An efficient one-pot expeditious synthesis of 3-phenyl-1-(6-phenyl-7H-[1,2,4] triazolo[3,4-b] [1,3,4] thiadiazin-3-yl)-1H-pyrazol-5-amines via multicomponent approach

Article abstract of DOI:10.1080/00397911.2018.1537398

An efficient synthesis of 3-phenyl-1-(6-phenyl-7H-[1,2,4] triazolo[3,4-b][1,3,4]thiadiazin-3-yl)-1H-pyrazol-5-amines was accomplished by a simple, atom-economical, and multicomponent approach. Reaction of 4-amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol with various phenacyl bromides and benzoylacetonitriles in ethanol and catalytic amount of acetic acid afforded the titled compounds. The structures of newly synthesized compounds were confirmed by their analytical and spectral (IR, ¹H-NMR, ¹³C-NMR, and Mass) data.

Full text of DOI:10.1080/00397911.2018.1537398

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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An efficient one-pot expeditious synthesis of
3-phenyl-1-(6-phenyl-7H-[1,2,4] triazolo[3,4-b]
[1,3,4] thiadiazin-3-yl)-1H-pyrazol-5-amines via
multicomponent approach
Kodam Sujatha, Ravindra Pramod Deshpande, Rajesh Kumar Kesharwani,
Phanithi Prakash Babu & Rajeswar Rao Vedula
To cite this article: Kodam Sujatha, Ravindra Pramod Deshpande, Rajesh Kumar Kesharwani,
Phanithi Prakash Babu & Rajeswar Rao Vedula (2018): An efficient one-pot expeditious synthesis
of 3-phenyl-1-(6-phenyl-7H-[1,2,4] triazolo[3,4-b] [1,3,4] thiadiazin-3-yl)-1H-pyrazol-5-amines via
multicomponent approach, Synthetic Communications, DOI: 10.1080/00397911.2018.1537398
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https://doi.org/10.1080/00397911.2018.1537398
An efficient one-pot expeditious synthesis of 3-phenyl-1-(6-
phenyl-7H-[1,2,4] triazolo[3,4-b] [1,3,4] thiadiazin-3-yl)-1H-
pyrazol-5-amines via multicomponent approach
a
b
c
Kodam Sujatha , Ravindra Pramod Deshpande
, Rajesh Kumar Kesharwani ,
b
a
Phanithi Prakash Babu
, and Rajeswar Rao Vedula
a
b
Department of Chemistry, National Institute of Technology, Warangal, India; Department of
Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, India;
c
Department of Advanced Science & Technology, NIET, Nims University Rajasthan, Jaipur, India
ABSTRACT
ARTICLE HISTORY
An efficient synthesis of 3-phenyl-1-(6-phenyl-7H-[1,2,4] triazolo[3,4-
b][1,3,4]thiadiazin-3-yl)-1H-pyrazol-5-amines was accomplished by a
simple, atom-economical, and multicomponent approach. Reaction
of 4-amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol with various phe-
nacyl bromides and benzoylacetonitriles in ethanol and catalytic
amount of acetic acid afforded the titled compounds. The structures
of newly synthesized compounds were confirmed by their analytical
Received 17 July 2018
KEYWORDS
Multicomponent reaction;
phenacyl bromide; 3-(2-
bromoacetyl)-2H-chromen-
2
-one; triazolothiadiazine
1
13
and spectral (IR, H-NMR, C-NMR, and Mass) data.
GRAPHICAL ABSTRACT
Introduction
Triazoles are important class of heterocyclic compounds for organic chemists on
account of their implications in the biological, pharmacological, medicinal, agricultural,
CONTACT Rajeswar Rao Vedula
rajeswarnitw@gmail.com
Department of Chemistry, National Institute of
Technology, Warangal, Telangana 506 004, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
ß 2018 Taylor & Francis Group, LLC

2
K. SUJATHA ET AL.
Figure 1. Design strategy of synthesized molecules.
[
1,2]
and industry.
heterocyclic ring its enhance the biological activity of the lead molecule
thiadiazines were associated with different biological activities such as anti-cancer,
When triazole ring is fused with a 5-membered or with a 6-membered
[
3,4]
and triazolo-
[
5,6]
[
7]
[8]
[9]
anti-tubercular,
anti-candidal,
and anti-microbial activity.
Triazolothiadiazines
having substituent’s such as substituted aryl, coumarin moieties are reported with better
[
10,11]
biological activity.
Pyrazoles are also important heterocyclic molecules.
tives are having predominant biological and pharmacological activities,
[
12,13]
Pyrazoles and their deriva-
[
14–17]
such as
anti-tubercular, anti-bacter-
[
18]
[19]
anti-hyperglycaemic,
anticonvulsant, anti-depressant,
[
20]
[21,22]
[23,24]
[25]
[26]
ial,
diabetic
ring directly linked to the 1,2,4-triazolo-[3,4-b]thiadiazines showed human (h) A
anti-viral,
anti-fungal,
anti-histaminic,
anti-inflammatory,
anti-
[
27]
[28]
and anti-leukaemia agent.
The existing literature revealed that pyrazole
3
[
29]
[30,31]
adenosine receptor
and better anti-proliferative activity (Figure 1).
Multicomponent reactions are widely used in organic synthesis due to advantages
such as high efficiency, atom economy, high yields, clear reactions, and simple proce-
[
32]
dures resulting in the formation of new structures.
Some of the reported biologically active molecules with triazolothiadiazine, pyrazolo-
triazolothiadiazines, and pyrazolocoumarin scaffolds.
Keeping the importance of triazoles, pyrazoles, and triazolothiadiazines, our present
study is focused on the development of new methodologies for the synthesis of thiadia-
zine fused to triazole and having pyrazole.

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3
Scheme 1. Synthesis of compounds 4a–4m.
[
33,34]
In continuation of our earlier work on MCR,
we have developed a one-pot mul-
ticomponent reaction for the synthesis of title compounds intending that these com-
pounds may have good biological activities (Schemes 1 and 2).
Results and discussion
4
-Amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol can be taken as useful tool in building
triazolothiadiazinylpyrazoles. It is prepared by reaction of thiourea with hydrazine
[
35]
hydrate under reflux conditions on water bath.
Condensation of 4-amino-5-hydra-
zinyl-4H-1,2,4-triazole-3-thiol (1), various phenacyl bromides or 3-(2-bromoacetyl)-2H-
chromen-2-ones (2), and benzoylacetonitriles (3) resulted in the formation of 4 and 6.
Reaction between compound 1, phenacyl bromide or 3-(2-bromoacetyl)-2H-chromen-
2-one and phenacyl cyanide is expected to produce compound 7 and 8 depending on
the mode of cyclization. The formation of compound 7 and 8 can be ruled on the basis
of spectral studies. In the present investigation, both NH and SH of 1 at a time under-
2
goes condensation with either 2 or 5 leading to first hetero cyclization. Then, the hydra-
zino group of 1 reacts with phenacyl cyanide to give the title compound. The desired
product was achieved in each case good to excellent yield. The work may trigger an
interesting chemistry involving new methodology. The very noticeable feature of the
synthesis is that different hetero atom bonds like C–S, 2N = C, and N–C (compounds 4
and 6) are formed concomitantly in one pot leading to selective new hetero cyclization
without formation of any other products (Table 1).
In the formation of fused thiadiazine ring on triazole, the highly nucleophilic sulfur
atom of mercapto group of 1 attacks on the carbon atom of the (CH -Br) of phenacyl
2
bromide or 3-(2-bromoacetyl)-2H-chromen-2-one to give an open chain α-thioketone.
Then, it undergoes intra molecular cyclization, leading to the formation of thiadiazine
ring. The hydrazino group of triazolothiadiazine undergoes cyclocondensation reaction
with benzoylacetonitrile leading to the formation of title compounds with better yields.
The structures of all the newly synthesized compounds were confirmed by their ana-
lytical and spectral data and are summarized in supporting information. The IR spec-
−
1
trum of Compound 4a shows prominent peaks at 3411 cm (NH Stretching), 1618
2
−1
1
cm (–C = N– stretching). The H-NMR spectrum of the compound 4a showed a

4
K. SUJATHA ET AL.
Scheme 2. Synthesis of compounds 6a–6d.
characteristic peak at δ 4.49 ppm corresponds to CH of thiadiazine and δ 5.90 ppm
2
corresponds to pyrazole proton. The 13C NMR of the 4a exhibits a characteristic peak
at δ 23.5 ppm. This is due to carbon atom of CH of thiadiazine. The compound 4a
2
exhibited the molecular ion peak at m/z 407.
Experimental
All the chemicals which were used in the present study were purchased from commer-
cial sources and used further without any purification. Melting points were determined
in open capillaries with a Stuart melting point apparatus Mumbai, India and were
1
uncorrected. IR spectra were recorded on Perkin Elmer Spectrum 100 s. H-NMR spec-
tra were recorded on Bruker WM-400 spectrometer in δ ppm using TMS as the stand-
ard, ESI-MS spectra were recorded on Jeol JMSD-300 spectrometer. Elemental analyses
were performed on a Carlo Erba EA 1108 automatic elemental analyzer, compounds
purity was checked by TLC plates (E Merck, Mumbai, India). The Supplemental
1
13
Materials contain H and C NMR spectra of products 4, 6.
General procedure for the synthesis of compounds (4a–m and 6a–d)
An equimolar amount of 4-amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol (1 mmol) and
phenacyl bromide (1 mmol) or 3-(2-bromoacetyl)-2H-chromen-2-one (1 mmol) in etha-
nol (5 ml) and catalytic amount of acetic acid (2 drops) was refluxed for 1 h. Then, the
reaction mixture was treated with benzoylacetonitrile (1 mmol) and further refluxed for
1
h. The reaction mixture was cooled to room temperature. The solid separated was fil-
tered and recrystallized from methanol to give final product.

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5
Table1. Different substitutions of the compounds 4a–4m and 6a–6d.
1
2
3
4
Entry
Product
R
R
R
R
R
Yields (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
6a
6b
6c
6d
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
H
Cl
H
H
Cl
Cl
Cl
H
H
–
–
–
–
–
–
–
–
–
–
–
–
–
H
Cl
H
Br
–
–
–
–
–
–
–
–
–
–
–
–
–
OEt
–
OEt
OCH
92
96
90
95
95
93
91
95
89
97
92
90
85
96
92
97
93
CH
Cl
F
OCH
H
3
H
H
H
H
H
H
H
Cl
H
H
H
CH
–
–
–
–
3
Br
CH
Cl
F
OCH
Ph
H
3
1
1
1
1
1
1
1
1
3
3
–
–
–
–
3
3
-(4-Chlorophenyl)-1-(6-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl)-1H-
pyrazol-5-amine (4a)
−
1
Pale yellow solid; mp 240–241 °C; Yield (92%); IR (KBr, ν , cm ): 3411 (NH
max
2
1
Stretching), 1618 (–C = N– stretching); H NMR (400 MHz, DMSO-d , ppm): δ 4.49 (s,
6
2
H, CH ), 5.90 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.51–7.60 (m, 3 H ArH and 2 H
2
NH ), 7.79 (d, J = 8.8 Hz, 2H), 7.93 (d, J = 7.2 Hz, 2H); 13C NMR (100 MHz, DMSO-
2
d , ppm): δ 23.5, 84.9, 127.5, 128.0, 129.1, 129.5, 130.7, 132.6, 133.1, 133.6, 142.8, 146.3,
6
+
1
5
51.9, 152.3, 156.6. ESI-MS, m/z (%): 408 (M + H) ; anal. calcd. for C H ClN S: C,
19
14
7
5.95; H, 3.46; Cl, 8.69; N, 24.04; S, 7.86. Found: C, 55.90; H, 3.41; Cl, 8.62; N, 24.10;
S, 7.82.
3
-(3-(5-Amino-3-phenyl-1H-pyrazol-1-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-
-yl)-8-ethoxy-2H-chromen-2-one (6a)
6
−
1
Brown solid; mp 219–220 °C; Yield (96%); IR (KBr, νmax, cm ): 3467 (NH Stretching),
1
2
1
722 (lactone C = O stretching), 1614 (–C = N– stretching); H NMR (400 MHz,
DMSO-d , ppm): δ 1.40 (t, J = 6.8 Hz, 3H), 4.19 (d, J = 6.8 Hz, 2H), 4.35 (s, 2H), 5.85
6
(
1
s, 1H), 6.02 (s, 2H), 7.31–7.35 (m, 3H), 7.39 (t, J = 6.0 Hz, 3H), 7.75 (d, J = 7.2 Hz,
H), 8.32 (s, 1H), 8.43 (s, 1H). ESI-MS, m/z (%): 486 (M + H) ; anal. calcd. for
+
C H N O S: C, 59.37; H, 3.94; N, 20.19; S, 6.60. Found: C, 59.32; H, 3.93; N, 20.15;
2
4
19 7 3
S, 6.65.
Conclusion
In conclusion, we report a novel one-pot multicomponent synthesis of some 3-phenyl-
1
-(6-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl)-1H-pyrazol-5-amines
by
using readily available starting materials. This synthetic method has more advantages
such as shorter reaction time, no use of harsh reaction conditions, easy work-up pro-
cedure, and good to excellent yields of the products.

6
K. SUJATHA ET AL.
Acknowledgments
The authors are thankful to the Director, National Institute of Technology, Warangal, Telangana,
India for providing the facilities. K. S thanks to the MHRD, India for fellowship.
ORCID
Ravindra Pramod Deshpande
http://orcid.org/0000-0002-4634-9967
Phanithi Prakash Babu
http://orcid.org/0000-0002-1528-8575
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