Full text of DOI:10.1002/jhet.5570390204

Mar-Apr 2002
A Convenient Synthesis of 5- and 8-
Nitroquinazoline-2,4-dione Derivatives
271
D. Aziane [a,b], M. Soukri [a,c], A. El Hakmaoui [a], S. Lazar [a],
*
*
E. M. Essassi [b], G. Guillaumet [c] and M. Akssira [a]
[a] Laboratoire de Chimie Bioorganique et Analytique, FST-Université Hassan II - Mohammedia,
BP 146, 20650 Mohammedia, Maroc
[b] Laboratoire de Chimie Hétérocyclique, FS-Université Mohamed V, Rabat, Maroc
[c] Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d’Orléans,
BP 6759, 45067 Orléans cedex 2, France
Received April 9, 2001
3-Nitrophthalic acid 1 was converted selectively to the two regioisomeric monoesters 2 and 3, which were
subsequently transformed via Curtius rearrangement to the corresponding 5- and 8-nitroquinazoline-2,4-
diones 4 and 5, respectively. The reduction of the nitro group produced 5- and 8-aminoquinazoline-2,4-
diones 6 and 7, respectively, in good yields. The condensation of compounds 7b and 7c with carbon disulfide
in pyridine afforded tricyclic derivatives 9, which are analogues of the HIV-1 reverse transcriptase inhibitor
4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one (TIBO).
J. Heterocyclic Chem., 39, 271 (2002).
Quinazolines are important medicinal agents and
in vivo [6], and more recently as potent fibrinogen receptor
antagonists [7]. Thus, several synthetic pathways for the
preparation of these heterocyclic compounds have been
described [8], most of them start from derivatives of
anthranilic acid.
We have also shown [9] previously that the phthalic
anhydride can be a versatile starting material for the
synthesis of quinazoline-2,4-diones. In the present work,
we describe a convenient and regioselective synthesis of
the two regioisomeric 5- and 8-nitroquinazoline-2,4-
diones 4 and 5 starting from commercially available
3-nitrophthalic acid 1. In fact, the key intermediates,
pharmacological tools that have been applied to a variety
of therapeutic areas [1]. In particular, quinazoline-2,4-
diones form an interesting class of heterocycles with broad
synthetic applications in medicinal chemistry as starting
materials for biologically active compounds [2].
Additionally, some quinazoline-2,4-diones derivatives
have been reported to exhibit anticonvulsant activity
against electroshock [3], to possess sedative and hypo-
tensive properties [4], and also to cause vasodilatation [5]
in animals. They are also characterized as phospho-
diesterase (PDE) inhibitors with antiinflammatory activity

272
D. Aziane, M. Soukri, A. El Hakmaoui, S. Lazar, E. M. Essassi, G. Guillaumet and M. Akssira
Vol. 39
monoesters 2 and 3, can be prepared on a large scale from
1 according to the literature methods [10]. First, the
addition of acetic anhydride to 1 in methanol afforded the
monoester 2 in good yield; on the other hand, treatment of
1 with a saturated solution of hydrogen chloride in
methanol gave the monoester 3 in excellent yield.
Activation of the monoesters 2 and 3 with ethyl chloro-
formate in the presence of triethylamine and subsequent
reaction with sodium azide afforded acyl azides. The
unpurified acyl azides were then heated in refluxing
xylene in the presence of various amines. Under these con-
ditions, rearrangement of the acyl azides to isocyanates,
trapping with the amines and cyclization to the corre-
sponding nitroquinazoline-2,4-diones 4a-f and 5a-f
occurred in one pot (Scheme 1).
The reduction of aromatic nitro compounds by catalytic
hydrogenation is probably the best known method to
synthesize aromatic amines. Thus, reduction of the nitro-
quinazoline-2,4-diones 4a-f and 5a-f, was achieved in
methanol in the presence of palladium on carbon to yield
the 5- and 8-aminoquinazoline-2,4-diones 6a-f and 7a-f,
respectively (Scheme 2).
or 7c were condensed with carbon disulfide in pyridine,
the desired tricyclic derivatives 9b or 9c were isolated in
good yield (Scheme 3).
Compounds 4-9 were fully characterized by NMR
spectroscopy, mass spectrometry and elemental analysis.
The HMQC and HMBC data for 4-9 are in agreement with
the proposed structures.
Anti-HIV activities of the synthetized compounds were
evaluated in HeLa/CD /cells. No significant activities
4
were observed against HIV. The toxicities of these
quinazolinediones were also assessed, and these
compounds did not exhibit any significant toxicities at
concentration up to 100 µM in HeLa cells.
In summary, we have described a versatile, simple,
reliable, and an efficient method for the preparation of the
two regioisomeric 5- and 8-nitroquinazoline-2,4-diones
4a-f and 5a-f and their amino derivatives 6a-f and 7a-f. The
reaction of aminoquinazoline-2,4-diones 7b,c with carbon
disulfide in pyridine gave the tricycles 9b,c in good yields.
We then turned our attention to obtain tricyclic
six-membered ring, analogues of the 4,5,6,7-tetrahydro-5-
methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one
(TIBO) [11] class of HIV-1 reverse transcriptase inhibitors
exemplified by 10 (Scheme 3). When 8-amino-3-
phenylquinazoline-2,4-dione 7b or 8-amino-3-(p-
methoxyphenyl)quinazoline-2,4-dione 7c were reacted
with carbon disulfide and potassium hydroxide in
refluxing methanol to obtain the tricyclic derivatives 9b or
9c, the 4-carbomethoxybenzimidazol-2-thione 8 was the
only product isolated. Obviously, 9b or 9c are formed in
this reaction but they are easily converted, under these
conditions, to 8 by a facile ring opening. This assumption
is based on the fact that the compounds 9b or 9c treated
with 1.1 equivalent of potassium hydroxide in methanol at
reflux during 24 hours lead to the desired derivative 8 in
80% yield, while the same treatment applied to 7a or 7c
leaves the starting material unchanged. However, when 7b
EXPERIMENTAL
1
13
The H nmr and C nmr spectra were obtained with a Bruker
Avance DPX250, 250 MHz instrument, in dimethyl-d sulfoxide
6
with TMS as internal standard, chemical shifts (δ values) were
reported in parts per million (ppm) and coupling constants (J val-
ues) in Hz. The ir spectra were recorded as a KBr pellet on a
Perkin-Elmer spectrometer FT PARAGON 1000PC, and ms
spectra were recorded on a Perkin-Elmer mass spectrometer
SCIEX API 300 (ionspray or heat nebuliser). Melting points were
measured using a Kofler hot stage apparatus and are uncorrected.
The solvents used were HPLC grade.
General Procedure for the Preparation of Nitroquinazoline-
diones 4a-f and 5a-f.
To a cold solution (-10 °C) of monoester 2 or 3 (1.2 g, 5.3 mmol)
and triethylamine (1.60 ml, 11.5 mmol) in tetrahydrofuran (25 ml)
was added dropwise ethyl chloroformate (0.80 ml, 8.4 mmol), and

Mar-Apr 2002
A Convenient Synthesis of 5- and 8-Nitroquinazoline
273
the resulting solution was stirred with ice cooling for 1 hour. A
Anal. Calcd. for C H N O : C, 50.53; H, 2.47; N, 24.55.
12 7 5 4
solution of NaN (Warning: explodes when heated) (0.93 g,
Found: C, 50.69; H, 2.30; N, 24.75.
3
14.3 mmol) in water (7 ml) was then added dropwise with
continued stirring for 1 hour. The salts were filtered off, the filtrate
was diluted with water (20 ml), and the tetrahydrofuran was evapo-
rated. The aqueous solution was extracted with ether (3x15 ml). The
combined organic phases were dried (magnesium sulfate), filtered
and concentrated to give the corresponding acyl azide. To a solution
of acyl azide (1.34 g, 5.36 mmol) in xylene (20 ml) were added
1.2 equivalents of aromatic amine. The solution was heated in an oil
bath for 8 hours to 140 °C. The solvent was then evaporated to
dryness, and the crude products were recrystallized from ethanol.
5-Nitro-3-pyridin-2-ylquinazoline-2,4-(1H,3H)-dione (4e).
This compound was obtained as a white amorphous solid
(70%), mp 315-316 °C, ir: ν 1679 (C=O), 1728 (C=O), 3370
-1
1
cm (NH); H nmr: δ 7.46 (d, 1H, H-6, J = 8.0 Hz), 7.50-7.55
(m, 3H, H-8 and H ), 7.88 (t, 1H, H-7, J = 8.0Hz), 7.97-8.07
arom
(m, 1H, H
), 8.55-8.65 (m, 1H, H
), 12.10 (broad s,
arom
13
arom
1H, NH); C nmr: δ 104.8 (C), 116.2 (CH), 118.1 (CH), 124.3
(CH), 125.0 (CH), 135.9 (CH), 138.7 (CH), 141.2 (C), 148.4 (C),
149.1 (CH), 149.2 (C=O), 149.3 (C), 158.6 (C=O); ms: m/z 285
(M+1).
N-[5-Nitro-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl]benza-
mide (4a).
Anal. Calcd. for C H N O : C, 54.94; H, 2.84; N, 19.71.
13
8 4 4
Found: C, 54.66; H, 3.04; N, 19.42.
This compound was obtained as a white amorphous solid
5-Nitro-3-pyridin-4-ylquinazoline-2,4-(1H,3H)-dione (4f).
(73%), mp 271-273 °C, ir: ν 1680 (C=O), 1710 (C=O), 1740
-1
1
(C=O), 3240 (NH), 3330 (NH) cm ; H nmr: δ 7.46 (d, 1H, H-6,
J = 8.0 Hz), 7.56-7.63 (m, 4H, H-8 and H ), 7.68-7.96 (m, 3H,
This compound was obtained as a yellow amorphous solid
arom
(70%), mp 327-328 °C, ir: ν 1680 (C=O), 1726 (C=O), 3380
H-7 and H
), 11.26 (broad s, 1H, NH), 12.27 (broad s, 1H,
arom
-1
1
(NH) cm ; H nmr: δ 7.41 (d, 1H, H-6, J = 8.0 Hz), 7.44 (d, 2H,
, J = 6.0 Hz), 7.53 (d, 1H, H-8, J = 8.0 Hz), 7.84 (t, 1H,
13
NH); C nmr: δ 104.2 (C), 116.7 (CH), 118.5 (CH), 127.7
(2CH), 128.7 (2CH), 131.3 (C), 132.6 (CH), 136.5 (CH), 140.5
(C), 148.3 (C=O), 149.2 (C), 157.1 (C=O), 165.2 (C=O); ms: m/z
327 (M+1).
H
arom
H-7, J = 8.0 Hz), 8.73 (d, 2H, H
, J = 6.0 Hz), 12.11 (broad s,
arom
13
1H, NH); C nmr: δ 105.0 (C), 116.2 (CH), 118.0 (CH), 124.4
(2CH), 135.9 (CH), 141.2 (C), 142.9 (C), 149.0 (C), 149.2
(C=O), 150.6 (2CH), 158.5 (C=O); ms: m/z 285 (M+1).
