Studies on quinazolines. Part I. Annelation to the quinazoline ring utilizing amino acid esters

Article abstract of DOI:10.1080/10426500211723

The reaction of quinazoline-4(3H)-thiones 2a-d with amino acid ester hydrochlorides in boiling solvents, under the basic catalysis, afforded the corresponding substitution products (3-6)a-e in low yield. The reaction could be improved by carrying it without a solvent yielding imidazo[1,2-c]- and pyrimido[1,2-c]quinazolines (7-10)a-e. The antibacterial and antifungal activities of the prepared compounds were tested.

Full text of DOI:10.1080/10426500211723

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Phosphorus, Sulfur, and Silicon and the Related
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Studies on Quinazolines. Part I. Annelation to the
Quinazoline Ring Utilizing Amino Acid Esters
A. A. F. Wasfy a
a Chemistry Department, Faculty of Science , Benha University , Benha, Egypt
Published online: 27 Oct 2010.
To cite this article: A. A. F. Wasfy (2002) Studies on Quinazolines. Part I. Annelation to the Quinazoline Ring Utilizing Amino
Acid Esters, Phosphorus, Sulfur, and Silicon and the Related Elements, 177:5, 1349-1358, DOI: 10.1080/10426500211723
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Phosphorus, Sulfur and Silicon, 2002, Vol. 177:1349–1358
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
DOI: 10.1080/10426500290092622
STUDIES ON QUINAZOLINES. PART I. ANNELATION
TO THE QUINAZOLINE RING UTILIZING AMINO
ACID ESTERS
A. A. F. Wasfy
Chemistry Department, Faculty of Science, Benha University,
Benha, Egypt
(Received June 6, 2001; accepted December 4, 2001)
The reaction of quinazoline-4(3H)-thiones 2a–d with amino acid ester
hydrochlorides in boiling solvents, under the basic catalysis, afforded
the corresponding substitution products (3–6)a–e in low yield. The
reaction could be improved by carrying it without a solvent yielding
imidazo[1,2-c]- and pyrimido[1,2-c]quinazolines (7–10)a–e. The an-
tibacterial and antifungal activities of the prepared compounds were
tested.
Keywords: Annelated quinazoline derivatives; antimicrobial activities;
quinazoline-4(3H)-thione derivatives
The recent literature contains much information concerning the syn-
4
thesis and pharmacological activity of the quinazolines.1 Particular
interest is focused on condensed quinazolines, where a synergistic ef-
fect resulting from the combination with other pharmacophores or new
types of activity is expected.2,5
Various tricyclic annelated derivatives of quinazoline have recently
received significant importance because of their diverse biological prop-
erties; many of them such as imidazo[1,2-c]- and pyrimido[1,2-c] quina-
zolines show marked adrenomimetic, psychoanaleptic, broncholytic,
8
and antidepressant properties.6 The most common route for prepa-
ration of the annelated quinazolines involves reaction of 4-chloro- or
2,4-dichloroquinazolines with aziridine, ethylenediamine, or amino al-
cohol followed by cyclization in the presence of a suitable condensation
The author is grateful to Dr. M. Amer, Botany Department, Faculty of Science, Benha
University, for biological screening.
Address correspondence to Ashraf Wasfy, Chemistry Department, Faculty of Science,
Benha University, Benha, Egypt. E-mail: wasfya@hotmail.com
1349

1350
A. A. F. Wasfy
agent.8,9 In continuation of our investigation on biologically active
derivatives among six-membered heterocycles,10,11 it was considered
worthwhile to extend our previous studies12,13 to synthesize some new
annelated quinazoline derivatives.
2-Methyl-4(3H)-quinazolinethione 1 is a convenient precursor to
the target 2-[2-(4-methoxy- or 4-nitro-phenyl)ethenyl]-, 2-(2-phenyl-1-
propenyl)-, 2-(1,3-dioxoindan-2-yl)-4(3H)-quinazolinethiones 2a–d. Di-
rect thionation of 2-methyl-4(3H)-quinazolinone14 with P2S5 in boiling
xylene afforded the corresponding 2-methyl-4(3H)-quinazolinethione 1
in low yield.15
Thus, we preferred to synthesize the starting thione 1 by reaction
of 2-methyl-4(3H)-quinazolinone14 with phosphorus pentachloride and
phosphorus oxychloride to give 4-chloro-2-methylquinazoline,16 which
upon subsequent reaction with thiourea in boiling ethanol furnished
the corresponding thione 1 in good yield.17 The target thiones 2a–d
were prepared by condensing thione 1 with appropriate aromatic alde-
hydes, namely, p-anisaldehyde or p-nitrobenzaldehyde, acetophenone,
and phthalic anhydride under different reaction conditions to yield
2-[2-(4-methoxy- or 4-nitro-phenyl)ethenyl]-4(3H)-quinazolinethiones
2a,b, 2-(2-phenyl-1-propenyl)-4(3H)-quinazolinethione 2c and 2-(1,3-
dioxoindan-2-yl)-4(3H)-quinazolinethione 2d respectively.
Unlike their oxy analogues, the enhanced leaving group ability of
sulfur in the thione 2 allows direct substitution of the thiol group
with an amino group of the corresponding amino acids. Thus, the
reaction of thiones 2a–d with the methyl ester hydrochloride of glycine,
L-serine, L-valine, L-leucine and -alanine in boiling solvents under
basic catalysis, furnished the corresponding substitution products
methyl N-{2-[2-(4-methoxy- or 4-nitro-phenyl)ethenyl]-, 2-(2-phenyl-
1-propenyl)- or 2-(1,3-dioxoindan-2-yl)-quinazolin-4-yl}amino-acetate,
-3-hydroxypropionate, -3-methylbutanoate, -4-methylpentanoate, or
-propanoate (3–6)a
in low yield. Variation of reaction condition
e
led us to the conclusion that esters of amino acids reacted very
reluctantly and that this approach is of little preparative value.
The procedure could be improved significantly by carrying it out
without a solvent. At the melting temperature, when the reaction
mixture becomes homogenous not only nucleophilic substitution was
facilitated but thermal cyclization also occurred to give directly 5-[2-
(4-methoxy- or 4-nitro-phenyl)ethenyl]-, 5-(2-phenyl-1-propenyl)- or
5-(1,3-dioxoindan-2-yl)-3-oxo-2H-imidazo[1,2-c]quinazolines (7–10)a;
5-[2-(4-methoxy- or 4-nitro-phenyl)ethenyl]-, 5-(2-phenyl-1-propenyl)-
or 5-(1,3-dioxoindan-2-yl)-2-hydroxymethyl-, 2-(2-propyl)- or 2-(2-
methylpropyl)-3-oxo-2H-imidazo[1,2-c]quinazolines (7–10)b
and 6-
d
[2-(4-methoxy- or 4-nitro-phenyl)ethenyl]-, 6-(2-phenyl-1-propenyl)- or

Studies on Quinazolines. Part I
1351
FIGURE 1
6-(1,3-dioxoindan-2-yl)-4-oxo-2H,
3H-pyrimido[1,2-c]quinazolines
(7–10)e. The structures of all prepared compounds (Figure 1) were
confirmed from their physical and spectral data (Table I and II).
SCREENING FOR AN ANTIMICROBIAL ACTIVITY
The performed antimicrobial activities of the synthesised derivatives
were determined in vitro by the filter paper disc method.18 All com-
pounds were tested for activity against gram-positive, gram-negative
bacteria, and selected fungi using methaqualone as a reference stan-
dard. The culture medium was normal nutrient agar (NA) supple-
mented with 1 g of yeast per mililiter. According to the solubility of the
tested compounds different polar and nonpolar solvents were used, and
a good solubility was found in 10% acetone (V/V) for all test compounds.
Based on the previous preliminary test, closely spaced test concentra-
tions (500, 250, 125 g/ml) were selected. Methaqualone was dissolved

