Preparation of new derivatives of thiazole, thiazolidine, and thiazol-2-ylpyrazolo[3,4-d]pyrimidine sulfonamido conjugates

Article abstract of DOI:10.1080/10426500490475049

Several new thiazoles (3-7), thiazolylpyrazole carbonitrile (10,11), and Thiazolidine sulfonamido conjugate derivatives (19-26) were prepared starting with p-Piperidinesulfonylacetophenones (1,2). The structure of these compounds was elucidated on the bases of elemental analysis, IR, PMR, and mass spectra. The antimicrobial activities of some selected compounds are also reported.

Full text of DOI:10.1080/10426500490475049

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Phosphorus, Sulfur, and Silicon and the Related
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PREPARATION OF NEW DERIVATIVES OF THIAZOLE,
THIAZOLIDINE, AND THIAZOL-2-YLPYRAZOLO[3,4-
D]PYRIMIDINE SULFONAMIDO CONJUGATES
Moustafa M. Khafagy a , Ahmed A. El-Maghraby a , Saber M. Hassan a & Mahmoud S. Bashandy
a
a Chemistry Department, Faculty of Science, Al-Azhar University , Nasr City, Cairo, Egypt
Published online: 16 Aug 2010.
To cite this article: Moustafa M. Khafagy , Ahmed A. El-Maghraby , Saber M. Hassan & Mahmoud S. Bashandy (2004)
PREPARATION OF NEW DERIVATIVES OF THIAZOLE, THIAZOLIDINE, AND THIAZOL-2-YLPYRAZOLO[3,4-D]PYRIMIDINE
SULFONAMIDO CONJUGATES, Phosphorus, Sulfur, and Silicon and the Related Elements, 179:10, 2113-2129, DOI:
10.1080/10426500490475049
To link to this article: http://dx.doi.org/10.1080/10426500490475049
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Phosphorus, Sulfur, and Silicon, 179:2113–2129, 2004
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490475049
PREPARATION OF NEW DERIVATIVES
OF THIAZOLE, THIAZOLIDINE, AND
THIAZOL-2-YLPYRAZOLO[3,4-D]PYRIMIDINE
SULFONAMIDO CONJUGATES
Moustafa M. Khafagy, Ahmed A. El-Maghraby,
Saber M. Hassan, and Mahmoud S. Bashandy
Chemistry Department, Faculty of Science, Al-Azhar University,
Nasr City, Cairo, Egypt
(Received January 15, 2004; accepted March, 27, 2004)
Several new thiazoles (3–7), thiazolylpyrazole carbonitrile (10,11),
and Thiazolidine sulfonamido conjugate derivatives (19–26)
were prepared starting with p-Piperidinesulfonylacetophenones
(1,2). The structure of these compounds was elucidated on the bases
of elemental analysis, IR, PMR, and mass spectra. The antimicrobial
activities of some selected compounds are also reported.
Keywords: p-Piperidinesulfonylacetophenones; thiazole; thiazolidine-
containing piperidine sulfonamide; thiazolylpyrazol
INTRODUCTION
Due to considerable interest in their bioactivity, the syntheses of thi-
azole and their derivatives from thioacetamide derivatives have been
explored with significant success.1–15 The thiazolidine moiety occurs
in different bioactive substances as an important pharmacophoric
group, for instance, the imidazo[2,1-b]thiazole system in the main moi-
ety of the well-known antihelmintic and immunomodulatory agent
levamisole.16,17 Thiazol[2,3-a]pyrimidines bear a structure analogous
to levamisol and have been well studied as immunomodulatory, anti-
cancer, analgesic, and psychotropic agents.16–18 In the present article
we detail the synthesis of thiazole, thiazolidine, and thiazolylpyra-
zolopyrimidine sulfonamido conjugates displaying improved biologi-
cal properties with respect to the nonsulfonamido-conjugated thiazole
Address correspondence to Moustafa M. Khafagy, Chemistry Department, Faculty of
Science, Al-Azhar University, Nasr City, 11884, Cairo, Egypt. E-mail: khafagy@dr.com
2113

2114
M. M. Khafagy et al.
compounds. The antibacterial and antifungal screening of some selected
compounds is also included.
RESULTS
p-Piperidinosulfonylacetophenone (1)19 and p-piperidinosulfonylaceto-
phenacyl bromide (2)20 were used as our starting materials. Thus,
treatment of 2 with thiourea and thioacetamide compounds in re-
fluxing ethanol afforded the corresponding thiazol-2-yl derivatives
(3a–d) (Scheme 1). Also, when 2 was subjected to the reaction with
p-anisaldehydethiosemicarbazone in boiling ethanol, the correspond-
ing thiazol-2-yl derivative (3e) was obtained. The thiazole derivative 3d
SCHEME 1

