A facile synthesis of 2-alkyl-3-α-carboxy-α-styryl/heterylvinyl quinazolin-4(3H)-ones and 3-arylidene/heterylmethylidene-4- aroyl-1H-[1,4]benzodiazepine-2,5(3H,4H)-diones and their transformation into novel heterocyclyl and heterocyclo analogues

Article abstract of DOI:10.1002/jhet.756

Condensation of 2-methyl-/2-ethyl- and 2-phenyl-/p-tolyl-4-arylidene-/ heterylmethylidene-2-oxazolin- 5-ones (γ-azlactones) 2 with o-aminobenzamide 1 in acetic acid resulted in the formation of two entirely different heterocyclic systems, differently substituted quinazoline compounds, 2-methyl-/2- ethyl-3-α-carboxy-α-styryl-/β-heteryl-α- carboxyvinyl-quinazolin-4(3H)-ones 3a-3e and 3′a-3′e and differently substituted 1,4-benzodiazepine compounds, 3-arylidene-/heteryl methylidene-4-aroyl-1H- [1,4]benzodiazepine-2,5(3H,4H)-diones 7a-7e and 7′a-7′e. Compounds 3a-3e and 3′a-3′e have been converted into compounds, 4a-4e and 4′a-4′e; 5a-5e, and 5′a-5′e; and 6a-6e and 6′a-6′e through different transformations. Benzodiazepines, 7a-7e and 7′a-7′e, on condensation with o-phenylenediamine have generated three novel heterocyclic systems 8a-8e and 8′a-8′e; 9a-9e and 9′a-9′e; and 10a-10e and 10′a-10′e..

Full text of DOI:10.1002/jhet.756

January 2012
A Facile Synthesis of 2-Alkyl-3-a-carboxy-a-styryl/Heterylvinyl
Quinazolin-4(3H)-ones and 3-Arylidene/Heterylmethylidene-4-
aroyl-1h-[1,4]benzodiazepine-2,5(3H,4H)-diones and Their
Transformation into Novel Heterocyclyl and Heterocyclo
Analogues
173
Poonam Gupta, Archana Sharma, and R. L. Sharma*
Department of Chemistry, University of Jammu, Jammu 180006, India
*E-mail: rlsharma_hod@rediffmail.com
Received July 10, 2010
DOI 10.1002/jhet.756
Published online 25 October 2011 in Wiley Online Library (wileyonlinelibrary.com).
Condensation of 2-methyl-/2-ethyl- and 2-phenyl-/p-tolyl-4-arylidene-/heterylmethylidene-2-oxazolin-
5-ones (c-azlactones) 2 with o-aminobenzamide 1 in acetic acid resulted in the formation of two
entirely different heterocyclic systems, differently substituted quinazoline compounds, 2-methyl-/2-
ethyl-3-a-carboxy-a-styryl-/b-heteryl-a-carboxyvinyl-quinazolin-4(3H)-ones 3a–3e and 30a–30e and dif-
ferently substituted 1,4-benzodiazepine compounds, 3-arylidene-/heteryl methylidene-4-aroyl-1H-
[1,4]benzodiazepine-2,5(3H,4H)-diones 7a–7e and 70a–70e. Compounds 3a–3e and 30a–30e have been
converted into compounds, 4a–4e and 40a–40e; 5a–5e, and 50a–50e; and 6a–6e and 60a–60e through dif-
ferent transformations. Benzodiazepines, 7a–7e and 70a–70e, on condensation with o-phenylenediamine
have generated three novel heterocyclic systems 8a–8e and 80a–80e; 9a–9e and 90a–90e; and 10a–10e
and 100a–100e.
J. Heterocyclic Chem., 49, 173 (2012).
INTRODUCTION
compounds are easily transformed into N-acyl-a, b-dide-
hydroamino acid derivatives, which are powerful syn-
thetic tools [12]. Some of the azlactone derivatives par-
ticularly 4-(p-N,N-dimethylaminophenyl methylene)-2-
phenyl-2-oxazolin-5-one, is embedded in a plasticized
PVC polymer film. On the other hand, compounds pos-
sessing quinazolinone nucleus show potent biological
activities including anticonvulsant [13], antihypertensive
[14], antidiabetic [15], anticoagulant [16], antidiuretic
[17], antibacterial [18], antiviral [19], anticancer [20],
and anti-HIV [21] activities. The benzodiazepines are a
class of drugs with hypnotic [22], anxiolytic, anticon-
vulsant, amnestic, and muscle relaxant properties. They
4-Benzylidene-2-substituted-2-oxazolin-5-ones (c-az-
lactones) are the compounds with a significant synthetic
potential and several biological and technological appli-
cations [1–7]. These compounds can be, for example,
used as inhibitors of the enzyme activity or as fluores-
cent sensors [3,6]. In addition, the oxazolone molecule
serves as a general template for the stereoselective syn-
thesis of amino acids and heterocyclic scaffolds [2]. It is
evident from the literature that azlactones substituted
unsaturatedly [8] at C4 have proved to be versatile inter-
mediates in the synthesis of amino acids [9], cycloali-
phatic [10], and cyclopropyl amino acids [11]. These
C
V
2011 HeteroCorporation

174
P. Gupta, A. Sharma, and R. L. Sharma
Vol 49
Scheme 1
serve as cholecystokinin A and B antagonists [23],
opioid receptor ligands [24], platelet-activating factor
antagonists [25], HIV inhibitors [26], and farnesyltrans-
ferase inhibitors [27]. Benzodiazepines can be used in
anxiety disorders, insomnia, involuntary movement dis-
orders, and in detoxification from alcohol and other sub-
stances. Pyrazole derivatives have been found to possess
varied biological activities. Pyrazole itself and several
N-subsituted pyrazoles are inhibitor and deactivators of
liver alcohol dehydrogenase [28–30]. A large number of
pyrazole derivatives were synthesized, which have
exhibited potent analgesic [31], antibacterial [32], anti-
fungal [33], AIDS [34], and hypoglycemic [35] activ-
ities. Triazepine [36,37] derivatives have a wide range
of biological activities including anti-angiogenesis, her-
bicidal effects, antimetastatic effects, and antibacterial
and fungicidal properties. Keeping this in view, it was
thought of interest to synthesize certain azlactones capa-
ble of attending the reactions, which could exploit them
in their transformation into various other heterocyclic
systems containing the aforementioned vital moieties
with the expectation of their activities supplemented or
at least comparable to those of quinozolinone, 1,5- and
1,4-benzodiazepine, 1,3,5-benzotriazepine and pyrazoli-
dine derivatives. These heterocyclic systems have been
prepared as per (Schemes 1 and 2), respectively.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2012
Facile Synthesis of 2-Alkyl-3-a-carboxy-a-styryl/Heterylvinyl Quinazolin-4(3H)-ones and
3-Arylidene/Heterylmethylidene-4-aroyl-1H-[1,4]benzodiazepine-2,5(3H,4H)-diones
175
Scheme 2
RESULTS AND DISCUSSION
acid at room temperature yielded [7] a colorless crystal-
line compound, mp 235ꢀC. Its mass spectrum revealed
the molecular ion peak at m/z 258 suggesting the loss of
elements of ammonia only from the starting materials.
The condensation reaction between o-aminobenza-
mide 1 and 2-methyl-4-benzylidene-2-oxazolin-5-one 2a
(R ¼ CH3, Ar ¼ C6H5) in 1:1 molar proportion in acetic
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

176
P. Gupta, A. Sharma, and R. L. Sharma
Vol 49
Table 1
Physical and analytical data of compounds 3–10.
Analysis % calcd./found
Compounds
R
Ar
Mp (ꢀC)
235
Yield (%)
93
Molecular formula
C18H14N2O3
C
H
N
3a
Methyl
Pheyl
70.58
70.52
71.25
71.19
65.57
65.51
64.86
64.8
69.56
69.51
71.25
71.18
71.85
71.8
4.57
4.56
5
9.1
9.03
3b
3c
Methyl
Methyl
Methyl
Methyl
Ethyl
4-Methylphenyl
3,4-Dimethoxy-phenyl
2-Furyl
240
220
212
240
247
242
245
248
218
140
148
160
146
153
146
142
165
148
154
202
213
201
208
215
205
224
236
225
85
80
81
79
90
87
84
80
85
86
82
85
88
79
88
85
82
86
87
76
79
74
77
71
76
72
82
71
C19H16N2O3
C20H18N2O5
C16H12N2O4
C20H15N3O3
C19H16N2O3
C20H18N2O3
C21H20N2O5
C17H14N2O4
C21H17N3O3
C17H14N2O
C18H16N2O
C19H18N2O3
C15H12N2O2
C19H15N3O
C18H16N2O
C19H18N2O
C20H20N2O3
C16H14N2O2
C20H17N3O
C18H16N4O2
C19H18N4O2
C20H20N4O4
C16H14N4O3
C20H17N5O2
C19H18N4O2
C20H20N4O2
C21H22N4O4
C17H16N4O3
8.75
8.71
4.8
4.91
4.9
7.65
7.6
3d
3e
4.05
4.03
4.34
4.33
5
9.45
9.42
12.17
12.13
8.75
3-Indolyl
30a
30b
30c
30d
30e
4a
Phenyl
4.9
8.71
8.38
Ethyl
4-Methylphenyl
3,4-Dimethoxy-phenyl
2-Furyl
5.38
5.37
5.26
5.24
4.51
4.5
8.33
7.36
7.31
9.03
Ethyl
66.31
66.25
65.8
Ethyl
65.73
70.19
70.14
77.86
77.77
78.26
78.17
70.8
8.98
Ethyl
3-Indolyl
4.73
4.71
5.34
5.33
5.79
5.77
5.59
5.58
4.76
4.74
7.38
7.37
5.79
5.77
6.2
6.19
5.95
5.94
5.26
5.25
5.39
5.38
5
11.69
11.62
10.68
10.65
10.14
10.09
8.69
Methyl
Methyl
Methyl
Methyl
Methyl
Ethyl
Phenyl
4b
4c
4-Methylphenyl
3,4-Dimethoxy-phenyl
2-Furyl
70.67
71.42
71.35
72.96
72.88
78.26
78.13
78.62
78.54
71.42
71.34
72.18
71.97
76.19
76.08
67.5
8.62
4d
4e
11.11
11.04
2.5
3-Indolyl
2.46
40a
40b
40c
40d
40e
5a
Phenyl
10.14
10.06
9.65
9.58
8.33
Ethyl
4-Methylphenyl
3,4-Dimethoxy-phenyl
2-Furyl
Ethyl
8.3
Ethyl
10.52
10.49
13.33
13.29
17.5
Ethyl
3-Indolyl
Methyl
Methyl
Methyl
Methyl
Methyl
Ethyl
Phenyl
67.38
68.26
68.18
63.15
62.99
61.93
61.86
66.85
66.76
68.26
68.17
68.96
68.85
63.95
63.87
62.96
62.87
4.9
17.44
16.76
16.71
14.73
14.68
18.06
18.01
19.49
19.43
16.76
16.71
16.09
16.03
14.21
14.16
17.28
17.23
5b
5c
4-Methylphenyl
3,4-Dimethoxy-phenyl
2-Furyl
5.38
5.36
5.26
5.25
4.51
4.5
5d
5e
3-Indolyl
4.73
4.72
5.38
5.37
5.74
5.73
5.58
5.57
4.93
4.92
50a
50b
50c
50d
Phenyl
Ethyl
4-Methylphenyl
3,4-Dimethoxy-phenyl
2-Furyl
Ethyl
Ethyl
(Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2012
Facile Synthesis of 2-Alkyl-3-a-carboxy-a-styryl/Heterylvinyl Quinazolin-4(3H)-ones and
3-Arylidene/Heterylmethylidene-4-aroyl-1H-[1,4]benzodiazepine-2,5(3H,4H)-diones
177
Table 1
(Continued)
Analysis % calcd./found
Compounds
R
Ar
Mp (ꢀC)
215
Yield (%)
76
Molecular formula
C21H19N5O2
C
H
N
50e
Ethyl
3-Indolyl
Phenyl
67.56
67.47
73.99
78.83
74.41
74.34
69.28
69.19
69.42
69.33
72.07
71.93
72.63
72.52
72.07
71.96
74.41
74.36
74.81
74.73
69.79
69.67
70.02
69.89
73.06
73.01
75
74.79
75.39
75.28
70.09
69.98
70.39
70.32
73.71
73.63
75.39
75.25
75.75
75.61
70.58
70.51
70.96
70.87
74.1
5.09
5.08
6.16
6.15
6.45
6.44
6.23
6.21
5.78
5.77
5.7
18.76
18.72
11.26
11.22
10.85
10.82
9.69
6ai
6bi
6ci
6di
6dii
6ei
6eiii
60ai
60bi
60ci
60di
60ei
7a
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Ethyl
240
245
225
230
232
222
220
242
228
231
224
243
234
220
260
228
212
243
232
250
236
224
222
227
202
245
260
241
80
83
79
81
85
83
80
78
84
82
78
85
80
78
85
87
78
82
86
90
88
82
68
72
70
73
69
72
C23H23N3O2
C24H25N3O2
C25H27N3O4
C21H21N3O3
C20H19N3O2
C25H25N4O2
C24H23N4O3
C24H25N3O2
C25H27N3O2
C26H29N3O4
C22H23N3O3
C26H27N4O2
C23H16N2O3
C24H18N2O3
C25H20N2O5
C21H14N2O4
C25H17N3O3
