Synthesis and characterization of novel pyridine associated 1,2,4-triazolo-1,3,4-thiadiazines

Article abstract of DOI:10.14233/ajchem.2016.19795

A series of novel 3-(1-methyl-1H-pyrazol-4-yl)-6-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadaizine and its derivatives (8a-f) were synthesized by using 1-methyl-1H-pyrazole-4-carboxylic acid (3) as starting material and by involving 1-methyl-1H-pyrazole-

Full text of DOI:10.14233/ajchem.2016.19795

Asian Journal of Chemistry; Vol. 28, No. 8 (2016), 1708-1712
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2016.19795
Synthesis and Characterization of Novel Pyridine Associated 1,2,4-Triazolo-1,3,4-thiadiazines
1
2
1,*
SUDUGU RAMAKRISHNA REDDY , CH. VENKATA RAMANA REDDY and B. SATYANARAYANA
1
2
Department of Chemistry, University College of Engineering, Osmania University, Hyderabad-500 007, India
Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad-500 085, India
Corresponding author: E-mail: ramkrishnajntu@gmail.com
Received: 24 December 2015; Accepted: 25 January 2016;
*
Published online: 30 April 2016;
AJC-17877
A series of novel 3-(1-methyl-1H-pyrazol-4-yl)-6-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadaizine and its derivatives (8a-f) were
synthesized by using 1-methyl-1H-pyrazole-4-carboxylic acid (3) as starting material and by involving 1-methyl-1H-pyrazole-4-carboxylic
acid ethyl ester (4), 1-methyl-1H-pyrazole-4-carboxylic acid hydrazide (5), 5-(1-methyl-1H-pyrazol-4-yl)-[1,3,4]oxadiazole-2-thiol (6)
and 4-amino-5-(1-methyl-1H-pyrazol-4-yl)-4H-[1,2,4]triazole-3-thiol (7) as intermediate.
Keywords: Pyrazoles, Thiadiazoles, Heterocyclic chemistry.
O
INTRODUCTION
O
S
N
O
N
S
O
Several five membered aromatic systems having three
N
O
N
NH2
heteroatoms at symmetrical positions such as thiadiazoles have
been studied extensively owing to their interesting pharma-
cological activities. Thiadiazole is a versatile moiety that
exhibits a wide variety of biological activities. Thiadiazole
moiety acts as “hydrogen binding domain” and “two-electron
donor system”. It also acts as a constrained pharmacophore.
Many drugs containing thiadiazole nucleus are available in
the market such as acetazolamide (1), methazolamide (2), etc.
Thiadiazole can act as the bio-isosteric replacement of
thiazole moiety. So it acts like third and fourth generation
cephalosporins, hence can be used in antibiotic preparations.
Thiadiazole is a 5-membered ring system containing two
nitrogen and one sulphur atom. They occured in nature in four
isomeric forms viz., 1,2,3-thiadiazole; 1,2,5-thiadiazole; 1,2,4-
thiadiazole and 1,3,4-thiadiazole. The 1,3,4-thiadiazole isomer
of thiadiazole series and its dihydro derivatives provide a bulk
of literature on thiadiazole. A glance at the standard reference
work shows that more work has been carried out on the 1,3,4-
thiadiazole than all other isomers combined. Members of this
ring system have found their way into such diverse application
as pharmaceuticals, oxidation inhibitors, cyanine dyes and metal
complex agents. The literature showed that thiadiazole nuclei
have antimicrobial [1-8], antiinflammatory [9-14], anticancer
S
NH2
N
H
S
O
N
1
2
Chemical properties of 1,3,4-thiadiazole have been
reviewed in the last few years. However, the usefulness of 1,3,4-
thiadiazole as a privileged system in medicinal chemistry has
prompted the advances on the therapeutic potential of this
system. A brief summary of the medicinal chemistry of 1,3,4-
thiadiazole system and highlights some examples of 1,3,4-
thiadiazole-containing drug substances in the current literature.
A survey of representative literature procedures for the pre-
paration of 1,3,4-thiadiazole is presented in by generalized
synthetic methods. The progress achieved in the synthesis of
heterocyclic compounds with biological potential is due to
improvement of the methodological study of tested substances
too. It is known that many 1,3,4-thiadiazole and derivatives
have biological activity, with their antibacterial [34-36], anti-
mycobacterial [37,38], antimycotic [39], antifungal [40,41],
antidepression [42] and cardiotonic [43] action being notable.
Recent research has also established for these heterocycles as
analgesic [44] and anti-inflammatory [45,46] activity. Taking
these data into account, in the present study, some new
substituted 5-([1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)-1,3-
benzoxazoles have been synthesized.
[
15-19], anticonvulsant [20-24], antidepressant [25,26], anti-
oxidant, radio protective [27-29] and antileishmanial activities
30,31], carbonic anhydrase inhibitors [32,33].
[

Vol. 28, No. 8 (2016)
Synthesis and Characterization of Novel Pyridine Associated 1,2,4-Triazolo-1,3,4-thiadiazines 1709
Five membered heterocyclic compounds show various
types of biological activity among them 1,3,4-thiadiazoles are
associated with diverse biological activity probably virtue of
ethyl ester (4) (0.01 mol) and hydrazine hydrate (0.025 mol)
in ethanol (20 mL) was refluxed for 6 h. After completion of
the reaction (observed by TLC), the mixture was cooled to
room temperature and filtered. The crude product was
recrystallized from ethanol to give 1H-indole-4-carboxylic acid
hydrazide (5) in pure form.
5-(1-Methyl-1H-pyrazol-4-yl)-[1,3,4]oxadiazole-2-thiol
(6): A mixture of 1-methyl-1H-pyrazole-4-carboxylic acid
hydrazide (5) (0.01 mol), potassium hydroxide (0.02 mol) and
carbon disulfide (0.03 mol) in ethanol (100 mL) was heated
under reflux with stirring for 12 h. After accomplishment of
the reaction (watched by TLC), the solvent was distilled in
vacuo, the residual mass was poured over crushed ice and
neutralized the alkaline solution with 10 % hydrochloric acid.
The precipitated crude product was filtered, washed with water,
dried and recrystallized from ethanol to get the pure compound
5-(1H-indole-4-yl)-[1,3,4]oxadiazole-2-thiol (6).
4-Amino-5-(1-methyl-1H-pyrazol-4-yl)-4H-[1,2,4]-
triazole-3-thiol (7): To a warm solution of 5-(1-methyl-1H-
pyrazol-4-yl)-[1,3,4]oxadiazole-2-thiol (6) (0.01 mol) in ethanol
(20 mL), 80 % hydrazine hydrate (0.03 mol) was added drop
wise and the reaction mixture was heated under reflux for 8 h.
After achievement of the reaction (examined by TLC), the
solvent was distilled off in vacuo, cooled and the solid separated
were filtered, washed with cold ethanol and recrystallized from
chloroform to give pure compound 4-amino-5-(1H-indol-4-
yl)-4H-[1,2,4]-triazole-3-thiol (7).
–
N=C–S– grouping. Therapeutic importance of these rings
prompted us to develop selective molecules in which substi-
tuent could be arranged in a pharmacophoric pattern to display
higher pharmacological activities. Thiadiazoles have occupied
an important place in drug industry e.g., 1,3,4-thiadiazoles
have wide applications in many fields. Earliest uses were
in the pharmaceutical area as an antibacterial with known
sulphonamides drugs. Some of other uses are antitumor, anti-
inflammatory, pesticides, dyes, lubricants, and analytical
reagents [47]. 1,3,4-Thiadiazole derivatives posses interesting
biological activity probably conferred to them due to strong
aromaticity of the ring system which leads to great in vivo
stability and generally, a lack of toxicity for higher vertebrates,
including humans when diverse functional group that interact
with biological receptor are attached to aromatic ring [48].
Approach to practice of medicinal chemistry has developed
from an empirical one involving synthesis of new organic
compounds based on modification of chemical compounds of
known biological activities could be better explored. It is well
established that slight alteration in the structure of certain
compounds are able to bring drastic changes to yield better
drug with less toxicity to the host it observed that chemical
modification not only alters physico-chemical properties but
also pharmacological properties [49,50].
Based on these observations and inspired by the biological
profile of pyrazoles, 1,3,4-triazoles and 1,3,4-thiadaizines, we
have introduced 1,3,4-triazoles and 1,3,4-thiadaizine moieties
into the pyrazole ring which leads to the synthesis of the title
compounds with three active pharmacophores in a single
molecular frame work for the intensified biological activities.
Thus we have designed and synthesized a series of novel 3-
3-(1-Methyl-1H-pyrazol-4-yl)-6-phenyl-7H-[1,2,4]-
triazolo[3,4-b][1,3,4]thiadaizines (8a-f): A mixture of 4-
amino-5-(1-methyl-1H-pyrazol-4-yl)-4H-[1,2,4]triazole-3-
thiol (7) (0.01 mol) and corresponding phenacyl bromide (0.02
mol) in absolute ethanol (20 mL) was refluxed for 10-12 h.
After completion of the reaction (monitored by TLC), the reac-
tion mixture was concentrated and cooled to room temperature,
and the remaining solvent was removed under reduced
pressure, then diethyl ether (25 mL) was added and the reaction
mixture was left at 0 °C for overnight. The precipitated solid
was filtered off. The crude product thus obtained was purified
by column chromatography on silica gel with hexane-ethyl
acetate as eluent to afford pure 3-(1H-indole-4-yl)-6-aryl-7H-
(1-methyl-1H-pyrazol-4-yl)-6-phenyl-7H-[1,2,4]triazolo[3,4-
b][1,3,4]thiadaizine and its derivatives (8a-f).
EXPERIMENTAL
All the reagents and solvents were used as purchased
without further purification. Melting points were determined
on a Fisher–Johns melting point apparatus and are uncorrected.
IR spectra were obtained on a Perkin-Elmer BX serried FTIR
[
1,2,4]-triazolo-[3,4-b][1,3,4]-thiadiazines (8a-f).
Physical and spectral data
5
000 spectrometer using KBr pellet. NMR spectra were recorded
1-Methyl-1H-pyrazole-4-carboxylic acid ethyl ester
(4):Yellow solid; yield 78 %; m.p. 185-187 °C; IR (KBr, νmax,
1
on aVarian 300 MHz spectrometer for H NMR and 100 MHz
13
-1
for C NMR. The chemical shifts were reported as ppm down
field using TMS as an internal standard. Mass spectra were
recorded on a VG-Micromass 7070H spectrometer operating
at 70 eV.
cm ): 3024 (=C-H), 2962 (C-H, CH
3
), 1742 (C=O), 1699
(C=N), 1588 (C=C), 1135 (C-O); H NMR (CDCl ) δ: 7.52 (s,
1H, pyrazole H), 7.42 (s, 1H, pyrazole H), 4.00 (q, 2H, J = 5.6
Hz, CH ), 3.24 (s, 3H, N-CH ), 1.24 (t, 3H, J = 5.6 Hz, CH );
C NMR (CDCl ) δ: 166.5, 136.4, 131.2, 106.8, 61.5, 41.4,
14.7; MS m/z: 154 (M ); Elemental analysis calculated for
: C-54.54, H-6.54, N-18.17. Found: C-52.98, H-
6.32, N-17.84.
1-Methyl-1H-pyrazole-4-carboxylic acid hydrazide
1
3
2
3
3
1
3
1
-Methyl-1H-pyrazole-4-carboxylic acid ethyl ester
4): To the solution of 1-methyl-1H-pyrazole-4-carboxylic acid
3) (0.01 mol) in absolute ethyl alcohol (15 ml), conc. H SO
2 mL) was added. The mixture was refluxed for 5 h. After
3
+
(
(
(
2
4
C
7
H
10
N O
2 2
completion of the reaction (monitored by TLC), the solvent
was removed under reduced pressure and the obtained residue
was recrystallized with petroleum ether to get pure 1H-indole-
(5): Brown solid; yield 81 %; m.p. 166-168 °C; IR (KBr, νmax
,
-1
cm ): 3318 (N-H, NH
(C-H, CH
(CDCl
(s, 1H, pyrazole H), 5.30 (s, 2H, NH
2
), 3218 (N-H, NH), 3047 (=C-H), 2984
), 1674 (C=O), 1645 (C=N), 1548 (C=C); H NMR
1
4
-carboxylic acid ethyl ester (4).
-Methyl-1H-pyrazole-4-carboxylic acid hydrazide
5): A mixture of 1-methyl-1H-pyrazole-4-carboxylic acid
3
1
3
) δ: 11.06 (s, 1H, NH), 7.58 (s, 1H, pyrazole H), 7.48
), 3.27 (s, 3H, N-CH );
(
2
3

1
710 Reddy et al.
Asian J. Chem.
1
3
-1
C NMR (CDCl
3
) δ: 167.4, 136.2, 128.7, 103.5, 47.6; MS
O: C-
solid; yield 74 %; m.p. 160-162 °C; IR (KBr, νmax, cm ): 3025
+
m/z: 140 (M ); Elemental analysis calculated for C
4
H N
5 8 4
(Ar-H), 2948 (C-H, CH
3
), 1646 (C=N), 1551 (C=C), 676 (C-
) δ: 7.69 (d, 2H, J = 7.4 Hz, Ar-H), 7.54
(s, 1H, pyrazole H), 7.47 (s, 1H, pyrazole H), 7.32 (d, 2H, J =
1
2.85, H-5.75, N-39.98. Found: C-41.23, H-5.56, N-38.28.
-(1-Methyl-1H-pyrazol-4-yl)-[1,3,4]oxadiazole-2-thiol
6): Pale yellow solid; yield 72%; m.p. 148-150 °C; IR (KBr,
S); H NMR (CDCl
3
5
1
3
(
ν
(
7.4 Hz, Ar-H), 3.41 (s, 3H, N-CH
NMR (CDCl ) δ: 160.6, 144.8, 142.6, 135.8, 130.2, 128.6,
126.7, 125.4 (2), 123.7 (2), 108.6, 45.7, 38.3; MS m/z: 375
3
), 1.92 (s, 2H, CH
2
); C
-1
max, cm ): 3028 (=C-H), 2978 (C-H, CH
3
), 2610 (S-H), 1648
) δ: 7.51 (s,
H, pyrazole H), 7.42 (s, 1H, pyrazole H), 3.81 (s, 1H, SH),
3
1
C=N), 1559 (C=C), 1155 (C-O); H NMR (CDCl
3
+
1
3
1
(M ); Elemental analysis calculated for C14
H
11
N SBr: C-44.81,
H-2.95, Br-21.29, N-22.40, S-8.55. Found: C-43.12, H-2.84,
Br-20.26, N-21.58, S-8.12.
6-(4-Nitro-phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-7H-
[1,2,4]triazolo[3,4-b][1,3,4]thiadaizine (8e): White solid;
yield 76 %; m.p. 144.146 °C; IR (KBr, νmax, cm ): 3022 (Ar-
H), 2938 (C-H, CH ), 1646 (C=N), 1552 (C=C), 1530 (N=O),
688 (C-S); H NMR (CDCl ) δ: 7.71 (d, 2H, J = 7.3 Hz, Ar-
H), 7.58 (s, 1H, pyrazole H), 7.45 (s, 1H, pyrazole H), 7.36
(d, 2H, J = 7.3 Hz, Ar-H), 3.40 (s, 3H, NCH ), 1.74 (s, 2H,
) δ: 166.3, 149.8, 147.5, 141.2, 136.8,
133.1, 129.7, 126.2 (2), 121.7 (2), 109.4, 48.7, 38.3; MS m/z:
6
13
.31 (s, 3H, N-CH
32.0, 108.7, 44.2; MS m/z: 182 (M ); Elemental analysis
OS: C-39.55, H-3.32, N-30.75, S-17.60.
Found: C-38.54, H-3.21, N-29.45, S-16.98.
-Amino-5-(1-methyl-1H-pyrazol-4-yl)-4H-[1,2,4]-
triazole-3-thiol (7): White solid; yield 70 %; m.p. 161-163 °C;
3
); C NMR (CDCl
3
) δ: 152.3, 148.5, 138.4,
+
calculated for C
6
H
N
6 4
-1
4
3
-1
1
IR (KBr, νmax, cm ): 3248 (N-H), 3018 (=C-H), 2968 (C-H, CH
2
(
3
),
3
1
648 (S-H), 1662 (C=N), 1552 (C=C); H NMR (CDCl
s, 1H, pyrazole H), 7.44 (s, 1H, pyrazole H), 3.85 (s, 2H, NH
3
) δ: 7.61
2
),
) δ:
3
13
13
3
.65 (s, 1H, SH), 3.31 (s, 3H, N-CH
51.5, 147.3, 135.2, 131.0, 107.8, 43.2; MS m/z: 196 (M );
S: C-36.72, H-4.11, N-
2.83, S-16.34. Found: C-35.23, H-4.05, N-41.58, S-15.98.
-(1-Methyl-1H-pyrazol-4-yl)-6-phenyl-7H-[1,2,4]-
triazolo[3,4-b][1,3,4]thiadaizine (8a): Pink solid; yield 70
3
); C NMR (CDCl
3
CH
2
); C NMR (CDCl
3
+
1
+
Elemental analysis calculated for C
H N
6 8 6
341 (M ); Elemental analysis calculated for C14
H
11
N
7
O S: C-
2
4
49.26, H-3.25, N-28.72, S-9.39. Found: C-48.26, H-3.12, N-
27.45, S-9.05.
6-(4-Hydroxy-phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-
7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadaizine (8f):Yellow solid;
3
-1
%
(
(
7
; m.p. 135-137 °C; IR (KBr, νmax, cm ): 3018 (Ar-H), 2965
1
-1
C-H, CH
CDCl ) δ: 7.74-7.41 (m, 5H, Ar-H), 7.63 (s, 1H, pyrazole H),
.51 (s, 1H, pyrazole H), 3.33 (s, 3H, N-CH ), 1.86 (s, 2H,
) δ: 164.2, 147.1, 145.6, 138.4, 132.4,
31.0, 129.4, 127.4 (2), 126.2 (2), 104.8, 42.6, 35.1; MS m/z:
96 (M ); Elemental analysis calculated for C14
3
), 1638 (C=N), 1548 (C=C), 680 (C-S); H NMR
yield 78 %; m.p. 150-152 °C; IR (KBr, νmax, cm ): 3412 (O-
3
H), 3024 (Ar-H), 2946 (C-H, CH
3
), 1652 (C=N), 1547 (C=C),
) δ: 7.64 (d, 2H, J = 7.2 Hz, Ar-
H), 7.58 (s, 1H, pyrazole H), 7.47 (s, 1H, pyrazole H), 7.31
(d, 2H, J = 7.2 Hz, Ar-H), 3.41 (s, 3H, NCH ), 1.74 (s, 2H,
) δ: 166.3, 145.3, 143.7, 140.2, 136.4,
133.2, 130.4, 129.7 (2), 125.2 (2), 108.1, 48.7, 36.2; MS m/z:
1
3
675 (C-S); H NMR (CDCl
3
13
CH
2
); C NMR (CDCl
3
1
2
5
2
3
+
13
H
12
6
N S: C-
CH
2
); C NMR (CDCl
3
6.74, H-4.08, N-28.36, S-10.82. Found: C-55.36, H-3.98, N-
7.85, S-10.12.
+
312 (M ); Elemental analysis calculated for C14
H
12
6
N OS: C-
6
-(4-Methoxy-phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-
53.83, H-3.87, N-26.91, S-10.27. Found: C-51.58, H-3.65, N-
25.87, S-9.74.
7
H-[1,2,4]triazolo[3,4-b][1,3,4]thiadaizine (8b): Pale yellow
solid; yield 68 %; m.p. 122-124 °C; IR (KBr, νmax, cm ): 3025
Ar-H), 2948 (C-H, CH
C-O), 688 (C-S); H NMR (CDCl ) δ: 7.78 (d, 2H, J = 7.0
Hz, Ar-H), 7.59 (s, 1H, pyrazole H), 7.48 (s, 1H, pyrazole H),
.32 (d, 2H, J = 7.0 Hz, Ar-H), 3.39 (s, 3H, N-CH
H, OCH
-1
RESULTS AND DISCUSSION
(
(
3
), 1644 (C=N), 1568 (C=C), 1142
1
3
The initial intermediate, 1-methyl-1H-pyrazole-4-
carboxylic acid ethyl ester (4) has been prepared through
esterification by boiling of a mixture of 1-methyl-1H-pyrazole-
4-carboxylic acid (3) and ethanol in presence of sulfuric acid
for 5 h. Formation of the compound 4 was confirmed by its
spectral analysis. The IR spectrum of compound 4 showed
7
3
1
1
3
), 2.85 (s,
) δ: 164.2,
13
3
), 1.78 (s, 2H, CH
2
); C NMR (CDCl
3
62.3, 146.8, 143.1, 135.8, 132.5, 130.4, 126.8, 125.7 (2),
23.5 (2), 106.2, 44.8, 38.1; MS m/z: 326 (M ); Elemental
+
analysis calculated for C15
S-9.82. Found: C-53.98, H-4.32, N-24.84, S-9.24.
-(4-Chloro-phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-
H-[1,2,4]triazolo[3,4-b][1,3,4]thiadaizine (8c): Brown
H
14
N
6
OS: C-55.20, H-4.32, N-25.75,
absorption bands at 3024 (=C-H), 2962 (C-H, CH ), 1742
3
-1
(C=O), 1699 (C=N), 1588 (C=C) and 1135 (C-O) cm . The
proton NMR spectrum of intermediate 4 showed a signal at δ
7.52 ppm as a singlet integrating for one proton is assigned to
pyrazole H. The other pyrazole H appeared as singlet for one
proton at δ 7.42 ppm. The resonance frequency at δ 4.00 ppm
6
7
-1
solid; yield 770 %; m.p. 150-152 °C; IR (KBr, νmax, cm ):
3
6
032 (Ar-H), 2955 (C-H, CH
3
), 1640 (C=N), 1554 (C=C),
1
77 (C-S); H NMR (CDCl
3
) δ: 7.69 (d, 2H, J = 7.2 Hz, Ar-
for two protons as quartet is allotted to CH
signal performed at δ 3.24 ppm for three protons corresponding
to N-CH group. The signal at δ 1.24 ppm as triplet integrating
for three protons is assigned to the CH
2
group. The singlet
H), 7.58 (s, 1H, pyrazole H), 7.48 (s, 1H, pyrazole H), 7.33
(
d, 2H, J = 7.2 Hz, Ar-H), 3.41 (s, 3H, N-CH
3
), 1.98 (s, 2H,
3
13
13
CH
2
3
); C NMR (CDCl ) δ: 166.7, 148.4, 146.2, 139.4, 133.1,
3
group. The C NMR
1
3
5
30.4, 128.4, 125.6 (2), 123.7 (2), 109.4, 46.7, 38.1; MS m/z:
spectrum of this compound showed the signals at different δ-
chemical shifts such as 166.5, 136.4, 131.2, 106.8, 61.5, 41.4
and 14.7 ppm. Mass spectrum showed molecular ion peak at
m/z 154 (M ), thus confirming the structure of compound 4.
The compound 4 was reacted with hydrazine hydrate in
absolute ethyl alcohol under reflux temperature for 6 h to get
+
30 (M ); Elemental analysis calculated for C14
H
11
6
N SCl: C-
0.83, H-3.35, Cl-10.72, N-25.41, S-9.69. Found: C-49.26,
+
H-3.28, Cl-9.97, N-24.87, S-9.12.
-(4-Bromo-phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-
H-[1,2,4]triazolo[3,4-b][1,3,4]thiadaizine (8d): Yellow
6
7

Vol. 28, No. 8 (2016)
Synthesis and Characterization of Novel Pyridine Associated 1,2,4-Triazolo-1,3,4-thiadiazines 1711
O
O
O
N
N
OH
O
NH
O
SH
SH
(i)
(ii)
(iii)
N
N
N
N
NH2
N
N
N
N
N
N
4
5
6
(iv)
3
N
N
N
N
N
S
N
(v)
N
N
NH2
N
8
a-f
7
R
8
: Ar = a) H; b) 4–OCH
, reflux, 5 h; (ii) NH –NH ·H O, EtOH, reflux, 6 h; (iii) CS
EtOH, reflux, 8 h; (v) ArCOCH Br, EtOH, reflux, 10-12 h
3
; c) 4–Cl; d) 4–Br; e) 4–NO
2
; f) 4–OH
Scheme-I: (i) EtOH, H
2
SO
4
2
2
2
2
, KOH, EtOH, reflux, 12 h; (iv) NH
2
–NH
2
·H O,
2
2
the next intermediate, 1-methyl-1H-pyrazole-4-carboxylic acid
hydrazide (5). Formation of the compound 5 is confirmed by
IR, H NMR, C NMR and mass spectral analysis. The IR
Further the compound 6 when reacted with hydrazine
hydrate in ethanol at reflux for 8 h resulted final intermediate,
4-amino-5-(1-methyl-1H-pyrazol-4-yl)-4H-[1,2,4]triazole-3-
1
13
1
13
spectrum of compound 5 showed the bands at 3318 (N-H,
thiol (7). Compound 7 is identified by IR, H NMR, C NMR
and mass spectral examination. The IR spectrum of compound
7 showed the bands at 3248 (N-H), 3018 (=C-H), 2968 (C-H,
NH
2
), 3218 (N-H, NH), 3047 (=C-H), 2984 (C-H, CH ), 1674
3
-1
1
(
C=O), 1645 (C=N) and 1548 (C=C) cm . In the H NMR
-1
1
spectrum, the precessional frequency at δ 11.06 ppm as singlet
for one proton is associated with NH group. The singlet signal
for one proton of pyrazole CH group linked with δ 7.58 ppm.
The resonance frequency at δ 7.48 ppm as singlet for one
proton is related to another pyrazole CH group. Two protons
CH ), 2648 (S-H), 1662 (C=N) and 1552 (C=C) cm . In the H
3
NMR spectrum, the precessional frequency at δ 7.61 ppm as
singlet for one proton is associated with pyrazole CH group.
The resonance frequency at δ 7.44 ppm as singlet for one
proton is related to another pyrazole CH group. The δ-chemical
shift at 3.85 ppm as singlet for two protons is corresponding
of NH
2
group as singlet is appeared at δ 5.30 ppm. The δ-
chemical shift at 3.27 ppm as singlet for three protons is
to NH
2
group. The singlet signal for one proton of SH group
group as
13
corresponding to N-CH
3
group. The C NMR spectrum of
linked with δ 3.65 ppm. Three protons of N-CH
3
13
this compound exhibited the signals at various δ-chemical
shifts such as 167.4, 136.2, 128.7, 103.5 and 47.6 ppm. The
mass spectrum of the compound 5 displayed a molecular ion
peak at m/z 140 (M+).
The intermediate, 5-(1-methyl-1H-pyrazol-4-yl)-[1,3,4]-
oxadiazole-2-thiol (6) for the synthesis of title compounds
was prepared by the cyclization of compound 5 with carbon
disulphide in the presence of potassium hydroxide in ethanol
at reflux for 12 h followed by acidification. Emergence of the
compound 6 is established by its different spectral study. The
IR spectrum of compound 6 display the bands at 3028 (=C-
singlet are appeared at δ 3.31 ppm. The C NMR spectrum of
this compound showed the signals at various δ-chemical shifts
such as 151.5, 147.3, 135.2, 131.0, 107.8 and 43.2 ppm. The
mass spectrum of the compound 7 performed a molecular ion
+
peak at m/z 196 (M ).
Finally, the compound 7 has been condensed successively
with a variety of phenacyl bromides in ethyl alcohol under
reflux for 10-12 h to get the title compounds, 3-(1-methyl-
1H-pyrazol-4-yl)-6-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]-
thiadaizine and its derivatives (8a-f). Evolution of the com-
pound 8a is confirmed by IR, H NMR, C NMR and mass
spectral investigation. The IR spectrum of compound 8a exhi-
bited the bands at 3018 (Ar-H), 2965 (C-H, CH ), 1638 (C=N),
1548 (C=C) and 680 (C-S) cm . In the H NMR spectrum, the
only one multiplet signal of all five aromatic protons is
appeared on δ-scale between 7.74-7.41 ppm. The signal
appeared at δ 7.63 ppm as singlet for one proton connected
with pyrazole CH group. Another one proton of pyrazole CH
group as singlet is appeared at δ 7.51 ppm. The singlet signal
1
13
H), 2978 (C-H, CH ), 2610 (S-H), 1648 (C=N), 1559 (C=C)
3
-1
1
and 1155 (C-O) cm . In the H NMR spectrum, the singlet
signal for one proton of pyrazole CH group linked with δ 7.51
ppm. The precessional frequency at δ 7.42 ppm as singlet for
one proton is associated with another pyrazole CH group. One
proton of SH group as singlet is appeared at δ 3.81 ppm. The
resonance frequency at δ 3.31 ppm as singlet for three protons
3
-1
1
13
is related to the N-CH group. The C NMR spectrum of this
3
compound displayed the signals at various δ-chemical shifts
such as 152.3, 148.5, 138.4, 132.0, 108.7 and 44.2 ppm. The
mass spectrum of the compound 6 exhibited a molecular ion
for three protons of N-CH
resonance frequency at δ 1.86 ppm as singlet for two protons
3
group linked with δ 3.33 ppm. The
1
3
is related to CH
2
group. The C NMR spectrum of this
+
peak at m/z 182 (M ).
compound disclosed the signals at various δ-chemical shifts

1
712 Reddy et al.
Asian J. Chem.
2
4. V. Jatav, P. Mishra, S. Kashaw and J.P. Stables, Eur. J. Med. Chem., 43,
such as 164.2, 147.1, 145.6, 138.4, 132.4, 131.0, 129.4, 127.4
2), 126.2 (2), 104.8, 42.6 and 35.1 ppm. The mass spectrum
of the compound 8a showed a molecular ion peak at m/z 296
1
945 (2008).
(
2
2
5. M.Yusuf, R.A. Khan and B.Ahmed, Bioorg. Med. Chem., 16, 8029 (2008).
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+
(
(
M ). The chemical structures of the different com-pounds
8b-f) of this order are evaluated with same strategy. Further the
2
2
2
3
3
3
title compounds have been used to evaluate their antimicrobial
activity.
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