C5-Alkyl-1,3,4-Oxadiazol-2-ones Undergo Dealkylation upon Nitrogen Insertion to Form 2H-1,2,4-Triazol-3-ones: Synthesis of 1,2,4-Triazol-3-one Hybrids with Triazolothiadiazoles and Triazolothiadiazines

Article abstract of DOI:10.1002/jhet.2813

The present study emphasizes on the dealklylation of 3-aryl-5-alkyl-2-oxo-Δ⁴-1,3,4-oxadiazoles when reacted with formamide resulting in the formation of 2-aryl-2H-1,2,4-triazol-3(4H)-ones as major product. Subsequent reactions of 2-aryl-2H-1,2,

Full text of DOI:10.1002/jhet.2813

Month 2017
C5-Alkyl-1,3,4-Oxadiazol-2-ones Undergo Dealkylation upon Nitrogen
Insertion to Form 2H-1,2,4-Triazol-3-ones: Synthesis of 1,2,4-Triazol-3-
one Hybrids with Triazolothiadiazoles and Triazolothiadiazines
a
a
a
b
a
*
Pramod P. Kattimani, Ravindra R. Kamble, Atukuri Dorababu, Raveendra K. Hunnur, Atulkumar A. Kamble, and
H.C. Devarajegowdac
aDepartment of Studies in Chemistry, Karnatak University, Dharwad 580003, India
bAPL Research Ltd., Batchupally, Hyderabad, Telangana 500090, India
cDepartment of Physics, Yuvaraja’s College, University of Mysore, Mysore 570005, India
*
E-mail: kamchem9@gmail.com
Additional Supporting Information may be found in the online version of this article.
Received March 25, 2016
DOI 10.1002/jhet.2813
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
The present study emphasizes on the dealklylation of 3-aryl-5-alkyl-2-oxo-Δ4-1,3,4-oxadiazoles when
reacted with formamide resulting in the formation of 2-aryl-2H-1,2,4-triazol-3(4H)-ones as major product.
Subsequent reactions of 2-aryl-2H-1,2,4-triazol-3(4H)-one gave triazolo[3,4-b][1,3,4]thiadiazoles and
triazolo[3,4-b][1,3,4]thiadiazines derivatives incorporated with 1,2,4-triazol-3-one.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
hydrazinehydrate [8] and thiosemicarbazide [9] have only
afforded 5-methyl-2-aryl-2H-1,2,4-triazol-3(4H)-one
Ring rearrangements and ring transformations of
heterocyclic compounds represent an important tool in the
synthesis of new molecules that are otherwise difficult to
synthesize. The triazolone nucleus is found in wide variety
of pharmaceutically active molecules including antibacterial,
antifungal, anti-inflammatory agents, Protoporphyrinogen
Oxidase (PPO) inhibitors and antitumor agents [1–6].
Our earlier reported reactions on ring transformation of
3-aryl-5-methyl-2-oxo-Δ4-1,3,4-oxadiazoles when treated
with primary amines namely, ethanolamine [7],
derivatives. On the contrary, in the present investigation,
heating 3-aryl-5-alkyl-2-oxo-Δ4-1,3,4-oxadiazoles with
formamide gave 5-alkyl-2-aryl-2H-1,2,4-triazol-3(4H)-
one (minor product) and serendipitously
a
new
dealkylated product 2-aryl-2H-1,2,4-triazol-3(4H)-one
(major product) which was unidentified earlier.
Ring transformations of 3-arylsydnone 1a–c have
gained much attention as they yield pharmaceutically
active heterocycles via 1,3-dipolar cycloaddition reaction
[10–13]. In our present study, 3-arylsydnone 1a–c was
© 2017 Wiley Periodicals, Inc.

P. P. Kattimani, R. R. Kamble, A. Dorababu, R. K. Hunnur, A. A. Kamble, and H. C. Devarajegowda Vol 000
transformed to
3-aryl-5-alkyl-2-oxo-Δ4-1,3,4-
ring
oxadiazole 2a–c which upon heating with formamide gave
predominantly 2-aryl-2H-1,2,4-triazol-3(4H)-one 4a–c.
Compounds incorporating fused heterocyclic ring
systems are of significant importance because the fusion
results in the enhancement of biological properties. In
this regard, triazolothiadiazoles and triazolothiadiazines
have received considerable attention and are extensively
used as scaffolds in various potent molecules [14]. In
view of this, we have successfully prepared substituted
1,2,4-triazolo[3,4-b]-thiadiazoles 10a–c, 11a–c and 12a–
c and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines 13a–c from
newly formed 2-aryl-2H-1,2,4-triazol-3(4H)-ones 4a–c.
Figure 1. Molecular structure of compound 4b. Displacement ellipsoids
are drawn at the 50% probability level. [Color figure can be viewed at
wileyonlinelibrary.com]
and finally, the structure was confirmed by single crystal
X-ray crystallographic studies (Fig. 1) [16].
It was interesting to note that, C5-dealkylation of 1,3,4-
oxadiazol-2-ones 2a–c occurred only during ring insertion
with formamide. However, ring insertion with other
primary amines, viz., ethanolamine, hydrazinehydrate,
and thiosemicarbazide afforded corresponding triazoles
with C5-alkyl group.
RESULTS AND DISCUSSION
Initially 3-arylsydnone (1a–c) was ring transformed into
3-aryl-5-methyl-2-oxo-Δ4-1,3,4-oxadiazole (2a–c) via
[3 + 2] cycloaddition with acetic anhydride followed by
loss of carbon dioxide. When the compound 2a–c was
heated with formamide at 170°C, we were also under the
impression that 5-methyl-2-aryl-2H-1,2,4-triazol-3(4H)-
one 3a–c would be the sole product as reported by
Badami et al. earlier [15] (Scheme 1). Interestingly, along
with the formation of 3a–c, thin layer chromatography
(TLC) showed the presence of another spot (more polar
and intense). We successfully isolated the compound by
column chromatography and analyzed for its structure
using spectroscopic techniques and single crystal X-ray
diffraction study of one of the compound 4b.
Initially,
heating
3-aryl-5-methyl-2-oxo-Δ4-1,3,4-
oxadiazole 2a–c with formamide at 170°C yielded
compounds 3a–c and 4a–c in 40:60%, respectively. On the
contrary, the reaction carried out at 200°C afforded 4a–c in
about 90% and 3a–c in about 10% yield (Scheme 2).
Similar investigation was carried out for 3-aryl-5-ethyl-
2-oxo-Δ4-1,3,4-oxadiazole 5a–c obtained by [3+2]
cycloaddition of 3-arylsydnone 1a–c with propionic
anhydride followed by loss of carbon dioxide (Scheme
3). When 5a–c was heated with formamide at 170°C, we
observed formation of two products in the ratio 40:60.
However, heating 5a–c with formamide at 200°C also gave
4a–c in about 90% and 6a–c in about 10%. From these
reactions (Schemes 2 and 3) we could confirm the C5-
dealkylation of 3-aryl-5-alkyl-2-1,3,4-oxadiazoles 3a–c and
5a–c when heated with formamide at elevated temperature
mainly afford 2-aryl-2H-1,2,4-triazol-3(4H)-one 4a–c.
The plausible mechanism for the formation of
compound 3a–c, 6a–c, and 4a–c has been depicted in
Scheme 4. The lone pair of electrons on nitrogen atom of
formamide attacks the carbonyl carbon of lactone. Ring
opening and intramolecular attack by nitrogen atom gave
lactum intermediate in both the cases (iii and vii).
However, an unstable N-formyl intermediate was
observed in the formation of 3a–c and 6a–c, while a
more favorable loss of carboxylic acid was observed
during the formation of 4a–c. Hence, 4a–c was formed
predominantly over 3a–c and 6a–c.
In 1H-NMR spectrum, a singlet around 2.50 ppm for C5
methyl protons was absent; however, a singlet at 8.12 ppm
for one proton had appeared. Similarly, in case of 13C-
NMR studies, signal around 136 ppm was observed and
the signal around 12 ppm corresponding to C5 methyl
carbon was absent. The mass spectral study also showed
molecular ion peak 14 units lesser than the molecular
mass corresponding to compound 3a–c. The chemical
shift values in NMR data affirmed the presence of an
imine proton. Consequently, we speculated the structure
of the compound would possess an imine proton with the
absence of methyl group. Further, we developed the
crystals of compound 4b by slow evaporation of ethanol,
Further, we have successfully explored 4a–c for the
synthesis of various fused heterocyclic compounds which
have been depicted in Schemes 5 and 6. 2-Aryl-2H-1,2,4-
triazol-3(4H)-one 4a–c undergone N-alkylation upon
reaction with ethylbromoacetate in presence of sodium
ethoxide under reflux condition. The ester 7a–c obtained
was heated with hydrazinehydrate (99%) to get
corresponding acid hydrazide 8a–c which was reacted
with carbon disulfide in presence of potassium hydroxide
Scheme 1. Earlier work. Synthesis of 5-methyl-2-aryl-2H-1,2,4-triazol-
3(4H)-one 3.
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General procedure for synthesis of 3-aryl-5-ethyl-2-oxo-Δ4-
1,3,4-oxadiazoles (5a–c). A mixture of 3-arylsydnone (1a–
Scheme 2. Present work. Synthesis of 2-aryl-2H -1,2,4-triazol-3(4H)-one
4a-c.
c, 1 g) and propionic anhydride (10 mL) was stirred at
0–5°C and to this bromine (0.5 mL) in propionic
anhydride (10 mL) was added drop-wise. After
completion of addition, the reaction mixture was stirred
at room temperature for half an hour. Then, the reaction
mixture was warmed on water bath at 60°C till the
evolution of CO2 ceases. The reaction mixture was
warmed with 2 N NaOH (20 mL) on water bath for 1 h.
The reaction mixture was cooled and neutralized with dil
HCl to get the solid which was filtered, washed with
water, dried, and recrystallized with ethanol to get 5a–c.
followed by heating with hydrazine hydrate to obtain 4-(4-
amino-5-mercapto-4H-1,2,4-triazol-3-yl)methyl)-2-aryl-2H-
1,2,4-triazol-3(4H)-one 9a–c. Upon heating 9a–c with acetic
acid in phosphorusoxychloride, corresponding 3,6-
disubstituted [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 10a–c
were obtained. Compound 9a–c when refluxed with formic
acid gave 3-substituted [1,2,4]triazolo[3,4-b][1,3,4]
thiadiazoles 11a–c. 3-Substituted 6-mercapto-[1,2,4]
triazolo[3,4-b][1,3,4]thiadiazoles 12a–c were obtained by
the reaction of 9a–c with carbon disulfide in presence of
potassium hydroxide. Corresponding 3,6-disubstituted
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines 13a–c were prepared
by refluxing compound 9a–c with phenacyl bromide. All
the newly synthesized compounds were characterized by
1H and 13C-NMR, mass spectral and elemental analyses.
And also, we have carried out the single crystal X-ray
diffraction studies for compound 10b (Figs. 2 and 3).
5-Ethyl-3-phenyl-1,3,4-oxadiazol-2(3H)-one (5a).
Yield:
1
76%; mp: 134–136°C; H-NMR (300 MHz, CDCl3): δ
1.38 (t, 3H, J = 7.8 Hz, CH3), 2.68 (q, 2H, J = 7.5 Hz,
CH2), 7.26–7.40 (m, 3H, ArH), 7.80 (d, 2H, J = 11.6 Hz,
ArH); 13C-NMR (75 MHz, CDCl3): δ 11.50, 33.98,
119.85, 124.96, 129.77, 136.85, 149.75, 155.70; MS
(EI): m/z 190 (M), 161, 133, 90; Anal. Calcd. for
C10H10N2O2 (190.2): C 63.15, H 5.30, N 14.73%.
Found: C 63.31, H 5.47, N 14.92%.
3-(4-Chlorophenyl)-5-ethyl-1,3,4-oxadiazol-2(3H)-one (5b). Yield:
1
72%; mp: 141–143°C; H-NMR (300 MHz, CDCl3): δ
1.35 (t, 3H, J = 7.5 Hz, CH3), 2.62 (q, 2H, J = 7.8 Hz,
CH2), 7.52 (d, 2H, J = 9.8 Hz, ArH), 7.88 (d, 2H,
J = 9.8 Hz, ArH); 13C-NMR (75 MHz, CDCl3): δ 11.32,
33.56, 121.67, 128.38, 129.91, 136.09, 149.69, 155.69;
MS (EI): m/z 226 (M + 2), 224 (M), 195, 167, 90; Anal.
Calcd. for C10H9N2O2Cl (224.6): C 53.47, H 4.04, N
12.47%. Found: C 53.71, H 4.24, N 12.52%.
EXPERIMENTAL
5-Ethyl-3-(4-methoxyphenyl)-1,3,4-oxadiazol-2(3H)-one (5c).
Yield:
All the reagents were of analytical grade and were
used directly when required. TLC was performed on
0.20 mm Aluchrosep silica gel 60 F254 plates (S.D.
Fine, Mumbai). Melting points were determined in open
capillaries and are uncorrected. The 1H-NMR spectra
were recorded at 400 MHz on Bruker Avance FT
NMR spectrometer in DMSO-d6 with tetramethylslane
as internal standard. 13C-NMR spectra were recorded at
100 MHz on Bruker Avance FT NMR spectrometer
(Bruker Corporation, Billerica, MA) in DMSO-d6 with
tetramethylslane as internal standard. The mass spectra
were recorded on Shimadzu GC–MS operating at 70 eV.
Compound 2a–c was prepared from 3-arylsydnone 1a–c
according to reported method [10].
1
75%; mp: 138–140°C; H-NMR (300 MHz, CDCl3): δ
1.36 (t, 3H, J = 7.5 Hz, CH3), 2.64 (q, 2H, J = 7.6 Hz,
CH2), 3.76 (s, 3H, CH3), 6.90 (d, 2H, J = 10.2 Hz, ArH),
7.78 (d, 2H, J = 10.2 Hz, ArH); 13C-NMR (75 MHz,
CDCl3): δ 11.28, 32.19, 55.58, 114.27, 121.81, 131.93,
137.22, 155.38, 158.07; MS (EI): m/z 220 (M), 191, 163,
90; Anal. Calcd. for C11H12N2O3 (220.2): C 59.99, H
5.49, N 12.72%. Found: C 60.21, H 5.61, N 12.89%.
General procedure for the preparation of 2-aryl-2H-1,2,4-
triazol-3(4H)-one (4a-c).
3-Aryl-5-methyl-2-oxo-Δ4-
1,3,4-oxadiazole (2a–c, 0.005 M) was refluxed with
formamide (10 mL) at 200°C for 6 h. The completion of
reaction was monitored by TLC using hexane:ethylacetate
Scheme 3. Synthesis of 2-aryl-2H -1,2,4-triazol-3(4H)-one 4a-c also from 5-ethyl-3-aryl-1,3,4-oxadiazol-2(3H)-one 5a-c.
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P. P. Kattimani, R. R. Kamble, A. Dorababu, R. K. Hunnur, A. A. Kamble, and H. C. Devarajegowda Vol 000
Scheme 4. Proposed mechanism for the formation of 3a–c and 4a–c.
[Color figure can be viewed at wileyonlinelibrary.com]
2-(4-Chlorophenyl)-2H-1,2,4-triazol-3(4H)-one (4b).
Yield:
1
85%; mp: 266–268°C; H-NMR (400 MHz, DMSO-d6):
δ 7.49 (d, 2H, J = 15.2 Hz, ArH), 7.92 (d, 2H,
J = 15.2 Hz, ArH), 8.12 (s, 1H, C5-H), 12.00 (bs, 1H,
NH); 13C-NMR (100 MHz, DMSO-d6): δ 119.26,
128.77, 128.84, 136.66, 136.72, 152.17; MS (ESI): m/z
197 (M + 2), 195 (M), 125, 111, 90; Anal. Calcd. for
C8H6N3OCl (195.6): C 49.12, H 3.09, N 21.48%. Found:
C 49.31, H 3.27, N 21.79%.
2-(4-Methoxyphenyl)-2H-1,2,4-triazol-3(4H)-one (4c).
Yield:
1
86%; mp: 225–227°C; H-NMR (400 MHz, DMSO-d6):
δ 3.78 (s, 3H, CH3), 6.92 (d, 2H, J = 12.2 Hz, ArH),
7.81 (d, 2H, J = 12.2 Hz, ArH),12.08 (bs, 1H, NH), 8.19
(s, 1H, C5-H); 13C-NMR (100 MHz, DMSO-d6, ppm): δ
55.61, 115.47, 121.66, 132.28, 137.22, 151.83,158.26;
MS (ESI): m/z 191 (M), 127, 113, 90, 55.31; Anal.
Calcd. for C9H9N3O2 (191.2): C 56.54, H 4.74, N
21.98%. Found: C 56.84, H 4.90, N 22.15%.
5-Ethyl-2-phenyl-2H-1,2,4-triazol-3(4H)-one (6a). Yield:
1
15%; mp: 175–177°C; H-NMR (300 MHz, DMSO-d6):
δ 1.30 (t, 3H, J = 7.5 Hz, CH3), 2.64 (q, 2H, J = 7.8 Hz,
CH2), 7.39–7.86 (m, 3H, ArH), 7.91 (d, 2H, J = 10.4 Hz,
ArH), 11.80 (bs, 1H, NH); 13C-NMR (75 MHz, DMSO-
d6): δ 10.68, 30.10, 120.03, 124.89, 129.14, 137.85,
152.65, 154.10; MS (EI): m/z 189 (M), 160, 131, 91;
Anal. Calcd. for C10H11N3O (189.2): C 63.48, H 5.86, N
22.21%. Found: C 63.66, H 6.01, N 22.41%.
(6:4) solvent mixture. The reaction mixture was poured into
ice cold water. The solid obtained was filtered, dried and
passed through silica gel and eluted using hexane:
ethylacetate (8:2) solvent mixture to get 4a–c.
5-Ethyl-2-aryl-2H-1,2,4-triazol-3(4H)-one 6a–c was
separated by column chromatographic technique using
hexane:ethylacetate (8:2) solvent mixture as an eluent.
2-(4-Chlorophenyl)-5-ethyl-2H-1,2,4-triazol-3(4H)-one (6b).
Yield:
1
10%; mp: 180–182°C; H-NMR (300 MHz, DMSO-d6):
δ 1.36 (t, 3H, J = 7.6 Hz, CH3), 2.62 (q, 2H, J = 7.8 Hz,
CH2), 7.50 (d, 2H, J = 11.2 Hz, ArH), 7.90 (d, 2H,
J = 11.2 Hz, ArH), 12.34 (bs, 1H, NH); 13C-NMR
(75 MHz, DMSO-d6): δ 10.57, 30.21, 121.37, 128.15,
129.94, 135.73, 152.87, 154.06; MS (EI): m/z 225
(M + 2), 223 (M), 125, 111, 90; Anal. Calcd. for
C8H6N3OCl (223.7): C 53.70, H 4.51, N 18.79%. Found:
C 53.90, H 4.63, N 18.87%.
2-Phenyl-2H-1,2,4-triazol-3(4H)-one (4a).
Yield: 82%;
mp: 214–216°C; 1H-NMR (400 MHz, DMSO-d6): δ
7.52–7.60 (m, 3H, ArH), 7.85 (d, 2H, J = 9.8 Hz, ArH),
8.24 (s, 1H, C5-H),12.10 (bs, 1H, NH); 13C-NMR
(100 MHz, DMSO-d6): δ 119.01, 128.06, 129.27, 136.81,
137.55, 152.35; MS (EI): m/z 161 (M), 127, 111, 90;
Anal. Calcd. for C8H7N3O (161.2): C 59.62, H 4.38, N
26.07%. Found: C 59.93, H 4.80, N 26.41%.
5-Ethyl-2-(4-methoxyphenyl)-2H-1,2,4-triazol-3(4H)-one (6c). Yield:
1
12%; mp: 164–166°C; H-NMR (300 MHz, DMSO-d6):
δ 1.34 (t, 3H, J = 7.5 Hz, CH3), 2.60 (q, 2H, J = 7.8 Hz,
Scheme 5. Synthesis of 4-(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)methyl)-2-aryl-2H-1,2,4-triazol-3(4H)-one 9a-c.
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Scheme 6. Synthesis of triazolo[3,4-b][1,3,4]thiadiazoles 10, 11, 12a-c and triazolo[3,4-b][1,3,4]thiadiazines 12a-c.
CH2), 3.76 (s, 3H, CH3), 6.96 (d, 2H, J = 10.6 Hz, ArH),
7.78 (d, 2H, J = 10.6 Hz, ArH), 12.88 (bs, 1H, NH); 13C-
NMR (100 MHz, DMSO-d6): δ 10.23, 30.31, 55.63,
115.28, 120.59, 132.86, 136.72, 152.43, 153.29, 158.55;
MS (EI): m/z 219 (M), 189, 161, 91; Anal. Calcd. for
C11H13N3O2 (219.2): C 60.26, H 5.98, N 19.17%.
Found: C 60.42, H 6.11, N 19.29%.
General procedure for the synthesis of ethyl 2-(5-oxo-1-
aryl-1H-1,2,4-triazol-4(5H)-yl)acetate (7a–c).
Compound
Figure 2. The molecular structure of the compound 10b. Displacement
ellipsoids are drawn at the 50% probability level. Hydrogen atoms are
shown as spheres of arbitrary radius. [Color figure can be viewed at
wileyonlinelibrary.com]
4a–c (0.01 M) was refluxed with equivalent amount of
natrium (0.01 M) in absolute ethanol for 2 h. Then,
ethylbromoacetate (0.01 M) was added and refluxed for
an additional 5 h. The completion of reaction was
monitored by TLC using hexane:ethylacetate (7:3)
solvent mixture, and solvent was removed under reduced
pressure to afford 7a–c.
Ethyl
2-(5-oxo-1-phenyl-1H-1,2,4-triazol-4(5H)-yl)acetate
1
(7a). Yield: 85%; mp: 94–96°C; H-NMR (400 MHz,
DMSO-d6): δ 1.34 (t, 3H, CH3), 4.20 (q, 2H, CH2), 4.64
(s, 2H, NCH2), 7.19–7.57 (m, 3H, ArH), 7.80 (d, 2H,
J = 12.8 Hz, ArH), 8.36 (s, 1H, C5-H); 13C-NMR
(100 MHz, DMSO-d6): δ 14.00, 51.37, 60.33, 118.25,
128.63, 129.74, 136.39, 138.28, 152.18, 169.44; MS
(EI): m/z 247 (M), 209, 153, 125, 111, 90; Anal. Calcd.
for C12H13N3O3 (247.2): C 58.29, H 5.30, N 16.99%.
Found: C 58.60, H 5.54, N 17.25%.
Ethyl 2-(1-(4-chlorophenyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)
acetate (7b).
Yield: 90%; mp: 77–79°C; 1H-NMR
(400 MHz, DMSO-d6): δ 1.27 (t, 3H, CH3), 4.09 (q, 2H,
CH2), 4.58 (s, 2H, NCH2), 7.68 (d, 2H, J = 14.2 Hz,
Figure 3. Unit cell packing diagram of the molecules of compound 10b.
[Color figure can be viewed at wileyonlinelibrary.com]
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P. P. Kattimani, R. R. Kamble, A. Dorababu, R. K. Hunnur, A. A. Kamble, and H. C. Devarajegowda Vol 000
ArH), 7.90 (d, 2H, J = 14.2 Hz, ArH), 8.26 (s, 1H, C5-H);
13C-NMR (100 MHz, DMSO-d6): δ 14.73, 49.74, 61.62,
119.15, 129.30, 129.99, 137.39, 138.68, 152.29, 168.13;
MS (EI): m/z 283 (M+2), 281 (M), 209, 153, 125, 111,
90; Anal. Calcd. for C12H12N3O3 (281.7): C 51.16, H
General procedure for the preparation of 4-(4-amino-5-
mercapto-4H-1,2,4-triazol-3-yl)methyl)-2-aryl-2H-1,2,4-
triazol-3(4H)-one (9a–c). To a solution of KOH (0.015 M)
in absolute ethanol (10 mL) and compound 8a–c (0.01 M),
carbon disulfide (0.015 M) was added, and the reaction
mixture was stirred at room temperature under guard tube
conditions for 16 h. It was then diluted with dry ether
(30 mL). The solid obtained was filtered and washed with
dry ether to get corresponding potassium salt in nearly
quantitative yield (98%). A suspension of potassium salt
(0.005 M), hydrazinehydrate (85%, 5 mL), and DM water
(1 mL) was refluxed with stirring for 6 h. The reaction
mixture was then poured into ice cold water and
neutralized with conc. HCl to pH = 5. The precipitate
obtained was filtered, dried, and recrystallized from
4.29, N 14.92%. Found: C 51.32, H 4.45, N 15.13%.
