Eco-friendly solvent-free synthesis of thiazolylpyrazole derivatives

Article abstract of DOI:10.1007/s00706-008-0930-4

Highly versatile ethyl 3-thiosemicarbazidobutanoate was ball-milled with phenacyl bromide to afford the corresponding ethyl 3-[(4-phenyl-2-thiazolyl) hydrazono]butanoate which underwent heterocyclization by heating in ethanolic sodium acetate to give thia

Full text of DOI:10.1007/s00706-008-0930-4

Monatsh Chem 139, 1329–1335 (2008)
DOI 10.1007/s00706-008-0930-4
Printed in The Netherlands
Eco-friendly solvent-free synthesis of thiazolylpyrazole derivatives
Samir Bondock, Hossam El-Azap, Ez-Eldin M. Kandeel, Mohamed A. Metwally
Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt
Received 31 December 2007; Accepted 19 March 2008; Published online 9 June 2008
# Springer-Verlag 2008
Abstract Highly versatile ethyl 3-thiosemicarbazido-
butanoate was ball-milled with phenacyl bromide to
afford the corresponding ethyl 3-[(4-phenyl-2-thiazo-
lyl)hydrazono]butanoate which underwent heterocy-
clization by heating in ethanolic sodium acetate to
give thiazolylpyrazolone that coupled chemoselec-
tively with aromatic diazonium salts to furnish arylhy-
drazonothiazolylpyrazoles. Vilsmeier-Haack reaction
of ethyl 3-thiosemicarbazidobutanoate furnished se-
lectively thiazolylpyrazole. A series of pyrazolyl-
thiosemicarbazones were synthesized by solid-state
technique which allowed waste-free production. The
reaction of pyrazolylthiosemicarbazones with phena-
cyl bromide afforded the corresponding 2-(arylidene-
hydrazino)-4-phenylthiazoles in quantitative yields.
anti-HIV agents [9]. In view of the various physio-
logical activities of thiazoles, several approaches for
their synthesis have been described by our group in
Refs. [10–12]. As part of our current studies on the
development of new routes for the synthesis of thia-
zoles incorporating a pyrazole moiety [13–16], we
report herein an efficient, solid-state synthesis of
highly functionalized thiazolylpyrazoles via the re-
action of ethyl 3-thiosemicarbazidobutanoate and=or
a variety of pyrazolylthiosemicarbazones with phe-
nacyl bromide.
Results and discussion
The reaction of ethyl acetoacetate with thiosemi-
carbazide has been reported to afford the highly ver-
satile ethyl 3-thiosemicarbazidobutanoate (1) [17]
which was used as a precursor for the synthesis of
a variety of heterocycles. The ball-milling of the
intermediate 1 with phenacyl bromide was carried
out at room temperature to afford the corresponding
thiazole derivative 2 in quantitative yield (98%). The
chemical structure of 2 was established on the basis
of spectral data. The IR spectrum confirmed the
presence of NH, CO, and C¼N stretching absorption
Keywords Thiazole; Pyrazole; Thiosemicarbazide; Ball-
milling.
Introduction
The development of simple synthesis routes for
widely used organic compounds from readily avail-
able reagents is one of the major tasks in organic
synthesis. Compounds containing the thiazole ring
system are known to possess pharmacological prop-
erties such as analgesic, antibacterial, anticonvulsant,
antiparasitic, antiinflammatory, and herbicidal ac-
tivity [1–8]. Some derivatives of thiazole are potent
1
bands at ꢀꢀ¼ 3300, 1720, and 1606 cmꢀ1. The H
NMR spectrum revealed a triplet signal at ꢁ ¼
1.28 ppm and a quartet signal at ꢁ ¼ 4.20 ppm due
to the methyl and methylene protons of the ethoxy
group, in addition to four singlets at ꢁ ¼ 2.10, 3.38,
6.8, and 9.05 ppm assigned to methyl, methylene,
thiazole H-5, and NH protons. The mass spectrum
Correspondence: Samir Bondock, Department of Chemistry,
Faculty of Science, Mansoura University, ET-31556
Mansoura, Egypt. E-mail: Bondock@mans.edu.eg

1330
S. Bondock et al.
showed a molecular ion peak (Mþ) at m=z ¼ 303,
corresponding to the molecular weight of the molec-
ular formula C15H17N3O2S.