Thiazoles and Sulfonamido Conjugates
2115
couples readily with benzene diazonium chloride in ethanolic sodium
acetate to afford the coupling product for which two isomeric structures
4 or 5 seemed possible. PMR provided a firm support for structure
4 and ruled out the other possible isomer 5, the lack of the sig-
nal due to methylene protons, and the appearance of the signal due
to the H-thiazole at δ 7.7 ppm. Also, the structure 4 was further
confirmed by an independent synthesis from the reaction of 2 with
2-phenylhydrazono-2-cyanoethanethioamide (6). On the other hand, 3d
was condensed with p-anisaldehyde in boiling ethanolic piperidine so-
lution successfully to give the corresponding thiazol-2-ylacrylonitrile
derivative (7), which was prepared independently from the reaction of 2
with p-methoxybenzylidenecyanothioacetamide (8) in refluxing ethanol
(Scheme 1). Evidence for structures for the latter compounds were pro-
vided on the basis of elemental analysis (Table I) and spectral data.
Cyclocondensation of 2 with an equimolar amount of 5-amino-4-
cyano-3-methylthio-pyrazole-1-thiocarboxamide (9)21 in boiling ethanol
yielded 5-amino-3-methylthio-1-[4-(4-piperidinosulfonylphenyl)-thia-
zol-2-yl]-1H-pyrazole-4-carbonitrile (10) (Scheme 2). Evidence for the
SCHEME 2

2116
M. M. Khafagy et al.
TABLE I Physical and Analytical Data for the Newly Prepared Compounds
Calc. (Found)
m.p
(solvent)
Color
(yield %)
M. formula
(M. wt.)
Comp.
C
H
3a
244
(Et./B.)
213
(Et.)
137
(Et./B.)
171
(Et./B.)
220
(Et./B.)
211
(Et./B.)
199
(Et./B.)
276
(Et./B.)
207
(Et./B.)
321
Dioxan
230
(Et./B.)
201
(Et.)
285
(Et.)
210
(Et./B.)
220
(Et./B.)
156
(Et.)
247
(Et./B.)
215
(Et./B.)
216
(Et.)
232
(Et./B.)
201
(Et./B.)
196
(Et./B.)
210
(Et.)
210
(Et.)
141
Yellow
(79)
Yellow
(85)
Yellow
(80)
Yellow
(80)
Yellow
(79)
Yellow
(70)
Yellow
(80)
Yellow
(70)
Yellow
(80)
Colorless
(66)
Pale yellow
(80)
Yellow
(78)
Yellow
(65)
Yellow
(80)
Yellow
(85)
Faint yellow
(80)
Yellow
(75)
Yellow
(77)
Yellow
(77)
Colorless
(85)
Yellow
(70)
Yellow
(80)
Pale yellow
(66)
Brown
(66)
C14H17N3O2S2
(323)
51.95
(52.01)
60.10
(60.15)
55.80
(55.90)
55.16
(55.33)
57.70
(57.89)
58.50
(58.54)
61.70
(61.91)
49.57
(49.57)
51.06
(51.16)
50.15
(50.20)
49.38
(49.41)
57.67
(57.69)
55.17
(55.19)
50.33
(50.53)
57.77
(57.89)
51.47
(51.50)
72.25
(72.36)
62.62
(62.77)
60.01
(60.16)
63.87
(63.97)
57.33
(57.53)
47.21
(47.32)
57.99
(58.02)
48.54
(48.61)
60.78
5.20
(5.26)
5.20
(5.26)
5.50
(5.59)
4.85
(4.90)
5.10
(5.26)
4.60
(4.66)
4.80
(4.98)
4.35
4.35)
4.55
(4.65)
4.28
(4.38)
5.66
(5.88)
5.65
(5.77)
5.52
(5.62)
5.22
(5.26)
5.16
(5.26)
5.48
(5.58)
6.43
(6.53)
5.12
(5.23)
4.57
(4.67)
5.04
(5.15)
5.41
(5.48)
5.79
(5.92)
5.31
(5.49)
5.28
(5.32)
5.18
3b
3c
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
20H21N3O2S2
(399)
15H18N2O2S2
(322)
16H17N3O2S2
(347)
22H24N4O3S2
(456)
22H21N5O2S2
(451)
24H23N3O3S2
(465)
19H20N6O2S3
(460)
22H24N6O3S3
(516)
21H22N6O3S3
(502)
14H20N4O2S2
(340)
20H24N4O2S2
(416)
27H33N5O4S3
(587)
16H20N4O3S2
(380)
22H24N4O3S2
(456)
20H26N4O5S2
(466)
24H26N4O4S2
(498)
3d
3e
4
7
10
11
12
13a
13b
14
15a
15b
16
19a
19b
19c
19d
20
30H30N4O4S2
(573)
C
29H27ClN4O3S2
(579)
C
29H28N4O3S2
(544)
C
28H32N4O6S2
(584)
22
C
C
C
C
14H21N5O2S2
(355)
22H25N5O2S2
(455)
16H21N5O3S2
(395)
32H33N5O5S2
(631)
23
24
26
Yellow
(82)
(Et./B.)
(60.86)
(5.23)
E.t, Ethanol; B, Benzene.

