An efficient synthesis of new benzo[1′,2′:6,7]quinolino[2,3-d]- pyrimidine derivatives via three-component microwave-assisted reaction

Article abstract of DOI:10.1002/jhet.5570450452

(Chemical Equation Presented) A series of benzo[1′,2′:6,7] quinolino[2,3-d]pyrimidine derivatives were synthesized via condensation of an aromatic aldehyde, 2-hydroxy naphthalene-1,4-dione and 2,6-diaminopyrimidin-4- one in mixed solvent of acetic acid and glycol (3:1,V:V) under microwave irradiation. This one-pot protocol has the advantage of good yield (86-91%), simple workup procedure and rapid reaction time (4-8min).

Full text of DOI:10.1002/jhet.5570450452

Jul-Aug 2008
1243
An Efficient Synthesis of New Benzo[1',2':6,7]quinolino[2,3-d ]-
pyrimidine Derivatives via Three-component Microwave-assisted
Reaction
Yan Chena, Shanshan Wub, Shujiang Tub, *, Feng Shib, Chunmei Lib
a School of Chemistry and Chemical Engineering, Xuzhou Institute of Technology College, Xuzhou, Jiangsu
221008, PR China, chenyan681110@126.com
b School of Chemistry and Chemical Engineering, Xuzhou Normal University, Key Laboratory of Biotechnology
on Medical Plant, Xuzhou, Jiangsu 221119, PR China, laotu2001@263.net
Received October 27, 2007
O
O
N
HN
+
+
ArCHO
OH
O
H2N
NH2
O
1
2
3
Ar
O
N
120°C
MW
NH
acetic acid / glycol
N
H
NH2
O
4
A series of benzo[1',2':6,7]quinolino[2,3-d]pyrimidine derivatives were synthesized via condensation of
an aromatic aldehyde, 2-hydroxy naphthalene-1,4-dione and 2,6-diaminopyrimidin-4-one in mixed solvent
of acetic acid and glycol (3:1,V:V) under microwave irradiation. This one-pot protocol has the advantage
of good yield (86-91%), simple workup procedure and rapid reaction time (4-8min).
J. Heterocyclic Chem., 45, 1243 (2008).
INTRODUCTION
Of these heterocycles, pyrido[2,3-d]pyrimidines
present interesting biological properties, and as some
recent applications, they have been used as antitumor
agents [7], some of them have shown antimicrobial
activity [8], diuretic acivity [9] and activity against
platelet aggregation [10]. Benz[g]quinoline-5,10-dione
exhibited the best overall activity against both bacteria
and fungi. Particularly noteworthy was its significant
antifungal activity, which was comparable to the
activity of the standard antifungal antibiotic ampho-
tericin B [11]. Pyrido[2,3-d]pyrimidines have been
reported widely in the literature [12], but the
construction of the skeletons incorporating both
pyrido[2,3-d]pyrimidine and benzo[g]quinoline-5,10-
dione has seldom been reported. Therefore, the develo-
pment of a simple and effective method for the
preparation of these skeletons is still strongly desirable.
Interested in the bioactivities of skeletons and effective
reaction procedure, we wish to report a facile three-
component reaction via aldehyde 1, 2-hydroxy-
naphthalene-1,4-dione 2 and 2,6-diamino-pyrimidin-4-
one 3 in a mixed solvent of acetic acid and glycol
under microwave irradiation to afford a new type of
heterocyclic compounds, 2-amino-5-aryl-benzo-[1ꢀ,2ꢀ:
6,7]quinolino[2,3-d]pyrimidine-4,6,11[3H,5H,12H]-
trione 4 (Scheme 1).
Multicomponent reactions, in which multiple reactions
are combined into one synthetic operation, have been used
extensively to form carbon-carbon bonds and carbon-
heteroatom in synthetic chemistry [1]. Such reactions
offer a wide range of possibilities for the efficient
construction of highly complex molecules in a single
procedural step, thus avoiding complicated purification
operations and allowing savings of both solvents and
reagents.
In the past few years, the utilization of microwave
irradiation in chemical transformations has attracted
considerable interest and is of significant importance in
the search for green synthesis and sustainable chemistry
[2]. More attractively, many reactions that typically
required hours or days to complete full conversion with
conventional heating could be realized in several minutes
utilizing microwave irradiation [3]. Microwave mediated
protocols have been widely applied to the formation of a
variety of carbon-heteroatom and carbon-carbon bonds.
Pyrimidine and pyridine derivatives have been studied
due to a variety of chemical and biological significance.
They have been reported as antibacterial, antiviral agents
[4] and calcium channel modulators [5]. A number of
heterocyclic compounds fused with pyrimidines are
known for their varied biological activities [6].

1244
Y. Chen, S. Wu, S. Tu, F. Shi, C. Li
Vol 45
Scheme 1
O
O
Ar
O
N
O
O
O
120oC
MW
NH
HN
+
+
ArCHO
glycol
acetic acid /
N
H
NH2
OH H2N
N
NH2
1
2
4
3
RESULTS AND DISCUSSION
Under these optimized reaction conditions [120 °C,
acetic acid/glycol (3:1, V/V)], a series of products 4 were
synthesized with this simple reaction procedure. The
results are summarized in Table 3. The reaction time was
4-8 minutes, and the yields were 86%-91%.
For comparison, the synthesis of 4b under classical heating
conditions at 120 °C was performed. The yield of 4b was
65% and the reaction time was 1 h (monitored by TLC).
Therefore, microwave irradiation exhibited advantages
over the conventional heating by reducing the reaction time
and improving the reaction yields. The electronic effect of
aryl was investigated, Under our reaction conditions, both
electron-withdrawing and electron-donating substituents
readily provided benzo[1',2':6,7] quinolino[2,3-d]-
pyrimidine derivatives in good yields (Table 3).
In order to search the optimum reaction condition,
different organic solvents, such as ethanol, N,N- dimethyl-
formamide (DMF), acetic acid (HOAc), glycol were
tested in the synthesis of 4b at 120 °C. All the reactions
were carryed out at the maximum power of 200 W. The
results are summarized in Table 1.
Table 1
Solvent optimization for the synthesis of 4b
Entry
Power
(W)
200
200
200
Time
(min)
Yield
(%)
88
75
84
Solvent
1
2
3
4
HOAc
EtOH
glycol
5
5
5
200
HOAc/glycol
(3:1,V:V)
DMF
5
5
91
88
Table 3
5
200
Synthesis of 4 under microwave irradiation
Time
/min
Yield
/%
Mp
°C
Entry Product
Ar
It is shown in Table 1 that the reaction using mixed
solvent of acetic acid and glycol gave the best result.
(Table 1, entry 4). Moreover, to further optimize the
reaction temperature, the same reaction was carried out at
the temperatures ranging from 90 to 140 °C in increments
of 10 °C each time in mixed solvent of acetic acid and
glycol. When the temperature was increased from 80 to
120 °C, the yield of 2-amino-5-(4-bromophenyl)-
benzo[1',2':6,7]quinolino[2,3-d]pyrimidine-4,6,11[3H,5H,
12H]-trione 4b was improved. However, no significant
increase in the yield of product 4b was observed as the
reaction temperature was raised from 120 to 140 °C
(monitored by TLC). Therefore, the temperature of 120
°C was chosen for all further microwave-assisted
reactions (Table 2).
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4-ClC6H4
4-BrC6H4
4
5
5
5
6
7
8
6
91
91
91
88
89
89
86
88
>300
>300
>300
>300
>300
>300
>300
>300
2-ClC6H4
C6H5
4-CH3C6H4
4-CH3OC6H4
3,4-(CH3O)2C6H3
2-Thienyl
4g
4h
In this study, all the products were characterized by IR
spectra, H NMR data and HRMS spectra. The IR spectra
of compound 4b showed strong absorptions at 1677, 1644
cm-1 due to C=O groups. The H NMR spectrum of 4b
showed a singlet at 10.64, 8.88 ppm due to two NH group,
a singlet at 6.51 ppm due to NH2, and a singlet at 5.15
ppm due to CH.
1
1
Table 2
Although the detailed mechanism of the above reaction
remains to be fully clarified, the formation of benzo-
[1',2':6,7]quinolino[2,3-d]pyrimidine derivatives 4 could
be explained by a presented in Scheme 2. We proposed
that the reaction might proceed through a reaction
sequence of condensation, addition, cyclization and
dehydration. Firstly, a condensation between aldehyde 1
and 2-hydroxynaphthalene-1,4-dione 2 would give the
Temperature optimization for the synthesis of 4b
Power
(W)
200
200
200
200
200
200
T
Time
(min)
10
8
Yield
(%)
75
84
89
Entry
(°C)
90
1
2
3
4
5
6
100
110
120
130
140
6
5
5
5
91
91
91

Jul-Aug 2008
An Efficient Synthesis of New Benzo[1',2':6,7]quinolino[2,3-d ]pyrimidine Derivatives
1245
Scheme 2
O
O
Ar
O
O
N
NH
+
+
ArCHO
OH
H2N
NH2
O
O
1
5
3
2
Ar
Ar
O
O
O
O
O
O
NH
NH
O
HN
N
NH2
O
H2N
N
O
NH2
6
7
O
O
Ar
O
Ar
O
N
-H2O
NH
NH
N
H
N
NH2
N
H
NH2
OH
O
8
4
EXPERIMENTAL
intermediate product 5. The addition of 5 to 2,6-di-
aminopyrimidin-4-one would then furnish the
3
Microwave irradiation was carried out with microwave oven
EmrysTM Creator from Personal Chemistry, Uppsala, Sweden.
Melting points were determined in open capillaries and were
intermediate product 7, which upon intermolecular
cyclization and dehydration would give rise to product 4.
Evidence supporting this proposed mechanism was
provided by the observation that when 5b and 3 were
subjected to the same conditions, the expected product 4b
was obtained in a yield similar to that obtained in the one-
pot reaction.
uncorrected. IR spectra were taken on
a TENSOR 27
spectrometer in KBr and reported in cm-1. 1H NMR spectra were
measured on a Bruke DPX 400 MHz spectrometer in DMSO-d6
with chemical shift ( ) given in ppm relative to TMS as internal
standard, HRMS spectra were taken on a TOF-MS spectrometer
from Miscromass, England.
General Procedure for the synthesis of 2-amino-5-aryl-
benzo[1',2':6,7]quinolino[2,3-d]pyrimidine-4,6,11[3H, 5H,
12H]-trione (4a-4h). The mixture of aldehyde 1,
2-hydroxynaphthalene-1,4-dione 2 and 2,6-diaminopyrimidin-4-
one 3 in the mixed solvent of acetic acid (1.5 mL) and glycol
(0.5 mL) was irradiated for 4-8 min at 200 W power and 120 °C.
Upon completion, monitored by TLC, the reaction mixture was
cooled to room temperature and then poured into cold water.
The solid product was collected by filtration to give the crude
product, which was further purified by recrystallization from
EtOH (95%).
Scheme 3
Br
Br
O
O
O
N
O
O
120°C MW
glycol
NH
NH2
NH
+
acetic acid /
N
H
H2N
N
NH2
O
O
3
4b
5b
2-Amino-5-(4-chlorophenyl)-benzo[1',2':6,7]quinolino[2,3-d]-
pyrimidine-4,6,11[3H,5H,12H]-trione (4a). This compound
was obtained according to above general procedure; ir
(potassium bromide): 3475, 3410, 3350, 2925, 1679, 1644,
1589, 1520, 1455, 1303, 1213, 724; 1H nmr: ꢀ10.62 (s, 1H, NH),
8.86 (s, 1H, NH), 8.02 (d, 1H, ArH, J = 7.2 Hz), 7.90 (d, 1H,
ArH, J = 7.2 Hz ), 7.76-7.85 (m, 2H, ArH ),7.32 (d, 2H, ArH, J
= 8.4 Hz ), 7.26 (d, 2H, ArH, J = 8.4 Hz), 6.51 (s, 2H, NH2),
5.17(s, 1H, CH). HRMS(EI): m/z calcd for C21H13ClN4O3
406.0647, found 406.0667.
In summary, we have demonstrated a rapid and
direct method that offered a simple and efficient route
for the one-pot, three-component synthesis of highly
function-alized benzo[1',2':6,7]quinolino[2,3-d]pyrim-
idine derivatives of potential biological importance in
excellent yields. Particularly valuable features of this
method included shorter reaction time, higher yields
and broader substrate scope. Most importantly, the
series of benzo[1',2':6,7]quinolino[2,3-d]pyrimidine
derivatives may prove to be of biological interest and
provide new classes of biological active compounds
for biomedical screening. This work is in progress in
our laboratories.
2-Amino-5-(4-bromophenyl)-benzo[1',2':6,7]quinolino[2,3-
d]pyrimidine-4,6,11[3H,5H,12H]-trione (4b) This compound
was obtained according to above general procedure; ir
(potassium bromide): 3468, 3349, 3326, 2916, 1677, 1644,
1
1589, 1454, 1303, 1212, 724; H nmr: ꢀ10.64 (s, 1H, NH), 8.88
(s, 1H, NH), 8.01 (d, 1H, ArH, J = 7.6 Hz ), 7.90 (d, 1H, ArH, J
= 7.6 Hz ), 7.78-8.83 (m, 2H, ArH), 7.40 (d, 2H, ArH, J = 8.4
Hz), 7.26 (d, 2H, ArH, J = 8.4 Hz), 6.51 (s, 2H, NH2), 5.15 (s,

1246
Y. Chen, S. Wu, S. Tu, F. Shi, C. Li
Vol 45
= 7.6 Hz ), 7.79-7.86 (m, 1H, ArH), 7.23 (d, 1H, ArH, J = 8.4
Hz), 6.81-6.85 (m, 2H, ArH), 6.52 (s, 2H, NH2), 5.48 (s, 1H,
CH). HRMS(EI): m/z calcd for C19H11N4O3S 375.0552, found
375.0562.
1H, CH). HRMS(EI): m/z calcd for C21H13BrN4O3 450.0151,
found 450.0147.
2-Amino-5-(2-chlorophenyl)-benzo[1',2':6,7]quinolino[2,3-
d]pyrimidine-4,6,11[3H,5H,12H]-trione (4c). This compound
was obtained according to above general procedure; ir
(potassium bromide): 3481, 3405, 3352, 2866, 1660, 1633,
Acknowledgement. We thank for the National Natural
Science Foundation of China (No. 20672090), the Nature
Science Foundation of the Jiangsu Province (No. BK2006033),
the Foundation of Qinglan Project (No. QL200512) and
Foundation of Xuzhou Institute of Technology College (No.
XKY2007105) the financial support.ꢀ
1
1588, 1351, 1299, 1199, 722; H nmr: ꢀ10.45 (s, 1H, NH), 8.76
(s, 1H, NH), 8.01 (d, 1H, ArH, J = 7.6 Hz ), 7.85-7.87 (m, 1H,
ArH ), 7.75-7.83 (m, 2H, ArH ), 7.39 (d, 1H, ArH, J = 8.0 Hz ),
7.26 (d, 1H, ArH, J = 8.0 Hz), 7.16-7.21 (m, 1H, ArH ), 7.09-
7.13 (m, 1H, ArH ), 6.48 (s, 2H, NH2), 5.51 (s, 1H, CH).
HRMS(EI): m/z calcd for C21H13ClN4O3 406.0647, found
406.0659.
REFERENCES
2-amino-5-phenyl-benzo[1',2':6,7]quinolino[2,3-d]pyrimid-
ine-4,6,11[3H,5H,12H]–trione (4d). This compound was
obtained according to above general procedure; ir (potassium
bromide): 3425, 3386, 3309, 3052, 2910, 1677, 1636, 1584,
1302, 1225, 722; 1H nmr: ꢀ10.58 (s, 1H, NH), 8.77 (s, 1H, NH),
8.02 (d, 1H, ArH, J = 7.2 Hz ), 7.90 (d, 1H, ArH, J = 7.2 Hz ),
7.77-7.85 (m, 2H, ArH), 7.30 (d, 2H, ArH, J = 7.6 Hz), 7.21 (t,
2H, ArH, J = 7.6 Hz), 7.11 (t, 1H, ArH, J = 7.6 Hz), 6.47 (s, 2H,
NH2), 5.20 (s, 1H, CH). HRMS(EI): m/z calcd for C21H14N4O3
370.1066, found 370.1063.
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1
1574, 1454, 1262, 1161, 722; H nmr: ꢀ10.58 (s, 1H, NH), 8.74
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(s, 1H, NH), 8.01 (d, 1H, ArH, J = 7.6 Hz), 7.90 (d, 1H, ArH, J
= 7.6 Hz ), 7.76-7.82 (m, 2H, ArH), 7.17 (d, 2H, ArH, J = 8.0
Hz), 7.01 (d, 2H, ArH, J = 8.0 Hz), 6.46 (s, 2H, NH2), 5.15 (s,
1H, CH), 2.19 (s, 3H, CH3). HRMS(EI): m/z calcd for
C22H16N4O3 384.1222, found 384.1223.
2-Amino-5-(4-methoxyphenyl)-benzo[1',2':6,7]quinolino-
[2,3-d]pyrimidine-4,6,11[3H,5H,12H]-trione (4f). This
compound was obtained according to above general procedure;
ir (potassium bromide): 3467, 3340, 3325, 2904, 1652, 1647,
1
1511, 1448, 1334, 1253, 1174, 1034, 722; H nmr: ꢀ10.58 (s,
1H, NH), 8.77 (s, 1H, NH), 8.01 (d, 1H, ArH, J = 7.6 Hz), 7.90
(d, 1H, ArH, J = 7.6 Hz ), 7.76-7.84 (m, 2H, ArH), 7.19 (d, 2H,
ArH, J = 8.4 Hz), 6.76(d, 2H, ArH, J = 8.4 Hz), 6.47 (s, 2H,
NH2), 5.13 (s, 1H, CH), 3.66 (s, 3H, OCH3). HRMS(EI): m/z
calcd for C22H16N4O4 400.1172, found 400.1167.
2-Amino-5-(3,4-dimethoxyphenyl)-benzo[1',2':6,7]quinol-
ino[2,3-d]pyrimidine-4,6,11[3H,5H,12H]-trione (4g). This
compound was obtained according to above general procedure; ir
(potassium bromide): 3456, 3338, 3305, 3071, 1632, 1591, 1515,
1450, 1302, 1209, 723; 1H nmr: ꢀ10.60 (s, 1H, NH), 8.77 (s, 1H,
NH), 8.15 (d, 1H, ArH, J = 7.6 Hz), 7.92 (d, 1H, ArH, J = 7.2 Hz
), 7.79-7.85 (m, 2H, ArH), 6.95 (s, 1H, ArH), 6.77(d, 2H, ArH, J
= 8.4 Hz), 6.71(d, 1H, ArH, J = 8.4 Hz), 6.48 (s, 1H, NH2), 5.13
(s, 1H, CH), 3.68 (s, 3H, OCH3), 3.65 (s, 3H, OCH3). HRMS(EI):
m/z calcd for C23H18N4O5 430.1277, found 430.1264.
2-amino-5-(thiophen-2-yl)-benzo[1',2':6,7]quinolino[2,3-d]-
pyrimidine-4,6,11[3H,5H,12H]-trione (4h). This compound
was obtained according to above general procedure; ir
(potassium bromide): 3429, 3326, 3302, 3068, 2866, 1642,
1
1630, 1514, 1351, 1227, 723, H nmr: ꢀ10.71 (s, 1H, NH), 9.08
(s, 1H, NH), 8.02 (d, 1H, ArH, J = 7.6 Hz), 7.99 (d, 1H, ArH, J