Studies on thiazolopyridines. Part 1: Antimicrobial activity of some novel fluorinated thiazolo[3,2-a]pyridines and thiazolo[2′,3′:1,6]pyrido[2,3-d]pyrimidines

Article abstract of DOI:10.1080/10426500210240

Ternary condensation of aromatic aldehydes, malononitrile and thioglycolic acid (2:2:1 molar ratio) in ethanol/piperidine afforded the corresponding thiazolo[3,2-a]pyridines 1a-d. Thiazolo/2′,3′:1,6]-pyrido[2,3-d]pyrimidine 4 was obtained by refluxing of compound 1a with acetic anhydride. Also, thiazolopyrido pyrimidine 6 was produced by refluxing of 1a with triethylorthoformate followed by treatment with hydrazine hydrate. Refluxing 1a with formic acid yielded the thiazolopyridopyrimidine 8 which on chlorination with thionyl chloride furnished the chloro derivative 9. Finally, amino thiazolo[2′,3′:1,6]pyrido[2,3-d]pyrimidine 10 was obtained by treatment of 1a with formamide. The structures of these compounds were established on the basis of elemental analyses, IR, ¹H NMR, and mass spectral data. Also, the antimicrobial activity of some synthesized compounds is reported.

Full text of DOI:10.1080/10426500210240

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Phosphorus, Sulfur, and Silicon and the Related
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Studies on Thiazolopyridines. Part 1: Antimicrobial
Activity of Some Novel Fluorinated Thiazolo[3,2-
a]Pyridines and Thiazolo[2′,3′:1,6]Pyrido[2,3-
d]Pyrimidines
Ahmed A. El-Maghraby a , Gameel A. M. El-Hag Ali a , Ahmed H. A. Ahmed a & Mohamed S. A.
El-Gaby b
a Chemistry Department, Faculty of Science , Al-Azhar University , Nasr City, Cairo, Egypt
b Chemistry Department, Faculty of Science , Al-Azhar University at Assuit , Assuit, 71524,
Egypt
Published online: 27 Oct 2010.
To cite this article: Ahmed A. El-Maghraby , Gameel A. M. El-Hag Ali , Ahmed H. A. Ahmed & Mohamed S. A. El-Gaby
(2002) Studies on Thiazolopyridines. Part 1: Antimicrobial Activity of Some Novel Fluorinated Thiazolo[3,2-a]Pyridines and
Thiazolo[2′,3′:1,6]Pyrido[2,3-d]Pyrimidines, Phosphorus, Sulfur, and Silicon and the Related Elements, 177:2, 293-302, DOI:
10.1080/10426500210240
To link to this article: http://dx.doi.org/10.1080/10426500210240
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Phosphorus, Sulfur and Silicon, 2002, 177:293–302
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
STUDIES ON THIAZOLOPYRIDINES. PART 1:
ANTIMICROBIAL ACTIVITY OF SOME NOVEL
FLUORINATED THIAZOLO[3,2-a]PYRIDINES AND
THIAZOLO[20,30:1,6]PYRIDO[2,3-d]PYRIMIDINES
Ahmed A. El-Maghraby,a Gameel A. M. El-Hag Ali,a
Ahmed H. A. Ahmed,a and Mohamed S. A. El-Gabyb
Chemistry Department, Faculty of Science, Al-Azhar University,
Nasr City, Cairo, Egypta and Chemistry Department,
Faculty of Science, Al-Azhar University at Assuit,
Assuit 71524, Egyptb
(Received June 2 2001.)
Ternary condensation of aromatic aldehydes, malononitrile and
thioglycolic acid (2:2:1 molar ratio) in ethanol/piperidine afforded
the corresponding thiazolo[3,2-a]pyridines 1a–d. Thiazolo[20,30:1,6]-
pyrido[2,3-d]pyrimidine 4 was obtained by refluxing of compound
1a with acetic anhydride. Also, thiazolopyrido pyrimidine 6 was
produced by refluxing of 1a with triethylorthoformate followed by
treatment with hydrazine hydrate. Refluxing 1a with formic acid
yielded the thiazolopyridopyrimidine 8 which on chlorination with
thionyl chloride furnished the chloro derivative 9. Finally, amino
thiazolo[20,30:1,6]pyrido[2,3-d]pyrimidine 10 was obtained by treat-
ment of 1a with formamide. The structures of these compounds were
established on the basis of elemental analyses, IR, 1H NMR, and mass
spectral data. Also, the antimicrobial activity of some synthesized com-
pounds is reported.
Keywords: Antimicrobial activity; thiazolo[3,2-a]pyridines; thiazolo-
[20,30:1,6]pyrido[2,3-d]pyrimidines
INTRODUCTION
A wide range of biological activities has been attributed to fused
thiazoles. For an example, thiazolopyridines are important as anti-
4
inflammatory and antibacterial agents.1 On the other hand, fused
pyrimidines were found to possess wide biological activities such as
Address correspondence to Mohamed S. A. El-Gaby, Chemistry Department,
Faculty of Science, Al-Azhar University of Assuit, Assuit 71524, Egypt. E-mail:
m elgaby@hotmail.com
293

294
A. A. El-Maghraby et al.
antimicrobial,5,6 antiparkinsonian,7 leishmanicidal, and herbicidal.8
11
In continuing our efforts9
to evaluate heterocyclic compounds for
antimicrobial activity, we synthesized the thiazolo[3,2-a]pyridines and
thiazolo[20,30:1,6]pyrido[2,3-d]pyrimidines.
RESULTS AND DISCUSSION
Ternary condensation of aromatic aldehydes, malononitrile and thio-
glycolic acid (2:2:1 molar ratio) in absolute ethanol in the presence of
a catalytic amount of piperidine yielded 5-amino-2-arylmethylidene-
7-aryl-6,8-dicyano-3-oxo-2,3-dihydro-7H-thiazolo[3,2-a]pyridines 1a–d
in good yields. The structures of 1a–d were determined on the basis of
1
elemental analyses, IR, H-NMR, and mass spectra. The IR spectrum
1
of thiazolopyridine 1a showed primary amino bands at 3400 cm and
1
1
3300 cm and a cyano stretch at 2200 cm 1. H-NMR spectrum of
1a in DMSO-d6 showed a signal in the region 4.67, attributed to the
pyridine10 H. Also, the mass spectra of 1a,b are fully consistent with as-
signed structures. Thus, compound 1a revealed a molecular ion peak at
SCHEME 1

Thiazolopyridines
295
FIGURE 1 Fragmentation pattern of compound 1a.
m/z 418 (18.3%) corresponding to the molecular formula C22H12F2N4OS
(Figure 1). A reaction mechanism12 is proposed for the formation of the
thiazolopyridines 1a–d and is illustrated in Scheme 1.
Compound 1a was refluxed with acetic anhydride to yield a 1:1
adduct, for which three possible structures 2, 3, and 4 were consid-
ered. The structure of 4 was established on the basis of its spectral
data. Thus, the IR spectrum showed the presence of a secondary amino
function (3400 cm 1), a cyano function (2200 cm 1), and carbonyl func-
tions at 1710 cm 1 (thiazolidinone) and 1665 cm 1 (pyrimidinone). The
1H-NMR spectrum exhibited a singlet at 2.34 and was assigned to the
methyl protons. A one proton singlet in the region 4.67 was assigned
to pyridine H and a multiplet at 7.16–7.89 was assigned to aromatic
protons. The formation of 4 from 1a and acetic anhydride is assumed
to proceed through Dimroth rearrangement13 of the initial cyclization
product 3 under the applied reaction conditions, Scheme 2.

296
A. A. El-Maghraby et al.
SCHEME 2
Ethoxymethylene derivative 5 was obtained by refluxing 1a with tri-
ethyl orthoformate in the presence of acetic anhydride. The structure of
compound 5 was determined on the basis of its elemental analyses and
spectral data. The IR spectrum revealed the absence of amino function.
The 1H-NMR spectrum in DMSO-d6 exhibited methyl (t) and methylene
SCHEME 3

Thiazolopyridines
297
(q) functions, attributed to the OCH2CH3 fragment, in addition to a
singlet at 4.65 ppm which was assigned to pyridine-H. Treatment of
5 with hydrazine hydrate in ethanol at room temperature furnished
the novel thiazolopyridopyrimidine derivative 6 in good yield. The
1H-NMR spectrum of compound 6 in DMSO-d6 showed the absence of
a OCH2CH3 fragment. Also, compound 5 underwent aminolysis and
cyclization by refluxing with isopropylamine in absolute ethanol to
give 7 (Scheme 3).
When compounds 1a,c were refluxed with formic acid, the reac-
tion afforded the thiazolopyridopyrimidine 8a,b. Chlorination of 8a
with thionyl chloride in dioxane under reflux produced the chloro
derivative 9. Also, cyclization of 1a,b with formamide13 under reflux
yielded the thiazolopyridopyrimidine 10a,b, Scheme 4.
SCHEME 4
ANTIMICROBIAL ACTIVITY
Antimicrobial activity of the compounds 1a, 5, 6, 8a, 9, and 10a
was tested in vitro against Sataphylococcus aureus (NCTC-7447),
Bacillus cereus (ATCC-14759), Serratia marcesents (IMRU-70), Pro-
teus merabitis (NCTC-289), Aspergillus ochraceus Wilhelm (AUCC-
230), and Penicillium chrysogenum Thom (AUCC-530). The tested

298
A. A. El-Maghraby et al.
TABLE I Antimicrobial Activity of Some Synthesized Compounds
Aspergillus Penicillium
ochraceus chrysogenum
Wilhelm Thom
(ATCC-14759) (IMRU-70) (NCTC-289) (AUCC-230) (AUCC-530)
Sataphylococcus
aureus
(NCTC-7447)
Serratia
Proteus
Compd.
no
Bacillus cereus marcesents merabitis
c
c
b
b
c
b
b
b
b
b
c
c
b
c
a
b
b
b
b
b
d
a
a
b
a
c
1a
5
6
8a
9
10a
Reference
b
c
b
b
c
b
c
c
b
d
b
d
c
d
d
d
aLess active (0.2–0.5 mm).
bModerately active (0.6–1.4 mm).
cHighly active (1.5–2.0 mm).
dVery highly active.
compounds were dissolved in DMF at a concentration of 250 mg/mL
by the agar diffusion technique.14 Streptomycin (25 ug) and Mycostatin
(30 ug) were used as reference for the antibacterial and antifungal ac-
tivities respectively. The inhibition zones were measured after 24 h
incubation (in mm), and the results were represented in Table I. The
majority of the synthesized compounds exhibited various antimicro-
bial activity toward all the microorganisms used with their minimal
inhibitory concentration (MIC).
EXPERIMENTAL
All melting points are uncorrected. IR spectra were recorded on a
Shimadzu 440 IR spectrophotometer using the KBr technique
(Shimadzu, Japan) 1H-NMR spectra were record in DMSO-d6 at
200 MHz on a Varian Gemeini NMR spectrometer using TMS as an
internal reference. Mass spectra were performed by a Shimadzu-GC-
MS-QP 100 EX (Shimadzu, Japan). Elemental analyses were carried
out by the Microanalytical Research Center, Faculty of Science, Cairo
University.
5-Amino-2-arylmethylidene-7-aryl-6,8-dicyano-3-oxo-
2,3-dihydro-7H-thiazolo[3,2-a]pyridines (1a--d)
A mixture of aromatic aldehyde (0.02 mol), malononitrile (0.02 mol) and
thioglycolic acid (0.01 mol) in absolute ethanol (20 mL) was refluxed for
2 h in the presence of piperidine (0.5 mL). The reaction mixture was
poured into ice/HCl and the obtained product was recrystallized to give
la–d (Table II).

Thiazolopyridines
299
TABLE II Physical and Analytical Data of the Synthesized Compounds
Calculated/found (%)
Compd. Yield
Solvent
cryst.
Mol. formula
(M.Wt)
no
(%)
m.p. ( C)
258–260
C
H
N
1a
85
DMF/EtOH
DMF/EtOH
DMF/EtOH
DMF/EtOH
EtOH
C22H12F2N4OS
(418)
C22H12Br2N4OS
(540)
C24H18N4OS
(410)
C22H12N6O5S
(472)
63.15 2.87 13.39
63.20 2.80 13.40
48.88 2.22 10.37
48.80 2.20 10.30
70.24 4.39 13.65
70.30 4.30 13.60
55.93 2.54 17.79
55.90 2.60 17.70
62.60 3.04 12.17
62.70 3.00 12.20
63.29 3.37 11.81
63.10 3.40 11.70
60.00 3.04 18.27
60.10 3.00 18.30
64.06 3.90 14.37
64.10 3.90 14.40
61.88 2.69 12.55
61.80 2.60 12.50
68.49 4.10 12.79
68.50 4.20 12.60
1b
1c
1d
4
82
77
75
62
78
70
65
90
76
65
80
81
278–280
240–242
243–245
200–202
246–248
182–183
170–172
272–274
215–217
120–122
>300
C
24H14F2N4O2S
(460)
C25H16F2N4O2S
(474)
5
EtOH
6
EtOH
C23H14F2N6OS
(460)
C26H19F2N5OS
(487)
23H12F2N4O2S
(446)
7
EtOH
8a
8b
9
DMF
C
DMF
C25H18N4O2S
(438)
benzene
DMF
C23H11ClF2N4OS 59.40 2.79 12.05
(464.5)
23H13F2N5OS
(445)
59.40 2.70 12.00
62.02 2.92 15.73
62.10 2.80 15.70
48.67 2.29 12.34
48.70 2.30 12.40
10a
10b
C
DMF
>300
C
23H13Br2N5OS
(567)
The mass spectrum of compound 1a exhibited a molecular ion peak
at m/z 418 (16.3%) with a base peak at m/z 323 (M+ C6H4F, 100%).
Other significant peaks were observed: 419 (10.2%), 420 (3.5%), 390
(3.5%), 295 (32%), 238 (1.3%), 296 (28%), 210 (1.0%), 200 (0.4%), and
76 (1.7%). Also the mass spectrum of compound 1b showed a molecular
ion peak at m/z 540 (11.2%) with a base peak at m/z 385.
2-(4-Fluorophenyl)methylidene-9-(4-fluorophenyl)-3,8-
dioxo-6-methyl-2,3,7,8-tetrahydro-9H-thiazolo[20,30 :1,6]-
pyrido[2,3-d]pyrimidin-10-carbonitrile (4)
A solution of la (0.01 mol) in acetic anhydride (5 mL) was refluxed for
4 h. The solid product, thus formed, after cooling was filtered off and
recrystallized to give 4 (Table II).

300
A. A. El-Maghraby et al.
2-(4-Fluorophenyl)methylidene-7-(4-fluorophenyl)-2,3-
dihydro-5-ethoxymethyleneamino-7H-3-oxo-thiazolo[3,2-
a]-pyri mi din-6,8-dicarbonitrile (5)
A mixture of 1a (0.01 mol) and triethyl orthoformate (2 mL) in acetic
anhydride (10 mL) was refluxed for 10 h. The reaction mixture was
cooled, diluted with cold water and solid product was collected and re-
crystallized to give 5 (Table II).
TABLE III Spectral Data of the Synthesized Compounds
Compd.
1
no
IR
(cm
)
1H-NMR (ppm) (DMSO-d6)
max
1a
3400, 3300 (NH2), 2200 (C N), 4,67 (s, 1H, pyridine H), 7.23–7.79 (m, 9H,
1700 (C O)
3400, 3250 (NH2), 2200 (C N),
1700 (C N)
Ar H + methine H), 7.89 (s, 2H, NH2).
1b
1c
3420, 3380 (NH2), 2200 (C N), 2.34 (s, 3H, CH3), 2.39 (s, 3H, CH3), 4.55
1715 (C N)
(s, 1H, pyridine H), 7.20–7.58 (m, 9H,
Ar H + methine H), 7.83 (s, 2H, NH2).
1d
4
3450, 3400 (NH2), 2200 (C N), 4.60 (s, 1H, pyridine H), 6.77–7.78 (m, 9H,
1690 (C N)
Ar H + methine H), 9.50 (broad, 2H,
NH2).
3400 (NH), 2200 (C N) 1710,
1665 (C O)
2.34 (s, 3H, CH3), 4.67 (s, 1H, pyridine H),
7.16–7.89 (m, 9H, Ar H + methine H),
8.20 (s, 1H, CH-pyrimidine),
12.4 (s, 1H, NH).
5
2000 (C N), 1712 (C O)
1.33 (t, 3H, CH3), 4.36 (q, 2H, OCH2),
4.65 (s, 1H, pyridine H), 7.25–7.82 (m, 9H,
Ar H + methine H), 8.21 (s, 1H,
N
CH).
6
7
3350, 3300 (NH2) 20 (C N),
1690 (C O)
4.50 (s, 1H, pyridine H), 6.40 (broad, 2H,
NH2), 7.15–7.46 (m, 9H, Ar H + NH +
methine H), 8.40 (s, 1H, pyrimidine H).
1.49 (m, 6H, 2CH3), 3.12 (m, 1H, N CH),
4.51 (s, 1H, pyridine H), 6.57 (s, 1H, NH),
7.19–7.44 (m, 9H, Ar H + methine H),
8.25 (s, 1H, pyrimidine H).
3300 (NH), 2980 (CH-aliph),
2200 (C N), 1700 (C O)
8a
9
3178 (NH), 2214 (C N), 1705, 4.9 (s, 1H, pyridine H), 7.23–7.75 (m, 9H,
1658 (C N)
Ar H + methine H), 8.21 (s, 1H,
pyrimidine H), 12.5 (broad, 1H, NH).
4.20 (s, 1H, pyridine H), 7.27–7.76 (m, 9H,
Ar H + methine H), 8.20 (s, 1H,
pyrimidine H).
2200 (C N), 1700 (C O)
10a
10b
3400, 3300 (NH2), 2200 (C N),
1700 (C O)
3380, 3200 (NH2), 2200 (C N), 4.20 (s, 1H, pyridine H), 6.40 (s, 2H, NH2),
1700 (C O)
7.20 (m, 9H, Ar H + methine H),
8.02 (s, 1H, pyrimidine H).

Thiazolopyridines
301
7-Amino-2-(4-Fluorophenyl)methylidene-9-
(4-fluorophenyl)-8-imino-3-oxo-2,3,7,8-tetrahydro-9H-
thiazolo[20,30 :1,6]pyrido[2,3d]pyrimidin-10-
carbonitrile (6)
To a solution of 5 (0.01 mol) in absolute ethanol (30 mL) was added
hydrazine hydrate and the reaction was stirred at room temperature
for 2 h. The solid obtained was filtered off to give 6 (Table II).
2-(4-Fluorophenyl)methylidene-9-(4-fluorophenyl)-7-
isopropyl-8-imino-3-oxo-2,3,7,8-tetrahydro-9H-
thiazolo[20,30:1,6]pyrido-[2,3d]pyrimidin-10-
carbonitrile (7)
A mixture of 5 (0.01 mol) and isopropylamine (0.02 mol) in absolute
ethanol (20 mL) was heated under reflux for 1 h. The reaction mix-
ture was allowed to cool. The solid product was filtered off to give 7
(Table II).
2-(4-Fluorophenyl)methylidene-9-(4-fluorophenyl)-3,8-
dioxo-2,3,7,8-tetrahydro-9H-thiazolo[20,30 :1,6]pyrido[2,3-
d]pyrimidin-10-carbonitrile (8)
A mixture of 1a (0.01 mol) and formic acid (10 mL) was refluxed for
10 h. The solid product thus formed after cooling was filtered off to give
8 (Table II).
2-(4-Fluorophenyl)methylidene-9-(4-fluorophenyl)-8-
chloro-2,3-dihydro-9H-3-oxo-thiazolo[20,30 :1,6]-
pyrido[2,3d]pyrimidin-10-carbonitrile (9)
To a suspension of 8 (0.01 mol) in anhydrous dioxane (20 mL), dimethyl-
formamide (2 mL) and thionyl chlaride (2 mL) were added . The reaction
mixture was refluxed for 2 h. The solvent was evaporated in vacuo and
the solid formed was collected by filtration to give 9 (Table II).
2-(4-Fluorophenyl)methylidene-9-(4-fluorophenyl)-8-
amino-2,3-dihydro-9H-3-oxo-thiazolo[20,30 :1,6]-
pyrido[2,3-d]pyrimidin-10-carbonitrile (10)
A solution of 1a (0.01 mol) in formamide (20 mL) was refluxed for 2 h.
After cooling the reaction mixture was diluted with water and solid
precipitate was collected by filtration to give 10 ( Table II).

302
A. A. El-Maghraby et al.
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