An efficient synthesis of pyrimido[4,5-b]quinoline derivatives via three-component reaction in aqueous media

Article abstract of DOI:10.1002/jhet.57

A series of pyrimido[4,5-b]quinoline derivatives was synthesized by three-component reaction of 6- aminopyrimidine, aromatic aldehydes and 1,3-cyclohexanedione or 5,5-dimethyl-1,3-cyclohexanedione in aqueous media in the presence of triethylbenzylammonium

Full text of DOI:10.1002/jhet.57

March 2009
An Efficient Synthesis of Pyrimido[4,5-b]quinoline Derivatives
via Three-Component Reaction in Aqueous Media
237
Da-Qing Shi,a,b,c* Li-Hui Niu,b Hao Yao,b and Hong Jiangc
aCollege of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Organic
Synthesis of Jiangsu Province, Soochow University, Suzhou 215123, People’s Republic of China
bCollege of Chemistry and Chemical Engineering, Xuzhou Normal University,
Xuzhou 221116, People’s Republic of China
cThe Key Laboratory of Biotechnology for Medical Plants of Jiangsu Province,
Xuzhou Normal University, Xuzhou 221116, People’s Republic of China
*E-mail: dqshi@263.net
Received February 25, 2008
DOI 10.1002/jhet.57
Published online 13 April 2009 in Wiley InterScience (www.interscience.wiley.com).
A series of pyrimido[4,5-b]quinoline derivatives was synthesized by three-component reaction of 6-
aminopyrimidine, aromatic aldehydes and 1,3-cyclohexanedione or 5,5-dimethyl-1,3-cyclohexanedione
in aqueous media in the presence of triethylbenzylammonium chloride. This protocol has the advantages
of higher yields, lower lost, easy work-up, and environmentally friendly procedure.
J. Heterocyclic Chem., 46, 237 (2009).
INTRODUCTION
have been used extensively to form carbon–carbon and
carbon-heteroatom bonds in synthetic chemistry [14].
Such reactions offer a wide range of possibilities for the
efficient construction of highly complex molecules in a
single procedural step, thus avoid complicated purifica-
tion operations and allow savings of both solvents and
reagents. The need to reduce the amount of toxic waste
and by-product arising from chemical process requires
increasing emphasis on the use of less toxic and
environmentally compatible materials in the design of
new synthetic methods. One of the most promising
approaches is using water as reaction media. Breslow
et al. [15], who showed that hydrophobic effects could
strongly enhance the rate of several organic reactions,
rediscovered the use of water as a solvent in organic
chemistry in the 1980s. There has been growing recog-
nition that water is an attractive medium for many
organic reactions [16]. Many MCRs in aqueous medium
have been reported [17]. As part of our current studies
on the development of new routes to heterocyclic sys-
tems [18], we now report an efficient and clean syn-
thetic route to pyrimido[4,5-b]quinoline derivatives in
aqueous media.
The importance of uracil and its annelated derivatives is
well recognized by synthetic [1] as well as biological [2]
chemists. With the development of clinically useful anti-
cancer and antiviral drugs [3], there has recently been re-
markable interest in the synthetic manipulations of uracils
[4]. Uracil derivatives have been reported in the literature
to be versatile building blocks for the synthesis of a wide
range of heterocyclic motifs, including pyridopyrimidines
[5] and pyrazolopyrimidines [6]. Pyrido[2,3-d]pyrimidines
have received considerable attention over the past years
because of their wide range of biological activities, such
as antitumor [7], antibacterial [8], anti-inflammatory [9],
antifungal [10], antileishmaniasis [11], and also act as
cyclin-dependent kinase 4 inhibitors [12]. Recently, Tu
et al. [13] reported the synthesis of pyrimido[4,5-b]quino-
line-4,6-dione through one-pot condensation of 2,6-diami-
nopyrimidine-4-one, aldehyde and cyclic a 1,3-dicarbonyl
compound in glycol under microwave irradiation without
catalyst. However, they were reacted in organic solvent
and needed a special reaction instrument.
Multicomponent reactions (MCRs), in which multiple
reactions are combined into one synthetic operation,
C
V
2009 HeteroCorporation

238
D.-Q. Shi, L.-H. Niu, H. Yao, and H. Jiang
Vol 46
Scheme 1
Scheme 2
RESULTS AND DISCUSSION
via an initial formation of a,b-unsaturated ketone, from
the Knoevenagel condensation of aldehyde and 1,3-
dicarbonyl compounds, which suffers nucleophilic attack
to give the Michael adduct 7. The intermediate product
7 then cyclizes and subsequently dehydrates to afford
the product 4.
