Reaction of isatoic anhydride with bifunctional reagents: Synthesis of some new quinazolone fused heterocycles, 2-substituted anilinoheterocyclic derivatives and other related compounds

Article abstract of DOI:10.1081/SCC-100106216

A new synthesis of quinazolone fused heterocycles (2, 5, 8), anilinoheterocycles (4, 7, 10, 12, 14) and substituted 2-aminoquinoline (15, 16) based on the reaction of isatoic anhydride (1) with different active bifunctional compounds in presence of glacial acetic acid and freshly fused sodium acetate is described. Structures of the newly prepared compounds are established by chemical and spectral data.

Full text of DOI:10.1081/SCC-100106216

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REACTION OF ISATOIC ANHYDRIDE WITH
BIFUNCTIONAL REAGENTS: SYNTHESIS OF SOME
NEW QUINAZOLONE FUSED HETEROCYCLES, 2-
SUBSTITUTED ANILINOHETEROCYCLIC DERIVATIVES
AND OTHER RELATED COMPOUNDS
A. A. Fadda a , Hala M. Refat b , M. E. A. Zaki c & Eman Monir a
a Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt
b Department of Chemistry, Faculty of Education, Suez Canal University, Al-Arish, Egypt
c National Research Centre, Dokki, Cairo, Egypt
Version of record first published: 22 Aug 2006
To cite this article: A. A. Fadda, Hala M. Refat, M. E. A. Zaki & Eman Monir (2001): REACTION OF ISATOIC ANHYDRIDE
WITH BIFUNCTIONAL REAGENTS: SYNTHESIS OF SOME NEW QUINAZOLONE FUSED HETEROCYCLES, 2-SUBSTITUTED
ANILINOHETEROCYCLIC DERIVATIVES AND OTHER RELATED COMPOUNDS, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 31:22, 3537-3545
To link to this article: http://dx.doi.org/10.1081/SCC-100106216
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SYNTHETIC COMMUNICATIONS, 31(22), 3537–3545 (2001)
REACTION OF ISATOIC
ANHYDRIDE WITH BIFUNCTIONAL
REAGENTS: SYNTHESIS OF SOME
NEW QUINAZOLONE FUSED
HETEROCYCLES, 2-SUBSTITUTED
ANILINOHETEROCYCLIC
DERIVATIVES AND OTHER
RELATED COMPOUNDS
A. A. Fadda,1, Hala M. Refat,2
*
M. E. A. Zaki,3 and Eman Monir1
1Department of Chemistry, Faculty of Science,
Mansoura University, Mansoura, Egypt
2Department of Chemistry, Faculty of Education,
Suez Canal University, Al-Arish, Egypt
3National Research Centre, Dokki, Cairo, Egypt
ABSTRACT
Anew synthesis of quinazolone fused heterocycles ( 2, 5, 8),
anilinoheterocycles (4, 7, 10, 12, 14) and substituted 2-amino-
quinoline (15, 16) based on the reaction of isatoic anhydride
(1) with different active bifunctional compounds in presence
*Corresponding author.
3537
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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3538
FADDA ET AL.
of glacial acetic acid and freshly fused sodium acetate is
described. Structures of the newly prepared compounds are
established by chemical and spectral data.
During the past 30 years several groups have described the use of
2H-3,1-benzoxazine-2,4(1H)-dione (isatoic anhydride) for the synthesis of
quinazolinedione,1 4-quinazolinones2 and benzodiazepine-5-ones.3 It has
been reported also that the reaction of isatoic anhydride with aromatic pri-
mary amines with ortho substituents to yield largely the abnormal prod-
ucts.4 In the last few years we have reported several syntheses of quinazoline
derivatives as a part of a program to develop new simple routes for the
synthesis of functionally substituted heterocycles of anticipated biological
activity that can be used as potential biodegradable agrochemicals.5–7 In the
present work we explore the synthetic potential of isatoic anhydride (1) to
obtain some novel quinazolone fused heterocycles, anilinoheterocycles and
substituted quinoline derivatives via the reaction with different bifunctional
reagents containing reactive hydrogen atoms. No details regarding the
synthesis of such compounds in the literature survey. The synthesized
compounds possess latent functional subsituents and appear promising for
utility in further chemical transformation and also biological studies. Thus,
compound 1 reacts with o-phenylenediamine in refluxing acetic acid
catalyzed by freshly fused sodium acetate to afford two products, benzoi-
midazolo[2,3-b]-quinazoline-6-one (2) and benzimidazole derivative (4) in
85% and 15% yield, respectively.
In a similar manner, it was found that, 1 reacts with 2,3-diaminopyr-
idine to afford pyridoimidazolo[2,3-b]-quinazoline-6-one (5), and 2-(o-ami-
nophenyl)-pyridoimidazole (7) in 70% and 30% yield respectively. The
structure of 5, 7 could be established for the reaction product based on
IR, 1H NMR and mass spectra. Moreover, it has been found that compound
1 reacts with 2-amino-3-hydroxypyridine in glacial acetic acid in the
presence of freshly fused sodium acetate to give a single product, pyridoox-
azolo[2,3-b]quinazolin-6-one (8) in 85% yield.
Structure 8 was established on the basis of spectral data, which the
mass spectra showed Mþ at 236 and the base peak of M þ 2 (238). On the
other hand, 1 reacts with aminothiophenol in presence of glacial acetic acid
containing a catalytic amounts of freshly fused sodium acetate to give a
single product with molecular formula C13H10N2S (Mþ ¼ 226). The product
was assigned as 2-(o-aminophenyl)benzothiazole structure (10), based on
spectral data. This result is in complete agreement with the previously
reported work8 of reaction of isatoic anhydride with mercaptans.

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ISATOIC ANHYDRIDE
3539

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3540
FADDA ET AL.
The formation of the reaction products 2–10 can be assumed according to
the following proposed reaction mechanism.
The condensation of isatoic anhydride (1) with o-substituted primary
aromatic amines has been found to yield the corresponding substituted
anthranilamides (A), earlier believed to be the sole normal products of
this reaction4 and, concurrently, the corresponding !-substituted o-urami-
dobenzoic acid (C), the latter, may undergo cyclization to form the 3-sub-
stituted benzoylene ureas (D) which followed by intramolecular cyclization
to give the corresponding quinazolone derivatives. All these primary amines
yielded both substituted anthranilamides and substituted uramidobenzoic
acids. Ring closure of the latter to 3-substituted benzoylene ureas, by action
of acetic acid/sodium acetate, occurred when R was amino and hydroxyl
groups, but was not observed to occur when R was a thiol group.
The obstruction to cyclization is probably steric, but is not satisfactorily
rationalized from the evidence at hand. The structures of R affected also the
proportions of Aand C formed in the initial reactions, as well as the ease of
cyclization of C to D.
The reaction of isatoic anhydride with ethylene diamine in the
presence of acetic acid and freshly fused sodium acetate occurs readily to
afford two products. The anthranilamide derivative (11) 2-imidazolylaniline
derivative (12). Similarly, 1 reacts with ethanolamine to afford two products,
one of them has the molecular formula C9H12N2O2 (35%, Mþ ¼ 180) 13 and
the other products C9H10N2O (65%, Mþ ¼ 162) 14.
Both structures (13) and (14) were established on their spectral data
(cf. experimental). Compounds 12 and 14 were assumed to be formed via the
direct intramolecular cyclization of its corresponding isolable anthranila-
mide 11 and 13 respectively. The formation of 11 and 13 derivatives are
in complete agreement with the previously reported work.9

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ISATOIC ANHYDRIDE
3541
Isatoic anhydride is capable of reacting with active methylene
compounds, as shown by its reaction with 2-cyanomethylbenzothiazole
and 2-cyanomethylbenzoimidazole to produce 3-(benzothiazol-2-yl)-2-
amino-4-hydroxyquinoline (15) and 3-(benzimidazol-2-yl)-2-amino-4-hydroxy-
quinoline (16) respectively.
The mechanism proposed for the reaction by route (a) is the attack of
the nuceophilic group on the No. 4 carbon atom of the anhydride ring. The
sodium acetate appears to act as a catalyst by ionizing the activated nitriles,
followed by cyclization reaction to give the isolable reaction products. Mass
spectral measurements and analytical data are in complete agreement with
structures 15 and 16.
The results presented have thus opened a direct and efficient routes to
access to the otherwise not readily obtainable quinazolone fused hetero-
cycles and o-anilinoheterocycles.
EXPERIMENTAL
All melting points are uncorrected. FTIR spectra (KBr) were recorded
on a Nicolet Magna Model 550 IR spectrophotometer. 1H-NMR spectra in
CDCl3 were determined on a Brucker WP Spectrometer at 200 MHz with

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3542
FADDA ET AL.
TMS as internal standard. Mass spectra were recorded at 70 eV with a
varian MAT 311 instrument. Elemental analyses (C.H) agree satisfactorily
with the calculated values.
Reaction of 1 with o-Phenylenediamine
Amixture of isatoic anhydride (1) (1 g, 0.006 mol), o-phenylenedia-
mine (0.86 g, 0.008 mol) and freshly fused sodium acetate (0.3 g) in glacial
acetic acid (30 mL) was refluxed for 2 h, during which time yellowish crystals
separated from the solution. The reaction mixture was then cooled to room
temperature, the crystals were collected by filtration then fractionally recrys-
tallized using dilute acetic acid to obtain (85%) of compound (2) and (15%)
of compound (4) (cf. Table 1, 2).
Reaction of 1 with 2,3-Diaminopyridine
Amixture of ( 1) (1.63 g, 0.01 mol), 2,3-diaminopyridine (3.27 g,
0.03 mol) and freshly fused sodium acetate (0.5 g) in glacial acetic acid
(50 mL) was refluxed for 4 h, during which time yellowish solid material
separated from the solution. The reaction mixture was then cooled to
room temperature, the crystals were collected by filtration then fractionally
Table 1. Characterization Data of the Newly Prepared Compounds
Analysis, Found (Calcd) %
Compound
no.
M.P.
(ꢀC)
Yield
%
Molecular
formula
C
H
2
4
5
7
8
120
210
215
165
200
140
240
220
55
85
15
60
35
85
80
80
20
60
40
70
60
C14H9N3O
C13H11N3
C13H8N4O
C12H10N4
C14H8N2O2
C13H10N2S
C9H13N3O
C9H11N3
C9H12N2O2
C9H10N2O
C16H11N3OS
C16H12N4O
71.3 (71.5)
74.5 (74.6)
66.0 (66.1)
68.5 (68.6)
71.1 (71.2)
69.2 (69.0)
60.1 (60.3)
66.1 (66.6)
59.7 (60.0)
66.5 (66.6)
65.3 (65.5)
69.1 (69.5)
3.8 (3.8)
5.3 (5.3)
3.4 (3.4)
4.6 (4.8)
3.5 (3.4)
4.3 (4.9)
7.2 (7.3)
6.8 (6.8)
6.7 (6.6)
6.1 (6.2)
3.7 (3.8)
4.3 (4.3)
10
11
12
13
14
15
16
90
> 300
> 300

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ISATOIC ANHYDRIDE
Table 2. Spectroscopic Data of the Newly Prepared Compounds
3543
Com-
pound
no.
IR (cmꢁ1
(Selected bands)
)
Mass spectra
(Base peak)
1H NMR (ppm)
2
4
3300 (NH), 1650 (-CON)
6.3–7.4 (m, 8H, Ar-H), 236 (M + 1)
8.3 (s, 1H, NH)
3350–3400 (NH2), 3300 (NH)
6.4 (s, 2H, NH2), 6.5–7.7
(m, 8H, Ar-H), 8.25 (s,
1H, NH)
209 (M+)
5
7
3292 (NH), 1630 (-CON)
6.4–8.2 (m, 7H, Ar-H),
8.4 (s, 1H, NH)
236 (M+)
210 (M+)
3300–3400 (NH2), 3260 (NH)
6.2 (s, 2H, NH2), 6.3–8.2
(m, 7H, Ar-H), 8.2 (s,
1H, NH)
8
10
1647 (-CON)
3350–3400 (NH2),
1600 (C¼N)
6.3–7.5 (m, 8H, Ar-H)
6.3 (s, 2H, NH2), 6.4–7.5
(m, 8H, Ar-H)
3.25 (t, 2H, CH2), 3.45
(t, 2H, CH2), 4.7 (bs,
2H, NH2), 6.4 (s, 2H,
NH2), 6.4–7.5 (m, 4H,
Ar-H), 8.3 (s, 1H, NH)
238 (M + 2)
226 (M+)
11
3330–3400 (NH2),
1630 (-CON)
179 (M+)
12
13
3350–3400 (NH2), 3300 (NH),
1600 (C¼N)
3.2 (t, 2H, CH2), 3.35 (t, 161 (M ꢁ 1)
2H, CH2), 6.4 (s, 2H,
NH2), 6.45–7.5 (m, 4H,
Ar-H), 8.2 (s, 1H, NH)
3350–3400 (NH2), 3350 (OH),
3300 (NH), 1650 (-CON)
1.8 (s, 1H, OH), 3.2 (t,
2H, CH2), 3.35 (t, 2H,
CH2), 6.3 (s, 2H, NH2),
6.4–7.5 (m, 4H, Ar-H),
8.3 (s, 1H, NH)
180 (M+)
14
3350–3400 (NH2), 1600 (C¼N) 3.2 (t, 2H, CH2), 3.4 (t,
162 (M+)
2H, CH2), 6.3 (s, 2H,
NH2), 6.4–7.5 (m, 4H,
Ar-H)
15
16
3360–3400 (NH2), 3350 (OH)
6.2 (s, 2H, NH2), 294 (M + 1)
6.35–8.0 (m, 8H, Ar-H),
8.3 (s, 1H, OH)
6.25 (s, 2H, NH2),
6.3–8.1 (m, 8H, Ar-H),
8.3 (s, 1H, OH), 8.45 (s,
1H, NH).
3350–3400 (NH2), 3350 (OH),
3300 (NH).
276 (M+)

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FADDA ET AL.
recrystallized using dilute acetic acid to give (60%) of compound (5), and
(35%) of compound (7) (cf. Table 1, 2).
Reaction of 1 with 2-Amino-3-hydroxypyridine
Amixture of (1) (1 g, 0.006 mol), 2-amino-3-hydroxypyridine (0.88 g,
0.008 mol) and freshly fused sodium acetate (0.3 g) in glacial acetic acid
(30 mL) was refluxed for 2 h, during which time yellowish crystals separated
from the solution. The mixture was then cooled to room temperature, the
crystals were collected by filtration then recrystallized from dilute ethanol to
obtain compound (8).
Reaction of 1 with 2-Aminothiophenol
Amixture of ( 1) (1 g, 0.006 mol), 2-aminothiophenol (1.0 g, 0.008 mol)
and freshly fused sodium acetate (0.4 g) in glacial acetic acid (40 mL) was
refluxed for 3 h. The reaction mixture was cooled and the precipitate solid
material filtered, dried, and crystallized from acetic acid to give compound
10 (cf. Table 1, 2).
Reaction of 1 with Ethylene Diamine
Amixture of ( 1) (1.63 g, 0.001 mol), ethylene diamine (1.8 g, 0.03 mol)
and freshly fused sodium acetate (0.5 g) in glacial acetic acid (50 mL) was
refluxed for 4 h. The reaction mixture was then cooled to room temperature,
the crystals were collected by filteration then fractionally recrystallized using
dilute acetic acid to give (80%) of compound (11) and (20%) of compound
12 (cf. Table 1, 2).
Reaction of 1 with Ethanolamine
Amixture of ( 1) (1.63 g, 0.01 mol), ethanolamine (1.83 g, 0.03 mol) and
freshly fused sodium acetate (0.5 g) in presence of glacial acetic acid (50 mL)
was refluxed for 4 h. The reaction mixture was then cooled to room tem-
perature, the crystals were collected by filteration then fractionally recrys-
tallized from dilute acetic acid to give (60%) of compound (13) and (40%) of
compound (14) (cf. Table 1, 2).

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ISATOIC ANHYDRIDE
Reaction of 1 with 2-Cyanomethylbenzothiazole
3545
Amixture of ( 1) (1 g, 0.006 mol) 2-cyanomethylbenzothiazole (1.04 g,
0.006 mol) and freshly fused sodium acetate (0.3 g) in presence of glacial
acetic acid (30 mL) was refluxed for 2 h. The reaction mixture was then
cooled to room temperature and the precipitated solid material filtered,
dried and recrystallized from ethanol to give 15 (cf. Table 1, 2).
Reaction of 1 with 2-Cyanomethylbenzimidazole
Amixture of ( 1) (1 g, 0.006 mol), 2-cyanomethylbenzimidazole (0.94 g,
0.006 mol) and freshly fused sodium acetate (0.3 g) in presence of glacial
acetic and (30 mL) was refluxed for 2 h. The reaction mixture was then
cooled and the separated solid material was recrystallized from ethanol to
give 16 (cf. Table 1, 2).
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2. Meyer, J.; Wagner, E. J. Org. Chem. 1943, 8, 239.
3. Arthur Santilli, A.; Osdene, T.S. J. Org. Chem. 1964, 29, 1998.
4. Clark, R.H.; Wagner, E.C. J. Org. Chem. 1944, 9, 55.
5. Fadda, A.A.; Etman, H.A.; Amer, F.A.; J. Chem. Tech. Biotechnology
1995, 62, 170.
6. Fadda, A.A.; Etman, H.A.; Amer, F.A. ibid 1994, 61, 343.
7. Fadda, A.A.; Hassan, H.M. Indian J. Chem. 1990, 29B, 1020.
8. Staiger, R.P.; Miller, E.B. J. Org. Chem. 1959, 24, 1214.
9. Coppola, G.M. J. Heterocycl. Chem. 1979, 16, 897.
Received in the USAJanuary 21, 2001

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