Synthesis of N′-cyclohexenecarbonyl-substituted hydrazides of 2-aminobenzoic acids and preparation of 3-cyclohexenyl-amido-1,2- dihydroquinazolin-4-ones based on them

Article abstract of DOI:10.1007/s10593-007-0122-x

N′-Cyclohexenecarbonyl-substituted hydrazides of 2-aminobenzoic acids were obtained from the reaction of isatoic anhydride with monohydrazides of cyclohexenedicarboxylic acid. Reaction of the 2-aminobenzoic acid hydrazides with substituted benzaldehydes g

Full text of DOI:10.1007/s10593-007-0122-x

Chemistry of Heterocyclic Compounds, Vol. 43, No. 6, 2007
SYNTHESIS OF N'-CYCLOHEXENECARBONYL-
SUBSTITUTED HYDRAZIDES OF 2-AMINOBENZOIC
ACIDS AND PREPARATION OF 3-CYCLOHEXENYL-
AMIDO-1,2-DIHYDROQUINAZOLIN-4-ONES
BASED ON THEM
D. Zicāne, I. Raviņa, Z. Tetere, and M. Petrova
N'-Cyclohexenecarbonyl-substituted hydrazides of 2-aminobenzoic acids were obtained from the
reaction of isatoic anhydride with monohydrazides of cyclohexenedicarboxylic acid. Reaction of the
2-aminobenzoic acid hydrazides with substituted benzaldehydes gave 3-cyclohexenylamido-
1,2-dihydroquinazolin-4-ones.
Keywords: benzaldehyde, isatoic anhydride, cyclohexenedicarboxylic acid, 3-cyclohexenylamido-
1,2-dihydroquinazolin-4-ones, N'-cyclohexenecarbonyl-substituted hydrazides.
Among the derivatives of dihydroquinazolin-4-ones (DHQ) are compounds with sedative effects on the
central nervous system [1,2] and also antiepileptic activity [3].
R
R
O
O
O
H2N
O
N
N
H
H
N
O
Me
H
Me
R1
+
HOOC
N
H
O
NH2
Cl
3a–e, 4 a–e
2a–e
1
H
O
3c
O
+
H
N
H
O
R2
5a–e
N
Me
R2
N
H
R1
6a–e, 7a–e
2−4 a R = H, b R = F, c R = Cl, d R = Br, e R = NO2; 3a−e R1 = COOH; 4a−e R1 = H; 5−7 a R2 = 4-FC6H4,
b R2 = 4-ClC6H4, c R2 = 2-OHC6H4, d R2 = 4-Et2NC6H4, e R2 = 4-NCC6H4; 6a−e R1 = COOH; 7a−e R1 = H
__________________________________________________________________________________________
Riga Technical University, Riga LV-1048, Latvia; e-mail: daina-zi@ktf.rtu.lv, e-mail: marina@osi.lv.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, 894-898, June, 2007. Original article
submitted April 4, 2005. Revised version submitted July 10, 2006.
0009-3122/07/4306-0755©2007 Springer Science+Business Media, Inc.
755

