Microwave induced efficient synthesis of (un)substituted benzaldehyde (5-aryl-1,3,4-thiadiazol-2-yl)hydrazones using silica-supported dichlorophosphate as a recoverable dehydrant

Article abstract of DOI:10.1002/jhet.5570450540

(Chemical Equation Presented) (Un)substituted benzaldehyde (5-aryl-1,3,4-thiadiazol-2-yl)hydrazones were efficiently synthesized by reactions of (un)substituted benzaldehyde thiocarbohydrazones with aromatic carboxylic acids by using silica-supported dichlorophosphate as a recoverable dehydrant under microwave irradiation. The protocol has advantages of short reaction time, high yield, easy work-up procedure and no environmental pollution.

Full text of DOI:10.1002/jhet.5570450540

Sep-Oct 2008
1489
Microwave Induced Efficient Synthesis of (Un)substituted
benzaldehyde (5-Aryl-1,3,4-thiadiazol-2-yl)hydrazones Using
Silica-supported Dichlorophosphate as a Recoverable Dehydrant
Zheng Li,* Xu Feng, Yanlong Zhao
Gansu Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Northwest
Normal University, Lanzhou, Gansu, 730070, P. R. China.
lizheng@nwnu.edu.cn
Received November 8, 2007
O
R
R
S
S
H2N
NH2
H2O/EtOH
+
H
N
NH2
N
H
N
H
N
H
N
H
reflux
1a-b
O
R
SiO2
O
OPCl2
R'
N
N
R'
1a-b
N
+
OH
MWI, 8 min
DMF
N
H
S
2a-k
(Un)substituted benzaldehyde (5-aryl-1,3,4-thiadiazol-2-yl)hydrazones were efficiently synthesized by
reactions of (un)substituted benzaldehyde thiocarbohydrazones with aromatic carboxylic acids by using
silica-supported dichlorophosphate as a recoverable dehydrant under microwave irradiation. The protocol
has advantages of short reaction time, high yield, easy work-up procedure and no environmental pollution.
J. Heterocyclic Chem., 45, 1489 (2008).
INTRODUCTION
In this paper, we report a new, expeditious and eco-
friendly route for the preparation of (un)substituted
The compounds bearing a 1,3,4-thidiazole moiety are of
interest in medicinal and agricultural fields because of
their wide range of biological activities, such as
antibacterial [1], fungicidal [2], anticancer [3], anti-
tubercular [4], anti-inflammatory [5] and leishmanicidal
[6] activities. Especially (un)substituted benzaldehyde (5-
aryl-1,3,4-thiadiazol-2-yl)hydrazones show the impor-
tance for their antitrypanosomal activity [7]. Fraga and
benzaldehyde
(5-aryl-1,3,4-thiadiazol-2-yl)hydrazones
using thiocarbohydrazide as starting material, easily
recoverable silica-supported dichlorophosphate as
dehydrant and microwave as heating source.
RESULTS AND DISCUSSION
Silica-supported dichlorophosphate was prepared by
reaction of silica gel with phosphorus oxychloride under
microwave irradiation (Scheme 1). The reaction could be
completed within 12 min to afford the desired product in
excellent yield.
coworkers [7] reported
a
synthetic route for
(un)substituted benzaldehyde (5-aryl-1,3,4-thiadiazol-2-
yl)hydrazones: Benzoic acid first reacted with
thiosemicarbazide in liquid phosphorus oxychloride to
synthesize 2-amino-5-phenyl-1,3,4-thiadiazole, then this
amino-heterocyclic derivative was converted into 2-
chloro-4-phenyl-1,3,4-thiadiazole by exploiting the
diazotation and Sandmeyer reaction with CuCl.
Heteroaromatic nucleophilic substitution of the chlorine
atom of 2-chloro-4-phenyl-1,3,4-thiadiazole using
hydrazine hydrate furnished the heterocyclic hydrazines,
then acid catalyzed condensation of the hydrazines with
the corresponding aromatic aldehydes in ethanol to give
the target hydrazone derivatives. However, this route has
long procedure, and need long reaction time, especially
the liquid phosphorus oxychloride was used, which could
cause corrosion and environmental pollution because of
difficult separation after the reaction.
Scheme 1
O
MWI
SiO2
SiO2
OH + POCl3
+
OPCl2 HCl (g)
12 min
In order to explore the availability of silica-supported
dichlorophosphate as a recoverable dehydrant under
microwave irradiation, the synthesis of (un)substituted
benzaldehyde
(5-aryl-1,3,4-thiadiazol-2-yl)hydrazones
(2a-k) was tested (Scheme 2, Table 1). Firstly,
thiocarbohydrazide reacted with equivalent of aromatic
aldehydes in aqueous ethanol medium at refluxing
condition to give (un)substituted benzaldehyde thiocarbo-

1490
Z. Li, X. Feng, Y. Zhao
Vol 45
Thiocarbohydrazide was prepared according to literature
procedure [12].
hydrazones (1a-b) in high yield. Provided the reactant
ratio was carefully controlled, the reactions could afford
the desired monosubstituted products in high selectivity,
and no 1,5-disubstituted by-products were observed. Then
the reactions of compounds 1a-b with various aromatic
acids to synthesize target products were attempted using
silica-supported dichlorophosphate as dehydrant under
microwave irradiation. It was found that the optimal
conditions for the desired compounds 2a-k were to
irradiate the reaction mixture for 8 min at the power of
650 W using DMF as solvent. Benzoic acids bearing
different substituentes could react well with no significant
difference. The silica-supported dehydrant could be
separated and recovered from the resulting reaction
mixture only by filtration, which could efficiently avoid
the environmental pollution caused by using liquid POCl3.
The preparation of silica-supported dichlorophosphate.
The mixture of silica gel (1 g) and phosphorus oxychloride (6
mL) was stirred for 10 min at room temperature. Then the
mixture was subjected to the microwave irradiation for total 12
min (1 min interval for each 3 min of irradiation) under the
power of 455 W. Then the resulting mixture was washed with
CH2Cl2 (3ꢀ5 mL) to remove the excess phosphorus oxychloride,
and the solid was dried to give the product. Yield: 98%. IR
(KBr): 571 (ꢁP-Cl ). The silica supporting capacity for POCl2 is ca
2.81 mmol/g.
The general procedure for the preparation of (un)substi-
tuted benzaldehyde thiocarbohydrazones (1a-b). To the
solution of thiocarbohydrazide (15 mmol) in 50 mL of H2O and 1
mL of acetic acid, aromatic aldehyde (10 mmol) in 20 mL of
ethanol was added dropwise within 1 h at refluxing condition. After
the addition, the mixture was further refluxed for 3 h. Then the
precipitate was collected by filtration and washed with water (3ꢀ10
mL). The resulting solid was recrystallized from ethanol to give the
product. The analytical data for 1a-b are given below.
1
Compounds 2a-k were confirmed by H NMR, IR and
1
elemental analyses. H NMR analyses show the proton
1
peaks at 12.51-12.59 ppm for NH and 8.14-8.18 ppm for
CH. IR spectra show the characteristic absorption at 3200-
3217 cm-1 for NH.
1a: Yield, 84%; m.p., 210-212°C (lit. 193-194°C) [13]. H
nmr (DMSO-d6, 400 MHz): ꢀ 11.42 (s, 1H, NH), 9.82 (bs, 1H,
NH), 8.03 (s, 1H, CH), 7.34-8.01 (m, 5H, Ar-H), 4.91 (bs, 2H,
NH2). ir (potassium bromide): 3258 (N-H), 3162 (N-H), 1263
(C=S) cm-1. ms: m/z, 194 (M+). Anal. Calcd. for C8H10N4S: C,
49.46; H, 5.19; N, 28.84. Found: C, 49.52; H, 5.20; N, 28.77.
In conclusion, silica-supported dichlorophosphate was
found an efficient and recoverable dehydrant for the
preparation of (un)substituted benzaldehyde (5-aryl-1,3,4-
thiadiazol-2-yl)hydrazones via a novel two-step route by
reactions of thiocarbohydrazide with equivalent of
aromatic aldehydes, followed by aromatic acids. This
protocol has the advantages of no environmental
pollution, short reaction period, high yield and simple
work-up procedure.
1
1b: Yield, 87%; m.p., 198-200°C. H nmr (DMSO-d6, 400
MHz): ꢀ 11.39 (s, 1H, NH), 9.81 (bs, 1H, NH), 8.02(s, 1H, CH),
7.54-7.95 (m, 4H, Ar-H), 4.90 (bs, 2H, NH2), 3.81 (s, 3H, CH3).
ir (potassium bromide): 3208 (N-H), 3100 (N-H), 1254 (C=S)
cm-1. ms: m/z, 224 (M+). Anal. Calcd. for C9H12N4OS: C, 48.20;
H, 5.39; N, 24.98. Found: C, 48.30; H, 5.38; N, 24.89.
The general procedure for the preparation of
(un)substituted benzaldehyde (5-aryl-1,3,4-thiadiazol-2-yl)-
hydrazones (2a-k). To the solution of (un)substituted
benzaldehyde thiocarbohydrazones (1a-b) (2 mmol) and
aromatic acids (2.2 mmol) in 6 mL of DMF, silica-supported
dichlorophosphate (2 mmol, based on supported POCl2) was
added. Then the mixture was subjected to the microwave
irradiation at the power of 650 W for total 8 min (2 min of
irradiation followed by 1 min of interval). The completion of the
reaction was monitored by TLC. The resulting mixture was
filtered to recover the silica-supported reagent. The filtrate was
poured into 20 mL of water, and the precipitate was collected by
filtration, washed by cold ethanol (2ꢀ5 mL) and recrystallized
EXPERIMENTAL
IR spectra were recorded using KBr pellets on a Digilab FTS
3000 FTIR spectrophotometer and 1H NMR spectra on a
Mercury-400BB instrument using (CD3)2SO as solvent and
Me4Si as internal standard. Elemental analyses were performed
on a Vario E1 Elemental Analysis instrument. Melting points
were observed in an electrothermal melting point apparatus.
Microwave reactions were conducted in a modified microwave
oven fitted with
a
condenser (LG-WP650, China).
Scheme 2
O
R
R
S
S
H2N
NH2
H2O/EtOH
+
H
N
NH2
N
H
N
H
N
H
N
H
reflux
1a-b
O
R
SiO2
O
OPCl2
R'
N
N
R'
N
+
OH
1a-b
MWI, 8 min
DMF
N
H
S
2a-k

Sep-Oct 2008
Synthesis of (Un)substituted Benzaldehyde (5-aryl-1,3,4-thiadiazol-2-yl)hydrazones
1491
Table 1
Synthesis of (un)substituted benzaldehyde (5-aryl-1,3,4-thiadiazol-2-yl)hydrazones (2a-k).
m.p. (lit.)
(°C)
Yield
(%)a
Compd.
R
H
R'
Product
N
N
242-244
(248) [8]
N
90
87
2a
H
N
H
S
N
N
N
N
H
2b
H
4-CH3O
S
234-236
OCH3
N
N
N
N
N
N
N
N
CH3
N
N
N
N
80
84
84
82
2c
2d
2e
2f
H
H
2-CH3
3-CH3
3-Cl
224-226
202-204
226-228
N
H
S
S
S
CH3
N
H
Cl
H
N
H
188-190
H
4-Cl
N
H
S
(254-256) [9]
Cl
N
N
H3CO
206-208
N
2g
2h
4-CH3O
4-CH3O
H
85
87
N
S
(200) [10]
H
N
N
H3CO
N
182-184
4-CH3O
N
S
H
(163-165) [11]
OCH3
N
N
H3CO
N
2i
4-CH3O
4-Cl
212-214
83
N
H
S
Cl
N
N
H3CO
N
Cl
2j
4-CH3O
4-CH3O
3-Cl
189-191
208-210
84
81
N
H
S
N
N
H3CO
CH3
N
2k
2-CH3
N
H
S
a Yields refer to the isolated products.
from DMF-EtOH-H2O (2:5:1) to give the product. The
analytical data for 2a-k are given below.
CH3). ir (potassium bromide): 3205 (N-H) cm-1. ms: m/z, 294
(M+). Anal. Calcd. for C16H14N4S: C, 65.28; H, 4.79; N, 19.03.
Found: C, 65.14; H, 4.80; N, 19.07.
2d: This compound was obtained as white crystal (DMF-
EtOH-H2O). 1H nmr (DMSO-d6, 400 MHz): ꢀ 12.53 (s, 1H,
NH), 8.15 (s, 1H, CH), 7.34-8.15 (m, 9H, Ar-H), 2.52 (s, 3H,
CH3). ir (potassium bromide): 3204 (N-H) cm-1. ms: m/z, 294
(M+). Anal. Calcd. for C16H14N4S: C, 65.28; H, 4.79; N, 19.03.
Found: C, 65.37; H, 4.77; N, 18.99.
2e: This compound was obtained as white crystal (DMF-
EtOH-H2O). 1H nmr (DMSO-d6, 400 MHz): ꢀ 12.59 (s, 1H,
NH), 8.15 (s, 1H, CH), 7.01-8.12 (m, 9H, Ar-H). ir (potassium
bromide): 3210 (N-H) cm-1. ms: m/z, 314 (M+). Anal. Calcd. for
C15H11ClN4S: C, 57.23; H, 3.52; N, 17.80. Found: C, 57.34; H,
3.53; N, 17.76.
2a: This compound was obtained as white crystal (DMF-
EtOH-H2O). 1H nmr (DMSO-d6, 400 MHz): ꢀ 12.59 (s, 1H,
NH), 8.14 (s, 1H, CH), 7.42-8.06 (m, 10H, Ar-H). ir (potassium
bromide): 3200 (N-H) cm-1. ms: m/z, 280 (M+). Anal. Calcd. for
C15H12N4S: C, 64.26; H, 4.31; N, 19.98. Found: C, 64.35; H,
4.29; N, 19.92.
2b: This compound was obtained as white crystal (DMF-
EtOH-H2O). 1H nmr (DMSO-d6, 400 MHz): ꢀ 12.52 (s, 1H,
NH), 8.16 (s, 1H, CH), 7.04-8.05 (m, 9H, Ar-H), 3.78 (s, 3H,
CH3). ir (potassium bromide): 3209 (N-H) cm-1. ms: m/z, 310
(M+). Anal. Calcd. for C16H14N4OS: C, 61.92; H, 4.55; N, 18.05.
Found: C, 62.04; H, 4.57; N, 18.01.
2c: This compound was obtained as white crystal (DMF-
EtOH-H2O). 1H nmr (DMSO-d6, 400 MHz): ꢀ 12.52 (s, 1H,
NH), 8.14 (s, 1H, CH), 7.33-8.14 (m, 9H, Ar-H), 2.53 (s, 3H,
2f: This compound was obtained as white crystal (DMF-
EtOH-H2O). 1H nmr (DMSO-d6, 400 MHz): ꢀ 12.58 (s, 1H,

1492
Z. Li, X. Feng, Y. Zhao
Vol 45
NH), 8.14 (s, 1H, CH), 7.06-8.04 (m, 9H, Ar-H). ir (potassium
bromide): 3211 (N-H) cm-1. ms: m/z, 314 (M+). Anal. Calcd. for
C15H11ClN4S: C, 57.23; H, 3.52; N, 17.80. Found: C, 57.30; H,
3.51; N, 17.85.
2g: This compound was obtained as white crystal (DMF-
EtOH-H2O). 1H nmr (DMSO-d6, 400 MHz): ꢀ 12.57 (s, 1H,
NH), 8.17 (s, 1H, CH), 7.06-8.06 (m, 9H, Ar-H), 3.75 (s, 3H,
CH3). ir (potassium bromide): 3213 (N-H) cm-1. ms: m/z, 310
(M+). Anal. Calcd. for C16H14N4OS: C,61.92; H, 4.55; N, 18.05.
Found: C, 61.88; H, 4.54; N, 18.00.
cm-1. ms: m/z, 324 (M+). Anal. Calcd. for C17H16N4OS: C, 62.94;
H, 4.97; N, 17.27. Found: C, 63.04; H, 4.96; N, 17.22.
Acknowledgement. The authors thank the National Natural
Science Foundation of China (20772096) and Gansu Natural
Science Foundation (3ZS061-A25-033) for the financial support
of this work.
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Xue, W.; Zhang, S. M.; Zou, Z. H.; Hu, D. Y.; Liu, G. Acta Chim. Sinica
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2h: This compound was obtained as white crystal (DMF-
EtOH-H2O). 1H nmr (DMSO-d6, 400 MHz): ꢀ 12.56 (s, 1H,
NH), 8.18 (s, 1H, CH), 7.04-8.05 (m, 8H, Ar-H), 3.76 (s, 6H,
CH3). ir (potassium bromide): 3216 (N-H) cm-1. ms: m/z, 340
(M+). Anal. Calcd. for C17H16N4O2S: C,59.98; H, 4.74; N, 16.46.
Found: C, 60.05; H, 4.75; N, 16.40.
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2i: This compound was obtained as white crystal (DMF-
EtOH-H2O). 1H nmr (DMSO-d6, 400 MHz): ꢀ 12.58 (s, 1H,
NH), 8.17 (s, 1H, CH), 7.05-8.06 (m, 8H, Ar-H), 3.75 (s, 3H,
CH3). ir (potassium bromide): 3216 (N-H) cm-1. ms: m/z, 344
(M+). Anal. Calcd. for C16H13ClN4OS: C, 55.73; H, 3.80; N,
16.25. Found: C, 55.80; H, 3.81; N, 16.21.
2j: This compound was obtained as white crystal (DMF-
EtOH-H2O). 1H nmr (DMSO-d6, 400 MHz): ꢀ 12.59 (s, 1H,
NH), 8.17 (s, 1H, CH), 7.01-8.14 (m, 8H, Ar-H), 3.74 (s, 3H,
CH3). ir (potassium bromide): 3217 (N-H) cm-1. ms: m/z, 344
(M+). Anal. Calcd. for C16H13ClN4OS: C, 55.73; H, 3.80; N,
16.25. Found: C, 55.66; H, 3.79; N, 16.29.
2k: This compound was obtained as white crystal (DMF-
EtOH-H2O). 1H nmr (DMSO-d6, 400 MHz): ꢀ 12.51 (s, 1H,
NH), 8.16 (s, 1H, CH), 7.33-8.13 (m, 8H, Ar-H), 3.79 (s, 3H,
CH3), 2.53 (s, 3H, CH3). ir (potassium bromide): 3213 (N-H)
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