Ethyl 2-(1-(4-methoxyphenyl)-5-oxo-1H-1,2,4-triazol-4(5H)-
yl)acetate (7c).
Yield: 90%; mp: 92–94°C; 1H-NMR
(400 MHz, DMSO-d6): δ 1.30 (t, 3H, CH3), 3.85 (s, 3H,
CH3), 4.11 (q, 2H, CH2), 4.60 (s, 2H, NCH2), 6.89 (d,
2H, J = 10.8 Hz, ArH), 7.86 (d, 2H, J = 10.8 Hz, ArH),
8.28 (s, 1H, C5-H); 13C-NMR (100 MHz, DMSO-d6): δ
13.92, 50.83, 54.82, 60.97, 115.85, 122.41, 132.78,
138.50, 151.83, 159.00, 167.40; MS (ESI): m/z 277 (M),
207, 154, 125, 111, 91; Anal. Calcd. for C13H15N3O4
(277.3): C 56.31, H 5.45, N 15.15%. Found: C 56.77, H
4.68, N 15.26%.
ethanol to get 9a–c.
4-(4-Amino-5-mercapto-4H-1,2,4-triazol-3-yl)methyl)-2-phe
nyl-2H-1,2,4-triazol-3(4H)-one (9a).
Yield: 64%; mp:
General procedure for the synthesis of 2-(5-oxo-1-aryl-1H-
1,2,4-triazol-4(5H)-yl)acetohydrazide (8a–c). A mixture of
compound 7a–c (0.01 M) and hydrazinehydrate (99%,
0.02 M) in ethanol was refluxed at 80°C for 4 h. After
completion of reaction [monitored by TLC using hexane:
ethylacetate (7:3) solvent mixture], the solvent was
1
220–222°C; H-NMR (400 MHz, DMSO-d6): δ 5.17 (bs,
2H, NH2), 5.33 (s, 2H, NCH2), 7.34–7.56 (m, 3H, ArH),
7.90 (d, 2H, J = 10.8 Hz, ArH), 8.28 (s, 1H, C5-H),13.82
(bs,1H, SH/NH); 13C-NMR (100 MHz, DMSO-d6): δ
40.96, 119.57, 129.20, 129.74, 137.41, 138.86, 151.26,
153.38,160.43; MS (EI): m/z 289 (M), 261, 195, 153, 125,
111, 90; Anal. Calcd. for C11H11N7OS (289.3): C 45.67,
removed under reduced pressure to obtain 8a–c.
2-(5-Oxo-1-phenyl-1H-1,2,4-triazol-4(5H)-yl)acetohydrazide
(8a). Yield: 92%; mp: 186–188°C; 1H-NMR (400 MHz,
H 3.83, N 33.89%. Found: C 45.92, H 4.06, N 34.11%.
4-(4-Amino-5-mercapto-4H-1,2,4-triazol-3-yl)methyl)-2-(4-c
hlorophenyl)-2H-1,2,4-triazol-3(4H)-one (9b). Yield: 65%;
DMSO-d6): δ 4.23 (s, 2H, NH2), 4.45 (s, 2H, NCH2), 7.35–
7.53 (m, 3H, ArH), 7.85 (d, 2H, J = 12.0 Hz, ArH), 8.16 (s,
1H, C5-H), 9.54 (bs, 1H, NH); 13C-NMR (100 MHz,
DMSO-d6): δ 45.87, 118.40, 129.13, 129.58, 136.37,
138.28, 151.64, 166.21; MS (EI): m/z 233 (M), 208, 179,
153, 125, 111, 90; Anal. Calcd. for C10H11N5O2 (233.2):
1
mp: 216–218°C; H-NMR (400 MHz, DMSO-d6): δ 5.21
(bs, 2H. NH2), 5.30 (s, 2H, NCH2), 7.68 (d, 2H,
J = 11.2 Hz, ArH), 7.95 (d, 2H, J = 11.2 Hz, ArH), 8.24
(s, 1H, C5-H),13.76 (bs, 1H, SH/NH); 13C-NMR
(100 MHz, DMSO-d6): δ 40.77, 120.57, 129.09, 130.70,
137.23, 139.56, 151.38, 154.03,162.49; MS (EI): m/z 325
(M + 2), 323 (M), 308, 253, 195, 153, 125, 111, 90;
Anal. Calcd. for C11H10N7OSCl (323.8): C 40.81, H
3.11, N 30.28%. Found: C 41.15, H 3.34, N 30.54%.
C 51.50, H 4.75, N 30.03%. Found: C 51.75, H 4.98, N
30.26%.
2-(1-(4-Chlorophenyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)aceto
1
hydrazide (8b). Yield: 95%; mp: 178–180°C; H-NMR
(400 MHz, DMSO-d6): δ 4.42 (s, 2H, NCH2), 5.01 (s,
2H, NH2), 7.71 (d, 2H, J = 11.8 Hz, ArH), 7.90 (d, 2H,
J = 11.8 Hz, ArH), 8.20 (s, 1H, C5-H), 9.57 (bs, 1H,
NH); 13C-NMR (100 MHz, DMSO-d6): δ 44.91, 119.36,
129.34, 130.76, 137.21, 138.00, 152.01,165.86; MS (EI):
m/z 269 (M + 2), 267 (M), 236, 208, 153, 125, 111, 90;
Anal. Calcd. for C10H10N5O2Cl (267.7): C 44.87, H 3.77,
4-(4-Amino-5-mercapto-4H-1,2,4-triazol-3-yl)methyl)-2-(4-m
ethoxyphenyl)-2H-1,2,4-triazol-3(4H)-one (9c). Yield: 60%;
1
mp: 193–195°C; H-NMR (400 MHz, DMSO-d6): δ 3.81
(s, 3H, CH3), 5.18 (bs, 2H, NH2), 5.28 (s, 2H, NCH2),
6.90 (d, 2H, J = 11.6 Hz, ArH), 7.80 (d, 2H,
J = 11.6 Hz, ArH), 8.33 (s, 1H, C5-H),13.80 (bs, 1H,
SH/NH); 13C-NMR (100 MHz, DMSO-d6): δ 38.29,
54.57, 115.37, 122.09, 132.21, 138.28, 151.69, 153.59,
158.81,163.50; MS (EI): m/z 319 (M), 308, 291, 195,
153, 125, 111, 90; Anal. Calcd. for C12H13N7O2S
(319.3): C 45.13, H 4.10, N 30.70%. Found: C 45.28, H
4.35, N 31.00%.
N 26.16%. Found: C 45.01, H 4.10, N 26.31%.
2-(1-(4-Methoxyphenyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)ace
1
tohydrazide (8c). Yield: 92%; mp: 166–168°C; H-NMR
(400 MHz, DMSO-d6): δ 3.80 (s, 3H, CH3), 4.20 (s, 2H,
NH2), 4.48 (s, 2H, NCH2), 6.91 (d, 2H, J = 9.2 Hz,
ArH), 7.82 (d, 2H, J = 9.2 Hz, ArH), 8.32 (s, 1H, C5-H),
9.60 (bs, 1H, NH); 13C-NMR (100 MHz, DMSO-d6):
δ 47.23, 55.85, 114.65, 121.49, 132.83, 139.46,
151.18, 158.20,166.79; MS (EI): m/z 263 (M), 232,
184, 153, 125, 111, 90; Anal. Calcd. for C11H13N5O3
(263.3): C 50.19, H 4.98, N 26.60%. Found: C 50.42,
H 5.11, N 26.87%.
General procedure for the preparation of 4-(6-methyl-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)methyl)-2-aryl-2H-
1,2,4-triazol-3(4H)-one (10a–c). A mixture of compound
9a–c (0.01 M) and acetic acid (0.01 M) in phosphorus
oxychloride (10 mL) was refluxed for 2 h at 80°C on water
bath. After completion of reaction [monitored by TLC
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of Novel 1,2,4-Triazolin-3-one Derivatives
using hexane:ethylacetate (7:3) solvent mixture], excess of
phosphorus oxychloride was expelled out, and the reaction
mixture was poured into ice cold water and neutralized
using solid sodium bicarbonate. The white solid obtained
was filtered, dried, and recrystallized from ethanol.
4-(6-Methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)methy
164.21, 167.07; MS (EI): m/z 299 (M), 127, 111, 91; Anal.
Calcd. for C12H9N7OS (299.3): C 48.15, H 3.03, N
32.76%. Found: C 48.39, H 3.21, N 32.97%.
4-([1,2,4]Triazolo[3,4-b][1,3,4]thiadiazol-3-yl)methyl)-2-(4-
chlorophenyl)-2H-1,2,4-triazol-3(4H)-one (11b).
Yield:
1
76%; mp: 218–220°C; H-NMR (400 MHz, DMSO-d6):
δ 5.39 (s, 2H, CH2), 7.58 (d, 2H, J = 9.6 Hz, ArH), 7.92
(d, 2H, J = 9.6 Hz, ArH), 8.31 (s, 1H, ÀN = CH-S-),
8.41 (s, 1H, C5-H); 13C-NMR (100 MHz, DMSO-d6): δ
37.48, 118.59, 129.17, 129.22, 136.56, 139.42, 151.37,
153.41, 163.89,167.37; MS (EI): m/z 335 (M + 2), 333
(M), 254, 123, 113, 91; Anal. Calcd. for C12H8N7OSCl
(333.8): C 43.18, H 2.42, N 29.38%. Found: C 43.31, H
l)-2-phenyl-2H-1,2,4-triazol-3(4H)-one (10a).
Yield: 78%;
1
mp: 201–203°C; H-NMR (400 MHz, DMSO-d6): δ 2.82
(s, 3H, CH3), 5.31 (s, 2H, CH2), 7.41–7.55 (m, 3H,
ArH), 7.75 (d, 2H, J = 10.8 Hz, ArH), 8.32 (s, 1H, C5-
H); 13C-NMR (100 MHz, DMSO-d6): δ 166.23, 160.24,
155.25, 151.31, 139.08, 136.74, 130.26, 129.52, 118.56,
37.05, 16.34; MS (EI): m/z 313 (M), 155, 125, 111, 91;
Anal. Calcd. for C13H11N7OS (313.3): C 49.83, H 3.54,
N 31.29%. Found: C 50.21, H 3.80, N 31.77%.
2.77, N 29.81%.
4-([1,2,4]Triazolo[3,4-b][1,3,4]thiadiazol-3-yl)methyl)-2-(4-m
ethoxyphenyl)-2H-1,2,4-triazol-3(4H)-one (11c).
Yield:
2-(4-Chlorophenyl)-4-(6-methyl-[1,2,4]triazolo[3,4-b][1,3,4]t
hiadiazol-3-yl)methyl)-2H-1,2,4-triazol-3(4H)-one (10b).
1
62%; mp: 196–198°C; H-NMR (400 MHz, DMSO-d6):
δ 3.79 (s, 3H, CH3), 5.30 (s, 2H, CH2), 6.90 (d, 2H,
J = 10.2 Hz, ArH), 7.82 (d, 2H, J = 10.2 Hz, ArH), 8.27
(s, 1H, ÀN = CH-S-), 8.38 (s, 1H, C5-H); 13C-NMR
(100 MHz, DMSO-d6): δ 36.77, 56.11, 114.73, 121.61,
132.27, 139.24, 151.78, 152.64, 158.31, 164.07, 166.85;
MS (EI): m/z 329 (M), 197, 125, 111, 90; Anal. Calcd.
for C13H11N7O2S (329.3): C 47.41, H 3.37, N 29.77%.
Found: C 47.78, H 3.59, N 29.97%.
Yield: 85%; mp: 222–224°C; 1H-NMR (400 MHz,
DMSO-d6): δ 2.71 (s, 3H, CH3), 5.35 (s, 2H, CH2), 7.52
(d, 2H, J = 9.2 Hz, ArH), 7.90 (d, 2H, J = 9.2 Hz, ArH),
8.36 (s, 1H, C5-H); 13C-NMR (100 MHz, DMSO-d6): δ
17.87, 36.40, 119.31, 129.09, 129.19, 136.38, 138.38,
150.61, 154.69, 161.96, 167.76; MS (EI): m/z 349
(M + 2), 347 (M), 153, 125, 111, 84; Anal. Calcd. for
C13H10N7OSCl (347.8): C 44.90, H 2.90, N 28.19%.
Found: C 45.21, H 3.07, N 28.39%.
2-(4-Methoxyphenyl)-4-(6-methyl-[1,2,4]triazolo[3,4-b][1,3,
4]thiadiazol-3-yl)methyl)-2H-1,2,4-triazol-3(4H)-one (10c).
General procedure for the preparation of 4-(6-mercapto-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)methyl)-2-aryl-2H-
1,2,4-triazol-3(4H)-one (12a–c).
To a solution of KOH
Yield: 79%; mp: 195–197°C; 1H-NMR (400 MHz,
DMSO-d6): δ 2.68 (s, 3H, CH3), 3.84 (s, 3H, CH3), 5.29
(s, 2H, CH2), 6.84 (d, 2H, J = 11.6 Hz, ArH), 7.84 (d,
2H, J = 11.6 Hz, ArH), 8.41 (s, 1H, C5-H); 13C-NMR
(100 MHz, DMSO-d6): δ 18.21, 37.08, 55.91, 114.82,
122.55, 131.52, 139.07, 151.67, 155.63, 158.27,
160.70,166.59; MS (EI): m/z 343 (M), 312, 156, 125,
111, 91; Anal. Calcd. for C14H13N7O2S (343.4): C 48.97,
H 3.82, N 28.55%. Found: C 49.20, H 4.03, N 28.83%.
(0.015 M) in absolute ethanol (10 ml) and compound 9a–
c (0.01 M), carbon disulfide (0.015 M) was added, and
the reaction mixture was refluxed for 2 h. After
completion of reaction [monitored by TLC using hexane:
ethylacetate (7:3) solvent mixture], the volume of solvent
was reduced under pressure and poured into ice cold
water. The white solid obtained was filtered, dried, and
recrystallized from ethanol.
4-(6-Mercapto-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)me
thyl)-2-phenyl-2H-1,2,4-triazol-3(4H)-one (12a).
Yield:
General procedure for the preparation of 4-([1,2,4]
triazolo[3,4-b][1,3,4]thiadiazol-3-yl)methyl)-2-aryl-2H-1,2,4-
triazol-3(4H)-one (11a–c). A mixture of compound 9a–c
72%; mp: 184–186°C; 1H-NMR (400 MHz,
DMSO-d6): δ 5.36 (s, 2H, CH2), 7.39–7.60 (m, 3H,
ArH), 7.81 (d, 2H, J = 9.8 Hz, ArH), 8.42 (s, 1H, C5-
H),13.48 (s, 1H, SH); 13C-NMR (100 MHz,
DMSO-d6): δ 36.28, 118.71, 129.19, 129.24, 130.67,
137.35, 138.39, 151.87, 154.77, 161.20, 167.83; MS
(EI): m/z 331 (M), 179, 127, 111, 91; Anal. Calcd. for
C12H9N7OS2 (331.4): C 43.49, H 2.74, N 29.59%.
Found: C 43.86, H 2.93, N 29.87%.
(0.01 M) and formic acid (0.01 M) in phosphorus
oxychloride (10 mL) was refluxed for 2 h at 80°C on water
bath. After completion of reaction [monitored by TLC
using hexane:ethylacetate (7:3) solvent mixture], excess of
phosphorus oxychloride was expelled out, and the reaction
mixture was poured into ice cold water and neutralized
using solid sodium bicarbonate. The white solid obtained
2-(4-Chlorophenyl)-4-(6-mercapto-[1,2,4]triazolo[3,4-b][1,3,4]
was filtered, dried, and recrystallized from ethanol.
4-([1,2,4]Triazolo[3,4-b][1,3,4]thiadiazol-3-yl)-methyl)-2-phe
thiadiazol-3-yl)methyl)-2H-1,2,4-triazol-3(4H)-one (12b). Yield:
1
nyl-2H-1,2,4-triazol-3(4H)-one (11a).
Yield: 74%; mp:
78%; mp: 200–202°C; H-NMR (400 MHz, DMSO-d6):
1
225–227°C; H-NMR (400 MHz, DMSO-d6): δ 5.36 (s,
2H, CH2), 7.38–7.58 (m, 3H, ArH), 7.72 (d, 2H,
J = 11.2 Hz, ArH), 8.25 (s, 1H, ÀN = CH-S-),8.37 (s, 1H,
C5-H); 13C-NMR (100 MHz, DMSO-d6): δ 36.61, 118.47,
129.48, 129.76, 130.51, 138.61, 139.29, 151.37, 152.69,
δ 5.42 (s, 2H, CH2), 7.62 (d, 2H, J = 10.2 Hz, ArH),
7.90 (d, 2H, J = 10.2 Hz, ArH), 8.32 (s, 1H, C5-H),
13.50 (s, 1H, SH); 13C-NMR (100 MHz, DMSO-d6): δ
37.05, 118.31, 129.40, 129.79, 136.39, 139.27, 151.67,
153.51, 162.57, 166.94; MS (EI): m/z 367 (M + 2), 365
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. P. Kattimani, R. R. Kamble, A. Dorababu, R. K. Hunnur, A. A. Kamble, and H. C. Devarajegowda Vol 000
(M), 184, 125, 111, 90; Anal. Calcd. for C12H8N7OS2Cl
(365.8): C 39.40, H 2.20, N 26.80%. Found: C 39.57,
H 2.62, N 26.98%.
4-(6-Mercapto-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)me
thyl)-2-(4-methoxyphenyl)-2H-1,2,4-triazol-3(4H)-one (12c).
121.32, 128.45, 129.37, 130.52, 132.25, 134.38, 139.47,
151.76, 158.41, 162.22, 155.11, 167.08; MS (EI): m/z
419 (M), 289, 125, 111, 91; Anal. Calcd. for
C20H17N7O2S (419.5): C 57.27, H 4.09, N 23.37%.
Found: C 57.57, H 4.33, N 23.62%.
Yield: 70%; mp: 194–196°C; 1H-NMR (400 MHz,
DMSO-d6): δ 3.82 (s, 3H, CH3), 5.41 (s, 2H, CH2), 6.88
(d, 2H, J = 10.6 Hz, ArH), 7.85 (d, 2H, J = 10.6 Hz,
ArH), 8.40 (s, 1H, C5-H), 13.42 (s, 1H, SH); 13C-NMR
(100 MHz, DMSO-d6): δ 37.16, 57.28, 115.61, 122.37,
132.53, 139.21, 151.14, 152.71, 158.34, 163.50, 167.24;
MS (EI): m/z 361 (M), 274, 127, 113, 90; Anal. Calcd.
for C13H11N7O2S2 (361.4): C 43.20, H 3.07, N 27.13%.
Found: C 43.66, H 3.39, N 27.55%.
CONCLUSION
We herein report the C5-dealkylation of 3-aryl-5-alkyl-2-
oxo-Δ4-1,3,4-oxadiazoles when reacted with formamide at
higher temperature affording 2-aryl-2H-1,2,4-triazol-
3(4H)-ones as major product which served as a useful
precursors in the synthesis of triazolo[3,4-b][1,3,4]
thiadiazoleandtriazolo[3,4-b][1,3,4]thiadiazinederivatives.
General procedure for the preparation of 2-aryl-4-(6-
phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl)methyl)-
2H-1,2,4-triazol-3(4H)-one (13a–c).
A
mixture of
compound 9a–c (0.01 M) and phenacylbromide (0.01 M)
in absolute ethanol (10 ml) is refluxed at 80°C for 8 h.
The completion of reaction was monitored by TLC using
hexane:ethylacetate (7:3) solvent mixture. The solvent
was removed under reduced pressure to get 11a–c which
was recrystallized from ethanol.
2-Phenyl-4-(6-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadia
zin-3-yl)methyl)-2H-1,2,4-triazol-3(4H)-one (13a). Yield:76%;
Acknowledgments. The authors are grateful to University
Scientific Instrumentation Centre (USIC), Karnatak University,
Dharwad, for providing mass spectral data. The authors are
thankful to Indian Institute of Science (IISc), Bengaluru, for car-
rying out 1H and 13C-NMR spectral analyses. The authors ac-
knowledge University Grants Commission (UGC), New Delhi,
for financial assistance under UPE program vide No. [F. No.
14-3/2012 (NS/PE) Dated: 14-03-2012] and DSA: F-540/2/
DSA/2013 (SAP-1). One of the authors (P.P.K.) acknowledges
University Grants Commission (UGC), New Delhi, for fellowship
under RFSMS program.
mp: 226–228°C; 1H-NMR (400 MHz, DMSO-d6): δ3.44 (s,
2H, ÀSCH2), 5.40 (s, 2H, CH2), 7.36–7.58 (m, 6H, ArH),
7.72 (d, 2H, J = 12.8 Hz, ArH), 7.84 (d, 2H, J = 10.4 Hz,
ArH), 8.43 (s, 1H, C5-H); 13C-NMR (100 MHz,
DMSO-d6): δ 33.97, 35.28, 118.59, 125.09, 128.06,
128.61, 129.41, 131.73, 134.23, 137.58, 139.47, 151.46,
154.21, 162.62, 166.37; MS (EI): m/z 389 (M), 127, 113,
91; Anal. Calcd. for C19H15N7OS (389.4): C 58.60, H
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3.88, N 25.18%. Found: C 58.80, H 4.02, N 27.30%.
2-(4-Chlorophenyl)-4-(6-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazin-3-yl)methyl)-2H-1,2,4-triazol-3(4H)-one (13b). Yield:
75%; mp: 230–232°C; 1H-NMR (400 MHz, DMSO-d6): δ
3.42 (s, 2H, ÀSCH2), 5.45 (s, 2H, CH2), 7.44–7.52 (m, 3H,
ArH), 7.62 (d, 2H, J = 11.8 Hz, ArH), 7.68 (d, 2H,
J = 10.2 Hz, ArH), 7.94 (d, 2H, J = 11.8 Hz, ArH), 8.44
(s, 1H, C5-H); 13C-NMR (100 MHz, DMSO-d6): δ
34.07, 36.56, 119.65, 128.72, 128.84, 129.08, 129.61,
132.98, 134.40, 138.19, 138.53, 150.75, 155.63,
163.49,167.05; MS (EI): m/z 425 (M + 2), 423 (M), 215,
195, 125, 111, 84; Anal. Calcd. for C19H14N7OSCl
(423.9): C 53.84, H 3.33, N 23.13%. Found: C 54.01,
H 3.49, N 23.27%.
2-(4-Methoxyphenyl)-4-(6-phenyl-7H-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazin-3-yl)methyl)-2H-1,2,4-triazol-3(4H)-one
(13c). Yield: 70%; mp: 198–200°C; 1H-NMR (400 MHz,
DMSO-d6): δ 3.38 (s, 2H, ÀSCH2), 3.80 (s, 3H, CH3),
5.37 (s, 2H, CH2), 6.85 (d, 2H, J = 12.2 Hz, ArH), 7.48–
7.53 (m, 3H, ArH), 7.72 (d, 2H, J = 11.2 Hz, ArH), 7.88
(d, 2H, J = 12.2 Hz, ArH), 8.30 (s, 1H, C5-H); 13C-NMR
(100 MHz, DMSO-d6): δ 33.75, 35.27, 56.43, 114.79,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet