Studies on the chemical behavior of the novel 6,8-dibromo-7- hydroxychromone-3-carboxaldehyde towards some carbon nucleophilic reagents

Article abstract of DOI:10.3987/COM-13-12709

A novel 6,8-dibromo-7-hydroxychromone-3-carboxaldehyde (4) was prepared by the Vilsemier-Haack formylation of 3,5-dibromo-2,4-dihydroxy acetophenone (3). The chemical reactivity of carboxaldehyde 4 was studied towards some carbon nucleophiles as cyclic and acyclic active methylene nucleophiles and also 1,3-C,N- and 1,3-C,C-binucleophiles as a route to achieve ring transformation to produce a variety of heterocyclic systems. Structures of the newly synthesized products have been deduced on the basis of elemental analysis and spectral data.

Full text of DOI:10.3987/COM-13-12709

HETEROCYCLES, Vol. 87, No. 5, 2013
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HETEROCYCLES, Vol. 87, No. 5, 2013, pp. 1075 - 1086. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 18th March, 2013, Accepted, 2nd April, 2013, Published online, 8th April, 2013
DOI: 10.3987/COM-13-12709
STUDIES ON THE CHEMICAL BEHAVIOR OF THE NOVEL 6,8-
DIBROMO-7-HYDROXYCHROMONE-3-CARBOXALDEHYDE
TOWARDS SOME CARBON NUCLEOPHILIC REAGENTS
Magdy A. Ibrahim,* Tarik E. Ali, Azza M. El-Kazak, and Amira M.
Mohamed
Department of Chemistry, Faculty of Education, Ain Shams University, Roxy,
11711, Cairo, Egypt
*E-mail: magdy_ahmed1977@yahoo.com
Abstract – A novel 6,8-dibromo-7-hydroxychromone-3-carboxaldehyde (4) was
prepared by the Vilsemier-Haack formylation of 3,5-dibromo-2,4-dihydroxy
acetophenone (3). The chemical reactivity of carboxaldehyde 4 was studied
towards some carbon nucleophiles as cyclic and acyclic active methylene
nucleophiles and also 1,3-C,N- and 1,3-C,C-binucleophiles as a route to achieve
ring transformation to produce a variety of heterocyclic systems. Structures of the
newly synthesized products have been deduced on the basis of elemental analysis
and spectral data.
INTRODUCTION
3-Formylchromone has been used as precursor to prepare a diversity of heterocyclic systems,1-5 owing to
the presence of an !,"-unsaturated keto-function, a conjugated formyl group at C-3 and in particular due
to the active center at C-2. The C-2 position is very reactive towards Michael addition of nucleophiles
with opening of the #-pyrone ring followed by a new cyclization.6-9 Numerous bromine-containing
heterocycles exhibit strong biological activity due to their ability to inhibit specific enzymes, good
solubility in lipids, and easy penetration through cell membranes.10-12 Furthermore, nitrogen-containing
heterocycles have well-known biological properties in medicinal and pharmaceutical fields.13-15 These
observations directed our attention to synthesis the novel 6,8-dibromo-7-hydroxychromone-3-
carboxaldehyde (4), as starting compound, to react with some carbon nucleophiles such as cyclic and
acyclic active methylene nucleophiles and also 1,3-C,N- and 1,3-C,C-binucleophiles as a route to obtain a
novel nitrogen heterocyclic systems such as chromonyloxazolone, chromonylthiazolidinone,

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HETEROCYCLES, Vol. 87, No. 5, 2013
chromonylxanthene, pyrano[3,2-c]chromene, pyrano[3,2-c]quinoline, pyridylpyridine, pyrido[1,2-a]-
benzimidazole, pyrido[3,2-d]pyrimidine and quinazolinone which would be expected to have biological
activities.
RESULTS AND DISCUSSION
Acetylation of resorcinol (1) with glacial acetic acid in the presence of freshly fused zinc chloride, using
the standard procedure,16 gave 2,4-dihydroxyacetophone (2) which upon bromination using bromine in
80% acetic acid afforded 3,5-dibromo-2,4-dihydroxyacetophenone (3).17 Applying Vilsemier-Haack
formylation on the latter compound produced the novel 6,8-dibromo-7-hydroxychromone-3-
carboxaldehyde (4).18 Compound 4 was also obtained via Vilsemier-Haack formylation of 2,4-dihydroxy-
acetophenone (2) to produce 7-hydroxychromone-3-carboxaldehyde (5)19 which upon bromination
afforded the target compound 4 (Scheme 1). Structure of carboxaldehyde 4 was deduced from its correct
elemental analysis and spectral data. Its IR spectrum showed two characteristic absorption bands at 1685
and 1667 cm-1 attributed to C=Oformyl and C=O#-pyrone, respectively. Its 1H-NMR spectrum consists of three
singlets at $ 8.16, 8.89 and 10.07 ppm due to H-5chromone, H-2chromone and CHO protons, respectively. 13C-
NMR spectrum of compound 4 showed two characteristic downfield signals at $ 172.8 and 187.9 ppm
attributed to the C-4 (as C=O) and the aldehydic carbons, respectively. Also, the mass spectrum of
compound 4 showed the molecular ion peak at m/z 346, and the base peak at m/z 320. In addition, the
relative intensities of M+, M+2 and M+4 are in the ratio 1:2:1 as expected for compounds contains two
bromine atoms.
Scheme 1

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1077
Chromone bearing heterocyclic systems at position 3 recorded variable biological activities.20 Thus, a
variety of heterocyclic systems linked to chromone moiety at position 3 were synthesized via reaction of
6,8-dibromo-7-hydroxychromone-3-carboxaldehyde (4) with some cyclic active methylene nucleophiles.
Thus, condensation of carboxaldehyde 4 with hippuric acid in boiling acetic anhydride containing freshly
fused sodium acetate gave 6,8-dibromo-3-[(5-oxo-2-phenyl-1,3-oxazol-4-ylidene)methyl]chromon-7-yl
acetate (6) (Scheme 2). The IR spectrum of compound 6 showed characteristic absorption bands at 1782
(C=Ooxazolone), 1718 (C=Oacetyl), 1654 (C=O#-pyrone) and 1610 cm-1 (C=N). Its 1H-NMR spectrum exhibited
characteristic singlets at $ 2.11 (CH3 acetyl), 6.43 (exocyclic CH=C), 7.89 (H-5chromone) and 8.32
(H-2chromone) ppm.
Also, Knoevenagel condensation of aldehyde 4 with thiazolidine-2,4-dione in glacial acetic acid
containing freshly fused sodium acetate afforded the target compound, 6,8-dibromo-3-[(2,4-dioxo-1,3-
1
thiazolidin-5-ylidine)methyl]chromone (7) (Scheme 2). Its H-NMR spectrum showed three singlets at $
7.64, 8.18 and 8.88 ppm attributed to exocyclic methine proton, H-5chromone and H-2chromone, respectively,
in addition to the NH proton which observed as a broad signal exchangeable with D2O at $ 12.50 ppm.
Also, its mass spectrum showed the molecular ion peak at m/z 445 and the base peak at m/z 376.
Scheme 2

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Interestingly, dimedone showed different behavior, than the previous cyclic active methylene compounds.
Thus, carboxaldehyde 4 reacted with two molecules of dimedone in dry pyridine to produce 9-(6,8-
dibromo-7-hydroxychromon-3-yl)-3,3,6,6-tetramethyl-1,2,3,4,5,6,7,8-octahydroxanthene-1,8-dione
(8)
1
(Scheme 2).21 The H-NMR spectrum showed characteristic singlets at $ 4.32, 8.03 and 8.38 ppm
13
attributed to H-9xanthene, H-5chromone and H-2chromone, respectively. Its C-NMR spectrum showed upfield
signals assigned to the methyl carbons at $ 25.9 and 26.2 ppm. The mass spectrum of compound 8
showed the molecular ion peak at m/z 590 which agrees well with the molecular formula (C26H24Br2O6).
Reaction of carboxaldehyde 1 with some acyclic active methylene nucleophiles was studied. Thus,
condensation of carboxaldehyde 4 with indole-3-acetic acid in boiling acetic anhydride containing freshly
fused sodium acetate gave 3-(1-acetyl-1H-indol-3-yl)-7,9-dibromo-2-oxo-2H,5H-pyrano[3,2-c]chromene-
5,8-diyl diacetate 9 (Scheme 3).22 The IR spectrum of compound 9 showed characteristic absorption
1
bands at 1780 (C =O!-lactone), 1736, 1719, 1645 (3 C=Oacetyl) cm-1. Its H-NMR spectrum showed three
characteristic singlets at $ 1.91, 2.05 and 2.73 ppm attributed to protons of three methyl groups, in
addition to three characteristic singlet signals at $ 6.40 (H-5 as OCHO), 7.70 (H-10), 8.26 (H-2indole) and
8.44 (H-4).
Scheme 3
Similarly, reaction of carboxaldehyde 4 with "-ketoacid 10,23 in boiling DMF containing few drops of
piperidine, furnished directly the cyclized product, 3-[(6,8-dibromo-7-hydroxychromon-3-
yl)methylidene]-6-ethyl-6H-pyrano[3,2-c]quinoline-2,4,5-(3H,5H) trione (11), in one step reaction. Under
these reaction conditions, the Knoevenagel condensation intermediate C was not isolated but underwent
intramolecular nucleophilic lactonization to form the cyclized product directly 11 (Scheme 4). The latter

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compound 11 was also obtained from the reaction of the pyrano[3,2-c]quinoline derivative 1224 with
carboxaldehyde 4 in glacial acetic acid containing freshly fused sodium acetate.25 The 1H-NMR spectrum
of 11 showed three characteristic singlets at $ 8.29 (H-5chromone), 8.39 (exocyclic CH=C) and 9.15 ppm
(H-2chromone).
Scheme 4
Next, we studied the reaction of carboxaldehyde 4 with some 1,3-C,N-binucleophiles which produced
some biheterocyclic systems via #-pyrone ring opening followed by ring closure. Thus, condensation of
carboxaldehyde 4 with 2-cyano-N-(pyridin-2-yl)acetamide and 1H-benzimidazol-2-ylacetonitrile, in
boiling EtOH containing few drops of piperidine, afforded 5-(3,5-dibromo-2,4-dihydroxybenzoyl)-2-oxo-
2H-1-(pyridin-2-yl)pyridine-3-carbonitrile (13)26 and 2-(3,5-dibromo-2,4-dihydroxybenzoyl)pyrido[1,2-
a] benzimidazole-4-carbonitrile (14), respectively (Scheme 5).27 The reaction proceeds via condensation
followed by nucleophilic attack at C-2 position with #-pyrone ring opening. Their IR spectra showed
characteristic absorption bands at 2209, 2240 (C%N) and 1637, 1630 (C=Obenzoyl) cm-1, respectively. The
1H-NMR spectra of compounds 13 and 14 showed two characteristic singlets for each one at $ 8.02, 8.63
and 7.97, 8.07 ppm, respectively, attributed to protons of pyridine rings. Moreover, the mass spectrum of
compound 14 showed the molecular ion peak at m/z 485 which agrees well with the molecular formula
(C19H9Br2N3O3).
Similarly, condensation of carboxaldehyde 4 with 6-amino-5H-1,3-dimethylpyrimidine-2,4-(1H,3H)-
dione gave the pyrido[3,2-d]pyrimidine derivative 15, through condensation of the formyl group with the
active methylene group, to give the intermediate F, which underwent #-pyrone ring opening by the imine
nitrogen as shown in Scheme 5.28 The 1H-NMR spectrum recorded characteristic singlet signals at $ 3.30
13
(CH3), 3.67 (CH3), 7.63 (H-6resorcinol), 8.53 (H-8), 8.99 (H-6) ppm. Also, its C-NMR spectrum showed

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characteristic signals attributed to the two methyl carbons at $ 28.2 and 29.5 ppm. The mass spectrum of
compound 15 showed the molecular ion peak at m/e 483 which agrees well with the molecular formula
(C16H11Br2N3O5) and supports the identity of the structure.
O
O
O
O
O
O
Br
CN
O
CN
N
CN
Br
CHO
Br
N
H
N
N
H
CN
HO
O
HN
N
HO
HO
Br
HN
EtOH
EtOH
piperidine
N
piperidine
Br
Br
4
O
D
E
Me
N
EtOH
p-TsOH
H2N
N
O
OH
Br
O
Me
Br
CN
O
OH
Br
O
O
O
N
CN
Br
Br
Me
O
HO
N
N
N
N
HO
N
HN
HO
O
Me
Br
13
F
14
O
OH
O
Br
Me
O
N
N
N
HO
Me
Br
15
Scheme 5
Finally, treatment of carboxaldehyde 4 with 1,3-C,C-binucleophile namely 6-methyl-2-thioxo-2,3-
dihydropyrimidin-4(1H)-one, in boiling DMF containing few drops of piperidine, produced 6-(3,5-
dibromo-2,4-dihydroxybenzoyl)-2-thioxo-1,3-dihydroquinazolin-4-one (16) as shown in Scheme 6. Its
1H-NMR spectrum showed two characteristic singlets at $ 7.95 and 8.14 ppm attributed to H-6resorcinol and
H-5quinazoline, respectively, while the H-7 and H-8 of quinazoline moiety appeared as doublets at 8.07 and
7.05 ppm, respectively. The mass spectrum of compound 16 showed the molecular ion peak at m/z 472
which agrees well with the suggested structure.
CONCLUSIONS
The novel 6,8-dibromo-7-hydroxychromone-3-carboxaldehyde (4) was efficiently synthesized and
utilized to react with some carbon nucleophiles such as cyclic and cyclic active methylene nucleophiles
and also 1,3-C,N- and 1,3-C,C-binucleophiles as a route to obtain a novel nitrogen heterocyclic systems
including chromonyloxazolone, chromonylthiazolidinone, chromonylxanthene, pyrano[3,2-c]chromene,
pyrano[3,2-c]quinoline, pyridylpyridine, pyrido[1,2-a]benzimidazole, pyrido[3,2-d]pyrimidine and

HETEROCYCLES, Vol. 87, No. 5, 2013
1081
quinazolinone.
Scheme 6
EXPERIMENTAL
Melting points were determined on a digital Stuart SMP3 apparatus. Infrared spectra were measured on
1
13
FTIR Nicolet IS10 spectrophotometer (cm-1), using KBr disks. H NMR (300MHz) and C NMR (75
MHz) spectra were measured on Mercury-300BB, using DMSO-d6 as a solvent and TMS ($) 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 at the Chemical War department, Ministry of Defense, Egypt.
3,5-Dibromo-2,4-dihydroxyacetophenone (3)
To a solution of 2,4-dihydroxyacetophenone (2) (15.2 g, 0.1 mol) in acetic acid (80%, 20 mL), bromine
(32 g, 10.4 mL, 0.2 mol) in acetic acid (10 mL) was added dropwise with continuous stirring for 15 min.
The pale red crystals obtained were filtered off and recrystallized from benzene to give compound 3 as
white crystals, yield (14.4 g, 46%), mp 173-174 ºC (lit. 172-173 ºC).17 IR (KBr, cm-1): 3399 (br, OH),
1624 (C=Ohydrogen bonded), 1559 (C=C).
6,8-Dibromo-7-hydroxychromone-3-carboxaldehyde (4).
Method A: Phosphoryl chloride (3 mL) was added dropwise with continuous stirring to a pre-cooled
DMF (10 mL) and the mixture was further stirred at room temperature for 30 min. Then 3,5-dibromo-2,4-
dihydroxyacetophenone (3) (0.93 g, 3 mmol) in DMF (10 mL) was added dropwise with continuous
stirring. The reaction mixture was stirred at room temperature for 2 h, left overnight and poured onto
crushed ice (50 g). The obtained solid was filtered off, air dried and crystallized from EtOH to give

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compound 4 as pale yellow crystals, yield (0.80 g, 77%), mp 250-251 oC.
Method B: A mixture of 7-hydroxychromone-3-carboxaldehyde (5) (0.57 g, 3 mmol) and bromine (0.96
g, 0.32 mL, 6 mmol) in acetic acid (80%, 5 mL) was stirred at room temperature for 1 h. The obtained
solid was filtered off and crystallized from EtOH to give compound 4 as pale yellow crystals, yield (0.61
g, 59%), mp 250-251 oC. IR (KBr, cm-1): 3235 (OH), 3058 (CHarom), 1685 (C=Oformyl), 1667 (C=O#-pyrone),
1
1599 (C=C). H-NMR (DMSO-d6): 8.16 (s, 1H, H-5chromone), 8.89 (s, 1H, H-2chromone), 10.07 (s, 1H,
CHO). 13C-NMR (DMSO-d6): 100.4 (C-8), 110.8 (C-6), 118.9 (C-3), 119.7 (C-4a), 127.6 (C-5), 153.1 (C-
8a), 156.9 (C-7), 163.2 (C-2), 172.8 (C=O), 187.9 (CHO). MS (m/z, I%): 350 (M+4, 2), 348 (M+2, 5),
346 (M+, 2), 322 (52), 320 (100), 318 (50), 296 (8), 294 (16), 292 (8), 280 (3), 278 (7), 276 (3), 215 (2),
213 (2), 199 (3), 197 (3), 187 (3), 185 (4), 175 (2), 173 (2), 159 (2), 157 (2), 133 (3), 119 (2), 91 (2).
Anal. Calcd for C10H4Br2O4 (347.94): C, 34.52; H, 1.16%. Found: C, 34.17; H, 1.16%.
6,8-Dibromo-3-[(5-oxo-2-phenyl-1,3-oxazol-4-ylidene)methyl]chromon-7-yl acetate (6).
A solution of hippuric acid (0.18 g, 1 mmol) in acetic anhydride (10 mL) containing freshly fused sodium
acetate (0.1 g) was heated under reflux for 1 h. The carboxaldehyde 4 (0.35 g, 1 mmol) was added to the
reaction mixture and further heated for 4 h. After cooling, the reaction mixture was poured onto crushed
ice. The obtained solid was filtered off and crystallized from acetic acid to give compound 6 as yellow
crystals, yield (0.31 g, 58%), mp > 300 °C. IR (KBr, cm-1): 3063 (CHarom), 1782 (C=Ooxazolone), 1718
1
(C=Oacetyl), 1654 (C=O#-pyrone), 1610 (C=N), 1590 (C=C). H-NMR (DMSO-d6): 2.11 (s, 3H, CH3 acetyl),
6.43 (s, 1H, exocyclic CH=C), 7.49-7.67 (m, 4H, Ar-H), 7.89 (s, 1H, H-5chromone), 7.96 (d, 1H, J=7.2 Hz,
Ar-H), 8.32 (s, 1H, H-2chromone). Anal. Calcd for C21H11Br2NO6 (533.13); C, 47.31; H, 2.08; N, 2.63%.
Found: C, 47.15; H, 2.01; N, 2.45%.
6,8-Dibromo-3-[(2,4-dioxo-1,3-thiazolidin-5-ylidine)methyl]chromone (7).
A mixture of carboxaldehyde 4 (0.35 g, 1 mmol) and thiazolidinedione (0.12 g, 1 mmol), in glacial acetic
acid (20 mL) containing freshly fused sodium acetate (0.1 g), was heated under reflux for 1 h. The yellow
crystals obtained after cooling were filtered off and crystallized from acetic acid to give compound 7 as
yellow crystals, yield (0.34 g, 76%), mp > 300 °C. IR (KBr, cm-1): 3455 (OH), 3197 (NH), 3058
1
(CHarom), 1733 (C=Othiazolidine), 1685 (C=Othiazolidine), 1664 (C=O#-pyrone), 1598 (C=C). H-NMR (DMSO-
d6): 7.64 (s, 1H, exocyclic CH=C), 8.18 (s, 1H, H-5chromone), 8.88 (s, 1H, H-2chromone), 12.50 (brs, 1H, NH
exchangeable with D2O). MS (m/z, I%): 449 (M+4, 25), 447 (M+2, 45), 445 (M+, 23), 404 (35), 376
(100), 359 (9), 279 (6), 85 (21). Anal. Calcd for C13H5Br2NO5S (447.06); C, 34.93; H, 1.13; N, 3.13; S,
7.17%. Found: C, 34.39; H, 1.15; N, 3.17; S, 7.07%.
9-(6,8-Dibromo-7-hydroxychromon-3-yl)-3,3,6,6-tetramethyl-1,2,3,4,5,6,7,8-octahydroxanthene-1,8-
dione (8).
A mixture of carboxaldehyde 4 (0.35 g, 1 mmol) and dimedone (0.28 g, 2 mmol) in dry pyridine (10 mL)

HETEROCYCLES, Vol. 87, No. 5, 2013
1083
was heated under reflux for 2 h. The obtained solid after acidification with diluted hydrochloric acid, was
filtered off and crystallized from acetic acid to give compound 8 as white crystals, yield (0.38 g, 64%),
mp > 300 ºC. IR (KBr, cm-1): 3219 (OH), 3087 (CHarom), 2959, 2936, 2871 (CHaliph), 1710, 1670
(2C=Oxanthene), 1660 (C=O#-pyrone), 1616 (C=C). 1H-NMR (DMSO-d6): 0.87 (s, 6H, 2 CH3), 1.02 (s , 6H, 2
CH3), 1.91 (s, 2H, CH2), 2.02 (s, 2H, CH2), 2.08 (s, 2H, CH2), 2.24 (s, 2H, CH2), 4.32 (s, 1H, H-9xanthene),
13
8.03 (s, 1H, H-5chromone), 8.38 (s, 1H, H-2chromone), 11.20 (s, 1H, OH exchangeable with D2O). C-NMR
(DMSO-d6): 25.9 (2CH3), 26.2 (2CH3), 28.7 (2CH2), 29.4 (C-9xanthene), 31.7 (2CMe2), 50.1 (2CH2), 99.7,
109.7, 110.2, 118.5 122.1, 127.3, 152.6, 155.6, 155.7, 164.6, 173.2, 196.1. MS (m/z, I%): 594 (M+4, 13),
592 (M+2, 23), 590 (M+, 12), 508 (43), 319 (5), 294 (3), 291 (4), 266 (11), 257 (24), 251 (8), 238 (8), 236
(8), 217 (18), 201 (9), 171 (13), 157 (12), 111 (85), 109 (71), 95 (86), 91 (37), 64 (100). Anal. Calcd for
C26H24Br2O6 (592.29); C, 52.73; H, 4.08%. Found: C, 52.68; H, 4.05%.
3-(1-Acetyl-1H-indol-3-yl)-7,9-dibromo-2-oxo-2H,5H-pyrano[3,2-c]chromene-5,8-diyl diacetate (9)
A mixture of carboxaldehyde 4 (0.35 g, 1 mmol) and indole-3-acetic acid (0.18 g, 1 mmol), in acetic
anhydride (5 mL) containing freshly fused sodium acetate (0.1 g), was heated under reflux for 3 h. After
cooling, the reaction mixture was poured onto crushed ice. The obtained solid was filtered off and
crystallized from acetic acid to give compound 9 as yellow crystals, yield (0.32 g, 51%), mp > 300 ºC. IR
(KBr, cm-1): 3071 (CHarom), 1780 (C=O!-lactone), 1736 (C=Oacetyl), 1719 (C=Oacetyl), 1645 (C=Oacetyl), 1602
(C=C). 1H-NMR (DMSO-d6): 1.91 (s, 3H, CH3), 2.05 (s, 3H, CH3), 2.73 (s, 3H, CH3), 6.40 (s, 1H, H-5 as
OCHO), 7.39-7.44 (m, 3H, Ar-H), 7.70 (s, 1H, H-10), 8.04 (d, 1H, J= 6.9 Hz, Ar-H), 8.26 (s, 1H, H-
2indole), 8.44 (s, 1H, H-4). MS (m/z, I%): 614 (M-CH3, 6), 569 (7), 544 (5), 524 (8), 396 (20), 321 (33),
294 (46), 278 (10), 264 (32), 185 (53), 171 (53), 121 (90), 113 (10), 91 (11), 65 (20), 57 (100). Anal.
Calcd for C26H17Br2NO8 (631.24); C, 49.47; H, 2.71; N, 2.22%. Found: C, 49.63; H, 2.77; N, 2.39%.
3-[(6,8-Dibromo-7-hydroxychromon-3-yl)methylene]-6-ethyl-6H-pyrano[3,2-c]quinoline-2,4,5-(3H,5H)-
trione (11)
Method A: A mixture of carboxaldehyde 4 (0.35 g, 1 mmol) and 3-(1-ethy1-4-hydroxy-2-oxo-(1H)-
quinolin-3-yl)-3-oxopropanoic acid (10) (0.275 g, 1 mmol), in DMF (5 mL) containing few drops of
piperidine, was heated under reflux for 2 h. After cooling, the reaction mixture was poured onto crushed
ice. The obtained solid was filtered off and crystallized from DMF/H2O to give compound 11 as yellow
crystals, yield (0.38 g, 65%), mp > 300 ºC.
Method B: A mixture of carboxaldehyde 4 (0.35 g, 1 mmol) and 4-hydroxypyrano[3,2-c]quinolin-
2(1H)one (12) (0.257 g, 1 mmol), in glacial acetic acid (10 mL) containing freshly fused sodium acetate
(0.1 g), was heated under reflux for 2 h. After cooling, the reaction mixture was poured onto ice. The
obtained solid was filtered off and crystallized from DMF/H2O to give compound 11 as yellow crystals,
yield (0.41 g, 70%), mp > 300 ºC. IR (KBr, cm-1): 3040 (CHarom), 2974 (CHaliph), 1731 (O-C=O), 1670

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1
(C=Oquinoline and C=Ochromone), 1623 (C=O), 1571 (C=C). H-NMR (DMSO-d6): 1.27 (t, 3H, J= 6.9 Hz,
CH3), 4.38 (q, 2H, J= 6.9 Hz, CH2), 7.54 (t, 1H, Ar-H), 7.72-7.92 (m, 2H, Ar-H), 8.15 (d, 1H, J= 7.8 Hz,
Ar-H), 8.29 (s, 1H, H-5chromone), 8.39 (s, 1H, exocyclic CH), 9.15 (s, 1H, H-2chromone), 13.85 (brs, 1H, OH
exchangeable with D2O). Anal. Calcd for C24H13Br2NO7 (587.18); C, 49.09; H, 2.23; N, 2.39%. Found:
C, 49.51; H, 2.43; N, 2.61%.
5-(3,5-Dibromo-2,4-dihydroxybenzoyl)-2-oxo-2H-1-(pyridin-2-yl)pyridine-3-carbonitrile (13).
A mixture of carboxaldehyde 4 (0.35 g, 1 mmol) and 2-cyano-N-(pyridin-2-yl)acetamide (0.16 g, 1
mmol) in absolute EtOH (20 mL) containing few drops of piperidine was heated under reflux for 2 h. The
obtained solid after cooling was filtered off and crystallized from EtOH to give compound 13 as pale
yellow crystals, yield (0.26 g, 53%), mp > 300 °C. IR (KBr, cm-1): 3292, 3172 (2 OH), 3072 (CHarom),
1
2209 (C%N), 1682 (C=Opyridone), 1637 (C=Obenzoyl), 1621 (C=N), 1595 (C=C). H-NMR (DMSO-d6):
6.77-6.90 (m, 1H, Ar-H), 7.29 (d, 1H, Ar-H), 7.64 (s, 1H, H-6resorcinol), 7.79-7.91 (m, 1H, Ar-H), 8.02 (s,
1H, H-4pyridone), 8.50 (d, 1H, Ar-H), 8.63 (s, 1H, H-6pyridone). Anal. Calcd for C18H9Br2N3O4 (491.09); C,
44.02; H, 1.85; N, 8.56%. Found: C, 44.40; H, 2.26; N, 8.69%.
2-(3,5-Dibromo-2,4-dihydroxybenzoyl)pyrido[1,2-a]benzimidazole-4-carbonitrile (14).
A mixture of carboxaldehyde 4 (0.35 g, 1 mmol) and benzimidazol-2-ylacetonitrile (0.16 g, 1 mmol) in
absolute EtOH (20 mL) containing few drops of piperidine was heated under reflux for 2 h. The obtained
solid after cooling was filtered off and crystallized from DMF/EtOH to give compound 14 as yellow
crystals, yield (0.30 g, 62%), mp > 300 °C. IR (KBr, cm-1): 3417 (2 OH), 3073 (CHarom), 2240 (C%N),
1630 (C=Obenzoyl), 1617 (C=N), 1605 (C=C). 1H-NMR (DMSO-d6): 6.25-6.94 (m, 4H, Ar-H), 7.88 (s, 1H,
H-6resorcinol), 7.97 (s, 1H, H-3pyridine), 8.07 (s, 1H, H-1pyridine), 10.27 (s, 1H, OH exchangeable with D2O),
11.88 (s, 1H, OH exchangeable with D2O). MS (m/z, I%): 489 (M+4, 16), 487 (M+2, 35), 485 (M+, 14),
407 (11), 295 (12), 216 (4), 193 (91), 192 (36), 188 (7), 157 (7), 165 (30), 102 (38), 90 (36), 77 (50), 64
(100). Anal. Calcd for C19H9Br2N3O3 (487.11); C, 46.85; H, 1.86; N, 8.63%. Found: C, 46.67; H, 1.92; N,
8.68%.
6-(3,5-Dibromo-2,4-dihydroxybenzoyl)-1,3-dimethylpyrido[3,2-d]pyrimidine-2,4-(1H,3H)-dione
(15).
A mixture of carboxaldehyde 4 (0.35 g, 1 mmol) and 6-amino-5H-1,3-dimethylpyrimidine-2,4-(1H,3H)-
dione (0.15 g, 1 mmol) in absolute EtOH containing p-toluenesulphonic acid (0.05 g) was heated under
reflux for 3 h. The obtained solid after cooling was filtered off and crystallized from EtOH to give
compound 15 as white crystals, yield (0.28 g, 58%), mp 291-292 ºC. IR (KBr, cm-1): 3343 (2 OH), 3066
1
(CHarom), 2949, 2890 (CHaliph), 1717 (2 C=O), 1656 (C=Obenzoyl), 1607 (C=N), 1601 (C=C). H-NMR
(DMSO-d6): 3.30 (s, 3H, CH3), 3.67 (s, 3H, CH3), 7.63 (s, 1H, H-6resorcinol), 8.53 (s, 1H, H-8), 8.99 (s, 1H,
H-6), 11.98 (brs, 1H, OH exchangeable with D2O). 13C-NMR (DMSO-d6): 28.2 (CH3), 29.5 (CH3), 101.0

HETEROCYCLES, Vol. 87, No. 5, 2013
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(C-2resorcinol), 101.4 (C-6resorcinol), 109.7, 115.7, 127.9, 134.4, 137.3, 150.8, 152.4, 154.1, 157.3, 158.2
(C=O), 160.4 (C=O), 193.4 (C=O). MS (m/z, I%): 487 (M+4, 11), 485 (M+2, 64), 483 (M+, 8), 469 (21),
310 (100), 295 (41), 294 (14), 278 (98), 267 (79), 251 (19), 237 (26), 157 (36), 121 (35), 94 (21), 77 (6),
64 (26). Anal. Calcd for C16H11Br2N3O5 (485.09); C, 39.62; H, 2.29; N, 8.66%. Found: C, 39.47; H, 2.15;
N, 8.38%.
6-(3,5-Dibromo-2,4-dihydroxybenzoyl)-2-thioxo-1,3-dihydroquinazolin-4-one (16).
A mixture of carboxaldehyde 4 (0.35 g, 1 mmol) and 6-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one
(0.14 g, 1 mmol) in DMF (10 mL) containing few drops of piperidine was heated under reflux for 2 h.
The obtained solid after cooling was filtered off and crystallized from DMF to give compound 16 as
yellow crystals, yield (0.26 g, 55%), mp > 300 ºC. IR (KBr, cm-1): 3067 (brs, 2 NH and 2 OH), 1690
1
(C=Oamide), 1609 (C=Obenzoyl), 1557 (C=C), 1259 (C=S). H-NMR (DMSO-d6): 6.25 (brs, 1H, NH
exchangeable with D2O), 7.05 (d, 1H, H-8), 7.95 (s, 1H, H-6resorcinol), 8.07 (d, 1H, H-7), 8.14 (s, 1H, H-
5
quinazoline), 11.80 (brs, NH exchangeable with D2O). MS (m/z, I%): 472 (M+2, 78), 453 (56), 426 (47),
248 (64), 178 (49), 149 (74), 105 (49), 91 (50), 77 (55), 64 (74), 57 (100). Anal. Calcd for
C15H8Br2N2O4S (472.11); C, 38.16; H, 1.71; N, 5.93; S, 6.79%. Found: C, 38.02; H, 1.62; N, 5.91; S,
6.58%.
REFERENCES
1. D. Ekinci, M. Al-Rashida, G. Abbas, M. &entürk, and C. T. Supuran, J. Enzy. Inhibit. Med. Chem.,
2012, 27, 744.
2. A. G. Neo, L. Garrido, J. Díaz, S. Marcaccini, and C. F. Marcos,Synlett, 2012, 23, 2227.
3. M. A. Ibrahim, M. A. Abdel-Hamed, and N. M. El-Gohary, J. Braz. Chem. Soc., 2011, 22, 1130.
4. M. A. Ibrahim, Tetrahedron, 2009, 65, 7687.
5. G. Haas, J. L. Stanton, A. Von Sprecher, and P. Wenk, J. Heterocycl. Chem., 1981, 18, 607.
6. A. Dziewulska-Ku'aczkowska and A. Bartyzel, J. Mol. Struct., 2013, 1033, 67.
7. M. Lácová, H. Stankovcova, A. Bohac, and B. Kotzianova, Tetrahedron, 2008, 64, 9646.
8. J. Quiroga, D. Mejia, B. Insuasty, R. Abonia, K. C. Ghosh, A. Ray, A. Patra, and J. N. Low, J.
Heterocycl. Chem., 2002, 39, 51.
9. C. K. Ghosh, D. K. Sinharoy, and K. K. Mukhopadhyay, J. Chem. Soc., Perkin Trans. 1, 1979, 1964.
10. H. P. Steenackers, J. Levin, J. C. Janssens, B. A. J. De Weerdt, J. Vanderleyden, D. E. De Vos, and S.
C. De Keersmaecker, Bioorg. Med. Chem., 2010, 18, 5224.
11. N. Ando and S. Terashima, Bioorg. Med. Chem. Lett., 2009, 9, 5461.
12. K.-B. Oh, H. B. Jeon, Y.-R. Han, Y.-J. Lee, J. Park, S.-H. Lee, D. Yang, M. Kwon, J. Shin, and H.-S.
Lee, Bioorg. Med. Chem. Lett., 2010, 20, 6644.

1086
HETEROCYCLES, Vol. 87, No. 5, 2013
13. M. A. Ibrahim and K. M. El-Mahdy, Phosphorus, Sulfur, Silicon Relat. Elem., 2009, 184, 2945.
14. T. E. Ali, Eur. J. Med. Chem., 2009, 44, 4385.
15. T. E. Ali and M. A. Ibrahim, J. Braz. Chem. Soc., 2010, 21, 1007.
16. R. Robinson and R. C. Shah, J. Chem. Soc., 1934, 1491.
17. W. Dahse, Ber., 1908, 41, 1619.
18. A. Nohara, T. Umetani, and Y. Sanno, Tetrahedron Lett., 1973, 14, 1995.
19. K. M. Hatzade, V. S. Taile, P. K. Gaidhane, V. D. Umare, A. G. M. Haldar, and N. V. Ingle, Indian J.
Chem., 2009, 48B, 1548.
20. C. K. Ghosh and A. Patra, J. Heterocycl. Chem., 2008, 45, 1529.
21. A. H. Abdel-Rahman, A. M. Khalil, and E. M. Keshk, Chem. Pap., 2000, 54, 324.
22. L. Ková(iková, R. Ga)parová, A. Bohá(, M. *urana, and M. Lácová, ARKIVOC, 2010, xi, 188.
23. M. A. Ibrahim, H. M. Hassanin, Y. Gabr, and Y. A. Alnamer, Eur. J. Chem., 2010, 1, 195.
24. W. T. Gao, W. D. Hou, M. R. Zheng, and L. J. Tang, Synth. Commun., 2010, 40, 732.
25. M. A. Ibrahim, H. M. Hassanin, Y. Gabr, and Y. A. Alnamer, Turk. J. Chem., 2012, 36, 682.
26. O. H. Hishmat, Sh. I. El-Naem, A. A. Magd-El-Din, N. M. Fawzy, and A. S. Abd El-Aal, Egypt J.
Chem., 2000, 43, 87.
27. K. V. Reddy and A. V. S. Rao, Org. Prep. Proced. Int., 1997, 29, 355.
28. S. B. Bharate, T. R. Mahajan, Y. R. Gole, M. Nambiar, T. T. Matan, A. Kulkarni-Almeida, S.
Balachandran, H. Junjappa, A. Balakrishnan, and R. A. Vishwakarma, Bioorg. Med. Chem., 2008, 16,
7167.