One-pot, Multicomponent Cascade Reaction for the Synthesis of Various Aralkyl/alkylthio-3,5-dimethyl-1H-pyrazolyl-4H-1,2,4-triazol-4-amine and Their Docking Studies

Article abstract of DOI:10.1002/jhet.3484

A facile and simple one-pot procedure for the synthesis of various aralkyl/alkylthio-3,5-dimethyl-1H-pyrazolyl-4H-1,2,4-triazol-4-amines has been described via a multicomponent reaction of 4-amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol, acetylacetone, and various aryl/alkyl halides in good yields. All the newly synthesized compounds were characterized by using analytical and spectral studies. Our in silico studies confirmed that 4e, 4f, 4g, and 4j have the best inhibition activity among the synthesized compounds with a high selective index against the Tubulin protein and showed best interactions with receptor structure. The present study provides a novel series of compounds with a promising inhibitor to prevent on Tubulin protein.

Full text of DOI:10.1002/jhet.3484

Month 2019
One-pot, Multicomponent Cascade Reaction for the Synthesis of Various
Aralkyl/alkylthio-3,5-dimethyl-1H-pyrazolyl-4H-1,2,4-triazol-4-amine
and Their Docking Studies
a
c
b
a
*
Parameshwara Chary Jilloju, Allam Vinaykumar, Perugu Shyam, and Rajeswar Rao Vedula
aDepartment of Chemistry, National Institute of Technology, Warangal, Telangana 506004, India
bDepartment of Biotechnology, National Institute of Technology, Warangal, Telangana 506004, India
cIndian Institute of Chemical Technology, Hyderabad, Telangana 500007, India
*E-mail: vrajesw@yahoo.com
Received September 19, 2018
DOI 10.1002/jhet.3484
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A facile and simple one-pot procedure for the synthesis of various aralkyl/alkylthio-3,5-dimethyl-1H-
pyrazolyl-4H-1,2,4-triazol-4-amines has been described via a multicomponent reaction of 4-amino-5-
hydrazinyl-4H-1,2,4-triazole-3-thiol, acetylacetone, and various aryl/alkyl halides in good yields. All the
newly synthesized compounds were characterized by using analytical and spectral studies. Our in silico stud-
ies confirmed that 4e, 4f, 4g, and 4j have the best inhibition activity among the synthesized compounds with
a high selective index against the Tubulin protein and showed best interactions with receptor structure. The
present study provides a novel series of compounds with a promising inhibitor to prevent on Tubulin protein.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
possessing C─S bonds are important in organic
chemistry [18–21]. Thioethers are beneficial and
important compounds in different branches such as
materials, agriculture, industry, pharmaceutical, medicine,
heterocyclic chemistry, and biological processes [22–30].
In the field of medicine, organosulfur compounds are
broadly used for treatment of different types of diseases
such as Alzheimer’s, cancer, tuberculosis, and Parkinson
[31–34].
Chemical reactions that use three or more different
starting materials as chemical structures and yields the
final product in a one-pot procedure are usually called as
multicomponent reactions. In multi component reaction
(MCR), a product is accomplished according to a cascade
of elementary chemical reactions. MCRs play an insignia
part in organic chemistry because they produce the
maximum yield of product and selectivity. They produce
very less by-products compared with stepwise synthesis.
Additionally, MCRs are operationally simple, cost-effective,
rapid, and involve easy experimental procedures [1].
RESULTS AND DISCUSSION
Triazole heterocyclic compounds is having a wide
range of biological activities [2], like antifungal, CNS-
stimulatory, antimicrobial, anticancer, antivirus, anti-HIV,
and analgesic activities [3–6]. Likewise, there are known
drugs consisting the triazole core ring, for example,
etizolam, triazolam, furacilin, and alprazolam [7–10].
In view of the importance of triazoles, pyrazoles, and
thioethers, we would like to incorporate all these units in
single heterocyclic system so that the resulting molecule
may exhibit good biological activity. In continuation of
earlier work on MCR [35–37], in the present work, we
are reporting the one-pot, multicomponent cascade
reaction for the synthesis of various aralkyl/alkylthio-3,5-
Pyrazole, which is
a
five-membered heterocyclic
compound consisting of two nitrogen atoms at adjacent
positions, and synthesis of pyrazoles were reported using
various procedures in the literature [11]. Pyrazole motifs
have been exhibiting interesting biological activities such
as anticancer, analgesic, antimicrobial, antidiabetic, anti-
inflammatory, and immunosuppressive activity [12–17].
Organosulfur chemistry is one of the most useful and
important branch in organic synthesis. Compounds
dimethyl-1H-pyrazolyl-4H-1,2,4-triazol-4-amines
their docking studies.
and
For the optimization of reaction conditions, the reaction
was conducted with 4-amino-5-hydrazino-4H-[1,2,4]
triazole-3-thiol (1), acetylacetone (2), and aralkyl/alkyl
halides (3) in the water under reflux condition, and no
product was formed. On the other hand, when the same
reaction was carried out in a mixture of equal amount of
© 2019 Wiley Periodicals, Inc.

P. C. Jilloju, A. Vinaykumar, P. Shyam, and R. R. Vedula
Vol 000
Table 1
explained due to high nucleophilicity of thiol group
compared with the amino group (Scheme 3). The yields
of products obtained were 78–90%.
Optimization conditions for the reaction 4a.
Entry
Solvent
Base
Yield (%) of 4a
The structures of the products were confirmed by their
spectral studies. For example, in the IR spectrum of
compound 4a displayed a peak at 3323 cmÀ1 (─NH2)
and 1584 cmÀ1(─C═C─). In the 1H-NMR (CDCl3)
spectrum of compound 4a gave characteristic singlets for
two ─CH3 groups of pyrazole at δ 2.26 and 2.53, a
singlet for ─SCH2─ at δ 4.46, ─NH2 two protons
showed as a singlet at δ 5.22, and the pyrazole ring
proton appeared as singlet at δ 6.02. The 13C-NMR
spectrum of compound 4a displayed the peaks at δ 12.3
and 13.6 for two methyl group carbons of pyrazole. The
benzylic (─S─CH2─) carbon appeared at δ 35.9, and
pyrazole carbon showed at δ 108.1. In mass spectrum,
the compound 4a appeared at m/z 301 [M + H]+.
In the present one-pot, multicomponent cascade
reaction conditions, the relative reactivities of various
aralkyl and alkyl halides were examined. When the
benzyl bromide (3a) and 4-nitrobenzyl bromide (3b)
were reacted with 1 and 2, they easily produced the
corresponding thioether derivatives (4a and 4b) in 90%
and 88% yields, respectively (Table 2). Similarly, when
the allyl halides such as propargyl bromide (3c) and
allyl bromide (3d) were used, the expected products (4c
and 4d) were formed in 86% and 82% yields,
respectively. When the reaction was carried out with
bromo ethyl acetate (3e) and chloro acetic acid (3f), the
expected products (4e and 4f) were obtained in 80% and
84% yields, respectively. Furthermore, various alkyl
halides (3g–m) were also utilized in the present reaction
conditions, to give corresponding derivatives in good
1
2
3
4
H2O
–
0
EtoH
EtoH
MeOH
DMF
Et3N
Et3N
90
40
25
Reaction conditions: 1 (1 mmol), 2 (1 mmol), and 3 (1 mmol) and base in
the solvents.
DMF, dimethylformamide.
Bold text indicates good optimized condition.
dry ethanol and dimethylformamide (DMF) (1:1) under
reflux produced the final compound in 90% yield.
Additionally, when the same reaction was examined by
using EtOH/Et3N or MeOH/Et3N produced lower yields
of the product when compared with a mixture of dry
ethanol and DMF. The optimized conditions for the
heterocyclization and alkylation are a mixture of dry
ethanol and DMF under reflux condition (Table 1).
When the reaction is carried out between 1, 2, and 3,
there is a possibility of formation of mixture of products
like 4, 5, or 6 or all of them. But in our case, only one
product [via thin-layer chromatography (TLC)] formation
is observed, that is, 4 only (Scheme 1). The alternative
products such as 5 and 6 from the reaction can be
rejected on the basis of spectral studies (Scheme 2).
In the present case, the reaction proceeds in such a way
that only the hydrazino part of compound 1 undergoes
condensation with 2 during heterocyclization followed by
aralkylation/alkylation of the ─SH group of compound 1
that lead to the formation of title compounds. The
formation of S-aralkylated/S-alkylated products can be
Scheme 1. Synthesis of various aralkyl/alkylthio-3,5-dimethyl-1H-pyrazolyl-4H-1,2,4-triazol-4-amines (4a–m). [Color figure can be viewed at
wileyonlinelibrary.com]
Scheme 2. Alternative possible products of the reaction of 2 and 3 with 1. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
One-pot,Multicomponent Cascade Reaction for the Synthesis of Various Aralkyl/alkylthio-
3,5-dimethyl-1H-pyrazolyl-4H-1,2,4-triazol-4-amine and Their Docking Studies
Scheme 3. Plausible mechanism for the one-pot, multicomponent cascade reaction for the synthesis of various aralkyl/alkylthio-3,5-dimethyl-1H-
pyrazolyl-4H-1,2,4-triazol-4-amine (4a–m).
yields (4g–m; 82–78%). From this investigation, we have
observed that the time required for the formation of the
products 4a–m depends on the type of aralkyl and
alkyl halides. When compared with the alkyl halides,
the aralkyl halides require less time and gave high
yields of products.
calculation of partial charge by keeping all other values
as default. The molecular docking was performed using
Ligand Fit module, and obtained results were scrutinized
based on highest dock score and number of H-bonds by
SS Viewer [39]. The docking studies revealed that all the
synthesized molecules exhibited excellent binding
energies towards the receptor active sites.
MOLECULAR MODELING STUDIES
RESULTS
Molecular docking tool is helpful to investigate and to
gain a profound insight into the mode of binding
interactions of each ligand molecules (4a–m) with
receptor structure. All chemical structures were drawn by
using ChemDraw Ultra 12.0 and 2D structures drawn
and converted to mol2 format by using Open Babel GUI
version 2.3.2 (OpenBableGUI; Chris Morley, USA).
Molecular energy was minimized using the Energy
Minimization module of Discovery Studio version 4.1
(Accelrys Inc., San Diego, CA) under the chemistry
at Harvard Macromolecular Mechanics (CHARMM)
force field.
The three-dimensional structure of Tubulin protein was
retrieved from Protein Data Bank (PDB ID:1SAO) [38].
Molecular docking studies for the synthesized
compounds of 4a to 4m were performed. The structure
preparation and correction protein were performed using
Discovery Studio 4.1 suite. The target protein file was
prepared by removing the structural water molecule,
hetero atoms, and co-factors by leaving only the residues
associated with protein by using Accelerys Discovery
Studio 4.1 (ADS) tool, which was used to prepare target
protein file addition of polar hydrogens to the
macromolecule, an essential step to correct the
We have carried out the docking studies and found the
binding site of the receptor that makes the synthesized
compounds easy to fit into the binding site, and it gives
supporting evidence in the results. Microtubules are
cytoskeletal polymers of Tubulin involved in numerous
cellular functions. Their dynamic instability is controlled
by several compounds and proteins, including Colchicine.
Molecular docking studies suggested the best-interacted
ligands at receptor site based on maximum possible
interactions with low binding energy and high docking
score. Table 3 represents the docking score and binding
energies of 4a–4m.
Docking analysis of most excellent active products in
the active site of 1SAO receptor of Tubulin-Colchicine
discovered that the hydrophobic interactions are
significant for the activity. All these compounds showed
good binding interactions with the receptor. The most
potent compounds of 4e, 4f, 4g, and 4j showed
maximum dock score good H-bond interactions with
receptor, and these compounds are tabularized in Table 3.
4e, 4f, 4g, and 4j show the superior docking score in
both open (PDB-1SAO) and closed conformations of the
protein, which confirms its high binding affinity. In
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. C. Jilloju, A. Vinaykumar, P. Shyam, and R. R. Vedula
Vol 000
addition, the high affinity of compounds can be further
testified by its optimal potential energy, columbic and
Van der Waals forces, interaction profile as well as
excellent hydrogen bonding efficiency in the active
site of the protein. The docking images of best
compounds of 4e, 4f, 4g, and 4j were shown in Figure 1
receptor structure (amino acids). Are shown in wireframe
representation and ligand structure as shown in
sticks representation, and H-bonds are visualized by
dotted lines.
Table 2
Synthesis of various aralkyl/alkylthio-3,5-dimethyl-1H-pyrazolyl-4H-1,2,4-triazol-4-amines (4a–m).
Compound 4
R–
M.F.
M.W.
300
Time (h)
8.00
Yield (%)
90
4a
C14H16N6S
4b
C14H15N7O2S
345
8.30
88
4c
4d
4e
C10H12N6S
C10H14N6S
C11H16N6O2S
248
250
296
8.20
8.40
8.50
86
82
80
4f
C9H12N6O2S
268
9.00
84
4g
4h
4i
C21H38N6S
C19H34N6S
C17H30N6S
C15H26N6S
406
378
350
322
9.20
9.20
9.30
9.30
82
83
81
85
4j
4k
4l
C14H24N6S
C13H22N6S
C12H20N6S
308
294
280
9.40
9.40
9.50
88
84
78
4m
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
One-pot,Multicomponent Cascade Reaction for the Synthesis of Various Aralkyl/alkylthio-
3,5-dimethyl-1H-pyrazolyl-4H-1,2,4-triazol-4-amine and Their Docking Studies
Table 3
The docking interactions of 4a–m compounds with active site of TUBULIN-COLCHICINE (1SAO).
Interacting residues
Ligand
name
Docking energy
(kcal)
Ligand
Receptor (1SAO)
Distance (A°)
4a
NH
NH
NH
NH
NH
NH
NH
O
O
NH
NH
NH
NH
NH
NH
NH
OD1-ASP98
OD2-ASP69
OE2-GLU71
OG-SER140
OG-SER140
OD1-ASN228
OG-SER140
NH-THR145
NH-GLY146
O-SER178
O-VAL177
O-SER178
OE2-GLU183
OG-SER140
O-SER178
O-VAL177
OG-SER140
OD1-ASN228
–
2.69
2.86
2.97
2.74
2.72
2.60
2.55
2.60
2.95
2.59
2.97
2.75
2.78
2.69
2.60
2.72
2.60
2.77
–
À88.2354
4b
4c
4d
4e
4f
À86.8753
À88.1245
À88.4578
À89.2546
À88.1124
4g
4h
À89.9887
À79.2456
4i
4j
À80.2013
À79.2451
4k
4l
4m
NH
NH
À79.2456
À79.2345
–
Not good interactions
Bold text signifies good interactions with receptors.
Figure 1. H-bonding interactions between amino acid residues at the active site of the TUBULIN and compounds 4e, 4f, 4g, and 4j. [Color figure can be
viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. C. Jilloju, A. Vinaykumar, P. Shyam, and R. R. Vedula
Vol 000
CONCLUSION
a 25-mL round bottom flask. Then to the reaction
mixture, appropriate aralkyl/alkyl halides (0.001 mol) and
DMF (2 mL) were added. The reaction mixture was
refluxed for 8–10 h at 80–90°C by monitoring TLC.
After completion of reaction, the resulting mixture was
cooled, and the separated solid was filtered and
recrystallized from 6- to 8-mL ethanol.
In summary, a facile and simple procedure for the
synthesis of various aralkyl/alkylthio-3,5-dimethyl-1H-
pyrazolyl-4H-1,2,4-triazol-4-amines 4a–m has been
achieved via a multicomponent approach using readily
available chemicals. The attractive and notable features of
this approach is as good yields, neat reaction conditions,
easy of product purification, metal free, atom economy,
and avoiding toxic catalyst. The synthesized compounds
could be useful for the medicinal chemistry applications.
The biological activity of these compounds is in progress.
4-Amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol
(1).
White color solid; yield 72%; mp 236–238°C; IR (KBr,
1
ʋ
max, cmÀ1): 3440, 3268, 3215, 3075, 2915, 2792. H-
NMR (400 MHz, DMSO-d6, δ ppm): 4.10 (s, 2H,
hydrazino ─NH2), 5.27 (s, 2H, ─NH2), 7.15 (s, 1H,
─NH─), 12.70 (s,1H, ─SH). 13C-NMR (100 MHz,
DMSO-d6, δ ppm): 155.1, 164.9. ESI-MS m/z 147
[M + H]+.
EXPERIMENTAL
3-(Benzylthio)-5-(3,5-dimethyl-1H-pyrazol-1-yl)-4H-1,2,4-
triazol-4-amine (4a). White color solid; yield 90%; mp
All the reagents and chemicals were pure, procured
commercially, and were used without further purification
unless otherwise stated. 4-Amino-5-hydrazinyl-4H-1,2,4-
triazole-3-thiol (1) was synthesized by the following
literature procedure [40]. A mixture of thiourea (0.5 mol,
38 g) and 98% hydrazine hydrate (100 mL) were refluxed
on water bath for 3 h. The reaction mixture was cooled,
diluted with 150-mL distilled water, neutralized (pH 6.5)
by adding approximately 10-mL Conc. HCl, and
refrigerated at 0°C for 30 min. The crude product was
filtered, washed with cold water, and digested in 75-mL
2 M HCl for 15 min. After removal of acid insoluble
impurities, the filtrate was neutralized to pH 6.5 with
NaOH and refrigerated at 0°C for 30 min. The solid was
formed gradually. It was filtered, washed several times
with water, dried, and recrystallized from water to give
4-amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol (1) as
white solid.
All the synthesized compounds purity was checked by
TLC (TLC plate) (E. Merck, Mumbai, India). Melting
points were recorded by using “VEEGO” programmable
melting point apparatus. IR spectra in KBr pellets were de-
termined on a PerkinElmer 100S FTIR spectrophotometer.
1H-NMR and 13C-NMR spectra were recorded on a Bruker
WM-400 spectrometer in δ ppm using tetramethylsilane as
the reference standard. Dimethyl sulfoxide (DMSO-d6)
and CDCl3 solvents were used for recording 1H-NMR
and 13C-NMR. ESI-MS spectra of compounds were
recorded on a PerkinElmer spectrometer operating at
12.5 eV. Carbon, Hydrogen, Nitrogen, Sulphur (CHNS)
analysis was done on a Carlo Erba EA 1108 CHNS-O El-
emental Analyzer.
140–142°C; IR (KBr, ʋmax, cmÀ1): 3323 (─NH2). 1H-
NMR (400 MHz, CDCl3, δ ppm): 2.26 (s, 3H, ─CH3),
2.53 (s, 3H, ─CH3), 4.46 (s, 2H, ─SCH2─), 5.22 (s, 2H,
─NH2), 6.02 (s, 1H, ─CH─ of pyrazole ring), 7.31 (m,
3H, Ar-H), 7.43 (d, 2H, J = 8 Hz, Ar-H). 13C-NMR
(100 MHz, CDCl3, δ ppm): 12.34, 13.57, 35.89, 108.11,
127.74, 128.68, 129.18, 136.75, 143.20, 147.66, 151.31,
151.83. ESI-MS m/z 301 [M + H]+. Analytical calculated
formulae C14H16N6S: C, 55.98; H, 5.37; N, 27.98; S,
10.67. Found: C, 55.95; H, 5.40; N, 27.93; S, 10.71.
3-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-((4-nitrobenzyl)thio)-4H-
1,2,4-triazol-4-amine (4b). White color solid; yield 88%;
mp 168–170°C; IR (KBr, ʋmax, cmÀ1): 3312 (─NH2).
1H-NMR (400 MHz, DMSO-d6, δ ppm): 2.24 (s, 3H,
─CH3), 2.35 (s, 3H, ─CH3), 4.56 (s, 2H, ─SCH2─), 5.92
(s, 2H, ─NH2), 6.10 (s, 1H, ─CH─ of pyrazole ring),
7.73 (d, 2H, J = 8 Hz, Ar-H), 8.16 (d, 2H, J = 8 Hz, Ar-
H). 13C-NMR (100 MHz, DMSO-d6, δ ppm): 11.6, 13.8,
33.9, 107.8, 123.9, 130.8, 143.1, 146.4, 147.1, 149.2,
151.1, 151.9. ESI-MS m/z 446 [M + H]+. Analytical
calculated formulae C14H15N7O2S: C, 48.69; H, 4.38; N,
28.39; S, 9.28. Found: C, 48.65; H, 4.33; N, 28.42; S, 9.25.
3-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-(prop-2-yn-1-ylthio)-4H-
1,2,4-triazol-4-amine (4c). White color solid; yield 86%;
mp 165–167°C; IR (KBr, ʋmax, cmÀ1): 3434 (─NH2).
1H-NMR (400 MHz, CDCl3, δ ppm): 1.26 (s, 1H,
─C≡C─H), 2.29 (s, 3H, ─CH3), 2.56 (s, 3H, ─CH3),
4.02 (s, 2H, ─SCH2─), 5.44 (s, 2H, ─NH2), 6.05 (s, 1H,
─CH─ of pyrazole ring). 13C-NMR (100 MHz,
CDCl3 + DMSO-d6, δ ppm): 12.1, 13.6, 19.7, 72.6, 78.7,
107.9, 142.9, 148.4, 150.4, 151.7. ESI-MS m/z 249
[M + H]+. Analytical calculated formulae C10H12N6S: C,
48.37; H, 4.87; N, 33.85; S, 12.91. Found: C, 48.34; H,
General procedure for the one-pot, multicomponent
4.84; N, 33.89; S, 12.95.
