432 JOURNAL OF CHEMICAL RESEARCH 2017
129.5, 129.6, 130.8, 131.0, 132.7, 132.8, 136.1, 145.6, 146.4, 150.2, 153.0
(aromatic and olefinic carbons), 154.4, 163.3, 191.0 (3C=O); MS m/z
(%): 388 (38). Anal. calcd for C20H12N4O5: C, 61.86; H, 3.11; N, 14.43;
found: C, 61.83; H, 3.09; N, 14.41%.
crude product obtained by extraction with EtOAc. The DES
was recovered from the aqueous phase by evaporation at 80 °C
under vacuum and was recycled for the next reaction. It was
recycled four consecutive times with almost unaltered catalytic
activity (the yield decreased from 92% to 87% after four runs).
We propose the following mechanism for the reaction
(Scheme 2). The DES may play a dual role in this reaction as
a solvent and catalyst, which in the latter case is by activation
of the carbonyl group via hydrogen bonding. The aldehyde,
which is activated by the DES and the activated carbonyl (a),
undergoes a Knoevenagel condensation with 1,3-indandione
(b) to afford intermediate (c). Then, 6-aminopyrimidin-
2,4(1H,3H)-dione 3 attacks the intermediate (c) and affords
intermediate (d) via Michael addition. The intermediate (d)
undergoes intramolecular cyclisation with participation of the
amino function and one of the 1,3-indandione carbonyl group to
form (e). Then the elimination of water from (e) forms the aryl
indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-2,4,6(3H,5H,11H)-
trione derivatives (4a–m) as the target molecules.
5- (4-Bromophenyl) -5,11-dihydro-1H-indeno [2 ′,1′:5,6]
pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione (4c): Red powder; m.p.
328–330 °C; yield 92%; IR (KBr) (νmax cm−1): 3420, 3215, 3135 (NH),
1698, 1668, 1657 (C=O); 1H NMR: δ 4.67 (1H, s, CH), 7.24, 7.44 (2H,
2d, 3JHH = 12 Hz, aromatic), 7.28–7.66 (4H, m, aromatic), 10.27–10.97
(3H, s, 3NH); 13C NMR: δ 33.8 (CH), 91.0, 109.4, 119.6, 121.3, 130.4,
130.9, 131.0, 131.3, 132.6, 132.9, 133.4, 135.9, 136.4, 145.0, 145.2, 150.2
(aromatic and olefinic carbons), 154.0, 163.3, 191.2 (3C=O); MS m/z
(%): 388 (38). Anal. calcd for C20H12N3O3Br: C, 56.89; H, 2.86; N, 9.95;
found: C, 56.80; H, 2.59; N, 10.03%.
5- (2,4-Dichlorophenyl)-5,11-dihydro-1H-indeno[2′,1′:5,6]
pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione (4d): Red powder;
m.p. 320–322 °C; yield 92%; IR (KBr) (νmax cm−1): 3450, 3165, 3150
1
(NH), 1703, 1687, 1627 (C=O); H NMR: δ 5.08 (1H, s, CH), 7.34
(1H, s, aromatic), 7.48 (1H, dd, JHH = 8.4, 2.0 HZ, aromatic), 7.64 (1H,
s, aromatic), 7.66 (1H, s, aromatic), 7.70 (1H, d, J = 2.0 Hz, 1H), 7.79
(1H, dt, J = 8.2, 2.0 Hz, aromatic), 7.87 (1H, s, aromatic), 7.96 (1H,
s, aromatic), 10.38–10.92 (3H, s, 3NH); 13C NMR: δ 29.2 (CH), 90.7,
107.2, 119.6, 124.1, 128.6, 128.8, 130.8, 131.0, 132.1, 132.6, 132.9,
133.4, 136.4, 141.9, 142.1, 150.2 (aromatic and olefinic carbons),
154.4, 163.0, 190.9 (3C=O); MS m/z (%): 411 (33). Anal. calcd for
C20H11N3O3Cl2: C, 58.27; H, 2.69; N, 10.19; found: C, 58.23; H, 2.65;
N, 10.16%.
In this study, we have developed a rapid, efficient and versatile
procedure for the synthesis of indeno-fused pyrido[2,3-d]
pyrimidine derivatives 4a–m in a regiochemical manner by
using an eco-friendly and biodegradable deep eutectic solvent
based on a choline chloride/urea mixture. The advantages of
this method are operational simplicity, green medium, DES
recoverability, short reaction times and high yields.
5-(3-Nitrophenyl)-5,11-dihydro-1H-indeno[2′,1′:5,6]pyrido[2,3-d]
pyrimidine-2,4,6(3H)-trione (4e): Red powder; m.p. 318–320 °C;
yield 91%; IR (KBr) (νmax cm−1): 3510, 3330, 3180 (NH), 1711, 1655,
Experimental
All melting points were determined with an Electrothermal 9100
apparatus. Elemental analyses were performed using a Costech ECS
4010 CHNS-O analyser at the analytical laboratory of Islamic Azad
University, Yazd branch. Mass spectra were recorded on a Finnigan-
Mat 8430 mass spectrometer operating at an ionisation potential of
70 eV. IR spectra were recorded on a Shimadzu IR-470 spectrometer.
1
1617 (C=O), 1519, 1339 (NO2); H NMR: δ 4.86 (1H, s, CH), 7.29
(1H, d, J = 7.2 Hz, aromatic), 7.38 (1H, dt, J = 7.2, 1.6 Hz, aromatic),
7.49 (1H, s, aromatic), 7.56 (1H, t, J = 8.0 Hz, aromatic), 7.78 (1H, t,
J = 8.0 Hz, aromatic), 8.04 (1H, dd, J = 8.0, 1.2 Hz, aromatic), 8.09 (1H,
s, aromatic), 10.35–11.01 (3H, s, 3NH); 13C NMR: δ 34.3 (CH), 90.6,
108.7, 119.8, 121.0, 121.8, 122.6, 130.0, 131.1, 132.7, 132.8, 133.5, 135.1,
136.4, 145.5, 147.6, 150.2 (aromatic and olefinic carbons), 154.4, 163.3,
191.2 (3C=O); MS m/z (%): 388 (35). Anal. calcd for C20H12N4O5: C,
61.86; H, 3.11; N, 14.43; found: C, 61.77; H, 3.08; N, 14.52%.
NMR spectra were obtained on
a Bruker DRX-400 Avance
spectrometer (1H NMR at 400 Hz, 13C NMR at 100 Hz) in DMSO-d6
using TMS as an internal standard. Chemical shifts (δ) are given in
ppm and coupling constants (J) are given in Hz. The chemicals used in
this work were purchased from Fluka (Buchs, Switzerland) and were
used without further purification.
5-(4-Chloro-3-nitrophenyl)-5,11-dihydro-1H-indeno[2′,1′:5,6]
pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione (4f): Red powder; m.p.
333–335 °C; yield 90%; IR (KBr) (νmax cm−1): 3445, 3215, 3165 (NH),
1
Synthesis of indeno fused pyrido[2,3-d]pyrimidine derivatives
(4a–m); general procedure
1706, 1684, 1663 (C=O), 1526, 1337 (NO2); H NMR: δ 4.83 (1H, s,
CH), 7.30–7.95 (7H, aromatic), 10.44–11.01 (3H, s, 3NH); 13C NMR:
δ 30.5 (CH), 90.1, 108.2, 119.9, 124.9, 127.6, 131.1, 131.4, 132.7, 132.9,
133.7, 136.0, 136.5, 142.1, 146.5, 147.9, 150.2 (aromatic and olefinic
carbons), 154.5, 163.3, 191.2 (3C=O); MS m/z (%): 422 (30). Anal.
calcd for C20H11N4O5Cl: C, 56.82; H, 2.62; N, 13.25; found: C, 56.70;
H, 2.55; N, 13.3%.
1,3-indanedione 1 (0.25 mmol), an aromatic aldehyde 2 (0.25 mmol)
and 6-aminopyrimidin-2,4(1H,3H)-dione 3 (0.25 mmol) were added to
a DES (choline chloride/urea, 1 mmol:2 mmol). The resulting mixture
was stirred for the specified time (Table 2) at 80 °C. After reaction
completion, (TLC, ethyl acetate/n-hexane, 2:1), the reaction mixture
was washed with water (10 mL) and the solid residue recrystallised
from ethanol to obtain the pure product.
5- (4-Fluorophenyl) -5,11-dihydro-1H-indeno [2 ′,1′:5,6]
pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione (4g): Red powder;
m.p. 327–329 °C; yield 88%; IR (KBr) (νmax
cm−1): 3440, 3220, 3125
5- (4-Methoxyphenyl) -5,11-dihydro-1H-indeno[2′,1′:5,6]
pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione (4a): Red powder; m.p.
323–325 °C; yield 89%; IR (KBr) (νmax cm−1): 3485, 3370, 3173 (3NH),
(NH), 1697, 1673, 1659 (C=O); 1H NMR: 4.70 (1H, s, CH), 7.07 (2H,
t, J = 8.4Hz, aromatic), 7.22 (1H, d, J = 8.8 Hz, aromatic), 7.36 (1H,
t, J = 8.4 Hz, aromatic), 7.44 (2H, d, J = 8.0 Hz, aromatic), 7.65 (1H,
d, J = 7.2 Hz, aromatic), 10.23–10.96 (3H, s, 3NH); 13C NMR: 33.4
(CH), 91.3, 109.8, 115.2 (JCF = 21 Hz, Cortho), 119.6, 129.9, 129.9, 130.5
(JCF = 9 Hz, Cmeta), 130.9, 132.6, 133.4, 136.2, 140.6 (JCF = 2 Hz, Cortho),
145.1, 150.2, 157.9 (JCF = 246 Hz, Cipso) (aromatic and olefinic carbons),
153.9, 163.3, 191.3 (3C=O); MS m/z (%): 361 (41). Anal. calcd for
C20H12N3O3F: C, 66.48; H, 3.35; N, 11.63; found: C, 66.41; H, 3.29; N,
11.59%.
1
1708, 1680, 1672 (3C=O); H NMR: δ 3.84 (3H, s, OCH3), 4.85 (1H,
3
s, CH), 6.92, 6.95 (4H, 2d, JHH = 12 Hz, aromatic), 7.61–7.88 (4H,
m, aromatic), 10.27–11.25 (3H, s, 3NH); 13C NMR: δ 28.9 (CH), 55.2
(OCH3), 91.9, 110.6, 115.1, 115.6, 121.2, 128.9, 129.8, 130.7, 132.5,
133.1, 133.3, 136.2, 136.3, 144.7, 150.3, 153.5 (aromatic and olefinic
carbons), 156.1, 163.3, 191.4 (3C=O); MS m/z (%): 373 (34). Anal.
calcd for C21H15N3O4: C, 67.56; H, 4.05; N, 11.25; found: C, 67.44; H,
3.99; N, 11.36%.
5-(4-Nitrophenyl)-5,11-dihydro-1H-indeno[2′,1′:5,6]pyrido[2,3-d]
pyrimidine-2,4,6(3H)-trione (4b): Red powder; m.p. 325–327 °C;
yield 95%; IR (KBr) (νmax cm−1): 3465, 3220, 3130 (NH), 1700, 1663,
5-(2-Hydroxy-3-methoxyphenyl)-5,11-dihydro-1H-indeno[2′,1′:5,6]
pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione (4h): Red powder; m.p.
319–321 °C; yield 87%; IR (KBr) (νmax cm−1): 3485, 3275, 3185 (NH),
3215 (OH), 1704, 1674, 1657 (C=O); 1H NMR: δ 4.88 (1H, s, CH), 6.65
(2H, d, J = 7.6Hz, aromatic), 6.73 (1H, t, J = 8.8 Hz, aromatic), 7.27
(1H, d, J = 8.8 Hz, aromatic), 7.37 (1H, dt, J = 7.2, 1.2 Hz, aromatic),
1
1539, 1336 (NO2); H NMR: δ 4.84 (1H, s, CH), 7.30–7.52 (4H, m,
3
aromatic) 7.58, 8.12 (4H, 2d, JHH = 12 Hz, aromatic), 10.42–11.01
(3H, 3s, 3NH); 13C NMR: δ 34.5 (CH), 90.5, 108.6, 119.8, 122.8, 123.7,