A facile synthesis of some new thiazolo[3,2-a]-pyridines containing pyrazolyl moiety and their antimicrobial activity

Article abstract of DOI:10.1080/10426500490494778

Condensation of 2-cyanomethyl-4-thiazolinone 1 with 1,3-diphenyl-pyrazole- 4-carboxaldehyde 2 in ethanol containing a few drops of piperidine yielded the novel methylene derivative 3. Compound 3 was refluxed with malononitrile to give the corresponding th

Full text of DOI:10.1080/10426500490494778

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A Facile Synthesis of Some
New Thiazolo[3, 2]pyridines
Containing Pyrazolyl Moiety
and Their Antimicrobial
Activity
T. I. El-Emary a , A. Khalil b , G. A. M. El-Hag Ali c
A. A. A. M. El-Adasy d
&
a Department of Chemistry, Faculty of Science,
Assiut University, Assiut, Egypt
b Department of Chemistry, Faculty of Science, Ain
Shams University, Cairo, Egypt
c Department of Chemistry, Faculty of Science, Al-
Azhar University, Nasr City, Cairo, Egypt
d Department of Chemistry, Faculty of Science, Al-
Azhar University at Assiut, Assiut, Egypt
Version of record first published: 01 Feb 2007
To cite this article: T. I. El-Emary, A. Khalil, G. A. M. El-Hag Ali & A. A. A. M. El-
Adasy (2005): A Facile Synthesis of Some New Thiazolo[3, 2]pyridines Containing
Pyrazolyl Moiety and Their Antimicrobial Activity, Phosphorus, Sulfur, and Silicon and
the Related Elements, 180:1, 19-30
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Phosphorus, Sulfur, and Silicon, 180:19–30, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490494778
A Facile Synthesis of Some New Thiazolo[3,2-a]-
pyridines Containing Pyrazolyl Moiety and Their
Antimicrobial Activity
T. I. El-Emary
Department of Chemistry, Faculty of Science, Assiut University,
Assiut, Egypt
A. Khalil
Department of Chemistry, Faculty of Science, Ain Shams University,
Cairo, Egypt
G. A. M. El-Hag Ali
Department of Chemistry, Faculty of Science, Al-Azhar University,
Nasr City, Cairo, Egypt
A. A. A. M. El-Adasy
Department of Chemistry, Faculty of Science, Al-Azhar University
at Assiut, Assiut, Egypt
Condensation of 2-cyanomethyl-4-thiazolinone 1 with 1,3-diphenyl-pyrazole-4-
carboxaldehyde 2 in ethanol containing a few drops of piperidine yielded the novel
methylene derivative 3. Compound 3 was refluxed with malononitrile to give the cor-
responding thiazolo[3,2-a]pyridine derivative 5. Also, treatment of compound 3 with
benzylidenemalononitriles gave the thiazolo[3,2-a]pyridine derivatives 6a–e. Re-
fluxing of compound 6d with triethyl orthoformate furnished the ethoxymethylide-
neamino derivative 7. Formic acid and malononitrile were reacted with compound
6d to produce thiazolo[3,2-a][1,8]naphthyridine derivative 8 and 11, respectively.
Condensation of 2 with cyanoacetohydrazide in ethanol containing piperidine as
catalyst gave the hydrazone derivative 12 which, on treatment with salicyaldehyde
and 2-cyano-3-(4-fluorophenyl)acrylic acid ethyl ester, yielded the novel chromene
13 and pyridinone 14, respectively. Structures of the synthesized compounds have
been established by elemental analysis and spectral data. Compounds 3, 5, 6a–d,
8, 11, 13, and 14 have been screened for antimicrobial activities.
Keywords 1,3-Diphenyl-pyrazole; thiazolo[3,2-a]pyridines; thiazolo-naphthyridines
and antimicrobial activity
Received April 28, 2004; accepted June 2, 2004.
Address correspondence to A. A. A. M. El-Adasy, Department of Chemistry, Fac-
ulty of Science, Al-Azhar University at Assiut, Assiut 71524, Egypt. E-mail: a eladasy@
yahoo.com
19

20
T. I. El-Emary et al.
INTRODUCTION
The interesting pharmacological properties of thiazole derivatives1–7 in
relation to the various changes in the structures of these compounds
is worth studying in order to synthesize less toxic and more potent
drugs. Therefore the fusion of other heterocyclic moieties to the thia-
zole ring may lead to the fulfillment of the objective. Pyrazolyl moiety
revealed antibacterial, antifungal, analgesic, antiflammatory,8,9 and
platelet antiaggregating properties.10–13 In continuation of our work on
the synthesis of thiazolo[3,2-a]pyridines from readily available start-
ing material14–17 we report here a facile synthesis of hitherto unknown
2-cyanomethyl-4,5-dihydro-4-oxo-5-(1,3-diphenylpyrazol-4-yl) methyli-
dene thiazole 3 and the result of its utility as building block for the
synthesis of novel thiazolo[3,2-a]pyridine derivatives having pyrazolyl
moiety in their structures.
RESULTS AND DISCUSSION
2-Cyanomethyl-4-thiazolinone 1 reacts with 1,3-diphenyl-pyrazole-4-
carboxaldehyde 2 in ethanol containing a few drops of piperidine to af-
ford the corresponding methylidene derivative 3. The structure of the
compound 3 is in agreement with its spectral data. The IR spectrum of
compound 3 exhibited absorption bands for NH2, C N, and C O (thi-
1
azoline) groups. Its H NMR spectrum recorded in DMSO-d6 revealed
singlet in the region at δ 5.25 ppm attributed to CH2CN in addition to
ethylene, pyrazole, and aromatic protons. The reaction of compound 3
with malononitrile in refluxing ethanol and piperidene led to the for-
mation of 5-amino-7-imino-2-[1,3-diphenyl-pyrazol-4-yl]methylidene-
3-oxo-2,3-dihydro-thiazolo[3,2-a]pyridine-6-carbonitrile 5 and thia-
zolopyran 4 was eliminated on the basis of analytical and specral data.
1H NMR spectrum of compound 5 displayed a singlet in the region δ 4.47
ppm due to pyridine-H. The formation of thiazolopyridine 5 is assumed
to proceed via the addition of the active methylene in malononitrile to
the cyano group in compound 3, followed by intramolecular cyclization
at the cyano group and tautomerization to furnish 5, (Scheme 1).
The formation of starting material 3 encouraged us to extend this
work to synthesize a novel thiazolo[3,2-a]pyridine derivatives 6a–e hav-
ing in their structure pyrazolyl moiety by cyclocondensation of com-
pound 3 with benzylidenemalononitriles (1:1 molar ratio) in ethanol
containing few drops of piperidine. The structures of these deriva-
tives were confirmed by elemental analysis and spectral data. The
1H NMR spectrum of compound 6a in (DMSO-d6) revealed singlet in
the region δ 4.76 ppm was attributed to pyridine-H. The formation

Containing Pyrazolyl Moiety and Their Antimicrobial Activity
21
SCHEME 1
of thiazolopyridine 6 is assumed to proceed via initial addition of ac-
tive methylene in compound 3 to benzylidene moiety to form Michael
adduct, followed by intramolecular cyclization,16 (Scheme 2). Also, the
structures of thiazolo[3,2-a]pyridines 6a–e were established by another
synthetic route via ternary condensation of compound 3, aromatic alde-
hyde and malononitrile (1:1:1 molar ratio) in refluxing ethanol contain-
ing piperidine.
The reactivity of thiazolopyridine 6, which contains chalcone and
enaminonitrile moieties, toward some electrophiles and nucleophiles

22
T. I. El-Emary et al.
SCHEME 2
was investigated. Thus compound 6d was reacted with triethyl or-
thoformate as electrophile yielded the corresponding ethoxymethylene
derivative 7. Spectral data and elemental analysis are in consistent
with its structure. Furthermore cyclization of compound 6d with formic
acid furnished thiazolo[3,2-a]-3-aza-[1,8]naphthyridine derivative 8.
Three possible structures 9, 10, and 11 can be formulated when com-
pound 6d was allowed to react with malononitrile in ethanol in the
presence of piperidine. Elemental analysis and spectral data are in
agreement with structure 11 and excluded the structures 9 and 10,
(Scheme 3). IR spectrum of compound 11 revealed presence of absorp-
1
tion band for C O (thiazolinone) group and its H NMR not showed
any specific signal for CH2C N group.
Compound 2 was condensed with cyanoacetohydrazide in boiling
ethanol containing piperidine as a base and gave hydrazone derivative
12, which was established by correct elemental analysis and spectral

Containing Pyrazolyl Moiety and Their Antimicrobial Activity
23
SCHEME 3
data. Its 1H NMR spectrum in (DMSO-d6) revealed singlet at δ 4.13 ppm
which due to CH2CN, singlet at δ 9.05 ppm assigned to CH N and
singlet at δ 11.63 ppm due to NH. Interaction of compound 12 with sal-
icyaldehyde and in ethanol afforded the hitherto unknown chromene
derivative 13. Finally, compound 12 was cyclized with 2-cyano-3-(4-
fluorophenyl)-acrylic acid ethyl ester in EtOH/ piperidine to furnish
pyridinone derivative 14. The formation of pyridine 14 was assumed
to proceed via the addition of active methylene in compound 12 to the

