Synthesis of a novel series of 2,3-disubstituted quinazolin-4(3H)-ones as a product of a nucleophilic attack at C(2) of the corresponding 4H-3,1-benzoxazin-4-one

Article abstract of DOI:10.1002/hlca.201000230

A new series of 2,3-disubstituted quinazolin-4(3H)-one derivatives was synthesized by nucleophilic attack at C(2) of the corresponding key starting material 2-propyl-4H-3,1-benzoxazin-4-one (Scheme 2). The reaction proceeded via amidinium salt formation (Scheme 3) rather than via an N-acylanthranilimide. The structure of the prepared compounds were elucidated by physical and spectral data like FTIR, ¹H-NMR, and mass spectroscopy.

Full text of DOI:10.1002/hlca.201000230

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Synthesis of a Novel Series of 2,3-Disubstituted Quinazolin-4(3H)-ones as a
Product of a Nucleophilic Attack at C(2) of the Corresponding 4H-3,1-
Benzoxazin-4-one
by Mahr A. El-Hashasha) and Yaser A. El-Badry*b)
a) Department of Organic Chemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
b) Organic Chemistry Lab., Faculty of Pharmacy, Ain Shams University, 11566 Abbasseya, Cairo, Egypt
(e-mail: yaser75moemen@yahoo.com)
A new series of 2,3-disubstituted quinazolin-4(3H)-one derivatives was synthesized by nucleophilic
attack at C(2) of the corresponding key starting material 2-propyl-4H-3,1-benzoxazin-4-one (Scheme 2).
The reaction proceeded via amidinium salt formation (Scheme 3) rather than via an N-acylanthranil-
imide. The structure of the prepared compounds were elucidated by physical and spectral data like FT-
IR, 1H-NMR, and mass spectroscopy.
Introduction. – The 2,3-disubstituted quinazolin-4(3H)-one derivatives possess a
broad spectrum of biological and pharmaceutical activities [1 – 4] such as sedative-
hypnotic [5], anticonvulsant [6], phosphorylation-inhibition [7][8], EGFR-inhibition
[9][10], and antidiabetic activity [11]. The most common approach toward quinazo-
linones is based on acylation of anthranilic acid (¼2-aminobenzoic acid) and ring
closure with Ac2O to afford corresponding benzoxazinones [12], which are then
submitted to react with various primary amines (as N-nucleophiles) to give a series of
new 2,3-disubstituted quinazolin-4(3H)-ones.
It was envisioned that the nucleophilic attack of the 4H-3,1-benzoxazin-4-one takes
place at C(2) as well as at C(4), even if the electrophilicity at C(2) is weaker than at
C(4).
Results and Discussion. – The key starting material 2-propyl-4H-3,1-benzoxazin-4-
one (2) was synthesized from butanoyl chloride and anthranilic acid in the presence of
pyridine via N-acylanthranilic acid 1, which on dehydration with Ac2O afforded the
desired benzoxazinone (Scheme 1).
Scheme 1
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Considering the structure of 4H-3,1-benzoxazin-4-one derivatives, there are two
sites available for nucleophilic attack, C(2) and C(4), i.e., two different sites with
partial positive charge that can lead to the opening of the oxazinone moiety by different
nucleophiles. In most cases, reclosure of the heterocyclic part of the molecule is favored
and provides a new compound with interesting chemical and biological properties [13].
The reaction of benzoxazinone 2 with a substituted aniline, namely 3-aminophenol
or 4-aminobenzoic acid, was chosen as model reaction which resulted in 3-aryl-2-
propylquinazolin-4(3H)-one derivative 3 or 4, respectively (Scheme 2). The structure
of 4 was confirmed chemically by its condensation with aromatic aldehydes like
veratraldehyde (¼ 3,4-dimethoxybenzaldehyde), 4-(dimethylamino)benzaldehyde,
and piperonal (¼1,3-benzodioxole-5-carboxaldehyde) in boiling glacial AcOH leading
Scheme 2

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391
to the corresponding 4-{2-[1-(arylmethylidene)propyl]-4-oxoquinazolin-3(4H)-yl}ben-
zoic acids 5a – 5c.
Moreover, 4H-3,1-benzoxazin-4-one 2 reacted with sulfanilamide (¼4-amino-
benzenesulfonamide) derivatives like sulfamethoxazol (¼4-amino-N-(5-methylisoxa-
zol-3-yl)benzenesulfonamide) or sulfathiazol (¼4-amino-N-(thiazol-2-yl)benzenesul-
fonamide) to afford the corresponding sulfonamides 6a or 6b, respectively (Scheme 2).
One can interpret these results as follows: The N-nucleophiles are attacking the
benzoxazinone 2 in a fashion in which the amino group first undergoes H-bonding to
the N-atom of the heterocycle. Then, the amino group reacts by nucleophilic addition at
the ꢂazavinylicꢃ C(2) to form an inner amidinium salt, which subsequently is dehydrated
to give the quinazolinone derivative (Scheme 3).
Scheme 3
In the case of the reaction of 2 with a substituted aniline derivative, we rejected the
nucleophilic attack at C(4) as the second possible pathway which would lead to the N-
acylanthranilamides. The supposed N-acylanthranilamide is reported [14] to be
difficult to recyclize and requires temperatures above 2008 to affect cyclization which
does not correspond with our reaction conditions.
It was reported that 4H-3,1-benzoxazin-4-one derivatives react with NH2OH · HCl
in boiling dry pyridine and undergo heterocycle opening and recyclization to give
hydroxyquinazolinone derivatives [15]. Thus, treatment of 2-propyl-4H-3,1-benzox-
azin-4-one (2) with NH2OH · HCl in dry pyridine at 1108 afforded 3-hydroxy-2-
propylquinazolin-4(3H)-one (7) (Scheme 2). The structure of 7 was inferred chemi-
cally by studying its behavior towards C-electrophiles. In this context, treatment of
compound 7 with boiling Ac2O afforded 3-(acetyloxy)quinazolin-4(3H)-one (8)
(Scheme 4). The 3-hydroxyquinazolinone 7 underwent also condensation with
aromatic aldehydes such as veratraldehyde, 4-(dimethylamino)benzaldehyde, and
piperonal in boiling glacial AcOH to give the corresponding 2-[1-(arylmethylidene)-
propyl]-3-hydroxyquinazolin-4(3H)-ones 9a – 9c. Moreover, the conversion of 7 into
ethyl 2-{[4-oxo-2-propylquinazolin-3(4H)-yl]oxy}acetate (10) was achieved via the
interaction with ClCH2COOEt in the presence of anhydrous K2CO3 in boiling dry
acetone. The structure of compound 10 was established chemically by the reaction with
NH2NH2 · H2O in boiling EtOH affording 2-[(4-oxo-2-propylquinazolin-3(4H)-yl)oxy]-
acetohydrazide (11) (Scheme 4).
Heating 4H-3,1-benzoxazin-4-one 2 in neat NH2NH2 · H2O or in NH2NH2 · H2O/
pyridine produced the 3-amino-2-propylquinazolin-4(3H)-one (12) (Scheme 2). On
the other hand, hydrazinolysis of benzoxazinone 2 with PhNHNH2 provided the
quinazolinone derivative 13 (Scheme 2). It has been reported that compounds having

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Scheme 4
the structure of quinazolinone derivative 13 are key starting materials for synthesizing
some interesting triazino-quinazoline derivatives [16].
The above results are in agreement with our assumption of a nucleophilic attack at
C(2). On the other hand, they are in disagreement with previous results which account
for the formation of 3-aminoquinazoline to rationalize the hydrazinolysis reaction in
the presence of anhydrous ZnCl2 [17] or when the substituent at C(2) is sterically bulky
[18].
When 3-aminoquinazolin-4(3H)-one 12 was treated with HNO2, it gave 3-
(chlorodiazenyl) compound 14 as a fleeting intermediate (not isolated), followed by
coupling with different active-methylene-containing compounds such as malononitrile,
ClCH2COOEt, and diethyl malonate resulting in the same sole product 3-ethyl[1,2,3]-
triazolo[5,1-b]quinazolin-9(1H)-one (15) (Scheme 5). When the fleeting intermediate
14 was treated with AcONa in the absence of active-methylene containing compounds
under identical reaction and work-up conditions, the product obtained was also 15.
Scheme 5
Finally, 2-propyl-4H-3,1-benzoxazinone 2, when treated with semicarbazide
(¼ hydrazinecarboxamide) or thiosemicarbazide (¼ hydrazinecarbothioamide) in boil-
ing glacial AcOH, afforded 5-propyl[1,2,4]triazolo[1,5-c]quinazolin-2(3H)-one (16a)
or 5-propyl[1,2,4]triazolo[1,5-c]quinazolin-2(3H)-thione (16b), respectively (Scheme 2).

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Conclusions. – We successfully converted the prepared 4H-3,1-benzoxazin-4-one 2
into the more stable and the higher functionalized 2,3-disubstituted quinazoline
derivatives (Scheme 2). The nucleophilic attack at C(2) of 2 by the NH2 moiety was
established, suggesting that the ring reclosure occurred readily via an amidinium
intermediate under mild reaction conditions (Scheme 3).
Experimental Part
General. M.p.: Stuart electric melting-point apparatus; uncorrected. IR Spectra: l FT-IR 8201PC
Shimadzu (Japan, 1995); KBr pellets; n˜ in cmꢀ1. 1H-NMR Spectra: Varian 300 MHz (Germany, 1999); in
CDCl3 or (D6)DMSO; d in ppm rel. to Me4Si as internal standard, J in Hz. EI-MS: GC/MS-Qploopx
Shimadzu (Japan, 1990); in m/z (rel. %). Elemental analysis were carried out in the Micro Analytical
Center, Cairo University, Giza, Egypt.
2-Propyl-4H-3,1-benzoxazin-4-one (2). A suspension of 2-[(1-oxobutyl)amino]benzoic acid (1;
2.07 g, 0.01 mol) in freshly dist. Ac2O (50 ml) was heated under reflux for 3 h and then concentrated. The
residue was crystallized from petroleum ether (40 – 608): 2 (78%). Colorless crystals. M.p. 598. IR (KBr):
1
1614 (C¼N), 1764 (CO). H-NMR (CDCl3): 1.07 (t, J ¼ 6.9, Me); 1.69 (ꢂsext.ꢃ, J ¼ 6.4, MeCH2); 2.58 (t,
J ¼ 13.4, MeCH2CH2); 7.22 – 7.98 (m, 4 arom. H). Anal. calc. for C11H11NO2: C 69.84, H 5.82; found: C
69.76, H 5.92.
3-(3-Hydroxyphenyl)-2-propylquinazolin-4(3H)-one (3). A mixture of 2 (1.89 g, 0.01 mol) and 3-
aminophenol (1.09 g, 0.01 mol) in boiling EtOH (20 ml) was refluxed for 3 h. The mixture was allowed to
stand overnight, and the solid obtained was filtered off and recrystallized from toluene: 3 (66%). M.p.
216 – 2188. IR (KBr): 1605 (C¼N), 1672 (CO), 2870, 2931, 2962 (CH, aliph.), 3055 (CH, arom.).
1H-NMR ((D6)DMSO): 0.96 (t, J ¼ 6.9, Me); 1.82 (ꢂsext.ꢃ, J ¼ 6.4, MeCH2); 2.33 (t, J ¼ 13.6, MeCH2CH2);
5.3 (s, OH); 7.53 – 8.12 (m, 8 arom. H). MS: 280 (Mþ), 251, 159, 145, 119, 105. Anal. calc. for C17H16N2O2:
C 72.81, H 5.75; found: C 73.04, H 5.68.
4-[4-Oxo-2-propylquinazolin-3(4H)-yl]benzoic Acid (4). A soln. of 2 (1.89 g, 0.01 mol) and 4-
aminobenzoic acid (1.37 g, 0.01 mol) in glacial AcOH (30 ml) was refluxed for 3 h. The solid, separated
after cooling, was filtered off and crystallized from EtOH: 4 (69%). M.p. 225 – 2268. IR (KBr): 1605
(C¼N), 1674, 1685 (CO), 2870, 2931, 2962 (CH, aliph.), 3055 (CH, arom.), 3400 (OH). 1H-NMR
((D6)DMSO): 0.97 (t, J ¼ 6.9, Me); 1.76 (ꢂsext.ꢃ, J ¼ 6.4, MeCH2); 2.48 (t, J ¼ 13.6, MeCH2CH2); 7.42 –
8.04 (m, 8 arom. H); 11.81 (s, OH). MS: 308 (Mþ), 293, 280, 279, 159, 122. Anal. calc. for
C18H16N2O3: C 70.12, H 5.23; found: C 69.84, H 5.41.
4-{2-[1-(Arylmethylidene)propyl]-4-oxoquinazolin-3(4H)-yl}benzoic Acids 5a – 5c. A soln. of
4
(3.08 g, 0.01 mol) and veratraldehyde, 4-(dimethylamino)benzaldehyde, or piperonal (0.01 mol) in
glacial AcOH was heated under reflux for 10 h. After cooling, the mixture was poured into cooled water.
The precipitated solid was collected, filtered off, and crystallized from EtOH: 5a – 5c.
4-{2-{1-[(3,4-Dimethoxyphenyl)methylidene]propyl}4-oxoquinazolin-3(4H)-yl}benzoic Acid (5a):
Yield 54%. M.p. 188 – 1898. IR (KBr): 1597, 1605 (C¼N), 1675 (CO), 2870, 2931, 2962 (CH, aliph.),
3055 (CH, arom.), 3450 (OH). 1H-NMR ((D6)DMSO): 1.13 (t, J ¼ 7.5, Me); 2.48 (q, J ¼ 16.7, CH2); 4.10
(s, 2 MeO); 6.64 (s, ¼CH); 6.94 – 7.83 (m, 11 arom. H); 11.83 (s, OH). Anal. calc. for C27H24N2O5: C 71.04,
H 5.30; found: C 71.37, H 5.52.
4-{2-{1-{[(4-Dimethylamino)phenyl]methylidene}propyl}-4-oxoquinazolin-3(4H)-yl}benzoic Acid
(5b): Yield 61%. M.p. 1738. IR (KBr): 1599, 1605 (C¼N), 1674 (CO), 2870, 2931, 2964 (CH, aliph.),
3050 (CH, arom.), 3450 (OH). 1H-NMR ((D6)DMSO): 1.13 (t, J ¼ 7.5, Me); 2.49 (q, J ¼ 16.9, CH2); 3.11
(s, 2 Me); 6.52 (s, ¼CH); 6.85 – 7.97 (m, 12 arom. H); 11.89 (s, OH). Anal. calc. for C27H25N3O3: C 73.78,
H 5.73; found: C 73.51, H 5.60.
4-{2-{1-[(1,3-benzodioxol-5-yl)methylidene]propyl}-4-oxoquinazolin-3(4H)-yl}benzoic Acid (5c):
Yield 71%. M.p. 201 – 2038. IR (KBr): 1603 (C¼N), 1677 (CO), 2870, 2930, 2965 (CH, aliph.), 3050
1
(CH, arom.), 3450 (OH). H-NMR ((D6)DMSO): 1.13 (t, J ¼ 7.5, Me); 2.33 (q, J ¼ 16.9, CH2); 5.85 (s,
OCH2O); 6.77 (s, ¼CH); 7.03 – 7.84 (m, 11 arom. H); 11.47 (s, OH). Anal. calc. for C26H20N2O5: C 70.90,
H 4.58; found: C 71.29, H 4.82.

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4-[4-Oxo-2-propylquinazolin-3(4H)-yl]benzenesulfonamides (6a and 6b). A mixture of 2 (0.01 mol)
and sulfamethoxazol or sulfathiazol (0.01 mol) in glacial AcOH (20 ml) was refluxed for 3 h. The mixture
was concentrated and the formed precipitate washed with water, filtered off, and crystallized from the
proper solvent: 6a and 6b.
N-(5-Methylisoxazol-3-yl)-4-[4-oxo-2-propylquinazolin-3(4H)-yl]benzenesulfonamide (6a): Yield
86%. M.p. 1858 (EtOH). IR (KBr): 1597, 1629 (C¼N), 1674 (CO), 2870, 2931, 2962 (CH, aliph.),
3054 (CH, arom.), 3200 (NH). 1H-NMR ((D6)DMSO): 0.94 (t, J ¼ 6.9, Me); 1.68 (ꢂsext.ꢃ, J ¼ 6.3,
MeCH2); 1.93 (s, Me); 2.48 (t, J ¼ 13.6, MeCH2CH2); 6.21 (s, ¼CH); 7.34 – 7.95 (m, 8 arom. H); 8.92 (s,
NH). MS: 424 (Mþ), 395, 298, 159, 145, 119, 115. Anal. calc. for C21H20N4O4S: C 59.42, H 4.75; found: C
59.73, H 4.71.
4-[4-Oxo-2-propylquinazolin-3(4H)-yl]-N-(thiazol-2-yl)benzenesulfonamide (6b): Yield 76%. M.p.
1718 (toluene). IR (KBr): 1598 (C¼N), 1668 (CO), 2872, 2930, 2962 (CH, aliph.), 3054 (CH, arom.),
3200 (NH). 1H-NMR ((D6)DMSO): 1.05 (t, J ¼ 6.9, Me); 1.64 (ꢂsext.ꢃ, J ¼ 6.3, MeCH2); 2.53 (t, J ¼ 13.6,
MeCH2CH2); 6.83 (d, ¼CH); 7.38 – 7.86 (m, 8 arom. H, ¼CH); 9.3 (s, NH). Anal. calc. for C20H18N4O3S: C
56.32, H 4.25; found: C 56.16, H 4.37.
3-Hydroxy-2-propylquinazolin-4(3H)-one (7). A soln. of 2 (1.89 g, 0.01 mol) and NH2OH · HCl in
boiling EtOH (25 ml) was refluxed for 3 h. The mixture was concentrated and the residue cooled and
recrystallized from EtOH: 7 (84%). M.p. 1688. IR (KBr): 1614 (C¼N), 1679 (CO), 2890, 2973 (CH,
aliph.), 3060 (CH, arom.), 3410 (OH). 1H-NMR (CDCl3): 0.94 (t, J ¼ 6.8, Me); 1.95 (ꢂsext.ꢃ, J ¼ 6.4,
MeCH2); 2.63 (t, J ¼ 13.6, MeCH2CH2); 7.51 – 7.81 (m, 4 arom. H); 12.30 (s, OH). Anal. calc. for
C11H12N2O2: C 64.69, H 5.92; found: C 65.12, H 5.71.
3-(Acetyloxy)-2-propylquinazolin-4(3H)-one (8). A soln. of 7 (2.04 g, 0.01 mol) in freshly dist. Ac2O
(10 ml) was refluxed for 3 h. The mixture was concentrated and the residue cooled and recrystallized
from petroleum ether (60 – 808): 8 (79%). M.p. 808. IR (KBr): 1605 (C¼N), 1676, 1728, 1800 (CO), 2877,
2931, 2970 (CH, aliph.), 3055 (CH, arom.). 1H-NMR (CDCl3): 0.97 (t, J ¼ 6.9, Me); 1.64 (ꢂsext.ꢃ, J ¼ 6.2,
MeCH2); 2.31 (s, MeCOO); 2.71 (t, J ¼ 13.5, MeCH2CH2); 7.43 – 7.79 (m, 4 arom. H). MS: 246 (Mþ); 217,
175, 159, 105, 77. Anal. calc. for C13H14N2O3: C 63.41, H 5.73; found: C 63.42, H 5.79.
2-[1-(Arylmethylidene)propyl]-3-hydroxyquinazolin-4(3H)-ones 9a – 9c. A mixture of 7 (2.04 g,
0.01 mol) and an aromatic aldehyde (0.01 mol) namely, veratraldehyde, 4-(dimethylamino)benzalde-
hyde, or piperonal, in glacial AcOH (10 ml) was refluxed for 8 h. The excess solvent was distilled off, and
the residue was poured on ice water. The produced solid was filtered off and recrystallized from the
proper solvent: 9a – 9c.
2-{1-[(3,4-Dimethoxyphenyl)methylidene]propyl}-3-hydroxyquinazolin-4(3H)-one (9a): Yield 53%.
M.p. 122 – 1238 (MeOH). IR (KBr): 1605 (C¼N), 1672 (CO), 2870, 2931, 2962 (CH, aliph.), 3055 (CH,
arom.), 3430 (OH). 1H-NMR (CDCl3): 1.40 (t, J ¼ 7.4, Me); 2.45 (q, J ¼ 17.2, MeCH2); 3.42 (s, 2 MeO);
6.60 (s, ¼CH); 6.82 – 7.94 (m, 7 arom. H); 11.72 (s, OH). MS: 352 (Mþ), 337, 324, 176, 145, 105. Anal. calc.
for C20H20N2O4: C 68.17, H 5.72; found: C 68.32, H 5.84.
2-{1-{[4-Dimethylamino)phenyl]methylidene}propyl}-3-hydroxyquinazolin-4(3H)-one (9b): Yield
64%. M.p. 113 – 1168 (MeOH). IR (KBr): 1602 (C¼N), 1677 (CO), 2870, 2931, 2959 (CH, aliph.),
3055 (CH, arom.), 3430 (OH). 1H-NMR (CDCl3): 1.17 (t, J ¼ 7.5, Me); 2.61 (q, J ¼ 16.9, MeCH2); 2.83 (s,
Me2N); 6.48 (s, ¼CH); 6.78 – 8.05 (m, 8 arom. H); 11.61 (s, OH). Anal. calc. for C20H21N3O2: C 71.62, H
6.31; found: C 71.76, H 6.38.
2-{1-[(1,3-Benzodioxol-5-yl)methylidene]propyl}-3-hydroxyquinazolin-4(3H)-one (9c): Yield 71%.
M.p. 134 – 1358 (MeOH). IR (KBr): 1605 (C¼N), 1675 (CO), 2870, 2931, 2957 (CH, aliph.), 3057 (CH,
arom.), 3424 (OH). 1H-NMR (CDCl3): 1.13 (t, J ¼ 7.4, Me); 2.49 (q, J ¼ 17.2, MeCH2); 5.64 (s, OCH2O);
6.68 (s, ¼CH); 7.05 – 8.07 (m, 7 arom. H); 11.65 (s, OH). Anal. calc. for C19H16N2O4: C 67.85, H 4.76;
found: C 67.97, H 4.60.
Ethyl 2-{[4-Oxo-2-propylquinazolin-3(4H)-yl]oxy}acetate (10). A mixture of 7 (2.04 g, 0.01 mol),
ClCH2COOEt (2.72 g, 0.02 mol), and anh. K2CO3 (0.04 mol) in dry acetone (50 ml) was refluxed for 24 h
on a water bath. The excess solvent was removed by distillation, and the residue was poured on to cold
water. The obtained solid was filtered off and recrystallized from benzene: 10 (89%). M.p. 1108. IR
(KBr): 1597, 1600 (C¼N), 1674, 1740 (CO), 2877, 2931, 2970 (CH, aliph.), 3024 (CH, arom.). 1H-NMR
(CDCl3): 1.08 (t, J ¼ 6.9, Me); 1.32 (t, J ¼ 7.1, MeCH2O); 1.73 (ꢂsext.ꢃ, J ¼ 6.4, MeCH2); 2.51 (t, J ¼ 13.4,

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MeCH2CH2); 3.94 (q, J ¼ 7.1, MeCH2O); 4.63 (s, OCH2CO); 7.42 – 7.92 (m, 4 arom. H). MS: 290 (Mþ),
261, 218, 190, 119, 105. Anal. calc. for C15H18N2O4: C 62.06, H 6.20; found: C 62.20, H 6.29.
2-{[4-Oxo-2-propylquinazolin-3(4H)-yl]oxy}acetic Acid Hydrazide (11). A soln. of 10 (2.90 g,
0.01 mol) and NH2NH2 · H2O (0.75 g, 0.015 mol) in EtOH (50 ml) was refluxed for 3 h. The mixture was
concentrated and then allowed to cool and the obtained solid filtered off and recrystallized from EtOH:
11 (68%). M.p. 1808. IR (KBr): 1597, 1600 (C¼N), 1684 (CO), 2887, 2925, 2977 (CH, aliph.), 3045 (CH,
arom.), 3298, 3322 (NH). 1H-NMR (CDCl3): 0.91 (t, J ¼ 6.8, Me); 1.60 (ꢂsext.ꢃ, J ¼ 6.2, MeCH2); 2.49 (t,
J ¼ 13.4, MeCH2CH2); 4.72 (s, OCH2CO); 7.46 – 7.84 (m, 4 arom. H); 8.84 (s, NH2); 8.97 (s, NH). Anal.
calc. for C13H16N4O3: C 56.53, H 5.79; found: C 56.81, H 5.90.
3-Amino-2-propylquinazolin-4(3H)-one (12). A mixture of 2 (1.89 g, 0.01 mol) and NH2NH2 · H2O
(5 ml) was heated in a water bath for 30 min, and then EtOH (50 ml) was added and the mixture heated
under reflux for 3 h. The mixture was concentrated, and the residue was poured on cooled water and the
formed precipitate dried and crystallized from petroleum ether (60 – 808): 12 (75%). M.p. 858. IR (KBr):
1
1596 (C¼N), 1673 (CO), 2875, 2935, 2965 (CH, aliph.), 3055 (CH, arom.), 3212, 3309 (NH). H-NMR
(CDCl3): 0.94 (t, J ¼ 7.0, Me); 1.86 (ꢂsext.ꢃ, J ¼ 6.5, MeCH2); 2.68 (t, J ¼ 13.4, MeCH2CH2); 7.49 – 7.79 (m, 4
arom. H); 8.8 (s, NH2). MS: 203 (Mþ), 174, 146, 120, 77. Anal. calc. for C11H13N3O: C 65.02, H 6.40;
found: C 64.81, H 6.54.
3-(Phenylamino)-2-propylquinazolin-4(3H)-one (13). A mixture of 2 (1.89 g, 0.01 mol) and
PhNHNH2 (2.16 g, 0.02 mol) in EtOH (30 ml) was refluxed for 3 h. The mixture was concentrated,
the residue poured over cold water, and the separated solid filtered off and recrystallized from benzene:
13 (79%). M.p. 136 – 1388. IR (KBr): 1597, 1605 (C¼N), 1674 (CO), 2870, 2931, 2962 (CH, aliph.), 3055
(CH, arom.), 3200 (NH). 1H-NMR (CDCl3): 0.94 (t, J ¼ 7.0, Me); 1.82 (ꢂsext.ꢃ, J ¼ 6.4, MeCH2); 2.53 (t,
J ¼ 13.7, MeCH2CH2); 6.68 – 7.94 (m, 9 arom. H); 8.92 (s, NH). MS: 279 (Mþ), 264, 237, 236, 146, 120.
Anal. calc. for C17H17N3O: C 73.10, H 6.13; found: C 73.28, H 6.34.
3-Ethyl[1,2,3]triazolo[5,1-b]quinazolin-9(1H)-one (15). A soln. of 12 (2.03 g, 0.01 mol) in AcOH/
conc. HCl soln. 1:3 (15 ml) was cooled to 08, and an eq. soln. of NaNO3 (1.38 g, 0.02 mol) was added. The
mixture was stirred at 08 for 15 min then added to a soln. of malononitrile, acetyl acetone (¼ pentane-2,4-
dione), or ethyl acetoacetate (¼ethyl 3-oxobutanoate) (0.01 mol) in EtOH (5 ml) containing AcONa
(4 g). The mixture was stirred overnight, and the obtained solid was dried and recrystallized from
MeOH: 15 (62%). M.p. 1988. IR (KBr): 1620 (C¼N), 1676 (CO), 2931, 2962 (CH, aliph.), 3167 (NH).
1H-NMR ((D6)DMSO): 2.10 (t, J ¼ 7.3, Me); 2.62 (q, J ¼ 13.9, CH2); 7.24 – 7.86 (m, 4 arom. H); 12.1 (s,
NH). Anal. calc. for C11H10N4O: C 61.68, H 4.67; found: C 61.81, H 4.54.
[1,2,4]Triazolo[1,5-c]quinazolin-2(3H)-one and -thione 16a and 16b. A mixture of 2 (1.89 g,
0.01 mol) and semicarbazide or thiosemicarbazide (0.01 mol) in glacial AcOH (25 ml) in the presence of
AcONa (0.05 mol) was heated under reflux for 4 h. The mixture was allowed to stand overnight, and the
separated solid was crystallized from the proper solvent to give 16a or 16b.
5-Propyl[1,2,4]triazolo[1,5-c]quinazolin-2(3H)-one (16a): Yield 72%. M.p. 219 – 2218 (EtOH). IR
(KBr): 1605 (C¼N), 1685 (CO), 2870, 2931, 2962 (CH, aliph.), 3055 (CH, arom.), 3310 (NH). 1H-NMR
((D6)DMSO): 0.93 (t, J ¼ 6.8, Me); 1.84 (ꢂsext.ꢃ, J ¼ 6.4, MeCH2); 2.48 (t, J ¼ 13.6, MeCH2CH2); 7.32 –
7.89 (m, 4 arom. H); 9.42 (s, NH). Anal. calc. for C12H12N4O: C 63.14, H 5.30; found: C 63.38, H 5.38.
5-Propyl[1,2,4]triazolo[1,5-c]quinazoline-2(3H)-thione (16b): Yield 82%. M.p. 2348 (EtOH). IR
(KBr): 1161 (CS), 1604 (C¼N), 2881, 2931, 2962 (CH, aliph.), 3055 (CH, arom.), 3361 (NH). 1H-NMR
((D6)DMSO): 0.93 (t, J ¼ 6.9, Me); 1.58 (ꢂsext.ꢃ, J ¼ 6.4, MeCH2); 2.37 (t, J ¼ 13.6, MeCH2CH2); 7.26 –
7.81 (m, 4 arom. H); 9.86 (s, NH). MS: 244 (Mþ), 230, 217, 216, 203, 145, 119, 92, 77. Anal. calc. for
C12H12N4S: C 58.99, H 4.95; found: C 59.34, H 5.18.
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Received June 11, 2010