Reactions of N′-acyl- and N′-tosyl-substituted hydrazides of 2-aminobenzoic acid with carbonyl compounds

Article abstract of DOI:10.1023/B:RUCB.0000012368.51042.bd

The reactions of N′-acyl and N′-tosyl-substituted hydrazides of 2-aminobenzoic acid with aliphatic, aromatic, and heterocyclic aldehydes or aliphatic ketones afforded 3-acyl- and 3-tosylamido-1,2-dihydroquinazolin-4-one derivatives, respectively. The stru

Full text of DOI:10.1023/B:RUCB.0000012368.51042.bd

2444
Russian Chemical Bulletin, International Edition, Vol. 52, No. 11, pp. 2444—2453, November, 2003
Reactions of N´ꢀacylꢀ and N´ꢀtosylꢀsubstituted hydrazides
of 2ꢀaminobenzoic acid with carbonyl compounds
a
a
b
b
G. A. Smirnov,a E. P. Sizova, O. A. Luk´yanov, I. V. Fedyanin, and M. Y. Antipin
ꢀ
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: smir@ioc.ac.ru
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5085
The reactions of N´ꢀacyl and N´ꢀtosylꢀsubstituted hydrazides of 2ꢀaminobenzoic acid with
aliphatic, aromatic, and heterocyclic aldehydes or aliphatic ketones afforded 3ꢀacylꢀ and
3ꢀtosylamidoꢀ1,2ꢀdihydroquinazolinꢀ4ꢀone derivatives, respectively. The structures of the reꢀ
action products were established by NMR spectroscopy and Xꢀray diffraction analysis.
Key words: N´ꢀacylꢀ and N´ꢀtosylhydrazides of 2ꢀaminobenzoic acid, aldehydes, ketones,
reactions; 2ꢀsubstituted 3ꢀacylamidoꢀ1,2ꢀdihydroquinazolinꢀ4ꢀones and 3ꢀtosylamidoꢀ
1,2ꢀdihydroquinazolinꢀ4ꢀones; nuclear Overhauser effect, Xꢀray diffraction analysis.
Scheme 1
1,2ꢀDihydroquinazolinꢀ4ꢀone (DHQ) derivatives exꢀ
ert targeted action on the central nervous system by exꢀ
hibiting anticonvulsive1 and sedative2,3 activities. To
search for DHQ possessing potential biological activities,
we synthesized DHQ containing amide substituents at the
N(3) atom. Data on procedures for the preparation of
compounds of this type are scarce in the literature. The
reactions of 2ꢀaminobenzoic acid hydrazides (ABAH)
containing acyl substituents at the N´ atom with carbonyl
compounds would be expected to open the simplest route
to these compounds. This is supported by the reaction of
an N´ꢀethoxycarbonyl derivative of ABAH with aldehyde
to give 3ꢀethoxycarbonylamidoꢀ1,2ꢀdihydroquinazolinꢀ
4ꢀone, which has been described earlier.4 However, the
structure of the latter reaction product has not been unꢀ
ambiguously proved in the cited study.4 The structures of
Schiff's bases,5—7 sevenꢀmembered triazepine rings,5,6,8
DHQ,5,7 and even threeꢀmembered aziridine rings9 were
assigned to the products of reactions of N´ꢀunsubstituted
ABAH with carbonyl derivatives.
In the present study, we examined the reactions of
N´ꢀacylꢀ and N´ꢀtosylꢀsubstituted hydrazides of 2ꢀamiꢀ
nobenzoic acid with carbonyl compounds.
The starting N´ꢀderivatives of ABAH 2a—f were synꢀ
thesized according to Scheme 1. Compounds 2a—e were
prepared by the addition of acetic, benzoic, 4ꢀbromoꢀ
benzoic, and 4ꢀnitrobenzoic acid hydrazides10 or monoꢀ
hydrazide of ethyl carbonate (1a—e) to isatoic anhydride.
N´ꢀTosylhydrazide (2f) was synthesized by tosylation
of ABAH.11
R = Ac (a), Bz (b), 4ꢀBrC6H4CO (c), 4ꢀO2NC6H4CO (d), EtO2C (e),
Ts (f)
The reactions of hydrazides 1a—d with isatoic anhyꢀ
dride were carried out in refluxing acetic acid. The reacꢀ
tion of hydrazide 1e was performed in anhydrous ethanol
(to prevent hydrolysis of the ester group). The low yields
of compounds 2a,b (57—59%) are attributable to subseꢀ
quent reactions attendant on this synthesis. For instance,
it was found that compound 2c underwent intramolecular
transformation into 2ꢀ(4ꢀbromophenyl)ꢀ3,4ꢀdihydroꢀ
1,3,4ꢀbenzotriazepinꢀ5ꢀone (3) (Scheme 2) (examples of
such transformations were published in the literature12).
Aldehydes, such as formaldehyde, acetaldehyde,
thiopheneꢀ2ꢀcarbaldehyde, and 2,4ꢀdichlorobenzaldeꢀ
hyde, and ketones, such as acetone and cyclohexanone,
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2311—2319, November, 2003.
1066ꢀ5285/03/5211ꢀ2444 $25.00 © 2003 Plenum Publishing Corporation

Synthesis of 1,2ꢀdihydroquinazolinꢀ4ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003 2445
Scheme 2
Scheme 3
R1 = Ac (a), Bz (b), 4ꢀBrC6H4CO (c), 4ꢀO2NC6H4 (d), EtO2C (e),
Ts (f)
were used as carbonyl compounds. The principal physiꢀ
cochemical characteristics of the compounds thus synꢀ
thesized are given in Tables 1—3.
R2 = H (4), Me (5),
(6),
(7)
It was found that the reactions of hydrazides 2a—f
with carbonyl compounds in EtOH have a general charꢀ
R2 = R3 = Me (8), R2—R3 = (CH2)5 (9)
Table 1. Melting points, yields, and elemental analysis data for 1,2ꢀdihydroquinazolinꢀ4(3H )ꢀone derivatives 4—9
Comꢀ
pound
m.p./°C
Yield
(%)
Found
Calculated
Molecular
formula
(%)
C
H
X
N
4a
4b
4c
4d
4e
4f
205—207
241—244
254—256
259—262
151—154
213—216
169—171
189—190
197—199
242—244
147—150
220—222
49
27
30
31
52
30
82
82
90
83
85
70
58.51
58.52
67.20
67.40
51.71
52.04
57.54
57.69
56.25
56.16
56.78
56.74
59.74
59.99
67.85
68.31
53.01
53.35
58.55
58.89
57.84
57.82
57.70
57.99
5.62
5.40
4.83
4.90
3.55
3.49
3.85
3.87
5.10
4.97
5.00
4.76
6.64
6.41
5.65
5.37
3.94
3.92
4.27
4.32
6.15
6.07
5.14
5.17
—
—
20.40
20.48
15.56
15.72
12.14
12.14
17.58
17.94
15.73
15.96
13.13
13.23
19.01
19.08
15.16
14.94
11.19
11.66
17.17
17.17
16.69
16.86
12.54
12.68
С10H11N3O2
С15H13N3O2
С15H12BrN3O2
С15H12N4O4
С11H13N3O3
С15H15N3O3S
С11H14N3O2
С16H15N3O2
С16H14BrN3O2
С16H14N4O4
С12H15N3O3
С16H17N3O3S
Br, 22.76
23.08
—
—
S, 9.58
10.09
—
5a
5b
5c
5d
5e
5f
—
Br, 21.78
22.18
—
—
S, 9.46
9.67
(to be continued)

2446
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003
Smirnov et al.
Table 1 (continued)
Comꢀ
pound
m.p./°C
Yield
(%)
Found
Calculated
Molecular
formula
(%)
C
H
X
N
6a
6b
6c
6d
6e
6f
252—254
215—216
237—239
247—249
213—216
216—219
235—23
75
75
78
85
72
66
64
76
85
80
75
78
98
73
87
93
90
79
85
60
75
71
61
82
58.48
58.52
65.50
65.31
53.02
53.28
57.69
57.86
56.64
56.77
56.92
57.13
54.89
54.88
61.33
61.18
51.61
51.35
55.16
55.16
53.86
53.82
54.43
54.55
61.64
61.79
69.01
69.14
54.62
54.56
59.89
60.00
59.53
59.30
59.14
59.11
65.64
65.91
71.55
71.62
58.10
57.98
63.34
63.15
63.34
63.31
62.25
62.29
4.47
4.56
4.31
4.33
3.41
3.29
3.54
3.58
4.76
4.76
4.35
4.29
3.67
3.74
3.70
3.67
3.01
2.87
3.07
3.09
3.92
3.72
3.79
3.71
6.54
6.48
6.03
5.80
4.55
4.31
4.89
4.74
6.44
6.51
5.63
5.54
6.94
7.01
6.34
6.31
4.88
4.87
5.41
5.30
6.97
7.01
5.95
6.01
S, 10.90
11.16
S, 9.24
9.18
Br, 18.23
18.66
S, 8.41
8.13
S, 10.54
10.10
S, 15.45
16.05
Cl, 21.00
20.25
Cl, 17.20
17.05
14.73
14.62
11.95
12.03
9.93
С14H13N3O2S
С19H15N3O2S
С19H14BrN3O2S
С19H14N4O4S
С15H15N3O3S
С19H17N3O3S2
С16H13Cl2N3O2
С21H15Cl2N3O2
С21H14BrCl2N3O2
С21H14Cl2N4O4
С16H15Cl2N3O3
С21H17Cl2N3O3S
С12H15N3O2
9.81
14.30
14.21
13.05
13.24
10.68
10.52
11.98
12.00
10.26
10.19
8.61
7a
7b
7c
7d
7e
7f
217—219
243—244
237—239
199—202
120—125
239—241
262—264
251—254
273—275
217—219
185—189
234—236
226—229
216—218
216—220
229—232
157—164
Cl+Br, 30.69
30.59
8.56
Cl, 15.33
15.51
Cl, 18.02
18.65
Cl, 15.69
15.33
12.24
12.25
10.83
11.10
9.40
9.13
8a
8b
8c
8d
8e
8f
—
18.21
18.01
14.16
14.23
11.44
11.23
16.47
16.46
15.75
15.96
12.19
12.22
15.49
15.37
12.67
12.53
10.16
10.16
14.95
14.73
13.74
13.90
10.81
10.89
—
С17H17N3O2
Br, 21.34
21.35
—
С17H17BrN3O2
С17H16N4O4
—
С13H17N3O3
S, 9.54
9.28
—
С17H19N3O3S
С15H19N3O2
9a
9b
9c
9d
9e
9f
—
С20H21N3O2
Br, 19.13
19.29
—
С20H20BrN3O2
С20H20N4O4
—
С16H21N3O3
S, 8.27
8.31
С20H23N3O3S
acter and afford 2ꢀsubstituted 3ꢀacylꢀ and 3ꢀtosylamidoꢀ
1,2ꢀdihydroquinazolinꢀ4(3H )ꢀones 4—9 (Scheme 3). The
exception is acetophenone, which was not involved in the
reaction under these conditions due, apparently, to steric
hindrance and low activity of the carbonyl group of this
reagent. To the contrary, the low yields in the reactions of
hydrazides 2a—f with formaldehyde are associated with
high reactivity of the latter reagent and side processes.

Synthesis of 1,2ꢀdihydroquinazolinꢀ4ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003 2447
1
Table 2. H NMR spectroscopic data (in DMSOꢀd6) for 1,2ꢀdihydroquinazolinꢀ4(3H )ꢀone derivatives 4—9
Comꢀ
pound
δ, J/Hz
C(8)H
N(1)H HC(2)
C(5)H
C(7)H
C(6)H
N(9)H
R2, R3
R1
4a
4b
6.90 (s) 4.65 (s) 7.65 (d,
J = 8.9)
6.85 (s) 4.85 (s) 7.70 (d,
J = 10)
7.30 (m)
6.75 (m)
6.78 (m)
10.20 (s)
Ac: 1.90 (s, 3 Н)
7.33 (t,
J = 9.5)
10.75 (s)
10.80 (s)
Ph: 7.90 (d, 2 Н, J = 10);
7.60 (t, 1 Н, J = 9.0);
7.55 (dd, 2 Н, J = 10,
J = 9.0)
4ꢀBrС6Н4: 7.70 (m, 2 Н);
7.85 (d, 2 Н, J = 10)
4c
4d
6.81 (s) 4.82 (s) 7.70 (m)
7.30 (dd,
J = 9.7,
J = 7.5)
7.35 (dd,
J = 8.5,
6.75 (m)
6.80 (m)
6.95 (s) 4.85 (s) 7.70 (d,
11.10
(br.s)
4ꢀNO2С6Н4: 8.36, 8.15
(both d, 2 H each,
J = 9.5)
J = 7.5)
J = 7.0)
7.30 (dd,
J = 8.7,
J = 7.4)
7.30 (dd,
J = 8.5,
J = 7.2)
7.30 (m)
4e
4f
6.75 (m) 4.70 (s) 7.65 (d,
6.75 (m)
9.40 (s)
CO2Et: 1.20 (t, 3 Н,
J = 5.5); 4.10 (q, 2 Н,
J = 5.5)
Ts: 2.35 (s, 3 Н);
7.30, 7.75 (both d,
2 H each, J = 8.0)
Ac: 2.10 (s, 3 Н)
J = 8.6)
6.90 (s) 4.15 (s) 7.50 (d,
6.70 (dd, 6.75 (d, 10.05 (s)
J = 8.4)
J = 8.4,
J = 7.2)
J = 8.5)
5a
5b
5.25
4.65
7.85 (d,
6.84 (m) 6.65 (d, 8.80 (s)
Me: 1.45 (d,
3 Н, J = 6.7)
Me: 1.42 (d,
3 Н, J = 8.0)
(br.s)
(br.s)
J = 9.4)
J = 9.2)
6.74 (m)
6.85 (s) 5.70 (q, 7.68 (d,
7.30 (t,
J = 9.5)
10.5 (s)
Ph: 7.92 (d, 2 Н, J = 10);
7.59 (t, 1 Н, J = 9.5);
7.50 (m, 2 Н)
J = 8.0) J = 10)
5c
5d
6.84 (s) 5.20 (q, 7.7 (m)
J = 7.0)
6.97 (s) 5.23 (q, 7.70 (d,
J = 7.0) J = 8.4)
7.30 (m)
6.85 (m)
6.75 (m)
10.60 (s) Me: 1.42 (d,
3 Н, J = 7.0)
10.90 (s) Me: 1.45 (d,
3 Н, J = 7.0)
4ꢀBrС6Н4: 7.70 (m, 2 Н);
7.85 (d, 2 Н, J = 10)
4ꢀNO2С6Н4: 8.35, 8.15
(both d, 2 H each,
J = 9.2)
CO2Et: 1.20 (br.s, 3 Н);
4.10 (q, 2 Н, J = 5.3)
7.33 (dd,
J = 8.0,
J = 6.4)
7.30 (dd,
J = 8.7,
J = 7.3)
7.25 (dd,
J = 8.6,
J = 7.2)
7.30 (m)
5e
5f
6.82 (s) 5.00
(br.s)
7.64 (d,
J = 8.5)
6.70 (m)
9.25 (s)
Me: 1.35
(br.s, 3 Н)
6.95 (s) 4.90
(br.s)
7.45 (d,
J = 8.4)
6.70 (dd, 6.65 (d, 10.00 (s) Me: 1.30
Ts: 2.35 (s, 3 Н);
7.30, 7.70 (both d,
2 H each, J = 8.1)
Ac: 1.80 (s, 3 Н)
J = 8.4,
J = 7.2)
J = 8.6)
(br.s, 3 Н)
6a
6b
7.10
6.22 (s) 7.70 (d,
6.75 (m) 9.90 (s)
3 CH:
6.95 (s, 1 Н);
7.45 (m, 2 Н)
(br.s)
J = 8.1)
7.18 (s) 6.42 (s) 7.72 (m)
7.35 (dd,
J = 9.5,
J = 8.0)
6.8 (dd,
J = 8.8,
J = 8.0)
6.85 (d, 10.45 (s) 3 CH:
J = 9.5)
Ph: 7.72 (m, 2 Н);
7.45 (m, 3 Н)
6.95 (m, 1 Н);
7.45 (m, 1 Н);
7.55 (m, 1 Н)
6c
6d
6e
7.15 (s) 6.40 (s) 7.73 (d,
7.35 (dd,
J = 8.5,
J = 7.3)
7.35 (dd,
J = 8.4,
J = 6.7)
7.35 (dd,
J = 8.5,
J = 7.2)
6.85 (dd, 6.80 (d, 10.60 (s) 3 CH:
4ꢀBrС6Н4: 7.70 (m, 2 Н);
7.75 (d, 2 Н, J = 9.6)
J = 8.7)
J = 8.7,
J = 7.3)
J = 8.5)
6.95 (m, 1 Н);
7.50 (m, 2 Н)
7.19
6.45 (s) 7.75 (d,
6.63 (dd, 6.75 (d, 10.95 (s) 3 CH:
4ꢀNO2С6Н4: 8.33, 8.0
(both d, 2 H each,
J = 8.4)
CO2Et: 1.15 (t, 3 Н,
J = 5.6); 4.05 (q, 2 Н,
J = 5.6)
(br.s)
J = 7.7)
J = 7.7,
J = 6.7)
6.75 (dd, 6.85 (d, 9.30
J = 8.4)
6.95 (m, 1 Н);
7.50 (m, 2 Н)
3 CH: 7.00
7.43 (s) 6.20 (s) 7.68 (d,
J = 8.4)
J = 8.4,
J = 7.2)
J = 8.5) (br.s)
(m, 1 Н); 7.16
(m, 1 Н); 7.52
(d, 1 Н, J = 4.8)
(to be continued)

2448
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003
Smirnov et al.
Table 2 (continued)
Comꢀ
pound
δ, J/Hz
C(8)H
N(1)H HC(2)
C(5)H
C(7)H
C(6)H
N(9)H
R2, R3
R1
6f
7.05
(br.s)
6.20 (s) 7.45 (d,
7.30 (dd,
J = 8.8,
J = 7.0)
6.65 (dd, 6.75 (d, 10.40 (s) 3 CH: 6.95
Ts: 2.35 (s, 3 Н);
7.30, 7.75 (both d,
2 H each, J = 8.2)
J = 8.4)
J = 8.4,
J = 7.0)
J = 8.8)
(m, 1 Н); 7.25
(m, 1 Н); 7.36
(d, 1 Н, J = 5.3)
3 CH: 7.50 (d,
1 Н, J = 9.6);
7.65 (m, 2 Н)
7a
7b
7.30
(br.s)
6.40 (s) 7.65 (m)
7.35 (m)
6.75 (m)
9.85 (s)
Ac: 1.75 (s, 3 Н)
7.25 (s) 6.61 (s) 7.84 (d,
7.33 (dd,
J = 9.1,
J = 8.0)
6.78 (m)
6.75 (m)
10.38 (s) 3 CH: 7.45 (d,
1 Н, J = 9.5);
7.50 (s, 1 Н);
7.72 (d, 1 Н,
J = 9.5)
10.45 (s) 3 CH: 7.42 (d,
1 Н, J = 9.5);
7.44 (s, 1 Н);
Ph: 7.68 (d, 2 Н, J = 9.4);
7.50 (m, 1 Н); 7.42 (dd,
2 Н, J = 9.4, J = 8.9)
J = 9.2)
7c
7.22 (s) 6.60 (s) 7.82 (d,
7.32 (dd,
4ꢀBrС6Н4: 7.60, 7.65
(both d, 2 H each,
J = 9.6);
J = 10.1) J = 8.6,
J = 7.4)
7.72 (d, 1 Н,
J = 9.5)
7d
7e
7f
7.27 (s) 6.65 (s) 7.85 (d,
7.35 (m)
6.80 (m)
6.75 (m)
6.70 (m)
6.70 (m)
6.72 (m)
10.80 (s) 3 CH: 7.50 (m, 4ꢀNO2С6Н4: 8.35, 8.05
J = 8.5)
2 Н); 7.75 (d,
1 Н, J = 9.3)
3 CH:
7.68 (s, 1 Н);
7.70 (m, 2 Н)
(both d, 2 H each,
J = 8.5)
CO2Et: 1.15 (t, 3 Н,
J = 5.5); 4.00 (q, 2 Н,
J = 5.5)
7.20 (s) 6.41 (s) 7.50 (d,
7.30 (dd,
J = 8.0,
J = 7.2)
7.25 (m)
9.20 (s)
J = 8.4)
7.15
6.35 (s) 7.45 (d,
10.35 (s) 3 CH: 7.50
(br.s, 2 Н);
Ts: 2.35 (s, 3 Н);
7.30, 7.70 (both d,
2 H each, J = 8.1)
Ac: 1.90 (s, 3 Н)
(br.s)
J = 8.4)
7.65 (s, 1 Н)
8a
8b
6.95 (s)
6.85 (s)
7.60 (d,
J = 8.8)
7.30 (m)
9.75 (s)
2 Me: 1.38,
1.42 (both s,
3 H each)
7.64 (d,
7.28 (t,
J = 9.5)
10.20 (s) 2 Me: 1.52
(s, 6 Н)
Ph: 7.92 (d, 2 Н, J = 7.6);
7.58 (t, 1 Н, J = 8.0);
7.50 (dd, 2 Н, J = 8.0,
J = 7.6)
J = 9.0)
8c
8d
8e
6.90 (s)
6.90 (s)
6.95 (s)
7.65 (d,
J = 9.2)
7.28 (dd,
J = 9.0,
J = 7.2)
7.30 (dd,
J = 8.8,
J = 7.0)
7.30 (dd,
J = 8.6,
J = 7.2)
6.70 (m)
6.72 (m)
6.70 (m)
10.20 (s) 2 Me: 1.50
(s, 6 Н)
4ꢀBrС6Н4: 7.70, 7.85
(both d, 2 H each,
J = 9.8)
4ꢀNO2С6Н4: 8.35, 8.15
(both d, 2 H each,
J = 9.1)
7.65 (d,
J = 8.5)
10.55 (s) 2 Me: 1.52
(s, 6 Н)
7.65 (d,
J = 8.5)
9.20 (s)
2 Me:
CO2Et: 1.10 (br.s, 3 Н);
4.20 (m, 2 Н)
1.35, 1.45
(both s,
3 H each)
2 Me:
1.25, 1.50
(both s,
8f
6.95 (s)
7.45 (d,
J = 8.8)
7.25 (dd,
J = 9.2,
J = 7.0)
6.70 (dd, 6.60 (d, 9.60 (s)
Ts: 2.35 (s, 3 Н);
7.30, 7.65 (both d,
2 H each, J = 8.0)
J = 8.8,
J = 7.0)
J = 9.2)
3 H each)
(CH2)5: 1.65
(m, 10 Н)
9a
9b
6.65 (s)
7.05 (s)
7.62 (d,
J = 8.4)
7.65 (d,
J = 8.25)
7.25 (m)
7.35 (m)
6.70 (m) 6.95 (d, 9.55 (s)
Ac: 1.95 (s, 3 Н)
J = 9.4)
6.75 (m)
10.25 (s) (CH2)5:
Ph: 7.95 (d, 2 Н, J = 7.5);
1.65 (m, 10 Н) 7.60 (t, 1 Н, J = 8.0);
7.50 (dd, 2 Н, J = 8.0,
J = 7.5)
(to be continued)

Synthesis of 1,2ꢀdihydroquinazolinꢀ4ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003 2449
Table 2 (continued)
Comꢀ
pound
δ, J/Hz
C(8)H
N(1)H HC(2)
6.70 (s)
C(5)H
C(7)H
C(6)H
N(9)H
R2, R3
R1
9c
9d
9e
9f
7.65 (d,
J = 8.5)
7.28 (dd,
J = 8.8,
J = 7.0)
7.35 (m)
6.68 (dd, 7.00 (d, 10.25 (s) (CH2)5:
4ꢀBrС6Н4: 7.68, 7.88
J = 8.5,
J = 7.0)
J = 8.8)
1.75 (m, 10 Н) (both d, 2 H each,
J = 9.9)
4ꢀNO2С6Н4: 8.4, 8.15
6.85 (m)
6.70 (m)
6.55 (m)
7.68 (d,
J = 8.3)
6.85 (m) 7.05 (d, 10.55 (s) (CH2)5:
J = 8.7)
1.75 (m, 10 Н) (both d, 2 H each,
J = 9.1)
