Microwave-Assisted Synthesis of Novel Bis(thiazoles) Incorporating Piperazine Moiety

Article abstract of DOI:10.1002/jhet.3531

Novel bis(hydrazinecarbothioamide) was prepared by the reaction of 1,4-bis[(3-formyl-4-hydroxyphenyl)methyl]piperazine with thiosemicarbazide. The bis(hydrazinecarbothioamide) was used as a building block for construction of a novel bis(thiazolyl)piperazines via its cyclocondensation with a series of each of α-halocarbonyl compounds and hydrazonoyl halides in dimethylformamide in the presence of triethylamine as a catalyst under microwave irradiation. The structure of the newly bis(thiazolyl)piperazine derivatives is elucidated via the spectral data as well as elemental analyses.

Full text of DOI:10.1002/jhet.3531

Month 2019
Microwave-Assisted Synthesis of Novel Bis(thiazoles) Incorporating
Piperazine Moiety
*
Ahmed E. M. Mekky
and Sherif M. H. Sanad
Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt
*E-mail: ataher2211@yahoo.com
Received December 6, 2018
DOI 10.1002/jhet.3531
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
Novel bis(hydrazinecarbothioamide) was prepared by the reaction of 1,4-bis[(3-formyl-4-hydroxyphenyl)
methyl]piperazine with thiosemicarbazide. The bis(hydrazinecarbothioamide) was used as a building block
for construction of a novel bis(thiazolyl)piperazines via its cyclocondensation with a series of each of α-
halocarbonyl compounds and hydrazonoyl halides in dimethylformamide in the presence of triethylamine
as a catalyst under microwave irradiation. The structure of the newly bis(thiazolyl)piperazine derivatives
is elucidated via the spectral data as well as elemental analyses.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
In addition, bis-heterocyclic compounds as well as hybrid
molecules, whose pharmacophores are integrated into a
single molecule, were reported to display various
The synthesis of heterocyclic rings has been an attractive
field in therapeutic science. Numerous heterocyclic
compounds containing nitrogen and sulfur are used in the
development and design of drugs [1]. Piperazine occupies
a principal place in medicinal chemistry. It is a vital core
scaffold present in many synthetic therapeutically
important compounds. The versatility of piperazine
nucleus is established by the fact that it is an essential
part of many currently notable drugs such as antianginals,
antidepressants, antihistamines, antiserotonergics, and
antipsychotics. Among the several Food and Drug
Administration-approved therapeutic drugs, the piperazine
ring was found in Celebrex, rimonabant, and leflunomide
(Figure 1) [2–6]. Also, thiazole and its derivatives are
one of the heterogeneous ring compounds that are
associated with many pharmaceutical and medical
applications. Thiazole derivatives demonstrate significant
biological properties such antifungal (abafungin),
antimicrobial (sulfazole), anti-inflammatory, anticancer,
anticonvulsant, anti-HIV, antihypertensive, anti-gout
(febuxostat), and antidiabetic activities (Figure 2) [7–14].
biological
antibacterial,
activities,
especially
as
fungicidal,
and
tuberculostatic,
anthelmintic,
antiamoebic [15–22]. Because of the significant
bioactivity and wide range of application of piperazine
and thiazole derivatives as well as bis-heterocyclic
compounds, several publications reported concerning the
synthesis of these derivatives [23–31].
Motivated by the above-mentioned findings, and in
continuation of our attention in the synthesis
bis(heterocycles) [32–41], we report, herein, the synthetic
utilities of the bis(thiosemicarbazone) as key intermediate
for the synthesis of novel bis(thiazole), under both
microwave irradiation and conventional methods.
RESULTS AND DISCUSSION
Initially, our goal was to hybridize the piperazine unit
with thiazole. For this purpose, 1,4-bis[(3-formyl-4-
hydroxyphenyl)methyl]piperazine 3 [42] was chosen as
© 2019 Wiley Periodicals, Inc.

A. E. M. Mekky and S. M. H. Sanad
Vol 000
Figure 1. Some pharmaceutical drugs containing piperazine core. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 2. Some biologically active drugs containing thiazole core. [Color figure can be viewed at wileyonlinelibrary.com]
the main intermediate, which was easily obtained from
5-(chloromethyl)-2-hydroxybenzaldehyde and
piperazine in dichloromethane and triethylamine (TEA).
Compound was obtained from the reaction of
salicylaldehyde and formaldehyde in the presence of
concentrated hydrochloric acid [43] (Scheme 1).
and 3.58 due to piperazine and methylene protons, two
2
doublet and one singlet signals in the region δ 6.95–7.63
due to aromatic protons, and a singlet signal at δ 8.35
due to one methine proton, in addition to three D2O-
exchangeable singlet signals at δ 8.10, 9.92, and 11.43
due to NH2, OH, and NH protons, respectively.
2
The reaction of bis(2-hydroxybenzaldehyde) 3 with
thiosemicarbazide 4 was carried out in dioxane in the
presence of a few drops of glacial acetic acid under
microwave irradiation produces one product that has been
The bis(hydrazinecarbothioamide) 5 has stimulated us to
study its synthetic facilities as a building block for
construction of
a
novel bis(thiazoles) via the
cyclocondensation with α-halocarbonyl compounds and
hydrazonoyl halides, respectively. Thus, the reaction of
the bis(hydrazinecarbothioamide) 5 with chloroacetone 6
in dimethylformamide (DMF) under microwave
irradiation in the presence of TEA as a catalyst afforded
bis(thiazolyl)piperazine 7 (Scheme 3). The infrared (IR)
identified as bis(hydrazinecarbothioamide)
5 within
10 min (Scheme 2).
The elemental analysis and spectral data were fully
1
consistent with the given structure 5. For example, its H-
NMR spectrum presented two singlet signals at δ 2.43
Scheme 1. Synthesis of bis(2-hydroxybenzaldehyde) 3.
Scheme 2. Synthesis of bis(hydrazinecarbothioamide) 5. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Microwave Assisted Synthesis of Novel Bis(thiazoles) Incorporating Piperazine
Moiety
Scheme 3. Synthesis of bis(thiazolyl)piperazines 7, 9, 11 and bis(4-oxothiazolyl)piperazine 13. [Color figure can be viewed at wileyonlinelibrary.com]
spectrum of the bis(thiazolyl)piperazine 7 revealed an
absorption band at 3413 and 3224 cmÀ1 due to (OH) and
(NH), respectively. Its NMR showed the presence of a
characteristic singlet signal at δ 8.80 due to methine
proton (–N=CH–). All other protons were seen at the
expected chemical shifts and integral values (see the
Experimental section).
derivatives 15a–e (Scheme 4). The structure of this series
of bis(arylazothiazolyl)piperazines 15a–e was established
on the basis of spectral data and elemental analysis.
Accordingly,
the
1H-NMR
spectrum
of
bis(phenylazothiazolyl)piperazine 15a, as
a
typical
example, showed three singlet signals at δ 2.43, 2.60, and
3.58 due to piperazine, methyl, and methylene protons,
accompanied by aromatic proton signals in the region δ
6.82–7.63 and a singlet signal at δ 8.78 due to methine
proton, in addition to two D2O-exchangeable singlet
signals identified as OH and NH protons at δ 10.66 and
10.70, respectively. In addition, the mass spectrum of 15a
showed a molecular ion peak at m/z = 784. An additional
justification for the structure of the aforementioned
reaction products comes from the treatment of benzene
diazonium chloride 16 with bis(thiazolyl)piperazines 7 in
pyridine afforded a product identical in all respects with
15a.
Analogously, 2-bromo-1-phenylethanone 8 and 3-(2-
bromoacetyl)-2H-chromen-2-one 10 were reacted with
bis(hydrazinecarbothioamide)
5
in DMF, under
microwave irradiation, in the presence of a catalytic
amount of TEA, which afforded bis(thiazolyl)piperazines
9 and 11, respectively. Moreover, ethyl chloroacetate 12
reacted with 5 under the same conditions to give the
corresponding
bis(4-oxothiazolyl)piperazine
13
(Scheme 3). The reaction time and the yield are shown in
Table 1.
A second series of bis(thiazolyl)piperazine derivatives
was prepared by a related pathway (Scheme 4). Thus, the
cyclocondensation of compound 5 with hydrazonoyl
chlorides 14a–e in DMF under microwave irradiation, in
the presence of TEA, gave bis(arylazothiazolyl)piperazine
Similarly, treatment of bis(hydrazinecarbothioamide) 5
with the appropriate hydrazonoyl chlorides 17a–e in
DMF containing TEA under microwave irradiation
afforded bis(5-arylhydrazono-4-oxothiazolyl)piperazines
Table 1
Synthesis of bis(thiazolyl)piperazines 7, 9, 11 and bis(4-oxothiazolyl)piperazine 13, under both microwave irradiation and conventional method.
Microwave irradiation
300 W/120°C
Conventional method
Entry
Compound
Time (min)
Yield (%)
Time (h)
Yield (%)
1
2
3
4
7
9
11
13
15
10
10
15
93
96
98
90
3
2
1.5
3
88
90
95
82
Journal of Heterocyclic Chemistry
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A. E. M. Mekky and S. M. H. Sanad
Vol 000
Scheme 4. Synthesis of bis(arylazothiazolyl)piperazines 15a–e and bis(5-arylhydrazono-4-oxothiazolyl)piperazines 18a–e. [Color figure can be viewed at
wileyonlinelibrary.com]
18a–e (Scheme 4). The structures of the formed products
18a–e were elucidated by elemental analyses and spectral
data (see the Experimental section). Again, the structure
was confirmed by alternative synthesis. Thus, the
coupling of bis(4-oxothiazolyl)piperazine 13 with
benzene diazonium chloride 16 in pyridine yielded the
same product 18a.
reactions from 1.5–6 h in conventional procedure to 10–
45 min. Also, an obvious improvement is seen in yields of
reactions under microwave irradiations.
CONCLUSION
Finally, to find the effect of microwave irradiation on the
synthesis of this series of bis(thiazole) derivatives, all
previous reactions were carried out under the same
conditions without microwave irradiation (Tables 1 and 2).
It was noticed that the reaction time increased
substantially and that yield of the products decreased.
Consequently, microwave irradiation was found to have
supportive effect on the synthesis of bis(thiazole)
derivatives by decreasing the time of aforementioned
In conclusion, we introduce an effective synthetic
pathway for a series of novel bis(thiazolyl)piperazines,
bis(4-oxothiazolyl)piperazine, bis(arylazothiazolyl)pipera-
zines, and bis(5-arylhydrazono-4-oxothiazolyl)piperazines
under microwave irradiation via cyclocondensation of
bis(hydrazinecarbothioamide) with appropriate α-
halocarbonyl compounds and hydrazonoyl halides.
Microwave irradiation gave access to high yields of
bis(thiazole) in
a
short reaction time than did
Table 2
Synthesis of bis(arylazothiazolyl)piperazines 15a–e and bis(5-arylhydrazono-4-oxothiazolyl)piperazines 18a–e, under both microwave irradiation and
conventional method.
Microwave irradiation 300 W/120°C
Conventional method
Time (h)
Entry
Compound
X
Time (min)
Yield (%)
Yield (%)
1
2
3
4
5
6
7
8
9
15a
15b
15c
15d
15e
18a
18b
18c
18d
18e
H
CH3
OCH3
Cl
COOEt
H
CH3
OCH3
Cl
30
30
30
15
45
30
15
30
30
45
92
95
82
95
85
88
90
80
92
80
5
5
5
4
6
5
4
5
5
5
80
85
77
90
70
78
84
68
57
66
10
COOEt
Journal of Heterocyclic Chemistry
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Month 2019
Microwave Assisted Synthesis of Novel Bis(thiazoles) Incorporating Piperazine
Moiety
conventional heating. The structure of the novel
bis(thiazole) series was established by spectral data in
addition to alternative synthesis.
was irradiated by microwave with a power of 300 W to
reach reaction temperature of 120°C under
autogenerated pressure for 10–15 min. The formed solid
was filtered off, washed with ethanol, and recrystallized
from DMF.
a
Method “B” (conventional method).
A mixture of
EXPERIMENTAL
bis(hydrazinecarbothioamide) 5 (1 mmol) and each of
chloroacetone 6, 2-bromo-1-phenylethanone 8, 3-(2-
All organic solvents were acquired from commercial
sources and used as received unless otherwise stated. All
other chemicals were acquired from Merck (Merck
KGaA, Darmstadt, Germany). These chemicals were used
without further purification. The melting points were mea-
sured on a Stuart melting point apparatus and are uncor-
rected. IR spectra were recorded on a Smart iTR, which is
an ultra-high-performance, versatile attenuated total reflec-
tance sampling accessory on the Nicolet iS10 Fourier trans-
form IR spectrometer. 1H-NMR and 13C-NMR spectra
were recorded on Varian Mercury (Varian, Inc., Palo Alto,
CA) at 300 and 75 MHz, respectively, spectrophotometer
using tetramethylsilane as an internal standard and
DMSO-d6 as solvent; and chemical shifts were expressed
as δ ppm units. Mass spectra were recorded on a GC-MS-
QP1000EX spectrometer using inlet type at 70 eV. Elemen-
tal analyses were carried out on a EuroVector instrument C,
H, N, S analyzer EA3000 Series. Microwave experiments
were performed using CEM Discover & Explorer SP mi-
crowave apparatus (300 W), utilizing 35-mL capped glass
reaction vessels automated power control based on temper-
ature feedback. Hydrazonoyl halides 14a–e and 17a–e [44]
were prepared according to the reported literature.
bromoacetyl)-2H-chromen-2-one
10,
or
ethyl
chloroacetate 12 (2 mmol) in DMF (20 mL) in the
presence of TEA (0.5 mL) was heated at reflux for 1.5–
3 h. The formed solid was filtered off, washed with
ethanol, and recrystallized from DMF.
1,4-Bis[(4-hydroxy-3-((2-(4-methylthiazol-2-yl)
hydrazineylidene)methyl)phenyl)methyl]piperazine (7).
Beige crystals; mp 242–244°C; IR (υ cmÀ1): 3413, 3224,
1
2945, 1608, 1480; H-NMR (DMSO-d6): δ 2.43 (s, 8H, 4
CH2), 2.59 (s, 6H, 2 CH3), 3.58 (s, 4H, 2 CH2), 6.55–
7.52 (m, 8H, Ar-H), 8.80 (s, 2H, 2 –N=CH–), 10.70 (s,
2H, 2 OH), 10.78 (s, 2H, 2 NH); MS (m/z): 576 (M+);
Anal. for C28H32N8O2S2: C, 58.31; H, 5.59; N, 19.43; S,
11.12. Found: C, 58.54; H, 5.68; N, 19.69; S, 11.02%.
1,4-Bis[(4-hydroxy-3-((2-(4-phenylthiazol-2-yl)
hydrazineylidene)methyl)phenyl)methyl]piperazine (9).
Colorless crystals; mp > 300°C; IR (υ cmÀ1): 3430,
1
3325, 3121, 2915, 1611, 1564, 1484; H-NMR (DMSO-
d6): δ 2.44 (s, 8H, 4 CH2), 3.57 (s, 4H, 2 CH2), 6.72–
7.80 (m, 18H, Ar-H), 8.29 (s, 2H, 2 –N═CH–), 10.00 (s,
2H,
2 OH), 12.07 (s, 2H, 2 NH); Anal. for
C38H36N8O2S2 (700.8): C, 65.12; H, 5.18; N, 15.99; S,
9.15. Found: C, 65.36; H, 5.01; N, 15.74; S, 9.33%.
Synthesis of 1,4-bis[(3-((2-carbamothioylhydrazineylidene)
methyl)-4-hydroxyphenyl)methyl]piperazine
(5).
A
1,4-Bis[(4-hydroxy-3-((2-(4-(2-oxo-2H-chromen-3-yl)
thiazol-2-yl)hydrazineylidene)methyl)phenyl)methyl]piperazine
(11). Colorless crystals; mp > 300°C; IR (υ cmÀ1): 3436,
mixture of bis(aldehyde)
3
(1 mmol) and
thiosemicarbazide 4 (2 mmol), in dioxane (10 mL) in the
presence of few drops of acetic acid, was placed in
process vial and was irradiated by microwave with a
power of 300 W to reach a reaction temperature of 120°C
under autogenerated pressure for 10 min. The formed
solid was filtered off, washed with ethanol, and
recrystallized from DMF as colorless crystals (78%); mp
264–266°C; IR (υ cmÀ1): 3401, 3235, 3161, 1605, 1532;
1H-NMR (DMSO-d6): δ 2.43 (s, 8H, 4 CH2), 3.58 (s, 4H,
2 CH2), 6.95–7.63 (m, 6H, Ar-H), 8.10 (s, 4H, 2 NH2),
8.35 (s, 2H, 2 –N=CH–), 9.92 (s, 2H, 2 OH), 11.43 (s,
1
3220, 3122, 2915, 1701, 1575, 1491; H-NMR (DMSO-
d6): δ 2.44 (s, 8H, 4 CH2), 3.57 (s, 4H, 2 CH2), 6.76–
7.75 (m, 16H, Ar-H), 8.34 (s, 2H, 2 –N═CH–), 8.51 (s,
2H, 2 coumarin-CH-4), 10.04 (s, 2H, 2 OH), 12.14 (s,
2H,
2
NH); MS (m/z): 836 (M+); Anal. for
C44H36N8O6S2: C, 63.14; H, 4.34; N, 13.39; S, 7.66.
Found: C, 63.01; H, 4.58; N, 13.47; S, 7.51%.
1,4-Bis[(4-hydroxy-3-((2-(4-oxo-4,5-dihydrothiazol-2-yl)
hydrazineylidene)methyl)phenyl)methyl]piperazine (13).
Colorless crystals; mp 228–230°C; IR (υ cmÀ1): 3434,
1
2H,
2
NH); MS (m/z): 500 (M+); Anal. for
2919, 1716, 1645, 1490; H-NMR (DMSO-d6): δ 2.44 (s,
C22H28N8O2S2 (500.6): C, 52.78; H, 5.64; N, 22.38; S,
12.81. Found: C, 53.01; H, 5.41; N, 22.56; S, 12.77%.
8H, 4 CH2), 3.57 (s, 4H, 2 CH2), 3.97 (s, 4H, 2 thiazole-
H5), 6.87–7.56 (m, 6H, Ar-H), 8.61 (s, 2H, 2 –N═CH–),
10.59 (s, 2H, 2 OH), 10.66 (s, 2H, 2 NH); Anal. for
C26H28N8O4S2 (580.6): C, 53.78; H, 4.86; N, 19.30; S,
11.04. Found: C, 53.98; H, 4.99; N, 19.08; S, 10.89%.
Synthesis of bis(thiazolyl)piperazines 7, 9, 11 and bis(4-
oxothiazolyl)piperazine 13. Method “A” (microwave
method). A mixture of bis(hydrazinecarbothioamide) 5
(1 mmol) and each of chloroacetone 6, phenacyl bromide
8, 3-(2-bromoacetyl)-2H-chromen-2-one 10, or ethyl
chloroacetate 12 (2 mmol) in DMF (10 mL) in the
presence of TEA (0.5 mL) was placed in process vial and
Synthesis of bis(arylazothiazolyl)piperazines 15a-e and
bis(5-arylhydrazono-4-oxothiazolyl)piperazines
Method “A” (microwave method).
18a–e.
mixture of
A
bis(hydrazinecarbothioamide) 5 (1 mmol) and each of
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A. E. M. Mekky and S. M. H. Sanad
Vol 000
hydrazonoyl chlorides 14a–e or 17a–e (2 mmol) in DMF
1,4-Bis[(4-hydroxy-3-((4-methyl-5-((4-chlorophenyl)
diazenyl)thiazol-2-yl
hydrazineylidene)methyl)phenyl)
(10 mL) in the presence of TEA (0.5 mL) was placed in
process vial and was irradiated by microwave with a
power of 300 W to reach a reaction temperature of 120°C
under autogenerated pressure for 15–45 min. The formed
solid was filtered off, washed with ethanol, and
recrystallized from DMF.
methyl]piperazine (15d). Red crystals; mp > 300°C; IR
(υ cmÀ1): 3417, 3220, 2954, 1605, 1480; 1H-NMR
(DMSO-d6): δ 2.44 (s, 8H, 4 CH2), 2.59 (s, 6H, 2 CH3),
3.57 (s, 4H, 2 CH2), 6.85–7.63 (m, 14H, Ar-H), 8.75 (s,
2H, 2 –N═CH–), 10.74 (s, 2H, 2 OH), 10.86 (s, 2H, 2
NH); Anal. for C40H38Cl2N12O2S2 (853.8): C, 56.27; H,
4.49; N, 19.69; S, 7.51. Found: C, 56.42; H, 4.33; N,
19.84; S, 7.64%.
Method “B” (conventional method).
A mixture of
bis(hydrazinecarbothioamide) 5 (1 mmol) and each of
hydrazonoyl chlorides 14a–e or 17a–e (2 mmol) in DMF
(10 mL) in the presence of TEA (0.5 mL) was heated at
reflux for 4–6 h. The formed solid was filtered off,
washed with ethanol, and recrystallized from DMF.
Method “C” (coupling method). A benzene diazonium
chloride solution 16 (2 mmol) was prepared via the
addition of sodium nitrite solution of (0.2 g into 2 mL of
water) to aniline hydrochloride (2 mmol in 2 mL of
concentrated HCl) with stirring in ice bath. The obtained
solution was then poured to a solution of each of
compound 7 or 13 (1 mmol) in pyridine (15 mL) with
stirring for 2 h at 0–5°C. The reaction mixture was stirred
for additional 4 h in ice bath and then left for 24 h at 4°C
in a refrigerator. The solids obtained were filtrated and
recrystallized from DMF to give the corresponding 15a
and 18a.
1,4-Bis[(4-hydroxy-3-((4-methyl-5-((4-
ethoxycarbonylphenyl)diazenyl)thiazol-2-ylhydrazineylidene)
methyl)phenyl)methyl]piperazine (15e).
Red crystals;
mp > 300°C; IR (υ cmÀ1): IR (υ cmÀ1): 3414, 3222, 2941,
1700, 1604, 1483; 1H-NMR (DMSO-d6): δ 1.30 (t,
J = 7.2 Hz, 6H, 2 CH2CH3), 2.43 (s, 8H, 4 CH2), 2.60 (s,
6H, 2 CH3), 3.57 (s, 4H, 2 CH2), 4.26 (q, J = 7.2 Hz, 4H, 2
CH2CH3), 6.83–7.88 (m, 14H, Ar-H), 8.66 (s, 2H, 2 –
N═CH–), 10.72 (s, 2H, 2 OH), 10.97 (s, 2H, 2 NH); Anal.
for C46H48N12O6S2 (929.0): C, 59.47; H, 5.21; N, 18.09;
S, 6.90. Found: C, 59.29; H, 5.08; N, 18.26; S, 6.77%.
1,4-Bis[(4-hydroxy-3-((2-(5-(2-phenylhydrazineylidene)-4-
oxo-4,5-dihydrothiazol-2-yl)hydrazineylidene)methyl)phenyl)
methyl]piperazine (18a).
Yellow crystals; mp 286–
288°C; IR (υ cmÀ1): 3436, 3254, 2912, 1705, 1634,
1
1543, 1484; H-NMR (DMSO-d6): δ 2.43 (s, 8H, 4 CH2),
1,4-Bis[(4-hydroxy-3-((4-methyl-5-(phenyldiazenyl)thiazol-
2-ylhydrazineylidene)methyl)phenyl)methyl]piperazine
3.58 (s, 4H, 2 CH2), 6.89–7.66 (m, 16H, Ar-H), 8.71 (s,
2H, 2 –N═CH–), 10.50 (s, 2H, 2 OH), 10.61 (s, 2H, 2
NH), 12.62 (s, 2H, 2 NH); MS (m/z): 788 (M+); Anal. for
C38H36N12O4S2: C, 57.85; H, 4.60; N, 21.31; S, 8.13.
Found: C, 57.72; H, 4.35; N, 21.44; S, 8.26%.
1,4-Bis[(4-hydroxy-3-((2-(5-(2-(p-tolyl)hydrazineylidene)-4-
oxo-4,5-dihydrothiazol-2-yl)hydrazineylidene)methyl)phenyl)
methyl]piperazine (18b). Yellow crystals; mp 255–257°C;
(15a).
Red crystals; mp > 300°C; IR (υ cmÀ1): 3415,
1
3224, 2962, 1607, 1481; H-NMR (DMSO-d6): δ 2.43 (s,
8H, 4 CH2), 2.60 (s, 6H, 2 CH3), 3.58 (s, 4H, 2 CH2),
6.82–7.63 (m, 16H, Ar-H), 8.78 (s, 2H, 2 –N═CH–), 10.66
(s, 2H, 2 OH), 10.70 (s, 2H, 2 NH); MS (m/z): 784 (M+);
Anal. for C40H40N12O2S2: C, 61.21; H, 5.14; N, 21.41; S,
8.17. Found: C, 61.47; H, 5.18; N, 21.24; S, 8.33%.
IR (υ cmÀ1): 3437, 3246, 2919, 1703, 1638, 1546, 1490;
1H-NMR (DMSO-d6): δ 2.25 (s, 6H, 2 CH3), 2.44 (s, 8H,
4 CH2), 3.58 (s, 4H, 2 CH2), 6.86–7.74 (m, 14H, Ar-H),
8.74 (s, 2H, 2 –N═CH–), 10.68 (s, 2H, 2 OH), 10.84 (s,
2H, 2 NH), 12.70 (s, 2H, 2 NH); MS (m/z): 816 (M+);
Anal. for C40H40N12O4S2: C, 58.81; H, 4.94; N, 20.57;
S, 7.85. Found: C, 58.96; H, 4.74; N, 20.71; S, 7.95%.
1,4-Bis[(4-hydroxy-3-((4-methyl-5-(p-tolyldiazenyl)thiazol-
2-ylhydrazineylidene)methyl)phenyl)methyl]piperazine (15b).
Red crystals; mp > 300°C; IR (υ cmÀ1): IR (υ cmÀ1):
1
3414, 3221, 2954, 1604, 1485; H-NMR (DMSO-d6): δ
2.24 (s, 6H, 2 CH3), 2.43 (s, 8H, 4 CH2), 2.58 (s, 6H, 2
CH3), 3.58 (s, 4H, 2 CH2), 6.82–7.61 (m, 14H, Ar-H),
8.84 (s, 2H, 2 –N═CH–), 10.68 (s, 2H, 2 OH), 10.85 (s,
2H, 2 NH); Anal. for C42H44N12O2S2 (813.0): C, 62.05;
H, 5.46; N, 20.67; S, 7.89. Found: C, 62.14; H, 5.20; N,
20.96; S, 7.65%.
1,4-Bis[(4-hydroxy-3-((2-(5-(2-(4-methoxyphenyl)
hydrazineylidene)-4-oxo-4,5-dihydrothiazol-2-yl)
hydrazineylidene)methyl)phenyl)methyl]piperazine (18c).
Yellow crystals; mp 258–260°C; IR (υ cmÀ1): 3437,
1
3244, 2933, 1704, 1632, 1549, 1496; H-NMR (DMSO-
1,4-Bis[(4-hydroxy-3-((4-methyl-5-((4-methoxyphenyl)
diazenyl)thiazol-2-ylhydrazineylidene)methyl)phenyl)methyl]
piperazine (15c). Red crystals; mp > 300°C; IR (υ cmÀ1):
d6): δ 2.43 (s, 8H, 4 CH2), 3.57 (s, 4H, 2 CH2), 3.75 (s,
6H, 2 OCH3), 6.84–7.65 (m, 14H, Ar-H), 8.70 (s, 2H, 2
–N═CH–), 10.47 (s, 2H, 2 OH), 10.66 (s, 2H, 2 NH),
12.49 (s, 2H, 2 NH); Anal. for C40H40N12O6S2 (848.9):
C, 56.59; H, 4.75; N, 19.80; S, 7.55. Found: C, 56.32; H,
4.52; N, 19.98; S, 7.67%.
1
IR (υ cmÀ1): 3414, 3220, 2957, 1603, 1480; H-NMR
(DMSO-d6): δ 2.43 (s, 8H, 4 CH2), 2.60 (s, 6H, 2 CH3),
3.58 (s, 4H, 2 CH2), 3.76 (s, 6H, 2 OCH3), 6.86–7.68 (m,
14H, Ar-H), 8.86 (s, 2H, 2 –N═CH–), 10.46 (s, 2H, 2
OH), 10.66 (s, 2H, 2 NH); MS (m/z): 845 (M+); Anal. for
C42H44N12O4S2: C, 59.70; H, 5.25; N, 19.89; S, 7.59.
Found: C, 59.92; H, 5.44; N, 19.76; S, 7.43%.
1,4-Bis[(3-((2-(5-(2-(4-chlorophenyl)hydrazineylidene)-4-
oxo-4,5-dihydrothiazol-2-yl)hydrazineylidene)methyl)-4-
hydroxyphenyl)methyl]piperazine (18d). Yellow crystals;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Microwave Assisted Synthesis of Novel Bis(thiazoles) Incorporating Piperazine
Moiety
mp > 300°C; IR (υ cmÀ1): 3432, 3240, 2923, 1701, 1644,
1545, 1491; H-NMR (DMSO-d6): δ 2.44 (s, 8H, 4 CH2),
3.57 (s, 4H, 2 CH2), 6.88–7.62 (m, 14H, Ar-H), 8.65 (s,
2H, 2 –N═CH–), 10.55 (s, 2H, 2 OH), 10.64 (s, 2H, 2
NH), 12.64 (s, 2H, 2 NH); Anal. for C38H34Cl2N12O4S2
(857.7): C, 53.21; H, 4.00; N, 19.60; S, 7.48. Found: C,
53.44; H, 4.14; N, 19.38; S, 7.24%.
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M.; Lucas, J. C.; Kang, Z.; Kupchinsky, S.; Ahlijanian, M. K.; Tate, B.;
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1
1,4-Bis[(3-((2-(5-(2-(4-ethoxycarbonylphenyl)
[20] Soural, M.; Bouillon, I.; Krchnak, V. J Comb Chem 2008, 10,
923.
hydrazineylidene)-4-oxo-4,5-dihydrothiazol-2-yl)
hydrazineylidene)methyl)-4-hydroxyphenyl)methyl]
piperazine (18e). Yellow crystals; mp 270–272°C; IR (υ
[21] Csuk, R.; Barthel, A.; Raschke, C.; Kluge, R.; Strohl, D.;
Trieschmann, L.; Böhm, G. Arch Pharm (Weinheim) 2009, 342, 699.
[22] Viegas-Junior, C.; Danuello, A.; da Silva Bolzani, V.;
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[23] Abdelriheem, N. A.; Mohamed, A. M. M.; Abdelhamid, A. O.
Molecules 2017, 22, 268.
[24] Gomha, S. M.; Farghaly, T. A.; Mabkhot, Y. N.; Zayed, M. E.;
Mohamed, A. M. Molecules 2017, 22, 346.
[25] Abdelhamid, A. O.; Gomha, S. M.; Abdelriheem, N. A.;
Kandeel, S. M. Molecules 2016, 21, 929.
1
cmÀ1): 3438, 3252, 2921, 1716, 1635, 1550, 1493; H-
NMR (DMSO-d6): δ 1.31 (t, J = 7.2 Hz, 6H, 2 CH2CH3),
2.43 (s, 8H, 4 CH2), 3.58 (s, 4H, 2 CH2), 4.26 (q,
J = 7.2 Hz, 4H, 2 CH2CH3), 6.85–7.94 (m, 14H, Ar-H),
8.73 (s, 2H, 2 –N═CH–), 10.57 (s, 2H, 2 OH), 10.91 (s,
2H,
2 NH), 12.79 (s, 2H, 2 NH); Anal. for
C44H44N12O8S2 (933.0): C, 56.64; H, 4.75; N, 18.01; S,
6.87. Found: C, 56.75; H, 4.63; N, 18.21; S, 6.69%.
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Chem 2015, 146, 149.
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Elwahy, A. H. M. RSC Adv 2016, 6, 10949.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet