Green Method for the Synthesis of Benzo[f]pyrimido[4,5-b]quinoline Derivatives Catalyzed by Iodine in Aqueous Media

Article abstract of DOI:10.1080/00397910902730929

A convenient one-pot synthesis of benzo[f]pyrimido[4,5-b]quinoline derivatives is described via three-component reaction of benzaldehydes, naphthalen-2-amine, and barbituric acid at room temperature in aqueous media catalyzed by iodine. Compared with othe

Full text of DOI:10.1080/00397910902730929

This article was downloaded by: [University Library Utrecht]
On: 22 February 2013, At: 11:36
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Green Method for the Synthesis
of Benzo[f]pyrimido[4,5-
b]quinoline Derivatives
Catalyzed by Iodine in Aqueous
Media
Xiang-Shan Wang a b , Qing Li a , Jian-Rong Wu a &
Mei-Mei Zhang b
a School of Chemistry and Chemical Engineering,
Xuzhou Normal University, Xuzhou, Jiangsu, China
b Key Laboratory of Biotechnology for Medical Plant,
Xuzhou Normal University, Xuzhou, Jiangsu, China
Version of record first published: 03 Aug 2009.
To cite this article: Xiang-Shan Wang , Qing Li , Jian-Rong Wu & Mei-Mei Zhang
(2009): Green Method for the Synthesis of Benzo[f]pyrimido[4,5-b]quinoline
Derivatives Catalyzed by Iodine in Aqueous Media, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:17,
3069-3080
To link to this article: http://dx.doi.org/10.1080/00397910902730929
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions

This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden.
The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to
date. The accuracy of any instructions, formulae, and drug doses should be
independently verified with primary sources. The publisher shall not be liable
for any loss, actions, claims, proceedings, demand, or costs or damages
whatsoever or howsoever caused arising directly or indirectly in connection
with or arising out of the use of this material.

Synthetic Communications1, 39: 3069–3080, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902730929
Green Method for the Synthesis
of Benzo[f]pyrimido[4,5-b]quinoline Derivatives
Catalyzed by Iodine in Aqueous Media
Xiang-Shan Wang,1,2 Qing Li,1 Jian-Rong Wu,1
and Mei-Mei Zhang2
1School of Chemistry and Chemical Engineering, Xuzhou Normal
University, Xuzhou, Jiangsu, China
2Key Laboratory of Biotechnology for Medical Plant, Xuzhou Normal
University, Xuzhou, Jiangsu, China
Abstract: A convenient one-pot synthesis of benzo[f]pyrimido[4,5-b]quinoline
derivatives is described via three-component reaction of benzaldehydes,
naphthalen-2-amine, and barbituric acid at room temperature in aqueous media
catalyzed by iodine. Compared with other methods, this three-component reac-
tion used a green solvent, gave good yields, and was operationally simple.
Keywords: Aqueous media, benzo[f]pyrimido[4,5-b]quinoline, iodine, three-
component reaction
INTRODUCTION
The development of multicomponent reactions (MCRs) has attracted
much attention from the vantage point of combinatorial and medicinal
chemistry.[1] Generally, the MCR strategy affords savings in time and
effort and has significant advantages over conventional two-component
reactions in several aspects, such as variability and high-bond-forming
efficiency. With a small set of starting materials, very large libraries
Received October 2, 2008.
Address correspondence to Xiang-Shan Wang, School of Chemistry and
Chemical Engineering, Xuzhou Normal University, Xuzhou, Jiangsu 221116,
China. E-mail: xswang1974@yahoo.com
3069