CO2Et: 1.20 (br.s, 3 Н);
7.60 (d,
J = 8.0)
7.30 (dd,
J = 8.0,
J = 7.6)
7.25 (m)
6.70 (m) 6.95 (d, 9.05 (s)
(CH2)5:
J = 8.0)
1.75 (m, 10 Н) 4.05 (m, 2 Н)
7.42 (d,
6.55 (m) 6.85 (d, 9.10 (s)
(CH2)5:
Ts: 2.40 (s, 3 Н); 7.25
J = 8.4)
J = 8.6)
1.75 (m, 10 Н) (m, 2 Н); 7.65 (d, 2 Н,
J = 8.0)
The structures of compounds 4—9 were established by
NOEs can belong only to a compound with structure A,
but not to a compound with structure B.
the comprehensive examination of the spectroscopic data
and the results of elemental
analysis.
For compounds with structure B, NOEs c, d, and f
should not be observed, but the interaction between the
carbonyl group of the fragment of the aminobenzoic acid
and the NH group of the hydrazide fragment could be seen.
The choice between the structures of DHQ and isoꢀ
meric Schiff's bases can reliably be made using the 1H and
13C NMR spectroscopic data for these compounds. The
most general and pronounced feature of these spectra is
the presence of signals of the C(2)Hꢀgroup protons of
DHQ at δ 4.82—5.23 and δ 6.40—6.65 for adducts derived
from aliphatic aldehydes and products derived from aroꢀ
matic aldehydes, respectively (see Table 2), which is charꢀ
acteristic of the corresponding protons of 1,2ꢀdihydroꢀ
quinazolinꢀ4(3H)ꢀones.13,14 On the contrary, if adducts
derived from aromatic aldehydes had structures of Schiff's
bases, signals of the CH=Nꢀgroup protons should be obꢀ
served at δ 8.2—8.5.15 However, no signals are present in
this area of the spectra of compounds 4—9 (except for
compounds 4d—9d, whose spectra have signals of the
aromatic ring containing the nitro group).
Analysis of the results of our
study indicates that these comꢀ
pounds have structures of the
same type. In particular, to esꢀ
tablish whether these compounds
have structures A or B, we carꢀ
ried out nuclear Overhauser efꢀ
fect (NOE) measurements and
R3 = H (4—7), Me (8),
R2—R3 = (CH2)5
experiments on selective proton magnetization transfer
(SPT) from the methyl group C(12)H3 to 13C nuclei and
from the proton of the N(10)H group to the carbonyl
C(11) atom (Scheme 4) for compound 8a.
Scheme 4
To establish the structures of the products of the reacꢀ
tions with ketones 8 and 9, it was necessary to measure
13C NMR spectra because these compounds are devoid of
protons at the C(2) atoms, and, hence, their structures
cannot be determined only by 1H NMR spectroscopy.
For Schiff's bases, the signals of the CH=Nꢀgroup carbon
atom are generally observed at δ 157—164,16 whereas the
signals of the C(2) atom in compounds 8 and 9 are present
at δ 67—76 (see Table 3), which agrees with the DHQ
The results of these studies provide evidence that the
atoms of the following groups are closely spaced: N(1)H
and H(8) (a), N(1)H and C(2)CH3 (b), C(2)CH3 and
N(9)H (c), N(9)H and COC(11)H3 (d), COC(11)H3 and
C(10)O (e), and N(9)H and C(10)O ( f ). The observed
structure (δ(C(2)) 68.7)13
.
Other spectroscopic characteristics of the compounds
under study are also in agreement with the DHQ strucꢀ
1
ture. The H NMR spectra have signals for the protons
of the N(1)H and N(9)H groups at δ 6.7—7.25 and

2450
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003
Smirnov et al.
Table 3. 13C NMR spectroscopic data for 1,2ꢀdihydroquinazolinꢀ4(3H )ꢀone derivatives 5—9 (in DMSOꢀd6)
Comꢀ
pound
δ, J/Hz
C(2) C(4) C(4a) C(5) C(6) C(7) C(8) C(8a)
R2, R3
R1
5а
5c
67.8 168.9 114.1 134.0 114.8 128.2 117.7 148.0
67.8 165.0 114.0 133.9 114.7 128.1 117.7 148.0
1 Me: 19.5
1 Me: 19.4
СОMe: 20.3 (Me), 162.8 (CO)
4ꢀBrС6Н4: 162.9, 131.4, 129.7,
126.0, 131.7
8а
8b
74.3 169.5 113.3 133.9 114.6 127.8 117.2 146.3
74.5 166.4 113.5 133.6 114.5 127.6 116.9 146.3
2 Me: 25.7, 26.3
2 Me: 26.0, 26.4
СОMe: 20.6 (Me), 161.4 (CO)
Ph: 161.1, 132.6, 128.3, 131.7,
127.5
8c
8d
8e
8f
74.7 165.8 113.5 134.0 114.7 127.9 117.2 146.5
74.9 165.4 113.4 134.1 114.8 128.0 117.3 146.6
74.7 162.1 113.5 134.2 114.9 128.1 117.4 146.7
75.3 164.4 112.4 134.2 114.6 127.8 116.9 146.4
75.4 169.3 114.2 133.6 115.2 127.6 117.2 145.6
76.0 166.8 114.6 133.8 115.5 127.8 117.5 145.9
75.9 165.9 114.4 133.8 115.0 127.7 117.4 148.8
75.7 165.1 114.8 133.5 115.3 127.4 117.2 145.5
75.9 162.5 114.3 134.1 115.6 127.9 117.6 146.0
76.2 164.2 113.2 133.7 115.1 127.3 116.9 142.6
2 Me: 26.1, 26.5
2 Me: 26.1, 26.6
2 Me: 26.1, 26.8
2 Me: 27.8, 23.4
4ꢀBrС6Н4: 161.3, 131.7, 129.9,
125.8, 131.6
4ꢀNO2С6Н4: 161.4, 138.4,
129.4, 149.6, 123.9
CO2Et: 156.9 (СО),
61.1 (СН2), 14.8 (Me)
Ts: 21.1, 129.0, 127.6, 142.8,
137.1
9а
9b
9c
9d
9e
9f
(CH2)5: 20.9, 21.3,
24.4, 32.5, 33.3
(CH2)5: 21.5, 21.4,
24.6, 33.0, 33.6
(CH2)5: 21.0, 21.3,
24.4, 32.9, 33.5
(CH2)5: 20.9, 21.1,
24.2, 32.7, 33.3
(CH2)5: 21.2, 21.6,
24.8, 32.8, 33.7
(CH2)5: 20.8, 21.4,
24.1, 30.0, 34.4
СОMe: 161.6 (СО), 20.7 (Me)
Ph: 161.7, 132.8, 128.6, 132.1,
127.9
4ꢀBrС6Н4: 161.6, 131.6, 129.9,
125.8, 131.6
4ꢀNO2С6Н4: 161.2, 138.2,
129.0, 149.3, 123.4
CO2Et: 157.0 (СО), 61.1 (СН2),
14.9 (Me)
Ts: 20.7, 127.5, 128.4, 145.3,
136.9
δ 10.1—10.78, respectively. Since, all signals of the NH
group of the sevenꢀmembered triazepine isomer should
be observed at δ 6.7—9.0,5 its formation can be excluded
as well.
3ꢀAcylꢀ and 3ꢀtosylamidoꢀ2ꢀRꢀ1,2ꢀdihydroquinazoꢀ
linꢀ4(3H )ꢀones were synthesized as crystalline comꢀ
pounds (from colorless to brightꢀyellow in color) with the
melting points varying from 160 to 275 °C depending on
the nature of substituents at positions 2 and 3.
When investigating17 the reactions of quinazolinone
derivatives with BuLi, the researchers of the cited study
prepared a compound to which structure 5a was assigned.
However, the latter compound differs from quinazolinone
5a prepared in the present study both in the spectroscopic
characteristics and melting point (the difference is larger
than 80 °C). Hence, we studied compound 5a (its crystals
were grown from an aqueous solution) by Xꢀray diffracꢀ
tion analysis, which confirmed the structure of this comꢀ
pound.
Xꢀray diffraction study demonstrated that quinazoꢀ
linone 5a crystallizes with one water molecule of solvaꢀ
tion as a racemate (space group P21/c). The selected bond
lengths and bond angles in compound 5a are close to the
expected values (Fig. 1, Table 4). The nitrogenꢀcontainꢀ
O(2)
C(11)
C(10)
O(1)
C(3)
C(1)
N(3)
N(2)
C(2)
C(4)
C(5)
C(8)
N(1)
C(7)
C(6)
C(9)
Fig. 1. Overall view of molecule 5a.
ing ring adopts a slightly distorted envelope conformation
with the C(8) atom deviating from the plane through the
remaining atoms of the ring by 0.6 Å. The N(1) atom has
a pyramidal configuration (the sum of the bond angles is
350.3°). A shortening of the N(1)—C(7) bond to 1.381 Å
is, apparently, caused by conjugation between the lone
electron pair of the N(7) atom and the aromatic system of
the benzene ring. The same situation has been obꢀ
served earlier in an analog of 5a, viz., 2,2ꢀdimethylꢀ3ꢀ
(1ꢀmethylethylidene)aminoꢀ4ꢀoxoꢀ1,2,3,4ꢀtetrahydroꢀ

Synthesis of 1,2ꢀdihydroquinazolinꢀ4ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003 2451
Table 4. Principal bond lengths (d) and bond angles (ω) in the
structure of 5a
DRX 500 (500 MHz) and Bruker AMꢀ300 (300 MHz) specꢀ
trometers. The 13C NMR spectra were recorded on a Bruker
WMꢀ250 spectrometer (62.9 MHz for 13C). The melting points
were measured on a Boetius hotꢀstage apparatus and were unꢀ
corrected. The yields and physicochemical data for products
2a—f are given in Table 5. The corresponding characteristics of
compounds 4—9 are listed in Tables 1—3. Compounds 1a—f
were prepared according to known procedures.10
Bond
d/Å
Angle
ω/deg
O(1)—C(1)
O(2)—C(10) 1.224(1)
N(1)—C(7)
N(1)—C(8)
N(2)—C(1)
1.230(1)
C(7)—N(1)—C(8) 116.9(1)
C(1)—N(2)—N(3) 115.89(9)
C(1)—N(2)—C(8) 120.83(9)
N(3)—N(2)—C(8) 115.38(9)
C(10)—N(3)—N(2) 118.8(1)
1.380(1)
1.445(2)
1.378(1)
Singleꢀcrystal Xꢀray diffraction study of compound 5a was
carried out on an automated Siemens P3/PC diffractometer
(graphite monochromator, λ(MoKα) = 0.71073 Å, θ/2θ scanꢀ
ning technique, θmax = 26°). Crystals of 5a (C11H13N3O2•H2O,
M = 237.26) are monoclinic, space group P21/c, at T = 293 K
a = 8.178(4), b = 9.746(9), c = 15.013(3) Å, β = 93.96(3)°,
V = 1193.9(4) Å3, Z = 4, dcalc = 1.320 g cm–3. The structure of
5a was solved by direct methods and refined by the fullꢀmatrix
N(2)—N(3) 1.390(1)
N(2)—C(8) 1.487(1)
N(3)—C(10) 1.358(2)
quinazoline.18 The dihedral angle between the amide fragꢀ
ment and the base of the envelope is 65.1°.
leastꢀsquares method based on F 2 with anisotropic thermal
hkl
parameters for all nonhydrogen atoms. The hydrogen atoms
were revealed from a difference electron density synthesis and
refined isotropically. The final reliability factors were as follows:
R1 = 0.0387 (based on F 2 for 2332 observed reflections with
I > 2σ(I )), wR2 = 1049, GOOF = 0.905, 214 parameters were
refined. The calculations were carried out on a personal comꢀ
puter using the SHELXTL PLUS program package.21
Synthesis of N´ꢀacetylꢀ (2a), N´ꢀbenzoylꢀ (2b), N´ꢀ(4ꢀbroꢀ
mobenzoyl)ꢀ (2c), N´ꢀ(4ꢀnitrobenzoyl)ꢀ (2d), and N´ꢀethoxyꢀ
carbonylhydrazides (2e) of 2ꢀaminobenzoic acid (general proceꢀ
dure). A mixture of isatoic anhydride (0.04 mol) and the correꢀ
sponding hydrazide 1a—d (0.04 mol) in acetic acid (30 mL) (the
reaction with 1e was carried out in anhydrous EtOH (30 mL))
was stirred with refluxing for 1 h and then cooled to ∼20 °C
for 2 h. The precipitate that formed was filtered off, washed with
Et2O, and dried at 40 °C.
Analysis of the crystal packing demonstrates that molꢀ
ecules 5a do not form intermolecular hydrogen bonds
with each other but are linked in a threeꢀdimensional
Hꢀbound framework through the weak N—H...O(1w) and
O(1w)—H(1w)...O bonds with the water molecules (N...O,
2.902(2)—3.042(2) Å; O...O, 2.719(2)...2.822(2) Å)
(Fig. 2). Taking into account these hydrogen bonds, the
coordination environment of the O(1w) atom can be deꢀ
scribed as a slightly distorted tetrahedron.
Experimental
The IR spectra were recorded on an M80 spectrometer in
KBr pellets. The 1H NMR spectra were measured on Bruker
O(1)
H(2W)
H(1N″)
O(1W)
H(3N´´´)
N(1″)
H(1W)
N(3´´´)
O(2´)
Fig. 2. Intermolecular hydrogen bonds in the crystal structure of 5a.

2452
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003
Smirnov et al.
Table 5. Yields, physicochemical properties, and 1H NMR spectroscopic data (in DMSOꢀd6) for 2ꢀaminobenzoic acid N´ꢀacylꢀ and
N´ꢀtosylhydrazides 2a—f
Comꢀ m.p./°C
pound (m.p.*/°C) (%)
Yield
δ, J/Hz
NH2
C(5)H
C(6)H
C(7)H
C(8)H
NHNH
R
2a
181
57
59
70
7.50 (d,
J = 8.8)
6.50 (m) 7.20 (m) 6.75 (d,
6.40 (br.s) 9.85 (br.s);
9.95 (br.s)
6.45 (br.s) 10.1 (br.s);
10.32 (s)
6.35 (br.s) 10.20 (br.s); 4ꢀBrCOС6Н4:
10.40 (br.s) 7.75, 7.90 (both d,
2 H each, J = 9.5)
COМе: 1.90 (s, 3 Н)
(181)19
177—179
(179)5
J = 9.5)
2b
7.55 (m) 6.55 (m) 7.20 (m) 6.75 (d,
COPh: 7.55 (m, 3 Н);
7.95 (d, 2 Н, J = 9.8)
J = 9.2)
6.60 (m) 7.20 (m) 6.75 (d,
2c**
216—218
7.60 (d,
J = 8.0)
J = 9.3)
2d
2e
2f
238—240
(238)5
81
70
75
7.60 (d,
J = 8.4)
6.55 (dd, 7.20 (dd, 6.75 (d,
6.42 (s)
10.25 (br.s); 4ꢀNO2COС6Н4:
J = 8.4,
J = 6.4)
J = 8.6,
J = 6.4)
J = 8.6)
10.70 (s)
8.15, 8.35 (both d,
2 H each, J = 9.1)
EtCO2: 1.10 (t, 3 Н,
J = 5.6); 4.00 (q, 2 Н,
J = 5.6)
117
(117)20
7.50 (d,
J = 8.6)
6.50 (dd, 7.20 (dd, 6.75 (d,
6.40 (br.s) 9.00 (br.s);
9.85 (s)
J = 8.6,
J = 6.8)
J = 8.8,
J = 6.8)
J = 8.8)
196—198
(198)11
7.45 (d,
J = 8.5)
6.50 (dd, 6.70 (dd, 7.15 (d,
6.10 (br.s) 9.65 (s);
10.30 (br.s)
Ts: 2.40 (s, 3 H);
7.40, 7.75 (both d,
2 H each, J = 8.2)
J = 8.5,
J = 7.0)
J = 9.3,
J = 7.0)
J = 9.3)
* Lit. data.
