Multicomponent synthesis of 2,5-dioxo- and 4-aryl-5-oxo-2-thioxo-1,2,3,4,5, 6,7,8-octahydroquinazolines

Article abstract of DOI:10.1023/B:COHC.0000023766.76924.78

Ten 2,5-dioxo- and 4-aryl-5-oxo-2-thioxo-1,2,3,4,5,6,7,8- octahydroquinazolines have been synthesized in three-component interactions of 1,3-cyclohexanedione or dimedone, urea or thiourea, and substituted benzaldehydes (3-bromo-, 4-bromo-, 4-fluoro-, 4-methoxy-, 3,4-methylenedioxy-, and 3-nitro-). 9-Aryl-4,5-dioxo-1,2,3,4,5,6,7,8-octahydro-9H-xanthenes were also formed in these reactions.

Full text of DOI:10.1023/B:COHC.0000023766.76924.78

Chemistry of Heterocyclic Compounds, Vol. 40, No. 1, 2004
MULTICOMPONENT SYNTHESIS OF
2,5-DIOXO- AND 4-ARYL-5-OXO-2-THIOXO-
1,2,3,4,5,6,7,8-OCTAHYDROQUINAZOLINES
N. N. Tonkikh, A. Strakovs, and M. V. Petrova
Ten 2,5-dioxo- and 4-aryl-5-oxo-2-thioxo-1,2,3,4,5,6,7,8-octahydroquinazolines have been synthesized
in three-component interactions of 1,3-cyclohexanedione or dimedone, urea or thiourea, and substituted
benzaldehydes (3-bromo-, 4-bromo-, 4-fluoro-, 4-methoxy-, 3,4-methylenedioxy-, and 3-nitro-). 9-Aryl-
4,5-dioxo-1,2,3,4,5,6,7,8-octahydro-9H-xanthenes were also formed in these reactions.
Keywords: 2,5-dioxo- and 5-oxo-2-thioxo-4-aryl-1,2,3,4,5,6,7,8-octahydroquinazolines, substituted
benzaldehydes, ureas, 1,3-cyclohexanediones, three-component synthesis.
Among the large diversity of multicomponent reactions involving 1,3-dicarbonyl compounds, aldehydes
and various C- and N-nucleophiles [1-14] the variant of the Bidginelli condensation involving
1,3-cyclohexanedione, an aromatic aldehyde, and urea, leading to quinazoline derivatives is unknown. In these
reactions the formation of the corresponding 9-aryl-4,5-dioxo-1,2,3,4,5,6,7,8-octahydroxanthenes might be
expected as side products.
H
R
R
R
R
O
R
R
N
X
H
O
R
R
OH
H2N
X
NH
+
+
O
O
NH2
2a,b
O
O
R1
R1
1a,b
3a-f
R1
5a-e
4a-j
1 a R= H; b R = Me; 2 a X= O; b X = S; 3 a R1= 3-Br, b R1 = 4-Br, c R1 = 4-F, d R1 = 4-OMe,
e R1 = 3,4-OCH2O, f R1 = 3-NO2; 4 a R, R1, X = H, 4-Br, O; b H, 4-F, O; c H, 4-F, S;
d H, 4-OMe, O; e H, 4-OMe, S; f H, 3,4-OCH2-O-, O; g H, 3-NO2, O; h Me, 3-Br, O;
i Me, 4-F, O; j Me, 4-OMe, O; 5 a R,R1 = H, 4-F; b R,R1 = Me, 4-F;
c R,R1 = H, OMe; d R,R1 = Me, OMe; e R,R1 = H, OCH2O
We used 1,3-cyclohexanedione (1a) or dimedone (1b), urea (2a) or thiourea (2b), and substituted
benzaldehydes 3a-f as starting materials. Reactions were carried out by continuously (9-10 h) boiling equimolar
quantities of diketone 1, aldehyde 3 and 3 equivalents of urea or thiourea 2 in ethanol in the presence of catalytic
amounts of H2SO4. In the case of 4-fluoro-, 4-methoxy-, or 3,4-methylenedioxybenzaldehydes a
__________________________________________________________________________________________
Riga Technical University, Riga LV-1048, Latvia; e-mail: marina@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 1, pp. 48-51, January, 2004. Original article submitted March 27, 2001.
0009-3122/04/4001-0043©2004 Plenum Publishing Corporation
43

precipitate of the corresponding octahydroxanthenes 5 formed from the reaction mixture on cooling. After
separating it and removing a portion of the solvent a mixture of octahydroquinazolines 4 and
octahydroxanthenes 5 was precipitated with water. Sequential treatment of the mixture with hot ethanol and
chloroform leads to pure quinazolines 4.
1
The structures of the quinazoline derivatives 4 were confirmed by data of H NMR spectra. In all cases
the proton signals at the neighboring C(4) (5.09-5.32 ppm, 3J = 3 Hz) and N(3) (7.65-7.83 ppm, 3J = 3 Hz) atoms
were clearly recorded. In the 2-thioxo derivatives 4c,e the signals of N(1)-H and N(3)-H were displaced towards
low field (4c 10.56 and 9.61, 4e 10.58 and 9.66 ppm) compared with the 2-oxo derivatives. The signals of the
protons of the carbocyclic fragment of molecules 4 and the proton at the C(4) atom, bearing an aromatic
substituent, are observed in the expected regions. Absorption bands for the vibrations of the NH bonds of
compound 4 were displayed in the IR spectra in the range of 3050-3370 cm-1, and the bands of the carbonyl
groups at 1700-1712 for C(2)=O and at 1610-1628 cm-1 for C(5)=O. Octahydroxanthenes 5c-e formed in the
reactions were obtained by the known procedures of [15,16] and the known compounds 5a,b were synthesized
by the procedure [16] for the first time (Tables 1, 2).
EXPERIMENTAL
The IR spectra were taken on a Specord IR 75 instrument for suspensions in nujol (1500-1800 cm-1) and
in hexachlorobutadiene (2000-3600 cm-1, the absorption bands for the C–H stretching vibrations at
1
2800-3050 cm-1 are not given). The H NMR spectra were recorded on a Bruker WH 90/DS (90 MHz)
spectrometer for solutions in CDCl3 and DMSO-d6, internal standard was HMDS.
TABLE 1. Characteristics of the Synthesized Compounds
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
H
N
Hal (S)
4a
4b
4c
4d
4e
4f
C14H13BrN2O2
C14H13FN2O2
C14H13FN2OS
C15H16N2O3
C15H16N2O2S
C15H14N2O4
C14H13N3O4
C16H17BrN2O2
C16H17FN2O2
C17H20N2O3
C19H17FO3
52.12
52.36
64.80
64.61
60.78
60.85
65.97
66.16
62.30
62.47
62.73
62.93
58.60
58.53
54.85
55.03
66.60
66.65
67.21
67.98
72.95
73.07
74.80
74.97
3.92
4.08
4.87
5.03
4.61
4.74
5.80
5.92
5.66
5.59
4.99
4.93
4.49
4.56
4.77
4.91
5.81
5.94
6.60
6.71
5.40
5.49
6.77
6.84
8.51
8.72
10.61
10.76
10.02
10.14
10.11
10.29
9.59
9.71
9.73
9.79
14.70
14.63
7.81
8.02
24.60
24.87
270-271
275-276
258-260
271-272
271-272
279-281
291-292
229-230
274-275
273-274
253-254
208-210
56
19
30
13
17
13
61
23
14
14
72
77
(11.40)
(11.60)
(10.90)
(11.12)
4g
4h
4i
22.60
22.88
9.60
9.72
9.12
9.33
4j
5a
5b
C23H25FO3
44

TABLE 2. Spectral Characteristics of the Synthesized Compounds
IR spectra,
Com-
pound
1Н NMR spectra, δ, ppm (coupling constant, J, Hz)
ν, cm-1
4а
1712, 1674, 1616,
1500; 3350,
3260-3150
DMSO-d6. 1.67-2.67 (6H, m, 3CH2); 5.16 (1H, d, 3J = 3, CH);
7.09-7.56 (4H, m, C6H4); 7.74 (1H, d, 3J = 3, NH);
9.46 (1H, br. s, NH)
4b
1702, 1672, 1650,
1624, 1510; 3350,
3260, 3150
DMSO-d6. 1.78-2.54 (6H, m, 3CH2); 5.23 (1H, d, 3J = 3, CH);
7.07-7.43 (4H, m, C6H4); 7.83 (1H, d, 3J = 3, NH);
9.58 (1H, br. s, NH)
4с
1630, 1610, 1570,
1515; 3250, 3200
DMSO-d6. 1.85-2.63 (6H, m, 3CH2); 5.21 (1H, d, 3J = 3, CH);
7.20-7.99 (4H, m, C6H4); 9.61 (1H, br. s, NH); 10.56 (1H, br. s, NH)
4d
1700, 1650, 1606,
1515; 3240, 3100
DMSO-d6. 1.78-2.67 (6H, m, 3CH2); 3.69 (3H, s, CH3);
5.12 (1H, d, 3J = 3, CH); 6.81 (2H, m, 3J = 8, С6Н4);
7.16 (2H, m, 3J = 8, C6H4); 7.65 (1H, br. s, NH);
9.38 (1H, br. s, NH)
4e
1628, 1572, 1510;
3260, 3200
DMSO-d6. 1.78-2.58 (6H, m, 3CH2); 3.71 (3H, s, CH3);
5.16 (1H, d, 3J = 3, CH); 6.87 (2H, m, 3J = 8, С6Н4);
7.27 (2H, m, 3J = 8, C6H4); 9.66 (1H, d, 3J = 3, NH);
10.58 (1H, br. s, NH)
4f
4g
4h
4i
1708, 1680, 1616,
1500; 3350-3050
DMSO-d6.1.74-2.53 (6H, m, 3CH2); 5.09 (1H, d, 3J = 3, CH);
5.92 (2H, s, CH2); 6.73 (3H, center m, С6Н4);
7.67 (1H, d, 3J = 3, NH); 9.45 (1H, br. s, NH)
DMSO-d6. 1.69-2.56 (6H, m, 3CH2); 5.32 (1H, d, 3J = 3, CH);
7.52-8.07 (5H, m, С6Н4, NH); 9.56 (1H, br. s, NH)
1710-1700, 1652,
1610, 1530; 3350,
3260, 3100
1702, 1660, 1622,
1575, 1535; 3370,
3260, 3140
DMSO-d6. 0.89 (3H, s, CH3); 1.07 (3H, s, CH3); 2.12 (2H, m, CH2);
2.41 (2H, m, СН2); 5.18 (1Н, d, 3J = 3, CH);
7.23-7.49 (4H, m, С6Н4); 7.81 (1H, br. s, NH); 9.56 (1Н, br. s, NH)
1707, 1660, 1615,
1530; 3300, 3220,
3130
DMSO-d6. 0.88 (3H, s, CH3); 1.07 (3H, s, CH3); 2.03 (2H, m, CH2);
2.34 (2H, m, СН2); 5.18 (1Н, d, 3J = 3, CH);
6.98-7.36 (4H, m, С6Н4); 7.81 (1H, br. s, NH); 9.54 (1Н, br. s, NH)
4j
1710, 1674, 1616,
1515; 3320, 3240,
3150
DMSO-d6. 0.92 (3H, s, CH3); 1.05 (3H, s, CH3); 2.05 (2H, m, CH2);
2.31 (2H, m, СН2); 3.72 (3H, s, CH3); 5.14 (1Н, d, 3J = 3, CH);
6.83 (2Н, m, 3J = 8, С6Н4); 7.25 (2Н, m, 3J = 8, C6H4);
7.74 (1H, br. s, NH); 9.45 (1Н, br. s, NH)
5a
5b
1680, 1660, 1622,
1602, 1510
DMSO-d6.1.93-2.66 (12H, m, 6CH2); 4.58 (1H, s, CH);
6.94-7.33 (4H, m, С6Н4, NH)
1685, 1668, 1633,
1518
СDCl3. 0.96 (6H, s, 2CH3); 1.09 (6H, s, 2CH3); 2.16 (4H, s, 2CH2);
2.46 (4H, s, 2CH2); 4.94 (1H, s, CH); 6.81-7.36 (4H, m, С6Н4)
4-(4-Bromophenyl)- (4a), 4-(4-Fluorophenyl)- (4b), 4-(4-Methoxyphenyl)- (4d), 4-(3,4-Methylene-
dioxyphenyl)- (4f), 4-(3-Nitrophenyl)-2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinazolines (4g), 4-(4-Fluoro-
phenyl)- (4c), 4-(4-Methoxyphenyl)-5-oxo-2-thioxo-1,2,3,4,5,6,7,8-octahydroquinazolines (4e), 4-(3-Bromo-
phenyl)- (4h), 4-(4-Fluorophenyl)- (4i), and 4-(4-Methoxyphenyl)-7,7-dimethyl-2,5-dioxo-1,2,3,4,5,6,7,8-
octahydroquinazolines (4j). Solution of diketone 1 (5 mmol), aldehyde 3 (5 mmol), and urea or thiourea
(15 mmol) in ethanol (30 ml) was boiled for 10 h in the presence of concentrated H2SO4 (0.15 ml). In the case of
quinazolines 4b,d,e,f,i,j a precipitate of the corresponding octahydroxanthene 5 (10-15% calculated on the
aldehyde, identification is given below) was formed on cooling the ethanolic solution. The xanthene 5 precipitate
was filtered off, ethanol (~20 ml) was distilled from the filtrate, the residue was poured into water (70 ml), the
solution neutralized to pH 7 with aqueous KOH solution, and left for 24 h. The precipitated solid, sometimes
oily, was filtered off or decanted from water. The substance obtained was triturated sequentially with hot ethanol
and chloroform to remove octahydroxanthene derivatives. The quinazolines 4, obtained in this way are pure
substances according to TLC data. Recrystallization of them from THF or DMF led to significant loss, but the
melting point did not change.
45

Octahydroxanthenes 5c, 5d, and 5e obtained in the synthesis of quinazolines 4d, 4f, and 4j gave no
depression of melting point with known samples [15,16]. 9-(4-Fluorophenyl)-4,5-dioxo-1,2,3,4,5,6,7,8-
octahydro-9H-xanthenes 5a,b were also obtained by us for the first time by the reaction of diketones 1a,b with
4-fluorobenzaldehyde. Their characteristics are given in Tables 1 and 2.
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