Thiazoles and Sulfonamido Conjugates
2117
structure of 10 was provided on the basis of elemental analysis and
spectral data. Treatment of 10 with triethylorthoformate in acetic an-
hydride under reflux gave the corresponding 5-ethoxymethyleneamino
derivative (11). Compound 11 treated with hydrazine hydrate in stirred
ethanol at room temperature led to the formation of a product that was
found to be identical in all respects (m.p., mixed m.p., and spectral
data) with 10. The formation of 10 was assumed to proceed via addi-
tion of hydrazine to give the hydrazino intermediate (A) followed by
elimination of ethyl formate hydrazone21 (Scheme 2). Interaction of 10
with refluxing acetic anhydride yielded a single product that was iden-
tified as 1-(thiazol-2-yl)pyrazolo[3,4-d]pyrimidine-4-one derivative (12)
on the basis of elemental analysis and spectral data (Scheme 2).
Condensation of p-piperidinosulfonylacetophenone (1) with thio-
semicarbazide gave the corresponding thiosemicarbazones (13a,b)
(Scheme 3). The structure of 13 was confirmed on the basis of elemental
SCHEME 3

2118
M. M. Khafagy et al.
analysis and spectral data. The mass spectrum of 13b gave a fragment
peak at m/z (intensity %) 323 (30.1) ([M+]-C6H5NH2) instead of molec-
ular ion peak. Treatment of 13a with phenacyl bromide derivative
2 gave the corresponding 2-aminothiazole derivative 14 bearing two
sulfonamide groups (Scheme 3). Cyclocondensation of 13a,b with
an equimolar ratio of ethyl bromoacetate afforded the corresponding
4-thiazolidinone (15a,b), respectively. Treatment of 13a with two
moles of ethyl bromoacetate gave N-ethoxycarbonylmethylthiazolidin-
4-one derivative (16). The structure of 16 was further confirmed
unequivocally by an independent synthesis from 15a and ethyl
bromoacetate in ethanolic sodium acetate solution (Scheme 3). At-
tempts to transform 4-thiazolidinone 15 into fused thiazolo[4,5-b]pyran
compound 18 through Michael addition of 15 with arylidene malononi-
trile 17 were unsuccessful, and the only isolatable products were iden-
tified as 5-arylmethylidenethiazolidine-4-one derivatives (19), which
were prepared from condensation of 15 with aromatic aldehydes.
The formation of 19 from 15 and 17 can be explained by the addi-
tion of active methylene of 15 to active olefinic bond of 17 forming
the intermediate (B), which undergoes spontaneous elimination of mal-
ononitrile to give the final product 19 (Scheme 4). Also, the thiazo-
lidinone 16 reacted with p-methoxybenzylidenemalononitrile (17a) or
p-methoxybenzaldeyde to give a single product with two possible iso-
meric structures (20, 21). The absence of thiazole CH2 proton signal at
δ 3.8 ppm and the existance of CH2 proton signal of acetate moiety at δ
4.7 ppm in its PMR spectrum provided firm support for the structure 20
SCHEME 4

Thiazoles and Sulfonamido Conjugates
2119
SCHEME 5
(Scheme 5). The structure 20 was further supported by an independent
synthesis from the reaction of 19a with ethyl bromoacetate.
The structures of 13–20 were supported by correct elemental analysis
(Table I) and spectral data.
Condensation of 1 with thiocarbohydrazide afforded thiocarbohydra-
zone derivative 22. Cyclocondensation of 22 with equimolar amount
of phenacyl bromide yielded 4-phenylthiazol-3-ylamine derivative 23
(Scheme 6). Also, 22 reacted with ethyl bromoacetate to give a
single product. Two possible isomeric structures were proposed: 3-
aminothiazolidin-4-one (24) and 1,3,4-thiadiazin-5-one (25) deriva-
tives. The absence of NH signal and the existence of NH2 signal
at δ 4.7 ppm (PMR spectrum) provided firm support for the struc-
ture 24. Further confirmation for structure 24 comes from its ready
condensation with two moles of p-anisaldehyde to afford the corre-
sponding 5-(4-methoxybenzylidene)-3-(4-methoxybenzylidene-amino)-
thiazolidin-4-one derivative (26) (Scheme 6). This condensation sup-
ports the presence of free NH2 and active CH2 groups in 24.
The above structures were established from elemental analysis
(Table I) and spectral data.
ANTIMICROBIAL ACTIVITIES
The results of antimicrobial screening (Table II) show that the com-
pound 15b is the most active compound against Klebsiella pneumo-

2120
M. M. Khafagy et al.
SCHEME 6
nia (NCIMB-9111) (IZ 20 mm), while compounds 3b, 16, 19a, 22 gave
IZ 19 mm and compound 13a gave IZ 18 mm. Also, the results indi-
cated that compounds 16, 13a exhibited highest activity against Rhi-
zopus fungi (IZ 24, 23 mm, respectively), while compounds 3b, 3d, 7,
15b, and 19a gave IZ 18–20 mm. The compound 19d exhibited high-
est activity against Aspergillus fungigatus (IZ 22 mm) while compounds
3a,b,d, 19a, and 22 gave IZ 19–20 mm. All remaining tested compounds
are weakly active against all of the tested microorganisms. It seems

2121

2122
M. M. Khafagy et al.
that most activity was exhibited by derivatives with thiazolidinone
nucleus.
EXPERIMENTAL SECTION
Melting points are uncorrected. Elemental analyses were carried out
in the Microanalytical Laboratories of the Faculty of Science, Cairo
University. Ultraviolet spectra were recorded on Perkin Elmer Lambda-
3B UV-visible spectrophotometer. IR spectra (KBr) were measured on a
Fourier transform infrared (FTIR)/5300 spectrometer, 1H NMR spectra
on a Varian Mercury (300/75 MHz) spectrometer and mass spectra on
a Shimadzu GC-MS-QP 1000 EX spectrometer.
Thiazol-2-yl Derivatives (3a–e)
A mixture of phenacyl bromide (2) (0.01 mol) and thiourea, thioac-
etamide compounds (0.01 mol) in ethanol (50 ml) was heated under
reflux for 4 h. The separated solid was filtered off, washed with ethanol,
and recrystallized from suitable solvent to give 3a–e (Table I).
3a: IR (film) ν = 3426, 3295 (NH2), 2946 (CH-aliph.), 1630 cm−1
(C N). MS (EI, 70 eV): m/z (%) = 323 (35.4) [M+], 239 (5.7), 175 (68.6),
133 (8), 84 (100).
3b: IR (film): ν = 3309 (NH), 2936 (CH-aliph.), 1595 cm−1 (C N).
MS (EI, 70 eV): m/z (%) = 399 (100) [M+], 316 (28.25), 251 (70.36), 133
(0.25), 84 (4.11).
3c: IR (film): ν = 3100 (CH-arom.), 2980 cm−1 (CH-aliph.). 1H
NMR (300.069 MHz, CDCl3): δ = 1.43 (br, 2H, CH2 (c), piperidine),
1.64 (t, 4H, 2CH2 (b), piperidine), 2.70 (s, 3H, CH3), 3.00 (t, 4H, 2CH2
(a), piperidine), 7.45 (s, 1H, CH-thiazole), 7.79 and 8.03 ppm (dd, 4H,
AB-ArH; J = 10.2 Hz). MS (EI, 70 eV): m/z (%) = 322 (17.6) [M+], 238
(10), 174 (38.5), 133 (8.3), 84 (100).
3d: IR (film): ν = 3090 (CH-arom.), 2855 (CH-aliph.), 2251 cm−1
(CN). 1H NMR (300.069 MHz, CDCl3): δ = 1.43 (br, 2H, CH2 (c), piperi-
dine), 1.64 (t, 4H, 2CH2 (b), piperidine), 3.00 (t, 4H, 2CH2 (a), piperi-
dine), 4.30 (s, 2H, CH2CN), 7.70 and 8.10 (dd, 4H, AB-ArH; J = 8.4 Hz),
7.80 ppm (s, 1H, CH-thiazole). MS (EI, 70 eV): m/z (%) = 347 (10) [M+],
263 (6.6), 199 (20.4), 133 (5.4), 84 (100).
3e: IR (film): ν = 3260 (NH), 3095 (CH-arom.), 2843 (CH-aliph.),
1603 cm−1 (C N). 1H NMR (300.069 MHz, CDCl3): δ = 1.35 (m, 2H, CH2
(c), piperidine), 1.59 (m, 4H, 2CH2 (b), piperidine), 2.95 (t, 4H, 2CH2 (a),
piperidine), 3.82 (s, 3H, OCH3), 6.80–7.98 ppm (m, 10H, (8ArH, CH N
and CH-thiazole)). MS (EI, 70 eV): m/z (%) = 456 (25) [M+], 323 (9), 239
(10), 175 (60), 133 (12), 84 (100).

Thiazoles and Sulfonamido Conjugates
2123
Phenylhydrazono{4-[4-(piperidine-1-sulfonyl)phenyl]-
thiazol-2-yl}acetonitrile (4)
Method (a)
To a solution of thiazol-2-ylacetonitrile derivative (3d) (0.01 mol) in
ethanol (20 ml) containing sodium acetate (0.08 mol), benzene diazo-
nium chloride (0.01 mol) was added dropwise with stirring. The ob-
tained product was collected and recrystallized to give compound 4
(Table I).
Method (b)
p-Piperidinosulfonylacetophenacylbromide (2) (0.01 mol) and 2-
phenylhydrazono-2-cyanoethanethioamide (6) (0.01 mol) in ethanol
(50 ml) was heated under reflux for 5 h, the obtained product was col-
lected to give 4, m.p. and mixed m.p. determined with authentic sample
gave no depression (Table I). IR (film): ν = 3120 (NH), 2215 cm−1 (CN).
1H NMR (300.069 MHz, CDCl3): δ = 1.43 (br, 2H, CH2 (c), piperidine),
1.64 (t, 4H, 2CH2 (b), piperidine), 3.00 (t, 4H, 2CH2 (a), piperidine),
7.10–7.40 (m, 5H, ArH), 7.70 (s, 1H, CH-thiazole), 7.90 and 8.00 (dd,
4H, AB-ArH; J = 9.9 Hz), 13.90 ppm (s, 1H, NH). MS (EI, 70 eV): m/z
(%) = 451 (18) [M+], 423 (1.7), 275 (3.1), 199 (1.9), 133 (2.6), 77 (100).
3-(4-Methoxyphenyl)-2-{4-[4-(piperidine-1-sulfonyl)-
phenyl]thiazol-2-yl}acrylonitrile (7)
Method (a)
A mixture of 3d (0.01 mol), p-anisaldehyde (0.012 mol), and piperi-
dine (1 ml) in ethanol (50 ml) was refluxed for 1 h to give 7 (Table I).
Method (b)
A mixture of phenacyl bromide (2) (0.01 mol) and p-methoxy-
benzylidene-cyanothioacetamine (8) (0.01 mol) in ethanol (50 ml) was
heated under reflux for 4 h, the separated solid was filtered off, washed
with ethanol and recrystallized to give 7, m.p. and mixed m.p. deter-
mined with authentic sample gave no depression (Table I). IR (film):
ν = 3110 (CH-arom.), 2942 (CH-aliph.), 2212 cm−1 (CN). MS (EI, 70
eV): m/z (%) = 465 (100) [M+], 381 (11.8), 317 (35.6), 133 (3.9), 84 (17.4).
5-Amino-3-methylsulfonyl-1-{4-[4-(piperidine-1-sulfonyl)-
phenyl]thiazol-2-yl}-1H-pyrazole-4-carbonitrile (10)
A mixture of phenacyl bromide (2) (0.01 mol) and 5-amino-4-cyano-
3-methyl-sulphonylpyrazole-1-thiocarboxamide (9)21 (0.01 mol) in

2124
M. M. Khafagy et al.
ethanol (50 ml) was heated under reflux for 7 h. The separated solid was
washed with ethanol and recrystallized to give 10 (Table I). IR (film):
ν = 3399, 3297 (NH2), 3097 (CH-arom.), 2216 cm−1 (CN). 1H NMR
(300.069 MHz, CDCl3): δ = 1.25 (m, 2H, CH2 (c), piperidine), 1.64 (m,
4H, 2CH2 (b), piperidine), 2.6 (s, 3H, CH3S), 3.00 (t, 4H, 2CH2 (a), piperi-
dine), 6.6 (s, 2H, NH2), 7.36 (s, 1H, CH-thiazole), 7.80 and 7.90 ppm (dd,
4H, AB-ArH; J = 7.8 Hz).-MS (EI, 70 eV): m/z (%) = 460 (48.2) [M+],
312 (20.6), 265 (23.3), 175 (3.3), 133 (4.1), 101 (4.9), 84 (100), 77 (3.8).
N-(4-Cyano-5-methylsulfonyl-2-{4-[4-(piperidine-1-
sulfonyl)phenyl]thiazol-2-yl}-2H-(pyrazole-3-yl)-
formimidic acid ethyl ester (11)
A mixture of 10 (0.01 mol) and triethyl orthoformate (0.01 mol) in acetic
anhydride (20 ml) was heated under reflux for 5 h and the separated
solid was recrystallized to give 11 (Table I). IR (film): ν = 3092 (CH-
arom.), 2929 (CH-aliph.), 2222 cm−1 (CN).
Reaction of Compound 11 with Hydrazine Hydrate
A mixture of 11 (0.01 mol) and hydrazine hydrate (0.12 mol) in ethanol
(40 ml) was stirred at room temperature for 2 h, and the solid that
formed was recrystallized to give 10. m.p. and mixed m.p. were deter-
mined with authentic sample gave no depression (Table I).
6-Methyl-3-methylsulfonyl-1-{4-[4-(piperidine-1-
sulfonyl)phenyl]thiazol-2-yl}-1,5-dihydropyrazolo[3,4-d]-
pyrimidin-4-one (12)
A mixture of 10 (0.01 mol) and acetic anhydride (30 ml) was heated
under reflux for 5 h. The reaction mixture was concentrated under re-
duced pressure and the separated solid was recrystallized to give 12
(Table I).-IR (film): ν = 3482 (NH), 3094 (CH-arom.), 2934 (CH-aliph.),
1686 cm−1 (C=O).-MS (EI, 70 eV): m/z (%) = 502 (23) [M+], 340 (23),
264 (17), 174 (10), 84 (100).
1-[4-(piperidine-1-sulfonyl)phenyl]ethanone
Thiosemicarbazone and Its Phenyl Derivatives (13a,b)
A mixture of p-piperidinosulfonylacetophenone (1) (0.01 mol) and
thiosemicarbazide or phenyl thiosemicarbazide (0.01 mol) in ethanol
(50 ml) was heated under reflux for 5 h. The separated solid was recrys-
tallized to give 13a,b (Table I).

Thiazoles and Sulfonamido Conjugates
2125
13a: IR (film): ν = 3431, 3316 (NH2), 3237 (NH), 2927 (CH),
1
1332 cm−1 (C=S). H NMR (300.069 MHz, CDCl3): δ = 1.40 (m, 2H,
CH2 (c), piperidine), 1.60 (m, 4H, 2CH2 (b), piperidine), 2.30 (s, 3H,
CH3), 3.00 (t, 4H, 2CH2 (a), piperidine), 6.4 (br, 2H, NH2), 7.70 and
7.80 (dd, 4H, AB-ArH; J = 8.4 Hz), 8.70 ppm (s, 1H, NH).
13b: IR (film): ν = 3318 (NH), 2937 (CH), 1292 cm−1 (C=S). MS (EI,
70 eV): m/z (%) = 323 (30.1) [M+−C6H5NH2 ], 265 (15), 223 (21.9), 117
(33.8), 90 (7.5), 84 (100).
N-{1-[4-(Piperidine-1-sulfonyl)phenyl]ethylidene}-Nꢀ-{4-
[4-(piperidine-1-sulfonyl)phenyl]thiazol-2-yl}hydrazine
(14)
A mixture of 13a (0.01 mol) and phenacyl bromide (2) (0.01 mol) in
ethanol (50 ml) was heated under reflux for 8 h. The separated solid
was recrystallized to give 14 (Table I). IR (film): ν = 3349 (NH), 2935
(CH), 1556 cm−1 (C N). MS (EI, 70 eV): m/z (%) = 587 (4.8) [M+], 323
(9.5), 265 (11.2), 240 (4.3), 175 (20.6), 133 (4.3), 84 (100).
3-Substituted-2-({1-[4-(piperidine-1-sulfonyl)-
phenyl]ethylidene}-hydrazono)thiazolidin-4-one (15a,b)
A mixture of 13a,b (0.01 mol), ethyl bromoacetate (0.01 mol) and sodium
acetate (0.08 mol) in ethanol (50 ml) was heated under reflux for 5 h.
The separated solid was recrystallized to give 15a,b (Table I).
15a: IR (film): ν = 3228 (NH), 2933 (CH), 1726 cm−1 (C=O). MS (EI,
70 eV): m/z (%) = 380 (22.4) [M+], 296 (2.5), 232 (11.4), 193 (16.2), 130
(25.6), 84 (100).
1
15b: IR (film): ν = 2932 (CH), 1729 cm−1 (C=O). H NMR (300.069
MHz, CDCl3): δ = 1.40 (m, 2H, CH2 (c), piperidine), 1.60 (m, 4H, 2CH2
(b), piperidine), 2.26 (s, 3H, CH3), 3.00 (t, 4H, 2CH2 (a), piperidine),
3.96 (s, 2H, CH2), 7.30–7.50 (m, 5H, ArH), 7.70 and 7.90 ppm (dd, 4H,
AB-ArH; J = 8.7 Hz).
[4-Oxo-2-({1-[4-(piperidine-1-sulfonyl)phenyl]-
ethylidene}-hydrazono)thiazolidin-3-yl] Acetic Acid
Ethyl Ester (16)
Method (a)
A mixture of 13a (0.01 mol), ethyl bromoacetate (0.02 mol), and
sodium acetate (0.08 mol) in ethanol (50 ml) was heated under