cascade reaction
aralkyl/alkylthio-3,5-dimethyl-1H-pyrazolyl-4H-1,2,4-triazol-
4-amine (4a-m). A mixture of 4-amino-5-hydrazino-4H-
for the synthesis
of various
3-(Allylthio)-5-(3,5-dimethyl-1H-pyrazol-1-yl)-4H-1,2,4-
triazol-4-amine (4d). White color solid; yield 82%; mp
93–95°C; IR (KBr, ʋmax, cmÀ1): 3319 (─NH2). H-NMR
1
[1,2,4]triazole-3-thiol (0.001 mol) and pentane-2,4-dione
(0.001 mol) was refluxed for 3 h in dry ethanol (2 mL) in
(400 MHz, CDCl3, δ ppm): 2.29 (s, 3H, ─CH3), 2.55
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
One-pot,Multicomponent Cascade Reaction for the Synthesis of Various Aralkyl/alkylthio-
3,5-dimethyl-1H-pyrazolyl-4H-1,2,4-triazol-4-amine and Their Docking Studies
(s, 3H, ─CH3), 3.91 (d, 2H, J = 8 Hz, ─SCH2─), 5.19
(d, 1HA, HX HA, J = 8 Hz), 5.33 (s, 1HB,), 5.38 (s, 2H,
─NH2), 6.03 (m, 1HX, ═CH─), 6.04 (s, 1H, ─CH─ of
pyrazole ring). 13C-NMR (100 MHz, CDCl3, δ ppm):
12.3, 13.6, 34.1, 108.1, 119.0, 132.7, 143.2, 147.6,
151.2, 151.8. ESI-MS m/z 251 [M + H]+. Analytical
calculated formulae C10H14N6S: C, 47.98; H, 5.64;
N, 33.57; S, 12.81. Found: C, 47.95; H, 5.60; N, 33.60;
11.5, 13.8, 14.4, 22.6, 28.5, 29.0, 29.1, 29.4, 29.6, 30.9,
31.8, 107.7, 143.1, 148.9, 151.0, 152.9. ESI-MS m/z 351
[M + H]+. Analytical calculated formulae C19H34N6S: C,
60.28; H, 9.05; N, 22.20; S, 8.47. Found: C, 60.23; H,
9.11; N, 22.25; S, 8.43.
3-(Decylthio)-5-(3,5-dimethyl-1H-pyrazol-1-yl)-4H-1,2,4-
triazol-4-amine (4i). White color solid; yield 81%; mp 78–
80°C; IR (KBr, ʋmax, cmÀ1): 3341 (─NH2). 1H-NMR
(400 MHz, CDCl3, δ ppm): 0.89 (t, 3H, J = 8 Hz,
─CH3), 1.28 (unresolved m, 12H, ─(CH2)6─), 1.47(m,
2H, ─CH2─), 1.82 (m, 2H, ─CH2─), 2.29 (s, 3H,
─CH3), 2.55 (s, 3H, ─CH3), 3.27 (t, 2H, J = 8 Hz,
─SCH2─), 5.35 (s, 2H, ─NH2), 6.04 (s, 1H, ─CH─ of
pyrazole ring). 13C-NMR (100 MHz, CDCl3, δ ppm):
12.3, 13.6, 14.1, 22.7, 28.8, 29.1, 29.3 29.4, 29.5, 31.2,
31.9, 108.1, 143.2, 147.6, 151.8, 152.2. ESI-MS m/z 351
[M + H]+. Analytical calculated formulae C17H30N6S: C,
58.25; H, 8.63; N, 23.98; S, 9.15. Found: C, 58.20; H,
S, 12.85.
Ethyl-2-((4-amino-5-(3,5-dimethyl-1H-pyrazol-1-yl)-4H-
1,2,4-triazol-3-yl)thio) acetate (4e). White color solid; yield
80%; mp 100–102°C; IR (KBr, ʋmax, cmÀ1): 3304
1
(─NH2). H-NMR (400 MHz, CDCl3, δ ppm): 1.30 (t,
3H, J = 8 Hz, ─CH3), 2.29 (s, 3H, ─CH3), 2.54 (s, 3H,
─CH3), 4.05 (s, 2H, ─SCH2─), 4.24 (q, 2H, ─CH2O─),
5.49 (s, 2H, ─NH2) 6.04 (s, 1H, ─CH─ of pyrazole
ring). 13C-NMR (100 MHz, CDCl3, δ ppm): 12.3, 13.6,
14.1, 33.6, 62.1, 108.1, 143.2, 147.9, 150.4, 151.9,
158.6. ESI-MS m/z 297 [M + H]+. Analytical calculated
formulae C11H16N6O2S: C, 44.58; H, 5.44; N, 28.36; S,
8.68; N, 23.95; S, 9.19.
3-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-(octylthio)-4H-1,2,4-
triazol-4-amine (4j).
White color solid; yield 85%; mp
10.82. Found: C, 44.62; H, 5.47; N, 28.39; S, 10.87.
2-((4-Amino-5-(3,5-dimethyl-1H-pyrazol-1-yl)-4H-1,2,4-
triazol-3-yl)thio) acetic acid (4f). White color solid; yield
95–97°C; IR (KBr, ʋmax, cmÀ1): 3325 (─NH2). 1H-
NMR (400 MHz, CDCl3, δ ppm): 0.88 (t, 3H, J = 8 Hz,
─CH3), 1.27 (unresolved m, 8H, ─(CH2)4─), 1.45 (m,
2H, ─CH2─), 1.80 (m, 2H, ─CH2─), 2.27 (s, 3H,
─CH3), 2.53 (s, 3H, ─CH3), 3.25 (t, 2H, J = 8 Hz,
─SCH2─), 5.34 (s, 2H, ─NH2), 6.02 (s, 1H, ─CH─ of
pyrazole ring). 13C-NMR (100 MHz, CDCl3, δ ppm):
12.4, 13.6, 14.1, 22.6, 28.8, 29.1, 29.2, 29.5, 31.3, 31.8,
108.1, 143.2, 147.5, 151.8, 152.2. ESI-MS m/z 323
[M + H]+. Analytical calculated formulae C15H26N6S: C,
55.87; H, 8.13; N, 26.06; S, 9.94. Found: C, 55.83; H,
84%; mp 202–204°C; IR (KBr, ʋmax, cmÀ1): 3293
1
(─NH2). H-NMR (400 MHz, DMSO-d6, δ ppm): 2.21
(s, 3H, ─CH3), 2.25 (s, ─NH2), 2.34 (s, 3H, ─CH3),
3.93 (s, 2H, ─SCH2─), 6.03 (s, 1H, ─CH─ of
pyrazole ring), 7.93 (s, 1H, ─OH). 13C-NMR
(100 MHz, DMSO-d6, δ ppm): 11.6, 13.8, 33.3, 107.7,
143.1, 149.0, 151.1, 152.4, 170.0. ESI-MS m/z 269
[M + H]+. Analytical calculated formulae C9H12N6O2S:
C, 40.29; H, 4.51; N, 31.32; S, 11.95. Found: C, 40.33;
H, 4.55; N, 31.35; S, 11.99.
8.10; N, 26.12; S, 9.90.
3-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-(tetradecylthio)-4H-
1,2,4-triazol-4-amine (4g). White color solid; yield 82%;
3-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-(heptylthio)-4H-1,2,4-
triazol-4-amine (4k). White color solid; yield 90%; mp
mp 96–98°C; IR (KBr, ʋmax, cmÀ1): 3340 (─NH2). H-
90–92°C; IR (KBr, ʋmax, cmÀ1): 3296 (─NH2). H-NMR
1
1
NMR (400 MHz, CDCl3, δ ppm): 0.88 (t, 3H, J = 8 Hz,
─CH3), 1.26 (unresolved m, 20H, ─(CH2)10─), 1.45(m,
2H, ─CH2─), 2.28 (s, 3H, ─CH3), 2.54 (s, 3H, ─CH3),
3.26 (t, 2H, J = 8 Hz, ─SCH2─), 5.32 (s, 2H, ─NH2),
6.03 (s, 1H, ─CH─ of pyrazole ring). 13C-NMR
(100 MHz, DMSO-d6, δ ppm): 11.6, 13.8, 22.6, 28.5,
29.0, 29.2, 29.4, 29.5, 30.9, 31.8, 107.6, 143.0, 148.9,
151.0, 152.9. ESI-MS m/z 407 [M + H]+. Analytical
calculated formulae C21H38N6S; C, 62.03: H, 9.42; N,
(400 MHz, CDCl3, δ ppm): 0.88 (t, 3H, J = 8 Hz,─CH3),
1.29 (m, 6H, ─(CH2)3─), 1.45 (m, 2H, ─CH2─), 1.80
(m, 2H, ─CH2─), 2.27 (s, 3H, ─CH3), 2.53 (s, 3H,
─CH3), 3.25 (t, 2H, J = 8 Hz, ─SCH2─), 5.33 (s, 2H,
─NH2), 6.02 (s, 1H, ─CH─ of pyrazole ring). 13C-NMR
(100 MHz, CDCl3, δ ppm): 12.4, 13.6, 14.1, 22.6, 28.7,
28.8, 29.5, 31.3, 31.7, 108.1, 143.2, 147.5, 151.8, 152.2.
ESI-MS m/z 309 [M + H]+. Analytical calculated
formulae C14H24N6S: C, 54.52; H, 7.84; N, 27.25; S,
20.67; S, 7.89. Found: C, 61.97; H, 9.38; N, 20.62; S, 7.93.
3-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-(dodecylthio)-4H-1,2,4-
triazol-4-amine (4h). White color solid; yield 83%; mp
10.40. Found: C, 54.55; H, 7.80; N, 27.29; S, 10.46.
3-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-(hexylthio)-4H-1,2,4-
triazol-4-amine (4l).
White color solid; yield 84%; mp
143–145°C; IR (KBr, ʋmax, cmÀ1): 3341 (─NH2). 1H-
NMR (400 MHz, CDCl3 + DMSO-d6, δ ppm): 0.80 (t,
3H, J = 8 Hz, ─CH3), 1.24 (m, 4H, ─(CH2)2─), 1.38
(m, 2H, ─CH2─), 1.71 (m, 2H, ─CH2─), 2.19 (s, 3H,
─CH3), 2.28 (s, 3H, ─CH3), 3.24 (t, 2H, J = 8 Hz,
─SCH2─), 4.26 (s, 2H, ─NH2), 5.96 (s, 1H, ─CH─ of
pyrazole ring). 13C-NMR (100 MHz, CDCl3 + DMSO-d6,
1
73–75°C; IR (KBr, ʋmax, cmÀ1): 3340 (─NH2). H-NMR
(400 MHz, CDCl3, δ ppm): 0.89 (t, 3H, J = 8 Hz,
─CH3), 1.29 (unresolved m, 16H, ─(CH2)8─), 1.47 (m,
2H, ─CH2─), 1.81 (m, 2H, ─CH2─), 2.26 (s, 3H,
─CH3), 2.56 (s, 3H, ─CH3), 3.29 (t, 2H, J = 8 Hz,
─SCH2─), 5.27 (s, 2H, ─NH2), 6.04 (s, 1H, ─CH─ of
pyrazole ring). 13C-NMR (100 MHz, DMSO-d6, δ ppm):
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. C. Jilloju, A. Vinaykumar, P. Shyam, and R. R. Vedula
Vol 000
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δ ppm): 11.1, 11.5, 13.7, 14.3, 29.5, 30.9, 31.2, 34.9,
107.8, 143.6, 144.8, 145.7, 151.5, 167.3. ESI-MS m/z
295 [M
+
H]+. Analytical calculated formulae
C13H22N6S; C, 53.03; H, 7.53; N, 28.54; S, 10.89.
Found: C, 52.97; H, 7.50; N, 28.57; S, 10.83.
3-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-(pentylthio)-4H-1,2,4-
triazol-4-amine (4m). White color solid; yield 78%; mp
126–128°C; IR (KBr, ʋmax, cmÀ1): 3341 (─NH2). 1H-
NMR (400 MHz, CDCl3 + DMSO-d6, δ ppm): 0.82
(t, 3H, J = 8 Hz, ─CH3), 1.31 (m, 4H, ─(CH2)2─), 1.71
(m, 2H, ─CH2─), 2.19 (s, 3H, ─CH3), 2.27 (s, 3H,
─CH3), 3.21 (t, 2H, J = 8 Hz, ─SCH2─), 4.02 (s, 2H,
─NH2), 5.96 (s, 1H, ─CH─ of pyrazole ring). 13C-NMR
(100 MHz, CDCl3 + DMSO-d6, δ ppm): 11.5, 13.8, 14.3,
22.1, 29.2, 30.7, 30.9, 107.8, 143.3, 148.9, 151.1, 151.4.
ESI-MS m/z 281 [M + H]+. Analytical calculated
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Acknowledgments. The authors are thankful to the Head of the
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet