Syntheses of new unsymmetrical 2,5-disubstituted-1,3,4-oxadiazoles and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles bearing thieno[2,3-c]pyrazolo moiety

Article abstract of DOI:10.1002/jhet.1584

New series of (thieno[2,3-c]pyrazolo-5-yl)-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazoles 10a, 10b, 10c and (thieno[2,3-c]pyrazol-5-yl)-1,3,4-oxadiazol-3(2H) -yl)ethanones 6a, 6b, 6c has been synthesized from thieno[2,3-c]pyrazole-5- carbohydrazide 3 by multi

Full text of DOI:10.1002/jhet.1584

368
Syntheses of New Unsymmetrical 2,5-Disubstituted-1,3,4-oxadiazoles and
1,2,4-Triazolo[3,4-b]-1,3,4-thiadiazoles Bearing Thieno[2,3-c]pyrazolo
Moiety
Vol 51
Shivaraj P. Patil, Shrikant B. Kanawade, Dinesh C. Bhavsar, Prashant S. Nikam,
*
Sachin A. Gangurde, and Raghunath B. Toche
Organic Chemistry Research Center, Department of Chemistry, KTHM College,
University of Pune, Gangapur Road, Nashik 422002, M S, India
*
E-mail: raghunath_toche@rediffmail.com
Received June 27, 2011
DOI 10.1002/jhet.1584
Published online 13 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
O
N
N
R
O
N
S
N
Ph
6
O
NH2
HN
N
N
O
O
N
S
R
O
N
S
N
N
S
N
N
Ph
Ph
3
Ph
4
2
N
N
N
N
S
N
S
N
Ar
Ph
10
New series of (thieno[2,3-c]pyrazolo-5-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 10a–c and (thieno[2,3-c]
pyrazol-5-yl)-1,3,4-oxadiazol-3(2H)-yl)ethanones 6a–c has been synthesized from thieno[2,3-c]pyrazole-5-
carbohydrazide 3 by multistep reaction sequence. (5-Aryl-1,3,4-oxadiazol-2-yl)-1H-thieno[2,3-c]pyrazoles 4a–c
were also synthesized from thieno[2,3-c]pyrazole-5-carbohydrazide 3 by cyclization with various aromatic
carboxylic acids. The hydrazide 3 was obtained by reaction of thieno[2,3-c]pyrazole-5-carboxylate 2 with
hydrazine hydrate in good yield, and compound 2 was obtained by the reaction of 5-chloro-3-methyl-1-phenyl-
1H-pyrazole-4-carbaldehyde 1 and 2-ethyl thioglycolate in presence of sodium alcoholate in good yield.
J. Heterocyclic Chem., 51, 368 (2014).
INTRODUCTION
1,3,4-oxadiazoles as a scaffold in medicinal chemistry
has established this moiety as a member of privileged
structural class. 1,3,4-Oxadiazoles are also important start-
ing material for the synthesis of furan derivatives [12] and
natural products [13] and were recently tested for their pos-
sible use in organic light-emitting diodes [14–16]. On the
other hand, thienopyrazole derivatives showed important
biological activity such as kinase inhibitors [17]. In recent
years, kinase has emerged as target in variety of therapeutic
areas such as cancer [18], diabetes [19], inflammation [20],
cardiovascular [21], and neurodegenerative disease [22],
and several kinase inhibitors have been approved by the
Oxadiazole derivatives are important heterocycles and
have been the subject of extensive studies in the recent
past. Numerous reports have highlighted their chemistry
and uses [1–3]. Compounds bearing 1,3,4-oxadiazole,
thiadiazole, and 1,2,4-triazole nucleus possess significant
anti-inflammatory activity [4–7]. Symmetrical and unsym-
metrical 1,3,4-oxadiazoles are biologically versatile com-
pounds displaying variety of biological activities such as
anti-inflammatory [8], antifungal [9], antiparasitic [10],
and antimicrobial activities [11]. The widespread use of
© 2013 HeteroCorporation

March 2014
Syntheses of New Unsymmetrical 2,5-Disubstituted-1,3,4-oxadiazoles and
369
1,2,4-Triazolo[3,4-b]-1,3,4-thiadiazoles Bearing Thieno[2,3-c]pyrazolo Moiety
Food and Drug Administration (FDA) for use in human be-
ing [23]. The importance of oxadiazole, triazole, thiadiazole,
and thienopyrazole moieties inspired us to club two active
molecules and to generate new 3-methyl-1-phenyl-5-(5-
aryl-1,3,4-oxadiazol-2-yl)-1H-thieno[2,3-c]pyrazole 4 and
3-(3-methyl-1-phenyl-1H-thieno[2,3-c]pyrazoles-5-yl)-6-
phenyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 10 by us-
ing as active intermediate 3-methyl-1-phenyl-1H-thieno
[2,3-c]pyrazole-5-carbohydrazide 3. 2,5-Disubstituted-
1,3,4-oxadiazoles are commonly prepared in good yield
by coupling reaction of acylhydrazides with carboxylic
acids followed by dehydration under mild reaction con-
ditions [24–31].
Previously, in literature, thieno[2,3-c]pyrazoles deriva-
tives [32–36] were reported with different substituted
groups. In present communication, we have prepared ethyl-
carboxylate derivatives of thieno[2,3-c]pyrazole by using
5-chloro-4-carbaldehyde 1 and ethylthioglycolate in the
presence of sodium ethoxide and ethanol afforded in 88%
yield. This active precursor ethyl-3-methyl-1-phenyl-1H-
thieno[2,3-c]pyrazole-5-carboxylate 2 was reacted with
hydrazine hydrate afforded corresponding carbohydrazide
3 in 76% yield, which exhibits very good synthetic utility
for the syntheses of 1,3,4-oxadiazole, 1,3,4-thiadiazole,
and 1,2,4-triazole derivatives.
gave Schiff’s bases 5a–c, the carbohydrazide functionality
of compounds 5a–c were cyclized in acetic anhydride
furnished 1-(2-aryl-5-(3-methyl-1-phenyl-1H-thieno[2,3-c]
pyrazol-5-yl)-1,3,4-oxadiazol-3(2H)-yl)ethanone 6a–c in
71–78% yield (Scheme 2), and these assigned structures
and molecular formulae were supported by MS, 1H
NMR, 13C NMR, IR spectroscopy, and elemental analysis
given in experimental protocol.
The carbohydrazide 3 gave thermoselective products
with carbon disulfide, potassium hydroxide in absolute
ethanol. This reaction furnished 5-(3-methyl-1-phenyl-
1H-thieno[2,3-c]pyrazol-5-yl)-1,3,4-oxadiazole-2(3H)-
thione 7 at reflux temperature, whereas at room temperature,
the potassium salt of hydrazinecarbodithioate, i.e. potassium2-
[(3-methyl-1-phenyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]
hydrazinecarbodithioate 8, was obtained. The IR spectra of 7
displayed stretching band at 3245 cmꢀ1 1H NMR of this com-
pound displays a singlet at d 13.78 assigned for -NH proton.
This salt 8 underwent ring closure with excess of 99% hydra-
zine hydrate in water gave 4-amino-5-(3-methyl-1-phenyl-
1H-thieno[2,3-c]pyrazol-5-yl)-4H-1,2,4-triazole-3-thiol 9 in
65% yield. The IR spectrum of 9 displayed stretching bands
at 3345 and 3256 cmꢀ1 for -NH2 and -SH groups, respec-
1
tively. H NMR spectrum of this compound displayed a
broad singlet at d 5.94 and d 13.94, which were accounted
for -NH2 and -SH, respectively. The resulting triazole was
further converted to (thieno[2,3-c]pyrazol-5-yl)-6-aryl-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole 10a–c in one-step
reaction by condensation with aromatic acids in POCl3
(Scheme 3).
The structures of compounds 2 and 3 were assigned on
the basis of IR, 1H and 13C NMR, mass spectra, and
elemental analysis. The IR spectra of 2 showed stretching
at 1708 cmꢀ1 for ester group. Its 1H NMR spectrum
revealed a triplet at 1.30 for -CH3 and quartet at 4.32 d
for -OCH2- protons, whereas 13C NMR showed chemical
shifts at d 14.3 and 61.42, respectively. IR spectra of 3
showed broad peak at 3346 cmꢀ1, 3270 and 1657 cmꢀ1
for NH2 and CONH2 carbonyl (Scheme 1).
CONCLUSION
Key intermediate thieno[2,3-c]pyrazolo-5-carbohydra-
zide 3 was successfully prepared by the reaction of hydra-
zine hydrate with ester 2 and used to obtain thiadiazole,
oxadiazole, and triazole derivatives in good yield by using
nonhazardous chemicals and reagents. The new com-
pounds were well characterized by spectroscopic and ana-
lytical methods.
The corresponding carbohydrazide 3 with aryl carbox-
ylic acid in phosphorusoxychloride underwent cyclization
gave 2,5-disubstituted-1,3,4-oxadiazole 4a–c (Scheme 2).
The structure of 4 was established on the basis of spectral
and analytical data, for example, IR sprectrum of com-
pound 4a, showed peak at 1643 cmꢀ1 because of C═N
streching vibration, and the absence of C═O, which help
1
to confirm oxadiazole ring formation. Its H NMR spec-
trum showed multiplet at d 7.29–8.16 for aromatic protons.
Mass spectrum of this compound showed m/z = 358, and
also, elemental analysis supported the proposed struc-
ture 4a. The reaction of 3 with various aldehydes in ethanol
EXPERIMENTAL
Melting points were determined on a Gallenkamp melting
point apparatus (S. d. fine-chem limited Mumbai MS, INDIA).
The 1H (300 MHz) and 13C (75 MHz) NMR spectra were
recorded on a Varian XL-300 spectrometer. Chemical shifts were
reported in ppm relative to TMS, and multiplicities are given as s
(singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), or
m (multiplet). Infrared spectra were recorded as KBr pellets on a
Shimadzu FTIR-408 spectrophotometer. Mass spectra were
recorded on a Shimadzu LC-MS: EI QP 2010A mass spectrome-
ter with ionization potential 70 eV. Elemental analyses were
performed on Thermo Quest Flash 1112 Series EA analyzer.
Reactions were monitored by TLC, carried out on 0.2 mm silica
Scheme 1
O
O
NHNH2
O
OEt
O
H
SH
EtO
H2NNH2.H2O
N
S
S
N
N
N
Ph
Cl
NaOEt
EtOH
N
Ph
2
EtOH
reflux
3 h
N
Ph
r.t.
3
6 h
1
76%
88%
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

370
S. P. Patil, S. B. Kanawade, D. C. Bhavsar, P. S. Nikam, S. A. Gangurde, and R. B. Toche
Vol 51
Scheme 2
N
N
O
Ar
4
a
Ar
O
Ar
OH
N
S
C6H5
N
POCl3,
90 °C,
3-4 h
Ph
4-MeC6H4
b
c
4a-c
68-74%
4-OMeC6H4
3
O
H
N
N
N
N
Ar
Ac2O
ArCHO,
EtOH
Ar
O
O
N
N
S
S
reflux, 3-4 h
N
N
AcOH
reflux,
3-4 h
Ph
Ph
Ar
5, 6
a
5a-c
81-85%
6a-c
4-ClC6H5
71-78%
b
c
3,4-Di-OMeC6H3
4-MeC6H4
Scheme 3
S
S-K+
H
N
N
N
N
H
CS2 / KOH
NH2NH2.H2O
SH
N
O
N
S
S
N
H2O, reflux
12 h
NH2
3
EtOH, rt
12 h
N
N
Ph
Ph
9
65%
8
80%
CS2 / EtOH
KOH
POCl
4-5 h
3, reflux
ArCOOH/
reflux
2 h
H
N
N
N
N
S
O
S
N
N
10 Ar
a
N
S
S
N
N
N
C6H5
Ar
Ph
Ph
4-OMeC6H4
4-MeC6H4
b
c
7
69%
10a-c
62-70%
gel 60 F254 (Merck) plates using UV light (254 and 366 nm) for
detection, and compounds were purified by column chroma-
tography by using silica gel of 5–20 mm (Merck, 60–120 mesh).
Column dimension 39 ꢁ 2 cm2, and eluent volume about 200–
400 mL was used for each product. Common reagent grade
chemicals are either commercially available and were used
without further purification or were prepared by standard
literature procedures.
Ethyl-3-methyl-1-phenyl-1H-thieno[2,3-c]pyrazole-5-carboxylate
(2). Ethyl thioglycolate (16.2 g, 0.135 mol) was added to cold
solution of sodium (3.9 g, 0.170 mol) in dry ethanol (60 mL) with
constant stirring. A solution of 5-chloro-3-methyl-1-phenyl-1H-
pyrazole-4-carbaldehyde 1 (29.48 g, 1.34 mol) in ethanol (25 mL)
was then added dropwise during 0.5 h at 0–5ꢂC. The mixture was
stirred overnight at room temperature, refluxed for 0.5 h (TLC
check chloroform/methanol, 9:1), cooled, and poured in water
(250 mL). The precipitated ester 2 was filtered, dried, and
recrystallized from ethanol. The yield was 25.1 g (88%), offwhite
prisms, mp 117–118ꢂC; IR: 2741 (m), 1708 (s), 1676 (s), 1533
(w), 1381 (w), 1285 (m) cmꢀ1 1H NMR (CDCl3): d 1.30 (t,
;
J= 7.2 Hz, 3H, CH3), 2.48 (s, 3H, CH3), 4.32 (q, J= 7.2 Hz, 2H,
CH2), 7.30–7.72 (m, 5H, ArH), 8.01 (s, 1H, ArH); 13C NMR
(CDCl3): d 13.4, 14.3, 61.42, 117.5, 122.7, 125.6, 129.6, 130.2,
130.5, 139.2, 143.9, 144.3, 162.9; MS: (m/z) = 287 (M + 1, 100%).
Anal. Calcd for C15H14N2O2S (286.35): C, 62.92; H, 4.93; N, 9.78;
found: C, 62.84; H, 4.97; N, 9.71.
3-Methyl-1-phenyl-1H-thieno[2,3-c]pyrazole-5-carbohydrazide
(3). A mixture of compound 2 (2.86 g, 0.01 mol) and hydrazine
hydrate (99%) (1mL, 0.02 mol) in ethanol (25 mL) was heated
under reflux for 2 h (TLC check chloroform/methanol, 9:1). The
reaction mixture was then allowed to cool. The solid product was
collected by filtration, dried, and recrystallized from (ethanol:
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
Syntheses of New Unsymmetrical 2,5-Disubstituted-1,3,4-oxadiazoles and
371
1,2,4-Triazolo[3,4-b]-1,3,4-thiadiazoles Bearing Thieno[2,3-c]pyrazolo Moiety
DMF, 8:2). The yield was 2.06 g (76%), colorless amorphous solid,
(E)-N0-(3,4-dimethoxybenzylidene)-3-methyl-1-phenyl-1H-
thieno[2,3-c]pyrazole-5-carbo hydrazide (5b). The yield was
0.357g (85%), colorless amorphous solid, mp 256ꢂC; IR: 3222
mp 120–121ꢂC; IR: 3346 (m), 3270 (m), 2908 (m), 1657 (s), 1612
1
(s), 1587 (w) cmꢀ1; H NMR (CDCl3): d 2.48 (s, 3H, CH3), 4.52
(bs, 2H, NH2), 7.29–7.74 (m, 5H, ArH), 7.84 (s, 1H, ArH), 9.89
(bs, 1H, NH); 13C NMR (CDCl3): d 12.7, 110.8, 120.9, 128.4,
130.1, 131.5, 134.2, 139.1, 141.5, 144.2, 166.3; MS: (m/z) = 272
(M+, 100%). Anal. Calcd for C13H12N4OS (272.33): C, 57.34; H,
4.44; N, 20.57; found: C, 57.25; H, 4.39; N, 20.51.
General procedure for the synthesis of 3-methyl-1-
phenyl-5-(5-aryl-1,3,4-oxadiazol-2-yl)-1H-thieno[2,3-c]pyrazole
(4). A mixture of 3-methyl-1-phenyl-1H-thieno[2,3-c]pyrazole-5-
carbohydrazide 3 (0.272g, 1 mmol) and the appropriate aromatic
acid (1mmol) in POCl3 (25mL) was refluxed for 3–4 h (TLC
check chloroform/methanol, 9:1). After completion of the
reaction, the excess POCl3 was removed under reduced pressure.
Resulting mass poured on crushed ice; the mixture was stirred and
neutralized with NaHCO3. The solid separated was filtered,
washed with cold water, and recrystallized from ethanol.
(m), 2837 (m), 1651 (s), 1624 (s), 1350 (w) cmꢀ1 1H NMR
;
(CDCl3): d 2.55 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 3.83 (s, 3H,
OCH3), 7.07–7.76 (m, 9H, ArH), 8.36 (s, 1H, C═CH), 12.02
(bs, 1H, NH); MS: (m/z) = 420 (M+, 20%). Anal. Calcd for
C22H20N4O3S (420.48): C, 62.84; H, 4.79; N, 13.32; found:
C, 62.76; H, 4.81; N, 13.30.
3-Methyl-N0-[(E)-(4-methylphenyl)methylidene]-1-phenyl-1H-
thieno[2,3-c]pyrazole-5-carbo hydrazide (5c). The yield was
0.306g (82%), colorless amorphous solid, mp 247–248ꢂC; IR:
3278 (m), 2851 (m), 1654 (s), 1621 (s), 1208 (w) cmꢀ1 1H
;
NMR (CDCl3): d 2.37 (s, 3H, CH3); 2.56 (s, 3H, CH3), 7.27–
7.81 (m, 10H, ArH), 8.33 (s, 1H, C═CH), 12.00 (bs, 1H, NH);
MS: (m/z) = 374 (M+, 33%). Anal. Calcd for C21H18N4OS
(374.46): C, 67.36; H, 4.85; N, 14.96; found: C, 67.43; H, 4.82;
N, 14.98.
General procedure for the synthesis 1-(2-aryl-5-(3-methyl-1-
phenyl-1H-thieno[2,3-c]pyrazol-5-yl)-1,3,4-oxadiazol-3(2H)-yl)
ethanone (6). A mixture of carbohydrazide (1 mmol) 5a–c and
excess of acetic anhydride (10 mL) was refluxed for 3–4 h (TLC
check chloroform/methanol, 9:1). After completion of the
reaction, the acetic anhydride was removed under reduced
pressure. The residue was poured on crushed ice; the solid
precipitated was collected by filtration, washed with water, and
recrystallized from ethanol/DMF (8:2).
3-Methyl-1-phenyl-5-(5-phenyl-1,3,4-oxadiazol-2-yl)-1H-thieno
[2,3-c]pyrazole (4a). The yield was 0.243 g (68%), yellow
crystalline solid, mp 147–148ꢂC; IR: 2900 (m), 2754 (m), 1646
1
(s), 1632 (s), 1378w, 1275 (m) cmꢀ1; H NMR (CDCl3): d 2.55
(s, 3H, CH3), 7.29–7.81 (m, 9H, ArH), 8.11–8.16 (m, 2H, ArH);
MS: (m/z) = 358 (M+, 66%). Anal. Calcd for C20H14N4OS
(358.42): C, 67.02; H, 3.94; N, 15.63; found: C, 67.11; H, 3.96;
N, 15.60.
3-Methyl-1-phenyl-5-(5-p-tolyl-1,3,4-oxadiazol-2-yl)-1H-thieno
[2,3-c]pyrazole (4b). The yield was 0.275 g (74%), yellow
crystalline solid, mp 219–220ꢂC; IR: 2945 (m), 1632 (s), 1589
1-(2-(4-Chlorophenyl)-5-(3-methyl-1-phenyl-1H-thieno[2,3-
c]pyrazol-5-yl)-1,3,4-oxadiazol-3(2H)-yl)ethanone (6a). The
yield was 0.327 g (75%), offwhite crystaline solid, mp 91–93ꢂC; IR:
2987 (m), 1652 (s), 1624 (s), 1262 (m), 1124 (w) cmꢀ1; 1H NMR
(CDCl3): d 2.24 (s, 3H, CH3), 2.54 (s, 3H, CH3), 7.06 (s, 1H,
CH), 7.29–7.85 (m, 10H, ArH); MS: (m/z) = 436 (M+, 100%), 438
(M + 2, 33%). Anal. Calcd for C22H17ClN4O2S (436.91): C,
60.48; H, 3.92; N, 12.82; found: C, 60.56; H, 3.91; N, 12.79.
1-(2-(3,4-Dimethoxyphenyl)-5-(3-methyl-1-phenyl-1H-thieno[2,3-c]
pyrazol-5-yl)-1,3,4-oxadiazol-3(2H)-yl)ethanone (6b). The yield
was 0.360 g (78%), colorless amorphous solid, mp 145–146ꢂC;
1
(m), 1364 (w), 1204 (w) cmꢀ1; H NMR (CDCl3): d 2.48 (s, 3H,
CH3), 2.57 (s, 3H, CH3), 7.01–7.74 (m, 8H, ArH), 8.03–8.07
(m, 2H, ArH); MS: (m/z) = 372 (M+, 66%). Anal. Calcd
for C21H16N4OS (372.44): C, 67.72; H, 4.33; N, 15.04; found:
C, 67.68; H, 4.31; N, 15.00.
5-(5-(4-Methoxyphenyl)-1,3,4-oxadiazol-2-yl)-3-methyl-1-phenyl-
1H-thieno[2,3-c]pyrazole (4c). The yield was 0.271 g (70%), pale
brown crystaline solid, mp 247–248ꢂC; IR: 2930 (m), 1628 (s),
1344 (w), 1228 (w) cmꢀ1; 1H NMR (CDCl3): d 2.54 (s, 3H, CH3),
3.88 (s, 3H, OCH3), 6.92–6.96 (d, 2H, J= 9.3 Hz, ArH), 7.00–8.05
(m, 8H, ArH); 13C NMR (CDCl3): d 12.7, 55.4, 113.8, 114.9,
116.9, 117.0, 122.9, 125.7, 125.9, 128.4, 130.0, 131.3, 138.4,
144.4, 148.8, 162.8, 167.0; MS: (m/z)=388 (M+, 66%). Anal.
Calcd for C21H16N4O2S (388.44): C, 64.93; H, 4.15; N, 14.42;
found: C, 64.99; H, 4.17; N, 14.39.
1
IR: 3010 (m), 1657 (s), 1621 (s), 1248 (m), 1110 (w) cmꢀ1; H
NMR (CDCl3): d 2.24 (s, 3H, CH3), 2.49 (s, 3H, CH3), 3.77 (s,
3H, OCH3), 3.79 (s, 3H, OCH3), 7.01 (s, 1H, CH), 7.07–7.79 (m,
9H, ArH); 13C NMR (CDCl3): d 12.6, 21.2, 55.6, 92.6, 110.1,
111.7, 117.0, 119.1, 120.2, 121.7, 123.3, 125.6, 125.8, 128.6,
130.0, 130.8, 138.6, 143.8, 148.8, 150.1, 166.5; MS: (m/z) = 462
(M+, 100%). Anal. Calcd for C24H22N4O4S (462.52): C, 62.32; H,
4.79; N, 12.11; found: C, 62.26; H, 4.77; N, 12.15.
General procedure for the synthesis of (E)-N0-(aryl)-3-
methyl-1-phenyl-1H-thieno[2,3-c]pyrazole-5-carbohydrazide
(5). Equimolar quantities of 3-methyl-1-phenyl-1H-thieno[2,3-
c]pyrazole-5-carbohydrazide 3 (0.272 g, 1 mmol) and aldehydes
(1 mmol) were refluxed in ethanol (10 mL) for 3–4 h in the presence
of few drop of glacial acetic acid (TLC check chloroform/methanol,
9:1). The reaction mixture on cooling was poured in cold water (50
mL). The precipitated solid was filtered and dried. The crude solid
was recrystallized from ethanol/DMF (8:2).
1-(5-(3-Methyl-1-phenyl-1H-thieno[2,3-c]pyrazol-5-yl)-2-p-tolyl-
1,3,4-oxadiazol-3(2H)-yl)ethanone (6c). The yield was 0.295 g
(71%), offwhite amorphous solid, mp 134–135ꢂC; IR: 2987 (m),
1
1652 (s), 1627 (s), 1256 (m), 1098 (w) cmꢀ1; H NMR (CDCl3):
d 2.25 (s, 3H, CH3), 2,41 (s, 3H, CH3), 2.55 (s, 3H, CH3), 6.98
(s, 1H, CH), 7.18–7.80 (m, 10H, ArH); MS: (m/z) = 416 (M+,
100%). Anal. Calcd for C23H20N4O2S (416.5): C, 66.33; H, 4.84;
N, 13.45; found: C, 66.39; H, 4.82; N, 13.49.
5-(3-Methyl-1-phenyl-1H-thieno[2,3-c]pyrazol-5-yl)-1,3,4-
oxadiazole-2(3H)-thione (7). To a mixture of 3-methyl-1-phenyl-
1H-thieno[2,3-c]pyrazole-5-carbohydrazide 3 (0.272 g, 1 mol) in
ethanol (15mL), carbon disulfide was added (0.08 mL, 1 mmol).
This was followed by addition of potassium hydroxide (0.056g,
1 mmol) dissolved in water (2 mL). The reaction mixture was
refluxed for 2 h (TLC check chloroform/methanol, 9:1). After
cooling the reaction mixture to room temperature, the solvent was
(E)-N0-(4-chlorobenzylidene)-3-methyl-1-phenyl-1H-thieno
[2,3-c]pyrazole-5-carbohydr azide (5a). The yield was 0.319g
(81%), colorless amorphous solid, mp 291–292ꢂC; IR: 3236 (m),
1
2878 (m), 1658 (s), 1632 (s), 1324 (w) cmꢀ1; H NMR (CDCl3):
d 2.54 (s, 3H, CH3), 7.36–7.86 (m, 8H, ArH), 8.01–8.03 (d, 2H,
J = 8.4 Hz, ArH), 8.32 (s, 1H, C═CH), 11.97 (bs, 1H, NH) ppm;
MS: (m/z) = 394 (M+, 30%), 396 (M + 2, 10%). Anal. Calcd for
C20H15ClN4OS (394.88): C, 60.83; H, 3.83; N, 14.19; found: C,
60.78; H, 3.80; N, 14.22.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

372
S. P. Patil, S. B. Kanawade, D. C. Bhavsar, P. S. Nikam, S. A. Gangurde, and R. B. Toche
Vol 51
removed. The residue was poured in ice cold water; separated solid
was collected by filtration, washed with cold water, and
recrystallized from ethanol/DMF (8:2). The yield was 0.216 g,
(69%), pale yellow crystalline solid, mp 177–179ꢂC; IR 2998
6-(4-Methoxyphenyl)-3-(3-methyl-1-phenyl-1H-thieno[2,3-c]
pyrazol-5-yl)-[1,2,4]triazolo-[3,4-b][1,3,4]thiadiazole (10b). The
yield was 0.311 g (70%), offwhite amorphous solid, mp 217–
219ꢂC; IR 2939 (m), 1642 (m), 1608 (w), 1156 (w) cmꢀ1
;
(m), 2705 (m), 1634 (w), 1612 (m), 1233 (m) cmꢀ1; H NMR
1H NMR (CDCl3): d 2.54 (s, 3H, CH3), 3.82 (s, 3H, OCH3),
7.00–7.02 (d, 2H, J= 6.9 Hz, ArH), 7.20–7.87 (m, 8H, ArH); MS:
(m/z) = 444 (M+, 100%). Anal. Calcd for C22H16N6OS2 (444.53):
C, 59.44; H, 3.63; N, 18.91; found: C, 59.37; H, 3.67; N, 18.86.
3-(3-Methyl-1-phenyl-1H-thieno[2,3-c]pyrazol-5-yl)-6-p-tolyl-
[1,2,4]triazolo[3,4-b]-[1,3,4]thiadiazole (10c). The yield was
0.287 g (67%), offwhite amorphous solid, mp 214–215ꢂC; IR
2947 (m), 2889 (m), 1633 (s), 1612 (w) cm–1; 1H NMR
(CDCl3): d 2.51 (s, 3H, CH3), 2.47 (s, 3H, CH3), 7.31–7.88
(m, 9H, ArH), 7.92 (s, 1H, ArH); 13C NMR (CDCl3): d 12.5,
23.4, 111.1, 116.8, 119.6, 119.7, 120.2, 122.3, 122.5, 125.7,
129.8, 130.3, 130.8, 138.1, 139.2, 141.0, 141.0 143.8, 156.5,
177.0; MS: (m/z) = 428 (M+, 100%). Anal. Calcd for
C22H16N6S2 (428.53): C, 61.66; H, 3.76; N, 19.61; found: C,
61.54; H, 4.80; N, 19.55.
1
(CDCl3): d 2.52 (s, 3H, CH3), 7.26–7.72 (m, 5H, ArH), 7.81 (s,
1H, ArH), 13.78 (bs, 1H, NH); MS: (m/z) = 314 (M+, 66%). Anal.
Calcd for C14H10N4OS2 (314.39): C, 53.49; H, 3.21; N, 17.82;
found: C, 53.54; H, 3.24; N, 17.76.
Potassium2-[(3-methyl-1-phenyl-1H-thieno[2,3-c]pyrazol-5-yl)
carbonyl]hydrazinecarbodithioate (8). Carbon disulfide
(0.160 mL, 2 mmol) was added to the stirring solution of
compound 3 (0.272 g, 1 mmol) in ethanol (5 mL), and potassium
hydroxide (0.112 g, 2 mmol) was dissolved in absolute ethanol
(15 mL) kept in ice bath. The reaction mixture was agitated
continuously for 12 h at room temperature. The precipitated
potassium thiocarbazinate was collected by filtration, washed
with cold ethanol (30 mL), and dried in vacuum. The potassium
salt thus obtained was used in the next step without further
purification. The yield was 0.320 g (80%), yellow amorphous solid,
mp 230–232ꢂC; IR 3102, 2946, 1658, 1624 cmꢀ1; MS: (m/z) = 386
(M+, 100%). Anal. Calcd for C14H11KN4OS3 (386.56): C, 43.50;
H, 2.87; N, 14.49; found: C, 43.58; H, 2.84; N, 14.52.
Acknowledgments. The authors thank CSIR New Delhi, India,
for the financial support to this research project. Authors also
thank the Department of Chemistry, University of Pune, and
IIT, Powai, Mumbai, for the spectral and analytical facilities
and the Principal of KTHM College, Nashik, for the facilities.
4-Amino-5-(3-methyl-1-phenyl-1H-thieno[2,3-c]pyrazol-5-
yl)-4H-1,2,4-triazole-3-thiol (9). A suspension of potassium
hydrazinecarbodithioate 8 (0.386g, 1 mmol) in water (5mL) and
hydrazine hydrate (99%) (0.064 mL, 2 mmol) was refluxed for
12h with occasional shaking. The colour of the reaction mixture
changed with evaluation of hydrogen sulfide gas, and
homogeneous reaction mixture was obtained during reaction
process (TLC check chloroform/methanol, 8:2). The reaction
mixture was cooled to room temperature and diluted with cold
water (20mL). On acidification with 10N HCl (15 mL), the
required triazole precipitated was filtered, washed, and
recrystallized from DMF/water (8:2). The yield was 0.213g
(65%), pale yellow crystlline solid, mp 240–242ꢂC; IR 3345 (m),
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3190 (m), 2946 (m), 2702 (m), 1637 (s), 1607 (w) cmꢀ1 1H
;
NMR (CDCl3): d 2.52 (s, 3H, CH3), 5.94 (bs, 2H, NH2), 7.30–
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
Syntheses of New Unsymmetrical 2,5-Disubstituted-1,3,4-oxadiazoles and
373
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