** Found/calculated: C, 50.32/50.63; H, 3.62/3.78; Br, 23.91/23.9; N, 12.58/12.31. C14H12BrN3O2.
Upon more prolonged storage of a solution of 2c in AcOH, a
precipitate formed. This precipitate was filtered off, recrystallized
from 95% EtOH, and dried. 2ꢀ(4ꢀBromophenyl)ꢀ3,4ꢀdihydroꢀ
1,3,4ꢀbenzotriazepinꢀ5ꢀone (3) was prepared in 6.2% yield.
M.p. 195—196 °C. Found (%): C, 53.39; H, 3.29; Br, 25.57;
N, 13.48. Calculated (%): C, 53.19; H, 3.19; Br, 25.27; N, 13.29.
1H NMR (DMSOꢀd6), δ: 5.63 (s, 2 H, 2 NH); 7.55 (m, 1 H,
CH(6)); 7.35 (m, 1 H, CH(7)); 7.75 (m, 1 H, CH(5)); 7.65 (d,
2 H, 4ꢀBrC6H4, J = 7.9 Hz); 7.80 (d, 2 H, 4ꢀBrC6H4, J =
7.9 Hz), 8.20 (d, 1 H, CH(8), J = 9.1 Hz).
Synthesis of 3ꢀacylꢀ and 3ꢀtosylamidoꢀ1,2ꢀdihydroquinazolinꢀ
4(3H )ꢀones (4a—f) (general procedure). A mixture of the correꢀ
sponding hydrazide 2a—f (2 mmol), CH2O as paraformaldeꢀ
hyde (3 mmol, 1.5ꢀfold excess), and K2CO3 (10 mg) was reꢀ
fluxed in 95% EtOH for 2 h. The reaction solution was concenꢀ
trated and the residue was recrystallized from a hexane—benꢀ
zene (1 : 1) (4a), 95% EtOH—hexane (1 : 1) (4b), or 95%
EtOH—benzene (1 : 3) (4c—f) mixture.
Synthesis of 3ꢀacylꢀ and 3ꢀtosylamidoꢀ2ꢀRꢀ1,2ꢀdihydroꢀ
quinazolinꢀ4(3H )ꢀones (6a—f, 7a—f, 9a—f) (general procedure).
A mixture of the corresponding hydrazide 2a—f (1.7 mmol) and
a carbonyl compound (2 mmol, a 1.2ꢀfold excess) in 95% EtOH
(15 mL) was refluxed for 3—6 h. Then the reaction mixture was
cooled and the precipitate that formed was recrystallized from a
95% EtOH—benzene mixture.
Synthesis of 3ꢀacylꢀ and 3ꢀtosylamidoꢀ2,2ꢀdimethylꢀ1,2ꢀ
dihydroquinazolinꢀ4(3H )ꢀones (8a—f). A solution of the correꢀ
sponding hydrazide 2a—f (1.7 mmol) in acetone (20 mL), which
was distilled over KMnO4, was refluxed for 5 h. Then the reacꢀ
tion solution was concentrated and the residue was recrystalꢀ
lized from a 1 : 1 benzene—hexane mixture.
We thank Yu. A. Strelenko for performing the nuclear
Overhauser effect measurements and interpreting
these data.
Synthesis of tosylhydrazide (2f). Compound 2f was syntheꢀ
sized according to a procedure described earlier.11 The physicoꢀ
chemical characteristics and NMR spectra are identical with
the data published in the literature.11 M.p. 196—198 °C (cf. lit.
data11: 198 °C). Found (%): C, 55.01; H, 4.95; N, 13.80; S, 10.24.
References
1. D. G. J. Wenzel, Am. J. Pharm., 1955, 44, 550.
2. S. Hayao, H. J. Havera, and W. G. Strycher, J. Med. Chem.,
1965, 8, 807.
3. N. I. Chernobrovin and I. V. Kozhevnikov, USSR Inventor's
Certificate No. 841.063.049.
4. S. Petersen and H. Heitzer, Liebigs Ann. Germ., 1972,
764, 44.a
5. P. P. Reddy, C. K. Reddy, and P. S. N. Reddy, Bull. Chem.
Soc. Jpn., 1986, 56, 1575.
C
14H15N3O3S. Calculated (%): C, 55.07; H, 4.95; N, 13.76;
S, 10.50.
Synthesis of 3ꢀacylꢀ and 3ꢀtosylamidoꢀ2ꢀmethylꢀ1,2ꢀ
dihydroquinazolinꢀ4(3H )ꢀones (5a—f) (general procedure).
Acetaldehyde (20 mmol, 10ꢀfold excess) was added to a soꢀ
lution of the corresponding hydrazide 2a—f (2 mmol) in
95% EtOH (20 mL). The reaction mixture was stirred in
a closed flask at ∼20 °C for 4 h and then concentrated.
The oily residue was recrystallized from a benzene—hexane
mixture.
6. P. S. N. Reddy and P. P. Reddy, Indian J. Chem., Sect. B,
1988, 27B, 135.

Synthesis of 1,2ꢀdihydroquinazolinꢀ4ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003 2453
7. M. J. Kornet, T. Varia, and W. Beaven, J. Heterocycl. Chem.,
1994, 21, 1533.
8. G. Shailaja and P. S. N. Reddy, Indian J. Chem., Sect. B,
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Received May 27, 2003;
in revised form September 17, 2003