to the methylene protons of the pyrazolone ring and
the appearance of the signal due to the thiazole H-5
around 6.62 ppm. Also, the structure 4 was further
confirmed by an independent synthesis via the cy-
clization of compound 1 by heating in ethanol con-
taining sodium acetate to give the corresponding
pyrazolone 6, which underwent coupling with aro-
matic diazonium salts to produce the arylhydrazono-
pyrazolone 7 that cyclized with phenacyl bromide
to afford the target compound 4. The IR spectrum
of 4a (for example) showed an absorption band at
ꢀꢀ¼ 3212 cmꢀ1 due to the hydrazono NH function
besides one amidic carbonyl absorption band at
ꢀꢀ¼ 1666cmꢀ1. The mass spectrum of 4b showed a
molecular ion peak at m=z ¼ 375 (intensity 7.8%)
corresponding to the mass of the molecular formula
C20H17N5OS.
Heterocyclization of ethyl 3-[(4-phenyl-2-thia-
zolyl)hydrazono]butanoate (2) by refluxing in
ethanolic sodium acetate solution afforded the cor-
responding thiazolyl-pyrazol-5-one 3. The chemical
structure of 3 was elucidated on the basis of spectral
techniques. The IR spectrum displayed the charac-
teristic absorption band for the amidic carbonyl at
1
ꢀꢀ¼ 1634 cmꢀ1. The H NMR spectrum displayed
three singlets at ꢁ ¼ 2.25, 5.30, and 6.78 ppm due
to methyl protons, pyrazolone H-4, and thiazole H-
5, in addition to a multiplet signal of the aromatic
protons at ꢁ ¼ 7.35–8.00 ppm. Also the spectrum
clearly indicated the absence of ethyl ester protons
(triplet and quartet signals). The mass spectrum
showed a molecular ion peak (Mþ) at m=z ¼ 257 (in-
tensity 100%) corresponding to a molecular formula
C13H11N3OS.
Treatment of compound 2 with phosphorus oxy-
chloride and DMF under Vislmeier-Haack reaction
conditions afforded selectively the formylpyrazole 8
rather than 9 in good yield (Scheme 2). The chemi-
cal structure of 8 was inferred based on spectral data.
The thiazolylpyrazol-5-one 3 couples with aro-
matic diazonium salts in pyridine at 0–5ꢁC to afford
the coupling product for which two isomeric struc-
tures 4 or 5 seemed possible. The 1H NMR spectrum
provided a firm support for structure 4 and ruled out
the other possible isomer 5 by lack of the signal due
1
The H NMR spectrum displayed a new downfield
singlet signal at ꢁ ¼ 9.84 ppm assigned to the formyl
proton, in addition to the absence of the activated
methylene protons. The IR spectrum showed two
Scheme 1

Synthesis of thiazolylpyrazole derivatives
1331
Scheme 2
strong absorption bands at ꢀꢀ¼ 1704 and 1695 cmꢀ1
characteristic for the two carbonyl groups.
The plausible mechanism for the formation of
formylpyrazole 8 maybe explained as follows: the
Vilsmeier-Haack reagent (formylating agent), formed
in situ from DMF and phosphorus oxychloride, is an
equilibrium mixture of iminium salts I and II [18].
Two moles of the mixture of I and II were used in the
reaction with the highly reactive methylene of the
hydrazone form 2. It is well known that the hydrogen
Scheme 3

1332
S. Bondock et al.
Scheme 4
of the methylene group in our moiety possesses a par-
tially positive charge due to hyperconjugation and
hence the methylene carbon is readily attacked by a
strong and reactive electrophile. In the first step, one
mole of the reagent is responsible for the cyclization
furnishing the pyrazole III. In the second step, the
other mole of reagent reacts with pyrazole intermedi-
ate III to give the formyl pyrazole 8 after hydrolysis
by alkaline solution. The reaction course is depicted in
Scheme 3.
Waste-free environmentally benign solid-state
reactions mean quantitative yield of one product
without any necessity for purifying workup by re-
crystallization, chromatography, etc. Organic solid-
state reactions in the gas-solid and stoichiometric
solid–solid versions are highly promising new tools
for solvent-free sustainable synthesis. More than
thousand waste-free quantitative syntheses in organic
solid-state chemistry are already known and have
been reported in a review article that covers more
than 25 reaction types [19–21]. These include sol-
vent-free salt formations, complexations, condensa-
tions of amines, heterocyclic syntheses, Knoevenagel
condensations, cascade reactions, halogen additions,
stereo- and regio-specific protective reactions, and
redox reactions. All of these may be of technical
importance. Some of these involve now easily ob-
tainable products that cannot be produced by solu-
tion reactions.
zones 10a–10c. The reaction proceeds at room tem-
perature, yields are quantitative in all cases, and the
products do not require purifying workup.
The technique of waste-free solid-state reaction
could be also applied to prepare the 2-(arylidenehy-
drazino)-4-phenylthiazoles 11a–11c. Stoichiometric
runs by ball milling of phenacyl bromide with the
arylidenethiosemicarbazone derivatives 10a–10c af-
forded the corresponding iminium hydrobromide
salts with 98% yield without the aid of basic cata-
lysts and solvents. The water of the reaction can be
removed by evaporation at 80ꢁC in vacuum without
loss by hydrolysis. Washings with aqueous Na2CO3
can easily liberate the free bases 11a–11c (Scheme 4).
The chemical structure of 11a–11c was elucidated
on the basis of spectral techniques. The IR spec-
trum of 11c (for example) showed the characteristic
absorption bands for NH and C¼N stretching at
1
ꢀꢀ¼ 3121 and 1614cmꢀ1. The H NMR spectrum of
11c displayed three singlets at ꢁ ¼ 6.62, 8.36, and
8.63 ppm due to the thiazole H-5, azomethine proton
(CH¼N), and NH proton, in addition to a multiplet
signal centered around the region 7.27–8.30 as-
signed to the aromatic and pyrazole-H-5 protons.
The mass spectrum of 11c showed a molecular ion
peak at m=z ¼ 466 (intensity 75.3%) corresponding
to the molecular weight of the molecular formula
C25H18N6O2S, in addition to other fragments at
344, 306, and 122.
Thus, a series of thiosemicarbazone derivatives
10a–10c were synthesized by solid-state technique
which allowed waste-free production. Ball-milling of
thiosemicarbazide with a series of 4-formylpyrazoles
9 [22] afforded the corresponding thiosemicarba-
Conclusion
In conclusion, several thiazolylpyrazole derivatives
were prepared from the readily available ethyl 3-[(4-

Synthesis of thiazolylpyrazole derivatives
1333
3-Methyl-1-(4-phenylthiazol-2-yl)-1H-pyrazol-5(4H)-one
phenyl-2-thiazolyl)hydrazono]butanoate either by
heating in ethanol in the presence of a catalytic
amount of sodium acetate or by treatment with
Vilsmeier-Haack reagent. A number of 2-(arylidene-
hydrazino)thiazole derivatives 11a–11c has been
synthesized by a solid-state solvent-free technique
which allowed waste-free production. These highly
functionalized derivatives may be of interest for
pharmaceutical purposes, yet to be explored.
(3, C13H11N3OS)
A solution of 0.6 g 2 (2mmol) in 20cm3 EtOH containing
25mmol sodium acetate was refluxed for 2 h. The reaction
mixture was allowed to cool, then poured into ice-H2O. The
formed precipitate was collected by filtration, dried, and
recrystallized from a mixture of EtOH:DMF (2:1). Buff crys-
tals; yield 0.36g (70%); mp 188–189ꢁC (Ref. [23] 190–
1
191ꢁC); IR (KBr): ꢀꢀ¼ 1634 (C¼O), 1620 (C¼N) cmꢀ1; H
NMR (DMSO-d6): ꢁ ¼ 2.25 (s, CH3), 5.30 (s, CH2), 6.78 (s,
thiazole-H5), 7.35–8.0 (m, 5Ar–H) ppm; 13C NMR (DMSO-
d6): ꢁ ¼ 16.2 (CH3), 42.1 (CH2), 107.8 (C5-thiazole), 126.2
(2CHAr), 128.1 (CHAr), 128.7 (2CHAr), 134.3 (CAr), 139.2
(C3-pyrazole), 155.9 (C4-thiazole), 164.3 (C¼O), 166.3 (C2-
thiazole) ppm; MS (EI, 70eV): m=z (%) ¼ 257 (Mþ, 100), 176
(16.4), 134 (41.8), 102 (31.1), 69 (28.3).
Experimental
All melting points were measured on an electrothermal
Gallenkamp melting apparatus. Elemental analyses were
carried out at the Microanalytical Unit of the Faculty
of Science, Cairo University, and all compounds gave sat-
isfactory elemental analyses. IR spectra (KBr) were de-
termined on a Mattson 5000 FTIR spectrometer (not all
frequencies are reported). 1H NMR (300 MHz) and 13C
NMR (75.5 MHz) spectra were measured on a Bruker WP
300 in CDCl3 or DMSO-d6 as solvents, using TMS as an
internal standard, and chemical shifts are expressed as ꢁ in
ppm. Mass spectra were obtained on a Finnigan MAT 212
instrument by electron impact (EI) at 70 eV. The ball-mill
was a Retsch MM 2000 swing mill with a 10-cm3 stainless
steel, double-walled beaker with fittings for circulating
coolants. Two stainless steel balls of 12 mm diameter were
used. Ball-milling was performed at 20225 Hz frequency,
usually at room temperature (without circulating liquid the
temperature did not rise above 30ꢁC). Water or methanol of
the appropriate temperature was circulated for heating or cool-
ing. Ethyl 3-thiosemicarbazidobutanoate (1) [17], 4,5-dihy-
dro-3-methyl-5-oxopyrazole-1-carbothioamide (6) [23], and
4-(2-arylhydrazono)-4,5-dihydro-3-methyl-5-oxopyrazole-1-
carbothioamide (7) [24] were prepared according to the re-
ported procedures.
Synthesis of 4-(2-arylhydrazono)-3-methyl-1-(4-phenyl-
thiazol-2-yl)-1H-pyrazol-5(4H)-ones 4a–4c
Method A: A mixture of 2 mmol 7 and 398 mg phenacyl bro-
mide (2mmol) was ball-milled at room temperature for 1 h.
The solid powders were washed with 5% Na2CO3 solution,
followed by H2O, and drying at 0.01 bar at 80ꢁC in vacuum to
liberate the free arylhydrazonothiazolylpyrazoles 4a–4c.
Method B: A well stirred solution of an aromatic amine
(5mmol) in 1.5 cm3 concentrated HCl and 3 cm3 H2O was
cooled in an ice-bath at 0–5ꢁC and diazotized with a solution
of 0.35 g NaNO2 in 5 cm3 H2O. Then, the above cold diazoni-
um solution was added dropwise to a well stirred cold solu-
tion of 0.51g 3 (5mmol) in 25cm3 pyridine. The reaction
mixture was stirred for 2 h until complete coupling reaction
was achieved. The solid product was collected by filtration,
washed with cold water, and recrystallized from a mixture of
EtOH:DMF (1:1) to give 4a–4c.
4-(2-Phenylhydrazono)-3-methyl-1-(4-phenylthiazol-2-yl)-
1H-pyrazol-5(4H)-one (4a, C19H15N5OS)
Brown crystals; yield 1.30g (72%); mp 214–215ꢁC; IR
1
(KBr): ꢀꢀ¼ 3212 (NH), 1666 (C¼O), 1595 (C¼N) cmꢀ1; H
NMR (DMSO-d6): ꢁ ¼ 2.32 (s, CH3), 6.62 (s, thiazole-H5),
7.00–7.48 (m, 10Ar–H), 13.32 (s, NH) ppm; 13C NMR
(DMSO-d6): ꢁ ¼ 11.4 (CH3), 106.9 (C5-thiazole), 119.8
(2CHAr), 125.6 (CHAr), 126.1 (2CHAr), 127.8 (CHAr), 128.8
(2CHAr), 129.5 (2CHAr), 131.9 (C3-pyrazole), 134.6 (CAr),
142.2 (CAr), 150.4 (C4-pyrazole), 156.1 (C4-thiazole), 159.6
(C¼O), 165.4 (C2-thiazole) ppm.
Ethyl 3-[(4-phenyl-2-thiazolyl)hydrazono]butanoate
(2, C15H17N3O2S)
A mixture of 0.41 g ethyl 3-thiosemicarbazidobutanoate
(2mmol) and 398 mg phenacyl bromide (2mmol) was ball-
milled at room temperature for 1 h. A quantitative yield of
thiazoleꢂ HBr 2 was obtained. The free base 2 was recovered
by washing the fine powder of the thiazoleꢂ HBr salt with
5% aqueous Na2CO3 solution followed by H2O and drying
at 0.01 bar at 80ꢁC in vacuum. Violet powder; yield 0.59g
(98%); mp 149–150ꢁC; IR (KBr): ꢀꢀ¼ 3300 (NH), 1720
4-(2-p-Tolylhydrazono)-3-methyl-1-(4-phenylthiazol-2-yl)-
1H-pyrazol-5(4H)-one (4b, C20H17N5OS)
1
Reddish brown crystals; yield 1.54g (82%); mp 195–196ꢁC;
(C¼O), 1606 (C¼N) cmꢀ1; H NMR (CDCl3): ꢁ ¼ 1.28 (t,
IR (KBr): ꢀꢀ¼ 3175 (NH), 1660 (C¼O), 1594 (C¼N) cmꢀ1
;
J ¼ 7.0 Hz, CH3CH2), 2.1 (s, CH3), 3.38 (s, CH2), 4.2 (q,
J ¼ 7.0 Hz, OCH2CH3), 6.80 (s, thiazole-H5), 7.27–7.74 (m,
5Ar–H), 9.05 (s, NH) ppm; 13C NMR (CDCl3): ꢁ ¼ 13.1
(CH3), 16.9 (CH3), 43.2 (CH2), 61.5 (OCH2), 105.2 (C5-thia-
zole), 126.4 (2CHAr), 128.1 (CHAr), 128.8 (2CHAr), 135.5
(CAr), 153.7 (C4-thiazole), 164.3 (C¼N), 167.3 (C¼O),
170.8 (C2-thiazole) ppm; MS (EI, 70 eV): m=z (%) ¼ 303
(Mþ, 28.7), 257 (100), 216 (61.6), 134 (81.2).
1H NMR (CDCl3): ꢁ ¼ 2.38 (s, CH3), 2.46 (s, CH3-pyrazole),
7.23–7.38 (m, 5Ar–H and thiazole-H5), 7.80–7.82 (d,
J ¼ 7.5Hz, 4-CH3–C6H4), 7.96–7.98 (d, J ¼ 7.5 Hz, 4-CH3–
C6H4), 13.3 (s, NH) ppm; 13C NMR (CDCl3): ꢁ ¼ 11.7 (CH3),
21.2 (CH3), 105.8 (C5-thiazole), 120.9 (2CHAr), 126.3
(2CHAr), 128.1 (CHAr), 128.8 (2CHAr), 129.8 (2CHAr),
132.6 (C3-pyrazole), 134.8 (CAr), 136.9 (CAr), 140.2 (CAr),

1334
S. Bondock et al.
150.7 (C4-pyrazole), 156.9 (C4-thiazole), 162.1 (C¼O), 165.8
(C2-thiazole) ppm; MS (EI, 70 eV): m=z (%) ¼ 375 (Mþ, 7.8),
317 (9.3), 269 (5.8), 202 (9.3), 97 (26), 57 (100), 69 (69.6).
9Ar–H, pyrazole-H5), 8.23 (s, NH2), 8.34 (s, CH¼N), 9.6 (s,
NH) ppm; 13C NMR (CDCl3): ꢁ ¼ 21.0 (CH3), 113.2 (C4-
pyrazole), 119.6 (2CHAr), 125.2 (2CHAr), 126.9 (2CHAr),
128.1 (CHAr), 129.3 (2CHAr), 134.8 (CAr), 137.8 (C3-pyra-
zole), 138.7 (CAr), 140.5 (CAr), 144.3 (C5-pyrazole), 149.6
(CH¼N), 177.4 (C¼S) ppm.
4-(2-(4-Methoxyphenyl)hydrazono)-3-methyl-1-(4-phenyl-
thiazol-2-yl)-1H-pyrazol-5(4H)-one (4c, C20H17N5O2S)
Reddish brown crystals; yield 1.66g (85%); mp 184–185ꢁC;
IR (KBr): ꢀꢀ¼ 3167 (NH), 1656 (C¼O), 1604 (C¼N) cmꢀ1
;
1-((3-(4-Nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)-
thiosemicarbazide (10c, C17H14N6O2S)
1H NMR (DMSO-d6): ꢁ ¼ 2.3 (s, CH3), 3.76 (s, OCH3),
7.00–7.62 (m, 5Ar–H, thiazole-H5), 7.78–7.80 (d, J ¼ 7.5 Hz,
4-CH3O–C6H4), 7.93–7.95 (d, J ¼ 7.5 Hz, 4-CH3O–C6H4),
13.3 (s, NH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 11.9 (CH3),
51.8 (OCH3), 107.2 (C5-thiazole), 119.7 (2CHAr), 127.1
(2CHAr), 128.0 (CHAr), 128.9 (2CHAr), 130.3 (2CHAr), 133.8
(C3-pyrazole), 134.9 (CAr), 137.4 (CAr), 140.6 (CAr), 151.3 (C4-
pyrazole), 155.8 (C4-thiazole), 164.2 (C¼O), 166.7 (C2-thia-
zole) ppm.
Deep yellow powder; yield 1.10g (98%); mp 294–295ꢁC;
IR (KBr): ꢀꢀ¼ 3174–3360 (NH2), 3136 (NH), 1597 (C¼N)
1
cmꢀ1; H NMR (DMSO-d6): ꢁ ¼ 7.42–8.0 (m, 9Ar–H, pyra-
zole-H5), 8.42 (s, NH2), 9.23 (s, CH¼N), 11.34 (s, NH) ppm;
13C NMR (DMSO-d6): ꢁ ¼ 115.2 (C4-pyrazole), 120.1
(2CHAr), 125.0 (CHAr), 127.8 (2CHAr), 129.1 (2CHAr), 129.4
(2CHAr), 135.8 (CAr), 137.8 (C3-pyrazole), 138.9 (CAr), 140.5
(CAr), 144.3 (C5-pyrazole), 150.6 (CH¼N), 178.4 (C¼S) ppm.
Ethyl 5-formyl-3-methyl-1-(4-phenylthiazol-2-yl)-1H-
pyrazole-4-carboxylate (8, C17H15N5S)
Synthesis of 2-(arylidenehydrazino)-4-phenylthiazoles
11a–11c
In a 50cm3 round bottom flask 0.6cm3 phosphourous oxy-
chloride (4mmol) were gradually added to well cooled (0–
5ꢁC) 20cm3 DMF with stirring for 30 min, then 0.6g 2
(2mmol) were added in one portion. The reaction mixture
was allowed to rise at room temperature for 5 min, then
refluxed on a water bath at 75ꢁC for 2 h. The reaction mixture
was cooled, poured into crushed ice; the solid product that
formed was filtered off, dried, and recrystallized from EtOH
to give 8. Yellow crystals; yield 0.40 g (58%); mp 140–141ꢁC;
A mixture of thiosemicarbazone 9 (2mmol) and 398 mg phe-
nacyl bromide (2mmol) was ball-milled at room temperature
for 60 min. After drying at 0.01 bar at 80ꢁC, a quantitative
yield of thiazoleꢂ HBr 11a–11c was obtained. The free base
11a–11c was recovered by washing the fine powder of the
HBr salt with 5% aqueous Na2CO3 solution followed by H2O
and drying in vacuum.
IR (KBr): ꢀꢀ¼ 1704, 1695 (2C¼O), 1600 (C¼N) cmꢀ1
;
2-((1,3-Diphenyl-1H-pyrazol-4-yl)methylene)-1-(4-phenyl-
thiazol-2-yl)-hydrazine (11a, C25H19N5S)
1H NMR (CDCl3): ꢁ ¼ 1.40 (t, J ¼ 7.5 Hz, CH3), 2.57 (s,
CH3), 4.36 (q, J ¼ 7.5 Hz, OCH2), 7.27–7.93 (m, 5Ar–H, thi-
azole-H5), 9.84 (s, CHO) ppm; 13C NMR (CDCl3): ꢁ ¼ 13.1
(CH3), 13.8 (CH3), 62.1 (OCH2), 105.1 (C5-thiazole), 112.6
(C4-pyrazole), 126.3 (2CHAr), 128.1 (CHAr), 128.5 (2CHAr),
136.3 (CAr), 137.8 (C3-pyrazole), 146.2 (C5-pyrazole),
156.3 (C4-thiazole), 165.5 (C¼O), 167.6 (C2-thiazole),
178.8 (HC¼O) ppm.
