Synthesis and antimicrobial evaluation of the novel heteroannulated furo[3′,2′:6,7]chromeno[2,3-b]pyridines: Part 1

Article abstract of DOI:10.1002/jhet.4082

The chemical behavior of 4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-carbonitrile (1) was investigated toward some acyclic and cyclic active methylene ketones namely acetylacetone, ethyl acetoacetate, ethyl benzoylacetate, acetoacetanilide, dimedone, indanedione, pyrazolidine-3,5-dione and 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one, barbituric acid and 1-allylthiobarbituric acid, and hippuric acid. A variety of novel heteroannulated furochromenopyridines were efficiently synthesized through a cascade reactions between 4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-carbonitrile (1) and the carbon nucleophilic reagents. Structures of the new products were inferred based on their analytical and spectral data.

Full text of DOI:10.1002/jhet.4082

Synthesis and Antimicrobial Evaluation of the Novel Heteroannulated
Furo[3`,2`:6,7]chromeno[2,3-b]pyridines: Part 1
b
b
Magdy A. Ibrahim,* Sami A. Al-Harbi and Esam Allehyani
a
Department of Chemistry, Faculty of Education, Ain Shams University, Heliopolis 11757,
Cairo, Egypt.
b
Department of Chemistry, University College in Al-Jamoum, Umm Al-Qura University, Makkah,
Saudi Arabia
*
E-mail: magdy_ahmed1977@yahoo.com
Graphical abstract:
O
R
OMe
O
O
O
R
O
R
R
O
N
OMe
OMe
CH3
OMe
OMe
O
O
N
O
O
CH3
N
CN
O
Ph
EtOH/DBU
N
O
N
O
N
Ph
OMe
OMe
O
NH
O
O
O
N
O
NH
H
O
O
N
N
H
O
OMe
Author to whom correspondence should be addressed; Magdy A. Ibrahim. E-mail address:
magdy_ahmed1977@yahoo.com
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/jhet.4082
This article is protected by copyright. All rights reserved.

Abstract
The chemical behavior of 4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-carbonitrile (1) was
investigated towards some acyclic and cyclic active methylene ketones namely; acetylacetone, ethyl
acetoacetate, ethyl benzoylacetate, acetoacetanilide, dimedone, indanedione, pyrazolidine-3,5-dione
and 5-methyl-2- phenyl-2,4-dihydro-3H-pyrazol-3-one, barbituric acid and 1-allylthiobarbituric acid
and hippuric acid. A variety of novel heteroannulated furochromenopyridines were efficiently
synthesized through a cascade reactions between 4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-
carbonitrile (1) and the carbon nucleophilic reagents. Structures of the new products were inferred
based on their analytical and spectral data.
Keywords: Khellin-6-carbonitrile, RORC, cascade reactions, furochromenopyridines,
furochromenopyridopyrimidines, cyclocondensation.
1
. INTRODUCTION
Khellin (4,9-dimethoxy-7-methyl-5H-furo[3,2-g]chromen-5-one) is
a
furochromone
derivative extracted from the seeds of Ammi visnaga [1]. Khellin used in the photochemotherapy of
dermatoses such as vitiligo and psoriasis [2], and possess a high antiatherosclerotic activity [3,4].
Determination of khellin in Ammi visnaga fruits was achieved by using capillary electrophoresis [5].
Khellin used for the treatment of angina [6], and kidney stone as well as a spasmolytic agent [7]. The
interaction and binding properties of khellin with DNA have been studied [8, 9]. Khellin prevent cell
damage caused by oxalate in renal epithelial cells [10]. DFT-theoretical calculations were used for
inspection of the optimized geometries of some furo[3,2-g]chromenes [11-13]. In addition, the
spectral properties, photoelectrical, photosensitivity, and photodiode studies were performed for a
diversity furo[3,2-g]chromenes [14-16]. Biological activity is well known for furo[3,2-g]chromenes
such as antimicrobial [17], anticancer [18], antitumor [19], anti-HIV [20], analgesic and anti-
inflammatory activities [21-23]. The ring-opening ring closure (RORC) reactions of chromone-3-
carbonitrile are well known [24-27]. Khellin-6-carbonitrile (4,9-dimethoxy-5-oxo-5H-furo[3,2-
g]chromene-6-carbonitrile) [28] may represent a good precursor for building of novel heterocyclic
systems fused furo[3,2-g]chromenes due to the unique position of carbonitrile functional group in
khellin-6-carbonitrile which is typically similar to chromone-3-carbonitrile. The present work is
devoted to study the chemical transformations of 4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-
carbonitrile (1) towards a variety of acyclic and cyclic active methylene compounds, bearing –CH2-
2
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CO- group, hoping to construct a series of novel heteroannulated furo[3`,2`:6,7]chromeno[2,3-b]
pyridines and evaluate their antimicrobial activity.
2
. RESULTS AND DISCUSSION
Treatment of 4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-carbonitrile (1) with
acetylacetone, in boiling ethanol containing 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a basic
catalyst, yielded 7-acetyl-4,11-dimethoxy-8-methyl-5-oxo-5H-furo[3`,2`:6,7]chromeno[2,3-
b]pyridine (2) (Scheme 1). The reaction may occur through Michael addition at C-7 position giving
intermediate A followed by retro-Michael reaction with ring opening giving intermediate B which
underwent two successive cycloaddition reactions forming intermediate C. Dehydration of the later
intermediate afforded the target product 2 as described in Scheme 1. Characteristic absorption bands
–1
appeared in the IR spectrum at 1694 (C=Oacetyl), 1651 (C=Oγ-pyrone) and 1608 cm (C=N). Also,
1
specific singlet signals observed in the H NMR spectrum at δ 2.67 (CH3 pyridine), 2.88 (CH3 acetyl) and
1
3
8
.56 ppm (H-6). The C NMR spectrum of compound 2 showed specific signals at δ 19.8 (CH
3
pyridine), 28.1 (CH3 acetyl), 176.6 (C=Oγ-pyrone) and 192.9 (C=Oacetyl). The structure of compound 2 was
also confirmed from its mass spectrum which recorded the molecular ion peak at m/z 353.
:
B
O
Me
OMe
O
O
OMe
OMe
O
O
A
Me
OMe
OMe
O
O
CN
H
CN
O
O
BH+
-
Me
O
EtOH/DBU
O
Me
+H
+
O
OH
B
O
Me
H
OMe
1
30 min, 70%
N
O
Me
OMe
O
O
O
O
OMe
OMe
O
H
Me
-
H O
Me
2
O
N
Me
O
O
C
N
Me
OH
OMe
2
Scheme 1: The suggested mechanism for reaction of carbonitrile 1 with acetylacetone.
Furochromenopyridine-6-carboxylates 3 and 4 were similarly prepared from reactions of
substrate 1 with ethyl acetoacetate and ethyl benzoylacetate (Scheme 2) [29]. Compounds 3 and 4
showed typical absorption bands in their IR spectra at 1690/1696 (C=Oester), 1656/1659 (C=Oγ-pyrone
)
3
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-1
1
and 1612/1611 cm (C=N), respectively. A distinctive singlet appeared in their H NMR spectra at δ
.75 and 8.78 ppm, assignable to H-6. The spectrum of compound 3 revealed specific singlet
8
attributed to CH3 pyridine at δ 2.75 ppm.
Under the previous reaction conditions, treatment of carbonitrile 1 with acetoacetanilide
produced furo[3`,2`:6,7]chromeno[2,3-b]pyridine-7-carboxamide 5 (Scheme 2). The IR spectrum of
compound 5 showed distinctive absorption bands at 1667 (C=Oamide), 1655 (C=Oγ-pyrone) and 1613
–
1
13
(
C=N) cm . The C NMR spectrum of compound 5 revealed typical signals at δ 19.3 (CH pyridine),
3
1
68.9 (C=Oamide) and 176.2 (C=Oγ-pyrone). Its mass spectrum exhibited the parent ion peak at m/z 430
which approves the proposed molecular formula C H N O .
24
18
2
6
O
CH3
OMe
O
O
O
O
COOEt
1%
O
N
Me
7
OMe
OMe
3
OMe
OMe
O
O
O
Ph
O
O
CN
O
COOEt
EtOH/DBU
0 min
O
O
3
O
4
N
Ph
76%
OMe
OMe
1
O
CH3
H
N
O
O
Ph
Ph
O
N
H
O
O
5
N
Me
73%
OMe
Scheme 2: Formation of furo[3`,2`:6,7]chromeno[2,3-b]pyridines 3-5.
Also, the present research was extended to study the behavior of carbonitrile 1 towards some
cyclic carbon nucleophiles aiming to construct a variety of novel heteroannulated furochromenes.
Therefore, reaction of dimedone with carbonitrile 1, gave furochromenoquinoline derivative 6, in
7
2% yield (Scheme 3) [30]. Distinctive absorption bands observed in the IR spectrum at 1683
–1
1
(
C=Oquinolinone), 1659 (C=Oγ-pyrone) and 1605 cm (C=N). Its H NMR spectrum exhibited singlet
signal assigned to H-6 at δ 8.76. Structure of compound 6 was also deduced from its mass spectrum
which revealed the molecular ion peak at m/z 393, and the base peak at m/z 365 corresponding to the
molecular ion after loss of CO molecule.
4
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In the same manner, the linear heteroannulated hexafused furo[3`,2`:6,7]chromeno[2,3-
b]indeno[2,1-e]pyridine derivative 7 was synthesized by reacting carbonitrile 1 with 1,3-indanedione
in absolute ethanol (Scheme 3) [31]. The IR spectrum of compound 7 showed distinctive absorption
-1
1
bands at 1720 (C=Oindanone), 1661 (C=Oγ-pyrone) and 1612 cm (C=N). Its H NMR spectrum showed
specific singlet at δ 8.57 assigned to H-4pyridine. The mass spectrum of compound 7 exhibited the
parent ion peak at m/z 399, as the base peak, which agrees well with the suggested molecular
formula C H NO and supports the structure.
2
3
13
6
O
OMe
O
O
O
Me
Me
O
Me
Me
OMe
O
O
O
N
72%
CN
OMe
OMe
O
6
EtOH/DBU
5 min
O
1
O
O
OMe
1
O
O
O
7
N
68%
OMe
Scheme 3. Formation of linear heteroannulated furochromenes 6 and 7.
