Facile one-pot synthesis of aryl, heteryl substituted hydrazono thiazolyl-pyrazolone derivatives via three-component reaction

Article abstract of DOI:10.1080/00397911.2010.536608

A facile, one-pot, three-component bis heterocyclized reaction for the synthesis of hydrazonothiazolyl-pyrazolones has been described. Reaction of phenacyl bromides or 3-(2-bromoacetyl)coumarins, with thiosemicarbazide and ethyl 2-(2-arylhydrazono)- 3-oxo

Full text of DOI:10.1080/00397911.2010.536608

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Facile One-Pot Synthesis of Aryl, Heteryl
Substituted Hydrazono Thiazolyl-
Pyrazolone Derivatives via Three-
Component Reaction
Venkata Sreenivasa Rao Chunduru a & Rajeswar Rao Vedula a
a Department of Chemistry, National Institute of Technology,
Warangal, India
Available online: 13 Oct 2011
To cite this article: Venkata Sreenivasa Rao Chunduru & Rajeswar Rao Vedula (2012): Facile One-
Pot Synthesis of Aryl, Heteryl Substituted Hydrazono Thiazolyl-Pyrazolone Derivatives via Three-
Component Reaction, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 42:8, 1154-1161
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Synthetic Communications1, 42: 1154–1161, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.536608
FACILE ONE-POT SYNTHESIS OF ARYL, HETERYL
SUBSTITUTED HYDRAZONO THIAZOLYL-
PYRAZOLONE DERIVATIVES VIA THREE-COMPONENT
REACTION
Venkata Sreenivasa Rao Chunduru and Rajeswar Rao Vedula
Department of Chemistry, National Institute of Technology, Warangal, India
GRAPHICAL ABSTRACT
Abstract A facile, one-pot, three-component bis heterocyclized reaction for the synthesis of
hydrazonothiazolyl-pyrazolones has been described. Reaction of phenacyl bromides or
3-(2-bromoacetyl)coumarins, with thiosemicarbazide and ethyl 2-(2-arylhydrazono)-
3-oxobutanoates in AcOH/NaOAc, gave the corresponding products in good yields. All
the synthesized compounds were characterized by their analytical and spectral data.
Keywords 3-(2-Bromoacetyl)coumarin; one-pot synthesis; phenacyl bromide;
thiazolyl-pyrazolone; thiosemicarbazide
INTRODUCTION
Nitrogen and sulfur heterocyclic systems are very interesting because of their
physicochemical properties, which have relevance to the design of new drugs and
new materials. Compounds containing the thiazole ring system are known to possess
pharmacological properties of great importance in biological systems. A large num-
ber of thiazoles obtained from microbial and marine life exhibit important biological
effects[1] such as antitumor, antifungal, antibiotic, and antiviral activities. Syntheti-
cally prepared substituted thiazoles are also known to possess a wide range of phar-
macological properties,[2–4] including very good novel Src family kinase inhibitory,[5]
antitumor,[6] and antimicrobial[7] activities. They have also other applications such as
in liquid crystals and cosmetic sunscreens.[8,9]
Received July 21, 2010.
Address correspondence to Rajeswar Rao Vedula, Department of Chemistry, National Institute of
Technology, Warangal 506 004, India. E-mail: vrajesw@yahoo.com
1154

HYDRAZONOTHIAZOLYL-PYRAZOLONE DERIVATIVES
1155
Pyrazoles, key substructures in a large variety of important medicinal com-
pounds, have attracted much attention.[10–12] Various therapeutic activities such as
antitumor, antiviral, analgesic, and anti-inflammatory properties have been reported
for pyrazoles.[13,14] Coumarin and its derivatives are also biologically active com-
pounds, occur widely in nature, and have a remarkably broad spectrum of pharma-
cological and physiological activities.[15–17] Also, in recent times there are references
to derivatives with anti-HIV activity.[18,19]
In view of the various physiological activities of coumarins, thiazoles, and pyr-
azoles, our current studies are focused on the development of new routes for the syn-
thesis of thiazole incorporating pyrazole and coumarin moieties. We have developed
a one-pot, multicomponent reaction for the synthesis of aryl and heteryl substituted
hydrazono thiazolyl-pyrazolone derivatives because these compounds possess
anthelmintic, analgesic, anti-inflammatory, antibacterial, and antifungal activities.[20]
RESULTS AND DISCUSSION
Hydrazonothiazolyl-pyrazolone derivatives were synthesized by Kalluraya
et al.[20] in a stepwise manner. In this method, diazotization of ethyl acetoacetate
with aryldiazonium salts gave the corresponding oxobutyrates, which on reaction
with thiosemicarbazide gave the respective thioamides. Reaction of these thioamides
with 3-(2-bromoacetyl)coumarin in a dimethylformamide (DMF)–ethanol mixture
gave the title products. However, this method has some limitations, such as multistep
synthesis and lower reaction yields. Hence, there is a need for a versatile, simple, and
friendly process for the synthesis of target compounds, which would enhance the
scope of their applications.
As a part of our continuing work on the synthesis of novel heterocyclic sys-
tems,[21–23] a facile and convenient root was developed for the synthesis of aryl,
heteryl substituted hydrazonothiazolyl-pyrazolone derivatives via a one-pot,
three-component reaction with excellent yields. In this method, thiazole and pyrazo-
lone rings can be synthesized chemoselectively in one pot. Reaction of an equimolar
mixture of phenacyl bromide, thiosemicarbazide, and ethyl 2-(2-arylhydrazono)-
3-oxobutanoate in AcOH=NaOAc gave the final products 4-(2-arylhydrazono)-
3-methyl-1-(4-arylthiazol-2-yl)-1H-pyrazol-5(4H)-ones 4 (Scheme 1). Reaction of
Scheme 1. One-pot synthesis of hydrazono phenyl thiazolyl-pyrazolones.

1156
V. S. R. CHUNDURU AND R. R. VEDULA
Scheme 2. One-pot synthesis of hydrazono-2-oxo-chromenyl thiazolyl-pyrazolones.
an equimolar mixture of 3-(2-bromoacetyl)coumarin, thiosemicarbazide, and ethyl
2-(2-arylhydrazono)-3-oxobutanoate in AcOH=NaOAc gave the target product
4-(2-arylhydrazono)-3-methyl-1-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)-1H-pyrazol-
5(4H)-one 6 in excellent yields (Scheme 2). In this reaction a sulfur atom of thiosemi-
carbazide undergoes nucleophilic substitution with 1 or 5 by eliminating HBr, fol-
lowed by dehydration to give the Hantzsch thiazole product. The hydrazine part of
thiosemicarbazide reacts with 3 to yield the hydrazonopyrazolone moiety.
The infrared (IR) spectrum of compound 4a showed prominent peaks at
1678 cmꢀ1 for ꢀC O of pyrazolone and 3178 cm for ꢀNH, whereas the 1H
ꢀ1
=
NMR spectrum of compound 4a showed characteristic singlets for Ar-CH3 and
ꢀCH3 of pyrazolone ꢀNH at d 2.38, 2.46, and 13.30. Similarly, the IR spectrum
of compound 6a showed prominent peaks at 1670 and 1722 cmꢀ1 for ꢀC O of pyr-
=
azolone and coumarin lactone. A characteristic absorption peak for –NH appeared
at 3122 cmꢀ1. The 1H NMR of compound 6a showed singlets for Ar-CH3 and ꢀCH3
of pyrazolone at d 2.39 and 2.49. The ꢀNH proton appeared as a broad singlet at
13.32. All the spectral data clearly show the formation of products 4a–f and 6a–f.
In conclusion, a novel, facile, one-pot, multicomponent reaction for the syn-
thesis of 4-(2-arylhydrazono)-3-methyl-1-(4-arylthiazol-2-yl)-1H-pyrazol-5(4H)-ones
and 4-(2-arylhydrazono)-3-methyl-1-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)-1H-
pyrazol-5(4H)-one has been developed via a one-pot reaction. The advantages of this
methodology are mild reaction conditions, easy workup, clean reaction profile, short
reaction time, and wide range of substrate applicability.
EXPERIMENTAL
All the reagents and solvents were purchased from commercial sources
and were used without further purification unless otherwise stated.
3-(2-Bromoacetyl)coumarins[24] and ethyl 2-(2-arylhydrazono)-3-oxobutanoates
were prepared by literature procedure.[25] Melting points were determined in open
capillaries with a ‘‘Cintex’’ melting-point apparatus (Mumbai, India) and were
uncorrected. CHNS analysis was done on a Carlo Erba EA 1108 automatic
elemental analyzer. The purity of the compounds was checked by thin-layer

HYDRAZONOTHIAZOLYL-PYRAZOLONE DERIVATIVES
1157
chromatogaphic (TLC) plates (E. Merck, Mumbai, India). IR spectra (KBr) were
1
recorded on a Bruker WM-4(X) spectrometer (577 model). H NMR spectra were
recorded on a Bruker WM-400 spectrometer in d ppm using tetramethylsilane
(TMS) as standard. Mass spectra (EI-MS) were determined on a Perkin-Elmer
(SCIEX API-2000, ESI) instrument at 12.5 eV.
Compounds 4a–f
Compound 1 (1 mmol), thiosemicarbazide (1 mmol), and ethyl 2-(2-arylhydra
zono)-3-oxobutanoate (1.2 mmol) were taken in acetic acid (10 mL) and stirred at
rt for about 1 h. Sodium acetate (2 mmol) was added to the reaction mixture and
heated at 80–85 ꢁC for about 2 h. The product obtained was cooled, filtered, washed
with water, and recrystallized from acetic acid.
4-(2-p-Tolylhydrazono)-1-(4-(4-chlorophenyl)thiazol-2-yl)-3-methyl-1H-
pyrazol-5(4H)-one (4a). Orange-yellow solid; yield 86%; mp 218–220 ꢁC; IR (KBr,
max): 1525 (C C), 1595 (ꢀC N), 1678 (ꢀC O, pyrazolone), 3178 (ꢀNH). 1H
=
=
=
t
NMR (400 MHz, CDCl3): d 2.38 (s, 3H, Ar-CH3), 2.46 (s, 3H, CH3 of pyrazolone),
7.24–7.26 (m, 3H, 2H-ArH, 1H-thiazole), 7.36–7.38 (m, 4H, ArH), 7.90 (d, 2H,
J ¼ 8.8 Hz, ArH), 13.30 (s, 1H, ꢀNH, D2O, exchangeable). EI-MS 410 (100%)
[M þ H]þ, 412 (33%). Anal. calcd. for C20H16ClN5OS: C, 58.60; H, 3.93; N, 17.09.
Found: C, 58.55; H, 3.90; N, 16.98.
4-(2-Phenylhydrazono)-1-(4-(4-chlorophenyl)thiazol-2-yl)-3-methyl-1H-
pyrazol-5(4H)-one (4b). Orange-yellow solid; yield 82%; mp 224–226 ꢁC; IR (KBr,
max): 1523 (C C), 1600 (ꢀC N), 1677 (ꢀC O, pyrazolone), 3140 (ꢀNH). 1H
=
=
=
t
NMR (400 MHz, CDCl3): d 2.47 (s, 3H, CH3 of pyrazolone), 7.26–7.48 (m, 8H,
7H-ArH, 1H-thiazole ArH), 7.90 (d, 2H, J ¼ 8.4 Hz, ArH), 13.26 (s, 1H, ꢀNH,
D2O, exchangeable). EI-MS 396 (100%) [M þ H]þ, 398 (33%). Anal. calcd. for
C19H14ClN5OS: C, 57.65; H, 3.56; N, 17.69. Found: C, 57.61; H, 3.51; N, 17.62.
4-(2-Phenylhydrazono)-1-(4-(4-bromophenyl)thiazol-2-yl)-3-methyl-1H-
pyrazol-5(4H)-one (4c). Yellow solid; yield 78%; mp 216–218 ꢁC; IR (KBr, tmax):
1
=
=
=
1523 (C C), 1597 (ꢀC N), 1668 (ꢀC O, pyrazolone), 3263 (ꢀNH). H NMR
(400 MHz, CDCl3): d 2.27 (s, 3H, CH3 of pyrazolone), 7.24–7.67 (m, 7H,
6H-ArH, 1H-thiazol), 7.92 (d, 1H, J ¼ 7.6 Hz, ArH), 8.95 (s, 1H, ArH), 9.49 (s,
1H, ArH), 13.08 (s, 1H, ꢀNH, D2O, exchangeable). Anal. calcd. for C19H14BrN5OS:
C, 51.83; H, 3.20; N, 15.91. Found: C, 51.80; H, 3.16; N, 15.98.
4-(2-p-Tolylhydrazono)-1-(4-(4-bromophenyl)thiazol-2-yl)-3-methyl-1H-
pyrazol-5(4H)-one (4d). Yellow solid; yield 80%; mp 208–210 ꢁC; IR (KBr, tmax):
1
=
=
=
1521 (C C), 1585 (ꢀC N), 1689 (ꢀC O, pyrazolone), 3259 (ꢀNH). H NMR
(400 MHz, CDCl3): d 2.25 (s, 3H, Ar-CH3), 2.31 (s, 3H, CH3 of pyrazolone), 7.27
(m, 3H, ArH), 7.54–7.67 (m, 3H, 2H-ArH, 1H-thiazol), 7.92 (d, 1H, J ¼ 7.6 Hz,
ArH), 8.97 (s, 1H, ArH), 9.48 (s, 1H, ArH), 13.10 (s, 1H, ꢀNH, D2O, exchangeable).
C20H16BrN5OS: C, 52.87; H, 3.55; N, 15.41. Found: C, 52.82; H, 3.51; N, 15.37.
4-(2-Phenylhydrazono)-3-methyl-1-(4-(4-nitrophenyl)thiazol-2-yl)-1H-
pyrazol-5(4H)-one (4e). Yellow solid; yield 80%; mp >300 ꢁC; IR (KBr, tmax):

1158
V. S. R. CHUNDURU AND R. R. VEDULA
1
=
=
=
1523 (C C), 1597 (ꢀC N), 1666 (ꢀC O, pyrazolone), 3261 (ꢀNH). H NMR
(400 MHz, CDCl3): d 2.38 (s, 3H, CH3 of pyrazolone), 7.26 (m, 1H, ArH), 7.47
(m, 2H, ArH), 7.70 (m, 2H, ArH), 8.23–8.35 (m, 5H, 4H-ArH, 1H-thiazole), 13.10
(s, 1H, ꢀNH, D2O, exchangeable). EI-MS 407 [M þ H]þ. Anal. calcd. for
C19H14N6O3S: C, 56.15; H, 3.47; N, 20.68. Found: C, 56.12; H, 3.43; N, 20.63.
4-(2-p-Tolylhydrazono)-3-methyl-1-(4-(4-nitrophenyl)thiazol-2-yl)-1H-
pyrazol-5(4H)-one (4f). Orange-yellow solid; yield 78%; mp >300 ꢁC; IR (KBr,
1
=
=
=
t
max): 1523 (C C), 1597 (ꢀC N), 1668 (ꢀC O, pyrazolone), 3260 (ꢀNH). H
NMR (400 MHz, CDCl3): d 2.33 (s, 3H, Ar-CH3), 2.37 (s, 3H, CH3 of pyrazolone),
7.28 (m, 2H, ArH), 7.57 (m, 2H, ArH), 8.23–8.34 (m, 5H, 4H-ArH, 1H-thiazole),
13.15 (s, 1H, ꢀNH, D2O, exchangeable). EI-MS 421 [M þ H]þ. Anal. calcd. for
C20H16N6O3S: C, 57.13; H, 3.84; N, 19.99. Found: C, 57.20; H, 3.76; N, 19.95.
Compounds 6a–f
Compound 5 (1 mmol), thiosemicarbazide (1 mmol), and ethyl 2-(2-arylhydra
zono)-3-oxobutanoate (1.2 mmol) were taken in acetic acid (10 mL) and stirred at
rt for about 1 h. Sodium acetate (2 mmol) was added to the reaction mixture heated
at 80–85 ꢁC for about 2 h. The product obtained was cooled, filtered, washed with
water, and recrystallized from acetic acid.
4-(2-p-Tolylhydrazono)-3-methyl-1-(4-(2-oxo-2H-chromen-3-yl)thiazol-
2-yl)-1H-pyrazol-5(4H)-one (6a). Orange-yellow solid; yield 85%; mp 274–276 ꢁC;
=
=
=
IR (KBr, tmax): 1533 (C C), 1604 (ꢀC N), 1670 (ꢀC O, pyrazolone), 1722 (lac-
1
=
tone ꢀC O), 3122 (ꢀNH). H NMR (400 MHz, CDCl3): d 2.39 (s, 3H, Ar-CH3),
2.49 (s, 3H, CH3 of pyrazolone), 7.26–7.67 (m, 8H, ArH), 8.33 (s, 1H, thiazole),
8.85 (s, 1H, C-4 of coumarin), 13.32 (s, 1H, ꢀNH, D2O, exchangeable). EI-MS
444 [M þ H]þ. Anal. calcd. for C23H17N5O3S: C, 62.29; H, 3.86; N, 15.79. Found:
C, 62.23; H, 3.81; N, 15.72.
4-(2-Phenylhydrazono)-3-methyl-1-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-
yl)-1H-pyrazol-5(4H)-one (6b). Orange-yellow solid; yield 84%; mp 268–270 ꢁC;
=
=
=
IR (KBr, tmax): 1534 (C C), 1598 (ꢀC N), 1657 (ꢀC O, pyrazolone), 1716 (lac-
1
=
tone ꢀC O), 3144 (ꢀNH). H NMR (400 MHz, CDCl3): 2.50 (s, 3H, CH3 of pyr-
azolone), 7.28–7.67 (m, 9H, ArH), 8.34 (s, 1H, thiazole), 8.85 (s, 1H, C-4 of
coumarin), 13.28 (s, 1H, ꢀNH, D2O, exchangeable). EI-MS 430 [M þ H]þ. Anal.
calcd. for C22H15N5O3S: C, 61.53; H, 3.52; N, 16.31, Found: C, 61.50; H, 3.50; N,
16.27.
4-(2-Phenylhydrazono)-1-(4-(8-methoxy-2-oxo-2H-chromen-3-yl)thiazol-
2-yl)-3-methyl-1H-pyrazol-5(4H)-one (6c). Yellow solid; yield 81%; mp >300 ꢁC;
=
=
=
IR (KBr, tmax): 1521 (C C), 1599 (ꢀC N), 1657 (ꢀC O, pyrazolone), 1724 (lac-
1
=
tone ꢀC O), 3143 (ꢀNH). H NMR (400 MHz, CDCl3): d 2.49 (s, 3H, CH3 of pyr-
azolone), 3.99 (s, 3H, ꢀOCH3), 7.08–7.48 (m, 8H, ArH), 7.92 (s, 1H, thiazole), 8.57
(s, 1H, C-4 of coumarin), 12.05 (s, 1H, ꢀNH, D2O, exchangeable). EI-MS 460
[M þ H]þ. Anal. calcd. for C23H17N5O4S: C, 60.12; H, 3.73; N, 15.24. Found: C,
60.16; H, 3.70; N, 15.29.

HYDRAZONOTHIAZOLYL-PYRAZOLONE DERIVATIVES
1159
4-(2-Phenylhydrazono)-1-(4-(6,8-dichloro-2-oxo-2H-chromen-3-yl)thiazol-
2-yl)-3-methyl-1H-pyrazol-5(4H)-one (6d). Yellow solid; yield 78%; mp >300 ꢁC;
=
=
=
IR (KBr, tmax): 1531 (C C), 1595 (ꢀC N), 1666 (ꢀC O, pyrazolone), 1737 (lac-
1
=
tone ꢀC O), 3140 (ꢀNH). HNMR (400 MHz, CDCl3): d 2.27 (s, 3H, CH3 of pyr-
azolone), 7.24–7.63 (m, 7H, ArH), 8.08 (s, 1H, thiazole), 8.54 (s, 1H, C-4 of
coumarin), 13.10 (s, 1H, ꢀNH, D2O, exchangeable). Anal. calcd. for
C22H13Cl2N5O3S: C, 53.02; H, 2.63; N, 14.05. Found: C, 53.00; H, 2.60; N, 13.98.
4-(2-Phenylhydrazono)-1-(4-(6,8-dibromo-2-oxo-2H-chromen-3-yl)thiazol-
2-yl)-3-methyl-1H-pyrazol-5(4H)-one (6e). Yellow solid; yield 85%; mp
>300 ꢁC; IR (KBr, tmax): 1525 (C C), 1602 (ꢀC N), 1678 (ꢀC O, pyrazo-
=
=
=
lone), 1735 (lactone ꢀC O), 3249 (ꢀNH). 1H NMR (400 MHz, CDCl3): d
=
2.50 (s, 3H, CH3 of pyrazolone), 7.26–7.62 (m, 7H, ArH), 8.35 (s, 1H, thia-
zole), 8.76 (s, 1H, C-4 of coumarin), 13.27 (s, 1H, ꢀNH, D2O, exchangeable).
Anal. calcd. for C22H13Br2N5O3S: C, 45.00; H, 2.23; N, 11.93. Found: C, 44.92;
H, 2.20; N, 11.09.
4-(2-Phenylhydrazono)-1-(4-(6-chloro-2-oxo-2H-chromen-3-yl)thiazol-2-
yl)-3-methyl-1H-pyrazol-5(4H)-one (6f). Yellow solid; yield 79%; mp >300 ꢁC; IR
=
=
=
(KBr, tmax): 1534 (C C), 1607 (ꢀC N), 1657 (ꢀC O, pyrazolone), 1714 (lactone
1
=
ꢀC O), 3151 (ꢀNH). H NMR (400 MHz, CDCl3): 2.36 (s, 3H, CH3 of pyrazo-
lone), 7.39–7.64 (m, 8H, ArH), 7.87 (s, 1H, thiazole), 8.39 (s, 1H, C-4 of coumarin),
12.76 (s, 1H, ꢀNH, D2O, exchangeable). Anal. calcd. for C22H14ClN5O3S: C, 56.96;
H, 3.04; N, 15.10. Found: C, 58.91; H, 3.00; N, 15.15.
ACKNOWLEDGMENTS
The authors are thankful to the director, NIT, Warangal, for providing facili-
ties. One of the authors (C. H. V. S. R.) is thankful to the director for an institute
fellowship.
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