K. Tabatabaeian et al. / Chinese Chemical Letters 25 (2014) 308–312
309
at elevated temperatures, safety, mildness, non-volatility, low
toxicity, reusability and biocompatibility.
2955, 2872, 1697, 1660, 1607, 1606, 1506, 1467, 1356, 1205, 838,
793, 736, 693, 675. Anal. Calcd. for C19H17ClFN3O3: C 58.54, H 4.40,
N 10.78; Found: C 58.40, H 4.22, N 10.55.
In addition to the above mentioned characteristics, higher
reactivity and excellent selectivity of this catalyst and along with
the important role of nitrogen-containing heterocyclic compounds
in medicinal chemistry also prompted us to explore the potential of
RuCl3ꢀxH2O in MCRs that could produce diversified heterocyclic
products with practically important biological and pharmacologi-
cal properties.
5-(4-Dimethylaminophenyl)-1,3-dimethyl-7,8,9,10-tetrahydro-
pyrimido[4,5-b]quinoline-2,4,6(1H,3H,5H)-trione (6b): Orange solid,
mp 278–280 8C; 1H NMR (400 MHz, DMSO-d6):
d 1.82, 1.81 (m,
1H), 1.92–1.99 (m, 1H), 2.22–2.26 (m, 2H), 2.58–2.63 (m, 1H),
2.73–2.75 (m, 1H), 3.10 (s, 3H), 3.34 (s, 6H), 3.45 (s, 3H), 4.82 (s,
1H), 6.55 (dd, 2H, J = 8.8, 4.8 Hz, ArH), 7.02 (dd, 2H, J = 8.4, 4.8 Hz,
ArH), 9.029 (s, NH). 13C NMR (100 MHz, DMSO-d6):
d 21.24, 26.92,
2. Experimental
28.11, 30.64, 32.66, 37.19, 40.38, 91.16, 112.6, 113.12, 128.45,
135.37, 143.83, 149.35, 151.3, 151.5, 161.24, 195.34. FT-IR (KBr,
IR spectra were obtained in KBr discs on a Perkin-Elmer model
Spectrum One FT-IR Spectrometer. 1H NMR spectra were obtained
on a Bruker DRX-400 Avance spectrometer and 13C NMR were
obtained on a Bruker DRX-100 Avance spectrometer. Samples were
analyzed in DMSO-d6, and chemical shift values are reported in
ppm relative to tetramethylsilane (TMS) as the internal reference.
Melting points were measured on an Electrothermal apparatus and
were uncorrected. Elemental analyses were made by a Carlo-Erba
EA1110 CNNO-S analyzer and agreed with the calculated values.
Sonication was performed in an Elmasonic S 40H ultrasonic
cleaning unit. All materials and solvents were purchased from
Merck and used without further purification.
cmꢁ1):
n
3436, 3187, 3078, 2925, 2885, 1697, 1659, 1640, 1608,
1517, 1495, 1379, 1352, 1199, 825, 754, 702, 661. Anal. Calcd. for
21H24N4O3: C 66.30, H 6.36, N 14.73; Found: C 66.19, H 6.20, N
C
14.51.
3. Results and discussion
Our literature search revealed that there are no reports on the
use of RuCl3ꢀxH2O as an efficient and effective catalyst, without any
toxic solvent in the synthesis of pyrimido[4,5-b]quinoline deriva-
tives via a three-component reaction conditions.
In this methodology, cyclic 1,3-diketones, uracil and aldehyde
react in one step in the presence of Lewis acid RuCl3ꢀxH2O in water.
Uracils are important compounds in the synthesis of anti-cancer
and antiviral drugs. In this study, 6-amino-1,3-dimethyl uracil was
used as an important partner in the synthesis of tricyclic fused ring
derivatives. This agent provided C5 and C6 carbons in the products.
Dimedone or 1,3-cyclohexanedione as a cyclic ketone with strong
nucleophilic properties, provided C2, C3 carbons in the products.
In order to increase yield, the reaction conditions were
optimized using 4-nitrobenzaldehyde, 6-amino-1,3-dimethyl ura-
cil and dimedone under different temperatures and amount of the
catalyst. (Scheme 1) The results are summarized in Table 1.
The optimum amount of RuCl3ꢀxH2O was evaluated. The highest
yield was obtained with 3 mol% of the catalyst. A further increase
in the amount of RuCl3ꢀxH2O did not have any significant effect on
product yield. In order to establish the true effectiveness of the
catalyst, a reaction of 4-nitrobenzaldehyde, dimedone and 6-
amino-1,3-dimethyl uracil was performed at 90 8C without any
catalyst in water. It was found that only trace amount of
pyrimido[4,5-b]quinoline was obtained after 120 min of heating
(Table 1, entry 6).
RuCl3ꢀxH2O (3 mol%) was added to a mixture of aldehyde
(1.0 mmol), 6-amino-1,3-dimethyluracil (1.0 mmol), and cyclic
1,3-diketone (1.0 mmol) in deionized water (10 mL). The reaction
mixture was heated to 85 8C and stirred magnetically for an
appropriate period of time. After the completion of the reaction as
indicated by TLC analysis, the mixture was cooled to room
temperature. The colored solid product was collected and washed
with warm ethanol to afford the pure product. For further
purification, some derivatives were recrystallized from ethanol.
Spectroscopic data for the selected products are as follows:
5-(2-Chloro-6-fluorophenyl)-1,3,8,8-tetramethyl-7,8,9,10-tetra-
hydropyrimido[4,5-b]quinoline 2,4,6(1H,3H,5H)trione (7a): Light
yellow solid, mp 302–304 8C; 1H NMR (400 MHz, DMSO-d6):
d
0.91 (s, 3H), 1.04–1.08 (m, 3H), 1.98 (d, 2H, J = 16 Hz), 2.21 (d, 2H,
J = 16.4Hz), 3.05 (s, 3H), 3.45 (s, 3H), 5.42 (s, 1H), 7.03 (t, 1H,
ArH),7.122–7.154 (m, 2H, ArH) 9.06 (s, NH). 13C NMR (100 MHz,
DMSO-d6):
113.46, 115.02, 122.27, 126.53, 127.94, 135.00, 146.16, 147.22,
150.01, 160.16, 161.42, 195.90. FT-IR (KBr, cmꢁ1):
3290, 3232,
d 21.53, 26.32, 28.15, 29.94, 30.20, 43.16, 50.52, 88.14,
n
3075, 2943, 2873, 1701, 1660, 1642, 1607, 1495, 1453, 1378, 1359,
1210, 886, 788, 730, 687. Anal. Calcd. for C21H21ClFN3O3: C 60.36, H
5.07, N 10.06; Found: C 60.23, H 4.90, N 9.8.
5-(3-Nitrophenyl)-1,3,8,8-tetramethyl-7,8,9,10-tetrahydropyri-
mido[4,5-b]quinolin2,4,6(1H,3H,5H)trione (8a): Yellow solid, mp
287–290 8C; 1H NMR (400 MHz, DMSO-d6):
d 3.16 (m, 16H), 5.69 (s,
Choice of solvent plays an important role in most of the MCRs.
To compare the efficiency of the solvent, various solvents,
including nonpolar solvents such as n-hexane, protic solvents,
such as water, ethanol and methanol, and aprotic polar solvents,
such as acetonitrile, were tested. The results, presented in Table 2,
1H), 7.51 (t, 1H, J = 8 Hz, ArH), 7.60 (d, 1H, J = 8.0 Hz, ArH), 7.88 (s,
1H, ArH), 7.92 (d, 1H, J = 8.0 Hz, ArH), 10.15 (s, NH). 13C NMR (100
Table 1
MHz, DMSO-d6):
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. FT-IR (KBr, cmꢁ1):
3391,
d 25.81, 27.72, 30.11, 30.53, 37.55, 41.90, 50.41,
Screening of the amount of the catalyst and temperature in one-pot synthesis of
model reaction.a
n
Entry
Catalyst (mol%)
Temperature (8C)
Time (min)
Yield (%)b
3068, 2953, 1702, 1668, 1653, 1607, 1594, 1525, 1500, 1380, 1350,
1212, 904, 873, 790, 734, 681. Anal. Calcd. for C21H22N4O5: C 61.45,
H 5.40, N 13.65; Found: C 61.32, H 5.28, N 13.44.
5-(2-Chloro,6-fluorophenyl)-1,3-dimethyl-7,8,9,10-tetrahydro-
pyrimido[4,5-b]quinoline-2,4,6-trione (2b): White solid, mp 298–
300 8C; 1H NMR (400 MHz, DMSO-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, 1H, J = 8.8 Hz, ArH), 7.123 (d, 1H, J = 8.0 Hz, ArH),
7.137 (d, 1H, J = 8.0 Hz, ArH), 9.11 (s, NH). 13C NMR (100 MHz,
1
2
3
4
5
6
7
8
9
10
20
10
7
90
90
60
50
80
85
90
50
89
5
90
40
90
3
90
30
94
–
90
120
60
Trace
71
3
70
3
80
45
30
85
3
85
100
95
3
30
92
DMSO-d6):
116.55, 126.01, 128.20, 128.40, 136.71, 145.05, 145.36, 150.00,
153.00, 160.00, 195.06. FT-IR (KBr, cmꢁ1):
3555, 3405, 3173,
d 21.00, 21.23, 26.96, 27.99, 30.76, 37.14, 87.81, 114.52,
a
All reactions were run with 4-nitrobenzaldehyde (1.0 mmol), dimedone
(1.0 mmol), and 6-amino-1,3-dimethyl uracil (1.0 mmol) in water (10 mL).
b
n
Isolated yield.