Anal. Calcd. for C
H N O : C, 55.22; H, 3.09; N, 17.17.
15 10 4 5
Found: C, 54.94; H, 3.21; N, 17.34.
Anal. Calcd. for C H N O : C, 54.94; H, 2.84; N, 19.71.
13
8 4 4
5-Nitro-3-phenylquinazoline-2,4-(1H,3H)-dione (4b).
Found: C, 54.69; H, 3.05; N, 19.51.
This compound was obtained as white crystals (75%), mp
N-[8-Nitro-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl]benza-
mide (5a).
337-338 °C, ir: ν 1680 (C=O), 1725 (C=O), 3330 (NH)
-1
1
cm ; H nmr: δ 7.25 (d, 1H, H-6, J = 8.0 Hz), 7.35 (d, 1H, H-8,
This compound was obtained as a white amorphous solid
J = 8.0 Hz), 7.38-7.54 (m, 5H, H
), 7.80 (t, 1H, H-7, J = 8.0
arom
(50%), mp 245-246 °C, ir: ν 1680 (C=O), 1710 (C=O), 1742
13
Hz) 11.95 (broad s, 1H, NH); C nmr: δ 105.1 (C), 116.1 (CH),
117.9 (CH), 128.4 (CH), 128.9 (2CH), 129.0 (2CH), 135.0 (C),
135.7 (CH), 141.1 (C), 149.3 (C=O), 149.6 (C), 158.9 (C=O);
ms: m/z 284 (M+1).
-1
1
(C=O), 3245 (NH), 3331 (NH) cm ; H nmr: δ 7.49 (t, 1H, H-6,
J = 8.0 Hz), 7.55-7.67 (m, 3H, H ), 7.98 (d, 2H, H , J = 7.0
arom
arom
Hz), 8.43 (d, 1H, H-5, J = 8.0 Hz), 8.62 (d, 1H, H-7, J = 8.0 Hz),
13
10.95 (broad s, 1H, NH), 11.40 (br s, 1H, NH); C nmr: δ 116.5
Anal. Calcd. for C H N O : C, 59.37; H, 3.20; N, 14.84.
14
9 3 4
(C), 123.0 (CH), 127.8 (2CH), 128.7 (2CH), 131.2 (CH), 132.2
(C), 132.6 (C), 133.5 (CH), 135.0 (C), 135.1 (CH), 147.8 (C=O),
159.0 (C=O), 165.1 (C=O); ms: m/z 327 (M+1).
Found: C, 59.65; H, 3.07; N, 14.64.
3-(4-Methoxyphenyl)-5-nitroquinazoline-2,4-(1H,3H)-dione (4c).
This compound was obtained as a white amorphous solid
Anal. Calcd. for C
H N O : C, 55.22; H, 3.09; N, 17.17.
15 10 4 5
Found: C, 55.07; H, 2.88; N, 17.20.
(80%), mp 353-354 °C, ir: ν 1680 (C=O), 1725 (C=O), 3379
-1
(NH) cm ; H nmr: δ 3.78 (s, 1H, OCH ), 7.00 (d, 2H, H
, J =
3
arom
8-Nitro-3-phenylquinazoline-2,4-(1H,3H)-dione (5b).
8.5 Hz), 7.22 (d, 2H, H
, J = 8.5 Hz), 7.41 (d, 1H, H-6, J = 8.0
arom
This compound was obtained as a yellow amorphous solid
Hz), 7.45 (d, 1H, H-8, J = 8.0 Hz), 7.82 (t, 1H, H-7, J = 8.0 Hz),
13
(55%), mp 228-229 °C, ir: ν 1680 (C=O), 1730 (C=O), 3367
11.97 (broad s, 1H, NH); C nmr: δ 55.6 (CH ), 105.3 (C), 114.3
3
-1
1
(NH) cm ; H nmr: δ 7.25-7.38 (m, 2H, H
), 7.48 (t, 1H, H-6,
(2CH), 116.3 (CH), 118.0 (CH), 127.7 (C), 130.1 (2CH), 135.9
(CH), 141.3 (C), 149.5 (C=O), 150.0 (C), 159.2 (C=O), 159.3
(C); ms: m/z 314 (M+1).
arom
J = 8.0 Hz), 7.50-7.60 (m, 3H, H
), 8.56 (d, 1H, H-5, J =
arom
8.0 Hz), 8.63 (d, 1H, H-7, J = 8.0 Hz), 10.60 (broad s, 1H, NH);
13
C nmr: δ 117.9 (C), 122.5 (CH), 128.3 (2CH), 129.5 (CH),
Anal. Calcd. for C H N O : C, 57.51; H, 3.54; N, 13.41.
15 11
3 5
129.8 (2CH), 130.1 (CH), 132.2 (C), 133.9 (C), 135.0 (CH),
Found: C, 57.80; H, 3.44; N, 13.65.
137.1 (C), 149.1 (C=O), 160.8 (C=O); ms: m/z 284 (M+1).
5-Nitro-3-pyrazin-2-ylquinazoline-2,4-(1H,3H)-dione(4d).
This compound was obtained as a white amorphous solid (72%),
Anal. Calcd. for C H N O : C, 59.37; H, 3.20; N, 14.84.
14
9 3 4
Found: C, 59.61; H, 3.11; N, 14.70.
-1
mp 347-348 °C, ir: ν 1680 (C=O), 1725 (C=O), 3380 (NH) cm ;
3-(4-Methoxyphenyl)-8-nitroquinazoline-2,4-(1H,3H)-dione (5c).
This compound was obtained as a white amorphous solid
1
H nmr: δ 7.46 (d, 1H, H-6, J = 8.0 Hz), 7.54 (d, 1H, H-8, J = 8.0
Hz), 7.88 (t, 1H, H-7, J = 8.0 Hz), 8.72-8.75 (m, 1H, H
), 8.78
arom
(d, 1H, H
, J = 3.0 Hz), 8.82-8.87 (m, 1H, H
), 11.92 (broad
(60%), mp 254-255 °C, ir: ν 1683 (C=O), 1725 (C=O), 3336
arom
13
arom
-1 1
s, 1H, NH); C nmr: δ 104.9 (C), 116.5 (CH), 118.5 (CH), 127.2
(CH), 136.1 (CH), 138.1 (C), 144.7 (CH), 148.2 (CH), 148.9 (C),
149.1 (C=O), 149.4 (C), 159.2 (C=O). ms: m/z 286 (M+1).
(NH) cm ; H nmr: δ 3.86 (s, 3H, OCH ), 7.01 (d, 2H, H
, J =
3
arom
8.3 Hz), 7.21 (d, 2H, H
, J = 8.3 Hz), 7.42 (t, 1H, H-6, J = 8.0
arom
Hz), 8.42 (d, 1H, H-5, J = 8.0 Hz), 8.55 (d, 1H, H-7, J = 8.0 Hz),

274
D. Aziane, M. Soukri, A. El Hakmaoui, S. Lazar, E. M. Essassi, G. Guillaumet and M. Akssira
Vol. 39
13
100.1 (CH), 108.3 (CH), 127.6 (2CH), 128.5 (2CH), 131.3 (C),
132.3 (CH), 135.5 (CH), 140.1 (C), 148.8 (C=O), 151.5 (C),
162.5 (C=O), 165.2 (C=O); ms: m/z 297 (M+1).
10.60 (broad s, 1H, NH); C nmr: δ 55.7 (CH ), 115.1 (2CH),
3
117.5 (C), 122.5 (CH), 124.6 (C), 126.3 (CH), 129.3 (2CH),
132.1 (C), 137.1 (CH), 137.9 (C), 149.5 (C=O), 159.2 (C=O),
161.0 (C); ms: m/z 314 (M+1).
Anal. Calcd. for C
H N O : C, 60.81; H, 4.08; N, 18.91.
15 12 4 3
Found: C, 60.57; H, 4.15; N, 19.13.
Anal. Calcd. for C H N O : C, 57.51; H, 3.54; N, 13.41.
15 11
3 5
Found: C, 57.39; H, 3.60; N, 13.70.
5-Amino-3-phenylquinazoline-2,4-(1H,3H)-dione (6b).
8-Nitro-3-pyrazin-2-ylquinazoline-2,4-(1H,3H)-dione (5d).
This compound was obtained as a white amorphous solid
(90%), mp 304-305 °C, ir: ν 1660 (C=O), 1721 (C=O), 3337
(NH), 3492 (NH) cm ; H nmr: δ 6.23 (d, 1H, H-6, J = 8.0 Hz),
This compound was obtained as a yellow amorphous solid
-1
1
(55%), mp 194-196 °C, ir: ν 1680 (C=O), 1725 (C=O), 3300
-1
1
6.35 (d, 1H, H-8, J = 8.0 Hz), 7.09 (broad s, 2H, NH ), 7.23
cm (NH); H nmr: δ 7.47 (t, 1H, H-6, J = 8.0 Hz), 8.39 (d, 1H,
2
(t, 1H, H-7, J = 8.0 Hz), 7.27-7.30 (m, 2H, H
), 7.35-7.50
H-5, J = 8.0 Hz), 8.56 (d, 1H, H-7, J = 8.0 Hz), 8.70-8.97 (m, 3H,
arom
13
13
(m, 3H, H
), 11.17 (broad s, 1H, NH); C nmr: δ 97.6 (C),
H
), 11.00 (broad s, 1H, NH); C nmr: δ 118.2 (C), 122.8
arom
arom
(CH), 124.0 (CH), 124.9 (CH), 132.4 (C), 134.0 (C), 135.1 (CH),
137.0 (CH), 139.1 (CH), 148.9 (C=O), 150.3 (C), 160.8 (C=O);
ms: m/z 286 (M+1).
99.8 (CH), 107.9 (CH), 127.8 (CH), 128.6 (2CH), 129.2 (2CH),
135.0 (CH), 135.6 (C), 140.8 (C), 149.8 (C=O), 151.4 (C), 164.4
(C=O); ms: m/z 254 (M+1).
Anal. Calcd. for C H N O : C, 50.53; H, 2.47; N, 24.55.
Found: C, 50.41; H, 2.71; N, 24.25.
Anal. Calcd. for C H N O : C, 66.40; H, 4.38; N, 16.59.
Found: C, 66.33; H, 4.20; N, 16.81.
12
7 5 4
14 11
3 2
8-Nitro-3-pyridin-2-ylquinazoline-2,4-(1H,3H)-dione (5e).
5-Amino-3-(4-methoxyphenyl)quinazoline-2,4-(1H,3H)-dione
(6c).
This compound was obtained as a yellow amorphous solid
(57%), mp 203-204 °C, ir: ν 1680 (C=O), 1716 (C=O), 3329
This compound was obtained as a white amorphous solid
-1
1
cm (NH); H nmr: δ 7.25-7.48 (m, 3H, H-6 and H
), 7.93
arom
(94%), mp 332-333 °C, ir: ν 1665 (C=O), 1725 (C=O), 3339
(t, 1H, H
, J = 5.0 Hz, H
), 8.54 (d, 1H, H-5, J = 8.0 Hz),
-1
1
arom
arom
(NH), 3474 (NH) cm ; H nmr: δ 3.80 (s, 3H, OCH ), 6.20
3
8.62 (d, 1H, H-7, J = 8.0 Hz), 8.69 (d, 1H, H
, J = 5.0 Hz),
arom
(d, 1H, H-6, J = 8.0 Hz), 6.35 (d, 1H, H-8, J = 8.0 Hz), 6.96
13
10.60 (broad s, 1H, NH); C nmr: δ 118.1 (C), 122.6 (CH),
123.9 (CH), 124.8 (CH), 132.3 (CH), 133.7 (C), 135.3 (CH),
136.9 (C), 139.0 (CH), 147.9 (C), 148.8 (C=O), 150.3 (CH),
160.5 (C=O); ms: m/z 285 (M+1).
(d, 2H, H
, J = 7.5 Hz), 7.05 (broad s, 2H, NH ), 7.18 (d, 2H,
arom
2
H
, J = 7.5 Hz), 7.22 (t, 1H, H-7, J = 8.0 Hz), 11.10 (broad s,
arom
13
1H, NH); C nmr: δ 55.3 (CH ), 97.7 (C), 99.9 (CH), 108.0
3
(CH), 114.0 (2CH), 128.1 (C), 130.2 (2CH), 135.1 (CH), 140.8
(C), 149.2 (C=O), 151.5 (C), 158.7 (C), 164.8 (C=O); ms: m/z
284 (M+1).
Anal. Calcd. for C H N O : C, 54.94; H, 2.84; N, 19.71.
13
8 4 4
Found: C, 54.67; H, 2.97; N, 19.55.
Anal. Calcd. for C
H N O : C, 63.60; H, 4.63; N, 14.83.
8-Nitro-3-pyridin-4-ylquinazoline-2,4-(1H,3H)-dione (5f).
15 13 3 3
Found: C, 63.29; H, 4.60; N, 14.98.
This compound was obtained as a yellow amorphous solid
(50%) from ethanol, mp 277-278 °C, ir: ν 1685 (C=O), 1731
5-Amino-3-pyrazin-2-ylquinazoline-2,4-(1H,3H)-dione (6d).
-1
1
(C=O), 3330 (NH) cm ; H nmr: δ 7.30-7.47 (m, 3H, H-6 and
), 8.37 (d, 1H, H-5, J = 8.0 Hz), 8.52 (d, 1H, H-7, J = 8.0
This compound was obtained as a yellow amorphous solid
H
arom
(89%), mp 244-245 °C, ir: ν 1678 (C=O), 1740 (C=O), 3384
13
Hz), 8.63-8.75 (m, 2H, H
), 10.96 (broad s, 1H, NH);
C
arom
-1
1
(NH), 3480 (NH) cm ; H nmr: δ 6.22 (d, 1H, H-6, J = 8.0
Hz), 6.40 (d, 1H, H-8, J = 8.0 Hz), 7.10 (broad s, 2H, NH ),
nmr: δ 117.4 (C), 122.3 (CH), 124.2 (2CH), 131.5 (CH), 131.6
(C), 134.0 (C), 134.7 (CH), 142.9 (C), 148.6 (C=O), 150.7
(2CH), 160.2 (C=O); ms: m/z 285 (M+1).
2
7.20 (t, 1H, H-7, J = 8.0 Hz), 8.70-8.90 (m, 3H, H
), 11.15
arom
13
(broad s, 1H, NH); C nmr: δ 97.3 (C), 100.4 (CH), 108.6
(CH), 135.8 (CH), 140.9 (C), 144.2 (CH), 144.7 (CH), 146.1
(CH), 146.4 (C), 149.7 (C=O), 151.8 (C), 164.6 (C=O); ms:
m/z 256 (M+1).
Anal. Calcd. for C H N O : C, 54.94; H, 2.84; N, 19.71.
13
8 4 4
Found: C, 55.18; H, 2.71; N, 19.59.
General Procedure for the Preparation of Aminoquinazoline-
diones 6a-f and 7a-f.
Anal. Calcd. for C H N O : C, 56.47; H, 3.55; N, 27.44.
12
9 5 2
Found: C, 56.67; H, 3.42; N, 27.50.
To solution of 4a-f or 5a-f (2.15 mmol) in methanol (25 ml)
was added palladium on carbon (10%) (90 mg). The mixture was
stirred in a Parr apparatus under hydrogen (1 atm) for 12 hours at
room temperature and then filtered through Celite. The filtrate
was evaporated under reduced pressure and the residue obtained
was recrystallized from methanol.
5-Amino-3-pyridin-2-ylquinazoline-2,4-(1H,3H)-dione (6e).
This compound was obtained as a white amorphous solid
(95%), mp 275-276 °C, ir: ν 1666 (C=O), 1710 (C=O), 3375
-1
1
(NH), 3436 (NH) cm ; H nmr: δ 6.26 (d, 1H, H-6, J = 8.0 Hz),
6.38 (d, 1H, H-8, J = 8.0 Hz), 7.11 (broad s, 2H, NH ), 7.24
2
N-[5-Amino-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl]benza-
mide (6a).
(t, 1H, H-7, J = 8.0 Hz), 7.40-7.55 (m, 2H, H
), 7.97 (t, 1H,
, J = 4.1 Hz), 11.30 (broad
arom
H
, J = 7.5 Hz), 8.58 (d, 1H, H
arom
arom
13
s, 1H, NH); C nmr: δ 97.47 (C), 100.12 (CH), 108.28 (CH),
124.00(CH), 124.73 (CH), 135.43 (CH), 138.62 (CH), 141.00
(C), 149.30 (CH), 149.36 (C), 149.74 (C), 151.63 (C=O), 164.56
(C=O); ms: m/z 255 (M+1).
This compound was obtained as a white amorphous solid
(90%), mp 316-317 °C, ir: ν 1680 (C=O), 1700 (C=O), 1730
-1
1
(C=O), 3299 (NH), 3389 (NH), 3496 (NH) cm ; H nmr: δ 6.26
(d, 1H, H-6, J = 8.0 Hz), 6.42 (d, 1H, H-8, J = 8.0 Hz), 7.11
Anal. Calcd. for C
Found: C, 61.22; H, 4.10; N, 22.11.
H N O : C, 61.41; H, 3.96; N, 22.04.
(broad s, 2H, NH ), 7.27 (t, 1H, H-7, J = 8.0 Hz), 7.60-7.90
13 10 4 2
2
13
(m, 5H, H
), 10.99 (broad s, 2H, NH); C nmr: δ 98.9 (C),
arom

Mar-Apr 2002
A Convenient Synthesis of 5- and 8-Nitroquinazoline
275
5-Amino-3-pyridin-4-ylquinazoline-2,4-(1H,3H)-dione (6f).
(CH), 123.2 (CH), 126.0 (C), 135.5 (C), 144.2 (CH), 144.4 (CH),
145.5 (CH), 146.3 (C), 149.7 (C=O), 162.4 (C=O); ms: m/z 256
(M+1).
This compound was obtained as a yellow amorphous solid
(93%), mp 364-365 °C, ir: ν 1653 (C=O), 1716 (C=O), 3353
Anal. Calcd. for C H N O : C, 56.47; H, 3.55; N, 27.44.
12
9 5 2
-1
1
(NH), 3469 (NH) cm ; H nmr: δ 6.23 (d, 1H, H-6, J = 7.4
Hz), 6.37 (d, 1H, H-8, J = 7.4 Hz), 6.85-7.60 (m, 5H, H-7,
Found: C, 56.60; H, 3.49; N, 27.61.
8-Amino-3-pyridin-2-ylquinazoline-2,4-(1H,3H)-dione (7e).
NH and H
), 8.69 (d, 2H, H
, J = 6.0 Hz), 11.29 (broad
2
arom
13
arom
s, 1H, NH); C nmr: δ 97.54 (C), 100.05 (CH), 108.28 (CH),
124.88 (2CH), 135.43 (CH), 140.85 (C), 143.69 (C), 149.35
(C), 150.45 (2CH), 151.62 (C=O), 164.01 (C=O); ms: m/z 255
(M+1).
Anal. Calcd. for C
Found: C, 61.30; H, 3.99; N, 22.01.
This compound was obtained as a white amorphous solid
(92%), mp 257-258 °C, ir: ν 1680 (C=O), 1735 (C=O), 3360
-1
1
(NH), 3467 (NH) cm ; H nmr: δ 5.73 (broad s, 2H, NH ),
2
6.93-7.06 (m, 2H, H-7 and H-6), 7.19 (t, 1H, H
, J = 8.0 Hz),
arom
H N O : C, 61.41; H, 3.96; N, 22.04.
13 10 4 2
7.45-7.60 (m, 2H, H-5 and H
), 7.99 (t, 1H, H
, J = 7.7
arom
arom
Hz), 8.60 (d, 1H, H
, J = 4.4 Hz), 10.82 (broad s, 1H, NH);
arom
13
C nmr: δ 114.28 (CH), 114.91 (CH), 118.90 (CH), 123.23
(CH), 124.13 (CH), 124.49 (CH), 126.29 (CH), 135.72 (C),
138.74 (C), 149.34 (C), 149.46 (C=O), 150.02 (CH), 162.54
(C=O); ms: m/z 255 (M+1).
N-[8-Amino-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl]-
benzamide (7a).
This compound was obtained as a white amorphous solid
(92%), mp 246-247°C, ir: ν 1680 (C=O), 1708 (C=O), 1730
Anal. Calcd. for C
Found: C, 61.30; H, 4.09; N, 21.87.
H N O : C, 61.41; H, 3.96; N, 22.04.
13 10 4 2
-1
1
(C=O), 3249 (NH), 3309 (NH), 3457 (NH) cm ; H nmr: δ 5.62
(broad s, 2H, NH ), 6.95-7.08 (m, 2H, H-5 and H ), 7.24
2
arom
8-Amino-3-pyridin-4-ylquinazoline-2,4-(1H,3H)-dione (7f).
(t, 1H, H-6, J = 8.0 Hz), 7.53-7.68 (m, 4H, H-7 and H
),
arom
7.95-7.99 (m, 1H, H
), 10.80 (broad s, 1H, NH), 11.13 (broad
This compound was obtained as a yellow amorphous solid
arom
13
(93%), mp 286-287 °C, ir: ν 1671 (C=O), 1728 (C=O), 3344
s, 1H, NH); C nmr: δ 114.4 (C), 114.6 (CH), 119.1 (CH), 123.6
(CH), 125.5 (C), 127.7 (2CH), 128.6 (2CH), 131.6 (C), 132.4
(C), 135.6 (CH), 149.1 (C=O), 160.8 (C=O), 165.1 (C=O); ms:
m/z 297 (M+1).
Anal. Calcd. for C
Found: C, 60.90; H, 3.97; N, 19.20.
-1
1
(NH), 3471 (NH) cm ; H nmr: δ 5.75 (broad s, 2H, NH ),
2
6.90-7.07 (m, 2H, H-7 and H-6), 7.12-7.25 (m, 1H, H
),
),
arom
7.38-7.52 (m, 2H, H-5 and H
), 8.64-8.80 (m, 2H, H
arom
arom
13
10.86 (broad s, 1H, NH); C nmr: δ 114.33 (C), 114.87 (CH),
118.82 (CH), 123.18 (CH), 124.67 (2CH), 126.17 (C), 135.72
(C), 143.86 (C), 149.62 (C=O), 150.53 (2CH), 162.14 (C=O);
ms: m/z 255 (M+1).
H N O : C, 60.81; H, 4.08; N, 18.91.
15 12 4 3
8-Amino-3-phenylquinazoline-2,4-(1H,3H)-dione (7b).
Anal. Calcd. for C
Found: C, 61.55; H, 4.02; N, 22.19.
H N O : C, 61.41; H, 3.96; N, 22.04.
13 10 4 2
This compound was obtained as a white amorphous solid
(91%), mp 324-325 °C, ir: ν 1680 (C=O), 1720 (C=O), 3300
-1
1
(NH), 3441 (NH) cm ; H nm: δ 5.57 (broad s, 2H, NH ),
2
Preparation of 4-Carbomethoxybenzimidazole-2-thione (8).
6.93-7.10 (m, 2H, H-5 and H
H-6 ), 7.27-7.36 (m, 2H, H
), 7.20 (t, 1H, H-6, J = 8.0 Hz,
), 7.40-7.55 (m, 3H, H-7 and
13
arom
To a solution of 7b or 7c (2 mmol) in methanol (20 ml) were
added potassium hydroxide (0.12 g, 2.2 mmol) and carbon
disulfide (1.5 ml, 25 mmol). The reaction mixture was refluxed
for 24 hours and then cooled to room temperature. After
evaporation of solvent and excess carbon disulfide, the residual
product was acidified by the addition of hydrochloric acid (3 N).
The crude product, which precipitated, was filtered and washed
with water and then purified by recrystallization in ethanol to
afford 4-carbomethoxybenzimidazole-2-thione 8 as a white
amorphous solid (60%), mp 254-255 °C; ir: ν 1360 (C=S), 1711
arom
H
), 10.64 (broad s, 1H, NH); C nmr: δ 114.5 (CH), 115.0
arom
(C), 118.6 (CH), 123.0 (CH), 126.2 (C), 128.0 (CH), 128.8
(2CH), 129.1 (2CH), 135.4 (C), 135.9 (C), 150.3 (C=O), 162.5
(C=O); ms: m/z 254 (M+1).
Anal. Calcd. for C H N O : C, 66.40; H, 4.38; N, 16.59.
14 11
3 2
Found: C, 66.30; H, 4.61; N, 16.68.
8-Amino-3-(4-methoxyphenyl)quinazoline-2,4-(1H,3H)-dione (7c).
This compound was obtained as a white amorphous solid
-1
1
(C=O), 3251 (NH) cm ; H nmr: δ 3.96 (s, 3H, OCH ), 7.25
(t, 1H, H-6, J = 7.9 Hz), 7.40 (d, 1H, H-5, J = 7.9 Hz), 7.68
3
(93%), mp 284-285 °C, ir: ν 1680 (C=O), 1720 (C=O), 3335
-1
1
(NH), 3479 (NH) cm ; H nmr: δ 3.80 (s, 3H, OCH ), 5.60
3
(d, 1H, H-7, J = 7.9 Hz), 12.33 (broad s, 1H, NH), 12.90 (broad s,
(broad s, 2H, NH ), 6.95-7.03 (m, 3H, H-5 and H
), 7.10-7.25
13
2
arom
1H, NH); C nmr: δ 54.76 (CH ), 114.61 (C), 116.46 (CH),
3
13
(m, 4H, H-6, H-7 and H
), 10.60 (broad s, 1H, NH); C nmr:
arom
124.84 (CH), 126.15 (CH), 134.29 (C), 136.10 (C), 167.61
(C=O), 172.52 (C=S); ms: m/z 209 (M+1).
δ 55.4 (CH ), 114.0 (2CH), 114.6 (CH), 115.0 (C), 118.5 (CH),
3
122.9 (CH), 126.2 (C), 128.4 (C), 130.0 (2CH), 135.3 (C), 150.5
Anal. Calcd. for C H N O S: C, 51.91; H, 3.87; N, 13.45; S,
9
8 2 2
+
(C=O), 158.8 (C), 162.7 (C=O); ms: m/z 284 (M +1).
15.40. Found: C, 52.11; H, 3.80; N, 13.50; S, 15.23.
Anal. Calcd. for C
H N O : C, 63.60; H, 4.63; N, 14.83.
15 13 3 3
Preparation of 5-Aryl-4H-imidazo[4,5,1-ij]quinazoline-
2,4,6(1H,5H)-thiones 9b and 9c.
Found: C, 63.77; H, 4.52; N, 15.01.
8-Amino-3-pyrazin-2-ylquinazoline-2,4(1H,3H)-dione (7d).
To a solution of 7b or 7c (2 mmol) in pyridine (15 ml) was
added carbon disulfide (2 ml, 33 mmol). The mixture was
refluxed for 24 hours and then cooled to room temperature. After
evaporation of solvent and excess carbon disulfide, the crude
product was recrystallized from ethanol to afford the tricyclic
compound 9b or 9c.
This compound was obtained as a white amorphous solid
(90%), mp 242-243 °C, ir: ν 1680 (C=O), 1720 (C=O), 3335
-1
1
(NH), 3479 (NH) cm ; H nmr: δ 5.62 (broad s, 2H, NH ),
2
6.85-7.3 (m, 3H, H-5, H-6 and H-7 ), 8.60-9.10 (m, 3H, H
10.86 (broad s, 1H, NH); C nmr: δ 114.2 (C), 114.5 (CH), 119.1
),
arom
13

276
D. Aziane, M. Soukri, A. El Hakmaoui, S. Lazar, E. M. Essassi, G. Guillaumet and M. Akssira
Vol. 39
2723 (1997); [e] M. R. Myers, N. N. Setzer, A. P. Spada, A. L. Zulli,
C-Y. J. Hsu, A. Zilberstein, S. E. Johnson, L. E. Hook and M. V. Jacoski,
Bioorg. Med. Chem. Lett., 7, 417 (1997).
5-Phenyl-4H-imidazo[4,5,1-ij]quinazoline-2,4,6(1H,5H)-thione
(9b).
This compound was obtained as a white amorphous solid
[2a] J. A. Lowe, III, R. L. Archer, D. S. Chapin, J. B. Cheng,
D. Helweg, J. L. Johnson, B. K. Koe, L. A. Lebel, P. F. Moore,
J. A. Nielsen, L. L. Russo and J. T. Shirley, J. Med. Chem., 34, 624
(1991); [b] W. F. Michne, J. D. Schroeder, J. W. Guiles,
A. M. Treasurywala, C. A. Weigelt, M. F. Stansberry, E. McAvoy,
C. R. Shah, Y. Baine, D. G. Sawutz, P. B. Miller, B. M. Stankunas,
J. Reid, E. Bump and D. Schlegel, J. Med. Chem., 38, 2557 (1995); [c]
A. L. Smith, C. G. Thomson and P. D. Leeson, Bioorg. Med. Chem. Lett.,
6, 1483 (1996).
(93%) from ethanol, mp 302-303 °C, ir: ν 1360 (C=S), 1667
-1
1
(C=O), 1740 (C=O), 3280 (NH) cm ; H nmr: δ 7.30-7.63
(m, 7H, H
), 7.66-7.78 (m, 1H, H
), 13.59 (broad s, 1H,
arom
arom
13
NH); C nmr: δ 111.73 (C), 113.98 (C), 119.46 (C), 126.03
(CH), 128.45 (CH), 128.51 (CH), 129.04 (2CH), 129.10 (2CH),
129.64 (CH), 135.80 (C), 145.72 (C=O), 160.85 (C=O), 169.01
(C=S); ms: m/z 296 (M+1).
Anal. Calcd. for C H N O S: C, 61.01; H, 3.07; N, 14.23; S,
15
9 3 2
10.86. Found: C, 61.17; H, 3.21; N, 14.15; S, 10.91.
[3] D. G. Wenzel, J. Am. Pharm. Assoc., 44, 550 (1955).
[4a] S. Hayao, H. J. Havera, W. G. Strycker, T. G. Leipzig,
R. A. Kulp and H. E. Hartzler, J. Med. Chem., 8, 807 (1965); [b]
Y. Nishikawa, T. Shindo, K. Ishii, H. Nakamura, T. Kon and H Uno, J.
Med. Chem., 32, 583 (1989).
5-(4-Methoxyphenyl)-4H-imidazo[4,5,1-ij]quinazoline-
2,4,6(1H,5H)-thione (9c).
This compound was obtained as a white amorphous solid
(95%), mp 296-297 °C, ir: ν 1355 (C=S), 1697 (C=O), 1736
[5] H. J. Havera and H. J. Vidrio, J. Med. Chem., 22, 1548 (1979).
[6] T. Glaser and J. Traber, Agents Actions, 15, 341 (1984).
[7] N. J. Liverton, D. J. Armstrong, D. A. Claremon, D. C. Remy,
J. J. Baldwin, R. J. Lynch, G. Zhang and R. J. Gould, Bioorg. Med. Chem.
Lett., 8, 483 (1998).
-1
1
(C=O), 3330 (NH) cm ; H nmr: δ 3.82 (s, 3H, OCH ), 7.05
3
(d, 2H, H
, J = 7.2 Hz), 7.27 (d, 2H, H
, J = 7.2 Hz),
arom
arom
7.41-7.60 (m, 2H, H
s, 1H, NH); C nmr: δ 55.33 (CH ), 111.69 (C), 113.89 (CH),
), 7.64-7.78 (m, 1H, H
), 13.97 (broad
arom
arom
13
3
[8a] S. M. Gadekar, A. M. Kotsen and E. Cohen, J. Chem. Soc., 4,
4666 (1964); [b] G. Pastor, C. Blanchard, C. Montginoul, E. Toreilles,
L. Giral and A. Texier, Bull. Soc. Chim. Fr., 1331 (1975); [c] H. Akgûn,
U. Hollstein and L. Hurwitz, J. Pharm. Sci., 77, 735 (1988); [d]
L. Gouilleux, J-A. Fehrentz, F. Winternitz and J. Martinez, Tetrahedron
Lett., 37, 7031 (1996); [e] M. F. Gordeev, H. C. Hui, E. M. Gordon and
D. V. Patel, Tetrahedron Lett. 38, 1729 (1997); [f] I. A. Rivero,
R. Somanathan and L. H. Hellberg, Synth. Commun., 28, 2077 (1998); [g]
H. Shao, M. Collucci, S. Tong, T. Zhang and A. L. Castelhano,
Tetrahedron Lett., 39, 7235 (1998).
114.21 (2CH), 119.43 (CH), 125.97 (CH), 128.16 (C), 129.57
(C), 130.05 (C), 131.20 (2CH), 145.86 (C=O), 159.06 (C),
160.96 (C=O), 169.00 (C=S); ms: m/z 326 (M+1).
Anal. Calcd. for C H N O S: C, 59.07; H, 3.41; N, 12.92; S,
16 11
3 3
9.86. Found: C, 59.21; H, 3.54; N, 12.78; S, 9.80.
REFERENCES AND NOTES
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