3070
X.-S. Wang et al.
can be developed within a short time, which can be applied to research on
medicinal chemistry.
Compounds bearing pyrimidoquinoline are common in a variety of
biologically important natural products and potent drugs. It is notewor-
thy that pyrimidoquinoline derivatives manifest a number of important
and therapeutically useful biological activities such as antibacterial,[2]
antifungal,[3] antimalarial,[4] and antifolate[5] activities and inhibitory
activity of lytic KSHV DNA synthesis.[6] Despite this broad range of
applications, only a few members of this family of compounds have been
reported.[7] The development of new methods for their assembly is there-
fore of considerable synthetic importance.
Recently, Kozlov and Basalaeva[7a] reported in 2007 that benzo[f]-
pyrimido[4,5-b]quinoline-9,11-diones could be obtained by a three-
component reaction of benzaldehyde, naphthalen-2-amine, and barbituric
acid in boiling butanol. However, this reaction suffers from the
drawbacks of poor yields (14–70%), use of organic solvent (butanol),
and harsh reaction condition. To obtain the desired products in an
experimentally friendly procedure and in better yields, we performed
the reaction of Schiff base with barbituric acid in water at 100ꢀC, with
benzo[f]quinolin-3-cabonyl urea being obtained in good yields.[8] In the
designed reaction, the ring of barbituric acid was unexpectedly opened.
Perhaps the reason the ring opened was the high reaction temperature.
So in our continuing study, we performed the three-component reaction
in water at room temperature. To our disappointment, the reaction
stayed at the stage of Knoevenagel reaction of benzaldehydes and barbi-
turic acid; the naphthalen-2-amine did not attend the reaction at all. Sub-
sequently, a little iodine was added to the reaction system, the desired
reaction took place smoothly, and the product of benzo[f]pyrimido[4,5-
b]quinoline-9,11-diones was isolated in good yields.
RESULTS AND DISCUSSION
The three-component reaction of substituted benzaldehydes 1, naphthalen-
2-amine 2, and barbituric acid 3 was performed at room temperature in
aqueous media catalyzed by 5 mol% iodine. The 12-aryl-7,8,9,10,11,12-
hexahydrobenzo[f]pyrimido[4,5-b] quinoline-9,11-diones 4 were obtained
in good yields (Scheme 1).
In our initial study, the reaction of 2,3-dichlorobenzaldehyde 1a,
naphthalen-2-amine 2, and barbituric acid 3 was used as a model reaction
to optimize the conditions. A summary of the optimization experiment is
provided in Table 1. The reaction was first carried out in water at room
temperature to avoid a ring-opening reaction. It turned out that no

Benzo[f]pyrimido[4,5-b]quinolines
3071
Scheme 1. Reaction of 1, 2, and 3 catalyzed by iodine in water.
reaction occurred without the catalyst (Table 1, entry 1). Similar
reactions were then attempted in the presence of 5, 10 and 20 mol% of
I2. The results from Table 1 (entries 2–4) showed that 5 mol% I2 at room
temperature in water was sufficient to push the reaction forward. Great
loading of the catalyst did not improve the yield to a great extent. In
addition, CH3CN, benzene, tetrahydrofuran (THF), and ClCH2CH2Cl
(Table 1, entries 5–8) were also tested as the solvents. In these cases,
product 4a was formed in slightly lesser yields (Table 1, entries 5–8).
To apply this reaction to a library synthesis, various kinds of benzal-
dehydes were reacted with 2 and 3 to give the corresponding benzo[f]-
pyrimido[4,5-b]quinoline derivatives 4, and representative examples are
shown in Table 2. All of the benzaldehydes gave the expected products
in good yields, either bearing electron-withdrawing groups (such as
halide, nitro) or electron-donating groups (such as alkyl group, alkoxyl
group) under the same reaction conditions. Therefore, we concluded that
the electronic nature of the substituents has no significant effects on this
reaction. The structure of the products 4c was confirmed by x-ray diffrac-
tion analysis, as shown in Fig. 1.
In conclusion, an efficient and green method for the synthesis of 12-
aryl-7,8,9,10,11,12-hexahydrobenzo[f]pyrimido[4,5-b]quinoline-9,11-dione
Table 1. Synthesis of 4a in water under different reaction conditionsa
Entry
Solvent
Amount (mol%)
Time (h)
Yieldsb (%)
1
2
3
4
5
6
7
8
H2O
H2O
0
5
10
8
0
92
91
92
80
76
90
78
H2O
H2O
CH3CN
Benzene
THF
10
20
5
5
5
8
8
8
8
8
8
ClCH2CH2Cl
5
aReagents and conditions: 1 (2 mmol), 2 (2mmol), 3 (2 mmol), and solvent (10 mL).
bIsolated yields.

3072
X.-S. Wang et al.
Table 2. Synthesis of 4 in water at room temperature catalyzed by iodine
Entry
Ar
Products
Time (h) Yields (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
2,3-Cl2C6H3
3-BrC6H4
2,4-Cl2C6H3
2-ClC6H4
2-NO2C6H4
4-CH3OC6H4
2,3-(CH3O)2C6H3
3-NO2C6H4
3,4-(CH3)2C6H3
C6H5
2-CH3OC6H4
3,5-(CH3O)2C6H3
2-BrC6H4
4a
4b
4c
4d
4e
4f
6
6
6
6
6
7
8
6
6
6
6
6
6
7
6
6
7
92
91
89
89
91
88
92
82
86
92
84
91
89
92
86
89
92
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4-FC6H4
2-FC6H4
4-HOC6H4
4-NO2C6H4
derivatives by a three-component reaction of benzaldehyde, naphthalen-2-
amine, and barbituric acid was successfully developed in water catal-
yzed by iodine. This new method has the advantages of good yields, mild
Figure 1. Crystal structure of 4c with a molecule of DMF solvent.

Benzo[f]pyrimido[4,5-b]quinolines
3073
reaction conditions, easy workup, inexpensive reagents, and
environmentally friendly procedure. In addition, water was chosen as a
green solvent.
EXPERIMENTAL
Melting points were determined in open capillaries and are uncorrected.
Infrared (IR) spectra were recorded on a Tensor 27 spectrometer in KBr
pellets. 1H NMR spectra were obtained in dimethyl sulfoxide (DMSO)-d6
solution with Me4Si as internal standard using a Bruker 400 spectro-
meter. Elemental analyses were carried out using a Perkin-Elmer 240 II
analyzer. X-ray diffraction was measured on a Rigaku Mercury
diffractometer.
General Procedure for the Synthesis of
12-Aryl-7,8,9,10,11,12-hexahydrobenzo[f]pyrimido[4,5-
b]quinoline-9,11-diones 4
A suspension of the mixture of benzaldehyde 1 (2.0 mmol), naphthalen-
2-amine 2 (2.0 mmol, 0.286 g), barbituric acid 3 (2.0 mmol, 0.256 g),
and iodine (0.1 mmol, 0.025 g) was stirred in water (10 mL) at room tem-
perature for 6–8 h. The powder formed was collected by filtration,
washed with water and recrystallized from dimethyiformamide (DMF)
and water, and kept at 80ꢀC for 5 h under vacuum to give pure
12-aryl-7,8,9,10,11,12-hexahydrobenzo[f]pyrimido[4,5-b]quinoline-9,11-
diones 4.
Data
12-(2,3-Dichlorophenyl)-7,8,9,10,11,12-hexahydrobenzo[f]pyrimido[4,5-
b]quinoline-9,11-dione 4a
Pale yellow crystals, mp > 300ꢀC. IR (KBr): 3196, 3074, 3014, 1710,
1644, 1588, 1544, 1470, 1446, 1420, 1399, 1347, 1308, 1236, 1180, 1153,
1045, 862, 811, 775, 747.1H NMR (DMSO-d6) d: 6.06 (s, 1H, CH),
7.14–7.18 (m, 1H, ArH), 7.31–7.38 (m, 4H, ArH), 7.45 (t, J ¼ 7.6 Hz, 1H,
ArH), 7.83 (d, J ¼ 8.8 Hz, 2H, ArH), 7.99 (d, J ¼ 8.41 Hz, 1H, ArH),
9.31 (s, 1H, NH), 10.48 (s, 1H, NH), 10.63 (s, 1H, NH). Anal. calcd. for
C21H13Cl2N3O2: C, 61.48; H, 3.19; N, 10.24. Found: C, 61.40; H, 3.35;
N, 10.30.

3074
X.-S. Wang et al.
12-(3-Bromophenyl)-7,8,9,10,11,12-hexahydrobenzo[f]pyrimido[4,5-
b]quinoline-9,11-dione 4b
Pale yellow crystals, mp > 300ꢀC. IR (KBr): 3202, 3072, 1725, 1682, 1638,
1589, 1541, 1470, 1426, 1387, 1304, 1231, 1195, 1160, 1180, 1118, 1073,
1038, 967, 818, 765, 743, 694. 1H NMR (DMSO-d6) d: 5.74 (s, 1H,
CH), 7.12–7.15 (m, 1H, ArH), 7.21–7.27 (m, 2H, ArH), 7.33–7.46 (m,
4H, ArH), 7.84–7.90 (m, 3H, ArH), 9.19 (s, 1H, NH), 10.48 (s, 1H,
NH), 10.70 (s, 1H, NH). Anal. calcd. for C21H14BrN3O2: C, 60.02; H,
3.36; N, 10.00. Found: C, 59.93; H, 3.50; N, 9.97.
12-(2,4-Dichlorophenyl)-7,8,9,10,11,12-hexahydrobenzo[f]pyrimido[4,5-
b]quinoline-9,11-dione 4c
Pale yellow crystals, mp > 300ꢀC. IR (KBr): 3158, 1618, 1319, 1288,
1253, 1223, 1181, 1144, 1103, 1045, 975, 882, 835, 802, 763, 736.1H
NMR (DMSO-d6) d: 5.98 (s, 1H, CH), 7.23 (dd, J1 ¼ 8.4 Hz,
J2 ¼ 1.6 Hz, 1H, ArH), 7.32–7.37 (m, 3H, ArH), 7.42–7.45 (m, 2H,
ArH), 7.83 (d, J ¼ 8.8 Hz, 2H, ArH), 8.01 (d, J ¼ 8.4 Hz, 1H, ArH),
9.23 (s, 1H, NH), 10.43 (s, 1H, NH), 10.62 (s, 1H, NH). Anal. calcd.
for C21H13Cl2N3O2: C, 61.48; H, 3.19; N, 10.24. Found: C, 61.56; H,
3.10; N, 10.38.
X-ray crystallography for 4c: Empirical formula C24H18Cl2N4O3,
FW ¼ 481.32, T ¼ 293(2) K, Monoclinic, space group
P
21=n,
ꢀ
˚
3
˚
˚
a ¼ 6.4798(16) A, b ¼ 20.595(5) A, c ¼ 16.723(4) A, b ¼ 95.267(7) ,
3
˚
˚
V ¼ 2222.3(9) A , Z ¼ 4, Dc ¼ 1.439 Mg=m , k(MoKa) ¼ 0.71070 A, l ¼
0.327 mmꢁ1, F(000) ¼ 992. 3.15ꢀ < h < 25.35ꢀ, R ¼ 0.0580, wR ¼ 0.1456.
ꢁ3
˚
S ¼ 1.147, Largest diff. Peak and hole: 0.541 and ꢁ0.270 e ꢂ A
.
12-(2-Chlorophenyl)-7,8,9,10,11,12-hexahydrobenzo[f]pyrimido[4,5-
b]quinoline-9,11-dione 4d
Pale yellow crystals, mp > 300ꢀC. IR (KBr): 3179, 3067, 3015, 1713,
1651, 1587, 1539, 1469, 1419, 1396, 1298, 1235, 1041, 830, 814,
1
768, 739. H NMR (DMSO-d6) d: 6.00 (s, 1H, CH), 7.05–7.09 (m, 1H,
ArH), 7.12–7.16 (m, 1H, ArH), 7.28 (d, J ¼ 8.0 Hz, 1H, ArH), 7.31–7.36
(m, 3H, ArH), 7.42–7.46 (m, 1H, ArH), 7.82 (d, J ¼ 8.4 Hz, 2H, ArH),
8.08 (d, J ¼ 8.8Hz, 1H, ArH), 9.19 (s, 1H, NH), 10.38 (s, 1H, NH),
10.56 (s, 1H, NH). Anal. calcd. for C21H14ClN3O2: C, 67.12; H, 3.75;
N, 11.18. Found: C, 67.25; H, 3.71; N, 11.10.

Benzo[f]pyrimido[4,5-b]quinolines
3075
12-(2-Nitrophenyl)-7,8,9,10,11,12-hexahydrobenzo[f]pyrimido[4,5-
b]quinoline-9,11-dione 4e
Pale yellow crystals, mp > 300ꢀC. IR (KBr): 3279, 3086, 1704, 1553, 1436,
1348, 1288, 1250, 1228, 1280, 1175, 1106, 1041, 810, 825, 807, 790, 768,
748, 701. 1H NMR (DMSO-d6) d: 6.07 (s, 1H, CH), 7.06 (dd,
J1 ¼ 8.0 Hz, J2 ¼ 1.2 Hz, 1H, ArH), 7.27–7.37 (m, 2H, ArH), 7.40–7.45
(m, 3H, ArH), 7.82–7.92 (m, 2H, ArH), 7.90 (d, J ¼ 8.8 Hz, 1H, ArH),
8.38 (d, J ¼ 8.4 Hz, 2H, ArH), 9.27 (s, 1H, NH), 10.45 (s, 1H, NH),
10.64 (s, 1H, NH). Anal. calcd. for C21H14N4O4: C, 65.28; H, 3.65; N,
14.50. Found: C, 65.20; H, 3.77; N, 14.34.
12-(4-Methoxyphenyl)-7,8,9,10,11,12-hexahydrobenzo[f]pyrimido[4,5-
b]quinoline-9,11-dione 4f
Pale yellow crystals, mp > 300ꢀC. IR (KBr): 3195, 3073, 1700, 1647, 1554,
1470, 1399, 1301, 1254, 1234, 1180, 1108, 1038, 972, 822, 769, 748.1H
NMR (DMSO-d6) d: 5.66 (s, 1H, CH), 6.72 (d, J ¼ 8.4 Hz, 2H, ArH),
7.6 (d, J ¼ 8.4 Hz, 2H, ArH), 7.31–7.44 (m, 3H, ArH), 7.81–7.83
(m, 2H, ArH), 7.91 (d, J ¼ 8.0 Hz, 1H, ArH), 9.09 (s, 1H, NH), 10.38
(s, 1H, NH), 10.63 (s, 1H, NH). Anal. calcd. for C22H17N3O3: C,
71.15; H, 4.61; N, 11.31. Found: C, 71.10; H, 4.71; N, 11.28.
12-(2,3-Dimethoxyphenyl)-7,8,9,10,11,12-hexahydrobenzo[f]pyri-
mido[4,5-b]quinoline-9,11-dione 4g
Pale yellow crystals, mp > 300ꢀC. IR (KBr): 3264, 3208, 3307, 2936, 2837,
1701, 1641, 1608, 1544, 1463, 1418, 1298, 1275, 1233, 1166, 1126, 1062,
1044, 897, 773, 748.1H NMR (DMSO-d6) d: 3.72 (s, 3H, CH3O), 3.95
(s, 3H, CH3O), 5.97 (s, 1H, CH), 6.71 (dd, J1 ¼ 2.8 Hz, J2 ¼ 6.8 Hz, 1H,
ArH), 6.80–6.85 (m, 2H, ArH), 7.29–7.33 (m, 2H, ArH), 7.43
(t, J ¼ 7.6 Hz, 1H, ArH), 7.75 (d, J ¼ 9.6 Hz, 2H, ArH), 8.29
(d, J ¼ 8.8 Hz, 1H, ArH), 9.07 (s, 1H, NH), 10.38 (s, 1H, NH), 10.59
(s, 1H, NH). Anal. calcd. for C23H19N3O4: C, 68.82; H, 4.77; N, 10.47.
Found: C, 68.96; H, 4.82; N, 10.37.
12-(3-Nitrophenyl)-7,8,9,10,11,12-hexahydrobenzo[f]pyrimido[4,5-
b]quinoline-9,11-dione 4h
Pale yellow crystals, mp > 300ꢀC. IR (KBr): 3402, 3077, 1730, 1471, 1409,
1346, 1294, 1253, 1206, 1187, 1097, 1041, 971, 906, 826, 815, 770, 743.

