2-Bromo-1-(1H-pyrazol-4-yl)ethanone: Versatile Precursor for Novel Mono- and Bis[pyrazolylthiazoles]

Article abstract of DOI:10.1002/jhet.2571

The synthesis of novel bis(thiazoles) 20a, 20b, 20c and 23a, 23b, 23c is reported. Thus, reaction of 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone (6) with the corresponding thioamide derivatives 7a,7b, in refluxing EtOH in the presence of triethylamine, afforded 4-pyrazolylthiazoles 8a, 8b in good yields. On the other hand, the novel bis(thiazoles) 20a, 20b, 20c and 23a, 23b, 23c were obtained from the reaction of 6 with the corresponding benzaldehyde thiosemicarbazones 19a, 19b, 19c, 22a, 22b, 22c in refluxing EtOH. Compounds 19a, 19b, 19c and 22a, 22b, 22c were obtained by condensation of the corresponding bis(aldehydes) 18a, 18b, 18c and 21a, 21b, 21c with thiosemicarbazide.

Full text of DOI:10.1002/jhet.2571

Month 2016
2-Bromo-1-(1H-pyrazol-4-yl)ethanone: Versatile Precursor for Novel
Mono- and Bis[pyrazolylthiazoles]
a
a
Mostafa E. Salem,a Ahmed F. Darweesh,a Ahmed E. M. Mekky,a,b Ahmad M. Farag, and Ahmed H. M. Elwahy
*
aDepartment of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
bOn leave to Chemistry Department, Faculty of Science, King Abdulaziz University, North Jeddah, P.O. Box 80203,
Jeddah 21589, Saudi Arabia
*
E-mail: aelwahy@hotmail.com
Additional Supporting Information may be found in the online version of this article.
Received July 28, 2015
DOI 10.1002/jhet.2571
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
The synthesis of novel bis(thiazoles) 20a–c and 23a–c is reported. Thus, reaction of 2-bromo-1-
(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone (6) with the corresponding thioamide derivatives 7a,b,
in refluxing EtOH in the presence of triethylamine, afforded 4-pyrazolylthiazoles 8a,b in good yields. On
the other hand, the novel bis(thiazoles) 20a–c and 23a–c were obtained from the reaction of 6 with the
corresponding benzaldehyde thiosemicarbazones 19a–c, 22a–c in refluxing EtOH. Compounds 19a–c and
22a–c were obtained by condensation of the corresponding bis(aldehydes) 18a–c and 21a–c with
thiosemicarbazide.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
analgesic, antimicrobial, anti-HIV, antihypertensive, and
herbicidal activity [15–21].
Compounds bearing pyrazole nucleus are well known to
exhibit a versatile range of biological activities such as an-
timicrobial [1–4], anti-inflammatory [5–7], antidepressant
[8], antiviral [9], and antitumor activities [10]. Among
these, 4-functionalized pyrazoles occupy a unique position
in medicinal chemistry because of their association with
antimicrobial [11], anti-inflammatory [12], antiparasitic
[13], and antitumor activities [14].
Furthermore, attention has been increasingly paid to the
synthesis of bis-heterocyclic compounds in recent years,
because of their diverse activities, especially, as antitumor
and as antimicrobial [22–40].
Motivated by these findings, we report herein the synthe-
sis of some novel mono- and bis-heterocyclic compounds
incorporating a combination of pyrazole and thiazole
pharmacophores. The combination of two pharmacophores
into a single molecular skeleton is a well-established
approach for designing more potent drugs with significant
increase in activity.
Moreover, thiazole derivatives have attracted increasing
attention because of their numerous pharmacological appli-
cations and biological activities, such as anti-inflammatory,
© 2016 HeteroCorporation

M. E. Salem, A. F. Darweesh, A. E. M. Mekky, A. M. Farag, and A. H. M. Elwahy
Vol 000
Scheme 2
RESULTS AND DISCUSSION
The desired starting building block; 2-bromo-1-
(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone (6) was ob-
tained by a series of reactions as outlined in Scheme 1.
Thus, reaction of phenylhydrazine 4 with 3-((dimethylamino)
methylene)pentane-2,4-dione (3), obtained upon treatment of
acetylacetone with dimethylformamide dimethylacetal
(DMFDMA), afforded l-aryl-5-methyl-4-acetypyrazole 5 in
good yield. Subsequent bromination of 5 with Br2 in AcOH
gave 6 in good yield [41–44] (Scheme 1).
Reaction of compound 6 with the appropriate thioamide
derivatives 7a,b, in refluxing EtOH/TEA, afforded the cor-
responding 4-pyrazolylthiazoles 8a,b. Similarly, 2-amino-
4-pyrazolylthiazoles 10a,b were obtained by the reaction
of 6 with thiourea derivatives 9a,b (Scheme 2). The
reaction was completed within 3–5 h and the products were
obtained in good yields.
Our study was extended to include the synthesis of the
new arylidenehydrazinyl-(1H-pyrazol-4-yl)thiazol deriva-
tives 12a–i as outlined in Scheme 3. Thus, reaction of the
appropriate bis(aldehydes) 18a–e with thiosemicarbazide (13)
in refluxing EtOH containing few drops of AcOH, afforded
the corresponding alkylenebis(oxy)bis(2,1-phenylene)bis
(methan-1-yl-1-ylidene))bis
(hydrazinecarbothioamide)
4-bromoacetylpyrazole
6
with the corresponding
19a–e. Subsequent reaction of the latter products with
6 in refluxing ethanol in the presence of few drops of
TEA, afforded 20a–e in 68–77% yields, respectively
(Scheme 5).
thiosemicarbazone derivatives 11a–i [45,46], in refluxing
EtOH in the presence of few drops of TEA, afforded
12a–i in 75–85% yields.
The new pyrazol-4-yl)ethylidene)hydrazinyl) arylthiazoles
16a–c in which ethylidenehydrazinyl is located between the
pyrazole and the thiazole ring were also synthesized as
outlined in Scheme 4. Thus, reaction of the 2-(1-(5-methyl-1-
phenyl-1H-pyrazol-4-yl)ethylidene)hydrazinecarbothioamide
(14) with the appropriate 2-bromo-1-arylethanone 15a–c
[45,46] in refluxing EtOH in the presence of few drops
of TEA afforded (pyrazol-4-yl)ethylidene)hydrazinyl)
arylthiazoles 16a–c in 60–65% yields. Similarly, 4-(1H-
pyrazol-4-yl)-2-(2-1H-pyrazol-4-yl)ethylidene)hydrazinyl)-
thiazole (17) in which ethylidene)hydrazinyl)thiazole is
located between two pyrazole rings was obtained in 73%
yield by the reaction of compound 6 with 14. Compound
14 was obtained in 73% yield upon treatment of 5 with
thiosemicarabazide (13) in refluxing ethanol containing
few drops of acetic acid (Scheme 4).
The same methodology was extended to the preparation of
bis(1H-pyrazol-4-yl)thiazol-2-yl)hydrazono)methyl)phenoxy)
arene 23a–c, in which the pyrazolylthiazolylhydrazones is
linked to benzene core via phenoxy group as depicted in
Scheme 6. Thus, reaction of the appropriate bis(aldehydes)
21a–c with thiosemicarbazide (13) in refluxing EtOH
containing few drops of AcOH, gave the corresponding
alkylenebis(oxy)bis(2,1-phenylene)bis(methan-1-yl-1-ylidene))
bis (hydrazinecarbothioamide) 22a–c which upon reaction
with 6 in refluxing ethanol in the presence of few drops of
TEA, gave 23a–c in 65–70% yields (Scheme 6).
All of the isolated compounds were characterized by ele-
mental analyses, as well as their spectral data which agree
with the proposed structures. The structure of aminothiazoles
1
10a,b was confirmed by IR, H-NMR and mass spectra.
Thus, the IR spectrum of 10a, as a representative example,
showed absorption bands at 3349 and 3295cmꢀ1 because
of NH2. Moreover, the absence of the absorption band corre-
sponding to carbonyl stretching frequency of the parent acyl
The utilization of the bis aldehydes 18a–e as intermediates
in the synthesis of novel bis(5-1H-pyrazol-4-yl)thiazol-2-yl)
hydrazono)methyl)phenoxy)alkane 20a–e, in which the
pyrazolylthiazolyl hydrazone is linked to alkyl spacer via
phenoxy group, was also investigated. Thus, reaction of the
1
bromide clearly confirmed the formation of 10a. The H
NMR spectra of compound 10a showed a D2O-exchangeable
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
A Synthesis of Novel Bis(thiazoles) 20a–c and 23a–c is Reported
Scheme 3
Scheme 4
Scheme 5
signal at δ 5.17 because of NH2 protons and a sharp singlet at
δ 6.42 attributed to C-5 proton of the thiazole ring and at δ
7.90 attributed to the C-3 proton of the pyrazole ring. All
other protons were seen at the expected chemical shifts and
integral values. Mass spectrum of compound 10a showed
an intense molecular ion peak at m/z 256, in agreement with
its respective molecular formula.
On the other hand, the IR spectrum of bis
(thiazolylhydrazone) 20e as a representative example of
these class of compounds revealed an absorption band at
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. E. Salem, A. F. Darweesh, A. E. M. Mekky, A. M. Farag, and A. H. M. Elwahy
Vol 000
Scheme 6
3427 cmꢀ1 because of (NH). Its 1H NMR spectrum showed
the presence of a characteristic singlet signal at δ 7.91 be-
cause of one methine proton (―N¼CH―). Mass spectra
of compound 20e showed a molecular ion peaks at m/z
804 (M+, 0.34%) which is in agreement with its respective
molecular formula. The spectra of other bis(thiazoles) 23a–c
showed similar spectral data which are listed in the experi-
mental part.
spectra were recorded in potassium bromide disks on a
Pye Unicam SP 3-300 and Shimaduz FTIR 8101 PC
infrared spectrophotometer. NMR spectra were recorded
with a Varian Mercury VXR-300 NMR spectrometer at
300 MHz (1H NMR) and at 75 MHz (13C NMR. Mass
spectra (EI) were obtained at 70eV with a type
Shimadzu GCMQP 1000 EX spectrometer. Analytical
thin-layer chromatography was performed using pre-
coated silica gel 60778 plates (Fluka), and the spots were
visualized with UV light at 254nm. The required bis-
aldehydes 18a–e and 21a–c were synthesized following
reported methods [47].
CONCLUSIONS
We have developed an efficient synthesis of hitherto unre-
ported pyrazolylthiazoles as well as bis(pyrazolylthiazoles)
which are linked to alkane or arene core via phenoxymethyl
group. Full characterization of these compounds is reported.
The new synthesized compounds are interesting both in their
own right as unusual molecules and for their promising
pharmacological and biological activities. Because of the
mild reaction condition, good yields, and selectivity, easily
accessible starting material and straightforward product iso-
lation, we think that the new synthetic approach discussed
here may offer effective new techniques for novel bis
(functionalized) heterocycles of expected biological and
pharmaceutical activities.
Synthesis of 4-pyrazolylthiazoles 8a,b. General procedure. To
a mixture of 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)
ethanone (6) (2 mmol) and the appropriate thioamide
derivatives 7 (2 mmol) in ethanol (20 mL), few drops of
TEA were added. The reaction mixture was heated
under reflux for 3–5 h, then allowed to cool. The
solvent was evaporated in vacuo, and the solid residue was
collected and recrystallized from ethanol to give the
corresponding 4-pyrazolylthiazoles 8a,b.
2-Methyl-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazole 8a.
Yellow crystals, (70% yield), mp. 100–102°C; IR:
(potassium bromide) 1589 (C¼N) cmꢀ1
;
1H-NMR: δ
2.55 (s, 3H, CH3), 2.77 (s, 3H, CH3), 7.03 (s, 1H,
thiazole-5-H), 7.47–7.49 (m, 5H, ArH), 7.96 (s, 1H,
pyrazole-3-H); 13C-NMR: δ 11.89, 18.78, 111.8, 116.2,
124.8, 127.7, 129.1, 135.7, 138.9, 139.2, 147.7, 164.8;
ms: m/z (%) 255 (100, M+). Anal. Calcd. for C14H13N3S:
C, 65.85; H, 5.13; N, 16.46; S, 12.56. Found: C, 65.52;
H, 5.05; N, 16.27; S, 12.33.
EXPERIMENTAL
General. Melting points were determined in open glass
capillaries with a Gallenkamp apparatus. The infrared
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A Synthesis of Novel Bis(thiazoles) 20a–c and 23a–c is Reported
2-(4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)thiazol-2-yl)acetonitrile
4.77; N, 19.48; S, 8.92. Found: C, 66.73; H, 4.56; N,
19.32; S, 8.82.
8b. Deep brown crystals, (65% yield), mp. 122–125°C; IR:
1
(potassium bromide) 2251 (CN), 1589 (C¼N) cmꢀ1; H-
2-(2-(4-Chlorobenzylidene)hydrazinyl)-4-(5-methyl-1-phenyl-
1H-pyrazol-4-yl)-thiazole 12b. Yellow crystals, (82% yield),
mp. 270–272°C; IR: (potassium bromide) 3352 (NH), 1594
NMR: δ 2.57 (s, 3H, CH3), 4.17 (s, 2H, CH2CN), 7.22
(s, 1H, thiazole-5-H), 7.42–7.53 (m, 5H, ArH), 7.96 (s, 1H,
pyrazole-3-H); ms: m/z (%) 280 (100, M+). Anal. Calcd. for
C15H12N4S: C, 64.26; H, 4.31; N, 19.98; S, 11.44. Found:
C, 64.12; H, 4.24; N, 19.76; S, 11.25.
1
(C¼N) cmꢀ1; H-NMR: δ 2.54 (s, 3H, CH3), 6.90 (s, 1H,
thiazole-5-H), 7.45–7.68 (m, 9H, ArH), 7.93 (s, 1H,
CH¼N), 8.02 (s, 1H, pyrazole-3-H), 12.19 (s, 1H, NH);
ms: m/z (%) 393 (10.90, M+). Anal. Calcd. for
C20H16ClN5S: C, 60.98; H, 4.09; N, 17.78; S, 8.14. Found:
C, 60.84; H, 4.15; N, 17.65; S, 8.19.
Synthesis of 2-amino-4-pyrazolylthiazoles 10a,b. General
procedure.
To a mixture of 6 (2 mmol) and the
appropriate thiourea derivatives 9 (2 mmol), in ethanol
(20 mL), few drops of TEA were added and the reaction
mixture was heated under reflux for 3–5 h, then allowed to
cool. The solvent was evaporated in vacuo, and the solid
residue was collected by filtration and recrystallized from
benzene-petroleum ether for 10a and ethanol for 10b to
give the corresponding 2-amino-4-pyrazolylthiazoles 10a,b.
4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)thiazol-2-amine 10a.
Pale yellow powder, (70% yield), mp. 260–262°C; IR:
(potassium bromide) 3349, 3295 (NH2), 1594 (C¼N)
4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-(2-(4-nitrobenzylidene)
hydrazinyl)-thiazole 12c. Red crystals, (85% yield), mp. 278–
280°C; IR: (potassium bromide) 3430 (NH), 1563 (C¼N)
1
cmꢀ1; H-NMR: δ 2.54 (s, 3H, CH3), 6.97 (s, 1H, thiazole-
5-H), 7.54–8.12 (m, 9H, ArH), 8.25 (s, 1H, CH¼N), 8.27
(s, 1H, pyrazole-3-H), 12.49 (s, 1H, NH); ms: m/z (%) 404
(44.92, M+). Anal. Calcd. for C20H16N6O2S: C, 59.39; H,
3.99; N, 20.78; S, 7.93. Found: C, 59.22; H, 3.68; N, 20.56;
S, 7.81.
1
cmꢀ1; H-NMR: δ 2.52 (s, 3H, CH3), 5.17 (s, 2H, NH2),
N,N-dimethyl-4-((2-(4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)
thiazol-2-yl)-hydrazono)methyl)aniline 12d. Yellow crystals,
(80% yield), mp. 248–250°C; IR: (potassium bromide)
6.42 (s, 1H, thiazole-5-H), 7.38–7.52 (m, 5H, ArH),
7.90 (s, 1H, pyrazole-3-H); ms: m/z (%) 256 (2.53, M+).
Anal. Calcd. for C13H12N4S: C, 60.91; H, 4.72; N,
21.86; S, 12.51. Found: C, 60.75; H, 4.56; N, 21.54; S,
12.45.
1
3435 (NH), 1564 (C¼N) cmꢀ1; H-NMR: δ 2.54 (s, 3H,
CH3), 2.95 (s, 6H, N(CH3)2), 6.82 (s, 1H, thiazole-5-H),
6.73–7.54 (m, 9H, ArH), 7.56 (s, 1H, CH¼N), 7.91
(s, 1H, pyrazole-3-H), 11.75 (s, 1H, NH); 13C-NMR: δ
11.99, 39.72, 101.01, 111.88, 116.91, 122.00, 124.85,
127.48, 127.63, 129.09, 135.36, 138.80, 139.32, 142.18,
144.31, 150.93, 168.30; ms: m/z (%) 402 (17.27, M+).
Anal. Calcd. for C22H22N6S: C, 65.65; H, 5.51; N, 20.88;
S, 7.97. Found: C, 65.84; H, 5.38; N, 20.79; S, 7.73.
4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-(2-(4-methylbenzylidene)
N-methyl-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazol-2-amine
10b. Off-white powder, (65% yield), mp. 160–162°C;
IR: (potassium bromide) 3428 (NH), 1562 (C¼N)
cmꢀ1 1H-NMR: δ 2.53 (s, 3H, CH3), 2.87 (s, 3H,
;
CH3), 6.64 (s, 1H, thiazole-5-H), 7.53–7.55 (m, 6H,
ArH and NH), 7.88 (s, 1H, pyrazole-3-H); ms: m/z (%)
270 (100, M+). Anal. Calcd. for C14H14N4S: C, 62.20;
H, 5.22; N, 20.72; S, 11.86. Found: C, 62.09; H, 5.14;
N, 20.59; S, 11.64.
Synthesis of arylidenehydrazinyl-(1H-pyrazol-4-yl)thiazol
12a–i. General procedure. To a mixture of 2-bromo-1-(5-
methyl-1-phenyl-1H-pyrazol-4-yl)ethanone (6) (1mmol) and
the appropriate thiosemicarbazone 11 (1 mmol) in ethanol
(20mL), few drops of TEA were added, and the mixture
was heated under reflux for 3–5 h. The reaction
mixture was allowed to cool, and the solvent was
evaporated in vacuo. The solid residue was collected
by filtration and recrystallized from ethanol except for
12c which was recrystallized from ethanol/DMF to
give the corresponding arylidenehydrazinyl-(1H-pyrazol-4-yl)
thiazoles 12a–i.
2-(2-Benzylidenehydrazinyl)-4-(5-methyl-1-phenyl-1H-pyrazol-
4-yl)thiazole 12a. Yellow crystals, (75% yield), mp. 222–
225°C; IR: (potassium bromide) 3426 (NH), 1567 (C¼N)
cmꢀ1; 1H-NMR: δ 2.49 (s, 3H, CH3), 6.88 (s, 1H, thiazole-
5-H), 7.35–7.94 (m, 10H, ArH), 8.03 (s, 1H, CH¼N), 8.04
(s, 1H, pyrazole-3-H), 12.11 (s, 1H, NH); ms: m/z (%) 359
(63.07, M+). Anal. Calcd. for C20H17N5S: C, 66.83; H,
hydrazinyl)-thiazole 12e.
Yellow crystals, (77% yield),
mp. 257–260°C; IR: (potassium bromide) 3424 (NH),
1
1559 (C¼N) cmꢀ1; H-NMR: δ 2.32 (s, 3H, CH3), 2.54
(s, 3H, CH3), 6.87 (s, 1H, thiazole-5-H), 7.22–7.55 (m, 9H,
ArH), 7.92 (s, 1H, CH¼N), 8.00 (s, 1H, pyrazole-3-H),
12.02 (s, 1H, NH); ms: m/z (%) 373 (29.60, M+). Anal.
Calcd. for C21H19N5S: C, 67.53; H, 5.13; N, 18.75; S,
8.59. Found: C, 67.48; H, 5.04; N, 18.66; S, 8.44.
2-(2-(4-Methoxybenzylidene)hydrazinyl)-4-(5-methyl-1-phenyl-
1H-pyrazol-4-yl)thiazole 12f.
Colorless crystals, (83%
yield), mp. 249–250°C; IR: (potassium bromide) 3426
1
(NH), 1566 (C¼N) cmꢀ1; H-NMR: δ 2.50 (s, 3H, CH3),
3.80 (s, 3H, OCH3), 6.85 (s, 1H, thiazole-5-H), 6.86–7.60
(m, 9H, ArH), 7.93 (s, 1H, CH¼N), 7.98 (s, 1H, pyrazole-
3-H), 11.94 (s, 1H, NH); ms: m/z (%) 389 (93.01, M+).
Anal. Calcd. for C21H19N5OS: C, 64.76; H, 4.92; N,
17.98; S, 8.23. Found: C, 64.62; H, 4.88; N, 17.85; S, 8.13.
4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-(2-(pyridin-4-ylmethylene)
hydrazinyl)-thiazole 12g. Brick red crystals, (80% yield),
mp. 280–282°C; IR: (potassium bromide) 3432 (NH),
1
1567 (C¼N) cmꢀ1; H-NMR: δ 2.54 (s, 3H, CH3), 6.97
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M. E. Salem, A. F. Darweesh, A. E. M. Mekky, A. M. Farag, and A. H. M. Elwahy
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(s, 1H, thiazole-5-H), 7.44–8.00 (m, 9H, ArH), 8.59
(s, 1H, CH¼N), 8.61 (s, 1H, pyrazole-3-H), 12.47
(s, 1H, NH); 13C-NMR: δ 11.95, 102.48, 116.53, 120.08,
124.88, 127.70, 129.11, 135.53, 138.21, 138.77, 139.25,
141.53, 150.10, 167.60; ms: m/z (%) 360 (41.78, M+).
Anal. Calcd. for C19H16N6S: C, 63.31; H, 4.47; N,
23.32; S, 8.90. Found: C, 63.22; H, 4.35; N, 23.39; S,
8.82.
154–156°C; IR: (potassium bromide) 3402 (NH), 1568
1
(C¼N) cmꢀ1; H-NMR: δ 2.32 (s, 3H, CH3), 2.56 (s, 3H,
CH3), 7.26–7.95 (m, 12H, ArH, thiazole-5-H, pyrazole-3-
H), 11.02 (s, 1H, NH); ms: m/z (%) 373 (100, M+). Anal.
Calcd. for C21H19N5S: C, 67.53; H, 5.13; N, 18.75; S,
8.59. Found: C, 67.39; H, 5.04; N, 18.67; S, 8.42.
4-(4-Methoxyphenyl)-2-(2-(1-(5-methyl-1-phenyl-1H-pyrazol-
4-yl)ethylidene)-hydrazinyl)thiazole 16b.
Orang crystals,
4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-(2-(pyridin-3-ylmethylene)
(65% yield), mp. 194–196°C; IR: (potassium bromide)
1
hydrazinyl)-thiazole 12h.
Yellow crystals, (78% yield),
3427 (NH), 1554 (C¼N) cm-1; H-NMR: δ 2.31 (s, 3H,
mp. 242–244°C; IR: (potassium bromide) 3425 (NH),
CH3), 2.56 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 6.94–7.95
(m, 11H, ArH, thiazole-5-H, pyrazole-3-H), 11.02 (s, 1H,
NH); 13C-NMR: δ 13.10, 15.80, 55.04, 101.19, 113.88,
119.19, 125.21, 126.78, 127.69, 128.02, 129.12, 136.68,
139.02, 139.46, 143.67, 158.68, 169.79; ms: m/z (%) 403
(100, M+). Anal. Calcd. for C22H21N5OS: C, 65.49; H,
5.25; N, 17.36; S, 7.95. Found: C, 65.32; H, 5.13; N,
17.29; S, 7.88.
1
1568 (C¼N) cmꢀ1; H-NMR: δ 2.54 (s, 3H, CH3), 6.93
(s, 1H, thiazole-5-H), 7.43–8.06 (m, 9H, ArH), 8.56
(s, 1H, CH¼N), 8.81 (s, 1H, pyrazole-3-H), 12.30 (s, 1H,
NH); ms: m/z (%) 360 (100, M+). Anal. Calcd. for
C19H16N6S: C, 63.31; H, 4.47; N, 23.32; S, 8.90. Found:
C, 63.22; H, 4.65; N, 23.19; S, 8.82.
4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-(2-(thiophen-2-ylmethylene)-
hydrazinyl)thiazole 12i. Yellow crystals, (75% yield), mp.
228–230°C; IR: (potassium bromide) 3435 (NH), 1571
4-(4-Bromophenyl)-2-(2-(1-(5-methyl-1-phenyl-1H-pyrazol-4-
yl)ethylidene)-hydrazinyl)thiazole 16c. Brown solid, (60%
yield), mp. 190–192°C; IR: (potassium bromide) 3431
1
(C¼N) cmꢀ1; H-NMR: δ 2.53 (s, 3H, CH3), 6.87 (s, 1H,
1
thiazole-5-H), 7.08–7.57 (m, 8H, ArH), 7.92 (s, 1H,
CH¼N), 8.21 (s, 1H, pyrazole-3-H), 12.05 (s, 1H, NH);
ms: m/z (%) 365 (100, M+). Anal. Calcd. for C18H15N5S2:
C, 59.15; H, 4.14; N, 19.16; S, 17.55. Found: C, 59.24;
H, 4.19; N, 19.02; S, 17.38.
(NH), 1568 (C¼N) cmꢀ1; H-NMR: δ 2.31 (s, 3H, CH3),
2.55 (s, 3H, CH3), 7.34–7.95 (m, 11H, ArH, thiazole-5-H,
pyrazole-3-H), 11.05 (s, 1H, NH); ms: m/z (%) 452
(20.41, M+). Anal. Calcd. for C21H18BrN5S: C, 55.76; H,
4.01; N, 15.48; S, 7.09. Found: C, 55.93; H, 3.88; N,
15.35; S, 7.16.
Synthesis of 2-(1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethylidene)
hydrazine-carbothioamide (14). General procedure. To a
solution of 1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone
(5) (10mmol) in absolute ethanol (25mL) containing few
drops of acetic acid, thiosemicarbazide (13) (10mmol) was
added. The reaction mixture was heated under reflux for
3h then left to cool. The solid formed was collected by
filtration and recrystallized from ethanol to give 14;
Colourless crystal, (73% yield), mp. 220–222°C; IR:
(potassium bromide) 3388, 3235 (NH2), 1557 (C¼N)
Synthesis
ethylidene)hydrazinyl)-thiazole (17). General procedure. To
mixture of 2-(1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)
of
4-(1H-pyrazol-4-yl)-2-(2-1H-pyrazol-4-yl)
a
ethylidene)hydrazine-carbothioamide (14) (1mmol) and
2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone (6)
(1 mmol) in ethanol (10 mL), few drops of TEA were
added. The reaction mixture was heated under reflux for
3–5 h then left to cool. The solvent was evaporated in
vacuo, and the solid residue was collected by filtration
and recrystallized from ethanol to give 17 as orange
crystals, (73% yield), mp. 230°C; IR: (potassium
1
cmꢀ1; H-NMR: δ 2.29 (s, 3H, CH3), 2.50 (s, 3H, CH3),
7.33–8.19 (m, 8H, ArH, pyrazole-3-H, NH2), 10.13 (s, 1H,
NH); Anal. Calcd. For C13H15N5S: C, 57.12; H, 5.53; N,
25.62; S, 11.73. Found: C, 57.05; H, 5.45; N, 25.48; S,
11.61.
bromide) 3428 (NH), 1568 (C¼N) cmꢀ1
;
1H-NMR: δ
2.32 (s, 3H, CH3), 2.55 (s, 3H, CH3), 2.57 (s, 3H, CH3),
6.84 (s, 1H, thiazole-5-H), 7.45–7.59 (m, 11H, ArH),
7.95 (s, 1H, pyrazole-3-H), 10.94 (s, 1H, NH); 13C-
NMR: δ 11.98, 13.11, 15.85, 94.23, 101.56, 116.89,
119.22, 124.85, 125.21, 127.65, 128.02, 129.11, 135.41,
136.68, 138.77, 139.02, 139.31 139.47, 143.74, 169.70;
ms: m/z (%) 453 (36.46, M+). Anal. Calcd. for
C25H23N7S: C, 66.20; H, 5.11; N, 21.62; S, 7.07. Found:
C, 66.10; H, 5.27; N, 21.98; S, 7.17.
Synthesis of (pyrazol-4-yl)ethylidene)hydrazinyl) arylthiazoles
16a–c.
General procedure.
To a mixture of 2-(1-(5-
methyl-1-phenyl-1H-pyrazol-4-yl)ethylidene)hydrazine-
carbothioamide (14) (1 mmol) and the corresponding
2-bromo-1-arylethanone 15a–c (1 mmol) in ethanol
(10 mL), few drops of TEA were added. The reaction
mixture was heated under reflux for 3–5 h then left to
cool. The solvent was evaporated in vacuo, and the solid
residue was collected by filtration and recrystallized from
ethanol to give the corresponding pyrazol-4-yl)ethylidene)
hydrazinyl) arylthiazoles 16a–c.
Synthesis of alkylenebis(oxy)bis(2,1-phenylene)bis(methan-1-
yl-1-ylidene))bis (hydrazinecarbothioamide) 19a–e.
procedure.
General
To a solution of the appropriate bis
(aldehyde) compounds 18a–e (10 mmol) in absolute
ethanol (25 mL) containing few drops of acetic acid,
thiosemicarbazide (13) (20mmol) was added. The reaction
2-(2-(1-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)ethylidene)hydrazinyl)-
4-phenyl-thiazole 16a. Orange crystals, (64% yield), mp.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
A Synthesis of Novel Bis(thiazoles) 20a–c and 23a–c is Reported
mixture was heated under reflux for 3h then allowed to cool.
The solid formed was collected by filtration and recrystallized
from ethanol/DMF to give 19a–e.
1,2-Bis(4-((2-(4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazol-2-
yl)hydrazono)-methyl)phenoxy)ethane 20a. Orange crystals,
(70% yield), mp. 265–267°C; IR: (potassium bromide)
1
2,2′-(4,4′-(Ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methan-
3426 (NH), 1566 (C¼N) cmꢀ1; H-NMR: δ 2.54 (s, 6H,
1-yl-1-ylidene)-bis(hydrazinecarbothioamide) 19a.
Yellow
CH3), 4.38 (s, 4H, CH2O), 6.86 (s, 2H, thiazole-5-H),
7.05–7.62 (m, 18H, ArH), 7.92 (s, 2H, CH¼N), 7.99 (s,
2H, pyrazole-3-H) 11.96 (s, 2H, NH); ms: m/z (%) 776
(0.11, M+). Anal. Calcd. For C42H36N10 O2S2: C, 64.93;
H, 4.67; N, 18.03; S, 8.25. Found: C, 64.67; H, 4.59; N,
18.31; S, 8.03.
crystals, (72% yield), mp. >300°C; IR: (potassium
bromide) 3475, 3411 (NH2), 3360 (NH), 1597 (C¼N)
1
cmꢀ1; H-NMR: δ 4.36 (s, 4H, CH2O), 6.99–8.00 (m,
12H, ArH, NH2), 8.08 (s, 2H, CH¼N), 11.29 (s, 2H,
NH); Anal. Calcd. For C18H20N6 O2S2: C, 51.90; H,
4.84; N, 20.18; S, 15.40. Found: C, 51.73; H, 4.67; N,
20.10; S, 15.29.
1,3-Bis(4-((2-(4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazol-2-
yl)hydrazono)-methyl)phenoxy)propane 20b. Orange crystals,
(75% yield), mp. 262–264°C; IR: (potassium bromide)
2,2′-(4,4′-(Propane-1,3-diylbis(oxy))bis(4,1-phenylene))bis(methan-
1
1-yl-1-ylidene)bis(hydrazinecarbothioamide) 19b.
Yellow
3432 (NH), 1567 (C¼N) cmꢀ1; H-NMR: δ 2.21 (m, 2H,
crystals, (74% yield), mp. 222–224°C; IR: (potassium
bromide) 3420, 3254 (NH2), 3151 (NH), 1536 (C¼N)
CH2), 2.54 (s, 6H, CH3), 4.21 (m, 4H, CH2O), 6.85 (s,
2H, thiazole-5-H), 7.01–7.60 (m, 18H, ArH), 7.92 (s, 2H,
CH¼N), 7.98 (s, 2H, pyrazole-3-H), 11.94 (s, 2H, NH);
13C-NMR: δ 11.97, 28.53, 64.31, 101.40, 114.80, 116.80,
124.85, 127.16, 127.72, 129.09, 135.40, 138.79, 139.29,
141.07, 159.37, 168.18; ms: m/z (%) 790 (0.09, M+).
Anal. Calcd. for C43H38N10 O2S2: C, 65.30; H, 4.84; N,
17.71; S, 8.11. Found: C, 65.06; H, 4.69; N, 17.46; S, 8.23
1,4-Bis(4-((2-(4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazol-2-
yl)hydrazono)-methyl)phenoxy)butane 20c. Orange crystals,
(77% yield), mp. 270–272°C; IR: (potassium bromide)
cmꢀ1 1H-NMR: δ 2.17 (m, 2H, CH2), 4.16 (m, 4H,
;
CH2O), 6.96–7.99 (m, 12H, ArH, NH2), 8.07 (s, 2H,
CH¼N), 11.28 (s, 2H, NH); Anal. Calcd. For
C19H22N6O2S2: C, 53.00; H, 5.15; N, 19.52; S, 14.90.
Found: C, 52.87; H, 5.01; N, 19.40; S, 14.71.
2,2′-(4,4′-(Butane-1,4-diylbis(oxy))bis(4,1-phenylene))bis(methan-
1-yl-1-ylidene)-bis(hydrazinecarbothioamide) 19c.
Yellow
crystals, (76% yield), mp. >300°C; IR: (potassium
bromide) 3338, 3268 (NH2), 3158 (NH), 1531 (C¼N)
cmꢀ1
;
1H-NMR: δ 1.87 (s, 4H, CH2), 4.16 (s, 4H,
3427 (NH), 1566 (C¼N) cmꢀ1; H-NMR: δ 1.90 (s, 4H,
1
CH2O), 6.94–7.99 (m, 12H, ArH, NH2), 8.07 (s, 2H,
CH¼N), 11.28 (s, 2H, NH); Anal. Calcd. For
C20H24N6O2S2: C, 54.03; H, 5.44; N, 18.90; S, 14.43.
Found: C, 53.88; H, 5.31; N, 18.74; S, 14.22.
2,2′-(2,2′-(Ethane-1,2-diylbis(oxy))bis(2,1-phenylene))bis
(methan-1-yl-1-ylidene)-bis(hydrazinecarbothioamide) 19d.
Yellow crystals, (72% yield), mp. 238–240°C, (Lit. [48];
245–247°C).
CH2), 2.54 (s, 6H, CH3), 4.09 (s, 4H, CH2O), 6.85 (s, 2H,
thiazole-5-H), 6.99–7.98 (m, 22H, ArH, CH¼N, pyrazole-
3-H), 11.93 (s, 2H, NH); ms: m/z (%) 804 (0.86, M+).
Anal. Calcd. for C44H40N10 O2S2: C, 65.65; H, 5.01; N,
17.40; S, 7.97. Found: C, 65.89; H, 4.83; N, 17.14; S, 7.76.
1,2-Bis(2-((2-(4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazol-2-
yl)hydrazono)-methyl)phenoxy)ethane 20d. Yellow crystals,
(68% yield), mp. 215–218°C; IR: (potassium bromide)
1
3424 (NH), 1565 (C¼N) cmꢀ1; H-NMR: δ 2.54 (s, 6H,
2,2′-(2,2′-(Butane-1,4-diylbis(oxy))bis(2,1-phenylene))bis(methan-
1-yl-1-ylidene)-bis(hydrazinecarbothioamide) 19e.
Yellow
CH3), 4.45 (s, 4H, CH2O), 6.84 (s, 2H, thiazole-5-H),
7.05–7.83 (m, 18H, ArH), 7.89 (s, 2H, CH¼N), 8.41 (s,
2H, pyrazole-3-H), 12.03 (s, 2H, NH); ms: m/z (%) 776
(1.05, M+). Anal. Calcd. For C42H36N10 O2S2: C, 64.93;
H, 4.67; N, 18.03; S, 8.25. Found: C, 64.77; H, 4.99; N,
18.21; S, 8.13.
crystals, (75% yield), mp. 228–230°C; IR: (potassium
bromide) 3430, 3358 (NH2), 3314 (NH), 1531 (C¼N)
1
cmꢀ1; H-NMR: δ 1.99 (s, 4H, CH2), 4.12 (s, 4H, CH2O),
6.92–8.10 (m, 12H, ArH, NH2), 8.51 (s, 2H, CH¼N),
11.45 (s, 2H, NH); Anal. Calcd. For C20H24N6O2S2: C,
54.03; H, 5.44; N, 18.90; S, 14.43. Found: C, 53.90; H,
5.37; N, 18.79; S, 14.31.
1,4-Bis(2-((2-(4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazol-2-
yl)hydrazono)-methyl)phenoxy)butane 20e. Yellow crystals,
(76% yield), mp. 230–232°C; IR: (potassium bromide)
Synthesis of bis(5-1H-pyrazol-4-yl)thiazol-2-yl)hydrazono)
1
3427 (NH), 1562 (C¼N) cmꢀ1; H-NMR: δ 2.01 (br, 4H,
methyl)phenoxy)-alkane 20a–e.
General procedure. To
a
mixture of alkylenebis(oxy)bis(2,1-phenylene)bis
CH2), 2.52 (s, 6H, CH3), 4.15 (br, 4H, CH2O), 6.86
(s, 2H, thiazole-5-H), 7.00–7.54 (m, 18H, ArH,), 7.91
(s, 2H, CH¼N), 8.45 (s, 2H, pyrazole-3-H), 12.08 (s, 2H,
NH); 13C-NMR: δ 11.95, 25.55, 67.74, 101.52, 112.61,
116.77, 120.69, 122.72, 124.84, 127.62, 129.07, 130.46,
135.42, 136.99, 138.79, 139.29, 144.43, 156.42, 168.05;
ms: m/z (%) 804 (0.34, M+). Anal. Calcd. for C44H40N10
O2S2: C, 65.65; H, 5.01; N, 17.40; S, 7.97. Found: C,
65.49; H, 4.79; N, 17.29; S, 7.85.
(methan-1-yl-1-ylidene))bis (hydrazine-carbothioamide)
19a–e (1 mmol) and 2-bromo-1-(5-methyl-1-phenyl-1H-
pyrazol-4-yl)ethanone (6) (2 mmol) in ethanol (25 mL),
few drops of TEA were added. The reaction mixture was
heated under reflux for 3–5 h then allowed to cool. The
solvent was evaporated in vacuo, and the solid residue
was collected by filtration and recrystallized from
ethanol/DMF to give 20a–e.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. E. Salem, A. F. Darweesh, A. E. M. Mekky, A. M. Farag, and A. H. M. Elwahy
Vol 000
Synthesis of alkylenebis(oxy)bis(2,1-phenylene)bis(methan-
1-yl-1-ylidene))bis (hydrazinecarbothioamide) 22a–c. General
procedure. To a mixture of the appropriate bis(aldehyde)
compounds 21a–c (10 mmol) and thiosemicarbazide (13)
(20 mmol) in absolute ethanol (25 mL), few drops of acetic
acid were added. The reaction mixture was heated under reflux
for 3h then left to cool. The solid formed was collected by
filtration and recrystallized from ethanol/DMF to give 22a–c.
2,2′-(4,4′-(1,2-Phenylenebis(methylene))bis(oxy)bis(4,1-phenylene))
bis(methan-1-yl-1-ylidene)bis(hydrazinecarbothioamide) 22a.
Yellow crystals, (61% yield), mp. 228–230°C, (Lit. [48];
220–221°C).
C48H40N10O2S2: C, 67.58; H, 4.73; N, 16.42; S, 7.52.
Found: C, 67.35; H, 4.58; N, 16.30; S, 7.18.
1,4-Bis((4-((2-(4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazol-
2-yl)hydrazono)-methyl)phenoxy)methyl)benzene 23c. Orange
crystals, (70% yield), mp. 270–274°C; IR: (potassium
;
bromide) 3431 (NH), 1566 (C¼N) cmꢀ1 1H-NMR: δ
2.53 (s, 6H, CH3), 5.16 (s, 4H, CH2O), 6.85 (s, 2H,
thiazole-5-H), 7.06–7.60 (m, 22H, ArH), 7.92 (s, 2H,
CH¼N), 7.97 (s, 2H, pyrazole-3-H), 11.95 (s, 2H, NH);
13C-NMR: δ 11.97, 69.05, 101.43, 115.17, 117.09,
124.87, 127.32, 127.69, 127.79, 129.11, 129.33, 135.42,
136.47, 138.78, 139.29, 141.01, 144.27, 159.20, 168.14;
ms: m/z (%) 853 (33.74, M+). Anal. Calcd. For
C48H40N10O2S2: C, 67.58; H, 4.73; N, 16.42; S, 7.52.
Found: C, 67.74; H, 4.55; N, 16.70; S, 7.41.
2,2′-(4,4′-(1,3-Phenylenebis(methylene))bis(oxy)bis(4,1-phenylene))
bis(methan-1-yl-1-ylidene)bis(hydrazinecarbothioamide) 22b.
Yellow crystals, (64% yield), mp. 222–224°C; IR:
(potassium bromide) 3495, 3434 (NH2), 3379 (NH), 1595
1
(C¼N) cmꢀ1; H-NMR: δ 5.17 (s, 4H, CH2O), 7.03–7.99
(m, 16H, ArH, NH2), 8.07 (s, 2H, CH¼N), 11.29 (s, 2H,
NH); ms: m/z (%) 492 (0.10, M+). Anal. Calcd. For
C24H24N6O2S2: C, 58.52; H, 4.91; N, 17.06; S, 13.02.
Found: C, 58.44; H, 4.83; N, 17.02; S, 12.92.
REFERENCES AND NOTES
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bis(methan-1-yl-1-ylidene)bis(hydrazinecarbothioamide) 22c.
Yellow solid, (66% yield), mp. 260–262°C, (Lit. [49];
250–252°C).
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methyl)phenoxy)-arene 23a–c.
General procedure. To a
mixture of alkylenebis(oxy)bis(2,1-phenylene)bis(methan-
1-yl-1-ylidene))bis (hydrazine-carbothioamide) 22a–c
(1mmol) and 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-
yl)ethanone (6) (2mmol) in ethanol/DMF [1:1] (25mL),
few drops of TEA were added. The reaction mixture was
heated under reflux for 3–5h then left to cool. The solvent
was evaporated in vacuo, and the solid residue was
collected by filtration and recrystallized from ethanol/DMF
to give 23a–c.
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1,2-Bis((4-((2-(4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazol-
2-yl)hydrazono)-methyl)phenoxy)methyl)benzene 23a. Yellow
crystals, (65% yield), mp. 250–252°C; IR: (potassium
bromide) 3433 (NH), 1568 (C¼N) cmꢀ1
;
1H-NMR: δ
2.52 (s, 6H, CH3), 5.29 (s, 4H, CH2O), 6.84 (s, 2H,
thiazole-5-H), 7.07–7.98 (m, 22H, ArH), 7.91 (s, 2H,
CH¼N), 7.98 (s, 2H, pyrazole-3-H), 11.95 (s, 2H, NH);
ms: m/z (%) 853 (21.03, M+). Anal. Calcd. For
C48H40N10O2S2: C, 67.58; H, 4.73; N, 16.42; S, 7.52.
Found: C, 67.44; H, 4.68; N, 16.33; S, 7.46.
1,3-Bis((4-((2-(4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)thiazol-
2-yl)hydrazono)-methyl)phenoxy)methyl)benzene 23b. Yellow
crystals, (65% yield), mp. 268–270°C; IR: (potassium
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bromide) 3425 (NH), 1565 (C¼N) cmꢀ1
;
1H-NMR: δ
2.53 (s, 6H, CH3), 5.18 (s, 4H, CH2O), 6.85 (s, 2H,
thiazole-5-H), 7.07–7.61 (m, 22H, ArH), 7.92 (s, 2H,
CH¼N), 7.98 (s, 2H, pyrazole-3-H), 11.95 (s, 2H, NH);
ms: m/z (%) 853 (16.56, M+). Anal. Calcd. For
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
A Synthesis of Novel Bis(thiazoles) 20a–c and 23a–c is Reported
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet