Microwave and ultrasound-assisted synthesis of thiosemicarbazones and their corresponding (4,5-substituted-thiazol-2-yl)hydrazines

Article abstract of DOI:10.1002/jhet.1856

Hantzsch cyclization of thiosemicarbazone intermediates is a very popular approach to the synthesis of substituted thiazoles. We developed a convenient microwave and ultrasound-assisted method both for the synthesis of 1-(alkyliden/cycloalkyliden/aryliden)thiosemicarbazone intermediates and their cyclization into (4,5-substituted-thiazol-2-yl)hydrazines. The search for optimal reaction conditions included the use of different catalysts (Lewis acids and resins) and solvents at discrete temperatures, pressures, and irradiation powers. Comparing yields, reaction times, and efforts proved that microwave and ultrasound-assisted techniques outmatch conventional heating and have a remarkable influence on the synthesis.

Full text of DOI:10.1002/jhet.1856

Month 2014 Microwave and Ultrasound-Assisted Synthesis of Thiosemicarbazones and
Their Corresponding (4,5-Substituted-thiazol-2-yl)hydrazines
*
Simone Carradori, Daniela Secci, Melissa D’Ascenzio, Paola Chimenti, and Adriana Bolasco
Department of Drug Chemistry and Technologies, “Sapienza” University of Rome, P.le A. Moro 5, 00185 Rome, Italy
*
E-mail: simone.carradori@uniroma1.it
Received June 25, 2012
DOI 10.1002/jhet.1856
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Hantzsch cyclization of thiosemicarbazone intermediates is a very popular approach to the synthesis of
substituted thiazoles. We developed a convenient microwave and ultrasound-assisted method both for the
synthesis of 1-(alkyliden/cycloalkyliden/aryliden)thiosemicarbazone intermediates and their cyclization into
(4,5-substituted-thiazol-2-yl)hydrazines. The search for optimal reaction conditions included the use of
different catalysts (Lewis acids and resins) and solvents at discrete temperatures, pressures, and irradiation
powers. Comparing yields, reaction times, and efforts proved that microwave and ultrasound-assisted
techniques outmatch conventional heating and have a remarkable influence on the synthesis.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
RESULTS AND DISCUSSION
Thiazole and thiosemicarbazone derivatives have raised
a considerable interest in recent years, as they occupy a
prominent position in the drug discovery process and have
been extensively employed in the preparation of several
important drugs [1]. Previous researches within our group
demonstrated that the (thiazol-2-yl)hydrazine moiety could
be used as a common scaffold for the synthesis of small mole-
cules that showed a widespread activity as human monoamine
oxidase (hMAO) inhibitors [2], epigenetic modulators [3],
anti-Candida [4], anti-Toxoplasma [5], and anti-Helicobacter
pylori agents [6]. Although many conventional synthetic
strategies have been developed for the synthesis of
thiazoles, no ultrasound (US) and a few microwave
(MW)-assisted methods (often reporting the use of domes-
tic household oven) are available at the moment [7–9].
Nowadays, the application of US and MW irradiation as
nonconventional energy sources in organic synthesis is
receiving an increasing acceptance and is becoming an
essential tool for organic chemists. Both techniques allow
achieving significant laboratory time saving and often
simplify the reaction work-up. Moreover, they are valuable
tools that help organic chemists to limit pollution, enhance
reaction rates, improve yields, and do green chemistry
[10,11]. Herein, we report on the results obtained by investi-
gating both steps needed for the synthesis of a large number
of (4,5-substituted-thiazol-2-yl)hydrazine derivatives using
different conditions (solvent, pressure, temperature, and
power) and catalysts, under US and MW irradiation.
Optimization of the synthesis of thiosemicarbazone
derivatives The synthesis of the simplest thiosemicarbazone
intermediate (1-(propan-2-yliden)thiosemicarbazide) was
used as a model for the following optimization studies. The
reaction was conducted under conventional heating and
US or MW irradiation (Table 1); diverse Brønsted acids,
Lewis acids, and acidic resins were screened (Table 2) as
well as different power, temperature, and pressure
conditions. According to the results reported in our previous
works, good yields were achieved in heating the reaction
mixture up to 50ꢀC for 24 h in the presence of catalytic
amounts of acetic acid (79%) [2]. To evaluate the effect of
MW and US irradiation on this reaction, we preserved the
original conditions of catalysis and solvent used in
conventional synthesis.
As shown in Table 1, reaction yields increased both using
MW and US in the presence of the acid catalyst (96% and
94%, respectively). Reaction times were reduced instead
from 24 h to 5 min and 30 min, respectively. Further studies
were performed to define which parameters were affecting
the efficiency of the reaction. Because ethanol was a
well-investigated solvent in MW-assisted reactions [12],
we conducted the thiosemicarbazone synthesis at two
discrete temperatures (88ꢀC and 103ꢀC) that had already
been reported to correspond to 18 and 33 psi of vial internal
pressure, respectively (Figure 1). The higher pressurization
of the sealed vessel led to higher yields at each applied
power (200–350 W) with a maximum at 300 W (87%).
© 2014 HeteroCorporation

S. Carradori, D. Secci, M. D'Ascenzio, P. Chimenti, and A. Bolasco
Vol 000
Table 1
Comparison of microwave (MW)-assisted, ultrasound (US)-assisted, and conventional synthesis of 1-(propan-2-yliden)thiosemicarbazide.
Solvent
Conditions
Yield %
EtOH
50ꢀC, 24 h
50ꢀC, 24 h
72
79
89
96
82
94
EtOH, CH3COOH (cat.)
EtOH
EtOH, CH3COOH (cat.)
EtOH
50ꢀC, 5 min, variable MW power
50ꢀC, 5 min, variable MW power
50ꢀC, 30 min, 40 kHz (40% of maximum power output)
50ꢀC, 30 min, 40 kHz (40% of maximum power output)
EtOH, CH3COOH (cat.)
Table 2
The effect of the substitution of acetic acid with different Lewis acids and acidic ion exchange resins under MW irradiation on yield.
Catalyst
Conditions
Yield %
Catalyst-free
CH3COOH
Amberlyst 15a (0.72 g)
Montmorillonite K10a (1 g)
LiCl
ZnCl2
Zn(OTf)2
BF3 ∙ 2 H2O
BF3 2 H2O
InCl3
EtOH, 103ꢀC, 5 min, 300 W
EtOH, 103ꢀC, 5 min, 300 W
EtOH, 103ꢀC, 5 min, 300 W
EtOH, 103ꢀC, 5 min, 300 W
EtOH, 103ꢀC, 5 min, 300 W
EtOH, 103ꢀC, 5 min, 300 W
EtOH, 103ꢀC, 5 min, 300 W
EtOH, 103ꢀC, 5 min, 300 W
Free solvent, 103ꢀC, 5 min, 300 W
EtOH, 103ꢀC, 5 min, 300 W
EtOH, 103ꢀC, 5 min, 300 W
EtOH, 103ꢀC, 5 min, 300 W
61
87
42
84
78
22
5
67
10
34
78
8
MgBr2
FeCl3
aThe recovered catalyst could be also recycled.
of Lewis acids or acidic ion exchange resins (Table 2). Not
one of the tested acid catalysts showed to be more effective
than acetic acid, even though Montmorillonite K10 confirmed
to be a good acidic support in MW-assisted synthesis [13].
The best conditions obtained were applied to the synthesis
of several thiosemicarbazone derivatives bearing aliphatic,
cycloaliphatic, and (hetero)cyclic moieties (Scheme 1). The
new MW-assisted method improved the yields and times of
reaction we reported for these compounds in our previous
communications [2].
Figure 1. Microwave-assisted synthesis of 1-(propan-2-yliden)thiosemicar-
bazide in different conditions of applied temperature (ꢀC) and power (W).
Optimization of the synthesis of (thiazol-2-yl)hydrazine
derivatives. According to the good results we obtained
As the MW best conditions of temperature, pressure, and
solvent were determined, we investigated the effect of
exchanging the Brønsted acid catalyst with a large number
using MW irradiation in the synthesis of the
thiosemicarbazone derivatives, we applied the same
methodology to the Hantzsch cyclization (Scheme 2).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Microwave and Ultrasound-Assisted Synthesis of (Thiazolyl)hydrazines
Scheme 1. Application of the optimized conditions to the synthesis of aliphatic, cycloaliphatic, and (hetero)cyclic thiosemicarbazones.
2
Yield= 87-99%
1
1
CH3COOH (cat.)
2
Yield= 86-99%
Yield= 82-99%
2
2
2 n
EtOH
2 n
103 °C, 5 min, 300W
2
1
Scheme 2. Hantzsch cyclization to (4,5-substituted-thiazol-2-yl)hydrazines. Reagents and conditions: EtOH or MeOH, 50ꢀC, 24 h; microwave (MW) or
ultrasound (US) irradiation, different solvents, 50ꢀC.
The optimization of reaction conditions also included the
screening of apolar (THF), polar protic (water, methanol,
and ethanol), and nonprotic (acetone, DMF, and MeCN)
solvents. Temperature and time parameters were set accord-
ing to those previously reported in the literature [14,15]. To
test the feasibility of the reaction under greener conditions,
we also performed this step in the absence of any solvent,
in water, or using only neutral alumina as a support
for dehydrohalogenation (Table 3). At 50ꢀC under MW
irradiation, the thiazole ring was formed in 10 min against
the 24h required by conventional synthesis [2]. The best
yields were obtained in polar solvents: methanol (98%) and
acetone (91%). This evidence could be explained by
considering that polar solvents tend to absorb the power
applied by MW irradiation and transfer it to the reagents
better than apolar ones. Moreover, high yields were obtained
even without the use of any solvent (79%) or in water (68%):
such results provided a scarcely polluting pathway toward
the synthesis of (thiazol-2-yl)hydrazine derivatives.
Further investigations were needed to determine the opti-
mum power to apply to reaction mixture to reach the highest
yield in methanol. Two new experiments were conducted
setting power values from 200 to 350 W at two discrete
temperatures (90ꢀC and 115ꢀC) that corresponded to 16
and 48 psi of vessel internal pressure, respectively (Figure 2).
The obtained results outlined how increasing both tem-
perature and power had a negative effect on final yields.
Moreover, although higher temperature seemed to give
better yields at high power values (see yield values at 250,
300, and 350 W), when the applied power decreased, the
two curves (90ꢀC and 115ꢀC) tended to coalescence.
Setting the temperature at 90ꢀC and applying to the reac-
tion, the highest power value reached in the variable power
test in methanol (150 W); it followed a surprising increase
in yield (95%). We concluded that the Hantzsch cyclization
was not compatible with high temperature, pressure, or
power values. The mild conditions required by Hantzsch
cyclization led us back to explore the US-assisted methodol-
ogy. The reaction was conducted at 50ꢀC under US irradia-
tion. Comparing the yields obtained for compound 2 using
the three different methodologies (conventional heating,
MW, and US), the best suitable approach resulted to be
the MW one (Table 4). To expand the scope of this procedure,
a variety of (4,5-substituted-thiazol-2-yl)hydrazine derivatives
were synthesized by reacting 1-(propan-2-yliden)thiosemicar-
bazide with differently functionalized halo-ketones (Table 4).
It is worth noting that the change of electronics in a-chloro
and a-bromo-ketones did not affect the overall yields. Even
if the yields obtained for Hantzsch reaction using MW, US,
and conventional methods were comparable (2a–2c), MW
irradiation allowed us to synthesize the desired compounds
in shorter times and very high yields (see compounds 1, 2a,
7, 9, 11–14). In conclusion, we developed an alternative
MW and US-assisted procedure both for the thiosemicarba-
zone synthesis and the following thiazole ring closure
(Hantzsch cyclization). The mild reaction conditions,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Carradori, D. Secci, M. D'Ascenzio, P. Chimenti, and A. Bolasco
Vol 000
Table 3
Hantzsch reaction: influence of apolar, polar protic, and aprotic solvents on final yields.
Solvent
Conditions
Yield (%)
THF
H2O
EtOH
MeOH
CH3COCH3
DMF
MeCN
Neutral Al2O3 (1.5 g)
Solvent-free
50ꢀC, 10 min, variable MW power
50ꢀC, 10 min, variable MW power
50ꢀC, 10 min, variable MW power
50ꢀC, 10 min, variable MW power
50ꢀC, 10 min, variable MW power
50ꢀC, 10 min, variable MW power
50ꢀC, 10 min, variable MW power
50ꢀC, 10 min, variable MW power
50ꢀC, 10 min, variable MW power
57
68
90
98
91
76
69
88
79
MW, microwave.
monitored by TLC on 0.2-mm thick silica gel plates (60 F254
Merck). Plates were visualized by exposing them to ultraviolet
(254 nm) radiation. Merck silica gel 60 70–230 mesh and
0.063–0.200 mm were used for preparative chromatography.
Some compounds have been previously reported by others
(Table 4), and their chemical–physical data were in full agree-
ment with those reported in the literature.
Procedure for the conventional heating synthesis of
1-(alkyliden/cycloalkyliden/aryliden)thiosemicarbazide. The
ketone/aldehyde (3.4 mmol), with or without catalytic amounts of
acetic acid, was added to a stirring suspension of thiosemicarbazide
(0.30 g, 3.4 mmol) in 10 mL of ethanol at 50ꢀC. After 24 h, the
suspension was filtered, and the obtained solid was washed with
petroleum ether, n-hexane, and diethyl ether. The crude mixture
was purified by column chromatography (SiO2, ethyl acetate/
Figure 2. Microwave-assisted Hantzsch cyclization at different applied
temperatures (ꢀC) and powers (W).
short reaction times, ease of work-up, and the environmentally
friendly nature of the synthetic pathway make the present
method an improvement to the known heterocyclic chemistry.
n-hexane).
Procedure for the ultrasound-assisted synthesis of
1-(alkyliden/cycloalkyliden/aryliden)thiosemicarbazide. The
ketone/aldehyde (3.4 mmol) was added to a stirring suspension
of thiosemicarbazide (0.30 g, 3.4 mmol) in 2 mL of absolute
ethanol in the presence or not of catalytic amounts acetic acid.
The reaction mixture was sonicated for 30 min at 50ꢀC in a US-
processor (285 W FALC ultrasonic processor operating at
40 kHz at 40% of the maximum power output). The final
suspension was filtered and the obtained solid washed with
petroleum ether, n-hexane, and diethyl ether. The crude
mixture was purified by column chromatography (SiO2, ethyl
EXPERIMENTAL
Microwave-assisted reactions were performed in a Biotage Ini-
tiator 2.0 (Sweden) US-assisted synthesis was performed in a
FALC ultrasonic processor (Italy). Chemicals, common solvents,
and spectral grade solvents were purchased from Aldrich (Italy)
and used without further purification. Melting points (uncor-
rected) were determined automatically on an FP62 apparatus
(Mettler-Toledo). H-NMR and 13C-NMR spectra were recorded
1
at 25ꢀC on a 400 MHz Bruker spectrometer using DMSO-d6 or
CDCl3 as solvent. Chemical shifts are expressed as d units (parts
per million) relative to the solvent peak. Coupling constants J
are valued in Hertz. Elemental analyses for C, H, and N were
recorded on a Perkin-Elmer 240 B microanalyzer, and the analyt-
ical results were within Æ0.4% of the theoretical values for all
compounds. Laboratory glassware was oven dried and cooled in
a desiccator (CaCl2 desiccant) prior to its use. All reactions were
acetate/n-hexane).
Procedure for the microwave-assisted synthesis of
1-(alkyliden/cycloalkyliden/aryliden)thiosemicarbazide. The
ketone/aldehyde (3.4 mmol) and the corresponding catalyst
(reported in Table 2) were added to
a suspension of
thiosemicarbazide (0.30 g, 3.4 mmol) in 2 mL of absolute
ethanol in a 5-mL vessel suitable for MW reactor (2.45 GHz
high-frequency microwaves, power range 0–300 W). The vessel
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Microwave and Ultrasound-Assisted Synthesis of (Thiazolyl)hydrazines
Table 4
Microwave (MW)-assisted synthesis of variously substituted (thiazol-2-yl)hydrazine derivatives in comparison with the ultrasound (US)-assisted and the
conventional ones.
Compound
R1
R2
Conditions
Yield %
1 [ref. 16]
2 [ref. 16]
CH3
Phenyl
H
H
MeOH, 90ꢀC, 10 min, MW
(a) MeOH, 90ꢀC, 10 min, MW
(b) MeOH, 50ꢀC, 24 h, conventional heating
(c) MeOH, 50ꢀC, 40 kHz, 30 min, US
MeOH, 90ꢀC, 10 min, MW
MeOH, 90ꢀC, 10 min, MW
MeOH, 90ꢀC, 10 min, MW
MeOH, 90ꢀC, 10 min, MW
MeOH, 90ꢀC, 10 min, MW
MeOH, 90ꢀC, 10 min, MW
MeOH, 90ꢀC, 10 min, MW
MeOH, 90ꢀC, 10 min, MW
MeOH, 90ꢀC, 10 min, MW
MeOH, 90ꢀC, 10 min, MW
MeOH, 90ꢀC, 10 min, MW
MeOH, 90ꢀC, 10 min, MW
MeOH, 90ꢀC, 10 min, MW
99
95
80
84
83
89
82
87
92
79
99
76
98
99
95
99
79
3
Phenyl
COOEt
3-Methoxy-phenyl
3-Nitro-phenyl
4-Methoxy-phenyl
4-Fluoro-phenyl
4-Chloro-phenyl
4-Bromo-phenyl
4-Phenyl-phenyl
2,4-Dichloro-phenyl
2,4-Dimethoxy-phenyl
Naphtalen-2-yl
CH3
H
H
H
H
H
H
H
H
H
H
H
H
4 [ref. 17]
5 [ref. 3b]
6
7
8
9 [ref. 18]
10
11 [ref. 19]
12
13
14
15 [ref. 7]
Coumarin-3-yl
was sealed; the mixture prestirred for 30 s and then heated by
MW irradiation for 5 min at fixed temperatures (50ꢀC, 88ꢀC,
and 103ꢀC). If not set, the irradiation power reaches its
maximum at the beginning of reaction and then decreases to
lower and constant values. The vial internal temperature was
controlled by an equipped IR sensor. After cooling in a stream
of pressurized air, the reaction mixture was filtered and the
obtained solid washed with petroleum ether, n-hexane, and
diethyl ether. The crude mixture was purified by column
chosen solvent (THF, water, ethanol, methanol, acetone, DMF,
or acetonitrile), directly mixed with the a-halo-ketone (solvent-
free conditions), or in presence of neutral alumina (1.5 g). The
mixture was prestirred in a sealed vessel for 3 min and then
heated up by MW irradiation for 10 min at fixed temperatures
(50ꢀC, 90ꢀC, and 115ꢀC). The reaction mixture was cooled
down with pressurized air and filtered, and the obtained solid
was washed with n-hexane and diethyl ether. The crude
mixture was purified by column chromatography (SiO2, ethyl
chromatography (SiO2, ethyl acetate/n-hexane).
Procedure for the conventional synthesis of 1-(2-
acetate/n-hexane 1:1).
Characterization data for new compounds
1-(5-Methyl-4-phenylthiazol-2-yl)-2-(propan-2-ylidene)hydrazine
phenylthiazol-4-yl)-2-(propan-2-ylidene)hydrazine (2b). 1-(2-
Propyliden)thiosemicarbazide (0.2 g, 1.5 mmol) was added to a
stirring solution of a-bromo-acetophenone (1.5 mmol) in methanol
(2mL) at 50ꢀC. After 24h, the suspension was filtered and the
obtained solid washed with n-hexane and diethyl ether. The crude
mixture was purified by column chromatography (SiO2, ethyl
(3). Gray solid, mp 235–237ꢀC. IR (KBr): n 3474, 3073, 2951,
1597 cmÀ1 1H-NMR (400 MHz, CDCl3, Me4Si): d 1.97 (s, 3H,
.
CH3), 1.99 (s, 3H, CH3), 2.33 (s, 3H, CH3), 7.38–7.41 (m, 1H, Ar),
7.54–7.58 (m, 2H, Ar), 7.59–7.62 (m, 2H, Ar), 12.46 (br s, 1H, NH,
D2O exch). 13C-NMR (100.57 MHz, CDCl3): d 8.52, 18.56, 23.85,
100.87, 126.84, 128.47, 130.73, 134.15, 142.64, 157.55, 169.37.
Anal. Calcd for C13H15N3S: C, 63.64; H, 6.16; N, 17.13. Found: C,
acetate/n-hexane 1:1).
Procedure for the ultrasound-assisted synthesis of 1-(2-
phenylthiazol-4-yl)-2-(propan-2-ylidene)hydrazine (2c).1-(2-
Propyliden)thiosemicarbazide (0.2 g, 1.5 mmol) was added to
a solution of a-bromo-acetophenone (1.5mmol) in methanol
(2mL). The reaction mixture was sonicated for 30min at 50ꢀC.
The final suspension was filtered and the obtained solid washed
with n-hexane and diethyl ether. The crude mixture was purified
63.40; H, 5.93; N, 17.01.
1-(4-(3-Nitrophenyl)thiazol-2-yl)-2-(propan-2-ylidene)hydrazine
(6). Light yellow solid, mp 215–216ꢀC. IR (KBr): n 3461, 3083,
2943, 1590cmÀ1 1H-NMR (400 MHz, CDCl3, Me4Si): d 2.08
.
(s, 3H, CH3), 2.11 (s, 3H, CH3), 6.97 (s, 1H, C5H-thiaz.), 7.62–
7.66 (m, 1H, Ar), 8.12–8.14 (m, 1H, Ar), 8.19–8.22 (m, 1H, Ar),
8.56–8.57 (m, 1H, Ar), 12.42 (bs, 1H, NH, D2O exch). 13C-NMR
(100.57MHz, CDCl3): d 19.89, 25.12, 101.98, 117.73, 127.60,
129.15, 147.12, 159.10, 161.24, 169.08. Anal. Calcd for
C12H12N4O2S: C, 52.16; H, 4.38; N, 20.28. Found: C, 52.30; H,
4.22; N, 20.16.
by column chromatography (SiO2, ethyl acetate/n-hexane 1:1).
General procedure for the microwave-assisted synthesis
of 1-(2,4-substituted-thiazol-2-yl)hydrazines (1–15).
1-(2-
Propyliden)thiosemicarbazide (0.2 g, 1.5 mmol) was added to a
solution of the correspondent a-halo-ketone in 2 mL of the
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S. Carradori, D. Secci, M. D'Ascenzio, P. Chimenti, and A. Bolasco
Vol 000
1-(4-(4-Methoxyphenyl)thiazol-2-yl)-2-(propan-2-ylidene)hydrazine
Acknowledgments. This work was supported by MIUR (Italy).
(7). Yellow solid, mp 230–231ꢀC. IR (KBr): n 3474, 3073, 2951,
1597 cmÀ1 1H-NMR (400 MHz, CDCl3, Me4Si): d 2.12 (s, 3H,
.
CH3), 2.21 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 6.53 (s, 1H, C5H-thiaz.),
6.98–7.00 (d, Jo = 8.7 Hz, 2H, Ar), 7.64–7.66 (d, Jo = 8.7 Hz, 2H, Ar),
12.29 (bs, 1H, NH, D2O exch). 13C-NMR (100.57 MHz, CDCl3):
d 19.44, 24.89, 55.83, 100.41, 116.23, 125.62, 128.45, 146.48, 159.61,
160.74, 169.12. Anal. Calcd for C13H15N3OS: C, 59.74; H, 5.79; N,
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16.08. Found: C, 59.87; H, 5.66; N, 15.85.
1-(4-(4-Fluorophenyl)thiazol-2-yl)-2-(propan-2-ylidene)hydrazine
(8). Light yellow solid, mp 185–187ꢀC. IR (KBr): n 3471, 3065,
2947, 1593, 1128 cmÀ1 1H-NMR (400 MHz, CDCl3, Me4Si):
.
d 2.06 (s, 3H, CH3), 2.22 (s, 3H, CH3), 6.65 (s, 1H, C5H-thiaz.),
7.21–7.23 (d, J= 7 Hz, 2H, Ar), 7.72–7.74 (d, J= 7 Hz, 2H, Ar),
12.64 (br s, 1H, NH, D2O exch.). 13C-NMR (100.57 MHz, CDCl3):
d 18.79, 24.58, 100.38, 116.27, 128.62, 130.09, 148.53, 159.60,
162.84, 170.11. Anal. Calcd for C12H12FN3S: C, 57.81; H, 4.85; N,
16.85. Found: C, 57.65; H, 4.79; N, 16.64.
1-(4-(4-Bromophenyl)thiazol-2-yl)-2-(propan-2-ylidene)hydrazine
(10). Light brown solid, mp 240–243ꢀC. IR (KBr): n 3477, 3060,
2943, 1586, 1027 cmÀ1 1H-NMR (400 MHz, DMSO-d6): d 1.94
.
(s, 3H, CH3), 1.96 (s, 3H, CH3), 7.32 (s, 1H, C5H-thiaz.), 7.60–7.63
(d, J= 10 Hz, 2H, Ar), 7.79–7.81 (d, J= 10 Hz, 2H, Ar), 10.78
(br s, 1H, NH, D2O exch.). 13C-NMR (100.57 MHz, DMSO-d6):
d 18.38, 25.26, 104.89, 121.27, 128.13, 132.02, 133.40, 147.50,
170.35. Anal. Calcd for C12H12BrN3S: C 46.46; H, 3.90; N, 13.55.
Found: C 46.59; H, 4.06; N, 13.32.
1-(4-(2,4-Dichlorophenyl)thiazol-2-yl)-2-(propan-2-ylidene)hydrazine
(12). Light brown solid, mp 183–185ꢀC. IR (KBr): n 3481,
3075, 2944, 1598, 1098 cmÀ1 1H-NMR (400 MHz, CDCl3,
.
Me4Si): d 2.15 (s, 3H, CH3), 2.21 (s, 3H, CH3), 7.01 (s, 1H,
C5H-thiaz.), 7.44–7.46 (dd, J = 8 Hz, J = 4 Hz, Ar), 7.57–7.58
(d, J = 4 Hz, 1H, Ar), 7.65–7.67 (d, J = 8 Hz, 1H, Ar), 12.84
(br s, 1H, NH, D2O exch.). 13C-NMR (100.57 MHz, CDCl3):
d 19.36, 24.78, 100.25, 127.44, 128.21, 130.27, 130.89,
133.64, 135.71, 148.73, 151.31, 169.88. Anal. Calcd for
C12H11Cl2N3S: C, 48.01; H, 3.69; N, 14.00. Found: C, 47.90;
[6] (a) Chimenti, F.; Carradori, S.; Secci, D.; Bolasco, A.;
Chimenti, P.; Granese, A.; Bizzarri, B. J Heterocycl Chem 2009, 46,
575. (b) Chimenti, F.; Bizzarri, B.; Bolasco, A.; Secci, D.; Chimenti, P.;
Granese, A.; Carradori, S.; D’Ascenzio, M.; Scaltrito, M. M.; Sisto, F. J
Heterocycl Chem 2010, 47, 1269.
[7] Ahluwalia, V. K.; Sharma, P. R.; Aggarwal, R. J Chem Res
1997, 1, 16.
[8] Ahluwalia, V. K.; Chibber, S. S.; Goyal, B. Indian J Chem
1996, 35B, 856.
H, 3.52; N, 13.86.
1-(4-(2,4-Dimethoxyphenyl)thiazol-2-yl)-2-(propan-2-ylidene)
hydrazine (13).
Light yellow solid, mp 110–112ꢀC. IR (KBr):
[9] Osman, H.; Arshad, A.; Lam, C. K.; Bagley, M. C. Chem
Central J 2012, 6, 32.
n 3474, 3073, 2951, 1597 cmÀ1
.
1H-NMR (400 MHz, CDCl3,
Me4Si): d 0.93 (s, 3H, CH3C═), 0.96 (s, 3H, CH3C═), 3.73 (s, 3H,
OCH3), 3.85 (s, 3H, OCH3), 6.02 (s, 1H, C5H-thiaz.), 7.35–7.41
(m, 1H, Ar), 7.53 (s, 1H, Ar), 7.62–7.68 (m, 1H, Ar), 11.06 (bs, 1H,
NH, D2O exch). 13C-NMR (100.57 MHz, CDCl3): d 19.31, 24.86,
55.79, 56.18, 100.13, 100.95, 107.38, 113.27, 130.67, 148.73,
148.91, 158.29, 163.16, 170.22. Anal. Calcd for C14H17N3O2S: C,
57.71; H, 5.88; N, 14.42. Found: C, 57.54; H, 5.69; N, 14.33.
1-(4-(Naphthalen-2-yl)thiazol-2-yl)-2-(propan-2-ylidene)hydrazine
(14). Gray solid, mp 222–223ꢀC. IR (KBr): n 3475, 3076, 2953,
[10] (a) van der Eycken, E.; Kappe, C. O. Microwave Assisted
Synthesis of Heterocycles; Springer: Berlin, 2006. (b) Loupy, A. Microwave
in Organic Synthesis; Wiley VCH Publishing Ltd.: Weinheim, 2006.
[11] Cella, R.; Stefani, H. A. Tetrahedron 2009, 65, 2619.
[12] Cun-De, W.; Jun, L.; Xin-Zhong, S.; Yun-Hua, F. Synth Commun
1999, 29, 3057.
[13] Gaikwad, S. A.; Patil, A. A.; Deshmukh, M. B. Phosphorus
Sulfur Silicon Relat Elem 2010, 185, 103.
[14] Khrustalev, D. P.; Suleimenova, A. A.; Fazylov, S. D. Russ J
Appl Chem 2008, 81, 900.
[15] Kikelj, D.; Urleb, U. In Science of Synthesis; Molander, G.-A.,
Ed.; Thieme: Stuttgart, 2002; Vol 11, p 627.
[16] Goldfarb, D. S. US 20090163545, 2009.
[17] Ohmoto, K.; Hatayama, A.; Hisaichi, K.; Tanaka, M.;
Yamada, H. PCT Int. Appl. WO 2005103012, 2005.
1602 cmÀ1 1H-NMR (400 MHz, CDCl3, Me4Si): d 2.14 (s, 3H,
.
CH3), 2.25 (s, 3H, CH3), 6.81 (s, 1H, C5H-thiaz.), 7.56–7.59
(m, 2H, Ar), 7.69–7.73 (m, 1H, Ar), 7.86–7.91 (m, 3H, Ar), 8.46
(s, 1H, Ar), 12.46 (br s, 1H, NH, D2O exch). 13C-NMR
(100.57 MHz, CDCl3): d 19.53, 24.88, 100.89, 122.19, 124.75,
125.57, 127.25, 127.66, 128.98, 129.52, 133.77, 134.15, 135.69,
140.589, 1459.69, 169.68. Anal. Calcd for C16H15N3S: C, 68.30; H,
5.37; N, 14.93. Found: C, 68.52; H, 5.46; N, 14.74.
[18] Yasumura, K.; Miyajima, K.; Nagahama, T.; Ishikawa, S.;
Tohyama, Y.; Sugiyama, K. PCT Int. Appl. WO 9419335, 1994.
[19] Tsuyoshi, Y.; Motoharu, I. PCT Int. Appl. WO 2001079478,
2001.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet