Synthesis of some new azole, azepine, pyridine, and pyrimidine derivatives using 6-hydroxy-4H-4-oxo[1]-benzopyran-3-carboxaldehyde as a versatile starting material

Article abstract of DOI:10.1002/hc.20048

Condensation of 3-formyl chromone 1 with hydroxylamine hydrochloride afforded the corresponding oxime 2 that was converted to nitrile 3. Refluxing of oxime 2 and/or nitrile 3 with aceturic or hippuric acid gave 16 and 17. Treatment of 1 with semicarbazide hydrochloride and thiosemicarbazide afforded the corresponding carbazones 5-6 that underwent cyclization with ethyl bromoacetate and/or chloroacetone yielding 7-8. Also 1 reacted with acyclic active methylene reagents, e.g. malononitrile, ethyl cyanoacetate, and ethyl acetoacetate to form compounds 11, 12, and 13. Reaction of 1 with bifunctional reagents, e.g. benzil, o-phenylenediamine, o-aminophenol, and o-aminothiophenol yielding the corresponding imidazolyl bezopyranone and azepine derivatives 14-20. Condensation of 1 with acyclic or heterocyclic compounds containing active methylene group, e.g. hippuric acid forming the condensed products 21-27.

Full text of DOI:10.1002/hc.20048

Heteroatom Chemistry
Volume 16, Number 1, 2005
S
ynthesis of Some New Azole, Azepine,
Pyridine, and Pyrimidine Derivatives Using
6
-Hydroxy-4H-4-oxo[1]-benzopyran-3-
carboxaldehyde as a Versatile Starting Material
A. H. Abdel-Rahman, M. A. A. Hammouda, and S. I. El-Desoky
Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt
Received 2 February 2004
[
1,2] in addition to their widespread occurrence in
ABSTRACT: Condensation of 3-formyl chromone 1
with hydroxylamine hydrochloride afforded the cor-
responding oxime 2 that was converted to nitrile
plants. These compounds possess coronary vasodi-
lating activity [3–5]. Recently, benzopyran deriva-
tives are shown to possess desirable altering ac-
tivity, for example, decreasing the atherogenic
VLDL + LDL cholesterol fraction and elevating an-
tiatherogenic HDL cholesterol fraction [6–11]. Also,
benzopyran derivatives produced crosslinks in pho-
toreaction with DNA [12]. Thus, the high pharmaco-
logical interest of the above derivatives prompted us
to synthesize some new heterocyclic compounds of
possible biological activity.
3
. Refluxing of oxime 2 and/or nitrile 3 with ace-
turic or hippuric acid gave 16 and 17. Treatment
of 1 with semicarbazide hydrochloride and thiosemi-
carbazide afforded the corresponding carbazones 5–6
that underwent cyclization with ethyl bromoacetate
and/or chloroacetone yielding 7–8. Also 1 reacted with
acyclic active methylene reagents, e.g. malononitrile,
ethyl cyanoacetate, and ethyl acetoacetate to form
compounds 11, 12, and 13. Reaction of 1 with bi-
functional reagents, e.g. benzil, o-phenylenediamine,
o-aminophenol, and o-aminothiophenol yielding the
corresponding imidazolyl bezopyranone and azepine
derivatives 14–20. Condensation of 1 with acyclic
or heterocyclic compounds containing active methy-
lene group, e.g. hippuric acid forming the con-
densed products 21–27. ꢀC 2005 Wiley Periodicals,
RESULTS AND DISCUSSION
The versatile starting compound, 6-hydroxy-4H-4-
oxo[l]benzopyran-3-carboxaldehyde (1) [13] was ob-
tained in good yield from Vilsmeier–Haack formy-
lation of 2,5-dihydroxy acetophenone. Compound 1
was condensed with hydroxylamine hydrochloride
in ethanol to give a quantitative yield of the corre-
sponding oxime 2 that was refluxed in acetic anhy-
dride to give 6-acetoxy-4H-4-oxo[1]-benzopyran-3-
carbonitrile (3). The infrared spectrum of 3 showed
clearly disappearance of the imino absorption band
Inc. Heteroatom Chem 16:20–27, 2005; Published online
in Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.20048
INTRODUCTION
−
1
−1
at ꢀ 1630 cm instead of new bands at ꢀ = 2237 cm
It is well known that benzopyran derivatives are
an important class of chemotherapeutic compounds
−
1
for cyano group and 1759 cm for acetoxy group.
Acid deformylation of 1 using concentrated sul-
furic acid afforded 6-hydroxy-4H[1]benzopyran-4-
one (4) that showed in its infrared spectrum the char-
acteristic keto chromone group at ꢀ = 1625 cm
Correspondence to: A. H. Abdel-Rahman; e-mail: arahman@
hotmail.com.
−
1
ꢀ
c 2005 Wiley Periodicals, Inc.
2
0

Synthesis of Some New Azole, Azepine, Pyridine, and Pyrimidine Derivatives 21
−
1
only, while the formyl peak at ꢀ = 1697 cm was
Ghosh et al. [16]. So the reaction of 1 with mal-
ononitrile or ethyl cyanoacetate in the presence
of ammonium acetate afforded 2-amino-3-cyano-5-
disappeared. Although refluxing of 1 with semicar-
bazide hydrochloride or thiosemicarbazide in alco-
hol, the corresponding carbazones 5 and 6 were ob-
tained in good yield. The infrared spectra of 5 and
were in agreement with the assigned structures.
Compound 5 revealed absorption bands at ꢀ = 3345,
223, 3173 cm for (OH, NH, and NH groups),
while the amide and chromone carbonyl groups were
ꢁ
ꢁ
(2 ,5 -dihydroxybenzoyl)pyridine (11) and 3-cyano-
ꢁ
ꢁ
5-(2 ,5 -dihydroxybenzoyl)-2-pyridone (12) respec-
tively (Scheme 1). The assigned structures of 11 and
12 were confirmed by spectral data in addition to
the correct elemental analysis; their infrared spec-
tra revealed a characteristic absorption band at ꢀ
6
−
1
3
2
−1
−1
appeared at 1699 and 1626 cm respectively.
The thiazole derivatives are well known as potent
2227 cm for a cyano group in addition to the hy-
1
droxyl and amino absorption bands. H NMR spectra
and selective human adenosine A
3
receptor antago-
of 11 and 12 showed the amino and hydroxyl signals
at 7.8, 9.2, and 9.6 ppm in addition to the aromatic
protons.
nists [14,15], therefore the reaction of the thiosemi-
carbazone 6 with ethyl bromoacetate or chloroace-
tone in the presence of sodium acetate afforded the
thiazole derivatives 7 and 8. The mass spectra of
Also, a mixture of 1 with ethyl acetoacetate (two
moles) in the presence of ammonium acetate was re-
+
ꢁ
ꢁ
the latter products gave molecular ion peaks [M ] at
fluxed in ethanol, diethyl-2 ,5 -dihydroxy-4-methyl-
benzophenone-3,5-dicarboxylate (13) was obtained.
The reaction involved an initial condensation be-
tween aldehydic group and the active methylene
group of ethyl acetoacetate to form the expected
arylidene product followed by the Michael addition
of another molecule of ethyl acetoacetate and sub-
sequent opening of the ꢁ-pyrone moiety then rear-
rangement to form the end product 13, as outlined
in Scheme 2.
m/z = 303 and 301 respectively which were in agree-
ment with their molecular weights.
Also, it was reported that the imidazole deriva-
tives possessed high biological importance in the
field of pharmaceutical chemistry as antimicrobials,
antitumor, antiarrhythemic, anti-inflammatory,
and antiulcer [17–19]. In light of these reports,
compounds having a combination of benzopyra-
none and imidazole moieties can be expected to
exhibit marked medicinal properties. Thus, reflux-
ing of 1 with benzil or o-phenylenediamine in glacial
On treatment of 1 with hydrazine hydrate or
phenylhydrazine (molar ratio 1:1) in ethanol, the
corresponding pyrazole derivatives 9 and 10 were
obtained in good yields. The reaction of aldehyde
function of 1 with active nitriles to furnish the cor-
responding pyridine derivatives was reported by
SCHEME 1

2
2 Abdel-Rahman, Hammouda, and El-Desoky
SCHEME 2
acetic acid and ammonium acetate, the corre-
sponding imidazolyl benzopyranone derivatives 14
and 15 were obtained. Their structure assignment
was based on the basis of the correct analytical
analyses of 16 and 17 in addition to their spec-
tral data were compatible with the proposed struc-
tures. Their infrared spectra revealed disappearance
of the cyano absorption band, whereas the signals at
1
−1
and spectral data; compound 14 showed in its H
ꢀ = 1752 and 1655 cm attributable to CH
3
COO and
1
NMR spectrum besides the aromatic protons, two
broad NH and OH signals at δ 9.5 and 11.5 ppm
respectively (Scheme 3).
Synthesis of fused benzopyranopyridine deriva-
tives that were used as potential antiarthritic agents
was reported in the literature [20].
Therefore, oxime 2 or nitrile 3 was reacted with
aceturic or hippuric acid in acetic anhydride, 7-
acetoxy-2-methyl (or 2-phenyl)-4H[1]benzopyrano-
C O (chromone) appeared. Also, H NMR spectrum
of compound 16 showed two singlet peaks at δ = 1.8
and 2.2 ppm for two methyl groups in addition to
multiplet aromatic protons at δ = 7.6–7.8 ppm.
Compounds containing diazepine moiety are re-
cently used as NNRTI-resistant HIV [21]. 3-Formyl
(or cyano) benzopyran-4-one contains three poten-
tial sites of nucleophilic attack: C-2, C-4, and 3-
formyl (or cyano) group, thus condensation of a suit-
able reactant at two of these sites afforded new ring
system. Aniline having a nucleophilic function H X
[3,2-e]-oxazolo[5,4-b]pyridin-5-one 16 and 17 were
obtained, respectively (Scheme 3). The elemental
SCHEME 3

Synthesis of Some New Azole, Azepine, Pyridine, and Pyrimidine Derivatives 23
(
X = NH, O, S) at its ortho position reacts easily
pyridines 16–17 and benzopyranoazepines 18–20
respectively. Compound 1 was also condensed
with several nitrogen acyclic and cyclic compounds,
e.g. hippuric acid, 1-phenyl-3-methyl-5-pyrazolone,
ethyl-2-cyano-2-(3-phenyl-5-oxo1,3-thiazolan-2-
ylidene)acetate, N-phenyl rhodanine, 4-aminoanti-
pyrine, barbituric acid, and thiobarbituric acid to
form compounds 21–27 with expected high biologi-
cal activity.
with 1 to give the corresponding azepine derivatives
1
1
8–20. The H NMR spectrum of 18 showed signals
at δ = 6.7–7.4 (m, 7H, Ar-H), 8.5 (br, s, 1H, NH), 8.6
(
s, 1H, 12-H), and 14.3 ppm (s, 1H, OH).
The Knoevenagel reaction of 3-formyl chro-
mones with heterocyclic compounds containing
active methylene group has been reported as a
synthetic route for the preparation of a wide variety
of heterocycles [22]. The reaction of 1 with acyclic
or heterocyclic compounds such as hippuric acid, 1-
phenyl-3-methyl-5-pyrazolone, ethyl-2-cyano-2-
EXPERIMENTAL
(
3-phenyl-5-oxo-1,3-thiazolan-2-ylidene)acetate,
Melting points were determined on a Gallenkamp
apparatus and uncorrected. Elemental analysis was
carried out in the Microanalytical Unit, National
Research Centre, Dokki, Giza, Cairo. Infrared spec-
tra were recorded on Matheson 5000 FTIR spectrom-
N-phenyl rhodanine, 4-aminoantipyrine, barbituric
acid, and thiobarbituric acid formed the correspond-
ing arylidene compounds 21–27. The structures of
the latter products could be directly deduced from
the good elemental analyses as well as their spectral
data (Scheme 4).
1
eter using KBr wafer technique. H NMR spectra
were determined on Varian-Gemini 200 MHz and
Jeol-Ex-270 MHz NMR spectrometer using TMS as
an internal standard with (chemical shift δ = 0 ppm).
Mass spectra were determined on AGC-MS. QP-
1000 Ex. Schimadzu (Japan). The purity of the syn-
thesized compounds was tested by thin-layer chro-
matography (TLC).
CONCLUSION
Hydrazines and active nitriles reacted with 6-
hydroxy-3-formyl chromone 1 through addition
followed by pyran ring opening affording dihydroxy-
benzoyl derivatives 9–12. Compound 1 was used
as a starting material to synthesize new chromone
derivatives containing heterocyclic rings fused
onto a chromone moiety. Compound 1 was reacted
with N-substituted glycine and o-aniline derivatives
to produce the corresponding benzopyranoxazolo-
Synthesis of 6-Hydroxy-4H-4-oxo[1]benzopyran-
3-carboxaldehyde (1)
To a stirred solution of 2,5-dihydroxyacetophenone
(1.52 g, 10 mmol) in dimethyl-formamide (20 mL),
SCHEME 4

2
4 Abdel-Rahman, Hammouda, and El-Desoky
phosphorous oxychloride (10 mL) was added drop-
(DMSO): δ = 6.3 (d, 1H, 3-H), 7.2–7.6 (m, 3H, Ar-H),
◦
wise at −5 C during about 10 min. The mixture
7.8 (d, 1H, 2-H), and 11.8 ppm (s, 1H, OH). Anal.
was stirred at room temperature for 13 h and de-
composed by ice water. The resulting precipitate
was collected by filteration, washed with water, and
recrystallized from ethyl acetate to afford 1 as
Calcd for C
9
H
6
3
O (162.14): C, 66.67; H, 3.73. Found:
C, 66.46; H, 3.50%.
◦
orange crystals, mp 234–236 C; yield (61%). IR
Condensation of 6-Hydroxy-3-formylchromone
with Semicarbazide Hydrochloride and
Thiosemicarbazide. Synthesis of Compounds 5
and 6
−
1
(
ꢀ /cm ) = 3450–3200 (br, OH bonded), 3370 (free
OH), 1697 (CHO), 1630 (CO chromone), and
593 cm (Ar.). Anal. Calcd for C10
−
1
1
H
6
4
O (190.15):
C, 63.16; H, 3.18. Found: C, 62.95; H, 3.00%.
General Method: A mixture of compound 1 (0.38 g,
2
2
mmol) and semicarbazide hydrochloride (0.22 g,
mmol) or (thiosemicarbazide) (0.18 g, 2 mmol) in
Synthesis of 6-Hydroxy-3-hydroxyiminomethyl-
4
H-4-oxo[1]benzopyran (2)
To a well-stirred solution of compound 1 (0.68 g,
mmol) in ethanol (30 mL), hydroxylamine hy-
ethanol (15 mL) was refluxed for 1 h. The precipitate
that was formed filtered off, dried, and recrystallized
from acetone to give 5 and 6.
4
Compound 5 was obtained as faint brown crys-
drochloride (0.139 g, 4 mmol) was added. The solu-
tion was stirred vigorously for 1 h. The solid obtained
was filtered off, washed with water, dried, and re-
crystallized from ethanol to give 2 as beige crystals,
◦
−1
tals, mp 260–262 C; yield (87%). IR (ꢀ /cm ) = 3600–
3
100 (bonded OH), 3445, 3223-3173 (OH free, NH
−
1
1
and NH
2
), 1690 (CONH ), and 1626 cm (CO). H
2
◦
−1
NMR (DMSO): δ = 6.7–7.6 (m, 5H, Ar-H and NH ),
mp 225 C, yield (95%). IR (ꢀ /cm ) = 3450–3000 (br,
OH), 3203 ( N OH free), 1630 (CO), and 1597 cm
Ar.). Anal. Calcd for C10 NO (205.17): C, 58.54; H,
.44; N, 6.83. Found: C, 57.99; H, 2.97; N, 6.45%.
2
−
1
7.9 (s, 1H, olefinic CH), 8.5 (s, 1H, 2-H), 9.0 (s,
1
H,NH), and 14.2 ppm (s, 1H, OH). Anal. Calcd
(247.21): C, 53.45; H, 3.67; N, 16.99.
(
3
H
7
4
for C11
H
9
N
3
O
4
Found: C, 53.40; H, 3.60; N, 17.15%.
Compound 6 was obtained as brown crystals, mp
Synthesis of 6-Hydroxy-4H-4-oxo[1]benzopyran-
-carbonitrile (3)
◦
−1
2
2
56–258 C; yield (90%). IR (ꢀ /cm ) = 3460, 3200–
120, 3100 (OH, NH , NH) and l646 cm (CO). H
),
3
−1
1
2
NMR (DMSO): δ = 6.6–7.6 (m, 5H, Ar-H and NH
2
A solution of compound 2 (0.41 g, 2 mmol) in acetic
◦
7.8 (s, 1H, olefinic CH), 8.4 (s, 1H, 2-H), 8.8 (s, 1H,
NH), and 14.1 ppm (s, 1H, OH). Anal. Calcd for
anhydride (10 mL) was heated at 100 C for 2 h.
The precipitate formed after cooling was filtered off,
washed with hot water, dried, and recrystallized from
ethyl acetate to give compound 3 as brown crystals,
C
11
H
9
N
3
3
O S (263.27): C, 50.18; H, 3.45; N, 15.96.
Found: C, 50.59; H, 3.86; N, 16.01%.
◦
−1
mp 164–165 C; yield (95%). IR (ꢀ /cm ) = 2237 (CN),
759 (CH COO), 1665 (C O), and 1616 cm (Ar.). H
NMR (DMSO): δ = 2.2 (s, 3H, CH ), 7.5–7.7 (m, 3H,
Ar-H), 8.5 ppm (s, 1H, 2-H). Anal. Calcd for C12 NO
223.41): C, 62.89; H, 3.08; N, 6,11. Found: C, 62.39;
H, 2.50; N, 5.75%.
−1
1
1
3
Synthesis of 2-{2-[-1-(6-Hydroxy-4-oxo-4H-3-
chromenyl)methylidene]-hydrazono}-1,3-
thiazolan-4-one (7)
3
H
7
4
(
A solution of compound 6 (0.52 g, 2 mmol), ethyl bro-
moacetate (0.41 g, 2.5 mmol), and anhydrous sodium
acetate (0.5 g) in ethanol (50 mL) was refluxed for
h. The precipitate that formed was filtered off,
washed with water, dried, and recrystallized from
Synthesis of 6-Hydroxy-4H-4-oxo[1]benzopyran
4)
1
(
A suspension of compound 1 (0.34 g, 2 mmol) in
sulfuric acid (3N 10 mL) was refluxed for 2 h. The
reaction mixture was allowed to cool and extracted
with ethyl acetate (4 × 50 mL). The organic ex-
ethanol/DMSO (2: 1) to give compound 7 as red crys-
◦
−1
tals, mp 270–272 C; yield (85%). IR (ꢀ /cm ) = 3600–
3400 (OH bonded), 3443 (OH free), 3140 (NH), 1702
−
1
1
(CONH), 1628 (CO), and 1610 cm (C N). H NMR
), 6.7–7.8 (m, 4H, Ar-
tract was washed with saturated aqueous NaHCO
3
(DMSO): δ = 4.1 (s, 2H, CH
2
followed by water several times, dried (MgSO
4
),
H, and NH), 8.0 (s, 1H, olefinic CH), 8.4 (s, 1H, 2-
+
and evaporated. The resulting residue was digested
with petroleum ether and recrystallized from ethanol
to give 4 as faint yellowish brown crystals, mp
H), and 9.5 ppm (s, 1H, OH). MS: m/z = 303 (M ,
56%), 261 (27%), 188 (100%), 136 (45%), 92 (12%),
52 (37%). Anal. Calcd for C13
H
9
N
3
4
O S (303.29): C,
◦
−1
1
1
82 C; yield (60%). IR (ꢀ /cm ) = 3500–2950 (OH),
625 (CO chromone), and 1571 cm (Ar.). H NMR
51.48; H, 2.99; N, 13.85. Found: C, 51.01; H, 3.87; N,
13.27%.
−1
1

Synthesis of Some New Azole, Azepine, Pyridine, and Pyrimidine Derivatives 25
Synthesis of 2-{2-[1-(6-Hydroxy-4-oxo-4H-3-
chromenyl)methylidene]hydrazono}-4-methyl-
,3-thiazolane (8)
mixture poured on crushed ice and the solid was
separated, filtered off, dried, and recrystallized from
◦
1
ethanol to give (11) as red crystals, mp 238–240 C;
−
1
yield (50%). IR (ꢀ /cm ) = 3450–3100 (br, OH), 3380,
A mixture of compound 6 (0.52 g, 2 mmol),
chloroacetone (0.3 g, 2 mmol), and sodium acetate
−
ꢁ
1
3
(
332 (NH ), 2227 (CN), 1679 (CO), and 1639 cm
2
1
ꢁ
ꢁ
C N). H NMR (DMSO): δ = 6.8–7.0 (m, 3H, 3 ,4 , 6 -
(0.5 g) in ethanol (20 mL) was refluxed for 1 h. The
H), 7.8 (s, 2H, NH
(
(
6
1
2
), 8.2 (d, 1H, C-4 pyridine-H), 8.5
d, 1H, C-6 pyridine-H), 9.2 (s, 1H, OH), and 9.6 ppm
s, 1H, OH). Anal. Calcd for C13 (255.23): C,
1.18; H, 3.55; N, 16.46. Found: C, 61.51; H, 3.37; N,
5.83%.
precipitate that was formed filtered off, washed with
water, dried, and recrystallized from ethanol/acetone
H
9
N
3
O
3
(
1:1) to give compound 8 as pale yellow crystals,
◦
−1
mp 250–252 C; yield (90%). IR (ꢀ /cm ) = 3450–
−
1
3
150 (OH), 3283 (NH), 1639 (CO), and 1624 cm
1
(
(
C N). H NMR (DMSO): δ = 2.4 (s, 3H, CH
3
), 6.5
ꢁ
ꢁ
Synthesis of 3-Cyano-5-[2 ,5 -dihydroxybenzoyl]-
-pyridone (12)
s, 1H, C-5 thiazole-H), 6.8–7.6 (m, 4H, Ar-H, and
2
NH), 8.1 (s, 1H, olefinic CH), 8.4 (s, 1H, 2-H), and
+
1
1
0.2 ppm (s, 1H, OH). MS: m/z = 301 (M , 55%),
A mixture of 1 (0.38 g, 2 mmol), ethyl cyanoacetate
(0.23 g, 2 mmol), and ammonium acetate (1.5 g) was
refluxed in glacial acetic acid (15 mL) for 5 h. After
cooling, the reaction mixture was poured on crushed
ice, the solid that separated was filtered off, dried
88 (18%), 166 (100%), 136 (40%), 114 (20%), 71
(14%). Anal. Calcd for C14
H
11
N
3
SO
3
(301.32): C,
55.80; H, 3.68; N, 13.95. Found: C, 55.88; H, 3.40;
N, 13.59%.
and recrystallized from acetone to give compound
◦
(
12) as yellow crystals, mp 220–222 C; yield (48%).
ꢁ
ꢁ
Synthesis of 4-(2 ,5 -Dihydroxybenzoyl)pyrazole
−1
IR (ꢀ /cm ) = 3450–3100 (br OH), 2227 (CN), 1692
ꢁ
ꢁ
and 2-Phenyl-4-(2 ,5 -dihydroxybenzoyl)-
pyrazole (9 and 10)
−1
1
(
6
CO), and 1666 cm (CO). H NMR (DMSO): δ =
ꢁ
ꢁ
.7–7.0 (m, 3H, 3 ,4 , 6‘-H), 8.1 (d, 1H, C-4 pyridine-
General Method: A mixture of compound 1 (0.38 g,
H), 8.4 (d, 1H, C-6 pyridine-H), 9.2 (s, 1H, OH),
and 9.6 ppm (s, 1H, OH). Anal. Calcd for C13
2
mmol) and hydrazine hydrate (0.09 mL, 2 mmol)
H
7
N
2
O
4
or phenylhydrazine (0.22 g, 2 mmol) in absolute
ethanol (30 mL) was refluxed for 3 h. The solvent was
concentrated to 10 mL, diluted with water, and left
to cool. The solid that was formed filtered off, dried,
and recrystallized from light petroleum ether/diethyl
ether (1:3) to give (9 and 10).
(255.21): C, 61.18; H, 2.76; N, 10.98. Found: C, 60.93;
H, 2.40; N, 11.01%.
ꢁ
ꢁ
Synthesis of Diethyl-2 ,5 -dihydroxy-4-methyl
benzophenone-3,5-dicarboxylate (13)
A mixture of compound 1 (0.38 g, 2 mmol), ethyl ace-
toacetate (0.51 g, 4 mmol), and ammonium acetate
Compound 9 was obtained as beige crystals, mp
◦
−1
above 300 C; yield (70%). IR (ꢀ /cm ) = 3400–3200
(2 g) was refluxed in ethanol (20 mL) for 4 h. After
−1
1
(
OH), 3119 (NH), and 1628 cm (CO). H NMR
cooling, the reaction mixture was poured on crushed
ice. The solid that was formed filtered off, dried,
and recrystallized from acetone to give compound 13
(
8
DMSO): δ = 7.0–7.4 (m, 5H, Ar-H), 8.1 (s, 1H, OH),
.4 (s, 1H, OH), and 9.3 ppm (s, 1H, NH). Anal. Calcd
for C10
H
8
N
2
3
O (204.18): C, 58.82; H, 3.95; N, 13.72.
◦
as colorless crystals, mp 140–142 C; yield (40%). IR
Found: C, 58.50; H, 3.85; N, 13.40%.
−
1
(
ꢀ /cm ) = 3500–3250 (br OH), 1722 (CO ester), 1694
CO), and 1600 cm (Ar). H NMR(CDCl
): δ = 1.20
), 2.88 (s, 3H, CH ), 3.9 and
), 6.1 (s, 2H, 2,6-H), 6.8–7.0 (m, 3H,
,4 , 6 -H), 7.8 (s, 1H, OH), and 8.2 ppm (s, 1H, OH).
(372.37): C, 64.51; H, 5.41.
Found: C, 64.13; H, 5.50%.
Compound 10 was obtained as yellow needles,
−
1
1
(
3
◦
−1
mp 188–190 C; yield (65%). IR (ꢀ /cm ) = 3362, 3300
OH), and 1630 cm (CO). H NMR(CDCl
): δ = 7.0–
.10 (m, 10H, Ar-H), 8.2 (s, 1H, OH), and 8.5 ppm
s, 1H, OH). Anal. Calcd for C16 (280.28): C,
and 1.40 (2t, 6H, 2CH
3
3
−1
1
(
7
(
3
4
3
.5 (2q, 4H, 2CH
2
ꢁ
ꢁ
ꢁ
H
12
N
2
O
3
Anal. Calcd for C20
H
20
O
7
6
9
8.56; H, 4.32; N, 9.90. Found: C, 68.09; H, 4.88; N,
.33%.
ꢁ
ꢁ
ꢁ
Synthesis of 6-Hydroxy-3-[4 ,5 -diphenyl-2 -
ꢁ
ꢁ
Synthesis of 2-Amino-3-cyano-5-[2 ,5 -dihydroxy
benzoyl]pyridine (11)
imidazolyl]-4H[l]benzopyran-4-one (14)
A mixture of 3-formyl derivative 1 (0.34 g, 2 mmol),
benzil (0.42 g, 2 mmol), and ammonium acetate (1 g)
was refluxed in glacial acetic acid (15 mL) for 2 h. The
precipitate that was formed filtered off, washed sev-
eral times with water, dried, and recrystallized from
A mixture of compound 1 (0.38 g, 2 mmol), malonon-
itrile (0.13 g, 2 mmol), and ammonium acetate (1.5 g)
was refluxed in either glacial acetic acid (15 mL) or
ethanol (15 mL) for 8 h. After cooling, the reaction

2
6 Abdel-Rahman, Hammouda, and El-Desoky
◦
ethanol to give 14 as yellow crystals, mp 220–222 C;
Synthesis of 9-Hydroxy-11H-11-
oxo[1]benzopyrano[2,3-b][1,5]benzo-diazepine,
Oxazepine and Thiazepine (18–20)
−1
yield (75%). IR (ꢀ /cm ) = 3500–3100 (OH), 3075
−1
1
(
NH), 1630 (CO), and 1593 cm (C N). H NMR
CDCl
): δ = 7.0–7.4 (m, 13H, Ar-H), 8.8 (s, 1H, 2-H),
.5 (br, s, 1H, NH), and 11.5 ppm (s, 1H, OH). Anal.
Calcd for C24 (380.40): C, 75.78; H, 4.24; N,
.36. Found: C, 75.58; H, 3.84; N, 7.06%.
(
3
General Method:
A
mixture of compound
1
9
(0.34 g, 2 mmol) and o-phenylenediamine (0.22 g,
H
16
N
2
O
3
2
mmol,) or o-aminophenol, (0.22 g, 2 mmol) or
7
o-aminothiophenol (0.25 g, 2 mmol) was refluxed in
absolute ethanol (30 mL) for 3 h. The precipitate
that was formed filtered off, dried, and recrystallized
from the suitable solvent to give 18–20.
ꢁ
Synthesis of 6-Hydroxy-3-[2 -benzimidazolyl]-
H[1]benzopyran-4-one (15)
4
Compound 18 was obtained as pale yellow
◦
A mixture of compound 1 (0.34 g, 2 mmol) and o-
phenylenediamine (0.22 g, 2 mmol) was refluxed in
glacial acetic acid (15 mL) for 2 h. Dilution of the
reaction mixture with crushed ice gave a precipi-
tate that was formed, filtered off, washed with water,
dried, and recrystallized from ethanol to give 15 as
crystals, mp 280–282 C (DMSO); yield (80%). IR
−
1
(ꢀ /cm ) = 3600–3100 (br, OH, and NH), 1655 (CO),
−
1
1
1620 (C N), and 1567 cm (Ar.). H NMR(DMSO):
δ = 6.7–7.4 (m, 7H, Ar-H), 8.5 (s, 1H, NH), 8.6 (s,
1H, 12-H), and 14.3 ppm (s, 1H, OH). Anal. Calcd
for C H N O (278.26): C, 69.06; H, 3.62; N, 10.07.
1
6
10
2
3
◦
colorless crystals, mp above 300 C; yield (70%). IR
Found: C, 68.80; H, 3.32; N, 9,88%.
−
1
(
ꢀ /cm ) = 3400–3200 (OH), 3147 (NH), 1639 (CO),
and 1610 cm (C N). H NMR (CDCl
): δ = 6.9–7.3
m, 7H, Ar-H), 8.6 (s, 1H, 2-H), 9.0 (br, s, 1H, NH),
and 11.4 ppm (s, 1H, OH). Anal. Calcd for C16
278.26): C, 69.06; H, 3.62; N, 10.06. Found: C, 68.70;
Compound 19 was obtained as orange crystals,
−
1
1
◦
−1
3
mp above 300 C (THF); yield (77%). IR (ꢀ /cm ) =
(
3500–3150 (br, OH), 1642 (CO), 1602 (C N), and
−
1
1
H
10
N
2
O
3
1580 cm (Ar). H NMR (DMSO): δ = 6.8–7.5 (m,
7H, Ar-H), 8.8 (s, 1H, 12-H), and 14.5 ppm (s, 1H,
OH). Anal. Calcd for C H NO (279.25): C, 68.82; H,
(
H, 3.22; N, 9.86%.
1
6
9
4
3
.25; N, 5.02. Found: C, 68.52; H, 3.00; N, 4.78%.
Compound 20 was obtained as yellow crys-
◦
Synthesis of 7-Acetoxy-2-methyl
tals, mp 280–282 C (ethyl acetate); yield (73%).
−
1
(
[
or 2-phenyl)-4H[l]benzopyran[3,2-e]oxazolo-
5,4-b]-pyridin-5-one (16 and 17)
IR (ꢀ /cm ) = 3500–3200 (OH), 1625 (CO), and
1589. cm (C N). H NMR (DMSO): δ = 6.6–7.3
m, 7H, Ar-H), 8.6 (s, 1H, 12-H), and 14.0 ppm (s,
−
1
1
(
General Method: A mixture of compound 3 (0.37 g,
1
6
4
H, OH). Anal. Calcd for C16
H
9
NO S (295.31): C,
3
2
2
mmol) was refluxed with N-acetyl glycine (0.23 g,
mmol) or N-benzoyl glycine (0.36 g, 2 mmol) in
5.07; H, 3.07; N, 4.74. Found: C, 64.70; H, 2.85; N,
.30%.
the presence of anhydrous sodium acetate (0.5 g)
in acetic anhydride (15 mL) for 2 h. The precipi-
tate was formed, filtered off, washed with water then
hot water–ethanol, dried, and recrystallized from
ethanol-DMSO (2: 1) to give 16 and 17.
Condensation of 1 with Hippuric Acid,
-Phenyl-3-methyl-5-pyrazolone, Ethyl
-cyano-2-[5-oxo-3-phenyl-1.3-thiazolan-2-
ylidene]acetate, N-phenyl rhodanine, 4-Amino-
antipyrine, Barbituric and Thiobarbituric Acids:
Syntheses of Compounds 21–27
1
2
Compound 16 was obtained as beige crystals,
◦
−1
mp above 300 C; yield (75%). IR (ꢀ /cm ) = 1753
−
1
(
(
3
1
6
8
CO ester), 1659 (CO), 1630 (C N), and 1592 cm
1
Ar.). H NMR (DMSO): δ = 1.8 (s, 3H, CH
3
), 2.2 (s,
), 7.6–7.8 (m, 3H, Ar-H), and 8.8 ppm (s,
H, 4-H). Anal. Calcd for C16 (311.26): C,
H, CH
3
General Method: A mixture of 3-formy1 chromone
derivative 1 (0.38 g, 2 mmol), the appropriate ac-
tive methylene derivative (2 mmol), and anhydrous
sodium acetate (0.2 g) in glacial acetic acid (15 mL)
was refluxed for 2 h. The precipitate that was formed,
filtered off, washed with hot water several times,
dried, and recrystallized from the suitable solvent to
give 21–27.
H
10
N
2
O
5
1.94; H, 3.25; N, 9.03. Found: C, 61.57; H, 2.90; N,
.55%.
Compound 17 was obtained as red crystals, mp
◦
−1
above 300 C; yield (80%). IR (ꢀ /cm ) = 1752 (CO
−
1
ester), 1655 (CO), and 1633 (C N) cm . MS: m/z =
+
3
29 (M -acetyl, 20%), 286 (32%), 244 (100%). Anal.
◦
Calcd for C21
.52. Found: C, 67.45; H, 3.19; N, 8.03%.
N.B. The compounds (16 and 17) were prepared
by applying the above procedure when the oxime 2
0.41 g, 2 mmol) was used instead of the nitrile 3.
H
12
N
2
O
5
(372.33): C, 67.74; H, 3.25; N,
Compound 21 as yellow crystals, mp 268–270 C
−
1
7
(ethanol); yield (90%). IR (ꢀ /cm ) = 1796 (CO es-
ter), 1763 (CO oxazolone), 1650 (CO chromone), and
−
1
1
1601 cm (C C). H NMR (DMSO): δ = 2.3 (s, 3H,
CH ), 7.4–8.3 (m, 9H, Ar-H, and C-2 pyranone-H),
(
3

Synthesis of Some New Azole, Azepine, Pyridine, and Pyrimidine Derivatives 27
and 9.8 ppm (s, 1H, olefinic C-H). Anal. Calcd for
(375.33): C, 67.20; H, 3.49; N, 3.73. Found:
10.5 (s, 1H, OH), and 11.4 ppm (s, 1H, NH). Anal.
Calcd for C14 S (316.29): C, 53.16; H, 2.55; N,
C
21
H
13NO
6
H
8
N
2
O
5
C, 67.44; H, 3.54; N, 3.53%.
8.86. Found: C, 52.90; H, 2.13; N, 8.53%.
Compound 22 as reddish yellow crystals, mp
◦
−1
−
above 320 C (ethyl acetate); yield (95%). IR (ꢀ /cm )
REFERENCES
1
=
3550–3200 (OH), 1682 (CONPh), and 1628 cm
1
[
1] Degen, S. J.; Mueller, K. L.; Shen, H. C.; Mulder, J.
A.; Golding, G. M.; Wei, L. L., Zificsak, C. A.; Neeno-
Eckwall, A.; Hsung, R. P. Bioorg Med Chem Lett 1999,
(
CO). H NMR (DMSO): δ = 2.3 (s, 3H, CH
3
), 7.1–
7
.9 (m, 9H, Ar-H, and C-2 pyranone-H), 10.3 (s,1H
,
3
olefinic C H), and 10.5 ppm (s, 1H, OH). MS: m/z =
9
, 973.
+
46 (M , 100%), 318 (49%), 301 (33%), 289 (28%),
[
[
[
[
[
2] Fawzy, N. M.; Swelam, S. A.; Batran, S. A. Bol Chim
Farm 2004, 143, 24.
3] Kandil, A.; Baraka, Y.M.; Bekemeier, H. J Drug Res
1
82 (24%), 77 (16%). Anal. Calcd for C20
346.34): C, 69.36; H, 4.07; N, 8.09. Found: C, 69.00;
H, 3.67; N, 7.88%.
H
14
N
2
O
4
(
1
977, 9, 195.
4] Oguro, K.; Hashimoto, K. Jpn J Pharmacol 1974, 24,
27.
Compound 23 as yellow crystals, mp above
2
◦
−1
3
00 C (ethanol); yield (95%). IR (ꢀ /cm ) = 3500,
5] Oguro, K.; Kubota, K.; Kimura, T.; Hashimoto, K. Jpn
J Pharmacol 1973, 23, 459.
6] (a) Stevens, T. J.; Schurr, P. E.; Gammill, R. B.; Day,
C. E. Atherosclerosis 1985, 56, 313; (b) Stevens, T. J.
Chem Abstr 1986, 104, 534.
3
150 (br OH), 2212 (CN), 1728 (CO ester), 1692 (CO
−
1
thiazole), 1626 (CO chromone), and 1596 cm (Ar.).
1
H NMR (DMSO): δ = 1.3 (t, 3H, CH
CH ), 7.5–9.00 (m, 10H, Ar-H), and 10.3 ppm. (s, 1H,
OH). Anal. Calcd for C24 S (446.45): C, 64.57;
3
), 4.2 (q, 2H,
2
[
[
[
7] Stevens, T. J.; Jones, B. W.; Vidmar, T. J.; Moran, J. J.;
Manni, D. S.; Day, C. E. Arzneim-Forsch 1985, 35(8),
1257.
8] (a) Stevens, T. J.; Vidmar, T. J.; Day, C. E.
Atherosclerosis 1985, 56, 301; (b) Stevens, T. J. Chem
Abstr 1986, 104, 533.
H
16NO
6
H, 3.61; N, 3.14. Found: C, 64.27; H, 3.20; N, 3.00%.
◦
Compound 24 as yellow crystals, mp 320 C
−1
(
ethanol); yield (95%). IR (ꢀ /cm ) = 3500–3200
−1
(
OH), 1704 (CONPh), 1628 (CO), and 1586 cm (Ar).
9] Yamashita, A.; Toy, A.; Scahill, T. A. J Org Chem 1989,
1
H NMR (DMSO): δ = 7.0–7.9 (m, 9H, Ar-H, and C-2
5
4, 3625.
pyranone-H), 9.5 (s, 1H, olefinic C H), and 10. 1 ppm
[10] El-Naser, H.; Abdel-Ghaffar, E.; Mahmoud, S. S.
Arzeneim-Forsch 1992, 42, 140.
(
s, 1H, OH). Anal. Calcd for C19
H
11NO
4
S
2
(381.42): C,
9.83; H, 2.91; N, 3.67. Found: C, 59.63; H, 2.69; N,
.37%.
Compound 25 as beige powder, mp 310–312 C
[
11] Gammill, R. B.; Hyde, R. H. J Org Chem 1983, 48,
863.
5
3
3
[
12] (a) Martelli, P.; Bovalini, L.; Ferri, S.; Franchi, G. G.;
Bari, M. FEBS Lett 1985, 189, 255; (b) Martelli, P.
Chem Abstr 1985, 103, 174715.
◦
−
−
1
(
(
(
ethanol); yield (95%). IR (ꢀ /cm ) = 3500–2950
OH), 1720 (CONPh), and 1642 cm (CO). H NMR
DMSO): δ = 2.5 (s, 3H, CH ), 3.1 (s, 3H, CH ), 7.1–
.9 (m, 9H, Ar-H, and C-2 pyranone-H), 8.1 (s, 1H,
CH N) and 10.5 ppm (s, 1H, OH). Anal. Calcd for
(376.39): C, 67,01; H, 4.82; N, 11.16.
l
1
[
[
13] El-Shaaer, H. M. Chem Pap 1996, 50(6), 349.
14] Jung, K.-Y.; Kim, S.-K.; Gao, Z.-G.; Gross, A. S;
Melman, N.; Jacoloson, K. A.; Kim, Y.-C. Bioorg Med
Chem 2004, 12, 613.
3
3
7
[
[
[
[
15] Phiel, C. J.; Wilson, C. A; Lee, V. M. and Klein, P. S.
Nature 2003, 423, 435.
16] Ghosh, C. K.; Ray, A.; Patra, A. J Heterocycl Chem
C
21
H
18
N
3
O
4
Found: C, 66.83; H, 4.50; N, 11.00%.
2
001, 38, 1459.
Compound 26 as yellow crystals, mp above
17] Varoli, L.; Burnelli, S.; Garuti, L.; Guarnieri, A.; Rossi,
M. Pharmazie 1997, 52, 578.
18] Wang, Y.; Stevens, M. F. G. J Org Chem 1997, 62, 7288.
◦
−1
3
00 C (ethanol); yield (95%). IR (ꢀ /cm ) = 3346,
−
1
3
(
202, 3073 (OH, 2NH), 1700 (CON), and 1675 cm
1
CO chromone). H NMR (DMSO): δ = 7.0–7.8 (m,
H, Ar-H, and C-2 pyranone-H), 9.2 (s, 1H, olefinic
C-H), 9.8–10.0 (br, s, 2H, 2NH), and 10.5 ppm (s,
H, OH). Anal. Calcd for C14
6.01; H, 2.69; N, 9.33. Found: C, 56.40; H, 2.80;
[19] He, H.; Yang, J.; Wu, B.; Robinson, D.; Sprankle, K.;
Kung, P.-P.; Lowery, K.; Mohan, V.; Hofstadler, S.;
Swayze, E.; Giffery, R. Bioorg Med Chem Lett 2004,
4
1
4, 695.
1
H
8
N
2
O
6
(300.22): C,
[
20] Kubo, K.; Ukawa, K.; Kuzuna, S.; Nohara, A. Chem
5
Pharm Bull 1986, 34, 1108.
N, 9.50%.
Compound 27 as faint green crystals, mp 280–
[21] Yoakim, C.; Bonneau, P. R.; Ziel, R. D.; Doyon, L.;
Duan, J.; Guse, I.; Landry, S.; Malenfant, E.; Naud,
J.; Ogilvie, W. W; Meara, J. A. O.; Plante, R.; Si-
moneau, B.; Thavonekham, B.; Bos, M.; Cordingley,
M. G. Bioorg Med Chem Lett 2004, 14, 739.
◦
−1
2
82 C (ethanol); yield (90%). IR (ꢀ /cm ) = 3351,
−
1
3
133, 3061 (OH, 2NH) and 1685, 1646 cm (CO).
1
H NMR (DMSO): δ = 7.2–7.8 (m, 4H, Ar-H, and C-2
[
22] Lacova, M.; Gasparova, R.; Loos, D.; Liptay, T.;
pyranone-H), 9.5 (s, 1H, olefinic C H), 9.5 (s, H, NH),
Pronayova, N. Molecules 2000, 5 , 167.