Synthesis of 15H-isoquino[2′,3′:3,4]imidazo[2,1-b]quinazoline- 7,13,15-triones and 14H-isoquino[2′,3′:3,4]imidazo[2,1-b]benzo[g] quinazoline-8,14,16-trione as new polycyclic fused-ring systems

Article abstract of DOI:10.1080/104265090507533

3-Thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-dione (3) and 2-substituted 3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-diones (4a-1) were prepared from the reaction of 2-thiohydantoin (2) and 3-substituted 2-thiohydantoin (5a-l) with 2-formyl benzoic acid (1). Alkylation of 3 under an anhydrous basic conditions afforded 4a-i. The alkylation of 3 in aqueous basic solution afforded 3-(alkyl-mercapto)imidazo[1,5-b]isoquinoline-1,5-diones (7a,b). Reactions of the aromatic amino acids 9a,b and 12 with 7a afforded 2-(2H-1,5-dioxoimidazo[1,5-b] isoquinazolin-3-ylideneamino)benzoic acids (Wa, b) and 3-(2H-1,5-dioxoimidazo[1, 5-b]isoquinazolin-3-ylideneamino)-2-naphthalenecarboxylic acid (13), which were then cyclyzed by heating in acetic anhydride to afford 15H-isoquino[2',3':3,4]- imidazo[2,1-b]quinazoline-7,13,15-triones (11a,b) and 14H-isoquino-[2′, 3′:3,4]imidazo[2,1-b]benzo[g]quinazoline-8,14,16-trione (14). Some of the new compounds were tested for their antitumor activities.

Full text of DOI:10.1080/104265090507533

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Phosphorus, Sulfur, and Silicon
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SYNTHESIS OF 15H-
ISOQUINO[2′,3′:3,4]IMIDAZO[2,1-
B]QUINAZOLINE-7,13,15-
TRIONES AND 14H-
ISOQUINO[2′,3′:3,4]IMIDAZO[2,1-
B]BENZO[G]QUINAZOLINE-8,14,16-
TRIONE AS NEW POLYCYCLIC
FUSED-RING SYSTEMS
Ahmed I. Khodair a , Jean-Pierre Gesson b & El-Sayed
H. El-Ashry c
a Chemistry Department, Faculty of Education,
Tanta University (Kafr El-Sheikh Branch), Egypt
b Laboratoire de Chimie XII, Université de Poitiers et
CNRS, Poitiers, France
c Department of Chemistry, Faculty of Science,
Alexandria University, Alexandria, Egypt
Published online: 16 Aug 2010.
To cite this article: Ahmed I. Khodair , Jean-Pierre Gesson & El-Sayed H. El-Ashry
(2004): SYNTHESIS OF 15H-ISOQUINO[2′,3′:3,4]IMIDAZO[2,1-B]QUINAZOLINE-7,13,15-
TRIONES AND 14H-ISOQUINO[2′,3′:3,4]IMIDAZO[2,1-B]BENZO[G]QUINAZOLINE-8,14,16-
TRIONE AS NEW POLYCYCLIC FUSED-RING SYSTEMS, Phosphorus, Sulfur, and Silicon and
the Related Elements, 179:12, 2653-2665
To link to this article: http://dx.doi.org/10.1080/104265090507533

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Phosphorus, Sulfur, and Silicon, 179:2653–2665, 2004
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090507533
SYNTHESIS OF 15H-ISOQUINO[2ꢀ,3ꢀ:3,4]IMIDAZO[2,1-
B]QUINAZOLINE-7,13,15-TRIONES AND
14H-ISOQUINO[2ꢀ,3ꢀ:3,4]IMIDAZO[2,1-
B]BENZO[G]QUINAZOLINE-8,14,16-TRIONE AS NEW
POLYCYCLIC FUSED-RING SYSTEMS
Ahmed I. Khodair,a∗ Jean-Pierre Gesson,b
and El-Sayed H. El-Ashryc
Chemistry Department, Faculty of Education, Tanta University
(Kafr El-Sheikh Branch), Kafr El-Sheikh, Egypt;a Laboratoire
de Chimie XII, Universite´ de Poitiers et CNRS, Poitiers, France;b
Department of Chemistry, Faculty of Science, Alexandria
University, Alexandria, Egyptc
(Received April 21, 2004; accepted May 7, 2004)
3-Thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-dione (3) and 2-sub-
stituted 3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-diones (4a–l) were
prepared from the reaction of 2-thiohydantoin (2) and 3-substituted
2-thiohydantoin (5a–l) with 2-formyl benzoic acid (1). Alkyla-
tion of 3 under an anhydrous basic conditions afforded 4a–i.
The alkylation of 3 in aqueous basic solution afforded 3-(alkyl-
mercapto)imidazo[1,5-b]isoquinoline-1,5-diones (7a,b). Reactions of
the aromatic amino acids 9a,b and 12 with 7a afforded 2-(2H-1,5-
dioxoimidazo[1,5-b]isoquinazolin-3-ylideneamino)benzoic acids (10a,
b) and 3-(2H-1,5-dioxoimidazo[1,5-b]isoquinazolin-3-ylideneamino)-
2-naphthalenecarboxylic acid (13), which were then cyclyzed by
heating in acetic anhydride to afford 15H-isoquino[2ꢁ,3ꢁ:3,4]-
imidazo[2,1-b]quinazoline-7,13,15-triones (11a,b) and 14H-isoquino-
[2ꢁ,3ꢁ:3,4]imidazo[2,1-b]benzo[g]quinazoline-8,14,16-trione (14). Some
of the new compounds were tested for their antitumor activities.
Keywords: 3-Thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-diones; 14H-
isoquino[2ꢁ,3ꢁ :3,4]imidazo[2,1-b]benzo[g]quinazoline-8,14,16-trione;
15H-isoquino[2ꢁ,3ꢁ :3,4]imidazo[2,1-b]quinazoline-7,13,15-triones;
antitumor agents; polycyclic fused-ring systems
We thank ADIR (Groupe Servier, Paris) for carrying out the antitumor testing of
the prepared compounds and Prof. Dr. J. Jochims, (Fachbereich Chemie, Universita¨t
Konstanz, Konstanz, Germany), for valuable discussions.
Address correspondence to Ahmed I. Khodair, Chemistry Department, Faculty of
Education, Tanta University (Kafr El-Sheikh Branch), Kafr El-Sheikh, Egypt. E-mail:
khodair 62@yahoo.com
2653

2654
A. I. Khodair et al.
INTRODUCTION
A number of 5H,10H-imidazo[1,5-b]isoquinazoline-1,3-diones has
been synthesized1,2 for pharmacological evaluation, and some of
these compounds have been found to exhibit a higher positive isotropic
activity in guinea pig isolated atria, in comparison to (−)-isoprenaline.3
These results indicated that there was merit in continuing further
the investigations of these potentially useful compounds by in-
troducing functional groups to the tetrahydroisoquinoline ring, in
order to initiate exploration of the exoreceptor environment. Fur-
thermore, the biological activities of polycyclic fused-ring systems4
stimulated our interest in the syntheses and the chemistry of this
class of compounds. Moreover, Polycyclic quinazolines display a
wide range of biological activities including antihypertensive,5,6
antiinflammatory,7 antifungal,8 antimelanoma,9 anticarcinoma,9
and inhibiting platelet properties antiplatelet.10 Polycyclic quina-
zolines are antimetabolites11 and α1-adrenoceptor antagonists.12–15
This article describes simple and efficient procedures for the syn-
thesis of 2-substituted 3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-
diones (4a–l), 15H-isoquino[2ꢁ,3ꢁ:3,4]-imidazo[2,1-b]quinazoline-7,13,
15-triones (11a,b), and 14H-isoquino[2ꢁ,3ꢁ:3,4]-imidazo[2,1-b]benzo-
[g]quinazoline-8,14,16-trione (14) as novel polycyclic fused-ring sys-
tems. Furthermore, some tests for the biological effectiveness of the
hitherto unreported compounds are presented.
Retrosynthetic analysis of the target heterocyclic compounds of type
11 revealed two possible disconnections i–ii. The disconnection i can
lead to 10, whose synthesis can be achieved from the nucleophilic dis-
placement of a leaving group in 7 by amino group of anthranilic acid
and its derivatives 9. The alternative disconnection ii requires A, which
could panel from the reaction of B with C. The first approach seems to
be the most reliable one for the synthesis of the leaner condensed het-
erocyclic system and its analogues (Scheme 1).
RESULTS AND DISCUSSION
The condensation of 2-formyl benzoic acid (1) with 2-thiohydantoin
(2) in boiling acetic acid containing sodium acetate afforded the 3-
thioxoisoquinoline 3.16 This compound could be alkylated with alkyl
halides in the presence of NaH in anhydrous dimethylformamide (DMF)
to furnish the products 4a–i of N-alkylation exclusively. Correspond-
ingly, reaction of 3-substituted 2-thiohydantoins (5a–l) with 1 in the
presence of sodium acetate in refluxing acetic acid gave compounds 4a–l

New Polycyclic Fused-Ring Systems
2655
SCHEME 1
(Scheme 2). The structures of 4a–l were assigned on the basis of ele-
mental analyses and spectral data (IR, NMR, and MS). For instance,
the IR absorption spectrum of compound 4a did not show a signal for
NH around 3180 cm−1. Signals at 1738 and 1691 cm−1 were assigned
to the carbonyl groups. Analytical data for compound 4a revealed a
1
molecular formula C12H8N2O2S (m/z 244). The H NMR spectrum of
compound 4a showed a singlet at δ = 3.27 ppm assigned to the methyl
protons. Signals for the protons of the isoquinoline ring were found at
7.65, 7.80, 7.90, 8.00, and 8.38 ppm, respectively. The 13C NMR spec-
trum of compound 4a showed a methyl signal at δ = 27.65 ppm. Signals
for the carbons of the imidazoisoquinoline ring were found at 108.87,
127.65, 129.01, 129.05, 130.15, 130.91, 133.62, 134.56, 157.48, 161.05,
and 174.19 ppm, respectively (Scheme 2).
Compound 3 was condensed with formaldehyde in the presence of
morpholine to afford 2-(4-morpholinomethyl)-3-thioxo-2H-imidazo[1,5-
b]isoquinoline-1,5-dione (6). On the other hand, compound 3 was re-
acted with alkyl halides in aqueous NaOH in methanol to give 3-
(alkylmercapto)imidazo[1,5-b]isoquinoline-1,5-diones (7a,b). Reaction
of 7a with 12 M HCl in refluxing ethanol resulted in the formation
of 2H-imidazo[1,5-b]isoquinoline-1,3,5-trione (8).16 The IR absorption
spectrum of compound 8 showed signals at 3065, 1786, 1735, and

2656
A. I. Khodair et al.
SCHEME 2
1672 cm−1 assigned to NH and the carbonyl groups, respectively. A
1
singlet at δ = 10.52 ppm in the H NMR spectrum of compound 8 can
be assigned to the NH. The 13C NMR spectrum of compound 8 showed
a singlet at δ = 136.52 ppm assigned to C-3 (Scheme 3).
When 7a was treated with anthranilic acid derivatives (9a,b)
in refluxing ethanol, 2-(2H-1,5-dioxoimidazo[1,5-b]isoquinazolin-3-
ylideneamino)benzoic acids (10a,b) were produced, which could be
cyclyzed by heating in acetic anhydride to afford 15H-isoquino[2ꢁ,3ꢁ:
3,4]imidazo[2,1-b]quinazoline-7,13,15-triones (11a,b). Correspond-
ingly, 3-(2H-1,5-dioxoimidazo[1,5-b]isoquinazolin-3-ylideneamino)-2-
naphthalenecarboxylic acid (13) was prepared from the reaction of 7a
with 3-amino-2-naphthoic acid (12) in refluxing ethanol, which could be
cyclyzed in the same manner described above, and the corresponding
14H-isoquino[2ꢁ,3ꢁ:3,4]-imidazo[2,1-b]benzo[g]quinazoline-8,14,16-tri-
one (14) was obtained. The structure of 11a was supported by its mass
spectrum, which showed a molecular ion peak at m/z 315. In its IR
absorption spectrum signals at 1779, 1717, and 1691 cm−1 assigned
1
to the carbonyl groups. The H NMR spectrum of compound 11a did

New Polycyclic Fused-Ring Systems
2657
SCHEME 3
not show signals for NH and COOH around 13.31 and 13.68 ppm,
respectively. Signals for nine aromatic protons were observed at δ
7.79–8.59 ppm. In the 13C NMR spectrum the resonance of C-12 was
found at δ 110.90 ppm (Scheme 4).
SCHEME 4
In conclusion, we have described the successful synthesis of 3-thioxo-
2H-imidazo[1,5-b]isoquinoline-1,5-diones (4a–l), 15H-isoquino[2ꢁ,3ꢁ:3,

2658
A. I. Khodair et al.
TABLE I Antitumor Activity of 2-[2-(4-morpholino)ethyl]-3-thioxo-2H-
imidazo[1,5-b]isoquinoline-1,5-dione (4e), 15H-isoquino[2ꢁ,3ꢁ:3,4] imidazo[2,1-
b]quinazoline-7,13,15-triones (11a,b), and 14H-isoquino-[2ꢁ,3ꢁ:3,4]-
imidazo[2,1-b]-benzo[g]-quinazoline-8,14,16-trione (14) Against
Leukemia-1210
Compound
IC50a(µM) cellules L-1210
4e
11a
4.90
>10
11b
14
Doxorubicin
Insoluble
22.40
0.02
a50% Inhibitory concentration: molar concentration of compound that causes 50%
inhibition for cell growth.
4]-imidazo[2,1-b]quinazoline-7,13,15-triones (11a,b) and 14H-iso-
quino[2ꢁ,3ꢁ:3,4]imidazo[2,1-b]benzo[g]quinazoline-8,14,16-trione (14)
via simple and efficient methods. These compounds were submitted to
antitumor tests. Compounds 4e, 11a,b, and 14 were screened against
leukemia-1210; however, they were found to be considerably less
active than doxorubicin (Table I). The antiviral and further antitumor
activities of the new prepared compounds are under investigation and
will be reported in the due time.
EXPERIMENTAL
Aluminum sheets coated with silica gel 60 F254 (Merk) were used
for thin layer chromatography (TLC). Detection was effected by view-
ing under a short wavelength UV lamp. IR spectra (KBr discs, cm−1
)
were obtained on a Pye Unicam Spectrometer 1000. 1H NMR spec-
tra were measured on a Bruker Advance DPX 300 MHz spectrometers
in dimethylsolfoxide (DMSO)-d6 and CDCl3 using tetramethylsilane
(TMS) as internal standard, δ values, couplings J in Hz. Mass spec-
tra were recorded on a Varian MAT 112 spectrometer. Analytical data
were obtained from the Service Central de Microanalyse (CNRS, Lyon).
The 3-substituted 2-thiohydantoins 5a–l were prepared according to the
published method15 for the preparation of 3-phenyl-2-thiohydantoin.
3-Thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-dione (3)
A mixture of 1 (1.50 g, 10 mmol), anhydrous sodium acetate (2.80 g,
34 mmol), and 2 (1.16 g, 10 mmol) in glacial acetic acid (14 ml) was
boiled under reflux for 4 h (TLC). After cooling to room temperature,

New Polycyclic Fused-Ring Systems
2659
the reaction mixture was poured into cold water. The separated crystals
were collected by filtration and recrystallization from ethanol to give
1.80 g (78%) of orange 3, m.p. 325–327◦C (Lit.16 m.p. 278–279◦C). IR:
1
ν 3176 (NH), 1739, 1690 (2 × CO). H NMR (DMSO-d6): δ 7.50 (s, 1H,
10-H), 7.75, 7.85 (2t, J = 7.8 Hz, 2-H, 7-H, 8-H), 7.96, 8.36 (2d, J = 7.8
Hz, 2H, 6-H, 9-H). 13.29 (s, 1H, NH). 13C NMR (DMSO-d6): δ 107.92,
128.92, 128.85, 129.10, 130.10, 130.68, 134.03, 134.43, 157.80 (C-Ar),
162.27 (C-1), 175.45 (C-3); MS, m/z = 230 (M+).
General Procedures for the Preparation of 2-substituted
3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-diones 4a–l
Method A
A mixture of 1 (0.15 g, 1 mmol), anhydrous sodium acetate (0.28 g,
3.40 mmol) and 5a–l (1 mmol) in glacial acetic acid (3 ml) was boiled un-
der reflux for 4 h (TLC). After cooling to room temperature, the reaction
mixture was poured into cold water. The separated crystals were col-
lected by filtration and recrystallization from ethanol to give the pure
products 4a–l (Scheme 2).
Method B
At room temperature compound 3 (230 mg, 1 mmol) was suspended
in anhydrous DMF (3 ml). NaH (60%, 45 mg, 1 mmol) was added and
the mixture was stirred for 30 min. Alkyl halide (1 mmol) was added
to the clear solution, and the mixture was stirred at 50–60◦C for 12 h
until the starting materials were consumed (TLC). Filtration and evap-
oration of the filtrate under reduced pressure afforded a residue, which
was purified by flash chromatography (eluent: diethyl ether/petroleum
ether, 40–60◦C) (1:1) and gave the pure products 4a–i (Scheme 2).
2-Methyl-3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-
dione (4a)
Yield 220 mg (90%; method A), 166 mg (72%; method B) of yellow
crystals, m.p. 240–242◦C (Lit.16 m.p. 242◦C). IR: ν 1738, 1691 (2 × CO).
1H NMR (DMSO-d6): δ 3.27 (s, 3H, CH3), 7.65 (s, 1H, 10-H), 7.80, 7.90
(2t, J = 7.8 Hz, 2-H, 7-H, 8-H), 8.00, 8.38 (2d, J = 7.8 Hz, 2H, 6-H,
9-H). 13C NMR (DMSO-d6): δ 27.65 (CH3), 108.87 (C-10), 127.65, 129.01,
129.05, 130.15, 130.91, 133.62, 134.56 (C-Ar), 157.48 (C-5), 161.05 (C-1),
174.19 (C-3); MS, m/z = 244 (M+).
2-Ethyl-3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-dione
(4b)
Yield 245 mg (95%; method A), 202 mg (78%; method B) of yellow
crystals, m.p. 211–213◦C. IR: ν 1736, 1691 (2 × CO). 1H NMR (CDCl3):

2660
A. I. Khodair et al.
δ 1.24 (t, J = 7.2 Hz, 3H, 2ꢁ-H), 3.88 (q, J = 7.2 Hz, 2H, 1ꢁ-H), 7.26 (s,
1H, H-10), 7.65–8.56 (m, 4H, 6-H, 7-H, 8-H, 9-H). MS, m/z = 258 (M+).
Calcd. for C13H10N2O2S (258.29): C, 60.45; H, 3.90; N, 10.84. Found: C,
60.28; H, 4.12; N, 10.63.
2-Hexyl-3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-dione
(4c)
Yield 250 mg (80%; method A), 192 mg (61%; method B) of yellow
crystals, m.p. 176–178◦C. IR: ν 1730, 1692 (2 × CO). 1H NMR (CDCl3):
δ0.88 (t, J = 7.5 Hz, 3H, 6ꢁ-H), 1.30 (m, 6H, 5ꢁ-H, 4ꢁ-H, 3ꢁ-H), 1.72
(m, 2H, 2ꢁ-H), 3.82 (t, J = 7.5 Hz, 2H, 1ꢁ-H), 7.27 (s, 1H, 10-H), 7.64–
8.54 (m, 4H, 6-H, 7-H, 8-H, 9-H). 13C NMR (CDCl3): δ 13.88 (C-6ꢁ),
22.39 (C-5ꢁ), 26.34 (C-4ꢁ), 27.04 (C-3ꢁ), 3.19 (C-2ꢁ), 41.19 (C-1ꢁ), 108.72
(C-10), 126.92, 128.05, 129.51, 129.84, 130.65, 133.02, 134.06 (C-Ar),
157.75 (C-5), 160.75 (C-1), 172.37 (C-3). MS, m/z = 314 (M+). Calcd. for
C17H18N2O2S (314.40): C, 64.94; H, 5.77; N, 8.91. Found: C, 65.06; H,
5.82; N, 8.66.
2-Allyl-3-thioxo-2H-imidazo[1,5-b]isoquinoline-
1,5-dione (4d)
Yield 225 mg (87%; method A), 180 mg (70%; method B) of yellow
crystals, m.p. 198–200◦C (Lit.16 m.p. 204◦C). IR: ν 1729, 1694 (2 × CO).
1H NMR (DMSO-d6): δ 4.60 (dd, J = 1.31, 5.6 Hz, 2H, 3ꢁ-H), 5.25 (m, 2H,
1ꢁ-H), 5.87 (m, 1H, 2ꢁ-H), 7.50 (s, 1H, 10-H), 7.73–8.48 (m, 4H, 6-H, 7-H,
8-H, 9-H). 13C NMR (DMSO-d6): δ 42.75 (C-3ꢁ), 118.56 (C-2ꢁ), 109.31,
125.68, 126.78, 129.24, 129.79, 130.72, 133.15, 134.23 (C-Ar), 157.61
(C-5), 160.17 (C-1), 172.27 (C-3). MS, m/z = 270 (M+).
2-[2-(4-Morpholino)ethyl]-3-thioxo-2H-imidazo[1,5-
b]isoquinoline-1,5-dione (4e)
Yield 302 mg (88%; method A), 257 mg (75%; method B) of yellow
crystals, m.p. 189–191◦C. IR: ν 1738, 1690 (2 × CO). 1H NMR (CDCl3):
δ 2.54 (t, J = 4.5 Hz, 4H, 2ꢁꢁ-H, 6ꢁꢁ-H), 2.72 (t, J = 6.0 Hz, 2H, 2ꢁ-H), 3.64
(t, J = 4.5 Hz, 4H, 3ꢁꢁ-H, 5ꢁꢁ-H), 4.16 (t, J = 6.0 Hz, 2H, 1ꢁ-H), 7.33 (s,
1H, H-10), 7.69-8.60 (m, 4H, 6-H, 7-H, 8-H, 9-H). 13C NMR (CDCl3): δ
38.12 (C-2ꢁ), 53.69 (C-2ꢁꢁ, C-6ꢁꢁ), 54.85 (C-1ꢁ), 66.95 (C-3ꢁꢁ, C-5ꢁꢁ), 109.12
(C-10), 126.98, 129.43, 129.67, 130.06, 130.88, 133.18, 134.28 (C-Ar),
158.01 (C-5), 160.97 (C-1), 172.60 (C-3). MS, m/z = 343 (M+). Calcd. for
C17H17N3O3S (343.41): C, 59.46; H, 4.99; N, 12.24. Found: C, 59.21; H,
5.30; N, 12.46.

New Polycyclic Fused-Ring Systems
2661
2-[3-(4-Morpholino)propyl]-3-thioxo-2H-imidazo[1,5-
b]isoquinoline-1,5-dione (4f)
Yield 300 mg (84%; method A), 260 mg (73%; method B) of yellow
crystals, m.p. 192–194◦C. IR: ν 1730, 1693 (2 × CO). 1H NMR (CDCl3):
δ 1.94 (m, 2H, 2ꢁ-H), 2.38 (t, J = 4.5 Hz, 4H, 2ꢁꢁ-H, 6ꢁꢁ-H), 2.46 (t, J =
6.4 Hz, 2H, 3ꢁ-H), 3.57 (t, J = 4.5 Hz, 4H, 3ꢁꢁ-H, 5ꢁꢁ-H), 4.13 (t, J = 6.5
Hz, 2H, 1ꢁ-H), 7.31 (s, 1H, H-10), 7.68–8.60 (m, 4H, 6-H, 7-H, 8-H, 9-H).
13C NMR (CDCl3): δ 23.20 (C-2ꢁ), 39.89 (C-3ꢁ), 53.65 (C-2ꢁꢁ, C-6ꢁꢁ), 56.23
(C-1ꢁ), 66.95 (C-3ꢁꢁ, C-5ꢁꢁ), 108.78 (C-10), 127.11, 129.42, 129.50, 129.98,
130.84, 133.07, 134.27 (C-Ar), 157.85 (C-5), 161.04 (C-1), 172.60 (C-3).
MS, m/z = 357 (M+). Calcd. for C18H19N3O3S (357.42): C, 60.49; H, 5.36;
N, 11.75. Found: C, 60.28; H, 5.48; N, 11.57.
2-(3-Dimethylaminopropyl)-3-thioxo-2H-imidazo[1,5-
b]isoquinoline-1,5-dione (4g)
Yield 250 mg (79%; method A), 233 mg (74%; method B) of yellow
crystals, m.p. 199–201◦C. IR: ν 1739, 1691 (2 × CO). 1H NMR (CDCl3):
δ 2.33 (m, 2H, H-2ꢁ), 3.00 (s, 6H, NMe2), 3.34 (m, 2H, H-3ꢁ), 4.21 (m,
2H, H-1ꢁ), 7.60 (s, 1H, H-10), 7.82–8.61 (m, 4H, 6-H, 7-H, 8-H, 9-H).
13C NMR (CDCl3): δ 23.49 (C-2ꢁ), 38.58 (C-3ꢁ), 44.37 (CH3), 56.76 (C-1ꢁ),
113.30 (C-10), 126.37, 129.24, 130.83, 130.99, 132.96, 133.77, 136.37
(C-Ar), 158.85 (C-5), 163.26 (C-1), 172.37 (C-3). MS, m/z = 315 (M+).
Calcd. for C16H17N3O2S (315.39): C, 60.93; H, 5.43; N, 13.32. Found: C,
60.78; H, 5.60; N, 13.56.
2-Benzyl-3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-
dione (4h)
Yield 300 mg (94%; method A), 282 mg (88%; method B) of yellow
crystals, m.p. 216–218◦C. IR: ν 1737, 1694 (2 × CO). 1H NMR (CDCl3):
d5.22 (s, 2H, H-1ꢁ), 7.29–8.56 (m, 10H, 6-H, 7-H, 8-H, 9-H, 10-H, C6H5).
MS, m/z = 320 (M+). Calcd. for C18H12N2O2S (320.37): C, 67.48; H, 3.78;
N, 8.74. Found: C, 67.25; H, 4.00; N, 8.62.
2-(2-Phenylethyl)-3-thioxo-2H-imidazo[1,5-b]isoquinoline-
1,5-dione (4i)
Yield 284 mg (85%; method A), 242 mg (72%; method B) of yellow crys-
tals, m.p. 210–212◦C. IR: ν 1730, 1691 (2 × CO). 1H NMR (CDCl3): δ 3.05
(t, J = 7.60 Hz, 3H, 2ꢁ-H), 4.28 (s, 2H, 1ꢁ-H), 7.55 (s, 1H, 10-H), 7.26–8.63
(m, 9H, 6-H, 7-H, 8-H, 9-H, C6H5). Dept-135 NMR (CDCl3): δ 33.26 (C-
2ꢁ), 43.23 (C-1ꢁ), 111.99 (C-10), 127.40, 129.07, 129.14, 130.43, 130.58,
132.22, 135.68 (Ar-HC). MS, m/z = 334 (M+). Calcd. for C19H14N2O2S
(334.39): C, 68.25; H, 4.22; N, 8.38. Found: C, 68.12; H, 4.45; N, 8.03.

2662
A. I. Khodair et al.
2-Phenyl-3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-
dione (4j)
Yield 300 mg (98%; method A) of yellow crystals, m.p. 343–345◦C
(Lit.16 m.p. 342◦C and Lit.17 m.p. 300◦C). IR: ν 1739, 1694 (2 × CO). 1H
NMR (DMSO-d6): δ 7.67 (s, 1H, H-10), 7.38–8.45 (m, 9H, 6-H, 7-H, 8-H,
9-H, C6H5). MS, m/z = 306 (M+).
2-(2-Chlorophenyl)-3-thioxo-2H-imidazo[1,5-
b]isoquinoline-1,5-dione (4k)
Yield 224 mg (66%; method A) of yellow crystals, m.p. 289–291◦C. IR:
ν 1738, 1694 (2 × C). 1H NMR (DMSO-d6): δ 7.43–8.50 (m, 9H, 6-H, 7-H,
8-H, 9-H, 10-H, C6H4). MS, m/z = 340 (M+). Calcd. for C17H9ClN2O2S
(340.78): C, 59.92; H, 2.66; N, 8.22. Found: C, 59.76; H, 2.58; N, 8.15.
2-(4-Methylphenyl)-3-thioxo-2H-imidazo[1,5-
b]isoquinoline-1,5-dione (4l)
Yield 300 mg (94%; method A) of yellow crystals, m.p. 310–312◦C.
1
IR: ν 1734, 1691 (2 × CO). H NMR (DMSO-d6): δ 2.39 (s, 3H, CH3),
7.27–8.43 (m, 9H, 6-H, 7-H, 8-H, 9-H, 10-H, C6H4). MS, m/z = 320 (M+).
Calcd. for C18H12N2O2S (320.37): C, 67.48; H, 3.78; N, 8.74. Found: C,
67.62; H, 3.98; N, 8.54.
2-(4-Morpholinomethyl)-3-thioxo-2H-imidazo[1,5-
b]isoquinoline-1,5-dione (6)
A mixture of 3 (230 mg, 1 mmol) and morpholine (87 mg, 1 mmol mole) in
EtOH (3 ml) was added to 36% aqueous formaldehyde (0.1 ml, 1 mmol).
After stirring at temperature for 12 h the precipitate was collected by
filtration. Recrystallization from EtOH gave the product 6, yield 299 mg
(91%) of orange crystals, m.p. 226–228◦C. IR: ν 1737, 1693 (2 × CO).
1H NMR (DMSO-d6): δ 2.30 (m, 4H, 2ꢁ-H, 6ꢁ-H), 3.50 (m, 4H, 3ꢁ-H, 5ꢁ-H),
4.57 (s, 2H, CH2), 7.25 (s, 1H, 10-H), 7.45, 7.65 (2t, J = 7.70 Hz, 2H,
7-H, 8-H), 7.76, 8.15 (2d, J = 7.8 Hz, 2H, 6-H, H-9). 13C NMR (DMSO-
d6): δ 51.13 (C-2ꢁ, C-6ꢁ), 65.86 (CH2), 66.28 65.96 (C-3ꢁ, C-5ꢁ), 107.65
(C-10), 128.87, 128.24, 129.10, 130.01, 130.56, 134.02, 134.34 (C-Ar),
157.71 (C-5), 162.63 (C-1), 175.82 (C-3). MS, m/z = 329 (M+). Calcd. for
C16H15N3O3S (329.37): C, 58.34; H, 4.59; N, 12.76. Found: C, 58.24; H,
4.58; N, 12.60.
3-(Alkylmercapto)imidazo[1,5-b]isoquinoline-1,5-
diones (7a,b)
Aqueous NaOH (2.2%, 10 ml) was added to a suspension of 3 (1.15 g,
5 mmol) in MeOH (20 ml). After addition of MeI (0.35 g, 5 mmol) or

New Polycyclic Fused-Ring Systems
2663
allyl iodide (0.84 g, 5 mmol), the reaction mixture was stirred at room
temperature for 12 h. Filtration and recrystallization of the residue
from MeOH afforded the products 7a,b, respectively.
3-(Methylmercapto)imidazo[1,5-b]isoquinoline-1,5-
dione (7a)
Yield 212 mg (87%) of red crystals, m.p. 294–296◦C. IR: ν 1718, 1675
(2 × CO). 1H NMR (DMSO-d6): δ 2.68 (s, 3H, SCH3), 7.56 (s, 1H, H-10),
7.70, 7.82 (2t, J = 8.1 Hz, 2H, 7-H, 8-H), 7.90, 8.36 (2d, J = 7.1 Hz,
2H, 6-H, 9-H). MS, m/z = 244 (M+). Calcd. for C12H8N2O2S (244.26): C,
59.01; H, 3.30; N, 11.47. Found: C, 59.23; H, 3.58; N, 11.34.
3-(Allylmercapto)imidazo[1,5-b]isoquinoline-1,5-
dione (7b)
Yield 201 mg (74%) of orange crystals, m.p. 222–224◦C. IR: ν 1718,
1676 (2 × CO). 1H NMR (CDCl3): δ 4.04 (d, J = 7.00 Hz, 2H, 3ꢁ-H), 5.40
(m, 2H, 1ꢁ-H), 6.06 (m, 1H, 2ꢁ-H), 7.42 (s, 1H, 10-H), 7.75–8.5 (m, 4H, 6-H,
8-H, 7-H, H-9). 13C NMR (CDCl3): δ 35.93 (C-3ꢁ), 111.73 (C-10), 120.54
(C-2ꢁ), 127.66 (C-1ꢁ), 125.90, 129.46, 129.99, 130.84, 134.69, 134.89 (C-
Ar), 157.45 (C-5), 172.60 (C-1), 179.11 (C-3). MS, m/z = 270 (M+). Calcd.
for C14H10N2O2S (270.31): C, 62.21; H, 3.73; N, 10.36. Found: C, 62.00;
H, 3.84; N, 10.32.
2H-Imidazo[1,5-b]isoquinoline-1,3,5-trione (8)
A solution of 7a (0.24 g, 1 mmol) in EtOH (10 ml) containing 12M HCl
(1 ml) was refluxed for 2 h. After cooling to room temperature, the
precipitate was filtered off and crystallized from AcOH to give product
8, yield 167 mg (78%) of pale yellow crystals, m.p. 286–288◦C (Lit.16 m.p.
278◦C). IR: ν 3065 (N H), 1786, 1735, 1672 (3 × CO). 1H NMR (DMSO-
d6): δ 7.34 (s, 1H, 10-H), 7.57–8.24 (m, 4H, 6-H, H-7, H-8, H-9), 10.52 (s,
1H, NH). 13C NMR (DMSO-d6): δ 106.31 (C-10), 127.08, 127.10, 127.18,
127.93, 128.46, 132.12, 134.43 (C-Ar), 136.52 (C-3), 161.33 (C-5), 162.93
(C-1). MS, m/z = 214 (M+).
2-(2H-1,5-Dioxoimidazo[1,5-b]isoquinazolin-3-
ylideneamino)benzoic Acid (10a)
A mixture of 7a (460 mg, 2 mmol) and anthranilic acid (300 mg, 2 mmol),
respectively 4,5-dimethoxy-2-aminobenzoic acid (400 mg, 2 mmol), re-
spectively 3-amino-2-naphthoic acid (374 mg, 2 mmol) in EtOH (10 ml)
was heated under reflux for 24 h. After cooling to room temperature the
precipitate was collected by filtration and recrystallized from DMF to

2664
A. I. Khodair et al.
give the product 10a: Yield 500 mg (75%) of yellow crystals, m.p. 258–
260◦C. IR: ν 3064 (NH), 1780, 1720, 1670 (3 × CO). 1H NMR (DMSO-d6):
δ 7.52 (s, 1H, 10-H), 7.33–8.77 (m, 8H, Ar-H), 13.31 (s, 1H, NH), 13.68
(br. s, 1H, COOH). MS, m/z = 333 (M+). Calcd. for C18H11N3O4 (333.31):
C, 64.86; H, 3.33; N, 12.60. Found: C, 64.62; H, 3.50; N, 12.49.
4,5-Dimethoxy-2-(2H-1,5-dioxoimidazo[1,5-
b]isoquinazolin-3-ylideneamino)benzoic Acid (10b)
From 400 mg (2 mmol) of 4,5-dimethoxy-2-aminobenzoic acid in the
manner described for 10a. Recrystallization from DMF afforded 10b,
yield 495 mg (62%) of yellow crystals, m.p. >300◦C. IR: ν 3067 (NH),
1776, 1718, 1674 (3 × CO). 1H NMR (DMSO-d6): δ 3.81, 3.91 (2s, 6H, 3
CH3), 7.37–8.61 (m, 7H, H-Ar), 13.57 (s, 1H, NH). MS, m/z = 393 (M+).
Calcd. for C20H15N3O6 (393.34): C, 61.07; H, 3.84; N, 10.68. Found: C,
60.85; H, 3.66; N, 10.52.
3-(2H-1,5-Dioxoimidazo[1,5-b]isoquinazolin-3-
ylideneamino)-2-naphthalenecarboxylic Acid (13)
From 374 mg (2 mmol) of 3-amino-2-naphthoic acid in the manner de-
scribed for 10a. Recrystallization from DMF afforded 13, yield 520 mg
(68%) of yellow crystals, m.p. >300◦C. IR: ν 3068 (NH), 1779, 1719, 1672
(3 × CO). 1H NMR (DMSO-d6): δ 7.51–9.68 (m, 11H, Ar-H), 12.30 (s, 1H,
NH). MS, m/z = 383 (M+). Calcd. for C22H13N3O4 (383.37): C, 68.93; H,
3.42; N, 10.96. Found: C, 68.78; H, 3.64; N, 10.71.
15H-Isoquino[2ꢀ,3ꢀ:3,4]imidazo[2,1-b]quinazoline-
7,13,15-trione (11a)
A mixture of 10a (333 mg, 1 mmol) and Ac2O (3 ml) was heated under
reflux for 2 h. The reaction mixture was poured into ice water. The pre-
cipitate was collected by filtration and recrystallized from DMF to give
the product 11a, yield 299 mg (95%) of orange crystals, m.p. >350◦C. IR:
ν 1779, 1717, 1691 (3 × CO). 1H NMR (DMSO-d6): δ 7.79–8.59 (m, 9H,
H-Ar). 13C NMR (DMSO-d6): δ 110.90 (C-12), 120.16, 122.18, 122.18,
122.84, 123.40, 127.86, 131.39, 131.76, 132.53, 133.94, 135.53, 135.77,
136.09, 136.65, 139.29, 140.48 (C-Ar), 149.42, 154.81, 156.35 (C-7, C-13,
C-15). (MS, m/z = 315 (M+). Calcd. for C18H9N3O3 (315.29): C, 68.57;
H, 2.88; N, 13.32. Found: C, 68.36; H, 3.09; N, 13.18.

New Polycyclic Fused-Ring Systems
2665
2,3-Dimethoxy-15H-isoquino[2ꢀ,3ꢀ:3,4]imidazo[2,1-b]-
quinazoline-7,13,15-trione (11b)
From 393 mg (1 mmol) of 10b in the manner described for 11a. Re-
crystallization from DMF afforded 11b, yield 337 mg (90%) of yellow
crystals, m.p. >300◦C. IR: ν 1779, 1718, 1691 (3 × CO). 1H NMR (DMSO-
d6): δ 3.66, 3.82 (2s, 6H, 3 CH3), 7.19–8.20 (m, 7H, H-Ar). MS, m/z = 375
(M+). Calcd. for C20H13N3O5 (375.34): C, 64.00; H, 3.49; N, 11.19. Found:
C, 63.83; H, 3.68; N, 10.90.
14H-Isoquino[2ꢀ,3ꢀ:3,4]imidazo[2,1-
b]benzo[g]quinazoline-8,14,16-trione (14)
From 383 mg (1 mmol) of 13 in the manner described for 11a. Re-
crystallization from DMF afforded 14, yield 314 mg (86%) of orange
crystals, m.p. >350◦C. IR: ν 1780, 1716, 1694 cm−1 (3 × CO). 1H NMR
(DMSO-d6): δ 7.76–8.60 (m, 11H, H Ar); (MS, m/z = 365 (M+). Calcd.
for C22H11N3O3 (365.35): C, 72.33; H, 3.03; N, 11.50. Found: C, 72.06;
H, 3.18; N, 11.28.
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