In summary, a series of pyrimido[4,5-b]quinoline
derivatives were synthesized via three-component reac-
tion of aldehydes, 6-amminopyrimidine and 1,3-cyclo-
hexanedione or 5,5-dimethyl-1,3-cyclohexanedione in
water in the presence of TEBAC. Compared with other
methods, this new method has the advantages of high
yields, mild reaction conditions, easy work-up, inexpen-
sive reagents, and environmentally friendly procedure.
When the three-component reaction of 2,6-diaminopyr-
imidine-4-one 1, aromatic aldehyde 2, and 1,3-cyclohexa-
nedione or 5,5-dimethyl-1,3-cyclohexanedione 3 was per-
formed in water in the presence of TEBAC at 90ꢀC, 2-
amino-5-aryl-8,9-dihydropyrimidino[4,5-b]quinoline-4,6
(1H,3H,5H,10H)-dione 4 were obtained in high yields
(Scheme 1). The results are summarized in Table 1.
As expected, when the 2,6-diaminopyrimidine-4-one 1
was replaced by 6-aminopyrimdine-1,3-dione 5, another
series of 5-aryl-8,9-dihydropyrimido[4,5-b]quinoline-
2,4,6(1H,3H,5H,10H)-trione 6 were obtained under the
same reaction conditions (Scheme 2). The results are
summarized in Table 2.
As shown in Tables 1 and 2, this protocol can be
applied not only to aromatic aldehydes with either elec-
tron-withdrawing groups (such as nitro- or halide-groups)
or electron-donating groups (such as alkoxy or alkyl
groups), but also to heterocyclic aldehydes with excellent
yields under same conditions. Therefore, we concluded
that the electronic nature of the substituents has no signifi-
cant effect on these reactions.
EXPERIMENTAL
Melting points were determined with a TX-5 microscopic
melting-point apparatus and were uncorrected. IR spectra were
1
recorded on a Tensor 27 spectrometer in KBr. H NMR spectra
were measured on a Bruker DPX-400 MHz spectrometer using
TMS standard and DMSO-d6 as solvent. Elemental analyses
were performed on Perkin-Elmer 2400II elemental analyzer.
General Procedure for the Synthesis of Pyrimido[4,5-
b]quinoline Derivatives. A suspension of a mixture of 6-ami-
nopyrimidine 1 or 5 (2 mmol), aldehyde 2 (2 mmol), 1,3-
In this study, all the products were characterized by
1
mp, IR, and H NMR spectral data as well as elemental
analyses.
A reasonable mechanism for the formation of the
product 4 is outlined in Scheme 3. The reaction occurs
cyclohexanedione or 5,5-dimethyl-1,3-cyclohexanedione
3
(2 mmol) and TEBAC (0.15 g, 0.66 mmol) was stirred in
water (10 mL) at 90ꢀC for several hours. After completion
monitored by TLC, the reaction mixture was allowed to cool
to room temperature. The crystalline powder formed recrystal-
lized from DMF to give pure 4 or 6.
2-Amino-5-(4-fluorophenyl)-8,9-dihydropyrimido[4,5-b]-
quinoline-4,6(3H,5H,7H,10H)-dione (4a). This compound was
obtained as white needles with mp > 300ꢀC; IR (potassium
Table 1
The synthesis of pyrimido[4,5-b]quinoline derivatives 4
in aqueous media.
Reaction
time (h)
Isolated
yield (%)
Entry
R
Ar
4-FC6H4
4-HOC6H4
3-NO2C6H4
4-NO2C6H4
4-ClC6H4
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
H
12
16
18
16
20
20
18
20
16
17
20
13
12
21
14
95
93
94
90
92
86
95
86
86
92
96
94
94
92
88
Table 2
H
H
The synthesis of pyrimido[4,5-b]quinoline derivatives 6
in aqueous media.
H
H
H
4-BrC6H4
4-ClC6H4
4-HOC6H4
Reaction
time (h)
Isolated
yield (%)
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Entry
R
Ar
4-NO2C6H4
3,4-(CH3O)2C6H3
3,4-Cl2C6H3
3-NO2C6H4
4-BrC6H4
6a
6b
6c
6d
6e
6f
H
H
3,4- Cl2C6H3
3-NO2C6H4
2,4-Cl2C6H3
2-NO2C6H4
4-NO2C6H4
3,4-(CH3O)2C6H3
4-HOC6H4
8
20
16
12
13
20
22
76
98
75
93
86
91
98
H
H
H
3,4-OCH2OC6H3
Pyridine-3-yl
CH3
CH3
6g
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2009
An Efficient Synthesis of Pyrimido[4,5-b]quinoline Derivatives via
Three-Component Reaction in Aqueous Media
239
Scheme 3
(DMSO-d6): 1.73–1.95 (m, 2H, CH2), 2.12–2.28 (m, 2H,
CH2), 2.51–2.63 (m, 2H, CH2), 4.95 (s, 1H, CH), 6.39 (br. s,
2H, NH2), 7.44 (d, J ¼ 8.8 Hz, 2H, ArH), 8.06 (d, J ¼
8.8 Hz, 2H, ArH), 9.51 (br. s, 1H, NH), 10.45 (br. s, 1H, NH).
Anal. Calcd. for C17H15N5O4: C, 57.79; H, 4.28; N, 19.82.
Found: C, 58.01; H, 4.16; N, 19.69.
2-Amino-5-(4-chlorophenyl)-8,9-dihydropyrimido[4,5-b]-
quinoline-4,6(3H,5H,7H,10H)-dione (4e). This compound was
obtained as pale yellow prisms with mp > 300ꢀC (Lit. [13] >
300ꢀC); IR (potassium bromide): 3358, 3151, 2955, 1683,
1647, 1617, 1519, 1488, 1457, 1426, 1370, 1290, 1267, 1230,
1
1204, 1188, 1137, 1089, 1014, 994, 832, 813 cmꢁ1; H NMR
(DMSO-d6): 1.72–1.95 (m, 2H, CH2), 2.13–2.27 (m, 2H,
CH2), 2.45–2.59 (m, 2H, CH2), 4.83 (s, 1H, CH), 6.34 (br. s,
2H, NH2), 7.17–7.24 (m, 4H, ArH), 9.40 (br. s, 1H, NH),
10.44 (br. s, 1H, NH). Anal. Calcd. for C17H15ClN4O2: C,
59.57; H, 4.41; N, 16.34. Found: C, 59.83; H, 4.26; N, 16.56.
2-Amino-5-(4-bromophenyl)-8,9-dihydropyrimido[4,5-b]-
quinoline-4,6(3H,5H,7H,10H)-dione (4f). This compound was
obtained as pale yellow prisms with mp > 300ꢀC (Lit. [13] >
300ꢀC); IR (potassium bromide): 3343, 3152, 2954, 1676,
1652, 1520, 1485, 1457, 1426, 1397, 1369, 1290, 1257, 1230,
1203, 1183, 1137, 1071, 1051, 1010, 994, 898, 831, 811, 777,
bromide): 3328, 3148, 2947, 1676, 1644, 1514, 1447, 1362,
1287, 1229, 1149, 1089, 1050, 1014, 994, 897, 839, 816, 770,
733, 706 cmꢁ1 1H NMR (DMSO-d6): 1.71–1.95 (m, 2H,
;
1
750, 735, 700 cmꢁ1; H NMR (DMSO-d6): 1.70–1.95 (m, 2H,
CH2), 2.11–2.27 (m, 2H, CH2), 2.45–2.60 (m, 2H, CH2), 4.82
(s, 1H, CH), 6.33 (br. s, 2H, NH2), 7.13 (d, J ¼ 8.4 Hz, 2H,
ArH), 7.35 (d, J ¼ 8.4 Hz, 2H, ArH), 9.40 (br. s, 1H, NH),
10.40 (br. s, 1H, NH). Anal. Calcd. for C17H15BrN4O2: C,
52.73; H, 3.90; N, 14.47. Found: C, 52.94; H, 3.86; N, 14.63.
2-Amino-5-(4-chlorophenyl)-8,8-dimethyl-8,9-dihydropyr-
imido[4,5-b]quinoline-4,6(3H,5H,7H,10H)-dione (4g). This com-
pound was obtained as yellow needles with mp > 300ꢀC (Lit.
[13] > 300ꢀC); IR (potassium bromide): 3397, 3169, 2965,
1679, 1647, 1621, 1515, 1478, 1446, 1363, 1303, 1279, 1246,
CH2), 2.13–2.25 (m, 2H, CH2), 2.45–2.73 (m, 2H, CH2), 4.85
(s, 1H, CH), 6.34 (br. s, 2H, NH2), 6.97 (dd, J1 ¼ 6.0 Hz,
J2 ¼ 8.8 Hz, 2H, ArH), 7.19 (dd, J1 ¼ 6.0 Hz, J2 ¼ 8.8 Hz,,
2H, ArH), 9.38 (br. s, 1H, NH), 10.44 (br. s, 1H, NH). Anal.
Calcd. for C17H15FN4O2: C, 62.57; H, 4.63; N, 17.17. Found:
C, 62.82; H, 4.48; N, 17.36.
2-Amino-5-(4-hydroxyphenyl)-8,9-dihydropyrimido[4,5-
b]quinoline-4,6(3H,5H,7H,10H)-dione (4b). This compound
was obtained as pale yellow prisms with mp > 300ꢀC; IR (po-
tassium bromide): 3556, 3335, 3151, 2955, 1679, 1651, 1519,
1455, 1372, 1267, 1187, 1049, 994, 896, 839, 818, 772, 734,
1217, 1198, 1155, 1140, 1090, 1014, 860, 805, 778, 690 cmꢁ1
;
1H NMR (DMSO-d6): 0.89 (s, 3H, CH3), 1.00 (s, 3H, CH3),
1.98 (d, J ¼ 16.0 Hz, 1H, CH), 2.17 (d, J ¼ 16.0 Hz, 1H,
CH), 2.38 (d, J ¼ 17.2 Hz, 1H, CH), 2.45 (d, J ¼ 17.2 Hz,
1H, CH), 4.79 (s, 1H, CH), 6.34 (br. s, 2H, NH2), 7.17 (d, J ¼
8.4 Hz, 2H, ArH), 7.21 (d, J ¼ 8.4 Hz, 2H, ArH), 9.35 (br. s,
1H, NH), 10.41 (br. s, 1H, NH). Anal. Calcd. for
C19H19ClN4O2: C, 61.54; H, 5.16; N, 15.11. Found: C, 61.76;
H, 5.09; N, 15.28.
700 cmꢁ1 1H NMR (DMSO-d6): 1.72–1.95 (m, 2H, CH2),
;
2.15–2.24 (m, 2H, CH2), 2.42–2.60 (m, 2H, CH2), 4.76 (s, 1H,
CH), 6.27 (br. s, 2H, NH2), 6.54 (d, J ¼ 8.4 Hz, 2H, ArH),
6.96 (d, J ¼ 8.4 Hz, 2H, ArH), 8.98 (s, 1H, OH), 9.28 (br. s,
1H, NH), 10.33 (br. s, 1H, NH). Anal. Calcd. for C17H16N4O3:
C, 62.95; H, 4.97; N, 17.27. Found: C, 63.05; H, 5.08; N,
17.13.
2-Amino-5-(4-hydroxyphenyl)-8,8-dimethyl-8,9-dihydropyri-
mido[4,5-b]quinoline-4,6(3H,5H,7H,10H)-dione (4h). This com-
pound was obtained as pale yellow prisms with mp > 300ꢀC;
IR (potassium bromide): 3440, 3330, 2955, 1675, 1647, 1615,
1514, 1455, 1372, 1284, 1250, 1226, 1202, 1173, 1168, 1139,
2-Amino-5-(3-nitrophenyl)-8,9-dihydropyrimido[4,5-b]-
quinoline-4,6(3H,5H,7H,10H)-dione (4c). This compound was
obtained as pale yellow prisms with mp > 300ꢀC (Lit. [13] >
300ꢀC); IR (potassium bromide): 3462, 3249, 2934, 1679,
1647, 1517, 1426, 1345, 1287, 1227, 1191, 1134, 1095, 1050,
1105, 1057, 1028, 975, 854, 808, 769 cmꢁ1
;
1H NMR
994, 913, 824, 802, 772, 759, 705 cmꢁ1 1H NMR (DMSO-
;
(DMSO-d6): 0.90 (s, 3H, CH3), 1.00 (s, 3H, CH3), 1.98 (d,
J ¼ 16.0 Hz, 1H, CH), 2.15 (d, J ¼ 16.0 Hz, 1H, CH), 2.36
(d, J ¼ 17.2 Hz, 1H, CH), 2.43 (d, J ¼ 17.2 Hz, 1H, CH),
4.71 (s, 1H, CH), 6.25 (br. s, 2H, NH2), 6.53 (d, J ¼ 8.0 Hz,
2H, ArH), 6.95 (d, J ¼ 8.0 Hz, 2H, ArH), 8.95 (br. s, 1H,
OH), 9.23 (br. s, 1H, NH), 10.31 (br. s, 1H, NH). Anal. Calcd.
for C19H20N4O3: C, 64.76; H, 5.72; N, 15.90. Found: C,
64.83; H, 5.84; N, 15.78.
2-Amino-5-(4-nitrophenyl)-8,8-dimethyl-8,9-dihydropyri-
mido[4,5-b]quinoline-4,6(3H,5H,7H,10H)-dione (4i). This com-
pound was obtained as yellow needles with mp > 300ꢀC (Lit.
[13] > 300ꢀC); IR (potassium bromide): 3470, 3335, 3256,
d6): 1.73–1.96 (m, 2H, CH2), 2.12–2.30 (m, 2H, CH2), 2.50–
2.65 (m, 2H, CH2), 4.96 (s, 1H, CH), 6.40 (br. s, 2H, NH2),
7.49 (t, J ¼ 8.0 Hz, 1H, ArH), 7.36 (d, J ¼ 8.0 Hz, 1H, ArH),
7.94–7.96 (m, 1H, ArH), 8.02 (s, 1H, ArH), 9.52 (br. s, 1H,
NH),10.44 (br. s, 1H, NH). Anal. Calcd. for C17H15N5O4: C,
57.79; H, 4.28; N, 19.82. Found: C, 57.98; H, 4.15; N, 20.05.
2-Amino-5-(4-nitrophenyl)-8,9-dihydropyrimido[4,5-b]-
quinoline-4,6(3H,5H,7H,10H)-dione (4d). This compound
was obtained as pale yellow prisms with mp > 300ꢀC (Lit.
[13] > 300ꢀC); IR (potassium bromide): 3328, 3149, 3028,
2957, 1681, 1639, 1618, 1522, 1458, 1426, 1367, 1349, 1289,
1
1268, 1231, 1205, 1183, 1138, 995, 823, 704 cmꢁ1; H NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

240
D.-Q. Shi, L.-H. Niu, H. Yao, and H. Jiang
Vol 46
3179, 3069, 2958, 1661, 1618, 1594, 1516, 1453, 1419, 1366,
1352, 1285, 1245, 1227, 1204, 1188, 1157, 881, 830, 805,
(d, J ¼ 16.0 Hz, 1H, CH), 2.38 (d, J ¼ 17.2 Hz, 1H, CH),
2.45 (d, J ¼ 17.2 Hz, 1H, CH), 4.77 (s, 1H, CH), 6.32 (br. s,
2H, NH2), 7.12 (d, J ¼ 8.4 Hz, 2H, ArH), 7.35 (d, J ¼8.4 Hz,
2H, ArH), 9.34 (br. s, 1H, NH), 10.38 (br. s, 1H, NH). Anal.
Calcd. for C19H19BrN4O2: C, 54.95; H, 4.61; N, 13.49. Found:
C, 55.06; H, 4.53; N, 13.41.
1
785, 739, 684 cmꢁ1; H NMR (DMSO-d6): 0.89 (s, 3H, CH3),
1.01 (s, 3H, CH3), 1.98 (d, J ¼ 16.0 Hz, 1H, CH), 2.18 (d,
J ¼ 16.0 Hz, 1H, CH), 2.41 (d, J ¼ 17.2 Hz, 1H, CH), 2.48
(d, J ¼ 17.2 Hz, 1H, CH), 4.91 (s, 1H, CH), 6.38 (br. s, 2H,
NH2), 7.43 (dd, J1 ¼ 6.8 Hz, J2 ¼ 6.0 Hz, 2H, ArH), 8.08
(dd, J1 ¼ 6.8 Hz, J2 ¼ 6.0 Hz 2H, ArH), 9.46 (br. s, 1H, NH),
10.43 (br. s, 1H, NH). Anal. Calcd. for C19H19N5O4: C, 59.84;
H, 5.02; N, 18.36. Found: C, 60.05; H, 4.97; N, 18.54.
2-Amino-5-(3,4-dimethylenedioxyphenyl)-8,8-dimethyl-8,9-
dihydropyrimido[4,5-b]quinoline-4,6(3H,5H,7H,10H)-dione (4n).
