Synthesis of 2-aryl-5H-[1,3,4]-thiadiazolo[2,3-b]quinazolin-5-ones

Article abstract of DOI:10.1007/s10593-006-0148-5

3-Amino-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-ones were converted into 2-aryl-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-5-ones on treatment with carboxylic acids and POCl₃. 3-Arylmethylidenamino-2-thioxo-1,2,3,4- tetrahydroquinazolin-4-ones also cyclized to 2-aryl-5H-[1,3,4]thiadiazolo[2,3-b] quinazolin-5-ones when oxidized with potassium chlorate in acetic acid, but on heating they were deaminated to give 2-thioxo-1,2,3,4-tetrahydroquinazolin-4-one and aryl nitriles. 2006 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-006-0148-5

Chemistry of Heterocyclic Compounds, Vol. 42, No. 5, 2006
SYNTHESIS OF 2-ARYL-5H-[1,3,4]-
THIADIAZOLO[2,3-b]QUINAZOLIN-5-ONES
V. N. Britsun, A. N. Esipenko, and M. O. Lozinskii
3-Amino-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-ones
were
converted
into
2-aryl-5H-
[1,3,4]thiadiazolo[2,3-b]quinazolin-5-ones on treatment with carboxylic acids and POCl3.
3-Arylmethylidenamino-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-ones also cyclized to 2-aryl-5H-
[1,3,4]thiadiazolo[2,3-b]quinazolin-5-ones when oxidized with potassium chlorate in acetic acid, but on
heating they were deaminated to give 2-thioxo-1,2,3,4-tetrahydroquinazolin-4-one and aryl nitriles.
Keywords: 3-amino-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-one, 3-arylmethylidenamino-2-thioxo-
1,2,3,4-tetrahydroquinazolin-4-ones, aryl nitriles, 2-aryl-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-5-ones,
2-thioxo-1,2,3,4-tetrahydroquinazolin-4-one, potassium chlorate, deamination, cyclization.
3-Amino-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-one (1) contains two reactive centers – thioxo and
amino groups – and can be used for the synthesis of condensed heterocycles [1-5], including some with
antihypertonic, antibacterial, and fungicidal properties [4, 5]. Hence it is a timely synthetic problem to prepare
new heterocycles containing the quinazolin-4-one unit.
The aim of the present study was the synthesis of 2-aryl-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-5-ones,
which, using the general methods for the synthesis of condensed systems containing 1,3,4-thiadiazole [6], may
be obtained by the condensation of compound 1 with carboxylic acids in the presence of dehydrating agents, and
also by the oxidative cyclization of 3-arylmethylidenamino-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-ones.
We have established that 2-aryl-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-5-ones 3a-e are formed when
compound 1 was heated with aromatic carboxylic acids 2a-e in POCl3 for 2 h. The yields of 3a-e were 66-73%.
1
In the H NMR spectra of compounds 3a-e there are characteristic signals of the protons of the
quinazoline and aromatic rings (7.11-8.41 ppm), while absorption bands for the C=O and C=N groups
(1690-1710 and 1580-1610 cm-1 respectively) were observed in their IR spectra.
3-Arylmethylidenamino-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-ones 5a-d were obtained in 67-79%
yields by the reaction of compound 1 with the aromatic aldehydes 4a-d in acetic acid. The characteristic signals
of the protons of the azomethine (N=CH) and thioamide groups (NH–C=S) at 8.51- 8.91 and 13.00-13.21 ppm
respectively were observed in the 1H NMR spectra of the azomethine 5a-d.
In attempting to carry out the oxidative cyclization of the azomethines 5a,b,d into the
[1,3,4]thiadiazolo[2,3-b]quinazolin-5-ones 3 by heating in nitrobenzene (as was suggested for the preparation of
[1,2,4]thiazolo[3,4-b][1,3,4]thiadiazole from 5-thioxo-4-phenylmethylidenamino-4H-1,2,4-thiazole [7]), we
established that cyclization did not occur under these conditions but instead the azomethines 5a,b,d underwent
deamination to give 2-thioxo-1,2,3,4-tetrahydroquinazolin-4-one 6 and the aryl nitriles 7a-c. The same
conversion occurred on heating azomethines 5a,b,d at 200°C without a solvent.
__________________________________________________________________________________________
Institute of Organic Chemistry, Ukraine National Academy of Sciences, Kiev 02094, Ukraine; e-mail:
esipenko@iflab.kiev.ua. Translated from Khimiya Geteotsiklicheskikh Soedinenii, No. 5, 787-791, May, 2006.
Original article submitted April 28, 2005.
0009-3122/06/4205-0693©2006 Springer Science+Business Media, Inc.
693

O
O
NH2
ArCOOH
N
S
N
N
2a–e
Ar
S
N
H
POCl3
N
3a–e
1
ArCHO
KClO3
MeCOOH
4a–d
MeCOOH
O
O
Ar
N
N
NH
ArCN
+
200 oC
S
S
N
N
7a–c
H
H
5a–d
6
O
N
Ph
1. EtONa
2. I2
N
N
5a
N
S
S
EtOH
N
N
Ph
O
8
2-7 a Ar = Ph, b Ar = 4-MeOC6H4; 2c–5c Ar = 3,4-(MeO)2C6H3; 2d, 3d Ar = 4- O2NC6H4;
4d, 5d, 7c Ar = 3-O2NC6H4; 2e, 3e Ar = 3-thienyl
In all probability, the deamination of the azomethines 5a,b,d is explained by the fact that the electron
density of atom N(3) of the 1,3-diazine ring of the azomethines 5a-d is partly shifted towards the C=O and C=S
acceptor groups and this, in turn, makes the N(3)–N bond unstable and makes possible its easy rupture at high
temperatures.
In an attempt to oxidatively cyclize azomethine 5a it was found that di(3-phenylmethylidenamino-3,4-
dihydro-4-oxoquinazolin-2-yl) disulfide 8 was formed from its reaction with iodine in the presence of sodium
ethoxide.
We have developed a new method for the oxidative cyclization of the azomethines 5 into
[1,3,4]thiadiazolo[2,3-b]quinazolin-5-ones 3 by reacting the azomethines 5 with potassium chlorate in boiling
acetic acid. However the reaction works only with the azomethines 5b,c which contain donor substituents in the
phenyl ring, and the yields of compounds 3b,c were only 32-38% as a result of side reactions. It is very likely
that this reaction has a free radical mechanism as in the case of the oxidative cyclization of
1-(R-methylidenamino)-2-amino(hydroxy)benzenes into 2-R-benzimidazole (2-R-benzoxazole) with lead
tetraacetate [8,9] and copper(II) acetate [10] in acetic acid.
So we have developed two methods for the synthesis of 2-aryl-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-5-
ones, one of which (heating 3-amino-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-one with aromatic carboxylic acids
in POCl3) has preparative value.
694

TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %
mp, °С
С
H
N
3a*
3b
3c
3d
3e
5a
5b
5c
5d
6
C15H9N3OS
64.72
64.50
61.85
62.12
59.89
60.17
55.82
55.55
55.01
54.72
63.82
64.04
62.00
61.72
60.07
59.81
3.41
3.25
3.81
3.58
4.02
3.86
2.20
2.49
2.24
2.47
4.21
3.94
4.04
4.21
4.19
4.43
15.29
15.04
13.33
13.58
12.60
12.38
17.01
17.28
14.97
14.73
15.17
14.94
13.22
13.50
12.52
12.31
227-230
225-227
262-265
308-310
262-264
272-274
282-284
278-280
273-275
73
68
69
70
66
75
73
67
79
64
C16H11N3O2S
C17H13N3O3S
C15H8N4O3S
C13H7N3OS2
C15H11N3OS
C16H13N3O2S
C17H15N3O3S
C15H10N4O3S
C8H6N2OS
55.50
55.21
54.15
53.92
2.80
3.09
3.20
3.39
16.92
17.17
16.00
15.72
299-302
(304-305 [11])
7a
7b
C7H5N
81.76
81.53
71.96
72.17
5.16
4.89
5.42
5.30
13.40
13.58
10.35
10.52
—*2
59
52
C8H7NO
53-55
(57-59 [13])
7c
C7H4N2O2
56.48
56.76
3.01
2.72
19.20
18.91
112-115
(115-117 [14])
111-117
49
69
8
C30H20N6О2S2
63.98
64.27
3.50
3.60
15.21
14.99
299-301
_______
* Found, %: S 11.22. Calculated %: S 11.48.
*2 Bp 185-188°C (760 mmHg); bp 191°C [12].
TABLE 2. IR and 1H NMR Spectra of the Compounds Synthesized
Com-
pound
IR spectrum, ν, cm-1
1Н NMR, δ, ppm (J, Hz)
1
2
3
3a
3b
3c
3100, 1700 (С=О), 1590 (C=N),
1565, 1555, 1505, 1475
7.54 (2Н, m, НAr); 7.64 (3Н, m, НAr);
7.87 (1Н, m, НAr); 8.00 (2H, m, НAr);
8.29 (1H, d, J = 7.5, НAr)
3000, 1700 (С=О), 1610 (C=N),
1580, 1550, 1505, 1460
3.84 (3Н, s, СН3О); 7.11 (2H, d, J = 8.1, p-С6Н4);
7.53 (1H, m, НAr); 7.65 (1H, d, J = 8.4, НAr);
7.88 (3H, m, НAr); 8.25 (1H, d, J = 8.4, НAr)
3100, 3000, 1690 (С=О), 1600
(C=N), 1580, 1560, 1520, 1470
3.86 (3Н, s, СН3О); 3.90 (3Н, s, СН3О);
7.14 (1H, d, J = 7.8, НAr); 7.46-7.57 (3H, m, НAr);
7.67 (1H, d, J = 7.8, НAr); 7.88 (1H, m, НAr);
8.26 (1H, d, J = 8.7, НAr)
3d
3e
3100, 1710 (С=О), 1600 (C=N),
1580, 1560, 1470, 1410
7.58 (1H, m, НAr); 7.70 (1H, d, J = 7.8, НAr);
7.91 (1H, m, НAr); 8.25-8.31 (3H, m, НAr);
8.41 (2H, d, J = 8.7, p-C6Н4)
3100, 1700 (С=О), 1610 (C=N), 7.31 (1Н, d. d, J1 = 5.1, J2 = 2.8, HHet-4);
1580, 1560, 1505, 1465
7.55 (1H, m, НAr); 7.68 (1Н, d, J = 7.8, HAr);
7.86-7.93 (2H, m, НAr); 8.03 (1H, d, J = 5.1,
HHet-3); 8.27 (1H, d, J = 8.4, HAr)
695

TABLE 2 (continued)
1
2
3
5a
5b
3250, 1680 (С=О), 1620 (C=N),
1540, 1490, 1410
7.32-7.40 (2Н, m, НAr); 7.59 (3Н, m, НAr);
7.74 (1Н, m, НAr); 7.95-8.01 (4H, m, НAr);
8.67 (1H, s, N=CH); 13.09 (1Н, s, NH)
3.87 (3Н, s, СН3О); 7.12 (2H, d, J = 8.5,
p-С6Н4); 7.36 (1H, m, НAr); 7.44 (1H, d,
J = 8.1, НAr); 7.76 (1H, m, НAr); 7.88 (2H, d,
J = 8.5, p-С6Н4); 8.01 (1H, d, J = 8.1, НAr);
8.53 (1H, s, N=CH); 13.00 (1Н, s, NH)
3250, 3000, 1660 (С=О), 1630
(C=N), 1610, 1570, 1540, 1490
5c
5d
8
3200, 3000, 1710 (С=О), 1620
(C=N), 1600, 1580, 1540, 1520
3.85 (3Н, s, СН3О); 3.87 (3Н, s, СН3О); 7.14 (1H,
d, J = 8.4, НAr); 7.37 (1H, m, НAr); 7.45 (2H, m,
НAr); 7.55 (1Н, d, J = 1.2, НAr); 7.78 (1H, m, НAr);
8.00 (1H, d, J = 7.2, НAr); 8.51 (1H, s, N=CH);
13.08 (1Н, s, NH)
3200, 3100, 3000, 1690 (С=О),
1620 (C=N), 1540, 1490
7.39 (1H, m, НAr); 7.47 (1H, d, J = 8.4, НAr);
7.81 (1H, m, НAr); 7.90 (1H, m, НAr); 8.02 (1H, d,
J = 7.5, НAr); 8.39 (1H, d, J = 7.8, НAr);
8.50 (1H, d, J = 8.4, НAr); 8.76 (1H, c, НAr);
8.91 (1Н, s, N=CH); 13.21 (1Н, s, NH)
3100, 1680 (С=О), 1600 (C=N),
1580, 1550, 1470
7.52-7.70 (4H, m, НAr); 8.02 (2Н, m, НAr);
8.15 (2Н, d, J = 7.5, НAr); 9.68 (2H, s, N=CH)
EXPERIMENTAL
1H NMR spectra were recorded with a Varian 300 (300 MHz) in DMSO-d6 with TMS as internal
standard. IR spectra of KBr disks were recorded on a UR-20 machine. The physico-chemical and spectroscopic
characteristics of the compounds synthesized are cited in Tables 1 and 2.
Synthesis of 2-Aryl-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-5-ones 3a-e. A. A solution of the acids
2a-e (2.1 mmol) and 3-amino-2-thioxo-1,2,3,4-tetrahydroquinazoline-4-one (0.386 g, 2 mmol) in POCl3 (2.30 g,
15 mmol) was refluxed for 2h. The mixture was cooled, poured into cold water (10 ml), the products 3a-e were
filtered off, washed with 5% NaOH solution (5 ml), water (10 ml), dried and recrystallized from acetic acid.
B. A solution of azomethine 5b,c (10 mmol) and potassium chlorate (0.49 g, 4 mmol) in acetic acid
(10 ml) was boiled for 30 min, cooled, and diluted with water (30 ml). The precipitate of 3b,c was filtered off,
dried, and recrystallized from acetic acid. Yields: 3b 38%, 3c 32%.
Synthesis of 3-Arylmethylidenamino-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-ones 5a-d. A solution
of an aldehyde 4a-d (10 mmol) and compound 1 (10 mmol) in acetic acid (15 ml) was boiled for 7 h, then cooled
and the azomethine 5a-d was filtered off, washed with diethyl ether (2 x 5 ml), and dried.
Deamination of Compounds 5a,b,d. The azomethines 5a,b,d (10 mmol) were heated at 200°C for
30 min, then cooled and treated with diethyl ether (10 ml). The precipitate of 2-thioxo-1,2,3,4-
tetrahydroquinazolin-4-one 6 was filtered off and dried. The ether solution was evaporated and compound 7a
was purified by distillation while compounds 7b,c were recrystallized from 2-propanol.
Synthesis of Di(3-phenylmethylidenamino-3,4-dihydro-4-oxoquinazolin-2-yl) Disulfide (8). A
solution of iodine (0,635 g, 2.5 mmol) in ethanol (10 ml) was added drop-wise to a solution of azomethine 5a
(1.405 g, 5 mmol) and sodium ethoxide (5 mmol) in anhydrous ethanol (10 ml). The precipitate of compound 8
was filtered off, dried and recrystallized from benzonitrile.
696

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