C24H18N2O3
C25H20N2O3
C26H22N2O5
C22H16N2O4
C26H19N3O3
C29H20N4O
C30H22N4O
C31H24N4O3
C27H18N4O2
C31H21N5O
C30H22N4O
4-Methylphenyl
3,4-Dimethoxy-phenyl
2-Furyl
9.62
11.57
11.51
12.61
12.56
13.55
13.51
12.61
12.57
10.85
10.81
10.47
10.41
9.39
2-Furyl
5.68
6.05
6.04
5.7
3-Indolyl
3-Indolyl
5.68
6.45
6.44
6.73
6.71
6.48
6.47
6.1
Phenyl
Ethyl
4-Methylphenyl
3,4-Dimethoxy-phenyl
2-Furyl
Ethyl
9.33
Ethyl
11.14
11.08
13.11
13.07
7.6
6.09
6.32
6.3
Ethyl
3-Indolyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
p-Tolyl
Phenyl
4.34
4.32
4.71
4.7
4.67
4.66
3.91
3.9
4.17
4.15
4.71
4.7
7.57
7.32
7b
4-Methylphenyl
3,4-Dimethoxy-phenyl
2-Furyl
7.25
6.54
7c
6.5
7.82
7d
7.78
7e
3-Indolyl
10.31
10.25
7.32
7.28
7.07
7.03
6.33
6.28
7.52
70a
70b
70c
70d
70e
8a
Phenyl
4-Methylphenyl
3,4-Dimethoxy-phenyl
2-Furyl
5.05
5.03
4.97
4.96
4.3
4.28
4.51
4.5
4.54
4.53
4.84
4.82
4.8
4.79
4.18
4.16
4.38
4.37
4.84
4.83
7.48
9.97
3-Indolyl
74.02
79.09
78.81
79.29
79.18
74.4
73.92
75.34
75.29
77.66
77.62
79.29
79.21
9.92
Phenyl
12.72
12.65
12.33
12.28
11.2
10.92
13.02
12.97
14.61
14.56
12.33
12.29
8b
4-Methylphenyl
3,4-Dimethoxy-phenyl
2-Furyl
8c
8d
8e
3-Indolyl
80a
Phenyl
(Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

178
P. Gupta, A. Sharma, and R. L. Sharma
Vol 49
Table 1
(Continued)
Analysis % calcd./found
Compounds
R
Ar
Mp (ꢀC)
243
Yield (%)
69
Molecular formula
C31H24N4O
C
H
N
80b
80c
p-Tolyl
4-Methylphenyl
79.48
79.35
74.7
5.12
5.11
5.05
5.04
4.5
11.96
11.92
10.89
10.84
12.61
12.57
14.19
14.14
15.87
15.8
p-Tolyl
p-Tolyl
p-Tolyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
3,4-Dimethoxy-phenyl
2-Furyl
252
228
223
238
244
256
243
247
236
240
238
250
253
232
238
202
245
250
236
243
264
250
250
71
73
69
75
69
74
68
71
72
75
68
74
69
71
74
75
66
68
72
75
69
73
76
C32H26N4O3
C28H20N4O2
C32H23N5O
C35H25N6
74.62
75.67
75.59
77.89
77.8
80d
80e
4.48
4.66
4.65
4.72
4.71
4.97
4.95
4.92
4.91
4.43
4.41
4.57
4.56
4.97
4.95
5.2
3-Indolyl
9a
Phenyl
79.39
79.33
79.55
79.5
9b
4-Methylphenyl
3,4-Dimethoxy-phenyl
2-Furyl
C36H27N6
15.46
15.4
9c
C37H29N6O2
C33H23N6O
C37H26N7
75.38
75.34
76.3
14.26
14.2
9d
16.18
16.12
17.25
17.2
15.46
15.4
76.23
78.16
78.07
79.55
79.51
79.71
79.65
75.62
75.57
76.54
76.48
78.35
78.3
9e
3-Indolyl
90a
90b
90c
Phenyl
C36H27N6
4-Methylphenyl
3,4-Dimethoxy-phenyl
2-Furyl
C37H29N6
15.08
15.01
16.18
16.13
15.75
15.69
16.83
16.76
12.22
12.18
11.86
11.81
10.81
10.77
12.5
5.19
5.14
5.12
4.69
4.68
4.81
4.8
C38H31N6O2
C34H25N6O
C38H28N7
90d
90e
3-Indolyl
10a
10b
10c
10d
10e
100a
100b
100c
100d
100e
Phenyl
C29H22N4O2
C30H24N4O2
C31H26N4O4
C27H20N4O3
C31H23N5O2
C30H24N4O2
C31H26N4O2
C32H28N4O4
C28H22N4O3
C32H25N5O2
75.98
75.91
76.27
76.22
71.81
71.75
72.32
72.27
74.84
74.78
76.27
76.23
76.54
76.47
72.18
72.11
72.72
72.66
75.14
75.08
4.8
4.78
5.08
5.07
5.01
4.99
4.46
4.44
4.62
4.61
5.08
5.06
5.34
5.33
5.26
5.24
4.76
4.75
4.89
4.88
4-Methylphenyl
3,4-Dimethoxy-phenyl
2-Furyl
12.46
14.08
14.05
11.86
11.81
11.52
11.48
10.52
10.47
12.12
12.07
13.69
13.62
3-Indolyl
Phenyl
4-Methylphenyl
3,4-Dimethoxy-phenyl
2-Furyl
3-Indolyl
Based on the elemental analysis and spectral data, the
structure of the compound was assigned as 3-(a-car-
boxy-a-styryl)-2-methylquinazolin-4(3H)-one 3a (R ¼
CH3, Ar ¼ C6H5). Structure assigned to the product 3a
was further supported by its decarboxylation on reflux-
ing it in THF for 2 h, resulting in the formation of a
colorless compound 4a, mp 142ꢀC. In the mass spec-
trum, the molecular ion peak of the product 4a was
observed at m/z 262 corresponding to the decarboxylated
product of 3-(a-carboxy-a-styryl)-2-methyl quinazolin-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2012
Facile Synthesis of 2-Alkyl-3-a-carboxy-a-styryl/Heterylvinyl Quinazolin-4(3H)-ones and
3-Arylidene/Heterylmethylidene-4-aroyl-1H-[1,4]benzodiazepine-2,5(3H,4H)-diones
179
4(3H)-one 3a (R ¼ CH3, Ar ¼ C6H5). Based on the rest
of spectral data and elemental analysis, the structure of
the compound was assigned as 2-methyl-3-(a-styryl)qui-
nazolin-4(3H)-one 4a. Exactly identical products 30a and
40a were obtained when 2-ethyl-4-benzylidene-2-oxazo-
lin-5-one 20a was reacted with o-aminobenzamide.
Using other differently substituted benzylidine/heteryl-
methylidene-2-methyl/2-ethyl-2-oxazolin-5-ones 2b–2e
and 20b–20e, analogously structured 3b–3e and 30b–30e
quinazoline compounds were generated in total confor-
mity with the expected results. Compounds 3 were con-
verted into their acid chloride with SOCl2 in benzene,
and the latter compounds were treated with piperidine,
pyrolidine, and morpholine to produce the corresponding
piperidide, pyrolidide, and morpholide cyclic tertiary
amides 6. The ethyl esters of compounds 3 on treatment
with hydrazine produced 3-(5-aryl/heteryl-3-oxo-pyrazo-
lidin-4-yl)-2-methyl/ethyl-quinazolin-4(3H)-ones 5.
Similar condensation of o-aminobenzamide 1 with 2-
phenyl-4-(p-methylbenzylidene)-2-oxazolin-5-one 2b (R
¼ C6H5, Ar ¼ p-CH3C6H4) in 1:1 molar proportion was
carried out by refluxing in dry benzene containing few
drops of acetic acid yielding a colorless crystalline com-
pound, mp 232ꢀC. Its mass spectrum revealed the molec-
ular ion at m/z 396 indicating again the loss of ammonia
from uniequimolar proportion of the starting materials.
Based on elemental analysis and spectral data, the struc-
ture of the compound was assigned as 3-(p-methylbenzy-
lidene)-4-benzoyl-1H-[1,4]benzodiazepine-2,5(3H,4H)-
dione 7b (R ¼ C6H5, Ar ¼ p-CH3C6H4). Again, the reac-
tion was carried with o-aminobenzamide and 2-(p-tolyl)-
4-(p-methyl benzylidene)-2-oxazolin-5-one 20b for the
formation of 70b and expected results were obtained.
Other benzodiazepine analogues 7a, 7c–7g and 7/a, 70c–
70g have been synthesized with positive results.
Conclusively, the formation of the entirely two dif-
ferent kinds of products, a quinazolinone 3 or a 1,4-
benzodiazepine 7 analog when an alkyl or aryl group
receptively is present at 2-position of the 2-oxazoli-
none can be explained by the nucleophilic attack by
the amino group of the o-aminobenzamide 1 on two
different sites, either C-2 (R ¼ CH3/C2H5) or C-5 (R
¼ C6H5/p-CH3C6H4) of 2 forming intermediates 11
and 12 of Scheme 1 or 14 and 15 of Scheme 2,
respectively. Nucleophilic attack of azomethine nitro-
gen of 11 or imide nitrogen of 14 on the amide
carbonyl carbon and subsequent cyclization of these
intermediates followed by elimination of ammonia
from 12 or 15 lead to the formation of stable 3 or 7
(Schemes 1 and 2).
with slight traces of 10a (TLC) and vise versa when the
reaction was carried out in same molar proportion in
DMF containing few drops of dilute (0.5%) aqueous
NaOH. When the reaction of compound 7a was carried
with double the quantity of o-phenylene diamine, that is,
in 1:2 molar ratio and for prolonged time in boiling
ethanol, it resulted in the formation of a doubly fused
compound 9a as the main product with slight traces of
8a and 10a (TLC). The products 8a, 9a, and 10a were
separated by fractional crystallization and purified by
repeated crystallization. Based on spectral data and ele-
mental analysis, these three novel condensed heterocy-
clic systems were characterized and assigned their struc-
tures. Condensation of other differently substituted 7b–
7e and 70a–70e with o-phenylenediamine under different
conditions have yielded differently substituted three
novel condensed heterocyclic systems, 8b–8e and 80b–
80e; 9b–9e and 90a–90e; and 10b–10e and 100a–100e in
good yields.
EXPERIMENTAL
General. Melting points were measured in open capilla-
ries on a perfit melting point apparatus and are uncorrected.
IR spectra on KBr were recorded on Bruker–4800 infrared
spectrometer. NMR and EIMS/HRMS spectra were recorded
on Bruker AC-400 (400 and 100 MHz) and JEOL D-300
mass spectrometer, respectively. Elemental analysis was car-
ried out on simple CHNS analyzer (CHNS-932, LECO Cor-
poration). 1H and 13C chemical shifts are reported in parts
per million (ppm) from tetramethylsilane as internal stand-
ard. All experiments were performed in oven-dried glass ap-
paratus. SISCO silica was usedign as adsorbent for TLC
(0.5-mm thick plates), and TLC plates were eluted with 1:9
ratios of ethyl acetate and n-hexane. The column chroma-
tography was performed over silica gel (60–120 mesh) with
graded solvent systems of ethyl acetate–petroleum ether
(60–80).
General procedures. 2-Methyl-/2-ethyl- and 2-phenyl-/p-
tolyl-4-arylidene/heterylmethylidene-oxazolin-5-ones
2 were
prepared by the erlenmayer synthesis of azlactones [38].
Procedure for the synthesis of 3a–3e and 30a–30e. o-Ami-
nobenzamide 1 (0.1 mol) was dissolved in acetic acid (5 mL)
in a boiling tube and a solution of 2-methyl-4-benzylidene-2-
oxazolin-5-one 2a (R ¼ CH3, Ar ¼ C6H5, 0.1 mol) was added
to it. The reaction mixture was heated at about 95ꢀC on a
water bath for 1 h and then set aside for cooling. Colorless
compound that separated out on cooling was filtered, washed
with few drops of methanol, and recrystallized from a mixture
of ethyl acetate and few drops of methanol. The pure 3-(a-car-
boxy-a-styryl)-2-methylquinazolin-4(3H)-one 3a (R ¼ CH3, Ar
¼ C6H5) was obtained. Similarly, 30a was obtained when o-
aminobenzamide 1 was treated with 2-ethyl-4-benzylidene-2-
oxazolin-5-ones 20a (R ¼ C2H5, Ar ¼ C6H5, 0.1 mol). The
other arylidene and heterylmethylidene analogs, 3b–3e and
30b–30e were obtained similarly.
Further, condensation of 3-benzylidene-4-benzoyl-1H-
[1,4]benzodiazepine-2,5(3H,4H)-dione 7a (R ¼ C6H5,
Ar ¼ C6H5) with o-phenylene diamine in 1:1 molar ra-
tio in acetic acid yielded 8a as the main product along
Procedure for the synthesis of 4a–4e and 40a–40e. A mix-
ture of 3-(a-carboxy-a-styryl)-2-methylquinazolin-4(3H)-one
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

180
P. Gupta, A. Sharma, and R. L. Sharma
Vol 49
3a (R ¼ CH3, Ar ¼ C6H5, 0.01 mol) and THF (10 mL) was
taken in 50-mL round-bottom flask and refluxed for 3 h. THF
was then removed by distillation at reduced pressure, and the
colorless residue that remained in the flask was collected and
crystallized from petroleum ether–chloroform mixture to give
2-methyl-3-(a-styryl)-quinazolin-4(3H)-one 4a. The other sub-
stituted styryl and heterylvinyl analogs 4b–4e were also
obtained. Similarly, the exact identical product 40a was
obtained from 30a. The other analogs 4b–4e and 40b–40e were
obtained from corresponding compounds, 3b–3e and 30b–30e,
respectively.
Procedure for the synthesis of 5a–5e and 50a–50e. 3-(a-Car-
boxy-a-styryl)-2-methylquinazolin-4(3H)-one 3a (R ¼ CH3, Ar
¼ C6H5, 0.025 mol) was converted into its ethyl ester with
ethanol and HCl as usual. To this ester was added hydrazine
hydrate in 1:1 molar ratio, and the reaction mixture was
refluxed for 2 h and poured into water. The colorless com-
pound that precipitated out in the flask was filtered and crystal-
lized from petroleum ether chloroform mixture to give 3-(5-
phenyl-3-oxopyrazolidin-4-yl)-2-methylquinazolin-4(3H)-one
5a. The other analogs 5b–5e and 50a–50e were obtained from
corresponding substrates in very good yield.
Procedure for the synthesis of 6a–6e and 60a–60e. 3-(a-Car-
boxy-a-styryl)-2-methylquinazolin-4(3H)-one 3a (R ¼ CH3, Ar
¼ C6H5, 0.025 mol) was converted into its acid chloride with
SOCl2 in benzene and worked up as usual. To this acid chlo-
ride was added piperidine (X ¼ CH2) and the reaction mixture
in 1:1 molar ratio was refluxed for 2 h and poured into water.
The colorless compound that precipitated out in the flask was
filtered and crystallized from petroleum ether chloroform mix-
ture to give the compound 6ai (X ¼ CH2). The other analogs
6b–6e and 60b–60e were also obtained in good yield. Starting
from 3d and using pyrrolidine (X ¼ 0) and starting from 3e
and using morpholine (X ¼ O), analogs 6dii and 6eiii were
also obtained.
Procedure for the synthesis of 7a–7e and 70a–70e. o-Ami-
nobenzamide 1 (0.1 mol) and 2-phenyl-4-benzylidene-2-oxa-
zolin-5-one 2a (R ¼ C6H5, Ar ¼ C6H5, 0.1 mol) were
taken in dry benzene (50 mL) and refluxed on a water
bath initially for about 3–4 h. The refluxing was continued
for a further period of 10–12 min after the addition of a
few drops of acetic acid. The colorless compound that sep-
arated out was filtered and crystallized from acetic acid.
The pure 3-benzylidene-4-benzoyl-1H-[1,4]benzodiazepine-
2,5(3H, 5H)-dione 7a was obtained in 80% yields, and the
other arylidene/heterylmethylidene analogs 7b–7e were
obtained similarly in good yields. Similar procedure was
adopted to generate 70a when o-aminobenzamide 1 (0.1
mol) was treated with 2-(p-tolyl)-4-benzylidene-2-oxazolin-5-
one 20a (R ¼ p-CH3C6H4, Ar ¼ C6H5) (0.1 mol) and its
other analogues 70b–70e were also generated similarly from
corresponding substrates.
solidified, could be separated by filtration and was washed
with acetic acid. The filtrate along with combined washings
contained only the minor product 10a (TLC). The product 8a
was crystallized from boiling ethanol. When the same reaction
was carried out in DMF containing few drops of 0.5% aqueous
NaOH solution, the observed results were reversed. The main
spot was due to 10a, whereas 8a was detected only as very
minor product (TLC). The reaction mixture was poured into
ice cold water when 10a separated out as fluffy solid leaving
at the bottom a sticky minor product 8a. Compound 10a was
crystallized from hot methanol. When the reaction of 7a with
o-phenylenediamine was carried out in 1:2 molar ratio in boil-
ing ethanol for a prolonged period (6 h), it resulted in the for-
mation of a doubly condensed compound 9a as the main prod-
uct with very slight traces of 8a and 10a. On cooling for over-
night, shining pale yellow crystals of 9a separated, which were
filtered, dried, and purified after two repeated crystallizations
from hot ethanol. The other analogs 8b–8e and 80b–80e, 9b–9e
and 90b–90e, and 10b–10e and 100b–100e were also obtained
from the corresponding substrates.
Spectral data of some constituent representatives
from each kind.
3-(a-Carboxy-a-styryl)-2-methylquinazo-
lin-4(3H)-one (3a). IR (KBr, m, cmꢁ1): 3334, 3224, 3156,
1
2640, 1720, 1642, 1515, 1238, 1215. H NMR (DMSO-d6) d:
2.30 (s, 3H, CH3), 7.21–7.90 (m, 9H, ArH), 7.98 (s, 1H,
¼¼C¼¼CH-AAr), 10.52 (s, 1H, COOH). 13C NMR (DMSO-d6)
d: 22.1, 120.3, 122.1, 124.2, 125.9, 126.2, 126.7, 127.3, 127.9,
128.2, 128.6, 129.1, 132.6, 135.8, 145.7, 162.6, 164.6, 165.8.
MS m/z: 306 (Mþ).
3-(a-Carboxy-a-styryl)-2-ethylquinazolin-4(3H)-one (30a). IR
(KBr, m, cmꢁ1): 3410, 3225, 3060, 2832, 1685, 1624, 1235,
1
1210. H NMR (DMSO-d6) d: 1.85 (t, 3H, CH3), 2.71 (q, 2H,
CH2), 7.10–7.80 (m, 9H, ArH), 7.92 (s, 1H, ¼¼C¼¼CHAAr),
10.82 (s, 1H, COOH). 13C NMR (DMSO-d6) d: 5.7, 24.2,
120.1, 122.7, 124.4, 125.8, 126.1, 126.9, 127.5, 128.6, 129.3,
129.7, 130.0, 132.0, 133.8, 145.3, 162.1, 164.5, 165.8. MS m/
z: 320 (Mþ).
2-Methyl-3-a-styryl-quinazolin-4(3H)-one (4a). IR (KBr, m,
cmꢁ1): 3233, 3114, 2976, 2940, 1660, 1632, 1525, 1548, 1215.
1H NMR (DMSO-d6) d: 2.21 (s, 3H, CH3), 7.10–7.62 (m, 9H,
ArH), 7.82 (d, J ¼ 14.5 Hz, 1H, ¼¼C¼¼CHAAr), 7.98 (d, J ¼
14.5 Hz, 1H, ACH¼¼C¼¼Ar). 13C NMR (DMSO-d6) d: 22.3,
111.8, 119.1, 120.2, 121.9, 125.2, 126.2, 127.3, 127.9, 128.0,
128.3, 133.1, 134.6, 140.7, 163.6, 164.6, 165.8. MS m/z: 262
(Mþ).
2-Ethyl-3-a-styryl-quinazolin-4(3H)-one (40a). IR (KBr, m,
cmꢁ1): 3360, 3245, 3090, 2948, 1668, 1584, 1527, 1205. 1H
NMR (DMSO-d6) d: 1.92 (t, 3H, CH3), 2.70 (q, 2H, CH2), 7.21–
7.70 (m, 9H, ArH), 7.74 (d, J ¼ 14.2 Hz, 1H, ¼¼C¼¼CHAAr),
7.82 (d, J ¼ 14.2 Hz, 1H, ACH¼¼C¼¼Ar). 13C NMR (DMSO-d6)
d: 5.9, 24.0, 111.9, 120.0, 121.7, 125.4, 125.9, 127.1, 128.0,
128.2, 128.4, 128.9, 133.0, 134.8, 140.9, 163.8, 164.9, 165.0. MS
m/z: 276 (Mþ).
3-[5-(3,4-Dimethoxyphenyl)-3-oxopyrazolidin-4-yl]-2-methyl-
quinazolin-4(3H)-one (5c). IR (KBr, m, cmꢁ1): 3432, 3376,
3225, 2980, 2870, 1715, 1670, 1668, 1320, 1270, 1248. 1H
NMR (DMSO-d6) d: 2.11 (s, 3H, CH3), 2.86 (d, 1H, CH),
2.94 (d, 1H, CH), 3.70 (s, 3H, OCH3), 3.73 (s, 3H, OCH3),
6.81–7.50 (m, 7H, ArH), 8.23 (s, 1H, NH, D2O exchang-
able), 8.54 (s, 1H, NH, D2O exchangable). MS m/z: 380
(Mþ).
Procedure for the synthesis of 8a–8e and 80a–80e, 9a–9e
and 90a–90e, and 10a–10e and 100a–100e. A well-grinded
mixture of 3-benzylidene-4-benzoyl-1H-[1,4]benzodiazepine-
2,5(3H,4H)-dione 7a (0.1) and o-phenylenediamine (0.1 mol)
(Thomas Baker Chm., Mumbai, India) was refluxed in acetic
acid (10 mL) for about 2 h. The reaction product was moni-
tored by TLC when a very prominent spot of the main product
8a was detected along with trailing spot of the minor product
10a. The reaction mixture was cooled when the main product
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2012
Facile Synthesis of 2-Alkyl-3-a-carboxy-a-styryl/Heterylvinyl Quinazolin-4(3H)-ones and
3-Arylidene/Heterylmethylidene-4-aroyl-1H-[1,4]benzodiazepine-2,5(3H,4H)-diones
181
2-Methyl-3-[a-(N-piperidinylcarbonyl)-4-methyl-a-styryl]-
quinazolin-4(3H)-ones (6bi) (X 5 CH2). IR (KBr, m, cmꢁ1):
3435, 3320, 3228, 1720, 1680, 1665, 1270, 1262, 1232. 1H
NMR (DMSO-d6) d: 2.10 (s, 3H, CH3), 2.32 (s, 3H, CH3),
1.90–3.10 (m, 10H, 5 ꢂ CH2), 6.82 (s, 1H, ¼¼C¼¼CHAAr),
7.10–7.51 (m, 8H, ArHs). 13C NMR (DMSO-d6) d: 22.0, 24.1,
24.6, 26.8, 26.8, 43.5, 43.5, 119.9, 121.6, 122.0, 125.4, 125.4,
126.9, 127.3, 128.5, 129.8, 129.8, 131.5, 132.5, 134.8, 136.7,
145.8, 164.5, 165.8. MS m/z: 387 (Mþ).
2-Methyl-3-[a-(N-pyrolidinylcarbonyl)-b-(2-furyl)vinyl]quina-
zolin-4(3H)-ones (6dii) (X 5 0). IR (KBr, m, cmꢁ1): 3392,
3242, 3115, 1718, 1690, 1685, 1275, 1260, 1235. 1H NMR
(DMSO-d6) d: 2.21 (s, 3H, CH3), 1.78–3.22 (m, 8H, 4 ꢂ
CH2), 6.91 (s, 1H, ¼¼C¼¼CHAAr), 7.20–7.64 (m, 7H, ArH,
HetH). MS m/z: 333 (Mþ).
2-Methyl-3-[a-(N-morpholinylcarbonyl)-b-(3-indolyl)vinyl]-
quinazolin-4(3H)-ones (6eiii) (X 5 O). IR (KBr, m, cmꢁ1):
3425, 3230, 3095, 2968, 1708, 1692, 1645, 1290, 1268, 1225.
1H NMR (DMSO-d6) d: 2.10 (s, 3H, CH3), 1.69–3.72 (m, 8H,
4 ꢂ CH2), 6.89 (s, 1H, ¼¼C¼¼CHAAr), 7.20–7.98 (m, 9H,
ArH, HetH), 9.20 (s, 1H, NH, D2O exchangable). 13C NMR
(DMSO-d6) d: 22.2, 42.8, 43.5, 67.9, 68.2, 110.8, 111.3, 119.6,
120.5, 120.4, 121.8, 122.5, 125.1, 126.8, 127.0, 128.5, 129.5,
130.3, 133.1, 133.5, 136.6, 145.6, 163.8, 165.9. MS m/z: 415
(Mþ).
3-Benzylidene-4-benzoyl-1H-[1,4]benzodiazepine-2,5(3H,4H)-
dione (7a). IR (KBr, m, cmꢁ1): 3296, 3205, 3010, 3330, 1685,
1660, 1640, 1465, 1220. 1H NMR (DMSO-d6) d: 7.21–7.80
(m, 14H, ArH), 7.95 (s, 1H, ¼¼C¼¼CHAAr), 9.64 (s, 1H, NH,
D2O exchangable). 13C NMR (DMSO-d6) d: 121.3, 122.5,
123.0, 124.6, 125.3, 126.2, 126.7, 127.3, 127.9, 128.0, 128.3,
128.6, 128.8, 128.9, 129.5, 129.8, 132.0, 134.6, 137.6, 138.8,
162.6, 163.6, 164.9. MS m/z: 368 (Mþ).
7-Benylidene-9-Phenyl-6,7-dihydro-5H-[1,4]benzodiazepino-
[5,4-b][1,3,5]benzo triazepin-6-one (8a). IR (KBr, m, cmꢁ1):
3390, 3325, 3276, 2986, 1697, 1685, 1660,1450, 1278, 1275,
1
1220. H NMR (DMSO-d6) d: 7.10–7.32 (m, 9H, ArH), 7.52–
7.80 (m, 9H, ArH), 7.84 (s, 1H, ¼¼C¼¼CHAAr), 9.20 (s, 1H,
NH, D2O exchangable). 13C NMR (DMSO-d6) d: 107.6, 119.8,
121.4, 122.8, 123.4, 124.2, 126.2, 126.4, 126.7, 126.8, 126.9,
128.0, 128.3, 128.4, 128.6, 128.9, 129.2, 129.6, 129.8, 130.6,
134.8, 135.8, 136.6, 143.5, 144.9, 147.3, 163.2, 164.5, 165.3.
MS m/z: 440 (Mþ).
7-(2-Furylmethylidene)-9-Phenyl-6,7-dihydro-5H-[1,4]benzo-
diazepino[5,4-b][1,3,5]benzotriazepin-6-one (8d). IR (KBr, m,
cmꢁ1): 3410, 3365, 3110, 2835, 1690, 1665, 1632, 1468, 1280,
1
1266, 1230. H NMR (DMSO-d6) d: 6.50–6.82 (m, 3H, ArH),
7.22–7.71 (m, 13H, ArH), 7.86 (s, 1H, ¼¼C¼¼CHAAr), 9.41 (s,
1H, NH, D2O exchangable). 13C NMR (DMSO-d6) d: 107.6,
108.3, 120.6, 121.5, 123.1, 123.5, 124.0, 124.3, 126.2, 126.7,
126.9, 128.2, 128.5, 128.7, 128.9, 129.2, 130.0, 130.3, 136.1,
139.3, 143.5, 144.6, 144.8, 146.5, 163.5, 164.2, 164.6. MS m/
z: 430 (Mþ).
17-(Indol-3-yl)-19-phenyl-10,16,17,17a-tetrahydro[1,5]benzo-
diazepino[20,30:2,3] [1,4] benzodiazepino[5,4-b][1,3,5]benzo-
triazepine (9e). IR (KBr, m, cmꢁ1): 3415, 3340, 3170, 2982,
1
2870, 1695, 1642, 1628, 1285, 1242, 1228. H NMR (DMSO-
d6) d: 4.51 (d, 1H, CH), 4.58 (d, 1H, CH), 6.34–6.80 (m, 5H,
ArH), 6.85–7.10 (m, 8H, ArH), 7.24–7.65 (m, 9H, ArH), 9.10
(s, 1H, NH, D2O exchangable), 9.40 (s, 1H, NH, D2O
exchangable), 9.62 (s, 1H, NH, D2O exchangable). 13C NMR
(DMSO-d6) d: 49.3, 52.7, 110.8, 113.6, 116.5, 116.8, 118.1,
118.4, 118.8, 119.2, 120.5, 121.8, 122.5, 122.9, 123.7, 125.2,
125.8, 127.1, 127.6, 127.8, 128.2, 128.5, 128.7, 128.7, 130.5,
131.2, 132.6, 133.9, 134.4, 134.7, 135.8, 136.3, 145.5, 146.9,
164.2, 164.5, 172.8. MS m/z: 568 (Mþ).
13-Benzoyl-12-(3,4-dimethoxyphenyl)-5,11,12,12a,13,14-
hexahydro[1,5]benzo diazepino[2,3-b][1,4]benzodiazepin-14-
one (10c) IR (KBr, m, cmꢁ1): 3450, 3230, 3205, 3110, 2975,
1725, 1708, 1272, 1260, 1225. 1H NMR (DMSO-d6) d: 3.70
(s, 3H, OCH3), 3.72 (s, 3H, OCH3), 4.80 (d, 1H, CH), 4.86 (d,
1H, CH), 6.52–7.0 (m, 4H, ArH), 7.05–7.30 (m, 3H, ArH),
7.36–7.84 (m, 9H, ArH), 8.25 (s, 1H, NH, D2O exchangable),
8.48 (s, 1H, NH, D2O exchangable). 13C NMR (DMSO-d6) d:
49.2, 52.3, 55.8, 56.2, 114.5, 115.6, 116.8, 118.1, 118.5, 118.8,
120.5, 123.8, 127.1, 127.6, 127.9, 128.2, 128.4, 128.6, 128.9,
132.7, 133.5, 134.8, 136.5, 137.2, 142.7, 145.8, 146.2, 147.4,
148.7, 163.8, 164.5. MS m/z: 518 (Mþ).
3-(4-Methylbenzylidene)-4-benzoyl-1H-[1,4]benzodiazepine-
2,5(3H,4H)-dione (7b). IR (KBr, m, cmꢁ1): 3445, 3316, 3250,
2965, 1720, 1651, 1648, 1454, 1212. H NMR (DMSO-d6) d:
2.30 (s, 3H, CH3), 7.23–7.88 (m, 13H, ArH), 7.95 (s, 1H,
¼¼C¼¼CHAAr), 9.56 (s, 1H, NH, D2O exchangable). 13C NMR
(DMSO-d6) d: 24.1, 121.5, 122.6, 123.1, 124.8, 125.2, 126.5,
126.8, 127.3, 127.6, 127.8, 127.9, 128.5, 128.9, 129.2, 129.5,
131.3, 132.5, 134.8, 135.5, 138.9, 162.1, 163.5, 164.8. MS m/
z: 382 (Mþ).
1
3-Benzylidene-4-(4-methylbenzoyl)-1H-[1,4]benzodiazepine-
2,5(3H,4H)-dione (70a) IR (KBr, m, cmꢁ1): 3510, 3276, 3245,
1
2970, 1720, 1656, 1632, 1467, 1216. H NMR (DMSO-d6) d:
2.30 (s, 3H, CH3), 7.10–7.79 (m, 13H, ArH), 7.90 (s, 1H,
¼¼C¼¼CHAAr), 9.8 (s, 1H, NH, D2O exchangable). 13C NMR
(DMSO-d6) d: 24.5, 121.8, 122.9, 123.5, 124.1, 125.5, 126.6,
126.9, 127.5, 127.7, 128.1, 128.6, 128.9, 129.3, 129.8, 131.8,
132.5, 133.6, 135.7, 137.9, 142.5, 162.8, 164.6, 164.5. MS m/z:
382 (Mþ).
Acknowledgments. The authors are thankful to the Department
of Chemistry, University of Jammu, Jammu, and IIIM Jammu for
providing research and library facilities.
REFERENCES AND NOTES
3-(4-Methylbenzylidene)-4-(4-methylbenzoyl)-1H-[1,4]benzo-
diazepine-2,5(3H,4H)-dione (70b). IR (KBr, m, cmꢁ1): 3270
(NH); 1680, 1642, 1632 (C ¼ 0); 1212 (CAN). 1H NMR
(DMSO-d6) d: 2.20 (s, 3H, CH3), 2.52 (s, 3H, CH3), 7.10–
7.91 (m, 12H, ArH), 7.95 (s, 1H, ¼¼C¼¼CHAAr), 9.50 (s,
1H, NH, D2O exchangable). 13C NMR (DMSO-d6) d: 23.7,
24.1, 121.2, 122.8, 123.5, 124.2, 126.2, 126.7, 127.1, 127.5,
127.7, 127.9, 129.3, 129.5, 129.8, 129.9, 131.5, 132.3,
133.8, 135.9, 138.7, 140.5, 162.6, 163.9, 164.5. MS m/z:
396 (Mþ).
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