Efficient, one-pot synthesis of triazolothiadiazinyl-pyrazolone and pyrazolyl-triazolothiadiazine derivatives via multicomponent reaction

Article abstract of DOI:10.1080/00397911.2012.721917

A one-pot, multicomponent reaction of 3-(2-bromo acetyl)coumarins, 4-amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol, and different derivatives of ethyl 2-(2-(aryl)hydrazono)-3-oxobutanoates provide an efficient and direct method for the synthesis of 4-(arylydrazono)-3-methyl-1-(6-(coumarin-3-yl)-7H- [1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl)-1H-pyrazol-5(4H)-ones (4a-h). A similar methodology was also developed for the synthesis of pyrazolyl- triazolothiadiazines (9a-f) using acetyl acetone, 4-amino-5-hydrazino-4H-[1,2,4] triazole-3-thiol, and different derivatives of phenacylbromide. The resulting products were characterized by analytical and spectral data.

Full text of DOI:10.1080/00397911.2012.721917

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Efficient, One-Pot Synthesis of
Triazolothiadiazinyl-pyrazolone and
Pyrazolyl-triazolothiadiazine Derivatives
via Multicomponent Reaction
Tewodros Birhanu Aychiluhim a & Vedula Rajeswar Rao a
a Department of Chemistry , National Institute of Technology ,
Warangal , India
Accepted author version posted online: 30 Jan 2014.Published
online: 29 Apr 2014.
To cite this article: Tewodros Birhanu Aychiluhim & Vedula Rajeswar Rao (2014) Efficient,
One-Pot Synthesis of Triazolothiadiazinyl-pyrazolone and Pyrazolyl-triazolothiadiazine
Derivatives via Multicomponent Reaction, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 44:10, 1422-1429, DOI:
10.1080/00397911.2012.721917
To link to this article: http://dx.doi.org/10.1080/00397911.2012.721917
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Synthetic Communications1, 44: 1422–1429, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.721917
EFFICIENT, ONE-POT SYNTHESIS OF
TRIAZOLOTHIADIAZINYL-PYRAZOLONE AND
PYRAZOLYL-TRIAZOLOTHIADIAZINE DERIVATIVES
VIA MULTICOMPONENT REACTION
Tewodros Birhanu Aychiluhim and Vedula Rajeswar Rao
Department of Chemistry, National Institute of Technology, Warangal, India
GRAPHICAL ABSTRACT
Abstract A one-pot, multicomponent reaction of 3-(2-bromo acetyl)coumarins, 4-amino-5-
hydrazino-4H-[1,2,4]triazole-3-thiol, and different derivatives of ethyl 2-(2-(aryl)hydra-
zono)-3-oxobutanoates provide an efficient and direct method for the synthesis of
4-(arylydrazono)-3-methyl-1-(6-(coumarin-3-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadia-
zin-3-yl)-1H-pyrazol-5(4H)-ones (4a–h). A similar methodology was also developed for the
synthesis of pyrazolyl-triazolothiadiazines (9a–f) using acetyl acetone, 4-amino-5-hydra-
zino-4H-[1,2,4]triazole-3-thiol, and different derivatives of phenacylbromide. The resulting
products were characterized by analytical and spectral data.
Keywords Multicomponent reaction; pyrazole; pyrazolone; triazolothiadiazine
INTRODUCTION
Multicomponent reactions, involving succession of processes with at least three
different substrates to generate complex molecular structures, have emerged as a
powerful synthetic strategy in the field of organic synthesis. It would be worthy to
conduct a series of simple steps in one pot, which would minimize the chemicals
used, waste produced, and the reaction time consumed. Thus, great attention has
been given to the development of cascade reactions.[1]
Coumarin derivatives have received significant attention as they possess several
types of pharmacological properties, such as antibacterial, anticancer, anti-HIV,
anticoagulant, antioxidant, and spasmolytic activities.[2]
Received June 25, 2012.
Address correspondence to Vedula Rajeswar Rao, Department of Chemistry, National Institute of
Technology, Warangal 506 004, A.P., India. E-mail: vrajesw@yahoo.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
1422

SYNTHESIS OF TRIAZOLOTHIADIAZINYL-PYRAZOLONE
1423
Triazoles and their heterocyclic derivatives are attractive compounds that
possess a wide range of biological activities.[3] In particular, the fused ring of tria-
zoles and thiadiazines, called triazolothiadiazines, is important class of nitrogen
bridgehead heterocyclic compounds with a wide range of activities. A recent litera-
ture survey revealed that a special attention was given to 1,2,4-triazolo[3,4-b][1,3,4]-
thiadiazine derivatives, which are demonstrated to have promising biological
activities such as antimicrobial, analgesic, antiviral, anti-HIV, CNS-stimulantory,
and antifungal activites.[4–8]
Compounds containing pyrazolone ring systems have been consistently
rewarded as promising molecules because of their broad-spectrum pharmacological
activities such as antitubercular,[9] antimicrobial,[10] anticancer,[11] antiviral,[12] anti-
inflammatory,[13] antipyretic,[13] analgesic,[14] ulcerogenic,[14] and lipid peroxidation
activities.[14]
Furthermore, the synthesis of pyrazole and its analogs has also been a subject
of consistent interest because of their wide range of applications in the pharma-
ceutical and agrochemical industries. Among their range of properties, they have
widespread potential biological activities such as anti-inflammatory,[15]
antipyretic,[16] antimicrobial,[17] antiviral,[18] antitumor,[19] anticonvulsant,[20] anti-
histaminic,[21] antidepressant,[22] insecticidal, and fungicidal activities.[23]
Extensive research efforts have been directed at the discovery of new hetero-
cycles with appropriate pharmacological effects. Taking into account the importance
of these heterocycles and starting materials for various applications, and in line with
our interest to develop a multicomponent approach for the synthesis of sulfur- and
nitrogen-containing heterocycles of biological importance, we became interested in
developing efficient synthetic methods for the triazolothiadiazineyl-pyrazolone sys-
tem incorporating coumarin derivatives and arylhydrazono moiety as substituents
and the pyrazolyl-triazolothiadiazine system with substituted phenyl derivatives.
RESULTS AND DISCUSSION
Earlier work from literature revealed that the syntheses of fused [1,2,4]triazolo-
[1,3,4]thiadiazines mainly involve reactions of heterocyclic amino thiols with bifunc-
tional reagents such as a-halo carbonyl compounds, dihalides, a-halo nitriles, and
1,3-diketones.[24–26] In addition, the literature survey clearly showed that ethylace-
toacetate was reacted with hydrazine hydrate in the presence of ethanol to afford
3-methyl-1H-pyrazol-5(4H)–one.[27,28]
4-Amino-5-hydrazino-4H-[1,2,4]triazole-3-
thiols can be considered as useful synthons in fusing to triazolothiadiazines. The
amino and mercapto groups are ready-made nucleophilic centers for the synthesis
of condensed heterocyclic rings.[29,30]
In the present work, various 3-(2-bromoacetyl)coumarin derivatives (1 and 5)
were reacted with 4-amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol (2) and ethyl-2-(2-
arylhydrazono)-3-oxobutanoate (3) in acetic acid in the presence of sodium acetate to
yield the compounds 4a–h and 6a–c (Scheme 1). 3-(3,5-Dimethyl-pyrazol-1-yl)-6-
aryl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine analogs (9a–f) were synthesized by
the reaction of acetyl acetone (8), 4-amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol,
with different phenacylbromides (7) under reflux for 3–4 h in methanol without using
any base.

1424
T. B. AYCHILUHIM AND V. RAJESWAR RAO
Scheme 1. Syntheses of 4-(arylydrazono)-3-methyl-1-(6-(coumarin-3-yl)-7H-[1,2,4] triazolo[3,4-b][1,3,4]-
thiadiazin-3-yl)-1H-pyrazol-5(4H)-ones.
During thiadiazine ring formation the highly nucleophilic mercapto group of
the 4-amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol attacks the carbon atom (-CH2-
Br) of 3-(2-bromoacetyl)coumarin to give a substituted intermediate. This undergoes
further intramolecular cyclization, leading to the formation of a thiadiazine ring
system.
Pyrazolone ring formation takes place by the condensation reaction between
the hydrazino group of 3-(3-hydrazino-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-
yl)-chromen-2-ones and ethyl-2-(2-arylhydrazono)-3-oxobutanoate (b-ketoester) to
give end products 4a–h and 6a–c, whereas the intermediates 1-(6-aryl-7H-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl)hydrazine react with acetyl acetone to give
the compounds 9a–f with pyrazole ring (Scheme 2).
The structures of all the newly synthesized compounds were characterized by
analytical and spectral data. The IR spectra of compounds in Scheme 1 show
absorption peak at 3117–3206 cmꢀ1 that is attributed to (N-H) and prominent peaks
at 1704–1744 cmꢀ1 and 1674–1699 cmꢀ1 corresponding to C O bond-stretching
=
frequencies of coumarin and pyrazolone respectively, and prominent peaks at
1539–1556 cmꢀ1 attributed to C N.
=

SYNTHESIS OF TRIAZOLOTHIADIAZINYL-PYRAZOLONE
1425
Scheme 2. Synthesis of 3-(3,5-dimethyl-pyrazol-1-yl)-6-aryl-7H-[1,2,4]triazolo[3,4-b] [1,3,4]thiadiazine.
1
In the H NMR spectra, the characteristic downfield signal at d 13.02–14.19
=
attributed to the (-NH-N C) peaks at d 7.13–8.42 are attributed to the aromatic ring
protons. The chemical shift of the S-CH2 protons in the thiadiazine moiety appears
at d 4.36–4.43 (4a–e and 6a–c), and d 3.99–4.49 (9a–f).
The 13C NMR spectrum of compound 4a, for instance, exhibits the expected
absorption peaks at d 11.65, 20.50, 24.40, 116.26, 116.69, 118.19, 122.41, 125.08,
125.86, 129.92, 130.00, 133.94, 135.78, 139.00, 143.28, 144.87, 150.59, 153.98,
154.41, 156.94, and 158.55. The peaks at 11.65 and 20.50 are due to -CH3 of
pyrazolone and of phenyl respectively, the peak at 24.40 ppm is attributed to the
S-CH2 in the thiadiazine ring, and peaks at downfield chemical shifts 156.94 and
158.55 are due to carbonyl carbons of pyrazolone and coumarin respectively.
CONCLUSION
In this work an efficient methodology for the synthesis of the title compounds
has been described. The methodology is a one-pot, three-component reaction leading
to a novel bicyclic heterocyclic ring system. The method has advantages of good
yield, short reaction time, and mild reaction conditions and is economical compared
to the stepwise synthesis.
EXPERIMENTAL
All reagents and solvents were purchased from commercial sources and were
used without further purification unless otherwise stated. 3-(2-Bromoacetyl)-
coumarin derivatives were prepared by literature procedure.[31] Ethyl-2-substituted
hydrazone-3-oxobutyrates were prepared by following literature procedure.[32]
Melting-point values were determined in open capillaries with a ‘‘Stuart’’
melting-point apparatus (model SMP30) and were uncorrected. Infrared (IR) spectra
in KBr pellets were recorded on a Bruker WM-4(X) FT-IR spectrophotometer (577
model). 1H NMR spectra were recorded in dimethylsulfoxide (DMSO-d6) and
CDCl3 on a Varian spectrometer (300 and 400 MHz) using tetramethylsilane

1426
T. B. AYCHILUHIM AND V. RAJESWAR RAO
(TMS) as an internal standard. The mass spectra were recorded on a Perkin-Elmer
instrument (SCIEX API- 2000, ESI) operating at 12.5 ev. CHNS analysis was done
on a Carlo Erba EA 1108 automatic elemental analyzer. The purity of the com-
pounds was checked by thin-layer chromatography (TLC) (E. Merck Mumbai,
India). Iodine and ultraviolet (UV) chambers were used for visualizing spots.
General Procedure for the Synthesis of 5-Methyl-4-(aryl-hydrazono)-
2-(6-(2-oxo-chromen-3-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-
3-yl)-2,4-dihydro-pyrazol-3-one (4a–h, 6a–c)
3-(2-Bromoacetyl)coumarin (0.001 mol), 4-amino-5-hydrazino-4H-[1,2,4]-
triazole-3-thiol (0.001 mol), and ethyl-2-substituted hydrazone-3-oxobutyrates
(0.001 mol) were taken in 5 ml acetic acid, and then fused sodium acetate
(0.002 mol) was added into the mixture. The mixture was refluxed for 3–5 h. After
completion of reaction (monitored with thin-layer chromatography, TLC), the reac-
tion mixture was allowed to cool. The solid obtained was filtered, washed with water,
dried, and crystallized from suitable solvent to give the title compound.
4-(2-p-Tolylhydrazono)-3-methyl-1-(6-(2-oxo-2H-chromen-3-yl)-7H-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl)-1H-pyrazol-5(4H)-one (4a)
3-(2-Bromoacetyl)-2H-chromen-2-one (0.001 mol), 4-amino-5-hydrazino-4H-
[1,2,4]triazole-3-thiol (0.001 mol), and ethyl 2-(2-p-tolylhydrazono)-3-oxobutanoate
(0.001 mol) were taken in 5 ml acetic acid, and then fused sodium acetate
(0.002 mol) was added into the mixture. The mixture was refluxed for 4 h. The reac-
tion mixture was cooled to rt. The solid was formed gradually. It was filtered,
washed with water, dried, and recrystallized from acetic acid. Orange color solid;
yield 87%; mp 176–179 ꢁC; IR (KBr, tmax, cmꢀ1): 3170 (N-H), 1722 (C O, cou-
=
1
=
=
marin), 1678 (C O, pyrazolone), 1539 (-C N). H NMR (300 MHz, DMSO-d6): d
2.28 (s, 3H, ꢀCH3), 2.31 (s, 3H, ꢀCH3 of pyrazolone), 4.36 (s, 2H, S-CH2- of thia-
diazine ring), 7.25 (d, 2H, J ¼ 8.7 Hz, Ar-H), 7.40 (t, 1H, J ¼ 7.5 Hz Ar-H), 7.49–7.57
(m, 3H, Ar-H), 7.70–7.75 (m, 1H, Ar-H), 7.87 (t, 1H, J ¼ 3.7 Hz, Ar-H), 8.51 (s, 1H,
C4 proton of coumarin), 13.09 (s, 1H, -NH, D2O, exchangeable). 13C NMR (DMSO-
d6, d ppm): 11.65, 20.50, 24.40, 116.26, 116.69, 118.19, 122.41, 125.08, 125.86, 129.92,
130.00, 133.94, 135.78, 139.00, 143.28, 144.87, 150.59, 153.98, 154.41, 156.94, 158.55.
MS (ES) m=z 499 ([M þ H]þ). Anal. calcd. for C24H18N8O3S: C, 57.82; H, 3.64; N,
22.48; S, 6.43. Found: C, 57.86; H, 3.60; N, 22.51; S, 6.48.
General Procedure for the Synthesis of 3-(3,5-Dimethyl-pyrazol-1-yl)-
6-aryl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (9a–f)
Phenacyl bromide (0.001 mol), 4-amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol
(0.001 mol), and acetyl acetone (0.001 mol), were taken in 5 ml absolute ethanol.
The mixture was refluxed for 3–4 h. After completion of reaction (monitored by
TLC), the reaction mixture was allowed to cool. The solid obtained was filtered.
In cases where no solid separation occurred upon cooling, the reaction mixture

SYNTHESIS OF TRIAZOLOTHIADIAZINYL-PYRAZOLONE
1427
was poured into ice-cold water. The solid obtained was filtered, dried, and
recrystallized.
6-(4-Chlorophenyl)-3-(3,5-dimethyl-1H-pyrazol-1-yl)-7H-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (9a)
2-Bromo-1-(4-chlorophenyl)ethanone (0.001 mol), 4-amino-5-hydrazino-4H-
[1,2,4]triazole-3-thiol (0.001 mol), and acetyl acetone (0.001 mol), were taken in
5 ml absolute ethanol. The mixture was refluxed for 3 h. The solid obtained was fil-
tered. The solid obtained was filtered, dried, and recrystallized. Pale yellow color,
solid; yield 81%; mp 199–201 ꢁC; IR (KBr, tmax, cmꢀ1): 1656 (C N), 1583 (C C),
=
=
1477 (N C-S); 1H NMR (300 MHz, CDCl3): 2.29 (s, 3H, -CH3), 2.44 (s, 3H,
=
ꢀCH3), 3.98 (s, 2H, S-CH2- of thiadiazine ring), 6.90 (s, 1H, pyrazole proton),
7.45 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.76 (d, 2H, J ¼ 8.7 Hz, Ar-H). 13C NMR (DMSO-
d6, d ppm): 10.80, 13.22, 22.96, 107.52, 129.18, 129.26, 131.89, 136.99, 142.45,
142.96, 146.39, 150.98, 155.48. MS (ES): m=z 344.9 ([M þ H]þ). Anal. calcd. for
C15H13ClN6S: C, 52.25; H, 3.80; N, 24.37; S, 9.30. Found: C, 52.29; H, 3.85; N,
24.34; S, 9.34.
ACKNOWLEDGMENT
The authors are thankful to the director, National Institute of Technology,
Warangal, A.P., India for providing support.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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