Facile and convenient synthesis of pyrimidine, 4H-3,1-benzoxazin-4-one, pyrazolo[5,1-b]quinazoline, pyrido[1,2-a]quinazoline, and chromeno[3′, 4′:4,5]pyrido[1,2-a]quinazoline derivatives

Article abstract of DOI:10.3906/kim-1104.54

A convenient synthesis of a series of pyrimidine, 4H-3,1-benzoxazin-4-one, pyrazolo[5,1- b]quinazoline, pyrido[1,2-a]quinazoline, and chromeno[3′, 4′:4,5]pyrido[1,2-a]quinazoline derivatives, via the reactions of versatile and readily accessible methyl 2-

Full text of DOI:10.3906/kim-1104.54

Turk J Chem
35 (2011) , 893 – 903.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-1104.54
Facile and convenient synthesis of pyrimidine,
4H-3,1-benzoxazin-4-one, pyrazolo[5,1-b]quinazoline,
pyrido[1,2-a]quinazoline, and
chromeno[3ꢀ,4ꢀ :4,5]pyrido[1,2-a]quinazoline derivatives
Yossry A. AMMAR1, Samir BONDOCK1,∗, Abdallah G. AL-SEHEMI1,
Mohamed S. A. El-GABY1, Ahmed M. FOUDA1, Hamdy Kh. THABET3
1Chemistry Department, Faculty of Science, King Khalid University,
9004 Abha-SAUDI ARABIA
e-mail: bondock@mans.edu.eg
2Chemistry Department, Faculty of Science, Mansoura University,
Mansoura-EGYPT
3Chemistry Department, Faculty of Science, Al-Azhar University,
Nasr City-EGYPT
Received: 22.04.2010
A convenient synthesis of a series of pyrimidine, 4H -3,1-benzoxazin-4-one, pyrazolo[5,1-b]quinazoline,
pyrido[1,2-a]quinazoline, and chromeno[3ꢀ ,4ꢀ :4,5]pyrido[1,2-a]quinazoline derivatives, via the reactions of
versatile and readily accessible methyl 2-(2-cyanoacetamido)benzoate (1) with the appropriate reagents, is
described here.
Key Words: Cyanoacetanilide, pyrimidine, quinazoline, pyrazolo[5,1-b]quinazoline, pyrido[1,2-a]quinazoline
Introduction
Quinazolines are considered to be important chemical synthons of various physiological significances and phar-
maceutical utilities. They possess a variety of biological effects, including antihypertensive,1,2 antimicrobial,3,4
antihyperlipidemic,5,6 antiinflammatory,7,8 and anticonvulsant9−13 activities. Moreover, many quinazolines
∗Corresponding author
893

Facile and convenient synthesis of pyrimidine, 4H -3,1-benzoxazin-4-one..., Y. A. AMMAR, et al.
contributed to the quest for an ultimate antitumor chemotherapeutic agent.14−18 This literature survey re-
vealed that the presence of a substituted aromatic ring at position 3 and a methyl group at position 2 are
necessary requirements for central nervous system depression and anticonvulsant activities. Modification of the
methyl group by some other chemical moiety yielded structural analogs with anticonvulsant activity. Recently,
we have been involved in a program aiming at the synthesis of new heterocyclic compounds that may possess bi-
ologically active properties to be used as potential antimicrobial agents from a cyanoacetanilide precursor.19−26
In the context of this program and because of increased interest in quinazoline derivatives, some new quinazoline
derivatives were required for the study of biological activity. Methyl 2-(2-cyanoacetamido)benzoate (1) seemed
to be a good precursor to fulfill this objective via its reactions with some electrophilic and nucleophilic reagents.
Experimental
General remarks
All melting points were recorded on a digital Gallen Kamp MFB-595 instrument and are uncorrected. The
IR spectra (KBr) (cm−1) were measured on a Shimadzu 440 spectrophotometer. 1 H-NMR spectra δ, ppm)
were obtained in deuterated dimethyl sulfoxide on a Varian Gemini 200 (200 MHz) spectrometer, using TMS
as an internal standard; chemical shifts are reported as δppm units. Mass spectra (m/z, %) were obtained on
a GC MS-QP 100 EX mass spectrometer at 70 eV. Elemental analyses were carried out by the Microanalytical
Unit of Cairo University, Cairo, Egypt. Methyl 2-(2-cyanoacetamido)benzoate (1) was prepared according to a
literature procedure reported previously.27
Synthesis of methyl 2-(2-cyano-3-(dimethylamino)acrylamido)benzoate (2)
A mixture of cyanoacetamide derivative 1 (2.18 g, 0.01 mol) and dimethylformamide dimethylacetal (DMF-
DMA) (1.19 g, 0.01 mol) in dry xylene (30 mL) was refluxed for 4 h, then allowed to cool. The precipitated
product that was obtained was filtered off, washed with petroleum ether (60-80 ◦ C), dried, and recrystallized
from ethanol, mp 170-172 ◦ C (80%). IR (KBr): υ (cm−1) = 3252 (NH), 3030 (CH-arom.), 2924 (CH-aliph.),
2188 (C≡N), 1700, 1670 (C=O), and 1618 (C=C); 1 H-NMR in DMSO-d6 : δppm = 3.25 (s, 6H, 2CH3), 3.89
(s, 3H, OCH3), 7.12-7.60 (m, 4H, Ar-H), 7.89 (s, 1H, CH=), 11.00 (s, 1H, NH). Anal. Calcd. for C14 H15 N3 O3
(273.29): C, 61.53%; H, 5.53%; N, 15.38%. Found: C, 61.50%; H, 5.48%; N, 15.40%.
Synthesis of 9-oxo-1,9-dihydropyrazolo[5,1-b]quinazoline-3-carbonitrile (6)
A mixture of compound 2 (2.73 g, 0.01 mol) and hydrazine hydrate (0.5 g, 0.01 mol) was refluxed in n-butanol
(20 mL) for 12 h, and the solid product that was obtained was filtered off, washed with ethanol, dried, and
recrystallized from a mixture of EtOH/DMF (2:1), mp 285-287 ◦ C (65%). IR (KBr): υ (cm−1) = 3180 (NH),
2216 (C≡N), and 1692 (C=O); 1 H-NMR in DMSO-d6 : δppm = 7.20-7.89 (m, 4H, Ar-H), 8.02 (s, 1H, pyrazole-
H5), 11.73 (s, 1H, NH). Anal. Calcd. for C11 H6 N4 O (210.19): C, 62.86%; H, 2.88%; N, 26.66%. Found: C,
62.64%; H, 2.67%; N, 26.42%.
894

Facile and convenient synthesis of pyrimidine, 4H -3,1-benzoxazin-4-one..., Y. A. AMMAR, et al.
Synthesis of methyl 2-(2,4-diaminopyrimidine-5-carboxamido)benzoate (8)
To a mixture of compound 2 (2.73 g, 0.01 mol) and guanidine hydrochloride (0.95 g, 0.01 mol) in absolute
ethanol (30 mL), triethylamine (0.5 mL) was added. The reaction mixture was refluxed for 10 h, then allowed
to cool to room temperature and diluted with water (20 mL). The solid product thus formed was filtered off,
washed with water, and recrystallized from DMF, mp 245-247 ◦ C (68%). IR (KBr): υ (cm−1) = 3386, 3324
(NH2), and 1710, 1662 (C=O); 1 H-NMR in DMSO-d6 : δppm = 3.84 (s, 2H, NH2), 3.87 (s, 3H, OCH3), 5.56
(s, 2H, NH2), 7.29 (s, 1H, pyrimidine-H6), 7.32-7.95 (m, 4H, Ar-H), 13.59 (s, 1H, NH). Anal. Calcd. for
C13 H13 N5 O3 (287.27): C, 54.35%; H, 4.56%; N, 24.38%. Found: C, 54.20%; H, 4.38%; N, 24.22%.
Synthesis of 3-(4-aryl)-2-cyano-N-(2-methoxycarbonylphenyl)acrylamides (9a, 9b)
To a solution of cyanoacetanilide 1 (2.18 g, 0.01 mol) and the appropriate aromatic aldehyde (0.01 mol) in
ethanol (30 mL) was added a few drops of piperidine, and the reaction mixture was refluxed for 4 h and then
allowed to cool. The precipitate that formed was filtered, washed with ethanol, and dried.
Methyl 2-[3-(4-chlorophenyl)-2-cyano-acryloylamino]benzoate (9a)
Recrystallized from EtOH, mp 170-172 ◦ C (75%). IR (KBr): υ (cm−1) = 3266 (NH), 2956 (CH-aliph.), 2210
(C≡N), and 1696, 1686 (C=O); 1 H-NMR in DMSO-d6 : δppm = 3.90 (s, 3H, OCH3), 7.26-8.39 (m, 8H, Ar-H),
8.49 (s, 1H, olefinic CH=), 11.51 (s, 1H, NH). Anal. Calcd. for C18 H13 ClN2 O3 (340.76): C, 63.44%; H, 3.85%;
N, 8.22%. Found: C, 63.23%; H, 3.67%; N, 8.04%.
Methyl 2-[3-(4-methoxyphenyl)-2-cyano-acryloylamino]benzoate (9b)
Recrystallized from EtOH, mp 196-198 ◦ C (79%). IR (KBr): υ (cm−1) = 3250 (NH), 2962 (CH-aliph.), 2216
(C≡N), and 1696 (broad C=O); 1 H-NMR in DMSO-d6 : δppm = 3.85, 4.01 (2s, 6H, 2OCH3), 7.26-8.19 (m,
8H, Ar-H), 8.42 (s, 1H, olefinic CH=), 12.01 (s, 1H, NH). Anal. Calcd. for C19 H16 N2 O4 (336.34): C, 67.85%;
H, 4.79%; N, 8.33%. Found: C, 67.64%; H, 4.52%; N, 8.19%.
Synthesis of 6-amino-1-(2-(methoxycarbonyl)-phenyl)-3,5-dicyano-4-(4-aryl)-2-oxo-2H-pyridines
(12a, 12b)
To a solution of compounds 9a and 9b (0.01 mol) in ethanol (30 mL) and malononitrile (0.66 g, 0.01 mol), a
few drops of piperidine were added. The reaction mixture was heated under reflux for 3 h and then left to cool.
The precipitated product thus formed was collected by filtration, washed with ethanol, and dried.
6-Amino-1-(2-(methoxycarbonyl)-phenyl)-3,5-dicyano-4-(4-chlorophenyl)-2-oxo-2H-pyridines
(12a)
Recrystallized from AcOH, mp 260-262 ◦ C (67%). IR (KBr): υ (cm−1) = 3174, 3130 (NH2), 2216 (C≡N),
and 1704, 1692 (2 C=O); 1 H-NMR in DMSO-d6 : δppm = 3.90 (s, 3H, OCH3), 7.20-8.49 (m, 10H, Ar-H +
895

Facile and convenient synthesis of pyrimidine, 4H -3,1-benzoxazin-4-one..., Y. A. AMMAR, et al.
NH2). Anal. Calcd. for C21 H13 ClN4 O3 (404.81): C, 62.31%; H, 3.24%; N, 13.84%. Found: C, 62.14%; H,
3.07%; N, 13.68%.
6-Amino-1-(2-(methoxycarbonyl)-phenyl)-3,5-dicyano-4-(4-methoxyphenyl)-2-oxo-2H-pyridines
(12b)
Recrystallized from AcOH, mp 275-277 ◦ C (63%). IR (KBr): υ (cm−1) = 3244, 3202 (NH2), 2956, 2850
(CH-aliph.), 2212 (C≡N), and 1702, 1684 (C=O); 1 H-NMR in DMSO-d6 : δppm = 3.87, 391 (2s, 6H, 2OCH3),
7.15-8.52 (m, 8H, Ar-H), 11.47 (s, 2H, NH2); MS (m/z, %): 401 (M+ + 1, 19), 400 (M+ , 16), 324 (25),
305 (17), 266 (56), 251 (9), 222 (100), 196 (12), 177 (18), 152 (27), 75 (18). Anal. Calcd. for C22 H16 N4 O4
(400.39): C, 66.00%; H, 4.03%; N, 13.99%. Found: C, 66.09%; H, 4.23%; N, 13.76%.
Synthesis of 3-(4-chlorophenyl)-1,6-dioxo-5,6-dihydro-1H-pyrido[1,2-a]-quinazoline-2,4-dicarbonit-
rile (13)
To a solution of compound 12a (0.41 g, 0.001 mol) in DMF (30 mL), 0.5 mL of triethylamine was added and
refluxed for 8 h, then allowed to cool and poured into ice cold water. The resulting precipitate was filtered off,
dried, and recrystallized from a mixture of EtOH/DMF (2:1), mp > 300 ◦ C (82%). IR (KBr): υ (cm−1) =
3158 (NH), 2216 (C≡N), and 1658 (C=O); 1 H-NMR in DMSO-d6 : δppm = 7.12-8.08 (m, 8H, Ar-H), 11.43 (s,
1H, NH). Anal. Calcd. for C20 H9 ClN4 O2 (372.76): C, 64.44%; H, 2.43%; N, 15.03%. Found: C, 64.29%; H,
2.31%; N, 14.84%.
Synthesis of 2-[2-amino-4-(4-chloro-phenyl)-5,6,7,8-tetrahydro-4H-chromen-3-yl]-benzo[d][1,3] oxa-
zin-4-one (16)
A mixture of compound 9a (0.43 g, 0.001 mol), cyclohexanone (0.1 g, 0.001 mol), and piperidine (0.5 mL) in
ethanol (30 mL) was heated under reflux for 10 h, then allowed to cool, poured into cold water (50 mL), and
acidified with dilute HCl. The solid product thus formed was collected by filtration and recrystallized from a
mixture of EtOH/DMF (1:1), mp > 300 ◦ C (63%). IR (KBr): υ (cm−1) = 3424, 3248 (NH2), 2936, 2858
(CH-aliph.), and 1706 (C=O); 1 H-NMR in DMSO-d6 : δppm = 1.61-1.71, 2.45 (m, 8H, cyclohexyl), 4.85 (s,
1H, pyran-H4), 6.83 (s, 2H, NH2), 7.29-7.66 (m, 8H, Ar-H). Anal. Calcd. for C23 H19 ClN2 O3 (406.86): C,
67.90%; H, 4.71%; N, 6.89%. Found: C, 67.76%; H, 4.55%; N, 6.63%.
Synthesis of 1’,3,6’-trioxo-1’,2’,5’,6’-tetrahydrospiro[cyclohexane-1,3’-pyrido[1,2-a]quinazoline]-2’,
4’-dicarbonitrile (18)
To a mixture of compound 1 (2.83 g, 0.01 mol), 1,3-cyclohexanedione (1.12 g, 0.01 mol), and malononitrile (0.66
g, 0.01 mol) in ethanol (40 mL), a few drops of piperidine were added. The reaction mixture was refluxed for
6 h, and the solid product that was produced upon heating was collected by filtration and recrystallized from
a mixture of EtOH/DMF (2:1), mp > 300 ◦ C (82%). IR (KBr): υ (cm−1) = 3160 (NH), 3016 (CH-arom.),
2930, 2860 (CH-aliph.), 2220 (C≡N), 1695 (C=O), and 1660 (amidic C=O); 1 H-NMR in DMSO-d6 : δppm
=
2.24-2.51 (m, 8H, 4CH2), 5.98 (s, 1H, pyridine-H), 6.81-6.86 (m, 4H, Ar-H), 12.71 (s, 1H, NH); MS (m/z, %):
896

Facile and convenient synthesis of pyrimidine, 4H -3,1-benzoxazin-4-one..., Y. A. AMMAR, et al.
346 (M+ , 15), 301 (17), 278 (21), 209 (42), 195 (100), 177 (56), 164 (72), 155 (73), 140 (48), 135 (20), 64 (31).
Anal. Calcd. for C19 H14 N4 O3 (346.34): C, 65.89%; H, 4.07%; N, 16.18%. Found: C, 65.71%; H, 3.88%; N,
15.97%.
Synthesis of 6-imino-7-oxo-12,13-dihydro-6H,7H-chromeno[3‘,4‘:4,5]-pyrido[1,2-a]quinazolinone 14-
carbonitrile (23) and 6-imino-7-oxo-12,13-dihydro-6H,7H-chromeno[3‘,4‘:4,5]pyrido[1,2-a]quinazo-
linone-14-carboxylic acid amide (24)
To a mixture of 19 (3.22 g, 0.01 mol) and an active methylene compound (either malononitrile or cyanoac-
etamide; 0.01 mol) in ethanol (50 mL) was added ammonium acetate (0.5 g), and the reaction mixture was
refluxed for 5 h and then allowed to cool. The precipitate that formed was filtered off, washed with ethanol,
and recrystallized from a mixture of EtOH/DMF (3:1).
23: Mp > 300 ◦ C (92%). IR (KBr): υ (cm−1) = 3334, 3218 (2NH), 2206 (C≡N), and 1686, 1656
(amidic C=O); 1 H-NMR in DMSO-d6 : δppm = 7.51-7.80 (m, 8H, Ar-H), 8.93, 8.97 (2s, 2H, 2NH). Anal. Calcd.
for C20 H10 N4 O3 (354.32): C, 67.80%; H, 2.84%; N, 15.81%. Found: C, 67.66%; H, 2.69%; N, 15.60%.
24: Mp > 300 ◦ C. IR (KBr): υ (cm−1) = 3420, 3306 (NH2) and 1670, 1608 (C=O); 1 H-NMR in
DMSO-d6 : δppm = 3.56 (s, 2H, NH2), 6.76-7.97 (m, 8H, Ar-H), 9.59, 9.71 (2s, 2H, 2NH). Anal. Calcd. for
C20 H12 N4 O4 (372.33): C, 64.52%; H, 3.25%; N, 15.05%. Found: C, 64.33%; H, 3.03%; N, 14.79%.
Results and discussion
The key intermediate, methyl 2-(2-cyanoacetamido)benzoate (1),27 was readily available from the solvent-free
reaction of ethyl cyanoacetate with methyl anthranilate. Compound 1 was allowed to react with DMF-DMA
in refluxing xylene to afford enaminonitrile 2 in a good yield. The structure of enaminonitrile 2 was confirmed
on the basis of its elemental and spectral data. The IR spectrum revealed absorption bands at 3252, 2188,
1700, and 1670 cm−1 assignable to NH, C≡N, carbonyl ester, and amidic carbonyl groups, respectively. The
1 H-NMR spectrum displayed 4 singlet signals at δ 3.25, 3.89, 7.89, and 11.0 ppm characteristic of 2 methyl
groups, methoxy protons, an olefinic proton (CH=), and a NH proton, respectively.
The reactivity of enaminonitrile 2 toward some nitrogen nucleophiles was investigated. Thus, treatment
of 2 with hydrazine hydrate in refluxing n-butanol afforded a colorless product for which 2 possible structures,
3 and 6, could be formulated. The spectroscopic data of the isolated product was in complete agreement with
structure 6 as its IR spectrum exhibited nitrile and carbonyl stretching frequencies at 2216 and 1692 cm−1
.
The 1 H-NMR spectrum of 6 displayed a lack of methoxy and NH signals and the appearance of 2 new singlets
at δ 8.0 and 11.73 ppm due to pyrazole H-5 and NH-pyrazole, respectively.
The formation of pyrazolo[5,1-b]quinazoline 6 is assumed to take place via a Michael-type addition of the
amino group of hydrazine to the enamine double bond in 2 to form nonisolable acyclic intermediate 4, followed
by loss of methanol to afford nonisolable quinoxaline 5, which was readily converted into the final product
through water elimination.
In contrast to the behavior of enaminonitrile 2 toward hydrazine, compound 2 reacted with guanidine
hydrochloride in ethanol at reflux in the presence of triethylamine to yield methyl 2-(2,4-diaminopyrimidine-5-
carboxamido)benzoate (8). The structure of pyrimidine derivative 8 was supported on the basis of its elemental
897

Facile and convenient synthesis of pyrimidine, 4H -3,1-benzoxazin-4-one..., Y. A. AMMAR, et al.
and spectral data. The infrared spectrum of compound 8 indicated the absence of a C≡N group in addition to
the presence of NH2 bands at 3386 and 3324 cm−1 . Its 1 H-NMR spectrum exhibited 2 singlet signals at δ 3.87
and 7.29 ppm, corresponding to OCH3 and pyrimidine-H6 protons, respectively. The formation of pyrimidine
8 is assumed to take place through the intramolecular cyclization of nonisolable intermediate 7 (Scheme 1).
CO2CH3
NH
NH2
O
N
H
N
3
CO2CH3
CO2CH3
-NH(CH3)2
NH
CN
NH2NH2
n-butanol
reflux
NH
CN
CO2CH3
DMFDMA
O
O
NHCOCH2CN
H
N(CH3)2
NH
2
1
NH2
HN
4
EtOH/TEA
reflux
NH
2 . HCl
H2N
-CH3OH
CO2CH3
O
NH2
O
HN
NH
N
C
N
O
NH2
NH
CN
N
H
5
7
-H2O
O
H
N
N
CO2CH3
N
NH
CN
NH2
N
6
O
N
NH2
8
Scheme 1
To explore the synthetic potentiality of cyanoacetanilide 1 in quinazoline synthesis, we investigated the
reactivity of compound 1 toward some electrophilic reagents. Thus, the Knoevenagel condensation of cyanoac-
etamide 1 with aromatic aldehydes such as p-chlorobenzaldehyde and p-methoxybenzaldehyde in ethanolic
piperidine solution at reflux temperature afforded the corresponding benzylidene derivatives 9a and 9b. The
structures of compounds 9a and 9b were assigned on the basis of their elemental analyses and spectral data.
898

Facile and convenient synthesis of pyrimidine, 4H -3,1-benzoxazin-4-one..., Y. A. AMMAR, et al.
For example, the 1 H-NMR spectrum of 9a revealed 3 singlet signals at δ 3.9, 8.49, and 11.51 ppm assignable
to the methoxy, olefinic, and NH protons, respectively, besides the aromatic protons centered around 7.26-8.39
ppm.
When compounds 9a and 9b were reacted with malononitrile in boiling ethanol containing a catalytic
amount of piperidine in an attempt to attain the quinazoline nucleus through double cyclization, aminopyridone
derivatives 12a and 12b were obtained as the sole products via intermediates 10 and 11. The 1 H-NMR
spectra of 12a and 12b exhibited the presence of a methoxy ester singlet at 3.9 ppm. Compound 12a could
be successfully cyclized into pyrido[1,2-a]quinazoline derivative 13 through refluxing in DMF in the presence
of triethylamine. The structure of 13 was confirmed based on its elemental analysis and spectral data. Its
1 H-NMR spectrum revealed a lack of the methoxy signal in addition to the appearance of a NH proton near
11.43 ppm, besides multiplet signals due to the aromatic protons.
In addition, we found that when benzylidene derivative 9a was heated with cyclohexanone in refluxing
ethanol containing a catalytic amount of piperidine, it afforded corresponding 4H -3,1-benzoxazin-4-one deriva-
tive 16. The structure of isolated product 16 was established on the basis of its elemental analysis and spectral
data. Its IR spectrum exhibited strong stretching frequencies in the region of 3424 and 3248 cm−1 , attributable
to the amino group, in addition to the presence of a strong absorption band at 1706 cm−1 due to a carbonyl
group. Its 1 H-NMR spectrum in DMSO-d6 showed no signals attributable to methoxy ester, but displayed a
singlet signal at δ 4.85 ppm assigned to the 4-H pyran in addition to the presence of a singlet signal at δ 6.83
ppm exchangeable with D2 O assignable to the NH2 protons. The formation of compound 16 is assumed to
proceed via the Michael-type addition of the active methylene group of cyclohexanone to the activated double
bond of 9 to form nonisolable acyclic intermediate 14, which underwent in situ intramolecular cyclization to
give intermediate 15 and the final product through elimination of the methanol molecule (Scheme 2).
Spiro compounds represent an important class of naturally occurring molecules characterized by highly
pronounced biological properties.28,29 In this context, we explored the synthetic versatility of cyanoacetanilide 1
for the synthesis of spiro compounds containing quinazoline moiety. Thus, the 1-pot cyclocondensation reaction
of cyanoacetanilide 1, 1,3-cyclohexanedione, and malononitrile (1:1:1 molar ratio) in a refluxing ethanolic
piperidine solution afforded pyrido[1,2-a]quinazoline derivative 18, as indicated by spectral data. The IR
spectrum of spiro compound 18 revealed absorption bands at 3160, 2220, 1695, and 1660 cm−1 characteristic
for NH, nitrile, ketonic carbonyl, and amidic carbonyl groups, respectively. Its 1 H-NMR spectrum showed
multiplet signals for protons of the methylene groups centered around δ 2.24-2.51 ppm in addition to the
presence of 2 singlets at 5.98 and 12.71 ppm exchangeable with D2 O attributable to pyridine-H and NH
phenyl group, respectively. The mass spectrum of compound 18 revealed a molecular ion peak at m/z = 346
(M+ , 15%), and a base peak was observed in the spectrum at m/z = 195 (100%), which is compatible with
its molecular formula of C19 H14 N4 O3 . The formation of spiropyridoquinazoline 18 is assumed to proceed
through the intramolecular cyclization of nonisolable intermediate 17 via the loss of the methanol molecule
(Scheme 3).
899

Facile and convenient synthesis of pyrimidine, 4H -3,1-benzoxazin-4-one..., Y. A. AMMAR, et al.
Ar
CO2CH3
O
H
H
CN
H
CH2(CN)2
NC
H
N
CN
H
H
O
N
NH
CO2CH3
EtOH/pip.
1
N
C
Ar
CN
ArCHO
EtOH/pip.
10
11
reflux
CO2CH3
Ar
N
NC
CN
NH
Ar
N
NH
CN
NC
O
CN
DMF / TEA
O
O
NH2
CO2CH3
heat
Ar
; Ar = C6H4Cl-p
9b
O
9a
; Ar = C6H4OCH3-p
12a,b
Ar= C6H4-Cl-p
13
CO2CH3
NH NH
CO2CH3
O
NH
N
C
O
O
O
O
H
EtOH/pip.
reflux
H
H
Cl
Cl
14
15
-CH OH
3
Cl
O
N
O
H
O
NH2
16
Scheme 2
O
O
O
O
NC
H
CN
NH
CN
NC
H
O
CO2CH3
-CH3OH
N
NH2
CO2CH3
O
N
CH2(CN)2
NHCOCH2CN
1
O
17
Scheme 3
18
900

Facile and convenient synthesis of pyrimidine, 4H -3,1-benzoxazin-4-one..., Y. A. AMMAR, et al.
It has been reported that compounds with a chromene backbone have a wide range of biological
properties.30−33 Thus, methyl 2-(2-imino-2H-chromone-3-carboxamido) benzoate (19) was prepared by con-
densing cyanoacetanilide 1 with salicylaldehyde using piperidine as a catalyst in ethanol at room temperature,
following the procedure described earlier by Bylov et al.34
Moreover, the resulting chromone derivatives have latent functional constituents, which have the potential
for further chemical transformations that give new routes for the preparation of substituted, polycondensed
quinazoline derivatives. Reaction of chromone 19 with malononitrile in refluxing ethanol containing a catalytic
amount of piperidine afforded chromeno[3’,4’:4,5]pyrido[1,2-a]quinazoline derivative 23 in high chemical yield.
The structure of 23 was inferred from its spectral data. The IR spectrum showed absorption bands at
3334, 3218, 2206, 1656, and 1686 cm−1 corresponding to 2 NH, 1 CN, and 2 amidic C=O functions, respectively.
Its 1 H-NMR spectrum showed a multiplet signal integrated for 8 protons centered at δ 7.51-7.80 ppm due to
aromatic protons and 2 singlet signals at 8.93 and 8.97 ppm, which were exchangeable with D2 O assigned to
2 NH protons. Based on the foregoing data, structure 23 was assigned to this product.The formation of 23 is
assumed to proceed via the Michael addition of the active methylene group of malononitrile to the activated
double bond center in 19, affording the acyclic Michael adduct that spontaneously cyclizes, aromatizes, and
loses methanol to yield the final product through intermediates 20, 21, and 22 (Scheme 4).
O
O
HN
H2N
N
O
O
NH
24
CN
EtOH/pip.
reflux
CH2CONH2
NC
H
CN
CHO
OH
O
O
CH2(CN)2
N
H
N
H
1
H
NH
EtOH/pip.
CO2CH3
CO2CH3
EtOH/pip.
O
O
NH
reflux
19
20
O
N
NH
NH2
N
H
HN
NC
NC
N
NC
H
-H2
-CH3OH
CO2CH3
CO2CH3
O
O
O
H
O
NH
NH
O
NH
O
23
21
22
Scheme 4
901

Facile and convenient synthesis of pyrimidine, 4H -3,1-benzoxazin-4-one..., Y. A. AMMAR, et al.
In a similar manner, the cyclization of chromone 19 with cyanoacetamide in ethanol in the presence of
piperidine under reflux furnished chromenopyrido- quinazoline derivative 24. The structure of 24 was confirmed
on the basis of elemental and spectral data. The IR spectrum exhibited absorption bands at 3420 and 3306
cm−1 characteristic of the NH2 function. Its 1 H-NMR spectrum revealed 2 singlet signals at δ 9.59 and 9.71
ppm, exchangeable with D2 O due to 2 NH protons.
Conclusion
We have reported a simple and facile synthesis of new pyrimidine, 4H -3,1-benzoxazin-4-one, pyrazolo[5,1-
b]quinazoline, pyrido[1,2-a]quinazoline, and chromeno[3ꢀ ,4ꢀ :4,5]pyrido[1,2-a]quinazoline derivatives starting
from the readily accessible methyl 2-(2-cyanoacetamido)benzoate. Plausible mechanisms to account for the
formation of the products were suggested. All of the reactions are ecofriendly, and no heavy metals or hazardous
solvents are involved (mostly ethanol, n-butanol, and acetic acid were used).
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903

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