Synthesis of N-(4-oxo-3,4-dihydroquinazolin-3-yl)succinimide and N-(4-oxoquinazolin-3-yl)succinamic acid derivatives based thereon

Article abstract of DOI:10.1134/S1070428007040215

The reaction of anthranilic acid hydrazide with diethyl oxalate under microwave irradiation was accompanied by decarboxylation with formation of 3-amino-3,4-dihydroquinazolin-4-one, and acylation of the latter with succinic anhydride gave N-(4-oxo-3,4-dihydroquinazolin-3-yl)siccinimide which was converted into various N-(4-oxo-3,4-dihydroquinazolin-3-yl)succinamic acid derivatives. Nauka/Interperiodica 2007.

Full text of DOI:10.1134/S1070428007040215

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 4, pp. 615–618. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © L.A. Shemchuk, V.P. Chernykh, P.S. Arzumanov, D.V. Levashov, L.M. Shemchuk, 2007, published in Zhurnal Organicheskoi
Khimii, 2007, Vol. 43, No. 4, pp. 617–620.
Synthesis of N-(4-Oxo-3,4-dihydroquinazolin-3-yl)succinimide
and N-(4-Oxoquinazolin-3-yl)succinamic Acid Derivatives
Based Thereon
L. A. Shemchuk, V. P. Chernykh, P. S. Arzumanov, D. V. Levashov, and L. M. Shemchuk
National Pharmaceutical University, ul. Pushkinskaya 53, Kharkov, 61002 Ukraine
Received October 7, 2005
Abstract—The reaction of anthranilic acid hydrazide with diethyl oxalate under microwave irradiation was
accompanied by decarboxylation with formation of 3-amino-3,4-dihydroquinazolin-4-one, and acylation of the
latter with succinic anhydride gave N-(4-oxo-3,4-dihydroquinazolin-3-yl)siccinimide which was converted into
various N-(4-oxo-3,4-dihydroquinazolin-3-yl)succinamic acid derivatives.
DOI: 10.1134/S1070428007040215
Quinazolin-4-one derivatives have long been
known as a promising class of biologically active com-
pounds [1, 2]. Up to now, a great number of various
procedures have been proposed for the synthesis of
quinazolin-4-ones [3]. Procedures utilizing microwave
activation are not laborious and are characterized by
high yields; these techniques have also found applica-
tion for the synthesis of the quinazoline system [4, 5].
quinazolin-4-one (II) was obtained by reaction of an-
thranilic acid hydrazide (I) with diethyl oxalate under
microwave irradiation. This result was surprising, for
the same reaction performed on heating is known to
produce ethyl 3-amino-4-oxo-3,4-dihydroquinazoline-
1
2-carboxylate [6]. The H NMR spectrum of II con-
tained a narrow singlet at δ 5.88 ppm from protons of
the amino group and a signal at δ 8.37 ppm from 2-H
in the pyrimidine ring, while no ethoxy group signals
were present.
The choice of the starting compound in the present
work was somewhat accidental. 3-Amino-3,4-dihydro-
Scheme 1.
O
O
O
O
H
N
NH2
(COOEt)2, MW
NHNH2
N
OEt
N
H
O
NH2
NH2
N
COOEt
I
A
B
O
NH2
N
–C2H4, –CO2
N
II
O
O
O
N
NH
NH
NH2
H2O
N
NH
N
A
II
–H2O
–H2O
–CO2
O
N
COOH
HN
O
O
C
D
E
615

SHEMCHUK et al.
616
Scheme 2.
O
O
H2O/OH–
or MeONa
or R1NH2
O
N
O
O
O
H
O
N
N
N
N
R1
HCOOH, Δ
AcOH
I
II
O
O
N
III
IVa–IVe
O
H
N
N
O
N
R2
R2R3C=O
R1 = NH2NH
N
H
O
R3
N
Va–Vc
O
O
H
N
H
N
I
N
N
N
H
O
O
NH2
N
O
HCOOH
or Ac2O
VI
III
R
N
O
H
II
N
N
N
H
O
O
N
VIIa, VIIb
IV, R1 = HO (a), MeO (b), PrNH (c), PhCH2NH (d), NH2NH (e); V, R2 = R3 = Me (a), R2 = H, R3 = Ph (b), 4-Me2NC6H4 (c);
VII, R = H (a), Me (b).
Scheme 1 shows several possible ways for forma-
tion of compound II from hydrazide I and diethyl
oxalate. Initially, acylation of hydrazide І with diethyl
oxalate gives compound A which undergoes intramo-
lecular transacylation with formation of ethyl quinazo-
linecarboxylate B. Analogous syntheses of 2-substi-
tuted 3-aminoquinazolinones via transacylation of
N-(2-aminobenzoyl)-N'-aroylhydrazines were reported
[7–9]. The subsequent decarboxylation of B yields
final product IІ. An alternative path includes intramo-
lecular acylation of amino ester A with formation of
1,4,5-benzotriazocane which is converted into quin-
azolinone II through intermediates D and E. The latter
can also be formed by hydrolysis of ester B. In order to
verify the possibility for the reaction to follow the first
path, we synthesized compound B according to the
procedure given in [6]. However, the product failed to
undergo decarboxylation even under more severe con-
ditions, i.e., under increased microwave irradiation
power and time (to 10 min); only the initial compound
was recovered from the reaction mixture. Therefore,
we believe that the second path is more probable.
We prepared quinazolinone II for further trans-
formations by a simpler procedure, by heating hydra-
zide I in formic acid [10]. The reaction of II with
succinic anhydride on heating in boiling glacial
acetic acid for a short time afforded N-(4-oxo-3,4-di-
hydroquinazolin-3-yl)succinimide (III) (Scheme 2).
The reaction involved intermediate formation of suc-
cinamic acid IVa which underwent cyclodehydration
to imide III. The ease of imide ring closure must be
noted. Even a slight heating of the reaction mixture
resulted in the formation of a mixture of acid IVa and
imide III, the latter prevailing. When the acylation of
II with succinic anhydride was carried out at room
temperature (by stirring for 48 h), a mixture of unre-
acted compound II and acid IVa was formed. There-
fore, 3-(4-oxo-3,4-dihydroquinazolin-3-ylcarbamoyl)-
propanoic acid (IVa) was synthesized by alkaline
hydrolysis of imide III.
Imide III readily reacts with various nucleophiles.
The reaction of III with sodium methoxide in boiling
methanol gave ester IVb, while heating with aliphatic
amines in ethanol led to the formation of the corre-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 4 2007

SYNTHESIS OF N-(4-OXO-3,4-DIHYDROQUINAZOLIN-3-YL)SUCCINIMIDE
617
sponding N,N'-disubstituted succinamides IVc and
IVd. By treatment of III with hydrazine hydrate in
dioxane we obtained hydrazide IVe. The latter can also
be synthesized by mixing imide III with hydrazine hy-
drate in a porcelain mortar according to the procedure
reported in [11]. However, in this case the reaction
is accompanied by partial decomposition of III with
formation of quinazolinone II as an impurity. Hydra-
zide IVe was converted into the corresponding hydra-
zones Va–Vc by heating with acetone and aromatic
aldehydes in dimethylformamide.
quinazolinone II and 0.01 mol of succinic anhydride in
glacial acetic acid was heated for 40 min. The mixture
was cooled and diluted with water, and the precipitate
was filtered off, dried, and recrystallized from acetic
1
acid. Yield 82%, mp 224°C. H NMR spectrum, δ,
ppm: 3.0 t (2H, CH2), 3.06 t (2H, CH2), 7.69 t (1H,
6-H), 7.83 d (1H, 8-H), 8.00 t (1H, 7-H), 8.22 d (1H,
5-H), 8.36 s (1H, 2-H).
3-(4-Oxo-3,4-dihydroquinazolin-3-ylcarbamoyl)-
propanoic acid (IVa). A mixture of 0.01 mol (2.4 g) of
compound ІІІ and 100 ml of a 0.1 M solution of so-
dium hydroxide was heated until it became homogene-
ous. The mixture was neutralized with hydrochloric
acid, and the precipitate was filtered off. Yield 60%,
Quinazolin-4-one derivatives VIIa and VIIb were
synthesized from compound VI which was prepared
by heating imide III with hydrazide I in dioxane or by
fusion of the initial compounds without a solvent. The
best results were obtained when the reaction was per-
formed in dioxane. Intramolecular cyclization of the
2-aminobenzohydrazide fragment in VI gave com-
pounds VIIa and VIIb. Symmetric N,N′-bis(4-oxo-3,4-
dihydroquinazolin-3-yl)succinamide (VIIa) was ob-
tained by heating compound VI in formic acid. Succin-
amide VIIa was also synthesized by fusion of imide
III with quinazolinone II, but the yield was lower, and
elevated temperature or prolonged time favored de-
composition of the initial compounds. Attempts to
react imide III with quinazolinone II in a solvent were
unsuccessful; only the initial compounds were isolated
when their mixture was heated in boiling ethanol, di-
oxane, acetic acid, and DMF. Unsymmetrical succin-
amide VIIb was obtained by heating compound VI
with an equimolar amount of acetic anhydride in
glacial acetic acid (Scheme 2).
1
mp 225°C (from ethanol). H NMR spectrum, δ, ppm:
2.5–2.65 m (4H, CH2CH2), 7.58 t (1H, 6-H), 7.74 d
(1H, 8-H), 7.90 t (1H, 7-H), 8.12–8.20 d (2H, 5-H,
2-H), 11.4–12.0 s (2H, NH, COOH).
Methyl 3-(4-oxo-3,4-dihydroquinazolin-3-ylcar-
bamoyl)propanoate (IVb). Compound ІІІ, 0.01 mol
(2.4 g), was dissolved on heating in 15 ml of methanol,
a solution of 0.01 mol (0.54 g) of sodium methoxide in
methanol was added, and the mixture was heated for
1 h. The mixture was cooled and diluted with water,
and the precipitate was filtered off and dried. Yield
1
40%, mp 147°C (from methanol). H NMR spectrum,
δ, ppm: 2.5 t (2H, CH2), 3.0 t (2H, CH2), 3.60 s (3H,
CH3), 7.55 t (1H, 6-H), 7.7 d (1H, 8-H), 7.85 t (1H,
7-H), 8.12 d (1H, 5-H), 8.15 s (1H, 2-H), 11.35 s (NH).
N-(4-Oxo-3,4-dihydroquinazolin-3-yl)-N'-propyl-
succinamide (IVc). A mixture of 0.01 mol (2.43 g) of
compound III and 0.01 mol (0.8 ml) of propylamine in
10 ml of ethanol was heated under reflux until it be-
came homogeneous. The mixture was cooled, and the
precipitate was filtered off, dried, and recrystallized
from water. Yield 63%, mp 212°C. 1H NMR spectrum,
δ, ppm: 0.8 t (3H, CH3), 1.4 m (2H, CH2), 2.4 m
(NCH2), 2.5 t (2H, COCH2), 3.0 t (2H, COCH2), 7.55 t
(1H, 6-H), 7.7 d (1H, 8-H), 7.85–7.9 t (2H, 7-H,
CONH), 8.12 d (1H, 5-H), 8.15 s (1H, 2-H), 11.2–
11.4 s (NNH).
EXPERIMENTAL
1
The H NMR spectra were measured on a Varian
M-200 spectrometer at 200MHz from solutions in
DMSO-d6 relative to tetramethylsilane as internal re-
ference. Microwave-assisted reactions were carried out
in a microwave furnace with a power of 800 W.
3-Amino-3,4-dihydroquinazolin-4-one (II).
A mixture of 0.01 mol (1.5 g) of anthranilic acid hy-
drazide (I) and 0.01 mol of diethyl oxalate was heated
for 7 min in a microwave furnace. After cooling, the
melt was crystallized from ethanol. Yield 89%,
N-Benzyl-N'-(4-oxo-3,4-dihydroquinazolin-3-yl)-
succinamide (IVd) was synthesized in a similar way.
1
Yield 67%, mp 201°C. H NMR spectrum, δ, ppm:
2.5 t (2H, CH2), 2.8 t (2H, COCH2), 4.6 d (2H, NCH2),
7.4 m (5H, C6H5), 7.55 t (1H, 6-H), 7.7 d (1H, 8-H),
7.85–7.9 t (2H, 7-H, CONH), 8.12 d (1H, 5-H), 8.15 s
(1H, 2-H), 11.2–11.4 s (NNH).
1
mp 208–210°C. H NMR spectrum, δ, ppm: 5.88 s
(2H, NH2), 7.55 t (1H, 6-H), 7.72 d (1H, 8-H), 7.81 t
(1H, 7-H), 8.18 d (1H, 5-H), 8.37 s (1H, 2-H).
1-(4-Oxo-3,4-dihydroquinazolin-3-yl)pyrroli-
dine-2,5-dione (ІІІ). A mixture of 0.01 mol of amino-
3-Hydrazinocarbonyl-N-(4-oxo-3,4-dihydro-
quinazolin-3-yl)propanamide (IVe). Compound III,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 4 2007

SHEMCHUK et al.
618
0.01 mol (2.43 g), was dissolved on heating in 10 ml
of 1,4-dioxane, and 0.015 mol (0.75 ml) of hydrazine
hydrate was added to the hot solution. A solid imme-
diately separated and was filtered off, dried, and re-
crystallized from water. Yield 65%, mp 237–239°C.
1H NMR spectrum, δ, ppm: 2.2 t (2H, CH2), 2.7 t (2H,
CH2), 4.15 d (2H, NH2), 7.55 t (1H, 6-H), 7.7 d (1H,
8-H), 7.85–7.9 t (1H, 7-H), 8.12 d (1H, 5-H), 8.15 s
(1H, 2-H), 9.0 t (1H, CONH), 11.2–11.4 s (NNH).
NH2), 6.5–8.2 m (8H, Harom), 9.8 (2H, NHNH), 11.2–
11.3 (1H, NH).
N,N′-Bis(4-oxo-3,4-dihydroquinazolin-3-yl)-
succinamide (VIIa). A mixture of 0.01 mol (3.94 g) of
compound VI and 5 ml of formic acid was heated to
the boiling point. A solid separated and was filtered
off, dried, and recrystallized from acetic acid. Yield
68%, mp 241–242°C. 1H NMR spectrum, δ, ppm: 2.7 s
(2H, CH2), 7.6 t (1H, 6-H), 7.72 d (1H, 8-H), 7.9 t (1H,
7-H), 8.18–8.22 t (5-H, 2-H), 11.4 s (1H, NH).
3-(Benzylidenehydrazinocarbonyl)-N-(4-oxo-3,4-
dihydroquinazolin-3-yl)propanamide (Vb). A mix-
ture of 0.01 mol of compound IVe and 0.01 mol (1 ml)
of benzaldehyde was heated in DMF. It was then
cooled and diluted with water, and the precipitate was
filtered off, dried, and recrystallized from ethanol.
N-(2-Methyl-4-oxo-3,4-dihydroquinazolin-3-yl)-
N'-(4-oxo-3,4-dihydroquinazolin-3-yl)succinamide
(VIІb). A mixture of 0.01 mol (3.94 g) of compound
VI and 0.01 mol (0.94 ml) of acetic anhydride in
glacial acetic acid was heated for 30 min. The precip-
itate was filtered off, dried, and recrystallized from
acetic acid. Yield 65%, mp 230–231°C. 1H NMR spec-
trum, δ, ppm: 2.5 s (3H, CH3), 2.9–3.2 m (4H, CH2CH2),
7.65 t (2H, 6-H), 7.89 d (2H, 8-H), 7.95 t (2H, 7-H),
8.19 d (2H, 5-H), 8.34 s (1H, 2-H), 11.4 s (2H, NH).
1
Yield 61%, mp 230–232°C. H NMR spectrum, δ,
ppm: 2.74 s (1H, =CH), 2.6–3.1 m (4H, CH2CH2), 7.4–
8.4 m (10H, Harom, NH=N), 11.2–11.4 (1H, NHCO).
Compounds Va and Vc were synthesized in a simi-
lar way.
3-(Isopropylidenehydrazinocarbonyl)-N-(4-oxo-
3,4-dihydroquinazolin-3-yl)propanamide (Va). Yield
55%, mp 187°C. H NMR spectrum, δ, ppm: 2.8–
REFERENCES
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(1H, 6-H), 7.7 d (1H, 8-H), 7.85–7.9 t (1H, 7-H),
8.12 d (1H, 5-H), 8.15 s (1H, 2-H), 9.0 s (1H, CONH),
11.2–11.4 s (NNH).
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nyl)-N-(4-oxo-3,4-dihydroquinazolin-3-yl)propan-
amide (Vc). Yield 65%, mp 250°C. H NMR spec-
trum, δ, ppm: 2.65 s (1H, =CH), 2.8–2.9 m (4H,
CH2CH2), 3.1 m [6H, N(CH3)2], 7.5–7.9 m (7H, 6-H,
7-H, 8-H, C6H4), 8.14 d (2H, 5-H, NH=N), 8.32 s (1H,
2-H), 11.2–11.4 (1H, CONH).
1
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oxo-3,4-dihydroquinazolin-3-yl)propanamide (VI).
Compound III, 0.01 mol (2.43 g), was dissolved on
heating in a minimal volume of 1,4-dioxane, the solu-
tion was cooled, a solution of 0.01 mol (1.5 g) of an-
thranilic acid hydrazide (I) in 1,4-dioxane was added,
and the mixture was left to stand for 3 days. The pre-
cipitate was filtered off, dried, and recrystallized from
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1
ethanol. Yield 52%, mp 244–245°C. H NMR spec-
trum, δ, ppm: 2.4–2.7 m (2H, CH2CH2), 6.32 s (2H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 4 2007