Synthesis and anti-HIV activity of new fused chromene derivatives derived from 2-amino-4-(1-naphthyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile

Article abstract of DOI:10.5560/ZNB.2013-2297

A new series of pyrano-chromene and pyrimido pyrano-chromene derivatives were synthesized starting from 2-amino-4-(1-naphthyl)-5-oxo-4H,5H-pyrano[3,2-c] chromene-3-carbonitrile (6). The structures of the synthesized compounds were elucidated by spectral data. Compounds 6-11, 13-15 and 18 have been selected for an inhibitory activity screening against HIV-1 and HIV-2 in MT-4 cells.

Full text of DOI:10.5560/ZNB.2013-2297

Synthesis and anti-HIV Activity of New Fused Chromene Derivatives
Derived from 2-Amino-4-(1-naphthyl)-5-oxo-4H,5H-pyrano[3,2-
c]chromene-3-carbonitrile
Najim A. Al-Masoudia, Hamid H. Mohammedb,c, Aws M. Hamdyb, Omer A. Akrawib,
Nadi Eleyab, Anke Spannenbergd, Christophe Pannecouquee, and Peter Langerb,d
a
Department of Chemistry, College of Science, University of Basrah, Basrah, Iraq. Present
address: Am Tannenhof 8, 78464 Konstanz, Germany
Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Department of Chemistry, College of Science, University of Al-Mustansiryah, Baghdad, Iraq
Leibniz-Institut fu¨r Katalyse an der Universita¨t Rostock e.V., Albert-Einstein-Str. 29a, 18059
b
c
d
Rostock, Germany
e
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
Reprint requests to Prof. Peter Langer. E-mail: peter.langer@uni-rostock.de or Najim A.
Al-Masoudi. najim.al-masoudi@gmx.de
Z. Naturforsch. 2013, 68b, 229 – 238 / DOI: 10.5560/ZNB.2013-2297
Received November 17, 2012
A new series of pyrano-chromene and pyrimido pyrano-chromene derivatives were synthesized
starting from 2-amino-4-(1-naphthyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (6). The
structures of the synthesized compounds were elucidated by spectral data. Compounds 6–11, 13–15
and 18 have been selected for an inhibitory activity screening against HIV-1 and HIV-2 in MT-4 cells.
Key words: Anti-HIV Activity, Chromenes, Pyrano-chromenes, Reverse Transcriptase Inhibitors
(NNRTIs)
Introduction
system (CNS) activities [30], and find application
in the treatment of Alzheimer’s disease [31] and
Chromenes and coumarins [1] have been the subject Schizophrenia disorder [32]. Satyanarayana et al. [33]
of considerable chemical interest in the past decades. reported the synthesis and antifungal screening of new
They occur widely in nature and exhibit important bi- Schiff bases of chromenes under conventional and
ological as well as pharmacological activities [2 – 5]. microwave conditions. Furthermore, Lee et al. [34]
Among chromene derivatives are biologically inter- have synthesized 30R,40R-di-(O)-(−)-camphanoyl-
esting compounds showing antimicrobial [6 – 10] and 20,20-dimethyldihydropyrano[2,3-f]chromone (DCP)
antifungal activities [11, 12], inhibitors of influenza (1) as a potent in vitro inhibitor of HIV-1 replication in
virus silidoses [13, 14], compounds with antihyperten- H9 lymphocyte cells with an EC50 of 6.78 × 10−4µM.
sive [15] and anti-allergic activity [16] and hair growth The family of 4-aryl-4H-chromenes has been recently
stimulant properties [17]. However, the chromenes are reported to possess anti-cancer activity. These com-
also well known for their biocidal [18, 19], wound pounds, which are potent apoptosis inducers (e. g.
healing [20], anti-inflammatory [21], and antiulcer [22] compound 2), were found to be highly active in the
activities.
growth inhibition MTT with the concentration causing
Some fused chromene derivatives were found 50% cell growth inhibition (IC50) values in the low
useful as antiviral [23], antiproliferation [24], antiox- nanomolar range [35]. Geiparvarin (3), a naturally
idative [25, 26], antileishmanial [27], antitumor [28], occurring compound bearing a coumarin residue, has
and anti-HIV agents [29], show central nervous been shown to possess a significant inhibitory activity
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N. A. Al-Masoudi et al. · Fused Chromene Derivatives
against a variety of cell lines including sarcoma 180, pyrano[3,2-c]chromene-3-carbonitrile (6) via reac-
Lewis lung carcinoma, P-388 lymphocytic leukaemia, tion of (1-naphthylmethylene)malononitrile (4) and 4-
and Walker 256 carcinosarcoma [36].
hydroxycoumarin (5). Compound 6 was selected as
In the present paper, we report the synthesis of new a key intermediate for the synthesis of new fused and
chromene derivatives and their in vitro activity on the non-fused chromene derivatives, aiming at an evalu-
replication of HIV-1 and HIV-2.
ation of their anti-HIV activity. Thus, treatment of 6
with triethyl orthoformate in acetic anhydride gave the
corresponding formimidate derivative 7 in 69% yield.
Benzoylation of 6 with benzoyl chloride afforded the
Results and Discussion
A number of synthetic strategies have been re- pyrimido derivative 10 (60%), while treatment of 7
ported for the construction of chromenes, for exam- with hydrazine hydrate or methyl amine at room tem-
ple, construction of the chromene ring by a two- perature afforded the anthracene derivatives 8 and 9 in
step sequence, typically involving prefunctionaliza- 50 and 52% yield, respectively. The reactions are sum-
tion of the arene (e. g., halogenation at the 2- marized in Scheme 1.
position) followed by Heck-type cyclization [37 – 41].
