Reaction of anthranilic acid 2-N-phenylhydrazide with cyclic anhydrides

Article abstract of DOI:10.1134/S1070428008070105

In the reaction with cyclic anhydrides the anthranilic acid 2-N-phenylhydrazide depending on conditions yielded either anthranilic acid 2-N-acyl-2-N′-phenylhydrazides, 2-R-3-anilinoquinazolin-4(3H)-ones, or derivatives of 1-phenylpyridazino[3,2-b]quinazol

Full text of DOI:10.1134/S1070428008070105

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 7, pp. 1006−1008. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © L.A. Shemchuk, V.P. Chernykh, O.S. Krys’kiv, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 7, pp. 1017−
1019.
Reaction of Anthranilic Acid 2-N-Phenylhydrazide
with Cyclic Anhydrides
L. A. Shemchuk, V. P. Chernykh, and O. S. Krys’kiv
National Pharmaceutical University, Kharkov, 61002 Ukraine
e-mail: orgchem@ukrfa.kharkov.ua
Received October 23, 2007
Abstract—In the reaction with cyclic anhydrides the anthranilic acid 2-N-phenylhydrazide depending on conditions
yielded either anthranilic acid 2-N-acyl-2-N '-phenylhydrazides, 2-R-3-anilinoquinazolin-4(3H)-ones, or derivatives
of 1-phenylpyridazino[3,2-b]quinazoline-2,10-dione.
DOI: 10.1134/S1070428008070105
Several procedures are known for the synthesis of
compounds containing pyridazino[3,2-b]quinazolinone
system. The first method employs as initial compounds
the anthranilohydrazide and cyclic anhydrides of
dicarboxylic acids [1]. Other procedures are based on
intramolecular cyclization of 2-R-3-amino-4-oxo-3,4-
dihydroquinazoline derivatives having substituents in the
position 2 either with a double bond or with a functionally
substituted carboxy group [2], and also on intermolecular
condensation of 3-amino-2-chloromethyl-4-oxo-3,4-di-
hydroquinazolines with reagents containing an activated
double bond (maleimides, nitroalkenes) [3]. The existing
methods for designing the pyridazino[3,2-b]quinazoli-
none system come mainly to the application of anthranilo-
hydrazide and 3-aminoquinazolinones unsubstituted by
the amino group. The described reaction of anthranilic acid
N-isopropylidenehydrazide with phthalic anhydride [4]
led to the formation of the corresponding imide or of
phthalazino-[1,2-b]quinazoline-5,8-dione in a low yield
(10%).
We investigated the reaction of anthranilic acid
2-N-phenyl-hydrazide (I) with cyclic anhydrides of
dicarb-oxylic acids (see the scheme).
Scheme.
O
X O
O
O
O
Ac2O
NHNHPh
NHNHPh
Δ
NH2
NHCOXCO2H
IIb, IIc
I
CH3
O
O
O
X O
O
mW, D
H
N Ph
AcOH
or
O
c
N
Δ
A
Ac2O,
AcONa
O
N
XCO2H
c 2
A
+
H
D
O
N
O
N
,
IVc
Ph
O
H 2
NH Ph
N
N
N
AcOH
Δ
O
X
XCO2H
Va_Vc
IIIb, IIIc
X = (CH2)2 (a), CH=CH (b), o-C6H4 (c).
1006

REACTION OF ANTHRANILIC ACID 2-N-PHENYLHYDRAZIDE
1007
Initial hydrazide I was prepared by acylating the
phenylhydrazine with isatoic anhydride. The reaction of
hydrazide I with cyclic anhydrides under mild conditions
(in the glacial acetic acid without heating) resulted in
acids IIb and IIc. We failed to isolate acid IIa both in
these conditions and at their modification (lower
temperature, replacement of the glacial acetic acid with
other solvents: dioxane, DMF). The 1H NMR spectrum
of the oily substance obtained revealed that it contained
alongside acid IIa its cyclization products.
recrystallized from ethanol. Yield 1.8 g (79%), mp 170–
171°C.
b. Amixture of 1.63 g (0.01 mol) of isatoic anhydride
and 2.4 ml (0.01 mol) of phenylhydrazine was heated to
the melting point and then maintained for 30 min. On
cooling the melt was dissolved in 5 ml of ethanol, and
the product was precipitated by adding 20 ml of cold
water. The precipitate was filtered off, dried, and
recrystallized from ethanol. Yield 1.87 g (82%), mp 170–
1
172°C. H NMR spectrum, δ, ppm: 6.40 br.s (2H, NH2),
The cyclization of acids IIb and IIc was carried out
under several different conditions. At heating to the
melting point, under the effect of microwave irradiation,
or at stirring without heating in acetic anhydride in the
presence of sodium acetate acids IIb and IIc were
converted into 2-R-3- anilinoquinazolin-4(3H)-ones IIIb
and IIIc. In the 1H NMR spectra of quinazolinones IIIb
and IIIc, in contrast to the spectra of acids IIb and IIc,
signals appeared from a single NH group and from OH
group.
6.55–7.65 m (9Harom), 10.2 br.s (1H, CONH) [5]. Found,
%: C.68; H 5.80; N 18.50. C13H13N3O. Calculated, %:
C 68.71; H 5.77; N 18.49.
2-[(3-Carboxyacryloyl)amino]-2-N-phenylbenzo-
hydrazide (IIb). In 5 ml of glacial acetic acid was
dissolved 2.27 g (0.01 mol) of hydrazide I, and 0.98 g
(0.01 mol) of maleic anhydride was added. After 30 min
the mixture was diluted with 50 ml of cold water. The
separated precipitate was filtered off, dried, and
recrystallized from ethanol. Yield 2.3 g (71%), mp 180–
1
The boiling of acid IIc in acetic anhydride led to the
formation of 2-{3-[acetyl(phenyl)amino]-4-oxo-3,4-
dihydroquinazolin-2-yl}benzoic acid (IVc) obtained also
from quinazolinone IIIc under similar conditions. The
acid hydrolysis of compound IVc yielded again quinazo-
linone IIIc.
182°C. H NMR spectrum, δ, ppm: 6.35–7.65 m (9Harom),
6.50–7.25 m (2H, CH=CH), 8.65 s (1H, NHPh), 10.45 s
(1H, CONH), 10.80 s (1H, NHCO), 12.15 s (1H, OH).
Found,%: C 62.77; H 4.67; N 12.88. C17H15N3O4.
Calculated, %: C 62.76; H.65; N.92.
2-[(2-Carboxybenzoyl)amino]-2-N-phenylbenzo-
hydrazide (IIc) was similarly prepared. Yield 3.0 g
The heating of acid IIb and IIc or quinazolinones
IIIb and IIIc in the glacial acetic acid provided
pyridazino[3,2-b]quinazolinones Vb and Vc as indicated
1
(80%), mp 172–174°C. H NMR spectrum, δ, ppm: 6.45–
8.05 m (13Harom), 8.50 s (1H, NHPh), 10.55 s (1H, CONH),
11.45 s (1H, NHCO), 12.95 s (1H, OH). Found, %:
C 67.18; H 4.53; N 11.17. C21H17N3O4. Calculated, %:
C 67.19; H.56; N 11.19.
1
by the absence in their H NMR spectra signals of NH
and OH groups. Diones Va–Vc were also obtained by
heating hydrazide I with an appropriate anhydride in
glacial acetic acid; the reaction was carried out without
isolation of acids IIa–IIc and quinazolones IIIa–IIIc.
3-(3-Anilino-4-oxo-3,4-dihydroquinazolin-2-
yl)acrylic acid (IIIb). a. In 3 ml of acetic anhydride
was dissolved 3.25 g (0.01 mol) of acid IIb, 0.01 mol
(0.83 g) of sodium acetate was added, and the mixture
was stirred for 15 min. On cooling the reaction mixture
was diluted with 50 ml of cold water. The separated
precipitate was filtered off, dried, and recrystallized from
ethanol. Yield 2.6 g (85%), mp 100–102°C.
EXPERIMENTAL
1H NMR spectra were registered on a spectrometer
Varian M-200 (200 MHz), from solutions in DMSO-d6
using TMS as internal reference. The microwave irradia-
tion was carried out in a microwave oven of a power
800 W. Elemental analyses were performed on an
analyzer Carlo Erba CHNS-O EA 1108.
b. Acid IIb (3.25 g, 0.01 mol) was heated to melting
and thus kept for 19 min. On cooling the melt was
dissolved in 5 ml of ethanol, and the product was
precipitated by adding 20 ml of cold water. The
precipitate was filtered off, dried, and recrystallized from
ethanol. Yield 2.71 g (88%), mp 101–103°C.
Anthranilic acid 2-N-phenylhydrazide I. a. In a small
quantity of DMF was dissolved 1.63 g (0.01 mol) of
isatoic anhydride, 1.4 ml (0.01 mol) of triethylamine,
and 2.4 ml (0.01 mol) of phenylhydrazine was added.
After 1 h the reaction mixture was diluted with cold water,
the separated precipitate was filtered off, dried, and
c. Acid IIb (3.25 g, 0.01 mol) was subjected to
microwave irradiation for 10 min. On cooling the melt
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 7 2008

SHEMCHUK et al.
1008
1-Phenyl-1H-pyridazino[6,1-b]quinazoline-2,10-
dione (Vb). a. Hydrazide IIb (3.25 g, 0.01 mol) was
dissolved in 3 ml of acetic acid and was heated for 30
min. On cooling the mixture was diluted with 50 ml of
cold water. The separated precipitate was filtered off,
dried, and recrystallized from ethanol. Yield 2.03 g
(70%), mp 180–182°C.
was dissolved in 5 ml of ethanol, and the product was
precipitated by adding 20 ml of cold water. The
precipitate was filtered off, dried, and recrystallized from
1
ethanol. Yield 2.71 g (88%), mp 101–103°C. H NMR
spectrum, δ, ppm: 6.45–8.20 m (9Harom), 6.60–6.85 m (2H,
CH=CH), 9.30 s (1H, NHPh), 12.95 s (1H, OH) [6].
Found, %: C 66.42; H 4.30; N.66. C17H13N3O3.
Calculated, %: C 66.44; H 4.26; N 13.67.
b. Quinazolinone IIIb (3.07 g, 0.01 mol) was dis-
solved in 3 ml of acetic acid and was heated for 15 min.
On cooling the mixture was diluted with 50 ml of cold
water. The separated precipitate was filtered off, dried,
and recrystallized from ethanol. Yield 1.94 g (67%), mp
179–181°C. 1H NMR spectrum, δ, ppm: 6.50–6.85 m (2H,
CH=CH), 7.10–8.15m(9Harom).Found, %: C 70.61; H 3.80;
N 14.51. C17H11N3O2. Calculated, %: C 70.58; H 3.83;
N 14.52.
2-(3-Anilino-4-oxo-3,4-dihydroquinazolin-2-
yl)benzoic acid (IIIc). a. Synthesis was carried out as
described for compound IIIb. Yield 3.01 g (84%), mp
120–122°C.
b. Quinazolinone IVc (4.00 g, 0.01 mol) was boiled
for 30 min in water acidified with HCl to pH 1. On
cooling the precipitate was filtered off, dried, and
recrystallized from ethanol. Yield 2.72 g (76%), mp 119–
1
6-Phenyl-6H-phthalazino[1,2-b]quinazoline-5,8-
dione (Vc) was obtained in the same way. Yield 2.54 g
120°C. HNMR spectrum, δ, ppm: 6.25–8.30 m (13Harom),
9.00 s (1H, NHPh), 12.50 s (1H, OH). Found, %: C 70.61;
H 4.26; N 11.75. C21H15N3O3. Calculated, %: C.58;
H 4.23; N 11.76.
1
(75%), mp > 200°C. H NMR spectrum, δ, ppm: 7.45–
8.60 m (13Harom) [7]. Found,%: C 74.30; H 3.89; N 12.40.
C21H13N3O2. Calculated, %: C.33; H 3.86; N 12.38.
2-{3-[Acetyl(phenyl)amino]-4-oxo-3,4-dihydro-
quinazolin-2-yl}benzoic acid (IVc). a. Hydrazide IIc
(3.57 g, 0.01 mol) was boiled in acetic acid for 30 min.
On cooling the mixture was diluted with 20 ml of cold
water. The separated precipitate was filtered off, dried,
and recrystallized from ethanol. Yield 2.83 g (71%), mp
>200°C.
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b. Quinazolinone IIc (3.57 g, 0.01 mol) was boiled in
acetic anhydride for 15 min. On cooling the mixture was
diluted with 20 ml of cold water. The separated pre-
cipitate was filtered off, dried, and recrystallized from
1
ethanol. Yield 2.9 g (73%), mp >200°C. H NMR
spectrum, δ, ppm: 2.00 s (3H, CH3), 6.25–8.30 m (13Harom),
11.65 s (1H, OH). Found, %: C 69.18; H 4.31; N 10.50.
C23H17N3O4. Calculated, %: C 69.17; H 4.29; N 10.52.
1-Phenyl-3,4-dihydro-1H-pyridazino[6,1-b]-
quinazoline-2,10-dione (Va). In 5 ml of glacial acetic
acid was dissolved 2.27 g (0.01 mol) of hydrazide I,
1.00 g (0.01 mol) of succinic anhydride was added, and
the mixture was boiled for 30 min. On cooling the mixture
was diluted with 50 ml of cold water. The separated
precipitate was filtered off, dried, and recrystallized from
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1
ethanol. Yield 1.97 g (67%), mp 114–116°C. H NMR
spectrum, δ, ppm: 2.55–3.01 m (4H, CH2CH2), 6.45–8.00
m (9Harom). Found, %: C 70.11; H 4.52; N 14.40.
C17H13N3O2. Calculated,%: C 70.09; H 4.50; N 14.42.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 7 2008