2126
M. M. Khafagy et al.
reflux for 8 h. The separated solid was recrystallized to give 16
(Table I).
Method (b)
A mixture of 15a (0.01 mol), ethyl bromoacetate (0.02 mol), and
sodium acetate (0.08 mol) in ethanol (50 ml) was heated under re-
flux for 8 h. The separated solid was recrystallized to give 16. m.p.
and mixed m.p. determined with authentic sample gave no depres-
sion (Table I). IR (film): ν = 2940 (CH), 1750 (CO-ester), 1727 cm−1
(C O). 1H NMR (300.069 MHz, CDCl3): δ = 1.31 (t, 3H, CH -CH2),
3
1.40 (m, 2H, CH2 (c), piperidine), 1.60 (m, 4H, 2CH2-(b), piperidine),
2.40 (s, 3H, CH3), 3.00 (t, 4H, 2CH2 (a), piperidine), 3.80 (s, 2H, S-
CH2CO), 4.20 (q, 2H, CH -CH3), 4.50 (s, 2H, N-CH2-COOEt), 7.70
2
and 7.90 ppm (dd, 4H, AB-ArH; J = 8.4 Hz). MS (EI, 70 eV): m/z
(%) = 466 (31.1) [M+], 318 (4.2), 232 (6.4), 117 (100), 102 (32.3), 84
(85.9).
3,5-Disubstituted-2-({1-[4-(piperidine-1-sulfonyl)phenyl]-
ethylidene}-hydrazono)- thiazolidin-4-one (19a–d)
Method (a)
A mixture of 15a,b (0.01 mol), respective benzylidine malononitrile
derivative (0.01 mol), and few drops of piperidine in ethanol (40 ml) was
heated under reflux for 4 h. The separated solid was recrystallized to
give 19a–d (Table I).
Method (b)
A mixture of 15a or b (0.01 mol), respective aromatic aldehyde
(0.01 mol), and a few drops of piperidine in ethanol (40 ml) was heated
under reflux for 4 h to give 19a–d; m.p. and mixed m.p. determined
with authentic sample gave no depression (Table I).
19a: IR (film): ν = 3113 (NH), 2937 (CH), 1702 cm−1 (C=O).
1
19b: IR (film): ν = 2928 (CH), 1709 (C=O), 1617 cm−1 (C=C). H
NMR (300.069 MHz, CDCl3): δ = 1.40 (m, 2H, CH2 (c), piperidine), 1.60
(m, 4H, 2CH2 (b), piperidine), 2.40 (s, 3H, CH3), 2.90 (t, 4H, 2CH2 (a),
piperidine), 3.80 (s, 3H, OCH3), 7.00–8.00 ppm (m, 14H, (13ArH and
=CH)).
19c: IR (film): ν = 2928 (CH), 1708 cm−1 (C=O).
19d: IR (film): ν = 2935 (CH), 1719 (C=O), 1613 cm−1 (C=C). MS
(EI, 70 eV): m/z (%) = 544 (31.8) [M+], 396 (2.4), 265 (6.9), 134 (100),
177 (24), 84 (39.4).

Thiazoles and Sulfonamido Conjugates
2127
[5-(4-Methoxybenzylidene)-4-oxo-2-({1-[4-(piperidine-1-
sulfonyl)phenyl]ethylidene}hydrazono)thiazolidin-3-yl]
Acetic Acid Ethyl Ester (20)
Method (a)
A mixture of 16 (0.01 mol), p-methoxybenzylidenemalononitrile or p-
anis-aldehyde (0.01 mol) and few drops of piperidine in ethanol (40 ml)
was heated under reflux for 5 h. The separated solid was recrystallized
to give 20 (Table I).
Method (b)
A mixture of 19a (0.01 mol), ethyl bromoacetate (0.01 mol), and
sodium acetate (0.08 mol) in ethanol (50 ml) was heated under reflux for
5 h. The separated solid was recrystallized to give 20. m.p. and mixed
m.p. determined with authentic sample gave no depression (Table I).
1
IR (film): ν = 2932 (CH), 1749 (CO-ester), 1706 cm−1 (CO).- H NMR
(300.069 MHz, CDCl3): δ = 1.30 (t, 3H, CH -CH2), 1.40 (m, 2H, CH2 (c),
3
piperidine), 1.60 (m, 4H, 2CH2 (b), piperidine), 2.40 (s, 3H, CH3), 3.00
(t, 4H, 2CH2 (a), piperidine), 3.80 (s, 3H, OCH3), 4.20 (q, 2H, CH -CH3),
2
4.70 (s, 2H, CH2-COOEt), 7.00 and 7.50 (dd, 4H, AB-ArH; J = 8.7 Hz),
7.70 (s, 1H, = CH), 7.70 and 8.00 ppm (dd, 4H, AB-ArH; J = 8.7 Hz).
N-{1-[4-(Piperidine-1-sulfonyl)phenyl]ethylidene}-
thicarbohydrazone (22)
A mixture of acetophenone derivative (1) (0.01 mol) and thiocarbohy-
drazide (0.01 mol) in ethanol (50 ml) was heated under reflux for 4 h.
The separated solid was recrystallized to give 22 (Table I). IR (film):
ν = 3443, 3263, 3170 (NH2, NH), 1164 cm−1 (C S). MS (EI, 70 eV): m/z
(%) = 355 (3.7) [M+], 323 (23), 265 (12.3), 249 (14.1), 223 (17.2), 117
(33), 84 (100).
4-Phenyl-2-({1-[4-(piperidine-1-sulfonyl)phenyl]-
ethylidene}hydrazono)thiazol-3-ylamine (23)
A solution of 22 (0.01 mol) and phenacyl bromide (0.01 mol) in ethanol
(30 ml) containing fused sodium acetate (0.02 mol) was heated under
reflux for 3 h. The separated solid was recrystallized to give 23 (Table I).
1
IR (film): ν = 3227, 3113 (NH2), 1587 cm−1 (C N). H NMR (300.069
MHz, CDCl3): δ = 1.20 (m, 2H, CH2 (c), piperidine), 1.60 (m, 4H, 2CH2
(b), piperidine), 2.50 (s, 3H, CH3), 3.00 (t, 4H, 2CH2 (a), piperidine), 4.70
(br, 2H, NH2), 6.10 (s, 1H, CH-thiazole), 7.40–7.50 (m, 5H, ArH), 7.70–
8.00 ppm (dd, 4H, AB-ArH; J = 8.4 Hz). MS (EI, 70 eV): m/z (%) = 455

2128
M. M. Khafagy et al.
(27.1) [M+], 265 (26.3), 190 (100), 134 (37.4), 117 (23.7), 84 (70.5), 77
(38.3).
3-Amino-2-({1-[4-(piperidine-1-sulfonyl)phenyl]-
ethylidene}hydrazono)thiazolidin-4- one (24)
A mixture of 22 (0.01 mol) and ethyl bromoacetate (0.01 mol) in ethanol
(30 ml) containing fused sodium acetate (0.02 mol) was heated under
reflux for 3 h. The obtained solid was recrystallized to give 24 (Table I).
IR (film): ν = 3446, 3240 (NH2), 3095 (CH-arom.), 2851 (CH-aliph.),
1724 cm−1 (C=O). 1H NMR (300.069 MHz, CDCl3): δ = 1.40 (m, 2H, CH2
(c), piperidine), 1.60 (m, 4H, 2CH2 (b), piperidine), 2.50 (s, 3H, CH3),
3.00 (t, 4H, 2CH2 (a), piperidine), 3.80 (s, 2H, CH2), 4.70 (s, 2H, NH2;
exchanged with D2O), 7.70 and 8.00 ppm (dd, 4H, AB-ArH; J = 10.3
Hz). MS (EI, 70 eV): m/z (%) = 395 (25.1) [M+], 265 (61.1), 117 (38.4),
84 (100).
5-(4-Methoxybenzylidene)-3-[(4-Methoxybenzylidene)-
amino]-2-({1-[4-(piperidine-1-sulfonyl)phenyl]-
ethylidene}hydrazono)thiazolidin-4-one (26)
A mixture of 24 (0.01 mol) and p-anisaldehyde (0.02 mol) in ethanol
(30 ml) contains few drops of piperidine was heated under reflux for
4 h. The separated solid was recrystallized to give 26 (Table 1). IR
1
(film): ν = 3098 (CH-arom.), 2920 (CH-aliph.), 1718 cm−1 (C=O). H
NMR (300.069 MHz, CDCl3): δ = 1.50 (br, 2H, CH2 (c), piperidine), 1.66
(br, 4H, 2CH2 (b), piperidine), 2.50 (s, 3H, CH3), 3.00 (s, 4H, 2CH2 (a),
piperidine), 3.87 and 3.88 (2s, 6H, 2OCH3), 7.80 (s, 1H, =CH), 9.20 (s,
1H, N=CH), 6.90–8.08 ppm (m, 12H, 3AB-ArH).
ANTIMICROBIAL SCREENING
The selected compounds were evaluated for their antimicrobial activity
using the agar diffusion technique.22,23 A mg/ml solution in dimethylfor-
mamide was used. The test organisms were Gram-positive Bacillus sub-
tilis (NCTC-1040), Staphylcococcus aureus (NCTC-7447), Sarcina max-
ima (ATCC-33910); Gram-negative Klebsiella peneumonia (NCIMB-
9111), Salmonella, Pseudomonas aeruginosa (ATCC-10145); Unicellu-
lar fungi Candida albicans (IMRU-3669); and Filamentous fungi Rhi-
zopus, Asperigillus fumigatus. DMF showed no inhibition zones. The
reference antibiotics were Ampicillin (AMD) and Calforan. The inhibi-
tion zones (IZ) of these compounds are listed in Table II.

Thiazoles and Sulfonamido Conjugates
2129
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