Synthesis and intramolecular cyclization of 2-methylsulfanyl-4-oxo-3(4H)- quinazolinylacetohydrazide

Article abstract of DOI:10.1002/jhet.5570430106

Treatment of ambident sodium salt of 2-methylsulfanyl-4(3H)-quinazolinone with methyl bromoacetate resulted in N₃-alkyl ester formation. Reaction of the resulted ester with hydrazine hydrate gave 2-methylsulfanyl-4- oxo-3(4H)-quinazolinyl)aceto

Full text of DOI:10.1002/jhet.5570430106

Jan-Feb 2006
Synthesis and Intramolecular Cyclization of 2-Methylsulfany-4-oxo-
(4H)-quinazolinyl)acetohydrazide
43
3
Milda M. Burbuliene*, Olegas Bobrovas and Povilas Vainilavicius
Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, LT-03225 Vilnius, Lithuania
Received April 11, 2005
Treatment of ambident sodium salt of 2-methylsulfanyl-4(3H)-quinazolinone with methyl bromoacetate
resulted in N(3)-alkyl ester formation. Reaction of the resulted ester with hydrazine hydrate gave 2-methyl-
sulfanyl-4-oxo-3(4H)-quinazolinyl)acetohydrazide, which underwent intramolecular cyclization under
heating in dimethylformamide to give 1-aminoimidazo[2,1-b]quinazoline-2,5(1H,3H)-dione. The latter took
place in acylation reaction and in condensation with aromatic aldehydes.
J. Heterocyclic Chem., 43, 43 (2006).
A number of bioactive naturally occuring products con-
conditions used. M. Hori and H. Ohtaka [25] studied effects
of 2-substituent (alkyl, aminoalkyl, alkyloxy etc) on the
ratio of N-alkyl/O-alkyl products. For the N-alkylation
sodium ethoxide in ethanol [26] was used. Others [12] using
potassium carbonate in dimethylformamide prepared mix-
tain 4(3H)-quinazolinone skeleton [1,2]. 4(3H)-
Quinazolinone derivatives were found to show hypolipi-
demic, vasorelaxant, antibacterial or anticonvulsant activity
[
3-6]. 4(3H)-Quinazolinones, particulary those N -substi-
(3)
tuted, have been attracting attention for a few decades and
have renewed continuing interest in recent years due to their
multitude important activities. Febrifugine as a representa-
tures of N - and O-alkyl derivatives. Predominant forma-
tion of N- versus O-alkyl derivatives was found to depend
on the 2-substituent in quinazolinone ring [12,13,26].
(3)
tive of N -substituted 4(3H)-quinazolinones is known to
Alkylation of the ambident anion 1a with methyl bro-
moacetate would occur either at N(3) or at the O-atom
(Scheme 1). We did not find any data on alkylation of 2-
alkylsulfanyl-4(3H)-quinazolinone derivatives. The thor-
ough study of the effects of solvent and base on regioselec-
tive N(3)-/O-alkylation of 2-alkylsulfanyl-4-pyrimidinones
was given in reference [27]. There was found, that in polar
(3)
be highly active against malaria [7-11]. 4(3H)-
Quinazolinone N -alkanoic acid derivatives exhibit anti-
(3)
inflammatory, antitumor [12], analgetic [13], antihistaminic
14], fungicidal or plant growth regulator properties [15,16].
The most common synthetic methods to N -alkyl 4-oxo-2-
[
(3)
mercaptoquinazolines are based on cyclocondensation reac-
tions of anthranilic acid or its derivatives with isothio-
cyanates [17-19], glycinates [20,21] or thiophosgene [22].
In this paper we report on the synthesis of methyl (2-
methylsulfanyl-4-oxo-3(4H)-quinazolinyl)acetate (2) by
the alkylation of 2-methylsulfanyl-4(3H)-quinazolinone
protic solvents a mixture of N /O-isomers is formed. In
(
3)
nonpolar or less polar aprotic solvents N(3)-alkylation took
place and O-isomers were obtained in aprotic dipolar sol-
vents. The latter also formed in triethylamine with a cata-
lyst tetrabutylammonium bromide.
(1) with methyl bromoacetate. Treatment of ester 2 with
hydrazine hydrate and further modifications of resulting
Scheme 1
hydrazide 3 will be discussed.
2
-Methylsulfanyl-4(3H)-quinazolinone (1) was pre-
pared by base-catalysed treatment of 2-thioxo-4(3H)-
quinazolinone with iodomethane. We used sodium
methoxide as a base instead of potassium hydroxide as ear-
lier reported [23,24]. This replacement allowed us to
increase yield of desired 2-methylsulfanyl derivative 1 to
9
1%. (According to the ref. [23,24] 2-methylsulfanyl-
4
(3H)-quinazolinone (1) was obtained in 55-56% yield.)
Formation of N -alkyl or (and) O-alkyl products in the
(3)
alkylation reactions of 4(3H)-quinazolinones is dependent
on substituents of the quinazoline ring as well as reaction

4
4
M. M. Burbuliene, O. Bobrovas and P. Vainilavicius
Vol. 43
Based on the above experience we explored the alkyla-
literature [20], however it was obtained using another syn-
thetic sequence. These mentioned data support the struc-
ture of compound 2, i.e., N(3) -alkylation.
tion of 1 with methyl bromoacetate in different solvents
and bases to find out the optimal conditions for N-alkyl
ester 2 formation. Heating at reflux for different amounts
of time (3-18 h) the equimolar amounts of 2-methylsul-
fanyl-4(3H)-quinazolinone (1), sodium methoxide and
methyl bromoacetate in methanol afforded the ester 2. The
best yield (63%) of compound 2 was obtained under heat-
ing of reaction mixture for 18 h. Performing the reaction
with dry sodium salt 1a (prior synthesized) in aprotic non-
polar solvent tetrachloromethane, ester 2 was obtained in
The reaction of ester 2 with an excess of hydrazine
hydrate at room temperature yielded hydrazide 3 (Scheme
2). In the ir spectra of hydrazide 3 two absorption bands of
-1
C=O group appeared at 1687 (amide) and 1668 cm (lac-
-1
1
tam) and the NH bands at 3294 and 3271 cm . The H nmr
spectra displayed NH and NH group proton signals at 4.35
2
and 9.42 ppm respectively. The signal of NCH group pro-
2
ton, if compared to that of ester 2, is shifted upfield by 0.24
ppm. (2-Methylsulfanyl-4-oxo-3(4H)-quinazolinyl)-
acetohydrazide (3) being an active N-nucleophile could
react with various electrophiles to yield potential biologi-
cally active compounds. On the other hand, compound 3
contains in its molecule (besides the nucleophilic hydrazine
moiety) the methylsulfanyl group at the position 2 of quina-
zolinone ring, which is sensitive to nucleophilic attack.
Heterocyclic structures with good leaving groups, such as
alkylsulfanyl, adjacent to nucleophilic substituents undergo
intramolecular cyclization [22,28]. As an example, there is
the formation of 1,2,3,4-tetrahydropyrimido[2,1-c]-1,2,4-
triazin-3,6-diones from (2-alkylsulfanyl-3,4-dihydro-6-
methyl-4-oxo-3-pyrimidinyl)acetohydrazides [28].
According to the cited work [28], we expected 2H-[1,2,4]tri-
azino[3,4-b]quinazoline-3,6(1H,4H)-dione (4a) formation
from the intramolecular cyclization of hydrazide 3.
However hydrazide 3 under heating at 150° temperature in
abs. dimethylformamide transformed into 1-aminoimi-
dazo[2,1-b]quinazoline-2,5(1H,3H)-dione (4). Heating of
hydrazide 3 in benzylamine (as a solvent and a more basic
1
7% yield. Using triethylamine as a base and a solvent
along with tetrabutylammonium bromide catalyst, ester 2
was isolated in only 7% yield. Formation of O-isomer 2a
was not detected by tlc and the unreacted 2-methylsul-
fanyl-4(3H)-quinazolinone (1) was separated quantita-
tively in each experiment. The above experiments showed,
that the direction of the alkylation reaction of 2-methylsul-
fanyl-4(3H)-quinazolinone 1 in contrast to that of 2-alkyl-
sulfanyl-4(3H)-pyrimidinone [27] is not dependent on the
reaction conditions used. The applied reaction conditions
influence only the yield of the product 2. The structure of
ester 2 was determined from spectral data. The ir spectra of
ester 2 gave two absorption peaks arising from C=O
stretching at 1744 (ester) and 1673 cm (lactam). The H
nmr spectra of 2 showed resonances at 4.94 and 2.67 ppm
characteristic for N-CH and SCH group protons respec-
tively. Noteworthy, analogous ethyl ester prepared by a
different method [21] exhibit characteristic signals of N-
-
1
1
2
3
CH and SCH group protons at 4.94 and 2.66 ppm. Mp of
compound 2 correspond to that previously reported in the
2
3

Jan-Feb 2006
Synthesis and Intramolecular Cyclization
45
catalyst) at 160-165° resulted in the formation of 1-ben-
zylimidazo derivative 5. The latter compound 5 was also
produced under treatment of ester 2 with equimolar amount
of benzylamine at 160°. When hydrazide 3 was heated at
reflux for 12 h in 4-methylmorpholine (function of a basic
catalyst and a solvent) imidazoquinazoline 4 was obtained.
Finally, under treatment of hydrazide 3 with sodium hydride
in abs. dimethylformamide formation of the same product 4
was confirmed. The structures were supported by spectral
for 3 h., cooled to room temperature, filtered and recrystallized
from methanol to give 1.75 g (91%) of compound 1, mp 222-223°
1
(
7
ref. [23] yield 55%, mp 210-211°); H nmr: δ 2.63 (s, 3H, SCH ),
3
.50 (m, 1H, Ar-H), 7.61 (d, 1H, Ar-H, J = 8.0 Hz), 7.84 (m, 1H,
Ar-H,), 8.50 (d, 1H, Ar-H, J = 8.2 Hz), 14.17 (s, 1H, NH).
Anal. Calcd. for C H N OS: C, 56.23; H, 4.19; N, 14.57.
9
8 2
Found: C, 56.56; H, 4.25; N, 14.69.
Methyl (2-methylsulfanyl-4-oxo-3(4H)-quinazolinyl)acetate (2).
Method A.
1
data and elemental analysis. In the H nmr spectra of com-
To a mixture of compound 1 (1.04 g, 5.4 mmol) in methanol
(10 mL) and sodium methoxide (0.124 g, 5.4 mmol of sodium
dissolved in 10 ml of methanol), methyl bromoacetate (0.84 g,
pounds 4 and 5 the peak of endocyclic NCH protons was
2
observed at 4.55 and 4.66 ppm respectively. In addition, a
0
.52 mL, 5.5 mmol) was added dropwise. The reaction mixture
broad singlet of NH group protons appeared at 5.26 ppm in
2
was heated at reflux for 18 h and cooled to room temperature.
The resulting precipitate was collected and stirred with 1%
potassium hydroxide solution (20 mL) at room temperature for
4, while compound 5 showed a peak at 4.93 ppm of exo-
cyclic NCH group. In both cases the resonances corre-
2
sponding to the NH and SCH group protons, characteristic
3
2
0 min. Then the remainder was collected by filtration and
for hydrazide 3, disappeared. The ir spectra of 4 and 5 dis-
recrystallized from isopropyl alcohol to give 0.91 g (63%) of
played absorption of C=O group of cyclic five-member and
compound 2, mp 114-115° (ref. [20] mp 117° from ethylacetate-
-
1
-1
1
six-member lactones in the region of 1755, 1744 cm
hexane); ir: 1744, 1673 cm (CO); H nmr: δ 2.67 (s, 3H,
-1
(
C =O) and 1696, 1694 cm (C =O) respectively.
SCH ), 3.74 (s, 3H, OCH ), 4.94 (s, 2H, CH ), 7.51 (m, 1H, Ar-
2
5
3 3 2
H), 7.62 (d, 1H, Ar-H, J = 8.5 Hz), 7.86 (m, 1H, Ar-H), 8.11 (d,
Additionally, the structure of 4 was confirmed perform-
ing the following reactions. Imidazoquinazoline-2,5-dione
was allowed to react with aromatic aldehydes to give
1
3
1
5
1
H, Ar-H, J = 8.0 Hz); C nmr: δ 15.40 (SCH ), 45.51 (NCH ),
3 2
3.35 (OCH ), 118.98, 126.79, 126.90, 127.21, 135.86, 147.54,
57.65 (C quinazoline), 161.11 (C =O), 168.35 (C=O).
3
4
4
hydrazones 6. Reactions with aldehydes were performed in
acetic acid. Acetylation of 4 with acetic anhydride was
performed in acetic acid. Phenylacetamide 7b was synthe-
sized using pyridine-acetonitrile mixture as a solvent
instead of acetic acid. The spectral data of derivatives 6a,b
and 7a,b were in accordance with the assigned structures.
Compounds were preliminary tested for their anti-
inflammatory activity. Several of compounds, i.e., 3, 6a,
Anal. Calcd. for C H N O S: C, 54.53; H, 4.58; N, 10.60.
1
2 12 2 3
Found: C, 54.78; H, 4.51; N, 10.78.
Method B.
A mixture of compound 1 (1.5 g, 7.8 mmol) in methanol (20
ml) and sodium methoxide (0.18 g, 7.8 mmol of sodium dis-
solved in 6 ml of methanol) was refluxed for 15 min. The solvent
was evaporated in vacuo and the resultant salt was dried per-
fectly. Then methyl bromoacetate (1.20 g, 0.75 mL, 7.9 mmol)
was added dropwise to stirred salt 1a in tetrachloromethane (25
mL) The reaction mixture was heated at reflux for 12 h. and
worked as above. Yield of 2 0.36 g (17%), mp 114-115°.
6
b and 7a, exhibited anti-inflammatory activity (induced
in rats by carrageenin or bentonite) for 35-39%.
EXPERIMENTAL
Method C.
Methyl bromoacetate (1.84 g, 1.14 mL, 1.2 mmol) was added
dropwise to a stirred solution of compound 1 (1.92 g, 10 mmol),
tetrabutylammonium bromide (0.32 g, 1 mmol) and triethy-
lamine (25 mL). The reaction mixture was maintained at 70-75°
temperature for 8 h and allowed to cool to room temperature.
Then the reaction mixture was diluted with water (30 mL) and
extracted with trichloromethane (3x20 mL). The solvent was
evaporated and the residue was treated at room temperature with
Melting points were determined in open capillaries and are
uncorrected. Nuclear magnetic resonance (nmr) spectra were
recorded on a Unity Varian INOVA spectrometer at 300 MHz for
1
13
H and 75 MHz for C using dimethyl sulfoxide-d as a solvent.
6
Chemical shifts (δ) are reported in ppm relative to TMS as inter-
nal standard. The ir spectra were recorded in Nujol mulls on a
Spectrum BX FT-IR (Perkin-Elmer, Sweden). The reactions and
purity of compounds was controlled by tlc on Silufol UV 254
plates (Kavalier, Czech Rep.) Elemental analyses were per-
formed at the Microanalyses Laboratory of the Department of
Organic Chemistry of Vilnius University.
1
% potassium hydroxide solution (20 mL) for 20 min. The
remainder was filtered and recrystallized from isopropyl alcohol
to give 2, 0.18 g (7%) mp 114-115°.
(
2-Methylsulfanyl-4-oxo-3(4H)-quinazolinyl)acetohydrazide (3).
2
-Thioxo-2,3-dihydro-4(1H)-quinazolinone was synthesized as
To a stirred suspension of ester 2 (1.32 g, 5 mmol) in methanol
15 ml) 85% hydrazine hydrate (1.0 g, 1 mL, 20 mmol) was
reported in [29].
(
2
-(Methylsulfanyl)-4(3H)-quinazolinone (1).
added dropwise and the reaction mixture was stirred at room tem-
perature for 20 h. Then the solid was collected by filtration,
washed properly with water and methanol and dried to yield 3 as
a white solid, 1.27 g (96%), mp 258-259° (decomp.); ir: 3294,
3271 (NH), 1687, 1668 cm (CO); H nmr: δ 2.63 (s, 3H,
SCH ), 4.35 (s broad, 2H, NH ), 4.70 (s, 2H, CH ), 7.48 (m, 1H,
To a stirred mixture of 2-thioxo-2,3-dihydro-4(1H)-quinazoli-
none (1.78 g, 10 mmol) and sodium methoxide (0.23 g, 10 mmol of
sodium dissolved in 15 mL of abs. methanol) in abs. methanol (30
mL) at room temperature iodomethane (1.42 g, 0.62 mL, 10 mmol)
was added dropwise. Then reaction mixture was heated at reflux
-
1
1
3
2
2

46
M. M. Burbuliene, O. Bobrovas and P. Vainilavicius
Vol. 43
Ar-H), 7.60 (d, 1H, Ar-H, J = 8.0 Hz), 7.83 (m, 1H, Ar-H), 8.08
was crystallized from isopropyl alcohol to give 5 as a white solid,
yield 0.95 g (65%), mp 184-185°.
1
3
(
1
1
d, 1H, Ar-H, J = 7.4 Hz), 9.42 (s broad, 1H, NH); C nmr: δ
5.36 (SCH ), 45.31 (NCH ), 119.40, 126.59, 126.68, 127.18,
3 2
General Procedure for the Synthesis of 1-[(Arylmethylidene)-
amino]imidazo[2,1-b]quinazoline-2,5(1H,3H)-diones (6a, 6b).
35.50, 147.65, 158.21 (C quinazoline), 161.32 (C =O), 165.86
4
(
C=O).
Anal. Calcd. for C H N O S: C, 49.99; H, 4.58; N, 21.20.
Found: C, 50.35; H, 4.60; N, 21.09.
A mixture of compound 4 (0.55 g, 2.55 mmol) and aromatic
aldehyde (2.55 mmol) in acetic acid (15 mL) was heated at reflux
for 3 h. An excess of solvent was removed in vacuo, the resulting
precipitate was collected by filtration, washed with methanol and
recrystallized to give compounds 6a, 6b.
11 12 4 2
1
-Aminoimidazo[2,1-b]quinazoline-2,5(1H,3H)-dione (4).
Method A.
A suspension of hydrazide 3 (1.32 g, 5 mmol) in dimethylfor-
mamide (15 mL) was heated at 150-155 °C temperature for 3 h.
The excess of solvent was removed in vacuo. The solid was col-
lected by filtration, washed with methanol, dried and recrystal-
lized from water. Yield 0.94 g (87%), mp 334-336°; ir: 3335
1-{[(2-Hydroxyphenyl)methylidene]amino}imidazo[2,1-
b]quinazoline-2,5(1H,3H)-dione (6a).
This compound was obtained as a white solid, 0.5 g (61%), mp
-
1
2
(
49-251° (acetic acid, decomp.); ir: 3161 (OH), 1757, 1690 cm
1
CO); H nmr: δ 4.66 (s, 2H, CH ), 7.01 (m, 2H, Ar-H), 7.46 (m,
2H, Ar-H), 7.66 (d, 1H, Ar-H, J = 8.6 Hz), 7.81 (m, 2H, Ar-H),
2
NH), 1755, 1696 cm- (CO); H nmr: δ 4.55 (s, 2H, CH ), 5.26
1
1
(
2
(
s, 2H, NH ), 7.43 (m, 1H, Ar-H), 7.61 (d, 1H, Ar-H, J = 8.2 Hz),
2
8.15 (d, 1H, Ar-H J = 7.9 Hz), 9.69 (s, 1H, CH), 10.75 (s broad,
1
3
7
4
1
.79 (m, 1H, Ar-H), 8.11 (d, 1H, Ar-H, J = 9.5 Hz); C nmr: δ
13
1
H, OH); C nmr: δ 46.96 (NCH ), 112.59, 117.38, 119.31,
2
6.45 (NCH ), 120.16, 125.51, 126.74, 126.82, 135.42, 149.16,
2
120.27, 120.35, 126.05, 126.77, 127.15, 128.57, 134.47, 135.56,
148.80, 149.22, 159.33 (C quinazoline, phenyl, N=CH), 158.86
(C =O), 166.30 (C =O).
51.57 (C quinazoline), 158.84 (C =O), 168.37 (C =O).
5
2
Anal. Calcd. for C H N O : C, 55.55; H, 3.73; N, 25.91.
1
0 8 4 2
5
2
Found: C, 55.22; H, 3.78; N, 25.89.
Anal. Calcd. for C H N O : C, 63.75; H, 3.78; N, 17.49.
1
7 12 4 3
Found: C, 63.44; H, 4.05; N, 17.39.
Method B.
A mixture of hydrazide 3 (1.32 g, 5 mmol) in 4-methylmor-
pholine (10 mL) was heated at reflux for 12 h. The solvent was
removed in vacuo, the solid was washed with methanol and
recrystallized from water to give 0.7 g (65%) of compound 4, mp
1-{[(4-Nitrophenyl)methylidene]amino}imidazo[2,1-b]quinazo-
line-2,5(1H, 3H)-dione (6b).
This compound was obtained as a yellow solid, 0.63 g (71%)
-1
mp 282-284° (acetic acid); ir: 1756, 1693 (CO), 1516, 1344 cm
3
34-336°.
1
(
NO ); H nmr: δ 4.69 (s, 2H, CH ), 7.49 (m, 1H, Ar-H), 7.73 (d,
H, Ar-H, J = 8.9 Hz), 7.95 (m, 1H, Ar-H), 8.15 (d, 1H, Ar-H, J =
.1 Hz), 8.23 (d, 2H, Ar-H J = 9.0 Hz), 8.40 (d, 2H, Ar-H, J = 8.9
Hz), 9.86 (s, 1H, CH); C nmr: δ 46.79 (NCH ), 120.28, 124.93,
26.34, 126.76, 127.32, 129.92, 135.62, 139.88, 148.58, 149.79,
2
2
1
Method C.
9
Sodium hydride (60%, 0.3 g, 12.5 mmol) was added over a
period of 20 min to a stirred suspension of hydrazide 3 (1.32 g, 5
mmol) in dimethylformamide (7 mL) at room temperature. The
reaction mixture was stirred under argon at room temperature for 5
h., cooled to 0° and diluted with ice-water (20 mL). The white solid
was collected by filtration, washed with water and recrystallized
from water to give 0.98 g (91%) of compound 4, mp 334-336°.
1
3
2
1
1
1
48.98, 156.85 (C quinazoline, phenyl, N=CH), 158.76 (C =O),
5
66.30 (C =O).
2
Anal. Calcd. for C H N O : C, 58.46; H, 3.17; N, 20.05.
1
7 11 5 4
Found: C, 58.77; H, 3.37; N, 20.16.
N-(2,5-Dioxo-2,3-dihydroimidazo[2,1-b]quinazolin-1(5H)-
yl)acetamide (7a).
1
-Benzylimidazo[2,1-b]quinazoline-2,5(1H,3H)-dione (5).
Method A.
A mixture of compound 4 (1.08 g, 5 mmol), acetic anhydride
(0.61 g, 0.57 ml, 6 mmol) and acetic acid (15 mL) was heated at
reflux for 8 h. After cooling to room temperature the solid was
collected by filtration, washed with cold methanol and recrystal-
lized from ethanol to yield 1.01 g (78%) of 7a, mp 152-154°; ir:
A mixture of ester 2 (1.32 g, 5 mmol) and benzylamine (0.54 g,
0
.55 mL, 5 mmol) was heated at 160-165° temperature for 3 h.
After cooling the mixture was washed with methanol, collected
by filtration and recrystallized from isopropyl alcohol to give
-
1
1
1
1
.09 g (75%) of compound 5 as a white solid, mp 184-185°; ir:
3420, 3184 (NH), 1790, 1694, 1652 cm (CO); H nmr: δ 2.12
744, 1694 cm-1 (CO); H nmr: δ 4.66 (s, 2H, CH ), 4,93 (s, 2H,
1
(s, 3H, CH ), 4.81 (m, 2H, CH ), 7.46 (m, 1H, Ar-H), 7.60 (d,
2
3
2
CH -C H ), 7.39 (m, 6H, Ar-H), 7.58 (d, 1H, Ar-H, J = 8.7 Hz),
1H, Ar-H, J = 8.2 Hz), 7.81 (m, 1H, Ar-H), 8.14 (d, 1H, Ar-H, J =
2
6 5
1
3
13
7
4
1
1
.79 (m, 1H, Ar-H), 8.13 (d, 1H, Ar-H, J = 7.9 Hz); C nmr: δ
7.9 Hz), 11.00 (s, 1H, NH); C nmr: δ 21.0 (CH ), 46.46
3
3.0 (NCH ), 47.89 (CH -Ph), 120.25, 125.67, 126.84, 128.25,
(NCH ), 120.34, 126.08, 126.87, 126.93, 135.63, 148.58, 149.26
2
2
2
29.19, 135.41, 136.33, 148.90, 151.20 (C quinazoline, phenyl),
58.89 (C =O), 169.54 (C =O).
(C quinazoline), 158.76 (C =O), 167.15 (C=O), 169.13 (C =O).
5
2
Anal. Calcd. for C H N O : C, 55.80; H, 3.88; N, 21.70.
5
2
12 10 4 3
Anal. Calcd. for C H N O : C, 70.09; H, 4.50; N, 14.42.
Found: C, 55.71; H, 3.83; N, 21.59.
1
7 13 3 2
Found: C, 70.36; H, 4.65; N, 14.29.
N-(2,5-Dioxo-2,3-dihydroimidazo[2,1-b]quinazolin-1(5H)-yl)-2-
phenylacetamide (7b).
Method B.
Suspension of hydrazide 3 (1.06 g, 4 mmol) and benzylamine
To a suspension of compound 4 (0.54 g, 2.5 mmol) in dry pyri-
dine-acetonitrile (1:1) solution (20 mL) phenylacetyl chloride
(0.46 g, 0.4 mL, 3 mmol) was added and the reaction mixture was
heated at reflux for 5 h. The solvent was removed in vacuo, and
(
15 mL) was heated at 160-165° for 3 h. The reaction mixture
was than allowed to cool to room temperature, filtered and the fil-
trate was distilled under reduced pressure to dryness. The residue

Jan-Feb 2006
Synthesis and Intramolecular Cyclization
47
the residue was diluted with water (30 mL). The resulting precip-
itate was collected by filtration and recrystallized from ethanol to
[10] Y. Takaya, H. Tasaka, T. Chiba, K. Uwai, M. Tanitsu, H.-S.
Kim, Y. Wataya, M. Miura, M. Takeshita and Y. Oshima, J. Med. Chem.
2, 3163 (1999).
4
yield 0.66 g (79%) of 7b, mp 125-126°; ir: 3346 (NH), 1787,
694, 1651 cm-1 (CO); H nmr: δ 3.77 (s, 2H, CH C H ), 4.82
1
[11] S. Kobayashi, M. Ueno, R. Suzuki and H. Ishitani,
1
(
2
6 5
Tetrahedron Lett., 40, 2175 (1999).
12] Q. Chao, L. Deng, H. Shih, L. M. Leoni, D. Genini, D. A.
m, 2H, CH ), 7.43 (m, 6H, Ar-H), 7.58 (d, 1H, Ar-H, J = 7.8
2
[
Hz), 7.82 (m, 1H, Ar-H), 8.15 (d, 1H, Ar-H, J = 8.9 Hz), 11.00 (s,
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67,944 (1990); Chem. Abstr., 114, 62107w (1991).
1
1
H, NH); 13C nmr: δ 46.53 (NCH ), 120.36, 126.13, 126.89,
2
26.95, 127.49, 129.07, 129.82, 135.19, 135.68, 148.54, 149.19
3
(
C quinazoline, phenyl), 158.73 (C =O), 167.09 (C=O),
[14] A. R. R. Rao and V. M. Reddy, Arzneim. Forsch, 43, 663
5
1
70.13 (C =O).
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2
Anal. Calcd. for C H N O : C, 64.67; H, 4.22; N, 16.76.
1
8 14 4 3
Found: C, 64.71; H, 4.23; N, 16.58.
[
Acknowledgement.
[
The authors thank Dr. Emilija Udrenaite from the Department
of Polymer Chemistry and Professor V. Gaidelis from the Faculty
of Medicine of Vilnius University for the in vivo evaluation of
anti-inflammatory activity.
Heterocycles, 26, 3193 (1987).
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(2000).
[19] K. Lempert and G. Doleschall, Acta Chim. Acad. Sci. Hung.,
3
7, 457 (1963) (in German); Chem. Abstr., 59, 12809e (1963).
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419 (2001).
[23] L. M. Yun, S. Yangibaev, Kh. M. Shakhidoyatov, V. Ya.
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[