The one step synthesis of 2-(2-bromo-5-methoxyphenyl)-5-(3-arylidene)-1,3- thiazolo[3,2-b ]-1,2,4-triazol-6-(5H)-ones and the evaluation of the anticonvulsant activity

Article abstract of DOI:10.1080/10426500500544170

A smooth one-step synthesis of 2-(2-bromo-5-methoxyphenyl)-5-(3-arylidene)- 1,3-thiazolo[3,2- b ]-1,2,4-triazol-6-(5 H )-ones (4a-n) is described. The newly prepared compounds are characterized by analytical and IR, 1 H NMR, 13 C NMR, and FABMS spectral a

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Phosphorus, Sulfur, and Silicon
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The One Step Synthesis of 2-(2-
Bromo-5- methoxyphenyl)-5-
(3-arylidene)-1,3-thiazolo[3,2-
b]- 1,2,4-triazol-6-(5H)-ones
and the Evaluation of the
Anticonvulsant Activity
K. K. Vijaya Raj a & B. Narayana a
a Department of Postgraduate Studies and Research
in Chemistry, Mangalore University, Mangalagangotri,
India
Version of record first published: 21 Sep 2006.
To cite this article: K. K. Vijaya Raj & B. Narayana (2006): The One Step Synthesis of
2-(2-Bromo-5- methoxyphenyl)-5-(3-arylidene)-1,3-thiazolo[3,2-b]- 1,2,4-triazol-6-
(5H)-ones and the Evaluation of the Anticonvulsant Activity, Phosphorus, Sulfur, and
Silicon and the Related Elements, 181:9, 1971-1981
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Phosphorus, Sulfur, and Silicon, 181:1971–1981, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500544170
The One Step Synthesis of 2-(2-Bromo-5-
methoxyphenyl)-5-(3-arylidene)-1,3-thiazolo[3,2-b]-
1,2,4-triazol-6-(5H )-ones and the Evaluation of the
Anticonvulsant Activity
K. K. Vijaya Raj
B. Narayana
Department of Postgraduate Studies and Research in Chemistry,
Mangalore University, Mangalagangotri, India
A smooth one-step synthesis of 2-(2-bromo-5-methoxyphenyl)-5-(3-arylidene)-1,3-
thiazolo[3,2-b]-1,2,4-triazol-6-(5H)-ones (4a–n) is described. The newly prepared
1
13
compounds are characterized by analytical and IR, H NMR,
C NMR, and
FABMS spectral analysis. A few compounds are screened for anticonvulsant ac-
tivity. Compounds 4i and 4n exhibit promising anticonvulsant activity and are
recommended for further studies.
Keywords Anticonvulsant activity; bromomethoxyphenyl; one step synthesis; thiazolo-
triazolones
INTRODUCTION
Multicomponent Reactions (MCRs) are very promising due to their ad-
vantages over conventional multistep reactions with respect to speed,
time, yield, and reproducibility. Among organic reactions, MCRs are
highly convergent1 and serve as superior tools for diversity-oriented
drug syntheses.2 Recent literature reviews show that one-pot synthesis
has importance in the syntheses of various biologically active hetero-
cyclic compounds.3,4
Thiazolo[3,2-b]-1,2,4-triazole-6-(5H)-one derivatives possess biolog-
ical activity, such as antiinflammatory5 and vasodilatory6 activity, as
Received October 26, 2005; accepted November 10, 2005.
The authors are thankful to Prof. N. Suchetha Kumari, Department of Biochemistry,
K. S. Hegde Medical Academy, Derarakatte, Mangalore, for helping to carry out the an-
ticonvulsant study. The authors are also thankful to Prof. A. Srikrishna, Department of
Chemistry, IISc, Bangalore, The Director, RSIC,Punjab University, Chandigarh, and The
Head, SAIF, CDRI Luknow for IR, mass, and NMR analysis.
Address correspondence to B. Narayana, Department of Postgraduate Studies and
Research in Chemistry, Mangalore University, Magalagangotri 574 199, India. E-mail:
nbadiadka@yahoo.co.uk
1971