Next, carbonitrile 1 was allowed to react with some heterocyclic compounds containing
active methylene group aiming to build a novel linear heteroannulated systems containing
furochromenes. Boiling substrate 1 with pyrazolidine-3,5-dione and 5-methyl-2-phenyl-2,4-dihydro-
3
H-pyrazol-3-one,
in
absolute
ethanol
containing
DBU,
furnished
the
novel
furo[3`,2`:6,7]chromeno[2,3-b]pyrazolo[4,3-e]pyridines 8 and 9, respectively (Scheme 4). The IR
spectra of compounds 8 and 9 showed specific bands corresponding to C=Oγ-pyrone at 1653 and 1664
-1
1
cm , respectively. The H NMR spectra of compounds 8 and 9 showed distinctive singlet signal
assignable to H-6 at δ 8.71 and 8.69, respectively. The spectrum of compound 9 showed upfield
singlet signal assigned to CH3pyrazole at δ 2.12, while the spectrum of compound 8 showed two D O-
2
exchangeable signals attributed to NH and OH protons at δ 11.21 and 13.64, respectively.
Furthermore, the mass spectra for compounds 8 and 9 recorded their molecular ion peaks that agree
with the proposed formula weights at 353.29 and 427.41, respectively.
5
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O
NH
NH
OMe
O
O
OH
N
O
N
7
5%
O
N
OMe
O
O
H
CN
OMe
OMe
8
EtOH/DBU
0 min
CH3
N
O
3
OMe
1
O
O
CH3
N
O
Ph
N
70%
N
O
N
Ph
OMe
9
Scheme 4. Formation of furo[3`,2`:6,7]chromeno[2,3-b]pyrazolo[4,3-e]pyridines 8 and 9.
Also, the novel furo[3``,2``:6`,7`]chromeno[3`,2`:5,6]pyrido[2,3-d]pyrimidines 10 and 11
were efficently prepared from base catalysed ring opening ring closure reactions of carbonitrile 1
with barbituric acid and 1-allylthiobarbituric acid, respectively (Scheme 5) [31]. The IR spectra of
-1
compounds 10 and 11 showed specific absorption bands at 1692/1707 and 1656/1649 cm assigned
1
to C=Opyrimidinone and C=Oγ-pyrone, respectively. Definite singlet observed in H NMR spectra of
compounds 10 and 11, attributed to H-6 at δ 8.82 and 8.85, respectively. The parent ion peaks
appeared in the mass spectra of compounds 10 and 11 at m/z 381 and 437 that agree well with the
proposed molecular formula weights C H N O and C H N O S and confirm the proposed
1
8
11
3
7
21 15
3
6
structures.
6
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O
NH
OMe
OMe
O
O
O
O
N
H
O
NH
75%
O
N
N
H
O
OMe
O
O
O
CN
10
EtOH/DBU
5 min
NH
1
O
OMe
O
N
S
O
O
OMe
1
NH
O
O
N
N
S
77%
OMe
11
Scheme 5. Formation of furo[3``,2``:6`,7`]chromeno[3`,2`:5,6]pyrido[2,3-d]pyrimidines 10 and 11.
Finally, reaction of compound 1 with hippuric acid in boiling acetic anhydride in the presence
of freshly fused sodium acetate produced the novel linear furo[3`,2`:6,7]chromeno[2,3-
b][1,3]oxazolo[4,5-e]pyridine 12 (Scheme 6) [29]. The reaction occurs via the preliminary formation
of 2-phenyloxazol-5-one (as a non-isolable intermediate) which reacted with compound 1 giving
intermediate D which cyclized through cycloaddition and cyclocondensation reactions leading to the
final product 12. In the IR spectrum, specific absorption band for only one carbonyl group appeared
-1
1
at 1653 cm (C=O
). The H NMR spectrum showed typical singlet signal attributable to H-6 at
γ-pyrone
δ 8.75. Compound 12 was also confirmed from its mass spectrum which revealed the parent ion peak
at m/z 414 that coincident well with the suggested formula weight (414.37).
7
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OMe
O
O
COOH
OMe
OMe
O
H C
CN
2
N
Ph
NHCOPh
O
O
Ac O/ NaOAc
O
2
OH
D
O
N
OMe
1
30 min, 67%
-
H O
2
OMe
OMe
O
O
N
Ph
O
O
N
12
Scheme 6: Formation of furo[3`,2`:6,7]chromeno[2,3-b][1,3]oxazolo[4,5-e]pyridine 12.
3
. ANTIMICROBIAL EVALUATION
The prepared compounds were tested for their in vitro antibacterial activity against Gram-
positive bacteria namely Staphylococcus aureus (ATCC25923) and Bacillus subtilis (ATCC6635),
and Gram-negative bacteria namely Salmonella typhimurium (ATCC 14028) and Escherichia coli
(
ATCC 25922). They were also estimated against yeast (Candida albicans ATCC 10231) and fungus
Asperigillus fumigatus). The test was performed on medium potato dextrose agar (PDA) which
(
contained infusion of 200 g potatoes, 6 g dextrose and 15 g agar [32]. Uniform size filter paper disks
3 disks per compound) were impregnated by equal volume (10 µl) from the concentrations of 500
(
and 1000 g/mL dissolved compounds in dimethylformamide (DMF) and carefully placed on
inoculated agar surface. After incubation for 36 h at 27 °C in the case of bacteria and for 48 h at
2
4°C in the case of fungi. The obtained results were recorded for each tested compound as average
diameter of inhibition zones of the bacteria and fungus around the disks in mm at the concentrations
00 and 1000 g/mL. The antimicrobial activities were determined by measuring the inhibition
5
zones, including the diameter of the disc (6 mm) (Table 1). The results represented in Table 1
appeared that:
[
1] Most of the investigated compounds presented different inhibitory effects on the growth of the
tested microorganisms, and the antimicrobial activity varies from low to high activities.
8
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[
2] Compounds 5 and 8 recorded high activity against Bacillus subtilis as Gram-positive bacteria,
Escherichia coli as Gram-negative bacteria and Asperigillus fumigatus as the fungal strain. Also,
compounds 9-11 revealed high antifungal activity towards Asperigillus fumigatus. In addition,
compound 11 recorded high antimicrobial activity against the Gram-negative bacteria,
Escherichia coli.
[
[
3] The high activity of some of the prepared compounds 5 and 8-11 towards certain
microorganisms, may attribute to the presence of additional electron rich nitrogen and oxygen
heteroatoms (NH, C=O and OH) within the molecule.
4] The above results appeared that, some of the prepared compounds recorded high antimicrobial
activity as comparable with the reference drugs and may serve as antimicrobial agents.
Table 1: In vitro antimicrobial evaluations of the prepared compounds at 500 and 1000 g/mL by
disc diffusion assay.
Mean* of zone diameter(mm)
Gram - positive bacteria
Gram - negative bacteria Yeasts and Fungi
Salmonella
typhimuriu
m
Asperigillus
Staphylococc Bacillus
Escherichia Candida
fumigatus
us aureus
subtilis
coli
albicans
1
000 500
1000 500 1000 500
1000 500
1000 500
1
000 500

g/
g/
g/
g/
g/m g/
ml
g/
g/
g/
g/

g/ml g/ml
ml
ml
ml
ml
l
ml
ml
ml
ml
2
3
4
5
6
7
8
9
1
1
1
9 L
11 L
6 L
7 L
6 L
11 L 7 L
10 L 6 L
14 I 8 L
14 I 10 I 18 I 13 I 18 I 14 I 15 I 10 I
18 I 14 I 16 I 11 I 17 I 12 I 17 I 12 I
16 I 11 I 17 I 11 I 20 I 14 I 16 I 10 I
10 L
17 I
12 I 24 H 19 H 17 I 13 I 25 H 19 H 18 I 13 I 27 H 20 H
18 I
13 I 13 I 7 L
7 L 10 L 6 L
16 I 10 I 15 I 9 I
13 I 10 I 14 I 9 I
15 I 10 I 14 I 9 I
16 I 11 I 15 I 9 I
10 L
16 I
11 I 16 H 20 H 16 I 11 I 29 H 22 H 15 I 10 I 26 H 21 H
13 I 20 I 13 I 19 I 14 I 19 I 12 I 16 I 12 I 28 H 22 H
10 I 18 I 11 I 21 I 15 I 18 I 14 I 19 I 14 I 25 H 19 H
10 I 19 I 14 I 19 I 13 I 27 H 21 H 21 I 15 I 26 H 19 H
17 I
0 14 I
1 16 I
2 11 L
8 L
26
10 L 6 L
35 25
19 I 16 I 17 I 12 I 16 I 11 I 19 I 14 I
36 28 38 27 35 28 37 26
S
35
*
Calculated from 3 values.
9
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L = Low activity, I = Intermediate activity, H = High activity, S: Standard drug
S: Standard drug such as Chloramphencol in the case of Gram-positive bacteria, Cephalothinin the
case of Gram-negative bacteria and cycloheximide in the case of yeast and fungi.
4
. CONCLUSIONS
In conclusion, the chemical transformations of electron deficient; 4,9-dimethoxy-5-oxo-5H-furo [3,2-
g]chromene-3-carbonitrile (1) was investigated towards some acyclic and cyclic active methylene
ketones containing –CH CO– moiety. Khellin-6-carbonitrile (1) represents a key intermediate for
2
construction of a new category of heteroannulated furochromens. A novel series of linear
furo[3`,2`:6,7]chromeno[2,3-b]pyridines, furo[3`,2`:6,7]chromeno[2,3-b]pyrazolo[4,3-e]pyridines,
furo[3``,2``:6`,7`]chromeno[3',2':5,6]pyrido[2,3-d]pyrimidines and furo[3`,2`:6,7]chromeno[2,3-
b][1,3]oxazolo[4,5-e]pyridine were efficiently synthesized. Reactions of 4,9-dimethoxy-5-oxo-5H-
furo[3,2-g]chromene-6-carbonitrile (1) with carbon nucleophilic reagents occur throughout a cascade
reactions involving ring opening followed by a diversity of ring closure (RORC) reactions.
5
. EXPERIMENTAL
Melting points were determined on a digital Stuart SMP3 apparatus. Infrared spectra were
-1
1
measured on FTIR Nicolet IS10 spectrophotometer (cm ), using KBr disks. H NMR (300 MHz)
1
3
and C NMR (75 MHz) spectra were measured on Mercury-300BB, using DMSO-d as a solvent
6
and TMS (δ) as the internal standard. Mass spectra were obtained using GC-2010 Shimadzu Gas
chromatography instrument mass spectrometer (70 eV). Elemental microanalyses were performed on
a Perkin–Elmer CHN-2400 analyzer. The purity of the synthesized compounds was tested using
TLC. 4,9-Dimethoxy-5-oxo-5H- furo[3,2-g]chromene-3-carbonitrile (1) was prepared according to
literature [28].