Brown powder; yield 0.82 (98%); mp 163–164ꢁC (Ref. [25]
162ꢁC); IR (KBr): ꢀꢀ¼ 3113 (NH), 1623 (C¼N) cmꢀ1
;
1H NMR (CDCl3): ꢁ ¼ 6.72 (s, thiazole-H5), 7.12–7.89
(m, 15Ar–H), 7.98 (s, pyrazole-H5), 8.3 (s, CH¼N), 9.6
(s, NH) ppm.
2-((1-Phenyl-3-p-tolyl-1H-pyrazol-4-yl)methylene)-1-(4-
phenylthiazol-2-yl)-hydrazine (11b, C26H21N5S)
Brown powder; yield 0.85 g (98%); mp 150–151ꢁC;
Preparation of thiosemicarbazones derivatives 10a–10c
A mixture of 273 mg thiosemicarbazide (3 mmol) and the
appropriate aldehydes 9 (3mmol) was ball-milled at room
temperature for 1 h. The solid products that formed were col-
lected and dried at 0.01 bar at 80ꢁC in vacuum.
IR (KBr): ꢀꢀ¼ 3112 (NH), 1622 (C¼N) cmꢀ1
;
1H NMR
(DMSO-d6): ꢁ ¼ 2.45 (s, CH3), 6.76 (s, thiazole-H5), 7.12–
7.80 (m, 14Ar–H, pyrazole-H5), 8.43 (s, CH¼N), 9.65 (s,
NH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 19.8 (CH3), 105.2
(C5-thiazole), 115.0 (C4-pyrazole), 119.9 (2CHAr), 124.6
(CHAr), 125.5 (CHAr), 126.5 (2CHAr), 127.8 (2CHAr), 128.1
(2CHAr), 129.7 (2CHAr), 129.9 (2CHAr), 134.0 (CAr), 134.5
(CAr), 137.1 (C3-pyrazole), 138.3 (CAr), 140.1 (CAr), 145.0
(C5-pyrazole), 148.6 (CH¼N), 154.2 (C4-thiazole), 168.7
(C2-thiazole) ppm; MS (EI, 70eV): m=z (%) ¼ 468 (Mþ þ 2,
3.8), 466 (Mþ, 75.3), 344 (15.8), 306 (29.3), 264 (45.8), 122
(100), 69 (67.6).
1-((1,3-Diphenyl-1H-pyrazol-4-yl)methylene)thiosemi-
carbazide (10a, C17H15N5S)
Buff powder; yield 0.94 g (98%); mp 228–230ꢁC (Ref. [25]
230ꢁC); IR (KBr): ꢀꢀ¼ 3255–3322 (NH2), 3139 (NH), 1616
1
(C¼N) cmꢀ1; H NMR (DMSO-d6): ꢁ ¼ 7.4–7.92 (m, 10Ar–
H, pyrazole-H5), 8.3 (s, NH2), 9.2 (s, CH¼N), 11.3 (s, NH)
ppm.
1-((1-Phenyl-3-p-tolyl-1H-pyrazol-4-yl)methylene)thiosemi-
carbazide (10b, C18H17N5S)
2-((3-(4-Nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)-
1-(4-phenylthiazol-2-yl)-hydrazine (11c, C25H18N6O2S)
Yellow powder; yield 0.91 g (98%); mp 230–231ꢁC;
White powder; yield 0.98g (98%); mp 198–200ꢁC; IR
(KBr): ꢀꢀ¼ 3253–3393 (NH2), 3139 (NH), 1595 (C¼N)
IR (KBr): ꢀꢀ¼ 3121 (NH), 1614 (C¼N) cmꢀ1
;
1H NMR
cmꢀ1
;
1H NMR (CDCl3): ꢁ ¼ 2.43 (s, CH3), 7.3–7.8 (m,
(DMSO-d6): ꢁ ¼ 6.62 (s, thiazole-H5), 7.23–8.30 (m, 14Ar–

Synthesis of thiazolylpyrazole derivatives
1335
H, pyrazole-H5), 8.36 (s, CH¼N), 8.63 (s, NH) ppm; 13C
NMR (DMSO-d6): ꢁ ¼ 104.9 (C5-thiazole), 114.8 (C4-pyra-
zole), 119.8 (2CHAr), 124.8 (CHAr), 125.7 (CHAr), 126.4
(2CHAr), 127.4 (2CHAr), 128.3 (2CHAr), 129.5 (2CHAr),
129.9 (2CHAr), 134.5 (CAr), 134.9 (CAr), 137.4 (C3-pyrazole),
139.1 (CAr), 141.4 (CAr), 144.8 (C5-pyrazole), 149.7 (CH¼N),
154.7 (C4-thiazole), 169.8 (C2-thiazole) ppm; MS (EI, 70eV):
m=z (%) ¼ 468 (Mþ þ 2, 3.8), 466 (Mþ, 75.3), 344 (15.8), 306
(29.3), 264 (45.8), 122 (100), 69 (67.6).
Pannecouque C, Rao A, Zappala M (2002) J Med Chem
45:5410
10. Metwally MA, Abdel-Latif E, Amer FA, Kaupp G (2004)
J Sulfur Chem 25:63
11. Abdel-Latif E, Bondock S (2006) Heteroatom Chem
17:299
12. Bondock S, Khalifa W, Fadda AA (2007) Eur J Med
Chem 42:948
13. El-desoky SI, Etman HA, Bondock SB, Fadda AA,
Metwally MA (2002) Sulfur Lett 25:199
14. El-desoky SI, Bondock SB, Etman HA, Fadda AA,
Metwally MA (2003) Sulfur Lett 26:127
15. Kaupp G, Amer FA, Metwally MA, Abdel-Latif E (2003)
J Heterocyclic Chem 40:963
References
1. Li YX, Wang SH, Li ZM, Su N, Zhao WG (2006)
Carbohyd Res 341:2867
2. Kucukguzel G, Kocatepe A, Clercq ED, Sahin F, Gulluce
M (2006) Eur J Med Chem 41:353
16. Abdel-Latif E, Metwally MA (2007) Monatsh Chem
138:771
3. Kato T, Ozaki T, Tamura K, Suzuki Y, Akima M, Ohi N
(1998) J Med Chem 41:4309
17. Jayasree S, Aravindakshan KK (1993) Polyhedron
12:1187
4. Tenorio RP, Carvalho CS, Pessanha CS, de Lima JG, de
Faria AR, Alves AJ, de Melo EJT, Goes AJS (2005)
Bioorg Med Chem Lett 15:2575
5. Kato T, Ozaki T, Tsuzuki K, Ohi N (2001) Org Process
Res Develop 5:122
6. Kucukguzel SG, Oruc EE, Rollas S, Sahin F, Ozbek A
(2002) Eur J Med Chem 37:197
7. Shih MH, Ke FY (2004) Bioorg Med Chem 12:4633
8. Kato T, Ozaki T, Tamura K, Suzuki Y, Akima M, Ohi N
(1999) J Med Chem 42:3134
18. Doznie IM, Earle MJ, Heaney H, Shuhaiber KF (1993)
Tetrahedron 49:4015
19. Kaupp G (2005) Top Curr Chem 254:95
20. Kaupp G (2003) Cryst Eng Commun 5:117
21. Rodriguez B, Bruckmann A, Rantanen T, Bolm C (2007)
Adv Synth Catal 349:2213
22. Prakash O, Pannu K, Kumar A (2006) Molecules
11:43
23. Harode R, Sharma TC (1989) J Indian Chem Soc
66:282
9. Barreca M, Balzarini J, Chimirri A, Clercq ED, Luca
LD, Holtje HD, Holtje M, Monforte AM, Monforte P,
24. Garg HG, Sharma RA (1970) J Pharm Sci 59:348
25. El-Emary TI, Bakhite EA (1999) Pharmazie 54:106