused heterocyclic
compounds, are incorporated by pyrimido-[4,5-b]quinoline-2,4(1H, 3H, 5H, 10H)-dione and [4,7]-phenantroline
motifs, both of which possess various important bioactivities. For example, not only are pyrimido-[4,5-b]quinoline-
2,4(1H, 3H, 5H, 10H)-dione derivatives antitumor, anticancer, antihypertensive, and antibacterial, they are also
inhibitors of Kaposi’s sarcoma-associated herpesvirus (KSHV) and topoisomerase, useful for the treatment of
topoisomerase-associated diseases and disorders [1–3]. At the same time, [4,7]-phenantroline derivatives exhibit
antitumor, anticancer, antiviral, antimalarial, antiinfective, cytotoxic activities, as well as being triple-helix DNA
stabilizing agents [4–6]. Hence, it is promising that the fused scaffolds of pyrimido-[4,5-b]quinoline-2,4(1H, 3H, 5H,
10H)dione with [4,7]phenanthroline, i.e., 7-aryl-11,12-dihydrobenzo[h]pyrimido-[4,5-b]quinoline-8,10(7H, 9H)-
diones, may display novel or enhanced significant bioactivities. However, survey of the literature revealed that the
synthesis of this important fused heterocyclic skeleton was neglected. Therefore, the investigation on the synthesis of
7-aryl-11,12-dihydrobenzo[h]pyrimido-[4,5-b]quinoline-8,10(7H,9H)-diones is of great necessity.
Multicomponent reactions (MCRs) are a powerful method for the synthesis of organic compounds, since the
products are formed in a single step and diversity can be achieved by simply varying each component [7]. Due to their
easy operations and good results, MCRs have attracted much attention [8,9].
In recent years, the room temperature ionic liquids are attracting increasing interest as a ‘green’ recyclable
alternative to classical molecular solvents for synthetic organic chemistry [10–12]. To date, some important reactions
* Corresponding author.
E-mail address: guohy63@163.com (H.Y. Guo).
1001-8417/$ – see front matter # 2010 Hong Yun Guo. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.07.017

[(Scheme_1)TD$FIG]
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H.Y. Guo, Y. Yu / Chinese Chemical Letters 21 (2010) 1435–1438
Scheme 1. The synthetic route of 7-aryl-11,12-dihydrobenzo[h]pyrimido-[4,5-b]quinoline-8,10(7H,9H)-diones.
have been carried out and investigated. Meanwhile, ionic liquids are able to generate an internal pressure and promote
the association of reactants in the solvent cavity during the activation process [13,14]. Thus ionic liquids are well
suited as reaction media for MCRs in which the entropy of the reaction is decreased in the transition state [15]. Herein
we would like to report a novel procedure for the preparation of 7-aryl-11,12-dihydrobenzo[h]pyrimido-[4,5-
b]quinoline-8,10(7H,9H)-diones (Scheme 1) through a three-component reaction of aldehydes 1, 1-naphthylamine 2
and barbituric acid 3 in an ionic liquid.
First, we examined the efficiency of different solvents in the three-component reaction of aldehyde, 1-
naphthylamine and barbituric acid. We found that the reaction occurred easily at 90 8C in ionic liquids and completed
within 0.5 h to give product in high yields. It can be seen from Table 1 that the reactions using ionic liquids as the
solvent resulted in higher yields and shorter reaction times than those using organic solvents. On the basis of the
obtained results, [bmim]BF4 was found to be superior in terms of low cost and high yield. Under these optimized
reaction conditions, a series of 7-aryl-11,12-dihydrobenzo[h]pyrimido-[4,5-b]quinoline-8,10(7H,9H)-dione deriva-
tives 4 were synthesized. The results are summarized in Table 2.
It was found out that the reaction of benzaldehyde (1a, 2 mmol), 1-naphthylamine (2, 2 mmol) and barbituric acid
(3, 2 mmol) went smoothly in 2 mL of [bmim]BF4 after being stirred for appropriate time at 90 8C (monitored by
TLC). Upon completion, the mixture was added with 5 mL water. The precipitate was collected by suction and purified
by recrystallization from EtOH to give the desired product 7-phenyl-11,12-dihydrobenzo[h]pyrimido-[4,5-b]
quinoline-8,10(7H, 9H)-dione 4a with a yield of 88% (Table 2, entry 1). The filtrate was concentrated under reduced
pressure and dried at 100 8C to recover the ionic liquid for subsequent use.
Avariety of aldehydes were then tried to determine the scope and generality of this method and the results are listed
in Table 2. To our delight, the following reaction went smoothly under this reaction conditions to afford the
1
corresponding products in high yields. All the products 4a–1 are new compounds, which were identified by IR, H
NMR, mass spectroscopy and elemental analysis [16].
The ionic liquid plays the dual role of solvent and promoter. Just 2 mL ionic liquid is sufficient to push the reaction
forward. More amounts of the ionic liquid did not improve the results to a greater extent. The high polarity of ionic
liquids made the condensation more efficiently. It should also be noted that [bmim]BF4 as reaction medium could be
recovered easily and reused for several times without any decrease in terms of efficiency in the reaction.
From the results of Table 2, it is obvious this protocol could be applied to various aromatic aldehydes with electron-
withdrawing groups or electron-donating groups. Besides, the results suggest that the substrates bearing electron-
Table 1
Solvent optimization for the synthesis of 4d.
Entrya
Solvent
Temperature ( 8C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
[bmim]BF4
[bmim]PF6
[bmim]Br
EtOH
90
0.5
0.5
0.5
10
92
88
90
20
35
23
0
90
90
Reflux
Reflux
Reflux
90
AcOH
10
CH3CN
H2O
10
24
a
All reaction were run with 4-fluorobenzaldehyde (2 mmol), 1-naphthylamine (2 mmol), barbituric acid (2 mmol), and 2 mL solvent.
Isolated yield.
b