General procedures for reaction of carbonitrile 1 with active methylene nucleophiles:
Formation of heteroannulated furochromenopyridines 2-11.
A mixture of carbonitrile 1 (0.54 g, 2 mmol) and the active methylene nucleophiles namely
acetylacetone, ethyl acetoacetate, ethyl benzoylacetate, acetoacetanilide, dimedone, indane-1,3-
dione, pyrazolidine-3,5-dione, 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one, barbituric acid and
1
-allylbarbituric acid (2 mmol) in absolute ethanol (20 mL) in the presence of DBU (0.1 mL) was
heated under reflux for 30 min.
1
0
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7
-Acetyl-4,11-dimethoxy-8-methyl-5-oxo-5H-furo[3`,2`:6,7]chromeno[2,3-b]pyridine
(2).
-
1
Crystallized from EtOH as pale yellow crystals, mp 285-286 ºC, yield (0.51 g, 72%). IR (KBr, cm ):
3
115 (CHfuran), 2962, 2933 (CHaliph.), 1694 (C=Oacetyl), 1651 (C=Oγ-pyrone), 1608 (C=N), 1575 (C=C).
1
H NMR (DMSO-d , δ, 300 MHz): 2.67 (s, 3H, CH3 pyridine), 2.88 (s, 3H, CH3 acetyl), 3.86 (s, 3H,
6
OCH ), 3.99 (s, 3H, OCH ), 7.14 (d, 1H, J=1.8 Hz, H-3furan), 7.92 (d, 1H, J=1.8 Hz, H-2furan), 8.56 (s,
3
3
1
3
1
5
1
H, H-4pyridine). C NMR (DMSO-d , δ, 75 MHz): 19.8 (CH3 pyridine), 28.1 (CH3 acetyl), 58.2 (OCH3),
6
9.1 (OCH ), 104.6, 106.1, 108.4, 114.6, 115.0, 126.4, 128.2, 140.3, 141.9, 145.4, 147.6, 152.8,
3
+
58.3, 176.6, 192.9. Mass spectrum (m/z, I %): 353 (M ; 29), 325 (100), 295 (41), 280 (23), 236
(28), 220 (47), 205 (16), 191 (28), 177 (7), 147 (10), 118 (21), 77 (63), 64 (38). Anal. Calcd for
C H NO (353.33): C, 64.59; H, 4.28; N, 3.96%. Found: C, 64.43; H, 4.04; N, 3.86%.
19
15
6
Ethyl
8-methyl-4,11-dimethoxy-5-oxo-5H-furo[3`,2`:6,7]chromeno[2,3-b]pyridine-7-
carboxylate (3). Crystallized from AcOH as white crystals, mp 275-276 ºC, yield (0.55 g, 71%). IR
-1
(
KBr, cm ): 3117 (CHfuran), 2974, 2926 (CHaliph.), 1690 (C=Oester), 1656 (C=Oγ-pyrone), 1612 (C=N),
1
1
567 (C=C). H NMR (DMSO-d , δ, 300 MHz): 1.43 (t, 3H, J = 7.2 Hz, CH CH ), 2.75 (s, 3H, CH
6
2
3
3
pyridine), 3.84 (s, 3H, OCH ), 3.95 (s, 3H, OCH ), 4.27 (q, 2H, J =7.2 Hz, CH CH ), 7.18 (d, 1H, J=2.1
3
3
2
3
1
3
Hz, H-3furan), 7.96 (d, 1H, J=2.1 Hz, H-2furan), 8.75 (s, 1H, H-4pyridine). C NMR (DMSO-d , δ, 75
6
MHz): 15.7 (CH ), 18.7 (CH
), 58.4 (OCH ), 59.6 (OCH ), 60.4 (CH ), 105.6, 107.4, 112.5,
3 pyridine 3 3 2
3
1
14.8, 119.4, 128.2, 140.2, 142.5, 144.8, 147.5, 152.3, 159.8, 160.7, 165.3, 176.2. Mass spectrum
+
(
m/z, I %): 383 (M ; 34), 353 (52), 338 (100), 310 (14), 282 (25), 242 (43), 220 (65), 205 (6), 147
(
14), 134 (32), 118 (72), 77 (38), 64 (66). Anal. Calcd for C H NO (383.35): C, 62.66; H, 4.47; N,
2
0
17
7
3
.65%. Found: C, 62.42; H, 4.25; N, 3.39%.
Ethyl
8-phenyl-4,11-dimethoxy-5-oxo-5H-furo[3`,2`:6,7]chromeno[2,3-b]pyridine-7-
carboxylate (4). Crystallized from DMF/EtOH as pale yellow crystals, mp> 300 ºC, yield (0.68 g,
-1
7
6%). IR (KBr, cm ): 3124 (CHfuran), 3061 (CHarom.), 2948, 2915 (CHaliph.), 1696 (C=Oester), 1659
1
(
C=Oγ-pyrone), 1611 (C=N), 1584 (C=C). H NMR (DMSO-d , δ, 300 MHz): 1.28 (t, 3H, J = 6.6 Hz,
6
CH CH ), 3.86 (s, 3H, OCH ), 3.97 (s, 3H, OCH ), 4.25 (q, 2H, J =6.6 Hz, CH CH ), 6.85-7.11 (m,
2
3
3
3
2
3
5
H, Ph-H), 7.24 (d, 1H, J=2.4 Hz, H-3furan), 7.93 (d, 1H, J=2.4 Hz, H-2furan), 8.78 (s, 1H, H-4pyridine).
C NMR (DMSO-d , δ, 75 MHz): 15.7 (CH ), 57.9 (OCH ), 58.8 (OCH ), 61.2 (CH ), 105.3, 107.5,
1
3
6
3
3
3
2
1
1
10.7, 112.4, 114.7, 126.3, 127.8, 128.3, 130.5, 136.2, 140.4, 142.1, 144.7, 147.2, 151.6, 152.8,
+
58.3, 166.1, 176.9. Mass spectrum (m/z, I %): 445 (M ; 100), 400 (39), 372 (33), 342 (51), 265
(17), 242 (100), 220 (43), 205 (11), 147 (8), 134 (43), 118 (24), 77 (14), 64 (51). Anal. Calcd for
C H NO (445.42): C, 67.41; H, 4.30; N, 3.14%. Found: C, 67.30; H, 4.05; N, 2.91%.
25
19
7
1
1
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4
,11-Dimethoxy-8-methyl-N-phenyl-5-oxo-5H-furo[3`,2`:6,7]chromeno[2,3-b]pyridine-7-
carboxamide (5). Crystallized from DMF as yellow crystals, mp> 300 ºC, yield (0.63 g, 73%). IR
-1
(
KBr, cm ): 3258 (NH), 3122 (CHfuran), 3065 (CHarom.), 2969, 2925 (CHaliph.), 1667 (C=Oamide), 1655
1
(
C=Oγ-pyrone), 1613 (C=N), 1571 (C=C). H NMR (DMSO-d , δ, 300 MHz): 2.63 (s, 3H, CH3 pyridine),
6
3
7
.84 (s, 3H, OCH ), 3.95 (s, 3H, OCH ), 7.23 (d, 1H, J=2.4 Hz, H-3furan), 7.39-7.52 (m, 5H, Ph-H),
3 3
.94 (d, 1H, J=2.4 Hz, H-2furan), 8.67 (s, 1H, H-4pyridine), 9.58 (bs, 1H, NH exchangeable with D O).
2
1
3
C NMR (DMSO-d , δ, 75 MHz): 19.3 (CH
), 58.5 (OCH ), 59.9 (OCH ), 105.8, 114.2,
3 pyridine 3 3
6
1
1
2
15.6, 121.8, 123.7, 125,4, 128.1, 130.3, 135,9, 140.3, 141.9, 144.5, 146.2, 147.6, 152.1, 158.6,
+
63.8, 168.9, 176.2. Mass spectrum (m/z, I %): 430 (M ; 29), 338 (100), 308 (28), 280 (8), 235 (16),
20 (60), 205 (27), 191 (39), 177 (22), 147 (19), 135 (25), 119 (11), 92 (100), 77 (19), 64 (51). Anal.
Calcd for C H N O (430.41): C, 66.97; H, 4.22; N, 6.51%. Found: C, 66.60; H, 3.88; N, 6.25%.
2
4
18
2
6
9
,9-Dimethyl-4,13-dimethoxyfuro[3`,2`:6,7]chromeno[2,3-b]quinoline-5,7(5H,7H)-dione
(6).
-
Crystallized from DMF/MeOH as white crystals, mp 290-291 ºC, yield (0.58 g, 72%).IR (KBr, cm
1
): 3109 (CHfuran), 2963, 2913 (CHaliph.), 1683 (C=Oquinolinone), 1659 (C=Oγ-pyrone), 1605 (C=N), 1579
1
(
C=C). H NMR (DMSO-d , δ, 300 MHz): 1.07 (s, 6H, 2CH ), 2.65 (s, 2H, CH ), 3.06 (s, 2H, CH ),
6
3
2
2
3
.94 (s, 3H, OCH ), 4.04 (s, 3H, OCH ), 7.19 (d, 1H, J=1.8 Hz, H-3furan), 7.96 (d, 1H, J=1.8 Hz, H-
3 3
1
3
2furan), 8.76 (s, 1H, H-4pyridine). C NMR (DMSO-d , δ, 75 MHz): 26.6, 27.1, 34.5, 46.2, 51.9, 58.9
6
(
OCH ), 60.1 (OCH ), 105.4, 107.2, 112.6, 114.7, 126.9, 129.5, 140.7, 142.6, 145.5, 147.3, 152.6,
3 3
1
59.4, 169.8, 179.3, 195.8. Mass spectrum (m/z, I %): 393 (78), 365 (100), 337 (63), 307 (13), 265
(
18), 239 (8), 215 (12), 202 (35), 187 (9), 103 (8), 80 (13), 65 (18). Anal. Calcd for C H NO
22 19
6
(393.39): C, 67.17; H, 4.87; N, 3.56%. Found: C, 66.80; H, 4.72; N, 3.25%.
