Synthesis of some new thiazolo[3,2-a]pyridines and related heterocyclic systems

Article abstract of DOI:10.1016/S0014-827X(99)00130-5

New 2,7-disubstituted 5-amino-6,8-dicyano-2,3-dihydro-3-oxo thiazolo[3,2-a]pyridines have been prepared. Their cyclization with formamide, nitrous acid and triethylorthoformate afforded a series of polycyclic heterocycles containing condensed pyrimidine and triazine rings. Antifungal tests were also performed. Copyright (C) 2000 Elsevier Science S.A.

Full text of DOI:10.1016/S0014-827X(99)00130-5

www.elsevier.nl/locate/farmac
Il Farmaco 55 (2000) 109–118
Synthesis of some new thiazolo[3,2-a]pyridines and related
heterocyclic systems
Marzoog S. Al-Thebeiti *
Department of Chemistry, Faculty of Applied Sciences, Umm Al-Qura Uni6ersity, Makkah Almukkarramah, PO Box 6876, Saudi Arabia
Received 15 July 1999; accepted 8 November 1999
Abstract
New 2,7-disubstituted 5-amino-6,8-dicyano-2,3-dihydro-3-oxo thiazolo[3,2-a]pyridines have been prepared. Their cyclization
with formamide, nitrous acid and triethylorthoformate afforded a series of polycyclic heterocycles containing condensed
pyrimidine and triazine rings. Antifungal tests were also performed. © 2000 Elsevier Science S.A. All rights reserved.
Keywords: Thiazolopyridines; Thiazolopyridopyrimidines; Thiazolopyridotriazines
1
. Introduction
and thioglycolic acid (2:2:1 molar ratio) in ethanol with
a catalytic amount of piperidine (Method A). The
treatment of 2 with thioglycolic acid in a molar ratio of
2:1 in the presence of a catalytic amount of piperidine
afforded the structural evidence of 3 (Method B)
(Scheme 1).
Fused heterocyclic-like thiazolopyridopyrimidine 4
and thiazolopyrido-1,2,3-triazines 5 were produced by
the reaction of thiazolo[3,2-a]pyridine (3) with for-
mamide and nitrous acid, respectively (Scheme 1).
Afterwards, our attempts were directed towards the
synthesis of polyfunctional 7-arylsubstituted 2,3-dihy-
Several annulated pyridines isolated from natural
sources possess a broad spectrum of therapeutic activ-
ity. Members of this class were found to be protectors
against gastric erosion [1] and coronary vasodilator and
blood-pressure-heightening agents [2]. They also proved
to be tuberculostatic, antiviral, fungicidal, insecticidal
and pesticidal [3,4]. In addition to the previously men-
tioned properties, many thiazolopyridines, thiazolopyr-
imidines and thiazolotriazines are used as therapeutic
tools [5–7]. The quinoline derivatives were reported to
be antibacterial and antifungal agents [8–13]. As a
continuation of our previous work [14–23] and consid-
ering the particular interest inherent in the above-men-
tioned properties, we aimed to synthesize the title
compounds in the hope that members of them would
find interesting biological applications.
dro-7H-2[8%-hydroxyquinolin-5%-yl
methylidene]thia-
zolo[3,2-a]pyridines by reaction of 6 with arylidene-
malonodinitriles or by using equimolar amounts of 1
and arylaldehyde instead of 2 mol of 1 as previously
described (Scheme 2).
The thiazolopyridine derivatives 7a–g proved to be a
useful key intermediate in the synthesis of fused hetero-
cyclic derivatives. Thus, when 7a–g were reacted with
triethylorthoformate they gave the corresponding ethy-
oxymethylene derivatives 8a–g, which by treatment
with aniline compounds underwent aminolysis and cy-
clization to give in a ‘one step reaction’ fused 9a–g.
Furthermore, 7a–g gave the corresponding thiazolopyr-
idopyrimidine derivatives 10a–g by treatment with for-
mamide and the thiazolopyridotriazine derivatives 11a–
g by means of diazotization with sodium nitrite in a
mixture of hydrochloric and acetic acid (Scheme 3).
2. Chemistry
5
-Amino-2,3-dihydro-7H-7-(8%-hydroxyquinolin-5%-
yl)-2-(8%%-hydroxyquinolin-5%%-yl methylidene)-3-oxothia-
zolo[3,2-a]pyridin-6,8-dicarbonitrile (3) was prepared
by the reaction of the aldehyde 1 with malononitrile
*
Tel.: +966-2-559 4010; fax: +966-2-558 5830.
E-mail address: althebeiti@yahoo.com (M.S. Al-Thebeiti)
0014-827X/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(99)00130-5

110
M.S. Al-Thebeiti / Il Farmaco 55 (2000) 109–118
The chlorine atom reactivity of 11c was highlighted by
its easy displacement with nucleophilic reagents such as
hydrazine hydrate to give the hydrazino derivative 12
which, in turn, proved to be a useful intermediate.
In fact, the triazolo derivatives 13 and 14 were pro-
duced from the reaction of 12 with formic acid and
carbon disulfide, respectively. In addition, treatment of
quinolin-5%-yl
methylidene)-9-phenyl-2,3,5,9-tetrahy-
drothiazolo[3,2-a] [1,8]naphthyridin-7,10-dicarbo-nitrile
(16).
3
. Experimental
All melting points are uncorrected. IR (cm ) spec-
1
2 in acetic acid and an aqueous solution of sodium
nitrite, at room temperature, gave the azido derivative
5, the structure of which was assigned on the basis of
−1
tra were recorded on a Pye–Unicam SP3-100 spec-
trophotometer. H NMR spectra were recorded on a 90
MHz Varian EM-390 NMR spectrometer in suitable
deuterated solvents using TMS as an internal standard.
Mass spectra were recorded on a Jeol JMS 600 instru-
ment. Elemental analyses were determined on a
1
1
−
1
its IR spectral data (N stretching at 2140 cm ), thus
3
ruling out the alternative tetrazolo structure 15c. Fi-
nally, the key intermediate 7c when reacted with ethyl
cyanoacetate afforded 8-amino-3,6-dioxo-2-(8%-hydroxy-
Scheme 1.
Scheme 2.

M.S. Al-Thebeiti / Il Farmaco 55 (2000) 109–118
111
Scheme 3.
Perkin–Elmer 240 C. Analyses indicated by the sym-
bols were within 90.4% of the theoretical values.
solvent was evaporated and the solid product was
collected by filtration and recrystallized from ethanol as
pale brown crystals, m.p. 230–232°C (58% yield). IR (w
−
1
3.1. 5-Amino-2,3-dihydro-7H-7-(8%-hydroxyquinolin-5%-
cm , KBr): 3250–3350 (NH
2
), 2200 (CN), 1700
(CꢀO). H NMR (l ppm, DMSO-d ): 6.00 (s, 2H,
NH ), 6.60–8.70 (m, 14H, arom.). MS, m/e 516. Anal.
C H N O S (C, H, N, S).
1
yl)-2-(8%%-hydroxyquinolin-5%%-yl methylidene)-3-
oxothiazolo[3,2-a]pyridin-6,8-dicarbonitrile (3)
6
2
28
16
6
3
3.1.1. General procedure
3
.2. 8-Amino-2,3-dihydro-9H-9-(8%-hydroxyquinolin-5%-
3.1.1.1. Method A. A solution of 1 (0.02 mol), malono-
yl)-2-(8%%-hydroxyquinolin-5%%-yl methylidene)-3-oxo
nitrile (0.02 mol) and thioglycolic acid (0.01 mol) in
ethanol (50 ml) and a catalytic amount of piperidine
was heated under reflux for 5 h. The reaction mixture
was cooled at room temperature (r.t.) and the solution
was concentrated by evaporation under reduced pres-
sure and then the product was collected and recrystal-
lized from ethanol as pale brown crystals, m.p.
thiazolo[2%,3%:1,6]pyrido[2,3-d]pyrimidin-10-carbonitrile
(4)
A mixture of 3 (0.01 mol) and formamide (15 ml) was
refluxed for 2 h. The solid product thus formed, after
cooling, was filtered off and recrystallized from dioxane
as yellowish–brown crystals, m.p. 296–298°C (dec.)
−
1
2
30–232°C (58% yield). Anal. C H N O S (C, H, N,
(51% yield). IR (w cm , KBr): 3500 (OH), 3200–3300
2
8
16
6
3
1
S).
(NH ), 2200 (CN), 1710 (CꢀO). H NMR (l ppm,
2
CF COOD): 7.20 (s, 1H, pyrimidine ring), 7.25 (s, 1H,
3
3.1.1.2. Method B. A solution of 2 (0.02 mol) and
pyridine ring), 7.40 (s, 1H, methylidene), 7.50–8.30 (m,
thioglycolic acid (0.01 mol) in ethanol (50 ml) and a
12H, arom.). MS, m/e 543. Anal. C H N O S (C, H,
29
17
7
3
catalytic amount of piperidine was refluxed for 5 h. The
N, S).

112
M.S. Al-Thebeiti / Il Farmaco 55 (2000) 109–118
3
.3. 8-Chloro-2,3-dihydro-9H-9-(8%-hydroxyquinolin-5%-
acetic acid as brown crystals, m.p. \310°C (42%
−
1
yl)-2-(8%%-hydroxyquinolin-5%%-yl methylidene)-3-
oxothiazolo[2%,3%:1,6]pyrido[2,3-d][1,2,3]-
triazin-10-carbonitrile (5)
yield). IR (w cm , KBr): 3500 (OH), 2210 (CN), 1700
1
(CꢀO). H NMR (l ppm, CDCl ): 6.90–8.10 (m, 14H,
3
arom.). MS, m/e 563/565. Anal. C H ClN O S (C, H,
28
14
7
3
Cl, N, S).
To a cold stirred solution of 3 (0.01 mol) in a mixture
of acetic acid (20 ml) and hydrochloric acid (10 ml)
3
.4. 2,3-Dihydro-4-oxo-5-(8%-hydroxyquinolin-5%-yl-
sodium nitrite (0.01 mol in 10 ml H O) was added for
2
methylidene)thiazolo-2-carbonitrile (6)
30 min and the stirring was continued for 3 h in an ice
bath. The product was collected and recrystallized from
A mixture of malononitrile (0.01 mol) and thiogly-
colic acid (0.01 mol) was heated under reflux at 120°C
for 30 min, then absolute ethanol (50 ml) and 8-hydroxy-
quinoline-5-carboxyaldehyde were added and the mix-
ture was refluxed for 6 h. The solvent was evaporated
and the solid product was collected and recrystallized
from dioxane as pale brown crystals, m.p. 211–213°C
Table 1
Antifungal activity of thiazolopyridopyrimidines and thiazolopyrido-
triazines a
Comp. P. chryso-
F. monili-
R. stalonifer A. terreus
genum
forme
−
1
3
4
5
6
7
7
7
7
7
7
7
8
8
8
8
8
8
8
9
9
9
9
9
9
9
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
9
7
5
9
(dec.) (39% yield). IR (w cm , KBr): 3490 (OH), 2200
1
10
12
8
8
16
(
CN), 2890 (CH aliph.), 1710 (CꢀO). H NMR (l ppm,
15
5
11
CDCl ): 4.50 (s, 2H, CH ), 6.80–7.90 (m, 7H, arom.).
3
2
MS, m/e 295. Anal. C H N O S (C, H, N, S).
