Microwave Assisted Synthesis of Novel Benzotriazole - IJGHC

E-ISSN: 2278-3229
International Journal of Green and Herbal Chemistry
Available online at www.ijghc.org
Green Chemistry
IJGHC; June-August, 2012; Vol.1.No.2, 108-119
Research Article
Microwave Assisted Synthesis of Novel Benzotriazole
- Pyrazoline derivatives and its Pharmacological
Evaluation
Kalmendra Singh Sisodiya 1 *, Manisha 2 , Amit Sahu 3 , V.K.Sharma 4 and Bharat Parashar 5
1 Department of Chemistry, Pacific University, Udaipur, India.
2 Skyline Institute of Engineering and Technology, Greater Noida (U.P.), India
3 Department of Chemistry, Techno India NJR instituted of technology Udaipur, India
4 Department of Chemistry, M.L. Sukhadia University, Udaipur, (Rajasthan)
5 Department of pharmaceutics, M.B.University; Solan (H.P.).
Received: 13 March 2012; Revised: 31 March 2012; Accepted: 8 April 2012
Abstract: A solvent free approach for organic synthesis is described here which
involve microwave exposure of neat reactants. A novel and simple method have
been developed for the synthesis of some Benzotriazole - Pyrazoline derivatives
under microwave irradiation. In addition, these compounds were obtained with
conventional heating procedures and microwave irradiation to compare them
with those obtained with solid support synthesis. All the compounds synthesized
were characterized by running TLC, Elemental analysis, IR, NMR and MS
spectra. Consequently, the solid support synthesis method provided nearly the
same and higher product yields in a very short period of time. These results
suggest that in addition, the use of solid supports in conjunction with microwave
leads to a higher yield, remarkable reactions rate enhancement and high
catalytic activity with the optimum utilization of energy. Solid support synthesis
method is more useful than the microwave irradiation method and conventional
method.
Keywords: Green chemistry, microwave irradiation, solid supported synthesis,
benzotriazole - pyrazoline derivatives, neat reaction technology
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INTRODUCTION
Classical methods require elaborate apparatus setup, longer heating time and large volume of organic
solvents and there is virtually no control over the energy input. Hazardous chemicals and by products of
various reactions increasing pollution in the environment. Keeping in view the need for avoiding
hazardous chemicals and solvents in chemical reactions, microwave technique was found to be
accelerating a wide variety of transformations. Neat reaction technology is a step forward in the direction
of solvent free reactions and an alternative approach that eliminates the use of a solid support as well as
solvent from the reaction. In recent years design of environmentally benign reactions is an important goal
in organic synthesis. Microwave induced Organic Reaction Enhancement (MORE) chemistry offers a
simple, non-conventional technique for the synthesis of a wide variety of compounds having medicinal,
pharmaceutical and commercial importance. In this expeditious and solvent free approach the reactants
were adsorbed over inorganic supports and exposed to microwave irradiation. In recent years the use of
microwaves 1,2 has been well established as a pollution free technique which allows reaction to occur on a
preparative scale in open vessels under solvent free conditions which avoids the risk of high pressures and
explosions. Microwave activation rather than conventional heating is preferred, as solid supports are rather
poor thermal conductors but strong microwave absorbents, which results in lesser evaporation of solvents
preventing pollution 3. Further the reactions are generally faster and the products obtained are of high
purity 4, 5 .
Pyrazole as well as pyrazolines containing compounds have been reported to show a broad spectrum of
biological activities such as antimicrobial 6-9 , anti-tumor 10, and antiinflammatory 11, 12 agents. Due to
bioactivity associated with pyrazole and pyrazolines containing compounds, researchers and chemist are
very much interested in pyrazole chemistry 13-15 . Pyrazolone are associated with broad spectrum of
biological activities 16 , Pyrazolone exhibit anti-inflammatory 17 and analagics activity 18 , anticancer
activity 19 , 20 antiamoebic activity 21 , antitubercular activity 22 and antitumor activity 23 .
Synthesis of some Benzotriazole - Pyrazoline derivatives under microwave irradiation using diethyl
malonate, acetyl acetone, 1- Chloro-hexane 2-4 dione, ethyl 2-cyanoacetate and phenyl isothiocynate by
solid support synthesis method, conventional heating procedures and microwave irradiation method were
done. The reaction carrierd out in absolute alcohol or DMF using conventional method required 4-10 h,
while microwave irradiation method require only 3.30-7 min and solid support method using silica gel
require only 4-6.50 min. The synthetic route of above mentioned compound is shown in Scheme 1,
(Table 1).
MATERIALS AND METHODS
Experimental Section: All the irradiation was carried out in a modified microwave oven (Kenstar, model
no: OM26.EGO). Melting points of synthesis compounds were determined in open capillaries in liquid
paraffin and are uncorrected. Purity of the compounds in addition to elemental analysis were verified by
percolated TLC using silica gel G as a adsorbent using ethyl acetate: n-hexane (7:3) as a eluent and spot
was detected by using iodine vapours. The IR (KBr pellets) spectra were recorded on a Perkin Elimer-
1800- spectrophotometer and H 1 NMR spectra were recorded on BRUKER DRX-300MHz
spectrophotometer, (TMS as a internal reference) and chemical shifts are expressed in δ. Mass spectra
were recorded on Jeol D30 spectrophotometer. Elemental analyses for C, H and N were conducted using a
Perkin -Elmer C, H, and N analyzer. Their result was found to be an in good agreement with the
calculated values (±0.4%).
Synthesis of ethyl 2-(1H-benzo[d][1,2,3]triazol-1-yl) acetate (I)
Conventional Method: A mixture of Benzotriazole (0.01 mol), ethyl chloro acetate ( 0.01 mol) and
potassium carbonate 3.0 gm in acetone 50.0 mL was stirred for 6 hours. Completion of reaction was 5
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Kalmendra Singh et al.
Synthesis of Compound (I) and (II)
HN
N
N
+
O
O
Cl
K 2 CO 3
N
N
N
O -
H 2 N NH
NH 2 NH 2 .H 2 O
N
N
N
O
( I ) (II)
O
Scheme No. 1
O
N
H 3 C
N
N
O
O
N
N
(2)
O
O
N HN
N
N
N
CH 2 (COOC 2 H 5 ) 2
O
S
O
N
N
(E)-N-(4-oxo-2-(phenylimino)thiazolidin-3-
yl)-1H-benzo[d][1,2,3]triazole-1-
carboxamide
O
NH
N N N
CH 3 COOH
Cl
O
N
N
N
N
N
(4)
O
N
N
(3)
O
N
N
N
CH 3
2-(1H-benzo[d][1,2,3]triazol-1-
yl)-1-(3,5-dimethyl-4,5-
dihydropyrazol-1-yl)ethanone
CH 3 COCH 2 COCH 3
ClCH 2 COCH 2 COCH 2 CH 3
1-(2-(1H-benzo[d][1,2,3]triazol-
1-yl)acetyl)-3-(chloromethyl)-
1H-pyrazol-5(4H)-one
(5)
N
N
N
CH 2 (COOC 2 H 5 ) 2
N
C 6 H 5 NCS
N
H 2 N
NH
N
(II)
O
2-(1H-
benzo[d][1,2,3]triazol-1-
yl)acetohydrazide
H 3 C
N
N
CH 3 COCH 2 COCH 2 CH 3
O
O
CNCH 2 COOCH 2 CH 3
H 2 N
O
(8)
N N N
N
O
N
(i)Morpholine
(ii)ClCH 2 COOC 2 H 5
H
N
N
H
O
1-(2-(1H-
benzo[d][1,2,3]triazol-1-
yl)acetyl)pyrazolidine-3,5-
dione
(1)
1-(2-(1H-benzo[d][1,2,3]triazol-1-
yl)acetyl)-2-acetylpyrazolidine-3,5-
dione
1-(2-(1H-benzo[d][1,2,3]triazol-1-
yl)acetyl)-4-phenylthiosemicarbazide
O
HN
1-(2-(1H-benzo[d][1,2,3]triazol-1-
yl)acetyl)-3-methyl-1H-pyrazol-5(4H)-
one
1-(2-(1H-benzo[d][1,2,3]triazol-1-yl)acetyl)-
3-amino-1H-pyrazol-5(4H)-one
(7)
(6)
S
N
N
N
Scheme-2
The synthetic route of compounds (1-8)
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Kalmendra Singh et al.
Table: 1- Comparative Analysis of Conventional and Microwave Methods
Comp
Molecular
formula
M.wt Condition Conventional
method
Yield
(%)
R time(h)
Microwave method m.
p
o C
In solvent On Solid
Yield
(%)
R time
(min)
Support
Yield
(%)
R time
(min)
1 C 11 H 9 N 5 O 3 259 A.A 70 6.00 82 3.00 88 6.10 17
2
2 C 13 H 11 N 5 O 4 301 A.A 68 5.10 80 5.10 86 6.30 18
9
3 C 13 H 13 N 5 O 257 - 71 8.10 84 3.10 90 3.30 16
9
4 C 12 H 10 ClN 5 O 2 291 - 72 5.22 81 3.30 88 5.30 20
1
5 C 12 H 11 N 5 O 2 257 A.A 71 6.12 83 3.00 90 5.20 16
9
6 C 11 H 10 N 6 O 2 258 - 73 4.55 84 3.00 92 2.20 18
2
7 C 15 H 14 N 6 OS 326 - 69 4.11 82 2.00 90 2.10 21
0
8 C 16 H 12 N 6 O 2 S 352 Morpholin 70 5.50 80 2.30 86 3.10 23
e
2
A.A= Acetic acid
R f
0.64
0.62
0.68
0.61
0.68
0.66
0.66
0.66
Synthesis of 1-(2-(1H-benzo[d][1,2,3]triazol-1-yl) acetyl)pyrazolidine-3,5-dione. (1)
Conventional Method: A mixture of (II) (0.01 mol), diethyl malonate (0.01mol) and two to three drops of
glacial acetic acid were taken in a round bottom flask in 50 mL of ethyl alcohol and was refluxed for
about 6 hr on a water bath. After completion of the reaction as indicated by TLC, the reaction mixture was
cooled and treated with ice cold water. The brown colour oily mass obtained was cooled and the crud
product was recrystallized from ethanol to give afford 1. Physical characteristic of compound is recorded
in Table No 1.
Microwave Method in solvent: A mixture of (II) (0.01 mol), diethyl malonate (0.01mol) and two to
three drops of glacial acetic acid in 30 mL of ethyl alcohol was subjected to microwave irradiation at 360
W for 3 min with an intermittently at 30 sec intervals. After completion of the reaction as indicated by
TLC, the reaction mixture was cooled and treated with cold water. The brown colour oily mass obtained
was cooled and the crud product was recrystallized from ethanol to give afford 1. Physical characteristic
of compound is recorded in Table No 1.
Solid Support Method: A mixture of (II) (0.01 mol), diethyl malonate (0.01mol) were dissolve in alcohol
and the mixture was absorbed on acidic alumina and was subjected to microwave irradiation at 500 W for
5.10 min with an intermittently at 10 sec intervals. After completion of the reaction as indicated by TLC,
the compound was separate out from di ethylethane and recrystallise from ethyl alcohol. Physical
characteristic of compound is recorded in Table No 1.
Physical and Elemental Analysis of Compound 1: Mol. Wt. 259; M.P. 172-174 °C; Yield: 88 %; R f
:0.64; IR ( KBr cm -1 ): 3303 (-NH), 3035 (Aromatic CH-Ar. str. ), 2260 (N=N), 1735, 1730,
1666,(C=O), ; 1 H NMR (400 MHz, DMSO-d 6 ) : 7.45- 7.80 (4H, m, Ar-H); 8.70 (s, H, NH), 4.75 (s,
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Kalmendra Singh et al.
2H, CH 2 ) , 3.35 (s, 2H, CH 2 ), MS (m/z+) [M + ] 259; Anal.Calc.for C 11 H 9 N 5 O 3 ; C, 50.97; H, 3.50; N,
27.02; Found: C, 51.26.; H, 3.30; N, 26.82.
Synthesis of 1- (2- (1H-benzo [d][1,2,3] triazol-1-yl)acetyl) -2-acetylpyrazolidine -3,5-dione
(2)
Conventional Method: A mixture of (II) (0.01 mol) and diethyl malonate (0.01 mol) in glacial acetic
acid (5 mL) were taken in a round bottom flask and was refluxed for about 5 hr on a water bath . After
completion of the reaction as indicated by TLC, the reaction mixture was cooled and treated with cold
water. The solid that precipitated was filtered, washed with water and recrystallized from ethanol to
afford 2. Physical characteristic of compound is recorded in Table No 1.
Microwave Method in solvent: A mixture of (II) (0.01 mol) and diethyl malonate (0.01 mol) in glacial
acetic acid (5 mL) was subjected to microwave irradiation at 360 W for 5.10 min with an intermittently at
20 sec intervals. After completion of the reaction as indicated by TLC, the reaction mixture was cooled
and treated with cold water. The solid that precipitated was filtered, washed with water and recrystallized
from ethanol to afford 2. Physical characteristic of compound is recorded in Table No 1.
Microwave Method on Solid Support: Compound (II) (0.01 mol) and diethyl malonate (0.01 mol) were
dissolved in acetone and the solution was absorbed on acidic alumina and was subjected to microwave
irradiation at 500 W for 4.30 min with an intermittently at 10 sec intervals . After completion of the
reaction as indicated by TLC compound was separate out from acetone and allows drying. Product was
recrystallised with di methyl ether to afford 2. Physical characteristic of compound is recorded in Table
No 1.
Physical and Spectral Analysis of Compound 2: Mol. Wt. 301; M.P. 189-191 °C; Yield: 86 %; R f :0.62;
IR ( KBr cm -1 ): 3130 (Aromatic CH-Ar, str. ), 2270 (N=N), 1740,1693, 1670, 1640, (C=O), ; 1 H NMR
(400 MHz, DMSO-d 6 ) : 7.32- 7.82 (4H, m, Ar-H); 4.60 (s, 2H, CH 2 ) , 3.30 (s, 2H, CH 2 ), 2.40 (s, 3H,
CH 3 ) : MS (m/z+) [M + ] 301; Anal. Calc.for C 13 H 11 N 5 O 4 ; C, 51.83; H, 3.68; N, 23.25; Found: C,
52.06.; H, 4.02; N, 23.72;
Synthesis of 2- (1H-benzo [d][1,2,3 ]triazol-1-yl) -1- (3,5-dimethy l-4,5-dihydropyrazol-1-yl)
ethanone(3)
Conventional Method: A mixture of 2-(1H-benzo[d][1,2,3]triazol-1-yl) acetohydrazide (II) (0.01 mol)
and acetyl acetone (0.01 mol) was taken in Erlenmeyer flask. The mixture was well stirred and then taken
in a round bottom flask and was refluxed for about 2 hr on a water bath. After completion of the reaction
as indicated by TLC the reaction- mixture was then allowed to stand at RT and the product formed was
washed with cold water and dissolved in methanol then filtered, dried and recrystallized from ethanol to
afford 3. Physical characteristic of compound is recorded in Table No 1.
Microwave Method in solvent: A mixture of 2-(1H-benzo[d][1,2,3]triazol-1-yl) acetohydrazide (II) (0.01
mol) and acetyl acetone (0.01 mol) was taken in Erlenmeyer flask. The mixture was well stirred subjected
to microwave irradiation at 360 W for 3.10 min with an intermittently at 10 sec intervals. After
completion of the reaction as indicated by TLC the reaction- mixture was then allowed to stand at RT and
the product formed was washed with cold water and dissolved in methanol then filtered, dried and
recrystallized from ethanol to afford 3. Physical characteristic of compound is recorded in Table No 1.
Microwave Method on Solid Support: A solution of (II) (0.01 mol) and acetyl acetone (0.01 mol) were
taken in beaker. The mixture was well stirred and then absorbed on neutral alumina and was subjected to
microwave irradiation at 500 W for 3.10 min with an intermittently at 20-25 sec intervals. After
completion of the reaction as indicated by TLC the compound was separate out from acetone and
recrystallized from ethanol to afford 3. Physical characteristic of compound is recorded in Table No 1.
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Kalmendra Singh et al.
Physical and Spectral Analysis of Compound 3: Mol. Wt. 257; M.P. 169-171 °C; Yield: 90 %; R f :0.68;
IR ( KBr cm -1 ): 3110 (Aromatic CH-Ar, str. ), 2265 (N=N), 1690, (C=O), 1553(C=N), : 1 H NMR (400
MHz, DMSO-d 6 ) : 7.32- 7.82 (4H, m, Ar-H); 5.71(s, 1H, CH) , 4.56 (s, 2H, CH 2 ) , 3.42 (s, 2H, CH 2 ),
3.35 (s, 3H, CH 3 ), 2.40 (s, 3H, CH 3 ): MS (m/z+) [M + ] 257 ; Anal. Calc.for C 13 H 13 N 5 O; C, 60.69; H,
5.88; N, 27.22; Found: C, 60.92; H, 5.62; N, 27.50.
Synthesis of 1-(2-(1H-benzo[d][1,2,3]triazol-1-yl)acetyl)-3-(chloromethyl)-1H-pyrazol-
5(4H)-one (4)
Conventional Method: A mixture of (II) (0.01 mol), 1- Chloro-hexane 2-4 dione (0.012 mol) was taken
in a round bottom flask and was refluxed for about 5 hr on a water bath. TLC monitored the reaction.
After completion of the reaction, reaction- mixture was allowed to stand at RT and the product formed
was filtered, washed with water, dried and recrystallized from ethanol to afford 4. Physical characteristic
of compound is recorded in Table No 1.
Microwave Method in solvent: A mixture of (II) (0.01 mol), 1- Chloro-hexane 2-4 dione (0.07 mol) was
taken in a borosil beaker (100 mL). The well-stirred mixture was irradiated inside the microwave oven for
a period of 3.30 minutes (at 480 W). TLC monitored the reaction. After completion of the reaction,
reaction- mixture was allowed to stand at RT and the product formed was filtered, washed with water,
dried and recrystallized from ethanol to afford 4. Physical characteristic of compound is recorded in Table
No 1.
Microwave Method on Solid Support: Compound (II) (0.01 mol), 1- Chloro-hexane 2-4 dione (0.07
mol) were dissolved in alcohol and the mixture was absorbed on neutral alumina and was irradiated inside
the microwave oven for a period of 5.30 minutes (at 500W). TLC monitored the reaction. After
completion of the reaction, product was separate out from aceton recrystallized from ethanol to afford 4.
Physical characteristic of compound is recorded in Table No 1.
Physical and Spectral Analysis of Compound 4: Mol. Wt. 291; M.P. 201-122 °C; Yield: 88 %; R f :0.61;
IR ( KBr cm -1 ): 3080 (Aromatic CH-Ar str. ), 2240 (N=N), 1695,1666 (C=O), 1606 (C=N), : 1 H NMR
(400 MHz, DMSO-d 6 ) : 7.7-7.8(m, 4H,), 2.80 (s, 2H, CH 2 ), 3.45 (s, 2H, CH 2 ): 7.32- 7.82 (4H, m, Ar-H);
5.71(s, 1H, CH) , 4.30 (s, 2H, CH 2 ) , 3.22 (s, 2H, CH 2 ), : MS (m/z+) [M + ] 291 ; Anal. Calc.for C 12 H 10
ClN 5 O 2 ; C, 49.41; H, 3.46; N, 24.01; Found: C, 49.64; H, 3.16; 1-; N, 24.24.
Synthesis of 1-(2-(1H-benzo[d][1,2,3]triazol-1-yl)acetyl)-3-methyl-1H-pyrazol--(4H)-one (5)
Conventional Method: Compound (II), hexane-2, 4-dione (0.01 mol), and (0.005 mol) acetic acid was
mixed thoroughly. This mixture was taken in a round bottom flask and was refluxed for about 6 hr on a
water bath. Upon completion of the reaction (monitored by TLC), the reaction mixture was poured onto
crushed ice. The solid mass obtained was filtered and washed several times with water. Purification by
recrystallization with alcohol gave product 5. Physical characteristic of compound is recorded in Table
No 1.
Microwave Method in solvent: Compound (II), hexane-2, 4-dione (0.01 mol), and (0.00- mol) acetic
acid was mixed thoroughly. This mixture was subjected to microwave irradiation (by keeping inside a
microwave oven) for 3.0 min at 480 W power levels with intermitted irradiation for 30 second. Upon
completion of the reaction (monitored by TLC), the reaction mixture was poured onto crushed ice. The
solid mass obtained was filtered and washed several times with water. Purification by recrystallization
with alcohol gave product 5. Physical characteristic of compound is recorded in Table No 1.
Microwave Method on Solid Support: Compound (II), hexane-2,4-dione (0.01 mol), were dissolved in
acetone and absorbed on acidic alumina and irradiated inside the microwave oven for a period of 5.20 min
at 500 W power levels with intermitted irradiation for 30 second. Upon completion of the reaction
(monitored by TLC), the reaction mixture was poured onto crushed ice. The solid mass obtained was
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Kalmendra Singh et al.
filtered and washed several times with water. Purification by recrystallization with alcohol gave product 5.
Physical characteristic of compound is recorded in Table No 1.
Physical and Spectral Analysis of Compound 5: Mol. Wt. 257; M.P. 169-171 °C; Yield: 90 %; R f :0.68;
IR ( KBr cm -1 ): 3115 (Aromatic CH-Ar str. ), 2262 (N=N), 1680, 1606 (C=O), 1530 (C=N), ; 1 H
NMR (400 MHz, DMSO-d 6 ) : 7.40- 7.88 (4H, m, Ar-H); 4.56 (s, 2H, CH 2 ) , 3.42 (s, 2H, CH 2 ), 3.35 (s,
3H, CH 3 ), : MS (m/z+) [M + ] 257 ; Anal. Calc.for C 12 H 11 N 5 O 2 ; C, 56.03; H, 4.31; N, 27.22; Found: C,
56.36; H, 4.64; N, 27.46.
Synthesis of 1-(2-(1H-benzo[d][1,2,3]triazol-1-yl)acetyl)-3-amino-1H-pyrazol--(4H)-one (6)
Conventional Method: 2-(1H-benzo[d][1,2,3]triazol-1-yl) acetohydrazide (0.01 mol) (II)and (0.01) and
ethyl 2-cyanoacetate (0.01) in -0 mL ethanol were taken in a round bottom flask and was refluxed for
about 4hr on a water bath and reaction progress was monitored by TLC. Then crude product so obtained
was poured into ice-cold water, filtered, dried, and recrystallized from methanol to give product 6.
Physical characteristic of compound is recorded in Table No 1.
Microwave Method in solvent: 2-(1H-benzo[d][1,2,3]triazol-1-yl) acetohydrazide (0.01 mol) (II) and
(0.01) and ethyl 2-cyanoacetate (0.01) were mixed together to form a paste and then subjected to
microwave irradiation for 3.0 min at 400 W power level and reaction progress was monitored by TLC.
Then crude product so obtained was poured into ice-cold water, filtered, dried, and recrystallized from
methanol to give product 6. Physical characteristic of compound is recorded in Table No 1.
Solid Support Method: 2-(1H-benzo[d][1,2,3]triazol-1-yl) acetohydrazide (0.01 mol) (II) and (0.01) and
ethyl 2-cyanoacetate (0.01) were dissolved in alcohol and absorbed on alumina. The mixture was
subjected to microwave irradiation at 500 W for 4.20 min with an intermittently at 30-35 sec intervals.
After completion of the reaction indicated by TLC the compound was separate out from acetone and
recrystallize from alcohol to give product 6. Physical characteristic of compound is recorded in
Table No 1.
Physical and Spectral Analysis of Compound 6: Mol. Wt. 258; M.P. 182-183 °C; Yield: 92 %; R f :0.66;
IR ( KBr cm -1 ): 3334, 3218(-NH 2 ), 3140 (Aromatic CH-Ar str. ), 2262 (N=N), 1698, 1672 (C=O),
1554 (C=N), ; 1 H NMR (400 MHz, DMSO-d 6 ) : 7.46- 7.68 (4H, m, Ar-H); 5.12 (s, 2H, NH2), 4.50 (s,
2H, CH 2 ) , 3.42 (s, 2H, CH 2 ),: MS (m/z+) [M + ] 258 ; Anal. Calc.for C 11 H 10 N 6 O 2 ; C, 51.16; H, 3.90; N,
32.54; Found: C, 51.36; H, 4.20; N, 32.74.
Synthesis of 1-(2-(1H-benzo[d][1,2,3]triazol-1-yl)acetyl)-4-phenylthiosemicarbazide (7)
Conventional Method: To a mixture of 2-(1H-benzo[d][1,2,3]triazol-1-yl) acetohydrazide (II) (0.01 mol )
and phenyl isothiocynate (0.01 mol e) in a 40 ml DMF was were taken in a round bottom flask and was
refluxed for about 4 hr on a water bath. TLC examined the progress of the reaction. The mixture was
poured into ice-cold water. The resulting solid was filtered, dried and recrystallized from benzene to give
product 7. Physical characteristic of compound is recorded in Table No 1.
Microwave Method in solvent: To a mixture of 2-(1H-benzo[d][1,2,3]triazol-1-yl) acetohydrazide (II)
(0.01 mol ) and phenyl isothiocynate (0.01 mol e) in a 20 ml DMF was taken in Erlenmeyer flask. The
mixture was irradiated under microwave for 2.00 min at 360 W powers with intermittent radiation of 15
sec interval. TLC examined the progress of the reaction. The mixture was poured into ice-cold water. The
resulting solid was filtered, dried and recrystallized from benzene to give product 7. Physical
characteristic of compound is recorded in Table No 1.
Microwave Method on Solid Support: 2-(1H-benzo[d][1,2,3]triazol-1-yl) acetohydrazide (II) (0.01 mol)
and phenyl isothiocynate (0.01 mol) were dissolved in acetone and the mixture was absorbed on neutral
alumina and was subjected to microwave irradiation at 500 W for 5.10 min with an intermittently at 15-20
sec intervals. After completion of the reaction the compound was separate out from acetone and
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Kalmendra Singh et al.
recrystallize from alcohol to give product 7. Physical characteristic of compound is recorded in
Table No 1.
Physical and Spectral Analysis of Compound 7: Mol. Wt. 326; M.P. 210-2111 °C; Yield: 90 %; R f
:0.66; IR ( KBr cm -1 ): 3416,3372, 3312(-NH), 3089 (Aromatic CH-Ar str. ), 2262 (N=N), 1708 (C=O),
1100 (C=S), ; 1 H NMR (400 MHz, DMSO-d 6 ) : 10.20 (s,H, HN-CO), 7.48- 7.80 (m, 9H, Ar-H); 4.34
(s,H,HN-Ph), 3.42 (s, 2H, CH 2 ), 2.20 (s,H,HN-N); : MS (m/z+) [M + ] 326 ; Anal. Calc.for; C 15 H 14 N 6 OS
; C, 55.20; H, 4.32; N, 25.75; Found: C, 55.20; H, 4.32; N, 25.75.
Synthesis of (E) -N- (4-oxo-2-(phenylimino) thiazolidin-3-yl)-1H-benzo[d][1,2,3]triazole-1-
carboxamide (8)
Conventional Method: A mixture of 7 (0.01 mol) and ethylchloroacetate in presence of catalytic amount
of morpholine in 40 mL of ethanol were taken in a round bottom flask and was refluxed for about 5.50 hr
on a water bath. After completion of the reaction as indicated by TLC, the reaction mixture was cooled
and treated with ice-cold water and recrystallized from ethanol to give product 8. Physical characteristic
of compound is recorded in Table No 1.
Microwave Method in solvent: A mixture of 7 (0.01 mol) and ethylchloroacetate in presence of catalytic
amount of morpholine were mixed thoroughly. Than the mixture was irradiated under microwave oven for
2.30 min at 480 W with an intermitted irradiation for 30sec. interval. After completion of the reaction as
indicated by TLC, the reaction mixture was cooled and treated with ice-cold water and recrystallized from
ethanol to give product 8. Physical characteristic of compound is recorded in Table No 1.
Microwave Method on Solid Support: A mixture of 7 (0.01 mol) and ethylchloroacetate were mixed
thoroughly and dissolved in alcohol and the mixture was absorbed on basic alumina and subjected to
microwave irradiation at500 W for 4.10 min with an intermittently at 15-20 sec intervals. After
completion of the reaction as indicated by TLC the compound was separate out from acetone and 1,2
dichloro methane. Physical characteristic of compound is recorded in Table No 1.
Physical and Spectral Analysis of Compound 8: Mol. Wt. 352; M.P. 232-334 °C; Yield: 86 %; R f :0.66;
IR ( KBr cm -1 ): 3080 (Aromatic CH-Ar str. ), 2282 (N=N), 1698, 1649 (C=O), 740 (S-C-S), ; 1 H NMR
(400 MHz, DMSO-d 6 ) : 10.20 (s, H, HN-CO), 9.67(s, H, HN) , 7.32- 7.88 (m, 9H, Ar-H); 4.10 (s, 2H,
CH 2 ), : MS (m/z+) [M + ] 352 ; Anal. Calc. for; C 16 H 12 N 6 O 2 S; C, 54.54; H, 3.43; N, 23.85; Found: C,
54.74; H, 3.24; N, 23.62.
BIOLOGICAL ASSAY
All the newly synthesized compounds were tested in vitro for antimicrobial activity against four bacterial
strains two-gram positive bacteria (Bacillus subtilis and staphylococcus aureus) and two-gram negative
bacteria (Escherichia coli and P.aeruginosa) and antifungal activity against Candida albicans and
Asperigillus niger at the concentration of 200,100,50, µg/ml by using the cup plate agar disk diffusion
method 24 , 25 and determination of minimum inhibitory concentration (MIC) by broth dilution method.The
concentration used in screening was choosen after determining MIC of each compound. The
dimethylsulfoxide (DMSO) was used as a solvent. For this method, Mueller-Hinton agar was used as the
growth medium for the bacterial strains and Sabouraud agar was growth medium for fungal species. The
sterilized agar media were poured in to petridishes and allow solidifying. On the surface of the media
microbial suspension were spread with the help of sterilized triangular loop. (Inoculums of standard
suspension 0.1 mL of the test organism strain which contains 106 bacilli/mL)
A stainless steel cylinder of 9 mm diameter (pre sterilized) was used to bore the cavities. In to these well
were added 0.1mL portion of the test compounds in solvent DMSO. The drug solution was allowed to
diffuse for about an hour in to the medium. The petridishes used for antibacterial screening were
115 IJGHC; 2012, Vol.1, No.2, 108-119.

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Kalmendra Singh et al.
incubated at 37 ±1°C for 24 h, while those for antifungal activity were incubated at 28 ±1°C for 48-72 h.
DMSO was used as a control for all the type of microorganisms. The control showed no activity against
the strains of microorganisms used. Antimicrobial activity and antifungal activity was measured as a
function of diameter of zone of inhibition (mm). The result was compared with standard drugs
Ciprofloxacin for antibacterial activity and fluconazole for antifungal activity by measuring the zone of
inhibition in mm at 200,100 and 50 µg/mL (Table -2 and Table-3). The lowest concentration, which
showed no visible growth, was taken as an end point minimum inhibitory concentration (MIC). For
antibacterial activity, in present protocol 50 µg/ml is considered as active as compared to the standard
drug Ciprofloxacin. For antifungal activity, 50 µg/mL is considered as active as compared to standard
fluconazole
Table: 2. Antifungal Activities of the synthesized compounds (1-8).
Antifungal activity
Compounds C. albicans A. niger
50µg
/ml
100
µg/ml
200
µg/ml
50µg
/ml
100µg
/ml
200µg
/ml
1 - ++ +++ - ++ ++
2 + ++ ++++ ++ +++ ++++
3 - ++ +++ - ++ +++
4 + ++ ++ + ++ ++
5 ++ ++ ++ ++ ++ ++
6 ++ +++ +++ ++ ++ +++
7 ++ +++ +++ +++ +++ +++
8 + +++ +++ - ++ +++
Fluconazole ++++ ++++ ++++ ++++ ++++ + + + +
(-)< 6mm; (+) = 7 - 10 mm; (++) =11 – 15 mm; (+++) = 16 - 21mm; (++++) = 22 - 28mm.
RESULTS AND DISCUSSIONS
The compound ethyl 2-(1H-benzo[d][1,2,3]triazol-1-yl) acetate (I) was synthesized by microwave
radiation of mixture of Benzotriazole, ethyl chloro acetate and potassium carbonate in acetone. The M.P.
of the synthesized compound was checked by the given literature. The compound 2-(1Hbenzo[d][1,2,3]triazol-1-yl)
acetohydrazide (II) was synthesized by ethanolic solution of compound (I)
and hydrazine hydrate under microwave radiation of 240W. The purity of the compound was analyzed by
TLC using ethyl acetate: n-hexane (7:3) as a mobile phase. The final compounds (1-8) were synthesized
as given below. The structure of the synthesized compounds was confirmed on the basis of spectral and
elemental analysis.
The compound (1) 1-(2-(1H-benzo[d][1,2,3]triazol-1-yl) acetyl)pyrazolidine-3,5-dione is synthesized by
irradiating mixture of compound (II), diethyl malonate and 2-3 drops of glacial acetic acid. The IR
spectrum exhibited bands due to 1735, 1730, 1666 (C=O), and 1 H NMR gives δ shift at 4.75 (s, 2H, CH 2 ),
3.35 (s, 2H, CH 2 o) and molecular ion peak [M + ] was found at 259 which confirmed the formation of
compound (1).
The compound (2) 1-(2-(1H-benzo[d][1,2,3]triazol-1-yl)acetyl)-2-acetylpyrazolidine-3,5-dione was
synthesized by irradiating mixture of compound (II), diethyl malonate and 5ml of glacial acetic acid. The
IR spectrum exhibited bands due to 1740,1693,1670,1640 (C=O), 1 H NMR gives δ shift at 4.60 (s, 2H,
CH 2 ) , 3.30 (s, 2H, CH 2 ), 2.40 (s, 3H, CH 3 ) molecular ion peak [M + ] was found at 301 which confirmed
the formation of compound (2).
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Kalmendra Singh et al.
Table: 3. Antibacterial Activities of the synthesized compounds (1-8).
Antibacterial activity
Comp E. coli P. aeruginosa B. subtitis S. aureus
ounds
50
µg
/ml
100
µg
/ml
200
µg
/ml
50
µg
/ml
100
µg
/ml
200
µg
/ml
50
µg
/ml
100
µg
/ml
200
µg
/ml
50
µg
/ml
100
µg
/ml
1 _ ++ ++ _ + ++ _ ++ ++ _ _ +
2 _ ++ +++ _ _ + _ ++ +++ _ ++ +++
3 + ++ ++++ _ ++ ++ _ ++ +++ _ ++ ++
4 + +++ ++++ _ + ++ _ ++ ++++ _ ++ +++
5 _ + +++ _ + +++ _ ++ ++ _ ++ +++
6 _ ++ +++ _ + + _ ++ +++ _ _ +++
7 _ + +++ _ + +++ _ ++ +++ _ + +++
8 _ +++ ++++ + ++ +++ + ++ +++ _ + +++
Ciprofl
oxacin
++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++
200
µg
/ml
(-)< 6mm; (+) = 7 - 10 mm; (++) =11 – 15 mm; (+++) = 16 - 21mm; (++++) = 22 - 28mm.
The compound (3) 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1-(3,5-dimethyl-4,5-dihydropyrazol-1-yl)ethanone
was synthesized by irradiating mixture of compound (II) and acetyl acetone. The IR spectrum exhibited
bands due to 1553(C=N) , 1 H NMR (400 MHz, DMSO-d 6 ) showed peaks due to 3.35(s, 3H, CH 3 ), 2.40 (s,
3H, CH 3 ) ) and molecular ion peak [M + ] was found at 257 which confirmed the formation of compound
(3).
The compound (4) 1-(2-(1H-benzo[d][1,2,3]triazol-1-yl)acetyl)-3-(chloromethyl)-1H-pyrazol-5(4H)-one
was synthesized by microwave irradiation of mixture of compound (II) and 1- Chloro-hexane 2-4 dione.
The IR spectrum exhibited bands due to 1695, 1666 (C=O), 1606(C=N), 1 H NMR (400 MHz, DMSO-d 6 )
showed peaks due to 4.30 (s, 2H, CH 2 ) , 3.22 (s, 2H, CH 2 ) and molecular ion peak [M + ] was found at
291; which confirmed formation of compound (4).
The compound (5) 1-(2-(1H-benzo[d][1,2,3]triazol-1-yl)acetyl)-3-methyl-1H-pyrazol-5(4H)-one was
synthesized by microwave irradiation of mixture of compound (II), hexane-2, 4-dione and acetic acid.
The IR spectrum exhibited bands due to 1680,1606(C=O),1530(C=N) and 1 H NMR (400 MHz, DMSOd
6 ) showed peaks due to 3.42 (s, 2H, CH 2 ), 3.35 (s, 3H, CH 3 ) and molecular ion peak [M + ] was found at
257 which confirmed formation of compound (5).
The compound (6) 1-(2-(1H-benzo[d][1,2,3]triazol-1-yl)acetyl)-3-amino-1H-pyrazol-5(4H)-one was
synthesized by microwave irradiation of mixture of compound (II) and ethyl 2-cyanoacetate. The IR
spectrum exhibited bands due to 1698, 1672 (C=O), 1554(C=N) and NMR (400 MHz, DMSO-d 6 ) showed
peaks due to 5.12 (s, 2H, NH2), 4.50 (s, 2H, CH 2 ) , 3.42 (s, 2H, CH 2 ) and molecular ion peak [M + ] was
found at 258 which confirmed formation of compound (6).
The compound (7) 1-(2-(1H-benzo[d][1,2,3]triazol-1-yl)acetyl)-4-phenylthiosemicarbazide was
synthesized by microwave irradiation of mixture of compound (II) and phenyl isothiocynate in DMF .
The IR spectrum exhibited bands due to 1100(C=S), NMR (400 MHz, DMSO-d 6 ) showed peaks due to (s,
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Kalmendra Singh et al.
2H, CH 2 ), 2.20 (s, H, HN-N), and molecular ion peak [M + ] was found at 326 which confirmed formation
of compound (7).
The compound (8) (E)-N-(4-oxo-2-(phenylimino) thiazolidin-3-yl)-1Hbenzo[d][1,2,3]triazole-1-
carboxamide was synthesized by irradiating mixture of compound (7) andethylchloroacetate in presence
of catalytic amount of morpholine. The IR spectrum exhibited bands due to1698, 1649(C=O), 740(S-C-S),
NMR (400 MHz, DMSO-d 6 ) showed peaks due to 4.10 (s, 2H, CH 2 ) and molecular ion peak [M + ] was
found at 352 which confirmed formation of compound(8).
CONCLUSION
Most of the synthesized compounds were found to possess mild to moderate antibacterial and antifungal
activity except a couple of compounds which showed excellent activity, almost equivalent to the
compounds will take place which may lead to a potentially improved compounds.
ACKNOWLEDGEMENTS
The authors are thankful to Dr.Suman Jain, Director of shri ram college of Pharmacy, for providing
laboratory facilities authors are also thankful to Director, CDRI Lucknow, India for providing spectral and
analytical data. Special thanks to Dr. Ashok Kumar Sharma (A.D.) Regional Disease Diagnostic Center,
Kota (Rajasthan) for antimicrobial screening.
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*Correspondence Author: Kalmendra Singh Sisodiya; Department of Chemistry,
Pacific University, Udaipur, India.
Email:kalmendrasisodiya@yahoo.in
119 IJGHC; 2012, Vol.1, No.2, 108-119.