This compound was obtained as yellow needles with mp >
300ꢀC (Lit. [13] > 300ꢀC); IR (potassium bromide): 3216,
3188, 2958, 2902, 1622, 1558, 1540, 1508, 1488, 1455, 1372,
2-Amino-5-(3,4-dimethoxyphenyl)-8,8-dimethyl-8,9-dihydro-
pyrimido[4,5-b]quinoline-4,6(3H,5H,7H,10H)-dione (4j). This
compound was obtained as yellow prisms with mp > 300ꢀC
(Lit. [13] > 300ꢀC); IR (potassium bromide): 3432, 3263,
3184, 2956, 1669, 1625, 1588, 1513, 1451, 1369, 1283, 1266,
1
1283, 1232, 1200, 1041, 1029, 931, 882, 784 cmꢁ1; H NMR
(DMSO-d6): 0.91 (s, 3H, CH3), 1.00 (s, 3H, CH3), 2.00 (d,
J ¼ 16.0 Hz, 1H, CH), 2.16 (d, J ¼ 16.0 Hz, 1H, CH), 2.38
(d, J ¼ 17.2 Hz, 1H, CH), 2.44 (d, J ¼ 17.2 Hz, 1H, CH),
4.73 (s, 1H, CH), 5.89 (s, 2H, OCH2O), 6.35 (br. s, 2H, NH2),
6.60 (d, J ¼ 8.0 Hz, 1H, ArH), 6.66–6.72 (m, 2H, ArH), 9.32
(br. s, 1H, NH), 10.46 (br. s, 1H, NH). Anal. Calcd. for
C20H20N4O4: C, 63.15; H, 5.30; N, 14.73. Found: C, 63.07; H,
5.42; N, 14.86.
1246, 1224, 1199, 1139, 1025, 803, 766 cmꢁ1 1H NMR
;
(DMSO-d6): 0.94 (s, 3H, CH3), 1.02 (s, 3H, CH3), 2.00 (d,
J ¼ 15.6 Hz, 1H, CH), 2.18 (d, J ¼ 15.6 Hz, 1H, CH), 2.38
(d, J ¼ 17.2 Hz, 1H, CH), 2.45 (d, J ¼ 17.2 Hz, 1H,
CH), 3.65 (s, 3H, CH3O), 3.67 (s, 3H, CH3O), 4.77 (s, 1H,
CH), 6.28 (br. s, 2H, NH2), 6.64 (d, J ¼ 8.0 Hz, 1H, ArH),
6.74 (d, J ¼ 8.0 Hz, 1H, ArH), 6.83 (s, 1H, ArH), 9.24 (br. s,
1H, NH), 10.33 (br. s, 1H, NH). Anal. Calcd. for C21H24N4O4:
C, 63.62; H, 6.10; N, 14.13. Found: C, 63.74; H, 6.02; N,
14.26.
2-Amino-5-(pyridin-3-yl)-8,8-dimethyl-8,9-dihydropyrimido
[4,5-b]quinoline-4,6(3H,5H,7H,10H)-dione (4o). This com-
pound was obtained as yellow needles with mp > 300ꢀC; IR
(potassium bromide): 3417, 3373, 3263, 3194, 2960, 1660,
1625, 1544, 1513, 1470, 1453, 1400, 1370, 1277, 1242, 1227,
2-Amino-5-(3,4-dichlorophenyl)-8,8-dimethyl-8,9-dihydro-
pyrimido[4,5-b]quinoline-4,6(3H,5H,7H,10H)-dione (4k). This
compound was obtained as white needles with mp > 300ꢀC;
IR (potassium bromide): 3462, 3252, 3059, 2957, 1677, 1603,
1519, 1461, 1372, 1307, 1284, 1228, 1191, 1173, 1140, 1097,
1197, 1154, 1140, 1044, 843, 804, 783, 752, 711 cmꢁ1 1H
;
NMR (DMSO-d6): 0.89 (s, 3H, CH3), 1.01 (s, 3H, CH3), 1.99
(d, J ¼ 16.0 Hz, 1H, CH), 2.18 (d, J ¼ 16.0 Hz, 1H, CH),
2.41 (d, J ¼ 16.8 Hz, 1H, CH), 2.47 (d, J ¼ 16.8 Hz, 1H,
CH), 4.79 (s, 1H, CH), 6.36 (br. s, 2H, NH2), 7.20 (dd, J1 ¼
4.8 Hz, J2 ¼ 8.0 Hz, 1H, ArH), 7.49 (dd, J1 ¼ 2.0 Hz, J2 ¼
4.8 Hz, 1H, ArH), 8.25 (dd, J1 ¼ 2.0 Hz, J2 ¼ 4.8 Hz, 1H,
ArH), 8.39 (d, J ¼ 2.0 Hz, 1H, ArH), 9.41 (br. s, 1H, NH),
10.42 (br. s, 1H, NH). Anal. Calcd. for C18H19N5O2: C, 64.08;
H, 5.68; N, 20.76. Found: C, 64.32; H, 5.54; N, 20.92.
1028, 878, 842, 818, 791, 748, 703 cmꢁ1 1H NMR (DMSO-
;
d6): 0.90 (s, 3H, CH3), 1.01 (s, 3H, CH3), 2.00 (d, J ¼
16.0 Hz, 1H, CH), 2.18 (d, J ¼ 16.0 Hz, 1H, CH), 2.40 (d,
J ¼ 17.2 Hz, 1H, CH), 2.46 (d, J ¼ 17.2 Hz, 1H, CH), 4.78
(s, 1H, CH), 6.39 (br. s, 2H, NH2), 7.12 (dd, J1 ¼ 2.0 Hz,
J2 ¼ 8.0 Hz, 1H, ArH), 7.33 (d, J ¼ 2.0 Hz, 1H, ArH), 7.44
(d, J ¼ 8.0 Hz, 1H, ArH), 9.42 (br. s, 1H, NH), 10.44 (br. s,
1H, NH). Anal. Calcd. for C19H18Cl2N4O2: C, 56.31; H, 4.48;
N, 13.82. Found: C, 56.48; H, 4.33; N, 13.97.
5-(3,4-Dichlorophenyl)-8,9-dihydropyrimido[4,5-b]quinol-
ine-2,4,6(1H,3H,5H,7H,10H)-trione (6a). This compound was
obtained as white prisms with mp > 300ꢀC; IR (potassium
bromide): 3247, 3207, 3078, 2949, 1714, 1682, 1629, 1609,
1522, 1476, 1439, 1378, 1330, 1303, 1252, 1228, 1182, 1143,
2-Amino-5-(3-nitrophenyl)-8,8-dimethyl-8,9-dihydropyri-
mido[4,5-b]quinoline-4,6(3H,5H,7H,10H)-dione (4l). This com-
pound was obtained as yellow needles with mp > 300ꢀC (Lit.
[13] > 300ꢀC); IR (potassium bromide): 3470, 3350, 3257,
3194, 2958, 1664, 1649, 1509, 1443, 1417, 1364, 1308, 1285,
1242, 1226, 1202, 1188, 1157, 1098, 1025, 881, 830, 806,
1
1112, 1029, 994, 955, 901, 820, 778 cmꢁ1; H NMR (DMSO-
d6): 1.71–1.96 (m, 2H, CH2), 2.10–2.30 (m, 2H, CH2), 2.54–
2.66 (m, 2H, CH2), 4.76 (s, 1H, CH), 7.16 (dd, J1 ¼ 2.0 Hz,
J2 ¼ 8.4 Hz, 1H, ArH), 7.38 (d, J ¼ 2.0 Hz, 1H, ArH), 7.47
(d, J ¼ 8.4 Hz, 1H, ArH), 9.00 (br. s, 1H, NH), 10.29 (br. s,
1H, NH), 10.80 (br. s, 1H, NH). Anal. Calcd. for
C17H13Cl2N3O3: C, 53.99; H, 3.46; N, 11.11. Found: C, 54.08;
H, 3.56; N, 11.04.
1
785, 738 cmꢁ1; H NMR (DMSO-d6): 0.90 (s, 3H, CH3), 1.02
(s, 3H, CH3), 1.99 (d, J ¼ 16.0 Hz, 1H, CH), 2.19 (d, J ¼
16.0 Hz, 1H, CH), 2.42 (d, J ¼ 17.6 Hz, 1H, CH), 2.49 (d,
J ¼ 17.6 Hz, 1H, CH), 4.92 (s, 1H, CH), 6.39 (br. s, 2H,
NH2), 7.50 (t, J ¼ 8.0 Hz, 1H, 1H, ArH), 7.64 (d, J ¼ 7.6 Hz,
1H, ArH), 7.95 (d, J ¼ 7.6 Hz, 1H, ArH), 7.99 (s, 1H, ArH),
9.45 (br. s, 1H, NH), 10.42 (br. s, 1H, NH). Anal. Calcd. for
C19H19N5O4: C, 59.84; H, 5.02; N, 18.36. Found: C, 59.98; H,
5.14; N, 18.19.
5-(3-Nitrophenyl)-8,9-dihydropyrimido[4,5-b]quinoline-
2,4,6(1H,3H,5H,7H,10H)-trione (6b). This compound was
obtained as pale yellow prisms with mp > 300ꢀC; IR (potas-
sium bromide): 3279, 3221, 3074, 2970, 1720, 1684, 1632,
1597, 1528, 1470, 1447, 1382, 1358, 1258, 1207, 1186, 1147,
1128, 1089, 994, 914, 845, 822, 772, 740 cmꢁ1 1H NMR
;
2-Amino-5-(4-bromophenyl)-8,8-dimethyl-8,9-dihydropyri-
mido[4,5-b]quinoline-4,6(3H,5H,7H,10H)-dione (4m). This com-
pound was obtained as yellow needles with mp > 300ꢀC; IR
(potassium bromide): 3471, 3323, 3250, 3186, 1659, 1621,
1515, 1486, 1451, 1370, 1284, 1238, 1227, 1204, 1155, 1070,
(DMSO-d6): 1.75–1.99 (m, 2H, CH2), 2.18–2.30 (m, 2H,
CH2), 2.53–2.69 (m, 2H, CH2), 4.91 (s, 1H, CH), 7.52 (t, J ¼
8.0 Hz, 1H, ArH), 7.66 (d, J ¼ 6.0 Hz, 1H, ArH), 7.98 (t, J ¼
8.0 Hz, 1H, ArH), 8.03 (s, 1H, ArH), 9.05 (br. s, 1H, NH),
10.32 (br. s, 1H, NH), 10.81 (br. s, 1H, NH). Anal. Calcd. for
C17H14N4O5: C, 57.63; H, 3.98; N, 15.81. Found: C, 57.81; H,
4.02; N, 15.69.
1
1011, 842, 809, 782 cmꢁ1; H NMR (DMSO-d6): 0.89 (s, 3H,
CH3), 1.01 (s, 3H, CH3), 1.98 (d, J ¼ 16.0 Hz, 1H, CH), 2.17
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2009
An Efficient Synthesis of Pyrimido[4,5-b]quinoline Derivatives via
Three-Component Reaction in Aqueous Media
241
(d, J ¼ 16.8 Hz, 1H, CH), 4.64 (s, 1H, CH), 6.56 (d, J ¼ 8.0
Hz, 2H, ArH), 6.96 (d, J ¼ 8.0 Hz, 2H, ArH), 8.70 (br. s, 1H,
OH), 9.09 (br. s, 1H, NH), 10.18 (br. s, 1H, NH), 10.72 (br. s,
1H, NH). Anal. Calcd. F or C19H19N3O4: C, 64.58; H, 5.42;
N, 11.89. Found: C, 64.63; H, 5.36; N, 11.97.
5-(2,4-Dichlorophenyl)-8,9-dihydropyrimido[4,5-b]quino-
line-2,4,6(1H,3H,5H,10H)-trione (6c). This compound was
obtained as white prisms with mp > 300ꢀC; IR (potassium
bromide): 3248, 3207, 3079, 2952, 1723, 1670, 1629, 1603,
1537, 1483, 1426, 1418, 1382, 1341, 1267, 1187, 1149, 1110,
1036, 994, 904, 862, 815, 760, 705 cmꢁ1 1H NMR (DMSO-
;
d6): 1.70–1.95 (m, 2H, CH2), 2.10–2.27 (m, 2H, CH2), 2.51–
2.60 (m, 2H, CH2), 5.03 (s, 1H, CH), 7.26 (dd, J1 ¼ 2.0 Hz,
J2 ¼ 8.4 Hz, 1H, ArH), 7.31 (d, J ¼ 8.4 Hz, 1H, ArH), 7.34
(d, J ¼ 2.0 Hz, 1H, ArH), 8.97 (br. s, 1H, NH), 10.21 (br. s,
1H, NH), 10.67 (br. s, 1H, NH). Anal. Calcd. for
C17H13Cl2N3O3: C, 53.99; H, 3.46; N, 11.11. Found: C, 54.07;
H, 3.28; N, 11.25.
Acknowledgment. We are grateful to the Foundation of the Key
Laboratory of Biotechnology on Medical Plants of Jiangsu Prov-
ince for financial support.
REFERENCES AND NOTES
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1483, 1438, 1411, 1380, 1348, 1265, 1207, 1188, 1148, 1109,
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1H, CH), 2.22 (d, J ¼ 16.0 Hz, 1H, CH), 2.42 (d, J ¼ 17.2 Hz,
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797, 786, 764 cmꢁ1; H NMR (DMSO-d6): 0.89 (s, 3H, CH3),
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

242
D.-Q. Shi, L.-H. Niu, H. Yao, and H. Jiang
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