15
9
3
2
a
b
c
d
e
f
g
a
b
c
d
e
f
g
a
b
5
9
5
8
10
11
8
10
6
3
.5. 7-Arylsubstituted 5-amino-2,3-dihydro-7H-2-
(8%-hydroxyquinolin-5%-yl-methylidene)-3-oxothiazolo-
3,2-a]pyridin-6,8-dicarbonitrile (7a–g)
12
8
7
11
8
[
5
10
10
11
11
9
3.5.1. General procedure
8
These compounds were prepared as previously de-
6
scribed in method A by using 1 (0.01 mol) and the
selected aldehydes (0.01 mol) instead of 1 (0.02 mol) or
by the interaction of 6 (0.01 mol) and arylidene-
malononitrile (0.01 mol) in ethanol (50 ml) on heating
under reflux for 7 h. The reaction mixture was cooled
and the product was collected by filtration and recrys-
tallized from the proper solvent.
13
9
11
8
11
8
7
c
d
e
f
11
10
8
6
9
12
9
9
7
12
7
a: Yellowish–brown crystals from dioxane, m.p.
g
−1
2
(
48–250°C (51% yield). IR (w cm , KBr): 3080–3180
NH ), 2200 (CN), 1690 (CꢀO). H NMR (l ppm,
DMSO-d ): 5.20 (s, 2H, NH ), 6.5–7.7 (m, 12H,
0a
0b
0c
0d
0e
0f
0g
1a
1b
1c
1d
1e
1f
1g
2
6
1
2
5
11
9
8
7
6
2
arom.). MS, m/e 490. Anal. C H N O S (C, H, N, S).
26
14
6
3
11
6
12
7
b: Brown crystals from ethanol, m.p. 296–298°C
−1
(
(
(
61% yield). IR (w cm , KBr): 3130–3230 (NH ), 2200
CN), 1700 (CꢀO). H NMR (l ppm, DMSO-d ): 5.20
s, 2H, NH ), 6.50–7.90 (m, 11H, arom.). MS, m/e 439.
2
9
10
12
10
11
14
12
10
11
11
9
11
16
13
15
17
14
15
13
10
14
12
9
1
6
22
17
19
25
18
17
17
7
19
17
20
21
19
18
18
13
17
19
11
6
2
Anal. C H N O S (C, H, N, S).
23
13
5
3
7
c: Brown crystals from diluted ethanol, m.p. 162–
−1
1
(
64°C (dec.) (53% yield). IR (w cm , KBr): 3200–3300
1
NH ), 2200 (CN), 1700 (CꢀO). H NMR (l ppm,
2
CF COOD): 6.90–8.20 (m, 13H, arom.). Anal.
3
3
4
5
6
12
16
8
C H N O S (C, H, N, S).
25
15
5
2
14
10
9
7
d: Yellowish–brown crystals from dioxane, m.p.
−1
2
3
05–207°C (dec.) (56% yield). IR (w cm , KBr):
230–3350 (NH ), 2200 (CN), 1700 (CꢀO). H NMR (l
ppm, CF COOD): 7.30–9.10 (m, 12H, arom.). Anal.
4
1
2
a
The activity is expressed as the diameter of the inhibitor zone
3
(mm) and only the active compounds are indicated.
C H ClN O S (C, H, Cl, N, S).
25
14
5
2

M.S. Al-Thebeiti / Il Farmaco 55 (2000) 109–118
113
Table 2
Analysis data of synthesized compounds
Comp.
Formula (mol. wt.)
Analysis (calc./found)
C
H
Cl
N
S
3
4
5
6
C28H16N O S
65.11
65.22
3.12
3.21
16.27
16.16
6.21
6.11
6
3
(516.53)
C29H17N O S
64.08
64.19
3.15
3.08
18.04
18.13
5.90
5.83
7
3
(543.56)
C28H14ClN O S
59.63
59.55
2.50
2.61
6.29
6.32
17.38
17.48
5.69
5.74
7
3
(563.98)
C15H N O S
61.01
61.11
3.07
2.96
14.23
14.21
10.86
10.76
9
3
2
(295.32)
7
7
7
7
7
7
7
8
8
8
8
8
8
8
9
9
9
9
9
9
a
b
c
d
e
f
C26H14N O S
63.67
63.77
2.88
2.82
17.13
17.21
6.54
6.46
6
3
(490.50)
C23H13N O S
62.86
62.78
2.98
3.04
15.94
15.87
7.30
7.39
5
3
(439.45)
C25H15N O S
66.80
66.71
3.36
3.44
15.58
15.67
7.13
7.22
5
2
(449.49)
C25H14ClN O S
62.05
62.11
2.92
2.86
7.33
7.28
14.47
14.54
6.62
6.56
5
2
(483.93)
C25H14N O S
60.72
60.83
2.85
2.76
17.00
16.91
6.48
6.58
6
4
(494.48)
C26H17N O S
67.37
67.48
3.70
3.80
15.11
15.16
6.92
7.02
5
2
(463.51)
g
a
b
c
d
e
f
C26H17N O S
65.13
65.23
3.57
3.49
14.61
14.55
6.69
6.80
5
3
(479.51)
C29H18N O S
63.73
63.83
3.32
3.41
15.38
15.42
5.87
5.97
6
4
(546.56)
C26H17N O S
63.02
63.12
3.46
3.52
14.13
14.27
6.47
6.42
5
4
(495.51)
C28H19N O S
66.52
66.43
3.79
3.72
13.85
13.92
6.34
6.41
5
3
(505.55)
C28H18ClN O S
62.28
62.39
3.36
3.41
6.57
6.66
12.97
12.89
5.94
5.87
5
3
(540.00)
C28H18N O S
61.09
61.20
3.30
3.36
6
5
(550.55)
15.26
5.82
C29H21N O S
67.04
67.14
4.07
4.12
13.48
13.56
6.17
6.22
5
3
(519.58)
g
a
b
c
d
e
f
C29H21N O S
65.04
65.12
3.95
3.86
13.08
13.14
5.99
5.91
5
4
(535.58)
C33H19N O S
66.77
66.88
3.23
3.29
16.52
16.61
5.40
5.34
7
3
(593.62)
C30H18N O S
66.41
66.32
3.34
3.30
15.49
15.41
5.91
5.99
6
3
(542.57)
C32H20N O S
69.55
69.66
3.65
3.71
15.21
15.31
5.80
5.90
6
2
(552.61)
C32H19ClN O S
65.47
65.57
3.26
3.31
6.04
6.11
14.32
14.25
5.46
5.42
6
2
(587.05)
C32H19N O S
64.32
64.20
3.20
3.12
16.41
16.49
5.36
5.42
7
4
(597.61)
C33H22N O S
69.95
70.05
3.91
4.01
14.83
14.91
5.66
5.72
6
2
(566.64)

1
14
M.S. Al-Thebeiti / Il Farmaco 55 (2000) 109–118
Analysis (calc./found)
Table 2 (Continued)
Comp.
Formula (mol. wt.)
C33H22N O S
C
H
Cl
N
S
9
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
g
68.03
68.18
3.81
3.92
14.42
14.51
5.50
5.44
6
3
(582.64)
0a
0b
0c
0d
0e
0f
0g
1a
1b
1c
1d
1e
1f
1g
2
C27H15N O S
62.66
62.76
2.92
3.01
18.95
19.02
6.19
6.27
7
3
(517.52)
C24H14N O S
61.80
61.91
3.03
3.12
18.02
18.16
6.87
6.96
6
3
(466.47)
C26H16N O S
65.54
65.65
3.38
3.44
17.64
17.71
6.73
6.69
6
2
(476.51)
C26H15ClN O S
61.12
61.23
2.96
3.03
6.94
7.03
16.45
16.56
6.27
6.33
6
2
(510.96)
C26H15N O S
59.88
59.75
2.90
3.01
18.80
18.71
6.15
6.22
7
4
(521.51)
C27H18N O S
66.11
66.12
3.70
3.62
17.13
17.07
6.54
6.61
6
2
(490.54)
C27H18N O S
64.02
64.12
3.58
3.62
16.59
16.67
6.33
6.21
6
3
(506.54)
C26H12ClN O S
58.05
58.17
2.25
2.34
6.59
6.54
18.23
18.17
5.96
6.06
7
3
(537.94)
C23H11ClN O S
56.74
56.88
2.28
2.36
7.28
7.33
17.26
17.34
6.58
6.62
6
3
(486.89)
C25H13ClN O S
60.43
60.53
2.64
2.71
7.13
7.23
16.91
16.94
6.45
6.39
6
2
(496.93)
C25H12Cl N O S
56.51
56.60
2.28
2.27
13.34
13.42
15.82
15.90
6.03
6.19
2
6
2
(531.38)
C25H12ClN O S
55.41
55.31
2.23
2.26
6.54
6.49
18.09
18.13
5.92
5.81
7
4
(541.93)
C26H15ClN O S
61.12
61.22
2.96
3.01
6.94
6.89
16.45
16.51
6.27
6.22
6
2
(510.96)
C26H15ClN O S
59.26
59.36
2.87
2.82
6.73
6.86
15.95
15.88
6.08
6.12
6
3
(526.96)
C25H16N O S
60.97
60.90
3.27
3.31
22.75
22.81
6.51
6.49
8
2
(492.51)
3
C26H14N O S
62.15
62.20
2.81
2.78
22.30
22.34
6.38
6.42
8
2
(
502.51)
C26H14N O S
2 2
4
58.42
58.34
2.64
2.66
20.96
20.91
11.99
12.07
8
(534.57)
5
C25H13N O S
59.64
59.58
2.60
2.57
25.04
25.10
6.37
6.42
9
2
(503.50)
6
C28H16N O S
65.11
65.16
3.12
3.15
16.27
16.22
6.21
6.25
6
3
(516.53)
1
7
e: Brown crystals from ethanol, m.p. 215–217°C
3200–3300 (NH ), 2210 (CN), 1720 (CꢀO). H NMR (l
2
−
1
(
3
(
1
dec.) (44% yield). IR (w cm , KBr): 3500 (OH),
150–3250 (NH ), 2220 (CN), 1720 (CꢀO). H NMR
l ppm, CDCl ): 5.50 (s, 2H, NH ), 6.80–8.10 (m,
2H, arom.). MS, m/e 494. Anal. C H N O S (C, H,
N, S).
7
ppm, CF COOD): 2.30 (s, 3H, CH ), 7.50–9.00 (m,
12H, arom.). Anal. C H N O S (C, H, N, S).
7g: Pale brown crystals, m.p. 275–277°C. (47%
yield). IR (w cm , KBr): 3500 (OH), 3230–3350
(NH ), 2200 (CN), 1700 (CꢀO). H NMR (l ppm,
CF COOD): 2.10 (s, 3H, CH ), 7.80–8.90 (m, 12H,
3
3
1
2
26 17 5 2
3
2
−
1
2
5
14
6
4
1
2
f: Yellowish–brown crystals from ethanol, m.p.
3
3
−
1
2
90–292°C. (42% yield). IR (w cm , KBr): 3500 (OH),
arom.). Anal. C H N O S (C, H, N, S).
26 17 5 3

M.S. Al-Thebeiti / Il Farmaco 55 (2000) 109–118
115
3
.6. 7-Arylsubstituted 2,3-dihydro-5-ethoxy-
3.7. 9-Arylsubstituted 2,3-dihydro-9H-2-(8%-hydroxy-
quinolin-5%-yl methylidene)-8-imino-3-oxo-7-
phenylthiazolo [2%,3%:1,6]pyrido[2,3-d]pyrimidin-10-
carbonitrile (9a–g)
methyleneamino-7H-2-(8%-hydroxyquinolin-5%-yl
methylidene)-3-oxothiazolo[3,2-a]pyri-
din-6,8-dicarbonitrile (8a–g)
3.7.1. General procedure
3.6.1. General procedure
A mixture of 8a–g (0.01 mol) and aniline (2 ml) in
A mixture of 7a–g (0.01 mol) and triethylortho-
ethanol (50 ml) was heated under reflux for 4 h. The
reaction mixture was concentrated and allowed to stand
overnight. The solid product was filtered off and recrys-
tallized from the proper solvent.
formate (3 ml) in acetic acid (20 ml) was refluxed
for 6 h. The reaction mixture was cooled, diluted with
cold water and the solid product was collected
and recrystallized from ethanol as pale brown crys-
tals.
9
a: Yellow crystals from ethanol, m.p. 318–320°C
−
1
(
dec.) (61% yield). IR (w cm , KBr): 3500 (OH), 3355
(NH), 2230 (CN), 1715 (CꢀO). H NMR (l ppm,
DMSO-d ): 7.30–8.50 (m, 18H, arom.), 9.70 (s, 1H,
1
−
1
8a: m.p. 274–276°C (dec.) (60% yield). IR (w cm
,
6
KBr): 3500 (OH), 2200 (CN), 1700 (CꢀO), 1610 (CꢀN).
1
NH). MS, m/e 593. Anal. C33
H N O S (C, H, N, S).
19 7 3
H NMR (l ppm, CDCl ): 2.10 (t, 3H, CH , J=7.10
3
3
9
b: Yellowish–brown crystals from ethanol, m.p.
Hz), 4.15 (q, 2H, CH , J=7.10 Hz), 7.20–8.00 (m,
2
−1
2
3
95–297°C (68% yield). IR (w cm , KBr): 3500 (OH),
350 (NH), 2200 (CN), 1720 (CꢀO). H NMR (l ppm,
CDCl ): 7.10–8.30 (m, 17H, arom.), 10.10 (s, 1H, NH).
1
3H, arom. +NꢀCH). Anal. C H N O S (C, H, N,
2
9
18
6
4
1
S).
8
−
1
3
b: m.p. 265–267°C (65% yield). IR (w cm , KBr):
MS, m/e 542. Anal. C H N O S (C, H, N, S).
1
30 18
6
3
3
500 (OH), 2200 (CN), 1690 (CꢀO), 1610 (CꢀN). H
NMR (l ppm, CDCl ): 2.10 (t, 3H, CH , J=7.10 Hz),
9
c: Pale brown crystals from dioxane, m.p. 230–
3
3
−1
2
3
33°C (dec.) (60% yield). IR (w cm , KBr): 3500 (OH),
350 (NH), 2200 (CN), 1720 (CꢀO). H NMR (l ppm,
CDCl ): 7.20–8.10 (m, 19H, arom.), 9.80 (s, 1H, NH).
4
.15 (q, 2H, CH , J=7.10 Hz), 7.30–8.25 (m, 12H,
1
2
arom. +NꢀCH). MS, m/e 495. Anal. C H N O S (C,
2
6
17
5
4
3
H, N, S).
c: m.p. 203–205°C (dec.) (56% yield). IR (w cm
Anal. C H N O S (C, H, N, S).
32
20
6
2
−
1
8
,
9
d: Brown crystals from ethanol, m.p. 268–270°C
−
1
KBr): 3490 (OH), 2200 (CN), 1710 (CꢀO), 1600 (CꢀN).
(
55% yield). IR (w cm , KBr): 3490 (OH), 3350 (NH),
2200 (CN), 1700 (CꢀO). H NMR (l ppm, CDCl ):
7.10–8.30 (m, 18H, arom.), 10.10 (s, 1H, NH). Anal.
1
1
H NMR (l ppm, CDCl ): 2.10 (t, 3H, CH , J=7.10
3
3
3
Hz), 4.15 (q, 2H, CH , J=7.10 Hz), 7.20–8.00 (m,
2
1
S).
4H, arom. +NꢀCH). Anal. C H N O S (C, H, N,
C H ClN O S (C, H, Cl, N, S).
2
8
19
5
3
32 19
6
2
9e: Brown crystals from ethanol, m.p. 286–288°C
−
1
−1
8
d: m.p. 230–232°C (51% yield). IR (w cm , KBr):
(51% yield). IR (w cm , KBr): 3500 (OH), 3320 (NH),
1
1
3
490 (OH), 2200 (CN), 1700 (CꢀO), 1600 (CꢀN). H
2200 (CN), 1690 (CꢀO). H NMR (l ppm, CDCl
):
3
NMR (l ppm, CDCl ): 1.95 (t, 3H, CH , J=6.95 Hz),
7.25–8.40 (m, 18H, arom.), 9.80 (s, 1H, NH). MS, m/e
97. Anal. C H N O S (C, H, N, S).
3
3
5
4.15 (q, 2H, CH , J=6.95 Hz), 7.30–8.20 (m, 13H,
32 19
7
4
2
9
f: Brown crystals from ethanol, m.p. 305–307°C
arom. +NꢀCH). Anal. C H ClN O S (C, H, Cl, N,
S).
28
18
5
3
−
1
(
dec.) (56% yield). IR (w cm , KBr): 3480 (OH), 3320
1
−
1
(NH), 2200 (CN), 1700 (CꢀO). H NMR (l ppm,
8
e: m.p. 250–252°C (55% yield). IR (w cm , KBr):
1
CF COOD): 2.10 (s, 3H, CH ) 7.30–8.10 (m, 18H,
3
3
3
500 (OH), 2200 (CN), 1690 (CꢀO), 1590 (CꢀN). H
arom.). Anal. C H N O S (C, H, N, S).
33
22
6
2
NMR (l ppm, CDCl ): 2.10 (t, 3H, CH , J=7.10 Hz),
3
3
9
g: Pale brown crystals from dioxane, m.p.\310°C
4.20 (q, 2H, CH , J=7.10 Hz), 7.30–8.35 (m, 13H,
2
−1
(
45% yield). IR (w cm , KBr): 3500 (OH), 3330 (NH),
220 (CN), 1700 (CꢀO). H NMR (l ppm, CF COOD):
.95 (s, 3H, CH ), 7.20–8.10 (m, 18H, arom.). MS, m/e
arom.). MS, m/e 550. Anal. C H N O S (C, H, N, S).
2
8
18
6
5
1
2
1
5
−
1
3
8
f: m.p. 278–280°C (48% yield). IR (w cm , KBr):
1
3
3
500 (OH), 2200 (CN), 1690 (CꢀO), 1600 (CꢀN). H
82. Anal. C H N O S (C, H, N, S).
33
22
6
3
NMR (l ppm, CDCl ): 2.10 (s, 3H, CH ), 2.30 (t, 3H,
3
3
CH , J=7.30 Hz), 4.30 (q, 2H, CH , J=7.30 Hz),
3
2
3
.8. 9-Arylsubstituted 8-amino-2,3-dihydro-9H-2-
7
.10–7.90 (m, 13H, arom. +NꢀCH). Anal.
(
8%-hydroxyquinolin-5%-yl methylidene)-3-oxo thiazolo-
C H N O S (C, H, N, S).
2
9
21
5
3
[2%,3%:1,6]pyrido[2,3-d]pyrimidin-10-carbonitrile (10a–g)
−
1
8g: m.p. 291–293°C (dec.) (49% yield). IR (w cm
,
KBr): 3480 (OH), 2200 (CN), 1710 (CꢀO), 1590 (CꢀN).
3
.8.1. General procedure
A mixture of 7a–g (0.01 mol) and formamide (15 ml)
1
H NMR (l ppm, CDCl ): 1.90 (s, 3H, OCH ), 2.40 (t,
3
3
3
H, CH , J=7.25 Hz), 4.15 (q, 2H, CH , J=7.25 Hz),
was refluxed for 2 h. The solid product thus formed
after cooling was filtered off and recrystallized from the
proper solvent.
3
2
7
.30–8.10 (m, 13H, arom. +NꢀCH). Anal.
C H N O S (C, H, N, S).
2
9
21
5
4

116
M.S. Al-Thebeiti / Il Farmaco 55 (2000) 109–118
1
0a: Brown crystals from dioxane, m.p. 288–290°C.
ml), sodium nitrite (0.01 mol in 10 ml H O) was added
with stirring for 30 min and the stirring was continued
for 3 h. The product was collected and recrystallized
from diluted acetic acid.
2
−
1
(
(
53% yield). IR (w cm , KBr): 3500 (OH), 3200–3300
1
NH ), 2220 (CN), 1730 (CꢀO). H NMR (l ppm,
2
CF COOD): 7.10 (s, 1H, pyrimidine ring), 7.25 (s, 1H,
3
pyridine ring), 7.50 (s, 1H, methylidene), 7.55–7.80 (m,
11a: Pale brown crystals, m.p. 277–279°C (dec.) (46%
−
1
1
0H, arom.). MS, m/e 517. Anal. C H N O S (C, H,
yield). MS, m/e 538. IR (w cm , KBr): 3520 (OH),
2
7
15
7
3
1
N, S).
2200 (CN), 1700 (CꢀO). H NMR (l ppm, CDCl ): 7.00
3
1
0b: Brown crystals from dioxane, m.p.\310°C (48%
(s, 1H, pyridine ring), 7.25 (s, 1H, methylidene), 7.40–
−
1
yield). IR (w cm , KBr): 3480 (OH), 3200–3300 (NH ),
220 (CN), 1700 (CꢀO). H NMR (l ppm, CF COOD):
.90 (s, 1H, pyrimidine ring), 7.00 (s, 1H, pyridine ring),
.25 (s, 1H, methylidene), 7.30–7.75 (m, 9H, arom.).
8.10 (m, 10H, arom.). Anal. C H ClN O S (C, H, Cl,
2
26 12
7
3
1
2
6
7
N, S).
3
11b: Pale brown crystals, m.p.\310°C. (41% yield).
−
1
IR (w cm , KBr): 3510 (OH), 2220 (CN), 1720 (CꢀO).
1
MS, m/e 466. Anal. C H N O S (C, H, N, S).
H NMR (l ppm, CDCl ): 7.10 (s, 1H, pyridine ring),
2
4
14
6
3
3
1
0c: Pale brown crystals from ethanol, m.p. 215–
7.30 (s, 1H, methylidene), 7.50–8.30 (m, 9H, arom.).
−
1
2
3
17°C (dec.) (43% yield). IR (w cm , KBr): 3500 (OH),
200–3300 (NH ), 2220 (CN), 1700 (CꢀO). H NMR (l
ppm, CF COOD): 7.10 (s, 1H, pyrimidine ring), 7.25 (s,
H, pyridine ring), 7.30 (s, 1H, methylidene), 7.45–8.00
m, 11H, arom.). MS, m/e 476. Anal. C H N O S (C,
H, N, S).
MS, m/e 487/489. Anal. C H ClN O S (C, H, Cl, N,
23
11
6
3
1
S).
2
11c: Yellowish–brown crystals from ethanol, m.p.
3
−
1
1
(
266–268°C (dec.) (46% yield). IR (w cm , KBr): 3500
1
(OH), 2200 (CN), 1700 (CꢀO). H NMR (l ppm,
26
16
6
2
CDCl ): 6.90 (s, 1H, pyridine ring), 7.15 (s, 1H, methyli-
3
1
0d: Pale brown crystals from diluted acetic acid, m.p.
dene), 7.35–7.80 (m, 11H, arom.). Anal. C H -
25
13
−
1
2
(
65–267°C (dec.) (51% yield). IR (w cm , KBr): 3500
OH), 3200–3300 (NH ), 2200 (CN), 1720 (CꢀO). H
NMR (l ppm, CF COOD): 7.00 (s, 1H, pyrimidine
ring), 7.25 (s, 1H, pyridine ring), 7.35 (s, 1H, methyli-
dene),
ClN O S (C, H, Cl, N, S).
6 2
1
11d: Brown crystals from ethanol, m.p. 295–297°C
2
−
1
(dec.) (38% yield). IR (w cm , KBr): 3510 (OH), 2200
3
1
(CN), 1710 (CꢀO). H NMR (l ppm, CDCl ): 6.90 (s,
3
7.50–8.10
(m,
10H,
arom.).
Anal.
1H, pyridine ring), 7.10 (s, 1H, methylidene), 7.25–8.00
C H ClN O S (C, H, Cl, N, S).
(m, 10H, arom.). Anal. C H Cl N O S (C, H, Cl, N,
2
6
15
6
2
25 12
2
6
2
1
0e: Brown crystals from ethanol, m.p. 287–289°C
S).
11e: Dark brown crystals from diluted acetic acid,
−
1
(
dec.) (46% yield). MS, m/e 521. IR (w cm , KBr):
500 (OH), 3230–3340 (NH ), 2230 (CN), 1700 (CꢀO).
H NMR (l ppm, CF COOD): 7.00 (s, 1H, pyrimidine
−
1
3
m.p. 267–269°C (dec.) (44% yield). IR (w cm , KBr):
2
1
1
3500 (OH), 2210 (CN), 1700 (CꢀO). H NMR (l ppm,
3
ring), 7.15 (s, 1H, pyridine ring), 7.35 (s, 1H, methyli-
CDCl ): 6.90 (s, 1H, pyridine ring), 7.10 (s, 1H, methyli-
3
dene), 7.50–8.10 (m, 10H, arom.). Anal. C H N O S
dene), 7.25–8.10 (m, 10H, arom.). Anal. C H ClN -
26
15
7
4
25 12
7
(
C, H, N, S).
0f: Brown crystals from ethanol, m.p.\310°C (40%
O S (C, H, Cl, N, S).
11f: Brown crystals from diluted acetic acid, m.p.
\310°C (40% yield). IR (w cm , KBr): 3500 (OH),
4
1
−
1
−1
yield). IR (w cm , KBr): 3480 (OH), 3200–3300 (NH ),
2
1
1
2
2
1
200 (CN), 1700 (CꢀO). H NMR (l ppm, CF COOD):
.30 (s, 3H, CH ), 7.20 (s, 1H, pyrimidine ring), 7.35 (s,
3230–3340 (NH ), 2200 (CN), 1700 (CꢀO). H NMR (l
3
2
ppm, CDCl ): 1.95 (s, 3H, CH ), 7.30 (s, 1H, pyridine
3
3
3
H, pyridine ring), 7.50 (s, 1H, methylidene), 7.55–8.15
ring), 7.45 (s, 1H, methylidene), 7.50–8.20 (m, 10H,
(
m, 10H, arom.). Anal. C H N O S (C, H, N, S).
arom.). Anal. C H ClN O S (C, H, Cl, N, S).
2
7
18
6
2
26 15
6
2
1
0g: Pale brown crystals from dioxane, m.p.\310°C
11g: Brown crystals from dioxane, m.p. \310°C
−
1
−1
(
(
45% yield). IR (w cm , KBr): 3520 (OH), 3200–3300
(42% yield). IR (w cm , KBr): 3480 (OH), 2220 (CN),
1
1
NH ), 2200 (CN), 1720 (CꢀO). H NMR (l ppm,
1700 (CꢀO). H NMR (l ppm, CDCl ): 2.40 (s, 3H,
2
3
CF COOD): 2.25 (s, 3H, CH ), 6.90 (s, 1H, pyrimidine
OCH ), 7.50 (s, 1H, pyridine ring), 7.70 (s, 1H, methyli-
3
3
3
ring), 7.10 (s, 1H, pyridine ring), 7.25 (s, 1H, methyli-
dene), 7.90–9.00 (m, 10H, arom.). Anal. C H ClN -
26
15
6
dene), 7.40–8.00 (m, 10H, arom.). Anal. C H N O S
O S (C, H, Cl, N, S).
3
27
18
6
3
(
C, H, N, S).
3.10. 2,3-Dihydro-8-hydrazino-2-(8%-hydroxyquinolin-
3.9. 9-Arylsubstituted 8-chloro-2,3-dihydro-2-
5%-yl methylidene)-3-oxo-9-phenyl thiazolo-
(
8%-hydroxyquinolin-5%-yl methylidene)-3-oxo-
[2%,3%:1,6]pyrido[2,3-d][1,2,3]triazin-10-carbonitrile (12)
thiazolo[2%,3%:1,6]pyrido[2,3-d][1,2,3]-
triazin-10-carbonitrile (11a–g)
A mixture of 11c (0.002 mol) and hydrazine hydrate
2 ml, 98%) in ethanol (30 ml) was heated under reflux
(
3
.9.1. General procedure
To an ice-cold solution of 7a–g (0.01 mol) in a
mixture of acetic acid (20 ml) and hydrochloric acid (10
for 5 h. The product obtained after cooling was filtered
off, washed with water and recrystallized from ethanol
as brown crystals, m.p. 288–290°C (81% yield). IR (w

M.S. Al-Thebeiti / Il Farmaco 55 (2000) 109–118
117
−
1
cm , KBr): 3530 (OH), 3280–3380 (NH ), 3180 (NH),
3.14. 8-Amino-3,6-dioxo-2-(8%-hydroxyquinolin-5%-yl
methylidene)-9-phenyl-2,3,5,9-tetrahydro
thiazolo[3,2-a][1,8]naphthyridin-7,10-dicarbonitrile (16)
2
1
2
220 (CN), 1690 (CꢀO). H NMR (l ppm, CF COOD):
.10 (s, 1H, pyridine ring), 7.20 (s, 1H, methylidene),
3
7
7
.25–7.70 (m, 11H, arom.). Anal. C H N O S (C, H,
2
5
16
8
2
N, S).
A mixture of 7c (0.002 mol) and ethyl cyanoacetate
(
0.002 mol) was fused at 180–200°C for 2 h. The
reaction mixture was allowed to cool and the solid
product was collected and recrystallized from acetic
3
.11. 2,3-Dihydro-11H-2-(8%-hydroxyquinolin-5%-yl
methylidene)-3-oxo-11-phenyl thiazolo-
2%,3%:1,6]pyrido[2,3-d][1,2,4]triazolo[3%%,4%%-f][1,2,3]-
acid as pale brown crystals, m.p. \340°C (62 yield).
[
−1
IR (w cm , KBr): 3520 (OH), 3280–3380 (NH ), 3180
2
triazin-12-carbonitrile (13)
1
(
NH), 1700, 1720 (CꢀO).
CF COOD): 7.20 (s, 1H, pyridine ring), 7.25 (s, 1H,
H
NMR (l ppm,
3
A mixture of 12 (0.001 mol) in formic acid (20 ml)
was heated under reflux for 6 h. The reaction mixture
was concentrated in vacuo and the solid product was
collected, washed with water and recrystallized from
ethanol to give brown crystals, m.p. 310–312 (dec.)
methylidene), 7.40–7.85 (m, 11H, arom.), 8.60 (s, 1H,
NH), 9.10 (s, 2H, NH ). Anal. C H N O S (C, H, N,
2
28 16
6
3
S).
−
1
(
78% yield). IR (w cm , KBr): 3520 (OH), 2210 (CN),
1
4. Antifungal activity
1
700 (CꢀO). H NMR (l ppm, CDCl ): 6.80 (s, 1 H,
3
CH–triazole ring), 7.20–7.65 (m, 13H, arom.). Anal.
The newly synthesized compounds were screened for
their antifungal activity against four species of fungi,
namely, Penicillium chrysogenum, Fusarium monili-
forme, Rhizopus stalonifer and Aspergillus terreus, using
the disk diffusion method [12,13].
C H N O S (C, H, N, S).
2
6
14
8
2
3
3
.12. 2-(8%-Hydroxyquinolin-5%-yl methylidene)-
-oxo-11-phenyl-2,3,9,11-tetrahydro-8-thioxo-
thiazolo[2%,3%:1,6]pyrido[2,3-d][1,2,4]triazolo[3%%,4%%-f]-
The tested compounds were dissolved in N,N-
dimethylformamide (DMF) to get a solution of 1%
concentration. Filter paper discs (Whatman, 5 mm
diameter) were saturated with this former solution. The
saturated filter paper discs were placed on the surface
of solidified Czapek’s Dox agar dishes seeded by the
test fungi. The inhibition zones were measured in mm
at the end of an incubation period of 48 h at 28°C. As
appears in Table 1, only compounds 5 and 11a–g
exhibited moderate activity. Analysis data of the syn-
thesized compounds are given in Table 2.
[1,2,3]triazin-12-carbonitrile (14)
A mixture of 12 (0.0012 mol), carbon disulfide (5 ml)
in ethanol (50 ml) and two pellets of potassium hydrox-
ide was heated under reflux on a water bath for 5 h.
The solid product obtained was dissolved in water and
then acidified with acetic acid. Recrystallization from
acetic acid gave dark yellow crystals, m.p. \340°C
−
1
(
2
62% yield). IR (w cm , KBr): 3515 (OH), 3180 (NH),
1
200 (CN), 1700 (CꢀO), 1190 (CS). H NMR (l ppm,
CDCl ): 7.20 (s, 1H, pyridine ring), 7.25 (s, 1H,
3
methylidene), 7.35–7.90 (m, 11H, arom.). Anal.
C H N O S (C, H, N, S).
2
6
14
8
2
2
References
[
1] D.E. Beattie, R. Crossley, A.C.W. Curran, G.T. Dixon, D.G.
Hill, A.E. Lawrence, R.G. Sheperd, 5,6,7,8-Tetrahydroquinoli-
nes. 4. Antiulcer and antisecretory activity of 5,6,7,8-tetrahy-
droquinolinenitriles and -thioamides, J. Med. Chem. 20 (1977)
3
.13. 8-Azido-2,3-dihydro-9H-2-(8%-hydroxy-
quinolin-5%-yl methylidene)-3-oxo-9-phenyl
thiazolo[2%,3%:1,6]pyrido[2,3-d][1,2,3]-
triazin-10-carbonitrile (15)
7
14–718.
[
[
2] S. Masahiko, K. Eiji, K. Mitsutaka, 5-Substituted aminoethyli-
dene-1-azadibenzo[a,d]-cycloheptadienes, Japan Patent No.
7200,811 (Cl. C07D, A61k) (15 Mar. 1969); Chem. Abstr., 76,
To a well-stirred solution of 12 (0.002 mol) in
1
40574 j (1972).
glacial acetic acid (50 ml) a solution of sodium nitrite
3] A. Studeneer, G. Salbeck, L. Emmel, W. Knauf, N,N,-Dialkyl-
aminocarbamic acid ester of substituted hydroxypyridine deriva-
tives, Ger. Offen. 2,361,438 (Cl. C07D) (26 Jun. 1975); Chem.
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(
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