Recently [4] a method was proposed for the synthesis of little known derivatives of DHQ with amide
residues in position 3 by the reaction of carbonyl compounds with N-acyl-substituted hydrazides of anthranilic
acid, obtained by reaction of isatoic anhydride 1 with acyl hydrazines. We have used this scheme with
monohydrazides of 2-arylcyclohexenyl-1,1-dicarboxylic acids 2a-e, which we had synthesized previously [5].
The hydrazides 3a-e were obtained in 60-70% yields by boiling an ethanol solution of the components.
Increasing the reaction temperature – by boiling the components in acetic acid – led only to partial
decarboxylation to give mixtures of 3a-e and 4a-e in a ratio of ~3-5 : 1, and on boiling in DMF a still more
complex mixture of products was obtained. The pure products of decarboxylation 4a-e were obtained only by
boiling individual compounds 3a-e in DMF solution.
We demonstrated the possibility of using the hydrazides 3, which we had made, to synthesize derivatives
of DHQ, by using the reaction of compound 3c with benzaldehydes 5a-e. It was established that when the
components were boiled for a relatively short time (10-60 min) in ethanol the quinazolinones 6a-e were formed
in 75-83% yields, while the products of decarboxylation 7a-e were produced in 59-74% yields on boiling the
components in DMF for 2 h.
Table 1. Characteristics of Compounds 3, 4, 6 and 7
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °C
Yield, %
C
H
Hal
N
3а
3b
3c
3d
3e
4a
4b
4c
4d
4e
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
С22Н23N3O4
66.96
67.16
64.26
64.22
61.99
61.76
55.54
55.94
60.30
60.27
71.97
72.18
68.51
68.65
65.69
65.71
58.98
58.89
63.72
63.94
65.41
65.24
63.50
63.28
65.81
65.72
67.83
67.51
66.82
66.60
68.82
68.64
5.77
5.89
5.19
5.39
5.06
5.18
4.77
4.69
5.08
5.06
6.65
6.63
6.01
6.04
5.62
5.78
5.06
5.18
5.62
5.62
4.90
4.72
4.50
4.58
5.00
4.93
6.06
6.01
4.83
4.66
5.38
5.14
11.34
10.68
10.21
10.21
9.70
9.82
8.72
8.90
12.87
12.78
12.03
12.03
11.42
11.44
10.93
10.95
9.73
9.81
14.30
14.20
8.02
7.87
7.42
7.63
8.04
7.90
9.72
9.54
10.58
10.36
8.73
8.58
192-193
200-202
62.1
73.2
70.0
68.3
63.1
53.4
56.8
60.3
57.8
58.2
76.3
81.6
80.1
75.0
83.1
58.8
60.2
63.0
62.4
74.2
С22Н22FN3O4
С22Н22ClN3O4
С22Н22BrN3O4
С22Н22N4O6
4.65
4.62
8.88
8.29
16.91
16.92
188-191
195-197
178-180
С21Н23N3O2
92-95
С21Н22FN3O2
С21Н22ClN3O2
С21Н22BrN3O2
С21Н22N4O4
4.69
5.17
9.17
9.24
18.64
18.66
104-107
128-130
171-175
156-158
C29H25ClFN3O4
C29H25Cl2N3O4
C29H26ClN3O5
C33H35СlN4O4
C30H25СlN4O4
C28H25СlFN3O2
C28H25Сl2N3O2
C28H26СlN3O3
C32H35СlN4O2
C29H25СlN4O2
220-223 (dec.)
248-250 (dec.)
253-255 (dec.)
190-193 (dec.)
239-240 (dec.)
143-145
13.03
12.88
7.00
6.66
6.15
6.03
6.83
6.55
66.72
66.71
58.04
57.98
71.02
70.77
69.92
70.08
5.12
4.98
5.43
5.37
6.73
6.50
5.18
5.07
7.12
7.00
7.41
7.27
6.78
6.53
7.30
7.13
8.62
8.30
7.17
7.06
10.58
10.32
11.40
11.27
160-161
168-170
123-125
203-205
756

The composition and structures of all the compounds synthesized were confirmed by elemental analysis
(Table 1) and 1H NMR spectroscopy (Table 2) and in the case of the derivatives of 1,2-dihydroquinazolin-4-ones
6a-e and 7a-e by comparison of their 1NMR spectra with those of analogous compounds reported elsewhere [1,
6-7].
Table 2. 1H NMR Spectra of the Compounds Synthesized 3, 4, 6, and 7
Com-
pound
Chemical shifts, δ, ppm, SSCC (J, Hz)
3а
3b
3c
3d
3e
4a
1.64 (3Н, s, СН3); 1.73-3.26 (4Н, m, 2СН2); 3.91 (1Н, m, СН);
5.42 (1Н, m, =СН); 6.46-7.54 (12Н, m, Ar, NH2, COOH); 9.67 (2H, br. s, 2NH)
1.57 (3Н, s, СН3); 1.81-3.36 (4Н, m, 2СН2); 3.89 (1Н, m, СН); 5.42 (1Н, m, =СН);
6.48 (11Н, m, Ar, NH2, COOH); 9.66 (1H, br. s, NH);12.51 (1H, br. s, NH)
1.61 (3Н, s, СН3); 1.72-3.24 (4Н, m, 2СН2); 3.90 (1Н, m, СН); 5.41 (1Н, m, =СН);
6.51-7.54 (11Н, m, Ar, NH2, COOH); 9.67 (1H, br. s, NH);10.10 (1H, br. s, NH)
1.57 (3Н, s, СН3); 1.76-3.22 (4Н, m, 2СН2); 3.86 (1Н, m, СН); 5.38 (1Н, m, =СН);
6.33-7.52 (11Н, m, Ar, NH2, COOH); 9.73 (1H, br. s, NH);10.12 (1H, br. s, NH)
1.65 (3Н, s, СН3); 1.78-3.36 (4Н, m, 2СН2); 4.02 (1Н, m, СН); 5.44 (1Н, m, =СН);
6.41-8.04 (11Н, m, Ar, NH2, COOH); 9.76 (1H, br. s, NH); 9.98 (1H, br. s, NH)
1.64 (3Н, s, СН3); 2.04 (2Н, m, СН2); 2.53 (2Н, m, СН2); 2.75 (1Н, m, СН);
3.36 (1Н, m, СН); 5.38 (1Н, m, =СН); 6.17 (2Н, br. s, NH2); 6.25-7.42 (9Н, m, Ar);
9.62 (1H, br. s, NH); 9.71 (1H, br. s, NH)
4b
4c
4d
1.76 (3Н, s, СН3); 1.82-2.56 (4Н, m, 2СН2); 2.86 (1Н, m, СН); 3.31 (1Н, m, СН);
4.96 (2Н, br. s, NH2); 5.06 (1Н, m, =CH); 6.38-7.48 (8Н, m, Ar); 8.34 (1H, br. s, NH);
8.76 (1H, br. s, NH)
1.68 (3Н, s, СН3); 2.04-2.58 (4Н, m, 2СН2); 2.81 (1Н, m, СН); 3.36 (1Н, m, СН);
5.01 (2Н, br. s, NH2); 5.44 (1Н, m, =CH); 6.62-7.71 (8Н, m, Ar); 8.53 (1H, br. s, NH);
9.02 (1H, br. s, NH)
1.64 (3Н, s, СН3); 2.04-2.56 (4Н, m, 2СН2); 2.78 (1Н, m, СН); 3.31 (1Н, m, СН);
5.41 (1Н, m, =CH); 6.12 (2H, br. s, NH2); 6.29-7.41 (8Н, m, Ar); 9.75 (1H, br. s, NH);
10.21 (1H, br. s, NH)
4e
6a
6b
6c
1.69 (3Н, s, СН3); 2.24-2.46 (4Н, m, 2СН2); 2.91 (1Н, m, СН); 3.54 (1Н, m, СН);
5.57 (1Н, m, =CH); 5.62 (2H, br. s, NH2); 6.71-8.07 (8Н, m, Ar); 8.24 (1H, br. s, NH);
9.28 (1H, br. s, NH)
1.58 (3Н, s, СН3); 1.61-2.72 (4Н, m, 2СН2); 3.69 and 4.30 (1Н, two m, СН);
4.94 and 5.16 (1Н, two m, =CH); 5.91 and 5.99 (1Н, two s, C(2)H);
6.69-7.61 (13Н, m, Ar, NH); 9.80 9.85 (1Н, two br. s, NH); 12.64 (1H, br. s, COOH)
1.51 (3Н, s, СН3); 1.71-2.42 (4Н, m, 2СН2); 3.68 and 3.78 (1Н, two m, СН);
5.03 and 5.26 (1Н, two m, =CH); 5.88 and 6.05 (1Н, two s, C(2)H);
6.74-7.79 (13Н, m, Ar, NH); 9.88 and 9.99 (1Н, two br. s, NH); 10.22 (1H, br. s, COOH)
1.49 (3Н, s, СН3); 1.64-2.67 (4Н, m, 2СН2); 3.32 and 3.69 (1Н, two m, СН);
4.93 and 5.22 (1Н, two m, =CH); 6.14 and 6.21 (1Н, two s, C(2)H);
6.61-7.75 (13Н, m, Ar, NH); 9.56 and 9.62 (1Н, two br. s, NH); 9.86 (1H, br. s, OH);
12.53 (1H, br. s, COOH)
6d
6e
1.13 and 1.18 (6Н, two t, J = 7, 2СН3); 1.76 (3Н, s, СН3);1.91-2.71 (4Н, m, 2СН2);
3.34 (4Н, m, 2СН2); 3.36 and 3.64 (1Н, two m, CH); 5.11 and 5.36 (1Н, two m, =CH);
6.02 (1Н, s, С(2)H); 6.48-7.82 (14Н, m, Ar, 2NH); 9.51 (1Н, br. s, COOH)
1.58 (3Н, s, СН3); 1.69-2.61 (4Н, m, 2СН2); 3.32 and 3.69 (1Н, two m, CH);
4.94 and 5.19 (1Н, two m, =CH); 5.94 and 6.03 (1Н, two s, С(2)H);
6.72-7.81 (13Н, m, Ar, NH); 9.86 and 9.94 (1Н, two br. s, NH); 12.61 (1H, br. s, COOH)
7a
7b
7c
7d
7e
1.61 (3Н, s, СН3); 1.93-2.41 (4Н, m, 2СН2); 2.69-3.29 (2Н, m, 2CH); 5.36 (1Н, m, =СH);
6.04 (1Н, s, С(2)H); 6.53-7.87 (14Н, m, 2NH)
1.64 (3Н, s, СН3); 1.93-3.26 (6Н, m, 2СН2, 2CH); 5.36 (1Н, m, =СH);
6.02 and 6.06 (1Н, two s, С(2)H); 6.51-7.89 (14Н, m, Ar, 2NH)
1.64 (3Н, s, СН3); 1.87-3.31 (6Н, m, 2СН2, 2СН); 5.25 and 5.29 (1Н, two m, =СH);
6.16 and 6.18 (1Н, two s, С(2)H); 6.62-7.93 (15Н, m, Ar, 2NH, ОН)
1.05 and 1.13 (6Н, two t, J = 7, 2СН3); 1.67 (3Н, s, СН3); 1.81-3.31 (6Н, m, 2СН2, 2CH);
5.37 (1Н, m, =СH); 5.67 and 5.81 (1Н, two s, С(2)H); 6.33-7.65 (14Н, m, Ar, 2NH)
1.67 (3Н, s, СН3); 1.95-3.38 (6Н, m, 2СН2, 2CH); 5.37 (1Н, m, =СH);
6.11 (1Н, s, С(2)H); 6.58-7.96 (14Н, m, Ar, 2NH)
757

EXPERIMENTAL
1H NMR spectra of CDCl3 (4b,c, 6d, 7a-c,e) or DMSO-d6 solutions (3a-e, 4a,d,e, 6a-c,e, 7d) with TMS
as internal standard were recorded on WH-90DS (90 MHz) instrument.
Purity of the compounds synthesized was monitored by TLC on Silufol plates with the eluents
dichloromethane-methanol, 0.5:5 (for 3a-e and 4a-e) and benzene-acetone-glacial acetic acid, 100:50:2 (for 6a-e
and 7a-e).
N'-[1-Hydroxycarbonyl-4-methyl-2-(4-R-phenyl)cyclohex-4-enyl-1-carbonyl]hydrazides of 2-Amino-
benzoic Acid 3a-e. A solution of anhydride 1 (1.54 g, 5 mmol) and an equimolar quantity of a monohydrazide
of cyclohexenedicarboxylic acid 2a-e in ethanol (30 ml) was boiled for 5 h. Half of the ethanol was evaporated,
an equal volume of water was added, and the mixture was kept for ~10 h. The product was filtered off and
recrystallized from 1:1 aqueous ethanol.
N'-[4-methyl-2-(4-R-phenyl)cyclohex-4-enyl-1-carbonyl]hydrazides of 2-Aminobenzoic Acid 4a-e.
N'-hydrazides 3a-e (5 mmol) were boiled in DMF (15 ml) for 2 h. The reaction mixture was cooled, poured into
water, filtered, and recrystallized from dilute ethanol (3:1).
2-Aryl-3-[2-(4-chlorophenyl)-1-hydroxycarbonyl-4-methylcyclohex-4-en-1-ylamido]-1,2-dihydroquin-
azolin-4(3H)-ones 6a-e. A solution of the N'-hydrazide 3c (0.7 mmol) and the corresponding benzaldehyde 5a-e
(0.9 mmol) was boiled in ethanol (5 ml) for 10 (6c,e), 20 (6a,b), or 60 min (6d). The mixture was cooled, kept
for ~8-10 h, and the precipitate was filtered off and washed on the filter with ethanol. Compounds 6a-c,e were
chromatographically pure without recrystallization. Compound 6d was recrystallized from 1:1 aqueous ethanol.
2-Aryl-3-[2-(4-chlorophenyl)-4-methyl-4-cyclohex-4-en-1-ylamido]-1,2-dihydroquinazolin-4(3H)-
ones 7a-e. A solution of the N'-hydrazide 3c (0.7 mmol) and the corresponding benzaldehyde 5a-e (0.9 mmol)
was boiled in DMF (5 ml) for 2 h. The mixture was cooled, poured into water, and filtered. The precipitate was
recrystallized from 1:1 aqueous ethanol.
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