The reaction of 2-aminoethyl- and 3-aminopropyl-substituted heterocycles with 2-formyl-1,3-cyclanediones and 4-oxo-3,1-benzoxazines

Article abstract of DOI:10.1023/A:1016087423462

The reaction of 2-formyl-1,3-cyclohexanedione, its 5,5-dimethyl, 5-phenyl and 5-(2-furyl) derivatives and of 2-formyl-1,3-indanedione and dehydroacetic acid with histamine, 3-(1-imidazolyl)propylamine, 3-(4-morpholyl)propylamine, 3-(2-pyrrolidon-1-yl)prop

Full text of DOI:10.1023/A:1016087423462

Chemistry of Heterocyclic Compounds, Vol. 38, No. 4, 2002
THE REACTION OF 2-AMINOETHYL-
AND 3-AMINOPROPYL-SUBSTITUTED
HETEROCYCLES WITH 2-FORMYL-
1,3-CYCLANEDIONES AND
4-OXO-3,1-BENZOXAZINES
A. Strakovs, N. N. Tonkikh, M. Petrova, K. V. Ryzhanova, and E. Palitis
The reaction of 2-formyl-1,3-cyclohexanedione, its 5,5-dimethyl, 5-phenyl and 5-(2-furyl) derivatives
and of 2-formyl-1,3-indanedione and dehydroacetic acid with histamine, 3-(1-imidazolyl)propylamine,
3-(4-morpholyl)propylamine,
3-(2-pyrrolidon-1-yl)propylamine,
2-(1-piperazinyl)ethylamine,
tryptamine, and 2-(aminomethyl)pyridine gave fifteen 2-aminomethylene derivatives. The reaction of
these amines with 2-methyl-4-oxo-3,1-benzoxazine gave the 3-substituted 2-methyl-4(3H)-
quinazolinones and with 4-oxo-2-phenyl-3,1-benzoxazine the monosubstituted N-benzoylanthranilic
acid amides.
Keywords: 2-aminoethyl- and 3-aminopropyl-substituted heterocycles, 2-formyl-1,3-cyclanediones,
dehydroacetic acid, 4-oxo-3,1-benzoxazines, 2-aminomethylene-1,3-cyclanediones, 3-substituted
4(3H)-quinazolinones, monosubstituted N-benzoylanthranilic acid amides.
In the last decade biologists, medics and chemists have carried out an intensive complex investigation of
histamine H3-receptor agonists and antagonists [1-17] directed towards broadening the treatment of a series of
diseases. As reported in [3] the rationale for structure activity relationships amongst histamine H3-receptors has
led us to introduce histamine and certain ethyl- and propylamines with heterocyclic substituents at the β- and,
respectively, γ-carbon atoms in the reaction with cyclanediones and benzoxazines. As cyclanediones 1 we used
2-formyl-1,3-cyclohexanedione (1a), its 5,5-dimethyl (1b), 5-phenyl (1c), and 5-(2-furyl) (1d) derivatives and
2-formyl-1,3-indanedione (1e) and, as amines 2, histamine (2a), 3-(1-imidazolyl)propylamine (2b),
3-(4-morpholyl)propylamine (2c), 3-(2-pyrrolidon-1-yl)propylamine (2d), 2-(1-piperazinyl)ethylamine (2e),
tryptamine (2f), and 2-(aminomethyl)pyridine (2g).
Reaction of 2-formyl-1,3-cyclohexanediones 1a-e with amines 2a-g give the 2-(aminomethylene)-1,3-
cyclanediones (3-17) and dehydroacetic acid 1f reacts with tryptamine 2f to form the
3-(1-[2-(3-indolyl)ethylamino]ethylidene)-6-methyl-2,4-pyrandione (18).
The synthesis of compounds 3-18 was carried out using one of the following four procedures. Reaction
of the free amines 2 with the formyl derivatives 1 gave the 2-aminomethylene derivatives 6, 7, 13-15, 17. To
synthesize the compounds 3, 5 and 8, the amine hydrochlorides 2 were treated with the potassium salts of the
corresponding formyl derivatives 1.
__________________________________________________________________________________________
Riga Technical University, Riga LV-1658, Latvia; e-mail: marina@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 4, pp. 515-521, April, 2002. Original article submitted November 26,
1999.
0009-3122/02/3804-0449$27.00©2002 Plenum Publishing Corporation
449

O
O
O
O
H2N–(CH ) –X
2a–g2 n
O
R
R
N
A
A
(CH2)
X
n
H
1a–f
3–18
O
O
N
N
(CH2)
X
O
n
R'
N
R'
2a–g
20–25
19a,b
CO
NH
X
(CH2)
n
NH
26–29
CO R'
1 a A = (CH2)3; b A = CH2C(CH3)2CH2; c A = CH2CH(Ph)CH2; d A = CH2CH(2-furyl)CH2;
e A = C6H4-1,2; f A = –O–C(CH3)=CH–; a–e R = H; f R = CH3
N
NH
N
N
d X =
N
;
2 a X =
; b X =
;
; c X =
N
O
O
N
;
e X =
g X =
; f X =
NH
N
N
H
a, e, f n = 2; b–d n = 3, g n = 1
A, n, X = 3a,a; 4a,b; 5b,a; 6b,b; 7b,d; 8b,f; 9c,d; 10d,b; 11d,e; 12e,a; 13e,b; 14e,c; 15e,d; 16e,f;
17e,g; 18f,f; 19: R' = a CH3; b C6H5; R', n, X = 20a,a; 21a,b; 22a,d; 23a,f; 24a,g; 25b,g; 26b,a; 27b,b; 28b,c; 29b,f
Compounds 12, 16, 18 were prepared from the 2-acyl-1,3-cyclanediones 1 and the amine hydrochlorides
2 in the presence of NaHCO3. The potassium salts of the 2-formyl-1,3-cyclohexanediones 1 and the free amines
2 in the presence of HCl gave the compounds 4 and 9-11.
1
The structure of the 2-aminomethylene-1,3-cyclanediones 3-17 was confirmed by IR and H NMR
spectroscopic data (Table 1). The 1H NMR spectra of 3-17, as in the spectra of previously studied compounds of
this series [18-22], show characteristic proton signals for the cyclanedione and trans-fixed =CH–NH– fragment.
The reaction of the 2-methyl-4-oxo-3,1-benzoxazine (19a) with the amines 2a,b,d,f,g, analogously to its
previously studied reactions with amino heterocycles [23, 24], gives the 3-substituted 4(3H)-quinazolinones 20-
24. Treatment of the 4-oxo-2-phenyl-3,1-benzoxazine (19b) with 2-(aminomethyl)pyridine (2g) also gives the
quinazolinone 25. The reaction of the benzoxazine 19b with the amines 2a,b,c,f gave the N-benzoylanthranilic
acid amides 26-29.
The spectra of the quinazolinones 20-25 and the N-benzoylanthranilic acid amides 26-29 are readily
1
distinguishable. The H NMR spectra of the latter show two additional signals for the NH group protons
(Table 1).
The synthesized compounds were prepared with the aim of investigating their histamine H3-receptor
agonist and antagonist activities since the amines used can be considered as histamine analogs.
450

TABLE 1. IR and 1H NMR Spectra of Synthesized Compounds
Com-
IR spectrum, ν, cm-1
1Н NMR spectrum, δ, ppm, J (Hz)*
pound
1
2
3
1670, 1610 (С=О),
1590, 1575; 3200,
3100 (NH)
CDCl3. 1.85 (2H, m, 3J = 7,СН2); 2.25-2.42 (4Н, m, 2СН2);
2.83 (2Н, t, 3J = 7, СН2); 3.65 (2Н, dt, 3J = 6, 3J = 7, СН2);
6.75 (1Н, s, =СН); 7.47 (1Н, s, =СН–); 7.96 (1Н, d, 3J = 14,
=СН–); 9.31 (1Н, br. s, NH); 11.13 (1H, br. m, NH)
3
4
5
1665 (C=O),
CDCl3. 1.78-2.43 (8H, m, 4СН2); 3.31 (2Н, dt, 3J = 6, 3J = 7,
СН2); 3.98 (2H, d, 3J = 7, СН2); 6.82 (1Н, s, =СН–);
7.01 (1Н, s, =СН–); 7.42 (1Н, s, =СН–);
1610-1570, 1515;
3200, 3140, 3110 (NH)
7.99 (1Н, d, 3J = 14, =СН–); 11.14 (1H, br. m, NH)
1675 (C=O), 1600;
3220, 3120 (NH)
DMSO-d6. 0.94 (6H, s, 2СН3); 2.16 (2H, s, CH2);
2.25 (2H, s, CH2); 2.78 (2H, t, 3J = 7,5 Hz, СН2);
3.72 (2H, dt, 3J = 6 Hz, 3J = 7 Hz, СН2);
6.82 (1Н, br. s, =СН–); 7.56 (1Н, s, =СН–);
7.96 (1Н, d, 3J = 14 Hz, =СН–); 10.94 (1Н, br. m, NН);
11.81 (1H, br. s, NH)
1665 (C=O), 1600,
1575, 1545, 1512;
3200, 3140 (NH)
DMSO-d6. 0.94 (6H, s, 2СН3); 2.03 (2H, m, 3J = 7, CH2);
2.21 (2H, s, CH2); 2.26 (2H, s, СН2); 3.40 (2H, dt, 3J = 7,
3J = 5, СН2); 3.96 (2Н, t, 3J = 7, СН2); 6.87 (1Н, s, =СН);
7.21 (1Н, s, =СН–); 7.61 (1Н, s, =СН–); 8.01 (1Н, d, 3J = 14,
=СН–); 10.85 (1Н, br. m, NН)
6
1680, 1670 (C=O),
1605, 1582, 1500;
3200 (NH)
CDCl3. 0.98 (6H, s, 2СН3); 1.76-2.43 (6Н, m, 3СН2);
2.24 (2Н, s, СН2); 2.82 (2Н, s, СН2); 3.33 (6Н, m, 3СН2);
8.01 (1Н, d, 3J = 14, =СН–); 11.06 (1H, br. m, NH)
CDCl3. 1.04 (6H, s, 2СН3); 2.27 (2Н, s, СН2); 2.36 (2Н, s,
СН2); 3.09 (2Н, t, 3J = 7, СН2); 3.72 (2Н, dt, 3J = 6, 3J = 7,
СН2); 7.08-7.66 (5Н, m, С6Н4, =СН–); 8.05 (1Н, d, 3J = 13,
=СН–); 8.33 (1Н, br. s, NH); 12.22 (1H, br. m, NH)
7
8
1668 (C=O),
1585, 1565;
3280, 3190 (NH)
1680–1665 (C=O),
DMSO-d6. 1.76-2.62 (11H, m, 5СН2, CH); 3.22 (6H, m,
9
1600, 1580, 1560, 1510; 3CH2); 7.21 (5H, m center, C6H5); 8.04 (1H, d, 3J = 14,
3280, 3220 (NH)
=СН–); 10.29 (1Н, br. m, NН)
1665 (C=O), 1610,
1590, 1575, 1500;
3200, 3160 (NH)
CDCl3. 2.14 (2H, m, 3J = 7, СН2); 2.76 (4Н, br. s, 2СН2);
3.40 (1H, m, СН); 3.42 (2Н, dt, 3J = 6, 3J = 7, СН2);
4.05 (2Н, t, 3J = 7, СН2); 6.05 (1Н, m, С4Н3О ); 6.32 (1Н, m,
С6Н3О); 6.92 (1Н, s, =СН–); 7.12 (1Н, s, =СН–);
7.36 (1Н, m, С4Н3О); 7.52 (1Н, s, =СН–); 8.12 (1Н, d, 3J = 14,
=СН–); 11.24 (1Н, br. m, NH)
10
1673 (C=O), 1612,
1688, 1555, 1510;
DMSO-d6. 2.06-3.53 (17H, m, 8СН2, CH ); 5.94 (1H, m,
C4H3O); 6.23 (1H, m, C4H3O); 7.50 (1H, m, C4H3O);
7.98 (2Н, br. s, =СН–, NН); 10.78 (1Н, br.m, NН)
11
12
3350, 3200, 3120 (NH)
1690, 1650 (C=O),
DMSO-d6. 2.78 (2H, t, 3J = 7, СН2); 3.69 (2Н, dt, 3J = 6,
1625, 1590, 1560, 1540; 3J = 7, СН2); 6.81 (1Н, s, =СН–); 7.53-7.69 (5Н, m, С6Н4,
3280, 3200-3170 (NH)
=СН–); 7.69 (1Н, d, 3J = 14, =СН–); 9.54 (1Н, br. m, NH);
11.62 (1Н, br. s, NH)
1690, 1650 (C=O), 1625, CDCl3. 2.13 (2H, m, СН2); 3.36 (2Н, dt, 3J = 5, 3J = 7, СН2);
13
14
15
16
17
18
1600, 1570, 1530;
3280, 3150 (NH)
4.05 (2Н, t, 3J = 7, СН2); 6.91 (1Н, s, =СН- ); 7.12 (1Н, s,
=СН–); 7.67 (6Н, С6Н4, 2=CH–); 9.25 (1Н, br. m, NH)
1710, 1675, 1650 (C=O), CDCl3. 1.95 (2H, m, СН2); 2.48 (6Н, m, 3NCH2);
1630, 1605-1560;
3280, 3100 (NH)
3.50 (2H, dt, 3J = 6, 3J = 7, NСН2); 3.82 (4Н, m, 2OСН2);
7.56-7.84 (5Н, m, С6Н4, =СН–); 9.38 (1Н, br. m, NH)
1710, 1695, 1645 (C=O), CDCl3. 1.78-2.54 (6H, m, 3СН2); 3.47 (6Н, m, 3CH2);
1635, 1620, 1600, 1500; 7.63 (5H, m, С6Н4,=СН–); 9.44 (1Н, br. m, NH)
3280, 3110, 3090 (NH)
1720-1705 (C=O),
1650-1580, 1565, 1550; СН2); 7.16-8.08 (10Н, m, 2С6Н4, 2=СН–);
3400, 3200, 3100 (NH) 9.23 (1Н, br. m, NH); 12.93 (1Н, br. s, NH)
CDCl3. 3.13 (2H, t, 3J = 7, СН2); 3.76 (2Н, dt, 3J = 6, 3J = 7,
1710, 1680, 1670, 1655 CDCl3. 4.67 (2H, d, 3J = 6, СН2); 7.23-7.75 (8Н, m, С6Н4,
(C=O), 1615, 1560;
3250 (NH)
1715-1700, 1660,
1640 (C=O), 1620,
1580-1550; 3300,
3200 (NH)
C5H4N); 7.86 (1Н, d,3J = 14, =СН–); 8.67 (1Н, m, С5Н4N);
9.76 (1Н, br. m, NH)
DMSO-d6. 2.02 (3H, s, СН3); 2.47 (3Н, s, CH3);
3.05 (2H, t, 3J = 7, СН2); 3.80 (2Н, dt, 3J = 6, 3J = 7, СН2 );
5.67 (1Н, s, =СН–); 6.97-7.62 (5Н, m, С6Н4, =СН–);
10.98 (1Н, br. s, NH); 13.83 (1Н, br. m, NH)
451

TABLE 1 (continued)
1
2
3
1665 (C=O), 1600,
DMSO-d6. 2.41 (3H, s, СН3); 2.92 (2Н, t, 3J = 7, CH2);
20
21
1575, 1560; 3130 (NH) 4.23 (2H, t, 3J = 7, СН2); 6.81 (1Н, s, =СН–);
7.50-7.78 (4Н, m, С6Н4, =СН–);
8.09 (1Н, dd, 3J = 8, 4J = 1.5, С(5)H); 11.87 (1Н, br. s, NH)
1680, 1665 (C=O),
1620, 1600, 1575,
1565, 1520
DMSO-d6. 2.13 (2H, m, 3J = 7, СН2); 2.43 (3Н, s, CH3);
4.07 (2H, t, 3J = 7, СН2); 4.15 (2Н, t, 3J = 7, СН2);
6.89 (1Н, s, =СН–); 7.29 (1Н, s, =СН–);
7.32-7.63 (4Н, m, С6Н4, =СН–); 8.29 (1Н, d, 3J = 8, С(5)H)
1660, 1650, 1640
(C=O), 1610, 1600,
1575, 1505
CDCl3. 2.02-2.46 (6H, m, 3СН2); 2.65 (3Н, s, СН3);
3.49 (4Н, m, 2СН2); 4.09 (2Н, m, СН2);
7.36-8.27 (4Н, m, С6Н4)
22
23
3
1705, 1660 (C=O),
DMSO-d6. 2.73 (3H, s, CH3); 3.09 (2H, dd, J = 5, 3J = 9,
1600, 1575; 3300 (NH) СН2); 4.31 (2Н, dd, 3J = 5, 3J = 9, CH2); 7.01-7.89 (8Н, m,
2С6Н4, =СН); 8.21 (1Н, d, 3J = 8, С(5)H); 10.91 (1Н, br. s, NH)
DMSO-d6. 2.48 (3H, s, CH3); 5.45 (2H, s, CH2);
1686 (C=O), 1628,
24
25
26
1590, 1576, 1568, 1504 7.18-8.44 (8H, m, С6Н4, С5Н4N)
1682 (C=O), 1588, 1568 DMSO-d6. 5.27 (2H, s, CH2);
7.11-8.43 (13H, m, С6Н4, С5Н4N, C6H5)
1665, 1655 (C=O),
1605, 1590, 1575,
1535, 1525; 3340,
3100 (NH)
DMSO-d6. 2.81 (2H, t, 3J = 6.5, СН2); 3.57 (2Н, dt, 3J = 6,
3J = 6.5, CH2); 6.85 (1Н, s, =СН–); 7.21-7.92 (9Н, m, С6Н5,
С6Н4, =СН–); 8.66 (1Н, d, 3J = 8, С(6)H); 8.98 (1Н, br. t,
3J = 6, NH); 11.83 (1Н, br. s, NH); 12.61 (1H, br. s, NH)
1675, 1665 (C=O),
1635, 1600, 1580,
1550, 1515, 1500;
3280, 3230,
DMSO-d6. 1.98 (2H, m, 3J = 7, СН2); 3.32 (2Н, dt, 3J = 5.5,
3J = 7, CH2); 4.05 (2Н, t, 3J = 7, СН2); 6.91 (1Н, s, =СН–);
7.24 (1Н, s, =СН); 7.26-7.98 (9Н, m, С6Н5, С6Н4, =СН–);
8.72 (1Н, d, 3J = 8, С(6)H); 8.94 (1Н, br. t, 3J = 5.5, NH);
12.52 (1H, br. s, NH)
27
3120 (NH)
1675, 1645 (C=O),
1605, 1585, 1580,
1540-1520, 1500;
3250-3180 (NH)
1675, 1645 (C=O),
1610, 1590, 1580,
1540, 1510; 3270,
3300, 3200 (NH)
DMSO-d6. 1.69 (2H, m, СН2); 3.28 (2Н, m, NСН2);
28
29
3.29 (6Н, m, 3NCH2); 3.51 (4Н, m, 2OCH2);
7.04-7.93 (8Н, m, С6Н5, С6Н4); 8.60 (1Н, dd, 3J = 8, 4J = 1.5,
С(6)H); 8.82 (1Н, br. t, 3J = 5, NH); 12.53 (1H, br. s, NH)
DMSO-d6. 2.98 (2H, m, СН2); 4.14 (2Н, m, CH2);
6.71-7.90 (15Н, m, С6Н5, С6Н4,=СН–, 2NH ); 8.30 (1Н, dd,
3J = 8, 4J = 1.7, С(6)H); 10.83 (1H, br. s, NH)
TABLE 2. Characteristics for Synthesized Compounds
Found, %
——————
Com-
pound
Empirical
formula
Crystallysation
solvent
Calculated, %
mp, °С
Yield, %
C
3
H
4
N
5
1
3
2
6
Toluene
7
8
C12H15N3O2
C13H17N3O2
C14H19N3O2
C15H21N3O2
C16H24N2O3
C19H22N2O2
C20H24N2O3
C17H18N3O3
61.57
61.79
6.40
6.48
17.88
18.01
164-165
151-153
170-171
159-161
139-141
110-112
113-116
88-90
34
80
59
76
95
60
47
89
62.95
6.81
16.83
Isopropanol
Ethanol
4
63.14
6.93
16.99
64.11
64.35
7.40
7.33
16.02
16.08
5
65.20
7.52
15.40
Isopropanol
Ethanol
6
65.43
7.65
15.26
65.50
65.73
8.21
8.27
9.40
9.58
7
73.26
7.01
9.20
Ethanol
8
73.52
7.14
9.02
70.44
70.57
7.10
7.11
8.08
8.08
Isopropanol
Ethanol
9
65.28
5.74
13.26
10
65.37
5.81
13.45
452

TABLE 2 (continued)
1
2
3
4
5
6
7
8
C17H23N3O3
C15H13N3O2
C16H15N3O2
C17H20N2O3
C17H18N2O3
C20H16N2O2
C16H12N2O2
C18H18N2O3
C14H14N4O
C15H16N4O
C16H19N3O2
C19H17N3O
C15H13N3O
C20H15N3O
C19H18N4O2
C20H20N4O2
C21H25N3O3
C24H21N3O2
64.11
64.33
7.11
7.31
13.01
13.24
Ethanol
135-136
62
11
12
13
14
15
16
17
18
20
21
22
23
24
25
26
27
28
29
67.19
4.80
15.55
Ethanol–water, 1:1 217-220
45
57
67.41
4.90
15.72
Ethanol
148-150
68.39
68.32
5.21
5.37
15.01
14.94
67.77
6.60
9.12
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Water
74-75
135-137
163-164
160-161
164-165
241-245
137-140
73-76
46
85
50
71
90
35
78
27
56
55
64
30
68
49
53
67.98
6.71
9.33
68.58
68.43
5.96
6.10
9.30
9.39
75.71
4.98
8.61
75.90
5.10
8,85
72.51
72.71
4.50
4.58
10.44
10.60
69.55
5.80
8.89
69.66
5.85
9.03
66.01
66.12
5.66
5.55
21.81
22.03
67.01
5.95
20.65
Ethanol
Methanol
Acetic acid
Water
67.15
6.01
20.88
67.12
67.35
6.60
6.72
14.88
14.73
75.02
5.51
13.70
227-229
80-81
75.23
5.65
13.85
71.49
71.69
5.02
5.21
16.60
16.72
76.50
4.77
13.28
Ethanol
98-100
76.66
4.82
13.41
68.18
68.25
5.33
5.43
16.53
16.76
Ethanol–water, 1:3 208-211
68.79
5.82
16.01
Isopropanol
Methanol
135-137
118-120
258-259
68.95
5.79
16.08
68.50
68.64
6.95
6.86
11.40
11.44
78.19
5.15
11.98
Acetic acid
78.45
5.76
11.44
EXPERIMENTAL
IR spectra were taken on a Specord IR-75 spectrometer for suspensions of the materials in vaseline oil
(1800-1500 cm-1) and in hexachlorobutadiene (3600-2000 cm-1). The frequencies of the stretching bands of the
C–H bonds in the region 3050-2800 cm-1 are not reported. 1H NMR spectra were taken on a Bruker WH-90/DS
(90 MHz) instrument using CDCl3 or DMSO-d6 solvents and TMS internal standard.
The β-substituted ethylamines and γ-substituted propylamines were obtained from the Acros and
Maybridge companies.
Parameters for the synthesized compounds are given in Tables 1 and 2.
2-[3-(1-Imidazolyl)propylaminomethylene]-5,5-dimethyl-1,3-cyclohexanedione (6), 5,5-Dimethyl-
2-[3-(2-oxopyrrolidin-1-yl)propylaminomethylene]-1,3-cyclohexanedione (7), 2-[3-(1-Imidazolyl)propyl-
aminomethylene]-1,3-indanedione (13), 2-[3-(4-Morpholyl)propylaminomethylene]-1,3-indanedione (14),
2-[3-(2-Oxopyrrolidin-1-yl)propylaminomethylene]-1,3-indanedione (15), and 2-(2-Pyridyl)methylamino-
methylene-1,3-indanedione (17). A solution of an equimolar amount of the free amine 2 in ethanol (15-20 ml),
at the same temperature, was added to a solution of the acylcyclanedione 1 (5 mmol) in ethanol (15 ml) which
had been heated to reflux. After 2 h, the product was filtered off and recrystallized.
2-[2-(4-Imidazolyl)ethylaminomethylene-1,3-cyclohexanedione (3), 2-[2-(4-Imidazolyl)ethylamino-
methylene-5,5-dimethyl-1,3-cyclohexanedione (5), and 2-[2-(3-Indolyl)ethylaminomethylene]-5,5-dimethyl-
1,3-cyclohexanedione (8). An aqueous solution of the amine hydrochloride 2 (3 mmol) in water (10 ml), at the
453

same temperature, was added to a solution of the acylcyclanedione 1 (3 mmol) in water (15 ml) which had been
heated to 70-80°C. After 2 h, the product was filtered off and recrystallized.
2-[2-(4-Imidazolyl)ethylaminomethylene]-1,3-indanedione (12), 2-[2-(3-Indolyl)ethylamino-
methylene]-1,3-indanedione (16), and 3-(1-[2-(3-Indolyl)ethylamino]ethylidene)-6-methyl-2,4-pyrandione
(18). The acylcyclanedione 1 (3 mmol), an equimolar amounts of NaHCO3 and the amine hydrochloride 2 were
refluxed for 15 min (in the case of the product 18, four hours) in ethanol (30 ml). The reaction mixture was
cooled, the NaCl filtered off, half of the solvent distilled off, and the product was left in the fridge for one day.
The precipitate was filtered off and recrystallized.
2-[3-(1-Imidazolyl)propylaminomethylene]-1,3-cyclohexanedione (4), 2-[3-(2-Oxopyrollidin-1-
yl)propylaminomethylene]-5-phenyl-1,3-cyclohexanedione
(9),
2-[3-1-(Imidazolyl)propylamino-
methylene]-5-(2-furyl)-1,3-cyclohexanedione (10), 2-[2-(1-Piperazinyl)ethylaminomethylene]-5-(2-furyl)-
1,3-cyclohexanedione (11). The potassium salt of the corresponding acylcyclanedione 1 (2.5 mmol), an
equimolar amount of amine 2, and 1 drop of concentrated HCl in ethanol (30 ml) were refluxed for 5 min. KCl
was filtered off from the hot reaction mixture and the filtrate was left in the fridge for one day. The precipitate
was filtered off and recrystallized.
3-[2-(4-Imidazolyl)ethyl]-2-methyl-4(3H)-quinazolinone (20). The benzoxazine 19a (0.81 g,
5 mmol), hydrochloride 2a (1.01 g, 5.5 mmol) and K2CO3 (1.52 g, 11 mmol) in DMF (30 ml) were refluxed for
1 h. Solvent (20-25 ml) was distilled off on a rotary evaporator and the residue was cooled. The precipitate was
filtered off and recrystallized from water.
3-[3-(1-Imidazolyl)propyl]-2-methyl-4(3H)-quinazolinone
(21)
and
2-Methyl-3-[3-(2-
oxopyrrolidin-1-yl)propyl]-4(3H-quinazolinone (22). The benzoxazine 19a (5 mmol) and an equimolar
amount of the amine 2b or 2d respectively in glacial acetic acid (15 ml) were refluxed for 8 h. The solvent was
evaporated off on a rotary evaporator and the remaining oily product was recrystallized.
3-[2-(3-Indolyl)ethyl]-2-methyl-4(3H)-quinazolinone (23). The benzoxazine 19a (5 mmol) and
hydrochloride 2f (5 mmol) in glacial acetic acid (15 ml) were refluxed for 4 h. The precipitate formed on
cooling was mixed with aqueous NaHCO3 solution, filtered, and recrystallized.
2-Methyl-3-(2-pyridinyl)methyl-4(3H)-quinazolinone (24) and 3-(2-Pyridyl)methyl-2-phenyl-
4(3H)-quinazolinone (25). Equimolar amounts of the amine 2g and benzoxazine 19 were melted in a wide tube
for 1.5 h at 150°C (bath temperature). The melt was cooled and recrystallized.
N-Benzoylanthranilic Acid 2-(4-Imidazolyl)ethylamide (26). The benzoxazine 19b (0.56 g,
2.5 mmol), dihydrochloride 2a (0.50 g, 2.7 mmol), and K2CO3 (0.75 g, 5.4 mmol) in DMF (15 ml) were refluxed
for 1 h. The precipitate was filtered off, the filtrate was evaporated to one third volume, and water (30 ml) was
added. The precipitated solid was filtered off and recrystallized.
N-Benzoylanthranilic Acid 3-(1-Imidazolyl)propylamide (27) and 3-(4-Morpholyl)propylamide
(28). Equimolar amounts of the benzoxazine 19b and the amine 2b or 2c were melted in a wide tube for 1.5 h at
150°C (bath temperature). The melt was cooled and recrystallized.
N-Benzoylanthranilic Acid 2-(3-Indolyl)ethylamide (29). The benzoxazine 19b and hydrochloride 2f
(each 2.5 mmol) in glacial acetic acid (15 ml) were refluxed for 8 h. The precipitate formed on cooling was
filtered off, mixed with aqueous NaHCO3 solution, and again filtered and recrystallized.
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