1972
K. K. Vijaya Raj and B. Narayana
well as the antibacterial and antifungal,7 anticonvulsant,8 pesticidal,9
and antiulcer10 activities.
Prompted by these observations, it was contemplated to syn-
thesize a new series of 2-(2-bromo-5-methoxyphenyl)-5-(3-arylidene)-
1,3-thiazolo[3,2-b]-1,2,4-triazol-6-(5H)-ones by the condensation of
5-(2-bromo-5-methoxyphenyl)-4H-1,2,4-triazole-3-thiol with appropri-
ate aromatic aldehydes and monochloroacetic acid in the presence of
acetic anhydride, acetic acid, and anhydrous sodium acetate in a mul-
ticomponent synthesis. The latter provides maximum structural com-
plexity and diversity in a minimum number of steps. In addition, it was
the intent to screen them for anticonvulsant activity. The outline of the
syntheses is given in Scheme 1.
RESULTS AND DISCUSSION
Chemistry
5-(2-Bromo-5-methoxyphenyl)-4H-1,2,4-triazole (3) was synthesized by
the reaction of 2-bromo-5-methoxybenzoic acid hydrazide (1) with
potassium thiocyanate and conc. HCl, followed by the cyclization of
the resulting 1-(2-bromo-5-methoxybenzoyl) thiosemicarbazide (2) with
sodium hydroxide,11 5-(2-bromo-5-methoxyphenyl)-4H-1,2,4-triazole-
3-thiol (3) was condensed with monochloroacetic acid and aromatic alde-
hydes in the presence of anhydrous sodium acetate, acetic anhydride,
and acetic acid to obtain 2-(2-bromo-5-methoxyphenyl)-5-(3-arylidene)-
1,3-thiazolo [3,2-b]-1,2,4-triazol-6-(5H)-ones (4a–n).
The newly synthesized compounds (4a–n) were characterized by
spectral analysis. The IR spectrum of the compound 4e showed a se-
ries of bands at 3074.8 cm−1 to 2837.8 cm−1 due to an alkyl and aryl
–CH stretch. A band at 1742.5 cm−1 was due to a keto group, and a
band at 1570.2 and 1514.8 cm−1 was due to a –C N stretch. A band
1
at 1233.9 cm−1 was due to an Ar-F stretch. The H NMR (δ in ppm)
spectrum of 4e showed a singlet at δ 3.84 is due to –OCH3 protons. A
doublet of a doublet at δ 6.9 (J = 8.7), a doublet at δ 7.47 (J = 3.0),
and a doublet at δ 7.54 (J = 8.7) were due to three protons in the
aromatic ring bearing the methoxy group. A doublet of doublets at δ
7.65 (J = 8.7) and a multiplet at δ 7.25 were due to 4 protons on the
aromatic ring containing a fluorine atom. The multiplet arose due to
an F-H coupling. A singlet at δ 8.21 was due to a benzylidene pro-
ton. The 13C NMR (δ in ppm) spectrum of 4e showed peaks at 55.51,
2
112.53, 116.82, 117.0 (d, JC−F = 22.5), 118.55, 123.67,128.87, 131.00,
132.98 (d, 3JC−F = 8.25), 135.12, 139.49,156.09, 158.87, 159.18, 164.53
1
(d, JC−F = 87.8), and 169.60. The FABMS spectrum showed peaks at
m/z 432 (M+, I = 60%), and m/z 434 (M+2, I = 70%) corresponded to

One Step Synthesis of Triazols
1973
SCHEME 1

1974
K. K. Vijaya Raj and B. Narayana
the molecular formula C18H11BrFN3O2S. Characterization data of the
compounds are given in Table I. Spectral data of other compounds are
given in the Experimental section.
Anticonvulsant Activity
Inbred male albino mice (Swiss strain) weighing between 20–30 g were
used in the study. They were housed under standard laboratory condi-
tions for one week before experiments were started and were kept in
groups of 3–4 per cage at a controlled temperature (23◦C) and humidity
(50%) with dark–light cycles beginning at 7 a.m. They received a stan-
dard diet and water ad libitum. Each mouse was used for one seizure
test only. Pentylenetetrazole (PTZ, Sigma Chemicals, USA) was used
as a convulsant and Diazepam (Ranbaxy Laboratories, India) was used
as a standard drug. The studies were carried out at the Department of
Chemistry, Mangalore University. The institutional ethical committee
(Mangalore University, Karnataka, India) approved the study. The data
obtained were analyzed using one-way analysis of variance (ANOVA).
p < 0.05 was considered as significant. Results are given in Table II.
Pentylenetetrazole was dissolved in normal saline. Test and standard
drugs were dissolved in 2% gum acacia suspension. Mice were divided
into seven groups of three each. Group 1 received diazepam; Group 2
received 4e; Group 3 received 4f; Group 4 received 4i; Group 5 received
4l; and Group-6 received 4n at a dose of 4 mg/Kg dissolved in 2% gum
acacia in a volume of 0.1 mL/10 g body weight; and Group 7 received
0.1 mL/10 g of 2% gum acacia orally by gavage feeding.
Convulsions were induced12 one h after the administration of stan-
dard and test drugs by injecting PTZ (80 mg/kg) dissolved in saline i.p.
in a volume of 0.1 mL/10 g body weight. The time needed for the devel-
opment of unequivocal sustained clonic seizure activity involving the
limbs (isolated mylonic jerks or other preconvulsive chewing behavior
were not counted) was carefully noted. The duration of the seizurewas
also noted. A seizure-free duration for a period of one h was taken as
protection.
The animals tested in the vehicle group exhibited seizures at the
dose of PTZ used in the study. The onset of seizures was found at 119 s,
and the meanseizure duration was 259 s. The standard drug diazepam
protected the animal from developing convulsions. Although none of the
tested compounds protected animals from developing convulsions, 4e
and 4i increased latency; 4n, 4i, and 4f reduced the duration of seizures,
and 4n and 4i prevented death.
Out of the tested compounds 4e, 4f, 4i, 4l and 4n, the compounds
having anticonvulsant action at a dose of 4 mg/kg were 4i and 4n,
bearing a 3,4-dimethoxybenzene moiety and 2-hydroxyphenyl moiety

One Step Synthesis of Triazols
1975
TABLE I The Characterization of 2-(2-Bromo-5-methoxyphenyl)-5-
(3-arylidene)-1,3-thiazolo [3,2-b]-1,2,4-triazol-6-(5H)-One (4a–n)
Nature
of
Calcd. Found crystals
% Nitrogen
Compound
no.
Yielda
%
Molecular
formula
M.P.b
◦C
Ar
4a
52
C19H14BrN3O2S 192–194 9.81 9.60 Yellow
crystals
4b
65
C19H14BrN3O3S 164–168 9.46 9.28 Off-white
powder
4c
62 C18H9BrCl3N3O2S 138–142 8.12 8.03 Yellow
crystals
4d
4e
4f
68
72
64
C18H12BrN3O3S 178–180 9.77 9.56 Yellow
crystals
C18H11BrFN3O2S 228–230 9.72 9.68 Yellow
crystals
C19H14BrN3O2S 198–200 9.81 9.67 Off-white
crystals
(Continued on next page)

1976
K. K. Vijaya Raj and B. Narayana
TABLE I The Characterization of 2-(2-Bromo-5-Methoxyphenyl)-5-
(3-Arylidene)-1,3-Thiazolo [3,2-b]-1,2,4-Triazol-6-(5H)-One (4a–n)
(Continued)
Nature
of
Calcd. Found crystals
% Nitrogen
Compound
no.
Yielda
%
Molecular
formula
M.P.b
◦C
Ar
4g
65 C20H17BrN4O3S 246–248 11.17 11.00 Reddish
orange
crystals
4h
4i
65 C23H16BrN3O3S 250–252 8.50
68 C20H16BrN3O4S 140–144 8.86
67 C19H14BrN3O4S 212–214 9.13
8.34 Yellow
crystals
8.65 Yellow
powder
4j
9.01 Off-white
crystals
4k
4l
72 C19H14BrN3O4S 222–224 9.13
9.01 Light
yellow
crystals
65 C18H11BrN4O4S 238–240 12.20 12.16 Yellow
crystals
4m
61 C21H18BrN3O5S 212–214 8.33
8.25 Yellow
crystals
4n
58 C18H14BrN3O3S 164–166 9.77
9.63 White
crystals
aYields are on an isolated basis.
bAll compounds are recrystallized in methanol/dimethyl formamide.

One Step Synthesis of Triazols
1977
TABLE II Anticonvulsant Activity Data of 2-(2-Bromo-5-
methoxyphenyl)-5-(3-arylidene)-1,3-thiazolo[3,2-b]-1,2,4-
triazol-6-(5H )-one (4e, 4i, 4f, 4l, 4n)
Duration of
seizure
mean SEM Mortality
Dose
(mg/kg)
Latency
Mean SEM
Group
Drug
1
2
3
4
5
6
7
Diazepam
4
4
4
4
4
4
3598.3 3.6046
0
No
Yes
Yes
No
Yes
No
4e
4f
4i
4l
4n
131 1.7016 258 0.4719
95 0.4719
180 0.9438
95.3 0.5449 278 0.9421
98 0.2724 27 0.4719
94 0.5449 259 0.7209
94 0.4719
25 0.4719
2% gum acacia 0.1 mL/10 g
(Control)
Yes
N = 3 in each group, p < 0.05.
respectively. Because as a correct correlation between structure and
activity is not clear at present, further studies have to be carried out
to establish the proper structure-activity relationship. Since all our in-
ference is based only on a screening test, further investigations using
larger samples have to be done to obtain conclusive data.
EXPERIMENTAL
Melting points were taken in open capillary tubes and were uncor-
rected. The purity of compounds was confirmed by TLC using Merck
silica gel 60 F254 coated aluminium plates. IR spectra were recorded on
Shimadzu-FTIR Infrared spectrometer in KBr (νmax in cm−1). 1H NMR
spectra were recorded in CDCl3 and in DMSO-d6 on a Varian (300 MHz)
spectrometer using TMS as internal standard, and 13C NMR spectra
were recorded in CDCl3 and in DMSO d6 on a Varian (75 MHz) spec-
trometer. FABMS spectra were recorded on a JEOL SX 102/DA-6000
mass spectrometer using argon/xenon (6 kv, 10 mA) as the FAB gas.
2-bromo-5-methoxybenzohydrazide was prepared from methyl 2-
bromo-5-methoxybenzoate13 by treating it with hydrazine hydrate in
methanol; m.p. 172–174◦C. 1H NMR (300 MHz)-δ 3.79 (s, 3H, –OCH3),
δ 6.84 (dd(J=8.8), 1H, Ar-H), δ 6.95 (d(J=2.96), 1H, Ar-H), δ 7.45 (d(J=8.8)
1H, Ar-H), δ 9.26 (bs, 1H, -NH).
,
The Synthesis of 1-(2-Bromo-5-methoxybenzoyl)
Thiosemicarbazide (2)
2-Bromo-5-methoxybenzohydrazide (1) (50 g, 0.204 mol), potassium
thiocyanate (25 g, 0.267 mol), and 40 mL of conc. HCl in 400 mL of

1978
K. K. Vijaya Raj and B. Narayana
water was refluxed for 4 h. A white solid appeared on cooling and was
filtered and dried Yield 51.2 g (74.4%); m.p. 190–192◦C. IR (KBr, cm−1):
3280 (NH), 1670 (CONH), 1360 (C S).
The Synthesis of 5-(2-Bromo-5-methoxyphenyl)-4 H-1,
2,4-triazole-3-thiol (3)
1-(2-Bromo-5-methoxybenzoyl)-thiosemicarbazide (50 g, 0.164 mol) was
refluxed with 500 mL of 5% sodium hydroxide solution for 4 h and was
cooled and filtered. The clear solution was then acidified with conc. HCl
to pH 5–6. The solid obtained was filtered and recrystallized (methanol)
to give white crystals. Yield, 42 g (89.3%), m.p. > 250; IR (KBr, cm−1):
1
2575 (SH), 1605 (C N), 1325 (C S); H NMR (300 MHz,)- δ 3.82 (s,
3H, -OCH3), δ 7.07 (dd(J=6.6), 1H, Ar-H), δ 7.23 (d(J=2.28), 1H, Ar-H), δ
7.68 (d(J=6.6), 1H, Ar-H), δ 13.66 (s, 1H, -SH), 13.75 (s, 1H,-NH); MS-
m/z 288 (90%,M+2), m/z 286 (80%, M+), m/z 254 (10%, M-SH), m/z
176(40%,C8H6N3S),m/z 154(100%,C6H3 Br).
The Synthesis of 2-(2-Bromo-5-Methoxyphenyl)-5-(3-
Arylidene)-1,3-Thiazolo[3,2-b]-1,2,4- triazol-6-(5H)-
one(4a–n)
5-(2-Bromo-5-methoxyphenyl)-4H-1,2,4-triazole-3-thiol (1) (0.003 mol),
mono chloroacetic acid (0.045 mol), aromatic aldehyde (0.003 mol), and
sodium acetate (0.045 mol) in a mixture of 15 mL acetic anhydride
and 30 mL of acetic acid was refluxed for 8 h. The reaction mixture
was cooled, and the solid separated was filtered and recrystallized from
methanol. All products were isolated in a 58–72% yield.
4a. 2-(2-Bromo-5-methoxyphenyl)-5-(3-methylbenzylidene)
[1,3]thiazolo[3,2-b]-1,2,4-triazol-6(5H)-one
1H NMR (300 MHz)- δ 2.35 (s, 3H, -CH3), δ 3.83 (s, 3H, -OCH3), δ
6.91 (dd(J=6.63), 1H, Ar-H),δ 7.25 (s, 1H, Ar-H), δ 7.31 (d(J=6.45), 1H, Ar-
H), 7.47 (d(J=2.31), 1H, Ar-H), δ 7.60 (d(J=6.63), 1H, Ar-H), δ 7.67 (dd(J=6.48),
2H, Ar-H), 8.24(s, 1H, CH); MS: m/z 474 (80%, M+ 2Na), m/z 472 (75%,
M-2+2Na), m/z 429 (20%,M+), m/z 431 (20%, M+2).
4c. 2-(2-Bromo-5-methoxyphenyl)-5-(2,3,5-
trichlorobenzylidene)[1,3]thiazolo[3,2-b]- 1,2,4-triazol-6(5H)-
one
IR (KBr, cm−1)- 3059 and 3009 (-CH), 1735 (C O), 1575 (C N),
1
735.25 and 700.85 (Ar-Cl); H NMR (300MHz)- δ 3.80(s, 3H, -OCH3),
δ 6.91(dd(J=8.94), 1H, Ar-H), δ 7.44 (s, 1H, Ar-H), δ 7.50–7.62 (m, 2H,

One Step Synthesis of Triazols
1979
Ar-H), δ 7.67(dd(J=4.91), 1H, Ar-H),8.10 (s, 1H, CH); MS: m/z 552 (80%,
M+Cl), m/z 550 (90%, M-2+Cl), m/z 518 (55%, M+), m/z 476 (30%, M-2).
4e. 2-(2-Bromo-5-methoxyphenyl)-5-(4-fluorobenzylidene)
[1,3]thiazolo[3,2-b]-1,2,4-triazol-6-(5H)-one
IR (KBr, cm−1)- 3074.8 and 2837.8 ( CH), 1742.5 (C O),1570.2 and
1514.8 (C N), 1233.9 (Ar-F); 1H NMR (300MHz)-δ 3.84 (s, 1H, –OCH3),
δ 6.9 (dd(J=8.7), 1H, Ar-H), δ 7.47(d(J=3.0), 1H, Ar-H), δ 7.54 (d(J=8.7), 1H,
Ar-H), δ 7.65 (dd(J=8.7), 2H, Ar-H), δ 7.25 (m, 2H, Ar-H), δ 8.21(s, 1H,
2
CH);13C NMR (75 Hz, ppm):55.51, 112.53, 116.82, 117.0 (d, JC−F
3
= 22.5), 118.55, 123.67, 128.87, 131.00, 132.98 (d, JC−F = 8.25),
135.12,139.49, 156.09, 158.87, 159.18, 164.53 (d, 1JC−F = 87.8),169.60.
2
3
DEPT: 55.66, 116.82, 117.0 (d, JC−F = 22.5), 118.57,133.01 (d, JC−F
= 9.75), 135.07, 139.62; MS: m/z 432 (60%, M+), m/z 434 (70%, M+2H).
4f. 2-(2-Bromo-5-methoxyphenyl)-5-(4-methylbenzylidene)
[1,3]thiazolo[3,2-b]-1,2,4-triazol-6(5H)-one
IR (KBr, cm−1)- 3065.94 and 2939.53 ( CH), 1746.32 (C O),1598.0
1
and 1512.43 (C N);
H NMR (300MHz)- δ 2.43 (s, 3H,-CH3) δ
3.84 (s, 1H, –OCH3), δ 6.89(dd(J=8.7), 1H, Ar-H), δ 7.34 (d(J=7.8)
,
1H, Ar-H), δ7.47(d(J=3.0),1H, Ar-H), δ 7.52 (d(J=8.4), 2H, Ar-H), δ
7.58 (d(J=9.0), 2H, Ar-H), δ 8.21(s,1H, CH); 13C NMR (75 Hz, ppm):
21.73, 55.66, 112.40, 116.55,118.5, 122.35, 129.62, 130.35 (2C), 130.95
(2C)135.03,141.14,143.08,156.39, 158.69 (2C), 159.4, 169.33; DEPT:
21.75, 55.66, 116.53,118.52, 130.35, 130.92, 135.05, 141.15; MS: m/z
432 (60%, M+4H), m/z 431 (20%, M +3H).
4k. 2-(2-Bromo-5-methoxyphenyl)-5-(4-hydroxy-3-
methoxybenzylidene)[1,3]thiazolo
[3,2-b]-1,2,4-triazol-6(5H)-one
IR (KBr, cm−1)- 3068 and 2940 ( CH), 1746.0 (C O), 1596.0 and 1512.0
(C N); 1H NMR (300MHz)- δ 2.35(s, 1H, -OH), δ 3.84 (s, 12H,–OCH3),
δ 3.92 (s, 12H, –OCH3), δ 6.91 (dd(J=8.8), 1H, Ar-H), δ 7.19 (d(J=3.86), 1H,
Ar-H), δ 7.23(s, 1H, Ar-H), δ 7.25 (dd(J=7.0), 1H, Ar-H), δ 7.47(d(J=3.3), 1H,
Ar-H), δ 7.59 (d(J=8.8), 1H, Ar-H), δ 8.21 (s, 1H, CH).
4m. 2-(2-Bromo-5-methoxyphenyl)-5-(3,4,5-
trimethoxybenzylidene) [1,3]thiazolo
[3,2-b]-1,2,4-triazol-6(5H)-one
IR (KBr, cm−1)- 3065.94 and 2939.53 ( CH), 1746.32 (C O), 1598.0 and
1
1512.43 (C N); H NMR (300MHz)-δ 3.91 (s, 12H, –OCH3), δ 6.83 (s,

1980
K. K. Vijaya Raj and B. Narayana
2H, Ar-H), δ 7.34 (dd(J=7.8), 1H, Ar-H), δ 7.45(d(J=3.0), 1H, Ar-H), δ 7.56
(d(J=8.7), 1H, Ar-H), δ 8.14 (s, 1H, CH);13C NMR (75 Hz, ppm): 55.65,
56.27(2C), 61.11, 108.12 (2C), 112.38, 116.56, 118.50,122.45, 127.60,
130.82, 135.08, 141.06, 141.58, 156.39, 153.75 (2C),156.21, 158.69,
159.15, 169.37; DEPT: 55.66, 55.27(2C), 61.11, 108.11, 116.55, 118.50,
135.08, 141.06; MS: m/z 504 (90%, M+), m/z 505 (100%, M+H), m/z 506
(100%, M+2H), m/z 336 (50%, M-(3xOCH3+Br)).
CONCLUSION
A new series of 2-(2-bromo-5-methoxyphenyl)-5-(3-arylidene)-1,3-
thiazolo[3,2-b]-1,2, 4-triazol-6-(5H)-ones were synthesized in a multi-
component one pot synthesis. A few of the synthesized compounds were
screened for their anticonvulsant activity in vitro. Among tested com-
pounds 4e, 4f, 4i, 4l, and 4n, compounds having an anticonvulsant
action at a dose of 4 mg/kg were 4i and 4n. These could become can-
didates for further study. As a correct correlation between structure
and activity is not clear at present, more studies have to be carried out
further to establish the proper structure-activity relationship.
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