4
,14-Dimethoxyfuro[3`,2`:6,7]chromeno[2,3-b]indeno[2,1-e]pyridine-5,7(5H,7H)-dione
(7).
-1
Crystallized from DMF/MeOH as white crystals, mp> 300 ºC, yield (0.54 g, 68%).IR (KBr, cm ):
3
118 (CHfuran), 3066 (CHarom.), 2968, 2924 (CHaliph.), 1720 (C=Oindanone), 1661 (C=Oγ-pyrone), 1612
1
(
C=N), 1584 (C=C). H NMR (DMSO-d , δ, 300 MHz): 4.03 (s, 3H, OCH ), 4.12 (s, 3H, OCH ),
6
3
3
7
1
1
1
.10 (d, 1H, J=2.1 Hz, H-3furan), 7.41-7.53 (m, 4H, Ar-H), 7.93 (d, 1H, J=2.1 Hz, H-2furan), 8.57 (s,
13
H, H-4pyridine). C NMR (DMSO-d , δ, 75 MHz): 59.4 (OCH ), 60.2 (OCH ), 105.8, 107.3, 113.9,
6
3
3
15.7, 117.9, 125.3, 126.4, 127.1, 128.6, 130.2, 132.8, 135.3, 140.0, 142.2, 144.3, 145.9, 152.6,
59.0, 163.4, 178.5, 191.4. Mass spectrum (m/z, I %): 399 (100), 369 (28), 312 (22), 242 (33), 228
(
18), 205 (12), 191 (7), 118 (41), 102 (62), 77 (24), 64 (11). Anal. Calcd for C H NO (399.35): C,
23 13 6
6
9.17; H, 3.28; N, 3.51%. Found: C, 68.87; H, 3.03; N, 3.38%.
1
2
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6
,10-Dimethoxy-3-hydroxy-5-oxo-5H-1-hydrofuro[3`,2`:6,7]chromeno[2,3-b]pyrazolo[4,3-e]
-
pyridine (8). Crystallized from DMF as pale yellow, mp> 300 ºC, yield (0.53 g, 75%). IR (KBr, cm
1
1
)
: 3441 (OH), 3263 (NH), 3112 (CHfuran), 1653 (C=Oγ-pyrone), 1616 (C=N), 1573 (C=C). H NMR
(
DMSO-d , δ, 300 MHz): 3.88 (s, 3H, OCH ), 4.03 (s, 3H, OCH ), 7.22 (d, 1H, J=2.1 Hz, H-3furan),
6
3
3
7
1
.87 (d, 1H, J=2.1 Hz, H-2furan), 8.71 (s, 1H, H-4pyridine), 11.21 (bs, 1H, NH exchangeable with D O),
2
1
3
3.64 (bs, 1H, OH exchangeable with D O). C NMR (DMSO-d , δ, 75 MHz): 59.1 (OCH ), 59.7
2
6
3
(
OCH ), 103.8, 105.6, 107.2, 113.8, 117.4, 128.3, 139.8, 140.7, 143.4, 145.6, 151.8, 152.7, 156.2,
3
1
1
5
61.6, 177.8. Mass spectrum (m/z, I %): 353 (27), 325 (42), 308 (100), 278 (35), 252 (21), 226 (13),
88 (9), 147 (11), 118 (15), 104 (25), 76 (11), 65 (21). Anal. Calcd for C H N O (353.29): C,
17
11
3
6
7.80; H, 3.14; N, 11.89%. Found: C, 57.55; H, 3.00; N, 11.63%.
6
,10-Dimethoxy-3-methyl-1-phenyl-5-oxo-5H-furo[3`,2`:6,7]chromeno[2,3-b]pyrazolo[4,3-e]
pyridine (9). Crystallized from DMF as pale yellow crystals, mp> 300 ºC, yield (0.60 g, 70%). IR
-1
(
KBr, cm ): 3124 (CHfuran), 3046 (CHarom.), 2958, 2923 (CHaliph.), 1664 (C=Oγ-pyrone), 1622 (C=N),
1
1
594 (C=C). H NMR (DMSO-d , δ, 300 MHz): 2.12 (s, 3H, CH ), 3.92 (s, 3H, OCH ), 4.08 (s, 3H,
6
3
3
OCH ), 6.87 (t, 1H, J=6.9 Hz, Ar-H), 7.18 (d, 1H, J=2.4 Hz, H-3furan), 7.29-7.52 (m, 4H, Ar-H), 7.96
3
1
3
(
d, 1H, J=2.4 Hz, H-2furan), 8.69 (s, 1H, H-4pyridine). C NMR (DMSO-d , δ, 75 MHz): 18.3 (CH ),
6 3
5
9.4 (OCH ), 60.1 (OCH ), 105.9, 107.6, 114.1, 117.8, 120.4, 121.3, 126.7, 128.2, 130.0, 139.6,
3 3
1
40.9, 141.5, 144.3, 146.2, 147.8, 150.5, 152.8, 159.7, 177.2. Anal. Calcd for C H N O (427.41):
24 17 3 5
C, 67.44; H, 4.01; N, 9.83%. Found: C, 67.32; H, 3.86; N, 9.51%.
7
2
,11-Dimethoxy-6H-furo[3``,2``:6`,7`]chromeno[3`,2`:5,6]pyrido[2,3-d]pyrimidine-
,4,6(1H,3H)- trione (10). Crystallized from DMF/H O as yellow crystals, mp> 300 ºC, yield (0.57
2
-1
g, 75%). IR (KBr, cm ): 3365 (2NH), 3124 (CHfuran), 2958, 2911 (CHaliph.), 1692 (C=Opyrimidinone),
1
1
656 (C=Oγ-pyrone), 1614 (C=N), 1588 (C=C). H NMR (DMSO-d , δ, 300 MHz): 3.94 (s, 3H,
6
OCH ), 4.06 (s, 3H, OCH ), 7.19 (d, 1H, J=1.8 Hz, H-3furan), 7.84 (d, 1H, J=1.8 Hz, H-2furan), 8.82 (s,
3
3
1
3
H, H-4pyridine), 11.52 (bs, 2H, 2NH exchangeable with D O). Mass spectrum (m/z, I %): 381 (100),
2
53 (22), 310 (19), 280 (62), 242 (31), 220 (27), 205 (11), 177 (8), 120 (35), 77 (14), 66 (14). Anal.
Calcd for C H N O (381.29): C, 56.70; H, 2.91; N, 11.02%. Found: C, 56.51; H, 2.73; N, 10.88%.
1
8
11
3
7
1
4
7
-Allyl-7,11-dimethoxy-2-thioxo-furo[3``,2``:6`,7`]chromeno[3`,2`:5,6]pyrido[2,3-d]pyrimidine-
,6(4H,6H)-dione (11). Crystallized from DMF as orange crystals, mp 296-297 ºC, yield (0.68 g,
-1
7%). IR (KBr, cm ): 3235 (NH), 3104 (CHfuran), 1707 (C=Opyrimidinone), 1649 (C=Oγ-pyrone), 1612
1
3
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1
(
C=N), 1572 (C=C), 1226 (C=S). H NMR (DMSO-d , δ, 300 MHz): 3.02 (s, 2H, CH , H-1`), 3.87
6 2
(
s, 3H, OCH ), 3.98 (s, 3H, OCH ), 4.89-4.93 (m, 2H, H-3`), 5.78-5.84 (m, 1H, H-2`), 7.15 (d, 1H,
3
3
J=1.8 Hz, H-3furan), 7.92 (d, 1H, J=1.8 Hz, H-2furan), 8.85 (s, 1H, H-6), 11.13 (bs, 1H, NH
13
exchangeable with D O). C NMR (DMSO-d , δ, 75 MHz): 37.9, 59.5 (OCH ), 60.2 (OCH ), 104.6,
2
6
3
3
1
1
05.9, 107.3, 109.0, 114.3, 115.4, 117.3, 127.6, 134.7, 140.5, 144.9, 146.1, 151.6, 155.9, 158.3,
62.2, 168.4, 177.3. Mass spectrum (m/z, I %): 437 (32), 410 (13), 382 (100), 349 (41), 276 (18), 228
(
33), 191 (13), 147 (7), 116 (21), 77 (43), 65 (18). Anal. Calcd for C H N O S (437.43): C, 57.66;
21 15 3 6
H, 3.46; N, 9.61; S, 7.33%. Found: C, 57.51; H, 3.20; N, 9.47; S, 7.10%.
6
,10-Dimethoxy-2-phenyl-11-oxo-11H-furo[3`,2`:6,7]chromeno[2,3-b][1,3]oxazolo[4,5-e]
pyridine (12).
Hippuric acid (0.36 g, 2 mmol) dissolved in acetic anhydride (10 mL) and fused sodium acetate (0.5
g) was heated under reflux for 15 min, then compound 1 (0.54 g, 2 mmol) was added. The reaction
mixture was heated under reflux for 30 min. The yellow crystals obtained after cooling were filtered
-1
and crystallized from AcOH, mp 281-282 ºC, yield (0.56 g, 67%). IR (KBr, cm ): 3120 (CHfuran),
1
3
060 (CHarom.), 2946, 2912 (CHaliph.), 1653 (C=Oγ-pyrone), 1621 (C=N), 1576 (C=C). H NMR
(
DMSO-d , δ, 300 MHz): 3.89 (s, 3H, OCH ), 4.07 (s, 3H, OCH ), 7.20 (d, 1H, J=2.1 Hz, H-3furan),
6 3 3
1
3
7
.30-7.47 (m, 5H, Ph-H), 7.90 (d, 1H, J=2.1 Hz, H-2furan), 8.75 (s, 1H, H-4pyridine). C NMR (DMSO-
d , δ, 75 MHz): 59.7 (OCH ), 60.5 (OCH ), 105.5, 107.1, 114.5, 117.6, 125.9, 127.4, 128.5, 129.4,
6
3
3
1
30.2, 133.6, 140.7, 142.6, 144.6, 146.3, 147.3, 151.8, 159.4, 161.6, 177.9. Mass spectrum (m/z, I
): 414 (21), 386 (45), 309 (15), 283 (23), 242 (100), 220 (32), 171 (12), 118 (14), 103 (9), 90 (6),
7 (48), 64 (21). Anal. Calcd for C H N O (414.37): C, 66.67; H, 3.41; N, 6.76%. Found: C,
%
7
6
2
3
14
2
6
6.30; H, 3.22; N, 6.48%.
6
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SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting Information section at the
end of the article.
1
6
This article is protected by copyright. All rights reserved.