H.Y. Guo, Y. Yu / Chinese Chemical Letters 21 (2010) 1435–1438
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Table 2
Preparation of 4 in ionic liquid [bmim]BF4.
Entry
Ar
Product
Time (min)
Yielda (%)
1
2
C6H5–
4a
4b
4c
4d
4e
4f
30
30
40
30
40
45
30
30
30
30
30
30
88
90
77
92
82
79
91
92
76
89
91
85
4-Cl–C6H4–
3
4-MeO–C6H4–
4-F–C6H4–
4
5
4-OH–C6H4–
4-CH3–C6H4–
4-NO2–C6H4–
3-Br–C6H4–
4-OH–3-OCH3–C6H3–
2-Cl–C6H4–
6
7
4g
4h
4i
8
9
10
11
12
4j
2,4-Cl2–C6H3–
2-OH–C6H4–
4k
4l
a
Isolated yield.
withdrawing groups have higher reactivity (higher yields and shorter reaction time) than those bearing electron-
donating groups. So, it is concluded that the electronic nature of the substituents on aldehydes has some effect on this
reaction. It seems that the electron-withdrawing groups in aldehydes enhanced the electropositive property of b–C in
the intermediates yielded from the Knoevenagel condensation of aldehydes 1 with barbituric acid 3, which facilitated
the nucleophilic attack thereafter.
In summary, a series of 7-aryl-11,12-dihydrobenzo[h]pyrimido-[4,5-b]quinoline-8,10(7H,9H)-diones were
synthesized in ionic liquid [bmim]BF4. The procedure offers several advantages including high yields, operational
simplicity, cleaner reactions, minimal environmental impact, and provides a useful and attractive protocol for the
synthesis of these compounds.
Acknowledgment
This work was financially supported by the Research Foundation of Zhejiang Provincial Education Department
(No. 20060811).
References
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[16] A typical procedure for the preparation of 4aÀ4l: Aldehyde (1, 2 mmol), 1-naphthylamine (2, 2 mmol), barbituric acid (3, 2 mmol) were added
to a 20 mL round bottom flask containing 2 mL [bmim]BF4. The mixture was then stirred at 90 8C for appropriate time (monitored by TLC).
After completion of the reaction, the reaction mixture was added with 5 mL water. The precipitate was collected by suction and purified by
recrystallization from EtOH to give products 4. The filtrate was concentrated under reduced pressure and dried at 100 8C to recover the ionic
liquid for subsequent use. Some selected data: 4c: mp >300 8C; 1H NMR (DMSO-d6, 500 MHz,): d 3.44 (s, 3H, OCH3); 5.13 (s, 1H, CH); 6.75–
7.95 (m, 10H, Ar–H); 9.09 (s, 1H, NH); 10.03 (s, 1H, NH); 10.69 (s, 1H, NH); IR (KBr, cmÀ1): vmax 3267, 3076, 2834, 1715, 1608, 1550, 1509,
1461, 1399, 1252, 1176, 1108, 1031, 810; MS (EI, 70 eV) (m/z, %): 371 (M+, 9.0), 368 (41.7), 369 (100), 264 (33.5), 207 (21.4); Anal. Calcd.

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H.Y. Guo, Y. Yu / Chinese Chemical Letters 21 (2010) 1435–1438
for C22H17N3O3: C, 71.15; H, 4.61; N, 11.31; Found C, 71.31; H, 4.57; N, 11.21. 4l: mp >300 8C; 1H NMR (DMSO-d6, 500 MHz,): d 5.56 (s,
1H, CH); 6.60–7.92 (m, 10H, Ar–H); 9.08 (s, 1H, NH); 9.69 (s, 1H, OH); 10.06 (s, 1H, NH); 10.77 (s, 1H, NH); IR (KBr, cmÀ1) vmax: 3345,
3210, 3042, 1705, 1601, 1551, 1458, 1401, 1353, 1268, 1216, 1126, 1031, 802; MS (EI, 70 eV) (m/z, %): 357 (M+, 4.0), 263 (100), 165 (31.0),
193 (56.6), 220 (40.8), 94 (14.6); Anal. Calcd. for C21H15N3O3: C, 70.58; H, 4.23; N, 11.76; Found C, 70.66; H, 4.19; N, 11.62.