3076
X.-S. Wang et al.
1H NMR (DMSO-d6) d: 5.91 (s, 1H, CH), 7.32–7.36 (m, 1H, ArH), 7.41 –
7.51 (m, 3H, ArH), 7.73 (d, J ¼ 8.0 Hz, 1H, ArH), 7.84–7.93 (m, 4H,
ArH), 8.10 (dd, J1 ¼ 3.6 Hz, J2 ¼ 1.6 Hz, 1H, ArH), 9.29 (s, 1H, NH),
10.55 (s, 1H, NH), 10.72 (s, 1H, NH). Anal. calcd. for C21H14N4O4: C,
65.28; H, 3.65; N, 14.50. Found: C, 65.33; H, 3.57; N, 14.47.
12-(3,4-Dimethylphenyl)-7,8,9,10,11,12-hexahydrobenzo[f]pyrimido[4,5-
b]quinoline-9,11-dione 4i
Pale yellow crystals, mp > 300ꢀC. IR (KBr): 3199, 3075, 1706, 1645, 1509,
1542, 1470, 1450, 1398, 1296, 1234, 1122, 1038, 819, 772, 750, 714.1H
NMR (DMSO-d6) d: 2.04 (s, 3H, CH3), 2.06 (s, 3H, CH3), 5.62 (s, 1H,
CH), 6.89 (d, J ¼ 8.0 Hz, 1H, ArH), 6.94 (d, J ¼ 8.0 Hz, 1H, ArH), 7.04
(s, 1H, ArH), 7.30–7.44 (m, 3H, ArH), 7.82 (d, J ¼ 8.8 Hz, 2H, ArH),
7.90 (d, J ¼ 8.4 Hz, 1H, ArH), 9.10 (s, 1H, NH), 10.41 (s, 1H, NH),
10.62 (s, 1H, NH). Anal. calcd. for C23H19N3O2: C, 74.78; H, 5.18; N,
11.37. Found: C, 74.59; H, 5.29; N, 11.40.
12-Phenyl-7,8,9,10,11,12-hexahydrobenzo[f]pyrimido[4,5-b]quinoline-
9,11-dione 4j
Pale yellow crystals, mp > 300ꢀC. IR (KBr): 3196, 3074, 1743, 1642, 1589,
1472, 1396, 1345, 1303, 1234, 1197, 1121, 1097, 1075, 1040, 1030, 969, 828,
813, 775, 746, 696.1H NMR (DMSO-d6) d: 5.71 (s, 1H, CH), 7.03–7.06 (m,
1H, ArH), 7.16 (t, J ¼ 7.6 Hz, 2H, ArH), 7.26–7.44 (m, 5H, ArH), 7.83 (d,
J ¼ 8.8 Hz, 2H, ArH), 7.92 (d, J ¼ 8.4 Hz, 1H, ArH), 9.11 (s, 1H, NH),
10.40 (s, 1H, NH), 10.65 (s, 1H, NH). Anal. calcd. for C21H15N3O2: C,
73.89; H, 4.43; N, 12.31. Found: C, 73.87; H, 4.26; N, 12.44.
12-(2-Methoxyphenyl)-7,8,9,10,11,12-hexahydrobenzo[f]pyrimido[4,5-
b]quinoline-9,11-dione 4k
Pale yellow crystals, mp > 300ꢀC. IR (KBr): 3178, 3133, 3065, 3012, 2955,
2812, 1710, 1043, 1584, 1539, 1490, 1463, 1417, 1392, 1326, 1300, 1250,
1234, 1182, 1098, 1026, 840, 815, 751.1H NMR (DMSO-d6) d: 3.88
(s, 3H, CH3O), 5.98 (s, 1H, CH), 6.74–6.77 (m, 1H, ArH), 6.91
(d, J ¼ 8.0 Hz, 1H, ArH), 7.00–7.04 (m, 1H, ArH), 7.21 (dd,
J1 ¼ 7.6 Hz, J2 ¼ 1.2 Hz, 1H, ArH), 7.28–7.32 (m, 2H, ArH), 7.40–7.43
(m, 1H, ArH), 7.75 (d, J ¼ 8.8 Hz, 1H, ArH), 7.78 (d, J ¼ 8.4 Hz, 1H,
ArH), 8.18 (d, J ¼ 8.4 Hz, 1H, ArH), 9.05 (s, 1H, NH), 10.33 (s, 1H,
NH), 10.50 (s, 1H, NH). Anal. calcd. for C22H17N3O3: C, 71.15; H,
4.61; N, 11.31. Found: C, 71.27; H, 4.57; N, 11.39.

Benzo[f]pyrimido[4,5-b]quinolines
3077
12-(3,5-Dimethoxyphenyl)-7,8,9,10,11,12-hexahydrobenzo[f]pyri-
mido[4,5-b]quinoline-9,11-dione 4l
Pale yellow crystals, mp > 300ꢀC. IR (KBr): 3270, 3203, 2936, 2837, 1704,
1647, 1610, 1590, 1542, 1463, 1397, 1327, 1315, 1233, 1201, 1161, 1071,
1055, 889, 865, 850, 821, 772, 745.1H NMR (DMSO-d6) d: 3.62 (s, 6H,
2 CH3O), 5.68 (s, 1H, CH), 6.23–6.24 (m, 1H, ArH), 6.39 (d, J ¼ 2.0 Hz,
*
Hz, 2H, ArH), 7.33–7.39 (m, 2H, ArH), 7.42–7.47 (m, 1H, ArH),
7.82–7.85 (m, 2H, ArH), 7.92 (d, J ¼ 8.4 Hz, 1H, ArH), 9.11 (s, 1H,
NH), 10.66 (s, 1H, NH). Anal. calcd. for C23H19N3O4: C, 68.82; H,
4.77; N, 10.47. Found: C, 68.99; H, 4.69; N, 10.53.
12-(2-Bromophenyl)-7,8,9,10,11,12-hexahydrobenzo[f]pyrimido[4,5-
b]quinoline-9,11-dione 4m
Pale yellow crystals, mp > 300ꢀC. IR (KBr): 3311, 3171, 3052, 1702, 1587,
1462, 1327, 1310, 1283, 1248, 1230, 1175, 1105, 1043, 1020, 827, 803, 769,
745, 713.1H NMR (DMSO-d6) d: 5.95 (s, 1H, CH), 6.96–6.99 (m, 1H,
ArH), 7.14–7.18 (m, 1H, ArH), 7.28–7.36 (m, 3H, ArH), 7.42–7.47 (m,
2H, ArH), 7.82 (d, J ¼ 8.4 Hz, 2H, ArH), 8.17 (d, J ¼ 8.8 Hz, 1H,
ArH), 9.20 (s, 1H, NH), 10.40 (s, 1H, NH), 10.58 (s, 1H, NH). Anal.
calcd. for C21H14BrN3O2: C, 60.02; H, 3.36; N, 10.00. Found: C, 59.90;
H, 3.38; N, 10.18.
12-(4-Fluorophenyl)-7,8,9,10,11,12-hexahydrobenzo[f]pyrimido[4,5-
b]quinoline-9,11-dione 4n
Pale yellow crystals, mp > 300ꢀC. IR (KBr): 3191, 3071, 1721, 1638, 1603,
1544, 1504, 1472, 1450, 1397, 1351, 1300, 1224, 1199, 1156, 1121, 1095,
1035, 833, 821, 801, 747, 714. 1H NMR (DMSO-d6) d: 5.74 (s, 1H,
CH), 6.96–7.00 (m, 2H, ArH), 7.27–7.35 (m, 3H, ArH), 7.37–7.44 (m,
2H, ArH), 7.71–7.76 (m, 2H, ArH), 7.83 (d, J ¼ 8.8 Hz, 1H, ArH), 9.13
(s, 1H, NH), 10.41 (s, 1H, NH), 10.67 (s, 1H, NH). Anal. calcd. for
C21H14FN3O2: C, 70.19; H, 3.93; N, 11.69. Found: C, 70.10; H, 3.85;
N, 11.77.
12-(2-Fluorophenyl)-7,8,9,10,11,12-hexahydrobenzo[f]pyrimido[4,5-
b]quinoline-9,11-dione 4o
Pale yellow crystals, mp > 300ꢀC. IR (KBr): 3172, 3086, 1708, 1634, 1608,
1559, 1486, 1474, 1399, 1277, 1236, 1203, 1126, 1086, 1036, 824, 773, 751,

3078
X.-S. Wang et al.
733.1H NMR (DMSO-d6) d: 5.74 (s, 1H, CH), 6.96–7.00 (m, 2H, ArH),
7.27–7.35 (m, 3H, ArH), 7.37–7.44 (m, 2H, ArH), 7.71–7.76 (m, 2H,
ArH), 7.83 (d, J ¼ 8.8 Hz, 1H, ArH), 9.13 (s, 1H, NH), 10.41 (s, 1H,
NH), 10.67 (s, 1H, NH). Anal. calcd. for C21H14FN3O2: C, 70.19; H,
3.93; N, 11.69. Found: C, 70.29; H, 3.90; N, 11.70.
12-(4-Hydroxyphenyl)-7,8,9,10,11,12-hexahydrobenzo[f]pyrimido[4,5-
b]quinoline-9,11-dione 4p
Pale yellow crystals, mp > 300ꢀC. IR (KBr): 3552, 3197, 1707, 1646, 1544,
1510, 1470, 1395, 1343, 1299, 1234, 1180, 1122, 1103, 1075, 1041, 970,
818, 772, 747.1H NMR (DMSO-d6) d: 5.61 (s, 1H, CH), 6.54
(d, J ¼ 8.4 Hz, 2H, ArH), 7.05 (d, J ¼ 8.4 Hz, 2H, ArH), 7.31–7.40 (m,
2H, ArH), 7.42–7.44 (m, 1H, ArH), 7.80–7.83 (m, 2H, ArH), 7.91
(d, J ¼ 8.4 Hz, 1H, ArH), 9.03 (s, 1H, OH), 9.10 (s, 1H, NH), 10.33 (s,
1H, NH), 10.61 (s, 1H, NH). Anal. calcd. for C21H15N3O3: C, 70.58;
H, 4.23; N, 11.76. Found: C, 70.67; H, 4.30; N, 11.82.
12-(4-Nitrophenyl)-7,8,9,10,11,12-hexahydrobenzo[f]pyrimido[4,5-
b]quinoline-9,11-dione 4q
Pale yellow crystals, mp > 300ꢀC. IR (KBr): 3200, 3075, 1704, 1642, 1590,
1515, 1468, 1395, 1347, 1300, 1235, 1185, 1109, 1050, 972, 892, 862, 823,
770, 750.1H NMR (DMSO-d6) d: 5.88 (s, 1H, CH), 7.32–7.36 (m, 1H,
ArH), 7.40–7.44 (m, 2H, ArH), 7.54 (d, J ¼ 8.8 Hz, 2H, ArH),
7.83–7.88 (m, 3H, ArH), 8.06 (d, J ¼ 8.0 Hz, 2H, ArH), 9.26 (s, 1H,
NH), 10.51 (s, 1H, NH), 10.72 (s, 1H, NH). Anal. calcd. for
C21H14N4O4: C, 65.28; H, 3.65; N, 14.50. Found: C, 65.43; H, 3.40; N,
14.39.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China
(20802061), the Natural Science Foundation (08KJD150019), and Qing
Lan Project (08QLT001) of Jiangsu Education Committee for financial
support.
REFERENCES
1. (a) Vijjay, N. C.; Rajesh, A. U.; Vinod, S.; Bindu, A. R.; Sreekanth, J. S.;
Lakshmi, B. Strategies for heterocyclic construction via novel

Benzo[f]pyrimido[4,5-b]quinolines
3079
multi-component reactions based on isocyanides and nucleophilic carbenes.
Acc. Chem. Res. 2003, 36, 899–907; (b) Anary-Abbasinejad, M.; Saidipoor,
A. One-pot, four-component reaction of aryl aldehydes, aryl ketones, phos-
phorus trichloride, and acetonitrile catalyzed by acetyl chloride: Synthesis of
b-acetamido ketones. Synth. Commun. 2008, 38, 354–360; (c) Tietze, L. F.
Domino reactions in organic synthesis. Chem. Rev. 1996, 96, 115–136; (d)
Bunce, R. A. Recent advances in the use of tandem reactions for organic
synthesis. Tetrahedron 1995, 51, 13103–13159; (e) Hatamjafari, F. New proto-
col to synthesize spiro-1,4-dihydropyridines by using a multicomponent reac-
tion of cyclohexanone, ethyl cyanoacetate, isatin, and primary amines under
microwave irradiation. Synth. Commun. 2006, 36, 3563–3570; (f) Wang, X.
S.; Zhang, M. M.; Jiang, H.; Shi, D. Q.; Tu, S. J.; Wei, X. Y.; Zong, Z. M.
An improved and benign synthesis of 9,10-diarylacridin-1,8-dione and indeno-
quinoline derivatives from 3-arylamino-5,5-dimethyl cyclohex-2-enone, arylal-
dehyde and 1,3-dicarbonyl compound in ionic liquid medium. Synthesis 2006,
4187–4199; (g) Wang, X. S.; Zhang, M. M.; Li, Q.; Yao, C. S.; Tu, S. J. An
unexpected ring-opening of 2-pyrone ring in the synthesis of 1-arylbenzo[f]-
quinoline-2-carboxmide derivatives in aqueous media catalyzed by TEBAC.
Synlett 2007, (20), 3141–3144.
2. (a) Ahluwalia, V. K.; Sahay, R.; Das, U. Synthesis and antimicrobial activity
of 1,3,5-triaryl-10-benzyl-1,2,3,4,6,7,8,9-octahydro-8,8-dimethyl-4,6-dioxo-2-
thioxo-5 h,10 h-pyrimido[4,5-b]quinolines. Indian J. Chem. Sect. B 1999, 38,
1136–1138; (b) Kumar, R. N.; Suresh, T.; Mohan, P. S. Synthesis and antibac-
terial activity of pyrimido[4,5-b]quinolines. Indian J. Chem. Sect. B 2003, 42,
688–689.
3. Kumar, R. N.; Suresh, T.; Mohan, P. S. A simple one-pot synthesis of
4-phenyl-3-oxopyrimido[4,5-b]quinolines and their biocidal studies. Asian J.
Chem. 2002, 14, 1405–1408.
4. Vishwanathan, C. L.; Arun, J. A.; Suresh, N. S. A Process for the synthesis of
substituted 2,4,5-triamino-8-chloropyrimido-[4,5-b]quinolines as novel antima-
larials. Indian Pat. IN 2003MU00627 A. 2005.
5. Naby, H. A. A.; Mekheimer, R. A.; Abd-Elhameed, A. M.; Sadek, K. U. A
Convenient one-pot synthesis of pyrimido[4,5-b]quinolines as 5-deaza
non-classical antifolate inhibitors. J. Chem. Res. 1999, (11), 678–679.
6. Dorjsuren, D.; Burnette, A.; Gray, G. N.; Chen, X. L.; Zhu, W. M.; Roberts,
P. E.; Currens, M. J.; Shoemaker, R. H.; Ricciardi, R. P.; Sei, S. Chemical
library screen for novel inhibitors of kaposi’s sarcoma-associated herpesvirus
processive DNA synthesis. Antiviral Res. 2006, 69, 9–23.
7. (a) Kozlov, N. G.; Basalaeva, L. I. Reaction of hexahydropyirimidine-2,4,6--
trione with naphthalen-2-amine and benzaldehydes. Russ. J. Org. Chem. 2007,
43, 432–438; (b) Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.;
Shivanyuk, A. N.; Tolmachev, A. A. A one-pot fusion of nitrogen-containing
heterocycles. Synthesis 2007, (18), 2872–2886; (c) Li, S.-Y.; Chen, Y.-L.;
Wang, C.; Tzeng, C.-C. Synthesis and antiproliferative evaluation of certain
pyrido[3,2-g]quinoline derivatives. Bioorg. Med. Chem. 2006, 14 (22), 7370–
7376; (d) Chao, W.; Mahajan, Y. R.; Weinreb, S. M. An approach to total

3080
X.-S. Wang et al.
synthesis of the cylindricine b pyridoquinoline subclass of tricyclic marine
ascidian alkaloids. Tetrahedron Lett. 2006, 47 (23), 3815–3818; (e)
Tverdokhlebov, A. V.; Gorulya, A. P.; Tolmachev, A. A.; Kostyuk, A. N.;
Chernega, A. N.; Rusanov, E. B. The tert-amino effect in the synthesis of
hetaryl- and arylsulfonyl-substituted pyrrolo- and pyrido[1,2-a]quinoline
derivatives and their pyrazolo annulated analogues. Synthesis 2005, (13),
2161–2170.
8. Wang, X. S.; Zhang, M. M.; Zeng, Z. S.; Shi, D. Q.; Tu, S. J.; Wei, X. Y.;
Zong, Z. M. A new synthesis method for benzo[f]quinolin-3-carbonyl urea
and thiourea derivatives in aqueous media catalyzed by TEBAC. J. Hetero-
cycl. Chem. 2007, 44, 441–447.