Design and synthesis of novel fused heterocycles using 4-chromanone as synthon

Article abstract of DOI:10.1134/S107036321512035X

A new series of heterocyclic systems, including azole, azolopyrimidine, and pyridopyrimidine derivatives, attached to 2H-chromene scaffold, was prepared by a convenient procedure through the reactions of (E)-2-dimethylamino-methylene chromanone with diffe

Full text of DOI:10.1134/S107036321512035X

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 12, pp. 2853–2860. © Pleiades Publishing, Ltd., 2015.
Design and Synthesis of Novel Fused Heterocycles
Using 4-Chromanone as Synthon1
K. A. Alia, N. A. A. Abdelhafeza, E. A. Ragabb, A. A. Ibrahima, and A. E. Amra,c
a Applied Organic Chemistry Department, National Research Centre, Dokki, Giza, 12622 Egypt
b Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
c Pharmaceutical Chemistry Department, College of Pharmacy, Drug Exploration & Development Chair (DEDC),
King Saud University, Riyadh, 11451 Saudi Arabia
e-mail: aeamr1963@yahoo.com
Received August 7, 2015
Abstract—A new series of heterocyclic systems, including azole, azolopyrimidine, and pyridopyrimidine
derivatives, attached to 2H-chromene scaffold, was prepared by a convenient procedure through the reactions
of (E)-2-dimethylamino-methylene chromanone with different nitrogen binucleophiles. Various substituted
chromeno[4,3-b]pyridine derivatives were also prepared through the reactions of (E)-2-dimethylamino-
methylene chromanone with a series of active methylene compounds.
Keywords: 4-chromanone, pyrazole, pyrimidine, pyridine
DOI: 10.1134/S107036321512035X
Enaminone derivatives are highly reactive inter-
mediates and their utility for preparation of important
heterocycles has recently gained considerable interest
[1–3]. On the other hand, chromenes are important
medicinal pharmacophores found in many important
natural products, such as flavonoids, tocopherols, antho-
cyanins, and natural alkaloids [4]. Chromene deriva-
tives also possess interesting biological activities, such
as anti-inflammatory, antivascular, antitumor, anti-
bacterial, antifungal, and antitubercular activity [5–7].
In continuation of our recent studies [8–14] aiming at
the development of new and simple methods for the
synthesis of a variety of biologically important
heterocyclic ring systems, we report herein a facile
route to synthesize various pyrazoles, isoxazoles,
pyrimidines, pyrazolopyrimidines, triazolopyrimidines,
and pyridines as fused with chromene scaffold.
hydrous sodium acetate gave 4H-chromeno[4,3-c]-
isoxazole (3), rather than the isomeric form 4. The H
1
NMR spectrum of the compound 3 has signal of
isoxazole H3 protons at 8.33 ppm. The formation of the
isomeric product 4 was excluded, because the
isoxazole H5 protons resonate at downfield around δ
9.30 ppm [17, 18]. Enaminone 2 was reacted with aryl-
hydrazines in glacial acetic acid under reflux tempera-
ture to give 1,4-dihydro-1-aryll chromeno[4,3-c]pyra-
zole (5a, 5b). The 1H NMR spectrum of compound 5a
has signal at 7.55 ppm, a characteristic of pyrazole H3.
The treatment of enaminone 2 with 4-aminobenzene-
sulfonamide under reflux condition yielded (E)-4-[4-
oxo-2H-chromen-3(4H-ylidene)methyl-amino]benzene-
sulfonamide (6) (Scheme 1).
The treatment of enaminone 2 with 4H-1,2,4-triazol-
3-amine 7 or 2-amino benzimidazole 9 in refluxing
glacial acetic acid always gave a single product, which
was identified as 6H-chromeno[3,4-e][1,2,4]triazolo-
[1,5-a]pyrimidine (10) and (E)-3-[(1H-benzo[d]imi-
dazol-2-ylamino)methylene]-2,3-dihydrochromen-4-one
(E)-2-Dimethylamino methylenechromanone 2,
assignable as E-configuration [15], was prepared by
the reaction of chroman-4-one (1) with dimethylform-
amide dimethyl acetal (DMF–DMA) in refluxing dry
toluene [16]. The treatment of enaminone 2 with
hydroxylamine hydrochloride in the presence of an-
1
(12) respectively. H NMR spectrum of the compound
10 has signals at 8.59 and 8.63 ppm, a characteristic of
triazole-H and pyrimidine-H, respectively, signals at
5.36 ppm, and multiplet signals at δ = 7.07–7.89 ppm,
which are due to CH2 and phenyl protons, respectively.
The reaction of aminotriazole 7 with enaminone 2 is
1 The text was submitted by the authors in English.
2853

2854
ALI et al.
Scheme 1. Synthetic pathway for the formation of compounds 3, 5a, 5b, and 6.
N
O
O
3
NH2OH
O
O
O
CH3COONa
EtOH/reflux
N
O
1
4
Ar
N
N
DMF−DMA
Dry toluene
reflux
ArNHNH2
AcOH/reflux
O
O
5a, 5b
N
O
O
2
NH2
O
S
S
O
H2N
NH2
O
O
N
H
EtOH/reflux
O
6
Ar =Ph (a), Ar = 2,4-(NO2)2C6H3 (b).
assumed to proceed via the initial Michael addition of
the exo-amino group of the amine to the enamine
double bond. The resulting product is a nonisolable
intermediate 8, which undergoes the intramolecular
oxidative cyclization with the elimination of the di-
methyl amine and water molecules to give a compound
10. The reaction of enaminone 2 with 2-aminobenz-
imidazole was sterically hindered at the stage of
formation of a compound 12 (Scheme 2).
intermediate 15, which undergoes intramolecular
oxidative cyclization and aromatization via the loss of
both dimethylamine and water molecules to yield a
compound 16 (Scheme 2).
2(E)-2-dimethylaminomethylenechromanone 2 was
reacted with 6-amino-2 thioxopyrimidin-4-one 20 in
boiling acetic acid. The progress of the reaction was
monitored by thin-layer chromatography (TLC), which
showed that after 6 h the conversion of the starting
material was complete. 1H NMR spectrum of the crude
mixture gave good evidence for the presence of two
products, 21 and 22, which were isolated by several
The treatment of enaminone 2 with 5-amino-3-
phenyl-1H-pyrazole 14 and 4-(aryldiazo)-1H-pyrazole-
3,5-diamine 17a, 17b in refluxing acetic acid gives the
condensed pyrazolopyridine and pyrazolopyrimidine
derivatives, compounds 16 and 19a, 19b, respectively.
The reaction of enaminone 2 with 5-amino-1H-
pyrazole 14 is assumed to proceed via the initial C-
nucleophilic addition of pyrazole-CH in 14 to the
enamine double bond in 2 to form a nonisolable
1
crystallizations (Scheme 3). H NMR spectrum of
compound 21 has signals at 12.5 and 13.1 ppm, a
characteristic of 2NH (pyrimidine NH) and singlet
signal of the pyridine-4H proton at 8.18 ppm, which is
in agreement with the structure 21 [18]. 1,3-Diketones,
β-keto esters, and β-ketonitriles are compounds of
special interest in organic synthesis. They may be used
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DESIGN AND SYNTHESIS OF NOVEL FUSED HETEROCYCLES
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Scheme 2. Synthetic pathway for the formation of compounds 10, 12, 16, 19a, 19b.
N
N
N
N
N
N
N
N
N
O
O
HN
N
OH
N
H
H
−H2O
−HNMe2
NMe2
O
O
8
10
9
N
N
AcOH
reflux
NH2
N
H
7
H
N
O
N
N
NH2
N
N
11
N
N
O
N
2
−H2O
H
H
AcOH
reflux
O
12
−HNMe2
13
Ph
NH2
N
N
N
HN
H
O
−HNMe2
−H2O
Ph
NMe2
14
N
NH2
AcOH
reflux
O
NH
Ph
N
O
15
16
N
N
Ar
H2N
N
Ar
Ar
H2N
N
N
N
NH2
N
N
H
N
−HNMe2
−H2O
NH2
O
17
N
O
N
HN
NMe2
N
AcOH
reflux
N
H
O
18
Ar =Ph (a), Ar = p-Cl–Ph (b).
19a, 19b
for the preparation of biologically active ingredients as
multi-functional building blocks and for the formation
of fused pyridines as key reagents [19].
Treatment of enaminone 2 with acetyl acetone,
ethyl acetoacetate, and ethyl benzoyl acetate in glacial
acetic acid in the presence of ammonium acetate gives
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ALI et al.
Scheme 3. Synthetic pathway for the formation of compounds 21, 22, 24–26.
O
S
NH
O
HN
NH
H2N
N
H
20
S
O
O
NH
N
O
N
N
H
S
AcOH/reflux
H
+
O
22
CH3
COCH3
21
O
O
N
23
AcOH/CH3COONH4
2
O
24
CH3
COOEt
N
O
O
O
O
AcOH/CH3COONH4
25
Ph
COOEt
N
O
O
O
Ph
O
AcOH/CH3COONH4
26
chromeno[4,3-b]pyridine derivatives 24–26, respec-
tively (Scheme 3). The 1H NMR spectra have signals at
8.31, 8.27, and 8.21 ppm, a characteristic of the pyridine-
4H protons of compounds 24–26, respectively.
EXPERIMENTAL
The melting points were measured on an Electro
thermal IA 9000 series digital melting point apparatus.
The IR spectra of samples (discs pressed with
potassium bromide) were recorded on a Pye Unicam
SP 3300 and a Shimadzu FT IR 8101 PC infrared
spectrophotometers. The 1H NMR spectra were
measured on a Varian Mercury VXR-500 MHz
spectrometer. Chemical shifts δ are given in ppm
downfield from tetramethylsilane (TMS) used as
Finally, 2-(4-chlorophenyl)-5H-chromeno[4,3-b]pyridine-
3-carbonitrile (30) and 2,5-dihydro-2-oxo-1H-chro-
meno[4,3-b]pyridine-3-carbonitrile (31) were formed
by the reaction of enaminone 2 with benzoyl aceto-
nitrile derivative 29 and ethyl 2-cyanoacetate, respec-
tively (Scheme 4).
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DESIGN AND SYNTHESIS OF NOVEL FUSED HETEROCYCLES
2857
Scheme 4. Synthetic pathway for the formation of compounds 30 and 31.
CH3
O
CH3
OH
O
−HNMe2
−H2O
COR
CH3COONH4
COR
O
NMe2
O
28
CH3
COR
27
N
O
O
O
H3C
R
24, 25
O
Ar
CN
CN
Ar
N
29
2
AcOH/CH3COONH4
O
30
O
O
NC
CN
O
HN
AcOH/CH3COONH4
O
31
Ar = Ph/4-Cl.
1
13
internal standard. H NMR (500 MHz) and C NMR
(125 MHz) spectra were run in deuterated chloroform
(CDCl3) or dimethylsulphoxide (DMSO-d6). Mass
spectra were recorded on a Shimadzu GCMS-QP1000
EX mass spectrometer at 70 eV. Elemental analysis
was carried out at the Microanalytical Centre of the
Cairo University, Giza, Egypt. All reactions were
monitored by thin-layer chromatography (Silica gel,
Aluminum Sheets 60 F254, Merck). Compounds 14
[20], 17 [21], 19 [22], and 20 [23] were prepared
according to the literature procedures.
formamide dimethylacetal (DMF–DMA) (1.33 mL,
10 mmol) in toluene (20 mL) was refluxed for 10 h.
After cooling, the solvent was evaporated under
reduced pressure and the obtained product was ground
with ether into the powder to form the solid product 2
in the form of pale yellow crystals. An analytically
pure sample was obtained by crystallization with
EtOH. Yield (1.61 g, 85%), mp: 138–139°C [15]. IR
1
spectrum, ν, cm–1: 1680 (C=O). H NMR spectrum
(CDCl3), δ, ppm: 3.16 s (6H, 2CH3), 5.62 s (2H, CH2),
6.9 d, 7.95 d (2H, ArH) 7.45 s (1H, CH=C), 7.03 t,
7.37 t (2H, ArH). 13C NMR spectrum (CDCl3), δ, ppm:
43.85, 66.95, 99.62, 116.590, 121.36, 123.79, 127.43,
133.68, 148.27, 160.30, 181.83. Mass spectrum: m/z
203 (40%). Calculated, %: C 70.92; H 6.45; N 6.89.
Synthesis of (E)-3-[(dimethylamino)methylene]-
2,3-dihydrochromen-4-one (2). A mixture of 2,3-di-
hydrochromen-4-one (1) (1.49 g, 10 mmol) and dimethyl-
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ALI et al.
C12H13NO2. Found, %: C 70.85; H 6.57; N 6.80. M
203.24.
Synthesis of (E)-3-[(4-aminophenylsulfonamido-
amino)methylene]chroman-4-one (6). To a solution
of enaminone 2 (0.2 g, 1 mmol) in EtOH (10 mL), p-
amino benzene sulfonamide (0.17 g, 1 mmol) was
added. The reaction mixture was heated under reflux
for 8 h. The solvent was distilled off under reduced
pressure and the residual brown solid was recrys-
tallized from ethanol to form a compound 6. Yield
(0.28g, 84%); pale yellow crystals (EtOH), mp 270–
272°C. IR spectrum, ν, cm–1: 3360, 3161 (NH, NH2),
Preparation of 4H-chromeno[4,3-c]isoxazole (3).
To a mixture of the enaminone 2 (0.2 g, 1 mmol) and
hydroxylamine hydrochloride (0.07g, 1 mmol) in
EtOH (10 mL) anhydrous sodium acetate (0.82 g,
1 mmol) was added. The reaction mixture was refluxed
for 5 h, cooled, and then diluted with water (30 mL).
The formed precipitate was collected by filtration,
washed with water, dried, and recrystallized from
EtOH to give 4H-chromeno[4,3-c]isoxazole (com-
pound 3). Yield (0.11 g, 64%); white ppt (EtOH), mp
1
1644 (C=O). H NMR spectrum (DMSO-d6), δ, ppm:
4.15 s (2H, CH2), 6.72 s (2H, NH2-SO2, D2O-ex-
changeable), 6.68–7.82 m (8H, ArH) 8.09 d (1H, CH-
enamine), 8.5 d (1H, NH, D2O-exchangeable). 13C NMR
spectrum (DMSO-d6), δ, ppm: 40.35, 111.68, 112.91,
118.92, 121.09, 123.25, 125.41, 127.83, 131.10, 134.71,
151.34, 154.91, 156.42, 176.83. Mass spectrum: m/z
330 (15%). Calculated, %: C 58.17; H 4.27; N 8.48.
C16H14N2O4S. Found, %: C 58.25; H 4.33; N 8.41. M
330.36.
1
130–131°C. H NMR spectrum (DMSO-d6), δ, ppm:
5.6 s (2H, CH2), 7.48–8.0 m (4H, ArH), 8.33 s (1H,
CH-isoxazole). 13C NMR spectrum (DMSO-d6), δ,
ppm: 67.11, 93.53, 116.73, 116.96, 121.64, 124.07,
128.58, 145.97, 157.40, 157.51. Mass spectrum: m/z
173 (5%). Calculated, %: C 69.36; H 4.07; N 8.09.
C10H7NO2.Found, %: C 69.25; H 4.22; N 8.19. M 173.17.
Synthesis of 1,4-dihydro-1-(arylchromeno[4,3-c]-
pyrazole (5a, 5b). To a solution of the enaminone 2
(0.2 g, 1 mmol) in glacial acetic acid (10 mL), the
appropriate aryl hydrazine (1 mmol) was added. The
reaction mixture was heated under reflux for 4–6 h,
cooled, and poured into an ice-cold solution of sodium
bicarbonate. The separated solid was filtered off,
repeatedly washed with water, dried, and recrystallized
from EtOH to give the corresponding pyrazole
derivative 5a, 5b.
Synthesis of compounds 10, 12, 16, and 19a, 19b
(general procedure). A mixture of enaminone 2 (0.2 g,
1 mmol) and the appropriate heterocyclic amines 7, 9,
14, or 17 (1 mmol) in glacial acetic acid (20 mL) was
heated under reflux for several hours (the reactions
were followed up by TLC). After cooling, the reaction
mixture was poured into ice cold water and neutralized
with sodium bicarbonate. The solid product was
collected by filtration, thoroughly washed with water,
dried, and finally recrystallized from EtOH into
compounds 10, 12, 16, and 19a, 19b, respectively.
1,4-Dihydro-1-phenylchromeno[4,3-c]pyrazole (5a).
Yield (0.18 g, 72%); pale yellow crystals (EtOH), mp
6H-Chromeno[3,4-e][1,3,4]triazolo[1,5-a]pyri-
midine (10). Yield (0.17 g, 75%); pale yellow crystals
(EtOH), mp 195–197°C. H NMR spectrum (CDCl3),
δ, ppm: 5.36 s (2H, CH2), 7.07–7.89 ( m, 4H, ArH),
8.59 s (1H, tiazole-H) and 8.63 s (1H, pyrimidine-H).
13C NMR spectrum (CDCl3), δ, ppm: 64.72, 112.28,
114.83, 117.64, 122.69, 129.58, 134.71. 138.35, 150.36,
156.20, 156.36. 157.45. Mass spectrum: m/z 224 (15%).
Calculated, %: C 64.28; H 3.60; N 24.99. C12H8N4O.
Found, %: C 64.15; H 3.48; N 24.85. M 224.22.
1
1
140–142°C. H NMR spectrum (CDCl3), δ, ppm: H
NMR spectrum, δ, ppm: 5.28 s (2H, CH2), 6.75–7.14
m (4H, ArH) 7.48–7.52 m (5H, ArH), 7.55 s (1H, CH-
pyrazole). 13C NMR spectrum (CDCl3), δ, ppm: 61.28,
114.63, 116.22, 117.74, 121.44, 122.65, 125.39, 128.81,
129.38, 129.52, 133.71, 134.83, 140.34, 153.90. Mass
spectrum: m/z 248 (100%). Calculated, %: C 77.40; H
4.87; N 11.28. C16H12N2O. Found, %: C 77.57; H 4.95;
N 11.35. M 248.28.
1
1,4-Dihydro-1-(2,4-dinitro-phenyl)chromeno-
(E)-3-[(1H-Benzo[d]imidazol-2-ylamino)methylene]-
2,3-dihydrochromen-4-one (12). Yield (0.19 g, 69%);
yellow crystals (EtOH), mp: 245–248°C. H NMR
[4,3-c]pyrazole (5b). Yield (0.25 g, 75%); pale yellow
1
1
crystals (EtOH), mp 161–162°C. H NMR spectrum
(DMSO-d6), δ, ppm: 5.5 s (2H, CH2), 7.17–7.60 m
(4H, Ar-H), 7.86 s (1H, CH-pyrazole), 7.87 d, 8.54 d
(2H, ArH), 9.33 s (1H, Ar-H). Mass spectrum: m/z 338
(100%). Calculated, %: C 56.81; H 2.98; N 16.56.
C16H10N4O5. Found, %: C 56.74; H 2.89; N 16.48. M
338.27.
spectrum (DMSO-d6), δ, ppm: 4.97 s (2H, CH2), 5.24 s
(1H, CH-enamine), 6.9–7.75 m (8H, ArH), 9.87 s (1H,
NH-enamine), 10.37 s (1H, benzimidazole NH). 13C
NMR spectrum (DMSO-d6), δH, ppm: 66.56, 109.58,
117.28, 119.35, 121.31, 121.53, 122.43, 126.76, 127.12,
129.54, 131.49, 133.76, 142.34, 145.0, 148.69, 155.13,
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DESIGN AND SYNTHESIS OF NOVEL FUSED HETEROCYCLES
2859
192.34. Mass spectrum: m/z 291 (10%). Calculated, %:
C 70.09; H 4.50; N 14.42. C17H13N3O2. Found, %: C
70.19; H 4.62; N 14.32. M 291.3.
trum (DMSO-d6), δ, ppm: 5.25 s (2H, CH2), 7.07–7.43
m (4H, ArH), 8.18 s (1H, pyridine-4H). 12.52 s, 13.1 s
(2H, 2NH). 13C NMR spectrum (DMSO-d6), δ, ppm:
63.45, 111.10, 115.8, 117.33, 121.51, 126.11, 128.12,
131.22, 147.8, 150.11, 152.91, 158.31, 162.01. 172.12.
Mass spectrum: m/z 283 (100%). Calculated, %: C
59.35; H 3.20; N 14.83. C14H9N3O2S. Found, %: C
59.55; H 3.45; N 14.67. M 283.31.
8-Phenyl-5H-chromeno[4,3-b]pyrazolo[4,3-e]-
pyridine (16). Yield (0.23 g, 79 %); yellow crystals
1
(EtOH), mp 170–172°C. H NMR spectrum (CDCl3),
δ, ppm: 5.26 s (2H, CH2), 7.05–7.53 m (9H, ArH),
13
8.07 s (1H, pyridine-4H), 9.52 s (1H, NH). C NMR
spectrum (CDCl3), δ, ppm: 65.04, 93.62, 110.38, 117.26,
122.27, 126.64, 128.79, 130.24, 132.85, 133.41, 135.88,
145.06, 149.06, 151.42, 156.10, 157.38. Mass spectrum:
m/z 299 (95%). Calculated, %: C 76.24; H 4.38; N 14.04.
C19H13N3O. Found, %: C 76.32; H 4.31; N 14.14. M
299.33.
6-{(E)-[4-Oxo-2H-chromen-3(4H)-ylidene]methyl-
amino}-2,3-dihydro-2-thioxopyrimidin-4(1H)-one
(22). Yield (0.1 g, 33%); yellow crystals (EtOH), mp
179–181°C. IR spectrum, ν, cm–1: 3302–3121 (2NH),
1
1685 (C=O). H NMR spectrum (DMSO-d6), δ, ppm:
4.21 s (1H, NH-enamine), 5.33 s (2H, CH2), 6.51 s
(1H, CH-enamine), 7.11–7.45 m (4H, ArH), 8.11 s
(1H, pyrimidiene-H), 8.8 br.s, 11.51 br.s (2H,
pyrimidiene-2NH). 13C NMR spectrum (DMSO-d6), δ,
ppm: 61.21. 72.10, 113.81, 118.11, 121.11, 122.46,
129.81, 132.58, 134.41, 159.11, 161.32, 166.52, 173.21,
184.21. Mass spectrum: m/z 301 (75%). Calculated, %:
C 55.80; H 3.68; N 13.95. C14H11N3O3S. Found, %: C
55.89; H 3.73; N 13.85. M 301.32.
2-Amino-1-(2-phenyldiazenyl)-5H-chromeno-
[4,3-e]pyrazolo[1,5-a]pyrimidine (19a). Yield (0.23 g,
67%); orange crystals (EtOH), mp 260–262°C. 1H NMR
spectrum (DMSO-d6), δ, ppm: 5.37 s (2H, CH2), 7.16–
7.83 m (9H, ArH), 8.52 s (1H, pyrimidine-H). 13C
NMR spectrum (DMSO-d6), δ, ppm: 64.98, 113.01,
114.66, 115.65, 117.98, 121.63, 122.32, 129.04, 129.59,
130.4, 134.61, 135.16, 146.95, 148.48, 152.47, 153.46,
158.04. Mass spectrum: m/z 342 (100%). Calculated,
%: C 66.66; H 4.12; N 24.55. C19H14N6O. Found, %: C
66.72; H 4.17; N 24.59. M 342.35.
Synthesis of compounds 24–26, 30, and 31 (general
procedure). To a mixture of compound 2 (0.2 g, 1 mmol)
and ammonium acetate (0.2 g) in glacial acetic acid
(10 mL), acetyl acetone, ethyl acetoacetate, ethyl benzoyl
acetate, benzoyl acetonitrile 29 or ethyl cyanoacetate
(1 mmol) was added. The reaction mixture was heated
under reflux for several hours and then poured into a
cold solution of sodium bicarbonate. The reaction
progress was monitored by TLC. The formed solid
products were collected by filtration, washed with
water, dried, and recrystallized from the proper solvent
to give the pyridine derivatives 24–26, 30, and 31,
respectively.
2-Amino-1-[2-(4-chlorophenyl)diazenyl]-5H-chro-
meno[4,3-e]pyrazolo[1,5-a]pyrimidine (19b). Yield
(0.30 g, 79 %); orange crystals (EtOH), mp: 290–292°C.
1H NMR spectrum (DMSO-d6), δ, ppm: 5.08 s (2H,
CH2), 6.98–7.85 m (8H, ArH), 8.15 s (1H, pyrimidine-
H). Mass spectrum: m/z 376 (100%). Calculated, %: C
60.56; H 3.48; N 22.30. C19H13ClN6O. Found, %: C
60.42; H 3.35; N 22.27. M 376.80.
Synthesis of compounds 21, 22. To a solution of 2
(0.2 g, 1 mmol) in acetic acid (10 mL) 6-amino-thio-
uracil 20 (0.143 g, 1 mmol) was added. The reaction
mixture was heated under reflux for 6 h, then con-
centrated and cooled to room temperature. The solid
part was collected by filtration, thoroughly washed
with EtOH, and crystallized with EtOH/dioxane into
the cyclic product 21. The liquid part was evaporated
under reduced pressure and the resulting solid was then
recrystallized with methanol to give 6-{(E)-[4-oxo-2H-
chromen-3(4H)-ylidene]methylamino}-2,3-dihydro-2-
thioxopyrimidin-4(1H)-one (22).
1-(2-Methyl-5H-chromeno[4,3-b]pyridin-3-yl)-
ethanone (24). Yield (0.18 g, 75%); colorless crystal
(EtOH), mp 115–117°C; IR spectrum, ν, cm–1: 1685
1
(C=O). H NMR spectrum (CDCl3), δ, ppm: 2.64 s,
2.84 s (6H, 2CH3), 5.4 s (2H, CH2), 6.99–7.74 m (4H,
ArH), 8.31 s (1H, CH-pyridine). 13C NMR spectrum
(CDCl3), δ, ppm: 25.23, 29.36, 67.51, 117.11, 122.44,
122.51, 122.79, 125.34, 131.93, 132.27, 133.23, 150.01,
156.59, 158.52, 199.47. Mass spectrum: m/z 239 (100%).
Calculated, %: C 75.30; H 5.48; N 5.85. C15H13NO2.
Found, %: C 75.43; H 5.55; N 5.77. M 239.27.
1,2,3,4,7-Pentahydro-3-thioxo-chromeno[4',3':4,5]-
pyrido[2,3-d]pyrimidine-1-one (21). Yield (0.13 g, 45%);
orange crystals (EtOH), mp 210–212°C. IR spectrum,
ν, cm–1: 3325–3120 (NH), 1680 (C=O). 1H NMR spec-
Ethyl 2-methyl-5H-chromeno[4,3-b]pyridine-3-car-
boxylate (25). Yield (0.19 g, 70%); colorless crystal
(EtOH), mp: 110–112°C. IR spectrum, ν, cm–1: 1721
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2860
ALI et al.
(C=O). 1H NMR spectrum (CDCl3), δ, ppm: 1.42 t (J =
8 Hz, 3H, CH3), 2.91 s (3H, CH3), 4.42 q (J = 8 Hz,
2H, CH2), 5.2 s (2H, CH2), 6.97–7.97 m (4H, ArH),
8.33 s (1H, CH-pyridine). 13C NMR spectrum (CDCl3),
δ, ppm: 14.32, 25.14, 61.21, 67.45, 117.19, 122.42,
122.46, 122.90, 123.78, 125.35, 132.19, 134.54, 150.34,
157.02, 160.03, 166.35. Mass spectrum: m/z 269 (100%).
Calculated, %: C 71.36; H 5.61; N 5.20. C16H15NO3.
Found, %: C 71.43; H 5.52; N 5.32. M 269.30.
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Ethyl 2-phenyl-5H-chromeno[4,3-b]pyridine-3-
carboxylate (26). Yield (0.24 g, 72%); colorless
crystals (EtOH), mp 130–132°C. IR spectrum, ν, cm–1:
1721 (C=O). 1H NMR spectrum (CDCl3), δ, ppm: 2.09
t (J = 8 Hz, 3H, CH3), 4.81 q (J = 8 Hz, 2H, CH2), 5.12
s (2H, CH2), 7.09–7.81 m (9H, ArH), 8.21 s (1H, CH-
13
pyridine). C NMR spectrum (CDCl3), δ, ppm: 21.22,
56.47, 61.15, 81.011, 116.11, 121, 122.46, 123.78,
126.41, 128.6, 128.8, 129.12, 132.32, 134.54, 136.51,
151.34, 157.02, 160.12, 166.35. Mass spectrum: m/z
331 (25%). Calculated, %: C 76.12; H 5.17; N 4.23.
C21H17NO3. Found, %: C 76.23; H 5.28; N 4.32. M
331.36.
2-(4-Chlorophenyl)-5H-chromeno[4,3-b]pyridine-
3-carbonitrile (30). Yield (0.21 g, 74%); orange
crystals (EtOH–dioxane), mp 225–227°C. IR spec-
trum, ν, cm–1: 2212 (CN). 1H NMR spectrum (CDCl3),
δ, ppm: 5.22 s (2H, CH2), 7.01–7.57 m (9H, ArH),
8.06 s (1H, CH-pyridine). Mass spectrum: m/z 318
(100%). Calculated, %: C 71.59; H 3.48, N,7.79.
C19H11ClN2O. Found, %: C 71.35; H 3.32; N 7.65. M
318.76.
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Org. Prep. Proced. Int., 2001, 33, 351.
2,5-Dihydro-2-oxo-1H-chromeno[4,3-b]pyridine-
3-carbonitrile (31). Yield (0.17 g, 75%); orange
crystals (EtOH–dioxane), mp 172–175°C. IR spec-
trum, ν, cm–1: 3320 (NH), 1650 (C=O). 1H NMR spec-
trum (CDCl3), δ, ppm: 5.07 s (2H, CH2), 6.93 m (4H,
ArH), 8.38 s (1H, CH-pyridine), 10.01 d (1H, NH,
D2O-exchangeable). 13C NMR spectrum (CDCl3), δH,
ppm: 56.47, 81.01, 111.21, 116.11, 121, 122.46, 123.78,
129.12, 132.32, 13454, 151.34, 157.02, 166.35. Mass
spectrum: m/z 224 (100%). Calculated, %: C 69.64; H
3.60; N 12.49. C13H8N2O2. Found, %: C 69.52; H 3.68;
N 12.44. M 224.21.
ACKNOWLEDGMENTS
The project was financially supported by King Saud
University, Vice Deanship of Research Chairs.
23. Youssif, S., El-Bahaie, S., and Nabih, E., Bull. Korean
Chem. Soc., 2003, vol. 24, p. 1429.
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