24
T. I. El-Emary et al.
SCHEME 4
benzylidene moiety followed by intramolecular cyclization by elimina-
tion of ethanol molecule (Scheme 4).
EXPERIMENTAL
All melting points are uncorrected (Stuart Scientific Co., UK). The IR
spectra were measured as KBr pellets on Shimadzu IR 200 spectropho-
tometer (Shimadzu, Japan). 1H NMR spectra were recorded in DMSO-
d6 at 200 MHz on a Varian Gemini NMR spectrometer (Varian, UK),
using tetramethylsilane as internal reference. Elemental analyses were
carried out at the Microanalytical Center of Cairo University (Egypt).
The characteristic data for the synthesized compounds are given in
Table I. The spectral data are collected in Table II. Compound 1 was
prepared according to reported method.18
2-Cyanomethyl-4,5-dihydro-4-oxo-5-(1,3-
diphenylpyrazol-4-yl)methylidene Thiazoline (3)
A mixture of thiazolinone 1 (0.01 mol) and 1,3-diphenyl pyrazole-
4-carboxaldehyde 2 (0.01 mol) in ethanol (20 ml) containing a few

Containing Pyrazolyl Moiety and Their Antimicrobial Activity
25
TABLE I Analytical Data of the Synthesized Compounds
Elemental analyses
calcd./found [%]
Compound Yield
M.P. Molecular formula
no.
(%)
Solvent crystal
[◦C]
(mol. wt.)
C%
H%
N%
3
75
EtOH/Benzene 200-2
C21H14N4OS
(370.44)
68.10 3.81 15.12
68.05 3.75 15.16
66.05 3.69 19.26
66.09 3.62 19.27
66.60 3.43 15.04
66.58 3.38 15.07
66.60 3.43 15.04
66.58 3.41 15.03
61.70 3.17 13.93
61.69 3.13 13.92
71.36 4.12 15.60
71.36 4.11 15.59
73.15 3.86 14.62
73.16 3.82 14.62
70.69 4.41 14.13
70.69 4.36 14.15
69.96 3.91 14.84
69.95 4.00 14.86
69.53 3.98 18.53
69.57 3.96 18.57
69.30 4.59 21.26
69.31 4.56 21.27
72.05 4.42 16.16
72.05 4.39 16.15
69.60 3.42 16.79
69.63 3.43 16.76
5
66
62
74
82
85
63
67
79
81
84
57
69
Benzene
Dioxane
Dioxane
Dioxane
Dioxane
EtOH
>300
280-2
270-2
263-5
270-1
260-2
C
24H16N6OS
(436.50)
6a
6b
6c
6d
6e
7
C
31H19ClN6OS
(559.05)
C31H19ClN6OS
(559.05)
C
31H19BrN6OS
(603.50)
C
32H22N6OS
(538.64)
C
35H22N6OS
(574.67)
EtOH/Benzene 230-1
EtOH/Benzene 140-2
C
C
35H26N6O2S
(594.70)
33H22N6O2S
(566.65)
8
11
Benzene
EtOH/Benzene 204-6
EtOH 155-7
EtOH/Benzene 295-7
293-5
C35H24N8OS
(604.70)
12
13
14
C
19H15N5O
(329.36)
C
26H19N5O2
(433.47)
C29H17FN6O2
(500.50)
drops of piperidine was refluxed for 6 hours. The solid product ob-
tained was filtered off and recrystallized from suitable solvent to
give 3.
7-Amino-5-imino-2(1,3-diphenylpyrazol-4-yl)methylidene-
3-oxo-2,3-dihydro-thiazolo [3,2-a]pyridine-
6-carbonitrile (5)
A mixture of thiazolinone 3 (0.01 mol) and malononitrile (0.01 mol)
in ethanol (20 ml) containing few drops of piperidine was refluxed for
8 hours. The solid product which produced on heating was collected and
recrystallized to give 5.

26
T. I. El-Emary et al.
TABLE II Spectral Data of the Synthesized Compounds
Compound
no.
IR (KBr, cm−1
)
1H NMR (δ, ppm) (DMSO-d6)
3
5
2200 (C N), 1700 (C
thiazolinone)
O
5.25(s, 2H, CH2CN), 6.18–8.07 (m,
11H, 10H Ar-H+pyrazole-H), 8.62 (s,
1H, methine-H)
4.47 (s, 1H, pyridine-H), 7.35–7.62 (m,
11H, 10H Ar-H+pyrazole-H), 7.89
(s, 1H, methine-H), 8.06 (s, 1H, NH),
8.40 (s, 2H, NH2)
3440, 3347, 3100 (NH2, NH),
2200 (C N), 1710 (C
thiazolinone)
O
6a
6b
6c
6d
6e
3394, 3317 (NH2), 2200
4.76 (s, 1H, pyridine-H), 7.42–7.68 (m,
15H, 14H Ar-H+pyrazole-H), 8.02 (s,
1H, methine-H) 8.80 (s, 2H, NH2)
(C N), 1710 (C
thiazolinone)
O
3400, 3280 (NH2), 2200
(C N), 1700 (C
thiazolinone)
O
3400, 3280 (NH2), 2200
4.74 (s, 1H, pyridine-H), 7.35–8.05(m,
15H, 14H Ar-H +pyrazole-H), 8.10
(s, 1H, methine-H), 8.38 (s, 2H, NH2)
(C N), 1700 (C
thiazolinone)
O
3400, 3371 (NH2), 2198
(C N), 1705 (C
thiazolinone)
O
3394, 3370 (NH2), 2191
4.73 (s, 1H, pyridine-H), 6.02–8.51
(m, 18H, 17H Ar-H+pyrazole-H),
8.67 (s, 1H, methine-H), 8.84 (s, 2H,
NH2)
(C N), 1705 (C
thiazolinone)
O
7
2198 (C N), 1718 (C
thiazolinone)
O
1.23(t, 3H, CH3), 2.49 (s, 3H, CH3),
3.20 (q, 2H, CH2), 4.21 (s, 1H,
pyridine-H), 7.42–7.69 (m, 15H, 14H
Ar-H+ pyrazole-H) 7.95(s, 1H,
methine-H, 9.10(s, 1H, N CH)
8
3344 (NH), 2216 (C N),
1700, 1654 (C
O
thiazolinone, amide)
11
3392, 3373 (NH2), 2194
1.63 (s, 2H, NH2), 2.31 (s, 3H, CH3),
4.50 (s, 1H, pyridine-H), 7.31–7.67
(m, 15H, Ar-H+pyrazole-H), 7.89
(s, 1H, methine-H), 8.90 (s, 2H, NH2)
4.13 (s, 1H, pyridine-H), 7.36–8.27
(m, 11H, 10H Ar-H+pyrazole-H),
9.03 (s, 1H, CH N), 11.63 (s, 1H,
NH)
4.13 (br, 1H, NH), 6.75 (s, 1H,
pyrazole-H), 7.06–8.33 (m, 15H, 14H
Ar-H+coumarin-H), 8.69 (s, 1H,
CH N), 10.05 (s, 1H, NH)
(C N), 1718 (C
thiazolinone)
O
12
13
14
3446 (NH), 2225 (C N), 1679
(C O thiazolinone)
3200 (NH), 1650 (C O)
3400 (OH) 2200 (C N), 1650
(C O)
6.60 (s, 1H, pyrazole-H) 7.10–7.50 (m,
14H, Ar-H), 8.55 (s, 1H, CH N), 9.9
(s, 1H, OH)

Containing Pyrazolyl Moiety and Their Antimicrobial Activity
27
5-Amino-2-(1,3-diphenylpyrazol-4-yl)methylidene-3-
oxo-6,8-dicyano-2,3,7-trihydro-7-aryl-thiazolo[3,2-a]
pyridines (6a–e)
Method A
A mixture of thiazolinone 3 (0.01 mol) and arylidenemalononitrile
(0.01 mol) in ethanol (20 ml) containing few drops of piperidine was
refluxed for 3 hours. The solid product which produced on heating was
filtered and recrystallized to give 6a–e.
Method B
A mixture of compound 3 (0.01 mol), aromatic aldehyde (0.01 mol)
and malononitrile (0.01 mol) in ethanol (30 ml) in the presence of pipri-
dine (0.5 ml) was refluxed for 3 hours. The solid product produced on
heating was collected to give 6.
5-Ethoxymethyleneamino-2-(1,3-diphenylpyrazol-4-yl)-
methylidene-3-oxo-6,8-dicyano-2,3,7-trihydro-7-
tolyl-thiazolo[3,2-a]pyridine (7)
A solution of 6d (0.01 mol) and triethyl orthoformate/acetic anhydride
mixture (10 ml; 1:1) was refluxed for 5 hours. The solid obtained was
filtered and recrystallized from suitable solvent to give 7.
2-(1,3-Diphenylpyrazol-4-yl)methylidene-3,8-dioxo-
2,3,9-trihydro-7-imino-9-tolyl-10-cyano-thiazolo
[3,2-a]-3-aza-[1,8]naphthyridine (8)
A solution of 6d (0.01 mol) in enough quantity of formic acid (10 ml)
was refluxed for 5 hours. The product obtained was filtered and recrys-
tallized from suitable solvent to give 8.
2-(1,3-Diphenylpyrazol-4-yl)methylidene-3-oxo-2,3,9-trihydro–
6,8-diamino-9-tolyl–7,10-dicyano-thiazolo
[3,2-a][1,8]naphthyridine (11)
A mixture of thiazolinone 6d (0.01 mol) and malononitrile (0.01 mol)
in ethanol (20 ml) containing few drops of piperidine was refluxed for
8 hours. The solid product obtained was filtered off and recrystallized
from suitable solvent to give 11.
Cyano-Acetic Acid (1,3-Diphenyl-1H-pyrazol-4-ylmethylene)-
hydrazide (12)
A solution of 2 (0.01 mol) and cyanoacetohydrazide (0.01 mol) in ethanol
(20 ml) containing few drops of piperidine was refluxed for 5 hours.

28
T. I. El-Emary et al.
The product obtained was filtered off and recrystallized from suitable
solvent to give 12.
2-Imino-2H-chromene-3-carboxylic Acid (1,3-Diphenyl-1H-
pyrazol-4-ylmethylene)-hydrazide (13)
A solution of 11 (0.01 mol), salicyaldehyde (0.01 mol) in ethanol (20 ml)
and catalytic amount of piperidine was refluxed for 6 hours. The solid
obtained was filtered off and recrystallized from suitable solvent to give
13.
1-[(1,3-Diphenyl-1H-pyrazol-4-ylmethylene)-amino]-4-
(4-fluorophenyl)-6-hydroxy-1,2-dihydro-2-pyridinone-
3,5-dicarbonitrile (14)
A solution of 11 (0.01 mol), 2-cyano-3-(4-fluorophenyl)-acrylic acid ethyl
ester and (0.01 mol) in ethanol (20 ml) and catalytic amount of piperi-
dine was refluxed for 6 hours. The solid obtained was filtered off and
recrystallized from suitable solvent to give 14.
BIOLOGICAL SCREENING
Most of the newly synthesized compounds were screened in vitro for
their antimicrobial activities against four strains of bacteria: Staphylo-
coccus aureus, Escherichia coli, Pseudomonas aeruginosa, and Bacillus
subtilis using the paper disc diffusion method.19 The tested compounds
were dissolved in, N N-dimethylformamide (DMF) to get a solution of
1 mg mL−1. The inhibition zones were measured in millimeters at the
end of incubation period of 48 h at 28◦C. Dimethylformamide showed
no inhibition zones. Chloramphenicol standard was used as reference
to evaluate the potency of the tested compounds. The inhibition zones
of microbial growth produced by different compounds are reported in
Table III. A novel compound 13 showed activity nearest from chloroam-
phenicol with respect to Escherichia coli, Staphylococcus, and Bacillus
Subtilis; This may be attributed to this compound having coumarinyl
moiety beside pyrazolyl moiety in its structure. Where compound 5 and
compounds 6a, 6c, and 8 exhibited the same activities with respect
to Bacillus Subtilis, Escherichia coli, and Pseudomonas aeruginosa re-
spectively. Also, this may be due to presence of pyridine and naphthyri-
dine moieties in their structures. Contrary to this, most of the synthe-
sized compounds showed moderate and lower activity with respect to
all tested microorganisms.

Containing Pyrazolyl Moiety and Their Antimicrobial Activity
29
TABLE III Antibacterial Activity of the Synthesized
Compounds
Compound
no.
Staphylococcus
aureus
Bacillus
subtilis
Escherichia
coli
Pseudomonas
aeruginosa
3
5
++
+
+
+++
++
++
++
+
++
++
++
+
6a
6b
6c
6d
8
11
13
14
+
+++
++
++
++
++
+
+
++
+
+++
++
++
++
+++
++
++
++
+++
+
+++
++
+++
++
++
+
+++
+
Standard
++++
++++
++++
++++
+: (0.2–0.5 cm) less active, ++: (0.6–1.4 cm) moderately active. +++:
(1.5–3.0 cm) highly active, ++++: (over 3.0 cm) very highly active.
Standard: Chloramphenicol (25 µg mL−1
)
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