The structures of 7 – 10 were confirmed by their 1H,
In the present study, we report on the syn- 13C NMR and mass spectra and by elemental analyses.
thesis of 2-amino-4-(naphthalen-1-yl)-5-oxo-4H,5H- The chromene and aromatic protons showed a simi-
Scheme 1. Synthesis of chromene-3-nitrile (6), chromen-2-yl-formimidate (7), 8,9-dihydrochromeno-pyrimidin-6-one (8) and
(9), and phenylchromeno-pyrimidin-6,8-dione (10) derivatives.
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N. A. Al-Masoudi et al. · Fused Chromene Derivatives
231
1
lar pattern. In the H NMR spectrum of 7, the sin-
glet at δ = 9.01 ppm was assigned to the CH=N pro-
ton, while the singlets at δ = 5.80, 5.82, 5.88, and
5.49 ppm were attributed to 5-H of compounds 7 – 10.
The 13C NMR spectra of 7 – 10 contained similar res-
onance signals of the coumarin and aromatic carbon
atoms. In the 13C NMR spectrum of 7, C-2 resonated
at δ = 162.3 ppm, while the resonances at δ = 154.9,
154.0 and 152.1 ppm were assigned to EtOHC =N,
C-11a and C-6a carbon atoms. The chemical shifts at
δ = 116.6, 116.4, 112.9 and 103.7 ppm were attributed
to CN, C-7, C-10a and C-4a, respectively, while the
resonance at δ = 83.2 ppm was assigned to C-3. In
the 13C NMR spectra of 8 – 10, the chemical shifts
between δ = 160.0 and 161.0 ppm were assigned to
the C=O carbon atom of the coumarin moiety (C-
6), while the resonances at δ = 158.0 ppm were as-
signed to C=NH carbon atom. C-7a, C-12a and C-13a
appeared in the ranges δ = 141.7 – 138.3, 154.0 and
152.0 – 151.1 ppm. The signal at δ = 157.0 ppm was
assigned to C-2 of 10, whereas the signals at δ = 133.3
and 135.3 ppm were attributed to the same atom of 8
and 9, respectively. C-5 appeared at δ = 31.4, 30.1 and
Fig. 1. Molecular structure of ethyl N-(3-cyano-4-(naphtha-
lene-1-yl)-5-oxo-4,5-dihydropyrano[3,2-c]chromen-2-yl)-
formimidate (7) in the crystal. Displacement ellipsoids are
drawn at the 30% probability level.
The structure of 7 was independently confirmed by
39.4 ppm, respectively. The signals of the other carbon a single-crystal X-ray diffraction analysis (Fig. 1 and
atoms were fully analyzed (cf. Experimental Section). Experimental Section).
Compound 9 has been selected for further NMR
Next, treatment of 6 with acetic anhydride in dry
studies. From the gradient selected HMBC [42] pyridine for 3 h afforded the monoacetyl derivative
2
spectrum, 5-H at δH = 5.80 ppm showed two JC,H 12, while the reaction with acetic anhydride in the
couplings: one with C-4a at δC = 75.0 ppm, and presence of sulfuric acid for 10 h led to the pyrimi-
the other with C-5a at δC = 105.0 ppm. Addition- dine derivative 13 in 55 and 75% yield, respectively.
3
ally, 5-H showed two JC,H couplings wih C=O at An attempt to construct a third heterocyclic ring con-
δC = 161.0 ppm and C=NH at δC = 158.0 ppm.
densed with coumarin was successful via reaction of
Scheme 2. Synthesis of [1,2,4]triazolo[1,5-a]quinoline-11-carbonitrile (11), chromen-2-yl-acetamide (12), and chromeno-
[30,40:5,6]pyrano[2,3-d]pyrimidine-dione (13) derivatives.
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N. A. Al-Masoudi et al. · Fused Chromene Derivatives
Scheme 3. Synthesis of chromene-9-dicarboxylate (14–17) and 2-(4-methoxybenzylideneamino)-chromene-3-carbonitrile
(18) derivatives.
6 with semicarbazide hydrochloride in refluxing dry
pyridine to give triazolo[1,5-a]quinolone 11 in 75% in toluene were stirred under reflux in the pres-
yield (Scheme 2). ence of SnCl4 as a Lewis acid catalyst, the fused
When mixtures of 6 and various β-ketoesters
The mass spectral data were consistent with the ring products 14 – 17 were obtained in 54, 53,
structures of the synthesized compounds 11 – 13. The 53, and 56% yield, respectively. Treatment of 6
structures of 11 – 13 were assigned by the IR, 1H, with p-anisaldehyde in a dioxane-piperidine mixture
13C NMR and mass spectra. In the case of com- gave the 2-(4-methoxybenzylideneamino)chromene-3-
1
pounds 11 and 12, the H NMR spectra were char- carbonitrile derivative 18 in 56% yield (Scheme 3).
acterized by the presence of 4-H signals at δ = 5.49
The 1H NMR and 13C NMR spectra of 14 – 17
and 5.77 ppm, while the 13C NMR spectra exhib- were in agreement with the suggested structures. The
ited signals at δ = 119.1 and 116.5 ppm, attributed to 1H NMR spectra were characterized by the presence
the CN carbons, respectively. The 13C NMR spec- of the 5-H signal in the range δ = 6.07 – 6.02 ppm,
trum of 13 exhibited a signal at δ = 161.6 ppm, whereas the 13C NMR spectra exhibited signals in
attributed to the carbonyl group (C4=O) of the the range δ = 39.5 – 36.5 ppm, attributed to C-5. Com-
pyrimidine residue, with disappearance of the CN pound 15 was selected for further NMR experiments.
3
group signal, which supported the formation of From a gradient HMBC NMR spectrum, a JC,H cou-
a pyrimidine ring in 13. The signals at δ = 31.5 pling between OCH2 protons at δ = 4.23 ppm and the
and 29.2 ppm were attributed to C-4 of 11 and carbonyl carbon atom at δ = 168.0 ppm of the ester
12, respectively, while the signal at δ = 30.0 ppm moiety at C-3, was observed. Further, the protons of
3
was assigned to C-5 of 13. The signals of the the 2-methyl group at δ = 2.49 ppm showed a JC,H
chromene and aromatic carbon atoms were fully coupling with C-3 at δ = 114.0 ppm, the same protons
analyzed (cf. Experimental Section). The structure revealved a 2JC,H coupling with C-2 at δ = 139.2 ppm.
of 13 was further confirmed by the gradient se- Similarly, 5-H at δ = 6.02 ppm showed two 2JC,H cou-
lected HMBC spectrum [42]. 5-H at δ = 5.75 ppm plings with carbon atoms 4a and 5a at δ = 116.6 and
3
showed JC,H couplings with the carbonyl groups 80.0 ppm, respectively, while the same proton demon-
3
of the pyrimidine ring (C4=O) and the chromene strated two JC,H couplings with carbon atom 4 and
residue at δ = 161.9 and 159.8 ppm, respectively. carbonyl carbon atom C-6 at δ = 155.3 and 161.0 ppm,
2
Further, JC,H couplings of H-5 with C-4a and C- respectively (Fig. 2). The mass spectra of the prepared
5a at δ = 102.3 and 106.4 ppm, respectively, were compounds showed the correct molecular ions sug-
observed.
gested by their molecular formulas.
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N. A. Al-Masoudi et al. · Fused Chromene Derivatives
233
2 replication in cell cultures with EC50 of > 2.27,
> 4.84, and > 3.64 µg mL−1, respectively, and a se-
lectivity index of < 1.
In conclusion, the structure-activity relationship
(SAR) suggested that the potency of compound 7 could
be attributed to the presence of the cyano and formim-
idate groups in the 3- and 4-positions, respectively, of
the pyrane ring. However, the anti-HIV activity and the
selectivity of these compounds are too limited to per-
form extensive mode-of-action studies, and 7 might be
considered as a new lead in the development of antivi-
ral agents as a non-nucleoside reverse transcriptase in-
Fig. 2. JC,H correlations in the HMBC NMR spectrum of 15.
1
The H and 13C NMR spectra of 18 showed pat- hibitor.
terns similar to those of 12; the OMe, 5-H and HC=N
protons appeared as three singlets at δ = 3.90, 6.09 Conclusion
and 9.41 ppm, respectively. The 13C NMR spectrum
In this paper we have reported the synthesis and
of 18 was characterized by the presence of signal at
δ = 161.0 ppm, assigned to HC=N together with the
aromatic carbon atom (C-OMe).
anti-HIV-1 and anti-HIV-2 evaluation of some pyrano-
chromene and pyrimido pyrano-chromene derivatives.
The preliminary in vitro anti-HIV data have demon-
strated that the ethyl N-(3-cyano-4-(naphthalene-yl)-5-
oxo-4,5-dihydropyrano[3,2-c]chromen-2-yl) formimi-
date (7) is more active than other chromene derivatives.
The synthesis of new analogs of these derivatives could
lead to the discovery of more potent and selective com-
pounds that will allow the elucidation of their molecu-
lar mode of action.
In vitro anti-HIV activity
Compounds 6–11, 13–15 and 18 were tested for
their in vitro anti-HIV-1 (strain IIIB) and HIV-
2 (strain ROD) activity in human (MT-4) cells.
based on an MTT assay [43]. The results are sum-
marized in Table 1, in which the data for nevi-
rapine (BOE/BIRG587) [44] and azidothymidine
(DDN/AZT) [45] are included for comparison pur-
poses.
Experimental Section
General
Compounds 7, 8 and 13 were found to be the only
Melting points are uncorrected and were determined on
compounds in the series inhibiting HIV-1 and HIV- a Micro heating table HMK 67/1825 Kuestner (Bu¨chi Appa-
Table 1. In vitro anti-HIV-1a and
HIV-2b activity of some new
chromene derivatives.
Entry
HIV-1 (IIIB)
HIV-2 (ROD)
CCd50
SIe
(IIIB)
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
> 80
> 11363
SIe
(ROD)
< 1
ECc50 (µg mL−1
)
ECc50 (µg mL−1
)
(µg mL−1
)
6
7
8
9
10
11
13
14
> 9.92
> 2.27
> 4.84
> 80.20
> 125.0
> 10.73
> 3.63
> 58.83
> 50.0
> 6.82
0.050
> 9.92
> 0.76
> 4.84
> 80.20
> 125.0
> 10.73
> 3.63
> 58.83
> 50.0
> 6.82
> 4.00
0.00094
9.92
> 2.27
4.84
> 80.20
> 125.0
10.73
3.63
58.83
> 50.0
6.82
≤ 3
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
< 1
15
18
Nevirapine
AZT
> 4.00
> 25
0.0022
> 26596
a Anti-HIV-1 activity measured with strain IIIB; b anti-HIV-2 activity measured with strain ROD;
c compound concentration required to achieve 50% protection of MT-4 cells from the HIV-1 and
2-induced cytopathogenic effect; d compound concentration that reduces the viability of mock-
infected MT-4 cells by 50%; e SI: selectivity index (CC50/EC50).
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N. A. Al-Masoudi et al. · Fused Chromene Derivatives
ratus), and a Leitz Labolux 12 Pol with heating table Mettler (m, 3H, Ar-H), 7.91 (d, 1H, J = 7.5 Hz, Ar-H), 8.01 (d, 1H,
FP 90. FT-IR spectra were recorded on a Nicolet 205 FT-IR J = 7.9 Hz, Ar-H), 8.17 (s, 1H, CH=N), 8.81 (br s., 1H,
and Nicolet Prote´ge 460 FT-IR instruments using the KBr NH). – 13C NMR (75.5 MHz, [D6]DMSO): δ = 31.4 (C-5),
1
technique. H NMR (300 MHz) and 13C NMR (75.5 MHz) 70.0 (C-4a), 104.6 (C-5a), 116.6 (C-11a), 119.1 (C-8), 122.4,
spectra were measured on Bruker AC 250, Bruker ARX 300 123.4, 124.7, 125.7, 125.8, 126.1, 127.4, 128.4, 130.9, 133.0
and Bruker ARX 500 instruments in [D6]DMSO as a solvent. (Carom), 133.3 (C-2), 140.7 (C-7a), 152.1 (C-13a), 154.0
Mass spectra (MS) were run on AMD MS40, Varian MAT (C-12a), 158.0 (C=NH), 160.0 (C=O). – MS ((+)-FAB):
CH 7, MAT 731 (EI, 70 eV), Intecta AMD 402, (EI, 70 eV m/z = 409 [M+H]+. – GC-MS (EI, 70 eV): m/z (%) = 408
and CI), and Finnigan MAT 95 (CI, 200 eV) spectrometers. (100) [M]+, 392 (52), 365 (21), 266 (58), 239 (15), 121 (19).
High-resolution mass spectrometry (HRMS) was performed – C24H17N4O3 (408.12): calcd. C 70.58, H 3.95, N 13.72;
on Varian MAT 311 and Intecta AMD 402 instruments.
found C 70.37, H 3.52, N 13.40.
(1-Naphthylmethylene)malononitrile (1) and
2-amino-4-(naphthalen-1-yl)-5-oxo-4H,5H-pyrano-
[3,2-c]chromene-3-carbonitrile (6)
8-Imino-9-methyl-7-(naphthalen-1-yl)-8,9-dihydro-
chromeno[30,40:5,6]pyrano[2,3-d]pyrimidin-6-one (9)
To a solution of 7 (0.40 g, 1.0 mmol) in EtOH (25 mL)
a solution of methylamine (0.03 g, 1.0 mmol) was added
and the mixture stirred for 1 h. Then it was allowed to
stand overnight. The precipitate formed was filtered, dried
and recrystallized from dioxane to afford 9 (0.21 g, 52%),
m. p. > 300 ◦C. – FT-IR (KBr, cm−1): ν = 3336, 3056, 2940
(w), 1718, 1659 (s), 1608, 1577 (m). – 1H NMR (300 MHz,
[D6]DMSO): δ = 3.28 (s, 3H, CH3), 5.80 (s, 1H, 5-H),
7.48 – 7.66 (m, 6H, Ar-H), 7.81 – 8.08 (m, 5H, Ar-H), 8.27 (s,
1H, CH=N), 8.89 (br s., 1H, NH). – 13C NMR (75.5 MHz,
[D6]DMSO): δ = 30.1 (CH3), 39.4 (C-5), 75.0 (C-4a), 105.0
(C-5a), 116.6 (C-11a), 120.1 (C-8), 122.0, 123.4, 124.9,
125.7, 125.8, 126.0, 127.4, 128.5, 130.9, 132.9 (Carom),
135.3 (C-2), 141.0 (C-7a), 152.1 (C-13a), 154.0 (C-12a),
158.0 (C=NH), 161.0 (C=O). – MS ((+)-FAB): m/z = 408
[M+H]+. – C25H18N3O3 (407.13): calcd. C 73.70, H 4.21,
N 10.31; found C 73.39, H 3.95, N 10.01.
These compounds were synthesized according to method
described previously [46].
Ethyl N-(3-cyano-4-(naphthalen-1-yl)-5-oxo-4,5-
dihydropyrano[3,2-c]chromen-2-yl)formimidate (7)
A mixture of 6 (0.36 g, 1.0 mmol), triethyl orthoformate
(2 mL) and acetic anhydride (10 mL) was heated under re-
flux for 8 h (TLC control). The reaction mixture was left
to cool overnight, and the solid formed was recrystallized
from dioxane to give 7 (0.29 g, 69%) as a pale-yellow solid,
m. p. 282 – 283 ◦C. – FT-IR (KBr, cm−1): ν = 3050, 2984
(w), 2215 (m), 1715, 1666, 1608 (s). – 1H NMR (300 MHz,
[D6]DMSO): δ = 1.38 (t, 3H, CH3), 4.42 (q, 2H, CH2),
5.80 (s, 1H, 4-H), 7.50 – 7.95 (m, 8H, Ar-H), 8.03 (d, 1H,
J = 8.0 Hz, Ar-H), 8.31 (d, 1H, J = 7.7 Hz, Ar-H), 8.57 (d,
1H, J = 7.6 Hz, Ar-H), 9.01 (s, 1H, CH=N). – 13C NMR
(75.5 MHz, [D6]DMSO): δ = 13.8 (CH3), 39.4 (C-4), 64.2
(CH2), 83.2 (C-3), 103.7 (C-4a), 112.9 (C-10a), 116.4 (C-7),
116.6 (CN), 123.5, 124.7, 125.8, 125.9, 126.4, 128.0, 128.5,
131.0, 133.1, 133.2 (Carom), 152.1 (C-6a), 154.0 (C-11a),
154.9 (HC=N), 159.5 (C=O), 162.3 (C-2). – MS ((+)-FAB):
m/z = 423 [M+H]+. – GC-MS (EI, 70 eV): m/z (%) = 422
(68) [M]+, 365 (12), 295 (100), 267 (16), 239 (89), 121 (36).
– C26H18N2O4 (422.42): calcd. C 73.92, H 4.29, N 6.63;
found C 73.71, H, 4.16, N 6.45.
7-(Naphthalen-1-yl)-10-phenylchromeno[30,40 : 5,6]pyrano-
[2,3-d]pyrimidin-6,8(7H,9H)-dione (10)
A mixture of 6 (0.36 g, 1.0 mmol) and benzoyl chloride
(0.15 g, 1.0 mmol) in pyridine (20 mL) was refluxed for 12 h
(TLC control). The obtained product was recrystallized from
dioxane to give 10 (0.28 g, 60%) as a yellow solid, m. p.
370 ◦C. – FT-IR (KBr, cm−1): ν = 3416, 3054, 2940 (w),
1713, 1660, 1605 (s), 1549 (m). – 1H NMR (300 MHz,
[D6]DMSO): δ = 5.88 (s, 1H, 5-H), 7.40 – 7.76 (m, 10H,
Ar-H), 7.81 – 7.87 (m, 3H, Ar-H), 7.97 (d, 1H, J = 7.76 Hz,
Ar-H), 8.52 (d, 2H, Ar-H), 8.79 (br s., 1H, NH). – 13C
9-Amino-8-imino-7-(naphthalen-1-yl)-8,9-dihydro-
chromeno[30,40:5,6]pyrano[2,3-d]pyrimidin-6-one (8)
To a solution of 7 (0.40 g, 1.0 mmol) in EOH (25 mL) NMR (75.5 MHz, [D6]DMSO): δ = 39.4 (C-5), 80.0 (C-
a solution of hydrazine hydrate (5 mL) was added, and the 4a), 104.6 (C-5a), 116.6 (C-11a), 119.1 (C-8), 122.4, 122.9,
mixture was stirred for 1 h, then allowed to stand overnight. 123.4, 124.0, 124.7, 125.7, 125.8, 126.0, 127.4, 128.4, 130.9,
The precipitate formed was filtered, dried and recrystallized 133.9 (Carom), 138.3 (C-7a), 152.0 (C-13a), 154.0 (C-12a),
from dioxane to afford 8, 0.20 g (50%), as a yellow solid, 157.0 (C-2) 158.0 (C=NH), 160.0 (C=O). – MS ((+)-FAB):
m. p. 256 – 258 ◦C. – FT-IR (KBr, cm−1): ν = 3308, 3342, m/z = 469 [M–H]+. – GC-MS (EI, 70 eV): m/z (%) = 470
3268, 3064, 3043 (w), 1730, 1664, 1606 (s), 1587, 1564. – (1) [M]+, 444 (89), 427 (5), 366 (2), 317 (100), 239 (12),
1H NMR (300 MHz, [D6]DMSO): δ = 5.64 (s, 2H, NH2), 189 (4). – C30H17N2O4 (470.13): calcd. C 76.59, H 3.86, N
5.82 (s, 1H, 5-H), 7.40 – 7.58 (m, 6H, Ar-H), 7.67 – 7.80 5.95; found C 76.20, H 3.45, N 5.63.
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235
10-Amino-12-(naphthalen-1-yl)-2-oxo-3,12-dihydro-
2H-pyrano[3,2-c][1,2,4]triazolo[1,5-a]quinoline-
11-carbonitrile (11)
der reflux for 10 h. A precipitate was formed after keeping
the mixture at room temperature for 24 h, which was filtered
and washed with water and EtOH. The product was recrys-
tallized from EtOH to give 13 (0.30 g, 75%) as a colorless
solid; m. p. 160 – 162 ◦C. – FT-IR (KBr, cm−1): ν = 3116,
3034, 3003, 2938, 2847 (w), 1737 (s), 1662 (s), 1595 (m).
– 1H NMR (300 MHz, [D6]DMSO): δ = 2.35 (s, 3H, CH3),
5.75 (s, 1H, 5-H), 7.29 – 7.57 (m, 5H, Ar-H), 7.61 – 7.79 (m,
3H, Ar-H), 7.90 (d, 1H, J = 7.9 Hz, Ar-H), 8.01 (d, 1H,
J = 7.6 Hz, Ar-H), 8.70 (d, 1H, J = 8.0 Hz, Ar-H), 12.60 (br
s., 1H, NH). – 13C NMR (75.5 MHz, [D6]DMSO): δ = 20.9
(CH3), 30.0 (C-5), 102.3 (C-4a), 106.4 (C-5a), 116.5 (C-
11a), 122.5, 124.8, 125.0, 125.5, 125.6, 126.0, 127.1, 127.4,
127.9, 131.4, 132.8, 132.8 (Carom), 151.9 (C-7a), 154.1
(C-2), 159.1 (C-12a), 159.3 (C-13a), 159.8 (C=O), 161.9
(C4=O). – MS ((+)-FAB): m/z = 408 [M]+. – GC-MS (EI,
70 eV): m/z (%) = 408 (30) [M]+, 281 (100), 240 (9), 128
(10). – C25H16N2O4 (408.11): calcd. C 73.52, H 3.95, N
6.86; found C 73.20, H 3.51, N 6.44.
To a solution of 6 (0.36 g, 1.0 mmol) in pyridine (20 mL),
semicarbazide hydrochloride (0.11 g, 1.0 mmol) was added,
and the mixture was heated under reflux for 6 h (TLC con-
trol). After cooling, the mixture was poured into cold wa-
ter with stirring. The solid crude product was filtered, dried
and recrystallized from dioxane to give 11 (0.30 g, 75%), as
an orange solid; m. p. 246 – 248 ◦C. – FT-IR (KBr, cm−1):
ν = 3291, 3257, 3176, 3056, 2959 (w), 2193, 1719, 1673
(s), 1597 (m). – 1H NMR (300 MHz, [D6]DMSO): δ = 5.49
(s, 1H, 4-H), 7.34 – 7.64 (m, 9H, NH2 + Ar-H), 7.72 – 8.00
(m, 4H, NH + Ar-H), 8.45 (d, 1H, J = 8.0 Hz, Ar-H). –
13C NMR (75.5 MHz, [D6]DMSO): δ = 31.5 (C-4), 58.5 (C-
3), 100.0 (C-4a), 112.9 (C-13a), 116.6 (C-10), 119.1 (CN),
122.4, 123.4, 124.7, 125.7, 125.8, 126.0, 127.4, 128.4, 130.9,
132.9, 133.2 (Carom), 140.7 (C-9a), 152.1 (C-14a), 153.8 (C-
5a), 157.8 (C-2), 163.0 (C=O). – MS ((+)-FAB): m/z = 405
[M]+. – GC-MS (EI, 70 eV): m/z (%) = 405 (1) [M]+, 404
[M–H]+ (5), 378 (25), 366 (5), 302 (100), 153 (71), 121 (88).
– C24H15N5O2 (405.12): calcd. C 71.10, H 3.73, N 17.27;
found C 70.82, H 3.42, N 16.98.
General preparation of alkyl 8-amino-(naphthalen-1-yl)-
6-oxo-10-alkyl-6,7-dihydro-[30,40 : 5,6]-
pyrano[2,3-b]pyridine-9-carboxylate 14 – 17
To a stirred solution of ester (1.0 mmol) in dry toluene
(20 mL) were added 6 (0.36 g, 1.0 mmol) and SnCl4 (2 mL).
The reaction mixture was stirred under argon at room tem-
perature for 30 min and then heated under reflux for 6 h (TLC
control). After cooling, the mixture was dispersed into water
and adjusted to pH = 12 – 13 with a saturated aq. solution of
Na2CO3. The mixture was filtered, and the filterate was ex-
tracted with ethyl acetate (3×15 mL). The combined organic
extracts were dried and evaporated to dryness to give a crude
product. Recrystallization from dioxane afforded the desired
product.
N-(3-Cyano-4-(naphthalen-1-yl)-5-oxo-4,5-dihydro-
pyrano[3,2-c]chromen-2-yl)acetamide (12)
To a solution of 6 (0.36 g, 1.0 mmol) in dry pyridine
(1.0 mL) was added acetic anhydride (3 mL), and the mixture
was refluxed for 3 h (TLC monitoring). On cooling, a precip-
itate was separated and washed with EtOH. Recrystallization
from dioxane afforded 12 (0.22 g, 55%) as a brown solid;
m. p. 160 – 162 ◦C. – FT-IR (KBr, cm−1): ν = 3201, 3055,
2957, 2223 (w), 1719 (s), 1675 (m), 1636 (w), 1608 (m). –
1H NMR (300 MHz, [D6]DMSO): δ = 2.35 (s, 3H, CH3),
5.77 (s, 1H, 4-H), 7.30 – 7.57 (m, 5H, Ar-H), 7.61 – 7.89
(m, 3H, Ar-H), 7.93 (d, 1H, J = 8.1 Hz, Ar-H), 8.03 (d, 1H,
J = 7.6 Hz, Ar-H), 8.71 (d, 1H, J = 7.6 Hz, Ar-H), 12.61 (br
s., 1H, NH). – 13C NMR (75.5 MHz, [D6]DMSO): δ = 20.9
(CH3), 29.2 (C-4), 57.0 (C-3), 102.3 (C-4a), 106.4 (C-10a),
116.5 (CN), 122.6, 124.8, 125.0, 125.5, 125.6, 126.0, 127.1,
127.4, 127.9, 131.4, 132.8 (Carom), 151.9 (C-2), 154.1 (C-
6a), 159.3 (C-11a), 160.1 (C=O), 162.0 (MeCO). – MS
((+)-FAB): m/z = 408 [M]+. – GC-MS (EI, 70 eV): m/z
(%) = 408 (35) [M]+, 366, (18), 342 (33), 314 (50), 299
(33), 239 (100), 152 (40), 121(50). – C25H16N2O4 (408.11):
calcd. C 73.52, H 3.95, N 6.86; found C 73.21, H 3.52, N
6.45.
Ethyl 8-amino-7-(naphthalen-1-yl)-6-oxo-10-propyl-
6,7-dihydrochromeno[30,40 : 5,6]pyrano[2,3-b]pyridine-
9-carboxylate (14)
From propyl 3-oxopentanoate (0.16 g). Yield: 0.27 g
(54%) as a yellow solid, m. p. 187 – 189 ◦C. – FT-IR
(KBr, cm−1): ν = 3475, 3307, 3055, 2960 (w), 1719 (s),
1677, 1651, 1605 (m). – 1H NMR (300 MHz, [D6]DMSO):
δ = 1.00 (t, 3H, J = 7.1 Hz, CH2CH2CH3), 1.25 (m, 5 H,
OCH2CH3 + CH2CH2CH3), 2.75 (t, 2H, J = 7.0 Hz,
CH2CH2CH3), 4.26 (q, 2H, J = 7.3 Hz, OCH2CH3), 5.95
(br s., 2H, NH2), 6.07 (s, 1H, 5-H), 7.47 – 7.79 (m, 6H, Ar-
H), 7.86 (d, 2H, Ar-H), 7.99 (d, 2H, Ar-H), 8.16 (d, 1H,
J = 8.0 Hz, Ar-H). – 13C NMR (75.5 MHz, [D6]DMSO):
δ = 13.0, 13.2 (2 × CH3), 22.4 (CH2CH2CH3), 28.6
(CH2CH2CH3), 39.5 (C-5), 60.1 (OCH2CH3), 70.0 (C-5a),
Methyl-7-(naphthalen-1-yl) chromeno[3,4 : 5,6]pyrano-
[2,3-d]pyrimidin-6,8-dione (13)
A solution of 6 (0.36 g, 1.0 mmol) in acetic anhydride 110.0 (C-3), 113.0 (C-4a), 115.6 (C-8), 121.3 (C-11a), 122.5,
(10 mL) containting conc. H2SO4 (5 mL) was heated un- 123.2, 124.4, 124.7, 125.0, 127.2, 127.6, 128.2, 128.3, 130.2,
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N. A. Al-Masoudi et al. · Fused Chromene Derivatives
131.3 (Carom), 139.2 (C-2); 151.5 (C-4), 154.3 (C-7a), 154.3 Methyl 8-amino-10-methyl-7-(naphthalen-1-yl)-6-oxo-
(C-13a), 155.0 (C-12a), 162.2 (C=O), 167.0 (CO2Et). – MS 6,7-dihydrochromeno[30,40 : 5,6]pyrano[2,3-b]pyridine-
((+)-FAB): m/z = 506 [M]+. – GC-MS (EI, 70 eV): m/z 9-carboxylate (17)
(%) = 506 (9) [M+], 478 (45), 406 (95), 379 (100), 333 (60),
From methyl 3-oxobutanoate (0.13 g). Yield: 0.26 g
315 (21), 278 (22), 207 (44). – C31H27N2O5 (506.18): calcd.
(56%) as a colorless solid, m. p. 313 – 315 ◦C. – FT-IR (KBr,
C 73.50, H,5.17, N 5.53; found C 73.18, H 4.88, N 5.20.
cm−1): ν = 3489, 3317, 3055, 2996, 2948 (w), 1720 (s),
1678, 1651, 1605 (m). – 1H NMR (300 MHz, [D6]DMSO):
Ethyl 8-amino-10-methyl-7-(naphthalen-1-yl)-6-oxo-6,7-
dihydrochromeno[30,40 : 5,6]pyrano [2,3-b]pyridine-
9-carboxylate (15)
δ = 2.47 (s, 3H, CH3), 3.73 (s, 3H, CO2CH3), 6.01 (s, 1H, 5-
H), 6.09 (s, 2H, NH2), 7.41 – 7.57 (m, 3H, Ar-H), 7.63 – 7.96
(m, 6H, Ar-H), 8.10 (d, 1H, J = 7.5 Hz, Ar-H), 8.83 (br s.,
From methyl 3-oxopentanoate (0.13 g). Yield: 0.25 g 1H, Ar-H). – 13C NMR (75.5 MHz, [D6]DMSO): δ = 24.4
(53%) as a colorless solid, m. p. 260 – 262 ◦C. – FT-IR (KBr, (CH3), 38.6 (C-5), 51.9 (CO2CH3), 60.0 (C-3), 109.1 (C-
cm−1): ν = 3500, 3399, 3055, 2970 (w), 1709, 1650(s), 3), 113.5 (C-4a), 116.5 (C-8), 122.8 (C-11a), 124.9, 125.81,
1
1607 (m). – H NMR (300 MHz, [D6]DMSO): δ = 1.24 (t, 126.7, 128.0, 128.2, 128.7, 131.4, 132.9 (Carom), 138.7
3H, J = 7.1 Hz, OCH2CH3), 2.49 (s, 3H, CH3), 4.23 (q, (C-2), 153.7 (C-4), 154.6 (C-7a), 154.9 (C-13a), 157.15
2H, OCH2CH3), 6.02 (s, 1H, 5-H), 6.10 (br s., 2H, NH2), (C=O), 160.0 (C-12a), 167.3 (CO2CH3). – MS ((+)-FAB):
7.39 – 7.75 (m, 7H, Ar-H), 7.82 (d, 1H, J = 7.7 Hz, Ar-H), m/z = 465 [M+H]+. – GC-MS (EI, 70 eV): m/z (%) = 464
7.94 (d, 1H, J = 8.1 Hz, Ar-H), 8.10 (d, 1H, J = 8.0 Hz, Ar- (49) [M]+, 404 (15), 351 (26), 337 (100), 319 (14), 305 (52),
H), 8.83 (d, 1H, J = 8.0 Hz, Ar-H). – 13C NMR (75.5 MHz, 278 (7), 250 (6), 216 (6), 127 (12). – C28H21N2O5(464.14):
[D6]DMSO): δ = 14.1 (OCH2CH3), 26.7 (CH3), 36.4 (C- calcd. C 72.14, H 4.34, N 6.03; found C 71.85, H 4.01, N
5), 61.1 (OCH2CH3), 80.0 (C-5a), 114.0 (C-3), 116.6 (C- 5.70.
4a + C-8), 122.3 (C-11a), 123.4, 124.3, 125.7, 126.0, 127.5,
128.7, 129.4, 131.2, 132.3 (Carom), 139.2 (C-2); 155.2 (C-4),
(Z)-2-((4-Methoxybenzylidene)amino)-4-(naphthalen-1-yl)-
5-oxo-4,5-dihydropyrano[3,2-c]chromene-
3-carbonitrile (18)
155.3 (C-7a), 155.9 (C-13a), 160.0 (C-12a), 161.0 (C=O),
168.0 (CO2Et). – MS ((+)-FAB): m/z = 478 [M]+. – GC-
MS (EI, 70 eV): m/z (%) = 478 (32) [M]+, 404 (7), 351
A solution of 6 (0.36 g, 1.0 mmol) in dioxane (20 mL) and
piperidine (0.5 mL) was treated with p-anisaldehyde (0.30 g,
1.0 mmol) and refluxed for 2 h. The mixture was poured onto
(100), 305 (67), 216 (3). – C29H22N2O5(478.15): calcd. C
72.79, H 4.63, N 5.85; found C 72.50, H 4.22, N 5.43.
ice/water, and the solid obtained was collected and recrystal-
Methyl 8-amino-10-ethyl-7-(naphthalen-1-yl)-6-oxo-
lized from diethyl ether to give 18 (0.27 g, 56%) as an orange
6,7-dihydrochromeno[30,40 : 5,6]pyrano[2,3-b]pyridine-
solid, m. p. 103 – 105 ◦C. – FT-IR (KBr, cm−1): ν = 3200,
9-carboxylate (16)
3027, 2982, 2219 (w), 2219 (s), 1713, 1674 (w), 1603 (s). –
1H NMR (300 MHz, [D6]DMSO): δ = 3.90 (s, 3H, OCH3),
From ethyl 3-oxobutanoate (0.13 g). Yield: 0.25 g (53%)
6.09 (s, 1H, 4-H), 7.22 – 7.50 (m, 4H, Ar-H), 7.73 – 7.84 (m,
as a colorless solid, m. p. 166 – 168 ◦C. – FT-IR (KBr, cm−1):
3H, Ar-H), 8.01 – 8.43 (m, 8H, Ar-H), 9.41 (s, 1H, CH=N).
ν = 3484, 3311, 3075, 3041, 2974, 2947, 2876 (w), 1719
–
13C NMR (75.5 MHz, [D6]DMSO): δ = 39.5 (C-4), 55.9
(s), 1681 (m), 1651 (s), 1605 (m). – 1H NMR (300 MHz,
[D6]DMSO): δ = 1.23 (t, 3H, J = 7.0 Hz, CH2CH3), 2.76
(q, 2H, CH2CH3), 3.76 (s, 3H, CO2CH3), 5.93 (s, 2H,
NH2), 6.05 (s, 1H, 5-H), 7.44 – 7.76 (m,7H, Ar-H), 7.85
(d, 1H, J = 7.4 Hz, Ar-H), 7.97 (d, 1H, J = 7.7 Hz, Ar-H),
8.12 (d, 1H, J = 7.5 Hz, Ar-H), 8.88 (br s., 1H, Ar-H). –
13C NMR (75.5 MHz, [D6]DMSO): δ = 13.5 (CH2CH3),
29.4 (CH2CH3), 38.8 (C-5), 52.1 (CO2CH3), 100.8 (C-5a),
109.7 (C-3), 113.5 (C-4a), 116.5 (C-8), 122.8 (C-11a), 123.5,
124.8, 125.8, 126.0, 127.0, 127.9, 128.1, 128.7, 131.1, 132.8,
133.0 (Carom), 139.9 (C-2), 153.1 (C-4), 154.6 (C-7a), 155.1
(C-13a), 160.0 (C=O), 160.8 (C-12a), 167.1 (CO2Me). –
MS ((+)-FAB): m/z = 478 [M]+. – GC-MS (EI, 70 eV): m/z
(OCH3), 76.9 (C-3), 113.2 (C-4a + Carom), 114.8 (C-10a),
115.2 (C-7), 115.4 (CN), 123. 8, 124.1, 125.4, 126.9, 127.2,
128.1, 128.1, 128.7, 128.9, 129.0, 130.8, 133.0, 133.4, 134.1,
135.3 (Carom), 150.0 (C-6a), 160.3 (C-11a), 160.4 (C=O),
161.0 (HC=N +C-OMe), 164.4 (C-2). – MS ((+)-FAB):
m/z = 484 [M]+. – GC-MS (EI, 70 eV): m/z (%) = 484 (20)
[M]+, 377 (18), 357 (30), 299 (100), 279 (32), 249 (23),
184 (42). – C31H20N2O4 (484.14): calcd. C 76.85, H 4.16,
N 5.78; found C 76.43, H 3.87, N 5.36.
Crystal structure determination of 7
Data were collected on a Bruker APEX II Duo diffrac-
(%) = 478 (32) [M]+, 418 (6), 351 (100), 319 (50) , 207 (8), tometer. The structure was solved by Direct Methods and
127 (5). – C29H22N2O5 (478.15): calcd. C 72.79, H 4.63, N refined by full-matrix least-squares procedures on F2 with
5.85; found C 72.52, H 4.20, N 5.41.
the SHELXTL software package [47]. Hydrogen atoms were
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237
˚
placed in idealized positions and included as constrained MoKα radiation, λ = 0.71073 A, 56177 collected refls. (hkl
into the refinement while all other atoms were refined with −21/20, ± 16, ±27), 5261 unique refls. (Rint = 0.062), 290
anisotropic displacement parameters.
refined parameters, R1 / wR2 = 0.0771 / 0.1363 (all data),
−3
˚
Crystal structure data: C26H18N2O4, Mr = 422.42, col- GOF = 1.023, ∆ρfin (max / min) = 0.39 / −0.21 e A
.
orless plates, crystal dimensions = 0.5 × 0.2 × 0.1 mm3,
CCDC 918360 contains the supplementary crystallo-
orthorhombic, space group Pbca, a = 15.9428(3), b = graphic data for this paper. These data can be obtained free
12.3953(2), c = 20.5395(4) A, Z = 8, Dcalcd. = 1.38 g cm−3
,
of charge from The Cambridge Crystallographic Data Centre
˚
µ(MoKα ) = 0.1 mm−1, F(000) = 1.760 e, T = 150(2) K. via www.ccdc.cam.ac.uk/data request/cif.
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