Synthesis of novel chromeno[4',3'-b]pyrano[6,5-b]quinoline derivatives

Article abstract of DOI:10.1515/HC.2011.047

New coumarin heteroanalogs were synthesized by condensation of 2-amino-4-aryl-3-cyano-5-oxo-4 H ,5 H-pyrano-[3,2-c] chromenes and 1,3-cyclohexanedione in 35-78 % yield. 2011 · Copyright by Walter de Gruyter.

Full text of DOI:10.1515/HC.2011.047

Heterocycl. Commun., Vol. 17(5-6), pp. 169–172, 2011 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/HC.2011.047
Preliminary Communication
Synthesis of novel chromeno[4′,3′-b]pyrano[6,5-b]quinoline
derivatives
COSY, HSQC, and HMBC experiments were conducted with
the selected compound 4h to establish the inter-fragment rela-
tionship and to assign the proton signals. The mass spectra
displayed molecular ion peaks at appropriate values.
Radineh Motamedi
Department of Chemistry, Payam Noor University,
Delijan, Iran
In summary, we have prepared new chromeno [4′,3′-b]
pyrano[6,5-b]quinolines of potential biological interest. Being
structurally similar to compounds 1 and tacrine, the biologi-
cal evaluation of compounds is the next step on our projected
structure activity relationship (SAR) analysis, directed to
define the key structural and functional elements that might
improve the pharmacological profile of these molecules.
e-mail: r_motamedi@pnu.ac.ir
Abstract
New coumarin heteroanalogs were synthesized by condensa-
tion of 2-amino-4-aryl-3-cyano-5-oxo-4H,5H-pyrano-[3,2-c]
chromenes and 1,3-cyclohexanedione in 35–78% yield.
Keywords: chromeno-pyranoquinolines; coumarin
heteroanalogs; malononitrile.
Experimental
1H-NMR spectra were taken in CDCl3 on a Bruker 500 MHz spec-
trometer (Bruker, Rheinstetten, Germany). The IR spectra were
acquired in KBr disks on a Nicollet FT-IR magna 550 instrument
(Nicollet, Madison, WI, USA). Electron-impact mass spectra were
obtained using a Finnegan MAT TSQ-70 spectrometer (Finnegan
Mat, Bremen, Germany). The purity of compounds was confirmed
by thin layer chromatography (TLC) using different mobile phases.
Introduction
Dihydropyrano[c]chromenes containing coumarin system
exhibit spasmolytic, diuretic, anti-coagulant, anti-cancer, and
anti-anaphylactic properties (Thaisrivongs et al., 1996; Yang
et al., 1999; Rappa et al., 2001). Coumarins fused to pyridines
have been reported to possess antiallergic (Ukawa et al., 1986),
antidiabetic (Heber, 1987; Thapa et al., 2011) and analgesic
(Heber and Berghaus, 1994) properties. Tacrine, a potent ace-
tylcholinesterase (AChE) inhibitor is the first approved drug
in the USA for palliative treatment of Alzheimer’s disease.
Similar drugs with a 4-aminopyridine moiety (Summers et
al., 1986; Sakakian et al., 1993), including highly potent tet-
racyclic tacrines 1 (Figure 1) have been synthesized (Marco
et al., 2001, 2006). In general, the fusion of a cyclohexanone
and a 4H-pyran to pyridine moiety results in remarkable
changes in pharmacological effects. These findings together
with our interest in novel coumarin derivatives (Miri et al.,
2011; Shafiee et al., 2011) prompted us to synthesize new
tetracyclic tacrines heteroanalogs, namely chromeno[4′,3′- b]
pyrano[6,5-b]quinoline-6,9-diones 4a–l.
Synthesis of 8-amino-7-aryl-10,11-dihydro-7H,
12H-chromeno[4′,3′-b]pyrano[6,5-b]quinoline-
6,9-diones 4a–l
A solution of 3a–l (5.4 mmol), 1,3-cyclohexanedione (0.6 g, 5.4
mmol) in acetic acid (50 mL) was heated under reflux for 12 h, then
cooled to room temperature and concentrated under reduced pres-
sure. The residue of the crude product was purified by silica gel
column chromatography eluting with ethyl acetate/petroleum ether
(20:80) to give 4a–l.
8-Amino-7-(2-chlorophenyl)-10,11-dihydro-7H,12H-
chromeno[4′,3′-b]pyrano[6,5-b]quinoline-6,9-dione (4a) Yield
46%; mp 243°C; IR: ν 3444, 3055, 2955, 1726, 1675 cm-1; 1H NMR:
δ 1.82–1.88 (m, 2H, H11), 2.10–2.29 (m, 2H, H12), 2.34–2.42 (m, 2H,
H10), 5.21 (s, 1H, H7), 7.12 (t, 1H, J=8.0 Hz, H18), 7.21 (t, 1H, J=8.0
Hz, H19), 7.29 (d, 1H, J=8.0, H20), 7.31–7.37 (m, 2H, H2, H4), 7.39
(d, 1H, J=8.0, H17), 7.61 (t, 1H, J=7.5 Hz, H3), 8.13 (d, 1H, J=7.5
Hz, H1); MS: m/z 444 (10) [M+], 409 (15), 334 (25), 263 (100), 199
(85), 171 (78). Anal. Calcd. for C25H17ClN2O4: C, 67.50, H, 3.85, N,
6.30. Found: C, 67.30, H, 3.79, N, 6.24.
Results and discussion
Our synthesis of compounds 4a–l is related to the chemistry
reported previously (Marco and Martinez-Grau, 1997; Marco
et al., 2001, 2006). The key starting materials are: 2-amino-
4-aryl-3-cyano-5-oxo-4H,5H-pyrano[3,2-c]chromenes 3a–l
(Abdolmohammadi and Balalaie, 2007), which were synthe-
sized as shown in Scheme 1. Condensation of these interme-
diate products with 1,3-cyclohexadione in boiling acetic acid
8-Amino-7-(3-chlorophenyl)-10,11-dihydro-7H,12H-
chromeno[4′,3′-b]pyrano[6,5-b]quinoline-6,9-dione (4b) Yield
76%; mp 220°C; IR: ν 3450, 3040, 2965, 1726, 1670 cm-1; 1H NMR:
δ 2.10–2.15 (m, 2H, H11), 2.38–2.49 (m, 2H, H12), 2.76–2.8 (m, 1H,
H10), 2.87–2.91 (m, 1H, H10), 4.97(s, 1H, H7), 7.14 (d, 1H, J=7.5 Hz,
H20), 7.18 (t, 1H, J=7.5 Hz, H19), 7.26 (s, 1H, H16), 7.31 (m, 3H, H2,
H4, H18), 7.58 (t, 1H, J=7.5, H3), 7.87 (d, 1H, J=7.5 Hz, H1); MS:
for 12 h yielded the desired products 4a–l. The H-1H shift
1

170 R. Motamedi
8-Amino-7-(3-bromophenyl)-10,11-dihydro-7H,12H-
chromeno[4′,3′-b]pyrano[6,5-b]quinoline-6,9-dione (4d) Yield
56%; mp 260°C; IR: ν 3550, 3050, 2950, 1731, 1674 cm-1; 1H NMR:
δ 2.11–2.18 (m, 2H, H11), 2.39–2.50 (m, 2H, H12), 2.76–2.80 (m, 1H,
H10), 2.88–2.93 (m, 1H, H10), 4.96 (s, 1H, H7), 7.14 (t, H, J=7.5 Hz,
H19), 7.30 (d, 1H, J=7.5 Hz, H20), 7.33 (d, 1H, J=7.5 Hz, H4), 7.38
(t, 1H, J=7.5 Hz, H2), 7.41–7.43 (m, 2H, H18, H16), 7.58 (t, 1H, J=7.5
Hz, H3), 7.89 (d, 1H, J=7.5 Hz, H1); MS: m/z 490 (10) [M++2], 488
(10) [M+], 420 (25), 353 (32), 333 (45), 263 (100), 120 (70), 76 (60).
Anal. Calcd. for C25H17BrN2O4: C, 61.36, H, 3.50, N, 5.72. Found:
C, 61.22, H, 3.43, N, 5.60.
X
NH2
O
NH2
Me
N
O
N
Me
Tacrine
X=H, F, CF3, Me, NO2, OMe
1
8-Amino-7-(4-bromophenyl)-10,11-dihydro-7H,12H-
chromeno[4′,3′-b]pyrano[6,5-b]quinoline-6,9-dione (4e) Yield
50%; mp 254°C; IR: ν 3530, 3080, 2939, 1716, 1667 cm-1; 1H NMR:
δ 2.00–2.11 (m, 2H, H11), 2.22–2.39 (m, 2H, H12), 2.50–2.66 (m,
2H, H10), 4.85 (s, 1H, H7), 7.21 (d, 2H, J=8.0 Hz, H20, H16), 7.44
(d, 2H, J=8.0 Hz, H17, H19), 7.35–7.39 (m, 2H, H2, H4), 7.62 (t, 1H,
J=7.5 Hz, H3), 7.81 (d, 1H, J=7.5 Hz, H1); MS: m/z 490 (18) [M++2],
488 (16) [M+], 409 (40), 418 (30), 420 (20), 353 (45), 333 (23), 263
(100), 120 (18), 92 (38), 66 (42). Anal. Calcd. for C25H17BrN2O4: C,
61.36, H, 3.50, N, 5.72. Found: C, 61.27, H, 3.40, N, 5.69.
Figure 1 Structure of compound 1 and tacrine.
m/z 446 (8) [M++2], 444 (25) [M+], 409 (15), 333 (55), 263 (100),
56 (35). Anal. Calcd. for C25H17ClN2O4: C, 67.50, H, 3.85, N, 6.30.
Found: C, 67.44, H, 3.75, N, 6.19.
8-Amino-7-(4-chlorophenyl)-10,11-dihydro-7H,12H-
chromeno[4′,3′-b]pyrano[6,5-b]quinoline-6,9-dione (4c) Yield
43%; mp 172°C; IR: ν 3456, 3030, 2968, 1710, 1680 cm-1; 1H NMR:
δ 2.09–1.98 (m, 2H, H11), 2.36–2.39 (m, 2H, H12), 2.72–2.92 (m, 2H,
H10), 4.71 (s, 1H, H7), 7.20 (d, 2H, J=8.5 Hz, H20, H16), 7.34 (d, 2H,
J=8.5 Hz, H17, H19), 7.45–7.50 (m, 2H, H2, H4), 7.71 (t, 1H, J=7.5
Hz, H3), 7.96 (d, 1H, J=7.5 Hz, H1); MS: m/z 446 (5) [M++2], 444
(18) [M+], 409 (35), 374 (20), 333 (25), 263 (100), 120 (42), 92 (28).
Anal. Calcd. for C25H17ClN2O4: C, 67.50, H, 3.85, N, 6.30. Found:
C, 67.39, H, 3.80, N, 6.20.
8-Amino-7-(2-methylphenyl)-10,11-dihydro-7H,12H-
chromeno[4′,3′-b]pyrano[6,5-b]quinoline-6,9-dione (4f) Yield
35%; mp 270°C; IR: ν 3462, 3078, 2965, 1731, 1677 cm-1; 1H NMR:
δ 2.06–2.20 (m, 2H, H11), 2.41–2.44 (m, 2H, H12), 2.75 (m, 1H, H10),
2.88 (m, 1H, H10), 2.88 (s, 3H, CH3), 5.11 (s, 1H, H7), 6.97 (m, 1H,
H20), 7.02–7.04 (m, 2H, H18, H19), 7.12 (m, 1H, H17), 7.30 (d, 1H,
J=7.5 Hz, H4), 7.36 (t, 1H, J=7.5 Hz, H2), 7.56 (t, 1H, J=7.5 Hz, H3),
NH2
CHO
OH
O
CN
O
EtOH-H2O
CN
CN
+
+
R
O
O
O
R
2
3
O
CH3COOH
O
11
12
10
9
12a
13
N
O
8a
13a
14
O
8
NH2
16
7a
1
4
14a
15
1a
7
17
2
6a
R
18
3
20
6
4a
O
5
O
19
4a-l
Scheme 1 4a: R=2-chloro, 4b: R=3-chloro, 4c: R=4-chloro, 4d: R=3-bromo, 4e: R=4-bromo, 4f: R=2-methyl, 4g: R=3-methyl, 4h:
R=4-methyl, 4i: R=2-methoxy, 4j: R=3-methoxy, 4k: R=4-methoxy, 4l: R=2-nitro.

Novel chromeno[4′,3′-b]pyrano[6,5-b]quinolines 171
7.89 (d, 1H, J=7.5 Hz, H1); MS: m/z 424 (16) [M+], 354 (18), 333
(45), 263 (100), 91 (20), 64 (35). Anal. Calcd for C26H20N2O4: C,
73.57, H, 4.75, N, 6.60. Found: C, 73.45, H, 4.50, N, 6.49.
197 (40), 120 (60). Anal. Calcd. for C26H20N2O5: C, 70.90, H, 4.58,
N, 6.36. Found: C, 70.85, H, 4.52, N, 6.28.
8-Amino-7-(2-nitrophenyl)-10,11-dihydro-7H,12H-
chromeno[4′,3′-b]pyrano[6,5-b]quinoline-6,9-dione (4l) Yield
45%; mp 275°C; IR: ν 3525, 3062, 2955, 1726, 1668, 1526, 1352
8-Amino-7-(3-methylphenyl)-10,11 dihydro-7H,12H-chromeno
[4′,3′-b]pyrano[6,5-b]quinoline-6,9-dione (4g) Yield 35%; mp
>300°C; IR: ν 3425, 3100, 2955, 1726, 1681 cm-1; 1H NMR:
δ 2.04–2.17 (m, 2H, H11), 2.29 (s, 3H, CH3), 2.37–2.48 (m, 2H,
H12), 2.72–2.79 (m, 1H, H10), 2.86–2.91 (m, 1H, H10), 4.96 (s, 1H,
H7), 6.97 (d, 1H, J=5.5 Hz, H18), 7.13–7.14 (m, 2H, H20, H19), 7.19
(s, 1H, H16), 7.31 (d, 1H, J=7.5 Hz, H4), 7.35 (t, 1H, J=7.5 Hz, H2),
7.56 (t, 1H, J=7.5 Hz, H3), 7.88 (d, 1H, J=7.5 Hz, H1); MS: m/z 424
(15) [M+], 409 (16), 354 (18), 333 (35), 263 (100), 91 (30), 65 (20).
Anal. Calcd. for C26H20N2O4: C, 73.57, H, 4.75, N, 6.60. Found: C,
73.52, H, 4.66, N, 6.53.
1
cm-1; H NMR: δ 2.08–2.15 (m, 2H, H11), 2.39–2.49 (m, 2H, H12),
2.77–2.88 (m, 1H, H10), 2.87–2.91 (m, 1H, H10), 4.96 (s, 1H, H7),
7.13 (d, 1H, J=7.5 Hz, H20), 7.19 (t, 1H, J=7.5 Hz, H18), 7.25
(d, 1H, J=7.5, H17), 7.32–7.45 (m, 3H, H2, H4, H19), 7.58 (t, 1H,
J=7.0 Hz, H3), 7.88 (d, 1H, J=7.0 Hz, H1); MS: m/z 455 (11) [M+],
385 (47), 333 (22), 263 (100), 143 (20), 122 (13), 83 (23), 55 (40).
Anal. Calcd. for C25H17N3O6: C, 65.93, H, 3.76, N, 9.23. Found: C,
65.86, H, 3.79, N, 9.18.
Acknowledgments
8-Amino-7-(4-methylphenyl)-10,11-dihydro-7H,12H-
chromeno[4′,3′-b]pyrano[6,5-b]quinoline-6,9-dione (4h) Yield
57%; mp 220°C; IR: ν 3443, 3068, 2955, 1733, 1680 cm-1; 1H NMR:
δ 2.13 (m, 2H, H11), 2.26 (s, 3H, CH3), 2.45 (m, 2H, H12), 2.78
(m, 1H, H10), 2.86 (m, 1H, H10), 4.97 (s, 1H, H7), 7.06 (d, 2H, J=7.5
Hz, H17, H19), 7.28 (d, 2H, J=7.5 Hz, H16, H20), 7.32–7.37 (m, 2H,
The author is thankful to Payam Noor University for support of this
work.
H2, H4), 7.56 (t, 1H, J=7.5 Hz, H3), 7.88 (d, 1H, J=7.5 Hz, H1); 13
C
References
NMR (75 MHz, DMSO-d6): δ 20.2, 21.1, 27.1, 32.9, 36.9, 106.92,
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136.6, 139.8, 152.5, 153.7, 160.6, 163.4, 196.1; MS: m/z 425 (20)
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8-Amino-7-(3-methoxyphenyl)-10,11-dihydro-7H,12H-
chromeno[4′,3′-b]pyrano[6,5-b]quinoline-6,9-dione (4j) Yield
70%; mp 162°C; IR: ν 3550, 3080, 2939, 1736, 1683 cm-1; 1H
NMR: δ 2.10–2.15 (m, 2H, H11), 2.39–2.50 (m, 2H, H12), 2.73–2.79
(m, 1H, H10), 2.85–2.90 (m, 1H, H10), 3.79 (s, 3H, CH3), 4.99 (s, 1H,
H7), 6.71 (d, 1H, J=7.5, 1.5 Hz, H20), 6.95 (s, 1H, H16), 6.98 (d, 1H,
J=7.5 Hz, H18), 7.18 (t, 1H, J=7.5 Hz, H19), 7.32–7.37 (m, 1H, H2,
H4), 7.56 (t, 1H, J=7.5 Hz, H3), 7.88 (d, 1H, J=7.5 Hz, H1); MS: m/z
440 (70) [M+], 425 (10), 343 (65), 263 (100), 120 (90), 76 (95). Anal.
Calcd. for C26H20N2O5: C, 70.90, H, 4.58, N, 6.36. Found: C, 70.82,
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8-Amino-7-(4-methoxyphenyl)-10,11-dihydro-7H,12H-
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δ 2.06–2.15 (m, 2H, H11), 2.39–2.49 (m, 2H, H12), 2.74 (m, 1H, H10),
2.86 (m, 1H, H10), 3.80 (s, 3H, CH3), 4.96 (s, 1H, H7), 6.7 (d, 2H,
J=7.5 Hz, H17, H19), 7.29 (d, 2H, J=7.5 Hz, H16, H20), 7.34–7.37
(m, 2H, H2, H4), 7.56 (t, 1H, J=7.5 Hz, H3), 7.88 (d, 1H, J=7.5 Hz,
H1); MS: m/z 440 (10) [M+], 409 (23), 370 (18), 333 (10), 263 (100),
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172 R. Motamedi
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Received August 26, 2011; accepted November 23, 2011

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