1352
A. A. F. Wasfy
TABLE I Analytical Data of Compounds (3–10)a–e
Yield [c]
Calcd. (found) (%)
Compd.
no.
MP [b]
m/ C
Mol.
formula
R [a]
A
R1
H
i
ii iii
C
H
N
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
6a
6b
6c
6d
6e
7a
7b
7c
166a 37 40
202e 34 35
192d 41 42
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
C20H19N3O3 68.8 5.4 12.0
(68.9 5.6 12.3)
C21H21N3O4 66.5 5.5 11.1
(66.7 5.7 11.3)
C23H25N3O3 70.6 6.4 10.7
(70.8 6.6 10.9)
C24H27N3O3 71.1 6.7 10.4
(71.4 6.9 10.6)
C21H21N3O3 69.4 5.8 11.6
(69.6 5.4 11.8)
C19H16N4O4 62.6 4.4 15.4
(62.8 4.8 15.8)
C20H18N4O5 60.9 4.6 14.2
(60.6 4.8 14.4)
C22H22N4O4 65.0 5.4 13.8
(65.3 5.6 13.5)
C23H24N4O4 65.7 5.7 13.3
(65.9 5.9 13.6)
C20H18N4O4 63.5 4.8 14.8
(63.8 5.0 14.4)
C20H19N3O2 72.1 5.7 12.6
(72.4 5.9 12.9)
C21H21N3O3 69.4 5.8 11.6
(69.8 5.7 11.7)
C23H25N3O2 73.6 6.7 11.2
(73.8 6.8 11.4)
C24H27N3O2 74.0 6.9 10.8
(74.1 6.6 10.5)
C21H21N3O2 72.6 6.1 12.1
(72.8 6.4 12.3)
C20H15N3O4 66.5 4.2 11.6
(66.7 4.4 11.8)
A
A
A
A
B
B
B
B
B
C
C
C
C
C
D
D
D
D
D
A
A
A
CH2OH
CH(CH3)2
CH2CH(CH3)2 175d 33 34
H
H
190d 40 43
200e 45 45
164b 37 38
177b 47 46
CH2OH
CH(CH3)2
CH2CH(CH3)2 190d 38 38
H
H
180d 47 47
160b 45 44
188d 36 38
178d 40 42
CH2OH
CH(CH3)2
CH2CH(CH3)2 167c 40 40
H
H
147a 44 45
156a 48 47
168c 37 38
195e 41 43
CH2OH
CH(CH3)2
C21H17N3O5 64.5 4.3 10.7
(64.6 4.6 10.8)
C23H21N3O4 68.5 5.2 10.4
(68.6 5.3 10.7)
C24H23N3O4 69.1 5.5 10.1
(69.3 5.8 10.5)
C21H17N3O4 67.2 4.5 11.2
(67.4 4.7 11.4)
CH2CH(CH3)2 182e 32 34
H
H
172d 47 47
247g
254h
239h
—
—
—
—
—
—
84 C19H15N3O2 71.9 4.7 13.2
(71.7 4.9 13.4)
81 C20H17N3O3 69.2 4.9 12.1
(69.3 5.1 12.3)
85 C22H21N3O2 73.5 5.8 11.7
(73.6 5.4 11.8)
CH2OH
CH(CH3)2

Studies on Quinazolines. Part I
1353
TABLE I Analytical Data of compounds (3–10)a–e (Continued)
Yield [c]
ii iii
Calcd. (found) (%)
Compd.
no.
MP [b]
m/ C
Mol.
formula
R [a]
A
R1
i
C
H
N
7d
7e
CH2CH(CH3)2 277g
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
80 C23H23N3O2 73.9 6.1 11.3
(73.8 6.3 11.5)
86 C20H17N3O2 72.5 5.1 12.7
(72.7 5.4 12.9)
79 C18H12N4O3 65.1 3.6 16.9
(65.3 3.9 16.7)
74 C19H14N4O4 62.9 3.9 15.5
(63.1 4.1 15.7)
76 C21H18N4O3 67.4 4.8 15.0
(67.6 4.6 14.8)
73 C22H20N4O3 68.0 5.2 14.4
(68.1 5.4 14.8)
79 C19H14N4O3 65.9 4.0 16.2
(65.8 4.2 16.4)
85 C19H15N3O
A
B
B
B
B
B
C
C
C
C
C
D
D
D
D
D
—
H
214 f
272d
262d
256d
8a
8b
CH2OH
CH(CH3)2
8c
8d
CH2CH(CH3)2 224d
8e
—
H
205d
220e
243 f
232 f
9a
75.7 5.0 14.0
(75.8 5.2 14.2)
9b
CH2OH
CH(CH3)2
80 C20H17N3O2 72.5 5.1 12.7
(72.8 5.3 12.9)
9c
82 C22H21N3O
80 C23H23N3O
87 C20H17N3O
76.9 6.1 12.2
(76.8 6.3 12.4)
77.3 6.4 11.8
(77.4 6.6 11.9)
76.2 5.4 13.3
(76.4 5.8 13.5)
9d
CH2CH(CH3)2 263g
9e
—
H
186d
227h
233h
243g
10a
10b
10c
10d
10e
90 C19H11N3O3 69.3 3.3 12.8
(69.4 3.5 12.7)
83 C20H13N3O4 66.9 3.6 17.8
(66.8 3.8 17.7)
81 C22H17N3O3 71.2 4.6 11.3
(71.4 4.8 11.5)
78 C23H19N3O3 71.7 4.9 10.9
(71.8 5.2 10.8)
CH2OH
CH(CH3)2
CH2CH(CH3)2 214 f
252g
—
85 C20H13N3O3 60.0 3.8 12.2
(60.2 4.1 12.5)
[a] A = 2-(4-methoxyphenyl)ethenyl; B = 2-(4-nitrophenyl)ethenyl; C = 2-phenyl-1-
propenyl; D = 1,3-dioxoindan-2-yl.
[b] solvent for crystallisation.
aBenzene-pet. ether (p.b. 40–60 ).
bBenzene.
cDioxane.
dEthanol.
eMethanol.
f Acetic acid.
g(Methanol + benzene).
h(Ethanol + dimethyl formamide).
[c] Yield was determined in different boiling solvent: i) tetrahydrofuran, ii) dioxane,
iii) without solvent (fusion).

TABLE II Spectral Data of Compounds (3a–10c)
1
Compd. no.
IR (KBr)cm
1H NMR (DMSO) /ppm a
3a
3340–3225 (NH);
1743–1720 (CO);
1610 (CN)
3.5 (s, 3H, OCH3); 3.9 (s, 3H, ArOCH3);
4.3 (s, 2H, NCH2O); 6.6 (d, 1H, J = 14 Hz,
CHAr); 6.9 (d, 1H, J = 14 Hz, CH-heteryl);
7.3–8.8 (m, 8H, Ar H); 12.5 (s, br, 1H, NH)
0.9 (d, 6 H, J = 7 Hz, 2 x CH3); 1.6 (m, 1H, CH);
3.4 (s, 3 H, OCH3); 3.85 (s, 3H, ArOCH3);
4.5 (d, 1H, J = 7 Hz, NCHCO); 6.7 (d, 1H,
J = 14 Hz, CH Ar); 6.95 (d, 1H, J = 14 Hz,
CH-heteryl); 7.4–8.8 (m, 8H, Ar H);
3c
3270–3200 (NH);
2935–2915
(alkyl-H);
1735–1715 (CO);
1603 (CN)
12.1 (s, br, 1H, NH)
3e
4b
4c
4e
3285–3160 (NH);
2975–2925
(alkyl-H);
1740–1725 (CO);
1608 (CN)
3500–3390 (OH);
3285–3170 (NH);
1745–1728 (CO);
1615 (CN)
2.6 (t, 2H, J = 7 Hz, CH2N); 3.3 (t, 2H, J = 7 Hz,
CH2CO); 3.5 (s, 3H, OCH3); 3.85 (s, 3H, ArOCH3);
6.6 (d, 1H, J = 14 Hz, CHAr); 6.9 (d, 1H,
J = 14 Hz, CH-heteryl); 7.4–8.7 (m, 8H, Ar H);
11.9 (s, br, 1H, NH)
2.1 (d, 2H, CH2); 3.4 (s, 3H, OCH3);
4.2 (t, 1H, NCHCO); 4.6 (t, 1H, CH2OH);
6.8 (d, 1H, J = 14 Hz, CHAr); 6.95 (d, 1H,
J = 14 Hz, CH-heteryl); 7.4–8.8 (m, 8H, Ar H);
12.8 (s, br, 1H, NH)
1.1 (d, 6H, J = 7 Hz, 2x CH3); 1.5 (m, 1H, CH);
3.5 (s, 3H, OCH3), 4.3 (d, 1H, J = 7 Hz, NHCO);
6.7 (d, 1H, J = 14 Hz, CHAr); 6.9 (d, 1H,
J = 14 Hz, CH-heteryl); 7.3–8.7 (m, 8H, Ar H);
12.6 (s, br, 1H, NH)
2.5 (t, 2H, J = 7 Hz, CH2N); 3.4 (t, 2H, J = 7 Hz,
CH2CO); 3.6 (s, 3H, OCH3); 6.7 (d, 1H,
J = 14 Hz, CHAr); 6.9 (d, 1H, J = 14 Hz,
CH-heteryl); 7.5–8.8 (m, 8H, Ar H);
3280–3100 (NH);
2930–2840
(alkyl-H);
1738–1725 (CO);
1606 (CN)
3290–3200 (NH);
2900–2860
(alkyl-H);
1735–1720 (CO);
1608 (CN)
12.7 (s, br, 1H, NH)
7a
8c
1668–1660 (CO);
1610 (CN)
3.9 (s, 3H, ArOCH3); 4.5 (s, 2H, cyclic NCH2CO);
6.7 (d, 1H, J = 14 Hz, CHAr); 6.9 (d, 1H,
J = 14 Hz, CH-heteryl); 7.2–8.8 (m, 8H, Ar H)
1.1 (d, 6H, J = 7 Hz, 2x CH3); 1.6 (m, 1H, CH);
4.8 (d, 1H, J = 7 Hz, cyclic NCHCO); 6.7 (d, 1H,
J = 14 Hz, CHAr); 6.85 (d, 1H, J = 14 Hz,
CH-heteryl); 7.2–8.7 (m, 8H, Ar H)
2920–2870
(alkyl-H);
1670–1650 (CO);
1605 (CN)
8e
9a
2930–2880
(alkyl-H);
1665–1655 (CO);
1610 (CN)
2850–2820
(alkyl-H);
1669–1660 (CO);
1602 (CN)
2.9 (t, 2H, J = 7 Hz, cyclic CH2N); 3.7 (t, 2H,
J = 7 Hz, cyclic CH2CO); 6.7 (d, 1H, J = 14 Hz,
CHAr); 6.9 (d, 1H, J = 14 Hz, CH-heteryl);
7.3–8.8 (m, 8H, Ar H)
2.1 (d, 3H, CH3 due to long range coupling);
4.5 (s, 2H, cyclic NCH2CO); 6.5 (s, 1H, CH);
7.2–8.8 (m, 9H, Ar H)
10c
2905–2840
(alkyl-H);
1778–1740 (CO);
1690–1670 (CO);
1610 (CN)
1.1 (d, 6H, J = 7 Hz, 2x CH3); 1.6 (m, 1H, CH);
4.8 (d, 1H, J = 7 Hz, cyclic NCHCO); 5.0 (s, 1H,
cyclic COCHCO), 7.3–8.8 (m, 8H, Ar H)
aAll NH signals were exchangeable with deuterium oxide.

Studies on Quinazolines. Part I
1355
TABLE III Activity (A) and Minimum Inhibitory Concentration (MIC)
Calculated as mmol/ml for Compounds (3b–10e)
Bacillus cereus
MIC
Bacillus subtilis
MIC
Escherichia coli
Aspergillus niger
MIC
Compd.
no.
A
A
A
MIC
A
2
2
3
3
3
3
3
3
3
3
3
3
3
3
3
2
2
3
2
3
3
3
3
3
3
3
2
3
3
3
3
3
2
2
2
3
3
3
3
3
3
2
2
2
2
3
3
3
3
2
2
2
2
2
3
2
3
3
3
3
3
2
3
3
3
3
3
2
3
3
3
2
3b
3d
4b
4c
4d
5b
5d
7d
7e
8b
8c
8d
8e
++ 0.13 10
++ 0.12 10
++ 0.63 10
++ 0.61 10
++ 0.13 10
++ 0.61 10
++ 0.31 10
++ 0.30 10
++ 0.59 10
+
+
0.65 10
0.61 10
++ 0.65 10
++ 0.12 10
++ 0.63 10
++ 0.30 10
++ 0.63 10
++ 0.30 10
++ 0.59 10
++ 0.14 10
+
+
+
0.29 10
0.69 10
0.64 10
+
+
+
+
+
0.29 10
0.69 10
0.64 10
0.13 10
0.75 10
+
+
0.69 10
0.64 10
+
0.12 10
++ 0.67 10
++ 0.75 10
+ + + 0.69 10
++ 0.33 10
++ 0.64 10
++ 0.36 10
++ 0.67 10
++ 0.15 10
++ 0.69 10
++ 0.33 10
++ 0.32 10
+ + + 0.72 10
++ 0.13 10
++ 0.15 10
+ + + 0.69 10
+ + + 0.66 10
++ 0.64 10
+ + + 0.36 10
++ 0.14 10
++ 0.15 10
++ 0.12 10
++ 0.34 10
+ + + 0.66 10
++ 0.32 10
++ 0.36 10
9d
9e
10d
10e
Ma
+
+
+
+
0.70 10
0.79 10
0.12 10
0.14 10
+
+
0.70 10
0.15 10
0.12 10
0.14 10
0.5 10
+
0.14 10
++ 0.79 10
+
++ 0.64 10
+
+
0.14 10
+
0.72 10
+ + + 0.5 10
++
+ + + 0.1 10
+ + + 0.1 10
The width of the zone of inhibition indicates the potency of antimicrobial activity.
(
) no antimicrobial activity; (+) weak activity with the diameter of the zone equal
to 0.7 cm.; (++) moderate activity with the diameter of the zone equal to 1.3 cm.;
(+ + +) marked activity with the diameter of the zone equal to 1.7 cm.
Origin of cultures: Botany Department, Faculty of Science, Benha University, Egypt.
The results of control samples were not included in the table; they show negative
response.
aMethaqualone.
in filter sterilized 10 mL of 10% acetone (V/V) and employed in simi-
lar concentration as control. A qualitative screen was performed on all
compounds while quantitative assays were done on active compounds
only. The results are summarized in Table III. Other biological studies
are still in progress.
EXPERIMENTAL
Melting points were taken in open capillary tubes and are uncorrected.
IR spectra in KBr were recorded on a Shimadzu 470 spectrophotome-
ter and 1H NMR spectra in DMSO on a JOEL Fx 90 Q 9 MHz (Fourier
transform NMR spectrometer) using TMS as internal reference (chem-
ical shifts are expressed as , ppm).

1356
A. A. F. Wasfy
The starting compounds 2-methyl-4(3H)-quinazolinone14 and 4-
chloro-2-methylquinazoline16 were prepared as described in the litera-
ture. Also, the amino acid methyl ester hydrochlorides were prepared
according to the published procedure.
Glycine methyl ester hydrochloride (81%), m.p. 173–175 C, lit.,19
m.p. 175 C; L-serine methyl ester hydrochloride (88%), m.p. 176–177 C,
20
lit.,20 m.p. 175 C, [ ]D + 0.96; L-valine methyl ester hydrochloride
20
(86%), m.p. 167–168 C, lit.,20 m.p. 165–167 C [ ]D + 15.8; L-leucine
methyl ester hydrochloride (85%), m.p. 148–150 C, lit.,21 m.p. 150–
20
151 C, [ ]D
13.5; -alanine methyl ester hydrochloride (79%), m.p.
95–96 C, lit.,22 m.p. 95 C.
2-Methyl-4(3H)-quinazolinethione (1)
A mixture of 4-chloro-2-methylquinazoline (32.1 g, 180 mmol) and
thiourea (35.7 g, 470 mmol) in anhydrous ethanol (200 mL) were re-
fluxed for 4 h. The product which separated on cooling was collected,
washed with ethanol and diethyl ether, and dried, 24.1 g (76%),
m.p. 217–219 C; IR; 3250–3150 (NH), 2250 (SH), 1625 (C N), 1270
1
cm (C S), NMR, = 2.1 (s, 3H, CH3), 7.9–8.8 (m, 4H, quinazo-
line ring), 9.2 (s br, 1H, NHC S ratio 55.7), 11.3 (s br, 1H, SH ratio
44.3).
2-[2-(4-Methoxy- or 4-Nitro-phenyl)ethenyl]-4(3H)-
quinazolinethiones (2a,b)
A mixture of 2-methyl-4(3H)-quinazolinethione 1 (13.2 g, 75 mmol)
and an aromatic aldehydes, namely, p-anisaldehyde (10.2 g, 76 mmol)
or p-nitrobenzaldehyde (11.5 g, 76 mmol) were heated for 3 h at
180–185 C. The mixture liquified after one-half hour of heating
and at the end of 3 h was semisolid. When cold, it was pul-
verized and boiled with ethyl alcohol (160 mL) to remove un-
changed starting material and crystallized from glacial acetic
acid to yield the corresponding quinazolinethione derivatives 2a,b
respectively.
2a: yield 18 g (82%), m.p. 265–267 C; IR; 3310–3220 (NH), 2570 (SH),
1640 (C C), 1615 (C N), 1265 cm 1 (C S), NMR, = 3.9 (s, 3H, OCH3),
6.6 (d, 1H, J = 14 Hz, olefinic H), 6.9 (d, 1H, J = 14 Hz, olefinic-H), 7.2–
8.8 (m, 8H, Ar H), 9.3 (s, 1H, NHC S, ratio 55.4), 11.1 (s, 1H, SH, ratio
44.6). Found: C, 69.6; H, 5.0; N, 9.8%. Calcd for C17H14 N2OS: C, 69.4;
H, 4.8; N, 9.5%.
2b: yield 18 g (78%), m.p. 238–240 C; IR; 3270–3220 (NH),
1
2560 (SH), 1630 (C C), 1595 (C N), 1260 cm
(C S). Found: C,

Studies on Quinazolines. Part I
1357
62.4; H, 4.0; N, 13.8%. Calcd for C16H11N3O2S: C, 62.1; H, 3.6; N,
13.6%.
2-(2-Phenyl-1-propenyl)-4(3H)-quinazolinethione (2c)
A mixture of compound 1 (14.8 g, 84 mmol) and acetophenone (10.2 g,
85 mmol) was refluxed in acetic acid/acetic anhydride mixture for 5 h.
The resulting solid was filtered off, washed with cold water, dried, and
recrystallized from aqueous alcohol to afford 2c, 18.6 g (80%), m.p. 278–
280 C, IR, 3200 (NH), 2986–2937 (alkyl-H), 2250 (SH), 1622 (C C),
1
1605 (C N), 1150 cm (C S), NMR, = 2.1 (d, 3H, CH3 due to long
range coupling), 6.5 (q, 1H, CH), 7.1 (m, 9H, Ar H), 9.7 (s br, 1H,
NHC S ratio 53.8), 11.5 (s br, 1H, SH ratio 46.2). Found: C, 73.5; H,
5.2; N, 10.3%. Calcd for C17H14N2S: C, 73.4; H, 5.0; N, 10.1%.
2-(1,3-Dioxoindan-2-yl)-4(3H)-quinazolinethione (2d)
A mixture of compound 1 (15.5 g, 88 mmol) and phthalic anhydride
(13.2 g, 89 mmol) was heated rapidly to about 200 C. The mass soon
solidified at this temperature, but the heating was continued for about
3 h to complete the reaction. The crystalline yellow cake thus obtained
was pulverized and extracted repeatedly with small amounts of boiling
alcohol, to remove unchanged starting materials, and crystallized twice
from glacial acetic acid to furnish 2d, 18.8 g (70%), m.p. 290–292 C;
IR, 3330–3280 (NH), 2535 (SH), 1780–1740 (cyclic dione system), 1610
1
(C N), 1350 cm (C S); NMR, = 4.5 (s, 1H, cyclic CH), 7.1–8.6 (m,
8H, Ar H), 9.4 (s br, 1H, NHC S ratio 56.3), 11.5 (s br, 1H, SH ratio
43.7). Found: C, 66.8; H, 5.1; N, 9.4%. Calcd for C17H10N2O2S: C, 66.7;
H, 4.9; N, 9.2%.
Methyl N-{2-[2-(4-methoxy- or 4-Nitro-phenyl)ethenyl]-,
2-(2-Phenyl-1-propenyl)- or 2-(1,3-Dioxoindan-2-yl)-
quinazolin-4-yl}amino-acetate, -3-Hydroxypropionate,
-3-Methylbutanoate, -4-Methylpentanoate, or
-Propanoate (3–6)a
e
Thiones 2a–d (2.1 mmol) were dissolved in THF or dioxane
(15 mL), amino acid methyl ester hydrochlorides (2.2 mmol) in
(15 mL) THF or dioxane were added with stirring followed by Et3N
(10 mmol). The reaction mixture was refluxed for 6 h, cooled, concen-
trated, and partitioned between ether and water, the ether extract was
worked up as usual. The residue crystallized from a suitable solvent
affording (3–6)a
.
e

1358
A. A. F. Wasfy
3-Oxo-2H-imidazo[1,2-c]- and 4-Oxo-2H,3H-pyrimido-
[1,2-c]-quinazolines Derivatives (7–10)a
e
A mixture of thiones 2a–d (2 mmol), amino acid methyl ester hydrochlo-
rides (2.1 mmol) and Et3N (10 mmol) was heated at its melting temper-
ature for 3 h. After cooling, water (100 mL) was added and the residue
and then extracted with ether; the ether extract was worked up as
usual. The remaining residue was crystallized from a suitable solvent
affording (7–10)a
.
e
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